A novel one-step synthesis of imidazo[5,1-α]isoquinolines via a tandem Pd-catalyzed alkylation-direct arylation sequence

Article abstract of DOI:10.1021/jo802584f

A palladium-catalyzed/norbornene-mediated one-step synthesis of highly functionalized imidazoles via a sequential alkyl-aryl and aryl-heteroaryl bond formation is devised. This method provides an efficient route to a wide variety of substituted imidazo[5,

Full text of DOI:10.1021/jo802584f

A Novel One-Step Synthesis of
Imidazo[5,1-a]isoquinolines via a Tandem
Pd-Catalyzed Alkylation-Direct Arylation
Sequence
Farnaz Jafarpour* and Parvaneh T. Ashtiani
School of Chemistry, UniVersity College of Science,
UniVersity of Tehran, P.O. Box 14155-6455, Tehran, Iran
jafarpur@khayam.ut.ac.ir
FIGURE 1. Biologically active compounds containing the imidazo[5,1-
a]isoquinoline framework.
ReceiVed NoVember 21, 2008
cal activities such as p38 mitogen-activated protein and B-Raf
kinase inhibition, cannabinoid CB1 receptor antagonism, and
antimicrobial, antitumor, and cytotoxic activities.7 Recently,
increasing attention has been devoted to the imidazo[5,1-
a]isoquinoline framework because they are important constitu-
ents in pharmaceutical drug candidates (Figure 1).8 For instance,
compounds of type 1 are considered to be of potential use in
the treatment of a broad array of diseases or disorders including
depression, anxiety, sleep disorders, cognitive disorders, low
alertness, psychosis, obesity, pain, Parkinson’s disease, Alzhe-
imer’s disease, neurodegenerative diseases, Down syndrome,
and benzodiazepine overdoses (Figure 1).8 Furthermore, a
pharmaceutically acceptable salts of compounds of type 2
(Figure 1) have demonstrated pharmacological activity in
processes known to be associated with one or more of
cardiovascular activity, inflammatory mechanisms, oncology,
and regulation of protein transport from cells and have been
used in the treatment of congestive heart failure, arrhythmia,
hypotension, cancer, Kaposi’s sarcoma, rheumatoid arthritis, and
osteoporosis.8 Thus, several approaches have been developed
for their syntheses consisting of multistep reaction processes
or intermolecular cyclizations via aryl radicals.8,9 However, these
reactions often suffer from low yields and poor selectivity. One
might therefore expect that general and versatile synthetic
methods for the construction of this framework would find
significant utility in organic synthesis.
A palladium-catalyzed/norbornene-mediated one-step syn-
thesis of highly functionalized imidazoles via a sequential
alkyl-aryl and aryl-heteroaryl bond formation is devised.
This method provides an efficient route to a wide variety of
substituted imidazo[5,1-a]isoquinolines from readily acces-
sible N-bromoalkyl imidazoles and aryl iodides.
Nitrogen-containing heterocycles have attracted considerable
attention as they are integral components of natural products,
dyes, agrochemicals, and pharmaceuticals. For instance, imi-
dazole is known to exhibit a broad range of uses in pharma-
ceutical and industrial applications. This type of compound is
present in important naturally occurring biological building
blocks such as histidine and histamine,1 are found in many drug
cores such as angiotensin II inhibitors2 and anti-inflammatory3
and anticancer agents,4 and play an important role as ligands
in metalloenzymes,5 and it is well-known that imidazolium salts
can serve as excellent precursors of stable carbene ligands in
various metal complexes.6 Furthermore, vicinal diaryl-substi-
tuted imidazoles have been shown to exhibit interesting biologi-
Here we report an efficient and straightforward route to annulated
imidazole derivatives based on a palladium-catalyzed/norbornene-
mediated sequential aromatic alkylation/aryl-heteroaryl coupling
reaction. This strategy has previously been applied with success
to the preparation of annulated heterocycles such as indoles,
azaindoles, and pyrroles.10 Very recently, a route very similar to
that described in this Note has been applied to prepare annulated
(1) (a) Iinuma, Y.; Kozawa, S.; Ishiyama, H.; Tsuda, M.; Fukushi, E.;
Kawabata, J.; Fromont, J.; Kobayashi, J. J. Nat. Prod. 2005, 68, 1109. (b)
Fresneda, P. M.; Molina, P.; Sanz, M. A. Tetrahedron Lett. 2001, 42, 851.
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Guolin, C.; Kenneth, S. U.S. Patent 6,528,649, 2003.
(3) Lee, J. C.; Laydon, J. T.; McDonnell, P. C.; Gallagher, T. F.; Kumar, S.;
Green, D.; McNulty, D.; Blumenthal, M. J.; Keys, J. R.; Land Vatter, S. W.;
Strickler, J. E.; McLaughlin, M. M.; Siemens, I. R.; Fisher, S. M.; Livi, G. P.;
White, J. R.; Adams, J. L.; Young, P. R. Nature 1994, 372, 739.
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(6) (a) Garrison, J. C.; Youngs, W. J. Chem. ReV. 2005, 105, 3978. (b)
Braband, H.; Kueckmann, T.; Theresa, I.; Abram, U. J. Organomet. Chem. 2005,
690, 5421. (c) Scott, N. M.; Nolan, S. P. Eur. J. Inorg. Chem. 2005, 1815.
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(10) (a) Laleu, B.; Lautens, M. J. Org. Chem. 2008, 73, 9164. (b)
Blaszykowski, C.; Aktoudianakis, E.; Alberico, D.; Bressy, C.; Hulcoop, D. G.;
Jafarpour, F.; Joushaghani, A.; Laleu, B.; Lautens, M. J. Org. Chem. 2008, 73,
1888. (c) Blaszykowski, C.; Aktoudianakis, E.; Bressy, C.; Alberico, D.; Lautens,
M. Org. Lett. 2006, 8, 2043. (d) Bressy, C.; Alberico, D.; Lautens, M J. Am.
Chem. Soc. 2005, 127, 13148. For the synthesis of annulated furans and
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1364 J. Org. Chem. 2009, 74, 1364–1366
10.1021/jo802584f CCC: $40.75 2009 American Chemical Society
Published on Web 01/02/2009

2H-indazoles and 1,2,3- and 1,2,4-triazoles.10a However, as a result
of the adjacent nitrogen coordinating to one of the palladium
intermediates in the catalytic cycle, only low to moderate yields
of the annulated pyrazole and 7-azaindole derivatives were
obtained.10b,c In line with this, we set out to explore the possibility
of constructing imidazo[5,1-a]isoquinolines via selective direct C-5
arylation of imidazole, where chelation to palladium is impossible.
To limit the degree of freedom in the system and avoid chemose-
lectivity challenges and also to overcome the catalyst poisoning
obstacle, a C2-substituted imidazole with an N-haloalkyl tether was
used. It is the first report on selective C-5 intermolecular arylation
of imidazoles and one-step construction of imidazo[5,1-a]isoquino-
lines.
TABLE 1. Synthesis of Annulated Imidazoles via
Palladium-Catalyzed/Norbornene-Mediated Tandem
Alkylation-Direct Arylation Reactiona
To test the feasibility of this reaction, we initially examined the
reaction of bromoalkyl phenyl imidazole 4 with 5-nitro-2-iodot-
oluene under various reaction conditions. With Pd(OAc)2 as the
catalyst, displacement of the bromide of the N-bromoalkyl hetero-
cycle with an acetate ion was observed. This reaction could be
prohibited by using PdCl2 instead of Pd(OAc)2.10b We were
delighted to see that under the optimized reaction conditions
[iodoarene 5 (0.2 mmol, 1 equiv), PdCl2 (10 mol %), TFP (22
mol %), Cs2CO3 (0.4 mmol, 2 equiv), norbornene (0.4 mmol, 2
equiv), and bromoalkyl imidazole 4 (0.6 mmol, 3 equiv) in CH3CN
(0.1 M) at 100 °C in a sealed tube for 24 h] the fused tricyclic
heterocycle 6 was obtained in 76% yield (Table 1, entry 1). Having
successfully generated highly functionalized six-membered ring-
annulated imidazole 6, we next investigated the scope of the
reaction using various substituted iodoarenes. The results showed
that various electron-withdrawing and electron-donating substitu-
ents, including nitro, alkyl, methoxy, trifluoromethyl, chloride, and
fluoride, were tolerated under the reaction conditions. The reactivity
of aryl halides is strongly enhanced by the presence of electron-
withdrawing substituents. Nitro and chloro substituents at the ortho
and para positions of aryl iodide gave excellent yields, and the
resulting compound 16 represents a very useful partner for further
functionalizations (entries 1, 2, 3, and 6). While low yield was
obtained for ortho-blocking CF3 group, presumably due to steric
effects, fluoro-substituted iodoarene resulted in the corresponding
annulated imidazole in good yield (entries 4 and 5). With alkyl-
substituted iodoarenes, good yields of the products 18 and 20 were
obtained (entries 7 and 8). However, with iodonaphtalene partner,
22 was obtained in only 43% yield (entry 9), presumably as a result
of steric hindrance between naphthalene and imidazole C-H bonds.
As aryl palladium species with the palladium ortho to a methoxy
group can undergo C-H activation with the methoxy C-H bond
to form a stable five-membered palladacycle,11 with 2-iodoanisole
coupling partner the desired product 24 was isolated in only 35%
yield (entry 10). We next investigated the scope of the reaction
using aryliodides with o-carbonyl substituents (methyl 2-iodoben-
zoate and 2-iodobenzophenone). The results showed that the
presence of carbonyl group at position 2 was not tolerated, which
was in accord with the results previously reported.12f
a All reactions were run under the following conditions: iodoarene
(0.20 mmol, 1 equiv), PdCl2 (10 mol %), TFP (22 mol %), Cs2CO3 (2
equiv), norbornene (2 equiv), and bromoalkyl imidazole (3 equiv) in
ACN (0.1 M) were heated in a sealed tube at 100 °C for 24 h.
The possible mechanism for the initial step is based upon
the findings of Catellani and involves a Pd(II)/Pd(IV) catalytic
(11) (a) Dyker, G. J. Org. Chem. 1993, 58, 6426. (b) Dyker, G. Angew.
Chem., Int. Ed. Engl. 1992, 31, 1023.
cycle (Scheme 1).12 A reductive elimination from the Pd(IV)
species followed by extrusion of norbornene gives an aryl-Pd(II)
species that then undergoes an intramolecular direct arylation
reaction forming the aryl-N-heteroaryl bond at the 5 position
of the N-heteroaryl compound. In fact, conflicting mechanistic
interpretations of the palladium-catalyzed direct C-arylation of
(12) (a) Catellani, M. Top. Organomet. Chem. 2005, 14, 21. (b) Tsuji, J.
Palladium Reagents and Catalysis-New PerspectiVes for the 21st Century; John Wiley
& Sons: New York, 2004; pp 409-416. (c) Catellani, M. Synlett 2003, 298. (d)
Catellani, M. In Handbook of Organopalladium Chemistry for Organic Synthesis;
Negishi, E.-I., de Meijere, A., Eds.; John Wiley & Sons: Hoboken, NJ, 2002; pp
1479-1489. (e) Catellani, M.; Mealli, C.; Motti, E.; Paoli, P.; Perez-Carreno, E.;
Pregosin, P. S. J. Am. Chem. Soc. 2002, 124, 4336. (f) Catellani, M.; Frignani, F.;
Rangoni, A. Angew. Chem., Int. Ed. Engl. 1997, 36, 119.
J. Org. Chem. Vol. 74, No. 3, 2009 1365

SCHEME 1. Proposed Pd(II)/Pd(IV) Species Involved in the
Catalytic Cycle
materials. We have explored the scope of tandem palladium-
catalyzed/norbornene-mediated sequential aromatic alkylation/
aryl-heteroaryl coupling reaction for construction of imidazo[5,1-
a]isoquinoline building blocks with a wide variety of biological
activities. The iodoarenes can be widely varied, which makes
the method extremely versatile for the preparation of these
structural motifs not easily accessible by conventional methods.
Further functionalization of the annulated products via bromi-
nation of imidazole ring at C-4 and subsequent cross-coupling
methodologies (Stille coupling and Suzuki coupling) are under
investigation.
SCHEME 2. Electrophilic Aromatic Substitution
Mechanism for Intramolecular Direct Arylation of the
Imidazole Ring
Experimental Section
General Procedure for the Annulation of Imidazoles. A vial
equipped with a stir bar was charged with aryl iodide (0.200 mmol,
1.0 equiv), tri-2-furylphosphine (0.044 mmol, 22 mol %), nor-
bornene (0.400 mmol, 2.0 equiv), Cs2CO3 (0.400 mmol, 2.0 equiv),
PdCl2 (0.020 mmol, 10 mol %), and bromoalkyl phenyl imidazole
(0.600 mmol, 3.0 equiv). Dry degassed CH3CN (0.1 M) was then
added, and the vial was capped and further degassed. The resulting
mixture was heated in an oil bath at 100 °C for 24 h, cooled, and
then filtered through a short plug of silica. Removal of the solvent
gave a crude mixture, which was purified by flash column
chromatography (hexane/EtOAc gradient).
10-Methyl-8-nitro-3-phenyl-5,6-dihydroimidazo[5,1-a]-iso-
quinoline (6). Following the general procedure for the annulation
of imidazoles, 5-nitro-2-iodotoluene 5 (53.0 mg, 0.200 mmol) and
bromoalkyl phenyl imidazole 4 (151.0 mg, 0.600 mmol) were
reacted at 100 °C for 24 h. The crude mixture was purified by flash
column chromatography on silica gel (EtOAc/hexane, 20%) to
afford 6 as a yellowish solid (46 mg, 76%): mp ) 215-217 °C;
1H NMR (300 MHz, CDCl3) δ 2.67 (s, 3H), 3.14 (t, J ) 6.3 Hz,
2H), 4.30 (t, J ) 6.3 Hz, 2H), 7.52 (m, 3H), 7.68 (m, 3H), 8.03 (s,
1H), 8.09 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 22.9, 30.9, 42.1,
121.2, 125.3, 128.2, 129.2, 129.3, 129.7, 130.1, 131.8, 133.4, 135.5,
145.5, 148.2; IR 1326, 1506, 2919, 3074 cm-1; MS m/z (%) 305
(M•+, 17%), 279 (25), 167 (58), 149 (100), 57 (88). Anal. Calcd
for C18H15N3O2: C, 70.81; H, 4.95; N, 13.76. Found: C, 70.99; H,
5.03; N, 13.88.
π-excessive heteroarenes have been reported in the literature.13
Recentstudiesindicatethattheconcertedmetalation-deprotonation
mechanism may be much more broadly implicated than previ-
ously supposed in Pd-catalyzed direct arylation reactions of
heteroarene substrates.14 However, there is also strong evidence
that most of the palladium-catalyzed arylation of π-excessive
heteroarenes occurs at the site most susceptible to electrophilic
attack.15 Therefore, in this case a mechanism involving an
electrophilic aromatic substitution followed by reductive elimi-
nation has to be considered as the most probable (Scheme 2).
In summary, we have developed a straightforward and
efficient one-step approach to highly functionalized six-
membered annulated imidazoles using readily accessible starting
Acknowledgment. We thank the Research Council of the
University of Tehran for financial support for this project
(27827/1/01).
(13) For recent reviews, see: (a) Roger, J.; Doucet, H. Org. Biomol. Chem.
2008, 6, 169. (b) Alberico, D.; Scott, M. E.; Lautens, M. Chem. ReV. 2007, 107,
174. (c) Fairlamb, I. J. S. Chem. Soc. ReV. 2007, 36, 1036. (d) Campeau, L.-C.;
Stuart, D. R.; Fagnou, K. Aldrichimica Acta 2007, 40, 35. (e) Satoh, T.; Miura,
M. Chem. Lett. 2007, 36, 200. (f) Godula, K.; Sames, D. Science 2006, 312, 67.
(14) Gorelsky, S. I.; Lapointe, D.; Fagnou, K. J. Am. Chem. Soc. 2008, 130,
10848.
(15) (a) Seregin, I. V.; Gevorgyan, V. Chem. Soc. ReV. 2007, 36, 1173. (b)
Chuprakov, S.; Chernyak, N.; Dudnik, A. S.; Gevorgyan, V. Org. Lett. 2007, 9,
2333. (c) Park, C.-H.; Ryabova, V.; Seregin, I. V.; Sromek, A. W.; Gevorgyan,
V. Org. Lett. 2004, 6, 1159. (d) Kondo, Y.; Komine, T.; Sakamoto, T. Org.
Lett. 2000, 2, 3111.
Supporting Information Available: Experimental proce-
dures and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO802584F
1366 J. Org. Chem. Vol. 74, No. 3, 2009