Operationally simple copper-promoted coupling of terminal alkynes with benzyl halides

Article abstract of DOI:10.1021/jo900444x

(Chemical Equation Presented) Benzyl chlorides and bromides are shown to undergo copper-promoted coupling with a variety of terminal alkynes including, for the first time, electron-poor acetylenes such as methyl propiolate. The reaction permits easy acces

Full text of DOI:10.1021/jo900444x

SCHEME 1. Synthesis of Heterocycles from Substituted
Propiolates and 2-Propynones
Operationally Simple Copper-Promoted Coupling
of Terminal Alkynes with Benzyl Halides
Katherine A. Davies, Ryan C. Abel, and Jeremy E. Wulff*
Department of Chemistry, UniVersity of Victoria, Victoria,
British Columbia, Canada, V8W 3V6
wulff@uVic.ca
ReceiVed February 26, 2009
Benzyl chlorides and bromides are shown to undergo copper-
promoted coupling with a variety of terminal alkynes
including, for the first time, electron-poor acetylenes such
as methyl propiolate. The reaction permits easy access to a
wide range of (functionalized) benzyl-substituted propiolates
(as well as several related alkynes) from commercially
available benzyl halides. These products should in turn
function as useful building blocks for the synthesis of
previously inaccessible (functionalized) benzyl-substituted
heterocycles.
GABAB receptor,6a the cholecystokinin-1 receptor,2b,c HMG-
CoA reductase,8 D3 dopaminergic and R1 adrenergic G protein-
coupled receptors,9 and the substance P receptor.10
Given the utility of substituted propiolates and related
compounds in the synthesis of small-molecule heterocycles with
useful medicinal properties and taking into account the likeli-
hood of both functionalized and unfunctionalized benzyl sub-
stituents acting as rigid lipophilic groups in pharmacophore
development, it is surprising that none of the reactions in Scheme
1 have been reported for 4-aryl-2-butynoates (i.e., 1a, R )
benzyl) or the corresponding ketones. This appears to be due
to difficulties in preparing the starting compounds; while there
exist excellent methods for the synthesis of alkyl- and aryl-
substituted propiolates,11 the benzyl-containing analogues are
more troublesome, since they are prone to isomerization to the
corresponding allenes.12 Moreover, benzyl alkynes contain a
rather acidic center, which might prove incompatible with the
Unsymmetrically substituted alkynes are useful intermediates
in the synthesis of natural products, drug candidates, supramo-
lecular constructs, and organic materials.1 In particular, substi-
tuted propiolates (1a, Scheme 1) and 2-propynones (1b) have
proven useful for the synthesis of small-molecule heterocycles
for medicinal chemistry programs. Such compounds have been
previously used in the preparation of pyrazoles (2),2 1,2,3-
triazoles (3),3 2-pyridones (4),4 pyrroles (5),5 pyrimidines (6),6
and pyridines (7),7 as illustrated in Scheme 1. Among other
useful properties, some of these compounds (and very closely
related structures) have been reported as inhibitors of the
(6) (a) Verron, J.; Malherbe, P.; Prinssen, E.; Thomas, A. W.; Nock, N.;
Masciadri, R. Tetrahedron Lett. 2007, 48, 377–380. (b) Chen, D.; Banphavichit,
V.; Reibenspies, J.; Burgess, K. Organometallics 2007, 26, 855–859. (c) Bagley,
M. C.; Hughes, D. D.; Lubinu, M. C.; Merritt, E. A.; Taylor, P. H.; Tomkinson,
N. C. O. QSAR Comb. Sci. 2004, 23, 859–867. (d) Johns, B. A.; Gudmundsson,
K. S.; Turner, E. M.; Allen, S. H.; Jung, D. K.; Sexton, C. J.; Boyd, F. L.; Peel,
M. R. Tetrahedron 2003, 59, 9001–9011.
(1) (a) Chemistry of Acetylenes; Viehe, H. G. Ed.; Marcel Dekker: New York,
1969. (b) Acetylene Chemistry: Chemistry, Biology, and Materials Science;
Diederich, F., Stang, P., Tykwinski, R. R. Eds.; Wiley-VCH GmbH and Co.
KGa: Weinheim, 2005.
(2) (a) Bagley, M. C.; Lubinu, M. C.; Mason, C. Synlett 2007, 704–708. (b)
Liang, J. T.; Mani, N. S.; Jones, T. K. J. Org. Chem. 2007, 72, 8243–8250. (c)
Gomez, L.; Hack, M. D.; McClure, K.; Sehon, C.; Huang, L.; Morton, M.; Li,
L.; Barrett, T. D.; Shankley, N.; Breitenbucher, J. G. Bioorg. Med. Chem. Lett.
2007, 17, 6493–6498.
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(4) Liu, W.; Hickey, E. R.; Cywin, C. L.; Fleck, R. W.; Spero, D. M.;
Morwick, T. M.; Proudfoot, J. R. PCT Int. Appl. WO2005035537.
(5) (a) Kamijo, S.; Kanazawa, C.; Yamamoto, Y. J. Am. Chem. Soc. 2005,
127, 9260–9266. (b) Bhattacharya, A.; Cherukuri, S.; Plata, R. E.; Patel, N.;
Tamez, V.; Grosso, J. A.; Peddicord, M.; Palaniswamy, V. A. Tetrahedron Lett.
2006, 47, 5481–5484. (c) Larionov, O. V.; de Meijere, A. Angew. Chem., Int.
Ed. 2005, 44, 5664–5667.
(7) (a) Xiong, X.; Bagley, M. C.; Chapaneri, K. Tetrahedron Lett. 2004, 45,
6121–6124. (b) Bohlmann, F.; Rahtz, D. Chem. Ber. 1957, 90, 2265–2272.
(8) Roth, B. D.; Blankley, C. J.; Chucholowski, A. W.; Ferguson, E.; Hoefle,
M. L.; Ortwine, D. F.; Newton, R. S.; Sekerke, C. S.; Sliskovic, D. R.; Wilson,
M. J. Med. Chem. 1991, 34, 357–366.
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252–261.
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P. J. Org. Process Res. DeV. 2005, 9, 490–498.
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(12) For direct access to allenes by coupling benzyl chlorides and terminal
alkynes, see ref 19a.
10.1021/jo900444x CCC: $40.75
Published on Web 04/09/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 3997–4000 3997

TABLE 1. Coupling Reaction Optimization
In our initial exploration of this chemistry, we subjected
p-(benzyloxy)benzyl bromide (8b) to reaction with methyl
propiolate (9a) under Spinella’s conditions17 for the coupling
of alkynes with propargyl chlorides (Cs2CO3, CuI, NaI, DMF).
We observed formation of both the desired 4-aryl-2-butynoate
(10a) and the corresponding allene in a combined yield of 46%.
Changing the solvent to acetonitrile prevented formation of the
allene, although the yield remained low (38%). Further experi-
mentation revealed that p-(benzyloxy)benzyl chloride (8a) was
also capable of coupling to 9a, albeit in poor yield (23%, Table
1, entry 1). We saw this as a significant result (benzyl chlorides
are more bench-stable and more readily available commercially
than are benzyl bromides) and sought to further optimize the
reaction between 8a and 9a.
As shown in Table 1, acetonitrile (entry 1) was a better
solvent for the reaction than was THF (entry 2). The addition
of water (entry 3) did not improve the percent conversion. The
use of longer reaction times (entry 4) had less of an impact on
the production of 10a than did the use of a slightly elevated
temperature (entry 5), although in the latter case the isolated
product was contaminated with uncharacterized byproducts. In
contrast to the reaction explored by Caruso and Spinella,17
sodium carbonate (entry 6) and potassium carbonate (entry 7)
were superior bases for our coupling. The addition of tetrabu-
tylammonium iodide as a phase-transfer catalyst (entry 8)
improved the percent conversion still further, although under
these conditions a small amount of allene could be detected in
the isolated product. The use of potassium carbonate at 40 °C
(entries 9 and 10) likewise led to high yields of 10a, contami-
nated with small amounts of allene.
Finally, we found that removal of the sodium iodide additive
from the reaction mixture (entries 11 and 13) permitted the
isolation of 10a in excellent yield with no detectable (by NMR)
allenic impurity. Reduction in the amount of alkyne from 2 to
1.2 equiv (entry 12) lowered the percent conversion. We
subsequently found (vide infra) that in the absence of sodium
iodide and cesium carbonate, higher temperatures and a phase
transfer catalyst could be employed to enhance the rate of the
reaction, without promoting isomerization.
Having thus optimized the coupling of 8a and 9a, we wanted
to explore the generality of this potentially useful reaction. We
therefore screened a number of benzyl halides (Table 2) and
terminal alkynes (Table 3) for their ability to undergo coupling
with one another.
base (equiv)
additive
solvent
MeCN
THF
temp/time conversion (%)a, b
1
2
3
4
5
6
7
8
9
Cs2CO3 (1.0) NaI
Cs2CO3 (1.0) NaI
Cs2CO3 (1.0) NaI
Cs2CO3 (1.0) NaI
Cs2CO3 (1.0) NaI
Na2CO3 (1.0) NaI
K2CO3 (1.0) NaI
rt, 24 h
rt, 24 h
25 (23)
<5
1:1 MeCN:H2O rt, 24 h
20
MeCN
MeCN
MeCN
MeCN
rt, 48 h
40 °C, h
rt, 24 h
36
80 (75)c
59
rt, 24 h
88
K2CO3 (1.0) NaI + Bu4NI MeCN
rt, 24 h
94 (91)d
98 (96)d
100 (95)d
99 (99)
62e
K2CO3 (1.0) NaI
MeCN
MeCN
MeCN
MeCN
MeCN
40 °C, 4 h
40 °C, 4 h
rt, 24 h
rt, 24 h
10 K2CO3 (2.0) NaI
11 K2CO3 (2.0) none
12 K2CO3 (2.0) none
13 K2CO3 (2.0) none
40 °C, 24 h
100 (92)
a Percent conversion was measured by NMR. b Numbers in
parentheses refer to isolated yield. c The isolated product was
contaminated with unidentified impurities. d The isolated product was
contaminated with traces of allene. e Only 1.2 equiv of methyl
propiolate were used.
above methods. These factors have substantially limited the
development of 4-aryl-2-butynoates and related electron-
deficient benzyl alkynes in the synthesis of complex molecules.13
The ideal synthesis of 4-aryl-2-butynoates would involve the
direct coupling of benzyl chlorides or bromides (>1000 of which
are commercially available) with an inexpensive propiolate (e.g.,
methyl, ethyl, and tert-butyl propiolates can all be purchased)
under conditions that do not require the use of strong bases,
expensive catalyst systems, or high temperatures. Existing
4-aryl-2-butynoate syntheses do not meet these criteria; such
preparations require either the use of dilithiated alkyne inter-
mediates14 or else proceed from arylpropyne starting materials,15
which are less readily available than benzyl halides.16
Inspired by literature reports describing the copper-mediated
addition of terminal alkynes to propargyl17 or allyl halides,18
we considered whether similar conditions might permit coupling
of methyl propiolate with benzyl chlorides or bromides. While
previous examples of the direct coupling of terminal alkynes
to benzyl halides are known in the literature,19 these appear to
be limited to the use of electron rich alkynes. Our methodology
would therefore be the first to afford synthetically valuable
4-aryl-2-butynoates from readily available benzyl halides under
mild conditions.
We found that several electron-neutral or electron-rich benzyl
chlorides and benzyl bromides could be efficiently coupled to
9a (Table 2, entries 1-7). We generally found benzyl chlorides
to give higher yields than benzyl bromides, presumably owing
to partial decomposition of the latter under the reaction
conditions. For most benzyl halides other than 8a or 8b, the
best yields were obtained by heating the reaction mixture to 40
°C and adding a phase-transfer catalyst.20 These conditions also
permitted the use of substoichiometric quantities of copper
iodide; for example, 10b was obtained in 75% isolated yield
using only 10 mol % CuI (entry 3).21
(13) Synthesis of benzyl-substituted acetylenic ketones (i.e., 1b, R ) benzyl)
appears to be less problematic than synthesis of the corresponding esters. These
ketones have been prepared from the appropriate lithiated 3-aryl-1-propyne, by
reaction with an aldehyde and subsequent oxidation. Although they have not
been extensively used in the preparation of nitrogen-containing heterocycles,
they have proven useful for the synthesis of furans. See: (a) Jeevanandam, A.;
Narkunan, K.; Ling, Y.-C. J. Org. Chem. 2001, 66, 6014–6020.
(14) Hooz, J.; Calzada, J. G.; McMaster, D. Tetrahedron Lett. 1985, 26, 271–
274.
(15) (a) Jung, M. E.; Hagenah, J. A. J. Org. Chem. 1987, 52, 1889–1902.
(b) Vasilevsky, S. F.; Trofimov, B. A.; Mal’kina, A. G.; Brandsma, L. Synth.
Commun. 1994, 24, 85–88.
(16) Only the parent 3-phenyl-1-propyne is available from Sigma Aldrich.
A few other 3-aryl-1-propynes are available from Anichem LLC, North
Brunswick, NJ.
The coupling reaction was tolerant of the presence of both
ortho substituents (entry 4) and bulky meta substituents (entry
5) on the benzyl halide. Even a benzyl halide containing a free
hydroxyl group (8g) was successfully coupled to 9a, albeit in
(17) Caruso, T.; Spinella, A. Tetrahedron 2003, 59, 7787–7790.
(18) (a) Jeffrey, T. Tetrahedron Lett. 1989, 30, 2225–2228. (b) Grushin, V. V.;
Alper, H. J. Org. Chem. 1992, 57, 2188–2192. (c) Bieber, L. W.; da Silva, M. F.
Tetrahedron Lett. 2007, 48, 7088–7090.
(19) (a) Larsen, C. H.; Anderson, K. W.; Tundel, R. E.; Buchwald, S. L.
Synlett 2006, 2941–2946. (b) Takahashi, T.; Li, S.; Huang, W.; Kong, F.;
Nakajima, K.; Shen, B.; Ohe, T.; Kanno, K. J. Org. Chem. 2006, 71, 7967–
7977.
(20) Preparation of 10c (Table 2) using method A gave only 25% conversion.
(21) By comparison, an attempt to prepare 10a using the conditions of method
A with only 10 mol % CuI resulted in only 6% conversion.
3998 J. Org. Chem. Vol. 74, No. 10, 2009

TABLE 2. Variation of the Benzyl Halide Coupling Partner
TABLE 3. Variation of the Alkyne Coupling Partner
a CuI (1 equiv) and Bu4NI (1 equiv) were added to all reactions.
b Percentage allene contaminant estimated by 1H NMR integration. c A
product mixture containing mostly propargyl sulfone was isolated
following chromatography over silica gel.
reaction times simplified purification and provided higher yields.
Because acetylenic sulfones are particularly useful building
blocks for the synthesis of biologically interesting small
molecules,24 and because benzyl-substituted acetylenic sulfones
(e.g., 10n) have not been reported, we attempted to use our
methodology to prepare these species as well. In the event,
reaction of sulfone 9g25 with benzyl halide 8a under optimized
conditions led to the observation (by NMR) of what we believe
to be acetylenic sulfone 10n. However, we were unable to isolate
this product in pure form following chromatography over silica
gel.26
a Method A: K2CO3 (2 equiv), CuI (1 equiv), rt. b Method B: K2CO3
(1 equiv), CuI (1 equiv), Bu4NI (1 equiv), 40 °C. c Percentage allene
contaminant estimated by 1H NMR integration. d Only 10 mol% of CuI
was used.
The copper-mediated coupling of commercially available
benzyl halides (8) to terminal alkynes (9) demonstrated here
provides a useful methodology for the assembly of 4-aryl-2-
butynoates and related synthetic building blocks (10). The
reaction proceeds under mild conditions (at or below 40 °C),
and requires only inexpensive reagents. We have found the
reaction to be relatively insensitive to the presence of small
quantities of moisture or air, suggesting that this coupling
strategy might be useful for parallel-synthesis approaches to
libraries of heterocycles (e.g., 2-7, Scheme 1).
reduced yield (entry 7). The reaction was less tolerant of
electron-withdrawing substituents; alkyne 10g (entry 8), made
by coupling p-chlorobenzyl chloride (8h) to 9a, was contami-
nated with ∼13% of the corresponding allene. Similarly, the
use of fluorinated benzyl chlorides (o-fluorobenzyl chloride, 8i,
and p-trifluoromethylbenzyl chloride, not shown) led to complex
mixtures of products.
Regarding the use of alkynes other than 9a, we were surprised
to find that more electron-rich alkynes (e.g., 9b and 9c) could
be efficiently coupled to 8a (Table 3, entries 1 and 2) using
this methodology. The use of representative acetylenic arenes
(e.g., 9d), amides (e.g., 9e22), and ketones (e.g., 9f23) was also
explored; these likewise appear to be reasonable substrates for
this reaction. For most of these couplings, the use of longer
(22) Kanner, C. B.; Pandit, U. K. Tetrahedron 1982, 38, 3597–3604.
(23) Prepared by addition of ethynylmagnesium bromide to benzaldehyde,
followed by oxidation with Dess-Martin periodinane. See: Chassaing, S.;
Kueny-Stotz, M.; Isorez, G.; Brouillard, R. Eur. J. Org. Chem. 2007, 2438–
2448. (b) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–4156.
(24) For leading references, see: (a) Back, T. G. Tetrahedron 2001, 57, 5263–
5301.
(25) Chen, Z.; Trudell, M. L. Synth. Commun. 1994, 24, 3149–3155.
(26) Acetylenic sulfones are particularly prone to isomerization. See: Back,
T. G.; Parvez, M.; Wulff, J. E. J. Org. Chem. 2003, 68, 2223–2233.
J. Org. Chem. Vol. 74, No. 10, 2009 3999

(CH3), 25.6 (CH2). IR (Neat, cm-1) 2240 (m), 1714 (s). MS (EI)
m/z (%) 286 (40), 271 (100), 215 (76), 203 (32), 57 (89). HRMS
calcd for C19H26O2 286.19328, found 286.19319.
Experimental Section
General Procedure for the Coupling of Methyl Propiolate
with Benzyl Halides: Method A. Methyl propiolate (9a, 0.0772
mL, 0.868 mmol) was added via microsyringe to a stirring mixture
of 4-benzyloxybenzyl chloride (8a, 0.101 g, 0.434 mmol), copper(I)
iodide (0.0823 g, 0.432 mmol), and potassium carbonate (0.120 g,
0.868 mmol) in dry acetonitrile (2 mL). The resulting slurry was
stirred at room temperature for 24 h. The reaction mixture was
then diluted with saturated aqueous ammonium chloride (5 mL)
and extracted twice with diethyl ether (20 mL). The combined
organic layers were dried using anhydrous sodium sulfate and
passed through a filter to remove the drying agent. The filtrate was
concentrated in vacuo and purified by flash-column chromatography
(hexanes/ethyl acetate, 4:1 to 2:1 gradient), to afford 10a as a clear,
yellow oil (0.120 g, 0.428 mmol, 99% yield). Rf ) 0.72 (hexanes/
General Procedures for the Coupling of Other Alkynes
with Benzyl Halides. Ethynyltrimethylsilane (9b, 0.071 mL, 0.51
mmol) was added via microsyringe to a stirring mixture of
4-benzyloxybenzyl chloride (0.100 g, 0.430 mmol), copper(I) iodide
(0.0824 g, 0.433 mmol), potassium carbonate (0.119 g, 0.861
mmol), and tetrabutylammonium iodide (0.159 g, 0.430 mmol) in
dry acetonitrile (2 mL). The resulting slurry was stirred at 40 °C
for 24 h. The reaction mixture was then diluted with saturated
aqueous ammonium chloride (5 mL), and extracted twice with
diethyl ether (20 mL). The combined organic layers were dried
using anhydrous sodium sulfate and passed through a filter to
remove the drying agent. The filtrate was concentrated in vacuo
and purified by flash-column chromatography (hexanes/ethyl ac-
etate, 4:1 to 2:1 gradient), to afford 10i as a clear, yellow oil (0.125
g, 0.424 mmol, 99% yield). Rf ) 0.76 (hexanes/ethyl acetate, 4:1).
1H NMR (250 MHz, CDCl3) δ 7.46-7.42 (m, 5H), 7.29 (d, J )
8.6 Hz, 2H), 6.97 (d, J ) 8.6 Hz, 2H), 5.08 (s, 2H), 3.63 (s, 2H),
0.24 (s, 9H). 13C NMR (75 MHz, CDCl3) δ 157.5 (C), 137.0 (C),
128.7 (CH), 128.6 (C), 128.5 (CH), 127.8 (CH), 127.3 (CH), 114.8
(CH), 104.7 (C), 86.5 (C), 69.9 (CH2), 25.2 (CH2), 0.03 (CH3). IR
(Neat, cm-1) 2175 (m). MS (EI) m/z (%) 294 (24), 91 (100), 65
(6). HRMS calcd for C19H22OSi 294.14399, found 294.14377.
1
ethyl acetate, 2:1). H NMR (300 MHz, CDCl3) δ 7.45-7.30 (m,
5H), 7.22 (d, J ) 8.6 Hz, 2H), 6.93 (d, J ) 8.6 Hz, 2H), 5.04 (s,
2H), 3.76 (s, 3H), 3.66 (s, 2H). 13C NMR (75 MHz, CDCl3) δ 158.1
(C), 154.3 (C), 137.0 (C), 129.2 (CH), 128.7 (CH), 128.1 (CH),
127.6 (CH), 126.4 (C), 115.3 (CH), 87.3 (C), 74.4 (C), 70.2 (CH2),
52.8 (CH3), 24.3 (CH2). IR (Neat, cm-1) 2237 (m), 1714 (s). MS
(EI) m/z (%) 280 (17), 91 (100), 65 (8). HRMS calcd for C18H16O3
280.10994, found 280.11003.
Method B. Methyl propiolate (9a, 0.124 mL, 1.39 mmol) was
added via microsyringe to a stirring mixture of 3,5-di-(tert-
butyl)benzyl bromide (8e, 0.197 g, 0.696 mmol), copper(I) iodide
(0.132 g, 0.693 mmol), potassium carbonate (0.0949 g, 0.687
mmol), and tetrabutylammonium iodide (0.255 g, 0.690 mmol) in
dry acetonitrile (2 mL). The resulting slurry was stirred at 40 °C
for 24 h. The reaction mixture was then diluted with saturated
aqueous ammonium chloride (5 mL), and extracted twice with
diethyl ether (20 mL). The combined organic layers were dried
using anhydrous sodium sulfate and passed through a filter to
remove the drying agent. The filtrate was concentrated in vacuo
and purified by flash-column chromatography (hexanes/ethyl ac-
etate, 40:1 to 20:1 gradient), to afford 10d as a clear, yellow-orange
oil (0.181 g, 0.632 mmol, 91% yield). Rf ) 0.57 (hexanes/ethyl
Acknowledgment. We are grateful to the University of
Victoria for startup funds, and to the Canada Foundation for
Innovation and the BC Knowledge Development Fund for
providing equipment. We further acknowledge NSERC and the
Merck Frosst Canadian Academic Development Program for
operating funds and also thank Nick Forrester for assistance
with the purification of 10b.
Supporting Information Available: Experimental proce-
dures and full spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
1
acetate, 4:1). H NMR (300 MHz, CDCl3) δ 7.34 (t, J ) 1.8 Hz,
1H), 7.16 (d, J ) 1.8 Hz, 2H), 3.78 (s, 3H), 3.73 (s, 2H), 1.34 (s,
18H). 13C NMR (75 MHz, CDCl3) δ 154.4 (C), 151.5 (C), 133.2
(C), 122.5 (CH), 121.4 (CH), 87.6 (C), 74.5 (C), 52.7 (CH3), 31.6
JO900444X
4000 J. Org. Chem. Vol. 74, No. 10, 2009