Gold-catalyzed intermolecular hetero-dehydro-Diels-Alder cycloaddition of captodative dienynes with nitriles: A new reaction and regioselective direct access to pyridines

Article abstract of DOI:10.1021/ja7112917

For the first time, nitriles are used as 2π electron component in a gold-catalyzed intermolecular Hetero-Dehydro-Diels-Alder cycloaddition with captodative enynes leading to the regioselective formation of pyridines. Copyright

Full text of DOI:10.1021/ja7112917

Published on Web 02/12/2008
Gold-Catalyzed Intermolecular Hetero-Dehydro-Diels-Alder Cycloaddition of
Captodative Dienynes with Nitriles: A New Reaction and Regioselective
Direct Access to Pyridines
Jose´ Barluenga,*,† Manuel AÄ ngel Ferna´ndez-Rodr´ıguez,‡ Patricia Garc´ıa-Garc´ıa,† and
Enrique Aguilar*,†
Instituto UniVersitario de Qu´ımica Organometa´lica “Enrique Moles”, Unidad Asociada al CSIC, UniVersidad de
OViedo, Julia´n ClaVer´ıa 8, 33006-OViedo, Spain and Instituto de InVestigaciones Qu´ımicas y Ambientales de
Barcelona (IIQAB)-CSIC, Jordi Girona 18-26, 08034-Barcelona, Spain
Received December 20, 2007; E-mail: barluenga@uniovi.es, EAH@uniovi.es
Table 1. Catalyst Screening for the Intermolecular HDDA
Cycloaddition of 1a
The Diels-Alder reaction is undoubtedly the most powerful
synthetic tool for the formation of six-membered cyclic structures.
However, the well-documented and closely related dehydro-Diels-
Alder reaction (DDAR) has been fairly less developed. That is
probably due to geometric constrictions, derived from the lineal
disposition imposed by the sp-hybridization of the triple bond
carbons. The state of the art for DDAR is mainly confined to
intramolecular versions,1 while intermolecular approaches are
limited to the employment of highly reactive intermediates such
as benzyne2 or to photochemical activation.3
On the other hand, a resplendent age of metal catalysis,
particularly gold,4 has bloomed in the last years. The notorious
ability of gold derivatives to activate triple bonds for the attack of
entry
[M]
2aa
3aa
different nucleophiles has resulted in the development of an
impressive array of organic transformations, mainly intramolecular
cyclizations.5 Remarkably, relatively few gold-catalyzed intermo-
lecular cycloadditions have been reported.6
1
2
3
4
5
6
7
8
none
AuCl3
AuCl
AuClPPh3/AgSbF6
AuClPEt3/AgSbF6
AuClP(p-MeO-C6H4)3/AgSbF6
AuClP(p-CF3-C6H4)3/AgSbF6
AuClP(o-Me-C6H4)3/AgSbF6
AuCl(IPr)b/AgSbF6
33
61
46
(63), 60
(69), 67
(34)
(23)
(52)
(51)
(72), 70
We have recently described an efficient and simple procedure
for the synthesis of captodative dienynes 1 (from commercially
available 2-methoxyfurane and Fischer alkynyl carbene com-
plexes),7 which could be appropriate substrates for metal-catalyzed
transformations; in fact, we have envisioned that the attack of an
unsaturated nucleophile to the metal-complexed triple bond could
be followed by cyclization. In this communication we present the
results using nitriles8 as nucleophiles: tetrasubstituted pyridines9
are regioselectively formed by a novel approach, this one being
the first case of a catalyzed intermolecular hetero-dehydro-Diels-
Alder reaction (HDDAR).10
The initial assays were carried out with dienyne 1a in neat
acetonitrile. Thus, spontaneous dimerization of 1a to form 2a was
observed on standing or when warmed in the absence of catalyst
(Table 1, entry 1). Several catalytic metals (Pt, Cu, Ag, or Pd) also
produced dimerization or the formation of complex reaction
mixtures. However, the [4 + 2]-cycloaddition reaction could be
achieved with different gold catalysts; for instance, AuCl3 and AuCl
gave 61% and 46% isolated yields of adduct 3a (entries 2 and 3).
The reactivity of Au(I) cationic catalysts was modulated by
employing several ligands such as phosphines (entries 4-8) or
N-heterocyclic carbenes (entry 9), which display a broad range of
electron-donating abilities; among them, the system AuClPEt3/
AgSbF6 exhibited the best result (entry 5). Interestingly, the reaction
yield was further improved by the employment of 1,2-dichloroet-
hane (DCE) as solvent, and the amount of acetonitrile could be
reduced to 20 equiv (entry 10).11
9
10c
AuClPEt3/AgSbF6
a Isolated yield based on the starting dienyne 1a; in brackets, yield
1
t
estimated by H NMR (400 Hz) employing BuOAc as internal standard.
bIPr: 1,3-bis(diisopropylphenyl)imidazol-2-ylidene. Reaction carried out
c
with acetonitrile (20 equiv) and 1a in DCE (0.1 M).
Once the optimum conditions for the desired transformation were
established, we turned to analyze its scope and limitations. A wide
variety of dienynes 1 and a set of commercially available nitriles
were tested. Thus, substitution at the 4-position of the pyridine ring
includes phenyl groups (Table 2, entries 1-7), aromatic rings with
electron-withdrawing (entry 8) or electron-donating groups (entry
9), and primary and tertiary alkyl (entries 10, 11), and alkenyl
(entries 12, 13) groups. On the other hand, primary, secondary,
and tertiary alkyl (entries 1-3), aromatic (entry 4), heteroaromatic
(entries 5-6), and olefinic (entry 7) nitriles, besides acetonitrile
(entries 8-13), reacted with 1,3-dien-5-ynes 1. In all cases, the
reaction proceeded satisfactorily yielding the expected pyridines
3. Only one regioisomer was detected as established by NMR
experiments (COSY, HSQC, HMBC, NOESY).
In order to analyze the substrate electronic requirements, the
intermolecular HDDAR conditions were tested in simpler sub-
strates: (a) (E)-1-phenyloct-1-en-3-yne 4 (a neutral enyne) did not
evolve under the optimized reaction conditions; (b) (Z)-methyl nona-
2-en-4-ynoate 5 (an electron-deficient enyne) just underwent partial
double bond isomerization, while (c) (E)-1-ethoxy-oct-3-en-1-yne
† Instituto Universitario de Qu´ımica Organometa´lica “Enrique Moles”.
‡ Instituto de Investigaciones Qu´ımicas y Ambientales de Barcelona.
9
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J. AM. CHEM. SOC. 2008, 130, 2764-2765
10.1021/ja7112917 CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Scope of the Intermolecular HDDA Cycloaddition
dienyne would therefore facilitate the regioselective nucleophile
attack of the nitrile, leading to the formation of species IIa. Both
steps: triple bond activation and subsequent nucleophile attack are
well documented for gold-mediated transformations.5 A cyclization
may occur through resonance structure IIb or, alternatively, by
intramolecular nucleophile attack through structure IIc. This last
option would involve the electron-withdrawing ester group in the
reaction mechanism and would explain why the reaction with 6
evolves by other routes. Consequently, dihydropyridine III would
be formed and a final metal decoordination would render the
reaction products 3 and allow the incorporation of the gold catalyst
into a new cycle.
In summary, we present here the first example of a catalyzed
intermolecular hetero-dehydro-Diels-Alder reaction which occurs
between captodative 1,3-dien-5-ynes and nonactivated nitriles. The
sequence is promoted by both gold(I) and gold(III) catalysts and
leads to the regioselective formation of tetrasubstituted pyridines.
Labeling and designed NMR experiments directed to prove the
proposed mechanism and work to expand this new methodology
to other unsaturated nucleophiles are currently underway in our
labs and will be reported in due course.
a Isolated yield based on the starting dienyne 1.
Scheme 1
Acknowledgment. We thank for the financial support received
from MCyT (Spain) (CTQ2004-08077-C02-01, fellowship to P.G.-
G. and Juan de la Cierva postdoctoral contract to M.A.F.-R.), Ppdo.
de Asturias (IB05-136), and Fundacio´n Ramo´n Areces. Dedicated
to the memory of the late Prof. A. I. Meyers.
Supporting Information Available: Experimental procedures and
characterization data for the new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
References
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6 (electron-rich enyne) did polymerize with all the tested catalysts,
even at low temperature (-20 °C). Apparently, the electronic nature
of the conjugated system is crucial for the intermolecular HDDAR
to occur: a push-pull (captodative) system is required. This
assumption is supported by the fact that, for dienyne 7, which
presents two triple bonds of different electronic nature, only the
electron-rich one partakes in the HDDR (eq 1).
(7) Barluenga, J.; Garc´ıa-Garc´ıa, P.; de Sa´a, D.; Ferna´ndez-Rodr´ıguez, M.
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paucity is limited to activated nitriles such as trichloroacetonitrile or tosyl
cyanide.
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(11) Regarding the catalyst loading, a 5 mol% provided the highest yield in a
reasonable reaction time. Other tested solvents (THF, toluene, 1,2-
dimethoxyethane), lower reaction temperatures, or less equiv of nitrile
led to longer reaction times and/or poor yields.
A mechanism that would explain the formation of pyridines 3 is
depicted in Scheme 1. An initial coordination of the triple bond to
the gold catalyst [Au+] would take place to form intermediate Ia,
which presents a resonance structure Ib, due to the electron-donating
group linked to the triple bond. The push-pull substitution on the
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