Letter Cite This: Org. Lett. 2018, 20, 5705−5708
pubs.acs.org/OrgLett
Iridium-Catalyzed Reductive Nucleophilic Addition to Secondary Amides Yoshito Takahashi, Risa Yoshii, Takaaki Sato,* and Noritaka Chida* Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1, Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan
Org. Lett. 2018.20:5705-5708. Downloaded from pubs.acs.org by UNIV OF SUNDERLAND on 09/21/18. For personal use only.
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ABSTRACT: An iridium-catalyzed reductive nucleophilic addition to secondary amides is reported. After the iridium-catalyzed reduction, the resulting imines can undergo the Strecker reaction, the Mannich reaction, allylation, and [3 + 2]-cycloaddition. The method shows high chemoselectivity in the presence of other functional groups such as methyl ester.
N
Scheme 1. Nucleophilic Addition to Secondary Amides
ucleophilic addition to amides is a promising synthetic tool to prepare biologically active alkaloids and pharmaceuticals because multisubstituted amines can be prepared from easily available amides in a one-step process.1 However, this reaction has been overlooked for a long time due to the poor electrophilicity of the amide carbonyl. To overcome this problem, a number of synthetic chemists have been exploring their original nucleophilic additions, and significant progress has been made in this field over the past ten years.2−5 A current hot topic is the development of a latestage nucleophilic addition6 and enables amides to serve as stable surrogates of multisubstituted amines toward concise syntheses of complex alkaloids and pharmaceuticals.1j,2e,3e−g,k,l,p However, most successful examples focus on nucleophilic addition to N-methoxyamides2 and tertiary amides.3 The case of secondary amides still remains an unsolved issue despite their large abundance (Scheme 1A).4 In this communication, we report an iridium-catalyzed reductive nucleophilic addition to secondary amides with a wide substrate scope in the presence of a variety of functional groups. The general scheme of nucleophilic addition to secondary amide 1 is depicted in Scheme 1A. The reaction starts with deprotonation of amide 1, followed by addition of the first organometallic reagent R1 M to metalated amide 2. The resulting N,O-acetal 3 is then transformed to imine 4, which undergoes the second nucleophilic addition with R2 M to provide secondary amine 5. The nucleophilic addition to secondary amides is more challenging than that to tertiary amides due to the poor electrophilicities of both metalated amide 2 and imine 4. Huang and co-workers achieved the nucleophilic addition to secondary amides via an in situ activation method with Tf2O.4c,f,h,j−l The groups of Ganem,4a Sato/Chida,3d,h and Stecko/Furman4e reported reductive nucleophilic addition with the Schwartz reagent [Cp2ZrHCl].7 Recently, Tokuyama and co-workers accomplished the total synthesis of histrionicotoxin, whose key step was the reductive © 2018 American Chemical Society
allylation of a secondary lactam by the modified Buchwald reduction [(Ti(Oi-Pr)4 and Et2SiH2].4i Unfortunately, most successful examples of nucleophilic addition to secondary amides have relied on the use of equimolar amounts of reducing agents.8 To solve this problem, we planned to use iridium-catalyzed dehydrosilylation and hydrosilylation (Scheme 1B). First, secondary amide 1 would be converted to N-silylamide 2a through dehydrosilylation. The resulting neutral intermediate 2a would undergo hydrosilylation of the Received: July 30, 2018 Published: September 7, 2018 5705
DOI: 10.1021/acs.orglett.8b02421 Org. Lett. 2018, 20, 5705−5708
Letter
Organic Letters Table 1. Optimization of Transition-Metal-Catalyzed Reductiona
Table 2. Combination of Two Iridium Catalysts for Reductive Nucleophilic Addition to the γ-Lactama
yields (%)b entry
reduction conditions
6a
1a
reduction conditions
1
Cp2ZrHCl (2.4 equiv), CH2Cl2 −40 °C to rt IrCl(CO)(PPh3)2 (1 mol %) (Me2SiH)2O (2 equiv), toluene, rt [Ir(COE)2Cl]2 (0.5 mol %) Et2SiH2 (2 equiv), toluene, rt [Ir(COE)2Cl]2 (0.5 mol %) Et2SiH2 (2 equiv), toluene, rt [Ir(COD)OMe]2 (0.5 mol %) Et2SiH2 (2 equiv), toluene, rt
76
0
[Ir]-1 (1 mol %), [Si−H]-1
23
72
84
0
80
0
82
0
2 3 4c 5
entry
[Ir]-2 (1 mol %), [Si−H]-2
1
[Ir(COE)2Cl]2, Et2SiH2 (2 equiv) none IrCl(CO)(PPh3)2, (Me2SiH)2O (2 equiv) none IrCl(CO)(PPh3)2, (Me2SiH)2O (1 equiv) [Ir(COE)2Cl]2, Et2SiH2 (1 equiv) [Ir(COE)2Cl]2, Et2SiH2 (1 equiv) IrCl(CO)(PPh3)2, (Me2SiH)2O (1 equiv)
2 3 4
Conditions: secondary amide 1a (200 μmol), reductant, solvent (0.2 M); then TMSCN (2 equiv), Yb(OTf)3 (10 mol %), MeCN (0.2 M), rt. bYield of isolated product after purification by column chromatography on silica gel. cThe reaction was performed with 1a (1 mmol). a
yields (%)b 6j 0
1j 100
56c
0
78d
0
0
100
a Conditions: lactam 1j, [Ir]-1 (1 mol %), [Si−H]-1, toluene (0.2 M), rt, 15 min; [Ir]-2 (1 mol %), [Si−H]-2, rt, 30 min; then TMSCN (2 equiv), Y(OTf)3 (10 mol %), rt, 1 h. bYield of isolated product after purification by column chromatography on silica gel. c6jα:6jβ = 1.6:1. d 6jα:6jβ = 1.6:1.
Scheme 2. Reductive Strecker Reaction of Secondary Amidesa,b
Scheme 3. Reductive Nucleophilic Addition to Secondary Amides
a Conditions: secondary amide 1, [Ir(COE)2CI]2 (0.5 mol %), Et2SiH2 (2 equiv), toluene (0.2 M), rt, 15 min; then TMSCN (2 equiv), Yb(OTf)3 (10 mol %), MeCN (0.2 M), rt, 1 h. bYield of isolated product after purification by column chromatography on silica gel. cTHF (0.2 M) was used instead of toluene. dY(OTf)3 (10 mol %) was used instead of Yb(OTf)3 (10 mol %) without MeCN. e [Ir(COE)2CI]2 (0.1 mol %) was used for reduction, and Yb(OTf)3 (20 mol %) without MeCN at −20 °C was used for nucleophilic addition.
metallic reagent R2 M′ to imine 4a would provide substituted secondary amine 5a. To test our hypothesis, we investigated the iridium-catalyzed reductive Strecker reaction of N-benzylbenzamide 1a (Table 1). After the reduction of amide 1a, the resulting imine was treated with TMSCN in the presence of Yb(OTf)3 (10 mol %).9 As a control experiment, the reduction using the Schwartz reagent [Cp2ZrHCl] was conducted to afford aminonitrile 6a in 76% yield (Table 1, entry 1). The group of Dixon reported
amide carbonyl and subsequent elimination to generate the transient imine 4a. Finally, addition of the second organo5706
DOI: 10.1021/acs.orglett.8b02421 Org. Lett. 2018, 20, 5705−5708
Letter
Organic Letters
the iridium-catalyzed reduction of 1a, addition of the silyl ketene acetal in the presence of Yb(OTf)3 provided secondary amine 7 in 65% yield (Scheme 3A). The reductive allylation was possible with allylstannane in the presence of SnCl2,3d,h giving 8 in 80% yield (Scheme 3B). The conspicuous application of our method was demonstrated through [3 + 2]-cycloaddition of an azomethine ylide (Scheme 3C).13,14 The amide-selective reduction of 1k generated the imine in the presence of the methyl ester, which was crucial for subsequent formation of azomethine ylide 9. [3 + 2]-Cycloaddition then took place with dimethyl fumarate, giving pyrrolidines 10 in 73% combined yield in a one-pot process (α:β = 1.3:1). In conclusion, we developed an iridium-catalyzed reductive nucleophilic addition to secondary amides. The reaction showed high amide selectivity in the presence of a variety of functional groups such as a methyl ester. The developed conditions were applicable to the reductive Strecker reaction, the Mannich reaction, allylation, and [3 + 2]-cycloaddition of the azomethine ylide. We believe that the developed method will facilitate the concise synthesis of complex alkaloids and pharmaceuticals.
seminal contributions to the iridium-catalyzed reductive Strecker reaction to tertiary amides3m using Nagashima’s conditions [IrCl(CO)(PPh3)2 (1 mol %) and (Me2SiH)2O].10 However, reduction of secondary amide 1a with IrCl(CO)(PPh3)2 (1 mol %) and (Me2SiH)2O gave aminonitrile 6a in 23% yield, along with the recovery of 1a in 72% yield (Table 1, entry 2). The best results were obtained when employing the Brookhart reduction with [Ir(COE)2Cl)]2 (0.5 mol %) and Et2SiH211 to afford 6a in 84% yield (Table 1, entry 3). The conditions were scalable on a 1 mmol scale to give aminonitrile 6a in 80% yield (Table 1, entry 4). We also found that the use of [Ir(COD)OMe]2 (0.5 mol %) and Et2SiH2, which were developed for arene C−H functionalization by Hartwig,12 yielded results comparable to Brookhart’s conditions (Table 1, entry 5, 6a: 82%). Both iridium-catalyzed reductions exhibited promising results, but further investigation was conducted with [Ir(COE)2Cl2] (0.5 mol %) due to its ease of handling. The scope of the iridium-catalyzed reductive Strecker reaction demonstrated good functional group tolerance (Scheme 2). The reaction of secondary amide 1b took place without affecting the more electrophilic methyl ester (6b: 95%). Substituents with either an electron-rich or electrondeficient group on the carbonyl side did not disturb the reaction (6c: 85%; 6d: 87%). Hydrosilylation of a double bond did not compete with reduction of the amide carbonyls (6e: 87%). An aromatic bromide was well tolerated under the developed conditions (6f: 86%). A carbamate is one of the most challenging functional groups to differentiate from amides due to its similar electrophilicity, but the reaction took place with high chemoselectivity (6g: 70%). One of the limitations in this method was inhibition of the reduction by Lewis basic functional groups such as a nitrile group (6h: 0%). The reaction of aliphatic secondary amides took place at a lower catalyst loading (0.1 mol %), giving 6i in 84% yield. We next turned our attention to the reductive Strecker reaction of five-membered lactam 1j (Table 2). To our surprise, the iridium-catalyzed reduction of 1j did not take place with [Ir(COE)2Cl]2 (0.5 mol %) and Et2SiH2 (2 equiv), resulting in the recovery of lactam 1j (Table 2, entry 1). However, use of Nagashima conditions [IrCl(CO)(PPh3)2 (1 mol %) and (Me2SiH)2O] provided pyrrolidines 6j in 56% combined yields (Table 2, entry 2). We then investigated the use of a combination of two iridium catalysts on the assumption that the best catalytic system might be different in the dehydrosilylation of lactam 1j and hydrosilylation of the resulting silylated lactam. Gratifyingly, treatment of 1j with IrCl(CO)(PPh3)2 (1 mol %) and (Me2SiH)2O (1 equiv), followed by addition of [Ir(COE)2Cl]2 (0.5 mol %) and Et2SiH2 (1 equiv), smoothly promoted the reduction of the lactam (Table 2, Entry 3). The resulting cyclic imine underwent the Strecker reaction to afford pyrrolidines 6j in 78% combined yield (α:β = 1.6:1). As a control experiment, addition of [Ir(COE)2Cl]2 and Et2SiH2 (1 equiv), followed by IrCl(CO)(PPh3)2 and (Me2SiH)2O (1 equiv), did not induce the reduction of the lactam carbonyl. Thus, although we did not observe any direct evidence, we revealed that the dehydrosilylation might require the use of IrCl(CO)(PPh3)2 and (Me2SiH)2O, and the subsequent hydrosilylation would prefer [Ir(COE)2Cl]2 (0.5 mol %) and Et2SiH2 in the case of the γ-lactam. The developed conditions allowed for not only the reductive Strecker reaction but also other types of nucleophilic addition such as the Mannich reaction and allylation (Scheme 3). After
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02421. Experimental details and compound characterization (PDF)
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Takaaki Sato: 0000-0001-5769-3408 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This research was supported by a Grant-in-Aid for Scientific Research (C) from MEXT (18K05127) and the Tobe Maki Foundation.
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REFERENCES
(1) For reviews and perspectives on nucleophilic addition to amides, see: (a) Seebach, D. Angew. Chem., Int. Ed. 2011, 50, 96−101. (b) Murai, T.; Mutoh, Y. Chem. Lett. 2012, 41, 2−8. (c) Pace, V.; Holzer, W. Aust. J. Chem. 2013, 66, 507−510. (d) Sato, T.; Chida, N. Org. Biomol. Chem. 2014, 12, 3147−3150. (e) Pace, V.; Holzer, W.; Olofsson, B. Adv. Synth. Catal. 2014, 356, 3697−3736. (f) Volkov, A.; Tinnis, F.; Slagbrand, T.; Trillo, P.; Adolfsson, H. Chem. Soc. Rev. 2016, 45, 6685−6697. (g) Kaiser, D.; Maulide, N. J. Org. Chem. 2016, 81, 4421−4428. (h) Chardon, A.; Morisset, E.; Rouden, J.; Blanchet, J. Synthesis 2018, 50, 984−997. (i) Więcław, M. M.; Stecko, S. Eur. J. Org. Chem. 2018, DOI: 10.1002/ejoc.201701537. (j) Sato, T.; Yoritate, M.; Tajima, H.; Chida, N. Org. Biomol. Chem. 2018, 16, 3864−3875. (2) For selected recent examples on nucleophilic addition to Nalkoxyamides, see: (a) Iida, H.; Watanabe, Y.; Kibayashi, C. J. Am. Chem. Soc. 1985, 107, 5534−5535. (b) Shirokane, K.; Kurosaki, Y.; Sato, T.; Chida, N. Angew. Chem., Int. Ed. 2010, 49, 6369−6372. 5707
DOI: 10.1021/acs.orglett.8b02421 Org. Lett. 2018, 20, 5705−5708
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Organic Letters (c) Vincent, G.; Guillot, R.; Kouklovsky, C. Angew. Chem., Int. Ed. 2011, 50, 1350−1353. (d) Jäkel, M.; Qu, J.; Schnitzer, T.; Helmchen, G. Chem. - Eur. J. 2013, 19, 16746−16755. (e) Shirokane, K.; Wada, T.; Yoritate, M.; Minamikawa, R.; Takayama, N.; Sato, T.; Chida, N. Angew. Chem., Int. Ed. 2014, 53, 512−516. (f) Nakajima, M.; Sato, T.; Chida, N. Org. Lett. 2015, 17, 1696−1699. (g) Katahara, S.; Kobayashi, S.; Fujita, K.; Matsumoto, T.; Sato, T.; Chida, N. J. Am. Chem. Soc. 2016, 138, 5246−5249. (3) For selected recent examples on nucleophilic addition to tertiary amides, see: (a) Larouche-Gauthier, R.; Bélanger, G. Org. Lett. 2008, 10, 4501−4504. (b) Xiao, K.-J.; Luo, J.-M.; Ye, K.-Y.; Wang, Y.; Huang, P.-Q. Angew. Chem., Int. Ed. 2010, 49, 3037−3040. (c) Bechara, W. S.; Pelletier, G.; Charette, A. B. Nat. Chem. 2012, 4, 228−234. (d) Oda, Y.; Sato, T.; Chida, N. Org. Lett. 2012, 14, 950−953. (e) Medley, J. W.; Movassaghi, M. Angew. Chem., Int. Ed. 2012, 51, 4572−4576. (f) Huo, H.-H.; Zhang, H.-K.; Xia, X.-E.; Huang, P.-Q. Org. Lett. 2012, 14, 4834−4837. (g) Jakubec, P.; Hawkins, A.; Felzmann, W.; Dixon, D. J. J. Am. Chem. Soc. 2012, 134, 17482−17485. (h) Nakajima, M.; Oda, Y.; Wada, T.; Minamikawa, R.; Shirokane, K.; Sato, T.; Chida, N. Chem. - Eur. J. 2014, 20, 17565−17571. (i) Gregory, A. W.; Chambers, A.; Hawkins, A.; Jakubec, P.; Dixon, D. J. Chem. - Eur. J. 2015, 21, 111−114. (j) Huang, P.-Q.; Ou, W.; Han, F. Chem. Commun. 2016, 52, 11967− 11970. (k) White, K. L.; Movassaghi, M. J. Am. Chem. Soc. 2016, 138, 11383−11389. (l) Tan, P.-W.; Seayad, J.; Dixon, D. J. Angew. Chem., Int. Ed. 2016, 55, 13436−13440. (m) Fuentes de Arriba, Á . L.; Lenci, E.; Sonawane, M.; Formery, O.; Dixon, D. J. Angew. Chem., Int. Ed. 2017, 56, 3655−3659. (n) Slagbrand, T.; Volkov, A.; Trillo, P.; Tinnis, F.; Adolfsson, H. ACS Catal. 2017, 7, 1771−1775. (o) Xie, L.G.; Dixon, D. J. Chem. Sci. 2017, 8, 7492−7497. (p) Yoritate, M.; Takahashi, Y.; Tajima, H.; Ogihara, C.; Yokoyama, T.; Soda, Y.; Oishi, T.; Sato, T.; Chida, N. J. Am. Chem. Soc. 2017, 139, 18386−18391. (q) Xie, L.-G.; Dixon, D. J. Nat. Commun. 2018, 9, 2841. (4) For selected recent examples on nucleophilic addition to secondary amides, see: (a) Xia, Q.; Ganem, B. Tetrahedron Lett. 2002, 43, 1597−1598. (b) Ref 3d. (c) Xiao, K.-J.; Wang, A.-E.; Huang, P.Q. Angew. Chem., Int. Ed. 2012, 51, 8314−8317. (d) Ref 3h. (e) Szcześniak, P.; Stecko, S.; Maziarz, E.; Staszewska-Krajewska, O.; Furman, B. J. Org. Chem. 2014, 79, 10487−10503. (f) Huang, P.-Q.; Lang, Q.-W.; Wang, A.-E.; Zheng, J.-F. Chem. Commun. 2015, 51, 1096−1099. (g) Huang, P.-Q.; Huang, Y.-H.; Xiao, K.-J.; Wang, Y.; Xia, X.-E. J. Org. Chem. 2015, 80, 2861−2868. (h) Huang, P. Q.; Lang, Q.-W.; Hu, X.-N. J. Org. Chem. 2016, 81, 10227−10235. (i) Sato, M.; Azuma, H.; Daigaku, A.; Sato, S.; Takasu, K.; Okano, K.; Tokuyama, H. Angew. Chem., Int. Ed. 2017, 56, 1087−1091. (j) Chen, H.; Ye, J.-L.; Huang, P.-Q. Org. Chem. Front. 2018, 5, 943−947. (k) Wang, A.-E.; Yu, C.-C.; Chen, T.-T.; Liu, Y.-P.; Huang, P.-Q. Org. Lett. 2018, 20, 999−1002. (l) Fan, T.; Wang, A.; Li, J.-Q.; Ye, J.-L.; Zheng, X.; Huang, P.-Q. Angew. Chem., Int. Ed. 2018, 57, 10352− 10356. (5) For selected recent examples on nucleophilic addition to thioamides, see: (a) Murai, T.; Mutoh, Y.; Ohta, Y.; Murakami, M. J. Am. Chem. Soc. 2004, 126, 5968−5969. (b) Murai, T.; Asai, F. J. Am. Chem. Soc. 2007, 129, 780−781. (6) For selected reviews on chemoselectivity, see: (a) Boudier, A.; Bromm, L. O.; Lotz, M.; Knochel, P. Angew. Chem., Int. Ed. 2000, 39, 4414−4435. (b) Shenvi, R. A.; O’Malley, D. P.; Baran, P. S. Acc. Chem. Res. 2009, 42, 530−541. (c) Afagh, N. A.; Yudin, A. K. Angew. Chem., Int. Ed. 2010, 49, 262−310. (7) (a) Wailes, P. C.; Weigold, H. J. Organomet. Chem. 1970, 24, 405−411. (b) Hart, D. W.; Schwartz, J. J. Am. Chem. Soc. 1974, 96, 8115−8116. (8) During the preparation of this manuscript, the group of Huang independently reported the elegant reductive nucleophilic addition to secondary amides using the Brookhart catalyst, see: Ou, W.; et al. Angew. Chem., Int. Ed. 2018, 57, 11354−11358. (9) Kobayashi, S.; Nagayama, S. J. Am. Chem. Soc. 1997, 119, 10049−10053.
(10) Nagashima originally reported the reduction of tertiary amides to enamines, see: Motoyama, Y.; Aoki, M.; Takaoka, N.; Aoto, R.; Nagashima, H. Chem. Commun. 2009, 1574−1576. (11) Cheng, C.; Brookhart, M. J. Am. Chem. Soc. 2012, 134, 11304− 11307. (12) (a) Boebel, T. A.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 7534−7535. (b) Robbins, D. W.; Boebel, T. A.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 4068−4069. (c) Simmons, E. M.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 17092−17095. (13) Huang reported 1,3-dipolar cycloaddition of azomethine ylides, which were derived from N-(trimethylsilylmethyl)amides. See ref 4h. (14) Dixon reported the reductive Strecker reaction of the tertiary amide seen in tripeptide Boc-Gly-Pro-Phe-OMe. See ref 3m.
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DOI: 10.1021/acs.orglett.8b02421 Org. Lett. 2018, 20, 5705−5708
