Domino addition/N-C heterocyclization of azides with allenyl magnesium bromide: Rapid synthesis of 5-butynyl-1,2,3-triazoles

Article abstract of DOI:10.1055/s-2007-977435

1,5-Disubstituted 1,2,3-triazoles are formed through a novel domino reaction involving the addition of aromatic azides to an excess of allenylmagnesium bromide with concomitant N-C heterocyclization followed by the addition of another mole of allenyl-magn

Full text of DOI:10.1055/s-2007-977435

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LETTER
1109
Domino Addition/N–C Heterocyclization of Azides with Allenyl Magnesium
Bromide: Rapid Synthesis of 5-Butynyl-1,2,3-triazoles1
R
apid Synthes
y
is of 5-Butyn
e
yl-1,2, 3-tr
d
iazoles Shafi, Abid Hussain Banday, Tabasum Ismail, H. M. Sampath Kumar*
Regional Research Laboratory, Canal Road, Jammu Tawi 180001, India
Fax +91(191)2548607; E-mail: hmskumar@yahoo.com
Received 20 August 2006
vated methylene compounds,19 1,3-dipolar cycloaddition
of 4-azido-8-(trifluoromethyl)quinoline with ethylace-
toacetate and acetylacetone,20 and cycloaddition of alkyl
azides with enol ethers under solvent-free conditions.21
Abstract: 1,5-Disubstituted 1,2,3-triazoles are formed through a
novel domino reaction involving the addition of aromatic azides to
an excess of allenylmagnesium bromide with concomitant N–C het-
erocyclization followed by the addition of another mole of allenyl-
magnesium species to generate the terminal acetylenic product in 1,3-Dipolar cycloadditions of azides with alkynes have
moderate to high yields.
been applied to synthesize triazoles as intermediates in the
total synthesis of several natural products. Contrary to the
existing innumerable methods for the generation of 1,4-
disubstituted triazoles, our literature survey reveals only
few methods for the generation of 1,5-disubstituted tri-
azoles which mainly employ the reactions of sodium, lith-
ium, or magnesium acetylides with organic azides22 where
1,5-disubstituted 1,2,3-triazoles are the major products of
these reactions. The wide range of pharmacological activ-
ities of triazole systems prompted us to attempt the
synthesis of 1,2,3-triazole via addition of resonance-stabi-
lized allenylmagnesium bromide to azides which resulted
in a serendipitous formation of 5-butynylated triazoles.
Herein we report an unprecedented synthesis of novel 5-
butynyl-1,2,3-triazoles through nucleophilic substitution
involving N–C heterocyclization followed by domino
cascade addition of allenylmagnesium bromide with
azides (Scheme 1).
Key words: allenylmagnesium bromide, azides, 5-but-1,2,3-tri-
azoles
1,2,3-Triazoles and their derivatives have attracted
considerable attention for the past few decades due to
their chemotherapeutical value.2 Many 1,2,3-triazoles are
found to be potent antimicrobial,3,4 analgesic,5 antiinflam-
matory, local anesthetic,6 anticonvulsant,7 antineoplastic,8
antimalarial,9 and antiviral agents.10 Some of them have
exhibited antiproliferative11 and anticancer activity,12
whereas several others are used as DNA cleaving agents11
and potassium channel activators.13 Thus 1,2,3-triazoles
have emerged as powerful pharmacophores in their own
right.14 1,3-Dipolar cycloaddition of azides to acetylenes
is one of the important routes for the preparation of vari-
ous biologically active 1,2,3-triazoles. However, they are
neither general nor reliable, and usually require a strong
electron-withdrawing substituent on the alkyne. A num-
ber of synthetic strategies have been developed for the
synthesis of different 1,4-substituted triazoles. For exam-
ple, copper(I)-catalyzed 1,3-dipolar cycloaddition of
azides with alkynes, which results in the formation of 1,4-
substituted 1,2,3-triazoles, is among the recent advances
in the chemistry of organic azides. Recently, improved
methods have been reported for the synthesis of different
substituted 1,2,3-triazoles including TBAF-catalyzed
[3+2] cycloaddition of 2-aryl-1-nitroethanes with TMSN3
under solvent-free conditions.15 Several other approaches
for the generation of 1,2,3-triazole moiety include step-
wise Huisgen cycloaddition process of copper(I)-cata-
lyzed regioselective ligation of azides with terminal
alkynes,16 regiospecific one-pot synthesis of 1,4,5-trisub-
stituted 1,2,3-triazoles promoted by copper(I) iodide,17
synthesis of triazole-based monophosphines for Suzuki–
Miyaura coupling and amination reactions of aryl chlo-
rides,18 synthesis of 1-[quinolyl(4)]-1,2,3-triazoles via
1,3-dipolar cycloaddition of 4-azidoquinolines with acti-
N
N
N
+
–
THF, r.t.
+
N
N
N
MgBr
R
R
6
1
2
Scheme 1 Domino addition of allenylmagnesium bromide to azides
Different types of azides were reacted with excess magne-
sium bromide in anhydrous tetrahydrofuran under an inert
atmosphere to generate triazoles in moderate to high
yields (65–83%). The reaction is found to be highly rapid
in case of aromatic azides as moderate to high yields of
products could be isolated within 10–20 minutes of the
reaction at ambient temperature (Table 1), whereas ali-
phatic azides failed to form the product under analogous
experimental conditions. However, at elevated tempera-
ture (>70 °C) and prolonged reaction time, triazoles were
isolated in moderate yields using aliphatic azides (6i and
6j; entries 9 and 10 in Table 1). The formation of 1,5-di-
substituted triazoles has been unequivocally established
through the characteristic chemical shift value of the tri-
azolyl proton (5-CH) at d = 7.70–7.75 in contrast to the
appearance of 4-CH signal at d = 8.30–8.38 in the case
SYNLETT 2007, No. 7, pp 1109–1111
2
4.
0
4.
2
0
0
7
Advanced online publication: 13.04.2007
DOI: 10.1055/s-2007-977435; Art ID: D25106ST
© Georg Thieme Verlag Stuttgart · New York

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1110
S. Shafi et al.
LETTER
Table 1 Synthesis of 5-Butynyl-1,2,3-triazoles26 (continued)
+
MgBr
N
Entry Azide 1,5-Disubstituted triazolea
Time
(min)
Yield
(%)b
+
N
–
–
N
N
N
N
N
N
1
6
N
1
+
N
R
MgBr
R
R
N
MgBr
N
3
4
1c
15
15
65
65
2
3
4
N
N
NO2
N
Ar
N
N
MgBr
N
N
Br
Mg
Br
N
Mg
N
R
1d
1e
Schlenk complex
5
6
Cl
N
Scheme 2 Plausible mechanism for the formation of 5-butynyl-
1,2,3-triazoles
N
N
5
6
7
20
20
25
70
70
65
of 1,4-disustituted triazoles.23 Sharpless et al. reported the
synthesis of 1,5-disubstituted triazoles through the addi-
tion of bromomagnesium acetylides to aryl azides.24 Their
proposed mechanism begins with the nucleophilic attack
of the acetylide on the terminal nitrogen atom of the azide,
followed by spontaneous closure of the linear intermedi-
ate to the 4-metallotriazole species. The reaction of bro-
momagnesium acetylides with azides, after hydrolysis,
preferentially gave the 1,5-disubstituted triazoles; how-
ever, the yields were low. A plausible mechanism for the
formation of unusual product in case of allenylmagnesium
bromide can also be explained through a similar pathway
involving the nucleophilic attack of the terminal carbon of
allenyl species on the terminal nitrogen of azide to gener-
ate the intermediate 3 (Scheme 2). This is followed by
concomitant ring closure through N–C heterocyclization
driven by the excess reagent, which undergoes subsequent
attack by the second mole of allenylmagnesium species
probably through a Schlenk25 type of equilibrium to gen-
erate the final product.
OMe
N
N
N
1f
N
N
N
1g
NO2
N
N
N
8
9
1h
1i
15
45
70
60
Table 1 Synthesis of 5-Butynyl-1,2,3-triazoles26
N
N
Entry Azide 1,5-Disubstituted triazolea
Time
(min)
Yield
(%)b
N
1
6
O
N
O
N
N
1
2
1a
10
20
60
65
N
10
1j
45
60
N
N
N
N
N
1b
NO2
a All products were characterized by IR, 1H NMR, 13C NMR, and
DEPT spectroscopy and mass spectrometry.
b Yields obtained after column chromatography.
Synlett 2007, No. 7, 1109–1111 © Thieme Stuttgart · New York

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LETTER
Rapid Synthesis of 5-Butynyl-1,2,3-triazoles
1111
(17) Wu, Y. M.; Deng, J.; Li, Y. L.; Chen, Q. Y. Synthesis 2005,
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In conclusion, we have presented in this paper, an unprec-
edented, rapid synthesis of 1,5-disubstituted 1,2,3-tri-
azoles through a domino addition/N–C heterocyclization
of azides with allenylmagnesium bromide.
(20) Holla, B. S.; Mahalinga, M.; Karthikeyan, M. S.; Poojary,
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Acknowledgment
The authors thank Dr. G. N. Qazi, Director of RRL for his interest
and encouragement. S.S. and A.H.B. thank CSIR, New Delhi for the
award of fellowships.
(22) (a) Akimova, G. S.; Chistokletov, V. N.; Petrov, A. A. Zh.
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References and Notes
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(2) Sanghvi, Y. S.; Bhattacharya, B. K.; Kini, G. D.;
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Heterocycl. Commun. 2000, 6, 421.
(25) Schlenk, W. Chem. Ber. 1929, 62B, 920.
(26) In a typical procedure, to a suspension of magnesium
turnings (1.6 g, 0.07 mol) in anhyd THF with mercury(II)
chloride (10 mg, 0.125 w/w of propargyl bromide) was
added propargyl bromide (7.5 mL of an 80 wt% solution in
toluene, 0.07 mol) in small portions while stirring the
reaction mixture at r.t. (Note: A small crystal of iodine is
generally required to promote formation of the Grignard
reagent). The mixture was stirred at r.t. for 15 min to give a
cloudy light green solution. The allenylmagnesium bromide
generated as above was cooled to ambient temperature and
to it was added dropwise a solution of p-methoxyphenyl
azide (1 g, 0.007 mol) and stirring was continued at ambient
temperature for 10 min followed by quenching with an aq
NH4Cl solution (10 mL) and diluting with EtOAc (50 mL).
The organic layer was separated and the aqueous layer was
extracted with EtOAc (2 × 20 mL). The combined organic
layers were dried (anhyd Na2SO4) and evaporated under
reduced pressure to afford the crude product which was
subjected to chromatography (basic aluminum oxide,
elution: n-hexane–EtOAc gradient) to afford pure 5-but-3-
yn-1-yl-1-(4-methoxyphenyl)-1H-1,2,3-triazole as a brown
colored syrupy liquid (1.066 g,70%).
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Pharm. Sci. 1999, 4, 202.
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Patent 4789680, 1986.
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A.; Cirrincione, G. Heterocycles 1998, 48, 1229.
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1998, 1677.
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IR: 3293, 2957, 2925, 2855, 1722, 1597, 1546, 1501, 1457,
1253, 1120, 1092, 1069, 917, 765, 693, 650 cm–1. 1H NMR
(CDCl3): d = 2.05 (t, J = 2.5 Hz, 1 H), 2.50 (m, 2 H), 2.90 (t,
J = 7.3 Hz, 2 H), 3.92 (s, 3 H), 7.30 (d, J = 8.9 Hz, 2 H), 7.45
(d, J = 8.9 Hz, 2 H ), 7.80 (s, 1 H). 13C NMR (500 MHz,
CDCl3): d = 17.83, 22.97, 55.64, 70.07, 81.81, 114.70,
126.84, 128.79, 132.48, 136.34, 162.51. ESI–MS: m/z = 227
[M+], 250 [M + Na]. Anal. Calcd for C13H13N3O: C, 68.71;
H, 5.77; N, 18.49; O, 7.04. Found: C, 68.60; H, 5.81; N,
18.60; O, 6.99.
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