PhICl2 and wet DMF: An efficient system for regioselective chloroformyloxylation/a-chlorination of alkenes/a,β-unsaturated compounds

Article abstract of DOI:10.1021/ol403321n

PhICl₂ in wet DMF was found to form an efficient system for realizing difunctionalization of various alkenes and olefinic derivatives possessing a wide range of functional groups. This novel methodology provides convenient access to either regioselective chloroformyloxylated products or a-chlorinated olefinic products, depending on the type of structure of the original unsaturated starting material. The mechanism of the reaction is proposed and discussed.

Full text of DOI:10.1021/ol403321n

Letter
pubs.acs.org/OrgLett
PhICl2 and Wet DMF: An Efficient System for Regioselective
Chloroformyloxylation/α-Chlorination of Alkenes/α,β-Unsaturated
Compounds
Le Liu,† Daisy Zhang-Negrerie,† Yunfei Du,*,‡ and Kang Zhao*,†
†Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology,
Tianjin University, Tianjin 300072, China
‡Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, China
S
* Supporting Information
ABSTRACT: PhICl2 in wet DMF was found to form an
efficient system for realizing difunctionalization of various
alkenes and olefinic derivatives possessing a wide range of
functional groups. This novel methodology provides convenient
access to either regioselective chloroformyloxylated products or
α-chlorinated olefinic products, depending on the type of structure of the original unsaturated starting material. The mechanism of
the reaction is proposed and discussed.
ifunctionalization of alkene and unsaturated compounds
represents a powerful methodology in organic synthesis
presence of (DHQD)2PHAL and (+)-CSA (Scheme 1, eq 2).
Dodd4c demonstrated that using PhI(OAc)2 in conjunction with
LiBr in ethanol allowed the regioselective ethoxybromination of
various enamides (Scheme 1, eq 3). Herein, we disclose another
approach for the regioselective chloroformyloxylation process of
unsaturated compounds with PhICl2 and wet DMF.
D
since in such reactions two new σ bonds and two stereogenic
centers are generated in one step.1 Among these methods,
halofunctionalization,2 also termed cohalogenation, has at-
tracted much attention for a long time, for the vicinal
halofunctionalized product can further be subjected to various
organic transformations.3 Taking advantage of the significant
synthetic potential of such compounds in their capability to
rapidly increase molecular complexity, many research groups
have been devoted to developing regio- and stereoselective
reaction systems in order to generate multifunctional alkane
derivatives.4 In 2013, Yeung4a disclosed a procedure involving
Ph2Se-catalyzed chloroamidation of olefinic substrates by using
NCS as the chloro source (Scheme 1, eq 1). Lately, Tang4b
reported the first highly enantioselective intermolecular bromoes-
terification of alkenes by using NBS as the bromo source in the
a
Table 1. Optimization of the Reaction Conditions
c
additive
(equiv)
time
(h)
yield
(%)
b
entry oxidant (equiv) solvent
concn
d
1
2
3
4
5
PhICl2 (1.0) DMF
PhICl2 (1.3) DMF
PhICl2 (1.5) DMF
PhICl2 (1.5) DCE
0.1
0.1
0.1
0.1
0.1
12
12
7
80
e
83
88
DMF (5)
12
9
trace
75
Scheme 1. General Methods for Halofunctionalization
Reactions of Olefinic Compounds
f
PhICl2 (1.5) DCE/
DMF
6
PhICl2 (1.5) HCOOH
PhICl2 (1.5) DMF
PhICl2 (1.5) DMF
PhICl2 (1.5) DMF
PhICl2 (1.5) DMF
PhICl2 (1.5) DMF
PhICl2 (1.5) dry DMF
0.1
5
2
30
91
84
87
82
75
0
7
0.15
0.2
8
2
9
0.15
0.15
0.15
0.15
H2O (1)
H2O (2)
H2O (5)
1.5
1
10
11
12
1
g
12
a
All reactions were carried out at room temperature with 1a
b
(0.4 mmol) under air. Commercial DMF containing 0.3% H2O (v/v)
c
d
unless otherwise noted. Isolated yield. Based on 70% conversion.
e
f
g
Based on 90% conversion. The ratio of DCE and DMF was 1:1. The
reaction was carried out under N2 atmosphere.
Received: November 16, 2013
Published: January 6, 2014
© 2014 American Chemical Society
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Letter
a
Table 2. Regioselective Chloroformyloxylation of Alkenes and Unsaturated Compounds with PhICl2
a
b
All reactions were carried out by treating substrates 1 (0.4 mmol) and PhICl2 (1.5 equiv) in wet DMF (2.7 mL, c = 0.15 M) under air. Isolated
c
d
e
f
1
yields. Determined by crude H NMR analysis. Based on 50% conversion. 2 equiv of PhICl2 was applied, based on 50% conversion. Ratio of
regioselectivity. The structure of 2m was confirmed through X-ray crystallographic analysis. DMA was adopted as the solvent, and 2 equiv of
g
h
PhICl2 was applied.
Although iodobenzene dichloride (PhICl2), a common
hypervalent organoiodine(III) reagent, has been widely used
as an oxidant as well as halogen source in organic reactions for a
long time, its involvement in chloroformyloxylation reactions
has not yet been reported.5 On the other hand, N,N-
dimethylformamide (DMF), aside from being an effective
polar solvent commonly employed in organic reactions, is a
multipurpose reagent broadly used in chemistry including as a
ligand in the preparation of metallic complexes,6 as a
dehydrating reagent7 and even as a catalyst.8 Furthermore,
DMF can also act as a multifunctional building block for
various subunits such as −NMe2, −CONMe2, −CHO, and
−OCHO, etc. in many different types of reactions.9 Based on
these facts, we ventured out the investigations of treating an
unsaturated compound with a combination of PhICl2 and DMF
in hopes of developing an alternative access to new
difunctionalized product from an unsaturated compound.
We first studied the reaction of the readily available
unsaturated amide, N-methyl-N-phenylcinnamamide 1a and
PhICl2 in DMF. To our delight, an 80% yield of chloro-
formyloxylated product 2a (which was confirmed by X-ray
crystallographic analysis) based on 70% conversion of the
starting material 1a was obtained after 12 h (Table 1, entry 1).
Increasing the dosage of the oxidant showed a positive result,
with the starting material consumed completely and the yield
improved to 88% (Table 1, entries 2 and 3). Considering that
DMF acts as the nucleophile in this reaction, two other control
experiments were set up. After switching the solvent to DCE
and employing 5 equiv of DMF as the reactant, only a trace
amount of the desired product was detected (Table 1, entry 4).
On the other hand, when DMF and DCE were used as
cosolvents in a ratio of 1:1, the reaction proceeded smoothly to
give the chloroformyloxylated product in a moderate yield of
75% (Table 1, entry 5). Counterintuitively, when DMF was
replaced by formic acid, which seemed a more direct source of
the formyloxyl group in the product, and only 30% yield of 2a
was obtained (Table 1, entry 6). Concentration screening
revealed that when the reaction was carried out at a
concentration of 0.15 M, the reaction time could be shortened
to 2 h and the yield increased to 91% (Table 1, entry 7). A
higher concentration only resulted in a slightly decreased yield
due to the formation of some unidentified byproducts (Table 1,
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Organic Letters
Letter
a
entry 8). Perceiving that the formyloxyl group installed to the
double bond is derived from the hydrolysis of DMF, we
subsequently evaluated the effect of H2O in the reaction
system. With the increase of the amount of H2O, the reaction
rate was visibly accelerated. However, the yield continued to
slightly decrease with the increase in H2O, down to 75% when
5 equiv of H2O was present. This can possibly be attributed to
the side reactions of hydrolysis of PhICl2. Our further control
experiments showed that when the reaction was run in well-
dried DMF under nitrogen atomsphere, no desired product was
detected. Based on all of the acquired test results, the optimized
conditions to obtain the chloroformyloxylated product were
concluded to be that of entry 7 in Table 1, namely, treatment of
compound 1 with 1.5 equiv of PhICl2 in slightly wet DMF
(0.15 M).
Table 3. α-Chlorination of Unsaturated Compounds
We continued to evaluate the scope and generality of the
methodology at the optimized conditions. We were pleased to
find that the chloroformyloxylation procedure was applicable
across a broad range of unsaturated compounds and smoothly
gave the trans-chloroformyloxylated products. Results show
that variation of the amide by replacing the aniline moiety with
diethylamine or morpholine had negligible influences on the
course of the reaction (Table 2, entries 1−3). All of these
substrates were transformed into the corresponding difunction-
alized products in good to excellent yield with satisfactory
diastereoselectivity. Moreover, switching R1 from a phenyl
group to an o-chloro-substituted phenyl group, which
introduced the steric hindrance effect to the substrate, caused
practically no effect on the reaction as the desired product was
obtained in 87% yield with 90% de (Table 2, entry 4). Indeed,
not only α,β-unsaturated amides but also α,β-unsaturated
esters, ketones, nitro compound, and nitrile were tolerable
under these reaction conditions, with the related chloroformy-
loxylated products all obtained in good to excellent yields
within the range of parameters established in the method
(Table 2, entries 5−9). To our delight, the procedure could
also be applied to unactivated double bonds such as internal or
terminal alkenes and afforded the difunctionalized product in
moderate to good yields (Table 2, entries 10−13). When the
solvent of the reaction was switched to DMA, the
corresponding chloroacetyloxylated products were achieved in
good yields and comparable selectivity (Table 2, entries 14−
16).
Interestingly, when the phenyl groups in compound 1f were
replaced by p-methoxylphenyl groups, the corresponding
substrate 1n was converted to an α-chloro-substituted chalcone
3n under the identical reaction conditions with no detection of
the difunctionalized product (Table 3, entry 1). Indeed, further
investigation revealed that this phenomenon was not the only
exceptional case. When unsaturated sulfone 1o was used, the
α-chloro-substituted product 3o was obtained in moderate 57%
yield (Table 3, entry 2). Unsaturated nitro compounds 1p−r
were also transformed to the related α-chloro-substituted
products, and unsaturated nitrile 1s reacted in a similar manner
and delivered the chloro-substituted product in 79% yield.
The extra step of elimination that takes place in this series of
compounds can be attributed to the following two aspects. On
the one hand, it is obvious that these strong electron-
withdrawing groups, e.g., sulfonyl and nitro groups, increased
the acidity of the α hydrogen which facilitated the elimination
of formyloxyl group from the resulting chloroformyloxylated
products. On the other hand, the elimination can be
understood as the extra stability gained from the extended
a
Reaction conditions: 1 (0.5 mmol), PhICl2 (2 equiv) in wet DMF
b
c
d
(3.3 mL) under air. Isolated yields. PMP = p-methoxylphenyl. 1.5
equiv of PhICl2 was used. Based on 50% conversion.
e
conjugation in these final products due to the push−pull feature
of the compounds in most cases. For instance, in comparison to
the compounds in Table 2, those in Table 3 carry either a more
electron-donating group on one side, e.g., R1 = PMP vs R1 =
phenyl, or a more electron-withdrawing group on the other
side, e.g., E = NO2 or SO2Ph vs R2 being ketones and esters.
The observation of highest yield from 1q is consistent with this
explanation as 1q contains the most electron-donating R1 group
and also the most electron-withdrawing E group among all the
compounds in Table 3, which yields the most pronounced
push−pull effect. This explanation is, in addition, supported by
the negative observation of only a trace amount of the desired
product in the case where R1 is a more electron-withdrawing
p-chlorophenyl and E is the nitro group (not shown), where
the push−pull feature is obviously much diminished. In
comparison between 1i and 1s, even though the presence of
the second phenyl group in the latter would not necessarily
promote the push−pull feature, it nevertheless increases the
amount of conjugation stability at the formation of the new
double bond and consequently leads to the olefinic product 3s
as the more thermodynamically favored product.
On the basis of the above experimental results, a plausible
mechanism has been proposed and is illustrated in Scheme 2.10
First, DMF nucleophilicly attacks dichloroiodobenzene to give
iminum salt A, which is converted to intermediate B through an
indespensable hydrolysis step. After tautomerization, a
Scheme 2. Plausible Mechanism
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Organic Letters
Letter
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dimethylamine is eliminated to generate the new I(III) species
D,11 which is the key intermediate for the process. The
nucleophilic attack of alkenes to D leads to intermediate E. The
chloride ion nucleophilicly attacks intermediate E and along
with the release of iodobenzene gives the product 2.
In conclusion, we have discovered an efficient, metal-free
system for a convenient regioselective chloroformyloxylation
which can be applied to a wide range of α,β-unsaturated
compounds including but not limited to unsaturated ketone,
amide, ester, and alkenes derivatives. For strong push−pull
systems such as α,β-unsaturated sulfone, aryl and nitro-
compounds, and nitriles, α-chloro substitution reaction takes
place instead. In view of the mild reaction conditions and
environmentally benign characteristics, the present method can
be regarded as an useful alternative to the existing
chloroformyloxylation reactions of unsaturated compounds.
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, spectral data for all new compounds,
crude NMR for dr ratio, and X-ray structural data of 2a and 2m.
This material is available free of charge via the Internet at
http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Authors
■
(6) For selected examples, see: (a) Jutand, A. Chem. Rev. 2008, 108,
2300. (b) Yamaguchi, S.; Shinokubo, H.; Osuka, A. Inorg. Chem. 2009,
48, 795.
*E-mail: duyunfeier@tju.edu.cn.
*E-mail: kangzhao@tju.edu.cn.
Notes
(7) Supsana, P.; Liaskopoulos, T.; Tsoungas, P. G.; Varvounis, G.
Synlett 2007, 2671.
(8) Liu, Y.; He, G.; Chen, K.; Jin, Y.; Li, Y.; Zhu, H. Eur. J. Org. Chem.
2011, 5323.
(9) For reviews on DMF as a multipurpose reagent, see: (a) Ding, S.;
Jiao, N. Angew. Chem., Int. Ed. 2012, 51, 9226. (b) Muzart, J.
Tetrahedron 2009, 65, 8313.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Y.D. acknowledges the National Natural Science Foundation of
China (No. 21072148) and the Foundation (B) for Peiyang
Scholar−Young Core Faculty of Tianjin University (2013XR-
0144) for financial support.
(10) For an alternative mechanistic pathway, see the Supporting
Information for details.
1
(11) Intermediate D has been detected by both crude H NMR and
LCMS analysis when PhICl2 was combined with DMF in the absence
of an alkene.
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