Catalytic intermolecular hetero-dehydro-diels-alder cycloadditions: Regioand diasteroselective synthesis of 5,6-dihydropyridin-2-ones

Article abstract of DOI:10.1021/ol202046y

A novel catalyzed intermolecular heterodehydro-Diels-Alder reaction between push-pull 1,3-dien-5-ynes and aldimines or silylaldimines is reported. The sequence is promoted both by gold(I) or silver(I) catalysts and leads to the diastereo- and regioselective formation of 5,6- dihydropyridin-2-ones.

Full text of DOI:10.1021/ol202046y

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5172–5175
Catalytic Intermolecular Hetero-Dehydro-
DielsÀAlder Cycloadditions: Regio-
and Diasteroselective Synthesis of
5,6-Dihydropyridin-2-ones†
‡
Jesus Manuel Fernandez-Garcıa, Manuel A. Fernandez-Rodrıguez, and
§
ꢀ
ꢀ
ꢀ
ꢀ
´
´
Enrique Aguilar*,‡
´
Instituto Universitario de Quımica Organometalica “Enrique Moles”, Universidad de
Oviedo, C/Julian Claverıa, 8, 33006 Oviedo, Asturias, Spain, and Departamento de
ꢀ
ꢀ
´
ꢀ
´
´
Quımica, Area de Quımica Organica, Facultad de Ciencias, Universidad de Burgos, Pza.
Misael Banuelos, s/n, 09001 Burgos, Spain
ꢀ
~
eah@uniovi.es
Received July 28, 2011
ABSTRACT
A novel catalyzed intermolecular heterodehydro-DielsÀAlder reaction between pushÀpull 1,3-dien-5-ynes and aldimines or silylaldimines is
reported. The sequence is promoted both by gold(I) or silver(I) catalysts and leads to the diastereo- and regioselective formation of 5,6-
dihydropyridin-2-ones.
The field of metal catalysis (together with bio- and
organocatalysis, one of the three feet of the vital catalytic
tripod in the current scenario of organic synthesis) has
achieved considerable improvement over the past decade.1
In this regard, the well-recognized ability of coinage metals
(especially gold derivatives) and platinum to activate triple
bonds for the attack of different nucleophiles has resulted
in the development of an impressive array of organic
transformations, mainly cyclizations;2 moreover, some of
them represent efficient routes to substituted heterocyclic
(2) Selected recent reviews: (a) Hummel, S.; Kirsch, S. F. Beilstein J.
Org. Chem. 2011, 7, 847–859. (b) Garayalde, D.; Nevado, C. Beilstein J.
Org. Chem. 2011, 7, 767–780. (c) Sengupta, S.; Shi, X. ChemCatChem 2010,
2, 609–619. (d) Shapiro, N. D.; Toste, F. D. Synlett 2010, 675–691.
(e) Wang, S.; Zhang, G.; Zhang, L. Synlett 2010, 692–706. (f) Gorin,
D. J.; Toste, F. D. Nature 2007, 446, 395–403. (g) Nolan, S. P. Nature 2007,
445, 496–497. (h) Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180–3211. (i)
Patil, N. T.; Yamamoto, Y. Arkivoc 2007, v, 6–19. (j) Yamamoto, Y. J. Org.
Chem. 2007, 72, 7817–7831; Erratum: J. Org. Chem. 2008, 73, 5210.
(3) For reviews on gold-catalyzed synthesis of heterocyclic motifs,
see: (a) Rudolph, M.; Hashmi, A. S. K. Chem. Commun. 2011, 47, 6536–
6544. (b) Hashmi, A. S. K.; Buhrle, M. Aldrichimica Acta 2010, 43, 27–
33. (c) Hashmi, A. S. K. Pure Appl. Chem. 2010, 82, 657–668. (d) Cossy,
J. Pure Appl. Chem. 2010, 82, 1365–1373. (e) Das, A.; Abu Sohel, S. M.;
Liu, R.-S. Org. Biomol. Chem. 2010, 8, 960–979. (f) Shen, C. Tetrahedron
2008, 64, 7847–7870. (g) Shen, C. Tetrahedron 2008, 64, 3885–3903. (h)
Krause, N.; Belting, V.; Deutsch, C.; Erdsack, J.; Fan, H.-T.; Gockel, B.;
Hoffmann-Roder, A.; Morita, N.; Volz, F. Pure Appl. Chem. 2008, 80,
1063–1069.
†Dedicated to Professor Rafael Suau, in memoriam.
‡Universidad de Oviedo.
§Universidad de Burgos.
(1) For selectedrecentreviewsoncatalysis:(a)Grondal, C.;Jeanty, M.;
ꢀ
´
Enders, D. Nat. Chem. 2010, 2, 167–178. (b) Dıez-Gonzalez, S.; Marion,
N.; Nolan, S. P. Chem. Rev. 2009, 109, 3612–3676. (c) Hargaden, G. C.;
€
Guiry, P. J. Chem. Rev. 2009, 109, 2505–2550. (d) Furstner, A. Chem. Soc.
Rev. 2009, 38, 3208–3221. (e) Gorin, D. J.; Sherry, B. D.; Toste, F. D.
Chem. Rev. 2008, 108, 3351–3378. (f) Dondoni, A.; Massi, A. Angew.
Chem., Int. Ed. 2008, 47, 4638–4660. (g) For an insight comprised of a
series of commentaries and reviews, see: Mitchinson, A., Finkelstein, J.,
Eds. Small Molecule Catalysis. Nature 2008, 455, 303À349. For recent
reviews on bio-catalysis, see: (h) Reed, M. T. Angew. Chem., Int. Ed. 2011,
50, 138–174. (i) Yu, H.-L.; Ou, L.; Xu, J.-H. Curr. Org. Chem. 2010, 14,
1424–1432. For a recent special issue on organocatalysis, see: (j) Jacobsen,
E. N., MacMillan, D. W. C., Eds. Proc. Nat. Acad. Sci. U.S.A. 2010, 107,
20648À20677. (k) For a highlight on gold and organocatalysis combined
see: Hashmi, A. S. K.; Hubbert, C. Angew. Chem., Int. Ed. 2010, 49, 1010–
1012.
(4) Recent examples: (a) Davies, P. W.; Cremonesi, A.; Dumitrescu
L. Angew. Chem., Int. Ed. Epub July 26, 2011 ahead of print, DOI: 10.1002/
anie.201103563. (b) Melhado, A. D.; Amarante, G. W.; Wang, Z. J.; Luparia,
M.; Toste, F. D. J. Am. Chem. Soc. 2011, 133, 3517–3527. (c) Melhado,
A. D.; Luparia, M.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 12638–
12639. (d) Asao, N.; Nogami, T.; Lee, S.; Yamamoto, Y. J. Am. Chem.
Soc. 2003, 125, 10921–10925.
r
10.1021/ol202046y
Published on Web 08/26/2011
2011 American Chemical Society

compounds.3 However, relatively few gold-catalyzedinter-
molecular cycloadditions have been reported.4
Table 1. Catalyst Screening for the Intermolecular HDDA
Cycloaddition of 1a with Aldimine 5a12
We have recently described an efficient and simple
procedure for the synthesis of pushÀpull dienynes 1 and
2,5 which have proved to be appropriate substrates for
metal-catalyzed transformations. For instance, the car-
boxylic acid substrates 2 undergo an unusual cycloaroma-
tization reaction6,7 to afford 2,3-disubstituted phenols 3
(Scheme 1); moreover, nonactivated nitriles regioselectively
attack the metal-complexed triple bond of esters 1 leading,
after cyclization, to tetrasubstituted pyridines 4,8 this being
the first example of an intermolecular catalyzed hetero-
dehydro-DielsÀAlder (HDDA) reaction.9
entry
[M]
7aa
1
2
AuCl3
39
(14)
(12)
(14)
43
AuClP(p-CF3-C6H4)3/AgSbF6
AuClPPh3/AgSbF6
AuClP(p-MeO-C6H4)3/AgSbF6
AuClPEt3/AgSbF6
PtCl4
3
4
5
Scheme 1. Metal-Catalyzed Transformations Involving
PushÀPull Dienynes 1 and 2
6
(15)
22
7
ZnCl2
8
Cu(OTf)2
35
9
AgBF4
39
10
AgSbF6
47
a Isolated yield based on the starting dienyne 1a; in brackets, NMR
estimated yield (7a not isolated) employing 1,3,5-trimethoxybenzene as
internal standard.
Taking into account our previous results in the reaction
with nitriles,8 the initial essays were carried out with
dienyne 1a (c = 0.1 M) and aldimine 5a (5 equiv). 1,2-
Dichloroethane (DCE) was used as the solvent, the tem-
perature was settled at 85 °C, and several transition metal
complexes were tested as catalysts for the desired transfor-
mation. No reaction was observed with transition metals
such as Pd, Fe, Ni;12 however, the reaction proceeded with
coinage metals (Table 1, entries 1À5, 8À10) as well as with
Pt and Zn (entries 6, 7). After workup, dihydropyridone 7a
was isolated, albeit in low yield, for Zn (entry 7), or
observed by NMR for Pt (entry 6) and for several cationic
Au(I) catalysts bearing aromatic phosphines (entries 2À4),
independent of the electronic nature of the phosphine
ligand. Moderate yields were reached for Cu(II) (entry 8),
Au(III) (entry 1), Ag (entries 9 and 10), and a cationic
Au(I) (generated in situ by mixing 5 mol % of AuClPEt3
and 5 mol % of AgSbF6, entry 5) complexes. After these
results, an extensive screening of other reaction condition
parameters (temperature, solvent, concentration, number
of equivalents of imine, catalyst loading) was performed,
employing either AgSbF6 by itself or the AuClPEt3/
AgSbF6 system as catalysts.13 Thus, the best conditions
found were AuClPEt3 (5 mol %)/AgSbF6 (5 mol %)
[entry 5, Method A] or AgSbF6 (5À10 mol %) [entry 10,
Method B] in DCE at 85 °C, which led only to moderate
yields of adduct 7a.
Continuing with our interest to explore the reactivity of
dienynes 1, we have considered testing their behavior
against aldimines 5, which through a HDDA reaction
should lead to 1,2-dihydropyridines 6 or, more probably,
to 5,6-dihydropyriridones 7 after hydrolysis; the methoxy-
substituted triple bond carbon would behave this way as a
masked carbonyl surrogate. Interestingly, the 5,6-dihydro-
pyridin-2-one skeleton is found in compounds presenting
antibacterial or antiviral activities, as well as in herbicides,
plant growth regulators,10 or free radical scavengers.
Moreover, properly substituted 5,6-dihydropyridin-2-ones
have been regarded as useful intermediates for the pre-
paration of spatially defined nonpeptidic scaffolds, con-
strained counterparts of natural amino acids.11
ꢀ ꢀ
(5) Barluenga, J.; Garcıa-Garcıa, P.; de Saa, D.; Fernandez-Rodrıguez,
´ ´ ´
ꢀ
ꢀ
M. A.; Bernardo de la Rua, R.; Ballesteros, A.; Aguilar, E.; Tomas, M.
Angew. Chem., Int. Ed. 2007, 46, 2610–2612.
ꢀ
(6) Garcı
Angew. Chem., Int. Ed. 2009, 48, 5534–5537.
(7) For a gold-catalyzed cyclization involving other 1,3-dien-5-yne
systems, such as o-(alkynyl)styrenes, see: Martınez, A.; Garcıa-Garcıa,
guez, F.; Sanz, R. Angew.
Chem., Int. Ed. 2010, 49, 4633–4637 and references therein.
´
a-Garcıa, P.; Fernandez-Rodrıguez, M. A.; Aguilar, E.
´
´
´
´
´
(11) (a) Cardillo, G.; Fabbroni, S.; Gentilucci, L.; Perciaccante, R.;
Piccinelli, F.; Tolomelli, A. Tetrahedron 2004, 60, 5031–5040 and
references therein. (b) Hanessian, S.; Seid, M.; Nilsson, I. Tetrahedron
Lett. 2002, 43, 1991–1994.
ꢀ
P.; Fernandez-Rodrıguez, M. A.; Rodrı
´ ´
ꢀ
(8) Barluenga, J.; Fernandez-Rodrı
guez, M. A.; Garcıa-Garcıa, P.;
´ ´ ´
Aguilar, E. J. Am. Chem. Soc. 2008, 130, 2764–2765.
(12) See Supporting Information.
€
(9) Wessig, P.; Muller, G. Chem. Rev. 2008, 108, 2051–2063.
(10) Fisyuk, A. S.; Bundel, Y. Chem. Heterocycl. Compd. 1999, 35,
125–145.
(13) For silver- or gold-catalyzed reactions see: Hashmi, A. S. K. In
Silver in Organic Chemistry; Harmata, M., Ed.; John Wiley & Sons, Inc.:
Hoboken, NJ, 2010; pp 357À379.
Org. Lett., Vol. 13, No. 19, 2011
5173

Once Method A or Method B conditions were estab-
lished as the best ones found for the desired transforma-
tion, a wide variety of aldimines 2 were tested to analyze
the scope and limitations of this novel HDDA cycload-
dition (Scheme 2). Usually, the reactions were completed
overnight (12À14 h) under both conditions. Interest-
ingly, except for compound 7a, whenever both methods
were employed to prepare the same adducts (7b,d),
Method B provided lower yields than Method A; there-
fore, the latter one was chosen to perform most of the
scope screening reactions. Indeed, the process works
nicely for aldimines with phenyl (7dÀi) or either elec-
tron-withdrawing (7b,c) or electron-donating (7j) aryl
substituents. Apparently, ortho-substitution does not
lead to a decrease in the reaction yield (7f). The sub-
stitution pattern at the nitrogen atom is of a wider scope
as it tolerates methyl, phenyl, and both electron-with-
drawing and electron-donating substituted phenyl rings.
Of particular relevance are the cases of the p-methoxy
phenyl (7e) and allyl (7i,j) groups, which are prone to
undergo removal leading to NH-dihydropyridones. In
all cases, complete diastereo- and regioselectivity were
observed in the cycloaddition.
The identity of compounds 7 was ascertained by NMR
spectroscopic experiments (including COSY, HSQC,
HMBC, and NOESY).12 Even though the relative config-
uration of the new stereogenic centers could be assigned
trans on the basis of the coupling constant values,14 and a
diaxial conformation could be deduced from NOESY
experiments, an X-ray structure elucidation of 7c was also
obtained, which allowed confirmation the proposed trans
stereochemistry.12
To analyze the substrate electronic requirements, the
intermolecular HDDA reaction conditions were tested in
simpler substrates. However, dihydropyridone formation
was not observed for either (E)-1-phenyloct-1-en-3-yne 8
(a neutral enyne; Figure 1) or (Z)-methyl nona-2-en-4-
ynoate 9 (an electron-deficient enyne), while just traces
were detected by GCÀMS for (E)-4-ethoxy-1-phenylbut-
1-en-3-yne 10 (electron-rich enyne). Therefore, as it hap-
pened for the reaction with nitriles, the electronic nature of
the conjugated system is crucial for the intermolecular
HDDA reaction to occur: a pushÀpull system is needed.
However, that is not the only requisite; interestingly,
methyl (E)-5-ethoxy-pent-1-en-3-ynoate 11 led only to
GCÀMS traces of the desired adduct, thus indicating that
remaining double bond of dienynes 1 may also play some
role in the reaction.
Scheme 2. Scope of the Intermolecular HDDA Cycloadditiona
Figure 1. Other enyne systems tested under the reaction conditions.
We envisioned that silyl aldimines 12 could be appro-
priate substrates to extend the reaction to the synthesis of
N-unsubstituted dihydropyridones, which are in principle
more appealing, interesting and versatile substrates. The
reactions were carried out employing the previously devel-
oped Method A conditions; in this case, a further hydrolysis
step was required15 and led to N-unprotected trans-5,6-
dihydropyridin-2-ones 13 in moderate yields (Scheme 3).
The scope of the reaction was explored regarding the
substitution both at the dienyne and the silyl aldimine
counterparts. Thus, several aryl groups with different elec-
tronic properties [phenyl (13a), bearing electron-donating
(14) (a) Cabrera, J.; Hellmuth, T.; Peters, R. J. Org. Chem. 2010, 75,
4326–4329. (b) Bennett, D. M.; Okamoto, I.; Danheiser, R. L. Org. Lett.
1999, 1, 641–644.
(15) Dihydropyridines 14a,b were isolated in just 29% and 13% yield
in preliminary reactions carried out between dienyne 1a and N-tri-
methylsilyl benzaldimines 12a,b. The low yield of 14, probably due to
product decomposition during chromatographic purification, prompted
us to perform an in situ additional hydrolysis step.
a All yields are isolated yields based on the starting dienyne 1. Numbers in
brackets correspond to reactions performed under Method A conditions.
b Reaction carried out with AuClPEt3 (10 mol %), AgSbF6 (10 mol %).
5174
Org. Lett., Vol. 13, No. 19, 2011

proposed for the reaction with nitriles.8 The selective
formation of the anti diastereoisomer can be understood
assuming that the cyclization step should take place
through preferredtransition stateIB, which islesshindered
than IA (Figure 2).
Scheme 3. Scope of the Intermolecular HDDA Cycloaddition
Employing Silyl Aldiminesa
Figure 2. Proposed origin of the diastereoselectivity.
In summary, we have reported a novel catalyzed
intermolecular heterodehydro-DielsÀAlder reaction
that occurs between pushÀpull 1,3-dien-5-ynes 1 and
aldimines or silylaldimines. The sequence is promoted
both by gold(I) or silver(I) catalysts and leads to the
diastereo- and regioselective formation of 5,6-dihydro-
pyridin-2-ones. Labeling, designed NMR experiments
and theoretical calculations directed to gain some in-
sight into the reaction mechanism and work to expand
this new method to other unsaturated nucleophiles
are currently underway in our laboratory and will be
reported in due course.
Acknowledgment. We are deeply grateful to Prof.
Barluenga (Universidad de Oviedo) for his constant
support and for fruitfully maintained discussions. We
also acknowledge the financial support received from
MICINN (Spain) (grants CTQ2009-09949, CTQ2010-
a All yields are isolated yields based on the starting dienyne 1.
ꢀ
16790, PTA2008-1524-P contract to J.M.F.-G. and Ramon y
Cajal postdoctoral contract to M.A.F.-R.) and FICYT
(project IB08-088).
groups (13c,d) or electron-withdrawing groups (13b,f)] and
substitution patterns [ortho (13c,f), para (13b,d,hÀl)], het-
eroaryl (13e), and tert-butyl (13g) substituents are toler-
ated at the silyl aldimine moiety while the R group at the
dienyne displays a wide scope as it may be a phenyl
(13aÀg), an electron-withdrawing substituted aryl group
(13h), an electron-donating substituted aryl (13i), a silyl
(13j), an alkyl (13k), or an alkenyl (13l) substituent.
The formation of dihydropyridones 5 (or 13) can be
explained according to a mechanism similar to the one
Supporting Information Available. Tables with a more
extensive list of catalyst and reaction conditions screen-
ing, a discussion regarding the preferred conformation of
dihydropyridones 7 (based on NOE experiments per-
formed on compound 7b), experimental procedures and
characterization data of all new compounds, compund 7c
in CIF format. This material is available free of charge via
the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 19, 2011
5175