Highly efficient induction of chirality in intramolecular [2 + 2] cycloadditions between ketenimines and imines

Article abstract of DOI:10.1021/jo991826q

Highly stereocontrolled, intramolecular [2 + 2] cycloadditions between ketenimines and imines leading to 1,2-dihydroazeto[2,1-b]quinazolines have been achieved. The source of stereocontrol is a chiral carbon atom adjacent either to the iminic carbon or nitrogen atom. In the first case, the stereocontrol stems from the preference for the axial conformer in the first transition structure. In the second case, the origin of the stereocontrol lies on the two-electron stabilizing interaction between the C-C bond being formed and the σ* orbital corresponding to the polar C-X bond, X being an electronegative atom. These models can be extended to other related systems for predicting the stereochemical outcome in this intramolecular reaction.

Full text of DOI:10.1021/jo991826q

J . Org. Chem. 2000, 65, 3633-3643
3633
High ly Efficien t In d u ction of Ch ir a lity in In tr a m olecu la r [2 + 2]
Cycloa d d ition s betw een Keten im in es a n d Im in es
Fernando P. Coss´ıo* and Ana Arrieta
Kimika Fakultatea, Euskal Herriko Unibertsitatea, P. K. 1072, 20080 San Sebastia´n-Donostia, Spain
Begon˜a Lecea
Farmazi Fakultatea, Euskal Herriko Unibertsitatea, P. K. 450, 01080 Vitoria-Gasteiz, Spain
Mateo Alajar´ın,* Angel Vidal, and Fulgencio Tovar
Departamento de Quı´mica Orga´nica, Facultad de Qu´ımica,Campus de Espinardo,
Universidad de Murcia, 30100 Murcia, Spain
Received November 29, 1999
Highly stereocontrolled, intramolecular [2 + 2] cycloadditions between ketenimines and imines
leading to 1,2-dihydroazeto[2,1-b]quinazolines have been achieved. The source of stereocontrol is a
chiral carbon atom adjacent either to the iminic carbon or nitrogen atom. In the first case, the
stereocontrol stems from the preference for the axial conformer in the first transition structure. In
the second case, the origin of the stereocontrol lies on the two-electron stabilizing interaction between
the C-C bond being formed and the σ* orbital corresponding to the polar C-X bond, X being an
electronegative atom. These models can be extended to other related systems for predicting the
stereochemical outcome in this intramolecular reaction.
In tr od u ction
character of the ketenimine is enhanced by the presence
of electron-withdrawing substituents (such as tosyl4 or
cyano5) on the nitrogen atom of the ketenimine function.
Additionally, these intermolecular [2 + 2] cycloadditions
of ketenimines with imines, in the few examples reported,
have shown erratic degrees of diastereoselectivity at the
3,4-positions of the four-membered products.4,5
Whereas the participation of ketenimines in [4 + 2]
cycloaddition reactions, where these heterocumulenes can
play the role of either the 2- or 4-atom component, is well
documented,1 [2 + 2] cycloadditions in which the keten-
imine function is directly involved as one of the reacting
partners are considerably less common.2 Closely related
to these last processes, [2 + 2] cycloadditions of keten-
iminium cations with imines have been successfully
applied in the field of â-lactam synthesis.3 By contrast,
the analogous reaction of ketenimines with imines to
furnish azetidin-2-imines has received limited attention,
taking place intermolecularly only if the electrophilic
As result of our studies on the chemistry of keten-
imines, we recently described the first examples of
entropically assisted intramolecular [2 + 2] cycloaddi-
tions of ketenimines with imines,6 starting from the
iminoketenimines of general structure 1, which led to the
previously unknown azeto[2,1-b]quinazolines 2 (n ) 1)
and azeto[2,1-b][1,3]benzodiazepines 2 (n ) 2).
(1) Ketenimines as two-atom components in [4 + 2] cycloadditions:
(a) Barbaro, G.; Battaglia, A.; Giorgianni, P. J . Org. Chem. 1988, 53,
5501. (b) Molina, P.; Alajar´ın, M.; Vidal, A. Tetrahedron Lett. 1991,
32, 5379. (c) Molina, P.; Alajar´ın, M.; Vidal, A. J . Org. Chem. 1992,
57, 6703. (d) Kee-J ung, L.; Heung-Taeck, K.; Boo-Geun, K. J . Hetero-
cycl. Chem. 1997, 34, 1795. Ketenimines as four-atom components in
[4 + 2] cycloadditions: (e) Ghosez, L.; de Pe´rez, C. Angew. Chem., Int.
Ed. Engl. 1971, 10, 184. (f) Sonveaux, E.; Ghosez, L. J . Am. Chem.
Soc. 1973, 95, 5417. (g) Dondoni, A. Heterocycles 1980, 14, 1547. (h)
Differding, E.; Ghosez, L. Tetrahedron Lett. 1985, 26, 1647. (i)
Differding, E.; Vandevelde, O.; Roekens, B.; Trieu, T.; Ghosez, L.
Tetrahedron Lett. 1987, 28, 397. (j) Molina, P.; Lo´pez-Leonardo, C.
Tetrahedron Lett. 1993, 34, 2809. (k) Molina, P.; Lo´pez-Leonardo, C.;
Alca´ntara, J . Tetrahedron 1994, 50, 5027. (l) Andrews, I. P.; Bannister,
R.; Etridge, S. K.; Lewis, N. J .; Mullane, M. V.; Wells, A. S. Tetrahedron
Lett. 1995, 36, 7743. (m) Kee-J ung, L.; Seong-Heon, K.; J ong-Hyuk,
K. Synthesis 1997, 1461. (n) Barluenga, J .; Ferrero, M.; Palacios, F.
Tetrahedron 1997, 53, 4521. (o) Alajar´ın, M.; Vidal, A.; Tovar, F.;
Conesa, C. Tetrahedron Lett. 1999, 40, 6127. For a review on pericyclic
reactions of ketenimines, see: Alajarı´n, M.; Vidal, A.; Tovar, F. Targets
Heterocycl. Syst. Manuscript in preparation.
(2) (a) Ulrich, H. Cycloaddition Reactions of Heterocumulenes;
Academic Press: New York, 1967. (b) Patai, S. The Chemistry of
Ketenes, Allenes and Related Compounds; Wiley: New York, 1980.
(3) (a) Ghosez, L.; Marchand-Brynaert, J . Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
1991; Vol. 5, pp 108-113. (b) Belzecki, C.; Rogalska, E. J . Chem. Soc.,
Chem. Commun. 1981, 57. (c) Ghosez, L.; Bogdan, S.; Ceresiat, M.;
Frydrych, C.; Marchand-Brynaert, J .; Moya-Portuguez, M.; Huber, I.
Pure Appl. Chem. 1987, 59, 393.
Recently, we reported a highly diastereoselective ver-
sion of these model reactions on the basis of the desym-
metrization of the ketenimine fragment by placing two
different substituents on its sp2 carbon terminus, thus
making its two faces enantiotopic. The combination with
an imine fragment of similar topicity gave rise to azeto-
[2,1-b]quinazolines 3 containing two stereogenic carbon
(4) Van Camp, A.; Goossens, D.; Moya-Portuguez, M.; Marchand-
Brynaert, J .; Ghosez, L. Tetrahedron Lett. 1980, 21, 3081.
(5) Arnold, B.; Regitz, M. Angew. Chem., Int. Ed. Engl. 1979, 18,
320.
(6) (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.
10.1021/jo991826q CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/18/2000

3634 J . Org. Chem., Vol. 65, No. 12, 2000
Coss´ıo et al.
Sch em e 1a
amine component of the imine, which is the carbon
atom/s linking the aromatic nucleus to the iminic nitro-
gen atom; (b) the carbonyl component of the imine, which
is the substituents on the iminic carbon; and (c) the
ketene precursor of the ketenimine, which is the substit-
uents on the carbon atom of the ketenimine fragment.
Herein, we report the results obtained in the study of
the intramolecular [2 + 2] cycloaddition of ketenimines
with imines when amines or aldehydes with an asym-
metric center were used to prepare the imine fragment,
cases (a) and (b) above. In addition, as we did in our
previous paper,7 we have performed a computational
study in order to understand the reasons underlying the
stereocontrol experimentally observed.
a
The substituents at the different positions are not specified.
atoms, C1 and C2, with the formation of a clear excess
of the cis diastereoisomer over the trans.7
Resu lts a n d Discu ssion
Ch ir a l Im in es Der ived fr om Ch ir a l Am in es. Reac-
tion of the racemic chiral amines 1-(o-azidophenyl)-
ethylamine 4a and 2-azido-R-phenylbenzylamine 4b with
aromatic, heteroaromatic, R,â-unsaturated, or aliphatic
aldehydes in the presence of anhydrous magnesium
sulfate9 or basic alumina10 gave rise to the corresponding
aldimines 5 in almost quantitative yields. Azidoimines
5 were generally used in the next reaction step as crude
products due to the partial hydrolytic cleavage of the
imino bond during purification attempts by crystalliza-
1
tion or column chromatography. In all cases, H and 13C
NMR data of 5 showed only one set of signals, which we
have associated with the unique formation of the aldi-
mines with E configuration of the imino CdN bond.6a
When crude azidoimines 5 were treated with a 1 M
toluene solution of trimethylphosphane, evolution of
dinitrogen was clearly observed indicating their conver-
sion into the corresponding trimethylphosphazenes 6.11
These compounds were not isolated but treated in the
same reaction flask with an equivalent amount of diphe-
nylketene. IR spectra of small aliquots of the resulting
reaction mixtures showed strong absorptions around
2000 cm-1, attributable to the CdCdN grouping of
iminoketenimines 7, which resulted from an aza-Wittig
reaction12 of the phosphazene with the ketene. After some
hours in solution at room temperature, iminoketenimines
7 converted into the corresponding azeto[2,1-b]quinazo-
lines 8 through a formal intramolecular [2 + 2] cyclo-
addition between the imino CdN and the cumulated
CdC bonds (Scheme 2). Compounds 8 were obtained in
moderate to good yields after purification by column
chromatography (Table 1) and were characterized by
their analytical and spectral data, which were essentially
similar to those of compounds 2 and 3 reported previ-
ously.6,7
In parallel to these experimental findings, we have
performed theoretical studies in order to understand the
mechanism of these transformations and to elucidate the
main variables that govern its stereochemical outcome.
In a previous study,7 we have found that the reaction
between neutral ketenimines and imines does not take
place via concerted mechanisms, but consists of a step-
wise process (Scheme 1). In a first step, the nitrogen lone
pair of the imine adds to the sp-hybridized carbon atom
of the ketenimine. The resulting zwitterionic intermedi-
ate is transformed into the corresponding azetidin-2-
imine via a conrotatory thermal ring closure. This
mechanism is qualitatively similar to the well-known
Staudinger reaction between ketenes and imines. How-
ever, in this latter reaction the limiting step is the second
one, in which the two new chiral centers are formed.8
Instead, the energetic balance in the reaction between
ketenimines and imines is more complex. In this reaction
the stereocontrol is actually transferred to the first step,
thus allowing remarkable levels of stereoselectivity even
when the torquoelectronic effects operating in the second
step are canceled.
These intramolecular [2 + 2] reactions of the imi-
noketenimines 7, which present an imino fragment with
diastereotopic faces due to the chiral center on the amine
component, yielded compounds 8 containing a new ste-
reogenic carbon atom C1, in a highly diastereoselective
manner, with a clear excess of the trans diastereoisomer
As a further step in the study of the intramolecular [2
+ 2] cycloaddition of ketenimines with imines, we have
devoted considerable efforts to find out appropriate ways
for inducing chirality into this reaction. Ideally there are
three sites on the iminoketenimines of general structure
1 where a chiral stereocenter may be located: (a) the
(9) Tamura, O.; Hashimoto, M.; Kobayashi, Y.; Katoh, T.; Nakatani,
K.; Kamada, M.; Hayakawa, I.; Akiba, T.; Tesashima, S. Tetrahedron
Lett. 1992, 33, 3483.
(10) Texier-Boullet, F. Synthesis 1985, 679.
(7) Alajar´ın, M.; Vidal, A.; Tovar, F.; Arrieta, A.; Lecea, B.; Coss´ıo,
F. P. Chem. Eur. J . 1999, 5, 1106.
(8) (a) Coss´ıo, F. P.; Arrieta, A.; Lecea, B.; Ugalde, J . M. J . Am.
Chem. Soc. 1994, 116, 2085. (b) Assfeld, X.; Sordo, T. L.; Sordo, J . A.;
Gonzalez, J . J . Org. Chem. 1993, 58, 7036.
(11) (a) Gololobov, Y. G.; Zhmurova, I. N.; Kasukhin, L. F. Tetra-
hedron 1981, 37, 437. (b) Gololobov, Y. G.; Kasukhin. L. F. Tetrahedron
1992, 48, 1353.
(12) (a) Eguchi, S.; Matsushita, Y.; Yamashita, K. Org. Prep. Proced.
Int. 1992, 24, 209. (b) Molina, P.; Vilaplana, M. J . Synthesis 1994, 1197.

Chirality in Intramolecular [2 + 2] Cycloadditions
J . Org. Chem., Vol. 65, No. 12, 2000 3635
Ta ble 2. Selected 1H NMR Da ta of
Sch em e 2a ,b
Azeto[2,1-b]qu in a zolin es 8
δ H1 (ppm)
δ H8 (ppm)
δ CH3-C8 (ppm)
compd trans-8 cis-8 trans-8 cis-8
trans-8
cis-8
8a
8b
8c
8d
8e
8f
8g
8h
8i
5.86
5.68
6.49
5.80
5.23
5.31
4.35
4.63
5.36
5.24
3.92
5.54
5.38
a
5.52
a
4.73
4.72
4.87
4.76
4.80
4.86
4.79
4.72
5.58
5.60
5.63
4.83
4.82
a
4.82
a
1.42
1.40
1.54
1.42
1.45
1.48
1.30
1.27
1.30
1.20
a
1.32
a
a
a
a
4.31
4.55
5.59
5.47
4.29
4.68
4.74
5.72
5.70
5.60
1.63
1.70
8j
8k
a
Diastereoisomers not obtained in this work.
Only in one case, 8h , both isomers were separated and
characterized as such (see the Experimental Section).
The cis/trans configuration of the diastereoisomeric
1
reaction products was assigned on the basis of their H
NMR data and by nuclear Overhauser (NOE) experi-
ments. Irradiation of the signal at δ 1.42 ppm corre-
sponding to the hydrogens of the methyl group CH3-C8
in the major isomer of compound 8a (R1 ) CH3, R2
)
4-O2N-C6H4) induced a 10.9% enhancement of the H1
signal (δ 5.86 ppm), whereas NOE enhancement could
not be observed on the H1 signal when the H8 proton (δ
4.73 ppm) was irradiated. These results evidence that
the major isomer formed in the [2 + 2] cycloaddition here
reported is the one with the hydrogens H1 and H8 in a
trans relative configuration, trans-8a . Similar outcomes
were obtained on the major isomers of the rest of
compounds 8. Moreover, the comparison of the chemical
shifts of the H8 and CH3-C8 protons in the 1H NMR
spectra of the major and minor isomers of the azeto-
quinazolines 8 bearing an aryl, heteroaryl, or vinyl
substituent at C1 (compounds 8a -f,i,j) serves to ascer-
tain the configurational assignment made above (Table
2). The trans isomers show the H8 proton shifted upfield,
when compared with the cis, due probably to the mag-
netic shielding exerted by the nearby aryl, heteroaryl,
or vinyl group at C1, in a relative cis position. A similar
anisotropic effect can explain the differences observed in
the chemical shifts of the CH3-C8 protons between both
isomers in compounds 8a -d , as well the shielding of the
H1 proton in the trans isomers of compounds 8i-k , in
this last case due to the phenyl group at C8 in a relative
cis position to this proton.
a
Key: (i) method A: R2-CHO, Et2O, anhyd MgSO4, 25 °C, 12
h; method B: R2-CHO, basic Al2O3, 25 °C, 12 h; (ii) PMe3, toluene,
25 °C, 30 min; (iii) Ph2CdCdO, toluene, 25 °C, 1 h. bOnly one
enantiomer is drawn for each compound.
Ta ble 1. Azeto[2,1-b]qu in a zolin es 8 a n d 9
compd
R1
R2
cis/transa yieldb (%)
8a
8b
8c
8d
8e
8f
8g
8h
8i
CH3 4-O2N-C6H4
CH3 4-CH3O-C6H4
CH3 1-naphthyl
CH3 3-thienyl
CH3 (E)-C6H5-CHdCH
CH3 (E)-2-O2N-C6H4-CHdCH
CH3 (CH3)2CH
11:89
4:96
<2:98
6:94
82
68
65
63
78
58
67
43
80
50
66
62
26
62
50
37
<2:98
<2:98
17:83
23:77
9:91
10:90
27:73
<2:98
20:80
<2:98
4:96
CH3 (CH3)3C
C6H5 4-O2N-C6H4
C6H5 4-H3C-C6H4
C6H5 (CH3)2CH
CH3 4-O2N-C6H4
CH3 (CH3)2CH
C6H5 4-O2N-C6H4
C6H5 4-H3C-C6H4
C6H5 (CH3)2CH
8j
8k
9a
9b
9c
9d
9e
15:85
a
As determined by 1H NMR (300 MHz) analysis of the crude
b
reaction mixtures. Yield of pure isolated major diastereoisomer.
In a previous work we have shown that trimethyl-
silylketene could be used as efficiently as diphenylketene
in a reaction sequence similar to the one reported in
Scheme 2, giving rise to 2-unsubstituted azeto[2,1-b]-
quinazolines due to protonolysis of the C2-silicon bond
during the chromatographic purification (SiO2 column)
of the reaction products.6b Sequential treatment of imines
5 with trimethylphosphane and trimethylsilylketene led,
after purification by column chromatography, to azeto-
quinazolines 9 (Scheme 3), unsubstituted at carbon C2,
with the same degree and sense of stereocontrol that in
the sequence leading to 8. Similarly to that results,
compounds 9 were also obtained with higher degree of
diastereoselectivity when the imine fragment derived
from aromatic instead of aliphatic aldehydes, and no
remarkable differences were observed by changing from
R-CH3 to R-Ph at the benzylic carbon atom (Table 1).
Although in this work we have not carried out reactions
over the cis (Table 1), thus showing the high stereocontrol
exerted by the R1 substituent on the benzylic carbon over
the configuration of the new chiral center. Higher dias-
tereoisomeric excesses were obtained from imine frag-
ments derived from aromatic, heteroaromatic, or R,â-
unsaturated aldehydes (compounds 8a -f,i,j) than from
aliphatic ones (8g,h ,k ). Only minor differences were
found by the employment of the R-CH3 or R-Ph substit-
uents on the preexisting chiral center (compare cis/trans
ratios of 8a vs 8i and 8g vs 8k ).
The ratio of isomers was calculated by integration of
the signals due to H1, H8, and/or CH3-C8 in the 1H NMR
(300 MHz) spectra of the crude reaction mixtures, before
the purification step. In the reactions that yielded
mixtures of diastereoisomers, the major one could be
separated in a pure form by column chromatography.

3636 J . Org. Chem., Vol. 65, No. 12, 2000
Coss´ıo et al.
Sch em e 3a ,b
Sch em e 4
a
Key: (i) PMe3, toluene, 25 °C, 30 min; (ii) Me3SiCHdCdO,
toluene, reflux, 2 h; (iii) silica gel. bOnly one enantiomer is drawn
for each compound.
of the C4 and C4′ carbons in the resulting single â-lactam
stereoisomer has been determined to be syn.8a,15,16 The
same is true for similar Staudinger reactions with imines
derived from other chiral R-amino aldehydes.17
on optically active iminoketenimines type 7, the easy
availability of enantiomerically enriched (S)-(-)-1-(o-
azidophenyl)ethylamine13 makes the reactions above
potentially useful for preparing 1,2-dihydroazeto[2,1-b]-
quinazolines, such as trans-8 and 9, in non racemic forms
given that the occurrence of racemization in the [2 + 2]
cycloadditions seems unlikely.
Ch ir a l Im in es Der ived fr om Ch ir a l Ald eh yd es. As
mentioned in the Introduction, a second site to locate a
chirality directing group may be the substituents on the
iminic carbon atom of the iminoketenimines of general
structure 1. For instance, it has been shown that the
Staudinger reaction between ketenes and imines to give
â-lactams occurs with high stereocontrol if a chiral carbon
atom, bearing one heteroatom attached to it, is directly
linked to the iminic carbon atom.14 Due to the apparent
similarity between the Staudinger reaction and the [2 +
2] cycloadditions here discussed, it was hoped that one
of those chiral substituents on the iminic carbon of 1
would serve to control efficiently the absolute configu-
ration of the C1 carbon atom in the putative products of
the intramolecular cycloaddition.
Com p u ta tion a l Stu d ies
Meth od s. All calculations reported in this paper have
been performed using either the GAUSSIAN9418 or
GAUSSIAN9819 series of programs, with the 3-21G and
6-31G* basis sets.20 Electron correlation was estimated
by means of density functional theory (DFT),21 in this
particular case by using the hybrid method developed by
Becke and usually denoted as B3LYP.22 All the reported
stationary points were fully optimized at the HF/3-21G
(15) (a) Palomo, C.; Coss´ıo, F. P.; Cuevas, C.; Lecea, B.; Mielgo, A.;
Roma´n, P.; Luque, A.; Mart´ınez-Ripoll, M. J . Am. Chem. Soc. 1992,
114, 9360. (b) Palomo, C.; Coss´ıo, F. P.; Cuevas, C. Tetrahedron Lett.
1991, 32, 3109. (c) J ayaraman, M.; Deshmukh, A. R., Bhawal; B. M.
Tetrahedron 1996, 52, 8989.
(16) J ayaraman, M.; Nandi, M.; Sathe, K. M.; Deshmukh, A. R. A.
S.; Bhawal, B. M. Tetrahedron: Asymmetry 1993, 4, 609.
(17) (a) Palomo, C.; Aizpurua, J . M.; Cuevas, C.; Roma´n, P.; Luque,
A.; Mart´ınez-Ripoll, M. An. Quim. Int. Ed. 1996, 92, 134. (b) Palomo,
C.; Aizpurua, J . M.; Cuevas, C.; Urchegui, R.; Linden, A. J . Org. Chem.
1996, 61, 4400. (c) Palomo, C.; Aizpurua, J . M.; Cabre´, F.; Garc´ıa, J .
M.; Odriozola, J . M. Tetrahedron Lett. 1994, 35, 2721. (d) Palomo, C.;
Coss´ıo, F. P.; Cuevas, C.; Odriozola, J . M.; Ontoria, J . M. Tetrahedron
Lett. 1992, 33, 4827.
(18) Gaussian 94, Revision B.2: Frisch, M. J .; Trucks, G. W.;
Schlegel, H. B.; Gill, P. M. W.; J ohnson, B. G.; Robb, M. A.; Cheeseman
J . R.; Keith, T.; Petersson, G. A.; Montgomery, J . A.; Raghavachari,
K.; Al-Laham, M. A.; Zakrzewski, V. G.; Ortiz, J . V.; Foresman, J . B.;
Peng, C. Y.; Ayala, P. Y.; Chen, W.; Wong, M. W.; Andres, J . L.;
Replogle, E. S.; Gomperts, R.; Martin, R. L.; Fox, D. J .; Binkley, J . S.;
Defrees, D. J .; Baker, J .; Stewart, J . S.; Head-Gordon, M.; Gonzalez,
C.; Pople, J . A. Gaussian, Inc., Pittsburgh, PA, 1995.
(19) Gaussian 98, Revision A.5: Frisch, M. J .; Trucks, G. W.;
Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J . R.;
Zakrzewski, V. G.; Montgomery, J r., J . A.; Stratmann, R. E.; Burant,
J . C.; Dapprich, S.; Millam, J . M.; Daniels, A. D.; Kudin, K. N.; Strain,
M. C.; Farkas, O.; Tomasi, J .; Barone, V.; Cossi, M.; Cammi, R.;
Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski, J .;
Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick, D. K.;
Rabuck, A. D.; Raghavachari, K.; Foresman, J . B.; Cioslowski, J .; Ortiz,
J . V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi,
I.; Gomperts, R.; Martin, R. L.; Fox, D. J .; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P.
M. W.; J ohnson, B.; Chen, W.; Wong, M. W.; Andres, J . L.; Gonzalez,
C.; Head-Gordon, M.; Replogle, E. S.; Pople, J . A. Gaussian, Inc.,
Pittsburgh, PA, 1998.
With this aim in mind, iminoketenimine 10 was
prepared starting from 2-azidobenzylamine by sequential
treatment with commercially available tert-butyl (S)-
(-)-4-formyl-2,2-dimethyl-3-oxazolidinecarboxylate (Gar-
ner’s aldehyde), trimethylphosphane, and diphenylketene,
a methodology analogous to that in Scheme 2. From the
intramolecular [2 + 2] cycloaddition of 10 only one
diastereoisomeric product 11 could be detected in the
crude reaction mixture and conveniently purified by
column chromatography and further crystallization
(Scheme 4). Its absolute configuration at C1 was set up
attending to the observed coupling constant between H1
and the adjacent hydrogen atom on the oxazolidine ring
3
(3J HH ) 9.6 Hz in CDCl3 at 328 K; J HH ) 9.3 Hz in
1
DMSO-d6 at 333 K) in its H NMR spectra, a value that
is in good accordance with the one described in the
literature for similarly 4-substituted â-lactams possessing
the same syn relative configuration between the two
adjacent stereocenters.15 Moreover, in all the [2 + 2]
cycloadditions reported to date of ketenes with chiral
imines derived from Garner’s aldehyde or other closely
related 4-formyl oxazolidines, the relative configuration
(20) Hehre, W. J .; Radom, L.; Schleyer, P. v. R.; Pople, J . A. Ab Initio
Molecular Orbital Theory; Wiley: New York, 1986; pp 71-82 and
references therein.
(21) (a) Parr, R. G.; Yang, W. Density-Functional Theory of Atoms
and Molecules; Oxford University Press: New York, 1989. (b) Kohn,
W.; Becke, A. D.; Parr, R. G. J . Phys. Chem. 1996, 100, 12974. (c)
Bartolott, L. J .; Pluchick, K. In Reviews in Computational Chemistry;
Lipkowitz, K. B., Boyd, D. B., Eds.; VCH Publishers: New York, 1996;
Vol. 7, pp 187-216.
(22) (a) Becke, A. D. J . Chem. Phys. 1993, 98, 5648. (b) Becke, A. D.
Phys. Rev. A 1988, 38, 3098. (c) Lee, C.; Yang, W.; Parr, R. G. Phys.
Rev. B 1980, 37, 785. (d) Vosko, S. H.; Wilk, L.; Nusair, M. Can. J .
Phys. 1980, 58, 1200.
(13) Molina, P.; Alajar´ın, M.; Vidal, A. J . Org. Chem. 1993, 58, 1687.
(14) For some good compilations of references on this theme, see:
(a) Georg, G. I.; Ravikumar, V. T. In The Chemistry of â-Lactams;
Georg, G. I., Ed.; VCH Publishers: New York, 1992; pp 295-368. (b)
J ayaraman, M.; Srijaran, V.; Deshmukh, A. R. A. S.; Bhawal, B. M.
Tetrahedron 1996, 52, 3741. (c) ref 8a.

Chirality in Intramolecular [2 + 2] Cycloadditions
J . Org. Chem., Vol. 65, No. 12, 2000 3637
Sch em e 5
Sch em e 6
level by analytical gradient techniques and characterized
by frequency calculations.23 Zero-point vibrational ener-
gies (ZPVEs) were scaled by 0.89.24 Solute-solvent
interactions were computed by means of the Onsager
model,25 which is denoted here as L1A1.26 Atomic charges
and two-electron interactions were calculated by the
natural bond orbital (NBO) method.27
Ch ir a l Im in es Der ived fr om Ch ir a l Am in es. We
have selected structures 12a ,b as model reactants for the
study of the intramolecular [2 + 2] reaction of compounds
7 (R1 ) Me, R2 ) alkyl, aryl, see Scheme 2). In this case,
the stereocontrol is dictated by the chiral carbon atom
adjacent to the iminic nitrogen, and formation of two
diastereomeric 2-iminoazetidines cis- and trans-13a ,b is
possible. We have depicted in Scheme 5 these structures
as well as the transition structures and intermediates,
which are conceivable from the mechanism previously
reported for this reaction.7
Assuming that the two substituents of the ketenimine
moiety are identical, formation of two diastereomeric
reaction intermediates and products is possible, as it is
shown in Scheme 6. If we define the ω dihedral angle as
indicated in this Scheme, in one zwitterionic intermedi-
ate, denoted as A, the sign of this dihedral angle is
positive. From this intermediate, the conrotatory motion
of lowest energy is counterclockwise, since as long as the
electrocyclization progresses the ω angle approaches to
zero. This conrotation leads to diastereomer C. Similarly,
the other possible intermediate B has a negative value
of ω. In this case, clockwise conrotation leads to diaste-
reomer D. It is noteworthy that given the (E) geometry
of the iminic part of the reactant and the substituents of
the ketenimine moiety (vide supra), direct interconver-
sion between A and B is not possible.8a,28
Intensive exploration of the corresponding HF/3-21G
potential energy surfaces led to the structures depicted
in Figures 1-4. Previous work from our laboratory has
shown that this theoretical level yields accurate enough
geometries.7 The computed relative energies are reported
in Table 3. In this table, the energy differences have been
defined according to the reaction profiles depicted in
Figure 5.
As we have previously reported,7 since the concentra-
tion of the intermediates is lower than those of the
reactants and/or the products, the steady-state ap-
proximation can be applied to the computed reaction
profiles. Under these conditions, the cis/trans ratio of
cycloadducts 13 is given by eq 1
[cis-13]
≈
[trans-13]
exp[-(∆Eca1 + ∆Eac2)/RT][exp(-∆Et-a1/RT) + exp(-∆Eat 2/RT)]
exp[-(∆Eta1 + ∆Eat 2)/RT][exp(-∆Ec-a1/RT) + exp(-∆Eac2/RT)]
(1)
where
∆Et-a1 ) ∆Eta1 - ∆Eitnt
∆Ec-a1 ) ∆Eca1 - ∆Eicnt
(2)
(23) McIver, J . M.; Komornicki, A. K. J . Am. Chem. Soc. 1972, 94,
2625.
(24) Pople, J . A.; Schleyer, B.; Krishnan, R.; DeFrees, D. J .; Binkley,
J . S.; Frish, H.; Whiteside, R.; Hout, R. F., J r.; Hehre, W. J . Int. J .
Quantum Chem. Symp. 1981, 15, 269.
and
(3)
(25) (a) Onsager, L. J . Am. Chem. Soc. 1936, 58, 1486. (b) Wong,
M. W.; Wiberg, K. B.; Frisch, M. J . J . Am. Chem. Soc. 1992, 114, 523.
(c) Wong, M. W.; Wiberg, K. B.; Frisch, M. J . J . Am. Chem. Soc. 1992,
114, 1645.
All magnitudes in eqs 1-3 are reported in Table 3.
According to our results, in both the 12a f 13a and 12b
(26) Morao, I.; Lecea, B.; Arrieta, A.; Coss´ıo, F. P. J . Am. Chem.
Soc. 1997, 119, 816.
(27) Reed, A. E.; Curtiss, L. A.; Weinhold, F. Chem. Rev. 1988, 88,
899.
(28) (a) Dumas, S.; Hegedus, L. S. J . Org. Chem. 1994, 59, 4967.
(b) Hegedus, L. S.; Montgomery, J .; Narukawa, Y.; Snustad, D. C. J .
Am. Chem. Soc. 1991, 113, 5784.

3638 J . Org. Chem., Vol. 65, No. 12, 2000
Coss´ıo et al.
Ta ble 3. En er gy Ba r r ier sa ,b (k ca l/m ol) a n d Dia ster eom er ic Ra tios (cis/tr a n s)c Com p u ted for th e Rea ction s In clu d ed in
Sch em es 5 a n d 7
∆Ea1
∆Eint
∆Ea2
∆Erxn
method
cis (syn) trans (anti) cis (syn) trans (anti) cis (syn) trans (anti) cis (syn) trans (anti) cis/ trans (syn/ anti)
12a f cis-13a + trans-13a
HF/3-21G
B3LYP/6-31G*
28.09
20.02
25.67
17.72
16.53
23.88
15.07
13.29
21.78
13.21
11.75
24.98
13.47
14.46
25.46
14.26
14.99
-18.95
-20.71
-21.18
-19.53
-20.91
-21.34
6:94
14:86
15:85
B3LYP(L1A1)/6-31G*d 18.94
12b f cis-13b + trans-13b
HF/3-21G
32.01
23.30
30.11
21.27
20.65
27.94
18.66
17.73
26.29
16.96
15.81
21.61
8.00
8.50
21.71
8.68
9.50
-15.78
-17.31
-17.58
-16.62
-17.41
-17.71
7:93
15:85
18:82
B3LYP/6-31G*
B3LYP(L1A1)/6-31G*d 22.64
12c f syn-13c + anti-13c
HF/3-21G
27.71
20.64
27.23
20.69
20.23
25.76
18.57
17.80
24.52
17.40
17.51
19.11
6.75
7.66
24.57
11.66
11.50
-21.09
-19.30
-19.07
-17.67
-18.78
-18.46
100:0
100:0
100:0
B3LYP/6-31G*
B3LYP(L1A1)/6-31G*d 19.93
a
b
See Figures 5 and 9 for the notation of these energy differences. Single-point energies computed from HF/3-21G geometries. The
scaled ZPVE corrections have been included. c Calculated from eqs 1-3. Values obtained in simulated toluene solution (ꢀ ) 2.38).
d
F igu r e 2. Main geometric features of the stationary points
cis-TS2a , trans-TS2a , cis-13a , and trans-13a found in the
second step of the reaction of 12a to form cis- and trans-13a
(see Scheme 5), computed in the gas phase. See Figure 1
caption for additional details.
F igu r e 1. Main geometric features of the stationary points
12a , cis-TS1a , trans-TS1a , cis-INTa , and trans-INTa found
in the first step of the reaction of 12a to form cis- and trans-
membered ring is formed. This new ring is in a half-chair
conformation, the methyl groups occupying axial or
equatorial positions. For instance, in both cis-TS1a and
cis-INTa the ω values are positive and the noniminic
methyl group is equatorial. This leads to a destabilizing
interaction between this group and the hydrogen atom
attached to the iminic carbon (Figure 1). In both trans-
TS1a and trans-INTa , the noniminic methyl group
occupies the axial position and therefore this destabiliz-
ing interaction is not present. Consequently, the cis
stationary points are of higher energy than their trans
13a (see Scheme 5), computed in the gas phase. Bond distances
are given in angstroms and angles in degrees. In this and the
following figures which incorporate ball-and-stick drawings,
atoms are represented by increasing order of shadowing as
follows: H, C, O, N.
f 13b transformations the first step is of higher activa-
tion energy than the second one. This first step consists
of the nucleophilic attack of the nitrogen atom of the
imine part of 12a ,b on the sp-hybridized carbon atom of
the ketenimine (Figures 1 and 3). In this step, a six-

Chirality in Intramolecular [2 + 2] Cycloadditions
J . Org. Chem., Vol. 65, No. 12, 2000 3639
F igu r e 4. Main geometric features of the stationary points
cis-TS2b, trans-TS2b, cis-13b, and trans-13b found in the
second step of the reaction of 12b to form cis- and trans-13b
(see Scheme 5), computed in the gas phase. See Figure 1
caption for additional details.
F igu r e 3. Main geometric features of the stationary points
12b, cis-TS1b, trans-TS1b, cis-INTb, and trans-INTb found
in the first step of the reaction of 12b to form cis- and trans-
13b (see Scheme 5), computed in the gas phase. See Figure 1
caption for additional details.
of the cis/trans ratios reported in Table 3 compare very
well with similar examples reported in Table 1 (com-
pounds 8a -h and 9a ,b).
analogues. The same analysis can be extended to TS1b
and INTb (see Figure 3).
In essence, our model predicts that in these reactions
the source of the stereocontrol lies in the proximity
between the group present at the chiral methine carbon
contiguous to the ortho-disubstituted phenyl ring and the
hydrogen atom attached to the iminic carbon. The major
isomer is the one that minimizes this proximity occupying
an axial position during the first step of the reaction. If
this model is correct, a trisubstituted iminic part derived
from a ketone should induce even larger diastereoselec-
tion.
Ch ir a l Im in es Der ived fr om Ch ir a l Ald eh yd es. We
have selected structure 12c as a model for compound 10,
in which the imine moiety is generated from Garner’s
aldehyde. The possible stationary points are shown in
Scheme 7, and their chief geometric features at HF/3-
21G level are reported in Figures 6 and 7. Given the
relative flexibility of these structures, several different
conformations were checked. In particular, the possible
rotamers of the formamide moiety were computed. The
structures reported and discussed are those found to be
the lowest energy conformers.
Counterclockwise conrotation from cis-INTa ,b (from
the position indicated by an asterisk in Figures 2 and 4)
leads to cis-13a ,b, cis-TS2a ,b being the respective transi-
tion structures. Similarly, clockwise conrotation of trans-
INTa ,b leads to trans-13a ,b via trans-TS2a ,b. In all
these second transition structures the substituents at the
iminic carbon atoms occupy the inward position, and
therefore, the torquoelectronic effects are similar for the
corresponding diastereomeric pairs. In addition, the
already formed six-membered rings are more planar as
long as the second step proceeds. Therefore, the energy
barriers associated with these second steps are quite
similar, as is shown by the ∆Ea2 data reported in Table
3.
In summary, in these transformations the stereocontrol
of the whole reaction lies in the first step, namely in the
formation of the N1-C2 bond. Applying eq 1, the trans-
cycloadducts must be the major reaction products under
kinetic control. In addition, the quantitative evaluations

3640 J . Org. Chem., Vol. 65, No. 12, 2000
Coss´ıo et al.
F igu r e 5. Reaction profile found for the 12a ,b f cis-/ trans-13a ,b transformation.
Sch em e 7
of the chiral oxazolidine moiety. Thus, the NBO analysis
at the B3LYP/6-31G* level shows that in syn-TS2c there
is a strong stabilizing interaction between the σ(C1‚‚‚C2)
bond being formed and the σ*(C-N) bond located on the
chiral N-formyloxazolidine ring, as it is depicted in Figure
8. The second-order perturbation energy associated with
this interaction is -12.93 kcal/mol.
This large value is due to the favorable steric environ-
ment imposed by the conrotatory geometry of the transi-
tion structure and the chirality of the center already
present. In particular, the arrangement between C2 and
C* is almost linear, thus allowing an efficient overlap (see
Figure 8). In contrast, in anti-TS2c the unfavorable
matching between the azetidine ring being formed and
the oxazolidine ring does not allow an antiperiplanar
arrangement between the C1‚‚‚C2 and C*-N bonds.
Therefore, the C-C bond of the oxazolidine must occupy
the antiperiplanar position. However, given that the C-N
bond is a better σ-acceptor than the C-C bond, the σ*-
(C-C) NBO is of higher energy than σ*(C-N), and
therefore, the second-order perturbation energy associ-
ated with the σ(C1‚‚‚C2) f σ*(C-C) is ca. 5.4 kcal lower
than that corresponding to the σ(C1‚‚‚C2) f σ*(C-N)
donation (Figure 8). As a consequence, anti-TS2c is of
higher energy than its syn analogue. From the syn/anti
ratio calculated from eq 1 (see Table 3), exclusive forma-
tion of syn-13c is predicted, in excellent agreement with
our experimental finding.
The general features of the first transition structures
and the reaction intermediates are similar to those found
for the two previous model reactions. In particular, the
six-membered ring has a half-chair conformation. How-
ever, given that there is one methylene group instead of
a chiral methine carbon atom, the energies of both first
transition structures and intermediates are quite similar,
as can be seen from the ∆Ea1 and ∆Eint data reported in
Table 3.
Therefore, the origin of the chiral control in the 12c f
syn-13c transformation lies in the second step of the
reaction as it is shown in the reaction profile depicted in
Figure 9. This result is in line with those obtained in
more conventional Staudinger reactions between ketenes
and imines and contrasts with that previously found for
the 12a ,b f 13a ,b transformations (vide supra).
In contrast, the second transition structures are of
quite different energies, syn-TS2c saddle point being ca.
4 kcal/mol more stable than anti-TS2c. As we have found
in previous computational work on the Staudinger reac-
tion between ketenes and imines,8a the reason for this
significant difference in energy lies in the two-electron
interaction between the C1‚‚‚C2 bond being formed and
either the σ* orbitals located on the C-N or C-C bond
Con clu sion s
In the present work, we have shown two ways for
inducing chirality at the C1 carbon atom of 1,2-dihy-
droazeto[2,1-b]quinazolines, as obtained in the intramo-
lecular [2 + 2] cycloadditions between ketenimine and
imine fragments placed on an ortho-benzylic scaffolding.
In the first one, the stereochemical outcome is controlled

Chirality in Intramolecular [2 + 2] Cycloadditions
J . Org. Chem., Vol. 65, No. 12, 2000 3641
F igu r e 7. Main geometric features of the stationary points
syn-TS2c, anti-TS2c, syn-13c, and anti-13c found in the
second step of the reaction of 12c to form syn- and anti-13c
(see Scheme 7), computed in the gas phase. See Figure 1
caption for additional details.
being formed and the C-X σ bond present in the
reactant, X being an electronegative atom. A high stereo-
control is predicted in this latter case, the syn cycloadduct
being the sole isomer formed.
F igu r e 6. Main geometric features of the stationary points
12c, syn-TS1c, anti-TS1c, syn-INTc, and anti-INTc found in
the first step of the reaction of 12c to form syn- and anti-13c
(see Scheme 7), computed in the gas phase. See Figure 1
caption for additional details.
Exp er im en ta l Section
For general experimental information see ref 7.
Ma ter ia ls. 2-Azidobenzylamine,29 1-(o-azidophenyl)ethyl-
amine,13 trimethylsilyl ketene,30 and diphenylketene31 were
prepared following previously reported procedures. N-(2-
Azidobenzyl)imines 5 were obtained by standard procedures
(Scheme 1, methods A9 and B10).
by a chiral benzylic carbon adjacent to the iminic nitrogen
atom, at two bonds of distance from the new stereogenic
center. The second one relies on the stereocontrol exerted
by a chiral carbon atom directly linked to the iminic
carbon, the future asymmetric C1, when the imine
fragment derives from a particular R-amino aldehyde
(Garner’s aldehyde). According to our computational
model, the sterecontrol can stem from the different steps
present in the proposed mechanism. If the chirality is
induced from the carbon atom contiguous to the iminic
nitrogen atom, the trans stereocontrol is determined by
the preferential axial disposition of the susbtituent at the
chiral methine carbon in the first transition state of the
reaction. In contrast, when a chiral aldehyde is used as
chiral template, the stereocontrol is dictated by the
preferential anti disposition between the new σ bond
P r ep a r a tion of 2-Azid o-r-p h en ylben zyla m in e (4b). A
solution of NaNO2 (2.07 g, 30 mmol) in H2O (50 mL) was added
dropwise to an ice-cooled solution of 2-amino-R-phenylbenzyl
alcohol (3.98 g, 20 mmol) in 6 N HCl (200 mL). The reaction
mixture was stirred at 0 °C for 30 min, and then a solution of
NaN3 (1.95 g, 30 mmol) in H2O (50 mL) was added. After 4 h
at room temperature, the reaction mixture was extracted with
dichloromethane (3 × 100 mL), and the extracts were dried
over MgSO4. The solvent was removed under reduced pressure,
(29) Smith, P. A. S.; Budde, G. F.; Shang-Shing, P. C. J . Org. Chem.
1985, 50, 2062.
(30) Valenti, E.; Perica´s, M. A.; Serratosa, F. J . Org. Chem. 1990,
55, 395.
(31) Taylor, E. C.; McKillop, A.; Hawks, G. H. Org. Synth. 1973,
52, 36.

3642 J . Org. Chem., Vol. 65, No. 12, 2000
Coss´ıo et al.
100 mL of tetrahydrofuran and 16 mL of ethanol. After 16 h
at room temperature, the suspension was heated at reflux
temperature for 8 h. After cooling, the mixture was filtered,
the solid was washed with tetrahydrofuran, and the solvent
was removed from the filtrate. The resulting material was
purified by column chromatography (silica gel; ethyl acetate/
methanol 1:1) to afford 2-a zid o-r-p h en ylb en zyla m in e
(4b): yield 91%; colorless oil; IR (Nujol) 3379, 3292, 2117, 1294
1
cm-1; H NMR (CDCl3) δ 1.77 (br s, 2 H), 5.45 (s, 1 H), 7.12-
7.44 (m, 9 H); 13C NMR (CDCl3) δ 54.21, 118.28, 125.09, 127.00,
127.06, 128.14, 128.28, 128.43, 136.86 (s), 137.33 (s), 144.45
(s); mass spectrum m/z (relative intensity) 224 (M+, 43), 196
(100). Anal. Calcd for C13H12N4: C, 69.62; H, 5.39; N, 24.98.
Found: C, 69.50; H, 5.09; N, 25.41.
Gen er a l P r oced u r e for th e P r ep a r a tion of Azeto[2,1-
b]qu in a zolin es 8, 9, a n d 11. Trimethylphosphane (3 mmol,
1 M toluene solution) was added to a solution of the corre-
sponding azidoimine (3 mmol) in dry toluene (15 mL), and the
reaction mixture was stirred at room temperature until the
evolution of nitrogen ceased (15-30 min). Then, diphenyl-
ketene or trimethylsilylketene (3 mmol) was added, and the
reaction mixture was stirred at room temperature or at reflux
temperature, respectively, until the ketenimine band around
2000 cm-1 was not observed by IR spectroscopy (1-12 h). The
solvent was removed under reduced pressure, and the result-
ing material was chromatographed on a silica gel column, with
hexanes/ethyl acetate as eluent.
tr a n s-2,2-Dip h en yl-8-m eth yl-1-(4-n itr op h en yl)-1,2-d i-
h yd r oa zeto[2,1-b]qu in a zolin e (tr a n s-8a ): yield 82%; mp
172-173 °C; colorless prisms (diethyl ether); IR (Nujol) 1669,
1519, 1343 cm-1; 1H NMR (CDCl3) δ 1.42 (d, 3 H, J ) 6.2 Hz),
4.73 (q, 1 H, J ) 6.2 Hz), 5.86 (s, 1 H), 6.95-7.11 (m, 7 H),
7.24-7.44 (m, 7 H), 7.71 (d, 2 H, J ) 8.7 Hz), 8.02 (d, 2 H, J
) 8.7 Hz); 13C NMR (CDCl3) δ 21.66, 48.95, 69.28, 69.63 (s),
123.37, 124.84, 125.58, 126.71 (s), 126.80, 127.16, 127.63,
127.70, 128.03, 128.25, 128.40, 128.56, 128.78, 137.07 (s),
140.19 (s), 142.11 (s), 142.93 (s), 147.53 (s), 163.61 (s); mass
spectrum m/z (relative intensity) 445 (M+, 43), 165 (100). Anal.
Calcd for C29H23N3O2: C, 78.18; H, 5.20; N, 9.43. Found: C,
78.41; H, 5.09; N, 9.25.
F igu r e 8. B3LYP/6-31G* second-order perturbational ener-
gies (∆E(2)) in syn- and anti-TS2c. The HF/3-21G fully
optimized geometries of both transition structures are repre-
sented by means of the space-filling model, to enphasize the
steric interactions between the forming ring and the chiral
oxazolidine moiety.
and the resulting material was purified by column chroma-
tography (silica gel; hexanes/diethyl ether 7:3) to give 2-a zid o-
r-p h en ylben zyl a lcoh ol (60%).
Diethyl azodicarboxylate (3.48 g, 20 mmol) was added at 0
°C to a solution of triphenylphosphane (5.24 g, 20 mmol) in
50 mL of dry tetrahydrofuran. The mixture was stirred for 30
min at that temperature, and then 2-azido-R-phenylbenzyl
alcohol (3.38 g, 15 mmol) and phthalimide (2.94 g, 20 mmol)
were added. The mixture was stirred 1 h at 0 °C and 24 h at
room temperature. The solvent was removed, and the residue
was chromatographed (silica gel; hexanes/ethyl acetate 4:1)
to obtain N-(2-a zid o-r-p h en ylben zyl)p h th a lim id e (75%).
Hydrazine hydrate (7.5 equiv) was added to a solution of
N-(2-azido-R-phenylbenzyl)phthalimide (3.54 g, 10 mmol) in
tr a n s-1-Isop r op yl-2,2,8-tr ip h en yl-1,2-d ih yd r oa zeto[2,1-
b] qu in a zolin e (tr a n s-8k ): yield 66%; mp 231 °C; white
1
prisms (diethyl ether); IR (Nujol) 1669, 1594, 1564 cm-1; H
NMR (CDCl3) δ 0.61 (d, 3 H, J ) 6.5 Hz), 0.95 (d, 3 H, J ) 6.5
Hz), 1.69-1.79 (m, 1 H), 3.92 (d, 1 H, J ) 9.9 Hz), 5.63 (s, 1
H), 6.82 (dd, 1 H, J ) 7.5, 1.2 Hz), 6.93 (ddd, 1 H, J ) 7.5, 7.2,
1.5 Hz), 7.05-7.39 (m, 15 H), 7.58-7.61 (m, 2 H); 13C NMR
(CDCl3) δ 19.22, 20.42, 30.23, 61.10, 65.71 (s), 73.21, 124.58,
125.73, 126.15 (s), 127.25, 127.29, 128.01, 128.07, 128.20,
F igu r e 9. Reaction profile found for the 12c f syn-/ anti-13c transformation.

Chirality in Intramolecular [2 + 2] Cycloadditions
J . Org. Chem., Vol. 65, No. 12, 2000 3643
128.37, 128.47, 128.85, 129.21, 129.24, 139.16 (s), 139.78 (s),
141.44 (s), 141.97 (s), 156.29 (s), one methine carbon was not
observed; mass spectrum m/z (relative intensity) 428 (M+, 63),
385 (100). Anal. Calcd for C31H28N2: C, 86.88; H, 6.58; N, 6.54.
Found: C, 86.65; H, 6.73; N, 6.62.
Hz), 6.91-7.01 (m, 1 H), 7.15-7.45 (m, 10 H), 7.64 (d, 2 H, J
) 7.1 Hz); mass spectrum m/z (relative intensity) 509 (M+, 30),
310 (100); [R]25 ) +176.8 (c 1.38, CHCl3). Anal. Calcd for
D
C32H35N3O3: C, 75.41; H, 6.92; N, 8.24. Found: C, 75.65; H,
6.81; N, 8.03.
tr a n s-8-Meth yl-1-(4-n itr op h en yl)-1,2-d ih yd r oa zeto[2,1-
b] qu in a zolin e (tr a n s-9a ): yield 62%; mp 155-156 °C;
colorless prisms (diethyl ether); IR (Nujol) 1663, 1596, 1520,
Ack n ow led gm en t. The work in Murcia was sup-
ported by the Direccio´n General de Ensen˜anza Superior
(Project PB95-1019), Fundacio´n Se´neca-CARM (Project
PB/2/FS/99), and by Acedesa (a division of Takasago).
The work in San Sebastia´n-Donostia was supported by
the Secretaria de Estado, Investigacio´n y Desarrollo
(Project PB96-1481) and by the Gobierno Vasco-Eusko
J aurlaritza (Projects EX-1998-126 and PI-1998-116).
One of us (F.T.) also thanks the MEC for a fellowship.
1
1349 cm-1; H NMR (CDCl3) δ 1.44 (d, 3 H, J ) 6.5 Hz), 3.01
(dd, 1 H, J ) 14.9, 2.8 Hz), 3.63 (dd, 1 H, J ) 14.9, 5.6 Hz),
4.68 (q, 1 H, J ) 6.5 Hz), 5.20 (dd, 1 H, J ) 5.6, 2.8 Hz), 6.95
(d, 1 H, J ) 7.8 Hz), 7.02-7.11 (m, 2H), 7.21 (td, 1 H, J ) 7.8,
1.5 Hz), 7.60 (d, 2 H, J ) 8.7 Hz), 8.26 (d, 2 H, J ) 8.7 Hz);
13C NMR (CDCl3) δ 21.47, 41.61, 49.22, 56.97, 124.24, 124.62,
124.81, 126.68, 126.96, 128.50, 141.80 (s), 145.72 (s), 147.94
(s), 159.59 (s), one quaternary carbon was not observed; mass
spectrum m/z (relative intensity) 293 (M+, 11), 278 (100). Anal.
Calcd for C17H15N3O2: C, 69.61; H, 5.15; N, 14.32. Found: C,
69.88; H, 5.01; N, 14.37.
Su p p or tin g In for m a tion Ava ila ble: Characterization
data for products 8b-j and 9b-e, as well as total energies
and zero-point vibrational energies of all stationary points of
the reactions studied by computational methods. This material
is available free of charge via the Internet at http://pub.acs.org.
Azeto[2,1-b]qu in a zolin e 11: yield 42%; mp 186-187 °C;
colorless prisms (diethyl ether); IR (Nujol) 1691, 1664, 1598
1
cm-1; H NMR (CDCl3, 328 K) δ 1.44 (s, 9 H), 1.49 (s, 3 H),
1.75 (s, 3 H), 3.55 (dd, 1 H, J ) 9.6, 5.1), 3.81 (d, 1 H, J ) 9.6
Hz), 3.85 (bs s, 1 H), 4.44 (d, 1 H, J ) 12.0 Hz), 4.50 (d, 1 H,
J ) 9.6 Hz), 4.54 (d, 1 H, J ) 12.0 Hz), 6.80 (d, 1 H, J ) 7.45
J O991826Q