Carbonylative cross-coupling of ortho-disubstituted aryl iodides. Convenient synthesis of sterically hindered aryl ketones

Article abstract of DOI:10.1021/ol802202j

(Chemical Equation Presented) A mild and general protocol for the carbonylative cross-coupling of sterically hindered ortho-disubstituted aryl iodides is reported. Carbonylative Suzuki-Miyaura couplings of a variety of aryl boronic acids provide an array of substituted biaryl ketones in modest to excellent yield. A carbonylative Negishi coupling that utilizes alkynyl nucleophiles is also described.

Full text of DOI:10.1021/ol802202j

ORGANIC
LETTERS
2008
Vol. 10, No. 22
5301-5304
Carbonylative Cross-Coupling of
ortho-Disubstituted Aryl Iodides.
Convenient Synthesis of Sterically
Hindered Aryl Ketones
B. Michael O’Keefe, Nicholas Simmons, and Stephen F. Martin*
Department of Chemistry and Biochemistry, The UniVersity of Texas at Austin, Austin,
Texas 78712
sfmartin@mail.utexas.edu
Received September 20, 2008
ABSTRACT
A mild and general protocol for the carbonylative cross-coupling of sterically hindered ortho-disubstituted aryl iodides is reported. Carbonylative
Suzuki-Miyaura couplings of a variety of aryl boronic acids provide an array of substituted biaryl ketones in modest to excellent yield. A
carbonylative Negishi coupling that utilizes alkynyl nucleophiles is also described.
Aryl ketones and flavanoids are common scaffolds in many
natural products and biologically active small molecules.1
Many of these compounds possess substitution at both
positions ortho to the ketone moiety. Chemists have most
often turned to reactions in the synthome2 that rely upon
strongly acidic or basic conditions in order to install the
carbonyl functional group. For example, the Friedel-Crafts
acylation,3a Fries rearrangement,3b-d and additions of
nucleophiles into a variety of acyl electrophiles, including
N-methoxy-N-methylamides,3e have allowed access to
ortho-disubstituted aryl ketones. However, obtaining steri-
cally more encumbered ketones is notoriously difficult via
the Friedel-Crafts acylation,4 and the Fries rearrangement
is limited to phenol derivatives.
An alternative method for the construction of aryl ketones is
the three-component coupling of aryl halides, carbon nucleo-
philes, and carbon monoxide that was pioneered by Heck.5 This
process is one of the most efficient and direct routes to aryl
ketones as it forms two carbon-carbon bonds in a single
operation, thereby alleviating the need to introduce the ketone
function in a stepwise fashion. The carbonylative coupling has
since been further developed to include a range of carbon
nucleophiles,6 including tin,7 copper,8 boron,9 zinc,10 alumi-
num,11 magnesium,12 and silicon.13
(1) For some examples, see: (a) Jiang, Y.; Tu, P. Chem. Pharm. Bull.
2005, 53, 1164. (b) Nilar; Nguyen, L.-H. D.; Venkatraman, G.; Sim, K.-
Y.; Harrison, L. J. Phytochemistry 2005, 66, 1718. (c) Lampe, J. W.;
Biggers, C. K.; Defauw, J. M.; Foglesong, R. J.; Hall, S. E.; Heerding,
J. M.; Hollinshead, S. P.; Hu, H.; Hughes, P. F.; Jagdmann, G. E., Jr.;
Johnson, M. G.; Lai, Y.-S.; Lowden, C. T.; Lynch, M. P.; Mendoza, J. S.;
Murphy, M. M.; Wilson, J. W.; Ballas, L. M.; Carter, K.; Darges, J. W.;
Davis, J. E.; Hubbard, F. R.; Stamper, M. L. J. Med. Chem. 2002, 45, 2624.
(d) Rancon, S.; Chaboud, A.; Darbour, N.; Comte, G.; Bayet, C.; Simon,
P.-N.; Raymond, J.; Di Pietro, A.; Cabalion, P.; Barron, D. Phytochemistry
2001, 57, 553. (e) Ito, H.; Nishitani, E.; Konoshima, T.; Takasaki, M.;
Kozuka, M.; Yoshida, T. Phytochemistry 2000, 54, 695. (f) Li, J.-C.; Nohara,
T. Chem. Pharm. Bull. 2000, 48, 1354.
During the course of an ongoing synthetic project, we
required a reliable method for preparing aryl ketones bearing
(4) For a recent example, see: Nakamura, H.; Arata, K. Bull. Chem.
Soc. Jpn. 2004, 77, 1893.
(5) (a) Heck, R. F. J. Am. Chem. Soc. 1968, 90, 5546. (b) Schoenberg,
A.; Bartoletti, I.; Heck, R. F. J. Org. Chem. 1974, 39, 3318. (c) Schoenberg,
A.; Heck, R. F. J. Org. Chem. 1974, 39, 3327. For a review on the synthesis
of diarylketones by carbonylative coupling, see: (d) Brunet, J.-J.; Chauvin,
R. Chem. Soc. ReV. 1995, 24, 89.
(2) Sunderhaus, J. D.; Dockendorff, C.; Martin, S. F. Org. Lett. 2007,
9, 4223.
(3) (a) Calloway, N. O. Chem. ReV. 1935, 17, 327. (b) Blatt, A. H. Org.
React. 1942, 1, 342. (c) Bellus, D.; Hrdlovic, P. Chem. ReV. 1967, 67, 599.
(d) Sibi, M. P.; Snieckus, V. J. Org. Chem. 1983, 48, 1935. (e) Sibi, M. P.
Org. Prep. Proced. Int. 1993, 25, 15.
(6) Tamaru, Y.; Kimura, M. Handbook of Organopalladium Chemistry
for Organic Synthesis, 1st ed.; Negishi, E., de Meijere, A., Eds.; Wiley
Interscience: New York, 2002; Vol. 2, Chapter 6, pp 2425-2454.
10.1021/ol802202j CCC: $40.75
Published on Web 10/24/2008
2008 American Chemical Society

two ortho substituents. While there are a plethora of methods
for synthesizing simple aryl ketones via carbonylative cross-
coupling,5d to the best of our knowledge, there is only one
example of a carbonylative cross-coupling involving an
ortho-disubstituted aryl halide with a carbon nucleophile.9b
We discovered, however, that the direct application of this
protocol to the problem with which we were confronted did
not lead to the desired ortho-disubstituted aryl ketone. It was
thus necessary to develop a new procedure that would enable
efficient carbonylative cross-coupling of different ortho-
disubstituted aryl halides with a variety of boronic acids and
other nucleophilic partners. We now report the results of
some of our findings.
Table 1. Carbonylative Cross-Coupling of
2,6-Dimethyliodobenzene and Phenylboronic Acida
Toward developing a more general process for preparing
hindered biaryl ketones, we examined the carbonylative
cross-coupling of 2,6-dimethyliodobenzene (1) with phenyl-
boronic acid under a variety of conditions (Table 1). In initial
experiments, we found that Cs2CO3 and dioxane was the
optimal base/solvent combination. Several common phos-
phine-containing catalyst systems were next examined.14 Use
of Pd(PPh3)4 and PdCl2(dppf) as catalysts at elevated
temperatures and pressures led to consumption of all the
starting material; however, the direct coupling product 3 was
the major product (entries 1-2) in each case.
After several other mono- and bidentate phosphine ligands
were found to be ineffective, we decided to probe the utility
of N-heterocyclic carbene (NHC) ligands.15 NHC ligands
have gained popularity in metal-catalyzed cross-coupling
reactions for several reasons: (1) the steric bulk that they
impart around the metal center facilitates reductive elimina-
tion; (2) their strong σ-donating character begets facile
oxidative addition; and (3) their greater stability at elevated
temperatures relative to phosphine ligands enables their use
over a broader range of reaction conditions.16
a Selected examples. Reaction conditions: 3 mol % Pd catalyst, 1.0 mmol
of 2,6-dimethyliodobenzene, 2.0 mmol of phenylboronic acid, and 3.0 mmol
of Cs2CO3 in the indicated solvent (5 mL) at the indicated temperature and
CO pressure for 24 h. b Ratios based on integration of the 1H NMR spectrum
of the reaction mixture after workup. c Isolated yield of 2 after chromatography.
d Ligand/Pd (2:1). e Ligand/Pd (1:1).
The first supporting ligand that we studied was SIMes-HBF4,
and we were pleased to find that the product distribution now
favored the desired ketone 2 (entry 3), although further
optimization was clearly necessary. We then discovered that
when the commercially available PEPPSI-IPr17 catalyst was
used under 60 psi of CO, an 82% yield of ketone 2 was
obtained; if the reaction was run under a balloon (1 atm) of
CO, the simple biaryl 3 was the sole product. To the best of
our knowledge, this is the first example of a carbonylative cross-
coupling that utilizes the PEPPSI-IPr catalyst. Because it is more
convenient to perform such cross-couplings under a balloon of
CO, we conducted a search for modified reaction parameters
that were amenable to lower CO pressures. Gratifyingly, after
screening several solvents, we found that amounts of the ketone
2 could be observed under a balloon of CO when aromatic
solvents were used. When the reaction was performed in
toluene, R,R,R-trifluorotoluene, anisole, or nitrobenzene, the
major product of the reaction was ketone 2; however, significant
amounts of starting aryl iodide 1 remained. After some
experimentation, we discovered that the optimal catalyst/solvent
combination for the carbonylative cross-coupling of 1 with
phenylboronic acid employed the PEPPSI-IPr catalyst in
(7) (a) Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997,
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Y.; Hiyama, T. Chem. Lett. 1989, 18, 2049.
(14) Miyaura, N; Suzuki, A. Chem. ReV. 1995, 95, 2457.
(15) Arduengo, A. J., III; Harlow, R. L.; Kline, M. J. Am. Chem. Soc.
1991, 113, 361.
(16) For reviews, see: (a) Kantchev, E. A. B.; O’Brien, C. J.; Organ, M. G.
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12, 4743.
5302
Org. Lett., Vol. 10, No. 22, 2008

chlorobenzene (PhCl) to deliver the ketone 2 in 95% yield (entry
9). Other catalysts, such as Pd(PPh3)4, PdCl2(dppf), Pd(OAc)2/
S-Phos,18 and Pd(OAc)2/Xantphos,19 were also examined using
PhCl as solvent, but the major product using each of these
catalysts was the biaryl 3.
Table 2. Synthesis of ortho-Disubstituted Aryl Ketones via
PEPPSI-IPr-Catalyzed Suzuki Coupling at Balloon Pressurea
It is intriguing that PhCl was found to be the best solvent
for this carbonylative coupling since the PEPPSI-IPr catalyst
has been shown to catalyze Suzuki cross-couplings of aryl
chlorides.17 We never detected, however, any benzophenone
that would arise from cross-coupling with solvent. One
possible explanation for this observation is that a CO ligand
is deactivating the palladium catalyst owing to its backbond-
ing ability, thus making oxidative addition more difficult.20
Having optimized the reaction conditions for the cross-
coupling of 1 with phenylboronic acid, several different
boronic acids and ortho-disubstituted aryl iodides were
examined to determine the scope of the process (Table 2).
Formation of the trisubstituted benzophenone 6a from 1 and
o-tolylboronic acid proceeded in 98% yield (entry 1). The
reaction of 1 with 4-methoxyphenyl boronic acid (entry 2)
was accompanied by 22% of the corresponding direct
coupling product. On the other hand, if this reaction was
conducted under 60 psi of CO, the desired biaryl ketone 6b
was formed in 92% yield. Use of electron-deficient boronic
acids was initially more problematic, and only 12% of the
desired ketone 6c was isolated from the reaction of 1 with
p-cyanophenylboronic acid (entry 3). Electron-deficient bo-
ronic acids are known to be more prone to side reactions
such as homocoupling, and they undergo slower transmeta-
lation than their electron-rich counterparts.21 Nevertheless,
we found that changing the solvent to dioxane and perform-
ing the reaction at elevated temperature and pressure gave
the biaryl ketone 6c in 42% yield. Reaction of 1 with 2,6-
dimethoxyphenylboronic acid furnished an excellent yield
of the tetra-ortho-substituted benzophenone 6d (entry 4). The
heteroaromatic ketone 6e was obtained from the reaction of
1 and thiophene-3-boronic acid in 64% yield (entry 5).
We then turned our attention to the reactions of more
electron-rich aryl iodides. In the event, 2-iodo-1,3,5-tri-
methoxybenzene (4a)22 was converted into several highly
oxygenated benzophenones (entries 6 and 7). Despite the
modest yields observed in these reactions, these experiments
were nonetheless promising as oxidative addition in such
cases is presumably disfavored by the highly electron-rich
nature of the aryl iodide. The more base-sensitive 2-iodo-
3,5-dimethylphenol23 was also carbonylatively coupled to
phenyl boronic acid under slightly modified conditions
employing K2CO3 as the base to give 6h (entry 8). Moreover,
a Reaction conditions: 3 mol % of PEPPSI-IPr, 1.0 mmol of aryl iodide,
2.0 mmol of boronic acid, and 3.0 mmol of Cs2CO3 in chlorobenzene (5
mL) at 80 °C for 24 h. Reactions were not further optimized unless otherwise
noted. The coupling could also be performed on a 1 g scale with no
appreciable loss in yield. b Isolated yields are an average of two runs.
c Dioxane was used as the solvent; CO pressure increased to 60 psi;
temperature increased to 140 °C. d K2CO3 used as base.
the electron-deficient aryl iodide 3-chloro-2-iodotoluene
underwent facile carbonylative coupling to give the expected
ketone 6i in 88% yield (entry 9). The selectivity of the
catalyst for the aryl iodide bond in the presence of the aryl
chloride bond poses a signifcant advantage because the aryl
chloride can then be further elaborated by subsequent cross-
couplings.
We next wished to expand the scope of the cross-coupling
to the synthesis of alkynyl ketones because they are syntheti-
cally useful intermediates en route to fused pyranone rings
found in natural products.8e,24 Unfortunately, the requisite
(18) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L.
J. Am. Chem. Soc. 2005, 127, 4685.
(19) Kranenburg, M.; van der Burgt, Y. E. M.; Kamer, P. C. J.; van
Leeuwen, P. W. N. M. Organometallics 1995, 14, 3081.
(20) Maerten, E.; Sauthier, M.; Mortreux, A.; Castenet, Y. Tetrahedron
2007, 63, 682.
(21) (a) Operamolla, A.; Omar, O. H.; Babudri, F.; Farinola, G. M.;
Naso, F. J. Org. Chem. 2007, 72, 10272. (b) Wong, M. S.; Zhang, X. L.
Tetrahedron Lett. 2001, 42, 4087.
(22) Orito, K.; Hatakeyama, T.; Takeo, M.; Suginome, H. Synthesis 1995,
1273.
(23) Narender, N.; Reddy, K. S. K.; Mohan, K. V. V. K.; Kulkami,
S. J. Tetrahedron Lett. 2007, 48, 6124.
Org. Lett., Vol. 10, No. 22, 2008
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alkynyl boronic acids were not readily available. Indeed,
stable alkynylboranes have been notoriously difficult to
prepare due to the lability of the C-B bond.25 Nevertheless,
we were able to synthesize the alkynylboronic ester 10 from
the corresponding lithium acetylide, and we were pleased
that upon reaction with 1 under CO, the acetylenic ketone
8a was obtained in modest yield (Table 3, entry 1).
PEPPSI-IPr precatalyst.29 It is noteworthy that the acetylenic
ketones produced from this transformation are valuable
synthetic intermediates that may be further transformed into
many biologically interesting molecules and natural products.
Table 3. Carbonylative Cross-Coupling of
2,6-Dimethyliodobenzene with Alkynyl Nucleophilesa
We then turned our attention toward employing carbony-
lative Stille (Sn),7 Sonogashira (Cu),8 Hiyama (Si),13 and
Suzuki9 couplings that involved air-stable potassium orga-
notrifluoroborates (KF3B-R). Despite reasonable experimen-
tation, most of these efforts were rewarded by limited
success. In the Sonogashira-, Hiyama-, and Suzuki-based
protocols, acetylenic ketone 8 was observed in the reaction
mixture, but the major product was invariably the direct
coupling product 9. Increasing the CO pressure in these
experiments did little other than to decrease the amount of
starting material that was consumed. On the other hand, the
carbonylative Stille coupling delivered a product ratio
favoring the desired ketone 8, although unreacted starting
material was the major component of the reaction mixture.
That the Stille reaction was superior to the other cross-
couplings is consistent with the hypothesis that transmeta-
lation is frequently the rate-determining step in the Stille
reaction.26
There are few examples of carbonylative Negishi (Zn)
cross-couplings in the literature, presumably because the
higher reactivity of the organozinc reagent tends to deliver
the direct coupling product.10 We were thus gratified to find
that we obtained the desired acetylenic ketone 8b in 79%
yield upon reaction of 1 with an alkynylzinc bromide in the
presence of LiBr as an additive (entry 2). Similarly, treatment
of 2,6-dimethyliodobenzene with the zinc reagent derived
from 4-ethynylanisole furnished a 75% yield of the acetylenic
ketone 8c (entry 3). A successful carbonylative cross-
coupling was also realized with the more electron-rich
2-iodo-3,5-dimethylanisole27 under slightly modified condi-
tions employing higher CO pressure and PPh3 as an additive
to deliver ketone 8d (entry 4).28 In this reaction, it was
essential to add PPh3 in order to fully consume the starting
material. Although the PEPPSI-IPr catalyst has been shown
to be highly efficient in Negishi cross-couplings with a wide
range of substrate classes, to the best of our knowledge, this
represents the first carbonylative Negishi coupling using the
a Reaction conditions: 3 mol % of catalyst, 1.0 mmol of aryl iodide,
2.0 mmol of nucleophile, 3.0 mmol of additive, 5 mL of solvent, 24 h
reaction time. b Ratios determined by 1H NMR. c Ratio could not be
determined. d 3 mol % of PPh3 was used.
In summary, we have discovered and developed a mild
and operationally simple carbonylative Suzuki protocol that
enables the efficient cross-coupling of ortho-disubstituted aryl
iodides with a range of substituted boronic acids utilizing
the commercially available PEPPSI-IPr catalyst. We also
found that the carbonylative Negishi cross-coupling of aryl
iodides with alkynylzinc reagents delivers acetylenic ketones
in good yields. Application of these processes to the synthesis
of biologically active natural products will be reported in
due course.
Acknowledgment. We thank the National Institutes of
Health General Medical Sciences (GM 31077), the Robert
A. Welch Foundation, Pfizer, Inc., Merck Research Labo-
ratories, and Boehringer-Ingelheim Pharmaceuticals for their
generous support of this research. N.S. thanks the Arnold
and Mabel Beckman Foundation for an undergraduate
research fellowship.
Supporting Information Available: Experimental pro-
cedures, spectral data, and copies of 1H and 13C NMR. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(24) Nakatani, K.; Okamoto, A.; Saito, I. Tetrahedron 1996, 52, 9427.
(25) Brown, H. C.; Bhat, N. G.; Srebnik, M Tetrahedron Lett. 1988,
29, 2631, and references therein.
OL802202J
(26) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585.
(27) For synthesis of this compound, see the Supporting Information.
(28) Batey, R. A.; Shen, M.; Lough, A. J. Org. Lett. 2002, 4, 1411.
(29) Organ, M. G.; Avola, S.; Dubovyk, I.; Hadei, N.; Kantchev,
E. A. B.; O’Brien, C. J.; Valente, C. Chem.sEur. J. 2006, 12, 4749.
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