Potassium iodide catalyzed reductive dehalogenation of α-halo-ketones using Hantzsch ester diethyl 1, 4-dihydro-2,6-dimethylpyridine-3,5- dicarboxylate as reductant

Article abstract of DOI:10.1016/j.cclet.2010.03.027

In the presence of diethyl 1,4-dihydro-2,6-dimethylpyridine-3,5- dicarboxylate (DHP) and a catalytic amount of potassium iodide, several a-halo ketones were easily reduced to the corresponding ketones in acetone media. The procedure presented here showed several merits such as short reaction time, practical experimental and isolated procedure, and excellent yields of products.

Full text of DOI:10.1016/j.cclet.2010.03.027

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Chinese Chemical Letters 21 (2010) 931–934
www.elsevier.com/locate/cclet
Potassium iodide catalyzed reductive dehalogenation
of a-halo-ketones using Hantzsch ester diethyl 1,
4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate as reductant
*
Hong Sheng Li, Yi Qun Li
Department of Chemistry, Jinan University, Guangzhou 510632, China
Received 18 December 2009
Abstract
In the presence of diethyl 1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate (DHP) and a catalytic amount of potassium
iodide, several a-halo ketones were easily reduced to the corresponding ketones in acetone media. The procedure presented here
showed several merits such as short reaction time, practical experimental and isolated procedure, and excellent yields of products.
# 2010 Yi Qun Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Dehalogenation; a-Halo ketones; Hantzsch ester; 1,4-Dihydro-2,6-dimethylpyridine-3,5-dicarboxylate; Potassium iodide
The reduced form of nicotinamide adenine dinucleotide coenzyme [NAD(P)H] plays a crucial role in biological
systems as a source of two electrons and a proton [1]. Over the past years, a number of 1,4-dihydropyridine derivatives,
including the Hantzsch ester, diethyl 1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate (DHP), have been widely
used as models of NAD(P)H to mimic the reduction of various unsaturated compounds [2].
As a mild reducing reagent, the use of DHP in organic reactions is of considerable interest. Studies on the
reductions of unsaturated substrates such as ketones, aldehydes [3] and alkenes [4] have been attracted much attention
from organic chemists. Additionally, using DHP as the reductant in the reductive amination of aldehydes [5], a,b-
unsaturated ketones [6] and multicomponent reaction [7] have been documented as well. Nevertheless, quite a few
reports have been published concerning to the dehalogenation of a-haloketones [8,9]. To the best of our knowledge,
the use of DHP as reductant for reductive dehalogenation has also not been reported.
Reductive dehalogenation of a-haloketones is one of the important reactions used in organic synthesis [10]. A great
number of methods have been introduced for this dehalogenation, such as using organometallic ionic liquid
[bmim][Co(CO)4] [11], palladium [12] as a catalyst, etc. However, many reported methods suffered from some
limitations such as lower yielding, longer reaction time, or using heavy metal as catalysts. As a continuation of our
research work in biomimetic synthesis, we wish to report an efficient and practical methodology for the reductive
dehalogenation of a-halo ketones in the presence of DHP under mild reaction conditions (Scheme 1).
* Corresponding author.
E-mail address: tlyq@jnu.edu.cn (Y.Q. Li).
1001-8417/$ – see front matter # 2010 Yi Qun Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.03.027

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H.S. Li, Y.Q. Li / Chinese Chemical Letters 21 (2010) 931–934
Scheme 1. Reductive dehalogenation using DHP as reductant in the presence of KI.
1. Experimental
Melting points were measured on an electrothemal X6 microscopy digital melting point apparatus. GC–MS spectra
were taken on Thermo Finnigan Trace GC–MS. 1H NMR spectra were performed with a 300 MHz Bruker Advance
instrument using CDCl3 as a solvent and TMS as an internal standard. The chemicals were obtained from commercial
sources and used as received. DHP was prepared according to the procedure reported in literature [18].
a-Halo ketone 1 (3.0 mmol), DHP 2 (3.0 mmol), and KI (20 mol%) were added to acetone (10 mL) in a round-
bottomed flask, then the mixture was stirred at room temperature for 3 h. After the reaction was completed (monitored
by TLC), the mixture was concentrated under reduced pressure to remove the solvent, 5 mL dilute HCl was added and
than the mixture was extracted with diethyl ether (5ꢀ 8 mL). The organic phases were combined, washed with dilute
hydrochloric acid (5ꢀ 5 mL), followed with NaHSO3 solution and water. The solvent was dried over anhydrous
Na2SO4 and then concentrated on a rotary evaporator to obtain the desired product 3, which was further purified by
preparative TLC. All compounds were characterized by MS or 1H NMR and compared with the authentic samples.
2. Results and discussion
Initially, we investigated the reactive dehalogenation of 2-bromo-40-nitroacetophenone in the presence of DHP in
ethanol solvent at ambient temperature. It was found that the reductive dehalogenation reaction took a long time and
many side productswere accompanied. Itiswellknownthat the halogen-exchange reactionproceed smoothlyinacetone,
so we tried the reaction using potassium iodide as an additive to promote the reductive reaction in several solvents. The
results are listed in Table 1. As can be seen from Table 1, acetone is best choice among the screened solvents, the reaction
afford the product 4-nitroacetophenone in the presence of potassium iodide with 84% yield in 5 h (entry 1, Table 1).
Encouraged by this result, we further demonstrated the influence of the amount of iodides of the present method by
the reaction of 2-bromo-40-nitroacetophenone reacted with DHP under the above unoptimum conditions (Table 2), the
reaction could not be occurred in the absence of the iodide, which indicated that the iodide plays a crucial role in the
process of the reaction (Table 2, entry 1). When the 5 mol% amount of the KI was used, the yield of the product
reached up to 83% at ambient temperature for 8 h. Increasing the amount of KI from 5 to 50 mol%, the reaction yields
ranged between 83% and 85%, respectively. Therefore, 20 mol% of KI was enough much to push the reaction forward
to complete. NaI was also found to be an effect additive in this reaction with slightly prolong reaction time and lower
yields (Table 2, entries 8–11).
Then, the scope and the generality of the present method were further demonstrated by the reaction of various a-
halo ketones 1 with DHP 2 on the basis of the optimized reaction conditions mentioned above. The results are listed in
Table 1
Effects of solvents on reductive dehalogenation reaction.
Entry
Solvents
Time (h)
Yield (%)a
1
2
3
4
5
6
CH3COCH3
CH3CH2OH
CH3CH2OH (95%, v/v)
CH3OH
5
8
84 (>90)b
38
8
51
8
20
CHCl3
24
24
Trace
–
C6H5CH3
a
Isolated yield.
b
GC yield.

H.S. Li, Y.Q. Li / Chinese Chemical Letters 21 (2010) 931–934
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Table 2
Influence of the amount of catalysts on reductive dehalogenation.
Entry
Amount of catalyst (mol%)
Time (h)
Yield (%)a
1
None
24
8
Trace
83
2
KI 5
3
KI 10
KI 15
KI 20
KI 25
KI 50
NaI 10
NaI 15
NaI 20
NaI 25
5
84
4
3.5
3
82
5
85
6
3
81
7
4
80
8
8
80
9
6
81
10
11
4
82
4
80
a
Isolated yield.
Table 3
The reductive dehalogenation reaction catalyzed by KI using DHP as reductant.
Entry
a-Halo ketones 1
Time (h)
Products 3
Yield (%)a
m.p. (8C)
lit. m.p. (8C)
1
2
3
4
5
6
2-Bromo-40-nitrophenylethanone 1a
2,40-Dibromophenylethanone 1b
2-Bromo-40-chlorophenylethanone 1c
2-Bromoacetophenone 1d
2-Bromo-40-methoxyphenylethanone 1e
2,40-Dichlorophenylethanone 1f
3
3a
3b
3c
3d
3e
3c
85
88
85
83
83
86
79–81
49–51
Liquid
Liquid
Liquid
Liquid
79–80 [13]
49–50 [14]
15–17 [15]
15–17 [15]
30–36 [16]
15–17 [15]
1.25
2
1.75
2.25
8
a
Isolated yield.
Table 3. As illustrated in Table 3, electronic effects and the nature of substituents on the aromatic ring did show certain
effects in terms of reaction time under the reaction conditions mentioned above. When aromatic ring containing
electron-withdrawing groups (such as nitro group, halide) were employed (Table 3, entries 1–3), a longer reaction time
was required than those of electron-donating groups (such as methoxyl group) (Table 3, entry 5). It is also observed
that the relatively reactive aryl bromides showed better results in all case than the chloride with higher yields and
shorter reaction time. It is also worthy of note that the substituted functional groups of NO2 on aromatic ring were
tolerant towards this reductive system conditions (Table 3, entry 1).
According to the reported mechanisms concerned about the transfers of hydrogen from NAD(P)H or its model
compounds [17] to substrates, we proposed a plausible hydrogen-transfer mechanism for this conversion involved in
the halogen-exchange reaction of a-halo ketone with Iꢁ (Scheme 2). First, a-halo ketone react with Iꢁ to give the a-
iodoacetophenone due to the Iꢁ serves as both a good nucleophile and a good leaving group. Then, on the next step, a-
iodoacetophenone was deiodinated by DHP to afford corresponding ketone and Iꢁ. The produced Iꢁ could directly go
into the next catalytic cycle.
Scheme 2. Proposed hydrogen-transfer mechanism for the reductive dehalogenation of a-halo ketones by DHP.

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H.S. Li, Y.Q. Li / Chinese Chemical Letters 21 (2010) 931–934
3. Conclusions
We have developed a practical, efficient and convenient dehalogenation procedure for converting a-halo ketones to
corresponding ketones by using DHP as reductant. This procedure offers several advantages such as short reaction
time, simple experimental and isolated procedure, satisfactory yields of products. Further application of the catalytic
system to other hydrogen-transfer is on progress.
Acknowledgments
We are grateful to the Guangdong Natural Science Foundation (No. 8151063201000016) and the National Natural
Science Foundation of China (No. 20672046) for financial support.
References
[1] J. Gebicki, A. Marcinek, J. Zielonka, Acc. Chem. Res. 37 (2004) 379.
[2] T.H. Babu, G. Shanthi, P.T. Perumal, Tetrahedron Lett. 50 (2009) 2881.
[3] G. Gelbard, J. Lin, N. Roques, J. Org. Chem. 57 (1992) 1789.
[4] Q. Liu, J. Li, X.X. Shen, Tetrahedron Lett. 50 (2009) 1026.
[5] T. Itoh, K. Nagata, M. Miyazaki, Tetrahedron 60 (2004) 6649.
[6] H.J. Xu, Y.C. Liu, Y. Fu, Chin. J. Chem. 26 (2008) 599.
[7] Z. Zhang, J. Gao, J.J. Xia, Org. Biomol. Chem. 3 (2005) 1617.
[8] S. Yasui, K. Nakamura, M. Fujii, J. Org. Chem. 50 (1985) 3283.
[9] D.D. Tanner, H.K. Singh, A. Kharrat, J. Org. Chem. 52 (1987) 2142.
[10] J.P. Depres, A.E. Greene, J. Org. Chem. 45 (1980) 2036.
[11] R.J.C. Brown, P.J. Dyson, D.J. Ellis, Chem. Commun. (2001) 1862.
[12] J. Chen, Y. Zhang, L. Yang, Tetrahedron 63 (2007) 4266.
[13] K.P. Peterson, R.C. Larock, J. Org. Chem. 63 (1998) 3185.
[14] A.R. Hajipour, S.E. Mallakpour, S. Khoee, Synth. Commun. 32 (2002) 9.
[15] V.N. Britsun, A.N. Esipenko, M.O. Lozinskii, Russ. J. Org. Chem. 42 (2006) 1719.
[16] M.S. Newman, J. Am. Chem. Soc. 67 (1945) 345.
[17] X.Q. Zhu, Y.C. Liu, J.P. Cheng, J. Org. Chem. 64 (1999) 8980.
[18] Y.H. Ding, Z.L. Zhou, Chem. World (2005) 668 (in Chinese).