Productive utilization of chlorobenzene: Palladium-catalyzed selective oxidation of alcohols

Article abstract of DOI:10.1021/ol0347287

(Matrix presented) The palladium/ligand-catalyzed activation of chlorobenzene provides a general, efficient, and functional group friendly method for the selective oxidation of alcohols to carbonyl compounds.

Full text of DOI:10.1021/ol0347287

ORGANIC
LETTERS
2
003
Vol. 5, No. 14
485-2487
Productive Utilization of Chlorobenzene:
Palladium-Catalyzed Selective Oxidation
of Alcohols
2
Anil S. Guram,* Xiaohong Bei,* and Howard W. Turner
Symyx Technologies, Inc., 3100 Central Expressway, Santa Clara, California 95051
aguram@symyx.com; xbei@symyx.com
Received May 1, 2003
ABSTRACT
The palladium/ligand-catalyzed activation of chlorobenzene provides a general, efficient, and functional group friendly method for the selective
oxidation of alcohols to carbonyl compounds.
2
The oxidation of alcohols to carbonyl compounds is one of
the most significant and widely used methods in organic
syntheses. Consequently, many oxidation reaction methods
be comparatively inert and hence of limited value. Recently,
the productive utilization of chloroarenes has been the subject
1
3
of intense investigations. These pioneering studies have
have been developed. Oxidation methods based on [O]-
containing oxidants, e.g., air, O , H O , metal oxides, NaOCl,
2 2 2
contributed enormously to the understanding of general
principles for the activation and functionalization of chloro-
arenes. In particular, the cross-coupling reactions of chloro-
and DMSO, are common and widely developed. But,
oxidation methods based on non-[O]-containing oxidants are
comparatively less common and underdeveloped. The de-
velopment of economical and efficient oxidation methods
based on non-[O]-containing oxidants are of potential
academic and industrial significance, particularly for the
oxidation of substrates with oxygen sensitive functionalities.
Herein, we describe a general palladium/ligand-catalyzed
chlorobenzene activation reaction that provides an economi-
cal, efficient, and functional group friendly method for the
selective oxidation of alcohols to carbonyl compounds.
Chloroarenes are readily available and inexpensive and,
therefore, represent attractive feedstock for commercial
applications. Historically, chloroarenes have been found to
3
arenes have been significantly advanced.
High-throughput methods at Symyx Technologies were
previously employed for the development of efficient cross-
4
coupling reactions of chloroarenes. These reactions required
precise combinations of catalysts and reaction conditions.
Dramatic inefficiencies resulted from less than optimum
reaction conditions. Hydrodechlorination of the chloroarenes
was one of the common inefficiencies observed particularly
(2) Grushin, V. V.; Alper, H. Chem. ReV. 1994, 94, 1047-1062.
(3) 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.,
Int. Ed. 1998, 37, 2046-2067. (c) Beletskaya, I. P. Chem. ReV. 2000, 100,
3
3
3
009-3066. (d) Grushin, V. V.; Alper, H. Top. Organomet. Chem. 1999,
, 193-226. (e) Riermeier, T. H.; Zapf, A.; Beller, M. Top. Catal. 1997, 4,
01-309.
(1) (a) Hudlicky, M. Oxidations in Organic Chemistry; ACS Monograph
(4) (a) Bei, X.; Uno, T.; Norris, J.; Turner, H. W.; Weinberg, W. H.;
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, 157-166.
Guram, A. S. Organometallics 1999, 18, 1840-1853. (b) Bei, X.; Turner,
H. W.; Weinberg, W. H.; Guram, A. S. J. Org. Chem. 1999, 64, 6797-
6803. (c) Bei, X.; Guram, A. S.; Turner, H. W.; Weinberg, W. 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.
1
0.1021/ol0347287 CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/19/2003

in the C-N and C-O cross-coupling reactions of chloro-
arenes with primary/secondary amines and alcohols, respec-
tively. Mechanistically, this inefficiency most likely resulted
2
Table 1. Pd(dba) /Ligand 1-Catalyzed Selective Oxidations of
Benzylic Alcoholsa
from â-hydrogen elimination from a L
n
Pd(Ar)(XR) (R )
CHR R ; X ) NR , O) intermediate, followed by reductive
elimination of ArH from a L Pd(Ar)(H) intermediate
Scheme 1). The formation of imine and aldehyde/ketone
1
2
3
n
(
byproducts in C-N and C-O cross-coupling reactions,
respectively, is also supported by this mechanistic hypothesis
(Scheme 1).
Scheme 1. Reductive and â-Hydrogen Elimination Pathways
High-throughput methods were now employed to exploit
the hydrodechlorination inefficiency of C-O cross-coupling
reactions for the development of an economical and efficient
palladium/ligand-catalyzed method for the selective oxidation
of alcohols to aldehydes and ketones.5 Chlorobenzene was
chosen as an inexpensive and industrially viable oxidant for
this study. The palladium/ligand-catalyzed reactions of
chlorobenzene with alcohols were investigated using our
computer-controlled automated manipulations of reaction
,6
7
components. It was observed that the reactions were
particularly influenced by the nature of the phosphine ligands
and bases. The recently described Buchwald ligand, 2-(di-
8
cyclohexylphosphino)biphenyl (1), and bases such as
t
K
3
PO
efficient.
The Pd(dba)
chlorobenzene-based selective oxidation reaction of a wide
4
, K
2
CO
3
, and NaO Bu were found to be the most
a
Unless otherwise indicated, the reactions were performed in toluene at
2
/ligand 1 catalyst efficiently catalyzed the
1
05 °C. Molar equivalents of the reagents and catalyst were as follows:
ROH (1.0 mmol), C6H5Cl (1.5 mmol), base (2.0 mmol), Pd(dba)2 (1.0 mol
), and ligand 1 (3.0 mol %). Reaction times were not optimized and ranged
9
%
2 3
variety of alcohols (Tables 1 and 2). The bases, K CO and
from 4 to 48 h. Yields correspond to isolated product of >95% purity by
1
GCMS and H NMR. Additional general experimental details including
(
5) Palladium-catalyzed oxidations based on chlorohydrocarbons: (a)
reaction times are provided in the Supporting Information. b Reaction
performed at 80 °C. c Reaction performed in xylene at 130 °C. d Reaction
performed at 100 °C. e Reaction performed at 110 °C.
Tamaru, Y.; Yamamoto, Y.; Yamada, Y.; Yoshida, Z. Tetrahedron Lett.
1
979, 1401-1404. (b) Tamaru, Y.; Yamada, Y.; Inoue, K.; Yamamoto,
Y.; Yoshida, Z. J. Org. Chem. 1983, 48, 1286-1292. (c) Nagashima, H.;
Tsuji, J. Chem. Lett. 1981, 1171-1172. (d) Zask, A.; Helquist, P. J. Org.
Chem. 1978, 43, 1619-1620. (e) Poetsch, E.; Lannert, H. Chem. Abstr.
1
996, 124, 145502d. (f) Bouquillon, S.; Henin, F.; Muzart, J. Organome-
3 4
K PO , were found to be most suitable for the oxidation of
tallics 2000, 19, 1434-1437.
primary and secondary benzylic alcohols. Primary and
secondary benzylic alcohols containing both electron-
withdrawing and electron-donating substituents reacted ef-
ficiently to afford the desired carbonyl compounds in high
isolated yields. Notably, oxygen-sensitive functionalities such
(6) Leading references for palladium-catalyzed oxidations based on
O-containing oxidants: (a) Blackburn, T. F.; Schwartz, J. J. Chem. Soc.,
Chem. Commun. 1977, 157-158. (b) Petersen, K. P.; Larock, R. C. J. Org.
Chem. 1998, 63, 3185-3189. (c) Nishimura, T.; Onoue, T.; Ohe, K.;
Uemura, S. J. Org. Chem. 1999, 64, 6750-6755. (d) Nagashima, H.; Tsuji
J. Bull. Chem. Soc. Jpn. 1981, 1171-1172. (e) Tsuji, J.; Nagashima, H.;
Sato, K. Tetrahedron Lett. 1982, 23, 3085-3088. (f) Kakiuchi, N.; Maeda,
Y.; Nishimura, T.; Uemura, S. J. Org. Chem. 2001, 66, 6620-6625.
2
as -CdC, -SR, and -NR were compatible and not
(
7) Details of high-throughput methods and additional experimental
results will be reported separately in a full article.
8) Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J. Am.
Chem. Soc. 1999, 121, 9550-9561.
9) Typical Experimental Procedure. A mixture of 4,4′-diflouroben-
purge cycles. Chlorobenzene (0.15 mL, 1.33 mmol) and toluene (4 mL)
were added, and the mixture was heated at 105 °C for 12 h. The reaction
mixture was taken up in ether (100 mL) and washed with H2O (30 mL)
and brine (30 mL). The organic phase was dried over MgSO4, filtered, and
concentrated under vacuum. The crude product was purified by column
chromatography on silica gel to afford 4,4′-diflourobenzophenone as an
off-white solid (215 mg, 98%) after drying under vacuum.
(
(
zhydrole (220 mg, 1.0 mmol), K2CO3 (276 mg, 2.0 mmol), Pd(dba)2 (6
mg, 10 µmol), and ligand 1 (10 mg, 30 µmol) was loaded into a Schlenk
reaction tube. The mixture was thoroughly degassed using vacuum and argon
2486
Org. Lett., Vol. 5, No. 14, 2003

reactions. It is remarkable that these sterically crowded
substrates favor the â-hydrogen elimination process over the
C-O reductive elimination process.
2
Table 2. Pd(dba) /Ligand 1-Catalyzed Oxidations of Sterically
1
2
Hindered Aliphatic Alcoholsa
In summary, we have developed a general palladium/
ligand-catalyzed chlorobenzene activation reaction that pro-
vides an economical, efficient, and functional group friendly
method for the selective oxidation of primary and secondary
alcohols. The chlorobenzene-based oxidation is economically
2 2 3
comparable to the popular DMSO, NaOCl, H O , and CrO
oxidant based oxidations, but precludes functional group
tolerance, selectivity, and hazard issues related to the DMSO,
1
H
2
O
2
, O
2
, NaOCl, and CrO
3
based oxidations. The utility
of this reaction in the oxidation of other commercially
significant alcohols, general oxidation of aliphatic alcohols,
kinetic resolution of racemic alcohols, and the desymmetri-
zation of meso-diols is currently being investigated.
a
The reactions were performed in toluene at 105 °C using molar
equivalents of reagents and catalyst as follows: ROH (1.0 mmol), C6H5Cl
1.5 mmol), base (2.0 mmol), Pd(dba)2 (0.2 mol %), and ligand 1 (0.6 mol
). Yields correspond to GC yields at a reaction time of 2 h.
(
%
Acknowledgment. We thank Dr. Alfred Hagemeyer, Dr.
Tetsuo Uno and Dr. Damodara Poojary for insightful
discussions and suggestions.
affected under these oxygen-free oxidation reaction condi-
tions (entries 7, 9, and 10; Table 1). The oxidation of 2,2′-
hydroxymethylbiphenyl resulted in the formation of the
lactone product in high isolated yield (entry 11; Table 1).
The formation of the lactone product most likely proceeded
in sequential steps, which presumably included palladium/
ligand-catalyzed oxidation of one of the alcohol functionality
to an aldehyde functionality, intramolecular reaction of the
newly formed aldehyde functionality with the remaining
alcohol functionality to form a hemiacetal intermediate, and
palladium/ligand-catalyzed oxidation of the hemiacetal in-
termediate to the lactone product.
Supporting Information Available: Details of experi-
mental procedures. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL0347287
(10) These intermediates are of significance as perfume additives in the
fragrance industry; see: (a) Naarden & Shell Aroma Chemicals. German
Patent Application DE 2,945,812, 1980. (b) Kao Corp. Japanese Patent
Application JP 92-77446, 1992.
(11) The Pd/L-catalyzed oxidation of sterically less hindered aliphatic
alcohols was not rigorously investigated or optimized. Aldol reaction induced
inefficiencies were observed in preliminary studies. However, it is
anticipated that such inefficiencies could be alleviated under optimized
reaction conditions.
2
The Pd(dba) /ligand 1 catalyst was also found to be
efficient in catalyzing the oxidation of sterically hindered
t
aliphatic alcohols. The base, NaO Bu, was found to be most
(12) Steric factors are known to favor the reductive elimination process;
suitable for these reactions. Thus, the sterically hindered
bicyclic alcohols reacted efficiently to afford the desired
industrially significant ketones10 in high yields (Table 2).
High catalyst turnover frequencies were observed in these
see: (a) Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1997,
1
3
19, 3395-3396. (b) Jones, W. D.; Kuykendall, V. L. Inorg. Chem. 1991,
0, 2615-2622. For pioneering studies of C-O bond forming reductive
11
elimination from nickel complexes, see: (c) Han, R.; Hillhouse, G. L. J.
Am. Chem. Soc. 1997, 119, 8135-8136.
Org. Lett., Vol. 5, No. 14, 2003
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