Synthesis of enantiopure 3-azabicyclo[3.2.0]heptanes by diastereoselective intramolecular [2+2] photocycloaddition reactions on chiral perhydro-1,3-benzoxazines

Article abstract of DOI:10.1021/jo034251c

[2+2] photocycloadditions involving chiral 3-acryloyl-2-vinylperhydro-1,3-benzoxazines derived from (-)-8-aminomenthol are highly diastereoselective reactions. The facial selectivity depends on the type of substitution at the vinyl double bond, and always leads to cis-fused bicyclic derivatives. The de is good for compounds with one substituent at the outer carbon of the double bond at C-2, but only one diastereomer is formed in cyclizations of compounds with two substituents at that position. The elimination of the menthol appendage gives enantiopure 3-azabicyclo[3.2.0]heptanes.

Full text of DOI:10.1021/jo034251c

Syn th esis of En a n tiop u r e 3-Aza bicyclo[3.2.0]h ep ta n es by
Dia ster eoselective In tr a m olecu la r [2+2] P h otocycloa d d ition
Rea ction s on Ch ir a l P er h yd r o-1,3-ben zoxa zin es
Rafael Pedrosa,* Celia Andre´s,* J avier Nieto, and Soledad del Pozo
Departamento de Quı´mica Orga´nica, Facultad de Ciencias, Universidad de Valladolid,
Dr. Mergelina s/ n, 47011-Valladolid, Spain
pedrosa@qo.uva.es
Received February 25, 2003
[2+2] photocycloadditions involving chiral 3-acryloyl-2-vinylperhydro-1,3-benzoxazines derived from
(-)-8-aminomenthol are highly diastereoselective reactions. The facial selectivity depends on the
type of substitution at the vinyl double bond, and always leads to cis-fused bicyclic derivatives.
The de is good for compounds with one substituent at the outer carbon of the double bond at C-2,
but only one diastereomer is formed in cyclizations of compounds with two substituents at that
position. The elimination of the menthol appendage gives enantiopure 3-azabicyclo[3.2.0]heptanes.
In tr od u ction
of their interest as target intermediates in synthesis8 and
pharmacologically active agents.9 In this way, such
compounds have been prepared by photochemical cy-
cloadditions on diallylamines,10 diallyl carbamates,11 and
3-allyl-4-vinyl-substituted oxazolidinones12 derived from
chiral glycine. Diastereoselective cyclizations promoted
by metals lead to this class of bicyclic compounds,13 and
3-azabicyclo[3.2.0]heptan-2-ones have also been obtained
by thermally induced intramolecular [2+2] cycloaddition
of keteniminium salts and olefinic bonds.14
Photochemical cycloaddition between two 2π-electron-
containing entities giving rise to four-membered ring
structures is one of the most successful contributions of
photochemistry to organic synthesis.1 Two new carbon-
carbon bonds are formed, and a maximum of four new
stereocenters are introduced in the process. Conse-
quently, it has been extensively applied toward the syn-
thesis of natural products and other complex molecules.2
The control of the regio- and/or stereoselectivity is an
important problem of bimolecular photocycloadditions
that limits its applications in organic synthesis; in the
intramolecular variant of the reaction these problems are
substantially reduced owing to geometrical constraints
imposed on the reacting functional groups.3 In general,
the regioselectivity can be satisfactorily predicted by the
“rule of five”,4 and the facial diastereoselectivity of the
reaction can be controlled by a stereogenic center within
the carbon chain. In contrast to the intermolecular
asymmetric cycloaddition,5 the intramolecular version
using a removable chiral auxiliary6 or chiral catalysis7
has been less studied.
In previous works we have shown that chiral perhydro-
1,3-benzoxazines derived from (-)-8-aminomenthol15 con-
stitute useful chiral auxiliaries in different diastereose-
lective cycloaddition processes leading to nitrogen hetero-
cyclic systems.16
We now report on the synthesis of enantiopure 3-aza-
byciclo[3.2.0]heptanes by intramolecular [2+2] photocy-
cloaddition of R,â-unsaturated amides with alkenes, each
(6) (a) Winkler, J . D.; Scott, R. D.; Williard, P. G. J . Am. Chem. Soc.
1990, 112, 8971. (b) Haag, D.; Schorf, H. D. J . Org. Chem. 1996, 61,
6127. (c) Faure, S.; Piva-Le Blanc, S.; Piva, O.; Pete, J . P. Tetrahedron
Lett. 1997, 38, 1045. (d) Faure, S.; Piva, O. Tetrahedron Lett. 2001,
42, 255. (e) Faure, S.; Piva-Le Blanc, S.; Bertrand, C.; Pete, J . P.; Faure,
R.; Piva, O. J . Org. Chem. 2002, 67, 1061.
Some of these efforts have been directed to the stereo-
selective synthesis of azabicyclo[3.2.0]heptanes because
(7) Lauger, K.; Mattey, J . J . Org. Chem. 1995, 60, 7256.
(8) Bach, T.; Kru¨ger, C.; Harms, K. Synthesis 2000, 305.
(9) Steiner, G.; Unger, L.; Behl, B.; Teschendorf, H. J .; Munschauer,
R. PCT Int., Appl. WO9400458, 1994; Chem. Abstr. 1994, 121, 205375.
(10) Steiner, G.; Munschauer, R.; Klebe, G.; Siggel, L. Heterocycles
1995, 40, 319.
(11) Salomon, R. G.; Ghosh, S.; Raychaudhuri, S. R.; Miranti, T. S.
Tetrahedron Lett. 1984, 25, 3167.
(12) Bach, T.; Pelkmann, C.; Harms, K. Tetrahedron Lett. 1999, 40,
2103.
(13) Baik, T. G.; Luis, A. L.; Wang, L. C.; Krische, M. J . J . Am. Chem.
Soc. 2001, 123, 6716.
(14) Dalle Monache, G.; Misiti, D.; Salvatore, P.; Zappia, G.; Pierini,
M. Tetrahedron: Asymmetry 2000, 11, 2653.
(15) Rassat, A.; Rey, P. Tetrahedron 1974, 30, 3315.
(16) (a) Andre´s, C.; Garc´ıa-Valverde, M.; Nieto, J .; Pedrosa, R. J .
Org. Chem. 1999, 64, 5230. (b) Pedrosa, R.; Andre´s, C.; Nieto, J . J .
Org. Chem. 2000, 65, 831. (c) Pedrosa, R.; Andre´s, C.; Heras, L.; Nieto,
J . Org. Lett. 2002, 4, 2513.
* To whom correspondence should be addressed. Phone: 34-
983423211 (R.P.). Fax: 34-983423013 (R.P.).
(1) (a) Crimmins, M. T. Comprehensive Organic Synthesis; Pergamon
Press: Oxford, 1991; Vol. 5, p 123. (b) Carruthers, W. Cycloaddition
Reactions in Organic Synthesis; Tetrahedron Organic Chemistry
Series; Pergamon Press: Oxford, 1990; Vol. 8, p 332.
(2) (a) Crimmins, M. T. Chem. Rev. 1988, 88, 1453. (b) De Keu-
keleire, D.; He, S. H. Chem. Rev. 1993, 93, 359. (c) Winkler, J . D.;
Mazur-Bowen, C.; Liotta, F. Chem. Rev. 1995, 95, 2003.
(3) Mattay, J .; Conrads, R.; Hoffmann, R. Stereoselective Synthesis;
Houben Weyl; Georg Thieme Verlag: Stuttgart, Germany, 1996; E 21,
Vol. 5, p 3085.
(4) (a) Srinivasan, R.; Carlough, K. H. J . Am. Chem. Soc. 1967, 89,
4932. (b) Lin, R. S. H.; Hammond, G. S. J . Am. Chem. Soc. 1967, 89,
4936.
(5) (a) Demuth, M.; Mikhail, G. Synthesis 1989, 145. (b) Ione, Y.
Chem. Rev. 1992, 92, 741. (c) Bach, T. Synthesis 1998, 683. See also
ref 3.
10.1021/jo034251c CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/21/2003
J . Org. Chem. 2003, 68, 4923-4931
4923

Pedrosa et al.
TABLE 1. P h otoch em ica l Cycloa d d ition s of Am id es
3a -j
SCHEME 1
time yielda
products
(ratio)b
entry amide
R1
R2 R3 (h)
(%)
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
Ph
H
H
H
H
H
Ph
H
H
H
H
H
H
H
30
15
25
5
6
39
61
54
58
4a (71), 5a (29)
4b(70), 5b (30)
4c (78), 5c (22)
2-OMePh
4-OMePh
2-NO2Ph
4-NO2Ph
Ph
92
55
60
4e (88), 5e (12)
5f (100)
4g (16) 5g (77),
6g (7)
3g
Ph
Me 68
8
9
10
3h
3i
3j
Ph
Me
Me
Ph Me 92
52
5h (100)
Me
H
H
H
80
90
24c 5i (100)
26c 4j (13), 5j (55),
6j (32)
a
Yields refer to isolated compounds after column chromatog-
raphy. Determined by 1H NMR of the reaction mixture. c Pho-
todecomposition acryloyl amides of (-)-8-aminomenthol were the
major products obtained in these cases.
b
The reactivity of styryl derivatives 3a -h (R1 and/or
R2 ) Ar) substantially differs from that shown by 2-allyl-
substituted perhydro-1,3-benzoxazines 3i-j (R1 and/or R2
) Me). 3i leads to 5i as a single diastereomer after 80 h
of irradiation in only 24%, and 3j, after 90 h of irradia-
tion, was also transformed (26%) into a mixture of
diastereomeric cyclobutane derivatives 4j, 5j, and 6j. In
these reactions the major byproducts detected were the
R,â-unsaturated amides of (-)-8-aminomenthol formed
by decomposition of the starting compounds. Perhy-
drobenzoxazines with aryl substituents at the outer
carbon of the vinyl moiety (3a -h ) react easier than 3i-
j, leading to the cyclization products in moderate to very
good yields. An exception to this general behavior was
2-nitrophenyl derivative 3d , which does not provide the
cyclization products after irradiation.
SCHEME 2
These results could be explained on the basis of the
maximum absorption in the ultraviolet spectra of the
starting amides, and the photocyclization was tested by
changing the Pyrex by a quartz immersion well, but
photodecomposition products were obtained as major
compounds. Some other experimental conditions, such as
the addition of Cu(I) salts11 or irradiation in the presence
of benzophenone as sensitizer,10 were tested, but neither
the chemical yields nor the ratio of diastereomers changed.
As expected for intramolecular [2+2] photocycloaddi-
tion in structures with a short tether connecting the
unsaturated units, the reaction occurs with total regi-
oselectivity, providing the fused adducts. The formation
of the initial bond gives a 1,4-diradical bearing a five-
membered ring, and bridgehead products were not ob-
served.
Interestingly, the facial diastereoselectivity is depend-
ent on the nature and number of substituents appended
to the double bonds. In this way, acryloyl amides 3a -e
with only one aryl substituent at the outer carbon in the
allyl group yield a mixture of two diastereomers (4a -e
and 5a -e) in moderate to good de. For these diastereo-
mers, the ring junction between the cyclobutane and the
γ-lactam ring is cis and the relative configuration of the
substituent at C-6 (see the numbering in Scheme 2) is
exo, but they differ in the relative configuration of the
hydrogen at the N,O-ketal carbon (H at C-4 in Scheme
2) and the bicyclic junction, being cis for compounds 4a -e
and trans for 5a -e.
attached to a chiral perhydro-1,3-benzoxazine acting as
a chiral template.
Resu lts a n d Discu ssion
The chiral perhydro-1,3-benzoxazines 3a -j used in the
photocyclizations were synthesized in two steps17 and
excellent yields (83-91%) from (-)-8-aminomenthol (1)
(Scheme 1). The condensation of 1 with R,â-unsaturated
aldehydes in toluene at room temperature afforded a
nearly quantitative yield of N-unsubstituted 2-alkenylp-
erhydro-1,3-benzoxazines 2a -j, which were acylated with
acryloyl or methacryloyl chloride and triethylamine at 0
°C in CH2Cl2.
Intramolecular [2+2] photocycloadditions were carried
out using a water-cooled Pyrex immersion well photore-
actor equipped with a 125 W mercury medium-pressure
lamp. The argon-purged solutions of 3a -j in acetonitrile
(0.07 M) were irradiated at room temperature until
disappearance of the starting compound was observed.
The progress of the reaction was monitored by TLC or
1H NMR, and the results are summarized in Scheme 2
and Table 1.
(17) Pedrosa, R.; Andre´s, C.; Nieto, J . J . Org. Chem. 2002, 67, 782.
4924 J . Org. Chem., Vol. 68, No. 12, 2003

Synthesis of 3-Azabicyclo[3.2.0]heptanes
are in an axial arrangement. This fact was confirmed by
X-ray diffraction analysis of compounds 4a and 5i. The
substituent at the nitrogen atom in 4a occupies an
equatorial position (trans fusion for the N,O-ketal and
lactam cycles), but it is in an axial position in diastere-
omer 5i (cis fusion for the same heterocycles).20 On the
other hand, H-1 for compounds 5 resonates downfield (ca.
0.23-0.30 ppm) of the same proton in diastereomer 4,
and the resonance for H-5 is shifted upfield (ca. 0.63-
0.71 ppm) in adducts 5 with respect to the same proton
in compounds 4. This general trend allowed the assigna-
tion of the stereochemistry for all these compounds.
F IGURE 1. 1H NOESY contacts recorded for compounds 4b
and 5g.
The stereochemistry of adducts 6g and 6j was also
1
established on the basis of their H and 13C NMR spectra.
The facial selectivity is complete for acryloyl (3f and
3i) or methacryloyl (3h ) amides with two substituents
at the terminal carbon of the allyl group at the N,O-ketal
carbon. In the same reaction conditions these compounds
gave 5f, 5h , and 5i, respectively, as single diastereomers.
Perhydro-1,3-benzoxazine 3g, with a methyl group at
the R-carbon of the R,â-unsaturated amide provides up
to three photocycloadducts: two exo products (4g and 5g),
and one diastereomer (6g) which differs from 5g only in
the endo orientation of the substituents at C-6. An 1H
NMR study of the course of the reaction of 3g shows that
the [2+2] photocycloaddition process occurred at the
same time as the Z-E isomerization18 of the styryl unit.
After 20 h of irradiation (ca. 25% conversion) the remain-
ing (E)-styryl derivative 3g was isomerized to a ca. 1:1
Z-E mixture. During the remainder of the reaction the
(Z)-styryl derivative predominates, although the final
cyclization product endo-6g was only obtained in 7%
yield.
Thus, H-4 appears as a doublet with a small coupling
constant (J ) 2.0 Hz) for 6g and as a singlet for 6j. The
shielding ring current effect of the endo-aryl group in 6g
shifts the 13C NMR signal of C-4 3.6 ppm upfield with
respect to the same carbon in 5g. On the other hand, the
13C NMR signal for the methyl group at C-6 in endo
adduct 6j is shifted upfield (∆δ ) 5 ppm) as compared
with that of the exo isomer 5j. This phenomenon has been
previously observed in related 3-azabicyclo[3.2.0]heptane
derivatives.8
The stereochemical course of these photocycloadditions
can be interpreted on the basis of the generally accepted
proposal for these reactions21 taking into account the
following facts: (i) The cis fusion of the cyclobutane and
the γ-lactam in all the diastereomers indicates that the
cyclization occurs by interaction of the Re face of one
double bond (R-carbon) with the Si face of the other, and
not by Re-Re or Si-Si interactions. (ii) The trans
junction (substituent at the nitrogen atom in an equato-
rial position) between the lactam and the N,O-heterocycle
for major stereoisomers 4a -e obtained from 3a -e or the
cis stereochemistry (substituent at the nitrogen in an
axial position) for compounds 5f-j obtained as major or
single isomers from 3f-j point to both diastereomers
being formed from different conformations of the starting
perhydro-1,3-benzoxazines or their exciplexes.22
On the basis of these facts the formation of the final
products can be proposed (Scheme 3) to occur from two
different conformations (A and B) of the starting com-
pounds, which undergo cyclization to form two different
1,4-biradicals that collapse to diastereomers 4 and 5,
respectively. Amides 3a -e (R2 ) H) preferably react in
conformation A where the acyl substituent at the nitro-
gen lies in an equatorial position, and the formation of
the five-membered heterocyclic biradicals occurs by
interaction of the Re face (R carbon) of the allylic double
bond with the Si face of the double bond of the amide. In
contrast, compounds 3f, 3h , and 3i (R2 * H) cyclize from
conformation B probably because of the A1,3 strain in
conformation A. The reaction in these cases occurs by
interaction of the Si face of the allylic substituent and
the Re face of the double bond of the R,â-unsaturated
amide in axial disposition.
Amide 3j also provides a mixture of three photocy-
cloadducts (exo-4j, exo-5j, and endo-6j), although in this
case, the photoisomerization of 3j is not observed when
the reaction is followed by 1H NMR. Dienes do not
equilibrate during the irradiation. The triplet 1,4-biradi-
cal initially formed in accord with the rule of five has a
lifetime sufficiently long to allow rotation prior to ring
closure, but does not revert to starting material.19
Photocycloadducts were isolated and purified by flash
chromatography and their stereochemistries determined
at this stage from their 1H NMR spectra and NOESY
experiments. For instance, the NOESY of compound 4b
shows one cross-peak between the signals for protons at
C-1 and C-4, indicating their cis relationship, and the
absence of this signal between protons at C-1 and C-6
and protons at C-4 and C-6 points to a relative trans
disposition between them. On the contrary, NOESY
experiments for 5g show a cross-peak between the signals
of protons at C-4 and C-6 (cis relationship), but there is
no cross-signal between the proton at C-4 and the methyl
group at C-1 or between the proton at C-6 and the methyl
group at C-1, indicating relative trans disposition be-
tween these atoms (Figure 1).
1
Interestingly, H NMR signals for H-4 in compounds
4 appear as doublets (J ) 6.0-6.6 Hz) but as a singlet
for diastereomers 5, indicating that for the latter the
dihedral angle between H-4 and H-5 is near 90°, and
therefore, the amide substituents at the nitrogen atom
(20) See the Supporting Information.
(21) Schuster, D. I.; Lem, G.; Kaprinidis, N. A. Chem. Rev. 1993,
93, 3.
(18) (a) Waldeck, D. H. Chem. Rev. 1991, 91, 415. (b) Arai, T.;
Tokumaru, K. Chem. Rev. 1993, 93, 23.
(19) Becker, D.; Nagler, M.; Sahali, Y.; Haddad, N. J . Org. Chem.
1991, 56, 4537.
(22) Whitesell, J . K.; Minton, M. A.; Tran, V. D. J . Am. Chem. Soc.
1989, 11, 1473.
(23) Pedrosa, R.; Andre´s, C.; Iglesias, J . M.; Pe´rez-Encabo, A. J . Am.
Chem. Soc. 2001, 123, 1817.
J . Org. Chem, Vol. 68, No. 12, 2003 4925

Pedrosa et al.
SCHEME 3
SCHEME 4a
Amide 3g, with a methyl substituent at the R-carbon
of the R,â-unsaturated amide, also reacts from conformer
B due to steric interactions between the methyl group
and the axial hydrogen at the N,O-ketal carbon. Due to
the methyl substitution, the rate of cyclization of 3g is
retarded, the exciplex decays back to the ground state,
and Z-E isomerization occurs. This trend is very similar
to the steric effect observed in the cyclization of 5-sub-
stituted 5-hexenyl radicals. Alternatively, endo photoad-
ducts 6g and 6j can be generated by free rotation in the
cyclized 1,4-biradical prior to ring closure.
a
Reagents and conditions: (i) AlH3, THF, -10 °C, 30 min; (ii)
(a) PCC, 3 Å molecular sieves, CH2Cl2, rt; (b) 2.5 M KOH, H2O,
MeOH, THF (1:1:2), rt, 12 h, then TsCl, DIPEA, EtOAc, rt, (47-
75%).
methodology constitutes a facile entry to enantiopure
3-azabicyclo[3.2.0] heptanes.
Exp er im en ta l Section
The transformation of the photocycloadducts into the
final enantiopure 3-azabicyclo[3.2.0]heptanes was achieved
with good chemical yields in two steps (Scheme 4).
Reductive ring opening of the N,O-acetal moiety and
concomitant reduction of the amide group with alane in
THF at -10 °C leads to the menthol derivatives in
excellent yields. After isolation, these menthol derivatives
were subjected to oxidation with PCC in CH2Cl2 at room
temperature, affording the menthone derivatives, which
without isolation, were treated with an aqueous solution
(2.5 N) of KOH in THF-MeOH, leading to the enan-
tiopure 3-azabicyclo[3.2.0]heptanes. These compounds
were isolated and characterized as N-tosyl derivatives
by treatment with tosyl chloride and diisopropylethy-
lamine in ethyl acetate.
Gen er a l Meth od s. All reactions were carried out under an
argon atmosphere in oven-dried glassware. Solvents were dried
by standard methods: acetonitrile was distilled from P2O5,
CH2Cl2 from CaH2 and THF, and toluene from sodium. 1H
NMR (300 MHz) and 13C NMR (75 MHz) spectra were
registered in CDCl3 as solvent, and chemical shifts are
reported relative to tetramethylsilane as internal reference.
Specific rotations were determined on a digital polarimeter
using a Na lamp, and concentration is given in grams per 100
mL. Melting points were determined in open capillary tubes
and are uncorrected. TLC was performed on glass-backed
plates coated with silica gel 60 with an F254 indicator; the
chromatograms were visualized under UV light and/or by
staining with I2 or phosphomolybdic acid. Flash chromatog-
raphy was carried out on silica gel 60 (230-240 mesh).
Gen er a l P r oced u r e for [2+2] P h otocycloa d d ition Re-
a ction s. A 0.07 M solution of the appropiate amide (10.5
mmol) in acetonitrile (150 mL) was poured into a water-cooled
Pyrex immersion well photoreactor, degassed by bubbling
argon through the solution for 15 min, and then irradiated
under an argon atmosphere with a medium-pressure mercury
lamp (125 W) until disappearance of the starting amide was
evident. The solvent was evaporated and the residue purified
by flash chromatography on silica gel using hexanes-EtOAc
as eluent.
The final 3-azabicyclo[3.2.0]heptanes obtained from exo
adducts 4a -c, 4e, and 4g were enantiomers of those
obtained from 5a -c, 5e, and 5g, respectively. The
absolute stereochemistry of the 3-azabicyclo derivative
ent-8g was established by X-ray diffraction analysis,20
corroborating the absolute configuration of the photocy-
cloadduct 5g.
In conclusion, [2+2] photocycloadditions on these pe-
rhydro-1,3-benzoxazines derived from (-)-8-aminomen-
thol, used as a chiral template, occur with moderate to
good yields and good to excellent de. The described
(2 R ,2 a S ,2 b S ,3 a R ,5 R ,7 a S ,1 0 a R )-2 -P h e n y l -5 ,8 ,8 -
tr im eth ylp er h yd r ocyclobu ta [3,4]p yr r olo[2,1-b]-[1,3]ben -
zoxa zin -10-on e (4a ). Colorless solid. Mp: 129-130 °C (from
hexane). [R]25D ) -163.8 (c ) 1.0, CHCl3). 1H NMR (δ): 0.88-
4926 J . Org. Chem., Vol. 68, No. 12, 2003

Synthesis of 3-Azabicyclo[3.2.0]heptanes
1.17 (m, 3H); 0.95 (d, 3H, J ) 6.5 Hz); 1.22 (s, 3H); 1.33 (m,
1H); 1.52 (m, 1H); 1.71-1.78 (m, 2H); 1.80 (s, 3H); 2.01 (m,
1H); 2.42-2.63 (m, 2H); 2.77 (m, 1H); 2.97 (ddd, 1H, J 1 ) 6.2
(c ) 0.99, CHCl3). 1H NMR (δ): 0.89-1.10 (m, 3H); 0.92 (d,
3H, J ) 6.5 Hz); 1.32 (s, 3H); 1.37-1.55 (m, 2H); 1.73-1.77
(m, 2H); 1.80 (s, 3H); 1.90 (m, 1H); 2.39-2.54 (m, 2H); 2.76 (t,
Hz, J 2 ) 6.6 Hz, J 3 ) 6.9 Hz); 3.46 (td, 1H, J 1 ) 4.2 Hz, J 2
)
1H, J ) 7.1 Hz); 3.04 (m, 1H); 3.25 (dt, 1H, J 1 ) 7.1 Hz, J 2
)
10.6 Hz); 4.02 (q, 1H, J ) 6.9 Hz); 5.07 (d, 1H, J ) 6.2 Hz);
7.14-7.32 (m, 5H). 13C NMR (δ): 18.2; 21.9; 23.8; 25.2; 29.3;
31.0; 34.4; 36.6; 36.9; 40.9; 42.2; 49.6; 56.7; 75.9; 85.6; 125.7;
126.3 (2C); 128.1 (2C); 144.4; 175.1. IR (Nujol): 3050, 1675,
760, 730, 700 cm-1. Anal. Calcd for C22H29NO2: C, 77.84; H,
8.61; N, 4.13. Found: C, 77.63; H, 8.80; N, 4.36.
8.4 Hz); 3.51 (td, 1H, J 1 ) 4.1 Hz, J 2 ) 10.6 Hz); 3.78 (s, 3H);
5.00 (s, 1H); 6.85 (d, 2H, J ) 8.6 Hz); 7.14 (d, 2H, J ) 8.6 Hz).
13C NMR (δ): 20.8; 21.9; 24.2; 25.0; 31.1; 31.3; 34.3; 37.6; 40.9;
41.0; 42.9; 50.8; 55.1; 57.7; 76.4; 90.2; 113.7 (2C); 127.2 (2C);
135.5; 158.0; 176.0. IR (film): 3060, 3040, 1680, 1610, 1580,
1510, 820, 790, 730, 700, 670 cm-1. Anal. Calcd for C23H31
-
NO3: C, 74.76; H, 8.46; N, 3.79. Found: C, 74.57; H, 8.62; N,
3.56.
(2 S ,2 a R ,2 b S ,3 a R ,5 R ,7 a S ,1 0 a S )-2 -P h e n y l -5 ,8 ,8 -
tr im eth ylp er h yd r ocyclobu ta [3,4]p yr r olo[2,1-b]-[1,3]ben -
zoxa zin -10-on e (5a ). Colorless oil. [R]25D ) +37.47 (c ) 0.86,
(2S,2a S,2bS,3a R,5R,7a S,10a R)-2-(4′-Nitr op h en yl)-5,8,8-
1
CHCl3). H NMR (δ): 0.86-1.11 (m, 3H); 0.93 (d, 3H, J ) 6.5
tr im eth ylp er h yd r ocyclobu ta [3,4]p yr r olo[2,1-b]-[1,3]ben -
zoxa zin -10-on e (4e). Pale yellow oil. [R]25 ) -182.90 (c )
Hz); 1.33 (s, 3H); 1.38-1.46 (m, 2H); 1.73-1.77 (m, 2H); 1.81
D
1.0, CHCl3). 1H NMR (δ): 0.90-1.18 (m, 3H); 0.97 (d, 3H, J )
6.5 Hz); 1.25 (s, 3H); 1.35 (m, 1H); 1.51 (m, 1H); 1.71-1.80
(m, 2H); 1.81 (s, 3H); 2.03 (m, 1H); 2.50-2.67 (m, 2H); 2.82
(m, 1H); 3.02 (dt, 1H, J 1 ) 6.3 Hz, J 2 ) 7.1 Hz); 3.51 (td, 1H,
(s, 3H); 1.92 (m, 1H); 2.41-2.58 (m, 2H); 2.82 (dd, 1H, J 1
)
6.9 Hz, J 2 ) 7.3 Hz); 3.06 (m, 1H); 3.31 (dt, 1H, J 1 ) 7.3 Hz, J 2
) 8.4 Hz); 3.52 (td, 1H, J 1 ) 4.1 Hz, J 2 ) 10.6 Hz); 5.02 (s,
1H); 7.22-7.26 (m, 3H); 7.30-7.35 (m, 2H). 13C NMR (δ): 20.9;
22.0; 24.3; 25.1; 31.2 (2C); 34.4; 37.8; 41.0; 41.7; 42.7; 50.9;
57.8; 76.6; 90.4; 126.3 (2C); 126.4; 128.5 (2C); 143.5; 176.2. IR
(film): 3060, 1680, 760, 700 cm-1. Anal. Calcd for C22H29NO2:
C, 77.84; H, 8.61; N, 4.13. Found: C, 77.98; H, 8.86; N, 4.05.
J 1 ) 4.2 Hz, J 2 ) 10.6 Hz); 4.12 (ddd, 1H, J 1 ) 7.1 Hz, J 2
)
8.7 Hz, J 3 ) 9.0 Hz); 5.12 (d, 1H, J ) 6.3 Hz); 7.40 (d, 2H, J
) 8.7 Hz); 8.16 (d, 2H, J ) 8.7 Hz). 13C NMR (δ): 18.3; 21.9;
23.8; 25.2; 28.9; 31.1; 34.4; 36.9 (2C); 40.9; 42.5; 49.7; 56.9;
76.1; 85.3; 123.5 (2C); 127.3 (2C); 146.1; 152.0; 174.5. IR
(film): 3065, 1688, 1597, 851, 742, 719, 698 cm-1. Anal. Calcd
for C22H28N2O4: C, 68.73; H, 7.34; N, 7.29. Found: C, 68.51;
H, 7.52; N, 7.38.
(2R,2a S,2bS,3a R,5R,7a S,10a R)-2-(2′-Meth oxyp h en yl)-
5,8,8-tr im eth ylper h ydr ocyclobu ta[3,4]pyr r olo[2,1-b]-[1,3]-
ben zoxa zin -10-on e (4b). Colorless solid. Mp: 123-124 °C
1
(from hexanes-EtOAc). [R]25 ) -178.6 (c ) 1.0, CHCl3). H
D
NMR (δ): 0.86-1.09 (m, 3H); 0.90 (d, 3H, J ) 6.8 Hz); 1.21 (s,
3H); 1.31 (m, 1H); 1.45 (m, 1H); 1.73-1.80 (m, 2H); 1.81 (s,
3H); 1.90 (m, 1H); 2.37-2.56 (m, 2H); 2.77 (m, 1H); 3.27 (dt,
(2S,2a R,2bS,3a R,5R,7a S,10a S)-2-(4′-Nitr op h en yl)-5,8,8-
tr im eth ylp er h yd r ocyclobu ta [3,4]p yr r olo[2,1-b]-[1,3]ben -
zoxa zin -10-on e (5e). Pale yellow oil. [R]25D ) +70.12 (c ) 1.0,
1H, J 1 ) 6.6 Hz, J 2 ) 6.9 Hz); 3.40 (td, 1H, J 1 ) 4.2 Hz, J 2
)
1
CHCl3). H NMR (δ): 0.91-1.12 (m, 3H); 0.94 (d, 3H, J ) 6.5
10.6 Hz); 3.79 (s, 3H); 4.07 (ddd, 1H, J 1 ) 6.9 Hz, J 2 ) 9.1 Hz,
J 3 ) 9.8 Hz); 5.08 (d, 1H, J ) 6.6 Hz); 6.81 (d, 1H, J ) 8.0 Hz);
6.90 (t, 1H, J ) 7.5 Hz); 7.17 (dd, 1H, J 1 ) 7.5 Hz, J 2 ) 8.0
Hz); 7.18 (d, 1H, J ) 7.5 Hz). 13C NMR (δ): 18.1; 21.9; 23.8;
25.2; 31.0; 31.4; 33.4; 34.4; 37.1; 38.8; 40.9; 49.5; 55.1; 56.6;
75.9; 85.9; 110.4; 120.2; 127.1; 127.5; 132.3; 157.3; 175.6. IR
Hz); 1.34 (s, 3H); 1.40-1.51 (m, 2H); 1.72-1.79 (m, 2H); 1.81
(s, 3H); 1.92 (m, 1H); 2.44-2.65 (m, 2H); 2.84 (t, 1H, J ) 7.2
Hz); 3.10 (m, 1H); 3.43 (ddd, 1H, J 1 ) 7.2 Hz, J 2 ) 8.4 Hz, J 3
) 8.7 Hz); 3.55 (td, 1H, J 1 ) 4.01 Hz, J 2 ) 10.7 Hz); 5.06 (s,
1H); 7.39 (d, 2H, J ) 8.7 Hz); 8.19 (d, 2H, J ) 8.7 Hz). 13C
NMR (δ): 20.9; 22.0; 24.3; 25.1; 30.9; 31.2; 34.4; 37.7; 40.9;
41.3; 42.6; 50.8; 58.0; 76.7; 90.0; 123.8 (2C); 127.2 (2C); 146.5;
151.1; 175.5). IR (film): 3110, 3077, 1691, 1598, 1519, 849,
752, 737, 686 cm-1. Anal. Calcd for C22H28N2O4: C, 68.73; H,
7.34; N, 7.29. Found: C, 68.81; H, 7.52; N, 7.12.
(Nujol): 3060, 1680, 770, 730 cm-1. Anal. Calcd for C23H31
-
NO3: C, 74.76; H, 8.46; N, 3.79. Found: C, 74.52; H, 8.67; N,
3.91.
(2S,2a R,2bS,3a R,5R,7a S,10a S)-2-(2′-Met h oxyp h en yl)-
5,8,8-tr im eth ylper h ydr ocyclobu ta[3,4]pyr r olo[2,1-b]-[1,3]-
ben zoxa zin -10-on e (5b). Colorless oil. [R]25 ) +28.49 (c )
(2 a S ,2 b S ,3 a R ,5 R ,7 a S ,1 0 a S )-2 ,2 -D i p h e n y l -5 ,8 ,8 -
tr im eth ylp er h yd r ocyclobu ta [3,4]p yr r olo[2,1-b]-[1,3]ben -
zoxa zin -10-on e (5f). Colorless solid. Mp: 154-155 °C (from
D
1.5, CHCl3). 1H NMR (δ): 0.89-1.11 (m, 3H); 0.93 (d, 3H, J )
6.4 Hz); 1.33 (s, 3H); 1.36-1.54 (m, 2H); 1.72-1.76 (m, 2H);
1.81 (s, 3H); 1.93 (m, 1H); 2.39-2.59 (m, 2H); 2.74 (t, 1H, J )
7.8 Hz); 3.00 (m, 1H); 3.44 (dt, 1H, J 1 ) 7.8 Hz, J 2 ) 8.7 Hz);
3.52 (td, 1H, J 1 ) 3.9 Hz, J 2 ) 10.6 Hz); 3.80 (s, 3H); 5.10 (s,
1H); 6.82 (d, 1H, J ) 8.1 Hz); 6.92 (t, 1H, J ) 7.4 Hz); 7.16-
7.22 (m, 2H). 13C NMR (δ): 20.6; 21.8; 24.1; 24.9; 28.5; 31.0;
34.2; 37.3; 37.9; 40.9; 41.8; 50.8; 54.9; 57.5; 76.4; 90.5; 109.9;
120.1; 126.3; 127.2; 130.8; 156.8; 176.1. IR (film): 3040, 1670,
780, 750, 730, 700 cm-1. Anal. Calcd for C23H31NO3: C, 74.76;
H, 8.46; N, 3.79. Found: C, 74.59; H, 8.31; N, 3.93.
hexanes-EtOAc). [R]25 ) +172.07 (c ) 1.0, CHCl3). 1H NMR
D
(δ): 0.74 (s, 3H); 0.78-0.86 (m, 2H); 0.92 (d, 3H, J ) 6.5 Hz);
1.04 (m, 1H); 1.27 (m, 1H); 1.45 (m, 1H); 1.61-1.65 (m, 2H);
1.66 (s, 3H); 1.95 (m, 1H); 2.94 (m, 1H); 3.06 (d, 1H, J ) 9.3
Hz); 3.07 (m, 1H); 3.21 (td, 1H, J 1 ) 4.1 Hz, J 2 ) 10.6 Hz);
3.40 (m, 1H); 4.61 (s, 1H); 7.13-7.20 (m, 4H); 7.25-7.34 (m,
6H). 13C NMR (δ): 18,7; 21.9; 24.0; 25.0; 31.1; 34.4; 36.1; 36.4;
41.0; 45.1; 50.3; 50.9; 57.4; 76.4; 87.5; 126.0; 126.1; 126.4 (2C);
127.2 (2C); 128.2 (2C); 128.4 (2C); 143.5; 148.5; 174.9. IR
(Nujol): 3020, 1670, 755, 700 cm-1. Anal. Calcd for C28H33
-
(2R,2a S,2bS,3a R,5R,7a S,10a R)-2-(4′-Meth oxyp h en yl)-
NO2: C, 80.93; H, 8.00; N, 3.37. Found: C, 81.08; H, 8.21; N,
3.52.
5,8,8-tr im eth ylper h ydr ocyclobu ta[3,4]pyr r olo[2,1-b]-[1,3]-
ben zoxa zin -10-on e (4c). Colorless oil. [R]25 ) -145.12 (c )
D
1.1, CHCl3). 1H NMR (δ): 0.87-1.16 (m, 3H); 0.95 (d, 3H, J )
6.5 Hz); 1.21 (s, 3H); 1.29 (m, 1H); 1.47 (m, 1H); 1.71-1.76
(m, 2H); 1.79 (s, 3H); 2.02 (m, 1H); 2.38-2.57 (m, 2H); 2.74
(m, 1H); 2.89 (dt, 1H, J 1 ) 6.3 Hz, J 2 ) 6.7 Hz); 3.43 (td, 1H,
(2R ,2a R ,2bS ,3a R ,5R ,7a S ,10a R )-2-P h e n yl-10a ,5,8,8-
tetr a m eth ylp er h yd r ocyclobu ta [3,4]p yr r olo[2,1-b]-[1,3]-
ben zoxa zin -10-on e (4g). Colorless oil. [R]25 ) -115.53 (c )
D
1
0.53, CHCl3). H NMR (δ): 0.91-1.17(m, 3H); 0.95 (d, 3H, J
J 1 ) 4.2 Hz, J 2 ) 10.6 Hz); 3.75 (s, 3H); 3.95 (ddd, 1H, J 1
)
) 6.5 Hz); 1.21 (s, 3H); 1.24 (s, 3H); 1.34 (m, 1H); 1.49 (m,
1H); 1.71-1.78 (m, 2H); 1.80 (s, 3H); 2.02 (m, 1H); 2.15 (dd,
1H, J 1 ) 9.7 Hz, J 2 ) 11.8 Hz); 2.60 (dd, 1H, J 1 ) 8.8 Hz, J 2
) 11.8 Hz); 2.68 (dd, 1H, J 1 ) 6.0 Hz, J 2 ) 6.3 Hz); 3.45 (td,
1H, J 1 ) 4.3 Hz, J 2 ) 10.6 Hz); 3.81 (ddd, 1H, J 1 ) 6.3 Hz, J 2
) 8.8 Hz, J 3 ) 9.7 Hz); 5.08 (d, 1H, J ) 6.0 Hz); 7.15-7.33
(m, 5H). 13C NMR (δ): 18.3; 21.2; 22.0; 23.9; 25.2; 31.1; 33.5;
34.4; 36.3; 40.9; 41.6; 48.4; 49.7; 56.6; 75.9; 84.5; 125.7; 126.5
(2C); 128.1 (2C); 144.7; 177.4. IR (film): 3020, 1685, 750, 730,
700 cm-1. Anal. Calcd for C23H31NO2: C, 78.15; H, 8.84; N,
3.96. Found: C, 78.29; H, 8.99; N, 4.08.
6.7 Hz, J 2 ) 8.7 Hz, J 3 ) 9.0 Hz); 5.04 (d, 1H, J ) 6.3 Hz);
6.83 (d, 2H, J ) 8.6 Hz); 7.15 (d, 2H, J ) 8.6 Hz). 13C NMR
(δ): 18.1; 21.8; 23.7; 25.1; 29.3; 30.9; 34.3; 35.9; 36.6; 40.8; 42.3;
49.5; 54.9; 56.5; 75.8; 85.5; 113.4 (2C); 127.2 (2C); 136.3; 157.5;
175.0. IR (film): 3060, 3040, 1680, 1610, 1580, 1510, 830, 730,
680 cm-1. Anal. Calcd for C23H31NO3: C, 74.76; H, 8.46; N,
3.79. Found: C, 74.52; H, 8.22; N, 3.90.
(2S,2a R,2bS,3a R,5R,7a S,10a S)-2-(4′-Met h oxyp h en yl)-
5,8,8-t r im e t h ylp e r h yd r ocyclob u t a [3,4]p yr r olo[2,1-b ]-
[1, 3]ben zoxa zin -10-on e (5c). Colorless oil. [R]25 ) +46.76
D
J . Org. Chem, Vol. 68, No. 12, 2003 4927

Pedrosa et al.
(2S ,2a S ,2b S ,3a R ,5R ,7a S ,10a S )-2-P h e n y l-10a ,5,8,8-
(δ): 0.86-1.13 (m, 3H); 0.93 (d, 3H, J ) 6.5 Hz); 1.16 (d, 3H,
J ) 6.2 Hz); 1.27 (s, 3H); 1.37 (m, 1H); 1.50 (m, 1H); 1.70-
1.75 (m, 2H); 1.76 (s, 3H); 1.89-1.98 (m, 2H); 2.13-2.23 (m,
3H); 2.95 (m, 1H); 3.49 (td, 1H, J 1 ) 4.1 Hz, J 2 ) 10.7 Hz);
4.88 (s, 1H). 13C NMR (δ): 20.5; 21.3; 21.9; 24.2; 25.1; 31.2;
31.3; 32.3; 34.4; 37.5; 41.0; 42.5; 50.7; 57.5; 76.5; 90.6; 176.5.
IR (film): 1680, 740, 670 cm-1. Anal. Calcd for C17H27NO2: C,
73.61; H, 9.81; N, 5.05. Found: C, 73.81; H, 9.64; N, 5.22.
(2R,2a R,2bS,3a R,5R,7a S,10a S)-2,5,8,8-Te t r a m e t h yl-
perhydrocyclobuta[3,4]pyrrolo[2,1-b]-[1,3]benzoxazin-10-one
(6j). Colorless solid. Mp: 100-101 °C (from hexane). 1H NMR
(δ): 0.86-1.11 (m, 3H); 0.94 (d, 3H, J ) 6.5 Hz); 1.07 (d, 3H,
J ) 7.2 Hz); 1.30 (s, 3H); 1.31 (m, 1H); 1.50 (m, 1H); 1.58 (m,
1H); 1.70-1.75 (m, 2H); 1.76 (s, 3H); 1.93 (m, 1H); 2.53-2.64
(m, 2H); 2.76 (m, 1H); 2.96 (m, 1H); 3.52 (td, 1H, J 1 ) 4.1 Hz,
J 2 ) 10.6 Hz); 5.13 (s, 1H). 13C NMR (δ): 16.6; 20.0; 22.0; 24.2;
25.1; 27.8; 31.2; 31.3; 34.4; 37.7; 38.2; 41.0; 50.5; 57.7; 76.8;
86.2; 176.8. IR (Nujol): 1670, 790, 750, 670 cm-1. Anal. Calcd
for C17H27NO2: C, 73.61; H, 9.81; N, 5.05. Found: C, 73.59;
H, 10.00; N, 5.23.
Syn th esis of Am in o Alcoh ols 7a -g a n d 9a -i. Gen er a l
Meth od . To a suspension of LiAlH4 (0.82 g, 21.6 mmol) in
anhydrous THF (40 mL) cooled to -10 °C and under an argon
atmosphere was added, in portions, dry AlCl3 (0.95 g, 7.13
mmol). The mixture was stirred for 15 min, and a solution of
the corresponding photocycloadduct (2.16 mmol) in dry THF
(30 mL) was slowly added. The reaction mixture was stirred
for 10 min at -10 °C and quenched by addition of a 10%
aqueous solution of NaOH (4 mL). The resulting mixture was
filtered, the solid was washed with EtOAc, and the organic
layer was dried over anhydrous MgSO4. The solvent was
eliminated under reduced pressure, and the residue was
chromatographed on silica gel using hexane/EtOAc (3:1) as
eluent.
tetr a m eth ylp er h yd r ocyclobu ta [3,4]p yr r olo[2, 1-b]-[1,3]-
ben zoxa zin -10-on e (5g). Colorless oil. [R]25 ) +37.00 (c )
D
1.3, CHCl3). 1H NMR (δ): 0.89-1.11 (m, 3H); 0.92 (d, 3H, J )
6.5 Hz); 1.32 (s, 3H); 1.36 (s, 3H); 1.41-1.50 (m, 2H); 1.67-
1.78 (m, 2H); 1.80 (s, 3H); 1.91 (m, 1H); 2.02 (dd, 1H, J 1 ) 8.8
Hz, J 2 ) 11.9 Hz); 2.54 (d, 1H, J ) 6.8 Hz); 2.64 (dd, 1H, J 1
)
11.9 Hz, J 2 ) 9.1 Hz); 3.09 (ddd, 1H, J 1 ) 6.8 Hz, J 2 ) 8.8 Hz,
J 3 ) 9.1 Hz); 3.51 (td, 1H, J 1 ) 4.1 Hz, J 2 ) 10.6 Hz); 4.98 (s,
1H); 7.18-7.26 (m, 3H); 7.30-7.34 (m, 2H). 13C NMR (δ): 21.0;
21.9; 22.4; 24.3; 25.1; 31.2; 34.4; 37.8; 38.2; 41.1; 42.7; 48.3;
51.0; 57.7; 76.4; 88.9; 126.3; 126.4 (2C); 128.4 (2C); 143.7; 178.6.
IR (film): 3040, 1680, 755, 730, 695 cm-1. Anal. Calcd for
C23H31NO2: C, 78.15; H, 8.84; N, 3.96. Found: C, 78.32; H,
8.67; N, 4.11.
(2R ,2a S ,2bS ,3a R ,5R ,7a S ,10a S )-2-P h e n yl-10a ,5,8,8-
tetr a m eth ylp er h yd r ocyclobu ta [3,4]p yr r olo[2,1-b]-[1,3]-
ben zoxa zin -10-on e (6g). Colorless oil. [R]25 ) +35.02 (c )
D
1.3, CHCl3). 1H NMR (δ): 0.75-1.06 (m, 3H); 0.89 (d, 3H, J )
6.5 Hz); 0.94 (s, 3H); 1.22-1.38 (m, 2H); 1.45 (s, 3H); 1.63-
1.67 (m, 2H); 1.71 (s, 3H); 1.87 (m, 1H); 2.31 (ddd, 1H, J 1
)
2.0 Hz, J 2 ) 9.8 Hz, J 3 ) 12.5 Hz); 2.43 (dd, 1H, J 1 ) 8.5 Hz,
J 2 ) 12.5 Hz); 2.58 (dt, 1H, J 1 ) 2.0 Hz, J 2 ) 9.2 Hz); 3.18 (td,
1H, J 1 ) 4.1 Hz, J 2 ) 10.6 Hz); 3.95 (ddd, 1H, J 1 ) 8.5 Hz, J 2
) 9.2 Hz, J 3 ) 9.8 Hz); 4.49 (d, 1H, J ) 2.0 Hz); 7.13-7.35
(m, 5H). 13C NMR (δ): 19.1; 20.9; 21.9; 24.0; 25.2; 31.1; 34.4;
34.6; 34.7; 41.0; 42.6; 45.2; 50.3; 57.4; 76.6; 85.3; 126.3; 127.4
(2C); 128.3 (2C); 139.7; 177.5. Anal. Calcd for C23H31NO2: C,
78.15; H, 8.84; N, 3.96. Found: C, 78.37; H, 8.91; N, 4.15.
(2a S ,2bS ,3a R ,5R ,7a S ,10a S )-2,2-Dip h e n yl-10a ,5,8,8-
tetr a m eth ylp er h yd r ocyclobu ta [3,4]p yr r olo[2,1-b]-[1,3]-
ben zoxa zin -10-on e (5h ). Colorless oil. [R]25D ) +186.33 (c )
1.0, CHCl3). 1H NMR (δ): 0.66 (s, 3H); 0.73-0.86 (m, 2H); 0.92
(d, 3H, J ) 6.5 Hz); 1.05 (m, 1H); 1.26 (m, 1H); 1.27 (s, 3H);
1.42 (m, 1H); 1.60-1.70 (m, 2H); 1.65 (s, 3H); 1.96 (m, 1H);
2.52 (d, 1H, J ) 12.7 Hz); 3.18 (s, 1H); 3.22 (m, 1H); 3.24 (d,
1H, J ) 12.7 Hz); 4.53 (s, 1H); 7.10-7.36 (m, 10H). 13C NMR
(δ): 18.6; 21.9 (2C); 23.9; 24.9; 31.0; 34.2; 41.0; 41.3; 42.1; 48.0;
49.5; 50.4; 57.2; 76.6; 86.4; 125.6; 125.8; 126.4 (2C); 127.2 (2C);
128.0 (2C); 128.2 (2); 143.4; 149.2; 177.3. IR (film): 3060, 3020,
1695, 750, 700 cm-1. Anal. Calcd for C29H35NO2: C, 81.08; H,
8.21; N, 3.26. Found: C, 81.26; H, 8.42; N, 3.05.
(1R,5S,6R)-N-(8-Men th olyl)-6-ph en yl-3-azabicyclo[3.2.0]-
h ep ta n e (7a ). Yield: 98%. Colorless solid. Mp: 71-72 °C
(from pentane). [R]25 ) -109.29 (c ) 1.0, CHCl3). 1H NMR
D
(333 K) (δ): 0.83-1.13 (m, 3H); 0.90 (s, 3H); 0.91 (d, 3H, J )
6.6 Hz); 1.23 (s, 3H); 1.45 (m, 1H); 1.57-1.68 (m, 3H); 1.98
(m, 1H); 2.15-2.32 (m, 2H); 2.38-2.46 (m, 2H); 2.71-2.78 (m,
2H); 2.91 (d, 1H, J ) 9.5 Hz); 3.08 (d, 1H, J ) 9.6 Hz); 3.15
(m, 1H); 3.72 (td, 1H, J 1 ) 3.8 Hz, J 2 ) 10.2 Hz); 7.13 (m, 1H);
7.19-7.24 (m, 4H); 8.24 (br s, 1H). 13C NMR (333 K) (δ): 16.3;
21.4; 21.8; 25.2; 30.3; 31.1; 32.3; 34.6; 42.0; 43.5; 44.0; 48.2;
50.4; 51.6; 58.2; 72.3; 124.9; 125.6 (2C); 127.5 (2C); 146.0. IR
(Nujol): 3180 (br), 3020, 1600, 750, 700 cm-1. Anal. Calcd for
(2a S ,2bS ,3a R ,5R ,7a S ,10a S )-2,2,5,8,8-P e n t a m e t h yl-
perhydrocyclobuta[3,4]pyrrolo[2,1-b]-[1,3]benzoxazin-10-one
(5i). Colorless solid. Mp: 115-116 °C (from hexane). [R]25
)
D
-24.90 (c ) 1.0, CHCl3). 1H NMR (δ): 0.85-1.11 (m, 3H); 0.93
(d, 3H, J ) 6.6 Hz); 1.07 (s, 3H); 1.22 (s, 3H); 1.29 (s, 3H);
1.36 (m, 1H); 1.46 (m, 1H); 1.69-1.80 (m, 3H); 1.76 (s, 3H);
1.93 (m, 1H); 2.11 (dd, 1H, J 1 ) 9.9 Hz, J 2 ) 12.4 Hz); 2.23 (d,
C
22H33NO: C, 80.68; H, 10.16; N, 4.28. Found: C, 80.89; H,
9.98; N, 4.46.
(1R ,5S ,6R )-N-(8-Me n t h olyl)-6-(o-m e t h oxyp h e n yl)-3-
a za bicyclo[3.2.0]h ep ta n e (7b). Yield: 95%. Colorless solid.
Mp: 75-76 °C (from hexane). [R]25D ) -69.12 (c ) 1.0, CHCl3).
1H NMR (333 K) (δ): 0.88-1.13 (m, 3H); 0.91 (s, 3H); 0.92 (d,
3H, J ) 6.4 Hz); 1.26 (s, 3H); 1.43 (m, 1H); 1.57-1.69 (m, 3H);
1.98 (m, 1H); 2.17 (m, 1H); 2.33 (m, 1H); 2.42 (m, 1H); 2.48
(m, 1H); 2.73 (m, 2H); 3.00 (d, 1H, J ) 9.4 Hz); 3.09 (d, 1H, J
) 9.4 Hz); 3.36 (m, 1H); 3.72 (m, 1H); 3.73 (s, 3H); 6.76 (d,
1H, J ) 8.2 Hz); 2.94 (ddd, 1H, J 1 ) 4.4 Hz, J 2 ) 8.2 Hz, J 3
)
12.4 Hz); 3.51 (td, 1H, J 1 ) 4.1 Hz, J 2 ) 10.6 Hz); 5.07 (s, 1H).
13C NMR (δ): 20.2; 22.0; 24.2; 24.3; 25.1; 31.2 (2C); 34.4; 34.6;
35.2; 37.4; 41.1; 44.2; 50.6; 57.7; 76.8; 86.9; 176.9. IR (Nujol):
3020, 1670, 800, 710 cm-1. Anal. Calcd for C18H29NO2: C,
74.18; H, 10.03; N, 4.81. Found: C, 74.02; H, 10.21; N, 4.62.
(2R,2a S,2bS,3a R,5R,7a S,10a R)-2,5,8,8-Te t r a m e t h yl-
perhydrocyclobuta[3,4]pyrrolo[2,1-b]-[1,3]benzoxazin-10-one
(4j). Colorless solid. Mp: 135-137 °C (from hexane). 1H NMR
(δ): 0.87-1.15 (m, 3H); 0.95 (d, 3H, J ) 6.5 Hz); 1.10 (d, 3H,
J ) 7.0 Hz); 1.18 (s, 3H); 1.27 (m, 1H); 1.45 (m, 1H); 1.60-
1.73 (m, 2H); 1.75 (s, 3H); 1.88 (m, 1H); 1.98 (m, 1H); 2.17
(ddd, 1H, J 1 ) 2.5 Hz, J 2 ) 8.4 Hz, J 3 ) 11.4 Hz); 2.48 (dt,
1H, J 1 ) 6.3 Hz, J 2 ) 7.4 Hz); 2.68 (ddd, 1H, J 1 ) 2.5 Hz, J 2
) 7.4 Hz, J 3 ) 9.6 Hz); 2.80 (m, 1H); 3.40 (td, 1H, J 1 ) 4.3 Hz,
J 2 ) 10.6 Hz); 4.98 (d, 1H, J ) 6.3 Hz). 13C NMR (δ): 18.2;
21.8; 22.0; 23.9; 25.3; 27.5; 31.2; 31.6; 34.5; 36.7; 41.0 (2C);
1H, J ) 8.1 Hz); 6.86 (t, 1H, J ) 7.5 Hz); 7.09 (dd, 1H, J 1
)
8.1 Hz, J 2 ) 7.5 Hz); 7.17 (d, 1H, J ) 7.5 Hz); 8.52 (br s, 1H).
13C NMR (333 K) (δ): 16.6; 21.8; 22.1; 25.6; 28.9; 30.8; 32.8;
35.0; 37.8; 43.5; 44.4; 48.6; 50.9; 52.1; 54.9; 58.6; 72.7; 110.1;
120.0; 126.3 (2C); 133.9; 157.1. IR (Nujol): 3100 (br), 3060,
1600, 1585, 750 cm-1. Anal. Calcd for C23H35NO2: C, 77.27;
H, 9.87; N, 3.92. Found: C, 77.46; H, 9.61; N, 4.11.
(1R ,5S,6R )-N-(8-Me n t h olyl)-6-(p -m e t h oxyp h e n yl)-3-
a za bicyclo[3.2.0]h ep ta n e (7c). Yield: 92%. Colorless solid.
Mp: 82-83 °C (from hexane). [R]25 ) -111.88 (c ) 1.0,
D
49.6; 56.6; 76.0; 86.2; 175.9. IR (Nujol): 1670, 710, 680 cm-1
.
1
CHCl3). H NMR (333 K) (δ): 0.85-1.13 (m, 3H); 0.93 (d, 3H,
Anal. Calcd for C17H27NO2: C, 73.61; H, 9.81; N, 5.05. Found:
C, 73.40; H, 9.65; N, 4.92.
(2S ,2a R ,2bS ,3a R ,5R ,7a S ,10a S )-2,5,8,8-Te t r a m e t h yl-
J ) 6.3 Hz); 0.94 (s, 3H); 1.27 (s, 3H); 1.45 (m, 1H); 1.59-1.71
(m, 3H); 1.98 (m, 1H); 2.16-2.28 (m, 2H); 2.43 (m, 1H); 2.47
(m, 1H); 2.76-2.81 (m, 2H); 2.94 (d, 1H, J ) 9.5 Hz); 3.11 (m,
1H); 3.12 (d, 1H, J ) 9.4 Hz); 3.74 (m, 1H); 3.75 (s, 3H); 6.81
(d, 2H, J ) 8.6 Hz); 7.12 (d, 2H, J ) 8.6 Hz); 8.52 (br s, 1H).
perhydrocyclobuta[3,4]pyrrolo[2,1-b]-[1,3]benzoxazin-10-one
(5j). Colorless oil. [R]25 ) -3.68 (c ) 1.2, CHCl3). 1H NMR
D
4928 J . Org. Chem., Vol. 68, No. 12, 2003

Synthesis of 3-Azabicyclo[3.2.0]heptanes
13C NMR (333 K) (δ): 17.0; 22.0; 22.4; 25.8; 31.0; 32.1; 32.9;
35.2; 42.0; 44.4; 44.6; 48.9; 51.1; 52.3; 55.2; 58.9; 73.0; 113.8
(2C); 127.2 (2C); 139.0; 157.8. IR (Nujol): 3120 (br), 3020, 1610,
1575, 820, 705 cm-1. Anal. Calcd for C23H35NO2: C, 77.27; H,
9.87; N, 3.92. Found: C, 77.08; H, 9.92; N, 3.71.
(1R ,5S ,6R )-N -(8-M e n t h o ly l)-6-(p -n i t r o p h e n y l)-3-
a za bicyclo[3.2.0]h ep ta n e (7e). Yield: 94%. Colorless oil.
[R]25D ) -131.16 (c ) 1.0, CHCl3). 1H NMR (333 K) (δ): 0.86-
1.14 (m, 3H); 0.93 (d, 3H, J ) 6.5 Hz); 0.96 (s, 3H); 1.29 (s,
3H); 1.49 (m, 1H); 1.61-1.72 (m, 3H); 1.98 (m, 1H); 2.20-2.41
(m, 2H); 2.48 (dd, 1H, J 1 ) 5.9 Hz, J 2 ) 9.6 Hz); 2.58 (dd, 1H,
J 1 ) 5.2 Hz, J 2 ) 9.7 Hz); 2.80-2.88 (m, 2H); 2.99 (d, 1H, J )
9.7 Hz); 3.16 (d, 1H, J ) 9.6 Hz); 3.28 (m, 1H); 3.74 (td, 1H, J 1
) 4.1 Hz, J 2 ) 10.3 Hz); 7.36 (d, 2H, J ) 8.7 Hz); 8.11 (d, 2H,
J ) 8.7 Hz); 8.47 (br s, 1H). 13C NMR (333 K) (δ): 17.0; 21.9;
22.3; 25.7; 30.9; 31.4; 32.8; 35.1; 42.4; 43.9; 44.5; 48.8; 50.8;
52.1; 58.9; 72.9; 123.4 (2C); 127.0 (2C); 146.2; 154.2. IR (film):
3100 (broad), 3040, 1595, 850, 750, 695 cm-1. Anal. Calcd for
(m, 1H); 2.72-2.81 (m, 2H); 2.87 (d, 1H, J ) 9.4 Hz); 3.16 (d,
1H, J ) 9.8 Hz); 3.21 (m, 1H); 3.72 (td, 1H, J 1 ) 4.0 Hz, J 2
)
10.4 Hz); 3.76 (s, 3H); 6.82 (d, 2H, J ) 8.6 Hz); 7.15 (d, 2H, J
) 8.6 Hz); 8.51 (br s, 1H). 13C NMR (333 K) (δ): 17.0; 22.0;
22.3; 25.8; 31.0; 32.4; 32.6; 35.2; 41.0; 44.7; 45.0; 48.9; 51.4;
52.1; 55.2; 58.9; 73.0; 113.8 (2C); 127.3 (2C); 139.2; 157.8. IR
(Nujol): 3120 (br), 3020, 1610, 1570, 820, 740, 720, 680 cm-1
.
Anal. Calcd for C23H35NO2: C, 77.27; H, 9.87; N, 3.92. Found:
C, 77.08; H, 10.03; N, 3.76.
(1S ,5R ,6S )-N -(8-M e n t h o ly l)-6-(p -n i t r o p h e n y l)-3-
a za bicyclo[3.2.0]h ep ta n e (9e). Yield: 97%. Colorless solid.
Mp: 147-148 °C (from hexane). [R]25 ) +76.10 (c ) 1.0,
D
CHCl3). 1H NMR (333 K) (δ): 0.93 (d, 3H, J ) 6.5 Hz); 0.96 (s,
3H); 1.02-1.14 (m, 3H); 1.29 (s, 3H); 1.46 (m, 1H); 1.61-1.72
(m, 3H); 1.99 (m, 1H); 2.24-2.27 (m, 2H); 2.50 (m, 1H); 2.59
(m, 1H); 2.84 (m, 2H); 2.93 (d, 1H, J ) 9.6 Hz); 3.22 (d, 1H, J
) 9.8 Hz); 3.40 (m, 1H); 3.75 (m, 1H); 7.38 (d, 2H, J ) 8.7 Hz);
8.12 (d, 2H, J ) 8.7 Hz); 8.45 (br s, 1H). 13C NMR (333 K) (δ):
17.1; 22.0; 22.3; 25.8; 31.0; 31.9; 32.7; 35.2; 41.6; 44.6 (2C);
48.9; 51.2; 52.0; 59.0; 73.1; 123.5 (2C); 127.2 (2C); 146.3; 154.5.
IR (Nujol): 3160 (br), 3060, 1600, 850, 750, 700 cm-1. Anal.
Calcd for C22H32N2O3: C, 70.94; H, 8.66; N, 7.52. Found: C,
70.77; H, 8.49; N, 7.66.
C
22H32N2O3: C, 70.94; H, 8.66; N, 7.52. Found: C, 71.16; H,
8.78; N, 7.33.
(1R ,5S ,6R )-N -(8-Me n t h o ly l)-1-m e t h y l-6-p h e n y l-3-
a za bicyclo[3.2.0]h ep ta n e (7g). Yield: 93%. Colorless oil.
[R]25D ) -84.36 (c ) 0.78, CHCl3). 1H NMR (333 K) (δ): 0.76-
1.05 (m, 3H); 0.85 (d, 3H, J ) 6.5 Hz); 0.88 (s, 3H); 1.18 (2s,
6H); 1.35 (m, 1H); 1.52-1.65 (m, 3H); 1.83-1.95 (m, 2H); 2.12
(d, 1H, J ) 9.3 Hz); 2.29 (dd, 1H, J 1 ) 5.2 Hz, J 2 ) 6.0 Hz);
2.46 (dd, 1H, J 1 ) 9.9 Hz, J 2 ) 12.4 Hz); 2.59 (dd, 1H, J 1 ) 6.0
Hz, J 2 ) 9.4 Hz); 2.86 (d, 1H, J ) 9.4 Hz); 2.95-3.02 (ddd,
1H, J 1 ) 5.2 Hz, J 2 ) 7.2 Hz, J 3 ) 9.9 Hz); 3.05 (d, 1H, J )
9.3 Hz); 3.65 (td, 1H, J 1 ) 4.1 Hz, J 2 ) 10.4 Hz); 7.05 (m, 1H);
7.13-7.21 (m, 4H); 8.50 (br s, 1H). 13C NMR (333 K) (δ): 17.0;
22.0; 22.2; 25.1; 25.9; 31.1; 35.3; 38.6; 39.4; 39.6; 44.7; 48.8;
49.8; 52.4; 58.1; 59.0; 73.1; 125.6; 126.6 (2C); 128.3 (2C); 146.6.
IR (film): 3160 (br), 3020, 1590, 760, 730, 700 cm-1. Anal.
Calcd for C23H35NO: C, 80.88; H, 10.33; N, 4.10. Found: C,
80.69; H, 10.22; N, 3.91.
(1S,5R)-N-(8-Men th olyl)-6,6-diph en yl-3-azabicyclo[3.2.0]-
h ep ta n e (9f). Yield: 95%. Colorless solid. Mp: 129-130 °C
(from hexane). [R]25D ) +127.41 (c ) 1.0, CHCl3). 1H NMR (333
K) (δ): 0.71-0.89 (m, 3H); 0.84 (s, 3H); 0.85 (d, 3H, J ) 6.7
Hz); 1.12 (s, 3H); 1.29-1.46 (m, 2H); 1.49 (m, 1H); 1.59 (m,
1H); 1.78 (m, 1H); 2.59 (m, 1H); 2.67-2.74 (m, 3H); 2.86-2.88
(m, 3H); 3.45-3.51 (m, 2H); 7.06-7.09 (m, 4H); 7.19-7.26 (m,
4H); 7.32-7.35 (m, 2H); 7.78 (br s, 1H). 13C NMR (333 K) (δ):
17.2; 22.0; 22.1; 25.7; 31.0; 32.0; 35.1; 38.6; 44.4; 47.1; 48.0;
48.4; 49.8; 51.4; 58.7; 72.7; 125.3; 125.4; 126.3 (2C); 127.0 (2C);
128.0 (2C); 128.2 (2C); 146.5; 149.9. IR (Nujol): 3160 (br), 3020,
1590, 750, 730, 700 cm-1. Anal. Calcd for C28H37NO: C, 83.33;
H, 9.24; N, 3.47. Found: C, 83.20; H, 9.41; N, 3.65.
(1S,5R,6S)-N-(8-Men th olyl)-6-ph en yl-3-azabicyclo[3.2.0]-
h ep ta n e (9a ). Yield: 88%. Colorless solid. Mp: 150-151 °C
(from hexane). [R]25D ) +44.53 (c ) 0.78, CHCl3). 1H NMR (333
K) (δ): 0.78-1.13 (m, 3H); 0.85 (d, 3H, J ) 6.5 Hz); 0.88 (s,
3H); 1.20 (s, 3H); 1.38 (m, 1H); 1.53-1.64 (m, 3H); 1.92 (m,
1H); 2.11-2.22 (m, 2H); 2.42 (m, 1H); 2.51 (m, 1H); 2.73-2.76
(m, 2H); 2.83 (d, 1H, J ) 9.5 Hz); 3.11 (d, 1H, J ) 9.6 Hz);
3.20 (ddd, 1H, J 1 ) 3.8 Hz, J 2 ) 6.7 Hz, J 3 ) 9.9 Hz); 3.66 (td,
1H, J 1 ) 4.1 Hz, J 2 ) 10.6 Hz); 7.06 (m, 1H); 7.16-7.23 (m,
4H); 8.55 (br s, 1H). 13C NMR (333 K) (δ): 17.2; 22.0; 22.3;
25.9; 31.1; 32.2; 32.8; 35.3; 41.8; 44.7; 44.8; 48.9; 51.5; 52.2;
59.1; 73,1; 125.6; 126.4 (2C); 128.2 (2C); 147.0. IR (Nujol): 3120
(1S ,5R ,6S )-N -(8-Me n t h o ly l)-1-m e t h y l-6-p h e n y l-3-
a za bicyclo[3.2.0]h ep ta n e (9g). Yield: 98%. Colorless solid.
Mp: 81-82 °C (from hexane). [R]25D ) +41.52 (c ) 1.0, CHCl3).
1H NMR (333 K) (δ): 0.89-1.12 (m, 3H); 0.92 (d, 3H, J ) 6.5
Hz); 0.95 (s, 3H); 1.24 (s, 6H); 1.43 (m, 1H); 1.59-1.71 (m, 3H);
1.98 (m, 1H); 1.97 (dd, 1H, J 1 ) 6.3 Hz, J 2 ) 12.4 Hz); 2.29 (d,
1H, J ) 9.2 Hz); 2.36-2.44 (m, 2H); 2.57 (dd, 1H, J 1 ) 6.2 Hz,
J 2 ) 9.6 Hz); 2.88 (d, 1H, J ) 9.2 Hz); 3.14 (d, 1H, J ) 9.6
Hz); 3.19 (m, 1H); 3.71 (td, 1H, J 1 ) 4.0 Hz, J 2 ) 10.4 Hz);
7.14 (m, 1H); 7.22-7.29 (m, 4H); 8.50 (br s, 1H). 13C NMR (333
K) (δ): 17.0; 22.0; 22.2; 24.7; 25.8; 31.0; 35.2; 38.4; 38.6; 39.0;
44.6; 48.5; 50.0; 51.5; 58.9; 59.0; 73.0; 125.4; 126.5 (2C); 128.1
(2C); 146.6. IR (Nujol): 3150 (br), 3020, 1600, 750, 730, 690
cm-1. Anal. Calcd for C23H35NO: C, 80.88; H, 10.33; N, 4.10.
Found: C, 80.71; H, 10.54; N, 3.92.
(br), 3020, 1600, 750, 740, 700 cm-1. Anal. Calcd for C22H33
-
NO: C, 80.68; H, 10.16; N, 4.28. Found: C, 80.43; H, 10.29;
N, 4.12.
(1S ,5R ,6S )-N-(8-Me n t h olyl)-6-(o-m e t h oxyp h e n yl)-3-
(1S ,5R )-N -(8-Me n t h o ly l)-1-m e t h y l-6,6-d ip h e n y l-3-
a za bicyclo[3.2.0]h ep ta n e (9h ). Yield: 95%. Colorless solid.
a za bicyclo[3.2.0]h ep ta n e (9b). Yield: 96%. Colorless oil.
1
[R]25 ) +38.24 (c ) 1.2, CHCl3). H NMR (333 K) (δ): 0.86-
Mp: 159-160 °C (from hexane). [R]25 ) +142.23 (c ) 1.0,
D
D
1.13 (m, 3H); 0.92 (d, 3H, J ) 6.7 Hz); 0.93 (s, 3H); 1.25 (s,
3H); 1.46 (m, 1H); 1.56-1.70 (m, 3H); 1.97 (m, 1H); 2.06 (m,
1H); 2.37 (m, 1H); 2.47 (m, 1H); 2.61 (m, 1H); 2.67-2.80 (m,
2H); 2.85 (d, 1H, J ) 9.2 Hz); 3.18 (d, 1H, J ) 9.5 Hz); 3.46
(m, 1H); 3.71 (td, 1H, J 1 ) 4.1 Hz, J 2 ) 10.2 Hz); 3.76 (s, 3H);
6.78 (d, 1H, J ) 8.2 Hz); 6.87 (t, 1H, J ) 7.5 Hz); 7.10 (dd, 1H,
J 1 ) 7.5 Hz, J 2 ) 8.2 Hz); 7.18 (d, 1H, J ) 7.5 Hz); 8.55 (br s,
1H). 13C NMR (333 K) (δ): 16.9; 21.9; 22.1; 25.6; 29.4; 30.8;
32.5; 35.1; 37.3; 43.9; 44.5; 48.6; 51.3; 52.0; 55.1; 58.6; 72.8;
110.4; 120.0; 126.3; 126.4; 134.0; 157.3. IR (film): 3100 (br),
3060, 1590, 1580, 750 cm-1. Anal. Calcd for C23H35NO2: C,
77.27; H, 9.87; N, 3.92. Found: C, 77.06; H, 9.99; N, 4.07.
CHCl3). 1H NMR (333 K) (δ): 0.57-0.64 (m, 3H); 0.76 (s, 3H);
0.79 (d, 3H, J ) 6.4 Hz); 1.02 (s, 3H); 1.06 (s, 3H); 1.12-1.27
(m, 2H); 1.42 (m, 1H); 1.53 (m, 1H); 1.68 (m, 1H); 2.44-2.52
(m, 2H); 2.58 (d, 1H, J ) 9.0 Hz); 2.78-2.85 (m, 2H); 2.91 (d,
1H, J ) 11.9 Hz); 3.18 (m, 1H); 3.38 (m, 1H); 6.95-7.37 (m,
10H); 7.50 (br s, 1H). 13C NMR (333 K) (δ): 17.2; 22.0; 22.1;
24.1; 25.8; 31.0; 35.2; 39.0; 43.7; 44.5; 47.6; 48.2; 48.8; 51.0;
58.7; 59.2; 72.6; 125.1; 125.2; 126.5 (2C); 126.9 (2C); 128.1 (2C);
128.2 (2C); 146.6; 150.6. IR (Nujol): 3140 (br), 3080, 3060,
3020, 1595, 1580, 740, 690 cm-1. Anal. Calcd for C29H39NO:
C, 83.40; H, 9.41; N, 3.35. Found: C, 83.68; H, 9.22; N, 3.34.
(1S,5R)-N-(8-Men th olyl)-6,6-dim eth yl-3-azabicyclo[3.2.0]-
h ep ta n e (9i). Yield: 82%. Colorless solid. Mp: 80-81 °C (from
(1S ,5R ,6S )-N-(8-Me n t h olyl)-6-(p -m e t h oxyp h e n yl)-3-
a za bicyclo[3.2.0]h ep ta n e (9c). Yield: 97%. Colorless solid.
pentane). [R]25 ) +9.28 (c ) 1.0, CHCl3). 1H NMR (333 K)
D
Mp: 124-126 °C (from hexane). [R]25 ) +53.05 (c ) 1.0,
(δ): 0.88-1.09 (m, 3H); 0.91 (d, 3H, J ) 6.4 Hz); 0.92 (s, 3H);
0.98 (s, 3H); 1.14 (s, 3H); 1.20 (s, 3H); 1.45 (m, 1H); 1.50 (dd,
1H, J 1 ) 7.0 Hz, J 2 ) 11.8 Hz); 1.58-1.76 (m, 4H); 1.96 (m,
1H); 2.25 (m, 1H); 2.37-2.46 (m, 2H); 2.63-2.78 (m, 2H); 3.12
D
1
CHCl3). H NMR (333 K) (δ): 0.85-1.13 (m, 3H); 0.92 (d, 3H,
J ) 5.8 Hz); 0.93 (s, 3H); 1.26 (s, 3H); 1.45 (m, 1H); 1.59-1.70
(m, 3H); 1.98 (m, 1H); 2.11-2.21 (m, 2H); 2.45 (m, 1H); 2.55
J . Org. Chem, Vol. 68, No. 12, 2003 4929

Pedrosa et al.
(d, 1H, J ) 10.3 Hz); 3.62 (td, 1H, J 1 ) 4.1 Hz, J 2 ) 10.4 Hz);
8.10 (br s, 1H). 13C NMR (333 K) (δ): 16.8; 21.8; 22.2; 23.2;
25.6; 30.6; 30.8; 31.7; 32.6; 35.1; 37.7; 44.6; 45.9; 46.9; 48.5;
50.8; 58.8; 72.6. IR (Nujol): 3120 (br), 830, 750 cm-1. Anal.
Calcd for C18H33NO: C, 77.36; H, 11.90; N, 5.01. Found: C,
77.20; H, 11.69; N, 5.14.
710, 700, 670 cm-1. Anal. Calcd for C20H23NO3S: C, 67.20; H,
6.49; N, 3.92. Found: C, 67.36; H, 6.32; N, 4.06.
(1S,5R,6S)-N-Tosyl-6-(p -m eth oxyp h en yl)-3-a za bicyclo-
[3.2.0]h ep ta n e (en t-8c). Yield: 47%. Colorless solid. [R]25
D
) -3.60 (c ) 0.94, AcOEt). Melting point, 1H NMR, 13C NMR,
and IR data are coincident with those reported for 8c.
(1R,5S,6R)-N-Tosyl-6-(p-n itr oph en yl)-3-azabicyclo[3.2.0]-
h ep ta n e (8e). Yield: 58%. Colorless solid. Mp: 146-147 °C
(from hexane/EtOAc). [R]25D ) +1.40 (c ) 1.0, EtOAc). 1H NMR
(δ): 2.33-2.38 (m, 2H); 2.43 (s, 3H); 2.64 (dd, 1H, J 1 ) 5.1
Hz, J 2 ) 9.8 Hz); 2.71 (dd, 1H, J 1 ) 6.4 Hz, J 2 ) 9.7 Hz); 2.87-
2.90 (m, 2H); 3.52 (m, 1H); 3.55 (d, 1H, J ) 9.7 Hz); 3.62 (d,
1H, J ) 9.8 Hz); 7.34 (m, 4H); 7.70 (d, 2H, J ) 8.2 Hz); 8.14
(d, 2H, J ) 8.7 Hz). 13C NMR (δ): 21.5; 31.4; 33.9; 41.6; 45.2;
54.1; 54.2; 123.7 (2C); 127.1 (2C); 128.0 (2C); 129.5 (2C); 131.4;
143.8; 146.2; 152.8. IR (Nujol): 3040, 1595, 810, 745, 695, 660
cm-1. Anal. Calcd for C19H20N2O4S: C, 61.27; H, 5.41; N, 7.52.
Found: C, 61.14; H, 5.29; N, 7.38.
E lim in a t ion of t h e Men t h ol Ap p en d a ge. Gen er a l
Meth od . A solution of the aminomenthol derivative (1.48
mmol) and PCC (2.56 g, 11.90 mmol) in anhydrous CH2Cl2 (35
mL) and 3 Å molecular sieves (1.5 g) was stirred under an
argon atmosphere until the oxidation was finished (TLC, 5-6
h). The solvent was removed under reduced pressure, the
residue was dissolved in a 10% aqueous solution of NaOH to
pH 12, and the resulting solution was extracted with CHCl3
(5 × 25 mL). The organic phase was washed with brine and
dried over anhydrous MgSO4. The solvents were removed
under vacuum, the residue was taken up in a 2.5 M solution
of KOH in THF/MeOH/H2O (2:1:1), and the solution was
stirred at room temperature for 24-48 h (TLC). After elimina-
tion of the solvents under reduced pressure the residue was
acidified with a 1 N solution of HCl to pH 2 and extracted
with Et2O (3 × 20 mL). The aqueous solution was neutralized
to pH 12 with a 10% aqueous solution of NaOH and extracted
with CHCl3 (5 × 20 mL). The organic layers were washed with
H2O and dried over anhydrous MgSO4, and the solvent was
removed under vacuum. The 3-azabicyclo[3.2.0]heptane de-
rivatives were characterized as N-tosyl derivatives.
(1S,5R,6S)-N-Tosyl-6-(p-n itr oph en yl)-3-azabicyclo[3.2.0]-
h ep ta n e (en t-8e). Yield: 56%. Colorless solid. [R]25D ) -1.78
1
(c ) 0.56, EtOAt). Melting point, H NMR, 13C NMR, and IR
data are coincident with those reported for 8e.
(1S ,5R )-N -T o s y l-6,6-d ip h e n y l-3-a za b ic y c lo [3.2.0]-
h ep ta n e (en t-8f). Yield: 58%. Colorless oil. [R]25 ) +86.00
D
(c ) 0.79, EtOAc). 1H NMR (δ): 2.42 (s, 3H); 2.62 (ddd, 1H, J 1
) 3.4 Hz, J 2 ) 8.1 Hz, J 3 ) 11.5 Hz); 2.78-2.89 (m, 2H); 2.91
(m, 1H); 2.94 (dd, 1H, J 1 ) 8.4 Hz, J 2 ) 10.8 Hz); 3.28 (dd,
1H, J 1 ) 2.3 Hz, J 2 ) 10.8 Hz); 3.39 (d, 1H, J ) 9.6 Hz); 3.60
(m, 1H); 7.02-7.05 (m, 2H); 7.11-7.16 (m, 2H); 7.23-7.32 (m,
8H); 7.58 (d, 2H, J ) 8.2 Hz). 13C NMR (δ): 21.5; 33.1; 36.6;
47.3; 49.5; 50.0; 53.4; 125.8; 125.9; 126.4 (2C); 127.0 (2C); 127.8
(3C); 128.3 (3C); 129.4 (2C); 132.6; 143.3; 144.7; 149.1. IR
(film): 3050, 3020, 1590, 810, 750, 700, 660 cm-1. Anal. Calcd
for C25H25NO2S: C, 74.41; H, 6.24; N, 3.47. Found: C, 74.36;
H, 6.11; N, 3.49.
(1R ,5S ,6R )-N -T o s y l-6-p h e n y l-3-a za b ic y c lo [3.2.0]-
h ep ta n e (8a ). Yield: 56%. Colorless solid. Mp: 135-137 °C
1
(from hexanes-EtOAc). [R]25 ) +1.45 (c ) 0.60, CHCl3). H
D
NMR (δ): 2.28-2.35 (m, 2H); 2.44 (s, 3H); 2.64 (dd, 1H, J 1
)
5.4 Hz, J 2 ) 9.7 Hz); 2.72 (dd, 1H, J 1 ) 6.5 Hz, J 2 ) 9.7 Hz);
2.80-2.91 (m, 2H); 3.36-3.43 (m, 1H); 3.54 (d, 1H, J ) 9.7
Hz); 3.59 (d, 1H, J ) 9.7 Hz); 7.16-7.26 (m, 3H); 7.29-7.36
(m, 4H); 7.71-7.75 (m, 2H). 13C NMR (δ): 21.5; 31.7; 34.0; 41.8;
45.6; 54.3; 54.4; 126.1; 126.3 (2C); 128.0 (2C); 128.4 (2C); 129.5
(2C); 131.7; 143.6; 145.3. IR (Nujol): 3040, 1600, 810, 770, 740,
700, 670 cm-1. Anal. Calcd for C19H21NO2S: C, 69.69; H, 6.46;
N, 4.28. Found: C, 69.47; H, 6.38; N, 4.35.
(1R,5S,6R)-N-Tosyl-1-m et h yl-6-p h en yl-3-a za b icyclo-
[3.2.0]h ep ta n e (8g). Yield: 48%. Colorless solid. Mp: 144-
145 °C (from hexanes-EtOAc). [R]25 ) -6.54 (c ) 0.26,
D
1
EtOAc). H NMR (δ): 1.18 (s, 3H); 2.03 (dd, 1H, J 1 ) 7.8 Hz,
J 2 ) 12.3 Hz); 2.39-2.44 (m, 2H); 2.44 (s, 3H); 2.52 (dd, 1H,
(1S ,5R ,6S )-N -T o s y l-6-p h e n y l-3-a z a b ic y c lo [3.2.0]-
h ep ta n e (en t-8a ). Yield: 55%. Colorless solid. [R]25D ) -2.14
J 1 ) 10.2 Hz, J 2 ) 12.3 Hz); 2.74 (dd, 1H, J 1 ) 5.6 Hz, J 2
)
9.8 Hz); 3.26 (ddd, 1H, J 1 ) 5.7 Hz, J 2 ) 7.8 Hz, J 3 ) 10.2
Hz); 3.57 (d, 1H, J ) 9.8 Hz); 3.56 (d, 1H, J ) 10.8 Hz); 7.16-
7.28 (m, 3H); 7.31-7.36 (m, 4H); 7.71-7.74 (m, 2H). 13C NMR
(δ): 21.5; 24.4; 38.5; 38.7; 41.1; 51.0; 54.4; 60.2; 126.0; 126.5
(2C); 128.0 (2C); 128.4 (2C); 129.5 (2C); 131.8; 143.6; 145.2.
IR (Nujol): 3020, 1600, 810, 760, 700, 670 cm-1. Anal. Calcd
for C20H23NO2S: C, 70.35; H, 6.79; N, 4.10. Found: C, 70.47;
H, 6.91; N, 3.96.
(1S,5R,6S)-N-Tosyl-1-methyl-6-phenyl-3-azabicyclo[3.2.0]-
h ep ta n e (en t-8g). Yield: 65%. Colorless solid. [R]25D ) +5.96
(c ) 1.0, EtOAc). Melting point, 1H NMR, 13C NMR, and IR
data are coincident with those reported for 8g.
1
(c ) 0.28, CHCl3). Melting point, H NMR, 13C NMR, and IR
data are coincident with those reported for 8a .
(1R,5S,6R)-N-Tosyl-6-(o-m eth oxyp h en yl)-3-a za bicyclo-
[3.2.0]h ep ta n e (8b). Yield: 60%. Colorless solid. Mp: 124-
125 °C (from hexanes-EtOAc). [R]25 ) +20.34 (c ) 1.0,
D
1
EtOAc). H NMR (δ): 2.13-2.21 (m, 1H); 2.43 (s, 3H); 2.43-
2.51 (m, 1H); 2.66 (dd, 1H, J 1)5.5 Hz, J 2)9.5 Hz); 2.74-2.80
(m, 3H); 3.52 (d, 1H, J ) 8.5 Hz); 3.59 (m, 1H); 3.68 (d, 1H, J
) 9.5 Hz); 3.79 (s, 3H); 6.83 (d, 1H, J ) 8.1 Hz); 6.92 (t, 1H, J
) 7.4 Hz); 7.15-7.25 (m, 2H); 7.33 (d, 2H, J ) 8.0 Hz); 7.74
(d, 2H, J ) 8.0 Hz). 13C NMR (δ): 21.4; 28.9; 33.9; 37.1; 44.9;
54.5; 54.6; 55.0; 110.0; 120.1; 126.2; 127.0; 128.0 (2C); 129.4
(2C); 131.8; 132.5; 143.4; 157.1. IR (Nujol): 3020, 1590, 810,
750, 700, 660 cm-1. Anal. Calcd for C20H23NO3S: C, 67.20; H,
6.49; N, 3.92. Found: C, 67.31; H, 6.60; N, 4.08.
(1S,5R)-N-Tosyl-1-m et h yl-6,6-d ip h en yl-3-a za b icyclo-
[3.2.0]h ep ta n e (en t-8h ). Yield: 46%. Colorless solid. Mp:
141-142 °C (from hexanes-EtOAc). [R]25 ) +112.97 (c )
D
1
0.74, EtOAc). H NMR (δ): 1.02 (s, 3H); 2.38 (s, 3H); 2.39 (d,
(1S,5R,6S)-N-Tosyl-6-(o-m eth oxyp h en yl)-3-a za bicyclo-
1H, J ) 9.3 Hz); 2.44 (dd, 1H, J 1 ) 3.0 Hz, J 2 ) 12.0 Hz); 2.88
(dd, 1H, J 1 ) 8.0 Hz, J 2 ) 10.7 Hz); 3.16 (d, 1H, J ) 12.0 Hz);
3.25 (m, 2H); 3.34 (d, 1H, J ) 9.3 Hz); 7.05-7.34 (m, 12H);
7.55 (d, 2H, J ) 8.3 Hz). 13C NMR (δ): 21.4; 22.3; 40.5; 42.2;
47.0; 50.4; 50.8; 59.4; 125.4; 125.6; 126.6 (2C); 127.0 (2C); 127.8
(2C); 128.3(2C); 128.2 (2C); 129.3 (2C); 132.3; 143.2; 144.5;
[3.2.0]h ep ta n e (en t-8b). Yield: 52%. Colorless solid. [R]D
)
1
-18.34 (c ) 0.92, EtOAc). Melting point, H NMR, 13C NMR,
and IR data are coincident with those reported for 8b.
(1R,5S,6R)-N-Tosyl-6-(p -m eth oxyp h en yl)-3-a za bicyclo-
[3.2.0]h ep ta n e (8c). Yield: 51%. Colorless solid. Mp: 116-
149.6. IR (Nujol): 3040, 1590, 830, 810, 760, 700, 660 cm-1
.
117 °C (from hexane/EtOAc). [R]25 ) +4.99 (c ) 1.0, EtOAc).
D
1H NMR (δ): 2.25-2.30 (m, 2H); 2.44 (s, 3H); 2.63 (dd, 1H, J 1
) 5.1 Hz, J 2 ) 9.6 Hz); 2.72 (dd, 1H, J 1 ) 6.4 Hz, J 2 ) 9.6
Hz); 2.78-2.86 (m, 2H); 3.33 (m, 1H); 3.53 (d, 1H, J ) 9.6 Hz);
3.58 (d, 1H, J ) 9.6 Hz); 3.78 (s, 3H); 6.85 (d, 2H, J ) 8.6 Hz);
7.13 (d, 2H, J ) 8.6 Hz); 7.34 (d, 2H, J ) 8.1 Hz); 7.72 (d, 2H,
J ) 8.1 Hz). 13C NMR (δ): 21.5; 32.0; 33.8; 41.1; 45.8; 54.3;
54.4; 55.2; 113.8 (2C); 127.3 (2C); 128.0 (2C); 129.5 (2C); 131.6;
137.4; 143.6; 157.8. IR (Nujol): 3100, 3040, 1610, 1600, 1580,
Anal. Calcd for C26H27NO2S: C, 74.79; H, 6.52; N, 3.35.
Found: C, 74.88; H, 6.65; N, 3.27.
(1S ,5R )-N -T o s y l-6,6-d im e t h y l-3-a za b ic y c lo [3.2.0]-
h ep ta n e (en t-8i). Yield: 75%. Colorless solid. Mp: 115-117
1
°C (from hexane). [R]25 ) -12.65 (c ) 1.0, EtOAc). H NMR
D
(δ): 1.02 (s, 3H); 1.12 (s, 3H); 1.64 (dd, 1H, J 1 ) 6.3 Hz, J 2
12.0 Hz); 1.87 (ddd, 1H, J 1 ) 1.9 Hz, J 2 ) 8.7 Hz, J 3 ) 12.0
Hz); 2.28 (m, 1H); 2.43 (s, 3H); 2.46 (dd, 1H, J 1 ) 7.2 Hz, J 2
)
)
4930 J . Org. Chem., Vol. 68, No. 12, 2003

Synthesis of 3-Azabicyclo[3.2.0]heptanes
10.2 Hz); 2.47 (dd, 1H, J 1 ) 5.8 Hz, J 2 ) 9.3 Hz); 2.75 (m, 1H);
3.32 (d, 1H, J ) 9.3 Hz); 3.59 (d, 1H, J ) 10.2 Hz); 7.32 (d,
2H, J ) 8.1 Hz); 7.70 (d, 2H, J ) 8.1 Hz). 13C NMR (δ): 21.5;
23.1; 31.2; 31.4; 32.7; 38.2; 46.8; 49.5; 53.6; 128.1 (2C); 129.4
(2C); 131.7; 143.4. IR (Nujol): 3020, 1600, 810, 755, 710, 670
cm-1. Anal. Calcd for C15H21NO2S: C, 64.48; H, 7.58; N, 5.01.
Found: C, 64.59; H, 7.71; N, 4.88.
for X-ray difraction analysis. S.d.P. is also thankful for
a predoctoral fellowship (FPU).
Su p p or tin g In for m a tion Ava ila ble: Synthesis and spec-
tral and physical data for perhydro-1,3-benzoxazines 2a -j and
3a -j, ORTEP representation of X-ray structures of 4a , 5i, and
1
ent-8g, H NMR spectra for compounds 4a -j and 5a -j, and
NOESY experiments for 4b and 5g. This material is available
Ack n ow led gm en t. We thank the Spanish Ministe-
rio de Educacio´n y Cultura (DGIC, Project BQU2002-
01046) for financial support and Dr. A. Pe´rez-Encabo
free of charge via the Internet at http://pubs.acs.org.
J O034251C
J . Org. Chem, Vol. 68, No. 12, 2003 4931