Thermal and Lewis acid catalyzed diastereoselective intramolecular Diels-Alder reaction on α,β-unsaturated amides derived from (-)-8- aminomenthol

Article abstract of DOI:10.1021/jo9904462

Stereochemical aspects of the intramolecular Diels-Alder reaction on perhydro-1,3-benzoxazines derived from (-)-8-aminomenthol bearing α,β- unsaturated amides and the dienic component attached at C-2 are described. The thermal cyclization of 2-(2'-furyl) derivatives 2, 6, and 7 exclusively afforded mixtures of exo adducts. The product selectivity was highly dependent on the solvent of the reaction. In CH₂Cl₂, the kinetic products 3, 8, and 9 always predominated, whereas in hexane or toluene, less polar solvents, the thermodynamic adducts 4, 10, and 11 were formed as major diastereoisomers. In cyclizations catalyzed with equimolar or 2-fold excess of Lewis acid, the kinetic stereiosomers were predominant. Some Lewis acids catalyzed the reaction, but diethylaluminum chloride was the most effective. The cyclization on the perhydro-1,3-benzoxazine 13, bearing an open dienic component, was much less stereoselective, and a mixture of two exo and two endo possible stereoisomers were formed. Elimination of the menthol appendage in two steps by reductive ring opening of the N,O-acetal moiety and oxidation-elimination yielded enantiomerically pure tetrahydroisoindoline derivatives.

Full text of DOI:10.1021/jo9904462

5230
J . Org. Chem. 1999, 64, 5230-5236
Th er m a l a n d Lew is Acid Ca ta lyzed Dia ster eoselective
In tr a m olecu la r Diels-Ald er Rea ction on r,â-Un sa tu r a ted Am id es
Der ived fr om (-)-8-Am in om en th ol
Celia Andre´s, Mar´ıa Garc´ıa-Valverde, J avier Nieto, and Rafael Pedrosa*
Departamento de Quı´mica Orga´nica, Facultad de Ciencias, Universidad de Valladolid,
Dr. Mergelina s/ n, 47011 Valladolid, Spain
Received March 11, 1999
Stereochemical aspects of the intramolecular Diels-Alder reaction on perhydro-1,3-benzoxazines
derived from (-)-8-aminomenthol bearing R,â-unsaturated amides and the dienic component
attached at C-2 are described. The thermal cyclization of 2-(2′-furyl) derivatives 2, 6, and 7
exclusively afforded mixtures of exo adducts. The product selectivity was highly dependent on the
solvent of the reaction. In CH2Cl2, the kinetic products 3, 8, and 9 always predominated, whereas
in hexane or toluene, less polar solvents, the thermodynamic adducts 4, 10, and 11 were formed as
major diastereoisomers. In cyclizations catalyzed with equimolar or 2-fold excess of Lewis acid,
the kinetic stereiosomers were predominant. Some Lewis acids catalyzed the reaction, but
diethylaluminum chloride was the most effective. The cyclization on the perhydro-1,3-benzoxazine
13, bearing an open dienic component, was much less stereoselective, and a mixture of two exo and
two endo possible stereoisomers were formed. Elimination of the menthol appendage in two steps
by reductive ring opening of the N,O-acetal moiety and oxidation-elimination yielded enantio-
merically pure tetrahydroisoindoline derivatives.
In tr od u ction
Recently, we have reported8 the synthesis of enan-
tiopure epoxy tetrahydroisoindolines 5 and ent-5 by
intramolecular Diels-Alder reaction on the chiral per-
hydro-1,3-benzoxazine 2 in excellent chemical yield and
good de (Figure 1). The reaction is reversible and easily
occurs at 0 °C, leading to the kinetically controlled adduct
3 as major stereoisomer. Although the cycloaddition on
2 shows a total exo:endo selectivity, the ratio of diaste-
reoisomers depends on the nature of the solvent, chang-
ing from 71:29 (3:4) in CH2Cl2 to 22:78 in hexane.
We present now a full account on the influence in the
stereoselectivity of the substituents at the dienophile, the
catalyses by Lewis acids, and the behavior of structures
with an open dienic component.
The intramolecular Diels-Alder reaction provides a
facile and stereoselective access to hetero- and carbopoly-
cyclic structures, and consequently it has been exten-
sively studied.1 Among different dienic components,
furane derivatives have received attention in recent
years, and different methodologies to enlarge the limits
of this reaction have been recently proposed.2 In this
respect, the effects of the solvent,3 the substituent at the
furane ring4 or at the dienophile,5 and the size of the
linkage between the two components6 on the reaction
ratio have been well studied. However, the asymmetric
version of the Diels-Alder reaction using furan as
dienophile is less documented.7
Resu lts a n d Discu ssion
* Phone: Int+ 34-983-423211. Fax: Int+ 34-983-423013. E-mail:
pedrosa @qo.uva.es.
The starting chiral 2-(R-furyl)-3-acryloyl-1,3-benzox-
azine 2 was prepared by acylation of 1, in turn obtained
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Synthesis; Pergamon Press: Oxford, 1991; Vol. 5, p 513. (i) Carruthers,
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1988, 44, 4605. (e) Hirst, S. C.; Hamilton, A. D. J . Am. Chem. Soc.
1991, 113, 382. (f) Keay, B. A. J . Chem. Soc., Chem. Commun. 1987,
419. (g) Blokzijl, W.; Blandamer, M. J .; Engberts, J . B. F. N. J . Am.
Chem. Soc. 1991, 113, 4241. (h) Mukaiyama, T.; Takahashi, T.;
Iwasawa, N. Chem. Lett. 1979, 697. (i) Takebayashi, T.; Iwasawa, N.;
Mukaiyama, T. Bull. Chem. Soc. J pn. 1983, 56, 1107. (j) Feringa, B.
L.; Gelling, O. J .; Meesters, L. Tetrahedron Lett. 1990, 31, 7201. (k)
Rogers, C.; Keay, B. A. Tetrahedron Lett. 1991, 32, 6477.
(3) (a) Sternbach, D. D.; Rossana, D. M. Tetrahedron Lett. 1982, 23,
303. (b) J ung, M. E.; Gervay, J . J . Am. Chem. Soc. 1989, 111, 5469. (c)
J ung, M. E. Synlett 1990, 186.
(4) (a) J ung, M. E.; Street, L. J . J . Am. Chem. Soc. 1984, 106, 8327.
(b) Klein, L. L. J . Org. Chem. 1985, 50, 1770. (c) J ung, M. E.;
Kiankarimi, M. J . Org. Chem. 1998, 63, 2968. (d) Choony, N.;
Dadabhoy, A.; Sammes, P. G. J . Chem. Soc., Chem. Commun. 1997,
513. (e) Choony, N.; Dadabhoy, A.; Sammes, P. G. J . Chem. Soc., Perkin
Trans. 1 1998, 2017. (f) Padwa, A.; Brodney, M. A.; Dimitroff, M. J .
Org. Chem. 1998, 63, 5304.
(5) Parker, K. A.; Adamchuk, M. R. Tetrahedron Lett. 1978, 19, 1689.
(6) (a) Sternbach, D. D.; Rossana, D. M.; Onan, K. D. J . Org. Chem.
1984, 49, 3428. (b) McNelis, B. J .; Sternbach, D. D.; MacPhail, A. T.
Tetrahedron 1994, 50, 6767. (c) Sternbach, D. D.; Rossana, D. M.;
Onan, K. D. Tetrahedron Lett. 1985, 26, 591. (d) J ung, M. E.; Gervay,
J . Tetrahedron Lett. 1988, 29, 2429. (e) Rogers, C.; Keay, B. A.
Tetrahedron Lett. 1989, 30, 1349. (f) Cauwberghs, S.; De Clercq, P. J .;
Tinant, B.; DeClercq, J . P. Tetrahedron Lett. 1988, 29, 2493. (g) J ung,
M. E.; Gervay, J . J . Am. Chem. Soc. 1991, 113, 224.
(7) (a) Mukaiyama, T.; Iwasawa, N. Chem. Lett. 1981, 29. (b) J ung,
M. E.; Street, L. J . Heterocycles 1988, 27, 45. (c) Kanematsu, K.;
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Prajapati, D.; Borthakur, D. R.; Sandhu, J . S. J . Chem. Soc., Perkin
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Asymmetry 1995, 6, 377.
(8) Andre´s, C.; Maestro, G.; Nieto, J .; Pedrosa, R.; Garc´ıa-Granda,
S.; Pe´rez-Carren˜o, E. Tetrahedron Lett. 1997, 38, 1463.
10.1021/jo9904462 CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/11/1999

Diels-Alder Reaction on R,â-Unsaturated Amides
J . Org. Chem., Vol. 64, No. 14, 1999 5231
derived from these data is that, as previously reported,9
the reaction occurs at lower temperature than for the
uncatalyzed reaction, although the starting product was
recovered unchanged after stirring for a long period of
time at -23 °C in the presence of titanium tetrachloride
or at -78 °C with diethylaluminum chloride.
The use of Lewis acids of moderate acidity, such as zinc
or titanium derivatives, did not affect the stereoselectivity
of the cycloaddition when methylene chloride was used
as solvent (compare entry 1 versus entries 2-4 in Table
1). Nevertheless, the presence of boron trifluoride ether-
ate, diethylaluminum chloride, or aluminum trichloride,
stronger Lewis acids,10 greatly increased the diastereo-
facial discrimination. The improvement of the diastereo-
meric ratios were noted even when a substoichiometric
quantity of acid was employed (compare entries 6 and 7
versus entry 1), but the best results were obtained by
addition of 2-fold excess of diethylaluminum chloride
(entry 9).
The reaction temperature also influences the reaction.
At room temperature, the reaction was much faster than
at -23 °C, but the facial discrimination diminished
(compare entries 9 versus 10).
The effect of the Lewis acid has been shown to be much
more critical when hexane is used as the reaction solvent.
First of all, the presence of diethylaluminum chloride
allowed the reaction to proceed at -23 °C, whereas in
the absence of the catalyst, the cyclization occurred only
at room temperature. In addition, the ratio of diastereo-
isomers 3:4 was changed in favor of the kinetic isomer 3
with the amount of Lewis acid, moving from 22:78 (3:4)
in the absence of catalyst to 80:20 when the reaction was
carried out in the presence of equimolar or 2-fold excess
of the aluminum derivative (entries 13-17 in Table 1).
The same trends were observed when the solvent was
toluene (entries 18-20).
The cyclization of R- and â-substituted acrylamides was
studied in compounds 6 and 7 (Scheme 1). Methacryl-
amide 6 was prepared by reaction of 1 with methacryloyl
chloride and TMEDA in methylene chloride at 0 °C,
whereas 7 was obtained by stirring a mixture of 1,
crotonyl chloride, and pyridine in CH2Cl2 at 0 °C. It is
noteworthy that although crotonylamide 7 can be isolated
and characterized, it was not possible to isolate 6 because
it cyclized up to 0 °C, and its formation can only be
followed by TLC.
F igu r e 1.
Ta ble 1. Diels-Ald er Rea ction s of 2 in Differ en t
Con d ition s
Lewis acid
(equiv)
temp time yield
(°C)
products
(dr)b
entry solvent
(h) (%)a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
CH2Cl2 none
20
20
0
15
15
120
5
96 3 (69) 4 (31)
86 3 (68) 4 (32)
96 3 (63) 4 (37)
31 3 (71) 4 (29)
57 3 (78) 4 (22)
94 3 (78) 4 (22)
92 3 (79) 4 (21)
93 3 (81) 4 (19)
96 3 (85) 4 (15)
90 3 (77) 4 (23)
91 3 (77) 4 (23)
96 3 (76) 4 (24)
96 3 (22) 4 (78)
92 3 (40) 4 (60)
94 3 (60) 4 (40)
88 3 (80) 4 (20)
96 3 (80) 4 (20)
90 3 (38) 4 (62)
93 3 (45) 4 (55)
95 3 (68) 4 (32)
CH2Cl2 ZnCl2 (1.1)
CH2Cl2 Ti (OiPr)4 (1.1)
CH2Cl2 TiCl4 (0.5)
CH2Cl2 BF3OEt2 (2.0)
CH2Cl2 Et2AlCl (0.2)
CH2Cl2 Et2AlCl (0.5)
CH2Cl2 Et2AlCl (1.0)
CH2Cl2 Et2AlCl (2.0)
CH2Cl2 Et2AlCl (2.0)
CH2Cl2 AlCl3 (2.0)
CH2Cl2 Me3Al (2.0)
hexane none
hexane Et2AlCl (0.2)
hexane Et2AlCl (0.5)
hexane Et2AlCl (1.0)
hexane Et2AlCl (2.0)
toluene none
0
-23 520
-23 310
-23 310
-23 265
-23 215
20
6
-23 385
-23 430
20
15
-23 430
-23 430
-23 430
-23 430
20
14
toluene Et2AlCl (0.2)
toluene Et2AlCl (2.0)
-23 385
-23 335
Cyclization of methacryloyl amide 6 was much slower
than that of the acryloyl derivative 2 (compare entries 1
and 2 in Table 2 versus entries 9 and 13 in Table 1). In
hexane as solvent, compound 2 was completely cyclized
after 15 h at room temperature, but it was necessary to
stir for 130 h to get the total cyclization of 6. In these
conditions, the reaction showed a very low degree of
stereoselection as an almost equimolar mixture of dia-
stereoisomers 8 and 10 was obtained. By contrast, in the
catalyzed cycloaddition, a good level of stereoselection
was maintained. The behavior of crotonyl amide 7 was
similar to that observed for 6. As expected, it reacted
slower than 4, but the stereochemical results were very
coincident with those obtained for the acrylamide deriva-
tive (compare entries 3-5 in Table 2 versus 13, 18, and
9 in Table 1).
a
Yields refer to pure compounds after column chromatography.
b
Diastereomeric ratios were determined by integration of the
signals in the 1H NMR spectra in the reaction mixtures.
by condensation of (-)-8-aminomenthol with furfural.
The acylation was carried out with acryloyl chloride at 0
°C, in the presence of triethylamine, using methylene
chloride as solvent. In these conditions, compound 2 was
not isolated because it immediately cyclized to a mixture
of exo diastereoisomers 3 and 4 (71:29, 88%). In contrast,
when the reaction was carried out in hexane, the stereo-
selection was reversed and the diastereisomers 3 and 4
were obtained in a 22:78 ratio (98% total yield) (entries
1 and 13 in Table 1).
Because our first concern was to control and improve
the stereoselectivity of the cyclization process, we initi-
ated a study on the influence of some Lewis acids of
different hardness in the cycloaddition of 2; the results
are collected in Table 1. The first general conclusion
(9) (a) Rogers, C.; Keay, B. A. Synlett 1991, 353. (b) Hunt, I. R.;
Rauk, A.; Keay, B. A. J . Org. Chem. 1996, 61, 751.
(10) Pindur, U.; Lutz, G.; Otto, C. Chem. Rev. 1993, 93, 741.

5232 J . Org. Chem., Vol. 64, No. 14, 1999
Andre´s et al.
Sch em e 1
respect, it is noteworthy that the resonance of this proton
in the major isomers 3, 8, and 9 appears downfield (ca.
0.2 ppm) from that for the minor components 4, 10, and
11, respectively.
COSY and NOESY experiments allowed the assign-
ment of the configuration for the major all-trans exo-14
as 3R,4aR,11bR and for the minor all-cis endo-17
(3S,4aR,11bS) isomers obtained from the cyclization of
13.
The transformation of the adducts 3, 4, 8-11, and 14-
17 into the final tetrahydroisoindoline derivatives was
performed in two steps. Treatment of adducts with
aluminum hydride11 in THF at -10 °C for 10 min led to
amino alcohols 18-27 in good to excellent yields (Scheme
3), in a process that implies the reductive ring opening
of the N,O-acetal moiety and the reduction of the amide
group. The elimination of the menthol appendage was
carried out by oxidation12 with PCC of the amino alcohols
to the aminomenthone derivatives, followed by elimina-
tion with a 2.5 M solution of KOH in THF/MeOH/ H2O
(2/1/1).13 This protocol allowed the isolation of the final
enantiopure tetrahydroisoindoline derivatives 5 and 28-
31 in good yields and (+)-pulegone, which is the starting
compound to prepare the (-)-8-aminomenthol14 used as
chiral adjuvant.
The structure of the final product led us to assign the
stereochemistry for adducts 4, 10, 11, 15, and 17. In fact,
spectral, analytical, and optical rotation data showed that
the epoxy terahydroisoindolines obtained from 3, 8, and
9 are enantiomers to those obtained from 4, 10, and 11,
and consequently the configuration of the newly formed
stereocenters in these compounds were 3R,4aS,11bR for
4, 3R,4aS,11bR for 10, and 3S,4S,4aS,11bR for 11. In
the same way, the enantiomeric relationship between the
tetrahydroisoindolines resulting from 14 and 17 and
those obtained from 15 and 16 respectively, made it
possible to establish the configurations of 3S,4aS,11bS
for 15 and 3R,4aS,11bR for 16.
It is also noticeable that cycloaddition of furane deriva-
tives is reversible. We have found that the major dia-
stereoisomers 3, 8, and 9, formed in the reaction in
CH2Cl2 or in any solvent in the presence of Lewis acid,
were the kinetically controlled products. After isolation,
they were transformed by refluxing in Decalin for 24 h
into the same mixture with 4, 10, and 11, obtained as
major components in the reaction carried out in hexane
under thermodynamic control. This fact had also been
observed for some related structures.15
The regiospecific formation of exo adducts for the
furane derivatives16 is a consequence of the constraints
imposed by the connecting bridge of the reacting func-
tions and the fact that the exo orientation is energetically
more favorable than endo in these substrates.9b In
contrast, the formation of both exo and endo regioisomers
The cycloaddition of perhydro-1,3-benzoxazines bearing
an open dienic component was studied on compound 13,
prepared as outlined in Scheme 2. Condensation of (-)-
8-aminomenthol with E,E-2,4-heptadienal, in benzene at
room temperature, give the N-unsubstituted perhydro-
1,3-benzoxazine 12 in 90% yield. Treatment of 12 with
acryloyl chloride and TMDA at room temperature yielded
13, which could not be isolated because it immediately
cyclized to a mixture of the four possible diastereomers
14-17 (Scheme 2).
Table 3 summarizes the results obtained in the cy-
clization of 13 depending on the experimental conditions.
It is worthy to note that in this case, both exo and endo
adducts were formed and that the regioselectivity was
poor and unaffected by the experimental conditions. The
ratio of exo/ endo regioisomers remained practically
constant (53-54/47-46) for all of the reactions tested.
In addition, the facial discrimination for the endo path-
way was moderate, and the experimental conditions had
little effect on the stereoselectivity for this cyclization
mode. By contrast, the exo cyclization pathway was
profoundly affected by the reaction conditions. In hexane
at room temperature or toluene at reflux (entries 2 and
3 in Table 3), 13 cyclized to a mixture of trans-exo adducts
14 and 15 with very low stereocontrol, whereas in
methylene chloride at -23 °C, in the presence of diethyl
aluminum chloride, the all-trans exo adduct 14 was
formed with good control of facial discrimination.
Diastereoisomers formed in each reaction were sepa-
rated by flash chromatography, and their stereochemistry
was determined at this stage. Thus, the absolute stereo-
chemistry for 3 was established by X-ray crystallography8
as 3S,4aR,11bS for the newly created stereocenters in
the epoxy tetrahydroisoindolone system. The assignation
of the contrary configuration at these stereocenters for
the minor diastereosiomer 4 was made by chemical
correlation (vide infra). The stereochemistry for the major
diastereoisomers 8 (3S,4aR,11bS) and 9 (3R,4R,4aR,11bS)
resulting from the cyclization of 6 and 7 respectively was
assigned on the basis of the chemical shift for the hy-
drogen attached to the N,O-acetalic carbon atom. In this
(11) Burgess, L. E.; Meyers, A. I. J . Org. Chem. 1992, 57, 1656.
(12) J ohnson, W. S.; Edington, C.; Elliot, J . D.; Silverman, I. R. J .
Am. Chem. Soc. 1984, 106, 7588.
(13) Choi, V. M.; Elliot, J . D.; J ohnson, W. S. J . Org. Chem. 1983,
48, 2294.
(14) Eliel, E.; He, X. C. J . Org. Chem. 1990, 55, 2114.
(15) (a) Van Royen, L. A.; Mijngheer, R.; de Clercq, P. J . Tetrahedron
Lett. 1982, 23, 3283. (b) Woo, S.; Keay, B. A. Tetrahedron: Asymmetry
1994, 5, 1411. See also ref 7c.
(16) (a) Rogers, C.; Keay, B. A. Can. J . Chem. 1992, 70, 2929. (b)
Zhao, Y.; Pratt, N. E.; Heeg, H. J .; Albizati, K. F. J . Org. Chem. 1993,
58, 1300. (c) Hudlicky, T.; Butora, G.; Fearnley, S. P.; Gum, A. G.;
Persichini, P. J ., III; Stabile, M. R.; Merola, J . S. J . Chem. Soc., Perkin
Trans. 1 1995, 2393. See also refs 1b, 4e, 2k, 7e, 7f, and 9a.

Diels-Alder Reaction on R,â-Unsaturated Amides
J . Org. Chem., Vol. 64, No. 14, 1999 5233
Ta ble 2. Diels-Ald er Rea ction s of 6 a n d 7 in Differ en t Con d ition s
entry
amide
solvent
Lewis acid (equiv)
temp (°C)
time (h)
yield (%)a
products (dr)b
1
2
3
4
5
6
6
7
7
7
hexane
CH2Cl2
hexane
toluene
CH2Cl2
none
Et2AlCl (2.0)
none
none
Et2AlCl (2.0)
20
-23
20
110
-23
130
430
350
6
89
92
82
80
83
8 (45) 10 (55)
8 (81) 10 (19)
9 (24) 11 (76)
9 (40) 11 (60)
9 (81) 11 (19)
530
a
b
Yields refer to pure compounds after column chromatography. Diastereomeric ratios were determined by integration of the signals
in the 1H NMR spectra in the reaction mixtures.
Sch em e 2
In summary, this study of an intramolecular Diels-
Alder reaction on chiral perhydro-1,3-benzoxazines has
demonstrated that the reaction of furane derivatives
occurs regiospecifically and with good diastereoselection
that is improved by using Et2AlCl as the Lewis acid
catalyst. On the contrary, a mixture of exo and endo
regioisomers is obtained when an open diene derivative
13 is used in the cycloaddition. More important, the
results show that both exo diastereoisomers can be
prepared from a common starting compound by simply
changing the solvent of the reaction. The thermodynami-
cally controlled process allows further improvement of
the de. Finally, the adducts are easily transformed into
enantiopure tetrahydroisoindoline derivatives in good
yield by removal of the menthol adjuvant in a two-step
process.
Exp er im en ta l Section
The reactions were carried out in anhydrous solvents, under
an argon atmosphere, and in oven-dried glassware. Melting
points were determined in capillary tubes and are uncorrected.
The 1H NMR (300 MHz) and 13C DEPT-NMR (75 MHz) spectra
were registered using CDCl3 as solvent and TMS as internal
standard. Mass spectra were recorded by electronic impact or
chemical ionization. IR spectra were registered as film or in
Nujol dispersion. Optical rotations were measured in a 1 dm
cell, and concentrations are given in g/100 mL. Products were
isolated by flash chromatography using 240-400 mesh silica
gel.
Syn th esis of Octa h yd r o-1,3-ben zoxa zin es 1 a n d 12. A
mixture of (-)-8-aminomenthol (5 g, 29.24 mmol), 4 Å molec-
ular sieves (2 g), and furfural (3.09 g, 32.16 mmol) or E,E-2,4-
heptadienal (3.54 g, 32.16 mmol) in benzene (50 mL) was
stirred at room temperature until the reaction was completed
(TLC, 30-40 h). The mixture was filtered through a pad of
Celite, the solvent was eliminated from the filtrate under
vacuum, and the residue was recrystallized from pentane for
1 or purified by flash chromatography on silica gel deactivated
with triethylamine with hexane/EtOAc 8/1 as eluent for 12.
2R-(2′-F u r yl)-4,4,7R-tr im eth yl-tr a n s-octa h yd r o-1,3-ben -
zoxa zin e (1). Yield 96%. Colorless solid, mp 32-34 °C (from
pentane). [R]25D ) +20.4 (c ) 1.0, CH2Cl2). 1H NMR (δ): 0.91-
1.04 (m, 2H); 0.93 (d, 3H, J ) 6.5 Hz); 1.08-1.13 (m, 2H); 1.15
(s, 3H); 1.17 (s, 3H); 1.49 (m, 1H); 1.69-1.71 (m, 2H); 1.98 (m,
in the cyclization of 13 is supported by the fact that the
endo transition state lies about 1.4 Kcal./mol below exo
for open dienic components.17
The transition state A leading to exo-3, 8, and 9 has a
neat dipole moment about the amide bond higher than
B, responsible for the formation of 4, 10, and 11 (Scheme
4). In these conditions, the formation of 3, 8, and 9 will
be favored in solvents with high dielectric constants
(CH2Cl2), and 4, 10, and 11 will be formed as major
diastereoisomers in nonpolar solvents.18 This fact is also
supported by the results obtained from Lewis acid
catalyzed reactions. The coordination of the Lewis acid
to the oxygen of the amide group and to the heteroatoms
of the system favors the displacement of the equilibrium
toward A even if nonpolar solvents are used, although
in our case, at least 1.1 equiv of Lewis acid was necessary
to improve the de.19
1H); 2.10-2.70 (broad s, 1H); 3.59 (dt, 1H, J 1 ) 4.2 Hz, J 2
10.4 Hz); 5.43 (s, 1H); 6.31-6.34 (m, 2H); 7.36 (dd, 1H, J 1
)
)
0.9 Hz, J 2 ) 1.6 Hz). 13C NMR (δ): 19.2; 22.1; 25.3; 29.6; 31.2;
34.7; 41.3; 51.2; 51.4; 75.2; 78.2; 106.3; 109.9; 141.8; 152.6. IR
(Nujol): 1670, 1200, 1040 cm-1. MS (m/z, %): 249 (M+, 8); 138
(11); 97 (49); 96 (100). Anal. Calcd for C15H23NO2: C, 72.25;
H, 9.30; N, 5.62. Found: C, 72.41; H, 9.12; N, 5.78.
2R-(E,E-2′,4′-H ep t a d ien yl)-4,4,7R-t r im et h yl-tr a n s-oc-
ta h yd r o-1,3-ben zoxa zin e (12). Yield 90%. Colorless oil. [R]25
D
1
) +18.37 (c ) 1.2, CH2Cl2). H NMR (δ): 0.90-1.10 (m, 4H);
0.92 (d, 3H, J ) 6.6 Hz); 0.97 (t, 3H, J ) 7.4 Hz); 1.09 (s, 3H);
1.10 (s, 3H); 1.46-1.74 (m, 4H); 1.94 (m, 1H); 2.08 (m, 2H);
3.47 (dt, 1H, J 1 ) 4.1 Hz, J 2 ) 10.2 Hz); 4.83 (d, 1H, J ) 4.9
Hz); 5.53 (dd, 1H, J 1 ) 4.9 Hz, J 2 ) 15.4 Hz); 5.75 (dt, 1H, J 1
) 6.8 Hz, J 2 ) 16.1 Hz); 5.99 (dd, 1H, J 1 )10.4 Hz, J 2 ) 15.1
Hz); 6.33 (dd, 1H, J 1 ) 10.4 Hz, J 2) 15.4 Hz). 13C NMR (δ):
(17) Gschwend, H. W.; Meier, H. P. Angew. Chem., Int. Ed. Engl.
1972, 11, 294.
(18) Cativiela, C.; Garc´ıa, J . I.; Mayoral, J . A.; Salvatella, L. Chem.
Soc. Rev. 1996, 25, 209 and references therein. See also ref 3b.
(19) Hunt, I. R.; Rogers, C.; Woo, S.; Rauk, A.; Keay, B. A. J . Am.
Chem. Soc. 1995, 117, 1049. See also ref 9.

5234 J . Org. Chem., Vol. 64, No. 14, 1999
Ta ble 3. Diels-Ald er Rea ction s of 13 in Differ en t Con d ition s
Andre´s et al.
products (dr)b
entry
solvent
Lewis acid (equiv)
temp (°C)
time (h)
yield (%)a
14
15
16
17
1
2
3
CH2Cl2
hexane
toluene
Et2AlCl (2.0)
none
none
-23
20
110
480
96
35
90
96
83
(45)
(29)
(32)
(9)
(24)
(22)
(35)
(39)
(34)
(11)
(8)
(12)
a
b
Yields refer to pure compounds after column chromatography. Diastereomeric ratios were determined by integration of the signals
in the 1H NMR spectra in the reaction mixtures.
appropriate anhydrous solvent (20 mL) at 0 °C was slowly
added acryloyl chloride (0.36 mL, 4.42 mmol). The stirring was
continued until the reaction was finished (TLC, 15-30 min).
Attempts to isolate 2 were not successful because the cycliza-
tion occurs at temperatures above 0 °C. This fact was also
observed in the formation of 6 from 1 (1 g, 4 mmol), meth-
acryloyl chloride (0.45 mL, 4.62 mmol), and TMDA (0.75 mL,
4.83 mmol) or 13 from 12 (1.05 g, 4 mmol), acryloyl chloride
(0.36 mL, 4.42 mmol), and TMDA (0.70 mL, 4.62 mmol).
The preparation of 7 was carried out by slow addition of
crotonyl chloride (0.42 mL, 4.42 mmol) to a mixture of 1 (1 g,
4.02 mmol) and pyridine (0.37 mL, 4.62 mmol) in dry CH2Cl2
(20 mL) at 0 °C. The mixture was allowed to reach room
temperature and was stirred for an additional 30 min. The
Sch em e 3
solvent was evaporated on
a rotary evaporator at room
temperature, and the residue was chromatographed on silica
gel with hexane/EtOAc 8/1 as eluent. In this way, 7 was
isolated after elimination of the eluent by rotary evaporator
at room temperature.
N-Cr oton yl-2R-(2-fu r yl)-4,4,7R-tr im eth yl-tr a n s-octa h y-
d r o-1,3-ben zoxa zin e (7). Yield 85%. Colorless oil. [R]25
)
D
-21.23 (c ) 3.0, hexane). 1H NMR (δ): 0.64-0.78 (m, 1H);
0.88-1.21 (m, 2H); 0.89 (d, 3H, J ) 6.6 Hz); 1.34-1.51 (m,
2H); 1.55 (s, 3H); 1.58 (s, 3H); 1.58-1.76 (m, 2H); 1.79 (dd,
3H, J 1 ) 1.7 Hz, J 2 ) 6.9 Hz); 2.04 (m, 1H); 3.75 (dt, 1H, J 1
)
4.0 Hz, J 2 ) 10.4 Hz); 6.00 (dq, 1H, J 1 ) 1.7 Hz, J 2 ) 14.9
Hz); 6.26 (s, 1H); 6.31 (dd, 1H, J 1 ) 0.8 Hz, J 2 ) 3.1 Hz); 6.41
(dd, 1H, J 1 ) 1.7 Hz, J 2 ) 3.1 Hz); 6.80 (dq, 1H, J 1 ) 6.9 Hz,
J 2 ) 14.9 Hz); 7.44 (dd, 1H, J 1 ) 0.8 Hz, J 2 ) 1.7 Hz).13C NMR
(δ): 18.2; 19.1; 21.9; 23.9; 25.2; 31.4; 34.3; 42.6; 45.6; 57.9; 73.5;
77.8; 107.7; 110.8; 124.7; 141.0; 142.2; 154.9; 167.1. IR (film):
1650, 1620 cm-1. Anal. Calcd for C19H27NO3: C, 71.89; H, 8.57;
N, 4.41. Found: C, 72.06; H, 8.71; N, 4.27.
Gen er a l P r oced u r e for Diels-Ald er Rea ction s. (a )
Un ca ta lyzed Rea ction s. Once the formation of the amides
was observed (TLC), the reaction mixture was stirred in the
appropriate solvent for the time and temperature given in
Tables 1-3. The formation of cycloadducts was followed by
TLC, and after the end of the reaction, the mixture was
quenched by addition of H2O. The organic phase was decanted,
and the aqueous layer was extracted with CH2Cl2. The
combined organic fractions were dried (MgSO4) and filtered,
and the solvent was eliminated under reduced pressure to yield
a yellow oil. The components were isolated by flash chroma-
tography as described below.
(b) Lew is Acid s Ca ta lyzed Rea ction s. After formation
of the amide in the appropriate solvent, the solution was cooled
to the temperature given in Tables 1-3, and the required
amount of Lewis acid was added. The mixture was stirred for
the period of time summarized in Tables 1-3, and the
evolution of the reaction was followed by TLC. Once finished,
the reaction was quenched by addition of NH4Cl solution, the
organic phase was decanted, and the aqueous layer was
extracted with CH2Cl2. The organics were dried (MgSO4) and
filtered, and the solvent was eliminated under reduced pres-
sure. Pure compounds were isolated by flash chromatography
as described below.
Sch em e 4
Adducts 3 and 4 were obtained from 2 and isolated by flash
chromatography on silica gel deactivated with triethylamine,
using hexane/EtOAc 3/1 as eluent.
(3S,4a R,6a S,9R,10a R,11a S,11b S)-5-Oxo-3,11b -ep oxy-
6,6,9-t r im et h yl-3,4,4a ,11b -t et r a h yd r oisoin d olyl-[2,3-a ]-
p er h yd r o-11,5a -ben zoxa zin e (3). Colorless solid, mp 236-
238 °C (from EtOH). [R]25D ) -39.69 (c ) 1.0, CH2Cl2).1H NMR
13.5; 19.6; 22.3; 25.5; 25.7; 29.9; 31.4; 35.0; 41.6; 51.3; 51.5;
74.8; 81.9; 128.4; 129.0; 132.2; 137.7. IR (neat): 3280, 1200,
1050 cm-1. Anal. Calcd for C17H29NO: C, 77.51; H, 11.10; N,
5.32. Found: C, 77.38; H, 11.21; N, 5.17.
P r ep a r a tion of Am id e Der iva tives. To a mixture of 1 (1
g, 4 mmol) and triethylamine (0.64 mL, 4.62 mmol) in the

Diels-Alder Reaction on R,â-Unsaturated Amides
J . Org. Chem., Vol. 64, No. 14, 1999 5235
Hz); 2.05-2.10 (m, 2H); 2.18-2.31 (m, 2H); 3.39 (dt, 1H, J 1
4.3 Hz, J 2 ) 10.6 Hz); 4.53 (d, 1H, J ) 8.3 Hz); 5.66 (dt, 1H,
J 1 ) 3.0 Hz, J 2 ) 9.8 Hz); 5.96 (dt, 1H, J 1 ) 1.0 Hz, J 2 ) 9.8
Hz). 13C NMR (δ): 12.2; 18.5; 22.0; 23.8; 25.9; 26.1; 28.7; 31.2;
34.4; 37.2; 41.0; 41.4; 44.6; 49.4; 56.7; 75.8; 86.6; 123.7; 134.6;
173.9. IR (Nujol): 1690, 1050 cm-1. MS (m/z, %): 317 (M+,
24); 182 (100); 81 (47). Anal. Calcd for C20H31NO2: C, 75.67;
H, 9.84; N, 4.41. Found: C, 75.82; H, 9.71; N, 4.57.
(δ): 0.88-1.13 (m, 2H,); 0.94 (d, 3H, J ) 6.5 Hz); 1.13-1.25
)
(m, 1H); 1.25 (s, 3H); 1.38-1.53 (m, 2H); 1.57 (dd, 1H, J 1
)
8.3 Hz, J 2 ) 11.4 Hz); 1.69-1.74 (m, 2H); 1.76 (s, 3H); 2.05
(m, 1H); 2.19-2.29 (m, 2H); 3.54 (dt, 1H, J 1 ) 4.3 Hz, J 2
)
10.6 Hz); 5.12 (dd, 1H, J 1 ) 1.6 Hz, J 2 ) 4.1 Hz); 5.46 (s, 1H);
6.40 (dd, 1H, J 1 ) 1.6 Hz, J 2 ) 5.8 Hz); 6.46 (d, 1H, J ) 5.8
Hz). 13C NMR (δ): 18.8; 22.0; 24.0; 25.5; 28.3; 31.2; 34.3; 40.7;
47.8; 49.0; 57.3; 76.8; 79.5; 82.8; 88.3; 132.1; 137.3; 172.6. IR
(Nujol): 1680, 1330 cm-1. MS (m/z, %): 303 (M+, 6); 288 (41);
112 (44); 55 (100). Anal. Calcd for C18H25NO3: C, 71.26; H,
8.31; N, 4.62. Found: C, 71.43; H, 8.16; N, 4.79.
(3S,4aS,6aS,9R,10aR,11aS,11bS)-3-Eth yl-6,6,9-tr im eth yl-
5-oxo-3,4,4a ,11b -t et r a h yd r oisoin d olyl-[2,3-a ]-p er h yd r o-
11,5a -ben zoxa zin e (15). Colorless solid, mp 60-62 °C (from
(3S,4a S,6a S,9R,10a R,11a S,11b R)-5-Oxo-3,11b -ep oxy-
6,6,9-t r im et h yl-3,4,4a ,11b -t et r a h yd r oisoin d olyl-[2,3-a ]-
p er h yd r o-11,5a -ben zoxa zin e (4). Colorless solid, mp 97-
98 °C (from hexane). [R]25D ) -45.09 (c ) 1.0, CH2Cl2). 1H NMR
(δ): 0.91-1.06 (m, 2H); 0.96 (d, 3H, J ) 6.5 Hz); 1.06-1.18
pentane). [R]25 ) -119.11 (c ) 1.1, CH2Cl2). 1H NMR (δ):
D
0.88-0.98 (m, 2H); 0.92 (d, 3H, J ) 6.6 Hz); 0.95 (t, 3H, J )
7.4 Hz); 0.98-1.17 (m, 1H); 1.24 (s, 3H); 1.26-1.57 (m, 4H);
1.59-1.74 (m, 3H); 1.71 (s, 3H); 1.90-2.07 (m, 2H); 2.19 (m,
1H); 2.33 (m, 1H); 2.49 (dt, 1H, J 1 ) 3.0 Hz, J 2 ) 12.7 Hz);
3.52 (dt, 1H, J 1 ) 4.0 Hz, J 2 ) 10.6 Hz); 5.09 (d, 1H, J ) 4.9
(m, 1H); 1.26 (s, 3H); 1.39-1.69 (m, 2H); 1.53 (dd, 1H, J 1
)
8.8 Hz, J 2 ) 11.7 Hz); 1.69-1.83 (m, 2H); 1.73 (s, 3H); 2.03
(m, 1H); 2.12 (ddd, 1H, J 1 ) 3.7 Hz, J 2 ) 4.4 Hz, J 3 ) 11.7
Hz); 2.55 (dd, 1H, J 1 ) 3.7 Hz, J 2 ) 8.8 Hz); 3.63 (dt, 1H, J 1
) 4.0 Hz, J 2 ) 10.6 Hz); 5.07 (dd, 1H, J 1 ) 1.6 Hz, J 2 ) 4.4
Hz); 5.19 (s, 1H); 6.34 (dd, 1H, J 1 ) 1.6 Hz, J 2 ) 5.8 Hz); 6.57
(d, 1H, J ) 5.8 Hz). 13C NMR (δ): 20.6; 22.0; 24.5; 25.3; 27.8;
31.3; 34.5; 41.1; 47.4; 51.5; 57.8; 77.3; 79.8; 84.4; 89.1; 132.6;
135.9; 173.5. IR (Nujol): 1670, 1040 cm-1. MS (m/z, %): 303
Hz); 5.66 (dt, 1H, J 1 ) 3.0 Hz, J 2 ) 9.8 Hz); 5.89 (dt, 1H, J 1 )
2.0 Hz, J 2 ) 9.8 Hz). 13C NMR (δ): 12.3; 21.6; 22.0; 24.6; 25.7;
26.4; 28.8; 31.3; 34.5; 37.4; 41.2; 41.2; 41.6; 51.4; 57.9; 76.4;
84.2; 123.6; 134.7; 176.2. IR (Nujol): 1705, 1330, 1220 cm-1
.
MS (m/z, %): 317 (M+, 6), 205 (31), 81 (41), 58 (100). Anal.
Calcd for C20H31NO2: C, 75.67; H, 9.84; N, 4.41. Found: C,
75.56; H, 9.98; N, 4.29.
Syn th esis of Am in o Alcoh ols 18-27. Gen er a l Meth od .
To a suspension of LiAlH4 (0.6 g, 15.8 mmol) in anhydrous
THF (40 mL) cooled to -10 °C was added, in portions, dry
AlCl3 (0.7 g, 5.25 mmol). The mixture was stirred for an
additional 10 min, and a solution of the corresponding adduct
(3.17 mmol) in dry THF was slowly added. The reaction
mixture was stirred for 5 min at -10 °C and quenched by
addition of H2O. The resulting mixture was filtered, the solid
was washed with EtOAc, and the organic layer was dried
(MgSO4). The solvents were eliminated under reduced pres-
sure, and the residue was chromatographed on silica gel using
hexane/EtOAc 3/1 as eluent.
(M+, 8); 191 (49); 136 (53); 112 (100). Anal. Calcd for C18H25
NO3: C, 71.26; H, 8.31; N, 4.62. Found: C, 71.12; H, 8.14; N,
4.76.
Adducts 8 and 10 were obtained from 6 and isolated by flash
chromatography on silica gel deactivated with triethylamine,
using hexane/EtOAc 5/1 as eluent.
-
(3S,4a R,6a S,9R,10a R,11a S,11b S)-5-Oxo-3,11b -ep oxy-
4a ,6,6,9-tetr a m eth yl-3,4,4a ,11b-tetr a h yd r oisoin d olyl-[2,3-
a ]-p er h yd r o-11,5a -ben zoxa zin e (8). Colorless solid, mp
239-240 °C (from hexane/EtOAc). [R]25 ) -59.20 (c ) 1.0,
D
CH2Cl2). 1H NMR (δ): 0.92-1.09 (m, 2H); 0.94 (d, 3H, J ) 6.5
Hz); 0.97 (s, 3H); 1.07 (d, 1H, J ) 11.8 Hz); 1.17-1.25 (m, 1H);
1.23 (s, 3H); 1.43-1.60 (m, 2H); 1.70-2.00 (m, 2H); 1.77 (s,
3H); 2.05 (m, 1H); 2.48 (dd, 1H, J 1 ) 4.7 Hz, J 2 ) 11.8 Hz);
3.53 (dt, 1H, J 1) 4.3 Hz, J 2 ) 10.6 Hz); 5.03 (dd, 1H, J 1 )1.3
Hz, J 2 ) 4.7 Hz); 5.36 (s, 1H); 6.43-6.49 (m, 2H).13C NMR
(δ): 18.5; 20.4; 21.9; 23.9; 25.5; 31.1; 34.3; 36.3; 40.7; 49.0; 52.4;
56.9; 76.8; 79.3; 82.2; 90.2; 130.3; 137.6; 176.3. IR (Nujol):
1660, 960 cm-1. MS (m/z, %): 317 (M+, 36); 302 (79); 182 (38);
126 (55); 81 (51); 69 (100); 41 (72). Anal. Calcd for C19H27NO3:
C, 71.89; H, 8.57; N, 4.41. Found: C, 72.01; H, 8.69; N, 4.29.
Adducts 9 and 11 were obtained from 7 and isolated by flash
chromatography on silica gel deactivated with triethylamine,
using hexane/EtOAc 3/1 as eluent.
N-(8-Men th olyl)-(3a S,6S,7a S)-3a ,6-ep oxy-3a ,6,7,7a -tet-
r a h yd r oisoin d olin e (18). Colorless solid, mp 109-111 °C
1
(from hexane). [R]25 ) +4.12 (c ) 1.0, CH2Cl2). H NMR (δ):
D
0.88-1.11 (m, 3H); 0.92 (d, 3H, J ) 6.5 Hz); 0.97 (s, 3H); 1.19
(s, 3H); 1.30-1.51 (m, 3H); 1.56-1.72 (m, 3H); 1.84-1.96 (m,
2H); 2.34 (m,1H); 3.02 (d, 1H, J ) 12.2 Hz); 3.19 (t, 1H, J )
7.6 Hz); 3.62 (m, 1H); 3.66 (dt, 1H, J 1 ) 4.1 Hz, J 2 ) 10.3 Hz);
4.98 (dd, 1H, J 1 ) 1.6 Hz, J 2 ) 4.4 Hz); 6.30 (dd, 1H, J 1 ) 1.6
Hz, J 2 ) 5.8 Hz); 6.39 (d, 1H, J ) 5.8 Hz); 8.75 (broad s, 1H).
13C NMR (δ): 17.1; 21.8; 22.1; 25.5; 29.5; 31.0; 35.0; 42.1; 44.1;
47.2; 48.6; 51.1; 59.4; 73.0; 79.8; 95.1; 135.6; 136.1. IR (Nujol):
3100, 1170, 1080 cm-1. CIMS (m/z, %): 292 (M+ + 1, 100);
178 (41); 138 (41). Anal. Calcd for C18H29NO2: C, 74.18; H,
10.03; N, 4.81. Found: C, 74.36; H, 10.19; N, 4.65.
(3R,4R,4aR,6aS,9R,10aR,11aS,11bS)-5-Oxo-3,11b-epoxy-
4,6,6,9-tetr a m eth yl-3,4,4a ,11b-tetr a h yd r oisoin d olyl-[2,3-
a ]-p er h yd r o-11,5a -ben zoxa zin e (9). Colorless solid, mp
N-(8-Men t h olyl)-(3a S,6S,7a S)-3a ,6-ep oxy-7a -m et h yl-
3a ,6,7,7a -tetr a h yd r oisoin d olin e (19). Yield 80%. Colorless
187-188 °C (from hexane). [R]25 ) -4.08 (c ) 1.0, CH2Cl2).
solid, mp113-115 °C (from hexane). [R]25 ) -30.06 (c ) 1.0,
D
D
1H NMR (δ): 0.88-1.00 (m, 2H); 0.93 (d, 3H, J ) 6.6 Hz); 0.97
(d, 3H, J ) 7.1 Hz); 1.17-1.24 (m, 1H); 1.24 (s, 3H); 1.37-
1.60 (m, 2H); 1.70-1.75 (m, 1H); 1.75 (s, 3H); 1.80 (d, 1H, J )
3.8 Hz); 2.04 (m, 1H); 2.62 (m, 1H); 3.53 (dt, 1H, J 1 ) 4.2 Hz,
J 2 ) 10.6 Hz); 4.92 (dd, 1H, J 1 ) 1.5 Hz, J 2 ) 4.3 Hz); 5.40 (s,
1H); 6.38 (dd, 1H, J 1 ) 1.5 Hz, J 2 ) 5.9 Hz); 6.57 (d, 1H, J )
5.9 Hz). 13C NMR (δ): 17.2; 18.7; 21.1; 23.9; 24.4; 31.1; 34.3;
37.1; 40.7; 49.0; 55.4; 57.2; 76.7; 82.6; 82.9; 88.9; 133.3; 135.4;
172.7. IR (Nujol): 1650 cm-1. MS (m/z, %): 317 (M+, 22); 138
CH2Cl2). 1H NMR (δ): 0.81-1.14 (m, 4H); 0.92 (d, 3H, J ) 6.4
Hz); 0.93 (s, 3H); 0.96 (s, 3H); 1.17 (s, 3H); 1.44 (m, 2H); 1.57-
1.70 (m, 2H); 1.95 (m, 1H); 2.04 (dd, 1H, J 1 ) 4.6 Hz, J 2
)
11.4 Hz); 2.69 (d, 1H, J ) 8.1 Hz); 2.86 (d, 1H, J ) 8.1 Hz);
3.09 (d, 1H, J ) 12.3 Hz); 3.54 (d, 1H, J ) 12.3 Hz); 3.67 (dt,
1H, J 1 ) 4.0 Hz, J 2 ) 10.3 Hz); 4.92 (d, 1H, J ) 4.6 Hz); 6.35
(s, 2H); 8.93 (s, 1H). 13C NMR (δ): 17.0; 21.6; 22.1; 22.5; 25.4;
31.0; 35.0; 38.4; 44.1; 46.2; 47.0; 48.9; 57.7; 59.4; 72.9; 79.8;
96.6; 134.0; 136.1. IR (Nujol): 3085, 1180, 1150 cm-1. CIMS
(m/z, %): 306 (M+ + 1, 100); 192 (55); 152 (45). Anal. Calcd
for C19H31NO2: C, 74.71; H, 10.23; N, 4.59. Found: C, 74.56;
H, 10.36; N, 4.42.
(26); 95 (28); 81 (37); 69 (100); 41 (55). Anal. Calcd for C19H27
NO3: C, 71.89; H, 8.57; N, 4.41. Found: C, 71.72; H, 8.42; N,
4.53.
-
Adducts 14-17 were obtained from 13 and isolated by flash
chromatography on silica gel deactivated with triethylamine,
using hexane/CH2Cl2/EtOAc 30/15/1 as eluent.
(3R,4aR,6aS,9R,10aR,11aS,11bR)-3-Eth yl-6,6,9-tr im eth yl-
5-oxo-3,4,4a ,11b-t et r a h yd r oisoin d olyl-[2,3-a ]-p er h yd r o-
11,5a -ben zoxa zin e (14). Colorless solid, mp 97-99 °C (from
pentane). [R]25D ) +2.21 (c ) 1.1, CH2Cl2). 1H NMR (δ): 0.86-
1.00 (m, 2H); 0.94 (t, 3H, J ) 6.8 Hz); 0.95 (d, 3H, J ) 6.3
Hz); 1.00-1.14 (m, 1H); 1.15 (s, 3H); 1.25-1.60 (m, 4H); 1.63-
1.77 (m, 3H); 1.71 (s, 3H); 1.87 (dt, 1H, J 1 ) 3.0 Hz, J 2 ) 12.5
N-(8-Men th olyl)-(3a S,6R,7R,7a S)-3a ,6-ep oxy-7-m eth yl-
3a ,6,7,7a -tetr a h yd r oisoin d olin e (20). Yield 87%. Colorless
solid, mp 113-115 °C (from hexane). [R]25 ) +36.9 (c ) 1.0,
D
CH2Cl2). 1H NMR (δ): 0.82 (d, 3H, J ) 7.1 Hz); 0.85-1.09 (m,
3H); 0.92 (d, 3H, J ) 6.5 Hz); 0.96 (s, 3H); 1.19 (s, 3H); 1.39-
1.48 (m, 3H); 1.57 (m, 1H); 1.67 (m, 1H); 1.93 (m, 1H); 2.11
(m, 1H); 2.37 (m, 1H); 2.94 (d, 1H, J ) 11.9 Hz); 3.26 (t, 1H,
J ) 7.6 Hz); 3.57 (m, 1H); 3.62 (dt, 1H, J 1 ) 4.0 Hz, J 2 ) 10.3
Hz); 4.80 (dd, 1H, J 1 ) 1.5 Hz, J 2 ) 4.3 Hz); 6.29 (dd, 1H, J 1
) 1.5 Hz, J 2 ) 5.8 Hz); 6.48 (d, 1H, J ) 5.8 Hz); 8.66 (broad s,

5236 J . Org. Chem., Vol. 64, No. 14, 1999
Andre´s et al.
1H). 13C NMR (δ): 16.6; 17.1; 21.8; 22.1; 25.5; 31.0; 35.0; 37.8;
44.2; 47.6; 48.6; 50.7; 50.7; 59.3; 72.9; 83.5; 96.0; 134.1; 136.8.
IR (Nujol): 3060, 1010 cm-1. CIMS (m/z, %): 306 (M+ + 1, 100);
192 (30); 152 (17). Anal. Calcd for C19H31NO2: C, 74.71; H,
10.23; N, 4.59. Found: C, 74.58; H, 10.41; N, 4.71.
NMR (δ): 1.44 (dd, 1H, J 1 ) 7.7 Hz, J 2 ) 11.5 Hz); 1.73 (ddd,
1H, J 1 ) 3.2 Hz, J 2 ) 4.4 Hz, J 3 ) 11.5 Hz); 1.95 (ddt, 1H, J 1
) 3.2 Hz, J 2 ) 7.7 Hz, J 3 ) 9.5 Hz); 2.63 (t, 1H, J ) 9.5 Hz);
3.27 (d, 1H, J ) 12.9 Hz); 3.29 (t, 1H, J ) 9.5 Hz); 3.39 (d, 1H,
J ) 12.9 Hz); 3.50 (s, 1H); 5.04 (dd, 1H, J 1 ) 1.6 Hz, J 2 ) 4.4
Hz); 6.36 (dd, 1H, J 1 ) 1.6 Hz, J 2 ) 5.8 Hz); 6.42 (d, 1H, J )
5.8 Hz). 13C NMR (δ): 31.0; 44.7; 47.6; 51.6; 79.9; 98.0; 135.1;
N-(8-Men th olyl)-(3a R,6R,7a R)-3a ,6-ep oxy-3a ,6,7,7a -tet-
r a h yd r o isoin d olin e (21). Colorless solid, mp 125-127 °C
(from hexane). [R]25 ) -11.64 (c ) 1.0, CH2Cl2). 1H NMR (δ):
136.5. IR (film): 3350, 1600, 1200 cm-1. Anal. Calcd for C8H11
-
D
0.86-1.06 (m, 3H); 0.91 (d, 3H, J ) 6.5 Hz); 0.97 (s, 3H); 1.19
(s, 3H); 1.32 (m, 1H); 1.43 (m, 1H); 1.54-1.70 (m, 4H); 1.89-
1.95 (m, 2H); 2.23 (t, 1H, J ) 9.2 Hz); 2.97 (d, 1H, J ) 11.7
Hz); 3.37-3.50 (m, 2H); 3.65 (dt, 1H, J 1 ) 4.0 Hz, J 2 ) 10.2
Hz); 4.98 (dd, 1H, J 1 ) 1.6 Hz, J 2 ) 4.3 Hz); 6.28 (dd, 1H, J 1
) 1.6 Hz, J 2 ) 5.7 Hz); 6.36 (d, 1H, J ) 5.7 Hz); 8.47 (broad s,
1H). 13C NMR (δ): 17.8; 21.3; 22.1; 25.8; 28.8; 31.1; 35.1; 42.6;
44.3; 47.4; 48.5; 50.3; 59.6; 72.8; 79.9; 94.8; 135.8; 136.1. IR
(Nujol): 3140, 1180 cm-1. CIMS (m/z, %): 292 (M+ + 1, 100);
178 (26); 138 (24). Anal. Calcd for C18H29NO2: C, 74.18; H,
10.03; N, 4.81. Found: C, 74.02; H, 10.21; N, 4.96.
NO: C, 70.04; H, 8.08; N, 10.21. Found: C, 70.21; H, 8.26; N,
10.09.
(3a R,6R,7a R)-3a ,6-Ep oxy-3a ,6,7,7a -tetr a h yd r oisoin d o-
lin e (en t-5). Colorless oil. [R]25 ) -30.12 (c ) 2.0, CH2Cl2).
D
1H NMR, 13C NMR, and IR data are coincident with those
reported for 5. Anal. Calcd for C8H11NO: C, 70.04; H, 8.08; N,
10.21. Found: C, 70.18; H, 8.18; N, 10.36.
(3a S,6S,7a S)-3a ,6-E p oxy-7a -m et h yl-3a ,6,7,7a -t et r a h y-
d r oisoin d olin e (28). Yield 70%. Colorless oil. [R]25D ) -23.64
1
(c ) 1.0, CH2Cl2). H NMR (δ): 0.95 (s, 3H); 1.08 (d, 1H, J )
11.4 Hz); 2.10 (dd, 1H, J 1 ) 4.7 Hz, J 2 ) 11.4 Hz); 2.97 (d, 1H,
J ) 10.3 Hz); 3.03 (d, 1H, J ) 10.3 Hz); 3.34 (d, 1H. J ) 13.1
N-(8-Men th olyl)-(3aR,6R,7aR)-6-eth yl-3a,6,7,7a-tetr ah y-
d r oisoin d olin e (24). Colorless solid, mp 79-80 °C (from
hexane). [R]25D ) +32.75 (c ) 1.0, CH2Cl2). 1H NMR (δ): 0.86-
1.04 (m, 3H); 0.90 (d, 3H, J ) 6.5 Hz); 0.92 (t, 3H, J ) 6.9
Hz); 0.93 (s, 3H); 1.14 (s, 3H); 1.27-1.79 (m, 9H); 1.93 (m, 1H);
2.14 (m, 2H); 2.33 (m, 1H); 2.62 (m, 1H); 2.93 (m, 1H); 3.01
(m, 1H); 3.63 (dt, 1H, J 1 ) 4.0 Hz, J 2 ) 10.2 Hz); 5.60 (m, 1H);
5.77 (m, 1H); 9.04 (m, 1H). 13C NMR (δ): 12.3; 16.7; 21.1; 22.2;
25.6; 29.3; 29.6; 31.0; 35.2; 37.2; 38.8; 42.9; 44.3; 49.2; 49.4;
Hz); 3.45 (d, 1H, J ) 13.1 Hz); 4.10 (s, 1H); 4.98 (dd, 1H, J 1
)
1.5 Hz, J 2 ) 4.7 Hz); 6.40 (d, 1H, J ) 5.8 Hz); 6.44 (dd, 1H, J 1
) 1.5 Hz, J 2 ) 5.8 Hz). 13C NMR (δ): 23.0; 39.5; 46.3; 49.3;
58.6; 79.9; 99.0; 133.6; 136.8. IR (film): 3300, 1305, 1210 cm-1
.
Anal. Calcd for C9H13NO: C, 71.49; H, 8.67; N, 9.26. Found:
C, 71.31; H, 8.49; N, 9.44.
(3aS,6R,7R,7aS)-3a,6-Epoxy-7-m eth yl-3a,6,7,7a-tetr ah y-
d r oisoin d olin e (29). Yield 66%. Colorless oil. [R]25D) +78.32
59.6; 72.8; 126.2; 133.2. IR (Nujol): 3120, 1165, 1025 cm-1
MS (m/z, %): 305 (M+, 1); 193 (13); 192 (100). Anal. Calcd for
20H35NO: C, 78.63; H, 11.55; N, 4.58. Found: C, 78.48; H,
.
1
(c ) 1.8, CH2Cl2). H NMR (δ): 0.86 (d, 3H, J ) 7.1 Hz); 1.49
(dt, 1H, J 1 ) 3.3 Hz, J 2 ) 8.7 Hz); 2.14 (ddq, 1H, J 1 ) 3.3 Hz,
J 2 ) 4.4 Hz, J 3 ) 7.1 Hz); 2.68 (t, 1H, J ) 8.7 Hz); 3.03 (s,
1H); 3.18 (d, 1H, J ) 12.6 Hz); 3.29 (d, 1H, J ) 12.6 Hz); 3.30
(t, 1H, J ) 8.7 Hz); 4.84 (dd, 1H, J 1 ) 1.5 Hz, J 2 ) 4.4 Hz);
6.34 (dd, 1H, J 1 ) 1.5 Hz, J 2 ) 5.8 Hz); 6.51 (d, 1H, J ) 5.8
Hz). 13C NMR (δ): 16.8; 39.9; 48.0; 51.1; 53.2; 83.4; 99.5; 134.5;
136.1. IR (film): 3300, 1320 cm-1. Anal. Calcd for C9H13NO:
C, 71.49; H, 8.67; N, 9.26. Found: C, 71.37; H, 8.82; N, 9.11.
(3a R ,6R ,7a R )-6-E t h yl-3a ,6,7,7a -t e t r a h yd r oisoin d o-
C
11.39; N, 4.69.
N-(8-Men th olyl)-(3aS,6S,7a S)-6-eth yl-3a ,6,7,7a -tetr a h y-
d r oisoin d olin e (25). Colorless oil. [R]25 ) -49.23 (c ) 1.0,
D
CH2Cl2). 1H NMR (δ): 0.85-1.07 (m, 3H); 0.91 (d, 3H, J ) 6.5
Hz); 0.92 (s, 3H); 0.93 (t, 3H, J ) 7.2 Hz); 1.17 (s, 3H); 1.25-
1.65 (m, 6H); 1.65-1.80 (m, 3H); 1.92 (m, 1H); 2.13 (m, 2H);
2.20-2.65 (broad, 2H); 2.91-3.32 (broad, 2H); 3.63 (dt, 1H, J 1
) 4.0 Hz, J 2 ) 10.3 Hz); 5.58 (m, 1H); 5.76 (m, 1H); 8.00-9.40
(broad s, 1H). 13C NMR (δ): 12.3; 18.6; 21.6; 22.1; 25.7; 29.1;
29.7; 31.0; 35.1; 37.2; 39.0; 43.1; 44.1; 48.5; 48.7; 59.3; 72.9;
126.3; 132.9. IR (film): 3120, 1160, 1020 cm-1. MS (m/z, %):
305 (M+, 1); 193 (15); 192 (100). Anal. Calcd for C20H35NO: C,
78.63; H, 11.55; N, 4.58. Found: C, 78.80; H, 11.72; N, 4.72.
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 menthol derivatives 18-27 (1.0
mmol) and PCC (1.29 g, 6 mmol) in CH2Cl2 (40 mL) and 4 Å
molecular sieves (1 g) was stirred at room temperature until
the oxidation was finished (TLC, 6-8 h). The solvent was
eliminated under reduced pressure, the residue was dissolved
in a 15% aqueous solution of NaOH (25 mL), and the resulting
solution was extracted with Et2O. The ethereal solution was
separated, washed with brine, and dried over anydrous
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 acidified
to pH ) 2 by addition of a 10% solution of HCl. The aqueous
layer was washed with Et2O to recover (+)-pulegone, and then
the residue was basified to pH ) 12 by addition of a 15%
solution of NaOH. The basic phase was extracted with CHCl3,
the organic layer was dried (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 (10/1) as eluent.
lin e (30). Yield 62%. Pale yellow oil. [R]25 ) +54.75 (c ) 0.5,
D
1
CH2Cl2). H NMR (δ): 0.94 (t, 3H, J ) 7.3 Hz); 1.23-1.51 (m,
2H); 1.58 (m, 1H); 1.72-1.85 (m, 2H); 2.12-2.31 (m, 2H); 2.66-
2.84 (m, 2H); 3.39-3.48 (m, 2H); 5.70 (m, 1H); 5.77 8d, 1H, J
) 10.0 Hz); 5.98 (broad s, 1H). 13C NMR (δ): 12.2; 28.6; 28.9;
37.0; 39.0; 43.1; 48.2; 48.8; 123.3; 134.3. IR (film): 3420, 1640
cm-1. Anal. Calcd for C10H17N: C, 79.41; H, 11.33; N, 9.26.
Found: C, 79.58; H, 11.50; N, 9.42.
(3a S,6S,7a S)-6-E t h yl-3a ,6,7,7a -t et r a h yd r oisoin d olin e
(en t-30). Yield 56%. Pale yellow oil. [R]25 ) -52.83 (c ) 0.6,
D
CH2Cl2). H NMR, 13C NMR, and IR data are coincident with
1
those reported for 30. Anal. Calcd for C10H17N: C, 79.41; H,
11.33; N, 9.26. Found: C, 79.60; H, 11.48; N, 9.40.
Ack n ow led gm en t. We thank the Spanish DGICYT
(Project PB95-707) for the financial support of this work.
Predoctoral felloships provided by the Spanish MEC
(FPU program) for J .N. and M.G.-V. are also acknowl-
edged.
Su p p or tin g In for m a tion Ava ila ble: Characterization
1
data (mp or bp, [R]25D, IR, MS, H and 13C NMR spectra, and
CHN analyses) for compounds 10, 11, 16, 17, 22, 23, 26, 27,
en t-28, en t-29, 31, and en t-31; copies of 13C NMR spectra for
compounds 1, 3-5, 7-12, and 14-31, and COSY and NOESY
experiments for 14, 16, and 17. This material is available free
of charge via the Internet at http://pubs.acs.org.
(3a S,6S,7a S)-3a ,6-Ep oxy-3a ,6,7,7a -tetr a h yd r oisoin d o-
1
lin e (5). Colorless oil. [R]25 ) + 30.24 (c ) 5.6, CH2Cl2). H
J O9904462
D