Chemistry of Pentavalent Organobismuth Reagents. Regioselective α-Arylation of α,β-Unsaturated Carbonyls and Related Systems

Full text of DOI:10.1021/jo9905928

J . Org. Chem. 1999, 64, 6915-6917
6915
Sch em e 1
Sch em e 2
Ch em istr y of P en ta va len t Or ga n obism u th
Rea gen ts. Regioselective r-Ar yla tion of
r,â-Un sa tu r a ted Ca r bon yls a n d Rela ted
System s
Thomas Arnauld and Derek H. R. Barton†
Department of Chemistry, Texas A&M University,
P.O. Box 30012, College Station, Texas 77842-3012
J ean-Franc¸ois Normant
Laboratoire de Chimie des Organoe´le´ments associe´ au
CNRS, Universite´ Pierre et Marie Curie, 4 place J ussieu,
75252 Paris Cedex 05, France
Eric Doris*
R-phenylation with concomitant deconjugation of the
olefinic moiety (Scheme 1).
Service des Mole´cules Marque´es, Baˆt. 547, De´partement de
Biologie Cellulaire et Mole´culaire, CEA/ Saclay,
91191 Gif sur Yvette Cedex, France
Resu lts a n d Discu ssion
Received April 5, 1999
A postulated reaction mechanism is illustrated for the
phenylation reaction of ethyl crotonate (Scheme 2). The
first step involves the formation of the anionic species
by LDA/HMPA.7 This species can exist as the vinylogous
enolate 1, which then undergoes reaction with Ph3BiCl2.
The existence of such an O-Bi bonded intermediate 2
has been well demonstrated in the case of phenols.8 The
subsequent rearrangement,9 via collapse of the postu-
lated intermediate, leads to the corresponding R-phen-
ylated compound 3. Complexation of the bismuth with
the anionic oxygen could allow for the exclusive phen-
ylation of the neighboring R-carbon atom. A radical
phenylation process was unambiguously disproved by
Barton and co-workers by conducting experiments on
analogous systems in the presence of appropriate traps
and by ESR studies.10
The overall yields are, in most cases, satisfactory. The
reaction has successfully been extended to various sub-
strates (see Table 1). As mentioned above, the phenyl-
ation reaction of ethyl crotonate led to the expected
product with synchronous deconjugation of the double
bond (entry 1). No reconjugation was observed under our
conditions. However, if the reaction is run over an
extended period of time (e.g., overnight instead of 2 h),
the reconjugated product, ethyl 2-phenylcrotonate, be-
comes predominant. In an analogous manner, the reac-
tion of ethyl 2-phenylcrotonate (entry 2) gave the ex-
pected hindered R-bisaryl ester.
In tr od u ction
The arylation of organic materials remains an arduous
task for the synthetic chemist. Using bismuth reagents,1
a wide range of functional groups can be arylated and,
in some cases, alkylated. The effect of copper salts, or in
some instances of metallic copper, permits the arylation
of amines2 and alcohols.3 In appropriate examples, very
hindered compounds can be prepared in good yields.4 The
anionic chemistry associated with pentavalent bismuth
has also been extensively studied, showing once again
that these derivatives are the reagents of choice for the
arylation of compounds that contain a labile proton.
Systematic studies demonstrated that â-dicarbonyls,
phenols, enolizable ketones, and related compounds could
be arylated with ease and often in good yields.5 Indeed,
triarylbismuth(V) has emerged as a particularly efficient
aryl cation equivalent for the arylation of a wide variety
of substrates under mild conditions.6 Nevertheless, to the
best of our knowledge, the bismuth-mediated arylation
process has never been investigated on R,â-unsaturated
systems. We report in the present paper that, upon
treatment with LDA/HMPA (1.1 equiv) in THF and
triphenylbismuth dichloride (1.1 equiv), R,â-unsaturated
carbonyls and related systems undergo regioselective
* To whom correspondence should be addressed, e.mail: eric.doris@
cea.fr.
The monophenylation of phorone (entry 3) employing
stoichiometric amounts of both reagents (Bi and base)
afforded a selective reaction; that is, the monoaryl ketone
was formed preferentially over the diphenylated analogue
† Deceased March 16, 1998.
(1) For reviews on bismuth chemistry see: Freedman, L. D.; Doak,
G. O. Chem. Rev. 1982, 82, 15-57. Finet, J . P. Chem. Rev. 1989, 89,
1487-1501.
(2) Arnauld, T.; Barton, D. H. R.; Doris, E. Tetrahedron 1997, 53,
4137-4144 and references cited. Barton, D. H. R.; Finet, J . P.; Khamsi,
J . Tetrahedron Lett. 1987, 28, 887-890.
(7) Herrmann, J . L.; Kieczykowski, G. R.; Schlessinger, R. H.
Tetrahedron Lett. 1973, 2433-2436.
(3) Barton, D. H. R.; Finet, J . P. Pure Appl. Chem. 1987, 59, 937-
946. Barton, D. H. R.; Finet, J . P.; Khamsi, J .; Pichon, C. Tetrahedron
Lett. 1986, 27, 3619-3622.
(8) Barton, D. H. R.; Finet, J . P. Pure Appl. Chem. 1987, 59, 937-
946. Barton, D. H. R.; Bhatnagar, N. Y.; Blazejewski, J . C.; Charpiot,
B.; Finet, J . P.; Lester, D. J .; Motherwell, W. B.; Barros Papoula, M.
T.; Stanforth, S. P. J . Chem. Soc., Perkin Trans. 1 1985, 2657-2665.
(9) The rearrangement proceeds by ligand coupling between the ipso
carbon of the aryl group and the dienolate R-carbon atom; see ref 5.
(10) Barton, D. H. R.; Finet, J . P.; Giannotti, C.; Halley, F. J . Chem.
Soc., Perkin Trans. 1 1987, 241-249. See also: Combes, S.; Finet, J .
P. Tetrahedron 1999, 55, 3377-3386.
(4) Barton, D. H. R.; Barros Papoula, M. T.; Guilhem, J .; Motherwell,
W. B.; Pascard, C.; Tran Huu Dau, E. J . Chem. Soc., Chem. Commun.
1982, 732-734.
(5) Fedorov, A.; Combes, S.; Finet, J . P. Tetrahedron 1999, 55, 1341-
1352.
(6) Suzuki, H.; Matano, Y. In The Chemistry of Arsenic Antimony
and Bismuth; Norman, N. C., Ed.; Blackie: London, 1998; Chapter 6.
10.1021/jo9905928 CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/13/1999

6916 J . Org. Chem., Vol. 64, No. 18, 1999
Notes
Ta ble 1. Exa m p les of P h en yla tion of r,â-Un sa tu r a ted
rated esters, ketones, and related substrates in the
presence of a suitable base. The reaction proceeds with
deconjugation of the double bond.
System s
Exp er im en ta l Section
Gen er a l Meth od s. Melting points were determined on a
Thomas-Hoover microscope and are uncorrected. 1H NMR and
13C NMR spectra were recorded at 300 and 75 MHz using
residual CHCl3 (7.25 ppm) and CDCl3 (77 ppm) as internal
standard, respectively. Flash column chromatography was per-
formed on Baxter S/P brand silica gel (60 Å, 230-400 mesh).
All reactions were performed under Ar in a flame-dried flask
using anhydrous THF (dried by distillation over sodium) or
CH2Cl2 (dried by distillation over CaH2). Reagents were pur-
chased from Aldrich Chemical Co. except (E)-2,2-dimethylhex-
4-en-3-one that was synthesized according to literature proce-
dures.13
A Gen er a l P r oced u r e for th e Ar yla tion of r,â-Un sa tu -
r a ted Ca r bon yl System s Is Given for th e P h en yla tion of
Eth yl Cr oton a te (En tr y 1). At -78 °C, to a solution of LDA
(0.55 mL of a 2 M solution in heptane/THF/ethylbenzene, 1.1
equiv) and freshly distilled HMPA (0.19 mL, 1.1 equiv) in 10
mL of anhydrous THF is added dropwise ethyl crotonate (0.114
g, 1 mmol, 1 equiv). The solution is stirred at -78 °C for 20 min.
Ph3BiCl2 is then added in one portion, and the mixture is allowed
to warm to rt. After 2 h, the reaction is quenched with 10%
NH4Cl, and the aqueous layer is extracted twice with Et2O. The
combined organic layers are washed twice with H2O, dried over
MgSO4, filtered, and evaporated under reduced pressure. The
crude is purified on silica (eluent, hexanes/Et2O, 95/5) to yield
the desired phenylated product:14 oil, 0.120 g, 63%; 1H NMR
(CDCl3) δ 1.23 (t, J ) 7.2 Hz, 3H), 4.16 (q, J ) 7.2 Hz, 2H), 4.30
(d, J ) 8.1 Hz, 1H), 5.15 (d, J ) 17.1 Hz, 1H), 5.21 (d, J ) 9.9
Hz, 1H), 6.22 (ddd, J ) 8.1 Hz, J ) 9.9 Hz, J ) 17.1 Hz, 1H),
7.31 (m, 5H); 13C NMR (CDCl3) δ 14.0, 55.8, 60.9, 117.3, 127.2,
127.9, 128.6, 135.8, 138.1, 172.2.
a
b
Isolated yields unless otherwise stated. 2.2 equiv of LDA/
HMPA/Ph3BiCl2. c 1H NMR yield. The mass balance was ac-
counted for as the unreacted starting material.
d
2,2-Dip h en yl-3-bu ten oic Acid Eth yl Ester (En tr y 2): oil,
1
0.141 g, 55%; H NMR (CDCl3) δ 1.22 (t, J ) 7.2 Hz, 3H), 4.24
(>95:5). Surprisingly, we observed the introduction of a
second aryl group at the R′ position when 2 equiv of
reagent was utilized (entry 4), although one might have
expected that the acidity of the adjacent R proton would
be enhanced by the presence of the first aryl group and
therefore give rise to a tetrasubstituted R-carbon atom.
The process works equally well on hindered ketones
such as 2,2-dimethylhex-4-en-3-one (entry 5) but is not
successful for cyclohexenone (entry 6) where the classical
C-6 arylation is priviledged. The procedure was also
applied to 1-nitrocyclohex-1-ene using triethylamine as
base in CH2Cl2 (without HMPA). The deconjugated
arylated product was obtained in 86% yield (entry 7).
However, the allylic nitro proved to be especially labile
and was subjected to partial decomposition during col-
umn chromatography over silica, as already observed by
others.11
In some cases (entries 4 and 5), the final product
comigrates on silica with Ph3Bi, which results from
dismutation of Ph2BiCl. A strongly acidic workup with
acetic acid/catalytic trifluoroacetic acid permitted the
conversion of Ph3Bi into insoluble (AcO)3Bi.12 This al-
lowed the removal, from the reaction mixture, of the
apolar triphenylbismuth. This procedure tends, unfor-
tunately, to decrease the isolated yield of product.
In conclusion, we have shown that pentavalent bis-
muth reagents selectively R-arylate selected R,â-unsatu-
(q, J ) 7.2 Hz, 2H), 4.57 (dd, J ) 1.2 Hz, J ) 17.4 Hz, 1H), 5.37
(dd, J ) 1.2 Hz, J ) 10.8 Hz, 1H), 6.82 (dd, J ) 17.4 Hz, J )
10.8 Hz, 1H), 7.17 (m, 4H), 7.28 (m, 6H); 13C NMR (CDCl3) δ
13.9, 61.4, 64.4, 117.8, 127.0, 127.8, 129.4, 141.0, 141.1, 173.5;
HRMS calcd for C18H18O2 (M+) 267.1385, found 267.1381.
2,6-Dim eth yl-3-p h en ylh ep t-1,5-d ien -4-on e (En tr y 3): oil,
0.190 g, 89%; 1H NMR (CDCl3) δ 1.76 (s, 3H), 1.85 (s, 3H), 2.16
(s, 3H), 4.40 (s, 1H), 4.72 (s, 1H), 5.01 (s, 1H), 6.10 (s, 1H), 7.27
(m, 5H); 13C NMR (CDCl3) δ 20.7, 22.4, 27.7, 66.6, 114.4, 123.9,
126.9, 128.3, 129.3, 137.3, 143.7, 156.3, 198.2; HRMS calcd for
C15H19O 215.1436, found 215.1418.
2,6-Dim eth yl-3,5-d ip h en ylh ep t-1,6-d ien -4-on e (En tr y 4).
The reaction is run on a 1 mmol scale using 2.2 equiv of LDA/
HMPA and 2.2 equiv of Ph3BiCl2. Elimination of the apolar
Ph3Bi is achieved by treatment of the mixture of phenylated
product/Ph3Bi obtained after silica gel chromatography with
CH3COOH/CF3COOH (20/1, 0.16 mL) in THF and under reflux
for 2 h. After filtration, evaporation of the solvents, and
chromatography on silica (eluent, hexanes/Et2O: 96/4), the
arylated product is obtained as a 1/1 meso (a) and dl (b)
mixture: oil, 0.096 g, 34%; 1H NMR (CDCl3) δ 1.66 (s, 3Ha), 1.73
(s, 3Hb), 4.53 (s, 1Ha), 4.55 (s, 1Hb), 4.62 (s, 1Ha), 4.81 (s, 1Hb),
4.98 (s, 1Ha), 5.03 (s, 1Hb), 7.08 (m, 4Ha+b), 7.26 (m, 16Ha+b);
13C NMR (CDCl3) δ 22.2 (a), 22.3 (b), 64.9 (a + b), 114.6 (a + b),
127.2 (a), 127.3 (b), 128.4 (a + b) 129.1 (a), 129.3 (b), 136.4 (a),
136.5 (b), 143.0 (a + b), 205.2 (a), 205.4 (b); HMRS calcd for
C21H22NaO (M + Na)+ 313.1569, found 313.1561.
2,2-Dim eth yl-4-p h en ylh ex-5-en -3-on e15 (En tr y 5). To re-
move the contaminating Ph3Bi, the reaction is worked up and
purified as described above to yield 0.079 g of pure product: oil,
1
39%; H NMR (CDCl3) δ 1.13 (s, 9H), 4.85 (d, J ) 8.4 Hz, 1H),
(11) Beresis, R. T.; Masse, C. E.; Panek, J . S. J . Org. Chem. 1995,
60, 7714-7715.
(12) Arnauld, T.; Barton D. H. R.; Smith, J . A. Unpublished results.
Acidolysis of Ph3Bi by methanesulfonic acid has recently been reported;
see: Labrouille`re, M.; Le Roux, C.; Gaspard, H.; Laporterie, A.; Dubac,
J .; Desmurs, J . R. Tetrahedron Lett. 1999, 40, 285-286.
(13) Oare, D. A.; Henderson, M. A.; Sanner, M. A.; Heathcock, C.
H. J . Org. Chem. 1990, 55, 132-157.
(14) Phan, T. H.; Dahn, H. Helv. Chim. Acta 1976, 59, 335-348.
(15) Collin, J .; Bied, C.; Kagan, H. B. Tetrahedron Lett. 1991, 32,
629-630.

Notes
J . Org. Chem., Vol. 64, No. 18, 1999 6917
5.07 (m, 2H), 6.14 (ddd, J ) 17.1 Hz, J )10.2 Hz, J ) 8.4 Hz,
1H), 7.25 (m, 5H); 13C NMR (CDCl3) δ 26.3, 45.5, 56.7, 116.0,
126.9, 128.1, 128.6, 138.3, 138.7.
pressure, and the crude is taken into ether. The precipitate is
filtered over neutral alumina. After evaporation of the solvent,
the crude is purified by chromatography on silica (eluent,
hexanes/Et2O, 95/5) to yield the desired phenylated compound:
6-P h en ylcycloh ex-2-en -1-on e (En tr y 6): white solid, mp
1
1
68-69 °C (lit.16 mp 65-67 °C), 0.098 g, 57%; H NMR (CDCl3)
oil, 0.018 g, 20%; H NMR (CDCl3) δ 1.53-1.72 (m, 2H), 2.08-
δ 2.29 (m, 2H), 2.47 (m, 2H), 3.61 (t, J ) 8.1 Hz, 1H), 6.16 (dt,
J ) 10.2 Hz, J ) 1.8 Hz, 1H), 7.03 (dt, J ) 10.2 Hz, J ) 3.9 Hz,
1H), 7.16 (m, 2H), 7.30 (m, 3H); 13C NMR (CDCl3) δ 25.4, 30.6,
53.3, 126.8, 128.2, 128.4, 130.2, 139.3, 149.9, 199.1.
1-Nitr o-1-p h en ylcycloh ex-2-en e (En tr y 7). To a solution
of 1-nitrocyclohex-1-ene (0.056 g, 0.44 mmol, 1 equiv) in 2 mL
of anhydrous CH2Cl2 are added, at 0 °C, Ph3BiCl2 (0.248 g, 1.1
equiv) and, dropwise, NEt3 (0.068 mL, 1.1 equiv). The reaction
is stirred for 2 h at rt. The solvent is evaporated under reduced
2.21 (m, 3H), 2.85-2.93 (m, 1H), 6.24 (m, 1H), 6.38 (d, J ) 10.2
Hz, 1H), 7.33-7.38 (m, 5H); 13C NMR (CDCl3) δ 19.0, 24.6, 34.5,
91.6, 125.5, 125.9, 128.3, 128.6, 134.4, 140.4.
Ack n ow led gm en t. Dr. J . Albert Ferreira is grate-
fully acknowledged for reviewing this manuscript.
Su p p or tin g In for m a tion Ava ila ble: Reproductions of 1H
and 13C NMR spectra of compounds described in entries 2-4
and 7. This material is available free of charge via the Internet
at http://pubs.acs.org.
(16) Reich, H. J .; Renga, J . M.; Reich, I. L. J . Am. Chem. Soc. 1975,
97, 5434-5447.
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