A catalytic approach for the synthesis of allylic azides from aryl vinyl carbinols

Article abstract of DOI:10.1016/j.tetlet.2013.02.094

A metal-free and catalytic approach for the preparation of allylic azides starting from aryl vinyl carbinols is described herein.

Full text of DOI:10.1016/j.tetlet.2013.02.094

Tetrahedron Letters 54 (2013) 2382–2385
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A catalytic approach for the synthesis of allylic azides from aryl vinyl carbinols
⇑
G. Srinu, P. Srihari
Division of Natural Products Chemistry, CSIR – Indian Institute of Chemical Technology, Hyderabad 500007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A metal-free and catalytic approach for the preparation of allylic azides starting from aryl vinyl carbinols
Received 28 December 2012
Revised 23 February 2013
Accepted 27 February 2013
Available online 13 March 2013
is described herein.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Azidation
Nucleophilic substitution
Lewis acid
Silylation
Azides have been the valuable intermediates in synthetic organ-
ic chemistry.1 Being stable and can be easily reduced to corre-
sponding amines that find applications in therapeutic agents,
amino acids, natural product synthesis and material science,2 they
have attained a significant importance. Recently, with the advent
of click chemistry, the azides have attained more prominence to-
wards their synthesis for triazole formation.3
The ready availability of the allylic alcohols makes them the
first preferred substrates for the preparation of allylic azides.
Though several methods4–6 are available for azidation reactions
(direct and non-direct approaches) involving nucleophilic displace-
ment of hydroxy group (either directly or through pre-activation as
the corresponding ester, or triflate or conversion to halide), many
of them utilize either metal catalysts (expensive) or employ heat-
ing conditions and thus a new procedure for the preparation of
allylic azide is always welcome to the existing literature.
Our own interest in exploration of acid catalysis for transforma-
tions involving C–C bond or C–X bond formation reactions such as
nucleophilic substitution reactions on benzyl and aryl propargyl
alcohols7 has initiated us to investigate a similar substitution reac-
tion with aryl vinyl substrates. We were delighted to observe that
these substrates easily undergo nucleophilic addition type of reac-
tion to get the allylic azides (terminal azides) rather than the ex-
pected nucleophilic substitution reaction (–OH displaced with –
N3). The present manuscript describes our results in identifying a
facile approach for the preparation of allylic azides (Scheme 1).
Initially, it was envisaged to explore the nucleophilic substitu-
tion reaction at benzylic and allylic site with the azide moiety. In
addition, if a substitution is present at the ortho position on aryl
moiety for example –OH group, it might also undergo an addition
type of reaction onto olefin with simultaneous internal migration
of the double bond resulting in cleavage of azido moiety to get
the chromene (see Scheme 2).
Thus, we began with salicylaldehyde to get the substrate for our
investigations. Salicylaldehyde was subjected to Grignard reaction
(in situ generated vinyl magnesium bromide) to yield the diol 1a
for our current investigation. The diol 1a was subjected to nucleo-
philic substitution reaction with TMSN3 (1 equiv) in the presence
of Lewis acid BF3ꢀOEt2 (0.1 equiv) to undergo azido substitution
at benzylic and allylic position or may further react to produce ex-
pected chromene. After 2 h of reaction duration, we observed the
formation of two new spots with low polarity compared to the
starting material present in minor amounts. After characterizing
the major product, we were indeed surprised to note that the prod-
uct obtained was the allylic azide 1b8 (see Scheme 3) rather than
the expected secondary azido substituted product 1b0 or chromene
(see Scheme 2). Simultaneously, the minor product was character-
ized to be the di-trimethylsilyl protected compound 1c.
This result has prompted us to further explore this methodology.
From the literature survey, it was found that TMSN3 itself acts as the
protective group reagent and aids in the masking of free hydroxyl
groups to the corresponding trimethylsilylether.9 As silylation was
known in THF, we tried a similar reaction in THF and found that
TMS protected compound was obtained and there was no signifi-
cant change in the reaction rate or in terms of yield. We further
investigated the effect of concentration for the Lewis acid BF3ꢀOEt2
and it was found that 20 mol % of BF3ꢀOEt2 was essential for opti-
mum yields. And when the concentration was increased to
50 mol %, there was no significant improvement in the yield and
thus we opted to proceed further with 20 mol % of the Lewis acid.
⇑
Corresponding author. Tel.: +91 4027191815; fax: +91 4027160512.
E-mail address: srihari@iict.res.in (P. Srihari).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.02.094

G. Srinu, P. Srihari / Tetrahedron Letters 54 (2013) 2382–2385
2383
N3
wherein the reaction was much faster compared to that of reaction
with BF3ꢀOEt2. However, the reaction was not complete even after a
prolonged duration of the reaction and minor amount of starting
material was always left over resulting in overall reduced yield.
In the case of reaction with BF3ꢀOEt2 as Lewis acid, complete con-
sumption of starting material occurred within 2 h. As the reaction
was best yielding with BF3ꢀOEt2, we proceeded further with the
same Lewis acid for further investigations.
R
R
OH
OH
OH
TMSN3/BF3.OEt2
CH2Cl2, 0 oC to rt
Expected product
R
N3
OH
Though, chromene was not formed in our preliminary studies
with 1a, we proceeded further to check the possibility with various
other substrates as given in Table 1. Aryl vinyl carbinols such as
bromo substituted, nitro substituted and methoxy-substituted aryl
containing diols (synthesized through Grignard reaction from the
correspondingly derived salicylaldehydes) were treated with
TMSN3 (1.0 equiv) and BF3ꢀOEt2 (20 mol %) (see Table 1). Interest-
ingly in all the cases, corresponding terminal allylic azides were
formed in a range of 65–90% yield with complete consumption of
the starting material. In no case we could observe the formation
of chromene. It was also observed that when electron donating
group like methoxy (entry 5 and 6) was present on the aromatic
system, the reaction progressed in longer durations and when elec-
tron withdrawing group like nitro moiety (entry 8) was present in
the ring system, the reaction was completed within 45 min at room
temperature.10
Obtained product
Scheme 1. Synthesis of allyl azides from aryl vinyl carbinols.
Scheme 2. Attempted nucleophilic substitution reaction towards chromene
formation.
Since the substrates having unsubstituted olefin have re-
sponded well to provide only allylic azides, we now turned our
attention to investigate the substrates with substituted olefins. It
was observed that the substrates with substituted olefin also react
in the present conditions and provide corresponding allylic azides
in good yields (entry 7, 8 and 11). Even the substrate with an ortho
substituted amine gave the corresponding allylic azide (entry
10).11
Mechanistically, we envisaged that the benzylic alcohol gets
activated as the corresponding trimethyl silyl ether and undergoes
nucleophilic addition (azide addition) onto the olefin with simulta-
neous elimination of the trimethyl silyloxy moiety through double
bond migration. This postulate was confirmed by a controlled
experiment wherein, the diol was treated with TMSN3 in DCM at
0 °C in the absence of Lewis acid to give a mixture of TMS protected
products 1c and 1d (characterized after their isolation) and no azi-
do product was observed in this reaction. (Scheme 4). However,
Scheme 3. Synthesis of allylic azide and disilylated product.
7d,e
7f
As we have earlier explored I2
and NbCl5 as mild Lewis
acids for nucleophilic substitution reactions, the diol was also trea-
ted with TMSN3 in the presence of these Lewis acids (20 mol %). It
was observed that the reaction ended up with multi spots leading
to decomposition of the starting material when I2 was used as Le-
wis acid. Interestingly, positive results were obtained with NbCl5
Table 1
Synthesis of allylic azides from aryl vinyl methanol
Entry no
1
Substrate
Product
Reaction time
90
Azide yieldain (%)
80
Disilylated producta in (%)
8
2
90
82
10
3
4
90
45
80
90
10
<5
5
120
75
15
(continued on next page)

2384
G. Srinu, P. Srihari / Tetrahedron Letters 54 (2013) 2382–2385
Table 1 (continued)
Entry no
Substrate
Product
Reaction time
120
Azide yieldain (%)
70
Disilylated producta in (%)
14
6
7
90
45
90
90
80
12
<5
10
8
8
90
9
85 E/Z (1:1:5)b
80 E/Z (4:1)c
10
11
120
65
15
a
Isolated yields.
b
Percentage based on LCMS analysis.
c
Percentage based on 1H NMR analysis
Scheme 5. Azidation reactions.
conditions and ended up with recovery of starting material even
after heating the reaction mixture for 2 h at reflux temperature.
In conclusion, a facile method for synthesis of allylic azides has
been developed starting from aryl vinyl methanol. Simple catalytic
reaction condition with easy work-up procedure and involvement
of no expensive metal catalyst make this method more attractive.
Application of this method for the synthesis of biologically potent
natural products is of current interest in our laboratory.
Scheme 4. Plausible mechanism for allylic azide formation.
after the addition of BF3ꢀOEt2 to these intermediates, the corre-
sponding allylic azide was formed as the only product. Thus, the
reaction was presumed to undergo a straight forward nucleophilic
addition (azide addition) onto the olefin displacing the –OTMS
moiety to get the allylic azide.
Acknowledgments
As we ended up with allylic azides and no chromene was
formed, we now investigated aryl vinyl methanol without hydroxyl
substitution on aryl moiety. Towards this, we experimented with
phenyl vinyl carbinol 12a and found that azidation occurs with
the azide moiety at the terminal end rather than the expected sub-
stitution at benzylic and allylic site to give 12b (Scheme 5). As we
were ending up with terminal azides in all the above cases, we at-
tempted similar reaction conditions on terminal allylic alcohols for
direct azidation reaction. Thus, when trans-cinnamyl alcohol
13a was subjected to our reaction conditions, we were gratified
to note that the reaction ended up with cinnamyl azide 13b (see
G.S. thanks UGC, New Delhi for financial assistance. P.S.H.
acknowledges funding from CSIR, New Delhi as a part of XII Five
year plan programme under title ORIGIN (CSC-0108).
Supplementary data
Supplementary data (1H and 13C NMR data of new compounds
are available as supplementary material) associated with this arti-
cle can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2013.02.094.
Scheme 5). Even a-methyl cinnamyl alcohol 14a yielded the corre-
sponding terminal cinnamyl azide 14b. Thus the present strategy
becomes an example for direct catalytic azidation reaction for cin-
namyl alcohols. Though cinnamyl alcohols responded well, crotyl
alcohol and benzyl alcohol did not respond to our present reaction
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