Mild and highly efficient metal-free oxidative α-cyanation of N-acyl/sulfonyl tetrahydroisoquinolines

Abstract

A highly efficient metal-free oxidative α-cyanation reaction of N-acyl/sulfonyl tetrahydroisoquinolines under mild conditions was developed. The reaction uses 2,2,6,6-tetramethylpiperidine N-oxide fluoroborate salt (T⁺BF₄⁻) as the oxidant and trimethylsilyl cyanide as the source of the cyano group.

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Direct functionalization of C–H bonds, especially C(sp³)–H bonds, is one of the most attractive strategies for the synthesis of natural products and biologically active compounds because it does not require substrate prefunctionalization.¹ For example, direct cyanation at the α-position of nitrogen-containing heterocycles such as tetrahydroisoquinolines (THIQs), which are common structural motifs in alkaloids,² is an attractive method for the formation of α-amino nitriles. α-Amino nitriles are highly versatile because the nitrile group can be hydrolyzed easily to produce α-amino acids, and nucleophilic addition to the nitrile group can provide access to α-amino aldehydes, ketones, and alcohols, as well as 1,2-diamines.³ Several approaches to the synthesis of N-aryl-α-amino nitriles have been established (Scheme 1, eqn (1)).^3,4 However, the difficulty in removing the N-aryl group limits the synthetic utility of these approaches. In sharp contrast, cyanation of the carbon adjacent to a readily hydrolyzed carbamate, amide, or sulfamide moiety has proved to be much more challenging, probably owing to the reduced reactivity of the C–H bond.⁵ To our knowledge, other than some electrochemical and photochemical methods that are operationally difficult and inefficient,^6,7 few examples of such α-cyanation reactions have been reported to date. Therefore, the development of a new method for direct α-C–H cyanation of N-acyl and N-sulfonyl compounds would be extremely useful. Herein, we report a novel method for direct α-C–H cyanation of carbamates, amides, and sulfamides of THIQ without the need for transition metal catalysis; the method uses a 2,2,6,6-tetramethylpiperidine-N-oxide (TEMPO) salt as the oxidant and trimethylsilyl cyanide (TMSCN) as the source of the cyano group (Scheme 1, eqn (2)).

Scheme 1 α-Cyanation of N-substituted THIQs.

We envisaged that an N-acyliminium species could be generated after α-oxidation and that this species would undergo nucleophilic addition by TMSCN to afford an α-amino nitrile. N-Cbz THIQ 1a was chosen as the substrate to optimize the reaction conditions (Table 1). The formation of N-acyliminium ions is difficult with commonly used oxidants, even in the presence of transition metal catalysts,⁵ so the selection of oxidant is important. We first examined the carbocation oxidant Ph₃CClO₄, which is reported to be highly effective in the formation of N-acyliminium ions.^5g However, the reaction of this oxidant in CH₂Cl₂ afforded tritylnitrile (Ph₃CCN) rather than desired product 2a, perhaps because the TMSCN nucleophile preferentially attacked the triphenylmethyl cation (Ph₃C⁺) (entry 1). When TMSCN was added after 1a and Ph₃CClO₄ had been allowed to react for 10 h, 2a was obtained, but in only 21% yield (entry 2). We next evaluated TEMPO tetrafluoroborate (T⁺BF₄⁻), which is a stable, nontoxic, mild, and readily accessible oxidation reagent that is generally used for the oxidation of alcohols to the corresponding carbonyl compounds.⁸ With T⁺BF₄⁻ as the oxidant, the yield of 2a improved to 63% (entry 3). Various solvents were then screened (entries 4–9), and CH₃CN was found to give an excellent yield (94%, entry 9). When the quantity of T⁺BF₄⁻ was decreased, the yields dropped slightly (entries 10 and 11). In particular, when only 1.0 equiv. of T⁺BF₄⁻ was used, 1a did not undergo complete conversion, perhaps because some of the T⁺BF₄⁻ was consumed by reaction with 2,2,6,6-tetramethylpiperidin-1-ol to form TEMPO (entry 10).⁹ This comproportionation reaction is inhibited under acidic conditions,¹⁰ so we added 1 equiv. of acetic acid and obtained an improved yield (97%, entry 12). Reducing the amount of TMSCN to 1.5 equiv. had no effect on the yield (entry 13).

Table 1 Optimization of reaction conditions^a

Entry	Solvent	Oxidant	Yield^b (%)
a Reaction conditions: 1a (0.2 mmol, 1 equiv.), oxidant (1.5 equiv.), TMSCN (2.5 equiv.) in solvent (1 mL) at rt under Ar for 2 h unless otherwise noted.b Isolated yield; n.d., not detected.c TMSCN was added after prereaction of 1 and Ph3CClO4 for 10 h.d T^+BF4^− (1 equiv.).e T^+BF4^− (1.2 equiv.).f AcOH (1 equiv.) was added.g TMSCN (1.5 equiv.).
1	CH2Cl2	Ph3CClO4	n.d.
2^c	CH2Cl2	Ph3CClO4	21
3	CH2Cl2	T^+BF4^−	63
4	CH3OH	T^+BF4^−	n.d.
5	THF	T^+BF4^−	55
6	Toluene	T^+BF4^−	67
7	DMF	T^+BF4^−	21
8	ClCH2CH2Cl	T^+BF4^−	74
9	CH3CN	T^+BF4^−	94
10^d	CH3CN	T^+BF4^−	79
11^e	CH3CN	T^+BF4^−	86
12^f	CH3CN	T^+BF4^−	97
13^f^,^g	CH3CN	T^+BF4^−	97

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With the optimized conditions in hand, we then investigated the substrate scope of the reaction (Table 2). A variety of carbamates, amides, and sulfamides of THIQ were examined. The reactions of ethyl carbamate 1b, tert-butyl carbamate 1c, phenyl carbamate 1d, and allyl carbamate 1e at rt for 2 h gave corresponding products 2b–e in high yields (entries 1–4). To explore the regioselectivity of the reaction, we used N,N-dimethyl carboxamide 1f and found that the reaction gave 2f as the only product in 81% yield; no N-methyl cyanation product was detected (entry 5). This result indicates that the cyanation proceeded selectively at the benzyl α-carbon of the N-methyl carbon. Amides such as acetamide 1g, n-hexanamide 1h (which has a long alkyl chain), pivaloylamide 1i (which is sterically bulky), and aromatic benzamide 1j underwent direct α-carbon cyanation to afford the expected products in good yields (entries 6–9). A halogen, a double bond, and a cyclopropyl group at the acyl group position were well tolerated, and protected α-amino nitriles 2k–m were obtained in good yields (entries 10–12). In addition, reactions of sulfamides 1n and 1o generated corresponding products 2n and 2o quantitatively (entries 13 and 14). We also investigated various substituents on the benzene ring of the THIQs. THIQs with electron-donating methoxy groups (1p and 1q), an electron-withdrawing nitro group (1r), and a halogen (1s) all underwent the cyanation reaction with good yields (entries 15–18). Substrates 1p and 1q reacted rapidly (they were completely consumed in 2 h), but the product yields were lower than the yield obtained with 1r, which took 30 h to react but afforded 2r in 97% yield (compare entries 15–17). It is noteworthy that 7-bromo THIQ derivative 1s gave 2s in a nearly quantitative yield (entry 18). Cbz-protected tetrahydro-β-carboline 1t was also well tolerated, but the yield of product was low (entry 19); the low yield may have been due to the unprotected NH group of the indole substructure.

Table 2 Substrate scope^a

Entry	1, R1 =, R2 =, Y =	Time (h)	Yield^b (%)
a Reaction conditions: 1a (0.4 mmol, 1 equiv.), oxidant (1.5 equiv.), TMSCN (1.5 equiv.) in MeCN (2 mL) at rt under Ar.b Isolated yield.
1	1b, H, H, COOEt	2	2b, 93
2	1c, H, H, Boc	2	2c, 78
3	1d, H, H, COOPh	2	2d, 89
4	1e, H, H, COOCH2CH=CH2	2	2e, 93
5	1f, H, H, CON(CH3)2	2	2f, 81
6	1g, H, H, Ac	12	2g, 86
7	1h, H, H, CO(CH2)4CH3	12	2h, 87
8	1i, H, H, COC(CH3)3	12	2i, 83
9	1j, H, H, COPh	12	2j, 86
10	1k, H, H, COCH2Cl	12	2k, 83
11	1l, H, H, COCH=CH2	12	2l, 82
12	1m, H, H, COcyclopropyl	10	2m, 86
13	1n, H, H, Ts	14	2n, >99
14	1o, H, H, Ms	16	2o, >99
15	1p, MeO, H, Cbz	2	2p, 83
16	1q, MeO, MeO, Cbz	2	2q, 86
17	1r, H, NO2, Cbz	30	2r, 97
18	1s, H, Br, Cbz	6	2s, >99
19	1t,	1	2t, 41

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Isochroman not only is an important structural unit in many natural products and biologically active compounds but also is a highly versatile building block in synthetic organic chemistry.¹¹ Therefore, we investigated the reaction of isochroman (3) with TMSCN under the optimized cyanation conditions and found that the reaction proceeded smoothly to give 4 in a good yield (Scheme 2). To the best of our knowledge, this is the first example of the direct oxidative α-cyanation reaction of isochroman.

Scheme 2 α-Cyanation of isochroman.

A plausible mechanism for the oxidative α-cyanation reaction is shown in Scheme 3. The first step involves hydride abstraction from the benzyl position of the protected THIQ to generate an N-acyliminium ion, and the second step is nucleophilic addition of TMSCN to the N-acyliminium ion to form an α-amino nitrile. There are two possible mechanisms for the oxidation step: a hydride transfer mechanism and a single-electron transfer mechanism, which has been proposed to form an N-centered radical cation intermediate.^5a,5d When we added 1.5 equiv. of TEMPO to the reaction system, we found that the result was the same as that when no TEMPO was added;¹² therefore, we infer that no radical intermediate was formed and that the protected THIQ underwent hydride transfer to generate the N-acyliminium intermediate.

Scheme 3 Proposed reaction mechanism.

In summary, we developed a highly efficient metal-free α-cyanation reaction of N-acyl/sulfonyl THIQs that proceeded under mild conditions. We propose that the oxidation occurred by means of a hydride transfer mechanism. This reaction provides a convenient method for the synthesis of α-amino nitriles and thus will be useful for the preparation of various natural products and biologically active compounds.

Acknowledgements

We are grateful to the National Natural Science Foundation of China (21132003, 21121002, 21372131), and the Specialized Research Fund for the Doctoral Program of Higher Education (20130031110017) for generous financial support for our programs.

Notes and references

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12. When 1.5 equiv. of TEMPO was added, 2a was obtained in 91% yield, which is essentially the same as the 94% yield obtained when TEMPO was not added.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra12922a

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