N-Heterocyclic carbene catalyzed dehydrogenative coupling of enals: synthesis of monobactams

Fangyi Li , Changgui Zhao and Jian Wang *
Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing, 100084, China. E-mail: wangjian2012@tsinghua.edu.cn

Received 14th November 2015 , Accepted 5th January 2016

First published on 7th January 2016


The first NHC-catalyzed dehydrogenative coupling of enals is described. With a suitable combination of NHC precatalyst, base, and solvent, the reaction proceeded smoothly to yield a wide range of monobactams. These substituted monobactams have been synthesized for the first time, and they are versatile synthetic intermediates toward other useful complex molecules.

image file: c5qo00372e-p1.tif

Jian Wang

Prof. Jian Wang received his PhD degree in synthetic chemistry from the University of New Mexico in 2007 under the supervision of Professor Wei Wang. He then moved to The Scripps Research Institute for his postdoctoral study with Professor Peter G. Schultz. In 2009, he began his independent academic career at the Department of Chemistry at National University of Singapore (NUS). In early 2013, Dr Wang moved to Tsinghua University and joined the faculty of the School of Medicine and the School of Pharmaceutical Sciences. His research program focuses on synthetic methodology (NHC catalysis) and drug discovery.


In nature, nucleotide transhydrogenase of Escherichia coli catalyzes the hydride transfer between reduced nicotinamide adenine dinucleotide (NADH) and reduced nicotinamide adenine dinucleotide phosphate (NADPH) coupled to translocation of protons across the cytoplasmic membrane.1 Inspired by nature's behavior, a variety of metal-promoted or catalyzed hydride transfer methods (e.g. hydrogenation) of imines or alkenes have been reported.2 Soon after that, organocatalytic hydride transfer reactions received some attention from chemists due to their environmentally benign features.3 Although N-heterocyclic carbene (NHC) catalyzed benzoin or Stetter reactions of aldehydes have been extensively studied,4 examples of carbene promoted or catalyzed hydride transfer are extremely few. In 2006, the Scheidt group reported the first NHC-catalyzed hydroacylation of activated ketones with aldehydes through a hydride transfer strategy (Scheme 1a).5 Later in 2013, Chen et al. disclosed an unprecedented 1,5-hydride transfer from the C–H group of an aldehyde to an activated alkene under a cascade amine and NHC catalysis.6 To the best of our knowledge, there are no further reports regarding the NHC-catalyzed hydride transfer process.
image file: c5qo00372e-s1.tif
Scheme 1 (a) NHC-catalyzed intermolecular hydroacylation; (b) NHC-catalyzed intermolecular dehydrogenative coupling.

The monobactam core is the key structural element of the most widely recognised family of antimicrobial agents.7 As shown in Fig. 1,7 Aztreonam is used primarily to treat infectious caused by Gram-negative bacteria; Tigemonam inhibited peptidoglycan subunit synthesis and transport; Tabtoxin is the precursor to the antibiotic tabtoxinine β-lactam. Nocardicin A exhibited a comparatively potent antimicrobial activity against Gram-negative organisms, especially Pseudomonas aeruginosa. Given the importance of monobactam in medicinal chemistry, the prospect of rapidly generating new monobactam-containing frameworks appeared particularly interesting. Among these known synthetic approaches, hydroxamate cyclization,8 enolate–imine condensation,9 carbene–imine reaction,10 isocyanate–alkene cycloaddition,11 and ketene–imine cycloaddition (Staudinger reaction),12 are the most commonly used tools for the construction of monobactams. In particular, the Staudinger reaction method has provided more economical entries to monobactam, mainly due to the readily availability of their starting materials. As part of a program aimed at developing new routes for the rapid buildup of monobactam derivatives, we considered a new reaction design in which an initial hydride transfer would ultimately result in the formation of the β-lactam ring.13 Herein, we disclose a novel intramolecular NHC-catalyzed dehydrogenative coupling reaction of enals for the synthesis of monobactams via a hydride transfer process (Scheme 1b).14

image file: c5qo00372e-f1.tif
Fig. 1 Selected examples of monobactam.

Results and discussion

We initiated our studies by investigating the intramolecular reaction of 1a under a variety of conditions. The model reaction of 1a in the presence of K2CO3 as a base additive and THF as a solvent was conducted at room temperature (Table 1, entries 1–7). As outlined in entry 3, cat. C resulted in a good yield (80%). However, cat. G afforded no product using similar conditions (entry 7). Various other reaction parameters were evaluated in order to improve the efficiency of this reaction and to maximize the yield of the desired product 2a. Different base additives are summarized in Table 1 (entries 8–16). Optimal results were obtained with 20 mol% of KHCO3 in THF (entry 8, 84%). Further screening of reaction media indicated no further improvement of yield (entries 17–22). Lowering reaction concentration led to a slight improvement in chemical yield (entry 23, 87%, 12 h). When a 5 mol% of cat. C was applied, a good chemical yield was still achieved at a plausible time (entry 24, 12 h).
Table 1 Optimization of reaction conditionsa

image file: c5qo00372e-u1.tif

Entry NHC Solvent Base Yield of 2a[thin space (1/6-em)]b (%)
a Conditions: 1 (0.2 mmol, Z/E mixture), cat. C (10 mol%), KHCO3 (0.04 mmol), THF (2.0 mL), 12 h. b Isolated yield after flash chromatography. c THF (1.0 mL). d Cat. C (5 mol%), 12 h.
1 A THF K2CO3 56%
2 B THF K2CO3 61%
3 C THF K2CO3 80%
4 D THF K2CO3 50%
5 E THF K2CO3 44%
6 F THF K2CO3 36%
7 G THF K2CO3 Trace
8 C THF KHCO3 84%
9 C THF Na2CO3 59%
10 C THF Cs2CO3 78%
11 C THF CsOAc 75%
12 C THF KOAc 61%
13 C THF NaOAc 42%
14 C THF DBU 73%
15 C THF DIPEA 26%
16 C THF DMAP 37%
17 C 1,4-Dioxane KHCO3 80%
18 C CH3CN KHCO3 64%
19 C iPr2O KHCO3 Trace
20 C Toluene KHCO3 39%
21 C DCM KHCO3 46%
22 C CHCl3 KHCO3 Trace
23 C THF KHCO 3 87%
24c,d C THF KHCO3 74%

Having the optimized conditions in hand, we then turned our attention to the substrate scope of enal 2 (Table 2). First, enals with differently substituted alkyl (e.g. Me, tBu) or aryl (e.g. Ph) moieties in the R1 position were tested and all gave good yields (2a–c, 77–87%). In addition, this new method can be applied to a range of substrates with different substitution patterns of the aromatic ring in the R2 position. Both electron-donating (2d, 2k, 2l) and -withdrawing (2e–j, 2o–p) substituents on the phenyl unit were tolerated. Notably, enals containing a naphthyl ring (2q and 2r) and a heteroaryl (2s and 2t) substituent at the R2 position also reacted well, leading to the desired products with moderate to good yields (63–86%). Pleasingly, the substrate containing a bulky alkyl group in the R2 position could be tolerated without any loss of yield (Table 2, 2u, 76%, 12 h). It should be noted that the above used enals all had a Z/E mixture. But the experimental results indicated that both Z/E converted to the same desired products via an inherent tautomerization. Furthermore, enals with substituents in both R2 and R3 positions could also be tolerated, but generally afforded the desired product with low chemical yields (Table 2, 2v and 2w).

Table 2 Scopea
a Conditions: 1 (0.2 mmol, Z/E mixture), cat. C (10 mol%), KHCO3 (0.04 mmol), THF (2.0 mL), 12 h. b Starting materials were recovered.
image file: c5qo00372e-u2.tif

A postulated mechanism of this reaction process is depicted in Scheme 2. Reaction of enal 1a with the NHC catalyst C in the presence of KHCO3 initially forms intermediate I. Elimination of the tetrahedron intermediate I through a hydride transfer leads to the acyl azolium intermediate II. The subsequent dehydration converts intermediate II to intermediate III. Lastly, an intramolecular cycloaddition of intermediate III eventually forms the desired product 2a along with the regeneration of the NHC catalyst C.

image file: c5qo00372e-s2.tif
Scheme 2 Plausible mechanism.


In summary, we have demonstrated that intramolecular dehydrogenative coupling of enals can be catalyzed by N-heterocyclic carbenes. A variety of monobactam products were obtained in moderate to high yields. Further investigations of the generality of this catalytic process and the development of asymmetric variants are currently ongoing and will be reported in due course.


The project described was supported by the grant from the Tsinghua University, the “Thousand Plan” Youth program of China, the Bayer Investigator Fellowship, and the Tsinghua-Peking Centre for Life Sciences (CLS).

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Electronic supplementary information (ESI) available. See DOI: 10.1039/c5qo00372e

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