Decarbonylative radical cyclization of α-amino selenoesters upon electrophilic alkenes. A general method for the 6-azabicyclo[3.2.1]octane synthesis

Article abstract of DOI:10.1021/jo0163849

α-Amino selenoester-tethered electronically poor alkenes on treatment with tributyltin hydride or TTMSS undergo intramolecular radical cyclization to provide 6-azabicyclo[3.2.1]octanes through 1-aminomethyl radical intermediates.

Full text of DOI:10.1021/jo0163849

J . Org. Chem. 2002, 67, 2323-2328
2323
Deca r bon yla tive Ra d ica l Cycliza tion of r-Am in o Selen oester s
u p on Electr op h ilic Alk en es. A Gen er a l Meth od for th e
6-Aza bicyclo[3.2.1]octa n e Syn th esis
J osefina Quirante,* Xavier Vila, Carmen Escolano, and J osep Bonjoch*
Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, 08028-Barcelona, Spain
bonjoch@farmacia.far.ub.es
Received December 18, 2001
R-Amino selenoester-tethered electronically poor alkenes on treatment with tributyltin hydride or
TTMSS undergo intramolecular radical cyclization to provide 6-azabicyclo[3.2.1]octanes through
1-aminomethyl radical intermediates.
In tr od u ction
radicals coming from either N-chloramines11 or amidyl
radical precursors,12 only the procedure reported in this
paper13 and that recently described by Weinreb6e using
ketyl radicals have been developed to achieve this azabi-
cyclic structure by means of carboradical species.
The 6-azabicyclo[3.2.1]octane nucleus is the backbone
of peduncularine1 and actinobolamine2 and appears as a
structural subunit in several alkaloids such as sarain A,3
aphanorphine,4 hetisine,5 and some of the securinega
group.6 Additionally, several 6-azabicyclo[3.2.1]octane
compounds are pharmacologically interesting; e.g., aza-
prophen7 is a muscarinic antagonist and the 6-methyl-
6-azabicyclo[3.2.1]octan-3â-ol benzoate has potent bind-
ing affinities to the cocaine site on the dopamine
transporter.8
In our approach to the 6-azabicyclo[3.2.1]octane nucleus,
we chose to explore the decarbonylative radical cycliza-
tion of R-amino selenoesters upon deactivated alkenes
(Scheme 1). Acyl radicals can be generated by hydride
treatment of selenoesters, and their reactions can be
classified into three types: (i) the atom or group transfer
reaction on the acyl carbon, as exemplified by hydrogen
abstraction to give the corresponding aldehydes; (ii) the
addition to unsaturated bonds; and (iii) the decarbonyl-
ation process by a fragmentation to give carbon monoxide
and an alkyl radical.14 We considered that the third
pathway would be favored in an R-aminoacyl radical,
since the stability of an R-amino-substituted radical is
enhanced as a result of the interaction of the nitrogen
lone pair with the radical center.15 Thus, the tributyltin
hydride treatment of R-amino selenoesters could be a new
entry to R-aminoalkyl radicals. Crich,16 Boger,17 and
Renaud18 in their studies on acyl radicals came across
decarbonylation analogue processes providing a nitrogen-
stabilized radical in lactam or carbamate functionalities,
but the reaction with amino compounds is unprecedented.
Despite the availability of many synthetic methods to
prepare the 6-azabicyclo[3.2.1]octane skeleton,9,10 so far
there has been little use of radical chemistry to build this
bridged framework. Apart from the studies on N-centered
(1) (a) Klaver, W. J .; Hiemstra, H.; Speckamp, W. N. J . Am. Chem.
Soc. 1989, 111, 2588-2595. (b) Rigby, J . H.; Meyer, J . H. Synlett 1999,
860-862. (c) Roberson, C. W.; Woerpel, K. A. Org. Lett. 2000, 2, 621-
623. (d) Lin, X.; Stien, D.; Weinreb, S. M. Tetrahedron Lett. 2000, 41,
2333-2337.
(2) Holmes, A. B.; Kee, A.; Ladduwahetty, T.; Smith, D. F. J . Chem.
Soc., Chem. Commun. 1990, 1412-1414.
(3) (a) Denhart, D. J .; Griffith, D. A.; Heathcock, C. H. J . Org. Chem.
1998, 63, 9616-9617. (b) Irie, O.; Samizu, K.; Henry, J . R.; Weinreb,
S. M. J . Org. Chem. 1999, 64, 587-595. (c) Downham, R.; Ng, F. W.;
Overman, L. E. J . Org. Chem. 1998, 63, 8096-8097. (d) Sung, M. J .;
Lee, H. I.; Chong, Y.; Cha, J . K. Org. Lett. 1999, 1, 2017-2019
(4) Tamura, O.; Yanagimachi, T.; Kobayashi, T.; Ishibashi, H. Org.
Lett. 2001, 3, 2427-2429 and references therein.
(5) Kwak, Y.-S.; Winkler, J . D. J . Am. Chem. Soc. 2001, 123, 7429-
Several procedures have been reported for the genera-
tion of R-aminoalkyl radicals:19 (a) tin hydride treatment
7430.
(6) (a) Horii, Z.; Hanaoka, M.; Yamawaki, Y.; Tamura, Y.; Saito, S.;
Shigematsu, N.; Kotera, K.; Yoshikawa, H.; Sato, Y.; Nakai, H.;
Sugimoto, N. Tetrahedron 1967, 23, 1165-1174. (b) Heathcock, C. H.;
von Geldern, T. W. Heterocycles 1987, 25, 75-78. (c) J acobi, P. A.;
Blum, C. A.; DeSimone, R. W.; Udodong, U. E. S. J . Am. Chem. Soc.
1991, 113, 5384-5392. (d) Magnus, P.; Rodr´ıguez-Lo´pez, J .; Mulhol-
land, K.; Matthews, I. Tetrahedron 1993, 49, 8059-8072. (e) Han, G.;
LaPorte, M. G.; Folmer, J . J .; Werner, K. M.; Weinreb, S. M. J . Org.
Chem. 2000, 65, 6293-6306. (f) Honda, T.; Namiki, H.; Kudoh, M.;
Watanabe, N.; Nagase, H.; Mizutani, H. Tetrahedron Lett. 2000, 41,
5927-5930. (g) Liras, S.; Davoren, J . E.; Bordner, J . Org. Lett. 2001,
3, 703-706.
(7) Triggle, D. J .; Kwon, Y. W.; Abraham, P.; Pitner, J . B.; Mas-
carella, S. W.; Carroll, F. J . Med. Chem. 1991, 34, 3164-3171.
(8) Abraham, P.; Pitner, J . B.; Lewin, A. H.; Boja, J . W.; Kuhar, M.
J .; Carroll, F. I. J . Med. Chem. 1992, 35, 141-144.
(9) For other approaches, see inter alia: (a) Pitner, J . B.; Abraham,
P.; J oo, Y. J .; Triggle, D. J .; Carroll, F. I. J . Chem. Soc., Perkin Trans
1, 1991, 1375-1381. (b) Callis, D. J .; Thomas, N. F.; Pearson, D. P. J .;
Potter, B. V. L. J . Org. Chem. 1996, 61, 4634-4640. (c). Davies, H. M.
L.; Cao, G. Tetrahedron Lett. 1998, 39, 5943-5946.
(10) For classical approaches, see: Bonjoch, J .; Mestre, E.; Corte´s,
R.; Granados, R.; Bosch, J . Tetrahedron 1983, 39, 1723-1728.
(11) Inter alia: (a) Surzur, J . M.; Stella, L.; Nouguier, R. Tetrahe-
dron Lett. 1971, 903-906. (b) Edwards, O. E.; Bernath, G.; Dixon, J .;
Paton, J . M.; Vocelle, D. Can. J . Chem. 1974, 52, 2123-2135.
(12) Inter alia: (a) Mackiewicz, P.; Furstoss, R.; Waegell, B.; Cote,
R.; Lessard, J . J . Org. Chem. 1978, 43, 3746-3750 (b) Lin, X.; Artman
III, G. D.; Stien, D.; Weinreb, S. M. Tetrahedron 2001, 57, 8779-8791.
(13) For a preliminary communication, see: Quirante, J .; Escolano,
C.; Bonjoch, J . Synlett 1997, 179-180.
(14) For a review on acyl radicals, see: Chatgilialoglu, C.; Crich,
D.; Komatsu, M.; Ryu, I. Chem. Rev. 1999, 99, 1991-2069.
(15) Bordwell, F. G.; Lynch, T.-Y. J . Am. Chem. Soc. 1989, 111,
7558-7562. (b) Schubert, S.; Renaud, P.; Carrupt, P.-A.; Schenk, K.
Helv. Chim. Acta 1993, 76, 2473-2489.
(16) Crich, D.; Eustace, K. A.; Ritchie, T. J . Heterocycles 1989, 28,
67-70.
(17) Boger, D. L.; Mathvink, R. J . J . Org. Chem. 1992, 57, 1429-
1443.
(18) Stojanovic, A.; Renaud, P. Synlett 1997, 181-182.
(19) For a review on 1-amino and 1-amidoalkyl radicals, see:
Renaud, P., Giraud, L. Synthesis 1996, 913-926.
10.1021/jo0163849 CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/08/2002

2324 J . Org. Chem., Vol. 67, No. 7, 2002
Quirante et al.
Sch em e 1. P r op osed In tr a m olecu la r Ra d ica l
Sch em e 3. Syn th esis of Selen oester -Teth er ed
Ester s
Cycliza tion of r-Am in o Selen oester s
Sch em e 2. Syn th esis of Selen oester -Teth er ed
Nitr iles
Sch em e 4. Str a igh tfor w a r d Syn th esis of
Selen oester -Teth er ed Ester s
of N,S-acetals, which in turn are prepared from iminium
salts and thiols;20 (b) treatment of iminium ions with
SmI2;21 (c) photoinduced single electron transfer from
R-trimethylsilylamines;22 and (d) 1,5-hydrogen transfer
in N-o-halobenzyl or -allyl derivatives.23
In this paper we describe a procedure to generate
R-aminoalkyl radicals consisting of treatment of R-amino
selenoesters with the hydride reagents Bu3SnH (TBTH)
or (Me3Si)3SiH (TTMSS), and we report a synthetic entry
to valuable functionalized 6-azabicyclo[3.2.1]octanes based
on an R-aminoalkyl radical cyclization.
Sch em e 5. Syn th esis of Selen oester -Teth er ed
Alk en es
Resu lts a n d Discu ssion
Efficient routes to the synthesis of R-amino ester-
tethered alkenes 2, 8, 12, and 18 were developed (Schemes
2-5), and these esters served as precursors of the
required selenoesters for the radical cyclizations. For the
series in which an R,â-unsaturated nitrile acts as the
radical acceptor, amino ester 2 was prepared by alkyla-
tion with methyl bromoacetate of the known secondary
amine 124 (Scheme 2). The synthesis of 1, starting from
4-benzylaminocyclohexanone,24 was improved by the
following synthetic sequence: formation of the corre-
sponding O-trimethylsilylcyanohydrin, dehydration with
POCl3, and hydrolysis of the generated phosphoramide
(50% overall yield for the three steps). From 2 the
methylselenoester 3a was synthesized following the
Kozikowski protocol,25 in which dimethylaluminum me-
thylselenolate reacts directly with the methyl ester 2,
while the Crich protocol26 was used for the phenylsele-
noester 3b, treating the corresponding carboxylic acid
with benzeneselanyl chloride in the presence of Bu3P in
a basic medium.
In the series in which an R,â-unsaturated ester is the
radical acceptor (Schemes 3 and 4), we needed intermedi-
ates with an ester group at the side chain that could be
converted chemoselectively to the required carboxylic
acids (9 or 13). For this reason, the tert-butyl ester 8 was
synthesized, starting from the known ketone 4.24 Treat-
ment of 4 with hydrazine monohydrate, followed by
oxidative cleavage of the formed hydrazone with iodine
in the presence of 2-tert-butyl-1,1,3,3-tetramethylguani-
dine, gave the vinyl iodide 5, which furnished the
compound 8 upon palladium-mediated methoxycarbonyl-
ation27 followed by a deprotection step and alkylation of
the secondary amine 7.24 Cleavage of tert-butyl ester in
(20) (a) Padwa, A.; Nimmesgern, H.; Wong, G. S. K. J . Org. Chem.
1985, 50, 5620-5627. (b) Curran, D. P.; Sun, S. Tetrahedron Lett. 1993,
34, 6181-6184.
(21) (a) Martin, S. F.; Yang, C.-P.; Laswell, W. L.; Ru¨eger, H.
Tetrahedron Lett. 1988, 29, 6685-6688. (b) Aurrecoechea, J .-M.; Lo´pez,
B.; Ferna´ndez, A.; Arrieta, A.; Coss´ıo, F. P. J . Org. Chem. 1997, 62,
1125-1135. (c) Katritzky, A. R.; Feng, D.; Qi, M.; Aurrecoechea, J . M.;
Suero, R.; Aurrekoetxea, N. J . Org. Chem. 1999, 64, 3335-3338. (d)
Aurrecoechea, J . M.; Ferna´ndez, A.; Gorgojo, J . M.; Saornil, C.
Tetrahedron 1999, 55, 7345-7362. (e) McDonald, C. E.; Galka, A. M.;
Green, A. I.; Keane, J . M.; Kowalchick, J . E.; Micklitsch, C. M.;
Wisnoski, D. D. Tetrahedron Lett. 2001, 42, 163-166.
(22) Khim, S.-K.; Cederstrom, E.; Ferri, D. C.; Mariano, P. S.
Tetrahedron 1996, 52, 3195-3222 and references therein.
(23) (a) Williams, L.; Booth, S. E.; Undheim, K. Tetrahedron 1994,
50, 13697-13708. (b) Robertson, J . R.; Peplow, M. A.; Pillai, J .
Tetrahedron Lett. 1996, 37, 5825-5828. (c) Gosain, R.; Norrish, A. M.;
Wood, M. E. Tetrahedron 2001, 57, 1399-1410.
(25) Kozikowski, A. P.; Ames, A. Tetrahedron 1985, 41, 4821-4834
(26) Batty, D.; Crich, D. Synthesis 1990, 273-275.
(27) Barton, D. H. R.; Chen, M.; J a´szbere´nyi, J . C.; Taylor, D. K.
Org. Synth. 1997, 74, 101-107.
(24) Quirante, J .; Escolano, C.; Massot, M.; Bonjoch, J . Tetrahedron
1997, 53, 1391-1402.

6-Azabicyclo[3.2.1]octane Synthesis via Radical Cyclization
J . Org. Chem., Vol. 67, No. 7, 2002 2325
Sch em e 6. Syn th esis of
6-Aza bicyclo[3.2.1]octa n es
Sch em e 7. Syn th esis of
2-Aza bicyclo[4.3.1]d eca n es
of R-amino radicals with tethered nonconjugated alkenes
have failed owing to their reduced radicaloid character,
due to the nitrogen lone pair interference.20a,30 In our
case, the reaction of 19 either with TTMSS/AIBN at 80
°C or TBTH/Et3B at room temperature was fruitless, the
noncyclized compound 26 being the only product iso-
lated.31
8 was followed by the conversion of carboxylic acid 9 into
the proradical phenyl selenoester 10.
A more straightforward synthesis for the N-methyl
analogue was achieved using our recently reported
procedure to obtain 4-alkylaminocyclohex-1-enecarboxyl-
ates. This method is based on the reductive amination
of the cyclohexenones 11 obtained from the conversion
of the Diels-Alder adduct formed by reaction of Dan-
ishefsky’s diene with methyl acrylate.28 The application
of this procedure, using the tert-butyl ester of sarcosine
and NaBH(OAc)3 in acetic acid medium in the reductive
amination step, led to the tertiary amine 12, from which
the selenoester 14 was prepared (Scheme 4).
In the alkene series in which the radical acceptor lacks
an electron-withdrawing group, we prepared the meth-
ylselanyl ester 19 from the aminocyclohexene 16 follow-
ing the sequence depicted in Scheme 5. Compound 16 is
available from ketone 4 through three procedures: (a)
sodium borohydride reduction, followed by dehydration
of the resulting alcohol using POCl3; (b) formation of the
tosylhydrazone and its cleavage with K-t-BuO in a
Shapiro-type process; or (c) formation of the correspond-
ing enol triflate and reduction with Et3SiH.
Finally, we studied how the â-aminoselenoester 28
reacted in the radical conditions previously used. Un-
surprisingly, the radical process occurs via a different
pathway (Scheme 7). Thus, the generated acyl radical
formed by treatment of 28 with TTMSS/AIBN did not
suffer decarbonylation, as this would lead to a â-ami-
noalkyl radical without any increase in the radical
intermediate’s stability, but instead reacted intramolecu-
larly with the double bond furnishing the 2-azabicyclo-
[4.3.1]decanes 29 and 30 in 71% yield (5:2 ratio). The
relative configuration at C-7 was inferred from the NMR
data. Hence, the isomer 29 that showed C-9 (δ 26.0) and
C-10 (δ 28.3) more upfield than isomer 30 (δ 29.1 for C-9
and δ 31.6 for C-10) was assigned to the compound
having the cyano group with an axial disposition. The
synthetic entry here reported for the homomorphan
skeleton present in compounds 29 and 30 constitutes one
of the few that have been described for this heterocycle.33
In summary, from a strategic viewpoint, the use of
R-aminoalkyl radicals, generated by decarbonylation from
R-amino selenoesters, tethered with electronically poor
double bonds constitutes an attractive entry to 6-azabi-
cyclo[3.2.1]octane compounds. Under other structural
circumstances, the initially formed acyl radical suffers
only a decarbonylative-reductive process without forma-
tion of a new C-C bond. When the radical process is
We now turned our attention to the behavior of
1-methylamino radical-tethered alkenes generated from
the selenoesters 3, 10, 14, and 19 (Scheme 6). Treatment
of 3a 29 or 3b with TTMSS/AIBN gave the 6-azabicyclo-
[3.2.1]octane derivatives 20 and 21 in 2:3 ratio and 69%
combined yield. When the reaction was carried out from
3b at room temperature using TBTH/Et3B, an equimo-
lecular ratio of both epimers was formed.
(30) For some interesting observations about the modification of
behavior of R-aminoalkyl radicals when the stabilizing influence of the
nitrogen lone pair is removed, allowing cyclization processes upon
alkenes, see: (a) Rios, L. A.; Dolbier, W. R., J r.; Paredes, R.; Lusztyk,
J .; Ingold, K. U.; J onsson, M. J . Am. Chem. Soc. 1996, 118, 11313-
11314. (b) Della, E. W.; Smith, P. A. J . Org. Chem. 1999, 64, 1798-
1806. (c) Pandey, G.; Kapur, M. Synthesis 2001, 1263-1267. See also
ref 21a
(31) Considering the overall transformation (18 f 26), this protocol
could be useful as a new procedure for decarboxylation of R-amino acids
and their derivatives.32 For example, R-amino ester i was converted
into the amino compound ii in two steps (60% yield).
Treatment of 10 with TTMSS/AIBN also gave the
normorphan nucleus and, as in the above series, a
mixture of epimers was formed (22 and 23, 45:55 ratio
determined by MS-GC). Working from the N-methyl
derivative 14 and promoting the reaction with TBTH, the
bicyclic compounds 24 and 25 were obtained in the same
45:55 ratio.
The stereochemistry of azabicyclic compounds 20-25
was proven by NMR techniques. Compounds with the
substituent group at C-2 in an equatorial disposition (21,
23, 25) showed more deshielded signals for C-4 and C-8
than compounds 20, 22, and 24, with the electron-
withdrawing group at C-2 (CN or CO2Me) axially located.
We next attempted to carry out the cyclization process
from the selenoester 19, since there are examples of
cyclization of R-amino radicals upon alkenes,23b although
it is true that several attempts to promote the cyclization
(32) For a radical decarboxylation of N-protected amino acids, see:
Boto, A.; Herna´ndez, R.; Sua´rez, E. J . Org. Chem. 2000, 65, 4930-
4937 and references therein.
(33) (a) May, E. L. J . Org. Chem. 1956, 21, 223-225. (b) Sasaki, T.;
Eguchi, S.; Okano, T.; Wakata, Y. J . Org. Chem. 1983, 48, 4067-4072.
(c) Mellor, J . M.; Pathirana, R.; Stibbard, J . H. A. J . Chem. Soc., Perkin
Trans 1 1983, 2541-2544. (d) Sole´, D.; Peidro´, E.; Bonjoch, J . Org.
Lett. 2000, 2, 2225-2228.
(28) Quirante, J .; Vila, X.; Bonjoch, J . Synthesis 2001, 1971-1974.
(29) For the use of acyl methyl selenides as acyl radical precursors,
see: Schwartz, C. E.; Curran, D. P. J . Am. Chem. Soc. 1990, 112, 9272-
9284.

2326 J . Org. Chem., Vol. 67, No. 7, 2002
Quirante et al.
1.54 (qd, J ) 11.5, 5.5, 1H), 2.12 (dm, J ) 12, 1H), 2.15-2.53
(m, 4H), 2.96 (m, 1H), 3.38 and 3.42 (2 d, J ) 17, 1H each),
3.80 and 3.88 (2 d, J ) 13.5, 1H each), 6.58 (br s, 1H), 7.20-
7.65 (m, 10H); 13C NMR 23.5 (t), 27.4 (t), 28.7 (t), 53.9 (d), 55.9
(t), 62.1 (t), 112.3 (s), 119.0 (s), 127.2, 127.7, 128.3, 128.6, 129.0,
129.1, 135.8 (d), 137.4 (s), 143.6 (d), 205.6 (s). Anal. Calcd for
C22H22N2OSe: C, 64.55; H, 5.38; N, 6.83. Found: C, 64.42; H,
5.42; N, 6.87.
Met h yl 4-[N-Ben zyl-N-(t er t -bu t oxyca r bon ylm et h yl)-
a m in o]cycloh ex-1-en eca r boxyla te (8). To a solution of
amine 7 (480 mg, 2.23 mmol) in CH3CN (67 mL) were added
tert-butyl bromoacetate (0.66 mL, 4.46 mmol) and Na2CO3
(0.71 g, 6.69 mmol). The mixture was heated at reflux for 24
h and concentrated. The residue was partitioned between
water and CH2Cl2 and the aqueous phase was extracted with
CH2Cl2. Concentration of the dried organic extracts gave a
residue, which was purified by chromatography (CH2Cl2), to
yield diester 8 as an orange oil (678 mg, 85%): IR (NaCl) 1717;
1H NMR 1.40-1.60 (m, 1H), 1.45 (s, 9H), 2.00-2.60 (m, 5H),
3.00 (m, 1H), 3.26 (s, 2H), 3.72 (s, 3H), 3.83, 3.89 (2 d, J ) 14,
1H each), 6.91 (br s, 1H), 7.20-7.40 (m, 5H); 13C NMR 24.8
(t), 25.6 (t), 28.1 (q), 29.8 (t), 51.6 (d), 52.0 (t), 54.7 (t), 55.6
(q), 80.7 (s), 126.8, 128.2, 128.4 (s), 129.8 (s), 138.4 (d), 139.8
(s), 167.5 (s), 171,5 (s). HRMS calcd for C21H29NO4 359.2097.
Found 359.2099. Anal. Calcd for C21H29NO4: C, 70.17; H, 8.13;
N, 3.90. Found: C, 70.28; H, 8.23; N, 3.88.
N-Ben zyl-N-ca r boxym eth yl-N-(4-m eth oxyca r bon ylcy-
cloh ex-3-en -1-yl)a m m on iu m Tr iflu or oa ceta te (9). TFA
(8.11 mL, 105 mmol) was added dropwise to an ice-cooled
solution of 8 (620 mg, 1.73 mol) in CH2Cl2 (2.3 mL), and the
mixture was stirred for 45 min at room temperature and
concentrated. The residue was triturated with Et2O to give
the trifluoroacetate salt 9 as a white solid (653 mg, 91%): mp
152-153 °C (Et2O); IR (KBr) 3425, 1706, 1687; 1H NMR (CD3-
OD) 1.80 (m, 1H), 2.25-2.40 (m, 2H), 2.50-2.85 (m, 3H), 3.70
(m, 1H), 3.72 (s, 3H), 4.04 (s, 2H), 4.56, 4.51 (2 d, J ) 13, 1H
each), 6.89 (br s, 1H), 7.40-7.55 (m, 3H), 7.55-7.65 (m, 2H);
13C NMR (CD3OD) 24.1 (t), 25.1 (t), 27.2 (t), 50.3 (t), 52.3 (q),
58.4 (t), 62.2 (d), 130.3, 131.3, 132.3 (d), 130.5, 131.2 (s), 135.9
(d), 167.9 (s), 168.8 (s). Anal. Calcd for C19H22F3NO6: C, 54.68;
H, 5.31; N, 3.36. Found: C, 54.78; H, 5.50; N, 3.43.
carried out upon â-amino selenoesters, the pathway
changes and the cyclization allows a carbonylative pro-
cess to give an azabicylic ketone through a surviving acyl
radical.
Exp er im en ta l Section 34
4-[N-Ben zyl-N-(m et h oxyca r b on ylm et h yl)a m in o]cyc-
loh ex-1-en eca r bon itr ile (2). To a solution of 124 (1.8 g, 8.6
mmol) in CH3CN (258 mL) were added Na2CO3 (2.7 g, 25.7
mmol) and methyl 2-bromoacetate (1.6 mL, 17.2 mmol). The
reaction mixture was heated at reflux for 4 h, concentrated,
and partitioned between water and CH2Cl2, and the aqueous
phase was extracted with CH2Cl2. The organic extracts were
dried and concentrated to leave a residue, which was purified
by chromatography (CH2Cl2) to give ester 2 (2.3 g, 96%) as a
1
yellow oil: IR (NaCl) 2225, 1739-1749; H NMR 1.54 (dddd,
J ) 13, 11.5, 11, 6, 1H), 2.06 (dm, J ) 12, 1H), 2.14-2.51 (m,
4H), 3.00 (m, 1H), 3.36 (s, 2H), 3.66 (s, 3H), 3.80 and 3.86 (2
d, J ) 14, 1H each), 6.56 (br s, 1H), 7.21-7.37 (m, 5H); 13C
NMR 25.0 (t), 27.2 (t), 29.7 (t), 51.0 (t), 51.5 (q), 54.5 (t), 54.8
(d), 112.1 (s), 119.2 (s), 127.1(d), 128.4 (2 d), 139.2 (s), 143.9
(d), 172.4 (s). Anal. Calcd for C17H20N2O2‚1/4H2O: C, 70.69; H,
7.15; N, 9.69. Found: C, 70.92; H, 7.22; N, 9.35.
4-{N-Ben zyl-N-[2-(m eth ylsela n yl)-2-oxoeth yl]a m in o}-
cycloh ex-1-en eca r bon itr ile (3a ). Dimethylaluminum me-
thylselenolate (2 M in toluene, 15 mL, 30 mmol) was added to
a cooled (0 °C) solution of ester 2 (1.4 g, 5 mmol) in degassed
CH2Cl2 (54 mL), and the mixture was stirred at 0 °C for 1 h
and at room temperature for 3 h. The mixture was concen-
trated and the residue was taken up with EtOAc and washed
with aqueous saturated Na2CO3 and brine. The organic
extracts were dried and concentrated, and the residue was
purified by chromatography (hexane/CH2Cl2 1:3) to give sele-
noester 3a (1.6 g, 83%) as a yellow solid: mp 85-86 °C (CH2-
Cl2); IR (KBr) 2213, 1694; 1H NMR (500 MHz, COSY) 1.52 (qd,
J ) 12, 6, 1H, H-5ax), 2.07 (s, 3H, SeCH3), 2.00-2.60 (m, 5H),
2.88 (m, 1H, H-4ax), 3.25 and 3.32 (2d, J ) 17, 1H each, CH2N),
3.73 and 3.80 (2d, J ) 13.5, 1H each, CH2Ar), 6.56 (br s, 1H,
H-2), 7.26-7.40 (m, 3H, ArH), 7.46 (d, J ) 7, 2H, ArH); 13C
NMR (HMQC) 3.9 (SeCH3), 23.3 (C-5), 27.4 (C-6), 28.6 (C-3),
53.7 (C-4), 55.5 (CH2Ar), 61.9 (CH2N), 112.2 (C-1), 119.0 (CN),
127.6, 128.5, 128.9 (Ar), 137.7 (C-ipso), 143.7 (C-2), 207.6 (CO).
Meth yl 4-{Ben zyl-[2-(ph en ylselan yl)-2-oxoeth yl]am in o}-
cycloh ex-1-en eca r boxyla te (10). Following the above pro-
cedure to prepare 3b using carboxylic acid 9 (300 mg, 0.72
mmol), the crude product was purified by chromatography
(hexane/EtOAc, 8:2) to give the phenylselanyl ester 10 (226
Anal. Calcd for:
C17H20N2OSe: C, 58.79; H, 5.80; N, 8.07.
Found: C, 58.58; H, 6.04; N, 7.91.
1
4-{N-Ben zyl-N-[2-(p h en ylsela n yl)-2-oxoeth yl]a m in o}-
cycloh ex-1-en eca r bon itr ile (3b). Ester 2 (1.8 g, 6.4 mmol)
in 6 N HCl (47 mL) was heated at 60 °C for 7 h. The mixture
was concentrated and the resulting solid was triturated with
Et2O. After removing the solvent, N-b en zyl-N-ca r b oxy-
m eth yl-N-[4-cya n ocycloh exen -3-en -1-yl]a m m on iu m ch lo-
r id e, structure not shown, was isolated as a white solid (1.70
g, 88%): IR (KBr) 2200, 1731. 1H NMR 2.01 (m, 1H), 2.43 (dm,
J ) 13, 1H), 2.51-3.02 (m, 4H), 3.89 (m, 1H), 4.22 (br s, 2H),
4.62 and 4.67 (2 d, J ) 13, 1H each), 6.74 (br s, 1H), 7.50-
7.75 (m, 5H); 13C NMR 24.2 (t), 28.3 (t), 51.0 (t), 59.5 (t), 62.5
(d), 114.1 (s), 120.1 (s), 131.2, 132.3, 133.4 (d), 143.0 (d), 169.5
(s). To a stirred solution of the obtained carboxylic acid (800
mg, 2.61 mmol) in CH2Cl2 (15 mL) was added a solution of
Et3N (0.83 mL, 6 mmol) in CH2Cl2 (5 mL). The mixture was
stirred for 30 min and concentrated to give the crude triethyl-
ammonium carboxylate as a yellow oil. To a solution of PhSeCl
(0.84 g, 4.42 mmol) in THF (22 mL) was added PBu3 (1.1 mL,
4.42 mmol) with stirring at room temperature. After 15 min
the above triethylammonium salt in THF (18 mL) was added
to the reaction mixture and stirred at room temperature for
24 h. The resulting solution was poured into EtOAc and
aqueous 2 N NaOH solution. The aqueous layer was further
extracted with EtOAc, and the combined organic extracts were
washed with water and brine. The concentrated dried organic
extracts were purified by chromatography (CH2Cl2) to give 3b
(754 mg, 70%) as a yellow solid: IR (KBr) 2200, 1710; 1H NMR
mg, 70%) as a white solid: mp 95-97 °C; IR (KBr) 1719; H
NMR 1.49 (qd, J ) 12, 6, 1H), 2.10-2.65 (m, 5H), 2.95 (m,
1H), 3.38, 3.44 (2 d, J ) 18, 1H each), 3.71 (s, 3H), 3.82, 3.88
(2 d, J ) 10, 1H each), 6.93 (br s, 1H), 7.10-7.40 (m, 10H);
13C NMR 23.9 (t), 24.9 (t), 28.5 (t), 51.6 (q), 54.8 (d), 55.9 (t),
62.2 (t), 127.5, 128.4, 129.0, 135.8 (d), 130.0 (s), 137.7 (s), 138.0
(d), 167.3 (s), 206.1 (s). Anal. Calcd for C23H25NO3Se: C, 62.44;
H, 5.70; N, 3.17. Found: C, 62.09; H, 5.71; N, 3.23.
Meth yl 4-(N-ter t-Bu toxycar bon ylm eth yl-N-m eth ylam i-
n o)cycloh ex-1-en -1-ca r boxyla te (12). Triethylamine (1.39
mL, 14 mmol) was added to a solution of tert-butyl methyl-
aminoacetate hydrochloride (2.41 g, 13.3 mmol) in 1,2-dichlo-
roethane (15 mL), to which sequentially was added a solution
of enones 11 (1.13 g, 7.34 mmol) in 1,2-dichloroethane (10.5
mL), NaBH(OAc)3 (2.34 g, 11.0 mmol), and AcOH (0.52 mL,
9.1 mmol). The mixture was stirred at room temperature for
24 h and concentrated. The residue was taken up in CH2Cl2
(40 mL) and washed with 10% aqueous K2CO3 solution. After
evaporation of the organic solvent, the residue was purified
by chromatography (98:2, CH2Cl2:MeOH) to give 12 (1.17 g,
1
56%) as a yellow oil: IR (film) 1714; H NMR 1.41 (qd, J )
11, 5, 1H), 1.46 (s, 9H), 1.90-2.60 (m, 5H), 2.43 (s, 3H), 2.80
(m, 1H), 3.26 (s, 2H), 3.73 (s, 3H), 6.92 (br s, 1H); 13C NMR
24.5 (t), 25.1 (t), 28.0 (q), 28.9 (t), 38.6 (q), 51.4 (q), 55.8 (t),
57.4 (d), 80.7 (s), 129.7 (s), 137.9 (d), 167.2 (s), 170.4 (s). Anal.
Calcd for
Found: C, 62.89; H, 8.92; N, 4.94.
C
15H25NO4‚1/4H2O: C, 62.59; H, 8.93; N, 4.87.
N-Meth yl-N-ca r boxym eth yl-N-(4-m eth oxyca r bon ylcy-
cloh ex-3-en -1-yl)a m m on iu m Tr iflu or oa ceta te (13). TFA
(34) For general procedures, see Supporting Information.

6-Azabicyclo[3.2.1]octane Synthesis via Radical Cyclization
J . Org. Chem., Vol. 67, No. 7, 2002 2327
(129 mL, 1.68 mol) was added dropwise to an ice-cooled
solution of 12 (7.8 g, 27.6 mol) in CH2Cl2 (37 mL) and the
mixture was stirred for 45 min at room temperature and
concentrated. The residue was triturated with Et2O to give
the trifluoroacetate salt 13 as a white solid (8.05 g, 86%): mp
mg, 0.06 mmol) in benzene (61 mL) was heated at reflux. Then,
TBTH (178 µL, 0,66 mmol) was added dropwise, and the
reaction mixture was stirred at this temperature for 3 h. After
evaporation of the solvent, the residue was dissolved in EtOAc
and extracted with aqueous 1 N HCl. The aqueous phase was
basified with saturated Na2CO3 and extracted with EtOAc.
Evaporation of the dried organic extracts afforded a residue,
which was purified by chromatography (Al2O3, hexane/EtOAc
98:2) to give a mixture of epimers 22 and 23 (57 mg, 74%) as
1
132-133 °C (Et2O); IR (KBr) 3425, 1709; H NMR (CD3OD)
1.76 (qd, J ) 12, 5, 1H), 2.15-2.80 (m, 5H), 2.95 (s, 3H), 3.62
(m, 1H), 3.72 (s, 3H), 4.11 (s, 2H), 6.88 (br s, 1H); 13C NMR
(CD3OD) 23.8 (t), 25.0 (t), 26.9 (t), 38.8 (q), 52.3 (q), 54.4 (t),
63.0 (d), 131.2 (s), 135.8 (d), 168.0 (s), 168.5 (s). Anal. Calcd
for C13H18F3NO6: C, 45.75; H, 5.32; N, 4.10. Found: C, 45.49;
H, 5.47; N, 4.27.
1
a yellow oil in a 45:55 ratio (estimated by H NMR and GC-
MS): IR 1732.(1RS,2RS,5RS) Meth yl 6-ben zyl-6-azabicyclo-
[3.2.1]octa n e-2-ca r boxyla te (22): 1H NMR (500 MHz, COSY)
1.44 (d, J ) 11.5, 1H, H-8ax), 1.50 (tdd, J ) 13.5, 6, 1.5, 1H,
H-4ax), 1.62-1.68 (m, 1H, H-4eq), 1.68-1.75 (m, 1H, H-8eq),
1.76-1.80 (m, 1H, H-3), 1.93-1.97 (m, 1H, H-3), 2.54 (m, 1H,
H-2eq), 2.72 (q, J ) 5, 1H, H-1eq), 2.75 (d, J ) 10.5, 1H, H-7endo),
2.90 (dd, J ) 10, 6, 1H, H-7exo), 3.10 (q, J ) 5, 1H, H-5eq), 3.63
(s, 3H, OCH3), 3.79, 3.83 (2 d, J ) 14, 1H each, CH2Ph), 7.20-
7.40 (m, 5H, ArH); 13C NMR (HMQC): 20.6 (C-3), 28.8 (C-4),
32.8 (C-8), 38.2 (C-1), 44.8 (C-2), 51.5 (OCH3), 58.2 (C-7), 58.8
(C-5), 59.0 (CH2Ph), 126.5, 128.1, 128.2 (C-o, C-m, C-p), 175.4
(CO). (1RS,2SR,5RS) Meth yl 6-ben zyl-6-a za bicyclo[3.2.1]-
octa n e-2-ca r boxyla te (23): 1H NMR (500 MHz, COSY) 1.30
(tdd, J ) 14, 6, 1,5, 1H, H-4ax),1.40 (d, J ) 11, 1H, H-8ax), 1.76-
1.80 (m, 1H, H-4eq), 1.80-1.87 (m, 2H, H-3), 1.89-1.95 (m, 1H,
H-8eq), 2.49 (ddd, J ) 12, 5.5, 1.5, 1H, H-2ax), 2.65 (t, J ) 5,
1H, H-1eq), 2.76 (dd, J ) 11, 5.5, 1H, H-7exo), 2.85 (d, J ) 11,
1H, H-7endo), 3.10 (q, J ) 5, 1H, H-5eq), 3.68 (s, 3H, OCH3),
3.80 (s, 2H, CH2Ph), 7.20-7.40 (m, 5H, ArH). 13C NMR
(HMQC) 22.1 (C-3), 30.3 (C-4), 36.6 (C-8), 38.2 (C-1), 45.6 (C-
2), 51.5 (OCH3), 55.3 (C-7), 58.1 (C-5), 58.6 (CH2Ph), 126.5,
Meth yl 4-{N-Meth yl-N-[2-(p h en ylsela n yl)-2-oxoeth yl]-
am in o}cycloh ex-1-en ecar boxylate (14). Following the above
procedure to prepare 3b using carboxylic acid 13 (7.48 g, 22
mmol), the crude product was treated with hexane to give the
phenylselanyl ester 14 (5.2 g, 65%) as a yellowish solid: mp
1
68-70 °C; IR (KBr) 1717, 1702; H NMR 1.51 (qd, J ) 12, 6,
1H), 2.00-2.70 (m, 5H), 2.51 (s, 3H, NMe), 2.87 (m, 1H), 3.32
(s, 2H), 3.74 (s, 3H), 6.95 (br s, 1H), 7.30-7.40 (m, 3H), 7.40-
7.50 (m, 2H); 13C NMR 24.8 (t), 24.9 (t), 28.5 (t), 39.4 (q), 51.6
(q), 59.0 (d), 65.5 (t), 128.0 (d), 128.3 (d), 129.0 (d), 130.0 (s),
135.7 (s), 137.8 (d), 167.3 (s), 206.9 (s). Anal. Calcd for C17H21
-
NO3Se: C, 55.74; H, 5.78; N, 3.83. Found: C, 55.74; H, 5.89;
N, 3.71.
Ra d ica l Cycliza tion of Selen oester 3a w ith TTMSS
a n d AIBN. A solution of 3a (150 mg, 0.43 mmol) and AIBN
(14 mg, 0.08 mmol) in benzene (85 mL) was heated at reflux.
TTMSS (0.29 mL, 0.95 mmol) was added dropwise and the
reaction mixture was stirred at this temperature for 3 h.
Concentration of the solvent gave a residue, which was
partitioned between EtOAc and 1 N HCl. The aqueous phase
was basified with saturated Na2CO3 and extracted with EtOAc.
The dried organic extracts were concentrated and purified by
chromatography (CH2Cl2/MeOH 98:2). The first eluate gave
26 mg (27%) of (1RS,2RS,5RS)-6-Ben zyl-6-a za bicyclo[3.2.1]-
octa n e-2-ca r bon itr ile (20) as a white solid: mp 173-175
128.1, 128.2 (C-o, C-m, C-p), 175.2 (CO). Anal. Calcd for C16H21
-
NO2‚1/5 H2O: C, 73.08; H, 8.20; N, 5.33. Found: C, 73.38; H,
8.06; N, 5.60.
(1RS,2RS,5RS)- a n d (1RS,2SR,5RS)-Meth yl 6-Meth yl-
6-a za bicyclo[3.2.1]octa n e-2-ca r boxyla te (24 a n d 25). Fol-
lowing the above procedure for the radical cyclization with
TBTH and AIBN, phenylselanyl ester 14 (1 g, 2.73 mmol) in
benzene (550 mL) was treated with AIBN (186 mg, 1.14 mmol),
and TBTH (1.25 mL, 4.64 mmol) was added dropwise at reflux
temperature, which was maintained for 3 h. The crude
material obtained after the workup was purified by chro-
matograpy (Al2O3, CH2Cl2) to give a mixture of epimers 24 and
25 (300 mg, 60%) as a yellow oil in a 45:55 ratio (estimated by
GC-MS); working on a 0.27 mmol scale, the yield increased
up to 67%: IR 1729. Compound 24: 1H NMR (CDCl3, 500 MHz,
COSY) 1.42 (d, J ) 11.5, 1H, H-8ax), 1.60 (m, 1H, H-4ax), 1.60-
1.71 (m, 3H, H-4eq, H-3, H-8eq), 1.90 (m, 1H, H-3), 2.44 (s, 3H,
NMe), 2.50 (m, 1H, H-2eq), 2.70 (q, J ) 5, 1H, H-1eq), 2.75 (d,
J ) 10.5, 1H, H-7endo), 2.86 (dd, J ) 10.5, 6, 1H, H-7exo), 2.98
(t, J ) 4.5, 1H, H-5eq), 3.63 (s, 3H, OCH3); 13C NMR (HMQC)
20.2 (C-3), 27.9 (C-4), 32.4 (C-8), 38.5 (C-1), 41.8 (NMe), 44.6
(C-2), 51.5 (OCH3), 59.5 (C-7), 60.9 (C-5), 175.1 (CO). Com-
pound 25: 1H NMR (500 MHz, COSY) 1.32 (tdd, J ) 14, 6,
1,5, 1H, H-4ax), 1.38 (d, J ) 11, 1H, H-8ax), 1.60-1.71 (m, 1H,
H-3), 1.72-1.81 (m, 1H, H-4eq), 1.80 (m, 1H, H-3), 1.90 (m,
1H, H-8eq), 2.42 (s, 3H, NMe), 2.45 (ddd, J ) 12.5, 5, 2, 1H,
H-2ax), 2.62 (t, J ) 5.5, 1H, H-1eq), 2.74 (dd, J ) 10.5, 5.5, 1H,
H-7exo), 2.83 (d, J ) 10, 1H, H-7endo), 2.98 (t, J ) 5, 1H, H-5eq),
3.68 (s, 3H, OCH3), 13C NMR (HMQC) 21.7 (C-3), 29.4 (C-4),
36.3 (C-8), 38.5 (C-1), 41.0 (NMe), 45.4 (C-2), 51.5 (OCH3), 56.5
(C-7), 60.0 (C-5), 175.1 (CO). HRMS calcd for C10H17NO2
183.1259, found 183.1260.
1
°C; IR (NaCl) 2250; H NMR (500 MHz, COSY) 1.55 (td, J )
13, 5, 1H, H-4ax), 1,71 (m, 1H, H-4eq), 1.80-1.90 (m, 2H, H-3eq,
H-8eq), 1.92 (d, J ) 12, 1H, H-8ax), 2.07 (m, 1H, H-3ax), 2.62
(m, 1H, H-1eq), 2.75 (m, 1H, H-2eq), 2.77 (d, J ) 10.5, 1H,
H-7endo), 2.85 (dd, J ) 10.5, 5.5 Hz, 1H, H-7exo), 3.17 (m, 1H,
H-5eq), 3.80 (s, 2H, CH2Ph), 7.20-7.40 (m, 5H, ArH); 13C NMR
(HMQC) 23.0 (C-3), 28.9 (C-4), 31.2 (C-2), 32.7 (C-8), 38.3 (C-
1), 57.5 (C-7), 58.4 (C-5), 59.5 (CH2Ar), 122.4 (CN), 126.9,
128.1, 128.2 (Ar), 140.0 (C-ipso). Anal. Calcd for C15H18N2‚1/2
H2O: C, 76.56; H, 8.14; N, 11.90. Found: C, 76.68; H, 8.09, N,
11.58. The second eluate gave 42 mg (42%) of (1RS,2SR,5RS)-
6-ben zyl-6-a za bicyclo[3.2.1]octa n e-2-ca r bon itr ile (21) as
a white solid: IR (NaCl) 2250; 1H NMR (500 MHz, COSY) 1.19
(m, 1H, H-4ax), 1.28 (d, J ) 11.5, 1H, H-8ax), 1.67 (dm, J )
12.5, 1H, H-4eq), 1.81-1.98 (m, 3H, H-8eq, H-3), 2.54 (br s, 1H,
H-1eq), 2.55 (dm, J ) 10.5, 1H, H-2ax), 2.77 (dd, J ) 10.5, 5.5,
1H, H-7exo), 2.99 (d, J ) 11, 1H, H-7endo), 3.04 (m, 1H, H-5eq),
3.73 (s, 2H, CH2Ph), 7.12-7.30 (m, 5H, ArH); 13C NMR
(HMQC) 23.7 (C-3), 30.4 (C-4), 31.9 (C-2), 35.5 (C-8), 39.0 (C-
1), 55.5 (C-7), 57.5 (C-5), 59.1 (CH2Ar), 122.3 (CN), 126.8,
128.1, 128.2 (Ar), 144.0 (C-ipso). HRMS calcd for C15H18N2:
226.1477, found 226.1469.
Ra d ica l Cycliza tion of Selen oester 3b w ith TBTH a n d
Et3B. Acyl selenide 3b (130 mg, 0.32 mmol) was dissolved in
benzene (64 mL) and stirred under an atmosphere of dry air
using a drying tube packed with Drierite. A 15% solution of
Et3B in hexane (3.7 mL, 0.38 mmol) was added, followed by
TBTH (0.13 mL, 0.48 mmol), and the mixture was stirred at
room temperature for 15 h. Then, additional Et3B (3.17 mL)
was added and stirring was maintained for 6 h. The reaction
mixture was concentrated, and the residue was taken up in
EtOAc and treated with aqueous saturated KF solution. The
precipitated Bu3SnF was removed by filtration through Celite
and the filtrate separated and dried. Removal of the solvent
yielded a mixture of 20 and 21 (51 mg, 70%) in a ratio 1:1
(1RS,6RS,7RS)- a n d (1RS,6RS,7SR)-2-Ben zyl-5-oxo-2-
a za bicyclo[4.3.1]d eca n e-7-ca r bon itr ile (29 a n d 30). Fol-
lowing the general procedure for the radical cyclization with
TTMSS and AIBN, methylselanyl ester 28 (70 mg, 0.19 mmol)
in benzene (38 mL) was treated with AIBN (6 mg, 0.034 mmol)
and TTMSS (0.12 mL, 0.41 mmol), and the crude material was
chromatographed (CH2Cl2/MeOH 99:1). The first eluate gave
1
29 (26 mg, 50%) as a white solid: IR (NaCl) 2240, 1710; H
NMR (500 MHz, COSY) 1.60 (dm, J ) 14.5, 1H, H-8eq), 1,77
(tm, J ) 15.5, 1H, H-9ax), 1.96 (dt, J ) 14.5, 3, 1H, H-9eq),
2.29 (tt, J ) 14.5, 5, 1H, H-8ax), 2.31 (ddd, J ) 15.4, 2.5, 1H,
H-10), 2.51 (m, W1/2 ) 8.5, 1H, H-6eq), 2.57 (ddd, J ) 13.5, 11.5,
1
ratio (estimated by H NMR and GC-MS).
Ra d ica l Cycliza tion of 10 w ith TBTH a n d AIBN. A
solution of selenoester 10 (132 mg, 0.30 mmol) and AIBN (10

2328 J . Org. Chem., Vol. 67, No. 7, 2002
Quirante et al.
5.5, 1H, H-4), 2.67 (dm, J ) 15.5, 1H, H-10), 2.75 (ddd, J )
13.5, 9, 3, 1H, H-4), 2.81 (td, J ) 13, 2.5, 1H, H-3), 2.84 (m,
1H, H-1eq), 2.92 (ddd, J ) 13.5, 9, 5, 1H, H-3), 3.22 and 3.93
(2 d, J ) 15, 1H each, CH2Ar), 3.73 (m, W1/2 ) 10, 1H, H-7eq),
7.18 (d, J ) 8, 2H, ArH), 7.24 (t, J ) 7, 1H, ArH), 7.33 (t, J )
7.5, 1H, ArH); 13C NMR (HMQC) 20.5 (C-8), 26.0 (C-9), 27.2
(C-7), 28.3 (C-10), 41.2 (C-4), 44.9 (C-3), 46.0 (C-6), 56.5 (C-1),
58.3 (CH2Ar), 122.3 (CN), 127.0, 127.8, 128.6 (Ar), 139.0 (C-
ipso), 206.7 (CO). HRMS calcd for C17H20N2O 268.1575, found
268.1574. The second eluate gave 30 (11 mg, 21%) as a white
1H each, CH2Ar), 7.19-7.34 (m, 5H, ArH); 13C NMR 21.8 (C-
8), 29.1 (C-9), 29.9 (C-7), 31.6 (C-10), 41.4 (C-4), 44.9 (C-3 and
C-6), 56.1 (C-1), 58.5 (CH2Ar), 121.4 (CN), 127.0, 127.9, 128.6
(Ar), 139.0 (C-ipso), 206.3 (CO). HRMS calcd. for C17H20N2O
268.1575, found 268.1570.
Ack n ow led gm en t. This work was supported by the
MCYT, Spain (project BQU2001-3551). Thanks are also
due to the DURSI, Catalonia, Spain for Grant SGR99-
0078 and a fellowship to X.V.
1
solid: IR (NaCl) 2240, 1712; H NMR (500 MHz, COSY) 1.42
(tm, J ) 14, 1H, H-9ax), 1.77 (dm, J ) 13.5, 1H, H-8eq), 1.83
(ddd, J ) 15, 3.5, 2, 1H, H-10), 2.04 (dm, J ) 14.5, 1H, H-9eq),
2.42 (qd, J ) 13.5, 4, 1H, H-8ax), 2.54 (ddd, J ) 13.25, 11.5, 6,
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and NMR data for compounds 1, 4-7, 15-19, and 26-
28. This material is available free of charge via the Internet
at http://pubs.acs.org.
1H, H-4), 2.65 (m, 1H, H-6eq), 2.69-2.76 (m, 3H, H-4, H-7ax
,
H-10), 2.77 (m, 1H, H-1eq), 2.82 (dd, J ) 11.25, 3, 1H, H-3),
2.87 (ddd, J ) 13.5, 9.5, 6, 1H, H-3), 3.20, 3.14 (2 d, J ) 15,
J O0163849