Systematic Evaluation of 2-Arylazocarboxylates and 2

Article pubs.acs.org/joc

Cite This: J. Org. Chem. 2018, 83, 4712−4729

Systematic Evaluation of 2‑Arylazocarboxylates and 2‑Arylazocarboxamides as Mitsunobu Reagents Daisuke Hirose,† Martin Gazvoda,§ Janez Košmrlj,*,§ and Tsuyoshi Taniguchi*,†,‡ †

Graduate School of Natural Science and Technology and ‡School of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan § Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, SI-1000 Ljubljana, Slovenia S Supporting Information *

ABSTRACT: 2-Arylazocarboxylate and 2-arylazocarboxamide derivatives can serve as replacements of typical Mitsunobu reagents such as diethyl azodicarboxylate. A systematic investigation of the reactivity and physical properties of those azo compounds has revealed that they have an excellent ability as Mitsunobu reagents. These reagents show similar or superior reactivity as compared to the known azo reagents and are applicable to the broad scope of substrates. pKa and steric effects of substrates have been investigated, and the limitation of the Mitsunobu reaction can be overcome by choosing suitable reagents from the library of 2-arylazocarboxylate and 2-aryl azocarboxamide derivatives. Convenient recovery of azo reagents is available by one-pot iron-catalyzed aerobic oxidation, for example. SC-DSC analysis of representative 2-arylazocarboxylate and 2-arylazocarboxamide derivatives has shown high thermal stability, indicating that these azo reagents possess lower chemical hazard compared with typical azo reagents.

■

INTRODUCTION

The Mitsunobu reaction has been widely used since the first report by Mitsunobu and co-workers in 1967.1 It is a condensation reaction between an alcohol and an acidic compound as a nucleophile and is induced by a betaine intermediate that is formed from the appropriate azo and phosphine reagents.2 A starting alcohol is activated through the formation of an alkoxyphosphonium intermediate and undergoes the Walden inversion in the reaction with the partnering nucleophile. Consequently, conversion of secondary alcohols into the corresponding condensation products is accompanied by inversion of stereochemistry. Owing to the fact that this transformation is viable under mild reaction conditions, the Mitsunobu reaction often appears in the syntheses of natural products, medicines, and materials. Nevertheless, a truly practical application of the Mitsunobu reaction is sometimes deterred due to some serious issues connected to the typical azo reagents like diethyl azodicarboxylate (1: DEAD, Figure 1A).3 First, these compounds are toxic and high-energy materials, potentially possessing an explosive character.4 Second, large amounts of hydrazine waste 2 that are produced during the reaction often make the purification process tedious and contaminate the target products. Third, due to the moderate basicity of typical betaine intermediates, the yields of the Mitsunobu products strongly depend on acidity of nucleophiles. Thus, with pronucleophiles having pKa values of 11−13, the yields are generally decreased whereas less acidic pronucleophiles (pKa > 13) are inactive partners in the Mitsunobu reaction.2 © 2018 American Chemical Society

Figure 1. Azo reagents used in Mitsunobu reaction.

With a strong focus on avoiding the above problems, many replacements of DEAD (1) have been developed.5 Representative examples are shown in Figure 1B. Curran and co-workers Received: February 20, 2018 Published: March 23, 2018 4712

DOI: 10.1021/acs.joc.8b00486 J. Org. Chem. 2018, 83, 4712−4729

The Journal of Organic Chemistry

Article

■

developed azo reagents having fluorous tags (F-DEAD), such as compound 3, the hydrazine waste of which can be removed by fluorous extraction techniques.6 Lipshutz and co-workers reported that the hydrazine compound produced from di(pchlorobenzyl)azodicarboxylate (4: DCAD) could be easily removed by filtration and chromatography due to its high polarity and insolubility in dichloromethane. 7 Di(2methoxyethyl)azodicarboxylate (5: DMEAD) is one of the newest azo reagents developed by Sugimura and co-workers, and the corresponding hydrazine byproduct can be removed by washing with water.8 Very recently, Soós and co-workers developed an orthogonal phase tagging approach for chromatography-free Mitsunobu reaction by using watersoluble (dimethylamino)methylazocarbonamide carboxylate and lipophilic derivatives of triphenylphosphine.9 Tsunoda and co-workers developed Mitsunobu reagents that are substantially improved in reactivity.10 As a representative example, 1,1′-(azodicarbonyl)dipiperidine (6, ADDP) performs well in the Mitsunobu reactions of moderately acidic substrates (pKa ≈ 11−13). This reagent generates a highly polar hydrazine byproduct, easily removable by filtration or chromatography, just like in the case of DCAD (4). They also reported highly reactive phosphorane reagents, including (cyanomethylene)tributylphosphorane (CMBP), which enable Mitsunobu reaction with less acidic pronucleophiles (pKa > 13).11 However, phosphorane reagents are extremely sensitive to air and moisture, and many modifications in reagents and methods are rather focused on waste removal.12,13 A few examples of reagents and methods aimed at improving the reactivity in the Mitsunobu reaction are notable.14,15 We recently developed catalytic Mitsunobu reactions using 2arylhydrazinecarboxylate derivatives, which provided the prerequisite azo reagent by in situ aerobic oxidation of hydrazine precursors with a catalytic amount of iron phthalocyanine [Fe(Pc)].16−20 2-Arylazocarboxylates have been identified as valuable alternatives to the previously developed azo compounds.16 Noteworthy are the stability and recyclability of 2-arylazocarboxylates: (i) these reagents are stable under ambient conditions at least for a few months and do not decompose even at 200 °C,16b and (ii) after the completion of the Mitsunobu reaction, they can be quantitatively recovered. In spite of the development of catalytic Mitsunobu reactions, the stoichiometric Mitsunobu protocol with traditional azo reagents is still used in synthesis because it is a reliable method to ensure results. We originally designed 2-arylazocarboxylates to realize the catalytic Mitsunobu reaction and to solve serious problems of traditional Mitsunobu reaction. However, the above features strongly suggested that these compounds could reduce the disadvantages of Mitsunobu reaction even in stoichiometric protocol from both the convenience and chemical safety aspects. In addition, the aryl group directly linked to the azo moiety enables a fine-tuning of its reactivity through a simple choice of substituents.21 Thus, we expected that disclosing the properties of our azo reagents will expand choice in Mitsunobu reaction, either in catalytic or stoichiometric protocol. In this study, we systematically evaluated the properties of 2arylazocarboxylates and their derivatives as Mitsunobu reagents. Development of new Mitsunobu protocols based on modified Mitsunobu reagents possessing good stability, recyclability, and reactivity is reported.

RESULTS AND DISCUSSION 1. Screening of Reagents and Scope of Typical Substrates. Our study was initiated by a brief screening of selected azo reagents (1.2 equiv) and conditions in a model reaction between (−)-(S)-ethyl lactate (9), 4-nitrobenzoic acid (10), and triphenylphosphine (PPh3) in toluene (Table 1). Table 1. Mitsunobu Reaction with Various Ethyl 2Arylazocarboxylates 7a−ja

entry

X

solvent

time (h)

yieldb (%)

erc

1 2 3 4 5 6 7 8 9 10 11 12 13

H (7a) 4-OMe (7b) 4-Me (7c) 4-Cl (7d) 4-Br (7e) 3-Cl (7f) 3,4-diCl (7g) 4-CF3 (7h) 4-CN (7i) 4-NO2 (7j) 3,4-diCl (7g) 3,4-diCl (7g) 3,4-diCl (7g)

toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene THF CH2Cl2 MeCN

48 72 72 8 8 5 5 5 5 5 5 5 3

19 0 0 79 81 81 99 99 93 74 92 87 84

>99:1

>99:1 >99:1 >99:1 >99:1 >99:1 97:3 90:10 >99:1 97:3 98:2

a Reaction conditions: 9 (0.5 mmol), 10 (0.6 mmol), 7a−j (0.6 mmol), PPh3 (0.6 mmol) in solvent (1 mL) at room temperature. b Yield of the isolated pure product. cDetermined by chiral HPLC analysis.

Although the reaction with 2-phenylazocarboxylate (7a) did not lead to the completion in as much as 48 h and gave (R)ester 11 in only low yield, it proceeded with full inversion of stereochemistry as indicated by chiral HPLC analysis (entry 1). While azo reagents 7b and 7c having electron-releasing 4methyl and 4-methoxy groups failed to provide any product (entries 2 and 3), those with electron-withdrawing 4-chloro (7d), 4-bromo (7e), 3-chloro (7f), 3,4-dichloro (7g), 4trifluoromethyl (7h), 4-cyano (7i), and 4-nitro (7j) groups enabled the formation of ester 11 in good yields (entries 4− 10). Especially effective were compounds 7g and 7h affording excellent results in both the yield and the enantiomeric ratio of 11 (entries 7 and 8). Interestingly, slight erosion of the enantiomeric ratio in ester 11 was observed in reactions with strongly electron-deficient azo reagents 7i and 7j (entries 9 and 10). Although thus far investigated reagents performed similarly, at this point azo compound 7g was tentatively identified as the reagent of choice over 7h, as based on the price and availability comparison. Namely, 3,4-dichlorophenyl derivative 7g can be prepared from considerably less expensive starting materials. Compound 7g was thus used in the subsequent solvent screening experiments (entries 11−13). The results indicate that toluene could be replaced by tetrahydrofuran whereas dichloromethane and acetonitrile decreased the yield and the enantiomeric ratio of ester 11. 4713


Article


18−21 in good yields and in high inversion ratios. The only exception was the reaction between (−)-(S)-ethyl lactate (9) and 3-phenylpropionic acid forming the corresponding ester 22 in moderate inversion ratio (er: 82:18). In this case, the replacement of azo reagent 7g with ethyl 2-(4-chlorophenyl)azocarboxylate (7d) improved the yield (97%) and inversion ratio (er: 97:3), though excessive amounts (2 equiv) of the reagents were required to complete the reaction. Incidentally, the reaction with DEAD (1) gave ester 22 in 83% yield and the same inversion ratio (er: 97:3) as with 7d. Dihydrocholesterol reacted with 4-nitrobenzoic acid (10) into the ester 23 in 88% yield as a single inverted isomer. Finally, phthalimide and pmethoxyphenol were efficiently converted with (S)-ethyl lactate (9) into highly enantiomerically rich N-substituted phthalimide 24 and ether 25. The yields of 24 and 25 were better than those of the reactions with typical azodicarboxylate reagents such as DEAD (1).12e,24,25 Thus, these experimental results illustrated that ethyl 2-(3,4-dichlorophenyl)azocarboxylate (7g) could work as a good reagent in general Mitsunobu reaction. An eight-membered ring construction through the Mitsunobu intramolecular alkylation was tested by using the model substrate 26 and the reaction conditions reported by Fukuyama (Table 2).26 The reaction with DEAD was readily reproduced

The results of substrate scope screening with azo reagent 7g in the Mitsunobu reaction are shown in Figure 2. Reactions of

Table 2. Cyclization of Amino Alcohol 26 into Sulfonamide 27a

entry

azo reagent

conc (M)

time (h)

yieldb (%)

1 2 3 4

DEAD 7g (3,4-diCl) 7i (4-CN) 7i (4-CN)

0.01 0.01 0.01 0.005

3 3 3 23

60 (59)c 30 52 64 (61)d

a

Reaction conditions: 26 (0.5 mmol), azo reagent (1.835 mmol), PPh3 (1.835 mmol) in toluene/THF (3:1) (50 or 100 mL) at room temperature. bNMR yield unless otherwise noted (internal standard: 1,3,5-trimethoxybenzene). cYield reported in ref 26. dYield of the isolated pure product.

to give cyclized product 27 in 60% yield (entry 1). However, under the same reaction conditions azo reagent 7g gave product 27 in only 30% yield with dimerization of 26 as the main side reaction (entry 2). An additional experimental work had indicated that the use of 7i in place of 7g gave the desired cycle 27 in 52% yield indicating that 7i could serve as a replacement for DEAD in this case (entry 3). The reaction under more diluted conditions improved the result, but the reaction time had to be prolonged (entry 4). 2. Reactions with Modestly Acidic Nucleophiles. We evaluated the performance of ethyl 2-arylazocarboxylates in the Mitsunobu reaction with modestly acidic nucleophiles. 3Phenylpropan-1-ol (28) and p-toluenesulfonamide 29 (pKa = 11.7) were selected as model substrates, and the results are collected in Table 3. With DEAD and PPh3 as the reagents, Nalkylated compound 30 was formed in low yield (Table 3, entry 1). Although the starting alcohol 28 was fully consumed, a competitive N-alkylation of the hydrazine byproduct that was produced by reduction of DEAD complicated the Mitsunobu reaction. On the other hand, a combination of ADDP and tri-n-

Figure 2. Examples of Mitsunobu reaction with 7g. Reaction conditions: alcohol (0.5 mmol), nucleophile (0.6 mmol), 7g (0.6 mmol), PPh3 (0.6 mmol) in toluene (1 mL) at room temperature (SM refers to starting material): (a) 2 equiv each of 7d and PPh3 were used; (b) 2 equiv each of DEAD and PPh3 were used. Ns = 2nitrobenzenesulfonyl.

3-phenylpropan-1-ol with different oxygen, nitrogen, and sulfur nucleophiles such as benzoic acid, phenol, phthalimide, Nbenzyl-4-nitrobenzenesulfonamide,22 and 2-mercaptobenzothiazole gave the corresponding products 12−16 in good yields. Surprisingly, malononitrile as a carbon pronucleophile afforded no alkylated product 17 but only unidentified products, unlike in the reaction with DEAD.23 However, this seemed to be a special case because other tested carbon pronucleophiles returned the desired alkylated products (vide infra, see Figure 4). The reactions between chiral secondary alcohols and benzoic acids provided the corresponding esters 4714


Article


amides 7k and 7l were prepared and tested in a model reaction between 28 and 29 as shown in Figure 3. With PBu3 as the

Table 3. Mitsunobu Reaction between Alcohol 28 and Sulfonamide 29a

entry

azo reagent

R

time (h)

yieldb (%)

1 2 3 4 5 6 7 8e 9 10 11 12e

DEAD ADDP 7g (3,4-diCl) 7d (4-Cl) 7f (3-Cl) 7i (4-CN) 7a (H) 7a (H) 7a (H) 7c (4-Me) 7b (4-OMe) 7b (4-OMe)

Ph Bu Ph Ph Ph Ph Ph Ph Bu Bu Bu Bu

3 24 3 18 16 3 72 18 24 40 72 40

29 (32)c 87c 73c,d 62 54 49 78 73 86c 56 59 87 (89)c

a Reaction conditions: 28 (0.5 mmol), 29 (0.6 mmol), azo reagent (0.6 mmol), PR3 (0.6 mmol) in toluene (1 mL) at room temperature unless otherwise noted. bNMR yield unless otherwise noted (internal standard: trioxane). cIsolated yield. dEthyl 2-(3,4-dichlorophenyl)-1(3-phenylpropyl)hydrazine-1-carboxylate was isolated in 22% yield as a side product. eThe reaction was performed in CH2Cl2. Ts = ptoluenesulfonyl.

Figure 3. Reaction of 2-phenylazocarboxamides 7k and 7l. Reaction conditions: Alcohol (0.5 mmol), 29 (0.6 mmol), 7k,l (0.6 mmol), PBu3 (0.6 mmol) in toluene (1 mL) at room temperature unless otherwise noted. Yields are determined by NMR analysis of the crude product (internal standard: 1,3,5-trimethoxybenzene). The yields in parentheses refer to the isolated pure product.

butylphosphine (PBu3) significantly improved the yield (87%) of product 30 (entry 2). The results of these control experiments are consistent with previous reports.10a,11a,27 Turning to 2-arylazocarboxylates, compound 7g enabled the formation of product 30 in good yield (73%) (entry 3). This implies that the range of nucleophile pKa values in the reaction with 7g is broader as compared to that of DEAD. As noted above for DEAD, in this case the N-alkylated hydrazine derivative formed from 7g and was isolated in 22% yield. Whereas chloro and cyano derivatives 7d, 7f, and 7i gave similar results (entries 4−6), unsubstituted ethyl 2-phenylazocarboxylate (7a) proved to work better in this model reaction, despite the considerably longer reaction times required (entry 7). Replacing the reaction solvent in this case with dichloromethane significantly accelerated the rate of the reaction (entry 8), whereas replacement of PPh3 with PBu3 resulted in almost the same outcome as that of ADDP (entry 9). Azo reagents 7c and 7b, having electron-releasing 4-methyl and 4-methoxy groups, in combination with PBu3 also gave product 30 in modest yield with the starting alcohol 28 remaining partially unconsumed (entries 10 and 11). A significant improvement in the performance of 7b/PBu3 was noted in dichloromethane as the reaction solvent, affording product 30 in improved yield (89%, entry 12). A conclusion from this part of the work could be drawn that ethyl 2-(3,4dichlorophenyl)azocarboxylate (7g) is an effective reagent for the Mitsunobu reaction of modestly acidic nucleophiles, with the electron-rich analogues 7a and 7b performing superiorly in combination with PBu3. Next, we considered 2-phenylazocarboxamides as a potential replacement for 2-arylazocarboxylate reagents. On the basis of the fact that in the Mitsunobu reaction the former reagents would produce betaines with increased basic character, this should be beneficial in the reactions with moderately acidic pronucleophiles.10 To prove the concept, 2-phenylazocarbox-

phosphine reagent, product 30 was obtained in excellent yields already at room temperature. As anticipated, an elevated reaction temperature decreased the reaction time. We thus confirmed that 7l afforded good results in the reaction of secondary alcohol 31 to produce the corresponding sulfonamide 32.27 Regarding the stability, azo reagent 7k slowly decomposed under ambient conditions whereas the analogue 7l proved to be stable for a few months. We tested the Mitsunobu reaction between representative pronucleophiles having modest acidity (pKa = ca. 11−14) and primary alcohol 28 using selected azo compounds (7a,b,l,m) and PBu3 as the reagents (Figure 4).10,11,24 Alkylation of 2(phenylsulfonyl)acetonitrile (33; pKa = 12.0) into 37 proceeded in excellent yield. The reaction of less acidic benzimidazole (34; pKa = 12.8) with 2-arylazocaroxylate reagents 7a and 7b provided low yields of alkylated benzimidazole 38 but could be increased by using 2phenylazocarboxamide 7l. Further improvement, especially at elevated temperature, was seen by applying 2-(4methoxyphenyl)azocarboxamide 7m. The above trend appears to be consistent in the reaction of diethyl malonate (35; pKa = 13.3) and N-benzyl-2,2,2-trifluoroacetamide (36; pKa = 13.6) of lesser acidity, further decreasing the yields of the alkylated product 39 and 40, while the results were comparable to those of the reactions with ADDP and related reagents.10 These reactions were not applicable to the catalytic reactions because reagents 7a, 7b, 7l, and 7m did not work well under the current catalytic conditions.16 In addition, PBu3 cannot be used in the catalytic reactions because it deactivates iron phthalocyanine.17b In our previous report, we indirectly estimated the rate of the reaction of ethyl 2-arylazocarboxylates with PPh3 to form betaine.16b Since the reaction was suggested to be reversible, unlike the reaction of DEAD, the rate constants were determined by pseudo-first-order kinetics using excess water 4715


Article


Table 4. Kinetic Data of the Reaction between Azo Reagents and Phosphines

kobs (10−3 min−1)

a

entry

azo reagent

PPh3

PBu3

1 2 3 4 5 6

X = OMe, R = OEt (7b) X = Me, R = OEt (7c) X = H, R = OEt (7a) X = Cl, R = OEt (7d) ADDP X = H, R = piperidyl (7l)

0.5a 2.1a 6.2a 19.5a 34.9

22.2 116 291 >1000 >1000 8.7

Values taken from ref 16b.

PPh3 or PBu3 (entries 7 and 9), but again, even less electrophilic 7b and 7c operated worse even with PBu3 as the phosphine reagent (entries 10 and 11). Those observations could be rationalized by the fact that in addition to the electrophilicity of the azo reagent, basicity of the intermediately formed betaine is also important in the reaction with modestly acidic pronucleophiles. Although the azo reagent electrophilicity and the betaine basicity are unrelated, these two parameters seem to be perfectly balanced in 7a for the reaction with modestly acidic pronucleophiles. As seen from Table 4 (entry 6), the reactions of 2-arylazocarboxamide derivative 7l with PBu3 are slow, but the Mitsunobu reaction of poorly acidic pronucleophiles (Figure 4) does not seem to be interfered by the slow reaction rate for the betaine formation. Probably, this is because the reaction of such pronucleophiles with highly basic betaines rather promotes the irreversible step in the betaine formation. 3. Reactions with Sterically Hindered Alcohols. The Mitsunobu reaction is generally sensitive to the bulkiness of the substrates.28 For instance, the reaction of (−)-menthol (41) with benzoic acids often provides the corresponding ester products in low yield. In such a case, the use of highly acidic 4nitrobenzoic acid (10) is known to improve the outcome in the reaction with DEAD. While we could easily reproduce the literature28a,b reaction between 41 and 10 with PPh3/DEAD into ester 45 (51% yield, Table 5, entry 1), surprisingly, a combination of ADDP and PBu3 gave no product (entry 2). With 7g and PPh3 as the reagents, a mixture of ester 45 and its diastereomer was obtained in 30% yield and only moderate inversion ratio (entry 3). While replacement of 7g with 7a failed to induce the transformation (entry 4), a 7a/PBu3 combination afforded the ester 45, although in modest yield and inversion ratio (entry 5). Now, turning to 4-methoxybenzoic acid (42), its reaction with (−)-menthol (41) with 7g/PPh3 or 7a/PBu3 combination gave the corresponding ester 46 as a single inverted isomer, but the yields were still low (entries 6 and 7). Although elevating the reaction temperature to 80 °C improved the product yield, it was accompanied by erosion of the inversion ratio (entry 8). Next, when 2-methyl-6nitrobenzoic acid (43) was used instead, the corresponding ester 47 was generally produced as a single isomer in improved yield (entries 9−11). Interestingly, with acid 43, the use of strongly electrophilic azo reagent 7j and PPh3 worked well

Figure 4. Effect of pKa of pronucleophiles in Mitsunobu reaction of 28. Reaction conditions: 28 (0.5 mmol), 29,33−36 (0.6 mmol), 7a,b,l,m (0.6 mmol), PBu3 (0.6 mmol) in toluene (1 mL) at room temperature or 80 °C unless otherwise noted. Yields are determined by NMR analysis of the crude product (internal standard: 1,3,5trimethoxybenzene) unless otherwise noted: ayields of the isolated pure product.

in THF, showing a Hammett plot with a positive value of ρ. Now, to compare the difference in reactivity between ethyl 2arylazocarboxylates and ADDP, we first tested the reaction of ADDP with PPh3 and found out that it was faster (kobs = 34.9 × 10−3 min−1, Table 4, entry 5) than that of ethyl 2-(4chlorophenyl)azocarboxylate (7d, kobs = 19.5 × 10−3 min−1, entry 4) but slower than that of ethyl 2-(3,4-dichlorophenyl)azocarboxylate (7g, kobs16b = 85.1 × 10−3 min−1, not shown in Table 4). Next, we turned our attention to PBu3. With this phosphorus reagent, the reaction of either ADDP or 7d was too fast for the rate constants to be determined (entries 4 and 5). On the other hand, this was not the case for less electrophilic azo reagents 7a−c where the correlation between the reaction rate and electrophilicity of the azo reagents was similar to the reaction with PPh3 (entries 1−3). The above results indicated that the reaction with PBu3 is about 50 times faster as compared to PPh3. The kinetic results from Table 4 appear to be partially inconsistent with the reactivity trend from Table 3. In production of compound 30, as compared to reagent 7g (Table 3, entry 3), neither less electrophilic 7d (entry 4) nor more electrophilic 7i (entry 6) worked better. On the other hand, poorly electrophilic 7a gave good yield of 30 either with 4716


Article

The Journal of Organic Chemistry Table 5. Mitsunobu Reaction between (−)-Menthol (41) and Carboxylic Acidsa

entry

acid

azo reagent

R

time (h)

1 2 3 4 5 6 7 8e 9 10 11 12 13e 14e,f 15e 16 17e 18e,f

10 10 10 10 10 42 42 42 43 43 43 43 43 43 43 44 44 44

DEAD ADDP 7g (3,4-diCl) 7a (H) 7a (H) 7g (3,4-diCl) 7a (H) 7a (H) 7g (3,4-diCl) 7i (4-CN) 7j (4-NO2) 7a (H) 7a (H) 7a (H) 7b (4-OMe) 7g (3,4-diCl) 7a (H) 7a (H)

Ph Bu Ph Ph Bu Ph Bu Bu Ph Ph Ph Bu Bu Bu Bu Ph Bu Bu

6 24 16 40 20 16 42 3 20 6 3 24 3 3 10 20 3 3

product, yieldb (%) 45, 45, 45, 45, 45, 46, 46, 46, 47, 47, 47, 47, 47, 47, 47, 48, 48, 48,

51 0 30 0 22 19 13 60% 43 63 81 (84)d 25 84 (83)d 95 (91)d 4 31 73 90 (92)d

drc >99:1 47:53 36:64 >99:1 >99:1 65:35 >99:1 >99:1 >99:1 >99:1 >99:1 >99:1 >99:1 97:3 >99:1 >99:1

a

Reaction conditions: 41 (0.5 mmol), 10,42−44 (0.6 mmol), azo reagent (0.6 mmol), PR3 (0.6 mmol) in toluene (1 mL) at room temperature unless otherwise noted. bNMR yield unless otherwise noted (internal standard: dimethyl sulfone). cDetermined by NMR analysis of the crude product. dYields of the isolated pure product. e The reaction was performed at 80 °C. f1.5 equiv each of 7a and PBu3 were used.

Figure 5. Reaction between some sterically hindered alcohols and 44 with 7a. Reaction conditions: 49−51 (0.5 mmol), 44 (0.6 mmol), 7a (0.75 mmol), PBu3 (0.75 mmol) in toluene (1 mL) at room temperature or 80 °C. (a) Yields of the isolated pure product. (b) Estimated by NMR analysis of the crude product.

(entry 11). The reaction of 43 with 7a/PBu3 gave ester 47 in low yield at room temperature (entry 12), while increasing the reaction temperature to 80 °C significantly improved the result, with no retention product being detected (entry 13). An increase in the amounts of the reagents further improved the outcome (entry 14). In contrast, less electrophilic azo reagent 7b hardly provided any product (entry 15). Finally, the esterification of (−)-menthol (41) with 2-nitrobenzoic acid (44) into 48 gave results comparable to those of 43 (entries 16−18). Other representative alcohols 49−51 were subjected along with 2-nitrobenzoic acid (44) to the reaction conditions from entry 18 in Table 5 (Figure 5). While alcohol 49 could be readily transformed with into the corresponding inversion products 52, attempts to do so with highly sterically demanding substrates 50 and 51 failed. With (−)-borneol (50), no ester product could be detected either conducting the reaction at room temperature or 80 °C. Instead, careful monitoring of the reaction by NMR and mass spectral techniques revealed a nearly quantitative formation of the corresponding alkoxyphosphonium salt intermediate 53, suggesting that bulky 2-

nitrobenzoic acid (44) is unable to approach the congested reactive center at 53 and complete the SN2 step of the Mitsunobu reaction. The alkoxyphosphonium salt intermediate exhibited characteristic resonance at δ + 98.7 ppm in the 31P NMR spectrum. The methyne resonance of the alcohol at δ 4.01 ppm was replaced by the resonance at δ 4.75 ppm. Highresolution electrospray ionization mass spectra of the reaction mixtures indicated m/z 355.3135 (calcd for C22H44OP+: 355.3124) in positive mode (ESI+). Although replacement of acid 44 with sterically less demanding chloroacetic acid seemed to be a sound solution of the problem, it surprisingly gave similar result (data not shown).29 Alcohol 51, on the other hand, could be esterified with 2-nitrobenzoic acid (44) in up to 60% yield (69% conversion) into 54 with exclusive retention of configuration as indicated by NMR analyses of the crude reaction mixtures. The esterification of 51 with retention of configuration could be explained by a reaction of acyloxyphosphorane intermediates that could be in equilibrium with alkoxyphosphonium salts as previously proposed by several research groups.30 4717


Article

The Journal of Organic Chemistry 4. Recovery of Ethyl 2-(3,4-Dichlorophenyl)azocarboxylate. Representative methods for recovery of azo reagent 7g are illustrated in this section. Intramolecular alkylation of sulfonamide 55 with 7g and PPh3 quantitatively produced pyrrolidine 56 (Scheme 1). However, purification of

recovery of 7g protocol was successfully conducted on a gram scale, though bubbling air was required to effectively promote the oxidation of 8g into 7g (Scheme 2). Scheme 2. Scale-up Reaction

Scheme 1. Recovery of 7g Using One-Pot Telescoped Aerobic Oxidationa

Polymer-supported phosphine reagents serve for an easy removal of generated phosphine oxides in the Mitsunobu reaction.32 Despite the fact that the generated phosphine oxides usually caused no trouble in our protocol, a polymer supported triphenylphosphine (PS-PPh3) was tested in the Mitsunobu cyclization of compound 55 using azo reagent 7g (Scheme 3). a

TLC analysis was performed by using n-hexane/EtOAc (3:1).

Scheme 3. Reaction Using a Polymer-Supported Triphenylphosphine

56 by silica gel chromatography was troublesome due to the similar polarity of 56 (Rf = 0.3) and hydrazide 8g (Rf = 0.2) produced from 7g, as well as tailing of 8g in TLC. When the reaction mixture from Scheme 1 was subjected to the conditions of previously reported iron-catalyzed aerobic oxidation,31 hydrazide 8g was fully converted to azo compound 7g in 12 h. Owing to the significantly lower polarity of azo compounds (Rf = 0.6 for 7g) as compared to the hydrazides, this enabled an easy separation of 7g and pyrrolidine 56 from the resulting mixture by chromatography and their isolation in excellent yields and in high purity. With comparable success, this method was then applied to reaction mixtures composed of substrates that are sensitive to the oxidative conditions (Figure 6). Products 57−60 having electron-rich (hetero)aromatic rings, alkene functionality, or sulfur atoms were intact under the applied aerobic oxidation conditions and were isolated from the reaction mixtures with concomitant recovery of azo reagent (7g), both in excellent yields. The conversion of 55 into 56 and

After the one-pot Mitsunobu reaction and reoxidation sequence, the generated phosphine oxide could be easily removed by filtration, while product 56 and recovered 7g were obtained in good yields. Similarly, the intermolecular process between alcohol 28 and phenol afforded product 13 and recovered 7g in good yields. Provided the Rf value of the Mitsunobu ester product is sufficiently high (Rf > 0.3) as compared to that of hydrazide 8g, its isolation is easily achieved without the necessity of the above aerobic oxidation step. It can easily be isolated from the silica gel column by elution with n-hexane/ethyl acetate as the mobile phase, whereas elution of the mixture of all other side products, including 8g, can be achieved with ethyl acetate. From this mixture of side products, azo reagent 7g should be easily regenerated and isolated by applying the abovementioned iron-catalyzed aerobic oxidation protocol. To prove the concept, the mixtures of side products from 10

Figure 6. Examples of one-pot Mitsunobu reaction and iron-catalyzed aerobic oxidation. Reaction conditions: Alcohol (0.5 mmol), pronucleophile (0.6 mmol), 7g (0.6 mmol), PPh3 (0.6 mmol) in toluene (1 mL) at room temperature, then Fe(Pc) (0.025 mmol) at room temperature under air (open flask). Percentages of yield and recovery of 7g were based on isolation by chromatography. 4718


Article

The Journal of Organic Chemistry different reactions shown in Figure 2 (0.6 mmol ×10) were collected, combined, and subjected to iron-catalyzed aerobic oxidation for 10 h at room temperature. The resulting reaction mixture was filtered through a short pad of silica gel with toluene as eluent to almost quantitatively recover pure 7g (Scheme 4). This procedure further illustrates convenient recovery of the azo reagent.

formation and decreased the amount of recovered 7g. Although additional wastes are generated from NBS and pyridine, this recovery protocol may serve as an alternative to the aerobic oxidation when the latter is undesirable. Although we have not tested these procedures in the case of recovery of 2-phenylazocarboxamide 7l, the 2-phenylhydrazinecarboxamide formed in the reaction with 2-phenylazocarboxamide 7l (e.g., reactions in shown Figure 4) did not interfere purification of the desired product by silica gel chromatography due to its high polarity [Rf: < 0.05 (n-hexane/EtOAc, 3:1); 0.3 (n-hexane/EtOAc, 1:1)]. Consequently, the hydrazine side product was easily recovered in around 80% yield by chromatography. More simply, a portion (53%) of the hydrazine could be recovered as crystalline solids by a filtration because it precipitated in toluene after the reaction. The recovered 2-phenylhydrazinecarboxamide was reconverted to 7l in 94% yield by iron-catalyzed aerobic oxidation in CH2Cl2 at room temperature (see the Supporting Information). It has been reported that nucleophilic aromatic substitutions at the benzene ring proceed with aromatic amines and alcohols under mild conditions at tert-butyl phenylazocarboxylates.34 In contrast, no products indicating such kind of reactions could be detected under Mitsunobu conditions. 5. SC-DSC Analysis of Representative Azo Reagents. Most of the azo reagents are high energy compounds possessing potential explosive character.4,8b For instance, DEAD violently decomposes below 200 °C, releasing high energy. Previously, we tested preliminary thermal stability of representative ethyl 2-arylazocarboxylates.16b Thermogravimetry-differential thermal analysis (TG-DTA) of azo compounds showed endothermic behavior with a weight loss at approximately 200 °C, indicating evaporation of the compounds. Importantly, clear exothermic decomposition was not observed by preliminary differential scanning calorimetry (DSC) analyses.16b The results implied that ethyl 2arylazocarboxylates have superior thermal stability compared with DEAD. Indeed, ethyl 2-arylazocarboxylates were stable for more than a few months under ambient conditions. However, TG-DTA analysis did not provide exact information on thermal stability of 2-arylazocarboxylates because the sample evaporated before thermal decomposition. The thermal stability of azo reagents should be strictly evaluated when stoichiometric amounts of azo reagents are used in reactions under high temperature or pressure on a large scale. Therefore, we performed sealed cell-differential scanning calorimetry (SCDSC) analysis of representative azo reagents, ethyl 2-phenylazocarboxylate (7a) and ethyl 2-(3,4-dichlorophenyl)azocarboxylate (7g), to reveal an exact decomposition temperature and energy (Table 6). The onset of exothermic decomposition of azo reagent 7a was observed at 289.7 °C, and the peak top was 312.0 °C. The calorific value in decomposition was estimated at 1231.3 J/g, and this large value

Scheme 4. Recovery of 7g from Combined Wastea

a

TLC analysis was performed by using n-hexane/EtOAc (3:1).

Despite the fact that relatively long reaction times are required for the reoxidations of hydrazides into the corresponding azo derivatives in the above purification procedures (Schemes 1−4, Figure 6), the efficiency in terms of clean reactions, i.e., inertness to the products under this investigation and excellent recovery yields, and the absence of additional workups render it an attractive alternative, especially to several consecutive chromatographic separations. Alternatively, we tested the recovery of 7g from the reaction between a thiophene functionalized alcohol 61 and carboxylic acid 10 by using N-bromosuccinimide (NBS) as an oxidant in a one-pot telescoped reaction (Scheme 5).33 After the ester formation step was completed, treating the resulting reaction mixture with NBS/pyridine afforded the target compound 57 and recovered 7g in good yields, though small amounts of brominated side product 62 was obtained. The NBS oxidation in the absence of pyridine increased the side product 62 Scheme 5. Recovery of 7g Using N-Bromosuccinimide (NBS) as a Reoxidizera

Table 6. SC-DSC Data of 7a,g,la azo reagent 7a 7g

7l a

a

Yields in parentheses refer to the reaction in the absence of pyridine. 4719

first peak second peak

extrapolated onset temp (°C)

temp in a peak top (°C)

heat of dec (J/g)

289.7 249.7 360.7

312.0 293.1 368.7

−1231.3 −791.0 −1272.2

251.5

263.8

−812.0

Heating rate is 10 °C/min. DOI: 10.1021/acs.joc.8b00486 J. Org. Chem. 2018, 83, 4712−4729

Article


superior over DEAD because the reaction of modestly acidic Nmethyl-p-toluenesulfonamide afforded the product in good yield. However, the screening of other moderately acidic substrates indicated that ethyl 2-phenylazocarboxylate (7a), 2phenylazocarboxamide (7l), and 2-(4-methoxyphenyl)azocarboxamide (7m) are more effective in the presence of PBu3 than PPh3. Overall, these are replacements for ADDP (Figure 7B). Although the performance of these reagents is sensitive to a steric hindrance of the alcohol substrates, similarly to the known Mitsunobu reagents, our experimental results indicate that by careful selection of the reaction conditions and partnering acids there is a room for further improvements. We have demonstrated that the azo reagents under this investigation can be easily recycled by utilizing iron-catalyzed aerobic oxidation under mild conditions. This feature was applicable to easy and scalable recovery of the reagents. The emergence of recyclable azo reagents in the Mitsunobu reaction shall inspire development of new protocols for the parent hydrazine oxidations.35 Most of the 2-arylazocarboxylates and 2-arylazocarboxamides were stable for more than a few months under ambient conditions. SC-DSC analyses of representative azo reagents revealed considerably higher exothermic decomposition points as compared to the typical Mitsunobu azo reagents such as DEAD. This strongly supports low explosiveness of the azo compounds under this investigation. Thus, the developed reagents could be handled safer than DEAD, though we did not evaluate the safety from a viewpoint of toxicity. In conclusion, ethyl 2-arylazocarboxylates and 2-arylazocarboxamides are safe in terms of chemical reactivity hazards, highly reactive, and easily recyclable Mitsunobu reagents which will in the future find wide applications in practical syntheses.

was consistent with that of typical azo compounds. On the other hand, analysis of azo reagent 7g showed two exothermic peaks. Onset of the first exothermic was observed at 249.7 °C, but the peak was broad showing the relatively low calorific value (791.0 J/g). Onset of the second exothermic was observed at 360.7 °C, and the peak was a sharp form having a top at 368.7 °C and a large calorific value (1272.2 J/g). To shed light into this interesting double exothermic behavior, we conducted mass spectrometry analysis of 7g in direct analysis in real time (DART) mode at different temperatures (200−500 °C). Fragmentation peaks based on [M − CO2Et]+ (m/z: 173, 175, 177) increased with decrease peaks of [M + H]+ (m/z: 247, 249, 251) by elevating the temperature. Small fragmentation peaks based on [M − OEt]+ (m/z: 201, 203, 205) were also observed. Fragmentation peaks based on [Ar]+ (m/z: 145, 147, 149) were detected at high temperatures (400−500 °C), though the peaks were very unintense. These results indicated that the first thermal decomposition was decarboxylation and that the second one was based on a release of a nitrogen molecule. This is consistent with the large calorific value in the second exothermic decomposition. Mass spectrometry analysis of azo reagent 7a gave a similar spectrum, but decarboxylation and nitrogen release of 7a occurred almost concurrently. Thus, thermal decomposition based on the azo groups of reagents 7a and 7g occurs at a temperature higher than that of typical azo reagents such as DEAD. On the other hand, the exothermic energy of these reagents was similar to that of typical azo compounds, but the potential explosiveness of high energy compounds largely depends on a decomposition temperature. These results strongly support that 2-arylazocarboxylate derivatives have high thermal stability and can be handled safely compared with typical azo reagents in Mitsunobu reaction. Decomposition of 2-phenylazocarboxamide 7l occurred at lower temperature as for 7a, but a calorific value (812.0 J/g) was small.

■

■

EXPERIMENTAL SECTION

General Remarks. Japan: All reactions were performed in ovendried glassware. All reagents purchased commercially were used without further purification unless otherwise noted. Iron phthalocyanine was purchased from Tokyo Chemical Industry Co., Ltd. Dehydrated THF, toluene, and CH2Cl2 were purchased from Kanto Chemical Co., Inc. Other solvents were dried with activated molecular sieves. Thin-layer chromatography (TLC) analysis was performed by illumination with a UV lamp (254 nm) or staining with phosphomolybdic acid (PMA) and heating. Silica gel column chromatography was carried out on silica gel 60N (Kanto Chemical Co., Inc., spherical, neutral, 40−50 μm). The chromatographic separation of enantiomers was performed using a JASCO PU-2080 Plus liquid chromatography equipped with Multi UV−vis (JASCO MD-910). Melting points were recorded on a Yanako melting point apparatus and were uncorrected. 1H and 13C NMR spectra were recorded with JEOL JNM ECS400 (400 and 100 MHz), JEOL JNM ECS500 (500 and 125 MHz), and JEOL JNM ECA600 (600 and 150 MHz) spectrometers at 293−295 K. Proton spectra were referenced to TMS as an internal standard. Carbon chemical shifts were determined relative to the 13C signal of CDCl3 (77.0 ppm). Coupling constants (J) are given in hertz. Multiplicities are indicated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), or br (broadened). IR spectra were recorded with a JASCO Fourier transform IR-460 spectrometer. Mass spectra were recorded on JEOL JMS-T100TD (direct analysis in real time, DART) or JEOL JMS-700 (fast atom bombardment, FAB), and exact mass values were calculated as neutral molecules by calibration using an appropriate internal standard (triphenylphosphine oxide or PEG). Optical rotations were measured on a JASCO P-1030 polarimeter. Absorption spectra were measured in a 0.1 mm quartz cell on a JASCO V-570 spectrophotometer. Differential scanning calorimetric (DSC) analysis was performed on

CONCLUSIONS We have systematically evaluated ethyl 2-arylazocarboxylate and 2-arylazocarboxamide derivatives as Mitsunobu reagents. Promising azo reagents selected in our study are shown in Figure 7. Ethyl 2-(3,4-dichlorophenyl)azocarboxylate (7g) can

Figure 7. Potent azo reagents selected in our study.

readily serve as a replacement of DEAD as it is applicable to a broad scope of substrates. Ethyl 2-(4-cyanophenyl)azocarboxylate (7i) works well in the medium ring construction. Overall, these serve as catalysts in the catalytic protocol or as replacement of DEAD (Figure 7A). From the standpoint of pKa limitations in substrates, 7g is likely to be 4720


Article


MHz, CDCl3) δ 161.5, 152.0, 132.9, 129.2, 123.5, 45.9, 44.5, 26.1, 25.5, 24.3; HRMS (ESI+) calcd for C12H16N3O+ ([M + H]+) 218.1288, found 218.1289.

a Seiko Instruments, Inc., EXSTAR 6000 DSC6200R (heating rate of 10.0 °C/min) under a nitrogen atmosphere. Slovenia: All reactions were performed in oven-dried glassware under nitrogen atmosphere. All reagents purchased commercially from Sigma-Aldrich were used without further purification unless otherwise noted. Toluene and tetrahydrofuran were distilled over sodium wire. Dichloromethane was distilled over calcium hydride. Thin-layer chromatography (TLC) analysis was performed on Fluka silica gel on TLC Al foils (silica gel matrix, with fluorescent indicator, 60 Å medium pore diameter). Visualization of compounds was done by illumination with a UV lamp (254 nm) or by using a solution of KMnO4/K2CO3/NaOH in water (prepared by dissolving 1.5 g of KMnO4, 10 g of K2CO3, and 1.25 mL of 10% NaOH in 200 mL of water) followed by heating. Silica gel column chromatography was carried out on silica gel 60N. Melting points were recorded on a Kofler micro hot stage and were uncorrected. 1H, 31P, and 13C spectra were recorded with a Bruker Avance III 500 MHz NMR (500, 202, and 126 MHz) instrument at 300 K or with a Bruker Avance DPX 300 spectrometer (300, 122, and 76 MHz) at 302 K. Proton spectra were referenced to TMS as an internal standard. Carbon chemical shifts were determined relative to the 13C signal of CDCl3 (77.0 ppm). 31P NMR spectra were referenced to external 85% phosphoric acid (δ = 0 ppm). Assignments of some proton, carbon and phosphorus resonances were performed by 2D NMR techniques (1H−1H gsCOSY, 1H−13C gs-HSQC, 1H−13C gs-HMBC, and 1H−31P gsHMBC). Coupling constants (J) are given in hertz. Multiplicities are indicated as follows: s (singlet), d (doublet), t (triplet), m (multiplet), or br (broadened). IR spectra were recorded with a PerkinElmer Spectrum 100 (equipped with a Specac Golden Gate Diamond ATR as a solid sample support). HRMS spectra were recorded on a time-offlight (TOF) mass spectrometer equipped with a double-orthogonal electrospray source at atmospheric pressure ionization (ESI) coupled to an HPLC instrument. Preparation of Azo Reagents. Ethyl 2-arylhydrazinecarboxylates 7a−j were prepared from the corresponding phenylhydrazine derivatives and ethyl chloroformate according to established methods.31,33 Synthesis of Azocarboxamides 7k, 7l, and 7m. Following a modified literature procedure,33 to a solution of 7a (713 mg, 4.0 mmol) or 7b (833 mg, 3.5 mmol) in ethanol (2 mL) was added piperidine (550 μL, 468 mg, 5.5 mmol) or dimethyl amine (1 mL of 33% (5.6 M) solution in ethanol, 5.5 mmol) at room temperature, and the mixture was stirred until TLC indicated complete consumption of the starting material. The mixture was evaporated to dryness, and the crude product was recrystallized from the mixture of n-hexane and ethyl acetate to obtain the corresponding pure azocarboxamide in high yield.

((4-Methoxyphenyl)diazenyl)(piperidin-1-yl)methanone (7m): 15 h; 88% yield (770 mg, 3.11 mmol) (after recrystallization); red solid; mp 90−91 °C (n-hexane/EtOAc); IR (ATR) 2932, 2851, 1660, 1603, 1502, 1411, 1250, 1015, 854 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.93 (2H, d, J = 9.1 Hz), 6.99 (2H, d, J = 9.1 Hz), 3.90 (3H, s), 3.75− 3.70 (2H, m), 3.66−3.62 (2H, m), 1.74−1.68 (4H, m), 1.64−1.59 (2H, m); 13C NMR (126 MHz, CDCl3) δ 163.6, 161.6, 146.4, 125.9, 114.2, 55.6, 45.9, 44.5, 26.1, 25.5, 24.3; HRMS (ESI+) calcd for C13H18N3O2+ ([M + H]+) 248.1394, found 248.1393.

N′-Phenylpiperidine-1-carbohydrazide (8l). To a solution of 7l (109 mg, 0.5 mmol) in chloroform (1 mL) was added tributylphosphine (190 μL, 151 mg, 0.75 mmol) under nitrogen atmosphere at room temperature, and the mixture was stirred for 30 min at room temperature. Then the reaction flask was opened and exposed to air for 5 h, followed by addition of 1 mL of water. The mixture was stirred for additional 15 h at room temperature. Water (10 mL) was added, and the mixture was extracted with dichloromethane (3 × 10 mL). Organic layers were combined and dried over sodium sulfate, filtered, and evaporated to dryness. Silica gel chromatography (n-hexane/ethyl acetate = 1:1) was performed to regenerate N′phenylpiperidine-1-carbohydrazide in 79% yield (86.2 mg, 0.393 mmol): beige solid; Rf 0.33 (n-hexane/EtOAc = 1:1); mp 180−182 °C (n-hexane/EtOAc); IR (ATR) 3338, 3286, 3037, 2933, 1633, 1592, 1513, 1470, 1436, 1261 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.23− 7.18 (2H, m), 6.91−6.84 (3H, m), 6.27 (1H, br s), 6.11 (1H, br s), 3.41−3.37 (4H, m), 1.65−1.36 (6H, m); 13C NMR (126 MHz, CDCl3) δ 158.2, 149.4, 129.0, 120.8, 113.8, 44.8, 25.6, 24.3; HRMS (ESI+) calcd for C12H18N3O+ ([M + H]+) 220.1444, found 220.1445. Aerobic Oxidation of 8l. According to a method reported previously,31 to a stirred solution of 8l (43.9 mg, 0.2 mmol) in dichloromethane (1.0 mL, 0.2 M) was added iron phthalocyanine (5.7 mg, 10 μmol, 5 mol %) at room temperature. The resultant mixture was stirred for 4 h at room temperature under an air atmosphere (balloon). The reaction mixture was filtered through filter paper, and the solvent was removed under reduced pressure. The crude material was purified by silica gel chromatography (eluent: n-hexane/EtOAc = 3:1) to give 7l (41.0 mg, 0.189 mmol, 95%). Experimental Details and Analytical Data for Synthesized Compounds. General Procedure for Stoichiometric Mitsunobu Reactions. To a stirred solution of alcohol (0.5 mmol) and nucleophile (0.6 mmol) in toluene (1.0 mL) were added azo reagent 7a−m (0.6 mmol) and phosphine (0.6 mmol, PPh3: 157 mg; PnBu3: 121 mg) at room temperature under N2 (balloon). The addition order of substrates and reagents did not usually affect the results. The reaction mixture was stirred for given time at given temperature (see below for details). After completion of the reaction, the solvent was removed under reduced pressure. As required, the conversion into desired product was determined by quantitative 1H NMR analysis of the crude product in the presence of an appropriate internal standard (e.g., trioxane, 1,3,5-trimethoxybenzene, or dimethyl sulfone). The crude material was purified by silica gel chromatography (eluent: nhexane/EtOAc) to give the corresponding product. Representative Data in Screening of Reagents and Scope of Typical Substrates (Table 1, Entry 7, and Figure 2). According to the general procedure, 7g (148 mg, 0.6 mmol) and triphenylphosphine (157 mg, 0.6 mmol) were used as reagents, and the reactions were conducted at room temperature unless otherwise noted.

N,N-Dimethyl-2-phenyldiazene-1-carboxamide (7k). 5 h. 74% yield (524 mg, 2.96 mmol) (after recrystallization); red solid; mp 64− 65 °C (n-hexane/EtOAc) (lit.36 mp 62−63 °C); IR (ATR) 2804, 1693, 1494, 1443, 1255, 1080, 770 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.94−7.91 (2H, m), 7.58−7.50 (3H, m), 3.20 (3H, s), 3.15 (3H, s); 13C NMR (126 MHz, CDCl3) δ 162.7, 152.0, 133.0, 129.2, 123.5, 36.56, 36.54; HRMS (ESI+) calcd for C9H12N3O+ ([M + H]+) 178.0975, found 178.0974.

(Phenyldiazenyl)(piperidin-1-yl)methanone (7l): 5 h; 81% yield (704 mg, 3.24 mmol) (after recrystallization); red solid; mp 77−78 °C (n-hexane/EtOAc) (lit.37 mp 78−79 °C); IR (ATR) 2942, 2858, 1695, 1424, 1254, 1188, 1131 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.93− 7.90 (2H, m), 7.58−7.51 (3H, m), 3.75−3.72 (2H, m), 3.60−3.56 (2H, m), 1.76−1.71 (4H, m), 1.65−1.59 (2H, m); 13C NMR (126 4721


Article


2-((3-Phenylpropyl)thio)benzo[d]thiazole (16).16b 3-Phenylpropanol (68.1 mg, 0.5 mmol) and 2-mercaptobenzothiazole (100 mg, 0.6 mmol) were used as substrates: 5 h. 100% yield (142 mg, 0.50 mmol); colorless oil; eluent n-hexane/AcOEt = 20:1; 1H NMR (500 MHz, CDCl3) δ 7.86 (1H, app d, J = 8.0 Hz), 7.74 (1H, app d, J = 8.0 Hz), 7.40 (1H, app t, J = 7.5 Hz), 7.31−7.27 (3H, m), 7.21−7.18 (3H, m), 3.34 (2H, t, J = 7.5 Hz), 2.81 (2H, t, J = 7.5 Hz), 2.16 (2H, quint, J = 7.5 Hz); 13C NMR (125 MHz, CDCl3) δ 166.9, 153.3, 140.9, 135.1, 128.48, 128.44, 126.1, 126.0, 124.1, 121.4, 120.9, 34.6, 32.8, 30.7.

(R)-1-(Ethoxycarbonyl)ethyl 4-Nitrobenzoate (11).16b (−)-(S)Ethyl lactate (9) (59.1 mg, 0.5 mmol, >99:1 er) and 4-nitrobenzoic acid (10) (100 mg, 0.6 mmol) were used as substrates: 5 h; 99% yield (132 mg, 0.49 mmol), 99:1 er; white solid; eluent n-hexane/AcOEt = 6:1; 1H NMR (500 MHz, CDCl3) δ 8.31 (2H, app d, J = 9.5 Hz), 8.26 (2H, app d, J = 9.5 Hz), 5.35 (1H, q, J = 7.0 Hz), 4.25 (2H, q, J = 7.5 Hz), 1.66 (3H, d, J = 7.5 Hz), 1.30 (3H, t, J = 7.5 Hz); 13C NMR (125 MHz, CDCl3) δ 170.2, 164.0, 150.7, 134.9, 130.9, 123.5, 69.9, 61.7, 17.0, 14.1. The enantiomeric ratio was determined by HPLC analysis using a chiral column. Chiral HPLC: Daicel-Chiralpak AD-H 46 × 250 mm, multi UV−vis detector (230 nm), room temperature eluent: (nhexane/i-PrOH) 5:1, flow rate: 0.5 mL/min, retention time (min) 14.1 (R isomer), 17.6 (S isomer). [α]D25 = −18.7 (c 1.00, CHCl3) [lit.16b (R)-1-ethoxycarbonylethyl 4-nitrobenzoate (>99:1 er), [α]D25 = −18.5 (c 1.00, CHCl3)].

(R)-2-Octyl 4-Nitrobenzoate (18).16b (+)-(S)-2-Octanol (65.1 mg, 0.5 mmol, 99:1 er) and 4-nitrobenzoic acid (10) (100 mg, 0.6 mmol) were used as substrates: 5 h; 93% yield (129 mg, 0.46 mmol), 99:1 er; pale yellow oil; eluent n-hexane/AcOEt = 30:1; 1H NMR (500 MHz, CDCl3) δ 8.29 (2H, app d, J = 9.0 Hz), 8.21 (2H, app d, J = 9.0 Hz), 5.21−5.17 (1H, m), 1.77−1.73 (1H, m), 1.66−1.62 (1H, m), 1.42− 1.26 (8H, m), 1.38 (3H, d, J = 6.5 Hz), 0.88 (3H, t, J = 6.5 Hz); 13C NMR (125 MHz, CDCl3) δ 164.3, 150.4, 136.3, 130.6, 123.4, 73.1, 35.9, 31.7, 29.1, 25.4, 22.5, 20.0, 14.0. The enantiomeric ratio was determined by HPLC analysis using a chiral column. Chiral HPLC: Daicel-Chiralpak OJ-H 46 × 250 mm, multi UV−vis detector (230 nm), room temperature eluent: (n-hexane/i-PrOH) 99.5:0.5, flow rate: 0.5 mL/min, retention time (min) 15.1 (S isomer), 18.6 (R isomer). [α]D25 = −36.8 (c 1.00, CHCl3) [authentic sample (retention): (S)-2octyl 4-nitrobenzoate (99:1 er), [α]D25 = +39.6 (c 1.00, CHCl3)16b].

3-Phenylpropyl Benzoate (12).16b 3-Phenylpropanol (68.1 mg, 0.5 mmol) and benzoic acid (73.3 mg, 0.6 mmol) were used as substrates: 3 h; 95% yield (129 mg, 0.46 mmol); colorless oil; eluent n-hexane/ AcOEt = 30:1; 1H NMR (500 MHz, CDCl3) δ 8.04 (2H, d, J = 7.0 Hz), 7.56 (1H, app t, J = 7.5 Hz), 7.44 (2H, app t, J = 8.0 Hz), 7.30 (2H, app t, J = 7.5 Hz), 7.23−7.19 (3H, m), 4.34 (2H, t, J = 6.5 Hz), 2.79 (2H, t, J = 7.5 Hz), 2.11 (2H, tt, J = 7.5, 6.0 Hz); 13C NMR (125 MHz, CDCl3) δ 166.6, 141.2, 132.9, 130.3, 129.5, 128.45, 128.41, 128.33, 126.0, 64.2, 32.3, 30.3. (3-Phenylpropoxy)benzene (13).16b 3-Phenylpropanol (68.1 mg, 0.5 mmol) and phenol (56.5 mg, 0.6 mmol) were used as substrates. Five 5h. 95% yield (100 mg, 0.47 mmol); colorless oil; eluent: nhexane/AcOEt = 20:1; 1H NMR (500 MHz, CDCl3) δ 7.30−7.26 (4H, m), 7.23−7.18 (3H, m), 6.93 (1H, app t, J = 7.5 Hz), 6.90−6.89 (2H, m), 3.96 (2H, t, J = 6.5 Hz), 2.81 (2H, t, J = 7.5 Hz), 2.10 (2H, tt, J = 7.5, 6.5 Hz); 13C NMR (125 MHz, CDCl3) δ 159.0, 141.5, 129.4, 128.5, 128.4, 125.9, 120.5, 114.5, 66.7, 32.1, 30.8.

(S)-1-Phenylethyl 4-Nitrobenzoate (19).16b (+)-(R)-1-Phenyl-1ethanol (61.1 mg, 0.5 mmol, 98:2 er) and 4-nitrobenzoic acid (10) (100 mg, 0.6 mmol) were used as substrates: 5 h; 86% yield (116 mg, 0.43 mmol), 94:6 er; colorless oil; eluent n-hexane/AcOEt = 30:1; 1H NMR (500 MHz, CDCl3) δ 8.28 (2H, app d, J = 9.0 Hz), 8.24 (2H, app d, J = 9.0 Hz), 7.46−7.44 (2H, m), 7.39 (2H, app t, J = 7.0 Hz), 7.33 (1H, app t, J = 7.5 Hz), 6.16 (1H, q, J = 7.0 Hz), 1.71 (3H, d, J = 7.0 Hz); 13C NMR (125 MHz, CDCl3) δ 163.9, 150.5, 140.9, 135.8, 130.7, 128.7, 128.2, 126.1, 123.5, 74.2, 22.2. The enantiomeric ratio was determined by HPLC analysis using a chiral column. Chiral HPLC: Daicel-Chiralpak OJ-H 46 × 250 mm, multi UV−vis detector (210 nm), room temperature eluent: (n-hexane/i-PrOH) 1:1 flow rate: 0.5 mL/min, retention time (min) 22.2 (R isomer), 26.5 (S isomer). [α]D25 = +47.0 (c 1.00, CHCl3) [authentic sample (retention): (R)-1-Phenylethyl 4-nitrobenzoate (98:2 er), [α]D25 = −49.0 (c 1.00, CHCl3)16b].

2-(3-Phenylpropyl)isoindole-1,3-dione (14).4 3-Phenylpropanol (68.1 mg, 0.5 mmol) and phthalimide (88.3 mg, 0.6 mmol) were used as substrates: 3 h; 100% yield (132 mg, 0.50 mmol); pale yellow oil; eluent n-hexane/AcOEt = 10:1; 1H NMR (500 MHz, CDCl3) δ 7.83−7.81 (m, 2H), 7.71−7.69 (m, 2H), 7.25 (2H, app t, J = 7.5 Hz), 7.19 (2H, app d, J = 7.0 Hz), 7.14 (1H, app t, J = 7.5 Hz), 3.74 (2H, t, J = 7.5 Hz), 2.68 (2H, t, J = 8.0 Hz), 2.03 (2H, tt, J = 8.0, 7.5 Hz); 13C NMR (125 MHz, CDCl3) δ 168.4, 141.0, 133.8, 132.0, 128.3, 128.2, 125.9, 123.1, 37.8, 33.1, 29.8.

(S)-1-Ethoxy-1-oxo-4-phenylbutan-2-yl 4-Nitrobenzoate (20).16b Ethyl (−)-(R)-2-hydroxy-4-phenylbutyrate (104 mg, 0.5 mmol, >99:1 er) and 4-nitrobenzoic acid (10) (100 mg, 0.6 mmol) were used as substrates: 5 h; 91% yield (161 mg, 0.45 mmol), 98:2 er; pale yellow oil; eluent n-hexane/AcOEt = 15:1; 1H NMR (500 MHz, CDCl3) δ 8.29 (2H, app d, J = 8.5 Hz), 8.17 (2H, app d, J = 8.5 Hz), 7.32−7.29 (2H, m), 7.23−7.20 (3H, m), 5.28 (1H, t, J = 6.5 Hz), 4.24 (2H, q, J = 7.5 Hz), 2.85 (2H, t, J = 7.5 Hz), 2.36 (2H, dt, J = 7.5, 6.5 Hz), 1.29 (3H, t, J = 7.5 Hz); 13C NMR (125 MHz, CDCl3) δ 169.4, 164.1, 150.7, 140.2, 134.7, 131.0, 128.6, 128.4, 126.3, 123.5, 73.0, 61.7, 32.5, 31.5, 14.1. The enantiomeric ratio was determined by HPLC analysis using a chiral column. Chiral HPLC: Daicel-Chiralpak OJ-H 46 × 250 mm, multi UV−vis detector (210 nm), room temperature eluent: (nhexane/i-PrOH) 5:1, flow rate: 1.0 mL/min, retention time (min) 48.8 (S isomer), 24.1 (R isomer). [α]D25 = −17.0 (c 1.00, CHCl3)

N-Benzyl-4-nitro-N-(3-phenylpropyl)benzenesulfonamide (15).16b 3-Phenylpropanol (68.1 mg, 0.5 mmol) and N-benzyl-2nitrobenzenesulfonylamide (175 mg, 0.6 mmol) were used as substrates: 5 h; 87% yield (178 mg, 0.43 mmol); pale yellow oil; eluent n-hexane/AcOEt = 5:1; 1H NMR (500 MHz, CDCl3) δ 7.91 (1H, d, J = 9.0 Hz), 7.70−7.58 (3H, m), 7.32−7.15 (8H. m), 6.98 (2H, d, J = 7.0 Hz), 4.52 (2H, s), 3.26 (2H, t, J = 7.5 Hz), 2.43 (2H, t, J = 7.0 Hz), 1.70 (2H, tt, J = 7.5, 7.0 Hz); 13C NMR (150 MHz, CDCl3) δ 147.9, 140.9, 135.6, 133.7, 133.4, 131.6, 130.9, 128.7, 128.4, 128.3, 128.2, 127.9, 126.0, 124.2, 51.2, 46.6, 32.6, 29.0.

4722


Article

The Journal of Organic Chemistry [authentic sample (retention): (R)-1-ethoxy-1-oxo-4-phenylbutan-2-yl 4-nitrobenzoate (99:1 er), [α]D25 = +19.6 (c 1.00, CHCl3)16b].

Ethyl (R)-2-(1,3-Dioxoisoindolin-2-yl)propanoate (24). 16b (−)-(S)-Ethyl lactate (9) (59.1 mg, 0.5 mmol) and phthalimide (88.3 mg, 0.6 mmol) were used as substrates: 8 h; 91% yield (113 mg, 0.466 mmol), >99:1 er; white solid; eluent n-hexane/AcOEt = 10:1; 1 H NMR (500 MHz, CDCl3) δ 7.87 (2H, app dd, J = 5.4, 3.2 Hz), 7.74 (2H, app dd, J = 5.4, 3.2 Hz), 4.97 (1H, q, J = 7.3 Hz), 4.25−4.18 (2H, m), 1.70 (3H, d, J = 6.9 Hz), 1.24 (3H, t, J = 7.2 Hz); 13C NMR (125 MHz, CDCl3) δ 169.7, 167.5, 134.1, 131.9, 123.5, 61.9, 47.6, 15.3, 14.1. The enantiomeric ratio was determined by HPLC analysis using a chiral column. Chiral HPLC: Daicel-Chiralpak OD-H 46 × 250 mm, multi UV−vis detector (230 nm), room temperature eluent: (n-hexane/i-PrOH) 99:1, flow rate: 0.5 mL/min, retention time (min) 36.5 (S isomer), 40.0 (R isomer). [α]D25 = + 18.8 (c 0.30, MeOH) [lit.16b ethyl (R)-2-(1,3-dioxoisoindolin-2-yl)propanoate, [α]D25 = + 18.4 (c 1.00, MeOH)].

(R)-1-(Ethoxycarbonyl)ethyl 4-Methoxybenzoate (21). 16b (−)-(S)-Ethyl lactate (9) (59.1 mg, 0.5 mmol) and 4-methoxybenzoic acid (91.3 mg, 0.6 mmol) were used as substrates: 5 h; 88% yield (111 mg, 0.44 mmol), >99:1 er; colorless oil; eluent n-hexane/AcOEt = 10:1; 1H NMR (500 MHz, CDCl3) δ 8.04 (2H, app d, J = 8.5 Hz), 6.93 (2H, app d, J = 8.5 Hz), 5.28 (1H, q, J = 7.0 Hz), 4.23 (2H, q, J = 7.0 Hz), 3.86 (3H, s), 1.61 (3H, d, J = 6.5 Hz), 1.28 (3H, t, J = 7.0 Hz); 13C NMR (125 MHz, CDCl3) δ 171.0, 165.6, 163.6, 131.8, 121.8, 113.6, 68.8, 61.3, 55.4, 17.0, 14.0. The enantiomeric ratio was determined by HPLC analysis using a chiral column. Chiral HPLC: Daicel-Chiralpak OD-H 46 × 250 mm, multi UV−vis detector (250 nm), room temperature eluent: (n-hexane /i-PrOH) 99.5:0.5, flow rate: 1.0 mL/min, retention time (min) 29.2 (S isomer), 32.9 (R isomer). [α]D25 = −30.9 (c 1.00, CHCl3) [authentic sample (retention): (S)-1-ethoxycarbonylethyl 4-methoxybenzoate (99:1 er), [α]D25 = +32.6 (c 1.00, CHCl3)16b].

Ethyl (R)-2-(4-Methoxyphenoxy)propanoate (25).25,38 (−)-(S)Ethyl lactate (9) (59.1 mg, 0.5 mmol) and 4-methoxyphenol (74.5 mg, 0.6 mmol) were used as substrates: 10 h; 96% yield (107 mg, 0.48 mmol), >99:1 er; pale yellow oil; eluent n-hexane/AcOEt = 13:1; 1H NMR (400 MHz, CDCl3) δ 6.82 (2H, app d, J = 4.6 Hz), 6.82 (2H, app d, J = 4.6 Hz), 4.65 (1H, q, J = 6.7 Hz), 4.21 (2H, q, J = 7.2 Hz), 3.76 (3H, s), 1.59 (3H, d, J = 6.9 Hz), 1.25 (3H, t, J = 7.1 Hz); 13C NMR (101 MHz, CDCl3) δ 172.4, 154.4, 151.6, 116.4, 114.6, 73.6, 61.2, 55.6, 18.6, 14.1. The enantiomeric ratio was determined by HPLC analysis using a chiral column. Chiral HPLC: Daicel-Chiralpak OD-H 46 × 250 mm, multi UV−vis detector (230 nm), room temperature eluent: (n-hexane/i-PrOH) 99:1, flow rate: 0.5 mL/min, retention time (min) 31.3 (minor), 47.2 (major). [α]D27 = + 55.9 (c 1.00, MeOH) [lit.25 ethyl (S)-2-(4-methoxyphenoxy)propanoate was synthesized by Mitsunobu reaction using DEAD and PPh3, [α]D29 = − 64.39 (c 1.0, CHCl3); lit.38 ethyl (S)-2-(4-methoxyphenoxy)propanoate was synthesized by an enantioselective reaction between a carbenoid and a phenol (99% ee, putative absolute configuration), [α]D28 = + 57.0 (c 1.6, EtOH).] Cyclization of Amino Alcohol 26 into Sulfonamide 27 (Table 2). To a solution of N-(7-hydroxyheptyl)-4-nitrobenzenesulfonamide (26)26 (158 mg, 0.5 mmol) was added triphenylphosphine (481 mg, 1.84 mmol) in toluene/THF (3:1) (50 or 100 mL), DEAD, or 7g or 7i (1.84 mmol) (in the case of 7g and 7i in one portion (solid compounds) dropwise in the case of DEAD) at room temperature, and the reaction mixture was stirred for the given time (1,3,5trimethoxybenzene was used as internal standard). Then the solvent was evaporated to dryness, and the crude reaction mixture was analyzed by quantitative NMR to determine the conversion into the desired product 27.

(R)-1-Ethoxy-1-oxopropan-2-yl 3-Phenylpropanoate (22).16b (−)-(S)-Ethyl lactate (9) (59.1 mg, 0.5 mmol) and 3-phenylpropionic acid (90.1 mg, 0.6 mmol) were used as substrates, and 7d (213 mg, 1.0 mmol) and triphenylphosphine (263 mg, 1.0 mmol) were used as the azo reagent: 8 h. 97% yield (121 mg, 0.48 mmol), 97:3 er; colorless oil; eluent n-hexane/AcOEt = 10:1; 1H NMR (500 MHz, CDCl3) δ 7.29 (2H, app t, J = 7.5 Hz), 7.22−7.19 (3H, m), 5.07 (1H, q, J = 7.5 Hz), 4.19 (2H, q, J = 7.5 Hz), 2.98 (2H, t, J = 7.5 Hz), 2.77−2.67 (2H, m), 1.47 (3H, d, J = 7.5 Hz), 1.26 (3H, t, J = 7.5 Hz); 13C NMR (150 MHz, CDCl3) δ 172.2, 170.8, 140.3, 128.4, 128.2, 126.2, 68.6, 61.3, 35.5, 30.7, 16.9, 14.0. The enantiomeric ratio was determined by HPLC analysis using a chiral column. Chiral HPLC: Daicel-Chiralpak OD-H 46 × 250 mm, multi UV−vis detector (210 nm), room temperature eluent: (n-hexane/i-PrOH) 99.5:0.5, flow rate: 1.0 mL/ min, retention time (min) 28.7 (S isomer), 34.3 (R isomer). [α]D25 = +30.1 (c 1.00, CHCl3) [authentic sample (retention): (S)-1-ethoxy-1oxopropan-2-yl 3-phenylpropanoate (99:1 er), [α]D25 = −29.5 (c 1.00, CHCl3)16b].

(3S)-5α-Cholestan-3-yl 4-Nitrobenzoate (23).16b Dihydrocholesterol (194 mg, 0.5 mmol) and 4-nitrobenzoic acid (3a) (100 mg, 0.6 mmol) were used as substrates: 8 h; 88% yield (237 mg, 0.44 mmol, as a single diastereomer in NMR analysis); pale yellow solid; eluent nhexane/AcOEt = 30:1; 1H NMR (600 MHz, CDCl3) δ 8.31 (2H, app d, J = 8.9 Hz), 8.22 (2H, app d, J = 8.9 Hz), 5.32−5.31 (1H, m), 1.99 (1H, dt, J = 12.5, 3.1 Hz), 1.89 (1H, br-d, J = 13.4 Hz), 1.84−1.79 (2H, m), 1.64−1.56 (8H, m), 1.40−0.93 (18H, m), 0.91 (3H, d, J = 6.5 Hz), 0.87 (3H, d, J = 6.5 Hz), 0.86 (3H, d, J = 6.5 Hz), 0.85 (3H, s), 0.79 (1H, dt, J = 16.2, 6.3 Hz), 0.67 (3H, s); 13C NMR (150 MHz, CDCl3) δ 164.0, 150.4, 136.5, 130.6, 123.5, 72.2, 56.5, 56.3, 54.4, 42.6, 40.5, 40.0, 39.5, 36.1, 35.9, 35.8, 35.4, 33.2, 32.9, 31.9, 28.3, 28.2, 28.0, 26.2, 24.1, 23.8, 22.8, 22.5, 20.8, 18.6, 12.1, 11.4. [The authentic sample of (3R)-5α-cholestan-3-yl 4-nitrobenzoate (epi-23) was previously prepared.16b No signal on C3 (δ 5.02−4.94 (1H, m)) of (3R)-5α-cholestan-3-yl 4-nitrobenzoate was detected in 1H NMR of the crude product including 23.]

1-((4-Nitrophenyl)sulfonyl)azocane (27) (Table 2).16b,26 Compound 7i (373 mg, 1.84 mmol) was used as an azo reagent, toluene/ THF (3:1) (100 mL; 75 mL of toluene, 25 mL of THF), 23 h; 61% yield (91.0 mg, 0.305 mmol); white solid; eluent n-hexane/EtOAc = 8:1). Rf 0.34 n-hexane/EtOAc = 3:1); 1H NMR (500 MHz, CDCl3) δ 7.94−7.91 (1H, m), 7.69−7.65 (2H, m), 7.60−7.57 (1H, m), 3.33 (4H, t, J = 6.0 Hz), 1.80−1.75 (4H, m), 1.69−1.63 (6H, m). Representative Data in the Reactions with Modestly Acidic Nucleophile (Table 3, Figures 3 and 4). According to the general procedure, the reactions were conducted at room temperature or 80 °C. When azo reagent 7l was used, the resultant hydrazide product 8l 4723


Article


(109 mg, 0.6 mmol) were used as substrates, and 7a (107 mg, 0.6 mmol) and tri-n-butylphosphine (121 mg, 0.6 mmol) were used as reagents: 20 h at room temperature; 75% yield (112 mg, 0.374 mmol); pale yellow oil; Rf 0.38 (n-hexane/AcOEt = 3:1); eluent n-hexane/ AcOEt = 4:1; IR (ATR) 3085, 3063, 2928, 2246, 1726, 1602, 1329 cm−1. 1H NMR (500 MHz, CDCl3) δ 8.00−7.97 (2H, m), 7.79−7.75 (1H, m), 7.66−7.62 (2H, m), 7.32−7.27 (2H, m), 7.24−7.20 (1H, m), 7.17−7.14 (2H, m), 3.88 (1H, dd, J = 10.6, 4.5 Hz), 2.69 (2H, t, J = 7.4 Hz), 2.26−2.17 (1H, m), 2.02−1.92 (2H, m), 1.86−1.77 (1H, m); 13 C NMR (126 MHz, CDCl3) δ 140.3, 135.5, 135.3, 129.61, 129.58, 128.6, 128.3, 126.4, 113.9, 57.4, 34.9, 28.2, 26.2; HRMS (ESI+) calcd for C17H18NO2S+ ([M + H]+) 300.1053, found 300.1051.

could be easily isolated in around 80% yield by silica gel chromatography (eluent: n-hexane/AcOEt = 1:1) as required. Alternatively, 8l precipitated after the reaction could be isolated in 53% yield (69.1 mg, 0.32 on 0.6 mmol scale) by filtration.

N-Methyl-N-(3-phenylpropyl)toluenesulfonamide (30).39 3-Phenylpropanol (28) (68.1 mg, 0.5 mmol) and N-methyl-p-toluenesulfoamide (29) (111 mg, 0.6 mmol) were used as substrates. 7g (148 mg, 0.6 mmol) and triphenylphosphine (157 mg, 0.6 mmol): 3 h at room temperature, 73% yield (110 mg, 0.36 mmol) [Table 3, entry 3]; 7a (107 mg, 0.6 mmol) and tri-n-butylphosphine (121 mg, 0.6 mmol): 24 h at room temperature, 86% yield (131 mg, 0.43 mmol) [Table 3, entry 9]; 7a (125 mg, 0.6 mmol) and tri-n-butylphosphine (121 mg, 0.6 mmol) in CH2Cl2 (1 mL): 40 h at room temperature, 89% yield (135 mg, 0.44 mmol) [Table 3, entry 12]; 7k (106 mg, 0.6 mmol) and tri-n-butylphosphine (121 mg, 0.6 mmol): 4 h at room temperature, 82% yield (124 mg, 0.41 mmol) [Figure 3]; 7l (130 mg, 0.6 mmol) and tri-n-butylphosphine (121 mg, 0.6 mmol): 4 h at room temperature, 77% yield (117 mg, 0.385 mmol) [Figure 3]: colorless oil; eluent n-hexane/AcOEt = 5:1; 1H NMR (600 MHz, CDCl3) δ 7.65 (2H, app d, J = 8.2 Hz), 7.31−7.27 (4H, m), 7.20−7.17 (3H, m), 3.03 (2H, t, J = 7.2 Hz), 2.71 (3H, s), 2.66 (2H, t, J = 7.9 Hz), 2.42 (3H, s), 1.85 (2H, tt, J = 7.2, 7.9 Hz); 13C NMR (150 MHz, CDCl3) δ 143.2, 141.3, 134.5, 129.6, 128.40, 128.37, 127.4, 126.0, 49.7, 34.7, 32.7, 29.3, 21.5. The alkylated hydrazine was obtained in the reaction shown in Table 3, entry 3. The structure was tentatively assigned as below.

1-(3-Phenylpropyl)-1H-benzimidazole (38).40 3-Phenylpropanol (28) (68.1 mg, 0.5 mmol) and benzimidazole (34) (71 mg, 0.6 mmol) were used as substrates, and 7m (148 mg, 0.6 mmol) and tri-nbutylphosphine (121 mg, 0.6 mmol) were used as reagents: 17 h at 80 °C, 89% yield (105 mg, 0.444 mmol); colorless oil; Rf 0.16 (nhexanes/EtOAc = 1:2); eluent n-hexane/EtOAc = 1:2; 1H NMR (500 MHz, CDCl3) δ 7.90 (1H, s), 7.84−7.81 (1H, m), 7.37−7.28 (5H, m), 7.25−7.21 (1H, m), 7.18−7.15 (2H, m), 4.18 (2H, t, J = 7.1 Hz), 2.66 (2H, t, J = 7.5 Hz), 2.28−2.22 (2H, m).

Diethyl 2-(3-Phenylpropyl)malonate (39).41 3-Phenylpropan-1-ol (28) (68.1 mg, 0.5 mmol) and diethyl malonate (35) (96 mg, 0.6 mmol) were used as substrates, and 7m (148 mg, 0.6 mmol) and tri-nbutylphosphine (121 mg, 0.6 mmol) were used as reagents: 15 h at 80 °C; 59% yield (81.8 mg, 0.294 mmol); colorless oil; Rf 0.65 (nhexanes/EtOAc = 3:1); eluent n-hexanes/EtOAc = 20:1; 1H NMR (500 MHz, CDCl3) δ 7.29−7.26 (2H, m), 7.20−7.15 (3H, m), 4.22− 4.15 (4H, m), 3.34 (1H, t, J = 7.6 Hz), 2.64 (2H, t, J = 7.8 Hz), 1.98− 1.91 (2H, m), 1.70−1.62 (2H, m), 1.26 (6H, t, J = 7.1 Hz).

Ethyl 2-(3,4-dichlorophenyl)-1-(3-phenylpropyl)hydrazine-1-carboxylate: 3 h; 22% yield (39.7 mg, 0.11 mmol); rotamer was observed by NMR measurements (ca. 1:6); pale yellow oil; eluent nhexane/AcOEt = 15:1; 1H NMR (500 MHz, CDCl3) δ 7.30−7.18 (6H, m), 6.83 (1H, d, J = 2.3 Hz: minor rotamer), 6.79 (1H, d, J = 2.3 Hz: major rotamer), 6.58 (1H, dd, J = 8.9, 2.3 Hz: minor rotamer), 6.55 (1H, dd, J = 8.9, 2.3 Hz: major rotamer), 5.94 (1H, br-s), 4.14 (2H, q, J = 6.9 Hz), 3.57 (2H, br-m:derived from rotamer), 2.65 (2H, t, J = 7.4 Hz), 1.96 (2H, tt, J = 7.5, 7.5 Hz), 1.19 (3H, t, J = 7.2 Hz); 13 C NMR (150 MHz, CDCl3) δ 156.8, 147.2, 141.2, 133.0, 130.8, 128.4, 128.2, 126.0, 123.5, 114.4, 112.4, 62.5, 49.7, 33.0, 29.7, 29.1, 14.5. IR (neat, cm−1) 3300, 1696, 1598, 1474, 1412, 1382, 1298, 1187, 1129; HRMS (DART+) calcd for C18H21Cl2N2O2 ([M + H]) 367.0980, found 367.0981.

N-Benzyl-2,2,2-trifluoro-N-(3-phenylpropyl)acetamide (40). 3Phenylpropan-1-ol (28) (68.1 mg, 0.5 mmol) and N-benzyl-2,2,2trifluoroacetamide (36) (122 mg, 0.6 mmol) were used as substrates, and 7m (148 mg, 0.6 mmol) and tri-n-butylphosphine (121 mg, 0.6 mmol) were used as reagents: 15 h at 80 °C; 53% yield (84.4 mg, 0.263 mmol); colorless oil; Rf 0.29 (n-hexanes/EtOAc = 15:1); elute nhexanes/EtOAc = 20:1; IR (ATR) 3087, 3064, 3028, 2946, 1684, 1496, 1452, 1196 cm−1. Compound 40 exists in the form of two rotamers in CDCl3 at 300 K in the ratio rotamer A/rotamer B = 1.1:1 (determined from integrals of benzyl protons): 1H NMR (500 MHz, CDCl3) (rotamer A) δ 7.38−7.18 (6H, m), 7.15−7.10 (4H, m), 4.60 (2H, s), 3.35−3.30 (2H, m), 2.60−2.54 (2H, m), 1.98−1.91 (2H, m). 1 H NMR (500 MHz, CDCl3) (rotamer B) δ 7.38−7.18 (6H, m), 7.15−7.10 (4H, m), 4.57 (2H, s), 3.35−3.30 (2H, m), 2.60−2.54 (2H, m), 1.89−1.82 (2H, m); 13C NMR (126 MHz, CDCl3) (rotamer A) δ 157.3 (q, J = 35 Hz), 140.3, 135.4, 129.1, 128.4, 128.2, 128.1, 127.4, 126.1, 116.6 (q, J = 289 Hz), 49.2, 46.0, 32.9, 29.7; 13C NMR (126 MHz, CDCl3) (rotamer B) δ 157.9 (q, J = 36 Hz), 140.8, 134.8, 128.9, 128.6, 128.2, 128.0, 127.4, 126.3, 116.5 (q, J = 289 Hz), 50.7 (q, J = 3 Hz), 46.0, 32.7, 27.7; HRMS (ESI+) calcd for C18H19F3NO+ ([M + H]+) 322.1413, found 322.1412.

N,4-Dimethyl-N-(4-phenylbutan-2-yl)benzenesulfonamide (32). 4-Phenyl-2-butanol (31) (75.1 mg, 0.5 mmol) and N,4-dimethylbenzenesulfonamide (29) (111 mg, 0.6 mmol) were used as substrates, and 7l (130 mg, 0.6 mmol) and tri-n-butylphosphine (121 mg, 0.6 mmol) were used as reagents: 16 h at room temperature; 85% yield (135 mg, 0.425 mmol); pale yellow oil; Rf 0.45 (n-hexane/AcOEt = 3:1). Eluent: n-hexane/AcOEt = 8:1. IR. (ATR) 3026, 2973, 2934, 1598, 1494, 1454, 1384, 1334, 1146 cm−1. 1H NMR (500 MHz, CDCl3) δ 7.69−7.66 (2H, m), 7.30−7.25 (4H, m), 7.20−7.16 (4H, m), 7.15−7.13 (2H, m), 4.11−4.00 (1H, m), 2.70 (3H, s), 2.63−2.57 (2H, m), 2.42 (3H, s), 1.68−1.59 (2H, m), 0.89 (3H, d, J = 6.8 Hz). 13 C NMR (126 MHz, CDCl3) δ 142.9, 141.7, 137.0, 129.6, 128.33, 128.29, 127.0, 125.8, 53.0, 36.2, 32.8, 27.4, 21.5, 17.1. HRMS (ESI+) calcd for C18H24NO2S+ ([M + H]+) 318.1522, found 318.1524.

5-Phenyl-2-(phenylsulfonyl)pentanenitrile (37). 3-Phenylpropan1-ol (28) (68.1 mg, 0.5 mmol) and 2-(phenylsulfonyl)acetonitrile (33) 4724


Article

The Journal of Organic Chemistry Representative Data in the Reactions with Sterically Hindered Alcohols (Table 5 and Figure 5). According to the general procedure, the reactions were conducted at room temperature or 80 °C.

(1H, dd, J = 7.3, 1.8 Hz), 7.45 (1H, app td, J = 7.6, 1.4 Hz), 7.45 (1H, app td, J = 7.6, 1.7 Hz), 5.51−5.49 (1H, m), 2.20−2.16 (1H, m), 1.78−1.73 (2H, m), 1.67−1.59 (1H, m), 1.50−1.41 (1H, m), 1.32− 1.26 (1H, m), 1.17−1.10 (1H, m), 1.09−1.02 (1H, m), 0.94 (3H, d, J = 6.4 Hz), 0.89 (6H, d, J = 6.9 Hz); 13C NMR (100 MHz, CDCl3) δ 164.7, 148.2, 132.6, 131.5, 129.9, 128.0, 123.7, 74.0, 46.9, 38.7, 34.7, 29.1, 26.6, 25.1, 22.2, 21.0, 20.8.

(1S,2S,5R)-Menthyl 4-Nitrobenzoate (45).16b (−)-Menthol (41) (78.1 mg, 0.5 mmol) and 4-nitrobenzoic acid (10) (100 mg, 0.6 mmol) were used as substrates, and 7g (148 mg, 0.6 mmol) and triphenylphosphine (157 mg, 0.6 mmol) were used as reagents: 16 h at room temperature; 30% NMR yield 47:53 dr in NMR analysis (Table 5, entry 3). The NMR yield and the diastereomeric ratio were determined from integration values of peaks of C1 [4.98 (1H, td, J = 10.8, 4.5 Hz, for major isomer [retention]), 5.50 (1H, br-s, for minor isomer [inversion])].

(1S,2S)-2-Phenylcyclohexyl 2-Nitrobenzoate (52). (1R,2S)-2-Phenylcyclohexan-1-ol (49) (88.3 mg, 0.5 mmol) and 2-nitrobenzoic acid (44) (100 mg, 0.6 mmol) were used as substrates: 5 h at 80 °C; 94% yield (153 mg, 0.47 mmol); yellow oil; Rf 0.46 (n-hexane/EtOAc = 3:1); purified by silica gel column chromatography, eluent n-hexane/ EtOAc = 4:1; IR (ATR) 3086, 2935, 2863, 1725, 1530, 1348, 1254 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.92−7.89 (1H, m), 7.63−7.57 (2H, m), 7.34−7.18 (6H, m), 5.53−5.48 (1H, m), 2.94−2.87 (1H, m), 2.37−2.28 (1H, m), 2.09−1.89 (2H, m), 1.85−1.44 (5H, m); 13C NMR (126 MHz, CDCl3) δ 164.6, 147.6, 142.8, 132.7, 131.2, 129.6, 128.4, 128.1, 127.8, 126.5, 123.7, 75.9, 46.4, 30.3, 25.8, 25.7, 20.2; HRMS (ESI+) calcd for C19H20NO4+ ([M + H]+) 326.1387, found 326.1385.

(1S,2S,5R)-Menthyl 4-Methoxybenzoate (46).42 (−)-Menthol (41) (78.1 mg, 0.5 mmol) and 4-methoxybenzoic acid (42) (91.3 mg, 0.6 mmol) were used as substrates, and 7g (148 mg, 0.6 mmol) and triphenylphosphine (157 mg, 0.6 mmol) were used as reagents: 16 h; 19% NMR yield, single diastereomer in NMR analysis (Table 5, entry 6). The NMR yield was determined from integration values of peaks of C1 [5.42 (1H, d, J = 2.3 Hz]. No signal of a minor isomer (retention) [4.90 (1H, td, J = 10.7, 4.2 Hz)]43 was observed.

(1R,2S)-2-Phenylcyclohexyl 2-Nitrobenzoate. (As a reference compound for determination of stereochemistry in the case of compound 52). To a stirred solution of (1R,2S)-2-phenylcyclohexan1-ol (49) (88.1 mg, 0.5 mmol), 2-nitrobenzoic acid (125 mg, 0.75 mmol), 4-(dimethylamino)pyridine (15 mg, 0.125 mmol, 25 mol %) in dry dichloromethane (2 mL), N,N′-dicyclohexylcarbodiimide (155 mg, 0.75 mmol) was added at 0 °C. The reaction mixture was stirred for 30 min at 0 °C and for an additional 16 h at room temperature. The reaction mixture was filtered and evaporated to dryness. The crude product was purified by column chromatography (n-hexane/ EtOAc = 5:1) to afford (1R,2S)-2-phenylcyclohexyl 2-nitrobenzoate in 79% yield (129 mg, 0.396 mmol) as a white solid: Rf 0.57 (n-hexane/ EtOAc = 3:1); IR (ATR) 3029, 2952, 1720, 1691, 1536, 1359, 1133 cm−1. 1H NMR (500 MHz, CDCl3) δ 7.86−7.83 (1H, m), 7.52−7.45 (2H, m), 7.31−7.19 (5H, m), 6.97−6.94 (1H, m), 5.29−5.23 (1H, m), 2.77 (1H, m), 2.40−2.34 (1H, m), 2.02−1.89 (2H, m), 1.85−1.79 (1H, m), 1.67−1.51 (3H, m), 1.44−1.35 (1H, m); 13C NMR (126 MHz, CDCl3) δ 164.8, 147.3, 142.8, 132.8, 131.0, 129.2, 128.5, 128.3, 127.6, 126.6, 123.7, 78.3, 49.7, 33.8, 31.5, 25.7, 24.7; HRMS (ESI+) calcd for C19H20NO4+ ([M + H]+) 326.1387, found 326.1385.

(1S,2S,5R)-Menthyl 2-Methyl-6-nitrobenzoate (47).16b (−)-Menthol (78.1 mg, 0.5 mmol) and 2-methyl-6-nitrobenzoic acid (43) (109 mg, 0.6 mmol) were used as substrates, and 7a (134 mg, 0.75 mmol) and tri-n-butylphosphine (152 mg, 0.75 mmol) were used as reagents; 3 h at 80 °C; 91% yield (136 mg, 0.46 mmol), single diastereomer in NMR analysis; no signal of a minor isomer (retention) [C1:4.99 (1H, dt, J = 12.8, 4.2 Hz)]16b was observed (Table 5, entry 14): white solid; eluent n-hexane/AcOEt = 20:1; 1H NMR (600 MHz, CDCl3) δ 7.99 (1H, d, J = 8.2 Hz), 7.53 (1H, d, J = 7.9 Hz), 7.45 (1H, t, J = 7.9 Hz), 5.57 (1H, app d, J = 2.1 Hz), 2.43 (3H, s), 2.37−2.32 (1H, m), 1.75− 1.69 (2H, m), 1.62−1.57 (1H, m), 1.51−1.45 (1H, m), 1.22 (1H, qd, J = 13.3, 3.7 Hz), 1.14 (1H, ddd, J = 15.0, 13.2, 2.4 Hz), 1.08−1.03 (1H, m), 1.01 (3H, d, J = 6.5 Hz), 0.96−0.90 (1H, m), 0.91 (3H, d, J = 6.5 Hz), 0.88 (3H, d, J = 6.9 Hz); 13C NMR (150 MHz, CDCl3) δ 166.1, 146.0, 137.2, 136.0, 130.3, 129.3, 121.8, 73.7, 47.1, 38.4, 34.7, 28.7, 26.6, 24.9, 22.1, 21.00, 20.96, 19.1.

(1S,2S,5R)-Menthyl 2-Nitrobenzoate (48).42 (−)-Menthol (78.1 mg, 0.5 mmol) (41) and 2-nitrobenzoic acid (44) (100 mg, 0.6 mmol) were used as substrates: 3 h; 92% yield (141 mg, 0.46 mmol), single diastereomer in NMR analysis. No signal of a minor isomer (retention) [C1:4.96 (1H, dt, J = 10.8, 4.5 Hz)]42 was observed (Table 5, entry 18); pale yellow oil; eluent n-hexane/AcOEt = 15:1; 1 H NMR (400 MHz, CDCl3) δ 7.86 (1H, dd, J = 7.6, 1.6 Hz), 7.74

(3aR,5R,6S,6aR)-5-(2,2-Dimethyl-1,3-dioxolan-4-yl)-2,2dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl 2-Nitrobenzoate (54). ( 3 a R ,5 S, 6S , 6a R ) - 5 - ( 2 , 2 - D i m e t h y l - 1 , 3 - d i o x o l a n -4 -y l ) -2 , 2 dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (51) and 2-nitrobenzoic acid (44) (100 mg, 0.6 mmol) were used substrates (130 mg, 0.5 mmol): 24 h at room temperature; 60% yield (123 mg, 0.30 mmol); 4725


Article

The Journal of Organic Chemistry viscous colorless oil; Rf 0.30 (n-hexane/EtOAc = 3:1); eluent nhexane/EtOAc = 4:1 (crude product contained only starting alcohol 51 and only one ester product 54); IR (ATR) 2988, 2938, 1738, 1533, 1483, 1454, 1372, 1350 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.97 (1H, dd, J = 7.9, 1.0 Hz), 7.76−7.65 (3H, m), 5.92 (1H, d, J = 3.7 Hz), 5.49 (1H, d, J = 3.0 Hz), 4.78 (1H, d, J = 3.7 Hz), 4.26 (1H, dd, J = 8.2, 2.9 Hz), 4.17−4.12 (1H, m), 4.06−3.98 (2H, m), 1.55 (3H, s), 1.43 (3H, s), 1.36 (3H, s), 1.31 (3H, s); 13C NMR (126 MHz, CDCl3) δ 164.2, 147.7, 133.3, 132.0, 129.8, 127.4, 124.1, 112.4, 109.4, 105.2, 82.4, 79.6, 77.9, 72.4, 67.4, 26.9, 26.7, 26.2, 25.3; HRMS (ESI+) calcd for C19H24NO9+ ([M + H]+) 410.1446, found 410.1439. Independent Preparation of Compound 54 as a Reference Compound for Determination of Stereochemistry. To a stirred solution of 51 (130 mg, 0.5 mmol), 2-nitrobenzoic acid (44) (125 mg, 0.75 mmol), and 4-(dimethylamino)pyridine (15 mg, 0.125 mmol, 25 mol %) in dry dichloromethane (5 mL) was added N,N′dicyclohexylcarbodiimide (155 mg, 0.75 mmol) at 0 °C. The reaction mixture was stirred for 30 min at 0 °C and for an additional 40 h at room temperature. The reaction mixture was filtered and evaporated to dryness. The crude product was purified by column chromatography (n-hexane/EtOAc = 3:1) to afford (3aR,5R,6S,6aR)-5-(2,2dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl 2-nitrobenzoate (54) in 74% yield (151 mg, 0.37 mmol) as a pale yellow oil. In the case of DCC coupling of alcohol 51 with 2-nitrobenzoic acid (44), the same product (54) was formed as under Mitsunobu conditions. The proton resonances of compound 54 were assigned by 1 H NMR, 1H−1H gs-COSY, 1H−13C gs-HSQC, and 1H−31P gs-HMBC NMR techniques The stereochemistry of 54 was determined from 1 H−1H NOESY NMR.

N-(p-Toluenesulfonyl)pyrrolidine (56).16b N-(4-Hydroxybutyl)-ptoluenesulfonamide (55)44 (122 mg, 0.5 mmol) was used as substrate: 3 h + 12 h; eluent n-hexane/AcOEt = 6:1−3:1; 99% yield (112 mg, 0.49 mmol); white solid; 1H NMR (500 MHz, CDCl3) δ 7.72 (2H, app d, J = 8.0 Hz), 7.32 (2H, app d, J = 8.0 Hz), 3.25−3.22 (4H, m), 2.44 (3H, s), 1.76−1.74 (4H, m); 13C NMR (125 MHz, CDCl3) δ 143.3, 133.9, 129.6, 127.5, 47.9, 25.2, 21.5. 7g was recovered in 95% yield (140 mg, 0.56 mmol). Scale-up reaction (Scheme 2): To a stirred solution of N-(4hydroxybutyl)-p-toluenesulfonamide (1.22 g, 5.0 mmol) and triphenylphosphine (1.57 g, 0.6 mmol) in toluene (10 mL) was added 7g (1.48 g, 6.0 mmol) at room temperature under a nitrogen atmosphere (balloon). The reaction mixture was stirred for 6 h at room temperature. After completion of the reaction, iron phthalocyanine (142 mg, 0.25 mmol) was added to the reaction mixture, and the resultant mixture was further stirred for 12 h at room temperature under bubbling of air. The reaction mixture was filtered through filter paper, and the solvent was removed under reduced pressure. The crude material was purified by silica gel chromatography (eluent: nhexane/EtOAc = 6:1−3:1) to give 56 (1.03 g, 4.57 mmol, 92% yield) and 7g (1.40 g, 5.67 mmol, 95% recovery).

2-(Thiophene-2-yl) Ethyl 4-Nitrobenzoate (57). 3-Thiopheneylethanol (64.1 mg, 0.5 mmol) and 4-nitrobenzoic acid (10) (100 mg, 0.6 mmol) were used as substrates: 3 h + 12 h; eluent: n-hexane/ AcOEt = 20:1; 98% yield (136 mg, 0.49 mmol); pale yellow solid; mp 82.0−83.0 °C; 1H NMR (500 MHz, CDCl3) δ 8.29 (2H, app d, J = 8.6 Hz), 8.22 (2H, app d, J = 9.2 Hz), 7.19 (1H, app d, J = 5.2 Hz), 6.97 (1H, dd, J = 5.2, 3.4 Hz), 6.92 (1H, d, J = 3.4 Hz), 4.59 (2H, t, J = 6.6 Hz), 3.33 (2H, t, J = 6.3 Hz); 13C NMR (125 MHz, CDCl3) δ 164.4, 150.5, 139.4, 135.4, 130.7, 126.9, 125.7, 124.2, 123.5, 66.0, 29.2; IR (KBr, cm−1) 3103, 1718, 1529, 1351, 1268; HRMS (FAB+) calcd for C13H12NO4S ([M + H]) 278.0487, found 278.0485. Compound 7g was recovered in 98% yield (145 mg, 0.59 mmol).

Reaction of (−)-Borneol. (−)-Borneol (77.3 mg, 0.5 mmol) and 2nitrobenzoic acid (44) (100 mg, 0.6 mmol) were used as substrates: 4 h at room temperature; 94% conversion into 53 as determined by 1H NMR (1,3,5-trimethoxybenzene was used as internal standard). The structure of alkoxyphosphonium 53 was determined by 1H NMR, 31P NMR, 1H−1H gs-COSY, and 1H−31P gs-HMBC NMR techniques (spectra are enclosed in the NMR spectra section) along with HRMS analysis. HRMS analysis of crude product revealed mass peaks for tributylphosphine oxide, alkoxyphosphonium 53 and betaine adduct (see Figure S1): 1H NMR (500 MHz, CDCl3, 53+) δ 4.77−4.72 (1H, m), 2.71−2.63 (6H, m, CH2CH2-P-), 2.53 (1H, m), 1.86−1.76 (3H, m), 1.68−1.37 (14H, m), 1.10 (1H, dd, J = 13.5 Hz, 3.0 Hz), 0.95 (9H, t, J = 7.2 Hz), 0.93 (3H, s), 0.89 (3H, s), 0.88 (3H, s); 31P NMR (202 MHz, CDCl3) δ + 98.7 (s); HRMS (ESI+) calcd for C22H44OP+ ([M+]) 355.3124, found 355.3135. General Procedure of One-Pot Mitsunobu−Aerobic Oxidation Reactions (Scheme 1 and Figure 6). To a stirred solution of alcohol (0.5 mmol) and nucleophile (0.6 mmol) in toluene (1.0 mL) were added 7g (148 mg, 0.6 mmol) and triphenylphosphine (157 mg, 0.6 mmol) at room temperature under a nitrogen atmosphere (balloon). The reaction mixture was stirred for given time at room temperature (see below for details). After completion of the reaction, iron phthalocyanine (14.2 mg, 25 μmol) was added to the reaction mixture, and the resultant mixture was further stirred at room temperature under an air atmosphere (open flask) until disappearance of the hydrazine product. The reaction mixture was filtered through filter paper, and the solvent was removed under reduced pressure. The crude material was purified by silica gel chromatography (eluent: nhexane/EtOAc). Usually, 7g was recovered from the first elution, and the following elution gave the corresponding Mitsunobu product.

N-Benzyl-N-cinnamyl-2-nitrobenzenesulfonamide (58). Cinnamyl alcohol (67.1 mg, 0.5 mmol) and N-benzyl-2-nitrobenzenesulfonamide (175 mg, 0.6 mmol) were used as substrates: 6 h + 12 h; eluent nhexane/AcOEt = 20:1. 91% yield (185 mg, 0.45 mmol); pale yellow oil. N-Benzyl-2-nitro-N-(1-phenylallyl)benzenesulfonamide (SN2′ product) was not detected in the 1H NMR spectrum of the crude product: 1H NMR (400 MHz, CDCl3) δ 8.05 (1H, d, J = 7.8 Hz), 7.68 (2H, d, J = 3.7 Hz), 7.62 (1H, td, J = 8.1, 4.1 Hz), 7.33−7.20 (10H, m), 6.32 (1H, d, J = 16.0 Hz), 5.93 (1H, dt, J = 16.0, 6.9 Hz), 4.56 (2H, s), 4.02 (2H, d, J = 6.4 Hz); 13C NMR (100 MHz, CDCl3) δ 136.0, 135.4, 134.8, 134.2, 133.4, 131.7, 131.1, 128.7, 128.6, 128.4, 128.0, 127.9, 126.4, 124.2, 123.0, 77.2, 50.6, 49.0. IR (neat, cm−1) 3027, 1737, 1542, 1496, 1440, 1371, 1163; HRMS (FAB+) calcd for C22H21N2O4S ([M + H]) 409.1222, found 409.1218. 7g was recovered in 93% yield (138 mg, 0.56 mmol).

2-((2-(1H-Indol-3-yl)ethyl)thio)benzo[d]thiazole (59).16b 3-Indoleethanol (80.6 mg, 0.5 mmol) and 2-mercaptobenzothiazole (100 mg, 0.6 mmol) were used as substrates: 3 h + 12 h; eluent n-hexane/ AcOEt = 15:1. 89% yield (139 mg, 0.45 mmol); white solid; 1H NMR (400 MHz, CDCl3) δ 8.07 (1H, br s), 7.90 (1H, dd, J = 8.2, 1.4 Hz), 7.75 (2H, d, J = 7.3 Hz), 7.42 (1H, app td, J = 7.8, 1.4 Hz), 7.36 (1H, dd, J = 7.8, 1.4 Hz), 7.31−7.27 (1H, m), 7.21 (1H, app td, J = 7.6, 1.4 Hz), 7.16 (1H, app td, J = 7.4, 1.2 Hz), 7.07 (1H, d, J = 2.3 Hz), 3.66 4726


Article

The Journal of Organic Chemistry (2H, t, J = 7.6 Hz), 3.30 (2H, t, J = 7.6 Hz); 13C NMR (100 MHz, CDCl3) δ 167.1, 153.3, 136.2, 135.2, 127.1, 126.0, 124.1, 122.2, 122.1, 121.4, 120.9, 119.5, 118.9, 114.1, 111.2, 34.2, 25.5. 7g was recovered in 89% yield (131 mg, 0.53 mmol).

washed with brine and dried over Na2SO4. After the solvent was evaporated, the crude product was purified by silica gel chromatography (eluent: n-hexane/EtOAc, 12:1) to afford 57 (120 mg, 0.43 mmol, 87%, the second elution) and 62 (13.0 mg, 0.036 mmol, 7%, the third eluction). 7g (121 mg, 0.49 mmol, 82%) was recovered from the first elution. In the absence of pyridine, 57 (90.6 mg, 0.33 mmol, 65%), 62 (54.4 mg, 0.15 mmol, 31%), and 7g (72.4 mg, 0.29 mmol, 49%) were obtained.

1,2,3-Trimethoxy-5-((4-methoxyphenoxy)methyl)benzene (60). (3,4,5-Trimethoxyphenyl)methanol (99.1 mg, 0.5 mmol) and 4methoxyphenol (74.5 mg, 0.6 mmol) were used as substrates: 2 h + 8 h; eluent: n-hexane/AcOEt = 8:1. 85% yield (129 mg, 0.42 mmol); pale yellow oil; 1H NMR (400 MHz, CDCl3) δ 6.92 (2H, app d, J = 9.2 Hz), 6.84 (2H, app d, J = 9.2 Hz), 6.66 (2H, s), 4.93 (2H, s), 3.86 (6H, s), 3.85 (3H, s), 3.77 (3H, s); 13C NMR (100 MHz, CDCl3) δ 153.9, 153.3, 152.8, 137.4, 132.8, 115.7, 114.5, 104.4, 70.9, 60.7, 56.0, 55.6; IR (neat, cm−1) 1736, 1592, 1508, 1463, 1421, 1379, 1334, 1229, 1127; HRMS (DART+) calcd for C17H21O5 ([M + H]) 305.1389, found 305.1389. 7g was recovered in 91% yield (135 mg, 0.54 mmol). General Procedure of One-Pot Mitsunobu−Aerobic Oxidation Reactions Using PS−PPh3 (Scheme 1 and Figure 5). To a stirred solution of alcohol (0.5 mmol) and nucleophile (0.6 mmol) in toluene (2.5 mL) were added 7g (148 mg, 0.6 mmol) and polymer-bound triphenylphosphine (PS−PPh3, 1% cross-linked with DVB, 200−400 mesh, 1.2−1.5 mmol/g, 500 mg) at room temperature under a nitrogen atmosphere (balloon). The reaction mixture was stirred for 6 h at room temperature (see below for details). After completion of the reaction, iron phthalocyanine (14.2 mg, 25 μmol) was added to the reaction mixture, and the resultant mixture was further stirred for 24 h at room temperature under an air atmosphere (open flask). The reaction mixture was filtered through filter paper (iron catalyst and waste generated from PS−PPh3 were removed by this operation), and the solvent was removed under reduced pressure. The crude material was purified by silica gel chromatography (eluent: n-hexane/EtOAc). 7g was recovered from the first elution, and the following elution gave the corresponding Mitsunobu product. N-(p-Toluenesulfonyl)pyrrolidine (56). N-(4-Hydroxybutyl)-p-toluenesulfonamide (55)44 (122 mg, 0.5 mmol) was used as a substrate: eluent n-hexane/AcOEt = 6:1−3:1; 90% yield (101 mg, 0.45 mmol). 7g was recovered in 89% yield (132 mg, 0.535 mmol). (3-Phenylpropoxy)benzene (13). 3-Phenylpropanol (28) (68.1 mg, 0.5 mmol) and phenol (56.5 mg, 0.6 mmol) were used as substrates: eluent n-hexane/AcOEt = 30:1. 88% yield (92.6 mg, 0.44 mmol); colorless oil. 7g was recovered in 85% yield (126 mg, 0.51 mmol). Recovery of 7g from Reaction Waste by Iron-Catalyzed Aerobic Oxidation (Scheme 4). Fractions after elution of products 12−16 and 18−22 (10 fractions containing the hydrazine product from 7g, ca. 0.6 × 10 mmol) were combined and concentrated. To a solution of this material in toluene (30 mL), iron phthalocyanine (171 mg, 0.3 mmol) was added, and the mixture was stirred for 10 h at room temperature under bubbling of air. Afterword, the reaction mixture was filtered through a short pad of silica gel, and the pad was washed with toluene a few times. The combined filtrate was evaporated to give 7g (1.40 g, 5.65 mmol, 95% recovery). One-Pot Mitsunobu-Oxidation Reactions Using N-Bromosuccinimide (Scheme 5). To a stirred solution of 3-thiophene-ylethanol (64.1 mg, 0.5 mmol) and 4-nitrobenzoic acid (10) (100 mg, 0.6 mmol) in toluene (1.0 mL) were added 7g (148 mg, 0.6 mmol) and triphenylphosphine (157 mg, 0.6 mmol) at room temperature under a nitrogen atmosphere (balloon), and the reaction mixture was stirred for 3 h at room temperature under a nitrogen atmosphere (balloon). After completion of the reaction, pyridine (51.4 mg, 0.65 mmol) and N-bromosuccinimide (116 mg, 0.65 mmol) were added to the reaction mixture, and the stirring was continued for 1 h at room temperature under a nitrogen atmosphere (balloon). The reaction mixture was filtered through filter paper, and the solvent was removed under reduced pressure. The filtrate was poured into water and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were

2-(5-Bromothiophene-2-yl)ethyl 4-nitrobenzoate (62): pale yellow solid; mp 76.5−77.0 °C; 1H NMR (500 MHz, CDCl3) δ 8.31 (2H, app d, J = 8.6 Hz), 8.22 (2H, app d, J = 9.2 Hz), 6.90 (1H, d, J = 4.0 Hz), 6.68 (1H, d, J = 4.0 Hz), 4.56 (2H, t, J = 6.3 Hz), 3.25 (2H, t, J = 6.3 Hz); 13C NMR (125 MHz, CDCl3) δ 164.4, 150.6, 141.3, 135.2, 130.7, 129.7, 126.2, 123.6, 110.3, 65.5, 29.7; IR (KBr, cm−1) 1714, 1525, 1346, 1275; HRMS (FAB+) calcd for C13H11BrNO4S ([M + H]) 355.9592, found 355.9602. Kinetic Studies of Reactions of Azo Reagents with Triphenylphosphine (Table 4). A solution of an azo reagent (50 mM), triphenylphosphine (500 mM), and water (500 mM) in THF (1.0 mL) was prepared in a 10 mL round-bottom flask at 25 °C under a nitrogen atmosphere, a small amount (ca. 0.5 mL) of a sample was taken from the reaction mixture, and absorption spectra of the sample were continuously measured in a 0.1 mm quartz cell (first measurement was defined as 0 min). Concentrations of the starting azo compound were estimated from the absorption intensity based on calibration curves.

■

ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00486.

■

Additional experimental details and copies of spectra (PDF)

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Janez Košmrlj: 0000-0002-3533-0419 Tsuyoshi Taniguchi: 0000-0002-4945-480X Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS

We are thankful to Japan Carlit Co., Ltd., for measuring SCDSC. D.H. and T.T. are thankful to Profs. Shigeyoshi Kanoh, Katsuhiro Maeda, and Tomoyuki Ikai (Kanazawa University) for their kind support. This work was supported by JSPS KAKENHI Grant-in-Aid for Scientific Research (C) (Grant No. 25460011 and 16K08159) and a Grant-in-Aid for JSPS Fellows (Grant No. 14J02441). J.K. and M.G. acknowledge the financial support from the Slovenian Research Agency (Research Core Funding Grant P1-0230 and Project J18147), and thank to Dr. Damijana Urankar (Research Infrastructure Centre at the Faculty of Chemistry and Chemical Technology, University of Ljubljana) for HRMS analyses. 4727


Article


■

Ozaki, F.; Hioki, H.; Itô, S. Carbon−Carbon Bond Formation with New Mitsunobu Reagents. Tetrahedron Lett. 1995, 36, 2531−2534. (11) (a) Tsunoda, T.; Ozaki, F.; Itô, S. Novel Reactivity of Stabilized Methylenetributylphosphorane: A New Mitsunobu Reagent. Tetrahedron Lett. 1994, 35, 5081−5082. (b) Tsunoda, T.; Nagino, C.; Oguri, M.; Itô , S. Mitsunobu-type Alkylation with Active Methine Compounds. Tetrahedron Lett. 1996, 37, 2459−2462. (12) For other examples of modified azo reagents, see: (a) Harned, A. M.; He, H. S.; Toy, P. H.; Flynn, D. L.; Hanson, P. R. Multipolymer Solution-Phase Reactions: Application to the Mitsunobu Reaction. J. Am. Chem. Soc. 2005, 127, 52−53. (b) Iranpoor, N.; Firouzabadi, H.; Khalili, D. 5,5′-Dimethyl-3,3′-azoisoxazole as a new heterogeneous azo reagent for esterification of phenols and selective esterification of benzylic alcohols under Mitsunobu conditions. Org. Biomol. Chem. 2010, 8, 4436−4443. (c) Figlus, M.; Wellaway, N.; Cooper, A. W. J.; Sollis, S. L.; Hartley, R. C. Synthesis of Arrays Using Low Molecular Weight MPEG-Assisted Mitsunobu Reaction. ACS Comb. Sci. 2011, 13, 280−285. (d) Maity, P. K.; Rolfe, A.; Samarakoon, T. B.; Faisal, S.; Kurtz, R. D.; Long, T. R.; Schätz, A.; Flynn, D. L.; Grass, R. N.; Stark, W. J.; Reiser, O.; Hanson, P. R. Monomer-on-Monomer (MoM) Mitsunobu Reaction: Facile Purification Utilizing Surface-Initiated Sequestration. Org. Lett. 2011, 13, 8−10. (e) Furkert, D. P.; Breitenbach, B.; Juen, L.; Sroka, I.; Pantin, M.; Brimble, M. A. Nonsymmetrical Azocarbonamide Carboxylates as Effective Mitsunobu Reagents. Eur. J. Org. Chem. 2014, 7806−7809. (13) For examples of Mitsunobu reactions without azo reagents, see: (a) Vanos, C. M.; Lambert, T. H. Development of a Catalytic Platform for Nucleophilic Substitution: Cyclopropenone-Catalyzed Chlorodehydration of Alcohols. Angew. Chem., Int. Ed. 2011, 50, 12222−12226. (b) Nacsa, E. D.; Lambert, T. H. Cyclopropenone Catalyzed Substitution of Alcohols with Mesylate Ion. Org. Lett. 2013, 15, 38− 41. (c) Tang, X.; Chapman, C.; Whiting, M.; Denton, R. Development of a redox-free Mitsunobu reaction exploiting phosphine oxides as precursors to dioxyphosphoranes. Chem. Commun. 2014, 50, 7340− 7343. (14) Mukaiyama and co-workers reported highly reactive oxidation− reduction condensation; see: (a) Mukaiyama, T.; Shintou, T.; Fukumoto, K. A Convenient Method for the Preparation of Inverted tert-Alkyl Carboxylates from Chiral tert-Alcohols by a New Type of Oxidation−Reduction Condensation Using 2,6-Dimethyl-1,4-benzoquinone. J. Am. Chem. Soc. 2003, 125, 10538−10539. (b) Shintou, T.; Mukaiyama, T. Efficient Methods for the Preparation of Alkyl−Aryl and Symmetrical or Unsymmetrical Dialkyl Ethers between Alcohols and Phenols or Two Alcohols by Oxidation−Reduction Condensation. J. Am. Chem. Soc. 2004, 126, 7359−7367. (c) Mukaiyama, T.; Yamabe, H. Alkyl Phosphinites: Versatile Synthetic Intermediates for Dehydration Condensation Reactions. Chem. Lett. 2007, 36, 2−7. (d) Mukaiyama, T.; Kuroda, K.; Maruyama, Y. A New Type of Oxidation-Reduction Condensation by the Combined Use of Phenyl Diphenylphosphinite and Oxidant. Heterocycles 2010, 80, 63−82. (15) (a) Huang, H.; Kang, J. Y. Oxidation−Reduction Condensation of Diazaphosphites for Carbon−Heteroatom Bond Formation Based on Mitsunobu Mechanism. Org. Lett. 2017, 19, 544−547. (b) Huang, H.; Kang, J. Y. Mitsunobu Reaction Using Basic Amines as Pronucleophiles. J. Org. Chem. 2017, 82, 6604−6614. (16) (a) Hirose, D.; Taniguchi, T.; Ishibashi, H. Recyclable Mitsunobu Reagents: Catalytic Mitsunobu Reactions with an Iron Catalyst and Atmospheric Oxygen. Angew. Chem., Int. Ed. 2013, 52, 4613−4617. (b) Hirose, D.; Gazvoda, M.; Košmrlj, J.; Taniguchi, T. Advances and mechanistic insight on the catalytic Mitsunobu reaction using recyclable azo reagents. Chem. Sci. 2016, 7, 5148−5159. (17) A dual catalytic system for Mitsunobu reactions has been reported; see: (a) Buonomo, J. A.; Aldrich, C. C. Mitsunobu Reactions Catalytic in Phosphine and a Fully Catalytic System. Angew. Chem., Int. Ed. 2015, 54, 13041−13044. Our study, however, suggested that this system did not work; see: (b) Hirose, D.; Gazvoda, M.; Košmrlj, J.; Taniguchi, T. The “Fully Catalytic System” in Mitsunobu Reaction Has Not Been Realized Yet. Org. Lett. 2016, 18, 4036−4039.

DEDICATION Dedicated to Professor Emeritus Slovenko Polanc on the occasion of his 70th birthday, recognizing his lifetime achievements in educational and scientific work.

■

REFERENCES

(1) (a) Mitsunobu, O.; Yamada, M.; Mukaiyama, T. Preparation of Esters of Phosphoric Acid by the Reaction of Trivalent Phosphorus Compounds with Diethyl Azodicarboxylate in the Presence of Alcohols. Bull. Chem. Soc. Jpn. 1967, 40, 935−939. (b) Mitsunobu, O.; Yamada, M. Preparation of Esters of Carboxylic and Phosphoric Acid via Quaternary Phosphonium Salts. Bull. Chem. Soc. Jpn. 1967, 40, 2380−2382. (2) (a) Mitsunobu, O. The Use of Diethyl Azodicarboxylate and Triphenylphosphine in Synthesis and Transformation of Natural Products. Synthesis 1981, 1−28. (b) Hughes, D. The Mitsunobu Reaction. L. Org. React. 1992, 42, 335−656. (c) But, T. Y. S.; Toy, P. H. The Mitsunobu Reaction: Origin, Mechanism, Improvements, and Applications. Chem. - Asian J. 2007, 2, 1340−1355. (d) Kumara Swamy, K. C.; Bhuvan Kumar, N. N.; Balaraman, E.; Pavan Kumar, K. V. P. Mitsunobu and Related Reactions: Advances and Applications. Chem. Rev. 2009, 109, 2551−2651. (e) Fletcher, S. The Mitsunobu reaction in the 21st century. Org. Chem. Front. 2015, 2, 739−752. (3) Examples: (a) Girardin, M.; Dolman, S. J.; Lauzon, S.; Ouellet, S. G.; Hughes, G.; Fernandez, P.; Zhou, G.; O’Shea, P. D. Development of a Practical Synthesis of Stearoyl-CoA Desaturase (SCD1) Inhibitor MK-8245. Org. Process Res. Dev. 2011, 15, 1073−1080. (b) Schmidt, G.; Reber, S.; Bolli, M. H.; Abele, S. Practical and Scalable Synthesis of S1P1 Receptor Agonist ACT-209905. Org. Process Res. Dev. 2012, 16, 595−604. (4) Berger, A.; Wehrstedt, K. D. Azodicarboxylates: Explosive properties and DSC measurements. J. Loss Prev. Process Ind. 2010, 23, 734−739. (5) For reviews on the modification of Mitsunobu reactions, see: (a) Dembinski, R. Recent Advances in the Mitsunobu Reaction: Modified Reagents and the Quest for Chromatography−Free Separation. Eur. J. Org. Chem. 2004, 2763−2772. (b) Dandapani, S.; Curran, D. P. Separation−Friendly Mitsunobu Reactions: A Microcosm of Recent Developments in Separation Strategies. Chem. - Eur. J. 2004, 10, 3130−3138. See also ref 2c−e. (6) (a) Dandapani, S.; Curran, D. P. Fluorous Mitsunobu reagents and reactions. Tetrahedron 2002, 58, 3855−3864. (b) Dandapani, S.; Curran, D. P. Second Generation Fluorous DEAD Reagents Have Expanded Scope in the Mitsunobu Reaction and Retain Convenient Separation Features. J. Org. Chem. 2004, 69, 8751−8757. (c) Chu, Q.; Henry, C.; Curran, D. P. Second-Generation Tags for Fluorous Chemistry Exemplified with a New Fluorous Mitsunobu Reagent. Org. Lett. 2008, 10, 2453−2456. (7) Lipshutz, B. H.; Chung, D. W.; Rich, B.; Corral, R. Simplification of the Mitsunobu Reaction. Di-p-chlorobenzyl Azodicarboxylate: A New Azodicarboxylate. Org. Lett. 2006, 8, 5069−5072. (8) (a) Sugimura, T.; Hagiya, K. Di-2-methoxyethyl Azodicarboxylate (DMEAD): An Inexpensive and Separation-friendly Alternative Reagent for the Mitsunobu Reaction. Chem. Lett. 2007, 36, 566− 577. (b) Hagiya, K.; Muramoto, N.; Misaki, T.; Sugimura, T. DMEAD: a new dialkyl azodicarboxylate for the Mitsunobu reaction. Tetrahedron 2009, 65, 6109−6114. (9) Szigeti, M.; Dobi, Z.; Soós, T. The Goldilocks Principle in Phase Labeling. Minimalist and Orthogonal Phase Tagging for Chromatography-Free Mitsunobu Reaction. J. Org. Chem. 2018, 83, 2869−2874. (10) (a) Tsunoda, T.; Yamamiya, Y.; Itô, S. 1,1′-(Azodicarbonyl)dipiperidine-tributylphosphine, a New Reagent System for Mitsunobu Reaction. Tetrahedron Lett. 1993, 34, 1639−1642. (b) Tsunoda, T.; Otsuka, J.; Yamamiya, Y.; Itô, S. N,N,N′,N′-Tetramethylazodicarboxamide (TMAD), A New Versatile Reagent for Mitsunobu Reaction. Its Application to Synthesis of Secondary Amines. Chem. Lett. 1994, 23, 539−542. (c) Tsunoda, T.; Nagaku, M.; Nagino, C.; Kawamura, Y.; 4728


Article

The Journal of Organic Chemistry (18) For the first example of Mitsunobu reaction catalytic in the azo reagent, see: (a) But, T. Y. B.; Toy, P. H. Organocatalytic Mitsunobu Reactions. J. Am. Chem. Soc. 2006, 128, 9636−9637. (b) But, T. Y. S.; Lu, J.; Toy, P. H. Organocatalytic Mitsunobu Reactions with 3,5Dinitrobenzoic Acid. Synlett 2010, 2010, 1115−1117. (19) Photocatalytic esterification under Mitsunobu conditions has recently been reported, but Walden inversion was not observed in this method; see: März, M.; Chudoba, J.; Kohout, M.; Cibulka, R. Photocatalytic esterification under Mitsunobu reaction conditions mediated by flavin and visible light. Org. Biomol. Chem. 2017, 15, 1970−1975. (20) An example of Mitsunobu reactions catalytic in the phosphine reagent: O’Brien, C. J. PCT Int. Appl. WO2010/118042A2, 2010. See also ref 17a. (21) Košmrlj, J.; Kočevar, M.; Polanc, S. Controlled oxidation of thiols to disulfides by diazenecarboxamides. J. Chem. Soc., Perkin Trans. 1 1998, 3917−3919. (22) For Mitsunobu reactions using 2-nitrobenzenesulfonyl (Ns)strategies, see: (a) Fukuyama, T.; Jow, C.-K.; Cheung, M. 2- and 4Nitrobenzenesulfonamides: Exceptionally Versatile Means for Preparation of Secondary Amines and Protection of Amines. Tetrahedron Lett. 1995, 36, 6373−6374. (b) Kan, T.; Fukuyama, T. Ns strategies: a highly versatile synthetic method for amines. Chem. Commun. 2004, 353−359. (23) Wada, M.; Mitsunobu, O. Intermolecular dehydration between alcohols and active hydrogen compounds by means of diethyl azodicarboxylate and triphenylphosphine. Tetrahedron Lett. 1972, 13, 1279−1282. (24) Mitsunobu, O.; Wada, M.; Sano, T. Stereospecific and stereoselective reactions. I. Preparation of amines from alcohols. J. Am. Chem. Soc. 1972, 94, 679−680. (25) Mahapatra, T.; Das, T.; Nanda, S. Asymmetric Synthesis of Stagonolide-D and Stagonolide-G. Bull. Chem. Soc. Jpn. 2011, 84, 511− 519. (26) Kan, T.; Fujiwara, A.; Kobayashi, H.; Fukuyama, T. Efficient macrocyclization by means of 2-nitrobenzenesulfonamide and total synthesis of lipogrammistin-A. Tetrahedron 2002, 58, 6267−6276. (27) Henry, R.; Marcin, L. R.; McIntosh, M. C.; Scola, P. M.; Harris, G. D., Jr.; Weinreb, S. M. Mitsunobu reactions of n-alkyl and n-acyl sulfonamides-an efficient route to protected amines. Tetrahedron Lett. 1989, 30, 5709−5712. (28) (a) Martin, S. F.; Dodge, J. A. Efficacious modification of the mitsunobu reaction for inversions of sterically hindered secondary alcohols. Tetrahedron Lett. 1991, 32, 3017−3020. (b) Dodge, J. A.; Trujillo, J. I.; Presnell, M. Effect of the Acidic Component on the Mitsunobu Inversion of a Sterically Hindered Alcohol. J. Org. Chem. 1994, 59, 234−236. (c) Tsunoda, T.; Yamamiya, Y.; Kawamura, Y.; Itô, S. Mitsunobu Acylation of Sterically Congested Secondary Alcohols by N,N,N′,N′-Tetramethylazodicarboxamide-Tributyiphosphine Reagents. Tetrahedron Lett. 1995, 36, 2529−2530. (29) Saïah, M.; Bessodes, M.; Antonakis, K. The Use of Chloroacetic Acid in the Mitsunobu Reaction. Tetrahedron Lett. 1992, 33, 4317− 4320. (30) (a) Camp, D.; Harvey, P. J.; Jenkins, I. D. The effect of solvent polarity on the rate of the Mitsunobu esterification reaction. Tetrahedron 2015, 71, 3932−3938. (b) Schenk, S.; Weston, J.; Anders, E. Density Functional Investigation of the Mitsunobu Reaction. J. Am. Chem. Soc. 2005, 127, 12566−12576. (c) Ahn, C.; DeShong, P. An Approach to the Stereoselective Synthesis of syn- and anti-1,3-Diol Derivatives. Retention of Configuration in the Mitsunobu Reaction. J. Org. Chem. 2002, 67, 1754−1759. (d) Ahn, C.; Correia, R.; DeShong, P. Mechanistic Study of the Mitsunobu Reaction. J. Org. Chem. 2002, 67, 1751−1753. Correction: Ahn, C.; Correia, R.; DeShong, P. J. Org. Chem. 2003, 68, 1176. (31) Hashimoto, T.; Hirose, D.; Taniguchi, T. Catalytic Aerobic Oxidation of Arylhydrazides with Iron Phthalocyanine. Adv. Synth. Catal. 2015, 357, 3346−3352. (32) (a) Amos, R. A.; Emblidge, R. W.; Havens, N. Esterification Using a Polymer-Supported Phosphine Reagent. J. Org. Chem. 1983,

48, 3598−3600. (b) Tunoori, A. R.; Dutta, D.; Georg, G. I. PolymerBound Triphenylphosphine as Traceless Reagent for Mitsunobu Reactions in Combinatorial Chemistry: Synthesis of Aryl Ethers from Phenols and Alcohols. Tetrahedron Lett. 1998, 39, 8751−8754. (c) Humphries, P. S.; Do, Q.-Q. T.; Wilhite, D. M. ADDP and PSPPh3: an efficient Mitsunobu protocol for the preparation of pyridine ether PPAR agonists. Beilstein J. Org. Chem. 2006. (33) Urankar, D.; Steinbücher, M.; Kosjek, J.; Košmrlj, J. N(Propargyl)diazenecarboxamides for ‘click’ conjugation and their 1,3dipolar cycloadditions with azidoalkylamines in the presence of Cu(II). Tetrahedron 2010, 66, 2602−2613. (34) Jasch, H.; Höfling, S. B.; Heinrich, M. R. Nucleophilic Substitutions and Radical Reactions of Phenylazocarboxylates. J. Org. Chem. 2012, 77, 1520−1532. (35) For a recent example, see: Kim, M. H.; Kim, J. Aerobic Oxidation of Alkyl 2-Phenylhydrazinecarboxylates Catalyzed by CuCl and DMAP. J. Org. Chem. 2018, 83, 1673−1679. (36) Bock, H.; Baltin, E.; Kroner, J. Azo Compounds. VIII. Substituent Effects in Phenyl-Azocarboxylic Acid Derivatives and Their Interpretation by Hueckel M.O. Calculations. Chem. Ber. 1966, 99, 3337−3349. (37) Quilico, A. Nitrosocarbohydrazines. Gazz. Chim. Ital. 1933, 63, 269−279. (38) Chen, C.; Zhu, S.; Liu, B.; Wang, L.; Zhou, Q. Highly Enantioselective Insertion of Carbenoids into O−H Bonds of Phenols: An Efficient Approach to Chiral α-Aryloxycarboxylic Esters. J. Am. Chem. Soc. 2007, 129, 12616−12617. (39) Nishikata, T.; Nagashima, H. N Alkylation of Tosylamides Using Esters as Primary and Tertiary Alkyl Sources: Mediated by Hydrosilanes Activated by a Ruthenium Catalyst. Angew. Chem., Int. Ed. 2012, 51, 5363−5366. (40) O’Connell, J. M.; Moriarty, E.; Aldabbagh, F. Access to Aromatic Ring-Fused Benzimidazoles Using Photochemical Substitutions of the Benzimidazol-2-yl Radical. Synthesis 2012, 44, 3371−3377. (41) Inés, B.; Palomas, D.; Holle, S.; Steinberg, S.; Nicasio, J. A.; Alcarazo, M. Metal-Free Hydrogenation of Electron-Poor Allenes and Alkenes. Angew. Chem., Int. Ed. 2012, 51, 12367−12369. (42) Shintou, T.; Kikuchi, W.; Mukaiyama, T. Efficient Method for the Preparation of Carboxylic Acid Alkyl Esters or Alkyl Phenyl Ethers by a New-Type of Oxidation−Reduction Condensation Using 2,6Dimethyl-1,4-benzoquinone and Alkoxydiphenylphosphines. Bull. Chem. Soc. Jpn. 2003, 76, 1645−1667. (43) Dyck, J.; Zavorine, S.; Robertson, A. J.; Capretta, A.; Larichev, V.; Britten, J.; McNulty, J. Dimethylmalonyltrialkylphosphoranes: probing the steric effect on phosphorus and its stereochemical consequence in esterification reactions of chiral secondary alcohols. J. Organomet. Chem. 2005, 690, 2548−2552. (44) Poloukhtine, A.; Rassadin, V.; Kuzmin, A.; Popik, V. V. Nucleophilic Cycloaromatization of Ynamide-Terminated Enediynes. J. Org. Chem. 2010, 75, 5953−5962.

4729


Systematic Evaluation of 2-Arylazocarboxylates and 2

Recommend Documents