Letter pubs.acs.org/OrgLett
Silver-Catalyzed Cascade Reaction of β‑Enaminones and Isocyanoacetates To Construct Functionalized Pyrroles Guichun Fang,†,∥ Jianquan Liu,†,§,∥ Junkai Fu,*,† Qun Liu,† and Xihe Bi*,†,‡ †
Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis, Department of Chemistry, Northeast Normal University, Changchun 130024, China ‡ State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China § School of Chemistry and Chemical Engineering, Jiangsu Key Laboratory of Green Synthesis for Functional Materials, Jiangsu Normal University, Xuzhou 221116, China S Supporting Information *
ABSTRACT: An unexpected silver-catalyzed cascade reaction of β-enaminones and isocyanoacetates affording functionalized pyrrole derivatives is reported. In this reaction, tautomeric equilibria of β-enaminones are utilized to generate imine partners in situ. A hypothesized sequential Mannich addition/ cyclization of imine tautomers and isocyanoacetates followed by an unprecedented ring-opening of the resultant 2-imidazolines and dehydration−condensation deliver the final 1,2,4,5-tetrasubstituted pyrrole products.
T
automeric phenomena, in general, are of great importance in many areas of chemistry and biochemistry.1 Different isomers of a molecule usually have different molecular characteristics, which provide an efficient entry to the access of some thermodynamically unstable or not easily synthesized compounds. Base- or metal-promoted sequential Mannich-type addition/ cyclization of isocyanoacetates and imine electrophiles provides a straightforward method to 2-imidazolines,2 versatile compounds3 used as precursors to 2,3-diamino acids4,2c,d and Nheterocyclic carbene ligands.5 However, this formal [3 + 2] dipolar cycloaddition is restricted to the imines bearing electron-deficient groups (eq 1 in Figure 1). Recently, Orru et al. developed a flexible multicomponent reaction by mixing aldehydes and amines to generate imines in situ (eq 2 in Figure 1).6 In spite of a comparatively long reaction time, this strategy broadly extends the scope of the substrates. A large range of aliphatic, aromatic, and olefinic substituents are allowed for both aldehyde and amine components. In this case, searching for some supplementary approaches to preform imines for this formal [3 + 2] dipolar cycloaddition is of great value. β-Enaminones are versatile, readily obtainable building blocks and have received considerable attention in recent years.7 One of the main characteristics of this chemistry is the tautomeric equilibrium of β-enaminone with β-ketoimine (eq 3 in Figure 1).8 Although the latter one is a minor tautomer, this equilibrium could yet be considered as a potential supply of imines.9 Therefore, we envisioned that β-enaminones might be serviced as a valid source of imines to take part in the formal [3 + 2] dipolar cycloaddition with isocyanoacetates. Compared to the normal methods, this strategy not only features employment of stable and readily available β-enaminones as the © XXXX American Chemical Society
Figure 1. Cascade reaction of β-aminoenones and isocyanoacetates to construct 1,2,4,5-tetrasubstituted pyrroles.
equivalent of imines, especially for the unstable aliphatic imines, but also facilitates potential cascade reactions due to the multifunctional groups on β-enaminones. Highly focused on its versatile functionality, our group has been making unremitting efforts on isocyanide chemistry.10,11 Herein, we report, for the first time, a silver-catalyzed11c cascade Received: January 21, 2017
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DOI: 10.1021/acs.orglett.7b00201 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters reaction of β-enaminones and isocyanoacetates to construct functionalized pyrrole derivatives.12 Initially, the reaction of α-ester-β-enaminone (1a) and ethyl isocyanoacetate (2a) in 1,4-dioxane at 80 °C was selected as a model system (Table 1). Various metal salts that could
Scheme 1. Construction of Pyrroles via Cascade Reaction of β-Enaminones and Isocyanoacetatesa,b
Table 1. Optimization of the Reaction Conditionsa
entry
catalyst
temp (°C)
solvent
yieldb (%)
1 2 3 4 5 6 7 8 9 10 11 12 13
Ag2O AgF AgOAc Ag2CO3 Pd(OAc)2 CuI DBU
80 80 80 80 80 80 80 80 80 80 80 60 100
1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane toluene DCE DMF 1,4-dioxane 1,4-dioxane
73 0 56 83 0 30 0 0 77 16 0 45 72
Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3
a
All reactions were carried out in 0.25 M solvent with 10 mol % of catalyst under nitrogen atmosphere. bIsolated yields. a
All reactions were carried out in 0.25 M 1,4-dioxane with 10 mol % of Ag2CO3 under a nitrogen atmosphere at 80 °C for 6−24 h. bIsolated yields. PMP = 4-MeOC6H4.
2c,d,f
promote deprotonation of isocyanoacetate were evaluated. Although the addition of AgF gave no desired product, other silver salts have proven to be active species (entries 1−4). When Ag2CO3 was employed as the catalyst, to our delight, the yield of pyrrole 3a was increased to 83%. Other types of metal salts, such as Pd(OAc)2 and CuI, made no effect on the reaction or resulted in a low yield (entries 5 and 6). Basic conditions, which were general promotors in formal [3 + 2] cycloaddition of imines and isocyanoacetates,2a were also tested. However, in this case, only starting material was recovered (entry 7). A control experiment in the absence of silver salts gave no desired product, indicating that Ag2CO3 played an essential role in the reaction (entry 8). Further screening of reaction solvents (entries 9−11) and reaction temperatures (entries 12 and 13) showed that 1,4-dioxane and 80 °C were the best choices. In light of these results, the optimized conditions for this reaction were Ag2CO3 (10 mol %) in 1,4-dioxane at 80 °C for 6 h. With the optimized reaction conditions in hand, we investigated the substrate scope, and the results are shown in Scheme 1. First, we tested different β-enaminones 1. Various substituted phenyl groups could be tolerated on the nitrogen atom, including both electron-deficient I−, Br−, Cl−, F− and CF3− (3b−g) and electron-rich MeO− and −OCH2O− (3h and 3i). Other types of aryl rings, such as naphthalene- and pyridine-derived β-enaminones, were also suitable partners for the reaction to give the corresponding pyrroles 3j and 3k in good yields. In addition, besides the methyl group, the R1 moiety could also be ethyl and n-propyl groups, and the products 3l and 3m were obtained in 81% and 89% yields, respectively. The structure of 3m was further confirmed by Xray crystallographic analysis.13 The R groups on the α-position of β-enaminone were proven to be various electron-with-
drawing groups (EWGs), including methyl and phenyl ketone (3r,s) and a number of esters, such as methyl, benzyl, n-pentyl, and propenyl esters (3n−q). Methyl isocyanoacetate 2b was also a suitable partner to give pyrrole 3t. The aldimine part of pyrrole products could be removed under basic conditions to give corresponding 1H-pyrroles (for details, see the SI). In an effort to better understand the reaction profile, control experiments were carried out (Scheme 2). Deuterium-labeling studies using 2.0 equiv of D2O resulted in the formation of pyrrole 3m with deuterium on the imine carbon (30%), which suggested that proton transfer occurred between the imine− metal complex intermediate and D2O in the reaction cycle (see Scheme 2. Mechanistic Investigations
B
DOI: 10.1021/acs.orglett.7b00201 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters Scheme 3). When 4-bromoaniline was added into the reaction mixture in the presence of β-enaminone 1n and isocyanoacetate
Scheme 4. Formation of 1H-Pyrroles in the Presence of H2O
Scheme 3. Plausible Mechanism
In conclusion, we have developed a novel silver-catalyzed cascade reaction of β-enaminones and isocyanoacetates to construct 1,2,4,5-tetrasubstituted pyrrole derivatives. In this reaction, stable and readily available β-enaminones are employed as a valid source of imines through tautomeric equilibria. An unprecedented ring-opening of 2-imidazoline intermediate is reported for the first time and is attributed to the existence of the EWGs on the α-position of β-enaminone. A detailed study suggests that the reaction might process through sequential Mannich addition/cyclization of imine tautomers with isocyanoacetates, followed by a ring-opening of 2imidazolines and dehydration−condensation.
2a, no 4-bromoaniline-containing pyrrole derivative 4 was detected, and the product 3n was obtained in 65% yield, indicating the imine moiety of pyrrole product was not formed through an intermolecular pathway. On the basis of the above experimental results, a plausible mechanism is illustrated in Scheme 3. Initially, isocyanoacetate 2a with an acidic α-H atom is activated by silver salt to generate α-metalated isocyanide A and its tautomer A′. In the meantime, tautomerization of β-enaminone 1 could afford imine species B, which would undergo a formal [3 + 2] dipolar cycloaddition with α-metalated isocyanide A to deliver 2-imidazoline C.14 To the best of our knowledge, there is no literature relating to the ring-opening of 2-imidazoline and only limited examples about the ring-opening of similar oxazolines under strong basic conditions15 or in the presence of ruthenium complex16 affording α-formylaminoacrylates. However, in our case, due to the existence of the electron-deficient ketone and EWG, the Ha in 2-imidazoline C is very acidic. For example, when EWG is ethyl ester group, pKa of Ha is approximately 11, while the pKa of Hb is around 20.17 The enhancement of acidity of Ha makes it possible to undergo a retro-hetero-Michael addition to facilitate the unprecedented ring-opening of 2-imidazoline. The resultant imidamide D would form alcohol E via a nucleophilic addition pathway. Subsequent proton transfer between alcohol E and isocyanoacetate 2a could regenerate α-metalated isocyanide A and deliver intermediate F. Finally, intermediate F undergoes dehydration and isomerization to give the pyrrole product 3. Later, we found that when 5.0 equiv of H2O was added into the reaction mixture, 1H-pyrroles 5a−e could be generated in excellent yields (Scheme 4). The product 5a is proposed to be formed through hydrolysis of imine tautomer F, followed by a sequential reaction similar to that in Scheme 3 of the resultant aldehyde G with isocyanoacetate 2a and final pyrrole-1carbaldehyde H hydrolysis.18 These reactions strongly support our proposal for the formation of imine tautomer intermediate. The structure of 5a was further confirmed by X-ray crystallographic analysis.13
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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.7b00201. Experimental procedures and spectra copies (PDF)
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Junkai Fu: 0000-0002-7714-8818 Author Contributions ∥
G.F. and J.L. contributed equally to this work.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the NSFC (21522202, 21502017, 21372038), the Ministry of Education of the People’s Republic of China (NCET-13-0714), the Jilin Provincial Research Foundation for Basic Research (20140519008JH), Fundamental Research Funds for Central Universities (2412015BJ005, 2412015KJ013, 2412016KJ040), and the Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis (No. 130028658). C
DOI: 10.1021/acs.orglett.7b00201 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
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(14) When β-enaminone 6 bearing a hydrogen atom on the αposition was tested, no desired product was detected, suggesting the positive impact of EWG for the reaction cycle.
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D
DOI: 10.1021/acs.orglett.7b00201 Org. Lett. XXXX, XXX, XXX−XXX
