Four-component synthesis of indazole through Ugi-Azide coupling

Article abstract of DOI:10.1055/s-0031-1290075

ortho-Nitrobenzaldehyde and trimethylsilyl azide were used in a Ugi-Cadogan cascade towards tetrazolyl indazoles. After the Ugi step, the intermediate tetrazoles were not purified but directly heated with triethyl phosphite to form the final indazoles. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0031-1290075

LETTER
295
Four-Component Synthesis of Indazole through Ugi-Azide Coupling
F
our-Componen
a
t
Synthesi
u
s
of
I
ndazole
r
through
e
U
gi-Azide
nCoupling t El Kaïm,* Laurence Grimaud,* Srinivas Reddy Purumandla
Laboratoire Chimie et procédés, UMR 7652 Ecole Polytechnique-ENSTA-CNRS, Ecole Nationale Supérieure de Techniques Avancées,
32 Bd Victor, 75739 Paris Cedex 15, France
Fax +33(1)45528322; E-mail: laurent.elkaim@ensta.fr; E-mail: grimaud@dcso.polytechnique.fr
Received 8 November 2011
amines. Using ortho-nitrobenzaldehyde as carbonyl com-
Abstract: ortho-Nitrobenzaldehyde and trimethylsilyl azide were
ponent, we could expect the isolation of indazole deriva-
used in a Ugi–Cadogan cascade towards tetrazolyl indazoles. After
tives (Scheme 1).
the Ugi step, the intermediate tetrazoles were not purified but direct-
ly heated with triethyl phosphite to form the final indazoles.
To evaluate this strategy, the Ugi tetrazole 1a was pre-
Key words: Ugi, tetrazole, phosphite, cadogan, indazole
pared in a 78% isolated yield by stirring overnight a stoi-
chiometric mixture of butyl amine, cyclohexyl
isocyanide, ortho-nitrobenzaldehyde and trimethylsilyl
azide in methanol (3 M) at room temperature. The reduc-
tive coupling was then performed in dimethylformamide
with an excess of triethyl phosphite (5–6 equiv). Starting
from 1a, the best conversion was obtained at 140 °C for
10 hours (Scheme 2). Microwave conditions gave faster
indazole formation but with slightly lower yields (61% af-
ter 30 min at 165 °C).
Driven by the interest for multicomponent reactions
(MCRs), the Ugi reaction has seen its synthetic potential
rapidly expanding with the preparation of numerous li-
braries of heterocycles.1 We have been active in this field
using both carboxylic acids and acidic phenol derivatives
(Ugi–Smiles) in Ugi reactions.2 While working on a one-
pot Ugi–Smiles access to benzimidazole derivatives, we
became interested in the potential of nitrosoaryl interme-
diates in diversity-oriented synthesis.3 Easily generated
from nitroarenes under heating with trialkyl phosphites,
these nitroso intermediates may be trapped by various car-
bon- and nitrogen-centered nucleophiles.4 We envisioned
that a N–N bond formation as Ugi postcondensation trans-
formation could lead to unusual scaffolds. In order to test
such strategy, we selected the Ugi synthesis of tetrazoles
(Ugi/azide reaction)5 from primary amines, which repre-
sents a very efficient multicomponent access to secondary
Triethyl phosphite was selected as reducing agent in this
reaction. Indeed various conditions have been reported for
the conversion of nitrobenzylamines into indazoles deriv-
atives: reductive [SnCl2, Pd/C/ammonium formate,
P(OEt)3, Zn–AcOH, etc.]6 as well as basic (with interme-
diate indazole N-oxide formation) conditions.7 However,
due to easier purification steps, we preferred the proce-
dure involving phosphites.
Previous work
R1HNOC
R2
R1HNOC
R2
Ar
R1NC
R2CO
NH2
P(OEt)3
DMF
MeOH
N
N
OH
NO2
N
Ar
+
Ar
MW, 165 °C
NO2
This work
N
O
N
N
N
N
N
R2
R1
N
H
R1NH2
TMSN3
N
R2
MeOH
P(OEt)3
+
NO2
N
R1
H
Δ
N
R2NC
N
NO2
R1
N
N
O
Scheme 1 Ugi access to indazole derivatives
SYNLETT 2012, 23, 295–297
x
x.
x
x.
2
0
1
2
Advanced online publication: 03.01.2012
DOI: 10.1055/s-0031-1290075; Art ID: D63911ST
© Georg Thieme Verlag Stuttgart · New York

296
L. El Kaïm et al.
LETTER
N
O
N
N
N
N
N
N
Cy
N
P(OEt)3
H
n-PrNH2
TMSN3
(5 equiv)
MeOH
Cy
n-Pr
+
NO2
CyNC
N
DMF (2 M)
140 °C, 10 h
70%
r.t., 12 h
78%
H
N
n-Pr
N
2a
NO2
1a
Scheme 2 Two-step formation of indazoles
We next examined the one-pot version of this sequence. tial molecular diversity are of high interest.10 In this case,
After the Ugi reaction, the residual methanol was evapo- tetrazolyl indazole have been obtained by a one-pot pro-
rated before introducing DMF and the phosphite required cedure involving two N–N bond formations as key steps.
for the next step. Under these conditions, compound 2a
could be isolated in 62% yield over two steps. Various
isocyanides and amines behave similarly, as shown by the
Acknowledgment
S.R.P. thanks the ANR-CP2D Program (ANR MUSE) for a post-
doctoral fellowship.
results gathered in Table 1.
Table 1 One-Pot Tetrazolyl Indazole Formation
O
References and Notes
N
N
N
N
R1NH2
TMSN3
1) MeOH (3 M)
r.t., 12 h
H
(1) For reviews concerning Ugi couplings, see: (a) Zhu, J. Eur.
J. Org. Chem. 2003, 1133. (b) Ugi, I.; Werner, B.; Dömling,
A. Molecules 2003, 8, 53. (c) Hulme, C.; Gore, V. Curr.
Med. Chem. 2003, 10, 51. (d) Bienaymé, H.; Hulme, C.;
Oddon, G.; Schmitt, P. Chem. Eur. J. 2000, 6, 3321.
(e) Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39,
3168. (f) Dömling, A. Chem. Rev. 2006, 106, 17.
(g) El Kaïm, L.; Grimaud, L. Tetrahedron 2009, 65, 2153.
(2) For a selection of studies involving Ugi–Smiles couplings,
see: (a) El Kaïm, L.; Grimaud, L.; Oble, J. Angew. Chem.
Int. Ed. 2005, 44, 7961. (b) El Kaïm, L.; Gizolme, M.;
Grimaud, L.; Oble, J. J. Org. Chem. 2007, 72, 4169.
(c) El Kaïm, L.; Grimaud, L.; Gizzi, M. Org. Lett. 2008, 10,
3417. (d) Coffinier, D.; El Kaïm, L.; Grimaud, L. Org. Lett.
2009, 11, 995. (e) El Kaïm, L.; Grimaud, L.; Wagschal, S.
J. Org. Chem. 2010, 75, 5343. (f) El Kaïm, L.; Grimaud, L.;
Wagschal, S. Chem. Commun. 2011, 47, 1887.
R2
+
NO2
2) P(OEt)3 (5 equiv)
DMF (2 M)
140 °C, 10 h
N
R1
R2NC
N
2
Entry R1
R2
Product (yield)
2a (62%)
2b (62%)
2c (60%)
2d (24%)
2e (54%)
2f (65%)
1
2
n-Pr
t-Bu
t-Bu
Cy
4-MeOC6H4CH2
Cy
3
4
3,4-Me2C6H3
t-Bu
4-MeOC6H4CH2
t-Bu
5
6
Cy
4-MeOC6H4CH2
t-Bu
(3) El Kaim, L.; Grimaud, L.; Purumandla, S. R. Eur. J. Org.
Chem. 2011, 6177.
7
Cy
2g (48%)
2h (59%)
2i (46%))
(4) For reviews on the reaction of phosphites with nitroarenes,
see: (a) Cadogan, J. I. G. Acc. Chem. Res. 1972, 5, 303.
(b) Söderberg, B. C. G. Curr. Org. Chem. 2000, 4, 727.
For a selection involving N–N bond formation, see:
(c) Cadogan, J. I. G.; Cameron-Wood, M.; Mackie, R. K.;
Searle, R. J. G. J. Chem. Soc. 1965, 4831. (d) Nyffenegger,
C.; Pasquinet, E.; Suzenet, F.; Poullain, D.; Jarry, C.; Leger,
J.-M.; Guillaumet, G. Tetrahedron 2008, 64, 9567.
(5) (a) Ugi, I. Angew. Chem. 1960, 72, 639. (b) Ugi, I.;
Steinbrückner, C. Chem. Ber. 1961, 94, 734. (c) See also
reviews in ref. 1.
8
i-Pent
Cy
9
t-Oct
4-ClC6H4CH2
10
11
12
Cy
4,3-(MeO)2C6H3(CH2)2 2j (44%)
MeO(CH2)2
4-ClC6H4CH2
Cy
2k (57%)
2l (49%)
4-MeOC6H4CH2
(6) (a) Paal, C.; Fritzweiler, E. Ber. 1892, 25, 3590. (b) Kumar,
R.; Maulik, P. R.; Kundu, B. Org. Lett. 2006, 8, 1525.
(c) Frontana-Uribe, B. A.; Moinet, C. Acta Chem. Scand.
1999, 53, 814. (d) Reddy, V. R. K.; Reddy, S. N.; Ratnam,
C. V. Synth. Commun. 1991, 21, 49. (e) Stanley, A. L.;
Stanford, S. P. J. Heteroatom. Chem. 1994, 31, 1399.
(7) (a) Johnston, D.; Smith, D. M.; Shepherd, T.; Thompson, D.
J. Chem. Soc., Perkin Trans. 1 1987, 495. (b) Avila, B.;
Solano, D. M.; Haddadin, M. J.; Kurth, M. J. Org Lett. 2011,
13, 1060.
(8) General Procedure for the Synthesis of Indazoles: To a 3
M solution of o-nitrobenzaldehyde (1 mmol) in MeOH were
added successively amine (1.0 equiv), isocyanide (1.0 equiv)
and trimethylsilyl azide (1.0 equiv). The resulting mixture
was stirred at r.t. overnight. After removal of the excess
The sequence turned out to be efficient even for sterically
hindered amines, as a tert-octyl group only led to a slight
decrease in yields (entry 9). Compared to aliphatic
amines, anilines gave sluggish indazole formation (entry
4). In this case, the lower nucleophilicity of the nitrogen
atom of the aniline is probably responsible for a less effi-
cient N–N bond formation and further reduction of the ni-
troso to nitrene intermediates.4
In conclusion, we have extended the scope of Ugi-azide
couplings with the disclosure of a new postcondensation
towards indazoles.8 These heterocycles represent privi-
leged medicinal scaffolds9 and new syntheses with poten-
Synlett 2012, 23, 295–297
© Thieme Stuttgart · New York

LETTER
Four-Component Synthesis of Indazole through Ugi-Azide Coupling
297
MeOH, the crude tetrazole product was used as such for the
(9) For a selection of recent reports on bioactive indazoles, see:
(a) Clutterbuck, L. A.; Posada, C. G.; Visintin, C.; Riddall,
D. R.; Lancaster, B.; Gane, P. J.; Garthwaite, J.; Selwood, D.
L. J. Med. Chem. 2009, 52, 2694. (b) Jones, P.; Altamura,
S.; Boueres, J.; Ferrigno, F.; Fonsi, M.; Giomini, C.;
Lamartina, S.; Monteagudo, E.; Ontoria, J. M.; Orsale, M.
V.; Palumbi, M. C.; Pesci, S.; Roscilli, G.; Scarpelli, R.;
Schultz-Fademrecht, C.; Toniatti, C.; Rowley, M. J. Med.
Chem. 2009, 52, 7170. (c) Qian, S.; Cao, J.; Yan, Y.; Sun,
M.; Zhu, H.; Hu, Y.; He, Q.; Yang, B. Mol. Cell. Biochem.
2010, 345, 13. (d)Akritopoulou-Zanze, I.; Wakefield, B. D.;
Gasiecki, A.; Kalvin, D.; Johnson, E. F.; Kovar, P.; Djuric,
S. W. Bioorg. Med. Chem. Lett. 2011, 21, 1480.
next step. A 2 M solution of tetrazole (1 mmol) and triethyl
phosphite (5.0 equiv) in DMF was heated at 140 °C for 10 h.
After completion of the reaction, the solvent was evaporated
under reduced pressure and the crude product was purified
by flash chromatography on silica gel.
3-(1-Cyclohexyl-1H-tetrazol-5-yl)-2-propyl-2H-indazole
(2a): Prepared on a 1-mmol scale according to the general
procedure, 2a was isolated as a yellow solid in 62% yield;
mp 110–111 °C; Rf 0.3 (petroleum ether–Et2O, 20:80). 1H
NMR (400 MHz, CDCl3): d = 7.85 (d, J = 8.6 Hz, 1 H), 7.39
(t, J = 7.8 Hz, 1 H), 7.34 (d, J = 8.6 Hz, 1 H), 7.23 (t, J = 7.8
Hz, 1 H), 4.48 (t, J = 7.3 Hz, 2 H), 4.19–4.29 (m, 1 H), 2.05–
2.18 (m, 2 H), 1.82–2.03 (m, 6 H), 1.63–1.72 (m, 1 H), 1.15–
1.33 (m, 3 H), 0.88 (t, J = 7.3 Hz, 3 H). 13C NMR (100.6
MHz, CDCl3): d = 148.1, 145.5, 126.5, 124.4, 122.1, 118.7,
117.5, 117.4, 58.7, 53.7, 33.4, 25.1, 24.5, 24.1, 11.0. IR (thin
film): 2937, 2857, 1574, 1500, 1454, 1411, 1354, 1095, 1005
cm–1. HRMS: m/z calcd for C17H22N6: 310.1906; found:
310.1901.
(10) (a) Schmidt, A.; Beutler, A.; Snovydovych, B. Eur. J. Org.
Chem. 2008, 4063. (b) Kumar, M. R.; Park, A.; Park, N.;
Lee, S. Org. Lett. 2011, 13, 3542. (c) Barluenga, J.; Aznar,
F.; Palomero, M. A. Chem. Eur. J. 2001, 7, 5318. (d) See
ref. 8d.
© Thieme Stuttgart · New York
Synlett 2012, 23, 295–297

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