Synthesis of biaryls via AlCl3 catalyzed domino reaction involving cyclization, dehydration, and oxidation

Article abstract of DOI:10.1021/ol202638m

A new chemical access has been developed to synthesize biaryls from substituted acetophenones, phenylacetones, dihydrochalcone, and 2-acetylnaphthalene in reasonably good yields at room temperature via a domino reaction sequence of AlCl₃ catalyzed cyclization, dehydration, and then oxidation.

Full text of DOI:10.1021/ol202638m

ORGANIC
LETTERS
2011
Vol. 13, No. 23
6140–6143
Synthesis of Biaryls via AlCl3 Catalyzed
Domino Reaction Involving Cyclization,
Dehydration, and Oxidation
Tadigoppula Narender,* Satinath Sarkar, Kandikonda Rajendar, and Sriniwas Tiwari
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute,
Lucknow-226001, U.P., India
t_narendra@cdri.res.in
Received July 27, 2011
ABSTRACT
A new chemical access has been developed to synthesize biaryls from substituted acetophenones, phenylacetones, dihydrochalcone, and
2-acetylnaphthalene in reasonably good yields at room temperature via a domino reaction sequence of AlCl3 catalyzed cyclization, dehydration,
and then oxidation.
Domino or cascade reactions are sequential transforma-
tions where one reaction occurs after the other in the same
reaction vessel. These cascading processes can include two
or more reactions in the same vessel without addition of
other reagents or modification of the reaction conditions.
Domino reactions are classified in various ways; examples
include cationic, anionic, radical, pericyclic, photochemi-
cal, and metal catalyzed.1 Pericyclic domino reactions such
as cycloadditions, sigmatropic rearrangements, electrocy-
clic reactions, ene reactions, and carbonyl-ene reactions
are frequently used for the synthesis of a carbocyclic frame-
work.2 We intended on developing a new method for the
synthesis of biaryls based on Lewis acid catalyzed pericyclic
domino reactions.
Figure 1. Examples of biaryl containing drugs and fungicide.
The biaryl scaffold is a widely occurring component
in many biologically active molecules (Figure 1) such
as Felbinac3 (anti-inflammatory), (()-Glaucine4 (anti-
inflammatory), Biphenomycin5 (antibiotic), Diovan6
(hypertension), Micardis7 (hypertension), and Boscalid8
(1) Tietze, L. F.; Brasche, G.; Gericke, L. Domino Reactions in
Organic Synthesis; Wiley-VCH: Weinheim, Germany, 2006; pp 1À9.
(2) Poulin, J.; Grise-Bard, C.; M. Barriault, L. Chem. Soc. Rev. 2009,
38, 3092.
(3) Hosie, G.; Bird, H. Eur. J. Rheumatol. Infllamm. 1994, 14, 21.
(4) Cortijo, J.; Villagrasa, V.; Pons, R.; Berto, L.; Marti-Cabrera, M.;
Martinez-Losa, M.; Domenech, T.; Beleta, J.; Morcillo, E. J. Br. J.
Pharmacol. 1999, 127, 1641.
(5) Markham, A.; Goa, K. L. Drugs 1997, 54, 299.
(6) Croam, K. F.; Keating., G. M. Am. J. Cardiovasc. Drugs 2004, 4,
395.
(7) (a) Sharpe, M.; Jarvis, B.; Goa, K. L. Drugs 2001, 61, 1501. (b)
Yusuf, S. Am. J. Cardiol. 2002, 89 (2A), 18A.
(8) Matheran, M. E.; Parchas, M. Plant Dis. 2004, 88, 66.
r
10.1021/ol202638m
Published on Web 10/31/2011
2011 American Chemical Society

(fungicide). Biaryls are also used in several industrial
applications such as polymers, advanced materials, and
liquid crystals (LCD).9
Scheme 1. Synthesis of Biaryl via AlCl3 Catalyzed Domino
Reaction from Substituted Acetophenonesa
The synthesis of biaryls has a long history from the
old Pschorr reaction (1896)10 to several transition metal
catalyzed cross-coupling reactions such as Kumada,11
Negishi,12 Stille,13 Suzuki,14 Hiyama,15 Sonogashira,16 and
further improvements in these procedures. Alternative
methods such as direct arylation through CÀH bond
activation17 anddecarboxylative cross-coupling reactions18
in place of conventional coupling reactions have begun to
emerge in the past few years. These methods also however
use transition metal catalysts. Synthesis of biaryls without
coupling reactions are also welcomed by the chemical
community. Recently, Shahzad and co-workers synthe-
sized the phenyl-naphthyl compounds through cyclization
ofβ-ketoestersubstitutedstilbenederivativesusingPhSeCl
as a electrophile in the presence of Lewis acids.19 Similarly
Qun Liu and co-workers developed a new route for p-
terphenyls and heteroaryl analogues including bipyridines
via [5C 1C(N)] annulation of aryl-alkenoyl ketene-(S,S)-
acetals (five carbon 1,5-bielectrophilic species) with ni-
troethane or ammonium acetate.20 In this letter we also
wish to report a new chemical access for the synthesis of
biaryls from substituted acetophenones, phenylacetones,
dihydrochalcones, and 2-acetylnaphthalene via an AlCl3
catalyzed domino reaction.21
a Reagents and conditions: (a) Prenyl bromide, NaH, DMF, À20 °C
to rt, 3.5À7 h; (b) 20 mol % AlCl3, Dry Dioxane, rt.
Table 1. Reaction Time and Isolated Yields of Biaryls from
Substituted Acetophenones
In order to synthesize biaryls without coupling reac-
tions, commercially available acetophenone (1a) was preny-
lated using NaH to generate the key intermediate 2a
(Scheme 1).21We anticipated that Lewis acids might induce
a carbonyl-ene reaction. To explore this idea the preny-
lated compound 2a was reacted with a few Lewis acids
(BF3 Et2O, ZnCl2, TiCl4, AlCl3) and also inorganic acids
3
at various molar ratios. Among them 20 mol % AlCl3 in
dry dioxane provided the desired biaryl 3a (3-methyl-
biphenyl) in moderate yield (Scheme 1 and Table1).21
Encouraged by these results the domino reaction was
explored with various substituted aromatic ketones 2bÀf
and obtained respective biaryls 3bÀf with moderate to
good yields (Table 1) under similar reaction conditions.
The versatility of this new method and reaction condi-
tions was further examined with substituted phenylace-
tones. The compounds 5aÀ5e were prepared from
respective phenylacetones (4aÀ4e) by a prenylation reac-
tion and subsequent reaction with 20 mol % AlCl3 in dry
dioxane provided the desired biaryls 6aÀ6e in good yields
(Scheme 2, Table 2).21 To expand the reaction utility, an
attempt was made to synthesize biaryls from geranylated
derivative 7 instead of prenylated derivatives (Scheme 2).
The biaryl 8 formed from 7 has an aryl fused tetrahydro-
naphthalene skeleton due to aromatization of a geranyl
group and subsequent cyclization of a C-5 side chain of the
geranyl group with a newly generated aromatic ring.
To synthesize phenyl-naphthalene, 2-acetylnaphthalene
(9) was prenylated to give an intermediate 10 and further
reaction with AlCl3 provided 2-m-tolyl-naphthalene (11) in
good yields (Scheme 3). Prenylated dihydrochalcone 13
which was obtained from 12 was also tested for the forma-
tion of biaryls using a similar reaction protocol, which gave
benzylated biaryl 14 with 72% yield (Scheme 3).
(9) Poetsch, E. Kontakte 1988, 2, 15.
(10) Pschorr, R. Ber. 1896, 29, 496.
(11) Tamao, K.; Sumitani, K.; Kumada, M. J. Am. Chem. Soc. 1972,
94, 4374.
(12) (a) Negishi, E. Acc. Chem. Res. 1982, 15, 340. (b) Negishi, E.;
Anastasia, I. Chem. Rev. 2003, 103, 1979.
(13) (a) Milstein, D.; Stille., J. K. J. Am. Chem. Soc. 1978, 100, 3636.
(b) Stille, J. K. Angew. Chem., Int. Ed. 1986, 2, 508.
(14) (a) Suzuki., A. J. Organomet. Chem. 1999, 576, 147. (b) Miyaura,
N.; Suzuki., A. Chem. Rev. 1995, 95, 2457.
(15) (a) Hiyama, T. In Metal-catalyzed Cross-coupling Reactions:
Diederich, F., Stang, J., Eds.; Wiley-VCH: Weinheim, Germany, 1998; p
421. (b) Hiyama, T.; Shirakawa, E. Top. Curr. Chem. 2002, 219, 61.
(16) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 16, 4467.
(17) Godula, K.; Sames, D. Science 2006, 312, 67.
(18) Forgione, P.; Brochu, M.-C.; St-Onge, M.; Thesen, K. H.;
Bailey, M. D.; Bilodeau, F. J. Am. Chem. Soc. 2006, 128, 11350.
(19) Shahzad, S. A.; Vivant, C.; Wirth, T. Org. Lett. 2010, 12, 1364.
(20) Zhang, L.; Liang, F.; Cheng, X.; Liu, Q. J. Org. Chem. 2009, 74,
899.
(21) Please see the Supporting Information for experimental proce-
dures.
Org. Lett., Vol. 13, No. 23, 2011
6141

acetophenones (Table 1). It appears that the chairlike
transition state requires partial carbonyl oxygen in the
equatorial position to provide high yields. Thus, transition
state coordinates of 2a and 2cÀ2f would push the bulky
aryl group in the axial position. On the other hand, the
transition state coordinates of 5aÀ5e could easily arrange
to give the partial carbonyl oxygen and the vicinal aryl
group a 1,2-diequatorial coordinate. In the cases of 2b and
13, the highly electron-donating methoxy group may have
changed the transition state toward the starting material.
The above argument is also applied for the naphthyl
compound 10, since naphthyl is much better electron-
donating than phenyl or tolyl. On the other hand, 7 has
gone through two cyclizations to give 8, the second of
which has to be the slower reaction when compared to the
related cyclization of 5b (2.5 h, 79% yield; entry 2, Table 2)
and hence is rate-determining.
Scheme 2. Synthesis of Biaryls via AlCl3 Catalyzed Domino
Reaction from Substituted Phenylacetonesa
a Reagents and conditions: (a) NaH, DMF, À20 °C to rt, 3À4 h; (b)
20 mol % AlCl3, Dry Dioxane, rt.
The reaction mechanism for the formation of biaryls
from prenylated acetophenones (2aÀ2f), phenylacetones
(5aÀ5e), geranylated phenylacetone (7), 2-acetylnaphtha-
lene (10), and dihydrochalcone (13) appears to be a Lewis
acid catalyzed intramolecular carbonyl-ene reaction22 to
provide cyclobutanol intermediate I/IV followed by ring
expansion to give a six-membered carbocyclic ring as in II/V.
Table 2. Reaction Time and Isolated Yields of Biaryls from
Substituted Phenylacetones
Scheme 4. Possible Reaction Mechanism for the Formation of
Biaryls from Acetophenones and Phenylacetones via AlCl3
Catalyzed Domino Reaction Sequence
Scheme 3. Synthesis of Biaryls via AlCl3 Catalyzed Domino
Reaction from Substituted 2-Acetylnaphthalene and Dihydro-
chalconea
a Reagents and conditions: (a) Prenyl bromide, NaH, DMF, À20 °C
to rt, 3À4 h; (b) 20 mol % AlCl3, Dry Dioxane, rt.
(22) (a) Snider, B. B. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 2; p 527. (b) Mikami,
K.; Shimizu, M. Chem. Rev. 1992, 92, 1021. (c) Snider, B. B. Acc. Chem.
Res. 1980, 13, 426. (d) Oppolzer, W.; Snieckus, V. Angew. Chem., Int. Ed.
Engl. 1978, 17, 476. (e) Hoffmann, H. M. R. Angew. Chem., Int. Ed. Engl.
1969, 8, 556. (f) Dias, L. C. Curr. Org. Chem. 2000, 4, 305.
Comparatively high yields and shorter reaction times
were observed in the biaryls formation from substituted
phenylacetones (Table 2) compared to those of substituted
6142
Org. Lett., Vol. 13, No. 23, 2011

The dehydration of II/V and subsequent dehydrogenation
(oxidative aromatization)23might be furnishing the desired
biaryl skeleton (Scheme 4). To find out the oxidative
aromatization process by a redox cycle (disproportion-
ation: formation of dihydro or tetrahydro derivatives of
III, VI, or VII), all the minor products were isolated from
the reaction mixture and their NMR spectral data exam-
ined. Our NMR data, however, indicated that none of them
belongs to such a class. We therefore anticipate that the
dehydrogenation of diene intermediate III, VI, or VII might
be due to air oxidation in the presence of AlCl3.23 Stabiliza-
tion of III, VI, or VII could be the driving force in losing the
hydrogen by air oxidation to form the aromatic compound.
Further studies however are required to confirm the exact
reaction mechanism in the formation of biaryls (Scheme 4).
In conclusion we have developed a novel chemical access
for the synthesis of substituted biaryls in moderate to good
yields for the first time from prenylated acetophenones,
phenylacetones, dihydrochalcone, 2-acetylnaphthalene,
and geranylated phenylacetone using AlCl3. The biaryl
formation appears to be via an AlCl3 catalyzed domino
reaction sequence, i.e. ring formation (intramolecular
carbonyl-ene reaction and ring expansion), dehydration,
and then oxidative aromatization. Some of the biaryls
synthesized using our method would not be readily acces-
sible from alternative methods (for example, compounds
6aÀ6e, 8, and 14). This new method avoids transition
metal catalyzed cross-coupling reactions, CÀH bond acti-
vation, and decarboxylative biaryl coupling. Further work
is in progress at our laboratory to demonstrate the applica-
tion of this methodology for the synthesis of stilbenes,
biarylethers, biphenylmethanes, and other natural pro-
ducts of biological importance without coupling reactions.
Acknowledgment. The authors thank Dr. T. K. Chak-
raborty, Director, CSIR-CDRI for constant encourage-
ment on the program of natural product’s synthesis; Dr. A.
Ravi Shankar, SAIF for 2D-NMR spectral data; Ms.
Anitha, KNMIPER, Ghaziabad and Ms. Tanu Sharma,
Career College, Bhopal for technical support; and CSIR
and DST, New Delhi for financial support. This is CDRI
Manuscript number 108/2011/TN and Communication
number 8152.
Supporting Information Available. Experimental pro-
cedures and spectroscopic characterization of all new
1
compounds along with their H and 13C NMR, mass,
and 2D-NMR spectral data for 3b, 6b, 8. This material
is available free of charge via the Internet at http://pubs.
acs.org.
(23) Corma, A.; Garcia, H. Chem. Rev. 2001, 102, 3837.
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