Tandem 1,5-hydride shift/6π electrocyclization of ketenimines and carbodiimides substituted with cyclic acetal and dithioacetal functions: Experiments and computations

Article abstract of DOI:10.1002/ejoc.201001372

N-Aryl ketenimines bearing five- and six-membered cyclic acetal functions - such as 1,3-dioxolane, 1,3-dithiolane, 1,3-dioxane, and 1,3-dithiane systems - at the ortho position of the N-aryl substituent transform on mild thermal treatment into quinolines, through a tandem sequence consisting of a [1,5]-H shift followed by a 6π electrocyclic ring closure. Structurally analogous N-aryl carbodiimides are converted into quinazolines in comparable tandem processes. Similar sequences can be successfully applied to N-thienyl and N-pyrazolyl ketenimines. DFT calculations have established a two-step mechanism for those conversions, consisting of an initial 1,5-hydride shift and subsequent 6π electrocyclization, and confirm the beneficial effect of the acetal function, which gives hydride character to the migrating hydrogen atom. The capability to promote the H shift depends on the type of acetal function (acetal better than dithioacetal), its ring size (five-membered better than six-membered) and the heterocumulenic fragment (ketenimine better than carbodiimide). Changing the benzene ring connecting the acetal and ketenimine functions for a heterocyclic ring has pronounced consequences for the magnitude of the energy barriers. Copyright

Full text of DOI:10.1002/ejoc.201001372

FULL PAPER
DOI: 10.1002/ejoc.201001372
Tandem 1,5-Hydride Shift/6π Electrocyclization of Ketenimines and
Carbodiimides Substituted with Cyclic Acetal and Dithioacetal Functions:
Experiments and Computations
Mateo Alajarin,*[a] Baltasar Bonillo,[a] Maria-Mar Ortin,[a] Pilar Sanchez-Andrada,*[a] and
Angel Vidal*[a]
Dedicated to Prof. Carmen Nájera on the occasion of her 60th birthday
Keywords: Density functional calculations / Reaction mechanisms / Ketenimines / Cyclization / Hydride shift / Hydricity
N-Aryl ketenimines bearing five- and six-membered cyclic
acetal functions – such as 1,3-dioxolane, 1,3-dithiolane, 1,3-
dioxane, and 1,3-dithiane systems – at the ortho position of
the N-aryl substituent transform on mild thermal treatment
into quinolines, through a tandem sequence consisting of a
[1,5]-H shift followed by a 6π electrocyclic ring closure.
Structurally analogous N-aryl carbodiimides are converted
into quinazolines in comparable tandem processes. Similar
sequences can be successfully applied to N-thienyl and N-
pyrazolyl ketenimines. DFT calculations have established a
two-step mechanism for those conversions, consisting of an
initial 1,5-hydride shift and subsequent 6π electrocyclization,
and confirm the beneficial effect of the acetal function, which
gives hydride character to the migrating hydrogen atom. The
capability to promote the H shift depends on the type of ace-
tal function (acetal better than dithioacetal), its ring size
(five-membered better than six-membered) and the hetero-
cumulenic fragment (ketenimine better than carbodiimide).
Changing the benzene ring connecting the acetal and keten-
imine functions for a heterocyclic ring has pronounced con-
sequences for the magnitude of the energy barriers.
reaction was found to be the spiroquinoline 4a, rather than
products originating from further transformations of the
expected initial radical 3. The formation of 4a seemed not
to involve any radical intermediate. In fact, we were able to
Introduction
Part of our recent research has been devoted to hetero-
cumulenes, with ketenimines being the members of this
class that we have most intensively explored.[1] The radical
chemistry of ketenimines was examined for the first time in
our studies on inter- and intramolecular addition reactions
of different types of radicals onto the central carbon
atom.[2] The success of this methodology prompted us to
investigate the feasibility of intramolecular additions of 1,3-
dioxolan-2-yl radicals, as synthetic equivalents of their acyl
counterparts, into ketenimine fragments. With this in mind
we designed the acetal-ketenimine 1a (Scheme 1) for at-
tempting the generation of the dioxolanyl radical 2, which
it was hoped might result from the abstraction of the ace-
talic H atom with tert-butoxy radicals. To this end we
treated 1a with tert-butyl peroxide in o-xylene at reflux.[3]
Unexpectedly, the reaction product resulting from such a
[a] Departamento de Quimica Organica, Facultad de Quimica,
Universidad de Murcia,
Campus de Espinardo, 30100 Murcia, Spain
Fax: +34-868-364149
E-mail: alajarin@um.es
andrada@um.es
vidal@um.es
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001372.
Scheme 1. Cyclization of ketenimine 1a and proposed mechanism.
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2011, 1896–1913
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Tandem 1,5-Hydride Shift/6π Electrocyclization
show that the conversion 1aǞ4a occurred on heating of a
toluene solution of 1a at reflux in the absence of any initia-
tor of radical reactions (Scheme 1).
The transformation of 1a into 4a was mechanistically in-
terpreted as an initial [1,5]-H migration of the acetalic H
atom to the central heterocumulene carbon, to provide the
ortho-azaxylylene 5a, followed by 6π electrocyclic ring clo-
sure of this intermediate yielding the final spiroquinoline.[4]
Ketenimines have been shown to participate in numerous
cycloaddition reactions and 6π electrocyclizations,[5] but
only a limited number of examples of sigmatropic re-
arrangements and sigmatropic shifts of atoms or groups of
atoms in ketenimines have been published.[6] Moreover, of
the reported examples only a limited number involve a H
transfer process.[6u–6x,7]
The interesting and almost unprecedented conversion of
1a into 4a prompted us to explore similar transformations
of other structurally related acetal-ketenimines and acetal-
carbodiimides. Here we report our results on the thermal
treatment of a variety of N-aryl ketenimines and carbodi-
imides with different acetal functions at the ortho positions
in their N-aryl substituents. We focused on testing cyclic
acetal functions such as 1,3-dioxolane, 1,3-dithiolane, 1,3-
dioxane and 1,3-dithiane as hydrogen donor fragments, to
determine the influence on this property of the heteroatom
(O vs. S) of the acetal grouping. A computational DFT
study has shown that the [1,5]-H shifts occurring in these
acetal-ketenimines and -carbodiimides can reasonably be
classified as hydride transfers.
Scheme 2. Preparation and cyclization of 1,3-dioxolane- and 1,3-
dithiolane-ketenimines.
Table 1. Spiroquinolines 4.
Results and Discussion
X
R1
R2
R3
% Yield
4a
4b
4c
4d
4e
4f
O
O
O
O
O
S
H
H
H
Cl
CH3
H
H
Cl
H
H
CH3
H
H
H
H
H
Ph
CH3
Ph
Ph
Ph
Ph
CH3
Ph
70
58
67
68
68
74
52
77
After these initial experiments, we first prepared a series
of differently substituted 1,3-dioxolane-ketenimines for test-
ing the desired tandem [1,5]-H/6π ERC sequences. Treat-
ment of the 2-azidobenzaldehydes 6 (Scheme 2) with eth-
ane-1,2-diol in benzene at reflux in the presence of catalytic
amounts of para-toluenesulfonic acid, with azeotropic re-
moval of water, yielded the 1,3-dioxolane-azides 7a–d. Sub-
sequent treatment of diethyl ether solutions of the azides
7a–d with triphenylphosphane produced the iminophos-
phoranes 8a–d. Aza-Wittig reactions between compounds
4g
4h
S
S
In a similar way we also prepared several 1,3-dithiolane-
8a–d and disubstituted ketenes in toluene at room tempera- ketenimines and tested their tandem [1,5]-H/6π ERC se-
ture afforded the 1,3-dioxolane-ketenimines 1a–e, the for- quences. Treatment of the 2-azidobenzaldehydes 6a and 6c
mation of which was confirmed by the presence of a very (Scheme 2) with ethane-1,2-dithiol, catalysed by BF3·Et2O,
strong absorption band around 2000 cm–1 in the IR spec- afforded the 1,3-dithiolane-azides 7e and 7f, which were
trum of each reaction mixture. The 1,3-dioxolane-ketenim- converted into the iminophosphoranes 8e and 8f by treat-
ines 1a–e remained unaltered when kept in toluene solution ment with triphenylphosphane. The 1,3-dithiolane-ketenim-
at room temperature overnight. As expected, when toluene ines 1f–h were generated in toluene at room temperature by
solutions of the ketenimines 1a–e were heated at reflux for treatment of compounds 8e and 8f with diphenylketene and
approximately 1 h the spiro[1,3-dioxolanequinolines] 4a–e methylphenylketene. The ketenimines 1f–h underwent cycli-
(Scheme 2) were formed, and were isolated from the final zation to the spiro[1,3-dithiolanoquinolines] 4f–h on heat-
reaction mixtures in fair to good yields (Table 1). The struc- ing in toluene at reflux for 16 h (Scheme 2). These spirohet-
tures of the spiroquinolines 4a–e were clearly deduced from erocycles[8] were also obtained in fair to good yields
their analytical and spectroscopic data.[8]
(Table 1).
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FULL PAPER
Although both the 1,3-dioxolane-ketenimines 1a–e and
We next investigated the optically active, C2-symmetric
the 1,3-dithiolane-ketenimines 1f–h converted into the cor- (R,R)-butane-2,3-diol as a chiral material for forming 1,3-
responding spiroquinolines 4 in toluene at reflux, the dithi- dioxolane fragments in similar ketenimines, with the goals
olane examples 1f–h required longer reaction times. It of reducing the number of final stereoisomeric spiroquino-
seems that the acetal function favours the occurrence of the lines (with a non-stereogenic C4Ј carbon atom) and also of
tandem [1,5]-H shift/6π electrocyclization process to a increasing the degree of diastereoselection in the formation
greater extent than the dithioacetal.
of the new stereogenic C3Ј centre on use of prochiral keteni-
We also tested the use of chiral 1,3-dioxolane groups as mine fragments (as in the 10 to 11 conversion). It is well
hydrogen-releasing fragments, with the aim of introducing known that molecules with a C2-symmetry element provide
stereocontrol into the tandem [1,5]-H/6π ERC sequence. We higher levels of absolute stereochemical control than those
hoped that a chiral acetal group might serve to induce ster- lacking any symmetry,[9] their most significant advantage
eoselection at the C3/C4 carbon atoms of the putative quin- being to minimize the complexity of diastereodifferentiating
olines efficiently if 1,3-dioxolane-ketenimines with two dif- events. Several C2-symmetric 1,2-diols have been used to
ferent substituents on the sp2 carbon terminus of the keten- induce high degrees of stereoselection in a variety of asym-
imine moiety were used as substrates. With this goal in metric syntheses.[10]
mind the 1,3-dioxolane-ketenimine 10 (Scheme 3) was pre-
We thus prepared the iminophosphorane 14 in the usual
pared from the starting 2-azidobenzaldehyde (6a) by se- way from 2-azidobenzaldehyde and (R,R)-butane-2,3-diol
quential treatment with racemic propane-1,2-diol, tri- (Scheme 4). Treatment with diphenylketene yielded the op-
phenylphosphane and methylphenylketene. Heating of com- tically active spiroquinoline 15 in 87% yield. More interest-
pound 10 in toluene at reflux temperature led to an unre- ingly, treatment of 14 with methylphenylketene at room
solvable mixture of four racemic diastereoisomers of the temperature and further heating of the resulting ketenimine
spiroquinoline 11, in a 1:1.4:3:4 relative ratio, as result of in toluene solution at reflux temperature for a short period
its three chiral carbon atoms (C3Ј and C4Ј in the dihy- of time led to the optically active spiroquinoline 16 as a
1
droquinoline ring and C4 in the dioxolane fragment). The 1:1.3 (more polar/less polar) mixture (as measured by H
1H and 13C NMR spectra of this mixture showed very com- NMR integration in the final crude reaction product) of the
plex signals, not allowing a reliable stereochemical assign- two expected diastereoisomers [(3ЈR,3R,4R) and
ment of its four components. Once we had the iminophos- (3ЈS,3R,4R)], which could be separated by column
phorane 9 to hand, we also investigated its reaction with chromatography on silica gel.
diphenylketene to yield the ketenimine 12, which on heating
provided an unresolvable mixture of the two expected race-
mic diastereoisomers of quinoline 13, in a 1:2 ratio.
Scheme 4. Preparation of spiroquinolines bearing C2-symmetric
1,3-dioxolane groups.
1
There are significant differences between the H NMR
spectra of the two obtained C3Ј epimers of 16, associated
with the chemical shifts of the methine and methyl protons
linked to the C3 and C4 atoms in the dioxolane fragment.
Thus, whereas in the less polar diastereoisomer the differ-
ence in chemical shifts between the two methyl doublets
[Δδ(CH3)] is 0.5 ppm and that between the two methine
multiplets [Δδ(CH)] is 0.72 ppm, in the second diastereoiso-
mer the relative values of these differences are Δδ(CH3) =
Scheme 3. Preparation and cyclization of the racemic ketenimines
10 and 12.
1898
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Tandem 1,5-Hydride Shift/6π Electrocyclization
0.07 ppm and Δδ(CH) = 1.41 ppm. Because of the unexpec- less reactive than ketenimines.[11] We were interested in test-
tedly low level of stereocontrol found in the preparation of ing whether or not carbodiimides structurally related to the
16, we did not make special efforts to assign the particular ketenimines investigated above might also participate in
structures of the major and minor diastereoisomers comparable hydride shift/cyclization sequences. To the best
unequivocally.
of our knowledge, no related example of a H shift to a
Our next objective was to explore similar [1,5]-H/6π ERC central carbodiimide carbon had been reported before these
processes in acetal-ketenimines in which the migrating hy- experiments. On treatment of the 1,3-dioxolane- and 1,3-
drogen atom is bound to the C2 carbon atom of a six-mem- dithiolane-iminophosphoranes 8 with a variety of aryl iso-
bered cyclic acetal function. To this end we prepared the cyanates we thus prepared the corresponding carbodiimides
1,3-dioxane- and 1,3-dithiane-ketenimines 19 (Scheme 5). 22 and 23 (Scheme 6). Study of their thermal behaviour in
Treatment of 2-azidobenzaldehyde (6a) and 2-azido-5-chlo- solution showed the 1,3-dioxolane-carbodiimides 22 to re-
robenzaldehyde (6c) with propane-1,3-diol and propane- quire notably harsher conditions (o-xylene, reflux, 24–36 h)
1,3-dithiol led to the azides 17, which were converted by the than their ketenimine partners in order to undergo similar
usual methodology, as shown in Scheme 5, into the corre- [1,5]-H shift/6π ERC sequences leading to spiroquinazolines
sponding iminophosphoranes 18 and then into the ketenim- 24a–i (Table 3).[8] As presumed in the light of the previous
ines 19. We were able to transform the ketenimines 19 into experiments with ketenimines, the 1,3-dithiolane-carbodii-
the [1,5]-H migration/6π electrocyclization products 21 mide thio analogues 23 were less reactive and we could not
when these heterocumulenes were heated in ortho-xylene at achieve their cyclization into the spiroquinazolines 25 even
reflux temperature for 12–24 h. The spiroquinolines 21 were under more drastic thermal conditions (o-xylene, reflux,
isolated in moderate to good yields (Table 2).
72 h or toluene, 180 °C, sealed tube, 48 h) (Scheme 6).
Scheme 6. Preparation and thermal behaviour of the 1,3-dioxolane-
and 1,3-dithiolane-carbodiimides.
Table 3. The spiroquinazolines 24.
R1
R2
Ar
% Yield
24a
24b
24c
24d
24e
24f
24g
24h
24i
H
H
H
H
H
Cl
CH3
CH3
CH3
H
H
CH3
CH3
CH3
H
H
H
H
4-CH3C6H4
4-CH3OC6H4
4-BrC6H4
47
81
98
96
99
49
77
85
46
Scheme 5. Preparation and cyclization of the 1,3-dioxane- and -
dithiane-ketenimines 19.
4-ClC6H4
4-CH3C6H4
4-CH3C6H4
4-BrC6H4
4-ClC6H4
4-CH3C6H4
Table 2. Spiroquinolines 21.
X
R1
R2
% Yield
21a
21b
21c
21d
21e
21f
O
O
O
S
S
S
H
H
Cl
H
H
Cl
Ph
CH3
Ph
Ph
CH3
Ph
90
81
92
71
60
88
In three of the reactions leading to 24 (those leading to
24a, 24f and 24i) a second class of spiroquinazolines, the
compounds 27 (Scheme 7), were also isolated as byproducts
in competitive yields. The structures of these species were
easily established from their analytical and spectroscopic
Like ketenimines, carbodiimides are known to react with data: their 1H NMR spectra, for instance, showed that they
nucleophilic species at their central sp-hybridized carbon did not contain the Ar fragments originating from the iso-
atoms, although in general terms carbodiimides are slightly cyanate components, but instead each had two different
Eur. J. Org. Chem. 2011, 1896–1913
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M. Alajarin, P. Sanchez-Andrada, A. Vidal et al.
FULL PAPER
aryl nuclei both corresponding to the dioxolane-substituted
3-Azidothiophene-2-carbaldehyde (28, Scheme 8) was
benzene fragments of the precursor carbodiimides, along converted into the 1,3-dioxolane-thieno-ketenimine 29 by
with two different 1,3-dioxolane rings, only one acetalic the usual sequence of reactions. When the crude material
proton and another one placed at the 2-position in the resulting from the heating of ketenimine 29 in benzene at
quinazoline nucleus. Reasonably, compounds 27 are the re- reflux was chromatographed on silica gel only the 2-
sult of tandem [1,5]-H shift/6π ERC processes of the corre- hydroxyethyl thiophene-2-carboxylate 31 could be isolated
sponding symmetrically substituted bis[2-(1,3-dioxolan-2- as a pure reaction product, in 52% yield. A reasonable ex-
yl)phenyl]carbodiimides 26, which in turn should form in planation for the conversion from 29 to 31 might be that
the reaction medium by metathesis of the reactants – the the starting ketenimine 29 underwent the expected [1,5]-H/
aryl(1,3-dioxolan-2-yl)carbodiimides 22 – after [2+2]/retro 6π electrocyclization sequence leading to the thieno-pyr-
[2+2] sequences (Scheme 7).
idine 30, which could be transformed into the isolated car-
boxylic ester 31 during the purification step by addition of
1
water. In support of this assumption, in the H NMR and
the 13C NMR spectra of the crude material obtained after
the thermal treatment of ketenimine 29 we observed signals
that could be attributed to the thieno-pyridine 30, whereas
those of compound 31 did not appear.
Scheme 7. Carbodiimide metathesis and cyclization to the spiro-
quinazolines 27.
Indeed, the symmetrical diaryl carbodiimides ArNCNAr
were also detected in the final reaction mixtures. Metathesis
of carbodiimides is a well known transformation, especially
with regard to its catalytic variants,[12] including those in-
volving some classes of iminophosphoranes as catalysts.[13]
We cannot discount the possibility that small amounts of
the starting iminophosphoranes 8 acting as catalysts might
Scheme 8. Preparation and cyclization of the 1,3-dioxolane-thieno-
ketenimine 29.
An interesting result was observed when a pyrazole ring
cause the partial metathesis of carbodiimides 22 and thus was used as connector unit. The 1,3-dioxolane-pyrazolo-ke-
originate the byproducts 27. The serendipitous presence of tenimine 33 (Scheme 9) was prepared from 5-azido-3-
such catalysts in the reaction medium might explain why methyl-1-phenyl-1H-pyrazole-4-carbaldehyde
the byproducts 27 appear only in the three particular reac- dichloromethane solution and at room temperature this ket-
tions cited above. enimine provided the expected pyrazolo-pyridine 34, al-
(32).
In
In the tandem processes described above, the initial [1,5]- though in low yield (15%), with the major reaction product
H shift involves the abolition of the aromaticity of the ben- surprisingly being the pyrazolo-pyridone 35, isolated in
zene ring connecting the donor and the acceptor units. It is 50% yield.[14]
predictable that changes in the characteristics of the con-
Obviously, the pyrazolo-pyridine 34 should be the result
nector tether, mainly in its degree of aromaticity, should of a [1,5]-H/6π ERC tandem process via the transient 3-
have notable consequences with regard to the values of the azahexatriene 36 (Scheme 10). The formation of the pyr-
activation energies in the two reaction steps, and therefore azolo-pyridone 35 could be understood as the trapping of
on the reaction conditions (temperature, time) required for the 3-azahexatriene intermediate 36 (similar to those o-
these processes to take place. We thus studied some similar azaxylylenes postulated in all previous mechanisms) by a
[1,5]-H/6π ERC sequences by changing the usual ortho- diphenylketene molecule through an intermolecular [4+2]
phenylene connectors for thiophene and pyrazole rings, cycloaddition reaction. Note that diphenylketene was used
choosing the 1,3-dioxolane group and the ketenimine func- as reactant in the in situ preparation of ketenimine 33
tion as the donor and acceptor units, respectively, because through its aza-Wittig reaction with the corresponding imi-
these had provided the best results in the previous cases.
nophosphorane.
1900
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Tandem 1,5-Hydride Shift/6π Electrocyclization
1,3-dithiane-ketenimine 37e,[16] the 1,3-dioxolane-carbodi-
imide 37f and the 1,3-dithiolane-carbodiimide 37g. To test
the influence of a heterocyclic ring connecting the acetalic
and ketenimine functions we also selected the dioxolane-
ketenimines 37h and 37i, each incorporating a pyrazole
ring, and 37j with a thiophene ring. For comparison we also
included the conversion of the N-(o-tolyl)ketenimine 37k,
lacking an acetal function at the benzylic C atom, into 3,4-
dihydroquinoline.
Scheme 9. Preparation and cyclization of the 1,3-dioxolane-pyr-
azolo-ketenimine 33.
Scheme 10. Proposed mechanism for the conversion 33Ǟ34 + 35.
The yield in which the pyrazolo-pyridine 34 was obtained
became higher (52%) when the ketenimine 33 was prepared k into the quinolines and quinazolines 38a–k investigated in the
by use of a slightly sub-stoichiometric amount of di-
Scheme 11. Conversions of the ketenimines and carbodiimides 37a–
computational study.
phenylketene, in benzene solution, and the reaction mixture
was heated at reflux temperature.
An intensive exploration of the potential energy surfaces
associated with these transformations showed that the reac-
Computational Study
tion paths each consist of an initial [1,5]-H shift through the
We carried out a computational study at the B3LYP/ transition structures TS1a–k leading to the o-azaxylylene
6–31+G** theoretical level on the transformations of N- intermediates INTa–k, which in a second step undergo a 6π
aryl ketenimines and N-aryl carbodiimides into the corre- electrocyclization to give the corresponding final hetero-
sponding spiroquinolines and spiroquinazolines, respec- cycles 38a–k. The computed energy barriers are gathered in
tively, with the three following aims:
Table 4.[17] We comment only on the values of the electronic
i) To explore the potential energy surfaces of the pre- energy barriers, unless otherwise stated.
sumed two steps of the tandem transformations, ii) to ex-
In all cases except for that of Entry 11 (see comments
plain the relative activating capabilities of the acetal and below) the first step is predicted to be the rate-limiting one
dithioacetal functions, and iii) to test the relative capabili- (ΔE1϶
=
23.3–40.2 kcalmol–1 vs. ΔE2϶
=
16.2–
ties of the ketenimine and carbodiimide moieties as hydro- 23.8 kcalmol–1).
gen acceptor units. The presence of an acetal function at the benzylic carbon
To this end we selected the reaction sequences shown in (Entries 1–12) accelerates the sigmatropic [1,5]-H shift by
Scheme 11 as model transformations, involving the pair of lowering its energy barrier, as can be deduced by compari-
1,3-dioxolane-ketenimines 37a and 37b,[15] the 1,3-dithiol- son with the unsubstituted case (Entry 13). The presence of
ane-ketenimine 37c, the 1,3-dioxane-ketenimine 37d, the a 1,3-dioxolane function notably decreases the energy bar-
Eur. J. Org. Chem. 2011, 1896–1913
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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M. Alajarin, P. Sanchez-Andrada, A. Vidal et al.
FULL PAPER
Table 4. Energy barriers in kcalmol–1 for the conversions of the
heterocumulenes 37a–k into the quinolines and quinazolines 38a–
k calculated at the B3LYP/6-31+G** + ΔZPVE theoretical level.[a]
Entry 37Ǟ38
ΔE϶1
ΔE϶2
ΔErxnINT ΔErxn
1
2
3
4
5
6
7
8
37aǞINTaǞ38a
29.0
24.0
31.1
34.4
36.2
32.9
34.0
37.1
37.7
23.3
19.3
28.3
40.2
19.3
22.2
20.3
19.0
18.2
19.4
0.0
20.2
4.7
20.7
27.6
23.8
16.2
8.5
4.4
–24.9
–9.9
37bǞINTbǞ38b
37cǞINTcǞ38c
37dǞINTdǞ38d
37eǞINTeǞ38e
37fǞINTfcis Ǟ38f
37fǞINTtrans Ǟ38f
37gǞINTgcis Ǟ38g
37gǞINTgtrans Ǟ38g
37hǞINThǞ38h
37iǞINTiǞ38i
13.2
15.4
19.3
17.1
20.0
23.9
25.5
–5.7
–8.9
–1.0
22.4
–19.9
–22.3
–18.9
–19.0
–19.0
–11.7
–11.7
–26.7
–10.7
–23.2
–19.5
9
10
11
12
13
37jǞINTjǞ38j
37kǞINTkǞ38k
[a] Some values of Entries 1, 3 and 9 have been reported previously;
see ref.[4a]
.
rier, by the order of 11 kcalmol–1 (Entry 1 vs. Entry 13),
and a 1,3-dithiolane function by approximately 9 kcalmol–1
(Entry 3 vs. Entry 13). The relative magnitude of the ΔE1϶
values also demonstrates that the ability of the acetal func-
tion to facilitate the [1,5]-H shift also depends on its ring
size. The energy barrier for the H migration is lower in five-
membered acetalic rings than in six-membered ones, as re-
vealed by comparison of the ΔE϶1 value of Entry 1 (1,3-
Scheme 12. Conversions of the carbodiimides 37f and 37g into the
spiroquinazolines 38f and 38g, showing the alternative transitions
states (TS1f,gcis/TS1f,gtrans and TS2f,gin/TS2f,gout) for the two-step
processes.
On comparison of the ΔE϶1 value of Entry 1 (conversion
dioxolane) with that of Entry 4 (1,3-dioxane), and of that of 37aǞINTa) with those of Entries 6 and 7 (conversions
Entry 3 (1,3-dithiolane) with that of Entry 5 (1,3-dithiane). 37fǞINTfcis and 37fǞINTftrans), as well as that of Entry 3
Consequently, the activating order for promoting the H (conversion 37cǞINTc) with those of Entries 8 and 9 (con-
shift of the acetal functions considered in this study is pre- versions 37gǞINTgcis and 37gǞINTgtrans), it is evident
dicted to be:
that the increase in the energy barrier associated with the
1,3-dioxolane Ͼ 1,3-dithiolane Ͼ 1,3-dioxane Ͼ 1,3-di- [1,5]-H shift is the result of the substitution of the ketenim-
thiane
ine fragment by a carbodiimide moiety.[19] Accordingly, for
These predictions are in agreement with the experimental the (dithio)acetal-ketenimines and (dithio)acetal-carbodi-
results.
The transformations of the acetalic carbodiimides 37f shift step is predicted to be:
and 37g take place through a mechanistic path similar to 1,3-dioxolane-ketenimines Ͼ 1,3-dithiolane-ketenimines
imides, the order of reactivity in the intramolecular [1,5]-H
that found for ketenimines, but it shows a particularity: Ͼ 1,3-dioxolane-carbodiimides Ͼ 1,3-dithiolane-carbodim-
there are two alternative transition structures (TS1f,gcis and ides
TS1f,gtrans) for the [1,5]-H shift as result of the cis or trans
When the benzene ring connecting the acetal and the
geometry acquired by the terminal C=N bond at the end heterocumulene functions is replaced by a pyrazole or thio-
of this step, leading to two stereoisomeric diazatrienic inter- phene the differences between ΔE϶1 and ΔE2϶ tend to be
mediates INTf,gcis and INTf,gtrans. Subsequently, each of smaller (compare Entry 10 with 12). Remarkably, in the
these intermediates undergoes electrocyclization, via the transformation 37iǞ38i (Entry 11) ΔE϶1 Ͻ ΔE2϶ and the
isomeric transition structures TS2f,gin and TS2f,gout
,
rate-limiting step is now the electrocyclization. The forma-
respectively (see Scheme 12). Whereas in TS2f, gin the hy- tion of the intermediates INTa–g and INTk is an endother-
drogen at the terminal nitrogen atom is placed inward to mic process in each case (see ΔErxnINT in Table 4). In con-
the σ C–N forming bond, in TS2f,gout that hydrogen atom trast, the formation of the o-azaxylylene-like intermediates
is placed outward. The TS1f,gcis transition states are INTh–j, containing either a pyrazole or a thiophene nucleus
slightly lower in energy than the TS1f,gtrans alternatives. In (Entries 10–12), is in each case an exothermic process, with
contrast, the TS2f,gout transition states are much lower in the highest ΔErxnINT value being found for INTi (Entry 11).
energy than TS2f,gin, and consequently the energy barriers These findings can be explained by considering that the
ΔE϶2 of Entries 7 and 9 are significantly smaller than those benzene ring connecting the acetal and ketenimine func-
of Entries 6 and 8. These results are reasonably explained tions in each of the structures 37a–g and 37k experiences a
by considering the assistance of the lone pair at the terminal loss of aromaticity when transforming into the correspond-
nitrogen atom of the diazatrienic fragment in the formation ing intermediates INTa–g and INTk in the first step,
of the new σ C–N bond in Entries 7 and 9.[18]
whereas in the second one (INTa–g,kǞ38a–g,k) an aroma-
1902
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Eur. J. Org. Chem. 2011, 1896–1913

Tandem 1,5-Hydride Shift/6π Electrocyclization
ticity recovery occurs. This should certainly penalize the ders (BOs) for the forming C1–H12 bonds are higher than
magnitude of the ΔE϶1 value and in contrast have a positive those of the breaking C6–H12 ones (see values in the Sup-
influence on ΔE϶2 . The striking differences shown by the porting Information), indicating that TS1a–g and TS1k are
heteroaryl-ketenimines 37h–j must have their origin in the late transition states, consistently with the Hammond–
lower aromaticity of the thiophene and, especially, the pyr- Leffer[22] postulate and the fact that the formations of the
azole rings connecting the hydride donor and acceptor intermediates INTa–g and INTk from the ketenimines
units.
37a–g and 37k are endothermic processes. In contrast, in
On comparing the ΔE϶1 values of Entries 1 versus 2 and TS1h and TS1i the BO values for the C1–H12 bond are
10 versus 11 it is evident that the substitution of hydrogen lower than those of the C6–H12 bond, whereas in TS1j the
atoms by phenyl groups in the terminal carbon atom of the BO value for the C1–H12 bond is only slightly greater than
ketenimine moiety facilitates the [1,5]-H shift. This behav- that of the C6–H12 bond.
iour is probably due to the decrease in the HOMO–LUMO
On the basis of the results presented above, we believe
energy gap that occurs with this substitution at the terminal that the [1,5]-H shifts occurring in the (dithio)acetalic-
atom of the heterocumulenic fragment.[20] In addition, the heterocumulenes 37a–j meet the appropriate characteristics
two phenyl groups probably stabilize the transition struc- to be classified as hydride transfer[23] processes from the
tures TS1b and TS1i and the intermediates INTb and INTi acetal function to the central carbon atom of the hetero-
by extending the conjugation. In contrast, this substitution cumulene moiety, in which the ability to impart hydricity of
of hydrogen atoms by phenyl groups at the sp2 heterocumul- the acetal functions is essential. Although not widespread
enic carbon atom has the opposite effect on the magnitude among chemists, the term hydricity has been coined as a
of the energy barrier associated with the 6π electrocyclic substitute for hydride transfer (or hydride donor) ability,
ring closure, increasing the magnitude of ΔE϶2 and decreas- and we find this term simple, clear and powerful. Typical
ing the exothermicity of the global process (see ΔErxn values chemicals displaying hydricity are mainly the metal hy-
in Table 4). The values computed for ΔE϶2 of Entries 2 and drides, but also NADH-like compounds and triarylmethane
11 are thus higher (by approximately 3 and 7 kcalmol–1) derivatives.[24] The thermodynamic[24,25] and kinetic[26] hy-
than those of Entries 1 and 10, respectively. The highest ΔE dricities of some of these hydride donors have been mea-
϶
2
is found in the conversion INTiǞ38i. These differences sured, and some hydricity scales are available.[24,25a,25c] In
can be interpreted on the basis of the greater steric inter- recent years, in the context of the search for new potential
ference of the two phenyl rings in the transition structures agents for chemical hydrogen storage, other classes of “or-
TS2b and TS2i as well as in the final spirofused pyridines ganic hydride” systems have emerged. Among them there
38b and 38i relative to the unsubstituted analogues TS2a,[21] are nitrogenated heterocycles such as the N,N-dimethyl-
TS2h, and 38a, 38h, respectively.
benzimidazoles 39,[23c,27] 2-benzoyl-N,N-dimethyl-perhy-
Note that the higher stability of INTi, relative to the rest dropyrimidine (40)[25c] and orthoformamides such as 41[28]
of the azahexatrienic intermediates considered in this study, (Figure 1).
and the relatively high value of ΔE϶2 for the conversion
INTiǞ38i could explain why the 3-azahexatriene interme-
diate 36 was partially trapped by diphenylketene to yield
the pyrazolo-pyridone 35 (Scheme 10).
Of the ketenimines, the lowest ΔE϶2 value is found in En-
try 13, and its origin must lie in the absence of steric hin-
drance, because the ketenimine 37k lacks the acetal func-
Figure 1. Some examples of “organic hydride” systems based on
tion. If all of the entries in Table 4 are considered, however,
nitrogenated heterocycles.
the lowest ΔE϶2 values correspond to Entries 7 and 9: in-
deed, the energy barrier is virtually nonexistent for the elec-
trocyclization of INTf into 38f via TS2fout. The remarkable
The noteworthy hydricity of 41 is explained as a conse-
difference between the ΔE϶2 values of Entries 7 and 9 and quence of its preference for the conformation shown in Fig-
the others has its origin, as commented on above, on the ure 1, in which the central C–H bond is weakened and pola-
configuration of the terminal C=N bond of the diazahex- rized by the three antiperiplanar lone pairs at nitrogen.[28]
atrienic intermediates INTf,gtrans, allowing the correspond- It is a hyperconjugative interaction between the lone pair
ing transition structures TS2f,gout to reach the optimal ge- electrons and the σ*(C–H) orbital that induces a weakening
ometry for the assistance of the lone pair at the terminal of the C–H bond and an increase in negative charge density
nitrogen in the formation of the new σ C–N bond.
at the hydrogen atom.
In order to gain further insight into the mechanistic
Until these studies the 1,3-dioxolane, 1,3-dithiolane, 1,3-
pathways of these transformations we analysed some elec- dioxane and 1,3-dithiane functions had not explicitly been
tronic and geometrical parameters of the stationary points documented as imparting hydricity.[29] However, they meet
involved in the conversions 37Ǟ38 in greater depth. With the criteria with two antiperiplanar O or S atom lone pairs
regard to the geometries of the transition states TS1a–k, that can confer hydride-like character to their H atoms at
the most relevant feature is their suprafacial nature. In the C2, as represented in structure A and expressed by reso-
transition states TS1a–g and TS1k the computed bond or- nance with the canonical structures B and C (Figure 2).
Eur. J. Org. Chem. 2011, 1896–1913
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1903

M. Alajarin, P. Sanchez-Andrada, A. Vidal et al.
FULL PAPER
going from the ketenimines 37a–k to the transition struc-
tures TS1a–k. We also calculated the sums of charges (∑q)
at the acetalic (hydride donor) functions for the conversions
37a–jǞ38a–j, and in the particular case of the transforma-
tion 37kǞ38k (we will refer to this fragment as the upper
fragment) also at the benzylic fragment, as well as the sums
of natural charges at the initially heterocumulenic (hydride
acceptor) moieties (named as lower fragments; see Figure
accompanying Table 6). It is apparent that the sums of the
natural charges in the upper fragments are positive and that
their values increase in going from the heterocumulenes
37a–k to the intermediates INTa–k. In the lower fragments,
in contrast, the signs of ∑q are negative, and their absolute
values also increase on going from ketenimines 37a–k to
the azahexatrienic intermediates INTa–k. These increases in
the positive and negative charge in the upper and lower
fragments are more pronounced in the conversions
37a,b,d,h–jǞ38a,b,d,h–j than in the conversions involving
dithioacetal-ketenimines (37c,eǞ38c,e), and much less im-
portant in the conversion of the N-(o-tolyl)-ketenimine
37kǞ38k. In addition, the charges on both fragments are
higher in the conversion of the dioxolane-carbodiimide 37f
than in the transformation of the dithiolane-carbodiimide
37g. These data are consistent with the relative hydride
character of the migrating hydrogen atom in each transfor-
mation considered in this study, which should be larger in
the acetal-heterocumulenes bearing 1,3-dioxolane or 1,3-di-
oxane functions than in those bearing 1,3-dithiolane or 1,3-
dithiane functions, and in turn much larger than in the N-
(o-tolyl)-ketenimine 37k.
Figure 2. 2-Monosubstituted 1,3-dioxolanes, 1,3-dithiolanes, 1,3-
dioxanes and 1,3-dithianes.
The computed natural bond orbital (NBO) analysis of
the heterocumulenes 37a–j and transition states TS1a–j
showed that the nx Ǟσ*C6–H12 hyperconjugative interac-
tions are dominant among those involving the acetalic C–
H bond and that the strengths of these interactions increase
on going from the heterocumulenes 37a–j to the transition
states TS1a–j, the “charge transfer” from the lone pairs at
the O and S atoms weakening that C–H bond. Table 5 illus-
trates the nx Ǟσ*C6–H12 interactions from the second-order
perturbation analysis of 37a, 37c, 37d, 37h and 37j and of
TS1a, TS1c, TS1d, TS1h and TS1j, showing that these in-
teractions are stronger in the acetal-ketenimines (37a, 37d,
37h, 37j) than in the dithioacetal-ketenimines (37c, 37e).[30]
Consequently, the acetalic C–H bonds in compounds 37a–
j are weakened and polarized by the lone pairs at the O
and S heteroatoms, inducing an increase in negative charge
density at the hydrogen atom.[28] In addition, the electro-
philic nature of the central carbon atom of the hetero-
cumulene function[11,31] matches with the nucleophilic char-
acter of the migrating hydrogen atom. Accordingly, the
[1,5]-H shifts occurring in compounds 37a–j can reasonably
be classified as hydride shifts.
The notable separation of charges between the upper and
lower fragments can be observed in all the stationary points
involved in the transformations 37a–kǞ38a–k, being at
their maxima in the intermediates INTa–k. In general, we
also found important increases in the dipole moments on
going from the heterocumulenes 37a–j (0.3–2.2 D) to the
intermediates INTa–j (5.0–8.6 D), except in the case of go-
ing from ketenimine 37i (1.0 D) to INTi (2.4 D). The di-
polar natures of the intermediates INTa–j can be also visu-
alized by computing the molecular electrostatic potential
(MESP) values, reflecting the electron-rich and electron-de-
ficient regions of each molecule (the MESP values calcu-
lated for INTa are represented in Figure S1 in the Support-
ing Information).
It would be expected that the notable dipolar natures of
the azahexatrienic intermediates INTa–j, with the positive
and negative charges delocalized on the upper and lower
fragments, respectively, should considerably favour the 6π
electrocyclic ring closure leading to the corresponding spi-
rocompounds 38a–j via the transition states TS2a–j. This
second step of the tandem sequence, the 6π electrocycliza-
tions through the TS2a–k transition states, deserves some
Table 5. nx Ǟσ*C6–H12 interactions from the second-order pertur-
bation analysis of 37a, 37c, 37d, 37h and 37j and of TS1a, TS1c,
TS1d, TS1h and TS1j [kcalmol–1].[a]
nx Ǟσ*C6–H12
Interaction
from
from
from
from
Lp1X1 Lp2X1 Lp1X2
Lp2X2
X1 = X2 = O
(dioxolane)
ring = C6H6
37a
TS1a
1.1
0.5
5.2
11.9
–
–
6.2
12.2
X1 = X2 = S
(dithiolane)
ring = C6H6
37c
TS1c
–
–
2.3
5.3
0.7
–
5.7
5.0
X1 = X2 = O
(dioxane)
ring = C6H6
37d
TS1d
1.8
1.1
4.0
11.4
1.7
–
4.6
12.8
X1 = X2 = O
(dioxolane)
ring = pyrazole
37h
TS1h
0.6
–
6.1
12.1
1.1
0.5
5.3
10.4
X1 = X2 = O
(dioxolane)
ring = thiophene
37j
TS1j
1.0
0.6
5.6
10.0
–
–
6.0
11.9
[a] For structures 37e, TS1e, 37f, TS1fcis, TS1ftrans, 37g, TS1gcis and
TS1gtrans see the Supporting Information.
We also calculated and analysed the natural charges for comment. Intrinsic reaction coordinates (IRCs) calculations
the heterocumulenes 37a–k, the transition structures TS1a– demonstrated that in the process going uphill from the in-
k and TS2a–k and the intermediates INTa–k. The most sig- termediates INTa–k toward the corresponding transition
nificant data are summarized in Table 6. With regard to the structures TS2a–k, the rotation around the C1–N3 single
[1,5]-H shift the charge analyses in all cases show decreases bond is gradually taking place, reaching the s-cis geometry
in the positive charge on the migrating hydrogen atoms on required for the cyclization along with the partial formation
1904
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Eur. J. Org. Chem. 2011, 1896–1913

Tandem 1,5-Hydride Shift/6π Electrocyclization
Table 6. Sums of natural charges[a] on the upper and lower fragments, natural charges on the C1, Y2, C6 and H12 atoms, and dipole
moments (Debyes) calculated for the heterocumulenes 37a–k, for the transition states TS1a–k and TS2a–k and for the intermediates
INTa–k.
∑q
∑q
upper fragment
lower fragment
qC1
qC6
qH12
qY2
μ
37a
0.017
0.255
0.356
0.335
–0.169
–0.339
–0.387
–0.367
0.420
0.235
0.144
0.254
0.602
0.668
0.710
0.722
0.224
0.188
0.191
0.223
–0.143
–0.110
–0.039
–0.112
0.62
5.22
6.53
6.25
37aǞINTaǞ38a
37bǞINTbǞ38b
37cǞINTcǞ38c
37dǞINTdǞ38d
37eǞINTeǞ38e
TS1a
INTa
TS2a
37b
0.019
0.264
0.377
0.590
–0.186
–0.313
–0.372
–0.485
0.460
0.293
0.203
0.320
0.602
0.666
0.720
0.842
0.223
0.191
0.199
0.223
–0.221
–0.172
–0.093
–0.263
0.87
4.90
6.39
6.73
TS1b
INTb
TS2b
37c
0.016
0.188
0.235
0.209
–0.175
–0.294
–0.335
–0.286
0.420
0.225
0.141
0.238
–0.247
–0.348
–0.328
–0.327
0.299
0.234
0.206
0.227
–0.142
–0.081
–0.001
–0.048
0.62
4.62
5.03
4.98
TS1c
INTc
TS2c
37d
0.013
0.280
0.342
0.390
–0.171
–0.361
–0.386
–0.399
0.419
0.237
0.143
0.252
0.587
0.676
0.712
0.744
0.214
0.181
0.189
0.222
–0.146
–0.130
–0.042
–0.138
0.94
5.65
6.50
7.29
TS1d
INTd
TS2d
37e
0.003
0.196
0.228
0.210
–0.174
–0.305
–0.334
–0.286
0.421
0.224
0.145
0.238
–0.272
–0.353
–0.338
–0.335
0.292
0.231
0.202
0.228
–0.142
–0.092
–0.009
–0.050
0.89
4.76
5.23
5.28
TS1e
INTe
TS2e
37f
0,014
0.334
0.419
0.484
0.318
0.395
0.535
–0.160
–0.420
–0.487
–0.503
–0.403
–0.462
–0.604
0.679
0.475
0.400
0.470
0.436
0.381
0.430
0.600
0.703
0.742
0.795
0.695
0.731
0.829
0.221
0.174
0.174
0.207
0.145
0.152
0.183
–0.303
–0.365
–0.351
–0.420
–0.332
–0.339
–0.445
2.06
4.90
7.06
6.57
7.28
8.23
6.16
37fǞINTfcis Ǟ38f
37fǞINTftrans Ǟ38f
TS1fcis
INTfcis
TS2fin
TS1ftrans
INTftrans
TS2fout
37g
0.015
0.297
0.314
0.383
0.263
0.290
0.448
–0.162
–0.394
–0.447
–0.440
–0.363
–0.432
–0.526
0.694
0.463
0.397
0.458
0.435
0.365
0.447
–0.249
–0.319
–0.310
–0.294
–0.336
–0.312
–0.230
0.296
0.216
0.188
0.211
0.192
0.168
0.195
–0.299
–0.350
–0.322
–0.374
–0.314
–0.313
–0.393
1.4
4.71
6.4
5.63
6.85
6.78
5.27
37gǞINTgcis Ǟ38g
37gǞINTgtrans Ǟ38g
TS1gcis
INTgcis
TS2gin
TS1gtrans
INTgtrans
TS2gout
37h
0.008
0.218
0.371
0.362
–0.149
–0.318
–0.434
–0.400
0.425
0.249
0.156
0.254
0.592
0.645
0.719
0.729
0.215
0.185
0.200
0.226
–0.119
–0.086
–0.048
–0.128
2.15
5.11
8.62
7.19
37hǞINThǞ38h
37iǞINTiǞ38i
37jǞINTjǞ38j
37kǞINTkǞ38k
TS1h
INTh
TS2h
37i
0.010
0.223
0.390
0.519
–0.174
–0.334
–0.464
–0.592
0.460
0.301
0.214
0.352
0.591
0.639
0.724
0.804
0.217
0.189
0.207
0.227
–0.220
–0.164
–0.101
–0.253
1.91
4.49
8.17
5.95
TS1i
INTi
TS2i
37j
0.012
0.181
0.296
0.269
–0.171
–0.300
–0.364
–0.338
0.411
0.236
0.147
0.252
0.592
0.616
0.665
0.666
0.231
0.191
0.196
0.225
–0.140
–0.091
–0.0239
–0.101
0.32
4.04
5.69
5.21
TS1j
INTj
TS2j
37k
0.057
0.143
0.115
0.119
–0.181
–0.286
–0.297
–0.233
0.417
0.192
0.136
0.240
0.057
0.143
0.115
0.119
0.262
0.223
0.210
0.235
–0.151
–0.066
0.008
0.97
2.67
2.40
2.08
TS1k
INTk
TS2k
–0.018
[a] To calculate the charges at the acceptor and donor carbon atoms C1 and C6 in TS1a–k we considered the C1–H12 and C6–H12 bond
orders and proportionally summed the charge of the migrating hydrogen atom into each carbon atom (see atomic numbering in the
Figure accompanying this Table).
Eur. J. Org. Chem. 2011, 1896–1913
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1905

M. Alajarin, P. Sanchez-Andrada, A. Vidal et al.
FULL PAPER
of the new C2–C6 σ bond in proximity to TS2a–k.[32] The associated with the conversions 37a,c–iǞ38a,c–i with the
analysis of the geometries of these transition states, the IRC aid of the new hybrid meta exchange correlation functional
calculations and the animation of their associated imagi- M06 of Truhlar and Zhao,[38] with the internal 6–31+G**
nary frequencies all point to a classical disrotatory ring clo- basis set, and the values obtained for the energy barriers
sure,[33] as required for a thermally allowed 6π electrocycl- and reaction energies are very similar to the values based
ization,[34] with the exceptions of TS2f,gout due to the lone on B3LYP geometries (see the Supporting Information).
pair assistance as explained above.
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 (ZPVEs), which were
not scaled. The intrinsic reaction coordinates (IRCs)[39]
were followed to verify the energy profiles connecting each
transition state to the correct local minima, by use of the
second-order Gonzalez–Schlegel integration method.[40]
Natural charges and second-order perturbation analyses
were evaluated by the natural bond orbital (NBO)
method.[41]
Conclusions
In conclusion, here we disclose that N-aryl ketenimines
ortho-substituted with five- and six-membered cyclic acetal
functions (1,3-dioxolane, dithiolane, dioxane and dithiane)
undergo thermally induced cyclizations to spiroquinolines
in toluene or xylene solutions. These conversions are inter-
preted as tandem 1,5-H shift/6π electrocyclization pro-
cesses, via reactive ortho-azaxylylene intermediates. Struc-
turally analogous N-aryl carbodiimides also undergo sim-
ilar tandem sequences to give spiroquinazolines. The ortho-
phenylene scaffold bearing the ketenimine and (dithio)ace-
tal functions can be successfully replaced by heteroaromatic
components such as thiophene and pyrazole. The mechan-
istic pathway and the hydride-like characteristics of the rate-
determining H-shift step were assessed by a computational
DFT study, which also accounted for the differences in the
reaction conditions demanded by the diverse acetal func-
tions, the ketenimine or carbodiimides moieties and the aro-
matic or heteroaromatic scaffolds. Ketenimines borne on
thiophene and pyrazole rings have been shown to be more
reactive than their N-phenyl counterparts as result of the
lower activation energies of their hydride-shift steps. In ad- benzaldehyde (6d),[43] 3-azidothiophene-2-carbaldehyde (28),[45] 5-
dition, the computations also show the dipolar natures of
the ortho-azaxylylene intermediates and the habitual dis-
rotatory mode of the final 6π electrocyclizations. This final
step turned out to be the rate-determining one in the case
of the pyrazole ring supporting scaffold and two phenyl
rings at the terminal carbon of the ketenimine fragment,
thus explaining the particular outcome of the analogous ex-
Experimental Section
General: All melting points are uncorrected. Infrared (IR) spectra
1
were recorded neat or as Nujol emulsions. H NMR spectra were
recorded in CDCl3 or [D6]DMSO at 300 or 400 MHz. 13C NMR
spectra were recorded in CDCl3 or [D6]DMSO at 75 or 100 MHz.
31P NMR spectra were recorded in CDCl3 at 121.4 or 161.9 MHz,
with H3PO4 as internal reference. The chemical shifts are given in
1
ppm, relative to Me4Si at δ = 0.00 ppm for H, whereas the chemi-
cal shifts for 13C are reported relative to the resonances of CDCl3
(δ = 77.1 ppm) or [D6]DMSO (δ = 39.5 ppm).
2-Azidobenzaldehyde
(6a),[42]
2-azido-3-methylbenzaldehyde
(6b),[43] 2-azido-5-chlorobenzaldehyde (6c),[44] 2-azido-5-methyl-
azido-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde (32),[46] di-
phenylketene[47] and methylphenylketene[48] were prepared by pub-
lished experimental procedures. The preparation of and analytical
and spectroscopic data for compounds 4, 7, 8 and 24b–e, 24g and
24h have been reported previously.[4a]
Compounds 9, 11 and 13 were obtained as mixtures of isomers.
In their NMR spectroscopic data only those signals that could be
assigned unambiguously are given.
perimental case, in which the corresponding intermediate is
4-Methyl-2-(2-triphenylphosphoranylideneaminophenyl)-1,3-dioxol-
ane (9) and (4R,5R)-4,5-Dimethyl-2-(2-triphenylphosphoranylidene-
partially captured by diphenylketene in a [4+2] cycload-
dition reaction. Further applications of the hydride-releas-
ing characteristics of the acetal functions are now underway
in our laboratories.
aminophenyl)-1,3-dioxolane
(14):
Propane-1,2-diol
(0.62 g,
8.2 mmol) or (2R,3R)-(–)-butane-2,3-diol (0.74 g, 8.2 mmol) and p-
toluenesulfonic acid monohydrate (0.1 g) were added to a solution
of 2-azidobenzaldehyde (6a, 1 g, 6.8 mmol) in benzene (75 mL).
The reaction mixture was heated at reflux temperature for 3 h, with
azeotropic removal of water with a Dean–Stark trap. After at the
mixture had cooled to room temperature, diethyl ether (50 mL) was
added and the resulting mixture was washed with saturated sodium
hydrogen carbonate solution (3ϫ50 mL) and brine (3ϫ50 mL).
The organic phase was dried with anhydrous magnesium sulfate.
The solvent was removed under reduced pressure and the resulting
material was purified by column chromatography on silica gel, with
hexanes/diethyl ether (7:3, v/v) as eluent, to provide either 2-(2-azi-
dophenyl)-4-methyl-1,3-dioxolane as a mixture of diastereoisomers
in a 1:0.75 cis/trans ratio (1.38 g, 99% yield), or (4R,5R)-2-(2-azi-
dophenyl)-4,5-dimethyl-1,3-dioxolane (1.47 g, 82% yield).
Computational Details
All calculations were carried out in the gas phase with
the Gaussian03[35] suite of programs. An intensive charac-
terization of the potential energy surfaces was carried out
at the HF/6–31G*[36] theoretical level and then with the hy-
brid three-parameter functional customarily denoted as
B3LYP[37] by use of the 6–31+G** basis set. All the re-
ported stationary points were fully optimized by analytical
gradient techniques. To check the accuracy and perform-
ance of the B3LYP functional in the study of these transfor-
mations we also optimized the molecular geometries of all
Triphenylphosphane (1.57 g, 6 mmol) was added in portions of
the stationary points found on the potential energy surfaces 0.4 g every two minutes to a solution of either 2-(2-azidophenyl)-4-
1906
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1896–1913

Tandem 1,5-Hydride Shift/6π Electrocyclization
methyl-1,3-dioxolane (1.23 g, 6 mmol) or (4R,5R)-2-(2-azi-
dophenyl)-4,5-dimethyl-1,3-dioxolane (1.31 g, 6 mmol) in anhydrous
diethyl ether (30 mL). The reaction mixture was stirred at room
temperature under nitrogen for 16 h. The precipitated compound 9
or 14 was then isolated by filtration and washed with anhydrous
diethyl ether (10 mL). This compound was used in the following
step without further purification. For analytical samples the imino-
phosphoranes 9 and 14 were recrystallized from diethyl ether.
(vs), 2931 (s), 1687 (w), 1620 (s), 1600 (s), 1496 (s), 1454 (vs), 1375
(m), 1228 (s), 1089 (vs), 1029 (m), 972 (m), 873 (w), 769 (s), 700
(vs) cm–1. HRMS (ESI): calcd. for C19H20NO2 [M + H]+ 294.1489;
found 294.1491.
4-Methyl-3Ј,3Ј-diphenylspiro[1,3-dioxolane-2,4Ј(3ЈH)-quinoline] (13):
Eluent for column chromatography: hexanes/diethyl ether (1:1,
v/v); yield 65% (0.25 g, mixture of two diastereoisomers in a 1:0.5
ratio); colourless prisms (diethyl ether). Major isomer: 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 1.16 (d, J = 6.0 Hz, 3 H, CH3-C4),
8.61 (s, 1 H, 2Ј-H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ =
17.8 (CH3-C4), 167.9 (C2Ј) ppm. Minor isomer: 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 0.79 (d, J = 5.9 Hz, 3 H, CH3-C4),
8.62 (s, 1 H, 2Ј-H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ =
4-Methyl-2-(2-triphenylphosphoranylideneaminophenyl)-1,3-dioxol-
ane (9): Mixture of diastereoisomers in a 1:0.8 cis/trans ratio; yield
86 % (2.27 g); colourless prisms (diethyl ether). cis Isomer: 1H
NMR (300 MHz, CDCl3, 25 °C): δ = 1.42 (d, J = 6.0 Hz, 3 H),
3.64 (t, J = 7.2 Hz, 1 H), 4.13 (t, J = 6.9 Hz, 1 H), 4.30–4.40 (m,
1 H), 6.75 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ =
18.9, 99.3 ppm. 31P NMR (121.4 MHz, CDCl3, 25 °C): δ =
16.4 (CH -C4), 167.7 (C2Ј) ppm. IR (Nujol): ν = 1616 (m), 1596
˜
3
(s), 1317 (m), 1253 (s), 1159 (s), 1091 (vs), 1060 (s), 1002 (s), 958
(s), 849 (m), 829 (w), 763 (vs), 703 (vs) cm–1. HRMS (ESI): calcd.
for C24H22NO2 [M + H]+ 356.1645; found 356.1650.
1
1.40 ppm. trans Isomer: H NMR (300 MHz, CDCl3, 25 °C): δ =
1.39 (d, J = 6.1 Hz, 3 H), 3.59 (t, J = 7.4 Hz, 1 H), 4.30–4.40 (m,
1 H), 4.41–4.48 (m, 1 H), 6.79 (s, 1 H) ppm. 13C NMR (75 MHz,
CDCl3, 25 °C): δ = 18.2, 98.8 ppm. 31P NMR (121.4 MHz, CDCl3,
(4R,5R)-4,5-Dimethyl-3Ј,3Ј-diphenylspiro[1,3-dioxolane-2,4Ј(3ЈH)-
quinoline] (15): Eluent for column chromatography: hexanes/diethyl
ether (3:2, v/v); yield 87% (0.35 g); colourless prisms; m.p. 139–
140 °C (diethyl ether). 1H NMR (400 MHz, CDCl3, 25 °C): δ =
0.80 (d, J = 5.6 Hz, 3 H), 1.15 (br. s, 3 H), 2.39 (br. s, 1 H), 3.53
(br. s, 1 H), 7.18–7.37 (m, 13 H), 7.63–7.65 (m, 1 H), 8.62 (s, 1
H) ppm. 13C NMR (100 MH, CDCl3, 25 °C): δ = 15.2, 16.3, 59.1
(s), 79.9, 106.7 (s), 122.7, 127.0, 127.1, 127.4, 127.6, 127.8, 128.3,
129.2, 130.4, 130.9, 132.0 (s), 140.3 (s), 140.7 (s), 142.4 (s),
25 °C): δ = 0.93 ppm. IR (Nujol): ν = 1594 (vs), 1564 (m), 1197
˜
(m), 1184 (m), 1155 (m), 1105 (vs), 1049 (vs), 1024 (s), 997 (s), 968
(s), 937 (m), 757 (s), 744 (s), 713 (vs), 694 (vs), 630 (w) cm–1. HRMS
(ESI): calcd. for C28H27NO2P [M + H]+ 440.1774; found 440.1784.
(4R,5R)-4,5-Dimethyl-2-(2-triphenylphosphoranylideneaminophen-
yl)-1,3-dioxolane (14): Yield 84% (2.28 g); colourless prisms; m.p.
151–152 °C (diethyl ether). [α]2D0 = 1.04 (c = 31.8ϫ10–3 gmL–1;
CH2Cl2). 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.38 (d, J =
5.6 Hz, 3 H), 1.44 (d, J = 5.6 Hz, 3 H), 3.83–3.90 (m, 2 H), 6.43
(d, J = 8.0 Hz, 1 H), 6.70 (t, J = 7.6 Hz, 1 H), 6.85 (s, 1 H), 6.85
(td, J = 7.6, 2.0 Hz, 1 H), 7.41–7.46 (m, 6 H), 7.49–7.54 (m, 4 H),
7.77–7.83 (m, 6 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ =
17.3, 17.7, 78.2, 79.9, 99.9, 117.3, 121.4 (d, J = 9.7 Hz), 126.6 (d,
J = 1.0 Hz), 128.5 (d, J = 12.0 Hz), 128.7, 131.3 (s), 131.5 (d, J =
2.6 Hz), 131.7 (d, J = 99.3 Hz) (s), 132.7 (d, J = 9.6 Hz), 149.7
(s) ppm. 31P NMR (121.4 MHz, CDCl3, 25 °C): δ = 0.07 ppm. IR
167.9 ppm. IR (Nujol): ν = 1621 (s), 1599 (vs), 1578 (m), 1496 (vs),
˜
1275 (s), 1248 (vs), 1154 (vs), 1090 (vs), 1039 (s), 957 (s), 919 (m),
840 (m), 778 (vs), 754 (vs), 698 (vs) cm–1. HRMS (ESI): calcd. for
C25H24NO2 [M + H]+ 370.1802; found 370.1808.
Less Polar Diastereoisomer of (4R,5R)-3Ј,4,5-Trimethyl-3Ј-phen-
ylspiro[1,3-dioxolane-2,4Ј(3ЈH)-quinoline] (16): Eluent for column
chromatography: hexanes/ethyl acetate (4:1, v/v); yield 25 %
(0.084 g). [α]2D0 = 0.45 (c = 21.1ϫ10–3 gmL–1; CH2Cl2). H NMR
1
(400 MHz, CDCl3, 25 °C): δ = 0.71 (d, J = 6.0 Hz, 3 H), 1.21 (d,
J = 6.0 Hz, 3 H), 1.50 (s, 3 H), 2.65–2.72 (m, 1 H), 3.37–3.44 (m,
1 H), 7.26–7.54 (m, 9 H), 8.18 (s, 1 H) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 15.0, 16.0, 17.3, 50.6 (s), 77.3, 80.0, 107.3 (s),
123.6, 127.5, 127.6, 127.7, 128.2, 129.6, 129.9, 130.1 (s), 139.3 (s),
142.5 (s), 170.8 ppm. HRMS (ESI): calcd. for C20H22NO2 [M +
H]+ 308.1645; found 308.1651.
(Nujol): ν = 1594 (vs), 1564 (m), 1436 (vs), 1333 (vs), 1285 (s), 1192
˜
(s), 1108 (vs), 1084 (vs), 1052 (vs), 1024 (vs), 999 (s), 970 (vs), 757
(vs), 749 (vs), 719 (vs), 695 (vs) cm–1. HRMS (ESI): calcd. for
C29H29NO2P [M + H]+ 454.193; found 454.1937.
Spiro[1,3-dioxolane-2,4Ј(3ЈH)-quinolines] 11, 13, 15 and 16: Either
methylphenylketene (0.15 g, 1.1 mmol) or diphenylketene (0.21 g,
1.1 mmol) in anhydrous toluene (5 mL) was added to a solution
either of 4-methyl-2-(2-triphenylphosphoranylideneaminophenyl)-
1,3-dioxolane (9, 0.48 g, 1.1 mmol) or of (4R,5R)-4,5-dimethyl-2-
More Polar Diastereoisomer of (4R,5R)-3Ј,4,5-Trimethyl-3Ј-phen-
ylspiro[1,3-dioxolane-2,4Ј(3ЈH)-quinoline] (16): Eluent for column
chromatography: hexanes/ethyl acetate (4:1, v/v); yield 19%
(0.064 g). [α]2D0 = 42.87 (c = 4ϫ10–3 gmL–1; CH2Cl2). 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 0.98 (d, J = 6.0 Hz, 3 H), 1.05 (d,
J = 6.0 Hz, 3 H), 1.51 (s, 3 H), 2.28–2.37 (m, 1 H), 3.69–3.78 (m,
1 H), 7.25–7.50 (m, 9 H), 8.17 (s, 1 H) ppm. 13C NMR (75 MHz,
CDCl3, 25 °C): δ = 16.0, 16.5, 17.3, 50.8 (s), 79.2, 80.1, 107.6 (s),
123.5, 127.5, 127.6, 127.9, 128.4, 129.4, 129.5, 130.3 (s), 138.7 (s),
142.5 (s), 170.6 ppm. HRMS (ESI): calcd. for C20H22NO2 [M +
H]+ 308.1645; found 308.1651.
(2-triphenylphosphoranylideneaminophenyl)-1,3-dioxolane
(14,
0.5 g, 1.1 mmol) in the same solvent (15 mL). The reaction mixture
was stirred at room temperature for 15 min and next heated at re-
flux temperature for 1 h. After the system had cooled, the solvent
was removed under reduced pressure. The resulting material was
purified by column chromatography on silica gel.
3Ј,4-Dimethyl-3Ј-phenylspiro[1,3-dioxolane-2,4Ј(3ЈH)-quinoline] (11):
Eluent for column chromatography: hexanes/diethyl ether (1:1, v/v);
yield 44% (0.14 g, mixture of four diastereoisomers in
a
2-(2-Triphenylphosphoranylideneaminophenyl)-1,3-dioxanes 18a and
18b: Propane-1,3-diol (1.29 g, 17 mmol) and p-toluenesulfonic acid
monohydrate (0.1 g) were added to a solution either of 2-azi-
dobenzaldehyde (6a, 2.06 g, 14 mmol) or of 2-azido-5-chlorobenz-
aldehyde (6c, 2.32 g, 14 mmol) in benzene (70 mL). The reaction
0.25:0.35:0.75:1 ratio); colourless oil. Isomer A: 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 0.80 (d, J = 5.7 Hz, 3 H, CH3-C4),
1.53 (s, 3 H, CH3-C3Ј), 8.18 (s, 1 H, H2Ј) ppm. Isomer B: 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 0.95 (d, J = 6.0 Hz, 3 H, CH3-C4),
1.52 (s, 3 H, CH3-C3Ј), 8.14 (s, 1 H, H2Ј) ppm. Isomer C: 1H NMR mixture was heated at reflux temperature for 3 h, with azeotropic
(400 MHz, CDCl3, 25 °C): δ = 1.03 (d, J = 6.0 Hz, 3 H, CH3-C4), removal of water with a Dean–Stark trap. After the system had
1.51 (s, 3 H, CH3-C3Ј), 8.12 (s, 1 H, H2Ј) ppm. Isomer D: 1H NMR cooled to room temperature, diethyl ether (50 mL) was added and
(400 MHz, CDCl3, 25 °C): δ = 1.25 (d, J = 5.8 Hz, 3 H, CH3-C4), the resulting mixture was washed with saturated sodium hydrogen
1.50 (s, 3 H, CH -C3Ј), 8.16 (s, 1 H, H2Ј) ppm. IR (neat): ν = 2975 carbonate solution (3ϫ50 mL) and brine (3ϫ50 mL). The organic
˜
3
Eur. J. Org. Chem. 2011, 1896–1913
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1907

M. Alajarin, P. Sanchez-Andrada, A. Vidal et al.
FULL PAPER
phase was dried with anhydrous magnesium sulfate. The solvent
was removed under reduced pressure and the resulting material was
purified by column chromatography on silica gel, with hexanes/
diethyl ether (7:3, v/v) as eluent, to give either 2-(2-azidophenyl)-
1,3-dioxane (17a, 2.84 g, 99% yield) or 2-(2-azido-5-chlorophenyl)-
1,3-dioxane (17b, 2.14 g, 64% yield).
(25 mL). The reaction mixture was stirred at room temperature un-
der nitrogen for 16 h. The precipitated compound 18 was then iso-
lated by filtration and washed with anhydrous diethyl ether
(15 mL). Compounds 18 were used in the following step without
further purification. For analytical samples, the iminophos-
phoranes 18c and 18d were recrystallized from diethyl ether.
Triphenylphosphane (1.05 g, 4 mmol) was added in portions of
0.21 g every two minutes to a solution of the corresponding 2-(2-
azidophenyl)-1,3-dioxane 17 (4 mmol) in anhydrous diethyl ether
(25 mL). The reaction mixture was stirred at room temperature un-
der nitrogen for 16 h. The precipitated compound 18 was then iso-
lated by filtration and washed with anhydrous diethyl ether
(15 mL). Compounds 18 were used in the following step without
further purification. For analytical samples, the iminophos-
phoranes 18a and 18b were recrystallized from diethyl ether.
2-(2-Triphenylphosphoranylideneaminophenyl)-1,3-dithiane
(18c):
Yield 90% (1.70 g); colourless prisms; m.p. 138–140 °C (diethyl
ether). 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.89–1.98 (m, 1
H), 2.12–2.16 (m, 1 H), 2.87–2.91 (m, 2 H), 3.07 (t, J = 12.4 Hz, 2
H), 6.34 (s, 1 H), 6.39 (d, J = 7.9 Hz, 1 H), 6.64 (t, J = 7.3 Hz, 1
H), 6.74–6.78 (m, 1 H), 7.40–7.53 (m, 10 H), 7.75–7.80 (m, 6
H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 25.8, 32.8, 47.6,
117.6, 121.2 (d, J = 9.6 Hz), 128.1 (d, J = 8.1 Hz), 128.6 (d, J =
11.8 Hz), 131.2 (d, J = 99.3 Hz) (s), 131.6 (d, J = 2.4 Hz), 132.6 (d,
J = 9.6 Hz), 132.8 (s), 148.1 (s) ppm. IR (Nujol): ν = 1351 (s), 1326
˜
2-(2-Triphenylphosphoranylideneaminophenyl)-1,3-dioxane
(18a):
(s), 1274 (m), 1107 (vs), 1053 (m), 1018 (m), 997 (w), 750 (m), 719
(vs), 692 (s), 676 (w) cm–1. 31P NMR (161.9 MHz, CDCl3, 25 °C):
δ = 2.1 ppm. HRMS (ESI): calcd. for C28H27NPS2 [M + H]+
472.1317; found 472.1323.
Yield 93% (1.63 g); colourless prisms; m.p. 171–172 °C (diethyl
ether). 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.36–1.40 (m, 1
H), 2.18–2.30 (m, 1 H), 3.97–4.03 (m, 2 H), 4.22–4.26 (m, 2 H),
6.36 (s, 1 H), 6.40–6.42 (m, 1 H), 6.67 (t, J = 7.4 Hz, 1 H), 6.81
(td, J = 7.4, 1.8 Hz, 1 H), 7.38–7.43 (m, 6 H), 7.45–7.49 (m, 3 H), 2-(5-Chloro-2-triphenylphosphoranylideneaminophenyl)-1,3-dithiane
7.53 (dt, J = 7.6, 2.1 Hz, 1 H), 7.73–7.79 (m, 6 H) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 26.2, 67.6, 99.7, 117.5, 121.5 (d, J
(18d): Yield 93% (1.88 g); colourless prisms; m.p. 173–174 °C (di-
ethyl ether). 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.89–2.00 (m,
= 9.5 Hz), 126.3, 128.5 (d, J = 11.8 Hz), 131.5 (d, J = 2.5 Hz), 1 H), 2.13–2.20 (m, 1 H), 2.91 (dt, J = 14.0, 3.2 Hz, 2 H), 3.06 (td,
131.6 (d, J = 99.2 Hz) (s), 132.3 (s), 132.5 (d, J = 9.6 Hz), 148.4
J = 14.0, 2.8 Hz, 2 H), 6.25 (s, 1 H), 6.28 (dd, J = 8.4, 1.2 Hz, 1
H), 6.71 (dd, J = 8.4, 2.8 Hz, 1 H), 7.43–7.47 (m, 7 H), 7.50–7.55
(m, 3 H), 7.73–7.79 (m, 6 H) ppm. 13C NMR (100 MHz, CDCl3,
25 °C): δ = 25.7, 32.7, 47.1, 121.9 (d, J = 9.6 Hz), 122.1 (s), 127.9,
128.1, 128.7 (d, J = 12.0 Hz), 130.9 (d, J = 100.4 Hz) (s), 131.8 (d,
J = 2.7 Hz), 132.6 (d, J = 9.8 Hz), 134.2 (d, J = 21.9 Hz) (s), 146.9
(s) ppm. 31P NMR (161.9 MHz, CDCl3, 25 °C): δ = 3.12 ppm. IR
(s) ppm. 31P NMR (161.9 MHz, CDCl3, 25 °C): δ = 0.9 ppm. IR
(Nujol): ν = 1351 (vs), 1274 (w), 1147 (w), 1103 (s), 1053 (w), 997
˜
(m), 977 (m), 925 (w), 757 (m), 742 (m), 719 (s), 711 (s), 692
(m) cm–1. HRMS (ESI): calcd. for C28H27NO2P [M
440.1774; found 440.1779.
+
H]+
2-(5-Chloro-2-triphenylphosphoranylideneaminophenyl)-1,3-dioxane
(Nujol): ν = 1583 (s), 1436 (vs), 1405 (vs), 1288 (vs), 1275 (vs),
˜
(18b): Yield 72% (1.36 g); colourless prisms; m.p. 166–167 °C (di-
1188 (s), 1106 (vs), 1019 (vs), 919 (s), 898 (m), 809 (s), 753 (s), 721
(vs), 692 (vs) cm–1. HRMS (ESI): calcd. for C28H26ClNPS2 [M +
H]+ 506.0927; found 506.0935.
Spiroquinolines 21. Method A (R2 = Ph): Diphenylketene (0.19 g,
1
ethyl ether). H NMR (400 MHz, CDCl3, 25 °C): δ = 1.42 (d, J =
13.6 Hz, 1 H), 2.19–2.31 (m, 1 H), 3.99 (t, J = 12.0 Hz, 2 H), 4.24
(dd, J = 12.0, 4.8 Hz, 2 H), 6.28 (s, 1 H), 6.31 (d, J = 8.4 Hz, 1 H),
6.76 (dd, J = 8.4, 2.8 Hz, 1 H), 7.43–7.48 (m, 6 H), 7.51–7.55 (m,
4 H), 7.73–7.78 (m, 6 H) ppm. 13C NMR (100 MHz, CDCl3, 1 mmol) in anhydrous ortho-xylene (5 mL) was added to a solution
25 °C): δ = 26.1, 67.6, 99.0, 122.5 (d, J = 9.0 Hz), 122.6 (s), 126.7
(d, J = 1.0 Hz), 128.4, 128.7 (d, J = 11.9 Hz), 131.0 (d, J = 99.7 Hz)
(s), 131.8 (d, J = 2.7 Hz), 132.6 (d, J = 9.6 Hz), 133.8 (d, J =
20.2 Hz) (s), 147.0 (s) ppm. 31P NMR (161.9 MHz, CDCl3, 25 °C):
of the corresponding iminophosphorane 18 (1 mmol) in the same
solvent (15 mL). The reaction mixture was stirred at room tempera-
ture for 15 min and next heated at reflux temperature for 12–24 h.
After the system had cooled, the solvent was removed under re-
duced pressure. The resulting material was purified by column
δ = 2.43 ppm. IR (Nujol): ν = 1592 (m), 1413 (s), 1344 (vs), 1258
˜
(m), 1099 (vs), 1039 (m), 998 (s), 886 (m), 745 (m), 723 (s), 693 chromatography on silica gel.
(s) cm–1. HRMS (ESI): calcd. for C28H26ClNO2P [M + H]+
474.1384; found 474.1389.
Method B (R2 = CH3): Methylphenylketene (0.13 g, 1 mmol) in an-
hydrous dichloromethane (5 mL) was added to a solution of the
2-(2-Triphenylphosphoranylideneaminophenyl)-1,3-dithianes 18c and corresponding iminophosphorane 18 (1 mmol) in the same solvent
18d: Boron trifluoride diethyl etherate (0.25 mL) was added under
nitrogen to a solution of propane-1,3-dithiol (1.62 g, 15 mmol) and
either 2-azidobenzaldehyde (6a, 1.47 g, 10 mmol) or 2-azido-5-
chlorobenzaldehyde (6c, 1.65 g, 10 mmol) in anhydrous dichloro-
methane (40 mL), and the reaction mixture was stirred at room
temperature for 12 h. NaOH solution (5%, 50 mL) was then added.
The organic layer was separated, washed with water (2ϫ40 mL)
and dried with anhydrous magnesium sulfate. The solvent was re-
moved under reduced pressure, and the resulting material was puri-
fied by column chromatography on silica gel, with hexanes/diethyl
ether (4:1, v/v) as eluent to give either 2-(2-azidophenyl)-1,3-dithiane
(17c, 2.06 g, 87% yield) or 2-(2-azido-5-chlorophenyl)-1,3-dithiane
(17d, 1.9 g, 70% yield).
(15 mL). The reaction mixture was stirred at room temperature for
15 min. The solvent was removed under reduced pressure and the
resulting material was purified by column chromatography on silica
gel, with hexanes/diethyl ether (9:1, v/v), as eluent to provide the
ketenimines 19 (R2 = CH3). A solution of these ketenimines
(0.5 mmol) in anhydrous ortho-xylene (15 mL) was heated at reflux
temperature for 12–24 h. After the system had cooled, the solvent
was removed under reduced pressure. The resulting material was
purified by column chromatography on silica gel.
3Ј,3Ј-Diphenylspiro[1,3-dioxane-2,4Ј(3ЈH)-quinoline] (21a): Eluent
for column chromatography: hexanes/diethyl ether (7:3, v/v); yield
90% (0.16 g); colourless prisms; m.p. 137–138 °C (diethyl ether).
1H NMR (400 MHz, [D6]DMSO, 25 °C): δ = 1.41–1.52 (m, 1 H),
1.70–1.81 (m, 1 H), 3.35 (t, J = 6.9 Hz, 1 H), 3.39 (t, J = 6.9 Hz,
1 H), 3.62 (t, J = 6.4 Hz, 1 H), 3.66 (t, J = 6.4 Hz, 1 H), 7.17–7.23
(m, 7 H), 7.29–7.37 (m, 6 H), 7.84–7.88 (m, 1 H), 8.55 (s, 1 H) ppm.
Triphenylphosphane (1.05 g, 4 mmol) was added in portions of
0.21 g every two minutes to a solution of the corresponding 2-(2-
azidophenyl)-1,3-dithiane 17 (4 mmol) in anhydrous diethyl ether
1908
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1896–1913

Tandem 1,5-Hydride Shift/6π Electrocyclization
13C NMR (100 MHz, [D6]DMSO, 25 °C): δ = 23.2, 58.2, 58.5 (s),
H), 1.72–1.93 (m, 2 H), 2.20–2.39 (m, 2 H), 2.62–2.70 (m, 1 H),
97.6 (s), 124.2, 126.0, 126.3, 126.4, 126.5, 128.4, 129.6, 129.9 (s), 7.00–7.14 (m, 5 H), 7.23 (d, J = 8.4 Hz, 1 H), 7.28 (dd, J = 8.4,
140.1 (s), 142.7 (s), 167.8 ppm. IR (Nujol): ν = 1618 (w), 1598 (w),
2.1 Hz, 1 H), 7.31–7.41 (m, 3 H), 7.61–7.64 (m, 2 H), 8.26 (d, J =
2.1 Hz, 1 H), 8.47 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3,
25 °C): δ = 22.3, 25.3, 27.5, 59.8 (s), 60.4 (s), 125.3, 127.0, 127.3,
127.8, 127.9, 128.4, 129.2, 129.9, 132.4, 133.9 (s), 135.3 (s), 138.9
˜
1240 (m), 1207 (w), 1145 (s), 1122 (m), 1095 (s), 1029 (m), 979 (w),
948 (w), 900 (w), 757 (s), 702 (vs) cm–1. HRMS (ESI): calcd. for
C24H22NO2 [M + H]+ 356.1645; found 356.1653.
(s), 139.6 (s), 141.1 (s), 165.0 ppm. IR (Nujol):ν = 1619 (s), 1493
˜
3Ј-Methyl-3Ј-phenylspiro[1,3-dioxane-2,4Ј(3ЈH)-quinoline]
(21b):
(vs), 1297 (s), 1112 (m), 1097 (m), 1080 (m), 971 (m), 915 (m),
886 (m), 830 (s), 756 (vs), 701 (vs) cm–1. HRMS (ESI): calcd. for
C24H21ClNS2 [M + H]+ 422.0798; found 422.0805.
Eluent for column chromatography: hexanes/diethyl ether (7:3, v/
v); yield 81% (0.12 g); colourless prisms; m.p. 154–155 °C (diethyl
ether). 1H NMR (300 MHz CDCl3, 25 °C): δ = 1.47 (s, 3 H), 1.55–
1.66 (m, 1 H), 1.72–1.84 (m, 1 H), 3.17–3.25 (m, 1 H), 3.53–3.73
(m, 3 H), 7.24–7.36 (m, 4 H), 7.37–7.40 (m, 1 H), 7.42–7.51 (m, 3
H), 7.63 (dd, J = 7.4, 1.0 Hz, 1 H), 8.06 (s, 1 H) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 16.7, 24.7, 51.4 (s), 58.2, 59.7, 98.7
(s), 125.3, 127.1, 127.2, 127.6, 128.8 (s), 129.4, 129.5, 138.9 (s),
Spiroquinazolines 24a, 24f, 24i and 27a-c: A solution of the aryl
isocyanate (2 mmol) in anhydrous dichloromethane (5 mL) was
added to a solution of the corresponding iminophosphorane 8
(2 mmol) in the same solvent (25 mL). The reaction mixture was
stirred at room temperature for 30 min. The solvent was removed
under reduced pressure, and the resulting material was purified by
column chromatography on silica gel, with hexanes/diethyl ether
(4:1, v/v) as eluent, to give the appropriate carbodiimide 22.
143.4 (s), 171.3 ppm. IR (Nujol): ν = 1618 (m), 1598 (w), 1496 (w),
˜
1215 (s), 1178 (w), 1141 (m), 1118 (s), 1093 (vs), 1054 (w), 1033
(m), 1024 (m), 973 (m), 962 (m), 929 (w), 904 (w), 877 (w), 846 (w),
773 (vs), 761 (m) cm–1. HRMS (ESI): calcd. for C19H20NO2 [M +
H]+ 294.1489; found 294.1492.
A solution of the carbodiimide 22 (1 mmol) in anhydrous ortho-
xylene (20 mL) was heated at reflux temperature for 24–36 h. After
the system had cooled, the solvent was removed under reduced
pressure. The corresponding mixtures of the spiroquinazolines 24
and 27 were separated by column chromatography on silica gel.
6Ј-Chloro-3Ј,3Ј-diphenylspiro[1,3-dioxane-2,4Ј(3ЈH)-quinoline] (21c):
Eluent for column chromatography: hexanes/diethyl ether (3:2,
v/v); yield 92% (0.36 g); colourless prisms; m.p. 220–221 °C (diethyl
ether). 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.48–1.58 (m, 1
H), 1.80–1.90 (m, 1 H), 3.33 (br. s, 2 H), 3.60 (br. s, 2 H), 7.20–
7.22 (m, 6 H), 7.27 (dd, J = 8.0, 2.4 Hz, 1 H), 7.31–7.34 (m, 5 H),
7.84 (d, J = 2.4 Hz, 1 H), 8.58 (s, 1 H) ppm. 13C NMR (100 MHz,
CDCl3, 55 °C): δ = 24.5, 58.9, 59.4 (s), 98.5 (s), 125.0, 127.1, 127.5,
129.1, 129.3, 130.7, 132.4 (s), 132.8 (s), 140.5 (s), 142.2 (s),
3Ј-(4-Methylphenyl)spiro[1,3-dioxolane-2,4Ј(3ЈH)-quinazoline] (24a):
Eluent for column chromatography: hexanes/diethyl ether (7:3, v/v);
yield 47% (0.13 g); colourless prisms; m.p. 160–161 °C (diethyl
ether). 1H NMR (300 MHz, CDCl3, 25 °C): δ = 2.38 (s, 3 H), 3.51–
3.62 (m, 2 H), 3.99–4.10 (m, 2 H), 7.19–7.28 (m, 3 H), 7.32–7.36
(m, 2 H), 7.37–7.41 (m, 3 H), 7.44–7.48 (m, 1 H) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 21.0, 66.3, 111.2 (s), 123.8 (s), 124.8,
124.9, 125.2, 129.5, 129.6, 129.8, 136.4 (s), 138.6 (s), 142.1 (s),
169.8 ppm. IR (Nujol): ν = 1623 (s), 1493 (s), 1222 (s), 1205 (s),
˜
1149 (vs), 1103 (vs), 1078 (vs), 1038 (vs), 826 (m), 765 (vs), 706
(vs) cm–1. HRMS (ESI): calcd. for C24H21ClNO2 [M + H]+
390.1255; found 390.1262.
146.2 ppm. IR (Nujol):ν = 1617 (vs), 1594 (vs), 1562 (vs), 1507 (vs),
˜
1334 (vs), 1231 (s), 1199 (s), 1156 (s), 1135 (vs), 1070 (vs), 1025
(vs), 978 (vs), 822 (vs) 773 (vs), 754 (vs) cm–1. HRMS (ESI): calcd.
for C17H17N2O2 [M + H]+ 281.1285; found 281.1286.
3Ј,3Ј-Diphenylspiro[1,3-dithiane-2,4Ј(3ЈH)-quinoline] (21d): Eluent
for column chromatography: hexanes/diethyl ether (1:1, v/v); yield
71% (0.14 g); colourless prisms; m.p. 205–206 °C (diethyl ether).
1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.59–1.87 (m, 3 H), 2.27–
2.34 (m, 2 H), 2.68–2.73 (m, 1 H), 7.04–7.10 (m, 5 H), 7.24–7.43
(m, 6 H), 7.65–7.67 (m, 2 H), 8.26 (d, J = 7.5 Hz, 1 H), 8.47 (s, 1
H) ppm. 13C NMR (100 MHz CDCl3, 25 °C): δ = 22.4, 25.3, 27.6,
60.2 (s), 60.7 (s), 125.2, 126.9, 127.1, 127.6, 127.7, 128.4, 128.5,
128.6, 129.3, 132.5, 133.4 (s), 139.8 (s), 140.3 (s), 141.5 (s),
6Ј-Chloro-3Ј-(4-methylphenyl)spiro[1,3-dioxolane-2,4Ј(3ЈH)-quinazo-
line] (24f): Eluent for column chromatography: hexanes/diethyl
ether (1:9, v/v); yield 49% (0.15 g); colourless prisms; m.p. 143–
145 °C (diethyl ether). 1H NMR (400 MHz, CDCl3, 25 °C): δ =
2.41 (s, 3 H), 3.57–3.60 (m, 2 H), 4.06–4.10 (m, 2 H), 7.23–7.25 (m,
2 H), 7.30–7.32 (m, 2 H), 7.34–7.37 (m, 3 H), 7.42 (d, J = 2.3 Hz,
1 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 21.2, 66.5,
110.9 (s), 124.9, 125.1 (s), 126.7, 129.9, 130.0, 130.1, 130.2 (s), 136.2
164.7 ppm. IR (Nujol): ν = 1625 (w), 1494 (s), 1301 (w), 914 (w),
˜
756 (vs), 719 (m), 705 (vs), 630 (s) cm–1. HRMS (ESI): calcd. for
C24H22NS2 [M + H]+ 388.1188; found 388.1189.
(s), 139.0 (s), 141.0 (s), 146.6 ppm. IR (Nujol):ν = 1617 (vs), 1594
˜
(vs), 1561 (vs), 1333 (vs), 1254 (s), 1209 (vs), 1200 (vs), 1144 (vs),
1096 (vs), 1051 (vs), 1001 (vs), 984 (vs), 871 (s) 777 (s) cm–1. HRMS
(ESI): calcd. for C17H16ClN2O2 [M + H]+ 315.0895; found
315.0902.
3Ј-Methyl-3Ј-phenylspiro[1,3-dithiane-2,4Ј(3ЈH)-quinoline]
(21e):
Eluent for column chromatography: hexanes/diethyl ether (7:3,
v/v); yield 60% (0.10 g); colourless prisms; m.p. 141–143 °C (diethyl
ether). 1H NMR (300 MHz, CDCl3, 25 °C): δ = 1.64 (s, 3 H), 1.66–
1.84 (m, 2 H), 2.15–2.32 (m, 2 H), 2.48–2.57 (m, 2 H), 7.25–7.39
(m, 5 H), 7.46 (dd, J = 7.5, 1.5 Hz, 1 H), 7.58–7.62 (m, 2 H), 7.95
(dd, J = 7.5, 1.5 Hz, 1 H), 8.16 (s, 1 H) ppm. 13C NMR (75 MHz,
CDCl3, 25 °C): δ = 18.7, 23.1, 26.9, 27.0, 51.2 (s), 60.6 (s), 126.3,
127.6, 127.8, 128.1, 128.7, 130.0, 132.2 (s), 138.7 (s), 140.9 (s),
6Ј-Methyl-3Ј-(4-methylphenyl)spiro[1,3-dioxolane-2,4Ј(3ЈH)-quinaz-
oline] (24i): Eluent for column chromatography: hexanes/diethyl
ether (1:9, v/v); yield 46% (0.13 g); colourless prisms; m.p. 144–
145 °C (diethyl ether). 1H NMR (400 MHz, CDCl3, 25 °C): δ =
2.38 (s, 6 H), 3.51–3.62 (m, 2 H), 4.01–4.12 (m, 2 H), 7.19–7.23
(m, 3 H), 7.25–7.27 (m, 2 H), 7.29–7.34 (m, 3 H) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 21.0, 21.2, 66.3, 111.4 (s), 123.5 (s),
124.7, 124.9, 129.6, 129.9, 130.8, 134.9 (s), 136.6 (s), 138.5 (s), 140.0
168.9 ppm. IR (Nujol):ν = 1633 (vs), 1591 (m), 1311 (s), 1274 (m),
˜
1213 (m), 1108 (w), 972 (w), 879 (w), 756 (s), 721 (s), 675 (m) cm–1.
HRMS (ESI): calcd. for C19H20NS2 [M + H]+ 326.1032; found
326.1037.
(s), 145.7 ppm. IR (Nujol):ν = 1623 (vs), 1611 (vs), 1597 (vs), 1568
˜
(s), 1336 (vs), 1063 (vs), 954 (vs), 828 (s) cm–1. HRMS (ESI): calcd.
for C18H19N2O2 [M + H]+ 295.1441; found 295.1446.
6Ј-Chloro-3Ј,3Ј-diphenylspiro[1,3-dithiane-2,4Ј(3ЈH)-quinoline] (21f):
Eluent for column chromatography: hexanes/diethyl ether (3:2,
v/v); yield 88% (0.37 g); colourless prisms; m.p. 211–212 °C (diethyl
ether). 1H NMR (300 MHz, CDCl3, 25 °C): δ = 1.59–1.69 (m, 1
Spiroquinazoline 27a: Eluent for column chromatography: hexanes/
diethyl ether (7:3, v/v); yield 43% (0.073 g); colourless prisms; m.p.
Eur. J. Org. Chem. 2011, 1896–1913
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1909

M. Alajarin, P. Sanchez-Andrada, A. Vidal et al.
FULL PAPER
175–176 °C (diethyl ether). H NMR (400 MHz, CDCl3, 25 °C): δ
1H NMR (300 MHz, CDCl3, 25 °C): δ = 3.91–4.02 (m, 2 H), 4.07–
4.18 (m, 2 H), 6.13 (d, J = 5.2 Hz, 1 H), 6.56 (s, 1 H), 6.88 (d, J =
1
= 3.34–3.41 (m, 1 H), 3.59–3.67 (m, 1 H), 3.88–3.93 (m, 1 H), 3.95–
4.01 (m, 1 H), 4.03–4.10 (m, 3 H), 4.15 (q, J = 6.5 Hz, 1 H), 5.99 5.2 Hz, 1 H), 7.39–7.53 (m, 9 H), 7.68–7.75 (m, 6 H) ppm. 13C
(s, 1 H), 7.25–7.29 (m, 1 H), 7.38 (s, 1 H), 7.41–7.42 (m, 1 H), 7.43–
7.44 (m, 1 H), 7.45–7.46 (m, 1 H), 7.47–7.76 (m, 4 H) ppm. 13C
NMR (100 MHz, CDCl3, 25 °C): δ = 65.4, 65.6, 66.3, 66.6, 99.8,
NMR (75 MHz, CDCl3, 25 °C): δ = 64.9, 99.8, 119.2 (d, J =
22.0 Hz) (s), 123.3, 123.9 (d, J = 7.2 Hz), 128.7 (d, J = 11.8 Hz),
130.8 (s), 131.5 (d, J = 98.9 Hz) (s), 131.6 (d, J = 2.7 Hz), 132.6
111.2 (s), 123.9 (s), 125.0, 125.4, 125.5, 127.4, 129.6, 129.8, 130.0, (d, J = 9.5 Hz), 148.8 (d, J = 1.6 Hz) ppm. 31P NMR (121.4 MHz
131.9, 137.3 (s), 138.1 (s), 142.3 (s), 146.9 ppm. IR (Nujol):ν = 1620
CDCl , 25 °C): δ = 3.3 ppm. IR (Nujol):ν = 3055 (s), 1533 (w),
˜
˜
3
(vs), 1601 (vs), 1327 (vs), 1269 (s), 1182 (s), 1159 (s), 1134 (s), 1088
1504 (w), 1479 (m), 1402 (vs), 1352 (w), 1275 (s), 1200 (s), 1107 (s),
(vs), 1080 (vs), 978 (s), 949 (vs) cm–1. HRMS (ESI): calcd. for 1049 (vs), 997 (w), 980 (w), 943 (m), 933 (m), 908 (w), 758 (m), 725
C19H19N2O4 [M + H]+ 339.1339; found 339.1342.
(s), 714 (s), 702 (s), 692 (m), 646 (m) cm–1. HRMS (ESI): calcd. for
C25H23NO2PS [M + H]+ 432.1182; found 432.1182.
Spiroquinazoline 27b: Eluent for column chromatography: hexanes/
diethyl ether (1:9, v/v); yield 40% (0.081 g); colourless prisms; m.p.
194–195 °C (diethyl ether). H NMR (400 MHz, CDCl3, 25 °C): δ
Diphenylketene (0.27 g, 1.4 mmol) in anhydrous benzene was
added to a solution of 2-(3-triphenylphosphoranylideneaminothi-
1
= 3.41–3.49 (m, 1 H), 3.66–3.70 (m, 1 H), 3.92 (q, J = 6.9 Hz, 1 ophen-2-yl)-1,3-dioxolane (0.6 g, 1.4 mmol) in the same solvent
H), 3.97–4.07 (m, 2 H), 4.09–4.14 (m, 2 H), 4.17 (q, J = 6.0 Hz, 1 (20 mL). The reaction mixture was stirred at room temperature for
H), 5.92 (s, 1 H), 7.27–7.35 (m, 2 H), 7.38–7.46 (m, 4 H), 7.72–7.73
15 min, and next heated at reflux temperature for 5 h. After the
(m, 1 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 65.5, 65.8, system had cooled, the solvent was removed under reduced pres-
66.4, 66.8, 99.4, 110.8 (s), 124.9, 125.1 (s), 127.1, 127.9, 130.0, sure. The resulting material was purified by column chromatog-
130.4, 130.6 (s), 133.2, 135.6 (s), 135.9 (s), 140.2 (s), 140.9 (s),
raphy on silica gel, with hexanes/diethyl ether (7:3, v/v) as eluent.
146.8 ppm. IR (Nujol):ν = 1624 (vs), 1595 (s), 1560 (s), 1390 (vs),
˜
2-Hydroxyethyl 3-(2,2-Diphenylvinylamino)thiophene-2-carboxylate
(31): Yield 52% (0.27 g); brown prisms; m.p. 138–139 °C (diethyl
ether). 1H NMR (400 MHz, CDCl3, 25 °C): δ = 3.73–3.75 (m, 2
H), 4.24–4.26 (m, 2 H), 6.95 (d, J = 5.5 Hz, 1 H), 7.02 (d, J =
11.6 Hz, 1 H), 7.14–7.28 (m, 6 H), 7.33–7.37 (m, 3 H), 7.39 (d, J
1198 (s), 1099 (vs), 1074 (vs), 1011 (s), 982 (vs), 839 (s) cm–1.
HRMS (ESI): calcd. for C19H17Cl2N2O4 [M + H]+ 407.056; found
407.0565.
Spiroquinazoline 27c: Eluent for column chromatography: hexanes/
diethyl ether (1:9, v/v); yield 44% (0.081 g); colourless prisms; m.p. = 5.5 Hz, 1 H), 7.44–7.47 (m, 2 H), 8.93 (d, J = 11.6 Hz, 1 H) ppm.
1
191–193 °C (diethyl ether). H NMR (300 MHz, CDCl3, 25 °C): δ
= 2.38 (s, 3 H), 2.43 (s, 3 H), 3.38–3.48 (m, 1 H), 3.62–3.67 (m, 1 116.2, 120.4 (s), 124.5, 126.2, 126.7, 127.6, 128.5, 129.2, 130.2,
H), 3.86–4.00 (m, 2 H), 4.03–4.12 (m, 3 H), 4.13–4.19 (m, 1 H), 132.9, 137.9 (s), 141.4 (s), 149.9 (s), 164.4 (s) ppm. IR (Nujol):ν =
13C NMR (100 MHz, CDCl3, 25 °C): δ = 61.6, 66.3, 102.4 (s),
˜
5.93 (s, 1 H), 7.23–7.28 (m, 4 H), 7.31 (s, 1 H), 7.38 (d, J = 8.0 Hz, 3373 (m), 3325 (m), 1664 (s), 1564 (vs), 1493 (m), 1402 (s), 1246
1 H), 7.54 (d, J = 1.6 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3, (vs), 1142 (m), 1117 (m), 1084 (m), 1074 (m), 877 (w), 864 (w),
25 °C): δ = 21.2, 21.3, 65.4, 65.6, 66.3, 66.6, 99.9, 111.4 (s), 123.6
(s), 125.0, 125.2, 127.8, 130.5, 131.1, 131.6, 135.0 (s), 135.2 (s),
771 (m), 762 (m), 706 (m), 644 (m) cm–1. HRMS (ESI): calcd. for
C21H20NO3S [M + H]+ 366.1158; found 366.1165.
137.5 (s), 139.7 (s), 140.2 (s), 146.5 ppm. IR (Nujol):ν = 1620 (s),
˜
Pyrazolo-pyridine 34 and the Pyrazolo-pyridone 35: Tetrabutylam-
monium tribromide (0.011 g, 0.022 mmol) was added to a mixture
of 5-azido-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde (32,
0.5 g, 2.2 mmol), trimethyl orthoformate (0.36 g, 2.4 mmol) and
ethylene glycol (0.54 g, 8.8 mmol). The reaction mixture was stirred
at room temperature under nitrogen for 8 h. Saturated sodium hy-
drogen carbonate solution (10 mL) was then added, and the re-
sulting mixture was extracted with ethyl acetate (2ϫ25 mL). The
organic phase was dried with anhydrous magnesium sulfate. The
solvent was removed under reduced pressure and the resulting ma-
terial was purified by column chromatography on silica gel, with
hexanes/diethyl ether (1:1, v/v) as eluent, to give 2-(5-azido-3-
methyl-1-phenyl-1H-pyrazol-4-yl)-1,3-dioxolane (0.49 g, 82% yield).
1601 (vs), 1327 (vs), 1269 (s), 1160 (s), 1088 (vs), 1080 (vs), 1010
(s), 949 (s) cm–1. HRMS (ESI): calcd. for C21H23N2O4 [M + H]+
367.1652; found 367.1654.
2-Hydroxyethyl 3-(2,2-Diphenylvinylamino)thiophene-2-carboxylate
(31): Ethylene glycol (0.79 g, 13 mmol) and p-toluenesulfonic acid
monohydrate (0.1 g) were added to a solution of 3-azidothiophene-
2-carbaldehyde (28, 1.6 g, 11 mmol) in benzene (75 mL). The reac-
tion mixture was heated at reflux temperature for 5 h, with azeo-
tropic removal of water with a Dean–Stark trap. After cooling to
room temperature, the resulting mixture was washed with KOH
solution (0.1 m, 50 mL) and water (50 mL). The organic phase was
dried with anhydrous magnesium sulfate. The solvent was removed
under reduced pressure and the resulting material was purified by
column chromatography on silica gel, with hexanes/diethyl ether
(1:9, v/v) as eluent, to give 2-(3-azidothiophen-2-yl)-1,3-dioxolane
(1.84 g, 85% yield).
Triphenylphosphane (0.8 g, 3 mmol) was added in portions of 0.2 g
every two minutes to a solution of 2-(5-azido-3-methyl-1-phenyl-
1H-pyrazol-4-yl)-1,3-dioxolane (0.8 g, 3 mmol) in anhydrous di-
ethyl ether (20 mL). The reaction mixture was stirred at room tem-
perature under nitrogen for 12 h. The precipitated 2-(3-methyl-1-
phenyl-5-triphenylphosphoranylideneamino-1H-pyrazol-4-yl)-1,3-di-
oxolane was then isolated by filtration and washed with anhydrous
diethyl ether (15 mL). This compound was used in the following
Triphenylphosphane (2.35 g, 9 mmol) was added in portions of
0.47 g every two minutes to a solution of 2-(3-azidothiophen-2-yl)-
1,3-dioxolane (1.8 g, 9 mmol) in anhydrous diethyl ether (20 mL).
The reaction mixture was stirred at room temperature under nitro-
gen for 12 h. The precipitated 2-(3-triphenylphosphoranylideneam- step without further purification. For an analytical sample 2-(3-
inothiophen-2-yl)-1,3-dioxolane was then isolated by filtration and
washed with anhydrous diethyl ether (15 mL). This compound was
used in the following step without further purification. For an ana-
lytical sample, 2-(3-triphenylphosphoranylideneaminothiophen-2-
yl)-1,3-dioxolane was recrystallized from diethyl ether.
methyl-1-phenyl-5-triphenylphosphoranylideneamino-1H-pyrazol-
4-yl)-1,3-dioxolane was recrystallized from diethyl ether.
2-(3-Methyl-1-phenyl-5-triphenylphosphoranylideneamino-1H-pyr-
azol-4-yl)-1,3-dioxolane: Yield 51% (0.77 g); colourless prisms; m.p.
1
124–125 °C (diethyl ether). H NMR (400 MHz, CDCl3, 25 °C): δ
2-(3-Triphenylphosphoranylideneaminothiophen-2-yl)-1,3-dioxolane:
Yield 79% (3.07 g); green prisms; m.p. 182–184 °C (diethyl ether).
= 2.25 (s, 3 H), 3.38–3.41 (m, 2 H), 3.82–3.85 (m, 2 H), 5.23 (s, 1
H), 7.14–7.26 (m, 2 H), 7.32–7.57 (m, 18 H) ppm. 13C NMR
1910
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1896–1913

Tandem 1,5-Hydride Shift/6π Electrocyclization
(100 MHz, CDCl3, 25 °C): δ = 13.9, 64.5, 100.1, 102.1 (d, J =
3.7 Hz) (s), 125.1 (s), 125.6, 125.8, 128.0, 128.7 (d, J = 27.4 Hz),
130.0 (d, J = 100.0 Hz) (s), 131.8 (d, J = 2.5 Hz), 133.5 (d, J =
8.9 Hz), 140.4 (s), 147.8 (s) ppm. 31P NMR (161.9 MHz, CDCl3,
[1]
For some representative examples, see: a) P. Molina, M. Alaja-
rin, A. Vidal, J. Feneau-Dupont, J. P. Declerq, J. Chem. Soc.,
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4008–4016; c) M. Alajarin, P. Molina, A. Vidal, F. Tovar, Tetra-
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Alajarin, A. Vidal, F. Tovar, A. Arrieta, B. Lecea, F. P. Cossio,
Chem. Eur. J. 1999, 5, 1106–1117; f) M. Alajarin, A. Vidal, F.
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44, 3027–3030; b) M. Alajarin, A. Vidal, M.-M. Ortin, Org.
Biomol. Chem. 2003, 1, 4282–4292; c) M. Alajarin, A. Vidal,
M.-M. Ortin, D. Bautista, New J. Chem. 2004, 28, 570–577; d)
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991–994.
a) K. Hayday, R. D. McKelvey, J. Org. Chem. 1976, 41, 2222–
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a) See our previous communication: M. Alajarin, B. Bonillo,
M.-M. Ortin, P. Sanchez-Andrada, A. Vidal, Org. Lett. 2006,
8, 5645–5648; b) For a recent related report, see: M. Alajarin,
B. Bonillo, M.-M. Ortin, P. Sanchez-Andrada, A. Vidal, R.-A.
Orenes, Org. Biomol. Chem. 2010, 8, 4690–4700.
For reviews in the chemistry of ketenimines, see: a) D. R. Krow,
Angew. Chem. Int. Ed. Engl. 1971, 10, 435–449; b) N. P.
Gambaryan, Usp. Khim. 1976, 45, 1251–1268; c) A. Dondoni,
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a) K. C. Branhock, R. D. Burpitt, J. Org. Chem. 1965, 30,
2564–2565; b) M. A. Walters, C. S. McDonough, P. S.
Brown Jr., A. B. Hoem, Tetrahedron Lett. 1991, 32, 179–182;
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C. S. McDonough, Tetrahedron Lett. 1993, 34, 1453–1456; d)
M. A. Walters, A. B. Hoem, J. Org. Chem. 1994, 59, 2645–
2647; e) M. A. Walters, J. Am. Chem. Soc. 1994, 116, 11618–
11619; f) M. A. Walters, J. Org. Chem. 1996, 61, 978–983; g)
P. Molina, M. Alajarin, C. Lopez-Leonardo, Tetrahedron Lett.
1991, 32, 4041–4044; h) P. Molina, M. Alajarin, C. Lopez-Leo-
nardo, J. Alcantara, Tetrahedron 1993, 49, 5153–5168; i) U.
Nubbemeyer, Synthesis 1993, 1120–1128. For articles dealing
with [1,3] migrations in ketenimines, see: j) A. B. Cheikh, J.
Chuche, N. Manisse, J. C. Pommelet, K.-P. Netsch, P. Lo-
rencak, C. Wentrup, J. Org. Chem. 1991, 56, 970–975; k) C. O.
Kappe, G. Kollenz, R. Leung-Toung, C. Wentrup, J. Chem.
Soc., Chem. Commun. 1992, 487–488; l) C. O. Kappe, G. Kol-
lenz, K.-P. Netsch, R. Leung-Toung, C. Wentrup, J. Chem.
Soc., Chem. Commun. 1992, 488–490; m) B. E. Fulloon,
H. A. A. El-Nabi, G. Kollenz, C. Wentrup, Tetrahedron Lett.
1995, 36, 6547–6550; n) B. E. Fulloon, C. Wentrup, J. Org.
Chem. 1996, 61, 1363–1368; o) V. V. Ramana Rao, C. Wentrup,
J. Chem. Soc. Perkin Trans. 1 1998, 2583–2586; p) C. Wentrup,
V. V. Ramana Rao, W. Frank, B. E. Fulloon, D. W. J. Moloney,
25 °C): δ = 4.7 ppm. IR (Nujol):ν = 1589 (m), 1558 (m), 1317 (w),
˜
1275 (m), 1219 (m), 1169 (s), 1115 (s), 1101 (s), 1059 (vs), 1009 (w),
964 (vs), 945 (m), 771 (m), 729 (s), 696 (s) cm–1. HRMS (ESI):
calcd. for C31H29N3O2P [M + H]+ 506.1997; found 506.1996.
Method A: Diphenylketene (0.12 g, 0.7 mmol) in anhydrous dichlo-
romethane (5 mL) was added to a solution of 2-(3-methyl-1-phenyl-
5-triphenylphosphoranylideneamino-1H-pyrazol-4-yl)-1,3-dioxol-
ane (0.3 g, 0.6 mmol) in the same solvent (15 mL). The reaction
mixture was stirred at room temperature for 24 h. The solvent was
removed under reduced pressure and the resulting material was
chromatographed on a silica gel column with hexanes/diethyl ether
(1:1, v/v) as eluent.
Pyrazolo-pyridine 34: Yield 15% (0.04 g); colourless prisms; m.p.
1
205–206 °C (diethyl ether). H NMR (400 MHz, CDCl3, 25 °C): δ
= 2.52 (s, 3 H), 3.04–3.08 (m, 2 H), 3.86–3.89 (m, 2 H), 7.23–7.28
(m, 7 H), 7.35–7.39 (m, 6 H), 7.71–7.74 (m, 2 H), 8.33 (s, 1 H) ppm.
13C NMR (100 MHz, CDCl3, 25 °C): δ = 13.5, 62.7 (s), 65.6, 108.4
(s), 109.4 (s), 122.8, 126.8, 127.6, 127.8, 128.9, 130.4, 138.6 (s),
[2]
[3]
140.2 (s), 143.6 (s), 145.2 (s), 169.4 ppm. IR (Nujol):ν = 1589 (s)
˜
1579 (m), 1562 (m), 1504 (vs), 1253 (m), 1143 (m), 1095 (m), 1059
(s), 1036 (m), 951 (m), 935 (m), 756 (vs), 702 (vs), 696 (s) cm–1.
HRMS (ESI): calcd. for C27H24N3O2 [M + H]+ 422.1863; found
422.1864.
Pyrazolo-pyridone 35: Yield 50% (0.18 g); colourless prisms; m.p.
1
281–282 °C (diethyl ether). H NMR (400 MHz, CDCl3, 50 °C): δ
= 2.22 (s, 3 H), 3.83 (br. s, 4 H), 6.47 (s, 1 H), 6.56 (d, J = 7.3 Hz,
2 H), 6.61 (d, J = 7.3 Hz, 2 H), 7.04–7.14 (m, 8 H), 7.21–7.24 (m,
9 H), 7.42 (br. s, 4 H) ppm. 13C NMR (100 MHz, CDCl3, 50 °C):
δ = 12.9, 68.8, 107.3 (s), 110.7 (s), 121.3, 124.6, 127.1, 127.4, 127.6,
127.7, 127.8, 128.0, 128.4, 128.9, 130.4, 136.0 (s), 137.5 (s), 138.0
(s), 138.4 (s), 138.7 (s), 140.4 (s), 145.0 (s), 172.0 (s) ppm. IR (Nu-
[4]
[5]
[6]
jol): ν = 1695 (vs), 1629 (w), 1593 (s), 1583 (m), 1525 (s), 1497 (s),
˜
1257 (s), 1186 (m), 1151 (m), 769 (s), 898 (vs), 642 (s) cm–1. HRMS
(ESI): calcd. for C41H34N3O3 [M + H]+ 616.2595; found 616.2600.
Method B: Diphenylketene (0.10 g, 0.5 mmol) in anhydrous benz-
ene (5 mL) was added to a solution of 2-(3-methyl-1-phenyl-5-
triphenylphosphoranylideneamino-1H-pyrazol-4-yl)-1,3-dioxolane
(0.3 g, 0.6 mmol) in the same solvent (15 mL). The reaction mixture
was stirred at room temperature for 15 min, and next heated at
reflux temperature for 1 h. After the system had cooled, the solvent
was removed under reduced pressure. The resulting material was
purified by column chromatography on silica gel, with hexanes/
diethyl ether (1:1, v/v) as eluent, to provide the pyrazolo-pyridine 34
(0.13 g, 52% yield).
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra of compounds 11, 13, 15, 16, 21a–
f, 24a, 24f, 24i, 27a–c, 31, 34 and 35. Details of computational
procedures, Cartesian coordinates, and energies for all the station-
ary points.
Acknowledgments
This work was supported by the Spanish Ministerio de Ciencia e
Innovacion (MICINN) (project number CTQ2008-05827/BQU),
and the Fundacion Seneca - CARM (project number 08661/PI/08).
B. B. and M.-M. O. thank the Fundacion Seneca - CARM and the
Fundacion Caja Murcia for fellowships.
Eur. J. Org. Chem. 2011, 1896–1913
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1911

M. Alajarin, P. Sanchez-Andrada, A. Vidal et al.
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The structure of the pyrazolo-pyridone 35 was unequivocally
determined by X-ray analysis, although the collected data are
of low quality for publication. Its analytical and spectroscopic
data are in full agreement with such structure.
Note that the 1,3-dioxolane-ketenimine 37b appears in the ex-
perimental study numbered as 1a, but for the sake of avoiding
confusion we have used a different numeration in the computa-
tional section.
We have not considered 1,3-oxathiolane-ketenimines in this
study because their thermal treatment leads to benzoisothiazol-
3-ones by very interesting mechanistic sequence (see ref. [1n]).
Nevertheless, we have now calculated that the barrier for the
[1,5]-H shift for conversion of N-[2-(1,3-oxathiolan-2-yl)
phenyl]ketenimine into the corresponding o-azaxylylene inter-
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[30]
[31]
[32]
[17]
The energy barriers are relative to the most stable conformers
of the reactant heterocumulenes and of the o-azaxylylene inter-
mediates.
1912
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1896–1913

Tandem 1,5-Hydride Shift/6π Electrocyclization
that bond before the electrocyclization step through a rota-
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Published Online: February 25, 2011
Eur. J. Org. Chem. 2011, 1896–1913
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1913