Nickel-on-charcoal-catalyzed reductions of aryl chlorides

Article abstract of DOI:10.1055/s-2001-14636

Exposure of (functionalized) aryl chlorides to catalytic quantities of nickel-on-charcoal in the presence of stoichiometric amounts of Me₂NH·BH₃/K₂CO₃ in refluxing acetonitrile leads to high yields of reduced arenes. PCBs are also reduced under these conditions. The method is highly tolerant of moisture.

Full text of DOI:10.1055/s-2001-14636

9
70
LETTER
Nickel-on-Charcoal-Catalyzed Reductions of Aryl Chlorides
Bruce H. Lipshutz,* Takashi Tomioka, Kimihiko Sato
Department of Chemistry & Biochemistry University of California, Santa Barbara, CA 93106, USA
Fax +1 805 8938265; E-mail: lipshutz@chem.ucsb.edu
Received 26 January 2001
Warmly dedicated to Professor Ryoji Noyori in recognition of his outstanding contributions to synthetic organic chemistry
onto an aryl ring. We now describe an operationally sim-
ple, environmentally friendly, and inexpensive method
for reducing aryl chlorides using nickel on charcoal as cat-
Abstract: Exposure of (functionalized) aryl chlorides to catalytic
quantities of nickel-on-charcoal in the presence of stoichiometric
amounts of Me NH•BH /K CO in refluxing acetonitrile leads to
2
3
2
3
high yields of reduced arenes. PCBs are also reduced under these alyst (Scheme 1).
conditions. The method is highly tolerant of moisture.
Key words: aryl chlorides, dechlorination, heterogeneous catalysis,
nickel-on-charcoal
Cl
H
Ni/C, PPh3
R
R
Me2NH•BH3 / K2CO3
Reduction of an aryl chloride to the corresponding arene Scheme 1
is usually accomplished via a process involving palladium
catalyzed transfer hydrogenation using formic acid or its
1
Previously, we have demonstrated that readily prepared
Ni/C is highly effective at catalyzing C-C bond construc-
salts as the source of hydrogen. While several other
methods have appeared over the years which, likewise, ef-
tions of the Negishi,1 Kumada,
5a
15b
and Suzuki types.
15c
2
fect a net aryl C-Cl to C-H conversion {e.g., Raney Ni,
3
4
5
More recently, Ni/C has been shown to catalyze amina-
tions of aryl chlorides.16 In turning our attention to a re-
ductive process which could take advantage of the ability
of Ni(0) to oxidatively insert into an aryl-chlorine bond, it
seemed reasonable that a suitable source of hydride could
be found which would participate in the catalytic cycle.
“
KCuH ”, cat Ni(II)/Zn(0)/EtOH, cat Pd(0)/NaOCH ,
2
3
6
7
8
cat NiCl /MgH , cat [Ru]/s-BuOH, cat [Rh]/HSiEt , cat
Cp La/NaH, and cat Cp TiCl /RMgBr}, functional
group compatibility is rarely addressed. Many reflect de-
velopment driven by environmental issues, specifically
2
2
3
9
10
3
2
2
1
1
the goals of modifying dioxins and PCBs, where only re-
duction of the carbon-chlorine bond(s) is of paramount
concern. In fine chemicals synthesis, however, clean and
chemoselective reductive methods which involve neutral
conditions and thus tolerate a variety of functionality, es-
pecially electrophilic centers, could prove to be quite
valuable. For example, nature provides a plethora of chlo-
rinated, physiologically active compounds, including
such topical examples as the antitumor agent cryptophy-
cin 1 and the clinically critical antibiotic vancomycin
Our initial attempts utilizing H at atmospheric pressure or
2
17
above (up to 27 psi in a Parr hydrogenator) were fruitless
i.e., no reaction occurred), as were reactions employing
(
1
either HCO H or HCO NH . Products of reduction could
2
2
4
be obtained in simple systems using Red-Al, although
functional group compatibility is likely to be compro-
mised with this potent hydride source on more highly de-
rivatized cases. Excellent results were eventually noted
using a commercially available, inexpensive amine-
1
2
1
3
1
8
1
4
borane in the presence of K CO . Thus, treatment of an
(
cf. aglycon below), the des-chloro derivatives of which
might be of interest from the perspective of structure-ac-
tivity relationships.
2 3
2
aryl chloride with 1.1 equivalents of both Me NH•BH3
and K CO under the influence of 5% Ni/C and 20% tri-
2
3
phenylphosphine in refluxing acetonitrile required only 5-
0 hours to effect complete reduction. Further streamlin-
1
OH
ing this methodology is the fact that prior reduction of the
Cl
O
O
Ni(II)/C to Ni(0)/C with two equivalents (i.e., 10 mol%)
of n-BuLi in an inert solvent (e.g., THF) is not neces-
O
HO
O
Cl
H
N
OH
15
O
O
O
H
N
O
N
H
N
H
NHCH
3
O
O
HN
Cl
O
N
H
sary. Thus, the slight excess of Me NH•BH /K CO (i.e.,
O
2
3
2
3
O
O
NH
1
0 mol%) being used is presumably responsible for in situ
O
N
O
OMe
NH
2
H
2
HO C
generation of the catalyst in active zero valent form.
OH
OH
cryptophycin 1
vancomycin aglycon
HO
Table 1 illustrates several representative aryl chlorides ex-
amined, including those bearing electrophilic centers (en-
tries 7, 8 and 10). Considering that a nitrile is used as
solvent, clearly this residue is inert as well (entries 1 and
Figure 1
2
). Based on the observation that relatively acidic protons
Moreover, a relatively strong C-Cl bond could be viewed
as a blocking group for an aryl site, and/or it might also
function stereoelectronically to direct electrophilic attack
on nitrogen in amide 2 and indole 3 did not interfere, an
experiment was conducted using moist acetonitrile as the
Synlett 2001, SI, 970–973 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Nickel-on-Charcoal-Catalyzed Reductions of Aryl Chlorides
971
Table 1 Representative Reductions of Aryl Chlorides Using 5%
the above observations are embodied in the efficient con-
version of a chlorinated racemic biaryl ether to its dechlo-
Ni/C+20% PPh as Catalyst
3
rinated derivative 4 (entry 10). Phenylalanine methyl ester
Time (h) Yield(%)a
Entry
1
Aryl chloride
NC
25
19
5
{[ ]D = -63.7° (c = 1.1, 95% EtOH; lit -64°} could be
smoothly reduced to 6 in high isolated yield essentially
25
without loss of optical purity {[ ]D = -44.4° (c = 1.0,
5
9
100
99
Cl
19
9
5% EtOH; lit. -45.3°; 98% ee; Scheme 3}. This method
1
is limited, however, to non-aldehyde- and -ketone-con-
taining educts, as p-chlorobenzophenone led mainly to
diphenylcarbinol.
CN
Cl
2
3
4
7.5
8
99
91
Cl
Cl
Cl
H
MeO
CF3
O
O
5
% Ni/C, 15% PPh3
OMe Me NH•BH / K CO
3
HN
HN
OMe
2
3
2
5
6
7
5
98
97
CH3CN, ∆, 10 h
O
O
Cl
Cl
5
6 (92%)
Scheme 3
F
O
Application of this Ni/C-amine-borane combination to re-
ductions of (poly)chlorinated biphenyls (PCBs) was also
EtO
11
7
8
100
Cl
Cl
possible. Mono-, di-, and trichlorobiphenyls, (7-9, respec-
O
tively) were all successfully converted to biphenyl (Figure
20
N
96b
2). In the case of 9, however, incomplete reduction was
observed even after 36 hours, the remaining material con-
sisting of ortho-chlorobiphenyl.
8
9
7
6
H
Ph
2
3
95
N
Cl
H
Cl
Cl
Cl
Cl
O
O
Cl
Cl
Cl
O
HN
96b
10
6
OEt
CF3
7
(7 h; 97%)
8 (6 h; 99%)
9 (36 h; 75%)
4
Figure 2
a
b
By quantitative GC. Isolated yield.
Prior experience with Ni(0)/C suggests that a phosphine
reaction medium. Treatment of 1 in 2% aqueous CH CN
under otherwise identical conditions (cf. Table 1, entry 1),
afforded the desired reduced arene quantitatively (Scheme
3
ligand (usually PPh ) is required for a synthetically useful
3
15
level of conversion, and ultimately, isolated yield. Typ-
ically, 3-4 equivalents are needed relative to the percent-
age of nickel loaded onto the solid support, an assumption
used in carrying out the examples illustrated in Table 1.
Although seemingly the norm for Ni(0)/C-mediated C-C
bond constructions, it is not obvious that a reductive pro-
2
).
CN
CN
5
% Ni/C, 20% PPh
Me NH•BH / K CO
% aqueous CH CN, ∆
3
16
cess will have identical requirements. Indeed, in the test
2
3
2
3
Cl
H
case of p-chlorobenzonitrile (1, Table 2), only two equiv-
2
3
1
(quant)
alents of PPh relative to nickel were needed to obtain the
3
desired product quantitatively. Moreover, the rate of this
reduction was actually somewhat faster than that noted
under conditions where twice the amount of phosphine
Scheme 2
(
i.e., 4 equivalents) was present (cf. Table 1, entry 1). In
Substrates bearing ortho-substituents were smoothly re-
duced (entries 2, 6, and 10), while both electron-rich and
electron-poor cases (entries 4 and 7, respectively) afford-
ed similar results at surprisingly similar rates. Several of
the complete absence of phosphine, the level of conver-
sion was dramatically reduced.
Synlett 2001, SI, 970–973 ISSN 0936-5214 © Thieme Stuttgart · New York

9
72
B. H. Lipshutz et al.
LETTER
Table 2
CN
CN
5
% Ni/C, 20% PPh3
CN
CN
5
% Ni/C, x equiv PPh3
Me2NH•BH3 / K2CO3
CH3CN, ∆, 5 h
Cl
H
Me2NH•BH3 / K2CO3
Cl
1
H
1
CH3CN, ∆
Run
1
2
3
x (equiv)a
time (h)
yield (%)
Yield (%)
95
97
99
0
2
4
18
3
5
8
100
99
Scheme 5
arelative to nickel
In an attempt to broaden the scope of this process, a silane
was envisioned as a particularly mild donor of hydride.
Tetramethyldisiloxane (TMDS) was therefore selected
to serve in this capacity. Although reduction of chloroke-
tone 10 to benzophenone required higher temperatures
simple (i.e., filtration and solvent evaporation), as is char-
acteristic of this type of catalysis. Several of the more
common electrophilic functional groups of interest are
tolerated,25 only stoichiometric amounts of hydride are
needed (1.0 equivalent relative to substrate), and given the
likely in situ generation of the kaliated form of
Me NH•BH , the reaction conditions are essentially neu-
2
1
(
i.e., refluxing dioxane), it took place very efficiently and
without competitive 1,2-carbonyl addition (Scheme 4).
Unfortunately, it was found that a considerable amount of
nickel had bled off the solid support. Thus, whereas anal-
2
3
tral.
2
2
yses via inductively coupled plasma (ICP) indicated that
reductions involving an amine-borane led to at most a 3% Acknowledgement
loss of nickel from the 5% Ni/C being used, 80% of the
Ni(II) which had been mounted on charcoal and used as
We warmly thank the NSF (97-34813) for support of our programs.
catalyst in the reaction of 10 could be detected in the aque-
ous sample prepared from the filtrate of the crude reaction References and Notes
mixture involving TMDS.
(1) (a) Pandey, P. N.; Purkayastha, M. L. Synthesis 1982, 876. (b)
Cortese, N. A.; Heck, R. F. J. Org. Chem. 1977, 42, 3491. (c)
Wiener, H.; Blum, J.; Sasson, Y. ibid. 1991, 56, 6145. (d)
Rajagopal, S.; Spatola, A. F. ibid. 1995, 60, 1347.
O
O
(
2) (a) Tashiro, M.; Fukata, G.; Oe, K. Org. Prep. Proceed. Int.
1975, 7, 183. (b) Liu, G-B.; Tsukinoki, T.; Kanda, T.; Mitoma,
Y.; Tasiro, M. Tetrahedron Lett. 1998, 39, 5991.
1
0% Ni/C, 40% PPh3
Ph
TMDS (2 equiv)
Ph
dioxane, reflux, 15 h
Cl
H
(3) Yoshida, T.; Negishi, E. J. Chem. Soc., Chem. Comm. 1974,
(96%)
762.
10
(
4) (a) Colon, I. J. Org. Chem. 1982, 47, 2622. (b) Sakai, M.; Lee,
M-S.; Yamaguchi, K.; Kawai, Y.; Sasaki, K.; Sakakibara, Y.
Bull. Chem. Soc. Jpn. 1992, 65, 1739.
Scheme 4
(
(
5) (a) Zask, A.; Helquist, P. J. Org. Chem. 1978, 43, 1619. (b)
Zoran, A.; Sasson, Y.; Blum, J. J. Mol. Catal. 1984, 27, 349.
6) (a) Carfagna, C.; Musco, A.; Pontellini, R. J. Mol. Catal.
This catalyst bleeding appears to be an unusual and unex-
pected phenomenon characteristic (thus far) exclusively
of silanes, as similar observations were made when
TMDS was replaced by polymethylhydrosiloxane (PM-
1
1
989, 57, 23. (b) Carfagna, C.; Musco, A.; Pontellini, R. ibid.
990, 63, L1.
(
(
(
7) Cucullu, M. E.; Nolan, S. P.; Belderrain, T. R.; Grubbs, R. H.
Organometallics 1999, 18, 1299.
8) Esteruelas, M. A.; Herrero, J.; Lopez, F. M.; Martin, M.; Oro,
L. A. Organometallics 1999, 18, 1110.
2
3
HS) or Et SiH.
3
Finally, the question of catalyst-recycling has been ad-
dressed using this procedure for aryl chloride reductions.
Thus, upon completion of the reduction of 1, filtration of
the reaction mixture through a sintered glass frit allowed
9) Qian, C.; Zhu, D.; Gu, Y. J. Mol. Catal. 1989, 54, L23.
(
10) Hara, R.; Sato, K.; Sum, W.-H.; Takahashi, T. Chem.
Commum. 1999, 845.
for recovery of the spent Ni/C. This marterial was subject- (11) (a) Yale, M.; Keen, C.; Bell, N. A.; Drew, P. K. P.; Cooke, M.
ed to two additional reaction cycles using fresh substrate
and amine-borane to afford essentially identical results
Appl. Organomet. Chem. 1995, 9, 297. (b) Tabaei, S.-H. H.;
Pittmann, C. U.; Mead, K. T. J. Org. Chem. 1992, 57, 6669.
(c) Lassova, L.; Lee, H. K.; Hor, T. S. A. ibid. 1998, 63, 3538.
d) Liu, Y.; Schwartz, J. Tetrahedron 1995, 51, 4471.
(
Scheme 5).
(
In summary, a new method has been developed which al- (12) Gribble, G. W. Acc. Chem. Res. 1998, 31, 141.
lows for high yield reductions of aryl chlorides to the cor- (13) Liang, J.; Moher, E. D.; Moore, R. E.; Hoard, D. W. J. Org.
Chem. 2000, 65, 3143.
(14) (a) Evans, D. A.; Wood, M. R.; Trotter, W.; Richardson, T. I.;
responding arenes mediated by the heterogeneous catalyst
2
4
Ni/C. The procedure involved is straightforward and es-
pecially forgiving with respect to levels of moisture
present in the medium. Reaction work-up is particularly
Barrow, J. C.; Katz, J. L. Angew. Chem. Int. Ed. 1998, 37,
2700. (b) Nicolaou, K. C.; Natarajan, S.; Li, H.; Jain, N. F.;
Synlett 2001, SI, 970–973 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Nickel-on-Charcoal-Catalyzed Reductions of Aryl Chlorides
973
Hughes, R.; Solomon, M. E.; Ramanjulu, J. M.; Boddy, C. N.
C.; Takayanagi, M. ibid. 1998, 37, 2708. (c) Boger, D. L.;
(22) Inductively Coupled Plasma Mass Spectrometry, (Ed.
Montaser, A.), Wiley-VCH, New York, 1998.
Miyazaki, S.; Kim, S. H.; Wu, J. H.; Loiseleur, O.; Castle, S.
L. J. Am. Chem. Soc. 1999, 121, 3226.
(23) Lawrence, N. J.; Drew, M. D.; Bushnell, S. M. J. Chem. Soc.,
Perkin Trans. 1 1999, 3381.
(
15) (a) Lipshutz, B. H.; Blomgren, P. A. J. Am. Chem. Soc. 1999,
(24) General procedure for reduction of aryl chlorides: To a flame-
dried 10 mL round-bottomed flask under a blanket of argon at
room temperature were added Ni(II)/C (69 mg, 0.05 mmol,
0.73 mmol/g), triphenylphosphine (52 mg, 0.20 mmol), 98%-
borane-dimethylamine complex (66 mg, 1.1 mmol), and
potassium carbonate (152 mg, 1.1 mmol). Dry, deoxygenated
acetonitrile (2 mL) was added via syringe and the slurry
allowed to stir for 2.5 h. Aryl chloride (1.0 mmol) and an
internal standard (1.0 mmol) were added with swirling, and
the mixture was then heated to reflux in a 100 °C sand bath.
Upon completion, the mixture was filtered through a silica
gel-glass wool plug loaded into a disposable pipet, and the
filtrate was analyzed by GC.
121, 5819. (b) Lipshutz, B. H.; Tomioka, T.; Blomgren, P. A.;
Sclafani, J. A. Inorg. Chim. Acta 1999, 296, 164. (c) Lipshutz,
B. H.; Sclafani, J. A.; Blomgren, P. A. Tetrahedron 2000, 56,
2
139.
16) Lipshutz, B. H.; Ueda, H. Angew. Chem. Int. Ed. 2000, 39,
492.
17) Yakovlev, V. A.; Terskikh, V. V.; Simagina, V. I.;
Likholobov, V. A. J. Mol. Catal. A; Chem. 2000, 153, 231.
18) (a) Lipshutz, B. H.; Buzard, D. J.; Vivian, R. W. Tetrahedron
Lett. 1999, 40, 6871. (b) Carboni, B.; Monnier, L.
Tetrahedron 1999, 55, 1197.
(
(
(
4
(
19) Gelbard, G.; Kagan, H. B.; Stern, R. Tetrahedron 1976, 32,
2
36.
(25) We have recently observed that isolated olefins,
unfortunately, are reduced under these conditions.
(
20) For both 7 and 8, 5% Ni/C was used, while for 9, a higher
loading of Ni/C (7.5%) was employed in hopes of driving this
reaction to completion.
(
21) Trost, B. M.; Braslau, R. Tetrahedron Lett. 1989, 30, 4657.
Article Identifier:
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