A novel approach to chiral, nonracemic pyrrolidines by 5-exo-trig diastereoselective radical cyclization on acrylamides derived from (-)-8- aminomenthol

Article abstract of DOI:10.1021/jo981693t

α,β-Unsaturated amides supported on perhydro-1,3-benzoxazines derived from (-)-8-aminomenthol as chiral auxiliaries undergo regio- and stereoselective 5-exo-trig radical cyclization leading to diastereomeric five-membered lactams. These cyclization products are transformed into enantiopure 3,4-disubstituted pyrrolidines by reduction with aluminum hydride followed by removal of the menthol appendage.

Full text of DOI:10.1021/jo981693t

4282
J . Org. Chem. 1999, 64, 4282-4288
A Novel Ap p r oa ch to Ch ir a l, Non r a cem ic P yr r olid in es by
5-exo-tr ig Dia ster eoselective Ra d ica l Cycliza tion on Acr yla m id es
Der ived fr om (-)-8-Am in om en th ol
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
R,â-Unsaturated amides supported on perhydro-1,3-benzoxazines derived from (-)-8-aminomenthol
as chiral auxiliaries undergo regio- and stereoselective 5-exo-trig radical cyclization leading to
diastereomeric five-membered lactams. These cyclization products are transformed into enantiopure
3,4-disubstituted pyrrolidines by reduction with aluminum hydride followed by removal of the
menthol appendage.
In tr od u ction
As a part of an ongoing project on the synthesis of
enantiopure nitrogen heterocycles,8 we have recently
demonstrated8b that a radical centered at a substituent
in C-2 of N-acryloyl-perhydro-1,3-benzoxazines cyclized
regioselectively in a 5-exo way leading to γ-lactams. Now
we report in full the results on the regio- and stereose-
lective cyclizations of radicals derived from chiral per-
hydro-1,3-benzoxazines derived from (-)-8-aminomenthol
directed to the synthesis of chiral, nonracemic C-3- and
C-4-substituted pyrrolidines.10
Asymmetric formation of carbon-carbon bonds by free-
radical addition is one of the most attractive, contempo-
rary topics in organic synthesis, and high levels of
stereoselectivity have been reported for intermolecular
addition of alkyl radicals to carbon-carbon double bonds.1
In this respect, R,â-unsaturated amides attached to a
chiral auxiliary (e.g., C2-pyrrolidine, camphorsultam,
oxazolidine, and oxazolidinones) have been used for
stereoselective free-radical addition due to their excellent
diastereoselection.2 More recently, enantioselective ca-
talysis using N-acyloxazolidinones as radical acceptors
has also been reported.3
The intramolecular version of these reactions remains
essentially unexplored,4 although some macrocycliza-
tions5 and intramolecular aryl radical additions directed
to the synthesis of lactams6 have been reported. Neverthe-
less, 5-hexenyl radical cyclizations concerning acrylamide
moieties as acceptors have not been described so far.7
F igu r e 1.
Resu lts
* To whom correspondence should be addressed. Phone: +34-983-
423211. Fax: +34-983-423013. E-mail: pedrosa@qo.uva.es.
(1) For general reviews, see (a) Curran, D. P.; Porter, N. A.; Giese,
B. Stereochemistry of Radical Reactions; VCH: Weinheim, 1996; (b)
Curran, D. P. in Comprehensive Organic Synthesis; Trost, B. M.;
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 4; (c) Porter, N. A.;
Giese, B.; Curran, D. P. Acc. Chem. Res. 1991, 24, 296; (d) Smadja, W.
Synlett 1994, 1.
(2) (a) Porter, N. A.; Scott, D. M.; Lacher, B.; Giese, B.; Zeitz, H.-G.;
Lindner, H. J . J . Am. Chem. Soc. 1989, 111, 8311; (b) Curran, D. P.;
Shen, W.; Zhang, J .; Heffner, T. A. J . Am. Chem. Soc. 1990, 112, 6738;
(c) Porter, N. A.; Swann, E.; Nally, J .; McPhail, A. T. J . Am. Chem.
Soc. 1990, 112, 6740; (d) Giese, B.; Zehnder, M.; Roth, M.; Zeitz, H. G.
J . Am. Chem. Soc. 1990, 112, 6741; (e) Porter, N. A.; Rosenstein, I. J .;
Breyer, R. A.; Bruhnke, J . D.; Wu, W.-X.; McPhail, A. T. J . Am. Chem.
Soc. 1992, 114, 7664; (f) Sibi, M. P.; J asperse, C. P.; J i, J . J . Am. Chem.
Soc. 1995, 117, 10779; (g) Tararov, V. I.; Kuznetzov, N. Y.; Bakhmutov,
V. I.; Ikonnikov, N. S.; Bubnov, Y. N.; Khrustalev, V. N.; Saveleva, T.
F.; Belokon, Y. N. J . Chem. Soc., Perkin Trans. 1 1997, 3101.
(3) (a) Wu, J . H.; Radinov, R.; Porter, N. A. J . Am. Chem. Soc. 1995,
117, 11029; (b) Sibi, M. P.; J i, J . J . Am. Chem. Soc. 1996, 118, 9200;
(c) Sibi, M. P.; J i, J . J . Org. Chem. 1997, 62, 3800.
(4) Colombo, L.; Di Giacomo, M.; Scolastico, C.; Manzoni, L.; Belvisi,
L.; Molteni, V. Tetrahedron Lett. 1995, 36, 625.
(5) (a) Porter, N. A.; Lacher, B.; Chang, V. H-T.; Magnin, D. R. J .
Am. Chem. Soc. 1989, 111, 8309; (b) Blake, A. J .; Hollingworth, G. J .;
Pattenden, G. Synlett 1996, 643.
(6) a) J ones, K.; Thompson, M.; Wright, C. J . Chem. Soc., Chem.
Commun. 1986, 115; (b) Clark, A. J .; J ones, K.; McCarthy, C.; Storey,
J . M. D. Tetrahedron Lett. 1991, 32, 2829; (c) Clark, A. J .; Davies, D.
I.; J ones, K.; Millbanks, C. J . Chem. Soc., Chem. Commun. 1994, 41;
(d) Cabri, W.; Candiani, I.; Colombo, M.; Franzoi, L.; Bedeschi, A.
Tetrahedron Lett. 1995, 36, 949.
The synthesis of the starting perhydro-1,3-benzoxa-
zines 3a -e starting from (-)-8-aminomenthol, prepared
from (+)-pulegone9 is summarized in Scheme 1. Conden-
sation of some R-phenylselenoaldehydes11 with (-)-8-
aminomenthol 1 afforded the N-unsubstituted perhy-
drobenzoxazines 2a -c in excellent yield.12 Obviously,
perhydrobenzoxazines 2b and 2c were obtained as equimo-
(7) An undesired 5-exo radical closure on a sulfenyl unsaturated
amide is described in Ozlu, Y.; Cladingboel, D. E.; Parsons, P. J . Synlett
1993, 357.
(8) (a) Garc´ıa-Valverde, M.; Pedrosa, R.; Vicente, M.; Garcı´a-Granda,
S.; Gutie´rrez-Rodriguez, A. Tetrahedron 1996, 52, 10761; (b) Andre´s,
C.; Duque-Soladana, J . P.; Iglesias, J . M.; Pedrosa, R. Tetrahedron Lett.
1996, 37, 9085.
(9) See the preceding paper in this issue and references therein.
(10) A background about the synthesis and interest of chiral
3-substituted pyrrolidines is found in Denmark, S. E.; Marcin, L. R.
J . Org. Chem. 1995, 60, 3221.
(11) For some methods of R-selenylation of aldehydes, see (a)
Sharpless, B.; Lauer, R. F.; Teranishi, A. Y. J . Am. Chem. Soc. 1973,
95, 6137; (b) J efson, M.; Meinwald, J . Tetrahedron Lett. 1981, 22, 3561;
(c) Miyoshi, N.; Yamamoto, Y.; Kambe, N.; Murai, S.; Sonoda, N.
Tetrahedron Lett. 1982, 23, 4813; (d) Lerouge, P.; Paulmier, C. Bull.
Soc. Chim. Fr. 1985, 1219; (e) Houllemare, D.; Ponthieux, S.; Out-
urquin, F.; Paulmier, C. Synthesis 1997, 101.
(12) These condensations contrast with those forming 1,3-oxazo-
lidines: Arse´niyadis, S.; Huang, P. Q.; Morellet, N.; Beloeil, J . C.;
Husson, H. P. Heterocycles 1990, 31, 1789.
10.1021/jo981693t CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/22/1999

5-exo-trig Diastereoselective Radical Cyclization on Acrylamides
J . Org. Chem., Vol. 64, No. 12, 1999 4283
Ta ble 1. Ra d ica l Cycliza tion of Am id es 3a -e
Sch em e 1
concn
(M)
yieldc
(%)
entry amide solventa
products ratiob
1
2
3
4
5
3a
3a
3a
3a
3b
PhMe
PhMe
PhH
PhH
PhH
0.2
0.02
0.02
4a (76), 5a (24)
4a (78), 5a (22)
4a (81), 5a (19)
64
66
70
94
87
0.004 4a (81), 5a (19)
0.02
4b (48), epi-4b (33),
5b (11), epi-5b (8)
4c (72), 5c(28)
4d (81), 5d (19)
4e
6
7
8
3c
3d
3e
PhH
PhH
PhH
0.03
0.02
0.02
82
84
81
a
All reactions have been carried out at reflux of the specified
b
solvent. Determined in the crude reaction mixture by integration
of the 1H NMR 300 MHz spectrum. c Combined percent yield after
chromatographic purification.
Sch em e 3
Sch em e 2
lowered when the reaction was carried out in refluxing
toluene (entries 1 and 2). Some other reagents such as
tristrimethylsilylsilane (TTMS)15 or nonthermal initiation
attempts (ultraviolet, triethylborane)16 failed to promote
the homolysis of the C-Se bond and therefore the
subsequent cyclization.
The N-crotonyl perhydro-1,3-benzoxazine 3d behaves
in a similar way as described for 3a . In this case, the
slow addition (6-7 h, syringe pump) of a 0.02 M solution
of tributyltin hydride and catalytic AIBN in benzene to
a refluxing 0.02 M solution of 3d in the same solvent
yielded a mixture of two diastereomeric lactams 4d and
5d in 81:19 ratio and 84% combined yield (Table 1, entry
7).
lar mixture of epimers at the carbon attached to selenium
(C-2′) because racemic R-selenoaldehydes were used. At
this stage, both diastereomers of 2b could be separated
by crystallization from hexanes and characterized by
hydrolysis into (+) and (-)-2-phenylselenopropanal.13
The introduction of the R,â-unsaturated amide group
was performed on 2a -c by treatment with acryloyl
chloride and triethylamine leading to 3a -c, whereas 3d
was obtained by reaction of 2a with crotonyl chloride in
the presence of pyridine and 3e by reaction of 2a with
methacryloyl chloride and TMEDA (Scheme 1). In a
similar way, diastereomerically pure (2′R)-3b and (2′S)-
3b were obtained from (2′R)-2b and (2′S)-2b, respectively,
by stirring with acryloyl chloride and triethylamine
(Scheme 2). In contrast with previous observations about
the acylation of related auxiliaries,14 the reaction of 2a -c
occurs in high to excellent chemical yield (78-98%).
The radical cyclization was initially examined on
acrylamide 3a . After testing some experimental reaction
conditions, the best chemical yield and stereoselectivity
(81:19) were achieved by refluxing a 0.004 M solution of
3a , tributyltin hydride (1.2 equiv), and AIBN (0.1 equiv)
in benzene. The chemical yield decreased when the
reaction was performed at higher concentration (Table
1, entry 3), whereas both the yield and the stereoselection
It is worthy to note that the cyclization of 3a and 3d
occurred with complete regioselectivity in a 5-exo way
leading to the five-membered lactams 4a , 5a and 4d , 5d ,
respectively, in good diastereomeric excess. In this sense,
our system resembles another related 3-aza-5-hexenyl
radicals, in which 1,5 ring closure is the only observed
cyclization.9 To probe the reliability of the 5-exo attack
on R,â-unsaturated amides, we tested the cyclization of
methacrylamide 3e, whose internal methyl group should
disfavor the 5-exo addition process.17 Interestingly, the
reaction of 3e with tributyltin hydride-AIBN (0.02 M,
syringe pump) afforded a single product corresponding
to the five-membered lactam 4e (Scheme 3). No traces
of 6-endo regioisomers18 or another byproduct were
1
observed by H NMR analysis (Table 1, entry 8).
The stereochemistry of the diastereomers formed in the
reactions of 3a and 3d was assigned on the basis of
NOESY experiments. The cis-relationship between the
acetalic proton and the R-H of the amide in major lactams
4a and 4d led us to assign the R configuration for the
(15) Chatgilialoglu, C. Acc. Chem. Res. 1992, 25, 188.
(16) Nozaki, K.; Oshima, K.; Utimoto, K. J . Am. Chem. Soc. 1987,
109, 2547.
(17) Spellmeyer, D. C.; Houk, K. N. J . Org. Chem. 1987, 52, 959.
(18) Knapp, S.; Gibson, F. S. J . Org. Chem. 1992, 57, 4802.
(13) Fitzner, J . N.; Shea, R. G.; Fankhauser, J . E.; Hopkins, P. B.
J . Org. Chem. 1985, 50, 419.
(14) Lee, J . Y.; Chung, Y. J .; Kim, B. H. Synlett 1994, 197.

4284 J . Org. Chem., Vol. 64, No. 12, 1999
Andre´s et al.
Sch em e 4
Sch em e 5
stereocenters in these compounds. Conversely, the con-
figuration of the R-carbon in the lactamic ring for the
minor diastereomers 5a and 5d was assigned as S.
To our knowledge these are the first examples of
stereoselective 5-exo-trig cyclizations performed on acryl-
amide acceptors as well as one of the few radical
approaches to nonracemic lactams. In view of the good
level of diastereoselection (i.e., 62%), we considered the
preparation of 3,4-disubstituted nonracemic lactam de-
rivatives by simultaneous formation of two stereocenters
in the cyclization. This method required the generation
of a secondary carbon-centered radical, so we first tried
the reaction on the (C-2′)-substituted perhydrobenzox-
azine 3b. When the 1:1 epimeric mixture of this com-
pound was refluxed with tributyltin hydride and AIBN
(0.02 M, syringe pump 8 h) in benzene, a set of four
cyclization products 4b, epi-4b, 5b, and epi-5b was
formed in 48:33:11:8 ratio (Table 1, entry 5) correspond-
ing to diastereomeric five-membered lactams (Scheme 4).
The same distribution was obtained when pure (2′R)-3b
or (2′S)-3b were independently subjected to the cycliza-
tion conditions.
All four diastereomers were separated by flash chro-
matography, and their structure was elucidated by NOE-
difference and NOESY experiments. The all-trans rela-
tionship found in lactam 4b and the all-cis relation
observed in epi-4b allowed us to assign R-R,â-R configu-
rations for the former and R-R,â-S for the latter. Simi-
larly, the assigned configuration for diastereoisomer 5b
was R-S,â-R whereas epi-5b shows the â-opposite con-
figuration, R-S,â-S. These data demonstrate that facial
discrimation of the acrylamide acceptor is maintained at
good levels (ca.. 81:19) but stereoselection at the radical
site is somewhat disappointing (59:41).
The transformation of cyclization products into the
final chiral, nonracemic pyrrolidines was carried out in
two steps. Treatment of major diastereomers 4a and 4d
with lithium aluminum hydride (5 equiv) and aluminum
chloride (2 equiv) in THF produced ring opening of the
N,O-acetalic moiety with concomitant reduction of the
amide group, yielding 8-pyrrolidinylmenthols 6a and 6d
in 95-99% yield (Scheme 5). Analogous cleavage reduc-
tion on minor lactams 5a and 5d led to pyrrolidinyl-
menthols 8a and 8d , respectively. Removal of the men-
thol appendage was achieved by PCC oxidation followed
by â-elimination with KOH in H2O/MeOH/THF. Accord-
ing to this protocol, (R)-3-alkylpyrrolidines 7a and 7d
were obtained as pure enantiomers from pyrrolidinyl-
menthols 6a and 6d , whereas the (S)-3-alkyl series (en t-
7a , en t-7d ) was isolated from 8a and 8d . These menthol
derivatives and substituted pyrrolidines have been previ-
ously described.9
A similar procedure was followed for isolation of 3,4-
disubstituted pyrrolidines (Scheme 6). Thus, (3R,4R)-3,4-
dimethylpyrrolidine 10b and (3S,4R)-4-methyl-3-phenyl-
pyrrolidine 10c were obtained from 9b and 9c, prepared
by reduction of lactams 4b and 4c, respectively. In the
same way (3S,4S)-4-methyl-3-phenylpyrrolidine 12c was
obtained from lactam 5c, whereas the symmetrical cis-
3,4-dimethylpirrolidine 12b arises from 5b or epi-4b.
Finally (3S,4S)-3,4-dimethylpyrrolidine en t-10b was the
final reduction-elimination product of the minor lactam
epi-5b.
Surprisingly, cyclization of the (C-2′)-phenyl benzoxa-
zine 3c led to a mixture of only two products 4c and 5c
in a ratio 72:28 (Table 1, entry 6). Once isolated, these
compounds were characterized as diastereomeric five-
membered lactams and their stereochemistry was as-
signed as R-R,â-S, and R-S,â-S, respectively. In this case,
the cyclization proceeds with total stereoselectivity at the
radical site.
It is interesting to note the total regioselective 5-exo
ring closure for the intramolecular radical additions in
all the amides presented here. Frontier orbital theory has
been used to justify the preferential 5-exo over 6-endo
attack in 5-hexenyl radicals because the SOMO-LUMO
interactions in the 5-exo transition state are more favor-
able than in the 6-endo pathway.20 Our results suggest
that this effective overlap should be also preferred when
an unsaturated amide is placed on the structure and that
the torsional strain controls the addition path.21
Some attempts to increase the diastereoselection by
Lewis acid complexation3 failed because no modification
of the diastereomeric ratio has been currently observed.19
(19) Radical cyclization of acrylamide 3d in the presence of titanium
tetraisopropoxide leads to identical results than in the absence of the
Lewis acid.
(20) Fleming, I., Frontier Orbitals and Organic Chemical Reactions,
J . Wiley and Sons, 1978. For an aplication of the Frontier Orbital
Theory to radical additions, see Giese, B. Angew. Chem., Int. Ed. Engl.
1983, 22, 753.
(21) A new set of MM2-parameters introduced by Houk indicate the
crucial role of the C(acyl)-C(rad)-C(alkene) torsion angle in related acyl-
5-hexenyl radical cyclizations. See Broeker, J . L.; Houk, K. N. J . Org.
Chem. 1991, 56, 3651. For early MM2 calculation on amides, see
Schnur, D. M.; Yuh, Y. H.; Dalton, D. R. J . Org. Chem. 1989, 54, 3779.

5-exo-trig Diastereoselective Radical Cyclization on Acrylamides
J . Org. Chem., Vol. 64, No. 12, 1999 4285
3c. In this case, two planar conformations C and D can
be proposed, but only C is highly stabilized by minimum
allylic strain.1a
In summary, R,â-unsaturated amides attached to an
(-)-8-aminomenthol-derived perhydro-1,3-benzoxazine
system have been shown as excellent radical acceptors
in intramolecular alkyl radical addition, providing five-
membered lactams in high yield. Removal of the menthol
auxiliary opens an access to enantiopure pyrrolidines.
Exp er im en ta l Section
General methods have been previously specified.9 Synthesis
and characterization of compounds 1, 2a , 6a , 6d , 7a , 7d , en t-
7a , en t-7d , 8a , and 8d are found in the preceding paper in
this issue.9
(()-2-P h en ylselen op r op ion a ld eh yd e.11 To a solution of
phenylselenyl bromide (3.78 g, 16 mmol) and diisopropylamine
(4.5 mL, 32 mmol) in anhydrous THF (50 mL), stirred under
argon atmosphere, was added propionaldehyde (1.2 mL, 16
mmol) at room temperature. The mixture was stirred for 1 h,
the solid was eliminated by filtration, and the solution was
concentrated in a vacuum. The oily residue was chromato-
graphed on silica gel (Et2O/hexane, 1/30) giving a racemic
mixture of 2-phenylselenopropionaldehyde (2.9 g, 86%) as a
F igu r e 2.
Sch em e 6
1
pale yellow oil. H NMR (CDCl3): δ 1.45 (d, 3H, J ) 7.5 Hz),
3.75 (dq, 1H, J ) 7.5 Hz, J ) 2.8 Hz), 7.20-7.50 (m, 5H), 9.45
(d, 1H, J ) 2.8 Hz). IR (neat, cm-1 ): 2800, 2700, 1690, 735,
690.
(()-2-P h en ylselen op h en yla cet a ld eh yd e.11 This com-
pound was prepared from acetaldehyde as described above.
Yield: 64%. Pale yellow oil. 1H NMR (CDCl3): δ 4.74 (d, 1H, J
) 4.9 Hz), 7.1-7.6 (m, 10H), 9.63 (d, 1H, J ) 4.9). IR (neat,
cm-1 ): 2800, 2720, 1700, 740, 690.
P er h yd r o-1,3-ben zoxa zin e (2b). A solution of (-)-8-
aminomenthol 1 (0.91 g, 5.3 mmol) and 2-phenylselenopropi-
onaldehyde (1.2 g, 5.9 mmol) in anhydrous benzene (40 mL)
was stirred overnight at room temperature. The solvent was
removed under vacuum to give a mixture of epimeric perhydro-
1,3-benzoxazines 2b (1.9 g). The isolation of the diastereoiso-
mers was carried out by flash chromatography (silica gel,
EtOAc/Hexane, 1/15) yielding (2′R)-2b (672 mg, 1.85 mmol,
35%) as white solid, mp 62-63 °C (hexanes); [R]20D ) +2.80 (c
1
1.00, CH2Cl2). H NMR (CDCl3): δ 0.85-1.10 (m, 4H), 0.91 (d,
3H, J ) 6.5 Hz), 1.09 (s, 3H), 1.10 (s, 3H), 1.45 (br. s., 1H),
1.54 (d, 3H, J ) 7.1 Hz), 1.60-1.70 (m, 2H), 1.85-1.95 (m,
1H), 2.00-2.10 (m, 1H), 3.30 (dq, 1H, J ) 7.1 Hz, J ) 2.4 Hz),
3.40 (dt, 1H, J ) 4.2 Hz, J ) 10.7 Hz), 4.31 (d, 1H, J ) 2.4
Hz), 7.20 (m, 3H), 7,65 (m, 2H). 13C NMR (CDCl3): δ 19.8; 22.2;
25.4; 29.8; 31.3; 34.8; 41.5; 46.1; 51.1; 51.5; 74.8; 84.6; 127.1;
128.8; 129.9; 134.1; 134.3. IR (neat, cm-1 ): 3265, 1575, 735,
690. CIMS (m/z, %): 368 (M + 1, 100), 210 (40), 182 (53). Anal.
Calcd for C19H29NOSe: C, 62.28; H, 7.98; N, 3.82. Found: C,
62.38; H, 7.84; N, 3.84. (2′S)-2b (576 mg, 16 mmol, 30%):
colorless oil, [R]20D ) +20.1 (c 1.14, CH2Cl2). 1H NMR (CDCl3):
δ 0.85-1.00 (m, 4H), 0.90 (d, 3H, J ) 6.5 Hz), 1.07 (s, 3H),
1.09 (s, 3H), 1.37 (d, 3H, J ) 7.1 Hz), 1.40-1.50 (m, 1H), 1.60-
1.70 (m, 3H), 1.85-1.95 (m, 1H), 3.35-3.45 (m, 2H), 4.40 (d,
1H, J ) 4.6 Hz), 7.20 (m, 3H), 7.65 (m, 2H). 13C NMR (CDCl3):
δ 17.2; 19.8; 22.2; 25.3; 29.8; 31.3; 34.9; 41.4; 43.2; 51.3; 51.6;
75.2; 85.0; 127.2; 128.7; 129.6; 134.8. IR (neat, cm-1): 3260,
1570, 735, 690. CIMS (m/z, %): 368 (M + 1, 100), 210 (31),
182 (41). Anal. Calcd for C19H29NOSe: C, 62.28; H, 7.98; N,
3.82. Found: C, 62.37; H, 7.94; N, 3.83.
P er h yd r o-1,3-ben zoxa zin e (2c). A mixture of of (-)-8-
aminomenthol 1 (1.03 g, 6 mmol) and 2-phenylselenophenyl-
acetaldehyde (1.82 g, 6.6 mmol) in anhydrous benzene (40 mL)
was stirred at room temperature for 10 h. The solvent was
evaporated under vacuum giving an equimolar mixture of
epimeric perhydro-1,3-benzoxazines 2c (2.68 g, 5.7 mmol, 95%),
which was used without further purification. 1H NMR (CDCl3):
δ 0.80-1.10 (m, 4H), 0.92 and 0.93 (d, 3H, J ) 6.5 Hz and J
) 6.8 Hz), 0.96 and 1.07 (s, 3H), 1.08 and 1.13 (s, 3H), 1.40-
The stereochemical results for the cyclization of acryl-
amide 3a could be explained on the basis of two different
radical intermediates A and B (Figure 2). The major
cyclization product 4a was formed from the most stable22
conformer A, whereas the less stable conformer B will
be the responsible for the formation of the minor dia-
stereoisomer 5a . The isolation of four diastereoisomers
from 3b (R ) Me) could be also explained on the basis of
the same intermediates. Taking into account the pyram-
idal structure of the carbon bearing the unpaired elec-
tron, the facial discrimination on the acrylamide double
bond is maintained, whereas the stereoselection at the
stereogenic radical center is very poor.
By contrast, when a phenyl group is attached to the
radical center, the intermediate adopts a planar struc-
ture,23 which is responsible for the total stereocontrol at
the benzylic stereocenter observed in the cyclization of
(22) Conformational searching and single point energy calculation
were performed using UHF/PM3 Hamiltonian and then submitted to
UHF/6-31G* optimization, as implemented in PcSpartan Plus (Wave
function Inc., 1997).
(23) Walling, C.; Cioffari, A. J . Am. Chem. Soc. 1972, 94, 6064.

4286 J . Org. Chem., Vol. 64, No. 12, 1999
Andre´s et al.
1.60 (m, 1H), 1.60-1.80 (m, 2H), 1.90-2.20 (m, 2H), 3.40 (m,
1H), 4.30 and 4.65 (d, 1H, J ) 1.9 Hz and J ) 3.8 Hz), 4.40
and 4.95 (d, 1H, J ) 1.9 Hz and J ) 3.8 Hz), 7.20 (m, 6H),
7.45 (m, 4H). Anal. Calcd for C24H31NOSe: C, 67.28; H, 7.29;
N, 3.27. Found: C, 67.03; H, 7.51; N, 3.46.
N-Acr yloyl-p er h yd r o-1,3-b en zoxa zin e (3a ). Gen er a l
P r oced u r e: To a solution of benzoxazine 2a (1.0 g, 2.8 mmol)
and triethylamine (3.2 mmol, 0.260 mL) in dry dichlo-
romethane (20 mL) under Ar at 0 °C was slowly added neat
acryloyl chloride (0.435 mL, 3.1 mmol). The mixture was
stirred for additional 30 min at room temperature and then
was diluted with hexane (50 mL). The solid was eliminated
by filtration, and the solvent was evaporated under vacuum.
The residue was chromatographed on silica gel using CH2Cl2
amide (2′R)-3b (936 mg) was obtained as a pale yellow oil and
used without further purification: [R]20D ) +115.0 (c 1.27, CH2-
1
Cl2). H NMR (CDCl3): δ 0.80-1.00 (m, 2H), 0.91 (d, 3H, J )
6.5 Hz), 1.10-1.30 (m, 1H), 1.16 (d, 3H, J ) 7.0 Hz), 1.35-
1.50 (m, 1H), 1.43 (s, 3H), 1.62 (s, 3H), 1.70 (m, 2H), 1.80-
2.00 (m, 2H), 3.65 (dt, 1H, J ) 4.6 Hz, J ) 11.1 Hz), 3.90 (dq,
1H, J ) 7.0 Hz, J ) 10.3 Hz), 5.33 (d, 1H, J ) 10.3 Hz), 5.50
(dd, 1H, J ) 1.8 Hz, J ) 10.5 Hz), 6.10 (dd, 1H, J ) 1.8 Hz, J
) 16.7 Hz), 6.37 (dd, 1H, J ) 10.5 Hz, J ) 16.7 Hz), 7.30 (m,
3H), 7.65 (m, 2H). 13C NMR (CDCl3): δ 18.5; 18.9; 21.9; 25.4;
25.6; 31.1; 34.2; 42.5; 47.3; 47.8; 58.5; 71.7; 86.2; 126.7; 128.0;
128.1; 128.9; 131.7; 136.7; 167.8. IR (neat, cm-1 ): 1640, 1600,
735, 690. CIMS (m/z, %): 422 (M + 1, 10), 268 (63), 264 (62),
236 (44), 208 (100). Anal. Calcd for C22H31NO2Se: C, 62.85;
H, 7.43; N, 3.33. Found: C, 63.09; H, 7.62; N, 3.16.
as eluent, yielding the acrylamide 3a (1.1 g, 2.5 mmol, 90%)
1
as a pale yellow oil, [R]20 ) +71.5 (c 1.12, CH2Cl2). H NMR
(2′S)-N-Acr yloyl-p er h yd r o-1,3-ben zoxa zin e [(2′S)-3b].
The named compound was obtained from (2′S)-2b by the above
D
(CDCl3): δ 0.85-1.20 (m, 3H), 0.94 (d, 3H, J ) 6.5 Hz), 1.40-
1.50 (m, 1H), 1.45 (s, 3H), 1.59 (s, 3H), 1.65-1.80 (m, 2H), 1.90
(m, 1H); 2.05 (m, 1H), 3.15 (dd, 1H, J ) 5.0 Hz, J ) 13.0 Hz),
3.49 (dd, 1H, J ) 9.0 Hz, J ) 13.0 Hz), 3.66 (dt, 1H, J ) 4.0
Hz, J ) 10.5 Hz), 5.40 (dd, 1H, J ) 2.5 Hz, J ) 9.9 Hz), 5.50
(dd, 1H, J ) 9.0 Hz, J ) 5.0 Hz), 6.05 (dd, 1H, J ) 2.5 Hz, J
) 16.6 Hz), 6.14 (dd, 1H, J ) 9.9 Hz, J ) 16.6 Hz), 7.30 (m,
3H), 7.55 (m, 2H). 13C NMR (CDCl3): δ 19.1; 22.2; 25.3; 25.6;
31.2; 34.1; 38.0; 43.0; 47.1; 58.2; 72.3; 82.2; 125.9; 126.8; 128.7;
128.9; 131.0; 134.1; 166.7. IR (neat, cm-1 ): 1635, 1600, 1570,
730, 685. EIMS (m/z, %): 407 (M, 0.36), 236 (94), 182 (89),
137 (30), 81 (57), 55 (100). Anal. Calcd for C21H29NO2Se: C,
62.06; H, 7.19; N, 3.45. Found: C, 61.94; H, 7.11; N, 3.41.
N-Cr oton yl-p er h yd r o-1,3-ben zoxa zin e (3d ). To a stirred
solution of 2a (1.8 g, 5.2 mmol) and pyridine (0.85 mL, 10.5
mmol) in dichloromethane (15 mL) at 0 °C under Ar atmo-
sphere was slowly added crotonyl chloride (1.1 mL, 10.4 mmol).
The stirring was continued for 2 h at room temperature, the
solvent was removed under vacuum, and the residue was
chromatographed (silica gel, CH2Cl2) to afford 2a (1.6 g, 75%)
procedure in 98% yield as a pale yellow oil, [R]20 ) +42.4 (c
D
1
1.43, CH2Cl2). H NMR (CDCl3): δ 0.80-1.05 (m, 2H), 0.93 (d,
3H, J ) 6.5 Hz), 1.10-1.25 (m, 2H), 1.45 (s, 3H), 1.47 (d, 3H,
J ) 7.0 Hz), 1.63 (s, 3H), 1.70 (m, 2H), 1.85 (m, 1H), 2.05 (m,
1H), 3.66 (dt, 1H, J ) 4.6 Hz, J ) 11.0 Hz), 3.80 (dq, 1H, J )
7.0 Hz, J ) 10.3 Hz), 5.33 (d, 1H, J ) 10.3 Hz), 5.65 (dd, 1H,
J ) 1.8 Hz, J ) 10.5 Hz), 6.20 (dd, 1H, J ) 1.8 Hz, J ) 16.8
Hz), 6.61 (dd, 1H, J ) 10.5 Hz, J ) 16.8 Hz), 7.20 (m, 3H),
7.55 (m, 2H). 13C NMR (CDCl3): δ 19.2; 20.1; 21.9; 25.5; 25.7;
31.1; 34.4; 43.3; 47.6; 49.4; 58.3; 71.9; 86.0; 126.3; 128.1; 129.0;
129.2; 132.3; 135.9; 167.9. IR (neat, cm -1): 1640, 1600, 735,
690. CIMS (m/z, %): 422 (M + 1, 9), 268 (45), 266 (27), 236
(29), 208 (100). Anal. Calcd for C22H31NO2Se: C, 62.85; H, 7.43;
N, 3.33. Found: C, 62.68; H, 7.59; N, 3.49.
N-Acr yloyl-p er h yd r o-1,3-ben zoxa zin e (3c). To a mixture
of epimeric benzoxazines 2c (856 mg, 2 mmol) and triethyl-
amine (0.24 mL, 3 mmol) in anhydrous CH2Cl2, cooled to 0
°C, under argon, was slowly added acryloyl chloride (0.3 mL,
2.2 mmol), and the mixture was stirred for 30 min at room
temperature. The solvent was evaporated under reduced
pressure giving an equimolar mixture of epimeric 3c (935 mg,
as oil, [R]20 ) +57.9 (c 1.00, CH2Cl2). 1H NMR (CDCl3): δ
D
0.85-1.20 (m, 3H), 0.93 (d, 3H, J ) 6.4 Hz), 1.35-1.45 (m,
1H), 1.44 (s, 3H), 1.59 (s, 3H), 1.65 (d, 3H, J ) 6.6 Hz), 1.70-
1.80 (m, 2H), 1.90 (m, 1H), 2.10 (m, 1H), 3.15 (dd, 1H, J ) 4.9
Hz, J ) 12.8 Hz), 3.48 (dd, 1H, J ) 9.1 Hz, J ) 12.8 Hz), 3.65
(dt, 1H, J ) 4.0 Hz, J ) 10.3 Hz), 5.48 (dd, 1H, J ) 9.1 Hz, J
) 4.9 Hz), 5.80 (d, 1H, J ) 14.8 Hz), 6.65 (m, 1H), 7.30 (m,
3H), 7.55 (m, 2H). 13C NMR (CDCl3): δ 17.9; 19.0; 22.1; 25.6;
25.7; 31.2; 34.1; 38.0; 42.8; 47.0; 58.3; 72.2; 82.3; 125.0; 127.2;
129.2; 129.4; 133.0; 140.4; 166.8. IR (neat, cm-1 ): 1650, 1620,
1575, 735, 685. CIMS (m/z, %): 422 (M + 1, 3), 268 (100), 250
1
1.94 mmol, 97%) as pale yellow oil. H NMR (CDCl3) mixture
of epimers at C-2′: δ 0.70-1.00 (m, 2H), 0.84 and 0.98 (d, 3H,
J ) 6.6 Hz and J ) 6.0 Hz), 1.10-1.35 (m, 2H), 1.40 and 1.46
(s, 3H), 1.67 and 1.72 (s, 3H), 1.80-2.10 (m, 4H), 3.60 and 3.75
(m, 1H), 4.76 and 5.01 (d, 1H, J ) 9.6 Hz), 5.13 and 5.71 (dd,
1H, J ) 1.6 Hz, J ) 10.8 Hz, and J ) 1.7 Hz, J ) 10.6 Hz),
5.50 and 6.26 (dd, 1H, J ) 1.6 Hz, J ) 16.8 Hz, and J ) 1.7
Hz, J ) 16.8 Hz), 5.83 and 5.99 (d, 1H, J ) 9.6 Hz), 5.97 and
6.74 (dd, 1H, J ) 10.8 Hz, J ) 10.6 Hz and J ) 10.8, J ) 16.8
Hz), 7.00-7.30 (m, 10H). Anal. Calcd for C27H33NO2Se: C,
67.21; H, 6.89; N, 2.90. Found: C, 67.14; H, 7.02; N, 3.14.
Cycliza tion of Acr yla m id es (3a -d ). Gen er a l P r oce-
d u r e: A 0.02 M solution (20 mL) of the corresponding amides
3a -d in benzene was placed in a two-necked flask equipped
with a reflux condenser and a magnetic bar, under argon
atmosphere. The solution was heated to reflux, and a 0.08 M
solution of Bu3SnH (6 mL, 1.2 equiv) and AIBN (0.1 equiv) in
benzene was slowly added (syringe pump, 7-12 h). The
heating was continued until disappearance of starting material
(TLC). When the reaction was finished, the solvent was
removed under vacuum, and the residues chromatographed
on silica gel using ethyl acetate/hexanes or dichloromethane
mixtures as eluent.
(42), 222 (63), 137 (20). C22H31NO2Se. Anal. Calcd for C22H31
-
NO2Se: C, 62.85; H, 7.43; N, 3.33. Found: C, 62.46; H, 7.18;
N, 3.25.
N-Meth a cr yloyl-p er h yd r o-1,3-ben zoxa zin e (3e). To a
solution of 2a (1.9 g, 5.3 mmol), TMEDA (1.2 mL, 8.2 mmol)
in dry dichloromethane (15 mL), was dropped methacryloyl
chloride (0.863 mL, 8.0 mmol), and the stirring was continued
at room temperature for 30 min. Then, the solvent was
removed and the residue was chromatographed (silica gel, CH2-
Cl2/hexane: 1/1) leading to 2a (1.82 g, 82%) as oil, [R]20
)
D
+87.0 (c 1.00, CH2Cl2). 1H NMR (CDCl3): δ 0.85-1.00 (m, 2H),
0.93 (d, 3H, J ) 6.6 Hz), 1.15 (m, 2H), 1.41 (s, 3H), 1.60 (s,
3H), 1.75 (m, 2H), 1.84 (s, 3H), 1.90 (m, 1H), 2.10 (m, 1H),
3.17 (dd, 1H, J ) 6.0 Hz, J ) 12.6 Hz), 3.43 (dd, 1H, J ) 8.3
Hz, J ) 12.6 Hz), 3.68 (dt, 1H, J ) 4.1 Hz, J ) 10.3 Hz), 4.97
(d, 2H, J ) 18.8 Hz), 5.50 (dd, 1H, J ) 9.1 Hz, J ) 4.9 Hz),
7.20 (m, 3H), 7.45 (m, 2H). 13C NMR (CDCl3): δ 18.0; 20.1; 21.9;
25.6; 25.9; 31.0; 34.2; 38.0; 43.3; 47.1; 57.8; 72.2; 83.0; 114.9;
127.0; 128.9; 130.1; 133.3; 142.4; 172.8. IR (neat, cm-1 ): 1630,
1620, 730. 685. CIMS (m/z, %): 422 (M + 1, 5), 268 (100), 250
(31), 222 (45), 137 (32). Anal. Calcd for C22H31NO2Se: C, 62.85;
H, 7.43; N, 3.33. Found: C, 62.52; H, 7.21; N, 3.25.
La cta m (4a ). White solid, mp 64-65 °C (from pentane),
[R]20 ) -35.8 (c 0.99, CH2Cl2). 1H NMR (CDCl3): δ 0.95 (d,
D
3H, J ) 6.6 Hz), 0.95-1.20 (m, 3H), 1.18 (s, 3H), 1.20-1.50
(m, 2H), 1.21 (d, 3H, J ) 7.0 Hz), 1.39 (ddd, 1H, J ) 7.5 Hz,
J ) 10.0 Hz, J ) 12.5 Hz), 1.60-1.90 (m, 2H), 1.73 (s, 3H),
2.05 (m, 1H), 2.24 (ddq, 1H, J ) 7.0 Hz, J ) 10.0 Hz, J ) 9.0
Hz), 2.41 (ddd, 1H, J ) 6.0 Hz, J ) 12.5 Hz, J ) 9.0 Hz), 3.41
(dt, 1H, J ) 4.1 Hz, J ) 10.3 Hz), 4.89 (dd, 1H, J ) 6.0 Hz, J
) 7.5 Hz). 13C NMR (CDCl3): δ 16.0; 18.2; 21.9; 24.0; 24.9; 31.1;
33.8; 34.4; 36.3; 41.1; 41.9; 58.0; 76.2; 84.1; 175.7. IR (neat,
cm-1): 1680, 1270, 735. CIMS (m/z, %): 252 (M + 1, 100), 236
(4), 139 (3). Anal. Calcd for C15H25NO2: C, 71.67; H, 10.02; N,
5.57. Found: C, 71.39; H, 9.79; N, 5.39.
(2′R)-N-Acr yloyl-p er h yd r o-1,3-ben zoxa zin e [(2′R)-3b].
To a mixture of (2′R)-2b (826 mg, 2.26 mmol) and triethyl-
amine (0.47 mL, 3.4 mmol) in dichloromethane (15 mL), at 0
°C, under argon, was slowly added acryloyl chloride (0.27 mL,
3.3 mmol), the reaction mixture was stirred for additional 30
min, and the solvent was evaporated under vacuum. The
La cta m (5a ). Colorless oil; [R]20 ) -61.5 (c 1.22, CH2Cl2).
D

5-exo-trig Diastereoselective Radical Cyclization on Acrylamides
J . Org. Chem., Vol. 64, No. 12, 1999 4287
1H NMR (CDCl3): δ 0.85-1.10 (m, 3H), 0.93 (d, 3H, J ) 6.6
Hz), 1.13 (d, 3H, J ) 7.4 Hz), 1.19 (s, 3H), 1.20-1.35 (m, 2H),
1.40-1.55 (m, 2H), 1.73 (s, 3H), 1.83 (ddd, 1H, J ) 6.2 Hz, J
) 6.6 Hz, J ) 13.7 Hz), 1.90-2.05 (m, 1H), 1.99 (ddd, 1H, J )
13.7 Hz, J ) 5.0 Hz, J ) 9.4 Hz), 2.55 (ddq, 1H, J ) 7.4 Hz,
J ) 6.6 Hz, J ) 9.4 Hz), 3.42 (dt, 1H, J ) 4.0 Hz, J ) 10.2
Hz), 5.02 (dd, 1H, J ) 6.2 Hz, J ) 5.0 Hz). 13C NMR (CDCl3):
δ 17.0; 18.9; 22.1; 24.0; 25.1; 31.2; 33.0; 34.1; 35.8; 41.0; 49.9;
57.0; 76.2; 84.1; 176.5. IR (neat, cm-1): 1680, 1270, 735. CIMS
(m/z, %): 252 (M + 1, 100), 137 (15), 139 (12). Anal. Calcd for
12.6; 19.2; 22.0; 24.1; 25.6; 31.2; 34.4; 40.7; 41.0; 47.5; 50.0;
57.3; 76.4; 87.8; 126.9; 128.2; 128.4; 137.4; 175.7. IR (neat,
cm-1): 1680, 695. CIMS (m/z, %): 328 (M + 1, 100), 211 (22),
172 (24), 137 (12).
La cta m (4d ). Colorless oil; [R]20D ) -53.8 (c 1.11, CH2Cl2).
1H NMR (CDCl3): δ 0.93 (t, 3H, J ) 7.5 Hz), 0.95 (d, 3H, J )
6.4 Hz), 0.95-1.15 (m, 3H), 1.17 (s, 3H), 1.20-1.35 (m, 1H),
1.35-1.50 (m, 3H), 1.65-1.80 (m, 2H), 1.72 (s, 3H), 1.83-2.05
(m, 2H), 2.10-2.25 (m, 1H), 2.30-2.45 (m, 1H), 3.40 (dt, 1H,
J ) 4.0 Hz, J ) 10.2 Hz), 4.88 (dd, 1H, J ) 6.4 Hz, J ) 7.3
Hz). 13C NMR (CDCl3): δ 10.9; 18.1; 22.2; 23.9; 24.1; 25.0; 30.9;
31.1; 33.9; 41.2; 42.1; 50.1; 56.7; 76.2; 84.0; 175.0. IR (neat,
cm-1 ): 1685, 1265. CIMS (m/z, %): 266 (M + 1, 100), 112
(16). Anal. Calcd for C16H27NO2: C, 72.41; H, 10.25; N, 5.28.
Found: C, 72.19; H, 9.98; N, 5.07.
C
15H25NO2: C, 71.67; H, 10.02; N, 5.57. Found: C, 71.57; H,
9.66; N, 5.21.
La cta m (4b). White solid, mp 68-69 °C (pentane), [R]20
D
) -54.5 (c 2.06, CH2Cl2). 1H NMR (CDCl3): δ 0.85-1.10 (m,
3H), 0.94 (d, 3H, J ) 6.5 Hz), 1.15 (d, 3H, J ) 6.7 Hz), 1.16 (s,
3H), 1.17 (d, 3H, J ) 7.3 Hz), 1.30 (m, 1H), 1.40-1.55 (m, 1H),
1.60-1.85 (m, 4H), 1.72 (s, 3H), 2.05 (m, 1H), 3.37 (dt, 1H, J
) 4.2 Hz, J ) 10.5 Hz), 4.42 (d, 1H, J ) 7.0 Hz). 13C NMR
(CDCl3): δ 14.0; 14.8; 17.9; 21.7; 23.6; 25.3; 30.9; 34.2; 40.8;
41.3; 43.5; 49.3; 56.3; 75.8; 89.3; 174.7. IR (neat, cm-1): 1690.
CIMS (m/z, %): 266 (M + 1, 100), 153 (4), 112 (18). Anal. Calcd
for C16H27NO2: C, 72.41; H, 10.25; N, 5.28. Found: C, 72.22;
H, 9.99; N, 5.41.
La cta m (5d ). Colorless oil, [R]20D ) -29.9 (c 0.85, CH2Cl2).
1H NMR (CDCl3): δ 0.90-1.10 (m, 3H), 0.93 (t, 3H, J ) 7.3
Hz), 0.95 (d, 3H, J ) 6.5 Hz), 1.19 (s, 3H), 1.25-1.55 (m, 4H),
1.65-1.80 (m, 2H), 1.74 (s, 3H), 1.90-2.00 (m, 3H), 2.45 (m,
1H), 3.43 (dt, 1H, J ) 4.0 Hz, J ) 10.2 Hz), 4.98 (t, 1H, J )
6.0 Hz). 13C NMR (CDCl3): δ 11.3; 18.9; 22.0; 24.1; 24.7; 25.3;
30.0; 30.7; 33.9; 41.1; 42.1; 50.1; 56.8; 76.2; 84.2; 176.1. IR
(neat, cm-1 ): 1685, 1265. CIMS (m/z, %): 266 (M + 1, 100),
112 (17).
La cta m epi-(4b). Colorless oil; [R]20D ) -36.0 (c 2.00, CH2-
1
Cl2). H NMR (CDCl3): δ 0.87 (d, 3H, J ) 7.0 Hz), 0.90-1.15
Cycliza tion of Am id e (3e). A solution of 3e (99 mg, 0.24
mmol) in refluxing benzene (12 mL) was treated with tribu-
tyltin hydride (0.1 mL, 0.35 mmol) and AIBN (3 mg) for 8 h.
After evaporation of the solvent under vacuum, the residue
was chromatographed on silica gel yielding the lactam 4e (51
(m, 3H), 0.95 (d, 3H, J ) 6.5 Hz), 1.10 (d, 3H, J ) 7.0 Hz),
1.16 (s, 3H), 1.20-1.35 (m, 1H), 1.40-1.55 (m, 1H), 1.60-1.80
(m, 2H), 1.70 (s, 3H), 2.05 (m, 1H), 2.30-2.50 (m, 2H), 3.39
(dt, 1H, J ) 4.2 Hz, J ) 10.5 Hz), 4.85 (d, 1H, J ) 7.0 Hz). 13
C
NMR (CDCl3): δ 8.2; 10.3; 18.0; 22.1; 23.9; 25.7; 31.2; 34.4;
34.5; 40.4; 41.0; 49.6; 56.4; 75.6; 85.6; 175.7. IR (neat, cm-1):
1690. CIMS (m/z, %): 266 (M + 1, 100), 153 (14), 112 (18).
Anal. Calcd for C16H27NO2: C, 72.41; H, 10.25; N, 5.28.
Found: C, 72.58; H, 10.08; N, 4.92.
mg, 81%) as a white solid, mp 58-59 °C (hexanes); [R]20
)
D
-39.1 (c 1.03, CH2Cl2). 1H NMR (CDCl3): δ 0.85-1.10 (m, 3H),
0.95 (d, 3H, J ) 6.5 Hz), 1.05 (s, 3H), 1.17 (s, 3H), 1.19 (s,
3H), 1.20-1.35 (m, 1H), 1.40-1.50 (m, 1H), 1.65 (dd, 1H, J )
13.0 Hz, J ) 6.8 Hz), 1.70-1.80 (m, 2H), 1.73 (s, 3H), 1.95 (m,
1H), 2.08 (dd, 1H, J ) 6.1 Hz, J ) 13.0 Hz), 3.40 (dt, 1H, J )
4.0 Hz, J ) 10.3 Hz), 4.93 (t, 1H, J ) 6.5 Hz). 13C NMR
(CDCl3): δ 18.1; 22.2; 24.0; 25.1; 25.4; 25.7; 31.1; 34.2; 40.1;
40.3; 41.0; 50.1; 55.8; 76.2; 83.2; 178.0. IR (neat, cm-1 ): 1685,
1275. CIMS (m/z, %): 266 (M + 1, 100), 153 (11), 112 (54).
Anal. Calcd for C16H27NO2: C, 72.41; H, 10.25; N, 5.28.
Found: C, 72.14; H, 10.04; N, 4.93.
La cta m (5b). Colorless oil; [R]20 ) -80.8 (c 3.50, CH2Cl2).
D
1H NMR (CDCl3): δ 0.85-1.15 (m, 3H), 0.94 (d, 3H, J ) 6.6
Hz), 1.01 (d, 3H, J ) 7.7 Hz), 1.05 (d, 3H, J ) 7.1 Hz), 1.16 (s,
3H), 1.30 (m, 1H), 1.40-1.55 (m, 1H), 1.70-1.80 (m, 2H), 1.72
(s, 3H), 2.05 (m, 1H), 2.17 (m, 1H), 2.51 (dq, 1H, J ) 8.7 Hz,
J ) 7.7 Hz), 3.38 (dt, 1H, J ) 4.2 Hz, J ) 10.5 Hz), 4.52 (d,
1H, J ) 6.3 Hz). 13C NMR (CDCl3): δ 11.4; 11.8; 18.5; 21.9;
23.9; 25.4; 31.1; 34.3; 36.0; 39.7; 40.9; 49.7; 56.5; 76.1; 90.0;
176.3. IR (neat, cm-1): 1690. CIMS (m/z, %): 266 (M + 1, 100),
153 (7), 112 (8). Anal. Calcd for C16H27NO2: C, 72.41; H, 10.25;
N, 5.28. Found: C, 72.60; H, 10.42; N, 5.14.
Red u ctive Clea va ge of La cta m s (4-5). Gen er a l P r o-
ced u r e: To a mixture of LiAlH4 (0.5 g, 13.1 mmol) and AlCl3
(713 mg, 5.34 mmol) in anhydrous THF (30 mL) at 0 °C was
slowly injected a solution of the corresponding lactams 4 or 5
(2.7 mmol). The solution was stirred for 10 min at 0 °C, and
then the mixture was carefully quenched with water (40 mL)
and extracted with chloroform (3 × 50 mL). The organic layer
was washed with brine, dried over anhydrous Na2SO4, and the
solvent evaporated under vacuum giving pure pyrrolidinyl-
mentols 6a ,9 6d ,9 8a ,9 8d ,9 9b, 9c, 11b, 11c, and 13b.
La cta m epi-(5b). Colorless oil; [R]20 ) -81.5 (c 0.52 CH2-
D
1
Cl2). H NMR (CDCl3): δ 0.85-1.05 (m, 3H), 0.93 (d, 3H, J )
6.6 Hz), 1.04 (d, 3H, J ) 7.0 Hz), 1.11 (d, 3H, J ) 7.3 Hz),
1.20 (s, 3H), 1.20-1.35 (m, 1H), 1.35-1.55 (m, 1H), 1.65-1.75
(m, 2H), 1.72 (s, 3H), 1.80-1.95 (m, 2H), 2.14 (quintuplet, 1H,
J ) 7.3 Hz), 3.43 (dt, 1H, J ) 4.2 Hz, J ) 10.5 Hz), 4.91 (d,
1H, J ) 6.0 Hz). 13C NMR (CDCl3): δ 12.6; 14.8; 20.1; 22.0;
24.2; 25.5; 31.2; 34.5; 38.0; 41.0; 44.1; 50.5; 57.3; 76.1; 85.3;
177.0. IR (neat, cm-1): 1690. CIMS (m/z, %): 266 (M + 1, 100),
153 (6), 112 (15). Anal. Calcd for C16H27NO2: C, 72.41; H,
10.25; N, 5.28. Found: C, 72.63; H, 10.38; N, 5.09.
(3′R,4′R)-8-(3′,4′-Dim et h ylp yr r olid in yl)-m en t h ol (9b ).
1
Yield: 96%. Colorless oil, [R]20 ) -0.55 (c 2.00, CH2Cl2). H
D
NMR (CDCl3): δ 0.90-1.05 (m, 15H), 1.14 (s, 3H), 1.45-1.70
(m, 7H), 1.95 (m, 1H), 2.20 (m, 1H), 2.65 (m, 1H), 2.95 (m,
2H), 3.50-3.60 (m, 1H). 13C NMR (CDCl3): δ 15.9; 16.3; 17.5;
21.3; 22.0; 25.4; 30.9; 35.0; 40.0; 40.1; 44.2; 48.4; 52.6; 54.1;
59.0; 72.7. IR (neat, cm-1 ): 3100, 1450. CIMS (m/z, %): 254
(M + 1, 100), 238 (8), 140 (90). Anal. Calcd for C16H31NO: C,
75.83; H, 12.33; N, 5.53. Found: C, 75.68; H, 12.21; N, 5.65.
(3′R,4′S)-8-(3′-Met h yl-4′-p h en ylp yr r olid in yl)-m en t h ol
La cta m (4c). White solid, mp 111-112 °C (hexanes), [R]20
D
) -63.3 (c 1.00, CH2Cl2). 1H NMR (CDCl3): δ 0.85-1.10 (m,
3H), 0.92 (d, 3H, J ) 6.5 Hz), 1.21 (s, 3H), 1.22 (d, 3H, J ) 7.0
Hz), 1.30-1.50 (m, 2H), 1.65-1.75 (m, 2H), 1.78 (s, 3H), 1.95
(m, 1H), 2.44 (dq, 1H, J ) 10.8 Hz, J ) 7.0 Hz), 2.80 (dd, 1H,
J ) 10.8 Hz, J ) 7.2 Hz), 3.33 (dt, 1H, J ) 4.3 Hz, J ) 10.5
Hz), 4.84 (d, 1H, J ) 7.2 Hz), 7.30-7.40 (m, 5H). 13C NMR
(CDCl3): δ 14.8; 18.4; 22.0; 23.9; 25.6; 31.2; 34.4; 41.0; 43.3;
49.6; 52.8; 57.0; 76.3; 89.1; 127.3; 127.9; 128.7; 138.8; 174.1.
IR (neat, cm-1): 1700, 690. CIMS (m/z, %): 328 (M + 1, 100),
282 (19). Anal. Calcd for C21H29NO2: C, 77.02; H, 8.92; N, 4.27.
Found: C, 77.24; H, 8.73; N, 4.31.
(9c). Yield: 99%. Colorless oil, [R]20 ) -11.5 (c 1.06, CH2-
D
1
Cl2). H NMR (CDCl3): δ 0.85-1.10 (m, 4H), 0.90 (d, 3H, J )
6.4 Hz), 0.91 (s., 6H), 1.18 (s, 3H), 1.35-1.50 (m, 2H), 1.55-
1.70 (m, 2H), 1.95-2.25 (m, 2H), 2.30-2.95 (m, 3H), 3.05-
3.25 (m, 2H), 3.66 (dt, 1H, J ) 4.2 Hz, J ) 10.5 Hz), 7.20-
7.40 (m, 5H). 13C NMR (CDCl3): δ 16.5; 18.0; 21.5; 22.1; 25.5;
31.0; 35.1; 44.3; 48.5; 52.4; 52.8; 53.7; 54.5; 59.4; 72.9; 126.3;
127.6; 128.4. IR (neat, cm-1 ): 3100, 1490, 700. CIMS (m/z,
%): 316 (M + 1, 100), 202 (24). Anal. Calcd for C21H33NO: C,
79.95; H, 10.54; N, 4.44. Found: C, 80.11; H, 10.68; N, 4.29.
8-(3′,4′-cis-Dim eth ylp yr r olid in yl)-m en th ol (11b). The
general cleavage-reduction protocol was followed starting from
La cta m (5c). White solid, mp 94-95 °C (hexanes), [R]20
D
1
) -172 (c 0.74, CH2Cl2). H NMR (CDCl3): δ 0.76 (d, 3H, J )
7.5 Hz), 0.85-1.10 (m, 3H), 0.92 (d, 3H, J ) 6.5 Hz), 1.28 (s,
3H), 1.30-1.55 (m, 2H), 1.70-1.90 (m, 2H), 1.80 (s, 3H), 1.95
(m, 1H), 2.86 (dq, 1H, J ) 9.2 Hz, J ) 7.5 Hz), 3.39 (dd, 1H,
J ) 9.2 Hz, J ) 5.3 Hz), 3.49 (dt, 1H, J ) 4.1, J ) 10.7), 5.22
(d, 1H, J ) 5.3 Hz), 7.10-7.40 (m, 5H). 13C NMR (CDCl3): δ
lactam 5c. Yield: 99%. Oil, [R]20 ) -17.1 (c 1.70, CH2Cl2).
D
1H NMR (CDCl3): δ 0.80-1.10 (m, 15H), 1.15 (s, 3H), 1.20 (s,

4288 J . Org. Chem., Vol. 64, No. 12, 1999
Andre´s et al.
1H), 1.35-1.70 (m, 4H), 1.90 (m, 1H), 2.00-2.30 (br., 3H),
2.50-3.30 (m, 3H), 3.56 (dt, 1H, J ) 4.2 Hz, J ) 11.0 Hz). 13C
NMR (CDCl3): δ 13.7; 14.0; 16.7; 21.2; 22.0; 25.5; 29.6; 30.9;
33.2; 34.9; 35.1; 44.2; 48.4; 52.6; 59.0; 72.6. IR (neat, cm-1 ):
3200, 1450, 1200. CIMS (m/z, %): 254 (M + 1, 100), 140 (47).
Anal. Calcd for C16H31NO: C, 75.83; H, 12.33; N, 5.53. Found:
C, 75.62; H, 12.15; N, 5.68. The same product was obtained
from lactam epi-4c by similar reduction.
(3′S,4′S)-8-(4′-Met h yl-3′-p h en ylp yr r olid in yl)-m en t h ol
(11c). Yield: 95%. Oil, [R]20D ) -69.8 (c 0.56, CH2Cl2). 1H NMR
(CDCl3): δ 0.55-0.80 (m, 3H), 0.85-1.10 (m, 3H), 0.93 (d, 3H,
J ) 6.5 Hz), 1.03 (s, 3H), 1.21 (s, 3H), 1.28 (s, 1H), 1.40-1.70
(m, 4H), 1.98 (m, 1H), 2.30-2.50 (br., 6H), 3.68 (dt, 1H, J )
4.3 Hz, J ) 10.5 Hz), 7.10-7.40 (m, 5H). 13C NMR (CDCl3): δ
15.8; 17.5; 21.5; 22.1; 25.6; 29.7; 31.0; 35.1; 44.3; 48.8; 53.2;
59.1; 72.8; 126.2; 128.1; 128.5. IR (neat, cm-1): 3100, 1490,
695. CIMS (m/z, %): 316 (M + 1, 100), 202 (25). Anal. Calcd
for C21H33NO: C, 79.95; H, 10.54; N, 4.44. Found: C, 79.79;
H, 10.72; N, 4.28.
(3R,4R)-4-Meth yl-3-p h en ylp yr r olid in e (10c). N-Ben z-
1
a m id e: oil, [R]20 ) +63.1 (c 0.32, CH2Cl2). H NMR (CDCl3)
D
mixture of rotamers: δ 0.89 and 1.00 (d, 3H, J ) 6.5 Hz), 2.28
and 2.45 (m, 1H), 2.81 and 2.90 (dt, 1H, J ) 7.5 Hz, J ) 10.9
Hz and J ) 8.2 Hz, J ) 10.6 Hz), 3.22 and 3.54 (t, 1H, J )
10.6 Hz), 3.35 and 3.75 (dd, 1H, J ) 12.0 Hz, J ) 10.6 Hz),
3.70-3.80 (m, 1H), 4.06 and 4.09 (t, 1H, J ) 12.7 Hz and J )
12.4 Hz), 7.10-7.60 (m, 10H). 13C NMR (CDCl3): δ 15.1 and
15.5; 39.0 and 41.5; 51.1 and 52.7; 53.5; 56.8 and 57.1; 127.1;
127.2; 127.5; 127.6; 128.2; 128.6; 129.9; 136.5 and 136.7; 138.7
and 139.4; 169.4. IR (neat, cm-1 ): 3060, 3020, 1625, 1575,
720, 700. EIMS (m/z, %): 265 (M, 21), 134 (9), 117 (11), 105
(100), 91 (14), 77 (54), 51 (16). Anal. Calcd for C18H19NO: C,
81.47; H, 7.22; N, 5.28. Found: C, 81.31; H, 7.39; N, 5.14.
cis-3,4-Dim eth ylpyr r olidin e (12b). Hydr och lor ide: 72%
yield. 1H NMR (CDCl3): δ 1.02 (d, 6H, J ) 6.6 Hz), 2.42 (m,
2H), 3.00 (m, 2H), 3.43 (m, 2H), 9.20-10.10 (br.s., 2H). 13C
NMR (CDCl3): δ 12.1; 35.3; 50.2. N-Benzoyl-cis-3,4-dimeth-
ylpyrrolidine: 1H NMR (CDCl3): δ 0.89 (d, 3H, J ) 6.9 Hz),
1.00 (d, 3H, J ) 6.9 Hz), 2.23 (septuplet, 1H, J ) 6.5 Hz), 2.34
(septuplet, 1H, J ) 6.6 Hz), 3.14 (dd, 1H, J ) 10.5 Hz, J ) 6.1
Hz), 3.38 (dd, 1H, J ) 12.2 Hz, J ) 6.0 Hz), 3.52 (dd, 1H, J )
10.5 Hz, J ) 6.5 Hz), 3.74 (dd, 1H, J ) 12.2 Hz, J ) 7.1 Hz),
7.30-7.60 (m, 5H). 13C NMR (CDCl3): δ 12.7; 13.3; 34.8; 36.7;
52.4; 55.6; 127.1; 128.2; 129.7; 137.0; 169.8. IR (neat, cm-1 ):
1620, 1570, 715, 695. EIMS (m/z, %): 203 (M, 47), 188 (47),
105 (100), 77 (35), 51 (7). Anal. Calcd for C13H17NO: C, 76.81;
H, 8.43; N, 6.89. Found: C, 76.58; H, 8.35; N, 6.53.
(3′S,4′S)-8-(3′,4′-Dim et h ylp yr r olid yl)-m en t h ol (13b ).
Yield: 99%, oil; [R]20 ) -37.7 (c 2.30, CH2Cl2). 1H NMR
D
(CDCl3): δ 0.85-1.05 (m, 15H), 1.13 (s, 3H), 1.25 (s, 1H), 1.45-
1.70 (m, 6H), 1.95 (m, 1H), 2.00-2.15 (br., 1H), 2.40-2.60 (br.,
1H), 2.75-2.90 (br., 1H), 3.10-3.30 (br., 1H), 3.62 (dt, 1H, J
) 4.2 Hz, J ) 11.0 Hz). 13C NMR (CDCl3): δ 16.9; 17.4; 19.4;
21.3; 22.2; 25.7; 31.1; 35.2; 39.3; 40.2; 44.4; 48.4; 52.3; 53.8;
58.7; 72.8. IR (neat, cm-1): 3150, 1450. CIMS (m/z, %): 254
(M + 1, 100), 140 (41). Anal. Calcd for C16H31NO: C, 75.83;
H, 12.33; N, 5.53. Found: C, 76.02; H, 12.14; N, 5.39.
Elim in a tion of th e Men th ol Ap p en d a ge. Syn th esis of
P yr r olid in e Der iva tives. The elimination of the chiral
appendage was carried out as previously described,9 and now
we describe the transformation of the pyrrolidinylmenthol 9b
into the dimethylpyrrolidine 10b as an example.
(3S,4S)-4-Meth yl-3-p h en ylp yr r olid in e (12c). N-Ben z-
a m id e: oil, [R]20D ) -56.8 (c 0.84, CH2Cl2). 1H NMR (CDCl3),
mixture of rotamers: δ 0.69 and 0.81 (d, 3H, J ) 6.5 Hz and J
) 7.0 Hz), 2.56 and 2.69 (septuplet, 1H, J ) 6.5 Hz and J )
7.0 Hz), 3.25 and 3.45 (dd, 1H, J ) 10.5 Hz, J ) 6.5 Hz and J
) 12.2 Hz, J ) 7.0 Hz), 3.38 and 3.51 (q, 1H, J ) 6.5 Hz and
J ) 7.0 Hz), 3.63 and 3.90 (dd, 1H, J ) 10.5 Hz, J ) 6.5 Hz
and J ) 12.2 Hz, J ) 7.0 Hz), 3.76 and 3.85 (dd, 1H, J ) 10.9
Hz, J ) 7.0 Hz), 4.04 (d, 1H, J ) 6.5 Hz), 6.90-7.60 (m, 10H).
13C NMR (CDCl3): δ 13.5 and 14.3; 36.1 and 37.7; 46.2 and
47.9; 50.3 and 52.4; 53.5 and 55.4; 126.7; 127.1; 127.2; 127.7;
128.0; 128.3; 128.4; 128.5; 129.9; 130.0; 136.8; 139.2; 139.3;
170.0. IR (neat, cm-1): 3060, 3020, 1620, 1570, 725, 695. CIMS
(m/z, %): 266 (M + 1, 100), 188 (3), 105 (2). Anal. Calcd for
C18H19NO: C, 81.47; H, 7.22; N, 5.28. Found: C, 81.25; H, 7.36;
N, 5.42.
(3R,4R)-3,4-Dim eth ylp yr r olid in e (10b). To a solution of
8-pyrrolidinylmenthol 9b (190 mg, 0.75 mmol) in CH2Cl2 (5
mL) were added a solution of PCC (680 mg) in CH2Cl2 (5 mL)
and molecular sieves (500 mg), and the mixture was stirred
at room temperature for 2 h. The mixture was poured into
aqueous NaOH solution and extracted with CHCl3 (3 × 25
mL). The solvent was eliminated under vacuum at low
temperature (10-20 °C), and the residue was treated with a
2.5 M solution (8 mL) of KOH in THF/MeOH/H2O (2/1/1) for 3
h at room temperature. After that, the solution was acidified
with diluted hydrochloric acid and concentrated under vacuum.
The residue was extracted with EtO2 (2 × 15 mL) to recover
the (+)-pulegone. The aqueous phase was alkalinized by
addition of diluted aqueous NaOH solution, and extracted with
chloroform (3 × 25 mL). Isolation of the pyrrolidine, as
hydrochloride, was accomplished by bubbling dry hydrogen
(3S,4S)-3,4-Dim et h ylp yr r olid in e (en t-10b ). N-Ben z-
a m id e: oil, [R]20 ) -104.4 (c 2.93, CH2Cl2). Anal. Calcd for
D
C13H17NO: C, 76.81; H, 8.43; N, 6.89. Found: C, 76.62; H, 8.17;
N, 6.72. The spectral data are identical to those described for
the benzamide of 10b.
chloride through the chloroformic solution giving 10b‚HCl (65
1
mg, 64%) as hygroscopic oil. [R]20 ) +35 (c 1.30, MeOH). H
D
NMR (CDCl3): δ 1.09 (d, 6H, J ) 5.2 Hz), 1.87 (m, 2H), 2.86
(m, 2H), 3.54 (m, 2H), 9.3-9.9 (br.s., 2H). 13C NMR (CDCl3): δ
14.8; 39.9; 51.5. Benzoylation of this salt afforded the following
compound.
Ack n ow led gm en t. Financial support of the Spanish
DGES (Project PB95-707) is gratefully acknowledged.
We also thank the Ministerio de Educacio´n y Ciencia
for a predoctoral scholarship to one of us (J .P.D.-S.).
(3′R,4′R)-N-ben zoyl-3,4-d im eth ylp yr r olid in e: Colorless
oil, [R]20 ) +117 (c 1.83, CH2Cl2). 1H NMR (CDCl3): δ 0.97
D
(d, 3H, J ) 6.2 Hz), 1.08 (d, 3H, J ) 6.2 Hz), 1.60-1.90 (m,
2H), 3.07 (t, 1H, J ) 10.2 Hz), 3.20 (dd, 1H, J ) 12.1 Hz, J )
9.8 Hz), 3.56 (dd, 1H, J ) 10.2 Hz, J ) 6.9 Hz), 3.88 (dd, 1H,
J ) 12.1 Hz, J ) 7.3 Hz), 7.30 (m, 3H), 7.55 (m, 2H). 13C NMR
(CDCl3): δ 15.1; 15.5; 39.3; 41.1; 53.6; 56.9; 127.1; 128.2; 129.7;
136.8; 169.4. IR (neat, cm-1 ): 1620, 1570, 720, 700. EIMS (m/
z, %): 203 (M, 47), 188 (47), 105 (100), 77 (35), 51 (7). Anal.
Calcd for C13H17NO: C, 76.81; H, 8.43; N, 6.89. Found: C,
76.23; H, 8.25; N, 6.83.
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 2b, 3a -b, 3d -e, 4a -e,
epi-4b, 5a -d , epi-5b, 9b-c, 10c, 11b-c, 12b-c, 13b, and
en t-10b; NOESY spectra of 4a , 4c, and 5a ; NOE difference
spectra of 4b, epi-4b, 5b-c, and epi-5b. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O981693T