Oxidative cross-esterification of dithiolanes with alcohols through a cross-dehydrogenative coupling (CDC)/deprotection sequence

Article abstract of DOI:10.1039/c1ob06890c

An unprecedented oxidative cross-esterification in an equimolar mixture of dithiolanes, alcohols and water through a CDC/deprotection sequence has been developed. The reaction itself features simple experimental procedures under very mild conditions and offers a new strategic protocol for the direct and efficient synthesis of structurally diverse esters.

Full text of DOI:10.1039/c1ob06890c

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Oxidative cross-esterification of dithiolanes with alcohols through a
cross-dehydrogenative coupling (CDC)/deprotection sequence†
Liang Fu, Chang-Jiang Yao, Ning-Jie Chang, Jia-Rong Chen, Liang-Qiu Lu* and Wen-Jing Xiao*
Received 8th October 2011, Accepted 9th November 2011
DOI: 10.1039/c1ob06890c
An unprecedented oxidative cross-esterification in an
equimolar mixture of dithiolanes, alcohols and water through
a CDC/deprotection sequence has been developed. The reac-
tion itself features simple experimental procedures under very
mild conditions and offers a new strategic protocol for the
direct and efficient synthesis of structurally diverse esters.
Ester moieties occur widely in a myriad of natural isolates,
synthetic compounds, and materials.1 They also represent ver-
satile intermediates for further synthetic transformations in both
industrial and academic settings.1,2 Ester synthesis has therefore
Scheme 1 Common strategies for the synthesis of esters.
intrigued and inspired chemists for over a century, and a variety
of well-established methods are documented in the literature.2,3
program developing cascade transformations,9 we have found
Traditionally, the most common approach to esters is the direct
that the combination of DDQ and copper salts can efficiently
condensation of carboxylic acids with alcohols catalyzed by strong
promote the CDC reaction of thioacetals with equimolar amounts
acids in the presence of a large excess of either substrate (Scheme
of alcohols to give 2-alkoxy-2-aryl-1,3-dithiolanes10 which are
further converted into synthetically useful esters under the reaction
conditions (path D). Herein, we communicate this general catalytic
oxidative cross-esterification of dithiolanes and alcohols under
mild conditions. To the best of our knowledge, no similar reactions
are documented to date.
1, path A).4 Alternative strategies have relied mainly upon the
stoichiometric activation of the corresponding acid as an acyl
halide, anhydride, or activated ester amenable to subsequent
nucleophilic reactions with alcohols (path B).3 In the last few years,
transition metal-catalyzed oxidative esterifications of alcohols
or aldehydes have become important tools for ester synthesis
(path C).5,6 Despite advances, some of these processes require
harsh reaction conditions, excess substrates, noble metals, large
amounts of condensing reagents or activators to attain satisfactory
conversion. Particularly, stoichiometric amounts of organic by-
products are generated in most cases. Therefore, more efficient
alternatives are still in strong demand.
Initially, we examined the reaction of 2-(4-methoxyphenyl)-
1,3-dithiolane (1a) with methanol in CHCl3, in the presence of
2,3-dichloro-5,6-dicyanoquinone (DDQ) (2.0 equiv.) and H2O
(1.0 equiv.) at room temperature for 12 h. To our delight, the
oxidative cross-esterification did indeed work and gave methyl 4-
methoxybenzoate (2) in 50% yield upon isolation (Table 1, entry
1). Thus, the influence of several metal salts was then investigated
to improve the reaction efficiency (Table 1, entries 2–9). Notably,
CuI (10 mol%) was identified to be the most efficient catalyst
toward the formation of 2 in CHCl3 (Table 1, entry 3). We also
examined other metal complexes known to be effective for CDC
reactions. For example, iron11 and palladium chlorides,12 which
were reported as efficient catalysts for oxidative cross-coupling
reactions, exhibited lower catalytic activities in this transformation
(Table 1, entries 8 and 9). As revealed in entries 3 and 10–14,
this oxidative esterification is readily accomplished in a variety
of solvents. The superior levels of reaction efficiency observed
with CuI in CHCl3 at room temperature (Table 1, entry 3, 92%
yield) prompted us to select these reaction conditions for further
exploration.
In recent years, cross-dehydrogenative coupling (CDC) re-
actions have significantly advanced state-of-the-art synthetic
methodologies.7 Cascade sequences that involve CDC reactions
became a powerful platform for the construction of new C–C or
C–heteroatom bonds. Critical to the success of these processes is
that the C–H bonds to be oxidized are usually adjacent to the
heteroatom, with nitrogen and oxygen being the most prevalent.7
In contrast, CDC reactions of dithiolanes with the sp3 C–H bond
adjacent to sulfur are very rare.8 As part of our ongoing research
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education,
College of Chemistry, Central China Normal University, 152 Luoyu Road,
Wuhan, Hubei 430079, China. E-mail: wxiao@mail.ccnu.edu.cn
† Electronic supplementary information (ESI) available: Experimen-
tal procedures and compound characterization data. See DOI:
10.1039/c1ob06890c
We next examined the scope of the reaction with a variety of
2-aryl-1,3-dithiolanes (1). As highlighted in Table 2, significant
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Table 1 Optimization of reaction conditionsa
both the C3 and C4 positions without significant loss in reaction
efficiency (Table 2, entries 1–9). Furthermore, the aryl framework
can be successfully extended to heteroaromatic (Table 2, entry
10) and naphthalene-derived systems (Table 2, entry 11). In the
case of 1,3-dithiolane 1l, derived from the cinnamaldehyde, we
got the tandem oxidation/isomerization/oxidation product 3l in
65% yield instead of the desired ester (Table 2, entry 12). To
demonstrate the preparative utility, the oxidative esterification
reaction of 1a (2.13 g) with EtOH (585 mL) was performed on
a 10-mmol scale in the presence DDQ and 5 mol% CuI to afford
the corresponding ester in 87% yield. Thus, our methodology is
feasible on a preparative scale.
More importantly, a wide array of structurally diverse alcohols
was also suitable for this oxidative cross-esterification reaction. As
revealed in Scheme 2, not only primary alcohols but also sterically
hindered secondary alcohols can react smoothly with 1a under
our optimal conditions. Importantly, the reaction appears quite
tolerant with respect to other functional groups in the alcohol
component (Scheme 2), such as triple bonds (product 4a). Note
that the synthesis of glycol monoester, an important building
block in the synthesis of natural isolates (e.g. sex pheromones
of Lepidoptera)13 and fine chemicals,14 is a difficult task.15
Gratifyingly, the glycol monoester was obtained in 76% yield
without the formation of diesters under our standard conditions
(Scheme 2, product 4b). Moreover, we were delighted to find that
an enantiopure N-Boc-L-prolinol was also suitable for the reaction
and afforded the corresponding ester in 76% yield without loss of
the stereochemistry (Scheme 2, product 4e).
Entry
Catalyst (mol %)
Solvent
Yield (%)b
1
2
—
CuI (5)
CHCl3
CHCl3
CHCl3
Neat
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
THF
toluene
CH3NO2
CH2Cl2
(CH2Cl)2
50
88
92
43
69
60
30
64
39
35
29
77
73
89
3
CuI (10)
CuI (10)
CuBr (10)
CuCl (10)
CuBr2 (10)
FeCl2 (10)
PdCl2 (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
4c
5
6
7
8
9
10
11
12
13
14
a Reaction conditions: 1a (0.5 mmol), methanol (20.5 mL, 0.5 mmol),
catalyst (10 or 5 mol%) and DDQ (1.0 mmol) in dried solvent (5 mL)
with stirring for an hour. Then water (9 mL, 0.5 mmol) was added and
the reaction mixture was stirred for 12 h at room temperature. b Yield of
isolated products. c 1a (10.0 mmol), methanol (405 mL, 10.0 mmol), CuI
(10 mol%), water (180 mL, 10.0 mmol) and DDQ (20.0 mmol). DDQ =
2,3-dichloro-5,6-dicyanoquinone.
Table 2 Oxidative cross-esterification of various 2-aryl-1,3-dithiolanes
(1) with ethanola
Entry
Ar
Product 3
t (h)
Yield (%)b
1
2
3
4
5
6
7
8
4-MeO-Ph (1a)
3-MeO-Ph (1b)
3,4-(MeO)2-Ph (1c)
4-Me-Ph (1d)
4-Br-Ph (1e)
3a
3b
3c
3d
3e
3f
3g
3h
3i
12
12
12
15
17
19
21
20
21
12
12
12
90
74
89
71
81
80
92
84
87
62
78
65
4-Cl-Ph (1f)
Scheme 2 Oxidative cross-esterification of 1a with various alcohols.
4-NO2-Ph (1g)
3-NO2-Ph (1h)
4-CN-Ph (1i)
2-thienyl (1j)
To gain insight into the possible reaction mechanism, a few
experiments were performed using 1a and ethanol as the substrates
under various reaction conditions (eqn (1)). It was found that the
oxidative esterification reaction passed through an intermediate
5a, which could be isolated in 56% yield in the early stage of the
reaction and could be readily converted into the product 3a.
9
10c
11c
12d
3j
3k
2-naphthyl (1k)
13e
4-MeO-Ph (1a)
3a
12
87
a Reaction conditions: 1 (0.5 mmol), ethanol (30 mL, 0.5 mmol), CuI (0.05
mmol) and DDQ (1.0 mmol) in dried CHCl3 (0.1 M) with stirring for an
hour. Then water (9 mL, 0.5 mmol) was added and the reaction mixture
was stirred for 12–24 h at room temperature. b Yield of isolated products.
c CHCl3 (0.05 M) was used. d DDQ (1.1 mmol) and ethanol (145 mL, 2.5
mmol) were used. e Reaction was carried out with 1a (10.0 mmol), ethanol
(585 mL, 10.0 mmol), DDQ (20.0 mmol), water (180 mL, 10.0 mmol) and
CuI (5 mol%).
(1)
While a precise reaction mechanism awaits further study, a
plausible catalytic cycle is depicted in Scheme 3. The oxidative
cross-esterification was initiated by copper(I)-catalyzed direct
hydrogen atom transfer to generate the benzylic radical A.7,11
Subsequent oxidation of A through single electron transfer (SET)
would afford thiocarbenium B. We assumed that the nucleophilic
attack of ethanol to B gave the key intermediate 5a, which then
structural variation in the 2-aryl-1,3-dithiolane component can be
realized. The reaction appears quite general with respect to the
electronic nature of the substituent on the aromatic ring (Table
2, entries 1–9, 71–92% yields). For example, Me, MeO, Cl, Br,
CN, and nitro groups can be introduced on the aromatic ring at
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4 For selected examples, see: (a) K. Ishihara, S. Ohara and H. Yamamoto,
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Scheme 3 Possible mechanism for the oxidative cross-esterification
reaction.
yielded the corresponding ester 3a by a copper(I)-assisted oxidative
deprotection.16
To support this proposed mechanism, we have carried out
an 18O-labeling experiment.17 When the model substrate 1a was
subjected to our standard conditions with H218O instead of H2O,
the 18O-labeling ethyl 4-methoxybenzoate was obtained in 87%
yield (eqn (2)).
9 (a) L.-Q. Lu, Y.-J. Cao, X.-P. Liu, J. An, C.-J. Yao, Z.-H. Ming and
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(2)
In conclusion, we have developed an unprecedented one-pot
oxidative cross-esterification of dithiolanes with alcohols and
water through a CDC/deprotection sequence. Notably, merging
DDQ with cuprous iodide was quite effective for the reaction of an
equimolar mixture of 2-aryl dithiolanes, alcohol, and water under
very mild conditions. The combination of two mechanistically
distinct transformations relying on the same catalytic system
makes this tandem reaction particularly useful. Future work will
be focus on the investigation of the precise reaction mechanism
and the extension of the current strategy to the esterification of
2-alkyl dithiolanes.
We are grateful to the National Science Foundation of China
(NO.21072069 and 21002036) for support of this research.
15 Basically, the synthesis of glycol monoester requires harsh reaction
conditions and accompanies with the formation of diesters. (a) S.
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Miyamura and S. Kobayashi, Chem.–Asian J., 2011, 6, 621; (c) R.
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Notes and references
1 J. Otera, Esterification: Methods, Reactions, and Applications, Wiley-
VCH, Weinheim, 2003.
2 (a) R. C. Larock, Comprehensive Organic Transformations: A Guide to
Functional Group Preparations, 2nd ed., Wiley-VCH, New York, 1999;
(b) P. G. M. Wuts and T. W. Greene, Protective Groups in Organic
Synthesis, John Wiley & Sons, New Jersey, 2007.
3 For representative reviews, see: (a) J. M. Humphrey and A. R.
Chamberlin, Chem. Rev., 1997, 97, 2243; (b) J. Otera, Acc. Chem. Res.,
2004, 37, 288; (c) K. Ekoue-Kovi and C. Wolf, Chem.–Eur. J., 2008, 14,
6302.
17 See the ESI for details†.
508 | Org. Biomol. Chem., 2012, 10, 506–508
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