Stereospecific synthesis of highly substituted skipped dienes through multifunctional palladium catalysis

Article abstract of DOI:10.1021/ol0269594

(equation presented) Multifunctional palladium catalysis is utilized in the one-pot stereocontrolled synthesis of tetrasubstituted alkenes. The homogeneous palladium dihalide catalyst utilized for bromo-/chloroallylation of alkynes is then reused in situ

Full text of DOI:10.1021/ol0269594

ORGANIC
LETTERS
2002
Vol. 4, No. 24
4317-4320
Stereospecific Synthesis of Highly
Substituted Skipped Dienes through
Multifunctional Palladium Catalysis
Avinash N. Thadani and Viresh H. Rawal*
Department of Chemistry, The UniVersity of Chicago, 5735 South Ellis AVenue,
Chicago, Illinois 60637
Vrawal@uchicago.edu
Received September 25, 2002
ABSTRACT
Multifunctional palladium catalysis is utilized in the one-pot stereocontrolled synthesis of tetrasubstituted alkenes. The homogeneous palladium
dihalide catalyst utilized for bromo-/chloroallylation of alkynes is then reused in situ for a subsequent Suzuki cross-coupling reaction.
The growing importance of green chemistry and the concept
of atom economy in organic synthesis has fueled the search
for transformations that result in less waste.1,2 A noteworthy
advance in this regard is the development of multifunctional
reagents capable of promoting two or more distinct trans-
formations sequentially in the same pot. Such sequencing
not only makes better use of precious reagents but, as an
added benefit, eliminates inefficient separation and purifica-
tion after each step.3,4 Palladium reagents, known to induce
a myriad of different reactions,5 are particularly well suited
for incorporation into multifunctional catalysis sequences.
We report in this Letter the development of a stereospecific
haloallylation/Suzuki cross-coupling sequence, in which the
same Pd catalyst promotes both reactions.6
In connection with our work in alkaloids synthesis, we
required a method for the stereocontrolled preparation of
tetrasubstituted alkenes, wherein one of the substituents was
an allyl unit. The plan was to utilize Pd(II) catalysis to
bromoallylate an alkyne, using the procedure developed by
Kaneda et al.,7 and then, in a second step, introduce the final
substituent by a Pd(0)-catalyzed Suzuki coupling (Scheme
1).8
(4) For recent reviews of domino reactions, see: (a) Ikeda, S. Acc. Chem.
Res. 2000, 33, 511-519. (b) Poli, G.; Giambastiani, G.; Heumann, A.
Tetrahedron 2000, 56, 5959-5989. (c) De Meijere, A.; Bra¨se, S. J.
Organomet. Chem. 1999, 576, 88-110. (d) Tietze, L. F. Chem. ReV. 1996,
96, 115-136. (e) Parsons, P. J.; Penkett, C. S.; Shell, A. J. Chem. ReV.
1996, 96, 195-206. (f) Malacria, M. Chem. ReV. 1996, 96, 289-306. (g)
Heumann, A.; Re´glier, M. Tetrahedron 1996, 52, 9289-9346.
(5) (a) Tsuji, J. Palladium Reagents and Catalysts: InnoVations in
Organic Synthesis; John Wiley & Sons: New York, 1995 (b) Poli, G.;
Giambastiani, G.; Heumann, A. Tetrahedron 2000, 56, 5959-5989. (c)
Tsuji, J. Transition Metal Reagents and Catalysts: InnoVation in Organic
Synthesis; John Wiley & Sons: New York, 2000.
(6) The sequencing of the haloallylation with Sonogashira cross-coupling
and Wacker-Tsuji oxidation is described in the accompanying Letter:
Thadani, A. N.; Rawal, V. H. Org. Lett. 2002, 4, 4321-4324.
(7) Kaneda, K.; Uchiyama, T.; Fujiwara, Y.; Imanaka, T.; Teranishi, S.
J. Org. Chem. 1979, 44, 55-63.
(1) For reviews on green chemistry, see: Anastas, P. T.; Kirchhoff, M.
M. Acc. Chem. Res. 2002, 35, 686-694.
(2) For a discussion of atom economy, see: (a) Trost, B. M. Acc. Chem.
Res. 2002, 35, 695-705. (b) Trost, B. M. Science 1991, 254, 1471-1477.
(3) For recent examples of tandem catalysis, see: (a) Yu, H.-B.; Hu,
Q.-S.; Pu, L. J. Am. Chem. Soc. 2000, 122, 6500-6501. (b) Bielawski, C.
W.; Louie, J.; Grubbs, R. H. J. Am. Chem. Soc. 2000, 122, 12872-12873.
(c) Evans, P. A.; Robinson, J. E. J. Am. Chem. Soc. 2001, 123, 4609-
4610. (d) Louie, J.; Bielawski, C. W.; Grubbs, R. H. J. Am. Chem. Soc.
2001, 123, 11312-11313. (e) Zezschwitz, P.; Petry, F.; de Meijere, A.
Chem. Eur. J. 2001, 4035-4046. (f) Drouin, S. D.; Zamanian, F.; Fogg,
D. E. Organometallics 2001, 5495-5497. (g) Choudary, B. M.; Chowdari,
N. S.; Jyothi, K.; Kumar, N. S.; Kantam, M. L. Chem. Commun. 2002,
586-587. (h) Teoh, E.; Campi, E. A.; Jackson, W. R.; Robinson, A. J.
Chem. Commun. 2002, 978-979.
10.1021/ol0269594 CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/05/2002

The mechanism of the initial bromoallylation of alkynes
utilizing palladium dihalide catalysts has been investigated
by Kaneda et al.7 and Ba¨ckvall and co-workers.10 On the
basis of the accepted mechanism, the catalytic cycle from
the bromoallylation is expected to produce a Pd(II) species
(Scheme 2).
Scheme 1
Scheme 2
The initial studies were directed at improving the original
protocol of Kaneda et al., which called for the use of the
allyl bromide or chloride in vast excesssoften as the reaction
solvent.7 A variety of Pd catalysts were examined for the
reaction between allyl bromide and 1-hexyne, but none were
found to be superior to that originally employed by Kaneda
and co-workers, PdBr2(PhCN)2.9 The addition of phosphine
ligands was determined to be detrimental to the haloallylation
reaction. The main reason for using the allyl bromide in
excess was to reduce the relative concentration of the alkyne,
since it is prone to oligomerization or polymerization in the
presence of the Pd catalyst. It was discovered that Pd
catalyzed side reactions can be circumvented by employing
dropwise addition of the alkyne. Under the optimized
protocol, a solution of the alkyne (1 equiv) in dimethoxy-
ethane (DME) is added dropwise to a solution of the allylic
halide (1 equiv) and the Pd(II) catalyst (3 mol %) in DME.
The modified procedure uses equimolar amounts of the two
reactants and is effective for the coupling of allyl bromide
to a variety of alkynes, affording the expected products
cleanly and in high isolated yields (Table 1). Additionally,
During the course of the optimization studies, we observed
that the catalyst remains completely homogeneous throughout
the reaction; Pd black does not precipitate out even after the
reaction has gone to completion. This observation suggested
the possibility of accomplishing the second transformation,
a Suzuki-Miyaura cross-coupling,11 in the same flask, using
the Pd(II) catalyst already present.12 Addition of the boronic
acid was expected to reduce the Pd(II) to Pd(0), the
catalytically active species for the Suzuki reaction. As a test
case, upon completion of the reaction between allyl bromide
and methyl propiolate (entry 1, Table 2), the reaction mixture
Table 2. One-Pot Tandem Bromoallylation/Suzuki
Cross-Coupling of Alkynes
Table 1. Palladium-Catalyzed Bromoallylation of Acetylenes
R1
R2
R4
yield [%]b
entry
R1
R2
yield [%]b
entry
1
2
3
4
H
CO2Me
H
H
nPr
82 (1a )
83 (1b)
85 (1c)
87 (1d )
1
2
3
4
5
6
H
CO2Me
H
H
H
nPr
Me
4-MeOC6H4
3-Me(O)CC6H4
4-MeOC6H4
4-MeOC6H4
3-O2NC6H4
Ph
82 (3a )
82 (3b)
86 (3c)
80 (3d )
78 (3e)
74 (3f)
nBu
CH2OTBS
C(Me)2OH
Ph
nPr
CH2OTBS
Ph
nPr
a Dropwise addition as a solution in DME. b Isolated yield.
a Dropwise addition as a solution in DME. b Isolated yield.
the workup is simplified compared to the original procedure,
since there is essentially no allyl bromide, a potent lacry-
mator, left at the end of the reaction.
was treated with cesium carbonate (2 equiv) and 4-methoxy-
phenylboronic acid (2 equiv) and heated to 80 °C for 16 h
(8) For other examples of bromo-/chloropalladation of alkynes, see: (a)
Llebaria, A.; Camps, F.; Moreto´, J. M. Tetrahedron 1993, 49, 1283-1296.
(b) Ma, S.; Lu, X. J. Org. Chem. 1993, 58, 1245-1250. (c) Ba¨ckvall, J.
E.; Nilsonn, Y. I. M.; Andersson, P. G.; Gatti, R. G. P.; Wu, J. Tetrahedron
Lett. 1994, 35, 5713-5716. (d) Xu, X.; Lu, X.; Liu, Y.; Xu, W. J. Org.
Chem. 2001, 66, 6545-6550.
(9) The following are among the catalysts screened: Pd(PPh3)4, PdCl2-
(PPh3)2, Pd2(dba)3, and Pd(OAc)2.
(10) Ba¨ckvall, J. E.; Nilsonn, Y. I. M.; Gatti, R. G. P. Organometallics
1995, 14, 4242-4246.
4318
Org. Lett., Vol. 4, No. 24, 2002

in the same reaction vessel.13 The desired tetrasubstituted
alkene 3a was obtained in high isolated yield (82%). The
success of the two-reaction process confirmed the presence
of the active palladium catalyst upon completion of the
bromoallylation step.
tert-butylphosphine (PtBu3) was found to be the most
effective additive in enabling the Suzuki coupling to proceed
at lower temperatures.17,18 Indeed, the addition of 6 mol %
of PtBu3 after the initial step enabled the tandem bromoal-
lylation/Suzuki coupling of methyl propiolate to proceed at
room temperature in THF. The functionalized skipped diene
3a was isolated in 83% yield, similar to that obtained in the
absence of any phosphine ligand (Table 2, entry 1). The
added PtBu3 is expected to convert the initial PdBr2(PhCN)2
catalyst to PdBr2(PtBu3)2,19 which presumably is reduced in
situ to a catalytically active Pd(0) species.
The tandem, one-pot bromoallylation/Suzuki coupling
sequence was extended to a variety of other alkynes, the
results of which are shown in Table 2. The coupling process
was effective for terminal and internal alkynes. Aliphatic and
aromatic substituents on the alkyne were compatible with
the process. The reaction tolerates both electron-donating and
electron-withdrawing substituents on the alkyne. The scope
of the tandem reaction was also established with a variety
of electron-rich (entries 1, 3, and 4) and electron-poor (entry
5) arylboronic acids as cross-coupling partners. The resulting
tetrasubstituted skipped dienes 3 were generated in good
yields and excellent regio- and stereoselectivities. Thus, this
tandem process represents the execution of two mechanisti-
cally distinct reactions catalyzed sequentially by the same
palladium catalyst in one pot.
This final modification is effective for carrying out the
room temperature, one-pot tandem bromoallylation/Suzuki
coupling of a wide range of alkynes and boronic acids (Table
3). Methallylbromide (entries 10 and 11) was shown to be
Table 3. One-Pot Tandem Bromoallylation/Suzuki
Cross-Coupling of Alkynes at Room Temperature
Encouraged by the results of the tandem catalysis se-
quence, we sought to investigate the possibility of conducting
the Suzuki coupling step under milder conditions. Toward
this end, various carbene and phosphine ligands were
investigated as additives to generate a new, presumably more
reactive, Pd(0) complex capable of catalyzing the cross-
coupling reaction at lower temperatures.14 Addition of
carbene precursor 4 (5 mol %)15 as a reagent during the
Suzuki coupling step allowed for the lowering of the reaction
temperature to 45 °C. Tetrasubstituted skipped diene 3a was
isolated in a slightly higher yield of 85% using this
modification (cf. Table 2, entry 1).
entry
R1
R2
R3
R4
yield [%]b
1
2
3
4
5
6
7
8
9
H
CO2Me
H
H
H
H
H
H
H
H
H
4-MeOC6H4
3-Me(O)CC6H4
4-MeOC6H4
4-MeOC6H4
3-O2NC6H4
Ph
4-MeOC6H4
(E)-C4H9CHdCH
(E)-PhCHdCH
83(3a )
86(3b)
81(3c)
83(3d )
79(3e)
81(3f)
83(3g)
83(3h )
86(3i)
81(3j)
83(3k )
CH2OTBS
C(Me)2OH
Ph
H
H
H
nPr
nPr
CH2OTBS Me
nBu
Ph
Ph
H
H
H
H
10
11
CH2OTBS
nPr
Me 4-MeOCC6H4
Me N-tosyl-3-indoyl
nPr
a Dropwise addition as a solution in THF. b Isolated yield (%).
A variety of triaryl and trialkyl phosphines were also
examined for the Suzuki coupling step.16 As expected, tri-
an equally effective partner in the initial bromoallylation step.
The nature of the boronic acid in the Suzuki coupling step
was expanded to include alkenyl (entries 8 and 9) and
heterocyclic (entry 11) variants. This protocol thus allows
(11) For recent reviews on the Suzuki reaction, see: (a) Miyaura, N.;
Suzuki, A. Chem. ReV. 1995, 95, 2457-2483. (b) Suzuki, A. J. Organomet.
Chem. 2002, 653, 83-90.
(12) The tandem bromoallylation/Stille coupling has been demonstrated,
albeit in modest yields, see: Kosugi, M.; Sakaya, T.; Ogawa, S.; Migita,
T. Bull. Chem. Soc. Jpn. 1993, 66, 3058-3061.
(16) PPh3, PCy3, PtBu3, and dppf were tested.
(17) For leading references on the use of PtBu3 for cross-coupling
reactions, see: (a) Nishiyama, M.; Yamamoto, T.; Koie, Y. Tetrahedron
Lett. 1998, 39, 617-620. (b) Yamamoto, T.; Nishiyama, M.; Koie, Y.
Tetrahedron Lett. 1998, 39, 2367-2370. (c) Hundertmark, T.; Littke, A.
F.; Buchwald, S. L.; Fu, G. C. Org. Lett. 2000, 2, 1729-1731. (d) Dai, C.;
Fu, G. C. J. Am. Chem. Soc. 2001, 123, 2719-2724. (e) Littke, A. F.; Fu,
G. C. J. Am. Chem. Soc. 2001, 123, 6989-7000. (f) Littke, A. F.; Schwarz,
L.; Fu. G. C. J. Am. Chem. Soc. 2002, 124, 6343-6348.
(13) Cesium carbonate was found to be the base of choice after screening
a variety of other bases including K2CO3, KF, NaHCO3, and NaOH.
(14) For leading references on the use of N-heterocyclic carbenes in cross-
coupling reactions, see: (a) Herrmann, W. A.; Elison, M.; Fischer, J.;
Ko¨cher, C.; Artus, G. R. J. Angew. Chem., Int. Ed. Engl. 1995, 34, 2371-
2373. (b) Zhang, C.; Huang, J.; Trudell, M. L.; Nolan, S. P. J. Org. Chem.
1999, 64, 3804-3805. (c) Bo¨hm, V. P. W.; Gsto¨ttmayr, C. W. K.; Weskamp,
T.; Herrmann, W. A. J. Organomet. Chem. 2000, 595, 186-190. (d) Grasa,
G. A.; Viciu, M. S.; Huang, J.; Zhang, C.; Trudell, M. L.; Nolan, S. P.
Organometallics 2002, 21, 2866-2873. (e) Hillier, A. C.; Nolan, S. P.
Platinum Metal ReV. 2002, 46, 50-64.
(18) For leading references on the use of PtBu3 for Suzuki reaction, see:
(a) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020-
4028. (b) Netherton, M. R.; Dai, C.; Neuschuetz, K.; Fu, G. C. J. Am. Chem.
Soc. 2001, 123, 10099-10100. (c) Kirchhoff, J. H.; Dai, C.; Fu, G. C.
Angew. Chem., Int. Ed. 2002, 41, 1945-1947.
(15) Arduengo, A. J., III; Dias, H. V. R.; Harlow, R. L.; Kline, M. J.
Am. Chem. Soc. 1992, 114, 5530-5534.
(19) Goel, R. G.; Ogini, W. O. Organometallics 1982, 1, 654-658.
Org. Lett., Vol. 4, No. 24, 2002
4319

for the stereocontrolled synthesis of functionalized skipped
dienes in good overall yields and under very mild conditions.
The final improvement to the process was to incorporate
the use of allyl chloride in the tandem catalysis sequence.
The advantages of using chlorides over bromides include
lower cost, higher stability, and commercial availability of
a broader range of compounds, issues that are of particular
importance for large-scale applications of this methodology.
During initial optmization studies, it was determined that
chloroallylation of alkynes using 1 equiv of allyl chloride
proceeded at a slower rate than the corresponding reaction
with allyl bromide. Nevertheless, after 6 h, only trace
amounts of the alkyne remained in the crude reaction
mixture. The resulting crude vinyl chloride 2 (R1 ) Ph; R2,
R3 ) H) was directly subjected to the Suzuki cross-coupling
conditions with 4-methoxyphenylboronic acid, PtBu3, and
cesium carbonate. Although the cross-coupling step pro-
ceeded slowly at room temperature (<20% conversion after
24 h), it proceeded nicely to full conversion when the
temperature was raised to 45 °C.
Table 4. One-Pot Tandem Chloroallylation/Suzuki
Cross-Coupling of Alkynes
entry
R1
R2
R4
yield [%]b
1
2
3
4
5
6
H
CO2Me
H
H
H
nPr
Me
4-MeOC6H4
3-Me(O)CC6H4
4-MeOC6H4
4-MeOC6H4
3-O2NC6H4
Ph
73 (3a )
68 (3b)
68 (3c)
70 (3d )
64 (3e)
72 (3f)
CH2OTBS
C(Me)2OH
Ph
nPr
CH2OTBS
a Dropwise addition as a solution in THF. b Isolated yield.
Several different alkynes were then subjected to this
protocol for the one-pot tandem chloroallylation/Suzuki
coupling (Table 4). As before, the desired skipped dienes
(3) were produced with complete regio- and stereochemical
integrity, albeit in slightly lower yields compared with the
corresponding tandem bromoallylation/Suzuki couplings
(Table 3). The lower yields are probably due to increased
oligo- and polymerization of the alkyne as a result of the
slow nature of the initial chloroallylation.
To summarize, we have demonstrated the capability of
using a palladium catalyst for two mechanistically distinct
chemical reactionssbromo- or chloroalllylation of an alkyne
followed, in the same flask, by a Suzuki cross-coupling
reaction. This tandem sequence produces functionalized,
tetrasubstituted skipped dienes in a stereocontrolled manner.
The advantages of this multifunctional catalysis include the
avoidance of intermediate workup steps and the atom
economy associated with not having to use a second set of
reagents and solvents, as well as the time and cost savings
of transforming the used catalyst in situ for a second reaction.
Acknowledgment. This work was supported by the
National Institutes of Health. A.N.T thanks the National
Science and Engineering Research Council of Canada for a
postdoctoral fellowship.
Supporting Information Available: Preparation proce-
dures and characterization data for 3. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL0269594
4320
Org. Lett., Vol. 4, No. 24, 2002