Palladium-catalyzed reaction of aryl iodides with acetic anhydride. A carbon monoxide-free synthesis of acetophenones

Article abstract of DOI:10.1021/ol027243b

(Matrix presented) The palladium-catalyzed reaction of aryl iodides with acetic anhydride provides a straightforward and experimentally simple carbon monoxide-free route to acetophenones. The reaction tolerates a wide range of funcfionalized aryl iodides. Acetophenones are isolated in excellent yield with a variety of neutral, slightly electron-rich, and slightly electron-poor aryl iodides, whereas moderate yields are obtained with aryl iodides containing strongly electron-withdrawing substituents.

Full text of DOI:10.1021/ol027243b

ORGANIC
LETTERS
2
003
Vol. 5, No. 3
89-291
Palladium-Catalyzed Reaction of Aryl
Iodides with Acetic Anhydride. A
Carbon Monoxide-Free Synthesis of
Acetophenones
2
Sandro Cacchi,* Giancarlo Fabrizi, Federica Gavazza, and Antonella Goggiamani
Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente AttiVe,
UniVersit a` degli Studi “La Sapienza”, P.le A. Moro 5, 00185 Roma, Italy
sandro.cacchi@uniroma1.it
Received November 6, 2002
ABSTRACT
The palladium-catalyzed reaction of aryl iodides with acetic anhydride provides a straightforward and experimentally simple carbon monoxide-
free route to acetophenones. The reaction tolerates a wide range of functionalized aryl iodides. Acetophenones are isolated in excellent yield
with a variety of neutral, slightly electron-rich, and slightly electron-poor aryl iodides, whereas moderate yields are obtained with aryl iodides
containing strongly electron-withdrawing substituents.
The reaction of aryl- and vinylpalladium complexes with
carbon-heteroatom multiple bonds is emerging as a stimu-
lating new frontier in palladium catalysis. In fact, recent
reports have shown that aryl- and vinylpalladium complexes
During our studies directed toward finding new methods
for the palladium-catalyzed formation of C-C bonds, we
have discovered that subjecting p-iodoanisole to acetic
2 3
anhydride in the presence of 1.25 mol % Pd (dba) and 2
1
,2,
equiv of Et N in DMF at 80 °C gives the corresponding
can undergo intramolecular reactions with aldehyde,
3
3
4
acetophenone product in 54% yield (the corresponding biaryl
was obtained in 43% yield).
ketone, and nitrile functionalities to afford indenone and
indanone derivatives and other cyclic alcohols and ketones.
The success of these reactions appears to be strongly
dependent on their intramolecular character.
(1) Larock, R. C.; Doty, M. J.; Cacchi, S. J. Org. Chem. 1993, 58, 4579.
(
2) Gevorgyan, V.; Quan, L. G.; Yamamoto, Y. Tetrahedron Lett. 1999,
4
0, 4089.
We now report that the reaction of arylpalladium com-
plexes with carbonyl compounds can also occur inter-
molecularly. In particular, the palladium-catalyzed reaction
of aryl iodides with acetic anhydride provides a straightfor-
ward and experimentally simple new route to acetophenones
(3) (a) Quan, L. G.; Gevorgyan, V.; Yamamoto, Y. J. Am. Chem. Soc.
999, 121, 3545. (b) Quan, L. G.; Lamrani, M.; Yamamoto, Y. J. Am. Chem.
Soc. 2000, 122, 4827.
1
(4) (a) Larock, R. C.; Tian, Q.; Pletnev, A. J. Am. Chem. Soc. 1999,
1
21, 3238 and references therein. (b) Pletnev, A.; Larock, R. C. Tetrahedron
Lett. 2002, 43, 2133.
5) For recent references, see for example: (a) Nayak, P. K.; Lenka, S.;
(
(Scheme 1), common structural units of a variety of
Nayak, P. L. J. Appl. Polym. Sci. 1991, 43, 2329. (b) Cotgreave, I. A.;
Moldeus, P.; Brattsand, R.; Hallberg, A.; Andersson, C. M.; Engman, L.
Biochem. Pharmacol. 1992, 43, 793. (c) Espinal, J.; Leesnitzer, T.; Hassman,
A.; Beggs, M.; Cobb, J. Drug DeV. Res. 1995, 35, 130. (d) Herencia, F.;
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M.; Alcaraz, M. J. Bioorg. Med. Chem. Lett. 1998, 8, 1169. (e) Favier, L.;
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biologically active compounds and useful intermediates for
the preparation of significant pharmaceuticals.5
(
f) Hsieh, H.-K.; Lee, T.-H.; Wang, J.-P.; Wang, J.-J.; Lin, C.-N. Pharm.
Scheme 1
Res. 1998, 15, 39. (g) Arabaci, G.; Guo, X.-C.; Beebe, K. D.; Coggeshall,
K. M.; Pei, D. J. Am. Chem. Soc. 1999, 121, 5085. (h) Muller, A. A.; Reiter,
S. A.; Heider, K. G.; Wagner, H. Planta Med. 1999, 65, 590. (i)
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1360.
1
0.1021/ol027243b CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/11/2003

To the best of our knowledge, the behavior of acetic
anhydride as an acetyl donor in a palladium-catalyzed
reaction of this type has never been reported.
Table 1. Palladium-Catalyzed Synthesis of Acetophenones
from Aryl Iodides and Acetic Anhydridea
This result prompted us to search for optimal reaction
conditions for this substrate. A survey of reactions with a
i
variety of bases (EtNPr
2
, DABCO, pyridine, K
2
3
CO ) and
solvents (DMA, DMSO, THF, toluene) showed that the best
results can be obtained by using 1.25 mol % Pd (dba) and
a 0.427 M solution of p-iodoanisole with a 1:5:2 molar ratio
of p-iodoanisole:acetic anhydride:EtNPri
in DMF at 100 °C
2
3
2
for 15 h. Under these conditions, p-methoxyacetophenone
was isolated in 70% yield and only trace amounts of the
biaryl byproduct were observed. Interestingly, though a lower
reaction rate was observed, the reaction can be successfully
carried out in the presence of 2.5 mol % 5% palladium on
charcoal (Table 1, entry 2).
Using the same conditions, we found that ethyl p-
iodobenzoate, a model electron-poor aryl iodide, gave the
biaryl derivative as the main reaction product: acetophenone
and biaryl products were isolated in 34 and 57% yields,
respectively. Utilization of phosphine ligands [PPh
3
, P(o-
tol) , P(2-furyl) , tris(p-chlorophenyl)phosphine, tris(2,4,6-
3
3
trimethoxyphenyl)phosphine] did not have any beneficial
effect on the reaction course. On the contrary, their employ-
ment tends to lower the yields of ethyl p-acetylbenzoate by
favoring the formation of the biaryl byproduct. The amount
of biaryl was found to decrease by adding LiCl and diluting
the reaction mixture. Indeed, in the presence of 5 equiv of
LiCl and with a 0.142 M solution of ethyl p-iodobenzoate,
acetophenone and biphenyl products were isolated in 70 and
1
0% yields, respectively. It was observed that LiCl is more
n
n
effective than Bu
4 4
NCl and Bu NBr in limiting the formation
of biaryls.
After observing the beneficial effect of LiCl and dilution
in limiting the formation of biaryls with ethyl p-iodobenzoate,
LiCl and 0.142 M solutions of aryl iodides were employed
in all the experiments we carried out, independent of the
nature of the aryl iodide. In practice, the conditions we used
when the procedure was extended to include other aryl
2
iodides are as follows: aryl iodide (1 equiv, 0.142 M), Pd -
(
(
dba)
5 equiv), LiCl (5 equiv) in DMF at 100 °C.
Under these conditions the reaction proceeds very smoothly
(0.0125 equiv), EtNPri
(2 equiv), acetic anhydride
3 2
a
Unless otherwise stated, reactions were run in DMF at 100 °C by using
i
0
.142 M solutions of 1 with the following molar ratios: 1:2:EtNPr 2:LiCl:
b
1
13
and, as shown in Table 1, appears to tolerate a wide range
of functionalized aryl iodides, including those containing
ether, ketone, ester, and nitro groups. The presence of ortho
substituents does not seem to hamper the reaction (Table 1,
entry 6). Acetophenones were isolated in excellent yield with
a variety of neutral, slightly electron-rich, and slightly
electron-poor aryl iodides, whereas moderate yields were
obtained with aryl iodides containing strongly electron-
withdrawing substituents. With the latter substrates, biaryl
byproducts were isolated in significant yield, even in the
presence of LiCl (Table 1, entries 16 and 17).
Pd (dba)3 ) 1:5:2:5:0.0125. All products gave appropriate H and
2
C
c
NMR and IR spectra and elemental analytical data. Iodoanisole 0.427 M.
In the absence of LiCl. d In the presence 0.025 equiv of 5% Pd/C. Complex
reaction mixture was obtained, containing about 20% 4 and other unidenti-
e
f
g
fied products. Corresponding biaryl was isolated in 20% yield. 1:2:
i
EtNPr 2:LiCl:Pd2(dba)3 ) 1:3:2:7:0.025. Corresponding biaryl was isolated
in 15% yield. h Corresponding biaryl was isolated in 25% yield.
the intermediacy of a five-membered ring, oxygen-containing
palladacycle, as suggested by Dyker in the palladium-
catalyzed C-H activation at methoxy groups, and its
conversion into a phenoxymethylpalladium complex that
subsequently reacts with acetic anhydride according to the
present procedure.
The extension of the procedure to other anhydrides has
been briefly explored. The reaction of p-iodoanisole with
propionic acid anhydride and hexanoic acid anhydride (24
6
Only o-iodoanisole, among the substrates that we have
investigated, produced a complex reaction mixture containing
the desired acetophenone derivative, phenoxyacetone 4, and
other compounds we have not further investigated (Scheme
2). The formation of 4 is interesting. Presumably, it involves
290
Org. Lett., Vol. 5, No. 3, 2003

Another possible mechanism, related to that proposed by
Larock for the formation of indenones from o-iodobenzal-
dehyde and internal alkynes, involves an oxidative insertion
Scheme 2
1
of the arylpalladium complex into the anhydride CO-O bond
to form the palladium(IV) intermediate 5 that could generate
the acetophenone product via reductive elimination. Inter-
mediate 5 could also form via oxidative addition of acetic
8
anhydride to Pd(0) followed by the oxidative insertion of
the resultant acetylpalladium complex into the aryl C-I bond.
h) afforded the corresponding aromatic ketone products in
3
8 and 37% yields, respectively (the biaryl byproduct was
In conclusion, we have demonstrated the first examples
of the palladium-catalyzed intermolecular reaction between
aryl iodides and carbonyl compounds. The reaction tolerates
important functional groups and could open up new and
exciting synthetic pathways. It compares well with most
common palladium-based procedures for the preparation of
acetophenones from aryl iodides (relying on the palladium-
isolated in 7 and 9% yields, respectively). No benzophenone
derivative was observed with benzoic acid anhydride.
A possible reaction mechanism accounting for the ob-
served unprecedented palladium-catalyzed formation of ac-
etophenones from aryl iodides and acetic anhydride is as
follows (Scheme 3): (a) oxidative addition of aryl iodide to
9
catalyzed reaction of aryl iodides with tetramethylstannane
1
0
or methyl zinc in the presence of carbon monoxide, with
7j,11
9
Scheme 3
vinyl ether,
and with zinc salts of enol ether anions) and
is particularly applicable to small-scale reactions where direct
use of carbon monoxide is impractical as in the synthesis of
1
2
compound libraries.
Research on the scope and limitations of this chemistry
are actively underway in our laboratory.
Acknowledgment. This work was supported by the
Ministero dell’Universit a` e della Ricerca Scientifica e
Tecnologica (MURST) and the Universit a` degli Studi “La
Sapienza”.
Supporting Information Available: Complete descrip-
tion of experimental details and product characterization. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Pd(0), (b) addition of the resultant arylpalladium intermediate
to the carbonyl group of the anhydride to give an alkoxy-
palladium intermediate, (c) formation of the acetophenone
product by â-elimination of an acetoxypalladium species,
and (d) regeneration of the Pd(0) catalyst by reduction.
Presumably, the reduction step is effected by the tertiary
OL027243B
7
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2,3a
3b
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3
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(
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