Article pubs.acs.org/joc
N‑Heterocycle-Forming Amino/Carboperfluoroalkylations of Aminoalkenes by Using Perfluoro Acid Anhydrides: Mechanistic Studies and Applications Directed Toward Perfluoroalkylated Compound Libraries Shintaro Kawamura,†,‡ Kento Dosei,‡,§ Elena Valverde,‡ Kiminori Ushida,§ and Mikiko Sodeoka*,†,‡ †
Center for Sustainable Resource Science, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan Synthetic Organic Chemistry Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan § Department of Chemistry, School of Science, Kitasato University, 1-15-1 Kitasato, Minami-ku, Sagamihara 252-0373, Japan ‡
S Supporting Information *
ABSTRACT: This work describes a practical and efficient method for synthesizing a diverse array of perfluoroalkylated amines, including N-heterocycles, to afford perfluoroalkylated chemical libraries as potential sources of drug candidates, agrochemicals, and probe molecules for chemical-biology research. Perfluoro acid anhydrides, which are commonly used in organic synthesis, were employed as a perfluoroalkyl source for intramolecular amino- and carbo-perfluoroalkylations of aminoalkenes, affording perfluoroalkylated N-heterocycles, including: aziridines, pyrrolidines, benzothiazinane dioxides, indolines, and hydroisoquinolinones. Diacyl peroxides were generated in situ from the perfluoro acid anhydrides with urea·H2O2, and allowed to react with aminoalkenes in the presence of copper catalyst to control the product selectivity between amino- and carboperfluoroalkylations. To illustrate the synthetic utility of bench-stable trifluoromethylated aziridine, which was prepared on a gram scale, we used it to synthesize a wide variety of trifluoromethylated amines including complex molecules, such as trifluoromethylated tetrahydroharmine and spiroindolone. A mechanistic study of the role of the copper catalyst in the aminotrifluoromethylation of allylamine suggested that Cu(I) accelerates CF3 radical formation via decomposition of diacyl peroxide, which appears to be the turnover-limiting step, while Cu(II) controls the product selectivity.
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INTRODUCTION High-throughput screening of chemical libraries is an effective methodology for discovery of new drug candidates and agrochemicals, as well as probe molecules for chemical-biology research.1 Since nitrogen-containing structures, including Nheterocycles, are privileged constituents of bioactive molecules,2 they are well represented in conventional libraries. Additionally, introduction of perfluoroalkyl groups, especially the trifluoromethyl group, into bioactive compounds often dramatically improves biological activity and pharmaceutical properties, such as lipophilicity, membrane permeability, metabolic stability, and pharmacokinetics.3,4 Indeed, a perfluoroalkyl group is often introduced as a part of the lead optimization process during drug development (Figure 1a); therefore, development of “late-stage” trifluoromethylation © 2017 American Chemical Society
reactions is an important topic. However, these reactions must work under mild conditions and tolerate all of the other functional groups on the lead molecules.5 Such methods may be useful but can be limited to the reaction of only specific substrates. As an alternative approach, if a divergent synthetic method for a large number of perfluoroalkylated compounds, especially perfluoroalkylated N-containing compounds, were available, it could contribute to the construction of a fruitful library in which unique perfluoroalkylated lead compounds would be identified (Figures 1b and c). Construction of such libraries is, however, very challenging, because a highly practical and economical perfluoroalkylation method is needed as well as Received: September 12, 2017 Published: October 20, 2017 12539
DOI: 10.1021/acs.joc.7b02307 J. Org. Chem. 2017, 82, 12539−12553
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The Journal of Organic Chemistry
rare.18,19 As for trifluoromethylated N-heterocycle synthesis with TFAA, only synthesis of trifluoromethylated oxyindole from a few types of N-methyl-N-phenylmethacrylamides via carbotrifluoromethylation with in situ-generated oxidized TFAAs has been reported. Specifically, Stephenson employed the combination of TFAA/pyridine N-oxide and photoredox catalyst,18 and we achieved the same transformation with TFAA/urea·H2O2 under metal-free conditions.19 In the present article, we disclose a practical and efficient method for synthesizing perfluoroalkylated N-heterocycles via intramolecular amino/carboperfluoroalkylation of aminoalkenes, using perfluoro acid anhydrides as the perfluoroalkyl source. Catalystcontrolled product switching greatly expands the scope of the reaction, and perfluoroalkylated aziridines, pyrrolidines, benzothiazinane dioxides, indolines, and hydroisoquinolinones were successfully obtained (Scheme 1). We also confirmed that Scheme 1. This Work
Figure 1. Strategies for discovery of perfluoroalkyl group-containing pharmaceuticals and chemical probes by using chemical libraries via (a) late-stage perfluoroalkylation and (b) generation of a perfluoroalkylated library. (c) Divergent synthetic strategy for generation of a perfluoroalkylated compound library.
trifluoromethylated N-tosyl (Ts) aziridines are excellent precursors of various acyclic and cyclic amines, further expanding the potential of this approach for generating perfluoroalkylated compound libraries. To illustrate the value of this methodology, we synthesized bench-stable trifluoromethylated aziridine on a gram scale and used it as an intermediate to synthesize a wide variety of trifluoromethylated amines including complex molecules such as trifluoromethylated tetrahydroharmine and spiroindolone. We also carried out mechanistic studies, which showed that Cu(I) species accelerates the reaction and Cu(II) species controls the product selectivity.
synthetic methods for versatile N-containing building block molecules. We have developed amino- and carbo-trifluoromethylation reactions of alkenes to provide trifluoromethylated N-heterocycles.6−8 In recent years, there has also been increasing interest in difunctionalization-type trifluoromethylation of alkenes.6,9−12 The success of these difunctionalization-type trifluoromethylations, enabling simultaneous construction of a C−CF3 bond and N-heterocycles,6−8,13,14 relied upon the excellent reactivity and selectivity of electrophilic trifluoromethylating reagents. Among them, Togni reagent (acid type) is most frequently used, and its excellent chemoselectivity may be useful to introduce a trifluoromethyl group at a late stage of synthesis. However, it is not suitable for the construction of large libraries of perfluoroalkylated compounds, because of its cost and also its potentially dangerous self-reactivity.15 Trifluoroacetic anhydride (TFAA) should be an excellent trifluoromethyl source for generation of perfluoroalkylated compound libraries because of its low cost and ready availability. In addition to TFAA, other perfluoro acid anhydrides are also commercially available and are widely used in diverse fields of organic synthesis. Although Yoshida pioneered the use of TFAA in aromatic trifluoromethylation almost 30 years ago,16,17 alkene trifluoromethylation using TFAA has been a long-standing challenge, and examples remain
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RESULTS AND DISCUSSION First, we attempted to synthesize β-trifluoromethylated aziridines via aminotrifluoromethylation of allylamines because of their expected utility as building blocks due to their ring strain. We and a few other groups have previously reported direct synthetic methods for trifluoromethylated aziridines, but the substrate scope was very limited.6,13a,20 For the purpose of practical application to construction of the compound libraries, commercial availability of the starting material and transformability of the aziridine for structural diversification should be important. In this work, we selected N-Ts-protected allylamine 1a as a suitable starting material for such purpose. However, under our previous conditions for aminotrifluor12540
DOI: 10.1021/acs.joc.7b02307 J. Org. Chem. 2017, 82, 12539−12553
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The Journal of Organic Chemistry
rate-determining step (Scheme 2c).6 On the other hand, a diacyl peroxide generated by the reaction of TFAA and urea· H2O2 undergoes decomposition to give CF3 radical upon single-electron transfer (SET) with Cu(I) catalyst, which should be the rate-determining step in this system (vide inf ra).19,21 The result of Scheme 2b using TFAA/urea·H2O2 suggested that selectivity control should be the key for obtaining the aziridine 2a efficiently. After careful optimization of the reaction conditions,22 the aziridine was found to be obtained selectively in 87% yield under the following conditions: CH2Cl2 (1.0 M) at 40 °C for 7 min (Table 1, entry 1). Furthermore, the amount of TFAA
omethylation of N-aryl and N-alkyl allylamines with the combination of Togni reagent and CuI as the catalyst in CH2Cl2 at 40 °C for 1 h,6 1a could not give the desired aziridine efficiently because of slow conversion and competition of the ring-opening of 2a with iodobenzoate affording an aminoalcohol derivative 3a′ (Scheme 2a). In contrast, we found Scheme 2. Trifluoromethylation of Allylamine 1a with TFAA/Urea·H2O2 in the Presence of Cu Catalyst
Table 1. Examination of Optimal Conditions for Each Product
yield (%)a,b entry 1
c
2 3 4e a
solvent CH2Cl2 (1.0 M) CH2Cl2 (0.4 M) CH2Cl2 (1.0 M) DCE (0.2 M)
conditions A conditions B
2a
3a
4a
d
3
6
d
−40 °C, 1 h
40 °C, 7 min
0 °C, 1 h
0 °C, 1 h
91
1
4
0 °C, 1 h
40 °C, 12 h
n.d.
80
5
0 °C, 1 h
60 °C, 2 h
n.d.
n.d.
86d
19
87
b
The yield was estimated by means of F NMR analysis. n.d. = not detected. c10 equiv of TFAA was used. dIsolated yield. eWithout catalyst.
could be reduced from 10 to 4.0 equiv, and 91% yield of the aziridine was obtained under conditions of CH2Cl2 (0.4 M) at 0 °C for 1h (entry 2). In addition, the unique structures of the other products as promising bioactive compounds prompted us to find optimal conditions for their selective production. The aminoalcohol derivative 3a was considered to be an overreaction product which would be formed via ring-opening reaction of 2a with in situ-generated trifluoroacetate (Scheme 2b), and it was selectively obtained in 80% yield when the reaction time was extended to 12 h at 40 °C in CH2Cl2 (1.0 M) (entry 3). The benzothiazinane dioxide 4a could be formed via carboperfluoroalkylation of 1a. Based on our previous study,19 our metal-free carboperfluoroalkylation conditions were applied to 1a; 4a was obtained in dichloroethane (DCE, 0.2 M) at a slightly higher temperature in 86% yield (entry 4). Hence, we successfully established procedures for the production of three types of compounds possessing attractive structures from the same starting materials. With the optimal conditions in hand, we then investigated the substrate scope of the amino/carboperfluoroalkylations by constructing N-heterocycles using various aminoalkenes and perfluoro acid anhydrides (Schemes 3 and 4). Scheme 3 summarizes the substrate scope of the aminoperfluoroalkylation. Substituents on the aromatic ring of aryl sulfonylamides, including a nosyl group, were well tolerated, affording the desired aziridines in good to excellent yields (2b−2e). The
that the combination of TFAA/urea·H2O2 and copper catalyst showed excellent reactivity despite low selectivity, providing a few types of compounds. Specifically, when 1a was reacted with diacyl peroxide, generated in situ from TFAA (10 equiv) and urea·H2O2 (1.2 equiv), at 40 °C for 3 h in the presence of a catalytic amount of [Cu(CH3CN)4]PF6 (10 mol%), the trifluoromethylated aziridine 2a (57%), an aminoalcohol derivative 3a (33%), and a benzothiazinane dioxide 4a (8%), were obtained (Scheme 2b). This excellent reactivity may be explained by comparison of the reactive intermediate given with TFAA/urea·H2O2 to that with Togni reagent. Our previous mechanistic study on the aminotrifluoromethylation with Togni reagent clarified that a hypervalent iodine intermediate activated by copper(II) catalyst as a Lewis acid is the reactive intermediate and reaction of the substrate with it should be the 12541
DOI: 10.1021/acs.joc.7b02307 J. Org. Chem. 2017, 82, 12539−12553
Article
The Journal of Organic Chemistry Scheme 3. Scope of the Aminoperfluoroalkylationa
a
For further details regarding the reaction conditions, see Supporting Information. b10 equiv of TFAA was used. cDCE instead of CH2Cl2 and 20 mol% of Cu cat. were used.
Scheme 4. Scope of the Carboperfluoroalkylationa
a
For further details regarding the reaction conditions, see Supporting Information.
contrast to the previous findings, the current method selectively provides trifluoromethylated hydroisoquinolinones (4q, 70% and 4r, 35%). Thus, our methodology provides convenient access to various types of perfluoroalkylated N-containing heterocycles from readily available substrates. Next, we examined derivatization of aziridine 2a in order to confirm its synthetic utility as a building block for constructing second-generation libraries of perfluoroalkylated compounds. Initially, we prepared 2.5 g (90%) of the bench-stable aziridine 2a (Scheme 5).26 The prepared aziridine 2a was subjected to
mesyl group, also widely used as a sulfonyl protecting group, was also available for the reaction (2f, 95%). Methyl-substituted allylamines including internal E-alkene were converted into the corresponding aziridines (2g, 56%; 2h, 30%). When 2cyclohexenylamine was used as the substrate, 40% yield of azabicyclic 2i was obtained. In addition, this method was applicable to aminoperfluoroalkylation of 1a using acid anhydrides bearing longer perfluoroalkyl chains, such as C2F5 and C3F7 instead of TFAA (2a′, 84%; 2a″, 83%). Furthermore, trifluoromethylated pyrrolidines (2j-2m) were successfully synthesized from the corresponding protected pentenylamines. Protecting-group-free 2-allylaniline 1n was also available, affording N-acylated indoline 2n.23 Next, the substrate scope of the metal-free carboperfluoroalkylation of allylamines was examined (Scheme 4). In addition to 4a, perfluoroalkylated benzothiazinane dioxide derivatives (4b, 4g, 4a′, 4a″) could be constructed by the reaction of N-allylsulfonylamides (1b, 1g). We also examined the reaction of N-aryl allylamines and N-allyl benzamides instead of N-sulfonylated allylamines. We found that N-aryl allylamines (1o, 1p) gave the corresponding indolines bearing a trifluoroethyl group at the 3-position (4o, 70% and 4p, 88%). Notably, the indoline 4o obtained by carbotrifluoromethylation is a regioisomer of 2n obtained by aminotrifluoromethylation. To our knowledge, trifluoromethylation of N-allyl benzamides (1q, 1r) affords trifluoromethylated oxazolines via oxytrifluoromethylation under the reported conditions for electrophilic trifluoromethylation.5b,24,25 In
Scheme 5. Gram-Scale Synthesis of 2a
ring-opening reactions with several nucleophiles under various conditions (Schemes 6 and 7). First, we evaluated its reactivity with various Grignard reagents (Scheme 6). Although the tosyl group can facilitate ring-opening reaction, it usually requires Cu catalysts to control the reactivity and/or regioselectivity.27,28 Fortunately, 2a gave the desired products 5 selectively in excellent yields without addition of catalyst. Aryl (5a and 5b), 12542
DOI: 10.1021/acs.joc.7b02307 J. Org. Chem. 2017, 82, 12539−12553
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The Journal of Organic Chemistry Scheme 6. Nucleophilic Ring-Opening Reaction of 2a with Grignard Reagents
Scheme 8. Preparation of Indole Alkaloids Bearing a Trifluoromethyl Group from Tryptamines 6a and 6b
a
The reaction was conducted with 3.0 equiv of Grignard reagent at 60 °C for 8 h.
Scheme 7. Trifluoromethylated Amine Synthesis via RingOpening of 2a under Various Conditions
A proposed mechanism of the aminotrifluoromethylation is illustrated in Scheme 9. At the initial step, bis(trifluoroacetyl) Scheme 9. Proposed Mechanism
a
Indole, Et 2 Zn, o-xylene, reflux. b Me 3 SiCN, cat. (2,4,6(MeO)3C6H2)3P, DMF, rt. cBnNH2, CH3CN, reflux. dArOH, Cs2CO3, toluene, reflux. ep-TolSH, K2CO3, DMF, rt.
peroxide (BTFAP) prepared from TFAA and urea·H2O2 generates CF3 radical via SET from Cu(I) catalyst.19,21,36 The resulting electrophilic CF3 radical readily reacts with the substrate, affording the alkyl radical. DFT calculation of this step indicated an energy barrier of + 9.0 kcal/mol.22 Then, the alkyl radical is oxidized by Cu(II) species, and cyclization of the carbocation intermediate provides the aziridine with recovery of the Cu(I) species. The benzothiazinane dioxide-forming cyclization of the alkyl radical requires a higher activation energy (+15.1 kcal/mol) than that for SET with the Cu(II) species (+10.7 kcal/mol), which is in agreement with the experimental observation of catalyst-controlled product switching.37 In order to identify the turnover-limiting step in the aminotrifluoromethylation, we examined the dependence of the initial conversion at 2 min on the concentration of the substrate 1a (Scheme 10a). The rate was found to be independent of the concentration, suggesting that the decomposition of BTFAP via SET, which is the only step not involving the substrate, is the turnover-limiting step. This result also suggests that SET of the substrate as the electron donor should not occur or should be very slow compared to that of the catalyst under the conditions used. Electronic effects of the arylsulfonyl groups of the substrate had no effect on the initial conversion, providing further support for the above conclusion (Scheme 10b).
alkenyl (5c), and alkyl (5d−5f) Grignard reagents were available for the reaction. In addition to Grignard reagents, a diverse array of nucleophiles such as indoles (6),29 cyanide (7),30 benzylamine (8),31 phenols (9), and tolylthiol (10) incorporated the β-trifluoromethylated amine motif under various conditions, demonstrating the versatility of N-Ts aziridine 2a as a building block. The trifluoromethylated amine products obtained (Schemes 6 and 7) are suitable for further diversification. Among them, we were especially interested in the tryptamines 6a and 6b as precursors of indole alkaloids (Scheme 8). After deprotection of the Ts group using SmI2,32 6a and 6b were subjected to Pictet-Spengler reaction with acetaldehyde and isatin, using a catalytic amount of TsOH.33 Gratifyingly, the corresponding trifluoromethylated tetrahydroharmine 12 (54% yield) and spiroindolone 13 (78% yield) were obtained from 11a and 11b, respectively. Since the original indole alkaloids have serotonin uptake-inhibitory activity34,35 and antimalarial activity,33 respectively, biological activities of these CF3-containing derivatives are of particular interest. Finally, we investigated the mechanism of the observed product switching, focusing on the role of the copper catalyst. 12543
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reaction time improved the conversion of the substrate with Cu(O2CCF3)2, and excellent selectivity for aminotrifluoromethylation over carbotrifluoromethylation was observed, despite the decrease of product selectivity for 2a over 3a (entry 4). These observations indicated that Cu(O2CCF3)2 does not accelerate the reaction, but strictly controls the product selectivity in the aminotrifluoromethylation. Then, we examined the reactivity of 1,3,5-(MeO)3C6H3 as an electron-rich aromatic compound that is known to accelerate the decomposition of BTFAP via SET (entry 5).16b Indeed, 1,3,5(MeO)3C6H3 accelerated the conversion and gave the carbotrifluoromethylation product 4a selectively in 13% yield. Thus, SET between BTFAP and electron donor accelerates the reaction, but does not induce aminotrifluoromethylation. Addition of 1,3,5-(MeO)3C6H3 to the reaction using Cu(O2CCF3)2 accelerated the aminotrifluoromethylation (entry 6), indicating that 1,3,5-(MeO)3C6H3 and Cu(O2CCF3)2 control the rate and the product selectivity, respectively. Based on the results of the mechanistic studies, we concluded that, in the aminotrifluoromethylation under the optimal conditions using [Cu(CH3CN)4]PF6 as the catalyst, Cu(I) species serves as an electron donor, accelerating the reaction via SET with BTFAP, while in situ-generated Cu(II) species controls the product selectivity by oxidizing the alkyl radical intermediate (Scheme 11). The mechanistic insights gained in this study may facilitate new reaction and catalyst designs using fluoro diacyl peroxides in the future, as well as providing deeper understanding of the current reaction.
Scheme 10. Reaction Rates at Initial Stage
In order to investigate the BTFAP decomposition step via SET with the copper catalyst, the reactivity of copper salts for decomposition of BTFAP was examined by means of 19F NMR monitoring (Table 2). In the absence of catalyst, 93% (0.22 mmol; δF = − 71.1 ppm) of BTFAP was recovered together with trifluoroacetic acid (δF = − 76.5 ppm) from 1 equiv (0.24 mmol) of urea·H2O2 and 8.3 equiv (2 mmol) of TFAA (entry 1).38 When 0.04 mmol of [Cu(CH3CN)4]PF6 was added to the solution of BTFAP generated in situ, consumption of BTFAP was equivalent to the amount of the copper salt (entry 2), and the decomposition appeared to stop within 30 min under these conditions (entry 3). A greater loading of [Cu(CH3CN)4]PF6 (0.12 mmol) gave the same outcome (entry 4). These results suggested that SET occurs only from Cu(I), and Cu(II) species cannot accelerate the decomposition of BTFAP. In addition, in the presence of 1a, 0.04 mmol of [Cu(CH 3 CN) 4 ]PF 6 completely decomposed BTFAP (entry 5). The combination of Cu(O2CCF3)2 and 1a consumed only a very small amount of BTFAP (entry 6), supporting the idea that Cu(II) species has negligible reactivity. Next, we investigated the role of the copper catalyst in the catalyst-controlled product switching by comparing the product selectivity with various copper catalysts (Table 3). Because of lower solubility of Cu(II) salt, the examination was conducted under the conditions using 10 equiv of TFAA at 40 °C for 7 min described in Table 1, entry 1. While [Cu(CH3CN)4]PF6 gave the aziridine product efficiently, the use of metal-free conditions at 40 °C resulted in very slow conversion, selectively affording benzothiazinane dioxide 4a in only 1% yield (entry 2), as expected from the result in Table 1, entry 4. Cu(O2CCF3)2 also resulted in slow conversion, but the aziridine was obtained as the sole product in 2% yield (entry 3). Extension of the
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CONCLUSION
In conclusion, we have developed efficient and practical Nheterocycle-forming perfluoroalkylations of aminoalkenes by using acid anhydrides as the perfluoroalkyl source. A wide range of N-heterocycles bearing perfluoroalkyl groups could be synthesized by copper-catalyzed aminoperfluoroalkylation and metal-free carboperfluoroalkylation. Bench-stable trifluoromethylated aziridine, prepared by aminotrifluoromethylation on a gram scale, was an excellent intermediate for synthesis of a wide variety of trifluoromethylated amines including complex molecules, such as trifluoromethylated tetrahydroharmine and spiroindolone, confirming its potential as a trifluoromethylcontaining building block. We believe this methodology will enable rapid access to chemical libraries of perfluoroalkylated N-containing compounds with potential for development as drug candidates, agrochemicals, and so on.
Table 2. Reactivity of Cu Species for Decomposition of BTFAP
a
entry
additive
recovery of BTFAP
1 2 3a 4 5 6
none [Cu(CH3CN)4]PF6 (0.04 mmol) [Cu(CH3CN)4]PF6 (0.04 mmol) [Cu(CH3CN)4]PF6 (0.12 mmol) [Cu(CH3CN)4]PF6 (0.04 mmol) + 1a (0.2 mmol) Cu(O2CCF3)2 (0.04 mmol) + 1a (0.2 mmol)
93% (0.22 mmol) 75% (0.18 mmol) 75% (0.18 mmol) 43% (0.10 mmol) no recovery 91% (0.22 mmol)
Run for 1.5 h in the second step. 12544
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The Journal of Organic Chemistry Table 3. Examination of the Role of Cu Catalysts
yield (%)a
a
entry
catalyst
recov. 1a (%)
2a
3a
4a
amino/carbo (2a+3a)/4a
1 2 3 4b 5 6
[Cu(CH3CN)4]PF6 none Cu(O2CCF3)2 Cu(O2CCF3)2 1,3,5-(MeO)3C6H3 Cu(O2CCF3)2 + 1,3,5-(MeO)3C6H3
