Organic synthesis using (diacetoxyiodo)benzene (DIB): Unexpected and novel oxidation of 3-oxobutanamides to 2,2-dihalo-N-phenylacetamides

Article abstract of DOI:10.3762/bjoc.8.38

A novel and reliable method for the direct preparation of 2,2-dihalo-N-phenylacetamides is reported. The key transformation involves the cleavage of a carbon-carbon bond in the presence of DIB and a Lewis acid as the halogen source, and thus this method s

Full text of DOI:10.3762/bjoc.8.38

Organic synthesis using (diacetoxyiodo)benzene
(DIB): Unexpected and novel oxidation of 3-oxo-
butanamides to 2,2-dihalo-N-phenylacetamides
Wei-Bing Liu*1, Cui Chen1, Qing Zhang1 and Zhi-Bo Zhu*2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 344–348.
1School of Chemistry and Life Science, Guangdong University of
Petrochemical Technology, Maoming 525000, China and 2College of
Pharmaceutical Sciences, Southern Medical University, Guangzhou
510515, China
doi:10.3762/bjoc.8.38
Received: 18 January 2012
Accepted: 14 February 2012
Published: 07 March 2012
Email:
Wei-Bing Liu* - lwb409@yahoo.com.cn; Zhi-Bo Zhu* -
zzb24@yahoo.com.cn
Associate Editor: B. Stoltz
© 2012 Liu et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
cleavage of carbon–carbon bond; (diacetoxyiodo)benzene;
difunctionalized acetamides; novel oxidation;
3-oxo-N-phenylbutanamides
Abstract
A novel and reliable method for the direct preparation of 2,2-dihalo-N-phenylacetamides is reported. The key transformation
involves the cleavage of a carbon–carbon bond in the presence of DIB and a Lewis acid as the halogen source, and thus this method
significantly expands the value of DIB as a unique and powerful tool in chemical synthesis. This protocol not only adds a new
aspect to reactions that use other hypervalent iodine reagents but also provides a wide space for the synthesis of disubstituted
acetamides.
Introduction
Hypervalent iodine(III) reagents [1-18] have received much 1-carbamoyl-2-oxopropyl acetate derivatives by using (diace-
attention, as reflected by the plethora of publications and toxyiodo)benzene (DIB) (Scheme 1) [31].
reviews [19-23]. This is due to their low toxicity, ready avail-
ability, easy handling, clean transformation, and reactivity, During the course of conditional optimization to synthesize
which is similar to heavy-metal-based oxidants, including 1-carbamoyl-2-oxopropyl acetate derivatives, we surprisingly
harmful elements, such as Pb(IV), Hg(II), and Tl(III), as well as found that almost none of the desired acetoxylation product was
transition metal-catalyzed processes [24-30]. Recently, we obtained, but 2,2-dichloro-N-phenylacetamide was provided as
reported an efficient acetoxylation approach to synthesize the major product, upon addition of Lewis acids such as FeCl3,
344

Beilstein J. Org. Chem. 2012, 8, 344–348.
Table 1: Optimization of reaction conditions.a
Scheme 1: Synthesis of 1-carbamoyl-2-oxopropyl acetates.
entry
solvent
additive
time yield
(1.5 equiv) (h)
(%)b
ZnCl2 and CuCl2 in the reaction system. Based on this result,
we developed a simple and efficient approach to the synthesis
of 2,2-dihalo-N-phenylacetamides, on which we report herein
(Scheme 2). To the best of our knowledge, there are several
reports on chlorination and bromination reactions with
PhI(OAc)2 and a halogen source such as TMSBr, lithium halide
or pyridinium halide [32-34]. Also, there are several reports on
the synthesis of difunctionalized acetamide derivatives [35-38],
but this report is the first to describe the synthesis of 2,2-dihalo-
N-phenylacetamides through an oxidative process with
PhI(OAc)2 and Lewis acids as the halogen source.
1
dioxane
dioxane
dioxane
dioxane
dioxane
cyclohexane
DCE
none
1
–
2
FeCl3
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
1
78
81
75
–
3
1
4c
5d
6
1
1
1
26
42
80
46
31
89
84
53
89
89
7
1
8
DMF
1
9
DMSO
1
10e
11f
12g
13f
14f
15f
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
1
1
1
0.5
1.5
2
a1a (0.25 mmol), solvent (2 mL), DIB (1.0 equiv); bGC yield; cZnCl2
(1.0 equiv); dwithout DIB; eDIB (0.5 equiv); fDIB (1.3 equiv); gDIB (2.0
equiv).
Scheme 2: Synthesis of 2,2-dihalo-N-phenylacetamides.
Results and Discussion
Initially, we used 3-oxo-N-phenylbutanamide (1a) as the model
substrate to optimize the reaction conditions in different
solvents, temperatures and amounts of DIB (Table 1). The best
result was obtained in dioxane in the presence of 1.3 equiv of
DIB and 1.5 equiv of zinc(II) chloride at room temperature for
one hour (Table 1, entry 11). For this transformation, FeCl3 and
ZnCl2 were suitable Lewis acids (Table 1, entry 2 and entry 3),
and dioxane and DMF were practical solvents among the
various solvents examined (Table 1, entry 3 and entry 8). It is
noteworthy that no product 2a was obtained when the reaction
was carried out without the addition of Lewis acids (Table 1,
entry 1) or without DIB (Table 1, entry 5).
After optimizing the reaction conditions, we used a range of
3-oxo-N-phenylbutanamides to explore the substrate scope and
limitations of this reaction. As shown in Scheme 3, all the reac-
tions proceeded smoothly and gave the corresponding N-phenyl
dichloroacetamides 2a–2k exclusively and in good to excellent
isolated yields. It was also found that the number and the elec-
tronic properties of the substituents on the benzene ring had
little effect on the reaction. For example, the reactions of 3-oxo-
Scheme 3: Synthesis of dichloroacetamides. Reagents and condi-
tions: 1 (1.0 mmol), dioxane (2 mL), DIB (1.3 equiv), ZnCl2(1.5 equiv);
yields % are isolated yields.
345

Beilstein J. Org. Chem. 2012, 8, 344–348.
N-phenylbutanamide (1a), 3-oxo-N-o-tolylbutanamide (1b), In spite of the widespread use of DIB, there is no direct prece-
N-(2,4-dimethoxyphenyl)-3-oxobutanamide (1j) and N-(4- dent for DIB-mediated cleavage of C–C bonds. In particular,
chloro-2,5-dimethoxyphenyl)-3-oxobutanamide (1k) all led to the application of this protocol to synthesize difunctionalized
their corresponding N-phenyl dichloroacetamides (Scheme 3, acetamides from 3-oxo-butanamides is reported here for the
2a, 2b, 2j, and 2k) in good isolated yields. In addition, the posi- first time. In order to probe the mechanism of this transforma-
tion of the substituents on the benzene ring also has little effect tion, we employed 2,2-dichloro-3-oxo-N-phenylbutanamide
on this transformation, such that N-(2-chlorophenyl)-3-oxobu- (1m) and 2,2-dibromo-3-oxo-N-phenylbutanamide (1n) as reac-
tanamide (1c), N-(4-chlorophenyl)-3-oxobutanamide (1d), tants under acidic conditions in the presence of Zn(OAc)2
N-(4-methoxyphenyl)-3-oxobutanamide (1e) and N-(2- (Scheme 5), and we found that the reaction can also give the
methoxyphenyl)-3-oxobutanamide (1f) could also serve as good corresponding product 2,2-dichloro-N-phenylacetamide (2a)
substrates in this protocol (Scheme 3, 2c, 2d, 2e, and 2f).
and 2,2-dibromo-N-phenylacetamide (3a).
Next, in order to expand the scope of this protocol, we
employed ZnBr2 as a reagent under the same reaction condi-
tions, and we were pleased to find that the corresponding
dibromo derivatives were obtained as the products. As shown in
Scheme 4, all tested substrates provided the corresponding
dibromoacetamides 3a–3l in good to excellent isolated yields,
which not only greatly expanded the application scope of this
protocol but also provided a wide space for the synthesis of
2,2-dihalo-N-phenylacetamides.
Scheme 5: Probe the mechanism.
On the basis of these preliminary results, a mechanistic proposal
for this transformation, exemplified by the formation of 2a, is
depicted in Scheme 6. Initially, the reaction involved genera-
tion of the known chlorinating agent (dichloroiodo)benzene
(PhICl2) [39], followed by dichlorination of the β-keto amide of
3-oxo-N-phenylbutanamide (1a) to give intermediate 4. It is
well known that Lewis acids can activate 1,3-diketones [40] to
produce intermediate 5 and 6. This complexation not only
increases the nucleophilicity of the methylene carbon atom, but
also simultaneously increases the electrophilicity of the carbon-
yl carbon atom. Consequently, nucleophilic attack of the acetate
ion on the carbonyl carbon atom affords intermediate 7. A
subsequent carbon–carbon bond cleavage of the labile α,α-
dichloro β-keto amide through a retro-Claisen condensation
reaction [41] generates intermediate 8. Finally, the electrophilic
attack of a proton on the carbon–carbon double bond resulted in
the final product 2,2-dichloro-N-phenylacetamide (2a).
Conclusion
In summary, we have shown an efficient and operationally
simple method to synthesize 2,2-dihalo-N-phenylacetamides.
The mild reaction conditions, good substrate scope and good to
excellent yields make the present protocol potentially useful in
organic synthesis. Moreover, it should be pointed out that this
transformation includes an oxidative process involving the
Scheme 4: Synthesis of dibromoacetamides. Reagents and condi-
tions: 1 (1.0 mmol), dioxane (2 mL), DIB (1.3 equiv), ZnBr2 (1.5 equiv);
yields % are isolated yields.
346

Beilstein J. Org. Chem. 2012, 8, 344–348.
Scheme 6: Tentative mechanism for the synthesis of 2,2-dihalo-N-phenylacetamides.
10.Yusubov, M. S.; Nemykin, V. N.; Zhdankin, V. V. Tetrahedron 2010, 66,
5745–5752. doi:10.1016/j.tet.2010.04.046
cleavage of a carbon–carbon bond, which significantly expands
the value of DIB as a unique and powerful tool in chemical syn-
thesis. Future studies on the application of this protocol to the
synthesis of other difunctionalized acetamides and detailed
investigations of the reaction mechanism are in progress.
11.Satam, V.; Harad, A.; Rajule, R.; Pati, H. Tetrahedron 2010, 66,
7659–7706. doi:10.1016/j.tet.2010.07.014
12.Uyanik, M.; Ishihara, K. Aldrichimica Acta 2010, 43, 83–91.
13.Merritt, E. A.; Olofsson, B. Angew. Chem., Int. Ed. 2009, 48,
9052–9070. doi:10.1002/anie.200904689
14.Merritt, E. A.; Olofsson, B. Synthesis 2011, 517–538.
doi:10.1055/s-0030-1258328
Supporting Information
15.Desjardins, S.; Andrez, J. C.; Canesi, S. Org. Lett. 2011, 13,
3406–3409. doi:10.1021/ol201149u
Supporting Information File 1
16.Singh, F. V.; Wirth, T. Org. Lett. 2011, 13, 6504–6507.
doi:10.1021/ol202800k
Experimental details and characterization of compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-38-S1.pdf]
17.Wang, X.; Ye, Y.; Zhang, S.; Feng, J.; Xu, Y.; Zhang, Y.; Wang, J.
J. Am. Chem. Soc. 2011, 133, 16410–16413. doi:10.1021/ja207775a
18.Guilbault, A.-A.; Legault, C. Y. ACS Catal. 2012, 2, 219–222.
doi:10.1021/cs200612s
Acknowledgements
The authors are grateful to the Guangdong University of Petro-
chemical Technology of China for financial support of this
work.
19.Varvoglis, A. Tetrahedron 1997, 53, 1179–1255.
doi:10.1016/S0040-4020(96)00970-2
20.Brand, J. P.; González, D. F.; Nicolai, S.; Waser, J. Chem. Commun.
2011, 47, 102–115. doi:10.1039/c0cc02265a
21.Niedermann, K.; Früh, N.; Vinogradova, E.; Wiehn, M. S.; Moreno, A.;
Togni, A. Angew. Chem., Int. Ed. 2011, 50, 1059–1163.
doi:10.1002/anie.201006021
References
1. Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299–5358.
22.Uyanik, M.; Yasui, T.; Ishihara, K. Angew. Chem., Int. Ed. 2010, 49,
2175–2177. doi:10.1002/anie.200907352
doi:10.1021/cr800332c
2. Wirth, T. Angew. Chem., Int. Ed. 2005, 44, 3656–3665.
doi:10.1002/anie.200500115
23.Koller, R.; Stanek, K.; Stolz, D.; Aardoom, R.; Niedermann, K.;
Togni, A. Angew. Chem., Int. Ed. 2009, 48, 4332–4336.
doi:10.1002/anie.200900974
3. Moriarty, R. M. J. Org. Chem. 2005, 70, 2893–2903.
doi:10.1021/jo050117b
24.Ochiai, M.; Miyamoto, K. Eur. J. Org. Chem. 2008, 4229–4239.
doi:10.1002/ejoc.200800416
4. Ladziata, U.; Zhdankin, V. V. ARKIVOC 2006, (ix), 26–58.
5. Zhdankin, V. V. ARKIVOC 2009, (i), 1–62.
6. Dohi, T.; Kita, Y. Chem. Commun. 2009, 2073–2085.
doi:10.1039/b821747e
25.Richardson, R. D.; Wirth, T. Angew. Chem., Int. Ed. 2006, 45,
4402–4404. doi:10.1002/anie.200601817
26.Kita, Y.; Tohma, H.; Yakura, T. Trends Org. Chem. 1992, 3, 113–128.
27.Kita, Y.; Takada, T.; Tohma, H. Pure Appl. Chem. 1996, 68, 627–630.
doi:10.1351/pac199668030627
7. Yusubov, M. S.; Zhdankin, V. V. Mendeleev Commun. 2010, 20,
185–191. doi:10.1016/j.mencom.2010.06.001
8. Uyanik, M.; Ishihara, K. Chem. Commun. 2009, 2086–2099.
doi:10.1039/b823399c
28.Stang, P. J.; Zhdankin, V. V. Chem. Rev. 1996, 96, 1123–1178.
doi:10.1021/cr940424+
9. Ngatimin, M.; Lupton, D. W. Aust. J. Chem. 2010, 63, 653–658.
doi:10.1071/CH09625
29.Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2002, 102, 2523–2584.
doi:10.1021/cr010003+
347

Beilstein J. Org. Chem. 2012, 8, 344–348.
30.Tohma, H.; Kita, Y. J. Synth. Org. Chem., Jpn. 2004, 62, 116–127.
31.Liu, W.-B.; Chen, C.; Zhang, Q.; Zhu, Z.-B. Beilstein J. Org. Chem.
2011, 7, 1436–1440. doi:10.3762/bjoc.7.167
32.Evans, P. A.; Brandt, T. A. J. Org. Chem. 1997, 62, 5321–5326.
doi:10.1021/jo970525i
33.Ngatimin, M.; Gartshore, C. J.; Kindler, J. P.; Naidu, S.; Lupton, D. W.
Tetrahedron Lett. 2009, 50, 6008–6011.
doi:10.1016/j.tetlet.2009.08.038
34.Hamamoto, H.; Hattori, S.; Takemaru, K.; Miki, Y. Synlett 2011,
1563–1566. doi:10.1055/s-0030-1260791
35.Pasquato, L.; Santoni, G.; Modena, G. Eur. J. Org. Chem. 2001,
3457–3460.
doi:10.1002/1099-0690(200109)2001:18<3457::AID-EJOC3457>3.0.C
O;2-C
36.Porzelle, A.; Woodrow, M. D.; Tomkinson, N. C. O. Org. Lett. 2010, 12,
1492–1495. doi:10.1021/ol100196a
37.Fujiu, T.; Izumi, K.; Sekiguchi, S. Bull. Chem. Soc. Jpn. 1985, 58,
1055–1056. doi:10.1246/bcsj.58.1055
38.Katagiri, N.; Niwa, R.; Furuya, Y.; Kato, T. Chem. Pharm. Bull. 1983,
31, 1833–1841. doi:10.1248/cpb.31.1833
39.Paquette, L. A., Ed. Encyclopedia of Reagents for Organic Synthesis;
Wiley: New York, 1995; Vol. 6, p 3984.
40.Christoffers, J. Chem. Commun. 1997, 943–944.
doi:10.1039/a700838d
41.Biswas, S.; Maiti, S.; Jana, U. Eur. J. Org. Chem. 2010, 2861–2866.
doi:10.1002/ejoc.201000128
License and Terms
This is an Open Access article under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
(http://www.beilstein-journals.org/bjoc)
The definitive version of this article is the electronic one
which can be found at:
doi:10.3762/bjoc.8.38
348