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
1
Department of Applied Chemistry, Graduate School of Science and Engineering,
Saitama University, Sakura-ku, Saitama 338-8570
2
Department 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)

InX3 (5 mol%)
BuOH (1 equiv)
R1R2R3+RCHO

R1neat, 100 °C
X = OTf, NTf 2R
R2R3as above( )nCHOn = 1-3O

CH2Cl2 or Cl(CH 2)2Cl0-80 °C( )nO

REPRINTED FROM

Vol.39 No.7

2010 p.766–767
CMLTAG
July 5, 2010

The Chemical Society of Japan
Published on the web June 12, 2010; doi:10.1246/cl.2010.766

doi:10.1246/cl.2010.766
Published on the web June 12, 2010766

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
1
Department of Applied Chemistry, Graduate School of Science and Engineering,
Saitama University, Sakura-ku, Saitama 338-8570
2
Department 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)
The combined use of a catalytic amount of InX3 (X = OTf andNTf2) 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 togood yields. Alkynals were eﬃciently converted into 5- to 7membered cyclic compounds by intramolecular alkyne­aldehyde
coupling.

The Lewis acid-promoted coupling between alkynes andaldehydes is known to form conjugated enones by cleavage ofthe aldehyde C=O bond and formation of new C=C and C=O
bonds (eq 1).1­3 The conventional methods for this formal
alkyne­aldehyde metathesis require stoichiometric Lewis
acids.1,2 Recent interest has been focused on catalytic alkyne­aldehyde metathesis.3 Several Lewis and Brønsted acids andtransition-metal compounds have been reported to act as thecatalyst, however there is much room to develop a new, eﬃcient
catalytic system. We herein report that the combined use of acatalytic amount of InX3 (X = OTf and NTf2) and 1-butanol(BuOH) is eﬀective in inter- and intramolecular coupling
between alkynes and aldehydes.4,5

Table 1. In(III)-catalyzed alkyne­aldehyde couplinga
R1R2+

12
3
4
5
6
7
8
9R1+RHOR1

ð1ÞR

We initially found that the In(OTf)3-catalyzed reaction ofphenylacetylene (1a) with benzaldehyde (2a) without solvent
gave chalcone (3aa) in 35% yield. We then examined the eﬀectof 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 andPh(CH2)2CHO, resulted in a complex mixture of products under
the same conditions. Arylalkynes 1b­1d, bearing an electrondonating group on the benzene ring, were as reactive as 1a(Entries 4­6). In contrast, arylalkyne 1e, bearing an electronwithdrawing group, was much less reactive than 1b­1d(Entry 7). Similarly 1-dodecyne was quite insensitive to 2a.
Thus electron-rich, nucleophilic alkynes showed high reactivity
toward the alkyne­aldehyde coupling. 1-Phenyl-1-propyne (1f)
was more reactive than 1a. The coupling of 1f with aromatic andaliphatic aldehydes proceeded eﬃciently under catalysis byIn(OTf)3 (Entries 8 and 9).7To clarify the role of In(OTf)3, we examined the eﬀect ofIn(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 hardlyaﬀected 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, 766­767

R1R

2

R1

R2

R

Yield/%b,cPhPh
Ph
4-MeOC6H4
4-MeC6H4
2-MeC6H44-CF3C6H4Ph
Ph

H (1a)H
H
H (1b)
H (1c)
H (1d)
H (1e)Me (1f)
MePh (2a)4-MeOC6H4 (2b)4-BrC6H4 (2c)
Ph
Ph
Ph
Ph
Ph
c-Hex (2d)73, 88d52, 58d58d
78
61
73
498
88

H

23 RaConditions: 1 (1.00 mmol), 2 (1.00 mmol), In(OTf)3 (0.05 mmol).
Isolated yield. cE:Z = >98:2 (Entries 1­7). E:Z = 96:4 (Entry 8).
E:Z = 92:8 (Entry 9). dWith 1.50 mmol of 1.
bTable 2. 13C NMR Data for 1a and 2a in CDCl3 at 25 °Ca
Ph C(1)

Lewis acid

OO

neat, 100 °C
0.5-2 hR

1EntryIn(OTf) 3 (5 mol%)
BuOH (1 equiv)

OC(2)H 1aPhC(3)HO2a13

Position
C(1)
C(2)
C(3)

C Chemical shifts (ppm)

No additiveIn(OTf)3b,cIn(OTf)3b,d + BuOHe

83.61
77.16
192.27

83.64
77.12
192.6383.62
77.10
193.01A 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). cPartially dissolved. dCompletely dissolved. eBuOH(0.25 mmol).
acarbon C(3). Combined use of In(OTf)3 and BuOH enhanced thedownﬁeld shift of C(3). These results suggest that In(OTf)3should serve as a Lewis acid to activate aldehydes but not as a³-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 thepresence 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, theproduct 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 indicatesthat the D­H exchange takes place on the reaction pathway tothe metathesis product.

© 2010 The Chemical Society of Japanwww.csj.jp/journals/chem-lett/

767
InRCHO2OR
In = In(OTf) 3R1InH1RH*O

R1R1RH BORRH

H H* CPhCHO− In− BuOH
InOR1R

R1− In*Without BuOH.

+Ph

2aneat, 100 °C, 1 h

1aOPhPhð2Þ

D
3aa-d, 72%, 36%dPhD
1a-d+In(OTf)3 (5 mol%)
2aneat, 100 °C, 1 h

3aa-d

ð3Þ

Without BuOH:
34%, 86%dWith BuOH (1 equiv): 64%, 53%d

The present reaction proceeds probably by two diﬀerent
mechanisms, paths a and b: the former involves the action ofBuOH and the latter is promoted only by In(OTf)3 (Scheme 1).
In both cases, the ﬁrst step is the In(OTf)3-promoted additionof 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 C­O bond formation. The
ring opening of C gives the product 3. In path b, 3 is formed bycyclization­cycloreversion of A via oxetene D. The rateaccelerating eﬀect of BuOH suggests that path a should be themajor 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 BuOHmediated reaction of 1a-d in the D-content of 3aa-d is probably
due to the presence of path b as the minor path.
The In(OTf)3-catalyzed metathesis reaction was applied tothe 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 6a­6c were smoothly cyclized to cyclohexenyl ketones 7a­7c under
mild conditions, while alkynal 6d was hardly cyclized. Use ofChem. Lett. 2010, 39, 766­767

O776%, 60%*
87%
69%
92%

In(OTf)3 (5 mol%)
BuOH (1 equiv)

PhO
972%

Scheme 2. Cyclization of alkynals.

Scheme 1. Plausible reaction mechanisms.
In(OTf)3 (5 mol%)
BuOD (1 equiv)R

Cl(CH2)2Cl (0.1 M)
0.25 h, 80 °C

8R
H or H*3

H*

InX3 (5 mol%)
BuOH (1 equiv)

6a (R = Ph), X = OTf, rt, 3 h:
6b (R = C6H4-4-OMe), X = OTf, rt, 1 h:
6c (R = (E )-CH=CHPh), X = OTf, 0 °C, 14 h:
6d (R = n -C6H13), X = NTf2, reflux, 15 h:In

1− BuOH* R

45%, 35%*
79%

CH2Cl2 (1 M)

H D

InOO

RCHO

RO
54a (X = CH2), CH2Cl2, rt, 24 h:
4b (X = O), Cl(CH2)2Cl, 60 °C, 1.5 h:

InO

In

PhX

CHO

path bpath aIn(OTf)3 (5 mol%)
BuOH (1 equiv)X

H A
BuOH*BuO
R1Ph

R1H

BuO

InO

In(NTf2)3 instead of In(OTf)3 eﬀectively promoted the cyclization of 6d to 7d. The present reaction was also usable for theconstruction of 7-membered carbocycle 9. Thus the InX3­BuOH
catalysis is valuable for the cyclization of ﬂexible alkynals
bearing a methylene tether.
In conclusion, we have developed a new catalytic system forthe 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 C­C bond formation bytrapping the unstable intermediate A.10
References and Notes
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.
2 a) A. Hayashi, M. Yamaguchi, M. Hirama, Synlett 1995, 195. b) G.
S. Viswanathan, C.-J. Li, Tetrahedron Lett. 2002, 43, 1613.
3 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 ofSbF5 (10 mol %) and EtOH (1 equiv) is eﬀective in the tandem
alkyne­aldehyde metathesis­Nazarov 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 Li and Viswanathan have reported that In(OTf)3 itself is not eﬀectivein the metathesis-type coupling. See ref. 2b.
6 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.
7 The high reactivity of 1f has been reported in refs. 3a and 3b.
8 T. Tsuchimoto, T. Maeda, E. Shirakawa, Y. Kawakami, Chem.
Commun. 2000, 1573.
9 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).
10 Supporting Information is available electronically on the CSJJournal Web site, http://www.csj.jp/journals/chem-lett/index.html.

© 2010 The Chemical Society of Japanwww.csj.jp/journals/chem-lett/