Productive chloroarene C-Cl bond activation: Palladium/phosphine-catalyzed methods for oxidation of alcohols and hydrodechlorination of chloroarenes

Article abstract of DOI:10.1021/jo048715y

The palladium/phosphine-catalyzed productive chloroarene C-Cl bond activation provides general, efficient, and functional group friendly methods for the selective oxidation of alcohols and the hydrodechlorination of chloroarenes.

Full text of DOI:10.1021/jo048715y

Productive Chloroarene C-Cl Bond Activation: Palladium/
Phosphine-Catalyzed Methods for Oxidation of Alcohols and
Hydrodechlorination of Chloroarenes
Xiaohong Bei, Alfred Hagemeyer, Anthony Volpe, Robert Saxton, Howard Turner, and
Anil S. Guram*,
†
Symyx Technologies, Inc., 3100 Central Expressway, Santa Clara, California 95051
aguram@symyx.com
Received July 26, 2004
The palladium/phosphine-catalyzed productive chloroarene C-Cl bond activation provides general,
efficient, and functional group friendly methods for the selective oxidation of alcohols and the
hydrodechlorination of chloroarenes.
Introduction
chloroarenes was a common side reaction observed in the
C-N and C-O cross-coupling reactions of aliphatic
amines and alcohols, respectively. Mechanistically, such
side reactions most likely result from â-hydride elimina-
Chloroarenes are generally readily available and in-
expensive and, therefore, the productive activation of
C-Cl bonds in chloroarenes is of significant industrial
interest. Traditionally, however, the C-Cl bond in chlo-
roarenes has been found to be comparatively inert.1
Recently, the productive activation of these C-Cl bonds
1
2
3
tion from a L
intermediate, followed by reductive elimination of Ar-H
from a L Pd(Ar)(H) intermediate (Scheme 1).
n
Pd(Ar)(XR) (R ) CHR R , X ) O, NR )
n
The formation of imine and aldehyde/ketone byprod-
ucts in C-N and C-O cross-coupling reactions, respec-
2
has been the subject of intense investigations. These
pioneering studies have contributed enormously to the
understanding of general principles for the activation and
functionalization of chloroarenes. In particular, their
cross-coupling reactions have been significantly ad-
(3) For leading references to cross-coupling reactions of chloroarenes,
see ref 4 and: (a) Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S.
L. J. Am. Chem. Soc. 1999, 121, 9550-9561. (b) Aranyos, A.; Old, D.
W.; Kiyomori, A.; Wolfe, J. P.; Sadighi, J. P.; Buchwald, S. L. J. Am.
Chem. Soc. 1999, 121, 4369-4378. (c) Wolfe, J. P.; Buchwald, S. L.
Angew. Chem. 1999, 111, 2570-2573; Angew. Chem., Int. Ed. 1999,
3
,4
vanced. Herein, we describe the development of two
related productive chloroarene C-Cl bond activation
reactions which provide general, efficient, and functional
group friendly methods for the selective oxidation of
alcohols to carbonyl compounds and the reduction
3
8, 2413-2416. (d) Ehrentraut, A.; Zapf, A.; Beller, M. Angew. Chem.
2000, 112, 4315-4317; Angew. Chem., Int. Ed. 2000, 39, 4153-4155.
e) Mann, G.; Incarvito, C.; Rheingold, A. L.; Hartwig, J. F. J. Am.
(
Chem. Soc. 1999, 121, 3224-3225. (f) Shaughnessy, K. H.; Kim, P.;
Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 2123-2132. (g) Nishiyama,
M.; Yamamoto, T.; Koie, Y. Tetrahedron Lett. 1998, 39, 617-620. (h)
Yamamoto, T.; Nishiyama, M.; Koie, Y. Tetrahedron Lett. 1998, 39,
(
hydrodechlorination) of chloroarenes.4e The oxygen-free
oxidations and hydrogen/hydride-free reductions are
comparable to the traditional oxygen and hydrogen/
hydride based reactions, but preclude functional group
tolerance, selectivity, and hazard issues associated with
the traditional reactions. The reactions are of potential
academic and industrial interest, particularly for the
oxidation and reduction of substrates with oxygen- and
hydrogen/hydride-sensitive functionalities.
High throughput methods at Symyx Technologies, Inc.
have been previously employed for the development of
efficient cross-coupling reactions of chloroarenes.4 These
reactions required precise combinations of catalyst and
reaction conditions. Less than optimum conditions led to
undesired side reactions. The hydrodechlorination of
2
367-2370. (i) Littke, A. F.; Fu, G. C. Angew. Chem. 1998, 110, 3586-
587; Angew. Chem., Int. Ed. 1998, 37, 3387-3388. (j) Littke, A. F.;
3
Fu, G. C. J. Org. Chem. 1999, 64, 10-11. (k) Littke, A. F.; Fu, G. C.
Angew. Chem. 1999, 111, 2568-2570; Angew. Chem., Int. Ed. Engl.
1
999, 38, 2411-2413. (l) Zhang, C.; Trudell, M. L. Tetrahedron Lett.
000, 41, 595-598. (m) Bohn, V. P. W.; Gstottmayr, C. W. K.;
2
Weskamp, T.; Herrmann, W. A. J. Organomet. Chem. 2000, 595, 186-
1
90. (n) Zapf, A.; Beller, M. Chem. Eur. J. 2000, 6, 1830-1833. (o)
Reddy, N. P.; Tanaka, M. Tetrahedron Lett. 1997, 38, 4807-4810.
Selected related references of particular significance: (p) Ben-David,
Y.; Portnoy, M.; Milstein, D. J. Am. Chem. Soc. 1989, 111, 8742-8744.
(
q) Portnoy, M.; Milstein, D. Organometallics 1993, 12, 1655-1664.
r) Zhang, C.; Huang, J.; Trudell, M. L.; Nolan, S. P. J. Org. Chem.
(
,5
1999, 64, 3804-3805. (s) Huang, J.; Grasa, G.; Nolan, S. P. Org. Lett.
1
999, 1, 1307-1309.
(
4) Cross-coupling reactions of chloroarenes developed at Symyx
Technologies: (a) Bei, X.; Uno, T.; Norris, J.; Turner, H. W.; Weinberg,
W. H.; Guram, A. S. Organometallics 1999, 18, 1840-1853. (b) Bei,
X.; Turner, H. W.; Weinberg, W. H.; Guram, A. S. J. Org. Chem. 1999,
6
4, 6797-6803. (c) Bei, X.; Guram, A. S.; Turner, H. W.; Weinberg, W.
†
Current address: Amgen Inc., One Amgen Center Drive, 29-1-A,
H. Tetrahedron Lett. 1999, 40, 1237-1240. (d) Bei, X.; Crevier, T.;
Guram, A. S.; Jandeleit, B.; Powers, T. S.; Turner, H. W.; Uno, T.;
Weinberg, W. H. Tetrahedron Lett. 1999, 40, 3855-3858. The prelimi-
nary studies of Pd/ligand-catalyzed oxidation of alcohol with PhCl
oxidant were recently communicated: (e) Guram, A. S.; Bei, X.; Turner,
H. W. Org. Lett. 2003, 5, 2485.
Thousand Oaks, CA 91320-1799. E-mail: aguram@amgen.com.
Phone: 805 313 5168.
(
1) Grushin, V. V.; Alper, H. Chem. Rev. 1994, 94, 1047-1062.
(
2) Reviews: (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J. F.; Buchwald,
S. L. Acc. Chem. Res. 1998, 31, 805-818. (b) Hartwig, J. F. Angew
Chem. 1998, 110, 2154-2177; Angew Chem., Int. Ed. 1998, 37, 2046-
(5) Recent combinatorial catalysis reviews: (a) Jandeleit, B.; Schaefer,
D. J.; Powers, T. S.; Turner, H. W.; Weinberg, W. H. Angew. Chem.
1999, 111, 2648-2699; Angew. Chem., Int. Ed. 1999, 38, 2494-2532.
(b) Dahmen, S.; Brase, S. Synthesis 2001, 1431-1449.
2
067. (c) Beletskaya, I. P. Chem. Rev. 2000, 100, 3009-3066. (d)
Grushin, V. V.; Alper, H. Top. Organomet. Chem. 1999, 3, 193-226.
e) Riermeier, T. H.; Zapf, A.; Beller, M. Top. Catal. 1997, 4, 301-309.
(
10.1021/jo048715y CCC: $27.50 © 2004 American Chemical Society
8626
J. Org. Chem. 2004, 69, 8626-8633
Published on Web 11/12/2004

Productive Chloroarene C-Cl Bond Activation
FIGURE 2. Structures of selected phosphines.
dimethylbicyclo[3.2.1]octane-8-ol (1a) with chlorobenzene,
using Pd(dba)
2
as the palladium catalyst source and
t
NaO Bu as the base (eq 1). The basic, sterically demand-
FIGURE 1. High throughput experimentation tools: (a)
Library Studio design, (b) dispensing of reagents into reactor
wells, (c) typical parallel reactor, and (d) parallel TLC station.
SCHEME 1. Mechanistic Pathways in Pd/
L-Catalyzed C-X (X ) N, O) Bond-Forming
Reactions
ing ligands A-D were found to be most effective (Figure
2
), affording the desired ketone product quantitatively
in a short reaction time (1 h). The Buchwald ligands, A
and B,3a in particular, were found to be more robust. The
commonly available phosphine ligands including a vari-
ety of triaryls (e.g., PPh
3
and derivatives thereof) and
trialkyls (e.g., PCy
to be inefficient.
In another study, six different commonly employed
bases in coupling reactions were screened for the oxida-
3
and derivatives thereof) were found
tively, is also supported by this mechanistic hypothesis.
High throughput methods were employed to exploit the
hydrodechlorination inefficiency of C-O cross-coupling
reactions to produce productive chloroarene C-Cl bond
activation reactions.
tion of piperanol (7a) with chlorobenzene with Pd(dba)
as the palladium catalyst source and phosphines A and
2
t
D as ligands (eq 2). NaO Bu, K
3 4
PO , K
2
CO
3
, and Cs
CO
2
CO
and
3
were found to be generally effective, while Na
2
3
Results
i
2
NEt( Pr) were not as effective.
Selective Oxidation of Alcohols to Carbonyl Com-
pounds. High throughput methods (Figure 1) were
employed for the development of the palladium/phos-
phine-catalyzed oxidations of alcohols to carbonyl com-
pounds. High throughput experiments were performed
with computer-controlled automated manipulations.
Symyx Library Studio software was used for the design
of libraries. Symyx Impressionist software was used for
the robotic mapping (aspirating and dispensing of reac-
tion components) of libraries into suitable glass-lined
multiwell reactors (8-, 12-, 48-, 96-well format). The
experiments were performed at the desired temperatures,
using a suitable heating mechanism and either magnetic
or orbital mixing. The experiments were analyzed with
automated parallel TLC and rapid serial GC methods.
The utility of the Pd(dba)
oxidation of alcohols to carbonyl compounds was further
investigated. The Pd(dba) /ligand A catalyst was efficient
2
/ligand A catalyst in general
2
(6) The related palladium/phosphine-catalyzed oxidations of alcohols
with aryl bromides as oxidants have been described previously, see:
(
a) Tamaru, Y.; Yamamoto, Y.; Yamada, Y.; Yoshida, Z. Tetrahedron
Lett. 1979, 1401-1404. (b) Tamaru, Y.; Yamada, Y.; Inoue, K.;
Yamamoto, Y.; Yoshida, Z. J. Org. Chem. 1983, 48, 1286-1292. The
simple extension of this methodology to chlorobenzene was not
achievable with the common phosphine ligands such as triphenylphos-
phine, tricyclohexylphosphine, and related derivatives thereof.
(7) For related palladium-catalyzed oxidations of alcohols with
aliphatic chlorohydrocarbons, see: (a) Nagashima, H.; Tsuji, J. Chem.
Lett. 1981, 1171-1172. (b) Tusji, J.; Nagashima, H.; Sato, K. Tetra-
hedron Lett. 1982, 23, 3085-3088. (c) Poetsch, E.; Lannert, H. Chem.
Abstr. 1996, 124, 145502d. (d) Bouquillon, S.; Henin, F.; Muzart, J.
Organometallics 2002, 19, 1434-1437. TEMPO-catalyzed: (e) Luca,
L. D.; Giacomelli, G.; Porcheddu, A. Org. Lett. 2001, 3, 3041-3043.
Chlorobenzene was chosen as a suitable oxidant be-
cause of its low cost and industrial viability.6,7 The
oxidation reactions were found to be mostly influenced
by the nature of the phosphine ligand, base, and the
alcohol reactant. In one study, a library of 96 different
phosphine ligands was screened for the oxidation of 1,5-
J. Org. Chem, Vol. 69, No. 25, 2004 8627

Bei et al.
TABLE 1. Pd/Ligand A-Catalyzed Oxidation of
Sterically Hindered Aliphatic Alcoholsa
aliphatic acyclic alcohols. The Pd(dba)
lyzed reactions of certain aliphatic alcohols in the pres-
/ligand A-cata-
2
3 4
ence of 2-chloro-m-xylene oxidant and K PO formed ester
products (Table 1).
The Pd(dba) /ligand A catalyst also efficiently catalyzed
2
the chlorobenzene-based selective oxidation of a wide
variety of primary and secondary benzylic alcohols.
2 3 3 4
K CO and K PO were suitable bases for these reactions.
Primary and secondary benzylic alcohols containing both
electron-withdrawing and electron-donating substituents
reacted efficiently to afford the desired carbonyl com-
pounds in high isolated yields (Table 2). Remarkably,
functionalities such as CdC, -SR, and -NR were found
2
to be compatible and unaffected under these oxidation
reaction conditions.
The oxidation of 2,2′-hydroxymethylbiphenyl (17a)
resulted in the formation of the lactone product 17b with
an isolated yield of 98% (eq 3).
Similarly, the oxidation of the ester group containing
benzyl alcohol 18a afforded the mixture of the expected
aldehyde product 18b along with ester 18c in a 1.5:1 ratio
and a 89% combined isolated yield (eq 4).
a
Unless indicated otherwise, all reactions were performed in
toluene with molar equivalents of reagents and catalyst as follows:
ROH (1.0 mmol), C6H5Cl (1.1-1.5 mmol), base (2.0 mmol),
Pd(dba)2 (1.0 mol %), and ligand A (2.0 mol %). Reaction times
are indicated in the Experimental Section, but are not exhaustively
optimized. Yields correspond to isolated products of >95% purity
b
as determined by NMR. Pd(dba)2 (0.2 mol %) and ligand A (0.6
mol %). c Yields correspond to GC yields. 2-Chlorotoluene was
d
e
used as the oxidant. 2-Chloro-m-xylene was used as the oxidant.
in catalyzing the chlorobenzene-based oxidation of cyclic
aliphatic alcohols. NaO Bu was found to be a suitable
base for sterically hindered bicyclic alcohols, while K CO
2 3
The formation of ester products 6b, 17b, and 18c most
likely results from sequential steps, which presumably
include (i) palladium/phosphine-catalyzed oxidation of the
alcohol functionality to an aldehyde functionality, (ii)
reaction of the newly formed aldehyde functionality with
an unreacted alcohol functionality to form a hemiacetal
intermediate, and (iii) palladium/phoshine-catalyzed de-
hydrogenation of the hemiacetal intermediate to the ester
t
was found to be a suitable base for less hindered
monocyclic alcohols. Thus, the sterically hindered bicyclic
alcohols reacted efficiently to afford the desired industri-
8
9
ally significant ketones in high yields (Table 1). High
catalyst turnover frequency and number were observed
in these oxidations. However, the Pd(dba)
catalyst was less efficient in catalyzing the oxidation of
2
/ligand A
10
product.
Hydrodechlorination of Chloroarenes. Similarly,
high throughput methods were also employed for the
development of the related palladium/phosphine-cata-
lyzed hydrodechlorination of chloroarenes. 2-Propanol
(8) Bicyclic ketones are of significance as perfume additives in the
fragrance industry, see. (a) German Patent Application DE 2,945,812
to Naarden & Shell Aroma Chemicals, 1980. (b) Japanese Patent
Application JP 92-77446 to Kao Corp., 1992.
(
K
IPA) was chosen as a suitable H-atom donor solvent and
(9) The palladium/phosphine-catalyzed oxidations of sterically less
hindered aliphatic alcohols were not rigorously investigated or opti-
mized. Inefficiencies resulting in undesired products were observed
in preliminary studies involving oxidations of unhindered primary
alcohols under the reaction conditions described for hindered secondary
alcohols. Although steric factors are known to favor the reductive
elimination process, see ref 2 and. (a) Palucki, M.; Wolfe, J. P.;
Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 3395-3396. (b) Jones,
W. D.; Kuykendall, V. L. Inorg. Chem. 1991, 30, 2615
2
CO was chosen as the base because of their low cost
3
(10) The proposed mechanism of ester formation is similar to the
mechanism proposed by Buchwald for the formation of amide side
products in the Ni-catalyzed amination of 4-chlorobenzaldehyde with
pyrolidine, see: Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1997,
119, 6054-6058.
8628 J. Org. Chem., Vol. 69, No. 25, 2004

Productive Chloroarene C-Cl Bond Activation
TABLE 2. Pd(dba)2/Ligand A-Catalyzed Selective Oxidation of Benzylic Alcoholsa
a
Unless indicated otherwise, the reactions were performed in toluene at 105 °C. Molar equivalents of the reagents and catalyst were
as follows: ROH (1.0 mmol), C6H5Cl (1.1-1.5 mmol), base (2.0 mmol), Pd(dba)2 (1.0 mol %), and ligand A (3.0 mol %). Reaction times
were not exhaustively optimized and ranged from 4 to 48 h (for details, see the Experimental Section). Yields correspond to isolated
1
b
product of >95% purity by GCMS and H NMR. Reaction performed in xylene.
and industrial viability.11 The hydrodechlorination reac-
tions were found to be most influenced by the nature of
the phosphine ligand and the chloroarene reactant.
A focused library of 12 different phosphine ligands
the hydrodechlorination of 4-chlorobenzophenone 19a,
the electron-rich and sterically crowded phosphine ligands
A-E were found to be generally effective (eq 5). The
(
ligand choice was narrowed based on its potential
demonstrated in oxidation studies) was screened for the
hydrodechlorination of the regioisomeric chlorobenzophe-
nones 19a and 20a with IPA as solvent, Pd(dba)
2
as the
palladium catalyst source, and K CO as the base. For
2
3
(11) (a) Dovganyuk, V. F.; Antokol’skaya, I. I.; Sharf, V. Z.; Bol’shakov,
L. I. Izv. Akad. Nauk SSR, Ser. Khim. 1988, 2, 492-493. (b) Ukisu,
Y.; Miyadera, T. J. Mol. Catal. A: Chem. 1997, 125, 135-142. (c) Ukisu,
Y.; Miyadera, T. Nippon Kagaku Kaishi 1998, 5, 369-371.
ligand D, in particular, was most efficient, affording
complete hydrodechlorination of 19a in 3 h. In contrast,
J. Org. Chem, Vol. 69, No. 25, 2004 8629

Bei et al.
TABLE 3. Pd/Ligand D-Catalyzed Hydrodechlorination
and aldehyde group containing chloroarenes exhibited
side products resulting from the reaction of the function-
alities. The catalyst was also found to be suitable for the
hydrodebromination of bromoarenes with high turnover
numbers and turnover frequencies.
a
of Chloroarenes
Discussion
Productive palladium/phosphine-catalyzed chloroarene
C-Cl bond activation reactions for the selective oxidation
of alcohols to carbonyl compounds and the reduction
(
hydrodechlorination) of chloroarenes are achieved from
precise combinations of catalyst and reaction conditions.
The reactions are influenced by the nature of phosphine
ligands, bases, and the chloroarene and alcohol reactants.
For the PhCl oxidant based selective oxidation of
alcohols to carbonyl compounds, the electron-rich, steri-
cally crowded phosphine ligands A-D in the presence of
t
suitable bases (e.g., NaO Bu, K
2 3 3 4 2 3
CO , K PO , and Cs CO )
provide efficient Pd/ligand catalysts. The Pd(dba)
2
/ligand
A catalyst, in particular, efficiently catalyzes the oxida-
tion of a variety of benzylic and sterically crowded
secondary aliphatic alcohols with various electronic and
steric substitution patterns. The reactions exhibit good
functional group tolerance. Notably, functional groups
2
such as -CdC, -SR, and -NR are compatible and
unaffected under these oxygen-free oxidation conditions.
Ester and lactone products are observed in reactions of
aliphatic acyclic primary alcohols. Overall, the palladium/
phosphine-catalyzed oxidation provides a general and
efficient method for the oxidation of alcohols to carbonyl
compounds. The method is similar to the previously
described alcohol oxidation methods based on aryl bro-
6
7
mides and aliphatic chlorohydrocarbons, but exhibits
broader scope and viability. The method compares favor-
ably to the traditional alcohol oxidation methods based
on [O]-containing oxidants (e.g., air, O
2
3,14
, H
2
O
2
, DMSO,
transition metal oxides, and NaOCl),1
but precludes
functional group tolerance, selectivity, and hazard issues
of the traditional methods.
For the IPA-based hydrodechlorination of chloroarenes,
the electron-rich sterically crowded phosphine ligands
a
All reactions were performed in IPA at 80 °C until all starting
chloroarene was consumed. Unless indicated otherwise, the molar
equivalents of the reagents and catalyst were as follows: ArCl
1.0 mmol), Pd(dba)2 (1.0 mol %), ligand D (3.0 mol %), and K2CO3
2.0 mmol). TON ) 551. TON ) 2000, K2CO3/ArBr ) 1.1. TON
1019.
(
b
c
d
(
A-D in the presence of K
2
CO
3
base provide efficient Pd/
/ligand D catalyst, in
)
ligand catalysts. The Pd(dba)
2
particular, efficiently catalyzes the hydrodechlorination
of chloroarenes with various functional groups. Notably,
for the hydrodechlorination of 2-chlorobenzophenone 20a,
the sterically less crowded ligand F was found to be most
effective. As with oxidation reactions, the commonly
available phosphine ligands including a variety of triaryls
1
2
(13) Leading references to traditional alcohol oxidations: (a) Hudlicky,
M. Oxidations in Organic Chemistry; ACS Monograph Series; American
Chemical Society: Washington, DC, 1990. (b) Sheldon, R. A.; Kochi,
J. K. Metal-Catalyzed Oxidations of Organic Compounds; Academic
Press: New York, 1981. (c) Smith, M. B.; March, J. March’s Advanced
Organic Chemistry: Reactions, Mechanisms, and Structure, 5th ed.;
Wiley-Interscience: New York, 2001; pp 1514-1517. (d) Sheldon, R.
A.; Arends, I. W. C. E.; Dijksman, A. Catal. Today 2000, 57, 157.
(
e.g., PPh
PCy and derivatives thereof) were found to be inefficient.
The utility of the Pd(dba) /ligand D catalyst for general
hydrodechlorination of chloroarenes was further inves-
tigated. The Pd(dba) /ligand D catalyst efficiently cata-
lyzed the selective hydrodechlorination of a variety of
chloroarenes in the presence of K CO base and IPA
solvent (Table 3). Notably, hydrogen/hydride-sensitive
functionalities such as -CdC, -CdO, and -NO were
3
and derivatives thereof) and trialkyls (e.g.,
3
2
2
(
14) Leading references to palladium-catalyzed oxidations based on
O]-containing oxidants: (a) Stahl, S. S. Angew. Chem., Int. Ed. 2004,
43, 3400-3420. (b) Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc.
001, 123, 7725-7726. (c) Blackburn, T. F.; Schwartz, J. J. Chem. Soc.,
[
2
3
2
Chem. Commun. 1977, 157. (d) Petersen, K. P.; Larock, R. C. J. Org.
Chem. 1998, 63, 3185. (e) Noronha, G.; Henry, P. M. J. Mol. Catal. A
1997, 120, 75. (f) Nishimura, T.; Onoue, T.; Ohe, K.; Uemura, S. J.
Org. Chem. 1999, 64, 6750-6755. (g) Nagashima, H.; Tsuji J. Bull.
Chem. Soc. Jpn. 1981, 1171-1172. (h) Tsuji, J.; Nagashima, H.; Sato,
K. Tetrahedron Lett. 1982, 23, 3085-3088. (i) Bouquillon, S.; Henin,
F.; Muzart, J. Organometallics 2000, 19, 1434-1437. (j) Jensen, D.
R.; Pugsley, J. S.; Sigman, M. S. J. Am. Chem. Soc. 2001, 123, 7475-
7476. (k) Steinhoff, B. A.; Fix, S. R.; Stahl, S. S. J. Am. Chem. Soc.
2002, 124, 766-767.
2
compatible, and not affected under these reduction condi-
tions. However, the hydrodechlorination reactions of ester
2
(12) PhPCy was also found to be a reasonably suitable ligand for
the palladium/phosphine-catalyzed hydrodechlorination of 2-chloroben-
zophenone affording the desired benzophenone product in 91% yield
under similar reaction conditions.
8630 J. Org. Chem., Vol. 69, No. 25, 2004

Productive Chloroarene C-Cl Bond Activation
functional groups such as NO , CdC, and CdO (ketone)
are compatible and unaffected under these hydrogen-free
reduction conditions. However, side reactions are ob-
served with functional groups such as esters and alde-
hydes. The hydrodebromination of bromoarenes can also
be efficiently accomplished with high TON. While Pd/
ligand D catalyst is not efficient for the hydrodechlori-
nation of certain sterically crowded chloroarenes, the
electron-rich, but sterically uncrowded phosphine ligand
1
2
2
elimination from Pd-O-CHR R and subsequent reduc-
tive elimination of ArH are influenced by combined steric
properties of the phosphine ligand, and the chloroarene
and alcohol reactants. Generally, sterically bulky electron-
rich phosphine ligands are required, but the optimum
extent of the phosphine ligand steric bulk depends on the
sterics of the chloroarene and alcohol reactants. When
alcohol reactants such as benzyl alcohols or sterically
crowded secondary aliphatic alcohols are involved, the
ortho-substituted phosphine ligands (e.g., ligands A, B,
and C) are suitable for the effective oxidation of such
reactants with the PhCl oxidant. For smaller alcohol
reactants such as IPA, more bulky ortho-disubstituted
phosphine ligands (e.g., ligand D) are more suitable for
the effective hydrodechlorination of typical chloroarenes.
However, for the IPA-based hydrodechlorinations, an
increase in sterics of the chloroarene requires a decrease
in sterics of the phosphine ligand. Thus, sterically
uncrowded electron-rich phosphine ligand F (no ortho
substituents) is suitable for the hydrodechlorination of
crowded chloroarenes.
2 3
F, in the presence of K CO base, appears to provide
efficient Pd/ligand catalyst for such chloroarene reac-
tants. Overall, the palladium/phosphine-catalyzed hy-
drodechlorination with IPA reductant provides a general
and efficient method for the hydrodechlorination of
15-19
chloroarenes.
reported IPA based hydrodechlorination methods;
however, it utilizes a milder K CO base instead of the
The method is similar to the previously
15f-k
2
3
high concentrations of strong bases such KOH and NaOH
typically utilized in the previous methods. The method
also exhibits high catalyst turnover frequency, which is
superior to that reported previously for the heterogeneous
3 2 4
Rh/C, Pd/C, and polymer supported RhCl and Na PdCl
catalyst systems, and comparable to the homogeneous
Ru/ligand system reported recently.15f The method offers
milder reaction conditions compared to the previous IPA/
Conclusion
The palladium/phosphine-catalyzed chloroarene C-Cl
bond activation reactions provide general, efficient, and
functional group friendly methods for the oxidation of
alcohols to carbonyl compounds and for the hydrodechlo-
rination of chloroarenes. The reactions are most influ-
enced by the nature of the phosphine ligand, base, and
the chloroarene and alcohol reactants. Optimum condi-
tions for productive reactions are produced by the subtle
interplay of steric and electronic properties of the phos-
phine ligand and the chloroarene and alcohol reactants.
The Pd/ligand A catalyst is suitable for the PhCl-based
oxidation of a variety of benzylic primary and secondary
alcohols, and crowded secondary aliphatic alcohols. While,
the Pd/ligand D catalyst is most suitable for the IPA
based hydrodechlorination of typical chloroarenes, the Pd/
ligand F catalyst is suitable for the IPA-based hydro-
dechlorination of crowded chloroarenes.
16
17
17
metal hydroxide, H
drazine hydrochloride reductant based hydrodechlori-
nation systems, and therefore it offers a complementary
2
,
HCOOH, HCOONa, and hy-
18
method, particularly for the hydrodechlorination of chlo-
roarenes with sensitive functionalities.19
The palladium/phosphine-catalyzed chloroarene acti-
vation reactions for the oxidation of alcohols and hydro-
dechlorination of chloroarenes most likely proceed by the
mechanism described in Scheme 1. The reactions are
mostly influenced by the nature of the phosphine ligand,
base, and the chloroarene and alcohol reactants. Par-
ticularly, the interaction of electronic and steric proper-
ties of the phosphine ligand and the chloroarene and
alcohol reactants play a critical role. The oxidative
addition of the ArCl to the Pd center is favored by
electron-rich phosphine ligands, and the â-hydrogen
The oxygen- and hydrogen/hydride-free palladium/
phosphine-catalyzed C-Cl bond activation reactions for
alcohol oxidations and chloroarene hydrodechlorinations,
respectively, are comparable to the traditional oxygen
and hydrogen/hydride based methods, but preclude func-
tional group tolerance, selectivity, and hazard issues
related to the traditional methods. The reactions offer
complementary, tunable, and attractive methodologies for
the productive utilization of the industrially significant
chloroarenes.
(
15) (a) Imai, H.; Nishiguchi, T.; Tanaka, M.; Fukuzumi, K. J. Org.
Chem. 1977, 42, 2309-2313. (b) Zhang, Y.; Liao, S.; Xu, Y. Tetrahedron
Lett. 1994, 35, 4599-4602. (c) Li, H.; Liao, S.; Xu, Y.; Yu, D. Synth.
Commun. 1997, 27, 829-836. (d) Angeloff, A.; Brunet, J. J.; Legars,
P.; Neibecker, D.; Souyri, D. Tetrahedron Lett. 2001, 42, 2301-2303.
(
e) Akita, Y.; Inoue, A.; Ishida, K.; Terui, K.; Ohta, A. Synth. Commun.
1
986, 16, 1067-1072. (f) Cucullu, M. E.; Nolan, S. P.; Belderrain, T.
R.; Grubbs, R. H. Organometallics 1999, 18, 1299-1304. (g) Ben-David,
Y.; Gozin, M.; Portnoy, M.; Milstein, D. J. Mol. Catal. 1992, 73, 173-
1
80. (h) Dovganyuk, V. F.; Antokol’skaya, I. I.; Sharf, V. Z.; Bol’shakov,
L. I. Izv. Akad. Nauk SSR, Ser. Khim. 1988, 2, 492-493. (i) Ukisu, Y.;
Miyadera, T. J. Mol. Catal. A: Chem. 1997, 125, 135-142. (j) Ukisu,
Y.; Miyadera, T. Nippon Kagaku Kaishi 1998, 5, 369-371. (k) Gopi-
nath, R.; Lingaiah, N.; Sreedhar, B.; Suryanarayana, I.; Prasad, P. S.
S.; Obuchi, A. Appl. Catal., B 2003, 46, 587.
Experimental Section
(
16) (a) Grushin, V. V.; Alper, H. Organometallics 1991, 10, 1620-
622. (b) Ferrughelli, D. T.; Horvath, I. T. J. Chem. Soc., Chem
Commun. 1992, 806-807.
17) Reference 15b and: (a) Atienza, M. A.; Esteruelas, M. A.;
Fernandez, M.; Herrero, J.; Olivan, M. New J. Chem. 2001, 25, 775.
1
General Comments. High throughput screening experi-
ments were performed by using computer controlled robotic
manipulations with Symyx proprietary software and hardware
tools. Subsequent scale-up reactions were performed under
argon atmosphere with standard oven-dried glassware and
Schlenk techniques. Bis(dibenzylideneacetone)palladium, al-
cohols, chloroarenes, and bases were purchased from com-
mercial sources and used as such. Anhydrous, sure-seal grade
solvents were used as purchased for all the reactions. The
(
(
b) Pandey, P. N.; Purkayastha, M. L. Synthesis 1982, 876-878. (c)
Wiener, H.; Blum, J.; Sasson, Y. J. Org. Chem. 1991, 56, 6145. (d)
Anwer, M. K.; Sherman, D. B.; Roney, J. G.; Spatola, A. F. J. Org.
Chem. 1989, 54, 1284. (e) Cortese, N. A.; Heck, R. F. J. Org. Chem.
1
(
977, 42, 3491. (f) Helquist, P. Tetrahedron Lett. 1978, 1913-1914.
g) Zask, A.; Helquist, P. J. Org. Chem. 1978, 43, 1619-1620.
18) Cellier, P. P.; Spindler, J.-F.; Taillefer, M.; Cristau, H.-J.
Tetrahedron Lett. 2003, 44, 7191.
19) Viciu, M. S.; Grasa, S. P.; Nolan, S. P. Organometallics 2001,
0, 3607-3612.
(
3,4
phosphine ligands were synthesized as described previously.
All reactions were performed until complete consumption of
the starting alcohols or chloroarenes, but the reaction times
(
2
J. Org. Chem, Vol. 69, No. 25, 2004 8631

Bei et al.
and conditions were not optimized. Stock solutions of the metal
precursor and ligand were used for high TON experiments in
which desired aliquots of stock solutions were added after the
addition of the alcohol and chloroarene. Column chromatog-
raphy was performed with commercially available Silica Gel
Acetophenone (9b): This compound was obtained as an
oil (82 mg, 68%) from the reaction of sec-phenethyl alcohol
(0.12 mL, 1.0 mmol), chlorobenzene (0.15 mL, 1.5 mmol),
2 3 2
K CO (276 mg, 2.0 mmol), Pd(dba) (6 mg, 10 µmol), and
ligand A (10 mg, 30 µmol) in toluene at 80 °C for 24 h.
2-Naphthaldehyde (10b): This compound was obtained as
a yellowish solid (149 mg, 96%) from the reaction of 2-naph-
thalenemethanol (158 mg, 1.0 mmol), chlorobenzene (0.15 mL,
1.5 mmol), K CO (276 mg, 2.0 mmol), Pd(dba)2 (6 mg, 10
60 (particle size: 0.063-0.100 mm), hexanes, and ethyl
acetate. The oxidation and hydrodechlorination products are
known compounds and are commercially available from Ald-
rich (5b, 7b-16b, 19b-28b) and TCI, Japan (3b, 4b). Isolated
yields correspond to products of >95% purity as determined
by GC and NMR. GC yields correspond to calibrated GC yields
with a suitable standard.
2
3
µmol), and ligand A (10 mg, 30 µmol) in toluene at 105 °C for
6 h.
9-Fluorenone (11b): This compound was obtained as a
yellow solid (179 mg, 100%) from the reaction of 9-hydroxy-
fluorene (182 mg, 1.0 mmol), chlorobenzene (0.15 mL, 1.5
General Procedure for PhCl-Based Oxidation Experi-
ments. A mixture of an alcohol, a base, Pd(dba) , and ligand
2
A was loaded into a Schlenk reaction tube. The mixture was
thoroughly degassed with vacuum and argon purge cycles.
Chlorobenzene and toluene were added and the mixture was
heated at reaction temperature until the reaction was com-
pleted (all starting alcohol was consumed as determined by
GC-MS). The reaction mixture was taken up in ether and
2 3 2
mmol), K CO (284 mg, 2.0 mmol), Pd(dba) (6 mg, 10 µmol),
and ligand A (11 mg, 33 µmol) in toluene at 105 °C for 12 h.
9-Anthraldehyde (12b): This compound was formed (99%
yield) from the reaction of 9-anthracenemethanol (208 mg, 1.0
mmol), chlorobenzene (0.15 mL, 1.5 mmol), K
2
CO
3
(276 mg,
2.0 mmol), Pd(dba)
2
(6 mg, 10 µmol), and ligand A (10 mg, 30
washed with H
2
O and brine. The organic phase was dried over
µmol) in toluene at 105 °C for 24 h.
MgSO , filtered, and concentrated under vacuum. The crude
4
p-Methylthiobenzyaldehyde (13b): This compound was
obtained as a yellow oil (125 mg, 82%) from the reaction of
p-methylthiobenzyl alcohol (154 mg, 1.0 mmol), chlorobenzene
product was purified by column chromatography on silica gel
to afford the desired product.
1
,5-Dimethylbicyclo[3.2.1]octane-8-on (1b): This com-
3 4 2
(0.15 mL, 1.5 mmol), K PO (425 mg, 2.0 mmol), Pd(dba) (6
pound was formed (quantitative calibrated GC yield, 86%
isolated yield) from the reaction of 1,5-dimethylbicyclo[3.2.1]-
mg, 10 µmol), and ligand A (10 mg, 30 µmol) in o-xylene at
130 °C for 4 h.
octane-8-ol (154 mg, 1.0 mmol), chlorobenzene (0.14 mL, 1.4
Dibenzosuberone (14b): This compound was obtained as
a yellow oil (197 mg, 95%) from the reaction of dibenzosuberol
t
mmol), NaO Bu (192 mg, 2.0 mmol), Pd(dba)
2
(0.29 mg, 2.0
µmol), and ligand A (2 mg, 6.0 µmol) in toluene at 105 °C for
h.
1S)-(-)-Camphor (2b): This compound was formed (quan-
titative GC yield) from the reaction of [(1S)-endo]-(-)-borneol
171 mg, 1.1 mmol), chlorobenzene (0.14 mL, 1.4 mmol),
(210 mg, 1.0 mmol), chlorobenzene (0.15 mL, 1.5 mmol), K
(425 mg, 2.0 mmol), Pd(dba) (6 mg, 10 µmol), and ligand A
10 mg, 30 µmol) in toluene at 105 °C for 48 h.
3 4
PO
2
2
(
(
trans-4-Stilbenecarboxaldehyde (15b): This compound
was obtained as an off-white solid (196 mg, 94%) from the
reaction of trans-stilbenemethanol (210 mg, 1.0 mmol), chlo-
robenzene (0.15 mL, 1.5 mmol), K
Pd(dba)
toluene at 110 °C for 14 h.
(
t
2
NaO Bu (192 mg, 2.0 mmol), Pd(dba) (0.29 mg, 2.0 µmol), and
3 4
PO (425 mg, 2.0 mmol),
ligand A (2 mg, 6.0 µmol) in toluene at 105 °C for 2 h.
2
(6 mg, 10 µmol), and ligand A (10 mg, 30 µmol) in
Cyclododecanone (3b): This compound was formed (94%
GC yield) from the reaction of cyclododecanol (185 mg, 1.0
4
,4′-Bis(dimethylamino)benzophenone (16b): This com-
2 3
mmol), 2-chlorotoluene (0.17 mL, 1.4 mmol), K CO (276 mg,
pound was obtained as an off-white solid (255 mg, 95%) from
2
2
.0 mmol), Pd(dba) (6 mg, 10 µmol), and ligand A (10 mg, 30
the reaction of 4,4′-bis(dimethylamino)benzhydrol (270 mg, 1.0
mmol), chlorobenzene (0.15 mL, 1.5 mmol), K PO (425 mg,
3 4
.0 mmol), Pd(dba)
µmol) in toluene at 110 °C for 18 h.
µmol) in toluene at 105 °C for 24 h. Chlorobenzene or 2-chloro-
m-xylene were also found to be effective oxidants.
2
2
(6 mg, 10 µmol), and ligand A (10 mg, 30
Cyclopentadecanone (4b): This compound was formed
(
98% GC yield) from the reaction of cyclopentadecanol (226
20
3
,4-Benzocoumarin (17b): This compound was obtained
mg, 1.0 mmol), 2-chlorotoluene (0.17 mL, 1.4 mmol), K
2
CO
3
as an off-white solid (202 mg, 96%) from the reaction of 2,2′-
(
(
276 mg, 2.0 mmol), Pd(dba) (6 mg, 10 µmol), and ligand A
2
biphenyldimethanol (214 mg, 1.0 mmol), chlorobenzene (0.15
10 mg, 30 µmol) in toluene at 105 °C for 24 h. Chlorobenzene
2 3 2
mL, 1.5 mmol), K CO (276 mg, 2.0 mmol), Pd(dba) (6 mg, 10
or 2-chloro-m-xylene were also found to be effective oxidants.
µmol), and ligand A (10 mg, 30 µmol) in toluene at 105 °C for
Tropinone (5b): This compound was obtained as a white
1
1.5 h.
solid (129 mg, 93%) from the reaction of tropine hydrate (156
Methyl 4-formylbenzoate (18b) and Ester 18c: Com-
t
mg, 1.0 mmol), chlorobenzene (0.14 mL, 1.4 mmol), NaO Bu
pounds 18b and 18c were isolated as white solids (89 mg for
2
(192 mg, 2.0 mmol), Pd(dba) (6 mg, 10 µmol), and ligand A
(10 mg, 30 µmol) in toluene at 105 °C for 6 h.
1
8b and 57 mg for 18c) from the reaction of methyl (4-
hydroxymethyl)benzoate (166 mg, 1.0 mmol), chlorobenzene
0.15 mL, 1.5 mmol), K CO (276 mg, 2.0 mmol), Pd(dba) (6
mg, 10 µmol), and ligand A (10 mg, 30 µmol) in toluene at 100
Ester 6b: This compound was obtained as a yellow oil (124
mg, 91%) from the reaction of 1-phenyl-3-propanol (137 mg,
(
2
3
2
1
.0 mmol), 2-chloro-m-xylene (0.18 mL, 1.4 mmol), K
mg, 2.0 mmol), Pd(dba) (6 mg, 10 µmol), and ligand A (10
mg, 30 µmol) in toluene at 95 °C for 12 h. C NMR (CDCl
3
PO
4
(425
1
°
3
C for 12 h. 18b: H NMR (CDCl ) δ 10.07 (1H, C(O)H), 8.16
1
2
(
d, 2H, ArH), 7.92 (d, 2H, ArH), 3.93 (s, 3H, OMe). 18c:
H
1
3
3
) δ
NMR (CDCl
3
) δ 8.15-8.0 ppm (m, 6H, ArH), 7.48 (d, 2H, ArH),
), 3.91 (s, 3H, OMe), 3.89 (s, 3H, OMe).
1
1
72.8 (C(dO)-O), 141.1, 140.4, 128.4, 128.3, 128.3, 128.2,
5
.40 (s, 2H, C(O)OCH
2
26.2, 125.9, 63.7, 35.8, 32.1, 30.9, 30.1.
13
3
C NMR (CDCl ) δ 166.6, 166.1, 165.4, 140.6, 134.1, 133.5,
Piperonal (7b): This compound was obtained as a pale
yellow solid (138 mg, 92%) from the reaction of piperonyl
alcohol (152 mg, 1.0 mmol), chlorobenzene (0.15 mL, 1.5 mmol),
130.1, 129.9, 129.6, 129.6, 127.7, 66.3, 52.4, 52.1.
General Procedure for Hydrodechlorination Experi-
ments. A reaction mixture of a chloroarene, base, Pd(dba) ,
2
and ligand was loaded into a Schlenk reaction tube. The
mixture was thoroughly degassed with vacuum and argon
purge cycles. Isopropanol was added and the mixture was
heated at 80 °C until the reaction was completed (all starting
chloroarene was consumed as determined by GC-MS). All
K
3
PO
4
(425 mg, 2.0 mmol), Pd(dba)
2
(6 mg, 10 µmol), and
ligand A (10 mg, 30 µmol) in toluene at 105 °C for 14 h.
4
,4′-Diflourobenzophenone (8b): This compound was
obtained as an off-white solid (215 mg, 98%) from the reaction
of 4,4′-diflourobenzhydrol (220 mg, 1.0 mmol), chlorobenzene
0.15 mL, 1.5 mmol), K CO (276 mg, 2.0 mmol), Pd(dba) (6
2 3 2
(
mg, 10 µmol), and ligand A (10 mg, 30 µmol) in toluene at 105
C for 12 h.
(
20) Zhou, Q. J.; Worm, K.; Dolle, R. E. J. Org. Chem. 2004, 69,
°
5147-5149.
8632 J. Org. Chem., Vol. 69, No. 25, 2004

Productive Chloroarene C-Cl Bond Activation
reactions were quantitative by GC-MS analysis. The mixture
80 °C. The reaction was completed within 1 h as determined
by GC-MS.
was taken up in ether and washed with H
2
O and brine. The
4
organic phase was dried over MgSO , filtered, and concen-
Hydrodechlorination of 2,4-dinitrochlorobenzene
(25a): The reaction mixture of 2,4-dinitrochlorobenzene (202
mg, 1.0 mmol), 2-propanol (4.0 mL), K CO (276 m, 2.0 mmol),
trated under vacuum. The crude product was purified by
column chromatography on silica gel to afford the desired
product.
2
3
Pd(dba) (6 mg, 10 µmol), and ligand D (13 mg, 30 µmol) was
2
Hydrodechlorination of 4-chlorobenzophenone (21a):
The reaction mixture of 4-chlorobenzophenone (418 mg, 1.9
heated at 80 °C. The reaction was completed within 1 h as
determined by GC-MS.
mmol), 2-propanol (7.0 mL), K
2 3
CO (481 mg, 3.5 mmol),
Hydrodechlorination of 5-chloro-o-anisidine (26a):
The reaction mixture of 5-chloro-o-anisidine (158 mg, 1.0
Pd(dba) (2 mg, 3.5 µmol), and ligand D (4 mg, 10 µmol) was
2
heated at 80 °C. The dechlorination reaction was completed
within 5 h as determined by GC-MS. The dechlorination
product was isolated as a white solid (335 mg, 95.4%) and
confirmed by NMR.
mmol), 2-propanol (4.0 mL), K
2
CO
3 2
(276 m, 2.0 mmol), Pd(dba)
(
6 mg, 10 µmol), and ligand D (13 mg, 30 µmol) was heated at
80 °C. The reaction was completed within 25 h as determined
by GC-MS.
Hydrodechlorination of 4′-chlorochalcone (22a): The
reaction mixture of 4′-chlorochalcone (243 mg, 1.0 mmol),
Hydrodebromination of 4-bromobenzophenone (27a):
The reaction mixture of 4-bromobenzophenone (1826 mg, 7.0
2
2 3 2
-propanol (4.0 mL), K CO (276 m, 2.0 mmol), Pd(dba) (6 mg,
mmol), 2-propanol (10.0 mL), K
2 3
CO (1063 mg, 7.7 mmol),
1
0 µmol), and ligand D (13 mg, 30 µmol) was heated at 80 °C.
Pd(dba) (2 mg, 3.5 µmol), and ligand D (4 mg, 10 µmol) was
2
The reaction was completed within 7 h as determined by GC-
MS.
heated at 80 °C. Reaction was completed within 4 h as
determined by GC-MS. The debromination product was iso-
lated as a white solid (1203 mg, 94.6%) and confirmed by NMR.
Hydrodebromination of 4-bromoacetophenone (28a):
The reaction mixture of 4-bromoacetophenone (710 mg, 3.6
Hydrodechlorination of 4-chloro-r-methylstyrene 23a:
The reaction mixture of 4-chloro-R-methylstyrene (0.14 mL,
1
.0 mmol), 2-propanol (4.0 mL), K
2
CO
3
(276 m, 2.0 mmol),
Pd(dba)
2
(6 mg, 10 µmol), and ligand D (13 mg, 30 µmol) was
mmol), 2-propanol (4.0 mL), K
2
CO
3
(481 mg, 3.5 mmol),
heated at 80 °C. The reaction was completed within 21.5 h as
determined by GC-MS.
Pd(dba)
2
(2 mg, 3.5 µmol), and ligand D (4 mg, 10 µmol) was
heated at 80 °C. The reaction was completed within 2 h as
determined by GC-MS.
Hydrodechlorination of 4-nitrochlorobenzene (24a):
The reaction mixture of 4-nitrochlorobenzene (168 mg, 1.1
mmol), 2-propanol (4.0 mL), K
2 3 2
CO (276 m, 2.0 mmol), Pd(dba)
(
6 mg, 10 µmol), and ligand D (13 mg, 30 µmol) was heated at
JO048715Y
J. Org. Chem, Vol. 69, No. 25, 2004 8633