Tin-free visible light photoredox catalysed cyclisation of enamides as a mild procedure for the synthesis of γ-lactams

Abstract

The first visible light mediated tin-free cyclisation of α-chloroenamides leading to the synthesis of substituted γ-lactams with excellent stereoselectivity is reported. The protocol employs the single-electron reduction of activated C–Cl bonds, which are typically inert towards reduction.

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The opportunity to realise unique transformations has attracted the attention of the chemistry community and stimulated, among others, the development of protocols involving the formation of free radicals by single-electron transfer (SET) processes.¹ In particular, free-radical generation from organohalides represents a straightforward way to achieve reactive, open-shell carbon-centred radicals, which has found outstanding applications in natural product synthesis.²

However, the requirement of highly toxic radical reducing agents and initiators such as tin hydrides or AIBN, as well as specific and hard to manage equipment stimulated the development of new methods for the generation of free-radicals under benign conditions.^3–6 An alternative is represented by visible light photocatalysis^7,8 that, by means of transition-metal polypyridyl complexes or metal free photosensitizers, provides a valuable and green methodology for the single-electron reduction of carbon–halogen bonds. Yet, this approach seems to be limited to activated carbon–bromine/iodine bonds⁹ while only a few examples are reported when the less reactive organochlorides are involved, due to a more negative reduction potential as a consequence of higher carbon–halide bond dissociation energy (BDE).¹⁰ Specifically in the latter case, it is known that the BDE for the carbon–chlorine bond is significantly higher than those measured for the carbon–bromine/iodine bonds (CH₃–Cl, 83 kcal mol⁻¹; CH₃–Br, 71 kcal mol⁻¹; CH₃–I, 57 kcal mol⁻¹),¹¹ and therefore the mesolysis by SET often requires prohibitive energies for most of the common visible light photocatalysts.

Nevertheless, the stability of organochloride derivatives, often along with their low cost compared to the corresponding bromide/iodide precursors, stresses the importance of available methods able to overcome the energetic and selectivity issues associated with the functionalisation of this bond. In this context, we wondered if visible light photoredox catalysis can be applied as an alternative to the less favorable agent Bu₃SnH in the synthesis of γ-lactams through a formal 5-endo-trig cyclisation.^12,13 This is initiated by the reduction of the carbon–halogen bond of α-haloenamide 1 to form the corresponding N-alkenyl α-carbamoylmethyl radical B (Scheme 1).¹⁴ Despite the stereoelectronic problems associated with this type of reaction (Baldwin–Beckwith's rule), γ-lactams are mainly formed compared to the directly reduced (non-cyclised) side-product 3.

Scheme 1 5-endo cyclisation of α-haloenamides through the formation of N-alkenyl α-carbamoylmethyl radicals.

With these considerations in mind we started our investigation with α-chloroenamide 1a as a model substrate. In the course of the optimisation study we first tested a series of amines as suitable stoichiometric reductive quenchers. At a concentration of 0.3 M we noticed the reaction to proceed with good reactivity, with the predominant formation of 3a after irradiation for 22 hours (Table 1, entries 1–3). Subsequently, we analysed the effect of more dilute concentrations on the product distribution, simultaneously increasing the reaction time from 22 to 40 hours. Low concentration mixtures (entries 5–7) encouraged the formation of the desired product 2a in good yields along with the regression of the direct reduction pathway. Surprisingly, increasing the catalyst loading from 1 to 2 mol% did not improve the yield of 2a, but rather enhanced the formation of side-product 3a (entry 8). A limit experiment under highly diluted conditions (0.01 M) with a prolonged reaction time (60 h) showed a general decrease in reactivity (entry 9). Solvent evaluation revealed good reactivity in DMSO (entry 12) and a drastic drop of yield in DMF (entry 10) or apolar solvents like toluene (entry 11).

Table 1 Optimisation of reaction conditions^a

Entry	Amine	Solvent	[mmol ml^−1]	2 [%]	3 [%]
a Reaction conditions: α-chloroenamide 1a (0.2 mmol), amine (0.4 mmol), PC = Ir(ppy)2(dtb-bpy)PF6 (1 mol%), degassed solvent, blue LEDs (450 nm, 11 W), r.t., 22 h, NMR-yield (internal standard: mesitylene); the yield of the isolated product in parenthesis. b 40 h reaction time. c 48 h reaction time. d 2 mol% PC. e 60 h reaction time. f α-Chloroenamide 1a (0.13 mmol).
1	Et3N	MeCN	0.3	19	43
2	n-Bu3N	MeCN	0.3	20	39
3	i-PrN(Et)2	MeCN	0.3	20	41
4^b	Et3N	MeCN	0.06	38	n.d.
5^b	n-Bu3N	MeCN	0.06	41	n.d.
6^b	n-Bu3N	MeCN	0.03	48	25
7^c	n-Bu3N	MeCN	0.02	592 (48)	9
8^b^,^d	n-Bu3N	MeCN	0.02	40	11
9^e	n-Bu3N	MeCN	0.01	42	7
10^c^,^f	n-Bu3N	DMF	0.02	11	14
11^c^,^f	n-Bu3N	Toluene	0.02	13	5
12^c^,^f	n-Bu3N	DMSO	0.02	69 (67)	17

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As part of the optimisation study, we investigated the role of different halogens in the mesolysis of the C–X bond and in the following cyclisation step (Table 2). As previously reported by Ishibashi¹⁵ and Curran,¹⁶ the nature of the radical precursor has an effect on the product distribution, and hence we assumed that the analogous mechanism using different catalytic systems could lead to the formation of the same radical intermediates (Scheme 4).¹⁷

Table 2 Product distribution as a function of the radical precursor^a

Entry	X	Additive	2a [%]	3a [%]	4a [%]	5a [%]
a Reaction conditions: α-haloenamide 1 (0.13 mmol), amine (0.26 mmol), PC (1 mol%), degassed DMSO, blue LEDs (450 nm, 11 W), r.t., 48 h.
1	Cl	—	69	17	—	—
2	Br	—	54	17	24	n.d.
3	Cl	NaI	<5	31	17	22

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When α-bromoenamide 1a′ was tested under the optimised reaction conditions, a mixture of the expected cyclised product 2a along with the directly reduced side product 3a was obtained, accompanied by 24% of the cyclised-oxidative product 4a (entry 2).

When sodium iodide (2 equiv.) was added to the reaction mixture in order to in situ generate the iodide precursor 1a′′, the reaction provided only traces of the desired product 2a, while a mixture of 3a (major product in 38% yield) and cyclised-oxidative products 4a and 5a was obtained. Taking note of the role of radical precursors in the product distribution, we began the synthesis of various α-chloroenamides in order to investigate the electronic and steric effects on the cyclisation reaction (Scheme 2).

Scheme 2 Scope for the photoredox catalysed 5-endo-trig cyclisation of substituted α-chloroenamides. Reaction conditions: α-chloroenamide 1 (0.13 mmol), n-Bu₃N (2 equiv.), PC (1 mol%), degassed DMSO, blue LEDs (450 nm, 11 W), r.t., 48 h; yield of the isolated product.

Although the 5-endo-trig pathway is considered disfavoured,¹⁸ the reaction generally proceeded in moderate to good yields with a broad range of substrates with different substitution patterns. Remarkably, in almost all cases, only one diasteroisomer was formed.¹⁹ The product was obtained in good yield when a heteroatom was introduced as part of the cyclohexane skeleton (1b), but slightly decreased when the substituents were placed in the 4,4′ positions (1c–e); in this particular case, the yield decreased along with the increasing bulkiness (2c, 2d and 2e). It is noteworthy to underline that when two methyl groups were placed in the 5,5′ position (1g) the reaction gave a comparable yield (2g) to the non-substituted one (2a). When the same pattern of substituents was arranged directly next to the olefin bond on the 3,3′ carbon atom (1f), the formation of product 2f dropped to 43% yield. This trend was also observed when a methyl group was placed alpha to the incoming radical (2h). Good yields were observed when different substituents were placed on the nitrogen atom (2i and 2j). Next, we wondered how the diastereoselectivity would be influenced by placing the chiral auxiliary (S)-1-phenethyl group as a removable protecting group in this position (2k).²⁰ Although the yield was modest, only one diastereoisomer was formed (Scheme 2). The cleavage of the phenethyl group upon treatment with Na/NH₃ in THF at −78 °C²⁰ led to the optically pure lactam 6. The absolute configuration of lactam 6 was assigned as 3aR,7aR by comparison with the literature reported compound.^20,21 The auxiliary mediated asymmetric induction furnishes a smooth access to the basic structural core of the angiotensin converting enzyme (ACE) inhibitor HOE 498 (Scheme 3).²² Furthermore, we also observed comparable reactivity for the opened-chain system giving 50% yield (2l).

Scheme 3 Influence of the chiral auxiliary (S)-1-phenethyl group on the asymmetric induction.

Regarding the mechanism, we assume that irradiation with visible light triggers the photoredox catalytic cycle of Ir³⁺, whose stable and long-lived (557 ns for Ir(ppy)₂(dtbbpy)⁺)^7j excited state Ir³⁺ acts as an oxidant towards trialkylamines (E^red_1/2 = +1.0 V vs. SCE for triethylamine),²³ generating the aminium radical cation A⁺˙ and Ir²⁺, which can reduce the α-chloroenamide 1 to the α-carbonyl radical B (Scheme 4). The latter species can then partition between the directly reduced product 3 and the 5-endo cyclised product 2.

Scheme 4 Postulated mechanism.

However, the ratio between the cyclised product 2 and the directly reduced product 3 depends on the ability of the radical precursor 1 to react with C, either by direct electron transfer (ET) or by halogen atom transfer (AT), to give an acyliminium ion that leads to D after deprotonation. This pathway is particularly favoured for iodo precursors, since they can compete with the hydrogen donor A⁺˙, while chlorides cannot. For the iodides it was further reported that the high amount of the directly reduced product 3 can be attributed to the formation of HI during the reaction, which, if not consumed fast enough by an acid/base reaction with the stannane or silane (n-Bu₃N in our case), might react ionically with 1 to form 3 and I₂.

In conclusion, we developed a mild and tin-free method for the preparation of synthetically valuable γ-lactams²⁴ in good yields and high diastereomeric ratios, using visible light photoredox catalysis. Therewith, we provide the first example of visible light mediated 5-endo-trig cyclisation of α-chloroenamides that, in spite of its synthetic utility, still remains a challenging transformation. Furthermore, the diastereoselective reaction resulted in the formation of a single diastereoisomer, which is of interest for the synthesis of enantiomerically enriched products. The use of α-chloroenamides for the generation of monocyclic γ-lactams is particularly appealing and further application of this photoredox catalysis methodology is currently under investigation.

Acknowledgements

The research leading to these results has received funding from the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013)/ERC Grant Agreement No. 617044 (SunCatChem). Financial support by KAUST is gratefully acknowledged.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6gc01099g

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