Letter Cite This: Org. Lett. 2017, 19, 6724−6727
pubs.acs.org/OrgLett
Esters as Alkynyl Acyl Ammonium and Azolium Precursors: A Formal [2 + 3] Annulation with Amidomalonates via Lewis Base/Lewis Acid Cooperative Catalysis Jing Cao,† Kewen Sun,† Shuding Dong, Tao Lu, Ying Dong,* and Ding Du* State Key Laboratory of Natural Medicines, Department of Organic Chemistry, China Pharmaceutical University, Nanjing 210009, P. R. China S Supporting Information *
ABSTRACT: Esters are for the first time used as α,β-unsaturated alkynyl acyl ammonium and azolium precursors to undergo a formal [2 + 3] annulation with amidomalonates through DMAP/LiCl or carbene/LiCl cooperative catalysis. A wide range of (Z)-5-amino-3furanones were obtained in moderate to high yields with high regioselectivity and stereoselectivity. In addition, a plausible mechanism based on the calculated charge distribution of the intermediates is proposed to explain the regioselectivity. rganocatalytic transformation of α,β-unsaturated carbonyl compounds has been a topic of interest for research over the past several decades. Within this area, α,β-unsaturated alkenyl acylammonium I has been explored as a highly versatile intermediate derived from the combination of acid derivatives with tertiary amines (Figure 1a).1 α,β-Unsaturated alkenyl
O
neglected and was rarely explored (Figure 1b). Previously, we reported the first application of alkynyl acylammonium III as an electrophilic 3C synthon in a formal [3 + 3] annulation with enolizable ketones for the regioselective synthesis of functionalized 4H-pyran-4-ones via a Lewis base/Lewis acid dualactivation strategy.5 Esters are a basic class of important carbonyl compounds that play a significant role in organic synthesis. NHC-catalyzed activation of esters for transesterifications has been well established.6 In recent years, the activation of enolizable esters or α,β-unsaturated alkenyl esters with NHCs for their α-, β-, or γ- functionalization has attracted much attention.7 Lupton8 pioneered the generation of α,β-unsaturated acylazoliums II from α,β-unsaturated enol esters with NHC catalysis in 2009, while Chi7e,9 later reported NHC-catalyzed activation of p-nitrophenyl esters as the acylazolium precursors. Recently, N-hydroxyphthalimide7d and N-hydroxybenzotriazole esters7c,g have also been successfully used as acylazolium precursors in various annulation reactions. Very recently, Smith reported a new general concept for alkenyl acylammonium catalysis using α,β-unsaturated p-nitrophenyl esters as the acylammonium precursors.1f Based on these findings, we assumed that upon reaction with an NHC or a tertiary amine, α,β-unsaturated alkynyl esters could be converted to α,β-unsaturated alkynyl azolium IV or ammonium III that may display unique reactivity for novel reaction design (Figure 1b). Therefore, we used stable but reactive p-nitrophenyl alkynyl esters 1 as the alkynyl acyl ammonium or azolium precursors that were employed to react with amidomalonates. Interestingly, instead of the pyranones formed via 6-endo-dig cyclization in our previous work, (Z)-5-amino-3-furanone products10 3 were obtained in a highly regioselective and stereoselective manner via a 5-exo-dig cyclization process. Herein, we report the first
Figure 1. (a) Alkenyl acyl ammonium and azolium; (b) alkynyl acyl ammonium and azolium.
acylazolium II represents another important intermediate generated from diverse precursors with N-heterocyclic carbene (NHC) catalysis (Figure 1a).2 These two classes of intermediates both have three disparate reactive sites that have been utilized in diverse annulations or tandem reactions. Although alkenyl acylammonium I and azolium II have been intensively investigated as versatile 3C synthons, the chemistry of alkynyl acyl ammonium III3 and azolium IV4 seems to be © 2017 American Chemical Society
Received: November 7, 2017 Published: December 1, 2017 6724
DOI: 10.1021/acs.orglett.7b03453 Org. Lett. 2017, 19, 6724−6727
Letter
Organic Letters Table 2. Scope of the Reactiona
application of alkynyl acyl ammonium and azolium in the formal [2 + 3] annulation through Lewis base/Lewis acid cooperative catalysis. We commenced our study with the reaction of 4-nitrophenyl 3-phenylpropiolate 1a and ethyl N-benzylmalonamide 2a using DIPEA as a base in CH3CN (Table 1 entry 1), which did not
yieldb (%)
Table 1. Optimization of the Reaction Conditionsa
entry
cat. (x mol %)
additive
yieldb (%)
1 2 3 4 5 6 7 8 9
none A (110) A (110) none A (10) B (10) C (10) D (10) E (10)
none none LiClc LiClc LiClc LiClc LiClc LiClc LiClc
0 70 95 0 92 trace 51 95 95
entry
R1, 1
R2, R3, 2
3
DMAP
E
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20d 21d 22 23 24 25 26 27 28 29
C6H5, a C6H5, a C6H5, a C6H5, a C6H5, a C6H5, a C6H5, a C6H5, a C6H5, a 4-FC6H4, b 4-ClC6H4, c 4-BrC6H4, d 4-MeC6H4, e 4-OMeC6H4, f 3-FC6H4, g 3-ClC6H4, h 3-MeC6H4, i 2-FC6H4, j 2-ClC6H4, k 2-MeC6H4, l 2-OMeC6H4, m 1-naphthyl, n 2-naphthyl, o 2-thienyl, p Me, q Et, r n-pentyl, s cyclopropyl, t H, u
Et, Bn, a Et, CH(Me)Ph, b Et, Ph, c Et, Me, d Et, Boc, e Et, Cbz, f Me, Bn, g Bn, Bn, h iPr, Bn, i Et, Bn, a Et, Bn, a Et, Bn, a Et, Bn, a Et, Bn, a Et, Bn, a Et, Bn, a Et, Bn, a Et, Bn, a Et, Bn, a Et, Bn, a Et, Bn, a Et, Bn, a Et, Bn, a Et, Bn, a Et, Bn, a Et, Bn, a Et, Bn, a Et, Bn, a Et, Bn, a
a b c d
92 99 99 62 c c 99 44 trace 76 81 51 41 50 71 60 63 60 50 trace trace 48 48 60 63 70 76 77 trace
95 99 99 77 c c 96 37 trace 71 68 56 41 42 68 60 69 55 50 trace trace 48 45 42 56 50 76 67 trace
All reactions were performed in a 10 mL flask on a 0.1 mmol scale with 1.0 equiv of 1a, 1.2 equiv of 2a, 1.2 equiv of DIPEA, 100 mg of 4 Å MS (molecular sieves), in anhydrous CH3CN (3 mL) at 65 °C under N2. bIsolated yields based on 1a. c1.1 equiv of LiCl was added. Mes = 2,4,6-(CH3)3C6H2. a
work in the absence of both a Lewis base and a Lewis acid. To our delight, a 70% yield of (Z)-5-amino-3-furanone product 3a was obtained as a single isomer when 1.1 equiv of DMAP (A) was used (entry 2). The structure of 3a was established by analysis of its NMR data and was further confirmed by X-ray crystallography. The combination of DMAP and LiCl as a cooperative catalysis system could enhance the reaction yield to 95% (entry 3). However, exclusive use of LiCl was ineffective for this transformation, which indicated that DMAP was critical to this reaction (entry 4). The reaction worked equally well with a comparable yield even if the catalyst loading was decreased to 10% (entry 5). As we have great interest in the investigation of novel NHC-bound intermediates and their chemical transformations,11 a series of NHC precursors were then screened to test the possibility of generation of alkynyl acylazolium intermediate that has not been intensively studied yet (entries 6−9). Compound C, D, and E were found to be effective for this reaction. Compounds D and E seemed to have similar catalytic efficiency, both affording product 3a in 95% yield (entries 8 and 9). Finally, DMAP (10%) (entry 5) and E (10%) (entry 9), respectively, were selected as the optimal catalysts used for further reaction scope exploration. With the optimized conditions in hand, we then focused our attention to probing the reaction scope with two different catalytic systems (Table 2). Initially, a variety of amidomalonates 2b−i with diverse substituents on nitrogen and oxygen were examined (entries 2−9). Amidomalonates 2b−d with N-phenyl or alkyl groups afforded the corresponding products 3b−d in moderate to excellent yields (entries 2−4), while N-Bocsubstituted 2e and N-Cbz-substituted 2f gave complex products (entries 5 and 6). The variation in the size of the ester group also
e f g h i j k l m n o p q r s t u v w
All reactions were performed in a 10 mL flask on a 0.1 mmol scale with 1.0 equiv of 1, 1.2 equiv of 2, 1.2 equiv of DIPEA, 1.1 equiv of LiCl, 10 mol % of DMAP or cat. E, 100 mg of 4 Å MS (molecular sieves), in anhydrous CH3CN (3 mL) at 65 °C under N2. bIsolated yields based on 1. cThe reaction was complex. dLow conversion of the substrates. a
affected the outcome significantly. The reaction of 2g and 2h with bigger ester groups either resulted in decreased yields or did not work at all (entries 8 and 9). Subsequently, the generality of the alkynyl esters 1 was evaluated (entries 10−29). Esters 1b−k with β-phenyl groups bearing electron-withdrawing or -donating substituents at various positions could be tolerated in the reaction, and the corresponding products 3g−p were isolated exclusively as Z-isomer in moderate to high yields under two different catalytic systems (entries 10−19). However, the more steric hindered esters 1l and 1m were not suitable for this protocol (entries 20 and 21). Esters 1n−p containing fused aryl rings or a heteroaromatic ring at β-position were also tolerated to both catalysts (entries 22−24). Then, β-aliphatic-substituted esters 1q−t were tested (entries 25−28). The size and length of the alkyl groups at β-position seemed to have little impact on the reaction results because both DMAP and E could produce the desired products 3t−w in moderate to good yields. Nevertheless, the presence of an aryl or an alkyl group at the β-position of esters was essential since 1u without β-substituents was not tolerated in 6725
DOI: 10.1021/acs.orglett.7b03453 Org. Lett. 2017, 19, 6724−6727
Letter
Organic Letters
low using either Sc(OTf)3 or LiCl as the Lewis acid (LA) (Scheme 1d). A scale-up synthesis was then carried out using DMAP and NHC precursor E as the catalyst, respectively (Scheme 1e). The reaction using DMAP or E afforded the desired product 3a equally in good yields. Finally, the derivatization of the product was demonstrated by the aminolysis of 3a or 3e with butan-1-amine affording amide 10 in high yields (Scheme 1f). A plausible mechanism for the regioselective synthesis of (Z)5-amino-3-furanone products 3 in the presence of DMAP or catalyst E is depicted in Scheme 2 using ester 1a and ethyl N-
both catalytic systems (entry 29). Basically, these two different protocols could tolerate a wide range of esters and certain amidomalonates, affording the desired products in comparable yields as well as excellent regioselectivity and stereoselectivity. To further explore the synthetic utility of this protocol, the reaction of β-ketoamide 4 with several alkynyl esters 1 was examined (Scheme 1a). It was found that β-substituents of Scheme 1. Synthetic Applications
Scheme 2. Proposed Mechanism
benzylmalonamide 2a as the model substrates. The nucleophilic attack of ester 1a with DMAP or NHC E′ generated upon the deprotonation of E with DIPEA affords the acyl ammonium intermediate III-1 and acyl azolium intermediate IV-1, respectively. The subsequent 1,2-addition of carbon-centered nucleophile 2a′ derived from 2a under DIPEA/LiCl conditions to III-1 or IV-1 produces intermediate 11 that might be unstable and was not isolated in the reaction system. Then, oxygen anion intermediate 12 was generated upon the deprotonation of 11 with DIPEA. There are two possible pathways for the subsequent intramolecular nucleophilic addition to the triple bond. If the oxygen anion of 12 attacked the α-carbon, 5-exo-dig cyclization product 3a will be formed (path a); if the oxygen anion attacked the β-carbon, 6-endo-dig cyclization product 3a′ will be formed (path b). Actually, 5-exo-dig cyclization product 3a was obtained in a highly regioselective manner that can be explained by the calculated charge distribution of intermediates 11 and 12. The αcarbons of intermediate 11 and 12 are both positively charged and the β-carbons are both negatively charged. Therefore, intramolecular nucleophilic attack of the oxygen anion to the αcarbon to form the 5-exo-dig cyclization products is favored. The high stereoselectivity of this process for the exclusive formation
alkynyl esters had great impact on the reaction results. The reaction between β-ketoamide 4 and β-phenyl alkynyl ester 1a afforded 3-furanone product 5, while the reactions of 4 with β-(4substituted or 3-substituted) phenyl alkynyl esters 1b, 1e, 1h and 1i or β-alkyl alkynyl esters 1q, 1s and 1t afforded γ-pyranone products 6a−g in low to moderate yields. Differing from above results, the reaction of 4-nitrophenyl propiolate 1u and pent-2ynoate 1r afforded α-pyranone products 7a and 7b, respectively. The structures of these compounds can be established by NMR analysis of their chemical shifts of carbons and coupling of the alkenyl hydrogens. The reaction between diethyl malonate and 1a was further examined in the presence of DMAP or E which produced C−C coupling product 8 in high yields (Scheme 1b).12 Since acyl ammoniums and acyl azoliums can be generated from the corresponding acyl chlorides with a Lewis base, we carried out the reaction of 2a with alkynyl acyl chloride 9. As a result, the reaction did not work either in the absence of DMAP or in the presence of catalyst E, while the reaction in the presence of DMAP afforded the desired product 3a in 35% yield within two steps (Scheme 1c). An in situ activation strategy used in our previous work5 was also tested; however, the reaction yields were 6726
DOI: 10.1021/acs.orglett.7b03453 Org. Lett. 2017, 19, 6724−6727
Letter
Organic Letters
Chem. Soc. Rev. 2015, 44, 5040. (c) Flanigan, D. M.; RomanovMichailidis, F.; White, N. A.; Rovis, T. Chem. Rev. 2015, 115, 9307. (d) Mahatthananchai, J.; Bode, J. W. Acc. Chem. Res. 2014, 47, 696. (e) Hopkinson, M. N.; Richter, C.; Schedler, M.; Glorius, F. Nature 2014, 510, 485. (f) Tang, W.; Du, D. Chem. Rec. 2016, 16, 1489. (g) Ryan, S. J.; Candish, L.; Lupton, D. W. Chem. Soc. Rev. 2013, 42, 4906. (h) De Sarkar, S.; Biswas, A.; Samanta, R. C.; Studer, A. Chem. Eur. J. 2013, 19, 4664. (i) Chen, X.-Y.; Ye, S. Org. Biomol. Chem. 2013, 11, 7991. (j) Izquierdo, J.; Hutson, G. E.; Cohen, D. T.; Scheidt, K. A. Angew. Chem., Int. Ed. 2012, 51, 11686. (3) Ucuncu, M.; Canturk, C.; Karakus, E.; Zeybek, H.; Bozkaya, U.; Soydas, E.; Sahin, E.; Emrullahoglu, M. Org. Biomol. Chem. 2016, 14, 7490. (4) Ma recently reported the direct oxidative N-acylation of primary amides with α,β-unsaturated alkynyl acylazoliums from ynals: Zheng, C.; Liu, X.; Ma, C. J. Org. Chem. 2017, 82, 6940. (5) Dong, S.; Fang, C.; Tang, W.; Lu, T.; Du, D. Org. Lett. 2016, 18, 3882. (6) (a) Grasa, G. A.; Kissling, R. M.; Nolan, S. P. Org. Lett. 2002, 4, 3583. (b) Hepperle, J. A. M.; Samanta, R. C.; Studer, A. Synlett 2013, 24, 1233. (c) Zeng, T.; Song, G.; Li, C.-J. Chem. Commun. 2009, 6249. (d) Singh, R.; Nolan, S. P. Chem. Commun. 2005, 5456. (e) Singh, R.; Kissling, R. M.; Letellier, M.-A.; Nolan, S. P. J. Org. Chem. 2004, 69, 209. (7) (a) Chauhan, P.; Enders, D. Angew. Chem., Int. Ed. 2014, 53, 1485 and references cited therein. (b) Xu, J.; Yuan, S.; Miao, M.; Chen, Z. J. Org. Chem. 2016, 81, 11454. (c) Que, Y.; Li, T.; Yu, C.; Wang, X.-S.; Yao, C. J. Org. Chem. 2015, 80, 3289. (d) Zhang, Z.; Zeng, X.; Xie, D.; Chen, D.; Ding, L.; Wang, A.; Yang, L.; Zhong, G. Org. Lett. 2015, 17, 5052. (e) Fu, Z.; Wu, X.; Chi, Y. R. Org. Chem. Front. 2016, 3, 145. (f) Candish, L.; Levens, A.; Lupton, D. W. Chem. Sci. 2015, 6, 2366. (g) Xia, W.; Yao, H.; Liu, D.; Zhao, L.; Zhou, Y.; Liu, H. Adv. Synth. Catal. 2016, 358, 1864. (8) Ryan, S. J.; Candish, L.; Lupton, D. W. J. Am. Chem. Soc. 2009, 131, 14176. (9) (a) Hao, L.; Du, Y.; Lv, H.; Chen, X.; Jiang, H.; Shao, Y.; Chi, Y. R. Org. Lett. 2012, 14, 2154. (b) Cheng, J.; Huang, Z.; Chi, Y. R. Angew. Chem., Int. Ed. 2013, 52, 8592. (c) Hao, L.; Chen, S.; Xu, J.; Tiwari, B.; Fu, Z.; Li, T.; Lim, J.; Chi, Y. R. Org. Lett. 2013, 15, 4956. (d) Fu, Z.; Jiang, K.; Zhu, T.; Torres, J.; Chi, Y. R. Angew. Chem., Int. Ed. 2014, 53, 6506. (10) 3-Furanone is the core structure of many natural products or synthetic compounds. For selected examples, see: (a) Irie, T.; Asami, T.; Sawa, A.; Uno, Y.; Hanada, M.; Taniyama, C.; Funakoshi, Y.; Masai, H.; Sawa, M. Eur. J. Med. Chem. 2017, 130, 406. (b) Raju, R.; Gromyko, O.; Fedorenko, V.; Herrmann, J.; Luzhetskyy, A.; Müller, R. Tetrahedron Lett. 2013, 54, 900. (c) Varghese, B.; Al-Busafi, S. N.; Suliman, F. O.; AlKindy, S. M. Z. New J. Chem. 2015, 39, 6667. (d) Kong, F.; Singh, M. P.; Carter, G. T. J. Nat. Prod. 2005, 68, 920. (e) Wang, F.; Lu, S.; Chen, B.; Zhou, Y.; Yang, Y.; Deng, G. Org. Lett. 2016, 18, 6248. (11) (a) Fang, C.; Lu, T.; Zhu, J.; Sun, K.; Du, D. Org. Lett. 2017, 19, 3470. (b) Xu, J.; Zhang, W.; Liu, Y.; Zhu, S.; Liu, M.; Hua, X.; Chen, S.; Lu, T.; Du, D. RSC Adv. 2016, 6, 18601. (c) Xu, J.; Hu, S.; Lu, Y.; Dong, Y.; Tang, W.; Lu, T.; Du, D. Adv. Synth. Catal. 2015, 357, 923. (d) Jiang, D.; Dong, S.; Tang, W.; Lu, T.; Du, D. J. Org. Chem. 2015, 80, 11593. (e) Zhang, Y.; Lu, Y.; Tang, W.; Lu, T.; Du, D. Org. Biomol. Chem. 2014, 12, 3009. (f) Lu, Y.; Tang, W.; Zhang, Y.; Du, D.; Lu, T. Adv. Synth. Catal. 2013, 355, 321. (g) Du, D.; Hu, Z.; Jin, J.; Lu, Y.; Tang, W.; Wang, B.; Lu, T. Org. Lett. 2012, 14, 1274. (12) On one hand, the calculated charge distribution (see the Supporting Information) of 8 shows that the two carbons of the triple bond are both negatively charged, which disfavors intramolecular nucleophilic attack to form a ring. On the other hand, 8 is stabilized via intramolecular hydrogen bonding between the ester carbonyl and enolic hydrogen.
of Z-isomers may be attributed to the less steric conflict between the alkenyl hydrogen and carbonyl group. In conclusion, we have demonstrated the first application of esters as alkynyl acyl ammonium and azolium precursors that have been utilized to undergo a formal [2 + 3] annulation with amidomalonates. In these two protocols with DMAP/LiCl and NHC/LiCl cooperative catalysis, respectively, a wide range of (Z)-5-amino-3-furanones were obtained in moderate to high yields with high regioselectivity and stereoselectivity. Additionally, a plausible mechanism is proposed to explain the formation of target compounds via 5-exo-dig cyclization that is favored by the charge distribution of the triple bond of the intermediate 12. The methods developed in this work offer a guideline for further investigation of the chemistry of α,β-unsaturated alkynyl acyl ammoniums and azoliums, which is currently underway in our laboratory.
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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.7b03453. Experimental procedures and spectral data for all compounds (PDF) Accession Codes
CCDC 1569434 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 data_
[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 Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Ying Dong: 0000-0002-4397-4695 Ding Du: 0000-0002-4615-5433 Author Contributions †
J.C and K.S. contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work is funded by the National Natural Science Foundation of China (No. 21572270), the Qing Lan Project of Jiangsu Province, and the Priority Academic Program Development of Jiangsu Higher Education Institutions.
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REFERENCES
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DOI: 10.1021/acs.orglett.7b03453 Org. Lett. 2017, 19, 6724−6727
