Heck-Type Arylation of 2-Cycloalken-1-ones with Arylpalladium Intermediates Formed by Decarboxylative Palladation and by Aryl Iodide Insertion

Article abstract of DOI:10.1021/ol0363467

(Matrix presented) A palladium-catalyzed decarboxylative arylation reaction was shown to produce Heck-type coupling products using a number of different arene carboxylic acid and 2-cycloalken-1-one substrates. The more conventional Heck coupling of an aryl iodide and a 2-cycloalken-1-one reactant was also briefly explored for comparison, where it was found that phosphine-free (Jeffery) conditions afforded the highest yield of product.

Full text of DOI:10.1021/ol0363467

ORGANIC
LETTERS
2
004
Vol. 6, No. 3
33-436
Heck-Type Arylation of
-Cycloalken-1-ones with Arylpalladium
4
2
Intermediates Formed by
Decarboxylative Palladation and by Aryl
Iodide Insertion
Daisuke Tanaka and Andrew G. Myers*
Department of Chemistry and Chemical Biology, HarVard UniVersity,
Cambridge, Massachusetts, 02138
myers@chemistry.harVard.edu
Received December 2, 2003
ABSTRACT
A palladium-catalyzed decarboxylative arylation reaction was shown to produce Heck-type coupling products using a number of different
arene carboxylic acid and 2-cycloalken-1-one substrates. The more conventional Heck coupling of an aryl iodide and a 2-cycloalken-1-one
reactant was also briefly explored for comparison, where it was found that phosphine-free (Jeffery) conditions afforded the highest yield of
product.
The Heck reaction, traditionally defined as the palladium-
catalyzed coupling of an aryl halide with an olefinic substrate
partners. The literature of the Heck reaction is dominated
by couplings of derivatives of styrene and acrylic acid,
substrates that are known to react with particular efficiency.
By contrast, successful Heck couplings with R,â-unsaturated
(forming a conjugated arene and hydrogen halide as prod-
ucts), is among the most useful carbon-carbon bond-forming
1
4
processes in synthesis. Since its inception, many new
ketones as substrates are relatively rare, and efficient Heck-
type couplings of 2-cycloalken-1-ones are almost unknown.5
-7
developments related to the Heck reaction have been
reported, leading to improvements in the catalytic efficiency
of the process and to the introduction of enantioselective
With these substrate classes, a conjugative addition process
7
,8
has been reported to occur instead. In the case of small-
2
variants of the Heck reaction. Although the pool of viable
aryl halide coupling partners in the Heck reaction has
effectively been expanded as a result of the exploration of
new ligand systems,1 less has been achieved with respect
to broadening the diversity of potential olefinic coupling
(4) (a) Jeffery, T. J. Chem. Soc., Chem. Commun. 1984, 1287-1289.
(
b) Arcadi, A.; Marinelli, F.; Cacchi, S. J. Organomet. Chem. 1986, 312,
C27-C32. (c) Amorese, A.; Arcadi, A.; Bernocchi, E.; Cacchi, S.; Cerrini,
S.; Fedeli, W.; Ortar, G. Tetrahedron 1989, 45, 813-828. (d) Larock, R.
C.; Lee, N. H. J. Org. Chem. 1991, 56, 6253-6254. (e) Arcadi, A.; Cacchi,
S.; Fabrizi, G.; Marinelli, F.; Pace, P. Tetrahedron 1996, 52, 6983-6996.
b,3
(
f) Hagiwara, H.; Eda, Y.; Morohashi, K.; Suzuki, T.; Ando, M.; Ito, N.
(
1) Recent reviews: (a) Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV.
000, 100, 3009-3066. (b) Whitcombe, N. J.; Hii, K. K.; Gibson, S. E.
Tetrahedron 2001, 57, 7449-7476.
2) Recent reviews: (a) Shibasaki, M.; Boden, C. D. J.; Kojima, A.
Tetrahedron Lett. 1998, 39, 4055-4058. (g) Cacchi, S.; Fabrizi, G.;
Gasparrini, F.; Villani, C. Synlett 1999, 345-347. (h) Kondolff, I.; Doucet,
H.; Santelli, M. Tetrahedron Lett. 2003, 44, 8487-8491.
(5) (a) Genet, J. P.; Blart, E.; Savignac, M. Synlett 1992, 715-717. (b)
Gelpke, A. E. S.; Veerman, J. J. N.; Goedheijt, M. S.; Kamer, P. C. J.; van
Leeuwen, P. W. M. N.; Hiemstra, H. Tetrahedron 1999, 55, 6657-6670.
(c) Costa, A.; Najera, C.; Sansano, J. M. J. Org. Chem. 2002, 67, 5216-
5225.
2
(
Tetrahedron 1997, 53, 7371-7395. (b) Dounay, A. B.; Overman, L. E.
Chem. ReV. 2003, 103, 2945-2963.
(3) Review: Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41,
4
176-4211.
1
0.1021/ol0363467 CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/09/2004

to medium-ring 2-cycloalken-1-ones, this is perhaps not
unexpected, in light of the fact that such substrates are
precluded stereochemically from undergoing the final step
both with respect to the arene carboxylic acid substrate (Table
1) and potential 2-cycloalken-1-one reactants (Table 2).
in the traditional Heck process, syn â-hydride elimination
1
(
following cis arylpalladium addition). Thus, the formation
Table 1. Decarboxylative Heck-Type Couplings of
a
of vinylic substitution products, which we refer to here as a
Heck-type” process, requires some variation in the tradi-
tional Heck mechanism, such as the invocation of an anti
2-Cyclohexen-1-one with Various Arene Carboxylic Acids
“
9,10
â-hydride elimination reaction, stereochemical inversion
of a C-Pd bond,5
a,6d,7b,c
or the like. We are aware of selected
cases of intramolecular Heck-type carbon-carbon bond
7
formations within 2-cycloalken-1-one-aryl iodide substrates,
but it is fair to say that no efficient procedure for inter- or
intramolecular Heck-type coupling reactions of 2-cycloalken-
1
-ones is in common use today, if at all.11
Our interest in Heck-type coupling reactions of 2-cy-
loalken-1-ones arose in the context of investigations of a
decarboxylative palladation of arene carboxylic acids, a
process that typically led to the formation of Heck-type
coupling products when an alkene was present in the reaction
1
2
mixture (eq 1). We were surprised to find that 2-cyclo-
hexen-1-one was a viable olefinic coupling partner in
decarboxylative Heck-type couplings, although only two
substrates (2,4-dimethoxybenzoic acid and mesitylene car-
1
2
boxylic acid) were investigated in our initial studies.
Byproducts arising from conjugative aryl addition were not
observed. Recognizing the potential utility that a general
process for Heck-type coupling reactions of 2-cycloalken-
1-ones might hold, we initiated a study to determine the scope
of the decarboxylative palladation coupling process and also
briefly explored more traditional Heck-type couplings using
aryl halides as coupling partners, to assess the relative merits
of the two processes, as detailed below.
We began our study by exploring the scope of the
palladium-catalyzed decarboxylative Heck-type coupling,
(6) Examples of intramolecular Heck-type couplings of 4-pyridones: (a)
Grigg, R.; Fretwell, P.; Meerholtz, C.; Sridharan, V. Tetrahedron 1994,
5
0, 359-370. (b) Comins, D. L.; Joseph, S. P.; Zhang, Y. Tetrahedron
Lett. 1996, 37, 793-796. (c) Yoneda, R.; Kimura, T.; Kinomoto, J.;
a
Conditions: carboxylic acid (1.0 mmol), 2-cycloalken-1-one (1.5
Harusawa, S.; Kurihara, T. J. Heterocycl. Chem. 1996, 33, 1909-1913.
mmol), Pd(O2CCF3)2 (0.2 mmol), Ag2CO3 (2.0 equiv), 5% DMSO-DMF.
(
2
4
d) Kirschbaum, S.; Waldmann, H. Tetrahedron Lett. 1997, 38, 2829-
b
These coupling reactions were reported in a previous publication (ref 12),
832. (e) Kirschbaum, S.; Waldmann, H. J. Org. Chem. 1998, 63, 4936-
c
but using 3.0 equiv of Ag2CO3, not 2.0 equiv, as presented here. All yields
946.
refer to isolated, pure products.
(7) (a) Zhang, Y.; O’Conner, B.; Negishi, E. J. Org. Chem. 1988, 53,
5
588-5590. (b) Friestad, G. K.; Branchaud, B. P. Tetrahedron Lett. 1995,
3
6, 7047-7050. (c) Ikeda, M.; Hirose, K.; El Bialy, S. A. A.; Sato, T.;
Yakura, T.; Bayomi, S. M. M. Chem. Pharm. Bull. 1998, 46, 1084-1089.
Critical reaction parameters previously identified, including
the catalyst (palladium(II) trifluoroacetate, 0.2 equiv) and
solvent (5% DMSO-DMF) remained the same in this study,
but the amount of silver(I) carbonate employed in the reaction
was reduced from 3.0 to 2.0 equiv; additional details of the
coupling procedures for specific substrates (time, tempera-
ture) appear in Table 1. As summarized in Table 1,
carboxylic acids that had been shown to undergo decarboxy-
lative coupling with styrene and butyl acrylate were found
to couple efficiently with the much more demanding reactant
(
8) Cacchi, S. Pure Appl. Chem. 1990, 62, 713-722.
(
9) Lautens, M.; Fang, Y.-Q. Org. Lett. 2003, 5, 3679-3682 and
references therein.
(
10) Review: Ikeda, M.; El Bialy, S. A. A.; Yakura, T. Heterocycles
999, 51, 1957-1970.
11) Heck-type coupling reactions of aryl halides with 2-cycloalken-1-
1
(
ones have been reported in the patent literature, without mention of coupling
efficiency. We have not obtained more than 30% yield in the coupling of
-bromobenzonitrile with 2-cyclohexen-1-one by the method reported in
the following patent reference (two attempts): Sucrow, W.; Fiedel, D.;
Poetsch, E.; R a¨ decker, G. German Patent DE 3827675, Aug 16, 1988.
1
3
4
(12) Myers, A. G.; Tanaka, D.; Mannion, M. R. J. Am. Chem. Soc. 2002,
1
24, 11250-11251.
434
Org. Lett., Vol. 6, No. 3, 2004

2
-cyclohexen-1-one as well. Among carboxylic acids we
examined were bromo- and nitro-substituted examples
entries 5 and 6, respectively) and many sterically hindered
(entries 1 and 2), 6 (entries 4-6 and Table 1), and 7 (entry
3) were all effective substrates. Furthermore, the reaction
appears to be tolerant of at least moderate steric encumbrance
within the 2-cycloalken-1-one reactants, for 4-isopropyl-2-
cyclohexen-1-one was found to couple as effectively as
2-cyclohexen-1-one (cf. entry 1, Table 1, with entry 4, Table
2, and entry 8, Table 1, with entry 5, Table 2), although
4,4-dimethyl-2-cyclohexen-1-one was less effective as a
substrate (entry 6, Table 2). We explored only one reactant
with substitution in the 2-position (2-methyl-2-cyclopenten-
(
substrates (entries 2, 3, and 5). The tolerance of the
decarboxylative palladation reaction to o,o′-disubstitution is
one of its more interesting features; at least one ortho
substituent appears to be required for decarboxylative pal-
1
2
ladation to occur. Results summarized in Table 2 suggest
1
-one), in which case none of the expected coupling product
Table 2. Decarboxylative Heck-Type Couplings with a Range
of 2-Cycloalken-1-one Reactantsa
was obtained. Rather, the double addition products 2 and 3
were isolated (24 and 5% yield, respectively).14 These
products are believed to arise by â-hydride elimination
(toward the methyl group) after initial cis arylpalladium
addition; a subsequent cis arylpalladium addition-â-hydride
elimination sequence then gives rise to 2 and 3 (Scheme 1).15
Scheme 1
To better assess the significance of the present findings,
we conducted a brief survey of conditions to achieve a similar
bond construction by using the more traditional Heck
reaction, initially investigating the coupling of 2,4-dimethoxy-
1-iodobenzene with 2-cyclohexen-1-one, which, if successful,
would form the same product that we had prepared by
decarboxylative coupling (entry 1, Table 1, 92% yield). This
was a demanding test case, for electron-rich aryl halides are
known to be poor substrates in conventional Heck reactions.
As summarized in Table 3, the coupling of 2,4-dimethoxy-
a
Conditions: carboxylic acid (1.0 mmol), 2-cycloalken-1-one (1.5
1b
mmol), Pd(O2CCF3)2 (0.2 mmol), Ag2CO3 (2.0 equiv), 5% DMSO-DMF
at 80 °C, except as noted. All yields refer to isolated, pure products.
Reaction conducted at 120 °C.
b
c
1-iodobenzene and 2-cyclohexen-1-one was indeed a sluggish
and poorly efficient reaction under a range of typically
4
a,c,f,7
conditions employed for Heck couplings.
Significantly,
that Heck-type coupling is possible with a range of different
the so-called “Jeffery” conditions (entries 6 and 7, Table 3)4a
emerged as superior for the reaction under study; however,
2-cycloalken-1-ones. 2-Cycloalken-1-ones of ring sizes 5
1
0-fold higher levels of palladium than are typically recom-
(
13) General Reaction Procedure. A mixture of arene carboxylic acid
1.0 mmol), 2-cycloalken-1-one (1.5 mmol), Pd(O2CCF3)2 (0.2 mmol), and
Ag2CO3 (2.0 mmol) in 5% DMSO-DMF (4.2 mL) was heated at 80 or
20 °C (as noted, Table 1 or 2) under air. After the time period indicated
(
mended were required to achieve a reasonably efficient
coupling (we used 0.1-0.2 equiv), and a higher reaction
temperature than is typical was also necessary (80 °C).
Preliminary evidence suggests that the Jeffery conditions may
1
in Table 1 or 2 (0.5-3.0 h), the reaction mixture was allowed to cool, then
was diluted with ethyl acetate (30 mL), and the resulting dark suspension
was filtered through a Celite pad. The filtrate was washed sequentially with
an aqueous solution of hydrochloric acid (1 M, 10 mL) and water (5 × 10
mL). The product solution was dried over MgSO4; the dried solution was
filtered, and the filtrate was concentrated. Purification of the residue by
flash column chromatography afforded the 3-aryl-2-cycloalken-1-one
product, typically in 50-90% yield.
(14) Structure 3 is believed to be the (E)-stereoisomer, as shown. This
assignment is based upon one-dimensional NOESY experiments.
(15) Arcadi, A.; Chiarini, M.; Marinelli, F.; Berente, Z.; Kollar, L. Org.
Lett. 2000, 2, 69-72.
Org. Lett., Vol. 6, No. 3, 2004
435

traditional Heck couplings and decarboxylative Heck-type
couplings with 2-cycloalken-1-ones may be somewhat
complementary, for decarboxylative palladation is not ef-
ficient with substrates that lack ortho substituents.12 It is
interesting that the optimal conditions for both traditional
Heck couplings and decarboxylative Heck-type couplings
were phosphine-free. In both cases, phosphine additives
served as effective catalyst poisons. This may be relevant
mechanistically. Specifically, the final step of the “Heck-
type” process, discussed in the introductory paragraphs,
which in one extreme may be viewed as an anti elimination
Table 3. Investigation of Different Protocols in a More
Conventional Heck-type Coupling Processa
entry
1
conditions (equiv)
yield
ref
7b
%)b
(
Pd(OAc)2 (0.1), PPh3 (0.2),
TEA (2.0), AgNO3 (1.3),
CH3CN, 80 °C, 19 h
3
9
,10
process, may require a highly electron-deficient organo-
palladium center to function as an effective electrofuge. 9
,16
2
3
4
5
6
Pd(OAc)2 (0.2), P(o-tolyl)3 (0.5),
Ag2CO3 (2.5),
12
14
25
29
55
57
7c
7a
4f
DMF, 150 °C, 3 h
Pd(PPh3)4 (0.1),
TEA (1.7),
CH3CN, 80 °C, 19 h
In summary, we have presented both decarboxylative
palladation and more traditional Heck processes to achieve
the vinylic arylation of 2-cycloalken-1-one reactants. Al-
though the latter must be regarded as poor reactants relative
to styrene or derivatives of acrylic acid, we have nevertheless
developed effective conditions for their coupling, which we
envision to be a useful process.
PdCl2(PPh3)2 (0.06), dppp (0.08),
NaHCO3 (2.0), LiBr (0.5),
DMF, 150 °C, 20 h
Pd(OAc)2 (0.1),
4c
4a
4a
NaOAc (2.1), Bu4NCl (1.0),
DMF, 80 °C, 22 h
Pd(OAc)2 (0.1),
NaHCO3 (3.0), Bu4NCl (1.0),
DMF, 80 °C, 17 h
Acknowledgment. Financial support from the National
Science Foundation is gratefully acknowledged. D.T. ac-
knowledges financial support from Dainippon Pharm. Co.,
Ltd. (Japan).
7
Pd(OAc)2 (0.2),
NaHCO3 (3.0), Bu4NCl (1.0),
DMF, 80 °C, 16 h
Supporting Information Available: Experimental pro-
cedures and spectral data for new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
a
Reactions were conducted using 0.05-0.08 mmol of the aryl iodide.
b
Yields were determined by HPLC analysis using 4-methoxybiphenyl as
an internal standard.
OL0363467
be more generally useful in Heck-type couplings of 2-cy-
cloalken-1-one reactants, for 4-iodotoluene was found to
couple with 2-cyclohexen-1-one in quantitative yield using
these conditions (eq 2). This is noteworthy and suggests that
(16) (a) Melnyk, P.; Gasche, J.; Thal, C. Tetrahedron Lett. 1993, 34,
449-5450. (b) Adams, N. J.; Bargon, J.; Brown, J. M.; Farrington, E. J.;
5
Galardon, E.; Giernoth, R.; Heinrich, H.; John, B., D.; Maeda, K. Pure
Appl. Chem. 2001, 73, 343-346.
436
Org. Lett., Vol. 6, No. 3, 2004