An efficient synthesis of 4,5-disubstituted-2: H -1,2,3-triazoles from nitroallylic derivatives via a cycloaddition-denitration process

Article abstract of DOI:10.1039/c7nj03292g

A metal-free convenient synthesis of 4,5-disubstituted N-unsubstituted 1,2,3-triazoles via a cycloaddition-denitration process has been described. A variety of readily available nitroallylic alcohols were reacted smoothly with sodium azide in the presence

Full text of DOI:10.1039/c7nj03292g

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ISSN 1144-0546
PAPER
Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
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Efficient synthesis of 4,5-disubstituted-2H-1,2,3-triazoles from
nitroallylic derivatives via cycloaddition-denitration process† ‡
Raju Jannapu Reddy,*,a Md. Waheed,a Thatikonda Karthik,a and Angothu Shankar a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
A metal-free convenient synthesis of 4,5-disubstituted N-unsubstituted 1,2,3-triazoles via cycloaddition-denitration
process have been described. A variety of readily available nitroallylic alcohols were reacted smoothly with sodium azide in
the presence of p-toluenesulfonic acid (p-TSOH) to form synthetically viable triazolylacetates in good to high yields.
Additionally, the nitroallylic acetates and sulfones were converted into a structurally-modifiable triazolylazides and sulfone
derived triazoles, respectively in moderate to good yields. The present protocol is a operationally simple, tolerates a broad
range of functional groups and also reliable in a gram scale reaction under optimised reaction condition. A practically-
straightforward gram scale reaction for synthesis of triazole directly from β-nitrostyrene via a sequential one-pot Morita-
Baylis-Hillman and cycloaddition reactions has been achived.
www.rsc.org/
recent years. In 2014, Guan and coworkers15g ingeniously
Introduction
recognised p-TSOH (p-toluenesulfonic acid) to promote the
cycloaddition effectively
and prohibited to form
1,2,3-Triazoles are structurally significant heterocycles across a
variety applications in synthetic organic chemistry,1 medicinal
chemistry,2 functional materials3 and other related fields.4 In
recent years, some of the triazoles have been used as efficient
auxiliaries for C-H activation5 and useful carbene precursors.6 A
powerful general method for synthesis of N-substituted 1,2,3-
triazoles by ‘click’ reaction of organic azides with alkynes
under different transition-metal catalysis.7 Several other
recent developments, which includes, the condensation of
organic azides with activated alkenes8, multicomponent
strategies9 and azide-free synthesis10 have been employed for
formation 1,2,3-triazoles. Recent potent method on
organocatalytic cyclo-addition of activated carbonyl
compounds with organic azides have also been developed.11
Following methods usually produce the N-substituted 1,2,3-
triazoles, however the NH-1,2,3-triazoles has become an
important building blocks in organic synthesis.12 Numerous
bioactive NH-1,2,3-triazoles has evolved13 however the
synthesis of NH-1,2,3-triazoles still limited.14 The cycloaddition
reaction of alkynes and TMSN3 followed by TMS group
deprotection afford NH-1,2,3-triazole.14a A direct cycloaddition
of vinyl bromides14b/1,1-dibromo olefins14c with sodium azide
was also developed. Alternatively, the cycloadditon reaction of
nitroalkenes with sodium azide has grown remarkably in
cyclotrimerization of nitroolefins. Regrettably, less attention
have been paid for synthesis of 4,5-disubstituted NH-triazoles
by using
reaction (Scheme 1). Only few examples known the use of
functionalized/ substituted nitroolefins, such as, -cyano- or
-carboethoxy nitroalkenes (
, Scheme 1a)15d and 1,3-diaryl-2-
α-functionalized nitroalkenes in cycloaddition
α
-
α
α
I
nitroprop-1-enes or 2-nitro-3-arylprop-2-en-1-ol (II, Scheme
1b),15f,i for cycloaddition-denitration reactions. Regardless, to
identify readily accessible α-functionalised nitroolefins (III and
IV) remain exclusive for construction of synthetically-viable
4,5-disubstituted NH-triazoles (Scheme 1c-d).
Previous works:
NO2
N
NO2
R
TMSN3
(a) Ar
N
N
NaN3
DMSO,80 o
NH
(b) Ar
HN
N
TBNF/SFC
EWG
C
I
(EWG = CN, CO2Et)
Ar
EWG
Ar
II (R = aryl, OH)
R
This work:
H
N
H
(d)
N
NaN3/pTSA
NO2
SO2Ar
NO2
R
(c)
N
Ar
Ar
NaN3/pTSA
N
N
N
DMSO, 80 o
C
DMSO, 80o
C
EtO2C
Ar
SO2Ar
Ar
R
EtO2C OH
OH
(IV)
R = H, CO2Et
(III)
• Easily accessible star ting materials.
• Sy nthetically-viable
functional groups
• Br oad f unctional group tolerance.
Scheme 1: Comparison of previous studies with our work.
Namboothiri and co-workers elegantly employed a variety of
conjugated nitroalkenes with activated non-enolizable
carbonyl compounds to give the densely functionalized
nitroallylic alcohols.16a,b Later on, Chen group re-examined this
method using catalytic thiourea to improve the yields.16c While
compared to the conventional Morita-Baylis-Hillman (MBH)
adducts,17 the nitroalkenes derived MBH adducts were little
explored in organic synthesis.18,19 To best of our knowledge,
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20
the nitroallylic alcohols (III
)
and nitroallylic sulfones (IV
)
Encouraged by this results, the substrate scope of
were unexplored, therefore it has attracted us to develop cycloaddition reaction was examined with the optimized
azide-cycloaddition reaction. We speculated the nitroallylic reaction conditions (Table 2). A wide range of 4,5-disubstituted
derivatives may have annoying interruption due to sensitive NH-1,2,3-triazoles have been accessed in good to high yields
functional groups, to our surprise, the anticipated NH-triazoles by using representative nitroallylic alcohols. In addition to
are formed exclusively. Herein, we report a rapid synthesis of triazole 2a, the 4-methyl and 4-isopropyl aryl substituted
4-aryl/hetereoaryl-5-multifuntional-2H-1,2,3-triazoles
from nitroallylic alcohols (1b and 1c) were also smoothly reacted
readily available nitroallylic derivatives with sodium azide in with sodium azide to provide the desired triazoles 2b and 2c in
the presence of p-TSOH via cycloaddition-denitration process.
87% and 84% yields, respectively. The 1-naphthyl (2d) and 2-
naphthyl (2e) triazoles were obtained in high yields under
optimised reaction conditions from the corresponding
nitroallylic alcohols 1d and 1e. The methoxy substituent’s on
aromatic ring derived alcohols (1f-i) provided similar results on
Results and discussion
Initially, we commenced to optimize the reaction conditions by
the formation of corresponding triazoles (2f
-i). The haloaryl
using nitroallylic alcohol, (E)-ethyl 2-hydroxy-3-nitro-4-
alcohols (1j-m) were also good substrates for this
phenylbut-3-enoate 1a and sodium azide as
a model
cycloaddition. In fact, the 4-haloaryl triazoles
substrates. Our investigation starts with the identification of
solvent, reagent/catalyst and temperature for the
cycloaddition-denitration process (Table 1). The use of p-TSOH
(30 mol%) in DMF and DMSO afford the desired
triazolylacetate 2a in 54% and 68% yields, respectively (entries
1 and 2). At 60 oC, there was no significant improvement in
DMF, however the yield was improved to 72% in DMSO
(entries 3 and 4). With slight excess of sodium azide in the
absence of p-TSOH the yield was dropped to 58% (entry 5).
Notably, a substantial progress have seen at 80 oC with a
varied amounts of sodium azide and p-TSOH (entries 6-9). To
our delight, a satisfactory yield (88%) obtained when the
reaction was carried out using with 1.5 equiv. of sodium azide
in the presence of 1 equiv. of p-TSOH (entry 7). The use of
amberlyst-15 provide the desired product 2a in 79% (entry 10)
whereas the use methanesulfonic acid (MsOH) and
trifluoroacetic acid (TFA) afford either mixture or no reaction
(entries 11 and 12), respectively. The role of p-TSOH was not
clear entirely in this cycloaddition, probably the more reactive
hydrozoic acid may formed in situ by acidification of sodium
azide with stoichiometric amount of p-TSOH. It is worth
mention here the structurally modifiable triazolylacetate 2a
has formed cleanly by involving tandem cycloaddition-
denitration (spontaneous loss of HNO2) without intrusive of
hydroxyl group.
Table 2. Substrate scope using various nitroallylic alcohols (1a-s).a
Table 1. Optimization of the reaction.a
Entry
1
2
3
4
5
6
7
8
Reaction conditions
time
24 h
24 h
6 h
6 h
6 h
Yield (2a)b
54%
68%
52%
72%
58%
80%
88%
83%
86%
79%
mix
NaN3 (1.2 eq.) + p-TSOH (0.3 eq.) in DMF at rt
NaN3 (1.2 eq.) + p-TSOH (0.3 eq.) in DMSO at rt
NaN3 (1.2 eq.) + p-TSOH (0.3 eq.) in DMF at 60 o
C
NaN3 (1.2 eq.) + p-TSOH (0.3 eq.) in DMSO at 60 o
NaN3 (1.5 eq.) in DMSO at 60 oC
C
C
C
NaN3 (1.5 eq.) + p-TSOH (0.5 eq.) in DMSO at 80 o
NaN3 (1.5 eq.) + p-TSOH (1 eq.) in DMSO at 80 oC
NaN3 (2.0 eq.) + p-TSOH (0.5 eq.) in DMSO at 80 o
NaN3 (2.0 eq.) + p-TSOH (1 eq.) in DMSO at 80 oC
NaN3 (1.5 eq.) + Amberlyst-15 in DMSO at 80 oC
NaN3 (1.5 eq.) + MsOH (1 eq.) in DMSO at 80 oC
1 h
0.5 h
0.5 h
0.5 h
1 h
1 h
1 h
9
10c
11
12
NaN3 (1.5 eq.) + TFA (1 eq.) in DMSO at 80 o
C
NR
a All reactions carried out on a 0.2 mmol scale in 1 mL of solvent. b Isolated yield; c
Amberlyst-15 (40 mg) used; NR: No Reaction.
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a All reactions performed on a 0.5 mmol of 1a-s (1 eq.), NaN3 (1.5 eq.) and p-TSOH
b
c
(1 eq.) in DMSO (2.5 mL). Isolated yields after column chromatography.
Reaction of 1a with 1.5 eq. of BnN3 (Bn: Benzyl).
2k and 2m were obtained in high yields, whereas little effect
on outcome in the case of 2-halo substituents may due to
steric hindrance. Similarly, 2,5-dichloroaryl triazolylacetate (2n
obtained in 72% yield and the structure was further confirmed
by single crystal X-ray data analysis (see ESI). On the other
hand, heteroaryl nitroallylic alcohols (1o and 1p) were also
compatible substrates to react with NaN3, however the yields
(64% and 59%) were rather low. In contrast, diethyl
ketomalonate derived alcohols (1q and 1r) were also reacted
with sodium azide to give the quaternary carbon containing
triazoles (2q and 2r) in diminished yields. Disappointingly,
nitroallylic amine (1s) sluggish to react with sodium azide to
)
a All reactions performed on a 0.5 mmol of 3a-c and 4a-f (1 eq.), NaN3 (3.0 eq. for 3 and
1.5 eq. for 4) and p-TSOH (1 eq.) in DMSO (2.5 mL). b Isolated yields after column
chromatography. c Mixture of regioisomers.
A varied functional groups on a triazole nucleus has emerged
as attractive in designing new type of inspired structural
entities. Therefore, the chemical transformation of 2a usually
require site-selective strategies, the N-alkylation12d and O-
acetylation have been explored. Remarkably, N-benzyl triazole
2t formed in 70% yield by treatment of 2a with benzyl bromide
(Scheme 2). Whereas, the reaction of triazole 2a with excess
provide desired triazole
(2s) under optimised reaction
condition. And also no conversion of 1a with benzyl azide to
form desired triazole 2t, however 2t obtained alternatively
(see Scheme 2). The alkyl substituted nitroallylic alcohol was a
challenging substrate for this transformation and formed
desired product in scarcely.21 All the structures of these
triazoles were established as a 2H-regioisomer on the basis of
acetyl chloride (3 equiv.) afford O-acetyl triazole
and has observed no N-acetylated product.
7 in 82% yield
X-ray crystallographic data analysis of 2n
.
The scope of the cycloaddition reaction can extend to more
valuable substrates, such as nitroallylic acetates and sulfones
were next probed under the present reaction conditions (Table
3). The acetates (3a
form azide derived triazoles (5a-c) in moderate yields (39-56%).
In fact, these triazolylazides 5a-c useful precursor for
successive cycloaddition reaction to generate bis-triazoles.22
Furthermore, the nitroallylic sulfones (4a ) were prepared
from corresponding nitroallylic acetates (3a ) with sodium
-c) were treated with 3 equiv. of NaN3 to
(
)
Scheme 2: Synthesis of N-benzyl triazole (2t) and O-acetyl triazole 7.
-f
To demonstrate the synthetic utility of cycloaddition, the gram
scale reaction was performed using 1a for formation of desired
triazole 2a under optimised reaction condition (Scheme 3). To
-c
sulfinates (see ESI). Pleasingly, newly prepared sulfones reacts
well with sodium azide to form anticipated triazolylsulfones
(6a-f) in good to high yields with a mixture of regioisomers develop a single synthetic operation is a valuable insights for
(see ESI). Notably, these triazole derived sulfones are suitable
precursor for Julia-Lythgoe olefination23 and desulfonylation24
would allow to prepare new type of triazoles with medicinal
benefits.
step-economical, thereby avoids the separation of the reaction
intermediates.25 Accordingly,
successive Morita-Baylis-
a
Hillman followed by azide-cycloaddition reactions performed
in a single-synthetic operation using nitrostyrene (Scheme 3).
A straightforward gram scale reaction of β-nitrostyrene with
ethyl glyoxalate in the presence imidazole and subsequently
treated with sodium azide under optimised reaction condition.
Although the desired product 2a obtained in low yield (30%),
but the process consist of step-economy, scalable and safer is
Table 3. Substrate Scope using nitroallylic acetates (3a-c) and sulfones (4a-f).a
especially notable (see ESI)
.
Scheme 3: A gram scale reaction and sequential one-pot synthesis of triazoles 2a.
A plausible mechanism for formation of triazoles in the
presence of p-TsOH via [3+2]-cycloaddition is presented in
Scheme 4, as previously described.15i,j The first step involve the
regioselective 1,3-dipolar cycloaddition of nitroallylic
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derivatives either with sodium azide or hydrozoic acid (possibly (101 MHz, CDCl3): δ = 171.0, 143.3, 140.0, 127.9, 127.8(2C), 127.7,
generated in situ) to form the triazoline intermediate. In the 127.1(2C), 64.2, 61.4, 12.8; LC/MS: m/z 248 [M+1]+; HRMS (ESI)
second step, probably the elimination of HNO2 has accelerated calculated for C12H14N3O3 [M+H]+: m/z 248.1035, found 248.1035.
by additional activation of nitro group with p-TsOH through H- The gram scale reaction has been carried out by using 1a (1.0 g, 4
bonding, thus leading to form desired 1,4-disubstituted mmol) and NaN3 (0.39 g, 6 mmol) in DMSO (10 mL) at 80 oC to
triazoles.
afford the title triazole 2a (0.76 g, 77%) as a pale-yellow gummy
liquid.
Ethyl
2-hydroxy-2-[5-(4-methylphenyl)-1H-1,2,3-triazol-4-yl]-
acetate (2b): Prepared according to general procedure using 1b
(132.5 mg, 0.5 mmol) to afford the title triazole 2b (114 mg, 87%) as
a colorless viscous liquid. IR (neat): ν = 3217, 2924, 1739, 1512,
1467, 1232, 1087, 1016, 823 cm-1; 1H NMR (400 MHz, CDCl3): δ =
7.59 (d, J = 7.9 Hz, 2H), 7.19 (d, J = 7.8 Hz, 2H), 5.52 (s, 1H), 4.22-
4.04 (app. m, 2H), 2.35 (s, 3H), 1.10 (app. td, J = 7.1, 1.0 Hz, 3H), two
exchangeable protons has not appeared; 13C NMR (101 MHz, CDCl3):
δ = 172.2, 143.9, 140.8, 139.0, 129.6(2C), 128.1(2C), 126.0, 65.4,
62.5, 21.4, 13.9; HRMS (ESI) calculated for C13H16N3O3 [M+H]+: m/z
262.1192, found 262.1191.
Scheme 4: A Plausible mechanism for formation of triazoles.
Conclusions
In summary, we have developed successfully azide-
cycloaddition reaction of nitroallylic alcohols, acetates and
sulfones were easily converted into a diverse NH-1,2,3-
triazoles in good to high yields. This metal-free protocol is
straightforward, operationally simple and various functional
groups were tolerated. Remarkably, the 4-aryl/heteraryl-5-
multifunctional triazoles were synthetically-malleable, which
can difficult to prepare by other methods. Our practical large
scale cycloaddition reaction and step-economical one-pot
operation can allow for rapid-elaboration of bioactive triazole
motifs.
Ethyl
2-hydroxy-2-[5-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl]-
acetate (2c): Prepared according to general procedure using 1c
(146.5 mg, 0.5 mmol) to afford the title triazole 2c (121 mg, 84%) as
a colorless viscous liquid. IR (neat): ν = 3215, 2960, 1739, 1508,
1463, 1236, 1089, 1014, 840 cm-1; 1H NMR (400 MHz, CDCl3): δ =
7.64 (d, J = 8.2 Hz, 2H), 7.26 (d, J = 8.2 Hz, 2H), 5.53 (s, 1H), 4.96 (bs,
1H), 4.22-4.06 (app. m, 2H), 2.91 (sept, J = 6.9 Hz, 1H ), 1.24 (d, J =
6.9 Hz, 6H ), 1.05 (t, J = 7.2 Hz, 3H), one exchangeable proton has
not appeared; 13C NMR (101 MHz, CDCl3): δ = 172.2, 149.9, 144.1,
140.8, 128.2(2C), 127.1(2C), 126.4, 65.4, 62.5, 34.0, 24.0(2C), 13.9;
HRMS (ESI) calculated for C15H19N3NaO3 [M+Na]+: m/z 312.1324,
found 312.1324.
Conflicts of interest
There are no conflicts to declare.
Ethyl
2-hydroxy-2-[5-(naphthalen-1-yl)-1H-1,2,3-triazol-4-yl]-
Experimental
acetate (2d): Prepared according to general procedure using 1d
(150.5 mg, 0.5 mmol) to afford the title triazole 2d (132 mg, 89%) as
a yellow liquid. IR (neat): ν = 3215, 2927, 1739, 1442, 1211, 1083,
Note: In general the azides are explosive and should be handled
with great care, in particular large scale reactions. During our study
we have encountered no problem.
1
1018, 804, 799 cm-1; H NMR (400 MHz, CDCl3): δ = 13.05 (bs, 1H),
8.02-7.79 (m, 3H), 7.70-7.37 (m, 4H), 5.31 (s, 1H), 4.21-4.3.76 (app.
m, 3H), 0.98 (t, J = 6.5 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ =
172.0, 142.8, 142.6, 133.7, 131.9, 129.8, 128.9, 128.4, 126.9, 126.3,
126.0, 125.4, 125.2, 65.2, 62.4. 13.7; HRMS (ESI) calculated for
General Procedure for synthesis of triazoles (2a-r): A hot air gun-
dried Schlenk tube was charged nitroallylic alcohol 1a-s (0.5 mmol,
1 equiv.), NaN3 (0.75 mmol, 1.5 equiv.) and p-TsOH (0.5 mmol, 1
equiv.) in DMSO (2.5 mL) and stirred at 80 oC under inert
atmosphere. The reaction was either complete or appeared to be
proceeding no progress further as monitored by TLC. Heating was
removed and allowed to room temperature, added water to
reaction mixture and extracted with EtOAc (3×40 mL). The
combined organic layers washed with brine (2x40 mL), dried over
anhydrous Na2SO4, and the solvent was removed under reduced
pressure. The resulting crude was subjected to flash
chromatography (silica gel, eluting with 30% to 50% petether/ethyl
acetate) to afford desired triazoles 2a-r.
C
16H16N3O3 [M+H]+: m/z 298.1192, found 298.1191.
Ethyl 2-hydroxy-2-[5-(naphthalen-2-yl)-1H-1,2,3-triazol-4-yl]-
acetate (2e): Prepared according to general procedure using 1e
(150.5 mg, 0.5 mmol) to afford the title triazole 2e (127.4 mg, 86%)
as a pale-yellow solid. mp: 121-123 oC; IR (neat): ν = 3213, 2927,
1739, 1463, 1232, 1085, 1016, 821, 750 cm-1; 1H NMR (400 MHz,
CDCl3): δ = 8.22 (s, 1H), 7.98-7.72 (m, 4H), 7.58-7.40 (m, 2H), 5.53 (s,
1H), 4.63 (bs, 1H), 4.24-4.02 (app. m, 2H), 1.07 (t, J = 7.0 Hz, 3H),
one exchangeable proton has not appeared; 13C NMR (101 MHz,
CDCl3): δ = 172.2, 144.7, 141.5, 133.4, 133.3, 128.8, 128.6, 127.8,
127.7, 126.9, 126.7, 126.5, 125.6, 65.5, 62.7, 14.0; HRMS (ESI)
calculated for C16H16N3O3 [M+H]+: m/z 298.1192, found 298.1191.
Ethyl 2-hydroxy-2-(5-phenyl-1H-1,2,3-triazol-4-yl)acetate (2a):
Prepared according to general procedure using 1a (125.5 mg, 0.5
mmol) to afford the title triazole 2a (106 mg, 86%) as a pale-yellow
gummy liquid. IR (neat): ν = 3236, 2928, 1742, 1567, 1445, 1221,
1090, 1018, 839 cm-1; 1H NMR (400 MHz, CDCl3): δ = 13.40 (bs, 1H),
7.73 (dd, J = 6.4, 1.8 Hz, 2H), 7.48-7.36 (m, 3H), 5.52 (s, 1H), 4.50
(bs, 1H), 4.22-4.09 (app. m, 2H), 1.10 (t, J = 7.2 Hz, 3H); 13C NMR
Ethyl
2-hydroxy-2-[5-(3-methoxyphenyl)-1H-1,2,3-triazol-4-yl]-
acetate (2f): Prepared according to general procedure using 1f
(140.5 mg, 0.5 mmol) to afford the title triazole 2f (101 mg, 73%) as
a colorless solid. mp: 114-116 oC; IR (neat): ν = 3215, 2924, 1739,
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1
1608, 1587, 1467, 1232, 1093, 1031, 860 cm-1; H NMR (400 MHz, liquid. IR (neat): ν = 3213, 2929, 1739, 1467, 1444, 1238, 1091,
1
CDCl3): δ = 12.11 (bs, 1H), 7.37 (d, J = 6.8 Hz, 1H), 7.36-7.31 (m, 2H), 1008, 831, 763 cm-1; H NMR (400 MHz, CDCl3): δ = 13.02 (bs, 1H),
7.00-6.96 (m, 1H), 5.49 (s, 1H), 4.27-4.15 (app. m, 2H), 3.86 (s, 3H), 7.63 (d, J = 8.6 Hz, 2H), 7.57 (d, J = 8.6 Hz, 2H), 5.47 (s, 1H), 4.29-
3.76 (bs, 1H), 1.14 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ = 4.10 (app. m, 2H), 1.13 (t, J = 7.2 Hz, 3H), one exchangeable proton
172.2, 159.9, 144.2, 141.1, 130.3, 130.1, 120.6, 115.3, 113.3, 65.4, has not appeared; 13C NMR (101 MHz, CDCl3): δ = 172.0, 143.9,
62.6, 55.4, 139.9; HRMS (ESI) calculated for C13H15N3O4 [M+Na]+: 141.0, 132.2(2C), 129.7(2C), 128.1, 123.5, 65.4, 62.8, 13.9; HRMS
m/z 300.0960, found 300.0962.
(ESI) calculated for C12H12BrN3O3 [M]+ and [M+2]+: m/z 325.0062,
found 325.0064 and 327.0042, found 327.0041.
Ethyl 2-hydroxy-2-[5-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl]-
acetate (2g): Prepared according to general procedure using 1g Ethyl 2-[5-(2-chlorophenyl)-1H-1,2,3-triazol-4-yl]-2-hydroxyacetate
(140.5 mg, 0.5 mmol) to afford the title triazole 2g (104 mg, 75%) as (2l): Prepared according to general procedure using 1l (142.5 mg,
a yellow liquid. IR (neat): ν = 3211, 2924, 1739, 1616, 1510, 1465, 0.5 mmol) to afford the title triazole 2l (97 mg, 69%) as colorless
1253, 1180, 1089, 1024, 839 cm-1; 1H NMR (400 MHz, CDCl3): δ = solid. mp: 109-110 oC; IR (neat): ν = 3211, 2926, 1739, 1444, 1433,
7.66 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 5.47 (s, 1H), 4.23- 1213, 1093, 1020, 761 cm-1; 1H NMR (400 MHz, CDCl3): δ = 13.76
4.15 (app. m, 2H), 3.84 (s, 3H), 1.14 (t, J = 7.2 Hz, 3H), two (bs, 1H), 7.55-7.42 (m, 2H), 7.41-7.27 (m, 2H), 5.54 (s, 1H), 4.56 (bs,
exchangeable protons has not appeared; 13C NMR (101 MHz, CDCl3): 1H), 4.19-4.00 (app. m, 1H), 4.06-3.96 (app. m, 1H), 1.08 (t, J = 7.1
δ = 172.2, 160.3, 143.9, 140.8, 129.6(2C), 121.3, 114.4(2C), 65.4, Hz, 3H); 13C NMR (101 MHz, CDCl3): δ = 171.8, 142.2, 141.3, 133.8,
62.5, 55.4, 14.0; HRMS (ESI) calculated for C13H16N3O4 [M+H]+: m/z 132.4, 130.7, 130.0, 128.3, 127.0, 65.6, 62.6, 13.9; HRMS (ESI)
278.1141, found 278.1143.
calculated for C12H13ClN3O3 [M+H]+: m/z 282.0645, found 282.0646.
Ethyl 2-[5-(3,4-dimethoxyphenyl)-1H-1,2,3-triazol-4-yl]-2-hydroxy- Ethyl 2-[5-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl]-2-hydroxyacetate
acetate (2h): Prepared according to general procedure using 1h (2m): Prepared according to general procedure using 1m (142.5
(155.5 mg, 0.5 mmol) to afford the title triazole 2h (110 mg, 72%) as mg, 0.5 mmol) to afford the title triazole 2m (122 mg, 87%) as
a pale-yellow viscus liquid. IR (neat): ν = 3259, 2924, 1741, 1612, colorless gummy liquid. IR (neat): ν = 3211, 2931, 1737, 1467, 1236,
1516, 1465, 1259, 1091, 1022, 862, 756 cm-1; 1H NMR (400 MHz, 1093, 1012, 835 cm-1; 1H NMR (400 MHz, CDCl3): δ = 7.63 (d, J = 8.6
CDCl3): δ = 7.35-7.28 (m, 2H), 6.93 (d, J = 8.1 Hz, 1H), 5.49 (s, 1H), Hz, 2H), 7.34 (d, J = 8.6 Hz, 2H), 5.52 (s, 1H), 4.28-3.98 (app. m, 2H),
4.23-4.14 (app. m, 2H), 3.91 (s, 6H), 1.13 (t, J = 7.1 Hz, 3H ), two 1.06 (t, J = 7.1 Hz, 3H), two exchangeable protons has not appeared;
exchangeable protons has not appeared; 13C NMR (101 MHz, CDCl3): 13C NMR (101 MHz, CDCl3): δ = 172.0, 143.8, 141.0, 135.2,
δ = 172.2, 149.7, 149.2, 144.2, 140.9, 121.7, 120.8, 111.4, 111.3, 129.5(2C), 129.2(2C), 127.6, 65.3, 62.7, 13.9; HRMS (ESI) calculated
65.5, 62.6, 56.0(2C), 13.7; HRMS (ESI) calculated for C14H18N3O5 for C12H13ClN3O3 [M+H]+: m/z 282.0645, found 282.0645.
[M+H]+: m/z 308.1246, found 308.1247.
Ethyl
2-[5-(2,4-dichlorophenyl)-1H-1,2,3-triazol-4-yl]-2-hydroxy-
Ethyl 2-hydroxy-2-[5-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-4- acetate (2n): Prepared according to general procedure using 1n
yl]acetate (2i): Prepared according to general procedure using 1i (160 mg, 0.5 mmol) to afford the title triazole 2n (113.5 mg, 72%) as
(170.5 mg, 0.5 mmol) to afford the title triazole 2i (114 mg, 68%) as a colorless solid. mp. 158-160 oC; IR (neat): ν = 3244, 2938, 1751,
a yellow jelly liquid. IR (neat): ν = 3250, 2926, 1741, 1589, 1463, 1587, 1435, 1228, 1092, 1021, 853, 799 cm-1; 1H NMR (400 MHz,
1
1242, 1126, 1002, 860 cm-1; H NMR (400 MHz, CDCl3): δ = 7.02 (s, DMSO-d6): δ = 15.30 (bs, 1H), 7.78 (s, 1H), 7.60-7.52 (m, 2H), 6.17
2H), 5.55 (s, 1H), 4.71 (bs, 1H), 4.24-4.07 (app. m, 2H), 3.86 (s, 3H), (bs, 1H), 5.24 (d, J = 5.2 Hz, 1H), 4.07-3.85 (app. m, 2H), 1.04 (t, J =
3.85 (s, 6H), 1.07 (t, J = 7.1 Hz, 3H), one exchangeable proton has 7.1 Hz, 3H); 13C NMR (101 MHz, DMSO-d6): δ = 171.0, 143.8, 141.3,
not appeared; 13C NMR (101 MHz, CDCl3): δ = 172.2, 153.6(2C), 134.5, 134.0(2C), 133.6, 129.3, 127.4, 64.9, 60.8, 13.9; HRMS (ESI)
144.5, 140.9, 138.5, 124.6, 105.4(2C), 65.5, 62.6, 61.0, 56.3(2C), calculated for C12H12Cl2N3O3 [M+H]+: m/z 316.0256, found 316.0255.
13.9; HRMS (ESI) calculated for C15H20N3O6 [M+H]+: m/z 338.1352,
Ethyl 2-hydroxy-2-[5-(thiophen-2-yl)-1H-1,2,3-triazol-4-yl]acetate
found 338.1351.
(2o): Prepared according to general procedure using 1o (128.5 mg,
Ethyl 2-[5-(2-bromophenyl)-1H-1,2,3-triazol-4-yl]-2-hydroxyacetate 0.5 mmol) to afford the title triazole 2o (81 mg, 64%) as brown
(2j): Prepared according to general procedure using 1j (165 mg, 0.5 liquid. IR (neat): ν = 3221, 2927, 1741, 1564, 1408, 1369, 1224,
mmol) to afford the title triazole 2j (124 mg, 76%) as a colorless 1091, 1018, 848, 707 cm-1; 1H NMR (400 MHz, CDCl3): δ = 7.47 (dd, J
solid. mp: 91-93 oC; IR (neat): ν = 3211, 2926, 1739, 1562, 1442, = 3.6, 1.0 Hz, 1H), 7.34 (dd, J = 5.1, 1.0 Hz, 1H), 7.06 (dd, J = 5.1, 3.6
1211, 1091, 1016, 761 cm-1; 1H NMR (400 MHz, CDCl3): δ = 13.27 Hz, 1H), 5.62 (s, 1H), 4.89 (bs, 1H), 4.24-4.09 (app. m, 2H), 1.11 (t, J
(bs, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.45 (dd, J = 6.0, 15 Hz, 1H), 7.38 (t, = 7.2 Hz, 3H), one exchangeable proton has not appeared; 13C NMR
J = 7.5, 1.4 Hz, 1H), 7.30 (td, J = 7.8, 1.5 Hz, 1H), 5.41 (s, 1H), 4.21- (101 MHz, CDCl3): δ = 171.9, 140.3, 139.9, 130.6, 128.0, 127.5,
3.98 (app. m, 2H), 1.12 (t, J = 7.2 Hz, 3H), one exchangeable proton 126.9, 65.5, 62.7, 13.9; HRMS (ESI) calculated for C10H12N3O3S
has not appeared; 13C NMR (101 MHz, CDCl3): δ = 171.7, 142.8, [M+H]+: m/z 254.0599, found 254.0598.
142.3, 133.2, 132.4, 130.8, 130.3, 127.4, 123.6, 65.5, 62.5, 13.8;
Ethyl 2-[5-(furan-2-yl)-1H-1,2,3-triazol-4-yl]-2-hydroxyacetate (2p):
HRMS (ESI) calculated for C12H13BrN3O3 [M+H]+ and [M+H+2]+: m/z
Prepared according to general procedure using 1p (120.5 mg, 0.5
326.0140, found 326.0140 and 328.0120, found 328.0120.
mmol) to afford the title triazole 2p (70 mg, 59%) as a reddish-
o
Ethyl 2-[5-(4-bromophenyl)-1H-1,2,3-triazol-4-yl]-2-hydroxyacetate brown solid. mp: 140-142 C; IR (neat): ν = 3169, 2924, 1741, 1458,
(2k): Prepared according to general procedure using 1k (165 mg, 0.5 1253, 1224, 1093, 1012, 738 cm-1; 1H NMR (400 MHz, CDCl3): δ =
mmol) to afford the title triazole 2k (147 mg, 90%) as a yellow 7.54 (d, J = 1.2 Hz, 1H), 6.88 (d, J = 3.4 Hz, 1H), 6.52 (dd, J = 3.4, 1.8
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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Hz, 1H), 5.69 (s, 1H), 4.32-4.19 (app. m, 2H), 3.83 (bs, 1H), 1.17 (d, J
= 6.9 Hz, 3H), one exchangeable proton has not appeared; 13C NMR
(101 MHz, CDCl3): δ = 171.1, 145.2, 143.3, 141.8, 136.5, 111.6,
109.1, 65.0, 60.6, 13.9 ; HRMS (ESI) calculated for C10H12N3O4
[M+H]+: m/z 238.0828, found 238.0827.
Notes and references
‡
CCDC-1571324 contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The
www.ccdc.cam.ac.uk/data_request/cif.
Crystal Structure of 2n: Ethyl 2-(5-(2,4-dichlorophenyl)-2H-1,2,3-
triazol-4-yl)-2-hydroxyacetate 2n (CCDC
12H11Cl2N3O3 (M 316.14), cubic, crystal dimensions:
0.24x0.24x 0.24 mm, monoclinic, space group: P21/c, a =
Cambridge
Crystallographic
Data
Centre
via
Diethyl 2-hydroxy-2-[5-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl]-
malonate (2q): Prepared according to general procedure using 1q
(176.5 mg, 0.5 mmol) to afford the title triazole 2q (69.5 mg, 40%)
as a yellow solid. mp: 138-140 oC; IR (neat): ν = 3238, 2931, 1748,
1569, 1441, 1356, 1241, 1095, 1019, 842, 699 cm-1; 1H NMR (400
MHz, CDCl3): δ = 12.66 (bs, 1H), 7.63 (d, J = 7.9 Hz, 2H), 6.90 (d, J =
7.9 Hz, 2H), 4.81 (bs, 1H), 4.27-4.04 (app. m, 4H), 3.80 (s, 3H), 1.09
(t, J = 6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3): δ = 168.6(2C), 160.2,
144.6, 141.1, 129.8(2C), 122.2, 114.2(2C), 76.3, 63.5(2C), 55.4,
13.8(2C); HRMS (ESI) calculated for C16H19N3O6Na [M+Na]+: m/z
372.1172, found 372.1172.
no.-1571324):
C
=
11.4912(9), b = 7.2015(5), c = 16.5491(13)Å, α = 90°,
β =
100.277 (2)°, γ = 90°, V = 1347.53(18) Å3, Z = 4, ρcalcd = 1.558
g/cm3, μ = 0.492 mm-1, F000 = 648.0, λΧυ−Κα = 1.54184 Å, T =
301(2) K, 2ϑmax =148.824°, 22992 reflections measured, 2369
independent reflections (Rint = 0.0422), R1 = 0.0465 (observed
reflections), wR = 0.1179 (all data), largest diff. peak and hole:
0.833 and -0.314 e.Å-3.
1
2
An excellent review on triazole applications, see: D. Huang, P.
Zhao and D. Astruc, Coord. Chem. Rev., 2014, 272, 145 and
references herein.
Diethyl 2-[5-(3,4-dimethoxyphenyl)-1H-1,2,3-triazol-4-yl]-2-hydro-
xymalonate (2r): Prepared according to general procedure using 1r
(191.5 mg, 0.5 mmol) to afford the title triazole 2r (68 mg, 36%) as a
yellow solid. mp: 168-169 oC; IR (neat): ν = 3242, 2931, 1752, 1568,
1465, 1232, 1098, 1019, 899 cm-1; 1H NMR (400 MHz, CDCl3): δ =
7.34 (s, 1H), 7.30 (d, J = 9.0 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 4.70 (br,
1H), 4.27-3.74 (m, 10H), 1.09 (t, J = 7.1 Hz, 6H), one exchangeable
proton has not appeared; 13C NMR (101 MHz, CDCl3): δ = 168.7(2C),
149.7, 149.0, 144.9, 141.2, 122.4, 120.9, 111.4, 111.2, 76.3,
63.5(2C), 56.01, 55.97, 13.8(2C); HRMS (ESI) calculated for
Selected articles and reviews: (a) I. Mohammed, I. R.
Kummetha, G. Singh, N. Sharova, G. Lichinchi, J. Dang, M.
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C
17H21N3O7Na [M+Na]+: m/z 402.1277, found 402.1278.
Ethyl 2-(2-benzyl-5-phenyl-2H-1,2,3-triazol-4-yl)-2-hydroxyacetate
(2t): A mixture of 2a (123.5 mg, 0.5 mmol), K2CO3 (138 mg, 1.0
mmol) and benzyl bromide (119 µL, 1.0 mmol) in CH3CN (3 mL) and
stirred at room temperature. After 15 h, the reaction mixture was
quenched with water (10 mL) and extracted with ethyl acetate
(2x30 mL). The combined organic layer was washed with brine (30
mL), dried over anhydrous Na2SO4 and solvent was removed under
reduced pressure. The crude product was purified by flash column
chromatography (silica gel, eluting with 30% petether/ethyl
acetate) to afford the desired N-benzyl triazole 2t (118 mg, 70%) as
a colorless liquid. IR (neat): ν = 3464, 2924, 1743, 1465, 1456, 1226,
1093, 1012, 871, 759 cm-1; 1H NMR (400 MHz, CDCl3): δ = 7.75 (dd, J
= 6.8, 1.5 Hz, 2H), 7.47-7.38 (m, 3H), 7.34-7.30 (m, 5H), 5.59 (s, 2H),
5.41 (d, J = 6.2 Hz, 1H), 4.29-4.10 (m, 2H), 3.59 (d, J = 6.4 Hz, 1H),
1.10 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ = 172.2, 146.9,
142.5, 135.1, 130.0, 128.82, 128.80(2C), 128.77, 128.6, 128.4,
128.14, 128.12(2C), 127.0, 65.3, 62.4, 58.9, 13.9; HRMS (ESI)
calculated for C19H20N3O3 [M+H]+: m/z 338.1505, found 338.1504.
3
4
5
For review articles, see: (a) J. E. Moses and A. D. Moorhouse.
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Acknowledgements
We thank SERB-ECR (File No. ECR/2015/000053), New Delhi for
financial assistance. RJR thanks to UGC for faculty position
under Faculty Recharge Programme. MW and AS thanks to
UGC and CSIR, New Delhi for their research fellowship,
respectively. T. Mounika is acknowledged for preliminary
investigations to this work. We also thanks to OUCFRD for
NMR facility.
6
7
For representative recent reviews: (a) M. Jia and S. Ma,
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6 | J. Name., 2012, 00, 1-3
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ARTICLE
V. V. Fokin, Chem. Soc. Rev., 2010, 39, 1302; (c) M. Meldal
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15 For cycloaddition-denitration reactions, see: (a) N. S. Zefirov,
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This journal is © The Royal Society of Chemistry 20xx
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ARTICLE
Y.-C. Chen and K. Chen, Chem.-Asian J., 2012, 7, 688; (i) S.
Journal Name
Roy and K. Chen, Org. Lett., 2012, 14, 2496; (j) R. J. Reddy, P.-
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21 The following nitroallylic alcohol was prepared from
isovaleraldehyde derived nitroalkene according to know
procedure.16c Upon treatment of this alcohol with sodium
azide undergoes degradation and formed desired triazole in
traces.
22 Z.-J. Zheng, D. Wang, Z. Xu and L.-W. Xu, Beilstein J. Org.
Chem., 2015, 11, 2557 and references herein. The poly-
nitrogen containing compounds generally explosive, however
during our study, we have encountered no problem.
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Tetrahedron Lett., 1973, 14, 4833; (b) G. E. Keck, K. A. Savin,
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8 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C7NJ03292G
Table of Contents
Efficient synthesis of 4,5-disubstituted-2H-1,2,3-triazoles from nitroallylic
derivatives via cycloaddition-denitration process
Raju Jannapu Reddy,* Md. Waheed, Thatikonda Karthik and Angothu Shankar
A variety of nitroallylic derivatives were smoothly reacted with sodium azide in the presence of p-TSOH
to form synthetically-viable triazoles have been described.