An Organocatalytic Regiospecific Synthesis of 1,5-Disubstituted 4-Thio-1,2,3-triazoles and 1,5-Disubstituted 1,2,3-Triazoles

Article abstract of DOI:10.1002/chem.201503302

Organocatalytic azide-ketone [3+2] cycloaddition (OrgAKC) of a variety of 1-aryl-2-(arylthio)ethanones and 1-alkyl-2-(alkylthio)ethanones with different aryl or alkyl azides is reported in dimethyl sulfoxide or solvent-free under ambient conditions to furnish 1,5-disubstituted 4-thio-1,2,3-triazoles in a regiospecific manner, which are further converted into useful 1,5-disubstituted 1,2,3-triazoles by treatment with Raney Ni at 25 ?C for 1-3 h. Notable features of the OrgAKC reaction include high rate and selectivity, solvent-free conditions, easily available substrates and catalysts, a wide range of synthetic and medicinal applications, and excellent yields generating a vast library of triazoles.

Full text of DOI:10.1002/chem.201503302

DOI: 10.1002/chem.201503302
Communication
&
Organocatalysis
An Organocatalytic Regiospecific Synthesis of 1,5-Disubstituted
4-Thio-1,2,3-triazoles and 1,5-Disubstituted 1,2,3-Triazoles
Dhevalapally B. Ramachary,* Patoju M. Krishna, Jagjeet Gujral, and G. Surendra Reddy[a]
tions in terms of structural evolution, reaction development,
Abstract: Organocatalytic azide–ketone [3+2] cycloaddi-
and applications in the chemical and biological sciences. Novel
tion (OrgAKC) of a variety of 1-aryl-2-(arylthio)ethanones
reaction discoveries in this field have included, zinc-, rutheni-
and 1-alkyl-2-(alkylthio)ethanones with different aryl or
um-, iridium-, and samarium-catalyzed azide–alkyne [3+2] cy-
alkyl azides is reported in dimethyl sulfoxide or solvent-
cloadditions,[5] strain-promoted azide–alkyne [3+2] cycloaddi-
free under ambient conditions to furnish 1,5-disubstituted
tion (SPAAC),[6] base-promoted azide–alkyne [3+2] cycloaddi-
4-thio-1,2,3-triazoles in a regiospecific manner, which are
tion,[7] azide–bromomagnesium acetylide [3+2] cycloaddition,[8]
further converted into useful 1,5-disubstituted 1,2,3-tri-
organocatalytic enamine- or enolate-mediated azide–carbonyl
azoles by treatment with Raney Ni at 258C for 1–3 h. No-
[3+2] cycloaddition,[9,10] copper- or iodine/tert-butyl peroxy-
table features of the OrgAKC reaction include high rate
benzoate-promoted reaction of N-tosylhydrazones with ani-
and selectivity, solvent-free conditions, easily available
lines,[11] iodine-promoted three-component reaction of N-tosyl-
substrates and catalysts, a wide range of synthetic and
hydrazones, arylketones and anilines,[12] and electronically con-
medicinal applications, and excellent yields generating
trolled active olefin–azide [3+2] cycloaddition.[13] Many of
a vast library of triazoles.
these reactions are suitable to synthesize a variety of 1,2,3-tri-
azoles, based on the availability of substrates and catalysts.
1,4-/1,5-Disubstituted 1,2,3-triazoles and 1,4,5-trisub-
stituted 1,2,3-triazoles have garnered much interest
as peptide bond isosteres and also as an important
family of heterocycles, which exhibit a vast spectrum
of properties and applications and are widely used in
pharmaceuticals.[1] In particular, 1,2,3-triazoles con-
taining 4-thiomethyl or 5-thio compounds and 1,5-
disubstituted 1,2,3-triazoles have found widespread
medicinal application in anticancer drugs, antifungal
agents, antibacterial drugs, anti-inflammatory drugs,
mPGES-1 inhibitors, bioorthogonal probes, and also
as human dUTPase inhibitors (Figure 1).[2] With these
applications, the development of more general and
green protocols for the synthesis of their analogues
is of significant interest.[3]
The regioselective copper-catalyzed azide–alkyne
Figure 1. Potential applications based on the 1,2,3-triazoles.
[3+2] cycloaddition (CuAAC) reaction, reported by
the groups of Sharpless and Meldal in 2002, led to
a huge expansion of interest in 1,4-disubstituted
1,2,3-triazoles.[4] After the discovery of this click reaction, many
researchers entered this field and made significant contribu-
In search of medicinally important 1,2,3-triazoles, we
thought of synthesizing 1,5-disubstituted 4-thio-1,2,3-tri-
azoles,[2] as their analogues have played significant roles in
pharmaceutical and biological chemistry (Figure 1).[2] Although
base-promoted SNAr reaction of 5-fluoro-1,2,3-triazoles with
alkyl thiols (Scheme 1a)[14] and iridium-catalyzed [3+2] cycload-
dition of thioalkynes with aryl azides (Scheme 1b)[15] have both
been reported as protocols to furnish 5-thio-1,2,3-triazoles
through metal catalysis, there is, to our knowledge, no reaction
available to prepare 4-thio-1,2,3-triazoles. Herein, we report
a general, rapid, and operationally simple organocatalytic
azide–ketone [3+2] cycloaddition (OrgAKC) reaction for the
[a] Prof. Dr. D. B. Ramachary, P. M. Krishna, J. Gujral, G. S. Reddy
Catalysis Laboratory, School of Chemistry
University of Hyderabad
Hyderabad-500 046 (India)
Fax: (+91)40-23012460
E-mail: ramsc@uohyd.ernet.in
ramchary.db@gmail.com
Homepage: http://chemistry.uohyd.ernet.in/~dbr/
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201503302.
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Communication
Table 1. Reaction optimization.[a]
Entry Catalyst 3 Solvent
Azide 2a [equiv] t [h] Yield 4aa [%][b]
1
2
3
4[c]
5[d]
6
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
3d
3e
3 f
DMSO
DMSO
DMSO
DMSO
1.2
1.2
1.5
1.5
2.5 65
6.0 85
6.0 90
1.0 90
24.0 50
2.0 76
17.0 42
24.0 <3
24.0 <5
24.0 <3
24.0 37
DMSO+H2O 1.5
DMF
CH3CN
CHCl3
EtOH
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
Scheme 1. Design for the enolate-mediated OrgAKC reaction.
7
8[e]
9[e]
10[e]
11
chemo- and regiospecific high-yielding synthesis of 1,5-disub-
stituted 4-thio-1,2,3-triazoles from aryl or alkyl azides and 1-
aryl-2-(arylthio)ethanones or 1-alkyl-2-(alkylthio)ethanones
(Scheme 1c). One very important benefit of this method is that
useful 1,5-disubstituted 1,2,3-triazoles could also be easily syn-
thesized from the common intermediate, 1,5-disubstituted 4-
thio-1,2,3-triazoles, through desulfurization with Raney Ni at
room temperature (Scheme 1c).
12[e]
13
14[e]
15[e]
16[e]
17
18[c]
24.0
24.0 22
24.0
–
–
3g
3h
3a
3a
24.0 <5
6.5 <5
1.5 85
1.5 90
solvent-free 1.5
solvent-free 1.5
Based on the above proposal, we first chose 1-phenyl-2-
(phenylthio)ethanone 1a and phenyl azide 2a as substrates
for the reaction optimization. We commenced optimization of
the OrgAKC reaction by using commercially available 1,8-diaza-
bicyclo[5.4.0]undec-7-ene (DBU) 3a (pKa of conjugate acid in
DMSO=12) as the organocatalyst for the click reaction of 1-
phenyl-2-(phenylthio)ethanone 1a (pKa of methylene CÀH
bonds in DMSO=16.9) with 1.2–1.5 equivalents of phenyl
azide 2a (Table 1). The click reaction of ketone 1a with
1.2 equivalents of 2a in DMSO, catalyzed by 10 mol% of 3a at
258C for 2.5 h furnished the expected 4-thio-1,2,3-triazole 4aa
as a single regioisomer in moderate yield (Table 1, entry 1). The
same reaction over an extended time (6 h) at 258C furnished
4aa in 85% yield (Table 1, entry 2). When the amount of azide
2a was increased from 1.2 to 1.5 equivalents, the same reac-
tion over 6 h furnished the 4aa in 90% yield (Table 1, entry 3).
At a reaction temperature of 508C, the same reaction of 1a
with 1.5 equivalents of 2a furnished 4aa in 90% yield within
1 h (Table 1, entry 4). To investigate whether the DBU-promot-
ed OrgAKC reaction is solvent dependent, we carried out the
click reaction in various other solvent systems, including aque-
ous dimethyl sulfoxide [DMSO+H2O (7:3 v/v)], DMF, CH3CN,
CHCl3, and EtOH. However, we obtained the click product 4aa
in decreased yields of 50%, 76%, 42%, <3%, and <5%, re-
spectively, and longer reaction times of up to 24 h were re-
quired, except in DMF (Table 1, entries 5–9). These results clear-
ly support our hypothesis of the involvement of reactive in
situ enolate formation from 1a with 3a during the course of
the reaction.
[a] Reactions were carried out in solvent (0.5m) or solvent-free with 1a
(0.5 mmol) and 2a (1.2–1.5 equiv) in the presence of 10 mol% of catalyst
3; [b] yields refer to product isolated by column chromatography; [c] T=
508C; [d] DMSO+H2O (7:3 v/v) was used as solvent; [e] starting materials
1a and 2a were recovered.
azabicyclodecene (3c), proline (3d), diethylamine (3e), pyrroli-
dine (3 f), K2CO3 (3g), and tBuOK (3h) in DMSO at 258C. How-
ever, with catalysts 3c and 3e, we obtained the 4aa in only
37% and 22% yield, respectively, and with the other catalysts
conversions of 0–<5% were obtained (Table 1, entries 10–16).
To make this click reaction greener, we tested the reaction
under solvent-free conditions. Pleasingly, the solvent-free reac-
tion of 1a (0.5 mmol, 114 mg) and 2a (0.75 mmol, 88.6 mL)
with 3a (0.05 mmol, 7.5 mL) at 25–508C for 1.5 h furnished 4aa
in 85–90% yields (Table 1, entries 17 and 18). In these reac-
tions, the phenylthio (PhÀS) group was electronically responsi-
ble for inducing the acidity of CÀH bonds in 1a, as proven by
the control experiments. No click reaction was observed be-
tween acetophenone (PhS=H) and phenyl azide through eno-
late or enamine formation catalyzed by of amines or amino
acids (see the Supporting Information, Table S1). We therefore
identified the optimized conditions as 25–508C in DMSO or
solvent-free, catalyzed by 10 mol% of DBU 3a, which furnished
the single isomer 4aa in 90% yield from 1a and 2a (Table 1,
entries 3, 4, and 18).
With the optimized conditions in hand, the scope and the
generality of the DBU-catalyzed OrgAKC reactions were investi-
gated. A variety of substituted aryl and alkyl azides 2b–p react-
ed with ketone 1a catalyzed by 10 mol% of 3a at 258C both
in solvent-free conditions and in DMSO for 0.75–6 h (Table 2).
To further investigate the reactivity of amine and non-amine
catalysts on OrgAKC reaction, we carried out the click reaction
with 10 mol% of various catalysts, including DABCO (3b), tri-
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nature of the reaction mixture because of the polar functional
groups. 1,2,3-Triazole formation from alkyl or sugar azides is
a useful reaction in click chemistry,[16] which highlights the im-
portance of the OrgAKC reaction in glycoscience.
Table 2. Azide scope.[a]
Having elucidated the solvent effects and the electronic and
steric factors of aryl, alkyl, and sugar azides 2 in the [3+2] cy-
cloaddition reaction, we further investigated the reaction
scope with different 1-aryl-2-(phenylthio)ethanones 1b–n and
1-(phenylthio)propan-2-one 1o in the OrgAKC reaction with
C6H5N3 (2a), 4-CF3C6H4N3 (2e), and 4-FC6H4N3 (2g) under both
sets of conditions (Table 3). In this reaction, 1-aryl-2-(phenyl-
Entry
ArÀN3 or RÀN3 2
Yield 4 [%][b,c]
1
2
3
4
5
6
7
8
2b (FG=4-NO2)
2c (FG=4-CO2Et)
2d (FG=4-CN)
2e (FG=4-CF3)
2 f (FG=4-CHO)
2g (FG=4-F)
2h (FG=4-Cl)
2i (FG=3-Cl)
2j (FG=4-Br)
2k (FG=4-Me)
2l (FG=4-OMe)
2m (FG=(R)-4-CH3COCH2CHOH)
2n (R=CH2Ph)
4ab: 93 (85)
4ac: 90 (90)
4ad: 93 (85)
4ae: 97 (85)
4af: 87 (81)
4ag: 95 (90)
4ah: 95 (88)
4ai: 96 (85)
4aj: 88 (92)
4ak: 90 (87)
4al: 55 (72)
4am: 65 (63)
4an: – (65)
4ao: – (40)
Table 3. Ketone scope: a-(Phenylthio)ketones.[a]
9
10[d]
11[d]
12[e]
13[d,f]
14[d,f]
Entry
1 (Ar1 or R)
Ar2ÀN3 2
Yield 4 [%][b]
2o (R=CH2CH2Ph)
1
2
3
4
5
6
7
8
1b (Ar1 =4-NO2C6H4)
1c (Ar1 =3-NO2C6H4)
1d (Ar1 =4-CNC6H4)
1e (Ar1 =4-CF3C6H4)
1 f (Ar1 =4-FC6H4)
1 f (Ar1 =4-FC6H4)
1g (Ar1 =4-ClC6H4)
1g (Ar1 =4-ClC6H4)
1h (Ar1 =4-BrC6H4)
1i (Ar1 =4-IC6H4)
1j (Ar1 =4-OMeC6H4)
1k (Ar1 =4-MeC6H4)
1l (Ar1 =2-Naphthyl)
1m (Ar1 =4-PhC6H4)
1n (Ar1 =Furan-2-yl)
1o (R=Me)
2e
2e
2e
2e
2a
2e
2g
2e
2e
2e
2e
2e
2e
2e
2e
2a
2e
95 (4be)
91 (4ce)
90 (4de)
85 (4ee)
95 (4 fa)
85 (4 fe)
85 (4gg)
90 (4ge)
83 (4he)
82 (4ie)
70 (4je)
93 (4ke)
90 (4le)
92 (4me)
62 (4ne)
65 (4oa)
80 (4oe)
15[d,f,g]
4ap: – (60)
[a] Reactions were carried out in DMSO (0.5m) or solvent-free with 1a
(0.5 mmol) and 2b–p (1.5 equiv) in the presence of 10 mol% of 3a;
[b] yields refer to product isolated by column chromatography; [c] values
in parentheses refer to the yields of the solvent-free reaction; [d] T=
508C; [e] ee of 2m is 75.9% and that of 4am is 75.7%, based on the
chiral HPLC analysis; [f] reaction performed in solvent-free conditions
only; [g] t=24 h.
9
10
11[c]
12
13
14
15[c]
16[c]
17
The aryl azides 2b–j, with substituents including NO2, CO2Et,
CN, CF3, CHO, F, Cl, and Br, furnished the expected 4-thio-1,2,3-
triazoles 4ab–aj in excellent yields within 0.75 h in both sets of
conditions, without showing much difference (Table 2, en-
tries 1–9). Reaction rates and yields of the 4-thio-1,2,3-triazoles
4ab–aj were increased by electron-withdrawing substituents
at the para position of 2, but rate and yields slightly decreased
with alkyl and electron-donating substituents. For example,
the DBU-catalyzed OrgAKC reaction of the aryl azides 4-
CH3C6H4N3 (2k) and 4-OCH3C6H4N3 (2l) with ketone 1a in
DMSO at 258C took longer time (6 h) for lower yields (65%
and 25%, respectively); but the same reactions at 508C for
2.0 h furnished the 4-thio-1,2,3-triazoles 4ak and 4al in 90%
and 55% yields, respectively (Table 2, entries 10 and 11). Similar
results were obtained with 2k and 2l in solvent-free condi-
tions, but the yield of 4al was increased compared to that in
DMSO. The reaction of 1a with chiral (R)-2m having 75.9% ee,
catalyzed by 10 mol% of 3a, furnished (R)-4am in 65% yield
with similar (75.7%) ee (Table 2, entry 12). Surprisingly, no reac-
tion was observed for the 3a-catalyzed OrgAKC reaction of 1a
with alkyl and sugar azides 2n–p in DMSO at 25–658C for
24 h, but the same reaction under solvent-free conditions at
508C for 3, 6, and 24 h furnished 4an, 4ao, and 4ap in 65%,
40%, and 60% yields, respectively (Table 2, entries 13–15). The
longer reaction time (24 h) required for the OrgAKC reaction of
1a with azido sugar 2p may be due to the highly viscous
1o (R=Me)
[a] Reactions were carried out in DMSO (0.5m) with 1b–o (0.5 mmol) and
2 (1.5 equiv) in the presence of 10 mol% of 3a; [b] yields refer to product
isolated by column chromatography; [c] yields of 66% (4je), 56% (4ne),
and 61% (4oa) were obtained through solvent-free reaction of 1j, 1n,
and 1o with 2e or 2a at RT for 1 h.
thio)ethanones 1b–n, containing functional groups including
4-NO2, 3-NO2, 4-CN, 4-CF3, 4-F, 4-Cl, 4-Br, 4-I, 4-OMe, 4-Me, 2-
naphthyl, 4-phenyl, and heteroaryl, were used as substrates for
the organocatalytic synthesis of single isomers of 1,4,5-trisub-
stituted 4-thio-1,2,3-triazoles 4be–ne, 4 fa, and 4gg in good to
excellent yields within 0.75–1.5 h (Table 3, entries 1–15). In
a similar manner, the OrgAKC reaction of 1-(phenylthio)pro-
pan-2-one 1o with aryl azides 2a and 2e catalyzed by 3a at
RT for 0.75 h in DMSO furnished 4oa and 4oe in 65% and
80% yields, respectively (Table 3, entries 16 and 17). The
OrgAKC reactions of 1j, 1n, and 1o with 2e or 2a in DMSO
gave click products 4je, 4ne, and 4oa in 70%, 62% and 65%
yields, whereas the same reactions under solvent-free condi-
tions also furnished the products in moderate yields (66%,
56% and 61%, respectively; Table 3, entries 11, 15, and 16).
The results in Table 3 demonstrate the broad scope of this
methodology, covering a structurally diverse group of 1-aryl-2-
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(phenylthio)ethanones 1b–n, 1-(phenylthio)propan-2-one 1o,
and aryl azides 2a, 2e, and 2g. Many of the OrgAKC product 4
yields obtained compared very well to iridium-catalyzed azide–
thioalkyne [3+2] cycloaddition[5] (Table 3 and Scheme 1). The
structure and the regiochemistry of the OrgAKC products 4aa–
ap/4ba–oa/4be–oe/4gg were confirmed by NMR spectrosco-
py. Moreover, the structure of 4je was definitively established
X-ray structure analysis (see the Supporting Information, Fig-
ure S1).[17]
Table 5. Synthesis of 1,5-disubstituted 1,2,3-triazoles 5 through desulfuri-
zation of 4-thio-1,2,3-triazoles 4.[a]
Entry 4 (R, Ar1, Ar2, or Ar3)
Yield 5 [%][b]
1
2
3
4
5[c]
6
7
8
4aa (Ar1 =C6H5; Ar2 =C6H5; Ar3 =C6H5)
87 (5aa)
85 (5ac)
90 (5ae)
90 (5ag)
70 (5aa)
60 (5ao)
60 (5ee)
60 (5le)
90 (5me)
4ac (Ar1 =C6H5; Ar2 =C6H5; Ar3 =4-CO2EtC6H4)
4ae (Ar1 =C6H5; Ar2 =C6H5; Ar3 =4-CF3C6H4)
4ag (Ar1 =C6H5; Ar2 =C6H5; Ar3 =4-FC6H4)
To further investigate the importance of the alkyl/aryl substi-
tution on the sulfur atom to the acidity of the a-methylene of
1-aryl-2-(arylthio)ethanones and 1-aryl-2-(alkylthio)ethanones
1p–w in the OrgAKC reaction, we chose the highly functional-
ized ketones 1p–w, which have low or high a-methylene acidi-
ty compared to 1-aryl-2-(phenylthio)ethanones 1a–o (Table 4).
4aj (Ar1 =C6H5; Ar2 =C6H5; Ar3 =4-BrC6H4)
4ao (Ar1 =C6H5; Ar2 =C6H5; Ar3 =CH2CH2C6H5)
4ee (Ar1 =4-CF3C6H4; Ar2 =C6H5; Ar3 =4-CF3C6H4)
4le (Ar1 =2-Naphthyl; Ar2 =C6H5; Ar3 =4-CF3C6H4)
4me (Ar1 =4-PhC6H4; Ar2 =C6H5; Ar3 =4-CF3C6H4)
4re (Ar1 =4-PhC6H4; Ar2 =4-ClC6H4; Ar3 =4-CF3C6H4) 60 (5re)
4te (Ar1 =4-PhC6H4; R=Octyl; Ar3 =4-CF3C6H4)
4ue (Ar1 =4-FC6H4; R=Decyl; Ar3 =4-CF3C6H4)
9
10
11
12
85 (5te)
85 (5ue)
Table 4. Ketone scope: Other a-(arylthio)ketones[a]
[a] Reactions were carried out in EtOH (0.05m) with Raney Ni (1.0 g) and
4 (0.5 mmol) at RT; [b] yields refer to product isolated by column chroma-
tography; [c] debromination also took place.
The advantage of the OrgAKC reaction was further depicted
by synthesizing medicinally useful 1,5-disubstituted 1,2,3-tri-
azoles 5 (Table 5). The reaction of 1,5-diphenyl-4-phenylthio-
1,2,3-triazole (0.5 mmol) 4aa with 1.0 g of freshly prepared Ra-
ney Ni in ethanol at 258C for 2.5 h furnished the 1,5-diphenyl-
1,2,3-triazole 5aa in 87% yield (Table 5, entry 1). This mild de-
sulfurization reaction was further exploited by using differently
substituted 4-arylthio-1,2,3-triazoles and 4-alkylthio-1,2,3-tri-
azoles 4 (Table 5). A library of synthetically and medicinally
useful 1,5-disubstituted 1,2,3-triazoles 5ac–ue were synthe-
sized in very good yields at room temperature by treatment of
the corresponding 4-thio-1,2,3-triazoles 4 with 1.0 g of Raney
Ni in ethanol through the desulfurization reaction.[18] In con-
trast, the reported conditions for the desulfurization required
high temperature and long reaction time.[18] The desulfuriza-
tion reaction worked well at 258C with different sulfur and aryl
substituents without showing the effects of steric or electronic
factors, except in the case of compound 4aj, where debromi-
nation occurred (Table 5, entry 5). The sequential one-pot
OrgAKC solvent-free reaction of 1a, 2c, and 3a followed by
Raney Ni desulfurization furnished the product 5ac in reduced
(65%) yield compared to the two-pot reaction (Table 5,
entry 2). Pleasingly, the reaction of 1,5-diphenyl-4-phenylthio-
1,2,3-triazole 4aa with 1.2 equivalents of m-chloroperbenzoic
acid in DCM at 258C for 18 h furnished selectively the mono-
oxidized 1,5-diphenyl-4-(phenylsulfinyl)-1H-1,2,3-triazole 6aa in
55% yield [Eq. (1)]. These results clearly show the advantages
of the OrgAKC methodology, which enables a high-yielding
synthesis of medicinally important 1,5-disubstituted 1,2,3-tri-
azoles 5 and 6.
Entry
1 (R, Ar1, or Ar2)
Ar3ÀN3 2
Yield 4 [%][b]
1
2
3
4
5
6
7
8
1p (Ar1 =4-PhC6H4; Ar2 =2-FC6H4)
1q (Ar1 =4-PhC6H4; Ar2 =2-ClC6H4)
1r (Ar1 =4-PhC6H4; Ar2 =4-ClC6H4)
1s (Ar1 =4-PhC6H4; Ar2 =2-BrC6H4)
1t (Ar1 =4-PhC6H4; R=octyl)
1u (Ar1 =4-FC6H4; R=decyl)
1v (Ar1 =4-MeC6H4; Ar2 =4-CF3C6H4)
1w (Ar1 =C6H5; R=CH2C6H5)
2e
2e
2e
2e
2e
2e
2e
2a
87 (4pe)
85 (4qe)
85 (4re)
85 (4se)
92 (4te)
92 (4ue)
92 (4ve)
87 (4wa)
[a] Reactions were carried out in DMSO (0.5m) with 1p–w (0.5 mmol) and
2 (1.5 equiv) in the presence of 3a (10 mol%); [b] yields refer to product
isolated by column chromatography;
The reaction of 1-[(1,1’-biphenyl)-4-yl]-2-[(2-fluorophenyl)thio]-
ethanone (1p) with 4-CF3C6H4N3 (2e) catalyzed by DBU at
258C for 1.5 h furnished the expected 4-thio-1,2,3-triazole 4pe
in 87% yield without showing the effects of steric or electronic
factors (Table 4, entry 1). In a similar manner, the reaction of 2-
chlorophenylthioethanone (1q), 4-chlorophenylthioethanone
(1r), and 2-bromophenylthioethanone (1s) with 4-CF3C6H4N3
(2e) catalyzed by DBU at 258C for 1.5 h furnished the 4-thio-
1,2,3-triazoles 4qe–se, each in 85% yield (Table 4, entries 2–4).
We also utilized three examples of 1-aryl-2-(alkylthio)ethanones
(1t, u, and w) for the OrgAKC reaction with 2a or 2e catalyzed
by DBU, which furnished the expected 1,4,5-trisubstituted 4-
thio-1,2,3-triazoles 4te, ue, and wa in excellent yields within
0.75 h without showing any electronic effects from the alkyl
substitution of sulfur (Table 4, entries 5, 6, and 8). The OrgAKC
reaction of richly functionalized 1-(p-tolyl)-2-[(4-(trifluorome-
thyl)phenyl)thio]ethanone (1v) with 4-CF3C6H4N3 (2e) catalyzed
by 3a at 258C for 0.75 h furnished the functionalized 4-thio-
1,2,3-triazole 4ve in 92% yield (Table 4, entry 7). The results in
Table 4 highlight the efficacy of this protocol in the click syn-
thesis of 4-thio-1,2,3-triazoles 4.
A proposed mechanism for the regiospecific synthesis of 4
through the reaction of 1, 2, and 3a is shown in Scheme 2. Re-
action of the amine 3a with ketone 1 generates the catalytic
enolate 7, which, on in situ treatment with Ar/RÀN3 2, fur-
nishes selectively the adduct 1,2,3-triazoline 8 in a concerted
Chem. Eur. J. 2015, 21, 16775 – 16780
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Communication
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Acknowledgements
We thank DST (New Delhi) for financial support. P.M.K., J.G.,
and G.S.R. thank CSIR (New Delhi) and UGC (New Delhi) for
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Received: August 20, 2015
Published online on October 7, 2015
Chem. Eur. J. 2015, 21, 16775 – 16780
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