Evidence for the in situ formation of copper acetylides during Pd/Cu catalyzed synthesis of enynes: A new synthesis of allenynols

Article abstract of DOI:10.1039/b309094a

The in situ formation of copper acetylide in Pd/Cu catalyzed coupling reactions of acetylenic derivatives has been demonstrated by the reaction with ethynyloxiranes, which provides allenynols; a new Cu catalyzed route to the latter has also been found.

Full text of DOI:10.1039/b309094a

View Article Online / Journal Homepage / Table of Contents for this issue
L E T T E R
Evidence for the in situ formation of copper acetylides during Pd/Cu
catalyzed synthesis of enynes: a new synthesis of allenynolsy
a
b
b
b
´
Philippe Bertus, Fabien Fecourt, Claude Bauder and Patrick Pale*
a
´
Laboratoire des Reactions Selectives et Applications (CNRS UMR 6519), Universite de
Reims-Champagne-Ardenne, BP 1039, 51687, Reims, France
´
´
b
`
Laboratoire de Synthese et Reactivite Organique (CNRS UMR 7123), Institut Le Bel,
Universite L. Pasteur, 4 rue B. Pascal, 67000, Strasbourg, France.
´
´
´
E-mail: ppale@chimie.u-strasbg.fr; Fax: þ33 3 9024 1517; Tel: þ33 3 9024 1517
Received (in Montpellier, France) 31st July 2003, Accepted 9th October 2003
First published as an Advance Article on the web 28th November 2003
The in situ formation of copper acetylide in Pd/Cu catalyzed
coupling reactions of acetylenic derivatives has been demon-
strated by the reaction with ethynyloxiranes, which provides
allenynols; a new Cu catalyzed route to the latter has also
been found.
Scheme 1 Inefficient cross-coupling of ethynyloxiranes to vinyl
triflates.
Pd/Cu catalyzed cross-coupling reactions between terminal
acetylenes and aryl or vinyl halides or triflates, the so-called
Sonogashira reaction, have been recognized since the mid-
seventies.1,2 The mildness and the efficiency of these methods
have since led to an impressive collection of applications in
numerous areas from medicinal chemistry to material
science.3,4 Despite being widely utilized, the exact mechanism
of this C–C bond formation has so far not been demonstrated.
Although the main features of the Pd catalytic cycle have been
established,5 the Cu catalytic cycle is still poorly understood.6
In this communication, we present chemical evidence for the
in situ formation of copper acetylides, which allow us to
propose a mechanism for the Cu catalytic cycle of Pd/Cu
catalyzed cross-coupling reactions.
Several research programs dedicated to the synthesis of
polyunsaturated natural products led us to study the forma-
tion of epoxyenynes by coupling reactions7,8 and to begin the
investigation of the mechanism of such reactions.9 The direct
synthesis of epoxyenynes starting from ethynyloxiranes and
vinyl triflates or halides proved to be inefficient with the
reported procedures.7a,10 In every trial,7 the ethynyloxirane
engaged was rapidly consumed while only a small amount of
the expected enyne was obtained (less than 25%, see Scheme
1) among various other polar side-products.
Even when the ethynyloxirane was slowly added to the other
components of the reaction, decomposition was still the major
process; the yield of enyne was nevertheless better but still
modest (40–50%). Whatever the conditions, reaction monitoring
indicated that the triflate component was almost unchanged
while the acetylenic epoxide was rapidly consumed.
To get some understanding on the evolution of epoxyacety-
lenes during Sonogashira coupling, we tested a model acety-
lenic epoxide (1a) with each reagent (palladium complexes,
amines and copper salts) and selected combinations of these,
depending on the expected reactivity (Table 1). The epoxide
1a was obtained by meta-chloroperbenzoic acid epoxidation
of the commercially available Z 3-methylpent-2-en-4-yn-1-ol
and protection as a tert-butyldiphenylsilyl ether.
In the presence of zero- or divalent palladium complexes in
DMF, no transformation of the acetylenic epoxide 1a was
observed (entries 1 and 2) at room temperature, even when
an amine was added (entries 4 and 5). These results are surpris-
ing since palladium complexes are known to catalyze the selec-
tive opening of related vinyloxiranes, especially in the presence
of certain amines.11 Although amines are known to selectively
open acetylenic epoxides,12 amines alone in DMF added to 1a
did not afford any significant transformation at room tempera-
ture (entry 3). In the presence of copper iodide alone, only a
slow evolution was observed (entry 6). However, when copper
iodide and an amine were added, a rapid evolution occurred
and a new polar product was formed along with only a few
polar side-products (entries 7–9). This major product was
isolated and characterized, mainly by spectroscopy.
The 1H NMR spectrum revealed the presence of the tert-
butyldiphenylsilyl group. However, the signal intensity of the
aromatic protons relative to the intensity of the other protons
suggested that two silyl groups are in fact present in this mole-
cule. In this spectrum, the presence of the typical signals of the
starting 2,3-epoxypent-4-ynol, a triplet at 3.1 ppm coupled to
an ABX system at 3.80–3.95 ppm, clearly showed that a frag-
ment identical to the starting epoxyalkyne was preserved in the
structure of the new product. Therefore, the new product may
result from the condensation of two molecules of the starting
silylated epoxyalkynol. The IR spectrum indeed exhibited a
signal corresponding to a disubstituted triple bond (n ¼ 2235
cmꢀ1). However, this spectrum also showed the presence of
new bands, one at 3400 cmꢀ1 typical of a hydroxyl function,
and another one at 1960 cmꢀ1 suggesting the presence of an
allene group. Further NMR analysis confirmed this attribu-
tion. The 13C NMR spectrum exhibited one signal at 210
ppm and two others located at around 76 ppm, which can
indeed be attributed to an allene. HMQC experiments showed
that the carbon signals at 210 and 77 ppm do not correlate
with any proton but the third signal at 76 ppm correlates with
a multiplet at 5.25 ppm corresponding to one proton. Others
correlations also support this attribution and allowed us to
propose the epoxyallenynol structure 2a for this compound
y The authors dedicate this work to the late Prof. J. Chuche,
´
Universite de Reims-Champagne-Ardenne, France.
T h i s j o u r n a l i s Q T h e R o y a l S o c i e t y o f C h e m i s t r y a n d t h e
C e n t r e N a t i o n a l d e l a R e c h e r c h e S c i e n t i f i q u e 2 0 0 4
12
N e w . J . C h e m . , 2 0 0 4 , 2 8 , 1 2 – 1 4

View Article Online
Table 1 Reaction of ethynyloxiranes in DMF at room temperature
Ethynyloxirane
Conditions
Time
Yielda
Product
— (1a recovered)
b
1
2
3
4
5
6
7
8
9
Pd(PPh3)4
Pd(OAc)2(PPh3)2
2 days
2 days
2 days
2 days
2 days
2 days
2 h
0
0
c
NR3
Pd(PPh3)4 , NR3
0
c
0
c
Pd(OAc)2(PPh3)2 , NR3
CuId
0
Traces
78%
67%
72%
CuI,e HNEt2
CuI,e NEt3
0.7 h
1 h
CuI,e EtNiPr2
10
CuI,e HNEt2
1 h
69%
a
b
Yields of isolated pure products. Increasing amounts from 0.1 to 0.5 equiv. have been used. Various amines (diethyl-, triethyl- and
c
d
e
ethyldiisopropylamine) have been used with similar results. Increasing amounts from 0.1 to 1 equiv. have been used. Results obtained with
0.1 equiv. of CuI.
(Scheme 2). The splitting of some NMR signals was clearly
indicative of the presence of diastereoisomers.
(Scheme 3, bottom left). However, during the coupling of ethy-
nyloxiranes, the in situ formed copper acetylide is too reactive
and it is consumed together with a second ethynyloxirane to
form allenynol, to the detriment of coupling products.
The present results demonstrate the in situ formation of
copper acetylide in Pd/Cu catalyzed coupling reactions with
acetylenic derivatives. They also offer the first catalytic route
to allenynols without resorting to pre-formed organometallics.
Work is now in progress in our group to clarify the stereo-
selectivity of this self-addition16 and to determine the scope
and limitations of this new reaction.
The corresponding non-protected derivative 1b reacted
under the same conditions, giving the corresponding unpro-
tected epoxyallenynol 2b with a slightly lower yield (entry
10). 2b exhibited spectroscopic properties very similar to 2a.
The epoxyallenynol structures determined for 2a and 2b
clearly showed that 1a or 1b added to itself through a SN02
reaction. Since 2a,b were only formed in the presence of cop-
per iodide and amine, it becomes obvious that a copper epox-
yacetylide was formed in situ under these conditions. The
copper(I) salt probably acted as a Lewis acid and coordinated
to the triple bond. This coordination should alter the electro-
nic density over the acetylenic C–H bond, rendering it more
acidic. The acetylenic proton could thus be deprotonated even
by simple amines, leading to a copper acetylide (Scheme 3,
first line). Copper acetylides can indeed be obtained by the
treatment of alkynes with an ammoniacal solution of copper
chloride.13
Starting from ethynyloxiranes, the copper acetylide formed
in situ is nucleophilic enough to react with the starting mate-
rial, leading to allenynol self-adducts (Scheme 3, bottom right).
SN02 reactions of organocopper derivatives to ethynyloxiranes
already have precedents in the literature. However, they always
refer to stoechiometric processes with pre-formed organo-
metallics.14,15 The reaction described here is thus, to our
knowledge, the first catalytic SN02 reaction of ethynyloxiranes
that does not involve pre-formed organometallics.
Experimental
Typical procedure
To a solution of alkyne (0.6 mmol., 1 equiv.) in DMF (10 mL)
were successively added diethylamine (1.2 mmol., 2 equiv.) and
copper iodide (11 mg, 0.06 mmol., 0.1 equiv.). The initially
slightly yellow solution gradually darkened. After disappear-
ance of the starting material as judged from TLC (2 h), diethyl
ether (10 mL) and then a saturated aqueous solution of ammo-
nium chloride (10 mL) were successively added to the reaction
mixture. After extraction with diethyl ether, the combined
organic layers were washed with water. After drying with
sodium sulfate, filtration and solvent evaporation, a yellowish
oil was obtained. Flash chromatography (petroleum ether–
ethyl acetate 9 : 1) provided pure product as a colorless oil
(see Table 1).
Since the same allenynol 2a has been detected in our
attempts to couple 1a with vinyl triflates in various Pd/Cu coup-
ling conditions (Scheme 1),7 it is now clear that copper acety-
lides are also formed in situ in these reactions. In Sonogashira
cross-coupling reactions, this copper acetylide reacts with the
organopalladium species resulting from oxidative addition of
a zero-valent palladium complex to vinyl or aryl halide or tri-
flate. This transmetallation step produces a diorganopalladium
species and liberates a copper ion, ready for another cycle
cis-1,10-Bis(tert-butyldiphenylsilyloxy)-8,9-epoxy-3,8-
dimethyl deca-3,4-dien-6-yn-2-ol (2a). Pale yellow oil. FT-IR
(film): n ¼ 3443, 2235, 1962 cmꢀ1
.
1H NMR (250 MHz,
0
CDCl3): d 1.05 (18H, s, tBuSi), 1.45–1.49 (3H, m, H8 ), 1.62–
0
1.67 (3H, m, H3 ), 2.51–2.56 (1H, m, OH), 3.11 (1H, t,
J ¼ 5.2, H9), 3.59–3.78 (2H, m, H1), 3.80–3.95 (2H, m, H10),
4.06–4.15 (1H, m, H2), 5.20–5.28 (1H, m, H5), 7.31–7.42
(12H, m, Ar), 7.60–7.70 (8H, m, Ar). 13C NMR (62 MHz -
0
0
CDCl3): d 14.55 and 14.67 (C3 ), 19.21 (tBuSi), 23.20 (C8 ),
26.76 (tBuSi), 52.27 (C8), 63.76 and 64.63 (C2 and C9), 65.88
(C10), 72.03 and 72.11 (C2), 76.07 and 76.36 (C5), 77.71 (C3),
86.70 (C6), 102.52 and 102.82 (C7), 127.66, 127.77, 129.65,
129.84, 132.94, 133.26, 133.47 and 135.51 (Ar), 209.75 (C4).
HRMS (EI): m/z 700.3394 (700.3404 calcd for C44H52O4Si2).
Scheme 2 Cu catalyzed condensation of ethynyloxiranes.
T h i s j o u r n a l i s Q T h e R o y a l S o c i e t y o f C h e m i s t r y a n d t h e
C e n t r e N a t i o n a l d e l a R e c h e r c h e S c i e n t i f i q u e 2 0 0 4
N e w . J . C h e m . , 2 0 0 4 , 2 8 , 1 2 – 1 4
13

View Article Online
Scheme 3 Proposed mechanisms for the Sonogashira coupling reaction and for the presented reaction of ethynyloxiranes.
7
8
(a) P. Bertus and P. Pale, Tetrahedron Lett., 1996, 37, 2019; (b) P.
Acknowledgement
Bertus and P. Pale, Tetrahedron Lett., 1997, 38, 8193; (c) P. Bertus
and P. Pale, J. Organomet. Chem., 1998, 567, 173.
(a) P. Bertus, U. Halbes and P. Pale, Eur. J. Org. Chem., 2001,
4391; (b) U. Halbes, P. Bertus and P. Pale, Tetrahedron Lett.,
2001, 42, 8641; (c) U. Halbes and P. Pale, Tetrahedron Lett.,
2002, 43, 2039.
`
P. B. thanks the ‘‘Ministere de l’Education Nationale, de
l’Enseignement Superieur et de la Recherche’’ for a doctoral
´
fellowship. P. P. thanks the Institut Universitaire de France
for financial support.
9
P. Bertus, S. Dillinger and P. Pale, Org. Lett., 2001, 3, 1661.
10 R. S. Reddy, S. Igushi, S. Kobayashi and M. Hirama, Tetrahedron
Lett., 1996, 37, 9335.
11 (a) B. M. Trost, G. H. Kuo and T. Benneche, J. Am. Chem. Soc.,
References
1988, 110, 621; (b) G. Ja¨hne, A. Muller, H. Kroha, M. Ro¨sner, O.
¨
1
2
K. Sonogashira, Y. Tohda and N. Hagihara, Tetrahedron Lett.,
1975, 4467.
Holzha¨user, C. Meischsner, M. Helsberg, I. Winkler and G. Riess,
Tetrahedron Lett., 1992, 33, 5335.
(a) V. Ratovelomanana and G. Linstrumelle, Tetrahedron Lett.,
1981, 22, 315; (b) V. Ratovelomanana and G. Linstrumelle,
Tetrahedron Lett., 1984, 25, 6001; (c) M. Alami, F. Ferri and
G. Linstrumelle, Tetrahedron Lett., 1993, 34, 6403.
K. Sonogashira, in Comprehensive Organic Synthesis, eds.
B. M. Trost and I. Fleming, Pergamon, Oxford, 1991, vol. 3,
pp. 521–549.
K. Sonogashira, in Comprehensive Functional Group Transforma-
tions, eds. A. Katritzky and C. Rees, Pergamon, Oxford, 1995,
vol. 1, pp. 995.
(a) R. Crabtree, The Organometallic Chemistry of the Transition
Metals, Wiley, New York, 1988; (b) For a more detailed analysis,
see: C. Amatore, A. Jutand and A. Suarez, J. Am. Chem. Soc.,
1993, 115, 9531; C. Amatore and A. Jutand, Acc. Chem. Res.,
2000, 33, 314.
(a) I. E. Campbell, in Organocopper Reagents, A Practical
Approach, ed. R. J. K. Taylor, Oxford University Press, Oxford,
1994, pp. 217–235; (b) L. Hegedus, Transition Metals in the Synth-
esis of Complex Organic Molecules, 2nd edn., University Science
Books, Sausalito, CA, USA, 1999, p. 91.
12 (a) M. S. Malinovskii, N. G. Krivosheeva, M. P. Khmel, A. G.
Yudasina and V. G. Dryuk, Ukr. Khim. Zh., 1973, 39, 1257; (b)
F. Y. Perveev, L. N. Shil’nikova and R. Y. Irgal, Zh. Org. Khim.,
1969, 5, 1373; (c) H. Galons, J. F. Girardeau, C. Combet-
Farnoux, M. Miocque, C. Dupont and J. Wepierre, Eur. J.
Med. Chem., 1979, 14, 165.
3
4
5
13 J. F. Normant, Synthesis, 1972, 70.
14 Two competitive mechanisms may contribute to SN02 substitu-
tions, leading to stereoisomers. See: A. Alexakis, I. Marek,
P. Mangeney and J. F. Normant, Tetrahedron, 1991, 47, 1677.
15 (a) P. R. Ortiz de Montellano, J. Chem. Soc., Chem. Commun.,
1973, 710; (b) P. Vermeer, J. Meijer, C. De Graaf and H. Schreurs,
Rec. Trav. Chim. Pays-Bas, 1974, 94, 46; (c) R. Epsztein and N. Le
Goff, J. Chem. Soc., Chem. Commun., 1977, 679; (d ) C. Cahiez, A.
Alexakis and J. F. Normant, Synthesis, 1978, 528; (e) A.
Doutheau, A. Saba and J. Gore, Tetrahedron Lett., 1982, 23,
2461; ( f ) N. Krause, A. Hoffmann-Ro¨der and J. Canisius,
Synthesis, 2002, 1759.
6
16 Depending on the exact mechanism, diastereoisomers can be
produced. See ref. 14.
T h i s j o u r n a l i s Q T h e R o y a l S o c i e t y o f C h e m i s t r y a n d t h e
C e n t r e N a t i o n a l d e l a R e c h e r c h e S c i e n t i f i q u e 2 0 0 4
14
N e w . J . C h e m . , 2 0 0 4 , 2 8 , 1 2 – 1 4