Diastereoselective intramolecular alder-ene reaction on chiral perhydro-1,3-benzoxazines. A rapid entry to enantiopure cis-3,4-disubstituted pyrrolidines

Article abstract of DOI:10.1021/jo050360a

Chiral 3-acryloyl-2-vinyl-substituted 1,3-perhydrobenzoxazines derived from (-)-8-aminomenthol participate in an ene reaction leading to 3,4-disubstituted pyrrolidinone derivates with excellent diastereoselectivity. The cycloadducts were transformed into

Full text of DOI:10.1021/jo050360a

Diastereoselective Intramolecular Alder-Ene Reaction on Chiral
Perhydro-1,3-benzoxazines. A Rapid Entry to Enantiopure
cis-3,4-Disubstituted Pyrrolidines
Rafael Pedrosa,* Celia Andre´s,* Laura Mart´ın, Javier Nieto, and Carlos Roso´n
Departamento de Quı´mica Orga´nica, Facultad de Ciencias, Universidad de Valladolid, Dr. Mergelina
s/n, 47011 Valladolid, Spain
pedrosa@qo.uva.es
Received February 26, 2005
Chiral 3-acryloyl-2-vinyl-substituted 1,3-perhydrobenzoxazines derived from (-)-8-aminomenthol
participate in an ene reaction leading to 3,4-disubstituted pyrrolidinone derivates with excellent
diastereoselectivity. The cycloadducts were transformed into enantiopure 3,4-disubstituted pyrro-
lidines after elimination of the chiral adjuvant.
Introduction
are generally required, although reactions catalyzed by
Lewis acids proceed under mild conditions and often with
improved stereoselectivity.
The intramolecular ene reaction10 generally takes place
more easily than the corresponding intermolecular reac-
tion due to the less negative entropy activation, and
generally occurs with high regio- and stereocontrol
depending on the tether connecting the ene and enophile
components.
The absolute stereochemistry of the final products can
be controlled by preexisting stereogenic centers11 or chiral
Lewis acids as promoters,12 but the use of chiral auxil-
iaries as controllers of chirality has not been studied
enough.13
Recently, we have shown that chiral perhydro-1,3-
benzoxazines derived from (-)-8-aminomenthol consti-
tute useful chiral auxiliaries in thermally induced keto-
ene cyclizations,14 and during our studies in intramolecular
Diels-Alder reaction of styrene derivatives, we found
that 2-(trans-1-methyl-2-phenylethenyl)perhydro-1,3-
benzoxacine derivative 5d was easily transformed by
The ene reaction1 represents one of the most important
and versatile bond-forming reactions in organic chemistry
owing to a great variety of suitable starting substrates.
Ene reactions involving alkenes2 (olefin-ene or Alder-
ene reaction), carbonyl functionalities3 (carbonyl-ene
reaction), azo compounds,4 singlet oxygen,5 nitroso groups,6
or phosphorus derivatives7 as enophiles have been used
in carbon-carbon and carbon-heteroatom transforma-
tions with olefins. Reactions involving hetero-ene com-
ponents such as enoles8 and enamines9 are also known.
The use of the ene reaction for synthetic purposes is often
limited due to its high activation energy, particularly in
olefin- and carbonyl-ene reactions. High temperatures
* To whom correspondence should be addressed. Fax: Int + 983
423 013.
(1) Carruthers, W. In Cycloaddition Reactions in Organic Synthesis;
Pergamon Press: Oxford, 1990; p 241.
(2) Snider, B. B. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Paquette, L. A., Eds.; Pergamon Press: Oxford, 1991; Vol.
5, p 1.
(3) Snider, B. B. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Heathcock, C. H., Eds.; Pergamon Press: Oxford, 1991;
Vol. 2, p 527.
(4) For a rewiew on imino-ene reactions, see: Borzilleri, R. H.;
Weinreb, S. M. Synthesis 1995, 347.
(5) (a) Stratakis, M.; Orfanopoulos, M. Tetrahedron 2000, 56, 1595.
(b) Prein, M.; Adam, W. Angew. Chem., Int. Ed. Engl. 1996, 35, 477.
(6) Adam, W.; Krebs, O. Chem. Rev. 2003, 103, 4131.
(7) For a review on phospha-ene reactions, see: Mackewitz, T. W.;
Regitz, M. Synthesis 1998, 125.
(8) For a review on Conia reaction, see: Conia, J. M.; Le Perchec,
P. Synthesis 1975, 1.
(9) Cossy, J.; Bouzide, A.; Pfau, M. J. Org. Chem. 1997, 62, 7106.
(10) Taber, D. F. In Intramolecular Diels-Alder and Alder-Ene
Rections; Springer-Verlag: Berlin, 1984; p 61. See also refs 1-3.
(11) See, for example: (a) Helmboldt, H.; Rehbein, J.; Hiersemann,
M. Tetrahedron Lett. 2004, 45, 289. (b) Alcaide, B.; Almendros, P.;
Pardo, C.; Rodriguez-Ranera, C.; Rodriguez-Vicente, A. J. Org. Chem.
2003, 68, 3106. (c) Watanabe, B.; Yamamoto, S.; Sasaki, K.; Nakagawa,
Y.; Miyagawa, H. Tetrahedron Lett. 2004, 45, 2767. (d) Noguchi, M.;
Matsushita, R.; Takamura, S.; Uchida, T.; Takehiko, U.; Kakehi, A.;
Shiro, M.; Yamamoto, H. Tetrahedron Lett. 2000, 41, 8489. (e) Nayak,
S. K.; Thijs, L.; Zwanenburg, B. Synlett 1998, 1187. (f) Mikami, K.;
Tereda, M.; Nakai, T. J. Am. Chem. Soc. 1990, 112, 3949.
10.1021/jo050360a CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/16/2005
4332
J. Org. Chem. 2005, 70, 4332-4337

Alder-Ene Reaction on Chiral Perhydro-1,3-benzoxazines
SCHEME 1
thermolysis into the ene cyclization product 6d instead
of the expected tetrahydrobenz[f]isoindoline derivative
cyloadduct.15
We present now a full account on the behavior of
3-acryloyl-2-vinylperhydro-1,3-benzoxazines derived from
(-)-8-aminomenthol16 in intramolecular Alder-ene reac-
tions and their use in preparation of enantiopure cis-3,4-
disubstituted pyrrolidines.17 This heterocycle is known
to constitute major frameworks of alkaloids which display
important biological activity.18 Nevertheless, general and
effective methods for the synthesis of enantioselective cis-
3,4-disubstituted pyrrolidines are noticeably rare.19
Results and Discussion
The starting chiral perhydro-1,3-benzoxazines 5a-g
were prepared in two steps as single diastereomers and
in good chemical yields, as summarized in Scheme 1.
Condensation of (-)-8-aminomenthol with R,â-unsatur-
ated aldehydes in CH2Cl2 at room temperature afforded
nearly quantitatively perhydro-1,3-benzoxazines 1-4,
which were transformed into the amides 5a-g by acy-
lation with acryloyl, methacryloyl, or crotonyl chloride
and triethylamine or TMEDA in CH2Cl2 at 0 °C.
SCHEME 2
Perhydro-1,3-benzoxazines 5a-g proved to be unstable
in the presence of acids, and purification must be done
on silica gel deactivated with triethylamine; otherwise,
these compounds epimerize at C-2 and partially hydro-
lyze to 8-(N-acryloyl)aminomenthol derivatives. This fact
makes impossible the study of the ene reaction of these
compounds in the presence of Lewis acids.
Fortunately, thermally induced ene cyclization reaction
of 5a-e occurred with excellent chemical yields and a
(12) For recent examples, see: (a) Matsubara, R.; Nakamura, Y.;
Kobayashi, S. Angew. Chem., Int. Ed. 2004, 43, 3258. (b) Guo, H.;
Wang, X.; Ding, K. Tetrahedron Lett. 2004, 45, 2009. (c) Aikawa, K.;
Kainuma, S.; Hatano, M.; Mikami, K.; Tetrahedron Lett. 2004, 45, 183.
(d) Caplan, N. A.; Hancock, F. E.; Bulman Page, P. C.; Hutchings, G.
J. Angew. Chem., Int. Ed. 2004, 43, 1685 (e) Yuan, Y.; Zhang, X.; Ding,
K. Angew. Chem., Int. Ed. 2003, 42, 5478. (f) Ruck, R. T.; Jacobsen, E.
N. Angew. Chem., Int. Ed. 2003, 42, 4771. (g) Lei, A.; He, M.; Zhang,
X. J. Am. Chem. Soc., 2002, 124, 8198. (h) Kezuka, S.; Ikeno, T.;
Yamada, T. Org. Lett. 2001, 3, 1937. (i) Koh, J. H.; Larsen, A. O.;
Gagne´, M. R. Org. Lett. 2001, 3, 1233. (j) Evans, D. A.; Tregay, S. W.;
Burgey, C. S.; Paras, N. A.; Wojkovsky, T. J. J. Am. Chem. Soc. 2000,
122, 7936.
(13) (a) Oppolzer, W. Angew. Chem., Int. Ed. Engl. 1984, 23, 876.
(b) Mikami, K.; Shimizu, M. Chem. Rev. 1992, 92, 1021. See also refs
1 and 10.
(14) Pedrosa, R.; Andre´s, C.; Roso´n, C. D.; Vicente, M. J. Org. Chem.
2003, 68, 1852.
(15) Pedrosa, R.; Andre´s, C.; Nieto, J. J. Org. Chem. 2002, 67, 782.
(16) Rassat, A.; Rey, P. Tetrahedron 1974, 30, 3315.
TABLE 1. Intramolecular Ene Reaction of Compounds
5a-g
entry
amide
time (h)
yielda (%)
products (ratio)b
1
2
3
4
5
6
7
5a
5b
5c
5d
5e
5f
5
10
30
3
15
45
60
95
92
86
90
90
88
85
6a (100)
6b (100)
6c (100)
6d (100)
6e (100)
6f (72), 7f (28)
6g (45), 7g (55)
5g
(17) For other examples of preparation of 3,4-disubstituted pyrro-
lidines by intramolecular ene reaction, see: (a) Oppolzer, W.; Thirring,
K. J. Am. Chem. Soc. 1982, 104, 4978. (b) Overman, L. E.; Lesuisse,
D. Tetrahedron Lett. 1985, 26, 4167. (c) Lei, A.; Waldkirch, J. P.; He,
M.; Zhang, X. Angew. Chem., Int. Ed. 2002, 41, 4526. (d) Cao, P.; Wang,
B., Zhang, X. J. Am. Chem. Soc. 2000, 122, 6490. (e) Choony, N.;
Sammes, P. G.; Smith, G.; Ward, R. W. Chem. Commun. 2001, 6062.
See too refs 10 and 14.
a Chemical yields refer to pure compounds after column chro-
matography. b Determined by integration of the signals in 1H NMR
spectra of the reaction mixtures.
high degree of stereocontrol (Scheme 2 and Table 1).
Thus, perhydro-1,3-benzoxazines 5a-g were transformed
into the cyclization products 6a-g and 7f-g by refluxing
in toluene with K2CO3 to prevent epimerization of start-
ing materials.
The reactivity of perhydrobenzoxazines varied depend-
ing on the substitution pattern of the double bond at C-2.
Perhydrobenzoxazines 5a-e, with two substituents at
the terminal position of this double bond, react with total
diastereoselectivity leading to 6a-e as single diastere-
omers in excellent yields (entries 1-5 in Table 1).
(18) Southon, I. W., Buckingham, J., Eds. Dictionary of Alkaloids;
Chapman and Hall: New York, 1989.
(19) For some examples of enantioselective synthesis of trans-3,4-
disubstituted pyrrolidines, see: (a) Denmark, S. E.; Marcin, L. R. J.
Org. Chem. 1995, 60, 3221. (b) Andre´s, C.; Duque-Soladana, J. P.;
Pedrosa, R. Chem. Commun. 1999, 31. (c) Karlsson, S.; Han, F.;
Ho¨gberg, H.-E.; Caldirola, P. Tetrahedron: Asymmetry 1999, 10, 2605.
(d) Karlsson, S.; Ho¨gberg, H.-E. Tetrahedron: Asymmetry 2001, 12,
1975. (e) Karlsson, S.; Ho¨gberg, H.-E. Tetrahedron: Asymmetry 2001,
12, 1977. (f) Johnson, T. A.; Jang, D. O.; Slafer, B. W.; Curtis, M. D.;
Beak, P. J. Am. Chem. Soc. 2002, 124, 11689. (g) Galeazzi, R.; Martelli,
G.; Mobbili, G., Orena, M.; Rinaldi, S. Tetrahedron: Asymmetry 2003,
14, 3353.
J. Org. Chem, Vol. 70, No. 11, 2005 4333

Pedrosa et al.
SCHEME 3
In contrast, perhydrobenzoxazine 5f, with only a meth-
yl group at the double bond, reacts slower (entry 6)
yielding a mixture (ca. 2.6:1) of two diastereomers 6f and
7f, whereas the cyclohexene derivative 5g cyclizes to an
almost equimolar mixture of diastereomeric spirocycles
6g and 7g (entry 7).
It is noteworthy that although the induced diastereo-
selectivity for ene cyclization of 5f and 5g was low, the
simple diastereoselectivity was complete for the forma-
tion of the cis-2,3-disubstituted products. This result is
in agreement with the general stereochemical trend for
kinetically controlled thermal or Lewis acid mediated
intramolecular ene reaction of 1,6-hexadienes to form cis-
disubstituted adducts as major diastereomers.20
The influence of a methyl group at the enophile was
tested in methacryloyl derivatives 5b and 5e, and in
crotonyl derivative 5c. As expected, they reacted slower
than 5a and 5d and longer reaction times were necessary,
probably due of steric hindrance and the electron-
donating effect of the methyl group that make the
enophile less reactive.21 However, the reaction was totally
diastereoselective, and only a single isomer was obtained.
Interestingly, intramolecular ene reactions of com-
pounds 5a-g occur with total regioselectivity, providing
the cyclic compounds that arise from a type I ene
cyclization reaction,22 and type IV23 or type II adducts
for amide 5g were not observed.
SCHEME 4
The stereochemistry of cycloadducts was assigned on
the basis of COSY and NOESY experiments after isola-
tion and purification by flash chromatography. The
NOESY contacts allowed the assignation of the substit-
uents at C-3, C-4, and the hydrogen atom at C-5 with a
cis relationship for compounds 6a,c,d,f,g in the pyrroli-
din-2-one ring. In contrast, the double bond at C-4 and
the substituent at C-3 are also cis for the spirocycle 7g,
but trans with respect to the hydrogen at C-5.24
The formation of the cis stereoisomers can be explained
by accepting that the reaction is a concerted process.25
In this way, two exo (A and B) and two endo (C and D)
transition states depending on the methyl group cis or
trans that participate in the ene reaction can be envis-
aged. Whereas the observed ene adducts 6a-c were
obtained from transition states exo-A or endo-C that lead
to the same product, transition states exo-B and endo-D
are sterically less favorable due to the steric hindrance
between the methyl group of the ene component in B, or
the substituent R3 in D, and the benzoxazine framework,
and no products were formed from these conformations
(Scheme 3). For amides 5d and 5e with a single cis-
methyl group at the ene component only two different
transition states (exo-A and exo-B) can be considered, and
the stereoisomers formed (6d and 6e) must arise from
transition state exo-A due to the same reasons discussed
above.
The same steric factors govern the formation of a
mixture of diatereoisomers 6f and 7f from amide 5f, with
only one trans-methyl group at the ene component. In
this case, it is possible to consider only two different endo
transition states C and D. The major diastereomer 6f
will be formed from the most stable transition state C,
but the steric constrain in endo-D (R3 ) H) is smaller
than for compounds 5a-e and then 7f is formed as minor
diastereomer.
In the same way, the ene reaction of amide 5g occurs
through endo transition states E and F (Scheme 4); both
of them are similar hindered and almost an equimolecu-
lar mixture of diastereomeric spirocycles 6g and 7g was
obtained.
The transformation of the ene adducts 6a-g into the
final enantiopure 3,4-disubstituted pyrrolidines was
achieved in two steps as depicted in Scheme 5. Treatment
(20) (a) Oppolzer, W.; Ba¨ttig, K. Tetrahedron Lett. 1982, 23, 4669.
(b) Oppolzer, W.; Strauss, H. F.; Simmons, D. P. Tetrahedron Lett.
1982, 23, 4673. See also refs 1, 2, and 10.
(21) Duncia, J. V.; Lansbury, P. T.; Miller, T., Jr.; Snider, B. B. J.
Am. Chem. Soc. 1982, 104, 1930.
(22) Oppolzer clasified intramolecular ene reactions into type I, II,
and III depending on the positioning of the bridge linking the enophile
and the ene component. Later, Snider observed additional type IV ene
reaction. (a) Oppolzer, W.; Snieckus, V. Angew. Chem., Int. Ed. Engl.
1978, 17, 476. (b) Snider, B. B.; Duncia, J. V. J. Org. Chem. 1980, 45,
3461.
(23) (a) Mayer, C. F.; Crandall, J. K. J. Org. Chem. 1970, 35, 2688.
(b) Iwasawa, N.; Takebayashi, T.; Mukaiyama, T. Chem. Lett. 1982,
513. See also ref 2.
(24) See the Supporting Information.
(25) (a) Loncharich, R. J.; Houk, K. N. J. Am. Chem. Soc. 1987, 109,
6947. (b) Uchimaru, T.; Tsuzuki, S.; Tanabe, K.; Hayashi, Y. J. Chem.
Soc., Chem. Commun. 1989, 1861. (c) Hoffmann, H. M. R. Angew.
Chem., Int. Ed. Engl. 1969, 8, 556.
4334 J. Org. Chem., Vol. 70, No. 11, 2005

Alder-Ene Reaction on Chiral Perhydro-1,3-benzoxazines
760, 645 cm-1. Anal. Calcd for C17H29NO: C, 77.51; H, 11.10;
N, 5.32. Found: C, 77.80; H, 10.96; N, 5.47.
SCHEME 5
(2S,4aS,7R,8aR)-N-Methacryloyl-2-(2-methylpropenyl)-
4,4,7-trimethyloctahydrobenz[e][1,3]oxazine (5b). Color-
1
less oil. [R]25 ) +53.1 (c ) 1.1, CH2Cl2). H NMR (δ): 0.84-
D
1.18 (m, 2H); 0.92 (d, 3H, J ) 6.5 Hz); 1.35-1.60 (m, 2H); 1.48
(s, 3H); 1.62 (s, 3H); 1.65 (s, 3H); 1.69-1.87 (m, 2H); 1.73 (s,
3H); 1.89-2.02 (m, 2H); 1.90 (s, 3H); 3.62 (td, 1H, J1)11.3 Hz,
J2 ) 4.0 Hz); 4.98 (s, 1H); 5.05 (s, 1H); 5.40 (d, 1H, J ) 5.6
Hz); 5.72 (d, 1H, J ) 5.6 Hz). 13C NMR (δ): 18.3; 18.5; 20.0;
21.9; 25.1; 25.4; 25.6; 31.5; 34.6; 43.1; 47.2; 57.9; 73.4; 80.4;
114.9; 127.4; 136.3; 142.6; 172.2. IR (film): 2910, 1645, 1610,
1450,1360, 940, 840, 810 cm-1. Anal. Calcd. for C19H31NO2: C,
74.71; H, 10.23; N, 4.95. Found: C, 74.87; H, 10.38; N, 5.09.
(2S,4aS,7R,8aR)-N-Crotonyl-2-(2-methylpropenyl)-4,4,7-
trimethyloctahydrobenz[e][1,3]oxazine (5c). Colorless oil.
1
[a]25 ) +48.7 (c ) 1.5, CH2Cl2). H NMR (δ): 0.92 (d, 3H, J
D
) 6.5 Hz); 0.95-1.46 (m, 3H); 1.48-1.84 (m, 2H); 1.49 (s, 3H);
1.60 (s, 3H); 1.74 (s, 3H); 1.77 (s, 3H); 1.81 (dd, 3H, J ) 6.8
Hz, J2 ) 1.6 Hz); 1.87-1.98 (m, 3H); 3.60 (td, 1H, J1) 11.4
Hz, J2 ) 4 Hz); 5.45 (d, 1H, J ) 5.6 Hz); 5.76 (d, 1H, J ) 5.6
Hz); 5.94 (dq, 1H, J1 ) 15.0 Hz, J2 ) 1.6 Hz); 6.72 (dq, 1H, J1
) 15.0 Hz, J2 ) 6.8 Hz). 13C NMR (δ): 18.1; 18.6; 19.0; 21.9;
24.7; 25.3; 25.6; 31.6; 34.6; 43.1; 46.9; 57.6; 73.1; 79.6; 125.3;
127.5; 137.5; 139.7; 166.3. IR (film): 2920, 1640, 1610, 1450,
1360, 960, 830 cm-1. Anal. Calcd for C19H31NO2: C, 74.71; H,
10.23; N, 4.95. Found: C, 74.62; H, 10.34; N, 4.82.
of the ene adducts with aluminum hydride in THF at -10
°C furnished the aminomenthol derivatives 8a-g, result-
ing from the ring opening N,O-acetal moiety and reduc-
tion of the amide group, in very good chemical yields (84-
95%). These amino alcohols, upon oxidation with PCC
in methylene chloride at room temperature, and treat-
ment with 2.5 M solution of KOH in THF-MeOH-H2O
yielded the pyrrolidine derivatives. These compounds
were isolated and characterized as the N-tosyl derivatives
9a-g (48-62% from 8a-g) by treatment with tosyl
chloride and diisopropylethylamine.
In summary, the ene reaction on N-acryloyl-2-vinyl-
substituted perhydro-1,3-benzoxazines constitutes a good
diastereoselective entry for 3,4-disubstituted pyrrolidi-
nones easily transformed into enantiopure 3,4-disubsti-
tuted pyrrolidines. The enantiopure final products were
obtained in 16-54% from the starting perhydro-1,3-
benzoxazines.
(2S,4aS,7R,8aR)-N-Methacryloyl-2-(trans-2-phenylpro-
pen-1-yl)-4,4,7-trimethyloctahydrobenz[e] [1,3]oxazine
1
(5e). Colorless oil. [R]25D_) +25.5 (c ) 4.6, CHCl3). H NMR
(δ): 0.88-1.20 (m, 3H); 0.89 (d, 3H, J ) 6.5 Hz); 1.38-152
(m, 1H); 1.53 (s, 3H); 1.68 (s, 3H); 1.74-1.82 (m, 2H); 1.93 (s,
3H); 1.97-2.05 (m, 2H); 2.09 (s, 3H); 3.69 (td, 1H, J1 ) 10.0
Hz, J2 ) 3.9 Hz); 5.05 (d, 1H, J ) 1.4 Hz); 5.08 (d, 1H, J ) 1.4
Hz); 5.91 (d, 1H, J ) 5.4 Hz); 5.95 (d, 1H, J ) 5.4 Hz); 7.26-
7.37 (m, 5H). 13C NMR (δ): 16.5; 18.2; 20.0; 21.8; 25.1; 25.3;
31.5; 34.5; 42.9; 47.3; 57.9; 73.4; 80.4; 115.1; 125.6 (2C); 127.4;
128.3 (2 C); 129.8; 138.5; 142.4 (2C); 172.0. IR (film): 3080,
3050, 2925, 1645, 1630, 760, 735, 700 cm-1. Anal. Calcd for
C24H33NO2: C, 78.43; H, 9.05; N, 3.81. Found: C, 78.29; H,
9.17; N, 3.98.
(2S,4aS,7R,8aR)-N-Acryloyl-2-cyclohexen-1-yl-4,4,7-
trimethyloctahydrobenz[e][1,3]oxazine (5g). Colorless oil.
1
[R]25 ) +52.9 (c ) 1.7, CHCl3). H NMR (δ): 0.83-1.27 (m,
D
Experimental Section
5H); 0.93 (d, 3H, J ) 6.5 Hz); 1.43 (m, 1H); 1.53 (s, 3H); 1.58-
1.77 (m, 5H); 1.63 (s, 3H); 1.92-2.11 (m, 4H); 2.18-2.30 (m,
1H); 3.66 (td, 1H, J1 ) 11.5 Hz, J2 )3.9 Hz); 5.39-5.40 (m,
1H); 5.55 (dd, 1H, J1 ) 7.7 Hz, J2 ) 4.8 Hz); 5.83-5.86 (m,
1H); 6.19 (d, 1H, J ) 7.7 Hz); 6. 20 (d, 1H, J ) 4.8 Hz). 13C
NMR (δ): 19.0; 22.0; 22.2; 22.4; 23.7; 24.9; 25.1; 25.6; 31.6;
34.6; 43.1; 45.3; 57.7; 73.9; 85.3; 124.8; 126.8; 131.2; 139.5;
166.9. IR (film): 3050, 2980, 1670, 1630, 970, 820 cm-1. Anal.
Calcd for C20H31NO2: C, 75.67; H, 9.84; N, 4.41. Found: C,
75.82; H, 9.71; N, 4.54.
General Methods. All reactions were carried out under
argon atmosphere in oven-dried glassware. Solvents were dried
by standard methods: CH2Cl2 from CaH2 and THF and toluene
from Na. 1H NMR (300 MHz) and 13C NMR (75 MHz) were
registered in CDCl3 as solvent, and chemical shifts are given
relative to TMS as internal reference. Specific rotations were
determined on a digital polarimeter using a Na lamp and
concentration is given in grams per 100 mL. Melting points
were determined in open capillary tubes and are uncorrected.
TLC was performed on glass-backed plates coated with silica
gel 60 with an F254 indicator; the chromatograms were visual-
ized under UV light and/or by staining with I2 or phosphomo-
lybdic acid. Flash chromatography was carried out on silica
gel 60 (230-240 mesh).
Intramolecular Ene-Cyclization Reactions. General
Procedure. A mixture of the amide (15 mmol), K2CO3 (1.0
g), and toluene (50 mL) was refluxed until the reaction was
finished (TLC, 3-60 h). The solvent was eliminated under
reduced pressure, and the residue was chromatographed on
silica gel with hexane/EtOAc as eluent. Adduct 6d15 has been
previously described.
(2S,3S,3aS,4aR,6R,8aS)-3-Isopropenyl-2,6,9,9-tetra-
methyloctahydro-4aH-pyrrolo[2,1-b][1,3]benzoxazin-
1(2H)-one (6a). Colorless solid. Mp: 92-93°C (from pentane).
[R]25D ) -173.5 (c ) 1.0, CH2Cl2). 1H NMR (δ): 0.91-1.15 (m,
3H); 0.93 (d, 3H, J ) 7.4 Hz); 0.94 (d, 3H, J ) 6.5 Hz); 1.20 (s,
3H); 1.28 (m, 1H); 1.49 (m, 1H); 1.62-1.80 (m, 2H); 1.72 (s,
3H); 1.74 (s, 3H); 2.01 (m, 1H); 2.62 (qd, 1H, J1 ) 8.4 Hz, J2 )
7.4 Hz); 2.69 (dd, 1H, J1 ) 8.4 Hz, J2 ) 6.3 Hz); 3.43 (td, 1H,
J1 ) 10.6 Hz, J2 ) 4.2 Hz); 4.84 (s 1H); 4.98 (d, 1H, J ) 6.3
Hz). 13C NMR (δ): 11.8; 18.3; 21.9; 22.7; 23.9; 25.5; 31.1; 34.3;
38.9; 41.0; 48.5; 49.7; 56.7; 76.2; 85.6; 112.2; 140.1; 175.2. IR
Compounds 1, 3, 5a and 5f26 and 2, 5d and 6a15 have been
previously described.
(2S,4aS,7R,8aR)-2-Cyclohexen-1-yl-4,4,7-trimethyl-
octahydrobenz[e][1,3]oxazine (4). Colorless oil. [R]25
)
D
+8.8 (c ) 1.1, CH2Cl2). 1H NMR (δ): 0.91 (d, 3H, J ) 6.5 Hz);
0.95-1.19 (m, 4H); 1.09 (s, 3H); 1.10 (s, 3H); 1.46-1.70 (m,
8H); 1.91-2.28 (m, 5H); 3.45 (td, 1H, J1 ) 4.2 Hz, J2 ) 10.6
Hz); 4.62 (s, 1H); 5.82 (m, 1H). 13C NMR (δ): 19.4; 22.2; 22.3
(2C); 23.9; 24.7; 25.5; 29.8; 31.2; 34.9; 41.5; 51.1; 51.6; 74.8;
85.3; 123.8; 136.6. IR (film): 3320, 3090, 1650, 820, 790, 780,
(26) Pedrosa, R.; Andre´s, C.; Nieto, J.; Del Pozo, S. J. Org. Chem.
2003, 68, 4923.
J. Org. Chem, Vol. 70, No. 11, 2005 4335

Pedrosa et al.
(Nujol dispersion): 3090, 1680, 790, 770, 750, 730 cm-1. Anal.
Calcd for C18H29NO2: C, 74.18; H, 10.03; N, 4.81. Found: C,
74.31; H, 1018; N, 4.94.
(2R,3S,3aS,4aR,6R,8aS)-2,6,9,9-Tetramethyl-3-vinyl-
octahydro-4aH-pyrrolo[2,1-b][1,3]benzoxazin-1(2H)-one
(7f). Purity 90%. Colorless oil. 1H NMR (δ): 0.83-1.12 (m, 3H);
0.93 (d, 3H, J ) 6.5 Hz); 1.03 (d, 3H, J ) 7.4 Hz); 1.18 (s, 3H);
1.27 (m, 1H); 1.49 (m, 1H); 1.68-1.80 (m, 2H); 1.72 (s, 3H);
1.98 (m, 1H); 2.41 (dq, J1 ) 7.9 Hz, J2 ) 7.4 Hz); 3.00 (ddd,
1H, J1 ) 10.2 Hz, J2 ) 7.9 Hz, J3 ) 5.5 Hz); 3.39 (td, 1H, J1 )
10.5 Hz, J2 ) 4.3 Hz); 4.93 (d, 1H, J ) 5.5 Hz); 5.12 (dd, 1H,
J1 ) 17.0 Hz, J2 ) 1.7 Hz); 5.17 (dd, 1H, J1 ) 10.2 Hz, J2 )
1.7 Hz); 5.71 (dt, 1H, J1 ) 17.0 Hz, J2 ) 10.2 Hz). 13C NMR
(δ): 11.5; 18.1; 22.0; 23.9; 25.7; 31.2; 34.4; 40.2; 40.9; 46.2; 49.7;
56.7, 76.0; 85.5; 118.5; 132.7; 175.5. IR (film): 3075, 2930,
1700, 1460, 760.
(3R,3aS,4aR,6R,8aS)-3-Isopropenyl-2,2,6,9,9-pentame-
thyloctahydro-4aH-pyrrolo[2,1-b][1,3]benzoxazin-1(2H)-
one (6b). Colorless solid. Mp: 126-127°C (from pentane).
[R]25D ) -116.0 (c ) 1.1, CH2Cl2). 1H NMR (δ): 0.80-1.11 (m,
3H); 0.82 (s, 3H); 0.90 (d, 3H, J ) 6.5 Hz); 1.15 (s, 3H); 1.22
(s, 3H); 1.28 (m, 1H), 1.46 (m, 1H); 1.63-1.73 (m, 2H); 1.70 (s,
3H); 1.78 (s, 3H); 1.99 (m, 1H); 2.37 (d, 1H, J ) 7.8 Hz); 3.37
(td, 1H, J1 ) 10.7 Hz, J2 ) 4.1 Hz); 4.80 (s, 1H); 4.87 (d, 1H,
J ) 7.8 Hz); 4.99 (s, 1H). 13C NMR (δ): 17.9; 20.2; 21.9; 23.7;
23.9; 25.2; 25.6; 31.2; 34.4; 41.0; 43.5; 49.6; 55.5; 56.5; 77.4;
84.7; 113.5; 139.8; 177.1. IR (Nujol dispersion): 3085, 1700,
1640, 790, 770, 750, 720 cm-1. Anal. Calcd for C19H31NO2: C,
74.71; H, 10.23; N, 4.59. Found: C, 74.62; H, 10.35; N, 4.73.
(2S,3S,3aS,4aR,6R,8aS)-3-Isopropenyl-2-ethyl-6,9,9-tri-
methyloctahydro-4aH-pyrrolo[2,1-b][1,3]benzoxazin-
1(2H)-one (6c). Colorless solid. Mp: 89-90°C (from pentane).
[R]25D ) -146.1 (c ) 1.1, CH2Cl2). 1H NMR (δ): 0.85-1.13 (m,
3H); 0.93 (d, 3H, J ) 6.5 Hz); 0.94 (t, 3H, J ) 7.4 Hz); 1.22 (s,
3H); 1.28 (m, 1H); 1.45 (qd, 2H, J1 )7.4 Hz, J2 ) 6.3 Hz); 1.48-
1.80 (m, 3H); 1.72 (s, 3H); 1.75 (s, 3H); 2.01 (m, 1H); 2.50 (dt,
1H, J1) 8.7 Hz, J2)6.3 Hz); 2.76 (dd, 1H, J1 ) 8.7 Hz, J2 )
6.0 Hz); 3.44 (td, 1H, J1 ) 10.6 Hz, J2 ) 4.2 Hz); 4.87 (s, 1H);
4.98 (d, 1H, J ) 6.0 Hz); 4.99 (s, 1H). 13C NMR (δ):12.0; 18.9;
20.2; 21.9; 22.4; 24.0; 25.5; 31.1; 34.4; 41.0; 45.0; 48.5; 49.9;
57.0; 76.2; 86.2; 112.8; 140.2; 174.6. IR (Nujol dispersion):
3090, 1720, 705 cm-1. Anal. Calcd for C19H31NO2: C, 74.71;
H, 10.23; N, 4.59. Found: C, 74.84; H, 10.38; N, 4.71.
(2′R,3′S,3a′S,4a′R,6′R,8a′S)-2′,6′,9′,9′-Tetramethylocta-
hydro-4a′H-spiro[cyclohex-2-ene-1,3′-pyrrolo[2,1-b][1,3]-
benzoxazin]-1′(2′H)-one (7g). Colorless solid. Mp: 172-173
1
°C (from pentane). [R]25 ) -99.0 (c ) 0.8, CHCl3). H NMR
D
(δ): 0.86-1.14 (m, 3H); 0.93 (d, 3H, J ) 6.6 Hz); 1.06 (d, 3H,
J ) 7.3 Hz); 1.16 (s, 3H); 1.23 (m, 1H); 1.44 (m, 1H); 1.59-
1.80 (m, 6H); 1.70 (s, 3H); 1.90-2.07 (m, 4H); 3.35 (td, 1H, J1
) 10.6 Hz, J2 ) 4.3 Hz); 4.52 (s, 1H); 5.44 (d, 1H, J ) 10.3
Hz); 5.92 (dt, 1H, J1 ) 10.3 Hz, J2 ) 3.6 Hz). 13C NMR (δ):
10.8; 17.8; 19.6; 21.9; 23.9; 24.8; 25.8; 31.2; 33.0; 34.3; 40.9;
43.8; 47.5; 49.3; 56.5; 75.8; 91.7; 125.3; 130.1; 175.0. IR (Nujol
dispersion): 3070, 1700, 690 cm-1. Anal. Calcd for C20H31-
NO2: C, 75.67; H, 9.84; N, 4.41. Found: C, 75.83; H, 10.01; N,
4.32.
(3S,4S)-N-(8-Mentholyl)-3-isoprenyl-4-methylpyrroli-
dine (8a). Yield: 87%. Colorless solid. Mp: 64-65°C (from
AcOEt/hexane). [R]25D ) -57.8 (c ) 1.1, CH2Cl2). 1H NMR (333
K) (δ): 0.78 (d, 3H, J ) 6.9 Hz); 0.82-1.07 (m, 3H); 0.91 (d,
3H, J ) 6.5 Hz); 0.95 (s, 3H); 1.17 (s, 3H); 1.39-1.52 (m, 2H);
1.55-1.69 (m, 2H); 1.71 (s, 3H); 1.93 (m,1H); 2.32 (m, 1H);
2.47 (m, 1H); 2.61 (m, 1H); 2.85-2.92 (m, 2H); 3.13 (m 1H);
3.62 (td, 1H, J1 ) 10.1 Hz, J2 ) 3.9 Hz); 4.66 (s, 1H); 4.84 (s,
1H); 8.51 (s broad, 1H). 13C NMR (333 K) (δ): 14.5; 16.5; 21.3;
21.9; 22.8; 25.5; 30.9; 33.4; 35.1; 44.3; 46.1; 47.9; 48.8; 53.1;
59.0; 72.6; 110.6; 143.2. IR (Nujol dispersion): 3300 (broad),
1630 cm-1. Anal. Calcd for C18H33NO: C, 77.36; H, 11.90; N,
5.01. Found: C, 77.48; H, 12.03; N, 4.90.
(3R,3aS,4aR,6R,8aS)-3-(1-Phenylvinyl)-2,2,6,9,9-pen-
tamethyloctahydro-4aH-pyrrolo[2,1-b][1,3]benzoxazin-
1(2H)-one (6e). Colorless solid. Mp: 163-164°C (from hex-
1
ane). [R]25 ) -16.4 (c ) 1.2, CH2Cl2). H NMR (δ): 0.82 (s,
D
3H); 0.83 (s, 3H); 0.92-1.16 (m, 3H); 0.95 (d, 3H, J ) 6.5 Hz);
1.21 (s, 3H); 1.35 (m, 1H); 1.50 (m, 1H); 1.74-1.77 (m, 2H);
1.76 (s, 3H); 2.06 (m, 1H); 3.08 (d, 1H, J ) 7.7 Hz); 3.45 (td,
1H, J1 ) 10.6 Hz, J2 ) 4.1 Hz); 5.04 (d, 1H, J ) 7.7 Hz); 5.17
(s, 1H); 5.34 (s, 1H); 7.26-7.36 (m, 5H). 13C NMR (δ): 17.8;
20.5; 21.9; 23.8; 24.9; 25.6; 31.1; 34.3; 41.0; 43.5; 49.5; 53.3;
56.4; 77.4; 85.0; 114.6; 127.0 (2C); 127.4; 128.0 (2C); 142.6;
144.7; 176.8. IR (Nujol dispersion): 3090, 1685, 1610, 780, 710
cm-1. Anal. Calcd for C24H33NO2: C, 78.43; H, 9.05; N, 3.81.
Found: C, 78.28; H, 9.22; N, 3.65.
(4R)-N-(8-Mentholyl)-4-isoprenyl-3,3-dimethylpyrroli-
dine (8b). Yield: 88%. Colorless oil. [R]25 ) -21.1 (c ) 0.8,
D
CH2Cl2). 1H NMR (333 K) (δ): 0.87-1.11 (m, 3H); 0.88 (s, 3H);
0.90 (d, 3H, J ) 6.5 Hz); 0.95 (s, 3H); 1.10 (s, 3H); 1.16 (s,
3H); 1.32-1.49 (m, 2H); 1.55-1.69 (m, 2H); 1.75 (s, 3H); 1.92
(m, 1H); 2.30 (dd, 1H, J1 ) 9.3 Hz, J2 ) 8.8 Hz); 2.54 (d, 1H,
J ) 8.8 Hz); 2.69 (m, 1H); 2.91-3.02 (m, 2H); 3.63 (td, 1H, J1
) 10.2 Hz, J2 ) 4.0 Hz); 4.72 (s, 1H); 4.88 (s, 1H); 8.50 (s broad,
1H). 13C NMR (333 K) (δ): 16.5; 21.2; 21.9 (2C); 22.8; 23.6;
25.6; 30.9; 35.1; 39.6; 44.4; 48.6; 48.7; 54.3; 59.2; 60.7; 72.7;
112.2; 142.8. IR (film): 3300 (broad), 1625 cm-1. Anal. Calcd
for C19H35NO: C, 77.76; H, 12.02; N, 4.77. Found: C, 77.60;
H, 12.16; N, 4.59.
(2S,3R,3aS,4aR,6R,8aS)-2,6,9,9-Tetramethyl-3-vinyl-
octahydro-4aH-pyrrolo[2,1-b][1,3]benzoxazin-1(2H)-one
1
(6f). Colorless oil. [R]25 ) -97.9 (c ) 1.1, CH2Cl2). H NMR
D
(δ): 0.86-1.13 (m, 3H); 0.93 (d, 3H, J ) 6.5 Hz); 1.02 (d, 3H,
J ) 7.6 Hz); 1.18 (s, 3H); 1.28 (m, 1H); 1.49 (m, 1H); 1.60-
1.79 (m, 2H); 1.73 (s, 3H); 2.01 (m, 1H); 2.60 (dq, 1H, J1 ) 8.7
Hz, J2 ) 7.6 Hz); 2.75 (td, 1H, J1 ) 8.7 Hz, J2 ) 6.3 Hz); 3.40
(td, 1H, J1 )10.6 Hz, J2 ) 4.2 Hz); 4.78 (d, 1H, J ) 6.3 Hz);
5.22 (d, 1H, J ) 10.3 Hz); 5.23 (d, 1H, J ) 17.2 Hz); 5.74 (ddd,
1H, J1 ) 8.7 Hz, J2 ) 10.3 Hz, J3 ) 17.2 Hz). 13C NMR (δ):
12.3; 18.5; 21.9; 23.9; 25.4; 31.1; 34.3; 40.1; 40.9; 46.2; 49.7;
56.8; 76.2; 87.5; 118.7; 133.7; 175.6. IR (film): 3090, 2940,
1710, 760, 720 cm-1. Anal. Calcd for C17H27NO2: C, 73.61; H,
9.81; N, 5.05. Found: C, 73.76; H, 9.92; N, 5.18.
(3S,4S)-N-(8-Mentholyl)-3-ethyl-4-isopropenylpyrroli-
dine (8c). Yield: 90%. Colorless oil. [R]25 ) -44.6 (c ) 1.0,
D
1
CH2Cl2). H NMR (C6D6, 351 K) (δ): 0.80 (s, 3H); 0.82-1.12
(m, 3H); 0.82 (t, 3H, J ) 7.3 Hz); 0.92 (d, 3H, J ) 6.4 Hz);
1.16 (s, 3H); 1.16-1.64 (m, 6H); 1.62 (s, 3H); 1.91 (m, 1H); 2.19
(m, 1H); 2.55-2.66 (m, 2H); 2.82-2.94 (m, 2H); 3.11 (m, 1H);
3.79 (td, 1H, J1 ) 10.0 Hz, J2 ) 4.0 Hz); 4.68 (s, 1H); 4.84 (s,
1H); 6.98 (s broad, 1H). 13C NMR (C6D6, 351 K) (δ): 12.3; 16.6;
21.1; 21.5; 21.8; 22.6; 25.8; 31.0; 35.2; 41.4; 44.8; 47.5; 47.8;
49.1; 50.3; 59.7; 72.3; 111.1; 143.3. IR (film): 3280 (broad), 1640
cm-1. Anal. Calcd for C19H35NO: C, 77.76; H, 12.02; N, 4.77.
Found: C, 77.89; H, 11.91; N, 4.89.
(2′S,3′R,3a′S,4a′R,6′R,8a′S)-2′,6′,9′,9′-Tetramethyl-
octahydro-4a′H-spiro[cyclohex-2-ene-1,3′-pyrrolo[2,1-b]-
[1,3]benzoxazin]-1′(2′H)-one (6g). Colorless solid. Mp: 153-
154 °C (from pentane). [R]25 ) -43.9 (c ) 1.0, CHCl3). 1H
D
NMR (δ): 0.88-1.13 (m, 3H); 0.93 (d, 3H, J ) 6.5 Hz); 1.01
(d, 3H, J ) 7.6 Hz); 1.18 (s, 3H); 1.25-1.73 (m, 7H); 1.72 (s,
3H); 1.91-2.03 (m, 4H); 2.30 (q, 1H, J ) 7.6 Hz); 3.40 (td, 1H,
J1 )10.5 Hz, J2 ) 4.2 Hz); 4.68 (s, 1H); 5.40 (d, 1H, J ) 10.2
Hz); 5.88 (dt, 1H, J1 ) 10.2 Hz, J2 ) 3.6 Hz). 13C NMR (δ):
11.3; 19.0; 19.3; 22.0; 24.1; 25.0; 25.6; 27.4; 31.2; 34.4; 41.0;
42.2; 47.3; 50.1; 57.0; 76.1; 89.9; 128.6; 130.7; 176.4. IR (Nujol
dispersion): 3060, 1700, 700 cm-1. Anal. Calcd. for C20H31-
NO2: C, 75.67; H, 9.84; N, 4.41. Found: C, 75.83; H, 9.96; N,
4.54.
(4R)-N-(8-Mentholyl)-3,3-dimethyl-4-(1-phenylvinyl)-
pyrrolidine (8e). Yield: 96%. Colorless oil. [R]25D ) +44.6 (c
1
) 0.9, CH2Cl2). H NMR (333 K) (δ): 0.22 (s, 3H); 0.83-1.16
(m, 3H); 0.84 (s, 3H); 0.91 (d, 3H, J ) 6.5 Hz); 0.98 (s, 3H);
1.18 (s, 3H); 1.40-1.49 (m, 2H); 1.50 (m, 1H); 1.68 (m, 1H);
1.96 (m, 1H); 2.55 (d, 1H, J ) 9.0 Hz); 2.76 (m, 1H); 2.91-
3.14 (m, 3H); 3.64 (td, 1H, J1 ) 10.4 Hz, J2 ) 4.0 Hz); 5.09 (s,
4336 J. Org. Chem., Vol. 70, No. 11, 2005

Alder-Ene Reaction on Chiral Perhydro-1,3-benzoxazines
1H); 5.23 (s, 1H); 7.20-7.35 (m, 5H); 9.50 (s broad, 1H). 13C
NMR (333 K) (δ): 16.5; 21.3; 21.9; 23.1; 25.6; 27.9; 30.9; 35.1;
39.5; 44.4; 48.6; 49.5; 51.6; 59.1; 61.1; 72.8; 113.9; 126.8 (2C);
127.0; 127.9 (2C); 144.0; 147.5. IR (film): 3385 (broad), 3085,
2950, 1625, 780, 700 cm-1. Anal. Calcd for C24H37NO: C, 81.07;
H, 10.49; N, 3.94. Found: C, 81.18; H, 10.36; N, 4.17.
Hz); 7.73 (d, 2H, J ) 8.2 Hz). 13C NMR (δ): 12.4; 20.0; 21.5;
22.6; 42.5; 48.2; 49.4; 51.6; 112.1; 127.3 (2C); 129.5 (2C); 134.1;
142.2; 143.2. IR (film): 3060; 2920, 1600, 1500, 1170, 880, 810
cm-1. Anal. Calcd for C16H23NO2S: C, 65.49; H, 7.90; N, 4.77.
Found: C, 65.52; H, 7.79; N, 4.65.
(4R)-N-Tosyl-3,3-dimethyl-4-(1-phenylvinyl)pyrroli-
(3R,4S)-N-(8-Mentholyl)-3-methyl-4-vinylpyrrolidine
dine (9e). Yield: 62%. Colorless oil. [R]25 ) +73.4 (c ) 2.0,
D
1
(8f). Yield: 84%. Colorless solid. Mp: 59-60 °C (from AcOEt/
CH2Cl2). H NMR (δ): 0.58 (s, 3H); 0.63 (s, 3H); 2.44 (s, 3H);
hexane). [R]25 ) -26.7 (c ) 1.0, CH2Cl2). 1H NMR (333 K)
2.97 (t, 1H, J ) 8.3 Hz); 3.06 (d, 1H, J ) 9.7 Hz); 3.19 (d, 1H,
J ) 9.7 Hz); 3.49 (dd, 1H, J1 ) 8.3 Hz, J2 ) 9.9 Hz); 3.67 (dd,
1H, J1 ) 8.3 Hz, J2 ) 9.9 Hz); 4.93 (s, 1H); 5.23 (s, 1H); 7.19-
7.30 (m, 5H); 7.35 (d, 2H, J ) 8.2 Hz); 7.76 (d, 2H, J ) 8.2
Hz). 13C NMR (δ): 21.3; 21.4; 26.3; 41.2; 51.0; 51.1; 60.9; 114.6;
126.5 (2C); 127.2 (2C); 127.4; 128.1 (2C); 129.5 (2C); 134.0;
143.0; 143.3; 146.1. IR (film): 3060, 3020, 2960, 1625, 1597,
1340, 1160,1095, 780, 735, 705, 665 cm-1. Anal. Calcd for
C21H25NO2S: C, 70.95; H, 7.09; N, 3.94. Found: C, 71.08; H,
6.98; N, 4.05.
D
(δ): 0.82-1.11 (m, 3H); 0.88 (d, 3H, J ) 6.8 Hz); 0.91 (d, 3H,
J ) 6.5 Hz); 0.94 (s, 3H); 1.16 (s, 3H); 1.31-1.52 (m, 2H); 1.53-
1.74 (m, 2H); 1.92 (m, 1H); 2.21 (m, 1H); 2.33 (m, 1H); 2.60-
2.78 (m, 2H); 2.98 (m, 1H); 3.08 (m, 1H); 3.62 (td, 1H, J1 )
10.3 Hz, J2 ) 4.0 Hz); 3.67 (s, 1H); 5.00 (d, 1H, J ) 16.1 Hz);
5.02 (d, 1H, J ) 9.8 Hz); 5.74 (ddd, 1H, J1 ) 8.6 Hz, J2 ) 9.8
Hz, J3 ) 16.1 Hz). 13C NMR (333 K) (δ):14.6; 16.7; 21.3; 21.8;
25.6; 30.9; 35.0; 35.1; 44.2; 45.2; 48.7; 52.8; 59.0; 63.5; 72.7;
115.4; 137.6. IR (Nujol dispersion): 3250 (broad), 1610. cm-1
.
Anal. Calcd for C17H31NO: C, 76.92; H, 11.77; N, 5.28. Found:
C, 77.07; H, 11.66; N, 5.37.
(3R,4S)-N-Tosyl-3-methyl-4-vinylpyrrolidine
(9f).27
Yield: 50%. Colorless solid. Mp: 65-67 °C (from pentane).
[R]25D ) +9.3 (c ) 1.0, CH2Cl2). 1H NMR (δ): 0.76 (d, 3H, J )
7.0 Hz); 2.20 (m, 1H); 2.44 (s, 3H); 2.65 (m, 1H); 2.97 (dd, 1H,
J1 ) 6.1 Hz, J2 ) 9.8 Hz); 3.20 (dd, 1H, J1 ) 6.1 Hz, J2 ) 9.8
Hz); 3.38-3.44 (m, 2H); 4.98 (dd, 1H, J1 ) 17.0 Hz, J2 ) 1.0
Hz); 5.02 (dd, 1H, J1 ) 10.4 Hz, J2 ) 1.0 Hz); 5.49 (ddd, 1H,
J1 ) 17.0 Hz, J2 ) 10.4 Hz, J3 ) 8.3 Hz); 7.33 (d, 2H, J ) 8.1
Hz); 7.72 (d, 2H, J ) 8.1 Hz). 13C NMR (δ): 13.5; 21.5; 36.5;
46.; 51.3; 53.9; 117.0; 127.3 (2C); 129.6 (2C); 133.9; 135.0; 143.3.
IR (Nujol dispersion): 3040, 1600, 1490, 1160, 1000, 910, 830
cm-1. Anal. Calcd for C14H19NO2S: C, 63.36; H, 7.22; N, 5.28.
Found: C, 63.23; H, 7.35; N, 5.26.
(4S,5R)-N-(8-Mentholyl)-4-methyl-2-azaspiro[4,5]dec-
6-ene (8g). Yield: 85%. Colorless oil. [R]25D ) -30.0 (c ) 1.2,
CHCl3). 1H NMR (333 K) (δ): 0.85-1.09 (m, 3H); 0.88 (d, 3H,
J ) 7.5 Hz); 0.90 (d, 3H, J ) 6.5 Hz); 0.91 (s, 3H); 1.13 (s,
3H); 1.32-1.69 (m, 8H); 1.84 (m, 1H); 1.89-1.98 (m, 3H); 2.27
(m, 1H); 2.59-2.66 (m, 2H); 3.16 (m, 1H); 3.62 (td, 1H, J1 )
10.3 Hz, J2 ) 4.1 Hz); 5.47 (d, 1H, J ) 10.2 Hz); 5.72 (dt, 1H,
J1 ) 10.2 Hz, J2 ) 3.7 Hz); 8.45 (s broad, 1H). 13C NMR (333
K) (δ):14.7; 16.9; 20.3; 21.3; 21.9; 25.1; 25.7; 31.0; 35.1; 36.0;
42.2; 42.9; 44.4; 48.4; 52.6; 58.6 (2C); 72.7; 127.3; 131.1. IR
(film): 3300; 2980, 1610, 1450, 1380, 710. cm-1. Anal. Calcd
for C20H35NO: C, 78.63; H, 11.55; N, 4.58. Found: C, 78.51;
H, 11.67; N, 4.61.
(4S,5R)-N-Tosyl-4-methyl-2-azaspiro[4,5]dec-6-ene (9g).
1
Yield: 48%. Colorless oil. [R]25 ) +39.4 (c ) 0.9, CHCl3). H
D
(3S,4S)-N-Tosyl-3-isoprenyl-4-methylpyrrolidine (9a).
NMR (δ): 0.78 (d, 3H, J ) 7.2 Hz); 1.28-1.66 (m, 4H); 1.83
(m, 1H); 1.92-1.98 (m, 2H); 2.44 (s, 3H); 2.95 (dd, 1H, J1 )
9.9 Hz, J2 ) 7.9 Hz); 3.05 (d, 1H, J ) 9.7 Hz); 3.29 (d, 1H, J
) 9.7 Hz); 3.50 (dd, 1H, J1 ) 9.9 Hz, J2 ) 7.9 Hz); 5.17 (d, 1H,
J ) 10.2 Hz); 5.68 (dt, 1H, J1 ) 3.7 Hz, J2 ) 10.2 Hz); 7.31 (d,
2H, J ) 8.3 Hz), 7.71 (d, 2H, J ) 8.3 Hz). 13C NMR (δ): 13.1;
20.2; 21.5; 25.0; 32.6; 42.3; 44.7; 53.5; 59.9; 127.4 (2C); 127.8;
129.1; 129.5 (2C); 133.8; 143.2. IR (film): 3060; 2980, 1610,
1460, 1350, 1180, 680 cm-1. Anal. Calcd for C17H23NO2S: C
66.85; H, 7.59; N, 4.59. Found: C, 66.79; H, 7.68; N, 4.31.
Yield: 58%. Colorless solid. Mp: 55-56°C (from pentane).
1
[R]25 ) +10.8 (c ) 0.8, CH2Cl2). H NMR (δ): 0.60 (d, 3H, J
D
) 7.0 Hz); 1.64 (s, 3H); 2.32 (m, 1H); 2.45 (s, 3H); 2.57 (m,
1H); 3.13 (dd, 1H, J1 ) 9.6 Hz, J2 ) 2.6 Hz); 3.28 (t, 1H, J )
9.6 Hz); 3.38-3.48 (m, 2H); 4.55 (s, 1H); 4.83 (s, 1H); 7.30 (d,
2H, J ) 8.3 Hz); 7.70 (d, 2H, J ) 8.3 Hz). 13C NMR (δ):13.2;
21.5; 22.7; 34.5; 48.2; 48.4; 54.8; 111.6; 127.3 (2C); 129.6 (2C);
134.1; 141.8; 143.2. IR (Nujol dispersion): 3100, 1590, 1170,
890, 810 cm-1. Anal. Calcd for C15H21NO2S: C, 64.48; H, 7.58;
N, 5.01. Found: C, 64.59; H, 7.51; N, 4.90.
(4R)-N-Tosyl-4-isoprenyl-3,3-dimethylpyrrolidine (9b).
Acknowledgment. We thank the Spanish Ministe-
rio de Educacio´n y Ciencia (DGICYT, Projects BQU2002-
01046) for financial support. C.D.R. also thanks the
MEC for a predoctoral fellowship (FPU).
1
Yield: 56%. Colorless oil. [R]25 ) +5.0 (c ) 1.5, CH2Cl2). H
D
NMR (δ): 0.73 (s, 3H); 0.96 (s, 3H); 1.66 (s, 3H); 2.28 (t, 1H,
J ) 8.3 Hz); 2.43 (s, 3H); 3.01 (d, 1H, J ) 9.6 Hz); 3.17 (d, 1H,
J ) 9.6 Hz); 3.35 (dd, 1H, J1 ) 8.3 Hz, J2 ) 9.9 Hz); 3.47 (dd,
1H, J1 ) 8.3 Hz, J2 ) 9.9 Hz); 4.60 (s, 1H); 4.85 (s, 1H); 7.33
(d, 2H, J ) 8.2 Hz); 7.72 (d, 2H, J ) 8.2 Hz). 13C NMR (δ):
21.4; 21.5; 23.3; 26.5; 41.2; 50.5; 54.0; 60.7; 113.5; 127.3 (2C);
129.6 (2C); 134.0; 141.7; 143.3. IR (film): 3080, 2920, 1600,
1500, 1160, 860, 800 cm-1. Anal. Calcd for C16H23NO2S: C,
65.49; H, 7.90; N, 4.77. Found: C, 65.63; H,;8.03 N, 4.82.
(3S,4S)-N-Tosyl-3-ethyl-4-isopropenylpyrrolidine (9c).
Yield: 52%. Colorless oil. [R]25D ) +11.5 (c ) 0.8, CH2Cl2). 1H
NMR (δ): 0.72 (m, 1H); 0.78 (t, 3H, J ) 6.8 Hz); 1.14 (m, 1H);
1.63 (s, 3H); 1.99 (m, 1H); 2.43 (s, 3H); 2.63 (m, 1H); 3.22-
3.44 (m, 4H); 4.54 (s, 1H); 4.81 (s, 1H); 7.32 (d, 2H, J ) 8.2
Supporting Information Available: General experimen-
1
tal methods and copies of H NMR for compounds 6a-g, 7g,
and 9a-g and COSY and NOESY experiments for compounds
6a-g and 7g. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO050360A
(27) We thank one of the reviewer by the notice that this compound
has been recently described as a mixture of stereoisomers: Hirashita,
T.; Tanaka, J.; Hasashi, A.; Araki, S. Tetrahedron Lett. 2005, 46, 289.
J. Org. Chem, Vol. 70, No. 11, 2005 4337