Aromatic homolytic substitution using solid phase synthesis

Article abstract of DOI:10.1016/j.tet.2006.02.071

Solid phase synthesis has been used to carry out intramolecular aromatic homolytic substitution with benzoimidazole precursors. The protocol attaches the radical precursors to the resins via the radical leaving groups (in the aromatic homolytic substitution). When the radical reactions are complete, the leaving group, unaltered starting material and reduced uncylised products remain attached to the resin, which facilitates easy separation of the cyclised products. Novel use of focussed microwave irradiation in solid phase radical reactions drastically shortens the reactions times. Tributylgermanium hydride has been used to replace the toxic and troublesome tributyltin hydride in the radical reactions.

Full text of DOI:10.1016/j.tet.2006.02.071

Tetrahedron 62 (2006) 4306–4316
Aromatic homolytic substitution using solid phase synthesis
a
b
Steven M. Allin,a W. Russell Bowman,a, Rehana Karim and Shahzad S. Rahman
*
aDepartment of Chemistry, Loughborough University, Loughborough, Leicestershire LE1 3TU, GB, UK
bGlaxoSmithKline, New Frontier Science Park North, Harlow, Essex CM19 5AW, GB, UK
Received 21 December 2005; revised 7 February 2006; accepted 23 February 2006
Available online 14 March 2006
Abstract—Solid phase synthesis has been used to carry out intramolecular aromatic homolytic substitution with benzoimidazole precursors.
The protocol attaches the radical precursors to the resins via the radical leaving groups (in the aromatic homolytic substitution). When the
radical reactions are complete, the leaving group, unaltered starting material and reduced uncylised products remain attached to the resin,
which facilitates easy separation of the cyclised products. Novel use of focussed microwave irradiation in solid phase radical reactions
drastically shortens the reactions times. Tributylgermanium hydride has been used to replace the toxic and troublesome tributyltin hydride in
the radical reactions.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
radical substitution of phenylthiyl radicals at 2-C gave good
results and used this in our initial study (Scheme 1).7
Solid phase synthesis has become a central tool in organic
synthesis. However, there have been surprisingly few
applications to radical chemistry. The small amount of
literature has been recently reviewed1 and more recent
references continue to show the untapped potential.2 Solid
phase radical reagents have also been developed and show
promise. For example, we have recently demonstrated that
solid phase triorganogermanium hydride gives good results
for a wide range of radical reactions and compares very well
with the corresponding solution-phase use of tributyltin or
tributylgermanium hydride.3 Other references to solid phase
radical reagents are included in our recent publications.3,4
We sought to further investigate the potential of radical
reactions on solid phase with a view to applications in
combinatorial chemistry.
N
SPh
Bu Sn-SePh
3
N
2
n
N
N
SPh
addition
N
n
Bu Sn•
SPh
n
PhSe
3
1a, n = 1
1b, n = 2
1c, n = 3
elimination
PhS•
N
3
PhSH
Bu SnH
N
3
N
n
4
Solid phase synthesis and combinatorial chemistry have
centred on the synthesis of heterocycles because of the
importance of these compounds to the pharmaceutical
industry as likely lead compounds.5 The use of radical
cyclisation for the synthesis of prospective biologically
active heterocyclic compounds has also continued to grow
in interest.6 Therefore, in this study we chose radical
cyclisation onto benzoimidazoles as a suitable methodology
for investigation. We have previously shown that alkyl
Scheme 1. Homolytic aromatic substitution.
This procedure of intramolecular aromatic homolytic
substitution was first developed by Caddick et al. as a
novel regioselective methodology for the synthesis of [1,2-
a]indoles in which SPh, SOPh or SO2Ar groups on the
indole-2-position act as radical leaving groups.8 Whereas
bimolecular homolytic aromatic substitution is relatively
unselective and therefore of limited synthetic application,
these substitutions are regioselective, controlled by stereo-
electronic effects and the good radical leaving groups.
Homolytic aromatic substitution has been recently
reviewed.9
Keywords: Aryl radicals; Radical cyclisation; Solid phase synthesis;
Microwave; Benzoimidazoles.
*
Corresponding author. Tel.: C44 1509 222569; fax: C44 1509 223925;
e-mail: w.r.bowman@lboro.ac.uk
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.02.071

S. M. Allin et al. / Tetrahedron 62 (2006) 4306–4316
4307
radical
reaction
N
N
N
N
N
N
S
HS
S
X
H
Scheme 2. Solid phase radical cyclisation protocol.
In our earlier synthetic studies, [1,2-a]fused-benzoimida-
zoles and -imidazoles were synthesised using new method-
ology.7 In this procedure, u-phenylselanyl-alkyl side chains
were used in place of u-bromoalkyl side chains to avoid
reaction between the basic benzoimidazole nitrogen atom
reacting with alkyl halides. The aromatic homolytic
substitution mechanism is shown in Scheme 1. The
tributyltin radical (Bu3Sn%) abstracts the phenylselanyl
group from the precursor 1 to yield an intermediate radical
2 by an SH2 mechanism. Cyclisation gives a stabilised
s-complex 3 with the unpaired electron delocalised over the
aromatic system. The eliminated phenylsulfanyl radical
(PhS%) is electrophilic and reacts extremely rapidly with the
nucleophilic tributyltin hydride (Bu3SnH) to complete the
chain cycle. This latter process has been termed polarity
reversal catalysis (PRC).10,11
2. Discussion
2.1. Solution-phase studies with alkyl radicals
Initially, we repeated earlier studies7 on the cyclisation of
the selanides 1a and 1b (see Scheme 1) in order to test the
conditions for solution-phase homolytic aromatic substi-
tution for comparison with solid phase studies. The five-
membered ring cyclisation of 1a gave low yields (4a, 25%
as opposed to 49% in earlier studies7). Use of hexamethyl-
ditin did not improve yields of 4a (26%). The six-membered
ring cyclisation of 1b to 4b gave much better yields. The
best yield (61%) was obtained using acetonitrile as solvent
(54% in the earlier study7) whereas toluene (4b, 25%) and
cyclohexane (4b, 23%) gave lower yields. Six-membered
ring cyclisations onto heteroarene rings are less strained
than the five-membered ring cyclisations and hence give
higher yields.7,11–13
We sought to use ‘building blocks’, which could be adapted
to combinatorial chemistry. The use of N-alkylation of NH-
heteroarenes provides a route for the addition of ‘radical’
building blocks. The application of N-(u-phenylselanyl)-
alkyl ‘building blocks’ is illustrated in Scheme 1. N-(u-
Phenylselanyl)alkyl and N-(u-bromo)alkyl ‘building
blocks’ have also been applied to cyclisation of N-(u-
alkyl)-radicals onto pyrroles,12 imidazoles12 and pyra-
zoles13 with electron withdrawing groups or radical
stabilising groups. We have recently shown that 2-(2-
bromophenyl)ethyl and 2-(2-bromophenyl)methyl ‘building
blocks’ can be used via aryl radical cyclisation.11 We sought
in the study to use these two groups of building blocks,
N-(u-phenylselanyl)alkyl and 2-(2-bromophenyl)alkyl, to
explore the use of radicals on solid phase.
Initially, we synthesised the 2-(phenylsulfanyl)benzoimida-
zole by lithiation of the 1-trityl protected bezimidazole
followed by reaction with diphenyl disulfide. The yields
were variable and not suited for the preparation of
precursors for solid phase studies. We therefore investigated
SNAr substitution by thiolate of chloride at the 2-C position.
2-Chlorobenzoimidazole 5 is commercially available and
cheap. Test reactions showed that chloride was easily
replaced from 2-chlorobenzoimidazole or 1-methyl-2-
chlorobenzoimidazole (Scheme 3). Potassium hydroxide
N
N
PhSH
85%
SPh
Cl
N
R
N
Me
The radical reactions were first carried out in solution-phase
to determine the best conditions and also to provide an
accurate comparison with the equivalent solid phase
reactions. The use of the three possible triorgano-metal
hydrides, Bu3SnH, tris-(trimethylsilyl)silane (TTMSS) and
tributylgermanium hydride (Bu3GeH) were investigated.
The latter two reagents have the advantage of low toxicity as
compared to Bu3SnH.
6, R = H
PhSH
NaH MeI
7, R = Me
66%
64%
N
N
ArSH
68%
S
Cl
N
H
N
H
5
8
NaH
CO H
2
n = 1
N
I
SePh
n
Our studies used the protocol shown in Scheme 2, that is, the
radical precursors are attached to the solid phase resin via
the arylsulfanyl radical leaving group. The advantage of this
protocol is that after the radical reaction, only the cyclised
product is released from the resin. Reduced uncyclised
products and unaltered starting materials remain attached
to the resin and hence do not need to be separated from
the desired product. The cyclised benzoimidazoles were
separated from the radical reagents by extraction into
dilute hydrochloric acid, thereby facilitating a very clean
separation.
N
N
ArSH
S
Cl
N
n
n
PhSe
PhSe
CO H
2
9a, n = 1 (61%)
9b, n = 2 (42%)
9c, n = 3 (51%)
10a, n = 1 (61%)
10b, n = 2 (98%)
10c, n = 3 (98%)
Scheme 3. Synthesis of precursors, ArSHZ4-(SH)-C6H4CO2H.

4308
S. M. Allin et al. / Tetrahedron 62 (2006) 4306–4316
(KOH) in ethanol proved best whereas potassium carbonate/
acetone, triethylamine/DCM and NaH/DMF gave poor
yields. Attempted SNAr substitution of 1-trityl-2-chloro-
benzoimidazole failed, probably due to steric hindrance.
reduced material 13a (51%) whereas the six-membered ring
cyclisation gave a reasonable yield (54%) with no
uncyclised reduced material 13b. The use of Bu3GeH
allows more time for intermediate radicals to cyclise and
syringe pump addition is not required.3 We suggest that the
mechanism is as shown in Scheme 1 (with SPhZCl).
Our original aim was to prepare the benzoimidazole with the
linker attached thereby allowing the possibility of alkylation
and radical cyclisation on the solid phase resin. SNAr
substitution with the unprotected 2-chlorobenzoimidazole 5
using the solid phase linker, 4-mercaptobenzoic acid,
proceeded in a good unoptimised yield (68%) but subsequent
alkylationsfailed(Scheme 3). Alkylationmayhavebeenmore
favourable with the resin acting as protection for the carboxyl
group but difficulties were encountered with selectively
attaching the 4-mercaptobenzoic acid via the carboxylate to
Wang resin. Selective thiol protection followed by attachment
also encountered problems. Selective S-trityl and S-acyl
protection of 4-mercaptobenzoic acid gave ca. quantitative
yields but trityl removal failed and acyl migration problems
were encountered. At this point, we successfully alkylated
2-chlorobenimidazole 5 to afford 9a–c and carried out the
SNAr substitutions to give 10a–c in good yields, that is,
alkylations were carried out prior to loading on the resins
(Scheme 3).
2.2. Solid phase studies with alkyl radicals
The alkyl radical precursors (with linker attached) 10a–c were
successfully attached to three resins, Wang, amino-Merrifield
and Rink, by standard procedures (Scheme 5). Each loading
1
was assessed by FTIR and MAS (magic angle) H NMR
spectroscopy. The FTIR showed formation of an ester linkage
for Wang resin attachments. The level of loading was
determined by cleavage of the loaded precursor from a portion
of each resin. The radical reactions were carried out using a
variety of conditions and the results are shown in Table 1. The
cyclised products 4a–c were isolated by filtration of the resin
whereas reduced uncyclised products 15a–c (if formed) and
unaltered precursors were cleaved from the resin by TFA
hydrolysis and analysed by LCMS and/or isolation. The five-
membered ring cyclisation on Wang resin 12a gave poor
yields (maximum 11% yield) as observed for the solution-
phase reactions. Slow addition of Bu3SnH by syringe pump
and repeat addition appeared to give better yields. One attempt
withthe amino-Merrifield precursor 12d gaveverypooryields
and was not further investigated.
We have also shown that chlorine is a good leaving group
and can replace phenylthiyl and phenylsulfonyl groups
in intramolecular aromatic homolytic substitutions
(Scheme 4). We tested two 2-chlorobenzoimidazoles 9a
and 12 under standard radical cyclisation conditions.
The five-membered ring cyclisation again gave a poor
yield of cyclisation (10%) with a large amount of uncyclised
The six-membered ring cyclisations, as for solution-phase
reactions, gave much better yields with the optimised
maximum yield of 60%, that is, very similar yields to
solution-phase reactions. A more useful comparison would
be the solution-phase cyclisation of the carboxylic acids
10a–c or their respective esters. However, these compari-
sons were not carried out. Extended addition and reflux
times gave much lower yields. The use of TTMSS and
Bu3GeH gave lower yields than Bu3SnH but further
optimisation is needed to determine the relative utility of
the three reagents in these reactions. The use of Rink resin in
place of Wang resin gave a similar yield of cyclised product
4b (44%). As for the solution-phase reactions, the seven-
membered ring cyclisation also gave very low yields (4c,
4%) with largely the reduced uncyclised product (14c to
15c, 72%) being formed.
N
N
Bu MH
N
N
3
4
Cl
Cl
n
X
n = 1, M = Sn;
13a (51%), 4a (10%)
n = 2, M = Ge;
9a, n = 1, X = SePh
12, n = 2, X = Br
13b (0%), 4b (54%)
Scheme 4.
N
S
N
N
N
HS
S
R MH
3
resin, DIC
4a-c
12a-e
10a-c
AIBN
DCM, DMF
PhSe
n
n
O
O
O
14a-e
13
-1
12a, n = 1, Wang, 0.96 mmol g
12b, n = 2, Wang, 0.95 mmol g
12c, n = 3, Wang, 0.94 mmol g
12d, n = 1, amino-Merrifield, 0.78 mmol g
12e, n = 2, Rink, 0.63 mmol g
-1
-1
10% TFA DCM
-1
N
N
HS
-1
S
10a-c
CO H
2
n
CO H
2
15a-c
Scheme 5. Radical reactions on solid phase (R3MHZBu3SnH, Bu3GeH, TTMSS).

S. M. Allin et al. / Tetrahedron 62 (2006) 4306–4316
4309
Table 1. Radical cyclisation of resin-bound 1-[u-(phenylselanyl)alkyl]benzoimidazoles 12a–e
Precursor
Reaction conditions
Yields
12a
Bu3SnH, syringe pump addition over 26 min, repeat addition after 3 h,
AIBN, toluene, reflux, 5 h
Bu3SnH, syringe pump addition over 2 h, AIBN, benzene, reflux, 5 h
Bu3SnH, syringe pump addition over 5 h, repeat addition over 5 h, AIBN,
benzene, reflux, 10 h
4a (11%), 10a and 15aa
12a
12a
4a (5%), 15aa
4a (5%), 15aa
12a
12a
12d
12b
12b
Bu3SnH, syringe pump addition over 7 h, AIBN, benzene, reflux, 10 h
Bu3SnH, AIBN, benzene, reflux, 24 or 48 h
Bu3SnH, AIBN, benzene, reflux, 18 h
Bu3SnH, syringe pump addition over 7 h, AIBN, benzene, reflux, 7 h
Bu3SnH, syringe pump addition over 2 h, repeat addition after 3 h, AIBN,
benzene, reflux, 6.5 h
Bu3SnH, syringe pump addition over 7 h, AIBN, benzene, reflux, 8 h
Bu3SnH, syringe pump addition over 7 h, AIBN, benzene, reflux, 7 h
Bu3SnH, syringe pump addition over 12 h, AIBN, benzene, reflux, 12 h
Bu3SnH, syringe pump addition over 12 h, AIBN, benzene, reflux, 24 h
Bu3SnH, AIBN, benzene, reflux, 48 h
Bu3GeH, AIBN, toluene, reflux, 8 h
TTMSS, AIBN, benzene, reflux, 10 h
TTMSS, syringe pump addition over 5 h, AIBN, benzene, reflux, 8 h
Bu3SnH, syringe pump addition over 6 h, AIBN, benzene, reflux, 7 h
Bu3SnH, syringe pump addition over 2.5 h, AIBN, tert-butylbenzene,
heating at 130 8C, 9 h
4a (3%), 10a (41%), 15a (10%)
4a (trace), 15aa
4a (trace)
4b (60%), 15ba
4b (58%, 49%), 15ba
12b
12b
12b
12b
12b
12b
12b
12b
12e
12c
4b (57%), 15ba
4b (49%)
4b (14%), 10b and15ba
4b (trace), 10b and15ba
4b (3%), 10b and15ba
4b (22%), 10ba
4b (20%), 15ba
4b (16%), 15ba
4b (44%), 10b and 15ba
4c (4%), 15c (72%)
12c
Bu3SnH, syringe pump addition over 5 h, AIBN, tert-butylbenzene,
heating at 130 8C, 10 h
4c (2%), 15ca
a Qualitative analysis by HPLC.
2.3. Solid phase radical cyclisation using microwave
irradiation
At the time of our study focussed microwave irradiation had
not been used for radical reactions on solid phase, but
recently an example has been published for the synthesis
of oxindoles by 5-exo cyclisation of aryl radicals onto
a,b-unsaturated amides.14 We believe that our studies
indicate potential for the use of microwave irradiation to
shorten reaction times of solid phase radical reactions.
Further study should improve yields and determine the most
suitable reaction conditions.
We used focussed microwave irradiation to cut down the
reactions times of the reactions from hours to minutes
(Table 2). Typically, non-radical solid phase reactions using
this technique take place in 1–5 min. Although the radical
reactions required the longer time of 10–20 min the time is
still considerably shorter than the non-irradiated reactions (see
Table 1). The technique gave comparable results to the non-
irradiated reactions with the highest yield (52%) achieved
using a mixture of propan-1-ol and benzene. Propan-1-ol was
found to be the most favourable solvent. Polar solvents tend to
give the best results with this technique. Propan-1-ol is a
reasonably good H-donor, which may account for the
formation of the reduced uncyclised (14b, and 15b after
cleavage from the resin). However, use of tert-butanol, which
is not a good H-donor did not improve the yields.
The technique was also applied to the five-membered ring
cyclisation of the amino-Merrifield bound 12d. Again, poor
results were obtained [4a (3%), 20 min, propan-1-ol/
benzene, 135 8C] showing no real improvement over the
non-irradiated reaction. The cyclisation of the equivalent
non-solid phase precursor 10b under similar condition using
microwave irradiation gave inferior yields suggesting that
the solid phase reaction may be more efficient [10 min,
PrOH/PhH, 1.25 cm3, Bu3SnH: (a) AIBN, 135 8C, 4b
(11%), (b) AMBN, 100 8C, 4b (14%)].
Table 2. Radical cyclisation with Wang resin-bound precursor 12b using
focussed microwave irradiation
2.4. Solution- and solid phase studies with aryl radicals
Reaction conditionsa
Yieldb
10 min, 10 min,c 100 8C, PrOH/PhH (1 cm3 each)
10 min, 10 min,c 135 8C, PrOH/PhH (1.25 cm3 each)
10 min, 135 8C, PrOH/PhH (1.25 cm3 each)
20 min, 135 8C, PrOH/PhH (1.25 cm3 each)
10 min, 10 min,c 100 8C, tert-BuOH/PhH
(1.25 cm3 each)
4b (52%)d
4b (44%)d
4b (44%)d
4b (38%)d
4b (44%)d
With the success of the alkyl radical cyclisation we sought
to show that aryl radicals could also be used in solid
phase synthesis. 2-(2-Bromophenyl)ethyl and 2-(2-bromo-
phenyl)methyl ‘building blocks’ have been suceessfully
used to generate aryl radicals for cyclisation onto
heteroarenes.11 The same methodology was applied as for
the alkyl radicals. The synthesis of aryl radical precursors
and attachement to the solid phase is shown in Scheme 6.
The methyl esters were prepared for prior testing of the
reactions in solution-phase in order to determine the best
conditions and to provide an accurate comparison with the
equivalent solid phase reactions.
10 min, 130 8C, PrOH (2.5 cm3)
4b (20%)d
4b (17%)d
4b (14%)d
10 min, 10 min,c 100 8C, MeCN/PhH (1.25 cm3 each)
10 min, 10 min,c 100 8C, DMF/PhH (1.25 cm3 each)
a Bu3SnH, AMBN [azobismethylisobutyronitrile or by IUPAC nomencla-
ture, 2-(1-cyano-1-methyl-propylazo)-2-methyl-butyronitrile], focussed
microwave irradiation.
b The % yield of 4b was measured using 1H NMR spectroscopy with an
internal standard.
c Second addition of reagents and further irradiation.
d Reduced uncyclised 15b was observed by LCMS analysis of products
cleaved from the resin.
2-Chloro-1H-benzoimidazole 5 was alkylated with suitable
aryl radical building blocks (16a and 16b) followed by the

4310
S. M. Allin et al. / Tetrahedron 62 (2006) 4306–4316
N
N
N
X
S
1. KOH, DMF
AcCl,MeOH
S
5
N
Y
n
t
2. KOBu , ArSH
n
n
16a, n = 1, X = Y = I
16b, n = 2, X = Br, Y = OMs
O
CO H
2
X
X
O
Z
17a, n = 1, X = I (100%)
17b, n = 2, X = Br (98%)
18a, n = 1, X = I, Z = Me (78%)
18b, n = 2, X = Br, Z = Me (76%)
Wang resin DIC, DMAP
DCM, DMF
-1
18c, n = 1, X = I, Z = Wang resin (0.60 mmol g )
-1
18d, n = 2, X = Br, Z = Wang resin (0.98 mmol g )
Scheme 6. Synthesis of aryl precursors, ArSHZ4-(SH)-C6H4CO2H.
SNAr protocol using 4-mercaptobenzoic acid to yield 17a
and 17b in near quantitative yield (Scheme 6). The
benzoimidazoles 17a and 17b were methylated to provide
precursors for the solution studies and attached to Wang
resin using carbodiimide-mediated coupling. Good loadings
were easily achieved and quantified by cleavage from the
resin (TFA/DCM, 9:1) and measurement of the radical
precursors. The IR spectrum of the solid supported
precursors showed the formation of the ester linkages at
more satisafactory with a high yield of 19b (71%) but
TTMSS with Et3B as initiator at room temperature gave a
lower yield (29%). Further optimisation would be likely
to give improved yields. The result again illustrates the
potential of the non-toxic Bu3GeH to replace the toxic
Bu3SnH. The by-products were cleaved from the resin and
analysed by GC–MS, which showed small amounts of the
reduced uncyclised product resulting from 21 and 17b
resulting from unreacted starting material 18d.
1
1713 cmK1 and MAS H NMR spectra showed complete
immobilisation (Scheme 7).
2.5. Homolytic aromatic substitution on imidazole
The solution-phase studies were similar to those observed
for alkyl radicals. Attempted five-membered cyclisation
with the radical precursor 18a using Bu3SnH gave only
reduced uncyclised material 20a (60%), even with the use of
a syringe pump. However, use of TTMSS, which is a poorer
H-donor than Bu3SnH gave a low yield of the cyclised
product 19a (20%) with 20a (40%) as the major product. As
expected the six-membered cyclisation gave a good yield of
cyclised material 19b (50%) with no traces of the reduced
uncyclised product 20b. The results show that homolytic
aromatic substitution by aryl radicals at 2-C of benzoimida-
zoles is a useful synthetic protocol.
We had earlier shown that cyclisation via homolytic
aromatic substitution onto 2-(phenylsulfanyl)imidazoles
gave good yields.7 We sought to extend the use of the
solid phase protocol for the synthesis of bi-and tri-cyclic
imidazoles. 2-Chloroimidazole is not readily available so
we developed an alternative procedure to widen the scope of
our protocol using the cheap and available 2-mercaptoimi-
dazole as shown in Scheme 8. The SNAr substitution, which
is reversed from the previous protocol gave a reasonable
yield of 22 (50%), which can be used for a variety of
alkylations on the imidazole-NH. The pyridine moiety has a
suitable ester handle for attaching to a solid phase resin as
required. Alkylation with the 2-(2-bromophenyl)ethyl
building block 16b gave a good yield of a radical precursor
for testing the solution-phase cyclisation. Hydrolysis of the
ester to the carboxylic acid would facilitate coupling to solid
phase resins using carbodiimide coupling.
The better yielding six-membered ring cyclisation was
chosen for study on solid phase using Wang resin. Syringe
pump addition of Bu3SnH gave the tetracycle 19b in a
reasonable yield (44%). The use of Bu3GeH proved much
N
N
S
N
TTMSS (18a)
18a
18b
N
Bu SnH (18b)
3
n
n
Ph
19a, n = 1 (20%)
19b, n = 2 (50%)
CO Me
2
20a, n = 1, Z = Me (40%)
20b, n = 2, Z = Me (0%)
N
N
HS
S
radical
19b, 44% (Bu SnH, AIBN)
3
18d
18d
71%, (Bu GeH, AIBN)
reaction
3
29%, (TTMSS, Et B)
3
Ph
O
13
21
O
Scheme 7. Cyclisation of aryl precursors on solid phase.

S. M. Allin et al. / Tetrahedron 62 (2006) 4306–4316
4311
CO Et
2
N
CO Et
CO Et
N
2
2
N
NaH, DMF
NaH, DMF
SH
N
S
N
N
H
N
Cl
N
S
N
16b
H
22 (50%)
X
CO Et
2
N
radical
23b, X = H
45% (TTMSS)
32% (Bu SnH)
N
23a, X = Br (75%)
N
reaction
3
SH
56%% (Bu GeH)
3
24, 45% TTMSS)
37% (Bu SnH)
25
3
20% (Bu GeH)
3
Scheme 8. Cyclisation of imidazole precursors.
The cyclisation was studied with the precursor 23a using
three radical-mediators of which TTMSS gave the best yield
of 5,6-dihydroimidazo[2,1-a]isoquinoline 24. The results
show that the pyridine thiol 25 is an equally good radical
leaving group in aromatic nucleophilic subsitution to that of
the earlier solid phase leaving group 13 or 4-mercapto-
benzoic acid methyl ester. TTMSS and Bu3SnH were added
by syringe pump to keep their concentration low to facilitate
cyclisation over reduction. The poor result with Bu3GeH
indicates that syringe pump addition is required. Further
studies are required to optimise the cyclisation and apply to
solid phase synthesis.
was carried by GlaxoSmithKline. MAS spectra of the resins
were recorded, and again once the radical precursor was
loaded. Mass spectra were recorded on a JEOL SX102 mass
spectrometer or carried out by the EPSRC Mass Spec-
trometry Service at University of Wales, Swansea. All mass
spectra are electron impact spectra (EI) unless otherwise
stated. TLC using silica gel as absorbent was carried out
with aluminium backed plates coated with silica gel (Merck
Kieselgel 60 F254). Column chromatography was carried
out using neutral alumina unless otherwise specified.
1-Iodo-3-(phenylselanyl)propane 11a,7 1-iodo-4-(phenyl-
selanyl)butane 11b,7 1-iodo-5-(phenylselanyl)pentane 11c,7
1H-benzo[d]imidazol-2-yl phenyl sulfide 6,7 1-[3-(phenylse-
lanyl)propyl]-2-(phenylsulfanyl)-1H-benzo[d]imidazole 1a,7
1-[4-(phenylselanyl)butyl]-2-(phenylsulfanyl)-1H-benzo[d]i-
midazole 1b,7 1-iodo-2-(iodomethyl)benzene 16a,11 2-(2-
bromophenyl)ethyl methanesulfonate 16b11 and tributyl-
germanium hydride4 were prepared by literature procedures.
3. Conclusions
The solid phase reactions gave very similar yields to
equivalent solution-phase reactions indicating the potential
use of radical reactions using solid phase synthesis. There
does not appear to be any side reactions in the solid phase
reactions of the radical intermediates reacting with the resin.
We believe that our results give further evidence1–3 that
solid phase synthesis should be fully considered as a useful
technique in radical synthesis.
4.1. General procedure for radical cyclisations. 2,3-
dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole 4a
4.1.1. Tributyltin hydride. A solution of tributyltin hydride
(0.83 cm3, 3.1 mmol) in toluene (50 cm3) was added to 1-[3-
(phenylselanyl)propyl]-2-(phenylsulfanyl)-1H-benzo[d]-
imidazole 1a (0.60 g, 1.4 mmol) in toluene (150 cm3) at
reflux over 5 h using a syringe pump. AIBN (0.16 g,
1.4 mmol) was added to the refluxing reaction mixture at
equal intervals. The solution was stirred and heated under
reflux for a further 1 h. Dil, hydrochloric acid was added to
the cooled reaction mixture to extract the protonated
benzoimidazole compounds into the aqueous layer and
washed with light petroleum to remove Bu3Sn-residues. The
acidic aqueous layer was basified with sodium carbonate
followed by aqueous sodium hydroxide (few drops) to
pH 14. The basic solution was extracted with DCM, and
evaporated under reduced pressure to give a pale yellow oil
crude product. The residue was purified by column
chromatography using silica gel as absorbent with light
petroleum and ethyl acetate as eluents to give 2,3-dihydro-
1H-benzo[d]pyrrolo[1,2-a]imidazole 4a as white crystals
(57 mg, 0.36 mmol, 25%), mp 105–107 8C (lit.7 mp
114–115 8C); dH 2.70 (2H, quintet, JZ7.4 Hz, 2-H), 3.05
(2H, t, JZ7.6 Hz, 3-C), 4.1 (2H, t, JZ7.2 Hz, 1-C),
7.25–7.40 (3H, m, ArH) and 7.67–7.73 (1H, m, ArH).
4. Experimental
Commercial dry solvents were used in all reactions except
for light petroleum and ethyl acetate, which were distilled
from CaCl2 and dichloromethane (DCM) was distilled over
phosphorus pentoxide. Light petroleum refers to the bp
40–60 8C fraction. Sodium hydride was obtained as 60%
dispersion in oil and was washed with light petroleum. Mps
were determined on an Electrothermal 9100 melting point
apparatus and are un-corrected. Elemental analyses were
determined on a Perkin Elmer 2400 CHN Elemental
Analyser in conjunction with a Perkin Elmer AD-4
Autobalance. IR spectra were recorded on a Perkin-Elmer
Paragon 1000 FT-IR spectrophotometer on NaCl plates. 1H
(250 MHz) and 13C (62.5 MHz) NMR spectra were
recorded on a Bruker AC-250 spectrometer as solutions of
CDCl3 with tetramethylsilane (TMS) as the internal
1
standard for H NMR spectra and deuteriochloroform the
standard for 13C NMR spectra unless otherwise specified.
Chemical shifts are given in parts per million (ppm) and J
values in hertz (Hz). MAS Magic angle NMR spectroscopy

4312
S. M. Allin et al. / Tetrahedron 62 (2006) 4306–4316
The spectroscopic data were identical to those reported in
the literature.7
MC, 240.0726. C14H12N2S requires 240.0721); nmax (KBr)/
cmK1 2373, 1577, 1441, 1409, 1324, 1276, 1078 and
739; dH 3.69 (3H, m, CH3), 7.20–7.29 (6H, m), 7.34 (2H, dd,
JZ8.2, 1.1 Hz) and 7.75–7.77 (1H, m); dC 30.7 (CH3),
109.4 and 119.8 (4- and 7-C), 122.4 and 123.2 (5- and 6-C),
127.6 (ArCH), 129.4 (ArCH), 130.2 (ArCH), 132.1 and
136.5 (3a- and 7a-C), 143.1 (Ph 1-C) and 147.6 (2-C); m/z
EI 239 (MC, 100%), 224 (11), 207 (14), 91 (14) and 77 (15).
4.1.2. Hexamethylditin. The reaction mixture of 1-[3-
(phenylselanyl)propyl]-2-(phenylsulfanyl)-1H-benzo[d]-
imidazole 1a (89 mg, 0.21 mmol) and hexamethylditin
(114 mg, 0.35 mmol) in tert-butylbenzene (10.0 cm3) was
irradiated with a sun lamp at 85 8C for 30 h. The work-up
was carried out as in the previous experiment to give 2,3-
dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole 4a (26%).
4.3.2. 4-[(1H-Benzo[d]imidazol-2-yl)sulfanyl]benzoic
acid 8. 4-Mercaptobenzoic acid and 2-chlorobenzoimi-
dazole 5 gave 8 as colourless crystals (68%), mp 270–
275 8C (Found: MHC, 271.0541. C14H10N2O2S requires
271.0544); nmax (DCM)/cmK1 3500, 3054, 2987, 1690,
1593, 1567, 1506, 1423 and 1265; dH (DMSO-d6) 7.23–7.26
(2H, m, benzoimidazole 5-H and 6-H), 7.51 (2H, d, JZ
8.2 Hz, 3- and 5-H), 7.50–7.70 (2H, m, benzoimidazole 4-
and 7-H) and 7.94 (2H, d, JZ8.3 Hz, 2- and 6-H); dC
(DMSO-d6) 122.0 (benzoimidazole 4- and 7-C), 126.5
(benzoimidazole 5- and 6-C), 129.5 (3- and 5-C), 130.1 (1-
C), 130.6 (2- and 6-C), 138.6 (4-C), 144.79 (benzoimidazole
2-C) and 167.1 (C]O); m/z EI 270 (MC, 72%), 269 (100),
225 (15), 150 (16), 77 (18) and 44 (91).
4.1.3. 1,2,3,4-Tetrahydrobenzo[4,5]imidazo[1,2-a]-
pyridine 4b. 1-[4-(Phenylselanyl)butyl]-2-(phenylsul-
fanyl)-1H-benzo[d]imidazole 1b was reacted using the
general procedure for radical cyclisations except that
acetonitrile was used in place of toluene to yield 1,2,3,4-
tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine 4b as colour-
less crystals (61%), mp 96–100 8C (lit.7 mp 99.8–100.1 8C).
The spectroscopic data were identical to the reported data.7
4.2. General procedure for alkylation
The azole was added slowly to a suspension of NaH
(1.15 equiv) in dry THF (240 cm3). The mixture was stirred
and heated at 80 8C for 1 h. A solution of the alkylating
agent (1.5 equiv) in THF (10 cm3) was added dropwise to
the reaction mixture, which was heated under reflux for a
further 2 h. The salts were removed by filtration on a Celite
bed and the solution evaporated under reduced pressure
to yield the crude product. The crude product was purified
by column chromatography using light petroleum–ethyl
acetate (1/4) as the eluent.
4.3.3. Radical cyclisation of 1-(4-bromobutyl)-2-chloro-
1H-benzo-[d]imidazole 12b. Tributylgermanium hydride
(0.56 cm3, 2.16 mmol) was added to 1-(4-bromobutyl)-2-
chloro-1H-benzo[d]imidazole 12b (0.31 g, 1.1 mmol) in
toluene (100 cm3) followed by portion wise addition of
AIBN (0.35 g, 2.2 mmol) to the refluxing reaction mixture
at equal intervals. The solution was stirred and heated under
reflux for 12 h. The reaction mixture was evaporated under
reduced pressure to yield a crude product, which was
purified by column chromatography with light petroleum
and ethyl acetate as eluents to give 1,2,3,4-tetrahydroben-
zo[4,5]imidazo[1,2-a]pyridine 4b as colourless crystals
(0.10 g, 0.58 mmol, 54%); nmax (KBr)/cmK1 1610, 1505,
1425, 1397, 1328, 1278 and 745; dH 1.98–2.09 (2H, m, 3-H),
2.10–2.13 (2H, m, 2-H), 3.09 (2H, t, JZ7.0 Hz, 4-H), 4.06
(2H, t, JZ7.0 Hz, 1-H), 7.21–7.30 (3H, m, ArH) and 7.66–
7.69 (1H, m, ArH). The data was identical to data reported
in the literature.7
4.2.1. 2-Chloro-1-[(3-phenylselanyl)propyl]-1H-benzo-
[d]imidazole 9a. 2-Chlorobenzoimidazole (2.00 g,
13.1 mmol) and 1-iodo-3-(phenylselanyl)propane 11a
gave 2-chloro-1-[(3-phenylselanyl)propyl]-1H-benzo[d]-
imidazole 9a as a pale yellow oil (2.79 g, 8.0 mmol, 61%)
(Found: C, 55.38; H, 4.40; N, 7.94 requires C, 54.95; H,
4.32; N, 8.01%); nmax (neat)/cmK1 2930, 1615, 1578, 1469,
1450, 1375, 1329, 1247, 1154, 1022, 761, 740 and 691; dH
2.12–2.33 (2H, m, CH2), 2.88 (2H, t, JZ6.9 Hz, CH2Se),
4.28 (2H, t, JZ7.1 Hz, CH2N), 7.20–7.23 (6H, m, ArH),
7.43–7.45 (2H, m, ArH) and 7.65–7.68 (1H, m, ArH); dC
24.1 (CH2), 29.3 (CH2Se), 43.8 (CH2N), 109.4 and 119.5
(4- and 7-C), 122.7 and 123.2 (5- and 6-C), 127.3 (PhCH),
129.1 (Ph 1-C), 129.2 (PhCH), 133.0 (PhCH), 135.0, 140.3
and 141.7 (2-3a, 7a-C); m/z EI 350 (MC, 43%) (Found: MC,
350.0091. C16H15ClN2Se requires 350.0089), 315 (55), 165
(62), 91 (100) and 77 (29).
4.4. Loading of alkyl radical precursors onto resins
4.4.1. General procedure. Wang resin-bound benzoimi-
dazole 12a. DCM (20 cm3) was added to a portion of Wang
resin (1.0 g, 1.7 mmol) and the resin was left to swell for 1 h
under an atmosphere of nitrogen. 4-({1-[3-Phenylselanyl)-
propyl]-1H-benzo[d]imidazol-2-yl}sulfanyl)benzoic acid
10a (0.55 g, 1.2 mmol), DMAP (0.36 g, 2.9 mmol) and
DIC (1.0 cm3, 5.8 mmol) were added sequentially. The
suspension was shaken for 48 h at room temperature. The
reaction mixture was filtered and washed with DCM,
MeOH, DMF, MeOH and DCM (20 cm3 each). The resin
was dried at 40 8C under vacuum for 24 h. The coupling
4.3. General procedure for SNAr substitution at 2-C
4.3.1. 1-Methyl-1H-benzo[d]imidazol-2-yl phenyl sulfide
7. Benzenethiol (0.31 cm3, 3.0 mmol) was dissolved in a
solution of KOH (0.17 g, 3.0 mmol) in EtOH (30 cm3) and
the mixture was stirred for 5 min. 2-Chloro-1-methyl-1H-
benzoimidazole (0.50 g, 3.0 mmol) was added to the
reaction mixture and the reaction mixture heated under
reflux for 18 h. The reaction mixture was filtered and
evaporated under reduced pressure to give 1-methyl-1H-
benzo[d]imidazol-2-yl phenyl sulfide 7 as colourless
crystals (0.62 g, 2.6 mmol, 85%), mp 66–69 8C (Found:
1
reaction was repeated. The (MAS) magic angle H NMR
spectrum showed complete immobilisation of 10a onto
the Wang resin. FTIR nmax (KBr)/cmK1 3025, 2920,
1713, 1591, 1511, 1447, 1265, 1173, 1097, 1010, 822, 738
and 693.

S. M. Allin et al. / Tetrahedron 62 (2006) 4306–4316
4313
4.4.2. Wang resin-bound benzoimidazole 12b. The
(MAS) magic angle H NMR spectrum showed complete
immobilisation of the compound onto the Wang resin. FTIR
nmax (KBr)/cmK1 3026, 2921, 2363, 1713, 1591, 1512,
1447, 1356, 1265, 1173, 1097, 1011, 822, 739 and 694.
The data were identical to authentic material. In several
reactions the reduced uncyclised 4-[(1-butyl-1H-benzo[d]-
imidazol-2-yl)sulfanyl]benzoic acid 15b was isolated using
HPLC and characterised. (Found: MHC, 327.1170.
C18H18N2O2S requires 327.1167); nmax (KBr)/cmK1 3490,
2934, 2363, 1700, 1594, 1420, 1364, 1258, 1199, 1179,
1122 and 1017; dH (DMSO-d6) 0.78 (3H, t, JZ7.4 Hz,
CH3), 1.16–1.25 (2H, m, CH2), 1.56–1.63 (2H, m, CH2),
4.27 (2H, t, JZ7.3 Hz, NCH2), 7.23–7.31 (2H, m, ArH),
7.43 (2H, d, JZ6.6 Hz, 3-H and 5-H), 7.62–7.65 (2H, m,
ArH) and 7.88 (2H, d, JZ6.4 Hz, 2-H and 6-H); dC (DMSO-
d6) 13.4 (Me), 19.3 (CH2), 31.3 (CH2), 44.0 (NCH2), 110.9
and 119.0 (benzoimidazole 4- and 7-C), 122.4 and 123.3
(benzoimidazole 5- and 6-C), 128.9 (ArCH), 129.7 (1-C),
130.3 (ArCH), 135.6 (benzoimidazole 7a-C), 138.1 (4-C),
142.5 (benzoimidazole 3a-C), 145.1 (benzoimidazole 2-C)
and 166.6 (C]O); m/z (FAB) 327 (MHC, 100%), 271 (12),
176 (12), 154 (33) and 136 (31).
1
4.4.3. Wang resin-bound benzoimidazole 12c. The (MAS)
magic angle H NMR spectrum showed complete immo-
1
bilisation of the compound onto the Wang resin. FTIR nmax
(KBr)/cmK1 3024, 2921, 2851, 1943, 1717, 1592, 1511,
1451, 1421, 1374, 1353, 1266, 1238, 1173, 1098, 1013, 824,
758, 738 and 697.
4.4.4. Amino-Merrifield resin-bound benzoimidazole
12d. FTIR nmax (KBr)/cmK1 3424, 3024, 2923, 1655,
1594, 1511, 1478, 1422, 1245, 1014, 838, 736 and 691.
4.4.5. Rink resin-bound benzoimidazole 12e. DCM
(15 cm3) was added to a portion of Rink resin (0.62 g,
0.5 mmol). The resin was left to swell for 1 h under
an atmosphere of nitrogen. 4-({1-[4-Phenylselanyl)butyl]-
1H-benzo[d]imidazol-2-yl}sulfanyl)benzoic acid 10b
(0.3 g, 0.6 mmol), HOAT (0.25 g, 1.8 mmol) and DIC
(0.5 cm3, 3.15 mmol) were added sequentially. The suspen-
sion was shaken for 48 h at room temperature. The reaction
mixture was filtered and washed with DCM, MeOH, DMF,
MeOH and DCM (20 cm3 each). The resin was dried at
40 8C under vacuum for 24 h. The coupling reaction was
repeated with equimolar reagents. The (MAS) magic angle
1H NMR spectrum showed immobilisation of the compound
onto the Rink resin. FTIR nmax (KBr)/cmK1 3413, 2921,
1659, 1503, 1349, 1207, 1026, 827, 742 and 695.
4.5.3. Radical cyclisations of Wang resin-bound benzo-
imidazole 12c. The general procedure for radical reactions
of resin-bound precursors was used and the conditions and
results are reported in Table 1. 7,8,9,10-Tetrahydro-6H-
1
benzo[4,5]imidazo[1,2-a]-azepine 4c was analysed by H
NMR spectroscopy using an internal standard. The data
were indentical to those reported in the literature.7 4-[(1-
Pentyl-1H-benzo[d]imidazol-2-yl)sulfanyl]benzoic acid
15c was isolated and characterised. (Found: MC,
340.1242. C19H20N2O2S requires 340.1246); nmax (KBr)/
cmK1 3056, 2928, 2477, 1910, 1689, 1596, 1463, 1385,
1272, 1115, 1007, 836 and 742; dH (DMSO-d6) 0.76 (3H, t,
JZ6.9 Hz, CH3), 1.15–1.24 (4H, m, CH2CH2), 1.62–1.68
(2H, m, CH2), 4.28 (2H, t, JZ7.3 Hz, NCH2), 7.26 (1H, t,
JZ8.1 Hz, ArH), 7.31 (1H, t, JZ7.9 Hz, ArH), 7.44 (2H, d,
JZ7.7 Hz, 3-H and 5-H), 7.64 (1H, d, JZ8.0 Hz,
benzoimidazole 7-H), 7.67 (1H, d, JZ7.9 Hz, benzoimida-
zole 4-H) and 7.91 (2H, d, JZ6.7 Hz, 2-H and 6-H); dC
(DMSO-d6) 13.6 (CH3), 21.6 (CH2), 28.1 (CH2), 28.8
(CH2), 44.1 (NCH2), 110.8 and 119.1 (benzoimidazole 4-
and 7-C), 122.2 and 123.2 (benzoimidazole 5- and 6-C),
128.7 (ArCH), 130.0 (1-C), 130.2 (ArCH), 135.6 and 138.2
(benzoimidazole 3a- and 7a-C), 142.7 (4-C), 144.9
(benzoimidazole 2-C) and 166.5 (C]O); m/z 339 (MC,
100%), 307 (14), 297 (34), 269 (86), 225 (26), 187 (28), 150
(30), 131 (24) and 73 (28).
4.5. Radical cyclisations of resin-bound 1-[u-(phenyl-
selanyl)]benzoimidazoles
4.5.1. General procedure. Radical cyclisation of Wang
resin-bound 12a. A solution of Bu3SnH (0.10 cm3,
0.4 mmol) and AIBN (26 mg, 0.16 mmol) in toluene
(2.0 cm3) was added to refluxing suspension of resin-
bound benzoimidazole 12a (170 mg, 0.16 mmol) in toluene
(4.0 cm3) over 26 min using a syringe pump. The reaction
was stirred at reflux for 3 h and then a further portion of
Bu3SnH and AIBN in toluene (1 cm3) was added over 5 min
and the reaction mixture was heated under reflux for a
further 1.5 h. The reaction mixture was filtered and the resin
washed with toluene, DCM and MeOH (20 cm3 each). The
resin was dried at 40 8C under vacuum for 24 h. The LCMS
analysis of the filtrate showed cyclised product 4a (3 mg,
0.018 mmol, 11%). The remaining products were cleaved
from the resin using 10% TFA in DCM. The LCMS analysis
of the cleaved sample from the resin showed the reduced
product 15a. 4a was isolated and characterised. All data
were identical to aunthentic material.
4.5.4. Radical cyclisation of Wang resin-bound 12b using
microwave irradiation. General method. A suspension of
the Wang resin-bound 12b (22 mg, 0.021 mmol) was
prepared in propan-1-ol/benzene (1.25 cm3 of each) was
prepared in a microwave pyrex tube. Bu3SnH (3.57 equiv)
and AIBN (3.57 equiv) were added and the pyrex tube
sealed and placed in an automated microwave apparatus
(Smiths Personnel Chemistry Synthesiser). This synthesiser
has an integrated liquid handler, which facilitates automated
microwave reactions for up to 96 separate reaction vessels.
The sample was irradiated for 10 min at 100 8C. A second
addition of reagents the sample was carried out and the
reaction irradiated for another 10 min. After 20 min the
reaction vessel was removed from the microwave apparatus,
cooled to room temperature and unsealed. The reaction
mixture was filtered and washed with toluene, DCM and
MeOH (20 cm3 each). LCMS analysis of the filtrate showed
The reaction was repeated under different conditions. The
conditions and yields are reported in Table 1.
4.5.2. Radical cyclisations of resin-bound 12b. The
general procedure was used with Wang and Rink resins.
The different conditions and yields are reported in Table 1.
1,2,3,4-Tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine 4b
was isolated by HPLC and characterised in each case.

4314
S. M. Allin et al. / Tetrahedron 62 (2006) 4306–4316
only the presence of the cyclised product 1,2,3,4-tetra-
hydrobenzo[4,5]imidazo[1,2-a]pyridine 4b (52%) and tri-
2-Chloro-1-[(2-iodophenyl)methyl]-1H-benzo[d]imidazole
(3.74 g, 10.1 mmol) was added to the reaction mixture and
heated under reflux overnight. The reaction mixture was
filtered and evaporated to dryness to give the crude product,
which was purified by column chromatography using silica
gel as absorbent and light petroleum–ethyl acetate (1/1) as
eluents to afford the benzoimidazole 17a as pale yellow
crystals (4.88 g, 10.0 mmol, 99%), mp 98.2–103.5 8C (Found:
MC, 485.9915. C21H15IN2O2S requires 485.9905); nmax
(KBr)/cmK1 3382, 3056, 2964, 1924, 1695, 1591, 1544,
1434, 1385, 1271, 1185, 838 and 734; dH 5.49 (2H, s, CH2),
6.31 (1H, dd, JZ7.6, 1.4 Hz, CH), 7.02 (1H, ddd, JZ7.6, 7.6,
1.4 Hz, CH), 7.19 (1H, ddd, JZ7.6, 7.6, 1.4 Hz, CH), 7.25–
7.28 (2H, m, CH), 7.34 (2H, dd, JZ6.6, 1.7 Hz, 3-H and 5-H),
7.40–7.44 (1H, m, CH), 7.69–7.73 (1H, m, CH), 7.81 (2H, dd,
JZ6.6, 1.7 Hz, 2-H and 6-H), and 7.91 (1H, dd, JZ7.6,
1.0 Hz, CH); dC 52.8 (CH2), 98.0 (C–I), 111.1 (CH), 119.5
(CH), 122.8 (CH), 123.8 (CH), 126.8 (CH), 129.0 (CH), 129.9
(CH), 129.9 (CH), 130.4 (CH), 133.0 (C), 136.3 (C), 137.8
(C), 138.3 (C), 139.7 (CH), 143.2 (C), 147.9 (C) and 167.9
(C]O); m/z (EI) 486 (MC, 4%), 465 (48), 431 (8), 378 (7),
262 (22), 217 (100), 178 (20), 154 (50), 90 (61) and 73 (58).
1
butyltin residues. The yield was determined by H NMR
spectroscopy using the internal standard.
The reaction was repeated under various conditions to
optimise the yield and minimise the time. Conditions and
yields of reactions are reported in Table 2 and the
discussion.
4.6. Alkylations of 2-chloro-1H-benzo[d]imidazole
4.6.1. 2-Chloro-1-[(2-iodophenyl)methyl]-1H-benzo[d]-
imidazole. (3.00 g, 19.7 mmol) was added to a vigorously
stirred suspension of ground potassium hydroxide (3.30 g,
59.0 mmol) in dry DMF (80 cm3) and stirred for 30 min.
1-Iodo-2-(iodomethyl)benzene 16a (13.53 g, 39.3 mmol)
was added in one portion. The reaction was stirred for 24 h,
partitioned between ethyl acetate and water and the organic
layer was removed. The organic extract was washed with
water followed by brine, dried and evaporated under
reduced pressure. The residue was purified by column
chromatography using neutral alumina as absorbent and
light petroleum–ethyl acetate (4/1) as eluents to afford
2-chloro-1-[(2-iodophenyl)methyl]-1H-benzo[d]imidazole
as cream coloured crystals (6.87 g, 18.7 mmol, 95%), mp
106.2–109.3 8C (Found: MC, 367.9573. C14H10ClIN2
requires 367.9577); nmax (KBr)/cmK1 3059, 2920, 1700,
1615, 1455, 1428, 1329, 1282, 1240, 1198, 1013, 986, 749
and 650; dH 5.38 (2H, s, CH2), 6.48 (1H, d, JZ8.0 Hz), 7.00
(1H, dd, JZ8.0, 8.0 Hz), 7.08–7.34 (4H, m), 7.75 (1H, d,
JZ8.0 Hz) and 7.91 (1H, d, JZ8.0 Hz); dC 52.9 (CH2), 96.7
(Ar 2-C), 109.9 (CH), 119.7 (CH), 123.1 (CH), 123.6 (CH),
126.6 (CH), 128.9 (CH), 130.1 (CH), 135.0 (3a-C), 136.8
(7a-C), 139.7 (CH), 141.0 (2-C) and 141.8 (Ar 1-C); m/z
(EI) 368 (MC, 62%), 241 (35), 217 (100), 205 (13), 152 (19)
and 90 (47).
4.8. Methylation of aryl radical precursors
4.8.1. Methyl 4-({1-[(2-iodophenyl)methyl]-1H-benzo-
[d]imidazol-2-yl}sulfanyl)benzene-1-carboxylate 18a.
Acetyl chloride (2.0 cm3, 28.0 mmol) was added dropwise
over 10 min to MeOH (25 cm3) cooled in an ice bath. The
solution was stirred for 5 min and 4-({1-[(2-iodophenyl)-
methyl]-1H-benzo[d]imidazol-2-yl}sulfanyl)benzene-1-
carboxylic acid (0.62 g, 1.3 mmol) was added in one portion
and the solution heated under reflux for 18 h. The solution
was cooled and evaporated under reduced pressure to give
the crude methyl ester hydrochloride. Water was added to
the crude and the aqueous layer was basified to pH 14 with
sodium carbonate and aqueous sodium hydroxide solution.
The basic solution was extracted with DCM. The organic
extracts were dried and evaporated under reduced pressure.
The residue was purified by column chromatography using
neutral alumina as absorbent and light petroleum–ethyl
acetate (1/1) as eluents to afford methyl ester 18a as
colourless crystals (0.5 g, 1.0 mmol, 78%), mp 179.1–
181.2 8C (Found: MHC, 501.0131. C22H17IN2O2S requires
501.0134); nmax (KBr)/cmK1 2940, 1713, 1589, 1544, 1428,
1351, 1277, 1107, 1012, 841, 824, 748 and 689; dH 3.79
(3H, s, CH3), 5.33 (2H, s, CH2), 6.19 (1H, d, JZ7.2 Hz),
6.81 (1H, dd, JZ7.6, 1.0 Hz), 6.94 (1H, dd, JZ7.6, 1.0 Hz),
7.07 (1H, d, JZ7.6 Hz), 7.17–7.27 (2H, m), 7.30 (2H, d, JZ
8.6 Hz, 3-H and 5-H), 7.72–7.74 (2H, m) and 7.76 (2H, d,
JZ8.6 Hz, 2-H and 6-H); dC 51.2 (CH3), 52.3 (CH2), 95.8
(C-I), 109.2 (CH), 119.3 (CH), 122.1 (CH), 123.1 (CH),
125.6 (CH), 127.6 (CH), 128.1 (1-C), 128.3 (6-C), 128.4
(CH), 129.3 (CH), 134.8 (CH), 136.2 (3a-C), 137.0 (7a-C),
138.5 (CH), 142.3 (benzoimidazole 2-C), 145.5 (1-C) and
165.2 (C]O); m/z (FAB) 501 (MHC, 32%), 327 (19), 281
(22), 217 (40), 147 (54) and 136 (100).
4.6.2. 1-[2-(2-Bromophenyl)ethyl]-2-chloro-1H-benzo-
[d]imidazole. The general procedure for alkylation was
used with 2-chlorobenzoimidazole and 2-(2-bromophenyl)-
ethyl methanesulfonate 16b to afford 1-[2-(2-bromophenyl)
ethyl]-2-chloro-1H-benzo[d]imidazole as cream coloured
crystals (98%), mp 73.5–75.4 8C (Found: MC, 333.9871.
C15H12BrClN2 requires 333.9872); nmax (KBr)/cmK1 3042,
2932, 1614, 1473, 1452, 1378, 1357, 1329, 1329, 1263,
1170, 1032, 1004, 758, 746, 729 and 655; dH 3.20 (2H, t, JZ
7.3 Hz, CH2), 4.40 (2H, t, JZ7.3 Hz, NCH2), 6.89 (1H, t,
JZ6.5 Hz), 7.05–7.10 (2H, m), 7.22–7.23 (3H, m), 7.51–
7.54 (1H, t, JZ8.0 Hz) and 7.64–7.68 (1H, m); dC 35.9
(CH2), 43.8 (NCH2), 109.3 (CH), 119.4 (CH), 122.6 (CH),
123.1 (CH), 124.4 (C), 127.8 (CH), 128.9 (CH), 131.1 (CH),
133.0 (CH), 134.9 (C), 136.4 (C), 140.4 (C) and 141.6 (C);
m/z (EI) 334 (MC, 22%), 255 (11), 182 (45), 165 (100), 129
(27), 90 (34) and 70 (32).
4.7. SNAr substitutions with 4-mercaptobenzoic acid
4.9. Radical cyclisations of methyl esters 18a and 18b
4.7.1. 4-({1-[(2-Iodophenyl)methyl]-1H-benzo[d]imidazol-
2-yl}sulfanyl)benzene-1-carboxylic acid 17a. 4-Mercapto-
benzoic acid (1.54 g, 10.0 mmol) was dissolved in EtOH
(60 cm3) followed by potassium tert-butoxide (1.70 g,
15.2 mmol) and the mixture was stirred for 5 min.
4.9.1. 5,6-Dihydrobenzo[4,5]imidazo[2,1-a]isoquinoline
19b. The general procedure for radical cyclisations was
carried out with the methyl ester 18b with Bu3SnH added at

S. M. Allin et al. / Tetrahedron 62 (2006) 4306–4316
4315
reflux over 5 h using a syringe pump. The solution was
stirred and heated under reflux for a further 3 h. Colourless
crystals (50%), mp 125.0–130.0 8C (Found: MC, 220.1000.
C15H12N2 requires 220.1001); nmax (KBr)/cmK1 2922,
2370, 2344, 1480, 1458, 1406, 1325, 1171 and 736; dH
3.30 (2H, t, JZ6.9 Hz, 5-H), 4.35 (2H, t, JZ6.9 Hz, 6-H),
7.26–7.43 (6H, m, ArH), 7.81–7.85 (1H, m, ArH) and 8.29–
8.32 (1H, m, ArH); dC 28.3 (5-C), 40.4 (6-C), 109.0 (CH),
119.8 (CH), 122.5 (CH), 122.7 (CH), 125.7 (CH), 126.6
(12b-C), 127.8 (CH), 128.1 (CH), 130.2 (CH), 134.3 (C),
134.6 (C), 143.9 (C) and 149.1 (C); m/z (EI) 220 (MC,
100%), 109 (9), 86 (10) and 77 (9).
4.11. Radical cyclisations of resin-bound benzoimidazole
18d
4.11.1. Bu3SnH. The general procedure for radical
cyclisation of Wang bound precursors with 18d (100 mg,
0.10 mmol) gave 5,6-dihydrobenzo[4,5]imidazo[2,1-a]iso-
quinoline 19b as colourless crystals (44%). The data were
indentical to authentic material.
4.11.2. Bu3GeH. The general procedure for radical
cyclisation of Wang bound precursors with 18d (140 mg,
0.14 mmol) using Bu3GeH added in one portion at the
beginning and heated for 8 h gave 19b (71%).
4.11.3. TTMSS. TTMSS (0.06 cm3, 0.19 mmol) and Et3B
(1.0 M in cyclohexane, 0.2 mmol) were added dropwise to a
suspension of the resin-bound benzoimidazole 18d
(111 mg, 0.11 mmol) in toluene (15 cm3), The flask was
fitted with a rubber septum and air was introduced through a
needle during stirring at room temperature for 5 h. Further
addition of TTMSS (0.12 mL, 0.38 mmol) and Et3B (1.0 M
in hexane, 0.3 mmol) was carried out and the reaction
mixture was stirred for another 10 h. Standard work-up gave
19b (29%).
4.9.2. 11H-Benzo[4,5]imidazo[1,2-a]isoindole 19a. The
general procedure for radical cyclisations was carried out
with the methyl ester 18a with TTMSS instead of Bu3SnH
to afford the tetracycle 19a as colourless crystals (20%), mp
144.0–149.0 8C (Found: MC, 206.0841. C14H10N2 requires
206.0844); nmax (KBr)/cmK1 2927, 2367, 1657, 1433, 1399,
1269 and 740; dH 5.27 (2H, s, CH2), 7.26–7.42 (7H, m, ArH)
and 7.70–7.72 (1H, m, ArH); dC 46.2 (CH2), 108.3 (CH),
118.9 (CH), 122.1 (CH), 122.6 (CH), 123.4 (C), 127.1 (CH),
127.5 (CH), 127.8 (CH), 128.8 (CH), 129.1 (C), 134.7 (C),
134.7 (C) and 143.9 (C); m/z (EI) 206 (MC, 46%), 149 (17),
119 (8), 91 (16) and 77 (18). The reduced uncyclised 4-[(1-
benzyl-1H-benzo[d]imidazole-2-yl)sulfanyl]benzene-1-car-
boxylate 20a was also isolated as a pale yellow oil (40%)
(Found: MC, 375.1167. C22H18N2O2S requires 375.1167);
nmax (KBr)/cmK1 2950, 1721, 1594, 1434, 1350, 1276,
1181, 1108, 1016, 824 and 760; dH 3.89 (3H, s, CH3),
5.45 (2H, s, CH2), 7.06–7.08 (2H, m, ArH), 7.23–7.34
(8H, m, ArH), 7.88 (1H, d, JZ7.6 Hz, ArH) and 7.90 (2H, d,
JZ7.9 Hz, 2-H and 6-H); dC 48.3 (CH3), 52.2 (CH2), 110.4
(CH), 120.3 (CH), 122.9 (CH), 123.9 (CH), 126.7 (CH),
128.0 (CH), 128.7 (CH), 128.9 (CH), 130.4 (CH), 128.9 (C),
135.5 (C), 136.0 (C), 138.8 (C), 143.5 (C), 146.0 (C) and
166.4 (C]O); m/z (FAB) 375 (MC, 74%), 322 (20), 243
(43), 167 (87), 154 (100) and 136 (74).
4.12. Ethyl 6-({1-[2-(2-bromophenyl)ethyl]-1H-imidazol-
2-yl}sulfanyl)pyridine-3-carboxylate 23a
4.12.1. Ethyl 6-[(1H-imidazol-2-yl)sulfanyl]pyridine-3-
carboxylate 22. 2-Mercaptoimidazole (2.00 g, 20.0 mmol)
was added slowly to a suspension of NaH (0.58 g,
24.2 mmol) in dry DMF (40 cm3). The mixture was stirred
and heated at 80 8C for 1 h, followed by addition of ethyl
6-chloronicotinate (3.71 g, 20.0 mmol) in DMF (10 cm3)
and the reaction mixture was heated at 80 8C for 12 h. The
reaction mixture was evaporated under reduced pressure
and the residue purified by column chromatography
using silica gel as absorbent and light petroleum–ethyl
acetate (1/1) as eluents to afford 22 as colourless crystals
(2.49 g, 50%), mp 145.7–146.9 8C (Found: MC, 249.0573.
C11H11N3O2S requires 249.0572); nmax (KBr)/cmK1 3079,
2986, 2745, 2502, 1866, 1715, 1574, 1444, 1275, 1113,
1011, 965, 851 and 767; dH 1.39 (3H, t, JZ7.2 Hz, CH3),
4.39 (2H, q, JZ7.2 Hz, OCH2), 7.12 (1H, dd, JZ8.6,
0.4 Hz, 5-H), 7.23–7.26 (2H, br s, imidazole 4,5-H), 8.10
(1H, dd, JZ8.6, 2.4 Hz, 4-H) and 8.98 (1H, dd, JZ2.4,
0.4 Hz, 2-H), NH was not observed; dC 14.2 (CH3), 61.5
(OCH2), 121.3 (5-C), 123.3 (imidazole 4,5-C), 133.2 and
135.1 (3-C and imidazole 2-C), 137.6 (4-C), 150.5 (2-C) and
163.2 and 164.8 (6-C and C]O); m/z (EI) 250 (MHC,
100%), 232 (33), 221 (7), 163 (11), 130 (12), 103 (21), 91
(10) and 77 (11).
4.10. Loading of aryl-radical precursors 17a and 17b
onto resins
4.10.1. Wang solid supported benzoimidazole 18d. The
general procedure for loading precursors to Wang resin was
carried out with the acid 17b. The loading on the resin
(0.98 mmol/g) was determined by cleaving a known amount
of resin using TFA–DCM (9/1). FTIR nmax (KBr)/cmK1
3023, 2919, 1713, 1590, 1441, 1263, 1170, 1095, 1090,
1010, 821, 742 and 694. The (MAS) magic angle 1H NMR
spectrum showed complete immobilisation of the com-
pound onto the Wang resin.
4.12.2. Ethyl 6-({1-[2-(2-bromophenyl)ethyl]-1H-imida-
zol-2-yl}sulfanyl)pyridine-3-carboxylate 23a. The stan-
dard procedure for alkylation was used with the imidazole
22 and 2-(2-bromophenyl)ethyl methanesulfonate 16b to
afford 23a as a pale yellow oil (75%) (Found: MC,
431.0312. C19H18BrN3O2S requires 431.0303); nmax
(neat)/cmK1 3105, 3056, 2981, 1716, 1584, 1472, 1456,
1429, 1366, 1283, 1269, 1173, 1128, 1025, 854 and 766; dH
1.38 (3H, t, JZ7.2 Hz, CH3), 3.13 (2H, t, JZ7.2 Hz, CH2),
4.32 (4H, t, JZ7.2 Hz, NCH2), 4.38 (4H, q, JZ7.2 Hz,
4.10.2. Wang solid supported benzoimidazole 18c. The
loading on the resin (0.60 mmol/g) was determined. FTIR
nmax (KBr)/cmK1 3424, 3058, 3024, 2919, 2365, 1944,
1717, 1596, 1510, 1492, 1445, 1371, 1266, 1239, 1173,
1099, 1011, 822, 743 and 696. The (MAS) magic angle 1H
NMR spectrum showed complete immobilisation of the
compound onto the Wang resin.

4316
S. M. Allin et al. / Tetrahedron 62 (2006) 4306–4316
OCH2), 6.88 (1H, dd, JZ8.4, 0.4 Hz, 5-H), 6.96 (1H, dd,
JZ7.5, 1.4 Hz, CH), 7.08 (1H, ddd, JZ7.5, 7.5, 1.4 Hz,
CH), 7.10 and 7.27 (2H, 2!s, imidazole 4,5-H), 7.16 (1H,
ddd, JZ7.5, 7.5, 1.4 Hz, CH), 7.49 (1H, dd, JZ7.5, 1.4 Hz,
CH), 8.04 (1H, dd, JZ8.4, 2.0 Hz, 4-H) and 8.96 (1H, dd,
2.0, 0.4, 2-H); dC 14.2 (CH3), 37.9 (CH2), 46.7 (NCH2), 61.4
(OCH2), 120.4 (5-C), 123.1 (Ar 2-C), 123.4 (imidazole
4-C), 124.4 (3-C), 127.7 (imidazole 5-C), 128.9 (CH), 131.0
(CH), 131.2 (CH), 133.0 (CH), 134.4 and 136.3 (Ar 1-C and
imidazole 2-C), 137.7 (4-C), 150.9 (2-C), 164.4 and 164.9
(6-C and C]O); m/z (EI) 431 (MC, 4%), 352 (11), 249 (46),
181 (100), 153 (64), 84 (45) and 49 (39).
References and notes
1. Review: Ganesan, A. In Renaud, P., Sibi, M. P., Eds.; Radicals
in Organic Synthesis; Wiley-VCH: Weinheim, 2001; Vol. 2,
pp 81–91.
2. Chevet, C.; Jackson, T.; Santry, B.; Routledge, A. Synlett
2005, 477–480. Qian, H.; Huang, X. J. Comb. Chem. 2003, 5,
569–576. Harrowven, D. C.; May, P. J.; Bradley, M.
Tetrahedron Lett. 2003, 44, 503–506. Miyabe, H.;
Nishimura, A.; Fufishima, Y.; Naito, T. Tetrahedron 2003,
59, 1901–1907. (e) Curran, D. P.; Yang, F.; Cheong, J.-H.
J. Am. Chem. Soc. 2002, 124, 14993–15000. (f) Dublanchet,
A.-C.; Lusinchi, M.; Zard, S. Z. Tetrahedron 2002, 58,
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4.12.3. 5,6-Dihydroimidazo[2,1-a]isoquinoline 24.
Bu3SnH. The standard procedure for radical cyclisations
was carried out using the imidazole 23a (150 mg) to afford
5,6-dihydroimidazo[2,1-a]isoquinoline 24 as a clear oil
(37%) (Found: MC, 170.0847. C11H10N2 requires
170.0844); nmax (neat)/cmK1 3171, 2923, 1708, 1499,
1466, 1329, 1250, 1195, 1099, 911, 772, 738 and 714; dH
3.16 (2H, t, JZ6.8 Hz, CH2), 4.17 (2H, t, JZ6.8 Hz,
NCH2), 6.94 (1H, d, JZ1.0 Hz, 2/3-H), 7.15 (1H, d, JZ
1.0 Hz, 2/3-H), 7.26–7.27 (3H, m, ArH) and 8.02 (1H, d,
JZ8.0 Hz, 10-H); dC 28.6 (6-C), 43.3 (5-C), 119.1 (CH),
123.6 (CH), 127.6 (CH), 127.8 (CH), 128.3 (CH), 129.1
(CH), 129.6 (C), 132.3 (C) and 142.9 (C); m/z EI 170 (MC,
4%), 149 (5), 128 (16), 115 (16), 77 (21) and 57 (23).
3. Bowman, W. R.; Krintel, S. L.; Schilling, M. B. Synlett 2004,
1215–1218.
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´
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TTMSS. 24 (45%). Bu3GeH. Bu3GeH was added in one
portion at the beginning of the reaction. 24 (20%).
Yields of isolated unreacted starting material 23a and
reduced uncyclised 23b are reported in Scheme 8.
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Acknowledgements
We thank GlaxoSmithKline and Loughborough University
for a Postgraduate Studentship (R.K.), GlaxoSmithKline for
generous financial support and the EPSRC Mass Spec-
trometry Unit, Swansea University, Wales for mass spectra.
9. Review: Studer, A.; Bossart, M. In Renaud, P., Sibi, M. P.,
Eds.; Radicals in Organic Synthesis; Wiley-VCH: Weinheim,
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Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet.2006.02.
071. Supplementary data includes syntheses of compounds
in which the general method and a representative example
has been included in the paper.
14. Akamatsu, H.; Fukase, K.; Kusumoto, S. Synlett 2004,
1049–1053.