Stereocontrolled IMDA reaction of styrene derivatives. A way to enantiopure 3a,4,9,9a-tetrahydrobenz[f]isoindolines

Article abstract of DOI:10.1021/jo010746v

IMDA reactions on chiral perhydro-1,3-benzoxazines, derived from (-)-8-amino menthol, bearing a styrene substituent at C-2 acting as diene and an acryl amide acting as dienophile occur with high stereoselection and excellent chemical yields. After elimination of the chiral appendage, enantiopure 3a,4,9,9a-tetrahydrobenz[f]isoindolines are prepared in this way. The effect of the substituents at both diene and dienophile are studied, showing that a methyl group at C-1 in the diene inhibited the reaction, while the ene adduct, instead of the IMDA product, was obtained when a methyl group was at C-2.

Full text of DOI:10.1021/jo010746v

782
J . Org. Chem. 2002, 67, 782-789
Ster eocon tr olled IMDA Rea ction of Styr en e Der iva tives. A Wa y to
En a n tiop u r e 3a ,4,9,9a -Tetr a h yd r oben z[f]isoin d olin es
Rafael Pedrosa,* Celia Andre´s,* and J avier Nieto
Departamento de Quı´mica Orga´nica, Facultad de Ciencias, Universidad de Valladolid,
Dr. Mergelina s/ n, 47011 Valladolid, Spain
pedrosa @qo.uva.es
Received J uly 25, 2001
IMDA reactions on chiral perhydro-1,3-benzoxazines, derived from (-)-8-amino menthol, bearing
a styrene substituent at C-2 acting as diene and an acryl amide acting as dienophile occur with
high stereoselection and excellent chemical yields. After elimination of the chiral appendage,
enantiopure 3a,4,9,9a-tetrahydrobenz[f]isoindolines are prepared in this way. The effect of the
substituents at both diene and dienophile are studied, showing that a methyl group at C-1 in the
diene inhibited the reaction, while the ene adduct, instead of the IMDA product, was obtained
when a methyl group was at C-2.
In tr od u ction
synthesis of heterocyclic systems8 we report now on the
synthesis of enantiopure 3a,4,9,9a-tetrahydrobenz[f]-
isoindolines 10 by using a styrene derivative as the diene
and an R,â-unsaturated amide as the dienophile attached
to a chiral perhydro-1,3-benzoxazine derived from (-)-
8-aminomenthol acting as chiral template (Figure 1).
These isoindoline derivatives are of biological interest
because some of them have analgesic,9 antidepressant,10
antihypertensive,11 or antiasthmatic or antiallergic12
activities.
The intramolecular Diels-Alder reaction (IMDA) con-
stitutes one of the most employed methods in the
construction of polycyclic systems because in addition to
the general features of the intermolecular version it
enjoys improved regio- and stereochemical control.1 The
synthesis of benzo derivatives by using styrenes as dienes
in both inter- and intramolecular Diels-Alder reactions
has been well-known for more than 25 years,2 although
styrenes are usually poor dienes because the initial step
entails loss of aromatic resonance stabilization and harsh
reaction conditions are needed for the intermolecular
processes. However, quite mild reaction conditions are
required for IMDA reactions, and styrene effectively
participates as the diene in the formation of benzannu-
lated systems after rearomatization by a 1,3-hydrogen
shift in the intermediate.3
Resu lts a n d Discu ssion
Chiral 2-styryl-3-acryloyl and methacryloyl perhydro-
1,3-benzoxazines 2a -h were prepared in two steps by
acylation of 2-styryl perhydro-1,3-benzoxazines, which in
turn were obtained by condensation of (-)-8-aminomen-
thol13 with cinnamaldehyde derivatives in toluene at
reflux (Scheme 1). All R,â-unsaturated aldehydes were
commercially available except trans-â-methylcinnamal-
dehyde, which was prepared by lithium aluminum hy-
dride reduction of ethyl trans-â-methylcinnamate to the
alcohol, followed by Swern oxidation to the aldehyde in
83% total yield.14
Recently, interest in the use of styrenes or their aza
analogues4 came up again in the synthesis of carbo- and
heterocycles in both inter-5 or intramolecular6 Diels-
Alder reactions, but there are only a few antecedents on
the diastereoselective IMDA reaction using styrenes as
dienes.7
In connection with a project directed toward the
exploitation of the IMDA reaction in the stereoselective
The acylation was carried out with acryloyl or meth-
acryloyl chloride at 0 °C in the presence of triethylamine
or TMEDA respectively, using methylene chloride as
solvent. The chromatographic purification of the com-
pounds must be done on silica gel deactivated with tri-
ethylamine; otherwise, the products were partially hy-
* To whom correspondence should be addressed. Phone: Int + 34-
983-423211. Fax: Int + 34-983-423013.
(1) (a) Fallis, A. G. Acc. Chem. Res. 1999, 32, 464. (b) Oppolzer, W.
In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Paquette, L. A., Eds; Pergamon: Oxford, 1991; Vol. 5, p 315. (c) Brieger,
G.; Bennett, J . N. Chem. Rev. 1980, 80, 63.
(2) (a) Klemm, L. H.; Hwang, Y. N.; McGuire, T. M. J . Org. Chem.
1976, 41, 3813. (b) Klemm, L. H.; McGuire, T. M.; Gopinath, K. W. J .
Org. Chem. 1976, 41, 2571. (c) Oppolzer, W.; Achini, R.; Pfenninger,
E.; Weber, H. P. Helv. Chim. Acta 1976, 59, 1186.
(8) (a) Andre´s, C.; Maestro, G.; Nieto, J .; Pedrosa, R.; Garc´ıa-Granda,
S.; Pe´rez-Carren˜o, E. Tetrahedron Lett. 1997, 38, 1463. (b) Andre´s, C.;
Nieto, J .; Pedrosa, R.; Vicente, M. J . Org. Chem. 1998, 63, 8570. (c)
Pedrosa, R.; Andre´s, C.; Nieto, J . J . Org. Chem. 2000, 65, 831.
(9) (a) Middlemiss, D. Ger. Pat. 2259498; Chem. Abstr. 1973, 79,
66171u. (b) Achini, R.; Oppolzer, W. Ger. Pat. 2348593; Chem. Abstr.
1974, 81, 13386c.
(10) (a) Achini, A.; Oppolzer, W.; Pfenninger, E. Swiss Pat. 611886,
1979; Chem. Abstr. 1979, 91, 140720p. (b) Achini, A.; Oppolzer, W.;
Pfenninger, E. Swiss Pat. 611884, 1979; Chem. Abstr. 1980, 92, 41756u.
(11) Debernardis, J . F.; Meyer, M. D.; Sippy, K. B. U.S. Pat. WO
9006927, 1990; Chem. Abstr. 1991, 114, 815704.
(3) Ciganek, E. Org. React. 1984, 32, 1.
(4) (a) Babu, G.; Perumal, P. T. Tetrahedron Lett. 1998, 39, 3225.
(b) Babu, G.; Perumal, P. T. Tetrahedron 1998, 54, 1627.
(5) (a) Carren˜o, M. C.; Mahugo, J .; Urbano, A. Tetrahedron Lett.
1997, 38, 3047. (b) Kolis, S. P.; Chordia, M. D.; Liu, R.; Kopach, M. E.;
Harman, W. D. J . Am. Chem. Soc. 1998, 120, 2218. (c) Stranix, B. R.;
Darling, G. D. J . Org. Chem. 1997, 62, 9001.
(6) (a) Dawson, J . R.; Mellor, J . M. Tetrahedron Lett. 1995, 36, 9043.
(b) Chackalamannil, S.; Doller, D.; Clasby, M.; Xia, Y.; Eagen, K.; Lin,
Y.; Tsai, H.-A.; McPhail, A. Tetrahedron Lett. 2000, 41, 4043.
(7) Sun, S.; Turchi, I. J .; Xu, D.; Murray, W. V. J . Org. Chem. 2000,
65, 2555.
(12) Bowman, R. M.; Gschwend, H. W. U.S. Pat. 4014899, 1977;
Chem. Abstr. 1977, 87, 53077h.
(13) He, X.-C.; Eliel, E. Tetrahedron 1987, 43, 4979.
(14) See the Supporting Information.
10.1021/jo010746v CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/11/2002

Stereocontrolled IMDA Reaction of Styrene Derivatives
J . Org. Chem., Vol. 67, No. 3, 2002 783
Sch em e 2
Ta ble 1. Diels-Ald er Rea ction of Am id es 2a -h , epi-2a ,
a n d epi-2d
F igu r e 1. Retrosynthetic analysis of tetrahydrobenz[f]isoin-
dolines.
time
(h)
T
(°C)
yielda
(%)
product
entry amide solvent
ratiob (%)
Sch em e 1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
2a
2a
2a
2a
2a
2a
2b
2b
2c
2c
2d
2d
2e
2e
2f
THF
48
66
69
82
60
110
153
55c
22d
65e
55f
88
81
86
82
81
78
85
90
75
84
5g
3a (72), 4a (28)
3a (75), 4a (25)
3a (79), 4a (21)
3a (78), 4a (22)
3a (80), 4a (20)
3a (86), 4a (14)
3b (86), 4a (14)
3b (81), 4b (19)
3c (89), 4c (11)
3c (96), 4c (4)
3d (85), 4d (15)
3d (83), 4d (17)
3e (75), 4e (25)
3e (90), 4e (10)
hexane 48
CH3CN 48
toluene 20
toluene
DMF
toluene
DMF
toluene
DMF
toluene
DMF
toluene
DMF
toluene 22
toluene
DMF
3
3
3.5 110
3.5 153
3.5 110
3.5 153
3.5 110
3.5 153
4.5 110
4
153
110
2g
2g
2h
3.5 110
3.5 153
3
86
83
90
79
3g (82), 5 (18)
3g (90), 5 (10)
6 (100)
epi-3a (87),
epi-4a (13)
epi-3d (89),
epi-4d (11)
toluene
110
epi-2a toluene
3.5 110
20
epi-2d toluene
3.5 110
89
a
b
Chemical yields of pure, isolated compounds. Determined by
integration of the signals in 1H NMR spectra of the reaction
mixtures. c 32%. 60%. e 8%. f 12% of amide 2a was recovered.
85% of amide 2e was recovered.
d
g
were observed in both the yield and the facial discrimina-
tion when toluene was changed to DMF as solvent.
The presence of an electron-withdrawing nitro group
in the aromatic styrene ring (entries 11, 12, and 20 in
Table 1) provided an example of an IMDA reaction
between two electron-deficient counterparts with excel-
lent chemical yields and good stereoselection. A similar
behavior was observed for dienes 2b and 2c with an
electron-donor methoxy substituent on the phenyl group
(entries 7-10 in Table 1). In this case, only traces of the
minor cycloadduct 4c were obtained when the cyclization
was carried out in DMF (entry 10 in Table 1). It is worth
noting that these reactions showed total exo/endo selec-
tivity, and endo adducts were not detected in the reaction
mixtures. These results contrast with those previously
reported for reactions with open dienes, where minor
endo cycloadducts are always formed.8b,15
drolyzed to 8-(N-acryloyl)amino menthol or were epimer-
ized at C-2. The epimerization could also be promoted
by acidic treatment. In this way, 2a and 2d were
transformed into epi-2a and epi-2d in moderate yield by
stirring, at room temperature, with a solution of anhy-
drous HCl in chloroform.
Thermal cyclization reactions were carried out under
different experimental conditions, and the results are
summarized in Scheme 2 and Table 1. Thermolysis of
the parent compound 2a was tested under different
reaction conditions (entries 1-4 in Table 1), observing
that the reaction was not complete after refluxing in
THF, hexane or acetonitrile for 48 h or by heating in
toluene at 60 °C for 20 h, and starting amide was
recovered in different amounts. On the contrary, 2a gave
a very clean conversion, with excellent yield, of two (of
the possible four) cycloadducts by refluxing for 3 h in
toluene or DMF (entries 5 and 6 in Table 1). Interest-
ingly, under these reaction conditions, improvements not
only in chemical yields but also in the diastereomeric
ratios were observed, although only negligible effects
The relative stereochemistry of the stereocenters where
diene and dienophile are attached was studied on epimer-
ized perhydro-1,3-benzoxazines epi-2a and epi-2d . The
cyclization of these substrates in refluxing toluene also
(15) (a) Turner, C. I.; Williamson, R. M.; Paddon-Row, M. N.;
Slurburn, M. S. J . Org. Chem. 2001, 66, 3963. (b) Coe, J . W.; Roush,
W. R. J . Org. Chem. 1989, 54, 915.

784 J . Org. Chem., Vol. 67, No. 3, 2002
Pedrosa et al.
Sch em e 3
Sch em e 5
Sch em e 6
Sch em e 4
gave exo adducts epi-3a ,d and epi-4a ,d in good chem-
ical yields and de (entries 19 and 20 in Table 1 and
Scheme 3).
The influence of substituents at both styrene and
dienophile was tested in compounds 2e and 2h . Perhydro-
1,3-benzoxazine 2e, with a methyl group at the inner
carbon of the dienophile, easily cyclized to the corre-
sponding adducts, although the facial discrimination
decreased to 3:1 when the reaction was carried out in
toluene at reflux (entry 13 in Table 1). Surprisingly,
compound 2f, with a methyl group at C-1 in the diene
component, was inefficient in the IMDA reaction, giving
rise to a mixture of cyclization products, in only 5% yield
after refluxing in toluene for 22h (entry 15 in Table 1).
On the contrary, compound 2g, with a phenyl group at
C-2 in the diene easily cyclized to exo adduct 3g along
with 10% of diastereomer 5 (entry 17 and Scheme 4). The
stereochemical relationship of the substituents at C-3a
and C-4 (benzoisoindoline numbering) in compounds 3g
and 5 shows that both are formed by rearomatization of
a single common exo cyclization intermediate A (Scheme
4). The migration of the hydrogen occurs by a formally
suprafacial 1,3-hydrogen shift, giving component 3g or
in a formally antarafacial fashion leading to the minor
isomer 5.
All diastereomers formed in the reactions were isolated
and purified by flash chromatography and obtained as
crystalline solids (except minor adducts 4c and epi-4a
that were not obtained pure), and the stereochemistry
was determined at this stage. COSY and NOESY experi-
ments allowed the establishment of the stereochemistry
for 3b-d , epi-3d , and 4b,d , whereas the configuration
for 3a ,g, 5, and epi-3a was determined by X-ray diffrac-
tion studies.
Adducts 3a -e,g were converted into enantiopure
3a,4,9,9a-tetrahydrobenz[f]isoindolines 10a -e,g and epi-
3a ,d and 4a into ent-10a ,d , respectively, as depicted in
Scheme 6. In this way, treatment of the adducts with
aluminum hydride in THF at -10 °C furnished amino-
menthol derivatives 9a -g or epi-9a ,d in very good
chemical yields (80-94%), which upon oxidation with
PCC in methylene chloride at rt, followed by treat-
ment with a 2.5 M solution of KOH in THF-MeOH,
yielded the final enantiopure isoindoline derivatives in
good yields (62-82%). The same treatment on adduct 6
led to the enantiopure pyrrolidine 8 in 82% yield
(Scheme 5).
Thermolysis of the compound 2h with a methyl sub-
stituent at C-2 in the diene gave a rapid reaction and
was totally stereoselective, providing the ene adduct 6
as a single compound in 90% yield, instead the IMDA
reaction product (Scheme 5)

Stereocontrolled IMDA Reaction of Styrene Derivatives
J . Org. Chem., Vol. 67, No. 3, 2002 785
21.9 mmol) in anhydrous CH2Cl2 (50 mL) at 0 °C was slowly
added a solution of acryloyl chloride (1.63 mL, 20.1 mmol) in
CH2Cl2 (25 mL). The stirring was continued until the reaction
was finished (TLC, 2-3 h), and then a saturated aqueous
solution of NaHCO3 (50 mL) was added and the resulting
mixture stirred at room temperature for additional 2 h. The
aqueous phase was extracted twice with CH2Cl2, and the
organic layer was washed with water and dried over anhy-
drous MgSO4. The solvent was evaporated, and the residue
was purified by flash chromatography on deactivated silica gel
with hexane/EtOAc 10/1 as eluent. Preparation of amide 2h
was carried out by a similar way by slow addition of a solution
of methacryloyl chloride (2.0 mL, 20.1 mmol) in CH2Cl2 to a
mixture of perhydrobenzoxazine 1a (5 g, 17.5 mmol) and
TMDA (3.3 mL, 21.9 mmol) in CH2Cl2 (50 mL).
In summary, the described IMDA reaction using
styrene derivatives as the diene provides a novel and
stereoselective synthesis of enantiopure 3a,4,9,9a-tet-
rahydrobenz[f]isoindolines. Both enantiomers can be
obtained simply by starting from epimeric perhydro-1,3-
benzoxazines.
Exp er im en ta l Section
Gen er a l Met h od s. All reactions were carried out in
anhydrous solvents, under argon atmosphere and in oven-dried
glassware. TLC was performed on glass-backed plates coated
with silica gel 60 with an F 254 indicator. Products were
isolated by flash chromatography using 240-400 mesh silica
gel. Melting points were determined in capillary tubes and are
uncorrected. 1H NMR (300 MHz) and 13C NMR (75 MHz) were
registered in CDCl3 or DMSO-d6 as solvent and TMS as
internal standard. Chemical shifts are given in ppm. Optical
rotations were determined on a digital polarimeter using a
sodium lamp, and concentration is given in g per 100 mL. Mass
spectra were recorded by electronic impact or chemical ioniza-
tion.
Syn th esis of P er h yd r oben zoxa zin es 1a -g. A mixture
of 8-(-)-aminomenthol (5 g, 29.24 mmol) and the appropriate
cinnamaldehyde derivative (30 mmol) in toluene (50 mL) was
refluxed until the reaction was completed (TLC, 3-5 h). The
solvent was evaporated under vacuum and the residue was
purified by recrystallization or by flash chomatography on
silica gel deactivated with triethylamine with hexane/EtOAc
8/1 as eluent. Perhydrobenzoxazines 1a ,b,f,g have been previ-
ously described.16
N-Acr yloyl-2r-(2-tr a n s-ph en yleth en yl)-4,4,7r-tr im eth yl-
tr a n s-octa h yd r o-1,3-ben zoxa zin e (2a ). Yield: 90%. Color-
less solid. Mp: 86-87 °C (from hexane). [R]25 ) -32.5 (c )
D
1
1.1, CHCl3). H NMR (CDCl3) δ: 0.85 (m, 1H); 0.93 (d, 3H, J
) 6.5 Hz); 1.03-1.19 (m, 2H); 1.47 (m, 1H); 1.56 (s, 3H); 1.63-
1.78 (m, 2H); 1.68 (s, 3H); 2.03-2.12 (m, 2H); 3.72 (dt, 1H, J 1
)3.9 Hz, J 2 ) 11.4 Hz); 5.59 (dd, 1H, J 1 ) 2.2 Hz, J 2 ) 10.2
Hz); 5.91 (dd, 1H, J 1 ) 1.9 Hz; J 2 ) 2.2 Hz); 6.24 (dd, 1H, J 1
) 2.2 Hz, J 2 ) 16.8 Hz); 6.38 (dd, 1H, J 1 ) 10.2 Hz, J 2 ) 16.8
Hz); 6.46 (dd, 1H, J 1 ) 2.4 Hz, J 2 ) 16.2 Hz); 6.57 (dd, 1H, J 1
) 1.9 Hz, J 2 ) 16.2 Hz); 7.27-7.42 (m, 5H). 13C NMR (CDCl3)
δ:18.9; 21.9; 24.5; 25.2; 31.5; 34.3; 43.7; 46.1; 58.0; 73.5; 81.9;
126.7(2C); 127.2; 128.2; 128.7(2C); 130.8; 131.5; 132.0; 135.8;
166.5. IR (Nujol): 3020; 1640; 1610; 750; 780; 770; 690 cm-1
.
MS (m/z): 340 (M+ + 1, 100); 263 (24); 208 (46); 186 (64). Anal.
Calcd for C22H29NO2: C, 77.84; H, 8.61; N, 4.13. Found: C,
77.62; H, 8.79; N, 4.30.
2r-[2-t r a n s-(4′-Me t h oxyp h e n yl)e t h e n yl]-4,4,7r-t r i-
m eth yl-tr a n s-octa h yd r o-1,3-ben zoxa zin e (1c). Yield: 92%.
Colorless oil. [R]25D ) +28.0 (c ) 1.1, CHCl3). 1H NMR (CDCl3)
δ: 0.09-1.21 (m, 4H); 0.93 (d, 3H, J ) 6.6 Hz); 1.11 (s, 3H);
1.14 (s, 3H); 1.38-1.55 (m, 1H); 1.63-1.70 (m, 3H); 1.98 (m,
1H); 3.50 (dt, 1H, J 1 ) 4.2 Hz, J 2 ) 10.5 Hz); 3.76 (s, 3H);
4.96 (dd, 1H, J 1 ) 1.1 Hz, J 2 ) 4.8 Hz); 6.04 (dd, 1H, J 1 ) 4.8
Hz, J 2 ) 16.0 Hz); 6.68 (dd, 1H, J 2 ) 1.1 Hz, J 2 ) 16.0 Hz);
6.81 (d, 2H, J ) 8.8 Hz); 7.31 (d, 2H, J ) 8.8 Hz). 13C NMR
(CDCl3) δ: 19.5; 22.2; 25.4; 29.7; 31.2; 34.8; 41.5; 51.2; 51.4;
55.0; 74.8; 82.1; 113.6 (2C); 125.8; 127.7 (2C); 129.1; 130.9;
159.1. IR (film): 3050; 2900; 1570; 800; 750 cm-1. MS (m/z):
315 (M+, 10); 160 (76); 134 (58); 55 (46); 41 (100).
N-Acr yloyl-2r-[2-tr a n s-(2′-m et h oxyp h en yl)et h en yl]-
4,4,7r-t r im et h yl-tr a n s-oct a h yd r o-1,3-b en zoxa zin e (2b ).
Yield: 92%. Colorless solid. Mp: 68-69 °C (from hexane/
EtOAc 10/1). [R]25D ) -46.6 (c ) 1.0, CHCl3). 1H NMR (CDCl3)
δ: 0.71-1.21 (m, 3H); 0.93 (d, 3H, J ) 6.5 Hz); 1.30-1.50 (m,
1H); 1.56 (s, 3H); 1.68 (s, 3H); 1.69-1.79 (m, 2H); 2.06-2.20
(m, 2H); 3.71 (dt, 1H, J 1 ) 3.9 Hz, J 2 ) 11.3 Hz); 3.83 (s, 3H);
5.57 (dd, 1H, J 1 ) 1.8 Hz, J 2 ) 10.4 Hz); 5.89 (dd, 1H, J 1 ) 1.8
Hz, J 2 ) 2.5 Hz); 6.21 (dd, 1H, J 1 ) 1.8 Hz, J 1 ) 16.8 Hz); 6.39
(dd, 1H, J 1 ) 10.4 Hz, J 1 ) 16.8 Hz); 6.46 (dd, 1H, J 1 ) 2.5
Hz, J 1 ) 16.4 Hz); 6.88-6.99 (m, 3H); 7.27 (dd, 1H, J 1 ) 6.9
Hz, J 1 ) 8.6 Hz); 7.40 (d, 1H, J ) 7.5 Hz). 13C NMR (CDCl3)
δ: 18.8; 21.8; 24.2; 25.2; 31.5; 34.3; 43.6; 45.8; 55.3; 58.0; 73.6;
82.3; 110.8; 120.5; 125.0; 126.7 (2C); 127.1; 129.1; 131.0; 132.4;
156.9; 166.7. IR (Nujol): 3050; 1640; 1600; 750 cm-1. MS (m/
2r-[2-tr a n s-(2′-Nitr op h en yl)eth en yl]-4,4,7r-tr im eth yl-
tr a n s-octa h yd r o-1,3-ben zoxa zin e (1d ). Yield: 94%. Color-
less oil. [R]25 ) +2.5 (c ) 1.0, CHCl3). 1H NMR (CDCl3) δ:
D
z): 370 (M+ + 1, 15); 208 (43); 177 (100). Anal. Calcd for C23H31
-
0.91-1.11 (m, 4H); 1.12 (d, 3H, J ) 6.2 Hz); 1.13 (s, 3H); 1.15
(s, 3H); 1.47-1.58 (m, 2H); 1.65-1.74 (m, 2H); 1.98 (m, 1H);
3.53 (dt, 1H, J 1 ) 4.1 Hz, J 2 ) 10.4 Hz); 5.03 (dd, 1H J 1 ) 1.0
Hz J 2 ) 4.4 Hz); 6.18 (dd, 1H J 1 ) 4.4 Hz J 2 ) 15.8 Hz); 7.25
(dd, 1H, J 1 ) 1.0 Hz, J 2 )15.8 Hz); 7.35-7.41 (m, 1H); 7.51-
7.62 (m, 2H); 7.90 (dd, 1H, J 1 ) 1.2 Hz, J 2 ) 8.2 Hz). 13C NMR
(CDCl3) δ: 19.5; 22.4; 25.8; 30.0; 31.6: 35.1; 41.9; 51.8 (2C);
75.2; 81.7; 124.5; 127.0; 128.2; 128.4; 132.3; 133.1; 133.8; 148.1.
IR (film): 3050; 2900; 1605; 1580; 780; 745 cm-1. MS (m/z):
332 (M+ + 2, 25); 331 (M+ + 1, 100); 329 (M+ - 1, 7).
NO3: C, 74.76; H, 8.46; N, 3.79. Found: C, 74.57; H, 8.32; N,
3.96.
N-Acr yloyl-2r-[2-tr a n s-(4′-m et h oxyp h en yl)et h en yl]-
4,4,7r-tr im eth yl-tr a n s-octa h yd r o-1,3-ben zoxa zin e (2c).
1
Yield: 92%. Colorless oil. [R]25 ) -46.9 (c ) 1.4, CHCl3). H
D
NMR (CDCl3) δ: 0.85-1.54 (m, 4H); 0.92 (d, 3H, J ) 6.6 Hz);
1.56 (s, 3H); 1.67 (s, 3H); 1.71-1.77 (m, 2H); 2.06-2.15 (m,
2H); 3.70 (dt, 1H, J 1 ) 3.9 Hz, J 2 ) 11.5 Hz); 3.81 (s, 3H);
5.58 (dd, 1H, J 1 ) 2.2 Hz, J 2 ) 10.2 Hz); 5.89 (dd, 1H, J 1
2.0, J 2 ) 2.6 Hz); 6.23 (dd, 1H, J 1 ) 2.2 Hz, J 2 ) 16.7 Hz);
6.31 (dd, 1H, J 1 ) 2.6 Hz, J 2 ) 16.2 Hz); 6.38 (dd, 1H, J 1
)
2r-(tr a n s-2-Meth yl-2-p h en yleth en yl)-4,4,7r-tr im eth yl-
)
tr a n s-octa h yd r o-1,3-ben zoxa zin e (1h ). Yield: 92%. Color-
10.2 Hz, J 2 ) 16.7 Hz); 6.51 (dd, 1H, J 1 ) 2.0 Hz, J 2 ) 16.2
Hz); 6.90 (d, 2H, J ) 8.8 Hz); 7.33 (d, 2H, J ) 8.8 Hz). 13C
NMR (CDCl3) δ: 18.7; 21.7; 24.3; 25.1; 31.4; 34.2; 43.6; 45.9;
55.1; 57.8; 73.4; 81.9; 114 (2C); 126.9; 127.7 (2C); 128.4; 129.5;
130.7; 130.8; 159.5; 166.4. IR (film): 3050; 1660; 1600; 730
cm-1. MS (m/z): 369 (M+, 10); 159 (33); 95 (48); 81 (94); 55
(100). Anal. Calcd for C23H31NO3: C, 74.76; H, 8.46; N, 3.79.
Found: C, 74.89; H, 8.27; N, 3.61.
1
less oil. [R]25 ) +12.5 (c ) 1.1, CHCl3). H NMR (CDCl3) δ:
D
0.90-1.09 (m, 4H); 0.92 (d, 3H, J ) 6.5 Hz); 1.10 (s, 3H); 1.17
(s, 3H); 1.46-1.70 (m, 4H); 1.93-2.00 (m, 1H); 2.14 (d, 3H, J
) 1.2 Hz); 3.52 (dt, 1H, J 1 ) 4.2 Hz, J 2 ) 10.4 Hz); 5.18 (d,
1H, J ) 6.8 Hz); 5.68 (dd, 1H, J 1 ) 1.2 Hz, J 2 ) 6.8 Hz); 7.17-
7.29 (m, 3H); 7.38-7.42 (m, 2H). 13C NMR (CDCl3) δ: 16.5;
19.4; 22.1; 25.4; 29.7; 31.2; 34.8; 41.5; 51.1; 51.2; 74.7; 79.9;
125.7 (2C); 126.1; 127.0; 127.8 (2C); 138.9; 142.4. IR (film):
3050; 2910; 755; 695 cm-1. MS (m/z): 301 (M+ + 2, 21); 300
(M+ + 1, 100); 182 (26).
N-Acr yloyl-2r-[2-tr a n s-(2′-n itr op h en yl)eth en yl]-4,4,7r-
tr im eth yl-tr a n s-octa h yd r o-1,3-ben zoxa zin e (2d ). Yield:
94%. Colorless solid. Mp: 134-135 °C (from hexanes-EtOAc
8:1). [R]25D ) -13.7 (c ) 1.2, CHCl3). 1H (CDCl3) δ: 0.89-0.99
(m, 1H); 0.94 (d, 3H, J ) 6.5 Hz); 0.98-1.50 (m, 3H); 1.57 (s,
3H); 1.69 (s, 3H); 1.67-1.79 (m, 1H); 1.80-1.85 (m, 1H); 2.08
(m, 1H); 2.19 (dt, 1H, J 1 ) 3.1 Hz, J 2 ) 11.5 Hz); 3.75 (td, 1H,
Syn th esis of Am id es 2a -h . To a mixture of the appropiate
perhydrobenzoxazine (17.5 mmol) and triethylamine (3.05 mL,
(16) Pedrosa, R.; Andre´s, C.; Iglesias, J . M., Pe´rez-Encabo, A. J . Am.
Chem. Soc. 2001, 123, 1817.
J 1 ) 4.0 Hz, J 2 ) 11.5 Hz); 5.63 (dd, 1H, J 1 ) 2.1 Hz, J 2
)

786 J . Org. Chem., Vol. 67, No. 3, 2002
Pedrosa et al.
10.3 Hz); 5.94 (dd, 1H, J 1 ) 2.2, J 2 ) 2.5 Hz); 6.24 (dd, 1H, J 1
) 2.1 Hz, J 2 ) 16.7 Hz); 6.38 (dd, 1H, J 1 ) 2.5 Hz, J 2 ) 15.9);
was added, the mixture was filtered, the solvent was elimi-
nated under vacuum, and the residue was purified by flash
chromatography on silica gel with hexane/EtOAc 12/1 as eluent
for epi-2a and hexane/EtOAc 10/1 for epi-2d .
6.41 (dd, 1H, J 1 ) 10.3 Hz, J 2 ) 16.7 Hz); 7.05 (dd, 1H, J 1
)
2.2 Hz, J 2 ) 15.9 Hz); 7.47 (ddd, 1H, J 1 ) 1.5 Hz, J 2 ) 7.8 Hz,
J 3 ) 8.2 Hz); 7.54 (dd, 1H, J 1 ) 1.5 Hz, J 2 ) 7.8 Hz); 7.64 (dt,
N-Acr yloyl-2â-(2-tr a n s-ph en yleth en yl)-4,4,7r-tr im eth yl-
1H, J 1 ) 1.1 Hz, J 2 ) 7.8 Hz); 8.01 (dd, 1H, J 1 ) 1.0 Hz, J 2
)
tr a n s-octa h yd r o-1,3-ben zoxa zin e (epi-2a ). Yield: 38%.
8.2 Hz). 13C NMR (CDCl3) δ: 19.0; 21.8; 24.4; 25.2; 31.5; 34.3;
43.4; 45.9; 58.0; 73.7; 81.6; 124.7; 127.3; 127.6; 128.6; 129.1;
130.7; 132.2; 133.4; 137.1; 147.6; 166.6. IR (Nujol): 3050; 1640;
1605; 780; 760; 730; 680. cm-1. MS (m/z): (M+ + 1, 46); 209
(14); 208 (100); 192 (55). Anal. Calcd for C22H28N2O4: C, 68.73;
H, 7.34; N, 7.29. Found: C, 68.52; H, 7.16; N, 7.38.
Colorless solid. Mp: 92-93 °C (from hexane). [R]25 ) -29.2
D
(c ) 1.0, CHCl3). 1H NMR (CDCl3) δ: 0.83-1.12 (m, 3H); 0.95
(d, 3H, J ) 6.6 Hz); 1.25-1.52 (m, 2H); 1.37 (s, 3H); 1.67 (s,
3H); 1.65-1.74 (m, 2H); 1.97-2.04 (m, 1H); 3.70 (dt, 1H, J 1
)
4.4 Hz, J 2 ) 10.5 Hz); 5.56 (dd, 1H, J 1 ) 1.7 Hz, J 2 ) 10.5
Hz); 6.14-6.22 (m, 3H); 6.56 (dd, 1H, J 1 ) 2.7 Hz, J 2 ) 16.9
Hz); 6.55 (dd, 1H, J 1 ) 10.5 Hz, J 2 ) 16.7 Hz); 7.24-7.37 (m,
5H). 13C NMR (CDCl3) δ:19.9; 21.9; 24.4; 27.6; 30.9; 34.2; 40.8;
49.9; 57.8; 68.1; 82.6; 126.4 (2C); 126.6; 128.0; 128.4; 128.5 (2C);
131.4; 132.8; 135.6; 167.6. IR (Nujol): 3020; 3070; 1640; 1590;
790; 750; 710; 690 cm-1. Anal. Calcd for C22H29NO2: C, 77.84;
H, 8.61; N, 4.13. Found: C, 77.68; H, 8.77; N, 3.96.
N-Meth a cr yloyl-2r-(2-tr a n s-p h en yleth en yl)-4,4,7r-tr i-
m eth yl-tr a n s-octa h yd r o-1,3-ben zoxa zin e (2e). Yield: 96%.
1
Colorless oil. [R]25 ) -4.1 (c ) 1.0, CHCl3). H NMR (CDCl3)
D
δ: 0.81-1.22 (m, 3H); 0.93 (d, 3H, J ) 6.5 Hz); 1.44-1.49 (m,
1H); 1.52 (s, 3H); 1.68 (s, 3H); 1.64-1.75 (m, 2H); 1.96 (s, 3H);
2.09-2.17 (m, 2H); 3.73 (dt, 1H, J 1 ) 4.1 Hz, J 2 ) 11.3 Hz);
5.04-5.07 (m, 2H); 5.94 (m, 1H); 6.39 (dd, 1H, J 1 ) 3.0 Hz, J 2
) 16.2 Hz); 6.60 (dd, 1H, J 1 ) 1.7 Hz, J 2 ) 16.2 Hz); 7.27-
7.40 (m, 5H). 13C NMR (CDCl3) δ: 18.1; 20.3; 21.7; 24.8; 25.1;
31.2; 34.1; 43.5; 46.0; 57.9; 72.9; 82.1; 114.2; 126.3 (2C); 127.9;
128.5 (2C); 130.9; 132.4; 135.8; 142.2; 172.3. IR (film): 3070;
3020; 1630; 750; 720; 685. cm-1. Anal. Calcd for C23H31NO2:
C, 78.15; H, 8.84; N, 3.96. Found: C, 78.34; H, 8.69; N, 4.14.
N-Acr yloyl-2r-(tr a n s-1-m eth yl-2-ph en yleth en yl)-4,4,7r-
N-Acr yloyl-2â-[2-tr a n s-(2′-n itr op h en yl)eth en yl]-4,4,7r-
t r im et h yl-tr a n s-oct a h yd r o-1,3-b en zoxa zin e
(ep i-2d ).
1
Yield: 42%. Colorless oil. [R]25 ) +22.7 (c ) 0.7, CHCl3). H
D
NMR (CDCl3) δ: 0.91-1.62 (m, 5H); 0.98 (d, 3H, J ) 6.6 Hz);
1.35 (s, 3H); 1.66 (s, 3H); 1.70-1.78 (m, 2H); 1.97-2.08 (m,
1H); 3.84 (dt, 1H, J 1 ) 4.3 Hz, J 2 ) 10.6 Hz); 5.64 (dd, 1H, J 1
) 1.7 Hz, J 2 ) 10.5 Hz); 6.04 (dd, 1H, J 1 ) 3.0 Hz, J 2 ) 15.9
Hz); 6.18-6.25 (m, 2H); 6.59 (dd, 1H, J 1 ) 16.7 Hz, J 2 ) 10.5
Hz); 7.08 (dd, 1H, J 1 ) 2.0 Hz, J 2 ) 15.9 Hz); 7.41-7.67 (m,
3H); 7.99 (dd, 1H, J 1 ) 1.2 Hz, J 2 ) 8.2 Hz). 13C NMR (CDCl3)
(δ): 19.9; 22.0; 24.5; 27.4; 31.0; 34.3; 40.8; 49.8; 57.9; 68.4; 82.1;
124.7; 127.1; 128.5; 128.6; 128.9; 131.7; 132.1; 133.3; 133.5;
tr im eth yl-tr a n s-octah ydr o-1,3-ben zoxazin e (2f).Yield: 85%.
1
Colorless oil. [R]25 ) -3.3 (c ) 1.1, CHCl3). H NMR (CDCl3)
D
δ: 0.83-1.39 (m, 3H); 0.93 (d, 3H, J ) 6.5 Hz); 1.45-1.56 (m,
1H); 1.58 (s, 3H); 1.71 (s, 3H); 1.67-1.77 (m, 2H); 1.99 (d, 3H,
J ) 1.0 Hz); 2.05-2.13 (m, 2H); 3.73 (dt, 1H, J 1 ) 3.8 Hz, J 2
) 11.6 Hz); 5.56-5.61 (m, 2H); 6.25-6.27 (m, 2H); 6.70 (d,
1H, J ) 1.0 Hz); 7.24-7.36 (m, 3H); 7.37-7.41 (m, 2H). 13C
NMR (CDCl3) (δ): 15.8; 19.1; 21.9; 24.0; 25.2; 31.7; 34.5; 43.2;
45.7; 58.0; 74.2; 86.4; 127.0; 127.2; 127.6; 128.3 (2C); 128.9 (2C);
131.1; 136.9; 139.7; 167.2. IR (film): 3040; 3005; 1640; 1600;
790; 740; 695. cm-1. MS (m/z): 354 (M+ + 1, 39); 236 (31); 208
(100); 200 (87). Anal. Calcd for C23H31NO2: C, 78.15; H, 8.84;
N, 3.96. Found: C, 77.92; H, 9.03; N, 3.78.
147.6; 167.7. IR (film): 3060; 1680; 1650; 1600; 730; 700 cm-1
.
MS (m/z): 384 (M+, 4); 182 (12); 112 (24); 81 (31); 55 (100).
Anal. Calcd for C22H28N2O4: C, 68.73; H, 7.34; N, 7.29.
Found: C, 68.78; H, 7.16; N, 7.12.
Gen er a l P r oced u r e for Diels-Ald er Rea ction s. A solu-
tion of the amide (15 mmol) in the appropriate solvent (50 mL)
was refluxed until the reaction was finished (TLC, 3-5 h). The
solvent was eliminated under reduced pressure and the residue
was chromatographed on silica gel with hexane/EtOAc as
eluent. When DMF was used as solvent, the reaction mixture
was diluted with 200 mL of Et2O, washed three times with
water and dried over anhydrous MgSO4.
N-Acr yloyl-2r-(2,2-d ip h en yleth en yl)-4,4,7r-tr im eth yl-
tr a n s-octa h yd r o-1,3-ben zoxa zin e (2g). Yield: 88%. Color-
less solid. Mp: 122-123 °C (from hexanes-EtOAc 10:1). [R]25
D
) -188.0 (c ) 1.1, CHCl3). 1H NMR (CDCl3) δ: 0.90-1.11 (m,
1H); 0.93 (d, 3H, J ) 6.5 Hz); 1.13-1.25 (m, 2H); 1.45-1.50
(m, 1H); 1.48 (s, 3H); 1.73 (s, 3H); 1.70-1.75 (m, 1H); 1.85 (m,
1H); 2.01-2.09 (m, 2H); 3.69 (dt, 1H, J 1 ) 3.8 Hz, J 2 ) 11.3
Hz); 5.24 (dd, 1H, J 1 ) 2.3 Hz, J 2 ) 10.1 Hz); 5.51 (d, 1H, J )
8.6 Hz); 5.85 (dd, 1H, J 1 ) 10.1 Hz, J 2 ) 16.8 Hz); 5.96 (dd,
1H, J 1 ) 2.3 Hz, J 2 ) 16.8 Hz); 6.29 (d, 1H, J ) 8.6 Hz); 7.23-
7.41 (m, 10H). 13C NMR (CDCl3) δ: 18.6; 21.7; 25.1; 25.4; 31.5;
34.4; 43.4; 47.7; 57.9; 73.0; 80.2; 125.9; 127.8 (2C); 128.0 (3C);
128.2 (3C); 128.9; 129.7 (2C); 130.6; 137.8; 141.4; 145.2; 166.7.
Cycloa d d u ct (3a ). Colorless solid. Mp: 192-193 °C (from
hexane). [R]25D ) -177.4 (c ) 1.0, CHCl3). 1H NMR (CDCl3) δ:
0.74-1.16 (m, 3H); 0.95 (d, 3H, J ) 6.5 Hz); 1.20 (s, 3H); 1.25
(m, 1H); 1.50 (m, 1H); 1.70-1.78 (m, 2H); 1.77 (s, 3H); 1.91-
2.16 (m, 3H); 2.76 (t, 1H, J ) 15.9 Hz); 2.81 (t, 1H, J ) 15.9
Hz); 3.18 (dd, 2H, J 1 ) 4.6 Hz, J 2 ) 15.9 Hz); 3.42 (dt, 1H, J 1
) 4.3 Hz, J 2 ) 10.6 Hz); 4.71 (d, 1H, J ) 7.4 Hz); 7.12-7.26
(m, 4H). 13C NMR (CDCl3) δ: 18.5; 22.0; 23.8; 25.9; 29.7; 31.2;
31.8; 34.4; 41.0; 42.4; 43.4; 49.4; 56.8; 76.0; 88.4; 126.1 (2C);
129.8; 130.1; 135.2; 135.3; 173.4. IR (Nujol): 3050; 1690; 750
cm-1. MS (m/z): 341 (M+ + 2, 25); 340 (M+ + 1, 100). Anal.
Calcd for C22H29NO2: C, 77.84; H, 8.61; N, 4.13. Found: C,
78.01; H, 8.75; N, 3.97.
IR (Nujol): 3010; 1680; 1620; 760; 750; 720; 700; 690. cm-1
.
MS (m/z): 416 (M+ + 1, 62); 262 (52); 236 (35); 223 (62), 208
(100). Anal. Calcd for C28H33NO2: C, 80.93; H, 8.00; N, 3.37.
Found: C, 81.12; H, 7.89; N, 3.52.
Cycloa d d u ct (3b). Colorless solid. Mp: 133-134 °C (from
1
N-Acr yloyl-2r-(tr a n s-2-m eth yl-2-ph en yleth en yl)-4,4,7r-
hexanes-EtOAc 10-1). [R]25 ) -168.4 (c ) 1.0, CHCl3). H
D
tr im eth yl-tr a n s-octa h yd r o-1,3-ben zoxa zin e (2h ). Yield:
NMR (CDCl3) δ: 0.75-1.10 (m, 3H); 0.88 (d, 3H, J ) 6.5 Hz);
1.13 (s, 3H); 1.26 (m, 1H); 1.44 (m, 1H); 1.56-1.72 (m, 2H);
1.69 (s, 3H); 1.86 (m, 1H); 1.93-2.06 (m, 2H); 2.33 (dd, 1H, J 1
78%. Colorless oil. [R]25 ) -6.1 (c ) 1.3, CHCl3). 1H NMR
D
(CDCl3) δ: 0.79-1.28 (m, 3H); 0.87 (d, 3H, J ) 6.5 Hz); 1.35-
1.53 (m, 1H); 1.55 (s, 3H); 1.66-1.81 (m, 2H); 1.68 (s, 3H);
1.98-2.04 (m, 2H); 2.16 (s, 3H); 3.67 (dt, 1H, J 1 ) 3.6 Hz, J 2
) 11.5 Hz); 5.55 (dd, 1H, J 1 )2.1 Hz, J 2 ) 10.3 Hz); 5.95-
5.98 (m, 2H); 6.16 (dd, 1H, J 1 ) 2.1 Hz, J 2 ) 16.8 Hz); 6.34
(dd, 1H, J 1 ) 10.3 Hz, J 2 ) 16.8 Hz); 7.24-7.41 (m, 5H). 13C
NMR (CDCl3) δ: 16.3; 18.5; 21.5; 24.4; 24.9; 31.1; 34.2; 42.5;
46.8; 57.4; 72.8; 79.3; 125.2 (2C); 125.9; 127.2; 128.0 (2C); 129.2;
130.8; 139.7; 141.8; 165.4. IR (film): 3015; 1680; 1640; 1600;
780; 750; 730; 690 cm-1. Anal. Calcd for C23H31NO2: C, 78.15;
H, 8.84; N, 3.96. Found: C, 78.33; H, 8.66; N, 3.87.
) 12.0 Hz, J 2 ) 16.6 Hz); 2.73 (dd, 1H, J 1 ) 12.5 Hz, J 2
16.2 Hz); 3.09 (dd, 1H, J 1 ) 4.8 Hz, J 2 ) 16.2 Hz); 3.24 (dd,
1H, J 1 ) 4.9 Hz, J 2 ) 16.6 Hz); 3.34 (dt, 1H, J 1 ) 4.2 Hz, J 2
)
)
10.6 Hz); 3.74 (s, 3H); 4.65 (d, 1H, J ) 7.6 Hz); 6.61 (d, 1H, J
) 8.1 Hz); 6.72 (d, 1H, J ) 8.1 Hz); 7.05 (t, 1H, J ) 8.1 Hz).
13C NMR (CDCl3) δ: 18.5; 22.0; 23.8; 25.9 (2C); 29.9; 31.2; 34.4;
41.0; 42.1; 43.0; 49.4; 55.2; 56.7; 75.9; 88.7; 107.4; 122.1; 124.5;
126.6; 136.8; 157.7; 173.5. IR (Nujol): 3050; 1690; 760; 710;
670 cm-1. MS (m/z): 371 (M+ + 2, 26); 370 (M+ + 1, 100). Anal.
Calcd for C23H31NO3: C, 74.76; H, 8.46; N, 3.79. Found: C,
74.59; H, 8.29; N, 3.94.
Syn th esis of Am id es epi-2a a n d epi-2d . A mixture of
amide 2a or 2d (6.0 mmol) and a chloroform solution of
hydrogen chloride (50 mL), obtained by bubbling dry hydrogen
chloride though of 50 mL of anhydrous chloroform for 5 s, were
agited at room temperature for 20 min. Anhydrous Na2CO3
Cycloa d d u ct (3c). Colorless solid. Mp: 165-166 °C (from
1
hexanes-EtOAc 10-1). [R]25 ) -131.1 (c ) 1.3, CHCl3). H
D
NMR (CDCl3) δ: 0.89-1.12 (m, 3H); 0.95 (d, 3H, J ) 6.5 Hz);
1.19 (s, 3H); 1.31 (m, 1H); 1.48 (m, 1H); 1.72-1.79 (m, 2H);

Stereocontrolled IMDA Reaction of Styrene Derivatives
J . Org. Chem., Vol. 67, No. 3, 2002 787
1.76 (s, 3H); 1.91-2.06 (m, 3H); 2.66 (t, 1H, J ) 14.0 Hz); 2.77
(t, 1H, J ) 12.4 Hz); 3.07-3.16 (m, 2H); 3.41 (dt, 1H, J 1 ) 4.0
Hz, J 2 ) 10.5 Hz); 3.75 (s, 3H); 4.69 (d, 1H, J ) 7.4 Hz); 6.68
(s, 1H); 6.69 (d, 1H, J ) 7.9 Hz); 7.01 (d, 1H, J ) 7.9 Hz). 13C
NMR (CDCl3) δ: 18.3; 21.9; 23.7; 25.7; 29.9; 30.8; 31.0; 34.2;
40.8; 42.5; 43.3; 49.3; 55.0; 56.6; 75.7; 88.2; 112.4; 114.2; 127.1;
130.4; 136.3; 157.6; 173.2. IR (Nujol): 3050; 1680; 790; 760
cm-1. MS (m/z): 369 (M+, 10); 159 (59); 81 (48); 58 (100); 55
(75); 41 (89). Anal. Calcd for C23H31NO3: C, 74.76; H, 8.46; N,
3.79. Found: C, 74.58; H, 8.62; N, 3.62.
1H, J 1 ) 3.9 Hz, J 2 ) 11.2 Hz); 5.23 (d, 1H, J ) 6.6 Hz); 7.29
(t, 1H, J ) 7.4 Hz); 7.42 (d, 1H, J ) 7.4 Hz); 7.70 (d, 1H, J )
7.4 Hz). 13C NMR (CDCl3) δ: 19.1; 21.8; 22.9; 24.2; 29.0; 30.3;
31.2; 34.1; 41.6; 41.8; 44.2; 46.9; 55.6; 74.3; 83.0; 122.4; 126.6;
130.0; 134.6; 138.3; 150.4; 171.9. IR (Nujol): 3050; 1690; 740
cm-1. MS (m/ z): 384 (M+, 8); 128 (61); 81 (61); 55 (82); 41
(100). Anal. Calcd for C22H28N2O4: C, 68.73; H, 7.34; N, 7.29.
Found: C, 68.90; H, 7.51; N, 7.12.
Cycloa d d u ct (6). Colorless oil. [R]25 ) -98.1 (c ) 1.6,
D
1
CHCl3). H NMR (CDCl3) δ: 0.79 (d, 3H, J ) 7.5 Hz); 0.90-
Cycloa d d u ct (3d ). Colorless solid. Mp: 194-195 °C (from
0.94 (m, 2H); 0.92 (d, 3H, J ) 6.3 Hz); 1.07 (q, 1H, J ) 12.0
Hz); 1.20 (s, 3H); 1.33 (m, 1H); 1.48 (m, 1H); 1.65-1.80 (m,
2H); 1.77 (s, 3H); 2.00 (m, 1H); 2.56 (m, 1H); 3.39 (m, 1H);
3.45 (dt, 1H, J 1 ) 4.0 Hz, J 2 ) 10.5 Hz); 5.12 (d, 1H, J ) 7.1
Hz); 5.19 (s, 1H); 5.49 (s, 1H); 7.11-7.36 (m, 5H). 13C NMR
(CDCl3) δ: 11.9; 17.7; 21.5; 23.5; 25.2; 30.7; 33.9; 38.8; 40.6;
45.4; 49.2; 56.2; 75.7; 85.7; 113.3; 125.4 (2C); 127.2; 127.9 (2C);
140.5; 143.3; 174.4. IR (film): 3050; 2930; 1730; 1680; 1640;
780; 720; 700 cm-1. Anal. Calcd for C23H31NO2: C, 78.15; H,
8.84; N, 3.96. Found: C, 78.33; H, 8.99; N, 4.08.
hexanes-EtOAc 8-1). [R]25 ) -496.9 (c ) 1.2, CHCl3). 1H
D
NMR (CDCl3) δ: 0.78-1.10 (m, 3H); 0.95 (d, 3H, J ) 6.5 Hz);
1.22 (s, 3H); 1.30 (m, 1H); 1.45 (m, 1H); 1.60-1.78 (m, 2H);
1.77 (s, 3H); 1.87 (m, 1H); 2.01 (m, 1H); 2.15 (dt, 1H, J 1 ) 5.1
Hz, J 2 ) 12.5 Hz); 2.90 (dd, 1H, J 1 ) 12.5 Hz, J 2 ) 16.5 Hz);
3.01 (dd, 1H, J 1 ) 12.5 Hz, J 2 ) 17.0 Hz); 3.27 (dd, 1H, J 1
)
5.1 Hz, J 2 ) 16.5 Hz); 3.33 (dd, 1H, J 1 ) 5.0 Hz, J 2 ) 17.0
Hz); 3.44 (dt, 1H, J 1 ) 4.2 Hz, J 2 ) 10.6 Hz); 4.79 (d, 1H, J )
7.5 Hz); 7.30 (t, 1H, J ) 7.6 Hz); 7.40 (d, 1H, J ) 7.6 Hz); 7.73
(d, 1H, J ) 7.6 Hz). 13C NMR (CDCl3) (δ): 18.5; 21.9; 23.7;
25.8; 29.1; 30.3; 31.1; 34.3; 40.8; 41.7; 42.2; 49.3; 57.0; 75.9;
88.0; 122.5; 126.7; 130.1; 134.8; 138.4; 150.6; 172.3. IR (Nu-
jol): 3050; 1690; 800; 780; 770; 740 cm-1. MS (m/z): 386 (M+
+ 2, 25); 385 (M+ + 1, 100). Anal. Calcd for C22H28N2O4: C,
68.73; H, 7.34; N, 7.29. Found: C, 68.90; H, 7.46; N, 7.11.
Syn t h esis of Am in o Alcoh ols 7 a n d 9a -g. Gen er a l
Meth od . To a suspension of LiAlH4 (0.57 g, 15 mmol) in
anhydrous THF (40 mL) cooled to -10 °C was added, in
portions, dry AlCl3 (0.67 g, 5 mmol). The mixture was stirred
for 10 min, and a solution of the corresponding adduct (3 mmol)
in dry THF (20 mL) was slowly added. The reaction mixture
was stirred fo 8 min at -10 °C and quenched by addition of
H2O (4 mL). The resulting mixture was filtered, the solid was
washed with EtOAc, and the organic layer was dried (MgSO4).
The solvent was eliminated under reduced pressure, and the
residue was chromatographed on silica gel using hexane/
EtOAc 3/1 as eluent.
Cycoa d d u ct (3e). Colorless solid. Mp: 149-150 °C (from
1
hexanes-EtOAc 10-1). [R]25 ) -146.4 (c ) 1.0, CHCl3). H
D
NMR (CDCl3) δ: 0.86-1.12 (m, 3H); 0.92 (s, 3H); 0.95 (d, 3H,
J ) 6.5 Hz); 1.91 (s, 3H); 1.30-1.36 (m, 1H); 1.40-1.62 (m,
1H); 1.72-1.80 (m, 2H); 1.79 (s, 3H); 2.00-2.09 (m, 2H); 2.77
(m, 1H); 2.79 (d, 1H, J ) 16.0 Hz); 2.94 (d, 1H, J ) 16.0 Hz);
3.07 (dd, 1H, J 1 ) 5.0 Hz, J 2 ) 15.9 Hz); 3.42 (dt, 1H, J 1 ) 4.1
Hz, J 2 ) 10.6 Hz); 4.75 (d, 1H, J ) 8.2 Hz); 7.13-7.26 (m,
4H). 13C NMR (CDCl3) δ: 15.3; 18.4; 21.9; 23.9; 25.9; 26.6; 31.2;
34.4; 37.9; 41.0; 41.9; 44.5; 49.5; 56.6; 76.0; 86.9; 125.8; 126.2;
129.7; 130.8; 134.6; 134.9; 177.4. IR (Nujol): 3050; 1685; 775;
750 cm-1. MS (m/z): 355 (M+ + 2, 25); 354 (M+ + 1, 100). Anal.
Calcd for C23H31NO2: C, 78.15; H, 8.84; N, 3.96. Found: C,
78.34; H, 8.72; N, 4.17.
(3a R,9a R)-N-(8-Men th olyl)-3a ,4,9,9a -tetr a h yd r oben z[f]-
isoin d olin e (9a ). Yield: 80%. Colorless solid. Mp: 148-149
°C (from hexane). [R]25 ) -54.6 (c ) 1.2, CHCl3). 1H NMR
D
(CDCl3, 333 K) δ: 0.85-1.13 (m, 3H); 0.91 (d, 3H, J ) 6.5 Hz);
0.97 (s, 3H); 1.19 (s, 3H); 1.49-1.36 (m, 2H); 1.57-1.70 (m,
2H); 1.73-1.90 (m, 2H); 1.93 (m, 1H); 2.52-2.64 (m, 4H); 2.91-
3.00 (m, 2H); 3.13-3.20 (m, 2H); 3.65 (dt, 1H, J 1 ) 4.0 Hz, J 2
) 10.4 Hz); 7.07 (s, 4H); 8.70 (broad s, 1H). 13C NMR (CDCl3,
333 K) δ: 16.5; 21.3; 22.0; 25.7; 31.0; 33.6 (2C); 35.2; 41.2 (2C);
44.3; 49.4; 51.3 (2C); 59.6; 72.9; 125.8 (2C); 129.5 (2C); 136.0
(2C). IR (Nujol): 3250 (broad); 750 cm-1. MS (m/ z): 329 (M+
+ 2, 26); 328 (M+ + 1, 100); 326 (20); 214 (26).
Cycloa d d u ct (3g). Colorless solid. Mp: 177-178 °C (from
1
hexanes-EtOAc 10-1). [R]25 ) -263.7 (c ) 1.2, CHCl3). H
D
NMR (CDCl3) δ: 0.86-1.01 (m, 2H); 0.98 (s, 3H); 0.99 (d, 3H,
J ) 6.8 Hz); 1.13 (q, 1H, J ) 11.8 Hz); 1.28 (m, 1H); 1.33-
1.62 (m, 1H); 1.63-1.80 (m, 2H); 1.71 (s, 3H); 2.14 (m, 1H);
2.27-2.37 (m,2H); 2.88 (m, 1H); 3.23-3.33 (m, 2H); 4.22 (d,
1H, J ) 7.6 Hz); 4.67 d, 1H, J ) 4.1 Hz); 6.92-7.31 (m, 9H).
13C NMR (CDCl3) δ: 18.0; 22.0; 23.7; 25.8; 29.8; 31.1; 34.3;
36.5; 41.0; 44.3; 46.5; 49.4; 56.5; 75.7; 85.4; 126.4 (2C); 126.6;
128.1 (2C); 129.7; 130.0 (2C); 131.1; 136.0; 137.7; 141.8; 172.5.
IR (Nujol): 3050; 1700; 1590; 750; 700 cm-1. MS (m/z): 417
(M+ + 2, 30); 416 (M+ + 1, 100). Anal. Calcd for C28H33NO2:
C, 80.93; H, 8.00; N, 3.37. Found: C, 81.14; H, 8.18; N, 3.22.
Cycloa d d u ct (epi-3a ). Colorless solid. Mp: 205-206 °C
(from hexanes-EtOAc 8-1). [R]25D ) +197.2 (c ) 1.7, CHCl3).
1H NMR (CDCl3) δ: 0.89-1.41 (m, 3H); 0.97 (d, 3H, J ) 6.5
Hz); 1.43 (s, 3H); 1.53 (s, 3H); 1.49 (m, 1H); 1.65-1.83 (m, 3H);
(3aR,9aR)-N-(8-Men th olyl)-5-m eth oxy-3a,4,9,9a-tetr ah y-
d r oben z[f]isoin d olin e (9b). Yield: 88%. Colorless oil. [R]25
D
1
) -61.3 (c ) 1.1, CHCl3). H NMR (CDCl3, 333 K) δ: 0.83-
1.10 (m, 2H); 0.91 (d, 3H, J ) 6.5 Hz); 0.94 (s, 3H); 1.11 (s,
3H); 1.26-1.50 (m, 2H); 1.55-1.90 (m, 4H); 1.94 (m, 1H); 2.21
(m, 1H); 2.48-2.58 (m, 3H); 2.87 (m, 1H); 3.03-3.17 (m, 3H);
3.63 (dt, 1H, J 1 ) 4.0 Hz, J 2 ) 10.4 Hz); 3.76 (s, 3H); 6.62 (d,
1H, J ) 8.0 Hz); 6.67 (d, 1H, J ) 7.7 Hz); 6.72 (dd, 1H J 1
)
7.7 Hz, J 2 ) 8.0 Hz); 9.50 (broad s, 1H). 13C NMR (CDCl3, 333
K) δ: 16.3; 21.0; 21.8; 25.5; 29.7; 30.8; 33.6; 35.0; 40.4; 40.7;
44.2; 49.2; 51.0; 51.3; 54.9; 59.4; 72.6; 107.2; 121.5; 125.0; 125.9;
137.2; 157.4. IR (film): 3400 (broad); 1570; 700; 680; 650 cm-1
.
MS (m/ z): 357 (M+, 0.5); 244 (100); 55 (16); 43 (40); 41 (32).
(3aR,9aR)-N-(8-Men th olyl)-6-m eth oxy-3a,4,9,9a-tetr ah y-
d r oben z[f]isoin d olin e (9c). Yield: 94%. Colorless solid.
1.87 (m, 1H); 2.00 (m, 1H); 2.22 (dt, 1H, J 1 ) 5.3 Hz, J 2
)
12.5 Hz); 2.75 (dd, 1H, J 1 ) 12.5 Hz, J 2 ) 15.6 Hz); 2.80 (dd,
1H, J 1 ) 12.5 Hz, J 2 ) 15.6 Hz); 3.12 (dd, 1H, J 1 ) 5.4 Hz, J 2
) 15.6 Hz); 3.15 (dd, 1H, J 1 ) 5.4 Hz, J 2 ) 15.6 Hz); 3.75 (dt,
1H, J 1 ) 4.0 Hz, J 2 ) 11.2 Hz); 5.14 (d, 1H, J ) 6.7 Hz); 7.16-
7.80 (m, 4H). 13C NMR (CDCl3) δ: 19.2; 21.9; 23.0; 24.3; 29.7;
31.3; 31.8; 34.3; 42.0; 42.9; 45.0; 47.0; 55.4; 74.3; 83.3; 126.0
(2C); 129.7; 130.0; 135.1 (2C); 172.9. IR (Nujol): 3040, 1680,
760, 740 cm-1. Anal. Calcd for C22H29NO2: C, 77.84; H, 8.61;
N, 4.13. Found: C, 77.96; H, 8.80; N, 4.02.
Mp: 110-111 °C (from hexanes-EtOAc 15/1). [R]25 ) -55.0
D
(c ) 1.1, CHCl3). 1H NMR (CDCl3, 333 K) δ: 0.83-1.08 (m,
3H); 0.91 (d, 3H, J ) 6.5 Hz); 0.96 (s, 3H); 1.18 (s, 3H); 1.40-
1.48 (m, 2H); 1.55-1.70 (m, 2H); 1.74-1.93 (m, 2H); 1.95 (m,
1H); 2.44-2.60 (m, 4H); 2.85-2.92 (m, 2H); 3.12-3.16 (m, 2H);
3.64 (dt, 1H, J 1 ) 4.0 Hz, J 2 ) 10.2 Hz); 3.74 (s, 3H); 6.61 (d,
1H, J ) 2.5 Hz); 6.66 (dd, 1H, J 1 ) 2.5 Hz, J 2 ) 8.4 Hz); 6.97
(d, 1H J ) 8.4 Hz); 8.55 (broad s, 1H). 13C NMR (CDCl3, 333
K) δ: 16.6; 21.3; 22.0; 25.8; 31.1; 32.9; 33.9; 35.3; 41.2; 41.5;
44.5; 49.5; 51.3 (2C); 55.2; 59.7; 72.9; 112.2; 114.4; 128.3; 130.2;
137.3; 157.9. IR (Nujol): 3100 (broad); 1610 cm-1. MS (m/ z):
357 (M+, 0.5); 244 (47); 110 (43); 70 (40); 55 (48); 43 (60); 41
(100).
Cycloa d d u ct (epi-3d ). Colorless solid. Mp: 188-189 °C
(from hexanes-EtOAc 8-1). [R]25D ) +470.3 (c ) 1.0, CHCl3).
1H NMR (CDCl3) δ: 0.78-1.28 (m, 3H); 0.97 (d, 3H, J ) 6.5
Hz); 1.36-1.61 (m, 1H); 1.43 (s, 3H); 1.54 (s, 3H); 1.68-1.81
(m, 4H); 1.82-2.04 (m, 1H); 2.26 (dt, 1H, J 1 ) 5.1 Hz, J 2
)
12.6 Hz); 2.89 (dd, 1H, J 1 ) 12.6 Hz, J 2 ) 16.3 Hz); 2.99 (dd,
1H, J 1 ) 12.5 Hz, J 2 ) 17.0 Hz); 3.21 (dd, 1H, J 1 ) 5.1 Hz, J 2
) 16.3 Hz); 3.27 (dd, 1H, J 1 ) 4.8 Hz, J 2 ) 17.0 Hz); 3.75 (dt,
(3a R,9a R)-N-(8-Men t h olyl)-5-n it r o-3a ,4,9,9a -t et r a h y-
d r oben z[f]isoin d olin e (9d ). Yield: 83%. Colorless solid.
Mp: 68-69 °C (from hexanes-EtOAc 8/1). [R]25 ) -342.3 (c
D

788 J . Org. Chem., Vol. 67, No. 3, 2002
Pedrosa et al.
) 1.0, CHCl3). 1H NMR (CDCl3, 333 K) δ: 0.85-1.07 (m, 3H);
0.92 (d, 3H, J ) 6.5 Hz); 0.98 (s, 3H); 1.19 (s, 3H); 1.39-1.49
(m, 2H); 1.57-1.85 (m, 4H); 1.92 (m, 1H); 2.61-2.83 (m, 4H);
3.04-3.22 (m, 4H); 3.64 (dt, 1H, J 1 ) 4.0 Hz, J 2 ) 10.4 Hz);
7.22 (dd, 1H, J 1 ) 7.5 Hz, J 2 ) 7.8 Hz); 7.32 (d, 1H J ) 7.5
Hz); 7.64 (d, 1H, J ) 7.8 Hz); 8.45 (broad s, 1H). 13C NMR
(CDCl3, 333 K) δ: 16.6; 21.3; 22.0; 25.7; 30.3; 31.1; 34.2; 35.2;
40.0; 40.5; 44.4; 49.5; 51.0; 51.3; 59.7; 72.9; 122.1; 126.3; 130.8;
127.1; 128.1 (2C); 142.2; 147.0. IR (film): 3100 (broad); 1620;
780; 710; 700 cm-1
.
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 amino derivatives 7 and 9a -g (1.0
mmol) and PCC (1.3 g, 6 mmol) in CH2Cl2 (40 mL) and 4 Å
molecular sieves (1 g) was stirred at room temperature until
the oxidation was finished (TCL, 6-8 h). The solvent was
eliminated under reduced pressure, the residue was dissolved
in 15% aqueous solution of NaOH (25 mL), and the resulting
solution was extracted with EtOAc. The organic phase was
washed with brine and dried over anhydrous magnesium
sulfate. The solvents were eliminated under vacuum, and the
residue was taken up in a 2.5 M solution (16 mL) of KOH in
THF/MeOH/H2O (2/1/1), and the solution was stirred at room
temperature for 5-6 h. After elimination of the solvents under
reduced pressure, the residue was dissolved in 50 mL of CH2-
Cl2 and washed with H2O. The organic layer was dried over
MgSO4 and filtered, and the solvent was eliminated under
vacuum to give an oily residue which was purified by flash
chromatography on silica gel using a mixture of CHCl3/EtOH
8/1 as eluent. The benzoisoindolines 10a -h , ent-10a , and end-
10d were characterized as hydrochorides and the pyrrolidine
8 as the tosylate.
134.0; 139.3; 150.8. IR (Nujol): 3100 (broad); 790; 730 cm-1
.
MS (m/ z): 372 (M+, 1); 259 (100); 115 (23); 70 (62); 41 (89).
(3aR,9aR)-N-(8-Men th olyl)-3a-m eth yl-3a,4,9,9a-tetr ah y-
d r oben z[f]isoin d olin e (9e). Yield: 91%. Colorless oil. [R]25
D
1
) -65.0 (c ) 1.4, CHCl3). H NMR (CDCl3, 333 K) δ: 0.83-
1.07 (m, 3H); 0.88 (s, 3H); 0.92 (d, 3H, J ) 6.5 Hz); 0.96 (s,
3H); 1.16 (s, 3H); 1.38-1.48 (m, 2H); 1.57-1.70 (m, 2H); 1.83-
1.95 (m, 2H); 2.48-2.85 (m, 7H); 3.04 (dd, 1H, J 1 ) 8.4 Hz, J 2
) 9.7 Hz); 3.64 (dt, 1H, J 1 ) 4.0 Hz, J 2 ) 10.3 Hz); 7.09 (broad
s, 4H); 8.55 (broad s, 1H). 13C NMR (CDCl3, 333 K) δ: 16.7;
17.1; 21.3; 22.0; 25.6; 28.9; 31.0; 35.2; 38.5; 41.9; 43.1; 44.4;
48.3; 49.4; 59.1; 59.4; 72.8; 125.6; 125.9; 129.4; 130.1; 135.4;
135.7. IR (film): 3100 (broad); 730; 720 cm-1. MS (m/ z): 341
(M+, 1); 228 (100); 104 (34); 91 (61); 41 (90).
(3a S,4R,9a R)-N-(8-Men t h olyl)-4-p h en yl-3a ,4,9,9a -t et -
r a h yd r oben z[f]isoin d olin e (9g). Yield: 93%. Colorless solid.
(3a R,9a R)-3a ,4,9,9a -Tetr a h yd r oben z[f]isoin d olin e Hy-
d r och or id e (10a ). Yield: 68%. Colorless solid. Mp: 208-209
Mp: 146-147 °C (from hexane). [R]25 ) -145.4 (c ) 1.1,
D
°C (from EtOH-Et2O). [R]25 ) -60.1 (c ) 0.9, MeOH). 1H
CHCl3). 1H NMR (CDCl3, 333 K) δ: 0.67 (s, 3H); 0.79-1.01
(m, 3H); 0.89 (d, 3H, J ) 6.5 Hz); 1.05 (s, 3H); 1.26-1.45 (m,
2H); 1.51 (m, 1H); 1.66 (m, 1H); 1.83-2.10 (m, 3H); 2.15 (m,
1H); 2.59-2.69 (m, 2H); 2.95 (dd, 1H, J 1 ) 6.1 Hz, J 2 ) 8.9
Hz); 3.01-3.11 (m, 2H); 3.57 (dt, 1H, J 1 ) 4.0 Hz, J 2 ) 10.3
Hz); 4.35 (d, 1H, J ) 5.8 Hz); 6.84-6.88 (m, 2H); 6.93-6.95
(m, 1H); 7.02-7.24 (m, 6H); 8.45 (broad s, 1H). 13C NMR
(CDCl3, 333 K) δ: 16.5; 21.2; 22.0; 25.8; 31.1; 33.6; 34.4; 35.4;
44.5 (2C); 46.5; 48.7; 49.4; 51.0; 59.8; 72.8; 126.2; 126.3 (2C);
127.8 (2C); 129.3; 129.9 (2C); 131.3; 136.8; 139.0; 142.8. IR
(Nujol): 3100 (broad); 760; 740; 730; 700 cm-1. MS (m/ z): 403
(M+, 1); 290 (100); 91 (82); 41 (74).
D
NMR (DMSO) δ: 2.29 (m, 2H); 2.94 (m, 2H); 3.22 (m, 2H);
3.37 (m, 2H); 3.91 (m, 2H); 7.48 (s, 4H); 9.50 (broad s, 2H).
13C NMR (DMSO) δ: 32.6 (2C); 40.4 (2C); 49.7 (2C); 126.8 (2C);
130.1 (2C); 135.5 (2C). IR (Nujol): 3400 (broad); 2700; 2400;
760 cm-1. Anal. Calcd for C12H16ClN: C, 68.73; H, 7.69; N,
6.68. Found: C, 68.51; H, 7.87; N, 6.52.
(3a R,9a R)-5-Meth oxy-3a ,4,9,9a -tetr a h yd r oben z[f]isoin -
d olin e h yd r och lor id e (10b). Yield: 80%. Colorless solid.
Mp: 294-295 °C (from EtOH-Et2O). [R]25 ) -90.7 (c ) 0.9,
D
MeOH). 1H NMR (DMSO) δ: 2.17 (m, 2H); 2.51 (m, 1H); 2.80-
2.91 (m, 1H); 3.12-3.24 (m, 2H); 3.25-3.40 (m, 2H); 3.86 (m,
2H); 4.04 (s, 3H); 7.03 (d, 1H, J ) 7.8 Hz); 7.07 (d, 1H, J ) 7.8
Hz); 7.42 (t, 1H, J ) 7.8 Hz). 13C NMR (DMSO) δ: 26.6; 32.4;
39.9; 40.1; 49.7; 49.9; 55.8; 108.4; 122.1; 123.9; 127.4; 136.8;
157.6. IR (Nujol): 2680; 1580; 760; 700; 690 cm-1. Anal. Calcd
for C13H18ClNO: C, 65.13; H, 7.57; N, 5.84. Found: C, 64.97;
H, 7.76; N, 5.65.
(3a S, 9a S)-N-(8-Men th olyl)-3a ,4,9,9a -tetr a h yd r oben z-
[f]isoin d olin e (epi-9a ). Yield: 87%. Colorless solid. Mp:
153-154 °C (from hexane). [R]25 ) +53.9 (c ) 1.3, CHCl3).
D
1H NMR (CDCl3, 333 K) δ: 0.84-1.08 (m, 3H); 0.91 (d, 3H, J
) 6.5 Hz); 0.96 (s, 3H); 1.19 (s, 3H); 1.43 (m, 1H); 1.52-1.63
(m, 2H); 1.67 (m, 1H); 1.74-1.91 (m, 2H); 1.93 (m, 1H); 2.48-
2.63 (m, 4H); 2.94 (dd, 2H, J 1 ) 2.6 Hz, J 2 ) 16.8 Hz); 3.26
(dd, 2H, J 1 ) 7.1 Hz, J 2 ) 7.9 Hz); 3.64 (dt, 1H, J 1 ) 4.0 Hz,
J 2 ) 10.2 Hz); 7.06 (s, 4H); 8.20 (broad s, 1H).13C NMR (CDCl3,
333 K) δ: 18.3; 21.5; 22.0; 26.0; 31.2; 33.8 (2C); 35.3; 41.3 (2C);
44.4; 48.9; 50.7 (2C); 59.3; 73.0; 125.8 (2C); 129.5 (2C); 136.3
(2C). IR (Nujol): 3150 (broad); 770 cm-1. MS (m/ z): 329 (M+
+ 2, 24); 328 (M+ + 1, 100); 326 (19); 214 (35).
(3a R,9a R)-6-Meth oxy-3a ,4,9,9a -tetr a h yd r oben z[f]isoin -
d olin e Hyd r och lor id e (10c). Yield: 78%. Colorless solid.
Mp: 243-244 °C (from EtOH-Et2O). [R]25 ) -73.6 (c ) 0.9,
D
MeOH). 1H NMR (DMSO) δ: 2.17 (m, 2H); 2.64-2.85 (m, 2H);
3.08-3.26 (m, 4H); 3.81 (m, 2H); 3.95 (s, 3H); 6.93 (d, 1H, J )
2.6 Hz); 6.97 (dd, 1H, J 1 ) 2.6 Hz, J 2 ) 8.4 Hz); 7.28 (d, 1H, J
) 8.4 Hz); 9.43 (broad s, 2H). 13C NMR (DMSO) δ: 31.7; 32.6;
40.7; 41.0; 49.9 (2C); 55.8; 113.2; 114.7; 127.6; 131.1; 136.9;
158.2. IR (Nujol): 3310 (broad); 2700; 2460; 1600; 820; 730
cm-1. Anal. Calcd for C13H18ClNO: C, 65.13; H, 7.57; N, 5.84.
Found: C, 64.91; H, 7.79; N, 5.70.
(3a S,9a S)-N-(8-Men t h olyl)-5-n it r o-3a ,4,9,9a -t et r a h y-
d r oben z[f]isoin d olin e (epi-9d ). Yield: 81%. Colorless oil.
1
[R]25 ) +256.5 (c ) 0.9, CHCl3). H NMR (CDCl3, 333 K) δ:
D
0.87-1.15 (m, 3H); 0.91 (d, 3H, J ) 6.5 Hz); 0.98 (s, 3H); 1.20
(s, 3H); 1.42 (m, 1H); 1.52-1.95 (m, 6H); 2.48-2.82 (m, 4H);
3.02-3.16 (m, 2H); 3.26-3.33 (m, 2H); 3.63 (dt, 1H, J 1 ) 4.0
Hz, J 2 ) 10.3 Hz); 7.21 (dd, 1H, J 1 ) 7.6 Hz, J 2 ) 7.8 Hz);
7.31 (d, 1H, J ) 7.6 Hz); 7.63 (d 1H, J ) 7.8 Hz); 9.31 (broad
s, 1H). 13C NMR (CDCl3, 333 K) δ: 18.1; 21.3; 21.9; 25.8; 30.4;
31.0; 34.2; 35.1; 39.9; 40.5; 44.2; 48.8; 50.4; 50.5; 59.3; 72.9;
121.9; 126.1; 130.8; 133.9; 139.3; 150.7. IR (film): 3110 (broad);
820; 790; 730 cm-1. MS (m/ z): 372 (M+, 1); 259 (75); 55 (64);
41 (100).
(3a R,9a R)-5-Nitr o-3a ,4,9,9a -tetr a h yd r oben z[f]isoin d o-
lin e Hyd r och lor id e (10d ). Yield: 62%. Yellow solid. Mp:
325-326 °C (from EtOH-Et2O). [R]25 ) -447.1 (c ) 0.7,
D
MeOH). 1H NMR (DMSO) δ: 2.22 (m, 2H); 2.85-3.05 (m, 2H);
3.17-3.24 (m, 2H); 3.30-3.46 (m, 2H); 3.86 (m, 2H); 7.65 (t,
1H, J ) 7.8 Hz); 7.75 (d, 1H, J ) 7.8 Hz); 7.97 (d, 1H, J ) 7.8
Hz); 9.51 (broad s, 2H). 13C NMR (DMSO) δ: 29.1; 32.5; 39.1;
39.7; 49.6 (2C); 122.7; 127.6; 129.6; 135.1; 139.0; 150.5. IR
(Nujol): 3350; 2700; 2420; 1490; 820; 800; 790; 760; 730 cm-1
.
Anal. Calcd for C12H15ClN2O2: C, 56.58; H, 5.94; N, 11.00.
Found: C, 56.39; H, 6.10; N, 10.89.
N-(8-Men th olyl)-3-m eth yl-4-(1-p h en yleth en yl)p yr r oli-
d in e (7). Yield: 82%. Colorless oil. [R]25 ) +15.4 (c ) 0.9,
D
1
CHCl3). H NMR (CDCl3, 333 K) δ: 0.68 (d, 3H, J ) 7.0 Hz);
(3a R,9a R)-3a -Meth yl-3a ,4,9,9a -tetr a h yd r oben z[f]isoin -
d olin e Hyd r och lor id e (10e). Yield: 76%. Colorless solid.
0.84-1.09 (m, 3H); 0.91 (d, 3H, J ) 6.5 Hz); 0.98 (s, 3H); 1.19
(s, 3H); 1.38-1.53 (m, 2H); 1.55-1.69 (m, 2H); 1.95 (m, 1H);
2.25 (dq, 1H, J 1 ) 2.6 Hz, J 2 ) 7.0 Hz); 2.43 (m, 1H); 2.97 (m,
1H); 3.05 (dd, 1H, J 1 ) 7.1 Hz, J 2 ) 9.0 Hz); 3.20 (m, 1H);
3.26 (m, 1H); 3.64 (dt, 1H, J 1 ) 4.0 Hz, J 2 ) 10.2 Hz); 5.00 (s,
1H); 5.33 (s, 1H); 7.18-7.35 (m, 5H); 8.45 (broad s, 1H). 13C
NMR (CDCl3, 333 K) δ: 15.2; 16.6; 21.5; 21.9; 25.6; 30.9; 33.1;
35.1; 44.3; 45.3; 47.0; 48.7; 53.3; 59.0; 72.7; 112.8; 126.0 (2C);
Mp: 286-287 °C (from EtOH-Et2O). [R]25 ) -80.8 (c ) 1.1,
D
1
MeOH). H NMR (DMSO) δ: 1.15 (s, 3H); 2.43 (m, 1H); 2.87
(m, 1H); 3.01 (d, 1H, J ) 16.1 Hz); 3.19 (d, 1H, J ) 16.1 Hz);
3.20-3.36 (m, 3H); 3.61 (d, 1H, J ) 10.9 Hz); 3.81 (dd, 1H, J 1
) 7.9 Hz, J 2 ) 10.9 Hz); 7.47 (s, 4H); 9.75 (broad s, 2H). 13C
NMR (DMSO) δ: 16.2; 27.9; 38.7; 40.5; 42.4; 47.3; 56.6; 126.6;
126.8; 130.1; 130.7; 134.6; 135.0. IR (Nujol): 2700; 2410; 1590;

Stereocontrolled IMDA Reaction of Styrene Derivatives
J . Org. Chem., Vol. 67, No. 3, 2002 789
750 cm-1. Anal. Calcd for C13H18ClN: C, 69.79; H, 8.11; N,
6.26. Found: C, 69.61; H, 8.20; N, 6.14.
MeOH). 1H NMR (CDCl3) δ: 0.41 (d, 3H, J ) 7.0 Hz), 2.16 (m,
1H); 2.41 (s, 3H); 3.11 (dd, 1H, J 1 ) 2.1 Hz, J 2 ) 10.0 Hz);
3.28 (m, 1H); 3.41 (dd, 1H, J 1 ) 9.3 Hz, J 2 ) 19.1 Hz); 3.43
(dd, 1H, J 1 ) 10.0 Hz, J 2 ) 16.2 Hz); 3.63 (dd, 1H, J 1 ) 7.0
Hz, J 2 ) 9.3 Hz); 4.87 (d, 1H, J ) 1.1 Hz); 5.27 (d, 1H, J ) 1.1
Hz); 7.20-7.30 (m, 5H); 7.33 (d, 2H, J ) 8.2 Hz); 7.77 (d, 2H,
J ) 8.2 Hz). 13C NMR (CDCl3) δ: 13.3; 21.2; 34.2; 45.2; 48.5;
54.6; 113.6; 125.9 (2C); 127.1 (2C); 127.3; 128.1 (2C); 129.4
(2C); 133.7; 141.0; 143.1; 145.4. Anal. Calcd for C20H23NO2S:
C, 70.35; H, 6.79; N, 4.10. Found: C, 70.18; H, 6.95; N, 4.26.
(3aS,4R,9aR)-4-P h en yl-3a,4,9,9a-tetr ah ydr oben z[f]isoin -
d olin e Hyd r och lor id e (10g). Yield: 80%. Colorless solid.
Mp: 273-275 °C (from EtOH-Et2O). [R]25D ) -183.9 (c ) 0.9,
1
MeOH). H NMR (CDCl3) δ: 2.18-2.36 (m, 2H); 2.41 (m, 1H);
2.72 (dd, 1H, J 1 ) 11.4 Hz, J 2 ) 16.2 Hz); 2.98 (m, 1H); 3.22
(dd, 1H, J 1 ) 5.2 Hz, J 2 ) 16.2 Hz); 3.50-3.60 (m, 2H); 4.45
(d, 1H, J ) 5.8 Hz); 6.81-6.92 (m, 2H); 7.96 (d, 1H, J ) 7.5
Hz); 7.07-7.28 (m, 6H); 9.44 (broad s, 1H); 9.72 (broad s, 1H).
13C NMR (CDCl3) δ: 33.0; 33.2; 44.0; 45.0; 47.6; 48.8; 126.7;
126.8; 127.1; 128.4 (2C); 129.1; 129.7 (2C); 131.1; 134.8; 137.1;
140.5. IR (Nujol): 2690; 1570; 750; 740; 730; 690 cm-1. Anal.
Calcd for C18H20ClN: C, 75.64; H, 7.05; N, 4.90. Found: C,
75.47; H, 7.22; N, 4.73.
Ack n ow led gm en t. We thank the Spanish DGICYT
(Project No. PB98-0361) and J unta de Castilla y Leo´n
(Project No. VA 040/01) for financial support. One of us
(J .N.) also thanks the EU for a TMR Marie Curie
Training Grant (Contract No. HPMF-CT-1999-00066).
(3a S,9a S)-3a ,4,9,9a -Tetr a h yd r oben z[f]isoin d olin e Hy-
d r och or id e (en t-10a ). Yield: 72%. Colorless solid. Mp: 211-
212 °C (from EtOH-Et2O). [R]25 ) -60.6 (c ) 0.7, MeOH).
D
1H NMR, 13C NMR, and IR data are coincident with those
reported for 10a .
Su p p or tin g In for m a tion Ava ila ble: Synthesis and spec-
troscopic data for trans-â-methyl cinnamaldehyde. Physical
and spectroscopic data for minor compounds 4a ,b,d ,e, epi-4d ,
and 5. X-ray structures for compounds 3a ,g, epi-3a , and 5.
COSY and NOESY experiments for compounds 3b-d , epi-3d ,
and 4b,d . This material is available free of charge via the
Internet at http://pubs.acs.org.
(3a S,9a S)-5-Nitr o-3a ,4,9,9a -tetr a h yd r oben z[f]isoin d o-
lin e Hyd r och lor id e (en t-10d ). Yield: 68%. Yellow solid.
Mp: 320-322 °C (from EtOH-Et2O). [R]25D ) +425.2 (c ) 0.8,
1
MeOH). H NMR, 13C NMR, and IR data are coincident with
those reported for 10d .
(3S,4S)-N-Tosyl-3-m eth yl-4-(1-p h en yleth en yl)p yr r oli-
d in e (8). Yield: 82%. Colorless oil. [R]25 ) +44.2 (c ) 2.9,
J O010746V
D