Room temperature palladium catalysed coupling of acyl chlorides with terminal alkynes

Article abstract of DOI:10.1039/b414826f

Conditions are reported for the facile, high-yielding coupling of acyl chlorides with terminal alkynes in a reaction involving palladium and copper iodide; the reaction is tolerant of a wide variety of acyl chlorides and terminal alkynes and provides a co

Full text of DOI:10.1039/b414826f

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Room temperature palladium catalysed coupling of acyl chlorides with
terminal alkynes{
Russell J. Cox,*a Dougal J. Ritson,a Thomas A. Dane,a John Berge,b Jonathan P. H. Charmantc and
Anob Kantachac
Received (in Cambridge, UK) 27th September 2004, Accepted 29th October 2004
First published as an Advance Article on the web 10th January 2005
DOI: 10.1039/b414826f
In order to reduce the chance of reaction between the acid
chloride component and the base, we reduced the base concentra-
tion and used 1.25 eq. of NEt3 in THF rather than neat base as the
solvent. Using these conditions with PdCl2(PPh3)2 (0.9 mol%) and
CuI (3.0 mol%) in dry THF at RT, the reaction between
phenylacetylene (1.0 eq.) and benzoyl chloride (1.5 eq.) was
complete by TLC analysis within 10 minutes (Table 1) (See ESI for
experimental procedures).{ The product 5 was isolated in 96%
yield after purification.
Conditions are reported for the facile, high-yielding coupling of
acyl chlorides with terminal alkynes in a reaction involving
palladium and copper iodide; the reaction is tolerant of a wide
variety of acyl chlorides and terminal alkynes and provides a
convenient one-pot route to acetylenic ketones.
Acetylenic ketones are useful precursors for organic synthesis,
especially as precursors during the synthesis of saturated
polycyclic1 and heterocyclic2 compounds. However their synthesis
is not straightforward because the addition of acetylenic
nucleophiles to acyl chlorides or acid anhydrides can be
accompanied by unwanted addition to the products, forming
bis-acetylenic tertiary alcohols.3 An alternative route involving
addition of acetylenic Grignard reagents, for example, to aldehydes
The reaction is tolerant of a wide range of functional groups on
the acetylene (Table 1), in particular alkyl, ester, silyl, silyloxy and
protected amino groups are compatible, all giving isolated purified
products in high yields. We also tested a range of aromatic acyl
chlorides (Table 2, entries 1–4. Once again, good to high yields of
purified products were obtained rapidly. p-Nitrobenzoyl chloride
yielded the highly crystalline 14 (Fig. 1).{
can be low-yielding and requires
reaction.2,4
a subsequent oxidation
We reasoned that because acyl chlorides are known to
oxidatively add to Pd(0) species, forming an acyl Pd(II)
intermediate,5 it should be possible to intercept this species with
a suitable nucleophile (Scheme 1). For example, others have
reported the use of boronic acids as nucleophiles in similar
processes.6 In the classical Sonogashira reaction, terminal alkynes
are activated as nucleophiles under basic conditions using a CuI
co-catalyst. The precise identity of the Pd catalyst active in these
reactions is not known, but could involve discrete Pd(0)L2 species
or Pd nanoclusters as has recently been demonstrated for Heck
reactions.7 Sonogashira also reported that terminal acetylenes
would react with acid chlorides when catalysed by Pd(0) and CuI,
but the reactions were limited by unwanted reaction between the
acid chlorides and the Et3N solvent, reducing yields.8 More
recently Najera and co-workers have reported a similar reaction,
but at high temperature and in the absence of Cu, giving moderate
isolated yields of products.9 We now report a simple procedure
which operates at RT giving high isolated yields of products.
In the case of the p-bromobenzoyl chloride, the expected
product 15 was obtained, and no reaction of the bromide was
observed. However, in the case of the p-iodobenzoyl chloride, the
acyl chloride and iodo groups appeared to be equally reactive, and
in the presence of two equivalents of acetylene, the bis-acetylene 16
was formed in high yield.
Table 1 Coupling reactions of benzoyl chloride
Entry
R
Product
Yield (%)a
1
2
3
4
5
6
7
8
a
C6H5
(CH2)2CO2Me
5
6
7
8
9
10
11
12
96
89
84
88
96
94
91
70
t
(CH2)2CO2 Bu
Scheme 1 Catalytic cycle for the Pd(0) catalysed coupling of acid
(CH2)3CH3
Si(CH3)2 Bu
chlorides.
t
t
CH2OSi(CH3)2 Bu
CH2NH(BOC)b
CH2NHAc
b
{ Electronic Supplementary Information (ESI) available: experimental
procedures, characterisation for compounds 5–28 and crystal structure
data for 14. See http://www.rsc.org/suppdata/cc/b4/b414826f/
*r.j.cox@bris.ac.uk
Isolated purified yield. 1 h reaction.
This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 1037–1039 | 1037

View Article Online
Table 2 Coupling reactions of phenylacetylene
Scheme 3 Reaction of linear aliphatic acyl chlorides.
Entry
R
Product
Yield (%)a
1
2
3
4
5
6
7
8
a
pMeOC6H4
pO2NC6H4
pBrC6H4
pIC6H4
13
14
15
16
17
18
19
21/22
98
50b
89
66e
86
tBuc
C6H11
(CH3)2CH
CH3(CH2)2
96
97
43d
b
Isolated purified yield. Recrystallised yield. overnight reaction.
c
d
e
using DIPEA as the base. using two equivalents of acetylene.
Scheme 4 Low-yielding coupling reactions. Reagents and conditions: (i)
HCCPh, PdCl2(PPh3)2, CuI, Et3N or DIPEA, THF, RT, 8%; (ii)
t
HCC(CH2)2CO2 Bu, PdCl2(PPh3)2, CuI, DIPEA, THF, RT, 4%.
Fig. 1 X-ray crystal structure of p-nitrophenyl ketone 14.{
O-isobutyryl-N,N-diethylcarbamate 24a formed by attack of the
base on the carbonyl. In the presence of DIPEA the desired
product 25 was formed but in 8% yield: the balance of the reaction
was the corresponding carbamate rotamers 24b and c. Similar
results were obtained when using methyloxalylchloride 26. Using
DIPEA as the base, this reacted to give a mixture of the desired
product 27 (4%), a decarbonylated product 28 (4%) and the
balance of the reaction as amide rotamers 29a and b. These reac-
tions, however, did indicate the intermediacy of an acyl-palladium
species. Oxalyl-palladium species are known to easily decarbonyl-
ate,11 and decarbonylation and interception by the amine12 clearly
compete with transfer of the acetylene in these cases.
Scheme 2 Reaction of linear aliphatic acid chlorides.
Pivaloyl chloride, cyclohexylcarboxylic acid chloride and
2-methylpropionyl chloride also reacted smoothly to give high
yields of the acetylenic ketones 17, 18 and 19. However, in the case
of butyryl chloride, oxetane 20 was obtained in 46% isolated yield
(Scheme 2). This presumably results from [2 + 2] cycloaddition
reactions of ketenes. Such compounds are known to arise from the
direct reaction of NEt3 with aliphatic acyl chlorides,10 and in
control reactions, using our standard reaction conditions but
lacking the Pd catalyst, we observed the formation of 20 by TLC
Thus the reaction of terminal acetylenes with acid chlorides
under room temperature Pd(0) catalysed conditions is a rapid and
high-yielding method for the construction of synthetically useful
acetylenic ketones. The product yields are significantly improved
over previous reports8 and a wide variety of substituents are
tolerated on the acetylene. Aromatic and a-branched aliphatic acid
chlorides bearing a variety of substituents can be used. Linear
aliphatic acid chlorides also react in the presence of DIPEA. The
reaction conditions are mild enough that aromatic bromo-
substituents, which could be used for subsequent organo-metallic
coupling reactions, do not react but aromatic iodides are reactive
under these conditions.
1
and H NMR.
However, in the presence of the more hindered base diisopro-
pylethylamine (DIPEA, Hunig’s base) the reaction of butyryl
chloride was more productive, giving a mixture of the desired
product 21, together with both isomers of the corresponding enol
22 (Scheme 3) in 43% combined yield.
In an effort to broaden the range of potential acyl
partners, we used isobutyryl chloroformate 23 in an
attempt to synthesise acetylenic esters (Scheme 4). In the
presence of Et3N, the only product was the corresponding
We thank the School of Chemistry and University of Bristol for
funding. TAD thanks EPSRC for an earmarked quota studentship
(00316697). DR thanks GlaxoSmithKline and BBSRC for a
CASE award (01/A2/B/07049).
1038 | Chem. Commun., 2005, 1037–1039
This journal is ß The Royal Society of Chemistry 2005

View Article Online
Russell J. Cox,*a Dougal J. Ritson,a Thomas A. Dane,a John Berge,b
Jonathan P. H. Charmantc and Anob Kantachac
2 P. Wipf, Y. Aoyama and T. E. Benedum, Org. Lett., 2004, 6,
3593–3595.
3 M. Kunishima, D. Nakata, S. Tanaka, K. Hioki and S. Tani,
Tetrahedron, 2000, 56, 9927–9935; M. J. Piggott and D. Wege, Aust.
J. Chem., 2000, 53, 749–754.
4 D. Rodriguez, M. F. Martinez-Esperon, L. Castedo, D. Dominguez and
C. Saa, Synlett, 2003, 10, 1524–1526.
5 P. Fitton, M. P. Johnson and J. E. McKeon, J. Chem. Soc., Chem.
Commun., 1968, 6.
aSchool of Chemistry, University of Bristol, Cantock’s Close, Bristol,
UK BS8 1TS. E-mail: r.j.cox@bris.ac.uk; Fax: +44 (0)117 9298611
bGlaxoSmithKline, New Frontiers Science Park (North), 3rd Avenue,
Harlow, Essex, UK CM19 5AW
cStructural Chemistry Laboratory, School of Chemistry, University of
Bristol, Cantock’s Close, Bristol, UK BS8 1TS
6 G. W. Kabalka, R. R. Malladi, D. Tejedor and S. Kelly, Tetrahedron
Lett., 2000, 41, 999–1001; H. Chen and M.-Z. Deng, Org. Lett., 2000, 2,
1649–1651.
7 M. R. Eberhard, Org. Lett., 2004, 6, 2125–2128.
8 Y. Tohda, K. Sonogashira and N. Hagihara, Synthesis,1977,11, 777–778.
9 D. A. Alonso, C. Najera and M. C. Pacheco, J. Org. Chem., 2004, 69,
1615–1619.
10 L. Hintermann and A. Togni, Helv. Chim. Acta, 2000, 83, 2425–2435;
R. W. Holder, H. S. Freiman and M. F. Stefanchick, J. Org. Chem.,
1976, 41, 20, 3303–3307; C. D. Hurd and C. A. Blanchard, J. Am.
Chem. Soc., 1950, 72, 1461–1462.
Notes and references
{ CCDC 252032. See http://www.rsc.org/suppdata/cc/b4/b414826f/ for
crystallographic data in .cif or other electronic format. Crystal data for
compound 14. C15H9NO3, M = 251.23, monoclinic, a = 7.6488(6), b =
3
¯
7.1371(6), c = 10.9816(9) uˆ, b = 97.617(2)oˆ, U = 594.20(8) uˆ , T =173(2) K,
space group P21 (no. 4), Z = 2, oˆc¸(Mo–Ka) = 0.099 mm21, 3914 reflections
measured, 2516 unique (Rint = 0.0185) which were used in all calculations.
The final R1 and wR2 were 0.0310 and 0.0796 (I>2sI).
1 M. E. Krafft, L. V. R. Bonaga, A. S. Felts, C. Hirosawa and
S. Kerrigan, J. Org. Chem., 2003, 68, 6039–6042; J.-C. Wang, S.-S. Ng
and M. J. Krische, J. Am. Chem. Soc., 2003, 125, 3682–3683.
11 E. D. Dobrzynski and R. E. Angelici, Inorg. Chem., 1975, 14, 59–63.
12 The presence of PdCl2(PPh3)2 in these reactions appeared to increase the
rate of formation, and the yield, of amide and carbamate products.
This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 1037–1039 | 1039