DOI: 10.1002/asia.201500405
Communication
Asymmetric synthesis
Catalytic Asymmetric 1,4-Addition Reactions of Simple Alkylnitriles Yasuhiro Yamashita, Io Sato, Hirotsugu Suzuki, and Shu¯ Kobayashi*[a] Abstract: The development of catalytic asymmetric carbon–carbon bond-forming reactions of alkylnitriles that do not have an activating group at the a-position, under proton-transfer conditions, is a challenging research topic. Here, we report catalytic asymmetric direct-type 1,4-addition reactions of alkylnitriles with a,b-unsaturated amides by using a catalytic amount of potassium hexamethyldisilazide (KHMDS) with a chiral macro crown ether. The desired reactions proceeded in high yields with good diastereo- and enantioselectivities. To our knowledge, this is the first example of catalytic asymmetric direct-type 1,4addition reaction of alkylnitriles without any activating group at the a-position.
Catalytic stereoselective carbon–carbon bond-forming reactions are one of the most important reactions available for the fine synthesis of medicines, agricultural chemicals, functional materials, etc.[1] Among them, catalytic addition reactions of pronucleophiles through carbanion formation by a base catalyst are highly desired because only proton transfer occurs between a substrate and a product, which means that the atom economy is perfect (100 %).[2] Recently, much effort in this area has led to the development of highly stereoselective reactions, including asymmetric variants of carbon–carbon bond formation.[3] In the base-catalyzed reactions, alkylnitriles are promising carbon pronucleophiles because the nitrile part can be transformed into several useful functional groups such as carboxylic acid, ester, amide, and aminomethyl groups.[4] However, without any activating group at the a-position, hydrogen atoms at the a-position of alkylnitriles are less acidic (pKa ca. 33 in DMSO) compared with typical carbanion precursors employed in several kinds of base-catalyzed reactions, even though the nitrile group itself has an effective electron-withdrawing nature that can stabilize a carbanion at the a-position.[5] Therefore, the introduction of further activating groups at the a-position is normally required before such alkylnitriles can be used as pronucleophiles, and successful examples of [a] Dr. Y. Yamashita, I. Sato, H. Suzuki, Prof. Dr. S. Kobayashi Department of Chemistry, School of Science The University of Tokyo Hongo, Bunkyo-ku, Tokyo (Japan) E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/asia.201500405. Chem. Asian J. 2015, 10, 2143 – 2146
catalytic asymmetric reactions conducted using simple alkylnitriles without any activating group at the a-position have been limited.[6] Verkade et al. reported catalytic aldol-type reactions and further transformations of alkylnitriles, including acetonitrile, by using an organosuperbase, proazaphosphatrane, as catalyst.[7] Knochel et al. also reported potassium tert-butoxidecatalyzed addition reactions of alkylnitriles to stylene derivatives.[8] Shibasaki and Kumagai et al. investigated catalytic carbon–carbon bond-forming reactions of simple alkylnitriles and revealed that Cu, Ru, and Rh catalyst systems were effective for aldol-type and Mannich-type reactions, including asymmetric variants.[9] Ozerov et al.,[10] Noyori and Saito et al.,[11] and Guan et al.[12] all reported aldol-type reactions of alkylnitriles using Ni or Rh catalysts. Oudeyer and Levacher et al. also reported direct-type Mannich reactions of alkylnitriles.[13] Recently, Cai et al. reported catalytic enantioselective aldol-type reactions of acetonitrile with isatin derivatives.[14] To our knowledge, however, catalytic asymmetric direct-type 1,4-addition reactions of simple alkylnitriles that do not have an activating group at the a-position have not been reported even in a nonasymmetric variant. Recently, our group has been investigating catalytic carbon– carbon bond-forming reactions of less acidic carbon pronucleophiles based on a concept of “product base mechanism”, in which an intermediate with a strong Brønsted basicity works as a base to deprotonate the next substrate directly to form a reactive nucleophile without catalyst regeneration.[15, 16] It was demonstrated that esters without any activating group at the a-position successfully reacted with N-arylimines to afford the desired Mannich adducts in high yields by using a catalytic amount of potassium hydride (KH).[15a] We have also revealed quite recently that simple amides without any activating group at the a-position undergo catalytic 1,4-addition reactions with a,b-unsaturated amides by using KH or KHMDS as catalyst, and that the desired 1,5-dicarbonyl compounds were obtained in high yields.[15b] As further proof of concept, we wished to develop catalytic 1,4-addition reactions of simple alkylnitriles without any activating group at the a-position and to attempt to conduct the reaction under asymmetric catalysis conditions. We first examined the catalytic 1,4-addition reaction of propionitrile (2 a) with an a,b-unsaturated carbonyl compound. N,N-Dimethylcinnamamide (1 a) was chosen as an electrophile, which has been revealed to be a reactive 1,4-addition acceptor.[15b] Although the use of lithium hexamethyldisilazide (LiHMDS) and NaHMDS showed lower catalyst activity (Table 1,
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Communication Table 2. Catalytic asymmetric 1,4-addition reactions of propionitrile.[a]
Table 1. Catalytic 1,4-addition reactions of propionitrile using metal amides as catalysts.[a]
Entry
Base
Additive
Solvent
Yield [%][b]
Anti/syn[c]
1[d] 2[d] 3 4 5 6 7
LiHMDS NaHMDS KHMDS KHMDS KHMDS KHMDS KHMDS
– – – – – – 18-Crown-6
toluene toluene toluene THF TBME CPME toluene
trace[e] 3[e] 73 65 83 84 89
– – 78:22 71:29 77:23 78:22 74:26
[a] The reaction of 1 a (0.400 mmol) with 2 a (0.800 mmol, 2.0 equiv) was performed for 18 h at 0.2 m in the presence of a catalyst prepared from M-HMDS (0.0400 mmol, 10 mol %) unless otherwise noted. [b] Isolated yield as a mixture of both diastereoisomers. [c] Determined by 1H NMR spectroscopic analysis of the crude mixture. [d] 0.13 m. [e] Determined by 1 H NMR analysis.
entries 1, 2), to our delight, the desired reaction proceeded smoothly with KHMDS as catalyst, and both good yield and good diastereoselectivity were obtained (entry 3). Further investigation of solvents was then conducted, and it was found that ether solvents such as THF, tert-butyl methyl ether (TBME), and cyclopentyl methyl ether (CPME), showed similar results to those obtained with toluene (entries 4–6). The inclusion of 18crown-6 ether as an additive to coordinate potassium cations had a positive effect in this reaction, and enhancement of reactivity was observed (entry 7). It should be noted that this is the first successful example of a catalytic direct-type 1,4-addition reaction of propionitrile without any activating group at the aposition. We then examined an asymmetric variant of the catalytic 1,4-addition reaction. Chiral crown ethers are known to be good ligands for chiral modification of potassium cations. Although typical chiral crown ethers L1–L3 showed poor enantioselectivities, chiral macro crown ether L4 gave very promising stereoselectivities (Table 2, entry 4 and Figure 1). Quite recently, we have found that L4 is an excellent chiral ligand for creating effective an asymmetric environment around the potassium cation of KHMDS in catalytic asymmetric 1,4-addition reactions of simple amides and esters without any activating group at the a-position.[15b] The effect of solvents was then examined. Whereas reactions performed in THF showed poor enantioselectivity (entry 5), the use of a less polar ether solvent, TBME, gave a similar selectivity to that observed with toluene (entry 6). Other aromatic solvents, such as benzotrifluoride (BTF) and xylene, were further examined; however, the selectivities were not improved significantly (entries 7 and 8). The selectivities were improved by conducting the reaction at lower temperature (entry 9), and the yield was also improved by using 4 equivalents of 2 a and a shorter reaction time (entry 10). Finally, the best result was obtained by conducting the reaction at ¢78 8C (entry 11). The catalyst loading was further decreased without any significant loss of stereoselectivity (entry 12). Chem. Asian J. 2015, 10, 2143 – 2146
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Entry
Base
L
Solvent
T [8C]
Yield [%][b]
Anti/ syn[c]
ee (Anti)
1 2 3 4[d] 5[d,e] 6 7[g] 8[g] 9 10[h,i] 11[h,i] 12[h,j]
KHMDS KHMDS KHMDS KHMDS KHMDS KHMDS KHMDS KHMDS KHMDS KHMDS KHMDS KHMDS
R-L1 S-L2 S-L3 S-L4[f] S-L4[f] S-L4[f] S-L4[f] S-L4[f] S-L4[f] S-L4[f] S-L4[f] R-L4
toluene toluene toluene toluene THF TBME BTF xylene toluene toluene toluene toluene
¢40 ¢40 ¢40 ¢40 ¢40 ¢40 ¢20 ¢20 ¢60 ¢60 ¢78 ¢78
63 65 90 61 62[c] 48[c] 55[c] 73 66 86 82 84
79:21 78:22 77:23 80:20 92:8 84:16 71:29 76:24 81:19 79:21 93:7 93:7
33 4 10 51 28 47 35 47 58 57 62 61[k]
[a] The reaction of 1 a (0.400 mmol) with 2 a (0.800 mmol, 2.0 equiv) was performed for 18 h at 0.13 m in the presence of a catalyst prepared from M-HMDS (0.0400 mmol, 10 mol %) with ligand L (0.0440 mmol, 11 mol %) unless otherwise noted. [b] Isolated yield as a mixture of both diastereoisomers. [c] Determined by 1H NMR spectroscopic analysis of the crude mixture. [d] 24 h. [e] 0.2 m. [f] S-L4 (5.5 mol %) was used. [g] 20 h. [h] 2 a (4.0 equiv) was used. [i] 3 h. [j] R-L4 (2.8 mol %) and KHMDS (5.0 mol %) were used. [k] Opposite enantiomer was obtained compared to the reactions in entries 1–11.
Figure 1. Chiral crown ethers used in this study.
The substrate scope of this reaction was then examined (Table 3). The reactions of 1 a–f, bearing different aryl substituents at the b-position, were first conducted. The o-tolyl group (1 b) was found to decrease the diastereoselectivity, but the enantioselectivity was improved slightly (entry 2). The presence of a m-tolyl group (1 c) decreased the enantioselectivity, and a p-tolyl group (1 d) also affected the diastereoselectivity (entries 3 and 4). The presence of an electron-donating MeO group (1 e) did not lead to a significant improvement in either diastereo- or enantioselectivity (entry 5). The use of substrates with an electron-withdrawing p-bromo group (1 f) decreased the yield and both the diastereo- and enantioselectivities (entry 6). The bulky aromatic 2-naphthyl substituent of 1 g also led to a decrease in both yield and selectivities (entry 7). Substrate 1 h, bearing a heteroaromatic 2-furyl group, worked well, affording the desired product in good yield with good diastereoselectivity and moderate enantioselectivity (entry 8). The a,b-unsaturated amide (1 i), bearing a cyclohexyl group at the b-position, showed high reactivity but lower diastereo- and enantioselectivities (entry 9). It was also found that other alkyl-
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Communication tion, propionitrile (2 a, 111 mL, 1.60 mmol) and N,N-dimethylcinnamamide (1 a, 70.1 mg, 0.400 mmol), which were put in another flame-dried tube inside the glove box, were added to the flask through a cannula with extra toluene (2.0 mL). The whole mixture was stirred for 18 h at ¢78 8C. The reaction was quenched with H2O (1.0 mL) and extracted with CH2Cl2 (10 mL) three times. The organic layers were combined and dried over anhydrous Na2SO4. After filtration and concentration under reduced pressure, the crude product was obtained. The crude product was purified by silica-gel preparative TLC (hexane/EtOAc) to afford the desired 1,4adduct 3 aa (84 %, 77.6 mg, 0.337 mmol). The diastereomer ratio (d.r.) was determined by 1H NMR spectroscopic analysis of the crude product. The relative stereochemical assignment was determined by NMR analysis.[17] The enantioselectivity was determined by chiral HPLC analysis. The absolute configuration was determined by analogy to 3 ab. The absolute configuration of 3 ab was determined by transforming it into a literature-known compound (see the Supporting Information).[18] Absolute configurations of other products were also determined by analogy to 3 ab.
Table 3. Substrate scope.[a]
Entry R1
R2, R3
3
Yield [%][b] Anti/ syn[c]
ee [%][d]
1 2 3e 4 5 6[e,h,i] 7[f,g,h,i] 8[e] 9[j] 10 11[e,h,i] 12
Me,H (2 a) Me,H (2 a) Me,H (2 a) Me,H (2 a) Me,H (2 a) Me,H (2 a) Me,H (2 a) Me,H (2 a) Me,H (2 a) Et,H (2 b) Me,Me (2 c)[l] H,H (2 d)[m]
3 aa 3 ba 3 ca 3 da 3 ea 3 fa 3 ga 3 ha 3 ia 3 ab 3 ac 3 ad
86 80 79 83 83 61 69 82 quant. 83 71 messy
61 65 55 60 65 46 53 50 45 70 33 –
Ph (1 a) o-MeC6H4 (1 b) m-MeC6H4 (1 c) p-MeC6H4 (1 d) p-MeOC6H4 (1 e) p-BrC6H4 (1 f) 2-naphthyl (1 g) 2-furyl (1 h) Cy (1 i) Ph (1 a) Ph (1 a) Ph (1 a)
93:7 75:25 92:8 83:17 82:18 73:27 77:23 84:16 54:46[k] > 99:1 – –
[a] The reaction of 1 a (0.400 mmol) with alkylnitrile 2 (1.60 mmol, 4.0 equiv) was performed at ¢78 8C for 18 h at 0.13 m in the presence of a catalyst prepared from KHMDS (0.0200 mmol, 5 mol %) and ligand R-L4 (0.0112 mmol, 2.8 mol %) unless otherwise noted. [b] Isolated yield as a mixture of both diastereoisomers. [c] Determined by 1H NMR spectroscopic analysis of the crude mixture. [d] Determined by HPLC analysis. [e] 0.2 m. [f] 0.1 m. [g] 24 h. [h] Reaction was conducted at ¢60 8C. [i] KHMDS (10 mol %) and R-L4 (5.5 mol %) were used. [j] 0.4 m. [k] Determined by HPLC analysis of the target product mixture after isolation. [l] 4.7 equiv of 2 c was used. [m] 19 equiv of 2 d was used.
Acknowledgements This work was partially supported by a Grant-in-Aid for Science Research from the Japan Society for the Promotion of Science (JSPS), Global COE Program, The University of Tokyo, MEXT, Japan, and the Japan Science and Technology Agency (JST). I.S. and H.S. thank the MERIT program, The University of Tokyo for financial support.
nitriles worked well, and higher diastereoselectivities (> 99:1) and the best enantioselectivity were obtained when butyronitrile (2 b) was used (entry 10); the use of isobutyronitrile (2 c), as an alkylnitrile with more steric bulk, gave lower enantioselectivity (entry 11). The simplest alkylnitrile, acetonitrile (2 d), was also tested; however, the reaction system was very messy, and no desired product was obtained (entry 12). In conclusion, we have developed catalytic 1,4-addition reactions of alkylnitriles that do not bear an activating group at the a-position. It was found that the desired reaction of simple alkylnitriles with a,b-unsaturated amides proceeded in high yields with good diastereoselectivities by using KHMDS as catalyst. Moreover, the asymmetric 1,4-addition reactions proceeded in high yields with good diastereo- and enantioselectivities. To our knowledge, these are the first examples of catalytic asymmetric 1,4-addition reactions of alkylnitriles. Studies to improve the selectivity of the reaction are ongoing in our laboratory.
Keywords: 1,4-addition · asymmetric synthesis · catalyst · nitrile · strong base
Experimental Section Typical experimental procedure for the asymmetric 1,4-addition reaction of propionitrile (Table 2, entry 12) KHMDS (4.1 mg, 2.1 Õ 10¢2 mmol) and binaphtho-34-crown-10 (RL4, 9.7 mg, 1.1 Õ 10¢2 mmol) were placed in a flame-dried 10 mL flask inside a glove box filled with argon. The flask was cooled to ¢78 8C, then toluene (1.0 mL) was added. The reaction mixture was stirred for 1 h at the same temperature. After catalyst preparaChem. Asian J. 2015, 10, 2143 – 2146
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[1] a) Comprehensive Organic Synthesis (Ed.: B. M. Trost), Pergamon Press, Oxford, 1991; b) Comprehensive Organic Synthesis, 2nd ed., (Eds.: P. Knochel, G. A. Molander), Elsevier Science, 2014. [2] a) Handbook of Green Chemistry (Ed.: P. T. Anastas), Wiley-VCH, Weinheim, 2009; b) S. Kobayashi, R. Matsubara, Chem. Eur. J. 2009, 15, 10694 – 10700. [3] For a recent review on catalytic asymmetric direct-type reactions under proton transfer conditions, see: N. Kumagai, M. Shibasaki, Angew. Chem. Int. Ed. 2011, 50, 4760 – 4772; Angew. Chem. 2011, 123, 4856 – 4868. [4] R. C. Larock, Comprehensive Organic Transformations, 2nd ed., WileyVCH, 1999. [5] F. G. Bordwell, Acc. Chem. Res. 1988, 21, 456. Also see: Bordwell pKa table (http://www.chem.wisc.edu/areas/reich/pkatable/index.htm). [6] a) S. Arseniyadis, K. S. Kyler, D. S. Watt, Org. React. 1984, 31, 1; b) F. F. Fleming, B. C. Shook, Tetrahedron 2002, 58, 1 – 23; c) J. G. Verkade, P. B. Kisanga, Aldrichimica Acta 2004, 37, 3 – 14. [7] a) B. A. D’Sa, P. Kisanga, J. G. Verkade, J. Org. Chem. 1998, 63, 3961 – 3967; b) P. Kisanga, D. McLeod, B. D’Sa, J. G. Verkade, J. Org. Chem. 1999, 64, 3090 – 3094; c) P. Kisanga, J. G. Verkade, J. Org. Chem. 2000, 65, 5431 – 5432; d) P. Kisanga, J. G. Verkade, Tetrahedron 2001, 57, 467 – 475; e) J. G. Verkade, P. Kisanga, Tetrahedron 2003, 59, 7819 – 7858. [8] A. L. Rodriguez, T. Bunlaksananusorn, P. Knochel, Org. Lett. 2000, 2, 3285 – 3287. [9] a) Y. Suto, N. Kumagai, S. Matsunaga, M. Shibasaki, Org. Lett. 2003, 5, 3147 – 3150; b) N. Kumagai, S. Matsunaga, M. Shibasaki, J. Am. Chem. Soc. 2004, 126, 13632 – 13633; c) Y. Suto, R. Tsuji, M. Kanai, M. Shibasaki, Org. Lett. 2005, 7, 3757 – 3760; d) N. Kumagai, S. Matsunaga, M. Shibasaki, Chem. Commun. 2005, 3600 – 3602; e) N. Kumagai, S. Matsunaga, M. Shibasaki, Tetrahedron 2007, 63, 8598 – 8608; f) Y. Kawato, N. Kumagai, M. Shibasaki, Chem. Commun. 2013, 49, 11227 – 11229; g) D. Sureshkumar, V. Ganesh, N. Kumagai, M. Shibasaki, Chem. Eur. J. 2014, 20, 15723 – 15726. Ó 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Communication [10] L. Fan, O. V. Ozerov, Chem. Commun. 2005, 4450 – 4452. [11] a) A. Goto, K. Endo, Y. Ukai, S. Irle, S. Saito, Chem. Commun. 2008, 2212 – 2214; b) A. Goto, H. Naka, R. Noyori, S. Saito, Chem. Asian J. 2011, 6, 1740 – 1743. [12] S. Chakraborty, Y. J. Patel, J. A. Krause, H. Guan, Angew. Chem. Int. Ed. 2013, 52, 7523 – 7526; Angew. Chem. 2013, 125, 7671 – 7674. [13] T. Poisson, V. Gembus, S. Oudeyer, F. Marsais, V. Levacher, J. Org. Chem. 2009, 74, 3516 – 3519. [14] T. Deng, H. Wang, C. Cai, Eur. J. Org. Chem. 2014, 7259 – 7264. [15] a) Y. Yamashita, H. Suzuki, S. Kobayashi, Org. Biomol. Chem. 2012, 10, 5750 – 5752; b) H. Suzuki, I. Sato, Y. Yamashita, S. Kobayashi, J. Am. Chem. Soc. 2015, 137, 4336 – 4339. [16] See also ref. 13 as a related example.
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[17] a) C. H. Heathcock, D. A. Oare, J. Org. Chem. 1985, 50, 3022 – 3024; b) C. H. Heathcock, M. H. Norman, D. E. Uehling, J. Am. Chem. Soc. 1985, 107, 2797 – 2799. [18] a) D. Enders, A. Plant, Synlett 1994, 1054 – 1056; b) M. Amat, M. P¦rez, N. Llor, J. Bosch, E. Lago, E. Molins, Org. Lett. 2001, 3, 611 – 614; c) J.-P. Chen, C.-H. Ding, W. Liu, X.-L. Hou, L.-X. Dai, J. Am. Chem. Soc. 2010, 132, 15493 – 15495.
Manuscript received: April 18, 2015 Accepted Article published: May 8, 2015 Final Article published: June 1, 2015
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Communication
Asymmetric synthesis
Catalytic Asymmetric 1,4-Addition Reactions of Simple Alkylnitriles Yasuhiro Yamashita, Io Sato, Hirotsugu Suzuki, and Shu¯ Kobayashi*[a] Abstract: The development of catalytic asymmetric carbon–carbon bond-forming reactions of alkylnitriles that do not have an activating group at the a-position, under proton-transfer conditions, is a challenging research topic. Here, we report catalytic asymmetric direct-type 1,4-addition reactions of alkylnitriles with a,b-unsaturated amides by using a catalytic amount of potassium hexamethyldisilazide (KHMDS) with a chiral macro crown ether. The desired reactions proceeded in high yields with good diastereo- and enantioselectivities. To our knowledge, this is the first example of catalytic asymmetric direct-type 1,4addition reaction of alkylnitriles without any activating group at the a-position.
Catalytic stereoselective carbon–carbon bond-forming reactions are one of the most important reactions available for the fine synthesis of medicines, agricultural chemicals, functional materials, etc.[1] Among them, catalytic addition reactions of pronucleophiles through carbanion formation by a base catalyst are highly desired because only proton transfer occurs between a substrate and a product, which means that the atom economy is perfect (100 %).[2] Recently, much effort in this area has led to the development of highly stereoselective reactions, including asymmetric variants of carbon–carbon bond formation.[3] In the base-catalyzed reactions, alkylnitriles are promising carbon pronucleophiles because the nitrile part can be transformed into several useful functional groups such as carboxylic acid, ester, amide, and aminomethyl groups.[4] However, without any activating group at the a-position, hydrogen atoms at the a-position of alkylnitriles are less acidic (pKa ca. 33 in DMSO) compared with typical carbanion precursors employed in several kinds of base-catalyzed reactions, even though the nitrile group itself has an effective electron-withdrawing nature that can stabilize a carbanion at the a-position.[5] Therefore, the introduction of further activating groups at the a-position is normally required before such alkylnitriles can be used as pronucleophiles, and successful examples of [a] Dr. Y. Yamashita, I. Sato, H. Suzuki, Prof. Dr. S. Kobayashi Department of Chemistry, School of Science The University of Tokyo Hongo, Bunkyo-ku, Tokyo (Japan) E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/asia.201500405. Chem. Asian J. 2015, 10, 2143 – 2146
catalytic asymmetric reactions conducted using simple alkylnitriles without any activating group at the a-position have been limited.[6] Verkade et al. reported catalytic aldol-type reactions and further transformations of alkylnitriles, including acetonitrile, by using an organosuperbase, proazaphosphatrane, as catalyst.[7] Knochel et al. also reported potassium tert-butoxidecatalyzed addition reactions of alkylnitriles to stylene derivatives.[8] Shibasaki and Kumagai et al. investigated catalytic carbon–carbon bond-forming reactions of simple alkylnitriles and revealed that Cu, Ru, and Rh catalyst systems were effective for aldol-type and Mannich-type reactions, including asymmetric variants.[9] Ozerov et al.,[10] Noyori and Saito et al.,[11] and Guan et al.[12] all reported aldol-type reactions of alkylnitriles using Ni or Rh catalysts. Oudeyer and Levacher et al. also reported direct-type Mannich reactions of alkylnitriles.[13] Recently, Cai et al. reported catalytic enantioselective aldol-type reactions of acetonitrile with isatin derivatives.[14] To our knowledge, however, catalytic asymmetric direct-type 1,4-addition reactions of simple alkylnitriles that do not have an activating group at the a-position have not been reported even in a nonasymmetric variant. Recently, our group has been investigating catalytic carbon– carbon bond-forming reactions of less acidic carbon pronucleophiles based on a concept of “product base mechanism”, in which an intermediate with a strong Brønsted basicity works as a base to deprotonate the next substrate directly to form a reactive nucleophile without catalyst regeneration.[15, 16] It was demonstrated that esters without any activating group at the a-position successfully reacted with N-arylimines to afford the desired Mannich adducts in high yields by using a catalytic amount of potassium hydride (KH).[15a] We have also revealed quite recently that simple amides without any activating group at the a-position undergo catalytic 1,4-addition reactions with a,b-unsaturated amides by using KH or KHMDS as catalyst, and that the desired 1,5-dicarbonyl compounds were obtained in high yields.[15b] As further proof of concept, we wished to develop catalytic 1,4-addition reactions of simple alkylnitriles without any activating group at the a-position and to attempt to conduct the reaction under asymmetric catalysis conditions. We first examined the catalytic 1,4-addition reaction of propionitrile (2 a) with an a,b-unsaturated carbonyl compound. N,N-Dimethylcinnamamide (1 a) was chosen as an electrophile, which has been revealed to be a reactive 1,4-addition acceptor.[15b] Although the use of lithium hexamethyldisilazide (LiHMDS) and NaHMDS showed lower catalyst activity (Table 1,
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Communication Table 2. Catalytic asymmetric 1,4-addition reactions of propionitrile.[a]
Table 1. Catalytic 1,4-addition reactions of propionitrile using metal amides as catalysts.[a]
Entry
Base
Additive
Solvent
Yield [%][b]
Anti/syn[c]
1[d] 2[d] 3 4 5 6 7
LiHMDS NaHMDS KHMDS KHMDS KHMDS KHMDS KHMDS
– – – – – – 18-Crown-6
toluene toluene toluene THF TBME CPME toluene
trace[e] 3[e] 73 65 83 84 89
– – 78:22 71:29 77:23 78:22 74:26
[a] The reaction of 1 a (0.400 mmol) with 2 a (0.800 mmol, 2.0 equiv) was performed for 18 h at 0.2 m in the presence of a catalyst prepared from M-HMDS (0.0400 mmol, 10 mol %) unless otherwise noted. [b] Isolated yield as a mixture of both diastereoisomers. [c] Determined by 1H NMR spectroscopic analysis of the crude mixture. [d] 0.13 m. [e] Determined by 1 H NMR analysis.
entries 1, 2), to our delight, the desired reaction proceeded smoothly with KHMDS as catalyst, and both good yield and good diastereoselectivity were obtained (entry 3). Further investigation of solvents was then conducted, and it was found that ether solvents such as THF, tert-butyl methyl ether (TBME), and cyclopentyl methyl ether (CPME), showed similar results to those obtained with toluene (entries 4–6). The inclusion of 18crown-6 ether as an additive to coordinate potassium cations had a positive effect in this reaction, and enhancement of reactivity was observed (entry 7). It should be noted that this is the first successful example of a catalytic direct-type 1,4-addition reaction of propionitrile without any activating group at the aposition. We then examined an asymmetric variant of the catalytic 1,4-addition reaction. Chiral crown ethers are known to be good ligands for chiral modification of potassium cations. Although typical chiral crown ethers L1–L3 showed poor enantioselectivities, chiral macro crown ether L4 gave very promising stereoselectivities (Table 2, entry 4 and Figure 1). Quite recently, we have found that L4 is an excellent chiral ligand for creating effective an asymmetric environment around the potassium cation of KHMDS in catalytic asymmetric 1,4-addition reactions of simple amides and esters without any activating group at the a-position.[15b] The effect of solvents was then examined. Whereas reactions performed in THF showed poor enantioselectivity (entry 5), the use of a less polar ether solvent, TBME, gave a similar selectivity to that observed with toluene (entry 6). Other aromatic solvents, such as benzotrifluoride (BTF) and xylene, were further examined; however, the selectivities were not improved significantly (entries 7 and 8). The selectivities were improved by conducting the reaction at lower temperature (entry 9), and the yield was also improved by using 4 equivalents of 2 a and a shorter reaction time (entry 10). Finally, the best result was obtained by conducting the reaction at ¢78 8C (entry 11). The catalyst loading was further decreased without any significant loss of stereoselectivity (entry 12). Chem. Asian J. 2015, 10, 2143 – 2146
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Entry
Base
L
Solvent
T [8C]
Yield [%][b]
Anti/ syn[c]
ee (Anti)
1 2 3 4[d] 5[d,e] 6 7[g] 8[g] 9 10[h,i] 11[h,i] 12[h,j]
KHMDS KHMDS KHMDS KHMDS KHMDS KHMDS KHMDS KHMDS KHMDS KHMDS KHMDS KHMDS
R-L1 S-L2 S-L3 S-L4[f] S-L4[f] S-L4[f] S-L4[f] S-L4[f] S-L4[f] S-L4[f] S-L4[f] R-L4
toluene toluene toluene toluene THF TBME BTF xylene toluene toluene toluene toluene
¢40 ¢40 ¢40 ¢40 ¢40 ¢40 ¢20 ¢20 ¢60 ¢60 ¢78 ¢78
63 65 90 61 62[c] 48[c] 55[c] 73 66 86 82 84
79:21 78:22 77:23 80:20 92:8 84:16 71:29 76:24 81:19 79:21 93:7 93:7
33 4 10 51 28 47 35 47 58 57 62 61[k]
[a] The reaction of 1 a (0.400 mmol) with 2 a (0.800 mmol, 2.0 equiv) was performed for 18 h at 0.13 m in the presence of a catalyst prepared from M-HMDS (0.0400 mmol, 10 mol %) with ligand L (0.0440 mmol, 11 mol %) unless otherwise noted. [b] Isolated yield as a mixture of both diastereoisomers. [c] Determined by 1H NMR spectroscopic analysis of the crude mixture. [d] 24 h. [e] 0.2 m. [f] S-L4 (5.5 mol %) was used. [g] 20 h. [h] 2 a (4.0 equiv) was used. [i] 3 h. [j] R-L4 (2.8 mol %) and KHMDS (5.0 mol %) were used. [k] Opposite enantiomer was obtained compared to the reactions in entries 1–11.
Figure 1. Chiral crown ethers used in this study.
The substrate scope of this reaction was then examined (Table 3). The reactions of 1 a–f, bearing different aryl substituents at the b-position, were first conducted. The o-tolyl group (1 b) was found to decrease the diastereoselectivity, but the enantioselectivity was improved slightly (entry 2). The presence of a m-tolyl group (1 c) decreased the enantioselectivity, and a p-tolyl group (1 d) also affected the diastereoselectivity (entries 3 and 4). The presence of an electron-donating MeO group (1 e) did not lead to a significant improvement in either diastereo- or enantioselectivity (entry 5). The use of substrates with an electron-withdrawing p-bromo group (1 f) decreased the yield and both the diastereo- and enantioselectivities (entry 6). The bulky aromatic 2-naphthyl substituent of 1 g also led to a decrease in both yield and selectivities (entry 7). Substrate 1 h, bearing a heteroaromatic 2-furyl group, worked well, affording the desired product in good yield with good diastereoselectivity and moderate enantioselectivity (entry 8). The a,b-unsaturated amide (1 i), bearing a cyclohexyl group at the b-position, showed high reactivity but lower diastereo- and enantioselectivities (entry 9). It was also found that other alkyl-
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Communication tion, propionitrile (2 a, 111 mL, 1.60 mmol) and N,N-dimethylcinnamamide (1 a, 70.1 mg, 0.400 mmol), which were put in another flame-dried tube inside the glove box, were added to the flask through a cannula with extra toluene (2.0 mL). The whole mixture was stirred for 18 h at ¢78 8C. The reaction was quenched with H2O (1.0 mL) and extracted with CH2Cl2 (10 mL) three times. The organic layers were combined and dried over anhydrous Na2SO4. After filtration and concentration under reduced pressure, the crude product was obtained. The crude product was purified by silica-gel preparative TLC (hexane/EtOAc) to afford the desired 1,4adduct 3 aa (84 %, 77.6 mg, 0.337 mmol). The diastereomer ratio (d.r.) was determined by 1H NMR spectroscopic analysis of the crude product. The relative stereochemical assignment was determined by NMR analysis.[17] The enantioselectivity was determined by chiral HPLC analysis. The absolute configuration was determined by analogy to 3 ab. The absolute configuration of 3 ab was determined by transforming it into a literature-known compound (see the Supporting Information).[18] Absolute configurations of other products were also determined by analogy to 3 ab.
Table 3. Substrate scope.[a]
Entry R1
R2, R3
3
Yield [%][b] Anti/ syn[c]
ee [%][d]
1 2 3e 4 5 6[e,h,i] 7[f,g,h,i] 8[e] 9[j] 10 11[e,h,i] 12
Me,H (2 a) Me,H (2 a) Me,H (2 a) Me,H (2 a) Me,H (2 a) Me,H (2 a) Me,H (2 a) Me,H (2 a) Me,H (2 a) Et,H (2 b) Me,Me (2 c)[l] H,H (2 d)[m]
3 aa 3 ba 3 ca 3 da 3 ea 3 fa 3 ga 3 ha 3 ia 3 ab 3 ac 3 ad
86 80 79 83 83 61 69 82 quant. 83 71 messy
61 65 55 60 65 46 53 50 45 70 33 –
Ph (1 a) o-MeC6H4 (1 b) m-MeC6H4 (1 c) p-MeC6H4 (1 d) p-MeOC6H4 (1 e) p-BrC6H4 (1 f) 2-naphthyl (1 g) 2-furyl (1 h) Cy (1 i) Ph (1 a) Ph (1 a) Ph (1 a)
93:7 75:25 92:8 83:17 82:18 73:27 77:23 84:16 54:46[k] > 99:1 – –
[a] The reaction of 1 a (0.400 mmol) with alkylnitrile 2 (1.60 mmol, 4.0 equiv) was performed at ¢78 8C for 18 h at 0.13 m in the presence of a catalyst prepared from KHMDS (0.0200 mmol, 5 mol %) and ligand R-L4 (0.0112 mmol, 2.8 mol %) unless otherwise noted. [b] Isolated yield as a mixture of both diastereoisomers. [c] Determined by 1H NMR spectroscopic analysis of the crude mixture. [d] Determined by HPLC analysis. [e] 0.2 m. [f] 0.1 m. [g] 24 h. [h] Reaction was conducted at ¢60 8C. [i] KHMDS (10 mol %) and R-L4 (5.5 mol %) were used. [j] 0.4 m. [k] Determined by HPLC analysis of the target product mixture after isolation. [l] 4.7 equiv of 2 c was used. [m] 19 equiv of 2 d was used.
Acknowledgements This work was partially supported by a Grant-in-Aid for Science Research from the Japan Society for the Promotion of Science (JSPS), Global COE Program, The University of Tokyo, MEXT, Japan, and the Japan Science and Technology Agency (JST). I.S. and H.S. thank the MERIT program, The University of Tokyo for financial support.
nitriles worked well, and higher diastereoselectivities (> 99:1) and the best enantioselectivity were obtained when butyronitrile (2 b) was used (entry 10); the use of isobutyronitrile (2 c), as an alkylnitrile with more steric bulk, gave lower enantioselectivity (entry 11). The simplest alkylnitrile, acetonitrile (2 d), was also tested; however, the reaction system was very messy, and no desired product was obtained (entry 12). In conclusion, we have developed catalytic 1,4-addition reactions of alkylnitriles that do not bear an activating group at the a-position. It was found that the desired reaction of simple alkylnitriles with a,b-unsaturated amides proceeded in high yields with good diastereoselectivities by using KHMDS as catalyst. Moreover, the asymmetric 1,4-addition reactions proceeded in high yields with good diastereo- and enantioselectivities. To our knowledge, these are the first examples of catalytic asymmetric 1,4-addition reactions of alkylnitriles. Studies to improve the selectivity of the reaction are ongoing in our laboratory.
Keywords: 1,4-addition · asymmetric synthesis · catalyst · nitrile · strong base
Experimental Section Typical experimental procedure for the asymmetric 1,4-addition reaction of propionitrile (Table 2, entry 12) KHMDS (4.1 mg, 2.1 Õ 10¢2 mmol) and binaphtho-34-crown-10 (RL4, 9.7 mg, 1.1 Õ 10¢2 mmol) were placed in a flame-dried 10 mL flask inside a glove box filled with argon. The flask was cooled to ¢78 8C, then toluene (1.0 mL) was added. The reaction mixture was stirred for 1 h at the same temperature. After catalyst preparaChem. Asian J. 2015, 10, 2143 – 2146
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Manuscript received: April 18, 2015 Accepted Article published: May 8, 2015 Final Article published: June 1, 2015
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