Improved carbonylation of heterocyclic chlorides and electronically challenging aryl bromides

Article abstract of DOI:10.1021/ol0498287

Optimized conditions are described that effect the carbonylation of diverse heterocyclic chlorides to yield the desired alkyl esters. In addition, bromoanilines and bromoanisoles, which normally are poor substrates under standard carbonylation protocols, were efficiently converted to the desired products under these new conditions. The nature of the metal bidentate ligand complex was found to be critical. Specifically, a correlation between ligand bite angle and catalytic efficiency is documented.

Full text of DOI:10.1021/ol0498287

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ORGANIC
LETTERS
2004
Vol. 6, No. 13
2097-2100
Improved Carbonylation of Heterocyclic
Chlorides and Electronically Challenging
Aryl Bromides
Jennifer Albaneze-Walker,* Charles Bazaral, Tanya Leavey, Peter G. Dormer, and
Jerry A. Murry
Process Research, Merck Research Laboratories, Merck & Co., Inc., P.O. Box 2000,
Rahway New Jersey 07065
jennifer_albanezewalker@merck.com
Received January 29, 2004
ABSTRACT
Optimized conditions are described that effect the carbonylation of diverse heterocyclic chlorides to yield the desired alkyl esters. In addition,
bromoanilines and bromoanisoles, which normally are poor substrates under standard carbonylation protocols, were efficiently converted to
the desired products under these new conditions. The nature of the metal bidentate ligand complex was found to be critical. Specifically, a
correlation between ligand bite angle and catalytic efficiency is documented.
The quest to activate aryl chloride bonds catalytically has
resulted in notable advances over the past decade.1 The metal-
catalyzed carbonylation of aryl chlorides is of particular
interest, as it provides synthetically useful carbonyl deriva-
tives.2 In addition, the aromatic chlorides are typically less
expensive and often more readily available compared to the
corresponding aromatic bromo, iodo, and triflate derivatives.
Metal catalysts employing bidentate ligands as part of their
coordination complex have been used successfully by both
the Milstein and Beller groups in the carbonylation of
chlorobenzene.3 Milstein et al.3a utilized a bis(diisopropyl
phosphino)propane (dippp) palladium complex, whereas
Beller et al. employed a palladium catalyst generated from
one of the commercially available Josiphos ligands.3b-e
Although these findings represent a significant advance in
the field and effect excellent carbonylation reactions of
simple aryl chlorides, they both have drawbacks. The dippp
ligand is currently not commercially available and can be
difficult to prepare, whereas the Josiphos ligands must be
used in large excess relative to the metal in order to keep
the palladium in solution. We recently required an efficient
(1) (a) Littke, A.; Fu, G. Angew. Chem., Int. Ed. 2002, 41, 4176-4211.
(b) Littke, A.; Schwarz, L.; Fu, G. J. Am. Chem. Soc. 2002, 124, 6343-
6348. (c) Dai, C.; Fu, G. J. Am. Chem. Soc. 2001, 123, 2719-2724. (d)
Littke, A.; Fu, G. J. Org. Chem. 1999, 64, 10-11. (e) LeBlond, C. R.;
Andrews, A. T.; Sun, Y.; Sowa, J. R., Jr. Org. Lett. 2001, 3, 1555-1557.
(f) Koike, T.; Mori, A. Synlett 2003, 12, 1850-1852. (g) Urgaonkar, S.;
Xu, J.-H.; Verkade, J. G. J. Org. Chem. 2003, 68, 8416-8423. (h) Bedford,
R. B.; Cazin, C. J.; Coles, S. J.; Gelbrich, T.; Horton, P. N.; Hursthouse,
M. B.; Light, M. E. Organometallics 2003, 22, 987-999. (i) Stambuli, J.
P.; Kuwano, R.; Hartwig, J. F. Angew. Chem., Int. Ed. 2002, 41, 4746-
4748. (j) Andrus, M. B.; Song, C. Org. Lett. 2001, 3, 3761-3764. (k)
Selvakumar, K.; Zapf, A.; Beller, M. Org. Lett. 2002, 4, 3031-3033. (l)
Remmele, H.; Koellhofer, A.; Plenio, H. Organometallics 2003, 22, 4098-
4103. (m) Spielvogel, D. J.; Davis, W. M.; Buchwald, S. L. Organometallics
2002, 21, 3833-3836. (n) Choudary, B. M.; Madhi, S.; Chowdari, N. S.;
Kantam, M. L.; Sreedhar, B. J. Am. Chem. Soc. 2002, 124, 14127-14136.
(2) (a) Blaser, H.-U.; Diggelmann, M.; Meier, H.; Naud, F.; Scheppach,
E.; Schnyder, A.; Studer, M. J. Org. Chem. 2003, 68, 3725-3728. (b)
Hayashi, T.; Tang, J.; Kato, K. Org. Lett. 1999, 1, 1487-1489. (c) Perry,
R. J.; Wilson, B. D. J. Org. Chem. 1996, 61, 7482-7485. (d) Takeuchi,
R.; Suzuki, K.; Sato, N. J. Mol. Catal. 1991, 66, 277-288. (e) Dufaud, V.;
Thivolle-Cazat, J.; Basset, J.-M. J. Chem. Soc., Chem. Commun. 1990, 426-
427. (f) Crettaz, R.; Wasser, J.; Bessard, Y. Org. Process Res. DeV. 2001,
5, 572-574.
(3) (a) Yehoshua, B.-D.; Portnoy, M.; Milstein, D. J. Am. Chem. Soc.
1989, 111, 8742-8744. (b) Magerlein, W.; Indolese, A. F.; Beller, M.
Angew. Chem., Int. Ed. 2001, 40, 2856-2859. (c) Beller, M.; Magerlein,
W.; Indolese, A. F.; Fischer, C. Synthesis 2001, 1098-1109. (d) J.
Organomet. Chem. 2002, 641, 30-40. (e) Beller, M.; Zapf, A. In Handbook
of Organopalladium Chemistry for Organic Synthesis; Negishi, E., Ed.; John
Wiley & Sons: Hoboken, NJ, 2002. (f) Beller, M.; Magerlein, W.; Indolese,
A. F.; Fischer, C. Synthesis 2001, 7, 1098-1109.
10.1021/ol0498287 CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/26/2004

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carbonylation of a halo-pyridine that would be practical and
amenable for large-scale synthesis. In this manuscript, we
disclose our findings in this regard and specifically document
a correlation between catalyst activity and bidentate ligand
bite angle.
Carbonylation of 2,5-dichloropyridine with 1 mol %
(BINAP)PdCl2 at 50 psig of CO pressure and 100 °C with
triethylamine (2 equiv) in methanol resulted in smooth
transformation to the dimethyl 2,5-dicarboxypyridine in 8 h
(Table 2, entry 2). There was no evidence of palladium black
We initiated a catalyst screening for the carbonylation of
halo-pyridines and noted an exceptional rate enhancement
with the use of the catalyst (rac-BINAP)PdCl2 in comparison
to palladium catalysts containing monodentate ligands. For
example, 2,5-dibromopyridine was dicarbonylated with (rac-
BINAP)PdCl2 to produce dimethyl-2,5-dicarboxypyridine in
99% yield and in only 1 h (Scheme 1).
Table 2. Carbonylation of Heterocyclic Chlorides
Scheme 1
Further screening of catalyst systems containing bidentate
ligands revealed an interesting trend (Table 1). The rate of
Table 1. Effect of Bite Angle on Conversion of
2-Chloropyridine5
a 3 mol% catalyst used.
conversion was markedly dependent upon the bite angle of
the ligand. The most active catalysts were those containing
bidentate phosphine ligands with a natural bite angle near
90°, with the one exception of Xantphos (110°).4 The optimal
ligands for carbonylation of 2-chloropyridine in methanol
under relatively low CO pressure conditions were rac-
BINAP, tol-BINAP, dppp, and Xantphos.
(rac)-BINAP is readily available, air-stable, and one of
the least expensive bidentate ligands. We decided to explore
the capabilities of (BINAP)PdCl2 as a carbonylation catalyst
for more challenging substrates: aromatic chlorides and
electron-rich aromatic bromides.
deposition during the course of the reaction, which indicates
the excellent stability of this catalyst system, and no reduced
pyridine products were noted.
Methanol was an adequate solvent; it was not necessary
to use the more CO-solubilizing solvent n-butanol.6 Attempts
to extend the scope of these conditions to chlorobenzene with
(BINAP)PdCl2 failed; however, other heterocyclic substrates
underwent good conversion to provide the desired ester
products. The carbonylation of 2,3-dichloropyridine (entry
(5) For a definition of natural bite angle see: Casey, C. P.; Whiteker,
G. T. Isr. J. Chem. 1990, 30, 299-304.
(6) For a comparative study of solubility of CO in alcohols, see: Tonner,
S. P.; Wainwright, M. S.; Trimm, D. L. J. Chem. Eng. Data 1983, 28,
59-61.
(4) Xantphos has been shown capable of both cis and trans coordination
modes. See: Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043-
6048. (b) Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Reek, J. N. H. Acc.
Chem. Res. 2001, 34, 895-904.
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3) was notably slower than that of 2,5-dichloropyridine (entry
2). 3-Chloropyridine is an exception (entry 4), as it was inert
under our conditions. Reaction of 2-fluoro-3-chloro-5-tri-
fluoromethylpyridine (entry 5) returned two products. The
major product was the expected 3-carboxypyridine com-
pound. The minor product, surprisingly, was the 2,3-dicar-
boxypyridine compound. The minor product is not formed
from the major, as resubjecting the major product to the
carbonylation conditions did not generate the minor product.
It is likely that a chloride ion in the reaction solution dis-
placed the fluoride at the 2-position of the pyridine ring,
followed by carbonylation at that position.
Carbonylation of bromoaniline substrates is difficult and
is usually accomplished by amine protection to modulate the
electron density of the aniline ring.7 Employing the mild
(BINAP)PdCl2 conditions, both o-bromoaniline and m-bro-
moaniline were smoothly transformed to the corresponding
esters in excellent yields overnight (Table 3). The conversion
aryl group and subsequent generation of the acyl palladium
complex. The acyl complex then reacts with a nucleophile
such as an alcohol or amine to give ester or amide products.9
Although the mechanism involving a palladium catalyst
containing a rigid bisphosphine bidentate ligand could occur
similarly, it would be less entropically favored for one of
the phosphines to dissociate completely.10 This suggests that
the carbonylation involving the bisphosphine ligands may
proceed via an alternate mechanism. A few possible path-
ways are outlined below and summarized in Scheme 2.
Scheme 2
Table 3. Carbonylation of Bromoanilines and Bromoanisoles
As in the standard mechanism, the process is initiated with
reduction of I to produce a reactive Pd(0) complex II, which
oxidatively adds to the Ar-X bond to generate complex III
(Scheme 2). At this point, CO may interact with III either
axially or equatorially. The axial approach to III leads to a
five-coordinate complex IV, reminiscent of the interaction
between CO and Vaska’s complex.11 The ∼90° ligand bite
angle is optimized for the square pyramidal geometry of IV.
Aryl migration to CO restores the square planar geometry
as the acyl complex.
The equatorial approach requires some reorganization of
ligands around the metal center, resulting in complexes of
the general type V, VI, and VII.
of p-bromoaniline was more sluggish and only 50% complete
at 48 h. Bromoanisoles were also cleanly carbonylated to
produce methoxybenzoic esters in excellent yields. o-Bro-
moanisole and p-bromoanisole both performed equally well
under these mild conditions.
The mechanism of palladium-catalyzed carbonylation reac-
tions employing monodentate ligands has been investigated
by several groups.8 The mechanism often invoked requires
a dissociation of one of the phosphine ligands to provide
the coordinatively unsaturated metal complex followed by
ligation to carbon monoxide, followed by migration of the
(8) (a) Schoenberg, A.; Bartoletti, I.; Heck, R. F. J. Org. Chem. 1974,
39, 3318-3326. (b) Stille, J. K.; Wong, P. K. J. Org. Chem. 1975, 40,
532-534. (c) Garrou, P. E.; Heck, R. F. J. Am. Chem. Soc. 1976, 98, 4115-
4127. (d) Moser, W. R.; Wang, A. W.; Kjeldahl, N. K. J. Am. Chem. Soc.
1988, 110, 2816-2820.
(9) (a) Milstein, D. Acc. Chem. Res. 1988, 21, 428-434. (b) Ozawa, F.;
Kawasaki, N.; Okamoto, H.; Yamamoto, T.; Yamamoto, A. Organometallics
1987, 6, 1640-1651. (c) Lin, Y.-S.; Yamamoto, A. Organometallics 1998,
17, 3466-3478. (d) van Leeuwen, P. W. N. M.; Zuideveld, M. A.;
Swennenhuis, B. H. G.; Freixa, Z.; Kamer, P. C. J.; Goubitz, K.; Fraanje,
J.; Lutz, M.; Spek, A. L. J. Am. Chem. Soc. 2003, 125, 5523-5539.
(10) (a) One example of monodentate coordination of BINAP has been
reported for an osmium cluster: Prestopino, F.; Persson, R.; Monari, M.;
Focci, N.; Nordlander, E. Inorg. Chem. Commun. 1998, 302-304. (b) For
an example of carbonylation of neutral palladium complexes containing
hemi-labile bidentate ligands, see: Frankcombe, K.; Cavell, K.; Knott, R.;
Yates, B. Chem. Commun. 1996, 781-782.
(7) Mahmud, H.; Lovely, C. J.; Dias, H. V. R. Tetrahedron 2001, 57,
4095-4105. (b) Lovely, C. J.; Mahmud, H. Tetrahedron Lett. 1999, 40,
2079-2082. (c) Torisawa, Y.; Nishi, T.; Minamikawa, J.-I. Bioorg. Med.
Chem. Lett. 2000, 10, 2493-2495. (d) Lapidus, A. L.; Petrovskii, K. B.;
Bruk, L. G.; Beletskaya, I. P. Russ. J. Org. Chem. 1999, 35, 1636-1639.
(e) Yun, W.; Li, S.; Wang, B.; Chen, L. Tetrahedron Lett. 2001, 42, 175-
177. (f) Cai, M.-Z.; Song, C.-S.; Huang, X. Synth. Commun. 1997, 27, 361-
366. (g) Devi, R.; Pardhasaradhi, M.; Iyengar, D. S. Tetrahedron 1994, 50,
2543-2550. (h) Davies, S. G.; Goodwin, C. J.; Pyatt, D.; Smith, A. D. J.
Chem. Soc., Perkin Trans. 1 2001, 1413-1420.
(11) (a) Vaska, L. J. Am. Chem. Soc. 1966, 88, 4100-4101. (b) Abu-
Hasanayn, F.; Krogh-Jerspersen, K.; Goldman, A. S. J. Am. Chem. Soc.
1994, 116, 5979-5980. (c) Aullon, G.; Alvarez, S. Inorg. Chem. 1996, 35,
3137-3144. (d) Kanzelberger, M.; Zhang, X.; Emge, T. J.; Goldman, A.
S.; Zhao, J.; Incarvito, C.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125,
13644-13645.
Org. Lett., Vol. 6, No. 13, 2004
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Trigonal bipyramidal complexes of Pd and Pt have been
described and have been postulated as intermediates in
reaction pathways.12 The coordinatively saturated intermedi-
ate V offers several advantages. For d8 metals, electron
density is greater in the xy plane than along the z axis in the
trigonal pyramidal geometry, and so bond formation should
be favored in the equatorial plane with back-bonding ligands
such as CO. To accommodate the incoming equatorial CO
ligand, the σ-donating Ar and X groups are both pushed out
of the plane. The axial σ-donating Ar and X ligands may
exert a stabilizing influence on the trigonal pyramidal
Pd(II) complex. The lability of the axial Ar group makes
migration facile. The preference for equatorial ligation of
good back-bonding ethylene ligands and the stabilizing
influence of the axial Ar group is precedented for trigonal
bipyramidal complexes (analogous to V) arising from the
analogous square planar Pd(II) and Pt(II) complexes contain-
ing chelating ligands with small bite angles.13
group may not necessarily come in cis to the Ar group as
drawn in Scheme 2. A trans arrangement would require
reorganization to enable migration and acyl complex forma-
tion. Complexes IV, V, and VII enforce the requisite cis
geometry. Complex VI may not be a productive intermediate
for the carbonylation reaction with bidentate ligands.
The cationic complex VII maintains the preferred square
planar geometry. Presumably VII is formed through a five-
coordinate intermediate where CO replaces the X group.
Although cationic Pd(II) complexes have been shown to be
very active catalysts for polymerization reactions of CO with
ethylene, preliminary experiments show minimal effects due
to changes of the counterion. After migration, an open
coordination site is filled by the returning X, which recon-
stitutes the square planar geometry. Studies are underway
to determine which pathway(s) is operative for our system.
In conclusion, we have developed the use of (BINAP)-
PdCl2 as an air-stable and robust carbonylation catalyst for
various heteroaromatic chlorides, as well as for electronically
challenging bromides. (BINAP)PdCl2 is simple to prepare,
relatively inexpensive, and stable to air. The conditions for
carbonylation are relatively mild (50 psig CO, 100 °C, and
a slight excess of tertiary amine base) and provide products
in good to excellent yields. (BINAP)PdCl2 is a practical and
economical alternative for the carbonylation of several
heterocyclic chlorides and aromatic bromides. We are
currently engaged in studies to elucidate the mechanism of
the carbonylation and identity of the active intermediates.
Complex VI arises from one of the phosphines of the
bidentate ligand moving into the axial position as CO
approaches. Here clearly, a ∼90° bite angle could stabilize
the intermediate. However, in complexes of type VI, the CO
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(b) Frankcombe, K.; Cavell, K.; Knott, R.; Yates, B. Organometallics 1997,
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G.-L.; Shu, B.-C.; Huang, T.-M.; Chen, Y.-S.; Lee, G.-H.; Cheng, M.-C.;
Wang, C.-C.; Wang, Y. Organometallics 1994, 13, 4804-4824. (d) Bryndza,
H. Organometallics 1985, 4, 1686-1687. (e) Macgregor, S.; Neave, G.
W. Organometallics 2003, 22, 4547-4556. (f) Anderson, G. K.; Cross, R.
J. Acc. Chem. Res. 1984, 17, 67-74. (g) Fanizzi, F. P.; Maresca, L.; Pacifico,
C.; Natile, G.; Lanfranchi, M.; Tiripicchio, A. Eur. J. Inorg. Chem. 1999,
1351-1358. (h) De Felice, V.; Albano, V. G.; Castellari, C.; Cucciolito,
M. E.; De Renzi, A. J. Organomet. Chem. 1991, 403, 269-277.
(13) (a) Albano, V. G.; Castellari, C.; Cucciolito, M. E.; Panunzi, A.;
Vitagliano, A. Organometallics 1990, 9, 1269-1276 and references therein.
(b) Maresca, L.; Natile, G. Comments Inorg. Chem. 1993, 14, 349-366
and references therein.
Supporting Information Available: Experimental details
and characterization data details. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL0498287
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