Regioselective cobalt-catalyzed formation of bicyclic 3- and 4-aminopyridines

Article abstract of DOI:10.1021/ol200417p

Bimolecular cobalt-catalyzed [2+2+2] cycloadditions between yne-ynamides and nitriles afford bicyclic 3- or 4-aminopyridines in up to 100% yield. The high regioselectivity observed depends on the substitution pattern at the starting ynamide. Aminopyridines bearing TMS and Ts groups are efficiently deprotected in an orthogonal fashion.

Full text of DOI:10.1021/ol200417p

ORGANIC
LETTERS
2011
Vol. 13, No. 8
2030–2033
Regioselective Cobalt-Catalyzed
Formation of Bicyclic 3- and
4-Aminopyridines
Pierre Garcia,† Yannick Evanno,§ Pascal George,§ Mireille Sevrin,§ Gino Ricci,‡
Max Malacria,*,† Corinne Aubert,*,† and Vincent Gandon*,†
ꢀ
UPMC, Universite Paris 06, IPCM 7201, 4 Place Jussieu, 75252 Paris Cedex 05,
France, Sanofi-Aventis, 45 Chemin de Meteline, 04200 Sisteron, France, and
ꢀ ꢀ
ꢀ
Sanofi-Aventis Recherche & Developpement, 1 Avenue Pierre Brossolette, 91385
Chilly-Mazarin, France
max.malacria@upmc.fr; corinne.aubert@upmc.fr; vincent.gandon@u-psud.fr
Received February 15, 2011
ABSTRACT
Bimolecular cobalt-catalyzed [2 þ 2 þ 2] cycloadditions between yne-ynamides and nitriles afford bicyclic 3- or 4-aminopyridines in up to 100%
yield. The high regioselectivity observed depends on the substitution pattern at the starting ynamide. Aminopyridines bearing TMS and Ts groups
are efficiently deprotected in an orthogonal fashion.
Nitrogen-substituted pyridines represent an important
class of compounds displaying promising biological
properties.1 Thus, to sustain pharmaceutical innovation,
synthetic methods allowing a rapid access to aminopyridine
frameworks are highly desirable (Figure 1).2 The known
procedures usually rely on the functionalization of a
preexisting pyridine ring (e.g., tandem ortho-metalation/
alkylation,2a,b Chichibabine aromatic substitution,2c or
Buchwald-Hartwig amination3).4 On the other hand, we
describe herein an approach based on the direct construction
†
ꢀ
Universite Paris.
§
ꢀ
Sanofi-Aventis Recherche & Developpement.
‡ Sanofi-Aventis.
ꢀ
(1) (a) Popowycz, F.; Merour, J.-Y.; Joseph, B. Tetrahedron 2007, 63,
8689. (b) Cao, R.; Peng, W.; Wang, Z.; Xung, A. Curr. Med. Chem. 2007,
(2) (a) For Pfizer, see: Devilliers, I.; Pevet, I.; Jacobelli, H.; Durand,
ꢁ
€
14, 479. (c) Chen, N.; Burli, R. W.; Neira, S.; Hungate, R.; Zhang, D.;
C.; Fasquelle, W.; Puaud, J.; Gaudilliere, B.; Idrissi, M.; Moreau, F.;
Yu, V.; Nguyen, Y.; Tudor, Y.; Plant, M.; Flynn, S.; Meagher, K. L.;
Lee, M. R.; Zhang, X.; Itano, A.; Schrag, M.; Xu, Y.; Ng, G. Y.; Hu, E.
Bioorg. Med. Chem. 2008, 18, 4137. (d) Liu, J.; Eaton, J. B.; Caldarone,
B.; Lukas, R. J.; Kozikowski, A. P. J. Med. Chem. 2010, 53, 6973. (e)
Ramnauth, J.; Surman, M. D.; Sampson, P. B.; Forrest, B.; Wilson, J.;
Freeman, E.; Manning, D. D.; Martin, F.; Toro, A.; Domagala, M.;
Awrey, D. E.; Bardouniotis, E.; Kaplan, N.; Berman, J.; Pauls, H. W.
Bioorg. Med. Chem. 2009, 19, 5359. (f) Whitman, D. B.; Askew, B. C.;
Duong, L. T.; Fernandez-Metzler, C.; Halczenko, W.; Hartman, G. D.;
Hutchinson, J. H.; Leu, C.-T.; Prueksaritanont, T.; Rodan, G. A.;
Rodan, S. B.; Duggan, M. E. Bioorg. Med. Chem. 2004, 14, 4411. (g)
Madsen-Duggan, C. B.; Debenham, J. S.; Walsh, T. F.; Yan, L.; Huo, P.;
Wang, J.; Tong, X.; Lao, J.; Fong, T. M.; Xiao, J. C.; Huang, C. R.-R.
C.; Shen, C.-P.; Stribling, D. S.; Shearman, L. P.; Strack, A. M.; Goulet,
M. T.; Hale, J. J. Bioorg. Med. Chem. 2010, 20, 3750.
Wrigglesworth, R. Bioorg. Med. Chem. Lett. 2004, 14, 3303. (b) For
Merck, see: Keen, S. P.; Cowden, C. J.; Bishop, B. C.; Brands, K. M. J.;
Davies, A. J.; Dolling, U.-H.; Lieberman, D. R.; Stewart, G. W. J. Org.
Chem. 2005, 70, 1771. (c) For AstraZeneca, see: Caulkett, P. W. R.,
McCoull, W.; Packer, M.; Whittamore, P. R. O. PCT Int. Appl.
WO2007135427, 2007; Chem. Abstr. 2007, 148, 33765.
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130, 6586. (b) Ogata, T.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130,
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(4) It is also possible via Diels-Alder reaction and extrusion of a
small molecule; see: (a) Taylor, E. C.; Macor, J. E.; Pont, J. L. Tetra-
hedron 1987, 43, 5145. (b) Frissen, A. E.; Marcelis, A. T. M.; Van der
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r
10.1021/ol200417p
Published on Web 03/17/2011
2011 American Chemical Society

of the pyridine nucleus by a cobalt-catalyzed [2 þ 2 þ 2]
regioisomers using yne-ynamides and readily available
nitriles (Figure 2, eq 2).
cycloaddition between two alkynes and one nitrile.5
Figure 1. Aminopyridines from pharmaceutical companies.
To make this reaction applicable to the synthesis of
3-amino- as well as 4-aminopyridines, we decided to use
ynamides6 as alkyne partners (Figure 2). Although various
[2 þ 2 þ 2] cycloadditions involving one ynamide and two
alkynes to give N-substituted benzenes have been reported,7
the formation of pyridines using such substrates has
not received much attention and is still limited to intramo-
lecular cyclizations (Figure 2, eq 1).8
Figure 2. [2 þ 2 þ 2] approaches to polycyclic aminopyridines.
The starting ynamides 2a-d could be prepared in quite
large amounts from sulfonamides (up to 5 g), in moderate
to good yields, using Zhang’s conditions (Table 1).10
Of course, only 3-aminopyridines can be formed in
the intramolecular version, at least with relatively short
tethers.9 We were interested in the development of a more
flexible method that could selectively provide the different
Table 1. Synthesis of the Ynamides
(5) For reviews on [2 þ 2 þ 2] cycloaddition reactions, see: (a)
Vollhardt, K. P. C. Angew. Chem., Int. Ed. Engl. 1984, 23, 539. (b)
ꢀ
Varela, J.; Saa, C. Chem. Rev. 2003, 103, 3787. (c)Kotha, S.; Brahmachary,
E.; Lahiri, K. Eur. J. Org. Chem. 2005, 4741. (d) Gandon, V.; Aubert, C.;
Malacria, M. Chem. Commun. 2006, 2209. (e) Chopade, P. R.; Louie, J.
Adv. Synth. Catal. 2006, 348, 2307. (f) Agenet, N.; Gandon, V.; Buisine,
O.; Slowinski, F.; Aubert, C.; Malacria, M. In Organic Reactions;
RajanBabu, T. V., Ed.; John Wiley and Sons: Hoboken, 2007; Vol. 68,
pp 1-302. (i) Heller, B.; Hapke, M. Chem. Soc. Rev. 2007, 36, 1085.
(g) Tanaka, K. Synlett 2007, 1977. (h) Maryanoff, B. E.; Zhang, H.-C.
entry
product
n
R
yield (%)
1
2
3
4
5
2a
1
2
3
3
4
TMS
TMS
TMS
Ph
35
79
72
65
59
2b
ꢀ
ARKIVOC 2007, 12, 7. (i) Varela, J.; Saa, C. Synlett 2008, 2571. (j)
2cTMS
2cPh
2d
Tanaka, K. Chem. Asian J. 2009, 4, 508. (k) Lebuf, D.; Gandon, V.;
Malacria, M. In Handbook of Cyclization Reactions; Ma, S., Ed.;
Wiley-VCH: Weinheim, 2009; Vol. 1, pp 367-406.
TMS
(6) For reviews on ynamides chemistry, see: (a) Evano, G.; Coste, A.;
Jouvin, K. Angew. Chem., Int. Ed. 2010, 49, 2840. (b) Dekorver, K. A.;
Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.; Yu, Z.; Hsung, R. P. Chem.
Rev. 2010, 110, 5064.
With these compounds in hand, we carried out [2 þ 2 þ
2] cycloadditions with several nitriles in the presence of 10
mol % of CpCo(CO)(dimethyl fumarate), an air-stable
catalyst recently developed in our laboratory (Table 2).11
Whatever the nitrile, total chemo- and regioselectivity
toward 3-aminopyridines was observed. Neither the re-
(7) (a) Witulski, B.; Stengel, T. Angew. Chem., Int. Ed. 1999, 38, 2426.
(b) Witulski, B.; Alayrac, C. Angew. Chem., Int. Ed. 2002, 41, 3281. (c)
Zhang, Y.; Hsung, R. P. Chemtracts 2004, 17, 442. (d) Tracey, M. R.;
Oppenheimer, J.; Hsung, R. P. J. Org. Chem. 2006, 71, 8629. (e) Tanaka,
K.; Takeishi, K.; Noguchi, K. J. Am. Chem. Soc. 2006, 128, 4586. (f)
Oppenheimer, J.; Hsung, R. P.; Figueroa, R.; Johnson, W. L. Org. Lett.
2007, 9, 3969. (g) Tanaka, K.; Takeishi, K. Synthesis 2007, 2930. (h)
Alayrac, C.; Schollmeyerb, D.; Witulski, B. Chem. Commun. 2009, 1464.
(8) (a) Garcia, P.; Moulin, S.; Miclo, Y.; Leboeuf, D.; Gandon, V.;
Aubert, C.; Malacria, M. Chem.;Eur. J. 2009, 15, 2129. (b) The
syntheses of metallated pyridines by formal intermolecular [2 þ 2 þ 2]
cycloaddition between one alkyne, one ynamide, and one nitrile have
also been reported: Tanaka, R.; Yuza, A.; Watai, Y.; Suzuki, D.;
Takayama, Y.; Sato, F.; Urabe, H. J. Am. Chem. Soc. 2005, 127, 7774.
1
gioisomers nor oligomers could be detected in the H
NMR spectra of the crude materials.
(10) (a) Yao, B.; Liang, Z.; Niu, T.; Zhang, Y. J. Org. Chem. 2009, 74,
4630. (b) This iron-catalyzed reaction is actually a modification of the
original Hsung procedure: Zhang, Y.; Hsung, R. P.; Tracey, M. R.;
Kurtz, K. C. M.; Vera, E. L. Org. Lett. 2004, 6, 1151.
~
(9) Bonaga, L. V. R.; Zhang, H.-C.; Moretto, A. F.; Ye, H.;
Gauthier, D. A.; Li, J.; Leo, G. C.; Maryanoff, B. E. J. Am. Chem.
Soc. 2005, 127, 3473.
(11) Geny, A.; Agenet, N.; Iannazzo, L.; Malacria, M.; Aubert, C.;
Gandon, V. Angew. Chem., Int. Ed. 2009, 48, 1810.
Org. Lett., Vol. 13, No. 8, 2011
2031

next. While 2cTMS reacted with furan-2-carbonitrile to
afford 7 in 84% yield (entry 6), its reaction with picolinoni-
trile proved less efficient, with 8 being isolated in a moder-
ate 50% yield (entry 7). This is presumably due to the
chelatingnatureof the2,20-bipyridinescaffoldwhichisable
to trap cobalt.13 We then turned our attention to alkyl-
substituted nitriles. Acetonitrile, which was used in large
excess to avoid excessive evaporation, gave rise to 9 in 72%
yield when reacted with 2cTMS (entry 8). The sterically
congested pivalonitrile furnished cycloadduct 10 in a
modest 36% yield (entry 9). Gratifyingly, 2-(dimethy-
lamino)acetonitrile allowed the formation of 11 from
2cPh in quantitative yield (entry 10) and of 12 from 2cTMS
in 83% yield (entry 11). In these two cases, the chelating
ability of the products is greatly diminished compared to
8, allowing higher yields. Bearing in mind the formation
of 2-aminopyridines by Co-catalyzed [2 þ 2 þ 2] cyclo-
additions involving cyanamides,14 we next engaged
N-cyanomorpholine with 2cTMS. By this means, the
expected 2,5-diaminopyridine 13 was obtained in 85%
yield (entry 12).
Table 2. Synthesis of Bicyclic 3-Aminopyridinesa
Figure 3. ORTEP view of compound 6.
The mechanism of the Co-catalyzed [2 þ 2 þ 2] cycload-
dition of two alkynes to one nitrile to give pyridines has
been studied by means of DFT computations.15 It was
shown that(nitrile)Cp-cobalta-cyclopentadiene intermedi-
ates (Scheme 1) are preferably formed over (alkyne)Cp-
azacobaltacyclopentadienes. They give rise to the pyridine
nucleus either by insertion or by intramolecular [4 þ 2]
cycloaddition between the complexed nitrile and the diene
framework of the metallacycle. Because all substrates used
in Table 1 are monosubstituted at the alkyne terminus and
give 3-aminopyridines exclusively, it transpires that the
C-C bond formation occursatthe least stericallydemand-
ing carbon of the metallacycle (Figure 2, eq 1). Following
this simple rationale, one can assume that a reversal of the
steric demand on the substrate would favor the formation
of 4-aminopyridines (Figure 2, eq 2) instead.
a 2: 0.3-0.6 mmol. b MeCN: 10 equiv. c 2cTMS: 1 g scale (3 mmol).
dmfu = dimethyl fumarate.
The formation of the 3-aminopyridine subunit was
evidenced by the presence of diagnostic 1H and 13C
pyridine signals. In addition, we were able to obtain
single crystals of 6 suitable for an X-ray diffraction study,
which unambiguously confirmed the proposed structure
(Figure3).12 Inthepresenceofbenzonitrile, thepropargylic
ynamide 2a did not furnish any cycloadduct (entry 1). In
contrast, the two-, three-, and four-carbon tethered sub-
strates 2b, 2cTMS, and 2d led to the desired products in
excellent yields (entries 2-4). The use of 4-(trifluoro-
methyl)benzonitrile did not alter the efficiency of the
reaction (entry 5), 6 being isolated in 90% yield (85% on
a 1 g scale). Nitriles bearing heteroaromatics were tested
(13) Hapke, M.; Kral, K.; Fisher, C.; Spannenberg, A.; Gutnov, A.;
Redkin, D.; Heller, B. J. Org. Chem. 2010, 75, 3993.
~
(14) Bonaga, L. V. R.; Zhang, H.-C.; Maryanoff, B. Chem. Commun.
2004, 2394.
(15) (a) Dazinger, G.; Torres-Rodriguez, M.; Kirchner, K.; Calhorda,
M. J.; Costa, P. J. J. Organomet. Chem. 2006, 691, 4434. (b) Dahy, A. A.;
Yamada, K.; Koga, N. Organometallics 2009, 28, 3636. (c) Dahy, A. A.;
Koga, N. J. Organomet. Chem. 2010, 695, 2240.
(12) CCDC 810231.
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Org. Lett., Vol. 13, No. 8, 2011

one could expect, to a mixture of the 3-amino- and 4-ami-
nopyridines 17 and 18.
Scheme 1. Putative Intermediates on Route to Aminopyridines
Scheme 3. Selective Deprotections of 6.a
To validate this hypothesis, we prepared compound
2e, displaying a monosubstituted ynamide moiety and a
Ph-substituted alkyne terminus (Scheme 2). Thus, in 2e,
the stericdemand lies atthe opposite sitecomparedto2cPh.
The latter was reacted with benzonitrile and tranformed
into the anticipated 3-aminopyridine 14 in 92% yield. In
contrast, and in agreement with our rationale, no trace of
3-aminopyridine could be observed when using 2e. Pro-
ducts that were attributed to oligomers of 2e as well as the
4-aminopyridine 15 were isolated in mixture. To avoid
autotrimerization of the ynamide, the reaction was carried
out in the presence of a large excess of benzonitrile. This
procedure eventually furnished 15 in 60% isolated yield.
Phenylacetonitrile also allowed the formation of the
4-aminopyridine 16, albeit in a lower 50% yield. Lastly, the
unsubstituted yne-ynamide 2f was tested and gave rise, as
a 0.2 mmol scale.
To find potential leads among aminopyridine deriva-
tives, large libraries of compounds have to be set up by
selective functionalization. Since most of the products
shown above exhibit the two orthogonal protecting groups
TMS and Ts,16 we wanted to make sure that they could be
easily and selectively cleaved. Starting from 6, the TMS
group was removed using TBAF in refluxing THF, afford-
ing 19 in 66% yield (Scheme 3). On the other hand, the Ts
groupwas removed bydissolutionof 6 inneat sulfuric acid,
giving 20 in 75% yield. Interestingly, when 20 was ab-
sorbed on silica gel for 2 h, protodesilylation occurred.17
Thus, the fully deprotected aminopyridine 21 could be
obtained in two steps from 6 in 90% yield.
In conclusion, we have developed an expedient way
to synthesize 3- and 4-aminopyridines selectively. Our
strategy provides a rapid access to a wide variety of
scaffolds such as dihydropyrrolopyridine, tetrahydro-
naphthyridine, tetrahydropyridoazepine, as well as 2,5-
diaminopyridine. We are now employing this procedure to
build a library of compounds which will be submitted to
biological investigations.
Scheme 2. 3-Amino- vs 4-Aminopyridinesa
Acknowledgment. We thank Sanofi-Aventis, the IUF,
ꢁ
Ministere de la recherche, and CNRS for financial support.
Supporting Information Available. Experimental pro-
cedures, characterization of the new products, and NMR
spectra.This material is available free of charge via the
Internet at http://pubs.acs.org.
(16) Miclo, Y.; Garcia, P.; Evanno, Y.; George, P.; Sevrin, M.;
Malacria, M.; Gandon, V.; Aubert, C. Synlett 2010, 2314.
(17) For a similar example of protodesilylation, see: Meissner, A.;
Groth, U. Synlett 2010, 1051.
Org. Lett., Vol. 13, No. 8, 2011
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