Tandem 1,5-hydride shift/1,5-S,N-cyclization with ethylene extrusion of 1,3-oxathiolane-substituted ketenimines and carbodiimides. An experimental and computational study

Article abstract of DOI:10.1021/jo100502p

Figure presented Under thermal activation in solution, N-[2-(1,3- oxathiolan-2-yl)]phenyl ketenimines and carbodiimides were converted into 2,1-benzisothiazol-3-ones bearing a pendant N-styryl or imidoyl fragment, respectively. These processes should occur with the concomitant formation of ethylene as result of the fragmentation of the 1,3-oxathiolane ring. The conversions of ketenimines took place under softer thermal conditions, toluene 110 °C, than those of carbodiimides, o-xylene 160 °C. A computational DFT study unveiled the mechanistic course of these transformations, rare tandem processes consisting of an initial 1,5-hydride shift of the acetalic hydrogen atom to the central carbon atom of the heterocumulene function leading to the respective o-azaxylylene. This transient intermediate then converts, in a single step, into ethylene and the experimentally isolated benzisothiazolone. This latter stage of the mechanism is rather peculiar, combining a 1,5-cyclization by S-N bond formation, aromaticity recovery at the benzene nucleus, and the fragmentation of the oxathiolane framework originating a new carbonyl group. It can be related with a vinylogous retro-ene reaction and shows pseudopericyclic characteristics. The computations also revealed that the alternative 6π electrocyclization of the transient o-azaxylylenes cannot compete, on kinetic and thermodynamic grounds, with the experimentally observed reaction channel. The two alternative reaction paths of a number of ketenimines and carbodiimides were computationally scrutinized, the results being in accord with the experimental outcomes. In addition, sulfur extrusion from the benzisothiazolones by the action of triphenylphosphine under two different reaction conditions led to three different types of heterocyclic products, 4(3H)-quinolones, quinolino[2,1-b]quinazolin-5,12-diones, and dibenzo[b,f][1,5]diazocin-6,12- diones, whose formation is explained by the initial formation of an intermediate imidoylketene. This reactive species could be trapped by a nucleophilic solvent, ethanol.

Full text of DOI:10.1021/jo100502p

pubs.acs.org/joc
Tandem 1,5-Hydride Shift/1,5-S,N-Cyclization with Ethylene Extrusion
of 1,3-Oxathiolane-Substituted Ketenimines and Carbodiimides.
An Experimental and Computational Study†
Mateo Alajarin,* Baltasar Bonillo, Pilar Sanchez-Andrada, and Angel Vidal
Departamento de Quimica Organica, Facultad de Quimica, Universidad de Murcia, Campus de
Espinardo, 30100 Murcia, Spain
alajarin@um.es
Received March 17, 2010
Under thermal activation in solution, N-[2-(1,3-oxathiolan-2-yl)]phenyl ketenimines and carbodi-
imides were converted into 2,1-benzisothiazol-3-ones bearing a pendant N-styryl or imidoyl fragment,
respectively. These processes should occur with the concomitant formation of ethylene as result of the
fragmentation of the 1,3-oxathiolane ring. The conversions of ketenimines took place under softer
thermal conditions, toluene 110 °C, than those of carbodiimides, o-xylene 160 °C. A computational
DFT study unveiled the mechanistic course of these transformations, rare tandem processes consisting
of an initial 1,5-hydride shift of the acetalic hydrogen atom to the central carbon atom of the
heterocumulene function leading to the respective o-azaxylylene. This transient intermediate then
converts, in a single step, into ethylene and the experimentally isolated benzisothiazolone. This latter
stage of the mechanism is rather peculiar, combining a 1,5-cyclization by S-N bond formation,
aromaticity recovery at the benzene nucleus, and the fragmentation of the oxathiolane framework
originating a new carbonyl group. It can be related with a vinylogous retro-ene reaction and shows
pseudopericyclic characteristics. The computations also revealed that the alternative 6π electrocycliza-
tion of the transient o-azaxylylenes cannot compete, on kinetic and thermodynamic grounds, with the
experimentally observed reaction channel. The two alternative reaction paths of a number of
ketenimines and carbodiimides were computationally scrutinized, the results being in accord with
the experimental outcomes. In addition, sulfur extrusion from the benzisothiazolones by the action of
triphenylphosphine under two different reaction conditions led to three different types of heterocyclic
products, 4(3H)-quinolones, quinolino[2,1-b]quinazolin-5,12-diones, and dibenzo[b,f ][1,5]diazocin-
6,12-diones, whose formation is explained by the initial formation of an intermediate imidoylketene.
This reactive species could be trapped by a nucleophilic solvent, ethanol.
Introduction
In the course of investigations directedtowardthefindingofnew
compounds that may act as potential hydrogen storage materi-
als, several covalent organic molecules have emerged as new
organic hydrides, among them 1,3-dinitrogenated heterocyclic
Compounds typically classified as possessing hydricity
(hydride donor ability) are predominantly metal hydrides,
structural analogues of NADH and triarylmethane derivatives.1
(1) Ellis, W. W.; Raebiger, J. W.; Curtis, C. J.; Bruno, J. W.; DuBois,
D. L. J. Am. Chem. Soc. 2004, 126, 2738–2743.
† In memory of Prof. Jose M. Concellon, who recently passed away.
DOI: 10.1021/jo100502p
r
Published on Web 05/12/2010
J. Org. Chem. 2010, 75, 3737–3750 3737
2010 American Chemical Society

Alajarin et al.
JOCArticle
SCHEME 1. Reaction Path Converting Ketenimines and Car-
bodiimides 1 into Quinolines and Quinazolines 3
character of the 2-monosubstituted 1,3-dioxolane and 1,3-
dithiolane functions. Additionally, the experimental work
and the computational calculations showed that the 1,3-dioxo-
lane fragment activated more efficiently such [1,5]-H shifts
than the thioanalogous 1,3-dithiolane functions.7
We also tested similar reactions involving carbodiimide
functions as the termini of these hydride migrations. The cycliza-
tion of 1,3-dioxolane-carbodiimides 1 (X = O; Y = NAr) to
spiroquinazolines 3 (X = O; Y = NAr), by a similar tandem
process, required stronger reaction conditions than the analo-
gous dioxolane-ketenimines. Furthermore, the 1,3-dithiolane-
carbodiimides 1 (X = S; Y = NAr) were less reactive and
could not be transformed into the putative spiroquinazolines 3
(X=S; Y=NAr) under a variety of thermal conditions.7
A logical next step of these investigations was to test the
ability of 1,3-oxathiolane functions, another class of acetalic
rings, to promote similar cyclizations. Herein we report our
results on the thermal treatment of N-[2-(1,3-oxathiolan-2-yl)]-
phenyl ketenimines and N-[2-(1,3-oxathiolan-2-yl)]phenyl-N0-
aryl carbodiimides, which unexpectedly converted these hetero-
cumulenes into 2,1-benzisothiazol-3-ones.8 A computational
DFT study will show that these transformations seem to occur
via a formal [1,5]-H shift/1,5 electrocyclization/[3 þ 2] cyclo-
reversion tandem process, with the concomitant formation of
ethylene. We here also disclose that sulfur extrusion from some
of the so obtained 2,1-benzisothiazol-3-ones yields three types
of heterocyclic products by the action of triphenylphosphine
under two different reaction conditions.
systems such as N,N-dimethylbenzimidazoles,2 2-benzoyl-
N,N-dimethylperhydropyrimidine,3 and orthoformamides.4
However, no structurally related compounds bearing two
oxygen or two sulfur atoms in relative 1,3 positions have
been included into the class of compounds having hydricity.
Exceptionally, the cationic polymerization of cyclic acetals
has been proposed to be initiated by the transfer of a hydride
from the acetalic carbon atom to the cationic initiator.5
While exploring new reactions of ketenimines,6 we have
recently found that N-[2-(1,3-dioxolan-2-yl)phenyl] ketenimines
1 (X = O; Y = CR2R3) and N-[2-(1,3-dithiolan-2-yl)phenyl]
ketenimines 1 (X = S; Y = CR2R3), under thermal conditions,
converted into spiroquinolines 3 (X = O, S; Y = CR2R3) by
a tandem [1,5]-H migration/6π electrocyclic ring closure
(6π-ERC) sequence involving the transient o-azaxylylenes
2 (Scheme 1).7 The [1,5]-H shifts leading from acetal-
(dithioacetal) ketenimines 1 to the intermediate azaxylylenes
2 were characterized as intramolecular hydride transfers from
the acetalic functions to the electrophilic central carbon atom
of the ketenimine moieties, on the basis of the weakening and
polarization of the acetalic C-H bond by hyperconjugative
interaction of its σ*(C-H) orbital with the lone-pair electrons
at the vicinal heteroatoms of the acetalic function. This
assumption was confirmed by means of a computational
DFT study, which also accounted for the modest activation
energies of these hydride shifts, considerably lower than similar
processes in the absence of the activating acetalic units.
Thus, these results first demonstrated the hydricity-imparting
Results and Discussion
The reaction of 2-azidobenzaldehydes 4 with 2-mercapto-
ethanol in the presence of p-toluenesulfonic acid as catalyst,
in refluxing benzene, yielded the 2-(2-azidophenyl)-1,3-oxathio-
lanes 5 in good yields (86-99%). The Staudinger imination of
triphenylphosphine with the azides 5, in anhydrous diethyl ether
at room temperature, provided the iminophosphoranes 6
(67-95%). The aza-Wittig reaction of compounds 6 with
diphenylketene or methylphenylketene, in anhydrous toluene
at room temperature, generated smoothly the N-[2-(1,3-ox-
athiolan-2-yl)]phenyl ketenimines 7, which were used in the
following step without further purification. After the toluene
solutions containing ketenimines 7 were heated under reflux for
a few hours, the 1-(β-styryl)-2,1-benzisothiazol-3-ones 8 were
isolated from the crude reaction mixture in fair to good yields
(Scheme 2, Table 1), instead of the quinolines 9 which could be
presumably expected as resulting from a [1,5]-H/6πelectrocyclic
ring-closure tandem process.
The structural determination of 1-(β-styryl)-2,1-benzi-
sothiazol-3-ones 8 was achieved following their analytical
and spectral data and confirmed by X-ray diffraction of a
monocrystal of compound 8a (R1 = R2 = H; R3=Ph).9
Benzisothiazolone 8e (R1=R2= H; R3=CH3) was isolated
as a mixture of E/Z isomers, in a relative ratio close to 4:1. Both
diastereoisomers E-8e and Z-8e could be separated by column
chromatography, and their configurations were elucidated by
means of NOESY experiments.
(2) (a) Schwarz, D. E.; Cameron, T. M.; Hay, P. J.; Scott, B. L.; Tumas,
W.; Thorn, D. L. Chem. Commun. 2005, 5919–5921. (b) Lee, I.-S. H.; Jeoung,
E. H. J. Org. Chem. 1998, 63, 7275–7279. (c) Montgrain, F.; Ramos, S. M.;
Wuest, J. D. J. Org. Chem. 1988, 53, 1489–1492.
(3) Zhang, X.-M.; Bruno, J. W.; Enyinnaya, E. J. Org. Chem. 1998, 63,
4671–4678.
(4) Brunet, P.; Wuest, J. D. J. Org. Chem. 1996, 61, 2020–2026 and
references cited therein.
(5) Penczek, S. Makromol. Chem. 1974, 175, 1217–1252 and references
cited therein.
(6) For some of our previous works on ketenimines, see: (a) Alajarin, M.;
Bonillo, B.; Marin-Luna, M.; Vidal, A.; Orenes, R.-A. J. Org. Chem. 2009,
74, 3558–3561. (b) Alajarin, M.; Bonillo, B.; Vidal, A.; Bautista, D. J. Org.
Chem. 2008, 73, 291–294. (c) Alajarin, M.; Bonillo, B.; Sanchez-Andrada, P.;
Vidal, A.; Bautista, D. J. Org. Chem. 2007, 72, 5863–5866. (d) Alajarin, M.;
Ortin, M.-M.; Sanchez-Andrada, P.; Vidal, A. J. Org. Chem. 2006, 71, 8126–
8139. (e) Alajarin, M.; Ortin, M.-M.; Sanchez-Andrada, P.; Vidal, A.;
Bautista, D. Org. Lett. 2005, 7, 5281–5284. (f) Alajarin, M.; Vidal, A.; Ortin,
M.-M. Tetrahedron 2005, 61, 7613–7621. (g) Alajarin, M.; Vidal, A.; Ortin,
M.-M. Org. Biomol. Chem. 2003, 1, 4282–4292. (h) Alajarin, M.; Vidal, A.;
Tovar, F.; Conesa, C. Tetrahedron Lett. 1999, 40, 6127–6130. (i) Alajarin,
M.; Molina., P.; Vidal, A. Tetrahedron Lett. 1996, 37, 8945–8948.
(7) Alajarin, M.; Bonillo, B.; Ortin, M.-M.; Sanchez-Andrada, P.; Vidal,
A. Org. Lett. 2006, 8, 5645–5648.
Following these initial experiments with ketenimines, we tested
similar conversions involving the 1,3-oxathiolane-carbodiimides
(8) For a preliminary communication, see: Alajarin, M.; Bonillo, B.;
Sanchez-Andrada, P.; Vidal, A.; Bautista, D. Org. Let. 2009, 11, 1365–1368.
(9) For the X-ray structure of compound 8a see ref 8.
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SCHEME 2. Preparation of 2,1-Benzisothiazol-3-ones 8
SCHEME 3. Preparation of 2,1-Benzisothiazol-3-ones 11
SCHEME 4. Mechanistic Proposal for the Conversions 7 f 8
and 10 f 11
TABLE 1. 1-(β-Styryl)-2,1-benzisothiazol-3-ones 8
compd
R1
R2
R3
yield (%)
8a
8b
8c
8d
8e
H
CH3
H
H
H
H
H
Cl
CH3
H
Ph
Ph
Ph
Ph
73
92
74
92
81
CH3
10, easily synthesized from the iminophosphoranes 6 via aza-
Wittig reaction with aryl isocyanates in anhydrous dichloro-
methane at room temperature. No conversion was observed
while toluene or o-xylene solutions of carbodiimides 10
were heated at reflux temperature for several hours. We could
accomplish the cyclization of carbodiimides 10 into the
1-(arylimino)methyl-2,1-benzisothiazol-3-ones11 when o-xylene
solutions of these heterocumulenes were heated at 160 °C in a
sealed tube for 24 h (Scheme 3).
Taking into account the structures of the starting keten-
imines 7 and carbodiimides 10 and those of the reaction
products obtained in their thermal treatment, the cyclizations
7 f 8 and 10 f 11 should occur with the simultaneous
formation of ethylene, although we did no efforts to ascertain
the presence of this hydrocarbon in the gaseous exhausts of
these reactions.
The presence of the hydrogen atom initially bonded to the
acetalic carbon atom of the 1,3-oxathiolane function in keten-
imines 7 and carbodiimides 10 at the styryl R-carbon atom
of benzisothiazolones 8 and the iminic carbon atom of the
1-(arylimino)methyl substituent of benzisothiazolones 11, re-
spectively, suggests a [1,5]-H shift as the first mechanistic step
for explaining the conversions 7 f 8 and 10 f 11, leading to the
transient o-azaxylylenes 12 (Scheme 4, R1 and R2 are omitted
for simplicity). The formation of the final benzisothiazolones 8
and 11 from these azaxylylenes can be envisaged as occurring
by a subsequent 1,5-electrocyclization via S-N bond formation
leading to the sulfur ylides 13 (withitsλ4-S canonical ylene form 14)
followed by a final [3 þ 2] cycloreversion at the 1,3-oxathiolane
ring which would account for the fragmentation of 13 to ethylene
and the experimentally isolated reaction products.
The first step of this mechanistic proposal is precedented in
the Introduction. The two following steps merit some comments.
Whereas the synthesis of isothiazole rings by S-N bond forma-
tion is not uncommon,10 the practically unique protocol reported
for the preparation of 2,1-benzisothiazole derivatives is the
oxidation of o-aminobenzylthiols11 and thioanthranilic acids.12
(10) Pain, D. L.; Peart, B. J.; Wooldridge, R. H. Isothiazoles and their
Benzo Derivatives. In Comprehensive Heterocyclic Chemistry; Katritzky,
A. R., Rees, C. W., Eds.; Pergamon Press: New York, 1984; Vol. 6, p 131.
(11) (a) Brown, D. W.; Sainsbury, M. Sci. Synth. 2002, 11, 573–626. (b)
Davis, M. Adv. Heterocycl. Chem. 1972, 14, 43–98.
€
(12) (a) Boshagen, H.; Geiger, W. Chem. Ber. 1973, 106, 376–378. (b)
Albert., A. H.; Robins, R. K.; O’Brien, D. E. J. Heterocycl. Chem. 1973, 10,
413. (c) Albert., A. H.; O’Brien, D. E.; Robins, R. K. J. Heterocycl. Chem.
1978, 15, 529–536.
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SCHEME 5. Electronic Relationship between 15 and the Pen-
tadienyl Anion 16
SCHEME 7. Conversions of Compounds 20a-e into 21a-e and
22a-e plus Ethylene Approached in the Computational Study
SCHEME 6. Conversion 17 f 19
the generation of a strong CdO double bond in benziso-
thiazolones 8 and 11 should be decisive for the success of
the prevailing reaction channel leading to these latter
compounds.
The peculiarities of these two latter individual steps of our
mechanistic proposal, converting the o-azaxylylenes 12
into the final benzisothiazolones 8/11, and the striking
differences experimentally found between the thermal beha-
vior of dioxolane/dithiolane heterocumulenes 1 and that of
their oxathiolane analogues 7 and 10, led us to analyze more
in depth the mechanistic sequence summarized in Scheme 4
by a detailed computational study.
No 6π-electrocyclization similar to the conversion 12 f 13 is,
to our knowledge, previously known out of the plethora of
1,5-cyclizations.13 In Huisgen’s notation,13b the core nucleus
15 of this electrocyclization relates with the 6π-electron five-
center carbon chain experiencing such a process, the penta-
dienyl anion 16, by isoelectronic exchange of the carbanionic
methylene by the sulfur atom and isoionic exchange of C5 by
the iminic nitrogen atom (Scheme 5).
Only a scarce number of 1,5-electrocyclizations have
been reported to convert neutral compounds into dipolar
structures,14 and in such cases, these latter species are
commonly transient intermediates which, as in the present
sequences 12 f 13 f 8/11, transform further into neutral
products through rearrangement or elimination reactions. A
particularly pertinent and representative instance of such
processes is the conversion of 1,4-dithiine 17 into thiophene
19 via the thiocarbonyl ylide 18,15 initially formed in small
equilibrium concentration, which gains aromaticity by elim-
ination of sulfur (Scheme 6). We believe that the electro-
cyclization 12 f 13 and the further dipolar cycloreversion16
13 f 8/11 may occur in a similar way, by combining the ring
closure to the new five-membered ring with the departure of
ethylene. The step 12 f 13 is associated with a change in the
valence of the sulfur atom, by involvement of its empty 3d-
orbitals, and the product 13 can be described by an ylidic
resonance structure 13 and a neutral resonance form 14 with
a hypervalent sulfur atom. Obviously, the recovery of the
aromatic resonance energy at the benzene nucleus of 12
should decisively help to the ongoing cyclization step. As
far as the third mechanistic step, the cycloreversion 13 f
8/11, is concerned, and taking into account that the thioa-
nalogues of intermediates 12, structures 2 (X = S), have been
shown to cyclize into quinolines 3 (X = S) instead of undergo
a similar sequence to 12 f 13 f 8/11, it seems clear that
Computational Study
In order to gain insight into the mechanistic path of the
transformation of 1,3-oxathiolane-ketenimines 7 and 1,3-ox-
athiolane-carbodiimides 10 into ethylene plus the benzisothi-
azolones 8 and 11, respectively, and also to answer why ana-
logous 1,3-dithiolane-ketenimines did not experience a similar
transformation, we have carried out a computational DFT
study by using the model molecules depicted in Scheme 7.17
We will discuss only the values of the calculated free energy
barriers, unless otherwise stated.
First, we approached the transformation of the oxathiolane-
ketenimine 20a into the initially expected spiroquinoline 21a
and also into the benzisothiazolone 22a (Scheme 7) resulting in
the mechanistic paths shown in Figure 1. The first step,
common to both reaction channels, consists of a [1,5]-H shift
via transition structure TS1a leading to the intermediate
o-azaxylylene Z-23a, which further can follow the two alter-
native pathways (a and b) depicted in Figure 1. Following path
a, the o-azaxylylene Z-23a undergoes a 6π-electrocyclic closure
through TS2a leading to spiroquinoline 21a, whereas through
path b, the azaxylylene ZfE isomerized its C1-N2 double
bond, via transition state TS3a, converting Z-23a into its
isomeric structure E-23a, which then is transformed into the
benzisothiazolone 22a plus ethylene. There is an alternative
channel for the initial [1,5]-H shift involving the transition
structure TS10a, very close in energy to TS1a, which connects
the oxathiolane ketenimine 20a with the intermediate Z-230a.
This intermediate differs from Z-23a in the geometry around
the C3-C4 double bond and can cyclize through transition
state TS20a to spiroquinoline 21a, although, due to the geo-
metry of the C3-C4 double bond, it cannot follow path b for
conversion into benzisothiazolone 22a. As the main electronic
and energetic characteristics of TS10a, Z-230a, and TS20a are
very similar to those of TS1a, Z-23a, and TS2a, we will only
comment on these latter structures.
(13) (a) Taylor, E. C.; Turchi, I. J. Chem. Rev. 1979, 79, 181–231. (b)
Huisgen, R. Angew. Chem., Int. Ed. Engl. 1980, 19, 947–973. (c) George,
M. V.; Mitra,A.;Sukumaran, K.B.Angew.Chem.,Int.Ed. Engl.1980, 19, 973–
983. (d) Bakulev, V. A.; Kappe, C. O.; Padwa, A. In Organic Synthesis: Theory
and Applications; Hudlicky, T., Ed.; JAI Press: Greenwich, 1996; Vol. 3, p 149.
(14) (a) Schultz, A. G.; DeTar, M. B. J. Am. Chem. Soc. 1976, 98, 3564–
3572. (b) Wolf, T.; Waffenschmidt, R. J. Am. Chem. Soc. 1980, 102, 6098–
6102. (c) Simmons, H. E.; Vest, R. D.; Blomstrom, D. C.; Roland, J. R.;
Cairns, T. L. J. Am. Chem. Soc. 1962, 84, 4746–4756. (d) Beyer., H.; Bulka,
E.; Beckhaus, F. W. Chem. Rev. 1959, 59, 2593–2599.
(15) Parham, W. E.; Traynelis, V. J. J. Am. Chem. Soc. 1954, 76, 4960–
4962.
(16) Bianchi, G.; De Michaeli, C.; Gandolfi, R. Angew. Chem., Int. Ed.
Engl. 1979, 18, 721–738.
(17) Although oxathiolane-ketenimine 20c appears in the experimental
study numbered as 7a, for the sake of avoiding confusion we have used a
different numbering system in the Computational Study section.
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FIGURE 1. Stationary points optimized at the B3LYP/6-31þG** found in the transformation of the oxathiolane-ketenimine 20a into the
spiroquinoline 21a and the benzisothiazolone 22a. Numbers under the arrows correspond to free energies barriers in kcal mol-1 calculated at
3
the B3LYP/6-31þG** þ ΔZPVE level. Numbers between parentheses correspond to relative free energies calculated at the same level.
TABLE 2. Sum of Natural Charges at the Oxathiolane and Ketenimine
Fragments Calculated for the Stationary Points Found in the Conversion
20a f Z-23a
The most relevant outcome of these calculations is that
formation of benzisothiazolone 22a plus ethylene does not
involve a transient sulfur ylide similar to 13; instead, inter-
mediate E-23a undergoes simultaneously the two previously
postulated pericyclic events, 1,5-electrocyclization/[3 þ 2] cyclo-
reversion, via the transition state TS4a.
P
charges
20a
TS1aa
Z-23a
oxathiolane ring
0.047
0.232
0.298
N-C-CH2 fragment
-0.171
-0.024
-0.368
Concerning the first mechanistic step, the [1,5-H] shift con-
verting 20a into o-azaxylylene Z-23a, the calculated energy
aFor calculating the charge at the donor and acceptor carbon atoms
C4 and C21 in TS1a we have considered the bond orders H-C4 and
H-C21 and summed proportionally the charge of the migrating hydro-
gen atom into each carbon atom (see the atomic numbering in Figure 2).
barrier (31.7 kcal mol-1) is similar to that previously found
for the analogous [1,5]-H shift occurring in dioxolane-
3
ketenimine 1 (X = O, Y = CH2) (31.3 kcal mol-1),7 showing
3
kcal mol-1].19 Besides, the analysis of the natural charges shows
that the hydricity of the 1,3-oxathiolane function is comparable
to that of the 1,3-dioxolane function. This [1,5]-H shift can be
described as a hydride shift, in which the acetalic C-H bond is
weakened and polarized by the lone pairs at the O and S
heteroatoms, inducing an increase of the negative charge density
at the hydrogen atom.4 Besides, the electrophilic nature of the
central carbon atom of the ketenimine function18 matches with
the nucleophilic character of the migrating hydrogen.
3
a significant increase of the sum of charges at the oxathiolane
ring going from oxathiolane-ketenimine 20a to the intermediate
Z-23a, whereas this value decreases at the initial ketenimine
fragment (Table 2).
On the other hand, we have found a noteworthy increase of
the dipole moment going from 20a (1.8 D) to TS3a (5.1 D) to
Z-23a (5.9 D), accounting for the dipolar character of the
intermediate Z-23a, with the negative charge delocalized over
the aza-allylic system (N1-C21dC24), and the positive charge
delocalized over the acetalic fragment (O-C4-S). It is also
worth commenting on the helical geometry of this intermediate.
The benzenoid ring of this polienic structure is not totally flat;
the values of the C5-C2-C3-C6 and C1-C2-C3-C4 dihe-
dral angles are 22.2° and 35.6°, respectively. In contrast, its
geometric isomer E-23a is nearly planar, with only the C8-C20
ethylene fragment and the C21-C24 double bond departing
from the plane containing the rest of the molecular framework.
In addition, the calculated dipole moment of E-23a (3.9 D) is
significantly lower than that found in Z-23a.
The computed natural bond orbital (NBO) analysis of transi-
tion structure TS1a shows that the nX f σ*C-H hyperconjuga-
tive interactions are the dominant among those involving the
acetalic C-H bond [n(2)O f σ*C-H = 11.69 kcal mol-1
,
3
n(1)S f σ*C-H = 1.75 kcal mol-1, n(2)S f σ*C-H = 5.35
3
(18) Barker, M. W.; McHenry, W. E. In The Chemistry of Ketenes, Allenes
and Related Compounds; Patai, S., Ed.; Wiley-Interscience: Chichester, UK,
1980; Part 2, p 701.
(19) It is known that the hyperconjugative interactions nx f σ*C-H
involving lone pairs at the oxygen atoms are stronger than those involving
sulfur atoms in analogous compounds. See: Alabugin, I. V. J. Org. Chem.
2000, 65, 3910-3919 and references cited therein.
J. Org. Chem. Vol. 75, No. 11, 2010 3741

Alajarin et al.
JOCArticle
FIGURE 3. B3LYP/6-31þG**-optimized geometry of TS4a
showing relevant bond distances (in A) and bond angles (in deg).
atom (from 0.22 to 0.28) also illustrate the rotational nature of
this ZfE isomerization.21 The computed barrier for this step is
very low, only 9.5 kcal mol-1, and therefore easily surmountable.
Undoubtedly, the step along path b that called powerfully our
attention was that converting intermediate E-23a into benzi-
sothiazolone 22a with simultaneous ethylene extrusion via the
transition state TS4a, whose main geometric parameters are
shown in Figure 3. This conversion can be formally viewed as the
combination of two chemical events, a 1,5-electrocyclization
and a [3 þ 2] cycloreversion, into a single mechanistic step.
We have found in the literature neither 1,5-electrocyclizations
of pentadienyl skeletons similar to the 1-thia-5-aza-2,4-penta-
diene fragment of E-23 nor [3 þ 2] cycloreversions involving 1,3-
oxathiolane rings like the one proposed above, and these two
transformations do not look easily amenable in an isolated
manner. Even so, the combination of both processes in a unique
mechanistic step results in a process of a discrete energy barrier,
FIGURE 2. MESP of Z-23a plotted onto the electron density surface
with an isovalue of 0.01 au showing its highly polar character. The
color coding is shown at the top.
The dipolar nature of o-azaxylylene Z-23a can be also visua-
lized by computing the molecular electrostatic potential (MESP)
values, which are shown in Figure 2, reflecting the electron-rich
and electron-deficient regions of the molecule.
In relation to the ring-closure step leading to spiroquinoline
21a, we could not locate a rotational transition state connect-
ing intermediate Z-23a with its s-cis rotamer along the
N1-C21 bond required for the 6π electrocyclization. Instead,
the IRC calculations showed that going uphill from intermedi-
ate Z-23a toward the transition structure TS2a the rotation
around that single bond takes place gradually along with the
partial formation of the new C4-C24 σ bond in the proximity
of TS2a. The analysis of the geometry of this stationary point,
the transition vector associated to its imaginary frequency and
the intrinsic reaction coordinate (IRC) calculations point to a
sort of disrotatory ring closure. The dipolar character of
intermediate Z-23a may well facilitate this cyclization, as
the ends of the 3-azahexatriene fragment are oppositely
charged (natural charges at C4 and C24 are 0.22 and -0.02,
close to 20 kcal mol-1. It seems that these two transformations
3
cooperate in a favorable way by occurring simultaneously. Such
cooperation may be interpreted by considering that the 1,5-
electrocyclization might be viable thanks to the simultaneous
ethylene extrusion, which probably occurs by virtue of the
concurrent formation of the strong CdO bond, which in turn
is favored by the S-N bond formation. Moreover, the aroma-
ticity recovery at the benzene ring along the way to 22a and the
inherent entropic assistance of this mechanistic step must be also
decisive factors for determining its success (see Figure 5).
The inspection of the geometry and some electronic para-
meters of the transition state TS4a revealed the especial char-
acteristics of this structure. The three rings of TS4a are in the
same plane; in fact, TS4a is nearly planar, and only the exocyclic
CdC double bond attached to the nitrogen atom projects out of
the molecular plane. The developing π system of ethylene and
that of the remaining molecular frame are perfectly perpendi-
cular, indicating that going backward from 22a plus ethylene to
TS4a the nonbonding lone pairs at the heteroatoms interact
with the p orbitals at the ethylene carbon atoms. In accor-
dance, the second-order perturbation analysis22 along the IRC
respectively). The calculated energy barrier ΔGq is 21.1
2
kcal mol-1, lower than that calculated for the archetypical
3
6π-electrocyclic ring closure of 1,3,5-hexatriene to 1,3-cyclo-
hexadiene (27 kcal mol-1).20
3
Following path b, intermediate Z-23a first undergoes the
ZfE isomerization of its C-N double bond through TS3a.
This process occurs by a rotational mechanism, instead of the
alternative inversion at the nitrogen atom, although the value of
the C2-N1-C21 bond angle (135.1°) could reflect a minor
contribution of inversional component to such isomerization
mechanism. The increase of the dipole moment going from
Z-23a (5.87 D) to TS3a (6.18 D), as well as the changes in the
natural charges at the N1 atom (from -0.49 to -0.57) and the C2
(20) (a) Rodrıguez-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.
(21) Raban, M Chem. Commun. 1970, 1415–1416.
(22) (a) Reed, 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.
3742 J. Org. Chem. Vol. 75, No. 11, 2010

Alajarin et al.
JOCArticle
FIGURE 4. Main results of the second order perturbation analysis calculated for several points along the IRC calculations at the B3LYP/6-
31þG** level of theory on TS4a (a), showing the relevant donor-acceptor interactions going forward from E-23a to TS4a (b) and backward
from 22a to TS4a (c).
coordinate shows as the more relevant donor-acceptor inter-
actions the Lp1Ofπ*C8-C11 and πC8-C11fσ*N-S. As
pointed out earlier, the geometry of the forming thiazole ring
in TS4a does not correspond to that expected for a disrotatory
6π-electron five-center electrocyclization as all the atoms are in
the molecular plane.23 Going forward from E-23a to TS4a, the
most relevant donor-acceptor interactions along the IRC are
LpNfσ*S-C11, Lp1Ofπ*C3-C4 and π*C3-C4fπ*N-C2.
The results of the IRC calculations for TS4a are shown in
Figure 4.
orbital topology of TS4a, containing orbital disconnections in
the cyclic array of overlapping orbitals (where orthogonal
bonding and nonbonding orbitals interchange roles), both con-
fer pseudopericyclic6e,24 characteristics to this transition state.
As the electronic reorganization only takes place at the
periphery of TS4a, the single C4-S7 bond not intervening, the
transformation of E-23a into 22a could be also viewed as a
particular case of vinylogous retro-thia-ene reaction (Figure 6)
in which the enophile component is ethylene and the vinylogous
ene partner is triheterosubstituted, the migrating atom being
sulfur.
The vinylogous ene processes are scarcely known, and we
could only locate two documents reporting on these kind of
reactions.25 It is not surprising that all-carbon vinylogous ene
reactions are so rarely reported. Whereas they would involve, if
concerted, cyclic transition states involving eight electrons, they
Therefore, the electronic movements in the direct and inverse
reaction paths passing through TS4a could be represented as
shown in Figure 5. Accordingly, the planar geometry and the
(23) Houk, K. N.; Li, Y.; Evanseck, J. D. Angew. Chem., Int. Ed. Engl.
1992, 31, 682–708 and references cited therein.
(24) (a) Ross, J. A.; Seiders, R. P.; Lemal, D. M. J. Am. Chem. Soc. 1976,
98, 4325–4327. (b) Birney, D. M. J. Org. Chem. 1996, 61, 243–251. (c) de
Lera, A. R.; Alvarez, R.; Lecea, B.; Torrado, A.; Cossio, F. P. Angew. Chem.,
Int. Ed. 2001, 40, 557–561. (d) Birney, D. M. Org. Lett. 2004, 6, 851–854. (e)
Jones, G. O.; Xuechen, L.; Hayden, A. E.; Houk, K. N.; Danishefsky, S. J.
Org. Lett. 2008, 10, 4093–4096.
(25) (a) Gollnick, K.; Griesbeck, A. Tetrahedron 1984, 40, 3235–3250. (b)
Maas, H.; Roeper, M. Preparation of alkoxydodecatrienes and analogous by a
vinylogous ene reaction. BASF AG, Germany, DE, 1995069, A1 20001005;
CAN 2000, 133, 281536.
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Alajarin et al.
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FIGURE 6. Vinylogous ene and retroene reactions and their ana-
logy with a simplified model of the key mechanistic step leading to
22a.
By analyzing the free energy barriers shown in Table 3 the
following conclusions can be drawn:
1. In all cases the first step, the [1,5]-H sigmatropic shift, is
predicted to be the rate limiting one.
2. By comparing the weights of the energy barriers calculated
for the [1,5]-H shifts (ΔGq ) in the transformations 20a,d f
1
Z-23a,d (entries 1 and 4), the decreasing predicted reactivity
order is oxathiolane-ketenimine>oxathiolane-carbodiimide26 and
the comparison of the conversions 20a,b f Z-23a,b (entries 1
and 2) shows that the [1,5]-H shift is easier in oxathiolane-
ketenimine than in dithiolane-ketenimine. In other words, the
hydride transfer occurs more easily in ketenimines than in carbo-
diimides, andthe ability of the oxathiolane fragment for imparting
hidricity is higher than that of the dithiolane function.
On the other hand, the substitution of hydrogen atoms by
phenyl rings in the sp2 carbon atom of the ketenimine function,
or in the terminal nitrogen atom of the carbodiimide fragment,
decreases the energy barrier associated at the [1,5]-H shift, as
could be inferred by comparing the ΔGq1 values of entries 1 and
3, those of entries 4 and 6, and those of entries 5 and 7. This
behavior is probably due to the decrease in the energy of the
LUMO orbital which takes place by substituting hydrogen
atoms by benzene rings at the terminal atom of the heterocu-
mulenic fragment.27
FIGURE 5. Proposed electronic reorganization going from Z-23a
to 21a through TS4a.
could hardly compete with the alternative Diels-Alder reaction
and other classical six-electron ene processes. Only the special
structural and electronic features of the transformations E-23
into 22 (heteroatoms, lone-pair interactions, pseudopericyclic
character, and aromaticity recovery) seem to explain why these
processes are easily amenable.
3. The 6π electrocyclic ring-closure step seems to be relatively
easy in all cases. Thus, the calculated energy barriers associated
to this step (ΔGq ) are close to 20 kcal mol-1 for the coversions
2
3
For the conversions 20b-e into 21b-e/22b-e we have only
considered the [1,5]-H shift leading to the correspond-
ing o-azaxylylenes Z-23c-e. The computations established the
same mechanistic paths for the conversions of 1,3-dithiolane-
ketenimine 20b, 1,3-oxathiolane-ketenimine 20c, and 1,3-oxa-
thiolane-carbodiimides 20d-e into the corresponding spiro-
quinolines 21b-e and benzisothiazolones 22b-e. However,
the energy barriers calculated for these transformations are
quite different as shown in Table 3. It is worth to stand out
that the [1,5]-H shifts in oxathiolane-carbodiimides 20d,e can
take place via two alternative isomeric transition structures
as result of the trans or cis geometry that the terminal CdN
bond acquires at the end of those processes, leading to azaxyl-
ylenes trans-Z-23d,e and cis-Z-23d,e, respectively. As a con-
sequence, these latter intermediates are converted into spiro-
quinolines 21d,e via two alternative transition structures:
TS2outd,e, where the substituent at the terminal nitrogen atom
is placed outward with relation to the σ C-N forming bond,
and TS2ind,e, where that substituent is placed inward. More-
over, in path b, the transformations of intermediates trans-Z-
23d,e and cis-Z-23d,e into their corresponding geometrical
isomers trans-E-23d,e and cis-E-23d,e occur via transition
structures E-TS3d,e and Z-TS3d,e, respectively. Then these
intermediates are transformed into the corresponding benzi-
sothiazolones E- and Z-22d,e through the respective transition
structures E-TS4d,e and Z-TS4d,e. This set of transformations is
summarized in Scheme 8.
Z-23a,b f 21a,b and cis-Z-20d,e f 21d,e (see entries 1, 2, 5, and
7). A significant increase in the barrier takes place when the
hydrogens at the terminal carbon atom of the ketenimine moiety
are substituted by phenyl groups, as revealed by comparing the
ΔGq2 values of entries 1 and 3. This fact can be rationalized on
the basis of the higher steric interference of the two benzene rings
in the transition structure TS2c when compared with the
unsubstituted TS2a.28
Additionally, the computed energy barriers of the transfor-
mations trans-Z-23d,e f 21d,e (ΔGq in entries 4 and 6) are
2
significantly lower than those associated to the remainder 6π
electrocyclic ring closures. In particular, the barriers of the
conversions trans-Z-23d,e f 21d,e (ΔGq in entries 4 and 6,
2
around 4 kcal mol-1) are considerably lower than those of their
3
(26) The energy of the LUMO orbital of carbodiimide is higher than that
of ketenimine; accordingly, it is expected that the donor-acceptor interac-
tion between the migrating hydride and the heterocumulenic acceptor
LUMO orbital should be less favorable in carbodimides than in ketenimines.
(27) It is known that conjugating substituents produce large accelerations
of the rate of nucleophilic additions to heterocumulenes such as ketenes, see:
Tidwell, T. T. Ketenes; J. Wiley and Sons: New York, 1995; p 581.
(28) (a) Marvel, E. N. In Thermal Electrocyclic Reactions; Academic Press:
New York, 1980; Vol. 43, p 422. (b) Lewis, K. E.; Steiner, H. J. Chem. Soc. 1964,
3080–3092. (c) Heller, H. G.; Salisbury, K. J. Chem. Soc. C 1970, 399–402. (d)
Spangler, C. W.; Jondahl, T. P.; Spangler, B. J. Org. Chem. 1973, 38, 2478–2484.
(e) Marvell, E. N. Tetrahedron 1973, 29, 3791–3796. (f) Reid, P. J.; Doig, S. J.;
Wickham, S. D.; Mathies, R. A. J. Am. Chem. Soc. 1993, 115, 4574–4763.
3744 J. Org. Chem. Vol. 75, No. 11, 2010

Alajarin et al.
JOCArticle
TABLE 3. Free and Electronic (in parentheses) Energy Barriersa (in kcal mol-1) for the Conversions 20a-e f 21a-c / (22a-e þ Ethylene) Calculated at
3
the B3LYP/6-31þG** þ ΔZPVE Theoretical Level
entry
30 f 31/32
ΔGq
ΔGq
ΔGq
ΔGq
4
ΔGrxn21
ΔGrxn22
ΔG 2
q
1
2
3
1
10
2
3
4
5
6
7
a
31.7 (29.9)
31.3 (29.3)
33.3 (31.1)
26.9 (24.9)
37.4 (35.8)
36.7 (35.1)
32.9 (30.8)
34.6 (32.8)
21.1 (20.2)
21.3 (20.4)
21.1 (20.2)
26.4 (24.2)
4.0 (3.0)
21.0 (19.9)
4.7 (3.3)
18.3 (16.4)
9.5 (9.2)
19.2 (19.1)
-21.1 (-23.4)
-21.1 (-23.4)
-17.4 (-19.9)
-1.4 (-5.7)
-14.6 (-16.6)
-14.6 (-16.6)
-8.3 (-10.8)
-8.3 (-10.8)
-12.5 (-9.6)
53.7 (53.9)
a0
b
c
10.4 (10.1)
9.5 (9.3)
4.1 (3.7)
4.9 (4.3)
3.7 (3.2)
4.1 (3.5)
27.5 (27.9)
20.5 (20.7)
16.8 (17.0)
18.7 (19.4)
17.7 (21.4)
21.5 (17.8)
1.9 (4.4)
-10.7 (-8.8)
-3.6 (-0.8)
-1.7 (1.3)
-4.9 (-2.4)
2.1 (4.7)
53.1 (53.3)
36.2 (36.3)
41.6 (41.7)
41.6 (41.7)
33.3 (33.2)
33.3 (33.2)
d (trans)
d (cis)
e (trans)
e (cis)
aSee Figure 1 and Scheme 8 for the notation of the energy barriers.
SCHEME 8. Mechanistic Paths Found at the B3LYP/6-31þG** Level for the Conversion of the Oxathiolane-Ketenimines 20d,e into
Spiroquinolines 21d,e and Benzisothiazolones 22d,e plus Ethylene
isomeric analogues cis-Z-23d,e f 21d,e (ΔGq2 in entries 5 and 7,
closures have been previously reported, and their characteriza-
tion as pericyclic or pseudopericyclic process have been the
object of several studies.24c,29
around 20 kcal mol-1). The assistance of the lone pair at the
3
terminal heteroatom of trans-Z-23d,e to the formation of the
new bond in the electrocyclization step can account for these
differences. A similar assistance is not feasible in the cyclizations
of cis-Z-23d,e given the geometry of the terminal CdN bond, as
shown in Figure 7, where the transition structures of both
transformations in case d are represented. In fact, the analysis
of the second order perturbative interactions displayed in the
NBO computations shows that the dominant orbital interac-
tions in TS2a-c and TS2ind,e take place between the C3dC4 and
C21dY24 π systems (see atomic numeration in Figure 7), as
expected for a classical pericyclic disrotatory process. In con-
trast, in TS2outd,e those interactions do not exist or are insig-
nificant when compared with the dominant interaction
LpY24fπ*C3dC4. Therefore, in these latter transitions states
the assistance of the lone pair at the Y heteroatom of the
hexatrienic fragment to the formation of the new σ bond,
confers pseudopericyclic characteristics to the electrocycliza-
tions of trans-Z-23d,e via TS2outd,e. Similar 6π electrocyclic ring
4. Concerning path b, the Z f E isomerization of the C2dN1
bond takes place via the transition structures TS3a-e involving
the rotation around this bond, and in all cases these processes
should occur very easily due to the small values of the computed
energy barriers (0.5-10.2 kcal mol).
3
5. As far as the conversion of o-azaxylylenes E-23a-e into the
benzisothiazolones 22a-e plus ethylene, through transition
structures ET4a-e are concerned, the magnitudes of the energy
barriers point out that these transformations are viable in all the
studied cases, being more feasible for azaxylylenes bearing an
oxathiolane ring (ΔGq = 17.7-21.5 kcal mol-1) than for the
4
3
dithiolane (ΔGq = 27.5 kcal mol-1).
6. By comparing the relative values of the 20 f 21 and 20 f 22
4
3
reaction energies (ΔGq
and ΔGqrxn22, respectively), the
rxn21
calculations predict that in the conversion of 20a,b,d,e the
spiroquinolines 21a,b,d,e should be the thermodynamically
controlled product, whereas in the transformation of 20c the
benzisothiazolone 22c should be both the thermodynamic and
kinetically controlled product. At this point, it is worth compar-
ing the reaction energy computed for the transformation of
(29) (a) De Lera, A. R.; Cossio, F. P. Angew. Chem., Int. Ed. 2002, 41,
1150–1152. (b) Rodriguez-Otero, J.; Cabaleiro-Lago, E. M. Chem.;Eur. J.
2003, 9, 1837–1843. (c) Alajarin, M.; Sanchez-Andrada, P.; Cossıo, F. P.;
´
Arrieta, A.; Lecea, B. J. Org. Chem. 2001, 66, 8470–8477. (d) Alajarin, M.;
Sanchez-Andrada, P.; Vidal, A.; Tovar, F. J. Org. Chem. 2005, 70, 1340–
1349. (e) Alajarin, M.; Vidal, A.; Sanchez-Andrada, P.; Tovar, F.; Ochoa, G.
Org. Lett. 2000, 2, 965–968. (f) Sakai, S. Theor. Chem. Acc. 2008, 120, 177–
183. (g) Duncan, J. A.; Calkins, D. E. G.; Chavartha, M. J. Am. Chem. Soc.
2008, 130, 6740–6748.
oxathiolane-ketenimine 20a into 22a (ΔGq
= -12.5
rxn22
kcal mol-1) with that of its thioanalogue, the conversion of
3
dithiolane-ketenimine 20b into 22b (ΔGqrxn22 = 1.9 kcal mol-1).
This large difference presumably arises from the thermodynami-
cally favorable generation of a strong CdO double bond in the
3
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Alajarin et al.
SCHEME 9. Sulfur Elimination in Benzisothiazolones and
Isothiazolones
JOCArticle
In contrast, if ΔGq , ΔGq and the spiroquinolines 21 can
2
4
not easily revert into Z-23 (high ΔGq-2 values), it is predictable
that only the spiroquinolines 21 are obtained, as in the case of
the conversion of 20b and 20d (entries 2 and 4). All these
predictions agree with the experimental results. Note that the
thermal treatment of the oxatiolane-ketenimine 7a (which in the
computational study appear as 20c) and the oxathiolane-carbo-
diimide 10b (whose structure is very similar to 20e) led exclu-
sively to the formation of benzisothiazolones 8a and 11a,
respectively, whereas 1,2-dithiolane-ketenimines under thermal
conditions were converted into the corresponding spiroquino-
lines (see ref 7), in agreement with the predictions of this
computational study.
Desulfurization of Benzisothiazolones 8
FIGURE 7. Stick representation of the B3LYP/6-31þG**-opti-
mized geometries of the transition states TS2ind and TS2outd show-
ing the lone pair (in purple, numbered as 25) at the terminal nitrogen
atom.
Among the papers we located in a bibliographic search of
synthetic methods and reactivity of benzisothiazolones, the one
by Davis and co-workers30 captured our attention. This paper
reports on the sulfur extrusion from benzisothiazolone 24 by
treatment with triethyl phosphite to yield 2-(2-aminophenyl)-
4H-3,1-benzoxazin-4-one 26 (Scheme 9). The authors propose
that the mechanistic course of the conversion 24 f 26 should
occur by the initial formation of intermediate 25, in which two
molecules of benzisothiazolone and the phosphorus reagent
coupled to form a unique dipolar species. Following an
exhaustive literature search on the chemistry of heterocyclic
systems structurally related to benzisothiazolones we located a
second interesting publication, this one due to Goerdeler and
co-workers,31 disclosing a related desulfurization process of
the most simple isothiazol-5(2H)-ones 27, which provided
imino-ketenes (imidoyl-ketenes) 28 as the initial reaction
products, which were further reacted with nucleophilic re-
agents for yielding a variety of carbonyl derivatives.
benzisothiazol-3-one 22a in comparison with the weaker CdS
bond of the benzisothiazole-3-thione 22b.
7. With the aim of correlating the results of the computational
study with those of the experimental work, it is essential to
compare the magnitude of the energy barriers computed for the
6π electrocyclic ring closure (ΔGq ) with those of the key step of
2
path b (ΔGq ), but also the reaction energies ΔGq
and
4
rxn21
ΔGqrxn22, and to evaluate the potential reversibility of each step
involved in these transformations. The key steps leading to the
benzisothiazolones 22 are irreversible processes because of the
accompanying ethyleneextrusion, whereas the spiroquinolines 21
could revert into their corresponding azaxylylenes Z-23 when the
energy differences between TS2 and 21 (ΔGq-2) are affordable.
Then, the benzisothiazolones 22 would be the predictable reac-
tion productsin those cases where: (a) ΔGq4 islower thanΔGq , as
2
in the case of the transformations of 20a,c and 20d (entries 1, 3,
and 5), and (b) ΔGq2 islower than ΔGq4 but the spiroquinolines 21
can revert into the azaxylylenes Z-23 (ΔGq-2 is surmontable), and
the corresponding ΔGq4 energy barriers are also reachable. This
could be the case of the conversion of 20e (entries 6 and 7).
(30) Davis, M.; Hook, R. J.; Wu, W. Y. J. Heterocycl. Chem. 1984, 21,
369–373.
(31) Goerdeler, J.; Yunis, M. Chem. Ber. 1985, 118, 851–862.
3746 J. Org. Chem. Vol. 75, No. 11, 2010

Alajarin et al.
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SCHEME 10. Desulfurization of 2,1-Benzisothiazol-3-ones 8
TABLE 4. Compounds 29-31
While the intermediacy of dipolar species 25 seemed to us
somewhat unlikely, we envisaged that the formation of 26
could be more reasonably explained by a [4 þ 2] dimerization
of an intermediate imidoyl-ketene, benzoanalogue of 28,
which would result from the initial desulfurization of 24 by
the action of the thiophilic phosphorus reagent, as occur with
isothiazolones 27. This reasoning directed our interest to the
study of similar desulfurization processes of the herein
obtained benzisothiazolones 8, taking into consideration
that the alkenyl chain linked to the N atom of 8 could result
involved in intramolecular processes at the stage of the put-
ative imidoyl-ketene intermediates.
yield (%)
reaction
conditionsa
compd 8
R1
R2
29
30
31
8a
8b
8b
8c
8d
8d
A
A
B
B
A
B
H
H
H
H
Cl
27
83
99
60
CH3
CH3
H
H
H
53
79
CH3
CH3
28
20
47
aSee main text and Scheme 10.
nazolindiones 30. Alternatively, the dibenzodiazocindiones
31 should form by coupling two molecules of 32 in a [4 þ 4]-
cycloadditive dimerization.
The first reaction conditions we essayed involved the
heating at 150 °C, in a sealed tube for 1-4 h, of equimole-
cular amounts of some benzisothiazolones 8 and triphenyl-
phosphine. Under these conditions (A) compounds 8a and
8d converted into mixtures of the 3,3-diphenyl-4(3H)-quino-
lones 29a,d and the quinolino[2,1-b]quinazolin-5,12-diones
30a,d, the 4(3H)-quinolone 29b being the only reaction
product when starting from benzisothiazolone 8b. Under softer
reaction conditions, stirring toluene solutions of benzisothiazo-
lones 8 and triphenylphosphine at room temperature for 12 h,
conditions (B), benzisothiazolone 8b converted into quinolone
29b, compound 8c transformed into dibenzodiazocindione 31c,
and 8d afforded a mixture of quinolone 29d and dibenzodia-
zocindione 31d (Scheme 10 and Table 4).
The formation of the three types of desulfurization pro-
ducts 29, 30, and 31 could be reasonably explained by
assuming the initial formation of the common transient
imidoyl-ketene intermediates 32 (Scheme 11). The desulfur-
ization of benzisothiazolones 8 by the action of triphenyl-
phosphine should provide the very reactive species 32
bearing a 5-aza-1-oxa-1,2,4,6-heptatetraene system. The cy-
clization of intermediate 32 by a 6π-electron electrocyclic
ring closure involving the C2-C3-C4-N5-C6-C7 aza-
triene fragment would then afford the 4(3H)-quinolones 29.
Thus formed compounds 29 could further undergo a [4 þ 2]
cycloaddition, acting as the dienophilic component across
their endocyclic CdN bond, with a second molecule of
imino-ketene 32 as the dienic partner, through its C2-C3-
C4-N5 1-azadiene fragment, for yielding the quinolinoqui-
The formation of products 29, 30, and 31 is in accordance with
the known reactivity of imidoyl-ketenes, which have been
shown to undergo 6π electrocyclic ring closures,32 [4 þ 2] cyclo-
additions33 and dimerization through [4 þ 4] cycloadditions.34
In general, under both reaction conditions quinolones 29
are formed in the product mixtures, with the rare exception
of the desulfurization of 8c under conditions B (Table 4).
Compounds 30 are usually the major products when the
reactions are run under reaction conditions A, whereas
[4 þ 4] cyclodimers 31 were only obtained under conditions
B. The exclusive formation of quinolone 29b in the two
experimental desulfurization reactions of 2,1-benzisothiazo-
lone 8b (R1 = CH3; R2 = H) can be rationalized by the steric
influence of the methyl group R1= CH3 at the ortho position
of the iminic carbon atom in the imidoyl-ketene intermediate
(32) (a) Kappe, C. O.; Kollenz, G.; Wentrup, C. J. Chem. Soc., Chem.
Commun. 1992, 485–486. (b) Clarke, D.; Mares, R. W.; McNab, H. J. Chem.
Soc., Chem. Commun. 1993, 1026–1027. (c) Clarke, D.; Mares, R. W.;
McNab, H. J. Chem. Soc., Perkin Trans. 1 1997, 1799–1804. (d) George,
L.; Netsch, K.-P.; Penn, G.; Kollez, G.; Wentrup, C. Org. Biomol. Chem.
2006, 4, 558–564.
(33) (a) Lisovenko, N. Y.; Krasnykh, O. P.; Aliev, Z. G.; Vostrov, E. S.;
Tarasova, O. P.; Maslivets, A. N. Chem. Heterocycl. Compd. 2001, 37, 1314–
1316. (b) Lisovenko, N. Y.; Maslivets, A. N.; Aliev, Z. G. Chem. Heterocycl.
Compd. 2003, 39, 132–134. (c) George, L.; Bernhardt, P. V.; Netsch, K.-P.;
Wentrup, C. Org. Biomol. Chem. 2004, 2, 3518–3523. (d) Semenova, T. D.;
Krasnykh, O. P. Russ. J. Org. Chem. 2005, 41, 1222–1227.
(34) (a) Ziegler, E.; Sterk, H. Monatsh. Chem. 1968, 99, 1958–1961. (b)
Zhou, C.; Birney, D. M. J. Org. Chem. 2004, 69, 86–94.
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Alajarin et al.
JOCArticle
SCHEME 11. Mechanistic Proposal for the Conversion 8 f 29 þ 30 þ 31
SCHEME 12. Desulfurization of 8c in Ethanol as Solvent
32b, which contributes to increase the population of its
optimal reactive conformation for accomplishing the 6π
electrocyclization step leading to quinolone 29b. At the same
time, this methyl group seems to make difficult the [4 þ 2]
cycloaddition of 32b with a molecule of quinolone 29b and
the [4 þ 4] cyclodimerization process.
With the aim of probing the participation of imidoyl-
ketenes 28 as reactive intermediates in the conversions 8 f
29/30/31, we carried out the treatment of 2,1-benzisothiazol-
3-one 8c with triphenylphosphine using anhydrous ethanol
as solvent (Scheme 12). This reaction provided, as the major
product, the ethyl anthranilate 33 (31%), accompanied by
the dibenzodiazocinedione 31c (15%). The formation of
anthranilate 33 seems to confirm that the desulfurization
of compounds 8c takes place via the imidoyl-ketene 32c,
which is then captured by the solvent through a nucleophilic
addition at the ketene carbon atom, also undergoing, in a
lesser extent, the cyclodimerization leading to 31c.
Procedure for the Preparation of the 2,1-Benzisothiazol-3-ones
8. To a solution of the corresponding 2-(2-triphenylphosphor-
anylideneaminophenyl)-1,3-oxathiolane 6 (1 mmol) in anhydrous
toluene (15 mL) was added methylphenylketene (0.13 g, 1 mmol)
or diphenylketene (0.19 g, 1 mmol) in the same solvent (5 mL). The
reaction mixture was first stirred at room temperature for 15 min
andthenatrefluxtemperaturefor1-7 h. After cooling, the solvent
was removed under reduced pressure, and the resulting material
was purified by column chromatography on silica gel, using
hexanes/diethyl ether as eluent.
1-(2,2-Diphenylethenyl)-2,1-benzisothiazol-3(1H)-one 8a: eluent
for column chromatography, hexanes/diethyl ether (9:1, v/v); yield
73%; mp 142 °C (yellow prisms, diethyl ether); IR (Nujol) 1663
(vs), 1625 (s) cm-1; 1H NMR (CDCl3, 400 MHz) δ 7.01-7.05 (m,
1 H), 7.03 (s, 1 H), 7.16-7.21 (m, 2 H), 7.22-7.26 (m, 6 H),
7.28-7.31 (m, 3 H), 7.49 (ddd, 1 H, J = 8.4, 7.0, 1.4 Hz), 7.70 (dd,
1 H, J = 8.0, 0.7 Hz); 13C NMR (CDCl3, 100 MHz) δ 113.1, 121.3
(s), 121.4, 123.1, 124.1, 127.8, 128.0, 128.5, 128.7, 128.8, 131.0,
133.4 (s), 134.3, 136.8 (s), 140.2 (s), 152.1 (s), 189.5 (s); MS (EI, 70
eV) m/z (rel int) 329 (Mþ, 96), 165 (100). Anal. Calcd for
C21H15NOS (329.42): C, 76.57; H, 4.59; N, 4.25. Found: C,
76.44; H, 4.44, N, 4.21.
Conclusions
In conclusion, we have disclosed a general fragmentation of
1,3-oxathiolane-ketenimines and -carbodiimides yielding the
corresponding N-substituted 2,1-benzisothiazol-3-ones plus
ethylene, and unveiled its mechanism by means of a computa-
tional DFT study. The tandem sequence of chemical events is
composed of a 1,5-hydride shift, activated by the oxathiolane
fragment, and a rare step of pseudopericyclic characteristics
combining a 1,5-S,N-cyclization and the fragmentation of the
oxathiolane ring in the transient o-azaxylylene intermediates.
The results of the computations also agree with the observed
reactivity order ketenimine > carbodiimide, discard alterna-
tive reaction channels, and fully explain the experimental
outcomes of this work. Sulfur extrusion from the prepared
benzisothiazolones by the action of triphenylphosphine is
shown to provide three different classes of complex hetero-
cycles whose relative ratio varies with the reaction conditions.
Procedure for the Preparation of the 2,1-Benzisothiazol-3-ones
11. To a solution of the 2-(2-triphenylphosphoranylideneamino-
phenyl)-1,3-oxathiolane 6 (1 mmol) in anhydrous dichloro-
methane (20 mL) was added a solution of the aryl isocyanate
(1 mmol) in the same solvent (5 mL). The reaction mixture was
stirred at room temperature for 30 min. The solvent was
Experimental Section
For the preparation of 2-(2-azidophenyl)-1,3-oxathiolanes 5
and 2-(2-triphenylphosphoranylideneaminophenyl)-1,3-oxathio-
lanes 6, see ref 8.
3748 J. Org. Chem. Vol. 75, No. 11, 2010

Alajarin et al.
JOCArticle
removed under reduced pressure, and the oily residue was
chromatographed on a silica gel column using hexanes/diethyl
ether (9:1, v/v) as eluent to give pure carbodiimides 10.
A solution of the carbodiimide 10 (0.5 mmol) in anhydrous
o-xylene (20 mL) was heated a 160 °C, in a sealed tube, for 24 h.
The solvent was removed under reduced pressure, and the
resulting material was purified by silica gel column chromato-
graphy using hexanes/diethyl ether as eluent.
Computational Methods
All calculations were carried out in the gas phase with the
Gaussian0335 suite of programs. An intensive characterization
of the potential energy surface was done at the HF/6-31G*36
theoretical level and then with the hybrid three-parameter
functional customarily denoted as B3LYP37 using the 6-31þ
G** basis set. All of the reported stationary points were fully
optimized by analytical gradient techniques. To check the
accuracy and performance of the B3LYP functional in the
study of these transformations we have also optimized the
molecular geometries of all the stationary points found in
the potential energy surface associated to the conversion 20a
f21a/22a and 20a0 f21a0 using the new hybrid meta exchange
correlation functional M06 of Truhlar and Zhao,38 with the
internal 6-31þG** basis set, and the values obtained for
the energy barriers and reaction energies are very similar to
the values based on B3LYP geometries (see the Supporting
Information). 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. The intrinsic reaction coordinates
(IRC)39 were followed to verify the energy profiles connecting
each transition state to the correct local minima by using the
second-order Gonzalez-Schlegel integration method.40 Nat-
ural charges and second order perturbation analyses were
evaluated using the natural bond orbital (NBO) method.22
To assess the possible biradical character of the species in-
volved in these conversions CASSCF41(6,6)/6-31G*//B3LYP/
6-31þG** calculations of all the stationary points found in the
transformation 20a f21a/22a were performed. The results
show that the closed-shell S0 wave function is largely the
predominant one (94-97%). Therefore, we can conclude that
these structures are adequately described with a single refer-
ence wave function.
(E)-1-[(4-Methylphenylimino)methyl]-2,1-benzisothiazol-3(1H)-
one 11a: eluent for column chromatography, hexanes/diethyl
ether (1:9, v/v); yield 51%; mp 144-145 °C (colorless prisms,
1
diethyl ether); IR (Nujol) 1689 (vs), 1612 (s) cm-1; H NMR
(CDCl3, 300 MHz) δ 2.44 (s, 3 H), 7.26-7.36 (m, 4 H), 7.52-7.57
(m,1H), 7.75-7.83(m,2H), 8.11 (s, 1 H), 8.36-8.38(m,1H); 13C
NMR (CDCl3, 75 MHz) δ 21.3, 122.5 (s), 126.8, 127.3, 127.6,
130.3, 134.6, 135.0 (s), 139.3 (s), 146.4, 148.0 (s), 161.0 (s). MS (EI,
70 eV) m/z (rel int) 236 (Mþ - 32, 100). Anal. Calcd for
C15H12N2OS (268.34): C, 67.14; H, 4,51; N, 10.44. Found: C,
66.89; H, 4.27; N, 10.17.
Procedure for the Desulfurization of 2,1-Benzisothiazol-3-ones
8. Method A. A mixture of the 2,1-benzisothiazol-3-one 8
(1 mmol) and triphenylphosphine (1 mmol) was heated at 160 °C,
in a sealed tube, for 1-4 h. After being cooled at room temperature,
the crude material was purified by silica gel column chromatography
using hexanes/diethyl ether as eluent.
Method B. A solution of the 2,1-benzisothiazol-3-one (1 mmol)
and triphenylphosphine (1 mmol) in anhydrous toluene was stirred
at room temperature for 12 h. The solvent was then removed under
reduced pressure, and the resulting material was purified by silica
gel column chromatography using hexanes/diethyl ether as eluent.
3,3-Diphenyl-4(3H)-quinolone 29a: eluent for column chro-
matography, hexanes/diethyl ether (1:1, v/v); yield 27%; mp
96-98 °C (colorless prisms, diethyl ether); IR (Nujol) 1672 (s)
1
cm-1; H NMR (CDCl3, 300 MHz) δ 7.12-7.46 (m, 11 H),
7.63-7.66 (m, 1 H), 7.69-7.75 (m, 1 H), 8.06-8.09 (m, 1 H),
8.37 (s, 1 H); 13C NMR (CDCl3, 75 MHz) δ 65.0 (s), 123.7 (s),
126.7, 128.3, 129.0, 129.1, 129.2, 129.3, 136.3, 138.6 (s), 146.8 (s),
168.9, 195.9 (s); MS (EI, 70 eV) m/z (rel int) 297 (Mþ, 100). Anal.
Calcd for C21H15NO (297.36): C, 84.82; H, 5.08; N, 4.71. Found:
C, 84.43; H, 4.99; N, 4.88.
Acknowledgment. This work was supported by the
Ministerio de Ciencia e Innovacion of Spain (Project
(35) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; 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,
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(37) (a) Parr, R. G.; Yang, W. Density-Functional Theory of Atoms and
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Fluchichk, K. In Reviews in Computational Chemistry; Lipkowitz, K. B., Boyds,
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Quinolino[2,1-b]quinazolin-5,12-dione 30a: eluent for column
chromatography, hexanes/diethyl ether (1:1, v/v); yield 60%;
mp 222-223 °C (colorless prisms, diethyl ether); IR (Nujol)
1674 (s) cm-1; 1H NMR (CDCl3, 400 MHz) δ 6.30 (s, 1 H), 6.49
(s, 1 H), 6.56 (t, 1 H, J = 7.3 Hz), 6.66 (d, 1 H, J = 8.3 Hz),
6.85-6.91 (m, 4 H), 6.97-7.03 (m, 3 H), 7.14-7.32 (m, 10 H),
7.34-7.39 (m, 6 H), 7.45 (d, 1 H, J = 8.1 Hz), 7.54-7.58 (m,
1 H), 7.90 (dd, 1 H, J = 8.1, 1.3 Hz); 13C NMR (CDCl3, 100
MHz) δ 70.6 (s), 78.0, 112.1, 114.7 (s), 118.5, 125.7, 126.4, 127.5,
127.6, 128.1, 128.2, 128.3, 128.4, 128.5, 128.8, 129.2, 130.2,
131.6, 133.9, 134.0, 134.8 (s), 137.4 (s), 137.7 (s), 138.5 (s),
139.6 (s), 142.5 (s), 146.6 (s), 160.9 (s), 197.7 (s); MS (EI,
70 eV) m/z (rel int) 594 (Mþ, 70), 297 (100). Anal. Calcd for
C42H30N2O2 (594.71): C, 84.82; H, 5.08; N, 4.71. Found: C,
84.96; H, 5.30; N, 4.92.
Dibenzo[b,f][1,5]diazocin-6,12-dione 31c: eluent for column
chromatography, hexanes/diethyl ether (9:1, v/v); yield 53%;
mp 171-172 °C (colorless prisms, diethyl ether); IR (Nujol)
1632 (s) cm-1; 1H NMR (CDCl3, 400 MHz) δ 7.06 (d, 2 H, J =
11.2 Hz), 7.11 (d, 2 H, J = 9.2 Hz), 7.19-7.33 (m, 14 H),
7.39-7.43 (m, 6 H), 7.77 (d, 2 H, J = 2.4 Hz), 9.71 (d, 2 H, J =
11.2 Hz); 13C NMR (CDCl3, 100 MHz) δ 110.7 (s), 114.3,
121.9, 122.3 (s), 123.9 (s), 126.6, 126.9, 127.8, 128.5, 129.2,
130.0, 131.5, 136.4, 137.5 (s), 141.2 (s), 145.6 (s), 162.7 (s); MS
(EI, 70 eV) m/z (rel int) 666 (Mþ þ 4, 3), 664 (Mþ þ 2, 16),
662 (Mþ, 25), 165 (100). Anal. Calcd for C42H28Cl2N2O2
(663.60): C, 76.02; H, 4.25; N, 4.22. Found: C, 76.35; H,
4.12; N, 4.51.
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J. Org. Chem. Vol. 75, No. 11, 2010 3749

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JOCArticle
CTQ2008-05827/BQU) and Fundacion Seneca-CARM
(Project 08661/PI/08). B.B. also thanks Fundacion Sene-
ca-CARM for a fellowship.
29b,d, 30d, 31d, and 33. 1H and 13C NMR spectra of compounds
8, 11, 29-31, and 33. Details of computational procedures,
Cartesian coordinates, and energies for all the stationary points.
This material is available free of charge via the Internet at http://
pubs.acs.org.
Supporting Information Available: Spectral data (NMR,
IR, MS, and elemental analyses) for compounds 8b-e, 11b-c,
3750 J. Org. Chem. Vol. 75, No. 11, 2010