Acetic anhydride generated imidazolium ylide in ring closures onto carboxylic acids; Part of the synthesis of new potential bioreductive antitumor agents

Article abstract of DOI:10.1055/s-0030-1260543

Acetic anhydride behaves as a traceless activating agent allowing thermal intramolecular condensation of 2-(benzimidazol-1-ylmethyl) benzoic and nicotinic acids. Autoxidation gives benzimidazo[1,2-b]isoquinoline-6,11-diones (intermediates characterized) a

Full text of DOI:10.1055/s-0030-1260543

LETTER
1097
Acetic Anhydride Generated Imidazolium Ylide in Ring Closures onto
Carboxylic Acids; Part of the Synthesis of New Potential Bioreductive
Antitumor Agents
Imidazolium
Y
l
a
ide in Ring
m
Closures to Carbox
o
ylic
A
cids nn Joyce, Patrick McArdle, Fawaz Aldabbagh*
School of Chemistry, National University of Ireland Galway, University Road, Galway, Ireland
Fax +353(91)525700; E-mail: fawaz.aldabbagh@nuigalway.ie
Received 10 January 2011
thermally, possibly via the acetate counter ion (releasing
AcOH). The ylide and NHC are then primed for six-mem-
bered annulation, and the required aromatic diones 3 form
upon autoxidation of N-benzyl methylene intermediates.
Abstract: Acetic anhydride behaves as a traceless activating agent
allowing thermal intramolecular condensation of 2-(benzimidazol-
1-ylmethyl) benzoic and nicotinic acids. Autoxidation gives benz-
imidazo[1,2-b]isoquinoline-6,11-diones (intermediates character-
ized) and benzimidazo[2,1-g]-1,7-naphthyridine-5,12-diones in a The synthesis is part of ongoing research in our group to
screen bioreductive antitumor agents.9,10 The alicyclic
facile, one-pot transformation. The 1,4-dimethoxy analogue of the
former is converted into benzimidazo[1,2-b]isoquinoline-1,4,6,11-
ring-fused diones 3 and (benzimidazole)quinone deriva-
tetrone using cerium ammonium nitrate (CAN). The 1,7-naphthyri-
tives are expected to be bioactivated through reduction at
dine-5,12-dione system readily ring-opens, and an X-ray crystal
the para-dione moieties prior to a cellular cytotoxic re-
sponse.
structure of the methanol adduct was obtained.
Key words: benzimidazoles, condensation, heterocycles, quin-
ones, ylides
O
R
R
R
R
N
N
N
N
1,3-Dialkylated imidazolium salts are weakly acidic and
will readily form an imidazolium ylide species that is iso-
electronic with the imidazolin-2-ylidene (N-heterocyclic
carbene, NHC).1 The electron-rich (nucleophilic) nature
of the singlet NHC has led to its use in a wide-range of ap-
plications in transition-metal-catalyzed and organocata-
lyzed reactions (including benzoin condensation and acyl
transfer).2 Moreover, the reactive intermediates have been
used to trap electrophiles and to functionalize imidazoles
at the 2-position.3,4 In 1977, seminal work by Regel and
Büchel established substitution of ketone and ester func-
tionality onto the 2-position of imidazole (and benzimida-
zole) using imidazolium ylide species.5,6 These reactions
used various acid chlorides or chloroformic esters in the
presence of triethylamine in polar solvents. Some years
later, the protocol was used in the regioselective acylation
of the electron-deficient position of imidazopyridines us-
ing benzoyl chloride under thermal or triethylamine-
mediated conditions.7 Imidazole (and benzimidazole) re-
acted with phthaloyl dichlorides in the presence of trieth-
ylamine to give imidazo[1,2-b]isoquinolinediones,5,8 and
an ylide intermediate was proposed.5
OH
O
O
Ac2O
reflux
O
O
AcO
X
X
1 X = CH, N
R = H, OMe
2
O
O
R
R
R
N
N
N
O
O
O
O
O
N
O
– AcOH
R
X
X
ylide
NHC
R
R
N
N
O
[O]
– Ac2O
O
X
3
Scheme 1 Proposed mechanism for intramolecular condensation of
(benzimidazol-1-ylmethyl) benzoic and nicotinic acids
Considering these reported reactions, we have devised a
facile new method for annulation directly onto a carboxy-
lic acid using acetic anhydride (Ac2O) under reflux. Ac2O
is the solvent with a dual role of mediating the in situ for-
mation of the reactive intermediates and the derived
leaving group from carboxylic acid 1 (Scheme 1). Depro-
tonation at the 2-position of the imidazole of salt 2 occurs
Carboxylic acids 1a–d were prepared in two synthetic
steps: alkylation in the presence of NaH in N,N-dimethyl-
formamide (DMF), and base-mediated hydrolysis of the
methyl ester adducts, which proceeded in yields of 71–77
and 80–91%, respectively (Scheme 2). Benzimidazole
and 4,7-dimethoxybenzimidazole reacted with methyl 2-
(bromomethyl)benzoate (4) to form methyl esters 7a and
7c, respectively, which were hydrolyzed to give 2-(benz-
imidazol-1-ylmethyl)benzoic acids 1a and 1c. Methyl 2-
SYNLETT 2011, No. 8, pp 1097–1100
x
x.
x
x.
2
0
1
1
Advanced online publication: 20.04.2011
DOI: 10.1055/s-0030-1260543; Art ID: D00611ST
© Georg Thieme Verlag Stuttgart · New York

1098
E. Joyce et al.
LETTER
R
R
R
R
R
N
N
N
N
N
(ii)
(i)
OMe
OH
MeO
O
N
H
O
O
R
Cl / Br
X
X
X
7a: X = CH, R = H (75%)
7b: X = N, R = H (71%)
7c: X = CH, R = OMe (72%)
7d: X = N, R = OMe (77%)
1a (91%)
1b (87%)
1c (84%)
1d (80%)
4 (Br): X = CH
5 (Br): X = N (for 7b)
6 (Cl): X = N (for 7d)
Scheme 2 Preparation of carboxylic acids. Reagents and conditions: (i) NaH, DMF, then 4, 80 °C, 1 h for 7a and 7c; or 5, r.t., 18 h for 7b; or
6, 80 °C, 18 h for 7d; (ii) NaOH (0.8 M), MeOH, r.t., 18 h.
(bromomethyl)nicotinate (5) and methyl 2-(chlorometh- rified by chromatography to yield the unstable
yl)nicotinate (6) were used to respectively alkylate benz- autoxidation alcohol 8a (which slowly converted into 3c)
imidazole and 4,7-dimethoxybenzimidazole to give and acetate derivative 8b (Scheme 4).12 It was not possi-
methyl esters 7b and 7d, which were hydrolyzed to 2- ble to isolate and characterize the non-oxidized cyclized
(benzimidazol-1-ylmethyl)nicotinic acids 1b and 1d.
adduct by attempted exclusion of air. Purified intermedi-
ates 8a and 8b were combined with the derived residue,
and converted into the required dione 3c in 78% yield
(from 1c) upon further heating in air at 50 °C for 18 hours.
It should be noted that methyl esters 7a–d remained un-
changed when heated in acetic anhydride or acetic acid
under reflux for prolonged times, and no annulations were
observed when acetic anhydride was replaced by acetic
acid under reflux for 1a–d.
Annulations11 via the proposed reactive intermediates re-
quired heating carboxylic acids 1a–d in acetic anhydride
under reflux for 15 minutes. TLC (except for 1c) indicated
complete consumption of acids, and the generation of a
complex mixture of products. After overnight stirring in
Ac2O at room temperature, benzimidazo[1,2-b]isoquino-
line-6,11-dione (3a) was isolated in 80% yield, and benz-
imidazo[2,1-g]-1,7-naphthyridine-5,12-diones 3b and 3d
were isolated in 91 and 71% yield, respectively Cerium (IV) ammonium nitrate (CAN) was found to
(Scheme 3). The crude reaction mixture of 1c was evapo- readily convert 3c into the target tetrone 9 in 79% yield
rated after the initial reflux, and part of the residue was pu- (Scheme 4),13 although under the same conditions no isol-
able products were obtained from 3d. We presume that the
more reactive benzimidazo[2,1-g]-1,7-naphthyridine-
5,12-dione system was hydrolytically ring-opened during
R
N
N
O
(i) Ac2O, reflux, 15 min
(ii) Ac2O, r.t., air, 18 h
the attempted oxidations. This proposal was supported by
the isolation of the ring-opened adduct 10 in 92% yield
when 3d was stirred in methanol (Scheme 5). X-ray crys-
tallographic analysis confirmed the structure of 10
(Figure 1),14 with the site of opening analogous to that re-
ported for 3a.8 The dimethoxy-substituted compound 10
was then readily converted into the corresponding benz-
imidazolequinone 1115 in 86% yield using CAN.
1a, b, d
R
O
X
3a: X = CH, R = H (80%)
3b: X = N, R = H (91%)
3d: X = N, R = OMe (71%)
Scheme 3 Acetic anhydride mediated annulations
OMe
N
OMe
O
N
N
N
N
O
O
O
Ac2O, reflux, 15 min
no solvent, air
50 °C, 18 h
CAN (aq)
1c
MeCN, –5 °C, 5 min
N
OMe
OMe
O
RO
O
O
3c (78%)
9 (79%)
8a: R = H + 8b: R = Ac
Scheme 4 Isolation of annulation intermediates followed by formation of the target tetrone
O
OMe
O
O
N
N
O
O
N
N
(ii)
(i)
3d
OMe
OMe
N
H
N
H
O
OMe
10 (92%)
11 (86%)
Scheme 5 Ring-opening of benzimidazo[2,1-g]-1,7-naphthyridine-5,12-dione. Reagents and conditions: (i) MeOH, r.t. 18 h; (ii) CAN (aq),
MeCN, –5 °C, 5 min.
Synlett 2011, No. 8, 1097–1100 © Thieme Stuttgart · New York

LETTER
Imidazolium Ylide in Ring Closures to Carboxylic Acids
1099
Carty, M. P.; Aldabbagh, F. Eur. J. Med. Chem. 2010, 45,
3762.
(10) Fagan, V.; Bonham, S.; Carty, M. P.; Aldabbagh, F. Org.
Biomol. Chem. 2010, 8, 3149.
(11) General Procedure for Annulation: Carboxylic acid 1a–d
(0.79 mmol) in Ac2O (50 mL) was heated under reflux for 15
min. The mixture was stirred at r.t. for 18 h, and evaporated
to dryness for 3a, 3b and 3d. Ac2O was evaporated
immediately after the reflux, and the dry residue (sample
purified12) heated in air at 50 °C for 18 h for 3c. Residues
were purified by dry column vacuum chromatography10,16
using silica gel as absorbent with gradient elution of hexane,
EtOAc and MeOH as eluent
(12) 11-Hydroxy-1,4-dimethoxybenzimidazo[1,2-b]-
isoquinolin-6 (11H)-one (8a): Yellow solid; Rf = 0.63
(EtOAc–MeOH, 9:1); mp 197–200 °C (dec.); IR (neat):
2927, 1676 (C=O), 1601, 1525, 1502, 1431, 1340, 1282,
1257, 1226, 1178, 1158, 1108, 1037 cm–1; 1H NMR (400
MHz, CDCl3): d = 8.37 (d, J = 8.0 Hz, 1 H), 7.82–7.75 (m,
2 H, 8,9-H), 7.63–7.60 (m, 1 H), 7.09 (s, 1 H, 11-H), 6.81 (d,
J = 8.6 Hz, 1 H, 2,3-H), 6.62 (d, J = 8.6 Hz, 1 H, 2,3-H),
5.44 (br. s, 1 H, OH, disappears with D2O), 4.11 (s, 3 H,
CH3), 3.98 (s, 3 H, CH3); 13C NMR (100 MHz, CDCl3): d =
174.1 (C=O), 148.3, 141.8, 140.0, 138.0, 136.3 (all C), 134.4
(8,9-CH), 130.3 (C), 130.0 (CH), 128.7 (8,9-CH), 127.5
(CH), 125.1 (C), 106.6 (2,3-CH), 103.8 (2,3-CH), 76.8 (11-
CH), 56.7 (CH3), 56.3 (CH3); HRMS (ESI): m/z calcd for
C17H15N2O4: 311.1032; found: 311.1018 [M + H]+.
1,4-Dimethoxy-6-oxo-6,11-dihydrobenzimidazo[1,2-
b]isoquinolin-11-yl acetate (8b): Yellow solid; Rf = 0.56
(EtOAc); mp 171–174 °C (dec.); IR (neat): 2922, 2847,
1746 (C=O), 1679 (C=O), 1599, 1527, 1506, 1455, 1418,
1367, 1354, 1290, 1263, 1204, 1180, 1108, 1079, 1009 cm–
1; 1H NMR (400 MHz, CDCl3): d = 8.43 (s, 1 H, 11-H), 8.36
(dd, J = 7.8, 1.4 Hz, 1 H), 7.93 (d, J = 7.7 Hz, 1 H), 7.74–
7.71 (m, 1 H, 8,9-H), 7.66–7.63 (m, 1 H, 8,9-H), 6.76 (d,
J = 8.6 Hz, 1 H, 2,3-H), 6.65 (d, J = 8.6 Hz, 1 H, 2,3-H),
4.01 (s, 3 H, CH3), 3.91 (s, 3 H, CH3), 2.01 (s, 3 H,
COOCH3); 13C NMR (100 MHz, CDCl3): d = 174.1 (C=O),
169.9 (C=O), 147.8, 143.2, 141.6, 136.6, 136.1 (all C), 134.7
(8,9-CH), 130.8 (C), 130.6 (8,9-CH), 128.9 (CH), 127.8
(CH), 124.9 (C), 106.9 (2,3-CH), 104.4 (2,3-CH), 76.0 (11-
CH), 56.4 (CH3), 55.9 (CH3), 21.2 (COOCH3); HRMS
(ESI): m/z calcd for C19H17N2O5: 353.1137; found: 353.1124
[M + H]+.
Figure 1 X-ray crystal structure of 10
In conclusion, a facile protocol for the formation of benz-
imidazo[1,2-b]isoquinoline-6,11-diones, and benzimida-
zo[2,1-g]-1,7-naphthyridine-5,12-diones from carboxylic
acids using only Ac2O, and studies on the transformation
of adducts into quinones have been carried out. Com-
pounds 3a–d, 9 and 11 are currently undergoing cyclic
voltammetry and antitumor evaluation.9,10
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett. Included are
a detailed experimental section and NMR spectra.
Acknowledgment
The authors thank the Irish Research Council for Science Enginee-
ring and Technology: funded by the National Development Plan for
an Embark Scholar Award for E.J.
References and Notes
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(13) Benzimidazo[1,2-b]isoquinoline-1,4,6,11-tetrone (9):
CAN (0.296 g, 0.54 mmol) in H2O (5 mL) was added to 3c
(83 mg, 0.27 mmol) in MeCN (20 mL) at –5 °C. After 5 min,
H2O (20 mL) was added and the product was extracted with
CH2Cl2 (30 mL). The organic extract was evaporated to
dryness and the residue was recrystallized from CHCl3.
Yield: 60 mg (79%); brown solid; mp 203–205 °C (dec.); IR
(neat): 1752 (C=O), 1684 (C=O), 1671 (C=O), 1583, 1515,
1494, 1396, 1358, 1287, 1259, 1239, 1189, 1062 cm–1; 1H
NMR (400 MHz, DMSO-d6): d = 8.32–8.30 (m, 1 H), 8.22–
8.20 (m, 1 H), 8.01–7.99 (m, 2 H, 8,9-H), 6.98 [d (AB-q),
J = 10.3 Hz, 1 H, 2,3-H], 6.93 [d (AB-q), J = 10.3 Hz, 1 H,
2,3-H]; 13C NMR (100 MHz, DMSO-d6): d = 181.3, 175.6,
173.7, 157.2 (all C=O), 146.6 (C), 143.4 (C), 139.1 (2,3-
CH), 136.0 (8,9-CH), 135.9 (8,9-CH), 135.8 (2,3-CH),
132.8, 131.0, 130.3 (all C), 130.1 (CH), 127.4 (CH); HRMS
(ESI): m/z calcd for C15H7N2O4: 279.0406; found: 279.0400
[M + H]+.
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(14) CCDC 805313 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data _request/cif, or by emailing
data_request@ccdc.cam.ac.uk or by contacting The
Synlett 2011, No. 8, 1097–1100 © Thieme Stuttgart · New York

1100
E. Joyce et al.
LETTER
Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB2 1EZ, UK; fax: +44 (1223)336033
1 H, Pyr-4-H), 7.86–7.83 (m, 1 H, Pyr-5-H), 6.78 (s, 2 H,
BnIm-5,6-H), 3.75 (s, 3 H, CH3), NH not observed; 13
C
(15) Methyl 3-[(4,7-Dioxo-4,7-dihydro-1H-benzimidazol-2-
yl)carbonyl]pyridine-2-carboxylate (11): Synthesis as
described previously13 with the residue recrystallized using
EtOAc and hexane. Yield: 72 mg (86%); brown solid; mp
109–111 °C; IR (neat): 3408, 1671 (C=O), 1623 (C=O),
1436, 1290, 1062, 1037 cm–1; 1H NMR (400 MHz, CD3OD):
d = 8.83 (d, J = 3.6 Hz, 1 H, Pyr-6-H), 8.22 (d, J = 7.5 Hz,
NMR (100 MHz, CD3OD): d = 184.1, 179.5 (×2), 165.3 (all
C=O), 150.6 (Pyr-6-CH), 148.2 (C), 146.4 (C), 138.3 (Pyr-
4-CH), 137.3 (2 × C), 137.0 (BnIm-5,6-CH), 135.4 (C),
127.2 (Pyr-5-CH), 52.5 (CH3); HRMS (ESI): m/z calcd for
C15H10N3O5: 312.0620; found: 312.0630 [M + H]+.
(16) (a) Harwood, L. M. Aldrichimica Acta 1985, 18, 25.
(b) Pedersen, D. S.; Rosenbohm, C. Synthesis 2001, 2431.
Synlett 2011, No. 8, 1097–1100 © Thieme Stuttgart · New York

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