Azidation vs [3?+?2]-cycloaddition: Chemoselective reaction of sodium azide towards o-alkynylaldehydes for the synthesis of N-heterocycles

Article abstract of DOI:10.1016/j.tetlet.2019.06.022

The chemoselective synthesis of functionalized azido- and triazolo-containing nitrogen heterocycles using sodium azide and o-alkynylaldehydes has been described. The azidation reaction was preferred in acetonitrile while the [3 + 2]-cycloaddition was favored in DMSO. Furthermore, the azido-pyranoquinolines were employed for the synthesis of benzonaphthyridines via the Staudinger reaction at room temperature.

Full text of DOI:10.1016/j.tetlet.2019.06.022

Tetrahedron Letters xxx (xxxx) xxx
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Tetrahedron Letters
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Azidation vs [3 + 2]-cycloaddition: Chemoselective reaction of sodium
azide towards o-alkynylaldehydes for the synthesis of N-heterocycles
⇑
Pradeep Kumar, Vineeta Garg, Akhilesh K. Verma
Department of Chemistry, University of Delhi, Delhi 110007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The chemoselective synthesis of functionalized azido- and triazolo-containing nitrogen heterocycles
using sodium azide and o-alkynylaldehydes has been described. The azidation reaction was preferred
in acetonitrile while the [3 + 2]-cycloaddition was favored in DMSO. Furthermore, the azido-pyra-
noquinolines were employed for the synthesis of benzonaphthyridines via the Staudinger reaction at
room temperature.
Received 24 April 2019
Revised 10 June 2019
Accepted 11 June 2019
Available online xxxx
Ó 2019 Published by Elsevier Ltd.
Keywords:
Azidation
Cycloaddition
Chemoselective
o-Alkynylaldehydes
Introduction
Organic azides are an important functional group for the syn-
thesis of N-containing compounds due to their unique reactivity
[1]. Their application in azide/alkyne [3 + 2]-cycloaddition and
the Staudinger reaction unambiguously demonstrate their utility
in various research fields [2]. Furthermore, the presence of the
azide moiety in organic compounds can enhance their biological
activities. Representative bioactive azido compounds include
azidothymidine (AZT), azidocillin, and colecoxib derivatives
(Fig. 1) [3].
Figure 1. Representative azide-containing drugs.
Results and discussion
The activation of unsaturated functionalities by polarised
reagents such as halonium ions represents one of the most com-
mon strategies to prepare carbocycles and heterocycles [4,5]. In
2012, Zhu and co-workers reported iodo-triazole formation from
azides and alkynes using NaI as an iodinating reagent (Scheme 1,
i) [6]. Electrophilic cyclization reactions of o-alkynyl aldehydes
using various nucleophiles have been previously reported
(Scheme 1, ii) [4]; however, the application of azides as a nucle-
ophile towards carbonyl centers remains challenging. Despite the
availability of numerous methods for the synthesis of organic
azides [7,8], the direct azidation [9] of carbonyl groups is rare. Con-
sidering our recent report [10], and our interest in alkynylaldehyde
chemistry [11], herein we report the chemoselective azidation and
[3 + 2]-cycloaddition of o-alkynylaldehydes using sodium azide
(Scheme 1, iii).
Optimization of the reaction conditions was achieved by initially
examining the model reaction of 2-(p-tolylethynyl)quinoline-3-car-
baldehyde 1a in the presence of NaN3 (2.0 equiv.), iodine (2.5 equiv.)
and K2CO3 (2.5 equiv.), in acetonitrile at 70 °C for 0.5 h; the desired
azidation product 2a was obtained in 87% yield (Table 1, entry 1).
Decreasing the amount of iodine and K2CO3 from 2.5 equiv. to 1.0
equiv. provided product 2a in 48% yield (Entry 2). Next we increased
the amount of K2CO3 to 2.5 equiv. keeping the amount of iodine
unchanged which gave 40% yield of the desired product 2a (Entry
3). Further, 2.5 equiv. of iodine with 1.0 equiv. of K2CO3 provided
the azidated product 2a in 50% yield (Entry 4). Among the various
solvents screened for the reaction, DMSO and DMF provided triazole
product 4a in 26% and 20% yield, respectively (Entries 5–6). The use
of methanol provided 1-azido-4-iodo-3-(p-tolyl)-1H-pyrano[4,3-b]
quinoline11c 2a’ as the sole product (Entry 7). The reaction in the
absence of both iodine and K2CO3 gave an increased yield of product
⇑
Corresponding author.
E-mail address: averma@acbr.du.ac.in (A.K. Verma).
https://doi.org/10.1016/j.tetlet.2019.06.022
0040-4039/Ó 2019 Published by Elsevier Ltd.
Please cite this article as: P. Kumar, V. Garg and A. K. Verma, Azidation vs [3 + 2]-cycloaddition: Chemoselective reaction of sodium azide towards o-alkyny-
laldehydes for the synthesis of N-heterocycles, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.06.022

2
P. Kumar et al. / Tetrahedron Letters xxx (xxxx) xxx
Scheme 1. i) Triazole formation in the presence of NaI; ii) Electrophilic cyclization of o-alkynyl aldehydes with various (C-, N-, O-)4 nucleophiles; iii) Chemoselective
azidation vs [3 + 2]-cycloaddition.
Table 1
Optimization of the reaction conditions.a,b
Entry
NaN3 (equiv.)
I2 (equiv.)
K2CO3 (equiv.)
Solvent
Temp (oC)
Time (h)
Yield 2a (%)b
Yield 4a (%)b
1
2
3
4
5
6
7
8
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.5
1.5
2.5
1.0
1.0
2.5
2.5
2.5
2.5
–
–
–
–
–
2.5
1.0
2.5
1.0
2.5
2.5
2.5
–
–
–
–
–
MeCN
MeCN
MeCN
MeCN
DMSO
DMF
MeOH
DMSO
DMSO
DMSO
MeCN
DMSO
MeCN
70
70
70
70
70
70
70
70
0.5
6.0
6.0
6.0
6.0
6.0
6.0
6.0
24
24
24
24
0.5
87
48
40
50
–
–
–
–
c
-
-
26
20
c
d
–
–
–
–
–
–
80
-
56
64
74
9
90
10
11
12
13
120
120
120
70
e
-
67
–
2.5
2.5
a
b
c
Reagents and conditions: 1a (0.50 mmol), NaN3, I2, K2CO3, solvent (2.0 mL).
Isolated yield.
Trace amounts of 2a was formed.
4-Iodo-1-methoxy-3-phenyl-1H-pyrano[4,3-b]quinoline was formed in 67% yield.
Trace amounts of 4a was formed.
d
e
4a (56%) at 70 °C for 6 h (Entry 8). An improvement in the yield was
observed when the temperature was increased to 90 °C (Entry 9).
Further increasing the temperature to 120 °C provided product 4a
in 74% yield (Entry 10). The reaction in MeCN provided product 4a
in trace amounts (Entry 11). Decreasing the amount of the azide
source from 2.0 equiv. to 1.5 equiv. gave lower yields of product
4a (Entry 12). Similarly, the yield of product 2a was also lower with
1.5 equiv. of the azide source (Entry 13). On the basis of the above
results, we concluded that iodine in acetonitrile was the best
conditions for azidation (Entry 1). However, the absence of iodine
in DMSO was suitable for the [3 + 2]-azide alkyne cycloaddition
(Entry 10).
With the optimized reaction conditions in hand, we next
explored the scope of the reaction for the synthesis of azido-
iodo-pyranoquinolines 2a-k and pyranopyridines 2l-m using
o-alkynylaldehydes 1a-m possessing electron-releasing, electron-
withdrawing, hetero-aromatic and aliphatic groups on the alkyne
(Table 2). The reaction of substrates 1a-b bearing p-Me- and
m-OMe-substituted alkynes afforded the desired product 2a-b in
87% and 85% yield, respectively (Entries 1 and 2). The structure of
Please cite this article as: P. Kumar, V. Garg and A. K. Verma, Azidation vs [3 + 2]-cycloaddition: Chemoselective reaction of sodium azide towards o-alkyny-
laldehydes for the synthesis of N-heterocycles, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.06.022

P. Kumar et al. / Tetrahedron Letters xxx (xxxx) xxx
3
Table 2
Synthesis of azido-iodo-pyranoquinolines and pyranopyridines.a,b
Table 2 (continued)
Entry Substrate 1
Product 2
Yield
(%)b
1h
2h
9
92
1i
2i
1i
2i
10
90
Entry Substrate 1
Product 2
Yield
(%)b
1
87
1j
2j
1j
2j
11
64
85
2a
1a
1a
2a
2
85
1k
2k
1k
2k
12c
2b
2c
2d
1b
1c
1d
1b
2b
2c
2d
3
86
88
90
2l
1l
1l
2l
13c
88
1c
4
2m
1m
1m
2m
a
Reagents and conditions: 1a (0.50 mmol), NaN3 (2.0 equiv.), I2 (2.5 equiv.),
K2CO3 (2.5 equiv.), solvent (2.0 mL).
1d
b
Isolated yield.
5
c
Reaction time 12 h. CCDC No of product 2b 1582016.
1e
1f
2e
2f
1e
2e
6
86
1f
2f
7
70
1g
1h
2g
2h
1g
2g
8
72
Scheme 2. Synthesis of azido-bromo-pyranoquinolines. aReagents and conditions:
1
(0.50 mmol), NBS (2.5 equiv.), K2CO3 (2.5 equiv.), NaN3 (2.0 equiv.), MeCN
(2.0 mL), 70 °C, 6 h. bIsolated yield.
Please cite this article as: P. Kumar, V. Garg and A. K. Verma, Azidation vs [3 + 2]-cycloaddition: Chemoselective reaction of sodium azide towards o-alkyny-
laldehydes for the synthesis of N-heterocycles, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.06.022

4
P. Kumar et al. / Tetrahedron Letters xxx (xxxx) xxx
Table 3
gave product 2g in 70% yield (Entry 7). The sterically hindered
Chemoselective [3 + 2]-cycloaddition reactions.
alkyne 1h gave product 2h in 72% yield (Entry 8), while substrates
1i-j gave products 2i and 2j in 92% and 90% yield, respectively
(Entries 9 and 10). To our delight, the reaction of o-alkynyl alde-
hyde 2-(3,3-dimethylbut-1-yn-1-yl)-6-methoxy quinoline-3-car-
baldehyde 1k possessing an aliphatic alkyne gave product 2k in
64% yield (Entry 11). Pyrido o-alkynyl aldehydes were also well tol-
erated and gave products 2l-m in 85–88% yield (Entries 12 and 13).
After successful activation of the alkyne by molecular iodine,
further attention was paid to the reactivity of N-bromosucci-
namide as the halonium ion source for the synthesis of
azido-bromo-pyranoquinolines 3 (Scheme 2). Alkynes possessing
electron-neutral and electron-donating substituents gave product
3a-c in 70–76% yield. Substrates with a functionalized quinoline
ring afforded the desired products 3d-f in moderate yields.
We next evaluated the scope of the [3 + 2]-azide alkyne
cycloaddition reaction with various o-alkynylaldehydes for the
synthesis of triazolyl compounds (Table 3). When the reaction
was performed with quinoline o-alkynyl aldehydes 1 in DMSO at
120 °C, triazole substituted aldehydes 4a and 4b were obtained
in 70–74% yield (Entries 1 and 2). Interestingly, the reaction condi-
tions were suitable for the synthesis of triazole substituted aldehy-
des of N-methyl indole (4c-d) in moderate yields (Entries 3 and 4).
The reactions of 2-(phenyl (1r) and p-tolyl (1s) ethynyl benzalde-
hydes gave the corresponding products 4e-f in 68% and 64% yield,
respectively (Entries 5 and 6).
After exploring the scope of the azidation and [3 + 2]-cycloaddi-
tion reactions, we further investigated the applicability of azidopy-
ranoquinolines in the Staudinger reaction12 (Scheme 3).
Surprisingly the reactions of product 2/3 with PPh3 in MeOH at
room temperature gave benzonaphthyridines 6 instead of amine 5.
A deuterium labeling experiment was performed in order to
understand the reaction pathway for the formation of benzonaph-
thyridines 6 from azido-iodo-pyranoquinolines 2 (Scheme 4). The
reaction of pyranoquinoline 2c with PPh3 in MeOD gave the
deuterated product 6c’ in 82% yield with 87% incorporation of deu-
terium at the C-4 position. The presence of deuterium at the C-4
position suggests that tautomerization occurs in the reaction
mechanism.
Entry
1
Substrate 1
Product 4
Yield (%)b
74
1a
4a
1a
4a
2
70
1o
1p
4b
4c
1o
4b
3
76
1p
4c
4
75
1q
On the basis of the above results and our previous reports
[10,11], a plausible mechanistic pathway was proposed (Scheme 5).
The reaction was initiated by activation of the alkyne triple bond of
o-alkynyaldehyde 1 by the electrophile (E+) which was generated
in situ by the reaction of K2CO3 and the halonium ion source
(I2/NBS) to form species A (Scheme 5a). Species A undergoes
6-endo-dig cyclization to form oxonium ion B. Subsequently, nucle-
ophilic addition of the azide anion gives the desired product 2/3. In
the Staudinger reaction [12] product 2/3 reacts with PPh3 to give
aza-ylide species C (Scheme 5b). This aza-ylide species C reacts
with MeOD to give species D which upon tautomerization leads
to the formation of species E. Attack of the nitrogen atom of species
E on the carbonyl group affords betaine [13a] species F or F’.
Benzonaphthyridine products 6 were formed from F/F’ upon the
4d
4e
1q
4d
5
68
1r
1s
1r
4e
6
64
liberation of triphenylphosphinoxide (PPh3 = O)13a and methyl
13b-c
hypohalite (HOX)
via attack of a methoxide anion.
4f
1s
4f
Conclusion
aReagents and conditions: 1 (0.50 mmol), NaN3 (2.0 equiv.), DMSO (2.0 mL), 120 °C,
b
24 h. Isolated yield.
In summary, we have demonstrated the chemoselective
addition of NaN3 to o-alkynyl aldehydes for the synthesis of
azido-iodo pyranoquinolines and pyridines via electrophilic
iodocyclization in acetonitrile and the formation of triazole prod-
ucts via [3 + 2]-cycloaddition in DMSO. We have also extended
the application of the azidated products in the Staudinger reaction
for the synthesis of benznaphthyridines through an aza-ylide
intermediate.
product 2b was further confirmed by X-ray crystallographic studies.
Electron rich thienyl alkyne 1c gave the desired product 2c in 86%
yield (Entry 3). A similar reaction pattern was observed for 1d-f, pro-
viding pyranoquinolines 2d-f in high yields (Entries 4–6).
Highly electron-withdrawing alkynes such as 6-methyl-2-
((4-(trifluoromethyl)phenyl)ethynyl)quinoline-3-carbaldehyde 1g
Please cite this article as: P. Kumar, V. Garg and A. K. Verma, Azidation vs [3 + 2]-cycloaddition: Chemoselective reaction of sodium azide towards o-alkyny-
laldehydes for the synthesis of N-heterocycles, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.06.022

P. Kumar et al. / Tetrahedron Letters xxx (xxxx) xxx
5
Scheme 3. Application of azido-halo-pyranoquinolines 2/3. aReagents and conditions: 2/3 (0.50 mmol), PPh3 (1.2 equiv.), MeOH (2.0 mL,) 25 °C, 0.5 h. bIsolated yield.
Scheme 4. Deuterium labelling experiment.
Scheme 5. Proposed reaction mechanism.
Acknowledgments
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https://doi.org/10.1016/j.tetlet.2019.06.022.
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laldehydes for the synthesis of N-heterocycles, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.06.022

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Please cite this article as: P. Kumar, V. Garg and A. K. Verma, Azidation vs [3 + 2]-cycloaddition: Chemoselective reaction of sodium azide towards o-alkyny-
laldehydes for the synthesis of N-heterocycles, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.06.022