Indium-catalyzed C(sp³)–H functionalization of 2-methylazaarenes through direct benzylic addition to trifluoromethyl ketones

Abstract

The application of trivalent indium for the Lewis acid-catalyzed C(sp³)–H functionalization of 2-methylazaarenes is reported. InCl₃ was discovered to catalyze the direct addition of the benzylic C–H bond in the azaarenes to trifluoromethyl ketones. An ample number of substrates were cogently demonstrated to give the products as trifluoromethylated alcohols whereby in some cases, up to quantitative yield (99%) could be obtained.

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A substantial degree of advancement has been achieved using indium metal and its salts in organic syntheses.¹ Among the plethora of applications, catalytic protocols based on the inexpensive, low toxic and high tolerance trivalent indium represent an important development in indium chemistry. This had contributed significantly to the establishment of the indium salts as efficient catalysts for carrying out various organic transformations under mild Lewis acid catalysis.²

Interest in Lewis acid catalysis has experienced a renaissance as synthetic organic chemists started to adapt to contemporary approaches for transformations leading to the construction of complex organic molecules through C–H functionalization.³ The azaarenes are among an important class of organic molecules whose synthesis have been described based on the concept of C–H functionalization.⁴ In recent developments relating to metal-catalyzed C–H functionalization,⁵ several metal salts, largely based upon the transition and rare metals, were utilized in catalytic methodologies for the direct functionalization of benzylic C–H bonds in alkylazaarenes.⁶ However, catalytic protocols using salts of the main group metal indium for this class of C–H functionalization remains elusive despite the emergence in the Lewis acid catalysis domain of indium chemistry.⁷

Therefore, we were consequently motivated to channel our endeavor towards a report on indium-catalyzed C(sp³)–H functionalization through the direct benzylic addition under Lewis acid catalysis. Specifically, we were interested in the addition of benzylic C–H bond in 2-methylazaarenes to the carbonyl carbons of trifluoromethyl ketones (TFMKs) which are widely regarded as important precursors for the preparation of trifluoromethyl-containing compounds.⁸ This approach is effusively welcomed given the astonishing properties of such fluorinated compounds either as pharmaceuticals, agrochemicals or functional materials.⁹ Furthermore, susceptibility of TFMKs towards the benzylic C–H additions had only been recently reported.¹⁰ With limited demonstrations conducted in the presence of excess methylazaarenes at a temperature of up to 110 °C, the lanthanide salt Yb(OTf)₃ was reported as a suitable Lewis acid catalyst for the addition reaction.

Inevitably, with our ongoing interests in the development of simple and mild methodologies for organic syntheses, the direct addition of C(sp³)–H bond in 2-methylquinoline (1a) to 2,2,2-trifluoro-1-phenylethanone (2a) was subsequently initiated. An initial trial under a mild condition consisting of 10 mol% InCl₃ in THF at 60 °C gave us an early boost whereby a 93% yield of 3aa was isolated after 24 h (Table 1, entry 1).

Table 1 Optimization studies^a

Entry	[M]	Solvent	Yield^b (%)
a General reaction conditions: 1a (2.5 equiv.), 2a (0.5 mmol), [M] (10 mol%), solvent (0.5 mL), 60 °C, 24 h.b Isolated yield.c 1a (1.5 equiv.).d 1a (1.5 equiv.), InCl3 (5.0 mol%).
1	InCl3	THF	93
2	InBr3	THF	91
3	In(CF3CO2)3	THF	90
4	In(OTf)3	THF	95
5	Yb(OTf)3	THF	92
6	CoCl2	THF	92
7	FeCl3	THF	90
8	CuCl2	THF	67
9	MnCl2	THF	73
10	NiCl2	THF	Trace
11	PdCl2	THF	Trace
12	—	THF	Trace
13	InCl3	H2O	94
14	InCl3	^tBuOH	99
15	InCl3	^tBuOH	99^c
16	InCl3	^tBuOH	99^d

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This observation concomitantly led us to justify the role of Lewis acid catalyst in which a set of screening experiments involving several other metal salts was conducted. With InBr₃, In(CF₃CO₂)₃, In(OTf)₃ and Yb(OTf)₃, similar yields of within the probable experimental error corresponding to 3aa were obtained (entries 2–5). However, results with the chlorides salts of several transition metals are widely diverse. While comparable yields of 92% and 90% were obtainable with CoCl₂ and FeCl₃ (entries 6 and 7), only 67% and 73% yields of 3aa were afforded from the reactions performed in the presence of catalytic CuCl₂ and MnCl₂ (entries 8 and 9). Moreover, the reaction significantly failed to proceed when either NiCl₂ or PdCl₂ was added to the reaction mixture (entries 10 and 11). The same observation was also made when the reaction was performed under metal-free conditions (entry 12).

Satisfied with the importance of Lewis acid catalyst for the reaction, further optimization studies were next contemplated. With our focus firmly set in capitalizing the advantages of indium catalysis, InCl₃ was undoubtedly selected due to its practicalities as a Lewis acid catalyst.¹¹ Water-stability is among the attractive features of InCl₃ of which we were keen to exploit due to the array of advantages associated with performing chemical reactions in an aqueous medium.¹² With 94% yield of 3aa (entry 13), formation of the C–H addition product under the In-catalyzed system is deemed insensitive to the presence of water. However, on the basis of compromising the reaction stoichiometry, ^tBuOH was delightfully found to be the best solvent whereby a quantitative yield of 3aa was achievable (entry 14). Efficiency of the reaction in ^tBuOH was also unaffected as we sequentially lowered the excess of 1a and InCl₃ loading. The standard reaction conditions were ultimately established with a catalyst loading of as low as 5 mol% for the quantitative conversion of 2a to 3aa in the presence of a slight excess (1.5 equivalent) of 1a (entry 16).

We next challenged the In-catalyzed protocol for the reactions involving 1a with various TFMKs. Under the standard reaction conditions, excellent yielding attribute of the protocol was maintained with our demonstrations using bromo-, chloro- and fluoro-substituted 2,2,2-trifluoro-1-phenylethanones (Table 2, entries 1–3). An excellent yield of 98% was also achieved corresponding to product 3ae which was prepared from trifluoromethyl-substituted TFMK 2e.

Table 2 Scope of TFMKs^a

Entry	R	Product	Yield^b (%)
a General reaction conditions: 1a (1.5 equiv.), 2b–2p (0.5 mmol), InCl3 (5.0 mol%) ^tBuOH (0.5 mL), 60 °C, 24 h.b Isolated yield.c N.R. = no reaction.d Reaction conducted with 10 mol% InCl3 at 120 °C.
1		3ab	99
2		3ac	99
3		3ad	98
4		3ae	98
5		3af	N.R.^c
		3ag
6		3ah	90
7		3ai	36/65^d
8		3aj	85
9		3ak	85
10		3al	73
11		3am	46
12		3an	34^d
13		3ao	56
14		3ap	88

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Impressed by the observed reactivity, we next decided to subject our In-catalyzed protocol under stern tests with attempts using 2f and 2g. However, under the mildness of our standard reaction conditions, the corresponding addition products as 3af and 3ag were disappointingly not formed. In these cases, the electron donating as well as steric natures of the substituents in 2f and 2g proved to be too severe in diminishing the electrophilicity of the carbonyl carbons to effect the catalytic addition of C(sp³)–H bond of 1a. Further studies aimed at improving the reactivity of the indium-catalyzed protocol for this class of reactions are ongoing in our laboratory.

Nonetheless, to further investigate the scope of TFMKs in our current studies, we next attempted the reaction between 1a and 2h which sumptuously resulted in the isolation of 3ah in 90% yield (entry 6). The successful demonstration with the thiophene-containing TFMK is an indication on the compatibility of heteroaromatic substrates for this class of reaction.

Though lower in reactivity under the standard reaction conditions, 2i was also found to be a suitable TFMK substrate when the reaction was conducted with 10 mol% InCl₃ at 120 °C for the exclusive synthesis of 3ai as the intended 1,2-addition product in a satisfactory yield of 65% (entry 7).

With 2j and 2k, both 3aj and 3ak were isolated in 85% yields (entries 8 and 9). No products resulting from 1,4-addition to the α,β-unsaturated alkene moiety were observed despite the excellent Michael acceptor nature of both TFMKs.¹³

Besides selectivity of the C–H addition, the reaction scope was also probed with respect to aliphatic TFMKs during which the Lewis acidity of InCl₃ was found to be generally sufficient in catalyzing formation of the intended products. However, addition of the benzylic C–H bond was found to be highly sensitive to the steric environment presented by the hydrocarbons in the vicinity of the carbonyl functionality of these TFMKs. This is evident with 2n where only 34% of 3an was isolated despite the influence of an increased catalyst loading and reaction temperature (entry 12).

Ester-functionalized substrates in the form of trifluoroacetoacetate (2o) and trifluoropyruvate (2p) were also attempted. These led to the isolation of 3ao and 3ap in 56% and 88% yields respectively (entries 13 and 14). However, with other types of ketone substrates such as acetophenone and benzophenone, no addition to the ketonic carbon was observed. The inability of these substrates to participate in the reactions indicates the importance of trifluoro moiety for the successful addition of the benzylic C–H bond to the carbonyl carbon.

Scope of 2-methylazaarenes was also explored as we sought to further examine the generality of the current In-catalyzed direct benzylic C–H addition (Table 3).

Table 3 Scope of 2-methylazaarenes^a

a General reaction conditions: 1b–1l (1.5 equiv.), 2a (0.5 mmol), InCl₃ (5.0 mol%) ^tBuOH (0.5 mL), 60 °C, 24 h.b Reaction conducted with 10 mol% InCl₃ at 120 °C.

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A series of halogenated substrates was screened for their reactivity in the reaction with 2a. Notably, chlorine-substituted azaarenes was found to be highly general in their applicability for this addition reaction. This is proven by yields of the addition products being consistently obtained in the excellent range (91–98%) from the azaarenes with chlorine substituent at several different positions on the 2-methylazaarene core (3ca, 3da, 3ea). However, with 6-fluoro substituent, only a good yield of 75% for 3fa was afforded as compared to the excellent 94% yield of 3ga obtained from 7-fluoro-2-methylquinoline. Incorporations of weakly and strongly electron donating groups at the 6-position also exhibited contrasting results with the respective 95% and 58% yields of 3ha and 3ia.

Apart from the efficient transformation of 1-methylisoquinoline to 3ja, substrates with the pyridine core were also tested. Without further optimization of the reaction conditions beyond the utilization of 10 mol% InCl₃ at 120 °C, both 2-picoline and 2,6-lutidine were found to participate in the reaction giving 3ka and 3la in 48% and 75% yields respectively.

Attempts with other methylheteroaryls such as 3-methylisoquinoline, 4-methylquinoline, 2-methylquinoxaline, 2-methylbenzo[d]oxazole, 2-methylbenzo[d]thiazole and 2-methylthiophene were also conducted. However, no addition products were observed under either the standard or modified reaction conditions.

As a means for understanding the role of In catalyst in our current studies, the deuterium exchange experiments involving 2-methylquinoline (1a) in D₂O were subsequently conducted. Under the influence of catalytic InCl₃ at 60 °C, a marked deuterium incorporation of 27% was observable as compared to result of a control experiment without InCl₃ loading (Fig. 1).

Fig. 1 Deuterium exchange experiments.

A plausible reaction mechanism was then proposed as depicted in Fig. 2.

Fig. 2 Proposed reaction mechanism.

It is believed that feasibility of the transformations described in this manuscript involves the acidity enhancement of the benzylic C–H bonds by action of the indium catalyst at the Lewis basic site of 2-methylazaarenes. This is brought about by coordination of the indium Lewis acid to the N atom on the substrates which effectively activates the C(sp³)–H bonds towards their cleavage. This subsequently leads to the formation of indium-enamide intermediates from which addition to the carbonyl carbons of TFMKs proceed to give the intended products.

In conclusion, a simple In-catalyzed C(sp³)–H functionalization through direct benzylic addition under Lewis acid catalysis was successfully developed. InCl₃ was found to catalytically promote the addition of benzylic C–H bonds in 2-methylazaarenes to the carbonyl carbons of TFMKs. This protocol is highly efficient in which products of up to quantitative yield could be obtained under mild conditions. In addition to the asymmetric variants, endeavors are also currently directed towards the development of In-catalyzed C(sp³)–H functionalization with other classes of alkylazaarenes and electrophilic acceptors for the C–H addition.

Acknowledgements

We would like to thank the National Institute of Education, Nanyang Technological University for their generous financial support.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, characterization data and NMR spectra for all new compounds. See DOI: 10.1039/c4ra17182a

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