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May 30, 2017 - Importantly, C−N bond-containing pharmaceuticals, Piribedil and Cinnarizine, have been synthesized in one step from the commercial am...
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Mitsunobu Reaction Using Basic Amines as Pronucleophiles Hai Huang and Jun Yong Kang* Department of Chemistry and Biochemistry, University of Nevada Las Vegas, 4505 S. Maryland Parkway, Las Vegas, Nevada 89154-4003, United States S Supporting Information *

ABSTRACT: A novel protocol for extending the scope of the Mitsunobu reaction to include amine nucleophiles to form C−N bonds through the utilization of N-heterocyclic phosphine-butane (NHP-butane) has been developed. Both aliphatic alcohols and benzyl alcohols are suitable substrates for C−N bond construction. Various acidic nucleophiles such as benzoic acids, phenols, thiophenol, and secondary sulfonamide also provide the desired products of esters, ethers, thioether, and tertiary sulfonamide with 43−93% yields. Importantly, C−N bond-containing pharmaceuticals, Piribedil and Cinnarizine, have been synthesized in one step from the commercial amines under this Mitsunobu reaction system.

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on the Fe(Pc) oxidation system in 2013.5 Recently, the Aldrich group showcased a fully catalytic protocol using a catalytic loading of both phosphine oxides and arylhydrazinecarboxamides, but showed only one working example (with the highly acidic 4-nitrobenzoic acid nucleophile).6 The scope of these catalytic Mitsunobu reactions continues to be limited to only highly acidic pronucleophiles. These catalytic protocols provide a foundation for potential solutions to overcome the use of a stoichiometric amount of P-reagents and azocompounds; however, the expansion of the nucleophile scope to include nonacidic or basic nucleophiles still remains a key, unresolved challenge in the Mitsunobu reaction. Novel P-reagents and azocompounds have been developed to improve the efficiency of the Mitsunobu reaction over the past decades. Selected examples7 include a multipolymer system,8 ADDP−TBP,9 CMBP,10 CMMP,11 and Ishikawa phosphorane.12 Despite these important advances, the pKa restriction of pronucleophiles using a stable P-reagent has not been realized with nonaromatic nitrogen heterocycles. It is important to note that the stability of P-reagents is key due to the potential application toward a phosphine-catalyzed Mitsunobu reaction. Compounds containing nitrogen heterocycles such as piperazine, morpholine, and piperidine are significant building blocks because of their both unique biological properties and broad

INTRODUCTION Owing to the mild reaction conditions and broad substrate scope, the Mitsunobu reaction has been widely recognized as an essential tool in organic synthesis for the substitution of primary or secondary alcohols with acidic pronucleophiles since its discovery in 1967.1 This method has been broadly adopted in the synthesis of a majority of functional groups from alcohols and used in a key step of biologically active natural product synthesis to invert the stereochemistry of alcohols with various nucleophiles.2 Mitsunobu reaction enables the formation of C−O, C−N, C−S, and C−C bonds in the presence of phosphines and azocompounds.2a,b,3 Despite these advantages, synthetic applications of the Mitsunobu reaction still face two major hurdles: (1. Catalytic Process) the use of a stoichiometric amount of phosphines and azocompounds as well as the generation of phosphine oxide and hydrazine byproducts, (2. Expansion of Scope) the requirement of acidic pronucleophiles with the pKa below 11 for a successful transformation. Thus, numerous efforts have been continuously devoted to address these hurdles. For the hurdle (1), the use of a catalytic amount of phosphine reagents and azocompounds is a potential solution to reduce the generation of toxic wastes in the Mitsunobu reaction. Toy and co-workers reported the first hydrazine-based redox catalytic protocol of the Mitsunobu reaction.4 However, a limited substrate scope of only acidic pronucleophiles has remained unresolved. As an alternative strategy, the Taniguchi group demonstrated azocarboxylate catalytic Mitsunobu reaction based © 2017 American Chemical Society

Received: March 15, 2017 Published: May 30, 2017 6604

DOI: 10.1021/acs.joc.7b00622 J. Org. Chem. 2017, 82, 6604−6614

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The Journal of Organic Chemistry pharmaceutical applications.13 A large number of medicines containing nitrogen heterocycles such as cinnarizine,14 flunarizine,15 piribedil,16 moclobemide,17 oxatomide,18 and fentanyl19 have been synthesized (Figure 1). Thus, various synthetic

restriction of the pronucleophiles, the high nucleophilicity of amines can prohibit a successful C−N bond formation, in which the undesired aza-Michael reaction competes with the desired phospha-Michael reaction. Therefore, amines can directly undergo aza-Michael reaction with azo-compound to form a triazine byproduct,32 preventing the desired phosphaMichael addition reaction between phosphines and azocompounds. Identifying the potential problems with amine nucleophiles in the Mitsunobu reaction, we hypothesized that the highly nucleophilic phosphines would promote the desired phospha-Michael reaction. Hence, this limitation could be addressed by employing a highly nucleophilic NHP A to preferentially form the desired betaine intermediate C, which deprotonates pronucleophile D to generate an azo-phosphonium intermediate E. The alcohol F attacks the intermediate E to produce alkoxyphosphonium G, which undergoes nucleophilic substitution reaction with the pronucleophile D to afford the target product H (Scheme 1, eq b). Alternatively, amine pronucleophiles D could directly attack the alkoxyphosphonium intermediate G to form the C−N bond. Herein, we report that the highly nucleophilic NHPs allow a significant expansion of the scope of the Mitsunobu reaction to include previously restricted nitrogen nucleophiles in C−N bond formation with aliphatic alcohols.

Figure 1. C−N bond-containing pharmaceuticals.

methods have been established for C−N bond formation to construct the nitrogen-containing heterocycles.20 For example, multiple groups have employed a borrowing hydrogen strategy for the N-alkylation of amines using alcohols to introduce the C−N bond. While this approach has advantages over the traditional halogenated−alkylating reagents,21 complex transition metal−ligand systems (e.g., Ru,22 Ir,23 Ni,24 Pd,25 and others26) are required. In addition, this approach often requires harsh reaction conditions (high reaction temperatures) and extra purification for the removal of metal impurities in final pharmaceuticals.27 Thus, a mild, metal-free amination reaction of alcohols is an important, attractive transformation especially for a rapid synthesis of C−N bond-containing pharmaceuticals.28 Our group has actively studied the reactivity of N-heterocyclic phosphine (NHP)-thioureas as bifunctional phosphonylation reagents.29 With the strong nucleophilicity and versatile application of the NHP units in organic synthesis,30 we turned our attention to explore their reactivity toward oxidation−reduction condensation reaction. Recently, we successfully demonstrated the utility of strongly nucleophilic diazaphosphites toward the redox condensation for carbon−heteroatom bond construction (Scheme 1, eq a).31 However, this redox reaction of diazaphosphites needs preactivation of alcohols and exhibits moderate overall yields from alcohol. Hence, to advance this methodology, we further explored the redox condensation reaction for C−N bond construction directly from alcohols and nonacidic amine pronucleophiles. The construction of C−N bonds using weakly acidic amines in the Mitsunobu reaction has remained underdeveloped due to the limitation of currently working pKa below 11. In addition to the pKa

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RESULTS AND DISCUSSION To test our hypothesis, benzyl alcohol 1a and morpholine 2a were chosen as model substrates to examine the feasibility of C−N bond formation, and the results are described in Table 1. Azo-1 (1,1′-(azodicarbonyl)dipiperidine) was first employed to screen P-reagents. Although TPP (P-1) and TBP (P-2) are common P-reagents in Mitsunobu reaction, they generated the corresponding product 3a in only 7−8% yield by NMR (entries 1 and 2). The modification of P-1 with stronger electron-donating properties did not help to improve the reactivity, providing again 7−8% yield by NMR of 3a (entries 3 and 4). Utilization of 2-ethoxy-1,3-diphenyl-1,3,2-diazaphospholidine P-5 (originally developed for a phosphonylation reagent29a in our group) produced 3a in an improved 44% NMR yield. Further modifications of P-5 to P-6 to improve the reactivity were unsuccessful due to the decomposition of the NHP-OtBu P-6 to NHP-oxide via the C−O bond cleavage. To prevent the decomposition process while maintaining the strong nucleophilicity of the NHP motif, we synthesized C−P bonded NHPs P-7, P-8, and P-9. Among them, the NHP-butane P-8 provided the desired product

Scheme 1. Exploration of NHPs for the Mitsunobu Reaction

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DOI: 10.1021/acs.joc.7b00622 J. Org. Chem. 2017, 82, 6604−6614

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The Journal of Organic Chemistry Table 1. Optimized Reaction Conditionsa

entry

P-reagent

azo-compound

solvent

t (°C)

yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23d 24e

P-1 P-2 P-3 P-4 P-5 P-6 P-7 P-8 P-9 P-10 P-11 P-8 P-8 P-8 P-8 P-8 P-8 P-8 P-8 P-8 P-8 P-8 P-8 P-8

Azo-1 Azo-1 Azo-1 Azo-1 Azo-1 Azo-1 Azo-1 Azo-1 Azo-1 Azo-1 Azo-1 Azo-2 Azo-3 Azo-4 Azo-5 Azo-1 Azo-1 Azo-1 Azo-1 Azo-1 Azo-1 Azo-1 Azo-1 Azo-1

THF THF THF THF THF THF THF THF THF THF THF THF THF THF THF DCM toluene CH3CN CHCl3 DCE DCE DCE DCE DCE

80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 40 80 80 60 80 40 rt 40 40

7 8 7 8 44 trace 9 99 18 99 (94)c >99 (91)c 90 (85)c 93 >99 (92)c

a

Reaction condition: benzyl alcohol 1a (0.1 mmol), morpholine 2a (1.5 equiv), P-reagent (1.5 equiv) and azo-compound (1.5 equiv) in solvent (0.5 mL) for 24 h. bYield was determined by crude 1H NMR using 1,3,5-trimethylbenzene as internal standard. cIsolated yield. d1.2 equiv of P-8. e 1.2 equiv of Azo-1.

afforded the desired products 3c and 3d in 66% and 80% yields, respectively. Various 4-substituted piperazines were also successfully employed in this reaction to give the corresponding products 3e−3g in good yields. 1-Methylpiperazine derivatives are important scaffolds of biologically active compounds, and they proved to be viable substrates, affording the desired products 3h and 3i in 86% and 56% yields, respectively. Moreover, noncyclic secondary amines such as dibenzyl amine 2j and N-benzylaniline 2k were also successful in affording the desired products 3j and 3k in 71% and 67% yields, respectively. Interestingly, diethyl amine 2l was not effective under the standard reaction conditions probably due to its higher basicity and unreacted 1a was recovered. Finally, we demonstrated that this Mitsunobu reaction protocol is a useful alternative route for a direct synthesis of secondary amines from various primary amines (2m and 2n), providing the corresponding secondary

3a in 99% yield by NMR (entries 7−9). Both aminodiphenylphosphine P-10 and phosphorus triamide P-11 were inferior to the NHP-butane P-8, affording 3a in 5% and 21% NMR yields, respectively (entries 10 and 11). With the optimized P-reagent P-8 in hand, we screened other azocompounds Azo-2−5, but they were less effective (entries 12−15). Solvent study revealed that DCE is superior to DCM, toluene, CH3CN, and CHCl3. It is noteworthy that this reaction performs well at room temperature, providing the desired product 3a with 85% yield (entry 22). Finally, the optimum reaction conditions were achieved with a slight excess of P-8 (1.5 equiv) and Azo-1 ADDP (1.2 equiv), furnishing the target product 3a in 92% yield (entry 24). With the optimum reaction conditions, we first explored the scope of amine nucleophiles (Scheme 2). Thio-morpoline provided the corresponding substitution product 3b with 71% yield. Piperidine and a 4-ethyl ester-substituted piperidine 6606

DOI: 10.1021/acs.joc.7b00622 J. Org. Chem. 2017, 82, 6604−6614

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The Journal of Organic Chemistry Scheme 2. Scope of Aminesa

Reaction conditions: 1a (0.1 mmol), 2 (1.5 equiv), P-8 (1.5 equiv) and Azo-1 (1.2 equiv) in DCE at 40 °C for 24−36 h. bIsolated yield (%). Reaction run for 36 h. dRatio assigned by using 1H NMR of crude reaction mixture. ND = not determined.

a c

Scheme 3. Scope of Acidic Nucleophilesa

Reaction conditions: 1a (0.1 mmol), 4 (1.5 equiv), P-8 (1.5 equiv) and Azo-1 (1.2 equiv) in DCE at 40 °C for 24−36 h. bIsolated yield (%). Reaction run for 36 h.

a c

Scheme 4. Scope of Alcoholsa

Reaction conditions: 1 (0.1 mmol), Nu (1.5 equiv), P-8 (1.5 equiv) and Azo-1 (1.2 equiv) in DCE at 40 °C for 24−36 h. bIsolated yield (%). Reaction run for 36 h.

a c

substituents 4a−4h were proceeded smoothly to provide the desired products in good yields (5a−5h). Aliphatic acids such as cyclohexanecarboxylic acid 4i also proved to be a useful substrate to furnish an ester product 5i under the standard

amine products 3m and 3n in 43% and 34% yields, respectively (with 2.7:1−1:1.7 ratio of secondary amines and tertiary amines). Next, acidic nucleophiles were evaluated in this Mitsunobu reaction system (Scheme 3). Benzoic acids with various 6607

DOI: 10.1021/acs.joc.7b00622 J. Org. Chem. 2017, 82, 6604−6614

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The Journal of Organic Chemistry

Azo-1-[R] byproducts in 71% and 83% yields, respectively (eq 1). In addition, there was no coupling product generated in the absence of azocompound Azo-1, confirming the requirement of azocompound (eq 2) for a successful coupling reaction. Furthermore, we demonstrated that this reaction maintains its high efficiency even at room temperature reaction conditions (eq 3). Finally, we evaluated the stereochemical outcome employing a chiral alcohol (S)-1o under our Mitsunobu reaction conditions. A complete inversion of configuration at the reaction center was observed when (S)-1-phenylethan-1-ol 1o was treated with benzoic acid 4a (eq 4). All the outcomes above suggest that this transformation follows the known Mitsunobu reaction mechanism.36

reaction conditions. A conjugated acid 4j was also successful in producing the desired product 5j in 88% yield. 2,2-Diphenylacetic acid 4k provided the corresponding ester 5k in 83% yield. The reaction of the benzyl alcohol 1a with phenol 4l gave the corresponding ether product 5l in 66% yield. While a disulfide is a major product with thiol nucleophiles in conventional Mitsunobu reaction,33 a thioether 5m was obtained as a major product (43% yield) from thiophenol 4m. A weakly acidic sulfonamide 4n also furnished the desired product 5n in 81% yield. Finally, the scope of alcohols was investigated, and the results are summarized in Scheme 4. Various substituted benzyl alcohols 1b−1i were well-tolerated and afforded the corresponding products 6a−6h in moderate to good yields. Benzyl alcohols containing electron-withdrawing groups provided lower yields than more electron-rich alcohols. Polycyclic aromatic alcohols such as quinolin-6-yl-methanol 1j and naphthalen-1-yl-methanol 1k also turned out to be suitable substrates in this system and furnished the desired products 6i and 6j in 77% and 84% yields, respectively. Cinnamyl alcohol 1m produced the allylamine product 6l in 79% yield with complete α-regioselectivity.34 The substitution product of an ester 6m from 2,2-diphenylethanol 1n was isolated in 86% yield without any appreciable elimination byproducts. Secondary alcohols (1o, 1p) were also suitable substrates for this reactionproviding the desired products 6n and 6o in 82% and 68% yields, respectively. Furthermore, aliphatic alcohols such as 3-phenylpropan-1-ol 1p were also suitable coupling partners in this Mitsunobu reaction system yielding the corresponding amine products 6p and 6q in 59% and 73% yields, respectively. This successful C−N bond formation between aliphatic alcohol and amines may rule out the possibility of formation of a carbocation intermediate, which is a suspected intermediate in Mitsunobu reaction employing allylic or benzylic alcohols.35 Finally, we applied this Mitsunobu reaction to the synthesis of two C−N bond-containing pharmaceuticals Piribedil 6r and Cinnarizine 6s, which were successfully isolated in 83% and 74% yields, respectively. To gain insights into the mechanism for this transformation, an exhaustive isolation−characterization process of all products and byproducts from the standard reaction was performed (Scheme 5). Along with the desired substitution product 3a, we isolated N-heterocyclic phosphine oxide P-8-[O] and hydrazine

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CONCLUSION In summary, an NHP-butane (1,3,2-diazaphospholidine) P-8 has been rationally developed for the expansion of the substrate scope to include previously restricted nitrogen nucleophiles in the Mitsunobu reaction. With the strong nucleophilicity of the NHP-butane P-8, nonacidic amine nucleophiles can undergo substitution reaction with aliphatic alcohols in the presence of ADDP. This transformation also provides an alternative entry to the synthesis of secondary amines. In addition, this reaction takes place under mild conditions and exhibits broad functional group tolerance. A practical application of this Mitsunobu reaction system for the synthesis of the C−N bond-containing pharmaceuticals Cinnarizine and Piribedil (anti-Parkinson agent) was also successfully demonstrated. Further studies on the catalytic Mitsunobu reaction employing the NHPs are underway in our laboratory and will be reported in due course.

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EXPERIMENTAL SECTION

General Information. All reactions were carried out under atmospheric conditions in oven-dried glassware with a magnetic stirring bar. Dry solvents (THF, toluene, and DCM) were obtained by a solvent purification system under argon. All commercially available reagents were used as received without further purification. Purification of reaction products was carried out by flash column chromatography using silica gel 60 (230−400 mesh). Analytical thin layer chromatography was performed on 0.25 mm aluminum-backed silica gel 60-F plates. Visualization was accompanied by UV light and KMnO4 solution. Concentration under reduced pressure refers to the removal of volatiles using a rotary evaporator attached to a dry diaphragm pump

Scheme 5. Control Experiments for Mechanism Study

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DOI: 10.1021/acs.joc.7b00622 J. Org. Chem. 2017, 82, 6604−6614

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The Journal of Organic Chemistry

(0.26 mL, 2.88 mmol) at 0 °C under an argon atmosphere. The resulting reaction mixture was stirred at 0 °C for 30 min. After stirring for 30 min at 0 °C, it was allowed to warm up to room temperature and stirred for 2 h at room temperature. The reaction mixture was diluted with DCM (20 mL), and the resulting solution was washed with aq. NaHCO3 and brine. The organic phase was dried over Na2SO4 and Na2SO4 was filtered off. After removal of the solvent under reduced pressure, the residue was purified by flash column chromatography on basic alumina (Hexane/EA = 5:1) to give corresponding product P-6 as a white solid; 236.7 mg, 39%; mp 111−112 °C (decomp.); IR ν (KBr, cm−1) 3038, 2954, 2895, 1600, 1502, 1491, 1476, 1302, 1287, 1224, 1133, 1036, 981, 784; 1H NMR (400 MHz, CDCl3) δ 7.36−7.30 (m, 4H), 7.30−7.24 (m, 4H), 7.08 (ddd, J = 8.2, 3.0, 1.2 Hz, 2H), 6.88 (t, J = 7.2 Hz, 2H), 3.92−3.82 (m, 2H), 3.68−3.56 (m, 2H), 1.19 (d, J = 0.8 Hz, 9H); 13C NMR (100.5 MHz, CDCl3) δ 145.4 (d, J = 17.1 Hz), 129.1, 119.5 (d, J = 1.5 Hz), 116.0 (d, J = 13.4 Hz), 74.7 (d, J = 7.4 Hz), 46.4 (d, J = 8.2 Hz), 31.0 (d, J = 7.5 Hz); 31P NMR (162 MHz, CDCl3): δ 106.0 ppm. HRMS (ESI-TOF) m/z: found [M + H]+ values corresponding to N1,N2-diphenylethane-1,2-diamine; [M + H]+ Calcd for C14H17N2: 213.1386; found: 213.1378. 1,3-Di-tert-butyl-2-butyl-1,3,2-diazaphospholidine (P-7). To a solution of NHP-Cl (142.2 mg, 0.6 mmol) in Et2O (4 mL) was added n-BuLi (1.24 M in hexane, 0.49 mL) at −78 °C under an argon atmosphere. The resulting reaction mixture was allowed to warm up slowly to room temperature. After stirring for 15 h at room temperature, the reaction mixture was diluted with Et2O (10 mL) and the resulting solution was washed with aq. NaHCO3 and brine. The organic phase was dried over Na2SO4 and Na2SO4 was filtered off. The organic solvent was evaporated under reduced pressure to give crude product P-7 as a colorless oil; 95.7 mg, 64%; IR ν (KBr, cm−1) 2963, 2933, 2873, 1465, 1392, 1378, 1363, 1272, 1248, 1220, 1209, 1059, 978; 1H NMR (400 MHz, CDCl3) δ 3.16− 3.08 (m, 2H), 3.07−2.99 (m, 2H), 1.40−1.20 (m, 6H), 1.18 (s, 18H), 0.89 (t, J = 6.8 Hz, 3H); 13C NMR (100.5 MHz, CDCl3) δ 53.0 (d, J = 17.8 Hz), 46.9 (d, J = 7.4 Hz), 35.5 (d, J = 21.6 Hz), 29.8 (d, J = 9.7 Hz), 26.7 (d, J = 15.7 Hz), 24.3 (d, J = 11.9 Hz), 14.0; 31P NMR (162 MHz, CDCl3): δ 94.8 ppm; HRMS (ESI-TOF): found [M + H]+ values corresponding to 1,3-di-tert-butyl-2-butyl-1,3,2-diazaphospholidine 2-oxide; [M + H]+ Calcd for C14H32N2OP: 275.2247; Found: 275.2253. 2-Butyl-1,3-diphenyl-1,3,2-diazaphospholidine (P-8). To a solution of NHP-Cl (828 mg, 3.0 mmol) in Et2O (15 mL) was added n-BuLi (1.3 M in hexane, 2.3 mL) at −78 °C under an argon atmosphere. The resulting reaction mixture was allowed to warm up slowly to room temperature. After stirring for 5 h at room temperature, the reaction mixture was diluted with Et2O (20 mL) and the resulting solution was washed with aq. NaHCO3 and brine. The organic phase was dried over Na2SO4 and Na2SO4 was filtered off. The organic solvent was evaporated under reduced pressure to give crude product P-8 as a white solid; 712.3 mg, 81%; IR ν (KBr, cm−1) 3059, 2958, 2870, 1597, 1496, 1298, 1284, 1112, 1091, 991, 925; mp 201−202 °C; 1H NMR (400 MHz, CDCl3) δ 7.28−7.22 (m, 4H), 7.02−6.97 (m, 4H), 6.81 (tt, J = 7.6, 0.8 Hz, 2H), 3.77 (t, J = 2.4 Hz, 4H), 1.62−1.56 (m, 2H), 1.42−1.26 (m, 4H), 0.81 (t, J = 7.2 Hz, 3H); 13C NMR (100.5 MHz, CDCl3) δ 146.6 (d, J = 17.1 Hz), 129.2 (d, J = 1.5 Hz), 118.4 (d, J = 2.2 Hz), 115.3 (d, J = 14.9 Hz), 46.9 (d, J = 8.9 Hz), 31.6 (d, J = 32.7 Hz), 25.8 (d, J = 14.1 Hz), 24.3 (d, J = 9.7 Hz), 13.8; 31P NMR (162 MHz, CDCl3): δ 95.6 ppm; HRMS (ESI-TOF) m/z: [M + K]+ Calcd for C18H23N2PK: 337.1230; Found: 337.1235. 1,2,3-Triphenyl-1,3,2-diazaphospholidine (P-9). To a solution of diamine (424.5 mg, 2.0 mmol) and Et3N (0.56 mL, 4.0 mmol) in DCM (10 mL) was added dichloro(phenyl)phosphine (0.27 mL, 2.0 mmol) at −78 °C under an argon atmosphere. The resulting reaction mixture was allowed to warm up slowly to room temperature, and it was stirred for 2 h at room temperature. After stirring for 2 h at room temperature, the reaction mixture was diluted with DCM (20 mL) and the resulting solution was washed with aq. NaHCO3 and brine. The organic phase was dried over Na2SO4 and Na2SO4 was filtered off. After removal of the solvent under reduced pressure, the residue was purified by flash column chromatography on basic alumina (Hexane/EA = 3:1) to give corresponding product P-9 as a white solid; 236 mg, 37%; mp 233−235 °C; IR ν (KBr, cm−1) 3066, 3023, 2862, 1596, 1496, 1296, 1288, 1185, 1115,

(10−15 mmHg), followed by pumping to a constant weight with an oil pump (