Tandem pseudopericyclic reactions: [1,5]-X sigmatropic shift/6π- electrocyclic ring closure converting N-(2-X-carbonyl)phenyl ketenimines into 2-X-quinolin-4(3H)-ones

Article abstract of DOI:10.1021/jo061286e

N-(2-X-Carbonyl)phenyl ketenimines undergo, under mild thermal conditions, [1l,5]-migration of the X group from the carbonyl carbon to the electron-deficient central carbon atom of the ketenimine fragment, followed by a 6π-electrocyclic ring closure of the resulting ketene to provide 2-X-substituted quinolin-4(3H)-ones in a sequential one-pot manner. The X groups tested are electron-donor groups, such as alkylthio, arylthio, arylseleno, aryloxy, and amino. When involving alkylthio, arylthio, and arylseleno groups, the complete transformation takes place in refluxing toluene, whereas for aryloxy and amino groups the starting ketenimines must be heated at 230 °C in a sealed tube in the absence of solvent. The mechanism for the conversion of these ketenimines into quinolin-4(3H)-ones has been studied by ab initio and DFT calculations, using as model compounds N-(2-X-carbonyl)vinyl ketenimines bearing different X groups (X = F, Cl, OH, SH, NH₂, and PH ₂) converting into 4(3H)-pyridones. This computational study afforded two general reaction pathways for the first step of the sequence, the [1,5]-X shift, depending on the nature of X. When X is F, Cl, OH, or SH, the migration occurs in a concerted mode, whereas when X is NH₂ or PH₂, it involves a two-step sequence. The order of migratory aptitudes of the X substituents at the acyl group is predicted to be PH₂ > Cl > SH > NH₂ > F > OH. The second step of the full transformation, the 6π-electrocyclic ring closure, is calculated to be concerted and with low energy barriers in all the cases. We have included in the calculations an alternative mode of cyclization of the N-(2-X-carbonyl)vinyl ketenimines, the 6π-electrocyclic ring closure leading to 1,3-oxazines that involves its 1-oxo-5-aza-1,3,5-hexatrienic system. Additionally, the pseudopericyclic topology of the transition states for some of the [1,5]-X migrations (X = F, Cl, OH, SH), for the 6π-electrocyclization of the ketene intermediates to the 4(3H)-pyridones, and for the 6π-electrocyclization of the starting ketenimines into 1,3-oxazines could be established on the basis of their geometries, natural bond orbital analyses, and magnetic properties. The calculations predict that the 4(3H)-pyridones are the thermodynamically controlled products and that the 1,3-oxazines should be the kinetically controlled ones.

Full text of DOI:10.1021/jo061286e

Tandem Pseudopericyclic Reactions: [1,5]-X Sigmatropic Shift/
6π-Electrocyclic Ring Closure Converting N-(2-X-Carbonyl)phenyl
Ketenimines into 2-X-Quinolin-4(3H)-ones†
Mateo Alajar´ın,* Mar´ıa-Mar Ort´ın, Pilar Sa´nchez-Andrada,* and AÄ ngel Vidal
Departamento de Qu´ımica Orga´nica, Facultad de Qu´ımica, Campus de Espinardo, UniVersidad de
Murcia, 30100 Murcia, Spain
alajarin@um.es
ReceiVed June 22, 2006
N-(2-X-Carbonyl)phenyl ketenimines undergo, under mild thermal conditions, [1,5]-migration of the X
group from the carbonyl carbon to the electron-deficient central carbon atom of the ketenimine fragment,
followed by a 6π-electrocyclic ring closure of the resulting ketene to provide 2-X-substituted quinolin-
4(3H)-ones in a sequential one-pot manner. The X groups tested are electron-donor groups, such as
alkylthio, arylthio, arylseleno, aryloxy, and amino. When involving alkylthio, arylthio, and arylseleno
groups, the complete transformation takes place in refluxing toluene, whereas for aryloxy and amino
groups the starting ketenimines must be heated at 230 °C in a sealed tube in the absence of solvent. The
mechanism for the conversion of these ketenimines into quinolin-4(3H)-ones has been studied by ab
initio and DFT calculations, using as model compounds N-(2-X-carbonyl)vinyl ketenimines bearing
different X groups (X ) F, Cl, OH, SH, NH2, and PH2) converting into 4(3H)-pyridones. This
computational study afforded two general reaction pathways for the first step of the sequence, the [1,5]-
X shift, depending on the nature of X. When X is F, Cl, OH, or SH, the migration occurs in a concerted
mode, whereas when X is NH2 or PH2, it involves a two-step sequence. The order of migratory aptitudes
of the X substituents at the acyl group is predicted to be PH2 > Cl > SH > NH2 > F> OH. The second
step of the full transformation, the 6π-electrocyclic ring closure, is calculated to be concerted and with
low energy barriers in all the cases. We have included in the calculations an alternative mode of cyclization
of the N-(2-X-carbonyl)vinyl ketenimines, the 6π-electrocyclic ring closure leading to 1,3-oxazines that
involves its 1-oxo-5-aza-1,3,5-hexatrienic system. Additionally, the pseudopericyclic topology of the
transition states for some of the [1,5]-X migrations (X ) F, Cl, OH, SH), for the 6π-electrocyclization
of the ketene intermediates to the 4(3H)-pyridones, and for the 6π-electrocyclization of the starting
ketenimines into 1,3-oxazines could be established on the basis of their geometries, natural bond orbital
analyses, and magnetic properties. The calculations predict that the 4(3H)-pyridones are the thermodynami-
cally controlled products and that the 1,3-oxazines should be the kinetically controlled ones.
Introduction
nucleophiles1 or radicals2 to its central carbon atom; (2) the
attack of electrophiles to its nitrogen atom, which also behaves
as a donor atom in the formation of metallic σ complexes;3 and
(3) its participation in pericyclic events such as 6π-electrocyclic
ring closures (ERC), cycloaddition reactions, and sigmatropic
rearrangements.1e Among these reactions, sigmatropic rear-
rangements in ketenimines have received minor attention, and
Ketenimines are nitrogenated heterocumulenes [R1-NdCd
CR2R3] employed in organic synthesis mainly for the construc-
tion of nitrogen-containing heterocycles, via (1) the addition of
† Dedicated to Prof. Marcial Moreno-Man˜as in memoriam.
* Corresponding author. Phone: +34 968 367497. Fax: +34 968 364149.
10.1021/jo061286e CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/19/2006
8126
J. Org. Chem. 2006, 71, 8126-8139

Tandem Pseudopericyclic Reactions in Ketenimines
SCHEME 1. [1,3]-Sigmatropic Shifts in C-Acyl Ketenimines
they have been scarcely reported. Some examples of [3,3]-,
[1,3]- and [1,5]-sigmatropic migrations in ketenimines have been
reported; in most of them the migrating group reaches the central
carbon atom of the ketenimine.
Concerning the [3,3]-sigmatropic migration, Brannock and
Burpitt,4 in a seminal paper in 1965, reported the conversion
of N-(2-alkenyl)amides into 4-pentenenitriles by the phosphorus
pentachloride/triethylamine combination of reagents. They
postulated N-(2-alkenyl) ketenimines as reaction intermediates,
suggesting that these species undergo a 3-aza-Claisen rear-
rangement to the unsaturated nitriles. Afterward, Walters5 and
some of us6 carried out an extensive investigation of this [3,3]-
rearrangement in a variety of new 2-(alkenyl) ketenimines,
which included the development of new methods for the
synthesis of this type of ketenimines, an experimental study of
the stereocontrol of this reaction, and a computational study of
the 3-aza-Claisen rearrangement of 3-aza-1,2,5-hexatrienes. This
thermally induced 3-aza-Claisen rearrangement of N-(2-alkenyl)
ketenimines has been used as a key step in efficient asymmetric
syntheses of the chiral natural products (+)-canadensolide, (+)-
santolinolide B, and (-)-santolinolide A.7
CHART 1. N-(2-X-Carbonyl)phenyl Ketenimines
when (N-aryl)imidoyl ketenes are formed they underwent further
6π-electrocyclization to quinolin-4(1H)-ones (Scheme 1).8b,d-f,9
To our knowledge, only three examples of [1,5]-sigmatropic
shifts in ketenimines have been described so far, and all of them
involve a [1,5]-hydrogen atom transfer to the central carbon of
the ketenimine. Goerdeler10 reported that C-imidoyl ketenimines
underwent, at room temperature, a [1,5]-H shift followed by
ERC to yield dihydropyrimidines. On the other hand, Foucaud11
demonstrated that in refluxing dichloromethane N-imidoyl
ketenimines converted into pyrrolotriazines by a consecutive
[1,5]-H shift/intramolecular [4 + 2]-cycloaddition. More re-
cently, Wentrup12 published that N-aryl ketenimines bearing
methyl groups at the ortho position suffer, under flash vacuum
thermolysis conditions, a facile [1,5]-H shift and subsequent
electrocyclization to dihydroquinolines.
The more important research works dealing with [1,3]-
sigmatropic shifts in ketenimines have been reported by
Wentrup,8a-h who carried out an extensive study of the reversible
C-acyl ketenimine to imidoyl ketene rearrangement, via [1,3]-
sigmatropic shifts of a variety of atoms or groups of atoms under
flash vacuum pyrolysis (FVP) conditions. In these processes,
(1) For reviews on the chemistry of ketenimines, see: (a) Krow, D. R.
Angew. Chem., Int. Ed. Engl. 1971, 10, 435-449. (b) Gambaryan, N. P.
Usp. Khim. 1976, 45, 1251-1268. (c) Dondoni, A. Heterocycles 1980, 14,
1547-1566. (d) Barker, M. W.; McHenry, W. E. In The Chemistry of
Ketenes, Allenes and Related Compounds; Patai, S., Ed.; Wiley-Inter-
science: Chichester, U.K., 1980; Part 2, p 701. (e) Alajar´ın, M.; Vidal, A.;
Tovar, F. Targets Heterocycl. Syst. 2000, 4, 293-326.
(2) (a) Alajar´ın, M.; Vidal, A.; Ort´ın, M.-M. Tetrahedron Lett. 2003,
44, 3027-3030. (b) Alajar´ın, M.; Vidal, A.; Ort´ın, M.-M. Org. Biomol.
Chem. 2003, 1, 4282-4292. (c) Alajar´ın, M.; Vidal, A.; Ort´ın, M.-M.;
Bautista, D. New J. Chem. 2004, 28, 570-577. (d) Alajar´ın, M.; Vidal, A.;
Ort´ın, M.-M.; Bautista, D. Synlett 2004, 991-994.
In the frame of a systematic development of new reactions
of ketenimines, we targeted the synthesis of a variety of N-(2-
X-carbonyl)phenyl ketenimines (Chart 1), with the aim of
examining the viability of the [1,5]-migration of diverse X
groups from the carbonyl carbon to the electron-deficient central
carbon atom of the ketenimine fragment. We focused on testing
the sigmatropic migration of electron-donor groups, such as
alkylthio, arylthio, arylseleno, aryloxy, amino, and halides, given
the electrophilic character of the presumed migration terminus.
In this paper, we report that in fact such ketenimines undergo
a facile [1,5]-sigmatropic migration of the X group under mild
thermal conditions and a subsequent 6π-electrocyclic ring
closure of the resulting ketene to afford 2-X-substituted quinolin-
4(3H)-ones. Furthermore, we have carried out a computational
study in order to gain insight on the mechanism of these
transformations and to evaluate the relative migratory aptitude
of the different X groups. In a previous communication, we
have reported that N-[2-(alkyl- or arylthio)carbonyl]phenyl
ketenimines undergo cyclization to afford 2-alkyl(aryl)thio-
(3) (a) Aumann, R. Chem. Ber. 1993, 126, 1867-1872. (b) Merlic, C.
A.; Burns, E. E. Tetrahedron Lett. 1993, 34, 5401-5404.
(4) Brannock, K. C.; Burpitt, R. D. J. Org. Chem. 1965, 30, 2564-
2565.
(5) (a) Walters, M. A.; McDonough, C. S.; Brown, P. S., Jr.; Hoem, A.
B. Tetrahedron Lett. 1991, 32, 179-182. (b) Walters, M. A.; Hoem, A.
B.; Arcand, H. R.; Hegeman, A. D.; McDonough, C. S. Tetrahedron Lett.
1993, 34, 1453-1456. (c) Walters, M. A.; Hoem, A. B. J. Org. Chem.
1994, 59, 2645-2647. (d) Walters, M. A. J. Am. Chem. Soc. 1994, 116,
11618-11619. (e) Walters, M. A. J. Org. Chem. 1996, 61, 978-983.
(6) (a) Molina, P.; Alajar´ın, M.; Lo´pez-Leonardo, C. Tetrahedron Lett.
1991, 32, 4041-4044. (b) Molina, P.; Alajar´ın, M.; Lo´pez-Leonardo, C.;
Alca´ntara, J. Tetrahedron 1993, 49, 5153-5168.
(7) Nubbemeyer, U. Synthesis 1993, 1120-1128.
(8) (a) Cheikh, A. B.; Chuche, J.; Manisse, N.; Pommelet, J. C.; Netsch,
K.-P.; Lorencak, P.; Wentrup, C. J. Org. Chem. 1991, 56, 970-975. (b)
Kappe, C. O.; Kollenz, G.; Leung-Toung, R.; Wentrup, C. J. Chem. Soc.,
Chem. Commun. 1992, 487-488. (c) Kappe, C. O.; Kollenz, G.; Netsch,
K.-P.; Leung-Toung, R.; Wentrup, C. J. Chem. Soc., Chem. Commun. 1992,
488-490. (d) Fulloon, B.; El-Nabi, H. A. A.; Kollenz, G.; Wentrup, C.
Tetrahedron Lett. 1995, 36, 6547-6550. (e) Fulloon, B. E.; Wentrup, C. J.
Org. Chem. 1996, 61, 1363-1368. (f) Ramana Rao, V. V.; Wentrup, C. J.
Chem. Soc., Perkin Trans. 1 1998, 2583-2586. (g) Wentrup, C.; Ramana
Rao, V. V.; Frank, W.; Fulloon, B. E.; Moloney, D. W. J.; Mosandl, T. J.
Org. Chem. 1999, 64, 3608-3619. (h) Finnerty, J. J.; Wentrup, C. J. Org.
Chem. 2004, 69, 1909-1918. For other papers dealing with [1,3]-migration
in ketenimines, see: (i) Aumann, R.; Heinen, H. Chem. Ber. 1988, 121,
1739-1743. (j) Clarke, D.; Mares, R. W.; McNab, H. J. Chem. Soc., Chem.
Commun 1993, 1026-1027. (k) Clarke, D.; Mares, R. W.; McNab, H. J.
Chem. Soc., Perkin Trans. 1 1997, 1799-1804. (l) Amsallem, D.; Mazie`res,
S.; Piquet-Faure´, V.; Gornitzka, H.; Baceiredo, A.; Bertrand, G. Chem.-
Eur. J. 2002, 8, 5306-5311.
(9) The 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, 944-948. The first report on the
observation of imidoyl ketenes in quinolone synthesis: Briehl, H.; Adelheid,
L.; Wentrup, C. J. Org. Chem. 1984, 49, 2772-2779.
(10) Goerdeler, J.; Lindner, C.; Zander, F. Chem. Ber. 1981, 114, 536-
548.
(11) Morel, G.; Marchand, E.; Foucaud, A. J. Org. Chem. 1985, 50, 771-
778.
(12) Ramana Rao, V. V.; Fulloon, B. E.; Bernhardt, P. V.; Koch, R.;
Wentrup, C. J. Org. Chem. 1998, 63, 5779-5786.
J. Org. Chem, Vol. 71, No. 21, 2006 8127

Alajar´ın et al.
SCHEME 2. Synthesis of Quinolin-4(3H)-ones 5a
a Reagents and conditions: (a) For X ) SR3: R3SH, DMAP, CH2Cl2, rt, 5 h. For X ) SeAr: ArSeSeAr, NaBH4, EtOH, rt, 3 h. For X ) OAr: ArOH,
DMAP, CH2Cl2, rt, 5 h. For X ) NR3R4: R3R4NH, pyridine, 0 °C, 1.5 h. (b) For X ) SR3, OAr, NR3R4: PPh3, Et2O, rt, 16 h. For X ) SeAr: PPh3, toluene,
rt, 4 h. (c) For X ) SR3, SeAr: PhR2CdCdO, toluene, rt, 15 min. For X ) OAr, NR3R4: PhR2CdCdO, CH2Cl2, rt, 15 min. (d) For X ) SR3, SeAr:
toluene, reflux, 1 h. For X ) OAr, NR3R4: neat, sealed tube, 230 °C, 1 h.
TABLE 1. Quinolin-4(3H)-ones 5
quinolin-4(3H)-ones by means of a consecutive 1,5-migration
R1
X
R2
yield (%)
of the alkyl(aryl)thio group/6π-electrocyclization.13
compd
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
5s
H
H
H
H
Cl
Cl
Cl
H
H
Cl
H
H
H
H
H
H
H
H
H
H
H
H
4-CH3C6H4S
4-CH3C6H4S
4-CH3OC6H4S
4-(C5H5N)S
4-CH3C6H4S
4-CH3OC6H4S
4-CH3OC6H4S
4-CH3OC6H4CH2S
C6H5(CH3)CHS
4-CH3OC6H4CH2S
C6H5CH2CH2S
2-IC6H4CH2CH2S
C6H5Se
Ph
Me
Ph
Ph
Ph
Ph
Me
Ph
Me
Ph
Ph
Ph
Ph
Me
Ph
Ph
Me
Ph
Me
Ph
Ph
Ph
74
52
89
79
97
95
76
83
58a
51
85
90
62
60
36
42
28
36
25
36
30
25
Results and Discussion
Experimental Study. First, we tested the migration of alkyl-
(aryl)thio groups in N-[2-alkyl(aryl)thiocarbonyl]phenyl keten-
imines 4a-l.14 The reaction of 2-azidobenzoyl chloride 1a and
2-azido-5-chlorobenzoyl chloride 1b with alkylthiols and aryl-
thiols, in dichloromethane solution, in the presence of a slight
excess of DMAP, afforded the S-alkyl and S-aryl 2-azidot-
hiobenzoates 2a-j. The treatment of the 2-azidothiobenzoates
2a-j, in diethyl ether solution, with triphenylphosphine provided
the 2-(triphenylphosphoranylideneamino)thiobenzoates 3a-j.
The reaction of triphenylphosphazene 3a (R1 ) H; X )
4-CH3C6H4S), in dichloromethane solution at room temperature,
with a stoichiometric amount of diphenylketene gave ketenimine
4a (R1 ) H; X ) 4-CH3C6H4S; R2 ) Ph), which was purified
by column chromatography on silica gel, isolated, and fully
identified.14 When a toluene solution of 4a was heated at reflux
temperature for approximately 1 h, an IR spectra of the reaction
mixture showed the total disappearance of the cumulenic band
around 2000 cm-1 associated with the NdCdC grouping, and
from the resulting crude material 2-(4-methylphenylthio)-3,3-
diphenylquinolin-4(3H)-one 5a (R1 ) H; X ) 4-CH3C6H4S;
R2 ) Ph) was isolated by column chromatography as the only
reaction product (Scheme 2).
C6H5Se
4-CH3OC6H4Se
4-CH3C6H4O
4-CH3C6H4O
3,4-(CH3O)2C6H3O
3,4-(CH3O)2C6H3O
(CH3)2N
5t
5u
5v
C6H5(CH3)N
(4-CH3C6H4)2N
a Isolated as a 1:1 mixture of two diastereoisomers.
provided the respective 2-alkyl(aryl)thioquinolin-4(3H)-ones
5a-l in acceptable yields (Scheme 2, Table 1). The conversions
4a-l f 5a-l also took place at room temperature, although
most of these reactions required up to 48 h to be completed.
The structural determination of the 2-alkyl(aryl)thioquinolin-
4(3H)-ones 5a-l was achieved following their analytical and
spectral data and was unequivocally established by the X-ray
structure determination of a monocrystal of 5a (R1 ) H; X )
4-CH3C6H4S; R2 ) Ph).14
Next, we prepared N-(2-arylselenocarbonyl)phenyl keten-
imines 4m-o from the Se-aryl 2-azidoselenobenzoates 2k,l via
a simple chemical sequence. Thus, treatment of solutions of
diphenyl diselenide and bis(4-methoxyphenyl) diselenide, in
anhydrous ethanol, with sodium borohydride provided sodium
benzeneselenolate and 4-methoxybenzeneselenolate, which re-
acted with 2-azidobenzoyl chloride 1a, leading to the respective
Following this initial experiment, the aza-Wittig reactions of
a series of organosulfur iminophosphoranes 3a-j with diphe-
nylketene and methylphenylketene were carried out in toluene
solution, at room temperature, to give the corresponding
ketenimines 4a-l, whose formation was confirmed by IR spectra
of the reaction mixtures. The heating of toluene solutions
containing ketenimines 4a-l at reflux temperature for 1 h
(13) Alajar´ın, M.; Ort´ın, M.-M.; Sa´nchez-Andrada, P.; Vidal, A.; Bautista,
D. Org. Lett. 2005, 7, 5281-5284.
(14) The experimental work related with the [1,5]-migration of alkyl-
(aryl)thio groups in N-[2-alkyl(aryl)thiocarbonyl]phenyl ketenimines has
been reported in our preliminary communication, ref 13.
8128 J. Org. Chem., Vol. 71, No. 21, 2006

Tandem Pseudopericyclic Reactions in Ketenimines
formation of Se-phenyl 2-azidoselenobenzoate 2k (R1 ) H; X
) C6H5Se) and Se-(4-methoxyphenyl) 2-azidoselenobenzoate
2l (R1 ) H; X ) 4-CH3OC6H4Se), in very low yields, whereas
the major product isolated from these reactions was ethyl
2-azidobenzoate.15 The sequential treatment at room tempera-
ture, and in the same reaction flask, of toluene solutions of the
2-azidoselenobenzoates 2k,l with triphenylphosphine and diphe-
nylketene or methylphenylketene led to the corresponding
ketenimines 4m-o, which converted into the respective 2-ar-
ylselenoquinolin-4(3H)-ones 5m-o when their toluene solutions
were heated at reflux temperature for 1 h (Scheme 2, Table 1).
The reaction of 2-azidobenzoyl chloride 1a with 4-meth-
ylphenol and 3,4-dimethoxyphenol, in dichloromethane solution
in the presence of DMAP, and the subsequent Staudinger
reaction of the aryl 2-azidobenzoates 2m,n with triphenylphos-
phine, in diethyl ether, provided in a straightforward manner
the aryl 2-(triphenylphosphoranylideneamino)benzoates 3m,n.
Our first try at the [1,5]-migration of aryloxy groups in N-(2-
aryloxycarbonyl)phenyl ketenimines was carried out by heating
in either refluxing toluene or o-xylene solutions of the C,C-
diphenyl ketenimine 4p (R1 ) H; X ) 4-CH3C6H4O; R2 ) Ph),
generated by reaction of compound 3m (R1 ) H; X )
4-CH3C6H4O) with diphenylketene in these solvents. We could
establish that after 48 h under both reaction conditions com-
pound 4p remained unaltered, and the same result was obtained
when 4p was heated for the same time at 180 °C in toluene
solution in a sealed tube. Afterward, ketenimine 4p was
generated in dichloromethane and, after removing the solvent,
the mixture containing this ketenimine and the triphenylphos-
phine oxide was heated at 230 °C in a sealed tube up to the
total disappearance of the cumulenic band in its IR spectrum,
approximately 1 h. The material obtained from this thermal
treatment was chromatographed, thus resulting in the isolation
of pure 2-(4-methylphenyloxy)-3,3-diphenylquinolin-4(3H)-one
5p, in 42% yield. The application of this procedure to the N-(2-
aryloxycarbonyl)phenyl ketenimines 4q-s yielded the corre-
sponding 2-aryloxyquinolin-4(3H)-ones 5q-s in low yields
(Scheme 2, Table 1).
CHART 2. N-(2-Bromocarbonyl)phenyl Ketenimine 4w and
N-(2-Chlorocarbonyl)phenyl Ketenimine 4x
SCHEME 3. Proposed Mechanism for the Conversion 4f5
chlorine atoms in the N-(2-bromocarbonyl)phenyl ketenimine
4w and the N-(2-chlorocarbonyl)phenyl ketenimine 4x, respec-
tively (Chart 2), unfortunately the strategies that we attempted
for the preparation of these two ketenimines failed. These
synthetic approaches involved either the use of starting materials
bearing an acyl halide function or the generation of this function
in the last step, in the presence of the ketenimine grouping.
We assume that the mechanism of the transformation of the
ketenimines 4 into the quinolin-4(3H)-ones 5 is initiated by the
[1,5]-migration of the X group from the carbonyl carbon to the
central carbon atom of the ketenimine moiety to give the imidoyl
ketenes 6, which are further converted into the reaction products
5 through a 6π-electrocyclic ring closure of their conjugated
3-azahexatriene fragment (Scheme 3). It is also conceivable that
the N-(2-X-carbonyl)phenyl ketenimines 4 may experience
cyclization to the 3,1-benzoxazines 7 via a 6π-electrocyclization
involving their conjugated 1-oxa-5-azahexatrienic system. How-
ever, it does not seem to be the case, as compounds 7 were
Finally, we were also able to achieve the [1,5]-shift of amino
groups in N-(2-carbamoyl)phenyl ketenimines. The acylation
of dialkyl, alkylaryl, or diaryl substituted secondary amines with
2-azidobenzoyl chloride 1a led to the 2-azidobenzamides 2o-
q, which by the habitual methodology were converted into their
respective N-(2-carbamoyl)phenyl ketenimines 4t-v. We could
convert ketenimines 4t-v into the 2-aminoquinolin-4(3H)-ones
5t-v only when these heterocumulenes were heated at 230 °C
in a sealed tube in the absence of solvent, although the yields
of these transformations were also low (Scheme 2, Table 1).
At this point of the discussion, it is worth mentioning that
although we planned to test the migration of bromine and
1
never detected in the H NMR spectra of the crude materials
obtained from the thermal treatment of ketenimines 4. Given
that all the reactions in Scheme 3 can be chemical equilibria,
the exclusive formation of quinolin-4(3H)-ones 5 in the thermal
treatment of ketenimines 4 may be a consequence of prevailing
thermodynamic versus kinetic control. At first sight, compounds
5 seem more stable, on thermodynamic grounds, than the
o-quinonoid benzoxazines 7. This matter will be treated in depth
in the following sections.
Computational Study. For simplicity, to model the trans-
formation of the ketenimines 4 into the quinolin-4(3H)-ones 5
presented in the experimental part of this work, we selected
the more simple structures 8c-e, where the vinyl group joining
the acyl and ketenimine functions models the benzene ring of
the ketenimines 4 and the OH, SH, and NH2 groups model the
OAr, SR3, and NR3R4 groups. In our previous communication,13
we have shown computationally that the transformation of
ketenimine 8d (X ) SH) into 2-thiohydroxy-4(3H)-pyridone
9d occurs by a two-step pathway that starts with the [1,5]-shift
in the SH group leading to an intermediate imidoyl ketene 10d,
which in a second step undergoes an electrocyclic ring closure
(15) We did not succeed in the synthesis of the Se-aryl 2-azidosele-
nobenzoates 2k,l by using other well-established reaction conditions for
the preparation of selenoesters, such as those used in the following
articles: (a) Grieco, P. A.; Jaw, J. Y. J. Org. Chem. 1981, 46, 1215-1217.
(b) Nicolaou, K. C.; Petasis, N. A.; Claremon, D. A. Tetrahedron 1985,
41, 4835-4841. (c) Gais, H.-J. Angew. Chem., Int. Ed. Engl. 1977, 16,
244-246. (d) Ireland, R. E.; Norbeck, D. W.; Mandel, G. S.; Mandel, N.
S. J. Am. Chem. Soc. 1985, 107, 3285-3294. Probably the o-azido group
of 1 interferes with the expected substitution at the acyl group. Only a
modification of the experimental procedure described by Odom for the
preparation of selenoesters from acyl chlorides and benzeneselenolates,
generated by reaction of diaryl diselenides and sodium borohydride, provided
the Se-aryl 2-azidoselenobenzoates 2k,l, although in very low yields, see:
(e) Mullen, G. P.; Luthra, N. P.; Dunlap, R. B.; Odom, J. D. J. Org. Chem.
1985, 50, 811-816.
J. Org. Chem, Vol. 71, No. 21, 2006 8129

Alajar´ın et al.
SCHEME 4. Intramolecular Cyclization Modes for the
Ketenimines 8a-f
been applied, but not scaled. We will comment only on the
results obtained at the B3LYP/6-31+G* theoretical level, unless
otherwise stated.
Path A. Transformation of Ketenimines 8a-f into the
4(3H)-Pyridones 9a-f. Surprisingly, depending on the nature
of the migrating group X, we have found two different general
pathways for the conversion of ketenimines 8a-f into the 4(3H)-
pyridones 9a-f. Thus, when X is F, Cl, OH, or SH (8a-d),
the [1,5]-X shift occurs in a concerted mode, whereas when X
is NH2 or PH2 (8e and 8f) the migration of the NH2 or the PH2
group involves a two-step mechanistic scheme. We next discuss
separately these two reaction pathways, concerted and stepwise.
Concerted [1,5]-X Sigmatropic Rearrangement of Keten-
imines 8a-d to Ketenes 10a-d and Subsequent 6π-Elec-
trocyclic Ring Closure Leading to 4(3H)-Pyridones 9a-d.
The intensive search along both HF/6-31G* and B3LYP/6-
31+G* potential energy surfaces revealed a similar mechanism
for the transformation of the four ketenimines 8a-d (X ) F,
Cl, OH, and SH) into their respective 4(3H)-pyridones 9a-d.
The first step consists of a [1,5]-shift of the X group, via the
transition structures TS1a-d (Figure 2), leading to the inter-
mediate ketenes 10a-d, which in a second step undergo an
electrocyclic ring closure, through the transition states TS2a-
d, to give the final 4(3H)-pyridones 9a-d.
to provide the 4(3H)-pyridone 9d. In this mechanistic scheme
the rate-determining step was the [1,5]-sigmatropic rearrange-
ment of the SH group. To gain insight on the migrating aptitudes
of the different X groups and a deeper understanding of the
mechanistic aspects of this process, we have considered in this
study, besides the migrating groups above-mentioned, the
fluorine and chlorine atoms and the PH2 group, by including
them on the ketenimines 8a, 8b, and 8f, respectively.
We have explored the potential energy surface associated with
the transformation of the ketenimines 8a-f into the 4(3H)-
pyridones 9a-f (Scheme 4, path A). On the other hand, the
1-oxo-5-aza-1,3,5-hexatrienic system present in ketenimimes 8
enables these compounds to experience a 6π-electrocyclic ring
closure, leading to the 2-methylene-6-substituted-1,3-oxazines
11 (path B). Due to its presumable pseudopericyclic nature, this
process is expected to occur easily,16 and consequently it could
compete with path A. This is the reason we have also included
in our calculations this alternative mode of cyclization of the
ketenimines 8.
It is worth emphasizing from the beginning of this discussion
that the structural characteristics of the ketenimines 8a-f and
the ketene intermediates 10a-f open the possibility that the
[1,5]-sigmatropic rearrangements and the two 6π-electrocyclic
ring closures delineated in Scheme 4 (8a-ff11a-f and 10a-
ff9a-f) can take place in a pseudopericyclic way. Note that
in the three reactions in that scheme a more or less nucleophilic
atom becomes linked to the central carbon of a heterocumulene
function. Thus, with the aim of knowing the precise nature of
these transformations, in this computational study we have paid
special attention to the characterization of the orbital topology
of their respective transition states.
Figures 1 and 4 display the qualitative reaction profiles at
the B3LYP/6-31+G* theoretical level and the location of the
stationary points for the transformation of ketenimines 8a-f
into 9a-f and 11a-f. Figures 2, 3, and 5-7 show the
geometries of the transition states TS1a-d, TS2a-d, and
TS3a-f and the stationary points found in the transformations
8e,ff9e,f/11e,f, including relevant bond distances. Table 2
includes the relative energies of the stationary points at the
B3LYP/6-31+G*//B3LYP/6-31+G* theoretical level and the
energy barriers. Zero-point vibrational energy corrections have
The computed energy barriers for the first step, the [1,5]-X
shift, range from 22.90 (X ) OH) to 15.76 (X ) Cl) kcal‚mol-1
,
the process being slightly endothermic (by 3.56-10.23
kcal‚mol-1). The energy barrier for the prototypical [1,5]-H shift
in cis-1,3-pentadiene, which has been calculated to be 32.6
kcal‚mol-1 from the s-cis conformer,17 is significantly higher
than those corresponding to the present [1,5]-X shifts converting
the ketenimines 8a-d into the ketenes 10a-d. The geometries
of the transition states TS1a-d are planar or nearly planar. In
contrast, the transition structure of the suprafacial [1,5]-H shift
in 1,3-pentadiene (TS1ref, see Supporting Information) re-
sembles a slightly flattened cyclohexane ring,18 the migrating
hydrogen projecting out of the plane and the HCCC dihedral
angle being 27.6°. The molecular skeletons of TS1a and TS1b
are essentially planar, the F and Cl atoms migrating in the
molecular plane (see the values of the dihedral angles in Figure
2), where the LUMO of the ketenimine moiety is placed. The
situation is similar in TS1c (X ) OH), but in this case, the OH
group projects slightly out the plane. In TS1d (X ) SH) the
molecular skeleton deviates more notably from planarity and
the values of the SC1N3C4 and SC6C5C4 dihedral angles are
28.9° and 18.0° respectively.
The computed energy barriers for the second step in the
cyclization 8a-df9a-d, that is, the 6π-electrocyclic ring
closure of 10a-d to 9a-d, are very low, ranging from 1.51 to
5.20 kcal‚mol-1, and in all the cases the process is exothermic.
By comparing the values of the barriers associated with these
ring closures with that calculated for the archetypical 6π-
electrocyclic ring closure of 1,3,5-hexatriene to 1,3-cyclohexa-
diene, which has been computed to be 26.6 kcal mol-1 19
it is
,
clear that the barriers for the cyclization of ketenes 10a-d to
(17) (a) Saettel, N. J.; Wiest, O. J. Org. Chem. 2000, 65, 2331-2336.
(b) Hess, B. A.; Baldwin, J. E. J. Org. Chem. 2002, 67, 6025-6033. (c)
Jursic, B. S. THEOCHEM 1998, 423, 189-194. (d) Jensen, F.; Houk, K.
N. J. Am. Chem. Soc. 1987, 109, 3139-3140.
(18) For comparative purposes, we have also optimized the transition
state corresponding to the [1,5]-H migration in 1,3-pentadiene, although it
has been extensively studied previously by others (see ref 17 and references
cited herein).
(16) We have reported that a similar ring closure transforming N-â-
(methyleneaminoacyl)vinyl ketenimine into 6-methyleneamino-2-methylene-
1,3-oxazine takes place trough a transition state of pseudopericyclic topology
and low energy barrier; see: Alajar´ın, M.; Sa´nchez-Andrada, P.; Vidal,
A.; Tovar, F. J. Org. Chem. 2005, 70, 1340-1349.
8130 J. Org. Chem., Vol. 71, No. 21, 2006

Tandem Pseudopericyclic Reactions in Ketenimines
FIGURE 1. Qualitative reaction profiles at the B3LYP/6-31+G* level for the transformation of the ketenimines 8a-d into the 4(3H)-pyridones
9a-d and the 1,3-oxazines 11a-d.
FIGURE 2. B3LYP/6-31+G*-optimized geometries of the transition
structures found in the transformation of the ketenimines 8a-d into
the ketenes 10a-d.
FIGURE 3. B3LYP/6-31+G*-optimized geometries of the transition
structures found in the cyclization of the ketenes 10a-d to the 4(3H)-
pyridones 9a-d.
the 4(3H)-pyridones 9a-d are unusually small. The geometries
of TS2a-d show their monorotatory nature (the hydrogen at
C5, C4, C5, C6, and O12 are in the same plane; see Figure 3).
The analysis of the imaginary frequency associated with each
transition structure revealed that the nuclear movements do not
involve rotation around the C5-C6 π system but only around
the C1-C2 ones. Both, the geometry of the transition states
TS2a-d and the small values of the energy barriers indicate
that their orbital topology could be qualified as pseudopericyclic
(see below).
Two-Step [1,5]-X Sigmatropic Rearrangement of Keten-
imines 8e,f to Ketenes 10e,f and Subsequent 6π-Electrocyclic
Ring Closure Leading to 4(3H)-Pyridones 9e,f. The intensive
search along the HF/6-31G* potential energy surface associated
J. Org. Chem, Vol. 71, No. 21, 2006 8131

Alajar´ın et al.
FIGURE 4. Qualitative reaction profiles at the B3LYP/6-31+G* level for the transformation of the ketenimines 8e,f into the 4(3H)-pyridones 9e,f
and the 1,3-oxazines 11e,f.
with the transformation of ketenimines 8e and 8f into the 4(3H)-
pyridones 9e and 9f revealed that the [1,5]-migration of the NH2
and PH2 groups leading to the ketene intermediates does not
occur in a concerted mode, but instead taking place in two
steps.20 The first one consists of the nucleophilic attack of the
lone pair at the nitrogen or phosphorus atom onto the central
carbon atom of the ketenimine moiety, through the transition
structures TS1Ae,f, to provide the dipolar intermediates INTe,f.
In a second step the breaking of the C6-X bond takes place,
via the transition states TS1Be,f, leading to the ketenes 10e,f
(see Scheme 5). The ability of nitrogen and phosphorus to exist
in a tetracoordinated state could explain why in these cases the
[1,5]-shift takes place involving the formation of the zwitterionic
intermediates. The ring closure of ketenes 10e,f occurs via the
transition states TS2e,f, whose geometries are analogous to those
found in TS2a-d. The exploration of the potential energy
surface at the correlated B3LYP/6-31+G* level led to the same
results, except for TS1Be, the ketene intermediate 10e, and the
transition structure TS2e, which could not be optimized at that
theoretical level. Instead, we found only a transition structure
TS4e involving the simultaneous breaking of the C6-N7 bond
and the formation of the C2-C6 bond. The IRC calculations
showed that TS4e connects with the dipolar intermediate INTe
and the 2-amino-4(3H)-pyridone 9e (see Scheme 6 and path A
in Figure 4).
At the B3LYP/6-31+G* theoretical level the computed
energy barriers for the formation of the polar intermediates
INTe,f from the ketenimines 8e,f were 18.09 and 14.38
kcal‚mol-1 respectively, both processes being slightly endo-
thermic. The energy barrier for the breaking of the C6-P7 bond
in INTf, leading to the ketene 10f, is very low (3.52 kcal‚mol-1).
The conversion INTef10e, at the HF/6-31G* theoretical level,
involves an almost imperceptible barrier (0.64 kcal‚mol-1). At
the B3LYP/6-31+G* level, the energy barrier calculated for
the transformation of the polar intermediate INTe into 2-amino-
4(3H)-pyridone (9e), via the transition structure TS4e, was only
3.45 kcal‚mol-1. The overall processes transforming the keten-
imines 8e,f into the final 4(3H)-pyridones 9e,f are exothermic
by 27.58 and 27.44 kcal‚mol-1, respectively. The stationary
points of these transformations are represented in Figures 5 and
6.
(19) (a) Rodr´ıguez-Otero, J. J. Org. Chem. 1999, 64, 6842-6848. (b)
Jiao, H.; Schleyer, P. v. R. J. Am. Chem. Soc. 1995, 117, 11529-11535.
(c) Evanseck, J. D.; Thomas, B. E., IV; Spellmeyer, D. C.; Houk, K. N. J.
Org. Chem. 1995, 60, 7134-7141. (d) Jefford, C. W.; Bernardinelli, G.;
Wang, Y.; Spellmeyer, D. C.; Buda, A.; Houk, K. N. J. Am. Chem. Soc.
1992, 114, 1157-1165. (e) Baldwin, J. E.; Reddy, V. P.; Schaad, L. J.;
Hess, B. A. J. Am. Chem. Soc. 1988, 110, 8554-8555.
(20) (a) An analogous finding was accomplished in the study of the effect
of several substituents in the vinylketene-acylallene rearrangement reported
by Wentrup et al.: the [1,3]-shift in the dimethylamino group takes place
involving the formation of a zwitterionic intermediate. See: Bibas, H.;
Wong, M. W.; Wentrup, C. Chem.-Eur. J. 1997, 3, 237-248. (b) Recently,
Wentrup et al. have also found zwitterionic intermediates in the [1,3]-shifts
of amino and dimethylamino groups in the imidoylketene-acyl ketenimine
rearrangement; see: Finnerty, J. F.; Wentrup, C. J. Org. Chem. 2005, 70,
9735-9739.
At this point, we can establish, according to the energy
barriers computed for the [1,5]-shifts studied in this work (see
∆E1 and ∆E1A in Table 2), the order of migratory aptitudes of
the X substituents at the acyl group in ketenimines 8a-f, which
is predicted to be, from highest to lowest, the following: PH2
> Cl > SH > NH2 > F> OH.
The groups based on the second-row elements (PH2, Cl, SH)
show higher migratory aptitude than those based on first-row
elements (NH2, F, OH), a fact that can be rationalized by taking
into account the values of the C-X bond dissociation energies,
which are smaller for C-P, C-Cl, and C-S than for C-N,
C-F, and C-O, respectively. On the other hand, as these [1,5]-
8132 J. Org. Chem., Vol. 71, No. 21, 2006

Tandem Pseudopericyclic Reactions in Ketenimines
FIGURE 5. B3LYP/6-31+G*-optimized geometries of the stationary
points found in the cyclization of the ketenimine 8e to the 4(3H)-
pyridone 9e.
shifts involve the interaction between a high-lying orbital of
the migrating group and the low-lying LUMO of the ketenimine
(see below), the activation barriers depending on the respective
nucleophilicities and electrophilicities of the reacting centers.
Therefore, as the second-row elements are known to be more
nucleophilic than those of the first-row, this fact serves to
explain why the energy barriers for the migration of the second-
row atoms are lower than those of their first-row isovalent
counterparts.
It is worthy to remark here that Wentrup and others have
systematically studied a number of equilibria between acyl
ketenimines and imidoyl ketenes by sigmatropic [1,3]-rear-
rangements of H and other atoms or groups and established their
pseudopericyclic nature and the relative migratory aptitude of
different groups.20a,21 However, [1,5]-sigmatropic rearrange-
ments in heterocumulenes as such here reported have not been
disclose up to now.
FIGURE 6. B3LYP/6-31+G*-optimized geometries of the stationary
points found in the cyclization of the ketenimine 8f to the 4(3H)-
pyridone 9f.
Path B: Cyclization of Ketenimines 8a-f to the 1,3-
Oxazines 11a-f. Our calculations show that the alternative
mode of cyclization of the ketenimines 8a-f, its 6π-electrocyclic
ring closure leading to 2-methylene-6-substituted-1,3-oxazines
11a-f, takes place via the transition structures TS3a-f (Figure
7). Interestingly, the geometry of all these transition structures
is planar, and the analysis of their imaginary frequencies showed
the nonrotatory nature of these cyclizations. The computed
energy barriers (∆E3) are very low (from 6.35 to 9.62
kcal‚mol-1), and their exothermicities range from 0.22 to 11.85
(21) (a) Koch, R.; Wentrup, C. Org. Biol. Chem. 2004, 2, 195-199. (b)
Nguyen, M. T.; Landuyt, L.; Nguyen, H. M. T. Eur. J. Org. Chem. 1999,
401-407. For similar [1,3]-sigmatropic shifts occurring in other heterocu-
mulenes see: (c) Koch, R.; Wentrup, C. J. Chem. Soc., Perkin Trans. 2
2000, 1846-1850. (d) Ammann, J. R.; Flammang, R.; Wong, M. W.;
Wentrup, C. J. Org. Chem. 2000, 65, 2706. (e) Wong, M. W.; Wentrup, C.
J. Org. Chem. 1994, 59, 5279-5285. (f) Bibas, H.; Wong, M. W.; Wentrup,
C. J. Am. Chem. Soc. 1995, 117, 9582-9583. (g) Finnerty, J.; Andraos, J.;
Yamamoto, Y.; Wong, M. W.; Wentrup, C. J. Am. Chem. Soc. 1998, 120,
1701-1704.
kcal‚mol-1
.
From the reaction profiles in Figures 1 and 4 and the values
of the energy barriers gathered in Table 2, the following
conclusions can be drawn: (i) the 4(3H)-pyridones 9a-f are
predicted to be the thermodynamically controlled products,
J. Org. Chem, Vol. 71, No. 21, 2006 8133

Alajar´ın et al.
the benzene ring of the ketenimines 4. The lack of this benzene
ring does not account for the loss of aromaticity, which is
expected to take place in both the sigmatropic rearrangement
of ketenimines 4 leading to ketenes 6 and the 6π-electrocy-
clization to lead to the benzoxazines 7. Therefore, it is expected
that the corresponding energy barriers for the transfomation of
ketenimines 4 into the quinolin-4(3H)-ones 5 and the benzox-
azine 7 will be higher than those obtained in the computational
study. However, we believe that this fact does not affect
significantly the results of the computational study, as the
penalty for sacrificing the aromaticity would be similar for both
processes.22 But, more notably, the benzoxazines 7 might be
more unstable, on thermodynamic grounds, than the correspond-
ing oxazines 11, and accordingly, the barrier for the conversion
of benzoxazines 7 into the corresponding quinolin-4(3H)-ones
5 would essentially be the barrier between 4 and 6, i.e., that
corresponding to the [1,5]-X shift (note that, due to the retrieval
of aromaticity, the barrier for the conversion of ketenes 6 into
the quinolin-4(3H)-ones 5 it is expected to be lower than that
of ketenes 10 into the 4(3H)-pyridones 9).
Characterization of the Pseudopericyclic Topology of the
Transition States TS1, TS2, and TS3. An added value to the
study of the mechanistic scheme for the two cyclization modes
of the ketenimines 8 is the characterization of the transition states
involved in these transformations as pseudopericyclic or not.
Before elucidating the mechanistic pathways, we already pointed
out that the structure of the ketenimines 8 enables these
processes to show pseudopericyclic characteristics.23
The characterization of a process as pseudopericyclic has been
usually established on the basis of the planar or nearly planar
geometry of the corresponding transition state.23b-f,24 In several
reports, the second-order perturbation interactions25 and the bond
order values of the NLMOs,25f,j from the NBO (natural bond
orbital) analyses, have been used to show the disconnections
in the orbital overlap of the transition states. The ACID method,
by Herges et al.,26 has also proved to be a useful tool in the
discrimination between pericyclic and pseudopericyclic path-
ways,25d,f,27 and recently, the topological analysis of the electron
localization function (ELF) has been proposed with this aim.28
FIGURE 7. B3LYP/6-31+G*-optimized geometries of the transition
structures found in the cyclization of the ketenimines 8a-f to the 1,3-
oxazines 11a-f.
whereas the 1,3-oxazines 11a-f should be the kinetically
controlled ones; (ii) in the cyclization of ketenimines 8a-d
leading to the 4(3H)-pyridones 9a-d, the first step (the [1,5]-
X shift, X ) F, Cl, OH or SH) is rate-limiting; (iii) in the
cyclization of ketenimines 8e,f leading to the 4(3H)-pyridones
9e,f (X ) NH2, PH2), the first step leading to the corresponding
zwitterionic intermediates (INTe,f) is rate-limiting (note that
when X ) NH2, PH2, the 1,5-shift takes place in a two-step
process through the formation of such intermediates). Therefore,
the exclusive formation of quinolin-4(3H)-ones 5 in the experi-
ments described above (modeled by the 4(3H)-pyridones 9 in
the theoretical study) can be rationalized as resulting from the
prevalence of the mechanistic pathway A of Scheme 3 under
thermodynamic control.
(22) The penalty for sacrificing the aromaticity in related [1,5]-shifts in
ketenimines is around 10 kcal‚mol-1; see ref 12.
(23) Pseudopericyclic reactions lack cyclic orbital overlap and have four
characteristics, as stated by Birney: (1) all are allowed, (2) they have
nonaromatic transition states, (3) they may have very low barriers, and (4)
they may have planar transition states. (a) For Lemal’s definition of a
pseudopericyclic process, see: Ross, J. A.; Seiders, R. P.; Lemal, D. M. J.
Am. Chem. Soc. 1976, 98, 4325-4327. For other examples of pseudoperi-
cyclic reactions, see, for example: (b) Birney, D. M.; Wagenseller, P. E. J.
Am. Chem. Soc. 1994, 116, 6262-6270. (c) Birney, D. M. J. Org. Chem.
1994, 59, 2557-2564. (d) Wagenseller, P. E.; Birney, D. M.; Roy, J. Org.
Chem. 1995, 60, 2853-2859. (e) Birney, D. M. J. Org. Chem. 1996, 61,
243-251. (f) Birney, D. M.; Xu, X.; Ham, S. Angew. Chem., Int. Ed. 1999,
38, 189-193. (g) Alajar´ın, M.; Sa´nchez-Andrada, P.; Coss´ıo, F. P.; Arrieta,
A.; Lecea, B. J. Org. Chem. 2001, 66, 8470-8477.
(24) See, for example: (a) Bornemann, H.; Wentrup, C. J. Org. Chem.
2005, 70, 5862-5868. (b) Wei, H.-X.; Zhou, C.; Ham, H.; White, J. M.;
Birney, D. M. Org. Lett. 2004, 6, 4289-4292. (c) Birney, D. M. Org. Lett.
2004, 6, 851-854. (d) Birney, D. M. J. Am. Chem. Soc. 2000, 122, 10917-
10925. (e) Shumway, W.; Ham, S.; Moer, J.; Wittlesey, B. R.; Birney, D.
M. J. Org. Chem. 2000, 65, 7731-7739. (f) Alajar´ın, M.; Vidal, A.;
Sa´nchez-Andrada, P.; Tovar, F.; Ochoa, G. Org. Lett. 2000, 2, 965-968.
(g) Bibas, H. K.; Wentrup, C. J. Org. Chem. 1998, 63, 2619-2626. (h)
Birney, D. M.; Ham, S.; Unruh, G. R. J. Am. Chem. Soc. 1997, 119, 4509-
4517. (i) Luo, L.; Bartberger, M. D.; Dolbier, W. R., Jr. J. Am. Chem. Soc.
1997, 119, 12366-12367. (j) Ham, S.; Birney, D. M. J. Org. Chem. 1996,
61, 3962-3968. (k) Koch, R.; Wong, M. H.; Wentrup, C. J. Org. Chem.
1996, 61, 6809-6813. (l) Wagenseller, P. E.; Birney, D. M.; Roy, D. J.
Org. Chem. 1995, 60, 2853-2859.
A qualitative measuring of the reaction time required for the
total transformation of the 1,3-oxazines 11 into the pyridones
9 can be inferred from the energy barriers gathered in Table 2.
From the addition of ∆E1 and (-∆Erxn11) the order of reaction
times required for the different groups X is predicted to be,
from lowest to highest, the following: Cl < F < SH < NH2 e
OH < PH2.
In the ketenimines 8a-f used in the computational study,
the vinyl group joining the acyl and ketenimine functions models
8134 J. Org. Chem., Vol. 71, No. 21, 2006

Tandem Pseudopericyclic Reactions in Ketenimines
TABLE 2. Energy Barriersa (∆E, kcal‚mol-1) Computed for the Alternative Cyclization Modes of Ketenimines 8a-f Leading to 9a-f and
11a-fb
method
∆E1
∆E2
∆E3
∆Erxn10
∆Erxn9
∆Erxn11
8af9a/11a (X ) F)
HF/6-31G* c
37.30
21.47
15.14
5.20
18.84
9.62
7.40
6.33
-24.17
-20.09
-1.48
-0.22
B3LYP/6-31+G* d
8bf9b/11b (X ) Cl)
HF/6-31G* c
31.25
15.76
16.38
3.50
17.98
9.06
2.11
5.54
-28.23
-21.62
-5.62
-2.49
B3LYP/6-31+G* d
8cf9c/11c (X ) OH)
HF/6-31G* c
35.04
22.90
11.68
2.76
17.75
8.50
12.07
10.23
-27.44
-24.14
-2.77
-2.65
B3LYP/6-31+G* d
8df9d/11d (X ) SH)
HF/6-31G* c
35.17
16.75
13.52
1.51
16.43
7.62
0.70
3.56
-31.01
-25.36
-8.63
-6.03
B3LYP/6-31+G* d
A
B
A
B
method
∆E1
∆E1
∆E2
∆E3
∆Erxn1
∆Erxn1
∆Erxn9
∆Erxn11
8ef9e/11e (X ) NH2)
HF/6-31G* c
29.63
18.09
0.64
6.02
14.59
6.35
14.75
5.77
-6.47
-
-30.41
-27.58
-7.80
-7.09
B3LYP/6-31+G* d
3.45
8ff9f/11f (X ) PH2)
HF/6-31G* c
32.46
14.38
2.78
3.52
17.00
4.12
16.42
6.47
14.16
1.80
-18.59
-4.23
-32.70
-27.44
-14.11
-11.85
B3LYP/6-31+G* d
A
a The energy barriers ∆E1, ∆E3, and ∆E1 have been calculated from the most stable conformer (around the C3-C4 and the C5-C6 single bonds) of
ketenimines 8a-f, as usual. b See Figures 1 and 4 for the notation of the energy barriers. c Energies computed on the fully optimized HF/6-31G* geometries.
The ZPVE corrections, computed at the same level, have been included. The ZPEs were not scaled. d Energies computed on the fully optimized B3LYP/
6-31+G* geometries. The ZPVE corrections, computed at the same level, have been included. The ZPEs were not scaled.
SCHEME 5. Mechanistic Scheme Found at the HF/6-31G*
Theoretical Level for the Cyclization of the Ketenimines 8e,f
to the 4(3H)-Pyridones 9e,fa
SCHEME 6. Mechanistic Scheme Found at the B3LYP/
6-31+G* Theoretical Level for the Cyclization of the
Ketenimine 8e to the 4(3H)-Pyridones 9e
plane, the intersection point being the (3,+1) ring critical point
as defined by Bader.31 Currently, the NICS values at different
points are frequently used to distinguish between pericyclic and
pseudopericyclic transition states.13,25d,f,27b,c,32 The ring current
model and the magnetic criteria, as showed by Coss´ıo et al.,
also allow the distinction among different kinds of aromatic-
ity: σ-, π1-, and π2-aromaticity.30e
a For 8f (X ) PH2), the same mechanistic pathway was found at the
B3LYP/6-31+G* level.
On the basis of the geometries of TS1a-d, TS2a-f, and
TS3a-f and the results of the second-order perturbation
One of the recognized characteristics of the pseudopericyclic
reactions is that they occur through nonaromatic transition states
as the orbital disconnections prevent the aromaticity. Accord-
ingly, the study of the magnetic properties of the transitions
states and their relation with aromaticity is one of the most useful
criteria to distinguish between pericyclic and pseudopericyclic
mechanisms, particularly the analysis of its nuclear independent
chemical shift (NICS) values pioneered by Schleyer et al.,29
who showed that large negative NICS values at the center of
the ring under consideration are associated with aromatic
character, whereas positive NICS values are a convenient
indicator of antiaromaticity. Coss´ıo et al.,30 and afterward some
of us,16,23g,25b have found that the magnetic behavior of aromatic
compounds or transition states can be described by the variation
of the NICS at different points above and below the molecular
(25) (a) Sadavisam, D. V.; Birney, D. M. Org. Lett. 2005, 7, 5817-
5820. (b) Alajar´ın, M.; Sa´nchez-Andrada, P.; Lo´pez-Leonardo, C.; AÄ lvarez,
A. J. Org. Chem. 2005, 70, 7617-7623. (c) Fukushima, K.; Iwahashi, H.
Heterocycles 2005, 65, 2605-2618. (d) Cabaleiro-Lago, E. M.; Rodr´ıguez-
Otero, J.; Gonza´lez-Lo´pez, I.; Pen˜a-Gallego, A.; Hermida-Ramo´n, J. M. J.
Phys. Chem. A 2005, 109, 5636-5644. (e) Zhou, C.; Birney, D. M. J. Org.
Chem. 2004, 69, 86-89. (f) Pen˜a-Gallego, A.; Rodr´ıguez-Otero, J.;
Cabaleiro-Lago, E. M. J. Org. Chem. 2004, 69, 7013-7017. (g) Rodriguez-
Otero, J.; Cabaleiro-Lago, E. M. Chem.-Eur. J. 2003, 9, 1837-1843. (h)
De Lera, A. R.; Coss´ıo, F. P. Angew. Chem., Int. Ed. 2002, 41, 1150-
1152. (i) Zhou, C.; Birney, D. M. J. Am. Chem. Soc. 2002, 124, 5231-
5241. (j) Fabian, W. M. F.; Kappe, C. O.; Bakulev, V. A. J. Org. Chem.
2000, 65, 47-53. (k) Fabian, W. M. F.; Bakulev, V. A.; Kappe, C. O. J.
Org. Chem. 1998, 63, 5801-5805.
(26) (a) Herges, R.; Geuenich, D. J. Phys. Chem. A 2001, 105, 3214-
3220. (b) Herges, R.; Papafilippopoulos, A. Angew. Chem., Int. Ed. 2001,
40, 4671-4674. (c) Kimball, D. B.; Herges, R.; Haley, M. M. J. Am. Chem.
Soc. 2002, 124, 1572-1573.
J. Org. Chem, Vol. 71, No. 21, 2006 8135

Alajar´ın et al.
analyses, showing the delocalization energies of electrons from
filled into empty NBOs, and the study of their magnetic
properties, we have been able to establish the pseudopericyclic
nature of these transition states. The optimized geometries of
TS1a-d, TS2a-f, and TS3a-f at the B3LYP/6-31+G* level
showing the points used to evaluate the NICS values are
depicted in the Figures S1-S3 of the Supporting Information.
Transition Structures TS1a-d. The NBO analysis of these
transition structures shows the new, partially formed σC1-X7
bond resulting mainly from the interaction between a lone pair
of the migrating heteroatom (which changes from a nonbonding
sp2 orbital to a bonding sp3 orbital) and a p orbital of the C1d
N3 system (the LUMO of the ketenimine moiety placed in the
molecular plane) and not from the interaction between the
σC6-X bond and the πC1dN3 system expected for a transition
state of pericyclic nature (see selected interactions from the
second-order perturbation analyses in the Supporting Informa-
tion). The initial sp2 σC6-X bond orbital changes to a
nonbonding sp3 orbital for accommodating a lone pair in the
migrating heteroatom of the final product. From these orbital
disconnections the pseudopericyclic topology of these transition
structures (TS1a-d) can thus be envisaged. These [1,5]-shifts
can be viewed as a swing of a negative group (the migrating
heteroarom) between the two positive termini (C1 and C6).
metric, energetic, and others magnetic criteria.34 We have also
optimized TS1ref and calculated the NICS values along the
z-axis perpendicular to the molecular plane which intersects the
(3,+1) critical point. According to the behavior of the diamag-
netic shielding along this z-axis in TS1ref (see Figure 8A), we
propose to classify the aromaticity of TS1ref as π1-aromaticity,
as there is only one maximum diamagnetic shielding above the
molecular plane, which corresponds to the ring current circulat-
ing on the side where the suprafacial transfer of hydrogen allows
a close proximity between the p atomic orbitals. The plot of
the NICS values versus z for the transition structures TS1a-d
differs notably from that found for TS1ref, and the computed
NICS values at the RCP (NICSRCP) and the maximum NICS
values (NICSmax) of TS1a-d are much lower than those
expected for an aromatic transition state. These results can be
seen in Table 3 and Figure 8A. Consequently, the transition
structures TS1a-d are clearly nonaromatic, confirming their
pseudopericyclic nature.
At this point, it is worth recalling the scarce precedents of
pseudopericyclic [1,5]-shifts that have been reported so
far.23e,24g,24k,25b,e,i,35 Among these processes, there are only a few
examples taking place in heterocumulenes: the degenerated
chlorine24k and hydrogen23e,35 rearrangement of â-(chlorocar-
bonyl)vinyl ketene and â-(formyl)vinyl ketene, respectively, and
the [1,5]-H shift in 1-propenyl ketene.24g The pseudopericyclic
character of these transition states has been established on the
basis of their planar geometries.
Transition Structures TS2a-f. The forming σ-bond C2-
C6 in TS2a-f is mainly due to the interaction between the
πC1-C2 and the π*C6-O12 (the LUMO of the ketene
fragment placed in the molecular plane) natural localized orbitals
(see Supporting Information), 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 of pericyclic
topology. Besides, the p orbital at the ketene oxygen atom
rehybridizes to an sp2 orbital to accommodate a lone pair in
the final product, whereas the new πCdO system results from
the interaction between a lone pair at the oxygen atom and the
p orbital at C6 perpendicular to the molecular plane. Therefore,
there are disconnections in the CdO terminus. Obviously, in
the C5dC6 end no role interchange between nonbonding and
bonding orbitals can take place, explaining the monorotatory
nature of these transition structures as showed by their geom-
etries. Again, the pseudopericyclic topology of these transition
states (TS2a-f) was confirmed by their magnetic properties
(see Table 3 and Figure 8B). We selected as the aromatic model
for a pericyclic 6π-electrocyclization the transition state cor-
responding to the cyclization of cis-1,3,5-hexatriene to 1,3-
cyclohexadiene, TS2ref. The shape of the plot curve (NICS
versus z) for TS2ref, whose aromaticity was defined by Coss´ıo
et al. as the prototype of π1-aromaticity,30e differs substantially
of those obtained for TS2a-f (Figure 8B). Also, the low
NICSRCP and NICSmax values clearly indicate the nonaromaticity
of these transition states and point to its pseudopericyclic nature.
We will now deal with the magnetic properties of the
transition states TS1a-d. To our knowledge, there are no
precedents on the characterization as pseudopericyclic of [1,5]-
shifts on the basis of the magnetic behavior of the corresponding
transition states. With the aim of comparing the magnetic
properties of TS1a-d with an adequate model of pericyclic
[1,5]-shift, we have selected the transition state TS1ref corre-
sponding to the [1,5]-H shift in (Z)-1,3-pentadiene. Schleyer
and Jiao, in their seminal publication in which they showed
magnetic evidence of the aromaticity of pericyclic transition
structures,33 demonstrated that the NICS value (-16.6 ppm) at
the geometrical center of that transition state agrees with their
high aromaticity, previously established on the basis of geo-
(27) (a) Kimball, D. M.; Weakley, T. J. R.; Herges, R.; Haley, M. M. J.
Am. Chem. Soc. 2002, 124, 13463-13473. (b) Cabaleiro-Lago E. M.;
Rodr´ıguez-Otero, J.; Garc´ıa-Lo´pez, R. M.; Pen˜a-Gallego, A.; Hermida-
Ramo´n, J. M. Chem.- Eur. J. 2005, 11, 5966-5974. (c) 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, 3921-3928. (d) Pen˜a-
Gallego, A.; Rodr´ıguez-Otero, J.; Cabaleiro-Lago, E. M. Eur. J. Org. Chem.
2005, 3228-3232.
(28) (a) Chamorro, E. E.; Notario, R. J. Phys. Chem. A 2004, 108, 4099-
4104. (b) Ca´rdenas, C.; Chamorro, E.; Notario, R. J. Phys. Chem. A 2005,
109, 4352-4358. (c) Matito, E.; Sola, M.; Duran, M.; Poater, J. J. Phys.
Chem. B 2005, 109, 7591-7593. (d) Rode, J. E.; Dobrowolski, J. Cz. J.
Phys. Chem. A 2006, 110, 207-218.
(29) (a) Schleyer, P. v. R.; Maerker, C.; Dransfeld, A.; Jiao, H.; Hommes,
N. J. R. v. E. J. Am. Chem. Soc. 1996, 118, 6317-6318. (b) Schleyer, P.
v. R.; Jiao, H.; Hommes, N. J. R. v. E.; Malkin, V. G.; Malkina, O. L. J.
Am. Chem. Soc. 1997, 119, 12669-12670. (c) Schleyer, P. v. R.; Manoharn,
M.; Wang, Z.-X.; Kiran, B.; Jiao, H.; Puchta, R.; Hommes, N. J. R. v. E.
Org. Lett. 2001, 3, 2465-2468. (d) See also Fallah-Bagher-Shaidaei, H.;
Wannere, C. S.; Corminboeuf, C.; Puchta, R.; Schleyer, P. v. R. Org. Lett.
2005, 7, 863-866 and references herein.
(32) See, for example: (a) Montero-Campillo, M. M.; Rodr´ıguez-Otero,
J.; Cabaleiro-Lago, E. M. J. Phys. Chem. A 2004, 108, 8373-8377. (b)
Zora, M. J. Org. Chem. 2004, 69, 1940-1947. (c) Coss´ıo, F. P.; Alonso,
C.; Lecea, B.; Ayerbe, M.; Rubiales, G.; Palacios, F. J. Org. Chem. 2006,
71, 2839-2847.
(33) Jiao, H.; Schleyer, P. v. R. J. Chem. Soc., Faraday Trans. 1994,
90, 1559-1567.
(34) Jiao, H.; Schleyer, P. v. R. J. Phys. Chem. 1998, 11, 655-662.
(35) Reva, I.; Breda, S.; Roseiro, T.; Eusebio, E.; Fausto, R. J. Org.
Chem. 2005, 70, 7701-7710.
(30) (a) Morao, I.; Lecea, B.; Coss´ıo, F. P. J. Org. Chem. 1997, 62,
7033-7036. (b) Morao, I.; Coss´ıo, F. P. J. Org. Chem. 1999, 64, 1868-
1874. (c) Coss´ıo, F. P.; Morao, I.; Jiao, H.; Scheleyer, P. v. R. J. Am. Chem.
Soc. 1999, 121, 6737-6746. (d) Vivanco, S.; Lecea, B.; Arrieta, A.; Prieto,
P.; Morao, I.; Linden, A.; Coss´ıo, F. P. J. Am. Chem. Soc. 2000, 122, 6078-
6092. (e) de Lera, A. R.; Alvarez, R.; Lecea, B.; Torrado, A.; Coss´ıo, F. P.
Angew. Chem., Int. Ed. 2001, 40, 557-561.
(31) Bader, R. F. W. Atoms in MoleculessA Quantum Theory; Clarendon
Press: Oxford, 1990; pp 13-52.
8136 J. Org. Chem., Vol. 71, No. 21, 2006

Tandem Pseudopericyclic Reactions in Ketenimines
TABLE 3. NICS Values Computed at the Ring Critical Point of
the Electron Density (NICSRCP) and Maximuma NICS Values along
the z Axis (NICSMax) in ppm‚mol-1 in TS1a-d, TS2a-f, and
TS3a-f Calculated at the GIAO-B3LYP/6-31+G*//B3LYP/6-31+G*
Theoretical Level
transition structure
NICSRCP
NICSmax
TS1a (X ) F)
TS1b (X ) Cl)
TS1c (X ) OH)
TS1d (X ) SH)
TS1refb
TS2a (X ) F)
TS2b (X ) Cl)
TS2c (X ) OH)
TS2d (X ) SH)
TS2ec (X ) NH2)
TS2f (X ) PH2)
TS2refd
TS3a (X ) F)
TS3b (X ) Cl)
TS3c (X ) OH)
TS3d (X ) SH)
TS3e(X ) NH2)
TS3f (X ) PH2)
-1.36 at 0.00 Å
-3.24 at 0.00 Å
+0.28 at 0.05 Å
-0.13at -0.11 Å
-14.48 at -0.16 Å
-3.01 at 0.07 Å
-2.86 at 0.12 Å
-3.21 at 0.08 Å
-3.20 at 0.13 Å
-2.17 at 0.12 Å
-2.83 at 0.14 Å
-14.92 at -0.09 Å
+0.75 at 0.00 Å
+1.73 at 0.00 Å
+0.84 at -0.03 Å
+1.85 at -0.02 Å
+0.82 at -0.04 Å
+2.46 at 0.04 Å
-1.36 at 0.00 Å
-3.24 at 0.00 Å
+0.40 at -0.45 Å
-0.84 at -0.86 Å
-16.27 at -0.41 Å
-3.87 at -0.43 Å
-4.82 at -0.63 Å
-3.57 at -0.41 Å
-4.71 at -0.62 Å
-3.25 at -0.63 Å
-5.50 at -0.61 Å
-16.32 at -0.34 Å
+0.87 at ( 0.5 Å
+1.84 at -0.24 Å
+1.29 at 0.47 Å
+2.34 at 0.23 Å
+1.38 at 0.46 Å
+3.11 at -0.21 Å
a Maximum NICS value by considering absolute values. b Transition state
corresponding to the [1,5]-H shift in 1,3-pentadiene. c NICS values computed
at the B3LYP/6-31+G* level in TS2e optimized at the HF/6-31G* level.
d Transition state corresponding to the 6π-electrocyclic ring closure of 1,3,5-
hexatriene leading to 1,3-cyclohexadiene.
interacts with the terminal CdC bond without disturbing so
much the planarity of the transition state. On the basis of these
geometries and the NICS values computed at the center of the
forming rings, Zora established the pseudopericyclic nature of
the cyclization of dienyl ketenes, although, recently, this
assumption has provoked some controversy.27c Another related
cyclization, that of o-vinylphenylisocyanate to quinolin-2(1H)-
one, occurring via a monorotatory transition state, has been
qualified by Dolbier as pseudopericyclic.24i
Transition Structures TS3a-f. The NBO analyses show that
in these transition structures the new partially formed σC1-
O12 bond results mainly from the interaction between a lone
pair of the carbonylic oxygen atom (which changes from a
nonbonding sp2 orbital to a bonding sp3 orbital) and a p orbital
of the C1dN3 system, and not from the interaction between
the πC6-O12 and the πC1dN3 systems expected for a
transition state of pericyclic nature (see selected interactions
from the second-order perturbation analyses in the Supporting
Information). From the geometries of these transition structures
and the NBO analyses, it can be inferred that the lone pair at
the nitrogen atom N3 is changing from a nonbonding sp2 orbital
to a p orbital for forming part of the new πN3dC4 system,
whereas the initial p orbital at the N3 atom changes to an sp2
orbital accommodating the lone pair in the final oxazine. In the
C6-O12 terminus, the initial p orbital at the carbonylic oxygen
atom rehibridizes to an sp3 orbital for accommodating a lone
pair in the final oxazine. The nonaromaticity of these structures
was confirmed by the low absolute values of the NICS along
the z axis, which are depicted in Figure 8C, along with those
corresponding to the transition structure TS2ref for comparison.
FIGURE 8. Plot of the calculated NICS values versus z for (A)
transition structures TS1a-d and TS1ref, (B) transition structures
TS2a-f and TS2ref, and (C) transition structures TS3a-f and again,
for comparative purposes, TS2ref. The NICS values have been obtained
at the GIAO-B3LYP/6-31+G*//B3LYP/6-31+G* level.
Closely related to these ring closures are the electrocycliza-
tions of dienyl ketenes to 2,4-cyclohexadienones, which have
been the subject of theoretical studies by Zora,32b,36 showing
that the corresponding transition structures adopt slightly
nonplanar conformations, in contrast to the boatlike conforma-
tion found for TS2ref. Those different geometries were ascribed
to the fact that the LUMO orbital of the ketene moiety easily
There are several reports dealing with pseudopericyclic
electrocyclizations closely related to the cyclization of keten-
imines 8 to the 1,3-oxazines 11,16,23g,24a,27b where the pseudo-
pericyclic nature of these processes was established on the basis
of the planar geometries of the corresponding transition states
or their magnetic properties.
(36) Zora, M.; Sahpaz, F.; Ozarslan, E. J. Mol. Structure (THEOCHEM)
2002, 589-590, 111-112.
J. Org. Chem, Vol. 71, No. 21, 2006 8137

Alajar´ın et al.
fully optimized by analytical gradient techniques. Harmonic
frequency calculations at each level of theory verified the identity
of each stationary point as a minimum or a transition state and
were used to provide an estimation of the zero-point vibrational
energies (ZPVE), which were not scaled. IRC calculations were
carried out in order to determine what minima each transition
structure connects. Second-order perturbation analyses were achieved
with the NBO (natural bond orbital) method.41 NICS values were
obtained at the B3LYP/6-31+G* level with the GIAO (gauge-
independent atomic orbital) method.42
Preparation of 2-Arylselenoquinolin-4(3H)-ones 5m-o. To a
solution of the corresponding Se-aryl 2-azidoselenobenzoate 2 (1
mmol) in anhydrous toluene (15 mL) was added triphenylphosphine
(0.26 g, 1 mmol), and the reaction mixture was stirred at room
temperature for 4 h. Next, a solution of diphenylketene (0.19 g, 1
mmol) or methylphenylketene (0.13 g, 1 mmol) in anhydrous
toluene (2 mL) was added. The new reaction mixture was first
stirred at room temperature for 15 min and then at reflux
temperature for 1 h. After cooling, the solvent was removed under
reduced pressure. The resulting material was chromatographed on
silica gel using hexanes/diethyl ether (7:3, v/v) as eluent.
Conclusions
In this study a peculiar tandem sequence of two pseudoperi-
cyclic events, [1,5]-X sigmatropic shift and further 6π-electro-
cyclic ring closure, has been unraveled both on experimental
and theoretical bases. Different X groups have been analyzed
when supported on a N-[2-(X-carbonyl)phenyl ketenimine
fragment. The relative migratory aptitude of such groups in the
sigmatropic step has been determined experimentally as being
RSe ≈ RS . R2N ≈ ArO. The migrating aptitudes of the
different X groups at the acyl substituent in the N-(2-X-
carbonyl)vinyl ketenimines considered in the theoretical study
is predicted to be PH2 > Cl > SH > NH2 > F > OH. The first
step of the transformation of the N-(2-X-carbonyl)vinyl keten-
imines into the final 2-X-4(3H)-pyridones, the sigmatropic shift,
is always rate-determining and may occur either in a concerted
or stepwise manner (via zwitterionic intermediates), depending
on the nature of the migrating group X. A pseudopericyclic
topology have been found for the transition states of some of
the [1,5]-X migration (X ) F, Cl, OH, SH), and those
corresponding to the second step, the 6π-electrocyclization of
the ketene intermediates to the pyridones. An alternative
cyclization mode of these ketenimines, the formation of 1,3-
oxazines via an initial 6π-electrocyclic ring closure, has been
also considered and calculated to be of pseudopericyclic nature.
The marked modal selectivity of the whole system found in
the experiments (exclusive formation of quinolin-4(3H)-ones
versus benzoxazines) could be rationalized on the basis of the
calculated energy barriers for the individual steps.
Some of the 2-arylselenoquinolin-4(3H)-ones 5 prepared could
not be obtained as crystalline solids. For these compounds, after
removing the chromatographic solvents under reduced pressure, the
resulting solids were triturated, dried at 50 °C under high vacuum
for 24 h, and used as such for characterization.
3,3-Diphenyl-2-phenylselenoquinolin-4(3H)-one 5m: yield 62%;
mp 182-184 °C (yellow prisms, Et2O); IR (Nujol) 1683 (vs), 1599
(w), 1580 (s), 1561 (vs), 1285 (m), 1154 (w), 1119 (w), 1068 (w),
891 (w), 777 (w), 767 (m), 751 (m), 700 (s), 657 (m), 633 (s) cm-1
;
1H NMR (CDCl3, 300 MHz) δ 7.17-7.20 (m, 2 H), 7.35 (s, 10
H), 7.40-7.43 (m, 3 H), 7.49 (td, 1 H, J ) 7.6, 1.4 Hz), 7.64-
7.67 (m, 2 H), 7.77 (dd, 1 H, J ) 7.9, 1.5 Hz); 13C NMR (CDCl3,
75 MHz) δ 72.1 (s), 121.8 (s), 126.5, 127.4, 127.7, 128.6, 128.7,
128.8, 129.0, 130.4, 135.8, 136.3, 137.5 (s), 146.2 (s), 178.9 (s),
197.1 (s); MS (EI, 70 eV) m/z (rel int) 453 (M+ for 80Se, 12), 451
(M+ for 78Se, 6), 296 (100). Anal. Calcd for C27H19NOSe
(452.41): C, 71.68; H, 4.23; N, 3.10. Found: C, 71.57; H, 4.24;
N, 3.01.
Experimental Section
Computational Methods. All calculations were carried out with
the Gaussian9837 and Gaussian0338 suite of programs. An intensive
characterization of the potential energy surface was done at the
HF/6-31G*39 theoretical level and then with the B3LYP40 functional
using the 6-31+G* basis set. All the reported stationary points were
Preparation of 2-Aryloxyquinolin-4(3H)-ones 5p-s and 2-Ami-
noquinolin-4(3H)-ones 5t-v. A solution of the corresponding
2-(triphenylphosphoranylideneamino)benzoate 3 (1 mmol) or the
2-(triphenylphosphoranylideneamino)benzamide 3 (1 mmol) in
anhydrous dichloromethane (5 mL) was introduced in a glass tube,
and a solution of diphenylketene (0.19 g, 1 mmol) or methylphe-
nylketene (0.13 g, 1 mmol) in the same solvent (2 mL) was added.
After stirring at room temperature for 15 min the solvent was
removed to dryness under reduced pressure. The glass tube was
sealed and the mixture containing the corresponding ketenimine 4
and triphenylphosphine oxide was heated at 230 °C for 1 h. After
cooling at room temperature, the crude mixture was dissolved in
dichloromethane (20 mL) and transferred to a round-bottom flask.
Finally, the solvent was removed under reduced pressure and the
resulting material was chromatographed on a silica gel column using
hexanes/diethyl ether as eluent.
(37) 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.; Baboul, A. G.; 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.; Replogle, E. S.; Pople, J. A. Gaussian
98, Revision A.9; Gaussian, Inc.: Pittsburgh, PA, 1998.
(38) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A.; Vreven, T.; Kudin, K. N.;
Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li,
X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Adamo, C.; Jaramillo, J.;
Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.;
Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels,
A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.;
Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.;
Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.: Piskorz,
P.; Komaromi, L.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Challacombe, M. P.; Gill, M. W.; Johnson,
B. G.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03,
Revision B.03; Gaussian, Inc.: Pittsburgh, PA, 2003.
Some of the 2-aryloxyquinolin-4(3H)-ones and 2-aminoquinolin-
4(3H)-ones 5 prepared could not be obtained as crystalline solids.
(40) (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,
12974-12980. (d) Ziegler, T. Chem. ReV. 1991, 91, 651-667.
(41) (a) Redd, A. E.; Weinstock, R. B.; Weinhold, F. J. Chem. Phys.
1985, 83, 735-746. (b) Reed, A. E.; Curtiss, L. A.; Weinhold, F. Chem.
ReV. 1988, 88, 899-926. (c) Reed, A. E.; Schleyer, P. v. R. J. Am. Chem.
Soc. 1990, 112, 1434-1445.
(39) Hehre, W. J.; Radom, L.; Schleyer, P. v. R.; Pople, J. A. In Ab
Initio Molecular Orbital Theory; Wiley: New York, 1986, pp 71-82, and
references therein.
(42) Wolinski, K.; Hilton, J. F.; Pulay, P. J. Am. Chem. Soc. 1990, 112,
8251-8260.
8138 J. Org. Chem., Vol. 71, No. 21, 2006

Tandem Pseudopericyclic Reactions in Ketenimines
For these compounds, after removing the chromatographic solvents
under reduced pressure, the resulting solids were triturated, dried
at 50 °C under high vacuum for 24 h, and used as such for
characterization.
128.7, 129.2, 136.3, 137.4 (s), 151.4 (s), 166.3 (s), 196.9 (s); MS
(EI, 70 eV) m/z (rel int) 340 (M+, 100). Anal. Calcd for C23H20N2O
(340.42): C, 81.15; H, 5.92; N, 8.23. Found: C, 81.01; H, 5.77;
N, 8.34.
2-(4-Methylphenyloxy)-3,3-diphenylquinolin-4(3H)-one 5p:
column chromatography, hexanes/diethyl ether (4:1, v/v); yield
42%; mp 201-202 °C (yellow prisms, Et2O); IR (Nujol) 1682 (vs),
1641 (vs), 1598 (vs), 1504 (vs), 1268 (vs), 1244 (vs), 1197 (vs),
Acknowledgment. We are grateful to the “Ministerio de
Educacio´n y Ciencia” of Spain and FEDER (Project CTQ2005-
02323/BQU) and the “Fundacio´n Se´neca-CARM” (Project PI-
1/00749/FS/01) for funding. M.-M.O. thanks Fundacio´n Caja-
murcia for a fellowship.
1
1013 (m), 861 (w), 761 (s), 702 (s) cm-1; H NMR (CDCl3, 300
MHz) δ 2.32 (s, 3 H), 6.93 (d, 2 H, J ) 8.3 Hz), 7.13 (d, 2 H, J
) 8.3 Hz), 7.21 (t, 1 H, J ) 7.4 Hz), 7.26 (d, 1 H, J ) 8.1 Hz),
7.30-7.36 (m, 10 H), 7.52 (td, 1 H, J ) 8.1, 1.5 Hz), 7.95 (d, 1 H,
J ) 7.7 Hz); 13C NMR (CDCl3, 75 MHz) δ 20.9, 67.1 (s), 121.4,
122.1 (s), 126.5, 127.3, 127.5, 128.0, 128.5, 129.6, 129.7, 135.0
(s), 136.2, 138.9 (s), 146.6 (s), 150.2 (s), 168.5 (s), 196.7 (s); MS
(EI, 70 eV) m/z (rel int) 403 (M+, 25), 77 (100). Anal. Calcd for
C28H21NO2 (403.48): C, 83.35; H, 5.25; N, 3.47. Found: C, 83.18;
H, 5.27; N, 3.32.
Supporting Information Available: Experimental details for
the synthesis of compounds 2k-q, 3k-q, and 4a and their
characterization (NMR, IR, MS, elemental analyses); spectroscopic
data for compounds 5n-o, 5q-s, and 5u,v; Table S1, including
the chief electronic and energetic features for all stationary points
discussed in the text; Cartesian coordinates of local minima and
transition structures discussed in the text; Table S2, including
selected interaction from the second-order perturbation theory
analysis of TS1a-d, TS2a-f, and TS3a-f; Figures S1-S3,
showing the B3LYP/6-31+G*-optimized geometries of TS1a-d,
TS1ref, TS2a-f, TS2ref, and TS3a-f and the points used to
evaluate the NICS. This material is available free of charge via the
Internet at http://pubs.acs.org.
2-(N,N-Dimethyl)amino-3,3-diphenylquinolin-4(3H)-one 5t:
column chromatography, hexanes/diethyl ether (2:3, v/v); yield
36%; mp 242-244 °C (yellow prisms, Et2O); IR (Nujol) 1670 (s),
1599 (m), 1544 (vs), 1492 (m), 1393 (s), 1292 (m), 1269 (m), 1217
(w), 1177 (m), 1142 (m), 999 (w), 871 (w), 763 (m), 742 (w), 696
1
(m) cm-1; H NMR (CDCl3, 400 MHz) δ 2.80 (s, 6 H), 6.90 (t, 1
H, J ) 7.4 Hz), 7.23-7.25 (m, 1 H), 7.27-7.35 (m, 6 H), 7.43-
7.47 (m, 5 H), 7.67 (dd, 1 H, J ) 7.8, 1.3 Hz); 13C NMR (CDCl3,
100 MHz) δ 40.0, 66.1 (s), 118.6 (s), 122.6, 125.9, 127.2, 127.8,
JO061286E
J. Org. Chem, Vol. 71, No. 21, 2006 8139