Efficient catalyst-free bi- and triaroylation of aromatic rings in a single step

Article abstract of DOI:10.1021/jo801890e

(Chemical Equation Presented) The exceptional leaving group ability of the trimethylstannyl group in electrophilic aromatic substitutions makes possible the synthesis, in a single step, of bi- and triaroylarenes through the catalyst-free, regioselective reaction of bi- and tristannylarenes with different aroyl halides in o-dichlorobenzene as solvent. Specific di- and triketones are obtained in good to excellent yields (45-83%).

Full text of DOI:10.1021/jo801890e

allowing the simultaneous introduction of more than one acyl
group in an aromatic ring. These antecedents are connected with
the palladium-catalyzed cross-coupling reaction of phenylene-
dizincs with acyl chlorides5 and with the palladium-catalyzed
carbonylative cross-coupling reaction of triorganoindiums with
di- and tri-iodobenzenes.6 Recently, based on the exceptional
leaving group ability of the trimethylstannyl group in electro-
philic aromatic substitutions, we have informed the synthesis
of unsymmetrical diarylketones by the reaction of aroyl chlorides
with arylstannanes, avoiding the use of catalysts.7 The results
obtained encouraged us to explore its application to efficient
reactions in which more than one bond is formed in one step.
In this paper we are pleased to inform that bi- and tristanny-
larenes are useful partners to synthesized bi- and triaroylarenes
in a simple step by their catalyst-free reaction with different
aroyl halides. As far as we know these are the first examples
involving organostannanes.
Efficient Catalyst-Free Bi- And Triaroylation of
Aromatic Rings in a Single Step
Marcos J. Lo Fiego, Mercedes A. Badajoz,
Gustavo F. Silbestri, Mar´ıa T. Lockhart,* and
Alicia B. Chopa*,†
INQUISUR, Departamento de Qu´ımica, UniVersidad
Nacional del Sur, AVenida Alem 1253,
8000 Bah´ıa Blanca, Argentina
abchopa@uns.edu.ar; lockhart@criba.edu.ar
ReceiVed August 29, 2008
The exceptional leaving group ability of the trimethylstannyl
group in electrophilic aromatic substitutions makes possible
the synthesis, in a single step, of bi- and triaroylarenes
through the catalyst-free, regioselective reaction of bi- and
tristannylarenes with different aroyl halides in o-dichlo-
robenzene as solvent. Specific di- and triketones are obtained
in good to excellent yields (45-83%).
We prepared a series of starting materials supporting two or
three trimethylstannyl moieties attached to the aromatic ring
(1-6)8 and we studied their reaction toward different com-
mercially available aroyl chlorides under the reaction conditions
previously established for the synthesis of diarylketones, that
is, in chlorobenzene as solvent, at 130 °C.7 The results obtained
are summarized in Table 1.
Ketones are vital building blocks in organic synthesis as well
as an important functionality found in several natural products
and in various pharmaceutical compounds. Electrophilic aro-
matic substitution such as Friedel-Crafts (F-C) acylation1 and
cross-coupling reactions of acyl chlorides with organometallic
reagents2 are presumed to be the preferences for the synthesis
of wholly aromatic ketones.
In the field of organic synthesis, one important way to achieve
efficiency in a reaction is to perform more than one reaction
type in a single pot. Usually, diacyl halides are the preferred
starting materials for the synthesis of diaroylbenzenes involving
either a F-C reaction with the appropriate aryl derivative3 or a
transition metal-catalyzed cross-coupling reaction with orga-
nometallic compounds.4 In contrast, there are only few ante-
cedents associated with an electronically counter process, i.e.,
the reaction of phenylendimetal compounds with acyl halides
At first, we carried out the reaction of 1,4-bis(trimethylstan-
nyl)benzene (1) with benzoyl chloride (7a) (1/7a, 1/2.4), and
we were pleased to observed that, after 42 h, the desired
(5) (a) Kawamoto, T.; Ejiri, S.; Kobayashi, K.; Odo, S.; Nishihara, Y.; Takagi,
K. J. Org. Chem. 2008, 73, 1601. (b) Saiga, A.; Hossain, K. M.; Takagi, K.
Tetrahedron Lett. 2000, 41, 4629.
(6) Pena, M. A.; Sestelo, J. P.; Sarandeses, L. A. Synthesis 2005, 485.
(7) Silbestri, G. F.; Bogel Masson, R.; Lockhart, M. T.; Chopa, A. B. J.
Organomet. Chem. 2006, 691, 1520.
(8) Physical and spectroscopic data are in agreement with those previously
reported: (a) Chopa, A. B.; Lockhart, M. T.; Silbestri, G. F. Organometallics
2001, 20, 3358. (b) Chopa, A. B.; Lockhart, M. T.; Dorn, V. B. Organometallics
2002, 21, 1425. (c) Fidelibus, P. M.; Silbestri, G. F.; Lockhart, M. T.; Mandolesi,
S. D.; Chopa, A. B.; Podesta´, J. P. Appl. Organometal. Chem. 2007, 21, 682.
† Member of CIC.
(1) Smith, M. B.; March, J. March’s AdVanced Organic Chemistry; John
Wiley: New York, 2001.
(2) For a review, see: Dieter, K. Tetrahedron 1999, 55, 4177.
(3) Rajakumar, P.; Srisailas, M.; Kanagalatha, R. Tetrahedron 2003, 59, 5365.
(4) Rao, M. L. N.; Venkatesh, V.; Banerjee, D. Tetrahedron 2007, 63, 12917.
9184 J. Org. Chem. 2008, 73, 9184–9187
10.1021/jo801890e CCC: $40.75 2008 American Chemical Society
Published on Web 10/25/2008

TABLE 1. Reactions of Arylstannanes with Aroyl Chlorides in
Chlorobenzenea
diketone, i.e., 1,4-phenylenebis(phenylmethanone) (8a) was
obtained in 56% yield (entry 1). A similar reaction carried out
with arylstannane 2 proceeded efficiently giving 1,3-phenyle-
nebis(phenylmethanone) (9a) (62%, 40 h) (entry 3). The results
obtained in the reactions of 1 or 2 with either 4-methylbenzoyl
chloride (7b) or 2-chlorobenzoyl chloride (7c) under similar
conditions demonstrate that the reactions also proceed with acid
chlorides bearing electron-donating or electron-withdrawing
groups (entries 5, 7, 9, and 11). Moreover, the reactions of
arylstannanes 3 and 5 with acid chlorides 7a and 7c also
rendered the desired diketones, i.e., (2,6-dimethyl-1,4-phenyle-
ne)bis(phenylmethanone) (10a, 72%, 23 h) (entry 13), (2,6-
dimethyl-1,4-phenylene)bis[2-chlorophenyl)methanone] (10c,
47%, 48 h) (entry 14), and naphthalene-1,4-diylbis(phenyl-
methanone) (12a, 50%, 48 h) (entry 15), respectively. It should
be mentioned that, in all the experiments, the desired tri-
aryldiketones were accompanied with 15-20% of the corre-
sponding diarylketones, probably as a result of the protodestan-
nylation of one stannyl group under the reaction conditions.
Moreover, in the reactions carried out with compound 3 (entries
13 and 14) there were detected (CG/MS) both isomeric
monoketones in comparable yields, indicating that there is not
a remarkable preference for the electrophilic attack on carbon-1
instead of carbon-4 as it was expected due to the existence of
neighboring groups on the arene system.7 We also studied the
reaction of 1,3,5-tris(trimethylstannyl)benzene (6) with benzoyl
chloride in order to determine the scope of this reaction for the
simultaneous triaroylation of the aromatic ring. With satisfaction
we found that the reaction led to benzene-1,3,5-triyltris(phe-
nylmethanone) (13a) even though in a low yield (25%)
accompanied with a large amount of 9a (65%).
With these results in hand and with the main goal of
reducing reaction times and subproducts, we decided to study
the influence of an increment of the ratio aroyl chloride/
substrate from 2.4/1 to 4/1. The results obtained demonstrated
the effectiveness of this change. In all the experiments carried
out, reaction times and monoketones yields were decreased
meanwhile yields of diketones were increased (entries 2, 4,
6, 8, 10, and 12). However, this method requires an important
excess of acid chlorides which were destroyed during the
usual aqueous workup leading to large amounts of waste.
Looking for alternative reaction conditions in order to
minimize the waste problem, we decided to carry out the
reactions at higher temperatures (180 °C) using 1,2-dichlo-
robenzene as solvent. To demonstrate the efficiency and scope
of the method, we applied this system to a variety of
organostannanes and of aroyl chlorides. The results sum-
marized in Table 2 demonstrate the efficiency of these
reaction conditions. Thus, reaction times decreased dramati-
cally at elevated temperatures without affecting the yield:
compare experiments 1, 2, 3, 7, 8, 9, 14, 16, and 22 in Table
2 with the analogous experiments resumed in Table 1.
Moreover, the undesired monoketones were detected only
in tiny amounts, irrelevant compared with the yields of the
diketones obtained, improving their isolated yields. The
results obtained in experiment 21 demonstrate that it is also
possible to insert two aroyl groups in adjacent positions of
the aromatic ring with high yields. Furthermore, experiments
24 and 25 enable us to say that this method could be also
applied to the triaroylation of the aromatic ring in a simple
step. Other methods available for the synthesis of such
a ArCOCl (2.4 equiv) was used unless otherwise stated. b Determined
by GC. c ArCOCl (4 equiv). d ArCOCl (3.6 equiv).
J. Org. Chem. Vol. 73, No. 22, 2008 9185

TABLE 2. Reactions of Arylstannanes with Aroyl chlorides in 1,2-Dichlorobenzenea
a ArCOCl (2.4 equiv) was used unless otherwise stated. b Determined by GC; isolated products between parentheses as an average of at least two
independent runs. c ArCOCl (3.6 equiv).
compounds are the cyclotrimerization of acetylenic ketones9
as well as the Pd-catalyzed carbonylative coupling of triiodo-
benzene with triphenylindium.6
It is important to mention that the reactions carried out with
3- (7d) and 4-nitrobenzoyl chloride (7g) with different substrates
could not be analyzed by CG/MS because the corresponding
diketones did not elute from the column. These reactions were
analyzed by NMR. In all these experiments there was detected,
together with the desired diketone, the presence of trimethyl-
stannylated nitrobenzophenone (10-20%) intermediates in the
diaroylation process. Although longer reaction times produced
a decreased amount of the intermediates, they also led to
decomposition of the diketone. So, the reaction times specified
in Table 2 (entries 4, 10, 13, 17, and 20) were optimal to avoid
decomposition of the desired dinitrodiketones, which were
isolated from the crude product by recrystallization. Further-
more, in the reaction carried out between 1 and 7c (entry 3),
the corresponding trimethylstannylated chlorobenzophenone
(16%, CG/MS) was also detected, even after 36 h of heating.
In conclusion, the method proposed is an efficient catalyst-
free straightforward route for di- and triaroylation of an aromatic
ring in a single step. Significantly, these products are known to
be very valuable precursors for the synthesis of a variety of
materials.3,10
(9) Zhou, Q.-F.; Yang, F.; Guo, Q.-X.; Xue, S. Synlett 2007, 215.
9186 J. Org. Chem. Vol. 73, No. 22, 2008

described below, and the organic layer was successively washed
with a 10% (m/v) solution of sodium hydroxide, brine, and water,
dried over sodium sulfate, filtered, and concentrated in vacuo. The
resultant solid was purified by flash chromatography on silica gel
(hexane/AcOEt ) 97:3) to provide 8a as a white solid (0.200 g,
70%): mp 141-143 °C (lit.4 mp 158-160 °C); 1H NMR (300 MHz,
CDCl3) δ 7.42 (t, 4H, J ) 7.8 Hz), 7.46-7.57 (m, 2H), 7.67-7.79
(m, 4H); 13C NMR (75.5 MHz, CDCl3) δ 195.8 (CO), 140.6 (C),
136.9 (C), 132.8 (CH), 129.9 (CH), 129.5 (CH), 128.3 (C); EIMS
m/z (rel intensity) 286 (M+, 55), 209 (62), 181 (12), 152 (15), 105
(100).
Disposal Method for Trimethyltin Chloride. The aqueous
solution (∼15 mL for 1.0 mmol scale reaction) was saturated with
potassium fluoride. Diethyl ether (10 mL) was added, and the
mixture was vigorously shaken. The precipitated trimethyltin
fluoride13 (0.297 g, 81%) was removed by filtration at reduced
pressure. The amorphous solid obtained was stored for future
applications.14
Taking into account that the starting arylstannanes may be
synthesized from the corresponding haloarenes,11 phenols8b or
anilines,8a the method proposed allows the regioselective
substitution of a chloro, a hydroxy or an amino group on an
aromatic ring, rendering specific di- and triketones in good
global yields.
Nevertheless, one disadvantage of the method is the genera-
tion of trimethyltin chloride soluble in the aqueous phase during
the workup of the reaction. Because of the environmental
problems caused by the well-known toxicity of triorganotin
residues, we considered really important to trap the Me3SnCl
generated. With this aim, the organotin chloride is removed in
ca. 80%, by filtration as the insoluble trimethyltin fluoride (see
the Experimental Section).
Experimental Section
Aryltins were prepared according to literature methods.8,11
Representative Procedure for Aroyldestannylation. Prepara-
tion of 1,4-Phenylenebis(phenylmethanone) (8a; Table 2, Entry
1). In an oven-dried 25 mL heavy walled Schlenk tube fitted with
a Teflon plug valve was added dropwise 0.28 mL (0.338 g, 2.40
mmol) of benzoyl chloride (7a) to a stirred solution of 1,4-
bis(trimethylstannyl)benzene (1, 0.403 g, 1.00 mmol) in 1,2-
dichlorobenzene (1.0 mL) under a nitrogen atmosphere. The system
was purged with nitrogen by means of three vac-refill cycles, and
the reaction mixture was heated at 180 °C (oil bath) for 5 h
(monitoring the disappearance of the stannane by TLC). A few
drops of DMSO (0.2 mL) were added,12 and the mixture was stirred
at room temperature for a few minutes, diluted with dichlo-
romethane (5 mL), and washed with water (3 × 5 mL). The
resulting aqueous solution was reserved for further treatment
Acknowledgment. This work was partially supported by the
Consejo Nacional de Investigaciones Cient´ıficas y Te´cnicas
(CONICET), the Comisio´n de Investigaciones Cient´ıficas de la
Provincia de Buenos Aires (CIC), the Agencia Nacional de
Promocio´n Cient´ıfica y Tecnolo´gica (ANPCYT), and the
Universidad Nacional del Sur, Bah´ıa Blanca, Argentina.
CONICET is thanked for a research fellowship to M.J.L.F.
Supporting Information Available: General experimental
procedures, compound characterization data, and copies of
spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO801890E
(10) (a) Zhao, W.; Carreira, E. M. Org. Lett. 2006, 8, 99. (b) Higuchi, M.;
Shomura, R.; Ohtsuka, Y.; Hayashi, A.; Yamamoto, K.; Kurth, D. Org. Lett.
2006, 8, 4723.
(11) Yammal, C. C.; Podesta´, J. C.; Rossi, R. A. J. Org. Chem. 1992, 57,
5720.
(12) The coordinating ability of DMSO competes with the ketone improving
the water solubility of trimethyltin chloride.
(13) Organotin fluorides are relatively benign compounds.They are high
melting, nonvolatile, insoluble (in both organic solvents and in water), and not
easily absorbed through the skin; therefore, the risks of organotin fluorides are
less than those of other organotins: Leibner, J. E.; Jacobus, J. J. Org. Chem.
1979, 44, 449.
(14) Mitchell, T. N.; Kwetkat, K.; Godry, B. Organometallics 1991, 10, 1633.
J. Org. Chem. Vol. 73, No. 22, 2008 9187