Four component reaction of aldehydes, isocyanides, Me3SiN 3, and aliphatic alcohols catalyzed by indium triflate

Article abstract of DOI:10.1016/j.tetlet.2012.04.046

In the presence of catalytic amount of indium(III) Lewis acids, the four component reaction of aldehydes, isocyanides, trimethylsilyl azide and aliphatic alcohols smoothly proceeded to give alkoxylated 1H-tetrazole products in good yields. In particular,

Full text of DOI:10.1016/j.tetlet.2012.04.046

Tetrahedron Letters 53 (2012) 3161–3164
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Tetrahedron Letters
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Four component reaction of aldehydes, isocyanides, Me3SiN3, and aliphatic
alcohols catalyzed by indium triflate
⇑
⇑
Hikaru Yanai , Takuji Sakiyama, Tomoko Oguchi, Takeo Taguchi
School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 February 2012
Revised 4 April 2012
Accepted 11 April 2012
Available online 17 April 2012
In the presence of catalytic amount of indium(III) Lewis acids, the four component reaction of aldehydes,
isocyanides, trimethylsilyl azide and aliphatic alcohols smoothly proceeded to give alkoxylated 1H-tetra-
zole products in good yields. In particular, In(OTf)3 and In(ONf)3 showed notably high level of catalytic
activity in this reaction.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Indium triflate
Multi-component reaction
Isocyanide
Tetrazole
Isocyanide based multi-component reactions (MCRs) are known
as powerful strategies to synthesize compounds with structural
diversity.1 One of the most well-known examples of isocyanide
based MCRs is the reaction of aldehydes, isocyanides and
carboxylic acids (Eq. 1).2 This reaction, so-called Passerini three
component (P3C) reaction, becomes a key methodology to prepare
chemically stable, soft, and mild Lewis acids such as In(OTf)3 per-
form as suitable catalysts to develop new isocyanide based MCRs.10
R3
O
O
O
O
R2
N
C
ð1Þ
ð2Þ
H
N
R1
H
H
R3
OH
OH
R1
R2
a
-acyloxyamides.3 In general, the replacement of
a reaction
O
component in MCRs to a substrate having different reactive func-
tionalities provides a potential synthetic approach toward a new
class of compounds, which cannot be obtained by established
MCRs.4 Therefore, recent progress of isocyanide based MCRs using
alcoholic component has attracted much attention from synthetic
chemists. For example, El Kaim and co-workers reported that, in
the presence of nitrophenols instead of carboxylic acids, the reac-
O
In(OTf)3
O
t-Bu
N C
R1
NHt-Bu
R1
O
1
2
tion of aldehydes with isocyanides gave a-aryloxyamide products
As shown in Figure 1, direct alkylative P3C reaction is initiated
in moderate to good yields (arylative P3C reaction).5 Recently,
the successful replacement of the carboxylic acid component with
silyl ethers6 and silanols7 was also developed. Related to these
studies, we reported that indium(III) triflate [In(OTf)3] nicely cata-
lyzes the three component reaction of aldehyde 1, isocyanide, and
by the In(OTf)3-catalyzed carboxonium formation from aldehyde 1
and free aliphatic alcohol. Subsequent nucleophilic attack of isocy-
anide to the carboxonium ion A gives nitrilium intermediate B.11
Since the adduct C could not be isolated from the reaction mixture,
amide product 2 would then be formed via hydrolysis of B or
decomposition of C.6a On the basis of this reaction pathway, we
thought that irreversible addition of a fourth reaction component
would provide a novel class of products. It is easily expected that
the fourth reaction component should have higher reactivity com-
pared to water, but at the same time the reaction of this compo-
nent with carboxonium intermediate A has to be so slow or
reversible under the reaction conditions. Keeping these issues in
our mind, we adopted azide ion as an acceptable reaction compo-
nent. Ugi and Meyr reported that the reaction of aldehydes,
free aliphatic alcohol giving rise to
a-alkoxyamide product 2 in
good yield (direct O-alkylative P3C reaction) (Eq. 2).8 While the
classical P3C reaction is often carried out in alcoholic solvents un-
der acidic conditions, the formation of
a-alkoxyamides had not
been reported for a long time.9 Our investigation clearly shows that
⇑
Corresponding authors. Tel./fax: +81 426 76 3257 (H. Y).
E-mail addresses: yanai@toyaku.ac.jp (H. Yanai), taguchi@toyaku.ac.jp
(T. Taguchi).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.046

3162
H. Yanai et al. / Tetrahedron Letters 53 (2012) 3161–3164
O
O
O
i-PrOH, In(OTf)3
H2O
t-BuNC
H2O
t-Bu
O
NHt-Bu
R
C
R
H
R
R
H
N
O
carboxonium A
nitrilium B
1
2
Nu
fourth component
O
O
O
R
R
Nu
N
t-Bu
C (not isolated)
N
Novel MCRs
t-Bu
Figure 1. Reaction pathway of direct alkylative P3C reaction and working hypothesis for novel MCRs.
isocyanides, and hydrazoic acid instead of carboxylic acid compo-
nent gives 1H-tetrazoles via irreversible 1,3-dipolar cycloaddition
of hydrazoic acid to the nitrilium intermediate.12–14 We also re-
ported that the aliphatic acetals can be reversibly converted into
yield of 3a was improved by decreasing the loading of In(OTf)3 (en-
tries 2–4). Indeed, the tetrazole 3a was obtained in 78% yield by
using only 2 mol % of In(OTf)3 and the catalyst loading can be re-
duced to 1 mol % without the notable decrease in the product yield
(entries 3 and 4).16,17 In these cases, tert-butyl isocyanide was
added in two parts for effective consumption of aldehyde sub-
strate. When tert-butyl isocyanide was added in one portion, poor
conversion of aldehydes was observed due to competitive hydroly-
sis of isocyanide. After further investigations, we found that In(-
ONf)3 (Nf = n-C4F9SO2) shows the similar catalyst activity, but
InCl3 results in poor conversion of the starting materials (entries
5 and 6). This result demonstrates that strong Lewis acidity plays
a crucial role for the smooth conversion of starting materials. In
addition, other metal triflates such as Al(OTf)3, Sc(OTf)3, Yb(OTf)3,
and Bi(OTf)3 were not good catalysts for the present reaction (en-
tries 7–10) and the reaction in the absence of any metal triflates re-
sulted in no formation of tetrazole product 3a (entry 11).18 Since
In(III)-isocyanide complexes favorably dissociated to free isocya-
nides at high reaction temperature, it is not surprising that In(III)
salt works as a suitable Lewis acid catalyst for this reaction
system.19
the corresponding
a-azido ethers by treating with trimethylsilyl
azide and a catalytic amount of In(OTf)3.15
Herein we describe that, in the presence of In(III) Lewis acid cat-
alysts, the reaction of aldehydes, isocyanides, and trimethylsilyl
azide in alcoholic solvents smoothly proceeds to give highly substi-
tuted 1H-tetrazoles as the four component reaction products in
good yields. Furthermore, the intramolecular version using mixed
acetals as a
x-hydroxy aldehyde equivalent also yielded 1H-tetra-
zole products containing a cyclic ether structure in good to excel-
lent yields.
Initially, we examined the reaction of cinnamaldehyde, tert-bu-
tyl isocyanide, and trimethylsilyl azide in propan-2-ol as a model
reaction. Selected results are shown in Table 1. In the presence of
10 mol % of In(OTf)3, reaction of cinnamaldehyde 1a, 2 equiv of
tert-butyl isocyanide, 4 equiv of trimethylsilyl azide, and 1 equiv
of trimethyl orthoformate in propan-2-ol produced the amide 2a
as the alkylative P3C product in moderate yield along with a small
amount of the desired tetrazole 3a (entry 1). Interestingly, the
To determine the scope of this four component synthesis, we
conducted the reactions of several aldehydes under the optimized
conditions (Table 2). In the presence of 2.0 mol % of In(OTf)3, the
reaction of crotonaldehyde 1b, tert-butyl isocyanide, and trimeth-
ylsilyl azide afforded tetrazole 3b in 61% yield (entry 1). Likewise,
tetrazole 3c was obtained in 49% yield by the reaction of hex-2-
enal 1c (entry 2). Aromatic aldehydes such as benzaldehyde 1d,
4-substituted benzaldehyde derivatives 1e–1f, and 2-naphthalde-
hyde 1g were the nice reaction components to give the corre-
sponding tetrazoles 3d–3g in good yields (entries 3–6).20 This
reaction could be applied to not only tert-butyl isocyanide but also
secondary and primary alkyl isocyanides. For example, the reaction
of cinnamaldehyde 1a with isopropyl isocyanide in propan-2-ol
afforded the 1-isopropyl-1H-tetrazole 3i in 68% yield under similar
conditions (entry 8). In addition, the reactions with cyclohexyl iso-
cyanide and with benzyl isocyanide gave the corresponding tetra-
zoles 3j and 3k in good yields, respectively (entries 9 and 10). In
contrast, the reaction with less nucleophilic 2,6-dichlorophenyl
isocyanide resulted in selective formation of the corresponding
amide in moderate yield. We also examined the reactions in sev-
eral alcoholic solvents. By the reactions in secondary alcohols such
as cyclopentanol and cyclohexanol, the corresponding products
3m and 3n were obtained in 61% and 60% yields, respectively (en-
tries 11 and 12). The structure of cyclopentyloxy derivative 3m
was also confirmed by an X-ray crystallographic analysis (Fig. 2).
Likewise, the reactions in primary alcohols such as ethanol, propa-
nol, and 2-methylpropan-1-ol smoothly gave the tetrazole prod-
ucts 3o–3q in good yields in each case (entries 13–15).
Table 1
Survey of effective acid catalystsa
Acid catalyst
t-BuNC, Me3SiN3
HC(OMe)3
CHO
Ph
i-PrOH, 80 °C
1a
O
O
t-Bu
N
N
NHt-Bu
Ph
Ph
N
O
3a
2a
N
Entry
Acid catalyst (mol%)
Yieldb 3a (%)
2a (%)
1
2
3
4
5
6
7
8
9
In(OTf)3 (10)
In(OTf)3 (5.0)
In(OTf)3 (2.0)
In(OTf)3 (1.0)
In(OTf)3 (2.0)
InCl3 (2.0)
Al(OTf)3 (2.0)
Sc(OTf)3 (2.0)
Yb(OTf)3 (2.0)
Bi(OTf)3 (2.0)
None
18
49
78
77
72
57
34
51
55
37
0
40
30
15
12
10
<5
<5
<5
<5
<5
0
10
11
a
Reaction conditions: 1a (1.5 mmol), t-BuNC (2.0 equiv), Me3SiN3 (4.0 equiv),
HC(OMe)3 (1.0 equiv), i-PrOH (6.0 mL), 80 °C, 2–5 h. t-BuNC was added in two
portions.
b
Isolated yield.

H. Yanai et al. / Tetrahedron Letters 53 (2012) 3161–3164
3163
Table 2
Four component synthesis of 1H-tetrazolesa
In(OTf)3 (2.0 mol%)
R3
R1
R3
R1
R2
O
O
HC(OMe)3 (1.0 equiv)
NHR2
R1 CHO
R2 NC
N
Me3SiN3
R3OH, 80 °C, 2-6 h
N
(2.0 equiv) (4.0 equiv)
N
O
1
3
N
2
Entry
1
R1
R2
R3
Yieldb (%)
1
2
1b
1c
1d
1e
1f
1g
1a
1a
1a
1a
1a
1a
1a
1a
1a
CH@CHMe
CH@CHn-C3H7
Ph
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
CMe2CH2t-Bu
i-Pr
c-Hex
Bn
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
c-C5H9
c-C6H11
Et
n-Pr
i-Bu
3b
3c
3d
3e
3f
3g
3h
3i
61
2b
2c
2d
2e
2f
2g
2h
2i
6
3
7
3
8
7
49
70
62
74
72
45
68
64
60
61
60
64
58
63
3c
4c
4-MeOC6H4
4-MeC6H4
2-Naphthyl
CH@CHPh
CH@CHPh
CH@CHPh
CH@CHPh
CH@CHPh
CH@CHPh
CH@CHPh
CH@CHPh
CH@CHPh
5c
6c
7
8
9
10
11d
12d
13d
14d
15d
Trace
Trace
3
5
4
3j
2j
3k
3m
3n
3o
3p
3q
2k
2m
2n
2o
2p
2q
t-Bu
t-Bu
t-Bu
t-Bu
5
Trace
Trace
Trace
t-Bu
a
b
c
Isocyanides were added in two portions.
Isolated yield.
2.5 mol % of In(OTf)3 and 4.0 equiv of t-BuNC were used.
6.0 mol % of In(OTf)3 was used.
d
As shown in Figure 1, the present reaction would be initiated by
In(OTf)3-catalyzed carboxonium formation from aldehyde 1 and
free aliphatic alcohol.21 By subsequent addition of isocyanide to
carboxonium ion A, nitrilium intermediate B is formed. Then, step-
wise 1,3-dipolar cycloaddition of hydrazoic acid, which is gener-
ated by alcoholysis of trimethylsilyl azide, to nitrilium B would
yield tetrazole product 3. Considering the relationship between
catalyst loading and tetrazole/amide selectivity, we believe that a
small loading of In(OTf)3 plays an important role to inhibit the
decomposition of intermediate C to amide product 2. Thus, since
the use of relatively large amount of In(OTf)3 results in rapid
decomposition of C to amide 2, the yield of tetrazole was improved
by decreasing the loading of In(OTf)3. Actually, the reaction of
benzaldehyde dimethyl acetal, tert-butyl isocyanide, and trimeth-
ylsilyl azide in propan-2-ol gave an essentially same result (3d,
67% yield; 2d, 6% yield) compared to the reaction of benzaldehyde
(Table 2, entry 3). This fact also supports that amide 2 is competi-
tively formed via the decomposition of intermediate C.
Figure 2. ORTEP drawing from X-ray crystallography of 3m.
In summary, we rationally developed the four component reac-
tion of aldehydes, isocyanides, trimethylsilyl azide, and free ali-
phatic alcohols. On the basis of this reaction, 1H-tetrazoles with
structural diversity were easily synthesized. In the protic reaction
media, In(OTf)3 and In(ONf)3 worked as suitable catalysts. In addi-
tion, the In(III) salts can be used as Lewis acids in the presence of
relatively basic isocyanides. These results also suggest that chem-
ically stable, soft, and mild In(III) Lewis acids perform as good cat-
alysts for the isocyanide based MCRs. Further studies on this
reaction are in progress in our laboratory.
N
N
N
N
In(OTf)3 (1.0 mol%)
t-BuNC (2.0 equiv)
Me3SiN3 (4.0 equiv)
OMe
O
t-Bu
O
t-BuOH, 80 °C, 2 h
n
n
4a (n = 0)
4b (n = 1)
5a 73%
5b 80%
Scheme 1. Intramolecular type reaction of cyclic acetals.
Supplementary data
As shown in Scheme 1, intramolecular version of this reaction
Supplementary data associated with this article can be found, in
also successfully proceeded. For example, the reaction of mixed
acetal 4a, tert-butyl isocyanide, and trimethylsilyl azide was nicely
catalyzed by 1.0 mol % of In(OTf)3 to give the desired tetrazole 5a
in 73% yield. In this case, it should be noted that the addition of
orthoformate was not required and the corresponding amide prod-
uct was not obtained. Under the same conditions, six-membered
product 5b was obtained in 80% yield from 4b.
the
online
version,
at
http://dx.doi.org/10.1016/j.tetlet.
2012.04.046.
References and notes
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lL,
l
l
l
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(350.8 mg, 1.17 mmol). Colorless crystals (EtOAc); Mp. 40.0–41.0 °C; IR (KBr)
m
3083, 3028, 2976, 1599, 1496, 1093 cmꢀ1 1H NMR (400 MHz, CDCl3) d 1.22
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J = 16.1 Hz), 7.25–7.29 (1H, m), 7.30–7.37 (2H, m), 7.43 (2H, d, J = 8.6 Hz); 13C
NMR (100 MHz, CDCl3) d 21.6 and 23.0, 30.1, 62.1, 69.9, 71.5, 126.3, 126.9, 128.5,
128.7, 134.3, 135.6, 154.2; MS (ESI-TOF) m/z 301 [M+H]+; HRMS calcd for
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20. Since the reaction of 3-phenylpropanal as an aliphatic aldehyde substrate gave
a complex mixture, we could not isolate the desired tetrazole.
21. The addition of trimethyl orthoformate possibly accelerates the formation of
carboxonium ion A, and at the same time, it inhibits the hydrolysis of nitrilium
ion B.