Raney Ni catalyzed azide-alkyne cycloaddition reaction

Article abstract of DOI:10.1039/c4ra07057g

Raney Ni efficiently catalyzes acetylene azide cycloaddition reactions to form 1,2,3-triazoles. Unlike the CuSO₄/sodium ascorbate reagent system, there is no need for a reducing agent under Raney Ni catalysis. Terminal acetylene selectivity, 1,

Full text of DOI:10.1039/c4ra07057g

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Raney Ni catalyzed azide-alkyne cycloaddition
reaction†
Cite this: RSC Adv., 2014, 4, 46040
*
H. Surya Prakash Rao and Guravaiah Chakibanda
Received 13th July 2014
Accepted 10th September 2014
DOI: 10.1039/c4ra07057g
www.rsc.org/advances
Raney Ni efficiently catalyzes acetylene azide cycloaddition reactions reactions with CuSO4 and sodium ascorbate have become
to form 1,2,3-triazoles. Unlike the CuSO4/sodium ascorbate reagent hugely popular, still, the need for a reducing agent is one of the
system, there is no need for a reducing agent under Raney Ni catalysis. disadvantages of the method. Alternatively, some catalysts
Terminal acetylene selectivity, 1,4-regioselectivity and mild reaction derived from Ag,9 Au,10 Al,11 Ru,12 and Ir13 complexes which work
conditions are prominent features of the method. Mechanistic probing without additional reducing agent have been employed to
revealed that the reaction does not go through nickel acetylides.
promote AAC, but the catalysts are difficult to make or expensive
and most of the times reactions are cumbersome to conduct.
Thus, there is a need to discover an alternative catalyst, which is
inexpensive, readily available, reusable and does not require an
additional reducing agent.
1. Introduction
The Huisgen's 1,3-dipolar cycloaddition of azides to alkynes for
the synthesis of 1,2,3-triazoles is one of the most prominent
name reactions.1 The reaction has become most applied for
covalently linking two divergent molecular entities: one with a
terminal acetylene group and the other with an azide,2 owing to
independent discoveries by Sharpless and Meldal that copper(I)3
catalysts efficiently promote azide alkyne cycloaddition (AAC) in
high yield as well as in a regio-(1,4- over 1,5-) and chemo-
(terminal alkyne vs. internal alkyne reactivity) selective manner.
The copper(I) mediated azide acetylene cycloaddition (CuAAC)
reactions have become premier examples for a click reaction as
they provide near quantitative yield of the regiochemically pure
1,4-disubstituted 1,2,3-triazoles, tolerate a wide variety of
functional groups and can be conducted under mild reaction
conditions including in aqueous medium. The CuAAC reaction
found applications4 in diversied elds such as medicinal,5
polymer,6 materials7 and bioorganic8 etc. Instead of employing
Cu(I) complexes or its salts, which are relatively unstable or
difficult to prepare, the CuAAC reactions are generally con-
ducted with a catalytic amount of CuSO4 and sodium ascorbate
where sodium ascorbate serves as the reducing agent for in situ
generation of Cu(I) species. According to well-accepted mecha-
nism Cu(I) species gets intimately involved in every stage of the
reaction and helps to bring azide and acetylene units in close
proximity for cycloaddition to take place. Although the click
2. Results and discussion
In a quest to discover such a catalyst, we screened several bench
top stable and inexpensive salts like Ni(OAc)2, NiCl2, NiCO3,
NiSO4, BiCl3, BiNO3, As2O3 and Sb2O3 in catalytic amounts
(10 mol%) for cycloaddition of phenyl propargyl ether 1a to
phenyl azide 2a to provide triazole 3a (Scheme 1). None of these
catalysts worked independent of a reducing agent. The nickel
salts like Ni(OAc)2, NiCl2, NiCO3 and NiSO4, catalysed the AAC
reaction and provided triazole 3a in moderate yield (<70%) in
presence of 20 mol% of the reducing agents like hydrazine,
glucose, lactose or particularly sodium ascorbate. Outcome of
the reaction indicated that reactive Ni(0) species could be the
catalyst in the reaction. Therefore, in sequel, we employed
Raney Ni as the catalyst and discovered that it catalyses the AAC
efficiently (Scheme 1). Notably, there was no need for a reducing
agent like sodium ascorbate when Raney Ni was employed.
Raney Ni is a classical reagent used extensively as a catalyst for
Department of Chemistry, Pondicherry University, Puducherry-605 014, India. E-mail:
hspr.che@pondiuni.edu.in
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra07057g
Scheme 1 Raney Ni catalyzed cycloadditions of phenyl azide 2a with
various propargyl ethers 1a–j.
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hydrogenation of carbon–carbon and carbon-hetero atom level. This result made us conclude that Ni is responsible for the
double or triple bonds.14 It is also used as a reagent for desul- AAC reaction.
furization. Thus, in continuation of our studies on the Huisgen
Building on the results from development of optimal
reaction,15 herein we report scope and limitations as well as conditions for the NiAAC reaction of phenyl propargyl ether 1a
some evidence for mechanism of the Raney Ni mediated AAC to phenyl azide 2a to give the regiochemically selective triazole
for a facile synthesis of several 1,2,3-traizoles.
3a, we wanted to probe the effect of different substitution on
The cycloaddition of phenyl propargyl ether 1a to phenyl propargyl ethers and azides. Nine propargyl ethers, namely, 4-t-
azide 2a to give cycloadduct 3a under 10 mol% of Raney Ni butylphenyl propargyl ether 1b, thymol propargyl ether 1c,
catalysis was selected to optimize the reaction conditions eugenol propargyl ether 1d, n-hexyl propargyl ether 1e, 1-(prop-
(Scheme 1, Fig. 1). Of different solvents like H2O (15 h, 70%), 2-ynyloxy)pent-2-yl propargyl ether 1f, benzyl propargyl ether 1g,
t-BuOH/H2O (1 : 2; 15 h, 82%), MeOH (16 h, 90%), DMF (16 h, cyclohexyl propargyl ether 1h, menthyl propargyl ether 1i,
90%), dioxane (16 h, 87%) and toluene (10 h, 98%) tried, the cholesteryl propargyl ether 1j were reacted with phenyl azide 2a
reaction worked best in toluene. Stirring the heterogeneous to realize exclusive formation of regiochemically pure triazoles
ꢀ
reaction mixture at 45 C for 12 h led to complete reaction in 3b–j, in excellent yield. The propargyl ethers were selected for
98% yield as evidenced by the absence of phenyl propargyl ether their structural diversity of being derived from an alcohol group
1a in TLC. A study to determine optimal temperature for the present on aromatic, benzylic, aliphatic or natural product
reaction revealed that 45 ꢀC is ideal for high yield and exclusive scaffolds. Signicantly, the NiAAC was not affected in terms of
regioselectivity (1,4-substitution over 1,5-substitution) of the yield or regioselectivity by subtle changes in steric and elec-
product. Although at higher temperatures still, both the rate of tronic environment in the aryl ring of the propargyl ethers.
the reaction and yield of the triazole were higher (99%), the Among all the products listed in Scheme 1, 3f is interesting as it
regio-chemical purity of the product was lower. For example, at proved that similar to CuAAC reactions, the NiAAC takes place
100 ꢀC the reaction took 1 h for completion but the product has on terminal alkyne rather than internal alkyne.
2 : 1 mixture of 1,4- and 1,5-regioisomers. At room temperature
Next, it was our endeavour to evaluate the efficiency of Raney
(30 ꢀC) the reaction took longer time for completion (24 h, 80%). Ni catalyst in the regioselectivity in the cycloaddition of benzyl
The fact that Raney Ni is practically immiscible with toluene and hexyl azides to aryl propargyl ethers. Accordingly two aryl
was used for the recovery of the product and to recycle the propargyl ethers, namely phenyl propargyl ether 1a and 4-t-
catalyst. Aer each reaction, the reaction mixture was centri- butylphenyl propargyl ether 1b were subjected to Raney Ni
fuged in a laboratory centrifuge at 2100 rpm for 1 min. Super- catalyzed AAC with benzyl azide 2b, and hexyl azide 2c in
natant solution was separated and the settled Raney Ni cake was combinatorial fashion to realize four 1,4-disubstituted triazoles
reused. The catalytic activity remained excellent for two runs 3k–n in near quantitative yield with exclusive regiochemistry
(94–98%). On further use, the yield started to decrease (84% in (Scheme 2).
the third run) with a concurrent increase in the time required to
The NiAAC reaction of benzyl 1c and cyclohexyl 1d prop-
complete the reaction. Concentration of copper impurities in argyl ethers to benzyl 2b and n-hexyl 2c azides was conducted
the Raney Ni sample was analyzed using ICP-MS to evaluate if in combinatorial fashion to evaluate efficiency of the catalyst
such copper impurities are responsible for AAC reaction. Using for promoting the reaction of alkyl propargyl ethers and alkyl
ICP-MS analysis technique one can identify copper, for that azides (Table 1). Raney Ni aided the cycloaddition of benzyl
matter, most of the metal impurities present even below ppb 2b and n-hexyl 2c azides to propargylic ethers 1c–d efficiently
levels.16 The analysis clearly showed that the Raney Ni sample in providing cycloadducts 3o–v in excellent yield. But, the
we were employing does not have copper impurities up to ppb regiochemistry, unfortunately, was scrambled to some extent
with the formation of major 1,4-regio isomers 3o–r and along
with the corresponding minor 1,5-regioisomers 3s–v
(Table 1). Ratios of the regio-isomers were calculated on the
basis of integration of relevant signals in the mixture 1H NMR
and 13C NMR spectra. The results indicate that two transition
states that lead to 1,4- or 1,5-disubstituted traizoles may not
have much difference in free energy and thus both orienta-
tions as shown in proposed mechanism are possible
(Scheme 4) (Table 2).
Fig. 1 The calculated concentrations (Y-axis) were plotted against the
obtained counts (X-axis) and linear regression considering minimum
3 points. Intercept value ꢁ17.689 ppb indicates that Cu is not present Scheme 2 Raney Ni mediated combinatorial cycloaddition of two aryl
in Raney Ni.
propargyl ethers to benzyl and n-hexyl azides.
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Table 1 The 1,4 and 1,5-isomers formed in the combinatorial NiAAC reaction of benzyl and cyclohexyl propargyl ethers to benzyl and n-hexyl
azides
1,4 and 1,5
%
S. no
1
Alkyne
Azide
1,4 and 1,5 isomers
isomers ratio
yield
C6H5CH2N3 2b
1 : 0.7
1 : 0.2
93
93
2
3
n-C6H13N3 2c
C6H5CH2N3 2b
1 : 1
91
89
4
n-C6H13N3 2c
1 : 0.5
since NiAAC reaction provided both the regioisomers it could go
through a mechanistic pathway different from CuAAC.
One of the principal and initial intermediates in the Sharp-
less–Meldal version of the CuAAC reaction is the copper acety-
lide 5 generated by oxidative insertion of Cu(I) into CH bond of a
terminal alkyne 4 (Scheme 3). This step appears to be crucial to
the cycloaddition of azides to the acetylenic triple bond. In the
next step copper gets involved in bringing together copper
acetylide and the azide through p-complexation with alkyne
and coordination to the terminal nitrogen of the azide. The
cycloaddition leads to organocopper intermediate 6, which gets
hydrolysed to provide 3 on addition of water. However, in
conned places like in zeolites, there may not be copper ace-
tylide formation and the cycloaddition could go through met-
allocycle.19 The Ni(0) catalyzed AAC reaction could also work in a
similar fashion, initiated by Ni acetylide formation. Or, Ni(0)
could play a role in bringing the reactants together though
p-complexation and coordination. To probe the mechanism of
the NiAAC reaction, experiments with deuterated phenyl prop-
Scheme 3 Accepted mechanism for the CuAAC.21
Scheme 4 Proposed mechanism for the NiAAC.
Finally, we conducted NiAAC of phenyl azide 2a with three
alkynes namely (((1-ethynylcyclohexyl)oxy)methyl)benzene 1e,
phenyl acetylene 1f and propargyl alcohol 1g to evaluate versa-
tility of NiAAC reaction. The NiAAC reaction of propagyl ether
1e, where C(1) carbon is disubstituted, provided the cycloadduct
4-(1-(benzyloxy)cyclohexyl)-1-phenyl-1H-1,2,3-triazole 3w exclu-
sively, indicating that the reaction is not effected by steric
hindrance close to the reaction site. The NiAAC reaction of
phenyl acetylene 1f with phenyl azide provided regiochemically
pure 1,4-diphenyl-1H-1,2,3-triazole17 3x indicating that NiAAC
reaction can be extended to aryl acetylenes. The NiAAC reaction
of propargyl alcohol 1g and phenyl azide, however, provided the
1,4- and 1,5-regioisomeric triazolyl methanols 3y and 3z in the
ratio of about 3 : 2. The AAC reaction of propargyl alcohol 1g
and phenyl azide 2a without any catalyst also provided the 1,4-
and 1,5-regioisomeric adducts 3y–z in 3 : 2 ratio but the reaction
required heating by microwaves to 140 ꢀC in polyethylene
glycol-200 for 2 min. The CuAAC reaction of propargyl alcohol
with phenyl azide, on the other hand, provided 1,4-regioisomer
3y exclusively.18 The results indicate that AAC under Ni catalysis
argyl ether ((((3-deuteroprop-2-yn-1-yl)oxy)methyl)benzene)20
4
with phenyl azide 2a were performed. The deuterium present on
terminal acetylenic carbon gets lost, if the reaction goes through
Ni acetylide formation. On the other hand, if the Ni(0) plays the
role of a coordinating species deuterium is retained. In the Ni(0)
catalyzed AAC reaction, we observed almost 100% retention of
deuterium in the product 8 (Scheme 4). This result indicates
that unlike that of CuAAC, in the rst step, Ni(0) does not insert
into CH of alkyne to form Ni acetylide. Mechanistically, the
reaction could go through complexation of the acetylene on
Raney Ni surface to form p-complex 7 (Scheme 4) followed by
cycloaddition of the azides to form adduct 9 via complex 8
where both acetylene and azide components are held by Ni. On
the other hand, the Ni complex with acetylene moiety could
undergo cycloaddition with azide moiety in the orientation as
ꢀ
ꢀ
takes place at much lower temperature (45 C vs. 140 C) and
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Table 2 The NiAAC reaction of phenyl azide with different alkynes
S. no
Alkyne
NiAAC products
1,4 and 1,5 isomers ratio
% yield
90
1
100 : 0
2
3
100 : 0
64 : 36
89
93
shown in 10. Steric and electronic characteristics of the azide present on each carbon. Although spectral data was obtained
and to some extent those of propargyl ether make the transition for all the compounds prepared in the present study, spectral
states 8 or 10 energetically more favourable to provide 1,4- data of only unknown compounds are provided here. Melting
adduct in preference to 1,5-adduct.
points were determined using open-ended capillary tubes on
VEEGO VMP-DS instrument and are uncorrected. The propargyl
ethers were prepared according to the literature procedure from
the corresponding alcohol or phenols.22 Phenyl, benzyl and
hexyl azides23 were prepared by following the literature proce-
dures. 3a,24 3k,25 3m,26 3l,27 3x,17 3y,18 3c, 3d, 3i and 3j15 are
known compounds. Spectral data of the unknown compounds
excepting 3a is given here. Where mixture of regioisomers were
obtained, spectral data of the 1,4-regioisomer culled from the
mixture NMR spectral data was given. Approximately 10 mol%
of Raney Ni present as a suspension in dry EtOH was transferred
into dry nitrogen ushed RB ask. Excess EtOH was removed
under reduced pressure using Schlenk line. The amount of
reactants was calculated on the basis of the accurate weight of
Raney Ni taken in the RB ask. The reactants were dissolved in
dry toluene before transferring into the RB. Contents of the RB
3. Conclusion
In conclusion, we have demonstrated that Raney Ni is an
alternative catalyst to copper(II) sulphate and sodium ascorbate
recipe for effecting AAC reaction. Notably, additional reducing
agent is not required when Raney Ni is used. Moreover, the
recovery of the products by the present method is greatly facil-
itated, because simple centrifugation and solvent evaporation
provide pure 1,4-disubstituted 1,2,3-triazoles. In most of the
cases, exclusive 1,4-disubstitution in triazole products is
observed. Mechanistic probing indicated that Raney Ni plays
the role of coordinating species in bringing together azide and
alkyne.
ꢀ
with constant stirring were heated to 45 C in a preheated oil-
4. Experimental section
4.1. General
bath. We evaluated if any Raney Ni catalyst leached by taking
the NiAAC of phenyl acetylene and phenyl azide as standard and
found that less than 0.4% of the catalyst reduced weight in each
of the three consecutive runs (see ESI for details†). Although we
cannot rule out absence of leaching, we attribute decrease in
weight of Raney Ni to experimental error.
Analytical thin-layer chromatography (TLC) was performed on
silica gel coated on glass plates (0.25 mm, silica gel G, LOBA
Chemicals, UV silica gel GF 254). TLC spots were visualized
under UV light and iodine. Column chromatography was
carried out using silica gel 100–200 mesh (LOBA Chemicals)
using a hexanes–ethyl acetate eluent mixture. 1H and 13C NMR
spectra were recorded on a Bruker Avance 400 spectrometer in
4.2. ICP-MS analysis of Raney Ni for detection of trace
amounts of copper
CDCl3 + CCl4 (1 : 1) and chemical shis values (d) are relative to
1
the residual solvent peak (d 7.26 for H, d 77.16 for 13C) where Five samples each having 10 mL of 460 ppb Raney Ni digested in
possible or alternatively to TMS (d 0.00) as internal standard. aq 2 N HNO3 (milli-Q water of specic resistance less than 15
Coupling constants (J) are given in Hz and multiplicities are mU) and spiked with 0, 1, 2, 3, 4 mL of 24.4 ppb Cu containing
designated as s (singlet), d (doublet), dd (doublet of doublet), t CuSO4$5H2O solution, were prepared and analyzed in ICP-MS
(triplet), q (quartet), m (multiplet). NMR spectra were recorded (Thermo Scientic, X SERIES 2) for determination of Cu content
for all the samples to determine the number of hydrogen atoms at ppb levels in blank by calibration method28 (Fig. 1). The data
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points which t into linear scale (three) were taken into procedure described by Bew and co-workers.18 The NMR
consideration while drawing Fig. 1.
spectral data showed that 1 was 90% enriched with deute-
The analysis did not indicate presence of even ppt rium as indicated by its 1H NMR spectrum. The NiAAC
amounts of copper in the Raney Ni sample used in the NiAAC reaction with 1 (50 mg, 0.4 mmol, 1 equiv.) and phenyl azide
reactions.
2a (54 mg, 0.45 mmol, 1.1 equiv.) under our optimised
conditions provided traizole 8 (R ¼ Ph) with complete
retention of deuterium.
4.3. Preparation of Raney Ni
4.4.3. 4-((4-tert-Butylphenoxy) methyl)-1-phenyl-1H-1,2,3-
triazole 3b.
Approximately 10 mol% of Raney Ni present as a suspension
in absolute EtOH was transferred into dry nitrogen ushed
RB ask. Excess EtOH was removed under reduced pressure
using Schlenk line. The amount of reactants was calculated
on the basis of the accurate weight of Raney Ni taken in the
RB ask. To Raney Ni (42 mg, 0.7 mmol) the azide (7.0 mmol)
and then the propargyl ether (7.0 mmol) dissolved in dry
toluene (10 mL each) were added. The reaction mixture was
placed in a preheated oil bath maintained at 45 ꢀC and stirred
for 14 h by which time reaction was complete (TLC). Contents
of the ask was transferred into centrifuge tubes and
centrifuged for 2 min at 2100 rpm. Supernatant clear solution
was withdrawn followed by washing of the catalyst twice with
10 mL dry toluene. Removal of toluene from pooled solutions
resulted in triazoles 3 in over 90% yield which was sufficiently
pure for spectral characterization. Column chromatography
was performed when necessary.
ꢀ
Yield 93% (151 mg), white solid, mp 68 C; IR (KBr): 3156,
3043, 2966, 2869, 1606, 1512, 1244, 1048, 858, 711, 548 cmꢁ1; 1H
NMR (CDCl3 + CCl4 (1 : 1), 400 MHz) d 8.02 (s, 1H), 7.76–7.74 (m,
2H), 7.54–7.49 (m, 2H), 7.44–7.40 (m, 1H), 7.30–7.28 (m, 2H),
6.93–6.91 (m, 2H), 5.28 (s, 2H), 1.31 (s, 9H) ppm; 13C NMR
(CDCl3 + CCl4 (1 : 1), 100 MHz) d 155.8, 145.3, 143.7, 137.0,
129.5, 128.5, 126.2, 120.4, 120.2, 114.1, 62.0, 34.0, 31.5 ppm;
HRMS m/z (ESI-MS): calcd for C19H21N3ONa (M + Na) 330.1582,
found 330.1580.
4.4.4. 4-(Hexyloxymethyl)-1-phenyl-1H-1,2,3-triazole 3e.
4.4. General procedure for the Raney Ni catalyzed [3 + 2]
cycloaddition of azides and terminal alkynes
4.4.1. Synthesis of 1-phenyl-4-(phenoxymethyl)-1H-1,2,3-
triazole 3a.
Yield 89% (164 mg),viscous liquid, IR (KBr) 3079, 3016,
2924, 2853, 1593, 1509, 1491, 1453, 693 cmꢁ1; 1H NMR (CDCl3
+ CCl4 (1 : 1), 400 MHz) d 7.75 (s, 1H), 7.66–7.63 (m, 2H), 7.53–
7.50 (m, 3H), 4.48 (s, 2H), 3.44 (t, J ¼ 4.0 Hz, 2H), 1.58–1.54
(m, 2H), 1.31–1.27 (m, 6H), 0.88 (t, J ¼ 4.0 Hz, 3H) ppm; 13C
NMR (CDCl3 + CCl4 (1 : 1), 100 MHz) d 136.6, 135.0, 133.9,
129.5, 124.7, 70.9, 60.8, 31.8, 29.7, 26.0, 22.8, 14.2 ppm;
HRMS m/z (ESI-MS): (M + H) calcd for C15H22N3O 260.1763,
found 260.1763.
To Raney Ni (42 mg, 0.7 mmol) taken under a blanket of dry
nitrogen, phenyl azide (1.0 g, 7.0 mmol) and then phenyl
propargyl ether (1.0 g, 7.0 mmol) dissolved in dry toluene (10
mL each) were added. The reaction mixture was placed in a
ꢀ
preheated oil bath maintained at 45 C. The reaction mixture
4.4.5. 4-((Pent-2-yn-1-yloxy)methyl)-1-phenyl-1H-1,2,3-tri-
azole 3f.
was stirred for 14 h by which time reaction was complete (TLC).
Contents of the ask was transferred into a centrifuge tube and
centrifuged for 2 min at 2100 rpm. Supernatant clear solution
was withdrawn followed by washing of the catalyst twice with 10
mL dry toluene. Removal of toluene from pooled solutions
resulted is 3a in 98% yield (186 mg) as a colorless viscous liquid,
which was sufficiently pure for spectral and analytical charac-
terization. IR (KBr) 3112, 3059, 3032, 1741, 1455, 1357, 1246,
1080, 752 cmꢁ1; 1H NMR (CDCl3 + CCl4 (1 : 1), 400 MHz) d 8.05
Yield 89% (175 mg), viscous liquid, IR (KBr) 3081, 3052,
1
3016, 2921, 2851, 1598, 1509, 1493, 1451, 1432, 696 cmꢁ1; H
(s, 1H), 7.75–7.72 (m, 2H), 7.55–7.44 (m, 3H), 7.33–7.29 (m, 2H), NMR (CDCl3 + CCl4 (1 : 1), 400 MHz) d 7.98 (s, 1H), 7.72 (d, J ¼
7.04–6.97 (m, 3H), 5.31 (s, 2H) ppm; 13C NMR (CDCl3 + CCl4 8.3 Hz, 2H), 7.50 (t, J ¼ 8.0 Hz, 2H), 7.41 (t, J ¼ 6.9 Hz, 1H), 4.78
(1 : 1), 100 MHz) d 158.3, 129.9, 129.7, 129.0, 121.5, 120.7, 114.9, (s, 2H), 4.23 (s, 2H), 2.25–2.23 (m, 2H), 1.15 (t, J ¼ 8.0 Hz, 3H)
62.1 ppm.
4.4.2. Experiments with deuterium labeled phenyl prop-
argyl ether 4. To elucidate if the NiAAC reaction goes through
Ni acetylide intermediate, deuterated phenyl propargyl ether
1 was employed and it was prepared according to the
ppm; 13C NMR (CDCl3 + CCl4 (1 : 1), 100 MHz) d 145.7, 137.2,
129.8, 128.8, 120.8, 120.6, 89.1, 74.9, 63.0, 58.4, 13.9, 12.6 ppm;
HRMS m/z (ESI-MS): calcd for C14H15N3ONa (M + Na) 264.1113,
found 264.1113.
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2930, 2860, 1597, 1494, 1240, 755 cmꢁ1; NMR spectral data of
the 1,5-regio isomer was culled from the mixture NMR spectra
by locating the signals meant for 1,4-regioisomer.29
4.4.6. 4-(Benzyloxymethyl)-1-phenyl-1H-1,2,3-triazole 3g.
4.4.9.1. 1-Benzyl-5-(benzyloxymethyl)-1H-1,2,3-triazole 3s.
Yield 97% (176 mg), viscous liquid, IR (KBr) 3103, 2956, 2923,
2863, 1504, 1285, 1098, 1061, 768, 692, 587 cmꢁ1; 1H NMR (CDCl3
+ CCl4 (1 : 1), 400 MHz) d 7.96 (s, 1H), 7.74–7.71 (m, 2H), 7.52–
7.43 (m, 2H), 7.43–7.27 (m, 6H), 4.75 (s, 2H), 4.64 (s, 2H) ppm; 13
C
Yield 89%, viscous liquid, IR (KBr) 3139, 3066, 2930, 2860,
NMR (CDCl3 + CCl4 (1 : 1), 100 MHz) d 146.0, 137.7, 137.1, 129.6,
128.5, 128.4, 127.8, 127.7, 120.4, 120.3, 72.6, 63.6 ppm; HRMS m/z
(ESI-MS): 288.1113 calcd for C16H15N3ONa (M + Na) 288.1112.
4.4.7. 4-(Cyclohexyloxymethyl)-1-phenyl-1H-1,2,3-triazole 3h.
1
1597, 1494, 1240, 755 cmꢁ1; H NMR (CDCl3 + CCl4 (1 : 1), 400
MHz) 7.32 (s, 1H), 7.28–7.07 (m, 10H), 5.42 (s, 2H), 4.56 (s, 2H),
4.30 (s, 2H), 13C NMR 137.9, 133.0, 134.8, 133.0, 129.0, 128.7,
28.50, 128.35, 128.30, 128.1, 127.7, 72.4, 59.8, 52.4 ppm; HRMS
m/z (ESI-MS): calcd for C17H18N3O (M + H) 280.1450, found
280.1452.
4.4.10. 4-(Benzyloxymethyl)-1-hexyl-1H-1,2,3-triazole, 5-
(benzyloxymethyl)-1-hexyl-1H-1,2,3-triazole 3p, 3t.
Yield 88% (163 mg), viscous liquid, IR (KBr) 3032, 2932,
2856, 1605, 1496, 1453, 1363, 1082, 722 cmꢁ1; 1H NMR (CDCl3 +
CCl4 (1 : 1), 400 MHz) d 7.80 (s, 1H), 7.66–7.64 (m, 2H), 7.55–7.50
(m, 3H), 4.53 (s, 2H), 3.34–3.29 (m, 1H), 1.84–1.69 (m, 6H), 1.53–
1.51 (m, 1H), 1.31–1.20 (m, 3H) ppm; 13C NMR (CDCl3 + CCl4
(1 : 1), 100 MHz) d 147.2, 137.4, 129.8, 128.7, 120.6, 120.3, 77.6,
61.7, 32.4, 26.0, 24.2 ppm; HRMS m/z (ESI-MS): calcd for
The regioisomers 3p and 3t were obtained in 1 : 0.2 ratio.
Overall yield 93% (173 mg), viscous liquid, IR (KBr) 3032, 3061,
2958, 2926, 2856, 1597, 1489, 1243, 755 cmꢁ1; NMR spectral
data of the 1,5-regio isomer was identied from the mixture
NMR by deducting the spectrum meant for 1,4-regio-isomer.
The 1,4-regioisomer 3p was prepared by Cu(I) mediated cyclo-
addition of benzyl propargyl ether and n-hexylazide by following
the general procedure described by us previously.15
C
15H20N3O (M + H) 258.1606, found 258.1602.
4.4.8. 4-((4-tert-Butylphenoxy)methyl)-1-hexyl-1H-1,2,3-tri-
azole 3n.
4.4.10.1. 4-(Benzyloxymethyl)-1-hexyl-1H-1,2,3-triazole 3p.
ꢀ
Yield 93% (155 mg), white solid, mp 69 C; IR (KBr): 3155,
2963, 1604, 1510, 1463, 1243, 1045, 822, 710, 547 cmꢁ1; 1H NMR
(CDCl3 + CCl4 (1 : 1), 400 MHz) d 7.52 (s, 1H), 7.23 (dd, J ¼ 8.4
Hz, 2H), 6.85 (dd, J ¼ 8.6, 1.4 Hz, 2H), 5.12 (d, J ¼ 2.5 Hz, 2H),
4.28–4.24 (m, 2H), 1.84 (t, J ¼ 5.6 Hz, 2H), 1.26 (s, 9H), 1.25 (s,
6H), 0.84 (t, J ¼ 1.6 Hz, 3H) ppm; 13C NMR (CDCl3 + CCl4 (1 : 1),
100 MHz) d 156.0, 144.2, 143.6, 126.2, 122.3, 114.2, 62.1, 50.2,
34.1, 31.2, 31.1, 30.2, 26.1, 22.4, 13.9 ppm; HRMS m/z (ESI-MS):
calcd For C19H29N3ONa (M + Na) 338.2208, found 338.2196.
Yield 98%, viscous liquid, IR (KBr) 3137, 3065, 2926, 2858,
1
1649, 1496, 1240, 736 cmꢁ1; H NMR (CDCl3 + CCl4 (1 : 1), 400
MHz) 7.48 (s, 1H), 7.28–7.25 (m, 5H), 4.60 (s, 2H), 4.52 (s, 2H),
4.26–4.22 (t, J ¼ 7.2 Hz, 2H), 1.82–1.79 (m, 2H), 1.27–1.22 (m,
6H), 0.85–0.82 (m, 3H) ppm; 13C NMR 144.8, 137.7, 128.3, 128.1,
122.1, 72.1, 63.4, 49.9, 31.0, 30.9, 25.9, 22.2, 13.7 ppm.
4.4.10.2. 5-(Benzyloxymethyl)-1-hexyl-1H-1,2,3-triazole 3t.
4.4.9. 1-Benzyl-4-(benzyloxymethyl)-1H-1,2,3-triazole,
(benzyloxymethyl)-1-bromo-1H-1,2,3-triazole (1 : 1) 3o, 3s.
5-
Yield 89%, viscous liquid, IR (KBr) 3081, 3052, 3016, 2921,
2851, 1598, 1509, 1493, 1451, 1432, 696 cmꢁ1; 1H NMR (CDCl3 +
CCl4 (1 : 1), 400 MHz) d 7.48 (s, 1H), 7.27–7.25 (m, 5H), 4.60 (d, J
¼ 0.4 Hz, 2H), 4.52 (s, 2H), 1.82–1.79 (m, 2H), 1.25–1.22 (m, 7H)
The regioisomers 3o and 3s were obtained in 1 : 0.7 ratio.
Overall yield 93% (177 mg), viscous liquid, IR (KBr) 3139, 3066,
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ppm; 13C NMR (CDCl3 + CCl4 (1 : 1), 100 MHz) d 144.7, 137.7,
128.3, 127.8, 127.7, 122.1, 72.1, 63.4, 49.9, 30.99, 30.93, 30.02,
25.9, 22.2, 13.7 ppm; HRMS m/z (ESI-MS): calcd for
4.4.12. 4-(Cyclohexyloxymethyl)-1-hexyl-1H-1,2,3-triazole,
5-(cyclohexyloxymethyl)-1-hexyl-1H-1,2,3-triazole 3r, 3v.
C
16H23N3ONa (M + Na) 296.1738, found 296.1723.
4.4.11. 1-Benzyl-4-(cyclohexyloxymethyl)-1H-1,2,3-triazole,
1-benzyl-5-(cyclohexyloxymethyl)-1H-1,2,3-triazole 3q, 3u.
The regioisomers 3r and 3v were obtained in 1 : 0.5 ratio.
Overall yield 89% (170 mg), viscous liquid, IR (KBr) 3034,
2987, 2854, 1605, 1496, 1453, 1082, 722 cmꢁ1; NMR spectral
data of the 1,5-regio isomer was identied from the mixture
NMR by deducting the spectrum meant for 1,4-regio-isomer.
The 1,4-regioisomer 3r was prepared by Cu(I) mediated
cycloaddition of benzyl propargyl ether and n-hexylazide
by following the general procedure described by us
previously.15
The regioisomers 3q and 3u were obtained in 1 : 1 ratio.
Overall yield 91% (178 mg), viscous liquid, IR (KBr) 3031,
2931, 2852, 1497, 1450, 1356, 1082 cmꢁ1; NMR spectral data
of the 1,5-regio isomer was identied from the mixture
NMR by deducting the spectrum meant for 1,4-regio-isomer.
The 1,4-regioisomer 3q was prepared by Cu(I) mediated
cycloaddition of benzyl propargyl ether and n-hexylazide
by following the general procedure described by us
previously.15
4.4.12.1. 4-(Cyclohexyloxymethyl)-1-hexyl-1H-1,2,3-triazole
3r.
4.4.11.1. 1-Benzyl-4-(cyclohexyloxymethyl)-1H-1,2,3-triazole 3q.
Yield 98%, viscous liquid, IR (KBr) 3137, 3065, 2926, 2858,
1496, 1458, 1368, 1072, 736 cmꢁ1; 1H NMR (CDCl3 + CCl4 (1 : 1),
400 MHz) 7.42 (s, 1H), 4.52 (s, 2H), 4.22 (t, J ¼ 7.2 Hz, 2H), 3.29
(m, 1H), 1.79 (d, J ¼ 9.2 Hz, 5H), 1.61 (s, 3H), 1.43–1.41 (m, 2H),
1.20–1.15 (m, 5H), 0.77 (s, 3H) ppm; 13C NMR (CDCl3 + CCl4
(1 : 1), 100 MHz) 146.0, 121.9, 77.4, 76.8, 69.8, 61.4, 50.1, 35.4,
31.1, 26.0, 23.9, 22.3, 13.8 ppm.
ꢀ
Yield 97%, white solid, mp 91–93 C, IR (KBr) 3140, 2930,
2857, 1454, 1368, 1089, 953, 730 cmꢁ1; 1H NMR (CDCl3 + CCl4
(1 : 1), 400 MHz) 7.40 (s, 1H), 7.33–7.32 (m, 3H), 7.24–7.23
(m, 2H) 5.47 (s, 2H), 4.60 (s, 2H), 3.35–3.32 (m, 1H), 1.90–1.87
(m, 2H), 1.71–1.69 (m, 2H), 1.51–1.50 (m, 1H), 1.28–1.19
(m, 2H) ppm; 13C NMR (CDCl3 + CCl4 (1 : 1), 100 MHz)
146.7, 134.8, 129.2, 128.8, 128.2, 122.1, 61.7, 54.2, 32.3, 25.9,
24.2 ppm.
4.4.12.2. 5-(Cyclohexyloxymethyl)-1-hexyl-1H-1,2,3-triazole
3v.
4.4.11.2. 1-Benzyl-5-(cyclohexyloxymethyl)-1H-1,2,3-triazole 3u.
Yield 91%, viscous liquid, IR (KBr) 3034, 2987, 2854, 1605,
1496, 1453, 1082, 722 cmꢁ1 1H NMR (CDCl3 + CCl4 (1 : 1),
;
Yield 89%, viscous liquid, IR (KBr) 3031, 2931, 2852, 1497,
1450, 1356, 1082 cmꢁ1; 1H NMR (CDCl3 + CCl4 (1 : 1), 400 MHz)
d 7.55 (s, 1H), 7.34–7.28 (m, 5H), 5.59 (s, 2H), 4.60 (s, 2H), 3.21–
3.17 (m, 1H), 1.87–1.69 (m, 5H), 1.27–1.20 (m, 5H) ppm; 13C
NMR (CDCl3 + CCl4 (1 : 1), 100 MHz) d 146.8, 134.8, 134.0, 133.9,
128.2, 127.5, 77.4, 76.8, 57.9, 52.2, 31.9, 25.7, 23.9 ppm; HRMS
m/z (ESI-MS): calcd for C16H21N3ONa (M + Na) 294.1582, found
294.1584.
400 MHz) d 7.57 (s, 1H), 4.66 (s, 2H), 4.35–4.30 (m, 3H), 3.41–
3.31 (m, 1H), 1.74–1.72 (m, 5H), 1.31–1.21 (m, 12H),
0.88–0.85 (m, 3H) ppm; 13C NMR (CDCl3 + CCl4 (1 : 1), 100
MHz) d 146.3, 122.1, 61.7, 50.4, 48.6, 32.3, 31.4, 30.3,
26.4, 25.8, 25.7, 24.2, 23.9, 22.5, 14.0 ppm; HRMS m/z
(ESI-MS): calcd for C15H27N3ONa (M + Na) 288.2052, found
288.2050.
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support. CG thanks to UGC for meritorious fellowship. We
thank Central Instrumentation Facility, Pondicherry University
and Organic Chemistry Department, Indian Institute of Science,
Bangalore for recording spectra.
4.4.13. Synthesis of 4-(1-(benzyloxy)cyclohexyl)-1-phenyl-
1H-1,2,3-triazole 3w.
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(d, J ¼ 8.0 Hz, 2H), 7.47–7.43 (m, 2H), 7.42–7.38 (m, 1H), 4.80
(s, 2H) ppm; 13C NMR (CDCl3 + CCl4 (1 : 1), 100 MHz) d 148.8,
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1H NMR (CDCl3 + CCl4 (1 : 1), 400 MHz) d 7.69 (s, 1H), 7.60 (d, J
¼ 7.7 Hz, 2H), 7.47–7.43 (m, 3H), 4.68 (s, 2H) ppm; 13C NMR
(CDCl3 + CCl4 (1 : 1), 100 MHz) d 137.5, 136.3, 129.63, 129.60,
124.7, 120.3, 53.1 ppm.
Acknowledgements
H.S.P.R thanks Special Assistance Program (SAP), University
Grants Commission (UGC), and Fund for Improvement of S & T
Infrastructure in Universities and Higher Educational Institu-
tions (FIST), Department of Science and Technology (DST) for
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noted that Day and Pathak isolated 1,4-regio isomer
although they have wrongly assigned it as 1.5-regioisomer.
The NMR data elicited from the spectra matched with the
1,4- rather than 1,5-isomer.
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