From ketenimines to ketenes to quinolones: Two consecutive pseudopericyclic events

Article abstract of DOI:10.1021/ol052189v

(Chemical Equation Presented) N-[2-(Alkyl- or arylthio)carbonyl]phenyl ketenimines undergo cyclization under mild thermal conditions to afford 2-alkyl(aryl)thio-3H-quinolin-4-ones by means of the 1,5-migration of the alkyl(aryl)thio group from the carbonyl carbon to the central carbon atom of the ketenimine fragment followed by the 6π-electrocyclization of the resulting vinyliminoketene. These 1,5-migration and electrocyclization processes occur via transition states whose pseudopericyclic characteristics have been established on the basis of their magnetic properties, geometries, and NBO analyses.

Full text of DOI:10.1021/ol052189v

ORGANIC
LETTERS
2005
Vol. 7, No. 23
5281-5284
From Ketenimines to Ketenes to
Quinolones: Two Consecutive
Pseudopericyclic Events
Mateo Alajar´ın,*,† Mar´ıa-Mar Ort´ın,† Pilar Sa´nchez-Andrada,† A
Ä
ngel Vidal,† and
Delia Bautista‡
Departamento de Qu´ımica Orga´nica, Facultad de Qu´ımica, UniVersidad de Murcia,
Campus de Espinardo, 30100 Murcia, Spain, and SerVicio UniVersitario de
Instrumentacio´n Cient´ıfica, UniVersidad de Murcia, Campus de Espinardo, 30100
Murcia, Spain
alajarin@um.es
Received September 12, 2005
ABSTRACT
N-[2-(Alkyl- or arylthio)carbonyl]phenyl ketenimines undergo cyclization under mild thermal conditions to afford 2-alkyl(aryl)thio-3H-quinolin-
4-ones by means of the 1,5-migration of the alkyl(aryl)thio group from the carbonyl carbon to the central carbon atom of the ketenimine
fragment followed by the 6π-electrocyclization of the resulting vinyliminoketene. These 1,5-migration and electrocyclization processes occur
via transition states whose pseudopericyclic characteristics have been established on the basis of their magnetic properties, geometries, and
NBO analyses.
Ketenimines are nitrogenated heterocumulenes R1NdCd
CR2R3 whose reactivity can be explained by (1) the elec-
trophilic character of their central carbon atom, accounting
for the addition of a variety of nucleophiles1 and radicals2
to that center, (2) the nucleophilic nature of their nitrogen
atom, which undergoes the attack of electrophilic species
and behaves as a donor atom in the formation of metal σ
complexes,3 and (3) their participation in pericyclic processes
such as electrocyclic ring closures, [2 + 2] and [4 + 2]
cycloaddition reactions, and sigmatropic rearrangements.1e
Among the above reactions, the sigmatropic rearrange-
ments of ketenimines have received minor attention. In 1965,
Brannock and Burpitt reported the conversion of N-(2-
alkenyl)amides into 4-pentenenitriles by the action of
phosphorus pentachloride and triethylamine.4 They postulated
N-(2-alkenyl)ketenimines as reaction intermediates, suggest-
ing that these species undergo a 3-aza-Claisen rearrangement
to the unsaturated nitriles. Afterward, Walters5 and some of
us6 carried out an extensive investigation of this [3,3]
rearrangement, which has been also employed as a key step
in an efficient asymmetric synthesis of chiral natural products
† Departamento de Qu´ımica Orga´nica.
‡ Servicio Universitario de Instrumentacio´n Cientifica.
(1) For reviews in the chemistry of ketenimines, see: (a) Krow, D. R.
Angew. Chem., Int. Ed. Engl. 1971, 10, 435. (b) Gambaryan, N. P. Usp.
Khim. 1976, 45, 1251. (c) Dondoni, A. Heterocycles 1980, 14, 1547. (d)
Barker, M. W.; McHenry, W. E. In The Chemistry of Ketenes, Allenes and
Related Compounds; Patai, S., Ed.; Wiley-Interscience: Chichester, U.K.,
1980; Part 2, p 701. (e) Alajar´ın, M.; Vidal, A.; Tovar, F. Targets Heterocycl.
Syst. 2000, 4, 293.
(2) (a) Alajar´ın, M.; Vidal, A.; Ort´ın, M.-M. Tetrahedron Lett. 2003,
44, 3027. (b) Alajar´ın, M.; Vidal, A.; Ort´ın, M.-M. Org. Biomol. Chem.
2003, 1, 4282. (c) Alajar´ın, M.; Vidal, A.; Ort´ın, M.-M.; Bautista, D. New
J. Chem. 2004, 28, 570. (d) Alajar´ın, M.; Vidal, A.; Ort´ın, M.-M.; Bautista,
D. Synlett 2004, 991.
(3) (a) Aumann, R. Chem. Ber. 1993, 126, 1867. (b) Merlic, C. A.; Burns,
E. E. Tetrahedron Lett. 1993, 34, 5401.
(4) Brannock, K. C.; Burpitt, R. D. J. Org. Chem. 1965, 30, 2564.
(5) (a) Walters, M. A.; McDonough, C. S.; Brown, P. S., Jr.; Hoem, A.
B. Tetrahedron Lett. 1991, 32, 179. (b) Walters, M. A.; Hoem, A. B.;
Arcand, H. R.; Hegeman, A. D.; McDonough, C. S. Tetrahedron Lett. 1993,
34, 1453. (c) Walters, M. A.; Hoem, A. B. J. Org. Chem. 1994, 59, 2645.
(d) Walters, M. A. J. Am. Chem. Soc. 1994, 116, 11618. (e) Walters, M.
A. J. Org. Chem. 1996, 61, 978.
(6) (a) Molina, P.; Alajar´ın, M.; Lo´pez-Leonardo, C. Tetrahedron Lett.
1991, 32, 4041. (b) Molina, P.; Alajar´ın, M.; Lo´pez-Leonardo, C.; Alca´ntara,
J. Tetrahedron 1993, 49, 5153.
10.1021/ol052189v CCC: $30.25
© 2005 American Chemical Society
Published on Web 10/12/2005

such as (+)-canadensolide, (+)-santolinolide B, and (-)-
santolinolide A.7
excess of 4-(dimethylamino)pyridine, afforded the 2-azido-
thiobenzoates 2. Triphenylphosphazenes 3 were prepared by
treating diethyl ether solutions of azides 2 with triph-
enylphosphane. Aza-Wittig reactions of compounds 3 with
a stoichiometric amount of diphenylketene or methylphe-
nylketene, in toluene solution, gave N-[2-alkyl(aryl)thiocar-
bonyl]phenyl ketenimines 4, whose formation was confirmed
by the presence of very strong absorptions around 2000 cm-1
in the IR spectra of the reaction mixtures, associated to the
NdCdC grouping. Furthermore, ketenimine 4a (R1 ) H;
R2 ) 4-CH3C6H4; R3 ) Ph) was isolated and fully identified.
The toluene solutions containing ketenimines 4 were heated
at reflux temperature up to total disappearance of the
cumulenic band in their IR spectra, approximately for 1 h.
Column chromatography of the final reaction mixtures
obtained from this thermal treatment allowed the isolation
of pure 2-alkyl(aryl)thio-3H-quinolin-4-ones 5 in acceptable
yields (Scheme 2, Table 1).
Wentrup has extensively studied the reversible acyl
ketenimine to imidoyl ketene rearrangement via [1,3] sig-
matropic shifts of a range of atoms and groups of atoms
under flash vacuum pyrolysis (FVP) conditions (Scheme
1).8a-h Within this framework, (N-aryl)imidoyl ketenes
Scheme 1. [1,3] Sigmatropic Shifts in Acylketenimines
underwent further 6π-electrocyclization to quinolones.8b,d-f,9
Only three examples of [1,5] sigmatropic shifts in keten-
imines have been reported, and all of them involve a [1,5]
hydrogen atom transfer to the central carbon atom of the
keteminine.10
Scheme 2. Synthesis of 3H-Quinolin-4-ones 5
In our effort to develop new reactions of ketenimines, we
decided to prepare N-[2-(alkyl- or arylthio)carbonyl]phenyl
ketenimines, with the aim of testing the viability of the [1,5]
migration of the electron-rich alkyl(aryl)thio group from the
carbonyl carbon to the electron-deficient central carbon atom
of the ketenimine fragment. Here, we report the results
obtained in the thermally induced cyclization of such
ketenimines, which, in fact, undergo a facile [1,5] sigmatropic
migration of the alkyl(aryl)thio group and subsequent 6π-
electrocyclic ring closure (ERC) to afford 2-alkyl(aryl)thio-
3H-quinolin-4-ones. We also present a computational study
of the mechanism of these conversions showing that both
the [1,5] migration and the electrocyclization steps take place
through transition states of pseudopericyclic nature.
The reactions of 2-azidobenzoyl chloride 1a and 2-azido-
5-chlorobenzoyl chloride 1b with alkyl and arylthiols, in
dichloromethane solution and in the presence of a slight
The utilization of a chiral thiol in the sequence leading to
5i yielded a 1:1 mixture of two diastereomeric quinolones.
The structural determination of the 2-alkyl(aryl)thio-3H-
quinolin-4-ones 5 was achieved following their analytical
and spectral data and unequivocally established by the X-ray
(7) Nubbemeyer, U. Synthesis 1993, 1120.
(8) (a) Cheikh, A. B.; Chuche, J.; Manisse, N.; Pommelet, J. C.; Netsch,
K.-P.; Lorencak, P.; Wentrup, C. J. Org. Chem. 1991, 56, 970. (b) Kappe,
C. O.; Kollenz, G.; Leung-Toung, R.; Wentrup, C. J. Chem. Soc., Chem.
Commun. 1992, 487. (c) Kappe, C. O.; Kollenz, G.; Netsch, K.-P.; Leung-
Toung, R.; Wentrup, C. J. Chem. Soc., Chem. Commun. 1992, 488. (d)
Fulloon, B.; El-Nabi, H. A. A.; Kollenz, G.; Wentrup, C. Tetrahedron Lett.
1995, 36, 6547. (e) Fulloon, B. E.; Wentrup, C. J. Org. Chem. 1996, 61,
1363. (f) Ramana Rao, V. V.; Wentrup, C. J. Chem. Soc., Perkin Trans. 1
1998, 2583. (g) Wentrup, C.; Ramana Rao, V. V.; Frank, W.; Fulloon, B.
E.; Moloney, D. W. J.; Mosandl, T. J. Org. Chem. 1999, 64, 3608. (h)
Finnerty, J. J.; Wentrup, C. J. Org. Chem. 2004, 69, 1909. For other papers
dealing with [1,3] migrations in ketenimines, see: (i) Aumann, R.; Heinen,
H. Chem. Ber. 1988, 121, 1739. (j) Clarke, D.; Mares, R. W.; McNab, H.
J. Chem. Soc., Chem. Commun. 1993, 1026. (k) Clarke, D.; Mares, R. W.;
McNab, H. J. Chem. Soc., Perkin Trans. 1 1997, 1799. (l) Amsallem, D.;
Mazie`res, S.; Piquet-Faure´, V.; Gornitzka, H.; Baceiredo, A.; Bertrand G.
Chem. Eur. J. 2002, 8, 5306.
(9) The old and well-stablished Conrad-Limpach synthesis of quinolones
by pyrolysis of esters probably proceeds via imidoyl ketene intermediates:
Conrad, M.; Limpach, L. Ber. Dtsch. Chem. Ges. 1887, 20, 944. The first
report of the observation of imidoyl ketenes in quinolone synthesis was:
Briehl, H.; Adelheid, L.; Wentrup, C. J. Org. Chem. 1984, 49, 2772.
(10) (a) Goerdeler, J.; Lindner, C.; Zander, F. Chem. Ber. 1981, 114,
536. (b) Morel, G.; Marchand, E.; Foucaud, A. J. Org. Chem. 1985, 50,
771. (c) Ramana Rao, V. V.; Fulloon, B. E.; Bernhardt, P. V.; Koch, R.;
Wentrup, C. J. Org. Chem. 1998, 63, 5779.
Table 1. 3H-Quinolin-4-ones 5
compd
R1
R2
R3
yield (%)
5a
5b
5c
5d
5e
5f
5g
5h
5i
H
H
H
H
Cl
Cl
Cl
H
H
Cl
H
H
4-CH3C6H4
4-CH3C6H4
4-CH3OC6H4
4-C5H4N
4-CH3C6H4
4-CH3OC6H4
4-CH3OC6H4
4-CH3OC6H4CH2
C6H5(CH3)CH
4-CH3OC6H4CH2
C6H5CH2CH2
2-IC6H4CH2CH2
Ph
Me
Ph
Ph
Ph
Ph
Me
Ph
Me
Ph
Ph
Ph
74
52
89
79
97
95
76
83
58a
51
85
90
5j
5k
5l
a Isolated as a 1:1 mixture of two diastereoisomers
5282
Org. Lett., Vol. 7, No. 23, 2005

structure determination of a monocrystal of 5a (R1 ) H; R2
) 4-CH3C6H4; R3 ) Ph) (Figure 1).
Table 2. Bis(3H-quinolin-4-ones) 8
compd
X
R3
yield (%)
8a
8b
8c
8d
8e
8f
CH2CH2CH2
CH2CH2CH2
1,2-C6H4
1,2-C6H4
1,3-C6H4
Ph
Me
Ph
Me
Ph
Me
89
61a
64
63a
70
59a
1,3-C6H4
a
Isolated as a 1:1 mixture of two diastereoisomers.
that ketenimines 4 may experience cyclization by an alterna-
tive pathway: a 6π electrocyclization involving their con-
jugated 1-oxa-5-azahexatrienic system to give the 3,1-
benzoxazines 10 (Scheme 4). This does not seem to be the
Figure 1. X-ray structure of 5a.
Scheme 4. Proposed Mechanism for the Conversion 4 f 5
The reactions of 2-azidobenzoyl chloride 1a with R,ω-
dithiols provided bis(azides) 6, which by a sequence of
reactions similar to that shown in Scheme 1 were converted
into the bis(3H-quinolin-4-ones) 8 (Scheme 3, Table 2). In
Scheme 3. Synthesis of Bis(3H-quinolin-4-ones) 8
case, as these compounds were not detected in the 1H NMR
spectra of the crude materials obtained from the thermal
treatment of ketenimines 4 before the purification step.
We have studied the mechanism of the sequence 4 f 9
f 5 by ab initio and DFT calculations using Gaussian 98.11
Geometry optimizations were attempted first at the RHF/6-
31G* level12 and then with the B3LYP13 functional using
the 6-31+G* basis set. Second-order perturbation analyses
were achieved with the NBO (natural bond orbital) method.14
(11) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.;
Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A.
D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi,
M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.;
Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick,
D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.;
Ortiz, J. V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi,
I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P. M.
W.; Johnson, B.; Chen, W.; Wong, M. W.; Andres, J. L.; Gonzalez, C.;
Head-Gordon, M.; Repogle, E. S.; Pople, J. A. Gaussian 98, revision A.9;
Gaussian, Inc.: Pittsburgh, PA, 1998.
(12) Hehre, W. J.; Radom, L.; Schleyer, P. v. R.; Pople, J. A. Ab Initio
Molecular Orbital Theory; Wiley: New York, 1986; pp 71-82 and
references therein.
(13) (a) Parr, R. G.; Yang, W. Density-Functional Theory of Atoms and
Molecules; Oxford University Press: New York, 1989. (b) Bartolotti, L.
J.; Fluchichk, K. In ReViews in Computational Chemistry; Lipkowitz, K.
B., Boyds, D. B., Eds.;VCH Publishers: New York, 1996; Vol. 7, pp 187-
216. (c) Kohn, W.; Becke, A. D.; Parr, R. G. J. Phys. Chem. 1996, 100,
12974. (d) Ziegler, T. Chem. ReV. 1991, 91, 651.
compounds 8, two quinolin-4-one rings are linked via their
respective C2 carbon atoms by a propylene, 1,2-phenylene,
or 1,3-phenylene dithioether chain. Bis(3H-quinolin-4-ones)
8b, 8d, and 8f, in which R3 is a methyl group, were obtained
as 1:1 mixtures of their two diastereoisomers.
The most reasonable mechanistic explanation for the
conversion of ketenimines 4 into the 3H-quinolin-4-ones 5
is as follows: first, the alkyl(aryl)thio group undergoes [1,5]
migration from the carbonyl carbon to the central carbon
atom of the ketenimine moiety, giving rise to vinylimi-
noketenes 9, which, in turn, are converted into the final 3H-
quinolin-4-ones 5 through a 6π electrocyclic ring closure
that involves the conjugated 3-azatriene fragment of their
1-oxa-5-aza-1,2,4,6-heptatetraene system. It is conceivable
Org. Lett., Vol. 7, No. 23, 2005
5283

NICS (nucleus-independent chemical shifts) values were
obtained at the B3LYP/6-31+G* level with the GIAO
(gauge-independent atomic orbital) method.15 For modeling
the ketenimines 4 used in the experimental study, we selected
the simplest structure 11 and explored the potential energy
surface associated to its transformation into 2-thiohidroxy-
4(3H)-pyridinone 13 (Figure 2). The theoretical study
structures, TS1 and TS2, are also notably different than those
expected for transition states with pericyclic topologies.
On the basis of the geometries and magnetic properties
of TS1 and TS2 and the results of the second-order
perturbation analyses showing the delocalization energies of
electrons from filled NBOs into empty NBOs, we have
established the pseudopericyclic18,19 nature of both transition
states. They are not aromatic (the computed NICS at the ring
critical point of the electronic density20 are +0.13 and -3.20
ppm‚mol-1, respectively). The NBO analysis of TS1 shows
bonding between a sulfur lone pair and the π*C1-N3 natural
localized orbital (∆E(2)Lp(2)S7fπ*C1-N3 ) 88.7 kcal‚mol-1).
Thus, the new, partially formed σ-C1-S7 bond results from
the interaction between a lone pair of the sulfur atom (which
changes from non bonding sp2 orbital to bonding sp3 orbital)
and a p orbital of the C1dN3 bond (the LUMO of the
ketenimine moiety initially placed perpendicular to the
molecular plane). In TS2, the forming σ-bond C2-C6 is due
mainly to the interaction between the πC1-C2 and the
π*C6-O (the LUMO of the ketene fragment placed in the
molecular plane) natural localized orbitals (∆E(2)πC1-C2fπ*C6-O
) 20.6 kcal‚mol-1), instead of the interaction between the
natural localized orbitals πC1-C2/π*C5-C6 and πC5-C6/
π*C1-C2 expected for a transition state with normal
pericyclic topology.
Figure 2. B3LYP/6-31+G*-optimized geometries and energetics
for the [1,5]-SH shift of 11 leading to 12 and the 6π-ERC of 12
into 13. Energies are given in kcal‚mol-1 relative to reactant (zero-
point vibrational energy corrections have been applied, but not
scaled).
Acknowledgment. This work was supported by the
MCYT and FEDER (Project BQU2001-0010) and Fundacio´n
Se´neca-CARM (Project 00458/PI/04). M.-M.O. thanks Fun-
dacio´n Cajamurcia for a fellowship.
predicts that this transformation occurs by a two-step pathway
starting by the [1,5] shift of the SH group via the transition
structure TS1 leading to the intermediate vinyliminoketene
12. In the second step, this ketene undergoes a 6π-ERC
through TS2 providing the pyridinone 13. At the B3LYP/
6-31+G* theoretical level, the energy barriers associated to
the first and second steps are 16.75 and 1.51 kcal‚mol-1,
respectively. The overall transformation of ketenimine 11
into the pyridinone 13 is exothermic by 25.36 kcal‚mol-1.
Both processes, i.e., the [1,5]-SH shift and the 6π-ERC,
have energy barriers lower than those expected for normal
pericyclic paths,16,17 and the geometries of their transition
Supporting Information Available: Experimental details
for the synthesis of compounds 2-5 and 6-8 and their
characterization (NMR, IR, MS, elemental analyses). X-ray
data and CIF file for 5a. B3LYP/6-31+G*-optimized Car-
tesian coordinates for minima and transition structures. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL052189V
(18) For reports on pseudopericyclic [1,5]-shifts, see: (a) Birney, D. M.
J. Org. Chem. 1996, 61, 243. (b) Zhou, C.; Birney, D. M. J. Org. Chem.
2004, 69, 86. (c) Bibas, H.; Koch, R.; Wentrup, C. J. Org. Chem. 1998,
63, 2619. (d) Koch, R.; Wong, M. H.; Wentrup, C. J. Org. Chem. 1996,
61, 6809. See also ref 10c.
(19) For reports on pseudopericyclic 6π-electrocyclic ring closures see
ref 17a and: (a) Luo, L.; Bartberger, M. D.; Dolbier, W. R. J. Am. Chem.
Soc. 1997, 119, 12366. (b) Zora, M. J. Org. Chem. 2004, 69, 1940. (c)
Alajar´ın, M.; Sa´nchez-Andrada, P.; Coss´ıo, F. P.; Arrieta, A.; Lecea, B. J.
Org. Chem. 2001, 66, 8470. (d) Alajar´ın, M.; Sa´nchez-Andrada, P.; Vidal,
A.; Tovar, F. J. Org. Chem. 2005, 70, 1340. (e) De Lera. A. R. ; Alvarez,
R.; Lecea, B.; Torrado, A.; Coss´ıo, F. P. Angew. Chem., Int. Ed. 2001, 40,
557. (f) Cabaleiro-Lago, E. M.; Rodr´ıguez-Otero, J.; Varela-Varela, S. M.;
Pen˜a-Gallego, A.; Hermida-Ramo´n, J. M. J. Org. Chem. 2005, 70, 3921.
(20) Bader, R. F. W. Atoms in MoleculessA Quantum Theory; Clarendon
Press: Oxford, 1990; pp 13-52.
(14) (a) Redd, A. E.; Weinstock, R. B.; Weinhold, F. J. Chem. Phys.
1985, 83, 735. (b) Reed, A. E.; Curtiss, L. A.; Weinhold, F. Chem. ReV.
1988, 88, 899. (c) Reed, A. E.; Schleyer, P. v. R. J. Am. Chem. Soc. 1990,
112, 1434.
(15) Wolinski, K.; Hilton, J. F.; Pulay, P. J. Am. Chem. Soc. 1990, 112,
8251.
(16) The calculated energy barrier for the prototypical [1,5]-H shift in
1,3-pentadiene is 36.6 kcal‚mol-1; see: (a) Hess, B. A.; Baldwin, J. E. J.
Org. Chem. 2002, 67, 6025 and references cited therein.
(17) The calculated energy barrier for the prototypical 6π-ERC of
hexatriene into cyclohexadiene is 29.9 kcal‚mol-1; see: Guner, V. A.; Houk,
K. N.; Davies, I. W. J. Org. Chem. 2004, 69, 8024 and references cited
therein.
5284
Org. Lett., Vol. 7, No. 23, 2005