Metallic salt promoted radical cyclization of β-keto carboxamides and their corresponding β-enamino carboxamides

Article abstract of DOI:10.1021/jo000084u

Substituted lactams and spirolactams were obtained by Mn(III)-induced radical cyclization of unsaturated β-keto carboxamides. Treatment of the corresponding tertiary enamines under similar reaction conditions and in the presence of K₂CO₃ afforded the same cyclized products but with inversion of diastereoselectivity. The oxidation of optically pure secondary enamines leads to diastereomeric spirolactams in an approximately 3:1 ratio.

Full text of DOI:10.1021/jo000084u

VOLUME 65, NUMBER 22
NOVEMBER 3, 2000
© Copyright 2000 by the American Chemical Society
Articles
Meta llic Sa lt P r om oted Ra d ica l Cycliza tion of â-Keto
Ca r boxa m id es a n d Th eir Cor r esp on d in g â-En a m in o Ca r boxa m id es
J anine Cossy,* Abderrahim Bouzide,† and Catherine Leblanc
Laboratoire de Chimie Organique, associe´ au CNRS, ESPCI, 10 rue Vauquelin,
75231 Paris Cedex 05, France
janine.cossy@espci.fr
Received J anuary 20, 2000
Substituted lactams and spirolactams were obtained by Mn(III)-induced radical cyclization of
unsaturated â-keto carboxamides. Treatment of the corresponding tertiary enamines under similar
reaction conditions and in the presence of K2CO3 afforded the same cyclized products but with
inversion of diastereoselectivity. The oxidation of optically pure secondary enamines leads to
diastereomeric spirolactams in an approximately 3:1 ratio.
Free radical cyclizations of alkenes constitute a valu-
able method for the synthesis of cyclic compounds.1 The
precursors for such cyclizations can vary according to the
method used to generate the radical. Radical generation
can be effected by reduction, isomerization, or oxidation.
Oxidative methods have considerable synthetic potential,
as highly functionalized products can be obtained. Among
the various oxidative processes available, reactions of
enolizable dicarbonyl compounds with metal salts can
lead to products with high regio- and stereoselectivity.3
Some years ago, we examined the Mn(III)-based radical
cyclization of unsaturated â-keto carboxamides4 (Scheme
1, eq 1), which affords substituted lactams and spirolac-
tams.5,6 In this paper, we would like to report our findings
on the transformation of â-keto carboxamides and their
related tertiary as well as secondary enamines into
lactams and spirolactams by metallic salts (Scheme 1,
eq 2).
Oxid a tive Ra d ica l Cycliza tion of â-Keto Ca r -
boxa m id es. â-Keto carboxamides were readily prepared
by aminolysis of â-keto esters7 or by photolysis of diazo-
diketones8 in the presence of various commercially avail-
(3) (a) Curran, D. P.; Morgan, T. M.; Schwartz, C. E.; Snider, B. B.;
Dombrosky, M. A. J . Am. Chem. Soc. 1991, 113, 6607. (b) Kates, S. A.;
Dombrosky, M. A.; Snider, B. B. J . Org. Chem. 1990, 55, 2427.
(4) Cossy, J .; Leblanc, C. Tetrahedron Lett. 1989, 30, 4531,
(5) (a) D’Annibale, A.; Resta, S.; Trogolo, C. Tetrahedron Lett. 1995,
36, 9039. (b) Bosman, C.; D’Annibale, A.; Resta, S.; Trogolo, C.
Tetrahedron 1994, 50, 13847.
(6) (a) Snider, B. B.; Yu-Fong Wan, B.; Buckman, B. O.; Foxman,
B. M. J . Org. Chem. 1991, 56, 328. (b) Zoretic, P. A.; Weng, X.; Biggers,
C. K.; Biggers, M. S.; Caspar, M. L.; Davis, D. G. Tetrahedron Lett.
1992, 33, 2637. (c) Snider, B. B.; Zhang, Q. Tetrahedron Lett. 1992,
33, 5921. (d) Zhang, Q.; Mohan, R. M.; Cook, L.; Kazanis, S.; Peisach,
D.; Foxman, B. M.; Snider, B. B. J . Org. Chem. 1993, 58, 7640.
(7) Cossy, J .; Belotti, D.; Bouzide, A.; Thellend, A. Bull. Soc. Chim.
Fr. 1994, 131, 723.
† Current adress: Pharmacor Inc. 535, bld. Cartier Ouest, Laval
QC, Canada H7N 4Z9.
(1) For selected general reviews and books see: (a) Curran, D. P.
In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: London, 1991; Vol. 4, p 779. (b) Porter, N. A.; Giese,
B.; Curran, D. P. Acc. Chem. Res. 1991, 24, 296. (c) Porter, N. A.; Giese,
B. Stereochemistry of Radical Reactions; VCH: Weinheim, 1995.
(2) For reviews see: (a) de Klein, W. J . In Organic Synthesis by
Oxidation with Metal Compounds; Mijs, W. J ., de J onge, C. R. H., Eds.;
Plenum Press: New York, 1986; p 216. (b) Melikyan, G. G. Synthesis
1993, 833. (c) Iqbal, J .; Bhatia, B.; Nayyar, N. K. Chem. Rev. 1994,
94, 519. (d) Snider, B. B. Chem. Rev. 1996, 96, 339. (e) Melikyan, G.
G. Org. React. 1997, 49, 427. (f) Melikyan, G. G. Aldrichimica Acta
1998, 31, 1998.
10.1021/jo000084u CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/03/2000

7258 J . Org. Chem., Vol. 65, No. 22, 2000
Cossy et al.
Ta ble 1. Ra d ica l Cycliza tion of â-Keto Ca r boxa m id es
Sch em e 1. F or m a tion of Sp ir ola cta m s
Med ia ted by Mn (OAc)3
able amines.9 Preliminary attempts to cyclize unsatur-
ated â-keto carboxamides were carried out on N,N-diallyl-
8,8-dimethyl-2-oxocyclopentanecarboxamide 1 (Table 1).
Treatment with manganese triacetate dihydrate [Mn-
(OAc)3‚2H2O] in AcOH,10,11 afforded azaspiro[4.4]nonanes
12a /12b as an 8:1 mixture in only 12% yield. The low
yield is probably due to competitive oxidation of AcOH,
which interferes with the oxidation of the â-keto car-
boxamides as these compounds presumably oxidize more
slowly than â-keto esters.12 When the reaction was
conducted with anhydrous manganese triacetate [Mn-
(OAc)3]13,14 in ethanol, the cyclized products 12a /12b were
obtained in 28% yield, accompanied by hydroperoxides
13a /13b, which were isolated in 16% yield as an 8:1
mixture. When the ethanol solvent was flushed with
argon for 20 min prior to use, the yield of 12a /12b
increased to 56% without affecting the reaction diaste-
reoselectivity and no hydroperoxides were detected. The
relative stereochemistry of lactams 12a and 12b were
unambiguously established by comparison of their spec-
troscopic data with authentic samples previously pre-
pared through ene reactions of enamines derived from
â-keto amides.15 The Mn(III)-based radical cyclization of
(8) Cossy, J .; Belotti, D.; Thellend, A.; Pete, J . P. Synthesis 1988,
720.
(9) N-Methyl butylamine was prepared in four steps from N-
methylformamide.
(10) (a) Heiba, E. I.; Dessau, E. M. J . Org. Chem. 1974, 39, 3456.
(b) Heiba, E. I.; Dessau, E. M.; Koehl, W. J ., J r. J . Am. Chem. Soc.
1968, 90, 2706. (c) Heiba, E. I.; Dessau, E. M.; Koehl, W. J ., J r. J . Am.
Chem. Soc. 1968, 90, 2706.
(11) (a) Ernst, A. B.; Fristad, W.; Tetrahedron, Lett. 1985, 26, 3761.
(b) Fristad, W.; Peterson, R. J . J . Org. Chem. 1985, 50, 10. (c) Fristad,
W.; Peterson, R. J .; Ernst, A. B.; Urbi, R. G. Tetrahedron 1986, 42,
3429.
(12) For the radical cyclization of â-keto esters see: (a) Snider, B.
B.; Mohan, R. M.; Kates, S. A. J . Org. Chem. 1985, 50, 3659. (b) Snider,
B. B.; Dombroski, M. A. J . Org. Chem. 1987, 52, 5487. (c) Snider, B.
B.; Patricia, J . J .; Kates, S. A. J . Org. Chem. 1988, 53, 2137. (d) Snider,
B. B.; Patricia, J . J . J . Org. Chem. 1989, 54, 38. (e) Snider, B. B.;
Buckman, B. J . Org. Chem. 1992, 57, 322. (f) Snider, B. B.; McCarthy,
B. A. J . Org. Chem. 1993, 58, 6217 and other references therein.
(13) (a) Chre´tien, A.; Varga, G. Bull. Soc. Chim. Fr. 1936, 3, 2385.
(b) Corey, E. J .; Ghoch, A. K. Chem. Lett. 1987, 225.
unsaturated â-keto carboxamides is general as the ana-
logues 2 and 3 afforded, respectively, 14a /14b (50% yield,
8/1 ratio) and 15a /15b (56% yield, 7/1 ratio). Treatment
of â-keto carboxamides 4 and 5 under the same conditions
provided azapiro[4.5]decanes 16a /16b (42% yield, 6/1
ratio) and 17a /17b (45% yield, 6/1 ratio). Azaspiro[4.5]-
decanes 18a /18b were obtained in 52% yield as a 5/1
mixture from homoallylic keto amide 6. Interestingly,
oxidation of â-keto carboxamide 7 under similar condi-
tions afforded γ-lactam 19 (40% yield) as a single isomer.
The relative stereochemistry of 19 was established by
NOE experiments. Treatment of propargylic â-keto car-
boxamides 8, 9, and 10 under similar conditions provided,
respectively, spirolactams 20 (60%), 21 (55%), and γ-lac-
tam 22 (40%). The results are summarized in Table 1.
We note that lactam 20 can also be obtained from the
allylic â-keto carboxamide 3 by treatment with 2 equiv
of Mn(OAc)3 and 1 equiv of Cu(OAc)2, which is known to
be an efficient radical oxidizing agent,16,17 in degassed
ethanol (Table 2). Other spirolactams substituted by an
(14) For a modified method for the preparation of anhydrous Mn-
(OAc)3, see the Experimental Section.
(15) Cossy, J .; Bouzide, A.; Pfau, M. J . Org. Chem. 1997, 62, 7106.
(16) For review on Cu(II) oxidation of radicals see: (a) Kochi, J . K.
Science 1967, 155, 415. (b) Kochi, J . K. In Free Radicals; Kochi, J . K.,
Ed.; Wiley: New York, 1973; Vol. 1, Chapter 11. (c) Nonhebel, D. C.
In Essays on Free-Radical Chemistry; Norman, R. O. C., Ed.; Special
Publication 24; The Chemical Society: London, 1970; p 409. (d) Nigh,
W. G. In Oxidation in Organic Chemistry, Part B; Trahanovsky, W.
S., Ed.; Academic Press: New York, 1973; p 1.

Radical Cyclization of â-Keto Carboxamides
J . Org. Chem., Vol. 65, No. 22, 2000 7259
Ta ble 2. Ra d ica l Cycliza tion of â-Keto Ca r boxa m id es
Sch em e 3. Mech a n ism for th e Oxid a tion of
Med ia ted by Mn (OAc)3/Cu (OAc)2
â-Keto Ca r boxa m id es of Typ e I
Sch em e 4. F or m a tion of th e Tr icyclic
Com p ou n d s 28 a n d 29
Sch em e 2. Ra d ica l Cycliza tion of â-Keto
Ca r boxa m id e 4
give acetaldehyde. Thus, the use of 2 equiv of Mn(OAc)3
or more are essential for complete reaction. If the ethanol
solution is not sufficiently degassed, radical c is trapped
by molecular oxygen to afford the hydroperoxides 13. On
the other hand, in the presence of Cu(OAc)2, primary
radicals are oxidized to carbocations,16,17 which afford,
after elimination, the unsaturated cyclized products 20
and 23-26.16 The unstable monovalent species CuOAc
will react with Mn(OAc)3 to regenerate Cu(OAc)2. Again,
2 equiv of Mn(OAc)3 are necessary.
The formation of tricyclic ketal 28 or hemiacetal 29 is
due to the nucleophilic attack by oxygen on the carbo-
cation of the ketone. Inspection of molecular models
shows that, in intermediate d c, the ketone group is close
to the carbocation and a nucleophilic attack by the oxy-
gen of the carbonyl can take place to afford the tri-
cylic carbocation e (Scheme 4). This carbocation is then
quenched with EtOH to give ketal 28 or with H2O to
afford the hemiacetal 29. In intermediate d t, the distance
between the carbocation and the ketone group does not
permit bonding. The carbocation intermediate d t thus
undergoes deprotonation to produce 27.
exo methylenic group such as 23-26 were obtained in
moderate to good yields from the corresponding â-keto
carboxamides 1, 2, 6, and 11.
On the other hand, treatment of â-keto carboxamides
4 under these conditions, [(Mn(OAc)3/Cu(OAc)2, 2 equiv/1
equiv)] led to a mixture of the expected product 27 (25%)
along with the tricyclic acetal 28 (65%) (Scheme 2). The
replacement of ethanol by wet acetonitrile furnished 27
(26%) accompanied by the hemiacetal 29 (67%).The
mechanism of Mn(III)-initiated free-radical cylization of
â-keto amides of type I starts by the loss of acetic acid to
give Mn(III) enolate a (Scheme 3). By analogy with the
metal oxidation of acetic acid11 or â-keto esters,12 forma-
tion of the Mn(III)-enolate is probably the rate-determin-
ing step. The next step is Mn-O bond homolysis, which
results in the formation of â-keto amide radical b. This
radical can undergo regioselective cyclization by a 5- or
6-exo trig process to give the cyclized radical c. In the
presence of EtOH, which is known to be an excellent
hydrogen donor, this primary radical is reduced to give
the final products 12 and 14-22. The hydroxyethyl
radical can undergo a second oxidation by Mn(OAc)3 to
To understand the diastereoselectivity of the reaction,
four transition states A1, A2, B1, and B2 were taken into
consideration (Scheme 5). Transition states B1 and B2
are disfavored because of the presence of an interaction
between the double bond and the carbocyclic framework.
Transition state A2 may be favored over A1 as, in this
latter transition state, electronic repulsions between the
two carbonyl groups can take place.
(17) (a) Kochi, J . K.; Bacha, J . D. J . Org. Chem. 1975, 33, 2746. (b)
Bacha, J . D.; Kochi, J . K. Tetrahedron 1968, 24, 2215. (c) J enkins, C.
L.; Kochi, J . K. J . Am. Chem. Soc. 1972, 94, 843.
Oxid a tive Ra d ica l Cycliza tion of Ter tia r y a n d
Secon d a r y â-Ca r boxa m id o En a m in es. We were un-

7260 J . Org. Chem., Vol. 65, No. 22, 2000
Cossy et al.
Sch em e 5. Dia ster eoselectivity a n d Tr a n sition
Sta tes for th e Ra d ica l Cycliza tion of â-Keto
Ca r boxa m id es
isolating 35 by chromatography on alumina were unsuc-
cessful, and only spirolactams 14a /14b were obtained.
The reaction was generalized to other tertiary enamines
such as 31-34.
As a result of the high control of stereoselectivity
observed in these radical cyclizations, the synthesis of
enantioenriched spirolactams was envisaged from the
optically active enamines. Unfortunately, the prepara-
tion of enantiomerically pure enamines by condensing
â-keto carboxamide 2 with (2R,5R)-dimethylpyrroli-
dine,24,25 (S)-2-(methoxymethyl)pyrrolidine,26 or with
bis-(R)-1-phenylethylamine,27 was unfruitful. This is
probably due to steric hindrance of the amines. The
starting â-keto amides were recovered and were ac-
companied, in some cases, by transamidation products
when the reaction was performed at high temperatures-
.Because of this failure, we turned our attention to the
radical cyclization of secondary â-carboxamido enamines.
The results are summarized in Table 3. The â-carbox-
amido enamines 36-39 were prepared by condensing the
corresponding â-keto carboxamides with benzylamine in
toluene at room temperature. These compounds are more
stable than the tertiary enamines as a result of intramo-
lecular hydrogen bonding between the NH and the
carbonyl of the amide. Some of them can be isolated after
purification by flash chromatography on silica gel (e.g.,
36-38).
Treatment of enamine 36 with 1 equiv of Mn(OAc)3 in
the presence of K2CO3 was sufficient to effect complete
reaction within 30 min. The cyclized products 42a /42b
were obtained in good yield (72%), but unfortunately the
diastereoselectivity was low (54/46). The â-imino lactams
42a and 42b were stable and were purified by flash chro-
matography on silica gel. Their hydrolysis was achieved
with aqueous AcOH in THF to give the corresponding
â-keto lactams 14a and 14b in high yield (90%). This
reaction is general as 37 and 38 led, respectively, to 43a /
43b (yield, 66%; ratio, 53/47) and 44 (yield: 75%). In the
case of imine-enamine 39, we were not able to isolate the
intermediate â-imino lactam. Purification of the reaction
mixture on silica gel led directly to â-keto lactams 16a /
16b in good yield (70%) and with moderate diastereose-
lectivity (67/33) (Table 3).
able to prepare enantioenriched spirolactams from â-keto
carboxamides bearing a chiral auxiliary on the amide
function.18 We therefore turned our attention to the
oxidation of â-carboxamido enamines containing a chiral
auxiliary in the enamine function. We anticipated that
the replacement of an enol double bond by an enamine
double bond19 would afford the imine or iminium cyclized
product, which after hydrolysis would led to chiral
spirolactams. While the addition of carbon radicals to
enamines have been widely used in the past few years
to generate 1-amino radicals,20,21 the generation of radi-
cals from enamines has received little attention.22
Enamines 30-34 were prepared according to the
conventional procedure by condensing â-keto amides 2-5
and 9 with pyrrolidine in toluene with azeotropic removal
of water (Scheme 6).23 Initial attempts at free radical
cyclization of enamine 30 under the conditions described
for â-keto carboxamides were discouraging as substantial
polymerization was observed and the cyclized products
14a /14b were isolated in only 12% yield after flash
chromatography on silica gel. Interestingly, the ratio of
14a /14b, obtained from the oxidation of enamine 30 was
1:19 as opposed to 8:1 obtained in the oxidation of the
corresponding â-keto carboxamide 2. The yield of 14a /
14b was increased to 42% when 3 equiv of Mn(OAc)3 were
used in the presence of a base such as K2CO3. The
reaction was very fast as the starting enamine was
entirely transformed within 5 min. The NMR spectrum
of the crude reaction mixture indicated the presence of
the enamine intermediate 35.15 Several attempts at
Treatment of enamines 36 and 37 with 2 equiv of Mn-
(OAc)3 in the presence of 1 equiv of Cu(OAc)2 led,
respectively, to â-imino lactams 45 (77%) and 44 (75%)
(Scheme 7). Under the same conditions imine-enamine
39 led to â-keto lactam 27 (37% yield).
The radical cyclization of tertiary and secondary enam-
ines may involve initial coordination of the enamine
nitrogen with Mn(OAc)3 which results in the formation
of Mn(III)-complexe f (Scheme 8). In the case of tertiary
enamines, a single electron transfer (SET) takes place
immediately to give rise to radical-cation h . This radical
cyclizes rapidly by a 5-exo mode to afford the cyclized
(18) For one example of asymmetric induction of â-keto amides
controlled by a chiral auxiliary on the amide functionality see: (a)
Cardillo, B.; Galeazzi, R.; Mobilli, G.; Orena, M. Synlett 1995, 1159.
(b) Galeazzi, R.; Mobbili, G.; Orena, M. Tetrahedron 1996, 52, 1069.
(c) Cossy, J .; Salle´, L. Unpublished results.
(19) For the radical cyclization of silyl enol ethers see: (a) Snider,
B. B.; Kwon, T. J . Org. Chem. 1992, 57, 2399. (b) Snider, B. B.; Kwon,
T. J . Org. Chem. 1990, 55, 4786.
(20) For a review see: Renaud, P.; Giraud, L. Synthesis 1996, 913
and references therein.
(21) (a) Mignani, S.; J anousek, Z.; Merenyi, R.; Viehy, H. G.
Tetrahedron Lett. 1984, 25, 1571. (b) Curran, D. P.; Thoma, G. J . Am.
Chem. Soc. 1992, 114, 4436. (c) Renaud, P.; Shubert, S. Angew. Chem.,
Int. Ed. Engl. 1990, 29, 433.
(22) (a) Shono, T.; Matsumura, Y.; Hamaguchi, H.; Yochida, K. Bull.
Chem. Soc. J pn. 1987, 51, 2179. (b) Chiba, T.; Okimoto, M.; Nagai,
N.; Takata, Y. J . Org. Chem. 1979, 44, 3519.
(24) (a) Whitessel, J . K. Chem. Rev. 1989, 89, 1581. (b) Whitessel,
J . K. Acc. Chem. Res. 1985, 18, 280. (c) Whitessel, J . K.; Felman, S.
W. J . Org. Chem. 1977, 42, 1663. (d) Short, R. P.; Kennedy, R. M.;
Masammune, J . J . Org. Chem. 1989, 54, 1755.
(25) We thank Prof. L. Ghosez from the Universite´ Catholique de
Louvain-La-Neuve (Belgique) for providing us with (+)-(2R,5R)-
dimethylpyrrolidine.
(23) (a) Sauve, G.; Rao, V. S. In Comprehensive Organic Functional
Group Transformations; Katritsky, A. R., Otto, M.-C., Rees, C.-W., Eds.
Pergamon Press: New York, 1995; p 737. (b) G. Hickmott, P. W.
Tetrahedron 1982, 38, 1975. (c) Stork, G.; Brizzolara, A. J . Am. Chem.
Soc. 1963, 85, 208. (d) Whitessel, J . K.; Whitessel, M. A. Synthesis
1983, 517.
(26) (a) Enders, D.; Fey. R.; Kiphardt, H. Org. Synthesis 1987, 65,
173. (b) Enders, D.; Fey. R.; Kiphardt, H. Org. Synth. 1987, 65, 183.
(c) Seebach, D.; Kalnowski, H. O.; Shmidt, H. A. Helv. Chim. Acta 1977,
60, 310.
(27) Overberger, C. G.; Marullo, N. P.; Hiskey, G. G. J . Am. Chem.
Soc. 1961, 83, 1374.

Radical Cyclization of â-Keto Carboxamides
J . Org. Chem., Vol. 65, No. 22, 2000 7261
Sch em e 6. Sp ir ola cta m s fr om Ter tia r y â-Ca r boxa m id o En a m in es
Ta ble 3. Ra d ica l Cycliza tion of Secon d a r y â-Ca r boxa m id o En a m in es Med ia ted by Mn (OAc)3
iminium-radical i, which after deprotonation leads to the
enamine-radical j. In the case of secondary enamines, the
generation of the free radical l may follow an analogous
pathway or it may be preceded by the loss of acetic acid
through intermediate k . Radical l undergoes regioselec-
tive cyclization by a 5-exo process to give imine-radical
m . As it was the case for â-keto carboxamides, the radi-
cals j and m can be reduced by abstraction of hydrogen
from EtOH or possibly from the starting secondary
enamine. These radicals can also undergo a second
oxidation in the presence of Cu(OAc)2 and be transformed
to the unsaturated spirolactams 44, 45, and 27.
The high stereoselectivity of the reaction involving
tertiary enamines can be attributed mainly to the
interactions created by the pyrrolidine moiety, disfavor-
ing transition states C1 and D1 where severe repulsions
between the methylenic groups of the pyrrolidine ring
and the alkyl group of the amide are developed (Scheme

7262 J . Org. Chem., Vol. 65, No. 22, 2000
Cossy et al.
as EtAlCl2 or ZnCl2,2 an ene reaction can be ruled out.33
Furthermore, when the reactions were performed with
metallic salts in the presence Cu(OAc)2 at room temper-
ature, the oxidized products were obtained as the major
products. For example, treatment of 30 and 36 with
AgOAc (2 equiv) in the presence of Cu(OAc)2 (1 equiv)
led, respectively, to 20 (61%) and 45 (85%). As Cu(OAc)2
is unable to promote the reaction at room temperature,
the reaction is initiated by Ag(I) with subsequent oxida-
tion of the radical by Cu(OAc)2. Interestingly, treatment
of 36 with only 1 equiv of Cu(OAc)2 led directly to the
oxidized product 45 in 85% yield. This is probably the
result of a dismutation of Cu(I) to Cu(II) and Cu(0). The
regenerated Cu(II) acts as previously noted to produce
the radical cation or to oxidize the cyclized radical to the
carbocation intermediate. On the other hand, 2 equiv of
Cu(I) will dismutate to Cu(II) and Cu(0).33 An arithmeti-
cal calculation shows that 1 equiv of Cu(II) can be
generated from the dismutation phenomena and that the
complete transformation of Cu(II) to Cu(0) follows the
arithmetical serial Sn ) Σj-1n(1/2)j (j is the number of
cycles to transform 36 to 45. When n tends to infinity,
Sn tends to 1).
Sch em e 7. Ra d ica l Cycliza tion Med ia ted by
Mn (III)/Cu (II)
9). Transition state C2 is also disfavored as a result of
steric interactions between the pyrrolidine ring and the
double bond, which is sterically more demanding than a
hydrogen atom.
The lack of diastereoselectivity observed in the case of
secondary enamines is probably due to the absence of
steric factors as well as electronic factors that could
control the approach of the double bond to the radical.
Thus, all the transition states E1, E2, F 1, and F 2 can exist
(Scheme 10).
Con clu sion
Asym m etr ic Syn th esis of Sp ir ola cta m s. Oxidation
of the (R)-1-phenylethylamine-derived propargylamido
enamine 40 with 1 equiv of Mn(OAc)3 led to the two
diastereoisomeric spirolactams 46 and 47, which were
separated by flash chromatography on alumina in iso-
lated yields of 45% and 15% (Scheme 11). The allylamido
enamine 41 afforded spirolactams 46 and 47 in 65% and
25% yield, respectively, when treated with 1 equiv of Mn-
(OAc)3 and 1 equiv of Cu(OAc)2. We have to point out
that we were not able to determinate the absolute
configuration of the spiro center. However, one can
suppose that the major isomer could be 46 in which the
stereochemistry of the newly formed center is (R) arising
from approach of the unsaturation from the less hindered
side, assuming a preferred conformation of the phenyl-
ethyl auxiliary as shown.
An efficient synthesis of lactams and spirolactams was
achieved by using Mn(III)-based radical cyclization of
â-keto carboxamides. Reversal of diastereoselectivity was
observed in the oxidative cyclization of the â-keto versus
tertiary â-enamino carboxamides. The oxidative cycliza-
tion of chiral secondary enamines showed a moderate
diastereoselectivity of 3-2.6:1. The diastereomeric prod-
ucts were readily separated by silica gel chromatography
and were obtained in enantiomerically pure form, suit-
able for use in the synthesis of natural products having
a 2-azaspiro framework.34
Exp er im en ta l P a r t:
Gen er a l. All experiments were run under an argon atmo-
sphere. H NMR and 13C NMR spectra were recorded at 300
1
Oth er Meta llic Sa lt P r om oted Ra d ica l Cyliza -
tion s of â-En a m in o Ca r boxa m id es. Electroanalytical
studies have shown that â-enamino carboxamides have
a low redox potential (<0.80 V vs. the standard calomel
electrode).29 This observation prompted us to examine
other low valent metallic salts with a low redox potential
such as AgOAc,30 Co(OAc)2,31 CuCN and Cu(OAc)2.32
Treatment of tertiary as well as secondary enamines such
as 30 and 36 with AgOAc, Co(OAc)2, and CuCN led,
respectively, to the cyclized products 14a /14b and 42a /
42b with good chemical yields (Table 4). The diastereo-
selectivity remained unchanged, indicating that the
metals are not involved in the cyclization process. When
Cu(OAc)2 is used, 30 and 36 were transformed, respec-
tively, to 20 and 45. The reactions with CuCN and Cu-
(OAc)2 required heating to 80 °C.
and 75 MHz, respectively, in CDCl3 unless otherwise indicated.
Mass spectra were run on a GC-MS instrument at 70 eV.
Microanalysis and HRMS were performed at Paris VI Uni-
versity. Flash chromatography was performed on Merck silica
gel 60 (230-400 mesh) or on alumina 507 C neutral (100-
125 mesh).
Syn th esis of â-Keto Ca r boxa m id es. â-Keto carboxamides
1-11 were prepared according to refs 7 and 8. Spectroscopic
and physical data of 1-5, 8, and 9 are reported in the same
references.
(29) Audebert, P.; Bekolo, H.; Cossy, J .; Bouzide, A. J . Electroanal.
Chem. 1995, 389, 215.
(30) (a) Bhatia, B.; Punniyamurthy, T.; Iqbal, J . J . Org. Chem. 1993,
58, 5518. (b) Bhatia, S.; Punniyamurthy, T.; Bhatia, B.; Iqbal, J .
Tetrahedron 1993, 49, 6101.
(31) (a) Chung, H. K.; Dunn, L. B., J r. J . Org. Chem. 1983, 48, 1125.
(b) Babler, J . H.; Sarussi, S. J . Org. Chem. 1987, 52, 3462. (c)
Kawabata, T.; Sumi, K.; Hiyama, T. J . Am. Chem. Soc. 1989, 111, 6843.
(32) For reviews on Lewis acid catalyzed ene reactions see: (a)
Mikami, K.; Shimizu, M. Chem. Rev. 1992, 92, 1021. (b) Mikami, K.;
Terada, M.; Narisawa, S.; Nakai, T. Synlett 1991, 255. (c) Snider, B.
B. Acc. Chem. Res. 1980. (d) Snider, B. B. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Press: Oxford,
1991; Vol. 5, Chapter 1.1.
(33) A deposit of copper(0) was observed on the wall of the flask.
(34) (a) Ibragimov, A. A.; Osmanov, Z.; Tashkhodzhaev, B.; Abdul-
laev, M. R.; Yagudaev, N. D.; Yunusov. S. Y. Khim. Prir. Soedin 1981,
623. (b) Nosgorodova, N. Y.; Maekl, S. K.; Yunusov, S. Y. Khim. Prir.
Soedin 1973, 196. (c) Osmanov, Z.; Ibraginov, A. A.; Yunusov, S. Y.
Khim. Prir. Soedin. 1982, 126. (d) Osmanov, Z.; Ibramimov, A. A.;
Yunusov, S. Y. Chem. Nat. Prod. 1981, 206.
Since no spirolactam products were obtained when
enamines 30 and 36 were treated with Lewis acids such
(28) When the reaction was conducted in refluxing toluene, benzene,
or cyclohexane, the desired enamines were obtained in low yields
because of a competitive transamidation reaction. For example the
condensation of 2 with benzylamine in refluxing toluene afforded the
desired enamine 39 in only 35% yield accompanied by 64% of the
transamidation product. Apparently the transamidation reaction oc-
curred first, followed by the formation of the enamine. When the
enamine 39 was heated in refluxing toluene in the presence of excess
BnNH2, no reaction took place.

Radical Cyclization of â-Keto Carboxamides
J . Org. Chem., Vol. 65, No. 22, 2000 7263
Sch em e 8. Mech a n ism for th e F or m a tion of Sp ir ola cta m s fr om â-Ca r boxa m id o En a m in es
Ta ble 4. Oxid a tion of En a m in es w ith Meta llic Sa lts
Sch em e 9. Tr a n sition Sta tes in th e Ra d ica l
Cycliza tion of Ter tia r y â-Ca r boxa m id o En a m in es
metallic salt
(equiv)
yield (%)
ratio (a /b)
enamine
temp
products
30
36
30
36
30
36
30
36
Co(OAc)2, (2)
Co(OAc)2, (1)
AgOAc (2)
AgOAc (1)
CuCN (2)
CuCN (2)
Cu(OAc)2 (2)
Cu(OAc)2 (1)
rt
rt
rt
rt
80 °C
80 °C
80 °C
80 °C
14a /14b
42a /42b
14a /14b
42a /42b
14a /14b
42a /42b
20
60 (1/19)
65 (1.2/1)
51 (1/24)
75 (1/1.5)
57 (1/16)
70 (1/1.3)
61
45
85
(t); 135.04 (d); 168.42 (s); 213.62 (s). Minor rotamer: δ 27.84
(q); 28.87 (q); 32.76 (t); 33.80 (q); 34.04 (s); 41.05 (t); 49.56 (t);
50.93 (d); 53.26 (t); 117.00 (t); 134.11 (d); 168.68 (s); 213.62
(s). MS: C13H21NO2 m/z 223 (M+, 100); 182 (57); 139 (42). Anal.
Calcd for C13H21NO2: C, 69.92; H, 9.48; N, 6.27. Found: C,
70.03; H, 9.48; N, 6.30.
Sch em e 10. Tr a n sition Sta tes in th e Ra d ica l
Cycliza tion of Secon d a r y â-Ca r boxa m id o
En a m in es.
N,N-Dia llyl-3-m eth yl-2-oxobu tyr a m id e (7). Colorless oil;
1
yield 70%. IR: 1700; 1620 cm-1. H NMR: δ 1.37 (d, J ) 7.0
Hz, 3H); 2.37 (s, 3H); 3.60 (q, J ) 6.9 Hz, 1H); 3.81-4.17 (m,
4H); 5.10-5.27 (m, 4H); 5.70-5.87 (m, 2H). 13C NMR: δ 13.92
(q); 27.01 (q); 48.13 (t); 49.30 (t); 51.52 (d); 116.81 (t); 117.43
(t); 132.62 (d); 132.74 (d); 170.37 (s); 205.05 (s). MS: C11H17
-
-
NO2 m/z 195 (M+, 28); 96 (77); 56 (100). Anal. Calcd for C11H17
NO2: C, 67.66; H, 8.78; N, 7.17. Found: C, 67.44; H, 8.64;
N,7.27.
N-Meth yl-N-p r opa r gyl-3-m eth yl-2-oxobu tyr a m id e (10).
Colorless oil; yield 64% (2 rotamers in a ratio ) 2/1). IR: 1725;
1645 cm-1 1H NMR Major rotamer: δ 1.37 (d, J ) 6.9 Hz,
.
3H); 2.17 (s, 3H); 2.29 (t, J ) 2.5 Hz, 1H); 3.13 (s, 3H); 3.75 (q,
J ) 7.0 Hz, 1H); 4.03-4.23 (m, 2H). Minor rotamer: δ 1.39
(d, J ) 7.0 Hz, 3H); 2.18 (s, 3H); 2.42 (t, J ) 2.5 Hz, 1H); 3.05
(s, 3H); 3.75 (q, J ) 7.0 Hz, 1H); 4.03-4.23 (m, 2H).13C NMR
Major rotamer: δ 13.13 (q); 26.94 (q); 34.49 (q); 36.44 (t); 51.46
(d); 71.95 (d); 78.03 (s); 169.80 (s); 204.47 (s). Minor rotamer:
δ 13.36 (q); 27.08 (q); 33.56 (q); 39.51 (t); 51.46 (d); 73.13 (d);
78.03 (s); 170.06 (s); 204.47 (s). MS: C9H13NO2 m/z 167 (M+,
2); 58 (100). Anal. Calcd for C9H13NO2: C, 64.65; H, 7.84; N,
8.37. Found: C, 64.56; H, 8.08; N, 8.45.
N -(Bu t -3-e n yl)-N -m e t h yl-2-oxocycloh e xa n e ca r b ox-
a m id e (11). Colorless oil; yield 69%. IR: 1710, 1635 cm-1. 1H
NMR Major rotamer: δ 2.90 (s, 3H). Minor rotamer: δ 2.95
(s, 3H). For both rotamers: δ 1.60-2.61 (m, 10H); 3.14-3.39
(m,1H); 3.47 (t, J ) 7.5 Hz, 1H); 3.55-3.62 (m, 1H); 5.00-
5.14 (m, 2H); 5.67-5.88 (m, 1H). 13C NMR Major rotamer: δ
23.28 (t); 26.92 (t); 30.03 (t); 31.55 (t); 35.45 (q); 41.76 (t); 47.46
(t); 54.37 (d); 116.35 (t); 135.23 (d); 169.21 (s); 207.22 (s). Minor
rotamer: δ 23.28 (t); 26.75 (t); 30.31 (t); 32.58 (t); 33.55 (q);
41.60 (t); 49.21 (t); 53.97 (d); 117.45 (t); 133.98 (d); 169.21 (s);
207.34 (s). MS: C12H19NO2 m/z 210 (MH+, 48); 209 (M+, 4);
168 (100); 125 (71); 55. Anal. Calcd for C12H19NO2: C, 68.87;
H, 9.15; N, 6.69. Found: C, 69.02; H, 9.13; N, 6.67.
Sch em e 11. Oxid a tion of Op tica lly Active
Secon d a r y â-Ca r boxa m id o En a m in es
N-(Bu t-3-en yl)-N-m eth yl-4,4-d im eth yl-2-oxocyclop en -
ta n eca r boxa m id e (6). Colorless oil; yield 95%. IR: 1745,
1645, 1635 cm-1. 1H NMR Major rotamer: δ 1.06 (s, 3H); 1.25
(s, 3H); 3.14 (s, 3H). Minor rotamer: δ 1.04 (s, 3H); 1.23 (s,
3H); 2.96 (s, 3H). For both rotamers: δ 1.87-2.45 (m, 6H),
Syn th esis of â-En a m in o Ca r boxa m id es. Tertiary enam-
ines 30-34 were prepared as follows. To a stirred solution of
â-keto carboxamide (10 mmol) in toluene (25 mL) was added
pyrrolidine (2.5 mL, 30 mmol). The mixture was stirred
overnight at reflux with azeotropic removal of water. It was
then concentrated at reduced pressure to give the desired
3.28-3.73 (m, 3H); 4.88-5.15 (m, 2H); 5.78-5.89 (m, 1H). 13
C
NMR Major rotamer: δ 27.91 (q); 28.87 (q); 31.55 (t); 34.14
(s); 35.88 (q); 40.45 (t); 47.76 (t); 51.27 (d); 53.26 (t); 116.48

7264 J . Org. Chem., Vol. 65, No. 22, 2000
Cossy et al.
enamine in quantitative yield. For spectroscopic and physical
data of 30-34, see ref 15.
(m, 1H). 13C NMR: δ 26.14 (s); 32.00 (q); 32.64 (q); 34.50 (t);
36.41 (d); 46.68 (t); 47.09 (t); 55.28 (t); 63.54 (s); 69.57 (t);
118.69 (t); 132.17 (d); 175.77 (s); 219.30 (s). 13b 1H NMR: δ
1.17 (s, 3H); 1.24 (s, 3H); 1.57-1.73 (m, 1H); 1.91-2.56 (m,
5H); 3.19-3.39 (m, 2H); 3.78-4.00 (m, 3H); 4.00-4.06 (m, 1H);
5.12-5.31 (m, 2H); 5.60-5.80 (m, 1H). 13C NMR: δ 29.33 (t);
44.65 (d); 45.70 (t); 49.95 (t); 51.94 (t); 63.61 (s); 69.57 (t);
109.47 (t); 132.17 (d); 172.98 (s); 218.70 (s).
2,5,9,9-Tetr am eth yl-2-azaspir o[4.5]decan e-1,7-dion e 18.
Colorless oil; yield 52%. IR: 1725; 1620 cm-1. MS: C13H21NO2
m/z 224 (MH+, 0.3); 223 (M+, 10); 140 (100); 83. Anal. Calcd
for C14H21NO4: C, 69.92; H, 9.48; N, 6.27. Found: C, 70.01;
H, 9.60; N, 6.34. 18a 1H NMR: δ 0.94 (d, J ) 6.7 Hz, 3H);
1.13 (s, 3H); 1.45-1.63 (m, 1H); 1.91-2.70 (m, 6H); 2.90 (s,
3H); 3.20-3.40 (m, 2H). 13C NMR: δ 16.50 (q); 26.48 (t); 30.53
(q); 30.91 (q); 32.55 (s); 33.08 (q); 37.28 (d); 44.18 (t); 48.10 (t);
54.69 (t); 62.07 (s); 171.13 (s); 217.24 (s). 18b 1H NMR: δ 1.03
(d, J ) 6.7 Hz, 3H); 1.29 (s, 3H); 1.45-1.63 (m, 1H); 1.91-
2.70 (m, 6H); 2.90 (s, 3H); 3.20-3.40 (m, 2H). 13C NMR: δ
17.06 (q); 26.17 (t); 29.97 (q); 30.13 (q); 32.76 (s); 34.88 (q) 37.55
(d); 44.35 (t); 48.73 (t); 55.47 (t); 62.00 (s); 170.98 (s); 217.12
(s).
P r oced u r e B. Oxid a tive Ra d ica l Cycliza tion of â-Ke-
toca r boxa m id es w ith Mn (OAc)3/Cu (OAc)2. To a degassed
stirred suspension of â-keto carboxamide (1 mmol) and Cu-
(OAc)2 (182 mg, 1 mmol) in ethanol (5 mL) was added dropwise
a degassed solution of anhydrous Mn(OAc)3 (464 mg, 2 mmol)
in ethanol (5 mL). The reaction mixture was stirred at room
temperature for 5 h, then filtered over Celite and concentrated.
The residue was dissolved in EtOAc and water. The organic
layer was dried (MgSO4) and concentrated under reduced
pressure. The crude was purified by chromatography on silica
gel using hexanes/AcOEt as eluent to afford the cyclized
products.
Secondary enamines 36-41 were prepared as follows. To a
stirred solution of â-keto carboxamide (10 mmol) in toluene
was added benzylamine (12 mmol) or (R)-phenylethylamine
(12 mmol) and activated molecular sieves 3 Å. The mixture
was stirred at room temperature for 2 days, then filtered and
concentrated under reduced pressure to give the desired
enamines. For spectroscopic and physical data of 36-39, see
ref 15.
(-)-N-Meth yl-N-p r op a r gyl-2-[(R)-(1-p h en yleth yl)a m i-
n o]cyclop en t-1-en eca r boxa m id e (40). This enamine was
purified by flash chromatography using hexanes/EtOAc (70/
30) as eluent. Yellow oil; yield 95%; [R]22 -302 (c 5; ethanol).
D
IR: 3290; 1600 cm-1
.
1H NMR: δ 1.80 (d, J ) 6.9 Hz, 3H);
1.60-1.80 (m, 2H); 2.05-2.20 (m, 1H); 2.22 (t, J ) 2.4 Hz, 1H);
2.64 (t, J ) 7.0 Hz, 2H); 3.35 (s, 3H); 4.12 (d, J ) 2.4 Hz, 2H);
4.54 (m, 1H); 7.20-7.35 (m, 5H); 8.60 (d, J ) 7.3 Hz, 1H (NH)).
13C NMR: δ 20.37 (t); 24.77 (q); 31.56 (t); 32.23 (t); 34.52 (q);
38.00 (t); 54.10 (d); 71.07 (d); 80.00 (d); 94.35 (s); 125.42 (2d);
126.72 (d); 128.40 (2d); 145.43 (s); 164.60 (s); 171.46 (s). MS:
C18H22ON2 m/z 282 (M+, 5); 184 (90); 156 (100). Anal. Calcd
for C18H22N2O: C, 76.56; H, 7.85; N, 9.92. Found: C, 76.67;
H, 7.80; N, 9.96.
(-)-N-Allyl-N-m eth yl-2-[(R)-(1-p h en yleth yl)a m in o]-cy-
clop en t-1-en eca r boxa m id e (41). This enamine was purified
by flash chromatography using hexanes/EtOAc (70/30) as
eluent. Yellow oil; yield 97%; [R]22 -375 (c 2; ethanol). IR:
D
3500; 1600; 1550 cm-1. H NMR: δ 1.48 (d, J ) 6.9 Hz, 3H);
1
1.58-1.80 (m, 2H); 2.08-2.20 (m, 1H); 2.38-2.50 (m, 1H); 2.60
(t, J ) 6.8 Hz, 2H); 2.93 (s, 3H); 3.95 (d, J ) 5.2 Hz, 2H); 4.55
(q, J ) 7.0 Hz, 1H); 5.15 (m, 2H); 5.75-5.90 (m, 1H); 7.15-
7.35 (m, 5H); 8.58 (d, J ) 7.6 Hz, 1H).13C NMR: δ 23.27 (t);
25.78 (q); 32.43 (t); 33.31 (t); 35.43 (q); 52.22 (t); 54.96 (d); 95.75
(s); 116.93 (t); 126.29 (2d); 127.41 (d); 129.25 (2d); 135.28 (d);
146.00 (s); 164.51 (s); 172.54 (s). MS: C18H24N2O m/z 284 (M+,
5); 184 (83); 156 (100). Anal. Calcd for C18H24N2O: C, 76.02;
H, 8.51; N, 9.85. Found: C, 76.12; H, 8.53; N, 9.79.
2-Allyl-8,8-dim eth yl-4-m eth ylen e-2-azaspir o[4.4]n on an e-
1,6-d ion e 23. Colorless oil; yield 52%. IR: 1740; 1690 cm-1
.
1H NMR: δ 1.18 (s, 3H); 1.27 (s, 3H); 1.87-1.96 (m, 1H); 2.22-
2.42 (m, 2H); 2.53-2.60 (m, 1H); 3.27-3.35 (m, 1H); 3.37-
4.08 (m, 2H); 4.16-4.26 (m, 1H); 5.06-5.30 (m, 4H); 5.68-
5.82 (m, 1H). 13C NMR: δ 28.82 (q); 29.56 (q); 33.08 (s); 45.24
(t); 45.49 (t); 51.20 (t); 53.02 (t); 65.33 (s); 107.99 (t); 117.91
Mod ified P r oced u r e for th e P r ep a r a tion of An h y-
d r ou s Mn (OAc)3.13 Ca u tion : The reaction must be run in a
well-ventilated hood. A dry, 250 mL, three-necked flask
containing a magnetic stirring bar was charged with manga-
nese(II) nitrate tetrahydrate [Mn(NO3)2‚4H2O] (6.0 g, 0.024
mol) and acetic anhydride. The mixture was stirred by warm-
ing gently with a heat gun until the solution became clear.
The stirring was then stopped before an exothermic reaction
took place. NO2 gas was evacuated with an argon flux every
20 min over 1 h. Mn(OAc)3 crystallized overnight. Anhydrous
diethyl ether (20 mL) was added, and the mixture was stirred
for 10 min, then allowed to settle for 20 min. The supernatant
was removed by means of a syringe. The operation was
repeated three times and the obtained Mn(OAc)3 was dried
under vacuum. Yield 95% (5.3 g).
P r oced u r e A. Ra d ica l Cycliza tion of â-Keto Ca r box-
a m id es w ith Mn (OAc)3. To a degassed solution of â-keto
carboxamide (1 mmol) in ethanol (5 mL) was added a degassed
solution of anhydrous Mn(OAc)3 (464 mg, 2 mmol) in ethanol
(5 mL). The suspension was stirred at room temperature for
6 h, then filtered over Celite and concentrated. The residue
was dissolved in EtOAc and water. The organic layer was dried
over MgSO4 and concentrated under reduced pressure. The
products were purified by flash chromatography. Spectroscopic
and physical data of 14, 15-17, 20, and 21 were consistent
with data described in ref 15. Spectroscopic and physical data
of 12, 19, 22 are reported in a preliminary communication.4
2-Allyl-8,8-d im eth yl-4-h yd r op er oxym eth yl-2-a za sp ir o-
[4.4]n on a n e-1,6-d ion e 13. This hydroperoxide was a side
product when the reaction was carried out in nondegassed
ethanol and was obtained in 17% yield as a colorless oil. IR:
3340; 1730; 1675 cm-1. MS: C14H21NO4 m/z 268 (MH+, 0.3);
267 (M+, 9%); 220 (72); 137 (100). Anal. Calcd for C14H21NO4:
C, 62.90; H, 7.92; N, 5.24. Found: C, 63.05; H, 7.95; N, 5.13.
13a 1H NMR: δ 1.14 (s, 3H); 1.27 (s, 3H); 1.57-1.73 (m, 1H);
1.91-2.56 (m, 5H); 3.19-3.39 (m, 2H); 3.78-4.00 (m, 3H); 4.38
(dd, J ) 13.8 and 4.9 Hz, 1H); 5.12-5.31 (m, 2H); 5.60-5.80
(t); 131.59 (d); 144.10 (s); 171.62 (s); 211.68 (s). MS: C14H19
-
NO2 m/z 233 (M+, 16); 150 (100). Anal. Calcd for C14H19NO2:
C, 72.07; H, 8.20; N, 6.00. Found: C, 71.90; H, 8.31; N,5.96.
2-Allyl-4-m eth ylen e-2azaspir o[4.4]n on an e-1,6-dion e 24.
Colorless oil; yield 65%. IR: 1740; 1690 cm-1 1H NMR: δ
.
1.98-2.70 (m, 6H); 3.80-4.20 (m, 4H); 5.07-5.32 (m, 4H);
5.68-5.82 (m, 1H). 13C NMR: δ 19.98 (t); 32.42 (t); 37.65 (t);
44.90 (t); 50.84 (t); 63.11 (s); 107.89 (t); 117.87 (t); 131.41 (d);
143.44 (s); 171.63 (s); 213.55 (s). MS:
C12H15NO2 m/z 206
(MH+, 7); 205 (M+, 36); 150 (100). Anal. Calcd for C12H15NO2:
C, 70.22; H, 7.36; N, 6.82. Found: C, 70.35; H,7.24; N, 6.74.
2-Met h yl-9,9-d im et h yl-5-m et h ylen e-2-a za sp ir o[4.5]-
d eca n e-1,7-d ion e 25. Colorless oil; yield 55%. IR: 1725; 1620
cm-1.1H NMR: δ 1.12 (s, 3H); 1.27 (s, 3H); 2.02-2.75 (m, 6H);
2.96 (s, 3H); 3.24-3.42 (m, 2H); 4.09-5.05 (m, 2H). 13C NMR:
δ 29.85 (q); 29.89 (q); 30.71 (t); 33.23 (s); 35.59 (q); 47.17 (t);
49.03 (t); 53.79 (t); 64.92 (s); 110.43 (t); 143.88 (s); 169.26 (s);
213.49 (s). MS: C13H19NO2 m/z 222 (MH+, 6); 221 (M+, 19);
138 (100). Anal. Calcd for C13H19NO2: C, 70.56; H, 8.65; N,
6.33. Found: C, 70.71; H, 8.63; N, 6.42.
2-Meth yl-5-m eth ylen e-2-a za sp ir o[5.5]u n d eca n e-1,7-d i-
on e 26. Colorless oil; yield 40%. IR: 1705; 1650; 1630 cm-1.1H
NMR: δ 1.83-2.22 (m, 7H); 2.38-2.49 (m, 3H); 2.98 (s, 3H);
3.18-3.42 (m, 2H); 514 (d, J ) 2.0 Hz, 1H); 5.18 (d, J ) 2.0
Hz, 1H). 13C NMR: δ 21.38 (t); 26.29 (t); 30.22 (t); 32.21 (t);
35.16 (q); 39.27 (t); 48.66 (t); 64.97 (s); 111.84 (t); 142.42 (s);
168.95 (s); 208.78 (s). MS: C12H17NO2 m/z 208 (MH+, 25); 207
(M+, 59); 179 (100); 164 (62). Anal. Calcd for C12H17NO2: C,
69.54; H, 8.27; N, 6.76. Found: C,69.32; H, 8.17; N, 6.74.
2-Allyl-4-m eth ylen e-2-azaspir o[4.5]decan e-1,6-dion e 27.
Colorless oil; yield 25% in ethanol; 26% in wet acetonitrile; Rf
0.40 (PE/AcOEt, 50/50). IR: 1700; 1650 cm-1 1H NMR:
. δ
1.22-1.42 (m, 1H); 1.60-2.15 (m, 4H); 2.20-2.60 (m, 2H);
2.70-2.90 (m, 1H); 3.80-4.05 (m, 4H); 5.10-5.30 (m, 4H);

Radical Cyclization of â-Keto Carboxamides
J . Org. Chem., Vol. 65, No. 22, 2000 7265
5.65-5.80 (m, 1H). 13C NMR: δ 21.00 (t); 26.00 (t); 35.79 (t);
39.54 (t); 45.03 (t); 50.45 (t); 63.41 (s); 110.32 (t); 118.03 (t);
131.56 (d); 143.07 (s); 171.25 (s); 206.40 (s); MS: C13H17NO2
m/z 219 (M+, 80); 191 (90); 190 (100); 163 (85). Anal. Calcd for
C13H17NO2: C, 71.20; H, 7.81; N, 6.39. Found: C, 71.24; H,
7.83; N, 6.42.
and the solution was stirred for 30 to 60 min. The spectroscopic
and physical data of the cyclized products 42-44 and 16 are
consistent with those described in ref 15.
2-Allyl-6-b e n zylim in o-4-m e t h yle n e -2-a za sp ir o[4.4]-
n on a n -1-on e 45. Colorles oil; yield 77%. 1H NMR: δ 1.90-
2.50 (m, 5H); 2.55-2.70 (m, 1H); 3.70-4.20 (m, 4H); 4.50 (s,
2H); 5.00 (t, J ) 2.2 Hz, 1H); 5.06 (t, J ) 1.9 Hz, 1H); 5.10-
5.22 (m, 2H); 5.60-5.80 (m, 1H); 7.10-7.30 (m, 5H). 13C
NMR: δ 22.47 (t); 28.00 (t); 33.99 (t); 45.07 (t); 51.99 (t); 57.13
(t); 63.44 (s); 107.87 (t); 117.08 (t); 126.19 (d); 127.39 (2d);
128.04 (2d); 131.96 (d); 139.82 (s); 143.68 (s); 175.32 (s); 181.21
(s). MS: C19H22N2O m/z 294 (M+, 15); 203 (78); 200 (100). Anal.
Calcd for C19H22N2O: C, 77.52; H, 7.53; N, 9.51. Found: C,
77.70; H, 7.63; N, 9.55.
Com p ou n d 28. Colorless oil; yield 65%; Rf 0.50 (hexanes/
1
AcOEt, 50/50). IR: 1685; 1475 cm-1. H NMR: δ 1.10 (t, J )
7.2 Hz, 3H); 1.24-1.41 (m, 2H); 1.47-1.59 (m, 1H); 1.63-1.80
(m, 2H); 1.90-2.12 (m, 2H); 2.20-2.32 (m, 1H); 2.60-2.72 (m,
1H); 3.20 (dd, J ) 7.4 and 1.5 Hz, 1H); 3.35 (dd, J ) 9.20 and
9.20 Hz, 1H); 3.47 (dq, J ) 7.2 and 0.2 Hz, 1H); 3.53 (dq, J )
7.2 and 0.2 Hz, 1H); 73.62-3.80 (m, 2H); 3.92-4.08 (m, 1H);
4.20 (dd, J ) 8.6 and 8.6 Hz, 1H); 5.13-5.30 (m, 2H); 5.67-
5.82 (m, 1H). 13C NMR: δ 15.32 (q); 21.85 (t); 22.02 (t); 29.00
(t); 34.08 (t); 45.10 (t); 45.22 (d); 52.08 (t); 54.54 (t); 57.81 (s);
70.53 (t); 106.32 (s); 117.30 (t); 132.43 (d); 174.11 (s); MS:
(+)-(5R)-2-Meth yl-4-m eth ylen e-6-[(R)-(1-p h en yleth yl)-
im in o]-2-a za sp ir o[4.4]n on a n -1-on e 46. Rf 0.25 (hexanes/
EtOAc, 90/10); [R]22D +22.7 (c 1.5, EtOH). IR: 1730; 1650 cm-1
.
C
15H23NO3 m/z 265 (M+, 5); 220 (87); 219 (100); 191 (77). Anal.
1H NMR: δ 1.36 (d, J ) 6.60 Hz, 3H); 1.75-1.95 (m, 2H); 2.12-
2.50 (m, 4H); 2.95 (s, 3H); 3.85 (dt, J ) 13.0 and 1.7 Hz, 1H);
4.23 (dt, J ) 13.0 and 2.4 Hz, 1H); 4.40 (q, J ) 6.6 Hz, 1H);
4.87 (t, J ) 2.2 Hz, 1H); 5.00 (t, J ) 1.8 Hz, 1H); 7.10-7.20
(m, 5H). 13C NMR: δ 22.71 (t); 24.76 (q); 29.00 (t); 29.61 (q);
34.17 (t); 54.01 (t); 60.85 (s); 61.67 (d); 106.32 (t); 126.24 (2d);
126.31 (d); 128.15 (2d); 146.11 (s); 147.22 (s); 175.45 (s); 178.11
(s). MS: C18H22N2O m/z 282 (M+, 5); 177 (70); 104 (100). Anal.
Calcd for C18H22N2O: C, 76.56; H, 7.85; N, 9.92. Found: C,
76.62; H, 7.83; N, 9.97.
Calcd for C15H23NO3: C, 67.90; H, 8.74; N, 5.28. Found: C,
67.89; H, 8.76; N, 5.29.
Com p ou n d 29. Colorless oil; yield 67%; Rf 0.25 hexanes-
(PE/AcOEt, 50/50). IR: 3300; 1660 cm-1 1H NMR: δ 1.20-
.
1.40 (m, 1H); 1.45-1.90 (m, 7H); 2.70-2.80 (m, 1H); 3.15 (m,
dd, J ) 10.3 and 1.0 Hz, 1H); 3.52 (dd, J ) 10.1 and 5.9 Hz,
1H); 3.71 (dd, J ) 10.0 and 4.6 Hz, 1H); 3.80 (m, 2H); 4.10 (t,
J ) 9.2 Hz, 1H); 5.20 (m, 2H); 5.60-5.70 (m, 1H); 6.14 (d, J )
1.7 Hz, 1H). 13C NMR: δ 21.67 (t); 22.37 (t); 27.29 (t); 32.96
(t); 38.60 (d); 45.16 (t); 50.65 (t); 54.24 (s); 70.00 (t); 105.11 (s);
118.47 (t); 131.61 (d); 177.08 (s). MS: C13H19NO3 m/z 237 (M+,
65); 205 (100); 178 (78); 151 (90). Anal. Calcd for C13H19NO3:
C, 65.80; H, 8.07; N, 5.80. Found: C, 66.02; H, 8.01; N, 5.83.
P r oced u r e C. Ra d ica l Cycliza tion of Ter tia r y En a m -
in es w ith Meta llic Sa lts. To a degassed suspension of
enamine (1 mmol) and K2CO3 (138 mg, 1 mmol) in ethanol
(10 mL) was added portionwise the metallic salt (2 mmol). The
reaction mixture was stirred at room temperature until
complete consumption of starting material (within 5-15 min).
The reaction mixture was concentrated and diluted with
EtOAc. HCl (10%) was then added until pH 5-6. The organic
layer was dried (MgSO4) and concentrated under reduced
pressure. The crude product was purified by chromatography
on silica gel using hexanes/EtOAc as eluent to afford respec-
tively spirolactams 12, 15-17, and 21 with the yields indicated
in Tables 3 and 5.
(-)-(5R)-2-Meth yl-4-m eth ylen e-6-[(S)-(1-p h en yleth yl)-
im in o]-2-a za sp ir o[4.4]n on a n -1-on e 47. Rf 0.30 (hexanes/
EtOAc, 90/10); [R]22D -99.0 (c 0.7, EtOH). IR: 1730; 1655; 1490
cm-1. 1H NMR: δ 1.33 (d, J ) 6.6 Hz, 3H); 1.85-2.00 (m, 2H);
2.10-2.50 (m, 4H); 2.94 (s, 3H); 3.85 (dt, J ) 13.0 and 1.7 Hz,
1H); 4.23 (dt, J ) 13.0 and 2.4 Hz, 1H); 4.40 (q, J ) 6.6 Hz,
1H); 4.95 (t, J ) 2.2 Hz,1H); 5.03 (t, J ) 2.2 Hz, 1H); 7.10-
7.20 (m, 5H). 13C NMR: δ 22.79 (t); 24.23 (q); 28.75 (t); 29.56
(q); 33.34 (t); 54.00 (t); 60.90 (s); 61.24 (d); 105.86 (t); 126.24
(2d); 126.31 (d); 128.17 (2d); 145.47 (s); 147.60 (s); 175.27 (s);
177.94 (s). MS: C18H22N2O m/z 282 (M+, 5); 178 (70); 104 (100).
Anal. Calcd. for C18H22N2O: C, 76.56; H, 7.85; N, 9.92.
Found: C, 76.70; H, 7.88; N, 10.01.
Ack n ow led gm en t. Pr. J . A. Marshall is acknowl-
edged for his assistance in the preparation of this
manuscript.
P r ocedu r e D. Radical Cyclization of Secon dar y En am -
in es 36-41 w ith Meta llic Sa lts. As in Procedure C, except
that the reaction was run with only 1 equiv of metallic salt
J O000084U