81

HLHLHLHL ISSN: 2231 – 3087(print) / 2230 – 9632 (Online)

http://heteroletters.org Vol. 3: (1), 2013, 81-109

SYNTHESIS OF β-LACTAM AND THEIR REACTIVITY

) N.A.A. El-Kanzi*

(a,b

a- Chemistry Department, Faculty of Science, Aswan University, Aswan, Egypt.

b- Chemistry Department, Faculty of Science, Al Jouf University, Sakaka, Al Jouf

E-mail:nadiaelkanzi88@yahoo.com

Abstract: The review summarizes literature dealing with the synthesis of, β-lactam and reactivity of β-lactam. Key words:, β-lactam, reactivity of β-lactam, synthesis.

Contents:

I- Synthesis of β-lactam 2

II- Reactivity of β-Lactams 16

1- Electrophilic attack at nitrogen 16

2- Electrophilic attack at carbon 17

3- Nucleophilic attack at carbon 19

4- Radicals and photochemical conversion 23 5- Reduction 24 6- Ring opening 25

7- Electrochemical transformations 28

8- Conversions into other heterocyclic 29

9- Reactivity of substituents attached to ring carbon atoms 29

10- References 32

Introduction

I- Synthesis of β-lactam

Jacek G. 20091 was reported that, α,β-unsaturated δ-thiolactams have been recognized as good

Michael acceptor, where, they form C-C bonds in reactions with C-nucleophiles: alkyl lithium, alkyl magnesium, lithium enolate and with aliphatic nitro compounds in the presence of a base catalyst. Also, he reported that, it is easy synthetic approach to mono- and bicyclic derivatives of 5,6-dihydro-1H-pyridine-2-thiones by ring closing metathesis (RCM) and thionation using Lawesson's reagent followed by isomerization of 3,6-dihydro-isomers. RCM/thionation/isomerization applied successfully to N,6-diallylic β,γ-unsaturated lactam (1)

82

providing unsaturated thiolactams (2) and (3) possessing bicyclic quinolizidine in high yields in the following Scheme.

ON

Mg

Bu

BuLi

+

SN

S

P

S

PMeO OMe

S

S

ON SN

i) 4(0.045 equiv.) 80°C PhMe, 3h

ii) LR (0.6 equiv.) 90°C, PHMe, 2h

"one-pot"

DBU

LR=

(1) (2) (3)

Emma L. Cropper et al.2 were reported that, Pd-catalysed C-N bond forming reactions between N-nucleophiles and aryl halides attracted a tremendous amount of attention and are becoming increasingly common in industrial processes. Also, pd-catalysed protocol was applied to synthesis of 1,5-benzo-diazin-2-one (6) according to the following Scheme. Where compound (4) was prepared by an aza-Michael reaction between 2-bromoaniline and ethyl acetate, followed by N-benzoylation to form the benzylamide (5) via standard procedures, followed by cyclization to form (6)

NH2

BrCO

2Et

H+

N

Br

R

CO2Et

Br

N

O

NHBn

N

N

OBn

Bn

, EtOH, reflux, 61%

4a (R = H)PhCH2Br,K2

4b (R = Bn)

NaOH,MeOH,76

BnNH2,BtOH,DDC

,Bn

(5)

Pd(OAc)2(5mol%)

P(t-Bu)3(7.5 mol%)

Cs2CO3,PhMe,

100°C,17h(6)

reflux,72%

Suleyman et al.

3 were reported that, a new synthetic procedure for the total synthesis of the alkaloide (±)-epiddasycarpidone by an acid ctalysed ring closure of racemic cis-3-ethyl-4-oxo-2,3,4,9-tetrahydro-carbazole derivatives. This leading to synthesize (±)-uleine (14) where, the uleine group starts either from 2(4-piperi-dinylmethyl)-indole, 3(2-iperidinylmethyl)indole, or with Fischer indolization of 2-azabicyclo[3.3.1]nonane. (±)-uleine can be accomplished by removing of the protecting group in compound (7) by treatment with [bis(trifluoroacetoxy)iodo]-benzene in acetonitrile : water (9:1) to give compound (8), which can be converted into compound (13). By treatment compound (8) with methyllithium can be transformed into alcohol (9). The dehydration of (9) with trifluoroacetic acid transformed into (13). The reduction of compound (13) with LiAlH4 in tetrahydrofuran led to the alkaloid (±)-uleine (14)

83

NH

H

HSS

N

Me

O

(CF3CO2)2IPh

NH

H

H

N

Me

O

O

NH

H

H

N

Me

O

OH

MeLi

CF3CO

2H

CH2Cl

2NH

H

H

N

MeO

OH+ N

H

H

H

N

Me

O

H2C

H

+NH

H

H

N

Me

O

+

NH

H

H

N

MeO

CH2

LiAlH4

NH

H

H

N

Me

CH2

71% 91%

(7) (8) (9)

73%

66%

(10) (11) (12)

(13)(14)

Makoto Oba et al., 20094 have reported that, (R)-baclofen can be synthesized by the treatment

of Michael acceptor (15) with Grignard-cuparates containing phenyl and 4-chlorophenyl groups to produce the 1,4-adducts (16) in 68% yield, which (R)-baclofen is known as a muscle relaxer and an antipastic and the preparation of (R) baclofen can be achieved by methanolysis of (16) followed by LiOH-promoted hydrolysis of methyl ester yielded pyroglutamic acid (19). The acid (19) can be converted to (R)-baclofen (20) as described.

NO

O

OO

Boc

NO

O

OO

Boc

Cl

NH

O

Cl

CO2Me

NO

Cl

CO2Me

Bn

PhCH2Br, NaH

NO

Cl

Bn

CO2HNH

2

Cl

HO2C

(4-ClC6H4)2CuMgB

(15)

HCl, MeOH, 75%

(16) (17)

(18)

THF, 55%THF, 98%

1M LiOH

(19)

ref 31, 32

(20) (R)-baclofen Johannes C. Vogel et al., 2008

5 have been reported that, 1,2,2-Triphenyl-1,2-diol can be prepared from R-mandelic acid with phenylmagnesium bromide and 4-bromophenylmagnesium bromide followed by TBAF deprotection of the resultant secondary alcohol to give (22).

84

OH

OH

O

Ph N

OTBDMS

H3CO

O

Ph

OHPh

Br

OH

1. SOCl2, MeOH, heat

2. HN(CH3)OMeHCl,

AlMe3,CH2Cl2,heat

3. TBDMSOTf,NEt3,

CH2Cl2, 0°C.

46% overall

1. PhMgBr, THF. O°C to rt, 98%

2. 1,4-dibromobezene Mg,I2cat., THF

O°C to rt, 70%3. TBAF,THF,rt,95%R-mandelic acid

(21)

(22)

Giordano Lesma et al., 20086 have been reported the allyl-proline derivative (24) was obtained

through a stereoselective allylation on precursor (23) using allylmagnisium bromide with CuBr:Me2S complex in the presence of BF3 etherate at - 78°C according to slight modifications of a reported protocol, the 5-allyl-N-Boc-proline ester. After trans esterification in refluxing methanol with an excess of K2CO3 the Boc group was removed with 30% TFA in CH2Cl2.

NMeO

Boc

COOBnNH

COOMe

1. allylMgBr, CuBr,SMe2,BF3, Et2O-78°C

2. K2CO3, MeOH, 65°C

3. 30% TFA/CH2Cl2

4. chromatogr. sep., 48% (four steps)

(23) (24) Luigino Troisi et al., 2008

7 have been reported that, N-alkyl-4-aryl-3-vinyl-2-azetidinones, (E)-arylidenalkyl amines, (26) have been synthetized following a palladium-catalyzed [2+2] cycloaddition with allyl bromide under Copressure (300-400psi), in THF and Pd(OAc)2/PPh3 as the catalyst system, in the presence of triethylamine.

S

N N t-BuN

Ot-Bu

N

S

ArEt

3N, Pd(OAc

2),

PPh3, CO

(25)

+

THF, 100°C

(26) Qian Yuan et al., 2008

8 said that, the ringe-closing enyne (29) metathesis reaction of alkyl 2-(N-alkyl acrylamido)ester using the first generation Grubbs' catalyst afforded five-membered lactams bearing a 1,3-diene in high isolated yields. In the reaction process, the presence of ethylene gas is essential. The reaction of (29) with ethylene in the presence of Ru catalyst in methylen chloride formed 4-vinyl α,β-unsaturated γ-lactam (30).

O

OMePh

NH

O

OMePh Cl

OBr

R

N

O

O

PhOMe

CH2=CH

2

O

ON

OMe

LiOH.H2O,4AMS

DMF, rt

(iPr)2.NEt,CH2Cl2,

0°C - rtNH3+Cl-

(27) (28) (29)

Ru catalyst, CH2Cl2

(30) Peter Cosomos et al., 2008

9 showed that with the starting 2-aminobenzyl chloride hydrochloride (31), which can be obtained by treatment of 2-aminobenzyl alcohol with thionyl chloride, fusion of (31) with thiobenzamides (32-37) [32, R1 = R2 = H; 33, R1 = Cl, R2 = H; 34, R1 = CH3, R

2 H;

85

35, R1 = H, R2 = Cl; 36, R1 = H, R2 = CH3; 37, R1 = H, R2 = OCH2CH3] provided the key intermediate 4H-3,1-benzothazine derivatives (38-43) [38, R1 = R2 =H; 39, R1 = Cl, R2 = H; 40, R1 = CH3, R

2 H; 41, R1 = H, R2 = Cl; 42, R1 = H, R2 = CH3; 43, R1 = H, R2 = OCH2CH3] the reaction of (38) with chloroacetylchloride in dichloromethane in the presence of triethyl-amine as catalyst. When the reaction was carried out in refluxing benzene, azeto[2,1-a][3,1]benzothiazin-1-one (44) can be synthesized.

NH2.HCl

ClH

2N

S R

R

2

1N

S R

R

2

1

N

S

ClCH2COCl

Et3N, reflux

toluene

S

N

O

+110-120°C

heat,30min

(31) (32-37) (38-43)

+

(38) (44)

Bahawana Singh et al., 2008

10 have been synthesized the diastere-omeric 2,4-disubstituted pyrano [2,3-b]quinolines (46/47), via intra-molecular cyclization of 3-homo-allyl-2-quinolines (45) with iodine and sodium bicarbonate in THF with either base or nucleophiles afforded tetracyclic pyranoquinolines (48). Thus, the variations in reaction times that alter the trans/cis ratios provide evidence for the intramolecular electrophilic/ nucleophilic cyclization to produce (48).

NH

O

OH

R

I2, NaHCO

3

CH3CN

N O

OH

I

R

ONH

HO

HR

N O

OH H

CH2R

NH

O

OH

R

CH3COOH

N

OH

OI

R

N O

O

R

Nu

NaO

Base

(DBU)+

+

48

(48)

(49)

(45) (46/47)

R = H, 6-Me, 7-MeO, 8-Me.

47

I2/HgO (4.8 equiv)+

R = H, 6-Me, 7-MeO, 8-Me,

(45)

(47)

(48) Aranapakam et al ., 2008

11 report that 6,5-fused bicyclic heterocyclic or 5,5,5-fused tricyclic heterocyclic are effective broad-spectrum β-lactamase inhibitors. Compounds (53,53´,53´´) were synthesized on the bases of both modeling experiments and mechanistic and were found to be potent both in vitro and in vivo, The tricyclic heterocyclic heterocyclic bearing 6-methylidine penem carboxylic acid sodium salt 12a-g were prepared by a novel two-step aldolcondensation and reductive elimination procedures.

86

S

N

NH2

OCOOH

S

N

Br

OCOOPNB

S

N

COOPNB

O

R

O

O

Br

S

NO

R

COONa

NO2

N

N

NH

N

N

O

N

N

S

(50)

6-APA (51)

PNB=

(c)Activated Zinc/605pH phosphate buffer/THF: acetonitrile/RT/0.1NaOH

(52)

(a)MgBr2/Et3N/THF:acetonitrile

(b)acetic anhydride/0°C,-20°C

(53,53´,53´´)53;R= 53´;R= 53´´;R=

Also, the aldehydes intermediates (60 and 61) can be synthesized as follows;

X

O

ClX S

NNH

2 X S

NN

CO2Et

X S

NN

CHO

54;X = CH55;X = O

56;X = CH57;X = O

58;X = CH59;X = O

60;X = CH61;X = O

Thiourea, EtOH

THF, reflux

BrCH2COCO2Et

DMF, reflux

LiAlH4, THF, 0°C

MnO2, CHCl3, reflux

Ferando et al., 1970

12 were reported that α-Halogenated (62) were prepared by interaction of

monochloroacetyl-chloride with Schiff bases derived from aliphatic or aromatic amines in the presence of NEt3. However, Ziegeler et al., 1986

13 were report that single isomer of diaryl-3-halo-2-azetidinone (63) had been prepared by the addition of haloacetic acid and phosphoryl chloride, in DMF, to imine .

ClCH2COCl N

R1

R2

R3

NEt3

ClCH2COOH PCl

5N

DMF

N

HCl O

R1

R2R3

N

HCl O

+

+ +

(62)

(63) Bose et al., 1972

14 have reported that three types of Schiff bases (a, b and c) and two types of acid chlorides (d and e) were prepared from the point of view of preparation of.

CH

N

N CHOEt CH2

X

COCl RCH2

COCl

N

(a) (b)

(c) (d) (e)

87

The acid chlorides possessing a nitrogen, oxygen, sulphur or chlorine atoms in the α-position (group d) and an alkyl or aryl group in this position (group e) reacted with Schiff bases (a) to give. The class (d) type of acid chlorides reacted wiyh Schiff bases (b) and (c) but the class (e) failed to react. The acid chlorides of class (e) gave only trans- with Schiff bases (a) whereas both geometric isomers were obtained from (a) and acid chlorides of class (d). Katagiri et al., 1983

15 and Moore et al., 1985

16 were reported that ketenes for example, ketene (64) and ketene (66) react with imines, formimidates, and thioformimidates to give 3-cyano-2-azetidinones with trans stereochemistry at C(3) and C(4).

ON

Ph

Ph

NPh

Ph

O

O

Cl

CN

N

R

Ph

C6H

6,

NRO

PhClHCN

. +100°C

. +

(64) (65)

(66)(67)

Soto et al., 198317

, Kawabata et al., 198818

, Ito et al., 198919 have reported that the reaction of

diketene (68) with imine gave β-Lactam (69).

O

O

O

N

H

OMe

OMeOPh

NH

N

OMe

MeO

N

O Ph

HHO

O+ toluene 30%

(68)(69)

Mazumdar et al., 198620 have reported that 1,3-diaza-1,3-dienes (70) react with diketene

(71) to give β-Lactam (72).

Ph

NPh

NMe2

O

NPhN

Ph

Ph

Ph

NMe2

O

Ph

Ph+ .

(70) (71) (72) The majority of synthesis of β-Lactams via the Staudinger reaction are produced from acid chlorides or other ketene precursors. Bari et al., 1992

21 and Bachi et al., 1993 22were reported that various imino substrates have been used including dithio carbonate imins, 2-aza-1,3-dienes (73) react with acid chloride to give β-Lactams (74) [Georg et., 1988

23, 1990

24 and 1993

25].

88

O

R3 R1

R2

N

R1

R2 Cl

O

Et3N, CH

2Cl

2

R3

12h, 0°C to RT

R1 = Ph, PhCH=CH, PhCH=CMe, Ph2C=CH; R2 = H, Me;

R3 = PhO,Phth

(73) (74)

Lasarte et al., 1989

26 was reported that the reaction of acid chloride with α,β unsaturated imines give β-Lactam, also Alcaide et al., 1992

27 report that 1,4-diaza-1,3-dienes (75) react with acid

chloride to give β-Lactam (76) Alcaide et al., 199227.

NNR1

R1Cl

O

R2

NO R1

R1R2

Et3N, CH

2Cl

2

R1 = PMP or CH(PMP)2; R2 = Ph,Me,PhS, PhCH2O, PhO, Et, Pri, Cl, Phth,Br,Vinyl.

32-90%(75) (76)

Also hydrazones and α-fluoro aldimines react with acid chloride to give β-Lactam Sharma et al.,

199028 and Yoshioka et al., 1984

29. Lunch et al., 1989 30and Alcaide et al., 1993

31 have reported that 1,2-iminoketones, for example, (77) react with acid chloride to give β-Lactam (78).

N O

R

O

MeO2C

Ph

O

ON

R

MeO2C

O

ClOPh

Et3N, toluene, RT

70-86%(77) R = Me, Ph (78)

Shridhar et al., 198432 have reported that the ketimines, for example, (79) react with (80) to give

β-Lactam (81).

NPh

Phth CO2H

N P

OPh

Me

Ph

O Cl

N

PhthN

O Ph

+Et3N, CH2Cl2, 12H,

20°C, 41%

(79) (80) (81) Evans et al., 1988

33 was reported that imines derived from chiral α,β-epoxyaldehydes, for example, (82), have been shown to be good chiral glyoxal imine synthons in ketene-imine cycloaddition reaction. This process, which proceeds with high levels of reaction diastereo-selection, affords enantiomerically pure cis-substituted 3-amino-4-alkyl-2-azetidinones (83, 84).

N

O

Ph

R1

Phth

O

Cl

Et3N

O

Ph

NO

Phth

R1

O

Ph

NO

PhthH H

R1

+

(82) (83) (84)

89

Herdewijn et al., 198334, Ghosez et al., 1991

35 and Vander Steen et al., 199136 had been

reported that several types of ketene precursors have been used, including carboxylic acid chlorides, also α,β-unsaturate acid chlorides (85) Manhas et al., 1990

37, α-fluoro acid chlorides (87) Welch et al., 1993

38, α-sulfenylated acid chlorides Palomo et al., 199139, and other α- or β-

functionalized carboxylic acid chlorides, Ghosez et al., 1991 35and Van der Steen et al., 199136.

NO

R1 R2

R3

Cl

OR1

NR3

R2

Et3N, CH

2Cl

2

O

ClR

F

N

OO

OMe

Et3N

NO

OOF

R

OMe

+

+R=H, 68%

R= H, Ph R = H, ee 99%

(85)

(86)

(87) (88) Evants et al., 1985

40 was reported that use of phenyl-oxazolidinylacetylchloride (89) has been successful as a homochiral ketene synthon, which reacts with N-benzyl imines to give β-Lactams (90) with exceptional levels of asymmetric induction.

NO

N

HHO

O

Ph

Ph

PhN

R

Ph Et3NNO

Cl

O

O

Ph

+80-90%

R = Ar, CH = CHAr1

(89) (90) This process had been utilized for the synthesis of cis-3(R)-hydroxyl-4(S)-phenyl-1-(4-methoxyphenyl)-2-azetidine, which is a suitable precursor to the taxol side chain, Holton et al.,

199341 and the synthesis of a conformational analog of deoxy-boyvardin via β-Lactam (93)

Boger et al., 199142.

Et3NNO

Cl

O

O

NO

N

HHO

O

Ph

Ph

N Ph

Ph

+

(91) (92) (93) Hegedus et al., 1991

43 was reported that the stereo-selectivity of the reaction of benzylideneamines and cinnamaldimines had been compared with ketenes. The ketenes include those generated by the reaction of optically active oxazolidinone acid chlorides with triethylamine and complexe ketenes, generated by photolysis of optically active oxazolidine, and oxazilidinone, chromium carbine complexes in the presence of Et3N. The absolute stereochemistry is determined primarily by the structure of the chiral auxiliary. The relative cis-trans stereochemistry is determine primarily by the structure of imine and the free or bound character of the ketene. Banilk et al., 1993

44 was reported that a simplified and stereo-controlled synthesis of β-Lactams (98) starting from an oxomalonate imine has been achieved in open vessels under microwave

90

irradiation in an unmodified domestic microwave oven. Also isomerization of alkenyl groups and reduction of the carbon-carbon double bond occurs efficiently under microwave irradiation.

N

OMe

EtO2C CO

2Et

Cl

ON

O

CO2Et

OMe

CO2Et

NO

CO2Et

OMe

CO2Et

NO

CO2Et

OMe

HCO2NH

4, Pd/C

HOCH2CH

2OH

NO

CO2Et

OMe

H H

N-Mem or pholine, DMF microwave irradiation

+

75% 25%

LiCl, DMF,microwave-irradiation, 66%

microwaveirradiation 100%

(94)(95) (96)

(97)(98)

Fremont et al., 1991

45 was reported that diphenyl-acetalimines (99) react with α-bromoacylbromides in the presence of pyridine to afford enamides (100) which undergo free radical cyclization to form β-Lactams (101).

NO

Ph

Ph

R1

R2

N

Ph

Ph

R1

Br

Br

O

R2

N

Br

O

Ph

Ph

R2

R1

Bu3SnH

AlBN, C6H

6

NO

Ph

Ph

R2

R1

pyridine

40-70%

(99) (100)

(101) Matthew et al., 1995

46 have reported that sequential and cascade ketene-imine [2+2] cycloaddition-palladium ctalyzed cyclization reactions occure in good yield. Racemic an homochiral examples incorporating of aromatic and heteroaromatic rings are reported. Thus, imines (102) and (103) underwent cycloaddition with ketenes RC: C: O (R = OCH2PH, R1, R2), to give lactams (104) and (105). The β-Lactams were then cyclized to give polycycles (106) (Z = CH) and (107) respectively.

XNI

X

NO

HH

R

I

XN

O

R

H HI

N

O

O

O

O

Ph

X

N

Br

NO

HH

R

X

Br

NO

R

H HX

cyclization

(102)(104) (105)

R = ,

RC : CO

cyclization

(103) (106) (107)

91

Jayaraman et al., 199647 was reported that the diastereo-selection in the synthesis of β-Lactams

(108) and (109) [R1 = PMP, PhCH2, furfuryl, (R)-PhMeCH, (S)-PhMeCh, R2 = PhThN, PhO, PhCH2, MeO, ACO, N3] via ketene-imine cyclo-addition (staudinger reaction) using different chiral auxiliaries has been examined. While sterically demanding imines derived from bicyclic aldehyde (110) (X = O) with a β-chiral center provided excellent selectivity, use of imines derived from bicyclic aldehyde (111) with a β chiral center was not effective. Improvement of stereoselectivity was also sought using imines (112) [X = NCHMePh-(R), -(S)] derived from chiral amines, (S)- and (R)-PhMeCHNH2, and chiral aldehyde (110) (X = O). The bicyclic terpenoid skeleton of the chiral auxiliary in (110) (X = O) was dissociation by ruthenium tetroxide to give multiply functionalized β-Lactams (112) in good yield.

MeN

H HMe Me

O

H H

R2

R1

Me

H HMe Me

XHC

Me

H

MeMe

H

OHC

CH2COMe

O

N

H HMe Me

O

H H

MeN

H HMe Me

O

H H

R2

R1

R2

R1

(108) (109)

(110) (111) (112) Shankar et al., 1996

48was reported that the asymmetric induction by several chiral alcs. In the reaction of their bromo-acetates with imines in the presence of activated Zn (Reformatsky reaction) was studied. (-)-trans-2-phenylcyclo-hexanol and (-)-phenylmethanol gave β-Lactam (113) in > 99% ee via cyclization of the diastereoisomeric β-aminoester intermediates. The resulting chiral 3-unsubstituted azetidin-2-one (113) was converted to 3-substituted products (114) (R = OH, R1 = F, X = O, Y = CH2; R = R1 = H, XY = CH = CH, COCH2).

F

OCH2Ph

NO

F

OCH2Ph

N

YX

HR

R1

(113) (114) Joachim et al., 1996

49 was reported that the photochemical rearrangement of diazoketones (derived from suitably protected α-amino acids) in the presence of imines led to the diastereoselective formation of aminoalkyl substituted β-Lactams (115) (R = Me, Bu-i, Pr-i, Bu-S, CH2Ph; R1 = Boc, Cbz; R2 = H; rlR2N = Phthaloyl). Two diastereo-isomeric trans-substituted ring systems were formed with selectivity up to 93:7 and yields up to 90%.

92

O

R

N

HH

NCH

2Ph

PhR1

R2

(115) Claudio et al., 1996

50 was reported that the reaction of a chiral oxazolidineacetyl chloride with α-bis(trimethylsilyl) methyl imines gave exclusively cis and trans β-Lactams (116) [R = Me, Et, Pr, (CH2)2Ph, CH2Ph, Pr-i, CH2OCH2-Ph, (CH2)2CO2Bu-t] with good to excellent diastereomeric selectivities and complete asymmetric induction at C3. (116)[R = Me] was deprotected in a multistep process to give (117) [R = Me].

NH

R

HH

BOCNH

ON

R

HH

N

O

OO

Ph TMS

TMS(116) (117)

Claudio et al., 1996 50have reported that the cis-azetidin-2-ones (118) [R = SiMe2CMe3; R1 =

Me, Ph; R2 = benzyl, (R), (S)-PhCH(CH3); R3 = Ph, (CH3)2CH, (CH3)3C] and (119) (R =SiMe2CMe3; R1 = Me, Ph) were stereoselectively prepared from the corresponding enantiomerically pure oxazolidinyl- or imidazolidinylacetyl chlorides and imines of lactalehyde or mandel-aldehyde. The absolute configuration of C3 and C4 positions of the azetidinones was mainly dictated by the intermediate ketene formed from the chiral acetyl chlorides. E.G., β-Lactam (120) (R = SiMe2CMe3) was formed in 56%yield as the major cis-diastereomer by stereo-selective cycloaddition of (S)-acetylchloride (121) and (S)-PhCH2N-CHCH-(Me)OSiMe2CMe3.

O

N

O

O

HHOR

R3

R1

R2

N

N

O

O

HH

N

OR

R1

PhPh

Me

Me

O

N

O

O

HH

N

Me

OR

PhPhN

O O

COClPh

(118) (119)

(120) (121) Krystyna et al., 1998

51 was reported that the reaction of phenylimines derived from β-phenyl-α,β-diketopropanoate, β-phenyl-α,β-diketopropanoic morpholide or α,β-diketo-propanoic morpholide with ketenes in the presence of Et3N yielded mixtures of diastereomeric azetidinones such as (122) (R = EtO , morpholino; R1 = Ph, PhO, Cl, phathalimido) as the major isomers. The

93

reaction of (122) (R = morpholino; R1 = Ph) with NaBH4 involved the reductun of the benzoyl moiety to afford the corresponding monohydroxy derivative.

N

COR

FO

O

Ph

Ph

R1

(122) Ronald et al., 1999

52 was reported that the synthesis of novel 4-(5'-pyrrolidinyl)-β-Lactams e.g. (123) [R1 = Et, OCH2Ph, phathal-imido, R2 = PMP, R3 = Me; R1 = OCH2Ph, phathalimido, R2 = Pme, R3 = Me; R1 = CMe3, R

2 = PMP, R3 = Me; R1 = OCH2Ph, R2 = allyl, CH2CH(OMe)2, R3 =

Me; PMP = C6H4OMe-4] and (124) (R1 = Et, R3 = Me; R1 = phathlimido, R3 = Me, H), from imines derived from 4-formyl-β-Lactams and α-amino esters via cascade imine-azo-methineylide-1,3-dipolar cycloaddition reactions is described. These cascades are endo-specific, exhibit facial stereoselectivity and occur in good to excellent yields.

NO

NH

N

H

H

H

O

O

Me

H H CO2MeR1

R2

R3

NPMPO

NH

H

H

H H CO2Me

CO2Me

R3

R1

(123) (124)

II- Reactivity of β-Lactams: 1- Electrophilic attack at nitrogen:

Cimarusti et al., 198353 reported that the reaction of the β-Lactams with sulfur trioxide

complexes to give Lactam-type structures.

NHO

NH

O

O

Bu+

NO

NH

O

O

SO3

Bu+

-

i, DMF, SO3

ii,KH2PO4(aq.)Bu4N

+

iii, Bu4N+HSO3

-

(125)(126 )

The preparation of organophosphorous substituted β-Lactams (128) had been suggested by Koster et al., 1983

54 and Just et al., 1983

55.

94

NHO

R2 R1

NO P

O

O

O

R2 R1

R3

R3

i, BuLi

ii, CIP(O)(OR3)2

Bu4N+

(127)

(128)

2) Electrophilic attack at carbon:

electrophilic reagent. The 3-position is activated by the carbonyl function, which makes it. The presence of a carboxyl group at C(4) does not interfere as the dilithium salt alkylated at C(3) with excellent stereocontrol, giving the trans-disubstituted lactam (129) Baldwion et al., 1990

56. Hydrolysis of leads to unprotected β-alkyl aspartates (130) Hanessian et al., 1992

57.

NO

CO2H

TBDMSN

O

CO2HR

TBDMS NH2

R

CO2H

HO2C

i, LDA (2 equiv.)

ii, RX

6N HCl

(129) 130 (131))(

The reaction of such amide enolates with alkyl halides or aldehydes has been proven to be very useful when the 3-position carried an additional heteroatom, for example, nitrogen, like conversion of (132) to (133) Holton et al.,1993

58.

NO

N

O

O

Ph

Ph

MeO

NO

Ph Cl NO

O

MeO

Ph

i, LHDMS,THF, CH2Cl2,

95 %

( 132 ) ( 133 ) Van der veen et al., 1989

59 report that sulfur like conversion of (134) to (135) and fluoro like conversion of (136) to (137) Welch et al., 1993

60.

95

NO

PhS R1

R2

NO

PhS

Cl R1

R2

N

F

O

OMe

R1

NO

OMe

R1

R2

SO2Cl2 (single isomer)

i, LDA, -90°C

ii, R2X

( 134 ) ( 135 )

( 136 ) ( 137 ) azidation with tosylazide via the enolate is an elegant approach to 3-amino-β-Lactams 3-Hydroxylations of 2-azetidinones have been executed using the MoOPh reagent like conversion of (138) to (139) Palomo et al., 1993

61,

NO

OMe

H

R

H

NO

O

NO

OMe

H

R

OH

NO

O

i, LiHDMS, -78°C,THFii, MoOPh, -78°C

(138 ) ( 139 ) When electron-withdrawing groups, for example, benzoyl, are present at C(4) the C(3) alkylation of (140) via the enolate can be performed with LDA/THF, but the benzoyl oxygen of (142) was alkylated when NaH/DMF is used, clearly underlying the importance of anion stabilizing substituents, either at C(3) or C(4) and the base solvent pairAlcaide et al., 1987

62

NO

OMe

O

Ph

Ph

NO

OMe

O

Ph Ph

NO

OMe

O

Ph

NO

OMe

O

Ph

i, LDA, THF, -15°C ii, EtI

48 %

i, NaH, DMF; ii, EtI

48 %

( 140 ) (141 )

(142 ) ( 143) Reactions at C(4) of β-Lactams require the presence of activating group. A method for the

96

synthesis of chiral azetidinones (144) with a C-C bond at C(4) consists of the stereoselective alkylation-reduction of a silylated 4-phenyl-sulfonyl azetidinone (145) Deeter et al., 1993

63.

NH

OO

PhO

N

SO2Ph

TBDMS

NH

OO

PhO

NH

SO2Ph

i, BuLiii, RX (X=halogen)

iii, LiAl(OBu+)3H

( 144 ) ( 145 ) The oxidative decarboxylation of 2-azetidinone-4-car-boxylic acids (146) to give 4-acetoxy-2-azetidinones (147) via reaction with lead(IV) acetate is a frequently used procedure in β-Lactam chemistry Fritz et al., 1986

64

ON

R1

CO2HR2

ON

OAc

R1

R2

Pb(OAc)4, Cu(OAc)

2

MeCN, 80°C

( 146 ) ( 147 ) 3) Nucleophilic attack at carbon:

The α-azidation of 1-hydroxy-2-azetidinones, for example, (148) with arenesulfonyl azides in the presence of triethylamine afforded 3-azetidinones (149) via O-tosaylation and SN

2-type displacement of the tosyloxy group Gasparski et al., 1992

65, Teng et al., 1993 66and Klich et al.,

199367. However, the SN

2-type displacement of 1-tosyloxy-2-azetidinones, for example, (150), with methanol occurs only in low to moderate yield but supports the proposed mechanism.

NO OTOS

N

O

O

Et3N, MeCN, MeOH,

NH

N

O

O O

OMe

ON

OH

TOSN3

Et3N

ON

OTOS OHN

OTOS ON

H

N3

14h

37%

N3-

( 148 ) ( 149 )

( 150 ) ( 151 ) It had been shown that 3-chloro-3-(phenylsulfenyl)-2-azetidines (153) undergo stereospecific methanolysis in the the presence of zinc chloride/silica gel to afford methoxylated β-lactams (152), while hydrolysis under similar conditions leads to azetidine-2,3-diones (154) Van der

Veen et al., 198959. Hydrolysis of 3,3-di(ethylthio)-2-azetidinones (156) with NBS in aqueous

acetonitrile, or with dimethylsulfide, dibromide, furnishes azetidine-2,3-diones (155), while 3,3-dimethoxy-2-azetidinones (157) are formed by iodine induced methanolysis [Cossio et al.,

198568

, 198869

and Palomo et al., 199070

]. Such azetidine (158) are readily attacked by nucleophiles at the 3-position. Oximation and subsequent reduction is a route to 3-amino-2-azetidinones (159) Kametani et al., 1985

71. Holton et al., 199372 was report that cis-3(3)-

hydroxy-4(S)-phenyl-β-lactam (161)was synthesized by reaction of 160 in presence of methanol and NaBH.

97

N

H

PhS

O

O

R1

R2

Me

N

H

PhS

O

O

R1

R2

N

O

R1

R2

O

N

EtS

O

EtS R1

R2

N

O

R1

R2

MeO

OMe

NO

R1

R2

O

O

O

N

OMe

OMe

TBDMS O

O

N

OMe

OMe

TBDMS

N

O

O pH

OMe

N

O

OH pH

OMe

ZnCl2(cat.),

moist silica gelCHCl3, heat

ZnCl2 (cat.)

NBS

MeCN (aq.)

I2

MeOH

i, NH2OH

ii, H2, Rh-Al2O3,

MeOH, 5 atm.

NaBH4, MeOH, 0°C

silica gel

( 152 ) ( 153 ) (154)

(155) (156) (157)

(158) (159)

(160) (161) Azetidine-2,3-diones (163) undergo a base-induced alkenation reaction with nitroalkanes affording nitroalkenes (164) which, are reduced and then oxidized to give 3-acyl-2-azetidinones (165) [Palomo et al., 1990

73]. The same substrates suffer alkenation reactions with Reformate-

sky type reagents affording 3-methylene-2-azetidinones, for example, (166) Palomo et al.,

199074.

N

O

R1

R2

R3

NO2

N

O

R1

R2

HHO

R3

N

O

R1

R2

ONO

2R2

O

O

OMe

N

OCl

O

R2 CO2Me

O

OMe

N

OCl

OCO2Me

i, Bu3SnH

base ii, O3, -78°C

TMS-Cl, THF

(162) (163) (164)

(165) (166) It had been shown that 3-amino-2-azetidinones (167) carrying an electron-withdrawing substituent at 3-amino substituent were methoxylated at the 3-position by oxidation to the 3-imino-2-azetidinone and subsequent nucleophilic addition of lithium methoxide Nishiada et al.,

198475.

O

O

NH

NHO

Ph O

O

NH

NHO

PhOMe i, Bu+OCl

ii, LiOMe, MeOH

iii, P(OMe)3

(167) (168) The classical functionalized of 4-acetoxy-2-azeti-dinones, for example, (169 ) at the 4-position

98

Davies et al., 198476 had been exploited several times with a variety of reagents, including a

Barier-type allylation using a Pb/Al bimetal redox system Tanaka et al., 198877,

diethylmethylmalonate Miura et al., 199378, tin(II) enolates Shirai et al., 1987

79 and Nagao et

al., 199280,81,82, thiols Barret et al., 1990

83, organozinc reagents Mori et al., 199384, and sodium

or potassium borohydrideOgilvie et al., 198885

S

N

SnOS

OSO2CF3

R1

R2

NH

OAc

O

NH O

HH

N

SO

O

R1

R2

NH

OAc

O

OHH

TBDMSZn, THF

ACNMe2, RT

Br

O

NH

OHO

O

TBDMS

NaBH4, EtOH

or KBH4, H2O NH

O

THF

+95 %

69-84 %

(169)

(170)

(171)

(172)(173)

The mechanism of these substitution reactions been investigated and it was shown that the reactions occur by an ElcB elimination-addition pathway in which a 1-azetin-4-one (174) acts as intermediate Fedor et al., 1984

86, Rao et al., 1990

87 and Gu et al., 1990

88, for N-substituted derivatives, substitution at the 4-position involves either elimination- addition via 4-azetinone intermediate (174) or direct displacement by SN

2 or SN1 mechanisms Rao et al., 1990

87. The intermediacy of 1-azetin-4-one in solution had been demonstrated via polymer-bound 2-azetidinones Gavia et al., 1990

89.

NH

O

z

NO

z

- NO N

O

NU

-NH

O

NUbase NU¯

nucleophil

( 174 ) The conversion of 4-sulfenylated-2-azetidinones into 4-fluoroazetidinones (176) or 4-chloro-2-azetidinones occurs by reaction with triethyloxonium tetrafluoroborate or chlorine, respectively Brennan et al., 1986

90 and Endo et al., 198791.

N

O

O

N

S

RO

CO2Me

N

O

O

N

S

RO

Et3O+BF4

-

dbu, MeCN

150°C to 0°C

(175) (176)

4) Radicals and photochemical conversion: Manhas et al., 1983

92was reported that dehalogenation of 3,3-dibromo-2-azetidinones occurs readily with tributyltin hydride the intermediate radicals add across methyl acrylate to give

99

highly functionalized β-Lactams (178) Sacripante et al., 198793.

NO

OMe

BrBr

Ph

i, Bu3SnH

CO2H

NO

OMe

HPh

H

MeO2C

ii,

46 %

(177) (178) . Stereospecific synthesis of chiral C(4) deuterated β-lactams (182) has been worked out in this way Basak et al., 1993

94. The reaction of 4-(t-butylthio)-β-lactams with tributyltin hydride affords 4-thiol-β-lactams. Wagle et al., 1988

95.

NH

OO

PhO

NR

SePh NH

OO

PhO

NR

SnPh

AlBN(cat), C6H

6

ONH

SePhTMSSu

3SnD, AlBN

ONH

TMSH

D

(179) (180)

(181) (182) The iodine atom transfer addition reaction of 3-fluoro-3-iodo-β-lactams (183) under photolytic conditions is a convenient stereoselective method for the functionalization of β-lactams at the position.

RON

OOF

I

N

OOF

OI

Phhv, CHCl3

(183) (184) 5) Reduction: The reduction of β-lactams (185) by diborane gives access to γ-amino alcohols (186) Sammes et

al., 198496

, while the microwave mediated catalytic transfer hydrogenation by means of ammonium format and pd/c has realized [Bose et al., 1993

97,98].

N

OO

N

H

O2C

Ph

Ph

OH

But

Pri

O2C

OH

NN

H O

O

H

Ph

Ph

But

Pri

B2H6, THF, 10°C, 4h

RT, 15h

(185) (186) Raney nickel reduces 2-azetidinethiones, for example, (187), in ethanol to afford azetidines, for example (188) Verkoyen et al., 1985

99. Derivatives with 4-phenyl substitutions give only

complex reaction mixtures, where as 3,3-disulfe-nylated β-lactams (189) are readily desulfurized by raney nickel [Cossio et al., 1987

100].

100

NS Ph

N

Ph

NO

EtS

EtSR1

R2N

O

R1

R2

RaNiEtOH, 2h

54 %

RaNi

(187) (188)

(189) (190) Highly selective reductions of β-lactams to the corresponding azetidines were successfully performed by using diisobutyl aluminum hydride Sagami et al., 1985

101 and Ojima et al.,

1991102

, monochloro-hydralane, and dichloroalane as reducing agents Yamashita et al., 1983103

,

Ojima et al., 1985104

, 1987105

,1991102

. Enantiomerically pure azetidines for example, (194) and (196) are readily synthesized without loss of enantiomeric purity Ojima et al., 1991

102.

NO

Ph

Ph

Ph

NO

OPh

Ph

Ph

N

Me

N

O

Ph

MeOH

Ph

N

OO

Ph

O Me

Ph

NO

O PhPh

OPh

Pri

NO

O PhPh

OPh

Pri

AlH2Cl, Et2O, 34°C, 15h

95 %

DIBAL, THF, 65°C, 3h

70 %

AIHCl2, Et2O, 34°C,

1.5h, 65%

(191) (192)

(193) (194)

(195) (196) Aluminum hydride reduces 4-(1-alkenyl)azetidin-2-ones (197) to give 2-(1-alkenyl)azetidines (199) but the reduction of the same substrates with lithium aluminum hydride also reduces the alkene moiety to afford 2,2-disuubstituted azetidines (198) Hassner et al., 1986

106, 1987

107.

NH

NH O

R1R2

R3

NH O

R1R2

R3

LiAlH4, Et2O

R1=Me; R2=R3=H

62%

AlH3, Et2O

(197)(198) (199) 6) Ring opening:

The hydrolysis of chiral β-lactams (200), after reductive removal of the N-benzyl substituent, in acid medium provides α-alkylated α-amino acids (201) in a stereospecific way Ojima et al.,

1988108,109

, 1990110

.

101

N

N

O O

ArR

Ph

Ph

NH2

R

Ar

CO2H

i, Li, NH3

ii, aq. HBr

(200) (201) Nucleophilic attack upon the β-lactam ring normally occurs at the carbonyl carbon atom and leads to opening of the ring Van Elburg 1985

111. When the ring contains a leaving group at the 4-position, nucleophilic displacement can also occur for exempl by substitutions of 4-acetoxy-2-azetidinones and related sudstrates. Such 4-acetoxy- and 4-aryloxy-2-azeti-dinones (202) undergo ring opening by aqueous alkaline solution to give 3-hydroxyacylamide or α-formyl-carbox-amides Fedor al., 1984

112.

NH

ORO OHCONH

2

R = AC, Ph

- OH

(202) (203)

Similarly, the ring opening of 4-chloro-β-Lactams (204) with sodium methoxide affords enamino esters (205) Rao et al., 1990

87. In contrast to the 4-chloro derivatives, the 4-(methylthio)-3-(tosyloxy) and 3-azidoazetidinones (206) in the presence of triethylamine undergo elimination of tosylate and azide in competition with loss of methanethiol. The methylthio group rearranges from C(4) to C(3) to afford enamino esters (209) Rao et al., 1990

87.

NOCl

R2

R1

NaOMe, MeOH

NHMeO2C

R1

R1

NaOMeMeOH OTOS

MeS

HN

CO2Me S

HN

Me

CO2MeR1 HN SMe

SMe

R1NOMeS

R2

R1

(204)(205)

(206) (207) (208) (209) Alkoxides with 3-(chloromethyl)-2-azetidinones (210) give ring opening to β-amino esters (211) which undergo ring closure to azetidine-3-carboxylic esters (212).

N

O

ClR1

R2

CO2

ClHNR1

R2

R3 N ClR1

R2

NaOR3

R3OH or DMF

(210) (211) (212) Fragmentation of β-Lactams (213) by ozonolysis, followed by reduction with sodium borohydride provides vinyl ethers (214) via intermediate N-nitroso-β-Lactams Alcaide et al.,

1993113.

102

NN

O

O

R2R1

R3

OR2 R1

i, O3, -78°C

ii, NaBH4, EtOH, H2O

44-64 %

(213)(214)

The hydrolysis of 2-azetideneammonium salts (215) in sodium hydroxide and in carbonate buffers yields 2-azetidinones and β-amino carboxylic amides by competitive endo and exocyclic C-N bond cleavage, the product ratio being pH and buffer dependent Page et al., 1987

114,

1988115

, 1990116

. The rate law for hydrolysis shows a third order term that is first order is substrate, hydroxide, and carbonate ions. It is interpreted as kinetically equivalent to general acid catalyzed breakdown of the ionized tetrahedral intermediate and as evidence for non facial C-N bond cleavage in the four-membere ring.

N

N

NO2

Ph

NO

NO2

Ph

O2N

NH

O

N

Ph+

- OH, H2O+

(215)(216) (217)

The ring opening of 3-oxygenated-4-phenyl-β-Lactams, for example, β-Lactam (218) by alkoxides has found an important application in the synthesis of tazol and related substances, delivering the correct stereochemistry of tazol side chain Holton et al., 1990

117, 1991

118, Ojima

et al., 1991119

, 1992120

, 1993121

, Endo et al., 1993122

, and Holton et al., 1994123

.

NO

O-TES

OPh

Ph

NH

OH

OR

O O

Ph

Ph

- OR

(218) (219) Intermolecular ring opening, via an in situ generated alkoxide from reduction of an acetyl moiety by hydride, furnishes ring expansion to lactone (221

) Farouz-Grant et al., 1993124

.

N

O

NO

O

OO Ph

PhH H

HNaBH

4, MeOH

O

NH

HNH

H

O

O

PhO

Ph

O

- 78°C

(221)(220)

The ring expansion of β-Lactam (222) by thiolate to give isoxazolidinone (223) was utilized as a key step in the synthesis of 2- alanyl-3-isoxazolin-5-one (224) Baldwin et al., 1985

125.

N

NH

OOH

BOC EtSNa

THF

ONH

NH

O

BOCO

NO

NH2 CO2H

(222) (223)(224)

103

Ring opining of β-lactams, for example, (225), by diborane Sammes et al., 198496, lithium

aluminium hydride, lithium triethylborohydrie and dissobutylaluminum hydride have been described Ojima et al., 1991

102 and Bartholomew et al., 1991

126. However, these reducing agents are better known for the conversion of β-lactams into azetidines. A high temperature catalytic transfer hydrogenation of β-lactams by means of ammonium format and Pd/c in ethylene glycol to afford carboxylic amides (228) has been realized in an a domestic microwave oven Bose et al., 1993

98.

NO Me NHMe

OH

O

PhR1

R2O

NHPh

R1

R2

B2H6, THF,

10°C, 4h 77%

HCO2NH4, Pd/c

ethylene glycol

(225) (226)

(227) (228) 7- Electrochemical transformations:

The anodic fluorination of 3-(phenylthio)-2-azetidines (229) is a useful method for the synthesis of 3-fluorinated β-lactams (230) Narizuka et al., 1993

127.

NO R

PhS

N

F

PhS

O R

-2e¯, Et3N.3HF

F¯, MeCN

(229) (230)

8- Conversions into other heterocyclic:

Ring expansion of β-Lactams, bearing a ῶ-haloalkyl substituent at the nitrogen atom, occurs with liquid ammonia to heterocycles (232) Crombie et al., 1983

128, 1986

129 A related ring

expansion to pyrrolidine occurs with 3-(2-chloroethyl)-2-azetidinones (234) Bose et al., 1986130

.

NO

X

NH

NH

O

2-5

NO

ClPh

Ph N

Ph

CO2Me

Ph

2-5

liq. NH3

X = halogen

NaCN, MeOH,

(231) (232)

(233)(234)

Ring expansion of 1-hydroxyazetidine-2-ones produces 2-imdazolidinones (237) via activation with MeOPOCl2 Krook et al., 1985

131,132.

104

NH

NOHPh

O

N

NH

O

O OH

PhNH

ON

O

Ph

MeOP(O)Cl2, MeCN,

N- Memorpholine, 0°C

.

H2O

36%

(235)(236) (237)

9- Reactivity of substituents attached to ring carbon atoms:

Michael addition of sodium borohydride or pipridine across 3-methyleneazetidin-2-one (238) affords the adducts (239) Mori et al., 1985

133. It has been shown that 4-(iodomethyl)azetidin-2-one undergoes nuclieophilic substitution by sodium azide in DMF to give the azide compound Knapp et al., 1988

134.

N

O

Ph

NaBH4

NHN

O

Ph

R

or

R = H, (CH2)5(238) (239)

The 3-vinyl substituent of β-lactam (240) was converted into a 1-hydroxyethyl group by oxymercuration and reductive demercuration Bose et al., 1993

98. The 1-hydroxyethyl substituent was readily oxidized by the Jones reagent and was further transformed to a hydromethyl substituent by silylation, ozonolysis, oxalylchloride treatment, and hydride reduction Ruediger et

al., 1991135.

N

O

H H

OMe

Ph

N

O

H H

OMe

Ph

OH

i, Hg(O2CCf3)2

ii, NaBH4

(240)(241)

Triethylborane mediated epimerization of the α-methyl diastereomer (242) proceeds with high stereo selectivity Bender et al., 1992

136. Enzyme-catalyzed hydrolyses of carboxlic ester groups, localized in the C(2) side chain, have been performed Schirmeister et al., 1993

137. Ozonolysis of 4-(1-alkenyl) substituents is a convenient rout towards 4-acyl-β-lactams Palomo et al., 1989

138.

O

HH

NH

O

CO2Me

TBDMS

O

HH

NH

O

CO2Me

TBDMSi, LDAii,Et3B

iii, HOAc

(242) (243) . The production of 3-ethylidine-2-azetidinones (245) is possible from fluoride-mediated desilylation and concomitant chloride elimination Buynak et al., 1987

139.

N

ClTMSR2

R1N

R2

R1O

KF, DMSO, 80°C

60-90%

·

(244) (245) 10-Reactivity of substituents attached to the ring nitrogen atom:

, while the 4-methoxyphenyl protective group is conveniently removed by ammonium nitrate Hanessian et al., 1985

140

105

N

O

OMeR1

R2

NHO

R1 R2

- e¯, aq.MeCN

(246) (247) The oxidative removal of the di-(p-anisyl)methyl group is readily accomplished using ceric ammonium nitrate Kawabata et al., 1986

141, 1988

142, or peroxodisulfate salts Terajima et al.,

1990143

.

O

HOH

H

N

OPh

OMe

OMe

O

HOH

H

N

OPh

(NH4)2Ce(NO3)6

aq. MeCN, 0°C

(248)(249)

It has been shown that N-phenacyl protected 2-azetidinones were converted in N-unsubstituted 2-azetidinones by oxidation with KMnO4 or via α-bromination and subsequent mercury assisted hydrolysis Cossio et al., 1985

144.

N

O OMe

z

N

O

z

OMe

N

O

R1 R2

R3

NH

O

R1 R2

-e-, MeOH, MeCNBu4N

+BF-4

61-63 %

Z = O, CH2

P, TOSOH, aq.dixane, 30°C

5 min., 79-92 %

KMNO4, acetone,

H2O, 0°C, 10 min

50-90 %

(250) (251)

(252)(253)

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Received on September 18, 2012.