Indium chloride catalyzed alkylative rearrangement of propargylic acetates using alkyl chlorides, alcohols, and acetates: Facile synthesis of α-Alkyl-α,β-unsaturated carbonyl compounds

Article abstract of DOI:10.1021/ol500046e

Indium chloride catalyzed alkylative rearrangement of propargylic acetates into α-alkyl-α,β-unsaturated carbonyl compounds has been achieved. Propargylic acetates functioned as α-acylvinyl anion equivalents to react with carbocations generated from alkyl

Full text of DOI:10.1021/ol500046e

Letter
pubs.acs.org/OrgLett
Indium Chloride Catalyzed Alkylative Rearrangement of Propargylic
Acetates Using Alkyl Chlorides, Alcohols, and Acetates: Facile
Synthesis of α‑Alkyl-α,β-Unsaturated Carbonyl Compounds
Yoshiharu Onishi, Yoshihiro Nishimoto, Makoto Yasuda, and Akio Baba*
Department of Applied Chemistry, Graduate School of Engineering, Osaka University 2-1, Yamada-oka, Suita, Japan
S
* Supporting Information
ABSTRACT: Indium chloride catalyzed alkylative rearrangement of prop-
argylic acetates into α-alkyl-α,β-unsaturated carbonyl compounds has been
achieved. Propargylic acetates functioned as α-acylvinyl anion equivalents to
react with carbocations generated from alkyl chlorides. Other alkyl electrophiles
such as alcohols and acetates were also applicable.
n α-acylvinyl anion, which couples with various electro-
philes to afford a beneficial α-substituted-α,β-unsaturated
Despite these remarkable developments, however, we were
unable to find a report of the reaction between an α-acylvinyl
anion equivalent and a carbocation.
Herein, we report the InCl3-catalyzed alkylative rearrange-
ment of propargylic acetates using alkyl chlorides (Scheme 2).
A
carbonyl compound, is one of the most useful nucleophiles
in carbon−carbon bond-forming reactions (Scheme 1).1,2
Scheme 1. Utilization of Propargylic Ester as α-Acylvinyl
Anion
Scheme 2. Alkylative Rearrangement of Propargylic Acetates
Using Alkyl Chlorides
In the present reaction, propargylic acetate directly reacts with the
carbocation generated from an alkyl chloride by indium catalyst to
give the corresponding α-alkylated-α,β-unsaturated ketone.
After the screening of catalysts in the reaction of alkyl
chloride 1a with propargylic acetate 2a, InCl3, InBr3, and InI3
smoothly accelerated the formation of the corresponding enone
3aa in 79%, 82%, and 78% yields, respectively (Table 1, entries
1−3). Indium halides, in contrast to other Lewis acids, can
generate the corresponding carbocation from an alkyl chloride
even in the presence of oxygen-containing functional groups
such as an acetoxy group.16 The use of ZnCl2 and FeCl3·6H2O,
which are effective catalysts in the carbohalogenation of alkynes
with alkyl chlorides,17 gave lower yields of 3aa (entries 4 and 5).
No reaction took place in the presence of representative
Lewis acids such as BF3·OEt2, AlCl3, and TiCl4 (entries 6−8).
While AuCl3, PtCl2, and AgBF4 are known to promote the
rearrangement of propargylic carboxylates to give allenyl
carboxylates,18 they did not catalyze this reaction (entries 9−11).
Low yields of 3aa were obtained in nonpolar solvents such
Recently, the strategy using propargylic alcohols and their
derivatives as α-acylvinyl anion equivalents has been intensively
studied because these are so readily available. In many cases, the
rearrangement of them to allenol derivatives is employed due to
the tautomerization between an α-acylvinyl anion and an allenoxy
anion. Scheidt reported that allenyl silyl ethers, which are produced
by Brook and retro-Brook rearrangements of propargylic alcohols
and silyl ethers, respectively, coupled with carbonyl compounds.3,4
Trost developed a coupling reaction employing Meyer−Schuster
rearrangement of propargylic alcohols into vanadium allenoates.5
Although methods using Au- and Ag-catalyzed rearrangements
of propargylic esters to allenyl carboxylates have also attracted
much attention,6 these have been limited to acyl migration7 and
cyclization using intramolecular electrophilic moieties such as
alkenes, alkynes, and imines.8−12 A Au-catalyzed intermolecular
reaction using isochromane acetal analogues was recently
reported.13 Also noteworthy has been the development of a
Au-catalyzed coupling of propargylic acetates with arylboronic
acids by Zhang, and a copper-catalyzed arylative Meyer−Schuster
rearrangement of propargylic alcohols was developed by Gaunt,
in which an allenyl carboxylate intermediate is uninvolved.14,15
Received: January 7, 2014
Published: February 4, 2014
© 2014 American Chemical Society
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dx.doi.org/10.1021/ol500046e | Org. Lett. 2014, 16, 1176−1179

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Letter
a
Table 1. Screening of Catalysts
Table 2. Reaction of Various Alkyl Chlorides 1 with
Propargylic Acetate 2a
a
b
entry
catalyst
InCl3
solvent
yield (%)
c
1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
hexane
toluene
MeCN
THF
79 (70)
2
InBr3
82
78
22
17
0
3
InI3
4
ZnCl2
FeCl3 6H2O
BF3 OEt2
AlCl3
5
6
7
0
8
TiCl4
0
9
AuCl3
PtCl2
0
10
11
12
13
14
15
16
0
AgBF4
InCl3
9
27
7
InCl3
InCl3
0
InCl3
0
InCl3
CH2Cl2
60
a
Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), catalyst
b
1
(0.05 mmol), CH2Cl2 (1 mL), rt, 3 h. Yield by H NMR analysis.
Internal standard is 1,1,2,2-tetrachloroethane. Isolated yield. 1a was
considerably recovered. 2a (0.5 mmol).
c
d
e
as hexane and toluene, and the employment of MeCN and THF
completely disturbed the reaction because of their coordination
toward InCl3 (entries 12−15). The use of 1 equivalent of 2a
slightly decreased the yield of 3aa (entry 16). For all of these
results, InCl3, which is cheaper and easier to handle than other
indium halides, was chosen as a standard catalyst.
Using InCl3 as a catalyst, the scope and limitations of alkyl
chlorides were investigated (Table 2). Benzhydryl chloride 1b
gave an excellent result (Table 2, entry 1). Both secondary
benzylic chlorides bearing electron-withdrawing and -donating
groups reacted with propargylic acetate 2a to produce α,β-
unsaturated ketones 3ca and 3da in 63% and 74% yields,
respectively (entries 2 and 3). Primary benzyl chloride 1e did not
afford the coupling product, even under the harsh conditions
(entry 4). By contrast, the reaction of p-methylbenzyl chloride 1f
proceeded smoothly under the same harsh conditions, although
only 20% yield was achieved at room temperature (entry 5).
These results indicate that the stability of carbocations generated
from alkyl chlorides is significant. Allylic chloride 1g was also
a suitable electrophile, and it provided the corresponding
product 3ga in a good yield (entry 6). Although the reaction
of adamantyl chloride 1h resulted in only 34% yield because the
corresponding carbocation is hardly generated, the correspond-
ing product 3ha was obtained in high yield under heating
conditions (entries 7 and 8). In the reaction of alkyl chloride 1i,
4 equiv of 2a were required to obtain a moderate yield of 3ia
because the electron-withdrawing effect of the intramolecular
ester moiety makes the corresponding carbocation intermediate
unstable (entry 9). Primary alkyl chloride moieties tolerated the
reaction conditions (entry 10).
a
Reaction conditions: 1 (1 equiv), 2a (2 equiv), InCl3 (0.1 equiv),
b
CH2Cl2 (1 mL), rt, 3 h. Yield by 1H NMR analysis. Internal standard
is 1,1,2,2-tetrachloroethane. Values in parentheses are isolated yields.
c
d
InCl3 (0.3 equiv), ClCH2CH2Cl (1 mL), 83 °C, 3 h. 1,4-
e
Dichlorobutane, 150 °C, 3 h. 2a (4 equiv), ClCH2CH2Cl (1 mL),
83 °C, 1 h.
ketone product 3bd in 92% yield (entry 3). This system was also
applicable to propargylic acetates possessing aliphatic alkyne
moieties. In particular, the cyclopropyl-substituted 2f provided
the desired product in an excellent yield (entries 4 and 5).
Unfortunately, a reaction using 2g did not afford the cor-
responding α,β-unsaturated aldehyde, and the starting materials
were recovered (entry 6). Secondary propargylic acetates 2h,
2i, and 2j reacted with alkyl chloride 1b to afford trisubstituted
olefin products 3bh, 3bi, and 3bj in 53%, 56%, and 30% yields,
respectively, with high E-selectivities (entries 7−9).19 The low
yield of the reaction using 3bj indicates that the steric hindrance
of the isopropyl group disturbed the reaction process. The
reaction using propargylic acetate 2k with an alkoxy acetylene
moiety successfully produced the corresponding α,β-unsaturated
ester 3bk in 74% yield (entry 10).
Both benzylic acetates and alcohols were applicable as
electrophiles (eqs 1−3).20 In particular, the reaction using
alkyl acetate 6 is noteworthy because the alkyl chloride that
corresponded to 6 was too unstable to be handled. This result
implies that the variety of products might be broadened by the
employment of alcohols and alkyl acetates.
Table 3 shows the results of the reactions for various
propargylic acetates 2. Propargylic acetates 2b and 2c furnished
the corresponding α,β-unsaturated ketones 3bb and 3bc in
99% and 91% yields, respectively (Table 3, entries 1 and 2).
Propargylic acetate 2d bearing a thiophene ring gave thienyl
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Letter
Table 3. Reaction of Diverse Propargylic Acetate 2 with
a
Alkyl Chloride 1b
Scheme 3. Plausible Mechanism
A plausible mechanism is shown in Scheme 3. First, InCl3
does not activate propargylic acetates 2 but activates alkyl
chloride 1 to generate carbocation 9. Carbocation 9 interacts
with propargylic acetate 2 to increase positive charge in the
alkyne moiety. Then, the electrophilic addition of 9 and the
nucleophilic addition of the intramolecular acetoxy group to
the alkyne moiety occur to give cation intermediate 10 (A).
The addition of a chloride anion to 10 provides oxyalkylated
intermediate 11. The coordination of the allylic oxygen atom
of 11 to InCl3 accelerates the cleavage of C−O bond to give
zwitterionic species 12. Then, the elimination of acetyl chloride
from 12 affords α-alkyl-α,β-unsaturated carbonyl compound 3,
and InCl3 is regenerated. It was observed the yield of acetyl
chloride was equivalent to that of enone 3aa (eq 5).22
a
Reaction conditions: 1b (0.5 mmol), 2 (1.0 mmol), InCl3 (0.05 mmol),
b
CH2Cl2 (1 mL), rt, 3 h. Yield by 1H NMR analysis. Values in
parentheses are isolated yields. 5 h. 40 °C. 30 min. E/Z = 85:15. 2
(2.5 mmol), rt, 30 min. E/Z = 93:7. E/Z = 77:23.
c
d
e
f
g
h
i
In conclusion, we have achieved the InCl3-catalyzed alkylative
transformation of propargylic acetates, which provided α-alkyl-
α,β-unsaturated carbonyl compounds. The novel usage of pro-
pargylic acetates as an α-acylvinyl anion equivalent has been
demonstrated. The employment of carbocations as coupling
partners, which were derived from alkyl chlorides, alcohols, and
alkyl acetates, led to the success of this reaction.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, full characterization of new products,
and copies of NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
The treatment of propargylic acetates 2a with InCl3 did
not give the corresponding allenyl acetates 8 and resulted in
the recovery of 2a in contrast with the rearrangement catalyzed
by Au, Pt, and Ag catalysts (eq 4).18,21 In addition, these
transition-metal catalysts did not cause the present alkylative
rearrangement (Table 1). These results imply that an allenyl
acetate intermediate was not involved in the reaction mechanism.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: baba@chem.eng.osaka-u.ac.jp.
Notes
The authors declare no competing financial interest.
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Letter
(13) Yu, Y.; Yang, W.; Rominger, F.; Hashmi, A. S. K. Angew. Chem.,
Int. Ed. 2013, 52, 7586−7589.
ACKNOWLEDGMENTS
■
This work was supported by the Ministry of Education,
Culture, Sports, Science and Technology (Japan). Y.O. thanks
JSPS Research Fellowships for Young Scientists.
(14) (a) Zhang, G.; Peng, Y.; Cui, L.; Zhang, L. Angew. Chem., Int. Ed.
2009, 48, 3112−3115. (b) Cui, L.; Zhang, G.; Zhang, L. Bioorg. Med.
Chem. Lett. 2009, 19, 3884−3887. (c) Collins, B. S. L.; Suero, M. G.;
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(15) Collins, B. S. L.; Suero, M. G.; Gaunt, M. J. Angew. Chem., Int.
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