Isonitrile alkylations: A rapid route to imidazo[1,5-a]pyridines

Article abstract of DOI:10.1039/c5cc08724d

Metalated arylmethylisonitriles readily add to 2-chloropyridines to afford imidazo[1,5-a]pyridines. Analogous additions to imidoyl chlorides and a chloroquinoline provide imidazoles and an imidazo[1,5-a]quinolone which, like imidazo[1,5-a]pyridines, are v

Full text of DOI:10.1039/c5cc08724d

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Isonitrile alkylations: a rapid route to
imidazo[1,5-a]pyridines†
Cite this:DOI: 10.1039/c5cc08724d
Yajun Li,a Allen Chaob and Fraser F. Fleming*a
Received 20th October 2015,
Accepted 17th December 2015
DOI: 10.1039/c5cc08724d
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Metalated arylmethylisonitriles readily add to 2-chloropyridines to afford
imidazo[1,5-a]pyridines. Analogous additions to imidoyl chlorides and a
chloroquinoline provide imidazoles and an imidazo[1,5-a]quinolone
which, like imidazo[1,5-a]pyridines, are valuable heterocycles for
pharmaceutical synthesis.
Fig. 1 Core imidazo[1,5-a]pyridines as pharmaceutical leads.
The imidazo[1,5-a]pyridine core is a valuable scaffold for preparing
electronic devices, N-heterocyclic carbenes, and pharmaceutical
leads.1 Representative of this bioactivity is the kinase inhibitor
1 that is currently in phase I trials as a tumour inhibitor2 and the
imidazo[1,5-a]quinolone 2 that was identified as a neurokinin
antagonist with potential for alleviating side effects from
chemotherapy and surgery.3 The role of imidazo[1,5-a]pyridine
as a pharmacophore, and the paucity of methods for synthesizing
(1)
Exploratory arylations were probed with 2-chloropyridine
the heterocycle core,4 stimulated a new strategy that exploits the (6a) and lithiated benzylisonitrile because benzylisonitrile (4a)
under-developed chemistry of metalated isonitriles (Fig. 1).5
is commercially available and readily deprotonated by treatment
Isonitriles are challenging to deprotonate because of the low with BuLi (Scheme 1).7b Optimization experiments revealed that
kinetic and thermodynamic acidity of the protons adjacent to deprotonation was best accomplished at ꢀ78 1C for 5 minutes;
the isonitrile group.6 Once deprotonated, metalated isonitriles longer reaction times led to a diminished yield through formation
are prone to self-condensation by nucleophilic attack onto the of high molecular weight materials assumed to arise from
carbenoid-like isonitrile carbon.7 Consequently, most metalated self-condensation. After generating lithiated benzylisonitrile,
isonitriles are generated from precursors bearing an adjacent 2-chloropyridine was added and, after 30 min, the reaction
electron withdrawing group to facilitate deprotonation, increasing was allowed to warm to rt. Reaction monitoring revealed that
the stability of the organometallic, with alkylation limited to the alkylation did not proceed until 0 1C, though the reaction
alkyl halide and carbonyl electrophiles.5 Described below is an was slow and best coaxed toward completion by warming to rt.
imidazo[1,5-a]pyridine synthesis8 that uses metalated arylmethyl- The optimized procedure gave imidazo[1,5-a]pyridine 8a9
isonitriles in condensations with 2-chloropyridine-type precursors in 29% yield (Scheme 1), though exactly the same procedure
3 to generate valuable heterocycles 5 while addressing the with 2-chloro-6-methylpyridine (6b) gave 8b in 72% yield. The
deficiencies in metalated isonitrile alkylations (eqn (1)).5
significant yield increase was suspected to arise from proton
transfers involving the 6-methyl group,10 a suspicion subsequently
a Department of Chemistry, Drexel University, 3141 Chestnut Street, Philadelphia,
PA 19104-2875, USA. E-mail: fleming@drexel.edu; Fax: +1 215 895 1265;
Tel: +1 215 895 2644
b Department of Chemistry, Duquesne University, 600 Forbes Ave, Pittsburgh,
PA 15282, USA
† Electronic supplementary information (ESI) available: Experimental procedures
and spectral characterization. CCDC 1430826. For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/c5cc08724d
Scheme 1 Metalated isonitrile route to imidazo[1,5-a]pyridines.
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Table 1 Metalated isonitrile condensations to heterocyclesa
Table 1 (continued)
Yield
(%)
Yield
(%)
Entry Isonitrile
1
Electrophile
Heterocycle
Entry Isonitrile
14
Electrophile
Heterocycle
77b
55
82b
15
76
2
a
b
KHMDS was employed as the base unless otherwise stated. BuLi was
c
employed in place of KHMDS. Use of BuLi as the base afforded 8e in
d
3
4
5
77c
59
51% yield. Accompanied by 30% of the isonitrile 8g0 resulting from
nucleophilic aromatic substitution of fluorine.
confirmed by deuterium labeling.11 Recognition of the potential
benefit of a weak acid led to screening of bases with conjugate acids
capable of facilitating proton transfer. KHMDS emerged as the
most effective base affording the imidazo[1,5-a]pyridine 8a in 53%
yield from benzylisonitrile (4a).
38d
Having gained insight into the imidazo[1,5-a]pyridine synthesis,
the substrate scope was examined (Table 1). Methyl substitution
on the pyridine ring is readily tolerated (entries 1 and 2) as are
bromine substituents (entries 3 and 4). However, the fluorine
substituent was competitively displaced through nucleophilic
aromatic substitution (entry 5).12 Phenyl and methoxy substituents
on the aromatic ring of benzylisonitrile are tolerated (4b and 4c,
entries 6 and 7) as are the furylmethylisonitriles 4d and 4e.13
In a related alkylation, the metalated arylmethylisonitriles
derived from 4a, 4b, and 4f were found to efficiently add to imidoyl
chlorides14 to form imidazoles 9 (entries 10 to 13).15 The reaction
extends the union of imidoyl chlorides with TosMIC16 to less
stabilized metalated isonitriles. Lithiated benzylisonitrile reacts with
a chloroquinoline to afford the quinoline 10a (entry 14) while the
isonitrile 4b was found to react with 2-chloro-4,6-dimethylpyrimidine
to afford 11a (entry 15).
6
90
7
84
8
63
9
56
Two mechanisms can be envisioned for the imidazo[1,5-a]-
pyridine synthesis (Scheme 2): an addition–cyclization–elimination
sequence (13 - 14 - 15 - 8) or an addition–elimination–
cyclization (13 - 16 - 17 - 8). Although no trace of inter-
mediate pyridine 16 was detected during the reaction,17 the
addition of lithiated (1-isocyanoethyl)benzene (12, R2 = Ph,
H = Me) afforded detectable amounts of the corresponding
pyridine 16 (R1 = H, R2 = Ph, H = Me) implying the cyclization
proceeds through 16 and 17.18
The efficacious role of KHMDS in these cyclizations is likely
related to the ability of hexamethyldisilazane, generated after
deprotonation of the isonitrile, to facilitate the proton transfers.6
Typically 1.3 equivalents of KHMDS are employed; one equivalent
is consumed in deprotonating the arylmethylisonitrile and a
second is required for the cyclization 16 - 17. Protonation of 17
10
11
50b
61b
12
13
60
57
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Scheme 2 Potential cyclization mechanisms for imidazo[1,5-a]pyridine
formation.
by hexamethyldisilazane regenerates KHMDS thereby avoiding
the requirement for two equivalents of base. Condensations
with BuLi require pyridines with an acidic substituent for
synthetically acceptable yields or imidoyl chlorides which
cyclize without excess base.19
Addition of metalated arylmethyl isonitriles to 2-chloropyridines
efficiently generates a range of substituted imidazo[1,5-a]pyridines.
Analogous additions to a chloroquinoline, a pyrimidine, and
imidoyl chlorides generates an imidazo[1,5-a]quinoline, an imidazo-
[1,5-a]pyrimidine, and imidazoles, respectively. Mechanistic analyses
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disilazane facilitates proton transfers. The heterocycle syntheses
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metalated isonitriles.
9 The identity of 8a was confirmed by X-ray crystallography (CCDC
1430826) because of a discrepancy in some of the NMR signals with
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10 In the absence of a suitable proton source the labile intermediate is
prone to polymerization (cf. Scheme 2).
11 The cyclization of dideuterated benzylisonitrile with 2-chloro-6-
methylpyridine leads to considerable deuterium incorporation
within the methyl group consistent with KHMDS facilitating the
proton transfer. Details provided in the ESI†.
12 Use of lithiated isonitrile afforded 8g in 12% and the substituted
isonitrile 8g0 in 51% yield.
13 Prepared from the corresponding amine: B. S. Fowler, P. J. Mikochik
and S. J. Miller, J. Am. Chem. Soc., 2010, 132, 2870–2871.
14 Prepared from the corresponding amides by treatment with thionyl
chloride: J.-P. Lin, F.-H. Zhang and Y.-Q. Long, Org. Lett., 2014, 16,
2822–2825.
15 Efforts to extend the strategy to metalated alkylisonitriles were not
successful.
Financial support for this research from NIH (2R15AI051352-04)
and release time from NSF (IRD) is gratefully acknowledged.
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417–679.
17 The cyclization of 16 (R1 = R2 = H) to 8 occurs in the presence of
¨
t-BuOK (30% yield): U. Schollkopf, E. Eilers and K. Hantke, Liebigs
Notes and references
Ann. Chem., 1976, 969–977.
18 Unfortunately the isonitrile was unstable to purification.
19 Presumably the intermediate imine is sufficiently nucleophilic to
attack the isonitrile without the need for added base although
deprotonation with catalytic base cannot be ruled out.
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Chem. Commun.