Photochemical intramolecular aromatic substitutions of the imidazol-2-yl radical are superior to those mediated by Bu3SnH

Article abstract of DOI:10.1039/b512729g

Six-membered photochemical cyclisations of 2-iodo-N-(2-arylethyl)imidazoles proceeded regioselectively in higher yields than the equivalent tin hydride-mediated reactions. The decrease in yield of cyclisation products, 5,6-dihydroimidazo[2,1-a]isoquinolines containing strongly deactivating substituents on the aryl ring confirmed the electrophilic nature of the σ-imidazol-2-yl radicals. The seven-membered cyclisation was only successful under photochemical conditions, as radical reduction occurred with tin hydride. Nitration of 5,6-dihydroimidazo[2,1-a]isoquinoline with nitric/sulfuric acid occurred at the 2- and 8-positions. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b512729g

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Photochemical intramolecular aromatic substitutions of the imidazol-2-yl
radical are superior to those mediated by Bu3SnH
Maire´ad A. Clyne and Fawaz Aldabbagh*
Received 12th September 2005, Accepted 10th November 2005
First published as an Advance Article on the web 5th December 2005
DOI: 10.1039/b512729g
Six-membered photochemical cyclisations of 2-iodo-N-(2-arylethyl)imidazoles proceeded
regioselectively in higher yields than the equivalent tin hydride-mediated reactions. The decrease in
yield of cyclisation products, 5,6-dihydroimidazo[2,1-a]isoquinolines containing strongly deactivating
substituents on the aryl ring confirmed the electrophilic nature of the r-imidazol-2-yl radicals. The
seven-membered cyclisation was only successful under photochemical conditions, as radical reduction
occurred with tin hydride. Nitration of 5,6-dihydroimidazo[2,1-a]isoquinoline with nitric/sulfuric acid
occurred at the 2- and 8-positions.
reports of preparative examples of the latter.6,15–19 In recent times,
Introduction
Park and co-workers have extensively studied photocyclisations
The use of tributyltin hydride (Bu3SnH) and azobisisobutyronitrile
of aryl and pyridyl radicals onto aromatics, and reported several
synthetically useful examples.18–19 As part of our studies towards
new bioreductive polycyclic diazoles,20 we were interested in
cyclising the imidazol-2-yl radicals 2 onto the aromatic ring of N-
(x-arylalkyl) substituents to give tricyclic [2,1-a] fused heterocycles
3 (Scheme 1). The following paper demonstrates that for the
present aromatic substitutions, UV-mediated radical cyclisations
give higher yields and allow for simpler work up procedures than
the Bu3SnH method. Some reports add tin radical sources to pho-
tochemical substitutions,1b,7 however in our case this was not nec-
essary. Generation of the radical at the imidazole-2-position was
chosen, because cyclisation of aryl radicals is non-regioselective,
as substitution can occur onto either the 2- or 5-position of the im-
idazole ring.8 We thus report the first examples of intramolecular
homolytic aromatic substitutions of imidazole radicals, although
there are two examples of intermolecular reactions.11,21 In the
photolysis, as well as Bu3SnH–AIBN-mediated reactions, r-
imidazol-2-yl radicals 2 and p-cyclohexadienyl radicals can be
assumed to be the reaction intermediates, as laser flash photolysis
has been used to detect and characterize analogous intermediates
in photocyclisations onto aromatics of 2-halopyridinium salts and
2-halo-N-pyridinylbenzamides.19
(AIBN) has become commonplace in the synthesis of fused
aromatics by intramolecular aromatic substitution of aryl and
heteroaryl radicals.1–9 Less toxic and more expensive silanes and
germanes have been used as substitutes for Bu3SnH.7–10 The reac-
tions have attracted mechanistic interest, because an “oxidative”
re-aromatisation occurs in the presence of the “reductant” metal
hydride.11–12 It is now perceived that upon radical addition, the
generated intermediate p-cyclohexadienyl radical surrenders a
hydrogen atom due to abstraction by the azo-initiator and/or
derived radical to give the aromatic product. A non-chain reaction
requiring more than stoichiometric amounts and sometimes large
excesses of azo-initiator in order to form adequate yields of
rearomatised product may be the outcome.11 The AIBN derived 2-
cyano-2-propyl radical can also be trapped by the relatively long-
lived p-cyclohexadienyl radical.2a,11–12 Further, there are serious
toxicity concerns associated with using Bu3SnH, as well as
problems of separation of tin residues from organic products,13
disposal of the wastes and reduction of the intermediate carbon-
centered radicals by Bu3SnH. These many disadvantages associ-
ated with the metal hydride/azo-initiator mediated reactions make
the search for alternative methodologies synthetically important.
Recent alternatives were reported by Harrowven and co-workers
including intramolecular aryl radical cyclisations onto pyridine
mediated by sodium cobalt(I) salophen5 and samarium(II) iodide
(SmI2)–HMPA in THF.7 Tanaka and co-workers showed that
in the absence of i-PrOH, rearomatised products were obtained
from intramolecular arylations mediated by SmI2–HMPA in THF
rather than spirocycles and/or reduced cine-cyclised products.14
Nevertheless, the simplest and most environmentally friendly
protocol has to be the simple generation of the r-aryl or
heteroaryl radical by UV-induced homolytic cleavage of an aryl
halide with subsequent intramolecular substitution onto a nearby
aromatic ring. Metal hydride–AIBN seems to have superseded
the photochemical reaction, although there are mostly older
The 2- and 5-nitroimidazoles (free imidazole numbering) are
well known bioreductive compounds that are used to selectively
target anaerobic diseases, and hypoxic tumours.22 However, ali-
cyclic fused nitroimidazoles are less known cytotoxins with only
limited patent information available on such compounds.23a There-
fore, attempts at nitrating tricyclic diazoles 3b, 3d–f (Scheme 1)
with the aim of forming bioreductive compounds, 2 or 3-nitro-
5,6-dihydroimidazo[2,1-a]isoquinolines 4 are also described.
Results and discussion
Radical cyclisations of the imidazole-2-yl radicals 2a–g
Bu3SnH–AIBN-mediated reactions. The conditions for the
Bu3SnH–AIBN procedure were optimised for the six-membered
radical cyclisation of the imidazol-2-yl radical 2b generated
Department of Chemistry, National University of Ireland, Galway, Ireland.
E-mail: Fawaz.Aldabbagh@nuigalway.ie; Fax: 353 (0)91 525700
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Scheme 1
from bromide 1b in acetonitrile. As with previous homolytic
aromatic substitutions using Bu3SnH–AIBN,11,12 an excess of
AIBN (3.0 equivalents) was required giving cyclised product, 5,6-
dihydroimidazo[2,1-a]isoquinoline 3b in 35% yield with the prod-
uct of Bu3SnH reduction of 2b, 1-(2-phenylethyl)-1H-imidazole
5b obtained in 26% yield (Scheme 2, method A in Table 1). The
poor mass balance in Bu3SnH–AIBN reactions can be primarily
attributed to the cumbersome work up procedure, which required
up to 20 washes with hexane of the acidic imidazolium salts
solution in order to eliminate tin halide residues. During the
course of our studies, Harrowven and Guy reported an improved
procedure for removal of tin residues using KF–silica as the
stationary chromatographic phase,13 which has improved isolation
of diazoles in other Bu3SnH-mediated reactions performed in
our group (radical cyclisations using benzimidazole substrates
to be published). However, for the present work, we wanted to
Scheme 2
completely avoid the use of metal hydride radical sources, and
this was achieved using the photochemical initiated cyclisations
discussed in the next section.
Table 1 Reactions of halides 1a–l
Products (% yields)b
Starting material (SM)
Methoda
Cyclised
Reduced
Recovered SM
1b
1a
1c
1d
1e
1j
1b
1g
1g
5b
1g
1g
1f
A
A
A
A
A
A
B
B
C
B
D
E
B
B
B
B
B
B
3b (35)
3a (0)
5b (26)
5a (45)
5c (65)
5d (19)
5e (31)
5f (51)
5b (0)
5b (0)
5b (0)
—
5b (0)
5b (0)
5a (45)
5a (0)
5c (0)
5e (0)
5f (0)
—
1b (0)
1a (0)
3c (0)
1c (0)
3d (32)
3e (20)
3f (21)
3b (10)
3b (70)
3b (0)
3b (0)
3b (61)
3b (0)
3a (0)
3a (0)
3c (48)
3e (66)
3f (53)
3g (32)
1d (0)
1e (0)
1j (0)
1b (60)
1g (7)
1g (100)
5b (100)
1g (14)
1g (97)
1f (5)
1k (100)
1h (10)
1i (13)
1j (15)
1l (36)
1k
1h
1i
1j
1l
a The methods used were as follows: A. Bu3SnH (1.2 equiv., 51 mM) and AIBN (3.0 equiv.) in acetonitrile were added over 8 h to SM (17 mM) in
acetonitrile under reflux and heated under reflux for a further 1 h. B. SM (20 mM) in acetonitrile (purged with N2) was irradiated at 254 nm for 4–10 h
(refer to the Experimental section). C. SM (20 mM) in acetonitrile (purged with N2) was irradiated at 366 nm for 15 h. D. SM (20 mM) in acetonitrile
(purged with O2) was irradiated at 254 nm for 4 h. E. SM (20 mM) and benzophenone (5.3 equiv.) in acetonitrile (purged with N2) were irradiated at
254 nm for 10 h. b Yields quoted are of the pure isolated compounds after column chromatography.
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Using the same conditions as for Bu3SnH-mediated cyclisation
of 1b, attempted 5-membered and 7-membered cyclisations of
bromides 1a and 1c gave only reduction products 5a and 5c in
45 and 65% isolated yield, respectively.
not be sensitised, and concluded that higher energy excited triplet
states may be involved in the rupture of the C–I bond.21 We
cannot rule out subtle mechanistic differences in our various
photochemical annulations, however most evidence supports the
formation of radical intermediates. Further, the presence of
residual oxygen may be advantageous, as it may be involved in
the rearomatisation of p-cyclohexadienyl radical intermediates 7
(Scheme 3). However, dehydrogenation of radicals 7 by the former
imidazole halogen atom substituent to give HI or HBr and tricyclic
aromatic products is the major source of rearomatisation in UV-
initiated reactions.17,19
Six-membered cyclisations of substrates containing electron-
withdrawing substituents were attempted, in order to deactivate
the fused aryl ring towards the subsequent nitration. 4-Fluoro
1d, 4-chloro 1e and 4-trifluoromethyl (–CF3) 1j substituted pre-
cursors gave tricyclic products 3d (32%), 3e (20%) and 3f (21%),
respectively in lower yield than the radical precursor containing
no aryl substituent 1b. Significant amounts of the respective
reduced products 5d (19%), 5e (31%) and 5f (51%) were also given
(Scheme 2). This procedure should now be compared with the
equivalent photochemical reaction (method B).
Attempts at the 5-membered cyclisation of radical 2a gener-
ated from iodide 1f under photochemical conditions (method
B) resulted in only radical reduction to 1-benzyl-1H-imidazole
5a. The formation of reduction product 5a is further evidence
for intermediate 2a, and a radical-mediated mechanism in the
photochemical initiated reactions. The result may be explained in
terms of strain, as proposed by Bowman and co-workers for the
lack of an anticipated 5-exo-trig cyclisation of a phenyl radical
onto the 5-position of imidazole-4-methylcarboxylate using either
Bu3SnH or tributylgermanium hydride (Bu3GeH) as initiators.8
However, Park and co-workers have reported the formation of the
same ring system, 5H-imidazo[5,1-a]isoindole in 40% yield from
the photochemical cyclisation of N-(o-chlorobenzyl)imidazole.18
Thus it is likely that any strain arguments only apply to the
formation of imidazo[2,1-a]isoindole 3a, and not 5-membered
cyclisations onto the imidazole-5-position. Failed 5-membered
cyclisations may also indicate that such processes are more akin
to proceed via 5-endo-trig rather than 5-exo-trig.7 However, the
low mass balance from the 5-membered photochemical reaction
(50%) is probably due to degradation of substrate and/or products
to unidentified intractable material. There are several successful
literature 5-membered photochemical cyclisations using aromatic
chloride radical precursors.16a,17b–19a 1-Benzyl-2-chloroimidazole
1k was thus irradiated at 254 nm in acetonitrile and 2 M
hydrochloric acid solution.18 It was anticipated that in the photo-
excited state the C–Cl bond may be weakened through co-
ordination of the electrophilic chlorine atom with the phenyl
ring or by Grimshaw’s proposed homolysis assisted by radical
complexation.17 The 2-chloro substituent may be held in closer
proximity to the tethered phenyl ring in 1k containing methylene
rather than for 2-halo substituents in precursors containing
ethylene connectors.19 However, only unaltered 1k was recovered
from both attempted reactions.
The superiority of the photochemical method was however
demonstrated with the seven-membered cyclisation16b to give
6,7-dihydro-5H-imidazo[2,1-a][2]benzazepine 3c in 48% yield via
irradiation of iodide 1h (10% recovered) at 254 nm for 6 h.
Bu3SnH–AIBN reaction of bromide 1c gave only the reduced
compound 1-(3-phenylpropyl)-1H-imidazole 5c (Table 1). The
absence of 5c as a product from the photochemical reaction
confirmed that a 1,5-hydrogen atom abstraction from the benzylic
position was not occurring, and that the cause of the reduction in
the Bu3SnH-mediated reaction was the slower cyclisation of 2c in
comparison to the intermolecular reduction by Bu3SnH. Jones and
Fiumana found that the indol-2-yl radical will undergo a similar
seven-membered cyclisation onto a phenyl ring, but as Bu3SnH
was used, significant reduction also occurred.3d Higher isolated
yields of 3c were not obtained because of degradation of 3c to
Photochemical initiated reactions
In pursuit of higher yields of the six-membered cyclisation product
3b and simpler work up procedures, we irradiated 1b in acetonitrile
for 10 h at 254 nm generated from mercury lamps using a Rayonet
photochemical reactor. This resulted in the isolation of 3b in 10%
yield with 60% unaltered 1b recovered. It seemed that the C–Br
bond is too strong for rapid photochemical generation of r-radical
2b, however we were encouraged by the lack of reduced product.
The photochemical reaction was repeated using iodide precursor
1g resulting in isolation of 3b in 70% yield after only 4 h of
irradiation with 7% recovery of unaltered 1g (method B in Table 1).
This represented a vast improvement on the Bu3SnH–AIBN-
mediated reaction for the following reasons; (i) elimination and
disposal of toxic tin residues was completely avoided, (ii) there was
no need for hazardous azo-initiators, (iii) syringe pump addition of
initiators was no longer required and thus shorter reaction times
were achieved, (iv) a simpler work up procedure allowing good
recovery of cyclised product (improved mass-balance) and (v) no
competitive reduction of 2b occurred.
Iodide precursors for photochemical reactions were generally
prepared in good and comparable yields to bromide precursors
for the Bu3SnH–AIBN reactions by alkylation of 2-iodo-1H-
imidazole rather than 2-bromo-1H-imidazole (refer to the Exper-
imental section). Although, there was no competitive reduction
in our six- and seven-membered photochemical cyclisations,
slow degradation of 3b–c and 3e–g to unidentified products
was observed with prolonged irradiation at 254 nm (monitored
by thin-layer chromatography, TLC) and the probable reversal
of the homolytic scission by combination of the imidazol-2-yl
radicals with released I• led to recovery of starting material (5–
36%). Reaction solutions turned brown after irradiation, and
crude product solutions appeared purple upon elution on column
chromatography indicating the presence of molecular iodine.
However, optimisation of yields by dilution of the reaction solution
was not carried out, as this would lessen the amount of recovered
product. The photolysis of 1g and 5b at the longer wavelengths
of 366 nm (method C) and 254 nm, respectively, gave no reaction
after 15 h of irradiation.
Irradiation of an oxygenated solution of 1g at 254 nm led to a
decrease in yield of 3b to 61% (method D) and the cyclisation of
1g could not be sensitised by benzophenone (method E). D’Auria
and co-workers observed that intermolecular photoarylations of
halogenothiophenes and 4(5)-nitro-2-iodoimidazoles also could
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Scheme 3
unidentifiable products with prolonged exposure to UV-light at
254 nm (as indicated by TLC).
product (3g given in 32% yield), which is indicative of the strong
electron-withdrawing nature of the nitro group (NO2). For the
photochemical reactions, this provides further support for a homo-
lysis mechanism, and the formation of r-imidazole radicals 2.
Therefore, all Bu3SnH–AIBN and photochemical mediated
cyclisations were selective giving only the 9-aryl substituted
isomeric products 3d–g, and no 8-substituted tricyclic products
8. The location of the aryl substituent at the 9- rather than the 8-
position of 3d–g was ascertained by careful NMR analysis (refer
to the Experimental section). For example the location of the 10-
H of 3f was obtained from its down field location, as a singlet
Mechanism of the six-membered cyclisation
The six-membered cyclisation was further investigated using
4-aryl substituents on the 2-halo-1-(2-arylethyl)-1H-imidazole
substrates. The formation of 3b may conceivably occur via an initial
5-exo-trig followed by a rearrangement to the six-membered ring
or 6-exo/endo-trig of the imidazol-2-yl radical 2b (Scheme 3). The
yield of 9-chloro-5–6-dihydroimidazo[2, 1-a]isoquinoline 3e was
much improved using method B in comparison to the Bu3SnH–
AIBN procedure (method A) giving 3e in 66% yield with 13%
unaltered 1i. In order to deactivate the aryl ring towards nitration,
and allow for selective nitration at the diazole-2 or 3-positions
(see nitration discussion), iodide 1j containing a 4-trifluoromethyl
substituent on the aryl ring was irradiated at 254 nm giving cyclised
product 3f in 53% yield. Thus, iodide 1j gave the lowest yield of
cyclised product of all the aryl halide-containing substrates. This is
in line with the electrophilic character of the imidazol-2-yl radical
due to the inductive electron-withdrawing effect of the adjacent
nitrogen atoms11 creating a slower cyclisation for 2f compared to 2b
and 2d–e, since the CF3 substituent is more strongly deactivating
(inductively electron-withdrawing) than the 4-fluoro and chloro
substituents. The photolysis of iodide 1l yielded least cyclised
1
at 8.31 ppm in the H NMR spectrum. This signal did not give
1
any NOE enhancement. The HMQC, H-13C NMR 2D spectra
allowed us to assign the 10-CH at 121–124 ppm for 3b, 3e–f. The
10-CH appeared relatively up field in 3d at 110.2–110.5 ppm, and
the magnitude of C–F couplings allowed us to assign all aromatic
signals. The preparation of 3g and nitration to 4e (see nitration
discussion, Scheme 4) allowed us to confirm that the aryl-NO2
substituent in 3g and 4e is at the 9-position, since 4e is the isomer
of 4a.
The 5-exo-trig cyclisations give spirocycles 6a and 6b, which
would rearrange to tricyclic cyclohexadienyl radicals 7a and 7b
respectively. Oxidative rearomatisation of 7a would give tricyclic
products 3b, 3d–g, while oxidation of 7b would give the isomeric
products 8 (Scheme 3). The rearrangements of 6a to 7a and 6b to 7b
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1-alkyl-4-nitroimidazoles, since the equivalent 5-nitro isomer has
4-CH at 132–133 ppm. Confirmation of assignments was obtained
using NOE irradiation at 8.62 ppm for the 3-CH of 4b, which gave
the required enhancement at 4.36–4.39 ppm for the NCH2 of the
fused six-membered ring.
Conclusions
Six-membered cyclisations of 2-iodo-N-(2-arylethyl)imidazoles
1g, 1i–j at 254 nm gave higher yields of 5,6-dihydroimidazo[2,1-
a]isoquinolines 3b, 3e–f than the equivalent radical cyclisations us-
ing 2-bromo(iodo)-N-(2-arylethyl)imidazoles 1b, 1e and 1j under
Bu3SnH–AIBN-mediated conditions. All Bu3SnH–AIBN reac-
tions gave a considerable amount of radical reduction products 5b,
5d–f, and the ratio of reduced/cyclised products increased for sub-
strates containing inductively electron withdrawing substituents at
the 4-position of the aryl ring (e.g. Cl and CF3). Yields of cyclised
product were also considerably less in photochemical reactions
of substrates containing 4-aryl deactivating substituents 1j and 1l
(CF3 and NO2, respectively) leading to the recovery of increasing
amounts of unaltered starting material. This is rationalised in
terms of slow cyclisation of an electrophilic r-imidazol-2-yl radical
onto a deactivated aromatic ring. The formation of 9-substituted
tricyclic imidazoles from the six-membered cyclisations inferred
that a 6-exo/endo cyclisation is the most likely route for formation
of tricyclic products.
Scheme 4
would involve 1,2-aryl (neophyl rearrangement) and 1,4-aryl shifts
respectively,24 and such rearrangements are thermodynamically
favoured since more stable ring-enlarged conjugated tertiary
cyclohexadienyl radicals 7a and 7b are formed. The absence of
isomeric products 8 from all our six-membered cyclisations would
support 5-exo- and 6-exo/endo pathways via intermediates 7a and
not 7b. However, we believe that the latter direct six-membered
cyclisation is more likely since rearrangement pathways via 6a–
b are most favoured at low tin hydride concentrations (i.e. the
photochemical reaction), and such spirocyclic intermediates were
not observed in flash photolysis studies of six-membered radical
cyclisations of r-pyridyl and aryl radicals onto aromatic rings.19
Further support for the 6-exo/endo pathway is provided by the
lack of a five-membered cyclisation for imidazol-2-yl radical 2a.
A rare example of a seven-membered photochemical homolytic
aromatic substitution is provided by the conversion of 2-iodo-
1-(3-phenylpropyl)imidazole 1h into 6,7-dihydro-5H-imidazo[2,1-
a][2]benzazepine 3c. The equivalent Bu3SnH–AIBN-mediated
reaction gave only reduced product 5c. Attempted five-membered
cyclisations of 1-benzyl-2-halo-1H-imidazoles 1a, 1f and 1k under
both photochemical and Bu3SnH–AIBN-mediated conditions
gave only radical reduction product 5a or recovery of starting
material for the irradiation of the 2-chloro substrate 1k at 254 nm.
Although yields for the photochemical reactions could not be
improved, because of decomposition of products over prolonged
irradiation times, yields were always substantially greater than
the equivalent Bu3SnH method. The photochemical method
circumvents the use of toxic and hazardous initiators and allowed
a simpler work-up procedure. Thus, it is possible that this method
may be applicable to other intramolecular aromatic substitution
reactions of r-aryl and heteroaryl radicals previously carried out
using Bu3SnH–AIBN.
Nitration of unsubstituted 3b and 9-fluoro 3d and chloro 3e
substituted tricyclic diazoles occurred at 2 and 8-positions. Deac-
tivation of the fused aryl moiety in 3f and 3g by 9-trifluoromethyl
and nitro substituents allowed selective nitration at the 2-position.
Future work in our group will attempt preparations of 3-nitro-5,6-
dihydroimidazo[2,1-a]isoquinolines in order to compare reductive
and cytotoxicity properties with the 2-nitroisomers prepared in
this paper.
Nitration of tricyclic diazoles 3b, 3d–g
1-Methylimidazoles usually give a mixture of 4 and 5-nitro
isomers upon nitration under electrophilic aromatic substitution
conditions with the 4-isomer predominating.25 However, it was not
clear from the literature, where the substitution of the nitro group
would occur upon treatment of tricyclic diazoles 3b, 3d–g with
mixtures of concentrated nitric and sulfuric acid. The resultant
2 or 3-nitro-5,6-dihydroimidazo[2,1-a]isoquinolines would be of
interest, because of their conjugated ring system possibly leading
to lower reductive potentials than commercially available 1-alkyl-
2(5)-nitroimidazole antibiotics (more stable radical anion would
be formed upon single-electron reductive activation). Reductive
potentials are known to influence the cytotoxicity and selectivity
of bioreductive compounds.20,22
All nitration reactions gave only one product with the 2-position
of the diazole ring found to be the most easily nitrated (Scheme 4).
However nitration occurred at the 8-position as well as the 2-
position for 3b, 3d and 3e giving 2,8-dinitro compounds 4a (50%),
4b (70%) and 4c (70%), respectively. Thus activation of the 8-
position through p-conjugation of the adjacent 9-fluoro- and
chloro-substituents is significant. Deactivation of the aryl ring
was achieved with CF3 and NO2 substituents leading to selective
nitration at the 2-position of 3f and 3g giving 2-nitro and 2,9-
dinitro compounds 4d (68%) and 4e (50%) respectively. Compound
4e is an isomer of 4a, and was required to confirm that the nitration
of 3b had resulted in the NO2 substituent being located at the 8-
rather than the 9-position of 4a.
Experimental
The location of the NO2 substituent at the 2-position rather
than the 3-position was ascertained using literature chemical
shifts for 4- and 5-nitro-1-alkylimidazoles.26 13C NMR spectra of
compounds 4a–e all contained CH at 123–125 ppm assigned to the
3-CH, which is of similar chemical shift magnitude to the 5-CH of
General
Materials. All chemicals were obtained from Aldrich, except
AIBN, which was obtained from DuPont Chemical Solution
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Enterprise, and was re-crystallized using methanol before use.
Monitoring of reactions by thin later chromatography (TLC) was
performed using aluminium backed plates coated with silica gel
(Merck Kieselgel 60 F254). Column chromatography using silica
gel was carried out using Merck Kiesel 60 H silica.
2-Bromo-1-(3-phenylpropyl)-1H-imidazole (1c). 2-Bromo-1H-
imidazole (0.16 g, 1.09 mmol), sodium hydride (0.03 g, 1.33 mmol)
and 3-(bromopropyl)benzene (0.26 ml, 1.74 mmol) in THF (15 ml)
gave title compound 1c (0.27 g, 93%) as a colourless oil; Rf 0.54
(1 : 1 hexane–ethyl acetate), (found: C, 54.0; H, 4.8; N, 10.6.
C12H13N2Br requires C, 54.4; H, 4.9; N, 10.6%); mmax/cm−11603,
1468, 1434, 1348, 1265, 1101, 908; dH (CDCl3) 2.04–2.13 (2 H, m,
2ꢀ-CH2), 2.62–2.66 (2 H, t, J 7.6, CH2Ph), 3.89–3.93 (2 H, t, J
7.1, NCH2), 6.95 (1 H, s, Im-5-H), 7.01 (1 H, s, Im-4-H), 7.16–
7.32 (5 H, m, Ph–H); dC (CDCl3) 31.6 (2ꢀ-CH2Ph), 32.4 (CH2Ph),
47.0 (NCH2), 119.4 (Im-2-C), 121.8 (Im-5-CH), 126.2 (CH), 128.2
(CH), 128.6 (CH), 129.9 (CH), 140.1 (Ph-1-C); m/z (EI) 266 (2),
264 (M+, 3%), 186 (17), 185 (100), 162 (30), 160 (31), 157 (14), 117
(29), 91 (50), 81 (28), 77 (15)
Measurements. Melting points were measured on a Stuart
Scientific melting point apparatus SMP3. Elemental analysis was
carried out on a Perkin-Elmer 2400 Series II analyser. IR spectra
were acquired using a Perkin-Elmer Spec 1 with ATR attached.
All 1H and 13C NMR spectra were recorded at 400 and 100 MHz
respectively using a Jeol GXFT 400 MHz instrument equipped
with a DEC AXP 300 computer work station. Chemical shifts
are given in parts per million (ppm) and J values are in Hz. NMR
assignments were supported by NOE difference spectra (400 MHz)
and heteronuclear multiple-quantum correlation (HMQC) 1H–13C
2D spectra for compounds 3b, 3f, 3g and 4b. HMQC 1H–13C 2D
spectra were also carried out on compounds 1l, 3c, 3d, 4c, 4d and
5f.
Low and high resolution electron impact (EI) and chemical
ionisation (CI) mass spectra were obtained on a Micro Mass
GTC spectrometer. EPSRC National Mass Spectrometry Service
carried out low resolution EI on the Micromass Quattro II triple
quadrupole instrument and high-resolution mass spectrometry on
the Finnigan MAT 900 XLT in CI mode for compounds 1l, 3g and
4a–d.
2-Bromo-1-[2-(4-fluorophenyl)ethyl]-1H-imidazole (1d). 2-
Bromo-1H-imidazole (0.50 g, 3.40 mmol), sodium hydride
(0.10 g, 4.08 mmol) and 1-(2-bromoethyl)-4-fluorobenzene (1.10 g,
5.44 mmol) in THF (40 ml) gave title compound 1d (0.78 g, 86%) as
a cream solid; Rf 0.46 (1 : 1 hexane–ethyl acetate), mp 80–82 ◦C;
mmax/cm−1 3099, 1601, 1509, 1464, 1279, 1220, 914; dH (CDCl3)
2.99–3.02 (2 H, t, J 7.1, CH2Ar), 4.10–4.14 (2 H, t, J 7.1, NCH2),
6.76–6.77 (1 H, d, J 1.5, Im-5-H), 6.96–7.05 (5 H, m, Ar–H); dC
(CDCl3) 36.0 (CH2Ar), 49.1 (NCH2), 115.5–115.7 (d, JC–F 21.1,
Ar-3,5-CH), 119.2 (Im-2-C), 121.9 (Im-5-CH), 129.8 (Im-4-CH),
130.2–130.3 (d, JC–F 9.0, Ar-2,6-CH), 132.6 (Ar-1-C), 160.7–163.7
(d, JC–F 243.9, Ar-4-C); m/z (EI) 268.0016 (5%, M+, C11H10N2BrF
requires M+ 268.0011), 189 (100), 109 (98).
Synthesis of radical precursors. 2-Bromo-1H-imidazole, 2-
chloro-1H-imidazole and 2-iodo-1H-imidazole were prepared us-
ing literature procedures.27 Radical precursors 1a–k were prepared
in mostly good to excellent yields of 59–93% (apart from 1j
prepared in 27% yield) by appropriate alkylation of the 2-halo-1H-
imidazoles with x-arylalkyl bromide using the procedure given for
1a as a representative example. Radical precursor 1l was prepared
differently, because 1-(2-bromoethyl)-4-nitrobenzene was found to
readily eliminate in the presence of sodium hydride to give 1-nitro-
4-vinylbenzene.
2-Bromo-1-[2-(4-chlorophenyl)ethyl]-1H-imidazole (1e). 2-
Bromo-1H-imidazole (0.38 g, 2.59 mmol), sodium hydride (0.07 g,
2.90 mmol) and 1-(2-bromoethyl)-4-chlorobenzene (0.57 g,
4.13 mmol) in THF (30 ml) gave title compound 1e (0.52 g, 71%) as
a yellow oil; Rf 0.66 (1 : 1 hexane–ethyl acetate); mmax/cm−1 1598,
1492, 1467, 1434, 1267, 1092, 1015, 908; dH (CDCl3) 2.98–3.02
(2 H, t, J 7.3, CH2Ar), 4.11–4.14 (2 H, t, J 7.3 Hz, NCH2), 6.77
(1 H, s, Im-5-H), 6.96 (1 H, s, Im-4-H), 6.99–7.01 (2 H, d, J 8.3,
Ar–H), 7.25–7.27 (2 H, d, J 8.3, Ar–H); dC (CDCl3) 36.2 (CH2Ar),
48.9 (NCH2), 119.1 (Im-2-C), 122.0 (Im-5-CH), 128.9 (CH), 129.8
(CH), 130.1 (CH), 132.7 (C), 135.3 (C); m/z 283.9714 (2%, M+,
C11H10N2BrCl requires M+ 283.9716), 286 (22), 284 (14), 205 (100),
160 (6), 158 (8), 139 (3), 138 (2), 127 (5), 125 (92), 103 (2).
1-Benzyl-2-bromo-1H-imidazole (1a). 2-Bromo-1H-imidazole
(0.20 g, 1.36 mmol), sodium hydride (0.04 g, 1.63 mmol) in THF
(15 ml) were stirred at reflux for 1 h under a nitrogen atmosphere.
Benzyl bromide (0.26 ml, 2.18 mmol) was added and stirred at
reflux for a further 3 h. The solution was filtered and evaporated
to dryness to yield a residue, which was purified by column
chromatography using silica as absorbent with gradient elution
of hexane–ethyl acetate–methanol to yield the title compound 1a
(0.27 g, 84%) as a colourless oil. Spectroscopic data were consistent
with the literature.28
1-Benzyl-2-iodo-1H-imidazole (1f). 2-Iodo-1H-imidazole (0.35 g,
1.81 mmol), sodium hydride (0.05 g, 2.08 mmol) and benzyl
bromide (0.26 ml, 2.17 mmol) in THF (25 ml) gave title compound
1f (0.30 g, 59%) as a cream solid; Rf 0.44 (1 : 1 hexane–ethyl
acetate), mp 99–100 ◦C (lit.,29 99–101 ◦C), (found: C, 42.4; H, 3.4;
N, 9.8. C10H9N2I requires C, 42.4; H, 3.2; N, 9.9%). Spectroscopic
data were consistent with the literature.29
2-Bromo-1-(2-phenylethyl)-1H-imidazole (1b). 2-Bromo-1H-
imidazole (0.50 g, 3.40 mmol), sodium hydride (0.10 g, 4.08 mmol)
and (2-bromoethyl)benzene (0.74 ml, 5.44 mmol) in THF (40 ml)
gave the title compound 1b (0.53 g, 62%) as a cream solid; Rf 0.56
(1 : 1 hexane–ethyl acetate), mp 99–101 ◦C; (found: C, 52.3; H, 4.6;
N, 11.1. C11H11N2Br requires C, 52.6; H, 4.4; N, 11.1%); mmax/cm−1
3099, 1603, 1497, 1460, 1276, 1167, 1113, 913; dH (CDCl3) 3.00–
3.03 (2 H, t, J 7.3, CH2Ph), 4.11–4.15 (2 H, t, J 7.3, NCH2), 6.78
(1 H, s, Im-5-H), 6.94 (1 H, s, Im-4-H), 7.24–7.31 (5 H, m, Ph–
H); dC (CDCl3) 36.8 (CH2Ph), 49.1 (NCH2), 119.1 (Im-2-C), 121.9
(Im-5-CH), 126.9 (CH), 128.7–129.6 (CH), 136.9 (Ph-1-C); m/z
(EI) 250 (M+, 3%), 171 (100), 105 (52), 91 (85).
2-Iodo-1-(2-phenylethyl)-1H-imidazole (1g). 2-Iodo-1H-imi-
dazole (0.40 g, 2.06 mmol), sodium hydride (0.06 g, 2.47 mmol)
and (2-bromoethyl)benzene (0.45 ml, 3.30 mmol) in THF (25 ml)
gave title compound 1g (0.51 g, 83%) as a cream solid; Rf 0.66 (ethyl
acetate), mp 99–101 ◦C, (found: C, 44.1; H, 3.5; N, 9.0. C11H11N2I
requires C, 44.3; H, 3.7; N, 9.4%); mmax/cm−1 1587, 1490, 1450,
1420, 1263, 1090, 1057, 933, 910; dH (CDCl3) 3.00–3.04 (2 H, t, J
7.3, CH2Ph), 4.10–4.14 (2 H, t, J 7.3, NCH2), 6.87 (1 H, s, Im-5-H),
7.04 (1 H, s, Im-4-H), 7.09–7.10 (2 H, d, J 6.8, Ph–H), 7.25–7.32
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(3 H, m, Ph–H); dC (CDCl3) 37.2 (CH2Ph), 50.9 (NCH2), 89.7 (Im-
2-C), 123.0 (Im-5-CH), 127.0 (CH), 128.7 (CH), 132.4 (CH), 136.9
(Ph-1-C); m/z (EI) 297.9962 (14%, M+, C11H11N2I requires M+
297.9967), 207 (63), 172 (100), 171 (78), 170 (49), 156 (72), 126
(77), 105 (56), 104 (29), 103 (26), 91 (78).
3.45 mmol) in DMF (80 ml) were stirred at reflux for 30 min.
1-(2-Bromoethyl)-4-nitrobenzene (0.42 g, 6.90 mmol) was added
and stirred at reflux for a further 2 h. The solution was filtered and
evaporated to dryness to yield a residue, which was purified by
column chromatography using silica as absorbent with gradient
elution of hexane–ethyl acetate–methanol to yield title compound
1l (0.46 g, 39%) as a yellow oil; Rf 0.44 (ethyl acetate); mmax/cm−1
1600, 1513 (NO2), 1424, 1343 (NO2), 1264, 1095; dH (CDCl3) 3.12–
3.16 (2 H, t, J 7.1, CH2Ar), 4.15–4.19 (2 H, t, J 7.1, NCH2),
6.84 (1 H, s, Im-5-H), 7.04 (1 H, s, Im-4-H), 7.23–7.25 (2 H, d,
J 8.5, Ar-2,6-H), 8.13–8.15 (2 H, d, J 8.5, Ar-3,5-H); dC (CDCl3)
37.1 (CH2Ar), 50.1 (NCH2), 90.0 (Im-2-C), 123.0 (Im-5-CH),
124.1 (Ar-3,5-CH), 129.9 (Ar-2,6-CH), 133.0 (Im-4-CH), 144.6
(C), 147.3 (C); m/z (CI) 343.9895 (66%, M + H+, C11H11N3O2I
requires M + H+ 343.9890), 314 (16), 216 (16), 188 (33), 186 (18),
91 (100).
2-Iodo-1-(3-phenylpropyl)-1H-imidazole (1h). 2-Iodo-1H-imi-
dazole (0.38 g, 1.96 mmol), sodium hydride (0.06 g, 2.45 mmol)
and 3-(bromopropyl)benzene (0.51 ml, 3.33 mmol) in THF (25 ml)
gave title compound 1h (0.51 g, 83%) as a cream solid; Rf 0.53 (ethyl
acetate), mp 97–99 ◦C, (found: C, 46.4; H, 4.3; N, 9.0. C12H13N2I
requires C, 46.2; H, 4.2; N, 9.0%); mmax/cm−1 1603, 1453, 1423,
1264, 1096, 908; dH (CDCl3) 2.06–2.14 (2 H, m, 2ꢀ-CH2Ph), 2.63–
2.67 (2 H, t, J 7.8, CH2Ph), 3.88–3.92 (2 H, t, J 7.3, NCH2), 7.01 (1
H, s, Im-5-H), 7.09 (1 H, s, Im-4-H), 7.17–7.32 (5 H, m, Ph–H); dC
(CDCl3) 31.9 (2ꢀ-CH2Ph), 32.5 (CH2Ph), 48.9 (NCH2), 90.0 (Im-2-
C), 122.8 (Im-5-CH), 126.3 (CH), 128.3 (CH), 128.6 (CH), 132.60
(CH), 140.2 (Ph-1-C); m/z (EI) 312 (8%), 208 (69), 185 (100), 127
(95), 117 (79), 91 (97).
General procedure for Bu3SnH-mediated radical cyclisations
(method A)
1-[2-(4-Chlorophenyl)ethyl]-2-iodo-1H-imidazole (1i). 2-Iodo-
1H-imidazole (0.50 g, 2.57 mmol), sodium hydride (0.07 g,
3.08 mmol) and 1-(2-bromoethyl)-4-chlorobenzene (0.85 g,
3.87 mmol) in THF (35 cm3) gave title compound 1i (0.53 g, 62%)
as a yellow oil; Rf 0.72 (ethyl acetate); mmax/cm−1 1597, 1491, 1458,
1423, 1265, 1090, 1015, 907; dH (CDCl3) 2.96–3.00 (2 H, t, J 7.1,
CH2Ar), 4.06–4.10 (2 H, t, J 7.1, NCH2), 6.83 (1 H, s, Im-5-H),
7.00–7.03 (2 H, d, J 8.2, Ar–H), 7.03 (1H, s, Im-4-H), 7.24–7.25
(2 H, d, J 8.2, Ar–H); dC (CDCl3) 36.6 (CH2Ar), 50.8 (NCH2), 89.9
(Im-2-C), 123.1 (Im-5-CH), 129.0 (CH), 130.0 (CH), 132.7 (CH),
133.0 (C), 135.3 (C); m/z (EI) 331.9576 (24%, M+, C11H10N2ClI
requires M+ 331.9577), 207 (60), 206 (10), 205 (100), 204 (15), 170
(24), 169 (13), 127 (24), 125 (82), 103 (20).
Attempted synthesis of 5H-imidazo[2,1-a]isoindole (3a)23b using
method A. Bu3SnH (0.67 ml, 2.53 mmol) and AIBN (1.04 g,
6.33 mmol) in acetonitrile (50 ml) was added over 8 h via syringe
pump to 1a (0.50 g, 2.11 mmol) in acetonitrile (125 ml) at reflux
under a nitrogen atmosphere. The solution was stirred at reflux for
a further 1 h, cooled to ambient temperature and evaporated to
dryness. Hydrochloric acid (4 M, 30 ml) was added, and the acidic
solution washed with hexane (20 × 30 ml). The aqueous solution
was basified with saturated sodium carbonate solution (40 ml),
extracted with dichloromethane (3 × 70 ml) and dried (MgSO4).
The organic extracts were evaporated to dryness to yield a brown
residue, which was purified by column chromatography using silica
gel as absorbent with gradient elution of hexane and ethyl acetate
as eluent to yield 1-benzyl-1H-imidazole 5a (0.15 g, 45%) as white
needles; mp 70–72 ◦C (mp30 70–72 ◦C), (found: C, 75.9; H, 6.3; N,
17.5. C10H10N2 requires C, 75.9; H, 6.3; N, 17.7%); spectroscopic
data were consistent with the literature.30
2-Iodo-1-{2-[4-(trifluoromethyl)phenyl]ethyl}-1H-imidazole (1j).
2-Iodo-1H-imidazole (0.37 g, 1.91 mmol), sodium hydride (0.06 g,
2.29 mmol) and 1-(2-bromoethyl)-4-(trifluoromethyl)benzene
(0.72 g, 2.86 mmol) in THF (35 ml) gave title compound 1j (0.19 g,
27%) as a yellow oil; Rf 0.50 (ethyl acetate); mmax/cm−1 1619, 1459,
1424, 1323, 1162, 1009, 1065, 1018; dH (CDCl3) 3.07–3.11 (2 H,
J 7.3, CH2Ar), 4.13–4.16 (2 H, t, J 7.3, NCH2), 6.87 (1 H, s, Im-
5-H), 7.05 (1 H, s, Im-4-H), 7.19–7.21 (2 H, d, J 8.3, Ar-2,6-H),
7.54–7.56 (2 H, d, J 8.3, Ar-3,5-H); dC (CDCl3) 36.9 (CH2Ar),
50.3 (NCH2), 89.8 (Im-2-C), 122.9 (Im-5-CH), 125.6 (CH), 129.1
(CH), 132.6 (CH), 140.9 (C); m/z (CI) 366.9912 (100%, M + H+,
C12H11N2F3I requires M + H+ 366.9919), 346 (14).
5,6-Dihydroimidazo[2,1-a]isoquinoline (3b)23c using method A.
Bu3SnH (0.32 ml, 1.20 mmol), AIBN (0.49 g, 2.99 mmol) in
acetonitrile (24 ml) and 1b (0.25 g, 1.00 mmol) in acetonitrile
(60 ml) gave title compound 3b (0.06 g, 35%) and 1-(2-phenylethyl)-
1H-imidazole (0.04 g, 26%) in order of elution after column
chromatography.
3b, yellow oil; Rf 0.30 (ethyl acetate); mmax/cm−1 1499, 1471,
1452, 1327, 1282, 1099; dH (CDCl3) 3.14–3.17 (2 H, t, J 6.8,
CH2Ar), 4.15–4.19 (2 H, t, J 6.8, NCH2), 6.94 (1 H, s, 3-H),
7.15 (1 H, s, 2-H), 7.22–7.36 (3 H, m, Ar–H), 8.03 (1 H, d, J 7.8,
10-H); NOE irradiation at dH 8.03 led to enhancement at dH 7.22–
7.36; dC (CDCl3) 28.5 (CH2Ar), 43.4 (NCH2), 119.3 (3-CH), 123.5
(10-CH), 126.6 (6a-C), 127.6 (CH), 127.8 (CH), 128.4 (CH), 128.6
(CH), 132.5 (10a-C), 144.0 (10b-C); m/z (EI) 170.0846 (100%, M+,
C11H10N2 requires M+ 170.0844), 169 (60), 168 (57), 128 (16).
1-Benzyl-2-chloro-1H-imidazole (1k). 2-Chloro-1H-imidazole
(0.14 g, 1.37 mmol), sodium hydride (0.04 g, 1.50 mmol) and
benzyl bromide (0.16 ml, 1.37 mmol) in THF (20 ml) gave title
compound 1k (0.22 g, 84%) as a colourless oil; Rf 0.61 (1 : 1
hexane–ethyl acetate); mmax/cm−1 1471, 1454, 1437, 1388, 1362,
1272, 1105, 910; dH (CDCl3) 5.07 (2 H, s, CH2), 6.87 (1 H, s, Im-
5-H), 6.95 (1H, s, Im-4-H), 7.13–7.15 (2 H, m, Ph–H), 7.30–7.35
(3 H, m, Ph–H); dC (CDCl3) 50.3 (CH2), 121.2 (Im-5-CH), 127.4
(Im-4-CH), 128.4 (CH), 128.6 (CH), 129.1 (CH), 132.3 (C), 135.5
(C); m/z (EI) 194 (30), 192.0449 (88%, M+, C10H9N2Cl requires M+
192.0454) 92 (100), 91 (92), 65 (31).
1-(2-Phenylethyl)-1H-imidazole (5b). yellow oil, Rf 0.50 (1 : 4
methanol–ethyl acetate); spectroscopic data were consistent with
the literature.31
Attempted synthesis of 6,7-dihydro-5H-imidazo[2,1-a][2]benz-
azepine (3c)23c using method A. Bu3SnH (0.54 ml, 2.04 mmol),
AIBN (0.84 g, 5.09 mmol) in acetonitrile (40 ml) and 1c (0.45 g,
2-Iodo-1-[2-(4-nitrophenyl)ethyl]-1H-imidazole (1l). 2-Iodo-1H-
imidazole (0.67 g, 3.45 mmol) and potassium carbonate (0.48 g,
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1.70 mmol) in acetonitrile (102 ml) gave 1-(3-phenylpropyl)-
1H-imidazole 5c (0.19 g, 65%) as a yellow oil; Rf 0.50 (1 : 4
methanol–ethyl acetate); spectroscopic data were consistent with
the literature.31
(7-CH), 129.7 (2-CH), 135.9 (10a-C) 143.2 (10b-C), 149.7 (9-C);
m/z (EI) 238.0723 (100%, M+, C12H9N2F3 requires M+ 238.0718),
203 (32), 168 (12).
1-{2-[4-(Trifluoromethyl)phenyl]ethyl}-1H-imidazole (5f).
colourless oil; Rf 0.50 (1 : 4 methanol–ethyl acetate); mmax/cm−1
1619, 1506, 1300, 1162, 1106, 1065, 1019, 906; dH (CDCl3) 3.09–
3.13 (2 H, t, J 6.8, CH2Ar), 4.18–4.21 (2 H, t, J 6.8, NCH2), 6.83 (1
H, s, Im-5-H), 7.05 (1 H, s, Im-4-H), 7.14–7.16 (2 H, d, J 7.8, Ar-
2,6-H), 7.30 (1 H, s, Im-2-H), 7.53–7.55 (2 H, d, J 7.8, Ar-3,5-H);
dC (CDCl3) 37.6 (CH2Ar), 48.0 (NCH2), 118.6 (Im-5-CH), 125.6
(Ar-3,5-CH), 128.9 (Ar-2,6-CH), 129.7 (Im-4-CH), 137.0 (Im-2-
CH), 141.4 (Ar-1-C); m/z (EI) 240.0874 (100%, M+, C12H11N2F3
requires M+ 240.0874), 203 (32), 168 (12).
9-Fluoro-5,6-dihydroimidazo[2,1-a]isoquinoline (3d) using method
A. Bu3SnH (0.77 ml, 2.90 mmol), AIBN (1.20 g, 7.26 mmol) in
acetonitrile (57 ml) and 1d (0.65 g, 2.42 mmol) in acetonitrile
(145 ml) gave title compound 3d (0.15 g, 32%) and 1-[2-(4-
fluorophenyl)ethyl]-1H-imidazole (0.09 g, 19%) in order of elution
after column chromatography.
3d, yellow oil; Rf 0.44 (ethyl acetate); mmax/cm−1 1615, 1504,
1467, 1449, 1282, 1210, 1168, 872; dH (CDCl3) 3.10–3.13 (2 H, t,
J 6.8, CH2Ar), 4.14–4.18 (2 H, t, J 6.8, NCH2), 6.93–6.97 (2 H,
m, Ar–H), 7.15–7.20 (2 H, m, Ar–H), 8.03 (1 H, m, 10-H); dC
(CDCl3) 27.9 (CH2Ar), 43.4 (NCH2), 110.2–110.5 (d, JC–F 25.1,
10-CH), 114.9–115.2 (d, JC–F 22.0, 8-CH), 119.5 (3-CH), 127.9 (6a-
C), 128.8–128.9 (d, JC–F 10.0, 10a-C), 129.3 (2-CH), 129.3–129.4
(d, J 7.0, 7-CH), 143.4 (10b-C), 161.1–163.5 (d, JC–F 244.8, C–F);
m/z (EI) 188.0750 (72%, M+, C11H9N2F requires M+ 188.0750),
187 (100), 146 (2).
Information on the photochemical reactor
The photochemical reactions were carried out at 254 and 366 nm
using Rayonet photochemical reactors, RPR-100, encompassing
sixteen mercury lamps.
General procedure for photochemical radical cyclisations
(method B)
1-[2-(4-Fluorophenyl)ethyl]-1H-imidazole (5d). yellow oil; Rf
0.45 (1 : 4 methanol–ethyl acetate); spectroscopic data were
consistent with the literature.31
5,6-Dihydroimidazo[2,1-a]isoquinoline (3b) using photochemical
reactor. A solution of 1g (0.41 g, 1.37 mmol) in acetonitrile
(70 ml) was degassed with N2 for 20 min in a cylindrical quartz
tube, and irradiated at 254 nm. The reaction was monitored by
TLC, and removed when the starting iodide 1g appeared to be
consumed, in this case after 4 h. The solution was evaporated
to dryness, and 30% sodium carbonate solution (30 ml) added,
and extracted with dichloromethane (2 × 30 ml). The combined
organic extracts dried (MgSO4) and evaporated to dryness to yield
a brown residue, which was purified by column chromatography
using silica gel as absorbent with gradient elution of hexane and
ethyl acetate as eluent to yield the title compound 3b (0.16 g, 70%),
and recovered starting material 1g (0.03 g, 7%).
Method C. The procedure for method B was repeated using 1g
(0.20 g, 0.67 mmol) in acetonitrile (34 ml) degassed with N2 for
20 min in a cylindrical Pyrex tube, and irradiated at 366 nm for
15 h giving recovered starting material 1g (0.20 g, 100%).
Method D. The procedure for method B was repeated using 1g
(0.20 g, 0.67 mmol) in acetonitrile (34 ml) purged with O2 for
20 min in a cylindrical quartz tube, and irradiated at 254 nm for
4 h giving 3b (0.07 g, 61%), and recovered starting material 1g
(0.03 g, 14%) after column chromatography.
9-Chloro-5,6-dihydroimidazo[2,1-a]isoquinoline (3e) using
method A. Bu3SnH (0.53 ml, 2.02 mmol) and AIBN (0.83 g,
5.04 mmol) in acetonitrile (40 ml) and 1e (0.48 g, 1.68 mmol) in
acetonitrile (100 ml) gave the title compound 3e (0.07 g, 20%) and
1-[2-(4-chlorophenyl)ethyl]-1H-imidazole (0.11 g, 31%) in order
of elution after column chromatography.
3e, white solid; Rf 0.50 (ethyl acetate), mp 63–66 ◦C; mmax/cm−1
1601, 1498, 1456 1426, 1281, 1088; dH (CDCl3) 3.11–3.14 (2 H, t,
J 6.8, CH2Ar), 4.15–4.18 (2 H, t, J 6.8, NCH2), 6.95 (1 H, s, 3-H),
7.05–7.26 (3 H, m, Ar–H), 8.02 (1 H, J 1.5 Hz, 10-H); dC (CDCl3)
28.1 (CH2Ar), 43.2 (NCH2), 119.5 (3-CH), 123.6 (10-CH), 128.2
(CH), 128.7 (C), 129.1 (CH), 129.5 (CH), 130.5 (C), 133.6 (C),
143.1 (10b-C); m/z (EI) 206 (9), 205 (3), 204.0449 (100%, M+,
C11H9N2Cl requires M+ 204.0454), 203 (33).
1-[2-(4-chlorophenyl)ethyl]-1H-imidazole (5e). colourless oil;
Rf 0.52 (1 : 4 methanol–ethyl acetate); spectroscopic data were
consistent with the literature.31
9-(Trifluoromethyl)-5,6-dihydroimidazo[2,1-a]isoquinoline (3f)
using method A. Bu3SnH (0.11 ml, 0.42 mmol) and AIBN (0.18 g,
1.06 mmol) in acetonitrile (8 ml) and 1j (0.13 g, 0.35 mmol)
in acetonitrile (21 ml) gave the title compound 3f (0.02 g, 21%)
and 1-{2-[4-(trifluoromethyl)phenyl]ethyl}-1H-imidazole (0.04 g,
51%) in order of elution after column chromatography, 3f, white
solid, Rf 0.45 (ethyl acetate); mp 130–132 ◦C; mmax/cm−1 1630,
1461, 1324, 1264, 1162, 1103, 1067, 902; dH (CDCl3) 3.20–3.24 (2
H, t, J 6.8, CH2Ar), 4.19–4.23 (2 H, t, J 6.8, NCH2), 6.98 (1 H, s,
3-H), 7.18 (1 H, s, 2-H), 7.34–7.36 (1 H, d, J 7.8, 7-H), 7.50–7.51
(1 H, d, J 7.8, 8-H), 8.31 (1 H, s, 10-H); NOE irradiation at dH
3.20–3.24 led to enhancement at dH 4.19–4.23 and dH 7.34–7.36.
Irradiation at dH 4.19–4.23 led to enhancement at dH 3.20–3.24
and dH 6.98. Irradiation at dH 7.34–7.36 led to an enhancement
at dH 3.20–3.24 and dH 7.50–7.51. Irradiation at dH 8.31 gave no
observed enhancement; dC (CDCl3) 28.5 (CH2Ar), 43.0 (NCH2),
119.6 (3-CH), 120.6 (10-CH), 124.8 (8-CH), 127.8 (6a-C), 128.3
Method E. The procedure for method B was repeated using 1g
(0.20 g, 0.67 mmol) and benzophenone (0.61 g, 3.56 mmol) in
acetonitrile (34 ml) degassed with N2 for 20 min in a cylindrical
quartz tube, and irradiated at 254 nm for 10 h giving recovered
starting material 1g (0.19 g, 97%) after column chromatography.
Attempted synthesis of 5H-imidazo[2,1-a]isoindole (3a) using
method B. A solution of 1f (0.20 g, 0.70 mmol) in acetonitrile
(35 ml) was irradiated at 254 nm for 10 h giving 1-benzyl-1H-
imidazole 5a (0.05 g, 45%) and recovered starting material (0.01g,
5%) after column chromatography.
A solution of 1k (0.20 g, 1.03 mmol) in acetonitrile (50 ml)
was irradiated at 254 nm for 10 h, but only unaltered starting
material 1k (0.02 g, 100%) was recovered. The reaction gave
identical results when carried out in 2 M hydrochloric acid
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solution under analogous conditions. Except to isolate 1k from the
acidic solution, the solution was basified with saturated sodium
carbonate solution. Extracted with dichloromethane (3 × 70 ml),
dried (MgSO4), and evaporated to dryness.
CH2Ar), 4.34–4.37 (2 H, t, J 7.1, NCH2), 8.06–8.09 (1 H, d,
J 8.7, 10-H), 8.19–8.22 (1 H, d, J 8.7, 9-H), 8.30 (1 H, s, 7-H), 8.57
(1 H, s, 3-H); dC {(CD3)2SO} 29.0 (CH2Ar), 42.3 (NCH2), 125.2
(CH), 125.3 (CH), 125.9 (CH), 127.1 (CH), 133.0 (C), 138.4 (C),
143.1 (C), 149.5 (C), 150.1 (C); m/z (CI) 261.0618 (31%, M + H+,
C11H9N4O4 requires M + H+ 261.0622), 163 (62), 102 (33), 52 (100).
6,7-Dihydro-5H-imidazo[2,1-a][2]benzazepine (3c) using method
B. A solution of 1h (0.32 g, 1.02 mmol) in acetonitrile (50 ml) was
irradiated for 6 h giving the title compound 3c (0.09 g, 48%) as a
yellow oil; Rf 0.41 (ethyl acetate); mmax/cm−1 2937, 1528, 1493, 1467,
1451, 1265, 1107, 1022, 915; dH (CDCl3) 2.28–2.31 (2 H, m, 6-CH2),
2.68–2.71 (2 H, t, J 7.1, CH2Ar), 3.87–3.90 (2 H, t, J 6.9, NCH2),
6.99 (1 H, s, 3-H), 7.11 (1 H, s, 2-H), 7.23–7.31 (3 H, m, Ar–H), 8.31
(1 H, d, J 7.3, 11-H); dC (CDCl3) 30.9 (6-CH2), 31.4 (CH2Ar), 44.6
(NCH2), 120.8 (3-CH), 127.2 (CH), 128.2 (CH), 128.6 (CH), 129.1
(CH), 129.3 (CH), 131.3 (7a-C), 138.1 (11a-C), 148.3 (11b-C); m/z
(EI) 184.1000 (100%, M+, C12H12N2 requires M+ 184.1000), 183
(82), 169 (16), 156 (8), 128 (4), and recovered starting material 1h
(0.03 g, 10%) after column chromatography.
9-Fluoro-2,8-dinitro-5,6-dihydroimidazo[2,1-a]isoquinoline (4b).
Nitric acid (0.40 ml, 65%), concentrated sulfuric acid (2.20 ml)
and 3d (0.125 g, 0.67 mmol) gave the title compound 4b (0.13 g,
70%) as an orange solid, mp 253–256 ◦C (from ethanol); mmax/cm−1
3121, 1531 (NO2), 1498, 1471, 1358 (NO2), 1338, 1330, 912; dH
{(CD3)2SO} ca. 3.31–3.33 (covered by water in DMSO, 2 H,
CH2Ar), 4.36–4.39 (2 H, t, J 6.8, NCH2), 7.93–7.95 (1 H, d, J
11.7, 10-H), 8.27–8.29 (1 H, d, J 7.8, 7-H), 8.62 (1 H, s, 3-H);
NOE irradiation at dH 4.36–4.39 led to enhancement at dH 8.62.
Irradiation at dH 8.62 led to enhancement at dH 4.36–4.39; dC
{(CD3)2SO} 25.9 (CH2Ar), 43.2 (NCH2), 112.7–112.9 (d, JC–F 23.1
10-CH), 123.2 (3-CH), 126.4 (7-CH), 131.2 (C), 131.6 (C), 136.8
(C), 139.8 (C), 147.1 (10b-C), 152.7–155-3 (d, JC–F 261.0, C–F);
9-Chloro-5,6-dihydroimidazo[2,1-a]isoquinoline (3e) using
method B. A solution of 1i (0.32 g, 0.96 mmol) in acetonitrile
(48 ml) was irradiated at 254 nm for 5 h giving the title compound
3e (0.13 g, 66%), and recovered starting material 1i (0.04 g, 13%)
after column chromatography.
+
m/z (CI) 296.0791 (100%, M + NH4 , C11H11N5O4 requires M +
+
NH4 296.0790), m/z (EI) 278 (M+, 65%), 248 (23), 193 (50), 158
(65), 147 (75), 132 (72), 120 (52).
9-Chloro-2,8-dinitro-5,6-dihydroimidazo[2,1-a]isoquinoline (4c).
Nitric acid (0.1 ml, 65%), concentrated sulfuric acid (0.6 ml) and
3e (0.04 g, 0.19 mmol) gave the title compound 4c (0.04 g, 70%) as a
orange solid, mp 245–247 ◦C (from ethanol); mmax/cm−1 3125, 1531
(NO2), 1351 (NO2), 1121, 1335, 1315, 943, 913; dH {(CD3)2SO} ca.
3.31–3.33 (covered by water in DMSO, 2 H, CH2Ar), 4.34–4.37
(2 H, t, J 6.8, NCH2), 8.09 (1 H, s, 10-H), 8.21 (1 H, s, 7-H),
8.61 (1 H, s, 3-H); dC {(CD3)2SO} 26.2 (CH2Ar), 43.1 (NCH2),
123.7 (3-CH), 124.8 (C), 126.2 (10-CH), 126.5 (7-CH), 130.3 (C),
135.5 (C), 140.2 (10b-C), 147.6 (C), 147.8 (C); m/z (CI) 295.0230
(100%, M + H+, C11H8N4O4Cl requires M + H+ 295.0229), m/z
(EI): 296 (9), 294 (M+, 3), 264 (5), 209 (6), 140 (11), 128 (10), 46
(100).
9-(Trifluoromethyl)-5,6-dihydroimidazo[2,1-a]isoquinoline (3f)
using method B. A solution of 1j (0.27 g, 0.74 mmol) in
acetonitrile (35 ml) was irradiated at 254 nm for 5 h giving the
title compound 3f (0.09 g, 53%), and recovered starting material
1j (0.04 g, 15%) after column chromatography.
9-Nitro-5,6-dihydroimidazo[2,1-a]isoquinoline (3g) using method
B. A solution of 1l (0.40 g, 1.17 mmol) in acetonitrile (55 ml)
was irradiated at 254 nm for 5 h giving the title compound 3g
(0.08 g, 32%), as a yellow solid; mp 218–220 ◦C; Rf 0.32 (ethyl
acetate); mmax/cm−1 1590, 1514 (NO2), 1499, 1337 (NO2), 1283,
1099, 1050; dH (CDCl3) 3.23–3.27 (2 H, t, J 6.9, CH2Ar), 4.21–
4.25 (2 H, t, J 6.9, NCH2), 6.99 (1 H, s, 3-H), 7.18 (1 H, s, 2-
H), 7.37–7.39 (1 H, d, J 8.4, 7-H), 8.06–8.08 (1 H, dd, J 8.4, J
2.0, 8-H), 8.82–8.83 (1 H, d, J 2.0, 10-H); NOE irradiation at
dH 3.23–3.27 led to enhancement at dH 4.21–4.25 and dH 7.37–
7.39. Irradiation at dH 8.06–8.08 led to enhancement at dH 7.37–
7.39. Irradiation of dH 8.83 gave no observed enhancement; dC
(CDCl3) 28.6 (CH2Ar), 42.7 (NCH2), 118.4 (10-CH), 119.9 (Im-3-
CH), 122.6 (8-CH), 128.4 (6a-C), 128.8 (7-CH), 130.0 (2-CH),
138.8 (10a-C), 142.3 (10b-C), 147.9 (9-C); m/z (CI) 216.0768
(100%, M + H+, C11H10N3O2 requires M + H+ 216.0768), 186
(74), and recovered starting material 1l (0.14 g, 36%) after column
chromatography.
2-Nitro-9-(trifluoromethyl)-5,6-dihydroimidazo[2,1-a]isoquinoline
(4d). Nitric acid (0.25 ml, 65%), concentrated sulfuric acid
(1.2 ml) and 3f (90 mg, 0.37 mmol) gave the ◦title compound 4d
(0.07 g, 68%) as a orange solid, mp 186–188 C (from ethanol);
mmax/cm−1 3141, 1530 (NO2), 1326 (NO2), 1301, 1165, 1113, 1067,
819, 737; dH {(CD3)2SO} ca. 3.31–3.33 (covered by water in
DMSO, 2 H, CH2Ar), 4.31–4.35 (2 H, t, J 6.8, NCH2), 7.62–7.64
(1 H, d, J 8.7, 7-H), 7.76–7.78 (1 H, d, J 8.7, 8-H), 8.05 (1 H, s,
10-H), 8.53 (1 H, s, 3-H); dC {(CD3)2SO} 27.4 (CH2Ar), 43.2
(NCH2), 120.2 (10-CH), 123.1 (3-CH), 126.3 (C), 126.9 (8-CH),
128.8 (C), 129.1 (C), 130.4 (7-CH), 139.5 (C), 141.7 (C), 147.4
(C); m/z (CI) 301 (22%, M + NH4 ), 284.0642 (67%, M + H+,
+
C12H9N3O2F3 requires M + H+ 284.0641), 254 (100), 239 (25),
General procedure for nitration
233 (36).
2,8-Dinitro-5,6-dihydroimidazo[2,1-a]isoquinoline (4a). Nitric
acid (0.15 ml, 65%) was added drop-wise to a stirred solution
of 3b (0.04 g, 0.23 mmol) in concentrated sulfuric acid (0.75 ml)
at 0 ◦C. The mixture was stirred at room temperature for 30 min,
poured onto ice-water (2.50 ml) and neutralised with ammonium
hydroxide (1.50 ml, 15 M). The title compound 4a was precipitated
(0.03 g, 50%) as a red solid, mp 230–232 ◦C (from ethanol);
mmax/cm−1 3164, 1528 (NO2), 1336 (NO2), 1307, 1121, 828, 795;
dH {(CD3)2SO} ca. 3.31–3.33 (covered by water in DMSO, 2 H,
2,9-Dinitro-5,6-dihydroimidazo[2,1-a]isoquinoline (4e). Nitric
acid (0.1 ml, 65%), concentrated sulfuric acid (0.6 ml) and 3g
(0.04 g, 0.19 mmol) gave◦the title compound 4e (0.03 g, 50%) as
a red solid, mp 204–206 C. mmax/cm−1 1517 (NO2), 1342 (NO2),
1299, 1055, 1051; dH {(CD3)2SO} ca. 3.31–3.33 (covered by water
in DMSO, 2 H, CH2Ar), 4.34–4.37 (2 H, t, J 6.5, NCH2), 7.67–7.69
(1 H, d, J 8.2, 7-H), 8.22–8.24 (1 H, d, J 8.2, 8-H), 8.50 (1 H, s,
3(10)-H), 8.54 (1 H, s, 3(10)-H); dC {(CD3)2SO} 27.6 (CH2Ar),
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43.2 (NCH2), 118.4 (10-CH), 123.1 (8-CH), 124.9 (3-CH), 126.5
(C), 128.3 (C), 130.8 (7-CH), 141.1 (C), 142.3 (C), 147.5 (C).
9 A. Ryokawa and H. Togo, Tetrahedron, 2001, 57, 5915.
10 (a) A. Nunez, A. Garc´ıa de Viedma, V. Mart´ınez-Barrasa, C.
Burgos and J. Alvarez-Builla, Synlett, 2002, 1093; (b) W. Zhang and
G. Pugh, Tetrahedron, 2003, 59, 3009.
11 P. T. F. McLoughlin, M. A. Clyne and F. Aldabbagh, Tetrahedron, 2004,
60, 8065.
Acknowledgements
12 A. L. J. Beckwith, V. W. Bowry, W. R. Bowman, E. Mann, J. Parr and
J. M. D. Storey, Angew. Chem., Int. Ed., 2004, 43, 95.
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The authors would like to thank Dr Niall W. A. Geraghty
(National University of Ireland, Galway) for use of the Rayonet
photochemical reactors. Mr Ger Fahy (National University of Ire-
land, Galway), and EPSRC National Mass Spectrometry Service,
University of Wales, Swansea for mass spectra of compounds. This
work was funded by Enterprise Ireland Basic Research Grant.
16 (a) D. E. Portlock, M. J. Kane, J. A. Bristol and R. E. Lyle, J. Org.
Chem., 1973, 38, 2351; (b) P. W. Jeffs, J. F. Hansen and G. A. Brine,
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