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Cite this: Chem. Commun., 2013, 49, 11227 Received 17th September 2013, Accepted 10th October 2013

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Direct catalytic asymmetric addition of acetonitrile to N-thiophosphinoylimines† Yuji Kawato,ab Naoya Kumagai*a and Masakatsu Shibasaki*ac

DOI: 10.1039/c3cc47117a www.rsc.org/chemcomm

Direct catalytic addition of acetonitrile pronucleophiles to thiophosphinoylimines is described. Soft Lewis acid–hard Brønsted base cooperative catalysis is crucial to promote this elusive carbon– carbon bond-forming reaction in an enantioselective fashion.

Enantioselective catalysis for carbon–carbon bond-forming reactions to construct enantioenriched carbon frameworks has been a sustained subject in organic chemistry. In contrast to extensive research devoted to catalytic carbon–carbon bond formation based on enolate nucleophiles,1 the catalytic asymmetric addition of a-cyano carbanions derived from nitriles has been much less explored.2 The rich chemistry of enolate as a privileged carbon nucleophile fostered the development of direct-type catalytic asymmetric addition of unmodified enolate precursors, in which enolates are catalytically generated in situ and undergo subsequent carbon–carbon bond-forming reactions. This directtype methodology obviates the mandatory preparation of enolate in a separate step and allows for atom-economical access to the identical reaction products. In contrast to the significant advances in direct-type reactions of carbonyl-type enolate precursors,3,4 direct carbanion formation from alkylnitriles has been rarely achieved in a catalytic fashion because of their poorly acidic nature (e.g., CH3CN: pKa = 31.3 in DMSO5). In fact, acetonitrile and propionitrile, the simplest alkylnitriles, are generally regarded as inert chemical entities and frequently used as solvents. To circumvent the intrinsic reluctance of nitriles to generate a-cyano carbanions, appendages of anion-stabilizing substituents, e.g., electron-withdrawing groups, aromatic groups, and a vinyl group have been used (Fig. 1a). Indeed, the introduction of an aromatic or vinyl group significantly increases the acidity of the a-proton, and phenylacetonitrile and allylic cyanide have been exploited as a

Institute of Microbial Chemistry (BIKAKEN), Tokyo, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan. E-mail: [email protected], [email protected]; Fax: +81-3-3441-7589 b Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Tokyo, Japan c JST, ACT-C, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan † Electronic supplementary information (ESI) available: Experimental procedures and characterization of new compounds. See DOI: 10.1039/c3cc47117a

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Fig. 1 Direct catalytic asymmetric addition of nitrile pronucleophiles 2 to imines 1.

reactive pronucleophiles under mild basic conditions.6–8 However, only a limited number of catalytic systems that were able to promote the direct addition of alkylnitriles have been revealed, even in racemic reactions (Fig. 1b).9 In 2005, we reported direct catalytic asymmetric addition of acetonitrile to aldehydes using a catalyst consisting of CuOtBu and chiral phosphine ligands, in which the highest enantioselectivity was 77% ee.10 Obviously, the direct use of a low acidic alkylnitrile as a pronucleophile in catalytic asymmetric carbon–carbon bond-forming reactions is still in its infancy and, to the best of our knowledge, there is no report on a catalytic asymmetric direct addition of alkylnitrile to imines.11,12 In our continuing program on nitrile pronucleophiles, we envisaged the enantioselective addition of in situ-generated a-cyano carbanions derived from acetonitrile to N-thiophosphinoylimines. The simultaneous activation strategy through soft–soft interaction was the key to promote this elusive reaction in a catalytic manner. In our study on the Cu-based soft Lewis acid–hard Brønsted base cooperative catalytic system,13 we were convinced that Chem. Commun., 2013, 49, 11227--11229

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activation of the nitrile functionality by a soft Lewis acid allowed for the deprotonation of acetonitrile under mild basic conditions. To facilitate the subsequent addition to imines, we envisioned that using imines bearing a soft Lewis basic functionality leads to the productive association of activated nucleophiles and electrophiles around the soft Lewis acid in a chiral environment. In this context, we selected N-thiophosphinoylimine 3a 14 derived from benzaldehyde as the electrophile of choice and conducted an initial screening of the reaction conditions (Table 1). With 10 mol% of the cationic copper source [Cu(CH3CN)4]PF6 as the soft Lewis acid and KOtBu as the hard Brønsted base, various types of chiral bisphosphine ligands were screened (entries 1–9). Low conversion was observed in reactions with (R,R)-Ph-BPE and (R)-QuinoxP (entries 1 and 2). (R)-DTBM-Segphos and (R,Rp)-Walphos produced the desired adduct 4a in high yield, albeit with low enantioselectivity (entries 5 and 7). Ferrocene-embedded bisphosphine ligand (R,Rp)-Ph-Taniaphos gave the highest enantioselectivity (30% ee)

Table 1

Initial screeninga

Time Yieldb eec Solvent (h) (%) (%)

Entry Ligand

Base

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

DMF KOtBu DMF KOtBu DMF KOtBu t DMF KO Bu DMF KOtBu DMF KOtBu DMF KOtBu t KO Bu DMF KOtBu DMF KOtBu THF KOtBu CPMEd t KO Bu DMEe Et3N DME DBU DME Barton’s base DME Barton’s base DME — DME Barton’s base DME

(R,R)-Ph-BPE (R)-QunioxP (R)-BINAP (R)-Difluorphos (R)-DTBM-Segphos (R)-Josiphos (R)-Walphos (R,Rp)-Cy-Taniaphos (R,Rp)-Ph-Taniaphos (R,Rp)-Ph-Taniaphos (R,Rp)-Ph-Taniaphos (R,Rp)-Ph-Taniaphos (R,Rp)-Ph-Taniaphos (R,Rp)-Ph-Taniaphos (R,Rp)-Ph-Taniaphos (R,Rp)-Ph-Taniaphos (R,Rp)-Ph-Taniaphos —

24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 40 40 40

31 22 34 61 95 72 99 81 77 65 21 44 — 65 75 81 — —

Chem. Commun., 2013, 49, 11227--11229

Attempts at reaction using N-phosphinoylimine 5.

(entry 9), which was further improved to 44% ee by changing the solvent from DMF to DME (entry 12). Although Et3N was totally ineffective as the Brønsted base,15 amidine or guanidine base promoted the catalytic generation of a-cyano carbanions from acetonitrile and higher yields were obtained without affecting the enantioselectivity (entries 14 and 15). The use of MS 3A was beneficial to prevent hydrolysis of imine 3a and higher chemical yield was observed with prolonged reaction time (entry 16). No reaction proceeded at all in the absence of soft Lewis acid Cu(I) or Brønsted base, suggesting that cooperative catalysis was crucial to catalytic generation of the a-cyano carbanion (entries 17 and 18). Moreover, under the optimized reaction conditions (entry 16), the reaction using analogous N-phosphinoylimine 5 without the soft Lewis basic functionality barely proceeded (Fig. 2), indicating that the simultaneous activation of acetonitrile and N-thiophosphinoylimines was operative.

Table 2 Direct catalytic asymmetric addition of acetonitrile to N-thiophosphinoylimines 3a

6 24 8 5 17 16 13 7 30 36 45 44 — 43 43 47 — —

a 3a: 0.2 mmol, solvent–CH3CN = 5/1, 0.1 M in 3a. b Yield was determined by 1H NMR analysis with 1,1,2,2-tetrachloroethane as an internal standard. c ee was determined by HPLC analysis. Minus sign indicates the formation of the S enantiomer as the major enantiomer. d Cyclopentyl methyl ether. e 1,2-Dimethoxyethane. f MS 3A was used as an additive. DME–CH3CN = 10/1. g Without [Cu(CH3CN)4]PF6.

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Fig. 2

a 3: 0.2 mmol, DME–CH3CN = 10/1, 0.1 M in 3. Isolated yields are shown.

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Fig. 3

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Transformation of the product.

Table 2 summarizes the substrate scope of the reaction. Imines bearing an ortho-substituent exhibited very low reactivity. Similar enantioselectivity to 4a was observed in the reactions using the imines without heteroatom functional groups (entries 1–3). Halogenated imines generally gave the corresponding product with slightly inferior enantioselectivity (entries 4–9). Catalyst loading could be reduced to 5 mol% without affecting the yield and ee (entry 5).16 Imines having the m-MeO substituent gave the corresponding adduct in 66% yield with the highest enantioselectivity (52% ee) (entry 10). Imines derived from heteroaromatic aldehydes afforded enantioselectivity above 50% ee, albeit with moderate yield (entries 12 and 13). The thiophosphinoyl group on nitrogen was readily removed by treatment with 4 N HCl–1,4-dioxane at 60 1C to give b-amino nitrile 7 (Fig. 3). The N-thiophosphinoyl group can serve as a protecting group. Nitrile was diversely transformed into primary amine 8 and tetrazole 9 17 by reduction with Red-Al and cycloaddition with NaN3, respectively. In conclusion, a direct catalytic asymmetric addition of acetonitrile to imines was developed. Simultaneous activation of acetonitrile and N-thiophosphinoylimine was the key to promote the elusive reaction in an enantioselective fashion. Although the yield and enantioselectivity were moderate, this work is an important first step towards this unprecedented reaction. This work was financially supported by JST, ACT-C, and KAKENHI (25713002) from JSPS. YK thanks JSPS for a predoctoral fellowship.

Notes and references 1 (a) Comprehensive Organic Synthesis, ed. B. M. Trost, I. Fleming and C.-H. Heathcock, Pergamon, Oxford, 1991, vol. 2; (b) Modern Aldol Reaction, ed. R. Mahrwald, Wiley-VCH, Weinheim, 2004. 2 For reviews: (a) S. Arseniyadis, K. S. Kyler and D. S. Watt, Org. React., 1984, 31, 1; (b) F. F. Fleming and B. C. Shook, Tetrahedron, 2002, 58, 1; (c) J. G. Verkade and P. B. Kisanga, Aldrichimica Acta, 2004, 37, 3. 3 For reviews of direct catalytic asymmetric aldol reactions, see: (a) B. Alcaide and P. Almendros, Eur. J. Org. Chem., 2002, 1595; (b) W. Notz, F. Tanaka and C. F. Barbas III, Acc. Chem. Res., 2004, 37, 580; (c) S. Mukherjee, J. W. Yang, S. Hoffmann and B. List, Chem. Rev., 2007, 107, 5471; (d) B. M. Trost and C. S. Brindle, Chem. Soc. Rev., 2010, 39, 1600.

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4 For reviews of direct Mannich(-type) reactions, see: (a) M. M. B. Marques, Angew. Chem., Int. Ed., 2006, 45, 348; (b) A. Ting and S. E. Schaus, Eur. J. Org. Chem., 2007, 5797; (c) J. M. M. Verkade, L. J. C. van Hemert, P. J. L. M. Quaedflieg and F. P. J. T. Rutjes, Chem. Soc. Rev., 2008, 37, 29. 5 F. G. Bordwell, Acc. Chem. Res., 1988, 21, 456. 6 Examples of catalytic asymmetric addition using benzylnitriles: ´, Org. Lett., 2008, (a) J. Aydin, C. S. Conrad and K. J. Szabo 10, 5175; (b) K. Hyodo, S. Nakamura, K. Tsuji, T. Ogawa, Y. Funahashi and N. Shibata, Adv. Synth. Catal., 2011, 353, 3385. 7 Examples of catalytic asymmetric addition using allyl cyanide: (a) R. Yazaki, T. Nitabaru, N. Kumagai and M. Shibasaki, J. Am. Chem. Soc., 2008, 130, 14477; (b) R. Yazaki, N. Kumagai and M. Shibasaki, J. Am. Chem. Soc., 2009, 131, 3195; (c) R. Yazaki, N. Kumagai and M. Shibasaki, J. Am. Chem. Soc., 2010, 132, 5522; (d) Y. Yanagida, R. Yazaki, N. Kumagai and M. Shibasaki, Angew. Chem., Int. Ed., 2011, 50, 7910; (e) Y. Otsuka, H. Takada, S. Yasuda, N. Kumagai and M. Shibasaki, Chem.–Asian J., 2013, 8, 354. 8 A review on silyl ketene imines as an alternative for a-cyanocarbanions: S. E. Denmark and T. W. Wilson, Angew. Chem., Int. Ed., 2012, 51, 9980. 9 Selected examples on catalytic generation of active nucleophile from alkylnitriles: (a) B. A. D’Sa, P. Kisanga and J. G. Verkade, J. Org. Chem., 1998, 63, 3961; (b) P. Kisanga, D. McLeod, B. D’Sa and J. G. Verkade, J. Org. Chem., 1999, 64, 3090; (c) A. L. Rodriguez, T. Bunlaksananusorn and P. Knochel, Org. Lett., 2000, 2, 3285; (d) P. Kisanga and J. G. Verkade, J. Org. Chem., 2000, 65, 5431; (e) P. Kisanga and J. G. Verkade, Tetrahedron, 2001, 57, 467; ( f ) J. G. Verkade and P. Kisanga, Tetrahedron, 2003, 59, 7819; ( g) Y. Suto, N. Kumagai, S. Matsunaga, M. Kanai and M. Shibasaki, Org. Lett., 2003, 5, 3147; (h) N. Kumagai, S. Matsunaga and M. Shibasaki, J. Am. Chem. Soc., 2004, 126, 13632; (i) L. Fan and O. V. Ozerov, Chem. Commun., 2005, 4450; ( j) N. Kumagai, S. Matsunaga and M. Shibasaki, Chem. Commun., 2005, 3600; (k) N. Kumagai, S. Matsunaga and M. Shibasaki, Tetrahedron, 2007, 63, 8598; (l ) A. Goto, K. Endo, Y. Ukai, S. Irle and S. Saito, Chem. Commun., 2008, 2212; (m) T. Poisson, V. Gembus, S. Oudeyer, F. Marsais and V. Levacher, J. Org. Chem., 2009, 74, 3516; (n) A. Goto, H. Naka, R. Noyori and S. Saito, Chem.–Asian J., 2011, 6, 1740; (o) S. Chakraborty, Y. J. Patel, J. A. Krause and H. Guan, Angew. Chem., Int. Ed., 2013, 52, 7523. 10 Y. Suto, R. Tsuji, M. Kanai and M. Shibasaki, Org. Lett., 2005, 7, 3757. 11 For catalytic addition of a-trimethylsilylnitrile to imines in racemic system: (a) Y. Kawano, H. Fujisawa and T. Mukaiyama, Chem. Lett., 2005, 1134; (b) T. Mukaiyama and M. Michida, Chem. Lett., 2007, 1244. For catalytic addition of allylic cyanides to imines in racemic ´, Org. Lett., 2008, 10, 2881; For system: (c) J. Aydin and K. J. Szabo catalytic decarboxylative addition of a-cyanoacetic acids to imines in racemic system: (d) J. C. Pelletier and M. P. Cava, Synthesis, 1987, 474; For catalytic asymmetric decarboxylative addition of a-cyanoacetic acids to imines; (e) L. Yin, M. Kanai and M. Shibasaki, J. Am. Chem. Soc., 2009, 131, 9610; ( f ) L. Yin, M. Kanai and M. Shibasaki, Tetrahedron, 2012, 68, 3497; (g) K. Hyodo, M. Kondo, Y. Funahashi and S. Nakamura, Chem.–Eur. J., 2013, 19, 4128. 12 For catalytic addition of non-activated alkylnitrile to imines in racemic system: see ref. 9h, k. 13 N. Kumagai and M. Shibasaki, Angew. Chem., Int. Ed., 2011, 50, 4760. 14 X. Xu, C. Wang, Z. Zhou, Z. Zeng, X. Ma, G. Zhao and C. Tang, Heteroat. Chem., 2008, 19, 238. ´ro, J. Chem. Soc., Perkin 15 D. H. R. Barton, J. D. Elliott and S. D. Ge Trans. 1, 1982, 2085. 16 Lower catalyst loading retarded the imine decomposition during the reaction and similar chemical yield was observed. 17 H. Yoneyama, Y. Usami, S. Komeda and S. Harusawa, Synthesis, 2013, 1051.

Chem. Commun., 2013, 49, 11227--11229

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Direct catalytic asymmetric addition of acetonitrile to N-thiophosphinoylimines.

Direct catalytic addition of acetonitrile pronucleophiles to thiophosphinoylimines is described. Soft Lewis acid-hard Brønsted base cooperative cataly...
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