MicrowaveAssisted Tandem Organocatalytic

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Oct 21, 2014 - unlike their ketone and aldehyde counterparts. Therefore, other types of ..... Mes=mesityl, Ts=tosyl, TFA=trifluoroacetic acid. Figure 1. Products ...

DOI: 10.1002/chem.201404596

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Microwave-Assisted Tandem Organocatalytic Peptide-Coupling Intramolecular aza-Michael Reaction: a,b-Unsaturated N-Acyl Pyrazoles as Michael Acceptors Mara Snchez-Rosell,[a, b] Cristina Mulet,[a] Marta Guerola,[a] Carlos del Pozo,*[a] and Santos Fustero*[a, b] Abstract: Conjugated N-acyl pyrazoles have been successfully employed in the organocatalytic enantioselective intramolecular aza-Michael reaction as ester surrogates. Bifunctional squaramides under microwave irradiation provided the best results in this transformation. Furthermore, this protocol has been combined with a peptide-coupling reaction in a tandem sequence. The final products were easily converted into the corresponding ethyl esters.

Ester functionality plays a central role in biological and synthetic organic transformations. However, its use in the area of organocatalysis is still quite limited because the most commonly employed organocatalytic activation modes, that is, the iminium and enamine pathways, cannot be applied to esters, unlike their ketone and aldehyde counterparts. Therefore, other types of activation, such as hydrogen bonding[1] or Nheterocyclic carbene organocatalysis, are required for the activation of esters and acid derivatives.[2] In general, a,b-unsaturated esters are poor Michael acceptors and their application in organocatalyzed conjugated additions is compromised by their low reactivity. This problem can be overcome by using activated ester surrogates, such as a,bunsaturated acyl phosphonates[3] or N-acyl pyrazoles,[4] which facilitate the activation of the electrophilic moiety. Specifically, conjugated pyrazole amides are able to act at the same time as ester equivalents, activating and directing groups, as well as good leaving groups for further transformations. Despite their versatility, the use of conjugated pyrazole amides as Michael acceptors in organocatalysis is very scarce, and only intermolecular sulfa- and aza-Michael processes have been reported to date.[5] [a] Dr. M. Snchez-Rosell, C. Mulet, M. Guerola, Dr. C. del Pozo, Prof. S. Fustero Departamento de Qumica Orgnica, Universidad de Valencia 46100-Burjassot (Spain) E-mail: [email protected] [email protected] [b] Dr. M. Snchez-Rosell, Prof. S. Fustero Centro de Investigacin Prncipe Felipe Laboratorio de Molculas Orgnicas 46012-Valencia (Spain) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201404596. Chem. Eur. J. 2014, 20, 15697 – 15701

Several years ago, a project aimed at the development of convenient methodologies to carry out the intramolecular azaMichael reaction (IMAMR) in an asymmetric organocatalytic fashion was started in our laboratory. This transformation provides access to a variety of enantioenriched nitrogen-containing heterocycles in a simple and efficient manner. Initially, we found that carbamates bearing a remote enal functionality underwent cyclization in the presence of chiral diaryl prolinols to render pyrrolidines and piperidines with excellent enantioselectivity.[6] The successful extension of this protocol to enones was later achieved by using quinine-derived primary amines as catalysts.[7] Consequently, we envisioned the possibility of extending this methodology to conjugated esters as Michael acceptors.[8] We anticipated that bifunctional catalysts that exhibit donor and acceptor hydrogen-bonding abilities could simultaneously exert the activation of a,b-unsaturated esters in an enantioselective fashion. In this context, chiral squaramides have proven to be very effective hydrogen-bonding organocatalysts and have been successfully applied in several asymmetric transformations.[9] In the aza-Michael reaction, squaramides bearing chiral amines could enhance the nucleophilicity of the nitrogen by deprotonation and simultaneously activate the conjugated ester by hydrogen bonding interactions.[10] The combination of squaramides as catalysts with pyrazolcrotonate derivatives as ester surrogates was the key issue that allowed us to develop the organocatalytic IMAMR with estertype Michael acceptors (Scheme 1). Additionally, we found that this process can be combined with a peptide-coupling reaction in a tandem manner, which permits the process to be performed from the starting crotonic acid derivatives. The results obtained in this study are depicted herein. Protected amines 1 (see Supporting Information for their preparation) were used as model substrates in order to find suitable conditions for the IMAMR. These included the evaluation of the nucleophilic nitrogen source, the Michael acceptor type, solvent, temperature and catalyst. Results obtained in this optimization process are summarized in Table 1. First attempts were performed on substrate 1 a containing a benzyloxycarbonyl (Cbz) protecting group (PG) and a conjugated ester as Michael acceptor. After 60 h, either at room temperature or in CHCl3 under reflux, the starting material remained unaltered (Table 1, entry 1). The same result was obtained with 2-pyridyl sulfonamide as the nucleophilic nitrogen source (1 b, Table 1, entry 2). In order to increase the electrophilicity of the Michael acceptor, a substrate containing the

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Scheme 1. Organocatalytic intramolecular aza-Michael reactions. Boc = tertbutoxycarbonyl.

3,5-dimethylpyrazol (DMP) moiety as ester surrogate was synthesized (1 c). Again, this starting material bearing the Cbz protecting group on the nitrogen was unreactive (Table 1, entry 3), neither with bifunctional squaramides I, II nor with quinine-thiourea derivative III. Interestingly, the combination of the 2-pyridyl sulfonamide with the DMP moiety (1 d) was crucial for achieving the desired transformation. In the presence of bifunctional squaramide I, the reaction took place to give piperidine 2 d in moderate yield (60 %) and acceptable enantio-

selectivity (89:11 e.r.) after 5 days in CHCl3 at room temperature (Table 1, entry 4). A slight improvement in e.r. (92.5:7.5) was observed with parent catalyst II (Table 1, entry 5). The best e.r. results were obtained when phenyl sulfonamide was used as nitrogen source (1 e), providing the aniline-derived catalyst II better enantioselection (98:2 e.r.) than its benzylamine counterpart I (96:4 e.r.) in the formation of the corresponding piperidine 2 e (Table 1, entries 6, 7). Bifunctional thiourea catalyst III was also tested on the optimized substrate 1 e, but results were less satisfactory (Table 1, entry 8). When the reaction was performed in other solvents such as toluene or THF, the starting material was recovered unaltered. (Table 1, entries 9, 10). In order to decrease the reaction times, the reaction was carried out under microwave irradiation. Thus, after 5 h at 90 8C, conversion of the IMAMR was complete and the desired product 2 e was isolated in 84 % yield and 95.5:4.5 e.r. (Table 1, entry 11). Finally, the use of cyclopentyl methyl ether as solvent resulted in a slight improvement of the isolated yield (92 %) and enantioselectivity (96.5:3.5 e.r.) (Table 1, entry 12). The reaction under thermal conditions gave rise to similar results after 24 h (Table 1, entry 13).[11] Therefore, the optimal conditions for our IMAMR in terms of yield and enantioselectivity were established as those in Table 1, entry 12, although a small erosion in e.r. was detected in this thermal reaction compared to the rt one (Table 1, entry 7). The extension of this protocol to other substrates 1, 3 was examined next and the results are displayed in Table 2. In order to prove the influence of the electronic requirements of the aromatic sulfonamide in the process, several substrates containing both electron-donating and electron-with-

Table 1. Optimization of the intramolecular aza-Michael reaction (IMAMR) conditions.[a]

Entry

1

PG

R

Catalyst

Solvent

Time [h]

T

2

Yield 2 [%][b]

e.r. 2

1 2 3 4 5 6 7 8 9 10 11 12 13

1a 1b 1c 1d 1d 1e 1e 1e 1e 1e 1e 1e 1e

Cbz SO2Py Cbz SO2Py SO2Py SO2Ph SO2Ph SO2Ph SO2Ph SO2Ph SO2Ph SO2Ph SO2Ph

OEt OEt DMP[c] DMP DMP DMP DMP DMP DMP DMP DMP DMP DMP

I–III I–III I–III I II I II III II II II II II

CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 THF Toluene CHCl3 CPME[c] CPME

60 60 60 120 120 120 120 120 120 120 5 4 24

rt/D rt/D rt/D rt rt rt rt rt rt rt 90 8C[d] 90 8C[d] 90 8C

2a 2b 2c 2d 2d 2e 2e 2e 2e 2e 2e 2e 2e

– – – 60 71 52 55 48 – – 84 92 90

– – – 89:11 92.5:7.5 96:4 98:2 90:10 – – 95.5:4.5 96.5:3.5 95:5

[a] All reactions were performed with 10 mol % catalyst loading. [b] Isolated yields. [c] CPME = cyclopentyl methyl ether. [d] Reactions performed under microwave irradiation.

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Communication At this point, we decided to employ an alternative synthetic approach to access the required IMAMR substrate 10. This route involved the CM between 5 k and tert-butyl acrylate, followed by ester deprotection on compound 6 k and peptide coupling of acrylic acid 7 k with 3,5-dimethyl pyrazole (DMP, 9). Unfortunately, under the conditions employed to effect the peptide coupling, racemic morpholine derivative 2 k arising from the IMAMR of intermediate 10 was directly obtained (Scheme 2). Despite this unexpected result, we envisioned the

Table 2. Extension of the organocatalytic IMAMR.

[a] The formation of 5-membered rings was performed at 60 8C under microwave irradiation. Scheme 2. Development of an organocatalytic tandem peptide couplingIMAMR. Mes = mesityl, Ts = tosyl, TFA = trifluoroacetic acid.

drawing substituents were synthesized. In all cases, piperidine derivatives 2 e–h were obtained in good yields (70–92 %) and excellent enantioselectivities (up to 96.5:3.5 e.r., Table 2, entries 1–4). However, the formation of the pyrrolidine counterparts took place with decreased enantioselectivity, giving rise to compounds 2 i, j with 90:10 and 88:12 e.r., respectively (Table 2, entries 5, 6).[12] This protocol was next extended to benzofused derivatives 3 (see Supporting Information for their preparation). Thus, isoindoline 4 a and tetrahydroisoquinoline 4 b were obtained in good yield (93 and 84 %, respectively) and enantioselectivity (90:10 and 93.5:6.5 e.r., respectively, Table 2, entries 7, 8). 1-Substituted tetrahydroisoquinoline 4 c was also efficiently synthesized, although enantioselection was lower in this case (85:15 e.r., Table 2, entry 9). The results presented in Table 2 show that this IMAMR is especially efficient in the formation of piperidine derivatives and therefore, we decided to evaluate the synthesis of different 6membered ring heterocycles by means of this methodology. To this end, we initially considered the possibility of synthesizing a morpholine derivative. The corresponding acrylamide substrate for the IMAMR should be obtained through a cross metathesis (CM) reaction between compound 5 k and 3,5-dimethylpyrazol acrylamide in the presence of second generation Hoveyda–Grubbs catalyst [Ru-I] in a similar way than other substrates 1, 3 had been previously prepared (see Supporting Information for details). However, this CM reaction on compound 5 k did not proceed, even when the reaction mixture was heated under reflux in the presence of a Lewis acid. Chem. Eur. J. 2014, 20, 15697 – 15701

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possibility of developing a tandem enantioselective process in the presence of chiral squaramide II. To our delight, treatment of acid 7 k with catalyst II, diisopropyl carbodiimide (DIC), and DMP (9) in CPME at 50 8C under microwave irradiation, led to the formation of the morpholine derivative 2 k in 83 % yield and 99.5:0.5 e.r. (Scheme 2). The tandem protocol was next extended to different substrates depicted in Figure 1. Besides morpholine derivative 2 k, this methodology was efficient in the formation of other 6membered rings such as keto piperazine 2 m or substituted piperidines 2 l and 2 n, which were obtained in moderate yields

Figure 1. Products obtained through the organocatalytic tandem peptidecoupling IMAMR. DMP = 3,5-dimethyl pyrazole. Reactions were performed with catalyst II, diisopropyl carbodiimide (DIC), and DMP in CPME under microwave irradiation at 50 8C unless otherwise indicated. [a] Reaction performed with 40 mol % of catalyst II added in two portions. [b] E = CO2Et. [c] Reaction performed at 90 8C.

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Communication and good enantioselectivities. Compound 2 f was also obtained through this tandem protocol with similar results in terms of enantioselectivity when compared to the stepwise process, although in lower yield (see Table 2, entry 2). In the formation of pyrrolidine 2 j some erosion of enantioselectivity also occurred (see Table 2, entry 6). The transformation of the pyrazole moiety of pyrrolidine 2 j into the ethyl ester derivative 8 j was successfully achieved by treatment with 4-dimethylaminopyridine (DMAP) in EtOH under reflux conditions (Scheme 3). Additionally, comparison of

formed in a tandem fashion combined with a peptide-coupling reaction. Therefore, the use of pyrazole amides as ester synthetic equivalents is a very convenient strategy to perform this transformation with conjugated esters as Michael acceptors, a process that has remained elusive to date.

Scheme 3. Determination of the absolute configuration.

Keywords: acyl pyrazoles · intramolecular aza-Michael reaction · organocatalysis · squaramides · tandem reactions

the [a]D value of 8 j with that reported in the literature led us to conclude that the newly created stereocenter holds the S absolute configuration (Scheme 3).[13] The same stereochemical outcome was assumed for all other compounds of the IMAMR. Finally, a possible mechanism that accounts for the S stereochemical assignment mentioned above is proposed. The preferred approach would result from a combination of p-stacking and multiple hydrogen bonding interactions. The sulfonamide group in the substrate would be deprotonated by the quinuclidine moiety in the squaramide catalyst. At the same time, two hydrogen bonds would be established between the oxygen atoms in the substrate and the N H bonds in the catalyst. Additionally, an aromatic sandwich induced by two p-stacking interactions would fix the transition state, thereby promoting the attack of the nitrogen nucleophile on the Si face of the double bond (Figure 2).[14]

[1] For recent representative examples, see: a) B. Qiao, X. Liu, S. Duan, L. Yan, Z. Jiang, Org. Lett. 2014, 16, 672; b) W. Sun, L. Hong, G. Zhu, Z. Wang, X. Wei, J. Ni, R. Wang, Org. Lett. 2014, 16, 544; c) Y. Kobayashi, Y. Taniguchi, N. Hayama, T. Inokuma, Y. Takemoto, Angew. Chem. Int. Ed. 2013, 52, 11114; Angew. Chem. 2013, 125, 11320; d) M.-X. Zhao, H.-L. Bi, H. Zhou, H. Yang, M. Shi, J. Org. Chem. 2013, 78, 9377; e) W. Sun, G. Zhu, C. Wu, L. Hong, R. Wang, Chem. Eur. J. 2012, 18, 6737; f) X. Yu, W. Wang, Chem. Asian J. 2008, 3, 516. [2] a) P. Chauhan, D. Enders, Angew. Chem. Int. Ed. 2014, 53, 1485; Angew. Chem. 2014, 126, 1509; b) J. Cheng, Z. Huang, Y. R. Chi, Angew. Chem. Int. Ed. 2013, 52, 8592; Angew. Chem. 2013, 125, 8754; c) G. Liu, M. E. Shirley, K. N. Van, R. L. MacFarlin, D. Romo, Nat. Chem. 2013, 5, 1049. [3] a) H. Jiang, M. W. Paix¼o, D. Monge, K. A. Jørgensen, J. Am. Chem. Soc. 2010, 132, 2775; b) P. Bachu, T. Akiyama, Chem. Commun. 2010, 46, 4112; c) T. Liu, Y. Wang, G. Wu, H. Song, Z. Zhou, C. Tang, J. Org. Chem. 2011, 76, 4119. [4] N-Acyl pyrazoles were introduced as ester surrogates in asymmetric catalysis by Sibi: M. P. Sibi, J. J. Shay, M. Liu, C. P. Jasperse, J. Am. Chem. Soc. 1998, 120, 6615. [5] a) M. P. Sibi, K. Itoh, J. Am. Chem. Soc. 2007, 129, 8064; b) X.-Q. Dong, X. Fang, H.-Y. Tao, X. Zhou, C.-J. Wang, Adv. Synth. Catal. 2012, 354, 1141; c) X.-Q. Dong, X. Fang, H.-Y. Tao, X. Zhou, C.-J. Wang, Chem. Commun. 2012, 48, 7238. [6] a) S. Fustero, D. Jimnez, J. Moscard, S. Cataln, C. del Pozo, Org. Lett. 2007, 9, 5283; b) S. Fustero, J. Moscard, D. Jimnez, M. D. Prez-Carrin, M. Snchez-Rosell, C. del Pozo, Chem. Eur. J. 2008, 14, 9868. [7] S. Fustero, C. del Pozo, C. Mulet, R. Lzaro, M. Snchez-Rosell, Chem. Eur. J. 2011, 17, 14267. [8] Only one example of an organocatalytic IMAMR involving conjugated esters as Michael acceptors has been reported to date: M. Bandini, A. Eichholzer, M. Tragni, A. Umani-Ronchi, Angew. Chem. Int. Ed. 2008, 47, 3238; Angew. Chem. 2008, 120, 3282. [9] For recent reviews, see: a) J. Alemn, A. Parra, H. Jiang, K. A. Jørgensen, Chem. Eur. J. 2011, 17, 6890; b) R. I. Storer, C. Aciro, L. H. Jones, Chem. Soc. Rev. 2011, 40, 2330; c) M. Tsakos, C. G. Kokotos, Tetrahedron 2013, 69, 10199. [10] Squaramides have recently been used as catalysts in intermolecular aza-Michael reactions: a) A. K. Ghosh, B. Zhou, Tetrahedron Lett. 2013, 54, 3500; b) W. Yang, H.-X. He, Y. Gao, D.-M. Du, Adv. Synth. Catal. 2013, 355, 3670; c) W. Yang, D.-M. Du, Chem. Commun. 2013, 49, 8842; d) H. Mao, A. Lin, T. Tan, Y. Shi, H. Hu, Y. Chen, C. Zu, Org. Lett. 2013, 15, 4062; e) A. Alcaine, E. Marqus-Lpez, R. P. Herrera, RSC Adv. 2014, 4, 9856. [11] The microwave acceleration of a process without affecting the enantioselectivity has been previously observed. See, for example: ref. [7]; a) K. Nushiro, S. Kikuchi, T. Yamada, Chem. Commun. 2013, 49, 8371; b) K. Nushiro, S. Kikuchi, T. Yamada, Chem. Lett. 2013, 42, 165.

Figure 2. Plausible transition state of the IMAMR.

In conclusion, an organocatalytic enantioselective IMAMR of sulfonamides bearing a remote a,b-unsaturated pyrazoleamide has been described. Squaramide II was found to be the best catalyst for this transformation that could also be perChem. Eur. J. 2014, 20, 15697 – 15701

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Acknowledgements We would like to thank the Spanish Ministerio de Economa y Competitividad (CTQ-2010-19774-C02-01) and Generalitat Valenciana (GV/Prometeo/2010/061) for their financial support. C.M. and M.G. would like to thank Spanish Ministerio de Economa y Competitividad and Generalitat Valenciana for predoctoral fellowships.

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Communication [12] The formation of five-membered rings by intramolecular organocatalytic reactions was found to be less effective than the corresponding sixmembered rings: a) W. J. Nodes, D. R. Nutt, A. M. Chippindale, A. J. A. Cobb, J. Am. Chem. Soc. 2009, 131, 16016; ref. [7]. [13] M. J. Silva, L. Cottier, R. M. Srivastasa, D. Sinou, A. Thozet, Carbohydr. Res. 2005, 340, 309. [14] A similar aromatic sandwich, based on theoretical calculations, was recently proposed to rationalize the stereochemical outcome of a BINOL-

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phosphoric-catalyzed reaction: J. Calleja, A. B. Gonzlez-Prez, A. R. de Lera, R. Alvarez, F. J. FaÇanas, F. Rodrguez, Chem. Sci. 2014, 5, 996.

Received: July 26, 2014 Published online on October 21, 2014

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