Organocatalytic triazole formation, followed by oxidative aromatization: Regioselective metal-free synthesis of benzotriazoles

Article abstract of DOI:10.1002/chem.201301412

Herein we report on our studies on the sequential one-pot combinations of amine-catalyzed multicomponent reactions (MCRs). We have developed the copper-free synthesis of functionalized bicyclic N-aryl-1,2,3-triazole and N-arylbenzotriazole products 4 and 5 from the simple unmodified starting materials through [3+2]-cycloaddition ([3+2]-CA) and oxidative aromatization reactions in one pot under amine catalysis. The sequential one-pot reaction proceeds in good yields with high selectivity by using pyrrolidine as the catalyst from the simple unmodified substrates of enones, aryl azides, and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). Furthermore, we have demonstrated the medicinal applications of products 4 and 5 through simple organic reactions. Organo-click approach to benzotriazoles: A practical synthesis of N-arylbenzotriazoles was achieved through the sequential one-pot combination of [3+2]-cycloaddition followed by 2,3-dichloro-5,6-dicyano-1,4- benzoquinone (DDQ)-mediated oxidative aromatization of unmodified cyclic enones with aryl azides. For the first time, the synthesis of privileged CF₃ containing N-arylbenzotriazoles through metal-free catalysis has been discovered (see scheme). Copyright

Full text of DOI:10.1002/chem.201301412

FULL PAPER
DOI: 10.1002/chem.201301412
Organocatalytic Triazole Formation, Followed by Oxidative Aromatization:
Regioselective Metal-Free Synthesis of Benzotriazoles
Dhevalapally B. Ramachary* and Adluri B. Shashank[a]
In memory of Professor A. Srikrishna
Abstract: Herein we report on our
studies on the sequential one-pot com-
binations of amine-catalyzed multicom-
ponent reactions (MCRs). We have de-
veloped the copper-free synthesis of
functionalized bicyclic N-aryl-1,2,3-tri-
ACHTUNGTRENNUNGazole and N-arylbenzotriazole products
4 and 5 from the simple unmodified
starting materials through [3+2]-cyclo-
addition ([3+2]-CA) and oxidative aro-
matization reactions in one pot under
amine catalysis. The sequential one-pot
reaction proceeds in good yields with
high selectivity by using pyrrolidine as
the catalyst from the simple unmodi-
fied substrates of enones, aryl azides,
and 2,3-dichloro-5,6-dicyano-1,4-benzo-
quinone (DDQ). Furthermore, we
have demonstrated the medicinal appli-
cations of products 4 and 5 through
simple organic reactions.
Keywords: amines · azides · click
chemistry · cycloaddition · multi-
component reactions · triazoles
Introduction
their structural and biological importance, the development
of new and selective practical methods for their preparation
is a challenging task.[2–4]
N-Arylbenzotriazoles can be prepared by palladium- or
copper-catalyzed Buchwald-Hartwig-type reactions of aryl-
triazenes (Figure 2a),[2] palladium- or copper-catalyzed ary-
N-Arylbenzotriazoles are an important class of heterocycles
that display a large spectrum of structural and biological ac-
tivities and are widely used in organic, medicinal, and mate-
rial chemistry.[1] For example, benzotriazole A is an inhibitor
of c-Kit protooncogene, compound B is potassium-channel
activator, and compounds C and D are antiplasmodial and
antibacterial agents, respectively (see Figure 1).[1] Based on
Figure 2. Summary of previous work and the design plan of this work.
Figure 1. Pharmaceutically active N-arylbenzotriazoles A–D.
Fg=functional group; EWG=electron-withdrawing group; Ar=aryl.
lation of NH-benzotriazoles (Figure 2a),[3] the [3+2]-cyclo-
addition reaction between aryne and organic azides (Fig-
ure 2b),[4] and the reaction of (Z)-1-aryl-3-hexen-1,5-diynes
with sodium azide.[5] In all the above methods, either they
used a limited number of available highly reactive in situ-
generated arynes or not so readily available aryltriazenes or
NH-benzotriazoles as starting materials. Also, from the
above reactions, benzotriazoles were formed as a mixture of
[a] Prof. Dr. D. B. Ramachary, A. B. Shashank
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
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201301412.
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Table 1. Reaction optimization.[a]
N-arylated isomers in all the cases except the synthesis in-
volving Buchwald–Hartwig-type reactions.[2] These limita-
tions inspired us to develop a new protocol for the high-
yielding regioselective synthesis of N-arylbenzotriazoles
based upon organocatalytic triazole formation followed by
oxidative aromatization, from readily available unmodified
substrates as shown in Figure 2c.
Recently, organocatalytic-triazole formation has emerged
as a powerful tool in copper-free click chemistry.[6] In 2008,
we have discovered a copper-free technology for the synthe-
sis of highly substituted NH-1,2,3-triazoles from commercial-
ly available unmodified enones and activated organic azides,
through domino [3+2]-cycloaddition/hydrolysis ([3+2]-CA/
H) reactions under proline catalysis.[6e] Later in 2011, Pons
and co-workers reported the clever synthesis of N-aryl-1,2,3-
triazoles from unactivated ketones with aryl azides under
proline catalysis.[6b] In the same year, Wang et al. reported
the cycloaddition of aryl azides with enamides, generated in
situ from activated ketones in the presence of catalytic
amount of a secondary amine.[6c,d] Recently, Paixao and co-
workers reported the cycloaddition of activated azidophenyl
arylselenides with b-keto-esters in the presence of a catalytic
amount of diethylamine.[6a] However, the strategies of Pons
and Wang require high temperatures for the synthesis of
less-functionalized N-aryl-1,2,3-triazoles, and Paixao synthe-
sized simple monocyclic N-aryl-1,2,3-triazoles, which may
not be suitable starting materials for the synthesis of N-aryl-
benzotriazoles. By taking the advantage of the organocata-
lytic click reaction, herein, we report the metal-free regiose-
lective synthesis of N-arylbenzotriazoles from the treatment
of highly functionalized unmodified cyclic enones with unac-
tivated aryl azides under amine catalysis at 258C followed
by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)-medi-
Entry
Catalyst 3
[mol%]
t
Product
G
[h]
yield [%][b] 4aa
1[c]
2
3a (20)
3a (20)
3b (10)
3b (10)
3c (10)
6
6
2
1
1
83
85
81
90
95
3
4[d]
5
[a] Reactions were carried out in DMSO (0.5m) with 1.5 equiv of 2a rela-
tive to the 1a (0.5 mmol) in the presence of 10–20 mol% of catalyst 3.
[b] Yield refers to the column chromatographically purified product.
[c] 0.5 equiv of 2a was used relative to 1a (0.5 mmol). [d] Reaction was
performed at 708C.
1.5 equiv of 2a in DMSO at 258C for 1 h with diethyl amine
3b (10 mol%) furnished the N-aryl-1,2,3-triazole 4aa in a
reduced (81%) yield (Table 1, entry 3). The same reaction
at 708C for 1 h furnished 4aa in 90% yield (Table 1,
entry 4). Treatment of 1a with 1.5 equiv of 2a in DMSO at
258C for 1 h with pyrrolidine 3c (10 mol%) furnished the
4aa in a very good (95%) yield (Table 1, entry 5). We con-
sidered the optimized conditions to be 258C in DMSO using
10 mol% of pyrrolidine 3c as the catalyst (Table 1, entry 5).
After successful demonstration of room temperature
[3+2]-CA reactions of 1a with 2a under the amine catalysis,
we investigated the effect of aryl substitution factor on the
amine-catalyzed [3+2]-CA reaction of 1a with the other
aryl azides 2b–h as shown in Table 2. A series of ortho- or
para-substituted aryl azides 2b–h were treated with 1a cata-
lyzed by pyrrolidine 3c (10 mol%) at 258C in DMSO for 1–
ated oxidative aromatization in
a sequential one-pot
manner. Herein, we explore the utility of highly functional-
ized bicyclic N-aryl-1,2,3-triazoles as starting materials for
the synthesis of medicinally important N-arylbenzotriazoles
through mild oxidative aromatization.
Table 2. Substituent effect on the N-aryl-1,2,3-triazole formation.[a]
Results and Discussion
With our previous experience,[6e] we first optimized the
high-yielding synthesis of functionalized bicyclic N-aryl-
1,2,3-triazoles from unmodified substrates at ambient condi-
tions. For this we initiated optimization of the organocatalyt-
ic triazole formation by screening a number of known orga-
nocatalysts for the reaction of activated cyclic enone 1a
with 0.5 to 1.5 equiv of p-nitrophenyl azide (4-NO2C6H4N3)
2a (Table 1). Surprisingly, treatment of 1a and 2a
(0.5 equiv) with proline 3a (20 mol%) in DMSO at 258C
for 6 h furnished N-aryl-1,2,3-triazole 4aa in 83% yield
(Table 1, entry 1). The same reaction with 1.5 equiv of 2a in
DMSO at 258C for 6 h furnished 4aa in 85% yield (Table 1,
entry 2). To improve the yield of triazole formation, we per-
formed the reaction under the secondary amine-catalysis as
shown in Table 1, entries 3–5. Treatment of 1a with
À
Entry
Ar N3 2
t
Product
[h]
yield [%][b]
1
2
3
4
2b (Fg=2-NO2)
2c (Fg=4-CF3)
2d (Fg=4-CO2Et)
2e (Fg=4-CN)
2 f (Fg=4-Br)
2g (Fg=4-Me)
2h (Fg=4-H)
1
1
1
95 (4ab)
93 (4ac)
92 (4ad)
97 (4ae)
75 (4af)
50 (4ag)
50 (4ah)
0.75
5
24
40
66
6[c]
7
[a] Reactions were carried out in DMSO (0.5m) with 1.5 equiv of 2b–h
relative to the 1a (0.5 mmol) in the presence of 10 mol% of 3c. [b] Yield
refers to the column chromatographically purified product. [c] Reaction
was performed at 708C.
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Regioselective Metal-Free Synthesis of Benzotriazoles
FULL PAPER
66 h (Table 2). Both electron-deficient- (NO2, CF3, CO2Et,
enones 1a–r were furnished the expected bicyclic N-aryl-
1,2,3-triazoles 4 in excellent to good yields (Table 3). Yields
of the organocatalytic [3+2]-CA products 4 were increased
by the aryl substitution at the C6 position of cyclic enones 1,
but yields slightly decreased with aliphatic substitution and
these required longer reaction times. For example, the pyr-
rolidine-catalyzed [3+2]-CA reaction of C6 aliphatic-substi-
tuted cyclic enones 1d, 1e, 1 f, and 1g with 4-CF3C6H4N3 2c
in DMSO at 258C for 4–17 h furnished the expected N-aryl-
1,2,3-triazoles 4dc, 4ec, 4 fc, and 4gc in 90, 60, 70, and 70%
yields, respectively (Table 3, entries 3–6). Fascinatingly, the
[3+2]-CA reaction of C6-aryl-substituted cyclic enones 1h–o
with 4-CF3C6H4N3 2c at 258C for 1 h in DMSO under pyrro-
lidine catalysis furnished the expected bicyclic N-aryl-1,2,3-
triazoles 4hc–oc in very good yields with excellent regiose-
lectivity (Table 3, entries 7–14). Surprisingly, the C2-substi-
tuted enone 1p and simple cyclic enones like 1q and 1r
gave the high-yielding pharmaceutically useful [3+2]-CA
products 4pc, 4qc, 4rc, 4ra, and 4rb with aryl azides 2a–c
under catalysis with 3c at 258C within one hour (Table 3,
entries 15–19). The structure and regiochemistry of [3+2]-
CA products 4bc–rb was confirmed by NMR spectroscopic
analysis and also finally confirmed by X-ray structure analy-
sis on 4bc as shown in Figure S1 (see the Supporting Infor-
mation).[7]
À
CN and Br) and neutral (CH3 and H) aryl azides (Ar N3) 2
furnished the expected bicyclic N-aryl-1,2,3-triazoles 4ab–ah
in excellent to good yields (Table 2). Surprisingly, pyrroli-
dine-catalyzed [3+2]-CA reaction of 1a with 4-MeOC6H4N3
2i did not furnished the expected product even at higher
temperatures (not shown in Table 2). The structure and re-
giochemistry of bicyclic N-aryl-1,2,3-triazoles 4 were con-
firmed by NMR spectroscopic analysis.
With the optimized reaction conditions in hand, the sub-
strate scope of the amine-catalyzed [3+2]-CA reaction was
investigated before the investigation of oxidative aromatiza-
tion. A variety of unmodified functionalized cyclic enones
1a–r was reacted with 1.5 equiv of CF3 and NO2 containing
aryl azides 2a–c catalyzed by pyrrolidine 3c (10 mol%) of
258C in DMSO for 1–17 h (Table 3). Interestingly, both the
aliphatic- and aromatic-functionalized unmodified cyclic
Table 3. Diverse libraries of N-aryl-1,2,3-triazoles 4.[a]
After successful synthesis of bicyclic N-aryl-1,2,3-triazoles
4, we then investigated the oxidative aromatization of 4 to
N-arylbenzotriazoles 5 in a sequential one-pot manner as
shown in Table 4. Surprisingly, treatment of crude product
4ac, obtained after aqueous workup from [3+2]-CA reac-
tion, with DDQ (2 equiv) in toluene at 1008C for 48 h fur-
nished the expected N-arylbenzotriazole 5ac with 50%
overall yield (Table 4). With this result in hand, a variety of
bicyclic N-aryl-1,2,3-triazoles 4 generated from unmodified
functionalized cyclic enones 1a–r and aryl azides 2a–f were
treated with DDQ (2 equiv) in toluene at 1008C for 48 h to
furnish the expected N-arylbenzotriazoles 5 in excellent to
good overall yields, in
a sequential one-pot manner
(Table 4). In this reaction, both the electron-withdrawing
(NO2, CF3, CO2Et, CN, and Br) substituted aryl azides 2
and C2/C6-substituted unmodified cyclic enones 1 were used
as substrates for the sequential one-pot synthesis of N-aryl-
benzotriazoles 5 (Table 4). The results in Table 4 demon-
strate the broad scope of this new methodology covering a
structurally diverse group of cyclic enones 1a–r and aryl
azides 2a–f. Many of the yields obtained were very good
compared with other routes. The structure and regiochemis-
try of products 5 was confirmed by NMR analysis and also
finally confirmed by X-ray structure analysis on 5rc (shown
in Figure S2 of the Supporting Information).[7]
With the medicinal applications in mind, we explored the
utilization of heterocycles 4 and 5 bearing aryl CF3 and NO2
in the high-yielding synthesis of functionalized N-aryl-1,2,3-
triazoles and N-arylbenzotriazoles 6–8 through simple re-
duction, epoxidation, ester hydrolysis, and decarboxylation
reactions (Scheme 1). Interestingly, direct oxidation of the
N-aryl-1,2,3-triazole 4rc with meta-chloroperbenzoic acid
[a] Yield refers to the column chromatographically purified product.
[b] Reaction was performed at 708C. [c] Azide used was 2a. [d] Azide
used was 2b.
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D. B. Ramachary and A. B. Shashank
Table 4. Diverse libraries of N-arylbenzotriazoles 5.[a,b]
Scheme 1. Synthetic applications of N-aryl-1,2,3-triazole 4rc and N-aryl-
benzotriazoles 5. Reaction conditions: i) mCPBA (1.2 equiv), DCM
(0.1m), 08C, 1 h, 85%; ii) LiAlH4 (4.0 equiv), Et2O (0.1m), 08C, 2 h, 70%;
iii) mCPBA (1.2 equiv), DCM (0.1m), 08C, 1 h, 85%; iv) LiOH
(6.0 equiv), MeOH+H2O+THF (1:1:4; 0.1m), RT, 4 h; v) Cu powder
(40 mol%), quinoline (0.1m), 2208C, 1 h; vi) see reference [1b].
channel activators, and antiplasmodial and antibacterial
agents, respectively), emphasizing the value of this organo-
catalytic triazole and benzotriazole approach to the pharma-
ceuticals (see Figure 1 and Scheme 1c).[1]
Based on their many medicinal applications, herein, we
have demonstrated the gram-scale synthesis of N-arylbenzo-
triazole 5ac (Scheme 2). By scaling up milligrams to 1.0 g of
enone 1a with 1.131 g of aryl azide 2c in DMSO (8.0 mL) at
258C for 1 h under the pyrrolidine catalysis furnished the
crude triazole product 4ac in >99% conversion with >95%
purity, which on further treatment with DDQ (2.5 g) in tol-
uene (30 mL) at 1008C for 12 h furnished the 5ac in>90%
conversion with 57% overall yield. The slightly improved
[a] Yield refers to the column chromatographically purified product.
[b] In the top two rows, Ar is 4-CF3C6H4.
(mCPBA; 1.2 equiv) in dry CH2Cl2 at 08C for 1 h furnished
the selective epoxide 6rc in 85% yield (Scheme 1a). Ester
reduction of N-aryl-1,2,3-triazole 4rc with 4 equiv of LiAlH4
in dry Et2O at 0–258C for 2 h followed by oxidation with
mCPBA (1.2 equiv) in dry CH2Cl2 at 08C for 1 h furnished
the functionalized epoxide 7rc in 85% yield (Scheme 1a).
Lithium hydroxide-mediated hydrolysis of N-arylbenzotri-
ACHTUNGTRENNUNGazoles 5aa and 5ra at 258C for 4–5 h furnished the acids in
very good yields, which on further treatment with copper
powder in quinoline at 2208C for 1 h furnished the decar-
boxylated N-arylbenzotriazoles 8aa and 8ra in good yields
(Scheme 1b). As we are interested to synthesize the biologi-
cally important N-arylbenzotriazoles, herein, we applied the
two-step hydrolysis/decarboxylation protocol to generate the
key intermediate 8rb for the synthesis of potassium-channel
activator B (Scheme 1c). Some of the compounds 8aa, 8ra,
and 8rb obtained from ester hydrolysis and decarboxylation
sequence are precursors for the synthesis of drug molecules
A–D (used as a c-Kit protooncogene inhibitor, potassium-
Scheme 2. Gram-scale synthesis of N-arylbenzotriazole 5ac. i) 1a (1.0 g,
5.5 mmol, 2c (1.131 g, 6.05 mmol), pyrrolidine 3c (46 mL, 10mol%),
DMSO (8 mL, 0.7m), RT, 1 h, >99% conv. ii) DDQ (2.5 g, 2 equiv),
CH3C6H5 (30 mL, 0.2m), 1008C, 12 h, >90% conv.
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Regioselective Metal-Free Synthesis of Benzotriazoles
FULL PAPER
yield of benzotriazole 5ac with a shorter reaction time in
gram-scale synthesis compared with milligram-scale synthe-
sis (see Table 4, entry 1) may be due to the slight change in
reaction concentration (see Scheme 2).[8]
Conclusion
We have developed the copper-free synthesis of N-aryl-
1,2,3-triazole and N-arylbenzotriazole products 4 and 5 from
the simple unmodified starting materials through [3+2]-CA
and oxidative aromatization reactions under amine catalysis.
The sequential one-pot reaction proceeds in good yields
with high selectivity by using pyrrolidine as the catalyst. Fur-
thermore, we have demonstrated the medicinal applications
of products 4 and 5. Further work is in progress to develop
an asymmetric version of [3+2]-CA reactions.
Reaction mechanism: The rationale for the observed differ-
ent reactivity and high selectivity of aryl azides 2a–i in
organo-click reactions could be explained by the mechanism
shown in Scheme 3. Mesomerism or resonance between the
azido group and the aromatic ring is the most fundamental
Experimental Section
General methods: The 1H NMR, 13C NMR, and 19F NMR spectra were
recorded at 400, 100, and 376.5 MHz, respectively. The chemical shifts
are reported in ppm downfield to TMS (d=0) for 1H NMR spectra and
relative to the central CDCl3 resonance (d=77.0) for 13C NMR spectra.
In the 13C NMR spectra, the nature of the carbons (C, CH, CH2 or CH3)
was determined by recording the DEPT-135 experiment, and is given in
parentheses. The coupling constants J are given in Hz. Column chroma-
tography was performed using Acmeꢁs silica gel (particle size 0.063–
0.200 mm). High-resolution mass spectra were recorded on micromass
ESI-TOF MS. IR spectra were recorded on JASCO FT/IR-5300 and
Thermo Nicolet FT/IR-5700. Elemental analyses were recorded on a
Thermo Finnigan Flash EA 1112 analyzer. The X-ray diffraction meas-
urements were carried out at 298 K on an automated Enraf-Nonious
Scheme 3. Proposed reaction mechanism. EDG=electron-donating
group.
MACH
3 diffractometer using graphite monochromated, MoKa (l=
0.71073 ꢂ) radiation with CAD4 software or the X-ray intensity data
were measured at 298 K on a Bruker SMART APEX CCD area detector
system equipped with a graphite monochromator and a MoKa fine-focus
sealed tube (l=0.71073 ꢂ). For thin-layer chromatography (TLC), silica
gel plates Merck 60 F254 were used and compounds were visualized by
irradiation with UV light and/or by treatment with a solution of p-anisal-
dehyde (23 mL), conc. H2SO4 (35 mL), acetic acid (10 mL), and ethanol
(900 mL) followed by heating.
factor to determine the reactivity of the aryl azides in organ-
ic synthesis.[8a] Some of the physicochemical properties of
the aryl azides can be explained by a consideration of their
mesomeric structures and we have shown the possible dipo-
lar mesomeric structures, when the azido group is connected
to different aryl groups (I–V). The excellent reactivity and
high regioselectivity of aryl azides 2a–e with in situ-generat-
ed nucleophiles of push–pull dienamines 9 is explained on
the basis of the probably major contributing mesomeric
structures III and IV (attack on N3 by 9) compared with I,
II, or V. Exploring the organo-click reaction with functional-
ized aryl azides 2a–i more clearly demonstrated that the
electron-withdrawing groups (EWG) around the aryl azides
are the key factor to enhance the reaction rate (see
Table 2). Notably, the reaction with para-methyl phenyl
azide 2g and phenyl azide 2h proceeded in about 40 h,
which is 66 times slower than 2a and there is no reaction
with para-methoxy phenyl azide 2i (Table 2), indicating that
the electronic nature of the substituent is a decisive factor
to affect the reaction rate. The possible mechanism for the
regioselective synthesis of 4 through the reaction of enones
Materials: All solvents and commercially available chemicals were used
as received. Functionalized enones 1a–p was prepared from alkyl aceto-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
tionalized enone 1r was prepared from trimethyl-(1-methylene-allyloxy)-
silane and ethyl propynoate in high yield according to a literature proce-
dure.[10c] The highly functionalized aryl azides 2a–i were prepared accord-
ing to the literature procedures.[11]
General experimental procedures for organo-click reactions
Pyrrolidine-catalyzed domino [3+2]-cycloaddition reactions: In an ordi-
nary glass vial equipped with a magnetic stirring bar, to 0.5 mmol of
enone 1 and 0.75 mmol of arylazide 2 dissolved in DMSO (1.0 mL), the
catalyst pyrrolidine 3c (0.05 mmol, 10 mol%) was added and the reaction
mixture was stirred at 258C for the time indicated in Tables 1–3. The
crude reaction mixture was worked up with aqueous NH4Cl solution and
the aqueous layer was extracted with dichloromethane (2ꢃ20 mL). The
combined organic layers were dried (Na2SO4), filtered and concentrated.
Pure domino products
4 were obtained by column chromatography
(silica gel, mixture of hexane/ethyl acetate).
À
1, Ar N3 2 and pyrrolidine 3c is illustrated in Scheme 3.
Sequential one-pot synthesis of benzotriazoles: In an ordinary glass vial
Treatment of 3c with enone 1 generates the push–pull dien-
equipped with
a magnetic stirring bar, pyrrolidine 3c (0.05 mmol,
amine 9,[6e,9] which on in situ-treatment with probably the
10 mol%) was added to enone 1 (0.5 mmol) and arylazide 2 (0.75 mmol)
dissolved in DMSO (1.0 mL), the catalyst and the reaction mixture was
stirred at 258C for the time indicated in Table 4. The crude reaction mix-
ture was worked up with aqueous NH4Cl solution and the aqueous layer
was extracted with dichloromethane (2ꢃ20 mL). The combined organic
layers were dried (Na2SO4), filtered, and concentrated. The crude triazole
À
major contributing mesomeric structure III of Ar N3 2 se-
lectively furnishes the adduct 10 through a concerted [3+2]-
cycloaddition, which further transforms into the product 4
through the rapid elimination of pyrrolidine 3c.
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D. B. Ramachary and A. B. Shashank
4 was preceded for next step without purification. In a 10 mL round-
bottom flask equipped with a magnetic stirring bar, triazole 4 (0.5 mmol)
was added in dry toluene (5.0 mL) as a solvent and then DDQ (2 equiv,
1.0 mmol) was added. The reaction mixture was heated at reflux and
monitored by using TLC. After the completion of reaction, the crude
product was purified by column chromatography on silica gel (hexane/
EtOAc) to afford the benzotriazoles 5.
[2] N-Arylbenzotriazoles from aryltriazenes, see: a) J. Zhou, J. He, B.
Wang, W. Yang, H. Ren, J. Am. Chem. Soc. 2011, 133, 6868–6870;
b) R. Kiran Kumar, M. A. Ali, T. Punniyamurthy, Org. Lett. 2011,
13, 2102–2105; c) Z. Zhu, Q. L. Liu, W. Li, Y M. Zhu, Heterocycles
2011, 83, 2057–2065; d) R. R. Kale, V. Prasad, H. A. Hussain, V. K.
Tiwari, Tetrahedron Lett. 2010, 51, 5740–5743; e) C. Mukhopadhyay,
P. K. Tapaswi, R. J. Butcher, Org. Biomol. Chem. 2010, 8, 4720–
4729; f) Q. L. Liu, D. D. Wen, C. C. Hang, Q. L. Li, Y. M. Zhu, Helv.
Chim. Acta 2010, 93, 1350–1354.
[3] N-Arylbenzotriazoles from arylation of NH-benzotriazoles, see:
a) C. Mukhopadhyay, P. K. Tapaswi, Synth. Commun. 2012, 42,
2217–2228; b) L. Alakonda, M. Periasamy, Synthesis 2012, 44,
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Direct epoxidation of triazoles: In an oven dried round-bottom flask,
mCPBA (1.2 equiv, 0.12 mmol) was added to a stirred solution of triazole
4rc (1.0 equiv, 0.1 mmol) in dry CH2Cl2 at 08C. After complete consump-
tion of the substrate (as monitored by TLC), the reaction mixture was di-
luted with CH2Cl2, washed with 10% aqueous K2CO3 solution, and brine,
and dried with Na2SO4. Evaporation of solvent under reduced pressure
gave crude product, which was further purified by column chromatogra-
phy on silica gel (hexane/EtOAc) to afford the 6rc in 85% yield.
Reduction followed by epoxidation of triazoles: In an oven dried round-
bottom flask, LiAlH4 (4 equiv, 3.6 mmol) was added to the solution of tri-
azole 4rc (1.0 equiv, 0.9 mmol) in dry ether at 08C. After 2 h, EtOAc was
added to consume excess LiAlH4, then the reaction was quenched with
water and extracted with ether. The combined ether extracts was washed
with brine and dried. Evaporation of the solvent and purification of resi-
due over silica gel column using EtOAc/hexane as eluent furnished the
allylic alcohol (70%) as a white solid. The above allylic alcohol was
taken in dry CH2Cl2 and then mCPBA (1.2 equiv) was added at 08C.
After complete consumption of the substrate (as monitored by TLC), the
reaction mixture was diluted with CH2Cl2, washed with 10% aqueous
K2CO3 solution, and brine, and dried with Na2SO4. Evaporation of sol-
vent under reduced pressure gave crude product, which was purified by
column chromatography on silica gel (hexane/EtOAc) to afford the 7rc
in 85% yield.
Hydrolysis followed by decarboxylation of functionalized benzotriazoles:
In a 10 mL round-bottom flask equipped with a magnetic stirring bar, a
mixture of MeOH (0.5 mL), H2O (0.5 mL), THF (2 mL) and then
LiOH·H2O (1.8 mmol, 6 equiv) was added to benzotriazole 5 (0.3 mmol)
and the reaction mixture was stirred for 4–5 h at 258C as indicated in
Scheme 1b and c. The reaction mixture was neutralized with 2n HCl and
then extracted with ethyl acetate (3ꢃ20 mL). The combined organic
layers were washed with water, brine, and dried over Na2SO4. The crude
acid was preceded for next step without purification. A mixture of the
above acid, copper powder (40 mol%) and quinoline (0.1m) were added
to a sealed glass tube and the mixture was heated at 2208C for 1 h. After
cooling to room temperature, the mixture was neutralized with 2n HCl
and extracted with ethyl acetate (3ꢃ20 mL). The combined organic
layers were washed with water, brine, and dried over Na2SO4. The resi-
due obtained upon evaporation of the solvent was purified by column
chromatography to yield the benzotrizoles 8.
[7] CCDC-932094 (4bc) and 932093 (5rc) contain the supplementary
crystallographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif. See the Supporting Informa-
tion for crystal structures.
Acknowledgements
This study was supported by the Department of Science and Technology
(DST), New Delhi. A.B.S. thanks the Council of Scientific and Industrial
Research (CSIR), New Delhi for his research fellowship. We thank Dr. P.
Raghavaiah for X-ray structural analysis.
[8] Azides are energy-rich molecules with many applications. Caution,
however, should be exercised when using azides. Both organic and
inorganic azides can be heat and shock-sensitive and can explosively
decompose with little input of external energy. In general, olefinic,
aromatic, or carbonyl azides are much less stable than aliphatic
azides. For these reasons, azides should not be distilled or treated in
a careless fashion. However, when common sense is employed, they
can be prepared, stored, and used without risk in the standard or-
ganic chemistry laboratory. We have never experienced a safety
problem with these organic azides, even at the gram-scale synthesis.
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Regioselective Metal-Free Synthesis of Benzotriazoles
FULL PAPER
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Received: April 14, 2013
Published online: && &&, 2013
Chem. Eur. J. 2013, 00, 0 – 0
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D. B. Ramachary and A. B. Shashank
Organo-click approach to benzotria-
zoles: A practical synthesis of N-aryl-
benzotriazoles was achieved through
the sequential one-pot combination of
[3+2]-cycloaddition followed by 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ)-mediated oxidative aromatiza-
tion of unmodified cyclic enones with
aryl azides. In this work, for the first
time we have discovered the synthesis
of privileged CF3 containing N-aryl-
benzotriazoles through the metal-free
catalysis (see scheme).
Organo-click Reactions
D. B. Ramachary,*
A. B. Shashank ............... &&&& — &&&&
Organocatalytic Triazole Formation,
Followed by Oxidative Aromatization:
Regioselective Metal-Free Synthesis of
Benzotriazoles
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www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!