Indium(III)-catalyzed coupling between alkynes and aldehydes to α,β-unsaturated ketones

Article abstract of DOI:10.1246/cl.2010.766

The combined use of a catalytic amount of InX₃ (X = OTf and NTf₂) and 1-butanol was found to be effective in formal alkynealdehyde metathesis. With this catalytic system, aromatic alkynes reacted with aromatic aldehydes to give chalcones in moderate to good yields. Alkynals were efficiently converted into 5- to 7-membered cyclic compounds by intramolecular alkyne-aldehyde coupling.

Full text of DOI:10.1246/cl.2010.766

doi:10.1246/cl.2010.766
766
Published on the web June 12, 2010
Indium(III)-catalyzed Coupling between Alkynes and Aldehydes to ¡,¢-Unsaturated Ketones
Katsukiyo Miura,*1 Kiyomi Yamamoto,2 Aya Yamanobe,2 Keisuke Ito,2 Hidenori Kinoshita,1 Junji Ichikawa,2 and Akira Hosomi2
1Department of Applied Chemistry, Graduate School of Science and Engineering,
Saitama University, Sakura-ku, Saitama 338-8570
2Department of Chemistry, Graduate School of Pure and Applied Sciences,
University of Tsukuba, Tsukuba, Ibaraki 305-8571
(Received May 6, 2010; CL-100441; E-mail: kmiura@apc.saitama-u.ac.jp)
Table 1. In(III)-catalyzed alkyne-aldehyde couplinga
The combined use of a catalytic amount of InX3 (X = OTf and
NTf2) and 1-butanol was found to be effective in formal alkyne-
aldehyde metathesis. With this catalytic system, aromatic alkynes
reacted with aromatic aldehydes to give chalcones in moderate to
good yields. Alkynals were efficiently converted into 5- to 7-
membered cyclic compounds by intramolecular alkyne-aldehyde
coupling.
In(OTf)3 (5 mol%)
BuOH (1 equiv)
O
O
R1
R2
+
R1
R
neat, 100 °C
0.5-2 h
R
H
1
R2
3
2
Entry R1
R2
R
Yield/%b,c
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
H (1a)
H
H
Ph (2a)
4-MeOC6H4 (2b)
4-BrC6H4 (2c)
Ph
Ph
Ph
Ph
73, 88d
52, 58d
58d
78
61
73
4
98
88
The Lewis acid-promoted coupling between alkynes and
aldehydes is known to form conjugated enones by cleavage of
the aldehyde C=O bond and formation of new C=C and C=O
bonds (eq 1).1-3 The conventional methods for this formal
alkyne-aldehyde metathesis require stoichiometric Lewis
acids.1,2 Recent interest has been focused on catalytic alkyne-
aldehyde metathesis.3 Several Lewis and Brønsted acids and
transition-metal compounds have been reported to act as the
catalyst, however there is much room to develop a new, efficient
catalytic system. We herein report that the combined use of a
catalytic amount of InX3 (X = OTf and NTf2) and 1-butanol
(BuOH) is effective in inter- and intramolecular coupling
between alkynes and aldehydes.4,5
4-MeOC6H4 H (1b)
4-MeC6H4
2-MeC6H4
4-CF3C6H4
Ph
H (1c)
H (1d)
H (1e)
Me (1f) Ph
Me c-Hex (2d)
Ph
aConditions: 1 (1.00 mmol), 2 (1.00 mmol), In(OTf)3 (0.05 mmol).
bIsolated yield. cE:Z = >98:2 (Entries 1-7). E:Z = 96:4 (Entry 8).
d
E:Z = 92:8 (Entry 9). With 1.50 mmol of 1.
Table 2. 13C NMR Data for 1a and 2a in CDCl3 at 25 °Ca
Ph C(1) C(2)
H
1a
PhC(3)HO 2a
Lewis acid
O
O
13C Chemical shifts (ppm)
R1
+
ð1Þ
Position
In(OTf)3b,d + BuOHe
R
H
R1
R
b,c
No additive
In(OTf)3
We initially found that the In(OTf)3-catalyzed reaction of
phenylacetylene (1a) with benzaldehyde (2a) without solvent
gave chalcone (3aa) in 35% yield. We then examined the effect
of additives on this coupling. When one equivalent of BuOH
was used, 3aa was obtained in 73% yield (Entry 1 in Table 1).6
An increased amount of 1a improved the yield.
The coupling with other aromatic aldehydes 2b and 2c gave
the corresponding enones 3 in moderate yields (Entries 2 and 3),
while the reaction with aliphatic aldehydes, c-HexCHO and
Ph(CH2)2CHO, resulted in a complex mixture of products under
the same conditions. Arylalkynes 1b-1d, bearing an electron-
donating group on the benzene ring, were as reactive as 1a
(Entries 4-6). In contrast, arylalkyne 1e, bearing an electron-
withdrawing group, was much less reactive than 1b-1d
(Entry 7). Similarly 1-dodecyne was quite insensitive to 2a.
Thus electron-rich, nucleophilic alkynes showed high reactivity
toward the alkyne-aldehyde coupling. 1-Phenyl-1-propyne (1f)
was more reactive than 1a. The coupling of 1f with aromatic and
aliphatic aldehydes proceeded efficiently under catalysis by
In(OTf)3 (Entries 8 and 9).7
C(1)
C(2)
C(3)
83.61
77.16
192.27
83.64
77.12
192.63
83.62
77.10
193.01
aA solution of 1a (0.05 mmol) and 2a (0.05 mmol) in CDCl3
(0.5 mL) was used for 67.7 MHz 13C NMR analysis. bIn(OTf)3
(0.05 mmol). Partially dissolved. Completely dissolved. BuOH
(0.25 mmol).
c
d
e
carbon C(3). Combined use of In(OTf)3 and BuOH enhanced the
downfield shift of C(3). These results suggest that In(OTf)3
should serve as a Lewis acid to activate aldehydes but not as a
³-Lewis acid to activate alkynes.8
Experiments using BuOD and deuterated phenylacetylene
(1a-d, >98%d) were also carried out to gain more mechanistic
insights. The In(OTf)3-catalyzed reaction of 1a with 2a in the
presence of BuOD gave 2-deuterated chalcone (3aa-d) with 36%
D-content (eq 2). The coupling between 1a-d and 2a without
BuOH proceeded in low yield with a slight loss of D-content.9
Use of BuOH effectively promoted the coupling, however, the
product D-content decreased largely (eq 3). Treatment of 3aa-d
(86%d) with BuOH (1 equiv) and In(OTf)3 (5 mol %) at 100 °C
for 1 h resulted in no erosion of the D-content. This indicates
that the D-H exchange takes place on the reaction pathway to
the metathesis product.
To clarify the role of In(OTf)3, we examined the effect of
In(OTf)3 on the 13C chemical shifts of 1a and 2a (Table 2).
Adding In(OTf)3 to a 1:1 solution of 1a and 2a in CDCl3 hardly
affected the chemical shifts of the sp-carbons C(1) and C(2). In
contrast, it brought about a downfield shift of the carbonyl
Chem. Lett. 2010, 39, 766-767
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

767
R1
H
In
In(OTf)3 (5 mol%)
BuOH (1 equiv)
Ph
In
O
1
In
Ph
O
RCHO
X
O
R1
R
X
2
CHO
R
H
A
H
5
In = In(OTf)3
BuOH*
path b
4a (X = CH2), CH2Cl2, rt, 24 h:
4b (X = O), Cl(CH2)2Cl, 60 °C, 1.5 h:
45%, 35%*
79%
path a
In
H*
H
In
BuO
R1
O
InX3 (5 mol%)
BuOH (1 equiv)
O
R
O
7
R1
R
R
CHO
R
CH2Cl2 (1 M)
B
H
D
6a (R = Ph), X = OTf, rt, 3 h:
6b (R = C6H4-4-OMe), X = OTf, rt, 1 h:
76%, 60%*
87%
In
In
O
O
6c (R = (E)-CH=CHPh), X = OTf, 0 °C, 14 h: 69%
O
BuO
R1
6d (R = n-C6H13), X = NTf2, reflux, 15 h:
92%
R
R1
R
− BuOH*
H
In(OTf)3 (5 mol%)
BuOH (1 equiv)
H H* C
Ph
Ph
− BuOH
− In
O
CHO
Cl(CH2)2Cl (0.1 M)
In
0.25 h, 80 °C
O
8
9
R1
R
72%
R1
R
*Without BuOH.
− In
H or H*
H*
3
Scheme 2. Cyclization of alkynals.
Scheme 1. Plausible reaction mechanisms.
In(NTf2)3 instead of In(OTf)3 effectively promoted the cycliza-
tion of 6d to 7d. The present reaction was also usable for the
construction of 7-membered carbocycle 9. Thus the InX3-BuOH
catalysis is valuable for the cyclization of flexible alkynals
bearing a methylene tether.
In conclusion, we have developed a new catalytic system for
the metathesis-type coupling of alkynes with aldehydes. The
combined use of indium Lewis acids and BuOH is effective in
the inter- and intramolecular coupling.4 We have proposed that
BuOH cooperatively serves for the C-C bond formation by
trapping the unstable intermediate A.10
In(OTf)3 (5 mol%)
O
BuOD (1 equiv)
+
2a
ð2Þ
ð3Þ
Ph
Ph
Ph
neat, 100 °C, 1 h
1a
D
3aa-d, 72%, 36%d
In(OTf)3 (5 mol%)
+
2a
3aa-d
Ph
D
neat, 100 °C, 1 h
Without BuOH:
1a-d
34%, 86%d
With BuOH (1 equiv): 64%, 53%d
References and Notes
The present reaction proceeds probably by two different
1
a) H. J. T. Bos, J. F. Arens, Recl. Trav. Chim. Pays-Bas 1963, 82,
845. b) H. Vieregge, H. J. T. Bos, J. F. Arens, Recl. Trav. Chim.
Pays-Bas 1959, 78, 664.
mechanisms, paths a and b: the former involves the action of
BuOH and the latter is promoted only by In(OTf)3 (Scheme 1).
In both cases, the first step is the In(OTf)3-promoted addition
of an alkyne 1 to an aldehyde 2, which reversibly forms
zwitterionic intermediate A. In path a, A irreversibly reacts with
BuOH. The resultant adduct B is cyclized to oxetane C by
intramolecular proton transfer and C-O bond formation. The
ring opening of C gives the product 3. In path b, 3 is formed by
cyclization-cycloreversion of A via oxetene D. The rate-
accelerating effect of BuOH suggests that path a should be the
major path. The irreversible reaction of A with BuOH would
lead to the successful coupling. The deuteration with BuOD
(eq 2) and the remarkable decrease of D-content with BuOH
(eq 3) can be well rationalized by path a. The difference
between the BuOD-mediated reaction of 1a and the BuOH-
mediated reaction of 1a-d in the D-content of 3aa-d is probably
due to the presence of path b as the minor path.
2
3
a) A. Hayashi, M. Yamaguchi, M. Hirama, Synlett 1995, 195. b) G.
S. Viswanathan, C.-J. Li, Tetrahedron Lett. 2002, 43, 1613.
a) M. Curini, F. Epifano, F. Maltese, O. Rosati, Synlett 2003, 552. b)
J. U. Rhee, M. J. Krische, Org. Lett. 2005, 7, 2493. c) P. O. Miranda,
D. Díaz, J. I. Padrón, M. A. Ramírez, V. S. Martín, J. Org. Chem.
2005, 70, 57. d) K. Tanaka, K. Sasaki, K. Takeishi, K. Sugishima,
Chem. Commun. 2005, 4711. Alkyne-ketone coupling: e) T. Jin, Y.
Yamamoto, Org. Lett. 2007, 9, 5259.
4
Hanzawa and co-workers have reported that the combined use of
SbF5 (10 mol %) and EtOH (1 equiv) is effective in the tandem
alkyne-aldehyde metathesis-Nazarov cyclization, and that SbF5-
EtOH may serve as a protic catalyst. A. Saito, M. Umakoshi, N.
Yagyu, Y. Hanzawa, Org. Lett. 2008, 10, 1783.
5
6
Li and Viswanathan have reported that In(OTf)3 itself is not effective
in the metathesis-type coupling. See ref. 2b.
The results with other alcohols are as follows. Alcohol (yield of 3aa/
%): MeOH (60), EtOH (64), i-PrOH (64), 1-hexanol (68). Catalytic
use of BuOH (0.1 equiv) gave 3aa in 56% yield.
The In(OTf)3-catalyzed metathesis reaction was applied to
the cyclization of alkynals (Scheme 2).3b,3d The reaction of 4a in
CH2Cl2 at room temperature gave the desired product 5a. The
yield decreased without BuOH. Alkynal 4b, having an ether
group, was efficiently cyclized to cyclic ether 5b. Alkynals 6a-
6c were smoothly cyclized to cyclohexenyl ketones 7a-7c under
mild conditions, while alkynal 6d was hardly cyclized. Use of
7
8
The high reactivity of 1f has been reported in refs. 3a and 3b.
T. Tsuchimoto, T. Maeda, E. Shirakawa, Y. Kawakami, Chem.
Commun. 2000, 1573.
The loss of D-content may be due to adventitious water or TfOH.
They possibly react with intermediate A as BuOH does (path a in
Scheme 1).
9
10 Supporting Information is available electronically on the CSJ-
Journal Web site, http://www.csj.jp/journals/chem-lett/index.html.
Chem. Lett. 2010, 39, 766-767
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/