Direct catalytic azidation of allylic alcohols

Article abstract of DOI:10.1021/ol203310h

A direct catalytic azidation of primary, secondary, and tertiary allylic alcohols has been developed. This new azidation reaction affords the corresponding allylic azides in high to excellent yields and regioselectivities. The reaction provides straightforward access to allylic azides that are valuable intermediates in organic synthesis, including the preparation of primary amines or 1,2,3-triazole derivatives.

Full text of DOI:10.1021/ol203310h

ORGANIC
LETTERS
2012
Vol. 14, No. 3
768–771
Direct Catalytic Azidation of Allylic
Alcohols
Magnus Rueping,* Carlos Vila, and Uxue Uria
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074
Aachen, Germany
magnus.rueping@rwth-aachen.de
Received December 11, 2011
ABSTRACT
A direct catalytic azidation of primary, secondary, and tertiary allylic alcohols has been developed. This new azidation reaction affords the
corresponding allylic azides in high to excellent yields and regioselectivities. The reaction provides straightforward access to allylic azides that
are valuable intermediates in organic synthesis, including the preparation of primary amines or 1,2,3-triazole derivatives.
The interest in the synthesis of allylic amines has
grown significantly due to the importance of these
compounds as building blocks for the synthesis of
various therapeutic agents,1 amino acids2 and natural
products.3 Due to their readily availability, allylic
alcohols are preferred substrates for the synthesis of
allylic amines. Substitution of the alcohol moiety by a
nitrogen nucleophile requires normally preactivation
of the alcohol in the form of a better leaving group
such as halide, carboxylate, phosphate, carbonate or
related compounds.4 Thus, direct catalytic substitu-
tion of allylic alcohols is of great interest for organic
synthesis in terms of atom-economy and environmen-
tal concerns.5
In this context, several methods have been reported
for the direct allylic amination using Brønsted acids,6
iodine,7 and various metal based catalysts.8 Despite a
large number of reported methodologies for the direct
amination of allylic alcohols,6À8 the related direct
azidation remains still underexplored.9 To date, only
(6) Sanz, R.; Martinez, A.; Miguel, D.; Alvarez-Gutierrez, J. M.;
Rodriguez, F. Adv. Synth. Catal. 2006, 348, 1841.
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P. W. H. Tetrahedron Lett. 2008, 49, 2620.
(8) For a review on Pd-catalyzed allylic amination: (a) Muzart, J.
Eur. J. Org. Chem. 2007, 3077. For bismuth-catalyzed reactions:
(b) Qin, H.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. Angew.
Chem., Int. Ed. 2007, 46, 409. For molybdenium-catalyzed reactions:
(c) Yang, H.; Fang, L.; Zhang, M.; Zhu, C. Eur. J. Org. Chem. 2009, 666.
For platinum-catalyzed reactions: (e) Utsunomiya, M.; Miyamoto, Y.;
Ipposhi, J.; Ohshima, T.; Mashima, K. Org. Lett. 2007, 9, 3371. (f)
Mora, G.; Piechaczyck, O.; Houdard, R.; Mezailles, N.; Le Goff, X.-F.;
le Floch, P. Chem.;Eur. J. 2008, 14, 10047. (g) Das, K.; Shibuya, R.;
Nakahara, Y.; Germain, N.; Oshima, T.; Mashima, K. Angew. Chem.,
Int. Ed. 2011, 51, 150–154. For silver-catalyzed reactions: (h) Giner, X.;
Trillo, P.; Najera, C. J. Organomet. Chem. 2011, 696, 357. For iridium-
catalyzed reactions: (i) Defieber, C.; Ariger, M. A.; Moriel, P.; Carreira,
E. M. Angew. Chem., Int. Ed. 2007, 46, 3139. (j) Roggen, M.; Carreira,
E. M. J. Am. Chem. Soc. 2010, 132, 11917. For gold-catalyzed reactions:
(k) Guo, S.; Song, F.; Liu, Y. Synlett 2007, 964. (l) Kothandaraman, P.;
Foo, S. J.; Hong Chan, P. W. J. Org. Chem. 2009, 74, 5947. (m)
Mukherjee, P.; Widenhoefer, R. A. Org. Lett. 2010, 12, 1184. (n)
Mukherjee, P.; Widenhoefer, R. A. Org. Lett. 2011, 13, 1334. For
calcium-catalyzed reactions: (o) Haubenreisser, S.; Niggemann, M. Adv.
Synth. Catal. 2011, 354, 469.
€
(1) (a) Petranyi, G.; Ryder, N. S.; Stutz, A. Science 1984, 224, 1239.
€
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€
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K., Eds.; John Wiley & Sons Ltd.: Chichester, 2010. For the direct azidation
of allylic alcohols with NaN3 and stoichiometric amounts of BF3 Et2O, see:
3
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r
10.1021/ol203310h
Published on Web 01/18/2012
2012 American Chemical Society

a few examples of catalytic allylic azidations with use
of preactivated allylic esters have been reported.10
The catalytic allylic azidation of free alcohols has not
been achieved although allylic azides are useful precursors
for primary amines and nitrenes11 and versatile synthetic
intermediates, e.g. 1,3-dipoles in the Huisgen 1,3-dipolar
cycloaddition12 providing 1,2,3-triazolo-heterocyclic com-
pounds which recently attracted much attention in medic-
inal and pharmaceutical chemistry13 as well as material
science (Scheme 1).14
respectively 1 mol % (entries 17 and 18) had a negative
effect on the selectivity of the reaction, resulting in an
increase of the undesired silylated alcohol 4a. Finally,
other azides were tested including NaN3, TosN3, and
(PhO)2PON3. However, in all of these cases, the formation
of the desired product 3a was not observed. The use of
triflic acid resulted in product formation with reduced
yields, indicating Brønsted acid catalysis.15 Interestingly,
if 2,6-lutidine was added, only formation of 4a was ob-
served. With the optimized conditions in hand, we ex-
plored the scope of the reaction with different primary
allylic alcohols 1aÀg (Table 2).
Hence, the development of a practical procedure for the
catalytic synthesis of allylic azides is highly desirable.
Herein, we present the first direct azidation of allylic
alcohols using silver salts as useful catalysts.
Table 1. Optimization of the Azidation of Allylic Alcoholsa
Scheme 1. Versatility of Allylic Azides
entry silver salt (mol %)
1
solvent
3a (%)b 4a (%) E:Zc
The reaction between (E)-3-phenylbut-2-en-1-ol (1a)
and TMSN3 (2) was chosen as a model reaction for the
optimizationstudy (Table 1). Amongvariousmetal salts as
well as different silver salts evaluated in the direct azidation
of allylic alcohol 1a, AgOTf showed the best chemo-
selectivity, affording the desired allylic azide 3a as single
product in 88% yield (entry 2). AgNTf2 also provided
the desired product 3a, along with traces of the silylated
alcohol 4a (entry 4). With other silver salts, the silylated
alcohol 4a was obtained either in a considerable amount
(entry 3) or as the major product (entries 5À11). Subse-
quently, different solvents were tested in the allylic azida-
tion reaction using AgOTf as the catalyst (entries 12À16).
The highest yield was obtained when toluene was used
as the solvent. A decrease of the catalyst loading to 2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
30
2
AgOTf (5)
AgSbF6 (5)
AgNTf2 (5)
AgCF3CO2 (5)
AgPhCO2 (5)
AgF (5)
88
65
83
3
7:1
7:1
7:1
3
25
4
4
5
76
92
79
73
56
44
44
6
3
7
4
8
Ag3PO4 (5)
AgBF4 (5)
AgPF6 (5)
AgCO3 (5)
AgOTf (5)
AgOTf (5)
AgOTf (5)
AgOTf (5)
AgOTf (5)
AgOTf (2)
AgOTf (1)
3
9
2
10
11
12
13
14
15
16
17
18
19d
20e
6
2
35
68
69
72
7:1
7:1
7:1
7:1
m-xylene
ether
CH2Cl2
CH3CN
toluene
toluene
toluene
toluene
54
15
30
74
45
69
7:1
7:1
5:1
(10) (a) Murahashi, S.-I.; Tanigawa, Y.; Imada, Y.; Taniguchi, Y.
Tetrahedron Lett. 1986, 27, 227. (b) Murahashi, S.; Tanigawa, Y.;
Imada, Y.; Taniguchi, Y. J. Org. Chem. 1989, 54, 3292. (c) Aufranc,
P.; Ollivier, J.; Stolle, A.; Bremer, C.; Es-sayed, M.; de Meijere, A.;
AgOTf (5)
68
a Reactions were performed with allylic alcohol 1a (0.175 mmol), 2 (3
equiv), and 5 mol % of catalyst in 0.5 mL of solvent for 14 h at room
temperature. b Yield after column chromatography. c E:Z ratio of the
product determined by NMR analysis. d 5 mol % of HOTf was used as
catalyst. e 5 mol % of 2,6-lutidine was added.
€
Salaun, J. Tetrahedron Lett. 1993, 34, 4193. (d) Trost, B. M.; Pulley, S. R.
J. Am. Chem. Soc. 1995, 117, 10143. (e) Trost, B. M.; Cook, G. C.
Tetrahedron Lett. 1996, 37, 7485.
ꢀ
(11) Labbe, G. Chem. Rev. 1969, 69, 345.
(12) (a) Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry; Padwa,
A., Ed.; Wiley: New York, 1984; pp 1À176. (b) Rostovtsev, V. V.; Green,
L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41,
2596.
In general, different substituted primary allylic alcohols
could be employed, and the corresponding azides 3aÀg
were isolated in good yields. Notably, in all cases almost
complete regioselectivity to the terminal azide 3 was
observed.
(13) (a) Wang, Q.; Chan, T. R.; Hilgraf, R.; Fokin, V. V.; Sharpless,
K. B. J. Am. Chem. Soc. 2003, 125, 3192. (b) Speers, A. E.; Cravatt, B. F.
Chem. Biol. 2004, 11, 535. (c) Speers, A. E.; Adam, G. C.; Cravatt, B. F.
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Sharpless, K. B.; Wong, C.-H. J. Am. Chem. Soc. 2003, 125, 9588.
(14) (a) Wu, P.; Feldman, A. K.; Nugent, A. K.; Hawker, C. J.; Sheel,
A.; Voit, B.; Pyun, J.; Frechet, J. M. J.; Sharpless, K. B.; Fokin, V. V.
Angew. Chem., Int. Ed. 2004, 43, 3928. (b) Diaz, D. D.; Punna, S.;
Holzer, P.; McPherson, A. K.; Sharpless, K. B.; Fokin, V. V.; Finn,
M. G. J. Polym. Sci., Part A 2004, 42, 4392.
After studying the azidation of primary alcohols, we
focused our attention on the reaction with secondary
(15) Dang, T. T.; Boeck, F.; Hintermann, L. J. Org. Chem. 2011, 76,
9353 and references therein.
Org. Lett., Vol. 14, No. 3, 2012
769

azidation with the (E)-1-phenylbut-2-en-1-ol 1s (Table 3,
entry 12) proceeded regioselectively to the γ product (3h)
in a very good yield of 96%.
Table 2. Substrate Scope for the Direct Azidation of Primary
Allylic Alcoholsa
Table 3. Substrate Scope for the Direct Azidation of Secondary
Allylic Alcoholsa
a Reactions were performed with allylic alcohol 1 (0.35 mmol), 2 (3
equiv), and 5 mol % of AgOTf in 1.0 mL of toluene for 4À16 h at rt.
b Yield (%) after column chromatography. c E:Z ratio of the product
determined by NMR analysis.
allylic alcohols 1hÀs (Table 3). First, the influence of the
substitution pattern at the R-position to the alcohol (Me,
Et, iPr, Ph, Table 3, entries 1À4) was studied. In all cases
we obtained excellent regioselectivity and high yields. In
the case of secondary alcohols the catalyst loading could
be decreased to 2 or even 1 mol %, without loss of
reactivity (entry 2, Table 3). The reaction of secondary
allylic alcohols bearing electron-donating and electron-
withdrawing aryl substituents 1lÀn proceeded smoothly
and provided the desired allylic azides 3lÀn in good
yields (62À96% Table 3, entries 5À7). The R,β,γ,δ-
unsaturated allylic alcohol (3E,5E)-6-phenylhexa-3,5-
dien-2-ol (1o) gave the azide 3o with good yield and high
regioselectivity. Different secondary alcohols 1pÀq with
a trisubstituted double bond were also tested (Table 3,
entries 9 and 10), and the corresponding azides 3pÀq
were obtained in high yields, though with a decrease
in the regioselectivity. The cyclohexenol 1r (Table 3,
entry 11) showed good reactivity, and the allylic azide 3r
was isolated in an excellent yield of 95%. Finally, the
a Reactions were performed with allylic alcohol 1 (0.35 mmol), 2 (3
equiv), and 5 mol % of AgOTf in 1.0 mL of toluene for 2À16 h at rt.
b Yield (%) after column chromatography. c E:Z ratio of the product
determined by NMR analysis. d 2 mol % of AgOTf was used. e 1 mol %
of AgOTf was used. f γ product had a 3:1 (E:Z) relation as determined by
NMR analysis (see Supporting Information).
770
Org. Lett., Vol. 14, No. 3, 2012

6 in a very good yield (Scheme 3, equation a). Moreover,
the primary amine 7 was obtained in 91% yield from
alcohol 1t by a simple one-pot procedure consisting of
azidation and subsequent reduction with PdÀC/H2
(Scheme 3, equation b).
Table 4. Substrate Scope for the Direct Azidation of Tertiary
Allylic Alcoholsa
Scheme 2. One-Pot Synthesis of 1,2,3-Triazoles
Scheme 3. Reduction of the Azides to Primary Amines
a Reactions were performed with allylic alcohol 1 (0.35 mmol), 2 (3
equiv), and 5 mol % of AgOTf in 1.0 mL of toluene for 1À4 h at rt.
b Yield (%) after column chromatography. c E:Z ratio of the product
determined by NMR analysis. d γ product had a relation 1.9:1 (E:Z)
determined by NMR analysis.
Regarding thereactionmechanism, weproposeareaction
pathway in which a carbocation intermediate is formed.16
Taking into consideration that Ag salts are reported to
interact with CÀC multiple bonds,8h,17 coordination of the
Ag(I) to the double bond cannot be ruled out.
In summary, we have developed an efficient and prac-
tical direct azidation of primary, secondary, and tertiary
allylic alcohols. The reaction proceeds in general with
excellent regioselectivities and yields, affording valuable
allylic azides, which can in a one-pot procedure be con-
verted into interesting products, including primary amines
or 1,2,3-triazole derivatives.
Following the successful azidation of primary and second-
ary allylic alcohols, we decided to examine different tertiary
allylic alcohols in order to expand the scope of this methodol-
ogy (Table 4). In general very good yields and excellent regio-
selectivities were obtained for various tertiary alcohols. In the
case of (E)-2,4-diphenylbut-3-en-2-ol 1x (Table 4, entry 5) a
decrease in the regioselectively was observed, and azide 3x was
obtained as a mixture of the Rand γproducts in a 1.7 to 1 ratio.
Once the scope of the azidation with different allylic
alcohols was assessed, we decided to study the applicability
of this methodology for the synthesis of different types
of interesting compounds. The one-pot synthesis of 1,2,3-
triazole 5was achieved using click chemistry (Scheme 2). The
1,2,3-triazole 5 was obtained in 82% yield from the corre-
sponding 3,3-diphenylprop-2-en-1-ol (1f) through azidation
and subsequent 1,3-cycloaddition with phenylacetylene.
The reduction of (E)-(3-azidopent-1-enyl)benzene 3i
by treatment with Ph3P led to the primary allylic amine
Acknowledgment. The authors acknowledge financial
support by the European Research Council. U.U. thanks
“Eusko Jaurlaritza-Gobierno Vasco” for a postdoctoral
fellowship.
Supporting Information Available. Experimental pro-
cedures and full characterization (1H and 13C NMR data
and spectra, MS and IR analyses) for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(16) When the azidation was performed with enantiomerically pure
alcohol 1h, racemic allylic azide 3h was obtained. Furthermore, in the
case of enantiomerically pure allylic alcohol 1s, azide 3h was obtained as
a racemic mixture.
~
(17) Alvarez-Corral, M.; Munoz-Dorado, M.; Rodriguez-Garcia, I.
Chem. Rev. 2006, 108, 3174.
Org. Lett., Vol. 14, No. 3, 2012
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