DOI: 10.1002/chem.201400321
Communication
& Synthetic Methods
Highly Diastereoselective and Regioselective Copper-Catalyzed Nitrosoformate Dearomatization Reaction under AerobicOxidation Conditions Weibo Yang,[a] Long Huang,[a] Yang Yu,[a] Daniel Pflsterer,[a] Frank Rominger,[a] and A. Stephen K. Hashmi*[a, b] Abstract: An unprecedented copper-catalyzed acylnitroso dearomatization reaction, which expands the traditional acylnitroso ene reaction and acylnitroso Diels–Alder reaction to a new type of transformation, has been developed under aerobic oxidation. Intermolecular and intra-/intermolecular reaction modes demonstrate an entirely different N- or O-acylnitroso selectivity. Hence, we can utilize this reaction as a highly diastereoselective access to a series of new pyrroloindoline derivatives, which are important structural motifs for natural-product synthesis.
The application of nitrosoformate or nitrosoarene compounds as a class of electrophilic reagents, able of introducing nitrogen and/or oxygen, is an important and appealing tool in the synthesis of biologically active molecules (Scheme 1).[1, 2] However, these compounds are highly reactive and extremely instable species. Therefore, the generation and utilization of nitrosoformate compounds need to be conducted through in situ oxidation of the corresponding hydroxamic acids.[3] The conventional oxidation protocols for hydroxamic acids utilize stoi-
Scheme 1. Synthesis of biologically active molecules from nitrosoformate compounds.
[a] W. Yang, L. Huang, Y. Yu, D. Pflsterer, Dr. F. Rominger, Prof. Dr. A. S. K. Hashmi Organisch-Chemisches Institut, Ruprecht-Karls-Universitt Heidelberg Im Neuenheimer Feld 270, 69120 Heidelberg (Germany) Fax: (+ 49) 6221-54-4205 E-mail: [email protected] [b] Prof. Dr. A. S. K. Hashmi Chemistry Department, Faculty of Science, King Abdulaziz University (KAU), Jeddah 21589, Saudi Arabia Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201400321. Chem. Eur. J. 2014, 20, 3927 – 3931
chiometric amounts of peroxides, periodates, as well as lead or silver oxide reagents, to generate the transient nitrosoformate intermediates. Despite these oxidants being common, the development of an environmentally benign method is highly desirable. The current state-of-the-art is the attractive protocol that Whiting’s and Read de Alaniz’s groups recently discovered. They generated the nitrosoformate species by aerobic oxidation in combination with copper catalysts.[4] They utilized this strategy successfully in the nitrosoformate hetero-Diels–Alder reaction[4a] and in the nitrosoformate ene reaction.[4b] Subsequently, the group of Read de Alaniz has presented the first examples of the N-selective or O-selective nitrosoformate aldol reaction by using copper as catalyst under aerobic-oxidation conditions.[5] Simultaneously, Yamamoto and co-workers described a Cu-catalyzed asymmetric O-nitrosoformate aldol reaction by using MnO2 as a mild oxidant.[6] This represented a revolution in the previously unexplored field of nitrosoformate aldol reactions,[7] compared to the intensively investigated nitrosoformate hetero-Diels–Alder reaction[3i, 8] and nitrosoformate ene reaction.[9] Recently, the dearomatization of indoles with appropriate electrophilic reagents has been widely recognized as a powerful transformation[10] for the generation of pyrroloindoline derivatives, which are frequent substructures of alkaloid natural products and exhibit important biological activities.[11] Nevertheless, the achievements in this area were considerable. Remarkably, there have been no reports on dearomatization of indoles with in situ generated electrophilic nitrosoformate compounds. This might result from the stability of the indole ring and the high instability of the nitrosoformate compounds, as well as potential rearomatization. The exploration of new types of nitrosoformate reactions is a significant challenge (Scheme 2). In continuation of our interest in the synthesis of indole derivatives,[12] we were inspired by the aerobic oxidation access of Whiting and Read de Alaniz.[4] We envisioned a new type of nitrosoformate transformation, with tryptamines and tryptophols serving as enamines and playing a similar role as enolates in Yamamoto’s and Read de Alaniz’s reaction. This role is to trap the nitrosoformate intermediate, followed by attack of an iminium intermediate, finally leading to formal nitrosoformate dearomatization reaction. Herein, we present an unprecedented highly diastereoselective and O-selective Cu-catalyzed formal nitrosoformate dearomatization reaction. This not only opens up new perspectives for nitrosoformate chemistry, but
3927
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Communication Table 1. Optimization of copper-catalyzed nitrosoformate dearomatization reaction.[a]
Entry
Catalyst
Solvent
t [h]
Yield [%]
1 2 3 4 5[b] 6 7 8
CuCl Cu(OTf)2 CuCl/Cu(OTf)2 CuCl/Cu(OAc)2·H2O CuCl/Cu(OTf)2 CuCl/Cu(OTf)2 CuCl/Cu(OTf)2 CuCl/Cu(OTf)2
MeOH MeOH MeOH MeOH MeOH CH2Cl2 THF iPrOH
24 24 24 24 24 24 24 48
42 0 70 45 31 trace 17 13
[a] Reaction conditions: substrate 1 a (100 mmol), substrate 2 a (110 mmol), [catalyst] (10 mol %), solvent (1 mL), in air. The reaction was monitored by TLC. [b] Substrate 1 a (150 mmol), substrate 2 a (100 mmol).
Scheme 2. Traditional nitrosoformate reaction and our strategy.
also provides a series of new pyrroloindoline derivatives, which are important building units in total synthesis. We chose carbobenzyloxy (Cbz)-protected hydroxylamine (1 a) with tryptamine (2 a, unprotected at the indole core) as the representative substrates to evaluate the copper-catalyzed nitrosoformate dearomatization reaction. When 2 a was treated with potential electrophilic reagent 1 a and 10 mol % CuCl in methanol at room temperature under aerobic-oxidation conditions for 24 h, we were delighted to find that the desired product (3 a) indeed was formed in 42 % yield as a single diastereomer (Table 1, entry 1). Importantly, we also determined that in the absence of CuI as a catalyst, no nitrosoformate dearomatization product (3 a) was observed (by using Cu(OTf)2 alone, entry 2). Encouraged by the pioneering work of Read de Alaniz,
we turned our attention to the dual copper combination catalysts. Gratifyingly, the corresponding product was isolated in 70 % yield (entry 3). To our surprise, the extremely similar catalytic system of Read de Alaniz’s and ours exhibited entire different N- or O-nitrosoformate selectivity.[5a] In the Read de Alaniz’s case, a high N-nitrosoformate selectivity was observed; however, our catalytic system provided high O-nitrosoformate selectivity. Replacement of the CuCl/Cu(OTf)2 with CuCl/Cu(OAc)2 ·H2O decreased the yield to 45 % (entry 4). Changing the ratio of 1 a and 2 a also diminished the reactivity and gave a much lower yield of 31 % (entry 5). Moreover, further solvent optimization did not improve the yield (entries 6–8), methanol was the best choice. With the best identified conditions, various substrates were then investigated, and the results are summarized in Scheme 3. As was mentioned in Table 1, the unprotected tryptamine with Cbz-substituted hydroxylamine the pyrroloindoline 3 a was isolated in 70 % yield. The N- or O-nitrosoformate selectivity can be efficiently identified with the aid of two-dimensional N H correlation NMR spectroscopy. In addition, various N-substituted hydroxylamines in combination with N-methyl-
Figure 1. Solid-state molecular structures of 3 c (left), 3 f (middle), and 3 n (right). Chem. Eur. J. 2014, 20, 3927 – 3931
www.chemeurj.org
3928
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Communication
Scheme 3. Products obtained from the copper-catalyzed intermolecular nitrosoformate dearomatization reaction.
protected tryptamine could be converted into the corresponding products 3 b–e. In addition to the good to high yields, excellent diastereoselectivities and regioselectivities were observed. The X-ray crystal-structure analysis[13] of 3 c unambiguously proved that the reaction had taken place on oxygen, and that the expected cis-anellation of the two five-membered rings forms diastereoselectively (Figure 1). To our delight, the 5-methyl substituted N-methyl-protected tryptamine in combination with the Boc-protected hydroxylamine gave the expected product 3 f in 90 % yield after 6 h (again, an X-ray crystal structure analysis confirmed the O-selectivity and the diastereoselectivity; Figure 1).[13] The N-methyl-protected tryptamine contains a 5-methoxy substituent; however, gave 3 g with a lower yield (48 %). Based on the successful application with tryptamines, we speculated that tryptophols could also be compatible with this catalytic system. Interestingly, the 7-ethyl-substituted N-methyl protected tryptophol gave 3 i and j in higher yields of 76 and Chem. Eur. J. 2014, 20, 3927 – 3931
www.chemeurj.org
66 %, respectively. The N-allyl-protected tryptophol and the N-methyl-protected substrates gave 3 l in moderate 58 % yield. To highlight the synthetic utility, we turned our attention to the copper-catalyzed intramolecular nitrosoformate dearomatization reaction. In addition, with this reaction model, two intriguing polycyclic indole compounds were obtained through an unusual [4+4] dimerization cycloaddition instead of a 3,2-alkyl migration or a [2+2] cycloaddition, albeit the isolated yields are low; 40 and 45 % (Scheme 4). A peak at d = 70.2 ppm was observed in the 13C NMR spectrum of 3 n, which indicated a sp3-hybridized quaternary carbon, demonstrating that the dearomatization had taken place. Moreover, the X-ray crystal-structure analysis of 3 n further proved the relative configuration of the four new stereocenters (Figure 1).[13] We next focused on the development of an diastereoselective nitrosoformate dearomatization transformation by using the enantioenriched tryptophan methyl esters (Scheme 5). Although moderate yields and poor d.r. values were obtained under the standard conditions, the possibility of a chirality transfer is very encouraging for this new reaction. The relative configuration of the stereocenters could be assigned by a NOESY NMR spectrum, showing a cross-peak between the two alkyl methine groups for the major diastereomer. The reaction mechanism, based on the pioneering literature,[4, 5, 6] is outlined in Scheme 6. Initially, the nitrosoformate intermediate was generated by aerobic copper-catalyzed oxidation. Subsequently, the tryptamines and tryptophols could serve as enamines, being attacked at the 3-positions by the electrophilic nitrosoformate intermediate. This results in an iminium-ion intermediate, which was trapped by the
Scheme 4. Preliminary investigation of copper-catalyzed intra-/intermolecular nitrosoformate dearomatization reaction.
3929
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Communication Acknowledgements W.Y. and Y.Y. are grateful to the CSC (Chinese Scholarship Council) for a fellowship. L.H. appreciates the HGMF scholarships from the Heinz Gçtze Memorial Fellowship programme of the Athenaeum Foundation fellowship. Gold salts were generously donated by Umicore AG&Co. KG. Keywords: aerobic oxidation · copper · dearomatization · nitrosoformate · regioselectivity [1] For reviews on nitrosocarbonyl chemistry, see: a) G. W. Kirby, J. G. Sweeny, J. Chem. Soc. Chem. Commun. 1973, 704; b) K. R. Flower, A. P. Lightfoot, H. Wan, A. Whiting, Chem. Commun. 2001, 1812. For selected examples of nitrosoarenes chemistry, see: a) N. Momiyama, H. Yamamoto, J. Am. Chem. Soc. 2003, 125, 6038; b) S. P. Brown, M. P. Brochu, C. J. Sinz, D. W. C. MacMillan, J. Am. Chem. Soc. 2003, 125, 10808; c) N. Momiyama, H. Yamamoto, J. Am. Chem. Soc. 2004, 126, 5360; d) N. Momiyama, H. Yamamoto, J. Am. Chem. Soc. 2005, 127, 1080; e) A. Yanagisawa, S. Takeshita, Y. Izumi, K. Yoshida, J. Am. Chem. Soc. 2010, 132, 5328; f) K. Shen, X. Liu, G. Wang, L. Lin, X. Feng, Angew. Chem. 2011, 123, 4780; Angew. Chem. Int. Ed. 2011, 50, 4684; g) M. D. Surman, M. J. Mulvihill, M. J. Miller, J. Org. Chem. 2002, 67, 4115. For selected examples of oxidation protocols, see: a) L. H. Dao, J. M. Dust, D. Mackay, K. N. Watson, Can. J. Chem. 1979, 57, 1712; b) S. F. Martin, M. Hartmann, J. A. Josey, Tetrahedron Lett. 1992, 33, 3583; c) N. E. Jenkins, R. W. Ware Jr., R. N. Atkinson, S. B. King, Synth. Commun. 2000, 30, 947; d) S. Iwasa, K. Tajima, S. Tsushima, H. Nishiyama, Tetrahedron Lett. 2001, 42, 5897; e) S. Iwasa, A. Fakhruddin, Y. Tsukamato, M. Kameyama, H. Nishiyama, Tetrahedron Lett. 2002, 43, 6159; f) J. A. K. Howard, G. Ilyashenko, H. A. Sparkes, A. Whiting, Dalton Trans. 2007, 2108; g) M. F. A. Adamo, S. Bruschi, J. Org. Chem. 2007, 72, 2666; h) J. A. K. Howard, G. Ilyashenko, H. A. Sparkes, A. Whiting, A. R. Wright, Adv. Synth. Catal. 2008, 350, 869; for reviews, see: i) B. S. Bodnar, M. J. Miller, Angew. Chem. 2011, 123, 5746; Angew. Chem. Int. Ed. 2011, 50, 5630; j) M. Baidya, H. Yamamoto, Synthesis 2013, 45, 1931. a) D. Chaiyaveij, L. Cleary, A. S. Batsanov, T. B. Marder, K. J. Shea, A. Whiting, Org. Lett. 2011, 13, 3442; b) C. P. Frazier, J. R. Engelking, J. Read de Alaniz, J. Am. Chem. Soc. 2011, 133, 10430; c) C. P. Frazier, A. Bugarin, J. R. Engelking, J. Read de Alaniz, Org. Lett. 2012, 14, 3620. a) D. Sandoval, C. P. Frazier, A. Bugarin, J. Read de Alaniz, J. Am. Chem. Soc. 2012, 134, 18948; b) C. P. Frazier, D. Sandoval, L. I. Palmer, J. Read de Alaniz, Chem. Sci. 2013, 4, 3857. M. Baidya, K. A. Griffin, H. Yamamoto, J. Am. Chem. Soc. 2012, 134, 18566. P. Selig, Angew. Chem. 2013, 125, 7218; Angew. Chem. Int. Ed. 2013, 52, 7080. For reviews on nitrosocarbonyl Diels–Alder reactions, see: a) J. Streith, A. Defoin, Synthesis 1994, 1107; b) C. Kibayashi, S. Aoyagi, Synlett 1995, 873; c) P. E. Vogt, M. J. Miller, Tetrahedron 1998, 54, 1317; d) Y. Yamamoto, H. Yamamoto, Eur. J. Org. Chem. 2006, 2031. For reviews on nitrosocarbonyl ene reactions, see: a) W. Adam, O. Krebs, Chem. Rev. 2003, 103, 4131; b) S. Iwasa, A. Fakhruddin, H. Nishiyama, Org. Chem. 2005, 2, 157. For selected examples of dearomatization of indoles with appropriate electrophilic reagents, see: a) O. Lozano, G. Blessley, T. Martinez de Campo, A. L. Thompson, G. T. Giuffredi, M. Bettati, M. Walker, R. Borman, V. Gouverneur, Angew. Chem. 2011, 123, 8255; Angew. Chem. Int. Ed. 2011,
Scheme 5. Copper-catalyzed diastereoselective nitrosoformate dearomatization reaction.
[2]
[3]
Scheme 6. Proposed mechanism of copper-catalyzed nitrosoformate dearomatization reaction.
[4]
pendant group X by an intramolecular cyclization, giving the final product. In summary, we developed the first Cu-catalyzed O-selective nitrosoformate dearomatization reaction under aerobic conditions. This transformation not only opens up new perspectives in the field of nitrosoformate chemistry, but also provides a series of new pyrroloindoline derivatives in high diastereoselectivity. These compounds are important building blocks in total synthesis. Moreover, the asymmetric nitrosoformate dearomatization reaction further emphasized the potential and important application value. Further investigation of the mechanistic studies and expansion of the scope of this nitrosoformate dearomatization transformation are underway.
Chem. Eur. J. 2014, 20, 3927 – 3931
www.chemeurj.org
[5]
[6] [7] [8]
[9]
[10]
3930
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Communication 50, 8105; b) C.-X. Zhuo, Wei. Zhang, S.-L. You, Angew. Chem. 2012, 124, 12834; Angew. Chem. Int. Ed. 2012, 51, 12662; c) S. Zhu, D. W. C. MacMillan, J. Am. Chem. Soc. 2012, 134, 10815; d) C. Liu, W. Zhang, L.-X. Dai, S.L. You, Org. Lett. 2012, 14, 4525; e) M. E. Kieffer, K. V. Chuang, S. E. Reisman, Chem. Sci. 2012, 3, 3170; f) X. Zhang, Z.-P. Yang, C. Liu, S.-L. You, Chem. Sci. 2013, 4, 3239. [11] Syntheses of pyrroloindolines derivatives: a) S. P. Govek, L. E. Overman, J. Am. Chem. Soc. 2001, 123, 9468; b) J. J. Kodanko, L. E. Overman, Angew. Chem. 2003, 115, 2632; Angew. Chem. Int. Ed. 2003, 42, 2528; c) S. P. Govek, L. E. Overman, Tetrahedron 2007, 63, 8499; d) J. J. Kodanko, S. Hiebert, E. A. Peterson, L. Sung, L. E. Overman, V. De Moura Linck, G. C. Goerck, T. A. Amador, M. B. Leal, E. Elisabetsky, J. Org. Chem. 2007, 72, 7909; e) M. Movassaghi, M. A. Schmidt, J. A. Ashenhurst, Org. Lett. 2008, 10, 4009; f) T. Newhouse, C. A. Lewis, K. J. Eastman, P. S. Baran, J. Am. Chem. Soc. 2010, 132, 7119; g) M. E. Kieffer, K. V. Chuang, S. E. Reisman, J. Am. Chem. Soc. 2013, 135, 5557.
Chem. Eur. J. 2014, 20, 3927 – 3931
www.chemeurj.org
[12] a) A. S. K. Hashmi, R. Salath, W. Frey, Eur. J. Org. Chem. 2007, 1648; b) A. S. K. Hashmi, M. Rudolph, J. W. Bats, W. Frey, F. Rominger, T. Oeser, Chem. Eur. J. 2008, 14, 6672; c) A. S. K. Hashmi, W. Yang, F. Rominger, Adv. Synth. Catal. 2012, 354, 1273; d) A. S. K. Hashmi, W. Yang, F. Rominger, Chem. Eur. J. 2012, 18, 6576; e) W. Yang, T. Wang, Y. Yu, S. Shi, T. Zhang, A. S. K. Hashmi, Adv. Synth. Catal. 2013, 355, 1523; f) S. Shi, T. Wang, W. Yang, M. Rudolph, A. S. K. Hashmi, Chem. Eur. J. 2013, 19, 6576; g) T. Wang, S. Shi, D. Pflsterer, E. Rettenmeier, M. Rudolph, F. Rominger, A. S. K. Hashmi, Chem. Eur. J. 2014, 20, 292. [13] CCDC-965122 (3 c), CCDC-965123 (3 f), CCDC-965124 (3 n) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. Received: January 25, 2014 Published online on March 3, 2014
3931
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Communication
& Synthetic Methods
Highly Diastereoselective and Regioselective Copper-Catalyzed Nitrosoformate Dearomatization Reaction under AerobicOxidation Conditions Weibo Yang,[a] Long Huang,[a] Yang Yu,[a] Daniel Pflsterer,[a] Frank Rominger,[a] and A. Stephen K. Hashmi*[a, b] Abstract: An unprecedented copper-catalyzed acylnitroso dearomatization reaction, which expands the traditional acylnitroso ene reaction and acylnitroso Diels–Alder reaction to a new type of transformation, has been developed under aerobic oxidation. Intermolecular and intra-/intermolecular reaction modes demonstrate an entirely different N- or O-acylnitroso selectivity. Hence, we can utilize this reaction as a highly diastereoselective access to a series of new pyrroloindoline derivatives, which are important structural motifs for natural-product synthesis.
The application of nitrosoformate or nitrosoarene compounds as a class of electrophilic reagents, able of introducing nitrogen and/or oxygen, is an important and appealing tool in the synthesis of biologically active molecules (Scheme 1).[1, 2] However, these compounds are highly reactive and extremely instable species. Therefore, the generation and utilization of nitrosoformate compounds need to be conducted through in situ oxidation of the corresponding hydroxamic acids.[3] The conventional oxidation protocols for hydroxamic acids utilize stoi-
Scheme 1. Synthesis of biologically active molecules from nitrosoformate compounds.
[a] W. Yang, L. Huang, Y. Yu, D. Pflsterer, Dr. F. Rominger, Prof. Dr. A. S. K. Hashmi Organisch-Chemisches Institut, Ruprecht-Karls-Universitt Heidelberg Im Neuenheimer Feld 270, 69120 Heidelberg (Germany) Fax: (+ 49) 6221-54-4205 E-mail: [email protected] [b] Prof. Dr. A. S. K. Hashmi Chemistry Department, Faculty of Science, King Abdulaziz University (KAU), Jeddah 21589, Saudi Arabia Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201400321. Chem. Eur. J. 2014, 20, 3927 – 3931
chiometric amounts of peroxides, periodates, as well as lead or silver oxide reagents, to generate the transient nitrosoformate intermediates. Despite these oxidants being common, the development of an environmentally benign method is highly desirable. The current state-of-the-art is the attractive protocol that Whiting’s and Read de Alaniz’s groups recently discovered. They generated the nitrosoformate species by aerobic oxidation in combination with copper catalysts.[4] They utilized this strategy successfully in the nitrosoformate hetero-Diels–Alder reaction[4a] and in the nitrosoformate ene reaction.[4b] Subsequently, the group of Read de Alaniz has presented the first examples of the N-selective or O-selective nitrosoformate aldol reaction by using copper as catalyst under aerobic-oxidation conditions.[5] Simultaneously, Yamamoto and co-workers described a Cu-catalyzed asymmetric O-nitrosoformate aldol reaction by using MnO2 as a mild oxidant.[6] This represented a revolution in the previously unexplored field of nitrosoformate aldol reactions,[7] compared to the intensively investigated nitrosoformate hetero-Diels–Alder reaction[3i, 8] and nitrosoformate ene reaction.[9] Recently, the dearomatization of indoles with appropriate electrophilic reagents has been widely recognized as a powerful transformation[10] for the generation of pyrroloindoline derivatives, which are frequent substructures of alkaloid natural products and exhibit important biological activities.[11] Nevertheless, the achievements in this area were considerable. Remarkably, there have been no reports on dearomatization of indoles with in situ generated electrophilic nitrosoformate compounds. This might result from the stability of the indole ring and the high instability of the nitrosoformate compounds, as well as potential rearomatization. The exploration of new types of nitrosoformate reactions is a significant challenge (Scheme 2). In continuation of our interest in the synthesis of indole derivatives,[12] we were inspired by the aerobic oxidation access of Whiting and Read de Alaniz.[4] We envisioned a new type of nitrosoformate transformation, with tryptamines and tryptophols serving as enamines and playing a similar role as enolates in Yamamoto’s and Read de Alaniz’s reaction. This role is to trap the nitrosoformate intermediate, followed by attack of an iminium intermediate, finally leading to formal nitrosoformate dearomatization reaction. Herein, we present an unprecedented highly diastereoselective and O-selective Cu-catalyzed formal nitrosoformate dearomatization reaction. This not only opens up new perspectives for nitrosoformate chemistry, but
3927
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Communication Table 1. Optimization of copper-catalyzed nitrosoformate dearomatization reaction.[a]
Entry
Catalyst
Solvent
t [h]
Yield [%]
1 2 3 4 5[b] 6 7 8
CuCl Cu(OTf)2 CuCl/Cu(OTf)2 CuCl/Cu(OAc)2·H2O CuCl/Cu(OTf)2 CuCl/Cu(OTf)2 CuCl/Cu(OTf)2 CuCl/Cu(OTf)2
MeOH MeOH MeOH MeOH MeOH CH2Cl2 THF iPrOH
24 24 24 24 24 24 24 48
42 0 70 45 31 trace 17 13
[a] Reaction conditions: substrate 1 a (100 mmol), substrate 2 a (110 mmol), [catalyst] (10 mol %), solvent (1 mL), in air. The reaction was monitored by TLC. [b] Substrate 1 a (150 mmol), substrate 2 a (100 mmol).
Scheme 2. Traditional nitrosoformate reaction and our strategy.
also provides a series of new pyrroloindoline derivatives, which are important building units in total synthesis. We chose carbobenzyloxy (Cbz)-protected hydroxylamine (1 a) with tryptamine (2 a, unprotected at the indole core) as the representative substrates to evaluate the copper-catalyzed nitrosoformate dearomatization reaction. When 2 a was treated with potential electrophilic reagent 1 a and 10 mol % CuCl in methanol at room temperature under aerobic-oxidation conditions for 24 h, we were delighted to find that the desired product (3 a) indeed was formed in 42 % yield as a single diastereomer (Table 1, entry 1). Importantly, we also determined that in the absence of CuI as a catalyst, no nitrosoformate dearomatization product (3 a) was observed (by using Cu(OTf)2 alone, entry 2). Encouraged by the pioneering work of Read de Alaniz,
we turned our attention to the dual copper combination catalysts. Gratifyingly, the corresponding product was isolated in 70 % yield (entry 3). To our surprise, the extremely similar catalytic system of Read de Alaniz’s and ours exhibited entire different N- or O-nitrosoformate selectivity.[5a] In the Read de Alaniz’s case, a high N-nitrosoformate selectivity was observed; however, our catalytic system provided high O-nitrosoformate selectivity. Replacement of the CuCl/Cu(OTf)2 with CuCl/Cu(OAc)2 ·H2O decreased the yield to 45 % (entry 4). Changing the ratio of 1 a and 2 a also diminished the reactivity and gave a much lower yield of 31 % (entry 5). Moreover, further solvent optimization did not improve the yield (entries 6–8), methanol was the best choice. With the best identified conditions, various substrates were then investigated, and the results are summarized in Scheme 3. As was mentioned in Table 1, the unprotected tryptamine with Cbz-substituted hydroxylamine the pyrroloindoline 3 a was isolated in 70 % yield. The N- or O-nitrosoformate selectivity can be efficiently identified with the aid of two-dimensional N H correlation NMR spectroscopy. In addition, various N-substituted hydroxylamines in combination with N-methyl-
Figure 1. Solid-state molecular structures of 3 c (left), 3 f (middle), and 3 n (right). Chem. Eur. J. 2014, 20, 3927 – 3931
www.chemeurj.org
3928
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Communication
Scheme 3. Products obtained from the copper-catalyzed intermolecular nitrosoformate dearomatization reaction.
protected tryptamine could be converted into the corresponding products 3 b–e. In addition to the good to high yields, excellent diastereoselectivities and regioselectivities were observed. The X-ray crystal-structure analysis[13] of 3 c unambiguously proved that the reaction had taken place on oxygen, and that the expected cis-anellation of the two five-membered rings forms diastereoselectively (Figure 1). To our delight, the 5-methyl substituted N-methyl-protected tryptamine in combination with the Boc-protected hydroxylamine gave the expected product 3 f in 90 % yield after 6 h (again, an X-ray crystal structure analysis confirmed the O-selectivity and the diastereoselectivity; Figure 1).[13] The N-methyl-protected tryptamine contains a 5-methoxy substituent; however, gave 3 g with a lower yield (48 %). Based on the successful application with tryptamines, we speculated that tryptophols could also be compatible with this catalytic system. Interestingly, the 7-ethyl-substituted N-methyl protected tryptophol gave 3 i and j in higher yields of 76 and Chem. Eur. J. 2014, 20, 3927 – 3931
www.chemeurj.org
66 %, respectively. The N-allyl-protected tryptophol and the N-methyl-protected substrates gave 3 l in moderate 58 % yield. To highlight the synthetic utility, we turned our attention to the copper-catalyzed intramolecular nitrosoformate dearomatization reaction. In addition, with this reaction model, two intriguing polycyclic indole compounds were obtained through an unusual [4+4] dimerization cycloaddition instead of a 3,2-alkyl migration or a [2+2] cycloaddition, albeit the isolated yields are low; 40 and 45 % (Scheme 4). A peak at d = 70.2 ppm was observed in the 13C NMR spectrum of 3 n, which indicated a sp3-hybridized quaternary carbon, demonstrating that the dearomatization had taken place. Moreover, the X-ray crystal-structure analysis of 3 n further proved the relative configuration of the four new stereocenters (Figure 1).[13] We next focused on the development of an diastereoselective nitrosoformate dearomatization transformation by using the enantioenriched tryptophan methyl esters (Scheme 5). Although moderate yields and poor d.r. values were obtained under the standard conditions, the possibility of a chirality transfer is very encouraging for this new reaction. The relative configuration of the stereocenters could be assigned by a NOESY NMR spectrum, showing a cross-peak between the two alkyl methine groups for the major diastereomer. The reaction mechanism, based on the pioneering literature,[4, 5, 6] is outlined in Scheme 6. Initially, the nitrosoformate intermediate was generated by aerobic copper-catalyzed oxidation. Subsequently, the tryptamines and tryptophols could serve as enamines, being attacked at the 3-positions by the electrophilic nitrosoformate intermediate. This results in an iminium-ion intermediate, which was trapped by the
Scheme 4. Preliminary investigation of copper-catalyzed intra-/intermolecular nitrosoformate dearomatization reaction.
3929
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Communication Acknowledgements W.Y. and Y.Y. are grateful to the CSC (Chinese Scholarship Council) for a fellowship. L.H. appreciates the HGMF scholarships from the Heinz Gçtze Memorial Fellowship programme of the Athenaeum Foundation fellowship. Gold salts were generously donated by Umicore AG&Co. KG. Keywords: aerobic oxidation · copper · dearomatization · nitrosoformate · regioselectivity [1] For reviews on nitrosocarbonyl chemistry, see: a) G. W. Kirby, J. G. Sweeny, J. Chem. Soc. Chem. Commun. 1973, 704; b) K. R. Flower, A. P. Lightfoot, H. Wan, A. Whiting, Chem. Commun. 2001, 1812. For selected examples of nitrosoarenes chemistry, see: a) N. Momiyama, H. Yamamoto, J. Am. Chem. Soc. 2003, 125, 6038; b) S. P. Brown, M. P. Brochu, C. J. Sinz, D. W. C. MacMillan, J. Am. Chem. Soc. 2003, 125, 10808; c) N. Momiyama, H. Yamamoto, J. Am. Chem. Soc. 2004, 126, 5360; d) N. Momiyama, H. Yamamoto, J. Am. Chem. Soc. 2005, 127, 1080; e) A. Yanagisawa, S. Takeshita, Y. Izumi, K. Yoshida, J. Am. Chem. Soc. 2010, 132, 5328; f) K. Shen, X. Liu, G. Wang, L. Lin, X. Feng, Angew. Chem. 2011, 123, 4780; Angew. Chem. Int. Ed. 2011, 50, 4684; g) M. D. Surman, M. J. Mulvihill, M. J. Miller, J. Org. Chem. 2002, 67, 4115. For selected examples of oxidation protocols, see: a) L. H. Dao, J. M. Dust, D. Mackay, K. N. Watson, Can. J. Chem. 1979, 57, 1712; b) S. F. Martin, M. Hartmann, J. A. Josey, Tetrahedron Lett. 1992, 33, 3583; c) N. E. Jenkins, R. W. Ware Jr., R. N. Atkinson, S. B. King, Synth. Commun. 2000, 30, 947; d) S. Iwasa, K. Tajima, S. Tsushima, H. Nishiyama, Tetrahedron Lett. 2001, 42, 5897; e) S. Iwasa, A. Fakhruddin, Y. Tsukamato, M. Kameyama, H. Nishiyama, Tetrahedron Lett. 2002, 43, 6159; f) J. A. K. Howard, G. Ilyashenko, H. A. Sparkes, A. Whiting, Dalton Trans. 2007, 2108; g) M. F. A. Adamo, S. Bruschi, J. Org. Chem. 2007, 72, 2666; h) J. A. K. Howard, G. Ilyashenko, H. A. Sparkes, A. Whiting, A. R. Wright, Adv. Synth. Catal. 2008, 350, 869; for reviews, see: i) B. S. Bodnar, M. J. Miller, Angew. Chem. 2011, 123, 5746; Angew. Chem. Int. Ed. 2011, 50, 5630; j) M. Baidya, H. Yamamoto, Synthesis 2013, 45, 1931. a) D. Chaiyaveij, L. Cleary, A. S. Batsanov, T. B. Marder, K. J. Shea, A. Whiting, Org. Lett. 2011, 13, 3442; b) C. P. Frazier, J. R. Engelking, J. Read de Alaniz, J. Am. Chem. Soc. 2011, 133, 10430; c) C. P. Frazier, A. Bugarin, J. R. Engelking, J. Read de Alaniz, Org. Lett. 2012, 14, 3620. a) D. Sandoval, C. P. Frazier, A. Bugarin, J. Read de Alaniz, J. Am. Chem. Soc. 2012, 134, 18948; b) C. P. Frazier, D. Sandoval, L. I. Palmer, J. Read de Alaniz, Chem. Sci. 2013, 4, 3857. M. Baidya, K. A. Griffin, H. Yamamoto, J. Am. Chem. Soc. 2012, 134, 18566. P. Selig, Angew. Chem. 2013, 125, 7218; Angew. Chem. Int. Ed. 2013, 52, 7080. For reviews on nitrosocarbonyl Diels–Alder reactions, see: a) J. Streith, A. Defoin, Synthesis 1994, 1107; b) C. Kibayashi, S. Aoyagi, Synlett 1995, 873; c) P. E. Vogt, M. J. Miller, Tetrahedron 1998, 54, 1317; d) Y. Yamamoto, H. Yamamoto, Eur. J. Org. Chem. 2006, 2031. For reviews on nitrosocarbonyl ene reactions, see: a) W. Adam, O. Krebs, Chem. Rev. 2003, 103, 4131; b) S. Iwasa, A. Fakhruddin, H. Nishiyama, Org. Chem. 2005, 2, 157. For selected examples of dearomatization of indoles with appropriate electrophilic reagents, see: a) O. Lozano, G. Blessley, T. Martinez de Campo, A. L. Thompson, G. T. Giuffredi, M. Bettati, M. Walker, R. Borman, V. Gouverneur, Angew. Chem. 2011, 123, 8255; Angew. Chem. Int. Ed. 2011,
Scheme 5. Copper-catalyzed diastereoselective nitrosoformate dearomatization reaction.
[2]
[3]
Scheme 6. Proposed mechanism of copper-catalyzed nitrosoformate dearomatization reaction.
[4]
pendant group X by an intramolecular cyclization, giving the final product. In summary, we developed the first Cu-catalyzed O-selective nitrosoformate dearomatization reaction under aerobic conditions. This transformation not only opens up new perspectives in the field of nitrosoformate chemistry, but also provides a series of new pyrroloindoline derivatives in high diastereoselectivity. These compounds are important building blocks in total synthesis. Moreover, the asymmetric nitrosoformate dearomatization reaction further emphasized the potential and important application value. Further investigation of the mechanistic studies and expansion of the scope of this nitrosoformate dearomatization transformation are underway.
Chem. Eur. J. 2014, 20, 3927 – 3931
www.chemeurj.org
[5]
[6] [7] [8]
[9]
[10]
3930
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Communication 50, 8105; b) C.-X. Zhuo, Wei. Zhang, S.-L. You, Angew. Chem. 2012, 124, 12834; Angew. Chem. Int. Ed. 2012, 51, 12662; c) S. Zhu, D. W. C. MacMillan, J. Am. Chem. Soc. 2012, 134, 10815; d) C. Liu, W. Zhang, L.-X. Dai, S.L. You, Org. Lett. 2012, 14, 4525; e) M. E. Kieffer, K. V. Chuang, S. E. Reisman, Chem. Sci. 2012, 3, 3170; f) X. Zhang, Z.-P. Yang, C. Liu, S.-L. You, Chem. Sci. 2013, 4, 3239. [11] Syntheses of pyrroloindolines derivatives: a) S. P. Govek, L. E. Overman, J. Am. Chem. Soc. 2001, 123, 9468; b) J. J. Kodanko, L. E. Overman, Angew. Chem. 2003, 115, 2632; Angew. Chem. Int. Ed. 2003, 42, 2528; c) S. P. Govek, L. E. Overman, Tetrahedron 2007, 63, 8499; d) J. J. Kodanko, S. Hiebert, E. A. Peterson, L. Sung, L. E. Overman, V. De Moura Linck, G. C. Goerck, T. A. Amador, M. B. Leal, E. Elisabetsky, J. Org. Chem. 2007, 72, 7909; e) M. Movassaghi, M. A. Schmidt, J. A. Ashenhurst, Org. Lett. 2008, 10, 4009; f) T. Newhouse, C. A. Lewis, K. J. Eastman, P. S. Baran, J. Am. Chem. Soc. 2010, 132, 7119; g) M. E. Kieffer, K. V. Chuang, S. E. Reisman, J. Am. Chem. Soc. 2013, 135, 5557.
Chem. Eur. J. 2014, 20, 3927 – 3931
www.chemeurj.org
[12] a) A. S. K. Hashmi, R. Salath, W. Frey, Eur. J. Org. Chem. 2007, 1648; b) A. S. K. Hashmi, M. Rudolph, J. W. Bats, W. Frey, F. Rominger, T. Oeser, Chem. Eur. J. 2008, 14, 6672; c) A. S. K. Hashmi, W. Yang, F. Rominger, Adv. Synth. Catal. 2012, 354, 1273; d) A. S. K. Hashmi, W. Yang, F. Rominger, Chem. Eur. J. 2012, 18, 6576; e) W. Yang, T. Wang, Y. Yu, S. Shi, T. Zhang, A. S. K. Hashmi, Adv. Synth. Catal. 2013, 355, 1523; f) S. Shi, T. Wang, W. Yang, M. Rudolph, A. S. K. Hashmi, Chem. Eur. J. 2013, 19, 6576; g) T. Wang, S. Shi, D. Pflsterer, E. Rettenmeier, M. Rudolph, F. Rominger, A. S. K. Hashmi, Chem. Eur. J. 2014, 20, 292. [13] CCDC-965122 (3 c), CCDC-965123 (3 f), CCDC-965124 (3 n) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. Received: January 25, 2014 Published online on March 3, 2014
3931
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
