Synthesis of fused triazolo-imidazole derivatives by sequential van Leusen/alkyne-azide cycloaddition reactions

Article abstract of DOI:10.1016/j.tetlet.2005.10.090

A facile synthesis of fused triazolo imidazole derivatives by a van Leusen/alkyne-azide cycloaddition synthetic sequence is reported. The two-step reaction sequence generates compounds of significant molecular complexity from simple starting materials in an expedient fashion with good overall yields.

Full text of DOI:10.1016/j.tetlet.2005.10.090

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 9053–9056
Synthesis of fused triazolo-imidazole derivatives by sequential
van Leusen/alkyne–azide cycloaddition reactions
Vijaya Gracias,* Daria Darczak, Alan F. Gasiecki and Stevan W. Djuric
Scaffold-Oriented Synthesis, Medicinal Chemistry Technologies, Abbott Laboratories, R4CP, AP10,
100 Abbott ParkRoad, Abbott Park, IL 60064-6099, USA
Received 8 August 2005; accepted 19 October 2005
Available online 10 November 2005
Abstract—A facile synthesis of fused triazolo imidazole derivatives by a van Leusen/alkyne–azide cycloaddition synthetic sequence
is reported. The two-step reaction sequence generates compounds of significant molecular complexity from simple starting materials
in an expedient fashion with good overall yields.
Ó 2005 Elsevier Ltd. All rights reserved.
The continuing demand for novel lead compounds has
led to the emergence of our scaffold-oriented synthesis
program that targets functionalized molecular skeletons
via multicomponent reactions1 (MCRs) combined with
a post-condensation modification. We have recently re-
ported sequential Ugi/Heck,2 Ugi/intramolecular nitrile
oxide cycloaddition,3 Ugi/intramolecular alkyne–azide
cycloaddition (IAAC)4 and Ugi/carbonylation intramo-
lecular amidation5 sequences.
closing metathesis strategies to access novel bicyclic
imidazoles.8
Herein, we report our efforts on post-modifications of
the van Leusen reaction using an alkyne–azide cycload-
dition as the ultimate step in our reaction sequence
(Fig. 1). The use of an azide functionality on the alde-
hyde and an alkyne functionality on the amine provides
bifunctional starting materials for the van Leusen reac-
tion resulting in substrate 1. Subsequent cyclization via
the IAAC will allow access to the fused triazolo imid-
azole scaffolds 2. Additionally, the availability of efficient
routes to synthesize substituted TosMIC reagents pro-
vides another site of diversity in the three-component
reaction.9 This concept has been previously reported by
us in the context of Ugi-type MCRs wherein azide–alkyne
During this endeavor, our group became interested in
the synthesis of fused bicylic imidazoles due to their
presence in a number of biologically active com-
pounds.6 It is in this context that we became interested
in the van Leusen imidazole synthesis7 and we have
recently reported on sequential van Leusen/ring-
R2
SO2Tol
R2
R1
R1
N
N
NC
R1
N
Intramolecular
alkyne-azide
cycloaddition
van Leusen
imidazole synthesis
N3
N
CHO
R3
N
N
N
R2
N3
1
2
R3
NH2
R3
Figure 1. General strategy.
Keywords: Multicomponent reactions; Imidazole; van Leusen; Cycloaddition.
*
Corresponding author. Tel.: +1 8479376324; fax: +1 8479350310; e-mail: vijaya.gracias@abbott.com
0040-4039/$ - see front matter Ó 2005Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.090

9054
V. Gracias et al. / Tetrahedron Letters 46 (2005) 9053–9056
Ref 10a
Br
NaN3/DMF
rt
LiAlH4
H2N
60%
N3
Me
Me
Ph
Me
N
Ref 10b
HO
O
PPh3, DEAD
phthalimide, THF
NH2NH2, MeOH
50%
H2N
95%
Ph
Ph
O
Ref 10c
NaN3/DMF
60 oC, 52%
CHO
N3
CHO
NO2
Ref 10c
NaN3/HMPA
60 oC, 30%
CHO
N3
O
O
CHO
NO2
O
O
Scheme 1. General synthetic routes for the preparation of the starting materials.
Table 1. Products obtained from the van Leusen and intramolecular azide–alkyne cycloaddition (IAAC) sequence
Entry
Aldehyde
Amine
TosMIC
van Leusen product
Yield
IAAC product
Yield (%)
65
CHO
SO2Tol
a
NH2
N
1
NC
N
N
N3
N3
Ph
Ph
N
N
N
N
11
3
a
F
F
SO2Tol
NC
N
CHO
N3
N
N3
N
NH2
2
72
N
N
N
N
F
12
4
N
SO2Tol
CHO
N3
N3
N
Ph
Ph
N
NH2
Ph
3
4
53
60
59
65
NC
N
N
Me
N
N
N
Me
N
5
13
Me
SO2Tol
NC
N
CHO
N3
N3
N
N
NH2
Ph
Ph
N
Ph
N
6
14
Ph
O
O
O
a
O
SO2Tol
NC
CHO
N3
O
O
N
N
NH2
5
83
N
N3
Ph
Ph
N
N
N
N
15
7

V. Gracias et al. / Tetrahedron Letters 46 (2005) 9053–9056
9055
Table 1 (continued)
Entry Aldehyde
Amine
TosMIC
van Leusen product
Yield
IAAC product
Yield (%)
O
O
O
O
a
SO2Tol
NC
CHO
N3
O
O
F
F
N
NH2
6
93
N
N
N3
F
N
N
N
N
16
8
O
O
O
O
SO2Tol
NC
CHO
N3
O
O
N
NH2
N
N3
Ph
7
43
40
N
Ph
Me
N
N
N
Me
N
9
17
Me
O
O
O
O
SO2Tol
NC
CHO
N3
O
O
N
NH2
N
N3
Ph
N
8
59
62
Ph
Ph
N
N
N
Ph
N
10
18
Ph
aThe intermediate van Leusen products were not isolated, 1,3-cycloaddition occurred in situ to afford the triazole products.
inputs were introduced into the reaction components
followed by a post-condensation IAAC reaction to
afford fused dihydrotriazolo[1,5-a]pyrazinones and
triazolobenzodiazepines.4
Azides and the propargyl amine building blocks were
purchased from commercial sources or prepared accord-
ing to known procedures as illustrated in Scheme 1.10
The condensation of the azido aldehyde with propargyl
amine in DMF at room temperature generates the imine
in situ, which is followed by the addition of phenyl
TosMIC and base (K2CO3).
It was observed that with unsubstituted alkynes the
intermediate van Leusen imidazoles were not isolated,
but the IAAC reaction proceeded in situ at room tem-
11
perature to afford the cycloaddition products (Table 1,
11
Figure 2. Crystal structure of 11.
entries 1, 2, 5and 6). This was confirmed by IR anal-
ysis (absence of the –N3 functionality in the products),
and 1H NMR data (absence of the alkyne –CH, appear-
ance of the –CH2 of the azepine ring and –CH of the tri-
azole ring). Additionally, a single-crystal X-ray for 11
was obtained (Fig. 2).
reaction, followed by an intramolecular 1,3-cycloaddi-
tion reaction, a variety of fused triazolo imidazoles
can be readily generated under mild conditions from
easily accessible starting materials. These compounds
represent useful scaffolds for lead generation. Other
van Leusen post-modification reactions are currently
in progress and will be reported in due course.
With the substituted alkynes, the intermediate van Leu-
sen imidazoles were isolated (Table 1, entries 3, 4, 7 and
8). The IAAC reaction was then effected by treating the
intermediate imidazole products with copper(II) sulfate
pentahydrate.12 Using this procedure, a diverse set of
fused triazolo imidazoles have been synthesized by vary-
ing the aldehyde, alkyne and TosMIC inputs.
Acknowledgements
The authors would like to thank the Structural Chemis-
try staff for NMR and MS data and Rodger Hendry for
the X-ray crystallography experiments.
In conclusion, we have demonstrated that by introduc-
ing azide and alkyne functionality via the van Leusen

9056
V. Gracias et al. / Tetrahedron Letters 46 (2005) 9053–9056
was added propargyl amine (110 mg, 2.0 mmol) and the
References and notes
reaction mixture was stirred at rt for 2.5h. This was
followed by the addition of phenyl TosMIC (271 mg,
1.0 mmol) and K2CO3 (138 mg, 2.0 mmol) and the reac-
tion mixture was allowed to stir for an additional 17 h at
rt. The reaction was quenched by the addition of water.
The aqueous layer was extracted with EtOAc, dried
(anhyd MgSO4), concentrated and purified by flash
chromatography (97:2.5:0.5, CH2Cl2–CH3OH–NH3) to
afford 185mg (62%) of 11 as a clear oil. 1H NMR
(300 MHz, CDCl3): d 5.01 (br s, 1H), 5.66 (br s, 1H), 7.30–
7.39 (m, 4H), 7.50–7.60 (m, 4H), 7.85 (s, 1H), 8.10 (m,
1H), 8.16 (s, 1H); MS (ESI): m/z 300 (M+H).
1. For reviews on Ugi 4-CC reaction and other MCRs with
isocyanides, see: (a) Do¨mling, A.; Ugi, I. Angew. Chem.,
Int. Ed. 2000, 39, 3168–3210; (b) Hulme, C.; Gore, V.
Curr. Med. Chem. 2003, 10, 51–80; (c) Do¨mling, A. Curr.
Opinion Chem. Biol. 2002, 6, 306–313; (d) Zhu, J. Eur. J.
Org. Chem. 2003, 1133–1144; (e) Gokel, G.; Ludke, G.;
¨
Ugi, I. In Isonitrile Chemistry; Ugi, I., Ed.; Academic:
New York, 1971; p 145.
2. Gracias, V.; Moore, J. D.; Djuric, S. W. Tetrahedron Lett.
2004, 45, 417–420.
3. Akritopoulou-Zanze, I.; Gracias, V.; Moore, J. D.; Djuric,
S. W. Tetrahedron Lett. 2004, 45, 3421–3423.
4. Akritopoulou-Zanze, I.; Gracias, V.; Djuric, S. Tetrahe-
dron Lett. 2004, 45, 8439–8441.
5. Vasudevan, A.; Verzal, K. M. Tetrahedron Lett. 2005, 46,
1697–1701.
6. (a) Frannowski, A.; Seliga, C.; Bur, D.; Streith, J. Helv.
Chim. Acta 1991, 74, 934–940; (b) Nishi, T.; Higashi, K.;
Soga, T.; Takemura, M.; Sato, M. J. Antibiot. 1994, 47,
357–369; (c) Browne, L. J.; Gude, C.; Rodriguez, H.;
Steele, R. E. J. Med. Chem. 1991, 34, 725–736; (d)
Aldabbagh, F.; Bowman, W. R.; Mann, E. Tetrahedron
Lett. 1997, 38, 7937–7940.
7. (a) van Leusen, A. M.; Wilderman, J.; Oldenzeil, O. H. J.
Org. Chem. 1977, 42, 1153–1159; (b) van Leusen, A. M.
Lect. Heterocycl. Chem. 1980, 5, S-111.
12. (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.;
Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2596–
2599; (b) A representative procedure for reactions with
substituted alkynes is demonstrated by the preparation of
13. To the azido aldehyde (221 mg, 1.5mmol) in DMF
(2 mL) was added but-2-yn-1-amine (138 mg, 2.0 mmol)
and the reaction mixture was stirred at rt for 2.5h. This
was followed by the addition of phenyl TosMIC (271 mg,
1.0 mmol) and K2CO3 (138 mg, 1.0 mmol) and the reaction
mixture was allowed to stir for an additional 17 h at rt. The
reaction was quenched by the addition of water. The
aqueous layer was extracted with EtOAc, dried (anhyd
MgSO4) concentrated and purified by flash chromatogra-
phy (97:2.5:0.5, CH2Cl2–CH3OH–NH3) to afford 145mg
1
(53%) of 5 as a clear oil. H NMR (300 MHz, CDCl3): d
1.81 (t, J = 3.0 Hz, 3H), 4.32 (d, J = 12.0 Hz, 1H), 4.50 (d,
J = 12.0 Hz, 1H), 7.12–7.33 (m, 6H), 7.44–7.54 (m, 3H),
7.88 (s, 1H); MS (ESI): m/z 314 (M+H); To 5 in t-BuOH–
H2O (1:1, 2 mL), sodium ascorbate (8.3 mg, 0.042 mmol),
copper(II) sulfate pentahydrate (1 mg, 0.0042 mmol) were
added and the reaction mixture was heated at 60 °C for
17 h. The reaction was cooled to rt, quenched with H2O.
The aqueous layer was extracted with EtOAc, dried (anhyd
MgSO4), concentrated and purified by flash chromatogra-
phy (97:2.5:0.5, CH2Cl2–CH3OH-NH3) to afford 78 mg
(59%) of 13 as a white solid. 1H NMR (300 MHz, CDCl3):
d 2.48 (s, 3H), 4.97 (br s, 1H), 5.29 (br s, 1H), 7.26–7.32 (m,
4H), 7.47–7.53 (m, 4H), 7.76 (s, 1H), 8.04 (d, J = 6.0 Hz,
1H); MS (ESI): m/z 314 (M+H).
8. Gracias, V.; Gasiecki, A.; Djuric, S. W. Org. Lett. 2005, 7,
3183–3186.
9. (a) Sisko, J.; Mellinger, M.; Sheldrake, P. W.; Baine, N. H.
Tetrahedron Lett. 1996, 37, 8113–8116; (b) Sisko, J.;
Mellinger, M.; Sheldrake, P. W.; Baine, N. H. Org. Synth.
2000, 77, 198–205.
10. (a) Trost, B. M.; Rudd, M. T. Org. Lett. 2003, 5, 1467–
1470; (b) Moody, C. J.; Rahimtoola, K. F.; Porter, B.;
Ross, B. C. J. Org. Chem. 1992, 57, 2105–2114; (c) Pelkey,
E. T.; Gribble, G. W. Tetrahedron Lett. 1997, 38, 5603–
5606.
11. A representative procedure for reactions with unsubsti-
tuted alkynes is demonstrated by the preparation of 11. To
the azido aldehyde (221 mg, 1.5mmol) in DMF (2 mL)