Divergent chemo-, regio-, and diastereoselective normal electron-demand povarov-type reactions with α-oxo-ketene dienophiles

Article abstract of DOI:10.1021/ol5018245

The reactions between electron-rich 2-aza-dienes and α-oxo-ketenes derived from the Wolff rearrangement of 2-diazocycloalkane-1,3-diones chemo- and regioselectively produced spiro hydropyrid-4-ones with good to excellent diastereoselectivities. These reactions are likely to proceed via a domino Wolff/Friedel-Crafts/intramolecular Mannich process. Prolonged domino sequences also allowed the expeditious preparation of a series of pyrazolopyridine and pyridopyrimidine heterocycles.

Full text of DOI:10.1021/ol5018245

Letter
pubs.acs.org/OrgLett
Divergent Chemo‑, Regio‑, and Diastereoselective Normal Electron-
Demand Povarov-Type Reactions with α‑Oxo-ketene Dienophiles
Jaime Galvez,† Juan-Carlos Castillo,‡ Jairo Quiroga,† Michel Rajzmann,‡ Jean Rodriguez,*,‡
and Yoann Coquerel*,‡
†Departamento de Química, Universidad del Valle, A.A. 25360, Cali, Colombia
‡Aix Marseille Universite,
́
Centrale Marseille, CNRS, iSm2 UMR 7313, 13397 Marseille, France
S
* Supporting Information
ABSTRACT: The reactions between electron-rich 2-aza-
dienes and α-oxo-ketenes derived from the Wolff rearrange-
ment of 2-diazocycloalkane-1,3-diones chemo- and regiose-
lectively produced spiro hydropyrid-4-ones with good to
excellent diastereoselectivities. These reactions are likely to
proceed via a domino Wolff/Friedel−Crafts/intramolecular
Mannich process. Prolonged domino sequences also allowed
the expeditious preparation of a series of pyrazolopyridine and
pyridopyrimidine heterocycles.
Scheme 1. Known and Proposed Aza-DA Cycloadditions with
α-Oxo-ketenes
he stereocontrolled formation of carbon−carbon bonds is
Tat the core of the science of organic synthesis. In the context
of economies in synthesis,1 multiple bond-forming trans-
formations (MBFTs)2 allowing for the sequential creation of
two or more C−C bonds in a single chemical operation are
particularly valuable. As to the formation of six-membered aza-
cycles, the aza-Diels−Alder (aza-DA) strategy, often involving
stepwise nonconcerted processes, counts among the most
reliable MBFT-based approaches.3 Formal aza-DA reactions
generally fall into two main categories according to the electronic
properties of the reaction partners: normal electron-demand
(NED) aza-DA with electron-rich dienes and electron-
impoverished imines and inverse electron-demand (IED) aza-
DA with electron-deficient 1- or 2-azadienes and electron-rich
olefins.3 It should be noted that only aza-DA cycloadditions with
2-aza-dienes allow for the formation of two C−C bonds. The
Povarov reaction, i.e., the IED aza-DA reaction between N-aryl
imines and electron-rich olefins to give tetrahydroquinolines, is
an archetypal example of the reactivity of 2-aza-dienes.3c,f The
realization of regio- and stereoselective NED Povarov-type
reactions with electron-enriched N-aryl imines and electron-poor
olefins would greatly expand the scope and possible applications
of this strategy. However, this complementary reactivity of N-aryl
imines has remained unstudied.
a
α-Oxo-ketenes are electrophilic reactive intermediates with a
rich chemistry.4 The microwave-assisted Wolff rearrangement of
2-diazo-1,3-diketones is an extremely efficient and convenient
source of α-oxo-ketenes,5,6 and this technology has recently
allowed revisiting their fundamental reactivity. α-Oxo-ketenes
normally react with imines as 4π reaction partners in formal IED
aza-DA cycloadditions to afford the corresponding oxazinones
(Scheme 1, top).7 It was recently uncovered that their reactions
with electron-rich 1-aza-dienes were following an alternative
path, involving formal NED aza-DA cycloadditions in which the
a
IED = inverse electron-demand; aza-DA = aza-Diels−Alder; NED =
normal electron-demand.
CC bond of the α-oxoketene is this time the 2π reaction
partner, leading to stereodefined δ-lactam products with
successive C−N and C−C bond-forming events (Scheme 1,
Received: June 24, 2014
Published: July 30, 2014
© 2014 American Chemical Society
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Letter
right).8 A similar reactivity was also observed in the 1,3-dipolar
cycloadditions of electron-rich hydrazones with α-oxoketenes.9
Lately, α-oxoketenes were found to be valuable electrophilic
reaction partners in Friedel−Crafts α-ketoacylations of hetero-
aromatic compounds.10 Herein, we report regioselective and
diastereoselective NED Povarov-type reactions with α-oxoke-
tene dienophiles for the preparation of stereodefined spiro
compounds (Scheme 1, gray highlight). This idea was based on
the mechanistic hypothesis that a catalyst-free domino Wolff
rearrangement/Friedel−Crafts α-ketoacylation/intramolecular
Mannich sequence would be possible.
Because of its excellent reactivity in Friedel−Crafts α-
ketoacylations10 and the availability of the corresponding 5-
amino derivatives,11 the pyrazolyl group was selected as the
prototypical N-aryl moiety to prepare electron-rich N-aryl imines
amenable to the planned transformation.12 It can be noted that
the first Povarov reactions (IED aza-DA) with aminopyrroles and
aminopyrazoles were reported only recently.13 The present study
was initiated with the reaction of the N-aryl imine 1a with the α-
oxoketene derived from diazodimedone (2a, 1.5 equiv) at 150 °C
under microwave irradiation for 6 min. Gratifyingly, the expected
spiro hydropyrid-4-one product 3a resulting from a formal regio-
and stereoselective NED Povarov-type reaction was obtained in
65% yield as a single diastereomer. In a modified protocol, the
addition of 2.4 equiv of the diazo compound 2a in two portions
afforded the same product 3a in an increased 75% yield (Scheme
2) together with some dimerization product of the α-oxo-
ketene.4a,b
a
Table 1. Generalization of the Reaction
b
c
entry
3; X, R1, R2, R3, R4, n
dr
yield (%)
1
3b; N, t-Bu, Ph, 4-Me-C6H4, Me, 1
3c; N, t-Bu, Ph, 4-OMe-C6H4, Me, 1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
11:1
81
70
79
72
51
76
80
57
36
30
81
73
63
41
31
58
2
3
3d; N, t-Bu, Ph, 3,4-(OCH2O)-C6H3, H, 1
3e; N, t-Bu, Ph, 4-Me-C6H4, H, 1
4
5
3f; N, t-Bu, Ph, 2-OMe-C6H4, H, 1
3g; N, Me, Ph, 4-OMe-C6H4, Me, 1
3h; N, t-Bu, Me, 4-OMe-C6H4, Me, 1
3i; N, t-Bu, Me, 4-CF3-C6H4, Me, 1
3j; N, t-Bu, Me, 3,5-(CF3)2-C6H4, Me, 1
3k; N, t-Bu, Me, 4-OMe-C6H4, H, 2
3l; N, Ph, Me, 4-OMe-C6H4, Me, 1
3m; N, 4-Me-C6H4, Me, 4-OMe-C6H4, Me, 1
3n; N, 4-Cl-C6H4, Me, 4-OMe-C6H4, Me, 1
3o; N, Ph, Ph, 4-OMe-C6H4, Me, 1
3p; N, 4-F-C6H4, Ph, 4-OMe-C6H4, H, 1
3q; CH, CN, t-Bu, 4-OMe-C6H4, Me, 1
6
7
8
9
4:1
10
11
12
13
14
15
16
>25:1
>25:1
>25:1
17:1
>25:1
>25:1
1.4:1
a
Reaction conditions: 1b−o (0.25 mmol), 2a−c (0.30−0.90 mmol)
added in 1−3 portions, anhydrous toluene (2 mL); see Supporting
b
Information for details. Determined by 1H NMR analysis of the crude
c
reaction mixture. Based on isolated product after silica gel
chromatography.
Scheme 2. Regio- and Diastereoselective NED Povarov-Type
Reaction
the study to obtain the desired NED Povarov-type spiro product
3k in 30% yield (Table 1, entry 10).
The structure of the spiro hydropyrid-4-one 3b was resolved
by X-ray diffraction techniques, which confirmed the chemo-,
regio-, and stereochemical outcome of the reaction.14 Remark-
ably, the NED Povarov-type reactions described herein allows for
the regio- and stereocontrolled formation of two C−C bonds and
two contiguous stereogenic carbon atoms, including a
challenging “all-carbon” quaternary center.15 Very interestingly,
the reaction could be extended to the pyrrole series in the case of
product 3q (Table 1, entry 16).16
The postulated mechanism of the reaction was examined by
DFT theoretical calculations using the B3LYP functional with
the extended base set 6-311++G** to account for long-range
interactions (Scheme 3 and Supporting Information). Our
preliminary results17 indicate that the proposed Friedel−Crafts/
Mannich sequence is very plausible, with reasonable transition
state energies (activation barrier of 13.8 kcal/mol). In the
calculated reaction path, the Friedel−Crafts α-ketoacylation step
(A → B → C) occurs through a nucleophilic addition/1,5-proton
shift involving the ketone oxygen atom of the α-oxoketene.18 The
intramolecular Mannich step (C → D) would then ensue as a
rare example of concerted asynchronous proton transfer/6-enol
exo-endo trig cyclization, which dictates the stereochemical
outcome of the reaction (Figure 1). It is believed that with
electron-impoverished substrates (e.g., in Table 1, entries 8 and
9) having a less basic nitrogen atom of the imine moiety looser
transition states of type TSCD with weaker stabilizing O−H−N
interactions are produced, leading to an erosion of the
diastereoselectivity.
The scope of the reaction was then investigated with several N-
pyrazolyl imines and a few cyclic 2-diazo-1,3-diketones (Table
1). The reaction was found to be general, and diversely
substituted and functionalized NED Povarov-type spiro products
3 could be stereoselectively prepared. Depending on the
substrate, reaction temperatures ranging from 150 to 250 °C
were required with reaction times varying from 2 × 2 min to 3 ×
15 min (see Supporting Information for experimental details). It
was found that the pyrazolyl group well tolerated either alkyl or
aryl R1 and R2 substituents, as well as electron-donating and
electron-withdrawing functional groups. In some cases,
especially those involving substrates bearing an electron-
withdrawing group, minor amounts of the other possible
diastereomer were also formed (Table 1, entries 8, 9, and 13).
As a general tendency, more electron-donating substituents on
the 2-aza-diene substrate led to higher yield and diastereose-
lectivity (compare for example Table 1, entries 7, 8, and 9). The
reaction appeared more difficult with the α-oxo-ketene derived
from the seven-membered diazo compound 2c (n = 2, R4 = H),
requiring the highest temperature and longest reaction time of
When the reactions presented in Table 1 were attempted with
the five-membered diazo compound 2d, the pyrazolopyridines
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Organic Letters
Letter
a
transformation might be either the starting imines 1 or the
intermediates 3 themselves, and oxidation is probably occurring
with dissolved oxygen gas.
Scheme 3. Theoretical Study of the Proposed Mechanism
The pyrazolopyridine ring system found in products 5a,b is a
heterocyclic core amenable to applications in medicinal
chemistry.19 It was reasoned that a straightforward access to
the related pyrazolopyridine derivatives 9a−d could rely on the
utilization of formimidamides 6a and 6b bearing a noninnocent
dimethylamino group. This could allow for an original domino
sequence initiated by the NED Povarov-type reaction described
above to give the intermediate cycloadducts 7, followed by a
dehydroamination/retro-Claisen-like/lactonization cascade
(Scheme 5). The N,N-dimethyl-N′-pyrazolylformimidamides
a
Scheme 5. Domino Approach to Functionalized
Pyrazolopyridine Derivatives
Energy profile computed at the B3LYP/6-311++G** level including
ZPE correction using the IEFPCM solvation model for toluene.
Figure 1. Calculated (left) and schematized (right) transition state
TSCD
.
6a and 6b suitable for the designed MBFT were prepared from
the corresponding aminopyrazoles and N,N-dimethylformamide
dimethyl acetal.12e Satisfactorily, their reactions with the diazo
compounds 2a and 2b afforded the tricyclic products 9a−d,
probably via the anticipated domino sequence. The structure of
product 9c was secured by X-ray diffraction analysis.14 The scope
of the domino reaction could be successfully extended to the
formimidamide 10 derived from 6-aminouracil to provide the
functionalized pyridopyrimidine 11 (Scheme 6).
products 5a and 5b were obtained instead of the expected spiro
cyclobutanone products 3r and 3s (Scheme 4). Because of the
intrinsic ring strain of cyclobutanones, the formation of products
5a and 5b is believed to result from a Lewis base catalyzed ring-
rearrangement/oxidation domino sequence via the zwitterionic
intermediates 4a and 4b, respectively. Although no external
Lewis base or oxidant was added to the reaction mixtures, the
nucleophilic species responsible for the prolonged domino
Scheme 4. Prolonged NED Povarov-Type Aza-DA
Scheme 6. Domino Approach to a Functionalized
Pyridopyrimidine
In summary, normal electron-demand Povarov-type cyclo-
additions proved possible between some electron-rich N-aryl
imines and cyclic α-oxo-ketenes. The reaction chemo- and
regioselectively produced spiro hydropyrazolopyrid-4-ones with
good to excellent diastereoselectivities, and is probably occurring
via a domino Wolff/Friedel−Crafts/intramolecular Mannich
process forming consecutively two carbon−carbon bonds. In a
series of divergent reactions, the ring recombination of the
Povarov-type products via prolonged domino processes has led
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Letter
8931. (c) Muravyova, E. A.; Shishkina, S. V.; Musatov, V. I.; Knyazeva, I.
V.; Shishkin, O. V.; Desenko, S. M.; Chebanov, V. A. Synthesis 2009,
to fused tricyclic pyrazolopyridine and pyridopyrimidine hetero-
cycles. The elaborate MBFTs described herein (up to 6 steps in
the domino process) were built on the functional group density
and rich chemistry of α-oxo-ketene reactive intermediates and
are expected to open new opportunities for heterocycle and
alkaloid synthesis.
1375. (d) Nascimento-Junior, N. M.; Mendes, T. C. F.; Leal, D. M.;
́
Correa
A. M. Bioorg. Med. Chem. Lett. 2010, 20, 74. (e) Quiroga, J.; Valencia, A.;
Perez, A.; Galvez, J.; Abonia, R.; Insuaty, B. Lett. Org. Chem. 2013, 10,
337.
̂
, C. N. M.; Sudo, R. T.; Zapata-Sudo, G.; Barreiro, E. J.; Fraga, C.
́
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(13) Brioche, J.; Courant, T.; Alcarez, L.; Stocks, M.; Furber, M.; Zhu,
J.; Masson, G. Adv. Synth. Catal. 2014, 356, 1719.
ASSOCIATED CONTENT
■
(14) The CIF for 3b and 9c are available as Supporting Information.
(15) (a) Quaternary Stereocenters: Challenges and Solutions for Organic
Synthesis; Christoffers, J., Baro, A., Eds.; Wiley-VCH: Weinheim,
Germany, 2005. (b) Trost, B. M.; Jiang, C. Synthesis 2006, 369.
(c) Steven, A.; Overman, L. E. Angew. Chem., Int. Ed. 2007, 46, 5488.
(d) Bella, M.; Gasperi, T. Synthesis 2009, 1583. (e) Das, J. P.; Marek, I.
Chem. Commun. 2011, 47, 4593.
S
* Supporting Information
Details for the mechanistic computational study presented in
Scheme 3 and Figure 1, detailed experimental procedures, full
characterization data, CIFs for compounds 3b and 9c, and copies
of 1H and 13C NMR spectra for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(16) The reactions of 2a with (E)-4-methoxy-N-(4-methoxybenzyli-
dene)aniline or 3-(tert-butyl)-N-cyclopentylidene-1-phenyl-1H-pyra-
zol-5-amine were found to be unproductive.
(17) A comprehensive theoretical study on the cycloaddition reactions
of α-oxo-ketenes with imines and aza-dienes is ongoing and will be
reported in due course.
(18) Mono- and bimolecular paths involving the ketene oxygen atom
of the α-oxo-ketene were also examined for the proton transfer step (1,3-
proton shift) and were found less favorable.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: jean.rodriguez@univ-amu.fr.
*E-mail: yoann.coquerel@univ-amu.fr.
Notes
The authors declare no competing financial interest.
(19) Pyrazolopyridines form a class of nonbenzodiazepine anxiolytic
drugs acting as positive allosteric modulators of the GABAA receptor at
the barbiturate binding site; known examples include Cartazolate,
Etazolate, ICI-190,622, and Tracazolate. See: Shi, D.; Padgett, W. L.;
Hutchinson, K. D.; Moore, S. P.; Daly, J. W. Drug Dev. Res. 1997, 42, 41.
ACKNOWLEDGMENTS
■
Dr. Michel Giorgi (Aix-Marseille University) is gratefully
acknowledged for the X-ray structural analyses of compounds
3b and 9c. Financial support from the Universidad del Valle,
́
COLCIENCIAS, Aix-Marseille Universite, and the Centre
National de la Recherche Scientifique (CNRS) is gratefully
acknowledged.
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