Radical cyclization in heterocycle synthesis. 6. A new entry to cyclic amino alcohols via stannyl radical cyclization of oxime ethers connected with aldehydes or ketones

Article abstract of DOI:10.1021/jo9822176

Oxime ethers connected by a tether to aldehydes or ketones efficiently cyclize via stannyl radical addition-cyclization to provide a new entry to cyclic amino alcohols. Upon treatment with tributyltin hydride in the presence of AIBN, oxime ethers connected with either an aldehyde or a ketone via a nitrogen atom smoothly underwent stannyl radical addition-cyclization to give five- to seven-membered cis- and trans-heterocyclic amino alcohols of which the trans-isomers were major products. The newly found radical cyclization provides a novel method for preparing not only bifunctionalized heterocyclic compounds but also adjacently functionalized amino alcohols carrying two quaternary carbons.

Full text of DOI:10.1021/jo9822176

J . Org. Chem. 1999, 64, 2003-2009
2003
Ra d ica l Cycliza tion in Heter ocycle Syn th esis. 6.1 A New En tr y to
Cyclic Am in o Alcoh ols via Sta n n yl Ra d ica l Cycliza tion of Oxim e
Eth er s Con n ected w ith Ald eh yd es or Keton es
Takeaki Naito,* Kazumi Nakagawa, Takako Nakamura, Akira Kasei, Ichiya Ninomiya, and
Toshiko Kiguchi
Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658-8558, J apan
Received November 5, 1998
Oxime ethers connected by a tether to aldehydes or ketones efficiently cyclize via stannyl radical
addition-cyclization to provide a new entry to cyclic amino alcohols. Upon treatment with tributyltin
hydride in the presence of AIBN, oxime ethers connected with either an aldehyde or a ketone via
a nitrogen atom smoothly underwent stannyl radical addition-cyclization to give five- to seven-
membered cis- and trans-heterocyclic amino alcohols of which the trans-isomers were major
products. The newly found radical cyclization provides a novel method for preparing not only
bifunctionalized heterocyclic compounds but also adjacently functionalized amino alcohols carrying
two quaternary carbons.
Ch a r t 1
In tr od u ction
Though free radical reactions have stimulated the
research interest of organic chemists for nearly a century,
it is only in the last two decades that this knowledge has
been widely utilized in various areas of organic chemis-
try.2 Strategies involving radical reactions have become
potential tools in organic synthesis, in particular; free
radical-mediated cyclization has developed as a preemi-
nent method for preparing diverse cyclic compounds via
carbon-carbon bond-forming processes. In the known2
radical cyclizations, the majority employ methods utiliz-
ing conventional radical acceptors such as alkenes or
typical radical precursors such as halides, selenides, and
xanthates. One drawback in the traditional procedures
using such radical acceptors and precursors is known to
be loss of the inherent functional groups.
Resu lts a n d Discu ssion
We have recently explored a new efficient carbon-
carbon bond-forming reaction based on the radical addi-
tion-cyclization of oxime ethers tethered to either a
carbonyl1,3 or an alkene group4 for the synthesis of highly
functionalized cyclic compounds. In this paper, we de-
scribe full details of a new entry to cyclic amino alcohols
via stannyl radical addition-cyclization. The newly found
radical addition-cyclization provides a synthetically
useful method for the construction of cyclic amino alco-
hols widely found in biologically active natural products
such as amino sugars,5 amino cyclitols,6 pseudodis-
tomins,7 dysiherbaine,8 and related compounds (Chart 1).
P r ep a r a tion a n d Ra d ica l Ad d ition -Cycliza tion
of Oxim e Eth er s Con n ected w ith Ca r bon yl Gr ou p s.
There have been a few examples of the radical cyclization
of oxime ethers connected with a carbonyl group employ-
ing either zinc-TMSCl,9 an electroreduction method,10
or SmI2.11,12 During the course of this study, the Fallis
and Fu groups have independently reported the related
(5) For recent syntheses of daunosamine, see: (a) Sibi, M. P.; Lu,
J .; Edwards, J , J . Org. Chem. 1997, 62, 5864-5872. For a review of
synthesis of 3-aminosugars, see: (b) Hauser, F. M.; Ellenberger, S. R.
Chem. Rev. 1986, 86, 35-67.
(6) For recent syntheses of trehazolamine, see: (a) Boiron, A.; Zillig,
P.; Giese, B. J . Org. Chem. 1998, 63, 5864-5882. (b) De Gracia, I. S.;
Dietrich, H.; Bobo, S.; Chiara, J . L. J . Org. Chem. 1998, 63, 5883-
5889.
(1) Part V: Miyabe, H.; Torieda, M.; Inoue, K.; Tajiri, K.; Kiguchi,
T.; Naito, T. J . Org. Chem. 1998, 63, 4397-4407.
(2) For recent reviews, see: (a) Fossey, J .; Lefort, D.; Sorba, J . In
Free Radicals in Organic Chemistry; Translated by Lomas, J .; J ohn
Wiley & Sons Inc.: New York, 1995; pp 151-158 and pp 243-255. (b)
Ryu, I.; Sonoda, N.; Curran, D. P. Chem. Rev. 1996, 96, 177-194. (c)
Snider, B. B. Chem. Rev. 1996, 96, 339-364. (d) Giese, B.; Kopping,
B.; Go¨bel, T.; Dickhaut, J .; Thoma, G.; Kulicke, K. J .; Trach, F. Org.
React. (N.Y.) 1996, 48, 301-856.
(7) For recent works on pseudodistomins, see: (a) Doi, Y.; Ishibashi,
M.; Kobayashi, J . Tetrahedron 1996, 52, 4573-4580. (b) Kobayashi,
J .; Ishibashi, M. Heterocycles 1996, 42, 943-970. (c) Freyer, A. J .; Patil,
A. D.; Killmer, L.; Troupe, N.; Mentzer, M.; Carte, B.; Faucette, L.;
J ohnson, R. K. J . Nat. Prod. 1997, 60, 986-990. (d) Ninomiya, I.;
Kiguchi, T.; Naito, T. In The Alkaloids; Brossi, A., Ed.; Academic
Press: New York, 1998; Vol. 50, pp 317-342. (e) Kiguchi, T.; Ikai, M.;
Shirakawa, M.; Fujimoto, K.; Ninomiya, I.; Naito, T. J . Chem. Soc.,
Perkin Trans. 1 1998, 893-900.
(8) For isolation of dysiherbaine, see: Sakai, R.; Kamiya, H.; Murata,
M.; Shimamoto, K. J . Am. Chem. Soc. 1997, 119, 4112-4116.
(9) Corey, E. J .; Pyne, S. G. Tetrahedron Lett. 1983, 24, 2821-
2824.
(3) (a) Naito, T.; Tajiri, K.; Harimoto, T.; Ninomiya, I.; Kiguchi, T.
Tetrahedron Lett. 1994, 35, 2205-2206. (b) Kiguchi, T.; Tajiri, K.;
Ninomiya, I.; Naito, T.; Hiramatsu, H. Tetrahedron Lett. 1995, 36,
253-256. (c) Naito, T.; Torieda, M.; Ninomiya, I.; Kiguchi, T. Chem.
Pharm. Bull. 1996, 44, 624-626. (d) Miyabe, H.; Torieda, M.; Kiguchi,
T.; Naito, T. Synlett 1997, 580-582.
(4) Miyata, O.; Muroya, K.; Koide, J .; Naito, T. Synlett 1998, 271-
272.
(10) Shono, T.; Kise, B.; Yamanami, A.; Nomura, R. J . Org. Chem.
1994, 59, 1730-1740.
10.1021/jo9822176 CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/27/1999

2004 J . Org. Chem., Vol. 64, No. 6, 1999
Naito et al.
studies on the radical cyclizations using a hydrazone13
or a carbonyl group14 as a radical acceptor.
Ta ble 1. Ra d ica l Cycliza tion of 5
To disclose the scope and limitations of stannyl radical
addition-cyclization of oxime ethers, we focused our
attention on a systematic study employing readily avail-
able starting compounds in which two functional groups,
oxime ether and carbonyl groups, are connected with a
nitrogen atom with different carbon chains. The requisite
substrates 5a -h for the radical reaction were prepared
via three different routes depending upon the stability
of the substrates. The amino alcohols 1 were alkylated
with an appropriate alkyl chloride having the oxime ether
group, followed by protection by acylation with benzyl-
oxycarbonyl chloride (Z-chloride) to give the alcohols
3a ,c-d ,f-h . The alcohol 3e was prepared via a slightly
different route involving the alkylation of 1 with 3-chlo-
ropropionaldehyde diethyl acetal and exchange of the
acetal group to the oxime ether. Oxidation of 3a ,c-h with
CrO3-pyridine gave the desired oxime ethers 5a ,c-h .
The most unstable substrate 5b was prepared via the
reduction of the ester group of 4 by DIBALH reduction.
The E/ Z geometrical ratios of the aldoxime ether group
in 3 and 5 thus prepared were deduced by 1H NMR
spectroscopy. In general, the signals due to the imino
hydrogen of the E-aldoxime ether are shifted downfield
by the influence of the alkoxy group of the aldoxime ether
moiety.15 In the case of 5a , a signal due to the imino
hydrogen of the E-isomer (δ 7.18) was shifted downfield
with respect to that of Z-isomer (δ 6.82).
Bartlett16 has reported that the geometry of the oxime
ether group does not influence the trans/cis selectivity
of radical cyclization. Therefore, we investigated the
radical addition-cyclization of a geometrical mixture of
oxime ethers 5 without their isolation17 (Table 1). A
solution containing tributyltin hydride (2 equiv) and
AIBN (0.2 equiv) in benzene was added dropwise (10 mL/
h) to a solution of the oxime ether 5a in boiling benzene
while stirring under nitrogen. The solution was then
refluxed for a further 3 h to give a 1:2.3 mixture of the
cyclized cis- and trans-products 6a and 7a . Other ex-
amples of the cyclization are shown in Table 1. Under
the same condition, the ketoxime ether 5b carrying a
formyl group gave almost the same result, leading to the
formation of a 1:3.5 mixture of cis- and trans-products
6b and 7b. In the case of 5c carrying a ketone carbonyl
group, the reaction took place slowly compared with the
substrates 5a b having a formyl group, even in the
presence of 1 equiv of AIBN, to afford a mixture of two
cyclized compounds 6c and 7c. It is important to note
that ketoxime ether 5d connected with the ketone car-
bonyl group underwent the highly stereoselective radical
cyclization to afford the cyclic amino alcohols 6d and 7d
containing two adjacent quaternary carbons as a cis/trans
mixture in a 1:14 ratio. Employment of 0.2 equiv of AIBN
(conditions A) gave the products 6d and 7d in only 16%
yield while an increased amount (1 equiv) of AIBN
(conditions B) improved the yield to 38% yield. Further-
more, the addition of AIBN (1 equiv) in five portions of
20% each over 1 h (conditions C) improved the yield to
61% as a result of high concentration of AIBN.
The Fu group18 has recently reported that attempted
stannyl radical addition-cyclization of ketoxime ether
connected with the ketone carbonyl group via only a
carbon chain was unsuccessful. This remarkably different
result would be explained as follows. 5d would be more
cyclizable than Fu’s substrate due to the presence of the
N-Z group which would put the ketone carbonyl and
ketoxime ether groups in close proximity, thereby ac-
celerating the cyclization.
(11) (a) Chiara, J . L.; Marco-Contelles, J .; Khiar, N.; Gallego, P.;
Destabel, C.; Bernabe´, M. J . Org. Chem. 1995, 60, 6010-6011. (b)
Grove, J . J . C.; Holzapfel, C. W. Tetrahedron Lett. 1997, 38, 7429-
7432. (c) Marco-Contelles, J .; Gallego, P.; Rodr´ıguez-Ferna´ndez, M.;
Khiar, N.; Destabel, C.; Bernabe´, M.; Mart´ınez-Grau, A.; Chiara, J . L.
J . Org. Chem. 1997, 62, 7397-7412.
(12) For our recent work in the radical cyclization of oxime ethers
connected by a tether to aldehydes by use of SmI2, see: Miyabe, H.;
Kanehira, S.; Kume, K.; Kandori, H., Naito, T. Tetrahedron 1998, 54,
5883-5892. See also ref 1.
(13) Sturino, C. F.; Fallis, A. G. J . Am. Chem. Soc. 1994, 116, 7447-
7448.
(14) Hays, D. S.; Fu, G. C.; J . Am. Chem. Soc. 1995, 117, 7283-
7284.
(15) (a) McCarty, C. G. In The Chemistry of Functional Groups; The
chemistry of the carbon-nitrogen double bond, Patai, S., Ed.; J ohn
Wiley & Sons Inc.: New York, 1970; pp 383-392. (b) Marco-Contelles,
J .; Pozuelo, C.; J imeno, M. L.; Martines-Grau, A. J . Org. Chem. 1992,
57, 2625-2631.
(16) Bartlett, P. A.; McLaren, K. L.; Ting, P. C. J . Am. Chem. Soc.
1988, 110, 1633-1634.
(17) We have also reported that the geometry of the oxime ether
group does not influence the stereoselectivity in its radical cyclization,
see ref 1.
(18) Tormo, J .; Hays, D. S.; Fu, G. C. J . Org. Chem. 1998, 63, 201-
202.

Radical Cyclization in Heterocycle Synthesis
J . Org. Chem., Vol. 64, No. 6, 1999 2005
Sch em e 1
The newly found radical addition-cyclization was
successfully extended to the oxime ethers 5e-g connected
with the formyl group via four or five atoms and gave
six- and seven-membered cyclic products 6e-g and 7e-g
of which trans-isomers 7e-g were major products in
every case. The yield of seven-membered products 6g and
7g improved from 44 to 71% yield when an increased
equivalent (1 equiv) of AIBN was used. Irrespective of
the length of the carbon chain between nitrogen and
either the carbonyl or oxime ether group, the radical
addition-cyclization proceeded smoothly to give the cyclic
compounds 6 and 7 which were adjacently functionalized
with the alkoxyamino and hydroxyl groups. However,
attempted formation of an eight-membered product was
unsuccessful, and the starting compound 5h was mostly
recovered. In every case, the two stereoisomeric products
were readily separated by repeated chromatography.
These results may suggest the following three charac-
teristic points. First, the radical addition-cyclization of
aldo- or ketoxime ether connected via a nitrogen atom
with a formyl or ketone carbonyl group proceeds smoothly
to give a mixture of five- to seven-membered cis- and
trans-cyclic amino alcohols of which the trans-isomers
are major products. Second, the reaction takes place
exclusively in exo-trig manner, and no endo-trig products
were formed. Third, the reduction products of neither the
carbonyl nor the oxime ether group are formed, and
employment of a stoichiometric amount of AIBN and its
portionwise addition improves the cyclization yield.
Ster eostr u ctu r es of Cyclized P r od u cts a n d P r o-
p osed Rea ction P a th w a y. The stereostructures of five-
membered cyclized products 6a -d and 7a -d were firmly
established by the chemical reactions in addition to their
spectral data (Scheme 2). Treatment of cis-amino alcohols
6a -d with dimethoxypropane (DMP) and p-TsOH gave
their corresponding acetonides 8a -d while trans-conge-
ners 7a -d were recovered completely under the same
reaction condition. Though the stereostructures of six-
membered products 6ef and 7ef were deduced from their
spectra, particularly 1H NMR spectroscopies, those of
seven-membered congeners 6g and 7g were firmly es-
tablished by the chemical conversion of one isomer 7g
into the authentic sample1 which was already character-
ized and employed as a crucial intermediate for the total
synthesis of (-)-Balanol. The polar isomer 7g was
converted into N-Boc trans-amino alcohol 9 which was
identical with the authentic sample1 used for Balanol
synthesis.
Next, we propose the possible reaction pathway of the
stannyl radical addition-cyclization of oxime ethers in
this study as follows (Scheme 3). The stannyl radical is
known to be oxygenphilic19 and, therefore, attacks the
carbonyl group to form the ketyl radical A which would
be trapped intramolecularly with the oxime ether. The
oxime ether group is known20,21 to be an excellent radical
acceptor, and the resulting alkoxyaminyl radical B is
stabilized by the adjacent oxygen atom. Therefore, the
exo-trig cyclization would be favored over an endo-trig
process. The trans-selectivity would be explained by the
electronic repulsion22 between the stannyloxy group and
the nitrogen and/or oxygen atom in the oxime ether group
in the transition state C. Possible steric repulsion
(20) For selected examples of intramolecular radical addition to
oxime ethers published in recent five years, see: (a) Grissom, J . W.;
Klingberg, D.; Meyenburg, S.; Stallman, B. L. J . Org. Chem. 1994, 59,
7876-7888. (b) Parker, K. A.; Fokas, D. J . Org. Chem. 1994, 59, 3927-
3932. (c) Della, E. W.; Knill, A. M. Aust. J . Chem. 1994, 47, 1833-
1841. (d) Booth, S. E.; J enkins, P. R.; Swain, C. J .; Sweeney, J . B. J .
Chem. Soc., Perkin Trans. 1 1994, 3499-3508. (e) Chiara, J . L.; Marco-
Contelles, J .; Khiar, N.; Gallego, P.; Destabel, C.; Bernabe´, M. J . Org.
Chem. 1995, 60, 6010-6011. (f) Keck, G. E.; McMardy, S. F.; Murry,
J . A. J . Am. Chem. Soc. 1995, 117, 7289-7290. (g) Santagostino, M.;
Kilburn, J . D. Tetrahedron Lett. 1995, 36, 1365-1368. (h) Holling-
worth, G. J .; Pattenden, G.; Schulz, D. J . Aust. J . Chem. 1995, 48,
381-399. (i) Marco-Contelles, J .; Destael, C.; Chiara, J . L.; Bernabe´,
M. Tetrahedron: Asymmetry 1995, 6, 1547-1550. (j) Bhat, B.; Swayze,
E. E.; Wheeler, P.; Dimock, S.; Perbost, M.; Sanghvi, Y. S. J . Org.
Chem. 1996, 61, 8186-8199. (k) Kim, S.; Lee, I. Y.; Yoon, J .-Y.; Oh, D.
H. J . Am. Chem. Soc. 1996, 118, 5138-5139. (l) Keck, G. E.; Wager,
T. T. J . Org. Chem. 1996, 61, 8366-8367. (m) Marco-Contelles, J .;
Destabel, C.; Gallego, P.; Chiara, J . L.; Bernabe´, M. J . Org. Chem. 1996,
61, 1354-1362. (n) Fallis, A. G.; Brinza, I. M. Tetrahedron 1997, 53,
17543-17594. (o) Kim, S.; Kim, Y.; Yoon, K. S. Tetrahedron Lett. 1997,
38, 2487-2490. (p) Marco-Contelles, J .; Balme, G.; Bouyssi, D.;
Destabel, C.; Henriet-Bernard, C. D.; Grimaldi, J .; Hatem, J . M. J .
Org. Chem. 1997, 62, 1202-1209. (q) Clive, D. L. J .; Zhang, J . Chem.
Commun. 1997, 549-550.(r) Noya, B.; Alonso, R. Tetrahedron Lett.
1997, 38, 2745-2748. (s) Mart´ınez-Grau, A.; Marco-Contelles, J . Chem.
Soc. Rev. 1998, 27, 155-162. See also ref 1, 3, 15b, 16, and 18.
(21) For our recent works in intermolecular radical addition to oxime
ethers, see: (a) Miyabe, H.; Ushiro, C.; Naito, T. Chem. Commun. 1997,
1789-1790. (b) Miyabe, H.; Shibata, R.; Ushiro, C.; Naito, T. Tetra-
hedron Lett. 1998, 39, 631-634. (c) Miyabe, H.; Shibata, R.; Sangawa,
M.; Ushiro, C.; Naito, T. Tetrahedron 1998, 54, 11431-11444.
(19) For selected examples of the radical cyclization of O-stannyl
ketyl radical to alkenes, see: (a) Enholm, E. J .; Prasad, G. Tetrahedron
Lett. 1989, 30, 4939-4942. (b) Enholm, E. J .; Burroff, J . A. Tetrahedron
Lett. 1992, 33, 1835-1838. (c) Hays, D. S.; Fu, G. C. J . Org. Chem.
1996, 61, 4-5. (d) Enholm, E. J .; Burroff, J . A. Tetrahedron 1997, 53,
13583-13602. (e) Parson, A. F.; Pettifer, R. M. J . Chem. Soc., Perkin
Trans. 1 1998, 651-660.

2006 J . Org. Chem., Vol. 64, No. 6, 1999
Naito et al.
apparatus. Mass spectra were obtained by EI method. Pre-
parative TLC separations were carried out on precoated silica
gel plates (E. Merck 60F254). Medium-pressure column chro-
matography was performed using Lobar gro¨sse B (E. Merck
310-25, Lichroprep Si60). Flash column chromatography was
performed using E. Merck Kieselgel 60 (230-400 mesh). Short
column chromatography was undertaken on a short glass filter
using E. Merck Kieselgel 60 (230-400 mesh) under reduced
pressure.
Sch em e 2
Gen er a l P r oced u r e for P r ep a r a tion of Alcoh ols 3. To
a solution of amino alcohol 1 (150 mmol) in MeOH (150 mL)
was added chloroacetaldehyde O-methyloxime24 or chloroace-
tone O-methyloxime25 (50 mmol) under a nitrogen atmosphere
at 0 °C. The reaction mixture was heated at reflux for 3 h.
After the solvent was evaporated at reduced pressure, the
resulting residue was diluted with saturated aqueous NaHCO3
and extracted with CHCl3. The organic phase was dried over
Na2SO4 and concentrated at reduced pressure. To a solution
of the resulting residue in acetone (100 mL) was added a
solution of Na2CO3 (50 mmol) in H2O (25 mL) under a nitrogen
atmosphere at room temperature. After a solution of benzyl-
oxycarbonyl chloride (ZCl) (55 mmol) in acetone (10 mL) was
added dropwise at 0 °C, the reaction mixture was stirred at
room temperature for 3 h. The resulting solution was filtered
through a pad of Celite, the filtrate was concentrated at
reduced pressure, and the residue was diluted with H2O and
extracted with CHCl3. The organic phase was dried over
Na2SO4 and concentrated at reduced pressure. Purification of
the residue by medium-pressure column chromatography or
flash column chromatography (AcOEt/hexane 1:1-2:1) af-
forded 3 as colorless oils and mixtures of E/ Z-oxime for
3a ,c,f-h and a mixture of rotamers for 3d .
Sch em e 3
P h en ylm eth yl (2-Hyd r oxyeth yl)[2-(m eth oxyim in o)-
eth yl]ca r ba m a te (3a ): yield 40%; IR (CHCl3) 3447 (OH), 1697
(NCOO) cm-1 1H NMR (200 MHz, CDCl3) δ 7.45-7.30 (28/
;
5H, m), 6.75 (2/5H, m), 5.18 (2H, s), 4.25 (4/5H, m), 4.16 (6/
5H, m), 3.90 (6/5H, s), 3.84 (9/5H, s), 3.82-3.41 (4H, m); HRMS
(EI, m/z) calcd for C13H18N2O4 (M+) 266.1265, found 266.1251.
P h en ylm eth yl (2-Hyd r oxyp r op yl)[2-(m eth oxyim in o)-
eth yl]ca r ba m a te (3c): yield 60%; IR (CHCl3) 3640-3220
(OH), 1696 (NCOO) cm-1; 1H NMR (300 MHz, CDCl3) δ 7.42-
7.31 (28/5H, m), 6.73 (2/5H, m), 5.15 (2H, s), 4.21-3.92 (3H,
m), 3.86 (6/5H, s), 3.81 (9/5H, s), 3.40-3.15 (2H, m), 1.17 (6/
5H, d, J ) 6 Hz), 1.16 (9/5H, d, J ) 6 Hz); HRMS (EI, m/z)
calcd for C14H20N2O4 (M+) 280.1422, found 280.1438.
P h en ylm eth yl (2-Hyd r oxyp r op yl)[2-(m eth oxyim in o)-
p r op yl]ca r ba m a te (3d ): yield 39%; IR (CHCl3) 3640-3350
(OH), 1697 (NCOO) cm-1; 1H NMR (300 MHz, CDCl3) δ 7.45-
7.20 (5H, m), 5.17 (2H, s), 4.20-3.90 (3H, m), 3.80 (3H, s),
3.40-3.15 (2H, m), 1.85 (1H, br s), 1.73 (2H, br s), 1.17 (3H,
m); HRMS (EI, m/z) calcd for C15H22N2O4 (M+) 294.1578, found
294.1572.
between the R group (particularly Me) and the oxime
ether group or the stannyloxy group would be not so large
because the oxime ethers 5bc gave preferably trans-
products 7bc as the main isomer via the transition state
D. Steric repulsion between two methyl groups over-
lapped with electron repulsion as mentioned above to
increase the instability of the transition state C, thus
giving trans-isomer 7d with high stereoselectivity.23
P h en ylm eth yl (3-Hyd r oxyp r op yl)[2-(m eth oxyim in o)-
eth yl]ca r ba m a te (3f): yield 34%; IR (CHCl3) 3640-3350
(OH), 1686 (NCOO) cm-1; 1H NMR (300 MHz, CDCl3) δ 7.42-
7.28 (28/5H, m), 6.63 (2/5H, br t, J ) 4 Hz), 5.15 (2H, s), 4.15-
3.38 (7H, m), 3.87 (6/5H, s), 3.83 (9/5H, s), 1.79-1.65 (2H, m);
HRMS (EI, m/z) calcd for C14H20N2O4 (M+) 280.1422, found
280.1412.
Con clu sion
We have developed a general method for the intramo-
lecular cyclization of oxime ethers tethered via a nitrogen
atom to carbonyl groups, which is a promising synthetic
method for preparing five- to seven-membered hetero-
cycles functionalized adjacently with the amino and
hydroxyl groups.
P h en ylm eth yl (4-Hyd r oxybu tyl)[2-(m eth oxyim in o)-
eth yl]ca r ba m a te (3g): yield 57%; IR (CHCl3) 3650-3355
1
(OH), 1694 (NCOO) cm-1; H NMR (60 MHz, CDCl3) δ 7.53-
7.26 (28/5H, m), 6.75 (2/5H, m), 5.25 (2H, s), 4.48-3.25 (6H,
m), 3.99 (6/5H, s), 3.95 (9/5H, s), 2.23-1.46 (4H, m); HRMS
(EI, m/z) calcd for C15H22N2O4 (M+) 294.1579, found 294.1582.
P h en ylm eth yl (4-Hyd r oxyp en tyl)[2-(m eth oxyim in o)-
eth yl]ca r ba m a te (3h ): yield 30%; IR (CHCl3) 3630-3340
(OH), 1694 (NCOO) cm-1; 1H NMR (200 MHz, CDCl3) δ 7.40-
7.22 (28/5H, m), 6.75 (2/5H, m), 5.12 (2H, s), 4.16-3.18 (6H,
m), 3.87 (6/5H, s), 3.82 (9/5H, s), 1.68-1.21 (6H, m); HRMS
(EI, m/z) calcd for C16H24N2O4 (M+) 308.1735, found 308.1732.
Exp er im en ta l Section
Gen er a l. Melting points are uncorrected. 1H and 13C NMR
spectra were recorded at 60, 200, 300, or 500 MHz and at 75
or 125 MHz, respectively. IR spectra were recorded using FTIR
(22) In the electroreductive cyclization of oxime ethers connected
by a tether to aldehydes, the trans-selectivity was explained by the
electronic repulsion between negative charge located on the oxygen
and nitrogen atom in the oxime ethers, see ref 10.
(23) Recently Fu group has reported that cis-selectivity is observed
in stannyl radical addition-cyclization of dicarbonyl compounds and
is explained via 1,3,2-dioxastannolane as a cyclic intermediate, see ref
14.
(24) Stach, L. J . U.S. Patent 3920772, 1975 (Chem. Abstr. 1976, 84,
89603d).
(25) See the Supporting Information.

Radical Cyclization in Heterocycle Synthesis
J . Org. Chem., Vol. 64, No. 6, 1999 2007
P h en ylm eth yl (3,3-Dieth oxyp r op yl)(2-h yd r oxyeth yl)-
ca r ba m a te (2). To 2-amino-1-ethanol (3 g, 50 mmol) was
added 3-chloropropionaldehyde diethylacetal (4.4 g, 25 mmol)
under a nitrogen atmosphere at 0 °C. After being stirred at
room temperature for 48 h, the reaction mixture was diluted
with 10% NaOH solution and extracted with AcOEt. The
organic phase was dried over Na2SO4 and concentrated at
reduced pressure to afford the crude amine. Following the
same procedure as for 3, the crude amine was protected with
the Z group to give 2 (3 g, 37%) as a colorless oil after
purification by medium-pressure column chromatography
(AcOEt/hexane 3:1): IR (CHCl3) 3436 (OH), 1691 (NCOO)
P h en ylm eth yl [3-(Meth oxyim in o)p r op yl](2-oxoeth yl)-
ca r ba m a te (5e): yield 48%; 1H NMR (60 MHz, CDCl3) δ 9.47
(1H, m), 7.40-7.12 (28/5H, m), 6.55 (2/5H, m), 5.12 (2H, s),
4.08-3.85 (2H, m), 3.82 (6/5H, s), 3.73 (9/5H, s), 3.62 (2H, br
t, J ) 6 Hz), 2.48 (2H, m).
P h en ylm eth yl [2-(Meth oxyim in o)eth yl](3-oxop r op yl)-
ca r ba m a te (5f): yield 59%; 1H NMR (60 MHz, CDCl3) δ 9.72
(1H, m), 7.45-7.11 (28/5H, m), 6.59 (2/5H, br t, J ) 4.5 Hz),
5.12 (2H, s), 4.24-3.37 (4H, m), 3.82 (6/5H, s), 3.79 (9/5H, s),
2.89-2.39 (2H, m).
P h en ylm eth yl [2-(Meth oxyim in o)eth yl](4-oxobu tyl)-
ca r ba m a te (5g): yield 58%; 1H NMR (60 MHz, CDCl3) δ 9.58
(1H, m), 7.38-7.10 (28/5H, m), 6.59 (2/5H, m), 5.12 (2H, s),
4.22-3.12 (4H, m), 3.84 (6/5H, s), 3.79 (9/5H, s), 2.61-1.50
(4H, m).
P h en ylm eth yl [2-(Meth oxyim in o)eth yl](5-oxop en tyl)-
ca r ba m a te (5h ): yield 81%; 1H NMR (60 MHz, CDCl3) δ 9.58
(1H, m), 7.38-7.10 (28/5H, m), 6.59 (2/5H, m), 5.14 (2H, s),
4.18-3.92 (2H, m), 3.87 (6/5H, s), 3.82 (9/5H, s), 3.42-3.22
(2H, m), 2.52-2.32 (2H, m), 1.68-1.48 (4H, m).
1
cm-1; H NMR (300 MHz, CDCl3) δ 7.42-7.29 (5H, m), 5.13
(2H, s), 4.52 (1H, m), 3.75 (2H, m), 3.68-3.32 (8H, m), 1.92
(2H, m), 1.56 (6H, t, J ) 7 Hz); HRMS (EI, m/z) calcd for
C
17H27NO5 (M+) 325.1887, found 325.1915.
P h en ylm et h yl (2-H yd r oxyet h yl)[3-(m et h oxyim in o)-
p r op yl]ca r ba m a te (3e). To a solution of 2 (1.3 g, 4.0 mmol)
in acetone (11 mL) was added 5 M HCl (12.5 mL) under a
nitrogen atmosphere at room temperature. After being stirred
at the same temperature for 4 h, the reaction mixture was
neutralized with saturated aqueous NaHCO3 and extracted
with AcOEt. The organic phase was dried over Na2SO4 and
concentrated at reduced pressure to afford the crude aldehyde.
To a solution of the resulting crude aldehyde in MeOH (23
mL) were successively added NaOAc (754 mg, 9.2 mmol) and
NH2OMe‚HCl (764 mg, 9.2 mmol) under a nitrogen atmo-
sphere at room temperature. After being stirred at the same
temperature for 1 h, the reaction mixture was concentrated
at reduced pressure. The resulting residue was diluted with
saturated aqueous NaHCO3 and extracted with Et2O. The
organic phase was dried over Na2SO4 and concentrated at
reduced pressure. Purification of the residue by medium-
pressure column chromatography (AcOEt/hexane 2:1) afforded
3e (1.12 g, 99%) as a colorless oil and a mixture of E/ Z-
P h en ylm eth yl (Eth oxyca r bon ylm eth yl)[2-(m eth oxy-
im in o)p r op yl]ca r ba m a te (4). To a solution of glycine ethyl
ester HCl (17.2 g, 123 mmol) and Et3N (9.6 g, 95 mmol) in
EtOH (125 mL) was added chloroacetone O-methyloxime (5
g, 41 mmol) under a nitrogen atmosphere at 0 °C. The reaction
mixture was heated at reflux for 3 h. After the solvent was
evaporated at reduced pressure, the resulting residue was
diluted with saturated aqueous NaHCO3 and extracted with
CHCl3. The organic phase was dried over Na2SO4 and concen-
trated at reduced pressure. To a solution of the resulting
residue in acetone (70 mL) was added a solution of Na2CO3
(4.3 g, 41 mmol) in H2O (20 mL) under a nitrogen atmosphere
at room temperature to give the crude amine. Following the
same procedure as for 3, the crude amine was protected with
the Z group to give 4 (6.3 g, 48%) as a colorless oil and a
mixture of rotamers after purification by flash column chro-
matography (AcOEt/hexane 1:4): IR (CHCl3) 1748 (COO), 1702
1
oxime: IR (CHCl3) 3436 (OH), 1693 (NCOO) cm-1; H NMR
(300 MHz, CDCl3) δ 7.45-7.23 (28/5H, m), 6.68 (2/5H, m), 5.13
(2H, s), 3.84 (6/5H, s), 3.81-3.65 (19/5H, m), 3.57-3.35 (3H,
m), 2.68-2.38 (3H, m); HRMS (EI, m/z) calcd for C14H20N2O4
(M+) 280.1422, found 280.1411.
1
(NCOO) cm-1; H NMR (300 MHz, CDCl3) δ 7.45-7.30 (5H,
m), 5.19 (1H, s), 5.16 (1H, s), 4.26-3.90 (6H, m), 3.83 (3/2H,
s), 3.82 (3/2H, s), 1.86 (3/2H, s), 1.78 (3/2H, s), 1.26 (3/2H, t, J
) 7 Hz), 1.18 (3/2H, t, J ) 7 Hz); HRMS (EI, m/z) calcd for
Gen er a l P r oced u r e for Oxid a tion of Alcoh ols 3. To a
solution of pyridine (24 mmol) in CH2Cl2 (30 mL) was por-
tionwise added CrO3 (12 mmol) under a nitrogen atmosphere
at room temperature. After the solution was stirred at room
temperature for 15 min, a solution of 3 (2 mmol) in CH2Cl2 (8
mL) was added to the reaction mixture. The reaction mixture
was stirred at the same temperature for 2 h and then the
solvent was evaporated at reduced pressure. The resulting
residue was diluted with Et2O and filtered through a pad of
Celite, and the filtrate was concentrated at reduced pressure.
Purification of the residue by medium-pressure column chro-
matography or flash column chromatography (AcOEt/hexane
1:1-3:2) afforded 5 as colorless oils and mixtures of E/ Z-oxime
for 5a ,c,e-h and a mixture of rotamers for 5d . After being
characterized by 1H NMR spectra, unstable aldehydes 5a ,e-h
were immediately subjected to the following radical cyclization.
C
16H22N2O5 (M+) 322.1527, found 322.1540.
P h en ylm eth yl [2-(Meth oxyim in o)p r op yl](2-oxoeth yl)-
ca r ba m a te (5b). To a solution of 4 (1 g, 3.1 mmol) in dry Et2O
(55 mL) was added dropwise DIBALH (0.95 mol in hexane)
(4.9 mL, 4.65 mmol) under a nitrogen atmosphere at -78 °C.
After the mixture was stirred at the same temperature for 1.5
h, H2O (0.55 mL) was added to the reaction mixture, and the
reaction mixture was allowed to warm to room temperature.
After the solution was stirred at room temperature for 0.5 h,
AcOEt and Celite were added to the reaction mixture, and the
whole was stirred at the same temperature for a further 0.5
h. The resulting solution was filtered through a pad of Celite,
and the filtrate was washed with H2O and brine. The organic
phase was dried over Na2SO4 and concentrated at reduced
pressure to afford the crude aldehyde 5b as a pale yellow oil
and a mixture of rotamers. After being characterized by NMR
spectra, unstable 5b was immediately subjected to the follow-
ing radical cyclization: 1H NMR (300 MHz, CDCl3) δ 9.62 (1/
2H, s), 9.53 (1/2H, s), 7.50-7.20 (5H, m), 5.18 (2H, br s), 4.30-
3.90 (4H, m), 3.82 (3H, br s), 1.85 (3/2H, s), 1.76 (3/2H, s).
Gen er a l P r oced u r e for Ra d ica l Cycliza tion . Con d i-
tion s A. To a boiling solution of 5 (1.5 mmol) in benzene (12
mL) was added dropwise (10 mL/h) a solution of Bu3SnH (3
mmol) and AIBN (0.3 mmol) in benzene (7 mL) under a
nitrogen atmosphere. The reaction mixture was heated at
reflux for a further several hours as shown (5a , 3 h; 5b, 2 h;
5c, 7 h; 5d ; 2 h; 5e, 6 h; 5f, 4 h; 5g, 7 h), and then the solvent
was evaporated at reduced pressure. The resulting residue was
diluted with acetonitrile, and the acetonitrile phase was
washed with hexane and concentrated at reduced pressure.
Purification of the residue by medium-pressure column chro-
matography (AcOEt/hexane 1:1-4:1) afforded 6 and 7. The
presence of rotamers precluded a comprehensive assignment
of all proton and carbon resonances.
P h en ylm eth yl [2-(Meth oxyim in o)eth yl](2-oxoeth yl)-
ca r ba m a te (5a ): yield 34%; 1H NMR (200 MHz, CDCl3) δ 9.61
(1H, m), 7.48-7.29 (5H, m), 7.18 (2/5H, br t, J ) 8 Hz), 6.82
(3/5H, br t, J ) 8 Hz), 5.18 (2H, s), 4.50-3.69 (4H, m), 3.88
(9/5H, s), 3.84 (6/5H, s).
P h en ylm eth yl [2-(Meth oxyim in o)eth yl](2-oxop r op yl)-
ca r ba m a te (5c): yield 70%; IR (CHCl3) 1720 (CO), 1705
(NCOO) cm-1 1H NMR (300 MHz, CDCl3) δ 7.38-7.23 (28/
;
5H, m), 6.82 (2/5H, dd, J ) 9, 5 Hz), 5.15 (6/5H, s), 5.10 (4/5H,
s), 4.18-3.99 (4H, m), 3.84 (6/5H, s), 3.80 (9/5H, s), 2.13 (9/
5H, s), 2.05 (6/5H, s); HRMS (EI, m/z) calcd for C14H18N2O4
(M+) 278.1265, found 278.1255.
P h en ylm eth yl [2-(Meth oxyim in o)p r op yl](2-oxop r o-
p yl)ca r ba m a te (5d ): yield 73%; IR (CHCl3) 1737 (COO), 1702
1
(NCOO) cm-1; H NMR (300 MHz, CDCl3) δ 7.40-7.25 (5H,
m), 5.18 (1H, s), 5.12 (1H, s), 4.20-3.95 (4H, m), 3.82 (3/2H,
s), 3.81 (3/2H, s), 2.14, 2.05, 1.85, 1.77 (each 3/2H, s); HRMS
(EI, m/z) calcd for C15H20N2O4 (M+) 292.1422, found 292.1433.

2008 J . Org. Chem., Vol. 64, No. 6, 1999
Naito et al.
Con d ition s B. To a boiling solution of 5 (1.5 mmol) in
benzene (12 mL) was added dropwise (10 mL/h) a solution of
Bu3SnH (3 mmol) and AIBN (1.5 mmol) in benzene (7 mL)
under a nitrogen atmosphere. The reaction mixture was heated
at reflux for 9 h followed by workup as in conditions A.
Con d ition s C. To a boiling solution of 5 (1.5 mmol) in
benzene (12 mL) was added dropwise (10 mL/h) a solution of
Bu3SnH (3 mmol) and AIBN (0.3 mmol) in benzene (7 mL)
under a nitrogen atmosphere. The reaction mixture was heated
at reflux, and additional solution of AIBN (0.3 mmol) in
benzene (3 mL) was added four times at 1 h intervals. After 6
h (total), the reaction mixture was treated by workup as in
conditions A.
IR (CHCl3) 3600-3300 (OH, NH), 1697 (NCOO) cm-1; 1H NMR
(500 MHz, CDCl3) δ 7.38-7.28 (5H, m), 5.85 (1H, br s), 5.11
(2H, s), 3.56 (1H, m), 3.55 (3/2H, s), 3.53 (3/2H, s), 3.46 (1/2H,
br d, J ) 10.5 Hz), 3.45 (1/2H, br d, J ) 10.5 Hz), 3.42 (1/2H,
d, J ) 12 Hz), 3.38 (1/2H, d, J ) 11.5 Hz), 3.37 (1/2H, d, J )
10.5 Hz), 3.33 (1/2H, d, J ) 10.5 Hz), 3.22 (1/2H, br s), 2.97
(1/2H, br s), 1.32 (3/2H, s), 1.29 (3/2H, s), 1.27 (3/2H, s), 1.26
(3/2H, s); HRMS (EI, m/z) calcd for C15H22N2O4 (M+) 294.1578,
found 294.1579.
P h en ylm eth yl tr a n s-3-Hyd r oxy-4-(m eth oxya m in o)-3,4-
d im eth yl-1-p yr r olid in eca r boxyla te (7d ): yield 15% (condi-
tions A), 35% (conditions B), 57% (conditions C); a colorless
1
oil; IR (CHCl3) 3600-3300 (OH, NH), 1696 (NCOO) cm-1; H
P h en ylm eth yl cis-3-Hyd r oxy-4-(m eth oxya m in o)-1-p yr -
r olid in eca r boxyla te (6a ): yield 16% (conditions A); a color-
NMR (500 MHz, CDCl3) δ 7.38-7.28 (5H, m), 5.26 (1 H, br s),
5.14 and 5.11 (1H, ABq, J ) 13 Hz), 5.12 (1H, s), 3.68 (1/2H,
d, J ) 11.5 Hz), 3.67 (1/2H, d, J ) 11 Hz), 3.57 (1/2H, br d, J
) 11.5 Hz), 3.56 (1/2H, br d, J ) 11.5 Hz), 3.48 (3/2H, s), 3.47
(1/2H, d, J ) 11 Hz), 3.46 (3/2H, s), 3.44 (1/2H, d, J ) 11 Hz),
3.37 (1/2H, d, J ) 11 Hz), 3.35 (1/2H, d, J ) 11.5 Hz), 1.97
(1/2H, br s), 1.93 (1/2H, br s), 1.25 (3/2H, s), 1.24 (3/2H, s),
1.23 (3/2H, s),1.22 (3/2H, s); 13C NMR (125 MHz, CDCl3) δ
155.1, 136.8, 128.4, 127.9, 127.8, 78.7, 77.9, 68.8, 68.0, 66.8,
63.0, 58.6, 58.2, 53.1, 52.8, 19.1, 19.0, 15.1, 14.9; HRMS (EI,
m/z) calcd for C15H23N2O4 [(M+H)+] 295.1656, found 295.1666.
P h en ylm eth yl cis-3-Hyd r oxy-4-(m eth oxya m in o)-1-p i-
p er id in eca r boxyla te (6e): yield 14% (conditions A); a color-
less oil; IR (CHCl3) 3600-3300 (OH, NH), 1697 (NCOO) cm-1
;
1H NMR (200 MHz, CDCl3) δ 7.45-7.24 (5H, m), 5.95 (1H, br
s), 5.11 (2H, s), 4.31 (1H, m, 3-H), 3.75-3.28 (5H, m), 3.55 (3H,
s), 3.17 (1H, m); 13C NMR (75 MHz, CDCl3) δ 155.0, 136.7,
128.5, 128.0, 127.9, 69.1, 68.3, 67.0, 62.4, 62.3, 62.2, 61.6, 53.2,
52.9, 45.8, 45.7; HRMS (EI, m/z) calcd for C13H18N2O4 (M+)
266.1265, found 266.1244.
P h en ylm eth yl tr a n s-3-Hyd r oxy-4-(m eth oxya m in o)-1-
p yr r olid in eca r boxyla te (7a ): yield 38% (conditions A); a
colorless oil; IR (CHCl3) 3600-3300 (OH, NH), 1692 (NCOO)
1
cm-1; H NMR (300 MHz, CDCl3) δ 7.40-7.27 (5H, m), 5.65
(1H, br s), 5.10 (2H, s), 4.30 (1H, m), 4.24-4.22 (3H, m), 3.74-
3.22 (5H, m), 3.52 (3H, s), 2.62 (1H, br s); 13C NMR (125 MHz,
CDCl3) δ 157.1, 138.7, 130.6, 130.1, 130.0, 74.6, 73.7, 69.1, 68.5,
67.9, 64.9, 64.8, 54.4, 54.0, 49.6, 49.4; HRMS (EI, m/z) calcd
for C13H18N2O4 (M+) 266.1265, found 266.1280.
less oil; IR (CHCl3) 3600-3150 (OH, NH), 1692 (NCOO) cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.40-7.25 (5H, m), 5.13 (2H, s),
4.28 (1H, br d, J ) 13 Hz), 4.17 (1H, m), 4.02 (1H, m), 3.55
(3H, s), 3.07 (1H, ddd, J ) 12, 6, 4 Hz), 2.96 (1H, br d, J ) 13
Hz), 2.88 (1H, m), 1.60 (1H, br qd, J ) 12, 4 Hz), 1.45 (1H, br
dq, J ) 12, 4 Hz); HRMS (EI, m/z) calcd for C14H20N2O4 (M+)
280.1422, found 280.1432.
P h en ylm eth yl cis-3-Hydr oxy-4-(m eth oxyam in o)-4-m eth -
yl-1-p yr r olid in eca r boxyla te (6b): yield 11% (conditions A);
a colorless oil; IR (CHCl3) 3600-3300 (OH, NH), 1698 (NCOO)
P h en ylm eth yl tr a n s-3-Hyd r oxy-4-(m eth oxya m in o)-1-
p ip er id in eca r boxyla te (7e): yield 57% (conditions A); a
colorless oil; IR (CHCl3) 3650-3100 (OH, NH), 1692 (NCOO)
1
cm-1; H NMR (500 MHz, CDCl3) δ 7.40-7.30 (5H, m), 5.95
(1H, br s), 5.12 (2H, s), 3.98 (1H, m), 3.67 (1/2H, dd J ) 12,
4.5 Hz), 3.63 (1/2H, dd, J ) 12, 5 Hz), 3.56 (3/2H, s), 3.55 (3/
2H, s), 3.52 (1H, m), 3.36-3.25 (2H, m), 2.93 (1/2H, br s), 2.83
(1/2H, br s), 1.26 (3H, s); 13C NMR (125 MHz, CDCl3) δ 154.9,
136.7, 128.5, 128.0, 127,9, 74.6, 73.8, 66.9, 66.1, 65.3, 63.1, 63.0,
53.1, 52.8, 52.6, 52.4, 20.7; HRMS (EI, m/z) calcd for C14H20N2O4
(M+) 280.1422, found 280.1402.
1
cm-1; H NMR (300 MHz, CDCl3) δ 7.40-7.25 (5H, m), 5.10
(2H, s), 4.29 (1H, br d, J ) 11 Hz), 4.15 (1H, m), 3.54 (3H, s),
3.53 (1H, m), 2.81 (1H, ddd, J ) 12, 9, 4 Hz), 2.78 (1H, m),
2.64 (1H, br t, J ) 12 Hz), 1.85 (1H, br dq, J ) 12, 4 Hz), 1.45
(1H, br qd, J ) 12, 5 Hz); 13C NMR (125 MHz, CDCl3) δ 155.2,
136.5, 128.5, 128.0, 127.9, 69.3, 68.2, 67.4, 64.1, 63.5, 62.9, 48.6,
42.8, 27.8, 27.4 HRMS (EI, m/z) calcd for C14H20N2O4 (M+)
280.1422, found 280.1414.
P h en ylm eth yl tr a n s-3-Hyd r oxy-4-(m eth oxya m in o)-4-
m eth yl-1-p yr r olid in eca r boxyla te (7b): yield 37% (condi-
tions A); a colorless oil; IR (CHCl3) 3600-3300 (OH, NH), 1697
P h en ylm eth yl cis-4-Hyd r oxy-3-(m eth oxya m in o)-1-p i-
p er id in eca r boxyla te (6f): yield 27% (conditions A); a color-
1
(NCOO) cm-1; H NMR (500 MHz, CDCl3) δ 7.40-7.30 (5H,
m), 5.37 (1H, br s), 5.12 (1H, s), 5.11 (1H, s), 4.22 (1H, m),
3.84 (1H, m), 3.51 (3/2H, s), 3.50 (3/2H, s), 3.42-3.30 (3H, m),
2.23 (1H, m), 1.26 (3H, s); 13C NMR (125 MHz, CDCl3) δ 155.0,
136.7, 128.5, 128.0, 127.9, 73.3, 72.5, 67.3, 67.0, 66.9, 66.4, 66.9,
63.3, 52.8, 52.5, 52.3, 51.9, 16.3; HRMS (EI, m/z) calcd for
less oil; IR (CHCl3) 3600-3100 (OH, NH), 1692 (NCOO) cm-1
;
1H NMR (200 MHz, CDCl3) δ 7.46-7.25 (5H, m), 5.15 (2H, s),
4.04 (1H, dt, J ) 6, 4 Hz), 3.80-3.18 (4H, m), 3.52 (3H, s),
3.10 (1H, m), 1.90-1.52 (2H, m); 13C NMR (75 MHz, CDCl3) δ
155.6, 136.7, 128.5, 128.1, 127.9, 67.3, 65.4, 62.6, 59.0, 41.7,
39.4, 30.4; HRMS (EI, m/z) calcd for C14H20N2O4 (M+) 280.1421,
found 280.1421.
C
14H20N2O4 (M+) 280.1422, found 280.1408.
P h en ylm eth yl cis-3-Hydr oxy-4-(m eth oxyam in o)-3-m eth -
yl-1-p yr r olid in eca r boxyla te (6c): yield 11% (conditions A),
14% (conditions B); a colorless oil; IR (CHCl3) 3600-3350 (OH,
NH), 1692 (NCOO) cm-1; 1H NMR (200 MHz, CDCl3) δ 7.45-
7.25 (5H, m), 5.87 (1H, br s), 5.11 (2H, s), 3.80-3.20 (5H, m),
3.55 (9/5H, s), 3.54 (6/5H, s), 2.98 (3/5H, s), 2.78 (2/5H, s), 1.40
(6/5H, s), 1.37 (9/5H, s); 13C NMR (75 MHz, CDCl3) δ 154.8,
136.7, 128.5, 128.0, 127.9, 75.8, 75.1, 66.9, 65.7, 65.0, 62.3, 62.2,
58.3, 58.0, 47.5, 24.6, 24.5; HRMS (EI, m/z) calcd for C14H20N2O4
(M+) 280.1422, found 280.1414.
P h en ylm eth yl tr a n s-4-Hyd r oxy-3-(m eth oxya m in o)-1-
p ip er id in eca r boxyla te (7f): yield 35% (conditions A); a
colorless oil; IR (CHCl3) 3600-3100 (OH, NH), 1692 (NCOO)
1
cm-1; H NMR (200 MHz, CDCl3) δ 7.46-7.26 (5H, m), 5.14
(2H, s), 4.32 (1H, m), 4.14 (1H, m), 3.64 (1H, ddd, J ) 11, 10,
4 Hz), 3.53 (3H, s), 2.96-2.70 (3H, m), 1.98 (1H, m), 1.50 (1H,
br qd, J ) 12, 4 Hz); 13C NMR (125 MHz, CDCl3) δ 155.3, 136.6,
128.5, 128.1, 127.9, 69.6, 67.3, 62.9, 62.8, 45.3, 42.3, 32.6;
HRMS (EI, m/z) calcd for C14H20N2O4 (M+) 280.1421, found
280.1417.
P h en ylm eth yl tr a n s-3-Hyd r oxy-4-(m eth oxya m in o)-3-
m eth yl-1-p yr r olid in eca r boxyla te (7c): yield 41% (condi-
tions A), 51% (conditions B); a colorless oil; IR (CHCl3) 3600-
P h en ylm eth yl cis-Hexa h yd r o-4-h yd r oxy-3-(m eth oxy-
a m in o)-1H-a zep in e-1-ca r boxyla te (6g): yield 14% (condi-
tions A), 22% (conditions B); a colorless oil; IR (CHCl3) 3630-
3300 (OH, NH), 1694 (NCOO) cm-1 1H NMR (200 MHz,
;
CDCl3) δ 7.40-7.20 (5H, m), 5.52 (1H, br s), 5.09 (2H, s), 3.86-
3.28 (5H, m), 3.48 (3H, s), 2.62 (1H, br s), 1.31 (3H, s); 13C
NMR (125 MHz, CDCl3) δ 154.8, 136.7, 128.4, 128.0, 127.8,
77.9, 77.1, 67.6, 67.0, 66.9, 62.2, 57.7, 57.4, 48.6, 48.5, 20.8;
HRMS (EI, m/z) calcd for C14H20N2O4 (M+) 280.1422, found
280.1433.
P h en ylm et h yl cis-3-H yd r oxy-4-(m et h oxya m in o)-3,4-
d im eth yl-1-p yr r olid in eca r boxyla te (6d ): yield 1% (condi-
tions A), 3% (conditions B), 4% (conditions C); a colorless oil;
3250 (OH, NH), 1694 (NCOO) cm-1 1H NMR (500 MHz,
;
CDCl3) δ 7.40-7.29 (5H, m), 5.73 (1/2H, br s), 5.67 (1/2H, br
s), 5.19-5.12 (2H, m), 4.08 (1H, m), 3.74-3.20 (4H, m), 3.55
(3/2H, s), 3.49 (3/2H, s), 3.14 (1/2H, dt, J ) 9, 4 Hz), 3.10 (1/
2H, dt, J ) 9, 4 Hz), 2.09-1.58 (4H, m), 2.79 (1/2H, br s), 2.55
(1/2H, br s); 13C NMR (75 MHz, CDCl3) δ 156.6, 156.2, 136.9,
128.5, 128.0, 127.8, 67.9, 67.2, 63.9, 63.6, 62.5, 62.3, 47.1, 47.0,
43.0, 42.4, 30.0, 29.8, 20.3, 19.7; HRMS (EI, m/z) calcd for
C
15H22N2O4 (M+) 294.1574, found 294.1590.

Radical Cyclization in Heterocycle Synthesis
J . Org. Chem., Vol. 64, No. 6, 1999 2009
56%; IR (CHCl3) 1697 (NCOO) cm-1 1H NMR (500 MHz,
CDCl3) δ 7.40-7.28 (5H, m), 5.13 (2H, s), 4.08 (1H, m), 3.86
(1H, m), 3.75 (1H, m), 3.57 (3/2H, s), 3.55 (3/2H, s), 3.48 (1H,
m), 3.21 (1H, m), 1.40 (3H, s), 1.34 (6H, s); HRMS (EI, m/z)
calcd for C17H24N2O4 (M+) 320.1735. found 320.1744.
P h en ylm et h yl tr a n s-H exa h yd r o-4-h yd r oxy-3-(m et h -
oxya m in o)-1H-a zep in e-1-ca r boxyla te (7g): yield 30% (con-
ditions A), 49% (conditions B); mp 108-110 °C (a colorless
needless from Et2O); IR (CHCl3) 3600-3300 (OH, NH), 1690
;
1
(NCOO) cm-1; H NMR (500 MHz, CDCl3) δ 7.40-7.28 (5H,
m), 6.15 (1/2H, br s), 5.95 (1/2H, br s), 5.19-5.11 (2H, m), 3.87
(1/2H, dd, J ) 14, 4 Hz), 3.74 (1/2H, dd, J ) 14, 4 Hz), 3.65-
3.07 (5H, m), 2.84 (1H, m), 3.53 (3/2H, s), 3.45 (3/2H, s), 2.03-
1.48 (4H, m); 13C NMR (125 MHz, CDCl3) δ 156.5, 156.0, 136.7,
128.5, 128.0, 127.8, 127.3, 72.8, 72.7, 67.2, 66.8, 66.5, 62.4, 47.2,
46.7, 45.9, 44.6, 31.7, 31.6, 23.5, 22.5; HRMS (EI, m/z) calcd
for C15H22N2O4 (M+) 294.1579, found 294.1565; Anal. Calcd for
P h en ylm eth yl cis-Hexa h yd r o-3-m eth oxy-2,2,6a -tr i-
m eth yl-5H-p yr r olo[3,4-d ]oxa zole-5-ca r boxyla te (8c): yield
42%; IR (CHCl3) 1692 (NCOO) cm-1 1H NMR (300 MHz,
;
CDCl3) δ 7.40-7.28 (5H, m), 5.14 (2H, s), 3.93-3.31 (5H, m),
3.60 (3H, s), 1.43, 1.42 and 1.30 (each 3H, s); HRMS (EI, m/z)
calcd for C17H24N2O4 (M+) 320.1735, found 320.1717.
P h en ylm eth yl cis-Hexa h yd r o-3-m eth oxy-2,2,3a ,6a -tet-
r a m eth yl-5H-p yr r olo[3,4-d ]oxa zole-5-ca r boxyla te (8d ):
yield 65%; IR (CHCl3) 1694 (NCOO) cm-1; 1H NMR (500 MHz,
CDCl3) δ 7.38-7.28 (5H, m), 5.12 (2H, s), 4.14 (1H, m), 3.84
(1/2H, d, J ) 12 Hz), 3.80 (1/2H, d, J ) 12 Hz), 3.61 (3/2H, s),
3.58 (3/2H, s), 3.19 (1/2H, d, J ) 12 Hz), 3.18 (1/2H, d, J ) 12
Hz), 1.39 (3H, s), 1.34, 1.32, 1.29, 1.28, 1.27, 1.26 (each 3/2H,
s); HRMS (EI, m/z) calcd for C18H26N2O4 (M+) 334.1891, found
334.1886.
C
15H22N2O4: C, 61.21; H, 7.53; N, 9.52. Found: C, 61.50; H,
7.39, N, 9.53.
Gen er a l P r oced u r e for Aceton id e F or m a tion of 6a -
d . To a solution of cis-product 6 (0.1 mmol) and p-TsOH (0.015
mmol) in C6H6 (1 mL) was added DMP (0.2 mmol) under a
nitrogen atmosphere at room temperature. After being heated
at reflux for 1-5 h, the reaction mixture was diluted with
saturated aqueous NaHCO3 and extracted with AcOEt. The
organic phase was washed with brine and dried over Na2SO4
and concentrated at reduced pressure. Purification of the
residue by medium-pressure column chromatography or pre-
parative TLC (AcOEt/hexane 2:1-2:3) afforded 8 as colorless
oils. The presence of rotamers precluded a comprehensive
assignment of all proton resonances.
Ack n ow led gm en t. We wish to thank the Ministry
of Education, Science, Sports and Culture of J apan and
the Science Research Promotion Fund of the J apan
Private School Promotion Foundation for research grants.
P h en ylm eth yl cis-Hexa h yd r o-3-m eth oxy-2,2-d im eth yl-
5H-p yr r olo[3,4-d ]oxa zole-5-ca r boxyla te (8a ): yield 98%; IR
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for the conversion of 7g to 9 and for the preparation
of chloroacetone O-methyloxime. Copies of 1H NMR spectra
for compounds 6a -g and 7a -g and 13C NMR spectra for
compounds 6a ,b,e-g and 7a -g. This material is available free
of charge via the Internet at http://pubs.acs.org.
(CHCl3) 1694 (NCOO) cm-1 1H NMR (200 MHz, CDCl3) δ
;
7.45-7.25 (5H, m), 5.15 (2H, s), 4.61 (1H, td, J ) 7, 2 Hz),
4.02-3.40 (5H, m), 3.60 (3H, s), 1.41 and 1.28 (each 3H, s);
HRMS (ELI, m/z) calcd for C16H22N2O4 (M+) 306.1578, found
306.1575.
P h en ylm eth yl cis-Hexa h yd r o-3-m eth oxy-2,2,4a -tr i-
m eth yl-5H-p yr r olo[3,4-d ]oxa zole-5-ca r boxyla te (8b): yield
J O9822176