Indium(III) triflate catalyzed tandem azidation/1,3-dipolar cycloaddition reaction of ω,ω-dialkoxyalkyne derivatives with trimethylsilyl azide

Article abstract of DOI:10.1016/j.tetlet.2005.10.053

The azidation reaction of dialkyl acetal derivatives with trimethylsilyl azide (TMSN₃) was efficiently catalyzed by 1-5 mol % of In(OTf) ₃. The major product differed depending on the substrate structure and molar ratio of TMSN₃

Full text of DOI:10.1016/j.tetlet.2005.10.053

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8639–8643
Indium(III) triflate catalyzed tandem
azidation/1,3-dipolar cycloaddition reaction of
x,x-dialkoxyalkyne derivatives with trimethylsilyl azide
Hikaru Yanai and Takeo Taguchi*
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received 21 September 2005; revised 14 October 2005; accepted 17October 2005
Abstract—The azidation reaction of dialkyl acetal derivatives with trimethylsilyl azide (TMSN
3
) was efficiently catalyzed by 1–
, that is, aliphatic
5
mol % of In(OTf) . The major product differed depending on the substrate structure and molar ratio of TMSN
3
3
acetals provided a-azido ether derivatives, while aromatic acetal (benzaldehyde dimethyl acetal) provided gem-diazide, respectively.
Furthermore, novel tandem azidation/1,3-dipolar cycloaddition reaction using alkynyl acetal derivatives gave bicyclic triazolo-het-
erocyclic compounds, recognized as chemically modified aza-sugar analogues, in high yields under mild conditions.
ꢀ
2005 Published by Elsevier Ltd.
1
. Introduction
which is well known as a typical example of Ôclick chem-
6
,7
istryÕ. Most of such copper-catalyzed reactions so far
6
b,7
Recently, 1,2,3-triazolo-heterocyclic compounds, in par-
ticular sugar analogues having triazole moiety, are
attracting much attention in medicinal chemistry field.
This is due to the fact that oligosaccharides play impor-
tant roles in many cellular functions and some of this
class of compounds have been reported to possess inter-
esting inhibitory activities against glycosidases. For
the synthesis of these triazole modified sugar deriva-
tives, copper-catalyzed cycloaddition reaction of azide
with an acetylenic compound is an efficient method,
reported are intermolecular versions,
although an
intramolecular reaction should provide a powerful meth-
od for the synthesis of structurally different analogues
difficult to obtain by an intermolecular reaction, in par-
ticular polycyclic fused triazole derivatives. Preparation
of an azide compound from unsaturated sulfonate and
1
2
,3
NaN followed by thermal intramolecular cycloaddition
3
8
has been known as a conventional protocol (Scheme 1).
4
,5
However, since most of the reported examples have
employed alkene moiety as a dipolarophile, thereby
R1
Y
R1
N3
1,3-dipolar
R1
N N N
X
N
N
N
X
X
azidation
cycloaddition
R2
R2
R2
Y = Leaving group
OR1
OR1
N N
TMSN3
OR1
X
X
present reaction
N
Lewis acid
R2
R2
Scheme 1.
Keywords: Indium(III) triflate; Azidation; 1,3-Dipolar cycloaddition; Tandem reaction; Triazolo-heterocyclic compounds.
*
Corresponding author. Tel./fax: +81 426 76 3257; e-mail: taguchi@ps.toyaku.ac.jp
0040-4039/$ - see front matter ꢀ 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.10.053

8640
H. Yanai, T. Taguchi / Tetrahedron Letters 46 (2005) 8639–8643
resulting in the formation of unstable triazolin deriva-
tives, product yields did not always meet at the expected
levels. Low yield in the conversion of triazolin into tri-
azole usually achieved by base or oxidizing reagent has
also been a problem to be solved. Moreover, due to the
thermally labile nature of organic azide compounds, it
is desirable for the reaction to proceed under mild
conditions.
(entries 3–5 vs 6). While aliphatic acetal 1a gave a-azido
ether 2a highly predominantly, in the case of aromatic
acetal 1b ratio of gem-diazide compound 3b over
mono-azide 2b increased depending on the amount of
TMSN used. That is, reaction of 1b with 1.1 equiv of
3
TMSN catalyzed by 0.5 mol % In(OTf) provided a
3
3
mixture of 2b and 3b in 44% yield, and the mono-azide
3b was the major product (2b:3b = 3.3:1, entry 7). How-
ever, as shown in entry 9, an excellent yield and highly
selective formation of gem-diazide 3b was observed in
the reaction with 2.0 equiv TMSN3 and 1 mol %
In(OTf)3.
According to one of our ongoing research projects, we
have been developing new synthetic methods using
conceptually unique Lewis acids. We have reported on
9
,10
novel bidentate Lewis acids
In(OTf) ] in aqueous media
or indium(III) triflate
1
1
[
for intramolecular
3
Diels–Alder reactions of ester-tethered substrates. Fur-
ther studies were undertaken to develop Lewis acid cat-
alyzed tandem azidation and 1,3-dipolar cycloaddition
3. Tandem azidation/1,3-dipolar cycloaddition reaction
As mentioned above, selective mono-azidation efficiently
1
2,13
of unsaturated acetal compounds with TMSN3.
In
proceeded in In(OTf) catalyzed reaction of aliphatic
3
this letter, we report that efficient tandem azidation
and 1,3-dipolar cycloaddition reaction of various x,x-
dialkoxy alkyne derivatives leading to the achievement
of the fused triazole derivatives by the use of In(OTf)3
as a Lewis acid.
acetal with TMSN giving rise to a-azido ether deriva-
tive. Based on these results, to develop tandem azida-
tion/1,3-dipolar cycloaddition reaction, we examined
3
the reaction of TMSN with x,x-dialkoxyalkyne deriva-
3
tives having an aliphatic acetal moiety and 1,3-dipolaro-
phile moiety. Results are summarized in Table 2.
2
. Azidation of dimethyl acetal derivatives
In the presence of 5 mol % In(OTf) , reaction of TMSN
3
3
(1.5 equiv) with dimethylacetal having ynone moiety 4a
Using 1,1-dimethoxyhexane 1a and TMSN as model
(R = COPh) was conducted at room temperature for
3
substrates, azidation reaction was conducted in the pres-
ence of various Lewis acids (Table 1). As shown in entry
30 min, then at 50 ꢁC for 3 h providing triazolopyridine
1
4
derivative 5a in 75% yield (entry 1) (Fig. 1). As a Lewis
1
, in the presence of 1 mol % In(OTf) , reaction of 1a
acid, Sc(OTf) and Bi(OTf) were found to be as effective
3
3
3
with 1.1 equiv TMSN in CH Cl proceeded at room
as In(OTf) (entries 3 and 4). Contrary to these, InCl or
3
2
2
3
3
temperature within 7h to give a-azido ether 2a along
with the formation of a small amount of gem-diazide
Yb(OTf) worked less effectively to give the product 5a
3
in moderate yields, 48% and 43%, respectively, along
with the recovery of 4a (entries 2 and 5). From these re-
sults and due to its moisture-insensitive and thermally
stable nature as well as its relatively low price, we used
3
a (81% yield, 2a:3a = >20:1). Increase in molar ratio
of TMSN to 2 equiv resulted in shortening the reaction
3
period (3 h at room temperature) and higher product
yield of 2a (91%), while any appreciable increase in the
gem-diazide 3a was not observed (entry 2). InCl3,
Sc(OTf) and Yb(OTf) showed similar catalytic activi-
1
5
In(OTf) in the following experiments.
3
To see the substituent effect on the reactivity, such
substrates having alkanoyl, ester, hydrogen and trimeth-
ylsilyl group on the acetylenic moiety 4b–f were used.
3
3
ties to that of In(OTf) , but under similar conditions
3
Bi(OTf)3 resulted in a somewhat lower yield of 2a
Table 1. Lewis acid catalyzed azidation of acetal derivatives (1a,b) with TMSN
3
TMSN3
Lewis acid
OMe
N3
N3
OMe
OMe
R
CH Cl
R
R
N3
2
2
1
a: R = n-C H
2
3
5
11
1
b: R = Ph
a
b
Entry
1
Lewis acid (mol %)
TMSN
3
(equiv)
Temperature (ꢁC)
Time (h)
Yield (%)
Ratio (2:3)
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1b
1b
1b
In(OTf)
In(OTf)
3
(1.0)
(1.0)
1.1
2.0
2.0
2.0
2.0
2.0
1.1
2.0
2.0
rt
rt
781
3
77 >20:1
783
77 >20:1
759
2
2
2
>20:1
c
3
91
>20:1
InCl
Sc(OTf)
Yb(OTf)
3
(1.0)
rt
rt
rt
rt
0
9
9
3
(1.0)
(1.0)
>20:1
>20:1
3
Bi(OTf)
In(OTf)
In(OTf)
In(OTf)
1
3
3
3
3
(1.0)
(0.5)
(0.5)
(1.0)
c
44
70
98
3.3:1
1:4.6
1:8.2
c
0
0
c
a
b
c
Yield was calculated by H NMR.
Ratio of mono-azide 2 and gem-diazide 3 was determined by H NMR.
1
Isolated yield.

H. Yanai, T. Taguchi / Tetrahedron Letters 46 (2005) 8639–8643
8641
Table 2. Tandem azidation/1,3-dipolar cycloaddition reaction of diethyl malonates (4) with TMSN
3
OMe
Lewis acid (5 mol%)
TMSN3 (1.5 eq)
OMe
OMe
EtO C
2
∆
N
N
N
EtO C
EtO C
2
2
EtO C
2
R
ClCH CH Cl
2
2
rt, 30 min
R
4
5
a
Entry
4
R
Lewis acid
In(OTf)
InCl
Sc(OTf)
Bi(OTf)
Yb(OTf)
Temperature (ꢁC)
Time (h)
5
Yield (%)
1
2
3
4
5
6
7
8
9
4a
4a
4a
4a
4a
4b
4c
4d
4e
4f
COPh
COPh
COPh
COPh
COPh
COCH
CO
H
SiMe
CF
CF
3
50
50
50
50
50
50
50
7
3
3
3
3
3
4
9
0
0
8
36
5a
5a
5a
5a
5a
5b
5c
5d
5e
5f
75
48
b
3
3
78
73
53
3
c
3
2
CH
2
Ph
In(OTf)
In(OTf)
In(OTf)
In(OTf)
In(OTf)
In(OTf)
3
3
3
3
3
3
81
72
2
Et
48 72
3
7
50
rt
20 93
38
d
1
1
0
1
2
Br
Br
4f
2
5f
60
a
b
c
Isolated yield.
Recovery of 4a, 37%.
Recovery of 4a, 32%.
d
Complex mixture was obtained.
Next we examined the effect of tether moiety linking
dimethyl acetal part and ynone part. Results are sum-
marized in Table 3. Compared to substrate 4a, the reac-
tion of one carbon-shortened substrate 4g at 50 ꢁC for
3
h gave the cyclized product 5g in 71% yield accom-
panying the formation of unidentified side products.
Improvement was not realized by lowering the reaction
temperature (room temperature) to give 5g in only 21%
yield. In both cases, the diastereomer ratio was 1.3:1
consisting of trans isomer as a major isomer determined
Figure 1. X-ray structure of 5a.
1
1
by 2D NMR experiment ( H– H COSY, HSQC,
1
6
HMBC and NOESY) (Scheme 3).
Under the similar conditions for 4a (entry 1), the alka-
noyl derivative 4b (R = COCH CH Ph) showed similar
Ether tethered substrates 6a and 6b also reacted
smoothly to give triazolooxazine derivatives 7a,b in
good yield (entries 3 and 4). It is noted that terminal
alkyne substrate 6b reacted much faster than the malon-
ate derivatives 4b shown in Table 2 (70 ꢁC, 48 h, 72%
from 4b to 5b vs 50 ꢁC, 17h, 75 % from 6b to 7b). Three
types of amino-tethered substrates 8a,b and 8c–d were
employed. N-Benzyl derivative 8a had a disappointing
result to give the cyclized product 9a in only a trace
amount, instead, several side reactions including 1,4-
addition of azide to ynone moiety predominantly
2
2
reactivity to give the cyclized product 5b in 81% yield
entry 6). The ester derivative 4c (R = CO Et) showed
(
2
lower reactivity requiring a longer reaction time (50 ꢁC,
9
h), to give the cyclized product 5c in 72% yield (entry 7).
Compared to the substrates 4a–c having an electron
deficient 1,3-dipolarophile part, the reactivity of termi-
nal alkyne 4d (R = H) and TMS-substituted substrate
4
e (R = SiMe ) decreased so much that a higher temper-
3
ature and much longer reaction time were needed. That
1
7
is, after 48 h at 70 ꢁC, 4d gave the cyclized product 5d in
occurred (entry 5). In the case of N-Boc derivative
8b, the removal of the Boc group was also accompanied
during the tandem reaction giving rise to the amino-free
7
2% yield and 4e gave 5e in 93% yield after 20 h at 70 ꢁC
(
entries 8 and 9). It is well documented that introduction
0
of fluorine atom into molecules often exerts an increase
in biological activity or enhancement of lipophilicity.
We examined the reaction using bromodifluoromethyl-
ated substrate 4f, since this group in the product 5f
would be expected to be utilized for further elaboration
of a variety of fluorinated derivatives. When optimized
reaction conditions (50 ꢁC) were employed, reaction
proceeded rather sluggishly to give the cyclized product
triazolopyridine derivative 9 in 39% yield (entry 6).
Reaction with N-tosyl derivative 8c proceeded smoothly
to give the cyclized product 9c in 87% yield (entry 7).
Likewise, N-4-nitrobenzenesulfonyl derivative 9d gave
an essentially similar result (entry 8).
Regarding the reaction pathway, the present tandem
reaction possibly involves In(OTf) catalyzed formation
3
5
(
f in only 38% yield. Although it took a longer period
36 h), room temperature reaction provided 5f in reason-
able yield (60%, entries 10 and 11).
of a-azido ether followed by the intramolecular 1,3-
dipolar cycloaddition to give fused triazolo derivatives.
As shown in Scheme 2, a-azido ether 10 was isolated

8642
H. Yanai, T. Taguchi / Tetrahedron Letters 46 (2005) 8639–8643
Table 3. Tandem azidation/1,3-dipolar cycloaddition reaction of various x,x-dialkoxyalkynes with TMSN
3
OR1
OR1
In(OTf)3 (5 mol%)
TMSN3 (1.5 eq)
∆
OR1
N
X
N
N
X
ClCH CH Cl
2
2
R2
rt, 30 min
R2
a
b
Entry
Substrates (4, 6, 8)
Temperature (ꢁC)
Time (h)
Products (5, 7, 9)
Yield (%)
dr
OMe
OMe
1
2
4g
50
rt
3
48
5g
5g
71
21
1.3:1
1.3:1
BnOCH2
OMe
N
N
N
4g
BnO
O
COPh
COPh
OEt
N
OEt
3
4
5
6a
50
50
7
2
N
7a
7b
9a
83
7
—
O
OEt
N
COPh
COPh
OEt
OEt
OEt
6b
17
5
—
O
N
N
N
O
OMe
OMe
BnN
N
c
8a
8b
0
48
N
N
Trace
—
—
BnN
OMe
COPh
COPh
OEt
OEt
OEt
HN
N
6
50
12
N
N
9b
39
BocN
COPh
COPh
OEt
OEt
OEt
R
N
N
N
N
7
8
8c R = Ts
8d R = 4-Ns
50
50
4
4
9c
9d
87—
87—
R
N
COPh
COPh
a
b
c
Isolated yield.
1
Ratio of diastereomers was determined by H NMR of the crude mixture.
Michael addition product was isolated in 28% yield.
OMe
MeO
MeO
N
N
In(OTf)3 (5 mol%)
OMe
N
N
In(OTf)3 (5 mol%)
CDCl , rt, 3 h
TMSN3 (1.5 eq)
EtO2C
EtO2C
N3
EtO C
N
N
2
OMe
SiMe3
EtO C
2
ClCH CH Cl
2
2
3
COPh
COPh
rt, 1 h
BnO
BnO
SiMe3
4e
10 42%
5g-cis
5g-trans
cis : trans = 4 : 1
cis : trans = 1 : 4
OMe
EtO C
2
∆
N
N
N
Scheme 3.
EtO C
2
SiMe3
e quant.
5
In conclusion, we found that the azidation reaction of
dialkoxy acetal derivatives with TMSN is efficiently
3
Scheme 2.
catalyzed by 1–5 mol % of In(OTf) . Using a variety of
3
x,x-dialkoxy acetylenic compounds as a substrate, bi-
cyclic 1,2,3-tirazolo-heterocyclic compounds could be
obtained in good yield through sequential azidation
and the intramolecular 1,3-dipolar cycloaddition reac-
tion. The present tandem reaction provides a convenient
and general method for the preparation of triazole-fused
cyclic compounds, some of which could be applied as
aza-sugar analogues.
when the azidation reaction was conducted at room
temperature.
Upon heating this isolated azide derivative 10 (70 ꢁC,
2
0 h), cyclized product 5e was formed in a quantitative
yield.

H. Yanai, T. Taguchi / Tetrahedron Letters 46 (2005) 8639–8643
8643
Acknowledgements
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1
The authors would like to thank Mr. H. Fukaya for the
X-ray crystallographic analysis.
1
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3
10 lmol) in 1,2-dichloroethane (1.5 mL), TMSN (41 lL,
3
0.35 mmol) and a solution of 4a (79.3 mg, 0.20 mmol) in
1,2-dichloroethane were added at room temperature. After
being stirred for 30 min, the resulting mixture was stirred
for 3 h at 50 ꢁC. The reaction mixture was quenched by
H O (3 mL) and extracted with CHCl (3 mL · 3). The
2
2
3
organic layer was washed with brine, dried over MgSO4
and evaporated under reduced pressure. The residue was
purified by column chromatography on silica gel (hexane–
EtOAc = 3:1) to give diethyl 3-benzoyl-7-methoxy-6,7-
dihydro[1,2,3]triazolo[1,5-a]pyridine-5, 5(4H)-dicarboxyl-
ate 5a (60.0 mg, 0.15 mmol, 75% yield) as colourless
3
4
7
805; (b) Mitchell, M. L.; Tian, F.; Lee, L. V.; Wong,
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ꢀ
1
. For examples of 1,3-dipolar cycloaddition reactions of
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1
1475, 1234. H NMR (400 MHz, CDCl ): d 1.21 (3H, t,
3
J = 7.1 Hz), 1.25 (3H, t, J = 7.1 Hz), 2.62 (1H, dd,
J = 14.7, 4.1 Hz), 2.43 (1H, ddd, J = 14.7, 2.6, 1.0 Hz),
3.26 (1H, d, J = 18.6 Hz), 3.57(3H, s), 4.13–4.28 (5H, m),
5.77 (1H, dd, J = 3.8, 3.0 Hz), 7.48 (2H, t, J = 8.1 Hz),
5
5
1
3
5
6
7.55–7.60 (1H, m), 8.41 (2H, br d, J = 8.1 Hz). C NMR
(100.6 MHz, CDCl ): d 13.7, 13.8, 27.8, 33.9, 49.5, 58.1,
3
62.0, 62.3, 85.6, 128.2, 130.5, 132.9, 136.9, 138.1, 142.4,
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4
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169.1, 169.6, 186.6. ESI-MS m/z: 402 [M+H] . HRMS
+
calcd for C H N O [M+H] : 402.1665. Found:
2
0
24
3
6
402.1689. The structure of 5a was confirmed by X-ray
crystallographic analysis (Fig. 1). Crystallographic data
have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication No. CCDC
284177. Copies of the data can be obtained, free of charge,
on application to the Director, CCDC (e-mail: deposit@
ccdc.cam.ac.uk).
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7
8
15. It has been reported that Bi(OTf)3 is moisture sensitive
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. Recently, synthesis of bicyclic triazoles from sequential
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16. Each isomer 5g-cis or 5g-trans was treated with In(OTf)3
aziridine using TMSN
3
and the intramolecular 1,3-dipolar
in CDCl for 3 h at room temperature to reveal that the
3
cycloaddition between alkyne and azide has been reported.
Kim, M. S.; Yoon, H. J.; Lee, B. K.; Kwon, J. H.; Lee, W.
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epimerization of N,O-acetal moiety occurs to some extent.
That is, under these conditions 5g-cis gave a 4:1 mixture of
the cis/trans isomer, while 5g-trans gave a cis/trans
mixture in a ratio of 1:4. These results indicate that
In(OTf)3 can catalyze the epimerization of N,O-acetal
moiety of the cyclized product 5g (Scheme 3).
9
. For examples of intramolecular Diels–Alder reaction, see:
(
a) Saito, A.; Ito, H.; Taguchi, T. Org. Lett. 2002, 4,
4
2
619; (b) Saito, A.; Yanai, H.; Taguchi, T. Tetrahedron
004, 60, 12239; (c) Saito, A.; Yanai, H.; Sakamoto, W.;
17. It was reported that c-alkoxy a,b-ynoate derivatives are
Takahashi, K.; Taguchi, T. J. Fluorine Chem. 2005, 126,
09.
0. For an example of intermolecular Diels–Alder reaction,
highly reactive substrates for 1,4-addition with N anion:
3
7
Laksmipathi, P.; Rao, A. V. R. Tetrahedron Lett. 1997, 38,
2551, in fact, the reaction of N-benzyl substrate 8a and
TMSN without In(OTf) gave the 1,4-adduct in 61% yield
1
see: Saito, A.; Yanai, H.; Taguchi, T. Tetrahedron Lett.
3
3
2
004, 45, 9439.
(70 ꢁC, 48 h).