Silver-catalyzed cyclization of N-(prop-2-yn-1-yl)pyridin-2-amines

Article abstract of DOI:10.1002/ejoc.201201258

We report herein the silver-catalyzed cycloisomerization of readily available N-(prop-2-yn-1-yl)pyridine-2-amines as a new and practical method for the synthesis of differently substituted 3-methylimidazo[1,2-a]pyridines. The isomerization reactions proce

Full text of DOI:10.1002/ejoc.201201258

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201201258
Silver-Catalyzed Cyclization of N-(Prop-2-yn-1-yl)pyridin-2-amines
Mourad Chioua,*[a] Elena Soriano,[b] Lourdes Infantes,[c] M. Luisa Jimeno,[d]
José Marco-Contelles,*[a] and Abdelouahid Samadi[a]
Keywords: Amines / Nitrogen heterocycles / Silver / Cyclization / Reaction mechanisms
We report herein the silver-catalyzed cycloisomerization of
readily available N-(prop-2-yn-1-yl)pyridine-2-amines as a
new and practical method for the synthesis of differently sub-
stituted 3-methylimidazo[1,2-a]pyridines. The isomerization
reactions proceeded under mild reactions conditions to give
good yields and excellent regioselectivity. A DFT-based
mechanistic analysis is also reported.
N-(prop-2-yn-1-yl)pyridin-2-amines (I),
mechanistic analysis and its application to the total synthe-
sis of saripidem (Scheme 1).
a
DFT-based
Introduction
Compounds containing the imidazo[1,2-a]pyridine ring
system,[1] for example, saripidem (Scheme 1), necopidem or
zolpidem, are of wide medicinal interest.[2] Consequently, a
number of synthetic methods have been reported[3] for the
synthesis of this heterocyclic system,[4–9] however, these
methods are compromised by the numerous steps needed to
obtain the required precursors and the narrow substrate
scope. Thus, new and more efficient synthetic methods are
sought.
Results and Discussion
Although silver-mediated coupling and heterocyclization
reactions are well documented, there are few precedents for
silver-catalyzed cyclizations of substituted aromatic or
heterocyclic N-propargylamines.[10] A recent communica-
tion on the silver-catalyzed 6-endo-dig cyclization reactions
of N-propargylated heterocyclic compounds[11] prompted
us to test this reaction on the readily available N-(prop-2-
yn-1-yl)pyridin-2-amine derivatives.[7,9]
The reaction of N-(prop-2-yn-1yl)pyridin-2-amine (1a)[7]
with cheap AgNO3 (10%) as catalyst in dry acetonitrile at
reflux under argon gave a mixture of the easily separable 3-
methylimidazo[1,2-a]pyridine (2a)[7,12] and imidazo[1,2-a]-
pyridine-3-carbaldehyde (3a),[9,13] isolated in yields of 69
Scheme 1. Structure of saripidem and a general approach to the
synthesis of diversely functionalized 3-methylimidazo[1,2-a]pyr-
idines (II) by silver-mediated cyclization of N-(prop-2-yn-1-yl)pyr- and 8%, respectively (entry a, Table 1). SeO2-promoted all-
idin-2-amines (I).
ylic oxidation of compound 2a gave aldehyde 3a in 58%
yield (see Scheme 2), which was reduced with sodium
borohydride to afford imidazo[1,2-a]pyridin-3-ylmethanol
(4a)[14] in 86% yield. Remarkably, only the 5-exo-dig cycli-
zation products 2a and 3a were formed,[6] in sharp contrast
to the results obtained from the silver-mediated cyclization
of 6-(prop-2-yn-1-ylamino)-2H-chromen-2-ones,[11] 1-alkyl-
In this communication we report a new method for the
preparation of imidazo[1,2-a]pyridine derivatives (II) based
on the unprecedented silver-mediated heterocyclization of
[a] Laboratorio de Química Médica, IQOG (CSIC),
Calle Juan de la Cierva 3, 28006 Madrid, Spain
Fax: +34-34-91-564853
6-(prop-2-yn-1-ylamino)quinolin-2(1H)-ones,[11]
1,3-di-
methyl-5-(prop-2-yn-1-ylamino)pyrimidine-2,4(1H,3H)-di-
ones,[11] N-(prop-2-yn-1-yl)benzo[d]oxazol-2-amines[15a] or
N9-propargylguanine,[15b] for which only the 6-endo prod-
ucts were isolated.
On the basis of these results, the reaction was optimized
(see Table 1). The use of a base, such as Et3N, resulted in a
slower reaction (17 h) giving the imidazo[1,2-a]pyridine 2a
in a lower yield (23%) and aldehyde 3a in a higher yield
(19%, entry b, Table 1). With regard the silver catalyst,
E-mail: iqoc21@iqog.csic.es
m.chioua@csic.es
Homepage: www.iqog.csic.es
[b] SEPCO, IQOG (CSIC),
Calle Juan de la Cierva 3, 28006 Madrid, Spain
[c] Instituto de Química-Física “Rocasolano” (CSIC),
Calle Serrano 119, 28006 Madrid, Spain
[d] CENQUIOR (CSIC),
Calle Juan de la Cierva 3, 28006 Madrid, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201258.
Eur. J. Org. Chem. 2013, 35–39
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35

M. Chioua, J. Marco-Contelles et al.
SHORT COMMUNICATION
Table 1. Silver-mediated heterocyclization of N-(prop-2-yn-1-yl)- azo-fused heterocycles 2h[18] and 2i[19] in variable yields.
pyridin-2-amine (1a).
Very interestingly, internal alkyne analogue 1j or N-Me-
substituted precursor 1k gave the corresponding triflates 2j
and 2k, respectively, in poor yields after long reaction times
(entries j and k, Table 2). However, when precursor 1j was
treated with AgTfO (1 equiv.), compound 2j was isolated in
92% yield in a quick reaction (30 min). The structure of
Table 2. Silver-mediated heterocyclization of N-(prop-2-yn-1-yl)-
pyridin-2-amines 1b–k.
readily available AgF, AgBF4 and AgOAc were investigated
and were found to give similar yields of compounds 2a and
3a (entries c–e, Table 1). With AgOTf, a mixture of 3-meth-
ylimidazo[1,2-a]pyridine (2a; 52%), aldehyde 3a (9%) and
alcohol 4a (18%) was obtained (entry f, Table 1). Interest-
ingly, when we carried out the reaction in deoxygenated
acetonitrile, not only did the yield of compound 2a increase
to 84%, but the yield of aldehyde 3a was reduced to 2% and
only traces of alcohol 4a were detected (entry g, Table 1).
Overall, the formation of the compounds 3a and 4a, al-
though obtained in low chemical yields, was totally unex-
pected, and to the best of our knowledge these results are
the first examples of the intramolecular dehydrogenative
aminooxygenation (IDA) of N-(prop-2-yn-1-yl)pyridin-2-
amines.[16] Finally, other catalysts, for example, CuCl2 (en-
try h), gave compound 2a in a clean and high-yielding reac-
tion, whereas with PtCl2 (entry i) and NaAuCl4 (entry j),
the yields of compound 2a were significantly lower than
those observed for AgOTf (entry g, Table 1).
Once the optimal experimental conditions had been de-
termined [AgOTf (10%) in dry deoxygenated acetonitrile at
reflux under argon], the scope and generality of the reaction
was next investigated with N-(prop-2-yn-1-yl)pyridin-2-
amine derivatives 1b–k[17] (Table 2). Methyl-substituted pre-
cursors (entries a–c), even when the Me group was located
at C-6 or the substrate also bore a bromine atom at C-
3, gave the corresponding imidazopyridines in moderate-to-
good yields in short reaction times (2–4 h). The cyclization
of the bromo- or chloro-substituted precursors (entries d–
f), regardless of the position of the halogen, afforded the
expected product, but the reaction was markedly slower
(16–24 h). Finally, the cyclization of N-propargylamines in
other heterocyclic ring systems, such as an imidazole (en-
try g) or a pyrazine (entry h), under the same experimental
conditions, was also possible, providing the expected imid-
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Silver-Catalyzed Cyclization of N-(Propynyl)pyridinamines
Figure 1. Free-energy profile (in kcal/mol) computed in solution (acetonitrile) for the Ag-catalyzed heterocyclization of 1a. B refers to 1a
acting as a base assisting the proton-shift steps.
compounds 2j,k were established by NMR spectroscopy, yield, taking into account the recovered unreacted precur-
and in the case of the 6-endo-dig cyclization product 2j, also sor (entry j; Table 3). Interestingly, when precursor 5j was
by X-ray diffraction analysis (see the Supporting Infor- treated with AgTfO (1 equiv.), compound 2l was isolated in
mation). Very interestingly, 2-[methyl(prop-2-yn-1-yl)- 94% yield after 30 min reaction time. In general, it is clear
amino]nicotinonitrile was recovered unreacted, which that for the same structural/functional motif, the free pro-
shows the strong deactivating effect of an electron-with- pargylamines 1 (Table 1 are Table 2) are better precursors
drawing substituent.
With these results in hand, we proposed and examined AgOTf-mediated synthesis of the imidazopyridines.
several potential mechanisms[20] for the cyclization of N-
At this point, comparison with the tBuOK/THF-pro-
than the corresponding Boc derivatives 5 (Table 3) for the
(prop-2-yn-1-yl)pyridin-2-amine (1a; Figure 1). For the for- moted cyclization reactions of N-propargylaminopyr-
mation of product 2a from precursor 1a, the more favour- idines[7] seems appropriate. As shown in Table 3, and for the
able mechanism computed in acetonitrile (Figure 1) in- same carbamate, the Ag-catalyzed method compares very
volves a kinetically favoured exo-dig rather than an endo favourably with the tBuOK-promoted cyclization (entries a
cyclization proceeding via intermediate I1EXO, followed by and g) taking place under milder conditions. In addition,
successive deprotonation/protonation events assisted by the for the N-propargylaminopyridine 1a (Table 1, entries a–g)
basic pyridine framework (denoted as B in Figure 1). This or the carbamates 5d, 5h and 5j (entries d, h and j; Table 3),
base-assisted deprotonation/protonation pathway was pro- the tBuOK-promoted cyclization did not lead to the ex-
posed by Gevorgyan and co-workers for a closely related pected heterocyclic derivatives, whereas the AgOTf-cata-
Ag-mediated cycloisomerization and supported by labelling lyzed reaction afforded the expected products in moderate-
studies.[21] The sequence involves a formal [1,4] hydrogen to-good yields.
shift from the amine group and a formal [1,3] hydrogen shift
Finally, to test the utility of our method, we carried out
from the endocyclic methylene to the exocyclic carbon. Our the total synthesis of the anxiolytic sarpidem[23] from 2-
calculations suggest that the former would take place before aminopyridine (6) in 11% overall yield with imidazo[1,2-a]-
the latter process.[22]
pyridine 2a as the key intermediate (Scheme 2). Heck reac-
On the basis of this mechanism, we hypothesized that
N-Boc-N-propargylaminopyridines, as readily available key
intermediates for the preparation of precursors 1 (Table 1
and Table 2), could also be substrates for the AgOTf-medi-
ated cyclization reaction leading to imidazopyridines if
triflic acid can trigger the elimination of isobutylene and
CO2, followed by cyclization of the resulting N-pyridyl
carbanion to the Ag-activated alkyne. To probe this hypoth-
esis, we investigated the silver-catalyzed cycloisomerization
of N-Boc-N-propargylaminopyridines 5a–j (Table 3). As
shown, and with the exception of precursor 5i, all the carb-
amates reacted to give the imidazopyridine (or imidazopyr-
imidine) derivatives in yields ranging form 12 (2f, entry f) to
92% (2a, entry a). Similarly, the internal alkyne substituted
analogue 5j gave the 6-endo-dig product 2l in moderate Scheme 2. Total synthesis of saripidem from 2-aminopyridine (6).
Eur. J. Org. Chem. 2013, 35–39
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37

M. Chioua, J. Marco-Contelles et al.
SHORT COMMUNICATION
Table 3. Silver-mediated heterocyclization of N-(prop-2-yn-1-yl)- dem via N-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]-
(pyridin-2-yl)carbamates 5a–j.
methyl}butyramide (9; see the Supporting Information).
Conclusions
We have reported herein for the first time the silver-medi-
ated cycloisomerization of readily available N-(prop-2-yn-1-
ylamino)pyridines as a new and practical method for the
regioselective synthesis of differently substituted 3-methyl-
imidazo[1,2-a]pyridines, suitable intermediates for further
synthetic transformations and modulation, that proceeds
under mild reaction conditions in good-to-high yields and
with excellent regioselectivity.
Experimental Section
General Method for the Silver-Mediated Cyclization of N-(Prop-2-
yn-1-yl)pyridin-2-amine Derivatives: A catalytic amount of AgOTf
(10 mol-%) was added to a solution of the corresponding N-(prop-
2-ynyl)pyridin-2-amines 1a–k (Method A) or N-(prop-2-yn-1-yl)-
N-(pyridin-2-yl)carbamates 5a–j (Method B) (1.0 mmol) in dry
acetonitrile. The mixture was deoxygenated with argon for 10 min
and then heated at 85 °C for the time indicated for each compound.
When the reaction was complete (TLC analysis), the solvent was
evaporated under reduced pressure and the residue purified by flash
chromatography to give the pure products.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, NMR spectra, computational re-
sults, X-ray analysis, and NMR analysis.
Acknowledgments
M. C. thanks the Instituto de Salud Carlos III (ISCIII) for a “Sara
Borrell” contract and A. S. thanks the Consejo Superior de Invest-
igaciones Científicas (CSIC) for a “.JAE-doc” contract. J. M. C.
thanks the Ministerio de Ciencia
(SAF2009-07271; SAF2012-33304) for financial support. E. S.
thanks the Ministerio de Ciencia Innovación
e Innovación (MICINN)
e
(MICINN) for a grant (CTQ2009-10478). L. I. thanks Comunidad
de Madrid (Spain) for financial support (BIPEDD-2: S2010-BMD-
2457). The authors thank Prof. J. Elguero (IQM, CSIC) for advice
and useful comments.
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Silver-Catalyzed Cyclization of N-(Propynyl)pyridinamines
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Received: September 21, 2012
Published Online: November 19, 2012
Eur. J. Org. Chem. 2013, 35–39
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