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Microwave-Assisted Tandem Organocatalytic Peptide-CouplingIntramolecular aza-Michael Reaction: a,b-Unsaturated N-AcylPyrazoles as Michael Acceptors

Mar�a S�nchez-Rosell�,[a, b] Cristina Mulet,[a] Marta Guerola,[a] Carlos del Pozo,*[a] andSantos Fustero*[a, b]

Abstract: Conjugated N-acyl pyrazoles have been success-fully employed in the organocatalytic enantioselective in-tramolecular aza-Michael reaction as ester surrogates. Bi-functional squaramides under microwave irradiation pro-vided the best results in this transformation. Furthermore,this protocol has been combined with a peptide-couplingreaction in a tandem sequence. The final products wereeasily converted into the corresponding ethyl esters.

Ester functionality plays a central role in biological and syn-thetic organic transformations. However, its use in the area oforganocatalysis is still quite limited because the most com-monly employed organocatalytic activation modes, that is, theiminium 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 N-heterocyclic carbene organocatalysis, are required for the acti-vation of esters and acid derivatives.[2]

In general, a,b-unsaturated esters are poor Michael accept-ors and their application in organocatalyzed conjugated addi-tions is compromised by their low reactivity. This problem canbe overcome by using activated ester surrogates, such as a,b-unsaturated acyl phosphonates[3] or N-acyl pyrazoles,[4] whichfacilitate the activation of the electrophilic moiety. Specifically,conjugated pyrazole amides are able to act at the same timeas ester equivalents, activating and directing groups, as well asgood leaving groups for further transformations. Despite theirversatility, the use of conjugated pyrazole amides as Michaelacceptors in organocatalysis is very scarce, and only intermo-lecular sulfa- and aza-Michael processes have been reported todate.[5]

Several years ago, a project aimed at the development ofconvenient methodologies to carry out the intramolecular aza-Michael reaction (IMAMR) in an asymmetric organocatalyticfashion was started in our laboratory. This transformation pro-vides access to a variety of enantioenriched nitrogen-contain-ing heterocycles in a simple and efficient manner. Initially, wefound that carbamates bearing a remote enal functionality un-derwent cyclization in the presence of chiral diaryl prolinols torender pyrrolidines and piperidines with excellent enantiose-lectivity.[6] The successful extension of this protocol to enoneswas later achieved by using quinine-derived primary amines ascatalysts.[7] Consequently, we envisioned the possibility of ex-tending this methodology to conjugated esters as Michael ac-ceptors.[8] We anticipated that bifunctional catalysts that exhib-it donor and acceptor hydrogen-bonding abilities could simul-taneously exert the activation of a,b-unsaturated esters in anenantioselective fashion. In this context, chiral squaramideshave proven to be very effective hydrogen-bonding organoca-talysts and have been successfully applied in several asymmet-ric transformations.[9] In the aza-Michael reaction, squaramidesbearing chiral amines could enhance the nucleophilicity of thenitrogen by deprotonation and simultaneously activate theconjugated ester by hydrogen bonding interactions.[10]

The combination of squaramides as catalysts with pyrazol-crotonate derivatives as ester surrogates was the key issue thatallowed us to develop the organocatalytic IMAMR with ester-type Michael acceptors (Scheme 1). Additionally, we found thatthis process can be combined with a peptide-coupling reactionin a tandem manner, which permits the process to be per-formed from the starting crotonic acid derivatives. The resultsobtained in this study are depicted herein.

Protected amines 1 (see Supporting Information for theirpreparation) were used as model substrates in order to findsuitable conditions for the IMAMR. These included the evalua-tion of the nucleophilic nitrogen source, the Michael acceptortype, solvent, temperature and catalyst. Results obtained inthis optimization process are summarized in Table 1.

First attempts were performed on substrate 1 a containinga benzyloxycarbonyl (Cbz) protecting group (PG) and a conju-gated ester as Michael acceptor. After 60 h, either at roomtemperature or in CHCl3 under reflux, the starting material re-mained unaltered (Table 1, entry 1). The same result was ob-tained with 2-pyridyl sulfonamide as the nucleophilic nitrogensource (1 b, Table 1, entry 2). In order to increase the electro-philicity of the Michael acceptor, a substrate containing the

[a] Dr. M. S�nchez-Rosell�, C. Mulet, M. Guerola, Dr. C. del Pozo,Prof. S. FusteroDepartamento de Qu�mica Org�nica, Universidad de Valencia46100-Burjassot (Spain)E-mail : carlos.pozo@uv.es

santos.fustero@uv.es

[b] Dr. M. S�nchez-Rosell�, Prof. S. FusteroCentro de Investigaci�n Pr�ncipe FelipeLaboratorio de Mol�culas Org�nicas46012-Valencia (Spain)

Supporting information for this article is available on the WWW underhttp ://dx.doi.org/10.1002/chem.201404596.

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3,5-dimethylpyrazol (DMP) moiety as ester surrogate was syn-thesized (1 c). Again, this starting material bearing the Cbz pro-tecting group on the nitrogen was unreactive (Table 1,entry 3), neither with bifunctional squaramides I, II nor withquinine-thiourea derivative III. Interestingly, the combination ofthe 2-pyridyl sulfonamide with the DMP moiety (1 d) was cru-cial for achieving the desired transformation. In the presenceof bifunctional squaramide I, the reaction took place to give pi-peridine 2 d in moderate yield (60 %) and acceptable enantio-

selectivity (89:11 e.r.) after 5 days in CHCl3 at room tempera-ture (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 beste.r. results were obtained when phenyl sulfonamide was usedas nitrogen source (1 e), providing the aniline-derived catalystII better enantioselection (98:2 e.r.) than its benzylamine coun-terpart I (96:4 e.r.) in the formation of the corresponding piper-idine 2 e (Table 1, entries 6, 7). Bifunctional thiourea catalyst IIIwas also tested on the optimized substrate 1 e, but resultswere less satisfactory (Table 1, entry 8). When the reaction wasperformed in other solvents such as toluene or THF, the start-ing material was recovered unaltered. (Table 1, entries 9, 10). Inorder to decrease the reaction times, the reaction was carriedout under microwave irradiation. Thus, after 5 h at 90 8C, con-version of the IMAMR was complete and the desired product2 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 result-ed in a slight improvement of the isolated yield (92 %) andenantioselectivity (96.5:3.5 e.r.) (Table 1, entry 12). The reactionunder thermal conditions gave rise to similar results after 24 h(Table 1, entry 13).[11] Therefore, the optimal conditions for ourIMAMR in terms of yield and enantioselectivity were estab-lished as those in Table 1, entry 12, although a small erosion ine.r. was detected in this thermal reaction compared to the rtone (Table 1, entry 7).

The extension of this protocol to other substrates 1, 3 wasexamined next and the results are displayed in Table 2.

In order to prove the influence of the electronic require-ments of the aromatic sulfonamide in the process, several sub-strates containing both electron-donating and electron-with-

Scheme 1. Organocatalytic intramolecular aza-Michael reactions. Boc = tert-butoxycarbonyl.

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 1 a Cbz OEt I–III CHCl3 60 rt/D 2 a – –2 1 b SO2Py OEt I–III CHCl3 60 rt/D 2 b – –3 1c Cbz DMP[c] I–III CHCl3 60 rt/D 2 c – –4 1 d SO2Py DMP I CHCl3 120 rt 2 d 60 89:115 1 d SO2Py DMP II CHCl3 120 rt 2 d 71 92.5:7.56 1 e SO2Ph DMP I CHCl3 120 rt 2 e 52 96:47 1 e SO2Ph DMP II CHCl3 120 rt 2 e 55 98:28 1 e SO2Ph DMP III CHCl3 120 rt 2 e 48 90:109 1 e SO2Ph DMP II THF 120 rt 2 e – –10 1e SO2Ph DMP II Toluene 120 rt 2 e – –11 1 e SO2Ph DMP II CHCl3 5 90 8C[d] 2 e 84 95.5:4.512 1 e SO2Ph DMP II CPME[c] 4 90 8C[d] 2 e 92 96.5:3.513 1 e SO2Ph DMP II CPME 24 90 8C 2 e 90 95:5

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

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drawing substituents were synthesized. In all cases, piperidinederivatives 2 e–h were obtained in good yields (70–92 %) andexcellent enantioselectivities (up to 96.5:3.5 e.r. , Table 2, en-tries 1–4). However, the formation of the pyrrolidine counter-parts took place with decreased enantioselectivity, giving riseto compounds 2 i, j with 90:10 and 88:12 e.r. , respectively(Table 2, entries 5, 6).[12] This protocol was next extended tobenzofused derivatives 3 (see Supporting Information for theirpreparation). Thus, isoindoline 4 a and tetrahydroisoquinoline4 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 cwas also efficiently synthesized, although enantioselection waslower in this case (85:15 e.r. , Table 2, entry 9).

The results presented in Table 2 show that this IMAMR is es-pecially efficient in the formation of piperidine derivatives andtherefore, we decided to evaluate the synthesis of different 6-membered ring heterocycles by means of this methodology.To this end, we initially considered the possibility of synthesiz-ing a morpholine derivative. The corresponding acrylamidesubstrate for the IMAMR should be obtained through a crossmetathesis (CM) reaction between compound 5 k and 3,5-di-methylpyrazol acrylamide in the presence of second genera-tion Hoveyda–Grubbs catalyst [Ru-I] in a similar way thanother substrates 1, 3 had been previously prepared (see Sup-porting Information for details). However, this CM reaction oncompound 5 k did not proceed, even when the reaction mix-ture was heated under reflux in the presence of a Lewis acid.

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

possibility of developing a tandem enantioselective process inthe presence of chiral squaramide II. To our delight, treatmentof acid 7 k with catalyst II, diisopropyl carbodiimide (DIC), andDMP (9) in CPME at 50 8C under microwave irradiation, led tothe formation of the morpholine derivative 2 k in 83 % yieldand 99.5:0.5 e.r. (Scheme 2).

The tandem protocol was next extended to different sub-strates depicted in Figure 1. Besides morpholine derivative 2 k,this methodology was efficient in the formation of other 6-membered rings such as keto piperazine 2 m or substituted pi-peridines 2 l and 2 n, which were obtained in moderate yields

Table 2. Extension of the organocatalytic IMAMR.

[a] The formation of 5-membered rings was performed at 60 8C under mi-crowave irradiation.

Scheme 2. Development of an organocatalytic tandem peptide coupling-IMAMR. Mes = mesityl, Ts = tosyl, TFA = trifluoroacetic acid.

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

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and good enantioselectivities. Compound 2 f was also ob-tained through this tandem protocol with similar results interms of enantioselectivity when compared to the stepwiseprocess, although in lower yield (see Table 2, entry 2). In theformation of pyrrolidine 2 j some erosion of enantioselectivityalso occurred (see Table 2, entry 6).

The transformation of the pyrazole moiety of pyrrolidine 2 jinto the ethyl ester derivative 8 j was successfully achieved bytreatment with 4-dimethylaminopyridine (DMAP) in EtOHunder reflux conditions (Scheme 3). Additionally, comparison of

the [a]D value of 8 j with that reported in the literature led usto conclude that the newly created stereocenter holds the Sabsolute configuration (Scheme 3).[13] The same stereochemicaloutcome was assumed for all other compounds of the IMAMR.

Finally, a possible mechanism that accounts for the S stereo-chemical assignment mentioned above is proposed. The pre-ferred approach would result from a combination of p-stackingand multiple hydrogen bonding interactions. The sulfonamidegroup in the substrate would be deprotonated by the quinucli-dine moiety in the squaramide catalyst. At the same time, twohydrogen bonds would be established between the oxygenatoms in the substrate and the N�H bonds in the catalyst. Ad-ditionally, an aromatic sandwich induced by two p-stacking in-teractions would fix the transition state, thereby promotingthe attack of the nitrogen nucleophile on the Si face of thedouble bond (Figure 2).[14]

In conclusion, an organocatalytic enantioselective IMAMR ofsulfonamides bearing a remote a,b-unsaturated pyrazole-amide has been described. Squaramide II was found to be thebest catalyst for this transformation that could also be per-

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

Acknowledgements

We would like to thank the Spanish Ministerio de Econom�a yCompetitividad (CTQ-2010-19774-C02-01) and Generalitat Va-lenciana (GV/Prometeo/2010/061) for their financial support.C.M. and M.G. would like to thank Spanish Ministerio de Econ-om�a y Competitividad and Generalitat Valenciana for predoc-toral fellowships.

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

[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 cat-alysis 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. Jim�nez, J. Moscard�, S. Catal�n, C. del Pozo, Org. Lett.2007, 9, 5283; b) S. Fustero, J. Moscard�, D. Jim�nez, M. D. P�rez-Carri-�n, M. S�nchez-Rosell�, C. del Pozo, Chem. Eur. J. 2008, 14, 9868.

[7] S. Fustero, C. del Pozo, C. Mulet, R. L�zaro, M. S�nchez-Rosell�, Chem.Eur. J. 2011, 17, 14267.

[8] Only one example of an organocatalytic IMAMR involving conjugatedesters 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. Alem�n, 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 intermolecularaza-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. Marqu�s-L�pez, R. P. Herrera, RSC Adv. 2014, 4, 9856.

[11] The microwave acceleration of a process without affecting the enantio-selectivity 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.

Scheme 3. Determination of the absolute configuration.

Figure 2. Plausible transition state of the IMAMR.

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[12] The formation of five-membered rings by intramolecular organocatalyt-ic reactions was found to be less effective than the corresponding six-membered 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 re-cently proposed to rationalize the stereochemical outcome of a BINOL-

phosphoric-catalyzed reaction: J. Calleja, A. B. Gonz�lez-P�rez, A. R.de Lera, R. Alvarez, F. J. FaÇanas, F. Rodr�guez, Chem. Sci. 2014, 5, 996.

Received: July 26, 2014

Published online on October 21, 2014

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