Free-radical initiated cascade methylation or trideuteromethylation of isocyanides with dimethyl sulfoxides

Abstract

The methylation or trideuteromethylation reaction of isocyanides with dimethyl sulfoxides in a radical way is developed, which offers a low-cost, easy-operation cascade methylation strategy for the synthesis of phenanthridines or isoquinolines.

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The introduction of methyl or trideuteromethyl groups into organic compounds could affect their biological and chemical properties.¹ Methylation reactions have been widely applied in synthetic organic chemistry.² Among them methyl metal reagents,³ MeI,⁴ DMSO,⁵ MeCOOH,⁶ peroxides⁷ etc. are usually used as methylating reagents to complete the corresponding reactions. Meanwhile, deuterated iodomethane,⁸ deuterated reducing reagents⁹ or d⁶-DMSO¹⁰ are selected as deuterated methyl sources to develop trideuteromethylation reactions. Although considerable numbers of methods have been developed, more economic and practical methylation or trideuteromethylation strategies are highly desirable.

The preparation of phenanthridines or isoquinolines have been considered as a study topic recently.^11,12 The methyl substituted phenanthridines which were produced by biphenyl isocyanides reacting with peroxides or methyl hydrazine have been developed by Liu,⁷ Mao¹³ and Cheng,¹⁴ et al. Antonchick¹⁵ and our group¹⁶ reported a cascade trideuteromethylation or methylation reaction of N-arylacrylamides with dimethyl sulfoxides respectively (Scheme 1a). However, a free radical cascade methylation or trideuteromethylation of isocyanides with dimethyl sulfoxides under analogous Fenton reaction condition was not finished now (Scheme 1b).¹⁷ Combined with our previous study,¹⁸ we wish to accomplish this reaction system.

Scheme 1 (a) Methylation or trideuteromethylation of N-arylacrylamides with dimethyl sulfoxides (previous work). (b) Methylation or trideuteromethylation of isocyanides with dimethyl sulfoxides (this work).

Initially, 2-isocyano-5-methyl-1,1′-biphenyl and dimethyl sulfoxide were selected as model substrates to optimize the reaction systems (Table 1, also see ESI for detail†). It was shown that the yield of the final product in 6 hour is better than that in 3 and 10 hour (entries 1–3). Adding 1 mL, 2 mL and 4 mL of dimethyl sulfoxide gained the product in 30%, 40%, 50% yields, respectively (entries 4–6). No reaction was found without any iron salts (entry 7). Variation of the amount of iron(II) chloride and hydrogen peroxide greatly affected reaction efficiency (entries 8–14). Higher temperature slightly reduced reaction yield (entry 15). Finally, 2,6-dimethylphenanthridine was isolated in 70% yield under the optimum conditions: isonitriles (1 equiv., 0.25 mmol), FeCl₂ (0.2 equiv., 0.05 mmol), H₂O₂ (30%, 3 equiv., 0.75 mmol) and DMSO (3 mL), 25 °C, N₂, 6 h, sealed tube.

Table 1 Modification of the typical reaction conditions^a

Entry	Iron(II) chloride (equiv.)	Hydrogen peroxide (30%), (equiv.)	t/h	Yield^b (%)
a Reaction conditions: 2-isocyano-5-methyl-1,1′-biphenyl (1 equiv., 0.25 mmol), DMSO (3 mL), 25 °C, N2.b Isolated yields.c DMSO (1 mL).d DMSO (2 mL).e DMSO (4 mL).f 50 °C.
1	0.5	3	3	52
2	0.5	3	6	55
3	0.5	3	10	52
4^c	0.5	3	6	30
5^d	0.5	3	6	40
6^e	0.5	3	6	50
7	—	3	6	n.r.
8	0.1	3	6	63
9	0.2	3	6	70
10	0.3	3	6	55
11	0.4	3	6	55
12	0.2	1	6	20
13	0.2	2	6	36
14	0.2	4	6	56
15^f	0.2	3	6	60

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To investigate the substrate scope, a variety of isocyanides were prepared and tested in Table 2. As can be seen, many functional groups substituted substrates could react well in this reaction system (1–10). Halogen atoms such as F, Cl substituted isocyanides gave the corresponding products in moderate yields, respectively (2, 5, 9–10). The substrates with large groups such as t-butyl and phenyl on 4′-position of the aromatic ring obtained the product 6 and 7 in 41% and 36% yields, which indicate that the steric effect is slightly obvious. The products 7 and 10 were isolated in 46% and 66% yields respectively by adding potassium carbonate in the system. It indicates potassium carbonate could weaken the impact on the yields of final products from methylsulfinyl acid as the side product. The electronic effect also influences the reaction yields, and the raw material with electron-withdrawing group such as nitro, cyano could not result the desirable product (11–12). And vinyl isocyanides gained the desired isoquinolines in 50–69% yields (13–16). Notably, the product 3 was isolated in 52% yield, when the reaction system was scaled up to the gram level.

Table 2 Iron-promoted free radical cascade methylation of isocyanides with dimethyl sulfoxide

a Reaction conditions: isocyanide (1 equiv., 0.25 mmol), iron(II) chloride (0.2 equiv., 0.05 mmol), hydrogen peroxide (30%, 3 equiv., 0.75 mmol), DMSO (3 mL), 25 °C, N₂, 6 h.b Isolated yields.c 10 h.d 21 h.e Isocyanide (1 equiv., 5.20 mmol, 1.0 g).f Adding 1 equiv. K₂CO₃ in the system.

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As can be seen in Table 3, diverse aryl isocyanides could react well with deuterated dimethyl sulfoxide in the typical condition (17–23). The halogen atoms such as F, Cl were tolerant in the system and gave the corresponding products in good yields (19, 22, 23). The t-butyl and phenyl substituted substrates obtained the product 20 and 21 both in 42% yields. Notably, the products 17, 20, 21 and 22 gave better yields by adding the base in the system under typical conditions. And vinyl isocyanides produced the trideuteromethyl substituted isoquinolines in 51–77% yields (24–27).

Table 3 Iron-promoted free radical cascade trideuteromethylation of isocyanides with deuterated dimethyl sulfoxide

a Reaction conditions: 2-isocyano-5-methyl-1,1′-biphenyl (1 equiv., 0.25 mmol), DMSO-d⁶ (1 mL), 20 °C, N₂, 12 h.b Isolated yields.c Adding 1 equiv. K₂CO₃ in the system.d 21 h.

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No reaction was deuterated when TEMPO was added to the reaction system, which suggests the reaction would be in process through a free radical way. According to the precedent literature^15,16,19 and experimental study, we design a possible mechanism in Scheme 2. First, dimethyl sulfoxide or deuterated dimethyl sulfoxide reacts with hydrogen peroxide and generates the intermediate A. With the induction of iron(II) chloride, free radical B and hydroxyl ion are produced by intermediate A occurring heterolysis reaction. Radical B gives methyl radical or trideuteromethyl radical along with methylsulfinyl acid or detected methylsulfinyl acid produced in the process of β-cleavage reaction. Next, radical C is formed from adding methyl radical or trideuteromethyl radical to the isocyanides. Then, radical C adds to the aromatic ring and generates radical D. Radical D can be oxidized by iron and yields the carbocation E, which is pulled the proton by hydroxyl ion and gains the terminal product.

Scheme 2 Plausible mechanism.

In summary, we have accomplished a free radical triggered cascade methylation or trideuteromethylation/cyclization reaction of isocyanides with dimethyl sulfoxides. It offers an economical and convenient protocol for preparing phenanthridines or isoquinolines. Further studies on cyclization reactions in a novel free radical way are ongoing in our laboratory.

Acknowledgements

This project is supported by the Natural Science Foundation of Hebei Province (B2017201043), the Fundamental Research Funds for The Midwest Universities Comprehensive Strength Promotion Project, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Key Laboratory of Chemical Biology of Hebei Province and College of Chemistry & Environmental Science, Hebei University.

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Footnotes

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c7ra08484f

‡ These authors contributed equally.

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