Nucleophilic substitution of secondary alkyl-substituted propargyl acetates: An economic and practical indium trichloride catalyzed access

Article abstract of DOI:10.1055/s-0030-1259557

An economic and practical transformation from secondary alkyl-substituted propargyl acetates to a variety of nucleophilic substitution products was described. This reaction was catalyzed by inexpensive InCl₃. High yields and excellent chemosele

Full text of DOI:10.1055/s-0030-1259557

LETTER
665
Nucleophilic Substitution of Secondary Alkyl-Substituted Propargyl Acetates:
An Economic and Practical Indium Trichloride Catalyzed Access
N
ucleophilic Substitut
i
S
n
econdar
y
A
lkyl-S
u
L
bstituted
P
ropa
i
rgyl
A
c
n
etates , Lu Hao, Xiao-tao Liu, Qing-zhen Chen, Feng Wu, Ping Yan, Su-xia Xu, Xin-liang Chen, Jia-jie Wen,
Zhuang-ping Zhan*
Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, Fujian, P. R. of China
Fax +86(592)2180318; E-mail: zpzhan@xmu.edu.cn
Received 25 December 2010
was limited to the construction of C–N bond. According-
Abstract: An economic and practical transformation from second-
ly, development of more economic, practical as well as
ary alkyl-substituted propargyl acetates to a variety of nucleophilic
general catalytic system for the substitution reaction of
secondary alkyl-substituted propargyl derivatives was
substitution products was described. This reaction was catalyzed by
inexpensive InCl3. High yields and excellent chemoselectivity were
obtained. The five-, six-, and seven-membered propargyl cyclo- highly desired.
ethers were also successfully constructed by this protocol.
Our recently reported iron(III) catalytic system provides
Key words: propargyl acetate, nucleophilic substitution, indium,
propargyl cycloether
an economic, practical, and efficient access to obtaining
propargyl derivatives. Propargyl alcohols 1 undergo
smooth conversion to the substitution products 3 but are
mainly limited to aryl- or tertiary alkyl-substituted prop-
argyl alcohols (Scheme 1, equation 1).9 This method
would be of even greater appeal if it was applicable to sec-
ondary alkyl-substituted propargyl systems, broadening
the scope of propargyl substrates. Thus, as a result of the
exploration in our group,10 herein we report the inter- and
intramolecualr nucleophilic substitution reaction of sec-
ondary alkyl-substituted propargyl acetates with a wide
range of nucleophiles (Scheme 1, equation 2).
The Lewis acid catalyzed propargyl nucleophilic substitu-
tion has turned into an important organic transformation,
as it provides a reliable and direct approach to a variety of
propargyl products.1 As a consequence, considerable at-
tention has been paid to develop efficient conditions for it
over the past decade. However, since the propargyl cation
is generally less stable than its allyl analogue,2 the vast
majority of studies are limited to the employment of sub-
strates possessing strong cation-stabilizing groups in the
propargyl position: aryls or dialkyls in almost all cases;3
and dicobalt complexes in the well-known Nicholas reac-
tion.4 Examples of nucleophilic substitution of secondary
alkyl-substituted propargyl substrates remain very limit-
ed.
Initial attempt on the FeCl3-catalyzed reaction between
readily available 4 and ethanol in MeCN failed (Table 1,
entry 1). On the basis of literature reports, the transforma-
tion undergoes an ionization (SN1) mechanism: a propar-
gyl cation intermediate was generated in the reaction
mixture prior to substitution. Thus, solvent effect came
into play as a dominant factor of stabilizing the propargyl
cation during charge separation of the transition state. To
test our hypothesis, we replaced MeCN with MeNO2 as
the solvent, which was generally considered stabilizing
carbocations more efficaciously but coordinating with
Lewis acid catalysts more weakly.
Recently, Gevorgyan et al. described an efficient
B(C6F5)3-catalyzed allylation of secondary alkyl-substi-
tuted propargyl acetates with allylsilanes.5 This pioneer
method allowed for the facile synthesis of 1,5-enynes in
good to high yields with excellent functionality tolerance.
Subsequently, in 2008, Brabander and co-workers dem-
onstrated a Pt(II)-catalyzed intramolecular cycloetherifi-
cation of secondary alkyl-substituted propargyl alcohol
derivatives.6 Also, Yoshimatsu et al. reported a Sc(OTf)3-
catalyzed substitution reaction of the phenylsulfanyl and
phenylselanyl propargyl alcohols.7 Despite the advantag-
es of those works, the high price of catalysts or the narrow
substrate scope was somewhat problematic, preventing
their practical and large-scale utilization. Very recently, a
cost-effective InCl3-catalyzed three-component coupling
of aldehydes, alkynes, and amines (A3 coupling) produc-
ing propargyl amines via C–H activation was reported by
Wang and co-workers.8 Nevertheless, Wang’s method
ref. 9 (1)
OH
Nu
FeCl3
R1
R2
R1
R2
+
NuH
C, O, N and S nucleophiles
R3
R3
2
1
3
41–95%
this
(2)
OAc
work
Nu
InCl3, MeNO2
+
NuH
Alkyl
Alkyl
65–93%
C, O, N and S nucleophiles
R
R
R = alkyl, aryl, alkenyl
Scheme 1 Formation of propargyl derivatives by metallic Lewis
acid catalyzed nucleophilic substitution reactions
SYNLETT 2011, No. 5, pp 0665–0670
x
x.
x
x.
2
0
1
1
Advanced online publication: 11.02.2011
DOI: 10.1055/s-0030-1259557; Art ID: W20510ST
© Georg Thieme Verlag Stuttgart · New York

666
M. Lin et al.
LETTER
Table 1 Initial Results and Catalyst Optimizationa
Table 2 Screening of Reaction Solventsa
OEt
OEt
n-Bu
n-Bu
n-Bu
Ph
Ph
Ph
catalyst
OAc
7b
InCl3
OAc
7b
(5 mol%)
(5 mol%)
n-Bu
+
n-Bu
+
EtOH
(3.0 equiv)
solvent
EtOH
(3.0 equiv)
solvent
n-Bu
Ph
Ph
4
4
Ph
5
5
Reactions conditions Yield (%)b
Entry Catalyst
Reaction conditions
Yield (%)b
Entry
Solvent
7b
0
5
7b
0
5
1
2
FeCl3
FeCl3
BiCl3
ZnCl2
AlCl3
InCl3
MeCN, 70 °C, 10 h
MeNO2, 70 °C, 20 min
MeNO2, 70 °C, 5 h
MeNO2, 70 °C, 10 h
MeNO2, 70 °C, 20 min
MeNO2, 70 °C, 20 min
MeNO2, reflux, 12 h
MeNO2, 70 °C, 1 h
MeNO2, reflux, 12 h
MeNO2, reflux, 12 h
MeNO2, 70 °C, 20 min
MeNO2, 80 °C, 4 h
MeNO2, 80 °C, 4 h
MeNO2, reflux, 10 h
MeNO2, reflux, 10 h
0
1
2
3
4
5
6
MeCN
DMF
reflux, 24 h
reflux, 24 h
reflux, 24 h
reflux, 10 h
reflux, 3 h
reflux, 10 h
36
0
49
58
59
53
86
0
41
25
12
37
0
0
3
DMSO
CH2Cl2
DCE
0
0
4
67
75
0
0
5
0
6
1,4-dioxane
0
a All reactions were carried out on a 0.5 mmol scale using 5 mol% of
InCl3, 3 equiv of EtOH under reflux conditions.
b Isolated yields.
7
RuCl3·3H2O
Cu(OTf)2
Zn(OTf)2
AgOTf
0
8
60
0
19
0
9
well as the elimination product in moderate yields
(Table 1, entries 8 and 11). On the basis of the results
shown above, we chose InCl3 as the catalyst for this prop-
argyl substitution.
10
11
12
13
14
15
18
67
61
43
0
0
Bi(OTf)3
TMSOTf
BF3·OEt2
CF3COOH
MeCOOH
26
24
26
0
The next solvent search demonstrated that replacement of
MeNO2 with less polar MeCN afforded only elimination
product (36%; Table 2, entry 1). Conversely, the more po-
lar DMF and DMSO resulted in neither desired product
7b nor elimination product 5 (Table 2; entries 2 and 3). It
was reasoned the catalytic activity of InCl3 was dramati-
cally suppressed by the strong coordination of DMF or
DMSO with the metal, although the cation-stabilizing
ability of MeNO2 was not efficient as those of DMF and
DMSO. Dichloromethane and 1,2-dicholoroethane exhib-
ited a similar chemoselectivity as MeNO2 despite lower
yields (67% and 75%, respectively; Table 2, entries 4 and
5). 1,4-Dioxane did not give any product (Table 2, entry
6).
0
0
a All reactions were carried out on a 1 mmol scale using 5 mol% of
catalyst, 3 equiv of EtOH at appropriate temperature.
b Isolated yields.
Gratifyingly, the use of MeNO2 at 70 °C substantially im-
proved the reaction outcome (49%; Table 1, entry 2), but
with poor chemoselectivity (41% of elimination product
5). Then, we scanned a variety of Lewis acids for the most
effective catalyst (Table 1). The screening results dis-
closed the InCl3 to be more efficient than any other cata-
lyst (86%; Table 1, entry 6). Neutral and covalent Lewis
acids such as AlCl3 and BF3 gave similar yields and
chemoselectivity as FeCl3 did (Table 1, entries 5 and 13).
Brønsted acids, including trifluoroacetic acid and acetic
acid had no effect on this substitution (Table 1, entries 14
and 15). Trifluoromethanesulfonate salts, such as
Cu(OTf)2, Zn(OTf)2, AgOTf, and Bi(OTf)3, were consid-
ered having stronger Lewis acidity and better catalytic ac-
tivity than corresponding halogen analogues by virtue of
the very strong electron-withdrawing property of trifluo-
romethanesulfonate anion. However, these catalysts
showed very different results, among which only
Cu(OTf)2 and Bi(OTf)3 afforded the desired product as
Examination of catalysts and solvents indicated that the
combination of InCl3 and MeNO2 was a reasonably effi-
cient catalytic system for the nucleophilic substitution of
secondary alkyl-substituted propargyl acetates. Impor-
tantly, compared with other combinations, no elimination
product was obtained, and higher yield was achieved.
Next, the generality of this nucleophilic transformation
was examined. We were pleased to find this transforma-
tion to be very general for a wide range of propargyl ace-
tates and nucleophiles (Table 3). Importantly, the reaction
proceeded smoothly without exclusion of moisture and
air. High yields and selectivity were observed in most cas-
es examined. Alkyne parts, bearing phenyl (Table 3, en-
tries 1–15), alkyl (Table 3, entries 16–19), and alkenyl
Synlett 2011, No. 5, 665–670 © Thieme Stuttgart · New York

LETTER
Nucleophilic Substitution of Secondary Alkyl-Substituted Propargyl Acetates
667
Table 3 InCl3-Catalyzed Nucleophilic Substitution of Propargyl
(Table 3, entries 20–24) substituents, underwent smooth
conversions upon treatment with a series of nucleophiles.
Primary and secondary alkyl alcohols, propargyl and ben-
zyl alcohols reacted well to furnish the propargyl ethers in
69–87% yields within one hour.
Acetates a (continued)
OAc
Nu
InCl3 (5 mol%)
AcOH
+
+ NuH
R2
R1
R1
MeNO2
conditions
R2
6
7
The terminal triple bond and bromo functionalities were
perfectly tolerated under the reaction conditions (Table 3,
entries 11, 19, and 22). Carbon nucleophiles, such as allyl-
trimethylsilane, showed higher reactivity and required
milder reaction conditions (Table 3, entries 1, 8, and 20).
Interestingly, the ambident nucleophiles involving naph-
thalen-2-ol and phenol resulted in complete Friedel–
Crafts arylated products 7g and 7m without any oxygen-
substituted products observed (Table 3, entries 7 and 13).
We also extended this protocol to heteroaromatic nucleo-
philes including furan. The a-substituted products 7n and
7w were given in good yields (Table 3, entries 14 and 23).
Metallic Lewis acid catalyzed substitution of propargyl
alcohols with thiols had been generally considered diffi-
cult to achieve, in large part because sulfur-containing
compounds were catalyst poisoning caused by the strong
coordination nature of sulfur atom. However, by using our
method, the construction of sp3 C–S bond was successful-
ly fulfilled with several representative nucleophiles
(Table 3, entries 3, 4, and 15). Propargylic acetate pos-
sessing an aryl substituent on the alkyne part reacted rap-
idly with benzenethiol affording the corresponding aryl
sulfide ether 7c in excellent yield with complete regiose-
lectivity (Table 3, entry 3). Finally, selected amides also
acted as an efficient nucleophile to provide the N-propar-
gyl sulfonamides in excellent yields and a clean formation
of two sulfonamides 7e and 7q were obtained in 92% and
91% yields, respectively (Table 3, entries 5 and 17). Un-
fortunately, the propargylation did not occur under these
conditions when acetamides, anilnes, and piperidine were
used as nucleophiles.
Entry Product
Conditions
Yield (%)b
79
Ph
S
3
50 °C, 0.5 h
n-pent
Ph
7c
OH
S
4
70 °C, 0.5 h
r.t., 0.5 h
65
92
n-pent
Ph
Ph
7d
H
Ts
N
5
n-pent
7e
OMe
6
35 °C, 0.4 h
88
86
n-pent
Ph
7f
HO
7
50 °C, 0.5 h
n-pent
Ph
7g
Table 3 InCl3-Catalyzed Nucleophilic Substitution of Propargyl
Acetates a
8c
r.t., 0.5 h
91
84
OAc
Nu
InCl3 (5 mol%)
Ph
AcOH
+
+ NuH
R2
R1
R1
7h
MeNO2
conditions
R2
O
6
7
9
70 °C, 0.5 h
Entry Product
Conditions
Yield (%)b
93
Ph
7i
1c
r.t., 0.5 h
n-pent
O
Ph
10
70 °C, 1.0 h
70 °C, 0.5 h
69
87
7a
Ph
Ph
O
7j
2
70 °C, 0.4 h
86
n-pent
O
Ph
11
7b
7k
Synlett 2011, No. 5, 665–670 © Thieme Stuttgart · New York

668
M. Lin et al.
LETTER
Table 3 InCl3-Catalyzed Nucleophilic Substitution of Propargyl
Table 3 InCl3-Catalyzed Nucleophilic Substitution of Propargyl
Acetates a (continued)
Acetates a (continued)
OAc
Nu
OAc
Nu
InCl3 (5 mol%)
InCl3 (5 mol%)
AcOH
AcOH
+
+ NuH
R2
+
+ NuH
R1
R1
R1
R1
MeNO2
conditions
MeNO2
conditions
R2
R2
R2
6
7
6
7
Entry Product
Conditions
Yield (%)b
85
Entry Product
Conditions
r.t., 0.5 h
Yield (%)b
O
Ph
12
70 °C, 0.5 h
20c
89
Ph
7l
OH
7t
O
Ph
13
70 °C, 0.5 h
83
83
21
22
50 °C, 0.5 h
82
85
Ph
Ph
7u
7m
Br
O
O
14
70 °C, 0.5 h
50 °C, 0.5 h
7n
7v
S
10
O
15
70 °C, 0.5 h
70 °C, 1.0 h
79
81
Ph
23
70 °C, 0.5 h
80
7o
O
16
7w
n-pent
OMe
n-Bu
7p
H
Ts
N
24
40 °C, 0.5 h
83
17
70 °C, 0.4 h
91
86
n-pent
n-Bu
7q
OMe
7x
a Reaction conditions: propargyl acetate (0.5 mmol), nucleophile (1.5
mmol), InCl3 (5 mol%), MeNO2 (2.0 mL).
18
50 °C, 0.4 h
b Isolated yields based on propargyl acetates 6.
c The allyltrimethylsilane was used as the nucleophile.
Propargyl cycloethers have received much attention in re-
cent years, and many synthetic and natural propargyl cyc-
loesters have displayed important biological activity or
been used as synthetic precursors.11 Although a number of
methods are available for their synthesis, the development
of general and efficient synthetic methodologies is still
highly attractive. Thus, we investigated the efficacy of in-
tramolecular cyclization toward five-, six-, and seven-
membered propargyl cycloethers by this method
(Table 4). To our delight, it was found that propargyl cy-
cloethers could be synthesized in moderate to excellent
7r
Br
O
19
50 °C, 0.5 h
84
7s
Synlett 2011, No. 5, 665–670 © Thieme Stuttgart · New York

LETTER
Nucleophilic Substitution of Secondary Alkyl-Substituted Propargyl Acetates
669
Denis, J. M. J. Am. Chem. Soc. 1974, 96, 5855. (c) Richey,
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87, 1381.
Table 4 Synthesis of Propargyl Cycloethers via InCl3-Catalyzed
Intramolecular Nucleophilic Substitution of Propargyl Acetatesa
OAc
OH
O
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InCl3 (5 mol%)
MeNO2, 60 °C, 1 h
n
n
R
R
8'
8
Product
8a
R
n
Yield (%)b
Ph
Ph
Ph
0
1
2
0
1
91
89
68
90
88
8b
8c
8d
cyclohex-1-en-1-yl
cyclohex-1-en-1-yl
8e
a Reaction conditions: propargyl acetate (1.0 mmol), InCl3 (5 mol%),
MeNO2 (2.0 mL).
b Isolated yields.
yields under mild reaction conditions. As can be seen
from Table 4, the yields of expected products from phe-
nyl- or cyclohexenyl-substituted propargyl acetates are of
slight difference in the formation of five- and six-mem-
bered propargyl cycloethers 8a,b,d,e, while the yield of
seven-membered product decrease dramatically, leading
to a moderate yield of 8c.12,13
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In summary, we have developed an economic, general,
and highly practical method for both intermolecular and
intramolecular nucleophilic substitution of secondary
alkyl-substituted propargyl acetates with a wide range of
nucleophiles, which provides an expeditious and efficient
route to various propargyl compounds. This work also
represents a valuable complement to existing procedures
for the synthesis of propargyl derivatives. Further studies
to extend the scope of synthetic utility for this InCl3-cata-
lyzed substitution reaction are in progress in our laborato-
ry.
(9) Zhan, Z.; Yu, J.; Liu, H.; Cui, Y.; Yang, R.; Yang, W.; Li, J.
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We gratefully acknowledge the financial support of the National
Natural Science Foundation of China (No. 21072159) and the Sci-
ence & Technology Bureau of Xiamen (No. 3502Z20093007).
(h) Fujimoto, K.; Aizawa, S.; Oota, I.; Chiba, J.; Inouye, M.
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References and Notes
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Synlett 2011, No. 5, 665–670 © Thieme Stuttgart · New York

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LETTER
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temperature until the reaction was completed as monitored
by TLC. The reaction mixture was cooled down to r.t., and
the solvent was removed under reduced pressure. Then the
residue was purified by flash chromatography on silica gel to
afford the substitution product.
(13) General Procedure B for the Intramolecular
Substitution Reactions of Alkyl-Substituted Propargyl
Acetates
(12) General Procedure A for the Intermolecular
Substitution Reactions between Alkyl-Substituted
Propargyl Acetates and Nucleophiles
To a 5 mL flask were successively added propargyl acetate
(1.0 mmol), MeNO2 (2 mL) and anhyd InCl3 (12 mg, 0.05
mmol) at r.t. Then, the mixture was magnetically stirred at
60 °C for 1 h. The reaction mixture was cooled down to r.t.,
and the solvent was removed under reduced pressure. The
residue was purified by flash chromatography on silica gel to
afford the intramolecular substitution product.
To a 5 mL flask were successively added propargyl acetate
(0.5 mmol, 1.0 equiv), nucleophile (1.5 mmol, 3.0 equiv),
MeNO2 (2 mL) and anhyd InCl3 (6 mg, 0.025 mmol) at r.t.
Then, the mixture was magnetically stirred at appropriate
Synlett 2011, No. 5, 665–670 © Thieme Stuttgart · New York

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