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Synlett 2014; 25(18): 2649-2653
DOI: 10.1055/s-0034-1379203
letter
© Georg Thieme Verlag Stuttgart · New York

Unprecedented C-Methylation at the 2-Position of 2-Carboxy-4-Chromanones – A Case Study with the Corey–Chaykovsky Reagent

Subrata Ghosh
a   Nano Characterization Unit, Advanced Key Technologies Division, National Institute of Material Science, Ibaraki 3050047, Japan
,
Nellore Bhanu Chandar
b   Computation and Simulation Unit (Analytical Discipline & Centralized Instrument Facility), Central Salt and Marine Chemicals Research Institute, G.B. Marg, Bhavnagar, Gujarat, 3624002 , India   Fax: +91(278)2567562   Email: ganguly@csmcri.org
e   Academy of Scientific and Innovative Research, CSIR-CSMCRI, Bhavnagar, Gujarat, 364002, India
,
Debayan Sarkar
c   Department of Chemistry, National Institute of Technology, Rourkela, Odissa, 769008, India
,
Manoj Kumar Ghosh
c   Department of Chemistry, National Institute of Technology, Rourkela, Odissa, 769008, India
,
Bishwajit Ganguly*
b   Computation and Simulation Unit (Analytical Discipline & Centralized Instrument Facility), Central Salt and Marine Chemicals Research Institute, G.B. Marg, Bhavnagar, Gujarat, 3624002 , India   Fax: +91(278)2567562   Email: ganguly@csmcri.org
e   Academy of Scientific and Innovative Research, CSIR-CSMCRI, Bhavnagar, Gujarat, 364002, India
,
Indrajit Chakraborty*
d   Department of Chemistry, KIIT University, Bhubaneswar, Odissa, 751024, India   Fax: +91(674)2725113   Email: indraji2001@gmail.com
› Author Affiliations
Further Information

Publication History

Received: 25 August 2014

Accepted after revision: 01 September 2014

Publication Date:
07 October 2014 (online)

 
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Corrected by:

Unprecedented C-Methylation at the 2-Position of 2-Carboxy-4-Chromanones – A Case Study with the Corey–Chaykovsky ReagentSynlett 2014; 25(18): e4-e4
DOI: 10.1055/s-0034-1378677

Corrected by:

Unprecedented C-Methylation at the 2-Position of 2-Carboxy- 4-Chromanones – A Case Study with the Corey–Chaykovsky ReagentSynlett 2015; 26(17): 2472-2472
DOI: 10.1055/s-0035-1560799

Abstract

An unprecedented C-methylation at the 2-position of 4-chromanone-2-carboxylates was achieved in good yield on treatment with dimethylsulfoxonium methylide. The reaction was performed with excellent chemo- as well as regioselectivity. It is the first synthetic report of alkylation at the 2-position of the chromanone framework through a very mild and simple approach. Such an uncommon behavioral pattern of the Corey–Chaykovsky reagent is justified by theoretical potential energy surface calculations.


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Key words

4-chromanone-2-carboxylate - C-methylation - regioselectivity - dimethylsulfoxonium methylide - theoretical calculations

The widespread versatility of ylide chemistry in functional-group transformations has generated considerable interest over more than 60 years.[1] The successful extension of this chemistry to sulfonium ylides as well as their oxidized analogues, the sulfoxonium ylides, was due to the pioneering work of Corey and Frazen.[2] Since then, sulfur ylide mediated chemistry has been exploited extensively in organic synthesis.[3] Dimethylsulfoxonium methylide (DIMSOY), popularly known as the Corey–Chaykovsky reagent, is one of the most versatile sulfur ylides for preparative organic chemistry.[4]

In organic chemistry, the nucleophilic reactivity of sulfur ylides is well recognized through three-membered ring (epoxide, cyclopropane, or aziridine) formation,[3a] although their enhanced stability is attributed to additional d-orbital participation.[5] The zwitterionic character of the ylides contributes significantly to their reactivity, conferring high stereo- and regiocontrol.[6] Another type of reaction exemplified by these reagents, although reportedly a more limited one, is methylation. Thus a number of C-methylation, N-methylation, O-methylation, and S-methylation reactions has been reported with DIMSOY.[4] [7] Regioselective C-methylation of various nitrobenzenes by DIMSOY was first reported by Traynelis et al.[7a] The tentative mechanistic explanations, however, could not furnish the reasons behind such a regioselective methylation process. Herein we wish to report DIMSOY-mediated one-step methylation at the 2-position of 4-chromanone-2-carboxylates in good yield and excellent regio- and chemoselectivity. We also present supporting evidence for such selectivity through computational calculations.

The chromanone framework abounds in a wide spectrum of natural products with pharmacological properties such as antioxidant, antitumor, and antibacterial activity.[8] This key motif for synthesizing chromone derivatives with biological activities[9] makes it a privileged structure. To synthesize chromone derivatives, a significant amount of work has been carried out over the last four decades.[10]

While much effort has been expended on synthesizing 2-aryl-substituted chromanones (flavones),[11] only a limited number of reports are available for installing an alkyl group at that same position.[12] However, the alkylation of chroman-2-carboxylates is documented.[13] The preparation of 2-alkyl-4-chromanone-2-carboxylates has been reported by three different groups,[14] although unlike the examples presented herein, none of them was based on a direct alkylation approach at the 2-position of 4-chromanone-2-carboxylates. Furthermore these earlier approaches failed to produce 2-alkylated products in good yields. As with other conjugated enones, 4-chromone-2-carboxylates may also be cyclopropanated in fair yield when treated with DIMSOY.[15] Subsequently changing the basic framework from chromone to chromanone, we envisaged the formation of epoxide 2 from the corresponding 4-chromanone-2-carboxylates 1a–e on treatment with DIMSOY. However, in the event, no such epoxide was formed, but rather the 2-alkylated products 3a–e were obtained exclusively. Careful monitoring of the reaction by TLC also indicated no starting material remaining (Scheme [1]). The best yield for this alkylation reaction was obtained using DMSO as solvent.

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Scheme 1 Regio- and chemoselective methylation of chromone-2-carboxylates 1 by DIMSOY

Computational calculations by Aggarwal et al. indicate good leaving-group ability for the sulfonium group.[16] This ability becomes all the more manifest for the sulfoxonium group, thus implying the role of trimethylsulfoxonium cation (TMSO+) as an active intermediate during methylation by DIMSOY. In our system, formation of TMSO+ is achievable through the uptake of an acidic proton by the ylidic carbon atom of DIMSOY (Scheme [2]). In fact, N-methylation of pyrimidines and the corresponding nucleosides has been reported using trimethylsulfoxonium hydroxide.[17]

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Scheme 2 A Simple mechanistic rationale for chromanone-2-carboxylate 2-methylation by DIMSOY

Although the ylide carbon of the sulfur ylide is nucleophilic in nature, various examples of methylation by DIMSOY[4] [7] as well as Aggarwal’s recent work on sulfonium ylide mediated cyclopropanation[18] clearly demonstrate that it can also act as a base. However, to the best of our knowledge no previous report is available in literature where the basic nature of DIMSOY prevailed over its nucleophilic nature in the presence of a keto functionality by performing selective alkylation at a less reactive sp3 carbon atom C(2). Reportedly, 4-chromanones are much more prone to undergo enolization, in the presence of a base, followed by alkylation at C(3).[19] From that point of view methylation at the 2-position of 4-chromanone-2-carboxylates by DIMSOY was totally unexpected. To explore this uncommon behavioral pattern of Corey–Chaykovsky reagent, a computational study was undertaken.

We first examined the formation of the epoxide of methyl 4-oxochroman-2-carboxylate 4 in the place of substituted ethyl 4-oxochroman-2-carboxylates 1a–c for computational simplicity. The Corey–Chaykovsky reaction mechanism was computationally investigated by Aggarwal et al.[20] The mechanistic pathways seem to suggest that C–C bond formation occurs via cisoid or transoid (see Supporting Information) addition of DIMSOY to the carbonyl compounds, which leads towards the formation of the betaine. In the subsequent step, the formation of the epoxide occurs with the elimination of DMSO. The elimination of DMSO can occur either via a syn or anti fashion in the transition state. The formation of epoxide of chromanone 4 with DIMSOY has been calculated employing M05-2X/6-31+G* in DMSO. The potential-energy profile obtained for the formation of epoxide suggests that only ­cisoid-type addition is possible in this case (Figure [1]). The attack of DIMSOY as a nucleophile to the carbonyl group of chromanone 4 leads to the formation of betaine, where the O–C–C–S dihedral angle is 40° (Figure [1]).

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Figure 1 Potential energy surface for epoxide formation of methyl 4-oxochroman-2-carboxylate with DIMSOY at M05-2X/6-31+G*(DMSO) level of theory. Selected bond distances are given in Å and the relative energies are given in kcal·mol–1.

The geometric constraints and steric effects do not allow the DIMSOY to approach the carbonyl group of chromanone 4 in a transoid fashion. Our efforts failed to locate the transoid transition states in this case. Furthermore, an alternative approach to arrive at the transiod betaine via the cisoid pathway also failed as the rotational transition state from cisoid to transoid form was also not accessible. The steric crowding in the cisoid betaine prevents the rotational transition state in this case. The cisoid betaine was found to be ca. 8.0 kcal·mol–1 energetically more stable compared to the separate reactants. A second transition-state geometry was identified for the ring closure to form the epoxide via the elimination of DMSO (Figure [1]).The O–C–C–S dihedral angle changes from 40° to 31° in the elimination transition state which supports the cisoid orientation of the molecule. The calculated activation barrier to form the epoxide is ca. 34.5 kcal·mol–1 compared to the cisoid betaine at M05-2X/6-31+G* level in DMSO.

The possibility for methyl 4-oxochroman-2-carboxylate (4) to undergo methylation at C(2) and/or C(3) positions with DIMSOY due to the availability of acidic protons was also examined (Figure [3] and Figure [4]). To examine the methylation processes, the potential energy surface was generated with M05-2X/6-31+G* in DMSO. The methylation of methyl 4-oxochroman-2-carboxylate with DIMSOY is a two-step process; the first step being the deprotonation at C(2) or C(3) by DIMSOY followed by methyl transfer to the respective carbons from DIMSOY. Both steps are concerted in nature (Scheme [2] and Scheme [3, ]Figures [3] and 4).

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Scheme 3 Methylation of chromanone 4 by DIMSOY at 3-position

The enolate complex formation after deprotonation at C(3) is energetically more stable compared to the separated reactants by ca. 7.0 kcal·mol–1; whereas, the enolate complex formed via C(2) deprotonation is ca. 3.0 kcal·mol–1 less stable than the reactant molecules (Figures [2–4]). In both cases, the methyl transfer process is the rate-determining step (Figure [2]). The activation energy barrier calculated with M05-2X/6-31+G* for methyl transfer to the C(2) position of chromanone 4 is 18.0 kcal·mol–1. However, the activation barrier calculated with respect to the stable enolate complex is relatively higher for the corresponding process at C(3). The calculated barrier was found to be 19.9 kcal·mol–1 (Figure [2]). These calculated results suggest that methyl 4-oxochroman-2-carboxylate can preferentially undergo C(2) methylation. Furthermore, the formation of the epoxide of chromanone 4 with DIMSOY is energetically unfavorable compared to the methylation processes (Figures [1] and [2]). The calculated transition states and corresponding enolate complexes for C(2) and C(3) methylation processes are given in Figures [3] and 4, respectively.

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Figure 2 The potential energy surface for C(2)-methylation and C(3)-methylation of methyl 4-oxochroman-2-carboxylate with DIMSOY at M05-2X/6-31+G* level of theory in DMSO
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Figure 3 Optimized geometries and selected bond distances (Å) for species involved in the C(2)-methylation of methyl 4-oxochroman-2-carboxylate with DIMSOY at M05-2X/6-31+G* level in DMSO (red = oxygen; white = hydrogen; yellow = sulfur; gray = carbon)
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Figure 4 Optimized geometries and selected bond distances (Å) for species involved in the C(3)-methylation of methyl 4-oxochroman-2-carboxylate) with DIMSOY at M05-2X/6-31+G* level in DMSO (red = oxygen; white = hydrogen; yellow = sulfur; gray = carbon)

In summary, we have reported the methylation at the 2-position of 4-chromanone-2-carboxylic acids with dimethylsulfoxonium methylide (DIMSOY). This is the first example of DIMSOY-mediated methylation at C(2) instead of C(3) in these systems. DFT calculations revealed that the epoxide formation with DIMSOY via ­Corey–Chaykovsky reaction mechanism is unfavored in this case, and the methylation at C(2) of the 4-chromanone-2-carboxylic acids can occur under such conditions.


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Computational Section

All geometries were fully optimized with M05-2X/6-31+G* level in DMSO with the polarizable continuum solvation model (PCM).[21] All calculations were performed with the Gaussian 09 suite program.[22] The stationary points were characterized by frequency calculations in order to verify that the transition structures had one, and only one, imaginary frequency. To verify that each saddle point connects two minima, intrinsic reaction coordinate (IRC) calculations of transition states were performed in both directions; that is, by following the eigenvectors associated to the unique negative eigenvalue of the Hessian matrix, using the González and Schlegel integration method.[23] The calculated M05-2X/6-31+G* electronic energies have been reported here.


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Typical Procedure for the 2-Methylation of 4-Chromanone-2-carboxylates 1 by DIMSOY

Freshly prepared trimethylsulfoxonium iodide (1.03 mmol) was weighed and dissolved in dry DMSO (2 mL). It was then added slowly to a stirred suspension of oil-free NaH (1.12 mmol) in dry DMSO (2 mL) under an inert atmosphere with cooling in an ice bath. After 30 min, a solution of ester 1 (1 mmol) in DMSO (2 mL) was slowly added in a dropwise manner and the reaction mixture stirred for 20 min at ice-bath temperature. Subsequently, it was allowed to warm to r.t. and stirred till completion of the reaction (verified by TLC; hexane–EtOAc, 10:1). The reaction mixture was then poured into ice water and extracted with Et2O. The solvent was removed under reduced pressure to obtain a crude mass which was purified by column chromatography on silica gel (hexane–EtOAc) to afford the pure compound 3.


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Acknowledgment

I.C. is grateful to KIIT University, Bhubaneswar and BG is grateful to the Central Salt and Marine Chemicals Research Institute (CSIR), Gujarat, for providing research facilities during this program. S.G. thanks Dr. A. Bandyopadhyay (NIMS) & MEXT for full support of laboratory facilities. We are also grateful to Dr. T. K. Paine and Dr. S. Ghosh of IACS, Kolkata for providing us with specific laboratory facilities. N.B.C. is grateful to the CSIR, New Delhi, for the award of a Fellowship and also thankful to AcSIR for enrolment into a PhD program. We thank the anonymous reviewers for their valuable comments/suggestions that have helped us to improve this manuscript.

Supporting Information

    for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/products/ejournals/journal/ 10.1055/s-00000083.
  • Supporting Information


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Zoom Image
Scheme 1 Regio- and chemoselective methylation of chromone-2-carboxylates 1 by DIMSOY
Zoom Image
Scheme 2 A Simple mechanistic rationale for chromanone-2-carboxylate 2-methylation by DIMSOY
Zoom Image
Figure 1 Potential energy surface for epoxide formation of methyl 4-oxochroman-2-carboxylate with DIMSOY at M05-2X/6-31+G*(DMSO) level of theory. Selected bond distances are given in Å and the relative energies are given in kcal·mol–1.
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Scheme 3 Methylation of chromanone 4 by DIMSOY at 3-position
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Figure 2 The potential energy surface for C(2)-methylation and C(3)-methylation of methyl 4-oxochroman-2-carboxylate with DIMSOY at M05-2X/6-31+G* level of theory in DMSO
Zoom Image
Figure 3 Optimized geometries and selected bond distances (Å) for species involved in the C(2)-methylation of methyl 4-oxochroman-2-carboxylate with DIMSOY at M05-2X/6-31+G* level in DMSO (red = oxygen; white = hydrogen; yellow = sulfur; gray = carbon)
Zoom Image
Figure 4 Optimized geometries and selected bond distances (Å) for species involved in the C(3)-methylation of methyl 4-oxochroman-2-carboxylate) with DIMSOY at M05-2X/6-31+G* level in DMSO (red = oxygen; white = hydrogen; yellow = sulfur; gray = carbon)