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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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