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DOI: 10.1055/s-0033-1341241
Synthesis of 3,3-Disubstituted 2-Aminoindolenines by Palladium-Catalyzed Allylic Amidination with Isocyanide
Publication History
Received: 19 February 2014
Accepted after revision: 24 March 2014
Publication Date:
30 April 2014 (online)
Abstract
Synthesis of 3,3-disubstituted 2-aminoindolenines was achieved by palladium-catalyzed allylic amidination with an isocyanide. It was found that isocyanides are effective building blocks in palladium-catalyzed allylic functionalizations, analogous to carbon monoxide. This approach enables the direct construction of the indolenine ring along with the formation of a quaternary carbon and the introduction of an amino substituent in one step under mild conditions.
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3,3-Disubstituted indole skeletons are one of the most important structures in alkaloid chemistry and are present in a wide range of natural products and pharmaceuticals.[1] Among these derivatives, 3,3-disubstituted 2-aminoindolenines and 2-aminoindolines are substructures found in biologically active natural products such as flustramine C,[2] perophoramidine,[3] and quinadoline B[4] (Figure [1]). These compounds are structurally complex, and much effort has been put into the synthetic study toward them.[5] There are three key aspects in the synthesis of 3,3-disubstituted 2-aminoindolenines; (i) construction of the indole ring, (ii) formation of the quaternary carbon at the 3-position, and (iii) introduction of the amino substituent at the 2-position (Scheme [1]). A direct, one-step method would be an efficient approach to these structures, but to date there have been no published reports on the direct construction of 3,3-disubstituted 2-aminoindolenines.
Our group has previously developed a synthetic method for indole derivatives which involves the formation of a C2–C3 bond.[6] Based on this characteristic retrosynthetic analysis, the efficient construction of various 3,3-disubstituted indole derivatives was achieved. We also applied this strategy to the synthesis of 2-iminoindolines via SmI2-mediated reductive cyclization of carbodiimides.[6b] Although this method is an effective approach for 3,3-disubstituted 2-aminoindolenine derivatives, stepwise introduction of the nitrogen unit and construction of the indolenine skeleton was required, meaning a one-step method was still needed. Herein we describe a direct and general approach for the construction of 3,3-disubstituted 2-aminoindolenines by palladium-catalyzed allylic amidination with an isocyanide (Scheme [1]).
a Yield of isolated product.
b Pd(PPh3)4 was used instead of Pd(dba)2.
c 10 mol % of ligand were used.
d The reaction was performed at 50 °C.
e Conditions: 5 mol% of Pd(dba)2 and 10 mol% of (2-furyl)3P were used.
f Conditions: 2 mol% of Pd(dba)2 and 4 mol% of (2-furyl)3P were used.
The reaction shown in Scheme [1] was designed to develop the direct method. Reaction of isocyanide 1 bearing an allyl ester moiety with an amine in the presence of a palladium catalyst would give 3,3-disubstituted 2-aminoindolenine 2 via oxidative addition and allylic amidination. Recent publications disclosed that isocyanides are useful building blocks for multicomponent reactions (e.g., Passerini and Ugi reactions) as well as for palladium-catalyzed reactions.[7] [8] [9] [10] However, there are only a few reports of palladium-catalyzed allylic functionalization reactions with isocyanides, unlike the well-developed chemistry of carbon monoxide, which is isoelectronic with an isocyanide.[11] Usually, palladium-catalyzed allylic functionalization reactions occur at the less sterically hindered site.[11a] [d] Our approach, however, would enable the formation of a quaternary carbon at the more sterically hindered site under mild conditions, owing to intramolecular cyclization. This method would also enable the introduction of various amino substituents at the 2-position by using a range of amines.
To investigate the allylic amidination, we synthesized substrate 1a bearing an isocyanide and an allyl carbonate moiety.[12] Treatment of 1a with piperidine and 10 mol% of Pd(PPh3)4 in toluene at room temperature afforded 2-aminoindolenine 2a in 18% yield (Table [1], entry 1). Using Pd(dba)2 and Ph3P instead of Pd(PPh3)4 increased the yield of 2a to 35% (Table [1], entry 2). Next, several ligands were screened. It was found that monodentate triarylphosphines were effective, and (2-furyl)3P gave the best results in this reaction (Table [1], entries 3–6), however, the yield of 2a was still below 50%. We assumed that the low yields were caused by high reactivity of the allyl carbonate moiety in substrate 1a, thus substrate 1b bearing an allyl acetate moiety was used instead. As a result, the yield of the desired product 2a increased to 55% (Table [1], entry 7). When substrate 1a was used, additional base was not necessary for this reaction, but the addition of two equivalents of Et3N when using 1b increased the yield of 2a (Table [1], entries 7, 8). Further optimization revealed that THF was the best solvent (Table [1], entries 9–13). Although lowering the amount of catalyst slightly decreased the yield of 2a, catalyst loadings as low as 2 mol% were sufficient for complete conversion (Table [1], entries 14, 15).
Next we investigated the substrate scope of the reaction under the optimal conditions (Scheme [2]).[13] [14] Initially, a range of amines were examined as the nucleophile. The reactions of simple cyclic amines gave the desired products 2b and 2c in 58% and 50% yields, respectively. Morpholine could also be used in this reaction (2d). The reaction of acyclic amines such as diethylamine and benzylmethylamine also gave good results (2e and 2f). However, using a primary amine gave a low yield of the desired 2-aminoindolenine 2g. When N-methylaniline was used, the desired product 2h was not obtained, probably because of the weaker nucleophilicity. Next the reaction was performed using several isocyanides. The reactions of substrates bearing trifluoromethyl and methoxy groups at the para position of the aromatic ring gave the corresponding products 2i and 2j in 45% and 69% yields, respectively. An alkyl substituent on the olefin did not significantly influence the yield of the products (2k and 2l).
Next we performed the reactions using a chiral amine and an allyl acetate 1g derived from a secondary alcohol (Scheme [3]). The optimal conditions were applied to the reaction using l-proline methyl ester as the nucleophile and interestingly, the desired product 2m was obtained as a 3:1 mixture of diastereomers at the 3-position of the indolenine ring (Scheme [3], eq 1). This result indicates that the configuration of the quaternary carbon was influenced by the steric effect of the nucleophile. When allyl acetate 1g was used, the desired product 2n was obtained as a 2:1 mixture of olefin geometric isomers (Scheme [3], eq 2).
A plausible mechanism is shown in Scheme [4]. Firstly, oxidative addition of allyl acetate 1b to palladium(0) generates allylpalladium complex A. There are two possibilities for the next step. One is that intramolecular isocyanide insertion proceeds to form intermediate B, and then C–N reductive elimination regenerates the palladium(0) species and affords the desired 2-aminoindolenine 2a (path A). The other possibility is that nucleophilic addition to the isocyanide, activated by the palladium(II), occurs to give palladacycle C followed by C–C reductive elimination (path B). Path B is analogous to the proposed catalytic cycle of the palladium-catalyzed decarboxylative cyclization reaction reported by Hayashi and co-workers.[11a] Considering the scope of this reaction and the nucleophilicity of the amine to isocyanide of intermediate A, we believe that path B is dominant.[15]
In summary, we have developed the synthesis of 3,3-disubstituted 2-aminoindolenine derivatives by palladium-catalyzed allylic amidination of isocyanides. This approach enables the direct construction of an indolenine ring along with the formation of a quaternary carbon and introduction of an amino substituent under mild conditions. We are currently investigating the mechanistic detail of the reaction and extending the strategy to an asymmetric reaction.
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Acknowledgment
This work was supported by a Grant-in-Aid for Scientific Research on the Innovation Area ‘Molecular Activation Directed toward Straightforward Synthesis’ from The Ministry of Education, Culture, Sports, Science and Technology, Japan (C.T.), and JSPS Research Fellowships for Young Scientists (T.N.).
Supporting Information
- for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synlett.
- Supporting Information
-
References and Notes
- 1a Dewick PM. Medicinal Natural Products: A Biosynthetic Approach. John Wiley and Sons; Chichester: 2009. 3rd ed. 311-420
- 1b Heterocyclic Scaffolds II: Reactions and Applications of Indole. In Topics in Heterocyclic Chemistry. Vol. 26. Gribble GW. Springer; Berlin: 2010
- 1c Eckermann R, Gaich T. Synthesis 2013; 45: 2813
- 1d Ishikura M, Abe T, Choshi T, Hibino S. Nat. Prod. Rep. 2013; 30: 694
- 2 Carlé JS, Christophersen C. J. Org. Chem. 1981; 46: 3440
- 3 Verbitski SM, Mayne CL, Davis RA, Concepcion GP, Ireland CM. J. Org. Chem. 2002; 67: 7124
- 4 Koyama N, Inoue Y, Sekine M, Hayakawa Y, Homma H, Ōmura S, Tomoda H. Org. Lett. 2008; 10: 5273
- 5a Kawasaki T, Shinada M, Ohzono M, Ogawa A, Terashima R, Sakamoto M. J. Org. Chem. 2008; 73: 5959
- 5b Lindel T, Bräuchle L, Golz G, Böhrer P. Org. Lett. 2007; 9: 283
- 5c Fuchs JR, Funk RL. Org. Lett. 2005; 7: 677
- 5d Zhang H, Hong L, Kang H, Wang R. J. Am. Chem. Soc. 2013; 135: 14098
- 5e Wu H, Xue F, Xiao X, Qin Y. J. Am. Chem. Soc. 2010; 132: 14052
- 5f Fuchs JR, Funk RL. J. Am. Chem. Soc. 2004; 126: 5068
- 5g Ishida T, Ikota H, Kurahashi K, Tsukano C, Takemoto Y. Angew. Chem. Int. Ed. 2013; 52: 10204
- 5h Wu M, Ma D. Angew. Chem. Int. Ed. 2013; 52: 9759
- 6a Tsukano C, Okuno M, Takemoto Y. Chem. Lett. 2013; 42: 753
- 6b Ishida T, Tsukano C, Takemoto Y. Chem. Lett. 2012; 41: 44
- 6c Hande SM, Nakajima M, Kamisaki H, Tsukano C, Takemoto Y. Org. Lett. 2011; 13: 1828
- 6d Yasui Y, Kamisaki H, Takemoto Y. Org. Lett. 2008; 10: 3303
- 6e Kobayashi Y, Kamisaki H, Yanada R, Takemoto Y. Org. Lett. 2006; 8: 2711
- 7a Vlaar T, Ruijter E, Maes BU. W, Orru RV. A. Angew. Chem. Int. Ed. 2013; 52: 7084
- 7b Qiu G, Ding Q, Wu J. Chem. Soc. Rev. 2013; 42: 5257
- 7c Lang S. Chem. Soc. Rev. 2013; 42: 4867
- 7d Tobisu M, Chatani N. Chem. Lett. 2011; 40: 330
- 7e Lygin AV, de Meijere A. Angew. Chem. Int. Ed. 2010; 49: 9094
- 8a Kobayashi K, Iitsuka D, Fukamachi S, Konishi H. Tetrahedron 2009; 65: 7523
- 8b Tokuyama H, Fukuyama T. Chem. Rec. 2002; 2: 37
- 8c Fukuyama T, Chen X, Peng G. J. Am. Chem. Soc. 1994; 116: 3127
- 8d Jones WD, Kosar WP. J. Am. Chem. Soc. 1986; 108: 5640
- 8e Ito Y, Kobayashi K, Seko N, Saegusa T. Bull. Chem. Soc. Jpn. 1984; 57: 73
- 8f Ito Y, Kobayashi K, Saegusa T. J. Am. Chem. Soc. 1977; 99: 3532
- 9a Estévez V, Baelen GV, Lentferink BH, Vlaar T, Janssen E, Maes BU. W, Orru RV. A, Ruijter E. ACS Catal. 2014; 4: 40
- 9b Liu B, Gao H, Yu Y, Wu W, Jiang H. J. Org. Chem. 2013; 78: 10319
- 9c Vlaar T, Cioc RC, Mampuys P, Maes BU. W, Orru RV. A, Ruijter E. Angew. Chem. Int. Ed. 2012; 51: 13058
- 9d Tyagi V, Khan S, Giri A, Gauniyal HM, Sridhar B, Chauhan PM. S. Org. Lett. 2012; 14: 3126
- 9e Wang Y, Zhu Q. Adv. Synth. Catal. 2012; 354: 1902
- 9f Qiu G, Liu G, Pu S, Wu J. Chem. Commun. 2012; 48: 2903
- 9g Baelen GV, Kuijer S, Rýček L, Sergeyev S, Janssen E, de Kanter FJ. J, Maes BU. W, Ruijter E, Orru RV. A. Chem. Eur. J. 2011; 17: 15039
- 9h Boissarie PJ, Hamilton ZE, Lang S, Murphy JA, Suckling CJ. Org. Lett. 2011; 13: 6256
- 9i Wang Y, Wang H, Peng J, Zhu Q. Org. Lett. 2011; 13: 4604
- 9j Miura T, Nishida Y, Morimoto M, Yamauchi M, Murakami M. Org. Lett. 2011; 13: 1429
- 9k Jiang H, Liu B, Li Y, Wang A, Huang H. Org. Lett. 2011; 13: 1028
- 9l Tobisu M, Imoto S, Ito S, Chatani N. J. Org. Chem. 2010; 75: 4835
- 9m Curran DP, Du W. Org. Lett. 2002; 4: 3215
- 9n Onitsuka K, Suzuki S, Takahashi S. Tetrahedron Lett. 2002; 43: 6197
- 9o Saluste CG, Whitby RJ, Furber M. Angew. Chem. Int. Ed. 2000; 39: 4156
- 10a Nanjo T, Tsukano C, Takemoto Y. Org. Lett. 2012; 14: 4270
- 10b Nanjo T, Yamamoto S, Tsukano C, Takemoto Y. Org. Lett. 2013; 15: 3754
- 11a Park S, Shintani R, Hayashi T. Chem. Lett. 2009; 38: 204
- 11b Kamijo S, Yamamoto Y. J. Am. Chem. Soc. 2002; 124: 11940
- 11c Kamijo S, Jin T, Yamamoto Y. J. Am. Chem. Soc. 2001; 123: 9453
- 11d Ohe K, Matsuda H, Ishihara T, Ogoshi S, Chatani N, Murai S. J. Org. Chem. 1993; 58: 1173
- 12 Substrates 1a and 1b were synthesized by Suzuki coupling of N-formyl-2-iodoaniline with vinyl boronic esters followed by formation of the carbonate or ester and then the isocyanide. See the Supporting Information for more detail.
- 13 General Procedure for the Synthesis of 3,3-Disubstituted 2-Aminoindolenines To a stirred solution of 1 (0.1 mmol), amine (0.2 mmol), and Et3N (0.028 mL, 0.201 mmol) in THF (2 mL) were added Pd(dba)2 (5.8 mg, 0.0101 mmol) and (2-furyl)3P (4.6 mg, 0.0198 mmol). After stirring for 12 h at r.t., the reaction mixture was diluted with toluene and extracted with 2 M aq HCl. The combined extracts were basified with 2 M aq NaOH and extracted with EtOAc. The resultant organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane–EtOAc) to give 2.
- 14 Analytical Data for 2a A colorless block, which was recrystallized from Et2O: mp 83.0–86.0 °C. 1H NMR (500 MHz, CDCl3): δ = 7.16–7.12 (m, 2 H), 6.92 (d, 1 H, J = 7.2 Hz), 6.86 (ddd, 1 H, J 1 = J 2 = 6.6 Hz, J 3 = 1.7 Hz), 5.90 (dd, 1 H, J 1 = 17.5 Hz, J 2 = 10.6 Hz), 5.35 (d, 1 H, J = 17.5 Hz), 5.22 (d, 1 H, J = 10.6 Hz), 3.71–3.63 (m, 4 H), 1.67–1.58 (m, 9 H). 13C NMR (126 MHz, CDCl3): δ = 176.2, 154.7, 140.6, 138.9, 128.1, 121.2, 120.8, 115.7, 113.6, 55.6, 47.4, 26.0, 24.3, 20.7. IR (ATR): 2934, 1632, 1542, 1458, 1448 cm–1. MS–FAB: m/z = 241 [M + H]+. HRMS–FAB+: m/z calcd for C16H21N2 [M + H]+: 241.1705; found: 241.1708.
- 15 As previously reported on the synthesis of amidines using palladium catalysis and isocyanides,9g,h path A is also possible. In this case, the diastereoselectivity of 2m would be derived from a selective reaction of one enantiomer of racemic B and l-proline methyl ester (i.e., matched pair).
Recent reviews:
For recent examples, see:
For recent reviews on the transformation of isocyanides, see:
For selected examples of indole synthesis using phenyl isocyanide, see:
For selected examples of palladium-catalyzed isocyanide insertion, see:
-
References and Notes
- 1a Dewick PM. Medicinal Natural Products: A Biosynthetic Approach. John Wiley and Sons; Chichester: 2009. 3rd ed. 311-420
- 1b Heterocyclic Scaffolds II: Reactions and Applications of Indole. In Topics in Heterocyclic Chemistry. Vol. 26. Gribble GW. Springer; Berlin: 2010
- 1c Eckermann R, Gaich T. Synthesis 2013; 45: 2813
- 1d Ishikura M, Abe T, Choshi T, Hibino S. Nat. Prod. Rep. 2013; 30: 694
- 2 Carlé JS, Christophersen C. J. Org. Chem. 1981; 46: 3440
- 3 Verbitski SM, Mayne CL, Davis RA, Concepcion GP, Ireland CM. J. Org. Chem. 2002; 67: 7124
- 4 Koyama N, Inoue Y, Sekine M, Hayakawa Y, Homma H, Ōmura S, Tomoda H. Org. Lett. 2008; 10: 5273
- 5a Kawasaki T, Shinada M, Ohzono M, Ogawa A, Terashima R, Sakamoto M. J. Org. Chem. 2008; 73: 5959
- 5b Lindel T, Bräuchle L, Golz G, Böhrer P. Org. Lett. 2007; 9: 283
- 5c Fuchs JR, Funk RL. Org. Lett. 2005; 7: 677
- 5d Zhang H, Hong L, Kang H, Wang R. J. Am. Chem. Soc. 2013; 135: 14098
- 5e Wu H, Xue F, Xiao X, Qin Y. J. Am. Chem. Soc. 2010; 132: 14052
- 5f Fuchs JR, Funk RL. J. Am. Chem. Soc. 2004; 126: 5068
- 5g Ishida T, Ikota H, Kurahashi K, Tsukano C, Takemoto Y. Angew. Chem. Int. Ed. 2013; 52: 10204
- 5h Wu M, Ma D. Angew. Chem. Int. Ed. 2013; 52: 9759
- 6a Tsukano C, Okuno M, Takemoto Y. Chem. Lett. 2013; 42: 753
- 6b Ishida T, Tsukano C, Takemoto Y. Chem. Lett. 2012; 41: 44
- 6c Hande SM, Nakajima M, Kamisaki H, Tsukano C, Takemoto Y. Org. Lett. 2011; 13: 1828
- 6d Yasui Y, Kamisaki H, Takemoto Y. Org. Lett. 2008; 10: 3303
- 6e Kobayashi Y, Kamisaki H, Yanada R, Takemoto Y. Org. Lett. 2006; 8: 2711
- 7a Vlaar T, Ruijter E, Maes BU. W, Orru RV. A. Angew. Chem. Int. Ed. 2013; 52: 7084
- 7b Qiu G, Ding Q, Wu J. Chem. Soc. Rev. 2013; 42: 5257
- 7c Lang S. Chem. Soc. Rev. 2013; 42: 4867
- 7d Tobisu M, Chatani N. Chem. Lett. 2011; 40: 330
- 7e Lygin AV, de Meijere A. Angew. Chem. Int. Ed. 2010; 49: 9094
- 8a Kobayashi K, Iitsuka D, Fukamachi S, Konishi H. Tetrahedron 2009; 65: 7523
- 8b Tokuyama H, Fukuyama T. Chem. Rec. 2002; 2: 37
- 8c Fukuyama T, Chen X, Peng G. J. Am. Chem. Soc. 1994; 116: 3127
- 8d Jones WD, Kosar WP. J. Am. Chem. Soc. 1986; 108: 5640
- 8e Ito Y, Kobayashi K, Seko N, Saegusa T. Bull. Chem. Soc. Jpn. 1984; 57: 73
- 8f Ito Y, Kobayashi K, Saegusa T. J. Am. Chem. Soc. 1977; 99: 3532
- 9a Estévez V, Baelen GV, Lentferink BH, Vlaar T, Janssen E, Maes BU. W, Orru RV. A, Ruijter E. ACS Catal. 2014; 4: 40
- 9b Liu B, Gao H, Yu Y, Wu W, Jiang H. J. Org. Chem. 2013; 78: 10319
- 9c Vlaar T, Cioc RC, Mampuys P, Maes BU. W, Orru RV. A, Ruijter E. Angew. Chem. Int. Ed. 2012; 51: 13058
- 9d Tyagi V, Khan S, Giri A, Gauniyal HM, Sridhar B, Chauhan PM. S. Org. Lett. 2012; 14: 3126
- 9e Wang Y, Zhu Q. Adv. Synth. Catal. 2012; 354: 1902
- 9f Qiu G, Liu G, Pu S, Wu J. Chem. Commun. 2012; 48: 2903
- 9g Baelen GV, Kuijer S, Rýček L, Sergeyev S, Janssen E, de Kanter FJ. J, Maes BU. W, Ruijter E, Orru RV. A. Chem. Eur. J. 2011; 17: 15039
- 9h Boissarie PJ, Hamilton ZE, Lang S, Murphy JA, Suckling CJ. Org. Lett. 2011; 13: 6256
- 9i Wang Y, Wang H, Peng J, Zhu Q. Org. Lett. 2011; 13: 4604
- 9j Miura T, Nishida Y, Morimoto M, Yamauchi M, Murakami M. Org. Lett. 2011; 13: 1429
- 9k Jiang H, Liu B, Li Y, Wang A, Huang H. Org. Lett. 2011; 13: 1028
- 9l Tobisu M, Imoto S, Ito S, Chatani N. J. Org. Chem. 2010; 75: 4835
- 9m Curran DP, Du W. Org. Lett. 2002; 4: 3215
- 9n Onitsuka K, Suzuki S, Takahashi S. Tetrahedron Lett. 2002; 43: 6197
- 9o Saluste CG, Whitby RJ, Furber M. Angew. Chem. Int. Ed. 2000; 39: 4156
- 10a Nanjo T, Tsukano C, Takemoto Y. Org. Lett. 2012; 14: 4270
- 10b Nanjo T, Yamamoto S, Tsukano C, Takemoto Y. Org. Lett. 2013; 15: 3754
- 11a Park S, Shintani R, Hayashi T. Chem. Lett. 2009; 38: 204
- 11b Kamijo S, Yamamoto Y. J. Am. Chem. Soc. 2002; 124: 11940
- 11c Kamijo S, Jin T, Yamamoto Y. J. Am. Chem. Soc. 2001; 123: 9453
- 11d Ohe K, Matsuda H, Ishihara T, Ogoshi S, Chatani N, Murai S. J. Org. Chem. 1993; 58: 1173
- 12 Substrates 1a and 1b were synthesized by Suzuki coupling of N-formyl-2-iodoaniline with vinyl boronic esters followed by formation of the carbonate or ester and then the isocyanide. See the Supporting Information for more detail.
- 13 General Procedure for the Synthesis of 3,3-Disubstituted 2-Aminoindolenines To a stirred solution of 1 (0.1 mmol), amine (0.2 mmol), and Et3N (0.028 mL, 0.201 mmol) in THF (2 mL) were added Pd(dba)2 (5.8 mg, 0.0101 mmol) and (2-furyl)3P (4.6 mg, 0.0198 mmol). After stirring for 12 h at r.t., the reaction mixture was diluted with toluene and extracted with 2 M aq HCl. The combined extracts were basified with 2 M aq NaOH and extracted with EtOAc. The resultant organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane–EtOAc) to give 2.
- 14 Analytical Data for 2a A colorless block, which was recrystallized from Et2O: mp 83.0–86.0 °C. 1H NMR (500 MHz, CDCl3): δ = 7.16–7.12 (m, 2 H), 6.92 (d, 1 H, J = 7.2 Hz), 6.86 (ddd, 1 H, J 1 = J 2 = 6.6 Hz, J 3 = 1.7 Hz), 5.90 (dd, 1 H, J 1 = 17.5 Hz, J 2 = 10.6 Hz), 5.35 (d, 1 H, J = 17.5 Hz), 5.22 (d, 1 H, J = 10.6 Hz), 3.71–3.63 (m, 4 H), 1.67–1.58 (m, 9 H). 13C NMR (126 MHz, CDCl3): δ = 176.2, 154.7, 140.6, 138.9, 128.1, 121.2, 120.8, 115.7, 113.6, 55.6, 47.4, 26.0, 24.3, 20.7. IR (ATR): 2934, 1632, 1542, 1458, 1448 cm–1. MS–FAB: m/z = 241 [M + H]+. HRMS–FAB+: m/z calcd for C16H21N2 [M + H]+: 241.1705; found: 241.1708.
- 15 As previously reported on the synthesis of amidines using palladium catalysis and isocyanides,9g,h path A is also possible. In this case, the diastereoselectivity of 2m would be derived from a selective reaction of one enantiomer of racemic B and l-proline methyl ester (i.e., matched pair).
Recent reviews:
For recent examples, see:
For recent reviews on the transformation of isocyanides, see:
For selected examples of indole synthesis using phenyl isocyanide, see:
For selected examples of palladium-catalyzed isocyanide insertion, see:
