Synthesis of 4-aryl-1H-1,2,3-triazoles through TBAF-catalyzed [3 + 2] cycloaddition of 2-aryl-1-nitroethenes with TMSN3 under solvent-free conditions

Article abstract of DOI:10.1021/jo0507845

TBAF-catalyzed [3 + 2] cycloaddition reactions of 2-aryl-1-cyano- or 2-aryl-1-carbethoxy-1-nitroethenes 1 with TMSN₃ under SFC allow the corresponding 4-aryl-5-cyano- or 4-aryl-5-carbethoxy-1H-1,2,3-triazoles 2 to be prepared under mild reactio

Full text of DOI:10.1021/jo0507845

Synthesis of 4-Aryl-1H-1,2,3-triazoles
through TBAF-Catalyzed [3 + 2]
gen 1,3-dipolar cycloaddition of azides with alkynes. The
efficiency of this process is generally related to the
10
presence of an electron-withdrawing group on the alkyne
Cycloaddition of 2-Aryl-1-nitroethenes with
and/or on the azide.1
1,12
Recently, significant progress in
TMSN under Solvent-Free Conditions
3
the synthesis of these heterocycles has been achieved by
Sharpless et al., who have defined a Click chemistry
process in which a Cu(I)-acetylenic organometallic com-
pound prepared in situ has been used as a 1,3-dipolaro-
phile either in aqueous medium13 or in organic solvent.
Recently, Sharpless et al. have also reported the use
of an alkylmagnesium bromide as 1,3-dipolarophile in dry
THF for the synthesis of 1,5-disubstituted 1,2,3-triazoles
David Amantini, Francesco Fringuelli,*
Oriana Piermatti, Ferdinando Pizzo, Ennio Zunino, and
Luigi Vaccaro*
14
CEMIN, Centro di Eccellenza Materiali Innovativi
Nanostrutturati, Dipartimento di Chimica, Universit a` di
Perugia, Via Elce di Sotto 8, I-06123 Perugia, Italy
frifra@unipg.it; luigi@unipg.it
Received April 18, 2005
15
under “Click conditions” and demonstrated that ace-
tylcholinesterase is an efficient catalyst for the reactions
of azides with acetylenic compounds.16
Alternative synthetic routes for the preparation of
1
7
1
,2,3-triazole moiety have been rarely pursued. In
particular, a very little attention has been devoted to
3+2] cycloaddition reactions of azides with electron-poor
[
18
olefins and subsequent elimination reaction (Scheme
).
The scarce application of these substrates is probably
1
due to the poor reactivity of the reactants, which require
harsh reaction conditions generally leading to unsatisfac-
TBAF-catalyzed [3 + 2] cycloaddition reactions of 2-aryl-1-
cyano- or 2-aryl-1-carbethoxy-1-nitroethenes 1 with TMSN3
under SFC allow the corresponding 4-aryl-5-cyano- or 4-aryl-
(
8) Brockunier, L. L.; Parmee, E. R.; Ok, H. O.; Candelore, M. R.;
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Weber, A. E. Bioorg. Med. Chem. Lett. 2000, 10, 2111-2114.
5
-carbethoxy-1H-1,2,3-triazoles 2 to be prepared under mild
reaction conditions and with good to excellent yields (70-
0%). The proposed protocol does not require dried glassware
or inert atmosphere.
(9) Palhagen, S.; Canger, R.; Henriksen, O.; van Parys, J. A.; Riviere,
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1
H-1,2,3-Triazoles are heterocycles with a wide range
1
of applications that are receiving a growing attention.
They are commercially employed as anticorrosive agents,
agrochemicals, photostabilizer photographic materials,
2
4
3
4
and dyes. In addition, they constitute the essential
5
moiety of a number of drugs, and they are also potent
HIV-1 inhibitors,6 anti-microbial agents,7 as well as
8
selective â
3
-adrenergic receptor agonists. They can also
9
act as antiviral and anticonvulsant agents.
,2,3-Triazole synthesis has been intensively studied,
and 1,2,3-triazoles are commonly prepared by the Huis-
(11) (a) Huisgen, R.; Knorr, R.; M oius, L.; Szeimies, G. Chem. Ber.
1
9
1
965, 98, 4014-4021. (b) Huisgen, R.; Blaschke, H. Chem. Ber. 1965,
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03, 1908-1917.
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3) Fan, W. In Comprehensive Heterocyclic Chemistry II; Katritzky,
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2
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(
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(
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1
(
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Antivir. Chem. Chemother. 1998, 9, 481-489.
(
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10.1021/jo0507845 CCC: $30.25 © 2005 American Chemical Society
6526
J. Org. Chem. 2005, 70, 6526-6529
Published on Web 07/09/2005

SCHEME 1. [3 + 2] Cycloaddition/Elimination
Strategy for the Synthesis of 1H-1,2,3-Triazoles
from Electron-Poor Olefins
SCHEME 2. Synthesis of 4-Aryl-Substituted
1H-1,2,3-Triazoles 2 Starting from Nitroethenes 1
tory yields. To the best of our knowledge, an efficient
catalyst for this process is still unavailable.
Considering that electron-poor olefins are widely ac-
cessible and despite current knowledge, we believe that
this alternative approach to 1,2,3-triazoles has not
showed its potential yet.
TABLE 1. Optimization of the Reaction of
a
(
E)-2-Phenyl-1-cyano-1-nitroethene (1a) with TMSN3 at
30 °C
Our research is mainly focused on the definition of new,
chemically efficient, easy-to-operate, and environmentally
responsible synthetic procedures for the preparation of
target molecules.1
9,20
To reach this goal, we have been
c
19
entry
catalystb
medium
time (h)
conversion (%)
performing reactions in water or under solvent-free
1
9
1
2
3
4
5
6
7
8
9
SFC
SFC
DCE
SFC
DCE
SFC
SFC
THF
DCE
24
24
24
24
24
15
3
conditions (SFC), searching for new catalysts that would
express their best efficiency in these alternative reaction
TiCl4
TiCl4
1
9,20
media.
TiCl4‚2THF
TiCl4‚2THF
TBABr
TBAF‚3H2O
TBAF‚3H2O
TBAF‚3H2O
Recently, we have reported an environmentally friendly
protocol for the preparation of 1H-tetrazoles by a tet-
rabutylammonium fluoride (TBAF)-catalyzed cycloaddi-
tion of aryl- or alkylnitriles with trimethylsilyl azide
98
99
99
91
10
11
(
TMSN
3
) under SFC.19 Starting from these results and
a
.0 equiv. b 0.1 equiv. c Reaction conversions determined by
2
considering that we have been investigating the synthetic
utility of R-cyano- and R-carbetoxy-R-nitroethenes 1,19b,c,h,20b
we have planned to use TBAF as a catalyst in the [3 +
] cycloadditions of these electron-poor olefins with
TMSN under SFC (Scheme 2). Acceptors 1 can open a
straightforward and environmentally friendly access
route to a new class of triazoles such 2.
To our knowledge, R-nitroethenes have never been
used as acceptors in the reaction with an azide except
for the preparation of 1H-1,2,3-triazoles 2 (X ) H, R )
H, p-Cl, p-Br) via reaction of the corresponding â-ni-
trostyrene 1 (X ) R ) H) with sodium azide in DMF.1
In these cases, yields were poor.
1
H NMR analyses.
2
cyano-1-nitroethene (1a) with TMSN3 at 30 °C. The
3
results are illustrated in Table 1.
Under SFC and in the absence of any additive, nitro-
ethene 1a did not react with TMSN
4 h (Table 1, entry 1). Similarly, TiCl
representative and commonly used Lewis acid catalyst
in many organic processes, and its THF complex TiCl
3
(2.0 equiv) even after
2
4
, chosen as a
4
‚
2
THF were not able to promote the cycloaddition of 1a
with TMSN both under SFC and in dichloroethane
3
8c
(
DCE) (Table 1, entries 2-5).
Initially, we have optimized the reaction conditions by
studying the cycloaddition reaction of (E)-2-phenyl-1-
By using 0.1 equiv of tetrabutylammonium bromide
TBABr) as catalyst under SFC at 30 °C, triazole 2a was
obtained as the sole reaction product after 15 h (Table 1,
entry 6). Under these reaction conditions HNO -elimina-
2
tion and tautomeric rearrangement always followed the
cycloaddition process.
A better result was achieved by using 0.1 equiv of
TBAF. In the presence of this salt, the reaction of 1a with
TMSN was complete in only 3 h at 30 °C (Table 1, entry
3
7). By using THF or DCE as reaction medium longer
times (10 and 11 h, respectively) were observed (Table
, entries 8 and 9). The excellent catalytic activity of
TBAF under SFC was then used for the preparation of a
variety of triazoles (2a-g). The results are illustrated
in Table 2.
In the presence of 0.1 equiv of TBAF, nitroethenes
3
a-e reacted at 30 °C with TMSN (2.0 equiv) under SFC
and in very short times and gave triazoles 2a-e in
excellent yields (75-90%) (Table 2, entries 1-5), inde-
pendently from the substituent at the phenyl ring. When
2-thienyl or 2-furfuryl was the aryl substituent (1f, 1g),
reaction rates and isolated yields of the corresponding
(
(
18) (a) Maiorana, S.; Pocar, D.; Dalla Croce, P. Tetrahedron Lett.
1
3
966, 7, 6043-6045. (b) Meek, J. S.; Fowler, J. J. Org. Chem. 1968,
3, 985-991. (c) Zefirov, M. S.; Chapovskaya, N. K.; Kolesnikov, V. V.
Chem. Commun. 1971, 1001-1002. (d) Beck, G.; G u¨ nther, D. Chem.
Ber. 1973, 2758-2766. (e) Shin, C. G.; Yonezawa, Y.; Yoshimura, J.
Tetrahedron Lett. 1974, 15, 7-10. (f) Chakrasali, R. T.; Ila, H.;
Junjappa, H. Synthesis 1988, 453-455. (g) Chakrasali, R. T.; Ila, H.;
Junjappa, H. Synthesis 1988, 851-854.
(
19) As representative papers, see: (a) Fringuelli, F.; Pizzo, F.;
Vaccaro, L. Synthesis 2000, 646-650. (b) Amantini, D.; Fringuelli, F.;
Piermatti, O.; Pizzo, F.; Vaccaro, L. Green Chem. 2001, 3, 229-232.
(
c) Fringuelli, F.; Matteucci, M.; Piermatti, O.; Pizzo, F.; Burla, M. C.
1
J. Org. Chem. 2001, 66, 4661-4666. (d) Fringuelli, F.; Pizzo, F.;
Tortoioli, S.; Vaccaro, L. Adv. Synth. Catal. 2002, 344, 379-384. (e)
Fioroni, G.; Fringuelli, F.; Pizzo, F.; Vaccaro, L. Green Chem. 2003, 5,
4
25-428. (f) Fringuelli, F.; Pizzo, F.; Rucci, M.; Vaccaro, L. J. Org.
Chem. 2003, 68, 7041-7045. (g) Fringuelli, F.; Pizzo, F.; Tortoioli, S.;
Vaccaro, L. J. Org. Chem. 2003, 68, 8248-8251. (h) Amantini, D.;
Fringuelli, F.; Piermatti, O.; Pizzo, F.; Vaccaro, L. J. Org. Chem. 2003,
1
6
8, 9263-9268. (i) Fringuelli, F.; Pizzo, F.; Vaccaro, L. J. Org. Chem.
004, 69, 2315-2321.
20) (a) Amantini, D.; Fringuelli, F.; Pizzo, F.; Vaccaro, L. J. Org.
2
(
Chem. 2001, 66, 6734-6737. (b) Amantini, D.; Fringuelli, F.; Pizzo, F.
J. Org. Chem. 2002, 67, 7238-7243. (c) Fringuelli, F.; Pizzo, F.;
Tortoioli, S.; Vaccaro, L. Tetrahedron Lett 2003, 44, 6785-6787. (d)
Amantini, D.; Beleggia, R.; Fringuelli, F.; Pizzo, F.; Vaccaro, L. J. Org.
Chem. 2004, 69, 2896-2898. (e) Fringuelli, F.; Pizzo, F.; Tortoioli, S.;
Vaccaro, L. J. Org. Chem. 2004, 69, 7745-7747. (f) Fringuelli, F.; Pizzo,
F.; Tortoioli, S.; Vaccaro, L. J. Org. Chem. 2004, 69, 8780-8785.
2
7).
f and 2g were still satisfactory (Table 2, entries 6 and
J. Org. Chem, Vol. 70, No. 16, 2005 6527

TABLE 2. Synthesis of 4-Aryl-5-cyano-1H-1,2,3-triazoles
TABLE 3. Synthesis of
a-g under SFC at 30 °Ca
4-Aryl-5-carbethoxy-1H-1,2,3-triazoles 2h-p under SFC
a
2
a
.1 equiv of TBAF‚3H2O and 2.0 equiv of TMSN3. b Yield of
0
isolated product.
The use of TBAF under SFC was then extended to the
reactions of 2-aryl-1-carbethoxy-1-nitroethenes 1h-p
3
with TMSN (Table 3). These 1,3-dipolarophiles although
less reactive than benzylydenes 1a-g, reacted with
TMSN (4.0 equiv) in the presence of 0.1 equiv of TBAF,
under acceptable mild conditions (50-80 °C). Also in this
case the nature of the substituent and its position in the
aromatic ring little influenced the reactivity of the
substrate. In all cases, [3 + 2] cycloadditions were
complete in a reasonable time (4-12 h) and triazoles
a 4 equiv of TMSN and 0.1 equiv of TBAF. b Yield of isolated
3
3
product.
fully characterized, and the corresponding charts, except
for 2h whose spectroscopic data have already been
10i
reported, are included in Supporting Information.
2
h-p were isolated in good yields (70-85%).
In conclusion, TBAF is the first organic catalyst able
to efficiently catalyze the cycloaddtion reaction of an
electron-poor olefin with TMSN making this approach
3
to 1H-1,2,3-triazoles a valid and viable alternative to
classic Huisgen 1,3-dipolar cycloaddition of azides with
alkynes. Following an easy procedure that does not
require dried glassware and inert atmposphere, a wide
variety of 4-aryl-1H-1,2,3-triazoles 2 have been prepared
under mild and environmentally friendly conditions.
All the reactions were performed by mixing under
vigorous stirring the heterogeneous mixture of a benzy-
2
1
lydene 1 with TMSN2
3
(2.0 or 4.0 equiv) in the presence
2
of 0.1 equiv of TBAF, at the temperature and for the
time reported in Tables 2 and 3. The reaction of 1a was
also performed on a 100 mmol scale without encountering
any additional problems, and triazole 2a was isolated in
8
7% yield. Triazoles 2 have been isolated in pure form
after silica gel column chromatography of the crude
reaction mixtures. All the prepared triazoles have been
Experimental Section
(
21) Z)-R-Cyanonitroethenes 1a-g were prepared as the pure (Z)
19b
Representative Experimental Procedure. General ex-
perimental details can be found in the Supporting Information.
CAUTION: Azides can be very explosive compounds and should
stereoisomer by the reported procedure. In the case of R-carbethox-
ynitroethenes 1h-p by following the reported procedure, E/Z mixtures
22
were sometimes obtained and used.
(22) Lehnert, W. Tetrahedron 1972, 28, 663-666.
be handled with great care. During our study, we used TMSN
3
6528 J. Org. Chem., Vol. 70, No. 16, 2005

and we encountered no problems.23 In a screw-capped vial
equipped with a magnetic stirrer, TBAF‚3H O (0.064 g, 0.2
mmol), (E)-1-cyano-2-pheny-l-nitroethene (1a) (0. 348 g, 2.0
mmol), and TMSN (0.460 g, 4.0 mmol) were consecutively
added, and the resulting mixture was left under vigorous stirring
at 30 °C for 3 h. The crude reaction mixture was charged on a
silica gel column chromatography (petroleum ether/ethyl acetate
(m), 3104 (m); H NMR (400 MHz, CD
1
OD) δ: 7.40-7.70 (m,
2H, 7.90-7.96 (m, 2H); C NMR ((400 MHz, CD OD) δ: 114.0,
117.9, 127.0, 127.7, 130.3, 132.2, 148.4. Anal. Calcd for C H N :
3
1
3
2
3
9
6
4
3
C, 52.55; H, 5.14; N, 30.64. Found: C, 52.59; H, 5.32; N, 30.80.
Acknowledgment. The Ministero dell’Istruzione
dell’Universit a` e della Ricerca (MIUR) and the Univer-
sit a` degli studi di Perugia (within the funding projects:
COFIN, COFINLAB (CEMIN), and FIRB 2001) are
thanked for financial support.
8
/2 (gradient); silica/sample 15:1). Pure 4-phenyl-1H-1,2,3-
triazole-5-carbonitrile (2a) was isolated as a white solid in 85%
yield (0.289 g). The product was recrystallizated from ethyl
f
acetate: white crystals; mp ) 185-186 °C; R ) 0.20 (Etp/AcOEt/
-
1
AcOH/80/17/3); IR (KBr, cm ): 687 (s), 775 (s), 687 (s), 775 (s),
273 (s), 1497 (m), 2241 (m), 2809 (m), 2845 (m), 2906 (m), 3076
1
Supporting Information Available: Detailed experi-
mental procedures and spectral data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(23) For a discussion on the hazards associated with azides, see:
Prudent Practice for Handling Hazardous Chemicals in Laboratories;
National Academic Press: Washington, DC, 1983; pp 87-88. For
human toxicity, see: The Merck Index, 12th ed.; Merck & Co.: Rahway,
NJ, 1996; pp 4818 and 8726.
JO0507845
J. Org. Chem, Vol. 70, No. 16, 2005 6529