A convergent radical-based route to biaryls

Article abstract of DOI:10.1021/ol9010294

A route to blaryl-3-carboxylate esters Involving a radical 1,2-aryl migration has been developed. This strategy hinges on the radical addition of xanthate 2 to olefin 1 causing a 1,2-aryl shift leading to α,β- unsaturated ester 5, which Is then converted

Full text of DOI:10.1021/ol9010294

ORGANIC
LETTERS
2009
Vol. 11, No. 13
2832-2835
A Convergent Radical-Based Route to
Biaryls
Be´atrice Quiclet-Sire, Guillaume Revol,* and Samir Z. Zard*
Laboratoire de Synthe`se Organique, CNRS UMR 7652, De´partement de Chimie,
Ecole Polytechnique, 91128 Palaiseau, France
reVol@dcso.polytechnique.fr; zard@poly.polytechnique.fr
Received May 11, 2009
ABSTRACT
A route to biaryl-3-carboxylate esters involving a radical 1,2-aryl migration has been developed. This strategy hinges on the radical addition
of xanthate 2 to olefin 1 causing a 1,2-aryl shift leading to r,ꢀ-unsaturated ester 5, which is then converted into biaryl 10 by treatment with
DBU under microwave heating.
Biaryls and, more generally, polyaryls are important building
blocks in organic chemistry. They are present in various
natural products,1 as pharmacophores in potential drugs,2 and
as ligands for many catalysts.3 The most common approaches
to these compounds involve a transition-metal-mediated
coupling of two monoaryl units such as the Suzuki,4 Stille,5
Negishi,6 and Kharasch7 coupling. Although these methods
are broadly used and very efficient, alternative strategies8
are still of interest for the synthesis of highly functionalized
biaryls. While radical chemistry is often used to create new
C-C bonds, there are only a few syntheses of biaryls
involving direct arylation of arenes under photochemical or
reductive radical conditions.9
unsaturated sulfone and the one-pot isomerization of the
resulting R,ꢀ-unsaturated ester, cyclization, elimination, and
aerial oxidation (Schemes 1 and 2).
Scheme 1. 1,2-Aryl Migration
We now describe a two-step sequence to biaryls by a two-
step sequence: the radical addition of a xanthate onto a δ,γ-
(1) Schmidt, U.; Leitenberger, V.; Griesser, H.; Schmidt, J.; Meyer, R.
Synthesis 1992, 1248.
(2) (a) Nicolaou, K. C.; Boddy, C. N. C.; Bra¨se, S.; Winssinger, N.
Angew. Chem., Int. Ed. 1999, 38, 2096. (b) Gossen, L. J.; Melzer, B. J.
Org. Chem. 2007, 72, 7473. (c) Boisnard, S.; Carbonnelle, A. C.; Zhu, J.
Org. Lett. 2001, 3, 2061.
(3) Brunel, J. M. Chem. ReV. 2005, 105, 857.
(4) Miyaura, N.; Suzuki, A. Chem. ReV. 2002, 102, 1359.
(5) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508.
(6) King, O.; Okukado, N.; Negishi, E. J. J. Chem. Soc., Chem. Commun.
1977, 683.
As part of our studies of the chemistry of xanthates,10 we
found that the radical addition of xanthate 2 to an alkene
such as 1 led to an R,ꢀ-unsaturated ester 5. The addition
gives first adduct radical 3, which undergoes a reversible
ipso cyclization to form intermediate radical 4 (Scheme 1).
(7) Tamao, K.; Sumitani, K.; Kumada, M. J. Am. Chem. Soc. 1972, 94,
4374.
(8) Stanforth, S. P. Tetrahedron 1998, 54, 262.
10.1021/ol9010294 CCC: $40.75
Published on Web 06/03/2009
 2009 American Chemical Society

on p-chlorobenzaldehyde, followed by conjugate addition of
vinylmagnesium cuprate onto the resulting R-unsaturated
ester. Our first attempt at an annulation-aromatization
sequence under classical conditions (MeNO2, K2CO3, EtOH)
afforded the expected nitro intermediate 6a but also sur-
prinsingly a little biaryl 10a.
Scheme 2. Annulation-Aromatization Process
We suspected that this biaryl arose from a one-pot, four-
step reaction (Scheme 2). The sequence began with the
isomerization of the double bond under basic conditions.
Deprotonation in the R-position of the ester group to give
7, followed by intramolecular cyclization on the ketone to
form alcohol 8, elimination of water to give 9, and aroma-
tization by aerial oxidation. We confirmed this sequence by
reacting 5a in ethanol with K2CO3 at 50 °C under air and
isolated the same product 10a in a useful yield of 55%. The
corresponding elimination intermediate 9a was observed by
NMR, suggesting that the limiting step is the oxidation to
the desired biaryl. It is important, at this stage, to emphasize
the crucial, even if indirect, role played by the aromatic ring
present in substrates 3 in controlling the regiochemistry of
the process. By facilitating and favoring the migration of
the olefin to give isomer 7 (this isomerization occurs readily
and practically quantitatively, even with a weak base such
as triethylamine), the possibility of initial unsaturated ester
acting as a Michael acceptor for the enolate of the ketone
The R,ꢀ-unsaturated ester 5 is then produced through a 1,2-
aryl shift11 and, for all practical purposes, irreversible loss
of a methanesulfonyl radical by ꢀ-elimination.12 The latter
gives off sulfur dioxide to form a methyl radical that can
propagate the chain.
We previously applied the aryl migration sequence to
efficiently form 3-arylpiperidines,13 yet the R,ꢀ-unsaturated
esters 3 could also be interesting precursors to biaryls. We
initially considered the approach in Scheme 2 involving a
Michael addition and Henry reaction of nitromethane fol-
lowed by elimination of the elements of water and nitrous
acid and ultimate oxidation.14
Olefin 1a was easily prepared in two steps by the
Knoevenagel condensation of ethyl methanesulfonylacetate
Table 1. Synthesis of R,ꢀ-Unsaturated Ester 5a-o (R ) 4-Chlorophenyl, R′ ) 3-Fluorophenyl)
a Yields refer to isolated pure product. b NMR calculated yield. All products were identified spectroscopically except 5c. Method A: Olefin 1 (1 equiv)
and xanthate 2 (1.5 equiv) were heated in refluxing 1,2-dichloroethane (2 mL/mmol), and 5 mol % of DLP was added every hour during 7 h. c The reaction
time was extended to 15 h. Method B: Olefin 2 (1 equiv) and xanthate 2 (1.5 equiv) were heated in refluxing chlorobenzene (2 mL/mmol), and 5 mol % of
DLP was added every 15 min for 2 h 15.
Org. Lett., Vol. 11, No. 13, 2009
2833

Table 2. Biaryls Obtained 4a-o (R ) 4-Chlorophenyl, R′ ) 3-Fluorophenyl)
a Yields refer to isolated pure product. b Yields refer to isolated slightly impure product. All products were identified spectroscopically. Method A:
Substrate 5 (1 equiv), K2CO3 (2 equiv), in ethanol (2 mL/mmol), 50 °C for 2 days. Method B: Substrate 5 (1 equiv), DBU (5 equiv), 20 °C, 5 days. Method
C: Substrate 5 (1 equiv), DBU (1 equiv), DMF (10 mL/mmol), 150 °C for 10 min under microwave irradiation then 20 °C for 2 days under air.
is completely eliminated. Such an alternate mode of cycliza-
tion leading to a simple cyclohexanone would have been
expected to dominate in the absence of the aromatic ring, in
view of the greater acidity of ketones as compared to ordinary
esters. Another indirect role of the aromatic ring is to
sterically force the alkene to adopt the E-geometry (as shown
for 7 in Scheme 2), which is absolutely necessary for the
ring closure.
Having inadvertently found a convenient route to biaryls,
we next prepared further precursors by radical addition of
various xanthates 2 to olefins 1a and 1b. (Table 1). This
method is effective in producing the required complex R,ꢀ-
unsaturated esters 5a-o in yields ranging from 52 to 81%.
Cyclobutanone xanthates 2k-m were obtained through a
new route we recently developed.15 Two sets of conditions
were used to carry out the radical addition: mild conditions
(refluxing 1,2-dichloroethane) for sligthly sensitive alkyl
xanthates such as cyclobutanone-, cyclopropyl ketone-, or
acetal-containing derivatives and harsher conditions (reflux-
(10) For reviews of the xanthate transfer, see: (a) Zard, S. Z. Angew.
Chem., Int. Ed. Engl. 1997, 36, 672. (b) Zard, S. Z. In Radicals in Organic
Synthesys; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001;
Vol. 1, p 90. (c) Quiclet-Sire, B.; Zard, S. Z. Chem.sEur. J. 2006, 12,
6002. (d) Quiclet-Sire, B.; Zard, S. Z. Top. Curr. Chem. 2006, 264, 201.
(e) Zard, S. Z. Org. Biomol. Chem. 2007, 5, 205.
(11) (a) Abeywickrema, A. N.; Beckwith, A. L. J.; Gerba, S. J. Org.
Chem. 1987, 52, 4072. (b) Parker, T. L.; Spero, D. M.; Irman, K.
Tetrahedron Lett. 1986, 27, 2833. (c) McNab, H. J. Chem. Soc., Chem.
Commun. 1990, 543. (d) Ishibashi, H.; Kobayashi, T.; Nakashima, S.;
Tamura, O. J. Org. Chem. 2000, 65, 9022. (e) Ishibashi, H.; Ohata, K.;
Niihara, M.; Sato, T.; Ikeda, M. J. Chem. Soc., Perkin Trans. 1 2000, 547.
(f) Ouvry, G.; Zard, S. Z. Synlett 2003, 1627.
(12) Quiclet-Sire, B.; Zard, S. Z. J. Am. Chem. Soc. 1996, 118, 1209.
(13) Georghe, A. Quiclet-Sire, B. Villa, X. Zard, S. Z. Tetrahedron 2007,
63, 7187. See also ref 11f.
(14) For conceptually similar approaches, see: (a) Zhang, Q.; Sun, S.;
Hu, J.; Liu, Q.; Tan, J. J. Org. Chem. 2007, 72, 139. (b) Ballini, R.; Palmieri,
A.; Rizhi, P. Tetrahedron 2007, 63, 12099.
(9) (a) Martinez-Barrasa, V.; Garca de Viedma, A.; Burgos, C.; Alvarez-
Builla, J. J. Org. Lett. 2000, 2, 3933. (b) Sharma, R. K.; Kharasch, N. Angew.
Chem., Int. Ed. Engl. 1968, 7, 36. (c) Taylor, E. C.; Kienzie, F.; McKillop,
A. J. Am. Chem. Soc. 1970, 92, 6088. (d) Bonfand, E.; Forslund, L.;
Motherwell, W. B.; Vasquez, S. Synlett 2000, 4, 475. (e) Terashima, M.;
Seki, K.; Yoshida, C.; Ohkura, K.; Kanaoka, Y. Chem. Pharm. Bull. 1985,
33, 1009, and references cited therein.
(15) Heng, R.; Quiclet-Sire, B.; Zard, S. Z. Tetrahedron Lett. 2009, 50,
3613.
2834
Org. Lett., Vol. 11, No. 13, 2009

ing chlorobenzene) leading to shorter reaction times and
suitable for more robust xanthates such as 2c-h.
These observations are supported by the two experiments
summarized in Scheme 4. Heating substrate 5m in the
Unfortunately, when we subjected the various substrates
to the above conditions, many biaryls were obtained in poor
yield (Table 2, entries 3, 5, 9, and 11). As mentioned
previously, we believed that the slow step was the aroma-
tization, but a more careful monitoring of the reaction
allowed us to also observe the intermediate alcohol resulting
from the cyclization 8. Clearly, the slow steps of the reaction
were both the elimination and the aromatization at 20 °C in
DBU. We chose therefore to use microwave heating to
enhance the elimination of the alcohol and improve the aerial
oxidation. Thus, alkene 5a was dissolved in DMF with 1
equiv of DBU and then heated to 150 °C for 10 min and
left at room temperature for 2 days under air. These proved
to be very useful conditions as triaryls 10d,g,h (Table 2,
entries 2-4 and 7-10) and biaryls from hindered ketones
10c,l,k, which did not form under the previous conditions,
could be readily obtained.
Scheme 4
In the case of 5i, the normal oxidative aromatization to
give 10i was in competition with aromatization through
elimination of one of the methoxy groups leading to 10i′
(Table 2, entry 9). Loss of the methoxy groups was the
dominant pathway for 5j (Table 2, entry 10), and compound
10j was practically the only product. The R,ꢀ-unsaturated
ester 5l featuring a cyclobutanone ring (Table 2, entry 12)
also did not react as expected. Indeed, two other biaryls 10l′
and 10l′′ were detected by NMR, and 10l′′ was isolated in
a small yield. These products result from the opening of the
aryl-cyclobutanone ring under the basic conditions. As
outlined in Scheme 3, it appears that the ring-opening is
microwawe oven in degassed DMF and under an inert
atmosphere gave rise to two ring-opened products 10m′ and
10m′′ in a good combined yield of 73%. In contrast, exposure
to DBU at room temperature furnished the intermediate
cyclized alcohol, which without purification, was treated with
p-toluenesulfonic acid in toluene at room temperature for 1
day to provide compound 10m in modest yield. Under these
conditions, hydrolysis and saponification occurred but the
cyclobutane ring remained intact.
Numerous approaches to biaryls already exist, as diverse
strategies as metal-catalyzed couplings,16 as Diels-Alder
cycloadditions,17 or through direct arylation, in addition to
radical couplings.9 The present route to complex bi- or
triaryls complements previous methods. It employs cheap
and readily available starting materials, enables the formation
of relativly sensitive biarylcylobutanones such as 4k-m, and
allows the introduction of a number of functional groups in
a pattern otherwise not easily accessible.
Scheme 3. Ring-Opening Mechanism
Acknowledgment. G.R. thanks Ecole Polytechnique for
a studentship.
Supporting Information Available: Experimental pro-
1
cedures, full spectroscopic data, and copies of H and 13C
NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL9010294
favored by the bromophenyl group which stabilizes the anion
and encourages the ring-opening. Indeed, no ring-opening
product was detected for cyclobutanone precurssor 5k (Table
2, entry 11) containing only an ethyl substituent.
(16) Goosen, L. J.; Rodriguez, N.; Meltzer, B.; Linder, C.; Deng, G.;
Levy, L. M. J. Am. Chem. Soc. 2007, 129, 4824.
(17) Naffziger, M. R.; Ashburn, B. O.; Perkins, J. R.; Carter, R. G. J.
Org. Chem. 2007, 72, 9857.
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