Efficient one-pot synthesis of functionalised imidazo[1,2-: A] pyridines and unexpected synthesis of novel tetracyclic derivatives by nucleophilic aromatic substitution

Article abstract of DOI:10.1039/c9ra10447j

Novel tetracyclic imidazo[1,2-a]pyridine derivatives have been prepared by intramolecular nucleophilic aromatic substitution of 5-fluoroimidazo[1,2-a]pyridines under basic conditions. Use of the non-nucleophilic alcoholic solvent tert-butanol, rather than methanol, increased the yield of the tetracycles by reducing the competing intermolecular reaction observed for methanol. In addition, a modified protocol for the dehydration of formamides to isocyanides has been found to be tolerant of an unprotected hydroxyl functional group and one-pot conversion to imidazo[1,2-a]pyridyl-aminocyclohexanol analogues is reported.

Full text of DOI:10.1039/c9ra10447j

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PAPER
Efficient one-pot synthesis of functionalised
imidazo[1,2-a]pyridines and unexpected synthesis
of novel tetracyclic derivatives by nucleophilic
aromatic substitution†
Cite this: RSC Adv., 2020, 10, 8104
Charles R. K. Changunda,
Amanda L. Rousseau,
B. C. Venkatesh, William K. Mokone,
Dean Brady, Manuel A. Fernandes
*
and Moira L. Bode
Novel tetracyclic imidazo[1,2-a]pyridine derivatives have been prepared by intramolecular nucleophilic aromatic
substitution of 5-fluoroimidazo[1,2-a]pyridines under basic conditions. Use of the non-nucleophilic alcoholic
solvent tert-butanol, rather than methanol, increased the yield of the tetracycles by reducing the competing
intermolecular reaction observed for methanol. In addition, a modified protocol for the dehydration of
formamides to isocyanides has been found to be tolerant of an unprotected hydroxyl functional group and
one-pot conversion to imidazo[1,2-a]pyridyl-aminocyclohexanol analogues is reported.
Received 12th December 2019
Accepted 15th February 2020
DOI: 10.1039/c9ra10447j
rsc.li/rsc-advances
mandates researchers to prepare most of the isocyanides that
are required to full their research requirements.
Introduction
More than one and a half centuries ago, Gautier and Hof-
mann11 rst described the preparation of isocyanides. Their apt
description of isocyanides as possessing ‘almost overpowering,
horrible and extremely distressing odours’ typies the chal-
lenges associated with the preparation and handling of iso-
cyanides even to this present day. Almost a hundred years later,
the rst generally applicable routes for accessing isocyanides
were described, via the dehydration of N-formamides using acyl
oxides of group IV–VI elements in the presence of bases.12 Due
to the high toxicity and handling difficulties associated with
using phosgene,13 phosphorus oxychloride (used together with
Et3N base), a method originally described by Ugi and Meyr,14
has become one of the most commonly employed N-formamide
dehydrating agents for the preparation of isocyanides in
synthetic chemistry today.
Nevertheless, the increasing enactment of tightened
environmental, health and safety management laws
continues to drive the search for safer synthetic routes for
accessing isocyanides. Thus, more research and development
is still needed to develop safer methodologies that provide
ease of access to a large variety of these key substrates. In an
interesting development, Wang and co-workers15 reported
the identication of triphenylphosphine and iodine as mild
and efficient N-formamide dehydrating agents for generating
aromatic isocyanides. Guchhait and colleagues16 reported the
development of a one-pot reaction which employed para-
toluenesulfonyl chloride (pTsCl) and DABCO for the dehy-
dration of N-formamide substrates to generate isocyanides in
situ for subsequent use in multicomponent reactions.
The imidazopyridine skeleton possesses unique electronic and
chemical properties that make it an attractive starting point in
the preparation of a broad spectrum of therapeutic agents1
ranging from sedative drugs such as zolpidem 1, antiviral
agents 2, anticancer compounds 3, immunomodulators 4 (ref.
2) and antitubercular agents 5 (ref. 3) (Fig. 1), to mention just
a few. Other reports indicate activity as gastric proton pump
inhibitors4 and as antifungal,5 antibacterial6 and anxiolytic7
agents.
Largely as a result of their biological importance, the
development of safe synthetic methodologies that efficiently
access imidazopyridines and their associated derivatives
continues to generate much research interest in synthetic
chemistry.8
The utility of the multi-component Groebke–Blackburn–
9
´
Bienayme reaction for preparation of imidazo[1,2-a]pyridines
by reaction of an aldehyde, 2-aminopyridine and an isocyanide
is well documented in synthetic chemistry literature.1a,10a,b
Given that 2-aminopyridines and aldehydes are generally
affordable, the versatility and robustness of this protocol is
primarily disadvantaged by the limited variety and high
procurement cost of commercially available isocyanides. This
Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand,
Private Bag 3, PO WITS 2050, Johannesburg, South Africa. E-mail: Moira.Bode@
wits.ac.za
† Electronic supplementary information (ESI) available: Copies of all NMR spectra
and crystallographic data. CCDC 1970362 and 1970363. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c9ra10447j
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Fig. 1 Biologically active imidazopyridines.
We have previously reported the identication of novel imi- (rac-8) was neutralised and formylated quantitatively to
dazo[1,2-a]pyridine derivatives as non-nucleoside inhibitors of generate formamide rac-9 using a previously reported method18
HIV-1 reverse transcriptase.17 The novel lead compound, 2-(2- (Scheme 1). Aer acetylation, compound rac-10 was then
chlorophenyl)-3-(cyclohexylamino)imidazo[1,2-a]pyridine-5-
dehydrated using POCl3/Et3N to produce the isocyanide rac-11
carbonitrile 6 (Fig. 2) exhibited good antiviral activity (whole cell for subsequent multi-component Groebke–Blackburn–Bien-
´
anti-HIV IC50 ¼ 0.18 mM) and displayed excellent selectivity (SI ayme reaction. Acetylation was used as a means of protecting
¼ 868) when screened against the wild-type HI virus. Molecular the OH group during the dehydration step, as free OH groups
modelling results indicated that introduction of groups capable are incompatible with the POCl3/Et3N methodology. Coupling
of hydrogen-bonding to amino acids in the allosteric site would of rac-11 with 2-chlorobenzaldehyde 12a and 6-substituted-2-
potentially lead to compounds with increased potency.
aminopyridine 13 (Scheme 1) produced the target acetates
Therefore, as part of our ongoing efforts to discover 14a–d in excellent yields, specically over the multicomponent
compounds with better antiviral activity proles against both coupling step (v, Scheme 1). Nonetheless, it is noteworthy to
wild-type and mutant viral strains we planned to expand our point out that a respectable 85% yield of the isocyanide (rac-11)
imidazo[1,2-a]pyridine library using compound 6 as a starting was only achieved at small scale (100 mg of rac-10) whilst efforts
point. Thus compounds of general structure 7 (Fig. 2) were to scale up the reaction progressively gave poorer conversions.
conceived for synthesis as promising targets for subsequent One of the difficulties of this reaction appeared to be
screening against the HI virus. In this paper, we report a highly a propensity of rac-11 to undergo a rehydration reaction to
efficient modied pTsCl/DABCO protocol16 as a safe and OH regenerate the N-formamide rac-10 during the aqueous work
functional group tolerant catalyst methodology for accessing up, given the non-stoichiometric imbalance between the acid
novel imidazo[1,2-a]pyridine heterocyclic targets. In addition, and base associated with this protocol.
we also report the unexpected ring-closure of 5-uoro-imidazo
The nal step in the synthesis was KOH-catalysed hydrolysis
[1,2-a]pyridine derivatives, giving rise to novel tetracyclic of the respective acetates in MeOH to obtain alcohols 7. Target
compounds.
compounds 7b and 7c were obtained in excellent yields from
14b and 14c, respectively, while unexpected hydrolysis of the
nitrile group of 14d under the basic conditions of the depro-
tection reaction gave rise to carboxamide 7e. Attempted
deprotection of compound 14a also did not lead to the expected
deprotected compound; instead a roughly equal mixture of two
compounds was obtained. On initial inspection of the 1H NMR
spectrum of the rst product 15 it was immediately evident that
the acetyl group had been removed. The rst clear indication
that the expected product had not been obtained was the
appearance of the signal at 6.17 ppm for H-6 as a doublet
showing one ortho-coupling (J ¼ 7.2 Hz). In the starting material
14a, this proton appears at 6.38 ppm as a triplet as a result of
ortho-coupling to both H-7 and F with very similar coupling
constants (J ¼ 7.1 Hz). The disappearance of F was further
conrmed in the 13C NMR spectrum of 15 where C-6 appeared
as a singlet at 96.6 ppm, rather than the doublet (2JC–F ¼ 18 Hz)
observed at 93.1 ppm for 14a. The signal for C-10 appeared at
Results and discussion
To access our initial small library of target compounds of
general structure 7, 2-trans-hydroxyammonium hydrochloride
Fig. 2 Imidazopyridine lead compound 6; modified target products 7.
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Scheme 1 Reagents: (i) NaOMe, MeOH, RT; (ii) methyl formate, RT, 12 h; (iii) Ac2O, pyridine, 4 h; (iv) POCl3/Et3N, DCM; (v) 2-chlorobenzaldehyde
12a, 6-substituted-2-aminopyridine 13a–d, K-10 clay, MW 150W, 100 ꢀC, 30 min; (vi) KOH, MeOH, RT, 4 h.
88.4 ppm, far more deshielded than for compound 14a, where imidazopyridine analogues derived from four randomly
this signal appeared at 76.4 ppm. Thus, it appeared that ring- selected aldehydes. Given the challenges encountered using the
closure of the newly-deprotected hydroxyl group onto the POCl3/Et3N reagents as highlighted above, we explored the
carbon atom originally carrying F had taken place, giving rise to utility of an alternative para-toluenesulfonyl chloride-based
15. The second product was identied as 7f, where the acetate protocol reported in literature16 that employs equimolar quan-
group had been removed, but where F had been replaced by tities of acid and base as dehydrating agents (Scheme 2).
OMe (Scheme 1). Only these two unexpected products were
In our case, we observed that the efficiency of the dehydra-
obtained from the basic deprotection reaction of 14a in MeOH, tion protocol was highly dependent on the purity of the pTsCl.
with none of the expected deprotected hydroxyl product being Thus, the literature reported purication procedure developed
observed at all. Repeating the KOH hydrolysis reaction of 14a in by Whitaker19 in 2001 was utilized to purify the pTsCl, which
the non-nucleophilic solvent tert-butanol instead of methanol was subsequently stored sealed to reduce moisture ingress. The
gave 15 as the sole product in 60% yield.
pTsCl/DABCO protocol proved to be highly convenient and
Excited by the unexpected formation of novel ring-closed efficient with its main attractive feature being the in situ
heterocyclic product 15, we explored the general applicability generation of the desired isocyanide rac-11 which obviated the
of this phenomenon using various uorine-containing oen tedious aqueous workups encountered during isocyanide
Scheme 2 Reagents: (i) DCM, anhydr. Na2SO4 (1 eq.), pTsCl/DABCO, 0 ꢀC–RT, 6 h, (ii) 0–5 ꢀC, aldehyde 12, 2-amino-6-fluoropyridine 13a,
anhydr. Na2SO4 (1 eq.); then 50 ꢀC, 12 h; (iii) KOH, MeOH or t-BuOH, RT, 4 h. Yields of 16 are quoted over two steps.
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purication which are commonplace when employing the
POCl3/Et3N protocol. In addition, it removed the unpleasant
odour usually associated with isocyanide isolation. The in situ
generated isocyanide rac-11 was then coupled with the requisite
aldehydes 12b–e and 2-amino-6-uoropyridine 13a under
sealed conditions at moderate temperatures (50 ꢀC) to obtain
the respective uorine-containing imidazopyridine acetates
16a–d, with the pTsCl/DABCO adducts formed during the
dehydration reaction subsequently catalysing the multicompo-
nent coupling reaction (Scheme 2). As a slight deviation from
the Guchhait protocol,16 we observed that the addition of
anhydrous Na2SO4 during the dehydration stage as well as the
multicomponent coupling step, not only obviated the need for
N2 purging, but further simplied the overall preparation of the
desired target compounds. These transformations translated to
a minimum 70% yield across both the isocyanide generation as
well as the multicomponent coupling phases. The pTsCl/
DABCO-catalysed reactions were easily scalable without any
discernible drop in target product yields, unlike the problems
experienced using POCl3-mediated dehydration. Secondly, the
non-stoichiometric addition of dehydrating agents that oen-
times characterises most POCl3/Et3N protocols makes it
mandatory for preliminary aqueous workups to remove salts
and excess reagents and purify the isocyanide. Such reactive
salts and excess reagents could also be responsible for catalys-
ing the hydration of the isocyanide to regenerate the form-
amide, thereby lowering yields.
Fig. 4 ORTEP diagrams (50% probability level) of 17a (left) and 17c
(right).
that exerted by the chlorine atom in the case of unoxidised ring-
closed product 15.
Given our failure to obtain the originally intended uorine-
containing imidazopyridine targets of general structure 7 via
base-catalysed hydrolysis of their respective acetates 14 as
explained above, an exploratory attempt was made to directly
dehydrate the unprotected 2-trans-hydroxyformamide rac-9
using the modied pTsCl/DABCO protocol and generate the
isocyanide rac-19 in situ for the subsequent multicomponent
reaction with 2-amino-6-uoropyridine 13a and selected alde-
hydes 12 (Scheme 3). To our delight, the expected novel
uorine-containing targets 20a–g were obtained in excellent
overall yield, which also demonstrated the excellent OH func-
tional group tolerance of the pTsCl/DABCO protocol. To the best
of our knowledge, no similar successful attempts have previ-
ously been reported. Guchhait et al.16 did not test their method
on functionalised isocyanides. Although rac-19 has not been
prepared previously by dehydration of rac-9, it has been
prepared by ring-opening of cyclohexene epoxide using TMSCN
and ZnI2, to give the TMS-protected alcohol that was subse-
quently deprotected.20 One example of dehydration of a form-
amide containing a hydroxyl group to the corresponding
isocyanide was reported by McCarthy et al. using Burgess
reagent, but the reaction was low-yielding (<50%) and took 2
Subsequent base-catalysed hydrolysis of the acetate 16a in
MeOH did indeed give rise to a ring-closed tetracycle 17a in 53%
yield (Scheme 2), together with compound rac-18 (Fig. 3), in
1
47% yield. Close examination of the H NMR spectrum for 17a
showed clearly that the uorine atom had been displaced, as the
proton at position 6 appeared as a dd, with one ortho and one
meta coupling.
However, the signal for the proton on the cyclohexyl ring
carbon atom carrying nitrogen had disappeared, together with
the NH proton signal, showing that in fact 17a was an imine,
representing the oxidised form of compound 15. Similarly,
base-catalysed hydrolysis of acetates 16b–c, this time in t-BuOH,
gave rise to oxidised tetracycles 17b–c in good yield (step iii,
Scheme 2). Hydrolysis of the bromine containing acetate 16d
gave rise to an irresolvable mixture. The identities of the ring-
closed products 17a and 17c were conrmed by single crystal
X-ray crystallographic analysis (Fig. 4). The formation of the
oxidised imine-containing products may possibly be attributed
to the stronger electron withdrawing effect on the imidazopyr-
idine skeleton by the nitro and the cyano groups as compared to
Scheme 3 Reagents: (i) NaOMe, methyl formate, MeOH, RT, 4 h; (ii)
DCM, anhydr. Na2SO4 (1 eq.), pTsCl/DABCO, 0 ꢀC–RT, 6 h, (iii) 0–5 ꢀC,
aldehyde 12, 2-amino-6-fluoropyridine 13a, anhydr. Na2SO4 (1 eq.),
then 50 ꢀC, 12 h. Yields for 20 are quoted over all three steps.
Fig. 3 Compound 18 formed from 16a.
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days.21 Thus, the method reported here is superior in terms of temperature. The reaction vessel was placed in an ice bath, and
ease of reaction and yield. The small library of novel imidazo excess methanol was added to the resulting solution to quench
[1,2-a]pyridines produced during the course of this research will the excess acetic anhydride. The excess pyridine was removed in
be screened for activity against the HI virus and the ndings will vacuo as an azeotropic mixture with toluene to give the desired
be reported in due course.
product rac-10 as a yellow solid (1.50 g, 97%). Mp: 85–88 ꢀC; IR
(cmꢁ1): 3271 (NH str.), 2868 and 2937 (CH str.), 1726 (C]O
ester), 1658 (C]O aldehyde); 1H NMR (300 MHz, CDCl3) d: 8.15–
8.00 (m, 1H), 6.56–6.25 (m, N–H), 4.75–4.52 (m, 1H), 4.03–3.88
(m, 0.8H), 3.35–3.20 (m, 0.2H), 2.12–1.92 (m, 5H), 1.83–1.69 (m,
2H), 1.54–1.19 (m, 4H); 13C NMR (75 MHz, CDCl3) d: 171.5,
170.3, 164.2, 160.9, 74.8, 74.3, 54.8, 51.1, 32.0, 31.7, 30.8, 30.6,
24.0, 23.9, 23.8, 23.5, 21.0, 20.9; HRMS (ES)+: calculated for
C9H16NO3 [M + H]+: 186.1125, found: 186.1127.
Experimental
General
All solvents were freshly distilled prior to use. Other reagents
were used as purchased from Sigma-Aldrich. All infrared
spectra were recorded neat using a Bruker TENSOR 27 single
channel infrared spectrometer. All melting points are uncor-
rected and were performed using open capillary tubes on
a Stuart SMP 10 melting point apparatus. 1H and 13C NMR
spectra were recorded using either a Bruker AVANCE 111 300,
400 or 500 MHz spectrometer in deuterated chloroform (CDCl3)
Synthesis of 2-trans-isocyanocyclohexyl acetate (rac-11).
Compound rac-10 (0.100 g, 0.540 mmol) and Et3N (1.82 g, 18.0
mol) were mixed in dry DCM (10 ml) and the mixture treated
with POCl3 (0.30 ml, 3.21 mmol) at 0 ꢀC. The reaction was
warmed to room temperature under N2, and le to stir for 24 h.
The resulting mixture was gradually added to ice-cold water over
a period of 30 min to quench the excess POCl3. The organic
layers were separated and the aqueous layer extracted with
CH2Cl2 (3 ꢂ 10 ml). The organic layers were combined and
washed with saturated NaHCO3 solution before being dried over
anhydrous Na2SO4. The solvent was removed in vacuo and the
residue puried by ash column chromatography (elution 4 : 1
EtOAc/Hex) to give the desired product rac-11 as a light yellow
1
with trimethylsilane (TMS) as internal standard (d ¼ 0) for H
NMR, and CDCl3 (d ¼ 77.0 ppm) for 13C NMR. The chemical
shi (d) is reported in ppm and the coupling constants (J) in Hz.
High resolution mass spectral data was collected on a Waters
Synapt G2 using an ESI positive source and a cone voltage of
15 V. TLC was performed on aluminium-backed Merck silica gel
60 F254 plates. The purication of compounds by column
chromatography was performed using gravity (particle size
0.063–0.200 mm) or ash (particle size 0.040–0.063 mm) silica
gel 60 purchased from Merck.
1
oil (0.077 g, 85%). IR (cmꢁ1): 1736 (C]O), 2141 (+N^Cꢁ); H
NMR (300 MHz, CDCl3) d: 4.83 (td, J ¼ 9.2, 4.2 Hz, 1H), 3.59–3.47
(m, 1H), 2.25–2.01 (m, 5H), 1.84–1.58 (m, 3H), 1.52–1.20 (m,
3H); 13C NMR (75 MHz, CDCl3) d: 170.0, 156.5 (t, JC–N ¼ 9.5 Hz),
Synthetic procedures
Synthesis of N-(2-trans-hydroxycyclohexyl)formamide (rac- 73.4, 55.1 (t, JC–N ¼ 13.5 Hz), 31.3, 29.4, 22.9, 22.7, 20.9 ppm;
9). 2-trans-Hydroxycyclohexylammonium chloride rac-8 (1 eq., HRMS (ES)+: calculated for C9H14NO2 [M + H] +: 168.1019,
5.00 g, 33.0 mmol) was dissolved in methanol (40 ml) and found: 168.1017.
treated with NaOMe (1.8 eq., 3.298 g, 10.0 ml, 61.0 mmol), to the
resulting mixture was added methyl formate (4 eq., 8.00 ml,
130.6 mmol), and the reaction was allowed to stir for 24 h. A
white solid precipitated out of the reaction mixture and was
General procedure for microwave-assisted synthesis of novel
imidazo[1,2-a]pyridine derivatives 14a–d
removed by ltration. An excess of hexane (relative to the A mixture of a 6-substituted-2-aminopyridine 13a–d (1 mmol), 2-
volume of methanol) was added to the collected reaction chlorobenzaldehyde 12a (1 mmol), isocyanide rac-11 (170 mg,
mixture and was allowed to stand overnight, the resulting 1.02 mmol) and montmorillonite K-10 clay (100 mg) in 1,4-
precipitate was again removed by ltration and the solvent dioxane (2.0 ml) was irradiated in a sealed tube for 30 min
removed in vacuo to obtain the desired product rac-9 as a white- (150 W, 100 ꢀC). Aer cooling to room temperature, the K-10
light grey solid (4.53 g, 96%). From NMR spectroscopy, it was clay was ltered off through Celite which was later washed
evident that in solution this product occurs as a mixture of with EtOAc and the combined organic solvents were removed in
rotamers. Mp: 136–139 ꢀC; IR (nmax/cmꢁ1): 3341 (N–H), 3283 vacuo to give a crude residue that was puried using ash silica
(O–H), 2858–2962 (C–H alkyl), 1635 (C]O); 1H NMR (300 MHz, by eluting with 20–60% EtOAc/Hex.
CDCl3) d: 8.26 (s, 0.7H), 8.06 (d, J ¼ 11.2 Hz, 0.3H), 6.61 (br s,
Synthesis of 2-((2-(2-chlorophenyl)-5-uoroimidazo[1,2-a]
0.3H), 6.28 (br s, 0.7H), 3.74–3.63 (m, 1H), 3.42–3.20 (m, 1.5H), pyridin-3-yl)amino)cyclohexyl acetate (rac-14a). MW irradia-
3.07–2.98 (m, 0.5H), 2.06–1.97 (m, 2H), 1.90–1.74 (m, 2H), tion of 2-chlorobenzaldehyde 12a (143 mg, 1.0 mmol), 2-amino-
1.31–1.25 (m, 4H); 13C NMR (75 MHz, CDCl3) d: 165.14, 162.54, 6-uoropyridine 13a (112 mg, 1.0 mmol) and isocyanide rac-11
74.41, 73.23, 58.69, 54.60, 34.38, 33.69, 32.31, 31.57, 24.79, (167 mg, 1.0 mmol) in the presence of K-10 clay (110 mg) gave
24.16, 24.44, 24.04; HRMS (ES)+: calculated for C7H14NO2 rac-14a (220 mg, 60%) as a black oil. IR (cmꢁ1): 3352 (NH str.),
[M + H]+: 144.1019, found: 144.1019.
2937 (CH str.), 1730 (C]O str.), 1651 (C]N). 1H NMR (500
Synthesis of 2-trans-formamidocyclohexyl acetate (rac-10). MHz, CDCl3) d 7.61–7.58 (m, 1H), 7.50–7.47 (m, 1H), 7.37–7.34
Compound rac-9 (1 eq., 1.20 g, 8.38 mmol) was dissolved in (m, 3H), 7.12–7.08 (m, 1H), 6.38 (t, J ¼ 7.4 Hz, 1H), 4.66–4.55 (m,
a solution of acetic anhydride (9 eq., 7.00 ml, 74.1 mmol) and 1H), 3.55–3.51 (m, 1H), 2.88–2.81 (m, 1H), 1.93–1.87 (m, 4H),
pyridine (6 eq., 4.20 ml, 52.1 mmol, 6 eq.) for 4 h at room 1.71–1.66 (m, 1H), 1.62–1.56 (m, 1H), 1.52–1.47 (m, 1H), 1.24–
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1.15 (m, 2H), 1.02–0.91 (m, 2H); 13C NMR (126 MHz, CDCl3)
Typical procedure for the preparation of compounds 16a–d
1
4
d 170.8, d 150.6 (d, JC–F ¼ 268.1 Hz), 143.6 (d, JC–F ¼ 3.4 Hz),
A mixture of 2-trans-hydroxycyclohexylammonium chloride rac-
8 (2.00 g, 17.12 mmol), sodium methoxide (20 ml, 6.58 mmol)
and methyl formate (2 ml) were stirred at room temperature for
2 h. Thereaer, MeOH (20 ml) was added to the reaction and the
4
136.2, 133.4, 133.2, 132.5, 129.6, 129.5, 126.8, 126.1 (d, JC–F
¼
2.8 Hz), 124.3 (d, 3JC–F ¼ 6.4 Hz), 113.8 (d, 3JC–F ¼ 5.0 Hz), 93.1
(d, 2JC–F ¼ 17.4 Hz), 76.4, 60.9, 30.9, 30.2, 23.7, 23.7, 21.1 ppm;
HRMS (ES+) calculated for C21H22ClFN3O2 [M + H]+: 402.1379,
found: 402.1400.
ꢀ
mixture was stirred at 40 C for 2 h, and then at room temper-
ature for a further 24 h. Aer removing the organic solvent in
vacuo, acetone (25 ml) was added to the off-white residue and
the precipitated salts were removed by ltration. The solvent
was evaporated in vacuo to afford an off-white oily product, 2-
trans-hydroxycyclohexyl formamide rac-9 (1.83 g. 99% yield). To
a mixture of the formamide rac-9 (1.70 g, 16.18 mmol) and
a catalytic amount of dimethylaminopyridine (171 mg) in
acetonitrile (20 ml) was added acetic anhydride (15 ml) and the
reaction mixture stirred at room temperature for 12 h. Aer
evaporating the solvent, the pale-yellow oil was diluted with
acetone (20 ml) and aer adding sodium bicarbonate (1.2 eq.),
the reaction mixture was ltered to afford 2-for-
mamidocyclohexyl acetate rac-10 as a pale yellow oil in quanti-
tative yield.
Synthesis of 2-((5-chloro-2-(2-chlorophenyl)imidazo[1,2-a]
pyridin-3-yl)amino)cyclohexyl acetate (rac-14b). Reaction of 2-
chlorobenzaldehyde 12a (87.5 mL, 0.778 mmol), 2-amino-6-
chloropyridine 13b (100 mg, 0.778 mmol) and isocyanide rac-
11 (130 mg, 0.778 mmol) under MW irradiation in the presence
of K-10 clay (110 mg) gave rac-14b (240 mg, 76%) as a black
solid. Mp: 89–91 C; IR (cmꢁ1): 3355 (NH str.), 2944 (CH str.),
ꢀ
1728 (C]O str.), 1653 (C]N); 1H NMR (500 MHz, CDCl3)
d 7.61–7.59 (m, 1H), 7.50–7.48 (m, 2H), 7.37–7.34 (m, 2H), 7.06–
7.02 (m, 1H), 6.78–6.76 (m, 1H), 4.57–4.52 (m, 1H), 3.67–3.64
(m, 1H), 2.89–2.84 (m, 1H), 1.91–1.84 (m, 4H), 1.61–1.53 (m,
2H), 1.48–1.43 (m, 1H), 1.22–1.07 (m, 2H), 1.02–0.92 (m, 2H);
13C NMR (126 MHz, CDCl3) d 170.6, 143.8, 138.3, 133.5, 133.4,
132.5, 129.6, 129.5, 127.6, 126.8, 126.3, 123.7, 116.8, 114.2, 76.9,
60.8, 30.3, 30.0, 23.6, 23.6, 21.1 ppm; HRMS (ES+) calculated for
An appropriate amount of 2-formamidocyclohexyl acetate
rac-10 (1.0 mmol (185 mg)–2 mmol (371 mg)), anhydrous
Na2SO4 (284 mg, 2 mmol) and a magnetic stirrer were added to
freshly distilled dichloromethane (10–15 ml) and chilled in an
ice bath (10 min). p-Toluenesulfonyl chloride (pTsCl) (1.0 mmol
(191 mg)–2.0 mmol (382 mg)) and DABCO (1.0 mmol (112 mg)–
2.0 mmol (225 mg)) were added in succession and the closed
reaction mixture was stirred under ice-chilled conditions for
1 h. Thereaer, the reaction mixture was allowed to gradually
warm to room temperature with stirring for a further 2 h. To this
chilled in situ generated isocyanide rac-11 crude mixture was
added anhydrous Na2SO4 (284 mg, 2 mmol), an appropriate
aldehyde 12 (1.0–2.0 mmol) and 2-amino-6-uoropyridine 13a
(1.0–2.0 mmol) and the sealed reaction mixture was heated at
50–60 ꢀC in an oil bath for 10–12 h. Thereaer, the reaction was
cooled to room temperature, diluted with DCM (20 ml) and
ltered. The ltrate was washed successively with distilled water
(2 ꢂ 10 ml) and saturated brine solution (10 ml). Aer drying
over Na2SO4, the solvent was removed in vacuo and the crude
mixture was puried by silica gel ash column chromatography,
eluting the title compounds 16a–d with 25–50% EtOAc/hexane.
Synthesis of 2-((5-uoro-2-(4-nitrophenyl)imidazo[1,2-a]pyridin-
3-yl)amino)cyclohexyl acetate (rac-16a). 4-Nitrobenzaldehyde
(303 mg, 2.0 mmol), 2-amino-6-uoropyridine 13a (225 mg, 2.0
mmol) and the in situ generated isocyanide rac-11 were reacted to
generate product rac-16a (454 mg, 74% from rac-10) as a yellow
solid. Mp: 196–197 ꢀC; IR (cmꢁ1): 3333 (NH str.), 3081 and
2943 (CH str.), 1727 (C]O str.), 1659 (C]N), 1566 (NH bend), 1451
(C]C); 1H NMR (500 MHz, CDCl3) d 8.53–8.48 (m, 2H), 8.30–8.26
(m, 2H), 7.36 (d, J ¼ 9.0, Hz, 1H), 7.17–7.12 (m, 1H), 6.41 (t, J ¼
7.3 Hz, 1H), 4.79 (td, J ¼ 10.0, 4.5 Hz, 1H), 3.63–3.61 (m, 1H), 3.11–
3.06 (m, 1H), 2.09–2.05 (m, 1H), 1.94 (s, 3H), 1.78–1.74 (m, 1H),
1.71–1.68 (m, 1H), 1.62–1.58 (m, 1H), 1.33–1.22 (m, 3H), 1.12–1.06
(m, 1H); 13C NMR (126 MHz, CDCl3) d 170.7, 150.5 (d, 1JC–F ¼ 262.5
C
21H22N3O2Cl2 [M + H]+: 418.1089, found: 418.1080.
Synthesis of 2-((5-bromo-2-(2-chlorophenyl)imidazo[1,2-a]
pyridin-3-yl)amino)cyclohexyl acetate (rac-14c). 2-Chlor-
obenzaldehyde 12a (81.2 mg, 0.578 mmol), 2-amino-6-
bromopyridine 13c (100 mg, 0.578 mmol) and isocyanide rac-
11 (96.5 mg, 0.578 mmol) were reacted under MW irradiation in
the presence of K-10 clay (110 mg) to give rac-14c (210 mg, 81%)
as a black oil. IR (cmꢁ1): 3352 (NH str.), 2938 (CH str.), 1732 (C]
O str.), 1652 (C]N); 1H NMR (500 MHz, CDCl3) d 7.62–7.60 (m,
1H), 7.55–7.52 (m, 1H), 7.49–7.47 (m, 1H), 7.38–7.34 (m, 2H),
7.00–6.94 (m, 2H), 4.58–4.53 (m, 1H), 3.64–3.60 (m, 1H), 2.88–
2.82 (m, 1H), 1.92–1.85 (m, 4H), 1.58–1.52 (m, 2H), 1.49–1.43
(m, 1H), 1.22–1.14 (m, 1H), 1.11–1.03 (m, 2H), 0.98–0.90 (m,
1H); 13C NMR (126 MHz, CDCl3) d 170.5, 143.9, 138.8, 133.6,
133.3, 132.4, 129.6, 129.5, 127.9, 126.8, 124.0, 118.8, 117.3,
112.5, 60.4, 30.1, 29.9, 23.7, 23.6, 21.1 ppm; HRMS (ES+) calcu-
lated for C21H22BrClN3O2 [M + H]+: 462.0578, found: 462.0555.
Synthesis of 2-((2-(2-chlorophenyl)-5-cyanoimidazo[1,2-a]
pyridin-3-yl)amino)cyclohexyl acetate (rac-14d). Reaction of 2-
chlorobenzaldehyde 12a (118 mg, 0.84 mmol), 2-amino-6-
cyanopyridine 13d (100 mg, 0.84 mmol) and isocyanide rac-11
(140.33 mg, 0.84 mmol) under MW irradiation in the presence
of K-10 clay (110 mg) gave rac-14d (150 mg, 44%) as a yellow
solid. Mp: 236–238 ꢀC. IR (cmꢁ1): 3348 (NH str.), 2939 (CH str.),
2215 (CN str.), 1733 (C]O str.), 1653 (C]N); 1H NMR (400 MHz,
CDCl3) d 7.81 (d, J ¼ 8.9 Hz, 1H), 7.68–7.64 (m, 1H), 7.55–7.51
(m, 1H), 7.45–7.40 (m, 3H), 7.20 (dd, J ¼ 9.0, 7.1 Hz, 1H), 4.59
(td, J ¼ 9.7, 4.4 Hz, 1H), 3.73–3.68 (m, 1H), 2.93–2.86 (m, 1H),
2.00–1.92 (m, 1H), 1.84 (s, 3H), 1.65–1.51 (m, 3H), 1.34–1.21 (m,
3H), 1.12–0.98 (m, 1H); 13C NMR (101 MHz, CDCl3) d 170.3,
141.3, 139.3, 133.2, 133.0, 132.4, 130.2, 129.9, 127.8, 127.3,
124.3, 123.0, 122.3, 113.8, 108.4, 77.1, 60.0, 30.4, 29.9, 23.8, 23.7,
21.1 ppm; HRMS (ES+) calculated for C22H22ClN4O2 [M + H]+:
409.1426, found: 409.1413.
4
Hz), 146.7, 144.1 (d, JCF ¼ 3.7 Hz), 140.5, 134.7, 127.7, 126.0 (d,
4JC–F ¼ 1.7 Hz), 125.4 (d, 3JC–F ¼ 6.8 Hz) 123.7, 114.2 (d, 3JC–F ¼ 4.9
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2
5
2
5
Hz), 93.4, (d, JCF ¼ 17.6 Hz), 77.4, 61.4 (d, JC–F ¼ 2.1 Hz), 31.2, Hz), 93.1 (d, JC–F ¼ 17.6 Hz), 77.6, 60.9 (d, JC–F ¼ 2.1 Hz), 31.1,
30.7, 24.1, 24.0, 21.1; HRMS (ES+) calculated for C21H22FN4O4 [M + 30.7, 24.1, 24.0, 21.1; HRMS (ES+) calculated for C21H2279BrN3O2
H]+: 413.1620, found: 413.1615.
[M + H]+: 446.0874, found: 446.0875.
Synthesis of 2-((5-uoro-2-(3-nitrophenyl)imidazo[1,2-a]pyridin-
3-yl)amino)cyclohexyl acetate (rac-16b). 3-Nitrobenzaldehyde
(303 mg, 2.0 mmol), 2-amino-6-uoropyridine 13a (225 mg, 2.0
mmol) and the in situ generated isocyanide rac-11 were reacted to
General procedure for the preparation of imidazo[1,2-a]
pyridines 7b–c, 7e, 18 and ring-closed products 15, 17a–c
give product rac-16b (406 mg, 70% from rac-10) as a yellow solid. An appropriate aminocyclohexyl acetate derivative (14 or 16)
Mp: 169–171 ꢀC; IR (cmꢁ1): 3341 (NH str.), 3083, 2967 and and powdered KOH (4 eq.) were stirred in MeOH or tert-butanol
2936 (CH str.), 1728 (C]O str.), 1654 (C]N), 1568 (NH bend), 1434 (3–5 ml) at room temperature for 4 h. Aer removing solvent in
(C]C);.1H NMR (500 MHz, CDCl3) d 9.20 (t, J ¼ 2.0 Hz, 1H), 8.66 vacuo, the crude residue was diluted with DCM (15–20 ml) and
(dt, J ¼ 7.9, 1.3 Hz, 1H), 8.17–8.15 (m, 1H), 7.60 (t, J ¼ 8.0 Hz, 1H), then washed successively with distilled water (2 ꢂ 10 ml) and
7.37 (d, J ¼ 9.0 Hz, 1H), 7.16–7.12 (m, 1H), 6.40 (t, J ¼ 7.2 Hz, 1H), saturated brine solution (10 ml). Aer drying over Na2SO4, the
4.77 (td, J ¼ 10.1, 4.5 Hz, 1H), 3.63–3.58 (m, 1H), 3.14–3.08 (m, 1H), solvent was removed in vacuo and the crude mixture was puri-
2.09–2.03 (m, 1H), 1.85 (s, 3H), 1.70–1.61 (m, 2H), 1.34–1.22 ed by silica gel ash column chromatography, eluting the title
(m, 4H), 1.16–1.08 (m, 1H); 13C NMR (75 MHz, CDCl3) d 170.1, compound with 25–50% EtOAc/hexane.
150.5 (d, 1JC–F ¼ 265.7 Hz), 148.6, 143.9 (d, 4JC–F ¼ 3.7 Hz), 135.8,
Synthesis of 2-((5-chloro-2-(2-chlorophenyl)imidazo[1,2-a]
3
134.8, 133.1, 129.2, 125.1 (d, JC–F ¼ 6.3 Hz), 122.1 (d, 3JC–F ¼ 9.5 pyridin-3-yl)amino)cyclohexanol (rac-7b). Compound rac-7b
Hz), 114.0 (d, 4JC–F ¼ 4.9 Hz), 93.4 (d, 2JC–F ¼ 17.6 Hz), 77.7, 61.1 (d, (72 mg, 83%) obtained as a yellow solid from the hydrolysis of
5JC–F ¼ 2.2 Hz), 31.2, 30.7, 24.1, 24.0, 21.0; HRMS (ES+) calculated acetate rac-14b (100 mg, 0.24 mmol) in methanol. IR (cmꢁ1):
for C21H22FN4O4 [M + H]+: 413.1620, found: 413.1617.
3423 (OH str.), 3340 (NH str.), 2943 (CH str.), 1651 (NH bend),
Synthesis of 2-((2-(3-cyanophenyl)-5-uoroimidazo[1,2-a] 1442 (C]C); Mp: 183–185 ꢀC; 1H NMR (500 MHz, CDCl3) d 7.60–
pyridin-3-yl)amino)cyclohexyl acetate (rac-16c). Reaction of 7.56 (m, 1H), 7.53–7.48 (m, 2H), 7.38–7.34 (m, 2H), 7.05 (dd, J ¼
3-cyanobenzaldehyde (262 mg, 2.0 mmol), 2-amino-6- 8.9, 7.2 Hz, 1H), 6.79 (dd, J ¼ 7.2, 1.1 Hz, 1H), 3.85–3.78 (m, 1H),
uoropyridine 13a (225 mg, 2.0 mmol) and the in situ gener- 3.27–3.21 (m, 1H), 2.70–2.63 (m, 1H), 2.43–2.38 (m, 1H), 1.92–
ated isocyanide rac-11 gave target product rac-16c (448 mg, 76% 1.86 (m, 1H), 1.61–1.54 (m, 2H), 1.50–1.44 (m, 1H), 1.16–1.07
from rac-10) as a yellow solid. Mp: 185–187 ꢀC; IR (cmꢁ1): 3335 (m, 2H), 1.11–0.89 (m, 1H), 0.78–0.71 (m, 1H); 13C NMR (126
(NH str.), 3055, 2937 and 2855 (CH str.), 2229 (CN str.), 1729 MHz, CDCl3) d 143.9, 138.1, 133.6, 133.5, 132.6, 129.8, 129.6,
(C]O str.), 1657 (C]N), 1583 (NH bend), 1443 (C]C); 1H NMR 127.8, 126.8, 126.0, 123.7, 117.0, 114.2, 74.6, 65.3, 33.4, 30.3,
(500 MHz, CDCl3) d 8.62 (d, J ¼ 1.7 Hz, 1H), 8.57 (dt, J ¼ 7.9, 24.4, 24.0; HRMS (ES+) calculated for C19H20N3OCl2 [M + H]+:
1.5 Hz, 1H), 7.52 (t, J ¼ 7.8 Hz, 1H), 7.34 (d, J ¼ 9.0 Hz, 1H), 7.15– 376.0983, found: 376.0974.
7.11 (m, 1H), 6.40 (t, J ¼ 7.2 Hz, 1H), 4.77 (td, J ¼ 10.0, 4.5 Hz,
Synthesis of 2-((5-bromo-2-(2-chlorophenyl)imidazo[1,2-a]
1H), 3.58–3.55 (m, 1H), 3.11–3.04 (m, 1H), 2.08–2.05 (m, 1H), pyridin-3-yl)amino)cyclohexanol (rac-7c). Compound rac-7c
1.94 (s, 3H), 1.77–1.73 (m, 1H), 1.70–1.66 (m, 1H), 1.63–1.57 (m, (60 mg, 83%) obtained as a yellow solid from the hydrolysis of
1H), 1.33–1.20 (m, 3H), 1.14–1.04 (m, 1H); 13C NMR (126 MHz, acetate rac-14c (80 mg, 0.204 mmol) in methanol. Mp: 156–
CDCl3) d 170.8, 150.4 (d, 1JC–F ¼ 265.9 Hz), 143.9 (d, 4JC–F ¼ 3.8 158 ꢀC; IR (cmꢁ1): 3431 (OH str.), 3328 (NH str.), 2940 (CH str.),
Hz), 135.2, 134.8, 131.4, 130.8, 130.7, 129.1, 125.1 (d, 3JC–F ¼ 6.3 1656 (NH bend), 1437 (C]C); 1H NMR (500 MHz, CDCl3) d 7.60–
4
3
Hz), 124.9 (d, JC–F ¼ 2.5 Hz), 119.0, 113.9 (d, JC–F ¼ 5.0 Hz), 7.54 (m, 2H), 7.51–7.47 (m, 1H), 7.37–7.33 (m, 2H), 7.02–6.95
2
5
112.5, 93.3 (d, JC–F ¼ 17.6 Hz), 77.3, 61.1 (d, JC–F ¼ 2.2 Hz), (m, 2H), 3.90 (s, 1H), 3.27–3.19 (m, 1H), 2.70–2.60 (m, 1H), 2.33
31.2, 30.7, 24.0, 21.0; HRMS (ES+) calculated for C22H22FN4O2 (s, 1H), 1.90–1.80 (m, 1H), 1.57–1.44 (m, 3H), 1.15–1.06 (m, 2H),
[M + H]+: 393.1721, found: 393.1719.
0.98–0.90 (m, 1H), 0.85–0.76 (m, 1H); 13C NMR (126 MHz,
Synthesis of 2-((2-(3-bromophenyl)-5-uoroimidazo[1,2-a] CDCl3): d 144.0, 138.5, 133.7, 133.5, 132.5, 129.8, 129.6, 128.0,
pyridin-3-yl)amino)cyclohexyl acetate (rac-16d). 3-Bromobenzalde- 126.8, 124.0, 118.8, 117.5, 112.2, 74.7, 64.7, 33.4, 30.1, 24.4, 24.1;
hyde (370 mg, 2.0 mmol), 2-amino-6-uoropyridine 13a (225 mg, HRMS (ES+) calculated for C19H20BrClN3O [M + H]+: 420.0473,
2.0 mmol) and the in situ-generated isocyanide rac-11 were reacted found: 420.0465.
to give title compound rac-16d (472 mg, 73% from rac-10) as
Synthesis of 2-(2-chlorophenyl)-3-((2-hydroxycyclohexyl)amino)
a yellow solid. Mp: 151–152 C; IR (cmꢁ1): 3341 (NH str.), 3083, imidazo[1,2-a]pyridine-5-carboxamide (rac-7e). Compound rac-7e
2957 and 2936 (CH str.), 1728 (C]O str.), 1654 (C]N), 1568 (NH (65 mg, 68%) obtained as a yellow solid from the hydrolysis of
bend), 1434 (C]C); 1H NMR (500 MHz, CDCl3) d 8.45 (t, J ¼ 1.9 Hz, acetate rac-14d (100 mg, 0.25 mmol) in methanol. Mp: 156–158 ꢀC;
1H), 8.24 (dt, J ¼ 7.8, 1.3 Hz, 1H), 7.44–7.42 (m, 1H), 7.34 (d, J ¼ IR (cmꢁ1): 3431 (OH str.), 3328 (NH str.), 2940 (CH str.), 1656 (NH
9.0 Hz, 1H), 7.31–7.27 (m, 1H), 7.11–7.07 (m, 1H), 6.36 (t, J ¼ bend), 1437 (C]C); 1H NMR (400 MHz, DMSO-d6) d 8.46 (s, 1H),
7.2, Hz, 1H), 4.75 (td, J ¼ 10.0, 4.5 Hz, 1H), 3.52 (s, 1H), 3.08–3.06 7.97 (s, 1H), 7.62–7.52 (m, 3H), 7.44–7.39 (m, 2H), 7.23–7.18 (m,
(m, 1H), 2.08–2.04 (m, 1H), 1.89 (s, 3H), 1.79–1.76 (m, 1H), 1.69– 1H), 7.11 (d, J ¼ 6.8 Hz, 1H), 4.36 (d, J ¼ 4.7 Hz, 1H), 4.24 (d, J ¼
ꢀ
1.66 (m, 1H), 1.61–1.58 (m, 1H), 1.32–1.20 (m, 3H), 1.10–1.08 (m, 3.2 Hz, 1H), 3.13–3.05 (m, 1H), 1.69–1.60 (m, 1H), 1.48–1.37 (m,
1
1H); 13C NMR (126 MHz, CDCl3) d 170.8, 150.5 (d, JC–F ¼ 265.7 1H), 1.33–1.21 (m, 2H), 1.09–0.92 (m, 2H), 0.79–0.57 (m, 2H); 13
C
4
Hz), 143.9 (d, JC–F ¼ 3.7 Hz), 136.0, 135.4, 130.4, 130.1, 129.8, NMR (101 MHz, DMSO) d 165.6, 140.7, 134.4, 133.2, 132.6, 131.8,
125.8, 125.7, 124.7 (d, 1JC–F ¼ 6.3 Hz), 122.6, 113.8 (d, 4JC–F ¼ 5.0 129.3, 129.2, 127.9, 126.6, 121.7, 118.8, 113.6, 71.9, 59.3, 32.6, 29.0,
8110 | RSC Adv., 2020, 10, 8104–8114
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23.0, 22.8.; HRMS (ES+) calculated for C20H22N4O2Cl [M + H]+: 148.4, 145.6, 138.6, 135.6, 134.1, 129.0, 127.8, 126.4, 123.7,
385.1431, found: 385.1418.
122.4, 112.1, 98.7, 83.8, 36.6, 31.7, 23.4, 21.0 ppm; HRMS (ES+)
Synthesis of 2-((2-(2-chlorophenyl)-5-methoxyimidazo[1,2-a] calculated for C19H17N4O3 [M + H]+: 349.1295, found: 349.1290.
pyridin-3-yl)amino)cyclohexanol (rac-7f). Both compound rac- Synthesis of 3-(7,8,9,10-tetrahydro-6aH-6-oxa-2,2a1,11-tri-
7f (30 mg, 40%) and rac-15 (50%), which were readily separated azadibenzo[cd,g]azulen-1-yl)benzonitrile (17c). Hydrolysis of
by silica gel column chromatography, were obtained from the rac-16c (100 mg, 0.25 mmol) with KOH (4 eq.) in tert-butanol
hydrolysis of rac-14a (80 mg, 0.21 mmol) in methanol. Rac-7f: 1H gave product 17c (60 mg, 71%) as a brown solid. Mp: 130–
NMR (500 MHz, CDCl3) d 7.58–7.56 (m, 1H), 7.48–7.46 (m, 1H), 132 ꢀC; IR (cmꢁ1): 3078 and 2955 (CH str.), 2225 (CN str.), 1653
1
7.35–7.30 (m, 2H), 7.17 (d, J ¼ 8.9 Hz, 1H), 7.05–7.3 (m, 1H), 5.97 (C]N), 1445 (C]C); H NMR (400 MHz, CDCl3) d 8.81 (t, J ¼
(d, J ¼ 7.4 Hz, 1H), 4.04 (s, 3H), 3.85–3.56 (m, 1H), 3.40 (s, 1H), 1.7 Hz, 1H), 8.66 (dt, J ¼ 8.0, 1.5 Hz, 1H), 7.60 (dt, J ¼ 7.7, 1.5 Hz,
3.26–3.18 (m, 1H), 2.58–2.51 (m, 1H), 2.00–1.92 (m, 1H), 1.67– 1H), 7.53 (t, J ¼ 7.8 Hz, 1H), 7.32 (d, J ¼ 8.9 Hz, 1H), 7.22 (dd, J ¼
1.56 (m, 2H), 1.51–1.44 (m, 1H), 1.18–1.01 (m, 2H), 0.99–0.89 8.9, 7.3 Hz, 1H), 6.38 (d, J ¼ 7.3 Hz, 1H), 4.71–4.68 (m, 1H), 2.94–
(m, 1H), 0.71–0.62 (m, 1H); 13C NMR (126 MHz, CDCl3) d 151.8, 2.88 (m, 1H), 2.65–2.61 (m, 1H), 2.42–2.40 (m, 1H), 2.01–1.93
143.4, 133.9, 133.8, 133.4, 132.6, 129.7, 129.4, 127.6, 126.8, (m, 3H), 1.80–1.78 (m, 1H), 1.71–1.64 (m, 1H); 13C NMR (101
124.6, 110.8, 88.4, 74.0, 66.0, 56.3, 33.1, 31.2, 24.8, 24.0; HRMS MHz, CDCl3) d 162.8, 148.6, 145.6, 138.8, 135.1, 132.6, 132.4,
(ES+) calculated for C21H23N3O2Cl [M + H]+: 372.1479, found: 131.0, 128.9, 127.8, 126.3, 119.2, 112.3, 112.1, 98.6, 83.8, 36.5,
372.1466.
31.6, 23.3, 20.9 ppm; HRMS (ES+) calculated for C20H17N4O [M +
Synthesis of 1-(2-chlorophenyl)-7,8,9,10,10a,11-hexahydro-6aH- H]+: 329.1397, found: 329.1394.
6-oxa-2,2a1,11-triazadibenzo[cd,g]azulene (rac-15). Compound rac-
Synthesis of 2-((5-methoxy-2-(4-nitrophenyl)imidazo[1,2-a]
15 (30 mg, 60%) was obtained as an orange oil from the hydrolysis pyridin-3-yl)amino)cyclohexanol (rac-18). Compound rac-18
of rac-14a (80 mg, 0.21 mmol) in tert-butanol. IR (cmꢁ1): 3301 (46 mg, 47%) was obtained as an orange solid co-product with 17a
(N–H), 3067 (]C–H), 2937 (C–H), 1638 (C]N); 1H NMR (500 MHz, from the hydrolysis of 2-((5-uoro-2-(4-nitrophenyl)imidazo[1,2-a]
CDCl3) d 7.67 (d, J ¼ 7.6 Hz, 1H), 7.46 (d, J ¼ 8.0 Hz, 1H), 7.35 (t, J ¼ pyridin-3-yl)amino)cyclohexyl acetate rac-16a (105 mg, 0.25
7.5 Hz, 1H), 7.30–7.26 (m, 1H), 7.17 (d, J ¼ 9.0 Hz, 1H), 6.92 (t, J ¼ mmol) in methanol. Mp: 179–180 C; IR (cmꢁ1): 3401 (OH str.),
ꢀ
8.1 Hz, 1H), 6.17 (d, J ¼ 7.2 Hz, 1H), 4.13–4.07 (m, 1H), 3.84 (s, 1H), 3343 (NH str.), 3079 and 2948 (CH str.), 1648 (C]N), 1559 (NH
3.42–3.35 (m, 1H), 2.29–2.23 (m, 1H), 2.06–2.00 (m, 1H), 1.87–1.81 bend), 1448 (C]C); 1H NMR (400 MHz, CDCl3) d 8.48 (d, J ¼
(m, 1H), 1.76–1.62 (m, 2H), 1.50–1.40 (m, 1H), 1.39–1.23 (m, 2H); 8.6 Hz, 2H), 8.24 (d, J ¼ 8.6 Hz, 2H), 7.19–7.07 (m, 2H), 5.97 (d, J ¼
13C NMR (126 MHz, CDCl3) d 147.6, 142.6, 133.4, 133.0, 132.4, 7.2 Hz, 1H), 4.49 (br s, 1H), 4.07 (s, 3H), 3.54–3.49 (m, 1H), 2.79–
129.8, 128.8, 128.2, 127.1, 124.3, 123.6, 111.7, 96.6, 88.4, 60.4, 2.74 (m, 1H), 2.04–1.95 (m, 1H), 1.70–1.61 (m, 1H), 1.56–1.47 (m,
32.8, 31.6, 23.9, 23.6 ppm; HRMS (ES+) calculated for C19H19N3OCl 2H), 1.28–1.17 (m, 3H), 1.04–0.93 (m, 2H); 13C NMR (101 MHz,
[M + H]+: 340.1217, found: 340.1205.
CDCl3) d 152.0, 146.3, 144.0, 141.5, 133.6, 128.2, 127.8, 125.9, 123.5,
Synthesis of 1-(4-nitrophenyl)-7,8,9,10-tetrahydro-6aH-6-oxa- 110.7, 88.6, 75.2, 65.5, 56.4, 34.2, 30.1, 24.4, 24.3; HRMS (ES+)
2,2a1,11-triazadibenzo[cd,g]azulene (17a). Compound 17a calculated for C20H23N4O4 [M + H]+: 383.1714, found: 383.1704.
(46 mg, 53%) was obtained as a dark brown solid and a co-
product with 18 (47%) from the hydrolysis of 2-((5-uoro-2-(4-
General procedure for the preparation of imidazo[1,2-a]
pyridines 20a–g
nitrophenyl)imidazo[1,2-a]pyridin-3-yl)amino)cyclohexyl acetate
ꢀ
rac-16a (105 mg, 0.25 mmol) in methanol. Mp: 188–189 C; IR
1
(cmꢁ1): 3082 and 2946 (CH str.), 1655 (C]N), 1445 (C]C); H To a chilled solution of 2-trans-hydroxycyclohexyl formamide
NMR (500 MHz, CDCl3) d 8.67–8.65 (m, 2H), 8.31–8.28 (m, 2H), rac-9 (287 mg, 2 mmol) (prepared as described previously) in
7.35 (dd, J ¼ 8.9, 1.0 Hz, 1H), 7.25–7.22 (m, 1H), 6.40 (dd, J ¼ 7.3, freshly distilled DCM (10–15 ml) was added a stirrer bar, dried
1.0 Hz, 1H), 4.72 (dd, J ¼ 9.4, 6.2 Hz, 1H), 2.96–2.90 (m, 1H), p-TsCl (382 mg, 2 mmol) and DABCO (225 mg, 2 mmol). The
2.69–2.61 (m, 1H), 2.46–2.41 (m, 1H), 2.06–1.94 (m, 3H), sealed reaction mixture was stirred under chilled conditions for
1.85–1.76 (m, 1H), 1.73–1.63 (m, 1H); 13C NMR (126 MHz, CDCl3) 1 h and allowed to warm to room temperature with stirring for
d 163.5, 148.7, 147.0, 145.8, 140.4, 138.7, 129.1, 128.0, 127.1, a further 3 h. Thereaer, an appropriate aromatic aldehyde 12
123.4, 112.3, 98.7, 83.8, 36.6, 31.6, 23.3, 20.9 ppm; HRMS (ES+) (2 mmol), 2-amino-2-uoropyridine 13a (2 mmol) and anhy-
calculated for C19H17N4O3 [M + H]+: 349.1295, found: 349.1287.
drous Na2SO4 (282 mg, 2 mmol) were added. The closed reac-
ꢀ
Synthesis of 1-(3-nitrophenyl)-7,8,9,10-tetrahydro-6aH-6-oxa- tion mixture was heated at 50–60 C in an oil bath for 10–12 h
2,2a1,11-triazadibenzo[cd,g]azulene (17b). Compound 17b and later cooled to room temperature. Thereaer, the mixture
(45 mg, 65%) was obtained as a yellow solid from the hydrolysis was washed consecutively with distilled water (2 ꢂ 15 ml) and
of rac-16b (85 mg, 0.20 mmol) in tert-butanol. Mp: 164–166 ꢀC; saturated brine solution (10 ml). Aer drying with anhydrous
IR (cmꢁ1): 3080 and 2952 (CH str.), 1653 (C]N), 1450 (C]C); Na2SO4, the organic was evaporated in vacuo to leave a crude
1H NMR (500 MHz, CDCl3) d 9.43 (t, J ¼ 2.0 Hz, 1H), 8.75 (d, J ¼ residue which was puried on ash silica gel by eluting with
7.8 Hz, 1H), 8.17 (dd, J ¼ 8.2, 2.4 Hz, 1H), 7.59 (t, J ¼ 8.9, 1H), 25–80% EtOAc/Hex to afford title compounds 20a–g.
7.34 (d, J ¼ 8.9 Hz, 1H), 7.22 (dd, J ¼ 8.9, 7.3 Hz, 1H), 6.39 (d, J ¼
Synthesis of 4-(5-uoro-3-((-2-hydroxycyclohexyl)amino)imi-
7.3 Hz, 1H), 4.73–4.69 (m, 1H), 2.96–2.91 (m, 1H), 2.69–2.62 (m, dazo[1,2-a]pyridin-2-yl)benzonitrile (rac-20a). 4-Cyanobenzalde-
1H), 2.44–2.41 (m, 1H), 2.05–1.94 (m, 3H), 1.85–1.75 (m, 1H), hyde (303 mg, 2.0 mmol), 2-amino-6-uoropyridine 13a (225 mg,
1.71–1.64 (m, 1H); 13C NMR (126 MHz, CDCl3) d 162.9, 148.6, 2.0 mmol) and the in situ generated isocyanide rac-19 were
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reacted to give product rac-20a (407 mg, 58% overall yield from rac-19 generated product rac-20d (460 mg, 62% overall yield
rac-8) as a brown solid. Mp: 102–103 ꢀC IR (cmꢁ1): 3305 (NH str.), from rac-8) as a brown solid. Mp: 218–220 C; IR (cmꢁ1): 3361
ꢀ
3016 and 2933 (CH str.), 2224 (CN str.), 1652 (C]N), 1555 (NH (OH str.), 3196 (NH str.), 2936 and 2858 (CH str.), 1652 (C]N),
1
bend), 1434 (C]C); H NMR (300 MHz, CDCl3) d 8.49–8.41 (m, 1515 (NH bend), 1439 (C]C); 1H NMR (500 MHz, CDCl3) d 8.55–
2H), 7.71–7.66 (m, 2H), 7.39 (d, J ¼ 9.0 Hz, 1H), 7.20–7.13 (m, 1H), 8.51 (m, 2H), 8.29–8.26 (m, 2H), 7.38 (d, J ¼ 9.0 Hz, 1H), 7.18–
6.41 (t, J ¼ 7.2 Hz, 1H), 3.97 (br. s, 1H), 3.57–3.53 (m, 1H), 7.13 (m, 1H), 6.41 (td, J ¼ 7.3, 0.9 Hz, 1H), 4.01 (s, 1H), 3.60–3.57
2.84–2.81 (m, 1H), 2.07–1.93 (m, 2H), 1.69–1.65 (m, 1H), 1.59– (m, 1H), 2.88–2.82 (m, 1H), 2.05–1.99 (m, 1H), 1.80 (s, 1H), 1.70–
1.50 (m, 2H), 1.31–1.20 (m, 2H), 1.07–0.97 (m, 2H); 13C NMR (126 1.49 (m, 3H), 1.32–1.22 (m, 2H), 1.09–0.98 (m, 2H); 13C NMR
MHz, CDCl3) d 150.6 (d, 1JC–F ¼ 267.1 Hz), 144.1 (d, 4JCF ¼ 2.5 Hz), (126 MHz, CDCl3) d 150.6 (d, 1JC–F ¼ 265.9 Hz), 146.8, 144.4 (d,
4
138.3, 135.9, 132.1, 128.5, 128.0, 125.6 (d, 3JCF ¼ 12.0 Hz), 119.2, 4JC–F ¼ 3.8 Hz), 140.7, 136.0, 128.1, 126.0 (d, JC–F ¼ 2.5 Hz),
113.9 (d, 3JC–F ¼ 5.0 Hz), 110.8, 93.5 (d, 2JC–F ¼ 17.6 Hz), 75.3, 65.0 125.5 (d, 3JC–F ¼ 7.6 Hz), 123.6, 114.1 (d, 3JC–F ¼ 5.0 Hz), 93.4 (d,
5
5
(d, JC–F ¼ 2.6 Hz), 34.4, 30.1, 24.4, 24.2 ppm; HRMS (ES+) 2JC–F ¼ 17.6 Hz), 75.3, 65.0 (d, JC–F ¼ 2.5 Hz), 34.5, 30.0, 24.4,
calculated for C20H20FN4O [M + H]+: 351.1616, found: 351.1617. 24.2 ppm; HRMS (ES+) calculated for C19H20FN4O3 [M + H]+:
Synthesis of 2-((5-uoro-2-(2-uorophenyl)imidazo[1,2-a] 371.1514, found: 371.1510.
pyridin-3-yl)amino)cyclohexanol (rac-20b). Reaction of 2-uo-
Synthesis of 3-(5-uoro-3-((2-hydroxycyclohexyl)amino)imi-
robenzaldehyde (245 mg, 2.0 mmol), 2-amino-6-uoropyridine dazo[1,2-a]pyridin-2-yl)benzonitrile (rac-20e). 3-Cyanobenzalde-
13a (225 mg, 2.0 mmol) and the in situ generated isocyanide hyde (263 mg, 2.0 mmol), 2-amino-6-uoropyridine 13a (225 mg,
rac-19 gave title compound rac-20b (430 mg, 61% overall yield 2.0 mmol) and the in situ generated isocyanide rac-19 were reac-
from rac-8) as a brown solid. Mp: 146–147 C; IR (cmꢁ1): 3389 ted and gave product rac-20e (365 mg, 52% overall yield from rac-
ꢀ
(NH str.), 3078, 2940 and 2861 (CH str.), 1651 (C]N), 1504 (NH 8) as a brown solid). Mp: 120–121 ꢀC; IR (cmꢁ1): 3328 (overlapping
1
bend), 1430 (C]C); H NMR (300 MHz, CDCl3) d 7.79 (td, J ¼ br. OH and NH str.), 2931 and 2858 (CH str.), 2229 (CN str.), 1652
7.6, 1.8 Hz, 1H), 7.43–7.34 (m, 2H), 7.30–7.25 (m, 1H), 7.20–7.09 (C]N), 1516 (NH bend), 1446 (C]C1H NMR (500 MHz, CDCl3)
(m, 2H), 6.40 (t, J ¼ 7.3 Hz, 1H), 3.58 (br. s, 1H), 3.37–3.31 (m, d 8.68–8.66 (m, 1H), 8.55 (dt, J ¼ 8.1, 1.5 Hz, 1H), 7.55 (dt, J ¼ 7.8,
1H), 3.18 (br s, 1H), 2.69–2.63 (m, 1H), 2.02–1.98 (m, 1H), 1.63– 1.5 Hz, 1H), 7.49 (t, J ¼ 7.8, Hz, 1H), 7.39 (d, J ¼ 9.0 Hz, 1H), 7.19–
1.58 (m, 2H), 1.51–1.44 (m, 1H), 1.27–1.12 (m, 2H), 1.03–0.93 7.15 (m, 1H), 6.42 (t, J ¼ 7.1 Hz, 1H), 4.04 (s, 1H), 3.58–3.52 (m,
(m, 1H), 0.79–0.65 (m, 1H); 13C NMR (126 MHz, CDCl3) 1H), 2.85–2.81 (m, 1H), 2.05–1.90 (m, 2H), 1.69–1.63 (m, 1H),
1
1
d 159.6 (d, JC–F ¼ 245.7 Hz), 150.5 (d, JC–F ¼ 268.4 Hz), 144.2 1.57–1.47 (m, 2H), 1.31–1.21 (m, 2H), 1.04–0.97 (m, 2H); 13C NMR
(d, JC–F ¼ 3.8 Hz), 133.2, 131.9 (d, JC–F ¼ 3.8 Hz), 129.9 (d, (126 MHz, CDCl3) d 150.6 (d, 1JC–F ¼ 267.1 Hz), 143.9 (d, 4JC–F
¼
¼
4
4
3JC–F ¼ 7.6 Hz), 126.5 (d, JC–F ¼ 2.5 Hz), 124.73, 124.69 (d, 3.8 Hz), 135.4, 134.8, 131.8, 131.2, 130.9, 129.1, 126.0 (d, 3JC–F
4
4JC–F ¼ 3.2 Hz), 121.6 (d, 3JC–F ¼ 15.1 Hz), 115.9 (d, 1JC–F ¼ 22.7 6.3 Hz), 125.1 (d, 3JC–F ¼ 6.3 Hz), 119.0, 113.5 (d, 4JC–F ¼ 5.0 Hz),
Hz), 113.7 (d, 3JC–F ¼ 5.0 Hz), 93.4 (d, 2JC–F ¼ 17.6 Hz), 74.2, 65.5, 112.3, 93.7 (d, 2JC–F ¼ 17.6 Hz), 75.0, 64.8 (d, 5JC–F ¼ 2.6 Hz), 34.4,
33.2, 30.9, 24.6, 24.0 ppm; HRMS (ES+) calculated for 30.0, 24.4, 24.2 ppm; HRMS (ES+) calculated for C20H20FN4O [M +
C
19H20F2N3O [M + H]+: 344.1582, found: 344.1569.
H]+: 351.1616, found: 351.1615.
Synthesis of 2-((2-(4-chloro-3-uorophenyl)-5-uoroimidazo
Synthesis of 2-(5-uoro-3-((2-hydroxycyclohexyl)amino)imi-
[1,2-a]pyridin-3-yl)amino)cyclohexanol (rac-20c). 4-Chloro-3- dazo[1,2-a]pyridin-2-yl)benzonitrile (rac-20f). 2-Cyanobenzalde-
uorobenzaldehyde (318 mg, 2.0 mmol), 2-amino-6- hyde (263 mg, 2.0 mmol), 2-amino-6-uoropyridine 13a (225 mg,
uoropyridine 13a (225 mg, 2.0 mmol) and the in situ generated 2.0 mmol) and the in situ generated isocyanide rac-19 were
isocyanide rac-19 were reacted to give product rac-20c (423 mg, reacted and generated title compound rac-20f (386 mg, 55%
56% overall yield from rac-8) as a brown solid. Mp: 105–107 ꢀC; IR overall yield from rac-8) as a brown solid. Mp: 152–153 ꢀC; IR
(cmꢁ1): 3400 (OH str.), 3328 (NH str.), 2932 and 2861 (CH str.), (cmꢁ1): 3328 (OH and NH br. str.), 2931 and 2851 (CH str.), 2225
1
1
1653 (C]N), 1512 (NH bend), 1435 (C]C); H NMR (500 MHz, (CN str.), 1652 (C]N), 1446 (C]C); H NMR (500 MHz, CDCl3)
CDCl3) d 8.19 (dd, J ¼ 8.3, 1.9 Hz, 1H), 8.04 (dd, J ¼ 8.3, 2.0 Hz, 1H), d 7.87 (dd, J ¼ 7.9, 1.2 Hz, 1H), 7.77 (dd, J ¼ 7.8, 1.5 Hz, 1H), 7.67
7.41 (t, J ¼ 8.1 Hz, 1H), 7.35 (d, J ¼ 8.9 Hz, 1H), 7.15–7.10 (m, 1H), (td, J ¼ 7.7, 1.4 Hz, 1H), 7.47 (td, J ¼ 7.7, 1.3 Hz, 1H), 7.39 (dd, J ¼
6.38 (t, J ¼ 7.3 Hz, 1H), 3.91 (s, 1H), 3.58–3.53 (m, 1H), 2.87–2.81 9.0, 0.9 Hz, 1H), 7.18–7.13 (m, 1H), 6.42 (t, J ¼ 7.3 Hz, 1H), 3.83–
(m, 1H), 2.07–1.99 (m, 2H), 1.69–1.65 (m, 1H), 1.59–1.52 (m, 2H), 3.77 (m, 1H), 3.34–3.30 (m, 1H), 2.78 (br s, 1H), 2.70–2.61 (m, 1H),
1.29–1.24 (m, 2H), 1.06–1.02 (m, 2H); 13C NMR (126 MHz, CDCl3) 1.92–1.88 (m, 1H), 1.61–1.55 (m, 1H), 1.54–1.42 (m, 2H), 1.19–
1
1
d 157.5 (d, JC–F ¼ 247 Hz), 150.5 (d, JC–F ¼ 265.9 Hz), 144.1 (d, 1.10 (m, 2H), 1.00–0.93 (m, 1H), 0.77–0.68 (m, 1H); 13C NMR (126
4JC–F ¼ 3.8 Hz), 136.4 (d, 3JC–F ¼ 5.0 Hz), 134.6 (d, 3JC–F ¼ 7.6 Hz), MHz, CDCl3) d 150.5 (d, JC–F ¼ 267.1 Hz), 144.3 (d, JC–F ¼ 3.8
1
4
130.3, 125.2 (d, 3JC–F ¼ 10.1 Hz), 124.5 (d, 4JC–F ¼ 1.3 Hz), 123.9 (d, Hz), 137.7, 136.7, 133.4, 132.6, 131.1, 128.2, 125.7 (d, 4JC–F ¼ 2.5
4JC–F ¼ 3.8 Hz), 119.4 (d, 2JC–F ¼ 17.6 Hz), 115.6 (d, 2JC–F ¼ 22.7 Hz), Hz), 125.3 (d, JC–F ¼ 6.3 Hz), 119.1, 114.1 (d, JC–F ¼ 5.0 Hz),
113.8 (d, 3JC–F ¼ 5.0 Hz), 93.2 (d, 2JC–F ¼ 17.6 Hz), 75.2, 64.9 (d, 5JC–F 112.4, 93.5 (d, 2JC–F ¼ 17.6 Hz), 74.3, 65.0 (d, 5JC–F ¼ 1.9 Hz), 33.5,
¼ 2.7 Hz), 34.4, 29.9, 24.8, 24.4, 24.2 ppm; HRMS (ES+) calculated 30.3, 24.2, 24.1 ppm; HRMS (ES+) calculated for C20H20FN4O [M +
3
3
for C19H19ClF2N3O [M + H]+: 378.1179, found: 378.1167.
H]+: 351.1616, found: 351.1615.
Synthesis of 2-((5-uoro-2-(4-nitrophenyl)imidazo[1,2-a]
Synthesis of 2-((2-(2-chlorophenyl)-5-uoroimidazo[1,2-a]
pyridin-3-yl)amino)cyclohexanol (rac-20d). Reaction of 4-nitro- pyridin-3-yl)amino)cyclohexanol (rac-20g). Reaction of 2-chlor-
benzaldehyde (303 mg, 2.0 mmol), 2-amino-6-uoropyridine obenzaldehyde (210 mg, 1.0 mmol), 2-amino-6-uoropyridine
13a (225 mg, 2.0 mmol) and the in situ generated isocyanide 13a (113 mg, 1.0 mmol) and the in situ generated isocyanide
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rac-19 gave product rac-20g (212 mg, 59% overall yield from rac- in the absence of any preliminary purging of the reaction with
8) as a brown solid. Mp: 149–151 C; IR (cmꢁ1): 3400 (OH br. nitrogen. Of particular importance is that it has also proved to
ꢀ
str.), 3221 (NH str.), 2928 and 2857 (CH str.), 1650 (C]N), 1432 be effective for preparing functionalised isocyanides in situ
1
(C]C); H NMR (500 MHz, CDCl3) d 7.62–7.57 (m, 1H), 7.52– without the requirement for protection of reactive hydroxyl
7.47 (m, 1H), 7.44–7.34 (m, 3H), 7.17–7.14 (m, 1H), 6.43 (t, J ¼ groups.
7.3, 1H), 3.53–3.36 (m, 1H), 3.30–3.25 (m, 1H), 3.08–2.71 (m,
1H), 2.66–2.59 (m, 1H), 2.00–1.94 (m, 1H), 1.66–1.58 (m, 2H),
1.53–1.44 (m, 1H), 1.20–1.10 (m, 2H), 1.02–0.93 (m, 1H), 0.73– Conflicts of interest
1
0.64 (m, 1H); 13C NMR (126 MHz, CDCl3) d 150.5 (d, JC–F
¼
4
There are no conicts to declare.
267.2 Hz), 143.6 (d, JC–F ¼ 3.2 Hz), 135.7, 133.2, 132.7, 132.6,
129.8, 129.7, 127.0, 126.2 (d, 4JC–F ¼ 2.9 Hz), 124.8 (d, 3JC–F ¼ 6.8
Hz), 113.8 (d, 3JC–F ¼ 5.0 Hz), 93.6 (d, 2JC–F ¼ 17.7 Hz), 74.1, 65.4,
Acknowledgements
-
33.2, 31.0, 24.6, 24.0 ppm; HRMS (ES+) calculated for C19H20
ClFN3O [M + H]+: 360.1273, found: 360.1272.
The authors would like to thank the National Research Foun-
dation (NRF) and the Medical Research Council (MRC) of South
Africa and the University of the Witwatersrand through the
School of Chemistry and Research Office for their support and
nancial assistance. The assistance of Mr Thapelo Mbhele with
the acquisition of HRMS data is gratefully acknowledged.
Crystallography
Crystal structure and renement. Intensity data for 17a and
17c were collected on a Bruker Apex-II CCD area detector
diffractometer with graphite monochromated Mo Ka radiation
(50 kV, 30 mA). The collection method involved u- and 4-scans
of width 0.5ꢀ and 1024 ꢂ 1024 bit data frames. Using Olex2,22
the crystal structures were solved by with the ShelXT structure
solution program using Intrinsic Phasing and rened with the
ShelXL renement package using Least Squares mini-
misation.23,24 Non-hydrogen atoms were rst rened isotropi-
cally followed by anisotropic renement by full matrix least-
squares calculations based on F2.
Notes and references
¨
1 (a) A. Boltjes and A. Domling, Eur. J. Org. Chem., 2019, 7007;
(b) J. Koubachi, S. El Kazzouli, M. Bousmina and
G. Guillaumet, Eur. J. Org. Chem., 2014, 5119.
2 L. Dyminska, Bioorg. Med. Chem., 2015, 23, 6087.
3 T. O'Malley, T. Alling, J. V. Early, H. A. Wescott, A. Kumar,
G. C. Moraski, M. J. Miller, T. Masquelin, P. A. Hipskind
and T. Parisha, Antimicrob. Agents Chemother., 2018, 62,
e02439-17.
Crystal data for 17a: C19H16N4O3 (M ¼348.36 g molꢁ1):
ꢀ
monoclinic, space group C2/c (no. 15), a ¼ 20.8879(15) A, b ¼
ꢀ3
ꢀ
ꢀ
ꢀ
7.2791(5) A, c ¼ 21.5015(15) A, b ¼ 96.086(5) , V ¼ 3250.8(4) A ,
Z ¼ 8, T ¼ 173.15 K, m(MoKa) ¼ 0.100 mmꢁ1, Dcalc
¼
¨
4 A. M. Palmer, S. Chrismann, G. Munch, C. Brehm,
1.424 g cmꢁ3, 10 492 reections measured (3.81ꢀ # 2q #
49.998ꢀ), 2857 unique (Rint ¼ 0.1096, Rsigma ¼ 0.1327) which
were used in all calculations. The nal R1 was 0.0444 (I > 2s(I))
and wR2 was 0.0847 (all data). CCDC 1970362.
P. J. Zimmermann, W. Buhr, J. Senn-Bilnger, M. P. Feth
and W. A. Simon, Bioorg. Med. Chem., 2009, 17, 368.
¨
5 F. Gokta¸s, N. Cesur, D. ¸Satana and M. Uzun, Turk. J. Chem.,
2014, 38, 581.
Crystal data for 17c: C20H16N4O (M ¼328.37 g molꢁ1):
6 N. M. Shukla, D. B. Salunke, E. Yoo, C. A. Mutz,
R. Balakrishna and S. A. David, Bioorg. Med. Chem., 2012,
20, 5850.
7 K. B. Puttaraju and K. Shivashankar, RSC Adv., 2013, 3,
20883.
8 A. K. Bagdi, S. Santra, K. Monir and A. Hajra, Chem.
Commun., 2015, 51, 1555.
9 (a) K. Groebke, L. Weber and F. Mehlin, Synlett, 1998, 661; (b)
C. Blackburn, B. Guan, P. Fleming, K. Shiosaki and S. Tsai,
ꢀ
monoclinic, space group P21/n (no. 14), a ¼ 12.0432(7) A, b ¼
ꢀ
ꢀ
ꢀ
7.3016(4) A, c ¼ 18.3346(12) A, b ¼ 96.116(4) , V ¼ 1603.07(17)
ꢀ3
A , Z ¼ 4, T ¼ 173.15 K, m(MoKa) ¼ 0.088 mmꢁ1, Dcalc
¼
1.361 g cmꢁ3, 11 067 reections measured (3.866ꢀ # 2q #
49.98ꢀ), 2831 unique (Rint ¼ 0.1479, Rsigma ¼ 0.2114) which were
used in all calculations. The nal R1 was 0.0410 (I > 2s(I)) and
wR2 was 0.0687 (all data). CCDC 1970363.
´
Tetrahedron Lett., 1998, 39, 3635; (c) H. Bienayme and
K. Bouzid, Angew. Chem., Int. Ed., 1998, 37, 2234.
Conclusions
In summary, we have successfully developed a methodology for 10 (a) M. L. Bode, D. Gravestock and A. L. Rousseau, Org. Prep.
the synthesis of novel tetracyclic derivatives through intra-
molecular nucleophilic aromatic substitution of uorine at
Proced. Int., 2016, 48, 89; (b) A. L. Rousseau, P. Matlaba and
C. J. Parkinson, Tetrahedron Lett., 2007, 48, 4079.
position 5 of the imidazo[1,2-a]pyridine ring. In addition, we 11 (a) A. Gautier, Liebigs Ann. Chem., 1867, 142, 289; (b)
have demonstrated the improved utility, convenience and A. W. Hofmann, Liebigs Ann. Chem., 1867, 144, 114.
practicality of the pTsCl/DABCO-catalysed isocyanide in situ 12 P. Doz, I. Ugi, U. Fetzer, U. Eholzer, H. Knupfer and
generation protocol over the conventional POCl3/Et3N protocol. K. Offermann, Angew. Chem., Int. Ed., 1965, 4, 472.
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