Rhodium-complex-catalyzed addition reactions of chloroacetyl chlorides to alkynes

Article abstract of DOI:10.1021/ol802260w

(Chemical Equation Presented) The addition reaction of chloroacetyl chloride derivatives with terminal alkynes was found to be catalyzed by Rh(acac)(CO)(AsPh3) to afford (2)-1,4-dichloro-3-buten-2-one derivatives, which displayed diverse reactivities in s

Full text of DOI:10.1021/ol802260w

ORGANIC
LETTERS
2008
Vol. 10, No. 23
5469-5472
Rhodium-Complex-Catalyzed Addition
Reactions of Chloroacetyl Chlorides to
Alkynes
Taigo Kashiwabara,† Kouichiro Fuse,† Ruimao Hua,‡ and Masato Tanaka*,†
Chemical Resources Laboratory, Tokyo Institute of Technology,
4259 Nagatsuta, Midori-ku, Yokohama 226-8503, Japan, and Department of
Chemistry, Tsinghua UniVersity, Beijing 100084, P. R. China
m.tanaka@res.titech.ac.jp
Received October 1, 2008
ABSTRACT
The addition reaction of chloroacetyl chloride derivatives with terminal alkynes was found to be catalyzed by Rh(acac)(CO)(AsPh3) to afford
(Z)-1,4-dichloro-3-buten-2-one derivatives, which displayed diverse reactivities in synthetic elaboration.
Addition of acid chloride derivatives with alkynes is a useful
reaction, affording ꢀ-chloroalkenyl ketones, which allow
numerous synthetic applications, in particular, the synthesis
of heterocyclic compounds.1 These reactions have been made
possible by using Lewis acids like AlCl3. However, as is
anticipated by the use of Lewis acid catalysts, the major
products are usually (E)-isomers with some exceptions
forming mixtures of (E)- and (Z)-isomers2 and the selective
synthesis of the (Z)-isomer still remains to be further
scrutinized.
role to prevent possible decarbonylation in these reactions.
For instance, pioneering work by Nomura, Miura, and co-
workers reported the addition reaction of aroyl chlorides with
alkynes. However, the reaction is not a neat addition of aroyl
chlorides; it proceeds with concomitant decarbonylation,
affording formal aryl chloride addition products.4,5 In view
of synthetic application, the products coming from CO-
retentive addition are more useful than the formal ArCl
adducts since the alkenyl-Cl bond is activated by the R,ꢀ-
unsaturated carbonyl linkage.1,6 Our continued study has
We have reported rhodium-catalyzed addition reactions
of chloroformates, ethoxalyl chloride, and perfluorinated acid
chlorides to terminal alkynes.3 The electronegative substitu-
ent bound to the carbonyl group appears to play an important
(2) (a) Manoiu, D.; Manoiu, M.; Dinulescu, I. G.; Avram, M. ReV. Roum.
Chim. 1984, 29, 193. (b) Manoiu, D.; Manoiu, M.; Dinulescu, I. G.; Avram,
M. ReV. Roum. Chim. 1984, 29, 201. (c) Haack, R. A.; Beck, K. R.
Tetrahedron Lett. 1989, 30, 1605. (d) Manoiu, D.; Manoiu, M.; Dinulescu,
I. G.; Avram, M. ReV. Roum. Chim 1984, 29, 671. (e) Manoiu, D.; Manoiu,
M.; Dinulescu, I. G.; Avram, M. ReV. Roum. Chim 1985, 30, 223. (f)
Martens, H.; Janssens, F.; Hoornaert, G. Tetrahedron 1975, 31, 177. (g)
Benson, W. R.; Pohland, A. E. J. Org. Chem. 1964, 29, 385. (h) Clayton,
J. P.; Guest, A. W.; Taylor, A. W. J. Chem. Soc., Chem. Commun. 1979,
† Tokyo Institute of Technology.
‡ Tsinghua University.
(1) Review: Pohland, A. E.; Benson, W. R. Chem. ReV. 1966, 66, 161.
(a) Triazole: Prodanchunk, N. G.; Megera, I. V.; Patratii, V. K. Pharm.
Chem. J. 1984, 18, 108. (b) Thiazoline: Mirskova, A. N.; Levkovskaya,
G. G.; Kalikhman, I. D.; Voronkov, M. G. Zh. Org. Khim. 1979, 15, 2301.
(c) Pyrazole: Levkovskaya, G. G.; Bozhenkov, G. V.; Malyushenko, R. N.;
Mirskova, A. N. Russ. J. Org. Chem. 2001, 37, 1795. (d) Levkovskaya,
G. G.; Bozhenkov, G. V.; Larina, L. I.; Mirskova, A. N. Russ. J. Org. Chem
2002, 38, 1501. (e) Arnaud, R.; Bensadat, A.; Ghobsi, A.; Laurent, A.; Le
Dre´an, I.; Lesniak, S.; Selomi, A. Bull. Soc. Chim. Fr. 1994, 131, 844. (f)
Isoxazole: Aliev, A. G. Russ. J. Org. Chem. 2005, 41, 1192. (g) Kochetkov,
N. K.; Nesmeanov, A. N.; Semenov, N. A. IzV. Akad. Nauk SSSR, Ser.
Khim. 1952, 87. (h) Thiophene: Alberola, A.; Andres, J. M.; Gonzalez, A.;
Pedrosa, R.; Pradanos, P. Synth. Commun. 1990, 20, 2537. (i) Diab, J.;
Laurent, A.; Le Dre´an, I. J. Fluorine Chem. 1997, 84, 145.
500
.
(3) (a) Hua, R.; Shimada, S.; Tanaka, M. J. Am. Chem. Soc. 1998, 120,
12365. (b) Hua, R.; Onozawa, S.-y.; Tanaka, M. Chem. Eur. J. 2005, 11,
3621–3630. (c) Kashiwabara, T.; Kataoka, K.; Hua, R.; Shimada, S.; Tanaka,
M. Org. Lett. 2005, 7, 2241
(4) Kokubo, K.; Matsumasa, K.; Miura, M.; Nomura, M. J. Org. Chem.
1996, 61, 6941
.
.
(5) A formal CO retentive reaction of aroyl chlorides with norbornene,
which proceeds through decarbonylation-carbonylation processes, has been
reported. See: Sugihara, T.; Satoh, T.; Miura, M.; Nomura, M. AdV. Synth.
Catal. 2004, 346, 1765, and references cited therein
.
(6) Hua, R.; Tanaka, M. New J. Chem. 2001, 25, 179
.
10.1021/ol802260w CCC: $40.75
Published on Web 11/08/2008
2008 American Chemical Society

uncovered that even chloroacetyl chloride adds to alkynes
to furnish (Z)-1,4-dichloro-3-buten-2-ones (Scheme 1) as
Table 1. Catalyst Screening for the Reaction of 1a with 2Aa
b
yield (%)
entry
catalyst
3aA (Z/E)
4aA
5A
Scheme 1
1
2
3
4
5
6
7
8
Rh(acac)(CO)(AsPh3)c
86 (93/7)
52 (52/48)
43 (58/42)
22 (77/23)
11 (85/15)
5 (60/40)
4 (75/25)
15 (67/33)
18 (73/27)
16 (50/50)
14 (64/36)
22 (73/27)
9 (66/34)
10 (50/50)
0
5
8
9
c
RhCl(CO)(AsPh3)2
14
21
19
29
4
c
Rh(acac)(AsPh3)2
Rh(acac)(CO)(PPh3)c
36
23
10
16
29
24
15
25
6
c
RhCl(CO)(PPh3)2
RhCl(PPh3)3
[Rh(CO)(PPh3)2][BF4]
RhCl(CO)[P(p-MeC6H4)3]2
5
c
10
22
8
<1
<1
3
c
9
RhCl(CO)[P(p-FC6H4)3]2
c
10
11
12
13
14
RhCl(CO)(dppb)2
c
RhCl(CO)(dppp)2
RhCl(CO)(dppe)c
RhCl(CO)(PMe3)2
[RhCl(CO)2]2
major products, which are even more synthetically versatile,
associated with the presence of extra chlorine at the R-posi-
tion.7
5
10
16
a Reaction conditions: 1a (2 mmol), 2A (2 mmol), catalyst (2 mol %),
toluene solvent (2 mL), 110 °C, 14 h. b Determined by 1H NMR
spectroscopy. c Generated in situ by treating [RhCl(CO)2]2 or Rh(acac)(CO)2
with the respective ligands.
In a representative experiment, a mixture of Rh(acac)(CO)2
(0.04 mmol), AsPh3 (0.04 mmol), chloroacetyl chloride 1a
(2.0 mmol), 1-octyne 2A (2.0 mmol), and toluene (2.0 mL)
was heated at 110 °C for 14 h. Analysis of the resulting
mixture revealed that (Z)-3aA and (E)-3aA were formed in
80 and 6% yield, respectively. HCl adduct 5A (5%) was also
formed in a small quantity. However, possible byproducts
such as 3aA′ and 4aA, which were indeed found in trial
experiments (vide infra), were not formed in this particular
reaction, thus showing that the addition reaction had taken
place regio- and stereoselectively. Routine workup allowed
isolation of (Z)-3aA and (E)-3aA, which were fully char-
acterized, inclusive of NOE experiment, reduction of (Z)-
3aA to the corresponding alcohol (Z)-3aA-red, and its
characterization and also X-ray crystallography in the case
of (Z)-3aI.8
Before the Rh(acac)(CO)2-AsPh3 catalyst system was
determined to be the catalyst of choice, we ran a series of
trial experiments to look mainly into the ligand effect (Table
1). In general, AsPh3 is far better performing than the other
ligands (entries 1-3), although its performance is dependent
on the conditions. For instance, under somewhat different
conditions (80 °C, 60 h), the reaction using a less selective
catalyst RhCl(CO)(AsPh3)2 afforded, besides (Z)-3aA (39%)
and (E)-3aA (8%), regioisomer 3aA′ (4%), 5A (40%), and
octyne oligomers. Strikingly different from the addition
reaction of heptafluorobutyryl chloride,3c PPh3 complexes
display very low performance, although the outcome is
variant depending on the particular structure (entries 4-7).
The low performance of PPh3 and other triarylphosphines
(entries 8 and 9) is associated mainly with the formation of
byproducts 4aA (vide infra) and 5A. In the reactions using
RhCl(PPh3)3, RhCl(CO)(dppb), RhCl(CO)(dppp), and
[RhCl(CO)2]2, the conversion of 1a was low as compared
with the conversion of 2A, indicative of more extensive
oligomerization having taken place (entries 6, 10, 11, and
14). On the other hand, RhCl(CO)(PMe3)2 and RhCl(CO)(d-
ppe) also resulted in low conversion of 1a due to their
intrinsic low activity toward both the desired reaction and
the oligomerization (entries 12 and 13).
The formation of byproduct 4aA appears to have come
from double-bond isomerization of initially formed 3aA.
Thus, heating a toluene-d8 solution of pure (Z)-3aA and
Rh(acac)(CO)(PPh3) (3 mol %) in an NMR tube at 110 °C
for 18 h resulted in a mixture comprising (Z)-4aA (69%)
and (Z)-3aA (31%). Note that (E)-3aA was not detected at
all. The time-course of the RhCl(CO)(PPh3)2 (5 mol %)-
catalyzed reaction at 110 °C further confirmed the isomer-
ization.9 The formation of (E)-3aA in the addition reactions
and the lack of isomerization of (Z)-3aA to (E)-3aA indicates
that (E)-3aA is a genuine product formed as primary product,
but not from the isomerization of initially formed (Z)-3aA.
As for the formation of 5A, we are unable to identify the
provenance of HCl. Although H-Rh-Cl species or HCl can
be generated through ꢀ-hydride elimination from a chloro-
acetyl-Rh intermediate (vide infra), we have not encountered
the formation of chloroketene or its derivatives, which should
have been simultaneously formed.
The representative procedure could be successfully applied
to a variety of terminal alkynes (Table 2). Besides 1-octyne,
other aliphatic alkynes such as tert-butylacetylene 2B (entry
2) and trimethylsilylacetylene 2C (entry 3) reacted, albeit
somewhat slowly due presumably to the steric congestion,
to afford high Z/E ratios, although trimethylsilylacetylene
underwent more extensive oligomerization. Alkynes substi-
tuted by chloro, cyano, methoxycarbonyl, and siloxy groups
2D-G also formed the corresponding adduct (entries 4-7).
However, the Z/E ratios were less satisfactory (vide infra).
The reaction of benzylacetylene 2H was also less Z-
selective, and (Z,Z)-1,6-diphenyl-2,5-dichloro-2,4-hexadiene
(7) R-Halo ketones are also useful intermediates in organic synthesis.
See: (a) Sci. Synth. 2005, 26, 869. (b) Sci. Synth. 2005, 26, 745.
(8) For X-ray crystallographic details, see the Supporting Informa-
tion.
(9) For details, see the Supporting Information.
5470
Org. Lett., Vol. 10, No. 23, 2008

having an electronegative group at the para-position. In view
of the extensive oligomerization found in the p-fluorophe-
nylacetylene reaction, one can expect the formation of
oligomers, which were indeed found in the reaction of 2N.
The reactivity of chloroacetyl chloride derivatives having
substituents at the R-position is highly dependent on the
nature of the substituent. Dichloroacetyl chloride 1b and
phenylchloroacetyl chloride 1c reacted with 2A normally
(Scheme 3). However, R-chlorobutyryl chloride 1d and
Table 2. Reaction of 1a with Terminal Alkynes 2A-Ma
entry
Product, R )
3 yieldb (%) Z/Eb
1c
2d
3e
4
3aA, n-hexyl
3aB, t-Bu
86
98
47f
76
36
57
85
35h
63
82
55f
98
42
93/7
100/0
100/0
82/12
53/47
58/42
63/37
71/29
87/13
84/16
85/15
93/7
3aC, trimethylsilyl
3aD, 3-chloropropyl
3aE, 3-cyanopropyl
3aF, 3-(methoxycarbonyl)propyll
3aG, tert-butyldimethylsiloxyethyl
3aH, benzyl
5
6g
7
8
9
3aI, phenyl
Scheme 3
10 3aJ, p-methoxyphenyl
11 3aK, p-fluorophenyl
12 3aL, 2-thienyl
13 3aM, ferrocenyl
ndi
a Reaction conditions: 1a (2 mmol), 2A (2 mmol), Rh(acac)(CO)(AsPh3)
(0.1 mmol), toluene solvent (2 mL), 110 °C, 14 h. b Determined by 1H
NMR spectroscopy. c Quantity of Rh(acac)(CO)(AsPh3) ) 0.04 mmol.
d Reaction time ) 24 h. e Reaction time ) 18 h. f Extensive oligomerization
proceeded. g Reaction time ) 8 h. h A large quantity of (Z,Z)-1,6-diphenyl-
2,5-dichloro-2,4-hexadiene was formed. i Not determined.
trichloroacetyl chloride 1e did not form the corresponding
adducts at all, and instead, (Z,Z)-7,10-dichlorohexadeca-7,9-
diene 6A was formed in 42 and 63% yield, respectively.10
In the reaction of 1d, 1,1-dichloropropane (10%) and
1-propenyl chloride (18%) were also formed, suggesting that
decarbonylation and ꢀ-hydride elimination processes were
also taking place.
The present catalysis is most likely to proceed through
three processes: oxidative addition of the C(O)-Cl bond of
1 to Rh(I), insertion of alkyne into the Rh-Cl bond, and
subsequent C-C reductive elimination (Scheme 4, illustrated
6H was formed as another type of byproduct (entry 8).10
On the other hand, aromatic and heteroaromatic acetylenes
2I-L (entries 9-12) displayed higher Z-selectivities. Note
that the nature of the para-substituent displays a distinct effect
on the extent of oligomerization, which was more serious
for p-fluorophenylacetylene as judged by 1H NMR analysis
of the reaction mixture. Ferrocenylacetylene 2M behaved
somewhat differently; the color of the reaction mixture was
dark purple, and a large quantity of a dark green solid was
also formed. This observation and the line-broadening of
1
Scheme 4
every H NMR signal of the reaction mixture suggest that
the ferrocene moiety was oxidized during the catalysis.
The reactions of conjugated alkynes such as methyl
propiolate, dimethyl acetylenedicarboxylate, and 1-ethynyl-
cyclohexene were not successful; the major event was oligo-
or polymerization. 4-Octyne having an internal triple bond
gave only a trace of oligomers.
1,4-Di(ethynyl)benzene 2N reacted with 1a (2 equiv) to
afford the corresponding diketone (Scheme 2). The somewhat
for RhCl(CO)L2-type catalysts). The following observations
substantiate the proposal, albeit partially.
Scheme 2
Attempted oxidative addition of 1a with Rh(acac)(CO)(As-
Ph3) did not proceed cleanly (room temperature in toluene,
3 h); the yellow solid obtained did not display satisfactory
IR or 13C and 1H NMR spectra. However, the reaction with
RhCl(CO)(AsPh3)2 7-AsPh3 (room temperature in benzene,
3 h) took place neatly to give RhCl2(CO)(AsPh3)2(COCH2Cl)
8-AsPh3 (88%). Although 8-AsPh3 was totally insoluble in
any common solvents, we were able isolate an analytically
pure sample, the structure of which was unequivocally
verified by X-ray analysis.8RhCl(CO)L2 (7-PMe3: L ) PMe3,
7-PMePh2: L ) PMePh2) also reacted cleanly to form
RhCl2(CO)L2(COCH2Cl) (8-PMe3, 92%; 8-PMePh2, >99%).8
Thus, oxidative addition of 1a is a clean and facile process
low yield may stem from the ease of oligomerization of the
initially formed adduct pro-3aN rather than the second
addition reaction. Intermediate pro-3aN is an aromatic alkyne
(10) Details will be reported separately.
Org. Lett., Vol. 10, No. 23, 2008
5471

as far as the Vaska type rhodium complexes are concerned,
as was reported by Cole-Hamilton and a co-worker.11
To gain information of the insertion process, 8-AsPh3 was
treated with 2 equiv of 2A in toluene-d8. Although 8-AsPh3
was insoluble, the mixture became homogeneous at 110 °C.
1H NMR analysis of the mixture after 12 h revealed
quantitative reductive elimination back to 1a having taken
place. The reaction of 8-PMe3 with 2A under identical
conditions also resulted in extensive reductive elimination
(61%) with 8-PMe3 (33%) remaining unchanged. Another
attempted reaction using 8-PMePh2 and 2A was not infor-
mative of the details of the insertion process either.
Synthetic utility of the products is exemplified for 3aI
(Scheme 5). The reaction with isopropylamine took place
Scheme 5
Although the foregoing attempts to confirm insertion of
alkyne failed due to the facile reductive elimination, we
presume that the insertion does take place during the catalysis
in the presence of a large quantity of 1a. In closely related
reactions of chloroformate, ethoxalyl chloride, and perflu-
orinated acid chloride,3 we have proposed that the insertion
takes place through chloro-rhodation (vs acyl-rhodation),
which agrees with cis-insertion forming a (Z)-isomer as near
a sole product. In contrast, the present reaction is somewhat
different in that the Z/E ratios are low, in particular, when
functional groups are introduced to the alkyne molecules
(entries 5-7, Table 2). The low ratio is not due to the Z-to-E
isomerization since (Z)-3aA did not isomerize to (E)-3aA
when exposed to Rh(acac)(CO)(PPh3) (vide supra). More-
over, the Z/E ratio in the reaction of 2F (entry 6, Table 2)
was basically constant throughout the time course, suggesting
that (E)-3aF is, at least partially, a genuine initial product
formed from the main event, not through possible secondary
processes like isomerization. Accordingly, we may have to
admit that there is possible involvement of trans-insertion
via external nucleophilic attack of chloride, as far as polar
alkynes are concerned.12 trans-Chlororhodation has not been
documented, but trans-chloropalladation is a well-known
process.13
exclusively at the ꢀ-chlorine but acetic acid replaced the
R-chlorine. Cyclization with hydroxylamine involved both
carbonyl group and the ꢀ-chlorine to afford isoxazole 12,
while another type cyclization involving both chlorine atoms
was possible in the palladium-catalyzed carbonylation,
affording 13.14
In conclusion, Rh(acac)(CO)(AsPh3) catalyzes the addition
reaction of chloroacetyl chloride with terminal alkynes to
furnish 1,4-dichloro-3-butene-2-ones, which are envisioned
to serve as versatile intermediates in organic synthesis.
Further extension to other acid chloride derivatives is in
progress.
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research on Priority Areas (No.
18065008) from the Ministry of Education, Culture, Sports,
Science and Technology, Japan, and by a research fellowship
to T.K. from the Japan Society for the Promotion of Science
and Technology.
Supporting Information Available: Experimental details,
spectral data of all new compounds, and details of the X-ray
analysis of (Z)-3aI, 8-AsPh3, 8-PMe3, and 8-PMePh2. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(11) Weston, S. W.; Cole-Hamilton, D. J. Inorg. Chim. Acta 1998, 280,
99.
(12) A solvent effect study to look into cis-/trans-insertion using polar
solvents like acetone and THF for the reaction of 1-octyne was hampered
by very low yields, which did not furnish reliable data of the Z/E ratio.
However, a lower Z/E ratio was observed when the reaction of entry 6
(Table 2) was repeated in the presence of (n-octyl)3MeNCl, although the
reaction was messy. For details, see the Supporting Information.
(13) Lu, X. In Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E.-i., Ed.; John Wiley & Sons: New York, 2002; Vol.
II, pp 2267-2287.
OL802260W
(14) For γ-alkylidenebutenolides in pharmaceutical applications, see:
Ahmed, Z.; Langer, P. J. Org. Chem. 2004, 69, 3753, and references cited
therein.
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Org. Lett., Vol. 10, No. 23, 2008