Three-component Nef-Huisgen access to 1,2,4-triazoles

Article abstract of DOI:10.1055/s-0028-1216738

We present herein a new three-component triazole synthesis involving a Nef-Huisgen cascade. After the α-addition of acyl chlorides onto isocyanides (Nef reaction), the resulting imidoyl chloride is treated with tetrazoles under suitable activation (ZnCl

Full text of DOI:10.1055/s-0028-1216738

LETTER
1315
Three-Component Nef–Huisgen Access to 1,2,4-Triazoles
T
hree-Compone
a
nt
N
ef/H
u
u
isgenAccess
r
to 1,2,4
e
-Triazoles nt El Kaim,* Laurence Grimaud,* Simon Wagschal
Laboratoire Chimie et Procédés, Ecole Nationale Supérieure de Techniques Avancées, 32 Boulevard Victor, 75739 Paris Cedex 15, France
Fax +33(1)45525587; E-mail: laurent.elkaim@ensta.fr; E-mail: laurence.grimaud@ensta.fr
Received 13 February 2009
equivalent of triethylamine. Under heating, the expected
Abstract: We present herein a new three-component triazole syn-
triazole 4a was obtained in moderate yield together with
oxadiazole 5a (Scheme 2). The formation of the side
product 5a may be explained by the reversibility of the
thesis involving a Nef–Huisgen cascade. After the a-addition of
acyl chlorides onto isocyanides (Nef reaction), the resulting imidoyl
chloride is treated with tetrazoles under suitable activation (ZnCl2).
The resulting adduct is unstable and evolves according to the Huis- Nef adduct, giving back the starting isocyanide and acyl
gen reaction.
chloride. The trapping of the latter with tetrazole, fol-
lowed by a Huisgen reaction of the resulting acyl tetrazole
finally affords oxadiazole 5a. This hypothesis is support-
ed by previous observations by Nef and Ugi.2,3a Indeed, at-
tempted acylamidine preparation by reaction of amines
with Nef adducts traditionally failed with the sole forma-
tion of simple amides due to the reversibility of the acyl
imidoyl formation in the presence of nucleophilic bases.
Substitution of triethylamine by Hünig’s base did not im-
prove the situation, the tetrazolyl anion being probably
able to attack both acyl and imidoyl chloride groups of the
Nef adduct.
Key words: Nef, isocyanide, tetrazoles, Huisgen, triazoles
In the field of multicomponent reactions, most efforts
have focused on the use of isocyanides (IMCRs) in rela-
tion with the high efficiency of Passerini and Ugi reac-
tions along with their further post-condensations.1 As a
consequence, a number of isocyanide reactions have seen
their potential largely unexplored. It is probably the case
with the Nef reaction, the a-addition of acyl chlorides
onto isocyanides forming imidoyl chlorides.2 In the light
of its early disclosure at the end of the 19th century, it is
impressive that so few studies have been devoted to this
reaction.3 The most important synthetic achievements
have been probably obtained by intramolecular trappings
of the Nef adducts with various nucleophiles.3a,f The
scope of the Nef reaction could certainly be further ex-
tended by adding external trapping agents prone to induce
new cascades and settle novel three-component processes
(Scheme 1).
Ar
O
Ar
1) MW, neat
60 °C
N
N
N
N
CyNC + ArCOCl
+
N
Cy
4a
O
2) C7H6N4, Et3N
toluene, 80 °C
5a
Ph
Ph
39%
35%
Nef reaction
neat, 60 °C
Ar = 4-FC6H4
Huisgen
rearrangement
H
N
Ph
Cy
Cl
Cy
O
N
Cy
N
N
N
R1
Cl
Ph
R1
N N
Ar
N
N
Ar
Ar
+
N
N
O
Nef reaction
N
N
Nu
R2
+
R2
R1NC
N
Et3N, toluene
Ph
O
Nu
O
N
N
R2
Cl
toluene
r.t. to Δ
N
O
O
Scheme 2 Nef–Huisgen sequence
Scheme 1 Trapping of Nef adducts
To address these issues, we tested the reaction of the tet-
razole without any added basic reagent. However, under
these conditions, the desired adduct 4a was only obtained
in 20% isolated yields due to the poor nucleophilic behav-
ior of neutral tetrazole. Finally, increasing the electrophi-
licity of the Nef adduct under Lewis acid activation
appeared to be the best approach. The use of silver triflate
to activate Nef imidoyl chlorides in various intramolecu-
lar Friedel–Craft reactions has already been reported by
Livinghouse et al.3f With less expensive zinc chloride
used in stoichiometric amount, we were first able to raise
the yield to 62%. This could be further improved to 79%
under catalytic activation with 10% ZnCl2. Under these
optimized conditions various isocyanides 1, acyl chlo-
rides 2 and tetrazoles 3 were converted to triazoles 4 in
moderate to good yields (Table 1).5
Searching for nucleophiles that might be involved in fur-
ther rearrangements, we assumed that additions of tetra-
zoles onto the Nef adducts might lead, via a Huisgen
reaction,4 to original three-component triazole scaffolds
from isocyanides (Scheme 2). The first attempts with cy-
clohexyl isocyanide and 4-fluorobenzoyl chloride were
encouraging. However, from the very outset of this study,
the reversibility of the Nef reaction turned out to be a se-
rious problem to handle. Indeed, after completion of the
Nef reaction (as shown by NMR analysis of an aliquot),
phenyl tetrazole was added to the medium along with one
SYNLETT 2009, No. 8, pp 1315–1317
x
x.
x
x.
2
0
0
9
Advanced online publication: 07.05.2009
DOI: 10.1055/s-0028-1216738; Art ID: D05409ST
© Georg Thieme Verlag Stuttgart · New York

1316
L. El Kaim et al.
LETTER
Table 1 Preparation of Triazoles 4
N
N
O
R1
N
O
N
R3
O
N
R2
CI
CI
neat
H
R2
R3
R2
+
toluene (0.5 M)
ZnCI2 (10 mol%)
80 °C
60 °C
R1NC
N
R1
N
N
Entry
R1
R2
R3
Product (yield)
1
2
3
4
5
6
7
Cy
Cy
Cy
Cy
Cy
Cy
Cy
4-FC6H4
4-FC6H4
4-FC6H4
Ph(CH2)2
3-MeC6H4
i-Pr
Ph
4a (79%)
4b (61%)
4c (63%)
4d (42%)
4e (58%)
4f (39%)
4g (36%)
4-F3CC6H4
4-MeOC6H4
Ph
Ph
4-MeOC6H4
Ph
4-MeOC6H4
8
9
Cy
4-FC6H4
4h (53%)
4i (27%)
4j (23%)
MeO
i-Pr
4-F3CC6H4
MeO
MeO
10
4-FC6H4
Ph
MeO
11
12
Cy
4-FC6H4
4-FC6H4
Me
Ph
–
–
t-Bu
The optimized sequence involves a microwave induced agents.6,7 We are currently exploring the potential of these
Nef solvent-free reaction as reported by Chen et al.3g In tetrazoles in various four-component formations of tria-
our case, the temperature was kept at 60 °C for one hour zoles.
(except for aliphatic acid chlorides which only required
heating for 5 to 10 min (Table 1, entries 4, 6 and 9). The
following Huisgen step was performed in 0.5 M toluene
Acknowledgment
Financial support was provided by the French Ministry of Defense
and ENSTA.
and ZnCl2 was introduced as a molar solution in THF.
Conversion to the final triazole was achieved by heating
overnight at 80 °C. Best yields were obtained for aromatic
acyl chlorides and tetrazoles. Aliphatic tetrazoles failed to
give the Huisgen rearrangement under these conditions,
higher temperatures merely brought decomposition of the
Nef adducts (Table 1, entry 11). The Nef reaction with
tert-butyl isocyanide also failed to give any acylimidoyl
with p-fluorobenzoyl chloride under these conditions
(Table 1, entry 12). The catalytic activity of the metal in
these triazole formations may be explained by a higher af-
finity of zinc chloride towards the acylimidoyl chloride
acting as an O,Cl-bidentate ligand.
References and Notes
(1) For general reviews on Ugi- and Passerini-based
multicomponent reactions, see: (a) Banfi, L.; Riva, R. Org.
React. (N.Y.) 2005, 65, 1. (b) Zhu, J. Eur. J. Org. Chem.
2003, 1133. (c) Ugi, I.; Werner, B.; Dömling, A. Molecules
2003, 8, 53. (d) Hulme, C.; Gore, V. Curr. Med. Chem.
2003, 10, 51. (e) Bienaymé, H.; Hulme, C.; Oddon, G.;
Schmitt, P. Chem. Eur. J. 2000, 6, 3321. (f) Dömling, A.;
Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3168. (g) Dömling,
A. Chem. Rev. 2006, 106, 17.
(2) Nef, J. U. Justus Liebigs Ann. Chem. 1892, 270, 267.
(3) (a) Ugi, I.; Fetzer, U. Chem. Ber. 1961, 94, 1116.
(b) Adlington, R. M.; Barrett, A. G. M. Tetrahedron 1981,
37, 3935. (c) Westling, M.; Smith, R.; Livinghouse, T.
J. Org. Chem. 1986, 51, 1159. (d) Van Wangenen, B. C.;
Cardellina, J. H. Tetrahedron Lett. 1989, 30, 3605.
(e) El Kaim, L.; Pinot-Périgord, E. Tetrahedron 1998, 54,
3799. (f) Livinghouse, T. Tetrahedron 1999, 55, 9947; and
In conclusion, we have disclosed a new isocyanide-based
three-component formation of triazoles. To the best of our
knowledge, this is the first use of the Huisgen reaction in
conjunction with isocyanide chemistry. This strategy
could find some further developments in Ugi-type reac-
tions with acidic tetrazoles acting as nitrilium trapping
Synlett 2009, No. 8, 1315–1317 © Thieme Stuttgart · New York

LETTER
references cited therein. (g) Chen, J. J.; Deshpande, S. V.
Three-Component Nef/Huisgen Access to 1,2,4-Triazoles
1317
afforded 4a as a yellow oil (280 mg, 79%).
Tetrahedron Lett. 2003, 44, 8873. (h) El Kaim, L.; Gaultier,
L.; Grimaud, L.; Vieu, E. Tetrahedron Lett. 2004, 45, 8047.
(4) (a) Huisgen, R.; Sauer, J.; Sturm, H. J. Angew. Chem. 1958,
70, 272. (b) Huisgen, R.; Sauer, J.; Seidel, M. Chem. Ber.
1960, 93, 2885. (c) Huisgen, R.; Sturm, H. J.; Seidel, M.
Chem. Ber. 1961, 94, 1555. (d) Huisgen, R. Angew. Chem.
Int. Ed. Engl. 1980, 19, 947. (e) Boyd, G. V.; Cobb, J.;
Lindley, P. F.; Mitchell, J. C.; Nicolaou, G. A. J. Chem. Soc.,
Chem. Commun. 1987, 99.
(5) Typical Procedure for 4a: Cyclohexyl isocyanide (1 mmol)
and p-fluorobenzoyl chloride (1 mmol) were heated neat for
1 h in a CEM microwave at 60 °C (50 W) and finally
dissolved in toluene (2 mL). To this solution was added
ZnCl2 in THF (0.1 mL of a 1 M solution) followed by the
addition of phenyl tetrazole (1 mmol, 1 equiv). The reaction
mixture was then heated overnight at 80 °C. Hydrolysis
followed by extraction and flash column chromatography
Spectroscopic Data for Triazole 4a: 1H NMR (400 MHz,
CDCl3): δ = 8.35 (dd, J H–H = 8.3, J H–F = 5.6 Hz, 2H), 7.65–
7.35 (m, 5H), 7.21 (t, J H–H = J H–F = 8.3 Hz, 2H), 4.33 (tt,
J = 12.3, 3.7 Hz, 1H), 2.15 (q, J = 11.8 Hz, 2H), 1.92 (d,
J = 11.8 Hz, 2H), 1.83 (d, J = 11.8 Hz, 2H), 1.65 (d, J = 10.6
Hz, 1H), 1.34–1.15 (m, 3H). 13C NMR (100.6 MHz, CDCl3):
δ = 183.6, 166.8 (d, JC–F = 256.1 Hz), 157.5, 151.9, 134.4 (d,
JC–F = 9.5 Hz), 133.5 (d, JC–F = 2.2 Hz), 131.1, 130.1, 129.3,
128.0, 116.1 (d, J C–F = 22.0 Hz), 59.2, 32.6, 26.3, 25.1.
IR (thin film): 2933, 2857, 2360, 1663, 1597, 1506, 1440,
1307, 1235, 1157 cm–1. HRMS: m/z calcd for C21H20FN3O:
349.1590; found: 349.1601.
(6) El Kaim, L.; Grimaud, L. Tetrahedron 2009, 65 in press.
(7) For a use of benzotriazole in Ugi-type couplings, see:
Katritzky, A. R.; Mohapatra, P. P.; Singh, S.; Clemens, N.;
Kirichenko, K. J. Serb. Chem. Soc. 2005, 70, 319.
Synlett 2009, No. 8, 1315–1317 © Thieme Stuttgart · New York

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