Multifunctional palladium catalysis. 2. Tandem haloallylation followed by Wacker-Tsuji oxidation or Sonogashira cross-coupling

Article abstract of DOI:10.1021/ol0269603

(equationpresented) Multifunctional palladium catalysis is utilized in the one-pot stereocontrolled synthesis of tetrasubstituted methyl ketones and enynes. The homogeneous palladium dihalide catalyst utilized for the bromo-/chloroallylation of alkynes is

Full text of DOI:10.1021/ol0269603

ORGANIC
LETTERS
2002
Vol. 4, No. 24
4321-4323
Multifunctional Palladium Catalysis. 2.
Tandem Haloallylation Followed by
Wacker−Tsuji Oxidation or Sonogashira
Cross-Coupling
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 methyl ketones and enynes. The
homogeneous palladium dihalide catalyst utilized for the bromo-/chloroallylation of alkynes is reused in situ for subsequent Wacker−Tsuji
oxidation or Sonogashira cross-coupling.
The importance of catalysis as a central tenet of the green
chemistry paradigm is well established.1 Palladium catalysis,
in particular, has been the driver of many advances in modern
day organic synthesis.2 In most instances, the function of
the palladium reagents is to catalyze a single type of
transformation. More desirable, from the viewpoint of
efficiency, are reagents capable of catalyzing multiple
reactions in a single pot.3 This multifunctional use of the
catalyst would not only generate less waste but it would also
obviate the tedious separation and purification of the
intermediate products.4
In the preceding paper,5 we reported that the atom
economical addition of allyl chlorides and bromides to
acetylenes, developed by Kaneda and co-workers, is ideally
(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.
(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.
(1) For a brief review on the concept of green chemistry, see: Anastas,
P. T.; Kirchhoff, M. M. Acc. Chem. Res. 2002, 35, 686-694.
(2) (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: InnoVations in Organic
Synthesis; John Wiley & Sons: New York, 2000.
(5) Thadani, A. N.; Rawal, V. H. Org. Lett. 2002, 4, 4317-4320.
10.1021/ol0269603 CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/05/2002

suited for “catalyst recycling”.6-8 We showed that the
haloallylation step can be followed, in the same pot and using
only the initial catalyst, with a Suzuki cross-coupling reaction
to afford tetrasubstituted alkenes in high yields and excellent
regio- and stereoselectivities.5 In this paper, we demonstrate
that the palladium(II) catalyst from the initial bromo-/
chloroallylation step can also be reused in situ for subsequent
Wacker-Tsuji oxidations and Sonogashira cross-coupling
reactions (Scheme 1).9
Table 1. One-Pot Tandem Bromo-/Chloroallylation
Wacker-Tsuji Oxidation of Alkynes
entry
R1
R2
X
yield [%]b
1
2
3
4
5
6
H
H
nBu
nPr
nPr
CO2Me
CO2Me
H
Br
Cl
Br
Br
Cl
Cl
74 (3a )
75 (3b)
70 (3c)
80 (3d )
77 (3e)
66 (3f)
Scheme 1
nPr
nPr
Me
CH2OTBS
a Dropwise addition as a solution in DME. b Isolated yield.
functionalized methyl ketones in moderate to high yields for
the two-step sequence. The synthetic potential of the resulting
products is highlighted by the synthesis of dihydrojasmone
by Tsuji and Yasuda from methyl ketone 3 (R1 ) C6H13; R2
) H; X ) Cl).11
The Wacker-Tsuji oxidation is particularly well-suited
for incorporation in a tandem sequence with the haloallylation
step, as both reactions are catalyzed by palladium(II)
species.10 A trial reaction was performed with 4-octyne and
an equimolar amount of allyl bromide. The initial bromoal-
lylation catalyzed by PdBr2(PhCN)2 (3 mol %) was carried
out in DME, as previously described.5 To the resulting crude
reaction mixture containing the alkenyl bromide 1 (R1 ) R2
) nPr; X ) Br) and the palladium catalyst was added copper-
(I) chloride (1 equiv) and water.11 The reaction mixture was
then stirred for 24 h under an oxygen atmosphere. Methyl
ketone 3a was subsequently isolated in 80% yield after
workup and chromatographic purification. This sequence
confirmed that the palladium(II) catalyst from the initial
bromo-/chloroallylation step can be effectively reused for a
second palladium(II)-catalyzed reaction.
The expected methyl ketone 3 (R1 ) Ph; R2 ) H),
however, was not produced when a terminal aromatic alkyne
was incorporated into the two-step, one-pot sequence outlined
above. Thus, subjecting phenylacetylene to the tandem
process afforded, instead, vinylogous diketone 5 in 77%
isolated yield (eq 1). The tandem chloroallylation/Tsuji-
Wacker oxidation of phenylacetylene also resulted in di-
ketone 5 albeit in a slightly lower yield (73%).
A variety of alkenes were subjected to the tandem bromo-/
chloroallylation-Wacker-Tsuji oxidation using the above
protocol (Table 1). Both internal (entries 4-6) and terminal
alkynes (entries 1-3) were converted into the corresponding
A reasonable path for the formation of the diketone is via
a Saegusa-type oxidation as shown in Scheme 2. The
(6) (a) Kaneda, K.; Uchiyama, T.; Fujiwara, Y.; Imanaka, T.; Teranishi,
S. J. Org. Chem. 1979, 44, 55-63. (b) For mechanistic studies on
haloallylation, see: Ba¨ckvall, J. E.; Nilsonn, Y. I. M.; Gatti, R. G. P.
Organometallics 1995, 14, 4242-4246.
(7) For a brief review on the concept of atom economy, see: Trost, B.
M. Acc. Chem. Res. 2002, 35, 695-705.
Scheme 2
(8) For other examples of halopalladation 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 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.
(10) (a) Tsuji, J. Palladium Reagents and Catalysts: InnoVations in
Organic Synthesis; John Wiley & Sons: Wiley: New York, 1995; pp 22-
30. (b) Tsuji, J. Synthesis 1984, 369-384.
(11) 3 was synthesized via a two-pot protocol: Tsuji, J.; Yasuda, H.
Synth. Commun. 1978, 8, 103-107.
expected product of the two-step sequence, haloenone 6, can
be hydrated with Pd(II) to yield organo-palladium halohydrin
4322
Org. Lett., Vol. 4, No. 24, 2002

7, which upon loss of HX and reductive elimination of Pd(0)
would yield the observed product.12,13
Table 2. One-Pot Tandem Bromoallylation-Sonogashira
Cross-Coupling of Alkynes
Scheme 3
entry
R1
R2
R3
yield [%]b
1
2
3
4
5
nBu
C(Me)2OH
Ph
nPr
nPr
H
H
H
nPr
nPr
C(Me)2OH
C(Me)2OH
C(Me)2OH
Ph
85 (4a )
73 (4b)
79 (4c)
84 (4d )
87 (4e)
C(Me)2OH
a Dropwise as a solution in DME. b Isolated yield.
We next turned our attention toward further expanding
the scope of such tandem reaction sequences. The Sono-
gashira cross-coupling, which is an important component in
the repertoire of carbon-carbon bond-forming methodolo-
gies, was an attractive process to include in the tandem
sequence.14 Incorporation of such a reaction after the
bromoallylation of alkynes would result in a one-pot ste-
reocontrolled synthesis of highly substituted functionalized
enynes.15 After extensive screening of conditions, it was
found that the Sonogashira cross-coupling step proceeded
best when conducted under the conditions previously reported
by Buchwald and Fu et al.16 The tandem reaction worked
well with a broad range of alkynes to afford enyne 4
stereospecifically and in good overall isolated yields (Table
2). The addition of tri-tert-butylphosphine (PtBu3) is expected
to convert the palladium dihalide species that results from
the bromoallylation step to PdBr2(PtBu3)2.17 In turn, this
palladium compound is presumably reduced in situ to a
catalytically active Pd(0) species.
formed. Formed, instead, was the interesting product of
alkyne cyclotrimerization, a hexasubstituted benzene deriva-
tive (7), in 59% isolated yield (Scheme 3). The yield of 7
was increased to 70% by simply subjecting 4-ocytne, but
without added crotyl chloride, to the same reaction condi-
tions.18
In conclusion, the stereocontrolled synthesis of function-
alized methyl ketones and enynes were accomplished via
multipurpose palladium catalysis. The palladium dihalide
catalyst left over from the initial bromo-/chloroallylation step
was shown capable of catalyzing a subsequent Wacker-Tsuji
oxidation in the same reaction vessel. The initial palladium
catalyst was also shown to successfully promote a Sono-
gashira cross-coupling reaction, which requires in situ
reduction of the Pd(II) species. The sequencing of two
distinct reactions in a one-pot process, as illustrated in this
and the preceding paper,5 not only makes better use of
precious reagents and solvents but also has the added benefit
of eliminating inefficient separation and purification after
each step. The resultant reduction in waste makes such
processes environmentally desirable.
Attempts at extending the tandem sequence to crotyl
chloride were unsuccessful. The initial chlorocrotylation step
was very sluggish and none of the desired diene (6) was
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.
(12) (a) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011-
1013. (b) Takayama, H.; Koike, T.; Aimi, N.; Sakai, S. J. Org. Chem. 1992,
57, 2173-2176.
(13) An alternate, albeit less likely path involves the rearrangement of
the haloenone 6 to afford a γ-chloroenone, which upon hydrolysis and
oxidation could yield the observed product.
(14) (a) Sonogashira, K. In Metal-Catalyzed Cross-Coupling Reactions;
Diederich, F., Stang, P. J., Eds.; Wiley-VCH: New York, 1998; Chapter
5. (b) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
16, 4467-4470.
Supporting Information Available: Preparation proce-
dures and characterization data for 3-5. This material is
available free of charge via the Internet at http://pubs.acs.org.
(15) For an interesting domino reaction of allyl electrophiles, alkynes,
and alkynyltins using Ni catalysis, see: Cui, D.-M.; Tsuzuki, T.; Miyake,
K.; Ikeda, S.; Sato, Y. Tetrahedron 1998, 54, 1063-1072.
(16) Hundertmark, T.; Littke, A. F.; Buchwald, S. L.; Fu, G. C. Org.
Lett. 2000, 122, 1729-1731.
OL0269603
(18) Similar palladium(II)-catalyzed cyclotrimerization of alkynes was
recently demonstrated: Li, J. H.; Jiang, H. F.; Chen, M. C. J. Org. Chem.
2001, 66, 3627-3629.
(17) Goel, R. G.; Ogini, W. O. Organometallics 1982, 1, 654-658.
Org. Lett., Vol. 4, No. 24, 2002
4323