Magnetically separable nano Fe3O4 catalyzed direct azidation of allylic and benzylic alcohols followed by copper-catalyzed click reaction

Article abstract of DOI:10.1055/s-0034-1378517

A competent one-pot method comprising magnetically separable nano Fe ₃O₄ catalyzed direct azidation of allylic and benzylic alcohols followed by the copper-catalyzed click reaction of the corresponding azides with alkynes is reported. This method gave a direct access to several 1,2,3-triazoles starting from various allylic and benzylic alcohols via their respective azides. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0034-1378517

LETTER
▌2201
lMettear gnetically Separable Nano Fe3O4 Catalyzed Direct Azidation of Allylic and
Benzylic Alcohols Followed by Copper-Catalyzed Click Reaction
Direct Conversion of Allyl/Benzyl Alcohols into 1,2,3-Triazoles
Naveen, Nayyar Ahmad Aslam, Srinivasarao Arulanda Babu,* Dharmendra Kumar Singh, Ameet Rana
Indian Institute of Science Education and Research (IISER) Mohali, Knowledge City, Sector 81, SAS Nagar, Mohali, Manauli P.O., Punjab,
140306, India
Fax +91(172)2240266; E-mail: sababu@iisermohali.ac.in
Received: 06.05.2014; Accepted after revision: 20.06.2014
With the aim of developing heterogeneous catalytic meth-
Abstract: A competent one-pot method comprising magnetically
ods with clean recovery of the catalyst after the reaction
separable nano Fe3O4 catalyzed direct azidation of allylic and ben-
and efficient recyclability of the catalyst, organic transfor-
zylic alcohols followed by the copper-catalyzed click reaction of the
corresponding azides with alkynes is reported. This method gave a
mations catalyzed by magnetic nanoparticles have attract-
direct access to several 1,2,3-triazoles starting from various allylic ed the attention of synthetic chemists.14
and benzylic alcohols via their respective azides.
Recently, Sreedhar’s group8 reported the synthesis of
Key words: alcohols, azides, click reaction, cycloaddition, tri-
1,2,3-triazoles from homoallyl alcohols via the palladi-
um-catalyzed azidation followed by click reaction. Click-
reaction protocols to synthesize 1,2,3-triazoles are well
established, and 1,2,3-triazoles are considered as very im-
portant biologically active synthetic moieties in medicinal
chemistry.15 To the best of our knowledge, the direct cat-
alytic azidation of allylic and benzylic alcohols has not
been explored using magnetically separable heteroge-
neous catalysts. In this paper, we report sequential pro-
cesses comprising the magnetic nano Fe3O4 catalyzed
direct azidation of allylic and benzylic alcohols, followed
by the copper-catalyzed click reaction of the correspond-
ing azides with alkynes affording several new 1,2,3-tri-
azoles (Scheme 1).
azoles, magnetite
In recent years numerous protocols have been developed
for the direct catalytic substitution of the hydroxyl group
in allylic and benzylic alcohols by various nucleophiles.1–
6
The direct catalytic substitution of allylic and benzylic
alcohols is considered as an atom-economical reaction.1–4
The construction of a C–C bond via the direct catalytic
substitution of allylic and benzylic alcohols using the car-
bon-based nucleophiles is also well explored.1–4 Similar-
ly, the Lewis acid/transition-metal-salt-catalyzed direct
substitution of allylic and benzylic alcohols using nitro-
gen-based nucleophiles leading to the formation of a C–N
bond is an attractive route for the synthesis of allylic and
benzylic amines/azides and other related compounds.5–13
In general, allylated nitrogen compounds including allylic
and benzylic amines/azides are considered as important
building blocks for the synthesis of heterocycles, natural
products, and biologically active molecules.13
Initially, we carried out optimization reactions to find out
the best reaction conditions to effect the direct azidation
of allylic alcohol 1a (0.5 mmol) with TMSN3 (1.25 mmol,
Table 1). Treatment of allylic alcohol 1a with TMSN3 in
the absence of any catalyst in DCE at room temperature or
70 °C did not provide the desired product (E)-(3-azido-
prop-1-ene-1,3-diyl)dibenzene (2, Table 1, entry 1). The
reaction of allylic alcohol 1a with TMSN3 in the presence
of nano Fe3O4 (15 mol%, particle size ≤50 nm) in 1,4-di-
oxane, MeCN, and MeOH was equally ineffective (Table
1, entries 2–4). The direct azidation of 1a with TMSN3 in
the presence of nano Fe3O4 (15 mol%) in acetone, THF,
There are notable reports on the direct azidation of allylic
and benzylic alcohols under homogeneous catalysis.6–12
Recently, Rueping’s group reported the direct catalytic
azidation of allylic and benzylic alcohols using silver salts
under homogeneous catalysis.12d
magnetic
nano Fe3O4
(10–15 mol%)
alkyne
CuSO4⋅5H2O
sodium L-ascorbate
Y
N
N
OH
Z
+
direct
azidation
and catalyst
recovery
N
click reaction
TMSN3
Scheme 1 Theme of this work
SYNLETT 2014, 25, 2201–2207
Advanced online publication: 04.08.2014
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1
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1
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DOI: 10.1055/s-0034-1378517; Art ID: st-2014-d0384-l
© Georg Thieme Verlag Stuttgart · New York

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Naveen et al.
LETTER
Table 2 Catalyst Recyclinga
and toluene gave 2 in 20–55% yields (Table 1, entries 5–
7). The product 2 was obtained in 85% and 92% yields
when the reaction was performed in CH2Cl2 at room tem-
perature or at reflux, respectively (Table 1, entries 8 and
9). The reaction of 1a (1 equiv) with TMSN3 (2.5 equiv)
in the presence of nano Fe3O4 (15 mol%) in DCE at room
temperature furnished the product 2 in 89% (Table 1, en-
try 10). Under the similar conditions, the reaction of alco-
hol 1a (1 equiv) with 1.1 equivalents or 1.5 equivalents of
TMSN3 gave the product 2 in 80% and 83% yields, re-
spectively (Table 1, entries 11 and 12).
Run
Time (h)
Yield (%) of 2
1
2
3
4
5
6
7
6
6
98
97
97
97
97
96
95
8
10
12
15
20
Table 1 Nano Fe3O4 Catalyzed Direct Azidation of 1a
OH
a The reaction was performed using 1a (0.5 mmol), TMSN3 (1.25
N3
nano MtxOy
mmol) and nano Fe3O4 (15 mol%) in DCE (1.5 mL) at 70 °C.
TMS N3
+
Ph
Ph
Ph
Ph
solvent (1.5 mL)
1a (0.5 mmol)
(1.25 mmol)
2
in the presence of 10 mol% of nano Fe3O4 in DCE at 70 °C
for 16 hours afforded the product 2 in 92% yield (Table 1,
entry 16). Use of other catalysts, such as nano Fe2O3 or
powdered Fe3O4 gave 2 in less than 5% and 35% yields,
respectively (Table 1, entries 17 and 18). We also tested
the recyclability of the magnetic nano Fe3O4 for the reac-
tion of direct azidation of allylic alcohol 1a, which gave
the product 2 in 95% yield in the seventh run (Table 2).16,17
Then, we analyzed the condition of the recovered nano
Fe3O4 catalyst after different runs. FT-IR spectroscopic
analysis of the fresh and recovered magnetic nano Fe3O4
revealed no distinctive changes. HRTEM analysis of the
used magnetic nano Fe3O4 showed no obvious change in
the morphology of the nanoparticles (see the Supporting
Information for FT-IR and HRTEM analysis data).
Entry Catalyst
(mol%)
Solvent
Conditions Yield
(%) of 2
1
2
–
DCE
70 °C, 40 h
0
nano Fe3O4 (15)
nano Fe3O4 (15)
nano Fe3O4 (15)
nano Fe3O4 (15)
nano Fe3O4 (15)
nano Fe3O4 (15)
nano Fe3O4 (15)
nano Fe3O4 (15)
nano Fe3O4 (15)
nano Fe3O4 (15)
nano Fe3O4 (15)
nano Fe3O4 (15)
nano Fe3O4 (15)
nano Fe3O4 (15)
nano Fe3O4 (10)
nano Fe2O3 (15)
1,4-dioxane r.t., 30 h
0
0
3
MeCN
MeOH
acetone
THF
r.t., 30 h
r.t., 30 h
r.t., 30 h
r.t., 30 h
r.t., 30 h
r.t., 10 h
reflux, 8 h
r.t., 15 h
r.t., 15 h
r.t., 15 h
70 °C, 6 h
70 °C, 6 h
70 °C, 6 h
4
0
5
23
20
55
85
92
89
80a
83b
98
85a
89b
6
7
toluene
CH2Cl2
CH2Cl2
DCE
8
9
Table 3 Magnetic Nano Fe3O4 Catalyzed Azidation of 1a Followed
by Click Reactiona
10
11
12
13
14
15
16
17
18
DCE
Ph
DCE
Ph
OH
Ph
Y
N
nano Fe3O4
(15 mol%)
1a (0.5 mmol)
CuSO4⋅5H2O
DCE
+
Ph
N
N
Z
alkyne
(1.2 mmol)
TMSN3
4
DCE
(1.25–1.5 mmol)
DCE
Entry Alkyne
1,2,3-Triazole 4, yield (%)
DCE
70 °C, 16 h 92
70 °C, 30 h <5
70 °C, 48 h 35
Ph
DCE
HO
Ph
N
N
powder Fe3O4 (15) DCE
1
N
N
OH
a In this case, 0.55 mmol of TMSN3 were used.
b In this case, 0.75 mmol of TMSN3 were used.
3a
4a 82
Ph
Ph
Ph
N
N
The reaction of 1a (1 equiv) with TMSN3 (2.5 equiv) in
the presence of nano Fe3O4 (15 mol%) in DCE at 70 °C
furnished the product 2 in 98% yield (Table 1, entry 13).
Under similar conditions, the reaction of alcohol 1a (1
equiv) with 1.1 equivalents or 1.5 equivalents of TMSN3
gave 2 in 85% and 89% yields, respectively (Table 1, en-
tries 14 and 15). The reaction of alcohol 1a with TMSN3
Ph
2
3b
4b 90
Synlett 2014, 25, 2201–2207
© Georg Thieme Verlag Stuttgart · New York

LETTER
Direct Conversion of Allyl/Benzyl Alcohols into 1,2,3-Triazoles
2203
Table 3 Magnetic Nano Fe3O4 Catalyzed Azidation of 1a Followed
Having optimized conditions for the direct azidation of 1a
(Table 1, entry 11), we envisaged performing the copper-
catalyzed click reaction using the product 2. Thus, we first
performed nano Fe3O4 catalyzed azidation of allylic alco-
hol 1a, followed by the copper-catalyzed click reaction of
the product (E)-(3-azidoprop-1-ene-1,3-diyl)dibenzene
(2) with various alkynes 3a–i, leading to the construction
of several new 1,2,3-triazole derivatives 4a–i in 75–93%
yields, respectively (Table 3).16
by Click Reactiona (continued)
Ph
Ph
OH
Ph
Y
N
nano Fe3O4
(15 mol%)
1a (0.5 mmol)
CuSO4⋅5H2O
+
Ph
N
N
Z
alkyne
(1.2 mmol)
TMSN3
4
(1.25–1.5 mmol)
Entry Alkyne
1,2,3-Triazole 4, yield (%)
Subsequently, we used various allylic alcohols 1b–g in
the nano Fe3O4 catalyzed direct azidation reaction, fol-
lowed by copper-catalyzed click reaction to give the cor-
responding 1,2,3-triazoles 4j–p in 45–82% yields (Table
4).16 Products 4j and 4k were obtained as a mixture of re-
gioisomers since the allylic alcohols 1b and 1c underwent
an allylic rearrangement under the reaction conditions,
thereby leading to their corresponding regioisomers. Sim-
ilarly, the products 4o and 4p were also obtained as a mix-
ture of regioisomers (Table 4).
Ph
O
Ph
N
N
O
O
3
N
O
3c
4c 93
Ph
Ph
Ph
Ph
Ph
COOMe
Ph
N
N
DMAD
COOMe
COOEt
4
3d
N
N
N
N
N
Subsequently, we tested the scope of the nano Fe3O4 cat-
alyzed direct azidation reaction of several benzylic alco-
hols 5a–e followed by the click reaction of the
corresponding azides with alkynes (Table 5)16 and suc-
cessfully obtained the corresponding 1,2,3-triazole deriv-
atives 6a–e in 35–71% yields. A gram-scale process
involving the direct azidation of 1a followed by the click
reaction gave 1,2,3-triazole 4b in 88% yield under the op-
timized reaction conditions (Scheme 2).
4d 86
EtOOC
Ph
N
N
5
3e
4e 86
Ph
N
N
6
To show the utility of the 1,2,3-triazoles obtained in this
work, we methylated 1,2,3-triazole 4k and observed the
formation of an ionic liquid 8 via elimination of the allylic
moiety present in 4k (Scheme 2). Since we found the al-
lylic moiety is eliminated in the reaction of 4k with MeI,
in a subsequent process we first hydrogenated the olefin
moiety present in 4b which gave the 1,2,3-triazole deriv-
ative 9. Further treatment of 9 with MeI gave an ionic liq-
uid product 10. Finally, the hydrogenation of (E)-(3-
azidoprop-1-ene-1,3-diyl)dibenzene (2) led to the forma-
tion of 1,3-diphenylpropan-1-amine (11) in 50% yield.
3f
4f 85
Ph
N
N
7
3g
4g 92
CHO
OHC
O
Ph
N
N
O
8
In summary, we have shown a competent catalytic proto-
col comprising the magnetically recoverable nano Fe3O4
catalyzed direct azidation of allylic and benzylic alcohols
followed by a click reaction. Construction of several new
1,2,3-triazole derivatives directly from allylic and benzyl-
ic alcohols via their respective azides was accomplished.
3h
4h 85
O
O
O
O
O
O
N
N
N
N
N
9
O
N
Acknowledgment
We thank IISER-Mohali for funding and NMR, HRMS and X-ray
facilities. Naveen and N. A. Aslam thank UGC for fellowships.
O
Ph
Ph
Ph
Ph
4i 75
3i
Supporting Information for this article is available online
a Reaction conditions: The azidation of 1a was carried out using nano
Fe3O4 (15 mol%) in DCE (1.5 mL) at 70 °C for 6 h, the solvent was
evaporated, and then the click reaction was carried out using alkyne
(1.2 mmol) in THF (3 mL) and H2O (3 mL) in the presence of Cu-
SO4·5H2O (30 mol%) and sodium L-ascorbate (30 mol%) at r.t. for 12
h.
at
http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000083.SunogIpimrfiantoSuIpg
n
fonirtat
ori
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 2201–2207

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Naveen et al.
LETTER
gram-scale reaction
Ph
Ph
OH
Ph
nano Fe3O4
(15 mol%)
1a (1.05 g, 5 mmol)
3b (10 mmol)
+
Ph
N
N
Ph
Ph
click conditions
TMSN3 (13 mmol)
N
4b 88%
Ph
N
Me
Ph
Me
I–
N
Me
MeI
N
N
N
N
N
I–
I
+
N
reflux
5 d
N
I
Me
8 85%
ionic liquid
Ar
Ph
Ar
Ph
4k
7
Ar = p-Tolyl
Ar
Ph
I–
Ph
Me
Ph
Ph
H2 (1 atm)
N
N
N
Pd/C (10 mol%)
MeI
N
N
N
N
N
N
reflux
4 d
THF (2 mL)
24 h
Ph
Ph
Ph
Ph
Ph
Ph
4b
9 91%
10 92%
ionic liquid
Ph
Ph
H2 (1 atm), Pd/C (10 mol%)
THF (2 mL), r.t., 24 h
Ph
NH2
Ph
N3
2
11 50%
(1 mmol)
Scheme 2 Gram-scale reaction and synthetic transformations
Table 4 Azidation of 1b–d Followed by Click Reactiona
OH
nano Fe3O4
R1
1b–d (1 mmol)
alkyne (2 mmol)
(15 mol%)
+
N
R2
CuSO4⋅5H2O (30 mol%)
sodium L-ascorbate (30 mol%)
THF–H2O (1:1, 6 mL)
r.t., 12 h
DCE (3 mL)
TMSN3
N
N
70 °C, time (h)
(2.5–3 mmol)
4j–p
Entry
Substrate 1
Time (h)
Alkyne
Product 4, yield (%)
OH
Ph
Ph
N
N
1
2
12
N
Br
Br
4j 82 (50:50)b
3f
1b
OH
Ph
Ph
15
3b
Ph
N
Ph
N
1c
N
4k 72 (50:50)b
Synlett 2014, 25, 2201–2207
© Georg Thieme Verlag Stuttgart · New York

LETTER
Direct Conversion of Allyl/Benzyl Alcohols into 1,2,3-Triazoles
2205
Table 4 Azidation of 1b–d Followed by Click Reactiona (continued)
OH
nano Fe3O4
R1
N
1b–d (1 mmol)
alkyne (2 mmol)
(15 mol%)
+
N
N
R2
CuSO4⋅5H2O (30 mol%)
sodium L-ascorbate (30 mol%)
THF–H2O (1:1, 6 mL)
r.t., 12 h
DCE (3 mL)
TMSN3
70 °C, time (h)
(2.5–3 mmol)
4j–p
Entry
Substrate 1
Time (h)
Alkyne
Product 4, yield (%)
Cl
OH
COOMe
COOMe
COOMe
3
14
Cl
Cl
COOMe
N
N
3d
N
1d
Cl
4l 52
Ph
N
OH
N
Ph
N
4
5
18
18
Ph
Ph
Ph
Ph
3b
Ph
Ph
1e
4m 62
OHC
OHC
O
OH
N
O
N
Ph
N
1e
3h
3e
Ph
Ph
4n 57
COOEt
N
OH
N
N
COOEt
Ph
6
7
30
24
Ph
Ph
1f
4o 62 (76:24)b
COOEt
N
OH
N
COOEt
N
Ph
Ph
3e
Ph
Ph
1g
4p 45 (88:12)b
a After the azidation reaction the magnetic nano Fe3O4 was separated then the click reaction was performed.
b Products were obtained as a mixture of regioisomers due to an allylic rearrangement under the experimental conditions.
© Georg Thieme Verlag Stuttgart · New York
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Naveen et al.
LETTER
Table 5 Nano Fe3O4 Catalyzed Azidation of 5a–e Followed by Click Reactiona
OH
Y
5a–e (1 mmol)
nano Fe3O4
CuSO4⋅5H2O
+
N
N
Z
alkyne (2 mmol)
TMSN3 (2.5–3 mmol)
N
6a–e
Entry
Alcohol
Alkyne
Yield (%) of 6
COOEt
N
OH
OH
OH
N
N
N
N
COOEt
1
3e
3e
3e
3e
5a
6a 71
6b 35
6c 70
COOEt
N
N
COOEt
COOEt
COOEt
2
3
4
5
5b
5c
5d
5e
COOEt
N
N
COOEt
N
OH
N
N
6d 52
N
OH
N
N
3f
6e 70
a Reaction conditions: The azidation of 1a was carried out using nano Fe3O4 (15 mol%) in DCE (3 mL) at 70 °C for 14–20 h, the solvent was
evaporated, and then the click reaction was carried out using alkyne (2 mmol) in THF (3 mL) and H2O (3 mL) in the presence of CuSO4·5H2O
(30 mol%) and sodium L-ascorbate (30 mol%) at r.t. for 12 h.
(3) Bandini, M. Angew. Chem. Int. Ed. 2011, 50, 994.
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Synlett 2014, 25, 2201–2207
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Direct Conversion of Allyl/Benzyl Alcohols into 1,2,3-Triazoles
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(16) General Procedure for the Magnetic Nano Fe3O4
Catalyzed Direct Azidation of Allylic Alcohol 1a
A mixture of alcohol 1a (0.5 mmol), trimethylsilyl azide
(1.25 mmol), and magnetic nano Fe3O4 (particle size <50
nm, 15 mol%; the particles can be handled using a Teflon
spatula) in DCE (3 mL) was stirred at 70 °C for 6 h. At this
stage a magnet was externally applied to the reaction flask to
attract the magnetic Fe3O4 nanoparticles, and the resulting
clear solution was transferred to another flask using a
pipette. The catalyst was washed using EtOAc (2 mL), and
the residual Fe3O4 nanoparticles were heated in an oven at
100–110 °C overnight, and the catalyst was reused in
subsequent cycles. The combined organic layers were
evaporated under vacuum and purified by column
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chromatography to give the product 2.
General Procedure for the One-Pot Magnetic Nano
Fe3O4 Catalyzed Direct Azidation of Allylic Alcohols and
Click Reaction
The direct azidation of 1a (0.5 mmol) was carried out as
above, the catalyst was removed using an external magnet,
and the solvent was evaporated. Then to the residue THF (3
mL), H2O (3 mL), alkyne (1 mmol), CuSO4·5H2O (30
mol%), and sodium L-ascorbate (30 mol%) were added, and
the mixture was stirred at r.t. for 12 h. The reaction mixture
was then extracted using EtOAc, the combined organic
layers were evaporated, and the resulting reaction mixture
was purified by column chromatography, eluting with
EtOAc–hexanes (50:50), to afford the product 4a as a
colorless liquid. Yield: 82% (238 mg). FT-IR (neat): ν =
3375, 2954, 1731, 1450, 1223, 1091 cm–1. 1H NMR (400
MHz, CDCl3): δ = 7.57 (s, 1 H), 7.41–7.28 (m, 10 H), 6.70
(dd, J1 = 15.6 Hz, J2 = 7.2 Hz, 1 H), 6.52–6.47 (m, 2 H), 4.79
(s, 2 H), 3.36 (br s, 1 H). 13C NMR (100 MHz, CDCl3): δ =
147.8, 137.7, 135.5, 134.7, 129.2, 128.8, 128.7, 128.6,
127.5, 126.9, 125.5, 121.2, 66.5, 56.4. ESI-HRMS: m/z calcd
for C18H18N3O [M + H]+: 292.1450; found: 292.1100.
(17) The nano Fe3O4 used in this work was purchased from
Sigma-Aldrich, and the size of the particles was checked
through HRTEM analysis/images (see the Supporting
Information) before using the nano Fe3O4. For
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Synlett 2014, 25, 2201–2207

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