379 A/Sld

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INTRAMOLECULAR [2+2] CYCLOADDITIONS OF

PHENOXYKETENES AND INTERMOLECULAR

[2+2] CYCLOADDITIONS OF

AMINOKETENES

DISSERTATION

Presented to the Graduate Council of the

University of North Texas in Partial

Fulfillment of the Requirements

For the Degree of

DOCTOR OF PHILOSOPHY

By

Yi Qi GU, B.S., M.S.

Denton, Texas

May, 1989

Gu, Yi Qi, Intramolecular [2+2] Cycloadditions of

Phenoxyketenes and Intermolecular [2+2] Cycloadditions of

Aminoketenes. Doctor of Philosophy (Chemistry), May, 1989,

116 pp., 4 tables, bibliography, 149 titles.

One objective of this study was to explore the

intramolecular [2+2] cycloadditions of phenoxyketenes to

carbonyl groups with isoflavones and benzofurans as target

compounds. The other objective was to investigate the

eyeloaddition reactions of rarely studied aminoketenes.

The conversion of 2-(carboxyalkoxy)benzils to the

corresponding phenoxyketenes leads to an intramolecular

[2+2] cycloaddition to ultimately yield isoflavones and/or

3-aroylbenzofurans. The product distributions are dependent

upon the substitution pattern in the original benzil acids.

The initial cycloaddition products, 3-lactones, are isolated

in some instances while some 3-lactones spontaneously

underwent decarboxylation and could not be isolated.

The ketene intermediate was demonstrated in the

intramolecular reaction of benzil acids or ketoacids with

sodium acetate and acetic anhydride. It is suggested that

sodium acetate and acetic anhydride could serve as a source

for the generation of ketenes directly from certain organic

acids. The treatment of ketoacids with acetic anhydride and

sodium acetate provides a simpler procedure to prepare

benzofurans than going through the acid chloride with

subsequent triethylamine dehydrochlorination to give the

ketenes.

N-Ary1-N-alkylaminoketenes were prepared for the first

time from the corresponding glycine derivatives by using

p-toluenesulfonyl chloride and triethylamine. These

aminoketenes underwent in situ cycloadditions with

cyclopentadiene, cycloheptene and cyclooctenes to yield only

the endo -bicyclobutanones. The cycloheptene and

cyclooctene cycloaddition products underwent dehydrogenation

under the reaction conditions to yield bicycloenamines. A

mechanism is proposed for this dehydrogenation involving a

radical cation of the arylalkylamine. (N-Phenyl-N-methyl)

aminomethylketene was also prepared and found to undergo an

intramolecular Friedel-Crafts type acylation to yield an

indole derivative when prepared by the acetic anhydride f

sodium acetate method.

The in situ cycloaddition of N-aryl-N-alkyl

aminoketenes with various imines was found to form

predominately cis—3—amino—2—azetidinones. A mechanism

involving a dipolar intermediate is provided whereby the

structure of the intermediate is determined by both

electronic and steric effects. The stereochemistry of the-

resulting 3 -lactams is dependent upon the structure of the

dipolar intermediate.

TABLE OF CONTENTS

Page

LIST OF TABLES I V

Chapter

I. INTRODUCTION 1

II. EXPERIMENTAL 23

III. RESULTS AND DISCUSSION 60

BIBLIOGRAPHY 1 0 5

1 1 1

LIST OF TABLES

Page

Table

I. Distributions of Isoflavone or Isoflavone

^-Lactones and 3-Aroylbenzofurans 64

II. Benzofurans 71

III. 3-(N-Alkyl-N-Arylamino)-2-Azetidinones 88

IV. 3-(N-Alkyl-N-Arylamino)-2-Azetidinones Prepared by Acetic Anhydride and Sodium Acetate Method 99

l v

CHAPTER I

INTRODUCTION

Ketenes are versatile organic compounds with a

functionality containing a carbon carbon double bond and a

carbon oxygen double bond cumulatively connected in an

orthogonal, nonconjugated manner (^C=C=0 ). Atomic charges

of ketene are shown in Figure 1 [1].

0.087 H 2 1

^ C ====• C = = 0

0.087 H ^ O . 2 4 6 0.259 -0.186

Figure 1

The charge distributions suggest that nucleophilic

attack will occur at carbon 1, while oxygen and carbon 2 are

susceptible to electrophilic attack. The combination of

electrophilic character at carbon 1 and nucleophilic

character at oxygen and carbon 2 results in the high

tendency for ketene to dimerize or polymerize. The

dimerization of ketenes may yield (3 -lactones or

X,3—cyclobutanediones depending on reaction conditions [2,

3, 4, 5, 6, 7, 8].

\ c=c=o /

H

( H ) R H

\ c=c=o / H

>

0

0

H

V R

Most aldoketenes (I), monosubstituted ketenes, are

unstable except for trimethylsilylketene (II), which is

unusually stable [9, 10]. Ketoketenes (III), disubstituted

ketenes, such as diphenylketene [11], di-(t-butyl)ketene

[12, 13], dimethylketene [14] are relatively stable and may

be isolated.

R •

\ c=c=o / H

(I)

Me3Si

\ c=c=o / H

(II)

\ c=c=o

(III)

There are only a few ketenes which have been isolated

and characterized, as most ketenes are generated in situ.

The most commonly used and most general methods for the

preparation of ketenes are the triethylamine

dehydrohalogenation of appropriately substituted acid

halides and the zinc dehalogenation of 2-haloacid halides

[15, 16, 17, 18, 19, 20] .

R1 EtoN \

Rj R2CHC0C1 *• C=C=0 + Et3 NHC1

R 2

Zn ^ R, RoCBrCOBr > C=C=0 + ZnBr?

/ R 2

The pyrolysis of certain compounds may be used for the

preparation of some specific ketenes [2, 9, 21, 22 ].

R 0 N3 R N3 9 N3 \ \

» c=c=o « / /

N3 0 R NC R 0 R

H

120°C ^ (Meh Si-CsC-OEt — » C=C=0

/ (Me)3 Si

MeCOMe 7 0 0 °C > H2C=C=0

Me 0

Me

H

120° C C=C=0

/ Me

The electrocyclic ring cleavage of cyclobutenones has

been used to prepare ethenyl ketenes [23, 24],

r, r .0

H

Recently, several new methods for the in situ generation

of ketenes have been reported. Activation of the carboxyl

group of the corresponding carboxylic acid with

p-toluenesulfony1 chloride [27] or Mukaiyama's reagent [28]

followed by elimination with triethylamine yields the

corresponding ketene directly from carboxylic acids.

R 1R 2CHCOOH TsCl or Mukaiyama agent, Et-jN \

c=c=o /

Another method involves the reaction of n-butyllithium

with 2,6-dibutyl-4-methylphenyl ester(a) to give the ester

enolates, which cleave to the ketenes above -20 C [25, 26].

n-BuLi, THF -20 V R 1R 2CHCOOR * R 1R2

c = c(OLi)OR > R 1R 2C-C-0

(a)

Ketenes are versatile reactive intermediates in organic

synthesis, and many synthetic applications have been found.

The most synthetically useful reaction of ketenes is the

[2+2] cycloaddition reaction to form a four membered ring

[29, 30]. This [2+2] ketene cycloaddition reaction may yield

cyclobutanones, 0-lactams or 3-lactones depending on the

ketenophile. It is generally considered that in the [2+2]

ketene cycloaddition reactions, the ketene is the

electrophilic component and the unsaturated ketenophiles are

the nucleophilic components [31],

The [2+2] cycloaddition of a ketene with an olefin is

probably the most important method for the preparation of

cyclobutanones [32], Molecular orbital studies indicate a

relatively low-lying LUMO and high-lying HOMO of the ketene

[8]. The low-lying LOMO of ketene makes it an extremely good

electrophile. As the energy difference between the HOMO of

an olefin and the LUMO of a ketene is smaller than the

energy difference between the LUMO of the olefin and the

HOMO of the ketene [31], the interaction between the HOMO of

the olefin and the LUMO of the ketene is expected to

dominate the early stage of the reaction. This has three

important consequences. Firstly, electron-releasing

substituents on the olefin, such as alkoxy or amino groups,

and the electron-withdrawing substituents on the ketene,

such as chlorine and cyano groups, will increase the rate of

reaction because of the reduced energy difference between

the olefin HOMO and the ketene LUMO as shown in Figure 2

[33 , 34] .

LUMO

HOMO

\ / c=c

D

/ \

D= electron-donating

group

LUMO

HOMO

W

\ c=c=o

H

H \ c=c=o / H

W= electron-withdrawing

group

(Figure 2)

Secondly, the regiochemistry of the cycloaddition is

controlled predominately by electronic factors. The most

electron-rich carbon of the olefin attacks the sp-hybridized

carbon of the ketene [35, 36, 37, 38, 39, 40, 41],

RjR2C=C=0 +

Ph \

/ Ph

c=c=o

\ OR

0

Ph

RO

R 1

R

This can be explained by the fact that the largest

coefficient carbon of the HOMO of the olefin prefer to

overlap with the largest coefficient carbon of the LUMO of

the ketene.

Ketene LUMO

Ketene HOMO

Olefin LUMO

Olefin HOMO

D = electron-donating

group

Thirdly, in the [2+2] cycloaddition of a ketene to an

olefin, the stereochemistry of the olefin is maintained in

the cyclobutanone [42, 43, 44, 45, 46].

H H H

\ / \ / 0 C=C R C=C 0

-f / \ \ / \ v -/ «Ji » J k

R H H

'/

The cycloaddition of an unsymmetrical ketene to

cyclopentadiene yields only the [2+2] cycloaddition product

and stereoselectively yields the isomer with the larger

substituent of the ketene in the endo position [47, 48, 49,

50, 51]. The larger the difference between the two

subtituents on the ketene , the greater amount of the endo

-isomer.

L O S

C=C=0 + \ fj > / — / L > >

/ S o

These results are in accord with a concerted [iT2s+'n'2a]

mechanism in which the ketene participates in an

antarafacial fashion and superafacially with respect to the

olefin component [52, 53]. As the interaction of the HOMO of

olefin and the LUMO of ketene dominates in the early stage

of the reaction, the approach of the olefin to the ketene

will occur in the plane of the ketene, so that steric

effects are expected to play an important role in the

cycloaddition. The least hindered orthogonal approach of the

two reacting species results in the most hindered products

as shown in Figure 4 [51, 54].

(Figure 4)

If the substituents on the ketene are extremely good

carbanion stabilizing groups, such as CF3 and CN, or the

ketenophiles are extremely electron-rich, such as ynamines

and imines, the stepwise mechanism is favored as these

substituents stabilize the zwitterion intermediate [55, 56

57, 58].

F3C CF 3 H \ / 1 + c c — N E t .

/ CH'

0

Ketenes will undergo [2+2] cycloaddition reactions with

carbonyl groups under the appropriate conditions to give

10

2-oxetanones (g-lactones). In many instances, the &

-lactones are quite susceptible to decarboxylation to form

olefins [59]-

Ph

\ c=c=o c=o

/ Ph

Ph

Ph*

0

"0

*C = CPh 2

Ketenes will readily react with imines to yield

2-azetidinones ( 0 -lactams). This is one of the most useful

methods for the synthesis of these important compounds [60,

61] .

Ph

\

/ Ph

C =C =0 N

+ C=N— /

Ph

Ph'

7

/

N

The cycloaddition of ketenes and a , 8-unsaturated

imines may yield [4+2] cycloaddition products [62, 63, 64,

65] .

CI

\ PhCH=CH-C=NR

/ c=c=o

CI

11

Similar [4+2] cycloaddition reactions are also observed in

the reaction of ketenes with certain activated vinyl

ketones [66, 67, 68, 69].

X ^ c - N R 2 NR 2 CI

+ C1 2C=C=0 > -CI

Nucleophilic addition reactions of ketenes have also

been actively studied in recent years both for synthetic and

mechanistic purposes [70]. Some of these addition reactions

are found to be useful in synthesis. The addition of

t-Butyllithium to di — (t-butyl)ketene is found to be

particular useful in the synthesis of the corresponding

enolate, which could not be prepared from the ketone with

strong bases [71],

OSiMe 3

1) t-BuLi . / (t-BuUC =C=0 (t-Bu) C=C

2 2)Me3SiC1 1 \ J t-Bu

0 t-BuOK -^/

J * * /

0 . /

12

Recently, intramolecular [2+2] ketene cycloadditions

have been successfully used in the synthesis of polycyclic

compounds, especially polycyclic natural products [71],

Excellent success has been obtained with alkoxyketenes [27,

28, 73, 74, 75, 76, 77], chloroketenes [78], and vinyl

ketenes [79, 80, 81, 82, 83, 84, 85, 86].

or""' v i-\—n-r=r\

o-c=c=o

I R

R 1

0-CB=C=0

Me

c=c=o

13

CH

H

3 CH CH

CH

H

! _ •

H

14

The intramolecular [2+2] ketene cycloadditions are

benefited by entropy factors due to the spatial proximity of

the two reacting functionalities. Thus, intramolecular

cycloaddition competes effectively with the troublesome

ketene polymerization to give desirable cycloaddition

products. Numerous recent articles on intramolecular [2+2]

ketene cycloadditions are concerned with the cycloaddition

of ketenes to alkenes. Only a few reports are related to the

intramolecular ketene cycloaddition to carbonyl groups.

f i r " " o-c=c=o

R

Consequently, one of the objective of this research project

was to explore further the synthetic application of the

intramolecular [2+2] cycloaddition to carbonyl groups. The

isoflavones are commom constituents of plants of the

Leguminosae family. These compounds show a variety of

biological activities, such as antimicrobial activity and

estrogenic activity [87, 88]. So the basic isoflavone

structure was targeted in this research project.

0

isoflavone

15

Although simple ketenes do undergo [2+2] cycloaddition

with some alkenes, satisfactory yields are generally not

obtained unless activated ketenes are used. Cycloadditions

of ketenes containing heteroatoms, such as chlorine, oxygen

or sulfur, are much more commonly used in synthesis.

Cyanoketenes, phenylketenes and vinylketenes have also been

used successfully in synthesis situations. It is interesting

to note that with all the studies on the above mentioned

ketenes, aminoketenes have received relatively little

attention.

R

\

c=c=o /

R 1 R 2 N

Aminoketenes

There are a few scattered reports in the literature on

aminoketenes, but these reports are limited to the nitrogen

atom bearing an electron-withdrawing substituent, such as

succinoyl, maleyl or phthaloyl [89]. In an effort to learn

more about the synthetic potential of aminoketenes, the

second objective of this research project was to prepare and

investigate cycloaddition reactions of aminoketenes with

different ketenophiles.

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CHAPTER II

EXPERIMENTAL

All nuclear magnetic resonance spectra (NMR) were

recorded on a 300 MHz VXR-300 spectrometer or 90 MHz

JEOL-FX-90Q FT nuclear magnetic resonance spectrometer

employing deuteriochloroform as the solvent with TMS as the

internal standard. Attached Proton Test(APT) NMR experiments

were performed in most cases to distinguish different

carbons. All the chemical shifts are reported in parts per

million (ppm). The infrared (IR) spectra were obtained on a

Perkin-Elmer 1330 spectrometer. Column chromatography was

performed on Florisil 100-200 mesh or Aldrich silica gel

100-200 mesh. Rotary preparative chromatography was

performed with silica gel 60PF254 from EM Science Co. or 7GF

form Baker Chem. Co. Ethyl acetate-hexane was used as

eluting solvent. GC-MS spectra were recorded on a

Hewlett-Packard 5790A Series GC/mass spectrometer. MS

samples were run by ICR Research Associates. All melting

points were determined on a Thomas Hoover capillary melting

point apparatus and uncorrected. Elemental analysis were

performed by Midwest Microlab, Indiana. Benzene and

triethylamine were dried by sodium and freshly distilled

before using.

23

24

Part I. Intramolecular [2+2] Ketene Cycloadditions to

Carbonyl Group.

A. Synthesis of Isoflavones and 3-Aroylbenzofurans

The starting 2-methoxybenzils la and lb were prepared

by a literature procedure [11 in 61% and 41% yield,

respectively, and lc was prepared by a different literature

procedure in 41% yield [2].

Preparation of 2-Hydroxybenzils 2a-c . Compound la [3]

was demethylated by using concentrated HC1 and pyridine to

give 2a in 71% yield: IR 1720, 1670, 1630 c m - 1 ; GC-MS(70ev),

m/e (relative intensity) 226(M +,5), 121(100), 105(38).

Compound 2b [4] was obtained by refluxing lb with 48%

HBr and AcOH for 1.5 h: IR 3420, 1630, 1595 cm"1; GC/MS

(70ev), m/e(relative intensity) 256(M+ ,5), 135(100),

121(19) .

Compound lc was heated on the steam bath with 3 eq. of

aluminum chloride for 2.5 h and workup with acid followed by

base yielded 2,2'-dihydroxy-4,4'-dimethoxybenzil, mp 135-137

C (lit.136-139°C [2]). This benzil was methylated with 1 eq.

of dimethyl sulfate in the presence of potassium carbonate

to give 2c, which crystalized from MeOH and hexane to give

a 26% yield, mp 110°C(lit. 110°C [5]).

25

General Procedure for 2-Acetoxybenzil Preparations

3a-f A solution of the 2-hydroxybenzil in acetone

containing 1.1 eq of ethyl a-bromoacetate or ethyl

a-bromopropionate and 1.5-2 eq of anhydrous potassium

carbonate was gently refluxed. Refluxing was continued until

the starting compounds were consumed as evidenced by TLC.

About 7-9 h are required for completion of the reaction as

the yellowish reaction solution becomes colorless. The

reaction solution is filtered and the acetone removed under

reduced pressure. The concentrated filtrate was hydrolyzed

with 2 eq of KOH in 90% alcohol. Some of the alcohol was

removed under reduced pressure, water was added , and then

the solution was acidified with diluted HC1. The acid

solution was extracted with ether and the ether extracts

were dried over anhydrous magnesium sulfate. Evaporation of

the ether resulted in the 2-acetoxybenzils. Infrared

revealed that the ester carbonyl absorptions at 1750 cm 1 had

disappeared and the acid carbonyl absorption at 1720 cm1 was

present.

General Procedure for Intramolecular Ketene

Cycloadditions. The 2-acetoxybenzils were stirred with 5-8

eq of oxalyl chloride in dry benzene for 8-12 h. When IR

revealed that the carbonyl group of the acid at 1720 cm 1 had

disappeared and the acid chloride carbonyl absorption at

1800 cm 1 had appeared, the excess oxalyl chloride and

26

benzene were removed under vacuum. The oily acid chlorides

were dissolved in dry benzene and added slowly using a

syringe to 3-4 eq of triethylamine in benzene. The solutions

were stirred for 8-12 h at about 50°C. The amine salt was

removed by filtration and the filtrate concentrated under

reduced pressure. The isoflavone or isoflavone ^-lactone and

3-aroylbenzofurans were separated by silica gel

chromatography using an eluting solvent of ethyl

acetate-hexane (1:9 to 1:7).

3-Benzoylbenzofuran (6a) and Isoflavone (8a). From

1.42g of 3a, a mixture of compounds 6a and 8a was obtained.

Silica gel chromatography resulted in 0.55 g (50%) of 6a and

0.25 g (23%) of 8a.

6a: mp 63-65°C (lit. 60°C [6]); IR 1650 c m - 1 ; GC/MS

(70eV), m/e (relative intensity) 222(M +, 73), 194(13),

145(100), 105(13), 77(33); LH-NMR 8.2(m, 1H), 8.05(s, 1H),

7.4-7.9(m, 8H).

8a: mp 133-135°C (lit. 132°C [7]); IR 1630 cm~h GC/MS

(70eV), m/e (relative intensity) 222(M +,77), 120(26),

92(27); lH-NMR 8.3(M, 1H), 8.0(s,lH), 7.85-7.4(m, 8H).

3-(2-Methoxybenzoyl)benzofuran (6b) and

2'-Methoxyisoflavone (8b). From 0.46 g of acid 3b, a

mixture of compounds 6b and 8b was obtained. Separation and

purification by silica qel chromatography resulted in 55 mg

27

(15%) of 6b as an oil and 0.2 g (55%) of 8b.

6b: IR 1645, 1595, 1550 cm"1 ; GC/MS (70eV), m/e

(relative intensity) 252(M+, 100), 235(23), 207(10),

145(14); *H-NMR 8.6(m,lH), 7.9(s, 1H), 7.7-8.1(m, 5H),

7.0(m, 2H), 3 . 8(s , 3H); I 3C-NMR 190.1 , 156.9, 155.7 , 153.7,

131.9, 129.7, 129.1, 125.6, 124.6, 124.5, 122.9, 122.8,

120.4, 111.6, 111.4, 55.7.

8b: rap 180-181° C (lit. 174-178 ° C [8] and 184°C [5]);

IR 1640, 1600, 1575 cm"1; GC/MS (70eV), m/e (relative

intensity) 252 (M+,100), 221(78), 131(42), 121(34); 1H-NMR

3 .8(s , 3H) , 7.0(m, 2H), 7.3- 7.5(m, 4H), 7.7(m, 1H), 8.0(s,

1H), 8.3 (m, 1H);13C-NMR (APT), 178.0(C), 157.5(C), 156.3(C),

154.2(CH), 133 . 4(CH) , 131.7(CH), 129.8(CH), 126.4(CH),

125.0(CH), 124.6(C), 122.7(C), 120.8(C), 120.6(CH),

118.0(CH), 111.2(CH) , 55 . 7(CH3).

Anal. Calcd. for C H 0 : C , 76.19; H, 4.76; Found: 16 12 3

C ,76 .18; H, 4.92.

2', 4', 7-Trimethoxyisoflavon.e, 8c. From 0.5 g of 3c,

0.23 g (59%) of compound 8c was obtained; mp 148-149°C (lit.

148°c [9]); IR 1630, 1600 cm1; GC/MS (70eV), m/e (relative

intensity) 312(M +, 100), 295(14), 283(10), 281(50), 266(10),

161(19), 151(25); 1 H-NMR 3.75(s, 3H), 3.85(s, 3H), 3.9(s,

3H), 6.5-7.3(m, 5H), 7.9(s, 1H), 8.2(d, 1 H ) ; U C - N M R (APT)

176.0(C), 163.8(C), 161.1(C), 158.5(C), 157.9(C), 153.7(CH),

132.3(CH) , 127.8(CH), 122.2(C), 118.0(C), 114.3(CH),

28

113.5(C), 104.4(CH) , 100.1(CH), 99.1(CH), 55.8(CH 3), 55.7

(CH3), 55.4(CH 3).

3-Benzoyl-2-methylbenzofuran, 6d and g-lactone of

2-Carboxyl-3-hydroxy-2-methyl-2,3-dihydroisoflavone, 7d.

From 0.5 g of acid 3d, a mixture of compounds 6d and 7d was

obtained. Separation by silica gel chromatography resulted

in 0.24 g (63%) of 6d and a trace of 7d.

6d: Obtained as an oil by initially column

chromatogrphy and then rotary chromatography: IR 1640, 1570

cm" 1; GC/MS (70eV), m/e (relative intensity) 236 (M+, 79),

207(10), 159(35), 105(15); 1 H - N M R 2 . 5 ( s , 3H), 7.25-7.7(m,

9H); 1 3C-NMR (APT) 191.9(C), 161.9(C), 153.6(C), 139.3(C),

132.6(CH), 129.0(CH), 128.5(CH), 126.8(C), 124.3(CH),

123.5(CH), 121.3(CH), 116.9(C), 110.8(CH), 14.7(CH 3).

7d: mp 91-93°C ; IR 1850, 1685, 1605 cm" 1; GC/MS

(70eV), m/e (relative intensity) 236 (M +-C02, 61), 235(100),

115(17), 92(11); l-H-NMR 1.45(s, 3H), 7.1-8.0(m, 9H); 1 3C-NMR

186.1, 168.3, 157.9, 137.2, 131.6, 130.1,128.9, 128.7,

125.5, 123.9, 119.4, 18.5, 90.9, 83.9, 18.8.

3-(2-Methoxybenzoyl)-2-methylbenzofuran, 6e and

B-Lactone of 2-Carboxyl-3-hydroxy-2-methyl-2'-methoxy-2,3-

dihydroisoflavone, 7e. From 0.5 g of acid 3e , a mixture

of compounds 6e and 7e was obtained. Separation by silica

gel chromatography resulted in 0.09g (24%) of 6e and 0.21 g

29

(49%) of 7e.

6e: mp 90-92°C; IR 1630, 1600, 1570 cm - 1; GC/MS (70eV).

m/e (relative intensity) 266 (M + , 100), 235(38), 234(10),

159(32), 135(44); 1H-NMR 2.4(s, 3H), 3.8(s, 3H), 7.0-7.6(m,

8H);13C-NMR 191. 1 , 163.2, 156.6, 153.2, 131.7, 130.6, 128.5,

126.2, 123.9, 123.5, 121.1, 120.6, 117.7, 112.2, 110.4,

55.4, 14.3.

Anal.Calcd. for C H 0 : C, 76.69; H, 5.26. Found: C, 13 14 3

76.67; H, 5.32.

7e: mp 110-111°C; IR 1850, 1690, 1605 cm - 1; GC/MS

(70eV), m/e (relative intensity) 310 (M+,3), 266(25),

251(43), 235( 100); * H-NMR 1.4(s, 3H), 3.7(s, 3H), 6.9-8.0(m,

8H); 1 3C-NMR (APT) 186.0(C), 169.2(C), 158.0(C), 155.4(C),

136.8(CH), 130.6(CH), 128.8(CH), 126.9(CH), 123.6(CH),

122.0(C), 121.4(CH), 118.9(C), 118.5(CH), 110.6(CH),

91.0(C), 84.0(C), 55.6(CH3), 18.0(CH3).

3-Lactone of 2-Carboxyl-3-hydroxy-2-methyl-2',4 ' ,

7-trimethoxy-2,3-dihydroisoflavone, 7f. A 0.48 g (57%)

portion of 7f was obtained from 1 g of 3f ; mp >135°C

(decom.) ; IR 1850, 1685, 1610 cm - 1; GC/MS (70eV), m/e

(relative intensity) 326 (M+-C02, 39), 312(8), 311(41),

295(100); ^ - N M R 1.5(s, 3H), 3.6(s, 3H), 3.8(s, 3H),

3.9(s , 3H) , 6.45-6.75(m, 4H), 7.4(d, 1H), 7.9(d, 1H);

13C-NMR(APT) 184.5(C), 169.5(C), 166.6(C), 161.8(C), 160.1(C),

156.3(C), 130.6(CH) , 127.6(CH), 114.7(C), 112.3(C),

30

112.2(CH) , 104.8(CH) , 101.3(CH), 98.9(CH), 90.9(C), 83.6(C),

55.8(CH3), 55.6(CH3), 55.4(CH3), 18.1(CH3).

Anal. Calcd. for C H 0 : C, 64.86; H, 4.86. Found: C, 20 18 7

65.35; H, 5.20.

General Procedure for Decarboxylation of g-Lactone,

7d-7f . A sample of the 6 -lactone was placed in a mp

capillary tube and heated in a mp apparatus. When the

temperature reached 135—140°C, small bubbles began to

appear. The temperature was kept at 150°C for 5 h. The tube

was broken and the contents recovered for analysis.

2-Methylisoflavone,8d . This isoflavone was recovered

as an oil; IR 1650 cm'1; LH-NMR 2.30(s, 3H), 7.25-8.25(m,

9H) .

2-Methyl-2'-methoxyisoflavone, 8e . This isoflavone was

also recovered as an oil; IR 1645, 1600, 1575 cm H—NMR

2.2(s , 3H), 3.8(s, 3H), 7.0-8.2(m, 8H).

2-Methyl-2',4',7-trimethoxyisoflavone, 8F. This

isoflavone was recovered as a crystalline solid; mp 185-187

°C; IR 1625, 1610 CIR'VH-NMR 2.2(s, 3H), 3.75(s, 3H),

3.8 5(S, 3H), 3.90(S , 3H), 6.6(M, 2H), 6.9(M, 2H), 7.L(M,

2H) , 8.1(d , 1H); L 3C-NMR(APT) 176.2(C), 163.7(C), 163.5(C),

160.9(C), 158.3(C), 157.6(C), 132.4(CH), 127.7(CH),

119.4(C), 117.2(C), 114.7(C), 113.8(CH), 104.7(CH),

99.9(CH), 99.0(CH) , 55.7(CH3), 55.6(CH3), 55.4(CH3), 19.2(CH3)

31

Anal. Calcd. for C H 0 : C, 69.94; H, 5.52. Found: C, 19 18 5

69.86; H , 5 .63.

B. Intramolecular [2+21 Ketene Cvcloaddition Reactions

Using Sodium Acetate and Acetic Anhydride.

6-Methyl-1-phenyl-2-oxa-3,4-benzobicyclo[3.2.01heptan

-7-one. 11a A 0.5g (1.87 mmol) portion of

[(o-propenylphenoxy)phenyl1acetic acid was refluxed with 2.0

g of sodium acetate and 15 mL of acetic anhydride for 4 h.

The reaction mixture was poured into a cold dilute NaOH

solution and extracted with ether. The ether extract was

dried over anhydrous magnesium sulfate and then evaporated

to give 0.5 g (90%) of 10a: IR 1760, 1680,1605, 1690 cm - 1;

GC/MS (70eV) m/e(relative intensity) 292(M+ , 13), 250(M+

-42, 78), 235(11), 222(27), 221(47), 205(59), 194(29),

178(22), 165(40), 42(100); 1H-NMR 1.9(s, 3H), 2.15(s, 3H),

3.8 ( s, 1H), 6.8-7.6(m, 10H);13C-NMR 166.8, 162.1, 137.5,

136.2, 134.1, 128.7, 128.5, 128.2, 127.9, 125.6,124.4, 120.6,

117.7, 93.7, 55.3, 20.6, 12.3. Compound 10a was treated with

a 50% aqueous potassium hydroxide solution containing

methanol. The methanol was removed under reduced pressure

and the aqueous residue extracted with ether. Upon drying

the ether extract over anhydrous magnesium sulfate, the

ether was evaporated to yield 0.3 g (64%) of lias mp 160-162

°C (lit. 162-163 °C [101). GC/MS 250(M+ , 2.0), 207(7.9),

32

194(100); The IR and NMR spectra were identical with those

previously reported [10],

Compounds lib and 11c were obtained by applying similar

procedures to acids 9b and 9c.

10b : IR 1760, 1690 cm" 1; GC/MS (70eV) m/e (relative

intensity) 244(M + ,22.9), 202(M + -42, 51.6), 187(46.7),

173(100). lib : IR 1780, 1590 cm" 1; GC/MS(70eV) m/e

(relative intensity) 202(M + ,1.0), 159(58.0), 146(86.3),

131(100). The NMR spectra of lib were identical with those

previously reported [10].

10c : IR 1760, 1680, 1590 cm - 1; GC/MS (70eV)

m/e(relative intensity) 258(M + , 13.3), 216(M + -42, 29.4),

201(34.9), 187(21.1), 174(36.8), 145(47.3). 11c : IR 1780,

1610, 1590 c m - 1 ; GC/MS (70eV), m/e (relative intensity)

173[M +-43(i-propyl), 23.6], 160(28.1), 145(100).

Cycloaddition of 3d and 3e Using Sodium Acetate and

Acetic Anhydride. A 0.5 g portion of 3d was refluxed with

1.5 eq of acetic anhydride and 2.0 eq of sodium acetate in

30 mL of benzene for 24 h. The reaction mixture was cooled

and filtered. The IR spectrum of the concentrated filtrate

revealed a strong 3-lactone peak at 1850 c m - 1 . Rotary

chromatography of the filtrate resulted in 0.1 g of 6d (25%)

and 0.08g of 7d (17%).

A 0.1 g portion of 3e was treated as described above.

An IR spectrum of an aliquot of the reaction mixture

33

revealed a strong 3-lactone peak at 1850 c m - 1 . Thin layer

chromatography revealed two spots with the same Rf value as

characterized for 6e and 7e. Preparative thin layer

chromatography gave a trace of 6e and 7e, which were

identified by IR and GC/MS.

General Procedure for Intramolecular Cycloadditions

Using Sodium Acetate and Acetic Anhydride for the

Preparation of Benzofurans

Method A. A 0.4 to 1.5 g portion of the

(o-carbonylphenoxy)acetic acid was treated with 10 mL of

acetic anhydride containing 2.0 g of sodium acetate and

refluxed under nitrogen atmosphere for 4-6 h. The reaction

mixture was cooled and diluted with 30 mL of benzene. This

mixture was cooled in an ice bath and 10-20% aqueous sodium

hydroxide solution was added with stirring. The benzene

layer was separated and dried over anhydrous magnesium

sulfate. Upon evaporation of the benzene under reduced

pressure, the residue was chromatographed over silica gel

using a rotary chromatography employing hexane as an eluting

solvent.

Method B. A 0.4 to 1.5 g portion of the

(o-carbonylphenoxy)acetic acid was dissolved in dry benzene

containing 1.5 eq of acetic anhydride and 2.0 eq of sodium

acetate. This mixture was refluxed for 18-24 h under a

34

nitrogen atmosphere. The reaction mixture was washed with 20

mL of 5% aqueous NaOH solution. The benzene solution was

then washed with water and dried over anhydrous magnesium

sulfate. The benzene layer was removed and the residue was

chromatographed as described above.

Benzofuran, 12b. From 1.5 g of 12a, 0.3 g (30%) of

oily 12b was obtained by Method A. No product was obtained

by Method B. The spectra data were identical with those in

the literature [11].

2-Methylbenzofuran, 13b. From 0.97 g of 13a, 0.34 g

(52%) of 13b was obtained by Method A. The compound 13b was

obtained by Method B in 31% yield; GC/MS (70eV) m/e

(relative intensity) 132(M+,65.4), 131(100), 103(13.2),

77(17.2). The spectra data were identical with those in the

literature [12]-

2-Phenylbenzofuran, 14b. From 0.5 g of 14a, 0.25 g

(66%) 14b was obtained; mp 120-122°C. (lit. 120°C) The

spectra were identical as those reported in the literature.

[13].

3-Methylbenzofuran, 15b. From 1 g of 15a, 0.5 g (74%)

of 15b was obtained; GC/MS (70eV) m/e (relative intensity)

132(M+, 66.7), 131( 100), 103(20.2), 77(21.2); The spectral

35

data were identical with those in the literature [14] .

2-phenyl-3-(2 '-phenylethyl)benzofuran , 16b. From 0.9

g of 16a, 0.65 g (87%) of 16b was obtained; GC/MS (70eV) m/e

( J-Q lative intensity) 2 9 8 (M ,10.8), 207(100), 179(32.6); The

spectral data were identical with those in the

literature [15].

6-Methoxy-2,3-diphenylbenzofuran,17b. From 0.4 g of

17a, 0.25 g (75%) of 17b was obtained; mp 120-122°C;(lit.

120-121°C) GC/MS (70eV) m/e (relative intensity) 300(M+»

100), 285(72.6), 228(20.8); The spectral data were

identical with those in the literature [15].

1—Phenylcyclopentene, 18.[16] Method A was used for

the preparation of 5-benzoylpentanoic acid and the reflux

time was 10 h. IR 2965, 2860, 1595 cm - 1; GC/MS (70eV), m/e

(relative intensity) 144(M+,78), 143(64), 129(100), 116(10),

115(51), 91(12), 77(13); *H-NMR 2.l(m, 2H), 2.6(m, 2H),

2.8(m, 2H), 6.25(t, 1H), 7.2-7.6(m, 5H);13C-NMR 142.5,

136.9, 128.3, 126.8, 126.1, 125.6, 33.4, 33.2, 23.4.

36

Part II. N,N-Disubstituted Aminoketenes.

A. Cycloadditions of N-Aryl-N-alkylaminoketenes with

Cycloalkenes

N-Aryl-N-alkyl Glycine Hydrochloride, 19a-19c . Ethyl

N-phenyl-N-methyl aminoacetate, ethyl N-phenyl-N-ethyl

aminoacetate and ethyl N-(p-tolyl)-N-methyl aminoacetate

were prepared by literature procedures in near quantitative

yield.[17] The hydrolysis of these esters was accomplished

by the following procedures. A 10 g portion of ethyl

N-phenyl-N-methyl aminoacetate was mixed with 150 mL of 10%

aqueous HC1 solution and refluxed for 3 h. After evaporating

about 100 mL of water, 150 mL of benzene were added and

azeotropic distillation was performed. During the

distillation, the solid N-phenyl-N-methyl glycine

hydrochloride precipitated. Filtration , washing with

acetone and drying resulted in 8.5 g of white solid

(19a),(82%); mp 217-219°C. N-Phenyl-N-ethyl glycine

hydrochloride and N-(p-tolyl)-N-methyl glycine hydrochloride

were prepared by the same procedure in 87% and 84% yields.

19b, mp 198-200°C, 19c, mp 210-211°C.

General Procedure for Preparation and Cycloaddition of

N,N-Disubstitutied Aminoketenes . The N-aryl-N-alkylglycine

hydrochlorides were stirred with 1.5-2 eq of

37

p-toluenesulfonyl chloride, 5 eq of triethylamine and 5 eq

of olefin in benzene at room temperature. The reactions were

conducted under a nitrogen atmosphere and in flame dried

glassware by using a magnetic stirrer. After 3 hours, cold

10% aqueous NaOH was added to the reaction mixture with

stirring and stirring continued for about 5 min at ice bath

temperature. The organic layer was separated and the aqueous

layer was extracted with ether and combined with the organic

layer. The combined solutions were dried over anhydrous

magnesium sulfate. After filtration and evaporation of the

solvent, the concentrated solution was mixed with a small

amount of florisil. The sample florisil was subjected to

column chromatography using 5% EtOAc-Hexane as eluting

solvent. Further purification was achieved by using rotary

preparative chromatography.

Endo-7-(N-methyl-N-phenylamino)biyclo[3.2.0]hept-2

-en-6-one, 20a .From 1g of 19a and an excess of

cyclopentadiene, 0.35g of oily 20a was obtained,(33%); IP,

1770,1600,1505 cm" 1; LH-NMR 7,2(m,2H), 6.7(m,3H), 5.8(m,lH),

5.7 5(m,1H), 5.05(dd , 1H, J=8.1Hz,2.7Hz), 3.9(m,lH),

3.4(m,1H), 2 . 8 5(s , 3H) , 2.65(m,lH), 2.45(m,lH). 1 3C-NMR(APT)

209.6(C), 148.3(C), 134.4(CH), 129.7(CH), 129.2(CH),

117.5(CH) , 112.4(CH), 77.3(CH), 54.9(CH), 46.9(CH), 35.5(CH3),

34.8(CH2); MS m/e (relative intensity) 214(M ++1, 18.4),

213(M +, 7.3), 194(100), 107(21.2).

38

Endo-7-(N-ethyl-N-phenylamino)bicyclo[3.2.0]hept-

2-en-6-one, 20b . From 2.15g of 19b and an excess of

eye 1 open tad iene , 0 . 9 g of 20b was obta med ,(39% ) ; IR>

1770,1600,1505 cm"1; 1H-NMR 7.2(m,2H), 6.7(m,3H),

5.85(m,1H), 5.7(m,1H), 5.05(dd,lH, 8.4Hz, 2.9Hz), 3.9(m,lH),

3.5 5(m,1H), 3 . 4 ( m ,2H), 2.8(m,lH), 2.5(m,lH), 1.2(t,3H).

13C-NMR(APT) 209.0(C), 146.7(C), 134.4(CH), 129.7(CH),

129.1(CH), 117.KCH),112.5(CH), 76.9(CH), 54.9(CH),

46.6(CH), 42.9(CH2), 34.9(CH2), 13.6(CH3); MS m/e (relative

intensity) 228(M++1,100) , 227(M+, 19.9), 199(21.9),

134(42.7), 122(47)

Endo-7-(N-p-tolyl-N-methylamino)bicvclo[3.2.0]hept-2

-en-6-one,20c . From 2.15 gof 19c and an excess of

cyclopentadiene, 1g of 20c was obtained, 44%; IR,

1770,1600,1505 cm-1; *H-NMR 7.2(m,2H), 6.7(m,2H), 5.8(m,lH),

5.7(m,1H), 5.2(dd , 1H, J=8.1Hz,2.7Hz), 4.0(m,lH), 3.5(m,lH),

2 .9(s , 3H) , 2.6-2.8(m,2H), 2.2(s,3H). 13C-NMR 209.0, 145.7,

133.5, 129.7, 129.a, 126.1, 112.1, 77.7, 54.1, 46.3, 35.0,

34.0, 19.4; MS m/e (relative intensity) 228(M++1, 100),

2 27(M+,11.9), 199(52.7), 160(13.0).

Endo-10-(N-methyl-N-phenylamino)bicyclo[6.2.0]decan

-9-one,21a . From 1g of 19a and an excess of cyclooctene,

0.3g of oily 21a was obtained, 23%; IR, 1770,1660,1505 cm * ;

39

lH-NMR 7.25(m,2H), 6.8(m,3H), 4.75(dd,lH, 8.7Hz,2.5Hz) ,

3.1(m,1H), 2.9(s,3H), 2.5(m,lH), 2.0-1.2(m,12H).

13C-NMR(APT) 211.0(C) , 149.1(C), 129.2(CH), 118.HCH),

113.9(CH), 78.9(CH) , 58.0(CH), 57.0(CH2), 35.4(CH3),

34.8 (CH ) , 30 .6 (CH2 ) , 28.8(CH2), 27.6(CH2), 26.0(CH2),

25.1(CH2); MS m/e (relative intensity) 258(M++1, 13.5),

257(M+,2.3) , 240(9.8).

Endo-10-(N-ethyl-N-phenylamino)bicyclo[6.2.0]decan

-9-0ne, (21b) and lO-(N-ethyl-N-phenylamino)bicyclo

(6.2.01dec-10-ene-9-one, (22b) . From 2.15g of 19b and an

excess of cyclooctene, a trace of 21b and 0.75g of 22b (28%)

were obtained. 21b IR, 1765,1595,1500 cm"1; LH-NMR

7.2(m,2H), 6.7(m,3H), 4.9(dd,1H,9Hz,3Hz), 3.5(m,lH),

3.3(m,1H), 2.95(m,lH), 2.75(m,lH), 1.9-1.1(m,15H) .

13C-NMR(APT) 207.3(C), 146.9(C), 129.3(CH), 116.7(CH),

111.4(C H) , 73.8(CH) , 55.7(CH), 43.1(CH2), 37.5(CH), 30.4(CH2),

27 .5(CH2) , 25 . 6(CH2), 25.1(CH2), 23.9(CH2), 20.7(CH2),

13.8(CH3); MS m/e (relative intensity) 271(M+, 2.2),

135(10.7), 135( 100), 106(22.9). 22b IR,- 1740, 1620, 1600,

1500 cm"1; GC/MS(70eV), m/e(relative intensity) 269(Mt 5.6),

212(100), 144(10.3), 104(31); 1H-NMR 7.3(m,2H), 6.9(m,3H),

3.8(m,2H), 3.3(m,1H), 2.2-1.4(m,10H), 1.2(t,3H);

13

C-NMR(APT) 190.1(C), 154.6(C), 143.8 (C), 140.6(C),

128.9(CH), 121.7(CH), 119.9(CH), 57.8(CH), 44.3(CH2),

29.6(CH2), 28.9(CH2), 27.7(CH2), 26.2(CH2), 24.1(CH2),

40

23.2(CH 2)t 14.3(CH 3)

Endo-10-(N-p-tolyl-N-methylamino)bicyclo[6.2.Oldecan

-9-one,21c . From 1g of 19c and an excess of cyclooctene, a

-1 1

trace of 21c was obtained. IR, 1755, 1605, 1510 cm ; H-NMR

7.1(d,2H) , 6 . 6(d , 2H ) , 4.9(dd,1H,9.3Hz,2.4Hz), 2.95(s,3H),

2.9-2.85(m,2H) , 2.2(s,3H), 1.2-1.9(m,12H); l 3C-NMR 208.1 ,

146.3, 129.7, 126.3, 111.7, 74.3, 55.6, 38.1, 35.4, 30.5,

27.6, 25.9, 25.7, 24.1, 20.7, 20.2; MS m/e (relative

intensity) 272(M ++1, 100), 243(36.9), 160(20.4), 132(35.9).

Endo-9-(N-methyl-N-phenylamino)bicyclo[5.2.0]nonane

-8-one,23a . From 1g of 19a and excess of cycloheptene, 0.3g

of 23a was obtained,(25%); IR, 1765, 1600,1505 cm" 1; 1H-NMR

7.25(m,2H), 6 . 75(3H) , 4.9(dd,lH, 8.7Hz, 2.6Hz),

3.3-3.35(m,1H), 3.1(s,3H), 2.9(m,lH), 2.0-1.2(m,10H);

1 3C-NMR(APT) 208.5(C), 148.3(C), 129.2(CH), 117.2(CH),

111.7(CH) , 72.0(CH) , 56.7(CH), 38.1(CH), 35.5(CH 3), 32.1(CH 2)

30.3(CH 2) , 27.8(CH 2), 26.5(CH 2), 25.4(CH 2); MS m/e

(relative intensity) 244(M ++1, 100), 243(M +, 12.9),

215(45.5), 144(26.7).

Endo-9-(N-ethyl-N-phenylamino)bicyclo [5.2.0]nonane

-8-one, 23b and 9-(N-ethyl-N-phenylamino)bicyclo[5.2.0]

non-9-ene-8-one, 24b . From 2.15g of 19b and a excess of

cycloheptene, a trace of 23b and 0.85g of 24b (34%) were

41

obtained. 23b IR, 1760, 1600,1505 cm" 1; ^ - N M R

7.25(m,2H), 6.75(m,3H), 4.85(dd,lH, 9Hz,3Hz), 3.5-2.8(m,4H),

2-1(m,13H); 1 3C-NMR(APT) 208.1(C), 147.1(C), 129.3(CH),

116.8(CH) , 111.7(CH), 71.8(CH), 56.7(CH), 43.1(CH2),

37.5(CH), 31. 9(CH 2)» 26.2(CH2), 27.7(CH2), 25.4(CH2),

22.7(CH2) , 13.8(CH3 ); MS m/e (relative intensity) 258(M++1,

100), 257(M+ , 14.4), 229(16.5). 24b IR, 1740, 1620, 1600,

+

1500 cm" 1; GC/MS(70eV), m/e (relative intensity) 255(M,5.5),

227(7.0), 198(100), 104(16.7), 77(32.2); lH-NMR 7.3(m,2H),

6.9(m,3H), 3.8(m,2H), 3.3(m,lH), 2.4-1.15(m,13H);

1 3C-NMR(APT) 189.0(C), 153.1(C), 143.4(C), 139.3(C),

128.8(CH), 122.1(CH), 120.0(CH), 59.1(CH), 44.3(CH 2),

31.9(CH2)f 31.1(CH2)r 30.4(CH 2), 28.9(CH2), 27.3(CH 2),

14.3(CH3).

Endo-9-(N-p-tolyl-N-methylamino)bicyclo[5.2.0]nonane,

23c . From 1g of 19c and an excess of cycloheptene,a trace

of 23c was obtained. IR, 1760,1610,1515 cm" 1; LH-NMR

7 .1(d , 2H) , 6.7(d , 2H) , 4.7(dd,1H , 8Hz,2.7Hz), 3.1(m,lH),

2.8(s , 3H) , 2.4(m,1H), 2.2(s,3H), 2-1.2(m,10H); 1 3C-NMR

209.5, 146.0, 128.5, 126.6, 113.6, 74.5, 58.3, 35.2, 34.4,

32.0, 30.9, 29.0, 27.7, 25.7, 19.2; MS m/e (relative

intensity) 258(M++1, 100), 257(M+,14.7), 229(58.8).

3-Acetoxy-l,2-Dimethylindole,26

N-phenyl-N-methylalanine hydrochloride, 25 was prepared from

42

aniline and ethyl a-bromo-propionate, followed by

methylation and hydrolysis. Mp 178-180°C. A 0.5 g portion of

25 was refluxed with 15 mL of acetic anhydride and 2 g of

sodium acetate for 5 h. Usual workup and column

chromatography gave 0.4 g of compound 26,(85%); IR,

1745,1585 cm"1; ^ - N M R 7.4-7.1(mf4H), 3.6(s,3H), 2.4(s,3H),

2.3(s,3H); 13C-NMR(APT), 167.9(C), 143.1(C), 126.0(C),

125.8(C), 124.2(CH), 120.5(C), 119.4(CH), 116.6(CH),

109.0 (CH) , 29 .5 (CH3 ) , 20.6(CH3), 9.1(CH'3).

3-Acetoxyl-l-Ethylindole, (27b) and Exo-7-(N-ethvl

-N-phenylamino)bicyclo{3.2.0]hept-2-en-6-one,(28b) . A 2.15

g portion of 19b was refluxed with 10 mL of acetic

anhydride, 4 g of sodium acetate and 8 g cyclopentadiene

for 3 h. The reaction mixture was poured into a cold 10%

aqueous NaOH solution. The aqueous solution was extracted

with ether. The ether solution was dried over anhydrous

magnesium sulfate. After evaporation of the ether, the

concentrated ether solution was subjected to column and

rotary thin layer chromatography. A 0.3 g portion of 27b

(15%) and 0.4 g of 28b(18%) were obtained. 27b IR,

1740,1610 cm'1; LH-NMR 8.1(d,lH), 7.4-7.2(m,4H), 4.2(q,2H),

2.4(s,3H), 1.4(t,3H). 13C-NMR(APT) 168.8(C), 132.7(C),

129.3(C), 122.2(CH), 120.2(C), 119.2(CH), 117.6(CH),

116.1(CH), 109 . 3 (CH) , 40. 9 (CH 2) , 20.9(CH3), 15.4(CH3); MS

m/e (relative intensity) 203(M+, 19.6), 161(84.3), 146(100).

43

28b IR, 1735, 1590, 1495 c n T ^ H - N M R 7.3(m,2H), 6.8(m,3H),

6.6(m,lH), 6.3(m,1H), 3.7(t,lH), 3.45(m,lH), 3.35(m,lH),

3.25(m,1H), 3.05(m,1H), 2.4(m,lH), 2.2(m,lH), 1.9(t, 3H);

13

C-NMR, 211.3, 147.8, 142.0, 133.7, 128.9, 129.1, 116.8,

60.3, 54.3, 46.2, 45.7, 44.2, 13.1; MS m/e (relative

intensity) 228(M ++1, 76.6), 227(M ,12.9), 199(53.1),

134(100).

3-Acetoxyl-l,5-Dimethylindole,(27c) and Exo-7-(N-p-

tolyl-N-methylamino)bicyclo[3.2.0]hept-2-ene-6-one,(28c) .

By the same procedure described as above, 0.3 g of 27c (15%)

and 0.3 g of 28c (13%) were obtained from 2.15 g of 19c.

27c IR, 1740, 1610 cm - 1; 1H-NMR 7.2-7(m,5H), 3.6(s,3H),

2 .4(s , 3H) , 2.35(s , 3H); 1 3C-NMR(APT), 168.8(C), 132.3(C),

128.7(C), 128.6(C), 124.1(CH), 120.3(C), 118.0(CH),

117.0(C), 109.1(C), 32.8(CH 3), 21.4(CH 3), 20.7(CH 3); MS m/e

(relative intensity) 204(M ++l,29.3), 203(M +,15.4), 160(100),

146(12.8). 28c IR, 1730, 1610,1510 cm"1? ^H-NMR

7.1(d,2H) , 6.8(d,2H), 6.6(m,lH), 6.3(m,lH), 3.7(d,lH),

3.2(m,1H), 3.1(m,1H), 2.9(s,3H), 2.4(m,lH), 2.3(s,3H),

2.2(m,1H); 1 3C-NMR(APT), 212.0(C), 147.8(C), 142.5(CH),

133.7(CH), 129 . 6(CH), 128.3(C), 115.4(CH), 61.6(CH),

54.4(CH), 46.8(C), 45.4(CH 2), 37.4(CH 3), 20.4(CH 3); MS m/e

(relative intensity) 228(M ++1, 21.9), 227(M +,3.7), 199(8.3).

44

B. Cycloadditions of N-Alkyl-N-Arylaminoketenes with

Imines. The Preparation of cis-3-Amino-2-azetidinones

The imines were prepared by standard literature

procedures.[18,19]

General Procedure for the Preparation of 3-Lactams . An

N-alkyl-N-arylglycine hydrochloride was stirred with 1 eq of

p-toluenesulfonyl chloride, 1 eq of an imine and 4-5 eq of

triethylamine in benzene at room temperature. The reactions

were conducted under a nitrogen atmosphere and in flame

dried glassware by using a magnetic stirrer. After 8 to 10

hours, cold 5% aqueous NaOH solution was added to the

reaction mixture. The organic layer was separated and the

aqueous layer was extracted with benzene and combined with

the organic layer. The benzene solution was washed with

water and dried over anhydrous magnesium sulfate. After

filtration and evaporation of the solvent, the concentrated

solution was subjected to the florisil column chromatography

using 3% EtOAc-Hexane to 15% EtOAc-Hexane as an eluting

solvent. In most cases, a crystalline product was obtained

after the evaporation of eluting solvent. Analytical samples

were obtained by recrystalization or rotary thin-layer

preparative chromatography.

C is-1,4-Diphenyl-3-(N-methyl-N-phenylamino)-2

-azetidinone,29. From 1g of 19a and the N-phenylimine of

45

benzaldehyde, 1.5 g(64%) of compound 29 was obtained; mp

180-182°C; IR 1735, 1605, 1510 cm" 1; lH-NMR

7.5-6.6(m,15H), 5.48(d,lH, J=5.lHz), 5.42(d, 1H, J=5.lHz),

2.6(s , 3H) ; I 3C-NMR(APT) 164.2(C), 147.9(C), 137.7(C),

134.1(C), 129.4(CH), 129.1(CH), 128.4(CH), 127.9(CH),

127.0(CH), 124.5(CH), 117.8(CH), 117.4(CH), 112.2(CH),

70.9(CH), 62.3(CH), 35.6(CH3); m / e (relative intensity)

329(M+ +1, 35.5), 329(M +, 10.1) , 182( 12.2), 118( 100)

Anal. Calcd for C2 2

H 2 0 N 2 ° : N ' 8 , 5 3 ? F o u n d : Nf 8.51.

C is-1,4-Diphenyl-3-(N-ethyl-N-phenylamino)

— 2—azetidinone,30 . From 1.1g of 19b and the N—phenylimine

of benzaldehyde, 1.2 g(70%) of compound 30 was obtained; mp

149-150°C; IR 1735, 1605, 1510 cm" 1; 1H-NMR 7.5-6.8(m,

15H), 5.46(d,1H, J=5.1Hz), 5.42(d, 1H, J=5.lHz) 3.4(m, 1H),

2.95(m,1H), 0.9(t, 3H); 1 3C-NMR(APT) 164.2(C), 146.7(C),

137.8(C), 134.2(C), 129.2(CH), 129.1(CH), 128.4(CH),

127.9(CH), 127.2(CH), 124.4(CH), 117.7(CH), 117.4(CH),

113.0(CH) , 71.6(CH), 62,6(CH), 43.6(CH2), 13.1(CH3); MS m/e

(relative intesity) 343(M+ + 1 , 100), 342(M +,96.7) ,

182(15.4).

C is-1,4-d iphenyl-3-(N-p-toly1-N-methylamino)-2

—azetidinone, 31 . From 1.8 g of 19c and the N—phenylimine of

benzaldehyde, 1.8g (63%) of compound 31 was obtained, mp

207-209°C; IR 1735, 1605, 1510 cm" 1; 1H-NMR 7.6-7.1(m,10H),

46

7 .1(d , 2H) , 6 . 6 (d , 2H) , 5.46(d,lH, J=5.lHz)f 5.42(d,

13 lH,J=5.lHz), 2 . 6 ( s , 3H) , 2.3(s,3H); C-NMR 164.3, 145.9,

134.3, 130.2, 130.0, 129.5, 129.1, 128.4, 127.9, 127.0,

124.4, 117.4, 112.5, 71.2, 62.5, 45.8, 35.6;MSm/e (relative

intensity) 343(M++1, 100).

Anal. Calcd for C H N 0: N, 8.19; Found: N, 8.11. 23 22 2

Cis-l-Phenyl-3-(N-methy1-N-phenylamino)-4-(2-

phenylethenyl)-2-azetidinone, 32 . From 1.5gof 19a and the

N-phenylimine of cinnamaldehyde, 1.9 g (71%) of compound 32

was obtained; mp 125-127°C; IR 1730, 1600, 1500 cm"1; ^H-NMR

7.6-6.6(m, 16H), 6.2(dd,lH, J=16Hz, 1.5Hz), 5.3(d, 1H,

J=4.8Hz), 5.0(dd, 1H, J = 7.5Hz, 4.8Hz), 3.2(s, 3H).

13C-NMR(APT) 163.7(C), 148.4(C), 137.9(C), 135.8(C),

135.1(CH), 129.2(CH) , 128.6(CH), 128.1(CH), 126.5(CH),

124.5(CH), 123.2(CH), 118.1(CH), 117.2(CH), 112.7(CH),

112.6(CH), 70.7(CH), 61.6(CH), 36.3(CH3).

Anal. Calcd for 0: C, 81.35; H, 6.21; N, 7.91; ^ " fa fa fa

Found; C, 81.19; H, 6.11; N, 7.83.

C is-1-Phenyl-3-(N-p-tolyl-N-methylamino)-4-(2-

phenylethenyl)-2-azetidinone,33 . From 2.15gof 19c and the

N-phenylimine of cinnamaldehyde, 2.1 g (57%) of compound 33

was obtained; mp 194-195°C; IR 1730, 1600, 1500 cm - 1; ^ - N M R

7 . 5-6.5(m,15H), 6.1(dd, 1H, J=16Hz, 7.5Hz), 5.2

(d, 1H, J=4.8Hz), 4.9(dd, 1H, J=7.5Hz, 4.8Hz), 3.1(s, 3H),

47

2.l(s, 3H); 1 3C-NMR(APT) 164.2(C), 146.3(C), 137.9(C),

135.9(C), 134.9(CH), 129.7(CH), 129.2(CH), 128.6(CH),

128.1(CH), 127.4(CH), 126.5(CH), 123.4(CH), 123.3(CH),

117.2(CH), 112.9(CH), 71.0(CH), 61.8(CH), 36.5(CH3),

20 . 3 (CH 3) .

Anal. Calcd for. C H N O: N, 7.61? Found: N, 7.46. 25 24 2

C is-l-Pheny1-3-(N-ethy1-N-phenylamino)-4-(p-

chlorophenyl)-2-azetidinone,34 . From 2.15g of 19b and the

N-phenylimine of p-chlorobenzaldehyde, 2g(53%) of compound

34 was obtained; mp 149-150°C; 1H-NMR 7.5-6.6(m, 14H),

5 .43(d , 1H, J=5.1Hz), 5 . 37(d, 1H, J=5.lHz), 3.3(m,lH),

3.0(m, 1H), 1.0(t, 3H);l3C-NMR 163.8, 146.5, 137.4, 133.8,

132.8, 129.7, 129.3, 129.1, 128.6, 124.5, 117.9, 117.2,

113.0, 71.4, 61.9, 43.7, 13.2.

Anal. Calcd for C H N CIO: C, 73.33; H, 5.57; N, 23 21 2

7.43; Found: 73.38; H, 5.50,; N, 7.40.

Cis-1-Pheny1-3-(N-methy1-N-phenylamino)-4-(p-

chlorophenyl)-2-azetidinone, 35 . From 1.5 gof 19a and the

N-phenylimine of p-chlorobenzaldehyde, 1.7g (61%) of

compound 35 was obtained; mp 157-160 C; ^H-NMR

7.5-6.7(m,14H), 5.5(d, 1H, J=5.lHz), 5.4(d,lH, J=5.lHz),

2.7(s, 3H); I3C-NMR(APT) 163.8(C), 147.4(C), 137.4(C),

133.9(C), 132,8(C), 129.3(CH), 129.2(CH), 128.7(CH),

128.4(CH), 124,7(CH), 118.0(CH), 117.3(CH), 112.3(CH),

48

71.0(CH) , 61.8(CH) , 35.7(CH3).

Anal. Calcd for C H N OC1: C, 72.83; Hf 5.24; N, 22 19 2

7.72; Found: C, 72.67; H, 5.34; N, 7.66.

C is-1-(t-Butyl)-3-(N-methyl-N-phenylamino)-

4-phenyl-2-azet idinone,36 . From 2 g of 19a and the

N-(t-butyl)imine of benzaldehyde, 2.1g (68%) of compound 36

was obtained; mp 139-140°C; IR 1735, 1600, 1510 cm - 1; *H-NMR

7.3-7.3(m,7H), 6.7-6.5(m, 3H), 5.08(d, 1H, J=4.8Hz), 5.01(d,

1H, J = 4.8Hz), 2 . 9(s , 3H), 1.4(s, 9H); I 3C-NMR 166.2, 147.7,

136.7, 128.7, 128.1, 127.8, 127.5, 117.1, 111.8, 70.2, 62.7,

54.5, 35.9, 28.1; MS m/e (relative intensity) 309(M++1, 100)

308(M"t 10.6), 209( 18), 162( 17), 118(92).

C is-1-(t-Butyl)-3-(N-ethyl-N-phenylamino)-4-

phenyl-2-azetidinone,37 . From 2.15gof 19b and the

N-(t-butyl)imine of benzaldehyde, 1.5g (47%) of oily

compound 37 was obtained; IR 1735, 1600, 1510 cm - 1; lH-NMR

7.0-6.1(m,10H), 4.61(d, 1H, J=4.8 Hz), 4.57(d,lH, J=4.8Hz),

3.2(m, 1H), 2.8(m, 1H), 1.0(s,9H), 0.9(t,3H);13C-NMR 165.9,

146.3, 136.6, 129.1, 128.7, 128.5, 127.5, 116.8, 112.4,

70.0, 62.5, 54.3, 43.7, 27.9, 13.1; MS m/e (relative

intensity) 323(M++1, 2.9), 276(1.6), 178(4.4).

C is-1-(p-Methoxyphenyl)-3-(N-ethyl-N-phenylamino)-4

49

-(p-methoxypheny1)-2-azetidinone,38• From 1.8g of 19b and

the N-(p-methoxyphenyl)imine of p-methoxybenzaldehyde, 2.3 g

(68%) of compound 38 was obtained; mp 125-127°C; IR 1730,

1610, 1530 cm" 1; lH-NMR 7.4-6.6(m, 13H), 5,37(d,lH,

J=5.0Hz), 5.32(d, 1H, J=5.0Hz), 3.8(s,3H), 3.7(s,3H), 3.4(m,

1H), 3.0(m,1H),1.0(t, 3H); 1 3C-NMR(APT) 163.5(C), 159.2(C),

156.3(C), 146.7(C), 131.3(C), 129.0(CH), 128.4(CH),

126.1(C), 118.6(CH), 117.5(CH), 114.4(CH), 113.8(CH),

112.8(CH), 71.3(CH), 62.3(CH), 55.5(CH 3), 55.2(CH 3),

43.7(CH 2), 13.2(CH 3).

Anal. Calcd for C H N 0 : C,74.62; H, 6.47; N,6.96; Zo Zb 2. 3

Found: C 74.52; H, 6.55; N, 6.92.

C is-1-(p-Methoxypheny1)-3-(N-methy1-N-phenylamino)

-4-(p-methoxypheny1)-2-azetidinone,39. From 1.5g of 19a

and the N-(p-methoxyphenyl)imine of p-methoxybenzaldehyde,

2.1 g(73%) of compound 39 was obtained; mp 150-153°C; IR

1730, 1610, 1530 c m - 1 ; ^ H - N M R 7.4-6.6(m, 13H), 5.42(d, 1H,

J=4.8Hz), 5.35(d , 1H, J=4.8Hz), 3.8(s, 3H), 3.7(s,3H),

2.8(s,3H); 1 3C-NMR 163.5, 159.3, 156.3, 147.9, 131.3, 129.0,

128.2, 126.0, 118.7, 117.6, 114.4, 113.8, 112.2, 70.8, 62.1,

55.5, 55.1, 35.7.

Anal. Calcd for C2 4

H2 4

N2 ° 3 : C, 74.23; H,6.18; N,7.21;

Found: C, 73.98; H, 6.10; N,7.21.

C is-1-(p-Methoxypheny1)-3-(N-methy1-N-phenylamino)

50

-4-phenyl-2-azetidinone, 40. From 1.5g of 19a and the

N-phenylimine of p-methoxybenzaldehyde, 1.85g (70%) of

compound 40 was obtained; mp 160-163 C; IR 1735, 1610, 1520

cm" 1; 1H-NMR 7.4-6.6(m, 14H), 5.47(d, 1H, J=4.8Hz), 5.40(d,

1H, J = 4.8Hz), 3.8(s , 3H) , 2.7(s,3H); 1 3C-NMR 164.0, 156.4 ,

147.9, 134.2, 131.3, 129.0, 128.3, 127.9, 127.0, 118.6,

117.7, 114.4, 112.2, 70.9, 62.4, 55.4, 35.6.

Anal. Calcd for C H N 0 : C, 77.09; H, 6.14; N, 7.82; 23 22 2 2

Found: C, 76.87; H, 5.97, N, 7.76.

C is-l-Phenyl-3-(N-ethyl-N-phenylamino)-4-

(o-nitrophenyl)-2-azetidinone, 41. From 1.5g of 19b and

the N-phenylimine of o-nitrobenzaldehyde, 1.9g (68%) of

compound 41 was obtained; mp 170-172°C; IR 1740, 1600, 1510

cm - 1 . 1 ; H-NMR 8.2-6.8(m, 14H), 6.3(d,lH, J=5.4Hz), 5.6(d,

1H, J=5.4Hz), 3.2(m, 1H), 2.8(m, 1H), 0.7(t,3H); 1 3C-NMR(APT)

165.6(C), 148.1(C), 146.4(C), 137.7(C), 133.7(C),

131.6(CH), 129.4(CH) , 129.2(CH), 129.0(CH), 128.8(CH),

125.7(CH), 124.7(CH), 119.8(CH), 117.2(CH), 116.3(CH),

73.8(CH) , 60.9(CH) , 43.7(CH2)f 12.5(CH3).

Anal. Calcd for C H N 0 ; C, 71.32; H,5.42; N,10.85; 23 21 3 3

Found: C, 71.20,; H, 5.37; N, 10.81.

C is-l-Phenyl-3-(N-methyl-N-phenylamino)-4-(o-

nitrophenyl)-2-azetidinone, 42 From 2 g of 19a and the

N-phenylimine of o-nitrobenzaldehyde, 2.3 g (62%) of compound

51

42 was obtained; mp 202-203°C; IR 1740, 1600, 1510 cm 1;

*H-NMR 8.2-6.8(m, 14H), 6.3(d,lh, J=5.4Hz), 5.7(d, 1H,

J=5.4Hz), 2.4(s,3H); 13C-NMR(APT) 165.3(C), 148.3(C),

148.0(C), 137.9(C), 134.0(CH), 131.8(C), 129.8(CH),

129.5(CH), 129.4(CH), 129.3(CH), 126.1(CH), 125.1(CH),

119.4(CH) , 117.5(CH) , 113.7(CH), 72.8(CH), 61.3(CH),

35.9(CH3 ) .

Anal. Calcd for C H N 0 : C, 70.77; H, 5.09; N,11.26; 22 19 3 3

Found; C, 70.69; H, 4.98; N, 11.23.

C is-1-(p-Methoxyphenyl)-3-(N-methyl-N-phenylamino)

-4-(p-nitrophenyl)-2-azetidinone, 43 From 1.5g of 19a and

the N-(p-methoxylpheny1)imine of p-nitrobenzaldehyde, 2.15g

(72%) of compound 43 was obtained; mp 135-137°C; IR 1745,

1600,1520 cm"1; 1H-NMR 7.9-6.5(m, 13H), 5.52(d, 1H,

J=4.8Hz), 5.46(d, 1H, J=4.8Hz), 3.8(s, 3H), 2.7(s, 3H);

13C-NMR(APT) 162.0(C), 156.6(C), 147.6(C), 147.2(C), 142.2(C),

130.7(C), 129.5(CH), 129.1(CH), 127.8(CH), 123.3(CH)r

118.2(CH) , 114.4(CH), 112.KCH), 71.4(CH), 61.8(CH),

55.3(CH3), 35.5(CH3).

Anal. Calcd for C H N O : C, 68.48; H, 5.21; N, 23 21 3 4

10.42; Found: C, 68.29; H, 5.22; N,10.36.

C is-1-Phenyl-3-(N-methyl-N-phenylamino)-4-(o-

methyoxyphenyl)-2-azetidinone,44a and Trans-l-Phenyl-3-(N-

methyl-N-phenylamino)-4-(o-methoxyphenyl)-2-azetidinone, 4 4b

52

From 2 g of 19a and the N-phenylimine of o-methoxy-

benzaldehyde, 1.9 g (53%) of 44a and 0.3 g (8%) of 44b

were obtained. The separation of the two isomers was

achieved by rotary chromatography with the cis isomer having

a larger Rf value than the trans isomer. 44a mp 143-145°C;

IR 1740, 1590, 1490 cm" 1; *H-NMR 7.6-6.6(m, 14H), 5.6(d,

1H, J = 4.8Hz) , 5.5(d , 1H, J = 4.8Hz), 3.1(s, 3H), 2.7(s, 3H);

13

C-NMR(APT) 165.0(C), 157.1(C), 148.2(C), 138.0(C),

129.1(CH), 128.9(CH) , 128.6(CH), 127.2(CH), 124.3(CH),

122.0(C), 120.2(CH), 117.8(CH), 112.7(CH), 112.6(CH),

109.8 (CH ) , 70 . 9 (CH ) , 58.7(CH), 54.5(CH 3), 35.5(CH 3); M S m / e

(relative intensity) 359(M ++1, 100), 358(M +,29.0),

212(24.2), 118(23.7).

Anal. Calcd for C H N 0 : C, 77.09; H, 6.14; N, 23 22 2 2

7.82; Found: C, 77.17; H, 6.22; N, 7.80.

44b mp 146-148°C ; IR 1740, 1590, 1495 c m - 1 ; XH-NMR

7.5-6.7(m, 14H), 5.3(d, 1H, J=2.5Hz) , 5.0(d, 1H, J=2.5Hz),

3.6(s , 3H), 3.0(s , 3H); 1 3C-NMR(APT) 165.3(C), 156.9(C),

148.9(C), 137.3(C), 129.3(CH), 129.0(CH), 128.9(CH),

126.6(CH) , 124.5(C), 124.1(CH), 120.9(CH), 118.6(CH),

117.5(CH) , 114.6(CH) , 110.7(CH), 76.3(CH), 55.6(CH),

55.2(CH 3), 34.7(CH 3); MS m/e (relative intensity) 359(M + +1,

100), 358(M +,30.4), 118(24.2).

53

C is-1-Phenyl-3-(N-ethyl-N-pheny1amino)-4-

(o-methoxyphenyl)-2-azetidinone, 45a and Trans-l-Phenyl-3

-(N-ethyl-N-phenylamino)-4-(o-methoxyphenyl)

-2-azetidinone,45b. From 2 . 1 5 g o f 19b and the

N-phenylimine of o-methoxybenzaldehyde, 1.7g (46%) of 45a

and 0.3 g(8%) of 45b were obtained. 45a mp 105-107°C ; IP

1740, 1600, 1500 cm" 1; 1H-NMR 7.5-6.7(m, 14H), 5.67(d,lH,

J=5.1), 5.54(d , 1H, J = 5.1), 3.5(s , 3H), 3.3(m, 1H), 2.8(m,

1H), 0.8(t, 3H); 1 3C-NMR(APT) 165.2(C), 157.2(C), 146.7(C),

137.8(C), 129.1(CH), 129.0(CH), 128.6(CH), 127.2(CH),

124 . 2(CH), 122.6(C), 120.2(CH), 117.4(CH), 117.3(CH),

113 . 8 (CH ) , 109.9 (CH) , 72.1(CH),. 58.9(CH), 54.6(CH 3), 43.1(CH2),

12.7(CH 3); MS m/e(relative intensity) 373(M ++1, 53.3),

3 7 2 (M* 81. 2), 212(46.1), 105( 100). _17b mp 136-137°C ; IR

1740, 1595, 1500 c m - 1 ; lH-NMR 7.5-6.6(m,14H), 5.35(d, 1H,

J=2.1Hz), 4.93(d,1H, J=2.1Hz), 3.7(s, 3H), 3.6(m, 2H),

1.3( t, 3H); 1 3C-NMR 166.2, 157.8, 147.9, 138.1 , 130.4,

130.1, 129.7, 127.4, 125.3, 124.7, 121.7, 119.1, 118.2,

115.7, 111.5, 76.2, 58.2, 56.0, 43.6, 14.6; MS m/e (relative

intensity) 373(M + +1, 100), 372(M +,92.7), 212(37.8).

C is—1-(p-Nitrophenyl)-3-(N-ethy1-N-phenylamino)-4-

(p-methoxypheny1)-2-azetidinone, 46a and Trans-l-(p

-Nitrophenyl)-3-(N-ethy1-N-phenylamino)-4-(p-methoxyphenyl)

-2-azetid inone,4 6b From 2 . 1 5 g o f 19b and the

N-(p-nitrophenyl)imine of p-methoxybenzaldehyde, 2.7 g (59%)

54

of 46a and 0.8 g(20%) of 46b were obtained; 46a rap

148-150 °C ; IR 1745, 1590, 1490 cm" 1; 1 H-NMR 8.2-6.7

(m,13H), 5.50(d, 1H, J=5.lHz), 5.48(d, 1H, J=5.lHz), 3.75(s,

3H), 3.8(m, 1H), 3.0(m,lH), 1.0(t, 3H); 1 3 C - N M R 164.8,

159.6, 146.4, 143.6, 142.7, 129.1, 128.2, 125.2, 124.6,

118.1, 117.3, 114.1, 113.1, 72.0, 62.8, 55.1, 43.9, 13.1; MS

m/e (relative intensity) 417(M +,2.4), 256(9.0), 240(14.3),

131(14.2), 105(100). 46b mp 205-207°C; IR 1745, 1600, 1495

cm" 1; 1 H-NMR 8.2-6.6(m, 13H), 4.95(d, 1H, J = 2.4Hz), 4.88(d,

1H, J=2.4Hz), 3.8(s , 3H), 3.6(m, 2H), 1.2(t, 3H); 1 3C-NMR

165.7, 160.2, 146.9, 144.0, 142.3, 129.4, 127.6, 127.4,

125.2, 119.5, 117.4, 115.4, 115.0, 75.5, 63.3, 55.3, 43.9,

13.9; MS m/e (relative intensity) 417(M +,8.3), 239(24.8),

132(12.1), 105(100).

Trans-l-Phenyl-3-chloro-4-(p-chlorophenyl)-2-

azetidinone, 47 . A benzene solution of 0.9q of chloroacetic

acid was added through a septa to a benzene solution of 2.5 g

of the N-phenylimine of p-chlorobenzaldehyde, 1.9 g of

p-toluenesulfonyl chloride and 4 gof triethylamine. The

addition took 1 h and the solution was stirred at room

temperature for an additional 2 h.The usual work up and

column chromatography resulted in 0.8 g(28%) of a pure

crystal 47; mp 105-106°C; IR 1765, 1610, 1490 cm" 1; 1H-NMR

7.5-7.3(m,9H), 5.2(d,lH, J = 2Hz), 4.6(d, 1H, J = 2Hz); 1 3C-NMR

160.4, 136.6, 135.5, 133.6, 129.7, 129.2, 127.5, 125.0,

55

117.5, 65.4, 63.1; MS m/e (relative intensity) 293(M +

+1,15.5), 292(M +,63.2), 214(14.5), 174(28.2), 137(47.4).

C is-l-Phenyl-3-methoxy-4-phenyl-2-azetidinone,48 This

compound was prepared by the same procedure as described

above in 52% yield; mp 139-141°C; (lit. 141-142° C [20]);

^ - N M R 7.4-7.25(m, 10H), 5.2(d,lH, J=5Hz), 4.8(d, 1H, J=5Hz),

3.1(s, 3H).

Benzoyloxyacetic acid was prepared by a literature

procedure.[21]

Trans-1,4-Diphenyl-3-benzoyloxy-2-azetidinone, 49 A

1.8 g portion of benzoyloxyacetic acid was stirred-with 1.8

g of the N-phenylimine of benzaldehyde, 1.9 g of

p-toluenesulfonyl chloride and 4 g of triethylamine at 50 ° C

for 4 h. The usual work up and column chromatography

resulted in 1.8 g of crystalline product 49, (52%); mp

130-132°C; ^ - N M R 8.15(m, 2H), 7.7-7.l(m, 13H), 5.62(d, 1H,

1 3

J=1.5Hz), 5.11(d, 1H, J=1.5Hz); C-NMR(APT) 165.4(C),

161.7(C), 136.9(C) , 135.2(C), 133.8(CH), 130.1(CH),

129.2(CH), 129.1(CH), 128.6(CH), 126.4(CH), 124.7(CH),

117.7(CH), 83.1(CH), 63.8(CH). This compound was obtained

from the reaction of benzoyloxyacetic acid chloride and the

N-phenylimine of benzaldehyde in the presence of

triethylamine in 35% yield.

56

Trans-1-(p-N itropheny1)-3-benzoyloxy-4-(p-

methoxyphenvl)-2-azetidinone,50 The reaction of 1.8 g of

benzoyloxyacetic acid with 2.56 g of the

N-(p-nitrophenyl)imine of p-methoxybenzaldehyde, 1.9 g of

p-toluenesulfony1 chloride and 4 g of triethylamine resulted

1.7 g of compound 50,(41%); IR 1755, 1705, 1580 cm"1;

1H-NMF 8.2-6.9(m, 13H), 5.6(d, 1H, J=2Hz), 5.1(d, 1H, J=2Hz),

3.8(s, 3H); 13C-NMR 165.1(C), 162.4(C), 160.4(C), 143.7(C),

141.9(C), 133.9(CH) , 130.0(CH), 128.5(CH),

127.5(C),126.5(CH), 125.9(C), 125.KCH), 117.4(CH),

114.8(CH) , 8 3.4(CH) , 63.8(CH), 55.2(CH3). This compound was

obtained from the reaction of benzoyloxyacetic acid chloride

and the N-(p-nitrophenyl)imine of p-methoxybenzaldehyde in

the presence of triethylamine in 31% yield.

General Procedure for the Preparation of &-Lactams—by.

the Acetic Anhydride, Sodium Acetate Method. A 1 g

portion of N-alkyl-N-arylaminoacetic acid hydrochloride was

refluxed with 1 eq of imine, 3g of sodium acetate and 10 mL

of acetic anhydride. After 3 h, the mixture was poured into a

cold 5% aqueous NaOH solution. The aqueous solution was

extracted with methylene chloride and the extract was dried

over magnesium sulfate. After evaporation of the solvent,

the concentrated filtrate was subjected to column

chromatography which resulted in a pure crystalline product.

57

C is—1-(p-Methoxyphenyl)-3-(N-p-tolyl-N-methylamino)

-4-(p-nitrophenyl)-2-azetidinone, 51 From 1g of 19c and

the N-(p-methoxyphenyl)imine of p-nitrobenzaldehyde, 0.5g

(26%) crystal product was obtained by column chromatography;

mp 161-163°C? LH-NMR 7.8-6.8(m, 12H), 5.2(d,lH, J=4.6Hz)

5 .1 ( d , 1H, J = 4.6Hz), 3.5(s,3H ) , 2.4(s, 3H), 2.1(s,3H);

13

C-NMR(APT) 162.9(C), 156.7(C), 147.6(C), 145.3(C),

142.4(C), 141.9(C), 129.8CH), 128.0(CH), 127.6(C),

123 . 6(CH) , 118.4(CH) , 114.6(CH), 112.4(CH), 71.9(CH),

62.KCH), 55. 5 (CH3) , 35.8(CH3), 20.3(CH3)

CHAPTER BIBLIOGRAPHY

1. Leonard, N.J.* Rapala, R.T.; Herzog, H.L.; Blout, E.R.,

J. Am. Chem. Soc. , 1949, 7_1 , 2997.

2. VanAllan, J.A., J. Org. Chem. , 1943, JU , 417.

3. Somin, I.N.; Kuznetsov, S.G., Khim. Nauka. I. Prom. ,

1959, 4 , 801.

4. Kuhn, R. ; Birkofer, L.; Moller, E.F., Ber. ,

1943, 7jil ' 9 0 0 *

5. Whalley, W.B.; Lloyd, G., J. Chem. Soc. , 1956, 3213.

6. Martynoff, M., Bull. Soc. Chim. Fr. , 1952, 1056.

7. Gowan, J. E.; Lynch, M.F.; O'Connor, N.S.,

J. Chem. Soc. , 1958, 2495.

8. Suginome, H.; Iwadare, T., Bull. Chem. Soc. Jpn. ,

1966, 39 , 1535.

9. Robertson, L.; Whalley, W.B., J. Chem. Soc. ,

1954, 1440.

10. Brady, W.T.; Giang, Y.F., J. Org. Chem. ,

1985, 50 , 5177.

11. Black, P.J.; Hefferhan, M.L., Aust. J. Chem. ,

1965, 18 , 353.

12. Nurunabi, I.B.I., Pakistan J. Sci. Inc. Res. ,

1960, 3 , 108.

13. Stetter, H.; Siehnhold, E. , Ber. , 1955, 8J3 , 271.

58

59

14. Wilholm, B. ; Thomas, A.F.; Gautschi, F.,

Tetrahedron , 1964, 2_0 , 1185.

15. Brady, W.T.; Giang, Y.F.; Marchand, A.P.; Wu, A.,

J. Org. Chem. , 1987, 5_2 , 3457.

16. Baddeley, G.; Chadwick, J.; Taylor, H.T.,

J. Chem. Soc. , 1956, 451.

17. Thorpe, W., J. Chem. Soc. , 1913, 103 , 1601.

18. Bigelow, L.A.; Eatough, H., Org. Syn. ,

Coll. Vol I, 1943, 80.

19. Layer, R.W., Chem. Rev. , 1963, 63_ , 489.

20. Arreta, A.; Lecea, B.; Palomo, C.,

J. Chem. Soc. Perkin Trans. 1 , 1987, 845.

21. Ringshaw, D.J.; Smith, H.J., J. Chem. Soc. ,

1964, 1559.

CHAPTER III

RESULTS and DISCUSSION

PART I.Intramolecular [2+2] Ketene Cycloaddition Reactions

to the Carbonyl Group.

A. Synthesis of Isoflavones and 3-Aroylbenzofurans.

Isoflavones are common constituents of plants of the

Leguminosae family. The crude preparation of isoflavones

have been used as fish narcotics [1], insecticides' and

antifungus [2, 3] for many years in Central and South

America. Benzofurans or coumarones have been widely used in

many areas but principally in pharmacology. These biological

properties have stimulated a lot of interest in the

syntheses of isoflavones and 3—aroylbenzofurans. Previous

synthesis of isoflavones fall into two main categories: (1)

Syntheses from chaleone based systems [4, 5].

60

61

Ha

M*0

0M« OKto

(2) Syntheses from deoxybenzoin precursors [6, 7]

Ck .COOEt

OH O

CICOCOOEi/py

COOH

OH O

In this study, the intramolecular [2+2] ketene

cycloaddition reaction to a carbonyl group was designed as a

key step in the synthesis of isoflavones. The starting

compounds for this synthesis are 2-methoxybenzils, la-c,

which were readily prepared by the oxidation of the

corresponding benzoins by standard literature procedures.

Demethylation of the benzils resulted in 2—hydroxybenzil

compounds, 2a-c. Conversion of these compounds to

2-carboxyalkoxybenziIs, 3a-c, was accomplished by reaction

with ethyl a-bromocarboxylates and subsequent

62

hydrolysis. The acids were converted to the corresponding

acid chlorides with a large excess of oxalyl chloride. The

acid chlorides upon treatment with triethylamine were

expected to undergo dehydrochlorination to the corresponding

phenoxyketenes, 4.

0 0 o o

U ^ ^ JU O M e / \

R, ̂ "a 1 a . R , - R , - R 3 - H 2 « , R , - R j - R3 » H b. r , - R 3 - H . R 2 « 0 M e b. R1 - R 3 - H ; R 2 - 0 M e

c, R , - f l 2 - R 3 - 0 M e c, R i - R 2 - R 3 - O M e

0 0 0 0

u ^

z'V /CH\, No Z C O O H

3a. R 1 - R 2 - R 3 - H ; Z = H b, R, - R 3 - H : R 2 ~ 0 M e . Z = H

c> r , - R 2 « R 3 « O M e . Z = H d. R 1 - R 2 - R 3 - H i Z = Me 6. R1 - R 3 » H; R 2 ~ OMe,

Z - M e

f r1 - r 2 » R 3 ~ 0 M e . Z « M e

The slow addition of a benzene solution of the acid

chloride of 3a-f to a benzene solution containing a large

excess of triethylamine resulted in the formation of

3-aroylbenzofurans, 6, and isoflavones, 8. The products are

the result of the triethylamine dehydrochlorination of the

acid chlorides to phenoxyketenes, 4, which undergo an

intramolecular [2+2] cycloaddition with one or the other of

the two carbonyl groups present to yield the expected B

-lactones. As revealed in the following scheme,

63

cycloaddition of the ketene function with the carbonyl group

bonded to the same ring results in S-lactone 5, which

readily decarboxylates to the 3-aroylbenzofurans, 6.

Conversely, cycloaddition of the ketene function to the

other carbonyl group results in the isoflavone 8-lactone, 7,

which in some instances, 7a-c , readily decarboxylate to the

isoflavones, 8, and in other instances, 7d-f, require

heating at 150°C for decarboxylation to occur.

c = o

The product distributions isoflavone or isoflavone 3

-lactone and 3-aroylbenzofurans are shown in Table 1. In

those preparations where a mixture of isoflavone or

isoflavone B-lactone and 3-aroylbenzofuran were obtained,

separation was accomplished by silica gel column

chromatography.

64

Table I. Distributions of Isoflavone or Isoflavone

B-Lactones and 3-Aroylbenzofurans

acid products yields (%) acid products yields

3a 6a 50 3d 6d 63

8a 23 7d trace

3b 6b 15 3e 6e 24

8 b 55 7e 49

3c 8c 59 3f If 57

The isoflavone or isoflavone B-lactones and

3-aroylbenzofurans were easily differentiated by GC/MS. The

3-aroylbenzofurans consistently reveal the major mass

fragments as shown in the follwincj scheme, while the

isoflavones and isoflavone B-lactones do not.

c=0 •nd R, C—O

CT

It is apparent from the data in Table 1 that the

presence of methoxy group(s) in an ortho and/or para

position influence the carbonyl group that undergoes

cycloaddition with the ketene functionality. If there is no

substituent on the benzene ring as in 3a, the total yield is

65

73% with a ratio of 3-aroylbenzofuran to isoflavone of 2.

Alternatively, if there is a methoxy substituent in the

ortho position as in 3b, the ratio of isoflavone to

3-aroylbenzofuran is 3.6 and if there are two methoxy groups

ortho and para as in 3c, no benzofuran is obtained, only

isoflavone. These results are quite consistent with an

intramolecular ketene cycloaddition process when the two

following resonance structures are considered for the two

different processes.

{ o ^ O 6 0 " ' C K -

^Sc=c=0 o

\=C=Q

The decarboxylation of the intramolecular [2+2] ketene

cycloaddition products,5 and 7 is interesting. The 3

-lactones derived from cycloaddition to the carbonyl group

bonded to the same benzene ring, 5, are not isolable and

decarboxylate during the cycloaddition process to yield the

3-aroylbenzofurans, 6. The formation of the resonance

stabilized benzofuran and the ring strain associated with a

four-membered ring fused to a five-membered ring that is

fused to a benzene ring must be responsible for this facile

66

decarboxylation. Conversely, the isoflavone 8-lactones were

isolable and quite stable in some instances and unstable in

other cases. It is pertinent to note that the isoflavone 0

-lactone could not be isolated when Z=H as in 7 although a

weak &-lactone band (1850 cm 1) in the infrared spectrum

was observable from an aliquot of the reaction mixture.

These results are quite consistent with recent reports on

the thermal decarboxylation of & -lactones [8,91. These

reports provide evidence of a zwitterionic intermediate for

this decarboxylation. The stabilization of the unsaturated

center at C-4 tremendously affects the rate of

decarboxylation. The better stabilized C-4 , the greater

the rate of decarboxylation.

o - - / o

1 H^H, * 3 - \ ~

R2

In our isoflavone B-lactone, 7, if Z = H, the 3-phenyl

group can rotate in the plane of the resulting sp2

hybridized carbon atom and C-3 is stabilized by phenyl

(when R2 = R3 = H) or more significantly, by anisyl

resonance stabilization (when R2 = R3 = OMe). Consequently,

decarboxylation occurs very readily. However, if Z=Me, the

zwitterions are forced to a twisted conformation and C-3

67

does not obtain the stabilizing influence of the phenyl

and/or anisyl substituents and thus decarboxylation occurs

only upon heating.

In summary, the above described synthesis provides a new

approach to the synthesis of isoflavones and

3-aroylbenzofurans.

B. Intramolecular [2+2] Ketene Cycloaddition Reactions

Using Sodium Acetate and Acetate Anhydride.

It is interesting to note that the earliest known

intramolecular ketene cycloaddition is the treatment of

geranic acid (1) with acetic anhydride and sodium acetate

[10, 11]. The geranic acid is converted to the mixed

anhydride which eliminates acetic acid to generate the

ketene intermediate (2). This ketene cyclizes to give

chrysanthenone (3) which is not stable under the reaction

conditions and rearranges to filifolone (4) [12, 13, 14].

This mechanistic proposal has been substantiated by recent

studies [15, 16] .

68

N a O A c

OAc

U4-(4) H Me (3)

M«

1 — M«

* r-4

Recently, it has been reported that the first stage of

the Perkin Reaction catalyzed by a tertiary amine is the

cycloaddition of a ketene to the carbonyl group [17, 18].

Spectroscopic evidence was provided for an intermediate g

-lactone but the lactone could not be isolated.

( C H 3 C O ) 2 0 + N E t 3 • H rc=c=o p-N^-^^-CHO

p - n c 2 CH? MeCOO I

0 — c = o P - N 0 - C H = C H - C 0 0 H

However, these scattered reports have not received much

69

attention. In order to determine if acetic anhydride and

sodium acetate could be used as a source for generation of

ketene, acid 3d was refluxed with acetic anhydride and

sodium acetate in benzene and both the 3-aroylbenzofuran 6d

and isoflavone 0-lactone 7d were obtained. Also these

reaction conditions on 3e resulted in the formation of the

3-aroylbenzofuran 6e and the isoflavone B-lactone 7e. This

suggests that treatment of the acid with sodium acetate and

acetic anhydride does generate the phenoxyketene which

undergoes a [2+2] cycloaddition to form the 3-lactone.

Q C C

O-CH-COOH tie

3d

O benzene

NaOAc, A C 2 0

0 Ph

O

O Q o-c=c=o

© c o II C-Ph

Me 6d

Futhermore, we treated (o-propenylphenoxy)acetic acids

9 with sodium acetate in acetic anhydride and refluxed for 4

70

h. The cyclobutanone enol esters 10 were formed and were

easily hydrolyzed in basic methanol to the expected

cyclobutanones 11. This further establishes that the ketenes

may be generated by the treatment of an acid with sodium

acetate and acetic anhydride.

O-^H-COOH

NaOAc, AC 20

reflux

9a R= Ph 9b R= Et 9c R= i-propyl

Q ( 1 0 )

V

OCOMe

OH MeOH

O

( 1 1 )

Whalley and co-workers have described that the

refluxing of some benziloxyacetic acids similar to 3 with

acetic anhydride and sodium acetate can yield the isoflavone

and 3-aroylbenzofurans [19, 20]. It became apparent to us

that these described cyclizations could in fact be

intramolecular [2+2] ketene cycloaddition reactions with

subsequent decarboxylation in refluxing acetic anhydride.

71

It has been reported that the treatment of

(o-carbonylphenoxy)acetic acid chlorides with triethylamine

can generate the corresponding phenoxyketenes, which undergo

the cycloaddition reactions to yield the benzofurans [21],

We have treated the (o-carbonylphenoxy)acetic acids,

12a-17a, with sodium acetate and acetic anhydride and

obtained benzofuran compounds, 12b-17b.

Table II.Benzofurans

o

k R! NaOAc . A c 2°

"0-1—COOH R." 0 P 2 " 2

12a-17a 12b-1"

product R R R yield(%)

12b H H H 30

13b H Me H 52

14b H Ph H 66

15b Me H H 74

16b -CH 2-CH 2-Ph Ph H 87

17b Ph Ph OMe 75

In the preparation of some benzofurans, 15b-17b,

benzene was used as a solvent instead of acetic anhydride in

72

which case 1.5 eq. of the acetic anhydride was employed. In

the preparation of benzofurans, 12b-14b, acetic anhydride

was used as the solvent and the higher reaction temperature

of refluxing acetic anhydride provided better yields of the

benzofurans from the aldehydes, 12a-14a.

It is interesting to note that in the preparation of

the benzofurans 12b-17b, the ketones consistently give

better yields (74-85%) than the aldehydes (30-66%), which is

very inconsistent with the classical Perkin Reaction

mechanism. However, this is quite consistent with the

intermediacy of a phenoxyketene followed by a two step

intramolecular [2+2] cycloaddition via a dipolar

intermediate which undergoes ring closure to the B-lactone.

Subsequent decarboxylaton under the reaction conditions

yields the benzofurans. When Ri=H in the dipolar

intermediate in the cases of aldehydes, the carbocation

portion of the intermediate is not as stabilized as when Rj

*H in the cases of ketones. So ketones are expected to give

better yields ofbenzofurans than aldehydes. Furthermore,the

phenoxyphenylacetic acids, R2= Ph, generally give higher

yields than the other phenoxyacetic acids. This is also very

consistent with the dipolar intermediate proposed because

when R2= Ph, there is a greater degree of stabilization or

derealization of the negative charge in the dipolar

intermediate.

73

R'^_ jTV"° ^ r r V

2 o o

* O A c

0

xjfr

Another interesting example of a different type of

ketoacid reacting under Perkin Reaction conditions is

5-benzoylpentanoic acid. Refluxing this acid with acetic

anhydride and sodium acetate resulted in a 56% yield of

1-phenylcyclopentene. This product ia apparently the result

of a ketene intermediate which undergoes a [2+2]

cycloaddition to give a 6-lactone, which readily

decarboxylated under the reaction conditions yielding

]_—phenyIcyclopentene• Refluxing this acid in benzene

containing sodium acetate and acetic anhydride did not yield

the 1-phenylcyclopentene. Apparently, the higher reaction

temperature provided by refluxing in the anhydride is

required for this cycloaddition.

74

OH NaOAc = 0

0 Ph

CR' < \ Ph is

The above described experiments clearly demonstrate

that acetic anhydride and sodium acetate can serve as a

reagent for the generation of ketenes directly from certain

acids. Hence, the use of Perkin Reaction conditions does note-

necessitate the normal Perkin Reaction mechanism involving

a carbanion addition to the carbonyl group. It is .quite

likely that some of those Perkin Reactions may proceed via

ketene intermediates which undergo a [2+2] ketene

cycloaddition reaction to the carbonyl group to yield g

-lactones followed by decarboxylation. Furthermore, the

treatment of the ketoacids with acetic anhydride and sodium

acetate in one pot to yield the cycloaddition products is a

simpler procedure than going through the acid chloride with

subsequent triethylamine dehydrochlorination to give the

ketene.

75

Part II. N,N-Disubstituted Aminoketenes.

A. Cycloadditions of N-Aryl-N-alkylaminoketenes with

Cycloalkenes

The stereospecific [2+2] ketene cycloaddition to

alkenes is a valuable method to synthesize cyclobutanones

and related compounds. Ketenes bearing heteroatoms adjacent

to the ketene functionality such as chlorine, oxygen and

sulfur show an increased reactivity in cycloaddition

reactions and have been successfully used in many syntheses

of cyclic compounds. However, there are only a few scattered

reports on the chemistry of aminoketenes and these reports

are limited to aminoketenes in which the nitrogen atom was

substituted by an electro-withdrawing substituent such as

succinoyl, maleyl or phthaloyl groups [22]. The aminoketenes

were prepared by the dehydrohalogenation of aminoacid

chlorides and used in the synthesis of penicillin-like 3-

lactams by cycloaddition with imines. The existence of

aminoketenes in such reactions is questioned because of an

alternative pathway to explain the formation of the (3-

lactams [23]. This study is to investigate the preparation

of N-aryl-N-alkylaminoketenes and the cycloaddition

reactions of these ketenes with different cycloalkenes.

The starting compounds for this study are

76

N-aryl-N-alkylglycine hydrochlorides. The use of

N,N-disubstituted ketenes is based on avoiding the possible

reaction between a primary or secondary amino group with the

ketene functionality. Attempts to change the

N-aryl-N-alkylglycine hydrochloride to the

N-aryl-N-alkylaminoacetic acid chloride with an excess of

oxalyl chloride in refluxing benzene were unsuccessful.

Therefore, p-toluenesulfonyl chloride was selected as the

reagent for the generation of N-aryl-N-alkylaminoketenes.

The aminoacid hydrochlorides were treated with

p-toluenesulfonyl chloride and an excess of triethylamine to

form the mixed anhydride which,based on our previous work

[24] , could eliminate p-toluenesulfonic acid to generate the

N-aryl-N-alkylaminoketene.

HC1 TsC1 R l ~ ^ l j ^ N - C H j C O O H — - — • R , - ( ( ) ) -N-CH 2 COOTS

( 1 9 )

1 9 a R t = H, R « Me 1 9 b R [ * H, R - . F t 1 9 c R j = Me, R = Me

-TsOH > R . - - N - C H = C = 0

R

The reaction mixture of N-phenyl-N-alkylglycine

77

hydrochlorides with 1.2 to 1.5 eq of p-toluenesulfonyl

chloride , 5 eq of olefin and triethylamine in benzene is a

dark red solution containing some insoluble salts. The

cycloadduction products were initially isolated by column

chromatography and then further purified by rotary

thin-layer chromatography. Cycloadditions utilizing

cyclopentadiene resulted in only the isolation of the

cis(endo) isomer which was established by ^H-NMR analysis.

• o TsCl 19

Et-iN

(20)

20a R i = H , R = Me

20b R,= H, R = Et

20c R = Me, R = Me

The proton ajacent to the carbonyl and amino group

consistently give a double doublet with a J value of 8-9Hz

and 2.7-2.9 Hz. These data are consistent with that reported

in the literature for the cyclobutanone system, much larger

coupling constants for vicinal ring protons in the cis

isomer are observed (Jcis 9-10Hz vs Jtrans 5Hz) along with

relatively large cross ring proton coupling(J 3Hz) [25].

This result is in complete accord with a concerted ff2a+ 2 s

ketene cycloaddition process in which the larger group

78

occupies the endo position [26] .

In the cycloadditions of 19b with cyclooctene or

cycloheptene two products were obtained in each case and

were separated by careful chromatography. Spectral data

suggested that these products were not isomers.

19

0 H

-Q-*t. VrT©"'

2 1 a , 2 1 b , 2 1 c 22b

r®-- °>yr€h

2 3 a , 2 3 b , 2 3 c

2 1 a , 2 3 a , 2 1 b , 2 2 b , 2 3 b , 2 4 b , R * E t , R ! » H

R » M E , RJ » H

2 1 c , 2 3 c , R »Me, r | * M ^

24b

Compounds 21a-c and 23a-c have carbonyl absorptions of 1760

cm - 1in the IR while compounds 22b and 24b exhibit an

absorption band at 1740 cm~l. The ^ - N M R spectra indicated

that compounds 21a-c and 23a-c have three cyclobutanone

proton signals with one signal relatively down field (about

79

6 5) which is the proton a to the carbonyl and amino groups.

The 1H-NMR spectra reveals that in compounds 22b and 24b

there is only one cyclobutanone proton as the other two

cyclobutanone proton signals have disappeared including the

signal at 6 5. The 13C-NMR spectra reveals that 22b and 24b

have two more sp2 hybridized carbons than 21b and 23b. A

carbon tetrachloride solution of 22b or 24b when treated

with bromine in carbon tetrachloride resulted in the

decolourization of the bromine color and the IR absorption

of 22b and 24b at 1740 cm"1 changed to 1760 c m - 1 after the

addition of the bromine solution. These data clearly

indicate that 22b and 24b are the dehydrogenation products

of compounds 21b and 23b. The LH-NMR data indicated that

compounds 21a-c and 23a-c are the endo isomers. The

formation of 22b and 24b depends on the reaction conditions

and the alkyl substituent on the amino group. When R is

methyl, only a trace of the dehydrogenation product was

formed. The IR spectrum of the reaction mixture has a strong

absorption at 1760 cm" 1 and only a shoulder peak at 1740 cm" 1

However, when R is ethyl, the main product is 22b or 24b and

the reaction mixture has a major IR absorption band at 1740

cm *. A higher reaction temperature and prolonged reflux

time resulted in more dehydrogenation product. The treatment

of 21b with p-toluenesulfonvl chloride, triethylamine

followed by a work up with a NaOH aqueous solution gave 22b.

These data suggest that 21b and 23b are the initially formed

80

cycloadducts and 22b and 24b are formed from 21b or 23b

under the reaction conditions.

We believe the presence of the arylalkylamino group in

the a position of the cyclobutanone is responsible for the

dehydrogenation. Horner and Nickel [27] reported the radical

cation of N,N,N 1,N'-tetramethyl-p-phenylenediamine

(Me ) j N- J\-N(Me)2

was observed in the reaction of benzenesulfony1 chloride and

N,N,N 1,N'-tetramethyl-p-phenylenediamine. Also, the anodic

oxidation of tertiary amines has been well studied and

enamines are one of the products [28]. The initial step of

the anodic oxidation of tertiary amines is the formation of

the radical cation of the tertiary amine. Therefore, we

propose that under the reaction conditions, the arylalkyl

amine radical cation is formed. The subsequent loss of the

relatively acidic proton a to the carbonyl and the amino

group and the disproportionation of the free radical will

yield the enamine (dehydrogenation products) products,

compounds 22b and 24b.

81

(3), (5)

Disproportionation

R. + Me TsCl

-S02* + CI"

(21),(23) (22) ,(24)

No dehydrogenation product was observed in the

cyclopentadiene cycloadducts. Apparently, the ring strain in

the bicyclo[3.2.0]hept-2-en-6-one prevents the

dehydrogenation or enamine formation.

It is interesting to note that more repulsive strain

would be expected in the endo isomer of the saturated

alicyclic ring as compared to the endo isomer of the

cyclopentadiene adducts [29]. Dehydrogenation results in the

relief of this repulsive strain as the arylalkyl amino group

is moved away from the alicyclic ring in compounds 22b and

24b. The more prevalent dehydrogenation when R is ethyl than

82

when R is methyl could be due to this repulsive strain. The

less repulsive strain in the cycloadducts of the

aminoketenes with cyclpentadiene could also responsible for

the resistance of these cycloadducts to the dehydrogenation.

The proton NMR spectrum reveals that the two methylene

protons of the ethyl group bonded to nitrogen in 21b and 23b

have different chemical shifts, while in 22b and 24b, these

two methylene protons have the same chemical shift. This

suggests that two methylene protons in 22b and 24b are not

diastereotopic.

The reaction of 19a with cyclohexene and n-butyl vinyl

ether gave a complex mixture of products. We were unable to

obtain purified cycloadducts although the IR spectra of the

reaction mixtures indicated that some cycloadducts were

formed. Similar results have recently been reported by

Motoyoshiya for the reaction of diethylphosphoroketenes with

hexene and ethyl vinyl ether [30].

Attempts to generate aminoketenes from

N,N-dimethylglycine hydrochloride and

(1-pyrrolodyl)propanoic acid hydrochloride by using tosyl

chloride were unsuccessful. The major products were

N,N-dimethylsulfonamide and pyrrolidyl sulfonamide. The

increased nucleophilicity and basicity of the nitrogen in

these tertiary alkylamines is probably the reason that no

aminoketene cycloadducts are formed.

8 3

Me

\

/ Me

n c h 2 c o o h

"C =N—

TsCl , Et3 N

Me 0

\ « N-S-

/ « Me 0

-Me

~ C = N -

n c h 2 c o o h >

TsCl, Et3N

O

\ II N-S-

' II O

— M e

In an effort to study a ketoketene, N-phenyl-N-methyl

alanine hydrochloride was prepared. Employing the same

reaction conditions as described above, we could not trap

the elusive N-phenyl-N-methylaminomethylketene with several

olefins or even using more reactive immes as trapping

agents. However when this amino acid was refluxed with

acetic anhydride and sodium acetate, compound 26 was formed

in good yield.

HC1 N—CHCOOH Ae Me

( 2 5 )

Ac 20, NaOAc J OCOMe N Me Me

( 2 6 )

The formation of indole derivatives by the reaction of amino

84

acid 19a and 19b with acetic anhydride and sodium acetate

has previously been reported [31]. As described in Part 1,

we have demonstrated the presence of ketene intermediates in

the reaction of substituted phenoxyacetic acids with acetic

anhydride and sodium acetate. Consequently, the formation of

compounds 27b and 27c is likely via the aminoketene.

Formation of the N-aryl-N-methylaminomethylketene with a

subsequent intramolecular Friedel-Crafts type acylation at

the ortho position of the activated benzene ring results in

the formation of the indole derivatives.

19b AC20, 19c NaOAc

0

?jJCH»C=0 J >

28b Rr = H, R = Et OCOMe 28c Rl= Me, R = Me

27b R,= H, R = Et 27c R i = Me, R = ,Me

The addition of cyc.lopentadiene to the mixture of 19b or

19c, acetic anhydride and sodium acetate results in the

cycloaddition products 28b or 28c, thus establishing the

intermediacy of the aminoketene. The ^H-NMR spectra analysis

indicated that compounds 28b and 28c are the exo isomers of

the compounds 20b and 20c. We treated compound 20b with

acetic anhydride and sodium acetate, exo isomer 28b was

85

isolated. This experiment suggests that the endo isomers are

initially formed and undergo isomerization under these

reaction conditions to the exo isomers.

In summary, the N-aryl-N-alkylaminoketenes were

prepared for the first time and the cycloadditions of these

ketenes with cycloalkenes are consistent with a concerted

7i2a + TT2S process. The use of p-toluenesulfony 1 chloride for

the generation of aminoketenes may result in some

side-reactions and makes purification of final cycloadducts

difficult. This could also be responsible for the relatively

low yield of the cycloadducts.

B. Cycloadditions of N-Aryl-N-alkylaminoketenes with

Imines. C is-3-Amino-2-Azetidinones

The discovery of lactam antibiotics has stimulated a

lot of interest in the synthesis of 3-lactams and their

derivatives [32]. The synthesis of cis-3—amino-&-lactams

continues to be a very active research area because of the

importance of this structural unit in penicillin and related

antibiotics [33, 34]. It has been reported that reactions of

azidoacetyl chloride or phthaloylglycyl chloride and imines

in the presence of triethylamine form B-lactams, which may

be converted to 3-amino-2-azetidinones [35]. More recently,

86

several improved methods for the synthesis of 3-amino-3

-lactams have been reported by the treatment of azidoacetic

acid, phthaloylglycine or a Dane salt of glycine and an

imine with a reagent for activating the carbonyl group in

the presence of triethylamine [36, 37, 38, 39, 40]. Some of

these methods offer a stereocontrolled synthesis of

cis-3-amino- 3-lactams. Since the cycloaddition of a ketene

and an imine is one of the most important methods for the

synthesis of ^-lactams [41], the reactions of

N-alky1-N-arylaminoketenes and imines and the

stereochemistry of the resulting 3-amino-3-lactams were

invest igated.

1 NCH 2COOH R

TsC 1

Et3 N

19a Ri= H, R = Me 19b R\ = H, R = Et 19c R1= Me,R = Me

t R,- -NCH=C =0 ] i R

R2CH=NR3

N-R

29-46

An N-alkyl-N-arylglycine hydrochloride was stirred with

87

1 eq of an imine, 1 eq of p-toluenesulfony1 chloride and 4-5

eq of triethylamine in benzene at room temperature for 8-10

h. The corresponding p—lactams were obtained in moderate to

good yield.

Imines with various substituents in the benzene rings

were prepared and used in this study as illustrated in Table

III.

The structures of the 3 —lactams were determined by IR,

MS, LH and C-NMR spectra. The stereochemistry at C 3 and C 4 of

the 3-lactam rings was established by ̂ H-NMR analysis. The

cis isomer gives a larger coupling constant (Jcis 5Hz) than

the trans isomer (Jtrans 2Hz) [42, 43]. All the £-lactams

prepared in this study (except 44b, 45b, 46b) were the cis

isomers based on the 1H-NMR data. To determine if the trans

isomer were the result of isomerization, the corresponding

cis isomers were subjected to the reaction conditions for

8-10 h. No evidence of the trans isomer could be found in

any of the three control experiments.

The above described results may be satisfactorily

explained by the reaction of the glycine derivatives with

p-toluenesulfony1 chloride to form a mixed anhydride. This

mixed anhydride can eliminate p—toluenesulfonic acid in the

presence of triethylamine to yield the aminoketene, which

has been trapped by us with cycloalkenes. Molecular orbital

studies suggest that electrophilic attack on ketene will

occur from above the plane of the ketene skeleton, while

88

Table III. 3-(N-Alkyl-N-Arylamino)-2-Azetidinones

Ro 0

\ _ / 1 2

4 3

R.

Cpd R Ri *2 *3 Isomer Yield%

29 Me H CIS 64

30 Et H CIS 70

31 Me Me

32 Me H -CH=CH

CIS

CIS

63

71

33 Me Me -CH=CH CIS 57

34 Et H CI CIS 6 1

35 Me H CI CIS 53

Table III (continued)

89

Cpd R Ri ^2 *3 Isomer Yield%

36 Me H -t-butyl cis 68

37 Et H

38 Et H

39 Me H OMe

-t-butyl cis

OMe cis

OMe cis

47

73

68

40 Me H OMe cis 70

41 Et H

OoN

CIS 68

42 Me H

O2N,

CIS 62

90

Table III(Continued)

Cpd R Rx £2 E3 Isomer Yield%

4 3 Me H NO2 OMe cis 72

44a Me H

MeO

cis 53

44b Me H

MeO.

Trans 8

45a Et H

MeO

cis 46

45b Et H

MeO

Trans 8

46a Et H OMe NOo cis 59

46b Et H OMe NO2 trans 20

91

nucleophilic attack will occur in the plane of ketene. The

nucleophilic attack of the nonbonding electrons on the

nitrogen of the imine on ketene would involve the LUMO of

the ketene.

* Q o ( L U M O )

0

( H O M O )

The substituents on the ketene are expected to determine the

preferred direction of attack. The approach of the imine

nitrogen should be from the least hindered side in the plane

of the ketene on the LUMO [44, 45]. It is the p lobe on the

sp hybridized carbon of the aminoketene anti to the large

amino group that is expected to react with the lone pair of

electrons of nitrogen in the imine [46]. Since the trans

conformation of the imine is preferred, the above approach

will give the zwitterrionic intermediate Ilia. This dipolar

intermediate may be represented by several different

resonance structures. Structure Ilia would be expected to be

a major contribution to the resonance hybrid of the dipolar

intermediate and a conrotatory ring closure of Ilia results

in the ^-lactams with cis conformation.

92

N — C

Ilia

Rf -N.

*2

r Cis isotner

11 lb

Trans J somer

When both R2 and R3 are cation stabilizing groups (29 to 40)

or R2 is not a good cation stabilizing group (41 to 43), the

resonance contribution of Ilia should be significantly more

stabilized by these substituents. So only cis isomers were

obtained from the above cases. When R2 is a better cation

stabilizing group than R3 (44 to 46), resonance structure

Illb should make a relatively greater contribution to the

dipolar intermediate. Thus, the thermodynamically controlled

ring closure of Illb results in the formation of the trans

93

isomer, which has been shown to be the more stable isomer by

epimerization studies [47]. In those ^-lactams with R=ethyl,

the two methylene protons of the ethyl group bonded to

nitrogen have different chemical shifts in the *H-NMR for

cis isomers, but the same chemical shift for the trans

isomers (45b, 46b). The bigger difference of chemical shift

of two methylene protons in the cis isomers is due to the

existence of cis benzene ring. This can serve as a means for

the charicterization of cis or trans isomers.

Although the dehydrohalogenation of acid halides by

triethylamine is a reliable method to generate ketenes, the

ketene pathway is controversial in the formation of 8

-lactams by the reaction of acid halides with imines in the

presence of triethylamine because it is difficult to

confidently predict the stereochemistry of the resulting 6

-lactams. Generally, the 6-lactams formed from the

reactions between chloroacetyl chloride, phenylacetyl

chloride, thioacetyl chloride or phthaloylacety1 chloride

with an imine in the presence of triethylamine are the trans

isomers, while the cis and trans £-lactams resulted from

azidoacetyl chloride or alkoxyacetyl chloride [48, 49], But

when azidoacetyl chloride reacts with the C=N bond of a

thiozoline or thiazine, only the trans isomer was obtained

[50, 51], Also, only trans isomer was obtained when ketenes

react with alkyl N-phenylformimidates, Ph-N=CHOR, or when

alkoxyketens react with the N-(p-nitrophenyl)imine of

94

p-methoxybenzaldehyde [381. We believe these results can be

explained by the mechanism described above. If the

substituent on the ketene is a good carbanion stabilizing

group, resonance structure IVb of the dipolar intermediate

could be expected to be a major contribution to the

resonance hybrid. The more thermodynamically stable trans

isomer should be formed predominately when structure IVb is

the major contributor. It is well known that chlorine,

sulfur, phenyl and phthaloyl [52] are good carbanion

stabilizing groups, thus the trans-$ -lactams are expected

to be observed. The alkoxy and azido substituents provide

much less stabilization of the carbanion [53]. Resonance

structure IVa should be a major contributor to the resonance

hybrid and the cis isomer is expected to be a major product.

The trans isomer resulted from the reaction of alkoxyketene

and azidoketene with imine could be via the intermediate

IVc. If R2 is a good cation stabilizing group, sach as

alkoxy or p-methoxypheny1 group, IVc would be a major

contributor to the resonance hybrid and the trans isomer

would be expected.

When the configuration of the imine is locked in the

cisoid conformation, such as with thiazoline, either

resonance structure Va or Vb of the dipolar intermediate

will result in the trans isomer.

95

H C "C • 0 + ^ C-N

1

H R2 j. -H

" N

c + ^ R"

X .

V R \ C - C ^

— \ "> *0

•N.

IV c

R-» 0 V'N-

+ ~ R3 0

I Va

/ N

R 2 ^ H

/ > H x R

Trans isome r

R-, JD

y j

R 2 R

Ci s 1sooer

+ R-

I Vb

N-

y~ H' - R

Trans i somer

N3. ' c « C » 0 +

H . S ^ M e

X _ T M e

COOMe

H H S Me ^ A M e

x , ^

COOMe

"3

\ H H ^Sv .Me

• Me

C N-0 ^ +

r COOMe

Va Vb

N3 H H ,Me ^ M e

H:00Me

Trans i some r

96

To further test the above decribed model we treated

chloroacetic acid, methoxyacetic acid and benzoxyacetic acid

with p-toluenesulfony1 chloride and imines in the presence

of an excess of triethylamme.

CICH2COOH

CI CH=NPh

TsCl, Et 3N CI

Ph 0 t#

H CI 47

MeOC H 2COOH

PhCH=NPh

TsCl, Et3 N

PhCH=NPh PhCOOCH 2COOH >

Et 3N, TsCl

Ph ̂

H

Ph

N-

48

Ph 0 N

Ph / H

OMe

H OCOPh 49

PhCOOCH2 COOH > MeO N-

Et 3N, TsCl

50

H OCOPh

97

The trans— B -lactam 47 was obtained in 28% yield from

chloroacetic acid and the cis-3 -lactam 48 was obtained in

52% yield from methoxyacetic acid. A considerable amount of

black tar was observed in the chloroacetic acid reaction,

which was probably the result of polymerization of

chloroketene and accounts for the low yield of the trans-3

-lactam. It is most significant that only trans isomers 49

and 50 were obtained in the reaction of benzoxyacetic acid

with imines. The benzoxyl group can provide a

dipolar-stabilization to carbanion just like phthaloyl group

[52,53]. Therefore the resonance structure of IVb is

predominated and the trans isomers are resulted. These

experiments further substantiate the mechanism we .proposed.

o o II - I + "

-C-Y-<f- * * -C = Y-<j>

Y= 0, NR

Benzoxyacetic acid was changed to benzoxyacetic acid

chloride with a excess of oxalyl chloride. The treatment of

benzoxyacetic acid chloride with triethylamine and imines

results in the trans isomers. Since the trans g-lactams are

obtained by both methods of preparation, these reactions

likely occur by the same process involving the ketene

intemediate.

98

PhCH=NPh

PhCOOCHoCOCl * Et 3N

OCOPh

M e ° — < ^ ^ ) - C H = N

PhC OOC H 2 C OC1 Et 3N

N02 OoN

OCOPh

Some N-alkyl-N-arylglycine hydrochlorides arid imines were

treated with acetic anhydride and sodium acetate.

HC1 yCH2COOH R

r 2CH=nr 3

AC2O, NaOAc

19a R = Me, R l= H 19b R = Et, R,= H 19c R = Me, R = Me

1

The resulting 8-lactams were obtained in low to modest yield

as illutrated in Table IV with predictable stereochemistry

based on the above discussion. This method provides an

alternative route to the 3—lactams but the yields are

somewhat lower.

99

Table IV. 3-(N-Alkyl-N-Arylamino)-2-Azetidinone

prepared by Acetic Anhydride and Sodium Acetate Method

N-

(J

/

1 2

4 3

/

Cpd R Ri R2 E3 Isomer Yield%

36 Me H

36 Me H

t-butyl cis

t-butyl cis

23i

45

44a Me H

MeO.

CIS Trace

44b Me H

51 Me Me

MeO

NO'

Trans

OMe cis

39

26

* Reaction was run in refluxing benzene

100

In conclusion, cis-3-amino-2-azetidinones were prepared

in this study by the cycloaddition of aminoketenes and

different imines. The stereochemistry of the resulting 8 —

lactams depend on the structure of the dipolar intermediate.

The structure of the dipolar intermediate that is formed m

the reaction of a ketene and an imine is determined by both

electronic and steric consideration. The model proposed as

above can not only explain the results of stereochemistry of 3

-lactams obtained in this study, but also explain the other

results of cycloadditions of different ketenes and imines in

the literature.

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