A practical two-step synthesis of imidazo[1,2-a]pyridines from N-(prop-2-yn-1-yl)pyridin-2-amines

Article abstract of DOI:10.1039/c1cc10641d

The Sandmeyer reaction of differently C-2 substituted N-(prop-2-yn-1- ylamino)pyridines is an efficient, mild, new and practical method for the stereospecific synthesis of (E)-exo-halomethylene bicyclic pyridones bearing the imidazo[1,2-a]pyridine heteroc

Full text of DOI:10.1039/c1cc10641d

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COMMUNICATION
A practical two-step synthesis of imidazo[1,2-a]pyridines from
N-(prop-2-yn-1-yl)pyridin-2-aminesw
David Sucunza,a Abdelouahid Samadi,a Mourad Chioua,a Daniel B. Silva,ab Cristina Yunta,c
c
b
a
a
´
Lourdes Infantes, M. Carmo Carreiras, Elena Soriano and Jose Marco-Contelles*
Received 1st February 2011, Accepted 1st March 2011
DOI: 10.1039/c1cc10641d
The Sandmeyer reaction of differently C-2 substituted N-(prop-2-
yn-1-ylamino)pyridines is an efficient, mild, new and practical
method for the stereospecific synthesis of (E)-exo-halomethylene
bicyclic pyridones bearing the imidazo[1,2-a]pyridine heterocyclic
ring system.
Two recent communications by Chernyak and Thiel reporting
the transition metal-catalyzed synthesis of imidazoheterocycles,1
and triazolopyridines,2 respectively, prompt us to report here
a practical two-step synthesis of imidazo[1,2-a]pyridines (3)
from N-(prop-2-yn-1-yl)pyridin-2-amines (2), prepared from
appropriate precursors 1, by a Sandmeyer reaction (SR),3
transition metal [CuCl2, CuCl, Pd(OAc)2, NaAuCl4 or PtCl2],
N-iodosuccinimide (NIS), or acid promoted heterocyclization
(Scheme 1).
Scheme 1 Synthesis of imidazo[1,2-a]pyridines (3) via 6-(prop-2-yn-1-yl-
amino)pyridines (2) from 2-amino-6-chloropyridines (1).
In the context of our current work on the synthesis of
2-chloro(4H-pyrano)pyridines from the corresponding 2-amino
substituted heterocycles,4 when 2-amino-6-(methyl(prop-2-yn-1-yl)-
amino)pyridine-3,5-dicarbonitrile (2a), prepared from 2-amino-
6-chloropyridine-3,5-dicarbonitrile (1a),6a was submitted to
SR5 (ESIw), instead of the expected product, a new compound
was isolated in 62% yield. This product was fully characterized
by its analytical, spectroscopic data, and X-ray diffraction
analysis (ESIw)7 as the diastereomerically pure, chlorinated
bicylic pyridone 3a, bearing an imidazo[1,2-a]pyridine hetero-
cyclic ring system (Scheme 2, eqn (1)).
the transition metal promoted heterocyclic ring synthesis,1,2,11
and the synthetic potential of our result, the scope and the
generality of this process were investigated. Based on our
current interest on highly substituted pyridine derivatives for
biological purposes,12 intermediates 2b,c (Table 1) have been
synthesized from easily available precursors,6 and submitted
to SR experimental conditions.
As shown in Table 1, SR of intermediate 2a, in the presence of
CuBr2 or CuI, afforded similar compounds 3b and 3c in 63% and
41% yields (entries a and b), respectively, as the only reaction
products, in clean and highly diastereoselective reactions. SR of
intermediates 2b and 2c gave the reaction products 3d and 3e
(entries c and d), respectively, in good yields. The configuration at
the double bond in compounds 3b–e, as well as in the other related
derivatives prepared here by the same or analogous methods, has
been unequivocally assigned by comparison of their NMR data
with those of compound 3a. Compound 2d,6c bearing an ethoxy
group at C2, gave the expected bicyclopyridone 3d in 76% yield
(Scheme 2, eqn (2)), identical to the product obtained from
compound 2b (Table 1, entry c). With these results in mind, next
we investigated the heterocyclization reaction, using intermediate
2a, without any added nitrite, and CuCl2 or CuCl as catalysts. The
reaction was still possible, but very surprisingly afforded the exo-
methylene product 3f in moderate to good yields (Table 1, entries e
and f). Similarly, other transition metal salts, such as Pd(OAc)2,
NaAuCl4 or PtCl2, promoted the reaction giving compound 3f in
Bicyclic pyridones,8 and imidazo[1,2-a]pyridines,9 such as
saripidem (Scheme 1), alpidem or zolpidem, are well known
pharmacologically active molecules.10
Consequently, and in view of the interest of these
compounds, the increased number of communications describing
a
´
Laboratorio de Radicales Libres y Quımica Computacional,
IQOG (CSIC), Juan de la Cierva, 3, 28006-Madrid, Spain.
E-mail: iqoc21@iqog.csic.es; Fax: +34 9156 44853;
Tel: +34 9156 22900
b iMed.UL, Research Institute for Medicines and Pharmaceutical
Sciences, Faculty of Pharmacy, University of Lisbon,
Av. Forc¸as Armadas, 1600-083 Lisbon, Portugal
c
´
Instituto de Quımica-Fısica ‘‘Rocasolano’’, Serrano, 119,
28006-Madrid, Spain
´
w Electronic supplementary information (ESI) available: Detailed
experimental procedures and analytical data. CCDC 785405. For
ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c1cc10641d
c
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Chem. Commun., 2011, 47, 5043–5045 5043

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catalysts. Based on these results, we tested, but without success,
the ‘‘one-pot’’ palladium-catalyzed [Pd2(dba)3, (+)-BINAP,
NaOtBu, toluene, reflux] Buchwald13a or the [(IPr)Ni(allyl)Cl]13b
promoted N-propargylation of 2-amino-6-halopyridines, followed
by in situ heterocyclization. Conversely, we have also found that
NIS,14 unlike NBS or NCS, promotes the heterocyclization
reaction of intermediate 2a to give compound 3c (Table 1),
identical to the product obtained in the SR protocol, in higher
(68% vs. 41%) yield, but similar diastereoselectivity.
Next the scope of the reaction was further investigated by
modifying the structure of the intermediates. Unfortunately,
SR of N2-(prop-2-yn-1-yl)pyridine-2,6-diamine (2e) or 6-fluoro-
N-(prop-2-ynyl)pyridin-2-amine (2f) (ESIw) gave complex
reaction mixtures, and 6-fluoro-N-methyl-N-(prop-2-yn-1-yl)-
pyridin-2-amine (2g) did not react. However, when we submitted
compound 2g to reaction with aqueous hydrochloric acid in
1,4-dioxane,8b 1,3-dimethylimidazo[1,2-a]pyridin-5(1H)-one (3g)
was obtained in 51% yield (Scheme 2, eqn (3)). Very interestingly,
under the usual SR conditions, 2-(prop-2-ynylamino)nicotino-
nitrile (2h) provided stereospecifically imidazo[1,2-a]pyridine 3h in
77% yield (Scheme 2, eqn (4)); similarly, when only CuCl was
used as catalyst, compound 3i was the sole product isolated in
moderate yield (Scheme 2, eqn (5)). Finally, SR of tert-butyl
prop-2-yn-1-yl(pyridin-2-yl)carbamate (2i), and N-(prop-2-yn-1-yl)-
pyridin-2-amine (2j),11c prepared from 2-aminopyridine,15
afforded the same reaction products 3j and 3k (Scheme 2,
eqn (6) and (7)) in moderate chemical yields, but still competitive
regarding the methods previously described in the literature for
the synthesis of aldehyde 3j16a and nitrile 3k.16b The use of CuCl2
or NIS to promote the heterocyclization reaction did not improve
these results, but only aldehyde 3j was isolated in 8% and 10%
yields, respectively. The unexpected formation of compounds 3j
and 3k shows that SR results on N-(prop-2-yn-1-ylamino)-
pyridines are very substrate-dependent, but has precedent in the
I2-mediated heterocyclization of ethyl 2-(pyridin-2-yl)pent-4-
ynoates leading to ethyl 3-formylindolizine-1-carboxylates.17 In
fact, under these reaction conditions, N-(prop-2-yn-1-yl)pyridin-
2-amine (2j) gave (E)-3-(iodomethylene)-2,3-dihydro-1H-imidazo-
[1,2-a]pyridin-4-ium iodide 4 (40%), and aldehyde 3j (11%) which
after a Heck reaction [DIPEA (4 equiv.), Ag2CO3 (0.7 equiv.),
PPh3 (0.11 equiv.), Pd(OAc)2 (0.05 equiv.), acetonitrile, reflux,
48 h],11d with 1-chloro-4-iodobenzene, afforded compound 5 in
15 % yield (not optimized) (Scheme 3), a known intermediate in
the synthesis of saripidem (Scheme 1).18
Scheme 2 Heterocyclization of diversely functionalized prop-2-yn-
1-ylamino substituted pyridines (2).
Table 1 Heterocyclization reaction of 2-amino-6-(prop-2-yn-1-ylamino)-
pyridines (2)
The transition metal promoted (or the NIS-mediated)
heterocyclization of 2-amino-6-(prop-2-yn-1-ylamino)pyridines
seems to proceed through an alkyne–metal complexation
followed by a pyridinic nitrogen NH2–(C2) assisted ring
closure, ending by protonolysis/demetallation, with recovery
of the catalyst,1 affording compound 3f (Table 1).
Entry
2
CuXn
3
Yield (%)
a
a
b
c
d
e
f
g
h
i
2a
2a
2b
2c
2a
2a
2a
2a
2a
CuBr2
CuIa
CuCl2a
CuCl2
CuCl2 (0.5 equiv.)
CuCl (0.25 equiv.)
Pd(OAc)2 (0.1 equiv.)
NaAuCl4 (0.1 equiv.)
PtCl2 (0.2 equiv.)
3b (X = Br)
3c (X = I)
3d
3e (X = Cl)
3f
3f
3f
3f
3f
63
41
67
55
46
80
72
76
68
a
a
Under Sandmeyer reaction conditions.
good yields (Table 1, entries g–i). However, compound 2c did not
Scheme
3
Formal total synthesis of saripidem from imidazo-
react under these experimental conditions with none of these
[1,2-a]pyridine-3-carbaldehyde (3j).
c
5044 Chem. Commun., 2011, 47, 5043–5045
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(SAF2006-08764-C02-01; SAF2009-07271), Comunidad de
Madrid (S/SAL-0275-2006) for support, and M. C. Nicasio
for a gift of [(IPr)Ni(allyl)Cl]. ES thanks CSIC for grant
200880I221 and MICINN for grant CTQ2009-10478.
Notes and references
1 N. Chernyak and V. Gevorgyan, Angew. Chem., Int. Ed., 2010, 49,
2743–2746.
2 O. R. Thiel, M. M. Achmatowicz, A. Reichelt and R. D. Larsen,
Angew. Chem., Int. Ed., 2010, 49, 8395–8398.
3 (a) H. H. Hodgson, Chem. Rev., 1947, 40, 251–277;
(b) E. B. Merkushev, Synthesis, 1988, 923–937.
4 D. B. da Silva, A. Samadi, M. Chioua, M. C. Carreiras and
J. Marco-Contelles, Synthesis, 2010, 2725–2730.
5 M. P. Doyle, B. Siegfried and J. F. Dellaria, J. Org. Chem., 1977,
42, 2426–2431.
Scheme 4 A tentative free radical based mechanism for the formation
of bicyclo pyridone 3a from 2-amino-4-phenyl-6-(prop-2-yn-1-ylamino)-
pyridine-3,5-dicarbonitrile (2a).
6 (a) J. R. Piper, G. S. McCaleb, J. A. Montgomery, R. L. Kisliuk,
Y. Gaumont and F. M. Sirotnak, J. Med. Chem., 1986, 29,
1080–1087; (b) T. J. Murray, S. C. Zimmerman and
S. V. Kolotuchin, Tetrahedron, 1995, 51, 635–648;
(c) C. Peinador, V. Ojea and J. M. Quintela, J. Heterocycl. Chem.,
1992, 29, 1693–1702.
In Scheme 4 we show a tentative reaction mechanism for SR
heterocyclization of 2-amino-6-(prop-2-yn-1-ylamino)pyridines,
exemplified for intermediate 2a, but extensive to other related
intermediates. As proposed for the SR mechanism,5,19 the
formation of nitrosyl complexes of anhydrous copper halides,
strongly coordinated to the alkyne moiety, should be the
first step.
7 CCDC 785405w.
8 (a) H. Yu, W. Jin, C. Sun, J. Chen, W. Du, S. He and Z. Yu,
Angew. Chem., Int. Ed., 2010, 49, 5792–5797; (b) D. Cheng,
L. Croft, M. Abdi, A. Lightfoot and T. Gallagher, Org. Lett.,
2007, 9, 5175–5178.
9 (a) F. Couty and G. Evano, in Comprehensive Heterocyclic
Chemistry III, ed. A. R. Katritzky, C. A. Rams den, E. F. V. Scriven
and R. J. K. Taylor, Elsevier, Oxford, 2008, vol. 11, pp. 409–499;
(b) C. Hulme and Y.-S. Lee, Mol. Diversity, 2008, 12, 1–15.
10 T. Okubo, R. Yoshikawa, S. Chaki, S. Okuyamac and
A. Nakazato, Bioorg. Med. Chem., 2004, 12, 423–438.
11 For alkyne tethering intramolecular nucleophile promoted cyclo-
Then, the weak RO–NO bond of the nitrite should be
broken, leading to an alkoxy radical that would trap a
hydrogen, breaking the weak H–NH(C2) bond, starting then
the free radical chain reaction by a 5-exo-dig free radical
heterocyclization of the nitrogen centered radical at N(1) into
the activated alkyne. Next, and possibly due to the steric
hindrance, the resulting vinyl radical stereospecifically would
afford the chlorinated E-exo-chloromethylene intermediate.
Final hydrolysis of the HNQ(C2)N moiety would afford the
bicyclic pyridone 3a.20 The formation of imidazo[1,2-a]-
pyridines 3j and 3k could be explained assuming that the
presumed (E)-exo-halomethylene intermediate is too unstable,
and decomposes in situ in the presence of traces of an external
water source to the corresponding aldehyde, that evolves to
aldehyde 3j by oxidation, and to nitrile 3k, by reaction with
hydroxylamine, or nitrous acid, followed by dehydration.
In conclusion, we have discovered that SR, in the presence
of organic nitrites and copper halides, of N-(prop-2-yn-1-yl-
amino)pyridines synthesized by reacting easily available or
commercial 2-halopyridines and N-propargylamines is a mild,
new and practical method for the stereospecific synthesis of
highly substituted (E)-exo-halomethylene bicyclic pyridones
bearing the imidazo[1,2-a]pyridine heterocyclic ring system of
potential biological interest. These are suitable intermediates
for further synthetic transformations and modulation. In the
course of this prospective study we have also found that
2-amino-6-(prop-2-yn-1-ylamino)pyridines afford exo/endo-
methylene bicyclopyridones in transition metal-catalyzed
[CuCl2, Pd(OAc)2, PtCl2], NIS, or HCl/H2O-mediated hetero-
cylization reactions in convenient chemical yields.
isomerizations
leading
to
imidazo[1,2-a]pyridines,
see:
(a) M. Bakherad, H. Nasr-Isfahani, A. Keivanloo and
N. Doostmohammadi, Tetrahedron Lett., 2008, 49, 3819–3822;
(b) P. Liu, L.-S. Fang, X. Lei and G.-g. Lin, Tetrahedron Lett., 2010,
51, 4605–4608; (c) J. Reisch and M. Scheer, J. Heterocycl. Chem., 1988,
25, 677–679. For the usual one-pot synthesis of imidazo[1,2-a]pyridines
by reaction of 2-aminopyridines and a-bromoketones, see:
(d) R. R. Singhaus, R. C. Bernotas, R. Steffan, E. Matelan,
P. Quinet, I. Nambi, C. Feingold, A. Huselton, A. Wilhelmsson,
J. Goos-Nilsson and E. Wrobel, Bioorg. Med. Chem. Lett., 2010, 20,
521–525; (e) M. Adib, A. Mohamadi, E. Sheikhi, S. Ansari and
H. R. Bijanzadeh, Synlett, 2010, 1606–1608.
´
12 A. Samadi, J. Marco-Contelles, E. Soriano, M. Alvarez-Pe
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rez,
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J. M. Roda, M. G. Lopez, M. Villarroya, A. G. Garcı
C. de los Rı
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´ ´
´
´
´
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´ ´
14 F. Rodrıguez and F. J. Fananas, in Handbook of Cyclization
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18 P. George and C. Giron, EP0172096 A1, 1986.
19 (a) W. A. Waters, J. Chem. Soc., Abstr., 1942, 266; (b) J. K. Kochi,
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20 We cannot rule out the formation of 1-iodoalkyne intermediates as an
alternative mechanism, as recently reported by Fokin and co-workers
(L. B. Krasnova, J. E. Hein and V. V. Fokin, J. Org. Chem., 2010, 75,
8662–8665) in the synthesis of 7-aza-5-deazapurine analogues via
copper(I)-catalyzed hydroamination of alkynes and 1-iodoalkynes.
AS thanks CSIC for a ‘‘JAE-Doc’’ contract. DS thanks
FCT (MCTES) (Portugal) for
a grant (PTDC/SAU-
NEU/64151/2006). MC thanks ISCIII (MCINN, Spain) for
a ‘‘Sara Borrell’’ contract. JMC thanks also MICINN
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 5043–5045 5045