Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2016 Oct 1.
Published in final edited form as: Synlett. 2015 Aug 21;26(16):2293–2295. doi: 10.1055/s-0035-1560186

A Scalable Protocol for the Regioselective Alkylation of 2-Methylcyclohexane-1,3-dione with Unactivated sp3 Electrophiles

Robert J Sharpe 1, Maribel Portillo 1, Robert A Vélez 1, Jeffrey S Johnson 1,✉
PMCID: PMC4625839  NIHMSID: NIHMS719172  PMID: 26525231

Abstract

graphic file with name nihms719172u1.jpg

A method for the C-selective alkylation of 2-methylcyclohexane-1,3-dione with unactivated sp3 electrophiles is accomplished via alkylation and subsequent deprotection of the derived ketodimethyl hydrazones. The present method provides a high-yielding entry to dialkyl cycloalkanones that cannot be accessed via direct alkylation of 2-methylcyclohexane-1,3-dione. The title reaction may be useful in the scalable preparation of terpene and steroidal building blocks in the arena of natural product synthesis.

Keywords: alkylation, regioselectivity, hydrazones, ketones, alkyl halides, steroids, terpenoids

The 2,2-dialkylcyclohexane-1,3-dione subunit has seen widespread use as a building block in the preparation of terpene and steroidal natural products.1 The preparation of these compounds is often accomplished via the alkylation of 2-methylcyclohexane-1,3-dione (1, Scheme 1) with activated sp3 electrophiles (e.g., MeI, H2C=CHCH2Br, BnBr, etc.) or π-electrophiles (e.g. α,β–unsaturated carbonyls). While alkylation with these electrophiles is efficient, the alkylation of 1 with unactivated sp3 electrophiles is a significant challenge due to preferential O-alkylation in these cases, limiting the effectiveness of this method in target-oriented synthesis.2 While a number of methods directed toward C-selective alkylation of 1 have been described,3 these methods have been primarily limited to activated alkyl electrophiles. Piers and others have described preparation of 2,2-dialkylcyclohexane-1,3-diones 3 via alkylation and hydrolysis of 1,5-dimethoxy-1,4-cyclohexadienes 2;4 however, the stoichiometric requirements of t-BuLi and HMPA limit scalability and practicality of this protocol.

Scheme 1.

Scheme 1

Open in a new tab

C-Selective alkylations of 2-alkylcyclohexane-1,3-diones and their derivatives

As part of a research problem in our previously described total synthesis of the indole diterpenoid paspaline,5 we required an efficient and scalable alkylation of 1 or its derivatives. We were encouraged by the work of Enders and co-workers,3d,6 which demonstrated C-selective alkylation of cyclic ketohydrazones 4 with activated electrophiles (MeI, HC≡CCH2Br, BnBr, EtO2CCH2Br) and EtI. We found that ketohydrazone 4 gave exclusively C-alkylation even with more hindered and functionalized electrophiles; subsequent hydrolysis gave the desired diones 5. Herein, we describe this extension as a scalable protocol for the preparation of 2,2-dialkylcyclohexane-1,3-diones for use in the arena of natural product synthesis.

A screen of reaction conditions revealed the optimal protocol: Deprotonation of ketohydrazone 4 with KH in THF followed by addition of the electrophile provided access to the intermediate dialkyl ketohydrazones in good yields (Table 1). Hydrolysis of the intermediate alkylation products was completed via Corey’s method [Cu(OAc)2, aq THF]7 or upon treatment with Oxone in aqueous acetone.8 Employing these conditions, alkylation of 4 with 1-iodooctane (entry 1) gave exclusively C-alkylation in 92% yield, which upon hydrolysis, gave diketone 5a in 97% yield (89%, two steps). Extending the carbon chain in the alkyl iodide (entries 2 and 3) gave the same C-alkylation selectivity in slightly decreased yields. Alkenyl halides (entries 4 and 5) also performed well (78% and 92%, respectively), which upon hydrolysis provided diketones 5d,e bearing valuable functional handles. Alkylation of 4 with an iodide bearing a protected hydroxyl group (entry 6) also underwent efficient alkylation (73%, two steps), although the analogous protected aminoiodide (entry 7) failed to react with 4 under any conditions examined. Secondary alkyl halides (entry 8) also underwent alkylation with complete C-regioselectivity, albeit in decreased yields (42%, two steps) to give diketone 5h. Furthermore, alkyl bromides (entries 9–11) also underwent C-selective alkylation. The alkyl bromide bearing an electrophilic epoxide functionality (entry 11) underwent alkylation (and not the undesired epoxide opening) to give the corresponding diketone upon hydrolysis (52%, two steps).

Table 1.

Substrate Scope of the Alkylation/Hydrolysis of Ketohydrazone 4a

graphic file with name nihms719172u2.jpg
Entry Alkyl halide Product Alkylation yield (%)b Hydrolysis method (yield, %)c
1 graphic file with name nihms719172t1.jpg 5a 92 1d (97)
2 graphic file with name nihms719172t2.jpg 5b 81 1 (81)
3 graphic file with name nihms719172t3.jpg 5c 90 1 (81)
4 graphic file with name nihms719172t4.jpg 5d 78 1 (91)
5 graphic file with name nihms719172t5.jpg 5e 92 1 (80)
6 graphic file with name nihms719172t6.jpg 5f 90 1 (81)
7 graphic file with name nihms719172t7.jpg 5g 0 –
8 graphic file with name nihms719172t8.jpg 5h 67 2e (63)
9 graphic file with name nihms719172t9.jpg 5i 68 1 (78)
10 graphic file with name nihms719172t10.jpg 5j 94 2 (80)
11 graphic file with name nihms719172t11.jpg 5k 67 1 (77)
Open in a new tab
a

Yields refer to isolated analytically pure products. Yields are reported as averages of at least two experiments.

b

Reactions were carried out with 1.0 mmol alkyl halide, 1.5 mmol 4, and 1.5 mmol of KH.

c

Reactions were carried out with 0.5 mmol of intermediate ketohydrazone.

d

Method 1: Cu(OAc)2 (2.0 equiv), THF–H2O (1:1), r.t.

e

Method 2: Oxone (4.0 equiv), acetone–H2O (1:3), r.t.

To demonstrate the scalability of this protocol, the reaction of ketohydrazone 4 with 5-iodo-2-methylpent-2-ene was carried out on an 11.00 gram (65 mmol) scale with complete C-alkylation selectivity (Scheme 2); the sequence provided >10 grams (76% yield) of diketone 5d over two steps. Notably, purification of the intermediate alkylated hydrazone was omitted, enabling preparation of 5d requiring only a single purification. Compound 5d is a critical intermediate in our previously described total synthesis of paspaline.5

Scheme 2.

Scheme 2

Open in a new tab

Large-scale synthesis of dialkyldiketone 5d (10 g scale)

In summary, a practical and scalable alkylation of 2-methyl-1,3-cyclohexanediones using unactivated electrophiles has been enabled via alkylation9 and deprotection10,11 of the corresponding ketohydrazones. The scalability and applicability of this protocol has been demonstrated via the 10 gram scale synthesis of diketone 5d. This methodology may be useful to synthetic chemists in the preparation of ‘quaternized’ cyclohexane building blocks for natural product synthesis.

Supplementary Material

Supporting Information

Acknowledgments

The project described was supported by Award No. R01 GM084927 from the National Institute of General Medical Sciences. R.J.S. acknowledges an NSF Graduate Research Fellowship and ACS Division of Organic Chemistry Graduate Fellowship. M.P. acknowledges a fellowship from the McNair Undergraduate Scholars Program. R.A.V. acknowledges support from the NSF REU program (CHE-1460874).

Footnotes

References and Notes

  • 1.For illustrative examples of the use of 2.2-dialkylcyclohexanediones in target-oriented synthesis, see: Corey EJ, Virgil SC. J Am Chem Soc. 1990;112:6429.Nicolaou KC, Yang Z, Liu JJ, Ueno H, Nantermet PG, Guy RK, Caliborne CF, Renaud J, Couladouros EA, Paulvannan K, Sorenson EJ. Nature (London, UK) 1994;367:630. doi: 10.1038/367630a0.Solé D, Bonjoch J, García-Rubio S, Peidró E, Bosch J. Angew Chem Int Ed. 1999;38:395. doi: 10.1002/(SICI)1521-3773(19990201)38:3<395::AID-ANIE395>3.0.CO;2-5.Nicolaou KC, Pfefferkorn JA, Kim S, Wei HX. J Am Chem Soc. 1999;121:4724.Phillips EM, Roberts JM, Scheidt KA. Org Lett. 2010;12:2830. doi: 10.1021/ol100938j.Chin ZH, Chen ZM, Zhang YQ, Tu YQ, Zhang FM, Bian Z, Marvin CC, Pettersson M, Martin SF. J Am Chem Soc. 2014;136:14184. doi: 10.1021/ja5074646.
  • 2.(a) House HO. Modern Synthetic Reactions. Benjamin; Menlo Park: 1972. pp. 520–532. [Google Scholar]; (b) Stowell JC. Carbanions in Organic Synthesis. Wiley; New York: 1979. pp. 205–210. [Google Scholar]; (c) Caine D. In: Comprehensive Organic Synthesis. Trost BM, Fleming I, editors. Vol. 3. Pergamon Press; Oxford: 1991. pp. 54–58. [Google Scholar]; (d) Johnson WS, Lunn WH, Fitzi K. J Am Chem Soc. 1964;86:1972. [Google Scholar]
  • 3.(a) Rajamannar T, Palani N, Balasubramanian KK. Synth Commun. 1993;23:3095. [Google Scholar]; (b) Fujiwara M, Hitomi K, Baba A, Matsuda H. Chem Lett. 1994:875. [Google Scholar]; (c) Bedekar AV, Watanabe T, Tanaka K, Fuji K. Synthesis. 1995:1069. [Google Scholar]; (d) Demir AS, Enders D. J Prakt Chem. 1997;339:553. [Google Scholar]
  • 4.(a) Piers E, Grierson JR. J Org Chem. 1977;42:3755. [Google Scholar]; (b) Tamai Y, Hagiwara H, Uda H. J Chem Soc, Chem Commun. 1982:502. [Google Scholar]; (c) Watanabe H, Iwamoto M, Nakada M. J Org Chem. 2005;70:4652. doi: 10.1021/jo050349a. [DOI] [PubMed] [Google Scholar]; (d) Sparling BA, Moebius DC, Shair MD. J Am Chem Soc. 2013;135:644. doi: 10.1021/ja312150d. [DOI] [PubMed] [Google Scholar]
  • 5.Sharpe RJ, Johnson JS. J Am Chem Soc. 2015;137:4968. doi: 10.1021/jacs.5b02631. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.(a) Corey EJ, Enders D. Chem Ber. 1978;111:1337. [Google Scholar]; (b) Corey EJ, Enders D. Chem Ber. 1978;111:1362. [Google Scholar]
  • 7.Corey EJ, Knapp S. Tetrahedron Lett. 1976;17:3667. [Google Scholar]
  • 8.Hajipour AR, Mahboubghah N. Org Prep Proced Int. 1999;31:112. [Google Scholar]
  • 9.Typical Procedure for Alkylation of 4KH (30% dispersion in oil, 0.20 g, 1.50 mmol, 1.50 equiv) was washed free of oil with PE and suspended in anhydrous THF (3.0 mL). The suspension was transferred to a flame-dried, 10 mL round-bottomed flask under an atmosphere of N2, and the suspension was cooled to −78 °C. Hydrazone 4 (0.25 g, 1.50 mmol, 1.50 equiv) was dissolved in THF (1.0 mL) and added dropwise to the KH suspension. The resulting solution was warmed to 0 °C and stirred 4.5 h. The reaction was recooled to −78 °C, and 1-iodooctane (0.18 mL, 1.00 mmol, 1.00 equiv) was added drop-wise. The mixture was allowed to stir overnight, allowing the reaction to slowly warm to r.t. as the dry ice bath evaporated. After 14 h, the reaction was quenched via addition of sat. NH4Cl aq (4.0 mL), and the mixture was partitioned in a separatory funnel. The organic layer was separated, and the aqueous layer was extracted with Et2O (3 × 10 mL). The combined organic extracts were washed with brine (10 mL), dried with MgSO4 and concentrated in vacuo. The product was purified via flash chromatography (hexanes–EtOAc, 80:20 to 70:30) to afford the product ketohydrazone (0.25 g, 91% yield) as a yellow oil.
  • 10.Typical Procedure for Hydrazone Hydrolysis (Method 1)A 10 mL round-bottomed flask was charged with Cu(OAc)2·H2O (0.20 g, 1.00 mmol, 2.00 equiv) and H2O (3.3 mL), and the solution was allowed to stir until complete dissolution of Cu(OAc)2·H2O was observed, typically 2 min. The intermediate ketohydrazone derived from alkylation of 4 with 1-iodooctane (0.14 g, 0.50 mmol, 1.00 equiv) was dissolved in THF (3.3 mL) and added to the Cu(OAc)2·H2O solution. The resulting reaction mixture was allowed to stir until complete conversion of the starting material was observed by TLC analysis, typically 12 h. The reaction mixture was concentrated on a rotary evaporator to remove THF, and the remaining solution was quenched with sat. NH4Cl aq (5 mL) and diluted with CH2Cl2 (5 mL). The mixture was partitioned in a separatory funnel, the organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The combined organic extracts were dried with Na2SO4 and concentrated in vacuo. The product was purified via flash chromatography (hexanes–EtOAc, 90:10 to 80:20) to afford diketone 5a (0.12 g, 99% yield) as a yellow oil.
  • 11.Typical Procedure for Hydrazone Hydrolysis (Method 2)A 20 mL scintillation vial was charged with acetone (2.0 mL) and Oxone (1.20 g, 2.00 mmol, 4.00 equiv) with magnetic stirring. The intermediate ketohydrazone derived from alkylation of 4 with 2-iodopropane (0.11 g, 0.50 mmol, 1.00 equiv) was dissolved in acetone (0.7 mL) and transferred to the Oxone solution at r.t., producing a white suspension. The resulting mixture was stirred 2 h, whereupon the solution was concentrated on a rotary evaporator to remove the acetone. The remaining solution was diluted with H2O (5 mL) and transferred to a separatory funnel. The aqueous layer was extracted with EtOAc (2 × 7 mL) and CH2Cl2 (2 × 7 mL), and the combined organic extracts were dried with MgSO4 and concentrated in vacuo. The product was purified via flash chromatography (hexanes–EtOAc, 90:10 to 80:20) to afford diketone 5h (0.051 g, 65% yield) as a yellow oil.

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supporting Information
NIHMS719172-supplement-Supporting_Information.pdf (2.5MB, pdf)

RESOURCES