Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
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Synthesis of α‑Methylene-β-lactams Enabled by Base-Promoted Intramolecular 1,2-Addition of N‑Propiolamide and C−C Bond Migrating Cleavage of Aziridine Lianpeng Zhang,*,† Lele Ma,† Hongwei Zhou,*,† Jinzhong Yao,† Xiaofang Li,‡ and Guanyinsheng Qiu*,† †
College of Biological, Chemical Science and Engineering, Jiaxing University, 118 Jiahang Road, Jiaxing 314001, China School of Chemistry and Chemical Engineering, Hunan University of Science and Technology, Xiangtan, Hunan 411201, China
‡
S Supporting Information *
ABSTRACT: A formal α-addition of N-propiolamide and 2-bromoacetate is reported for the synthesis of α-methylene-β-lactam in good yields. The transformation proceeds smoothly in the presence of K2CO3 as a base and KI as an additive. An excellent reaction scope is observed. A 2 mmol scaled synthesis of α-methylene-β-lactams and synthetic applications of αmethylene-β-lactams are also reached. In the process, it is believed that an intramolecular 1,2-addition of N-propiolamide and sequential C−C bond migrating cleavage are involved.
Scheme 1. Base-Mediated Intramolecular α-Addition of NPropiolamide for the Synthesis of α-Methylene-β-lactams
R
egioselective alkyne-based chemistry has attracted extensive interest from chemists due to its versatility toward the synthesis of diverse useful architectures.1 Among them, activated C−C triple bonds, known as classical acceptors in the Michael addition reaction, were also inclined to react with various reagents in an α-addition.2−4 To the best of our knowledge, nucleophilic α-addition of activated alkynes resorted to an umpolung strategy, and many established achievements suggested that organophophine catalysis enabled this nucleophilic α-addition.3 Mechanism investigation indicated that an allene-containing zwitterionic species was recognized as an intermediate in the process (Scheme 1, eq 1). To date, nucleophilic α-addition of activated alkynes was employed to synthesize a number of acyclic and cyclic compounds. On the other hand, α-methylene-β-lactams, a kind of smallring molecules, were ubiquitous in many marketed drugs and biologically interesting compounds.5 For examples, asparenomycin A, exhibiting a high bioactivity against β-lactamase, was a structural core containing α-methylene-β-lactams. As such, tremendous effort was focused toward its synthetic methodology development.6−9 Generally, α-methylene-β-lactams could be reached through three major pathways: [2 + 2]-cycloaddition,6 transitional-metal-catalyzed carbonylation of prop-2yn-1-amine, 7 and intramolecular condensation of 2(aminomethyl)acrylic acid.8 These reported publications were often ascribed to the use of transition metals and relatively harsh reaction conditions. Inspired by what is mentioned above, we would like to develop a distinctive strategy to construct αmethylene-β-lactams. Considering our continuous interest in © XXXX American Chemical Society
regioselective addition of alkynes,10 we envisioned that αmethylene-β-lactams could be achieved through α-addition of activated C−C triple bonds. Different from the previous findings,2−4 α-addition of activated C−C triple bonds reported herein proceeded smoothly in the absence of nucleophilic Received: March 6, 2018
A
DOI: 10.1021/acs.orglett.8b00742 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
elaborate other various bases with a wish to improve the reaction efficiency. We assumed that a stronger base than NaHCO3 was probably helpful for improving reaction efficiency. As expected, K2CO3-mediated reaction gave rise to the desired product 3a in a 87% yield (Table 1, entry 3). Other bases, including DBU, K3PO4, and Cs2CO3 did not provide better yields. A blank experiment without a base implied that base played a pivotal role in the reaction (Table 1, entry 6). Subsequentially, the solvent effect was also screened. The screening results showed that acetonitrile (MeCN) was the best choice. Inferior yields were observed when DMSO, DMF, THF, toluene, and EtOH were employed as solvents (Table 1, entries 7−11). A decrease of reaction temperature was unfavorable. The corresponding reaction afforded the desired product 3a in a 45% yield, and the reaction time was prolonged to 15 h (Table 1, entry 12). The reaction delivered the desired product 3a in a 84% yield when the reaction was treated at 80 °C (Table 1, entry 13). Reduction of the loading of base retarded the reaction (Table 1, entry 14). With the optimized conditions in hand (Table 1, entry 3), we then started to explore the reaction scope and generality. The results are illustrated in Schemes 2 and 3. From the results, we were pleased to find that a series of α-methylene-β-lactams 3 were achieved in good yields. Various alkyl bromide 2 were initially explored (Scheme 2). From the results, the substituent R1 in alkyl bromide 2 could be equal to ketone, ester, amidyl, and cyano. A series of
phosphine catalysis (Scheme 1, eq 2). An appropriate base enabled the α-addition of activated C−C triple bonds to offer α-methylene-β-lactams. In the process, we hypothesized that an anion species A was afforded when treating N-propiolamide 1 and alkyl bromide 2 with a proper base. 1,2-Addition of the resulting intermediate A and sequential C−C bond migrating cleavage of an aziridinecontaining intermediate B provided the desired products 3. As we know, our projected transformation represented a formal αaddition of N-propiolamide for the synthesis of α-methylene-βlactams. For the whole pathway, it seemed that conversion of the aziridine-containing intermediate B to an intermediate C probably served as an efficiency-determining step. To our delight, Carrillo and co-workers in 2014 observed a similar C− C bond cleavage of 2,2-dialkoxylaziridine, thus proving the above assumption theoretically reliable.11 To verify the possibility of the above projected transformation, we started to optimize the reaction conditions. Initially, the reaction of N-phenyl propiolamide 1a and 2bromoacetophene 2a was employed as a model reaction. In order to facilitate the reaction, 20 mol % of KI was used as an additive. Our primary effort was focused on optimizing various bases. Pleasingly, a preliminary result illustrated that the use of NaHCO3 as a base enabled the α-addition of N-propiolamide, leading to the desired product 3a in an 17% isolated yield (Table 1, entry 1). The exact structure of compound 3a was identified by NMR, HRMS, IR, and diffraction of X-ray (CCDC: 1535460). The positive result encouraged us to Table 1. Synthesis of 3a: Survey of Reaction Conditions
Scheme 2. Effect of Various N-Protecting Groupsa
a
entry
base
solvent
temp (°C)
yield (%)b
1 2 3 4 5 6 7 8 9 10 11 12 13 14c
NaHCO3 DBU K2CO3 K3PO4 Cs2CO3 − K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3
MeCN MeCN MeCN MeCN MeCN MeCN DMSO DMF THF toluene EtOH MeCN MeCN MeCN
70 70 70 70 70 70 70 70 70 70 70 50 80 70
17 46 87 82 85 nd 83 77 64 35 67 45 84 72
a
Standard conditions: N-propiolamide 1a (0.2 mmol), 2-bromoacetophene 2a (0.22 mmol), KI (20 mol %), base (0.6 mmol), solvent (2.0 mL), 8 h. bIsolated yield based on N-propiolamide 1a. cK2CO3 (0.5 mmol).
a
Isolated yields based on 1 bThe reaction using DMSO as the solvent at 80 °C.
B
DOI: 10.1021/acs.orglett.8b00742 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters Scheme 3. Effect of Various Alkynylamides
Scheme 4. Effect of Various Secondary Alkylbromide
Scheme 5. Modified Procedure for the Synthesis of 3a via a 2 mmol Scaled Experiment
corresponding products 3a−3n was afforded in good yields. For example, the reactions of substrates connected 2-acetonaphthalenyl, 3-acetothiophenyl, and acetyl at R1 provided corresponding products 3f, 3g, and 3h in 75%, 86%, and 86% yields, respectively. The exact structure of the product 3h was also identified by diffraction of X-ray (CCDC: 1827418). Similar yields were obtained when cyano-linked and esterlinked substrates were used as starting materials. It is noteworthy that the reaction of amidyl-connected substrate 1m in DMSO as the solvent at 80 °C could also offer the desired product 3m in an 88% yield. Additionally, the substituent R2 in propiolamide 1 could be replaced by benzyl and another alkylamine such as dehydroabietylamine. The corresponding α-methylene-β-lactams 3o and 3p were observed in good yields. Subsequently, various substituent R in propiolamide were also explored accordingly. The results are shown in Scheme 3. From the results, it was determined that the electron effect and hindrance steric effect of the substituent R did significantly impact the reaction efficiency. For instance, similar yields were afforded when 4-methylphenyl and 2-methylphenyl-connected substrates 1q and 1s were employed. Moreover, 2-naphthalenesubstituted and 4-methoxylphenylethyne-connected starting materials 1t and 1v were compatible for the reaction, leading to the corresponding β-lactams 3t and 3v in 85% and 87% yields, respectively. Particularly, the reaction of N-(2-oxo-2phenylethyl)-N-phenylpropiolamide under standard conditions gave 3w in an 83% yield. The reactions of propiolamide 1a and various activated secondary alkyl bromides 2 were also investigated. The results are shown in Scheme 4. To our delight, 4,4-disubstituted αmethylene-β-lactams 3x and 3y were afforded in moderate to good yields. Differently, the corresponding reactions were conducted in DMSO at 80 °C, probably because of poor solubility of substrates. A 2 mmol scale experiment of 3a was carried out under standard conditions. The result is illustrated in Scheme 5. To our delight, the desired β-lactam 3a was achieved in an 82% yield. To determine the synthetic applications of α-methylene-βlactams, we then investigated chem-selective reduction of βlactam 3h. Switchable reduction between the ketone carbonyl
and activated double bond was reached when reaction conditions were changed from NaBH4 to H2/Pd/C (Scheme 6). Scheme 6. Application Exploration of the Product 3h
To gain insight into the reaction mechanism, two control experiments were conducted. As shown in Scheme 7, comparable results are observed with or without TEMPO as an additive, probably suggesting that the reaction did not undergo a radical pathway. The deuterium-labeling experiment indicated an anion intermediate was formed in the process. In light of the aforementioned results, a plausible mechanism was proposed (Scheme 7). In the presence of K2CO3 and KI, N-alkylation of N-propiolamide took place to offer an intermediate A. Deprotonation of intermediate A occurred to produce a key anion intermediate B. An intramolecular 1,2addition of the intermediate B provided an aziridine-containing intermediate C. Owing to the ring strain of aziridine, a C−C bond migrating cleavage happened to the intermediate C, producing a β-lactam-containing anion species D. Protonation of the anion D finally offered the desired products 3. However, we did not exclude another possibility that the reaction underwent a direct α-addition of N-propiolamide A to provide the products 3.9d,e In conclusion, we have developed a formal α-addition of Npropiolamide for the synthesis of α-methylene-β-lactams in good to excellent yields. The transformation worked well in the presence of 3.0 equiv of K2CO3 and 20 mol % KI, and an excellent functional group tolerance was observed. A 2 mmol C
DOI: 10.1021/acs.orglett.8b00742 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters Notes
Scheme 7. Control Experiments and Plausible Mechanism
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Financial support from the Natural Science Foundation of China (Nos. 21502069 and 21772067), the Natural Science Foundation of Zhejiang Province (LQ18B020005), Science and Technology Project of Jiaxing (2017AY13019), and the Ph.D. Scientic Research Starting Foundation of Jiaxing University (No. 70516046) is gratefully acknowledged.
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scaled synthesis of α-methylene-β-lactams and synthetic applications of α-methylene-β-lactams were also demonstrated. In the process, it was believed that an intramolecular 1,2addition of N-propiolamide and sequential C−C bond migrating cleavage accounted for the synthesis of αmethylene-β-lactams.
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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.8b00742. Experimental procedures, product characterization data, 1 H and 13C NMR spectra for new compounds (PDF) Accession Codes
CCDC 1535460 and 1827418 contain 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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REFERENCES
AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected] (G.Q.). *E-mail:
[email protected] (L.Z.). *E-mail:
[email protected] (H.Z.). ORCID
Hongwei Zhou: 0000-0001-8308-960X Guanyinsheng Qiu: 0000-0002-6587-8522 D
DOI: 10.1021/acs.orglett.8b00742 Org. Lett. XXXX, XXX, XXX−XXX
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DOI: 10.1021/acs.orglett.8b00742 Org. Lett. XXXX, XXX, XXX−XXX
