Approach for the direct synthesis of β-dichlorosubstituted acetanilides using iodine trichloride (ICl3) as the oxidant and catalyst

Article abstract of DOI:10.1002/cjoc.201300007

A reliable method for direct synthesis of β-dichlorosubstituted acetanilides is reported. The key transformation involves the oxidative and catalytic cleavage of a carbon-carbon bond in the presence of iodine trichloride (ICl₃). In this protoco

Full text of DOI:10.1002/cjoc.201300007

COMMUNICATION
DOI: 10.1002/cjoc.201300007
Approach for the Direct Synthesis of β-Dichlorosubstituted
Acetanilides Using Iodine Trichloride (ICl3) as
the Oxidant and Catalyst
Qing Zhang,* Weibing Liu, Cui Chen, and Liquan Tan
School of Chemistry and Life Science, Guangdong University of Petrochemical Technology,
Maoming, Guangdong 525000, China
A reliable method for direct synthesis of β-dichlorosubstituted acetanilides is reported. The key transformation
involves the oxidative and catalytic cleavage of a carbon-carbon bond in the presence of iodine trichloride (ICl3). In
this protocol ICl3 is used not only as the catalyst but also as the oxidant which widely broadens the scope of its ap-
plication in organic synthetic chemistry.
Keywords iodine trichloride (ICl3), cleavage of carbon-carbon bond, 3-oxo-N-phenylbutanamides, β-dichlorosub-
stituted acetanilides
Introduction
results are summarized in Table 1. The model reaction
of 3-oxo-N-phenylbutanamide 1a in dioxane at room
temperature occurred in the presence of iodine trichlo-
ride (ICl3). After the screening of reaction time, we
found that 3 h was the optimal reaction time for the com-
pletion of this transformation (Entries 1－3). Among the
various solvents examined, 1,2-dichloroethane (DCE)
Our group has great interest in the fields of cleavage
or construction of C—C and C-hetero bond using hyper-
valent iodine reagents as oxidant or (and) catalyst (Eq.
1).[1-8] This paper reports a new approach for direct syn-
thesis of β-dichlorosubstituted acetanilides in the pres-
ence of iodine trichloride (ICl3). Nowadays, hypervalent
iodine reagents, as oxidants, have received much atten-
tion due to their low toxicity, mild reactivity, ready
availability, high stability, easy handling, etc.[9-20]
Herein, the ICl3 in this work was used not as the oxidant
but also as the catalyst (Eq. 2).
Table 1 Optimization of reaction conditionsa
Cl
H
H
N
ICl3 (1.1 equiv.)
solvent, r.t.
N
Cl
O
O
O
1a
2a
R1
NH
ZnX2
X
Yieldb/%
30
O
hypervalent iodine
Entry Solvent
Reaction time/h
X
(1)
O
X=Cl, Br, OAc
1
Dioxane
Dioxane
Dioxane
1
3
5
3
3
3
3
3
3
3
HN R1
O
2
48
3
49
O
4
Cyclohexane
CH2Cl2
DCE
37
O
Cl
ICl3 (1.30 equiv.)
DCE, 3 h, r. t.
5
88
R1
(2)
NH Cl
6
91
N
O
R1
H
7
DMF
35
8
9c
10d
DMSO
DCE
21
Experimental
96
DCE
96
Initially, we tried to establish an effective reaction
system based on the above-mentioned transformation. A
brief optimization about the reaction solvent, amount of
ICl3 and time on the model reaction was carried out. The
a The reaction was carried out using 0.25 mmol of 1a, 1.10 equiv.
of ICl3, 2.0 mL of solvent; GC yield; 1.30 equiv. of ICl3; d 1.50
b
c
equiv. of ICl3.
*
E-mail: mmczhang@yeah.net; Tel.: 0086-0668-2923216
Received January 3, 2013; accepted March 10, 2013; published online April 3, 2013.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201300007 or from the author.
Chin. J. Chem. 2013, 31, 453—455
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
453

Zhang et al.
COMMUNICATION
was more efficient for the explored reaction than others
(Entries 4－8) and resulted in the desired product in
91% GC yield (Entry 6). It is noteworthy that this trans-
formation appears quite sensitive to the solvent. For
example, the reaction resulted in an obvious decrease of
the yield in N,N-dimethylformamide (DMF) and di-
methyl sulfoxide (DMSO) (Entries 7 and 8). Finally, we
investigated the effect of the amount of iodine trichlo-
ride on the reaction (Entries 9 and 10), the result indi-
cated that 1.3 equivalent of ICl3 was sufficient for the
completion of this reaction (Entry 9).
Next, we conducted a survey of the reaction scope.
As shown by the results compiled in Scheme 1, a range
of reactions were performed with various β-ketobutyl-
anilides 1. It was observed that all reactions appeare
quite sensitive to electronic contribution of substituted
groups on benzene ring of β-ketobutylanilides, the sub-
strates, such as 1e, 1f, 1i and 1j, with strong electron-
donating substituted groups on benzene ring, all af-
forded the corresponding β-dichlorosubstituted acetani-
lide 2e, 2f, 2i and 2j with lower isolated yield compar-
ing to the substrates with weak electron-withdrawing or
weak electron-donating groups, such as chloro- and
methyl, on benzene ring (1a－1d).
the reaction rates of the two reactions, we found that the
two reactions both need 3 h to complete the reaction,
but the sufficient amount to catalyze the reaction was
different. HI needed 2.0 equiv., while ICl3 only needed
0.3 equiv., to complete the reaction in 3 h.
Scheme 2 Probe the mechanis
Cl
DCE (2 mL)
Cl Cl
H
H
N
N
HI (2.0 equiv.)
Cl
Cl
O
O
O
r.t. 3 h
2a
96%
Cl Cl
DCE (2 mL)
ICl3 (0.3 equiv.)
H
H
N
N
Cl
O
O
r.t. 3 h
O
2a
96%
On the basis of these preliminary results, a hypo-
thetic reaction pathway was listed in Scheme 3, exem-
plified by the formation of 2a. The first step involves
the dichlorination of the β-keto amide of 3-oxo-N-
phenylbutanamide (1a) to give intermediate 3 and the
release of HCl and HI. It is well known that iodide and
Brønsted acid are often used as the activating agent in
organic synthetic chemistry to activate the electron-
deficient functional groups,[21-26] such as, carbonyl
group.[27] Therefore, the coordination of the carbonyl to
the X (X＝I(III) and H＋) generates intermediate 4, and
5. The nucleophilic attacks of chloridion on the carbonyl
carbon of 5 and results in intermediate 6. The following
carbon-carbon bond cleavage of the labile α,α-dichloro-
β-keto amide 6[28] generates intermediate 7 by elimina-
tion one equivalent of AcCl. Finally, under the acid
conditions, through an isomerization process, the final
product 2,2-dichloroacetanilide (2a) was produced from
the intermediate 7.
Scheme 1 The synthesis of dichloroacetamides (Notes: All the
reactions were carried out with 1 (1.0 mmol), DCE (2 mL), ICl3
(1.30 equiv.); All the listed yields were isolated yield.)
O
O
Cl
ICl3 (1.30 equiv.)
DCE, 3 h, r. t.
R1
NH Cl
N
H
O
R1
Cl
2
1
Cl
H
O
N
NH Cl
Cl
Cl
N
H
O
Cl
O
Cl
2c 82%
2a 87%
2b 90%
Cl
Scheme 3 Tentative mechanism for the synthesis of 2,2-dihalo-
N-phenylacetamides
Cl
O
H
Cl
H
H
N
N
N
Cl
Cl
Cl
Cl
Cl
O
Cl Cl
O
O
O
H
N
O
O
Cl
Cl
X
Ph
ICl3
+
2f 51%
Ph
HI
2e 57%
2d 87%
Cl
X = I(III), H+
N
O
O
H
Cl
Cl
O
Cl
HCl
X
H
N
3
1a
H
H
N
N
Cl
O
Cl Cl
+
X
O
O
H
O
O
O
O
O
N
Cl
Cl
Ph
Ph
2i 66%
2g 81%
Ph
2h 91%
N
H
N
O
O
Cl Cl
H
X
Cl Cl
O
O
Cl
Cl
4
H
5
6
Cl
N
H
N
O
Cl
X O
Cl
Cl
O
H
Cl
O
Ph NH Cl
O
Ph NH Cl
AcCl
2a
2j 50%
7
2k 69%
To probe the mechanism of this transformation, we
Conclusions
ran two control experiments (Scheme 2). Interestingly,
we were pleased to find that the reaction proceeded
smoothly and almost gave the quantitative product 2a
under the two reaction conditions. Also, we investigated
In summary, we have shown an efficient and opera-
tionally simple method to synthesize β-dichlorosub-
stituted acetanilides. Nowadays, due to the favorable
454
www.cjc.wiley-vch.de
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2013, 31, 453—455

Approach for the Direct Synthesis of β-Dichlorosubstituted Acetanilides
571.
characteristics, such as safety, mildness, and environ-
mental friendiness of hypervalent iodine reagents, they
are widely utilized in synthetic processes as oxidant.
This work successfully realized the duel role of ICl3 as
the oxidant and catalyst. The current direction for future
research is aimed at extending the scope and potential
synthesis applications.
[9] Sheng, Q. J.; Liu, G. R.; Liu, H. Q. Chin. J. Org. Chem. 2007, 27,
902.
[10] Zhao, Y. D. Chin. J. Org. Chem. 1996, 16, 11.
[11] Wang, L.; Chen, Z. C.; Zheng, Q. G. Chin. J. Chem. 2010, 20, 1457.
[12] Kumar, P. Chin. J. Chem. 2009, 27, 1487.
[13] Desjardins, S.; Andrez, J. C.; Canesi, S. Org. Lett. 2011, 13, 3406.
[14] Singh, F. V.; Wirth, T. Org. Lett. 2011, 13, 6504.
[15] Fujita, M.; Mori, K.; Shimogaki, M.; Sugimura, T. Org. Lett. 2012,
14, 1294.
[16] Yoshimura, A.; Banek, C. T.; Yusubov, M. S.; Nemykin, V. N.;
Zhdankin, V. V. J. Org. Chem. 2011, 76, 3812.
[17] Beaulieu, M. A.; Guérard, K. C.; Maertens, G.; Sabot, C.; Canesi, S.
J. Org. Chem. 2011, 76, 9460.
Acknowledgement
We thank the Guangdong Natural Science Founda-
tion (No. S2012040007868) and Guangdong University
of Petrochemical Technology of China for financial
support of this work.
[18] Jacquemot, G.; Canesi, S. J. Org. Chem. 2012, 77, 7588.
[19] Tian, J.; Gao, W. C.; Zhou, D. M.; Zhang, C. Org. Lett. 2012, 14,
3020.
[20] Wang, X.; Ye, Y. X.; Zhang, S. N.; Feng, J. J.; Xu, Y.; Zhang, Y.;
Wang, J. B. J. Am. Chem. Soc. 2011, 133, 16410.
[21] Meijer, A.; Ellervik, U. J. Org. Chem. 2004, 69, 6249.
[22] Zhou, C. X.; Dubrovsky, A. V.; Larock, R. C. J. Org. Chem. 2006,
71, 1626.
[23] Li, C. W.; Wang, C. I.; Liao, H. Y.; Chaudhuri, R.; Liu, R. S. J. Org.
Chem. 2007, 72, 9203.
[24] Waldo, J. P.; Mehta, S.; Larock, R. C. J. Org. Chem. 2008, 73, 6666.
[25] Yao, T. L.; Campo, M. A.; Larock, R. C. Org. Lett. 2004, 6, 2677.
[26] Ercegovic, T.; Meijer, A.; Magnusson, G.; Ellervik, U. Org. Lett.
2001, 3, 913.
References
[1] Liu, W. B.; Jiang, H. F.; Huang, L. B. Org. Lett. 2010, 12, 312.
[2] Liu, W. B.; Chen, C.; Zhang, Q. Org. Biomol. Chem. 2011, 9, 6484.
[3] Liu, W. B.; Chen, C.; Zhang, Q.; Zhu, Z. B. Beilstein J. Org. Chem.
2011, 7, 1436.
[4] Liu, W. B.; Chen, C.; Zhang, Q.; Zhu, Z. B. Beilstein J. Org. Chem.
2012, 8, 344.
[5] Liu, W. B.; Chen, C.; Zhang, Q.; Zhu, Z. B. Bull. Korean Chem. Soc.
2012, 33, 1823.
[6] Liu, W. B.; Chen, C.; Zhang, Q. Heteroatom. Chem. 2012, 23, 290.
[7] Liu, W. B.; Chen, C.; Zhang, Q. J. Chem. Res. 2012, 36, 175.
[8] Hu, W. J.; Deng, Z. H.; Chen, C.; Liu, W. B. J. Chem. Res. 2012, 36,
[27] Christoffers, J. Chem. Commun. 1997, 943.
[28] Biswas, S.; Maiti, S.; Jana, U. Eur. J. Org. Chem. 2010, 2861.
(Cheng, F.)
Chin. J. Chem. 2013, 31, 453—455
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
455