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

Abstract

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.

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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.

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Introduction

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.

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

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 conditions^a

Entry	NHC	Solvent	Base	Yield of 2a ^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%
24^c^,^d	C	THF	KHCO3	74%

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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 Scope^a

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.

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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.

Scheme 2 Plausible mechanism.

Conclusions

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.

Acknowledgements

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).

Notes and references

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Footnote

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

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