Studies in Acyl C-H activation via aryl and alkyl to acyl "through space" migration of palladium

Article abstract of DOI:10.1021/ol900940k

Examples of the 1,4-migration of a palladium moiety in aryl- and alkylpalladium intermediates to the acyl position of an aldehyde or formamide have been observed. The resulting acylpalladium intermediate can undergo ester or carbamate formation by reaction with an alcohol; decarbonylation, followed by β hydride elimination to an alkene; reaction with an organomercurial to form an ester; or alkene insertion. Deuterium-labeling studies have been used to confirm the palladium migration mechanism.

Full text of DOI:10.1021/ol900940k

ORGANIC
LETTERS
2009
Vol. 11, No. 12
2591-2593
Studies in Acyl C-H Activation via Aryl
and Alkyl to Acyl “Through Space”
Migration of Palladium
Tanay Kesharwani,† Akhilesh K. Verma,‡ Daniel Emrich,† Jeffrey A. Ward,† and
Richard C. Larock*,†
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011, and Department
of Chemistry, UniVersity of Delhi, Delhi 110007, India
larock@iastate.edu
Received April 29, 2009
ABSTRACT
Examples of the 1,4-migration of a palladium moiety in aryl- and alkylpalladium intermediates to the acyl position of an aldehyde or formamide
have been observed. The resulting acylpalladium intermediate can undergo ester or carbamate formation by reaction with an alcohol;
decarbonylation, followed by ꢀ hydride elimination to an alkene; reaction with an organomercurial to form an ester; or alkene insertion.
Deuterium-labeling studies have been used to confirm the palladium migration mechanism.
The migration of palladium along an alkyl chain has been
employed for the synthesis of long-chain compounds and
heterocycles.1 This chemistry involves migration of pal-
ladium down a saturated carbon chain by a palladium hydride
elimination/addition sequence until a stable palladium in-
termediate is formed (Scheme 1).
† Iowa State University.
‡ University of Delhi.
(1) (a) Larock, R. C.; Ilkka, S. J. Tetrahedron Lett. 1986, 27, 2211. (b)
Larock, R. C.; Stolz-Dunn, S. K. Tetrahedron Lett. 1989, 30, 3487. (c)
Larock, R. C.; Leung, W. Y. J. Org. Chem. 1990, 55, 6244. (d) Larock,
R. C.; Lu, Y. D.; Bain, A. C.; Russell, C. E. J. Org. Chem. 1991, 56, 4589.
(e) Larock, R. C.; Wang, Y.; Lu, Y.; Russell, C. E. J. Org. Chem. 1994,
59, 8107. (f) Larock, R. C.; Leuck, D. J.; Harrison, L. W. Tetrahedron
Lett. 1987, 28, 4977. (g) Larock, R. C.; Leuck, D. J.; Harrison, L. W.
Tetrahedron Lett. 1988, 29, 6399. (h) Larock, R. C.; Yang, H. Synlett 1994,
748. (i) Larock, R. C.; Yang, H.; Pace, P.; Cacchi, S.; Fabrizi, G.
Tetrahedron Lett. 1998, 39, 237. (j) Larock, R. C.; Yang, H.; Pace, P.;
Cacchi, S.; Fabrizi, G. Tetrahedron Lett. 1998, 39, 1885. (k) Larock, R. C.;
Pace, P.; Yang, H. Tetrahedron Lett. 1998, 39, 2515. (l) Larock, R. C.;
Yang, H.; Pace, P.; Narayanan, K.; Russell, C. E.; Cacchi, S.; Fabrizi, G.
Tetrahedron 1998, 54, 7343. (m) Larock, R. C.; Pace, P.; Yang, H.; Russell,
C. E.; Cacchi, S.; Fabrizi, G. Tetrahedron 1998, 54, 9961.
Scheme 1
Recently, we2 and others3 have reported the “through
space” migration of palladium in o-iodobiaryls, where
palladium migrates from one ring to the other by the apparent
(2) (a) Campo, M. A.; Larock, R. C. J. Am. Chem. Soc. 2002, 124,
14326. (b) Campo, M. A.; Zhang, H.; Yao, T.; Ibdah, A.; McCulla, R. D.;
Huang, Q.; Zhao, J.; Jenks, W. S.; Larock, R. C. J. Am. Chem. Soc. 2007,
129, 6298. (c) Campo, M. A.; Huang, Q.; Yao, T.; Tian, Q.; Larock, R. C.
J. Am. Chem. Soc. 2003, 125, 11506.
(3) Karig, G.; Moon, M.-T.; Thasana, N.; Gallagher, T. Org. Lett. 2002,
4, 3115.
10.1021/ol900940k CCC: $40.75
Published on Web 05/15/2009
 2009 American Chemical Society

formation of a five-membered-ring palladacycle. These
migration reactions provide an alternate way to introduce a
palladium moiety into organic molecules and have been
found to be quite general. Recently, aryl to aryl,2,3 vinylic
to aryl,4 alkyl to aryl,5 aryl to alkyl,6 vinylic to aryl to allylic,7
benzylic to aryl,8 aryl to benzylic,9 and aryl to imidoyl10
migrations have been reported to be a useful tool for the
synthesis of a variety of carbocyclic and heterocyclic ring
systems.
palladium(IV) intermediate 4 or cyclize to palladium(II)
intermediate 5. Intermediate 5 can also be formed by the
loss of HI from intermediate 4. Acylpalladium species 6,
which can be formed from either 4 or 5, can be trapped by
butanol to furnish the corresponding carbamate 2.
The formation of carbamate 2 can also be explained by a
mechanism similar to one first proposed by Wei and co-
workers11 in their esterification-hydroarylation reaction of
2-(1-alkynyl)benzaldehydes (Scheme 4). The intermediate
Herein, we report that an acyl C-H bond can also be
activated under palladium migration reaction conditions to
form carbamates when starting from formamide 1 (Scheme
2). Although there are currently more efficient routes for the
Scheme 4
Scheme 2
synthesis of carbamates, this migration chemistry provides
a unique new route to acylpalladium intermediates of
considerable value in organic synthesis.
A possible mechanism for this palladium migration reac-
tion is outlined in Scheme 3. After oxidative addition of the
3 can produce six-membered ring palladacycle 7 by reaction
of the alcohol at the acyl carbon and nucleophilic displace-
ment of the halide on palladium. Intermediate 7 can undergo
ꢀ-hydride elimination to form arylpalladium intermediate 8,
which can then undergo reductive elimination to generate
carbamate 2.
To further study the mechanism of this reaction, deuterium-
labeled compound 1-D was subjected to our standard
palladium migration conditions, affording 60% incorporation
of deuterium into the ortho position of carbamate 2-D
(Scheme 5). While this experiment establishes the migration
Scheme 3
Scheme 5
of deuterium from an acyl position to an aryl position, the
results are consistent with either of the two proposed
mechanisms. H-D exchange, presumably with the solvent,
accounts for the fact that there is less than 100% deuterium
incorporation in the product.
To better understand the mechanism of these reactions,
we decided to examine the reaction of aldehyde 9 in the
absence of an alcohol nucleophile. If the reaction proceeds
through the mechanism described in Scheme 3, then an
acylpalladium intermediate analogous to 6 should be formed.
aryl halide 1 to Pd(0), the resulting intermediate 3 can insert
palladium into the neighboring acyl C-H bond to form
(4) (a) Larock, R. C.; Tian, Q. J. Org. Chem. 2001, 66, 7372. (b) Tian,
Q.; Larock, R. C. Org. Lett. 2000, 2, 3329. (c) Zhao, J.; Larock, R. C. J.
Org. Chem. 2006, 71, 5340. (d) Zhao, J.; Larock, R. C. Org. Lett. 2005, 7,
701. (e) Bour, C.; Suffert, J. Org. Lett. 2005, 7, 653. (f) Mota, A. J.; Dedieu,
A.; Bour, C.; Suffert, J. J. Am. Chem. Soc. 2005, 127, 7171.
(5) Huang, Q.; Fazio, A.; Dai, G.; Campo, M. A.; Larock, R. C. J. Am.
Chem. Soc. 2004, 126, 7460.
(6) Baudoin, O.; Herrbach, A.; Gueritte, F. Angew. Chem., Int. Ed. 2003,
42, 5736.
(7) Zhao, J.; Campo, M. A.; Larock, R. C. Angew. Chem., Int. Ed. 2005,
44, 1873.
(10) (a) Zhang, X.; Larock, R. C. In Handbook of C-H Transformations;
Dyker, G., Ed.; Wiley-VCH: Weinheim, 2005; p 309. (b) Zhao, J.; Yue,
D.; Campo, M. A.; Larock, R. C. J. Am. Chem. Soc. 2007, 129, 5288.
(11) Wei, L.-L.; Wei, L.-M.; Pan, W.-B.; Wu, M.-J. Synlett 2004, 1497.
(8) Wang, L.; Pan, Y.; Jiang, X.; Hu, H. Tetrahedron Lett. 2000, 41,
725.
(9) Kesharwani, T.; Larock, R. C. Tetrahedron 2008, 64, 6090.
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Org. Lett., Vol. 11, No. 12, 2009

In the absence of a nucleophile, the acylpalladium intermedi-
ate should undergo decarbonylation, followed by ꢀ-hydride
elimination, to give the corresponding styrene derivative 10
(Scheme 6). Indeed, we were pleased to see the formation
carboxaldehydes also afford modest yields of decarbonylation
products. Thus, we obtained olefins 15, 17, and 19 in 42,
41, and 35% yields, respectively, from the corresponding
aldehydes (entries 3-5). Acyclic carboxaldehyde 20 gave
only one stereoisomer 21 in a 33% overall yield (entry 6).
When aldehyde 22 was subjected to our standard reaction
conditions along with 20 equiv of n-BuOH, ester 23 was
formed in 38% yield (entry 7). When 22 was subjected to
reaction conditions developed by Wei and co-workers,11
methyl ester 24 was obtained in a much higher yield of 76%
(entry 8).
Scheme 6
These acyl C-H activation processes appear to be quite
general. For example, the reaction of norbornene,
ClHgCH2CHO, and Li2PdCl4 affords products most consis-
tent with rearrangement of an initially formed aldehyde-
containing norbornylpalladium species to an acylpalladium
species, which can be trapped by reaction with the starting
organomercurial, an excess of norbornene, or an alcohol
(Scheme 7). Deuterium-labeling experiments are consistent
with an alkyl- to acylpalladium rearrangement.
of styrene 10 in a 39% yield. This strongly suggests the
formation of an acylpalladium species, which in turn implies
the migration of palladium from an aryl position to an acyl
position.
We have found that aryl bromide 11 undergoes an
analogous migration/decarbonylation reaction producing 12
in a 33% yield (Table 1, entry 1). The corresponding aryl
iodide affords olefin 12 in a 47% yield (entry 2). Other cyclic
Scheme 7
Table 1. Scope of the Aryl- to Acylpalladium Migrationa
In summary, we have found a unique way of activating
an acyl C-H bond. “Through space” migration of palladium
from an aryl or alkyl position to an acyl position by a five-
membered ring palladacycle results in an acylpalladium
species. The acylpalladium species can be trapped by an
alcohol or in the absence of an alcohol, olefin products result
from decarbonylation, followed by ꢀ-hydride elimination.
Acknowledgment. We thank the National Science Foun-
dation for support of this research and Johnson Matthey, Inc.,
and Kawaken Fine Chemicals Co., Ltd., for donations of
palladium catalysts. A.K.V. is thankful to the Department
of Science and Technology, Government of India, for the
BOYSCAST fellowship.
a Unless otherwise stated, all reactions were performed using 0.5 mmol
of aldehyde, 5 mol % of Pd(OAc)2, 5 mol % of dppm, and 2 equiv of
cesium pivalate in 6 mL of DMF at 110 °C for 12 h. b 20 equiv of n-BuOH
was added under the above-mentioned reaction conditions. c These reactions
were performed using 0.5 mmol of aldehyde, 5 mol % of Pd(PPh3)4, and
1.5 equiv of K2CO3 in 8 mL of MeOH at 65 °C for 24 h.
1
Supporting Information Available: H and 13C NMR
spectra and experimental preparations for all previously
unknown compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
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