Synthesis of fused imidazole rings by sequential van Leusen/C-H bond activation

Article abstract of DOI:10.1016/j.tetlet.2006.10.051

A concise route to access fused imidazole rings employing the van Leusen three-component reaction followed by a Pd/Cu catalyzed intramolecular C-arylation is reported. The reaction was found to be general and the products were formed in moderate to excell

Full text of DOI:10.1016/j.tetlet.2006.10.051

Tetrahedron Letters 47 (2006) 8873–8876
Synthesis of fused imidazole rings by sequential van
Leusen/C–H bond activation
Vijaya Gracias,* Alan F. Gasiecki, Thomas G. Pagano and Stevan W. Djuric
Scaffold-Oriented Synthesis, Medicinal Chemistry Technologies, Abbott Laboratories, R4CP, AP10,
100 Abbott Park Road, Abbott Park, IL 60064-6099, United States
Received 13 September 2006; revised 9 October 2006; accepted 11 October 2006
Abstract—A concise route to access fused imidazole rings employing the van Leusen three-component reaction followed by a Pd/Cu
catalyzed intramolecular C-arylation is reported. The reaction was found to be general and the products were formed in moderate to
excellent yields using the two-step reaction sequence.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Multicomponent reactions (MCRs) have been exten-
sively exploited in organic and diversity-oriented synthe-
sis mostly due to their ability to rapidly assemble
complex structures in simple one-step transformations
from readily available starting materials.1 Combined
with post-modification reactions, MCRs allow access
to richly functionalized heterocyclic molecules.2 As part
of our efforts to develop new routes to access novel
heterocyclic structures using MCRs coupled with
post-modification reactions, we have recently reported
the synthesis of imidazoles employing sequential van
Leusen/RCM, van Leusen/enyne metathesis, van Leusen/
alkyne–azide cycloadditions and van Leusen/Heck
reactions.3 We now present a van Leusen imidazole syn-
thesis4 followed by an intramolecular C-2 arylation to
form fused imidazoles.
R2
N
R1
SO2Tol
NC
NH2 1. van Leusen
reaction
N
R1
+
2. C-Arylation
X
R3
R2CHO
X = Br, I
R3
Figure 1. General strategy to fused imidazoles.
This chemistry allows access to 5H-imidazo[2,1-a]iso-
indole, 5,6-dihydroimidazo[2,1-a]isoquinoline and 6,7-
dihydro-5H-benzo[c]imidazo[1,2-a]azepine rings depen-
ding on the tether length of the amine used. An alternate
route to synthesize the 5,6-dihydroimidazo[2,1-a]-
isoquinoline system, utilizing radical cyclization reac-
tions of tethered aryl halides onto imidazole rings has
been reported.9 The imidazole precursors in this report
were prepared via alkylation chemistry. Our method
uses the van Leusen reaction to assemble the imidazoles
followed by transition metal catalyzed C–C bond
formation.
The direct C–H activation of heteroaromatics represents
an important carbon–carbon bond forming reaction in
organic synthesis.5 There are reports of palladium-cata-
lyzed6 and rhodium-catalyzed7 C-arylation of azoles
with aryl halides that allow for direct C–C bond forma-
tion without the need for prior functionalization of the
azole core. More recently, this reaction has been found
to proceed even under base-free and ligand-free condi-
tions.8 Herein, we report an intramolecular variant of
this chemistry between a tethered aryl halide and the
imidazole ring via a C-arylation reaction to give fused
imidazoles (Fig. 1).
Isovaleraldehyde was condensed with 2-iodo piperonyl-
amine 1 in DMF to form the imine, followed by the
addition of phenyl tosylmethylisocyanide (TOSMIC)
and K2CO3. The reaction was heated at 60 ꢁC for 14 h
to provide imidazole 2 in an 85% yield. Substrate 2
was subsequently converted to imidazole 3 in a 78%
yield using Pd-mediated conditions. A combination of
Pd(OAc)2 (10 mol %), PPh3 (0.2 equiv), CuI (2.0 equiv),
CsCO3 (1.0 equiv) in DMF at 140 ꢁC for 14 h (method
*
Corresponding author. Tel.: +1 847 937 6324; fax: +1 847 935
0310; e-mail: vijaya.gracias@abbott.com
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.10.051

8874
V. Gracias et al. / Tetrahedron Letters 47 (2006) 8873–8876
Ph
ers were also investigated namely, Pd(OAc)2 (5 mol %),
O
CuI (2.0 equiv) in DMF at 140 ꢁC for 14 h (method
B); however, the cyclized product 3 was obtained in a
30% yield (Scheme 1). A series of imidazole precursors
were synthesized to evaluate the scope of the C-arylation
reaction. The results are outlined in Table 1. The reac-
tion was found to be general for various van Leusen
imidazole substrates, substituted phenylTosMIC’s and
aromatic aldehydes. Finally, in addition to simple
primary amines, amino esters could also be used.
H2N
i
-Bu
N
H
a
N
O
O
I
SO2Tol
NC
I
1
2
b or c
O
O
i
-Bu
N
N
The cyclization reaction of the imidazole precursors
using the optimized reaction conditions (method A)
gave access to a variety of fused bicyclic imidazoles.
Arylbromides were found to be comparable to the aryl-
iodides in the C-arylation reaction (Table 1, entries 1
and 2). Five-membered fused rings, 5H-imidazo[2,1-a]-
isoindoles were obtained from the 2-halobenzylamines
(Table 1, entry 1). Six-membered and seven-membered
rings were accessible when the amine precursors were
the 2-iodophenethylamines and 2-iodophenylpropyl-
amines, respectively.11 In the case of entry 6 (Table 1),
78% method A
30% method B
O
Ph
O
3
Scheme 1. Reagents and conditions: (a) DMF, K2CO3, 85%; (b)
Pd(OAc)2, PPh3, CuI, Cs2CO3, DMF 140 ꢁC, 14 h, (method A); (c)
Pd(OAc)2, CuI, DMF, 140 ꢁC, 14 h, (method B).
A) was optimal for the cyclization.10 The base-free and
ligand-free conditions reported by Bellina and co-work-
Table 1. van Leusen and C-arylation products
Entry TOSMIC
R2–CHO
R3–NH2
van Leusen product (yield %) C-arylation product
-Bu
Yield (%)
i
NH2
Ph
i-Bu
SO2Tol
O
H
N
1
R = Br, 29 R = I, 37
N
X
X
N
Ph
Ph
NC
N
Ph
X = I, Br
(X = Br, 95%)
(X = I, 93%)
Br
H2N
i
-Bu
i
-Bu
SO2Tol
NC
O
H
N
N
Ph
2
65
N
Ph
N
Br
(95%)
I
i
-Bu
Ar
H2N
N
N
SO2Tol
NC
i
-Bu
O
H
Ar
O
3
4
O
O
68
63
O
Ar
N
O
N
Ar = p-C6H4Cl
O
I
Ar = p-C6H4Cl
(65%)
i
-Bu
Ph
SO2Tol
NC
O
H
i
-Bu
3NH2
N
N
N
N
Ph
Ph
I
I
Ph
(92%)
Me
Me
Me
O
H2N
I
O
SO2Tol
NC
O
5
6
O
O
73
N
N
Ph
Ph
O
O
N
CHO
I
N
(50%)
Ph
O
O
I
i-Bu
MeO2C
NH2
MeO2C
SO2Tol
NC
O
H
i-Bu
72a
N
N
N
Ph
(70%)
CO2R
N
Ph
I
LiOH/MeOH
74%
R = Me
R = H
a The crude reaction was treated with TMSCHN2/MeOH to form the ester.

V. Gracias et al. / Tetrahedron Letters 47 (2006) 8873–8876
8875
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-Bu
MeO
-Bu
N
N
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MeO
COOMe
i
Ph
N
6
CO2Me
, 15%
40%
Scheme 2. Reagents and conditions: (a) DMF, K2CO3, 62%; (b)
LiOH, MeOH, 70%; (c) Pd(OAc)2, PPh3, CuI, Cs2CO3, DMF 140 ꢁC,
14 h, (method A); (d) TMSCHN2, MeOH.
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we found that the C-arylation reaction was significantly
cleaner with the acid. Thus the ester was hydrolyzed to
the acid using LiOH/MeOH prior to the cyclization
reaction. The crude reaction mixture was then treated
with TMS–diazomethane to reform the ester in order
to ease purification of the final product.
Attempts to apply this chemistry to obtain the synthe-
tically more challenging eight-membered rings were suc-
cessful albeit, in a low yield. Compound 5 was subjected
to the reaction conditions employed in method A. In
addition to yielding the desired product 6 in a 15%
yield,12 significant deiodination of substrate 5 was
observed under the reaction conditions (Scheme 2).
In conclusion, a two-step reaction sequence utilizing the
van Leusen imidazole synthesis, followed by the intra-
molecular C–H activation allowing access to functional-
ized fused imidazoles, has been developed. This reaction
sequence utilizes readily available starting materials to
afford products in an efficient and concise manner. Fur-
thermore, the final products obtained are structural
chemotypes that could be useful scaffolds for lead gener-
ation. Other van Leusen post-modification reactions as
well as application of the C-arylation methodology to
other multicomponent reactions are currently in pro-
gress and will be reported in due course.
Acknowledgements
The authors would like to thank Dr. Rajesh Iyengar for
the purification of compound 6 and the Structural
Chemistry staff for NMR and MS data.
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References and notes
1. For reviews on Ugi 4-CC reaction and other MCRs with
isocyanides, see: (a) Do¨mling, A.; Ugi, I. Angew. Chem.,

8876
V. Gracias et al. / Tetrahedron Letters 47 (2006) 8873–8876
8. (a) Bellina, F.; Cauteruccio, S.; Rossi, R. Eur. J. Org.
7.41 (m, 5H), 7.64–7.67 (m, 2H); MS (ESI): m/z 475
(M+H); To a solution of 2 (238 mg, 0.5 mmol) in DMF
(6 mL) was added Pd(OAc)2 (11.2 mg, 0.05 mmol), PPh3
(26.2 mg, 0.1 mmol), CuI (190 mg, 1.0 mmol) and Cs2CO3
(163 mg, 0.50 mmol) and the reaction mixture was heated
at 140 ꢁC for 14 h. The reaction was cooled to room
temperature diluted with EtOAc (20 mL). A solution of
saturated aqueous NH4Cl was added and the reaction
mixture was stirred at room temperature for 30 min. The
aqueous layer was separated and extracted with EtOAc
(2 · 50 mL). The combined organic layers were dried
(anhyd MgSO4), concentrated and purified by flash
chromatography (10% EtOAc/hexane) to afford 135 mg
(78%) of 3 as a light brown oil. 1H NMR (300 MHz,
CDCl3): d 0.92 (d, J = 6.0 Hz, 6H), 1.91 (m, 1H), 2.70 (d,
J = 9.0 Hz, 2H), 3.06 (t, J = 9.0 Hz, 2H), 4.01 (t, J =
6.0 Hz, 2H), 5.98 (s, 2H), 6.71 (s, 1H), 7.23–7.42 (m, 3H),
7.62 (s, 1H), 7.73 (m, 2H); MS (ESI): m/z 347 (M+H).
11. For the synthesis of the starting materials see: (a)
Reimann, E.; Ettmayr, C. Monatshefte fu¨r Chemie 2004,
135, 1143–1155; (b) Tietze, L. F.; Schirok, H. J. Am.
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9. Allin, S.; Bowman, W. R.; Elsegood, M. R. J.; McKee, V.;
Karim, R.; Rahman, S. S. Tetrahedron Lett. 2005, 61,
2689–2696; for other methods to access similar structural
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chemotypes see: (a) Toja, E.; Omodei-Sale, D.; Favara,
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10. A representative procedure is demonstrated by the prep-
aration of 3-isobutyl-2-phenyl-5,6-dihydro-[1,3]dioxolo[4,5-g]-
imidazo[2,1-a]isoquinoline (3). To the isovaleraldehyde
(215 mg, 2.5 mmol) in DMF (12 mL) was added 2-
˚
iodohomopiperonylamine 1 (1.0 g, 3.44 mmol) and 4 A
sieves (400 mg) and the reaction mixture was heated at
60 ꢁC for 4 h. This was followed by the addition of phenyl
TOSMIC (542 mg, 2.0 mmol) and K2CO3 (276 mg,
2.0 mmol) and the reaction mixture was allowed to stir
for an additional 14 h at 60 ꢁC. The reaction mixture was
quenched by the addition of water. The aqueous layer was
extracted with EtOAc, dried (anhyd MgSO4) concentrated
and purified by flash chromatography (80% EtOAC/
hexane) to afford 805 mg (85%) of 2 as a yellow oil. 1H
NMR (300 MHz, CDCl3): d 0.85 (d, J = 9.0 Hz, 6H), 1.86
(m, 1H), 2.66 (d, J = 6.0 Hz, 2H), 3.09 (t, J = 9.0 Hz, 2H),
4.07 (t, J = 9.0 Hz, 2H), 5.95 (s, 2H), 6.55 (s, 1H), 7.21–
12. Compound 6 was purified by Reverse phase-HPLC on an
Agilent Zorbax RX-C18 column using acetonitrile/water
as the eluent.