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DOI: 10.1039/D4CC03797A (Communication) Chem. Commun., 2024, Advance Article

Rh(III)-catalyzed aldehydic and aryl C–H alkylation with cyclopropanols via C–H/C–C bond activation†

Om Prakash Dash, Divya Garg and Chandra M. R. Volla*
Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai-400076, India. E-mail: chandra.volla@chem.iitb.ac.in

Received 28th July 2024 , Accepted 28th August 2024

First published on 29th August 2024

Abstract

Herein, we report Rh(III) catalyzed aldehydic or aryl C–H alkylation via C–C bond activation of cyclopropanols, facilitating the synthesis of β-functionalized ketones. The protocol employs cyclopropanol as the alkylating agent with 2-aminobenzaldehyde or aniline derivatives to access a variety of unsymmetrical 1,4-diketones or β-aryl ketones, respectively. The practicality of these transformations is showcased through the modification of natural products, gram-scale synthesis, broad substrate scope and postfunctionalizations.

1,4-Diketones are intriguing motifs found in many biologically relevant compounds1 and serve as key precursors in the synthesis of various heterocycles.2 Given their widespread importance, considerable efforts have been devoted to developing diverse synthetic routes to access these compounds. Recent advancements include methods such as the Stetter reaction of aldehydes with α,β-unsaturated carbonyl compounds,3 addition of enolates with α-haloketones4 and the oxidative coupling of enolates.5 However, these approaches often involve multiple steps and the use of non-readily available starting materials, require harsh reaction conditions and generally suffer from low efficiency and poor selectivity. Alternatively, acyl radical addition to alkenes followed by radical–radical coupling was also studied to access 1,4-diketones.6 But these strategies are either confined to symmetric 1,4-diketones or constrained by the limited range of acyl radicals or alkenes. Hence, a mild and efficient strategy that allows rapid access to a broad range of 1,4-diketones is highly desirable.

On the other hand, transition-metal-catalyzed C–H7 and C–C8 bond activations have drawn significant attention due to their ability to build molecular complexity rapidly. While both these strategies gained considerable importance independently, of late the integration of C–H bond activation with C–C bond cleavage has proven to be an efficient approach for C–H alkylation.9 In this context, strained ring systems, particularly cyclopropanols through C–C bond activation, offer unique opportunities as homoenolates for accessing β-functionalized ketones.10 Li and co-workers in pioneering studies demonstrated Rh(III)-catalyzed C–H alkylation of arenes with cyclopropanols.11 Their findings have established cyclopropanols as a new class of alkylating agents. Since then, many research groups have illustrated the versatility of cyclopropanols as alkylating agents by merging C–H and C–C activation. However, these strategies have so far been limited to aryl sp2 C–H alkylation reactions for realizing β-aryl ketones (Scheme 1a, top).12


image file: d4cc03797a-s1.tif
Scheme 1 (a) Cyclopropanol as alkylating agent. (b) Current work.

Considering the importance of 1,4-diketones and the intriguing reactivity of highly strained cyclopropanols, we envisioned that aldehydic C–H activation followed by C–C bond activation of cyclopropanols would provide a novel disconnection to γ-diketones (Scheme 1a, bottom). Herein, we present a Rh(III)-catalyzed aldehydic C–H alkylation method to access 1,4-diketones (Scheme 1b). Furthermore, this approach is extended to C–H alkylation of anilines to afford β-aryl ketones.

We commenced our studies with N-tosyl 2-aminobenzaldehyde 1 and cyclopropanol 2 as the model substrates (Table 1). After rigorous optimization, we found that the ring-opening alkylation proceeds smoothly with 1.0 eq. of 1, 1.5 eq. of 2, 2.5 mol% of [RhCp*Cl2]2, 1.0 eq. of Ag2CO3 and 1.0 eq. of NaOAc in DCE at 70 °C for 8 h, resulting in the desired 1,4-diketone 3 with an isolated yield of 78% (entry 1). Various polar protic and aprotic solvents such as TFE, MeOH, toluene, CH3CN, and THF were screened but were found to be inferior compared to DCE (entry 2). Other oxidants like AgOAc, Ag2O and Cu(OAc)2 instead of Ag2CO3 were less effective (entry 3). The use of Na2CO3, CsOAc, Cs2CO3 or K2CO3 instead of NaOAc was found to be deleterious (entry 4). No product was formed in the absence of a Rh(III)-catalyst or Ag2CO3 (entries 5 and 6) and no reaction occurred at room temperature and lower yields were observed at higher temperatures, suggesting that 70 °C is optimal (entry 7). Additionally, the Co(III) catalyst was ineffective for the current protocol (entry 8), highlighting the superior reactivity of Cp*Rh(III)-catalysts.

Table 1 Reaction optimization

image file: d4cc03797a-u1.tif
Entry Variation from standard conditions Yield
1 None 78%
2 TFE, toluene, MeCN, THF, MeOH instead of DCE <75%
3 AgOAc, Ag2O, Cu(OAc)2 instead of Ag2CO3 <58%
4 Na2CO3, CsOAc, Cs2CO3, K2CO3 instead of NaOAc <54%
5 Without [RhCp*Cl2]2 N.R.
6 Without Ag2CO3 N.R.
7 T = rt, 24 h N.R.
8 [Cp*Co(CO)I2] instead of Rh(III) N.R.

With the optimized conditions in hand, we proceeded to illustrate the scope and generality of both 2-aminobenzaldehydes 1 and cyclopropanols 2 (Scheme 2). Cyclopropanols with electronically varied substituents on the aromatic ring reacted smoothly with N-tosyl 2-aminobenzaldehyde 1 to deliver the desired products 3–7 in 72–84% yields (Scheme 2a). Further, thienyl derived cyclopropanol afforded 8 in 75% yield. Benzyl as well as aliphatic cyclopropanols also performed well to provide 1,4-diketones 9–20 in 70–86% yields. The effect of electron donating and withdrawing substituents on 1 was then studied employing cyclopropanol 2 and products 21–26 were obtained in 72–82% yields (Scheme 2b). Other sulfonyl protecting groups were also amenable to produce 27 and 28 in 78% and 76%, respectively (Scheme 2c). Cyclopropanols derived from drug derivatives like ibuprofen, gemfibrozil and abietic acid were compatible to deliver the corresponding products 29–31 in good yields (75–80%) (Scheme 2d). The reaction was found to be scalable up to 0.5 g of N-tosyl 2-aminobenzaldehyde (Scheme 2e). Next, to demonstrate the synthetic utility of 1,4-diketone 3, further transformations were carried out to access different heterocycles. When 1,4-diketone 3 was treated with hydroxylamine, condensation occurred selectively at the more reactive carbonyl, yielding oxime 32 in 60%. Treatment of 3 with NH4OAc led to pyrrole derivative 33 in 75% yield. Reacting 1,4-diketone 3 with hydrazine hydrochloride resulted in double condensation to deliver pyridazine derivative 34 in 70%. Interestingly, the nucleophilic nature of the protecting group itself led to the immediate cyclization of 3 to afford 2-alkyl indole 35 in 95% yield using 10 mol% of p-TsOH (see the ESI† for the plausible mechanism). The structure of 35 was confirmed by single-crystal X-ray diffraction analysis. Inspired by this result, we explored the scope of this dehydrative cyclization using diversely substituted 1,4-diketone derivatives and obtained a library of functionalized indole scaffolds 35–40 in excellent yields (89–95%) (Scheme 2f).


image file: d4cc03797a-s2.tif
Scheme 2 (a)–(d) Scope of the reaction with aldehydes. (e) and (f) Scale-up and functionalizations. (g) and (h) Scope of the reaction with anilines.

Continuing this study, we developed C–H alkylation of aniline derivatives with cyclopropanols. After optimization studies (see the ESI†), we found that the reaction of 1 eq. of N-phenyl aminopyridine 41 with 1.5 eq. of cyclopropanol 2 in the presence of 2.5 mol% [Rhcp*Cl2]2, 2.0 eq. of AgOAc and 1.0 eq. of NaOAc in MeOH at 70 °C for 6 h afforded the alkylation product 42 in 90%. We then explored the substrate scope of the reaction (Scheme 2g). Anilines bearing electronically variant groups at the para-position reacted effortlessly with 2 to provide the corresponding products 43–46 in 80–88% yields. Notably, α-naphthylamine and 2-aminofluorene were also amenable to furnish 48 and 49 in 89% and 80%, respectively. Cyclopropanols bearing substituents such as benzyl, furanyl or aliphatic chains also well tolerated and led to the products 50–53 in 82–92% yields. To our delight, anilines as well as cyclopropanols derived from biologically relevant molecules such as aminoglutethimide, ibuprofen, gemfibrozil and abietic acid furnished the corresponding alkylated products 54–57 in 75–90% yields (Scheme 2h). We then performed modular synthesis of an aniline conjugate by employing aminoglutethimide-derived aniline with cyclopropanol decorated with gemfibrozil to access structurally complex β-aryl ketone derivative 58 in 88% yield.

To gain some insights into the reaction mechanism, deuterium incorporation and control experiments were carried out. H/D scrambling experiments with N-phenyl aminopyridine in the absence of 2, using a 4[thin space (1/6-em)]:[thin space (1/6-em)]1 mixture of MeOH and D2O, resulted in 50% deuterium incorporation at the ortho-position of the phenyl ring and 20% deuteration at the NH proton (Scheme 3a). This suggests that C–H bond cleavage is reversible. Similar scrambling studies in the presence of 2 showed 52% deuteration on the CH2 α to the carbonyl. In order to confirm the nature of this deuteration, ketone 42 was subjected to reaction under standard conditions with a mixture of D2O and MeOH, which revealed 35% deuteration at the methylene position. This indicates that deuteration is likely due to the acidic nature of α-protons. When 1 or 41 was treated with phenyl vinyl ketone 59, the corresponding products 3 and 42 were isolated in 28% and 32% yields, respectively (Scheme 3b). These experiments suggest the possibility of α,β-unsaturated ketone as an intermediate in the catalytic cycle. When carbamate derived benzaldehyde 60 was treated with cyclopropanol in the presence of the Rh(III)-catalyst, lactone derivative 61 was isolated in 23% yield (Scheme 3c). Further, in the absence of the Rh(III)-catalyst, 60 readily undergoes Michael addition onto the in situ generated α,β-unsaturated ketone followed by aldol condensation to deliver dihydroquinoline derivative 62 in 76% yield. These results highlight the importance of the N-sulfonyl protecting group for the success of the transformation. C–H Alkylation of aniline derivative was also scalable and 42 undergoes NaBH4 mediated reduction to deliver 63 in 82% yield (Scheme 3d). Tetrahydroquinoline derivative 64 was isolated in 80% under reductive cyclization conditions. Notably, the N-tosyl group can be deprotected under acidic conditions to isolate 65 in 70%. Based on the control studies, we proposed the reaction mechanism (see the ESI†).


image file: d4cc03797a-s3.tif
Scheme 3 (a) Mechanistic studies. (b) Control experiments. (c) Other protecting groups. (d) Scale-up and functionalizations.

In conclusion, we have developed mild and efficient Rh(III)-catalyzed aldehydic or aryl C–H alkylation to access 1,4-diketones or β-aryl ketones. Both these protocols were compatible with a wide range of functionalities delivering the products under mild conditions in good to excellent yields. The reactions were scalable and the products were shown to undergo further transformations for the synthesis of heterocycles like pyrrole, pyridazine and indole derivatives. Preliminary mechanistic studies were carried out to shed light on the reaction mechanism.

This study was supported by the SERB, India (CRG/2023/004060). O. P. D. is grateful to the CSIR, India for the fellowship.

Data availability

General information, experimental procedures for the synthesis of starting and final compounds, spectroscopic characterization data, NMR spectra of all the obtained compounds, and X-ray crystallographic analysis data for compounds 7, 35 and 42 are available in the ESI.†

Conflicts of interest

There are no conflicts to declare.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 2372466, 2372581 2372583. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d4cc03797a
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