Cyclopropenium-Activated DMSO for Swern-Type Oxidation

Abstract

Swern oxidation is widely used to convert alcohols into their corresponding carbonyl compounds. However, the conventional method with use of the volatile oxalyl chloride as an activator requires the reaction to be conducted below −60 °C. We discovered that 3,3-dichloro-1,2-diphenylcyclopropene (DDC) can be used as a new activator for Swern-type oxidations of alcohols, which can be conducted at −20 °C. This new protocol features mild and fast reactions with easy operation. Furthermore, the activator DDC is easy to handle, and diphenylcyclopropenone can be recovered quantitively. This new type of Swern oxidation shows a broad scope of substrates including benzylic, allylic, aliphatic, and biobased alcohols, and gives high yields of up to 93%.

The oxidation of alcohols to carbonyl compounds is an important and frequently used reaction in both synthetic laboratories and chemical industries.[1] Among the oxidants applied for oxidizing alcohols, activated dimethylsulfoxide (DMSO)[2] is one of the most widely used reagents. The general mechanism of this oxidation is that DMSO has been utilized as a reagent by applying dimethylalkoxysulfonium salts; they react with a base to give the carbonyl compound and dimethyl sulfide. A variety of electrophilic reagents as activators such as acetic anhydride,[3] phosphorous pentoxide,[4] SO₃ ·pyridine complex,[5] trifluoracetic anhydride (TFAA),[6] and oxalyl chloride[7] have been reported. Because of the advantages of fewer side reactions, high yields, and consistent efficiency over a broad range of substrates, oxalyl chloride has been widely used as the electrophile for DMSO, which later became known as Swern oxidation. Although oxalyl chloride is generally effective, problems remain: (1) oxalyl chloride reacts violently and exothermically with DMSO; therefore, it requires low temperature (below –60 °C).[7] (2) Oxalyl chloride itself is a volatile and toxic reagent, which is difficult to deal with. Thus, many substitutions of oxalyl chloride have been found to solve these problems.[8]

Among the substitutions of oxalyl chloride, alternative chloride-bearing reagents,[7] such as cyanuric chloride,[8a] triphenylphosphine dihalide,[8b] and 1,1-dichlorocycloheptatriene,[8c] have been reported recently (Figure [1]). Most notably, the first example that DMSO was activated by chlorinated hydrocarbon was demonstrated with use of 1,1-dichlorocycloheptatriene by Nguyen and co-workers[8c] in the dearomatization/rearomatization of tropylium systems. Inspired by the tropylium ion and following our ongoing research interest[9] in germinal dichloride chemistry, we envisioned that DDC 1, a germinal dichloride, would act as a new DMSO activator for efficient Swern-type oxidation.

DDC 1 was firstly synthesized by Breslow in 1957.[10] Subsequently, extensive studies by Breslow and others revealed many synthesis routes and applications of the cyclopropenium cation because of to its Hückel aromaticity.[11] Recently, the Lambert group used the cyclopropenium ion to facilitate dehydrative reactions such as chlorodehydration,[12] Beckmann rearrangement,[13] and nucleophilic acyl substitution.[14] Most recently, the Hu group reported the use of 3,3-difluoro-1,2-diarylcyclopropenes for the deoxyfluorination of alcohols,[15] and Huy’s group reported a diethylcyclopropenone-catalyzed protocol for alcohol halogenations.[16] The principle behind these applications is that aromatic cations are special molecules that have both the properties aromatic stability and ionic charge. This duality gave these molecules the ability to easily shuttle between charged and neutral states through a reversible association with an anion or a heteroatom lone pair (Figure [2]).[12a] On this basis, we explored the possibility of using cyclopropenium ion to activate DMSO for Swern-type oxidation.

For our research, we investigated the possibility of using the cyclopropenium cation as an electrophile for Swern-type oxidation. We found that DDC-activated DMSO for Swern-type oxidation provided good to excellent yields even at –20 °C for both primary and secondary alcohols. We also proposed a possible mechanism for this reaction.

At the outset, activator 1 was prepared and characterized[17] (see Supporting Information). 2-Phenylethanol was chosen as the substrate for a model reaction.[8c] A series of reactions were carried out to obtain the optimal reaction conditions in a general procedure,[18] and the results are summarized in Table [1]. The reaction in MeCN at –30 °C resulted the highest yield of 90% after screening different solvents (Table [1], entry 1–5). Even though DCM is frequently used in Swern oxidation for its low polarity that can minimize the formation of methylthiomethyl ethers,[8b] [c] [19] the yields in this and other media were inferior than that in MeCN (entry 1–5). We supposed that the polar solvent separated the cyclopropenium cation and chloride anion more in MeCN than in DCM, which facilitated the reaction between the cyclopropenium ion and DMSO. We observed that activator 1 was insoluble in MeCN at −30 °C, but it dissolved a few minutes after the addition of DMSO, which caused the reaction between these two reagents. We also found negligible differences in yields by changing the activating time from 5 to 10 or 20 minutes. To make sure that DMSO was fully activated, we activated it for 20 minutes in every batch. Then, the influence of the temperature was explored. The reaction proved to be efficient even at –20 °C, which is milder compared to Swern-type oxidations activated by oxalyl chloride,[19b] cyanuric chloride,[8] triphenylphosphine dihailide,[9] and 1,1-dichlorocycloheptatriene.[10] Only trace amounts of product were found at 0 and 25 °C, which matched the instability of intermediate 4 (Scheme [2]) above –20 °C (entries 5–8).[20] Swern oxidation reactions were usually carried out at up to –78 °C[8b] [19b] because of the strongly exothermic DMSO-activating step. In our case, we aborted two experiments at –78 and –40 °C because of the frozen MeCN. The amount of DMSO and trimethylamine could be reduced to 3.0 equivalents at –20 °C without any noticeable decrease in yield (entries 9–11). However, the decrease in the amount of activator had an apparent side-effect on the yields (entries 11–12). Finally, substitution of triethylamine by Hünig’s base[21] led to an even better yield, offering an alternative base for this reaction system as in the case of triethylamine-sensitive reactions (entry 13).[22]

Table 1 Optimization of the Reaction Conditions^a

Entry	Solvent	Activator (equiv)	DMSO (equiv)	Base	Temp. (°C)	Yieldb (%)
1	DCM	1.5	5.0	Et3N, 5.0 equiv	−30	50
2	acetone	1.5	5.0	Et3N, 5.0 equiv	−30	2
3	THF	1.5	5.0	Et3N, 5.0 equiv	−30	5
4	toluene	1.5	5.0	Et3N, 5.0 equiv	−30	20
5	MeCN	1.5	5.0	Et3N, 5.0 equiv	−30	90
6	MeCN	1.5	5.0	Et3N, 5.0 equiv	−20	91
7	MeCN	1.5	5.0	Et3N, 5.0 equiv	0	trace
8	MeCN	1.5	5.0	Et3N, 5.0 equiv	25	trace
9	MeCN	1.5	3.0	Et3N, 5.0 equiv	−20	92
10	MeCN	1.5	5.0	Et3N, 3.0 equiv	−20	90
11	MeCN	1.5	3.0	Et3N, 3.0 equiv	−20	93
12	MeCN	1.2	3.0	Et3N, 3.0 equiv	−20	80
13	MeCN	1.5	3.0	i Pr2NEt, 3.0 equiv	−20	95

^a See Supporting Information for reaction conditions.

^b Yield was determined by GC.

Having the optimized conditions in hands, we explored the scope of primary and secondary alcohols. The products were obtained from those substrates in good to excellent yields (Scheme [1]). Electron-donating groups on benzylic alcohols, such as ethyl (3c), isopropyl (3d), hydroxyl (3f), methoxyl (3g) groups, provided good yields, except the bulky tert-butyl group (3e). However, electron-withdrawing groups on benzylic alcohols, such as Cl (3h), Br (3l), ester (3j), nitrile (3k), nitro (3l) groups, afford lower yields compared to those obtained from electron-donating groups. The oxidation of heterocyclic (3m, 3n), nonactivated (3o), and activated alcohols (3p) proceeded smoothly under the developed reaction conditions. Low yield was obtained for the diol, and no significant improvement was achieved with one more equivalent of activator (3q). Unexpectedly, with additional steric hindrance, the oxidation of secondary alcohols gave equally good yields compared to those obtained from primary alcohols (3r–x). Both long-chain alkyl and cyclic secondary alcohols gave good results (3v, 3w). Furthermore, a biologically relevant substrate was oxidized to the corresponding carbonyl compound in reasonable yield (3x). Long-chain alkyl primary alcohols, an amide group, Boc-carbamate, and biologically relevant substrates (β-ionol) were ineffective in this reaction (see Supporting Information). The products could be isolated by column chromatography from concentrated reaction mixtures. The precursor of the activator, cyclopropenone 7, could be recovered from reaction mixtures in about 80% yield. Furthermore, no trace of competing reactions, namely chlorodehydration and Pummerer rearrangement, have been observed in all reactions (Table [1] and Scheme [1]).

To further demonstrate the utility of this method, we performed the conversion of benzyl alcohol to benzyl aldehyde on a 1.0 g scale (equation 1, Scheme [2]): the yield of this transformation was 90%. Moreover, the recyclability of diphenylcyclopropenone was investigated. In the first trial, we recovered 80% of diphenylcyclopropenone (equation 2). In a reaction reusing the recovered diphenylcyclopropenone, 78% of diphenylcyclopropenone could be recovered (equation 3). Hence, two experiments showed high scale-up potential and good recyclability of this method.

The mechanism of this reaction is proposed in Scheme [3]. Initially, 1 is prepared and isolated from cyclopropenone and oxalyl chloride to exclude confusion by oxalyl chloride. Then, 1 and DMSO react and form sulfonium ether intermediate 6', which equilibrates with its ionic form 6. Here, we have two possibilities. On the one hand, cationic ether 6 is highly reactive and its cyclopropenium part is likely to revert and form chlorodimethylsulfonium chloride 4 and 7, which later reacts as part of the conventional mechanism (path b). On the other hand, alcohol 2 reacts with 6 to form intermediate 5 without any Pummerer product, which is analogous to the mechanisms proposed by Giacomelli[8a] and Singh[8b] (path a). We failed to obtain the structural evidence of the intermediates 6 by NMR spectroscopy, MS, or TLC because of its fast transformation even at –40 °C. However, a similar intermediate, formed by DMSO and oxalyl chloride, decomposed quickly to 4 even at –140 °C.[23] Singh[8b] and Nguyen[8c] [24] also suggested similar intermediates for their activation of DMSO by triphenylphosphine dihalide and 1,1-dichlorocycloheptatriene, respectively. Hence, we suppose that alcohol 2 then reacts with the in situ generated chlorodimethylsulfonium chloride 4 to form alkoxydimethylsulfonium chloride intermediate 5, which is turned into dimethyl sulfide and carbonyl compound 3 by adding a base.

In conclusion, we developed a mild and alternative method to activate DMSO for efficient Swern-type oxidation of alcohols to their corresponding carbonyl compounds. Compared with the previous methods, this one requires warmer temperature, short activation time, and it is nonhazardous and gentle. It also adapts to a scope of both primary and secondary alcohols. Moreover, we envisaged that further structural modification of the three-membered ring of the cyclopropenium ion could allow optimization of Swern-type oxidation. This work not only provides a new platform for promotion of the Swern oxidation, but further extends the scope of cyclopropenium ion chemistry.

• References and Notes

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• 17 NMR spectra of 1: ¹H NMR (400 MHz, CDCl₃): δ 8.23–8.20 (m, 4 H), 7.75–7.70 (m, 2 H), 7.68–7.64 (m, 4 H). ¹³C NMR (100 MHz, CD₃CN): δ 131.5, 129.9, 129.3, 125.2, 123.0.
• 18 General procedureA solution of DMSO (5.0 equiv) in dichloromethane (DCM) was added to a solution of 1 (1.5 equiv) in DCM at –30 °C, and the mixture was stirred for 20 min at the same temperature. Then, a solution of 2-phenylethanol (1.0 equiv) in DCM was added and continuously stirred for another 20 min before the dropwise addition of Et₃N (5.0 equiv). The mixture was subsequently left to warm to room temperature and concentrated under reduced pressure. The product was analyzed by gas chromatography (GC) and isolated by column chromatography.
• 19a Corey EJ, Kim CU. J. Am. Chem. Soc. 1972; 94: 7586
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• 19b Omura K, Swern D. Tetrahedron 1978; 34: 1651
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• 20 Tojo G, Fernandez MI. Oxidation of Alcohols to Aldehydes and Ketones . Springer; New York: 2006
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• 21 Hünig S, Kiessel M. Chem. Ber. 1958; 91: 380
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• 22a Walba DM, Thurmes WN, Haltiwanger RC. J. Org. Chem. 1988; 53: 1046
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• 22c Evans DA, Gage JR, Leighton JL. J. Am. Chem. Soc. 1992; 114: 9434
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• 23 Mancuso AJ, Brownfain DS, Swern D. J. Org. Chem. 1979; 44: 4148
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• 24 Nguyen TV, Bekensir A. Org. Lett. 2014; 16: 1720
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• References and Notes

• 1 Haines AH. In Methods for Oxidation of Organic Compounds . Haines AH. Academic Press; New York: 1988: 5
  CrossrefSearch in Google Scholar
• 2a Mancuso AJ, Swern D. Synthesis 1981; 165
  Thieme Connect
• 2b Tidwell TT. Synthesis 1990; 857
  Thieme Connect
• 3 Albright JD, Goldman L. J. Am. Chem. Soc. 1965; 87: 4214
  CrossrefSearch in Google Scholar
• 4 Onodera K, Hirano S, Kashimura N. J. Am. Chem. Soc. 1965; 87: 4651
  CrossrefSearch in Google Scholar
• 5 Parikh JR, Doering W.v.E. J. Am. Chem. Soc. 1967; 89: 5505
  CrossrefSearch in Google Scholar
• 6 Omura K, Sharma A, Swern D. J. Org. Chem. 1976; 41: 957
  CrossrefSearch in Google Scholar
• 7 Mancuso AJ, Huang S.-L, Swern D. J. Org. Chem. 1978; 43: 2480
  CrossrefSearch in Google Scholar
• 8a De Luca L, Giacomelli G, Porcheddu A. J. Org. Chem. 2001; 66: 7907
  CrossrefPubMedSearch in Google Scholar
• 8b Bisai A, Chandrasekhar M, Singh VK. Tetrahedron Lett. 2002; 43: 8355
  CrossrefSearch in Google Scholar
• 8c Nguyen TV, Hall M. Tetrahedron Lett. 2014; 55: 6895
  CrossrefSearch in Google Scholar
• 9 Gao Y, Liu J, Li Z, Guo T, Xu S, Zhu H, Wei F, Chen S, Gebru H, Guo K. J. Org. Chem. 2018; 83: 2040
  CrossrefPubMedSearch in Google Scholar
• 10 Breslow R. J. Am. Chem. Soc. 1957; 79: 5318
  Search in Google Scholar
• 11a Komatsu K, Kitagawa T. Chem. Rev. 2003; 103: 1371
  CrossrefPubMedSearch in Google Scholar
• 11b Lyons DJ. M, Crocker RD, Blümel M, Nguyen TV. Angew. Chem. Int. Ed. 2017; 56: 1466
  CrossrefPubMedSearch in Google Scholar
• 11c D’yakonov IA, Rafael RK. Russ. Chem. Rev. 1967; 36: 557
  CrossrefSearch in Google Scholar
• 11d Yoshida Z.-i. Top. Curr. Chem. 1973; 40: 47
  Search in Google Scholar
• 11e Krivun SV, Alferova OF, Sayapina SV. Russ. Chem. Rev. 1974; 43: 835
  CrossrefSearch in Google Scholar
• 12a Kelly BD, Lambert TH. J. Am. Chem. Soc. 2009; 131: 13930
  CrossrefPubMedSearch in Google Scholar
• 12b Vanos CM, Lambert TH. Angew. Chem. Int. Ed. 2011; 50: 12222
  CrossrefPubMedSearch in Google Scholar
• 13 Vanos CM, Lambert TH. Chem. Sci. 2010; 1: 705
  CrossrefSearch in Google Scholar
• 14 Hardee DJ, Kovalchuke L, Lambert TH. J. Am. Chem. Soc. 2010; 132: 5002
  CrossrefPubMedSearch in Google Scholar
• 15 Li L, Ni C, Wang F, Hu J. Nat. Commun. 2016; 7: 13320
  CrossrefPubMedSearch in Google Scholar
• 16 Stach T, Dräger J, Huy PH. Org. Lett. 2018; 20: 2980
  CrossrefPubMedSearch in Google Scholar
• 17 NMR spectra of 1: ¹H NMR (400 MHz, CDCl₃): δ 8.23–8.20 (m, 4 H), 7.75–7.70 (m, 2 H), 7.68–7.64 (m, 4 H). ¹³C NMR (100 MHz, CD₃CN): δ 131.5, 129.9, 129.3, 125.2, 123.0.
• 18 General procedureA solution of DMSO (5.0 equiv) in dichloromethane (DCM) was added to a solution of 1 (1.5 equiv) in DCM at –30 °C, and the mixture was stirred for 20 min at the same temperature. Then, a solution of 2-phenylethanol (1.0 equiv) in DCM was added and continuously stirred for another 20 min before the dropwise addition of Et₃N (5.0 equiv). The mixture was subsequently left to warm to room temperature and concentrated under reduced pressure. The product was analyzed by gas chromatography (GC) and isolated by column chromatography.
• 19a Corey EJ, Kim CU. J. Am. Chem. Soc. 1972; 94: 7586
  CrossrefSearch in Google Scholar
• 19b Omura K, Swern D. Tetrahedron 1978; 34: 1651
  CrossrefSearch in Google Scholar
• 20 Tojo G, Fernandez MI. Oxidation of Alcohols to Aldehydes and Ketones . Springer; New York: 2006
  Search in Google Scholar
• 21 Hünig S, Kiessel M. Chem. Ber. 1958; 91: 380
  CrossrefPubMedSearch in Google Scholar
• 22a Walba DM, Thurmes WN, Haltiwanger RC. J. Org. Chem. 1988; 53: 1046
  CrossrefSearch in Google Scholar
• 22b Evans DA, Polniaszek RP, DeVries KM, Guinn DE, Mathre DJ. J. Am. Chem. Soc. 1991; 113: 7613
  CrossrefSearch in Google Scholar
• 22c Evans DA, Gage JR, Leighton JL. J. Am. Chem. Soc. 1992; 114: 9434
  CrossrefSearch in Google Scholar
• 23 Mancuso AJ, Brownfain DS, Swern D. J. Org. Chem. 1979; 44: 4148
  CrossrefSearch in Google Scholar
• 24 Nguyen TV, Bekensir A. Org. Lett. 2014; 16: 1720
  CrossrefPubMedSearch in Google Scholar

• Supplementary Material