Hydricity-promoted [1,5]-H shifts in acetalic ketenimines and carbodiimides

Article abstract of DOI:10.1021/ol062373w

2-Monosubstituted 1,3-dioxolanes and dithiolanes act as hydride-releasing fragments, transferring intramolecularly their acetalic H atom to the central carbon of ketenimine functions. The presumed products of these migrations, o-quinomethanimines, undergo in situ 6π-electrocyclization. A computational study supports this mechanism and the hydride-shift character of the first step. Carbodiimides were also suitable substrates, although less reactive.

Full text of DOI:10.1021/ol062373w

ORGANIC
LETTERS
2006
Vol. 8, No. 24
5645-5648
Hydricity-Promoted [1,5]-H Shifts in
Acetalic Ketenimines and Carbodiimides
Mateo Alajar´ın,* Baltasar Bonillo, Mar´ıa-Mar Ort´ın, Pilar Sa´nchez-Andrada, and
AÄ ngel Vidal
Departamento de Qu´ımica Orga´nica, Facultad de Qu´ımica, UniVersidad de Murcia,
Campus de Espinardo 30100, Murcia, Spain
alajarin@um.es
Received September 27, 2006
ABSTRACT
2-Monosubstituted 1,3-dioxolanes and dithiolanes act as hydride-releasing fragments, transferring intramolecularly their acetalic H atom to the
central carbon of ketenimine functions. The presumed products of these migrations, o-quinomethanimines, undergo in situ 6 -electrocyclization.
π
A computational study supports this mechanism and the hydride-shift character of the first step. Carbodiimides were also suitable substrates,
although less reactive.
While investigating the addition of carbon radicals to
ketenimines1 we attempted the generation of a “protected
acyl” radical by abstracting the acetalic H atom of the acetal-
ketenimine 1a with tert-butoxy radicals.2 Our aim was that
once formed, the new radical would add to the central carbon
atom of the ketenimine function for leading to the (2-indolyl)-
(diphenyl)methyl radical 2a and from this to more complex
indoles.1a-c We found that the actual product of this reaction
turned out to be the carbonyl-protected 4-quinolone 3a
(Scheme 1). In compound 3a the original acetalic hydrogen
of 1a is now situated at carbon 2 of its 3,4-dihydroquinoline
ring system, whereas the new six-membered ring appearing
in 3a is formed by connecting the original acetalic carbon
of 1a with the terminal carbon of its ketenimine function.
We interpreted this result in mechanistic terms as the [1,5]
migration of the acetalic proton of 1a to the central
heterocumulenic carbon, thus leading to the reactive inter-
mediate o-quinomethanimine 4a, followed by its 6π-elec-
trocyclization to 3a (Scheme 2).
Scheme 2. Proposed Mechanism for the Conversion 1a f 3a
Scheme 1. Cyclization of Ketenimine 1a
In fact, we proved that the conversion 1a f 3a occurred
by refluxing a toluene solution of 1a for 1 h, in the absence
(1) (a) Alajar´ın, M.; Vidal, A.; Ort´ın, M.-M. Tetrahedron Lett. 2003,
44, 3027. (b) Alajar´ın, M.; Vidal, A.; Ort´ın, M.-M. Org. Biomol. Chem.
2003, 1, 4282. (c) Alajar´ın, M.; Vidal, A.; Ort´ın, M.-M.; Bautista, D. New
J. Chem. 2004, 28, 570. (d) Alajar´ın, M.; Vidal, A.; Ort´ın, M.-M.; Bautista,
D. Synlett 2004, 991.
10.1021/ol062373w CCC: $33.50
© 2006 American Chemical Society
Published on Web 10/28/2006

of radical-promoting reagents. The proposed intermediate 4a
Whereas ketenimines are known to participate in a variety
of cycloaddition reactions and 6π-electrocyclizations,3 only
a few examples of sigmatropic rearrangements4 and sigma-
tropic shifts of atoms or groups of atoms5 in ketenimines
have been reported so far.
was neither isolated nor detected by following the reaction
1
by H and 13C NMR experiments (toluene-d8, 100 °C, 1.5
h), in which starting 1a and final 3a revealed as the only
components of the reaction mixture.
Following these initial experiments, we examined similar
transformations for a series of acetal-ketenimines 1a-e (X
) O) and dithioacetal-ketenimines 1f-h (X ) S), prepared
from the corresponding 2-azidobenzaldehydes 5 by the
synthetic sequence summarized in Scheme 3, via the azido-
From these latter, the [1,3] sigmatropic shifts of different
electron-rich groups to the central carbon of ketenimines
reported by Wentrup5a-h are the best studied. To our
knowledge, only five cases of [1,5] sigmatropic shifts5m-r
involving ketenimine functions have been reported, four of
them involving a H transfer to their central carbon.5m-p
One of these, also due to Wentrup,5o is closely related to
our present results. It occurs in N-aryl ketenimines bearing
a methyl group at the ortho position, which experience [1,5]
shift of one of the CH3 protons and subsequent 6π-
electrocyclization to 3,4-dihydroquinolines when they were
generated under flash vacuum thermolysis conditions (400-
700 °C). To check if such N-(o-tolyl)ketenimines would also
behave similarly under the mild thermal conditions of the
conversion 1 f 3 we submitted the known ketenimine 86 to
heating in toluene solution at reflux temperature, but after
48 h it still remained unchanged (Scheme 4). After the same
solution was heated in a sealed tube at 180 °C for 24 h
compound 8 was also recovered intact.
Scheme 3. Preparation of 3,4-Dihydroquinolines 3
(2) (a) Hayday, K.; McKelvey, R. D. J. Org. Chem. 1976, 4, 2222. (b)
Malatesta, V.; Ingold, K. U. J. Am. Chem. Soc. 1981, 103, 609. (c) Beckwith,
A. L. J.; Easton, C. J. J. Am. Chem. Soc. 1981, 103, 615. (d) Venkateswara,
R. B.; Chan, J. B.; Moskowitz, N.; Fraser-Reid, B. Bull. Soc. Chim. Fr.
1993, 130, 428.
(3) For reviews in the chemistry of ketenimines, see: (a) Krow, D. R.
Angew. Chem., Int. Ed. Engl. 1971, 10, 435. (b) Gambaryan, N. P. Usp.
Khim. 1976, 45, 1251. (c) Dondoni, A. Heterocycles 1980, 14, 1547. (d)
Barker, M. W.; McHenry, W. E. In The Chemistry of Ketenes, Allenes and
Related Compounds; Patai, S., Ed.; Wiley-Interscience: Chichester, UK,
1980; Part 2, p 701. (e) Alajar´ın, M.; Vidal, A.; Tovar, F. Targets Heterocycl.
Syst. 2000, 4, 293.
(4) (a) Brannock, K. C.; Burpitt, R. D. J. Org. Chem. 1965, 30, 2564.
(b) Walters, M. A.; McDonough, C. S.; Brown, P. S., Jr.; Hoem, A. B.
Tetrahedron Lett. 1991, 32, 179. (c) Walters, M. A.; Hoem, A. B.; Arcand,
H. R.; Hegeman, A. D.; McDonough, C. S. Tetrahedron Lett. 1993, 34,
1453. (d) Walters, M. A.; Hoem, A. B. J. Org. Chem. 1994, 59, 2645. (e)
Walters, M. A. J. Am. Chem. Soc. 1994, 116, 11618. (f) Walters, M. A. J.
Org. Chem. 1996, 61, 978. (g) Molina, P.; Alajar´ın, M.; Lo´pez-Leonardo,
C. Tetrahedron Lett. 1991, 32, 4041. (h) Molina, P.; Alajar´ın, M.; Lo´pez-
Leonardo, C.; Alca´ntara, J. Tetrahedron 1993, 49, 5153. (i) Nubbemeyer,
U. Synthesis 1993, 1120.
acetals and dithioacetals 6, their respective iminophospho-
ranes 7, and finally by the aza-Wittig reaction of the latter
with disubstituted ketenes. When toluene solutions of acetal-
ketenimines 1a-e (X ) O) were heated at reflux temperature
for 1 h, the corresponding spiro[1,3-dioxolane-2,4′(3′H)-
quinolines] 3a-e (X ) O), members of a previously
unknown heterocyclic system, were cleanly obtained in fair
to good yields (Table 1). In a similar way, the dithioacetal-
(5) For articles dealing with [1,3] migrations in ketenimines, see: (a)
Cheikh, A. B.; Chuche, J.; Manisse, N.; Pommelet, J. C.; Netsch, K.-P.;
Lorencak, P.; Wentrup, C. J. Org. Chem. 1991, 56, 970. (b) Kappe, C. O.;
Kollenz, G.; Leung-Toung, R.; Wentrup, C. J. Chem. Soc., Chem. Commun.
1992, 487. (c) Kappe, C. O.; Kollenz, G.; Netsch, K.-P.; Leung-Toung, R.;
Wentrup, C. J. Chem. Soc., Chem. Commun. 1992, 488. (d) Fulloon, B.;
El-Nabi, H. A. A.; Kollenz, G.; Wentrup, C. Tetrahedron Lett. 1995, 36,
6547. (e) Fulloon, B. E.; Wentrup, C. J. Org. Chem. 1996, 61, 1363. (f)
Ramana Rao, V. V.; Wentrup, C. J. Chem. Soc., Perkin Trans. 1 1998,
2583. (g) Wentrup, C.; Ramana, Rao, V. V.; Frank, W.; Fulloon, B. E.;
Moloney, D. W. J.; Mosandl, T. J. Org. Chem. 1999, 64, 3608. (h) Finnerty,
J. J.; Wentrup, C. J. Org. Chem. 2004, 69, 1909. (i) Aumann, R.; Heinen,
H. Chem. Ber. 1988, 121, 1739. (j) Clarke, D.; Mares, R. W.; McNab, H.
J. Chem. Soc. Chem. Commun. 1993, 1026. (k) Clarke, D.; Mares, R. W.;
McNab, H. J. Chem. Soc., Perkin Trans. 1 1997, 1799. (l) Amsallem, D.;
Mazie`res, S.; Piquet-Faure´, V.; Gornitzka, H.; Baceiredo, A.; Bertrand G.
Chem. Eur. J. 2002, 8, 5306. For articles dealing with [1,5] migrations in
ketenimines, see: (m) Goerdeler, J.; Lindner, C.; Zander, F. Chem. Ber.
1981, 114, 536. (n) Morel, G.; Marchand, E.; Foucaud, A. J. Org. Chem.
1985, 50, 771. (o) Ramana, Rao, V. V.; Fulloon, B. E.; Bernhardt, P. V.;
Koch, R.; Wentrup, C. J. Org. Chem. 1998, 63, 5779. (p). Alajar´ın, M.;
Vidal, A.; Ort´ın, M.-M. Tetrahedron 2005, 61, 7613. (q) Alajar´ın, M.; Ort´ın,
M.-M.; Sa´nchez-Andrada, P.; Vidal, A.; Bautista, D. Org. Lett. 2005, 7,
5281. (r) Alajar´ın, M.; Ort´ın, M.-M.; Sa´nchez-Andrada, P.; Vidal, A. J.
Org. Chem. 2006, 71, 8126-8139.
Table 1. Quinolines 3
compd
X
R1
R2
R3
yield (%)
3a
3b
3c
3d
3e
3f
O
O
O
O
O
S
H
H
CH3
Cl
H
H
H
H
H
CH3
H
H
Ph
CH3
Ph
Ph
Ph
Ph
CH3
Ph
70
58
68
68
67
74
52
77
H
3g
3h
S
S
H
Cl
H
ketenimines 1f-h (X ) S) were converted into the spiro-
heterocycles 3f-h (X ) S), although with the remarkable
difference of requiring longer reaction times (16 h in
refluxing toluene).
(6) Stevens, C. L.; Singhal, G. H. J. Org. Chem. 1964, 29, 34.
5646
Org. Lett., Vol. 8, No. 24, 2006

hydride donors have been measured, and some hydricity
scales are available.8,9a,c Apart from these, other classes of
“organic hydride” systems have emerged in the last years,
mainly in the search of new opportunities for chemical
hydrogen storage. Among them there are nitrogenated
heterocycles such as N,N-dimethylbenzimidazoles 18,7c,11
2-benzoyl-N,N-dimethylperhydropyrimidine 19,9c and ortho-
formamides 2012 (Chart 1).
Scheme 4. Thermal Treatment of Ketenimine 8
The comparison of the thermal stability of 8 in solution
with the easy transformation of ketenimines 1 into spiro-
heterocycles 3 under milder conditions clearly reveals that
the acetal function of 1 (and, to a lesser extent, the
dithioacetal group) favors the occurrence of the tandem [1,5]-
H shift/electrocyclization. To find reasons for explaining the
beneficial influence of the acetal and dithioacetal functions
to such conversions we carried out a computational study at
the B3LYP/6-31+G** theoretical level of the three reaction
sequences shown in Scheme 5: model ketenimines with
Chart 1. Examples of “Organic Hydride” Systems
The remarkable hydricity of 20 is explained as a conse-
quence of its preference for the conformation drawn in Chart
1, in which the central C-H bond is weakened and polarized
by the three antiperiplanar lone pairs at nitrogen.12 It is a
hyperconjugative interaction between the lone pair electrons
and the σ*(C-H) orbital that induces a weakening of the
C-H bond and an increase of negative charge density at
the hydrogen atom.
Scheme 5. B3LYP/6-31+G** Energy Barriers (kcal‚mol-1
)
Although the 1,3-dioxolane and dithiolane functions have
not been explicitly recognized as imparting hydricity yet,13
they count with two antiperiplanar O or S atom lone pairs
which can confer hydride-like character to their H atoms at
C2, as represented in structure A and expressed by resonance
with the canonical structure B (Chart 2). Taking this into
Chart 2. 2-Monosubstituted 1,3-Dioxolanes and
1,3-Dithiolanes
acetal (9 f 11) and dithioacetal (12 f 14) functions at the
benzylic carbon and the unsubstituted case (15 f 17) for
comparison. The results of this study are summarized in that
scheme.
By comparing the computed energy barriers it seems
obvious that in all cases the [1,5]-H shift is the rate
determining step, and that the presence of the acetal function
is favorable (lowering more than 11 kcal‚mol-1 the barrier
of the first step, in relation to the unsubstituted case) as well
as that of the dithioacetal group although in a lesser extent,
in coincidence with the experimental work.
How to explain the positive role of the acetal and
dithioacetal functions in these [1,5]-H shifts? Our proposal
is that these migrations can be understood as hydride shifts7
and are facilitated by the hydricity of the acetalic functions.
The term hydricity has been coined as substitutive of
hydride transfer (or hydride donor) ability. Typical chemicals
possessing hydricity are mainly the metal hydrides, but also
NADH-like compounds and triarylmethane derivatives.8 The
thermodynamic8,9 and kinetic10 hydricities of some of these
account as well as the electrophilic nature of the central
carbon atom of a ketenimine function,3d the [1,5]-H shift
occurring in compounds 1 can be reasonably qualified as a
hydride shift.
(7) Many H shifts have been qualified as “hydride shifts”. For a review
on hydride shifts and transfers, see: (a) Watt, C. I. F. AdV. Phys. Org.
Chem. 1988, 24, 57. For some representative recent examples, see: (b)
Kawai, H.; Takeda, T.; Fujiwara, K.; Suzuki, T. J. Am. Chem. Soc. 2005,
127, 12172. (c) Schwarz, D. E.; Cameron, T. M.; Hay, P. J.; Scott, B. L.;
Tumas, W.; Thorn, D. L. Chem. Commun. 2005, 5919. (d) Birsa, M. L.;
Jones, P. G.; Hopf, H. Eur. J. Org. Chem. 2005, 3263. (e) O’Leary, J.;
Formosa, X.; Skranc, W.; Wallis, J. D. Org. Biomol. Chem. 2005, 3, 3273.
(f) Burk, S.; Gudat, D.; Nieger, M.; Du Mont, W.-W. J. Am. Chem. Soc.
2006, 128, 3946.
(8) Ellis, W. W.; Raebiger, J. W.; Curtis, C. J.; Bruno, J. W.; DuBois,
D. L. J. Am. Chem. Soc. 2004, 126, 2738.
(9) (a) Ellis, W. W.; Ciancanelli, R.; Miller, S. S.; Raebiger, J. W.;
DuBois, M. R.; DuBois, D. L. J. Am. Chem. Soc. 2003, 125, 12230 and
references cited therein. (b) Sarker, N.; Bruno, J. W. Organometallics 2005,
20, 55. (c) Zhang, X.-M.; Bruno, J. W.; Enyinnaya, E. J. Org. Chem. 1998,
63, 4671.
Org. Lett., Vol. 8, No. 24, 2006
5647

In fact, the computed NBO analysis of ketenimines 9 and
12 shows that the nx f σ*C-H hyperconjugative interactions
are the dominant ones among those involving the acetalic
C-H bond (see the Supporting Information). The “charge
transfer” from the lone pairs at the O and S atoms weakens
that C-H bond, and this interaction is stronger in acetal-
ketenimine 9 than in dithioacetal-ketenimine 12.14
We have also tested similar reactions involving carbodi-
imide functions in compounds 21, easily prepared from
iminophosphoranes 7 (X ) O) and aryl isocyanates by aza-
Wittig type reactions (Scheme 6). The cyclization of carbo-
Table 2. Quinazolines 22
compd
R1
R2
Ar
yield (%)
22a
22b
22c
22d
22e
22f
H
H
H
H
CH3
CH3
H
4-CH3O-C6H4
4-Br-C6H4
4-Cl-C6H4
4-CH3-C6H4
4-Br-C6H4
4-Cl-C6H4
81
98
97
99
77
85
CH3
CH3
CH3
H
H
As expected, dithioacetalic carbodiimides 23 were less
reactive and we were not able to achieve their cyclization
under two different thermal conditions essayed (either
o-xylene, reflux, 72 h or toluene, 180 °C, sealed tube, 48
h).
Scheme 6. Preparation of Spirocyclic Dioxolanoquinazolines
22
In summary, we have disclosed in this letter new [1,5]-H
shifts that occur under unusually mild thermal conditions
and proposed a rational explanation based on their charac-
terization as hydride shifts. We believe that our results allow
the inclusion of the monosubstituted 1,3-dioxolane and
dithiolane functions into the ensemble of hydricity-imparting
functionalities. To our knowledge this is the first synthetic
utilization of hydride-releasing fragments for promoting
intramolecular H shifts, a strategy that presumably will find
further applications. Our current efforts are directed to this
end.
diimides 21 to the spirocyclic dioxolanoquinazolines 22,
presumably via similar consecutive [1,5]-H shifts and elec-
trocyclizations, required stronger conditions (refluxing o-
xylene, 24-36 h) than their analogous ketenimines 1
(Scheme 6 and Table 2).
Acknowledgment. This work was supported by the
DGES and FEDER (Project CTQ2005-02323/BQU) and
Fundacio´n Se´neca-CARM (Project 00458/PI/04). Two of us
(M.-M.O. and B.B.) thank Fundacio´n Cajamurcia and
Fundacio´n Se´neca-CARM for the respective fellowships.
(10) (a) Cheng, T.-Y.; Bullock, R. M. Organometallics 2002, 21, 2325.
(b) Cheng, T.-Y.; Brunschwing, B. S.; Bullock, R. M. J. Am. Chem. Soc.
1998, 120, 13121. (c) Cheng, T.-Y.; Bullock, R. M. Organometallics 1995,
14, 4031.
(11) (a) Lee, I.-S. H.; Jeoung, E. H. J. Org. Chem. 1998, 63, 7275. (b)
Montgrain, F.; Ramos, S. M.; Wuest, J. D. J. Org. Chem. 1988, 53, 1489.
(12) Brunet, P.; Wuest, J. D. J. Org. Chem. 1996, 61, 2020 and references
cited therein.
(13) Exceptionally, the cationic polymerization of cyclic acetals has been
proposed to be initiated by an hydride transfer step from the acetal to the
cationic initiator, see: Penczek, S. Makromol. Chem. 1974, 175, 1217-
1252 and references cited therein.
(14) It is known that the hyperconjugative interactions nx f σ*C-H
involving lone pairs at oxygen atoms are stronger than those involving sulfur
atoms in analogous compounds. See: Alabugin, I. V. J. Org. Chem. 2000,
65, 3910-3919 and referenced cited therein.
Supporting Information Available: Experimental details
for the synthesis of compounds 6, 7, 1a, 3, 21, and 22 and
their full characterization; details of computational proce-
dures, geometries, Cartesian coordinates, and energies for
all the stationary points; selected interactions from the NBO
analyses; and NMR spectra of compounds 1a, 3, and 22.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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