Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Three-Component Reactions to Spirocyclic Pyrrolidinonylformimidamides: α‑Isocyano Lactams as Two-Atom Unit in Silver-Catalyzed Formal [3 + 2] Cycloaddition Reactions Jimil George, Seong-Yoon Kim, and Kyungsoo Oh* Center for Metareceptome Research, College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak, Seoul 06974, Republic of Korea
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S Supporting Information *
ABSTRACT: A facile approach to spirocyclic pyrrolidinonylformimidamides has been developed via three-component reactions of isocyanides, alkenes, and amines. The reaction proceeds through a sequence of two distinct reaction pathways; the base-catalyzed conjugate addition of α-isocyano lactams to electron-deficient alkenes and the Ag(I)-catalyzed amine insertion to the isocyanide moiety. Both reactions display markedly different reaction kinetics, allowing the one-pot three-component reactions to be performed in the presence of respective catalysts, a Brønsted base and a silver salt. The formation of spirocyclic pyrrolidin-2-ones represents an unusual use of α-isocyano lactam as a two-atom unit in a formal [3 + 2] cycloaddition reaction. The successful identification of ways to defy the typical three-atom unit role of α-isocyano carbonyl compounds in the [3 + 2] cycloaddition pathways manifests a rapid assembly of medicinally important spirocyclic scaffolds from readily available starting materials.
M
formation of an enolate species that typically serves as threeatom unit dipoles in the [3 + 2]9 and [3 + 3]10 cycloaddition reactions (Scheme 1B). While a wide variety of heterocycles have been prepared from the [3 + 2] cycloaddition reaction pathways of α-isocyano carbonyl compounds as the three-atom unit, the utilization of α-isocyano enolates in the multicomponent reactions has not been explored, due to the facile intramolecular reactions of the isocyanide moiety with transient internal nucleophiles. While the electrophilic isocyanide characters have been recently investigated,11 the use of α-isocyano carbonyl compounds in the multicomponent reaction setting is rare.12 Herein, we report the use of electrophilic α-isocyano carbonyl compounds in the multicomponent reactions, where the base- and silver-catalyzed reactions of α-isocyano lactams, α,β-unsaturated esters, and primary amines provide facile access to spirocyclic pyrrolidinones via a novel [3 + 2] cycloaddition reaction (Scheme 1C). The key to the successful development of practical and one-pot multicomponent reactions is a clear understanding of the markedly different reaction rates between the conjugate
ulticomponent reactions enable the rapid assembly of a variety of drug candidates with ample structural diversification.1 In this regard, the diversity-oriented synthesis2 and the biology-oriented synthesis3 have significantly contributed to the advancement of rational design strategies for new multicomponent reactions.4 While there are classical multicomponent reactions with proven synthetic utility such as isocyanide-based multicomponent reactions,5 the utilization of multicomponent reactions has not caught up with the preparation of emerging pharmaceutical building blocks such as spirocyclic compounds6 with high degrees of practicality, atom economy, and one-pot efficiency. The bottleneck in designing new multicomponent reactions resides in the difficulty associated with altering the fundamental reactivity of functional groups. For example, in order to uncover new reaction pathways, one should consider the reaction pathway involving the carbon atom of isocyanides as an electrophile as opposed to its inherent nucleophilic character in the multicomponent Passerini- and Ugi-type reactions (Scheme 1A).7 The electrophilic isocyanides can be postulated during the cycloaddition reactions of α-isocyano carbonyl compounds.8 In addition to the isocyanide moiety, α-isocyano carbonyl compounds provide an additional reaction site through the © XXXX American Chemical Society
Received: September 30, 2018
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DOI: 10.1021/acs.orglett.8b03118 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 1. (A) Nucleophilic Isocyanides (B) Electrophilic Isocyanides (C) Formal [3 + 2] Cycloaddition Reaction of α-Isocyano Lactams
Table 1. Optimization of the Three-Component [3 + 2] Cycloaddition Reaction between α-Isocyano Lactam, Methyl Acrylate, and 4-F-Benzylaminea
addition of α-isocyano enolates and the amine insertion to the isocyanide moiety. Motivated by the increasing number of pharmaceutically relevant spirocyclic building blocks in drug discovery,6 we aimed to prepare spirocyclic compounds with structural novelty. Previously, we observed the “click” reactions of αisocyano carbonyl compounds where the angle strain-induced 1,2-shift provided the regioselective synthesis of highly functionalized pyrrole derivatives.13 Upon further examining the reactivity of α-isocyano lactams, we found a facile Michael reaction of α-isocyano lactam (Scheme 1C). Thus, the αisocyano lactam enolate rapidly attacked the Michael acceptor in the presence of a catalytic amount of base and Ag(I) salt within 1 min at ambient temperature. The reaction proceeded well in a polar medium such as THF, CH3CN, and DMF, and the choice of base was t-BuOK and Cs2CO3. Unlike the facile conjugate addition pathway, the isocyanide moiety of the resulting Michael adduct did not undergo the expected [3 + 2] cycloaddition reaction as a three-atom unit. Intrigued by the starkly different reaction profiles between the conjugate addition and the subsequent intramolecular Mannich-type cyclization, we explored the synthetic utility of the Michael adduct with an external nucleophile, leading to a one-pot three-component reaction. Table 1 summarizes the optimization process of newly discovered [3 + 2] cycloaddition reactions between α-isocyano lactam 1a, methyl acrylate 2a, and 4-F-benzylamine 3a to give a novel spirocyclic skeleton, 1,7-diazaspiro[4.4]nonane-2,6-dione with a formimidamide moiety, 4a. The reaction optimization started with the catalytic use of t-BuOK (10 mol %) in THF with different Ag(I) salts (entries 1−2). No significant effect of Ag(I) salts was observed where the 5/5-spirocyclic product 4a was obtained in 38−41% yields. The reaction temperature was next examined using other solvents (entries 3−5). The elevated reaction temperature between 80 and 110 °C was more suitable for the N−H addition to the isocyanide moiety, where the product 4a was obtained with an improved yield of 55%. The use of other
entry
base
cat.
solvent
yield (%)b
1 2 3 4 5 6 7 8 9c 10c 11d 12d 13d 14d 15d 16d 17d 18d 19d,e
t-BuOK t-BuOK t-BuOK t-BuOK t-BuOK Cs2CO3 K2CO3 t-BuOK t-BuOK t-BuOK t-BuOK t-BuOK t-BuOK t-BuOK t-BuOK t-BuOK t-BuOK t-BuOK t-BuOK
AgNO3 AgOAc AgOAc AgNO3 AgNO3 AgNO3 AgNO3 CuOAc CuOAc AgNO3 AgNO3/CuOAc AgNO3/CuOAc AgNO3/CuOAc AgNO3/CuOAc AgNO3/CuOAc AgNO3/CuOAc AgNO3/CuOAc AgNO3 AgNO3/CuOAc
THF THF CH3CN CH3CN PhCH3 CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN PhCH3 CH3CN/PhCH3 (1:1) THF/PhCH3 (1:1) CH3CN/PhCH3 (1:2) CH3CN/PhCH3 (1:4) CH3CN/PhCH3 (1:10) CH3CN/PhCH3 (1:4) CH3CN/PhCH3 (1:4)
41 38 28 55 55 39 16 22 52 17 60 46 71 39 70 75 41 60 34
a
Unless stated otherwise, reaction used 1a (0.22 mmol), 2a (0.20 mmol), 3a (0.24 mmol), base catalyst (10 mol %), and metal catalyst (10 mol %) in solvent (0.1 M) at reflux for 12 h. bIsolated yields after column chromatography. cUse of 20 mol % metal catalyst. dReaction for 6 h. eUse of 5 mol % metal catalysts.
bases did not improve the overall yield of 4a (entries 6−7). The possible role of Cu(I) salt was examined (entries 8−9), and the isolated yield of 4a remained at 22%. Interestingly, the increased catalyst amount of CuOAc to 20 mol % further improved the yield of 4a to 52%; however, the polymerization of methyl acrylate 2a could not be avoided upon using higher loadings of catalyst and elevated reaction temperature. The Cu(I) catalyst dependence indicated the possibility of the Ag(I) salt decomposition during the reaction since the higher AgNO3 loading led to a poor yield of 4a (17%, entry 10). Indeed, the formation of a silver mirror was often observed after the reaction as well as when the low yields of 4a were obtained. Since the reduction of Ag(I) salt is initiated by the isocyanides,14 it was necessary to minimize the interaction between the Ag(I) salt and the isocyanides. To this end, the combination of both Ag(I) and Cu(I) salts was tested since the reaction time could be reduced significantly (entries 11−17). Thus, the employment of Ag(I) and Cu(I) salts provided the desired product 4a in 60% yield within the reaction time of 6 h (entry 11). Further optimization using single and mixed solvent systems led to the identification of a suitable solvent system of CH3CN/PhCH3 (1:4), where the product 4a was obtained in 75% yield (entry 16). Also, the use of AgNO3 alone in our optimized conditions provided a less optimal yield of 4a, demonstrating the necessity of the combination of both Ag and Cu catalysts (entry 18). A control experiment using 5 B
DOI: 10.1021/acs.orglett.8b03118 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
3:2 diastereomeric ratio. In conjunction with electron-rich amine, the methyl crotonate increased the isolated yield of product 4r to a 61% yield. It should be noted that all 5/5spirocyclic pyrrolidinonylformimidamides were stable during the workup and subsequent purification procedures, illustrating the structural robustness of the (E)-formimidamide moiety. The Ag-catalyzed three-component reactions were further extended to 6- and 7-membered α-isocyano lactams 1b−1c (Scheme 3). While the use of 6-membered α-isocyano lactam
mol % of both metal catalysts led to the formation of 4a in 34% yield (entry 19). The scope of the silver-catalyzed three-component [3 + 2] cycloaddition to 5/5-spirocyclic bislactams was investigated using a variety of primary amines with different electronic and steric characters (Scheme 2). Benzylamines with different Scheme 2. Scope of Ag(I)-Catalyzed Three-Component [3 + 2] Cycloaddition Reactions to 5/5-Spirocycles
Scheme 3. Scope of Three-Component Reactions to 5/6-, 5/ 7-Spirocyclic and Non-Spirocyclic Lactams
a Major product of 95:5 dr. bIsolated overall yield using stepwise reactions.
1b provided the desired 5/6 spirocyclic bislactam 4s−4w in slightly lower yields than those of 5-membered α-isocyano lactam 1a, the 7-membered α-isocyano lactam 1c provided 5/ 7-spirocyclic pyrrolidinonylformimidamides 4x−4z that are readily hydrolyzed to give an N-formyl spirocyclic product 5c upon workup and purification procedures.15 The noncyclic αisocyano amide 1d and α-isocyano ester 1e are also suitable substrates for the current three-component cycloadditions; however, the pyrrolidin-2-one products 4za−4zb were obtained in 22−36% yields after the spontaneous hydrolysis of the corresponding pyrrolidinonylformimidamides followed by the deformylation. The preferential reaction pathway to pyrrolidinonylformimidamides over the conventional [3 + 2] cycloaddition products was scrutinized using the Michael addition product 6a (Scheme 4). It was quite interesting to observe the conjugate addition of α-isocyano lactam 1a to methyl acrylate 2a immediately after the addition of base even at 0 °C. After the quantitative formation of 6a was confirmed, the Ag(I) and Cu(I) catalysts were introduced into the reaction mixture. No reaction was observed in the absence of an added nucleophile, benzylamine. Considering the known stepwise [3 + 2] cycloaddition reaction pathway for azomethine ylides and electron-deficient alkenes,16 it is rather unexpected to find that the Michael addition product 6a did not undergo the
a
Major product of 87:13 dr. bMinor product in parentheses.
electronic characters provided good to excellent isolated yields of 5/5-spirocycles (4a−4d), in particular higher yields for electron-rich benzylamines in 88−90% yields. The use of other primary alkyl amines also provided the desired products (4e− 4g) in 56−63% yields, indicating the preferential addition of amines to an isocyanide moiety of the Michael addition product over the simple amidation between the methyl ester and the amine. The optimized three-component reaction conditions could be applied to other amines such as furfuryl amine (4h), aniline derivatives (4i−4j), and 2-pyridylamine (4k). The effect of N-substitutions on the α-isocyano lactam 1a was minimal since other benzyl groups (4l−4n) and the pOMe-phenyl group (4o) were well tolerated under the conditions. The use of methyl crotonate under the optimized reaction conditions provided the diastereomeric Michael addition products in an 87:13 ratio, eventually producing a diastereomerically pure product 4p in 47% yield. The relative stereochemical outcome has been established by X-ray crystallographic analysis of 4p (CCDC 1861276). The use of methyl cinnamate resulted in the formation of product 4q in a C
DOI: 10.1021/acs.orglett.8b03118 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 4. Mechanistic Pathways between Concerted [3 + 2] Cycloaddition and Michael Addition Reactions
Scheme 5. A Plausible Reaction Mechanism for the Stepwise Ag(I)-Catalyzed Three-Component Reactions
a
preferential silver coordination to the isocyanide moiety of the Michael addition product, not the α-isocyano lactam starting material. The subsequent amine coordination to the Ag(I) metal promotes the nucleophilic attack of the amine to the carbon atom of the isocyanide moiety,21 resulting in the formation of formimidamines after the protodesilveration (see the Supporting Information for the silver complexation study by 13C NMR). The formimidamine can undergo isomerization followed by the intramolecular lactamization to give the desired spirocyclic pyrrolidinonylformimidamides. In summary, we have developed the Ag(I)-catalyzed [3 + 2] cycloaddition reactions of α-isocyano lactams where the isocyanide moiety serves as a two-atom unit with nucleophilic character. The typical three-atom unit role of α-isocyano carbonyl compounds in the [3 + 2] cycloaddition reactions has been altered for the first time, where an extra reaction component, amines, could be introduced to the reaction scheme, allowing direct access to novel spirocyclic bislactam derivatives. The facile three-component reaction for spirocyclic pharmaceutical building blocks has been achieved in good to excellent yields with an unusual isocyanide activation mode. Recognizing the different rates of reaction pathways was instrumental in the development of multicomponent reactions, where the unprecedented dianionic character of the isocyanide moiety has been showcased for the first time. Further extension of the Ag(I)-catalyzed multicomponent reaction is currently underway, and our results will be reported in due course.
Isolated yield after column chromatography. bIsolated yield in a onepot reaction from α-isocyano lactam 1 and acrylate 2.
intramolecular Mannich-type cyclization to form the conventional [3 + 2] cycloaddition product 7a, even at the higher reaction temperature of 110 °C. While the reversal addition of base and metal catalysts only led to the decomposition of αisocyano lactam 1a and methyl acrylate 2a, the expected [3 + 2] cycloaddition products 7b−c were obtained in 52−74% yields under the reverse addition conditions when methyl methacrylate and methyl cinnamate were employed. In addition, when the N-Bn group of the α-isocyano lactam was replaced with an N-p-OMePh group, the formation of the normal [3 + 2] cycloaddition product 7d was observed in about 20% yield.17 To further scrutinize the reaction mechanism, we prepared the intermediate Michael addition products 6b−d by adding a base first. The fact that the Michael products 6b−d did not undergo the intramolecular Mannichtype cyclization under the subsequent metal catalysts conditions demonstrated the concerted [3 + 2] cycloaddition reactions to the product 7b−d, not from the stepwise reaction pathway via the Michael product 6b−d.18 The above experiments suggested the two distinctive reaction pathways: the concerted [3 + 2] cycloaddition reaction pathway when both metal and base catalysts were present, but the fast Michael reaction pathway with the base catalyst alone. Also, our results confirmed that the conventional [3 + 2] cycloaddition products from the reaction of α-isocyano lactam and acrylate would not be formed via the stepwise reaction pathway, but through the concerted reaction pathway. While it was evident that the concerted [3 + 2] cycloaddition pathway could compete for some substrates such as crotonates and cinnamates, such reaction pathways were avoided through a one-pot procedure using base and metal catalysts in the presence of amine nucleophiles.19 Since the Michael addition of α-isocyano lactam 1 to acrylate 2 is extremely fast, the presence of an amine nucleophile in the reaction mixture exclusively led to the formation of pyrrolidinonylformimidamide 4 in excellent yields. Our control experiments also demonstrated that the amine nucleophile did not attack the Michael acceptor 2a, and an N-benzylacrylamide did not undergo the reaction with 1a under the varied reaction conditions, demonstrating the nucleophilic attack of the amine to the isocyanide moiety of 6a under the reaction conditions.20 Based on the experimental observations and the reaction outcomes, a plausible reaction mechanism for the formation of pyrrolidinonylformimidamides is depicted in Scheme 5. The facile Michael reaction of α-isocyano lactams ensures the
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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.8b03118. Experimental procedures and characterization data for all new compounds (PDF) Accession Codes
CCDC 1861276 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. D
DOI: 10.1021/acs.orglett.8b03118 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters ORCID
(11) (a) Tong, S.; Wang, Q.; Wang, M.-X.; Zhu, J. Angew. Chem., Int. Ed. 2015, 54, 1293−1297. (b) Tong, S.; Wang, Q.; Wang, M.-X.; Zhu, J. Chem. - Eur. J. 2016, 22, 8332−8338. (c) Clemenceau, A.; Wang, Q.; Zhu, J. Org. Lett. 2017, 19, 4872−4875. (d) Zhang, L.; Li, J.; Hu, Z.; Dong, J.; Zhang, X.-M.; Xu, X. Adv. Synth. Catal. 2018, 360, 1938−1942. (12) (a) Meng, T.; Zou, Y.; Khorev, O.; Jin, Y.; Zhou, H.; Zhang, Y.; Hu, D.; Ma, L.; Wang, X.; Shen, J. Adv. Synth. Catal. 2011, 353, 918− 924. (b) Clemenceau, A.; Wang, Q.; Zhu, J. Org. Lett. 2018, 20, 126− 129. (13) (a) George, J.; Kim, H. Y.; Oh, K. Adv. Synth. Catal. 2016, 358, 3714−3718. (b) George, J.; Kim, H. Y.; Oh, K. Org. Lett. 2017, 19, 628−631. (14) Xiao, P.; Yuan, H.; Liu, J.; Zheng, Y.; Bi, X.; Zhang, J. ACS Catal. 2015, 5, 6177−6184. (15) The 5/7-spirocyclic pyrrolidinonylformimidamides, 4x−4z, were prepared from the purified conjugate addition products due to the facile deformylation in the products, requiring rapid column chromatographic separations. The 5/5- and 5/6-spirocyclic pyrrolidinonylformimidamides could be hydrolyzed to obtain the corresponding N-formyl spirocyclic products 5a and 5b (see Supporting Information for details). (16) (a) Kim, H. Y.; Li, J.-Y.; Kim, S.; Oh, K. J. Am. Chem. Soc. 2011, 133, 20750−20753. (b) Li, J.-Y.; Kim, H. Y.; Oh, K. Adv. Synth. Catal. 2016, 358, 984−993. (17) The addition order of catalysts is important to give the conventional [3 + 2] cycloaddition product 7c, since the first introduction of base catalyst, t-BuOK, only led to the formation of the single Michael product that did not further react; see the Supporting Information for more details. (18) Likewise the [3 + 2] cycloaddition product 7d must have been formed from the concerted [3 + 2] cycloaddition reaction between αisocyano lactam 1ad and dimerized methyl acrylate, not from the stepwise reaction of double Michael addition followed by the intramolecular Mannich-type cyclization. Our control experiment using an authentic sample of dimerized methyl acylate, and 1ad clearly demonstrated the facile formation of 7d in 38% yield with 3:2 dr under the reaction conditions; see the Supporting Information for details. (19) The sequestration of metal catalysts by the primary amine nucleophile should have promoted the Michael addition pathway; thus, the elevated reaction temperature was needed to free the metal complexes for the following amine insertion to the isocyanide moiety. In our NMR experiments, we have observed the competitive metal binding role of the amine nucleophile with the isocyanide moiety; see the Supporting Information for details. (20) The possible involvement of radical species from the amide enolate of α-isocyano lactam was ruled out from the reaction using a radical inhibitor TEMPO (1 equiv), where the formation of spirocyclic pyrrolidinonylformimidamide 4b was obtained in 52% yield as opposed to an 88% yield in the absence of TEMPO. (21) For the silver−amine complexes, see: (a) Hancock, R. D. J. Chem. Soc., Dalton Trans. 1980, 416−418. For a comprehensive review, see: (b) Di Bernardo, P.; Melchior, A.; Portanova, R.; Tolazzi, M.; Zanonato, P. L. Coord. Chem. Rev. 2008, 252, 1270−1285. (c) Á lvarez-Corral, M.; Muñoz-Dorado, M.; Rodríguez-García, I. Chem. Rev. 2008, 108, 3174−3198.
Kyungsoo Oh: 0000-0002-4566-6573 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This research was supported by the Chung-Ang University Research Scholarship Grants in 2017 and the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (NRF-2015R1A5A1008958).
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REFERENCES
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DOI: 10.1021/acs.orglett.8b03118 Org. Lett. XXXX, XXX, XXX−XXX
