Regio- and stereoselective 5-exo radical cyclizations on a chiral perhydro-1,3-benzoxazine moiety. An access to enantiopure 3-alkylpyrrolidines

Article abstract of DOI:10.1021/jo9816921

Both enantiomers of chiral, nonracemic 3-alkyl-substituted pyrolidines are prepared by diastereo-selective 5-exo-trig cyclization on (-)-8- aminomenthol-derived perhydro-1,3-benzoxazines used as chiral auxiliaries, followed by elimination of the menthol appendage. The diastereoselective radical cyclization is promoted by tributyltin hydride and occurs on a 3- aza-5-hexenyl-type radical, leading to five-membered rings in high yield. The stereocontrol of the cyclization is strongly influenced by 1,3-allylic strain so that an appropriate substitution pattern on the olefin-acceptor and the presence of a vicinal stereocenter are crucial for achieving good diastereoselectivity. The enantiopure pyrrolidines are obtained in three steps with concomitant recovering of the starting (+)-pulegone auxiliary.

Full text of DOI:10.1021/jo9816921

J . Org. Chem. 1999, 64, 4273-4281
4273
Regio- a n d Ster eoselective 5-exo Ra d ica l Cycliza tion s on a Ch ir a l
P er h yd r o-1,3-ben zoxa zin e Moiety. An Access to En a n tiop u r e
3-Alk ylp yr r olid in es
Celia Andre´s, J uan P. Duque-Soladana, and Rafael Pedrosa*
Departamento de Quı´mica Orga´nica, Facultad de Ciencias, Universidad de Valladolid,
Dr. Mergelina s/ n, 47011, Valladolid, Spain
Received August 20, 1998
Both enantiomers of chiral, nonracemic 3-alkyl-substituted pyrolidines are prepared by diastereo-
selective 5-exo-trig cyclization on (-)-8-aminomenthol-derived perhydro-1,3-benzoxazines used as
chiral auxiliaries, followed by elimination of the menthol appendage. The diastereoselective radical
cyclization is promoted by tributyltin hydride and occurs on a 3-aza-5-hexenyl-type radical, leading
to five-membered rings in high yield. The stereocontrol of the cyclization is strongly influenced by
1,3-allylic strain so that an appropriate substitution pattern on the olefin-acceptor and the presence
of a vicinal stereocenter are crucial for achieving good diastereoselectivity. The enantiopure
pyrrolidines are obtained in three steps with concomitant recovering of the starting (+)-pulegone
auxiliary.
In tr od u ction
radical cyclizations is quite limited to date, and chiral
auxiliaries play an attractive role in this kind of reaction,
whose enantioselective version remains almost unex-
plored.6 This fact encouraged us to perform a diastereo-
selective approach to pyrrolidine derivatives by cycliza-
tion of 3-aza-5-hexenyl radical structure attached to an
N,O-acetalic chiral auxiliary7 derived from (-)-8-amino-
menthol (1).8 In view of the structure of our system, two
possibilities emerge for the starting perhydro-1,3-
benzoxazines, which are positional isomers and differ in
the attachment of the precursor of the radical site and
the double bond (A and B in Figure 1). The choice of the
starting compound is not trivial because aryl radicals
derived from related positional isomers behave in a quite
different way.7d If, as expected, both isomers participate
in a 5-exo cyclization process, the pyrrolidine derivative
will be formed, although the newly created stereocenters
will appear in opposite configuration, thereby ensuring
the synthesis of both enantiomers.
Radical cyclizations are considered a modern, powerful
tool in the synthesis of carbocycles and heterocycles,1 and
aza radicals have been used in the preparation of four-
to seven-membered nitrogen rings in several alkaloids
and antibiotics.2,3 The pyrrolidine nucleus is one of the
most common target structures due to the widespread
occurrence in numerous natural products,4 and the main
strategy to form this ring by radical cyclization is based
on intramolecular addition of aza-5-hexenyl radicals
previously generated by homolysis of sensitive carbon-
heteroatom bonds present in the skeleton. The ring
closure arises predominantly by addition to the inner
olefinic position (C-5) to give a five-membered ring (5-
exo attack), although the 6-endo addition is also possible,
leading to piperidine derivatives. The position of nitrogen
in the 5-hexenyl skeleton seems to determine the rate of
cyclization, so that 3-aza-5-hexenyl radicals are known
to be very useful and selective precursors.5 On the other
hand, the asymmetric synthesis of pyrrolidines using
We report here on radical cyclizations of chiral posi-
tional isomeric N-alkylperhydro-1,3-benzoxazines A and
B, using tributyltin hydride as promoter and the labile
C-Se bond as a source of alkyl radicals.
* Corresponding author. Phone: Int + 34-983-423211. Fax: Int +
34-983-423013. E-mail: Pedrosa@qo.uva.es.
(1) (a) Curran, D. P. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Semmelhack, M. F., Eds.; Pergamon: Oxford, 1991;
Vol 4, p 779. (b) J asperse, P.; Curran, D. P.; Fevig, T. L. Chem. Rev.
1991, 91, 1237. (c) Aldabbagh, F.; Bowman, W. R. Comtemp. Org.
Synth. 1997, 261. (d) Fallis, A. B.; Brinza, I. M. Tetrahedron 1997, 53,
17543. (e) Rousseau, G.; Homsi, F. Chem. Soc. Rev. 1997, 26, 453.
(2) For early synthesis of alkaloids by radical cyclizations see for
example: Hart, D. J .; Tsai, Y. J . Am. Chem. Soc. 1984, 106, 8201 and
8209.
(3) (a) Bachi, M. D.; Frolow, F.; Hoornaert, C. J . Org. Chem. 1983,
48, 1841. (b) Boger, D. L.; Coleman, R. S. J . Am. Chem. Soc. 1988,
110, 1321 and 4796. (c) Boger, D. L.; Wysocki, R. J . J . Org. Chem. 1989,
54, 1238.
Resu lts
The cyclization study was started on the 2-vinyl-
substituted perhydro-1,3-benzoxazines 4a -d prepared
from (-)-8-aminomenthol (1)9 in three steps (Scheme 1).
The condensation of 1 with phenylselenoacetaldehyde in
dichloromethane afforded 2-(phenylseleno)methylperhy-
dro-1,3-benzoxazine 2 as a single compound. The pres-
(4) (a) Krogsgaard-Larsen, P. In Comprehensive Medicinal Chem-
istry; Hansch, C., Sammes, P. G., Taylor, J . B., Eds.; Pergamon:
Oxford, 1990; Vol. 3. (b) Dictionary of Alkaloids; Southon, I. W.,
Buckingham, J ., Eds.; Chapman-Hall: London, 1989.
(5) (a) Padwa, A.; Nimmesgern, H.; Wong, G. S. K. J . Org. Chem.
1985, 50, 5620. (b) Ishibashi, H.; So, T. S.; Okochi, K.; Sato, S.;
Nakamura, N.; Nakatani, H.; Ikeda, M. J . Org. Chem. 1991, 56, 95.
(c) Parsons, T. S.; Taylor, R. J . K. J . Chem. Soc., Chem. Commun. 1993,
1224. (d) Della, E. W.; Knill, A. M. J . Org. Chem. 1996, 61, 7529. (e)
Gupta, V.; Besev, M.; Engman, L. Tetrahedron Lett. 1998, 39, 2429.
(6) (a) Gennari, C.; Poli, G.; Scolastico, C.; Vasallo, M. Tetrahe-
dron: Asymm. 1991, 2, 793. (b) Cardillo, B.; Galeazzi, R.; Mobbilli,
G.; Orena, M.; Rossetti, M. Heterocycles 1994, 38, 2663.
(7) (a) Alberola, A.; Andre´s, C.; Pedrosa, R. Synlett 1990, 763. (b)
Andre´s, C.; Nieto, J .; Pedrosa, R.; Villaman˜a´n, N. J . Org. Chem. 1996,
61, 4130. (c) Andre´s, C.; Duque-Soladana, J . P.; Iglesias, J . M.; Pedrosa,
R. Tetrahedron Lett. 1996, 37, 9085. (d) Andre´s, C.; Duque-Soladana,
J . P.; Iglesias, J . M.; Pedrosa, R. Synlett 1997, 1391.
(8) Rassat, A.; Rey, P. Tetrahedron 1974, 30, 3315.
(9) He, X.-C.; Eliel, E. Tetrahedron 1987, 43, 4979.
10.1021/jo9816921 CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/22/1999

4274 J . Org. Chem., Vol. 64, No. 12, 1999
Andre´s et al.
Ta ble 1. Ra d ica l Cycliza tion s of
P er h yd r o-1,3-ben zoxa zin es 4a -d
entry no. oxazine
R1
R2
yield (%)a
products ratiob
1
2
3
4
4a
4b
4c
4d
H
H
H
H
Me
82
85
90
89
5a (56), 6a (44)
5b (61), 6b (39)
5c (53), 6c (47)
6d (100)c
Me
Ph
Me
a
b
Combined chemical yield of pure isolated compounds. Num-
bers in parentheses refer-to-diastereomeric ratio determined by
integration of the signals of 1H NMR spectra of reaction mixture.
c A single diastereomer is observed in the reaction mixture by 1H
NMR.
Sch em e 2
F igu r e 1.
Sch em e 1
of the acetalic substituent on the tetrahydrooxazine
chair.12
Radical cyclizations were accomplished by syringe
pump addition (5-8 h) of 0.02 M solutions of tributyltin
hydride and AIBN in benzene to 0.02 M solutions of 4a -c
in refluxing benzene. After a period of 24-48 h at reflux
the conversion was completed, providing a mixture of two
diastereoisomers, 5a -c and 6a -c, which could be iso-
lated and purified by flash chromatography with some
contamination of organotin derivatives (Table 1, Scheme
1
2). H NMR analysis revealed that the compounds are
the 5-exo ring closure diastereomers, and NOESY experi-
ments led us to establish a 2,3-cis relationship between
the acetalic hydrogen and that attached to the vicinal
stereocenter for the major diastereomers 5a -c and the
trans stereochemistry for the minor ones, 6a -c.
In general the facial discrimination in the cyclization
of perhydro-1,3-benzoxazines 4a -c is modest, although
compound 4d behaves in a different way. In the same
reaction conditions cyclization of 4d proceeds with a
complete diastereoselection, yielding a single product, 6d ,
whose stereochemistry was found to be 2,3-trans in the
five-membered ring. On the other hand, NOESY studies
showed an N-axial layout of the -CH2-N- group for
each diastereomer 5 and 6. This fact is consistent with a
generalized anomeric effect exhibited by many tetra-
hydro-1,3-oxazines in which N-axial conformers dominate
in the nitrogen inversion equilibrium.13 Additionally, MO
calculations performed on our system clearly confirmed
this trend.14 According to these observations, the slight
preference toward 2,3-cis selectivity observed during the
ring closure of precursors 4a -c is in agreement with the
ence of the tautomeric hydroxyimine found in the prepa-
ration of related N-unsubstituted 1,3-oxazines10 has not
been detected. The experimental conditions for the reduc-
tive ring opening of 2 have been shown to be crucial.
Thus, treatment of 2 with a mixture of sodium boro-
hydride (1 equiv) and boron trifluoride-etherate (2.5
equiv) in THF at room temperature yielded the amino
alcohol 3 in 92% yield, whereas the use of equimolar
mixtures of NaBH4 and BF3‚OEt2 highly decreased the
yield, and the reduction with DIBALH produced signifi-
cant amounts of diphenyldiselenide as byproduct.11 Fi-
nally, condensation of 3 with acrolein, crotonaldehyde,
cinnamaldehyde, and senecialdehyde in refluxing ben-
zene led to perhydro-1,3-benzoxazines 4a -d in good to
excellent yields (73-99%). It is worthy to note that all
the perhydro-1,3-benzoxazines 2 and 4a -d have the
same configuration at C-2, determined as S by NOE
experiments. This implies that condensation of (-)-8-
aminomenthol with aldehydes takes place in a completely
stereoselective way, leading to an equatorial arrangement
(12) This behavior clearly contrasts with that described for 1,3-
oxazolidines. See for example: Higashiyama, H.; Inoue, H.; Yamauchi,
T.; Takahashi, H. J . Chem. Soc., Perkin Trans. 1 1995, 111.
(13) (a) Riddell, F. G.; Lehn, J . M. J . Chem. Soc. (B) 1968, 1224. (b)
Katritzky, A. R.; Baker, V. J .; Brito-Palma, F. M. S. J . Chem. Soc.,
Perkin Trans. 2 1980, 1739.
(10) Szakonyi, Z.; Fu¨lop, F.; Berna´th, G.; Evanics, F.; Riddell, F. G.
Tetrahedron 1998, 54, 1013, and references therein.
(11) Clive, D. L. J .; J oussef, A. C. J . Org. Chem. 1990, 55, 1096.
(14) Preliminary SCF-MO calculations indicate a preference toward
the N-axial invertomer of about 1.9 kcal mol-1 (UHF/PM3) or 1.2 kcal
mol-1 (UHF/6-31G*//UHF/3-21G*) in our benzoxazine radicals.

5-exo Radical Cyclizations
J . Org. Chem., Vol. 64, No. 12, 1999 4275
Sch em e 4
F igu r e 2. Transition structures for radical cyclization of
4a -d .
Sch em e 3
Ta ble 2. Ra d ica l Cycliza tion s of
P er h yd r o-1,3-ben zoxa zin es 8a -d
entry no. oxazine
R1
R2
yield (%)a
products ratiob
1
2
3
4
8a
8b
8c
8d
H
Me
Ph
H
H
H
84
89
90
90
9a (68), 10a (32)
9b (65), 10b (35)
9c (58), 10c (42)
9d (66), 10d (34)
Me Me
a
b
Combined chemical yield of pure isolated compounds. Num-
bers in parentheses refer-to-diastereomeric ratio determined by
integration of the signals of 1H NMR spectra of reaction mixture.
intermediate N,O-acetals with sodium borohydride led
to the N-allylic-8-aminomenthols 7a -d that were con-
densed with phenylselenoacetaldehyde in refluxing
benzene to yield 2-(phenylselenomethyl)perhydro-1,3-
benzoxazines 8a -d . Nevertheless, variable amounts (5-
10%) of diphenyldiselenide (PhSeSePh) were formed
during this condensation, and a careful chromatographic
purification is needed to remove the excess of aldehyde
and the formed PhSeSePh because of inhibition of the
radical cyclization step in favor of a rapid intermolecular
hydrogen abstraction.18 A better approach, which avoids
the formation of the organoselenium impurity, implies
the N-alkylation of the perhydrobenzoxazine 2. Treat-
ment of 2 with allyl, crotyl, cinnamyl, and prenyl bromide
and potassium carbonate in acetonitrile as solvent pro-
vides respectively 8a -d , in very good yields.
The cyclization reaction was carried out by slow
additions (5-7 h, syringe pump) of a 0.02 M solution of
tributyltin hydride (1.25 equiv) and a catalytic amount
(0.05 equiv) of AIBN in benzene to a 0.02 M solution of
the crude perhydro-1,3-benzoxazine 8a -d in refluxing
benzene. After 1-2 h of additional heating a mixture of
diastereomeric 5-exo cyclization products 9a -d and
10a -d was obtained in excellent yield (82-90%) but in
modest de (Scheme 4, Table 2).
5-hexenyl radical cyclization model proposed by Beckwith
and Houk.15 The formation of the pyrrolidine derivatives
could be interpreted taking into account the transition
structures A and B (Figure 2). The chairlike structure A
should be preferred on the basis of the Beckwith model,
and therefore a 2,3-cis relationship will arise predomi-
nantly leading to the major diastereoisomers 5a -c. On
the contrary, the minor products 6a -c would emerge
from the less favored boatlike structures B. Obviously a
different pathway should be followed when R2 * H,
because 4d cyclized in a 2,3-trans fashion and a single
diastereomer was obtained. This complete reversal of
diastereoselection can be accounted for by an overwhelm-
ingly preference for the boatlike transition structure B.
The origin of this strong effect has been nicely investi-
gated by Rajanbabu in some sugar-derived radicals,
finding that a local allylic strain at the olefinic group
plays a key role in the formation of trans-cyclic diaster-
eomers.16 By analogy we propose that the boatlike
structures B compensate the normal stereoelectronic
effects of standard 5-hexenyl radicals when R2 ) Me
because this arrangement contains the most favorable
allylic conformation.17 As a consequence, the trans-
diastereomer 6d is the single product observed.
Diastereomers 9a -c and 10a -c were easily separated
by flash chromatography,19 but it was not possible to
assign the absolute configuration at this stage. However,
their transformation into the known substituted pyrro-
lidines allowed us to determine the configuration at the
newly created stereocenter.
The stereoselection for the cyclization of N-allylperhy-
dro-1,3-benzoxazines 8a -d could be rationalized by tak-
ing into account the two possible chair-boat transition
The cyclization process on perhydrobenzoxazines bear-
ing the radical acceptor on the nitrogen substituent was
tested on compounds 8a -d . The preparation of the
starting compounds was carried out in two different ways
(Scheme 3). Sequential reaction of (-)-8-aminomenthol
(1) with R,â-unsaturated aldehydes and reduction of the
(18) Crich, D.; J iao, X.-Y.; Harwood, J . S. J . Org. Chem. 1996, 61,
2368, and references therein.
(15) (a) Beckwith, A. L. J .; Schiesser, C. H. Tetrahedron 1985, 41,
3925. (b) Spellmeyer, D. C.; Houk, K. N. J . Org. Chem. 1987, 52, 959.
(16) Rajanbabu, T. V. Acc. Chem. Res. 1991, 24, 139.
(19) Cyclization products 9d and 10d could not be separated by
chromatography. The other diastereomers were isolated by flash
chromatography, although many attempts to remove the residual
organotins were not successful in some cases.
(17) Hoffman, R. W. Chem. Rev. 1989, 89, 1841.

4276 J . Org. Chem., Vol. 64, No. 12, 1999
Andre´s et al.
Sch em e 6
F igu r e 3. Transition structures for radical cyclization of
8a -d .
Sch em e 5
solution in methanol-THF, leading to the enantiopure
3-substituted pyrrolidines 13a -d or en t-13a -c, respec-
tively, with the concomitant release of (+)-pulegone.
In summary, the above protocol constitutes a novel
stereoselective approach to enantiopure 3-alkyl-substi-
tuted pyrrolidines based on a 5-exo-trig radical cyclization
performed on a chiral perhydrobenzoxazine template.
Both enantiomeric pyrrolidine derivatives can be ob-
tained as major product by changing the substituents at
C-2 and the nitrogen atom in the starting chiral per-
hydro-1,3-benzoxazine.The high level of diastereoselec-
tion disclosed under local minimum allylic strain is being
investigated, and aplications will be reported in due
course.
structures depicted in Figure 3. The favored chairlike
radical C leads to the major stereoisomers 9a -d with
2,4-cis relationship, whereas the boatlike D provides the
minor compounds 10a -d with 2,4-trans configuration.
The low level of stereodifferentiation is in agreement with
the absence of a strong local allylic strain even in the
case in which R2 ) Me.
The transformation of the cyclization products into the
final enantiopure 3-alkyl-substituted pyrrolidines was
achieved with good chemical yields in two steps (Schemes
5 and 6). Reductive ring opening of the N,O-acetal moiety
in 6a -d , the minor stereoisomers obtained from the
cyclization of 4a -d , with LAH/AlCl3 affords 8-pyrrolidi-
nylmenthols 11a -d in excellent yields (92-99%). In turn,
compounds 11a -c were also obtained by reduction of
9a -c, the major cyclization stereoisomers obtained from
8a -c. This fact allows us to assign the proposed stereo-
chemistry for 9a -c.
The epimeric 8-pyrrolidinylmenthols 12a -c were ob-
tained by reductive ring opening of the major diastere-
omers 5a -c resulting from cyclization of 4a -c, or instead
by reduction of the minor ones 10a -c, isolated from the
cyclization of 8a -c.
PCC oxidation of 11a -d or 12a -c yielded the corre-
sponding 8-pyrrolidinylmenthones, which were submitted
to â-elimination by treatment with an aqueous KOH
Exp er im en ta l Section
Gen er a l Meth od s. 1H NMR spectra were registered at 300
MHz in CDCl3 as solvent. 13C NMR (75 MHz) spectra were
obtained by the DEPT technique. Mass spectra were performed
by electronic impact (EI) at 70 eV or chemical ionization (CI).
Optical rotations were measured on a digital polarimeter.
Melting points were measured on a capillary open tube and
are uncorrected. Column chromatography was carried out on
silica gel 60 using the flash technique.
(-)-8-Am in om en th ol (1). A solution of (-)-8-benzylami-
nomenthol9 (80 g, 0.31 mol) in ethanol (300 mL) containing 5
g of 10% Pd-C catalyst was stirred under hydrogen (10 atm)
for 24 h. The mixture was filtered through a pad of Celite, the
solution was concentrated under vacuum, and the residue was
recrystallized from hexane, leading to (-)-8-aminomenthol (52
g, 99%) as a white solid, mp 68-69 °C (hexanes); [R]20D ) -6.81
(c 0.53, MeOH) (lit.8 [R]20 ) -7; c 0.5, MeOH). 1H NMR
D
(CDCl3) δ: 0.91 (d, 3H, J ) 6.5 Hz); 0.91-1.10 (m, 4H); 1.11
(s, 3H); 1.17 (s, 3H); 1.30-1.50 (m, 1H); 1.60-1.70 (m, 2H);
1.85-2.05 (m, 1H); 3.35 (br s, 3H); 3.62 (dt, 1H, J ) 10.2 Hz,
J ) 4.1 Hz). 13C NMR (CDCl3) δ: 21.8; 22.0; 25.9; 30.7; 33.7;
34.6; 44.2; 52.0; 53.0; 72.1. IR (Nujol, cm-1): 3320, 3260, 1600.
CIMS (m/z, %): 172 (M + 1, 100), 155 (20), 137 (69).
P h en ylselen oa ceta ld eh yd e.20 To a vigorously stirred
solution of diphenyldiselenide (PhSeSePh, 5.8 g, 18.6 mmol)
(20) See footnote 3 in: Kowalski, C. J .; Dung, J .-S. J . Am. Chem.
Soc. 1980, 102, 7951.

5-exo Radical Cyclizations
J . Org. Chem., Vol. 64, No. 12, 1999 4277
in THF (60 mL) under argon atmosphere at 0 °C was added
dropwise an equimolar amount of bromine (0.9 mL). After 15
min neat ethylvinyl ether (3.6 mL, 37.2 mmol) was added in
one portion, and the purple color instantaneously changed to
pale yellow. After stirring for 10 min, hydrochloric acid (2 N
solution) was added, and the mixture was stirred for an
additional 2 h at room temperature. Diethyl ether (50 mL) was
added to the reaction mixture and, after separation, the
aqueous layer was extracted with ether (2 × 50). The organic
layer was washed with brine and dried over anhydrous MgSO4.
The solvent was removed under vacuum to afford phenyl-
selenoacetaldehyde (7.3 g, 36.7 mmol, 99%), yellow oil; bp 150-
NMR (CDCl3) δ: 0.89 (d, 3H, J ) 6.4 Hz); 1.04 (s, 3H); 1.08 (s,
3H); 1.63 (dd, 3H, J ) 1.5 Hz, J ) 6.5 Hz); 2.50-3.00 (m, 4H);
3.40 (dt, 1H, J ) 4.1 Hz, J ) 10.5 Hz); 4.70 (d, 1H, J ) 6.5
Hz), 5.42 (ddd, 1H, J ) 1.5 Hz, J ) 6.4 Hz, J ) 15.4 Hz); 5.78
(ddq, 1H, J ) 0.7 Hz, J ) 6.5 Hz, J ) 15.4 Hz); 7.10-7.40 (m,
5H). Anal. Calcd for C22H33NOSe: C, 65.01; H, 8.18; N, 3.45.
Found: C, 64.89; H, 8.01; N, 3.72.
N-(P h en ylselen o)eth yl-2r-stir yl-4,4,7r-tr im eth yl-tr a n s-
octa h yd r o-1,3-ben zoxa zin e (4c). Yield: 99%. 1H NMR
(CDCl3) δ: 0.89 (d, 3H, J ) 6.6 Hz); 0.90-1.10 (m, 2H); 1.11
(s, 6H); 1.30-1.50 (m, 3H); 1.53-1.70 (m, 2H); 1.89-1.91 (m,
1H); 2.73-2.79 (m, 1H); 2.87-2.93 (m, 2H); 2.99-3.04 (m, 1H);
3.43 (dt, 1H, J ) 4.1 Hz, J ) 10.5 Hz); 5.03 (d, 1H, J ) 5.1
Hz), 6.20 (dd, 1H, J ) 5.1 Hz, J ) 16.1 Hz); 6.63 (d, 1H, J )
16.1 Hz); 6.83 (t, 2H, J ) 7.6 Hz); 6.97 (t, 1H, J ) 7.2 Hz);
7.18-7.40 (m, 7H). 13C NMR (CDCl3): 18.2; 22.0; 24.7; 26.3;
29.2; 30.9; 34.5; 40.9; 45.1; 46.7; 56.9; 75.1; 86.8; 126.0; 126.3;
127.5; 128.1; 128.2; 128.5; 129.3; 131.5; 132.4; 136.0. IR (neat,
cm-1): 3080, 1680, 1600, 1480, 970, 740, 690. Anal. Calcd for
1
152 °C (4 Torr). H NMR (CDCl3) δ: 3.51 (d, 2H, J ) 4.0 Hz);
7.25 (m, 3H); 7.50 (m, 2H); 9.48 (t, 1H, J ) 4.0 Hz). IR (neat,
cm-1): 2820, 2720, 1570, 1470, 1430, 735, 690. EIMS (m/z,
%): 200 (M, 8), 157 (21), 91 (100).
2-(P h en ylselen o)m eth ylp er h yd r o-1,3-ben zoxa zin e (2).
A mixture of (-)-8-aminomenthol (1) (5.6 g, 33 mmol) and
phenylselenoacetaldehyde (7.3 g, 37 mmol) in dichloromethane
(100 mL) was stirred for 18 h at room temperature. The solvent
was removed under vacuum, yielding the compound 2 (12.3 g,
99%) as a yellow oil, [R]20D ) +17.8, (c 0.92, CH2Cl2). 1H NMR
(CDCl3) δ: 0.85-1.07 (m, 4H); 0.91 (d, 3H, J ) 6.5 Hz); 1.07
(s, 3H); 1.08 (s, 3H); 1.40-1.52 (m, 1H); 1.60-1.85 (m, 3H);
1.90-2.00 (m, 1H); 3.01 (dd, 1H, J ) 4.8 Hz, J ) 7.1 Hz); 3.18
(dd, 1H, J ) 4.8 Hz, J ) 7.1 Hz); 3.42 (dt, 1H, J ) 4.1 Hz, J
) 10.4 Hz); 4.56 (t, 1H, J ) 4.8 Hz); 7.20 (m, 3H); 7.55 (m,
2H). 13C NMR (CDCl3) δ: 20.3; 22.2; 25.0; 30.0; 31.4; 34.0; 35.2;
42.3; 50.9; 51.4; 74.8; 82.1; 126.4; 128.1; 131.3; 132.0. IR (neat,
cm-1) : 3270, 730, 685. EIMS (m/z, %): 352 (M, 0.23), 182
(100), 137 (33), 41 (21).
C
27H35NOSe: C, 69.21; H, 7.53; N, 2.99. Found: C, 69.56; H,
7.81; N, 2.85.
N-(P h en ylselen o)eth yl-2r-(2′,2′-d im eth ylvin yl)-4,4,7r-
tr im eth yl-tr a n s-octa h yd r o-1,3-ben zoxa zin e (4d ). Yield:
1
85%, pale yellow oil; [R]20 ) -10.63 (c 1.1, CHCl3). H NMR
D
(CDCl3) δ: 0.85-1.05 (m, 3H); 0.90 (d, 3H, J ) 6.5 Hz); 1.09
(s, 6H); 1.28 (m, 1H); 1.45 (m, 1H); 1.60-1.70 (m, 2H); 1.64 (s,
6H); 1.90 (m, 1H); 2.55-2.65 (m, 1H); 2.70-2.80 (m, 1H); 2.80-
3.00 (m, 2H); 3.42 (dt, 1H, J ) 4.1 Hz, J ) 10.5 Hz); 5.05 (d,
1H, J ) 7.0 Hz); 5.13 (d, 1H, J ) 7.0 Hz); 7.20-7.28 (m, 3H);
7.45-7.51 (m, 2H). 13C NMR (CDCl3) δ: 17.7; 18.7; 22.2; 25.0;
25.7; 26.7; 30.2; 31.2; 34.8; 41.3; 45.4; 47.5; 56.8; 75.3; 84.0;
124.1; 126.6; 128.9; 129.8; 132.5; 136.8. IR (neat, cm-1): 1680,
1580, 1480. Anal. Calcd for C23H35NOSe: C, 65.70; H, 8.39;
N, 3.31. Found: C, 66.02; H, 8.28; N, 3.27.
N-(P h en ylselen o)eth yl-8-a m in om en th ol (3). To a mix-
ture of sodium borohydride (11.6 g, 116 mmol) and boron
trifluoride-ether complex (94 mL, 290 mmol) in dry THF (300
mL) at 0 °C, under argon atmosphere, was added dropwise a
solution of benzoxazine 2 (29.2 g, 83 mmol) in THF (100 mL),
and the mixture was stirred at room temperature for 8 h. Then,
the reaction mixture was quenched with methanol (120 mL),
the solvent was evaporated under vacuum, and the residue
was refluxed for 1 h with 20% NaOH aqueous solution (120
mL). The reaction mixture was extracted with chloroform (3
× 75 mL), and the organic layer was washed with brine and
dried over anhydrous Na2SO4. The solvent was evaporated
Ra d ica l Cycliza tion of P er h yd r oben zoxa zin es 4a -d .
Gen er a l Meth od . In a two-necked rounded flask equipped
with a condenser and a septum, a solution of 4a -d (1.0 mmol)
in dry benzene (50 mL) was heated to reflux. Then, a previouly
prepared solution of tributyltin hydride (0.35 mL, 1.25 mmol)
and azobisisobutyronitrile (16 mg, 0.1 mmol) in the same
solvent (12 mL) was added (syringe pump) over a period of
6-8 h. The reaction was monitored by TLC, and after comple-
tion (24-48 h) the solvent was removed and the residue
under vacuum to give 3 (27 g, 92%) as a pale yellow oil, [R]20
D
1
analyzed by H NMR. Flash chromatography yielded diaster-
1
) -13.3 (c 0.73, CH2Cl2). H NMR (CDCl3) δ: 0.80-0.94 (m,
eomers 5a -c and 6a -d in 82-90% combined yield.
5H); 0.83 (d, 3H, J ) 6.5 Hz); 0.94 (s, 3H); 1.01 (s, 3H); 1.10-
1.25 (m, 1H); 1.30-1.42 (m, 1H); 1.50-1.65 (m, 2H); 1.80-
1.90 (m, 1H); 2.68 (ddd, 1H, J ) 5.0 Hz, J ) 7.2 Hz, J ) 12.7
Hz); 2.81-3.00 (m, 3H); 3.53 (dt, 1H, J ) 4.1 Hz, J ) 10.4
Hz); 7.20 (m, 3H); 7.45 (m, 2H). 13C NMR (CDCl3) δ: 21.6; 22.1;
25.7; 26.2; 28.8; 31.0; 34.9; 40.2; 44.3; 49.7; 56.6; 72.6; 127.2;
129.1; 129.1; 133.0. IR (neat, cm-1): 3300, 1590, 1490, 740,
690. Anal. Calcd for C18H29NOSe: C, 61.00; H, 8.25; N, 3.95.
Found: C, 61.29; H, 8.51; N, 3.76.
Con d en sa tion of Selen oa m in om en th ol 3 w ith Un sa t-
u r a ted Ald eh yd es. Gen er a l P r oced u r e. A mixture of
selenoaminomenthol 3 (708 mg, 2.0 mmol) and the correspond-
ing R,â-unsaturated aldehyde (3.1 mmol) was refluxed in
benzene (50 mL) for 3 days. The solvent was removed under
vacuum, and the residue was used without further purifica-
tion. Flash chromatography on silica gel deactivated with
triethylamine and ethyl acetate/hexanes as eluent yielded
analytical samples.
N-(P h en ylselen o)eth yl-4,4,7r-tr im eth yl-2r-vin yl-tr a n s-
octa h yd r o-1,3-ben zoxa zin e (4a ). Yield: 73%. 1H NMR
(CDCl3) δ: 0.90 (d, 3H, J ) 6.5 Hz); 1.07 (s, 3H); 1.08 (s, 3H);
1.15-1.50 (m, 4H); 1.53-1.78 (m, 3H); 1.89-1.98 (m, 1H);
2.55-2.75 (m, 1H); 2.75-3.00 (m, 3H); 3.42 (dt, 1H, J ) 4.1
Hz, J ) 10.5 Hz); 4.82 (d, 1H, J ) 5.4 Hz), 5.14 (dt, 1H, J )
1.5 Hz, J ) 10.4 Hz); 5.31 (dt, 1H, J ) 1.5 Hz, J ) 17.3 Hz);
5.76 (ddd, 1H, J ) 5.4 Hz, J ) 10.4, J ) 17.3 Hz); 7.10-7.25
(m, 3H); 7.45-7.55 (m, 2H). Anal. Calcd for C21H31NOSe: C,
64.27; H, 7.96; N, 3.57. Found: C, 64.57; H, 8.01; N, 3.58.
N-(P h en ylselen o)eth yl-2r-(2′-pr open yl)-4,4,7r-tr im eth yl-
tr a n s-octa h yd r o-1,3-ben zoxa zin e (4b). Yield: 98%. 1H
Com p ou n d 6a . Colorless oil; [R]20 ) -57.7 (c 1.00, CH2-
D
1
Cl2). H NMR (CDCl3) δ: 0.80-1.00 (m, 3H); 0.84 (d, 3H, J )
6.6 Hz); 0.97 (d, 3H, J ) 6.8 Hz); 1.02 (s, 3H); 1.05 (s, 3H);
1.10-1.45 (m, 3H); 1.50-1.65 (m, 2H); 1.80 (m, 1H); 1.98 (m,
2H); 2.76 (dt, 1H, J ) 3.0 Hz, J ) 8.7 Hz); 1.95 (q, 1H, J ) 8.0
Hz); 3.30 (dt, 1H, J ) 4.2 Hz, J ) 10.6 Hz); 4.21 (d, 1H, J )
1.8 Hz). 13C NMR (CDCl3) δ: 18.9; 19.6; 22.3; 24.8; 26.8; 29.5;
31.3; 34.9; 38.6; 41.5; 43.4; 44.8; 53.1; 74.8; 93.0. IR (neat,
cm-1): 1450, 1380, 1050, 1030. Anal. Calcd for C15H27NO: C,
75.88; H, 11.47; N, 5.90. Found: C, 75.52; H, 11.14; N, 5.42.
Com p ou n d 5a . Colorless oil; [R]20 ) -43.2 (c 1.00, CH2-
D
1
Cl2). H NMR (CDCl3) δ: 0.84 (d, 3H, J ) 6.6 Hz); 0.85-1.05
(m, 3H); 0.91 (d, 3H, J ) 6.9 Hz); 1.04 (s, 3H); 1.09 (s, 3H);
1.20-1.75 (m, 5H); 1.80 (m, 1H); 1.90 (m, 1H); 2.10 (m, 1H);
2.83 (dt, 1H, J ) 4.7 Hz, J ) 8.8 Hz); 3.00 (ddd, 1H, J ) 5.5
Hz, J ) 8.7 Hz, J ) 10.6 Hz); 3.30 (dt, 1H, J ) 4.1 Hz, J )
10.5 Hz); 4.51 (d, 1H, J ) 4.0 Hz). 13C NMR (CDCl3) δ: 14.1;
22.0; 22.3; 24.9; 26.5; 29.0; 31.3; 35.2; 37.4; 41.6; 42.8; 44.0;
53.1; 74.2; 87.8. IR (neat, cm-1): 1460, 1370, 1050. Anal. Calcd
for C15H27NO: C, 75.88; H, 11.47; N, 5.90. Found: C, 76.19;
H, 11.71; N, 5.51.
Com p ou n d 6b. Colorless oil; [R]20 ) -42.6 (c 1.02, CH2-
D
1
Cl2). H NMR (CDCl3) δ: 0.85-1.10 (m, 3H); 0.88 (t, 3H, J )
7.4 Hz); 0.91 (d, 3H, J ) 6.8 Hz); 1.09 (s, 3H); 1.11 (s, 3H);
1.20-1.75 (m, 7H); 1.85 (m, 2H); 2.00 (m, 1H); 2.80 (dt, 1H, J
) 2.6 Hz, J ) 8.4 Hz); 3.01 (q, 1H, J ) 8.1 Hz); 3.36 (dt, 1H,
J ) 4.1 Hz, J ) 10.5 Hz); 4.36 (d, 1H, J ) 1.5 Hz). 13C NMR
(CDCl3) δ: 12.1; 19.5; 22.2; 25.2; 27.1; 27.2; 27.4; 31.5; 35.0;
41.6; 43.5; 44.5; 46.5; 53.2; 75.1; 91.5. IR (neat, cm-1): 1460,

4278 J . Org. Chem., Vol. 64, No. 12, 1999
Andre´s et al.
1380, 1200, 1030. Anal. Calcd for C16H29NO: C, 76.44; H,
11.63; N, 5.57. Found: C, 76.69; H, 11.40; N, 5.81.
hydrolyzed by addition of 10% aqueous solution of HCl (50 mL)
and extracted with ethyl acetate (3 × 75 mL). The organic layer
was washed with brine and dried over MgSO4. Evaporation of
the solvent under vacuum afforded a residue (5.7 g, 25 mmol),
which was further purified by recrystallization to yield 7b
(84%) as a white solid, mp 50-51 °C (hexanes); [R]20D ) -29.0
Com p ou n d 5b. Colorless oil, 1H NMR (CDCl3) δ: 0.85-
1.05 (m, 3H); 0.88 (t, 3H, J ) 7.4 Hz); 0.91 (d, 3H, J ) 6.8
Hz); 1.10 (s, 3H); 1.17 (s, 3H); 1.20-1.75 (m, 7H); 1.85 (m, 1H);
2.00 (m, 2H); 2.90 (m, 1H); 3.07 (ddd, 1H, J ) 4.8 Hz, J ) 8.9
Hz, J ) 10.7 Hz); 3.34 (dt, 1H, J ) 4.2 Hz, J ) 10.6 Hz); 4.66
(d, 1H, J ) 3.6 Hz). 13C NMR (CDCl3) δ: 12.7; 22.0; 22.2; 24.7;
26.3; 27.0; 29.6; 31.3; 35.1; 41.4; 42.7; 43.8; 45.0; 53.6; 74.2;
86.9. IR (neat, cm-1): 1460, 1380, 1200, 1030. Anal. Calcd for
1
(c 1.19, CH2Cl2). H NMR (CDCl3) δ: 0.90-1.10 (m, 4H); 0.91
(d, 3H, J ) 6.5 Hz); 1.11 (s, 6H,); 1.28 (m, 1H); 1.45 (br s, 1H);
1.60-1.70 (m, 5H); 1.95 (m, 1H); 3.10 (dd, 1H, J ) 5.9 Hz, J
) 12.4 Hz); 3.20 (dd, 1H, J ) 5.1 Hz, J ) 12.4 Hz); 3.61 (dt,
1H, J ) 4.1 Hz, J ) 10.2 Hz); 5.44-5.65 (m, 2H); 8.45 (br s,
1H). 13C NMR (CDCl3) δ: 17.6; 21.7; 22.0; 25.6; 26.2; 30.9; 35.0;
43.0; 44.3; 49.2; 56.3; 72.4; 127.1; 128.9. IR (Nujol, cm-1): 3240;
960; 840. CIMS (m/z, %): 226 (M + 1, 100); 137 (20); 112 (43).
Anal. Calcd for C14H27NO: C, 74.61; H, 12.08; N, 6.61. Found:
C, 74.43; H, 11.87; N, 6.39.
C
16H29NO: C, 76.44; H, 11.63; N, 5.57. Found: C, 76.74; H,
11.75; N, 5.63.
Com p ou n d 6c. Colorless oil, 1H NMR (CDCl3) δ: 0.85-
1.10 (m, 3H); 0.90 (d, 3H, J ) 6.6 Hz); 1.13 (s, 6H); 1.25-1.50
(m, 3H); 1.55-1.75 (m, 2H); 1.85 (m, 1H); 1.95 (m, 1H); 2.35
(m, 1H); 2.51 (dd, 1H, J ) 9.2 Hz, J ) 13.6 Hz); 2.90 (m, 2H);
3.03 (q, 1H, J ) 8.3 Hz); 3.35 (dt, 1H, J ) 4.1 Hz, J ) 10.4
Hz); 4.50 (d, 1H, J ) 1.2 Hz); 7.13-7.28 (m, 5H). 13C NMR
(CDCl3) δ: 20.3; 22.2; 24.8; 26.9; 27.4; 31.2; 35.0; 40.2; 41.5;
43.5; 43.9; 45.4; 53.0; 74.7; 90.9; 125.7; 128.1; 128.8; 140.8. IR
(neat, cm-1): 1460, 1380. Anal. Calcd for C21H31NO: C, 80.46;
H, 9.97; N, 4.47. Found: C, 80.29; H, 10.30; N, 4.81.
N-Cin n a m yl-8-a m in om en th ol (7c). Following the proce-
dure described for 7b this amino alcohol was obtained by
condensation of 1 with cinnamaldehyde followed by reduction
with NaBH4 in a 98% total yield, white solid, mp 43-45 °C
1
(hexanes); [R]20 ) -46.4, (c 1.29, CH2Cl2). H NMR (CDCl3)
D
δ: 0.90-1.10 (m, 5H); 0.91 (d, 3H, J ) 6.5 Hz); 1.14 (s, 6H);
1.32 (m, 1H); 1.43 (br s, 1H); 1.68 (m, 2H); 1.98 (m, 1H); 3.33
(ddd, 1H, J ) 1.3 Hz, J ) 6.3 Hz, J ) 13.1 Hz); 3.44 (ddd, 1H,
J ) 1.3 Hz, J ) 6.3 Hz, J ) 13.1 Hz); 3.64 (dt, 1H, J ) 4.0 Hz,
J ) 10.3 Hz); 6.24 (dt, 1H, J ) 6.3 Hz, J ) 15.9 Hz); 6.49 (dt,
1H, J ) 1.3 Hz, J ) 15.9 Hz); 7.20-7.38 (m, 5H). 13C NMR
(CDCl3) δ: 21.9; 22.1; 25.7; 26.3; 30.9; 35.0; 43.5; 44.4; 49.1;
56.6; 72.5; 126.2; 127.4; 127.7; 128.4; 131.3; 136.8. IR (Nujol,
cm-1): 3050, 1590, 740, 690. EIMS (m/z, %): 287 (M, 1); 174
Com p ou n d 5c. Colorless oil, [R]20 ) -62.1 (c 1.48, CH2-
D
1
Cl2). H NMR (CDCl3) δ: 0.85-1.05 (m, 3H); 0.90 (d, 3H, J )
6.5 Hz); 1.06 (s, 3H); 1.10 (s, 3H); 1.20-1.75 (m, 5H); 1.85-
2.00 (m, 2H); 2.40-2.46 (m, 1H); 2.57 (dd, 1H, J ) 7.2 Hz, J
) 13.4 Hz); 2.87 (dd, 1H, J ) 8.3 Hz, J ) 13.4 Hz); 2.93 (dt,
1H, J ) 4.5 Hz, J ) 8.8 Hz); 3.11 (ddd, 1H, J ) 5.6 Hz, J )
8.9 Hz, J ) 10.5 Hz); 3.34 (dt, 1H, J ) 4.1 Hz, 10.4 Hz); 4.55
(d, 1H, J ) 3.9 Hz); 7.13-7.27 (m, 5H). 13C NMR (CDCl3) δ:
22.0; 22.1; 25.0; 26.5; 27.5; 31.5; 35.5; 35.7; 42.0; 43.0; 44.2;
45.2; 54.1; 74.5; 87.2; 125.5; 128.5; 129.0; 142.1. IR (neat,
(46); 117 (100), 115 (25), 91 (13), 41 (16). Anal. Calcd for C19H29
-
NO: C, 79.39; H, 10.17; N, 4.87. Found: C, 79.54; H, 9.91; N,
5.08.
cm-1): 3050, 1600, 1500, 1450, 750, 690. Anal. Calcd for C21H31
-
NO: C, 80.46; H, 9.97; N, 4.47. Found: C, 80.31; H, 9.71; N,
4.63.
N-P r en yl-8-a m in om en th ol (7d ). Yield: 96%, white solid,
1
mp 55-57 °C (hexanes); [R]20 ) -22.4, (c 1.00, CH2Cl2). H
D
Com p ou n d 6d . Colorless oil; [R]20 ) -52.6 (c 1.03, CH2-
NMR (CDCl3) δ: 0.90-1.10 (m, 4H); 0.91 (d, 3H, J ) 6.4 Hz);
1.11 (s, 3H); 1.13 (s, 3H); 1.27 (m, 1H); 1.45 (br s, 1H); 1.60-
1.75 (m, 3H); 1.64 (s, 3H); 1.68 (s, 3H); 1.93 (m, 1H); 3.14 (dd,
1H, J ) 6.0 Hz, J ) 7.0 Hz); 3.20 (dd, 1H, J ) 6.0 Hz, J ) 7.0
Hz); 3.61 (dt, 1H, J ) 4.1 Hz, J ) 10.2 Hz); 5.20 (t, 1H, J )
7.0 Hz).13C NMR (CDCl3) δ: 17.8; 21.5; 22.1; 25.6; 25.7; 26.2;
31.0; 35.1; 38.7; 44.5; 49.7; 56.5; 72.6; 122.2; 134.8. IR (Nujol,
cm-1): 3350, 3140, 1670. CIMS (m/z, %): 240 (M + 1, 100).
Anal. Calcd for C15H29NO: C, 75.26; H, 12.21; N, 5.85. Found:
C, 75.58; H, 12.42; N, 5.91.
Con den sation of N-Allylic-8-am in om en th ols with P h en -
ylselen oa ceta ld eh yd e. Gen er a l P r oced u r e. A mixture of
the corresponding amino alcohol 7a -d (5.7 mmol) and phen-
ylselenoacetaldehyde (1.7 g, 8.5 mmol) in anhydrous benzene
(20 mL) was heated at reflux for 48 h. The solvent was removed
and the residue was filtered through Celite, obtaining 8a -d
as dark yellow oils acompanied by variable amounts of
PhSeSePh as impurity.
N-Alk yla tion of Ben zoxa zin e 2 w ith Allylic Br om id es.
Gen er a l P r oced u r e. A mixture of benzoxazine 2 (1.7 g, 5.8
mmol), potasium carbonate (1.7 g, 12.0 mmol), and the
corresponding allylic bromide (7.0 mmol) in dry acetonitrile
was heated in an oil bath at 80-90 °C for 48 h. The reaction
mixture was diluted with ether, the solid was filtered off, and
the solvent was concentrated under vacuum. The oily residue
was used without further purification for the radical cyclization
protocol. Analytical samples were obtained by flash chroma-
tography on silica gel pretreated with triethylamine (5%) and
EtOAc/hexane as eluent.
N-Allyl-2r-(ph en ylselen o)m eth yl-4,4,7r-tr im eth yl-tr a n s-
octa h yd r o-1,3-ben zoxa zin e (8a ). Pale yellow oil, 97% yield.
1H NMR (CDCl3) δ: 0.98-1.15 (m, 3H); 0.91 (d, 3H J ) 6.5
Hz); 1.12 (s, 6H); 1.40 (m, 1H); 1.45-1.52 (m, 2H); 1.60-1.75
(m, 2H); 1.90 (m, 1H); 3.05 (d, 2H, J ) 6.1 Hz); 3.20 (dd, 1H,
J ) 5.2 Hz, J ) 17.9 Hz); 3.40-3.52 (m, 2H); 4.83 (t, 1H J )
6.0 Hz); 4.99 (dd, 1H, J ) 1.8 Hz, J ) 10.2 Hz); 5.21 (dd, 1H,
J ) 1.8 Hz, J ) 17.1 Hz); 5.87-5.98 (m, 1H); 7.20-7.30 (m,
3H); 7.45-7.52 (m, 2H).13C NMR (CDCl3) δ: 20.3; 22.2; 25.0;
26.8; 31.3; 31.4; 34.9; 41.2; 45.3; 46.1; 57.4; 76.3; 87.2; 114.0;
126.8; 128.9; 131.3; 132.0; 140.8. IR (neat, cm-1) : 3090, 1640,
D
1
Cl2). H NMR (CDCl3) δ: 0.85 (d, 3H, J ) 6.5 Hz); 0.85-1.05
(m, 3H); 0.90 (d, 3H, J ) 6.5 Hz); 0.93 (d, 3H, J ) 6.5 Hz);
1.09 (s, 3H); 1.11 (s, 3H); 1.34-1.50 (m, 3H); 1.50-1.80 (m,
4H); 1.90 (m, 2H); 2.70 (dt, 1H, J ) 2.6 Hz, J ) 8.1 Hz); 3.00
(q, 1H, J ) 8 Hz); 3.40 (dt, 1H, J ) 4.2 Hz, J ) 10.5 Hz); 4.50
(d, 1H, J ) 2.1 Hz). 13C NMR (CDCl3) δ: 19.4; 19.9; 21.3; 22.2;
24.9; 25.7; 27.0; 31.0; 31.3; 35.0; 41.6; 43.7; 44.6; 51.8; 53.0;
74.7; 90.0. IR (neat, cm-1): 1450, 1380. Anal. Calcd for C17H31
-
NO: C, 76.92; H, 11.77; N, 5.28. Found: C, 77.12; H, 12.02;
N, 5.19.
N-Allyl-8-a m in om en th ol (7a ). To a mixture of (-)-8-
aminomenthol 1 (10 g, 58.5 mmol) and anhydrous potasium
carbonate (8.9 g, 64 mmol) in dry acetonitrile (200 mL) under
argon atmosphere, and cooled to 0 °C, was slowly added (4 h)
allyl bromide (5.4 mL, 64 mmol). The mixture was stirred at
room temperature for 2 days, and then, the solids were
eliminated by filtration and the solution was concentrated in
vacuo. The residue was recrystallized from hexanes, obtaining
7a (9.0 g, 42.7 mmol, 73%) as white solid, mp 53-54 °C
1
(hexanes); [R]20 ) -27.9, (c 1.11, CH2Cl2). H NMR (CDCl3)
D
δ: 0.86 (d, 3H, J ) 6.5 Hz); 0.90-1.07 (m, 5H); 1.08 (s, 3H);
1.09 (s, 3H); 1.30 (m, 1H); 1.45 (br. s, 1H); 1.56 (m, 2H); 1.92
(m, 1H); 3.16 (ddt, 1H, J ) 1.3 Hz, J ) 5.5 Hz, J ) 13.3 Hz);
3.26 (ddt, 1H, J ) 1.3 Hz, J ) 5.5 Hz, J ) 13.3 Hz); 3.58 (dt,
1H, J ) 4.0 Hz, J ) 10.2 Hz); 5.02 (dq, 1H, J ) 1.3 Hz, J )
10.2 Hz); 5.12 (dq, 1H, J ) 1.3 Hz, J ) 17.9 Hz); 5.84 (ddt,
1H, J ) 5.5 Hz, J ) 10.2 Hz, J ) 17.9 Hz). 13C NMR (CDCl3)
δ: 21.9; 22.1; 25.8; 26.3; 31.0; 35.0; 43.9; 44.4; 49.3; 56.6; 72.5;
115.8; 136.3. IR (Nujol, cm-1): 3200, 1640. CIMS (m/z, %): 212
(M + 1, 100); 210 (3). Anal. Calcd for C13H25NO: C, 73.88; H,
11.92; N, 6.63. Found: C, 73.69; H, 11.66; N, 6.82.
N-Cr otyl-8-a m in om en th ol (7b). A mixture of (-)-8-ami-
nomenthol (1) (5 g, 29 mmol) and crotonaldehyde (2.7 mL, 32
mmol) in dichloromethane (50 mL) was stirred at room
temperature for 24 h. The solvent was removed under vacuum,
and the residue was redissolved in methanol (50 mL) and
cooled to 0 °C. To this solution sodium borohydride (3.4 g, 90
mmol) was added in portions over 1 h and the mixture stirred
at room temperature overnight. The reaction mixture was

5-exo Radical Cyclizations
J . Org. Chem., Vol. 64, No. 12, 1999 4279
1600, 740, 690. Anal. Calcd for C21H31NOSe: C, 64.27; H, 7.96;
N, 3.57. Found: C, 64.61; H, 7.89; N, 3.49.
4.7 Hz); 0.91 (d, 3H, J ) 6.0 Hz); 1.13 (s, 3H); 1.15 (s, 3H);
1.20-1.70 (m, 7H); 1.80-1.90 (m, 1H); 1.90-2.15 (m, 1H);
2.15-2.25 (m, 1H); 2.69 (t, 1H, J ) 8.2 Hz); 3.02 (t, 1H, J )
8.0 Hz); 3.39 (dt, 1H, J ) 4.3 Hz, J ) 10.5 Hz); 4.84 (dd, 1H,
J ) 1.2 Hz, J ) 5.3 Hz). 13C NMR (CDCl3) δ: 12.8; 20.7; 22.2;
24.8; 27.1; 28.8; 31.2; 35.0; 36.9; 38.2; 41.5; 43.3; 50.2; 53.1;
74.6; 86.6. IR (neat, cm-1): 1460, 1380, 1100, 1080. Anal. Calcd
for C16H29NO: C, 76.44; H, 11.63; N, 5.57. Found: C, 76.23;
H, 11.86; N, 5.72.
N-Cr ot yl-2r-(p h en ylselen o)m et h yl-4,4,7r-t r im et h yl-
tr a n s-octa h yd r o-1,3-ben zoxa zin e (8b). Pale yellow oil, 98%
yield. 1H NMR (CDCl3) δ: 0.90-1.15 (m, 3H); 0.99 (d, 3H, J )
6.5 Hz); 1.20 (s, 3H); 1.23 (s, 3H); 1.25-1.55 (m, 2H); 1.58-
1.75 (m, 2H); 1.73 (s, 3H); 1.90 (m, 1H); 3.07 (d, 2H, J ) 6.3
Hz); 3.13 (d, 1H, J ) 15.6 Hz); 3.37 (d, 1H, J ) 15.6 Hz); 3.43
(dt, 1H, J ) 4.0 Hz, J ) 10.4 Hz); 4.80 (t, 1H, J ) 6 Hz); 5.50-
5.54 (m, 2H); 7.20-7.30 (m, 3H); 7.45-7.55 (m, 2H). 13C NMR
(CDCl3) δ: 17.8; 20.1; 22.6; 25.1; 27.0; 31.4; 31.7; 35.0; 41.3;
44.7; 46.3; 57.3; 76.3; 87.4; 124.8; 126.5; 128.9; 131.4; 132.1;
Com p ou n d 10b. Colorless oil; [R]20 ) -31.2 (c 0.62, CH2-
D
1
Cl2). H NMR (CDCl3) δ: 0.85-1.12 (m, 3H); 0.87 (t, 3H, J )
7.4 Hz); 0.91 (d, 3H, J ) 6.4 Hz); 1.12 (s, 6H); 1.35-1.65 (m,
6H); 1.65-1.75 (m, 1H); 1.85-1.95 (m, 2H); 2.15-2.30 (m, 1H);
2.50 (dd, 1H, J ) 5.1 Hz, J ) 8.8 Hz); 3.20 (t, 1H, J ) 8.8 Hz);
3.39 (dt, 1H, J ) 4.2 Hz, J ) 10.4 Hz); 4.75 (dd, 1H, J ) 1.7
Hz, J ) 4.7 Hz). 13C NMR (CDCl3) δ: 12.7; 19.9; 22.3; 24.8;
26.8; 29.3; 31.3; 35.1; 36.0; 38.4; 41.6; 43.8; 49.8; 53.1; 74.7;
87.0. Anal. Calcd for C16H29NO: C, 76.44; H, 11.63; N, 5.57.
Found: C, 76.56; H, 11.83; N, 5.61.
133.4. IR (neat, cm-1): 3030, 1600, 760. Anal. Calcd for C22H33
-
NOSe: C, 65.01; H, 8.18; N, 3.45. Found: C, 65.17; H, 8.03;
N, 3.42.
N-Cin n am yl-2r-(ph en ylselen o)m eth yl-4,4,7r-tr im eth yl-
tr a n s-octa h yd r o-1,3-ben zoxa zin e (8c). Pale yellow oil, 85%
yield. 1H NMR (CDCl3) δ: 0.92 (d, 3H, J ) 6.5 Hz); 0.95-1.20
(m, 3H); 1.16 (s, 3H); 1.18 (s, 3H); 1.40-1.55 (m, 2H); 1.62 (m,
1H); 1.70 (m, 1H); 1.92 (m, 1H); 3.11 (d, 2H, J ) 6 Hz); 3.39
(dd, 1H, J ) 5.5 Hz, J ) 17.9 Hz); 3.48 (dt, 1H, J ) 4.0 Hz, J
) 10.5 Hz); 3.62 (dd, 1H, J ) 5.6 Hz, J ) 17.9 Hz); 4.85 (t,
1H, J ) 6.0 Hz); 6.32 (dt, 1H, J ) 5.3 Hz, J ) 15.9 Hz); 6.52
(d, 1H, J ) 15.9 Hz); 7.30-7.40 (m, 8H); 7.45-7.55 (m, 2H).
13C NMR (CDCl3) δ: 20.3; 22.2; 25.0; 26.9; 31.3; 31.5; 35.0;
41.3; 45.0; 46.4; 57.4; 76.4; 87.3; 126.1; 126.5; 127.0; 128.4;
128.9; 129.1; 131.5; 132.1; 132.7; 137.5. IR (neat, cm-1): 3080,
1660, 1600, 740, 690. Anal. Calcd for C27H35NOSe: C, 69.21;
H, 7.53; N, 2.99. Found: C, 69.39; H, 7.42; N, 3.02.
N-P r en yl-2r-(p h en ylselen o)m et h yl-4,4,7r-t r im et h yl-
tr a n s-octa h yd r o-1,3-ben zoxa zin e (8d ). Pale yellow oil, 85%
yield. [R]20D ) -9.64 (c 0.28, CH2Cl2). 1H NMR (CDCl3) δ: 0.91
(d, 3H, J ) 6.6 Hz); 0.95-1.10 (m, 3H); 1.11 (s, 3H); 1.13 (s,
3H); 1.25-1.50 (m, 3H); 1.58 (s, 3H); 1.60-1.80 (m, 1H); 1.66
(d, 3H, J ) 1.3 Hz); 1.90 (m, 1H); 3.07 (d, 2H, J ) 5.9 Hz);
3.07-3.16 (m, 1H); 3.35-3.54 (m, 2H); 4.78 (t, 1H, J ) 5.9
Hz); 5.25-5.30 (m, 1H); 7.20-7.30 (m, 3H); 7.45-7.50 (m, 2H).
13C NMR (CDCl3) δ: 17.9; 19.8; 22.2; 25.0; 25.7; 27.0; 31.3;
31.6; 35.0; 41.1; 41.2; 46.4; 57.1; 77.0; 87.3; 126.4; 127.8; 128.8;
129.3; 131.4; 132.0. IR (neat, cm-1): 1670, 1580, 1480. Anal.
Calcd for C23H35NOSe: C, 65.70; H, 8.39; N, 3.31. Found: C,
65.98; H, 8.54; N, 3.38.
Com p ou n d 9c. Colorless oil; [R]20 ) -33.6 (c 0.78, CH2-
D
1
Cl2). H NMR (CDCl3) δ: 0.90-1.08 (m, 3H); 0.92 (d, 3H, J )
6.6 Hz); 1.08 (s, 3H); 1.12 (s, 3H); 1.40-1.50 (m, 3H); 1.50-
1.60 (m, 1H); 1.65-1.75 (m, 1H); 1.80-1.90 (m, 1H); 2.18 (ddd,
1H, J ) 5.2 Hz, J ) 10.3 Hz, J ) 13.6 Hz); 2.42-2.49 (m, 1H);
2.69-2.82 (m, 3H); 2.93 (t, 1H, J ) 8 Hz); 3.41 (dt, 1H, J )
4.2 Hz, J ) 10.5 Hz); 4.84 (dd, 1H, J ) 1.2 Hz, J ) 5.2 Hz);
7.13-7.28 (m, 5H). 13C NMR (CDCl3) δ: 20.6; 22.2; 24.8; 27.1;
31.2; 35.0; 36.5; 38.2; 41.5; 41.8; 43.4; 50.1; 53.1; 74.6; 86.5;
125.6; 128.1; 128.5; 141.3. Anal. Calcd for C21H31NO: C, 80.46;
H, 9.97; N, 4.47. Found: C, 80.61; H, 10.10; N, 4.52.
Com p ou n d 10c. Colorless oil; [R]20 ) -40.2 (c 2.00, CH2-
D
1
Cl2). H NMR (CDCl3) δ: 0.85-1.10 (m, 3H); 0.90 (d, 3H, J )
6.5 Hz); 1.03 (s, 3H); 1.13 (s, 3H); 1.30-1.50 (m, 2H); 1.50-
1.70 (m, 3H); 1.80-1.92 (m, 2H); 2.57-2.69 (m, 4H); 3.13 (dd,
1H, J ) 3.8 Hz, J ) 8.2 Hz); 3.39 (dt, 1H, J ) 4.2 Hz, J ) 10.5
Hz); 4.80 (dd, 1H, J ) 1.4 Hz, J ) 4.7 Hz); 7.13-7.28 (m, 5H).
13C NMR (CDCl3) δ: 20.5; 22.3; 24.8; 26.8; 31.3; 35.1; 35.6;
38.6; 41.6; 42.2; 43.4; 49.3; 53.1; 74.5; 86.9; 125.8; 128.2; 128.7;
141.3. Anal. Calcd for C21H31NO: C, 80.46; H, 9.97; N, 4.47.
Found: C, 80.55; H, 10.13; N, 4.50.
Com p ou n d s 9d a n d 10d . As a mixture of diastereoisomers.
1H NMR (CDCl3) δ: 0.91 and 0.93 (d, 6H, J ) 6.5 Hz and J )
7.5 Hz); 0.85-1.10 (m, 3H); 0.95 (d, 3H, J ) 7.5 Hz); 1.16 and
1.17 (s, 3H); 1.17 and 1.18 (s, 3H); 1.35-1.65 (m, 5H); 1.65-
1.90 (m, 3H); 1.90-2.05 and 2.05-2.20 (m, 1H); 2.87 (t, J )
8.0 Hz) and 2.63 (dd, 1H, J ) 3.5 Hz, J ) 8.5 Hz); 3.00 and
3.20 (t, 1H, J ) 8.0 Hz and J ) 8.5 Hz); 3.43 (dt, 1H, J ) 4.0
Hz, J ) 10.0 Hz,); 4.77 and 4.89 (dd, 1H, J ) 1.3 Hz, J ) 5.3
Hz and J ) 1.7 Hz, J ) 3.4 Hz).
Red u ctive Rin g Op en in g of Com p ou n d s 5, 6, 9, a n d
10. Gen er a l P r oced u r e. A mixture of lithium aluminum
hydride (39 mg, 2.0 mmol) and aluminum chloride (55 mg, 0.4
mmol) in dry THF (10 mL) was stirred under argon atmo-
sphere in an ice-salt bath (ca. -10 °C). Then, a solution of
compound 5, 6, 9, or 10 (0.4 mmol) in THF (10 mL) was slowly
added and the reaction stirred for 10 min. The reaction mixture
was quenched by careful addition of water. The solvents were
removed under vacuum, and the residue was diluted with
water and extracted with chloroform (3 × 25 mL). The organic
layer was washed with brine and dried over anhydrous sodium
sulfate. After evaporation of the solvent, the corresponding
pyrrolidinylmenthols 11a -d and 12a -c were obtained as
colorless oils in 95-99% yield.
Ra d ica l Cycliza tion of Ben zoxa zin es 8a -d . Following
the general method described for 4a -d , to a refluxing solution
of the corresponding benzoxazine 8a -d (1.0 mmol) in dry
benzene (50 mL) was slowly added (syringe pump, 6 h) a
solution of tributyltin hydride (0.35 mL, 1.25 mmol) and AIBN
(8 mg, 0.05 mmol) in anhydrous benzene (10 mL). The reaction
was completed after additional reflux of 1-2 h. The solvent
was removed under vacuum, and the residue was chromato-
graphed on silica gel (ethyl acetate/hexanes 1:15), affording
diastereomers 9a -c and 10a -c in 84-90% combined yield.
Compounds 9d and 10d could not be separated.
Com p ou n d 9a . Colorless oil; [R]20 ) -36.7 (c 1.05, CH2-
D
1
Cl2). H NMR (CDCl3) δ: 0.85-1.10 (m, 3H); 0.91 (d, 3H, J )
6.5 Hz); 1.08 (d, 3H, J ) 6.4 Hz); 1.12 (s, 3H); 1.15 (s, 3H);
1.20-1.50 (m, 3H); 1.50-1.75 (m, 2H); 1.85 (m, 1H); 2.20 (m,
2H); 2.66 (t, 1H, J ) 8 Hz); 3.03 (t, 1H, J ) 8 Hz); 3.39 (dt,
1H, J ) 4.2 Hz, J ) 10.5 Hz); 4.85 (dd, 1H, J ) 1.2 Hz, J )
5.3 Hz). 13C NMR (CDCl3) δ: 20.6; 20.7; 22.2; 24.8; 27.1; 29.4;
31.2; 35.0; 40.1; 41.5; 43.3; 52.0; 53.2; 74.6; 87.8. Anal. Calcd
for C15H27NO: C, 75.88; H, 11.47; N, 5.90. Found: C, 75.61;
H, 11.79; N, 5.53.
Com p ou n d 10a . Colorless oil; [R]20 ) -26.7 (c 1.06, CH2-
D
1
Cl2). H NMR (CDCl3) δ: 0.85-1.10 (m, 3H); 0.91 (d, 3H, J )
(3′R)-8-(3′-Meth ylpyr r olidin yl)m en th ol (11a). Yield: 99%.
6.5 Hz); 1.04 (d, 3H, J ) 6.6 Hz), 1.11 (s, 3H); 1.12 (s, 3H);
1.20-1.45 (m, 3H); 1.45-1.70 (m, 2H); 1.80-2.00 (m, 2H);
2.40-2.45 (m, 2H); 3.24 (t, 1H, J ) 10.2 Hz); 3.39 (dt, 1H, J )
4.2 Hz, J ) 10.4 Hz); 4.75 (dd, 1H, J ) 1.9 Hz, J ) 4.9 Hz).
13C NMR (CDCl3) δ: 19.6; 21.5; 22.2; 24.7; 26.7; 28.4; 31.3;
35.0; 40.3; 41.5; 43.9; 51.5; 53.1; 74.6; 87.5. Anal. Calcd for
Colorless oil; [R]20 ) -14.7 (c 1.08, CH2Cl2). 1H NMR (330 K,
D
CDCl3) δ: 0.85-1.10 (m, 3H); 0.90 (d, 3H, J ) 6.2 Hz); 1.05
(s, 3H); 1.10 (d, 3H, J ) 7.3 Hz); 1.20-1.50 (m, 3H); 1.35 (s,
3H); 1.50-1.70 (m, 4H); 1.95-2.10 (m, 2H); 2.20 (m, 1H); 2.70-
3.40 (broad, 3H); 3.77 (dt, 1H, J ) 4.2 Hz, J ) 10.5 Hz). 13C
NMR (330 K, CDCl3) δ: 13.3; 17.6; 20.9; 21.7; 25.8; 26.6; 27.7;
31.0; 31.8; 32.2; 34.7; 44.3; 48.6; 53.4; 71.8. IR (neat, cm-1):
3400, 1440. CIMS (m/z, %): 240(M + 1, 100), 126 (75). Anal.
Calcd for C15H29NO: C, 75.24; H, 12.22; N, 5.85. Found: C,
74.96; H, 12.47; N, 6.04.
C
15H27NO: C, 75.88; H, 11.47; N, 5.90. Found: C, 75.55; H,
11.72; N, 5.62.
Com p ou n d 9b. Colorless oil; [R]20 ) -41.8 (c 1.00, CH2-
D
1
Cl2). H NMR (CDCl3) δ: 0.85-1.13 (m, 3H); 0.87 (t, 3H, J )

4280 J . Org. Chem., Vol. 64, No. 12, 1999
Andre´s et al.
(3′R)-8-(3′-Eth ylpyr r olidin yl)-m en th ol (11b). Yield: 97%,
by addition of a 2 N aqueous solution of HCl and concentrated
in vacuo to remove the organic solvents. The remaining acidic
solution was extracted with Et2O (2 × 25 mL) to recover (+)-
pulegone. The aqueous layer was alkalinized with concentrated
NaOH solution and extracted with chloroform (4 × 25 mL).
The organic layer was washed with brine and dried over
anhydrous sodium sulfate. The pyrrolidines were isolated as
hydrochlorides by bubbling dry HCl throughout the solution
and removing the solvent. Chromatographic purification of this
salt in alumina afforded analytical samples.
1
colorless oil; [R]20 ) -14.5 (c 1.02, CH2Cl2). H NMR (330 K,
D
CDCl3) δ: 0.85-1.10 (m, 3H); 0.88 (t, 3H, J ) 7.5 Hz); 0.90 (d,
3H, J ) 6.2 Hz); 0.91 (s, 3H); 1.16 (s, 3H); 1.20-1.75 (m, 8H);
1.85-2.10 (m, 3H); 2.35-3.20 (br, 3H); 3.62 (dt, 1H, J ) 4.2
Hz, J ) 10.5 Hz); 7.40-8.20 (br s, 1H). 13C NMR (330 K,
CDCl3) δ: 12.0; 17.1; 21.5; 22.0; 25.5; 28.0; 29.6; 31.0; 34.8;
39.3; 43.8; 58.6; 58.9; 72.8. IR (neat, cm-1): 3100, 1450. CIMS
(m/z, %): 254 (M +1, 100), 238 (8), 140 (41), 113 (5). Anal.
Calcd for C16H31NO: C, 75.83; H, 12.33; N, 5.53. Found: C,
75.76; H, 12.38; N, 5.50.
(R)-3-Meth ylp yr r olid in e (13a ). Hydrochloride: 61% yield;
[R]20 ) + 6.9 (c 1.67, MeOH). 1H NMR (CDCl3) δ: 1.15 (d,
(3′S)-8-(3′-Ben zylpyr r olidin yl)m en th ol (11c). Yield: 99%,
D
1
colorless oil; [R]20 ) +4.6 (c 1.02, CH2Cl2). H NMR (330 K,
D
3H, J ) 7.1 Hz); 1.50-1.65 (m, 1H); 2.10-2.20 (m, 1H); 2.35-
2.50 (m, 1H); 2.80 (dd, 1H, J ) 9.0 Hz, J ) 11.0 Hz); 3.25-
3.35 (m, 1H); 3.40-3.50 (m, 2H); 9.40-10.1 (br. s, 2H). 13C
NMR (CDCl3) δ: 17.0; 31.8; 33.0; 44.7; 51.3. EIMS (m/z, %):
85 (M-HCl, 16), 68 (3), 43 (100). N-Benzoyl derivative: white
solid, mp 64-65 °C (hexanes); [R]20D ) +70.2 (c 1.03, CH2Cl2).
1H NMR (CDCl3), 1:1 mixture of rotamers δ: 1.01 (d, 3H, J )
6.6 Hz); 1.13 (d, 3H, J ) 6.6 Hz); 1.40-1.60 (m, 2H); 1.90-
2.15 (m, 2H); 2.15-2.40 (m, 2H); 3.01 (dd, 1H, J ) 8.4 Hz, J
) 10.2 Hz); 3.18 (dd, 1H, J ) 8.4 Hz, J ) 12.0 Hz); 3.40-3.60
(m, 3H); 3.63-3.72 (m, 1H); 3.73 (dd, 1H, J ) 8.4 Hz, J ) 3.5
Hz); 3.83 (dd, 1H, J ) 7.4 Hz, J ) 12 Hz); 7.30-7.60 (m, 10H).
13C NMR (CDCl3), mixture of rotamers, δ: 17.2 and 17.7; 32.3
and 34.1; 46.0 and 49.3; 53.1 and 56.5; 125.2; 127.0; 128.1;
CDCl3) δ: 0.95 (s, 3H); 0.90-1.15 (m, 3H); 0.97 (d, 3H, J )
6.6 Hz); 1.20 (s, 3H); 1.35-1.80 (m, 6H); 1.80-2.05 (m, 2H);
2.35-2.55 (m, 2H); 2.70 (d, 2H, J ) 7.4 Hz); 2.75-3.00 (m,
3H); 3.70 (dt, 1H, J ) 4.2 Hz, J ) 10.5 Hz); 7.06-7.20 (m,
5H). 13C NMR (330 K, CDCl3) δ: 16.6; 21.6; 22.0; 25.6; 30.5;
31.0; 35.1; 38.8; 40.9; 44.5; 44.8; 48.6; 50.8; 58.9; 72.8; 125.7;
128.1; 128.6; 140.9. IR (neat, cm-1): 3200, 3050, 1600, 740,
690. Anal. Calcd for C21H33NO: C, 79.95; H, 10.54; N, 4.44.
Found: C, 80.12; H, 10.65; N, 4.38.
(3′S)-8-(3′-Isop r op ylp yr r olid in yl)m en th ol (11d ). Yield:
98%, colorless oil; [R]20 ) -12.9 (c 1.04, CH2Cl2). 1H NMR
D
(acetone-d6) δ: 0.85-1.10 (m, 3H); 0.88 (d, 6H, J ) 7.0 Hz);
0.91 (d, 3H, J ) 6.7 Hz); 1.03 (s, 3H); 1.23 (s, 3H); 1.25-2.15
(m, 10H); 2.40-3.20 (br, 3H); 3.59 (dt, 1H, J ) 4.0 Hz, J )
10.5 Hz); 8.20 (br s, 1H). 13C NMR (acetone-d6) δ: 17.1; 21.3;
21.6; 21.7; 22.5; 26.8; 29.5; 31.7; 33.1; 35.7; 45.4; 45.9; 49.2;
50.8; 61.4; 72.7. IR (neat, cm-1): 3200, 1380. Anal. Calcd for
129.0; 129.7; 137.0 and 137.8; 169.6. Anal. Calcd for C12H15
-
NO: C, 76.16; H, 7.99; N, 7.40. Found: C, 75.84; H, 8.12; N,
7.39.
(S)-3-Meth ylp yr r olid in e (en t-13a ). Hydrochloride: 65%
yield; [R]20D ) - 6.0 (c 1.0, MeOH). Spectral data are identical
to those of 13a .
C
17H33NO: C, 76.34; H, 12.44; N, 5.24. Found: C, 76.14; H,
12.67; N, 5.20.
(3′S)-8-(3′-Meth ylpyr r olidin yl)m en th ol (12a). Yield: 92%,
(R)-3-Eth ylp yr r olid in e (13b). Hydrochloride: 54% yield;
colorless oil; [R]20 ) -14.2 (c 1.02, CH2Cl2). 1H NMR (CDCl3)
D
[R]20 ) + 6.9 (c 1.25, MeOH). 1H NMR (CDCl3) δ: 0.96 (t,
D
δ: 0.85-1.10 (m, 3H); 0.90 (d, 3H, J ) 6.2 Hz); 0.91 (d, 3H, J
) 3.1 Hz); 0.95 (s, 3H); 1.15 (s, 3H); 1.16 (s, 3H); 3.67 (dt, 1H,
J ) 4.2 Hz, J ) 10.5 Hz); 8.8-9.0 (br s, 1H). 13C NMR (CDCl3)
δ: 17.1; 19.2; 21.3; 22.0; 25.5; 30.8; 31.1; 31.9; 35.4; 43.5; 45.0;
48.6; 53.4; 59.0; 62.3. IR (neat, cm-1): 3120, 1440, 1025. CIMS
(m/z, %): 240 (M +1, 100), 126 (50), 102 (66). Anal. Calcd for
3H, J ) 7.4 Hz); 1.40-1.70 (m, 3H); 2.10-2.30 (m, 2H); 2.85
(dd, 1H, J ) 9.2 Hz, J ) 11.3 Hz); 3.25-3.35 (m, 1H); 3.40-
3.50 (m, 2H); 9.30-9.70 (br. s, 2H). 13C NMR (CDCl3) δ: 13.0;
25.2; 30.1; 39.8; 44.9; 50.2. EIMS (m/z, %): 99 (M - HCl, 20),
68 (9), 43 (100). N-Benzoyl derivative: oil; [R]20 ) +104 (c
D
1
0.70, CH2Cl2). H NMR (CDCl3), mixture of rotamers δ: 0.88
C
15H29NO: C, 75.24; H, 12.22; N, 5.85. Found: C, 75.48; H,
(t, 3H, J ) 7.4 Hz); 0.98 (t, 3H, J ) 7.4 Hz); 1.30-1.65 (m,
6H); 1.90-2.20 (m, 4H); 3.05 (dd, 1H, J ) 8.8 Hz, J ) 10.3
Hz); 3.22 (dd, 1H, J ) 8.8 Hz, J ) 12 Hz); 3.40-3.70 (m, 4H);
3.74 (dd, 1H, J ) 3.1 Hz, J ) 8.8 Hz); 3.85 (dd, 1H, J ) 7.6
Hz, J ) 12 Hz); 7.40 (m, 6H); 7.55 (m, 4H). 13C NMR (CDCl3)
mixture of rotamers, δ: 12.4 and 12.5; 25.6 and 26.2; 30.1 and
32.1; 39.5 and 41.4; 46.0 and 49.4; 51.6 and 54.9; 127.0; 128.1;
130.1; 137.2; 137.9; 170.0. IR (neat, cm-1): 1620, 1570, 715,
700. C13H17NO. Anal. Calcd for C13H17NO: C, 76.81; H, 8.43;
N, 6.89. Found: C, 76.50; H, 8.10; N, 6.59.
12.51; N, 5.59.
(3′S)-8-(3′-Eth ylp yr r olid in yl)m en th ol (12b). Yield: 98%,
colorless oil; [R]20 ) -14.5 (c 1.03, CH2Cl2). 1H NMR (CDCl3)
D
δ: 0.85-1.10 (m, 3H); 0.87 (t, 3H, J ) 7.3 Hz); 0.91 (d, 3H, J
) 6.5 Hz); 0.91 (s, 3H); 1.15 (s, 3H); 1.25-1.50 (m, 5H); 1.50-
1.75 (m, 3H); 1.95 (m, 3H); 2.20-3.20 (br, 3H); 3.61 (dt, 1H, J
) 4.2 Hz, J ) 10.5 Hz); 8.80 (br s, 1H). 13C NMR (CDCl3) δ:
12.6; 17.9; 21.2; 22.0; 25.3; 28.9; 30.8; 35.4; 38.3; 44.0; 48.2;
58.5; 73.5. IR (neat, cm-1): 3200, 1440. CIMS (m/z, %): 254
(M +1, 100), 238 (8), 140 (82), 113 (38). Anal. Calcd for C16H31
NO: C, 75.83; H, 12.33; N, 5.53. Found: C, 75.74; H, 12.48;
N, 5.40.
-
(S)-3-Eth ylp yr r olid in e (en t-13b). Hydrochloride: 53%
yield; [R]20D ) -5.9 (c 1.04, MeOH). Spectral data are identical
to those of 13b.
(3′R)-8-(3′-Ben zylpyr r olidin yl)m en th ol (12c). Yield: 99%,
colorless oil; [R]20 ) -26.4 (c 1.00, CH2Cl2). 1H NMR (CDCl3)
(R)-3-Ben zylp yr r olid in e (en t-13c). This pyrrolidine was
isolated and characterized as N-benzoyl derivative: oil, 49%
D
δ: 0.85-1.05 (m, 3H); 0.90 (d, 3H, J ) 6.5 Hz); 0.91 (s, 3H);
1.07 (s, 3H); 1.12 (s, 1H); 1.25-1.50 (m, 4H); 1.60 (m, 1H);
1.70-2.20 (m, 2H); 2.00-3.10 (m, 7H); 3.60 (dt, 1H, J ) 4.2
Hz, J ) 10.5 Hz); 7.10-7.30 (m, 5H). 13C NMR (CDCl3) δ: 17.0;
21.9; 22.1; 25.6; 30.1; 31.0; 35.0; 39.0; 41.5; 44.2; 44.3; 48.3;
51.0; 58.8; 72.8; 125.8; 128.3; 129.0; 141.5. IR (neat, cm-1):
3200, 1600, 740, 690. Anal. Calcd for C21H33NO: C, 79.95; H,
10.54; N, 4.44. Found: C, 80.22; H, 10.75; N, 4.51.
yield; [R]20 ) -57.4 (c 0.76, CH2Cl2). 1H NMR (CDCl3),
D
mixture of rotamers, δ: 1.53-1.74 (m, 2H); 1.89-1.98 (m, 1H);
2.00-2.08 (m, 1H); 2.40 (quintuplet, 1H, J ) 7.2 Hz); 2.52
(quintuplet, 1H, J ) 7.2 Hz); 2.61-2.70 (m, 2H); 2.72-2.81
(m, 2H); 3.17 (dd, 1H, J ) 8.0 Hz, J ) 10.5 Hz); 3.32 (dd, 1H,
J ) 8.6 Hz, J ) 12.1 Hz); 3.41 (dd, 1H, J ) 2.9 Hz, J ) 9.5
Hz); 3.45-3.54 (m, 2H); 3.58 (dd, 1H, J ) 4.2 Hz, J ) 8.1 Hz);
3.64-3.82 (m, 2H); 7.0-7.6 (m, 20H). 13C NMR (CDCl3)
mixture of rotamers, δ: 29.9 and 31.9; 38.5 and 39.1; 39.4 and
41.1; 45.5 and 49.0; 51.3 and 54.2; 126.1; 126.9; 128.0; 128.3;
128.4; 128.5; 129.6; 138.0; 139.6; 139.8; 170.0. IR (neat, cm-1):
3030, 3010, 1640, 1580, 1500. Anal. Calcd for C18H19NO: C,
81.48; H, 7.22; N, 5.28. Found: C, 81.84; H, 7.02; N, 5.32.
Au xilia r y Rem ova l P r oced u r e. Syn th esis of 3-Alk yl
P yr r olid in es. Gen er a l Met h od . A mixture of pyrrolidyl-
menthol 11a -d or 12a -c (2.4 mmol), pyridinium chlorocro-
mate (2.1 g, 9.7 mmol), and molecular sieves (4 Å) in diclo-
romethane (40 mL) was stirred for 2 h at room temperature.
Then, the mixture was added to a 15% aqueous solution of
NaOH (25 mL) and extracted with chloroform (4 × 30 mL).
The organic layer was decanted, washed with H2O, and
concentrated in vacuo without heating. The residue was
immediately treated with a 2.5 M solution (16 mL) of KOH in
THF/MeOH/H2O (2:1:1) for 2-3 h at room temperature. After
completion of the reaction (TLC), the mixture was acidified
(S)-3-Ben zylp yr r olid in e (13c). This pyrrolidine was iso-
lated and characterized as N-benzoyl derivative: oil, 52% yield;
[R]20 ) +56.2 (c 0.64, CH2Cl2). Anal. Calcd for C18H19NO: C,
D
81.48; H, 7.22; N, 5.28. Found: C, 81.66; H, 7.49; N, 5.02.
Spectral data coincide with those described for the benzoyl
derivative of ent-13c.

5-exo Radical Cyclizations
J . Org. Chem., Vol. 64, No. 12, 1999 4281
(S)-3-Isopr opylpyr r olidin e (13d).N-Tosylderivative: white
acknowledged. One of us (J .P.D.-S.) thanks the Minis-
terio de Educacion y Cultura for a predoctoral fellowship
(FPU).
solid, 63% yield, mp 69-70 °C (pentane); [R]20 ) +22.17 (c
D
1
0.46, CH2Cl2). H NMR (CDCl3) δ: 0.84 (d, 6H, J ) 6.6 Hz);
1.26-1.39 (m, 2H); 1.70 (m, 1H); 1.90 (m, 1H); 2.44 (s, 3H);
2.78 (t, 1H, J ) 9.6 Hz); 3.15 (dt, 1H, J ) 6.9 Hz, J ) 9.9 Hz);
3.37 (dt, 1H, J ) 2.3 Hz, J ) 8.6 Hz); 3.45 (dd, 1H, J ) 7.7
Hz, J ) 9.6 Hz); 7.35 (m, 3H); 7.72 (m, 2H). 13C NMR (CDCl3)
δ: 20.9; 21.3; 21.5; 29.9; 31.7; 46.3; 48.1; 52.1; 127.4; 129.5;
133.7; 143.2. IR (Nujol, cm-1): 1600, 1470, 1460, 1340. Anal.
Calcd for C14H21NO2S: C, 62.89; H, 7.92; N, 5.24. Found: C,
63.04; H, 7.72; N, 5.37.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
and 13C DEPT spectra of compounds 2, 3, 4d , 5a -c, 6a -d ,
7a -d , 8a -d , 9a -c, 10a -c, 11a -d , 12a -c, 13a -c (N-Bz),
13d (N-Ts), and en t-13a ,b (HCl); COSY and NOESY spectra
of 5a -c, 6a ,b,d and NOE difference spectra of 5c and 6c. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Ack n ow led gm en t. Financial support provided by
the Spanish DGES (Project PB 95-707) is gratefully
J O9816921