Microwave-mediated heterocyclization to benzimidazo[2,1-b]quinazolin-12(5H) -ones

Article abstract of DOI:10.1021/jo0618066

An effective route to benzimidazo[2,1-b]quinazolin-12(5H)-ones from commercially available o-aryl isothiocyanate esters and o-phenylenediamines is reported. This method accommodates a variety of substituents on either starting material and proceeds under microwave irradiation in the presence of barium hydroxide, conditions that do not hydrolyze methyl ester substituents. The pharmacologically pertinent benzimidazoquinazolinone heterocycle is delivered in excellent yield and purity via both solution- and solid-phase protocols, the latter involving traceless release from the resin.

Full text of DOI:10.1021/jo0618066

SCHEME 1. Initial Experimental Efforts toward
Benzimidazoquinazolinones
Microwave-Mediated Heterocyclization to
Benzimidazo[2,1-b]quinazolin-12(5H)-ones
Richard D. Carpenter,† Kit S. Lam,‡ and Mark J. Kurth†*
Department of Chemistry, UniVersity of California, DaVis, One
Shields AVe., DaVis, California 95616, and DiVision of
Hematology and Oncology, UC DaVis Cancer Center,
UniVersity of California, DaVis, California
mjkurth@ucdaVis.edu
ReceiVed August 31, 2006
number of examples of µW-mediated heterocyclization,6 and
our reports of carbanilide cyclization employing a barium
hydroxide catalyst7 as well as a thiourea to guanidine cyclization
utilizing 1,3-diisopropylcarbodiimide (DIC)8 are part of this
literature. Herein, we report a simple and efficient two-step
protocol that delivers benzimidazoquinazolinones in good to
excellent yields from aryl isothiocyanate esters. This method
has been elaborated to accommodate both solution- and solid-
phase methods wherein the last step employs µW irradiation
together with stoichiometric barium hydroxide.
In earlier work, we reported a mild, one-pot synthesis of N-2-
arylaminobenzimidazoles from aryl isothiocyanate esters.9 As
shown in Scheme 1, treating aryl isothiocyanate with o-
phenylenediamine forms an intermediate thiourea and subse-
quent heterocyclization with DIC delivers the benzimidazole
ester. When the isothiocyanate derived from methyl anthranilate
was employed in this one-pot procedure, the expected benz-
imidazole derivative was obtained in 70% yield and the further
cyclized benzimidazoquinazolinone 2a was obtained in a 30%
yield. Moveover, attempts to saponify methyl ester 1 to the
corresponding acid 3 using 5 equiv of LiOH produced a yellow
precipitate that proved to be benzimidazoquinazolinone 2a (55%
yield); none of the benzimidazole acid 3 was detected.
An effective route to benzimidazo[2,1-b]quinazolin-12(5H)-
ones from commercially available o-aryl isothiocyanate esters
and o-phenylenediamines is reported. This method accom-
modates a variety of substituents on either starting material
and proceeds under microwave irradiation in the presence
of barium hydroxide, conditions that do not hydrolyze methyl
ester substituents. The pharmacologically pertinent benzimi-
dazoquinazolinone heterocycle is delivered in excellent yield
and purity via both solution- and solid-phase protocols, the
latter involving traceless release from the resin.
Benzimidazo[2,1-b]quinazoline-12(5H)-ones are potent im-
munosuppressors in doses as low as 0.1 mg/kg.1 This class of
compounds has also recently been found to present promising
antitumor activity with the benzimidazole and quinazolinone
moieties serving to intercalate DNA, thereby effectively truncat-
ing proliferation of human tumor cell lines.2 Nearly all existing
synthetic routes to this medicinally pertinent heterocycle involve
prolonged heating of precursors such as 1 (see Scheme 1), often
times resulting in low yield as a result of thermal decomposition.
The pioneering work of Giguere and Gedye,3 coupled with the
increased prevalence of microwave (µW) applications in organic
synthesis,4 has allowed for reaction acceleration while minimiz-
ing decomposition.4,5 Indeed, the literature cites an increasing
This result with 1 in the formation of 2a was surprising in
light of Lunn and Harper’s reported saponification of the methyl
ester derived from the corresponding naphthalothiazole sytem
where the carboxylic acid was isolated and characterized.11
(4) For recent reviews, see: (a) Mingos, D. M. P.; Baghurst, D. R. Chem.
Soc. ReV. 1991, 20, 1. (b) Caddick, S. Tetrahedron 1995, 51, 10403. (c)
Bram, G.; Galons, H.; Labidalle, S.; Loupy, A.; Miocque, M.; Petit, A.;
Pigeon, P.; Sansoulet, J. Bull. Soc. Chim. Fr. 1989, 247. (d) Strauss, C. R.;
Trainor, R. W. Aust. J. Chem. 1995, 48, 1665. (e) Majetich, G.; Hicks, R.
Radiat. Phys. Chem. 1995, 45, 567. (f) Galema, S. A. Chem. Soc. ReV.
1997, 26, 233. (g) Bose, A. K.; Banik, B. K.; Lavlinskaia, N.; Jayaraman,
M.; Manhas, M. S. CHEMTECH 1997, 27, 18.
(5) Cablewski, T.; Faux, A. F.; Strauss, C. R. J. Org. Chem. 1994, 59,
3408.
(6) Majetich, G.; Wheless, K. In MicrowaVe-Enhanced Chemistry;
Kinsington, H, M., Haswell, S. J., Eds.; American Chemical Society:
Washington, DC, 1997; pp 455-505.
(7) (a) Gong, Y.-D.; Kurth, M. J. Tetrahedron Lett. 1998, 39, 3379. (b)
Gong, Y.-D.; Sohn, H.-Y.; Kurth, M. J. J. Org. Chem. 1998, 63, 4854.
(8) Wang, X.; Dixon, S. M.; Yao, N.; Kurth, M. J.; Lam, K. S.
Tetrahedron Lett. 2005, 46, 5747.
* To whom correspondence should be addressed. Tel: (530) 752-8192.
FAX: (530) 752-8995.
† Department of Chemistry.
‡ UC Davis Cancer Center.
(1) Lunn, W. H. W.; Harper, R. W.; Stone, R. L. J. Med. Chem. 1971,
14, 1069-1071.
(2) Dalla Via, L.; Gia, O.; Marciani Magno, S.; Da Settimo, A.; Marini,
A. M.; Primofiore, G.; Da Settimo, F.; Salerno, S. Il Farmaco 2001, 56,
159.
(3) (a) Giguere, R. J.; Bray, T. L.; Duncan, S. M.; Majetich, G.
Tetrahedron Lett. 1986, 27, 4945. (b) Gedye, R.; Smith, F.; Westaway, K.;
Ali, H.; Baldisera, L.; Laberge, L.; Rousell, J. Tetrahedron Lett. 1986, 27,
279.
(9) Carpenter, R. D.; Deberdt, P. B.; Lam, K. S.; Kurth, M. J. J. Comb.
Chem. 2006, in press.
(10) Perkins, J. J.; Zartman, A. E.; Meissner, R. S. Tetrahedron Lett.
1999, 40, 1103.
10.1021/jo0618066 CCC: $37.00 © 2007 American Chemical Society
Published on Web 12/07/2006
284
J. Org. Chem. 2007, 72, 284-287

SCHEME 2. Known Routes to
Benzimidazo[2,1-b]quinazoline-12(5H)-one (2a)
FIGURE 1. Regioselectivity in 1 f 2 and the tautomeric options for
2.
SCHEME 4. Solution-Phase Synthesis of
Benzimidazoquinazolinones 2a-k
SCHEME 3. Optimization Variables of Reaction
Conditionsa
demands, provide the impetus for the general and high yielding
route to benzimidazoquinazolinones reported here.
Subsequent in situ acid chloride formation in their work followed
by heterocyclization upon heating delivered the napthalothia-
zoloquinazolinone.11
To optimize the quinazoline-forming step, we investigated
the various parameters detailed in Scheme 3 employing test
tubes as reaction vessels. Each test tube was charged with either
acid or base in catalytic or stoichiometric quantities together
with various solvents. Although all reactions were monitored
by TLC, we also noted that successful reactions generated a
yellow precipitate that provided a colorimetric indication of
success. The best reaction conditions involved heating a dioxane
solution of 1 plus Ba(OH)2 to 160 °C under µW irradiation for
26 min, delivering 2a in 96% yield.
As delineated in Schemes 4 and 5, we established the utility
of this method by preparing benzimidazoquinazolinones 2a-k
under these optimal conditions with substrates that featured
substituents with various electron-donating/-withdrawing prop-
erties in both solution and solid phases. Briefly, Scheme 4 shows
the thiophosgenation of aniline esters to deliver aryl isothiocy-
anate esters 4-6 in 88-93% yield. These aryl isothiocyanates
were then reacted with o-phenylenediamines, followed by
tandem DIC-mediated benzimidazole cyclization and µW-
mediated benzimidazoquinazolinone cyclization with barium
hydroxide to deliver derivatives 2a-k in 91-98% overall yield
from the starting aryl isothiocyanate. To our surprise, these
cyclization conditions were mild enough that saponification of
the substituent methyl esters were not observed (e.g., 5/6 to
2h-k).
Scheme 2 outlines the most common approaches to benzim-
dazoquinazolinone 2a. Review of this literature suggests that
none of these methods can accommodate a full spectrum of
substituents, both electron-donating and -withdrawing, in both
reacting partners.11 Bird’s thermal rearrangement of 3-oxo-2-
phenyl-2,3-dihydro-1H-indazole-1-carbonitrile at 270 °C (Method
1)12 gives 2a in 40% yield. Method 2 illustrates that treatment
of 2-aminobenzimidazole with either o-bromobenzoic acid under
copper-mediated Ullman conditions (170 °C)2 or Popov’s route13
involving o-chlorobenzoyl chloride, which delivers 2a in
moderate yield. Method 314 highlights the attack of isatoic
anhydride by o-phenylenediamine in refluxing acetic acid to
afford 2a in 85% yield together with an aryl benzimidazole
byproduct. Finally, refluxing a leaving-group-adorned (R ) Cl,
SCH3, SO3H; Method 411,15) benzimidazole with either the
hydrochloride salt of anthranoyl chloride or zwitterionic an-
thraniloate provides 2a, but yields are not reported. The
relatively uncommon synthetic precursors of some of these
methods, in addition to their electronic and temperature
(11) Lunn, W. H. W.; Harper, R. W. J. Heterocycl. Chem. 1971, 8, 141-
147.
(12) (a) Bird, C. W. Tetrahedron 1965, 21, 2179. (b) Bird, C. W.; Kapilli,
M. Tetrahedron 1987, 43, 4621.
(13) Popov, I. I.; Boroshko, S. L.; Tertov, B. A.; Tyukavina, E. V. Khim.
Geterotsikl. Sodein. 1989, 2, 272.
(14) Fadda, A. A.; Refat, H. M.; Zaki, M. E. A.; Monir, E. Synth.
Commun. 2001, 31, 3537.
It is noteworthy that all of the 2-(1H-benzo[d]imidazol-2-
ylamino)benzoates (1; Figure 1) investigated cyclize to benz-
imizoquinazolinones 2 with complete regioselectivity relative
to the R2 substituent. Whereas the imidazol-2-ylamino moiety
(15) Popov, I. I.; Boroshko, S. L.; Tertov, B. A. U.S.S.R. Patent SU
1182043, 1985; 19830412, 1985.
J. Org. Chem, Vol. 72, No. 1, 2007 285

SCHEME 5. Solid-Phase Synthesis of Benzimizoquinazolinones 2a-h
with substituents in the R2 position exists in tautomeric
equilibrium, the deprotonated intermediate cyclizes through the
meta nitrogen when R2 is electron-withdrawing (e.g., R2 ) CO2-
CH3 at C9) and through the para nitrogen when R2 is electron-
donating (R2 ) OCH3, CH3, Cl, and Br at C8). These R2
placements derive from comparative melting point analyses with
authentic and unambiguous 2e, 2f, and 2g.12b Also, although
these benzimidazoquinazolinones can potentially exist in three
tautomeric forms (see Figure 1), the 1H and 13C NMR data are
consistent with one compound on the NMR time scale.
Furthermore, the phenolic and the N6NH tautomers can be ruled
out as the predominant structures based upon (i) IR data that
show a relatively sharp N-H band (∼3300 cm-1) and a strong
amide carbonyl band (∼1680 cm-1); (ii) an amide carbonyl
carbon (∼160 ppm) in the 13C NMR; and (iii) extensive IR and
UV-vis studies by Lunn and Harper that suggest that the N-H
should be placed at N5 rather than at N6.11
For the solid-phase route shown in Scheme 5, (4-hydroxy-
butyl)polystyrene resin was first swollen in DMF and then
esterified with o-nitrobenzoic acid derivatives under HBTU/
DIEA conditions. Subsequent tin(II) chloride dihydrate reduction
of the aryl nitro group followed by thiophosgenation of the
resulting amine delivers the aryl isothiocyanate resins 7 and 8.
These aryl isothiocyanate resins were split into different flasks
and treated with o-phenylenediamines to give the intermediate
thioureas. DIC promoted thiourea to benzimidazole cyclization
followed by barium hydroxide/µW-mediated benzimidazo-
quinazolinone cyclization and concomitant resin release deliv-
ered 2a-h in 85-93% overall yield from the starting 4-hy-
droxybutyl resin. As in the solution phase work, these solid-
phase reaction conditions do not hydrolyze esters. This
cycloelimination strategy delivered benzimidazoquinazolinones
2a-h in g95% purity as determined by LCMS analysis.
The mild, one-pot cyclization effecting aryl isothiocyanate
ester f benzimidazole ester and subsequent benzimidazole ester
f benzimidazoquinazolinone µW-mediated cyclization delivers
the pharmaceutically relevant heterocycle 2 in high yield and
purity under either solution- or solid-phase conditions. This
generalized method accommodates various substituents and does
not result in the hydrolysis of alkyl esters. With the assistance
of µW irradiation, the heating time required for the final
heterocyclization step is compatible with a resin-supported
protocol.
treated dropwise with a solution of triethylamine (60.1 mmol, 8.37
mL) in ethyl acetate (80 mL) over 30 min. After 10 min of vigorous
stirring, a solution of the appropriate anthranilate (e.g., methyl
anthranilate; 4.12 g, 27.3 mmol) in ethyl acetate (80 mL) was added
over 30 min, followed by stirring at room temperature for 12 h.
Workup consisted of dilution with ethyl acetate followed by
washing sequentially with water (200 mL × 2) and brine (200 mL).
The organic layer was dried (MgSO4) and concentrated, and the
crude product was purified via short path column chromatography
(hexanes/ethyl acetate, 9:1) to give the aryl isothiocyanate (e.g., 4;
4.79 g, 91% yield, the analytical data are in accord with literature
values).16
General Procedure for Aryl Isothiocyanate Ester Resins. (4-
Hydroxybutyl)polystyrene o-isothiocyanatobenzoate (7). (4-
Hydroxybutyl)polystyrene resin (1 g, 3.5 mmol) was swollen in
DMF (30 mL) for 16 h, followed by the coupling of the appropriate
o-nitrobenzoic acid (e.g., o-nitrobenzoic acid; 2.92 g, 17.5 mmol)
with 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexaflu-
orophosphate (HBTU; 6.64 g, 17.5 mmol) and DIEA (17.5 mmol,
3.09 mL) for 8 h. After filtration and washing, this aryl nitro resin
was reduced with SnCl2‚2H2O (23.7 g, 105 mmol) in DMF (30
mL) for 4 h. Following filtration, washing, and a positive chloranil
test,17 this aniline resin was slowly treated with a solution of
thiophosgene (10.5 mmol, 804 µL) and Et3N (23.0 mmol, 3.20 mL)
in EtOAc (30 mL). After 16 h, the resin was filtered, washed, and
vacuum dried to give the aryl isothiocyanate resin [7, IR (neat)
2125, 1740, 688 cm-1].
General Procedure for Solution-Phase Benzimidazoquinazoli-
nones. Benzimidazo[2,1-b]quinazoline-12(5H)-one (2a). To a
solution of an appropriate diamine (e.g., o-phenylenediamine; 176
mg, 1.63 mmol) in CH2Cl2 (8 mL) was added an appropriate aryl
isothiocyanate ester (e.g., 4; 300 mg, 1.55 mmol) in CH2Cl2 (8
mL) dropwise over 30 min. After 16 h, DIC (4.65 mmol, 691 µL)
was added, and the reaction was monitored by TLC. In most
instances, the reaction was completed in 10 h, although the reaction
times ranged between 6 and 18 h. Following completion, the solvent
was removed by concentration, and subsequent recrystallization with
CHCl3/petroleum ether afforded a mixture of the benzimidazole
ester (e.g., 1; 70%) and the benzimidazoquinazoline (e.g., 2a; 30%).
This mixture (480 mg) was dissolved in dioxane and transferred to
a 5 mL round-bottom microwave vial. Barium hydroxide octahy-
drate (2.57 g, 8.15 mmol) was added, followed by sealing of the
vessel and heating to 160 °C for 26 min in a microwave reactor
(Personal Chemistry, Emrys Optimizer). The reaction temperature
increased from 25 to 160 °C in 155 s and was maintained at 160
°C for the duration. The bright yellow precipitate was filtered and
washed with aqueous NH4Cl, H2O, dioxane, CH2Cl2, and EtOAc
to afford 2 (e.g., 2a; 350 mg, 96% yield, the analytical data are in
accord with literature values).14
Experimental
General Procedure for Aryl Isothiocyanate Esters. Methyl
2-Isocyanatobenzoate (4). A solution of thiophosgene (30.0 mmol,
2.30 mL) in ethyl acetate (130 mL) was cooled to -78 °C and
(16) Ivachtenko, A.; Kovalenko, S.; Tkachenko, O. V.; Parkhomenko,
O. J. Comb. Chem. 2004, 6, 573.
(17) Marik, J.; Song, A.; Lam, K. S. Tetrahedron Lett. 2003, 44, 4319.
286 J. Org. Chem., Vol. 72, No. 1, 2007

General Procedure for Solid-Phase Benzimidazoquinazoli-
nones. 8-Bromobenzimidazo[2,1-b]quinazoline-12(5H)-one (2b).
Aryl isothiocyanate resin 7 (1.0 g, 3.5 mmol) was equally divided
into two flasks, and each flask received an appropriate o-
phenylenediamine (4-bromo-o-phenylenediamine; 982 mg, 5.25
mmol) and was allowed to react for 16 h. DIC (5.25 mmol, 779
µL) was then added, and the reaction was shaken for an additional
16 h. The resulting benzimidazole resin was transferred to a 5 mL
microwave vial to which was added barium hydroxide octahydrate
(2.77 g, 8.75 mmol) in DMF (3 mL). The vessel was sealed and
heated to 160 °C for 26 min in a microwave reactor (Personal
Chemistry, Emrys Optimizer). The reaction temperature increased
from 25 to 160 °C in 155 s and was maintained at 160 °C for the
remaining heating period, at which point the resin was filtered and
washed with warm DMF. The filtrate was diluted with 0.5 M NH4-
Cl (15 mL) and extracted with EtOAc (2 × 10 mL). The combined
organic layers were washed with water (3 × 20 mL) and brine (1
× 10 mL) followed by drying (MgSO4) and concentration to afford
2 (e.g., 2b; 505 mg, 92%) as a yellow solid: mp 368-369 °C; IR
J ) 1.5 Hz, J ) 6.3 Hz); 13C NMR (75 MHz, DMSO-d6) δ 159.9,
155.2, 151.0, 145.4, 134.6, 128.3, 127.9, 127.2, 124.1, 116.5, 114.6,
114.4, 113.9, 107.7; ESI MS m/z 314, 316 (M + H)+. Anal. Calcd
for C14H8BrN3O: C, 53.53; H, 2.57; N, 13.38. Found: C, 53.39;
H, 2.56; N, 13.35. Purity of the crude product was determined to
be 97% by HPLC analysis on the basis of absorption at 220 nm.
Acknowledgment. R.D.C. would like to thank Professor
Makhluf Haddadin for stimulating discussions of heterocyclic
chemistry. The authors also thank the National Cancer Institute
(U19CA113298), the National Institute for General Medical
Sciences (RO1-GM076151), and the National Science Founda-
tion (CHE-0614756) for their generous support of this research.
The National Science Foundation (CHE-0443516 and CHE-
9808183) also supported the NMR spectrophotometers that were
used to obtain analytical data.
Supporting Information Available: Experimental procedures
as well as NMR spectra for aryl isothiocyanates (5, 6, and 8) and
benzimidazoquinazolinones (2c-j). This material is available free
of charge via the Internet at http://pubs.acs.org.
1
(neat) 3331 (sh), 1685, 1050 cm-1; H NMR (300 MHz, DMSO-
d6) δ 8.34 (d, 1H, J ) 6.3 Hz), 8.23 (dd, 1H, J ) 1.0 Hz, J ) 5.1
Hz), 7.63-7.58 (m, 1H), 7.56 (d, 1H, J ) 1.2 Hz), 7.50 (dd, 1H,
J ) 2.1 Hz, J ) 6.3 Hz), 7.35 (d, 1H, J ) 6.3 Hz), 7.18 (dd, 1H,
JO0618066
J. Org. Chem, Vol. 72, No. 1, 2007 287