Synthesis of fused imidazo azepine derivatives by sequential van Leusen/enyne metathesis reactions

Article abstract of DOI:10.1016/j.tetlet.2005.10.089

A facile synthesis of fused imidazo azepine derivatives by a van Leusen/intramolecular enyne metathesis 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.2005.10.089

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 9049–9052
Synthesis of fused imidazo azepine derivatives by sequential
van Leusen/enyne metathesis reactions
Vijaya Gracias,* 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;revised 14 September 2005;accepted 19 October 2005
Available online 10 November 2005
Abstract—A facile synthesis of fused imidazo azepine derivatives by a van Leusen/intramolecular enyne metathesis 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.
Multicomponent reactions (MCRs) are widely em-
ployed for the construction of diversely functionalized
molecules via simple one-step transformations.1
Recently, isocyanide-based MCRs like the Passerini
three-component and the Ugi four-component reactions
have been combined with secondary transformations to
produce even more functionalized and specialized het-
erocyclic molecules. Some examples of post-condensa-
tion reactions include Diels–Alder reactions, amino-
cyclizations, nucleophilic aromatic substitutions, lacton-
izations and ring-closing metathesis.2 As part of our
groupÕs efforts to develop short and versatile routes to
access novel heterocyclic structures, we have recently
reported sequential Ugi/Heck,3 Ugi/intramolecular nitrile
oxide cycloaddition,4 Ugi/intramolecular alkyne-azide
cycloaddition5 and Ugi/carbonylation intramolecular
amidation6 sequences.
The imidazole nucleus is present in a variety of natural
products and medicinally relevant heterocycles7 includ-
ing antiviral and antibacterial agents.8 It is in this context
that we became interested in the van Leusen imidazole
synthesis9 as part of a program to identify and synthesize
novel heterocyclic skeletons. We have recently reported
on sequential van Leusen/ring-closing metathesis strate-
gies to access novel bicyclic imidazoles.10
Herein, we report on our efforts on post-modifications of
the van Leusen reaction using an enyne metathesis11 as
the ultimate step in our reaction sequence (Fig. 1). The
O
H
Me
Me
Ph
Ph
DMF/K2CO3
1.p-TsOH, CH2Cl2
2.
N
H2N
N
N
N
92%
Me
SO2Tol
Mes
N
N
Mes
1
2
Cl
Ru
PCy3
NC
Ph
Cl
CH2Cl2
82%
Figure 1. General strategy.
Keywords: Multicomponent reactions;van Leusen;Enyne metathesis.
*
Corresponding author. Tel.: +1 8479 376324;fax: +1 8479 350310;e-mail: vijaya.gracias@abbott.com
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.089

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V. Gracias et al. / Tetrahedron Letters 46 (2005) 9049–9052
use of an alkene functionality on the aldehyde and an al-
kyne functionality on the amine provides bifunctional
starting materials for the van Leusen reaction resulting
in substrate 1. Subsequent cyclization via the intramolec-
ular enyne metathesis results in the formation of the cyc-
lized product 2 containing a diene functionality.
in situ, which is followed by the addition of phenyl
TosMIC and base (K2CO3) to afford the van Leusen
imidazole product 1 in 92% yield. As with the alkene
metathesis post-modification, the imidazole was pre-
treated with an equivalent of p-TsOH before subjecting
it to the enyne ring closure.12 The subsequent reaction
catalyzed by the second-generation Grubbs catalyst
(10 mol %) in refluxing CH2Cl2 gave the fused bicyclic
imidazole 2 in 82% yield.13
The condensation of 4-pentenal with but-2-yn-1-amine
in DMF at room temperature generates the imine
Table 1. Products obtained from the van Leusen/enyne metathesis reaction sequence
Entry Aldehyde
Amine
TosMIC
van Leusen product
Yield (%) Enyne product
Yield (%)
<5
SO2Tol
O
Ph
NH2
1
48
Ph
NC
H
N
N
N
N
Me
SO2Tol
NC
O
Ph
NH2
NH2
NH2
2
Ph
45
54
82
71
Me
Me
Me
Me
Me
N
N
H
N
N
Me
SO2Tol
NC
O
Ph
3
92
Ph
N
N
H
N
N
F
F
SO2Tol
NC
Me
O
4
87
H
N
N
N
N
F
Me
BOC
HN
Me
Boc-NH
Ph
SO2Tol
BOC
NH2
HN
5
53
64
63
54
NC
Ph
Me
N
N
CHO
N
N
N
Me
H2N
COOMe
SO2Tol
NC
O
Ph
Me
COOMe
Ph
N
6
87
COOMe
N
N
H
Me
Me
F
F
H2N
COOMe
SO2Tol
NC
O
Me
COOMe
7
86
COOMe
H
N
N
N
Me
F
N
Me
Ref 15a
NaN3/DMF
LiAlH4
H2N
60%
Br
N3
Me
Me
Me
Ref 15b
·HCl
H2N
Ph
CO2Et
NaH
Ph
N
Ph
1N HCl
40%
N
CO2Et
CO2Et
Ph
Br
Me
Me
Me
80%
Ref 15c
Sn, allyl bromide
THF, H2O
NaIO4, CH2Cl2
H2O
O
O
H
OH
H
H
85%
~12% by wt
in CH2Cl2
O
OH
Scheme 1. General synthetic routes for the preparation of the starting materials.

V. Gracias et al. / Tetrahedron Letters 46 (2005) 9049–9052
9051
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Aldehyde and amine components of varying chain
length were used in the van Leusen reaction to provide
the corresponding C1/C5-substituted metathesis pre-
cursors. These were subjected to the intramolecular
enyne metathesis sequence to provide products of var-
ied ring size (Table 1). A diverse set of 5,6- 5,7- and
5,8-fused bicyclic functionalized imidazoles was gener-
ated via this reaction sequence. With terminal alkynes
low yields of the metathesis product was observed
(Table 1, entry 1).14 In addition to simple primary
amines and aldehydes, secondary amino aldehydes
and amino esters were used as building blocks to pro-
vide another functional group for further elaboration
of the skeleton (Table 1, entries 4–6). The requisite
building blocks were purchased from commercial
sources or prepared according to known procedures
as illustrated in Scheme 1.15 Finally, the availability
of efficient routes to synthesize substituted TosMIC
reagents provides another site of diversity in the
three-component reaction.16 In conclusion, we have
demonstrated that by incorporating alkene–alkyne
inputs in the van Leusen reaction, followed by an
enyne metathesis reaction a variety of fused bicyclic
imidazoles can be readily generated. Each of the bicy-
clic scaffolds generated by this reaction sequence had
the diene functionality, which could then serve as a site
for further diversification. Elaboration of the bicyclic
dienes via cycloaddition reactions and other van Leu-
sen post-modification reactions are currently in pro-
gress and will be reported in due course.
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Acknowledgement
The authors would like to thank the Structural Chemis-
try staff for NMR and MS data.
9. (a) van Leusen, A. M.;Wilderman, J.;Oldenzeil, O. H. J.
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References and notes
10. Gracias, V.;Gasiecki, A.;Djuric, S. W. Org. Lett. 2005, 7,
3183–3186.
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.
Opin. Chem. Biol. 2002, 6, 306–313;(d) Zhu, J. Eur. J.
11. Poulsen, C. S.;Madsen, R. Synthesis 2003, 1–18.
12. This treatment results in the formation of the imidazolium
ion, preventing the lone pair of the imidazole nitrogen
from inactivating the Grubbs catalyst. See reference:
Chen, Y.;Dias, H. V. R.;Lovely, C. J.
Tetrahedron
Org. Chem. 2003, 1133–1144;(e) Gokel, G.;Lu dke, G.;
Ugi, I. In Isonitrile Chemistry;Ugi, I., Ed.;Academic:
New York, 1971;p 145.
Lett. 2003, 44, 1379–1382. Our reaction failed to yield the
enyne product in the absence of this pretreatment
procedure.
¨
2. Examples of post-Ugi transformations include the follow-
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hedron Lett. 1999, 40, 1851–1854;(b) Wright, D. L.;
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Strocker, A. M.;Keating, T. A.;Tempest, P. A.;
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13. A representative procedure is demonstrated by the prep-
aration of 6-isopropenyl-1-phenyl-8,9-dihydro-5H-imi-
dazo[1,5-a]azepine (2). To the 4-pentenal (126 mg,
1.5 mmol) 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 2.5 h. This was followed by the addition of phenyl
TosMIC (271 mg, 1.0 mmol) and K2CO3 (138 mg,
2.0 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 chromatography (97–2.5–0.5: CH2Cl2–
CH3OH–NH3) to afford 230 mg (92%) of 1 as a clear oil.
1H NMR (300 MHz, CDCl3): d 1.84 (t, J = 3.0 Hz, 3H),
2.38 (m, 2H), 2.92 (m, 2H), 4.59 (m, 2H), 5.05 (m, 2H),
5.85 (m, 1H), 7.22–7.42 (m, 3H), 7.65 (m, 3H);MS (ESI):
m/z 251 (M+H). To a solution of 1 (190 mg, 0.76 mmol) in

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V. Gracias et al. / Tetrahedron Letters 46 (2005) 9049–9052
CH2Cl2 (20 mL) was added p-TsOH (145 mg, 0.76 mmol)
14. The use of ethylene gas is reported to give improved yields
in the enyne metathesis of terminal alkynes. See reference:
Mori, M.;Sakakibara, N.;Kinoshita, A. J. Org. Chem.
1998, 63, 6082–6083. We did not try the enyne metathesis
of terminal alkynes using ethylene gas.
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and the reaction mixture was heated at reflux for 30 min.
The reaction was cooled to rt and the Grubbs catalyst
(65 mg, 0.076 mmol) was added and the reaction mixture
was refluxed for an additional 2 h (TLC indicated disap-
pearance of the starting material). The reaction was
quenched by adding aq satd K2CO3 and extracted with
EtOAc. The organic layer was dried (anhyd MgSO4),
concentrated and purified by flash chromatography
(97–2.5–0.5: CH2Cl2–CH3OH–NH3) to afford 155 mg
(82%) of 2 as a light brown oil. 1H NMR (300 MHz,
CDCl3): d 1.93 (s, 3H), 2.59 (m, 2H), 3.17 (d, J = 6.0 Hz,
2H), 4.83 (s, 2H), 5.02 (d, J = 9.0 Hz, 2H), 5.95
(t, J = 3.0 Hz, 1H), 7.25 (m, 1H), 7.38 (m, 2H), 7.46
(s, 1H), 7.62 (d, J = 6.0 Hz, 2H);MS (ESI): m/z 251
(M+H).