Intramolecular ketenimine-ketenimine [2 + 2] and [4 + 2] cycloadditions

Article abstract of DOI:10.1021/jo0704661

(Chemical Equation Presented) Bis(ketenimines), in which the two heterocumulenic functions are placed in close proximity on a carbon skeleton to allow their mutual interaction, show a rich and not easily predictable chemistry. Intramolecular [2 + 2] or [4 + 2] cycloadditions are, respectively, observed when both ketenimine functions are supported on either ortho-benzylic or 2,2′-biphenylenic scaffolds. In addition, nitrogen-to-carbon [1,3] and [1,5] shifts of arylmethyl groups in N-arylmethyl-C,C-diphenyl ketenimines are also disclosed.

Full text of DOI:10.1021/jo0704661

metrical dimers 1,2- or 1,3-bis(imino)cyclobutanes5 and 1,3-
diazetidines.4b,6
Intramolecular Ketenimine-Ketenimine [2 + 2]
and [4 + 2] Cycloadditions†
Despite the fascinating chemistry of ketenimines, only a few
reactions have been conducted on bis(ketenimines): (1) the
addition of dicarboxylic acids,7 diamines,8 and phosphinidene
complexes9 to bis(ketenimines) of general structure R2CdCd
N-Z-NdCdCR2 (Z ) p-C6H4, m-C6H4, p-C6H4-CH2-C6H4-
p) forming poly(N-acylamides), polyamidines, and bis(phos-
phindoles), respectively; (2) double electrocyclic ring closures
of bis(ketenimines) in which two N-vinyl ketenimine moieties
are placed on a heteroaromatic five-membered ring (pyrrole,
furan, or thiophene) that occur with the simultaneous formation
of two pyridine rings for producing dipyridopyrroles, furodipy-
ridines, and thienodipyridines;10 (3) double [1,5] migrations of
alkyl(aryl)thio groups from carbonyl carbon atoms to the central
carbon of ketenimine functions, to yield bis(3H-quinolin-4-ones)
linked via their respective C2 carbon atoms by dithioether
chains;3a and (4) an intramolecular Diels-Alder cycloaddition
involving two different ketenimine functions, N-aryl and N-
vinyl, yielding a benzonaphthyridine.11
Mateo Alajar´ın,*,‡ Baltasar Bonillo,‡ Pilar Sa´nchez-Andrada,‡
AÄ ngel Vidal,‡ and Delia Bautista§
Departamento de Qu´ımica Orga´nica, Facultad de Qu´ımica,
UniVersidad de Murcia, Campus de Espinardo,
30100 Murcia, Spain, and SerVicio UniVersitario de
InVestigacio´n Cient´ıfica, UniVersidad de Murcia, Campus de
Espinardo, 30100 Murcia, Spain
alajarin@um.es
ReceiVed March 6, 2007
Our interest in the chemistry of ketenimines led us to prepare
some new examples of bis(ketenimines) in which the two
functions are supported in proximal positions of a variety of
carbon scaffolds, with the aim of exploring putative intramo-
lecular [2 + 2] cycloadditions between the two ketenimine
moieties, in their different regiochemical modes.
Bis(ketenimines), in which the two heterocumulenic func-
tions are placed in close proximity on a carbon skeleton to
allow their mutual interaction, show a rich and not easily
predictable chemistry. Intramolecular [2 + 2] or [4 + 2]
cycloadditions are, respectively, observed when both keten-
imine functions are supported on either ortho-benzylic or
2,2′-biphenylenic scaffolds. In addition, nitrogen-to-carbon
[1,3] and [1,5] shifts of arylmethyl groups in N-arylmethyl-
C,C-diphenyl ketenimines are also disclosed.
To this end, we first chose an ortho-xylene scaffold as the
platform for placing two ketenimine functions. The preparation
of the diazide 1 was carried out simply by reaction of R,R′-
dichloro-o-xylene with sodium azide, as previously reported.12
The sequential treatment, at room temperature, in the same
reaction flask, of a toluene solution of 1 with triphenylphosphine
and diphenylketene led to the bis(ketenimine) 2 (Scheme 1),
whose formation was secured by a very strong absorption band
near 2000 cm-1 in the IR spectrum of the reaction mixture,
associated with the NdCdC groupings. Bis(ketenimine) 2
remained unaltered when kept in the toluene solution at room
temperature. However, when it was heated at reflux temperature
until the total disappearance of the cumulenic band in its IR
spectrum (approximately 2 h), the dinitrile 3 was formed in 51%
yield (calculated global yield from 1). A similar chemical
behavior was observed for the bis(ketenimine) 5, derived from
2,2′-bis(azidomethyl)biphenyl 4, which yielded the related
Ketenimines are excellent building blocks for the synthesis
of differently ring-sized nitrogen heterocycles, thanks to their
ability for adding nucleophiles1 and carbon-centered radicals2
to their central carbon atom. They are also commonly involved
in pericyclic events1 such as cycloaddition reactions, 6π-
electrocyclic ring closures, and sigmatropic rearrangements.3
Among these types of reactions, only a few symmetric and
unsymmetric [2 + 2] dimerizations of ketenimines have been
reported. The known [2 + 2] modes have provided 2-imino-
azetidines,4 an unsymmetrical type of dimer, and the sym-
(4) (a) Barker, M. W.; Rosamund, J. D. J. Heterocycl. Chem. 1972, 9,
1147. (b) Del’tsova, D. P.; Gambaryan, N. P.; Zeifman, Yu. V.; Knunyants,
I. L. Zh. Org. Khim. 1972, 8, 856. (c) Dondoni, A.; Barbaro, G.; Battaglia,
A.; Bertolapi, V.; Giorgianni, P. J. Org. Chem. 1984, 49, 2200.
(5) 1,2-Bis(imino)cyclobutanes: (a) Aumann, R.; Heinen, H.; Krueger,
C. Angew. Chem. 1984, 96, 234. (b) Aumann, R.; Heinen, H. Chem. Ber.
1985, 118, 952. 1,3-Bis(imino)cyclobutanes: (c) Cristau, H.-J.; Jouanin,
I.; Taillefer, M. J. Organomet. Chem. 1999, 584, 68. (d) Froeyen, P.
Phosphorus, Sulfur Silicon Relat. Elem. 1991, 63, 283.
(6) Gambaryan, N. P.; Avetisyan, E. A. IzV. Akad. Nauk SSSR, Ser. Khim.
1976, 358.
(7) Kurita, K.; Sakata, H.; Iwakura, Y.; Koyanagi, M. J. Polym. Sci.
Polym. Chem. Ed. 1978, 16, 667.
(8) Kurita, K.; Kusayama, Y.; Iwakura, Y. J. Polym. Sci. Polym. Chem.
Ed. 1977, 15, 2163.
(9) Slootweg, J. C.; Vlaar, M. J. M.; Vugts, D. J.; Eichelsheim, T.;
Merhai, W.; de Kanter, F. J. J.; Schakel, M.; Ehlers, A. W.; Lutz, M.; Spek,
A. L.; Lammertsma, K. Chem.sEur. J. 2005, 11, 4808.
(10) Molina, P.; Alajar´ın, M.; Vidal, A. Tetrahedron 1995, 44, 12127.
(11) Molina, P.; Alajar´ın, M.; Vidal, A. J. Org. Chem. 1992, 57, 6703.
(12) Ju, Y.; Kumar, D.; Varma, R. S. J. Org. Chem. 2006, 71, 6697.
† Dedicated to Prof. Miguel Yus on his 60th birthday.
‡ Facultad de Qu´ımica.
§ Servicio Universitario de Investigacio´n Cient´ıfica.
(1) For reviews on the chemistry of ketenimines, see: (a) Krow, G. 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.
(2) (a) Alajar´ın, M.; Vidal, A.; Ort´ın, M.-M. Tetrahedron Lett. 2003,
44, 3027. (b) Alajar´ın, M.; Vidal, A.; Ort´ın, M.-M. Org. Biomol. Chem.
2003, 1, 4282. (c) Alajar´ın, M.; Vidal, A.; Ort´ın, M.-M.; Bautista, D. New
J. Chem. 2004, 28, 570. (d) Alajar´ın, M.; Vidal, A.; Ort´ın, M.-M.; Bautista,
D. Synlett 2004, 991.
(3) For some recent examples, see: (a) Alajar´ın, M.; Ort´ın, M.-M.;
Sa´nchez-Andrada, P.; Vidal, A.; Bautista, D. Org. Lett. 2005, 7, 5281. (b)
Alajar´ın, M.; Ort´ın, M.-M.; Sa´nchez-Andrada, P.; Vidal, A. J. Org. Chem.
2006, 71, 8126 and references therein.
10.1021/jo0704661 CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/21/2007
J. Org. Chem. 2007, 72, 5863-5866
5863

SCHEME 1. Bis(ketenimines) 2 and 5
SCHEME 2. Bis(ketenimines) 10
TABLE 1. Azeto[2,1-b]quinazolines 11
compound
R1
R2
R3
yield (%)
11a
11b
11c
11d
11e
11f
H
H
Br
Cl
CH3
H
H
H
H
H
H
CH3
H
H
H
49
77
78
76
51
16a
o-C6H4
H
a The major product was nitrile 12 (61%).
dinitrile 6. These results were not unprecedented. It is known
that N-benzyl ketenimines experience, under thermal conditions,
1,3-migration of the benzyl group from nitrogen to carbon for
yielding rearranged 3-phenylpropionitriles.13
temperature into the azeto[2,1-b]quinazolines 11, which were
isolated from the final reaction mixtures in moderate yields
(Table 1).
The structure of these fused 2-iminoazetidines was determined
following their analytical and spectral data and was confirmed
by the X-ray structure determination of a monocrystal of 11d
(R1 ) Cl, R2 ) R3 ) H) (see Supporting Information).
The regioselective conversion of 10 f 11, involving the Nd
C bond of the N-benzyl ketenimine fragment and the CdC bond
of the N-aryl ketenimine moiety, most likely occurs by a
stepwise mechanism similar to that of the intramolecular
ketenimine-imine [2 + 2] cycloaddition.14 Thus, the more
nucleophilic nitrogen atom, that of the N-benzyl ketenimine
fragment, should add to the electrophilic sp-hybridized carbon
atom of the other ketenimine unit to give a zwitterionic
intermediate, which in the second step of the reaction would
ring close to form the azetidine ring present in compounds 11.
Surprisingly, bis(ketenimine) 10f, built on a naphthalene-
methyl scaffold, furnished as the major reaction product the
nitrile 1215 (61%), accompanied by the expected [2 + 2]
cycloadduct 11f (16%). It seems reasonable to assume that the
formation of 12 is the result of a 1,5-rearrangement of the (2-
naphthyl)methyl group to an ortho position of one of the phenyl
substituents at the ketenimine terminal carbon atom. This
rearrangement probably involves a geminate radical pair,
similarly to what has been proposed for the 1,3-migrations
previously mentioned.13 To our knowledge, this is the first
observation of a 1,5-rearrangement in N-arylmethyl ketenimines.
The failure of the intramolecular ketenimine-ketenimine
[2 + 2] cycloaddition in compounds 2 and 5 led us to look for
other scaffolds. In a series of articles,14 we have demonstrated
that imino-ketenimines in which the nitrogen atoms of the
imine and ketenimine functions are linked by an ortho-benzylic
framework undergo intramolecular [2 + 2] cycloadditions
involving both nitrogenated functions. We reasoned that the
substitution of the imine group in this type of imino-
ketenimines by a second ketenimine function should give us a
chance for finding an intramolecular ketenimine-ketenimine
[2 + 2] cycloaddition.
The reaction of the 2-azidobenzyl halides 7 with sodium
azide, in DMSO solution, and the subsequent Staudinger reaction
of the diazides 8 with triphenylphosphine in diethyl ether
provided the bis(iminophosphoranes) 9. Bis(ketenimines) 10
were generated in dichloromethane by reaction of 9 with
diphenylketene (Scheme 2). Compounds 10 converted at room
(13) (a) Lee, K.-W.; Horowitz, N.; Ware, J.; Singer, L. A. J. Am. Chem.
Soc. 1977, 99, 2622. (b) Neuman, R. C.; Sylwester, A. P. J. Org. Chem.
1983, 48, 2285.
(14) (a) Alajar´ın, M.; Molina, P.; Vidal, A. Tetrahedron Lett. 1996, 37,
8945. (b) Alajar´ın, M.; Molina, P.; Vidal, A.; Tovar, F. Tetrahedron 1997,
53, 13449. (c) Alajar´ın, M.; Vidal, A.; Tovar, F.; Arrieta, A.; Lecea, B.;
Coss´ıo, F. P. Chem.sEur. J. 1999, 5, 1106. (d) Coss´ıo, F. P.; Arrieta, A.;
Lecea, B.; Alajar´ın, M.; Vidal, A.; Tovar, F. J. Org. Chem. 2000, 65, 3633.
(e) Alajar´ın, M.; Vidal, A.; Tovar, F.; Ram´ırez de Arellano, M. C.; Coss´ıo,
F. P.; Arrieta, A.; Lecea, B. J. Org. Chem. 2000, 65, 7512. (f) Alajar´ın,
M.; Vidal, A.; Tovar, F.; Ram´ırez de Arellano, M. C. Tetrahedron:
Asymmetry 2004, 15, 489.
(15) The structure of nitrile 12 was unequivocally determined by X-ray
analysis, although the collected data are of low quality for publication. Its
analytical and spectral data are in full agreement with such structure.
5864 J. Org. Chem., Vol. 72, No. 15, 2007

SCHEME 3. Bis(ketenimine) 14
ketenimine fragments on a 2,2′-biphenylene skeleton led to their
interaction through an intramolecular Diels-Alder reaction.
Experimental Section
Sample Procedure for the Preparation of Azeto[2,1-b]-
quinazolines 11. To a solution of bis(iminophosphorane) 9 (1
mmol) in anhydrous dichloromethane (20 mL) was added a solution
of diphenylketene (0.58 g, 3 mmol) in the same solvent (5 mL).
The reaction mixture was stirred at room temperature for 24 h.
The solvent was removed under reduced pressure, and the resulting
material was purified by column chromatography using hexanes/
diethyl ether as eluent.
2,2-Diphenyl-1-diphenylmethylidene-1,2-dihydroazeto[2,1-b]-
quinazoline 11a: eluent for column chromatography, hexanes/
diethyl ether (7:3, v/v); yield 49%; mp 236 °C (colorless prism,
diethyl ether/n-pentane); IR (Nujol) 1713 (s), 1635 (vs), 1601 (vs),
1570 (s), 1470 (s), 1294 (m), 1201 (s), 1131 (vs), 1119 (s), 1093
(m), 1073 (m), 1030 (m), 940 (w), 862 (w), 784 (m), 764 (vs), 723
(s), 701 (vs), 694 (vs), 664 (m) cm-1; 1H NMR (CDCl3, 400 MHz)
δ 4.23 (s, 2H), 6.69-6.73 (m, 3H), 6.93-7.00 (m, 3H), 7.03-
7.07 (m, 1H), 7.13-7.16 (m, 2H), 7.26-7.37 (m, 15H); 13C NMR
(CDCl3, 100 MHz) δ 44.7, 70.0 (s), 114.7 (s), 121.2 (s), 125.0,
126.4, 126.6, 127.0, 127.4, 127.7, 127.9, 128.0, 128.5, 128.6, 129.9,
131.1, 138.4 (s), 138.6 (s), 138.9 (s), 142.0 (s), 145.5 (s), 164.2
(s); MS (EI, 70 eV) m/z (rel int) 474 (M+, 26), 204 (100). Anal.
Calcd for C35H26N2 (474.60): C, 88.58; H, 5.52; N, 5.90. Found:
C, 88.30; H, 5.61; N, 6.03.
Procedure for the Preparation of Compound 15. To a
suspension of bis(iminophosphorane) 13 (0.70 g, 1 mmol) in
anhydrous toluene (30 mL) was added a solution of diphenylketene
(0.43 g, 2.25 mmol) in the same solvent (5 mL). The reaction
mixture was stirred at 50 °C for 30 min, and the resulting solution
was heated in a sealed tube at 160 °C for 8 h. The solvent was
removed to dryness, and the solid residue was triturated with
dichloromethane (25 mL). The precipitated yellow solid was filtered
and dried: yield 64%; mp 204 °C; IR (Nujol) 3350 (s), 1660 (vs),
1610 (s), 1558 (s), 1492 (s), 1268 (m), 1226 (w), 1158 (w), 1110
(w), 1093 (w), 1032 (w), 767 (vs), 752 (vs), 727 (s), 704 (vs) 656
(s) cm-1; 1H NMR (DMSO-d6, 400 MHz, 100 °C) δ 5.27 (s, 1H),
6.21 (d, 1H, J ) 7.8 Hz), 6.45-6.50 (m, 3H), 6.62 (dd, 1H, J )
7.7, 0.9 Hz), 6.92-7.19 (m, 16H), 7.28-7.37 (m, 4H), 7.42-7.46
(m, 2H); 13C NMR (DMSO-d6, 100 MHz, 100 °C) δ 64.8 (s), 118.7
(s), 119.1, 122.4, 124.2, 124.9, 125.5, 125.7 (s), 125.8, 125.9, 126.1,
126.3, 126.7, 127.2, 127.3, 127.6, 127.8, 128.6, 128.8, 129.2, 129.4,
131.3, 134.6 (s), 135.1 (s), 135.4 (s), 136.2 (s), 139.4 (s), 139.8
(s), 140.1 (s), 142.9 (s), 148.1 (s), 166.2 (s); MS (EI, 70 eV) m/z
(rel int) 536 (M+, 100). Anal. Calcd for C40H28N2 (536.67): C,
89.52; H, 5.26; N, 5.22. Found: C, 89.33; H, 5.38; N, 5.29.
At this moment, we have no arguments to explain the difference
in the reaction pathway for the bis(ketenimine) 10f when
compared with its N-benzyl analogous 10a-e.
In addition, we explored the reactivity of biphenylene bis-
(ketenimine) 14, in which both ketenimine nitrogens are linked
to aryl carbon atoms. Treatment of a suspension of bis-
(iminophosphorane) 1316 with diphenylketene in toluene at 50
°C resulted in the smooth formation of bis(ketenimine) 14. By
heating in toluene solution at 160 °C in a sealed tube, this bis-
(ketenimine) underwent a clean intramolecular cyclization to
furnish the pentacyclic compound 15 (Scheme 3). The structure
of 15 could not be established unambiguously from its analytical
and spectroscopic data, and so we directed our efforts to obtain
monocrystals. The very low solubility of 15 in the usual organic
solvents led us to crystallize it from nitrobenzene. Unexpectedly,
the X-ray diffraction study of the crystals disclosed the structure
of hydroperoxide 16 (see Supporting Information). Furthermore,
part of this compound was recovered from the crystallization
flask and could be fully characterized by its analytical and
spectroscopic data. Hydroperoxide 16 probably formed by
spontaneous oxidation of compound 15 by the action of the
atmospheric oxygen during the crystallization process. Previous
to this work, we have observed oxidations in air of compounds
with NH-CdC fragments similar to the one which becomes
oxidized in 15, although in those cases, the reaction products
were instead the corresponding tertiary alcohols.17
The conversion of 14 f 15 can be interpreted as a formal [4
+ 2] cycloaddition, in which one of the ketenimine cumulated
CdC bonds forms part of an all-carbon diene,17,18 and the other
one plays the role of the dienophile.19
In summary, here we have shown the preparation and
chemical behavior of bis(ketenimines) with structures that allow
the mutual interaction of their two heterocumulenic functions.
Whereas the combination of two N-benzyl ketenimine moieties
led to independent 1,3-migrations at both heterocumulene
fragments, the adequate positioning of N-benzyl and N-aryl
ketenimine functions in an ortho-benzylic scaffold resulted in
regioselective intramolecular ketenimine-ketenimine [2 + 2]
cycloadditions. In contrast, the disposition of two N-aryl
Acknowledgment. This work was supported by the Minis-
terio de Educacio´n y Ciencia of Spain and FEDER (Project
(18) For examples of reactions involving ketenimines as all-carbon dienes
in the synthesis of heterocycles, see: (a) Sonveaux, E.; Ghosez, L. J. Am.
Chem. Soc. 1973, 95, 5417. (b) Barbaro, G.; Battaglia, A.; Giorgianni, P.
J. Org. Chem. 1987, 52, 3289. (c) Differding, E.; Ghosez, L. Tetrahedron
Lett. 1985, 26, 1647. (d) Schmittel, M.; Steffen, J.-P.; Angel, M. A. W.;
Engels, B.; Lennartz, C.; Hanrath, M. Angew. Chem., Int. Ed. 1998, 37,
1562. (e) Schmittel, M.; Rodr´ıguez, D.; Steffen, J.-P. Angew. Chem., Int.
Ed. 2000, 39, 2152. (f) Shi, C.; Wang, K. K. J. Org. Chem. 1998, 63, 3517.
(g) Molina, P.; Alajar´ın, A.; Vidal, A.; Sa´nchez-Andrada, P. J. Org. Chem.
1992, 57, 929. (h) Molina, P.; Lo´pez-Leonardo, C.; Alca´ntara, J. Tetrahedron
1994, 50, 5027. (i) Alajar´ın, M.; Vidal, A.; Tovar, F.; Conesa, C.
Tetrahedron Lett. 1999, 40, 6127. (j) Alajar´ın, M.; Vidal, A.; Ort´ın, M.-
M.; Tovar, F. Synthesis 2002, 2393.
(19) For examples of reactions involving ketenimines as dienophiles, via
their CdC bond, in the synthesis of heterocycles, see: (a) Roeding, A.;
Ritschel, W.; Foure, M. Chem. Ber. 1980, 113, 811. (b) Barbaro, G.;
Battaglia, A.; Giorgianni, P. J. Org. Chem. 1988, 53, 5501. (c) Alajar´ın,
M.; Vidal, A.; Tovar, F. Tetrahedron Lett. 2000, 41, 7029.
(16) Molina, P.; Alajar´ın, M.; Sa´nchez-Andrada, P.; Elguero, J.; Jimeno,
M. L. J. Org. Chem. 1994, 59, 7306.
(17) Alajar´ın, M.; Vidal, A.; Tovar, F.; Sa´nchez-Andrada, P.; Bautista,
D. Tetrahedron 2003, 59, 9913.
J. Org. Chem, Vol. 72, No. 15, 2007 5865

IR, MS, elemental analyses) for compounds 3, 6, 8, 9, 11b-f, 12,
and 16. X-ray data and CIF files of 11d and 16. 1H and 13C NMR
spectra of compounds 3, 6, 11a-f, 12, 15, and 16. This material is
available free of charge via the Internet at http://pubs.acs.org.
CTQ2005-02323/BQU), and Fundacio´n Se´neca-CARM (Project
00458/PI/04). B.B. also thanks Fundacio´n Se´neca-CARM for
a fellowship.
Supporting Information Available: Experimental details for
the synthesis of compounds 3, 6, 8, and 9. Spectral data (NMR,
JO0704661
5866 J. Org. Chem., Vol. 72, No. 15, 2007