Platinum on carbon-catalyzed precise reduction control of trichloromethyl to Geminal-dichloromethyl groups

Article abstract of DOI:10.1002/adsc.201100778

Geminal-dichloromethyl derivatives could be efficiently synthesized by the highly chemoselective platinum on carbon-catalyzed mono-dechlorination of trichloromethyl substrates in dimethylacetamide (DMA) as a specific solvent at 25 °C under a hydrogen atmosphere. Copyright

Full text of DOI:10.1002/adsc.201100778

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DOI: 10.1002/adsc.201100778
Platinum on Carbon-Catalyzed Precise Reduction Control of
Trichloromethyl to Geminal-Dichloromethyl Groups
Takahiro Imanishi,a Yuta Fujiwara,a Yoshinari Sawama,a Yasunari Monguchi,a
and Hironao Sajikia,*
a
Laboratory of Organic Chemistry, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan
Fax : (+81)-58-230-8109; e-mail: sajiki@gifu-pu.ac.jp
Received: October 7, 2011; Revised: November 30, 2011; Published online: March 7, 2012
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201100778.
Abstract: Geminal-dichloromethyl derivatives could
be efficiently synthesized by the highly chemoselec-
tive platinum on carbon-catalyzed mono-dechlori-
nation of trichloromethyl substrates in dimethyl-
ACHTUNGTRENNUNGacetamide (DMA) as a specific solvent at 258C
under a hydrogen atmosphere.
of mono-dechlorination methods using trichlorometh-
yl derivatives as the starting materials have been ea-
gerly investigated.[3,4]
We have recently developed the Pd/C-catalyzed ef-
ficient dechlorination method of aromatic chlorides
including polychlorinated biphenyls (PCB) and 1,1,1-
trichloro-2,2-bis(p-chlorophenyl)ethane
(p,p’-DDT)
Keywords: chemoselectivity; gem-dichloromethyl
group; heterogeneous catalysis; mono-dechlorina-
tion; platinum
which are poisonous environmental pollutants.[5]
During the time-course study of the multi-dechlorina-
tion of p,p’-DDT, a significant amount (69%) of the
trichloromethyl group of p,p’-DDT was partially and
selectively mono-dechlorinated to a gem-dichloro-
methyl derivative accompanied by the smooth de-
AHCTUNGTRENNUNG
chlorination of the aromatic chlorides (Scheme 2).[5d]
The gem-dichloromethyl group (-CHCl2) is an impor-
tant substructure of pharmaceuticals (e.g., chloram-
phenicol as an antibiotic,[1a] trichlormethiazide as a di-
uretic[1b] and halogenated monoterpenes possessing
anti-esophageal cancer activity[1c]) and an equivalent
of aldehydes generated by the hydrolysis of the corre-
sponding gem-dichloromethyl groups under basic con-
ditions.[2] While the gem-dichloromethyl groups could
be directly synthesized by the mono-dechlorination of
À
trichloromethyl groups ( CCl3), the suppression con-
trol of the over-reduction to form chloromethyl
À
À
ACHTUNGTRENNUNG( CH2Cl) or methyl ( CH3) functionalities is quite
Scheme 2. Pd/C-catalyzed dechlorination of p,p’-DDT.
difficult (Scheme 1). The dechlorination activity is
strongly influenced by the electronic and steric envi-
ronment of the substituents connected to the trichlor-
Encouraged by these results, we investigated in
omethyl group. Therefore, there seems to be no effi- detail the mono-dechlorination reaction of trichloro-
cient and widely applicable methods, although plenty methyl groups to gem-dichloromethyl groups. The
À
cleavage of the carbon-chlorine (C Cl) bond is
known to be favoured in the order carbonylmethyl>
benzylic>aromatic>aliphatic chlorides.[6] Therefore,
the reduction control of strongly-reactive a,a,a-tri-
chloromethylcarbonyl derivatives to gem-dichlorome-
thylcarbonyls, which are useful synthetic precursors
for diacylfurans,[7a] 1,4-diones,[7b] 1,2,3-triazoles,[7c] a,b-
Scheme 1. Mono-dechlorination of the trichloromethyl
group to the gem-dichloromethyl group.
unsaturated ketones,[7d] chloroaziridines,[7e] cyclopro-
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Takahiro Imanishi et al.
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Table 1. Solvent effect on the mono-dechlorination of 2,2,2-
trichloroacetophenone (1a).
a slightly longer reaction time was required for the re-
action completion (2 h, entry 2) compared to the 10%
Pt/C-catalyzed reaction (0.7 h, entry 1). On the other
hand, Ir/C (entry 3) and Pd/C[9] (entry 4) led to lower
selectivities, and Ru/C and Au/C exhibited no catalyst
activities for the mono-dechlorination (entries 5 and
6). Consequently, Pt/C was found to be the best cata-
lyst and 2a was effectively obtained in 88% isolated
yield (entry 1).
The Pt/C-H2-DMA combination was applicable for
the mono-dechlorination of various a,a,a-trichloro-
carbonyl compounds (Table 3). The a,a,a-trichloroa-
cetophenone derivatives (1b–f) bearing both electron-
donating and electron-withdrawing groups on the aro-
matic ring were efficiently transformed into 2b–f in
good to excellent yields (entries 2–6), while the reac-
tion of the ortho-substituted substrate (1d) required
an increase of Pt/C up to 10 mol% to complete the
Entry Solvent
Time [h] Ratio [%][a] of 1a/2a/3a/4a
1
2
3
4
5
6
7
MeOH
cyclohexane
DMF
AcOEt
acetone
MeCN
0.5
4
2
1.3
0.8
5
0/32/58/10
0/70/16/14
0/60/28/12
0/84/12/4
0/82/12/6
0/92/8/0
DMA
0.7
0/95/5/0
[a]
1
Ratio was determined by H NMR.
panes,[7f] etc., is expected to be comparatively difficult mono-dechlorination (entry 4). The aliphatic a,a,a-
and challenging, because the in-situ produced gem-di- trichloro ketone derivative (1g) and ester, amide and
chloromethylcarbonyls also could be easily over- heteroaromatic (pyrrole and indole) derivatives (1h–
dechlorinated to the corresponding monochlorome- m) were also successfully mono-dechlorinated in good
thylcarbonyl and methylcarbonyl products under the to excellent yields (entries 7–13).
same conditions. 2,2,2-Trichloroacetophenone (1a)
Heterogeneous catalysts possess some advantages
was chosen as the substrate and the solvent effect was such as the separability from the reaction mixture by
investigated at 258C under atmospheric H2 gas in the simple filtration and reusability. Therefore, the reuse
presence of Pt/C[8] as a catalyst (Table 1). The over-re- test of Pt/C was examined in terms of the utilities of
duction to form the corresponding monochloromethyl the present reaction especially based upon its envi-
(3a) and methyl (4a) products was not efficiently sup- ronmental harmony and cost perfomance (Table 4).
pressed in MeOH, cyclohexane, DMF, AcOEt and Pt/C was found to be efficiently reusable for at least
acetone (entries 1–5), although the desired gem-di- up to five reaction cycles without any decrease in its
chloromethyl compound (2a) was mainly obtained in catalyst activity.
MeCN or DMA (entries 6 and 7). Since the highest
The two proposed reaction mechanisms are depict-
generation ratio (95%) of 2a was obtained when ed in Scheme 3. The anion radical intermediate (A)
using DMA, DMA was chosen as the most promising was generated by a single electron transfer (SET)
solvent (entry 7).
from the H2-activated Pt metal to the carbonyl group
We next compared the catalyst efficiencies among of the substrate and the following elimination of the
a wide variety of platinum metals on activated carbon chloride anion afforded the enolate radical (B), which
(Table 2). Rh/C also provided 2a with a high effciency was transformed into the gem-dichloro product by the
and selectivity for the mono-dechlorination, although hydrogen radical donation from the Pt-activated H2
(route a). Alternatively, the mono-dechlorination pro-
ceeded via the dichloromethyl radical (C) generated
by the direct SET to the trichloromethyl carbon and
Table 2. Catalyst efficiencies.
the subsequent chloride anion elimination (route b).
A similar reactivity between the aromatic (1a) and
aliphatic (1g) a,a,a-trichloro ketone derivatives
(Scheme 3 and Table 1, entries 1 and 6) indicated that
the Pt/C-catalyzed mono-dechlorination preferentially
proceeded via route b, in which the reactivity should
not be significantly affected by the chemical proper-
ties of the substituents (R in Scheme 3).[10,11]
Entry Catalyst
Time [h] Ratio [%][a] of 1a/2a/3a/4a
1
2
3
4
5
6
10% Pt/C
10% Rh/C
10% Ir/C
10% Pd/C
10% Ru/C
10% Au/C
0.7
2
3
0/95 (88)[b]/5/0
0/94/6/trace
0/86/13/1
According
to
the
mechanistic
prediction
2
6
trace/72/10/18
100/0/0/0
(Scheme 3) and primary results as shown in Scheme 2,
the present reaction should be applicable for the
mono-dechlorination of various types of trichloro-
methyl derivatives even without a,a,a-trichlorome-
thylcarbonyl moieties. 1,1-Bis(4-methoxyphenyl)-
6
100/0/0/0
[a]
[b]
1
Ratio was determined by H NMR.
Isolated yield.
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Platinum on Carbon-Catalyzed Precise Reduction Control of Trichloromethyl to Geminal-Dichloromethyl
Table 3. Scope of substrates.
Entry
1
Substrate
Product
Time [h]
0.7
Yield [%]
88
2
3
0.8
0.8
77
86
4
24 (0.5)[a]
29 (73)[a]
5
6
0.5
78
93
0.25
7
8
9
0.7
0.8
1
86
56
79[b]
10
6
88
11
12
2
1
55[b]
87
13
1.3
80[b]
[a]
10 mol% of Pt/C was used.
Yield was determined by H NMR due to the inseparable property of 2 and over-reduced products.
[b]
1
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Takahiro Imanishi et al.
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Table 4. Reuse of Pt/C.[a]
and 1q) could be also mono-dechlorinated to the cor-
responding gem-dichloromethyl compounds (2p and
2q) without deprotection (entries 3 and 4).[13] The
2,2,2-trichloroethylphenyl ester (1r) underwent the
mono-dechlorination to 2r using only 1 mol% Pt/C
(entry 5).
Run
Yield of 2a [%]
In conclusion, we have established a simple and ef-
ficient Pt/C-catalyzed mono-dechlorination method
for various trichloromethyl derivatives to the corre-
sponding gem-dichloromethyl derivatives as useful
synthetic precursors under mild hydrogenation condi-
tions at 258C in DMA as a specific solvent. The pres-
ent method is widely applicable without particular re-
action control, and the Pt/C was efficiently reusable.
We anticipate that this approach will offer an alterna-
tive synthetic strategy for the practical construction of
1st
88
87
88
89
89
2nd
3rd
4th
5th
[a]
Reaction conditions: 1a (0.5 mmol), 10% Pt/C (1 mol%)
in DMA at 258C under atmospheric H2 gas for 0.7 h.
2,2,2-trichloroethane (1n, methoxychlor) and a-(tri- the gem-dichloromethyl functionality.
chloromethyl)benzyl acetate (1o) were effectively ap-
plicable for the highly selective mono-dechlorination,
and gem-dichloromethyl products (2n and 2o) were
Experimental Section
isolated in 71 and 66% yields, respectively, by using
up to 10 mol% of Pt/C (Table 5, entries 1 and 2).[12]
Meanwhile, the recovered 10% Pt/C was also reusable
without any decrease in its catalyst activity. 2,2,2-Tri-
chloroethoxycarbonyl (Troc)-protected amines (1p
General Procedure for Mono-Dechlorination
A solution of the substrate (0.5 mmol), 10% Pt/C (1 mol%
of substrate) and DMA (1 mL) in a test tube was stirred
Scheme 3. Proposed reaction mechanism.
Table 5. Scope of the mono-dechlorination using carbonyl-unconjugated trichloromethyl substrates.
Entry
1
Substrate
Product
Time [h]
9 (9)[a]
Yield [%]
71 (75)[a]
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Platinum on Carbon-Catalyzed Precise Reduction Control of Trichloromethyl to Geminal-Dichloromethyl
Table 5. (Continued)
Entry
Substrate
Product
Time [h]
Yield [%]
66 (65)[a]
2
9 (9)[a]
3
4
24 (24)[a]
54 (59)[a]
12
53
5[b]
24
34
[a]
Using recovered Pt/C.
1 mol% of Pt/C was used.
[b]
using a personal organic synthesizer (1500 rpm, Chemista-
tion, EYELA, Tokyo) under ordinary (balloon) hydrogen
pressure at 258C for the appropriate time. After the trichlor-
omethyl substrate was completely consumed, the mixture
was passed through a Celite pad to remove the Pt/C. The fil-
trate was extracted with EtOAc (10 mL) and H2O (10 mL),
and then the aqueous layer was further extracted with
EtOAc (10 mLꢁ2). The combined organic layers were dried
over Na2SO4 and concentrated under vacuum. The residue
was purified by flash column chromatography on silica gel
(n-hexane/EtOAc) to give the corresponding dichloromethyl
product.
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Acknowledgements
We thank the N.E. Chemcat Corporation for the kind gift of
the catalysts and the Sugiyama Drugs Co., Ltd. for providing
the continuation of T.I.ꢀs university research.
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[8] We have obtained some information from the mono-
dechlorination using 1,1,1-trichloroacetone as a sub-
strate. The mono-dechlorination was efficiently cata-
lyzed by Pt/C from among the various platinum metals
on activated carbon, although the quantitative optimi-
zation could not be investigated due to the volatile
nature of the substrate and dechlorinated products.
[9] The Pd/C-catalyzed mono-dechlorination of a trichloro-
methyl group using Pd/C was reported in reference (T.
Isokai, Nihonkagakuzasshi 1960, 81, 1594–1598), while
the selectivity and reaction efficiency were quite low.
[10] We presumed that the rate-determining step may be
the mono-dechlorination pathway due to no detection
of the homo-coupling product of B and C which should
be generated if the radical intermediates B and C sur-
vive for a relative long period of time, although the
mono-dechlorination via route a cannot be completely
ruled out.
[11] If the rate-determining step were the mono-dechlorina-
tion pathway and the reduction proceeded via route a,
the mono-dechlorination of the aromatic substrate 1a
should be faster than that of the aliphatic 1g due to the
aromatic nuclei-induced stabilization of the radical in-
termediate A.
[12] The use of 1 mol% of 10% Pt/C as a catalyst did not
lead to completion of the mono-dechlorination and the
starting substrate remained unchanged even after
a 24 h reaction.
[13] Deprotection via the dichloromethyl radical intermedi-
ate was considerable as below. A related deprotection
method of 2,2,2-trichloroethyl ester was reported in
ref..[4t]
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