Palladium-catalyzed stereocontrolled vinylation of azoles and phenothiazine

Article abstract of DOI:10.1021/ol0172370

(formula presented) Vinylation of various azoles (pyrrole, indole, carbazole, and their derivatives) and phenothiazine with vinyl bromides catalyzed by palladium-phosphine complexes results in the respective N-vinylazoles in 30-99% yields. This reaction w

Full text of DOI:10.1021/ol0172370

ORGANIC
LETTERS
2002
Vol. 4, No. 4
623-626
Palladium-Catalyzed Stereocontrolled
Vinylation of Azoles and Phenothiazine
Artyom Y. Lebedev, Vyatcheslav V. Izmer, Denis N. Kazyul’kin,
Irina P. Beletskaya, and Alexander Z. Voskoboynikov*
Department of Chemistry, Moscow State UniVersity,
V-234, Moscow 119899, Russian Federation
Voskoboy@org.chem.msu.su
Received December 15, 2001
ABSTRACT
Vinylation of various azoles (pyrrole, indole, carbazole, and their derivatives) and phenothiazine with vinyl bromides catalyzed by palladium−
phosphine complexes results in the respective N-vinylazoles in 30−99% yields. This reaction with cis- and trans-â-bromostyrenes is stereospecific
giving the respective products with full retention of configuration.
For the past several years we have seen a vigorous growth
of the chemistry of palladium-catalyzed coupling reactions
due to the discovery and application of new phosphine and
carbene ligands, particularly for Pd-catalyzed arylation of
amines.1-4 Although the palladium-catalyzed arylation of
azoles is used for the synthesis of N-arylazoles,2c,5 the
respective reaction with vinyl halides has not yet been
realized. N-Vinylazoles have been shown to serve as
monomers for the synthesis of poly(N-vinylazoles),2c,6 which
can be used as semiconductors and photosensitive materials.
However, so far, only a few methods of the synthesis of
N-vinylazoles have been described.6b,7 These procedures are
rather limited in scope and selectivity. For example, while
Z-adducts can be prepared, the respective E-isomers were
altogether inaccessible. Therefore a straightforward pal-
ladium-catalyzed vinylation of azoles by vinyl halides is
undoubtedly an attractive alternative for the known methods.
Beyond other advantages this reaction, as other Pd-catalyzed
cross-coupling reactions, should be stereospecific to give pure
Z- and E-enamines, as soon as pure diastereomers of vinyl
halides with desired stereochemistry are readily available.
The main problem in realizing Pd-catalyzed vinylation of
amines is competitive elimination. A common procedure for
Buchwald-Hartwig Pd-catalyzed amination of arylhalides
suggests the use of an excess of strong bases, such as
t-BuOM (M ) Na, K). Even in the course of arylation in
(1) For reviews, see: (a) Hartwig, J. F. Angew. Chem., Int. Ed. Engl.
1998, 37, 2046. (b) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S.
L. Acc. Chem. Res. 1998, 31, 805. (c) Yang, B. H.; Buchwald, S. L. J.
Organomet. Chem. 1999, 576, 125.
(2) For applications of P(t-Bu)3, see: (a) Nishiyama, M.; Yamamoto,
T.; Koie, Y. Tetrahedron Lett. 1998, 39, 617. (b) Yamamoto, T.; Nishiyama,
M.; Koie, Y. Tetrahedron Lett. 1998, 39, 2367. (c) Hartwig, J. F.; Kawatsura,
M.; Hauck, S. I.; Shaughnessy, K. H.; Alcazar-Roman, L. M. J. Org. Chem.
1999, 64, 5575. (d) Lee, S.; Jørgensen, M.; Hartwig, J. F. Org. Lett. 2001,
3, 2729.
(3) For applications of other bulky, electron-rich phosphines, see: (a)
Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem., Int. Ed.
1995, 34, 1348. (b) Louie, J.; Hartwig, J. F. Tetrahedron Lett. 1995, 36,
3609. (c) Zhao, S. H.; Miller, A. K.; Berger, J.; Flippin, L. A. Tetrahedron
Lett. 1996, 37, 4463. (d) Reddy, N. P.; Tanaka, M. Tetrahedron Lett. 1997,
38, 4807. (e) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1998, 120,
7369 and references therein. (f) Alt, M. H.; Buchwald, S. L. J. Org. Chem.
2001, 66, 2560 and references therein.
(4) For applications of carbene ligands, see: (a) Huang, J.; Grasa, G.;
Nolan, S. P. Org. Lett. 1999, 1, 1307. (b) Stauffer, S. R.; Lee, S.; Stambuli,
J. P.; Hauck, S. I.; Hartwig, J. F. Org. Lett. 2000, 2, 1423. (c) Caddick, S.;
Cloke, F. G. N.; Clentsmith, G. K. B.; Hitchcock, P. B.; McKerrecher, D.;
Titcomb, L. R.; Williams, M. R. V. J. Organomet. Chem. 2001, 617-618,
635.
(5) (a) Watanabe, M.; Nishiyama, M.; Yamamoto, T.; Koie, Y. Tetra-
hedron Lett. 2000, 41, 481. (b) Alcazar-Roman, L. M.; Hartwig, J. F.;
Rheingold, A. L.; Liable-Sands, L. M.; Guzei, I. A. J. Am. Chem. Soc.
2000, 122, 4618. (c) Old, D. W.; Harris, M. C.; Buchwald, S. L. Org. Lett.
2000, 2, 1403.
(6) (a) Trofimov, B. A.; Mikhaleva, A. I.; Morozova, L. V. Russ. Chem.
ReV. 1985, 54, 1034. (b) Brustolin, F.; Castelvetro, V.; Ciardelli, F.; Ruggeri,
G.; Colligiani, A. J. Polym. Sci., A: Polym. Chem. 2001, 39, 253.
(7) (a) Reppe, W. Liebigs Ann. Chem. 1956, 132, 601. (b) Tzalis, D.;
Koradin, C.; Knochel, P. Tetrahedron Lett. 1999, 40, 6193. (c) Shostak-
ovsky, M. F.; Skvortsova, G. G.; Domnina, E. S. Russ. Chem. ReV. 1969,
38, 892. (d) Trofimov, B. A.; Mikhaleva, A. I. Chem. Heterocycl. Compds.
(Rus.) 1980, 1299.
10.1021/ol0172370 CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/24/2002

some cases a side elimination-addition route including
benzyne intermediates can compete with the Pd-catalyzed
route to give mixtures of isomeric anilines.8 For vinyl halides,
the elimination by t-BuOM should occur readily to give the
respective alkynes.9
Table 1. Vinylation of Indole Derivatives by
trans-â-Bromostyrene Catalyzed by Pd(dba)2/P(t-Bu)3
a
yield (%) of
entry
indole derivative
trans-â-N-indolylstyrene
Nevertheless, we have found that indole and trans-â-
bromostyrene in the presence of 2 equiv of KOBu-t and 4
mol % of Pd(dba)2/2t-Bu2PC6H4Ph-o give 1-[(E)-2-phen-
ylethenyl]-1H-indole in 84% yield upon 20 h at 80 °C. No
starting trans-â-bromostyrene was recovered, but a side
product, [(3E)-4-phenyl-3-buten-1-ynyl]benzene (1), was
isolated in 6% yield. In a separate experiment we have found
that, in the absence of indole, trans-â-bromostyrene gives 1
under the same conditions in almost quantitative yield (eq
1).10,11 These observations, as well as the result of a control
1
2
3
4
5
6
7
[indolyl]K
[indolyl]Na
[indolyl]Li
[indolyl]MgBr
indole, K3PO4
indole, K2CO3
[N-indolyl]SnEt3
<1b
9
99b
65
64
8
22
a 1 mol % Pd(dba)2/2P(t-Bu)3, toluene-DME, 2.5 h, 82 °C. b Also for
equimolar mixture of indole and t-BuOM, where M ) K, Li.
HBr, can be realized only for activated Michael-type olefins
BrCHdCMeR bearing electron-withdrawing substituents,
such as R ) CN, COOMe.12 A more common alternative,
pathway B, includes an elimination-addition sequence. Phe-
nylacetylene is well-known for the ability to add an amine
molecule in the presence of base.7b However, in our reaction
this is not the case, since on the evidence of HPLC, only
phenylacetylene was formed in the absence of Pd-catalyst
and the addition had not taken place.
experiment showing that trans-â-bromostyrene amination
does not take place without Pd-catalyst, favor a reaction
mechanism including an addition of vinyl bromides to Pd0
(pathway A, Scheme 1) rather than noncatalytic pathways.
Despite the success of palladium-catalyzed vinylation of
indole, the attempts to extend this protocol to vinylation of
other azoles, such as of 2,4-dimethylpyrrole, carbazole, and
pyrrole gave 1 as the only product. The same occurred with
readily available P(t-Bu)3 ligand in place of expensive t-Bu2-
PC6H4Ph-o, as with the former even indole failed to react.
Naturally, we expected that the competition between
elimination and Pd-catalyzed route could be resolved in favor
of the latter by a judicious choice of basic reagent. For this
study we have chose indole as NH-reagent since it gave a
positive result even in the presence of t-BuOK, and we
employed P(t-Bu)3 as a more practical ligand.
Scheme 1. Catalytic and Noncatalytic Pathways for
Amination of Nonactivated Vinyl Bromides
Table 2. Vinylation of Indolyllithium by trans- and
cis-â-Bromostyrene Catalyzed by Pd(dba)2/Phosphinea
entry phosphine ligand [Pd], mol. % time, min yield, %
trans-â-bromostyrene
1
2
3
4
5
6
7
8
9
PPh3
DPPP
rac-BINAP
DPPF
DPPF
P(t-Bu)3
P(t-Bu)3
P(t-Bu)3
P(t-Bu)3
t-Bu2PC6H4Ph-o
1.0
1.0
1.0
1.0
1.0
1.0
2.0
4.0
1.0
1.0
150
150
150
15
150
15
15
15
150
15
0.8
1.6
4.6
39
76
47
68
87
99
99
The alternative pathway, including an addition of amine
to the activated double bond and successive elimination of
(8) (a) Beletskaya, I. P.; Bessmertnykh, A. G.; Guilard, R. Tetrahedron
Lett. 1999, 40, 6393. (b) Beller, M.; Breindl, C.; Riermeier, T. H.;
Eichberger, M.; Trauthwein, H. Angew. Chem., Int. Ed. Engl. 1998, 37,
3389. (c) Beller, M.; Breindl, C.; Riermeier, T. H., Tillack, A. J. Org. Chem.
2001, 66, 1403.
(9) Huntsman, W. D. In The Chemistry of the Carbon-Carbon Triple
Bond; Patai, S., Ed.; Wiley: New York, 1978; pp 553-620.
(10) Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang,
P. J., Eds.; Wiley-VCH: New York, 1997; p 2.
10
cis-â-bromostyrene
11
12
13
DPPF
P(t-Bu)3
1.0
1.0
30
30
30
83
86
99
t-Bu2PC6H4Ph-o
1.0
a Pd(dba)2/phosphine (Pd/P ) 1/2), toluene-DME; 85 °C.
(11) Mori, A.; Kawashima, J.; Shimada, T.; Suguro, M.; Hirabyashi, K.;
Nishihara, Y. Org. Lett. 2000, 2, 2935.
624
Org. Lett., Vol. 4, No. 4, 2002

Table 3. Catalytic Vinylationa of Azoles and Phenothiazine
Figure 1. Molecular structure of 10-[(Z)-2-phenylethenyl]-10H-
phenothiazine, showing the 50% thermal ellipsoids and atom
labeling scheme. Selected bond lengths (Å) are N(1)-C(13)
1.396(4), N(1)-C(1) 1.420(4), N(1)-C(12) 1.432(4), C(14)-C(13)
1.338(5), C(14)-C(15) 1.462(5); selected bond angles (deg) are
C(13)-N(1)-C(1) 121.5(3), C(13)-N(1)-C(12) 119.8(3), C(1)-
N(1)-C(12) 116.2(3), C(13)-C(14)-C(15) 131.1(3), C(14)-
C(13)-N(1) 128.3(3).
the conditions studied (Table 1). Indolylpotassium and
-sodium as well as indole/K2CO3, on the other hand, gave
poor results, while the soluble base K3PO4 gave the desired
product in 64% yield. Good yield was also observed with
indolylmagnesium bromide, which is, similarly to N-lithio-
indole, a covalent compound. A covalent nonbasic N-
indolyltriethyltin13 gives the desired product in low yield.
Thus, it is evident that a proper choice of basicity, neither
too strong nor too weak, is a key to success.
The screening of phosphine ligands (Table 2) confirmed
the preliminary result that Pd(dba)2/2t-Bu2PC6H4Ph-o is the
most active catalytic system for indole vinylation by trans-
â-bromostyrene and also by cis-â-bromostyrene. Catalysts
based on P(t-Bu)3 and DPPF ligands possess lower activity,
though good to high yields can be achieved with these readily
available ligands. The reaction with both Z- or E-bromo-
styrenes were stereospecific, giving the respective products
with full retention of configuration.
a 4 mol % Pd(dba)2/2P(t-Bu)3, toluene-DME. b Byproducts of this
reaction were not identified. c Conversion of vinyl bromide (HPLC). d This
reaction produces also [(3E)-4-phenyl-3-buten-1-ynyl]benzene (6%) and 2,5-
dimethyl-3-[(E)-2-phenylethenyl]-1H-pyrrole (4%). e This reaction produces
also 9-[(E)-2-phenylethenyl]-9H-carbazole (2%) and 9-vinyl-9H-carbazole
(3%). f In toluene-dioxane. g The formation of 1-[(E)-2-phenylethenyl]-
1H-indole (10%) was also observed. h Conversion of azole (HPLC). i The
following byproducts are formed: 9-[(1E)-prop-1-enyl]-9H-carbazole (15%),
9-[(1Z)-prop-1-enyl]-9H-carbazole (5%), 9-allyl-9H-carbazole (5%).
We then proceeded to study the scope of vinylation of
other azoles employing a readily available Pd(dba)2/
2P(t-Bu)3 system (Table 3, eq 2). As is evident from the
We showed that the addition of coordinating solvent DME
to toluene favors the indole vinylation reaction. Surprisingly,
we found that either preformed indolyllithium or indole/
t-BuOLi were the most reactive and selective reagents,
resulting in 1-[(E)-2-phenylethenyl]-1H-indole in almost
quantitative yield in the presence of Pd(dba)2/2P(t-Bu)3 under
(12) Texier, F.; Bourgois, J. Bull. Soc. Chim. Fr. 1976, 487.
Org. Lett., Vol. 4, No. 4, 2002
presented data the reaction is general in the series of common
625

azoles including pyrrole, indole, carbazole, and their deriva-
tives. Moreover, in all cases the reaction was stereospecific
to give pure diastereomers of N-2-phenylethenylazoles, the
configuration of which was controlled by the configuration
of starting bromostyrene.14 No isomerization of the starting
bromostyrenes and the resulted vinylazoles was observed
under reaction conditions. Besides azoles, the reaction is
applicable to phenathiazine. For example, this substrate and
cis-â-bromostyrene gave 10-[(Z)-2-phenylethenyl]-10H-
phenathiazine in almost quantitative yield. The molecular
structure of this compound, established by X-ray crystal
structure analysis,15 corresponds to cis-enamine (Figure 1).
The vinylation of indole by geminal bromoolefins such
as R-bromostyrene and 2-bromopropene is accompanied by
a partial isomerization. The amination of CH2dCHBr is not
as smooth and quantitative as the reaction with bromo-
styrenes. The respective products, 1-vinyl-1H-indole and
9-vinyl-9H-carbazole, turned out to be thermally unstable
compounds that polymerized readily. However, we succeeded
in developing mild conditions for their synthesis by carefully
controlling time and temperature and deliberately stopping
the reaction, not allowing it to run to quantitative conversions.
Thus, the desired N-vinylazoles were successfully obtained
in 61% and 59% yields (on 65% conversion of azoles),
respectively.
Because N-vinylazoles are widely used as building blocks
for photosensitive and photoelectronic polymers and com-
posites, the Pd-catalyzed vinylation of azoles is an appealing
method, suitable for industrial application. It can be a good
alternative to the direct hydroamination of acetylene,6a,b,10
since the latter method can lead to a formation of explosive
byproducts in industrial equipment. It should be noted that
the above-described Pd-catalyzed reaction for azoles and
phenathiazine, i.e., for substrates with low nucleophilicity,
gives enamines that cannot be prepared by the routine
condensation of amines with aldehydes or ketones. Moreover,
this method for cis- and trans-â-bromostyrenes provides a
predictable and controlled stereoselectiVity.
Acknowledgment. Financial support from the Russian
Foundation for Basic Research (grant 01-03-32474a), Inter-
national Science and Technology Center (grant 1036/99),
INTAS (grant 2000-00841), and ExxonMobil Chemical
Company is gratefully acknowledged.
(13) For the palladium-catalyzed reaction of cis-â-bromostyrene with
n-Bu3SnNEt2, see: Kosugi, M.; Kameyama, M.; Sano, H.; Migita, T. Nippon
Kagaku Kaishi 1985, 3, 547; Chem. Abstr. 1985, 104, 129990.
(14) The reaction of 2,5-dimethylpyrrole with cis-â-bromostyrene gives
2,5-dimethyl-1-[(E)-2-phenylethenyl]-1H-pyrrole (17%), 2,5-dimethyl-3-
[(E)-2-phenylethenyl]-1H-pyrrole (31%), and [(3E)-4-phenyl-3-buten-1-
ynyl]benzene (5%) but not the desired 2,5-dimethyl-1-[(Z)-2-phenylethenyl]-
1H-pyrrole.
Supporting Information Available: Synthetic proce-
dures, analytical and spectral data for all compounds newly
synthesized, and results of crystal structure analysis of 10-
[(Z)-2-phenylethenyl]-10H-phenathiazine. This material is
available free of charge via the Internet at http://pubs.acs.org.
(15) Crystal data: monoclinic, P2(1)/a, a ) 15.502(9) Å, b ) 5.792(4)
Å, c ) 16.587(10) Å, â ) 97.569(16)°, V ) 1476.3(15) Å3, Z ) 4.
OL0172370
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Org. Lett., Vol. 4, No. 4, 2002