In situ generation of 1-propyne: A useful introduction of 1-propyne on unsaturated halogenated compounds through the sonogashira reaction

Article abstract of DOI:10.1055/s-2002-19769

Reaction of (E/Z)-1-bromopropene with exactly 1.42 equivalents of nBuLi followed by addition of water produces in situ a THF solution of propyne. Addition of a vinylic or aromatic halogenated substrates, Pd(PPh₃)₂Cl₂, CuI and an amine to this solution give high yield of the corresponding coupling product beating a propyne moiety. This practical procedure avoids the use of expensive and inflammable propyne gas which need a special apparatus for bubbling it into the reaction flask.

Full text of DOI:10.1055/s-2002-19769

328
LETTER
In Situ Generation of 1-Propyne: A Useful Introduction of 1-Propyne on
Unsaturated Halogenated Compounds through the Sonogashira Reaction
In
Situ
G
enerati
s
on of 1-Pr
t
opyne:
e
Introductio
l
n of 1-
l
P
ropyn
e
e
on Unsaturated
A
Halogenated Com
b
pounds raham, Jean Suffert*
Laboratoire de Pharmacochimie de la Communication Cellulaire (UMR 7081 CNRS/ULP), Faculté de Pharmacie, 74 route du Rhin
67401 Illkirch-Cedex, France
Fax +33(390)244310; E-mail: jeansu@aspirine.u-strasbg.fr
Received 6 November 2001
This reaction is related to the well known Fritsch-Butten-
Abstract: Reaction of (E/Z)-1-bromopropene with exactly 1.42
berg-Wiechell4 rearrangement (Scheme 1). Herein, we re-
port that propyne 3 can be generated in situ in anhydrous
equivalents of nBuLi followed by addition of water produces in situ
a THF solution of propyne. Addition of a vinylic or aromatic halo-
genated substrates, Pd(PPh3)2Cl2, CuI and an amine to this solution
THF solution at -78 °C and smoothly reacts through a
give high yield of the corresponding coupling product bearing a Sonogashira5 coupling reaction with vinyl or aromatic ha-
propyne moiety. This practical procedure avoids the use of expen-
logenated starting material in the presence of a palladium
sive and inflammable propyne gas which need a special apparatus
for bubbling it into the reaction flask.
catalyst and CuI to give in high yields the corresponding
product substituted with a propyne moiety. When a solu-
tion of (Z/E)-1-bromopropene in anhydrous THF at
Key words: alkyne, palladium, catalysis, cross-coupling
–78 °C is treated with 1.42 equivalents of nBuLi, propy-
nyllithium is quantitatively formed and reacts either with
It is of general interest to find new protocols in preparative electrophiles such aldehydes, ketones, Weinreb amides
organic synthesis for the reaction of reagents, which have and acid chlorides or, when quenched at low temperature
several disadvantages for laboratory purposes. Propyne by 2.2 equivalent of H2O, produces a solution of propyne
gas is one of those compounds, it is only sold in steel bot- in the reaction mixture (Scheme 2). This THF solution of
tles, is very expensive and very flammable. In addition it propyne can be directly used in Sonogashira coupling re-
needs special equipment to be introduced in the reaction action by introduction of an appropriate substrate and a
vessel. There are many reports in the literature on the re- palladium catalyst.
action of propyne with halogenated organic compounds in
the presence of a palladium catalysis intermediates for the
preparation of biologically active compounds.1 Mainly
these compounds are synthesized from propyne gas by
bubbling the gas directly in the reaction mixture contain-
ing the substrate, the catalyst and the co-catalyst. In some
cases propyne gas has been replaced by the cheap welding
gas mixture MAPP,2 (methylacetylene, propanediene,
propene) which contains up to 13.5% of propyne in the
preparation of propynyllithium. Unfortunately this mix-
ture of gas is not useful in the Sonogashira type reaction
because of the small percentage of propyne. In a recent
publication3 we have proposed a new and very efficient
preparation of propynyllithium from simple, inexpensive
commercially available starting material. In this way pro-
pynyllithium 2 can be generated in anhydrous THF in
high yield by reaction at –78 °C of the commercially
available mixture of Z/E 1-bromopropene 1 with nBuLi
H3C
Li
2
+ E+
+ H2O
ref. 3
this work
O
H3C
Hal
H
H3C
3
R
Pd(Ph3P)2Cl2
CuI
OH
R
THF/iPr2NH or Et3N
RT
H3C
H3C
H
OH
R2
R1
CH3
Scheme 2
nBuLi
1.42 eq.
Br
Typically, addition of 1 equivalent of the halogenated
starting compound followed by addition of 5%
Pd(Ph3P)2Cl2, 10% of copper iodide and an excess of
amine (iPr2NH or Et3N depending of the halogenated sub-
strate) furnished the corresponding propynylated products
in high yields (see Table). The reaction proceeded effi-
ciently at room temperature with a variety of bromides
and iodides.6
H3C
Li
H3C
2
1
THF / – 78 °C
2 h
Scheme 1
Synlett 2002, No. 2, 01 02 2002. Article Identifier:
1437-2096,E;2002,0,02,0328,0330,ftx,en;G32501ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
In Situ Generation of 1-Propyne: Introduction of 1-Propyne on Unsaturated Halogenated Compounds
329
Table Pd-Catalysed Propynylation of Halogenated Compoundsa
Entry
1
Aryl or vinyl halide
Product
Yield
93d
OH
Br
OH
CH3
2
98d
O
O
O
O
SiMe3
SiMe3
Br
CH3
OH
3
4
5
96d
82d
75d
OH
Br
Ph2(tBuO)SiO
tBuMe2SiO
Ph2(tBuO)SiO
tBuMe2SiO
CH3
OH
I
OH
CH3
Br
CH3
6
77d
Br
CH3
7
8
0b
OH
98d
OH
X = Br
X = I
X
CH3
9
64c
O
H
O
H
CH3
Br
H3CO
O
H3CO
O
CH3
CH3
10
11
73c
92c
H
H
CH3
Br
O
H
O
H
CH3
I
NMe2
NMe2
12
61d
I
CH3
N
N
MeO
N
N
MeO
a Reaction conditions: Pd(PPh3)2Cl2 CuI, 10%, THF/iPr2NH or Et3N, r.t.
b Experiment repeated 3 times.
c Et3N used as a base.
d iPr2NH used as a base.
Synlett 2002, No. 2, 328–330 ISSN 0936-5214 © Thieme Stuttgart · New York

330
E. Abraham, J. Suffert
LETTER
Bennett, M. S.; Champness, J. N.; Summers, W. C.;
The use of THF as the solvent allowed a rapid elimination/
metallation reaction of 2-bromopropene with nBuLi and a
rapid quenching of the lithio species by H2O. Use of ether
as the solvent for the metallation does not give any traces
of propynyllithium. Pd(PPh3)2Cl2 was found to be the best
source of palladium. The choice of the amine is crucial for
the reaction to proceed cleanly. For aldehydes (entry 9–
11) only Et3N is suitable to give good yields of products,
while iPr2NH gave mainly decomposition. Surprisingly
the o-bromobenzylic alcohol did not give a single trace of
the corresponding propynylated product (entry 7). This
lack of reactivity has been observed in only one case on
such an electron rich aromatic ring. In contrast, the iodide
(entry 8) furnished the expected compound with an excel-
lent 98% yield. Only 1.55 equiv of (Z/E)-1-bromopropene
are necessary for the completion of the reaction while the
use of propyne gas needs a large excess of the gas.
Sanderson, M. R.; Herdewijn, P. J. Med. Chem. 1998, 41,
4343. (l) Pschirer, N. G.; Bunz, U. H. F. Tetrahedron Lett.
1999, 40, 2481. (m) Froehler, B. C.; Wadwani, S.; Terhorst,
T. J.; Gerrard, S. R. Tetrahedron Lett. 1992, 33, 5307.
(n) Sakamoto, T.; An-naka, M.; Kondo, Y.; Yamanaka, H.
Chem. Pharm. Bull. 1986, 34, 2754. (o) Al-Hassan, M. I. J.
Organomet. Chem. 1990, 395, 227. (p) Bleckmann, W.;
Hanack, M. Chem. Ber. 1984, 117, 3021.
(2) Jauch, J.; Schmalzing, D.; Schurig, V.; Emberger, R.; Hopp,
R.; Köpsel, M.; Silberzahn, W.; Werkhoff, P. Angew. Chem.,
Int. Ed. Engl. 1989, 28, 1022.
(3) (a) Suffert, J.; Toussaint, D. J. Org. Chem. 1995, 60, 3550.
(b) Toussaint, D.; Suffert, J. Organic Synthesis 1999, 76,
214.
(4) (a) Fritsch, P. Liebigs Ann. Chem. 1894, 272, 319.
(b) Buttenberg, W. P. Liebigs Ann. Chem. 1894, 272, 324.
(c) Wiechell, H. Liebigs Ann. Chem. 1894, 272, 337.
(5) Sonogashira, K.; Toha, Y.; Hagihara, N. Tetrahedron Lett.
1975, 4467.
In summary, we have found a practical alternative to effi-
ciently replace propyne gas by 2-bromopropene for an
easy introduction of a propynyl group on aromatic and vi-
nylic halogenated compounds. We are currently applying
this methodology for the synthesis of unsaturated polycy-
clic substrates.
(6) Representative Procedure (Table, Entry 2):
[2,2-Dimethyl-5-(2-pent-1-en-3-ynyl-phenyl)-[1,3]dioxolan
-4-ylethynyl]-trimethyl-silane: A solution of nBuLi (1.8 mL,
1.54 M in hexane, 2.73 mmol, 2.2 equiv) was slowly added
to a cooled solution of (Z/E)-1-bromopropene (0.233 g, 1.92
mmol, 1.55 equiv) in anhydrous THF (2.5 mL) under argon.
This solution was stirred at -78 °C during 2 hours. H2O (0.05
mL, 2.73 mmol, 2.2 equiv) was then added in one portion at
-78 °C via syringe and the reaction mixture warmed to 0 °C.
The halogenated substrate (0.470 g, 1.24 mmol, 1 equiv)
dissolved in THF (2 mL) was added via syringe to the
propyne solution, followed by Pd(Ph3P)2Cl2 (43.5 mg, 0.062
mmol, 0.05 equiv), CuI (23.6 mg, 0.124 mmol, 0.1 equiv)
and iPr2NH (2.2 mL). The temperature was raised to 20 °C
and the reaction followed by TLC. Then the reaction was
quenched with 20 mL of a saturated NH4Cl in water and
extracted with the appropriate solvent (3 10 mL). The
organic phase was dried over Na2SO4, decolored by
charcoal, filtered and the solvent was removed under reduce
pressure. The crude propynylated product was purified by
flash chromatography (1:99, ether–hexane) on silica gel to
give the desired compound (0.418 g 98%). 1H NMR (200
MHz, CDCl3) 0.21 (s, 9 H, Si(CH3)3); 1.61 (s, 3 H,); 1.62
(s, 3 H); 2.01 (d, 3 H, J = 2.4 Hz); 4.38 (d, 1 H, J = 7.9 Hz);
5.38 (d, 1 H, J = 7.9 Hz); 6.05 (dq, 1 H, Jtrans = 16 Hz, 5J =
2.4 Hz); 7.25–7.38 (m, 2 H, arom. H); 7.47 (d, 1 H, Jtrans = 16
Hz); 7.43–7.57 (m, 2 H, arom. H). 13C NMR (50 MHz,
CDCl3): 0.44 [Si(CH3)3]; 4.5, 26.3, 26.8, 73.1, 79.2, 79.4,
88.5, 93.3, 100.8, 110.4, 111.5, 125.6, 126.2, 128.4, 128.5,
134.0, 135.6, 137.2. IR (CHCl3, cm–1) 3668 (w); 3026 (m,
CH); 2991 (m, CH); 2962 (s); 2918 (m); 2217 (m); 2177 (m,
C C); 1600 (m); 1453 (m); 1383 (w); 1255 (w); 1210 (w);
1163 (w); 1100 (w); 1052 (w); 990 (w); 956 (m).
Acknowledgement
The author thank professor D. Uguen for stimulating discussions
concerning the Sonogashira reaction.
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Synlett 2002, No. 2, 328–330 ISSN 0936-5214 © Thieme Stuttgart · New York