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Synlett 2023; 34(07): 868-872
DOI: 10.1055/a-1970-8537
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Chemical Synthesis and Catalysis in India

Chelation-Assisted Rhodium-Catalyzed Alkylation of a 1-Arylpyrazole C–H Bond with Cyclopropanols

Kuppan Ramachandran
,
Pazhamalai Anbarasan  ∗

We thank DST-SERB, New Delhi, India (Project No. SB/SJF/2020-21/15) for funding this work.
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Abstract

A general and efficient rhodium-catalyzed ortho-alkylation of N-arylpyrazoles has been accomplished with cyclopropanols as coupling partners. The reaction involves cleavage of both a C–H bond of the arene and a C–C bond of the cyclopropanol, and it offers access to a diversity of substituted 1-(ortho-alkylaryl)-1H-pyrazoles in good to excellent yields. In addition, nonsymmetrical dialkylation and a preliminary mechanistic investigation are also discussed.


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Key words

alkylation - cyclopropanols - C–H bond functionalization - rhodium catalysis - arylpyrazoles

Cyclopropane and its derivatives are important structural subunits, present in various natural products and therapeutically important molecules.[1] In particular, cyclopropanols are present in toblerols, which are antibiosis modulators of methylobacteria.[2] In addition, cyclopropanols have attracted considerable attention due to the possibility of generating various reactive species through C–C bond cleavage.[3] Among such reactions, the generation of homoenolates from cyclopropanols in the presence of a transition metal and the functionalization of these products have been well studied in conventional organic synthesis. Recently, an application of homoenolates formed from cyclopropanols in C–H bond functionalizations has been realized. Li and co-workers used cyclopropanols as alkylating reagents in a chelation-assisted Rh-catalyzed alkylation of C–H bonds,[4] which permitted the introduction of an aryl or alkyl ethyl ketone unit. Subsequently, a number of methods employing cyclopropanols as coupling reagents in C–H bond functionalizations have been disclosed.[5]

Due to their presence in various bioactive molecules[6] and the possibility of late-stage functionalizations, N-arylpyrazoles are important substrates that can be effectively employed in C–H bond functionalizations. In addition, pyrazole as a directing group has a unique advantage over the other N-heterocycles, due to its possible conversion into a useful functional group.[7] In this context, various C–C and C–heteroatom bond formations have been demonstrated for N-arylpyrazoles through pyrazole-assisted functionalizations of C–H bonds; however, the alkylation reactions of N-arylpyrazoles are rather limited. Most alkylations of C–H bonds of N-arylpyrazoles use either activated alkenes[8] or alkyl bromides (Scheme [1a]).[9] The use of cyclopropanols as alkylating reagents in C–H bond functionalizations of N-arylpyrazoles has not previously been documented. To further expand our interest in transition-metal-catalyzed C–H bond functionalization[10] with strained ring systems such as cyclopropenes,[11] and due to the importance of N-arylpyrazoles and the versatility of cyclopropanols, we envisaged the possibility of a rhodium-catalyzed C–H bond alkylation of N-arylpyrazoles with cyclopropanols (Scheme [1b]). The successful development of such a method would offer access to various ortho-alkylated N-arylpyrazoles with ketone functionalities, which could be readily functionalized.

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Scheme 1 Transition-metal-catalyzed alkylations of the C–H bonds of N-arylpyrazoles

We began by examining the alkylation of a C–H bond of N-phenylpyrazole (1a) with 1-phenylcyclopropanol (2a) in the presence of Cp*Rh(III) catalysts (Cp* = η5-pentamethylcyclopenta-1,3-dienyl). To our delight, the reaction of one equivalent of N-phenylpyrazole (1a) with three equivalents of cyclopropanol 2a in the presence of 5 mol% of [Cp*RhCl2]2, 10 mol% of AgSbF6, and 10 mol% or NaOAc in methanol at 100 °C for 24 hours afforded the alkylated product 3aa in 39% yield (Table [1], entry 1). Next, the reaction conditions were optimized to obtain a high yield of 3aa. When NaOAc was replaced by KOAc (10 mol%) in EtC(Me2)OH, 3aa was obtained in 48% yield (entry 2). Next, the use of a stoichiometric amount of Cu(OAc)2·H2O produced a significant improvement, giving 3aa in 61% yield together with the cyclopropanol-dimerized product, 1,6-diphenylhexane-1,6-dione in 6% yield (entry 3). Interestingly, changing the solvent from EtC(Me2)OH to MeOH under similar conditions afforded 3aa in the best yield of 88% along with 5% of the dialkylated product (entry 4). An attempt to lower the Cu(OAc)2·H2O loading was unsuccessful (entry 5). A similar result was obtained when the amount of Cu(OAc)2·H2O was increased to 200 mol% (entry 6). Likewise, when the temperature of the reaction was reduced to room temperature, 3aa was obtained in a very low yield (entry 7). Subsequently, screening of polar aprotic solvents (DMF and DMSO) failed to give the expected product 3aa (entries 8 and 9), suggesting the importance of a polar protic solvent for the present alkylation reaction. Replacement of Cu(OAc)2·H2O with silver salts also gave inferior results (entries 10 and 11). Use of cationic [Cp*Rh(CH3CN)3](SbF6)2 (10 mol%) in the absence of AgSbF6 gave product 3aa in 68% yield (entry 12). Based on these investigations, 1a (1 equiv), 2a (3 equiv), [Cp*RhCl2]2 (5 mol%), AgSbF6 (10 mol%), and Cu(OAc)2·H2O (100 mol%) in methanol at 100 °C were chosen as the optimized conditions for further exploration.

With the optimized conditions in hand, we investigated the scope and limitations of the substituted N-arylpyrazole and cyclopropanol. First, reactions of various N-arylpyrazoles 1 with cyclopropanol (2a) were examined under the optimized conditions; all afforded the corresponding alkylated products 3 in good yields (Scheme [2]). For instance, 1-arylpyrazoles with electron-donating (methoxy or methyl) groups in the para-, meta-, and ortho-position of the aryl group reacted smoothly to afford the corresponding products 3aa–ga in good to excellent yields of 74–93%. On the other hand, the reaction of 1-(4-nitrophenyl)-1H-pyrazole, containing an electron-withdrawing nitro substituent, gave product 3ha in a comparatively low 55% NMR yield, suggesting better reactivity of electron-rich arenes. Interestingly, the heteroarene-substituted 1-(2-thienyl)-1H-pyrazole was well tolerated under the optimized conditions, delivering the C3-alkylated thiophene derivative 3ia in 70% yield. To our delight, the use of 1-(2-pyridyl)-1H-pyrrole as a substrate gave 3jb in 34% yield under our standard conditions; thus, a C2-alkylation of a pyrrole was also established. Next, the effect of substitution of the pyrazole directing group was examined. Thus, various 3,5-disubstituted and 3,4,5-trisubstituted 1-aryl-1H-pyrazoles 1 were treated with 1-phenylcyclopropanol (2a) under the optimized conditions. 1-Aryl-3,5-dimethyl-1H-pyrazoles (aryl = Ph, 4-MeOC6H4, 4-i-PrC6H4) effectively gave products 3ka–ma in good to excellent yields. Moreover, 3,5-dimethyl-1-phenyl-4-(phenylsulfanyl)-1H-pyrazole also gave the corresponding product 3na in 83% yield.

Table 1 Optimization of the Rh-Catalyzed Alkylation of N-Phenylpyrazole (1a)a

Entry

Additive (mol%)

Solvent

Yieldb (%) of 3aa

 1

NaOAc (10)

MeOH

39

 2

KOAc (10)

EtC(Me2)OH

48

 3

Cu(OAc)2·H2O (100)

EtC(Me2)OH

61 (6)c

 4

Cu(OAc)2·H2O (100)

MeOH

88 (5)d (8)c

 5

Cu(OAc)2·H2O (50)

MeOH

54 (12)c

 6

Cu(OAc)2·H2O (200)

MeOH

44 (32) c

 7e

Cu(OAc)2·H2O (100)

MeOH

14

 8

Cu(OAc)2·H2O (100)

DMF

–

 9

Cu(OAc)2·H2O (100)

DMSO

–

10

AgOAc (20)

MeOH

26

11

AgNO3 (20)

MeOH

 5

12f

Cu(OAc)2·H2O (100)

MeOH

68

a Reaction conditions: 1a (1.0 equiv), 2a (3.0 equiv), [Cp*RhCl2]2 (5 mol%), additive, solvent (2 mL for 0.28 mmol of 1a), 100 °C, 24 h.

b Isolated yield.

c Yield of 1,6-diphenylhexane-1,6-dione.

d Yield of the dialkylated product.

e At room temperature.

f With [Cp*Rh(CH3CN)3](SbF6)2 (10 mol%).

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Scheme 2 Scope of the pyrazoles. a Yield based on 1H NMR

Having inspected the scope of various 1-arylpyrazoles, we next examined the effect of substitution of the 1-arylcyclopropanol. Initially, various 1-(alkylaryl)- and 1-(alkoxyaryl)-substituted cyclopropanols were treated with 1a under the optimized conditions to give products 3ab–ad and 3fc in yields of ~85% (Scheme [3]). Electronically moderate and labile fluoro- and chloro-substituted arylcyclopropanols gave the desired products 3ae, 3af, and 3ef in yields of 67, 85, and 74%, respectively. However, a cyclopropanol with a strongly electron-withdrawing nitro substituent did not afford the expected product 3ag. Interestingly, on replacing the aryl group with a 1-phenoxymethyl or a 1-(arylmethyl) group, the expected products 3ah–aj were obtained in good yields. We therefore subjected several alkyl-substituted cyclopropanols to the optimized conditions. 1-Hexyl and 1-adamantylcyclopropanols reacted smoothly to afford 3ak and 3al, respectively, in yields of 81 and 71%; 3ak was isolated along with a small amount (11%) of the dialkylated product. Next, a 1,2-disubstituted cyclopropanol was synthesized and subjected to the optimized conditions, and product 3am was successfully obtained in 68% yield and with an excellent regioselectivity in which the less-substituted carbon was involved in the alkylation process. Furthermore, the reaction of 3,5-dimethyl-1-phenyl-1H-pyrazole with various aryl-substituted cyclopropanols also provided the corresponding products 3kn–ke in good yields.

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Scheme 3 Scope of the cyclopropanols. a Isolated as the alcohol after reduction with NaBH4 (1.1 equiv). b Yield based on 1H NMR. c Yield of the dialkylated product.

To establish the synthetic viability of the present method, a scaled-up reaction was performed under optimized conditions; this afforded product 3aa in 84% yield (Scheme [4a]).[12] [13] Having observed the possible formation of a dialkylated product, we investigated the synthesis of a nonsymmetrical dialkylated product. Thus, the reaction of 1a with 2a under the optimized conditions gave an 87% yield of 3aa, which, on subsequent reaction with cyclopropanol 2c under the optimized conditions, gave the nonsymmetrical dialkylated product 4 in 71% yield (Scheme [4b]). On the other hand, only a 33% yield of 4 was isolated from a one-pot nonsymmetrical dialkylation without the isolation of 3aa.

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Scheme 4 Synthetic applications

Next, we directed our attention to understanding the mechanism of the present reaction through a series of control experiments. Initially, the importance of the catalyst and additives was investigated with 1a and 2a (see Supporting Information for more details). In the absence of the catalyst, AgSbF6, or the additive, no reaction was observed, and 1-phenyl-1H-pyrazole was recovered quantitatively. These experiments revealed the essential role of the catalyst, AgSbF6, and the additive in the present reaction. Subsequently, an intermolecular competitive experiment was performed to understand the reaction mechanism (Scheme [5a]). The reaction of an equimolar ratio of the 1-arylpyrazoles 1c and 1h with 2a under the standard conditions afforded a 4:1 mixture of the alkylated products 3ca and 3ha. The preferential alkylation of the electron-rich arene implied that the reaction might proceed by an electrophilic metalation pathway; however, a concerted metalation–deprotonation (CMD) pathway cannot be completely ruled out.[12] Similarly, a slight preference toward the electron-rich aryl-substituted cyclopropanol 2b was observed when a competitive experiment was performed with a mixture of 1a with 2b and 2f. This result suggested that electron-rich 2b undergoes Cp*Rh(III)–alkoxide formation followed by a β-carbon elimination process faster than does the electron-deficient cyclopropanol. Furthermore, this observation is in accordance with the poor reactivity of 1-(4-nitrophenyl)cyclopropan-1-ol.

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Scheme 5 Mechanistic investigation

Later, a deuterium-exchange experiment was carried out to support the formation of a Rh–C bond during the C–H bond functionalization (Scheme [5b]). Thus, treatment of 1a in the absence of 2a under the optimized conditions in methanol-d 4 resulted in selective incorporation of deuterium (10%) at the ortho-position of aryl group and at the C4 and C5 carbons (15 and 13%) of the pyrazole ring. This revealed the reversible formation of a Rh–C bond through C–H bond functionalization.

Having identified the involvement of a Rh–C bond, our next attempts were directed toward characterizing the potential intermediate involved in the reaction by means of stoichiometric reactions (Scheme [5c]). A stoichiometric reaction of 1a with [Cp*RhCl2]2 under the optimized conditions led to the possible intermediate 5, identified by HRMS analysis; however, attempts to isolate the observed intermediate 5 were unsuccessful. Furthermore, subsequent addition of cyclopropanol 2a to the reaction mixture furnished the expected alkylated product 3aa in 43% yield. This observation provided further support for the generation and involvement of 5 as a potential intermediate.

A plausible mechanism for the current reaction is proposed based on our preliminary mechanistic investigations and reports in the literature[4] (Scheme [6]). The reaction of the intermediate catalytically active species A, generated from the precatalyst and Cu(OAc)2·H2O/AgSbF6, with the 1-arylpyrazole 1 forms the rhodacyclic intermediate B through C–H bond functionalization. Interaction of cyclopropanol 2 with intermediate B gives the Rh–alkoxide species C. Intermediate C then initiates ring-opening of the cyclopropanol through a β-carbon elimination to provide the Rh(III)–alkyl intermediate D. The formation of product 3 can be rationalized through a reductive elimination from intermediate D, which also produces the reduced Rh species E. Oxidation of E by the copper salt regenerates the active catalyst A to continue the catalytic cycle.

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Scheme 6 Plausible mechanism

In conclusion, an efficient Cp*Rh(III)-catalyzed alkylation of N-arylpyrazoles has been established by employing cyclopropanols as efficient alkylating reagents. A number of alkylated N-arylpyrazoles were synthesized in good to excellent yields with a broad functional-group tolerance. Interestingly, nonsymmetrical dialkylation was also achieved, demonstrating the further potential of the developed method. In addition, a plausible mechanism for the developed reaction is proposed based on preliminary mechanistic investigations.


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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

K.R. thanks the University Grants Commission (UGC) for a fellowship.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-1970-8537.
  • Supporting Information

Corresponding Author

Pazhamalai Anbarasan
Department of Chemistry, Indian Institute of Technology Madras
Chennai – 600036
India   

Publication History

Received: 20 July 2022

Accepted after revision: 02 November 2022

Accepted Manuscript online:
02 November 2022

Article published online:
23 December 2022

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   Permissions and Reprints All articles of this category
Zoom Image
Scheme 1 Transition-metal-catalyzed alkylations of the C–H bonds of N-arylpyrazoles
Zoom Image
Scheme 2 Scope of the pyrazoles. a Yield based on 1H NMR
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Scheme 3 Scope of the cyclopropanols. a Isolated as the alcohol after reduction with NaBH4 (1.1 equiv). b Yield based on 1H NMR. c Yield of the dialkylated product.
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Scheme 4 Synthetic applications
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Scheme 5 Mechanistic investigation
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Scheme 6 Plausible mechanism