Access to aromatic ring-fused benzimidazoles using photochemical substitutions of the benzimidazol-2-yl radical

Article abstract of DOI:10.1055/s-0032-1316775

Photochemical five-, six-, and seven-membered cyclizations from 2-iodo-1-(ω-arylalkyl)-1H-benzimidazoles are described. This method of producing aromatic ring-fused benzimidazoles is significantly more efficient than literature radical protocols using chemical initiators, although 2-iodo-1-(ω-pyridin-2-ylalkyl)-1H-benzimidazoles preferentially undergo a nucleophilic ipso-substitution onto the benzimidazole-2-position.

Full text of DOI:10.1055/s-0032-1316775

PAPER
▌3371
paper
Access to Aromatic Ring-Fused Benzimidazoles Using Photochemical
Substitutions of the Benzimidazol-2-yl Radical
Synthesis of Aromatic Ring-Fused Benzimidazoles
Joanne M. O’Connell, Eoin Moriarty, Fawaz Aldabbagh*
School of Chemistry, National University of Ireland Galway, University Road, Galway, Ireland
Fax +353(91)495576; E-mail: Fawaz.Aldabbagh@nuigalway.ie
Received: 26.07.2012; Accepted after revision: 20.08.2012
a][2]benzazepine in 70 and 48% yield respectively.6 The
present article details the photochemical conditions re-
quired in order to achieve optimized five-, six-, and seven-
membered homolytic aromatic substitutions of the benz-
Abstract: Photochemical five-, six-, and seven-membered cycliza-
tions from 2-iodo-1-(ω-arylalkyl)-1H-benzimidazoles are de-
scribed. This method of producing aromatic ring-fused
benzimidazoles is significantly more efficient than literature radical
protocols using chemical initiators, although 2-iodo-1-(ω-pyridin- imidazol-2-yl radical. Scheme 1 shows the greater yields
2-ylalkyl)-1H-benzimidazoles preferentially undergo a nucleophil-
ic ipso-substitution onto the benzimidazole-2-position.
of annulation product now achieved in comparison to the
literature radical method. Further advantages of our proto-
Key words: cyclization, diazoles, heterocycles, nucleophilic aro-
matic substitution, radical reaction
col include the use of more accessible radical (iodo) pre-
cursors and the reaction proceeds in the absence of
hazardous chemical initiators, thus eliminating separation
and waste-disposal issues. New examples of this photo-
Trialkylmetal hydrides (usually Bu3SnH) with an azo- chemical substitution are now described, as well as, limi-
initiator (usually 2,2-azobisisobutyronitrile, AIBN) has tations in extending the UV-mediated annulation to a
become a standard reagent combination for homolytic diverse range of heterocyclic radical precursors.
aromatic substitution.1 Nowadays where a hydrogen atom
is substituted, a nonchain mechanism is accepted. This
typically requires excess amounts of azo-initiator, and/or
Bowman & co-workers
Bu3SnH,
oxygen to give the ‘oxidized’ aromatic substitution prod-
Bu3GeH,
N
N
N
N
or TTMSS
AIBN
uct in the presence of full equivalents of the ‘reductant’
Bu3SnH.2–13 Other disadvantages of this inherently ineffi-
cient reaction include the requirement for slow syringe
pump addition of initiators, and the separation, then dis-
posal of toxic organotin waste. Bowman and co-workers
reported intramolecular five and six-membered aryl radi-
cal displacements of phenylsulfanyl groups at the benz-
imidazole-2-position to give aryl ring-fused adducts
(Scheme 1).14 However, reported yields were low for the
five-membered (20%), and variable for the six-membered
cyclizations (44–71%) using a range of group 14 hy-
drides, including Bu3SnH, and the weaker, but expensive
reductants (Me3Si)3SiH (TTMSS), and Bu3GeH with
AIBN. The main product for the more difficult five-mem-
bered cyclizations was due to aryl radical reduction,
which interestingly occurs via a straight forward radical
chain pathway. Alternatively nonradical palladium-cata-
lyzed cyclizations from aryl or imidazole halides to give
aryl ring-fused diazoles in higher yields have been report-
S
X
COOZ
n
n
2a: n = 1 (20%)
2b: n = 2 (44–71%)
X = Br, I
Z = Me, Wang resin
This paper (optimized conditions)
N
N
hυ
(see Table 2)
I
– HI
N
N
n
n
2a: n = 1 (50%)
2b: n = 2 (80%)
2c: n = 3 (85%)
1a–c
Scheme 1 Summary of radical routes to aryl ring-fused benzimid-
azoles
ed.15,16 However, we were interested in accomplishing 2-Iodo-1-(ω-phenyl and 1-naphthylalkyl)-1H-benzimid-
these annulations without metal catalysts or chemical ini- azole photochemical reaction precursors 1a–d were pre-
tiators given that our group had previously reported UV- pared in good yields by reaction of 2-iodo-1H-
mediated six- and seven-membered cyclizations from 2- benzimidazole with various aromatic alkyl bromides in
iodo-1-(2-phenylethyl)-1H-imidazole and 2-iodo-1-(3- the presence of NaH in THF (Table 1). However, this
phenylpropyl)-1H-imidazole to give 5,6-dihydroimid- method could not be used in the preparation of 2-iodo-1-
azo[2,1-a]isoquinoline and 6,7-dihydro-5H-imidazo[2,1- [2-(2-thienyl)ethyl]-1H-benzimidazole (1e), and t-BuOK
in DMF17 was used with the appropriate mesylate 3 (Table
1).
SYNTHESIS 2012, 44, 3371–3377
Advanced online publication: 31.08.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1316775; Art ID: SS-2012-T0615-OP
© Georg Thieme Verlag Stuttgart · New York

3372
J. M. O’Connell et al.
PAPER
weakly basic solutions that were claimed to prevent pyri-
dinium salts from being deposited.18 We thus decided to
investigate the effect of the addition of 0.05 M Na2CO3
(9.5% v/v, Method B), where it was assumed that the add-
ed base neutralizes HI. The weakly basic solution was
successful in eliminating all traces of reduction in the six-
and seven-membered cyclizations from 1b and 1c (entries
5 and 7), which now proceeded to give 2b and 2c in 80 and
85% yield, although the presumably constrained5–7,14,19
five-membered cyclization from 1a remained unsuccess-
ful (entry 2). The marginally higher yields for the seven-
membered cyclizations are probably due to better product
recovery after purification by column chromatography,
although all entries in Table 2 reflect qualitative observa-
tions of reaction mixtures before purification by 1H NMR
spectroscopy (and TLC). Since there is no HI generation
in the attempted five-membered cyclizations (entries 1
and 2), the only alternative hydrogen donor is the solvent
MeCN giving 1-benzyl-1H-benzimidazole (4a) in yields
of 80–85%. Further literature attempts to form 11H-isoin-
dolo[2,1-a]benzimidazole (2a) using radical cyclizations
of the phenyl radical onto the benzimidazole-2-position
were either reported as low yielding (20% in Scheme 1)14
or failed when using solutions of 1-(2-iodobenzyl)-1H-
benzimidazole at 254 nm in MeCN.20 Subsequently 2
equivalents of camphorsulfonic acid (CSA) were added to
1a in MeCN (entry 3, Method C), and to our delight this
gave 2a albeit in modest yield of 50%, with some 4a (9%),
and recovered 1a (12%). CSA is believed to act as an ac-
tivating agent by protonation of the basic 3-N of benz-
imidazole, so making the benzimidazol-2-yl radical more
electrophilic allowing a faster cyclization, akin to a con-
ventional electrophilic aromatic substitution. Thus the po-
lar effect is in the opposite direction to that reported by
Minisci et al.,2 Barton et al.,21 and Aldabbagh et al.9,12
whereby the heteroaromatic base (e.g., pyridine or imid-
azole) is protonated, thus making it more susceptible to at-
tack by nucleophilic alkyl radicals.
Table 1 Synthesis of Radical Precursors
Method A:
(i) NaH, THF, reflux
(ii)
Ar
Br
N
N
N
( )
n
I
I
Method B:
N
H
(i) t-BuOK, DMF, 0 °C
Ar
(ii)
( )
MsO
S
n
3
Entry
1
Method
A
Product (Yield, %)
N
N
I
1a (75)
N
N
I
2
3
A
A
1b (75)
1c (71)
N
N
I
N
N
I
4
5
A
B
1d (59)
1e (76)
N
N
I
S
The diversity of the protocol was increased to a wider
range of 2-iodo-1-[ω-hetero(aryl)alkyl]-1H-benzimid-
azoles. Photochemical six-membered cyclizations onto
the 2-position of naphthalene or 3-position of thiophene
using 1d (Method A) and 1e (Method C) proceeded to
give substitution products 2d and 2e in 73% and 63%
yield, respectively. In the case of the 1-naphthyl deriva-
tive, no attempt was made to consume recovered 1d
(12%), while the cyclization with the 2-thienyl derivative
gave recovered 1e in 26% yield under the optimized con-
ditions for forming the substitution product 2e, which in-
volved adding CSA (Method C). The quinone derivative
of the highly conjugated compound 2d is expected to
show specificity towards cancer cell lines expressing ele-
vated levels of the reductase enzyme, NQO1
[NAD(P)H:quinone oxidoreductase 1].13,22
Using the conditions reported by Aldabbagh and Clyne,7
2-iodo-1-(ω-phenylalkyl)-1H-benzimidazoles 1a–c in
acetonitrile (17 mM) were subjected to 254 nm in a
Rayonet photochemical reactor for 3 hours (Method A,
Table 2). This resulted in the attempted five-membered
cyclization giving mainly 1-benzyl-1H-benzimidazole
(4a) (85%) due to radical reduction, although the six- and
seven-membered cyclizations gave high yields of substi-
tution products 2b and 2c in 64% and 62% yield, respec-
tively. This represents the first report of fused azepine 2c.
The main by-product was the result of reduction of the
benzimidazol-2-yl radical in 10–17% yield (Table 2, en-
tries 4 and 6). The substitution by-product HI may act as
H•-donor for reduction, and/or regenerate the starting 2-
iodo-1-(ω-phenylalkyl)-1H-benzimidazole, where it acts
as I•-donor. Park et al. have previously described the pho-
tochemistry of 2-halo-N-pyridinylbenzamides using
The photochemical precursor, 2-iodo-1-(2-pyridin-2-yl-
ethyl)-1H-benzimidazole (1f), was prepared in 67% yield
for cyclization onto pyridine (Scheme 2) using NaH and
2-pyridin-2-ylethyl methanesulfonate. But to our surprise,
Synthesis 2012, 44, 3371–3377
© Georg Thieme Verlag Stuttgart · New York

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Synthesis of Aromatic Ring-Fused Benzimidazoles
3373
Table 2 Photochemical Cyclizations from 2-Iodobenzimidazoles
N
N
N
N
N
N
N
N
hυ ( 254 nm)
I
Ar
+
Method A–C
Ar
Ar
Ar
( )
n
( )
( )
( )
n
n
n
benzimidazol-2-yl radical
1a–e
2a–e
4a–e
Entry SMa
n
Ar
Methodb
Products (Yield, %)c
Cyclized
Reduced
SMd
N
N
N
N
1
2
3
1a
1a
1a
0
0
0
Ph
Ph
Ph
A
B
C
2a (0)
2a (0)
2a (50)
4a (85)
4a (80)
4a (9)
1a (7)
1a (0)
1a (12)
N
N
N
N
4
5
1
1
Ph
Ph
A
B
2b (64)
2b (80)
4b (17)
4b (0)
1b (0)
1b (0)
1b
1b
N
N
N
N
6
7
2
2
Ph
Ph
A
B
2c (62)
2c (85)
4c (10)
4c (0)
1c (16)
1c (0)
1c
1c
N
N
N
N
8
9
1d
1e
1
1
1-naphthyl
2-thienyl
A
C
2d (73)
2e (63)
4d (0)
4e (0)
1d (12)
1e (26)
N
N
N
N
S
S
a SM: starting material.
b Reaction conditions: Method A: SM (17 mM), MeCN, 3 h, quartz flask; Method B: Method A and Na2CO3 (0.05 M, 9.5% v/v); Method C:
Method A and CSA (2 equiv).
c Isolated yields.
d Recovered.
compound 1f isomerized to give iodide salt 5 on standing
N
N
NaH, THF, reflux, 6 h
I
overnight at room temperature in CDCl3 (or CHCl3).
Tholander and Bergman reported the synthesis of the
hexafluorophosphate analogue of salt 5 using nucleophil-
ic ipso-substitution of a chloro-substitutent at the 2-posi-
tion of benzimidazole.17
I
N
N
H
N
N
OMs
1f (67%)
I–
Further, the required photochemical precursor 1g for the
five-membered cyclization onto pyridine could not be iso-
lated in pure form due to a rapid cyclization to give adduct
6 (Scheme 3). In this case, an iodide salt is not obtained,
and ipso-substitution at the benzimidazole-2-position is
followed by aromatization with loss of HI.
N
N
CHCl3, r.t., 18 h
+
N
5 (90%)
Scheme 2 Six-membered nucleophilic ipso-substitution
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3371–3377

3374
J. M. O’Connell et al.
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by dry column vacuum chromatography using silica gel as absor-
bent with gradient elution of hexanes and EtOAc to give 2-iodo-1-
trityl-1H-benzimidazole (2.382 g, 59%); cream solid; mp 153–
154 °C; Rf = 0.54 (hexanes–EtOAc, 3:2).
N
N
N
NaH, THF, reflux, 6 h
I
I
N
H
N
IR (neat): 1491, 1446, 1418, 1259, 1203 cm–1.
OMs
N
1H NMR (CDCl3): δ = 6.75–6.79 (m, 1 H, 7-H), 7.08–7.10 (m, 1 H,
5,6-H), 7.19–7.22 (m, 1 H, 5,6-H), 7.25–7.38 (m, 15 H), 7.69 (d, J =
8.2 Hz, 1 H, 4-H).
1g
13C NMR (CDCl3): δ = 82.1 (Ph3C), 102.5 (2-C), 114.8 (7-CH),
119.2 (4-CH), 122.1, 122.5 (5,6-CH), 127.4, 128.0, 131.1 (all CH),
137.2, 142.0, 146.9 (all C).
N
CHCl3, r.t., 2 h
– HI
N
N
Anal. Calcd for C26H19IN2: C, 64.2; H, 3.9; N, 5.8. Found: C, 64.2;
H, 4.2; N, 5.9.
6 (89%)
Deprotection Reaction: Concd HCl (1 mL) was added to 2-iodo-1-
trityl-1H-benzimidazole (1.000 g, 2.1 mmol) in wet MeOH (50 mL)
and the solution was heated at reflux for 3 h. The solution was al-
lowed to cool, evaporated to dryness, and H2O (25 mL) was added.
The acidic aqueous mixture was extracted with CH2Cl2 (2 × 25 mL)
to remove the trityl alcohol, and the aqueous layer was concentrated
by evaporation to 10 mL of solution. The benzimidazole was pre-
cipitated as the free base by addition of solid Na2CO3 until foaming
ceased. The precipitate was recovered by filtration and recrystal-
lized from EtOH to give 2-iodo-1H-benzimidazole (0.384 g, 75%);
white solid; mp 185–188 °C.
Scheme 3 Five-membered nucleophilic ipso-substitution
In conclusion, photochemical five-, six-, and seven-
membered aromatic substitutions of the benzimidazol-2-
yl radical are shown to proceed in good to excellent
yields. The protocol avoids the use of chemical initiators,
which have accompanying hazards, and waste disposal is-
sues. The nucleophilic pyridine-N atom prevents the use
of the analogous 2-iodobenzimidazoles as radical precur-
sors due to a more facile ipso-substitution.
IR (neat): 2772, 1495, 1395, 1343, 1264, 1214, 1184, 1004 cm–1.
1H NMR (CDCl3): δ = 2.47 (br s, 1 H, N-H), 7.09–7.11 (m, 2 H),
7.47–7.49 (m, 2 H).
13C NMR (CDCl3): δ = 100.6 (2-C), 114.7, 122.5 (CH), 141.6 (C).
All chemicals were obtained from Sigma-Aldrich and solvents were
purified and dried prior to use according to conventional methods.
All reactions were conducted under N2 atmosphere unless hydroly-
sis is involved. Monitoring of reactions by TLC was performed us-
ing aluminum-backed plates coated with silica gel (Merck Kieselgel
60 F254). Column chromatography was carried out using Merck
Kieselgel silica 60 (particle size 0.040–0.063 mm) or Aldrich, acti-
vated, neutral, Brockmann 1, STD grade, 150 mesh, 58 Å alumina.
Dry column vacuum chromatography was carried out using Merck
Kieselgel silica 60 (particle size 0.015–0.040 mm) using the speci-
fied eluents. 1-Trityl-1H-benzimidazole was prepared on multi-
gram scale accord to the literature.23 2-Pyridin-2-ylethyl methane-
sulfonate,24 2-pyridin-1-ylmethyl methanesulfonate,25 and 2-(2-
thienyl)ethyl methanesulfonate (3)25 were prepared using
MeSO2Cl, Et3N, and the respective alcohol.
Anal. Calcd for C7H5IN2: C, 34.4; H, 2.1; N, 11.4. Found: C, 34.5;
H, 2.2; N, 11.3.
2-Iodo-1-(ω-arylalkyl)-1H-benzimidazoles 1a–d; General Pro-
cedure
2-Iodo-1H-benzimidazole (1.091 g, 4.47 mmol) and NaH (0.108 g,
4.50 mmol) in THF (60 mL) were stirred at reflux for 1 h. The ap-
propriate alkylphenyl bromide or 1-(2-bromoethyl)naphthalene for
1d (4.50 mmol) in THF (30 mL) was added over 30 min and the so-
lution heated at reflux for 3 h. The cooled solution was filtered
through Celite, the filtrate evaporated to dryness, and the residue
purified by column chromatography using alumina as absorbent
with gradient elution of hexanes and EtOAc.
Melting points were measured on a Stuart Scientific melting point
apparatus SMP3. Elemental analysis was carried out on a Perkin-
Elmer 2400 Series II analyzer. IR spectra were acquired using a
PerkinElmer Spec 1 with ATR attached. High-resolution mass spec-
trometry was carried out by manual peak matching using ESI on a
Waters LCT Premier XE spectrometer, and using CI at the EPSRC
National Mass Spectrometry Service on the Finnigan MAT 900
1-Benzyl-2-iodo-1H-benzimidazole (1a)
Yield: 1.120 g (75%); white solid; mp 112–113 °C; Rf = 0.46 (hex-
anes–EtOAc, 1:1).
IR (neat): 1496, 1447, 1427, 1355, 1221 cm–1.
1H NMR (CDCl3): δ = 5.32 (s, 2 H, CH2), 7.10–7.30 (m, 8 H), 7.75
(d, J = 7.8 Hz, 1 H).
13C NMR (CDCl3): δ = 50.7 (CH2), 104.7 (2-C), 110.1 (7-CH),
119.4 (4-CH), 122.6, 123.4 (5,6-CH), 126.8, 128.2, 129.1 (all Ph-
CH), 135.4, 136.0, 145.9 (all C).
1
XLT. All H and 13C NMR spectra were recorded at 400 and 100
MHz using a Joel GXFT 400 MHz instrument equipped with a DEC
AXP 300 computer workstation. All NMR data are expressed in
ppm downfield from SiMe4 as internal standard or relative to CHCl3
unless otherwise stated. Coupling constants (J) are expressed in Hz.
NMR assignments were supported by DEPT, 1H-13C NMR 2D spec-
tra. UV absorbance measurements were carried out on a Cary 50
UV/Vis spectrophotometer. The photochemical reactions were car-
ried out at 254 nm using a RPR-100 Rayonet photochemical reactor,
encompassing sixteen mercury lamps.
UV/Vis (MeCN): λmax = 253 nm (ε = 10015).
Anal. Calcd for C14H11IN2: C, 50.3; H, 3.3; N, 8.3. Found: C, 50.7;
H, 3.1; N, 8.0.
2-Iodo-1-(2-phenylethyl)-1H-benzimidazole (1b)
Yield: 1.167 g (75%); white needles; mp 102–103 °C; Rf = 0.42
(hexanes–EtOAc, 4:2).
2-Iodo-1H-benzimidazole
IR (neat): 1491, 1451, 1404, 1369, 1345, 1323, 1241, 1028, 1007
cm–1.
1H NMR (CDCl3): δ = 3.07 (t, J = 7.5 Hz, 2 H, CH2), 4.36 (t, J = 7.5
Hz, 2 H, NCH2), 7.10–7.11 (m, 2 H), 7.20–7.28 (m, 6 H), 7.71–7.75
(m, 1 H).
2-Iodo-1-trityl-1H-benzimidazole: n-BuLi (1.6 M in hexane, 5.3
mL, 8.5 mmol) was added over 10 min to 1-trityl-1H-benzimidazole
(3.000 g, 8.3 mmol) in THF (100 mL) at –78 °C. The solution turned
pink-red and allowed to reach r.t. over 1 h. I2 (2.100 g, 8.3 mmol) in
THF (10 mL) was added over 10 min, and the mixture stirred for 18
h. The solution was evaporated to dryness and the residue purified
Synthesis 2012, 44, 3371–3377
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PAPER
Synthesis of Aromatic Ring-Fused Benzimidazoles
3375
13C NMR (CDCl3): δ = 36.0 (CH2), 48.7 (NCH2), 103.8 (2-C),
109.5 (7-CH), 119.4 (4-CH), 122.4, 123.1 (5,6-CH), 127.2, 128.9,
129.1 (all CH), 135.5, 137.2, 145.7 (all C).
2-Iodo-1-(2-pyridin-2-ylethyl)-1H-benzimidazole (1f)
General procedure was adopted using 2-pyridin-2-ylethyl methane-
sulfonate with a reaction time of 6 h; yield: 1.045 g (67%); clear oil;
Rf = 0.62 (Et2O).
Anal. Calcd for C15H13IN2: C, 51.7; H, 3.7; N, 8.0. Found: C, 51.5;
H, 4.1; N, 7.8.
IR (neat): 1452, 1405, 1366, 1323, 1277, 1216, 1144, cm–1.
1H NMR (CDCl3): δ = 3.24 (t, J = 7.2 Hz, 2 H), 4.57 (t, J = 7.2 Hz,
2 H, NCH2), 6.83 (d, J = 7.7 Hz, 1 H), 7.14–7.17 (m, 3 H), 7.24–
7.26 (m, 1 H), 7.44–7.48 (m, 1 H), 7.66–7.68 (m, 1 H), 8.59 (d, J =
5.8 Hz, 1 H).
13C NMR (CDCl3): δ = 38.1 (CH2), 47.0 (NCH2), 103.4 (2-C),
109.6 (4-CH), 119.3 (7-CH), 122.2, 122.3, 123.1, 123.8 (all CH),
135.6 (C), 136.8 (CH), 145.6 (C), 149.8 (pyridyl-6-CH), 157.2
(pyridyl-2-C).
UV/Vis (MeCN): λmax = 254 nm (ε = 8680).
2-Iodo-1-(3-phenylpropyl)-1H-benzimidazole (1c)
Yield: 1.149 g (71%); yellow solid; mp 80–82 °C; Rf = 0.32 (hex-
anes–EtOAc, 1:1).
IR (neat): 1453, 1419, 1406, 1342, 1265, 1228, 1148, 1083 cm–1.
1H NMR (CDCl3): δ = 2.35–2.42 (m, 2 H), 2.74 (t, J = 6.9 Hz, 2 H,
PhCH2), 4.10 (t, J = 6.9 Hz, 2 H, NCH2), 7.25–7.30 (m, 4 H), 7.38–
7.42 (m, 3 H), 7.86–7.88 (m, 1 H), 7.97–7.99 (m, 1 H).
HRMS (ESI): m/z [M + H]+ calcd for C14H13IN3: 350.0154; found:
13C NMR (CDCl3): δ = 31.0, 33.0 (CH2), 46.7 (NCH2), 103.5 (2-C),
109.4 (7-CH), 119.4 (4-CH), 122.3, 123.1 (5,6-CH), 126.5, 128.4,
128.7 (all Ph-CH), 135.6, 140.4, 145.7 (all C).
350.0155.
Ring-Fused Benzimidazoles 2a–e, General Procedure
Appropriate iodide 1a–e (0.64 mmol) in MeCN (38 mL) was purged
with N2 for 20 min in a cylindrical quartz tube and irradiated at 254
nm for 3 h. See Table 2 for modifications to give optimized yields.
The solution was evaporated to dryness, and sat. aq Na2CO3 (50
mL) was added, and the mixture was extracted with CH2Cl2 (2 × 50
mL). The combined organic extracts were dried (MgSO4) and evap-
orated to dryness. The resultant brown residue was purified by col-
umn chromatography using silica gel as absorbent with gradient
elution of hexanes and EtOAc.
Anal. Calcd for C16H15IN2: C, 53.0; H, 4.1; N, 7.7. Found: C, 53.1;
H, 4.4; N, 7.9.
UV/Vis (MeCN): λmax = 254 nm (ε = 8028).
2-Iodo-1-[2-(1-naphthyl)ethyl]-1H-benzimidazole (1d)
Yield: 1.050 g (59%); white solid; mp 180–181 °C; Rf = 0.57 (hex-
anes–EtOAc, 1:1).
IR (neat): 1456, 1405, 1393, 1352, 1261, 1226 cm–1.
1H NMR (CDCl3): δ = 3.54 (t, J = 7.5 Hz, 2 H), 4.50 (t, J = 7.5 Hz,
2 H, NCH2), 7.14 (d, J = 6.8 Hz, 1 H, naphthyl-2-H), 7.18–7.23 (m,
3 H), 7.31–7.35 (m, 1 H), 7.50–7.60 (m, 2 H), 7.71–7.73 (m, 1 H),
7.77 (d, J = 8.2 Hz, 1 H), 7.88 (d, J = 8.6 Hz, 1 H, naphthyl-5,8-H),
8.10 (d, J = 8.4 Hz, 1 H, naphthyl-5,8-H).
11H-Isoindolo[2,1-a]benzimidazole (2a)
Yield: 66 mg (50%); white solid; mp 173–174 °C (Lit.14 mp 144–
149 °C); Rf = 0.44 (hexanes–EtOAc, 1:1).
IR (neat): 1539, 1471, 1448, 1421, 1395, 1378, 1330, 1314, 1231,
1158, 1142 cm–1.
13C NMR (CDCl3): δ = 33.1 (CH2), 47.9 (NCH2), 103.4 (2-C),
109.3 (7-CH), 119.5 (4-CH), 122.4, 123.1, 123.2, 125.7, 125.9,
126.6 (all CH), 127.4 (naphthyl-2-CH), 128.1 (naphthyl-4-CH),
129.2 (naphthyl-5,8-CH), 132.0, 133.3, 134.1, 135.6, 145.7 (all C).
1H NMR (CDCl3): δ = 5.03 (s, 2 H, CH2), 7.27–7.29 (m, 2 H), 7.43–
7.45 (m, 1 H), 7.47–7.58 (m, 3 H), 7.83–7.86 (m, 1 H), 8.06 (d, J =
7.0 Hz, 1 H).
13C NMR (CDCl3): δ = 47.3 (CH2), 109.4 (9-CH), 120.7 (6-CH),
122.2, 122.3, 122.8, 124.0, 128.9 (all CH), 129.5 (C), 129.6 (CH),
132.8, 143.6, 148.5, 158.6 (all C).
Anal. Calcd for C19H15IN2: C, 57.3; H, 3.7; N, 7.0. Found: C, 57.3;
H, 3.2; N, 6.6.
HRMS (CI): m/z [M + H]+ calcd for C14H11N2: 207.0927; found:
UV/Vis (MeCN): λmax = 280 nm (ε = 17353).
207.0922.
2-Iodo-1-[2-(2-thienyl)ethyl]-1H-benzimidazole (1e)
t-BuOK (0.110 g, 0.98 mmol) was suspended in DMF (20 mL) at
0 °C. 2-Iodo-1H-benzimidazole (0.200 g, 0.81 mmol) in DMF (5
mL) was added over 10 min and the mixture stirred at 0 °C for 2 h.
Mesylate 3 (0.135 g, 0.65 mmol) in DMF (5 mL) was added over 15
min and the mixture stirred at r.t. for 4 h. The solution was evapo-
rated to dryness, and CH2Cl2 (25 mL) added and washed with sat.
aq NaHCO3 (2 × 25 mL). The combined organic layers were dried
(Na2SO4) and evaporated to dryness. The residue was purified by
dry column vacuum chromatography using silica gel as absorbent
with gradient elution of hexanes and EtOAc to give 1e (0.174 g,
76%); yellow oil; Rf = 0.57 (hexanes–EtOAc, 5:6).
UV/Vis (MeCN): λmax = 304 nm (ε = 19770).
5,6-Dihydrobenzimidazo[2,1-a]isoquinoline (2b)
Yield: 113 mg (80%); yellow solid; mp 132–135 °C (Lit.14,26 mp
125–130 °C, 148-149 °C); Rf = 0.36 (hexanes–EtOAc, 3:2).
IR (neat): 1731, 1481, 1447, 1408, 1325, 1233, 1171, 1101 cm–1.
1H NMR (CDCl3): δ = 3.26 (t, J = 6.8 Hz, 2 H, 5-CH2), 4.30 (t, J =
6.8 Hz, 2 H, 6-CH2), 7.26–7.42 (m, 6 H), 7.81–7.83 (m, 1 H), 8.28–
8.30 (m, 1 H).
13C NMR (CDCl3): δ = 28.3 (5-CH2), 40.5 (6-CH2), 109.2 (8-CH),
119.8 (11-CH), 122.6, 122.8 (9,10-CH), 125.8 (CH), 126.6 (C),
127.9, 128.2, 130.3 (all CH), 134.4, 134.7, 143.8, 149.2 (all C).
IR (neat): 1482, 1463, 1414, 1358, 1339, 1318, 1253, 1031, 1010
cm–1.
1H NMR (CDCl3): δ = 3.28 (t, J = 7.3 Hz, 2 H), 4.37 (t, J = 7.3 Hz,
2 H, NCH2), 6.66 (dd, J = 0.5, 3.4 Hz, 1 H, thienyl-3,5-H), 6.88 (dd,
J = 3.4, 5.2 Hz, 1 H, thienyl-4-H), 7.14–7.28 (m, 4 H), 7.71–7.73
(m, 1 H, 7-H).
13C NMR (CDCl3): δ = 29.9 (CH2), 48.7 (NCH2), 103.7 (2-C),
109.3 (7-CH), 119.5 (4-CH), 122.5, 123.2 (5,6-CH), 124.7, 126.4
(thienyl-3,5-CH), 127.4 (thienyl-4-CH), 135.5, 138.8, 145.7 (all C).
HRMS (CI): m/z [M + H]+ calcd for C15H13N2: 221.1074; found:
221.1079.
UV/Vis (MeCN): λmax = 307.9 nm (ε = 28737).
6,7-Dihydro-5H-benzimidazo[2,1-a][2]benzazepine (2c)
Yield: 127 mg (85%); yellow solid; mp 88–91 °C; Rf = 0.42 (hex-
anes–EtOAc, 1:1).
IR (neat): 1451, 1393, 1332, 1244, 1160 cm–1.
1H NMR (CDCl3): δ = 2.34–2.41 (m, 2 H), 2.76 (t, J = 7.0 Hz, 2 H,
5-CH2), 4.08 (t, J = 7.0 Hz, 2 H, 7-CH2), 7.27–7.31 (m, 3 H), 7.36–
7.43 (m, 3 H), 7.85–7.87 (m, 1 H), 7.96–7.99 (m, 1 H).
HRMS (ESI): m/z [M + H]+ calcd for C13H12IN2S: 354.9766; found:
354.9778.
UV/Vis (MeCN): λmax = 275 nm (ε = 9447).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3371–3377

3376
J. M. O’Connell et al.
PAPER
13C NMR (CDCl3): δ = 30.7, 31.0 (CH2), 41.4 (7-CH2), 109.1 (9-
CH), 120.1 (12-CH), 122.2, 122.6 (10,11-CH), 127.4 (CH), 129.6
(2 × CH), 130.3 (CH), 130.9, 135.5, 138.9, 143.3, 154.5 (all C).
HRMS (ESI): m/z calcd for C14H13I N3: 350.0154; found: 350.0151
[M + H]+.
Pyrido[1′,2′:3,4]imidazo[1,2-a]benzimidazole (6)
2-Iodo-1H-benzimidazole (1.000 g, 4.09 mmol) gave the title com-
pound 6 (Scheme 3), as a precipitate from CHCl3 (10 mL) (0.754 g,
89%); green solid; mp 154–158 °C.
HRMS (CI): m/z calcd for C16H15N2: 235.1124; found: 235.1232 [M
+ H]+.
UV/Vis (MeCN): λmax = 297 nm (ε = 20622).
IR (neat): 2124, 1620, 1411, 1264 cm–1.
1-(3-Phenylpropyl)-1H-benzimidazole (4c)
Yield: 15 mg (10%); colorless oil; Rf = 0.27 (hexanes–EtOAc, 1:1).
1H NMR (DMSO-d6): δ = 6.88 (t, J = 7.2 Hz, 1 H), 7.02–7.06 (m, 1
H), 7.51 (t, J = 7.4 Hz, 1 H), 7.59–7.63 (m, 1 H), 7.70 (d, J = 9.7 Hz,
1 H), 7.88 (d, J = 8.2 Hz, 1 H), 8.19 (dd, J = 0.7, 7.2 Hz, 1 H), 8.29
(d, J = 8.1 Hz, 1 H), 8.54 (s, 1 H, 12-H).
13C NMR (DMSO-d6): δ = 99.1 (12-CH), 113.7, 114.4, 114.9,
118.7, 122.4, 123.2, 123.7 (all CH), 124.4 (C), 127.1 (CH), 130.4,
134.8, 136.5 (all C).
IR (neat): 1494, 1451, 1397, 1330, 1284, 1203, 1158 cm–1.
1H NMR (CDCl3): δ = 2.16–2.23 (m, 2 H), 2.62 (t, J = 7.1 Hz, 2 H,
PhCH2), 4.11 (t, J = 7.1 Hz, 2 H, NCH2), 7.13–7.32 (m, 8 H), 7.84
(s, 2 H).
13C NMR (CDCl3): δ = 31.0 (CH2), 32.8 (PhCH2), 44.3 (NCH2),
109.8 (7-CH), 120.5 (4-CH), 122.2, 123.0, 126.5 (all CH), 128.5
(C), 128.8 (2 × CH), 130.1 (CH), 140.3 (C), 143.1 (2-CH), 144.0
(C).
HRMS (ESI): m/z calcd for C13H10IN3: 208.0851; found: 208.0849
[M + H]+.
HRMS (CI): m/z calcd for C16H17N2: 237.1392; found: 237.1391 [M
+ H]+.
Acknowledgment
The M.Sc. of J. O’C. was supported by Clare County Council. The
Ph.D. studies of E. M. were supported by the Environmental Protec-
tion Agency (EPA) Doctoral Scheme (2006-PhD-ET-6). We thank
the EPA, Department of Environment, Heritage and Local Govern-
ment funded under the National Development Plan 2000–2006 for
financial support.
5,6-Dihydrobenzimidazo[2,1-a]benzo[f]isoquinoline (2d)
Yield: 0.126 g (73%); white solid; mp 248–250 °C; Rf = 0.58 (hex-
anes–EtOAc, 1:1).
IR (neat): 1507, 1479, 1416, 1380, 1325, 1309 cm–1.
1H NMR (CDCl3): δ = 3.66 (t, J = 7.1 Hz, 2 H, 5-CH2), 4.42 (t, J =
7.1 Hz, 2 H, 6-CH2), 7.28–7.31 (m, 2 H), 7.36–7.39 (m, 1 H), 7.52–
7.59 (m, 2 H), 7.83–7.86 (m, 1 H), 7.88 (d, J = 8.3 Hz, 2 H), 8.05
(d, J = 8.3 Hz, 1 H), 8.41 (d, J = 8.6 Hz, 1 H).
13C NMR (CDCl3): δ = 23.8 (5-CH2), 40.1 (6-CH2), 109.2 (8-CH),
119.9 (11-CH), 122.6, 122.8, 122.9, 123.6 (all CH), 124.0 (C),
126.9, 127.0, 128.0, 129.2 (all CH), 130.8, 131.1, 134.5, 134.9,
144.3, 149.7 (all C).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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References
HRMS (CI): m/z calcd for C19H15N2: 271.1235; found: 271.1236 [M
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1H NMR (CDCl3): δ = 3.39 (t, J = 7.1 Hz, 2 H, 4-CH2), 4.38 (t, J =
7.1 Hz, 2 H, 5-CH2), 7.23–7.34 (m, 4 H), 7.67 (d, J = 5.2 Hz, 1 H,
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IR (neat): 1593, 1568, 1476, 1461, 1405, 1366, 1348, 1322, 1277,
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1H NMR (DMSO-d6): δ = 3.93 (t, J = 6.8 Hz, 2 H, 5-CH2), 4.61 (t,
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H, 1-H).
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CH), 120.6 (11-CH), 124.7, 125.5, 126.9 (all CH), 129.0 (4-CH),
134.4 (C), 139.4 (1-CH), 140.3, 142.4 (C), 149.0 (CH), 152.2 (C).
Synthesis 2012, 44, 3371–3377
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Aromatic Ring-Fused Benzimidazoles
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3371–3377