Efficient synthesis of allylic azides and one-pot regioselective synthesis of 1,4-disubstituted 1,2,3-triazoles from homoallyl alcohols

Article abstract of DOI:10.1016/j.tetlet.2010.05.097

This protocol is for an expedient and operationally simple synthesis of allylic azides and one-pot synthesis of 1,4-disubstituted 1,2,3-triazoles from homoallyl alcohols. Synthesis of allylic azides involves the palladium-catalyzed hydroazidation of unact

Full text of DOI:10.1016/j.tetlet.2010.05.097

Tetrahedron Letters 51 (2010) 4037–4041
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Efficient synthesis of allylic azides and one-pot regioselective synthesis
of 1,4-disubstituted 1,2,3-triazoles from homoallyl alcohols
*
P. Surendra Reddy, V. Ravi, B. Sreedhar
Inorganic and Physical Chemistry Division, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
This protocol is for an expedient and operationally simple synthesis of allylic azides and one-pot synthe-
sis of 1,4-disubstituted 1,2,3-triazoles from homoallyl alcohols. Synthesis of allylic azides involves the
palladium-catalyzed hydroazidation of unactivated olefins with migration of double bond. This hydroaz-
idation can be coupled to Cu(I) promoted 1,3-dipolar cycloaddition to afford the corresponding 1,4-disub-
stituted 1,2,3-triazoles.
Received 18 January 2010
Revised 19 May 2010
Accepted 22 May 2010
Available online 2 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Allylic azides
Homoallylic alcohols
Triazoles
Palladium chloride
Cycloaddition
Amines and related functional groups are ubiquitous in natural
products as well as in pharmaceutical substances. Consequently,
the development of methods for the introduction of nitrogen into
simple organic compounds is an intense focus of research.1 While
the enormous interest in the chemistry of azides and azido-related
compounds2 dates from the 19th century, only recently have the
synthesis and reactivity of multifunctional allylic azides become
an area of active research.3 Allylic azides are versatile building
blocks for the synthesis of natural products and nitrogen-contain-
ing heterocycles of pharmacological relevance.4 Copper(I)-cata-
lyzed cycloaddition with terminal alkynes, which results in
1,4-disubstituted 1,2,3-triazoles, is among the recent advances in
the chemistry of organic azides.5 The rare chemical orthogonality
of the azide and alkyne functionalities (that is, inertness to acidic
and mildly basic conditions) has enabled unique applications of
this process in chemical biology, organic synthesis, and materials
science.6 However, the propensity of allylic azides to undergo dy-
namic [3,3]-sigmatropic rearrangement7 at an ambient tempera-
ture must be taken into account, because the thermodynamic
ratio of the two equilibrating regioisomeric azides is normally sub-
strate-dependent.8 Therefore, the development of simple and effi-
cient methods to selectively access allylic azides of structural
complexity is highly desirable.
with hydrazoic acid sources is limited to alkenes that give rise to
stabilized carbocations and require excess HN3, TMSN3, or zeo-
lite-supported NaN3, unactivated monosubstituted olefins being
described as unreactive in these processes.10 Recently, Wang and
co-workers reported palladium-catalyzed hydroalkoxydation of
unactivated alkenes for the synthesis of a variety of allylic ethers.11
Herein, we report the hydroazidation of homoallyl alcohols to the
corresponding allylic azides with migration of the double bond
using PdCl2 as a catalyst and TMSN3 as an azide source. Moreover,
as it is a part of our research program directed toward the synthe-
sis of triazoles under various reaction conditions,12 the formed
allylic azides were subsequently converted to 1,4-disubstituted
1,2,3-triazoles through CuI-catalyzed 1,3-dipolar cycloaddition
with terminal alkynes without isolation and purification of azides
(Scheme 1).
In our initial studies, various palladium catalysts in combination
with different solvents were investigated using 1-phenylbut-3-en-
1-ol 1 as a model substrate for the synthesis of allylic azides
(Table 1). The conditions were optimized and the best condition
was found to be 2 mol % of PdCl2, 1.2 equiv of TMSN3 with dichloro-
methane as the solvent and the results are summarized in Table 1,
entry 1. By virtue of these optimized conditions, the reaction affor-
ded the desired product in 92% yield. Reactions with other palladium
catalysts such as Pd(OAc)2, Pd(PPh3)4, and Pd/C did not generate the
desired product (Table 1, entries 2–4). However, the reaction with Pd
(CH3CN)2Cl2 gave the product in a moderate yield (Table 1, entry 5).
As can be seen from Table 1, the nature of the counter ion as well as
the oxidation state of the palladium plays a significant role in this
reaction. Subsequently, the reaction conditions were optimized by
The most common access route to alkyl/allyl azides involves the
substitution reaction of primary or secondary alkyl/allyl halides or
tosylates with inorganic azides.9 The direct reaction of alkenes
* Corresponding author. Tel.: +91 40 27193510; fax: +91 40 27160921.
E-mail address: sreedharb@iict.res.in (B. Sreedhar).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.097

4038
P. Surendra Reddy et al. / Tetrahedron Letters 51 (2010) 4037–4041
R
N
N3
OH
N
3 mol% PdCl2
5 mol% CuI
N
1.5 equiv TMSN3
CH2Cl2, rt, 3 h
R
H2O, rt, 6 h
3
1
2
One-pot operation
Scheme 1.
Table 1
Catalyst and solvent screening for the synthesis of allyl azides from homoallylic alcoholsa
N3
OH
catalyst
TMSN3
solvent, rt
1
2
Entry
Solvent
Catalyst
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
PdCl2
3
12
12
12
12
3
92
0
0
Pd(OAc)2
Pd(PPh3)4
Pd/C
Pd(CH3CN)2Cl2
PdCl2
0
53
90
60
0
PdCl2
PdCl2
12
12
DMF, H2O ACN 1,4-dioxane CH3NO2
a
Reaction conditions: homoallyl alcohol (1 mmol), trimethylsilyl azide (1.5 mmol), catalyst (3 mol %), solvent (3 mL).
employing different solvents. Thus, various polar and non-polar sol-
vents were examined and it was found that the product was ob-
tained in a moderate yield with toluene and all other solvents had
negative influenceon the reaction and no productwas formed (Table
1, entry 8). Instead of TMSN3 as azide source when sodium azide was
used, no reaction was observed.
On the basis of these results, together with the literature re-
ports,13 we propose a plausible mechanism as shown in Scheme
OH
N3
TMSN3
+
PdCl2
2
1
HN3
N3
OTMS
OTMS
Pd2+
Pd+
+
Pd 2+
HN3
Pd2+
I
OTMS
OTMS
+ H+
IV
TMSOH
Pd+
H+
+
Pd+
II
OTMS
Pd2+
OTMS
Pd2+
+
III
Scheme 2.

P. Surendra Reddy et al. / Tetrahedron Letters 51 (2010) 4037–4041
4039
Table 2
Pd(II) may be visualized as a heterolytic cleavage of CH bond by
Pd(II). Then, the structure of
-allyl-palladium IV17 is built up
through the departure of the TMS-protected hydroxyl group. The
cationic -allylpalladium intermediate IV generated should be
Synthesis of allylic azides from different homoallylic alcoholsa
p
Entry Homoallyl alcohol
Allylic azide
Yield
(%)
p
electrophilic enough to be attacked by the nucleophile hydrazoic
acid which results in the stable product, allylic azide 2 without
any [3,3]-sigmatropic rearrangement.
OH
N3
1
92
82
85
84
With reliable procedure in hand, we proceeded to examine the
scope of the hydroazidation reaction with different homoallyl alco-
hols, and the generality of this methodology and the results are
summarized in Table 2. As can be seen from the table, various
homoallyl alcohols were converted into the corresponding allylic
azides in good to excellent yield (Table 2, entries 1–7) as single reg-
ioisomer exclusively without any [3,3]-sigmatropic rearrange-
ment. It is presumably because of its increased stability due to
conjugation of the double bond with the phenyl ring. Such compat-
ibility is further demonstrated by homoallyl alcohol derived from
terephthalaldehyde, where the product bis-allylic azide is formed
predominantly (Scheme 3). However, the allylic azide derived from
homoallyl alcohols having aliphatic substituent, engaged in [3.3]-
sigmatropy, and product obtained as regioisomers in the ratio of
9:1 (Table 2, entry 8).18
The mild conditions of the hydroazidation reaction permitted us
to examine various processes that effect the conversion of the
product to other useful compounds without the need of isolation
and purification of azides themselves. Recently, Lee et al. reported
CH2Cl2/H2O as an effective solvent for Cu(I)-catalyzed azide and al-
kyne cycloaddition.19 The formed allylic azide from the homoallyl
alcohol through palladium-catalyzed hydroazidation was treated
with terminal alkyne, CuI, and water to furnish 1,4-disubstituted
1,2,3-triazoles in a one-pot operation. Water plays an important
role in the formation of copper acetylide from copper iodide and
acetylene, without using any amine base and accelerates the
reaction.
As exemplified in Table 3, the reaction proceeds smoothly to
completion and the products were obtained in good yields with
excellent purity without isolating the intermediate allylic azide.
Various allylic alcohols were subjected to reaction with TMSN3 fol-
lowed by terminal alkynes and it was found that the reaction was
fairly general and tolerated a variety of substituted secondary alco-
hols (Table 3, entries 1–7). To extend the general applicability of
this reaction, several terminal alkynes were reacted with allylic
azides that are generated in situ from alcohol 1 and TMSN3 under
optimized reaction conditions and the results are presented in Ta-
ble 4. Structurally and electronically diverse terminal alkynes were
used in this study. 4-Methyl, 2,4,5-trimethyl and 3-F phenylacetyl-
enes reacted smoothly to give the desired products in good yields
(Table 4, entries 1–4). Whereas, the reaction with 2-nitrophenyl-
acetylene was observed to be slow and product obtained was in
a low yield. The reaction with heterocyclic alkynes such as 2-ethy-
nyl pyridine gave the product in a moderate yield. In addition, ali-
phatic alkynes underwent the reaction smoothly to give the
corresponding products in excellent yield under these optimized
reaction conditions.
OH
N3
2
Br
Br
OH
N3
3
OH
N3
4
5
H3CO
H3CO
OH
N3
90
90
OCH3
OCH3
OH
N3
H3CO
H3CO
H3CO
H3CO
6
OCH3
OCH3
OH
N3
7
8
80
67
OH
N3
a
Reaction conditions: homoallylic alcohol (1 mmol), TMSN3 (1.5 mmol), PdCl2
(3 mol %), dichloromethane (3 mL) stirred at room temperature for 3 h.20
2. The silylation of 1 with TMSN3 takes place at the first step and
gives the intermediate trimethylsilylether and hydrazoic acid
(HN3). The observations made in the optimization of reaction con-
ditions such as low yield of the product obtained with the
Pd(CH3CN)2Cl2 and no product was formed with Pd (PPh3)4, would
rule out a mechanism involving the oxidative addition of an allylic
CH bond to the metal, since the propensity to undergo oxidative
addition should increase with increasing electron density on the
metal.14 The key intermediate in the proposed mechanism is incip-
ient carbocation I generated through the interaction of the alkene
with Pd(II) center, loss of H+ from I would yield the cationic allyl
compound, II.15 The proton then cleaved the Pd–C bond in a well
precedented step16 to produce the isomerized alkene III and regen-
erating the catalyst. The formation of II and H+ from alkene and
To show the convenience of our approach for the synthesis of
multivalent structures, compound 1 and 1,3-diethynyl benzene
OH
3 equiv TMSN3
3 mol% PdCl2
N3
N3
CH2Cl2, 5 h, rt
87 %
OH
Scheme 3.

4040
P. Surendra Reddy et al. / Tetrahedron Letters 51 (2010) 4037–4041
Table 3
One-pot synthesis of 1,4-disubstituted 1,2,3-triazoles from homoallyl alcohols using PdCl2 and Cu(I) catalystsa
Entry
1
Homoallyl alcohol
Allyl triazoles
Yield (%)
85
OH
N
N
Ph
N
OH
N
Ph
2
3
4
75
80
80
N
N
Br
Br
OH
N
Ph
N
N
OH
N
Ph
N
N
H3CO
H3CO
OH
O
O
O
O
N
Ph
5
6
7
82
80
68
N
N
OH
H3CO
H3CO
H3CO
H3CO
N
Ph
N
N
OCH3
OCH3
OH
N
N
Ph
N
a
Reaction conditions as exemplified in typical experimental procedure.21
N
N
3 mol % PdCl2
1.5 equivTMSN3
N
OH
CH2Cl2, rt, 3h
+
5 mol% CuI,
H2O, rt 6h.
5
1
N
N
N
N
N
N
4
Ph
Ph
6
Product 5/6 ratio : 1/9, yield: 82 %
Scheme 4.
were reacted under the optimized reaction conditions to afford
high yields of bistriazoles showing the versatility of the catalytic
system for generating multivalent structures (Scheme 4).
In conclusion, we have developed an efficient route for the syn-
thesis of allylic azides from homoallyl alcohols through palladium-
catalyzed hydroazidation with double bond migration. This
conceptually new approach provides a straightforward and effi-
cient access to allylic azides. In addition, the reaction can be cou-
pled to copper-catalyzed 1,3-dipolar cycloaddition to generate
1,4-disubstituted 1,2,3-triazoles in one-pot without isolating the
azide intermediate and should prove to be useful for generating
multivalent structures

P. Surendra Reddy et al. / Tetrahedron Letters 51 (2010) 4037–4041
4041
Table 4
88, 297; (d) Hassner, A. In Azides and Nitrenes; Scriven, E. F. V., Ed.; Academic:
New York, NY, 1984.
One-pot synthesis of 1,4-disubstituted 1,2,3-triazoles from different terminal alkynes
and homoallylic alcohol (1) using PdCl2 and Cu(I) catalystsa
3. (a) Feldman, A. K.; Colasson, B.; Sharpless, K. B.; Fokin, V. V. J. Am. Chem. Soc.
2005, 127, 13444; (b) Mangelinckx, S.; Boeykens, M.; Vliegen, M.; Van der
Eycken, J.; De Kimpe, N. Tetrahedron Lett. 2005, 46, 525; (c) Cardillo, G.;
Fabbroni, S.; Gentilucci, L.; Perciaccante, R.; Piccinelli, F.; Tolomelli, A. Org. Lett.
2005, 7, 533; (d) Takasu, H.; Tsuji, Y.; Sajiki, H.; Hirota, K. Tetrahedron 2005, 61,
11027; (e) Khanetskyy, B.; Dallinger, D.; Kappe, C. O. J. Comb. Chem. 2004, 6,
884; (f) Papeo, G.; Posteri, H.; Vianello, P.; Varasi, M. Synthesis 2004, 2886.
4. (a) Trost, B. M.; Pulley, S. R. Tetrahedron Lett. 1995, 36, 8737; (b) Trost, B. M.;
Cook, G. R. Tetrahedron Lett. 1996, 37, 7485; (c) Capaccio, C. A. I.; Varela, O.
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N
1
2
85
87
Ph
Ph
Ph
N
N
N
N
N
N
N
N
3
4
85
80
5. (a) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057; (b)
Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed.
2002, 41, 2596.
N
N
Ph
Ph
N
N
6. For representative applications of the Cu(I)-catalyzed azide–alkyne
cycloaddition, see: (a) Wang, Q.; Chan, T. R.; Hilgraf, R.; Fokin, V. V.;
Sharpless, K. B.; Finn, M. G. J. Am. Chem. Soc. 2003, 125, 3192; (b) Speers, A.
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Angew. Chem., Int. Ed. 2004, 30, 3928.
F
F
N
N
5
56
NO2
O2N
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N
N
N
6
7
8
9
75
80
70
75
Ph
Ph
Ph
Ph
N
N
N
N
N
OH
HO
N
N
N
N
HO
N
N
HO
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Reaction conditions as exemplified in typical experimental procedure.21
a
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Acknowledgments
17. (a) McGrath, D. C.; Grubbs, R. H. Organometallics 1994, 13, 224; (b) Cadierno, V.;
Garrido, S. E. G.; Gimeno, J.; Alvarez, A. V.; Sordo, J. J. Am. Chem. Soc. 2006, 128,
1360; (c) Uma, R.; Crevisy, C.; Gree, R. Chem. Rev. 2003, 103, 27.
18. The ratio was determined by 1H NMR and spectra is given in the
Supplementary data.
19. Lee, B. Y.; Park, S. R.; Jeon, H. B.; Kim, K. S. Tetrahedron Lett. 2006, 47, 5105.
20. Typical procedure for the hydroazidation of homoallyl alcohols: a mixture of
homoallyl alcohol (1 mmol), TMSN3 (1.5 mmol), and palladium chloride
(3 mol %) in dichloromethane (3 mL) was stirred at room temperature for
3 h. After completion of the reaction, as indicated by TLC, the reaction mixture
was diluted with water and extracted with dichloromethane (2 Â 10 mL). The
combined organic layers were dried over anhydrous Na2SO4, concentrated in
vacuo, and purified by column chromatography on silica gel to afford the pure
product.
P.S.R. thanks the Council of Scientific and Industrial Research,
New Delhi for the award of Senior Research Fellowship and V.R.
thanks Indo French Centre for the Promotion of Advanced Research
(IFCPAR), New Delhi for financial assistance.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.05.097.
21. Typical procedure for the one-pot synthesis of 1,4-disubstituted 1,2,3-triazoles
from homoallyl alcohols: a mixture of homoallyl alcohol (1 mmol), TMSN3
(1.5 mmol), and palladium chloride (3 mol %) in dichloromethane (3 mL) was
stirred at room temperature for 3 h, and the reaction was monitored by TLC.
Phenylacetylene (1.2 mmol), CuI (5 mol %) and water (2 mL) were added and
the reaction mixture was stirred at room temperature for 6 h. After completion
of the reaction (as monitored by TLC), the reaction mixture was filtered
through Celite and the product was extracted with dichloromethane
(2 Â 10 mL). After removing the solvent under vacuum, the crude product
was purified by column chromatography on silica gel using (hexane–ethyl
acetate) to afford pure product. All products were characterized by IR, 1H NMR,
13C NMR and mass spectroscopic techniques. Please see Supplementary data
for spectral data of all compounds.
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