A new and versatile Ugi/SNAr synthesis of fused 4,5-dihydrotetrazolo[1,5-a]quinoxalines

Article abstract of DOI:10.1016/j.tetlet.2006.01.027

A combinatorial synthetic route yielding fused tetrazolo[1,5-a]quinoxalines is described. The use of 2-fluorophenylisocyanide in the Ugi-tetrazole reaction (tetrazole-U-4CR) followed by a nucleophilic aromatic substitution (S _NAr) affords the t

Full text of DOI:10.1016/j.tetlet.2006.01.027

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 2041–2044
A new and versatile Ugi/SNAr synthesis of fused
4,5-dihydrotetrazolo[1,5-a]quinoxalines
a,b,
a
a
a
*
´
Cedric Kalinski,
Michael Umkehrer, Sebastien Gonnard, Nadine Ja¨ger,
Gunther Rossa and Wolfgang Hillerb
¨
aPriaton GmbH, Bahnhofstr. 9-15, D-82327 Tutzing, Germany
bTechnical University Munich, Lichtenbergstr. 4, D-85747 Garching, Germany
Received 29 November 2005; revised 20 December 2005; accepted 9 January 2006
Abstract—A combinatorial synthetic route yielding fused tetrazolo[1,5-a]quinoxalines is described. The use of 2-fluorophenyliso-
cyanide in the Ugi-tetrazole reaction (tetrazole-U-4CR) followed by a nucleophilic aromatic substitution (SNAr) affords the tri-
cylic tetrazolo[1,5-a]quinoxaline moiety in good yields and with high diversity.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Synthetic sequences that enable the parallel automated
synthesis of polysubstituted heterocycles have attracted
considerable attention in recent years.1,2 Robust synthe-
sis of ‘drug-like’ compounds permits the fast prepara-
tion of compound libraries suitable for lead discovery
and optimization.3,4 Therefore, the easily automated
multi-component reactions (MCRs) are powerful tools
for this high-throughput screening strategy.5,6
4CR) between amine, aldehyde, carboxylic acid and iso-
cyanide affords peptidic structures in high diversity. In
the last years, many research groups extended the poten-
tial of the U-4CR by using bi-functional starting mate-
rials.8–11 Hulme and co-workers combined the U-4CR
with different post-condensation reactions to produce a
large range of biologically relevant heterocycles.12–15
For example, the combination of the Ugi-reaction with
a post-condensation(SNAr) generates indazolinones,
benzazepines and benzoxazepines16,17 or product-like
biaryl ether containing macrocycles.18–20
One of the most reported multi-component reactions is
the Ugi-reaction.7 The four-component reaction (U-
NC
R2
R3
H+
R1
O
R1
R2
R3
N
N+
R1
R2
R3
F
R1 NH2
1
+
H
N+
F
N
H2O
R2
R3
H
3
2
R2
R2 R3
R3
N
R2
R1
N
R3
N
N+
N
N
R1
N
H
R1
N
N
H
N
N 3
SNAr
N
N
N
N
F
N
5
F
4
Scheme 1. Two-step combinatorial synthesis of 4,5-dihydrotetrazolo[1,5-a]quinoxalines.
Keywords: Ugi-reaction; Multi-component reaction; Tetrazole; Fused tetrazoloquinoxaline; Nucleophilic aromatic substitution.
*
Corresponding author. Tel.: +49 81 58 90 40 18; e-mail: kalinski@priaton.de
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.027

2042
C. Kalinski et al. / Tetrahedron Letters 47 (2006) 2041–2044
H
O
NC
F
NH2
F
1. POCl3 / NEt3
2. Na2CO3
NH
F
3
Scheme 2. Synthesis of the 2-fluorophenylisocyanide.
Table 1. SNAr optimization
Following this strategy, we report a new and versatile
two-step solution-phase synthesis of fused tetra-
zolo[1,5-a]quinoxalines. The first step of this synthesis
consists in a classical Ugi-tetrazole reaction21,22 yielding
bis-substituted tetrazoles (Scheme 1). We involved 2-flu-
orophenylisocyanide 3 as a new bifunctional starting
material in this multi-component synthesis to enable a
subsequent nucleophilic aromatic substitution (SNAr).
Ex
Base
Equivalent
Solvent
T (ꢁC)
Y (%)
1
2
3
NaHCO3
Cs2CO3
Cs2CO3
1.3
1.3
1.3
MeOH
DMF
DMF
80
25
100
1
2
96
In summary, a novel two-step solution phase procedure
for the preparation of highly substituted 4,5-dihydrotet-
razolo[1,5-a]quinoxalines has been described. Amines
and carbonyles can be varied broadly, yielding tricyclic
tetrazoles with three potential diversity points. There-
fore, an access to thousands of diverse analogues with
the aforementioned core structure is now feasible. At
least, the use of some bifunctional starting materials
could enable further extension of the tetrazolo[1,5-a]quin-
oxaline moiety.
2-Fluorophenylisocyanide 3 is obtained in two steps by
formylation of the commercially available amine fol-
lowed by dehydration using phosphoroxychloride23
(Scheme 2).
The Ugi-tetrazole synthesis is a variation of the classical
Ugi-reaction where azidotrimethylsilane (TMSN3) is
employed as acid component. This reaction is initiated
by condensation of an aldehyde or ketone 2 with an
amine 1. Subsequent reaction with isocyanide produces
the intermediate nitrilium ion, as a key intermediate.
The desired tetrazole is obtained by reaction with the
azide, followed by sigmatropic rearrangement. Experi-
mentally, we used to mix the four components amine/
aldehyde/TMSN3/3 in a ratio 1/1/1.5/1.5 to obtain the
best yields.24 Under these conditions, a two-step one-
pot synthesis could not be envisaged because an excess
of compound 3 would be a source of secondary reac-
tions during the subsequent nucleophilic aromatic sub-
stitution. Therefore, the resulting tetrazoles were
purified by crystallization or chromatographic methods
before they were involved in the second step of the U-
4CR/SNAr synthetic strategy. The synthesized tetrazoles
4a–i are shown in Table 2. They were obtained in good
yields (Y1) and with general high purity (>95%).
Current efforts are now focusing on the use of this reac-
tion for the development of new pharmacological
scaffolds.
References and notes
1. Hermkens, P. H. H.; Ottenheijm, H. C. J.; Rees, D. C.
Tetrahedron 1997, 53, 5643.
2. Gordon, E. M.; Gallop, M. A.; Patel, D. V. Acc. Chem.
Res. 1996, 29, 144.
3. Gallop, M. A.; Barrett, R. W.; Dower, W. J.; Fodor, S. P.
A.; Gordon, E. M. J. Med. Chem. 1994, 37, 1233.
4. Gordon, E. M.; Barrett, R. W.; Dower, W. J.; Fodor, S. P.
A.; Gallop, M. A. J. Med. Chem. 1994, 37, 1385.
5. Do¨mling, A. Combinat. Chem. High Throughput Screen.
1998, 1, 1.
6. Do¨mling, A. Chem. Rev. 2006, 106, 17.
Afterwards, the tetrazoles have to be treated with a base
to afford the desired post-condensation (SNAr). Differ-
ent experiments have been realized with tetrazole 4a in
different solvents and bases to optimize the reaction con-
ditions (Table 1). Conversions (Y) were evaluated by
HPLC-MS after 3 h of reaction time. Results prove that
cesium carbonate in combination with a reaction tem-
perature of 100 ꢁC seems to be the ideal base.
7. Ugi, I.; Meyer, R.; Fetzer, U.; Steinbruckner, C. Angew.
¨
Chem. 1959, 71, 386.
8. Wright, D. L.; Robotham, C. V.; Aboud, K. Tetrahedron
Lett. 2002, 43, 943.
9. Xiang, Z.; Luo, T.; Cui, J.; Shi, X.; Fathi, R.; Chen, J.;
Yang, Z. Org. Lett. 2004, 18, 3155.
10. Pirrung, M. C.; Das Sarma, K. J. Am. Chem. Soc. 2004,
126, 444.
11. Gedey, S.; Van der Eycken, J.; Fulop, F. Org. Lett. 2002,
11, 1967.
12. Hulme, C.; Ma, L.; Romano, J.; Morrissette, M. Tetra-
hedron Lett. 1999, 40, 7925.
13. Hulme, C.; Ma, L.; Cherrier, M. P.; Romano, J.; Morton,
G.; Duquenne, C.; Salvino, J.; Labaudiniere, R. Tetrahe-
dron Lett. 2000, 41, 1883.
Thus, all SNAr-reactions were performed under these
conditions.25 Results and synthesized fused 4,5-dihydro-
tetrazolo[1,5-a]quinoxalines 5a–i are reported in Table 2
with specific yields (Y2).
14. Tempest, P.; Ma, V.; Thomas, S.; Hua, Z.; Kelly, M. G.;
Hulme, C. Tetrahedron Lett. 2001, 42, 4959.
15. Nixey, T.; Kelly, M.; Semin, D.; Hulme, C. Tetrahedron
Lett. 2002, 43, 3681.
16. Tempest, P.; Ma, V.; Kelly, M. G.; Jones, W.; Hulme, C.
Tetrahedron Lett. 2001, 42, 4963.
The reaction times (rt) for the SNAr are generally short,
and the conversion is excellent for all compounds. Chro-
matography methods allow the obtention of products
with high purity (>95%). The reaction is very convenient
and does not affect the versatility of the starting materials.

C. Kalinski et al. / Tetrahedron Letters 47 (2006) 2041–2044
Table 2. Synthesized fused 4,5-dihydrotetrazolo[1,5-a]quinoxalines
2043
R2
R3
N
R3
R2
N
R1
N
N
N
N
H
O
N
R1
TMSN3 / 3
DMF
N
R1 NH2
F
N
N
+
R2
R3
Cs2CO3
MeOH
4
5
2
1
Entry
R1
R2
R3
Y1 (%)
Product
4a26
Reaction time (h)
3a
Y2 (%)
Product
5a27
1
H
H
62
96
*
*
*
2
C2H5
17
4b
3a
95
5b
MeO
3
4
H
H
29
61
4c
4d
3a
95
92
5c
5d
O2N
*
*
*
3a
*
MeOOC
O
O
*
5
6
H
H
58
46
4e
4f
3a
95
94
5e
5f
*
Boc
15b
*
*
N
H
*
*
*
7
8
H
65
52
4h
4g
10c
48b
74
57
5g
CH3
CH3
5h28
*
*
*
9
44
4i
10c
96
5i29
a 1.3 equiv Cs2CO3.
b 2.3 equiv Cs2CO3.
c 1.8 equiv Cs2CO3.
17. Tempest, P.; Pettus, L.; Gore, V.; Hulme, C. Tetrahedron
Lett. 2003, 44, 1947.
18. Cristau, P.; Vors, J. P.; Zhu, J. Org. Lett. 2001, 25,
was added dropwise. The precipitate was removed by
filtration, and the organic layer was washed two times with
30 mL brine, dried over potassium carbonate and evapo-
rated under vacuum. Distillation by 11 mbar (bp = 47 ꢁC)
afforded 2.52 g (20 mmol) of compound 3 as a green oil.
1H NMR (CDCl3, 250.13 Hz): 7.16–7.21 (m, 2H, aryl),
7.37–7.43 (m, 2H, ar-H). 13C NMR (CDCl3, 62.89 MHz):
4079.
19. Cristau, P.; Vors, J. P.; Zhu, J. Tetrahedron Lett. 2003, 44,
5575.
20. Cristau, P.; Vors, J. P.; Zhu, J. Tetrahedron 2003, 59,
2
4
7859.
116.66 (d, J(C–F) = 18.38 MHz, C3), 124.68 (d, J(C–F)
=
=
3
21. Ugi, I.; Steinbruckner, C. Chem. Ber. 1961, 94, 734.
3.68 Hz, C5), 128.01 (s, C6), 130.95 (d, J(C–F)
¨
22. Ugi, I. Angew. Chem., Int. Ed. Engl. 1962, 1, 8.
7.36 Hz, C4), 155.42 (s, C1), 159.51 (s, C2), 170.19 (NC).
24. General procedure (GP1) for the synthesis of tetrazoles
4a–i: amine 1 (3 mmol) and carbonyle 2 (3 mmol) were
stirred in 3 mL MeOH for 2 h. Then, azidotrimethylsilane
TMSN3 (3.8 mmol) and isocyanide 3 (3.8 mmol) was
added and the reaction mixture was stirred for 48 h. After
evaporation of the solvent, 15 mL methylene chloride was
added and the organic layer was washed with 2 · 10 mL
23. 2-Fluorophenylisocyanide 3: 5.55 g (50 mmol) of 2 was
dissolved in 50 mL methylene chloride. Triethylamine
(12.14 g) was added and the mixture was cooled to 0 ꢁC.
Phosphoroxychloride (7.66 g/50 mmol) was added drop-
wise to the reaction mixture between 0 ꢁC and 5 ꢁC. The
mixture was then stirred for 1 h by room temperature.
Then, 10 g (94 mmol) sodium carbonate in 40 mL water

2044
C. Kalinski et al. / Tetrahedron Letters 47 (2006) 2041–2044
brine, dried over MgSO4 and the solvent was removed.
2 · 25 mL of ethyl acetate. The organic layer was dried
over MgSO4 and the resulting crude product was purified
on silica gel with eluent ethyl acetate/hexane 1/2 to afford
5h as a colourless oil (135 mg/57%). 1H NMR (CDCl3,
250.13 MHz): 0.60–0.67 (m, 2H, CH2), 1.01–1.09 (m, 2H,
CH2), 1.73 (s, 6H, C–(CH3)2), 2.36–2.42 (m, 1H, CH),
7.02–7.09 (m, 1H, ar-H), 7.34–7.40 (m, 2H, ar-H), 7.89–
7.92 (dd, 1H, 3J = 6.95 Hz, 4J = 1.42 Hz, ar-H). 13C
NMR (CDCl3, 62.89 MHz): 10.10 (CH2), 22.96 (C–
(CH3)2), 25.00 (CH), 57.51 (C–(CH3)2), 116.85, 117.75,
120.36, 122.05, 129.02, 137.08 (ar), 154.72 (R2C@NR).
m/z (%) = 242 (100) [MH+].
The obtained 1,5-disubstituted tetrazole 4 was purified by
chromatographic methods or crystallization.
25. General procedure (GP2) for the synthesis of 4,5-dihy-
drotetrazolo[1,5-a]quinoxalines 5a–i: 0.2 mmol of com-
pound 4 was dissolved in 2 mL DMF and 0.33 mmol
Cs2CO3 was added. Then, the reaction was stirred until
HPLC–MS analysis confirmed that the reaction was
completed. Then, 10 mL water were added and the
mixture was extracted with 2 · 15 mL of ethyl acetate.
The organic layer was dried over MgSO4 and the resulting
crude product was purified by flash chromatography.
26. Compound 4a was prepared according to GP1 and purified
by chromatography on silica gel with eluent ethyl acetate/
hexane 2/1. The tetrazole 4a was obtained as a yellow oil
(62%). 1H NMR (CDCl3, 250.13 MHz): 0.35 (s, 4H, CH2),
2.07 (t, 1H, 3J = 4.17 MHz, CH cyclopropyl), 2.83 (s, 1H,
NH), 4.99 (s, 1H, CH-C6H5), 7.1–7.32 (m, 8H, ar-H), 7.52–
7.61 (m, 1H, ar-H). m/z (%) = 310 (100) [MH+].
29. Compound 5i was prepared according to GP2: 221 mg
(0.7 mmol) of 4i was dissolved in 5 mL DMF and 586 mg
(1.8 mmol) Cs2CO3 was added. Then, the reaction was
stirred for 10 h by 100 ꢁC. After HPLC–MS analysis
which confirmed that the reaction was completed, 15 mL
water was added and the mixture was extracted with
2 · 20 mL of ethyl acetate. The organic layer was dried
over MgSO4 and the resulting crude product was purified
on silica gel with eluent ethyl acetate/hexane 1/3 to afford
5i as a white solid. Mp: 138.3–138.5 ꢁC. 1H NMR (CDCl3,
250.13 MHz): 1.61–1.76 (m, 6H, cyclohexyl), 1.89–2.08
(m, 2H, cyclohexyl), 2.15–2.20 (m, 2H, cyclohexyl), 6.35
(dd, 1H, 3J = 8.37 Hz, 4J = 0.95 Hz, ar-H), 6.93 (ddd, 1H,
3Ja = 7.82 Hz, 3Jb = 8.69 Hz, 4J = 1.11 Hz, ar-H), 7.08
27. Compound 5a was prepared according to GP2 and
purified by chromatography on silica gel with eluent ethyl
acetate/hexane 1/2 to afford 5a (mixture of two conform-
1
ers in a ratio 1/0.85) as a yellow oil (96%). H NMR of
major isomer (CDCl3, 250.13 MHz): 0.80–0.90 (m, 4H,
CH2), 2.62–2.70 (m, 1H, CH), 7.15–7.48 (m, 10H, ar-H
and CH–C6H5). m/z (%) = 290 (100) [MH+].
3
4
28. Compound 5h was prepared according to GP2: 258 mg
(1 mmol) of 4h was dissolved in 6 mL DMF and 586 mg
(1.8 mmol) Cs2CO3 was added. Then, the reaction was
stirred for 1 d at 100 ꢁC. Then, 163 mg (0.5 mmol) Cs2CO3
were added and the mixture was stirred for a following
24 h. Despite the reaction was not being completed, 15 mL
water was added and the mixture was extracted with
(dt, 1H, J = 8.69 Hz, J = 1.58 Hz, ar-H), 7.21–7.26 (m,
2H, ar-H), 7.44–7.51 (m, 3H, ar-H), 7.99 (dd, 1H, 3J =
7.82 Hz, 4J = 1.58 Hz, ar-H). 13C NMR (CDCl3, 62.89
MHz): 22.35 (cyclohexyl), 24.98 (cyclohexyl), 34.44 (cyclo-
hexyl), 60.16 (Cq), 117.10, 117.58, 119.31, 120.75, 128.48,
129.16, 129.97, 131.96, 136.57, 140.20 (ar), 151.82 (R2C@
NR). m/z (%) = 318 (100) [MH+].