Copper triflate: An efficient catalyst for direct conversion of secondary alcohols into azides

Article abstract of DOI:10.1055/s-0033-1340550

A simple, practical, and efficient strategy has been demonstrated for the direct synthesis of organic azides from alcohols using azidotrimethylsilane (TMSN₃) as azide source in the presence of copper(II) triflate [Cu(OTf)₂]. A variet

Full text of DOI:10.1055/s-0033-1340550

LETTER
▌515
lCettoerpper Triflate: An Efficient Catalyst for Direct Conversion of Secondary
Alcohols into Azides
Direct Conversion of Secondary Alcohols into Azides
Poonam Khedar, Kasiviswanadharaju Pericherla, Anil Kumar*
Department of Chemistry, Birla Institute of Technology and Science, Pilani 333031 , India
Fax +91(1596)244183; E-mail: anilkumar@pilani.bits-pilani.ac.in
Received: 22.10.2013; Accepted after revision: 09.12.2013
and NaN3/CCl4–DMF.28 Although the reported methods
Abstract: A simple, practical, and efficient strategy has been dem-
are effective, they suffer from limitations such as inacces-
sible and expensive reagents and long reaction times as
well as cumbersome separation from the generated
onstrated for the direct synthesis of organic azides from alcohols us-
ing azidotrimethylsilane (TMSN3) as azide source in the presence of
copper(II) triflate [Cu(OTf)2]. A variety of alcohols was converted
into the corresponding azides in good to excellent yields. The for- Ph3P=O and unreacted Ph3P.
mation of an intermediate carbocation was confirmed by the synthe-
sis of bis(diphenylmethyl) ether.
Thus, in this communication we wish to report our prelim-
inary results for the direct conversion of alcohols into
azides using azidotrimethylsilane (TMSN3) and cop-
per(II) triflate [Cu(OTf)2, Scheme 1].
Key words: azides, azidotrimethylsilane, copper triflate, Lewis
acid
R
Cu(OTf)2, TMSN3
CH2Cl2
R
Organic azides are a versatile class of compounds fre-
quently used in synthetic organic chemistry.1–4 They are
useful precursors for the preparation of amines,5,6 ni-
trenes,7 and heterocyclic compounds. For example, glyco-
syl azides are key intermediates in the synthesis of
glycosyl amino acids.8 They are also substrates for the
copper-catalyzed azide–alkyne cycloaddition (CuAAC)
reaction,9,10 which has received great attention in recent
decades for the synthesis of druglike molecules, bioconju-
gation, and in areas of material science.11,12 The azide
group itself is the key component of the HIV/AIDS drug,
zidovudine.13
Ar
OH
Ar
N3
Scheme 1 One-pot synthesis of azide from benzyl alcohols
Our study began with the direct reaction of 1-phenyletha-
nol (1a) with TMSN3 in the presence of InBr3 (20 mol%)
in dichloromethane to give (1-azidoethyl)benzene (2a) in
83% yield (Table 1, entry 1). The structure of 2a was de-
termined by NMR and IR spectroscopy. A peak at 2096
cm–1 in the IR spectrum of 2a indicated the presence of the
azide group. Encouraged with these results we screened
different Lewis and Brønsted acids to improve the yields
of 2a, and the results are summarized in Table 1. Among
the catalysts screened, Cu(OTf)2 was found to be most ef-
fective and produced 2a in an excellent isolated yield
(94%) with 5 mol% of catalyst loading (Table 1, entry 6).
Other copper salts such as CuSO4·5H2O, CuOTf,
CuCl2·2H2O, CuCl, and CuBr also gave good yields of 2a
(Table 1, entries 3–8, 10, and 11), but a poor yield of 2a
was observed with Cu(OAc)2·H2O and no conversion was
observed in the case of CuI, CuBr2, and CuO (Table 1, en-
tries 2, 12, and 13). Other Lewis acids such as BF3·OEt2,
AlCl3, FeCl3, AgOTf, Yb(OTf)3, Zn(OTf)2, and In(OTf)3
also resulted in good yields of 2a. Montmorillonite K10
gave good yields of 2a (Table 1, entry 14) whereas Brøn-
sted acids such as PTSA and acetic acid were found not to
be suitable for this conversion (Table 1, entries 15 and
16).
Transformation of alcohols to azides is an attractive pro-
cedure for the synthesis of a variety of organic com-
pounds. The most common approach for this
transformation involves a two-step protocol: conversion
of the alcohol into the corresponding halide or sulfonate
and subsequent nucleophilic substitution by azide anion.14
Direct conversion of alcohols into azides can be achieved
by the Mitsunobu reaction.15,16 This is an attractive meth-
od for synthesis of azides in which the reaction can be
conducted under mild and neutral conditions, and gener-
ally gives excellent yields of products. However, it in-
volves the use of hydrazoic acid. Several modifications of
this method have been reported using TPP/CBr4/NaN3,17
TPP/DDQ/n-Bu4NN3,18
2,4,4,6-tetrabromo-2,5-cyclo-
hexadienone/Ph3P/Zn(N3)2·2py,19 bis(p-nitropheny)phos-
phorazidate/DBU,20 diphenyl phosphorazidate/DBU,21,22
and TPP/I2/imidazole/NaN3.23 Other methods for the
direct conversion of alcohols into azides include the
use of NaN3/BF3·OEt2,24 2,4,6-trichloro[1,3,5]triazine/
n-Bu4NN3,25 2-azido-1,3-dimethylimidazolinium hexa-
fluorophosphate (2-ADMP)/DBU,26 TsIm/TBAI/NaN3,27
After establishing Cu(OTf)2 as catalyst of choice for this
transformation, different solvents were screened and it
was found that highest yield of 2a was achieved in dichlo-
romethane (Table 1, entry 6). Other solvents such as
CHCl3, CCl4, and DMF gave good yields of 2a, whereas
THF and MeCN resulted in poor yields (Table 1, entries
24–28). It is worth to note that no conversion was ob-
served in aqueous medium (Table 1, entry 29). The reac-
SYNLETT 2014, 25, 0515–0518
Advanced online publication: 16.01.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340550; Art ID: ST-2013-D0992-L
© Georg Thieme Verlag Stuttgart · New York

516
P. Khedar et al.
LETTER
tion failed to give the azido product when sodium azide
was used as an azide source; albeit a trace amount of sym-
metrical ether was found after prolonged reaction times.
Table 1 Optimization of Reaction Conditions for Azidation of
1-Phenylethanola
OH
N3
TMSN3, catalyst
solvent, time
We then studied the scope of different alcohols for azida-
tion reaction using TMSN3 as azide source under the op-
timized conditions (Table 1, entry 6), and the results are
summarized in Scheme 2. Alcohols with diverse substitu-
tions on the aryl ring produced good to excellent yields of
azides 2b–q. For example, substrates bearing methoxy,
hydroxy, fluoro, chloro, and bromo groups were well tol-
erated under the optimized conditions and gave good
yields of the corresponding azides 2e–k. Biphenyl metha-
nol and its derivatives also reacted smoothly to give bi-
phenyl methyl azides in good yields (2l,m). Substrates
with heterocyclic rings such as pyridine, thiophene, and
thiazole also participated in azidation and provided good
yields of azides 2n–p. Gratifyingly, azidation proceeded
smoothly with a tertiary alochol to give the corresponding
azide in good yield (2q).29 When allylic and propargylic
alcohols were reacted under the standard azidation condi-
tions, varying results were observed. For cinnamyl alco-
hol the symmetrical ether was also detected along with the
azido product. Similarly, propargyl alcohol also resulted
in a mixture of products, where the alkyne hydration prod-
uct was also found along with propargyl azides. When cy-
clohexanol was reacted under the optimized conditions,
no conversion was observed.
2a
1a
Entry Catalyst (mol%)
Solvent
Time (min) Yield (%)b
1
2
InBr3 (20)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
30
120
360
30
83
c
CuI (20)
–
3
CuSO4·5H2O (20)
CuOTf (20)
50
80
92
94
88
82
20
78
82
4
5
Cu(OTf) (20)2
Cu(OTf)2 (5)
CuCl2·2H2O (20)
CuCl2·2H2O (5)
8
6
20
7
10
8
20
9
Cu(OAc)2·H2O (20) CH2Cl2
300
240
45
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
CuCl (20)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
CCl4
CuBr (20)
c
CuBr2 (20)
360
360
45
–
c
The mechanism for the reaction is believed to be through
formation of the carbocation intermediate via heterolytic
cleavage of the C–O bond of the alcoholic group with the
assistance of TMSN3/Cu(OTf)2.29,30 The catalyst simulta-
neously assists in the generation of azide from TMSN3.
The attack of azide to the carbocation intermediate results
in the formation of the desired substitution product.
CuO (20)
–
Mont. K10d (20)
PTSA (20)
60
c
180
360
30
–
c
AcOH (20)
BF3·OEt2 (20)
AlCl3 (20)
–
80
82
57
68
47
54
76
75
68
78
35
42
Formation of the intermediate carbocation is further sup-
ported by the fact that when diphenylmethanol (1l) was
treated with Cu(OTf)2 under identical conditions in the
absence of TMSN3, bis(diphenylmethyl) ether (3l) was
obtained as the major product (Scheme 3). We further re-
acted 1j and 1p with Cu(OTf)2 under TMSN3-free condi-
tions and obtained the corresponding ethers 3j,p in good
yields.
30
FeCl3 (20)
120
240
240
240
30
AgOTf (20)
Yb(OTf)3 (20)
Zn(OTf)2 (20)
In(OTf)3 (20)
Cu(OTf)2 (5)
Cu(OTf)2 (5)
Cu(OTf)2 (5)
Cu(OTf)2 (5)
Cu(OTf)2 (5)
Cu(OTf)2 (5)
In summary, we have developed a simple and efficient
method for the preparation of organic azides via direct
azidation of alcohols using TMSN3 as azide source and
Cu(OTf)2 as catalyst. A variety of benzylic alcohols can
be converted into the corresponding azides in short reac-
tion time (20 min) with good to excellent yields. Forma-
tion of intermediate carbocation was confirmed by the
synthesis of bis(diphenylmethyl) ether. The protocol can
be used for in situ generation of azides for further trans-
formations.
20
20
DMF
20
THF
20
MeCN
H2O
20
c
20
–
a Reaction conditions: 1-phenylethanol (1.0 mmol), TMSN3 (1.5
mmol), catalyst, solvent, r.t. (ca. 30 °C), time.
b Isolated yield.
General Procedure for Azidation
c No conversion was observed.
To a stirred solution of alcohol 1 (1.0 mmol) and azidotrimethylsi-
lane (TMSN3; 1.5 mmol) in CH2Cl2 (2.0 mL) was added Cu(OTf)2
(5 mol%), and the reaction mixture was stirred at r.t. (ca. 30 °C) for
d Montmorillonite K10.
Synlett 2014, 25, 515–518
© Georg Thieme Verlag Stuttgart · New York

LETTER
Direct Conversion of Secondary Alcohols into Azides
517
R
N3
R
OH
TMSN3, Cu(OTf)2 (5 mol%)
CH2Cl2, 20 min
Ar
Ar
1
2
N3
N3
N3
N3
N3
OMe
2a, 94%
2b, 93%
2c, 89%
2d, 92%
N3
2e, 86%
N3
N3
N3
N3
Cl
MeO
OMe
OH
F
Cl
Cl
2f, 89%
2g, 48%
2h, 71%
2i, 57%
2j, 70%
N3
N3
N3
N3
S
OBn
O
Br
OBn
OMe
N3
2k, 50%
2l, 91%
2m, 94%
2n, 96%
N3
N
N3
S
N
2o, 87%
2p, 94%
2q, 63%
Scheme 2 Direct azidation of alcohols using TMSN3
2-(1-Azidoethyl)thiazole (2p)
R1
R1
Cu(OTf)2 (5 mol%)
CH2Cl2, 20 min
Yellow liquid; yield 94%. 1H NMR (300 MHz, CDCl3): δ = 7.62 (d,
J = 3.4 Hz, 1 H), 7.22 (d, J = 3.4 Hz, 1 H), 5.14–5.04 (m, 1 H), 1.57
(d, J = 6.5 Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ = 174.5, 140.2,
117.0, 65.9, 22.2. IR (NaCl): 2977, 2931, 2106, 1650, 1504, 1434,
1195, 1149, 1110, 1064 cm–1.
OH
R2
O
R1
1j,l,p
R2
R2
3j,l,p
Scheme 3 Synthesis of bis(diarylmethyl) ether
Bis(diphenylmethyl) Ether (3l)
1
White solid; yield 87%; mp 104–105 °C (lit.31 109 °C). H NMR
20 min. On completion of the reaction as indicated by TLC, the re-
action was diluted with H2O and extracted with EtOAc. The organic
layers were dried with anhydrous Na2SO4, filtered, and evaporated
under vacuum. The crude residue was purified by column chroma-
tography (60–120 mesh silica gel, 1:9; EtOAc–hexane).
(300 MHz, CDCl3): δ = 7.37 (t, J = 1.9 Hz, 2 H), 7.35–7.33 (m, 8
H), 7.30 (d, J = 1.7 Hz, 4 H), 7.28 (d, J = 1.4 Hz, 2 H), 7.26 (t, J =
1.6 Hz, 2 H), 7.24–7.20 (m, 2 H), 5.40 (s, 2 H). 13C NMR (75 MHz,
CDCl3): δ = 142.2, 129.2, 128.4, 127.5, 127.3, 80.0. IR (NaCl):
2931, 2846, 1643, 1546, 1488, 1450, 1180, 1118, 1049 cm–1.
Spectroscopic Data for Selected Compounds
Bis[(thiazol-2-yl)ethyl] Ether (3p)
Yellow liquid; yield 79%. 1H NMR (300 MHz, CDCl3): δ = 7.72 (d,
J = 3.1 Hz, 2 H), 7.30 (d, J = 3.1 Hz, 2 H), 5.17 (q, J = 6.5 Hz, 2 H),
1.65 (d, J = 6.5 Hz, 6 H). 13C NMR (75 MHz, CDCl3): δ = 176.0,
142.2, 118.9, 68.0, 24.1. IR (NaCl): 2970, 2923, 1650, 1504, 1195,
1103, 1072, 790 cm–1.
(Azidomethylene)dibenzene (2l)
Colorless liquid; yield 91%. 1H NMR (300 MHz, CDCl3): δ = 7.38–
7.34 (m, 2 H), 7.32–7.25 (m, 8 H), 5.70 (s, 1 H). 13C NMR (75 MHz,
CDCl3): δ = 139.6, 128.7, 128.1, 127.4, 68.6. IR (NaCl): 2939,
2098, 1650, 1496, 1450, 1388, 1249, 1095 cm–1.
4-{Azido[3-(benzyloxy)phenyl]methyl}-1-(benzyloxy)-2-me-
thoxybenzene (2m)
Acknowledgment
White solid; yield 94%; mp 95–96 °C. 1H NMR (300 MHz, CDCl3):
δ = 7.43–7.33 (m, 7 H), 7.32–7.28 (m, 2 H), 7.28–7.19 (m, 2 H),
6.91 (dd, J = 4.3, 1.7 Hz, 2 H), 6.87 (d, J = 2.1 Hz, 1 H), 6.81 (dd, J
= 7.1, 5.1 Hz, 2 H), 6.74 (dd, J = 8.2, 2.0 Hz, 1 H), 5.58 (s, 1 H),
5.11 (s, 2 H), 5.00 (s, 2 H), 3.81 (s, 3 H). 13C NMR (75 MHz,
CDCl3): δ = 159.0, 149.8, 148.1, 141.37, 137.1, 136.8, 132.5, 129.8,
128.6, 128.6, 128.1, 127.9, 127.6, 127.3, 119.95, 119.94, 114.2,
114.0, 113.7, 111.0, 71.0, 70.0, 68.2, 56.1. IR (NaCl): 2962, 2931,
2098, 1643, 1604, 1512, 1458, 740, 694, 647 cm–1.
The authors thank UGC New Delhi for financial support. PK and
KP are grateful to UGC, New Delhi for Junior Research Fellow-
ships.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SupInpfioomgrattr
o
nSupprigI
o
tnnofrmat
© Georg Thieme Verlag Stuttgart · New York
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P. Khedar et al.
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Synlett 2014, 25, 515–518
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