AD-A258 925

CH EM ICAL
RESEARCH,
DEVELOPMENT
ENGINEERING
CENTER CRDEC-TR.

S ELEC T Ffl

s JAN 8193

PIPERIDINE SYNTHESIS C

Harold D. Banks

RESEARCH DIRECTORATE

September 1992

Approved for public releas; dfisbribudon in unimited.

U.S. ARMY \Il

ARMAMENT
MUNfTiONS
* ~CHEMICAL COMMAND

Abemee Prov ig Ground. Morylbnd r2MO443

93-00502
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1992 September Final, 92 Apr - 92 Jun
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PIPERIDINE SYNTHESIS PR-1O161102A71A

6. AUTHOR(S)
Banks, Harold D.

7. PERFORMING ORGANIZATION NAME(S) AND ADORESS(ES) B. PERFORMING ORGANIZATION

CDR, CRDEC, ATTN: SMCCR-RSC-O, APG, MD REPORT NUMBER
CRDEC-TR-409
21010-5423

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Approved for public release; distribution is
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13. ABSTRACT (Maximum 200 words)

Methods of synthesizing piperidines have been reviewed. The older
reviews are cited; however, much of the review is occupied with the
research of the last 3 years.

I
*
S
1.4L.€,US.C7 T: 15. ,WUMI.R OF PAGES
Piperidines 26
Synthesis 16 PRICE CODE
Review
117. SECURITY CLASSIFICATION 18. SECURITY CLASSIFICATION 19. SECURITY CLASSIFICATION 20. LIMITATION OF ABSTRACT
OF REPORT OF THIS PAGE OF ABSTRACT U1
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2
 PREFACE

The work described in this report was authorized under

Project No. 10161102A71A, Research in CW/CB Defense. This work
was started in April 1992 and completed in June 1992.

The use of trade names or manufacturers' names in this

report does not constitute an official endorsement of any commer-
cial products. This report may not be cited for purposes of
advertisement.

Reproduction of this document in whole or in part is prohib-

ited except with permission of the Commander, U.S. Army Chemical
Research, Development and Engineering Center (CRDEC), ATTN:
SMCCR-SPS-T, Aberdeen Proving Ground, MD 21010-5423. However,
the Defense Technical Information Center and the National
Technical Information Service are authorized to reproduce the
document for U.S. Government purposes.

This report has been approved for release to the public.

Acknowledgments

Successful completion of this project would have been

impossible without the assistance of the dedicated staff of the
CRDEC Technical Library. Particularly helpful were Corky Smith
and Patsy D'Eramo.

TJAumpS2GOED
DTIC 5

AcV"5~1
I uBcr

Dist

- . -*--
Blank

4
 CONTENTS

Page

1. INTRODUCTION ........................... 7

2. SYNTHETIC METHODS .......................... 9

3. CONCLUSIONS ............................ 22

LITERATURE CITED ....................... 23

5
Blank

6
 PIPERIDINE SYNTHESIS

1. INTRODUCTION

Given the prevalence of the strain-free cyclohexane system in

nature, it is not surprising that its heterocyclic relative,
azacyclohexane, or piperidine, is a common structural unit- in
natural products. The plieridine ring bkbtem is found
in a large number of alkaloids having a diverse spectrum of
physiological activity. Structurally simple 4-coniine, found in
hemlock, is a powerful poison. Extraction of the leaves of the
coca bush, and further purification produces cocaine, a powerful,
33

I~QCOPh

cocaine
a-coniine

pipezrine

morphine

addictive stimulant. The active principal of black pepper is

piperine. The powerful analgesic morphine is derived from the
dried latex of the opium poppy. The piperidine ring is found

7.
in alkaloids derived from pomegranate, sedum, lobelia, pine
species, papaya, the scent gland of the musk deer and betel nuts.'

While we have been provided with an impressive array of

physiologically active piperidines, it is tempting and often
challenging to design and synthesize molecules that are
predicted to have superior properties to those of their natural
counterparts. For example, in the realm of analgesics that are
derived from morphine, the umbra of respiratory depression
accompanies its beneficial effects. One approach to this
problem was to assume that unwanted side effects were produced
because the dose at which morphine had to be administered for
effective analgesia exceeded the threshold for respiratory
depression mechanisms. If an extremely potent drug were found,
it might be possible to administer it in a dose low enough that
those mechanisms leading to respiratory depression would not be
triggered. Research at Janssen Pharmaceuticals in Belgium in
the 1960's led to the discovery of the drug fentanyl. This
relatively simple molecule is almost 300 times more potent than
morphine in animal studies. While one side effect, cardiac
depression, can be minimized, respiratory depression still
must be dealt with at therapeutic doses. Many derivatives of
fentanyl have been prepared, some of which are almost 30 times
the potency of fentany'. All appear to retain fentanyl's
untoward side effects.

We have been interested for some time in studying the

metabolites of fentanyl, as possible analgesics in their own
right, and for clues as to how unacceptable side effects might be
minimized. As part of this program, the literature has been
searched for methods of preparing piperidines, with special
emphasis on those substituted at the 3- and 4-positions. This
review is a compilation of the best and most recent synthetic
methods. Hopefully it will prove useful in leading the researcher
to an efficient route for synthesis of a target piperidine.

8
 2
2. SYNTHETIC METHODS

The preparation of piperidine itself is conveniently

accomplished by the catalytic hydrogenation of pyridine, most
often with a nickel catalyst at 170 - 2000. Other reducing agents
are sodium in ethanol or tin in hydrochloric acid.

1,5-Dichloropentanes, obtained by treatment of

tetrahydropyrans with concentrated hydrochloric acid, can be
cyclized to piperidines by treatment with primary amines. 5-
Amino-l-haloalkanes, 1,5-diaminopentanes, 8-aminocarbonyl compounds
and 5-aminoalkanols are also sources of piperidines.

Piperidones are useful intermediates for the preparation of

the subject compounds. 3,4-Substituted 2-piperidones can be
reduced to the corresponding piperidines with a variety of
reducing agents, eg., LiAlH4 or NaBH4 . Substituted 3-piperidones
upon reduction are a source of the 3-hydroxy derivatives, while 4-
piperidones are frequently employed in the synthesis of fentanyl
and its derivatives.

Sundberg and coworkers 3 shook a mixture of vinylacrylic acid,

conc. aqueous ammonia and a trace of hydroquinone in a high
pressure bomb at 1800 for 14 h. A 30% yield of pure 5,6-dihydro-
2(1lH)-pyridone was obtained.

001%+ NH3
N 0
H

8-Valerolactams can be prepared by the reductive cyclization

of oy-carboalkoxynitriles, y-carboalkoxyimines (shown below), 8-
aminoamides or 8-haloamides.

9
 OH

01101N

NH Br tau
tBu
Ph Ph Ph
hNH 4H I h) h

Alkylation of commercially available 3-hydroxypyridine with

iodomethane or benzyl chloride followed by sodium borohydride
reduction and HBr cleavage of the enol ether is yet another
effective route to 3-piperidones.

4011. RX 113:

2. NaBH 4
N R
R

4-Piperidones are most often synthesized by means of the

addition of a primary amine to two moles of ,n alkyl acrylate,
followed by the Dieckmann condensation, hydrolysis and
decarboxylation.

10
 0
R COOR,

R
N

The Nazarov cyclization can be performed on ynedienes

obtained from the dehydration of vinyl propargyl alcohols.
Chemoselective hydration of the triple bond with sulfuric acid in
the presence of Hg(II) followed by double Michael addition to the
dienone provided the 4-piperidone.

0 0 0

11I
 In the Petrenko-Kritschenko reactiont two moles of an
aromatic aldehyde are condensed with a primary amine and a dialkyl
0-ketocarboxylate in a double Mannich reaction. The initial
mechanistic steps and the total reaction are given below.

+ H2 NR ArCH-N +HR
ArCHO

R'OOCCH2 R'OOC
0 ____ OH

R' OOCCH2 R'OOCCH2

A COOR'
ArCHO R'OOCCH 2
R2++0R.N 0
ArCHO ROCH
Ar COOR'

Heathcock 4 has conducted elegant studies on the synthesis of

daphniphyllum alkaloids. In the first study, a synchronous inverse
electron demand Diels-Alder reaction of a 2-aza-1,3-butadiene
obtained by the Swern oxidation of a diol followed by treatment
with ammonia and then acetic acid, was exploited for the closure
of a second piperidine ring. In another investigation 5 the

NMAN

HO2. 1%4
3. CH34OM

(74 - M overall)

12
 tetracyclic amino alcohol is oxidized to a carboxylic acid. Upon
treatment with formaldehyde and adjustment of the pH to 7, iminium
ion formation occurs, initiating the addition of the carboxylate
function to the double bond, and formation of a second piperidine
ring.
0u0

1. CEO3 , Nat 4

a 6N2. C"230, PH 7

Cycloaddition chemistry has also been recently exploited by

6
Hays who prepared 4-piperidinols via a concerted olefin-iminium
ion cyclization by means of an extension of the work of Grieco's
group. 7 ,8

) nRNH2 'HCl -

n -0-2
OH R

2, 1h, lPl,,,,

2
",NO "%%COOH COOCH 3

L"P -Ph H

Palladium (II) is an effective catalyst for cyclization

chemistry of a bromodiene. 9 A ruthenium catalyst is an effective

Srd(.)

13
 10 1 1" found
means of cyclizing 8-ketonitriles. Naota and Murahashi

for S-amino-1-
effected ring formation
catalyst
that the same acceptor was
present.
a hydrogen
alkanols, providing 4
RIN2(PPh3)

c
C
MeNH (CH2) 50H
benzalacetone
(H-acceptor) a
N 00
Me

cyclize unsaturated
were able to
N-bromosuccinimide.12
coworkers
and
Tamura with
tosylamides

3
and coworkers.-
by Buncf
red
was repo
reaction
An interesting
the 5-haloalkene,
synthesized frompresence of benzylamine
An alkyl 7-iodoacrylate, and
the
in intramolecular
an
nucleophilic
heated
addition
when
underwent a Michael
reaction
displacement
and triethylamine.

14
 zEt 3N, RIM. A

A formal heterocyclic Diels-Alder reaction of 2-aza-1,3-

butadiene to styrene occurs in the presence of ferric chloride.14
The best yield of product is 80% when X is the isocyanide
functionality.

Ph
xI~~k FSCV13- 0 xs k

Ph Ph

Lewis acid catalysis is an effective means of accomplishing

4 + 2 cycloaddition chemistry between electron-rich dienes and
imines. 15 ,1 6 Another method for imine cycloaddition employs

S~Ph
IPh 0

17
a triflate in methylene chloride.

15
 h

Ph 1. TfOSiTBDM
I 2 C12
CH
+ N H
2. NaHC03

R OTMS
OTMS

Solid-liquid phase transfer catalysis conditions were

utilized to effect the cyclization reaction of the 2,6-
dibromocarboxylic ester and trichloroacetamide. Upon hydrolysis,
an amino acid is produced.15

KaC0a
+ C13 CCONH2 cH3CM

RR

Aquadruply protected piperidine may be synthesized as shown

below. 1 9 After preparation of the mesylate, and N-deprotection
cyclization occurred in refuxing ethanol. The product is a point
of entry for synthesis of several of the stereoisomers of the
potent glucosidase I inhibitor, castanospermine, a natural product
relevant to the treatment of the HIV-1 virus.

16
 1. HSCl. Et3 N can
can 0en
0 2. MeNH 2

jph@L 3.

Cba U

In the presence of p-toluenesulfonic acid the aminoallene

smoothly cyclizes to a 4-piperidone precursor. 2 0

i ,

000-

An interesting ring expansion reaction using alkyl azides has

been reported. 2 1 Unfortunately, the yields in reactions resulting
in piperidines are disappointing.

(N> n-Hex N3

TiC14
I
n-Hex

17
 A recent transformation of a pyridinium salt is noteworthy in
that epoxidation occurs smoothly in the presence of a tertiary
nitrogen. 2 2 This may be an effective means of preparing 3-hydroxy-
4-anilinopiperidines.

Ph %"" oa Ph o""OR

4MCPBA

Et Et
R= OAc
INH NO
2

kNaBH4

SRNO
2

Et

The Dieckmann condensation has recently been used for ring

23
closure in the synthesis of 2,4-diketopiperidines.

18
 >-NH2 + \~COOMe - j

Et OO\ DCC, DMAP

N 0

Herdies 2 4 was able to transform S-glutamic acid to S-5-

hydroxy-2-piperidone, which was converted in a series of
25 This is an
stereocontrolled reactions into the R-amino acid.
extension of earlier work in which 3-hydroxy-2-piperidone is
reduced first to the ketoamide, and then to the hydroxyamide.

HO
HO H2 /Pd-C NaBH4 -o

N oN 0 N H
HH
R

H H

19
 Overman has explored the cyclization chemistry of
26
aminoalkynes.

Eat,CwM"~
O3. "I. "
CCH3
CH3-
N
K,Ph
X

N --

L"'Ph LPh
R - CH3 , (CHO3Si,
3 8
X - Br, I, N3

A 13.31 sigmatropic shift 2 7 has been reported for preparation

of 1,2,3,6-tetrahydropyridines, complementing the reduction

R (2
a •2

R ~ BF3F't 2O R

NH CC1 1 o

COOEt

R - Ph, nC69 1 3 , 3,4-(MeO) 2 CfH3

R2 - H, SiMe 3

28
chemistry which continues to be exploited in research projects.

20
 Cl Cl

N&
H3 C N R
BOC

Radical cyclization of a A4 -l,3-oxazolin-2-one can be

effected with high diastereoselection. 29 Oxidation of the initial
product produces a highly functionalized 3-hydroxypiperidine.

CH2 OH

/II7 0 Bu3 SnH 0 O

AIBN
N 0
0 0 CH2CH20H
CHRCH 2 CH 2 CBr-CH2 R

Hassner was able to convert 5-ethoxyoxazoles to 2-

30
piperidinones via the oxazolium salts.

t Oft --
NCH2COOE~t

Br

An interesting ring expansion reaction has been reported by

Marson. 31 The reaction can be used in stereospecific synthesis.

21
 00
0 H
NH NH____
+ -
PhCHO

H2 N M sO Ph
SH Ph

When allenic amines are treated with carbon monoxide and

32
methanol in the presence of Pd(II) a useful ring closure occurs.

III1KPd +, COI 2

I R coocH3
R
R - H,,Bn,,SO2pTol,,COOMe

Photochemical amine-enone cyclization routes to piperidines

33
have been summarized by Mariano.

Finally, the collaborative efforts of Padwa's group at Emory

and Rodriguez at Clark Atlanta University have resulted in elegant
cycloaddition chemistry using 2, 3-bis (phenylsulfonyl).l, 3-butadiene
with oximes, enamines (and amidines corresponding to enamine
3 4,35
equivalents) and ynamines.

3. CONCLUSIONS

Due to the importance of the piperidine ring system in

natural products and in synthetic compounds with physiological
potency, an increasing number of new and versatile syntheses have
been reported. It is likely that activity in this area will
continue unabated.

22
 LITERATURE CITED
1. Pelletier, S.W., "Chemistry of the Alkaloids," Van
Nostrand Reinhold Company, New York, pp 395 - 411, 1970.

2. Reviews:
(a) Rubiralta, M.; Giralt, E.; Diez, A., Piperidine,
Elsevier, New York, 1991.
(b) Armardgo, W.L.F., "Stereochemistry of Heterocyclic
Compounds, Part 1," John Wiley & Sons, New York, 1977.
(c) Mosher, H. S., in Heterocycllc Compounds,
"Piperidines and Partially Hydrogenated Pyridines," R. C.
Elderfield, Ed., John Wiley & Sons, New York, pp 617 - 646,
1950.

3. Sundberg, R. J.; Bukowick, P.A.; Holcombe, F.O., "The

Preparation of 4-Alkyl-2,4-pentadienoic Acids by the
Phosphonate Modification of the Wittig Reaction," J. rg.
Cham-., Vol. 32, pp 2938 - 2941 (1967).

4. Heathcock, C.H.; Stafford, J.A.; Clark, D.L.,

"Daphniphyllum Alkaloids. 14. Total Synthesis of (+/-)
Bukitinggine," J. Org. Chem-, Vol. 57, pp 2575 - 2585 (1992).

5. Heathcock, C.H.; Ruggeri, R.B.; McClure,

K.F.,"Daphniphyllum Alkaloids. 15. Total Synthesis of (+/-)
Homodaphniphyllate and (+/-) Daphnilactone A," J
Chem., Vol. 57, pp 2585 - 2594 (1992).

6. Hays, S.J.; Malone, T.C.; Johnson, G., "Synthesis of cis-

4-(Phosphonooxy)-2-piperidinecarboxylic Acid, an N-Methyl-D-
aspartate Antagonist," J. Org. Chem., Vol. 56, pp 4084 -
4086 (1991).
7. Larson, S.D.; Grieco, P.A., "Aza Diels-Alder Reactions in
Aqueous Solution: Cyclocondensations of Dienes with Simple
Iminium Salts Generated under Mannich Conditions," 3-.Am-
Q _n, Vol. 107 , pp 1768 - 1769 (1985).

8. Larson, S.D.; Grieco, P.A.; Fobare, W.F., "Reactions of

Allylsilanes with Simple Iminium Salts in Water: A Facile
Route to Piperidines via an Aminomethano Desilylation-
Cyclization Process," J. Am. ChemSa.
o-, Vol. 108, pp 3513 -
3515 (1986).

9. Harris, Jr., G.D.; Herr, J.R.; Weinreb, S.M., "A.

Palladium-Mediated Approach to Construction of Nitrogen
Heterocycles," J. Org. Chem., Vol. 57, pp 2528 - 2530 (1992).

10. Murahashi, S-I.; Sasao, S.; Saito, E., Naota, T.,

"Ruthenium Catalyzed Hydration of Nitriles and Transformation

23
of d-Keto Nitriles to Ene-Lactams," J. Org. Chem., Vol. b7,
pp 2521 - 2523 (1992).

11. Naota, T.; Murahashi, S., "Ruthenium-catalyzed

Transformations of Aminoalcohols to Lactams," S•ynlet., pp
693 - 694 (1991).
12. Tamura, Y.; Kawamura, S-i.; Bando, T.; Hojo, M.; Yoshida,
Z-i., "Stereoselective Intramolecular Haloamidation of N-
Protected 3-Hydroxy-4-pentenylamines and 4-Hydroxy-5-
hexeneylamines," J. Org. Chem., Vol. 53, pp 5491 - 5501
(1988).

13. Bunce, R.A.; Peeples, C.J.; Jones, P.B., "Tandem SN2 -

Michael Reactions for the Preparation of Simple Five- and
Six-Membered-Ring Nitrogen and Sulfur Heterocycles," J. Qrg.
Chem., Vol. 57, pp 1721 - 1733 (1992).

14. Leardini, R.; Nanni, D.; Tundo, A.; Zanardi, G.;

Ruggieri, F., "Annulation Reactions with Iron(III) Chloride:
Oxidation of Imines," J. Org. Chem-, Vol. 57, pp 1842 - 1848
(1992).

15. Midland, M.M.; Koops, R.W., "Diastereoselection in the

Lewis Acid Catalyzed Cycloaddition Reaction of G-Alkoxy
Imines," J. Org. Chem., Vol. 57, pp 1158 - 1161 (1992).

16. Hattori, K.; Yamamoto, H., "Asymmetric Aza-Diels-Alder

Reaction Mediated by Chiral Boron Reagent," J- Org. Chem.,
Vol. 57, pp 3264 - 3265 (1992).

17. Nague, D.; Paugam, R.; Wartski, "Reactions of Dienes and

Aniline Derived Imines," Tet.._Lett,., Vol. 33, pp 1265 - 1268
(1992).

18. Albanese, D.; Landini, D.; Penso, M, "Synthesis of 2-

Amino Acids via Selective Nono-N-alkylation of
Trichloroacetamide by 2-Bromo Carboxylic Esters under Solid-
Liquid Phase Transfer Catalysis Conditions," J. Org. ChLm.,
Vol. 57, pp 1603 - 1605 (1992).

19. Burgess, K.; Chaplin, D.A.; Henderson, I.; Pan, Y.T.;

Elbein, A.D., J. Org. Chem., Vol. 57, pp 1103 - 1109 (1992).

20. Goldstein, S.W.; Overman, L.E.; Rabinowitz, M.H., "The

First Enantioselective Total Synthesis of Allopumilotoxin A
Alkaloids 267A and 339B," J. Org. Chem., Vol. 57, pp 1179 -
1190 (1992).

24
21. Aube, J.; Milligan, G.L.; Mossman,. C.J., "TiC1 4 Mediated
Reactions of Alkyl Azides with Cyclic Ketones," J. Org.
Chem., Vol. 57, pp 1635 - 1637 (1992)

22. Diez, A.; Vilasea, L.; Lopez, I.; Rubiralta, M.;

Marazamo, C.; Grieson, D.S.; Husson, H.P., "Preparation of
New Chiral Piperidine Epoxides," Heterocycles, Vol. 32, pp
2139 - 2149 (1991).

23. Ambrose, L.; Chassagnard, C.; Revial, G.; D'Angelo, J.,

"The Use of 3-Alkyl-2,4-Diketopiperidines in Asymmetic
Michael Additions," Tetrahedron* Asvm., Vol. 2, pp 407 - 410
(1991).

24. Herdies, C.; Engel, W.,"Synthesis of Unnatural 2R,5S-5-

Hydroxypipecolic Acid Via Homochiral Acyliminium Ion-
Pipecolic Acids. Part III," Tetrahedron!As-m., Vol. 2, pp 945
- 948 (1991).

25. Herdies, C., "Chirospecific Synthesis of (S)-(+)- and

(R)-(-)-5-Amino-4-hydroxypentanoic Acid from L- and D-
Glutamic Acid via (5)-(+)- and (R)-(-)-Hydroxy-2-
oxopiperidine," Synthesis, pp 232 - 233 (1986).
26. Arnold, H.; Overman, L.E.; Sharp, M.J.; Witschel, M.C.,
"(E)-l-Benzyl-3-(1-Iodoethylidene)-piperidine: Nucleophile-
Promoted AlkyneIminium Ion Cyclizations," ogS , Vol.
70, pp 111 - 119 (1991).

27. Wang, C-L.J.; Calabrese, J.C., "Decarboxylative

Cyclization of Allylic Cyclic Carbamates: Applications to the
Total Synthesis of (-)-Codonopsine," J. Org. Chem., Vol. 56,
pp 4341 - 4343 (1991).

28. Comins, C.M.; Weglarz, M.A., "Stereocontrolled

Preparation of cis- and trans-2,6-Dialkylpiperidines via 1-
Acyldihydropyridine Intermediates. Synthesis of (+/-)-
Solenopsin A and (+/-)-Dihydropinidine," J. Org. Chem., Vol.
56, pp 2506 - 2512 (1991).

29. Yoko, Y.; Kamo, S.; Shibuya, S., "Diasteroselective

Synthesis of a 2,6-Disubstituted 3-Hydroxypipiperidine
Derivatives by an Application of Radical Cyclization,"
Heterocyglgs, Vol. 32, pp 2311 - 2314 (1991).

30. Hassner, A.; Fischer, B., "Multipath Reactions between

Intramolecularly Formed Oxazolium Salts and Nucleophiles," JI.
O- , Vol. 57, pp 3070 - 3075 (1992).

25
31. Marson, C.M.; Grabowska, U.; Walgrove, T.; Egleston,
D.S.; Baures, P.W., "Stereoselective Synthesis of Substituted
)"-Lactams from 3-Alkeneamides," J. Org. Chem., Vol. 56, pp
2603 - 2605 (1991).
32. Lathbury, D.; Vernon, P.; Gallagher, T., "Palladium (II)
Mediated Routes to Functionalized Heterocycles," l,
Vol. 27, pp 6009 - 6012 (1985).

33. Yoon, U.C.; Mariano, P.S., "Mechanistic and Synthetic

Aspects of Amine-Enone Single Electron Transfer
Photochemistry," Act.. Chem. Ret., Vol. 25, pp 233 - 240
(1991).

34. Norman, B.H.; Gareau, Y.; Padwa, A., "Tandem Addition-

Cycloaddition Reaction of Oximes with 2,3-
Bis(phenylsulfonyl)-1,3-butadiene as a Method for 4-
Piperidone Synthesis," 3- Org. Chem-, Vol. 56, pp 2154 - 2161
(1991).

35. Padwa, A.; Gareau, Y.; Harrison, B.; Rodriguez, A.,

"Cycloaddition Chemistry of 1,3- and 2,3-Bis(phenylsulfonyl)
1,3-Dienes with Enamines and Ynamines," J. Org. Chem., Vol.
57, pp 3540 - 3545 (1992).

.26