Cyclopropenium-Activated DMSO for Swern-Type Oxidation

Article abstract of DOI:10.1055/s-0037-1611183

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%.

Full text of DOI:10.1055/s-0037-1611183

SYNLETT
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© Georg
Thieme Ver-
lag Stuttgart
A
· New York
2019, 30, A–
T. Guo et al.
Letter
Synlett
Cyclopropenium-Activated DMSO for Swern-Type Oxidation
Tianfo Guo
Yu Gao
O
S
Cl Cl
R
OH
R
O
Zhenjiang Li*
Jingjing Liu
Kai Guo*
R'
primary &
secondary alcohols
R = aliphatic, aromatic, (hetero)aryl
R' = H, aliphatic, aromatic
R'
(up to 93% yield)
Ph
Ph
S
activator
scalable (>1 g)
operationally simple
recyclable by-product
State Key Laboratory of Materials-Oriented Chemical Engineering,
College of Biotechnology and Pharmaceutical Engineering, Nanjing
Tech University 30 Puzhu Road South, Nanjing 211816, P. R. of China
guok@njtech.edu.cn
up to 24 substrates
zjli@njtech.edu.cn
Received: 12.11.2018
Accepted after revision: 07.01.2019
Published online: 18.01.2019
(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-dichlorocyclohepta-
triene,8c have been reported recently (Figure 1). Most nota-
bly, the first example that DMSO was activated by chlori-
nated hydrocarbon was demonstrated with use of 1,1-di-
chlorocycloheptatriene by Nguyen and co-workers8c in the
dearomatization/rearomatization of tropylium systems. In-
spired by the tropylium ion and following our ongoing re-
search interest9 in germinal dichloride chemistry, we envi-
sioned that DDC 1, a germinal dichloride, would act as a
new DMSO activator for efficient Swern-type oxidation.
DOI: 10.1055/s-0037-1611183; Art ID: st-2018-w0739-l
Abstract Swern oxidation is widely used to convert alcohols into their
corresponding carbonyl compounds. However, the conventional meth-
od with use of the volatile oxalyl chloride as an activator requires the
reaction to be conducted below −60 °C. We discovered that 3,3-di-
chloro-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 opera-
tion. Furthermore, the activator DDC is easy to handle, and diphenylcy-
clopropenone 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%.
Key words alcohols, carbonyl compounds, cyclopropenium ion, gem-
inal dichloro compounds, Swern oxidation
Cl
Cl Cl
Cl
Cl
Ph
X
P
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 gen-
eral 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 pentox-
ide,4 SO3·pyridine complex,5 trifluoracetic anhydride
(TFAA),6 and oxalyl chloride7 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) ox-
alyl chloride reacts violently and exothermically with DMSO;
therefore, it requires low temperature (below –60 °C).7
N
N
Ph
Ph
X = Cl, Br
Singh, 2002
X
Ph
our work
Ph
Cl
N
Cl
1
Giacomelli, 2001
Nguyen, 2014
Figure 1 Substitutes of oxalyl chloride
DDC 1 was firstly synthesized by Breslow in 1957.10
Subsequently, extensive studies by Breslow and others re-
vealed many synthesis routes and applications of the cyclo-
propenium cation because of to its Hückel aromaticity.11
Recently, the Lambert group used the cyclopropenium ion
to facilitate dehydrative reactions such as chlorodehydra-
tion,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 deoxyfluo-
rination of alcohols,15 and Huy’s group reported a diethyl-
cyclopropenone-catalyzed protocol for alcohol halogena-
tions.16 The principle behind these applications is that aro-
matic cations are special molecules that have both the
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

B
T. Guo et al.
Letter
Synlett
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 cycloprope-
nium ion to activate DMSO for Swern-type oxidation.
triethylamine by Hünig’s base21 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 Conditionsa
O
OH
1, DMSO
Cl
Cl Cl
base, solvent, temperature
Cl–
R
2b
3b
R
R
R
Temp. Yieldb
(°C) (%)
Figure 2 Charged and neutral states of DDC12a
Entry
Solvent
Activator DMSO Base
(equiv)
(equiv)
1
DCM
1.5
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
3.0
5.0
3.0
3.0
3.0
Et3N, 5.0 equiv
Et3N, 5.0 equiv
Et3N, 5.0 equiv
Et3N, 5.0 equiv
Et3N, 5.0 equiv
Et3N, 5.0 equiv
Et3N, 5.0 equiv
Et3N, 5.0 equiv
Et3N, 5.0 equiv
Et3N, 3.0 equiv
Et3N, 3.0 equiv
Et3N, 3.0 equiv
−30
50
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.
2
acetone 1.5
THF 1.5
toluene 1.5
−30
−30
−30
−30
−20
0
2
3
5
4
20
90
91
trace
trace
92
90
93
80
95
5
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.2
1.5
6
At the outset, activator 1 was prepared and character-
ized17 (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 re-
sulted the highest yield of 90% after screening different sol-
vents (Table 1, entry 1–5). Even though DCM is frequently
used in Swern oxidation for its low polarity that can mini-
mize 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 sep-
arated the cyclopropenium cation and chloride anion more
in MeCN than in DCM, which facilitated the reaction be-
tween the cyclopropenium ion and DMSO. We observed
that activator 1 was insoluble in MeCN at −30 °C, but it dis-
solved 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 acti-
vating 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 ex-
plored. The reaction proved to be efficient even at –20 °C,
which is milder compared to Swern-type oxidations acti-
vated by oxalyl chloride,19b cyanuric chloride,8 triphenyl-
phosphine 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 °C8b,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
7
8
25
9
−20
−20
−20
−20
10
11
12
13
iPr2NEt, 3.0 equiv −20
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 al-
cohols, such as ethyl (3c), isopropyl (3d), hydroxyl (3f), me-
thoxyl (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 com-
pared 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 al-
cohols gave equally good yields compared to those obtained
from primary alcohols (3r–x). Both long-chain alkyl and cy-
clic secondary alcohols gave good results (3v, 3w). Further-
more, 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 (-ionol)
were ineffective in this reaction (see Supporting Informa-
tion). The products could be isolated by column chromatog-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

C
T. Guo et al.
Letter
Synlett
raphy 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 reac-
tions (Table 1 and Scheme 1).
Cl Cl
OH
O
Ph
Ph
, DMSO
(1)
Et3N, MeCN, 40 min, –20 °C
1 gram scale
90% yield
raw material for caprolactam
O
Cl Cl
1 (1.5 equiv), DMSO (3.0 equiv)
R
OH
R
O
OH
R'
2
R'
3
Et3N (3.0 equiv), MeCN, –20 °C
Ph
Ph
, DMSO
92% yield
O
(2)
Et3N, MeCN, 40 min, –20 °C
O
O
O
O
O
Ph
Ph
Cl
Cl
80% recovered
3a, 90% yield
3c, 91% yield
O
3b, 93% yield
3d, 92% yield
O
Cl Cl
O
OH
O
O
O
Ph
Ph
, DMSO
Cl
HO
O
O
(3)
89% yield
O
Et3N, MeCN, 40 min, –20 °C
3g, 91% yield
3f, 90% yield
3h, 65% yield
3e, 67% yield
O
O
O
O
Ph
Ph
78% recovered
NC
Br
O2N
O
3i, 45% yield
3l, 88% yield
3k, 58% yield
Scheme 2 1-gram scale oxidation of cyclohexanol and recyclability of
3j, 51% yield
diphenylcyclopropenone
O
O
O
O
N
N
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 interme-
diate 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 re-
vert 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 Giacomelli8a and
Singh8b (path a). We failed to obtain the structural evidence
of the intermediates 6 by NMR spectroscopy, MS, or TLC be-
cause 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 Singh8b and
Nguyen8c,24 also suggested similar intermediates for their
activation of DMSO by triphenylphosphine dihalide and
1,1-dichlorocycloheptatriene, respectively. Hence, we sup-
pose that alcohol 2 then reacts with the in situ generated
chlorodimethylsulfonium chloride 4 to form alkoxydimeth-
ylsulfonium chloride intermediate 5, which is turned into
dimethyl sulfide and carbonyl compound 3 by adding a
base.
3o, 91% yield
3n, 88% yield
3m, 93% yield
3p, 85% yield
O
O
O
O
O
F
3qa, 38% yield
3t, 89% yield
3r, 90% yield
3s, 91% yield
O
O
O
O
3v, 92% yield
3w, 90% yield
3u, 81% yield
3x, 70% yield
Scheme 1 The scope of substrates; a with the addition of 2.5 equiva-
lents of 1
To further demonstrate the utility of this method, we
performed the conversion of benzyl alcohol to benzyl alde-
hyde 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 diphenylcycloprope-
none, 78% of diphenylcyclopropenone could be recovered
(equation 3). Hence, two experiments showed high scale-
up potential and good recyclability of this method.
In conclusion, we developed a mild and alternative
method to activate DMSO for efficient Swern-type oxida-
tion of alcohols to their corresponding carbonyl com-
pounds. Compared with the previous methods, this one re-
quires warmer temperature, short activation time, and it is
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

D
T. Guo et al.
Letter
Synlett
S+
Cl–
S+
Cl–
Ph
Ph
Ph
O
O
ClH–
Cl
Ph
path a
6'
6
O
S
Cl–
S
R'
R
O
R
O
base
R
OH
Cl–
Cl
Cl
R'
3
5
R'
path b
O
Ph
Ph
Cl
Cl
S+
1
Ph
Ph
O
4
7
O
Cl
Scheme 3 Mechanism of cyclopropenium-activated DMSO for Swern oxidation
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.
(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.
(10) Breslow, R. J. Am. Chem. Soc. 1957, 79, 5318.
(11) (a) Komatsu, K.; Kitagawa, T. Chem. Rev. 2003, 103, 1371.
(b) Lyons, D. J. M.; Crocker, R. D.; Blümel, M.; Nguyen, T. V.
Angew. Chem. Int. Ed. 2017, 56, 1466. (c) D’yakonov, I. A.; Rafael,
R. K. Russ. Chem. Rev. 1967, 36, 557. (d) Yoshida, Z.-i. Top. Curr.
Chem. 1973, 40, 47. (e) Krivun, S. V.; Alferova, O. F.; Sayapina, S.
V. Russ. Chem. Rev. 1974, 43, 835.
(12) (a) Kelly, B. D.; Lambert, T. H. J. Am. Chem. Soc. 2009, 131, 13930.
(b) Vanos, C. M.; Lambert, T. H. Angew. Chem. Int. Ed. 2011, 50,
12222.
(13) Vanos, C. M.; Lambert, T. H. Chem. Sci. 2010, 1, 705.
(14) Hardee, D. J.; Kovalchuke, L.; Lambert, T. H. J. Am. Chem. Soc.
2010, 132, 5002.
(15) Li, L.; Ni, C.; Wang, F.; Hu, J. Nat. Commun. 2016, 7, 13320.
(16) Stach, T.; Dräger, J.; Huy, P. H. Org. Lett. 2018, 20, 2980.
(17) NMR spectra of 1: 1H NMR (400 MHz, CDCl3):  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):  131.5, 129.9, 129.3, 125.2, 123.0.
Funding Information
This work was supported by the National Key Research and Develop-
ment Program of China (2017YFC1104802), the National Natural Sci-
ence Foundation of China (U1463201, 21522604), the Natural Science
Foundation of Jiangsu Province, China (BK20150031), the Jiangsu Na-
tional Synergetic Innovation Center for Advanced Materials (SICAM),
the project funded by the Priority Academic Program Development of
Jiangsu Higher Education Institutions (PAPD), and the Top-Notch Aca-
demic Programs Project of Jiangsu Higher Education Institutions
(TAPP), and the Postgraduate Research & Practice Innovation Program
(18) General procedure
of Jiangsu Province.
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A 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.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611183.
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References and Notes
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D