Two palladium-catalyzed domino reactions from one set of substrates/reagents: Efficient synthesis of substituted indenes and cis-stilbenoid hydrocarbons from the same internal alkynes and hindered Grignard reagents

Article abstract of DOI:10.1021/ol062885a

(Chemical Equation Presented) Two types of domino reactions from the same internal alkynes and hindered Grignard reagents based on carbopalladation, Pd-catalyzed cross-coupling reaction, and a C-H activation strategy are described. The realization of thes

Full text of DOI:10.1021/ol062885a

ORGANIC
LETTERS
2007
Vol. 9, No. 2
363-366
Two Palladium-Catalyzed Domino
Reactions from One Set of Substrates/
Reagents: Efficient Synthesis of
Substituted Indenes and cis-Stilbenoid
Hydrocarbons from the Same Internal
Alkynes and Hindered Grignard
Reagents
Cheng-Guo Dong, Pik Yeung, and Qiao-Sheng Hu*
Department of Chemistry, College of Staten Island and the Graduate Center of the
City UniVersity of New York, Staten Island, New York 10314
qiaohu@mail.csi.cuny.edu
Received November 28, 2006
ABSTRACT
Two types of domino reactions from the same internal alkynes and hindered Grignard reagents based on carbopalladation, Pd-catalyzed
cross-coupling reaction, and a C H activation strategy are described. The realization of these domino reactions relied on the control of the
−
use of the ligand and the reaction temperature. Our study provides efficient access to useful polysubstituted indenes and cis-substituted
stilbenes and may offer a new means of development of tandem/domino reactions in a more efficient way.
The development of transition-metal-catalyzed tandem or
“domino” reactions, which combine two or more bond-
forming reactions into one synthetic operation, represents
one of the most attractive subjects in synthetic organic
chemistry.1,2 Such tandem/domino reactions allow the con-
comitant formation of two or more bonds with a rapid
increase in molecular complexity with minimized separation/
purification efforts. Because arranging two or more bond-
forming reactions to occur in a tandem or domino fashion is
always challenging, it is not surprising to observe that almost
all tandem/domino reactions were developed on the basis of
one type of tandem/domino reaction per one set of substrates/
reagents.1-3 Developing two or more types of tandem/domino
reactions from the same substrates and reagents, which
represents a strategy that could further heighten the efficiency
of conducting reactions in a tandem/domino fashion, is
apparently very attractive but remains largely unexplored.4
(1) (a) Wasilke, J.-C.; Obrey, S. J.; Baker, R. T.; Bazan, G. C. Chem.
ReV. 2005, 105, 1001-1020. (b) Tietze, L. F.; Rackelmann, N. Pure Appl.
Chem. 2004, 76, 1967-1983. (c) Nicolaou, K. C.; Montagnon, T.; Snyder,
S. A. Chem. Commun. 2003, 551-564. (d) Parsons, P. J.; Penkett, C. S.;
Shell, A. J. Chem. ReV. 1996, 96, 195-206. (e) Tietze, L. F. Chem. ReV.
1996, 96, 115-136 and references cited therein.
(2) (a) de Meijere, A.; von Zezschwitz, P.; Brase, S. Acc. Chem. Res.
2005, 38, 413-422. (b) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. ReV. 2002,
102, 1731-1770. (c) Ikeda, S.-i. Acc. Chem. Res. 2000, 33, 511-519. (d)
Montgomery, J. Acc. Chem. Res. 2000, 33, 467-473. (e) Heumann, A.;
Reglier, M. Tetrahedron 1996, 52, 9289-9346. (f) Malacria, M. Chem.
ReV. 1996, 96, 289-306 and references cited therein.
We have recently documented the palladium-catalyzed
tandem reaction of 1,2-dihalobenzenes and 2-haloaryl tos-
ylates with hindered Grignard reagents to form substituted
fluorenes,5 in which palladium-associated arynes were be-
10.1021/ol062885a CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/22/2006

lieved to be the intermediates when the reaction was carried
out in the absence of phosphines or N-heterocyclic carbene
ligands.5b The triple bond nature of arynes led us to consider
that alkynes might also function similarly as in situ generated
arynes. We thus envisioned that carbopalladation of alkynes
could generate vinylpalladium(II)X complexes I (Scheme 1).6
and (b) undergo transmetalation followed by reductive
elimination (cross-coupling process) to yield cis-stilbenoid
hydrocarbons, which are potentially useful in the fields of
molecular sensors and molecular electronics.11,12 Therefore,
two types of domino reactions, namely, domino carbopal-
ladation-cyclization to form polysubstituted indenes and
domino carbopalladation-cross-coupling to form cis-stil-
benoid hydrocarbons containing highly substituted phenyl
groups, might be developed from the same alkynes and
hindered Grignard reagents if the two competing pathways
could be controlled (Scheme 1). Herein, we report our
successful realization of these two types of reactions by
controlling the use of ligands and the reaction temperature.
On the basis of the consideration that the activation of a
C-H bond would involve the interaction of a C-H bond
with a Pd(II) center and that such an interaction would be
disfavored at higher reaction temperature and/or in the
presence of ligands, we surmised the cyclization via an sp3
C-H activation process would be favored in the absence of
ligands and at lower reaction temperature. We thus began
our study by examining the reaction of diphenylacetylene
with 2-mesitylPd(II)(OAc), in situ generated from 2-mesit-
ylmagnesium bromide with Pd(OAc)2. We found that the
domino carbopalladation-cyclization product 4,6-dimethyl-
2,3-diphenylindene was the major product with only Pd-
(OAc)2 as the promoter, at room temperature, 60 °C, or
refluxing (Table 1, entries 1, 2, and 5). The use of PPh3 as
a ligand decreases the formation of the cyclization product
and slows down the reaction (Table 1, entries 2-4). By using
4 equiv of PPh3 in refluxing THF, the domino carbopalla-
dation-cross-coupling product became the major product,
along with the self-coupling of the Grignard reagent as the
main side reaction (Table 1, entry 7). Our results suggested
that by controlling the use of the ligand and reaction temper-
ature, it is possible to control the domino reaction pathways.
As Pd(II)X2 would be reduced to Pd(0) after every reaction
cycle, after establishing factors that influence the reaction
competing pathways, we next turned our attention to
developing the catalytic version of these two types of domino
reactions by identifying oxidants that could oxidize Pd(0)
species to Pd(II) species. We have tested several commonly
Scheme 1. Domino Carbopalladation-Cyclization via sp3
C-H Activation vs Domino Carbopalladation-Cross-Coupling
Reaction
I could then (a) undergo cyclization via C-H activation7,8
to afford substituted indenes, which are structural constituents
of metallocene-based catalysts for olefin polymerizations, of
biologically active compounds, and of functional materials,9,10
(3) Selected recent examples of Pd-catalyzed tandem/domino reactions:
(a) Mariampillai, B.; Alberico, D.; Bidau, V.; Lautens, M. J. Am. Chem.
Soc. 2006, 128, 14436-14437. (b) Bertrand, M. B.; Wolfe, J. P. Org. Lett.
2006, 8, 2353-2356. (c) Leclerc, J.-P.; Andre, M.; Fagnou, K. J. Org. Chem.
2006, 71, 1711-1714. (d) Henderson, J. L.; Edwards, A. S.; Greaney, M.
F. J. Am. Chem. Soc. 2006, 128, 7426-7427. (e) Pinto, A.; Neuville, L.;
Retailleau, P.; Zhu, J. Org. Lett. 2006, 8, 4927-4930. (f) Martins, A.;
Marquardt, U.; Kasravi, N.; Alberico, D.; Lautens, M. J. Org. Chem. 2006,
71, 4937-4942. (g) Hay, M. B.; Wolfe, J. P. J. Am. Chem. Soc. 2005, 127,
16468-16476. (h) Tsang, W. C. P.; Zheng, N.; Buchwald, S. L. J. Am.
Chem. Soc. 2005, 127, 14560-14561. (i) Bressy, C.; Alberico, D.; Lautens,
M. J. Am. Chem. Soc. 2005, 127, 13148-13149. (j) Zhao, J.; Larock, R.
C. Org. Lett. 2005, 7, 701-704. (k) Ohno, H.; Yamamoto, M.; Iuchi, M.;
Tanaka, T. Angew. Chem., Int. Ed. 2005, 44, 5103-5106. (l) Yang, Q.;
Ney, J. E.; Wolfe, J. P. Org. Lett. 2005, 7, 2575-2578. (m) Cheung, W.
S.; Patch, R. J.; Player, M. R. J. Org. Chem. 2005, 70, 3741-3744. (n)
Zhao, J.; Larock, R. C. Org. Lett. 2005, 7, 701-704. (o) Ganton, M. D.;
Kerr, M. A. Org. Lett. 2005, 7, 4777-4779. (p) Abbiati, G.; Arcadi, A.;
Canevari, V.; Capezzuto, L.; Rossi, E. J. Org. Chem. 2005, 70, 6454-
6460. (q) Huang, Q.; Fazio, A.; Dai, G.; Campo, M. A.; Larock, R. C. J.
Am. Chem. Soc. 2004, 126, 7460-7461. (r) Wolfe, J. P.; Rossi, M. A. J.
Am. Chem. Soc. 2004, 126, 1620-1621. (s) Ney, J. E.; Wolfe, J. P. Angew.
Chem., Int. Ed. 2004, 43, 3605-3608.
(9) (a) Alt, H. G.; Ko¨ppl, A. Chem. ReV. 2000, 100, 1205-1222. (b)
Korte, A.; Legros, J.; Bolm, C. Synlett 2004, 13, 2397-2399 and references
therein. (c) Barbera, J.; Rakitin, O. A.; Ros, M. B.; Torroba, T. Angew.
Chem., Int. Ed. 1998, 37, 296-299.
(4) For examples: (a) Nakhla, J. S.; Kampf, J. W.; Wolfe, J. P. J. Am.
Chem. Soc. 2006, 128, 2893-2901. (b) Ney, J. E.; Wolfe, J. P. J. Am.
Chem. Soc. 2005, 127, 8644-8651. Also see refs 1 and 2.
(5) (a) Dong, C.-G.; Hu, Q.-S. Org. Lett. 2006, 8, 5057-5060. (b) Dong,
C.-G.; Hu, Q.-S. Angew. Chem., Int. Ed. 2006, 45, 2289-2292.
(6) Recent reviews for carbopalladation of alkynes: (a) Zeni, G.; Larock,
R. C. Chem. ReV. 2004, 104, 2285-2310. (b) de Meijere, A.; von
Zezschwitz, P.; Brase, S. Acc. Chem. Res. 2005, 38, 413-422.
(10) Substituted indenes were typically prepared in more than one step.
For recent examples of one-pot access to substituted indenes with different
substitution patterns from 2-(2-(1-alkynyl)phenyl)malonates or 2-(2-halo-
phenyl)malonate: (a) Guo, L.-N.; Duan, X.-H.; Bi, H.-P.; Liu, X.-Y.; Liang,
Y.-M. J. Org. Chem. 2006, 71, 3325-3327. (b) Zhang, D.; Yum, E. K.;
Liu, Z.; Larock, R. C. Org. Lett. 2005, 7, 4963-4966. Also see: (c)
Kuninobu, Y.; Nishina, Y.; Takai, K. Org. Lett. 2006, 8, 2891-2893. (d)
Nakamura, I.; Bajracharya, G. B.; Wu, H.; Oishi, K.; Mizushima, Y.;
Gridnev, I. D.; Yamamoto, Y. J. Am. Chem. Soc. 2004, 126, 15423-15430.
(11) (a) Rathore, R.; Lindeman, S. V.; Kochi, J. K. Angew. Chem. 1998,
110, 1665-1667; Angew. Chem., Int. Ed. 1998, 37, 1585-1587. (b) Irie,
M. Chem. ReV. 2000, 100, 1685-1716.
(12) The most efficient preparation methods reported so far involve the
use of 1,2-dibromoalkenes with hindered Grignard reagents: (a) Rathore,
R.; Deselnicu, M. I.; Burns, C. L. J. Am. Chem. Soc. 2002, 124, 14832-
14833. For other methods: (b) Maeda, K.; Okamoto, Y.; Morlender, N.;
Haddad, N.; Eventova, I.; Biali, S. E.; Rappoport, Z. J. Am. Chem. Soc.
1995, 117, 9686-9689. (c) Bottino, F. A.; Finocchiaro, P.; Libertini, E.;
Reale, A.; Recca, A. J. Chem. Soc., Perkin Trans. 2 1982, 77-81.
(7) Recent reviews for C-H activation: (a) Dyker, G., Ed. Handbook
of C-H Transformations: Application in Organic Synthesis; Wiley-VCH:
Weinheim, 2005; Vol. 2. (b) Kakiuchi, F.; Chatani, N. AdV. Synth. Catal.
2003, 345, 1077-1101. (c) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. ReV.
2002, 102, 1731-1770. (d) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc. Chem.
Res. 2001, 34, 633-639.
(8) For examples of Pd-catalyzed cyclizations via sp3 C-H activation:
(a) Baudoin, O.; Herrbach, A.; Gueritte, F. Angew. Chem., Int. Ed. 2003,
42, 5736-5740. (b) Suau, R.; Lopez-Romero, J. M.; Rico, R. D.
Tetrahedron Lett. 1996, 37, 9357-9360. (c) Dyker, G. J. Org. Chem. 1993,
58, 6426-6428. (d) Dyker, G. Angew. Chem., Int. Ed. 1994, 33, 103-105.
(e) Dyker, G. Angew. Chem., Int. Ed. 1992, 31, 1023-1025.
364
Org. Lett., Vol. 9, No. 2, 2007

Table 1. Pd(OAc)2-Promoted Domino Reaction of
Diphenylacetylene with 2-Mesitylmagnesium Bromidea
Table 3. Pd(OAc)2-Catalyzed Cyclizations of Internal Alkynes
with Hindered Grignard Reagentsa
ratiob
entry
ligand
none
none
2 equiv of PPh3 60
4 equiv of PPh3 60
temp conversion
I
II
III
1
2
3
4
5
6
7
rt
85%
99%
75%
60%
99%
99%
81%
97
90
81
20
93
69
2
:
:
:
:
:
:
:
2
2
9
24
3.5
12
67
:
:
:
:
:
:
:
1
8
60
10
56
3.5
19
31
none
reflux
2 equiv of PPh3 reflux
4 equiv of PPh3 reflux
a Reaction conditions: diphenylacetylene (1.0 equiv), Grignard reagent
b
1
(2.5 equiv), Pd(OAc)2 (1 equiv), THF (2 mL), 20 h. Based on H NMR.
available oxidants and found 1,2-dibromoethane can be used
as an excellent oxidizer (Table 2). By using a stoichiometric
Table 2. Pd(II)-Catalyzed Domino Reaction of
Diphenylacetylene with Mesitylmagnesium Bromidea
entry
additives
yield (%)
1
2
3
4
5
6
none
<2b
<2b
<2b
15
5
87
CuCl2
CuSO4
FeCl3
Ag2CO3
a Reaction conditions: diphenylacetylene (1.0 equiv), Grignard reagent
b
1
(2.5 equiv), THF (2 mL). Conversion based on H NMR.
a Reaction conditions: alkyne (1.0 equiv), Grignard reagent (2.5 equiv),
Pd(OAc)2 (3%), 1,2-dibromoethane (1.0 equiv), THF (2 mL), 60 °C.
bIsolated yields. cRatio based on 1H NMR. dReaction conditions: room
temperature, 30 h. e15% cross-coupling product was observed. f21% cross-
amount of 1,2-dibromoethane and 3% Pd(OAc)2, the domino
carbopalladation-cyclization process proceeded smoothly to
give 4,6-dimethyl-2,3-diphenylindene in excellent yield
(Table 2, entry 6).
g
coupling product was observed. Reaction time: 45 h.
With 1,2-dibromoethane as the oxidant, a number of
alkynes were examined for the Pd(OAc)2-catalyzed domino
carbopalladation-cyclization reaction, and our results are
listed in Table 3. We found that diaryl-, dialkyl-, and
alkylarylacetylenes were all suitable substrates. When un-
symmetrical alkylarylacetylenes were employed as the
substrates, we found the domino reaction occurred mainly
from the alkyl sides of alkylarylacetylenes,13 as evidenced
by the ratio of the two isomeric products (Table 3, entries
9-13). To determine whether other types of hydrogens
(nonbenzylic 1° hydrogens and benzylic 2° and 3° hydro-
gens) could also be activated under our conditions, we have
tested 2-ethyl-6-methylphenylmagnesium bromide and 2-iso-
propyl-6-methylphenylmagnesium bromide for the domino
reaction. We found that the sp3 C-H activation exclusively
occurred at the benzylic methyl group, suggesting that
nonbenzylic 1° hydrogens (nonbenzylic methyl group) and
2° (ethyl group) and 3° (isopropyl group) benzylic hydrogens
could not be activated (Table 3, entries 14 and 15). This
was further confirmed by the fact that no reaction was
observed for 2,6-diethylphenylmagnesium bromide with
diphenylacetylene (Table 3, entry 16).
By using 1,2-dibromoethane as the oxidant and 4 equiv
of PPh3 relative to Pd(OAc)2 in refluxing THF, we were also
able to realize the second type of domino reaction, carbo-
palladation followed by cross-coupling, to form cis-stil-
benes,11,12 in a catalytic fashion. Cis-substituted stilbenes
(13) A similar regioselectivity trend was observed in Pd-catalyzed three-
component reactions of aryl iodides, internal alkynes, and arylboronic
acids: Zhou, C.; Larock, R. C. J. Org. Chem. 2005, 70, 3765-3777.
Org. Lett., Vol. 9, No. 2, 2007
365

refluxing THF to give cis-substituted stilbenes12a most likely
also proceeded with alkynes and I as the reaction intermedi-
ates.14
Table 4. Pd(OAc)2-Catalyzed Domino
Carbopalladation-Cross-Coupling of Internal Alkynes and
Hindered Grignard Reagentsa
In summary, we developed two types of Pd-catalyzed
domino reactions from the same alkynes and hindered
Grignard reagents by controlling the use of ligands and the
reaction temperature. We also showed that only benzylic
methyl hydrogens might be activated by Pd(II) species. Our
study provided efficient access to useful polysubstituted
indenes and cis-substituted stilbenes from simple, com-
mercially available starting materials/reagents. The ligand
and temperature factors for controlling the domino reaction
pathways identified in this study may also be applicable for
other cross-coupling and C-H activation-based tandem/
domino reactions. Work toward this direction is underway.
Acknowledgment. We gratefully thank the NIH
(GM69704) for funding. Partial support from the Petroleum
Research Fund, administered by the American Chemical
Society (44428-AC1) and PSC-CUNY Research Award
Programs is also gratefully acknowledged. We also thank
Dr. Hsin Wang at the College of Staten Island for his help
on the NMR NOE experiments and Frontier Scientific, Inc.
for its generous gifts of palladium acetate. This work also
benefited from the “Undergraduate Summer Research”
Program at the College of Staten Island.
Supporting Information Available: General procedures
and product characterizations for palladium-catalyzed domino
reactions. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL062885A
a Reaction conditions: alkyne (1.0 equiv), Grignard reagent (4.0 equiv),
1,2-dibromoethane (1.5 equiv), Pd(OAc)2 (5%), PPh3 (20%), THF (2 mL),
refluxing, 30-40 h. Isolated yields.
b
(14) Pd(PPh3)2Cl2-catalyzed reactions of trans-1,2-dibromoalkenes with
Grignard reagents in refluxing THF were reported to give cis-substituted
stilbenes in excellent yields (ref 12a). In our hands, we found Pd(PPh3)2-
Cl2-catalyzed reaction of trans-1,2-dibromo-1,2-diphenylethene with pen-
tamethylphenylmagnesium bromide indeed gave cis-substituted stilbene in
86% yield. However, we also found Pd(PPh3)2Cl2-catalyzed reactions of
trans-1,2-dibromo-1,2-diphenylethene or trans-3,4-dibromo-3-hexene with
2-mesitylmagnesium bromide or 2,6-dimethylphenylmagnesium bromide
in refluxing THF gave significant amounts of substituted indenes (>18%).
When the reaction temperature was 60 °C, substituted indenes were obtained
in 70-98% yields.
containing highly substituted phenyl groups were obtained
in good yields from the same alkynes and hindered Grignard
reagents that form polysubstituted indenes (Table 4). Our
results also suggested that Pd(PPh3)2Cl2-catalyzed reactions
of trans-1,2-dibromoalkenes with Grignard reagents in
366
Org. Lett., Vol. 9, No. 2, 2007