Suppression of β-hydride elimination in the intramolecular hydrocarboxylation of alkynes leading to the formation of lactones

Article abstract of DOI:10.1002/adsc.200600507

Palladium-catalyzed intramolecular cyclization of the alkynoic acids was studied which gave the five- and six-membered lactones in moderate yields. The reaction can be conducted simply by heating a toluene solution of alkynoic acids at 100 °C in the prese

Full text of DOI:10.1002/adsc.200600507

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DOI: 10.1002/adsc.200600507
Suppression of b-Hydride Elimination in the Intramolecular
Hydrocarboxylation of Alkynes leading to the Formation of
Lactones
a
a
a
a
Zhibao Huo, Nitin T. Patil, Tienan Jin, Nirmal K. Pahadi,
a,
and Yoshinori Yamamoto *
Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
a
Fax : (+81)-22-795-6784; e-mail: yoshi@mail.tains.tohoku.ac.jp
Received: October 5, 2006
th
Dedicated to Professor Masakatsu Shibasaki on occasion of his 60 birthday.
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Palladium-catalyzed intramolecular cycli- additive. Similar to our previously developed catalyt-
zation of the alkynoic acids was studied which gave ic system the use of carboxylic acid, instead of (o-
the five- and six-membered lactones in moderate tol) P, resulted into the exclusive formation of the
3
yields. The reaction can be conducted simply by diene.
heating a toluene solution of alkynoic acids at 1008C
in the presence of catalytic amounts of Pd
A
H
R
U
G
Keywords: asymmetric catalysis; CÀC bond forma-
3
4
and (o-tol) P. The key for this transformation is the tion; cross-coupling; enzyme catalysis; homogeneous
3
use of phosphines, instead of carboxylic acids, as an catalysis
Introduction
amounts of a carboxylic acid was crucial for the palla-
dium-catalyzed process. We have also reported the
The metal-catalyzed intramolecular cyclization of palladium-catalyzed intermolecular hydrocarboxyla-
carbon and heteroatom nucleophiles with tethered ac- tion reaction between alkynes (R=Ar) and carboxyl-
[
1]
[2]
tivated CÀC bonds such as alkenes, allenes, and al- ic acids which provided allyl carboxylates in good to
[
3]
[9]
kynes is one of the most powerful tools for the gen- high yields [Eq. (2)]. In the similar line, we envi-
eration of carbocycles and heterocycles in an atom sioned that the intramolecular cyclization of alkynoic
[
4]
economical manner. Although tremendous amounts acid might afford the lactone 3 under the Pd(0)-
of the related work have been carried out in the field RCOOH combined catalytic system and if the hy-
of hydrocarbonation, hydroamination and hydroal- pothesis proved realistic a new method for the synthe-
koxylation reactions, very few reports are known for sis of lactones would be realized. To test this possibili-
hydrocarboxylation reactions, partly due to the dimin- ty, the alkynoic acid 1a was treated with Pd(PPh )
[
5]
ACHTREUNG
3
4
[
6]
ished nucleophilicity of the carboxylic acids. There- and benzoic acid (10 mol%) in 1,4-dioxane at 1008C.
fore, the development of suitable methods for the for- To our disappointment, the desired lactone 3a was
mation of CÀC and CÀX bond by these processes is not formed at all; instead the diene 2 was isolated in
highly desired.
92% yield [Eq. (3)]. A precise reason for this obser-
Lactones hold an important place in the natural vation can be rationalized on the basis of lower nucle-
product field and are widely spread all over the bioge- ophilicity of the carboxylic acid oxygen which ham-
netic categories. Particularly, there are numerous ex- pers the intramolecular nucleophilic attack on p-allyl
amples of five- and six-membered lactones, which palladium complex, resulting in the formation of the
often exhibit pheromonal, medicinal, flavoring, or ol- diene 2 via b-elimination process. Our initial research
[
7]
factory properties. Recently, we have been exploring was focused on the study of solvents, concentration,
the palladium-catalyzed addition of various nucleo- and catalyst loading. However, in all the cases, the
[
10]
philes to allenes, generated in situ from the corre- isomerization via b-hydride elimination mechanism
[
8]
sponding alkynes [Eq. (1)]. The addition of catalytic occurred giving the corresponding diene 2 exclusively.
680
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Intramolecular Hydrocarboxylation of Alkynes
All the attempts to suppress the b-hydride elimination
product 2 by using various palladium catalysts in com-
bination with many ligands such as dppb, dppe, dppm,
and dppf failed. A challenge was to obtain the lactone
by suppressing the b-hydride elimination product 2.
In the hope of finding a new catalyst system for the
intramolecular hydrocarboxylation, we decided to
pursue the search for alternative catalytic systems in
these hydrocarboxylation reactions. We reasoned that
proper tuning of ligands attached to palladium might
prove beneficial for this purpose. Thus, we have un-
dertaken a search for a suitable ligand. After studying
various ligands in the absence of the external carbox-
ylic acid additive, we found that (o-tol) P in combina-
3
tion with Pd
to synthesize five- and six-membered lactones [Eq.
4)]. The detailed results of the work are reported
herein.
A
C
H
T
R
E
U
N
G
(PPh ) gave the best results allowing us
3 4
(
[a]
Table 1. Effect of phosphine additives on the cyclization of 1a.
[
a]
The reactions of 1a (0.2 mmol) in the presence of metal catalysts and phosphine additives were
carried out at 1008C in toluene (0.1M) for 12 h.
Yields were determined by H NMR spectroscopy with dibromomethane as an internal standard.
Isolated yields are shown in parentheses.
dppe=1,3-bis(diphenylphosphino)-ethane.
The reaction mixture was heated at 1208C.
[
[
[
[
b]
c]
d]
e]
1
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Zhibao Huo et al.
Results and Discussion
Table 2. Palladium-catalyzed cyclization of various alkynoic
acids.
[a]
5-Hexynoic acid 1a was selected as a substrate to opti-
mize the cyclization process. The results are summar-
ized in Table 1. The reaction 1a in the absence of
[
11]
either (o-tol) P or Pd
A
H
R
U
gave only trace
amounts of the product 3a or no reaction took place
entries 1 and 2). The use of 5 mol% Pd(PPh ) and
0 mol% (o-tol) P in toluene afforded the lactone 3a
3
(
ACHTREUNG
3
4
1
3
in 80% isolated yield as the E-isomer (entry 3).
Other phosphine ligands in the absence of external
carboxylic acid were also effective for this reaction
(
entries 4–7). Various solvents such as benzene, THF,
acetonitrile, CH Cl and 1,4-dioxane, instead of tolu-
2
2
ene, gave the product in moderate yields (entries 8–
2). Decreasing the amount of ligand and catalyst re-
1
sulted in moderate yields (entries 13 and 14). The in-
crease in reaction temperature up to 1208C gave the
product in 76% yield (entry 15).
We carried out the cyclization reaction of various
alkynoic acids 1 under the optimized conditions, and
the results are summarized in Table 2. The substrate
1b having a methoxy group at the para position of the
aromatic ring afforded the corresponding cyclized
product 3b in 56% yield (entry 1). The p- and m-
methyl-substituted alkynoic acids 1c and 1d gave the
products 3c and 3d, respectively, in good yields (en-
tries 2 and 3). Unfortunately, the lactone 3e could be
obtained only in a lower (30%) yield even after in-
creasing the amount of palladium catalyst/ligand/reac-
tion time and/or reaction temperature, and 11% of
the starting material 1e was recovered (entry 4). The
reaction of the alkynoic acid 1f, having trifluorometh-
yl group at the para position in the aromatic ring, also
proceeded smoothly to afford the product 3f in 45%
yield (entry 5). The substrates 1g and 1h afforded the
desired products 3g and 3h, respectively, in good
yields (entries 6 and 7). The reaction of 1i, having an
n-pentyl group at the alkyne terminus, under the stan-
dard conditions proceeded smoothly to give a 9:1
mixture of trans and cis isomers of the lactone 3i in
good yield (entry 8). The six-membered lactone 3j
was also obtained from 1j, albeit in somewhat lower
yield. (entry 9).
[a]
The reactions of 1 (0.2 mmol) in the presence of Pd-
(PPh ) (5 mol%) and (o-tol) P (10 mol%) were carried
out at 1008C in toluene (0.1M) for 12 h.
Isolated yields.
AHCTREUNG
3
4
3
[
[
[
b]
c]
d]
11% of starting material 1e was recovered.
A mixture of trans and cis isomers (9:1) was obtained.
A proposed mechanism for the palladium-cata-
lyzed intramolecular cyclization of alkynoic acids is
somewhat similar to our previously reported mecha-
1
The ratio was determined by H NMR spectral analysis.
[
8]
nism and is illustrated in Scheme 1. The oxidative
insertion of Pd(0) to RCOOÀH bond of the acid 1a
generates catalytically active hydridopalladium com-
plex 4. Hydropalladation of the alkyne with the hy- along with regeneration of the catalyst. Although the
dridopalladium species produces the vinylpalladium precise role of the (o-tolyl) P is not clear at present,
3
species 5, which gives the substituted phenylallene 6 we believe that the added phosphine might be in-
on b-elimination. Subsequent hydropalladation of creasing the rate of oxidative addition into the car-
the allene 6 gives the p-allylpalladium species 7. In- boxylic acid or helping to promote the initial hydro-
tramolecular nucleophilic substitution in the p-allyl- palladation step.
palladium complex 7 gives the desired product 3a
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had been stirred for 12 h at 1008C, TLC was taken in order
to confirm complete disappearance of the starting material.
The solvent was removed under reduced pressure, and the
residue was purified on a short silica gel column with hex-
ane:ethyl acetate, 9:1, as eluent to give 3a; yield: 30.1 mg
(
80%).
Supporting Information
1
Experimental details, characterization data, H NMR spec-
tra of newly synthesized compounds are available in the
Supporting Information.
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