Palladium-catalyzed (Ullmann-type) homocoupling of aryl halides: A convenient and general synthesis of symmetrical biaryls via inter- and intramolecular coupling reactions

Article abstract of DOI:10.1021/ol990872+

(matrix presented) A convenient new procedure is described for both inter-and intramolecular homocoupling of aryl halides (Ullmann reaction) using catalytic palladium in the presence of hydroquinone, a homogeneous reductant. Optimal conditions for the reductive coupling include the use of a 1:1 molar ratio of Pd(OAc)₂ and As(o-tolyl)₃ in catalytic amounts under basic conditions.

Full text of DOI:10.1021/ol990872+

ORGANIC
LETTERS
1999
Vol. 1, No. 8
1205-1208
Palladium-Catalyzed (Ullmann-Type)
Homocoupling of Aryl Halides: A
Convenient and General Synthesis of
Symmetrical Biaryls via Inter- and
Intramolecular Coupling Reactions
D. David Hennings, Tetsuo Iwama, and Viresh H. Rawal*
Department of Chemistry, The UniVersity of Chicago, 5735 South Ellis AVenue,
Chicago, Illinois 60637
V-rawal@uchicago.edu
Received July 27, 1999
ABSTRACT
A convenient new procedure is described for both inter- and intramolecular homocoupling of aryl halides (Ullmann reaction) using catalytic
palladium in the presence of hydroquinone, a homogeneous reductant. Optimal conditions for the reductive coupling include the use of a 1:1
molar ratio of Pd(OAc)2 and As(o-tolyl)3 in catalytic amounts under basic conditions.
The importance of the biaryl motif in biologically significant
natural products as well as its pivotal role in unnatural
systems of interestsparticularly as the chiral scaffold of
many asymmetric catalysts1shas stimulated the development
of numerous methods for its construction.2 The original and
most widely used route to biaryls is via the Ullmann reaction,
the copper-mediated homocoupling of aryl halides.3 The need
to avoid the harsh conditions typically required for Ullmann
couplings (neat, >200 °C) has motivated the search for
milder variations.4,5 Of particular significance are methods
that utilize zerovalent nickel catalysts, wherein a co-reductant
such as zinc or electrochemical reduction regenerates the
catalytically active species.6 The relatively few palladium
mediated homocouplings reported to date have either not
been general or, as with the nickel procedures, require
inconvenient reaction conditions to regenerate the active Pd0
species.7,8 In connection with our interest in aryl coupling
reactions,9 we have examined many different conditions for
(4) (a) Cohen, T.; Cristea, I. J. Org. Chem. 1975, 40, 3649-3651. (b)
Ziegler, F. E.; Chliwner, I.; Fowler, K. W.; Kanfer, S. J.; Kuo, S. J.; Sinha,
N. D. J. Am. Chem. Soc. 1980, 102, 790-798.
(5) A remarkably mild procedure was recently reported for the Ullmann
coupling. The procedure requires the use of 3 equiv of copper(I) thiophene
carboxylate and necessitates the presence of a ligating functionality ortho
to the aryl halide: Zhang, S.; Zhang, D.; Liebeskind, L. S. J. Org. Chem.
1997, 62, 2312-2313.
(6) (a) Semmelhack, M. F.; Helquist, P. M.; Jones, L. D. J. Am. Chem.
Soc. 1971, 93, 5908-5910. (b) Jutand, A.; Mosleh, A. Synlett 1993, 568-
570. (c) Percec, V.; Bae, J.-Y.; Zhao, M.; Hill, D. H. J. Org. Chem. 1995,
60, 1066-1069.
(7) For an excellent overview on the use of palladium reagents in organic
synthesis, see: Tsuji, J. Palladium Reagents and Catalysts; Wiley: New
York, 1995.
(1) (a) Noyori, R.; Takaya, H. Acc. Chem. Res. 1990, 23, 345-350. (b)
Rosini, C.; Franzini, L.; Raffaelli, A.; Salvadori, P. Synthesis 1992, 503-
517.
(2) (a) Sainsbury, M. Tetrahedron 1980, 36, 3327-3359. (b) Bringmann,
G.; Walter, R.; Weirich, R. Angew. Chem., Int. Ed. Engl. 1990, 29, 977-
991. (c) Bringmann, G.; Walter, R.; Weirich, R. In StereoselectiVe Synthesis;
Houben-Weyl, 4th ed.; Helmchen, G., Hoffmann, R. W., Mulzer, J.,
Schaumann, E., Eds.; Georg Thieme Verlag: Stuttgart, 1995; Vol. E21a,
pp 567-586.
(3) (a) Fanta, P. E. Synthesis 1974, 9-21. For recent applications, see:
(b) Meyers, A. I. J. Heterocycl. Chem. 1998, 35, 991-1002. (c) Degnan,
A. P.; Meyers, A. I. J. Am. Chem. Soc. 1999, 121, 2762-2769.
(8) (a) Clark, F. R. S.; Norman, R. O. C.; Thomas, C. B. J. Chem. Soc.,
Perkin Trans. 1 1975, 121-125. (b) Uchiyama, M.; Suzuki, T.; Yamakazi,
Y. Chem. Lett. 1983, 1165-1166. (c) Torii, S.; Tanaka, H.; Morisaki, K.
Tetrahedron Lett. 1985, 26, 1655-1658. (d) Jutand, A.; Negri, S.; Mosleh,
A. J. Chem. Soc., Chem. Commun. 1992, 1729-1730.
10.1021/ol990872+ CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/17/1999

Table 1. Effect of Changing Reagents and Reaction Conditions on the Yield of 2a
the homocoupling of aryl halides and report here a simple,
general method for carrying out such couplings.10
more slowly when DMA was added to a mixture of all the
reagents. Hydroquinone is essential for the success of the
reaction; its omission or replacement with catechol or
benzoquinone resulted in recovery of most of the starting
material.12 The coupling proceeded more rapidly using As-
(o-tol)3 than with P(o-tol)3 (entries 2 and 4; also Table 2,
entries 5 and 7). The reaction worked almost as well with
NaOH and K2CO3 as bases. Of the different solvents
The initial serendipitous discovery of the palladium
catalyzed homocoupling reaction followed an attempted
intermolecular arylation of hydroquinone (HQ) with 4-iodo-
anisole (1a) under our standard conditions [5 mol % of
Herrmann’s palladacyclic catalyst (HC),11 Cs2CO3 (300 mol
%), in N,N-dimethylacetamide (DMA) at 95 °C].9 The
product of this reaction was not the expected 2-arylhydro-
quinone, but 4,4′-dimethoxybiphenyl (2a), which was isolated
in quantitative yield. A careful examination of the reaction
Table 2. Palladium-Catalyzed Ullmann Coupling of
Substituted Aryl Iodides and Bromides
conditions uncovered interesting aspects of this homocou-
pling reaction (Table 1). First, the HC-mediated reaction
worked well even when the reaction temperature was lowered
to 50 °C (entry 1). The use of a preformed palladacyclic
catalyst was not essential for a successful coupling. The
product was formed in comparably high yield when a
solution of 1:1 Pd(OAc)2-P(o-tol)3 in DMA was added to
the remaining reagents (entry 2). The order of mixing of the
reagents is important, however, and the reaction proceeded
(9) (a) Rawal, V. H.; Florjancic, A. S.; Singh, S. P. Tetrahedron Lett.
1994, 35, 8985-8988. (b) Hennings, D. D.; Iwasa, S.; Rawal, V. H. J.
Org. Chem. 1997, 62, 2-3. (c) Hennings, D. D.; Iwasa, S.; Rawal, V. H.
Tetrahedron Lett. 1997, 38, 6379-6382.
(10) This work is taken from the Ph.D. dissertation of D.D.H., The
University of Chicago, 1997. After this work had been completed and the
dissertation submitted, Lemaire and co-workers reported another example
of a palladium catalyzed Ullmann coupling reaction: Hassan, J.; Penalva,
V.; Lavenot, L.; Gozzi, C.; Lemaire, M. Tetrahedron 1998, 54, 13793-
13804 and references therein.
(11) (a) Herrmann, W. A.; Brossmer, C.; Ofele, K.; Reisinger, C.-P.;
Priermeier, T.; Beller, M.; Fischer, H. Angew. Chem., Int. Ed. Engl. 1995,
34, 1844-1848. (b) Beller, M.; Fischer, H.; Herrmann, W. A.; Ofele, K.;
Brossmer, C. Angew. Chem., Int. Ed. Engl. 1995, 34, 1848-1849.
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Org. Lett., Vol. 1, No. 8, 1999

examined (DMA, DMF, DME, MeCN, PhMe), the amide
solvents were the best. Intriguingly, in DMA or DMF, it was
possible to use substoichiometric quantities of hydroquinone
and still obtain the product in good yield (vide infra). The
rate of the reaction became progressively longer with
decreasing catalyst loading (entries 5-7).
Table 3. Inter- and Intramolecular Ullmann Coupling
Catalyzed by Palladium
The palladium-catalyzed homocoupling protocol that we
have developed is applicable to a wide range of aryl halides,
as evident from Table 2. The reactions were performed in
DMA using 2-4 mol % of Pd(OAc)2, an equal amount of
As(o-tol)3, 50 mol % of HQ, and 100 mol % of Cs2CO3.
The coupling reaction of both electron-rich and electron-
poor aryl iodides worked well. Substrates having a substituent
at the meta or para positions reacted particularly well and
afforded the corresponding biaryls in 86-99% yields (entries
1, 3, 5, 9, 10, 12, 13, and 15). The coupling of substrates
with ortho substitution progressed more slowly under the
standard conditions (conditions A, see Table 2), but pro-
ceeded well at a higher temperature and with 4 mol % of
the catalyst (conditions B; entries 4, 11). The clean formation
of 2,2′-dimethoxybiphenyl stands in contrast to Dyker’s
observed formation of triaryl products from the same starting
material under similar reaction conditions.13 As expected,
aryl bromides were less reactive than aryl iodides under the
standard conditions (entries 2, 8, and 14). However, the
Ullmann product is produced in high yield if the substrate
possesses an electron-withdrawing group (entry 14). Entry
6 is interesting in that it shows that the homocoupling
proceeds even at room temperature using 2 mol % of the
palladium catalyst (entry 6). Attempts to extend this coupling
methodology to aryl triflates failed due to the ready hydroly-
sis of the triflates to phenols under the reaction conditions.
The present method promotes the Ullmann coupling of
other aryl systems, as well as intramolecular couplings (Table
3). The reaction of 1-bromonaphthalene using 4 mol %
catalyst loading gave 1,1′-binaphthyl in 90% yield (entry 1).
However, the couplings of more hindered naphthyls, such
as 1-iodo-2-methoxynaphthalene or 1-bromo-2-methylnaph-
thalene, were unsuccessful; the main products in these cases
were the deiodinated monomers (cf. entry 2). The coupling
of 2-bromopyridine afforded 2,2′-dipyridyl in good yield
(entry 3). Symmetrical medium-ring biaryls can also be
formed using intramolecular Ullmann couplings, although
the rates of conversion were slower than expected for
intramolecular processes, presumably due to the steric
influence of the ortho substituents (entries 4-6). Under more
vigorous conditions, however, all three cyclization reactions
proceeded well and did not necessitate high dilution condi-
tions.
A plausible mechanism for the hydroquinone-mediated
palladium-catalyzed Ullmann reaction is shown in Scheme
1. Under the basic conditions used, the intermediate PdII
species (II) can eliminate benzoquinone (BQ) to form an
anionic arylpalladium species III, similar to the intermediates
proposed by Jutand.14 The reaction of III with Ar-I with
loss of I- would produce diarylpalladium species IV, from
which reductive elimination of Pd0 would give the Ullmann
product. An alternate possibility is that species II reacts
directly with the aryl iodide to produce a PdIV intermediate15
(V, eq 2), the redox chemistry of which would generate diaryl
(12) Hydroquinone evidently mediates the redox chemistry at the
palladium during these reductive coupling reactions. To our knowledge,
the use of hydroquinone as an in situ stoichiometric reductant of oxidized
forms of palladium has not previously been reported. The use of hydro-
quinone in this capacity complements the more widely recognized use of
benzoquinone to reoxidize Pd0 formed during a reaction. Cf.: Weider, P.
R.; Hegedus, L. S.; Asada, H.; D’Andreq, S. V. J. Org. Chem. 1985, 50,
4276-4281. We thank Professor Hegedus (Colorado State University) for
helpfull discussions.
(13) Dyker, G. Angew. Chem., Ind. Ed. Engl. 1992, 31, 1023-1025. The
present work shows that in the presence of a reducing agent the putative
palladacycle proposed by Dyker proceeds on to the Ullmann coupling stage
but not further.
Org. Lett., Vol. 1, No. 8, 1999
1207

The procedure is relatively mild and appears to have broad
applicability, being useful for the coupling of both electron-
deficient and electron-rich aromatic iodides and bromides.
In addition, this procedure also represents, to our knowledge,
the first use of hydroquinone as a stoichiometric in situ
reductant of higher oxidized palladium species.
Scheme 1
Acknowledgment. We thank The University of Chicago
and Pfizer Inc. for financial support. D.D.H. thanks the
Department of Education for a GAANN Fellowship.
Supporting Information Available: Experimental pro-
cedures and physical data. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL990872+
with 10 mol % of HQ it is possible to get the biaryl product in up to 50%
yield. These observations necessitate a pathway for regeneration of the HQ
from BQ during the reaction. A likely possibility is the Michael addition
of a carbonate ion to BQ to yield 1,2,4-trihydroxybenzene, after loss of
CO2 and tautomerization.17a,b Under the basic reaction conditions, the
trihydroxybenzene can then either directly reduce an oxidized form of Pd
or reduce a molecule of BQ to HQ and form hydroxybenzoquinone. More
highly oxidized benzenes can be formed similarly by further Michael
additions of carbonate onto oxidized benzoquinones.17c We have extensively
investigated the reaction of BQ with bases in various solvents and, consistent
with literature reports,17 have found that in DMA in the presence of Cs2-
CO3 or KOH BQ (room temperature, 4 h; or 70 °C, 2 h) is completely
converted to HQ, which was isolated in 40-50% yield, along with some
intractable black material.17a This formation of HQ from BQ under basic
conditions explains the inability to recover BQ at the end of a coupling
reaction as well as the feasibility of using less than a full 1 equiv of HQ
and yet get good yields of the biaryl products.
palladium IV and benzoquinone. Given the probable mecha-
nistic scenario, the complete absence of benzoquinone at the
end of the reaction is at first inexplicable and raises questions
as to the role of hydroquinone in the reaction.16
In summary, we have developed a convenient palladium-
catalyzed alternative to the Ullmann coupling of aryl halides.
(14) Jutand, A.; Mosleh, A. J. Org. Chem. 1997, 62, 261-274.
(15) For a review of PdIV species, see: Canty, A. J. Acc. Chem. Res.
1992, 25, 83-90.
(16) Although necessary for the present coupling method, a significant
percentage of the hydroquinone was recovered at the end of the coupling
reactions. Factoring in the recovered HQ (see Table 1), the present method
uses substoichiometric amounts of HQ. Indeed, we have found that even
(17) (a) Erdtman, H.; Granath, M. Acta Chem. Scand. 1954, 8, 811-
816. (b) Eigen, M.; Matthies, P. Chem. Ber. 1961, 94, 3309-3317. (c)
Fukuzumi, S.; Nakanishi, I.; Maruta, J.; Yorisue, T.; Suenobu, T.; Itoh, S.;
Arakawa, R.; Kadish, K. M. J. Am. Chem. Soc. 1998, 120, 6673-6680.
1208
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