Transmetalation of palladium enolate and its application in palladium-catalyzed homocoupling of alkynes: A room-temperature, highly efficient route to make diynes

Article abstract of DOI:10.1021/jo011098i

A novel pathway for the homocoupling reaction has been achieved using a similar protocol as the cross-coupling reaction. Ethyl bromoacetate is chosen to initiate the coupling reaction through oxidatlve addition to a Pd(0) species, and an PdBr(enolate) intermediate is formed. This intermediate can undergo double transmetalation with an alkynyl copper reagent, and reductive elimination produces a variety of diynes in high yields.

Full text of DOI:10.1021/jo011098i

J . Org. Chem. 2002, 67, 1969-1971
1969
Sch em e 1. New P a th w a y in P d -Ca ta lyzed
Hom ocou p lin g Rea ction s
Tr a n sm eta la tion of P a lla d iu m En ola te a n d
Its Ap p lica tion in P a lla d iu m -Ca ta lyzed
Hom ocou p lin g of Alk yn es:
A Room -Tem p er a tu r e, High ly Efficien t
Rou te To Ma k e Diyn es
Aiwen Lei, Manisha Srivastava, and Xumu Zhang*
Department of Chemistry, Pennsylvania State University,
152 Davey Laboratory, University Park, Pennsylvania 16802
Xumu@chem.psu.edu
Received November 26, 2001
coupling product IV (Scheme 1, path A). In this paper,
we have explored an alternate pathway to form a homo-
coupling product VI (Scheme 1, path B). The intermedi-
ate III formed by the first transmetalation can undergo
a second transmetalation with R2M to generate the
intermediate V. Subsequently, reductive elimination of
V produces the coupling product VI. Although there are
many reports of Pd-catalyzed coupling reactions using
path A in Scheme 1, no systematic study of path B has
been conducted. Research into path B is of significant
interest in exploring the scope of palladium-catalyzed
coupling reactions.
There are some major differences in the two different
pathways depicted in Scheme 1. In path A, the product
R1R2 consists of two parts: one part comes from R1X (I),
and the other originates from R2M. Due to the low
activity of some R1X species such as an aryl chloride or
sterically hindered aryl halide, oxidative addition can be
slow and the overall process to form R1R2 may be
inhibited.3 In contrast, the homocoupling product R2R2
in path B derives from a transmetalation reagent, R2M.
A reagent that readily undergoes oxidative addition, R1X,
can be selected. We propose that the key step in our
desired homocoupling reaction is the second transmeta-
lation of the intermediate III through displacement of
R1M to R2M. In this paper, a new pathway has been
utilized in the palladium-catalyzed homocoupling reac-
tion of alkynes by choosing ethyl bromoacetate as an
appropriate R1X species and an alkynyl copper reagent
as R2M. We propose that a palladium enolate species is
the key intermediate for the transmetalation step.
Palladium enolate chemistry has recently received
considerable attention and enjoyed great progress.2a,f,4
Reaction of Pd(0) complexes with R-halo carbonyl com-
pounds has been reported to produce halopalladium
enolate complexes.5 While it is well-known that the halide
anion can serve as a good leaving group in a transmeta-
Abstr a ct: A novel pathway for the homocoupling reaction
has been achieved using a similar protocol as the cross-
coupling reaction. Ethyl bromoacetate is chosen to initiate
the coupling reaction through oxidative addition to a Pd(0)
species, and an PdBr(enolate) intermediate is formed. This
intermediate can undergo double transmetalation with an
alkynyl copper reagent, and reductive elimination produces
a variety of diynes in high yields.
Over the past several decades, transition-metal-
catalyzed carbon-carbon bond-forming reactions have
been extensively studied and widely applied in organic
synthesis.1 The palladium-catalyzed coupling reaction
has proved to be an extremely powerful tool to construct
carbon-carbon or carbon-heteroatom bonds.2 In a typi-
cal Pd-catalyzed process, oxidative addition of the pal-
ladium(0) species I and an aryl or vinyl halide or triflate
occurs first. Transmetalation of II via a metal reagent
to displace the halide or triflate anion on the palladium
center followed by reductive elimination of III gives the
(1) (a) Tsuji, J . Transition Metal Reagents and Catalysts: Innovations
in Organic Synthesis; Wiley: Chichester, U.K., 2000. (b) Cornils, B.;
Hermann, W. A. Applied Homogeneous Catalysis with Organometallic
Compounds; Wiley: Weinheim, Germany, 1999. (c) Diederich, F.;
Stang, P. J . Metal-catalyzed Crosscoupling Reaction; Wiley-VCH:
Weinheim, Germany, 1998. (d) Beller, M.; Bolm, C. Transition Metals
for Organic Synthesis; Wiley-VCH: Weinheim, Germany, 1998. (e)
Farina, V. In Comprehensive Organometallic Chemistry II; Abel, E.
W., Stone, F. G. A., Wilkinson. G., Eds.; Pergamon: Oxford, U.K., 1995;
Vol. 12, pp 161-240. (f) Leong, W. W.; Larock, R. C. In Comprehensive
Organometallic Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson,
G., Eds.; Pergamon: Oxford, U.K., 1995; Vol. 12, pp 131-160. (g) Grigg,
R.; Sridharan, V. In Comprehensive Organometallic Chemistry II; Abel,
E. W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon: Oxford, U.K.,
1995; Vol. 12, pp 299-321. (h) Tsuji, J . Palladium Reagents and
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Principles and Applications of Organotransition Metal Chemistry;
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Chem. Soc. 2000, 122, 1360-1370. (b) Beletskaya, I. P.; Cheprakov,
A. V. Chem. Rev. 2000, 100, 3009-3066. (c) Hartwig, J . F. In Modern
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J . Org. React. 1997, 50, 1-652. (m) Miyaura, N.; Suzuki, A. Chem.
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3187-3204. (b) Stille, J . K.; Lau, K. S. Y. Acc. Chem. Res. 1977, 10,
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10.1021/jo011098i CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/28/2002

1970 J . Org. Chem., Vol. 67, No. 6, 2002
Notes
Ta ble 1. P a lla d iu m -Ca ta lyzed Hom ocou p lin g Rea ction
of Ter m in a l Alk yn esa
lation step, an enolate anion as a leaving group to
promote transmetalation is a relatively unexplored pro-
cess. Herein, we report the first example of transmeta-
lation of a palladium enolate anion with an alkynylcopper
species. Double transmetalation of an alkynylcopper
compound to replace both the halo and enolate anion
groups on palladium produces a variety of diynes under
mild conditions and in high yields. This new coupling
reaction has certain advantages compared to Glaser and
Sonogashira-Hagihara coupling reactions6 for the for-
mation of diynes: (1) the reaction can be carried out
under an inert atmosphere to avoid side reactions of
diynes associated with the Glaser coupling reaction,
which uses O2 as the oxidant; (2) formation of an alkynyl
halide in the Sonogashira-Hagihara coupling reaction
is avoided; (3) many terminal alkynes with alkyl groups
can be effectively coupled in this reaction, wherein no
activity and low yields are observed in the corresponding
Glaser coupling reaction.
In our experiments, trimethyl(phenylacetylenyl)silane
(1 mmol) was used as the substrate for the sp-sp
homocoupling reaction. In the presence of 0.05 mmol of
PdCl2(PPh3)2 and 1.0 mmol of methyl R-phenylbromoac-
etate in THF, no reaction was observed. When tetra-
butylammonium fluoride was added to this mixture, a
small amount of the desired homocoupling product was
obtained (<10%). In another experiment, tributyl(phenyl-
acetylenyl)tin (1; 0.5 mmol) in the presence of PdCl2-
(PPh3)2 (0.05 mmol) and methyl R-phenylbromoacetate
(1.0 mmol) at room temperature furnished the desired
product, 1,4-diphenylbut-1,3-diyne (2a ) in 20% yield after
3 days (eq 1). Although the reaction yield was low, the
a
All reactions were performed using 60 mol % ethyl bromoac-
etate, 120 mol % diisopropylethylamine, 2 mol % PdCl2(PPh3)2,
and 2 mol % CuI in 5 mL of THF. The reactions were done at
room temperature for 2-24 h, and the progress of the reaction
b
was monitored by TLC. Isolated yields were reported.
was used as catalyst, only a 39% yield was obtained.
Further optimization showed that only catalytic amounts
of Cu(I) are required and an inexpensive R-halo carbonyl
compound, ethyl bromoacetate, can be used to replace
methyl R-phenylbromoacetate. For example, homocou-
pling of phenylacetylene proceeds in 98% yield in the
presence of 0.05 mmol of CuI and no sp-sp3 cross-
coupling product was detected. We have also performed
a number of control experiments: (1) in the absence of
the palladium catalyst, no reaction occurred; (2) in the
absence of CuI, the reaction proceeded slowly (3 days) in
low yield (40%); (3) a low yield was observed when
diisopropylethylamine was replaced by K2CO3 (34% yield
in THF); (4) in the absence of ethyl bromoacetate, the
diyne was formed in 10% yield after 12 h.
Under these optimized conditions, we have examined
the substrate scope of this reaction. Our experiments
indicate that a variety of functional groups can be
tolerated in this reaction (Table 1). Alkenyl (entry 5),
nitrile (entry 8), and hydroxyl (entries 9-13) are some
functional groups on the terminal alkynes, which are not
affected under the reaction conditions. Generally, termi-
nal aliphatic alkynes are sluggish in undergoing Glaser
dimerization due to the weaker acidity of the acetylenic
proton.8 Using our new protocol, the coupling reactions
of 3f-h were carried out to afford the corresponding
coupling products in moderate yields (66%, 47%, and
feasibility of the reductive elimination between sp-sp
carbon species at room temperature prompted us to
explore a highly efficient sp-sp coupling reaction.
Inspired by the well-known Sonogashira-Hagihara
coupling protocol,7 an alkynylcopper reagent was chosen
as a transmetalation reagent for the Pd-catalyzed sp-
sp coupling reaction. Phenylacetylene (1 mmol) was
coupled to form 1,4-diphenylbut-1,3-diyne in 99% yield
in the presence of CuI (1.5 mmol), methyl R-phenyl-
bromoacetate (1.2 mmol), diisopropylethylamine (1.5
mmol), and PdCl2(PPh3)2 (0.05 mmol). When Pd(PPh3)4
(6) Copper-mediated Hay modification of the Glaser reaction is a
commonly used synthetic methodology for the construction of diynes:
(a) Hay, A. S. J . Org. Chem. 1962, 27, 3320-3321. Recently, some new
copper-mediated sp-sp coupling reactions have been developed: (b)
Nishihara, Y.; Ikegashira, K.; Hirabayashi, K.; Ando, J .-I.; Mori, A.;
Hiyama, T. J . Org. Chem. 2000, 65, 1780-1787. (c) Nishihara, Y.;
Ikegashira, K.; Mori, A.; Hiyama, T. Tetrahedron Lett. 1998, 39, 4075-
4078. The palladium-catalyzed Sonogashira-Hagihara coupling reac-
tion between a terminal alkyne and a halo alkyne (alkynyl halide) is
an effective way to form a diyne: (d) Lee, G. C. M.; Tobias, B.; Holmes,
J . M.; Harcourt, D. A.; Garst, M. E. J . Am. Chem. Soc. 1990, 112, 9330-
9336. Other palladium-mediated sp-sp coupling reactions include: (e)
Liu, Q.; Burton, D. J . Tetrahedron Lett. 1997, 38, 4371-4374. (f)
Wright, M. E.; Porsch, M. J .; Buckley, C.; Cochran, B. B. J . Am. Chem.
Soc. 1997, 119, 8393-8394. (g) Rossi, R.; Carpita, A.; Bigelli, C.
Tetrahedron Lett. 1985, 26, 523-526. (h) Vlassa, M.; Ciocan-Tarta, I.;
Margineanu, F.; Oprean, I. Tetrahedron 1996, 52, 1337-1342. (i)
Huang, X.; Wang, J .-H. Synth. Commun. 2000, 30(1), 9-14 and
references therein.
(7) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
16, 4467-4470.
(8) Brandsma, L.; Verkruijsse, H. D.; Walda, B. Synth. Commun.
1991, 21, 137-139.

Notes
Sch em e 2. P a lla d iu m -Ca ta lyzed Hom ocou p lin g
J . Org. Chem., Vol. 67, No. 6, 2002 1971
reductive elimination is faster than the reductive elimi-
nation of the intermediate formed after the first trans-
metalation.
Rea ction w ith Alk yla lk yn es
In conclusion, we have successfully developed a novel
pathway for the palladium-catalyzed homocoupling reac-
tion, using ethyl bromoacetate to initiate the reaction.
We propose that the double transmetalation of palladium
enolate takes place with a suitable alkynylmetal reagent.
High yields have been achieved in the palladium-
catalyzed homocoupling of many alkynes. Further ap-
plication of intramolecular cross-coupling of diynes and
polymerization of alkynes using this methodology is
ongoing and will be reported in due course.
Sch em e 3. P r op osed Rea ction Mech a n ism
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were carried out in an inert
atmosphere using standard Schlenk techniques. Column chro-
matography was performed on EM silica gel 60 (200-400 mesh).
1H NMR (360 MHz) and 13C NMR (90 MHz) spectra were
acquired in deuterated chloroform (CDCl3), methanol (CD3OD),
and methylene chloride (CD2Cl2). THF was freshly distilled
under nitrogen from sodium benzophenone ketyl. Alkynes were
purchased from commercial sources (Aldrich, Lancaster, and
Acros) and used without further purification.
Gen er a l P r oced u r e for th e Hom ocou p lin g of Alk yn es
Ca ta lyzed by P a lla d iu m . In a Schlenk tube, PdCl2(PPh3)2 (14.1
mg, 0.02 mmol), CuI (3.8 mg, 0.02 mmol), and base (1.2 mmol)
were added and stirred under nitrogen. The tube was evacuated
and refilled with nitrogen. THF (5 mL) and alkyne (1 mmol) were
added under nitrogen to the above mixture. To this tube was
added ethyl bromoacetate (100.2 mg, 0.6 mmol), and the reaction
mixture was stirred at room temperature for 2-24 h. Progress
of this reaction was monitored by TLC. After the reaction was
complete, 5 mL of ethyl acetate and 2-3 g of silica gel was added
and the solvent was removed under vacuum. The solid residue
was then subjected to column chromatography.
62%, respectively). However, excellent yields (up to 99%)
for coupling of 3f-h were achieved when DABCO was
chosen as a base (Scheme 2). These breakthrough results
are critical for the polymerization of diynes with different
linkers.
Scheme 3 illustrates our proposed mechanism for the
sp-sp homocoupling of alkynes. The alkynylcopper in-
termediate A is formed from the reaction of a terminal
alkyne and CuI in the presence of diisopropylethylamine,
and it undergoes double transmetalation with a pal-
ladium bromide enolate.6e The transmetalation yields the
dialkynylpalladium intermediate B, and then the reduc-
tive elimination from the dialkynylpalladium species
leads to the sp-sp homocoupling product and Pd0Ln
(Scheme 3). Oxidative addition of Pd0Ln and ethyl
bromoacetate affords the intermediate C; isomerization
of C generates the oxygen-bound palladium enolate
bromide D. The formation of oxygen-bound palladium
enolate bromide plays a crucial role in the sp-sp homo-
coupling reaction, by making the second transmetalation
possible and providing the homocoupling product. The
absence of sp-sp3 cross-coupling product indicates that
the process of the second transmetalation followed by
1
Deca -4,6-d iyn e Din itr ile (2h ). H NMR: δ 2.64 (t, J ) 6.4
Hz, 4H), 2.57 (t, J ) 6.4 Hz, 4H). 13C NMR δ 118.0, 74.3, 67.8,
17.5, 17.0. MS: m/e 156, 129, 116, 102, 89, 76, 63. HRMS: calcd
for C10H8N2 (M+ + 1), 157.0766; found, 157.0752.
Ack n ow led gm en t. The Camille and Henry Dreyfus
Teacher-Scholar Award supported this work. We ac-
knowledge a generous loan of precious metals from
J ohnson Matthey Inc.
Su p p or tin g In for m a tion Ava ila ble: Text giving char-
acterization data for the new compound 2h (1H and 13C NMR
spectra) and details of the characterization of diynes 2a -m .
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O011098I