37?
/Sj B t ci
/V q , 0^ 0/
(4+2)-CYCLOADDITION REACTIONS OF KETENES; PYRANONES
Dissertation
Presented to the Graduate Council of the
North Texas State University in Partial
Fulfillment of the Requirements
For the Degree of
DOCTOR OF PHILOSOPHY
By
Michael O. Agho, B.S., M.S,
Denton, Texas
August, 1983
8
© 1984
MICHAEL OSARENOGOWU AGHO
All Rights Reserved
Agho, Michael 0., (4+2)-Cycloaddition Reactions of
Ketenes; Pyranones.
Doctor of Philosophy (Chemistry),
August, 1983, 99 pp., 6 tables, bibliography, 135 titles.
This study deals with the (4+2)-cycloaddition reactions
of 4-TT electron compounds with ketenes.
Chloroketenes were generated in situ from the corresponding chlorinated acid chlorides in the presence of the
ketenophiles.
Chloro-, dichloro- and diphenylketenes reacted with
1-methoxy-3-trimethylsiloxy-l,3-butadiene, and 2,4-bis(trimethylsiloxy)-1,3-pentadiene to yield the corresponding
dihydropyrans.
The dihydropyrans yielded substituted
4-pyranones on hydrolysis.
Diphenylketene reacted similarly with 1,3-dimethoxy-ltrimethylsiloxy-1,3-butadiene and 3-methyl-l,1-bis(trimethylsiloxy) -1 , 3-butadiene to give dihydropyrans which
yielded dihydro-2-pyranones on hydrolysis.
Chloro- and
dichloroketenes reacted with 1,3-dimethoxy-l-trimethylsiloxy1,3-butadiene to give dihydropyrans (which, on hydrolysis,
gave dihydro-2-pyranones) as well as acyclic products which
were determined to be due to the reactions of the acid
chlorides with the diene.
The dihydro-2-pyranones gave
2-pyranones on treatment with triethylamine.
The cycloaddition reaction of dichloroketene with
3-methyl-l,1-bis(trimethylsiloxy)-1,3-butadiene resulted
in (4+2) and (2+2) cycloadducts, and dichloro-, diphenylketenes cycloadded to 1,1-bis(trimethylsiloxy)-1,3-butadiene to give the (2+2)-cycloadducts only.
Dichloro- and phenylchloroketenes reacted with
4-methoxy-3-buten-2-one and (Z)-2-methoxymethylenecyclohexanone to give dihydro-2-pyranones.
The dihydro-2-
pyranones were treated with zinc in moist acetic acid to
give the corresponding 2-pyranones.
Diphenylketene reacted
similarly with the unsaturated ketones at 82 + 5°C to give
the respective dihydro-2-pyranones.
The cycloaddition reactions of diphenyl- and phenylethylketenes with $-methoxymethylene-a-tetralone at 8 2 + 5°C
resulted in the isolation of the corresponding (4+2)cycloaddition products.
The reactions of dichloro-, methylchloro-, and phenylchloroketenes with 3-methoxymethylene-a-tetralone yielded
the corresponding 3,4-dihydro2-pyranones.
The dihydro-2-
pyranones were treated with zinc in moist acetic acid or
triethylamine in refluxing benzene to give 5,6-dihydrobenzocoumarins.
The 5,6-dihydrobenzocoumarins were treated with NBS
to give substituted 7,8-benzocoumarins.
3-Methyl-5,6-
dihydrobenzocoumarin was oxidized with DDQ to 3-methyl-7,8benzocoumarin.
The substitution in the 3-position of dienes, along
with the ketene substituents, play a key role in the
cyclization step in the cycloaddition reactions of ketenes
and the activated dienes.
Also, the described reactions
represent new routes in the synthesis of pyranones, and
substituted benzocoumarins.
TABLE OF CONTENTS
Page
LIST OF TABLES
Chapter
I.
INTRODUCTION
1
II.
EXPERIMENTAL
22
RESULTS AND DISCUSSION
50
III.
BIBLIOGRAPHY
in
LIST OF TABLES
Table
Page
I.
II.
III.
IV.
V.
VI.
C-13 Chemical Shifts and Assignments for
4-pyranones, 4a-4f
53
C-13 Chemical Shift and Assignments for
dihydro-2-pyranones, 7a-d
61
C-13 Chemical Shifts and Assignments for
2-pyranones, 8a-8e
64
Chemical Shifts and Assignments for Compounds 15_ and lf[
76
Chemical Shifts and Assignments for
Compounds 21a-e
83
Non-assigned Chemical Shifts for 7,8benzocoumarins, 22a-e
87
IV
CHAPTER I
INTRODUCTION
Cycloaddition reactions (1,2,3,4) may be defined as
reactions in which two or more molecules condense to form
a new ring by transferring electrons from pi or nonbonding
orbitals to developing sigma orbitals.
In the case of
ketene cycloadditions, as in most cycloaddition reactions,
the terms 1,2- and 1,4- cycloaddition are frequently used
to describe the termini of the unsaturated compound (ketenophile) involved in cycloaddition (5,6).
The designation
(2+2) or (4+2) refers to the number of pi or nonbonding
electrons contributed by each reaction partner (7,8).
These
designations have also been used to indicate the number of
ring atoms contributed by each partner (9).
Either of these
two designations may be used to describe the work presented
in this dissertation, but in order to avoid any ambiguity,
the former interpretation is assumed throughout.
Ketenes are a class of highly reactive electrophilic
molecules characterized by olefinic and carbonyl groups in
cumulative linkage.
Ketenes are generally not isolable
because of their kinetic instability, and are usually
trapped in situ with a suitable substrate.
However, there
are a few ketenes that are relatively stable and isolable
(10,11,12,13,14,15).
The spearhead of the reactivity of
ketenes is the sp-hybridized carbon of the heterocumulene.
This carbon is the electrophilic site of ketenes as is apparent
from the contributing resonance structures.
+ -
-
'c=c-o:
C=C=0
+
C—c=o
<
>
Ketenes have
—
-fc-c=o
been subjected to several theoretical studies (16,17,18,19),
and like the valence bond treatment, indicate the
sp-hybridized carbon of ketenes as the electrophilic site.
The frontier orbitals of ketene are shown below (along with
their energies in eV) where the sizes of the orbitals are
roughly proportional to the sizes of the coefficients.
The
major orbital interaction in ketene cycloaddition reaction
LUMO
3.8
, w
HOMO
-12.4
is bond formation between the atom having the largest coefficient in the highest occupied molecular orbital (HOMO) of
the ketenophile and the central atom of the ketene which has
the largest coefficient in the lowest unoccupied molecular
orbital (LUMO) of the ketene.
The consequence of substi-
tuting electron-withdrawing groups on the ketene is to
lower the energy of the LUMO, and hence increase the
reactivity of the ketene.
An order of reactivity for
variously substituted ketenes with olefinic compounds is
(20):
Cl2C=C=0>Ph2C=C=0>Me2C=C=0>H2C=C=0.
The reactivity
of olefins in these reactions parallels their nucleophilicities and/or the energies of their HOMOs.
The first reported synthesis (10) of a ketene was
around the turn of this century when Staudinger reported
the synthesis of the isolable diphenylketene.
Staudinger
and co-workers reported on several studies of the cycloaddition reactions of unsaturated hydrocarbons with substituted ketenes, notably with diphenylketene, to give
(2+2) cycloaddition products (21,22,23,24,25,26).
The
first review of ketene chemistry (27) was written by
Staudinger in 1912 and ketene cycloaddition reactions have
attracted considerable attention since that time, primarily
for use in synthetic sequences.
The preparations of ketenes
(20,28,29,30) and their synthetic applications (20,31,32,
33,34,35) have been treated extensively in reviews.
The most synthetically useful reaction of ketenes is
the (2+2)-cycloaddition reaction with unsaturated compounds
to give cycloaddition products containing 4-membered rings
(36,37,38,39).
There are several reported results of (2+2)-
ketene cycloadditions with symmetrical and unsymmetrical
olefins to give stereo- and regiospecific products.
results are consistent with a concerted mechanism.
EtO
Me
c=c=o
H
^
Ketene
ref. 40
c=c
H
X
Me
/
\
These
/
<tra"scyclooctene
\
H
R c=C=0
2
cis-cyclo-^
octene
ref. 41
R,
cycloadditions are believed to follow
2
9
(t s + ir a)* path with
the ketene participating in the antarafacial way.
2
The
2
(TT s + IT a) process involves orthogonal approach of the
reacting species, and the resulting transition state, I,
accounts for the observed stereochemical results.
The least
hindered approach of the reacting species leads to the most
hindered product.
In addition to these stereochemical re-
sults, there are a whole range of reported studies that are
compatible with the concerted process; a negative activation
entropy
(42), negligible solvent effects on rate
Hammet rho,
(42), a
p, of only -0.7 3 for addition of diphenylketene
*The symbols s and a describe the stereochemical entry
of the participating species in the eyeloadd.ition reaction,
and mean suprafacial and antarafacial respectively.
H
H
H
\
/
C=C
/
H
+
Et0CH=C=0
:0
\
H
H
EtO^
'0,
R
'A
(I)
V
H
\.^-
H
ref. 40
EtO
X)
H-\
R
to substituted styrenes
effects for deuterium
(4 3), and observed secondary isotope
(44) and
14
2
Although the concerted
C/12C
(45).
2
(ir s + i a) process has been
impressively successful in explaining the stereochemical
results of ketene cycloadditions, there are reported examples
of ketene additions that occur by a stepwise path
49).
(46,47,48,
The trend from a concerted to a stepwise mechanism
seems to become significant as the cation-stabilizing ability
6
of the ketenophile substituents is increased as is evident
from the recent reports in the literature on the addition
of ketenes to highly nucleophilic unsaturated systems (50,51,
52,53,54,55,56,57,58,59,60,61).
Ph2C=C=0
Ph
Some examples are shown below.
R-N=C=N-R
//>
Ph0 C — C
©®
i
N=C—N
R'
^R
2 g-C
<—>
R-N=C—N
©
\
R
H2O
SO,
refs. 47,48
y
0
II
Ph2CH^
C
C
R
0
PH
0
II
v
'-ri
H
^ N H R ^_ 2°
-SO,
0„S N
' Y
Me
H2C=C(OEt)2 +
^C=C-0
>
CI
RCH=C(OMe)2 + Ph2C=C=0
" • r f
R-N 4 N
0
(EtO)2C=CHCCHCH3
ref. 6 3
CI
->
(MeO)z0C=CCCHPh
I
R
ref. 6 2
Likewise, the increase in anion-stabilizing ability of the
ketene substituents favor the stepwise pathway as demonstrated by the studies of England and Krespan (64).
(F,C)oC=C=0 + CH o =CH0Et
3
2
(F 3 C) 2 C.
—>
0°C
hexane
2
0
(F 3 C) 2
\
OEt
EtO
(F C)f
3
— 0
OEt
hexane
v
(F_C) „C n Q
5 I o -
50°C
,0
(F
0
(F 3 C) 2 CH-C-CH=CH-0Et
uH
II
©OEt
3C)2
\
EtO
The reaction bias of ketenes is, perhaps, best illustrated by the 1,2-cycloaddition of ketenes to dienes.
While
one might expect stabilized dipolar or diradical intermediates in the reaction of ketenes with dienes, and hence possible loss of stereochemistry, the reaction is, nonetheless,
stereospecific and periselective.
Diphenylketene adds
stereospecifically to the cis double bond of cis,transhexadiene, II, to give III (65).
There are other examples
Me
Ph2C=C=0
+
Mev
Me
\__
H Me
(ID
(HI)
in the literature that show the periselectivity or site
selectivity of ketene reactions.
Diphenylketene reacts
with isoprene, IV, to give products Va and Vb in the indicated ratio (66), and with 1-cyano cis-butadiene, VI, to
Ph2C=C=0
+
(IV)
%
0,
+
Ph.
Ph.
Me
Me
Vb;30%
give VII (66).
Va; 70%
The reaction of ketenes with cyclopentadiene,
which has the TT-system locked in the cisoid configuration,
is probably the most instructive.
readily undergoes the (U 4 s +
TT 2 S)
While cyclopentadiene
Diels-Alder cycloaddition
0
Ph 2 C=C=0
CN
CN
+
Ph
(VI)
(VII)
reaction, it reacts with ketenes (67,68,69,70,71) to give
bicyclo[3•2•0]hept-2-ene-6-one, VIII, rather than IX.
It
is noteworthy that while X is a possible product, none of
O
\
c=c=o
( VIII)
> C
0
( IX)
this cycloadduct is produced.
(X)
The explanation
(7,72) for
the total exclusion of the (4+2) cycloaddition product is
that if ketene were to participate as a TT S component of a
4
2
( N s + TT s) reaction, the orbitals on the carbon-carbon
double bond would be involved.
However, these T r - o r b i t a l s
are orthogonal to those of the carbonyl group of the ketene.
The result is that the carbon-carbon i r - b o n d has a normal
LUMO comparable to that of ethylene i.e. the LUMO is not
low-lying, and hence a non-efficient dienophile.
In the
10
2
2
(it s + TT a) process, the LUMO of the carbonyl Tr-bond is
involved, and this LUMO is low-lying, and hence a favored
4
2
concerted pathway over the (tt s + tt s). Another feature of
the cycloaddition of ketenes to cyclopentadiene is the high
stereoselectivity to yield the cycloaddition product with
the larger substituent in the more crowded endo position
(73,74,75,76,77,78,79).
H,
c=c=o
+
x = alkyl, aryl, CI, F, N 3
Despite the preferred tendency of ketenes to undergo
(2+2)-cycloaddition reaction with dienes, there have recently
appeared in the literature some isolated reports on the 1,4cycloaddition of ketenes to activated vinyl ketones and
dienes.
The addition of 2 moles of dimethylketene to a mole
of 1-ethoxy-N,N-dimethylvinylamine, XI, gave XIII in good
yields (80).
The pyranone apparently results from the 1,4-
cycloaddition of a second molecule of dimethylketene to
compound XII and a subsequent loss of ethanol.
11
O
OEt
Meo2C=C=0 + CH„=C
2 n
OEt
Me2CH-C-CH=C
NMe,
NMe.
(XI)
(XII)
Me2C=C=0
NMe,
Me.
Me
(XIII)
Scarpati et al (62) reported the 1,4-cycloaddition of
a second molecule of diphenylketene to the acylketene
0
(OR)
.Ph.
Ph2C=C=0
+
(RO)~C=C-C-CHPh9
I
*
Ph 2 Crf^ 0
(XIV)
acetal, XIV, to form the pyranone, XV.
(XV)
12
Similarly, dichloroketene cyloadds to (a-chloropropionyl)
ketene diethyl acetal, XVI, to form the corresponding pyranone, XVII (63).
(0R)
C12C=C=0
+
0
II
(RO)2C=C-C-CH-CH3
C1
(XVI)
2C1
CH^-Cir^- o
3 c|
l
(XVII)
Schenone et al reported the 1,4-cycloaddition of substituted ketenes to a series of N,N-disubstituted vinyl
ketones, XVIII, to yield pyranones, XIX (81,82,83,84,85,86,
87, 88) .
C=C=0
+
0
ll
R„N-CH=CH-C-R
2
(XVIII)
(XIX)
Martin and co-workers (89) studied the reactions of 1and 2-methoxy-l,3-butadienes with substituted ketenes.
DimethyIketene
cycloadds to 1,3-butadienyl methyl ether,
XX, at room temperature across the 3,4-olefinic bond to
give the 1,2-cycloadduct, XXI.
However, when a methoxy
group is introduced in the ^-position of 1,3-butadiene,
13
O
Me2C=C=0
+
MeO-CH=CH-CH=CH2
>
MeO-CH=CH
Me1
(XXI)
(XX)
XXII, reaction selectivity changes to give the 1,4-cycloadduct, XXIII, with diphenyl- and butylethylketenes.
The
1,4-cycloadduct rearranges to XXIV.
MeO
l
R 2 C=C=O
+
,0
H 2 C=C-CH=CH 2
MeC
(XXIII)
(XXII)
a
CR
2
MeA
(XXIV)
Brady and Lloyd (9 0) observed the same selectivity
and regiochemistry in the cycloaddition of dichloro- and
methylchloroketenes with 1-siloxy-l,3-butadiene, XXV;
again, cycloaddition occurs away from the 1,2-double bond
to give the cyclobutanone, XXVI.
R2C=C=0
+
Me3SiO-CH=CH-CH=CH2Me3SiO-CH=CtT—
(XXV)
(XXVI)
R,
14
Gouesnard (91) reported the cycloaddition of diphenylketene with a series of alkoxy conjugated dienes, XXVII,
to give the dihydropyran, XXVIII, and/or the cyclobutanone,
XXIX, depending on the substitution in the 3-position of
the diene.
Ph7C=C=0
R"
+
H0C=C-C=C
OR,
(XXVII)
p
h CK /
\/
+
_Ph,
0R
(XXVIII)
,C=C. 1
S
R"
R R'
(XXIX)
The (4+2)-cycloaddition reactions of ketenes have been
rationalized in terms of the dipolar mechanism (62,6 3,65,
81,89); the initial nucleophilic attack of the ketenophile
on the sp-hybridized carbon of the ketene to give a stabilized dipolar intermediate, and the subsequent cyclization
of this intermediate to give the cycloaddition product(s).
It is intriguing that the scattered reports on the
cycloaddition reactions of ketenes with the activated dienes
observed different products with the 1-and 2-substituted
dienes.
However, there is no detailed and systematized
15
study of this system in the literature, and hence it was
proposed to conduct a systematic study of the cycloaddition
reaction of ketenes with activated 4-tt electron systems.
It was hoped that such a study would show the influence
or non-influence of the ketene and ketenophile substituents
on the selectivity patterns and/or the cyclization step.
It was also anticipated that such a study would provide new
synthetic routes to six-membered heterocyclics that continue
to be of great attraction to synthetic organic chemists
because of their common occurrence in natural and industrial
products.
Among these hopes was the goal to explore the
chemistry and secondary synthetic utilities of the original
cycloadducts.
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(1978).
~
—
57.
Brady, W.T., Watts, R.D., J. Org. Chem., 45, 3525
(1980).
~
—
58.
Zaitseva, G.S., Baukov, Y.I., Maltsev, V.V., Lutsenko,
I.F., Zh. Obshch. Khim., 44, 1415 (1974).
59.
Hoffman, R.W., Angewandte Chemie Int. Ed. Encrl.. 11.
324 (1972) .
—
—
60.
Bellus, D., Fisher, H.P., Greuter, H., Martin, P.,
Helv. Chim. Acta, 61, 1784 (1978).
61.
Bellus, D., J. Org. Chem., 44, 1208 (1979).
62.
Scarpati, R., Sica, D., Santacroce, C., Tetrahedron,
20_, 2735 (1964).
Brady, W.T. Watts, R.D., J. Org;. Chem. , 46_, 4047 (1981).
63.
64.
England, D.C., Krespan, C.G., J. Org. Chem., 35, 3312
(1970) .
~
—
65
Ghosez, L., O'Donnell, M.J., Pericyclic Reactions, Vol.
II, edited by A.P. Marchand and R.E. Lehr, New YorkSan Francisco-London, Academic Press, 1977, p. 79.
66.
Huisgen, R., Otto, P., Chem. Ber., 102, 3475 (1969).
67.
Nee, M., Roberts, J.D., J. Org. Chem., 46, 67 (1981).
68.
Brady, W.T., Hoff, E.F., Jr., Roe, R., Jr., Parry, F.H.,
III, J. Amer. Chem. Soc., 91, 5679 (1969).
20
69.
Ghosez, L., Montaigne, R., Roussel, A., VanLierde, H.,
Mollet, P., Tetrahedron, 27, 615 (1971).
70
Grieco, P.A., J. Org. Chem., 37, 2363 (1972).
71.
Rey, M., Huber, U.A., Dreiding, A.S., Tetrahedron
Letters, 3585 (1968).
72.
Fleming, I., Frontier Orbitals and Organic Chemical
Reactions, Chichester-New York-Brisbane-Toronto,
John Wiley, 1978.
73.
Brady, W.T., Hoff, E.F., Jr., J. Org. Chem., 35, 3733
(1970) .
~
—
74.
Brady, W.T., Roe, R., Jr., J. M e r , Chem. Soc., 92,
4618 (1970).
~
—
75.
Brady, W.T., Hoff, E s F , Roe, R., Jr., Parry, F.H., Jr.,
J. Amer. Chem. Soc., 91, 5679 (1969).
76.
Brady, W.T., Roe, R., Jr., Hoff, E.F., Parry, F.H., III,
£• A m e r • Chem. Soc., 9_2, 146 (1970).
*
Brook, P.R., Duke, A.J., Duke, J.R.C., Chem. Commun.
574 (1970) .
78.
Brook, P.R., Harrison, J.M., Duke, A.J., Chem. Commun.,
589 (1970) .
79.
Rey, M., Roberts, S., Dieffenbacher, A., Dreiding, A.S.,
Helv. Chem. Acta, 53, 417 (1970).
80 . Hasek, R.H., Gott, P.G., Martin, J.C., J. Org. Chem.,
29, 2513 (1964).
~
81.
Bignardi, G., Schenone, P., Evangelisti, F., Ann. Chim.
(Rome), 61_, 326 (1971).
82.
Bignardi, G., Evangelisti, F., Schenone, P., Bargagna,
A., J. Heterocycl. Chem., 9, 1071 (1972).
83.
Schenone, P., Bignardi, G., Bargagna, A., Evangelisti,
F./ J. Heterocycl. Chem., 13, 1105 (1976).
84.
Mosti, L., Bignardi, G., Evangelisti, F., Schenone,
p
*/ J- Heterocycl. Chem., 13, 1201 (1976).
85.
Mosti, L., Schenone, P., Menozzi, G., J. Heterocycl.
Chem., 15, 181 (1978).
~
21
86.
Bargagna, A., Evangelisti, p., Schenone, P., J.
Heterocycl. Chem., 16_, 93 (1979).
~
87.
Mosti, L., Schenone, P., Menozzi, G., J. Heterocycl.
Chem., 16_, 913 (1979).
~
88.
Bargagna, A., Cafaggi, S., Schenone, P., J. Heterocycl. Chem., 14, 249 (1977).
~
89.
Martin, J.C., Gott, P.G., Goodlett, V.W., Hasek, R.
H., J. Org. Chem., 30, 4175 (1965).
90.
Brady, W.T., Lloyd, R.M., J. Org. Chem., 46, 1322
(1981) .
~
—
91.
Gouesnard, J.P., Tetrahedron, 30, 3113 (1974).
CHAPTER II
EXPERIMENTAL
Proton nuclear magnetic resonance (^H-nmr) spectra were
recorded on a 60 MHz Hitachi Perkin-Elmer R-24B spectrometer
employing deuteriochloroform as solvent, with tetramethylsilane as the internal standard.
Carbon-13 spectra* were
determined at 90 MHz in the Fourier mode using a JEOL-FX-90Q
spectrometer equipped with a JEC-980B computer.
Deuterio-
chloroform was used as a lock solvent and as the internal
standard, unless where indicated differently, and all chemical
shifts are reported in parts per million.
The infrared (ir)
spectra were obtained on a Beckmann 1330 spectrophotometer.
Chromatographic separations were performed on Sargent Welch
Silica Gel 60, 70-230 mesh using ether/petroleum ether (1:9)
or ethyl acetate/petroleum ether (1:9) as eluent.
Flash
chromatography was performed as described by Still (1)
using J.T. Baker Silica Gel, product number 7024-1, > 25 yM.
All melting points were determined on a Thomas Hoover
capillary melting point apparatus, and like the boiling
*A11 carbon-13 spectral data are reported in Chapter
III.
22
23
points, are uncorrected.
Elemental analyses were carried
out by Midwest Microlab, Ltd., Indianapolis, Indiana, and
Galbraith Laboratories, Inc., Knoxville, Tennessee.
Hexanes and tetrahydrofuran were dried by refluxing
over, and distilling from sodium-potassium alloy.
Tri-
ethylamine was distilled from sodium metal, and diethyl
ether was refluxed over, and distilled from lithium
aluminum hydride.
Benzene was dried by washing with sul-
furic acid, and then distilling at atmospheric pressure.
Trimethylsilyl 3,3-Dimethylacrylate (2).
A 39.1 g
(0.24 mol) portion of hexamethyldisilazane was added to a
stirred solution of 24.3 g (0.24 mol) of 3,3-dimethylacrylic
3-cid in 50 mL of dry tetrahydrofuran and 13 mL of pyridine
at 0°C under a nitrogen atmosphere.
This was followed by
the dropwise addition of 12.8 g (0.12 mol) of chlorotrimethylsilane, and stirring was continued at room temperature
for another 17 hours.
The reaction mixture was then filtered
through Celite, concentrated on a rotatory evaporator and
vacuum-distilled at 38-39°C (2 mm) to give 30 g (71%) of
the ester; ir (neat), 1690, 1645, 850 cm - 1 ; nmr, 6, 0.22
(s, 9 H), 1.74 (s, 3 H), 2.00 (s, 3 H), 5.39 (s, 1 H).
Trimethylsilyl Crotonate (2).
A 39.1 g (0.24 mol)
portion of hexamethyldisilazane was added to a stirred
solution of 20,7 g (0.24 mol) of crotonic acid in 50 mL of
24
dry tetrahydrofuran and 13 mL of pyridine at 0°C under a
nitrogen atmosphere.
This was followed by the dropwise
addition of 12.8 g (0.12 mol) of chlorotrimethylsilane
and stirring was continued at room temperature for another
17 hours.
The reaction mixture was then filtered through
Celite, concentrated on a rotatory evaporator, and distilled at 42-44°C (9 mm) to yield 30 g (80%) of the ester;
ir (neat), 1700, 1650, 850 cm
nmr, 6, 0.20 (s, 9 H) ,
1.67 and 1.78 (dd, 3 H), 5.30 and 5.54 (dd, 1 H), 6.206.82 (m, 1 h) .
Typical Method for Diene Synthesis; A 3-necked 500 mL
round bottom oven-dried flask was equipped
with a pressure
equalizing dropping funnel and a magnetic stirrer.
The
system was swept with dry nitrogen and a hexane solution
of 1.6 M n-butyllithium
the flask.
(62.5 mL, 0.10 mol) was added to
The flask was then cooled in an ice bath, and
10 g (0.10 mol) of diisopropylamine in 75 mL of dry tetrahydrofuran was then added over a 5-minute period.*
The
mixture was stirred an additional 30 minutes, and the bath
was then changed to a dry ice-acetone bath.
The diene
precursor, functionalized ester or ketone (0.10 mol), was
then added to the lithium diisopropylamide (LDA) mixture
*The order of addition could be reversed; See C.
Ainsworth, Y.N. Kuo, J. Organometal. Chem., 46, 73 (1972).
25
over a 5-minute period.
The mixture was stirred for another
30 minutes with the temperature maintained at -78°C, followed
by addition of chlorotrimethylsilane.
The mixture was
allowed to warm to room temperature, and then stirred for
another 2 hours.
Petroleum ether was added and the mixture
was then filtered through Celite, concentrated and vacuumdistilled to give the pure diene.
l-riethoxy-3-trimethylsiloxy-l, 3-butadiene, la (3).
This diene was prepared from commercially available 4-methoxy3-buten-2-one and purified by distillation; b.p. 53-55°C
(5 mm) .
2,4-Bis(trimethylsiloxy)-1,3-pentadiene, lb (4).
This
diene was prepared from 4-trimethylsiloxy-3-penten-2-one
and purified by distillation:
b.p. 73-75°C (5 mm).
The
unsaturated ketone was prepared from acetylacetone as
described in reference (5).
1,3-Pimethoxy-l-trimethylsiloxy-l,3-butadiene, lc (6).
This diene was prepared from methyl (E)-3-methoxy-2butenoate (9):
b.p. 60-63°C (1 mm).
1,1-Bis(trimethylsiloxy)-3-methyl-l,3-butadiene, Id.
This diene was prepared from 0.172 mol of LDA, 29.5 g
(0.172 mol) of trimethylsilyl 3,3-dimethylacrylate and 55 mL
(0.43 mol) of chlorotrimethylsilane.
The residue, after
26
filtration and concentration on a rotatory evaporator, was
vacuum-distilled at 60-62°C (1 nun) to yield 31.1 g (74%) of
the diene; ir (neat), 1645, 1605, 920, 850 cm ^; nmr, 6,
0.15 (s, 9 H), 0.20 (s, 9 H), 1.76 (s, 3 H), 4.05 (s, 1 H),
4.29 (s, 1 H), 4.50 (s, 1 H).
Anal. Calcd. for
Found:
c
1i
H
24°2 S i 2 :
C
'
54
*10;
H
' 9 -84.
C, 53.97; H, 10.07.
1,1-Bis(trimethylsiloxy)-1,3-butadiene, le.
diene was prepared from trimethylsilyl crotonate.
This
Distilla-
tion at 42-44°C (0.05 mm) gave 9 per cent yield of the
diene; ir (neat), 1640, 1600, 920, 850; nmr, 6, 0.15, 0.17
(s, s, 18 H), 4.35 (m, 2 H) , 4.65 (d, 1 H), 6.25 (m, 1 H) .
Anal. Clacd. for c io H 22°2 Si 2 :
Found:
C
'
52
* 1 7 ' H ' 9-57.
C, 52.30; H, 9.40.
Typical Procedure for the Preparation of 4-Pyranones via
Chloro- and Dichloroketene Cycloadditions.
A solution of
freshly distilled chloroacetyl or dichloroacetyl chloride
(0.025 mol) in dry ether (50 mL) was added over a one hour
period to a stirred solution of the diene (0.025 mol) and
triethylamine (0.0275 mol) in dry ether (250 mL) at 22-25°C
under a nitrogen atmosphere.
The resulting mixture was
stirred for 30 minutes after the addition is complete.
The
amine salt was removed by suction filtration and the filtrate was concentrated on a rotatory evaporator.
To the
27
stirred residue was added 5 mL of dry methanol containing
3-5 drops of concentrated hydrochloric acid.
Stirring was
continued for 6 hours, and the methanol was then removed
under vacuum.
The 4-pyranones from the substituted butadiene,
la, were purified by vacuum distillation and the 4-pyranones
from the pentadiene, lb, were extracted with hot hexane
which upon cooling yielded a solid that was recrystallized
from hot hexane or benzene/hexane.
Typical Procedure for the Preparation of 4-Pyranones via
Diphenylketene (7) Cycloadditions.
To a stirred solution
of the diene (0.025 mol) in dry ether (30 mL) was added
freshly distilled diphenylketene (0.025 mol) in 20 mL of
dry ether under a nitrogen atmosphere at 22-25°C.
The
reaction was monitored by infrared, and when the ketene
band had disappeared, the solution was concentrated on a
rotatory evaporator and then hydrolyzed with methanol (10
mL) containing 6-10 drops of concentrated hydrochloric acid
as described for the chloro- and dichloroketene cycloadditions above.
The residue from the hydolysis was recrystal-
lized from benzene/hexane.
2-Chloromethyl-4-pyranone, 4a.
From.2.8 2 g (0.0 25 mol)
of chloroacetyl chloride, 4.3 g (0.025 mol) of 1-methoxy3-trimethylsiloxy-l,3-butadiene, and 2.78 g (0.0275 mol) of
triethylamine was isolated, after hydrolysis and distillation, 1.98 g (55%) of the pyranone; b.p. 102-103°C (0.025 mm);
28
ir (neat), 1650, 1615 cm
nmr, 6, 4.25 (s, 2 H), 6.10
(m, 2 H) , 6.70 (d, 1 H) .
Anal. Calcd. for CgHgClC^:
Found:
C, 50.00; H, 3.47.
C, 48.87; H, 3.85.
2-Dichloromethyl-4-Pyranone, 4b.
From 3.6 8 g (0.025
mol) of dichloroacetyl chloride, 4.3 g (0.025 mol) of
l-methoxy-3-trimethylsiloxy-l,3-butadiene, and 2.78 g
(0.0275 mol) of triethylamine was isolated, after hydrolysis and distillation, 2.5 g (56%) of the pyranone; b.p.
110-120°C (0.025 mm); ir (neat), 1655, 1620 cm -1 ; nmr, 6,
6.2 (m, 1 H), 6.36, 6.40 (s,s, 2 H), 7.65 (d, 1 H).
Anal. Calcd. for C6H4C12C>2:
Found:
C, 40.45; H, 2.25.
C, 40.41; H, 2.37.
2-Chloromethyl-5-methyl-4-pyranone, 4d.
From 2.8 2 g
(0.025 mol) of chloroacetyl chloride, 6.1 g (0.025 mol) of
2,4-bis(trimethylsiloxy)-l,3-pentadiene, and 2.78 g (0.0275
mol) of triethylamine was isolated, after hydrolysis, 1.9 g
(48%) of the pyranone; m.p. 88-89°C; ir (film), 1690, 1660,
1610 cm -1 ; nmr, 6, 2.20 (s, 3 H), 4.13 (s, 2 H), 5.90
(s, 1 H), 6.07 (br, 1 H).
Anal. Calcd. for C ^ C I C ^ :
C, 53.00; H, 4.42.
Found:
C, 52.91; H, 4.51.
2-Dichloromethy1-5-methy1-4-pyranone, 4e.
From 3.6 8 g
(0.025 mol) of dichloroacetyl chloride, 6.1 g (0.025 mol) of
29
2,4-bis(trimethylsiloxy)-1,3-pentadiene, and 2.78 g (0,0275
mol) of triethylamine was isolated, after hydrolysis, 2.5 g
(52%) of the pyranone; m.p. 90-91°C; ir (film, 1660, 1615
cm -1 ; nmr, 6, 2.25 (s, 3 H), 5.91 (s, 1 H), 6.27, 6.30
(s , s, 2 H) .
Anal. Calcd. for C ? H CI 0
Found:
C, 43.54; H, 3.11.
:
C, 43.54; H, 3.25.
2-Diphenylmethyl-4-pyranone, 4c.
From 4.85 g (0.025
mol) of diphenylketene and 4.3 g (0.025 mol) of 1-methoxy3-trimethylsiloxy-l,3-butadiene was isolated, after hydrolysis, 3.6 g (55%) of the pyranone; m.p. 134-135°C; ir (film),
1650, 1615, 1600 cm "S nmr, 6, 5.2 (s, 1 H), 5.85, 6.00
(m,d, 2 H), 6.90 (s, 10 H), 7.25 (d, 1 H).
Anal. Calcd. for
c
1g
H
0
14
:
2
C
'
82
-44; H, 5.34.
Found:
C, 82.72; H, 5.43.
2-Diphenylmethy1-5-methy1-4-pyranone, 4f.
From 4.85 g
(0.025 mol) of diphenylketene and 6.1 g (0.025 mol) of 2,4bis(trimethylsiloxy)-1,3-pentadiene was isolated, after
hydrolysis, 4.83 g (70%) of the pyranone; m.p. 90-92°C; ir
(film), 1660, 1620, 1600 cm -1 ; nmr, <5, 2.70 (s, 3 H) , 5.50
(s, 1 H), 5.76 (d, 1 H), 5.85 (br, 1 H), 7.00 (s, 10 H).
Anal. Calcd. for
C, 82.46; H, 5.88.
82.61; H, 5.80.
Found:
30
Typical Procedure for the Preparation of Substituted5,6-dihydro-2H-pyran-2-ones via Chloro- and Dichloroketene
Cycloadditions.
A solution of 0.0275 mol of freshly
distilled chloroacetyl or dichloroacetyl chloride in 50 mL
of dry ether was added over a one hour period to a stirred
solution of 0.025 mol of the diene and 0.025 mol of triethylamine in 250 mL of dry ether at 22-25°C under a nitrogen
atmosphere.
The resulting mixture was stirred for an addi-
tional 30-minute period.
The amine salt was then removed
by filtration, and the filtrate was concentrated on a
rotatory evaporator.
Hydrolysis was accomplished by
dissolving the residue in 5-6 mL of dry mathanol and adding
3-4 drops of concentrated hydrochloric acid.
The solution
was stirred for two hours and the methanol was removed under
vacuum.
The resulting residue was purified by column chro-
matography on Sargent Welch Silica Gel 60, 70-230 mesh
using ether/petroleum ether (1:9) as eluent.
Typical Procedure for the Preparation of Substituted5/6-dihydro-2H-pyran-2-ones via Diphenylketene (7) Cycloaddition.
To a stirred solution of 0.025 mol of the diene
in 15-20 mL of dry ether was added 0.025 mol of diphenylketene under a nitrogen atmosphere at 22-25°C.
The reaction
was monitored by infrared, and when the ketene band at 2100
cm
1
had disappeared (usually about 15-20 minutes after
addition), the ether was evaporated under reduced pressure.
The resulting residue was hydrolysed with 5-6 mL of methanol
31
and 3-4 drops of concentrated hydrochloric acid.
The solvent
was then evaporated, and the residue was purified by column
chromatography.
6-Chloromethylene-4-methoxy-5,6-dihyro-2H-pyran-2-one,
7a and Methyl 6-Chloro-5-keto-3-methoxy-3-mexenoate, 10a.
From 3.10 g (0.0275 mol) of chloroacetyl chloride, 5.05 g
(0.0 25 mol) of 1,3-dimethoxy-l-trimethylsiloxy-l,3-butadiene
and 2.73 g (0.025 mol) of triethylamine was isolated, after
hydrolysis and chromatography, 1 g (23%) and 2.5 g (48%) of
7a and 10a respectively;
7a; m.p. 74-75 C; ir (film), 1720, 1660, 1620 cm"1; nmr,
6, 3.15 (s, 2 H), 3.63 (s, 3 H), 5.02 (s, 1 H), 5.23 (s, 1 H).
Anal. Calcd. for C7H7C1C>3:
C, 4 8 .27; H, 4.02.
Found:
C, 47.87; H, 4.10.
10a? ir (neat), 1735, 1680, 1590 cm"1; nmr, 6, 3.58
(s, 2 H), 3.65 (s, 3 H), 3.66 (s, 3 H), 3.92 (s, 2 H), 5.68
(s, 1 H) .
Anal. Calcd. for CgH^ClO^:
C, 46 .60; H, 5.34.
Found:
C, 46.89; H, 5.59.
6-Dichloromethylene-4-methoxy-5,6-dihydro-2H-pyran-2one, 7b and Methyl 6—Dichloro—5—keto—3—methoxy—3—hexenoate,
10b»
From 4.05 g (0 .0275 mol) of dichloroacetyl chloride,
5.05 g (0.0 25 mol) of 1,3-dimethoxy-l-trimethylsiloxy-l,3butadiene and 2.78 g (0.025 mol) of triethylamine were
isolated after hydrolysis and chromatography, 1.56 g (30%)
and 2.0 g (34%) of 71d and 10b respectively.
32
7b_: m.p. 129-130°C; ir (film), 1730, 1645, 1624 cm" 1 ;
nmr, 6, 3.40 (s, 2 H) , 3.72 (s, 3 H) , 5.1 (s, 1 H) .
Anal. Calcd. for C_H CI 0 :
/ o Z 6
Found; C, 40.29; H, 2.97.
C, 40.38; H, 2.88.
10b; ir (neat), 1740, 1690, 1595 cm - 1 ; nmr, 6, 3.55
(s, 2 H), 3.65 (s, 3 H), 3.68 (s, 3 H), 5.63 (s, 1 H),
5.75 (s, 1 H).
Anal. Calcd. for
Found:
C
8H10C12°4:
C
'
39
*83;
H
'
4
-15-
C, 39.48; H, 4.32.
6-Diphenylmethylene-4-methoxy-5,6-dihydro-2H-pyran2-one, 7c.
From 4.85 g (0.0 25 mol) of diphenylketene, and
5.05 g (0.025 mol) of 1,3-dimethoxy-l-trimethylsiloxy-l,3butadiene was isolated, after hydrolysis, 4.10 g (56%) of
the pyranone; m.p. 164-165°C; ir (film), 1710, 1635, 1600
cm - 1 ; nmr, <5, 3.20 (s, 2 H), 3.52 (s, 3 H), 5.03 (s, 1 H),
7.00 (s, 10 H).
Anal. Calcd. for C 1 9 H 1 6 C> 3 :
C, 78 .08; H, 5.48.
Found:
C, 78.27; H, 5.36.
6—Diphenylmethylene-4-methyl-5,6-dihydro-2H-pyran2-one, 7d.
From 4.85 g (0.0 25 mol) of diphenylketene and
6.1 g (0.025 mol) of 1,1-bis(trimethylsiloxy)-3-methyl-l,3butadiene was isolated, after hydrolysis, 4.69 g (68%) of
the pyranone; m.p. 123-124 C; ir (film), 1740, 1640, 1635
cm 1 ; nmr, <5,
6, 1.79 (s, 3 H
H), 3.08 (s, 2 H), 5.66 (s, 1 H) ,
7.00 and 7.08 (s,s, 10 H).
33
Anal. Calcd. for c i9 H i5°2 :
C
' 82.61; H, 5.80.
Found:
C, 82.85; H, 5.74.
Typical Procedure for the Preparation of Substituted-2Pyranones from Substituted-5,6-dihydro-2H-pyranone-2-ones,
8a-d.
To a solution of 0.2 g of substituted-5,6-dihydro-
2H-pyran-2-one in 10-15 mL of benzene was added 2-3 drops
of triethylamine.
The reaction mixture was stirred for
2 hours at 22-25°C, after which the solvent was removed.
The resulting solid was recrystallized from hexane
or benzene/hexane.
6-Chloromethyl-4-methoxy-2-pyranone, 8a.
From 0.2 g
(1.15 mmol) of 6-chloromethylene-4-methoxy-5,6-dihydro-2Hpyran-2-one, 7ci, was isolated 0.18 g (89%) of the pyranone;
m.p. 120-121°C; ir (film), 1730, 1665, 1620 cm -1 ; nmr, 6,
3.67 (s, 3 H), 4.07 (s, 2 H), 5.26 (d, 1 H), 5.86 (d, 1 H).
Anal. Calcd. for C 7 H 7 C10 3 :
C, 4 8.27; H, 4.02.
Found:
C, 48.21; H, 4.26.
6~Dichloromethyl-4-methoxy-2-pyranone, 8b.
From 0.2 g
(0.96 mmol) of 6-dichloromethylene-4-methoxy-5,6-dihydro-2Hpyran-2-one, 7b, was isolated 0.19 g (96%) of the pyranone;
m.p. 132-133 C; ir (film), 1719, 1658 cm
nmr, 6, 3.69
(s, 3 H), 5.30 (d, 1 H), 6.01 (s, 1 H), 6.09 (d, 1 H).
Anal. Calcd. for
Found:
C, 4 0.30; H, 2.96.
C, 40 .38; H, 2.88.
34
6-Diphenylmethyl-4-methoxy-2-pyranone, 8c.
From 0.2 g
(0.68 iranol) of 6-diphenylmethylene-4-methoxy-5,6-dihydro2H-pyran-2-one, 7c, was isolated 0.19 g (95%) of the
pyranone; m.p. 129-130°C; ir (film), 1720, 1640, 1600 cm"1;
nmr, 6, 3.60 (s, 3 H), 5.00 (s, 1 H), 5.25 (d, 1 H), 5.45
(d, 1 H), 7.00 (m, 10 H).
Anal. Calcd. for
C
H
19
16°3:
C, 78.08; H, 5.48.
Found:
C, 77.95; H, 5.55
6-Diphenylmethyl-4-methyl-2-pyranone, 8d.
From 0.2 g
(0.72 mmol) of 6-diphenylmethylene-4-methyl-5,6-dihydro2H-pyran-2-one, 7d, was isolated 0.18 g (90%) of the
pyranone; m.p. 142-143°C; ir (film), 1720, 1640, 1600 cm -1 ;
nmr, 6, 1.97 (s, 3 H), 4.98 (s, 1 H), 5.48 (s, 1 H), 5.70
(s, 1 H) , 7.00 (m, 10 H) .
Anal. Calcd. for
C
19
H
16°2
:
C
'
82
-61; H, 5.80.
Found:
C, 82.64; H, 5.94.
6-Dichloromethyl-4-methyl-2-pyranone, 8e, and 2-(2,2Dichloro-l-methyl-3-oxocyclobutyl) Ethanoic acid, 11.
A
solution of 3.68 g (0.025 mol) of freshly distilled dichloroacetyl chloride in 50 mL of dry ether was added over a one
hour period to a stirred solution of 6.1 g (0.025 mol) of
1,1-bis(trimethylsiloxy)-3-methyl-l,3-butadiene and 2.78 g
(0.0275 mol) of triethylamine in 250 mL of dry ether at
22-25°C under a nitrogen atmosphere.
The resulting mixture
35
was stirred for an additional 30-minute period.
The amine
salt was removed by filtration, and the filtrate was concentrated on a rotatory evaporator.
Hydrolysis was
accomplished by dissolving the residue in 5-6 mL of dry
methanol and adding 3—4 drops of concentrated hydrochloric
acid.
The solution was then stirred for two hours, and the
methanol removed under vacuum.
Purification of the
residue by column chromatography gave 8e and 11 in 33%
(1.6 g) and 55% (2.9 g) respectively.
8e; m.p. 122-123°C; ir (film), 1720, 1640, 1620 cm"1;
nmr, 6, 2.15 (s, 3 H), 5.92 (s, 1 H), 6.13 (s, 1 H), 6.19
(s, 1 H) .
Anal. Calcd. for C^H^C^C^:
C, 43.75; H, 3.25.
Found:
C, 43.76; H, 3.17.
11; m.p. 99.5-100°C; ir (film), 3010-3660, 1805, 1710
cm -1 ; nmr, 6, 1.49 (s, 3 H), 2.83 (s, 2 H), 2.89 (d, 1 H),
3.42 (d, 1 H), 10.70 (s, 1 H).
Anal. Calcd. for C ^ H g C l ^ :
C, 40.00; H, 3.81.
Found:
C, 39.81; H, 3.99.
2-(2, 2-Diphenyl-3-oxocyclobut.yl) Acetanilide, 12 . The
carboxylic acid resulting from the chromatographed and hydrolyzed cycloaddition product from 0.7 g (3.0 mmol) of 1,1-bis(trimethylsiloxy)-1,3-butadiene and 0.6 g (3.0 mmol) of
diphenylketene was treated with thionyl chloride in refluxing benzene for 6 hours.
The benzene and excess thionyl
36
chloride were removed under vacuum, and the residue was
dissolved in 10 mL of benzene and 1 mL of aniline was
added dropwise at room temperature.
The reaction mixture
was stirred for five hours and then transferred to a
separatory funnel.
The mixture was washed sequentially w i t h
5 mL of water, 5 mL of 10% HC1, 5 mL of benzene, 10% NaOH
and a final 5 mL of water.
The solution was dried over
MgSO^ and then concentrated under vacuum.
The oily residue
was crystallized from hot benzene and hexane to yield 0.2 g
(19% based on diene or ketene); m.p. 155-156°C; ir
3200-3500, 1765, 1650 cm
3.60
(m, 3 H), 3.9
1
; nmr, 5, 2.32
(quintet, 1 H), 5.06
(film),
(d, 2 H), 2.80(s, 1 H), 7.13
(m, 15 H) .
Anal. Calcd. for
3.94.
Found:
c
24
H
2lN°2:
C
'
81
* 1 3 »*
H
>
5.92; N,
C, 81.09; H, 5.95; N, 4.11.
(Z) - 2-Methoxymethylenecyclohexanone, lg.
This enol ether
was prepared in 74% yield from 2-hydroxymethylenecyclohexanone
tion of
(8) using the procedure described for the preparaB-methoxymethylene-a-tetralone; b.p. 84-86°C
(2 mm); ir
2.23
(neat), 1660, 1610 cm
(Br, 4 H),
3.73
(s, 3 H) , 6.88
nmr, 6, 1.68
(Br, 4 H) ,
(t, 1 H) .
(Z)-g-Hydroxymethylene-a-tetralone.
A 3-necked 2 L
oven-dried flask, equipped with a mechanical stirrer, was
swept with dry nitrogen.
To the flask was added 500 mL of
37
dry ether, 11.5 g (0.50 g-atom) of sodium metal*, 73 g
(0.50 mol) of freshly distilled a-tetralone, 55 g (0.75 mol)
of
ethyl formate and 5 mL of absolute ethanol.
The flask
was then placed in an ice-bath and stirred vigorously for
six hours.
After standing overnight at room temperature,
13 mL of absolute ethanol was added to the reaction mixture,
and the mixture was stirred for another two hours.
The
mixture was then treated with 100 mL of water and the
organic layer was washed twice with 50 mL of water.
The
combined aqueous extracts were washed twice with 50 mL of
ether, and then acidified with 82.5 mL of 6N hydrochloric
acid solution.
The acidified aqueous solution was extracted
thrice with 150 mL of ether.
The combined ether extracts
were washed with saturated sodium chloride solution, and
then dried over anhydrous magnesium sulfate.
Concentration
and fractional distillation of the residue gave 63 g (72%)
of the functionalized alcohol; b.p. 107-114°C (0.025 mm);
ir (neat), 3100-3700 (weak, broad OH band), 1625, 1600 cm -1 ;
nmr, 6, 2.50 (m, 2 H), 2.85 (m, 2 H), 7.1 (m, 3 H), 7.73
(m, 1 H), 7.91 (s, 1 H), 14.20 (s, 1 H).
(Z)-g-Methoxymethylene-a-tetralone, lh.
A 3-necked 500 mL
round bottom oven-dried flask was equipped with a pressure
*For best results, the sodium metal was cut into very
small cubes.
38
equalizing dropping funnel, a reflux condenser, a calcium
chloride drying tube and a magnetic stirrer.
To the flask
was added 300 mL of dry reagent acetone, 24.2 g (0.175 mol)
of anhydrous potassium carbonate and 20.3 g (0.117 mol) of
freshly distilled 3-hydroxymethylene-a-tetralone.
The
mixture w a s heated to a gentle reflux with vigorous stirring,
and 15 g (0.119 mol) of dimethylsulfate was added over a
20-minute period.
The reaction mixture was stirred under
continued gentle reflux for another 14 hours.
On cooling,
the mixture was filtered, concentrated and distilled at
125-135°C
(0.025 mm).
Recrystallization of the solidified
distillate from hexanes gave 18.7 g (85%) of lh; m.p.
57.5-59°C; ir (film), 1675, 1610, 1585 c m - 1 ;
(Br, 4 H), 3.74
(s, 3 H), 7.15
Anal. Calcd. for C 1 2 H 1 2 C > 2 :
Found:
(m, 4 H), 7.73
nmr, 5, 2.70
(m, 1 H).
C, 76.69; H, 6.38.
C, 76.34; H, 6.32.
Typical Procedure for the Cycloaddition Reaction of
Diphenylketene
(7) with the B-Methoxy-a,g-unsaturated ketones,
A mixture of freshly distilled diphenylketene
and methoxy vinyl ketone
(5.67 mmol)
(5.67 mmol) was heated at 82 + 5°C.
The reaction w a s monitored by infrared, and when the
ketene band at 2100 cm ^ had disappeared
(usually after
2-3 hours), the reaction mixture was allowed to cool to
about 50°C.
The mixture w a s treated with about 5-7 mL of
39
petroleum ether, and stirred gently.
The resulting crystal-
line product was recrystallized from benzene/hexane.
3, 3-Diphenyl-4-methoxy-6-methy1-3,4-dihydro-2Hpyran-2-one, 13c. From 1.1 g (5.67 mmol) of diphenylketene
and 0.57 g (5.67 mmol) of commercially available 4-methoxy3—buten—2—one was isolated 1.30 g (78%) of the pyranone;
m.p. 160-161°C; ir (film), 1750, 1700, 1590 cm -1 ; nmr, 6,
1.76 (s, 3 H), 3.20 (s, 3 H), 4.40 (d, 1 H), 5.42 (d, 1 H),
7.25 (s, 10 H) .
Anal. Calcd. for
C
H
19
18°3:
C, 77.55; H, 6.12.
Found:
C, 77.25; H, 6.21.
3,3-Dipheny1-4-methoxy-5,6-tetramethylene-3,4-dihydro2H-pyran-2-one, 15c. From 1.1 g (5.67 mmol) of diphenylketene and 0.79 g (5.67 mmol) of 2-methoxymethylenecyclohexanone was isolated 1.7 g (90%) of the pyranone; m.p.
135-136.5°C; ir (film, 1760, 1700, 1600 cm -1 ; nmr, 6,
1.10-1.73 (Br, 4 H), 1.74-2.53 (Br, 4 H), 3.10 (s, 3 H),
4 .20 (s, 1 H), 7.21 (s, 10 H) .
Anal. Calcd. for C 2 2 U 22°3 :
C
'
79
-04'* H ' 6.59.
Found:
C, 78.93; H, 6.76.
3,3-Dipheny1-4-methoxy-3,4,5,6-tetrahydro-2H-naphtho[2r1—e]pyran-2—one, 18.
From 1.1 g (5.67 mmol) of diphenyl-
ketene and 1.0 7 g (5,67 mmol) of 3-methoxymethylene-atetralone was isolated 1.78 g (82%) of the pyranone; m.p.
40
161-162 C; ir (film), 1760, 1760, 1600 cm
2.85
(Br, 4 H), 3.05
(s, 3 H), 4.25
nmr, 6, 2.30-
(s, 1 H), 6.70-7.30
(aromatic, 14 H).
Anal. Calcd. for
C
H
26
22°3:
C
'
81
- 68 '*
H
' 5.76.
Found:
C, 81.50; H, 5.81.
3-Ethyl-3-phenyl-4-methoxy-3,4,5,6-tetrahydro-2Hnaphtho-[2,l-e3pyran-2-one, 19.
A mixture of 0.415 g
(2.84 mmol) of phenylethylketene and 0.54 g (2.84 mmol) of
3-methoxymethylene-a-tetralone was heated at 82 + 5°C.
The
reaction was monitored by infrared, and when the ketene
band at 2100 cm
had disappeared
(usually about 4 hours) ,
the reaction mixture was allowed to cool to room temperature,
The 2-pyranone was purified by flash chromatography on
Silica Gel to afford 0.62 g (65%); m.p., 122-123 C; ir
(film), 1750, 1660, 1590 c m - 1 ; nmr, 6, 0.72
(quart, 2 H), 2.39-2.58
3.38 (s, 3 H), 4.25
(Br, 2 H),
(s, 1 H), 6.88-7.54 (m, 9 H).
Anal. Calcd. for
Found:
(Br, 2 H), 2.58-2.78
(t, 3 H), 2.22
C
22
H
22°3:
C
'
79
-04'
H
' 6.59.
C, 79.22; H, 6.57.
Typical Procedure for the Cycloaddition Reaction of
Halogenated Ketenes with g-Methoxy-a,B-Unsaturated Ketones.
A solution of 0.0125 mol of the freshly distilled chlorinated acetyl chloride in 50 mL of dry hexane was added over
41
a two hour period to a stirred, refluxing solution of
0.0125 mol of the 3-methoxy-a,6-unsaturated ketone and
0.0125 mol of triethylamine in 100 mL of dry hexane under
a nitrogen atmosphere.
The resulting mixture was stirred
for an additional 30-minute period.
The amine salt was
then removed by filtration, and the filtrate was concentrated on a rotatory evaporator.
The residue was then
subjected to one of two treatments:
Zinc/Acetic Acid Treatment; to the concentrated residue
was added 40 mL of acetic acid and 2 mL of water.
The
mixture was stirred at room temperature, and 4 g of powdered
zinc was added in one portion.
24 hours.
The mixture was stirred for
Excess zinc and the zinc salt were filtered
and washed with 40 mL of chloroform.
The filtrate was
taken into a separatory funnel and washed several times
with water until the aqueous layer tested neutral with
litmus paper.
The chloroform layer was dried over MgSO^
and concentrated to give the substituted 2-pyranones.
*
Triethylamine Treatment; To the concentrated residue
was added 40 mL of dry benzene and 6 mL of dry triethylamine.
The mixture was stirred and refluxed overnight,
cooled, filtered, and then concentrated under vacuum to
give compounds 21d-e.
*Applicable only in the cycloaddition of chlorinated
ketenes and B-methoxymethylene-a-tetralone, lh.
42
3-Chloro-6-methyl-2-pyranone, 14a.
From 1.84 g
(0.0125 mol) of dichloroacetyl chloride, 1.25 g (0.0125
mol) of 4-methoxy-3-buten-2-one, If, and 1.26 g (0.0125
mol) of triethylamine was isolated, after treatment with
zinc, 0.5 g (28%) of the pyranone; m.p., 83-84°C; ir
(film), 1695, 1625, 1545 cm 1 ; nmr, 6, 2.29 (Br, 3 H),
6.12 (d, 1 H), 7.50 (d, 1 H).
Anal. Clacd. for C 6 H 5 C10 2 :
Found:
C, 50.00; H, 3.47.
C, 49.88; H, 3.60.
3-Phenyl-6-methyl-2-pyranone, 14b.
From (0.0125 mol)
of a-chlorophenylacetyl chloride, 1.25 g (0.0125 mol) of
4-methoxy-3-buten-2-one and 1.26 g (0.0125 mol) of triethylamine was isolated, after the zinc treatment, 0.6 g
(26%) of the pyranone; m.p., 69-70°C; ir (film), 1700,
1620, 1590, 1555, cm 1 ; nmr,
, 2.18 (Br, 3 H), 6.01
(d, 1 H), 7.14-7.71 (m, 6 H).
Anal. Calcd. for C 1 2 H 1 ( ) 0 2 :
Found:
C, 77.42; H, 5.38.
C, 77.60; H, 5.11.
3-Chloro-4-methoxy-3-phenyl-5,6-tetramethylene-3,4dihydro-2H-pyran-2-one, 15b.
From 2.36 g (0.0125 mol) of
a-chlorophenylacetyl chloride, 1.75 g (0.0125 mol) of
2-methoxymethylenecyclohexanone, lc[, and 1.26 g (0.0125
mol) of triethylamine was isolated, after treatment of the
cycloaddition residue with ether, 2.5 g (68%) of the
43
dihydro-2-pyranone; m.p., 111-112°C; ir (film), 1765, 1685
cm 1 ; nmr, 5, 1.41-2.20 (m, 4 H), 3.52 (s, 3 H), 4.13
(s, 1 H), 7.35 (s, 5 H).
Anal. Calcd. for C ^ H ^ C I C ^ :
Found:
C, 65.75; H, 5.82.
C, 65.52; H, 6.04.
3-Chloro-5,6-tetramethylene-2-pyranone, 16a.
From
1.84 g (0.0125 mol) of dichloroacetyl chloride, 1.75 g
(0.0125 mol) of 2-methoxymethylenecylohexanone, l£, and
1.26 g (0.0125 mol) of triethylamine was isolated, after
the zinc treatment 1.3 g (56%) of the pyranone; m . p . ,
124-125°C; ir (film), 1700, 1625, 1535 cm"1; nmr, 6,
1.61-1.94 (m, 2 H), 2.30-2.69 (Br, 2 H), 7.27 (s, 1 H).
Anal. Calcd. for C g H g Cl0 2 :
Found:
C, 58.70; H, 4.89.
C, 59.00; H, 4.86.
3-Phenyl-5,6-tetramethylene-2-pyranone, 16b.
From
2.36 g (0.0125 mol) of a-chlorophenylacetyl chloride,
1.75 g (0.0125 mol) of 2-methoxymethylenecyclohexanone,
lg, and 1.26 g (0.0125 mol) of triethylamine was isolated
after the zinc treatment, 1.3 g (47%) of the pyranone;
m . p . , 116-117°C; ir (film), 1690, 1625, 1550 cm"1
nmr,
6, 1.44-1.72 (m, 2 H), 2.12-2.49 (m, 2 H), 7.03-7.58
(m, 6 H).
Anal. Calcd. for C15H14C>2:
Found:
C, 79.40; H, 5.96.
C, 79.65; H, 6.19.
44
3-Chloro-5,6-dihydro-7,8-benzocoumarin, 21a.
From
1.84 g (0.0125 mol) if dichloroacetyl chloride, 2.35 g
(0.0125 mol) of 3-methoxymethylene-a-tetralone, 111, and
1.26 g (0.0125 mol) of triethylamine was isolated, after
the zinc treatment, 2.1 g (72%) of the substituted dihydrobenzocoumarin; m.p., 145-146°C; ir (film), 1715, 1695,
1615 cm
1
; nmr, 6, 2.47-2.83 (m, 2 H), 2.82-3.03 (m, 2 H),
6.95-7.40 (m, 4 H), 7.57-7.76 (m, 1 H).
Anal. Calcd. for C 1 3 H g C 1 0 2 :
Found:
C, 67.24; H, 3.88.
C, 6 7.03; H, 3.77.
3-Phenyl-5,6-dihydro-7,8-benzocoumarin, 21b.
From
2.36 g (0.0125 mol) of a-chlorophenylacetyl chloride,
2.35 g (0.0125 mol) of 3-methoxymethylene-a-tetralone, lh,
and 1.26 g (0.0125 mol) of triethylamine was isolated,
after the zinc treatment, 2.0 g (58%) of the substituted
dihydrobenzocoumarin; m.p., 143-144°C; ir (film), 1690,
1615, 1525 cm
1
; nmr, 6, 2.55-2.74 (m, 2 H), 2.82-3.01
(m, 2 H), 7.14-7.85 (m, 10 H).
Anal. Clacd. for
Found:
c
1
9Hl402:
C
' 83.21; H, 5.11.
C, 83.04; H, 4.93.
3-Methy1-5,6-dihydro-7,8-benzocoumarin, 21c.
From
1.59 g (0.0125 mol) of a-chloropropionyl chloride, 2.35 g
(0.0125 mol) of B-methoxymethylene-a-tetralone, lh, and
1.26 g (0.0125 mol) of triethylamine was isolated, after
the zinc treatment, 1.0 g (38%) of the substituted
45
dihydrobenzocoumarin; m.p., 133-134°C; ir (film), 1690,
1625, 1590, 1570, 1540 cm 1 , nmr, 6, 2.00 (d, CH^) , 2.372.64 (m, 2 H), 2.64-2.92 (m, 2 H), 6.92-7.72 (m, 5 H).
C, 79.25; H, 5 . 6 6 .
Anal. Calcd. for C 14 H 12 C> 2 :
Found:
C, 78.94; H, 5.78.
3-Chloro-4-methoxy-5,6-dihydro-7,8-benzocoumarin, 2Id.
From 1.84 g (0.0125 mol) of dichloroacetyl chloride, 2.35 g
(0.0125 mol) of B-methoxymethylene-a-tetralone, lh, and
1.26 g (0.0125 mol) of triethylamine was isolated, after
the triethylamine treatment, 2.3 g (70%) of the substituted dihydrobenzocoumarin; m.p., 138-139°C; ir (film),
1700, 1618 cm 1 ; nmr, 6, 2.18-2.66 (m, 4 H), 3.82 (s, 3 H),
6.71-7.05 (m, 3 H), 7.20-7.39 (dd, 1 H).
Anal. Calcd. for C ^ H ^ C I C ^ :
Found:
C, 64.12; H, 4.20.
C, 6 3.69; H, 4.15.
3-Phenyl-4-methoxy-5,6-dihydro-7,8-benzocoumarin, 21e.
From 2.36 g (0.0125 mol) of a-chlorophenylacetyl chloride,
2.35 g (0.0125 mol) of B-methoxymethylene-a-tetralone, lh,
and 1.26 g of triethylamine was isolated, after the triethylamine treatment, 2.2 g (58%) of the substituted
dihydrobenzocoumarin; m . p . , 137-138°C; ir (film), 1680,
1615, 1530 cm"1; nmr, 6, 2.57-2.99 (m, 4 H), 3.38 (s, 3 H),
7.09-7.88 (m, 9 H).
Anal. Calcd. for
Found:
C, 79.02; H, 5.42.
C, 78.95; H, 5.26.
46
Typical Procedure for the Synthesis of Substituted
7,8-Benzocoumarins via the use of NBS*.
A mixture of lg
of 5,6-dihydrobenzocoumarin, an equivalent amount of NBS
and 0.1 g of benzoyl peroxide in 50 mL of CC14 was refluxed
for 18 hrs.
The reaction mixture was filtered hot under
suction, and the resulting filtrate was concentrated under
vacuum to give the crude product.
The product was re-
crystallized from ether or chloroform.
3-Chloro-7,8-benzocoumarin, 22a.
From 1.0 g (4.31
mmol) of 21a, 0.77 g (4.31 mmol) of NBS and 0.1 g of benzoyl
peroxide was isolated 0.79 g (80%) of the benzocoumarin;
m.p., 166-167°C; ir (film), 1725, 1705, 1620, 1590 cm"1;
nmr, 6, 7.26-7.92 (m, 6 H), 8.40-8.51 (dd, 1 H).
Anal. Calcd. for C 1 3 H 7 C10 2 :
Found:
C, 6 7.83; H. 3.04.
C, 67.48; H, 3.03.
3-Phenyl-7,8-benzocoumarin, 22b.
From 1.0 g (3.65
mmol) of 21b, 0.65 g (3.65 mmol) of NBS and 0.1 g of
benzoyl peroxide was isolated 0.7 g (71% of the benzocoumarin; m.p., 212-213°C; ir (film), 1690, 1660,
(weak), 1625 (weak), 1590 (weak); nmr, 6, 7.13-7.91
(m, 1 H), 8.41-8.60 (m, 1 H).
Anal. Calcd. for
Found:
C
H
:
19 12°2
C
'
83
* 8 2 ' H ' 4.41.
C, 82.28; H, 4.34.
*N-bromosuccinimide from Aldrich was recrystallized
from water prior to use.
47
3-Chloro-4-methoxy-7,8-benzocoumarin, 22d.
From 0.6 g
(2.29 mmol) of 21d, 0.41 g (2.29 mmol) of NBS, and 0.05 g
of benzoyl peroxide was isolated 0.45 g (76%) of the
benzocoumarin; m.p., 166-167°C; ir (film), 1705, 1625,
1585 cm -1 ; nmr, 6, 4.34 (s, 3 H), 7.49-7.87 (m, 5 H),
8.21-8.49 (dd, 1 H).
Anal. Calcd. for C14H9C1C>3:
Found:
C, 64.62; H, 3.46.
C, 64.78; H, 3.29.
3-Phenyl-4-methoxy-7,8-benzocoumarin, 22e.
From 1.0 g
(3.29 mmol) of 21e, 0.59 g (3.29 mmol) of NBS, and 0.1 g of
benzoyl peroxide was isolated 0.7 g (71%) of the benzocoumarin; m.p., 152-153°C; ir (film), 1690, 1620, 1580,
1550 cm - 1 ; nmr, 6, 3.54 (s, 3 H), 7.31-7.90 (m, 5 H),
8.30-8.60 (dd, 1 H).
Anal. Calcd. for
Found:
c
2o
H
14°3 :
C
'
79
- 4 7 ; H, 4.64.
C, 79.53; H, 4.53.
3-Methyl-7,8-benzocoumarin, 22c.
A solution of 0.15 g
(0.71 mmol) of 21c and 0.18 g (0.78 mmol) of DDQ in 30 mL
of dry benzene was stirred and refluxed for 18 hrs.
The
solution was filtered, and the filtrate was concentrated
in vacuo.
The resulting black residue was purified by
chromatography on a column of acidic alumina upon elution
with hexane/ethyl acetate (1:1) to yield 0.10 g (68%) of
the benzocoumarin; m.p., 129-130 .5°C; ir (film), 1690,
48
1630, 1605 cm
nmr,
, 2.23 (d, 3 H) , 7.27-7.92 (m, 6 H) ,
8.31-8.58 (m, 1 H).
Anal. Calcd. for C ^ H ^ C ^ :
Found:
C, 78.30; H, 4.91.
C, 80.00; H, 4.76.
CHAPTER BIBLIOGRAPHY
1.
Still, W.C., J. Org. Chem., £3, 2933 (1978).
2.
This procedure is patterned after the one described by
Wissner, A., J. Org. Chem., 44, 4617 (1979).
3.
Danishefsky, S., Kitahara, T., J. Amer. Chem. Soc., 96,
7807 (1974) .
~
—
4.
Krageloh, K., Simchen, G., Synthesis, 30 (1981).
5.
Torkelson, S., Ainsworth, C., Synthesis, 722 (1976).
6.
Savard, J., Brassard, P., Tetrahedron Letters, 4911
(1979) .
7.
Taylor, E.C., McKillop, A., Hawks, G.H., Org. Syn., 52,
36 (1972) .
—
8.
Ainsworth, C., Org. Syn., 39, 27 (1959).
9.
Smissman, E.E., Voldeng, A.N., J. Org. Chem., 29, 3161
(1964).
~ —
—
49
CHAPTER III
RESULTS AND DISCUSSION
Siloxy and/or alkoxy substituted dienes are electronrich conjugated dienes which have recently found widespread
use in the syntheses of natural and industrial products
through Diels-Alder reactions (1,2,3,4).
The highly nucleo-
philic nature of these dienes makes them excellent ketenophiles; these dienes readily undergo (4+2) and/or (2+2) cycloaddition reactions with chloro-, dichloro- and diphenylketenes
to give dihydropyrans and/or substituted vinylcyclobutanones
that smoothly undergo hydrolysis to give pyranones and/or
substituted cyclobutanones (5,6).
The direction of polari-
zation within the dienes controls the regiochemistry observed
in these reactions, and the substitution in the 3-position of
the dienes controls periselectivity.
From the reactions of
these dienes, it is apparent that carbon atom 4 is the most
reactive nucleophilic site of the dienes; an observation consistent with theoretical predictions and polarization
expectations (7,8,9).
Chloro- and dichloroketenes were generated in situ in
the presence of the dienes by the dehydrohalogenation of
chloro- and dichloroacetyl chlorides respectively, using
50
51
triethylamine.
Diphenylketene is an isolable ketene and
was prepared according to the procedure described by
Taylor and McKillop (10).
For best results, this ketene
was freshly distilled prior to each cycloaddition reaction.
The cycloaddition of chloro-, 2a, dichloro-, 2b, and
diphenylketenes, 2c, with 1—methoxy—3—trimethylsiloxy—1,3—
butadiene, la, (11) and 2,4-bis(trimethylsiloxy)-1,3pentadiene, lb, (12) occurred readily at room temperature
to yield exclusively the corresponding dihydropyrans, 3.
The dihydropyrans were not isolated, but were easily
(HTC)qSiO
R
J J |
/
H-C=C-CH=C
x
OR
X
\
1
c=c=o
X
R 2 =H
la
R =CH.
lb
R =Si(CH-,)
3 3
2b
X^Cl, X 2 =H
1 2
X =X =C1
2c
X 1 =X 2 =Ph
2a
R 2 =CH.
O-SI (CH3) 3
CH 3 OH/HCI
4a-f
52
hydrolysed on treatment with methanol containing a few drops
of concentrated hydrochloric acid to give the substituted
4-pyranones, 4a-f, in respectable yields.
also resulted in £.
Heating of 3
The structural proof of compounds
4a-f was based on the measured spectroscopic data.
The
infrared spectra showed the characteristic pyranone
absorption ranging from 1615 to 1660 cm - 1 .
The 1H-NMR
spectra exhibited absorptions for typical pyranone hydrogens
from 5.85 to 6.40 p.p.m.
Compounds 4a-c showed AB patterns
for the hydrogen on the 5-position of the pyranone suggesting
slight couplings between the hydrogen on the 3- and
5-positions.
The hydrogen on the 6-position centered around
7.25 to 7.65 p.p.m., and showed up as doublets.
All of these
spectral characteristics are consistent with literature
reports (13,14,15).
The
13
C-NMR exhibited 5 resonances for
the pyranone nucleus in the completely decoupled spectra as
revealed in Table 1.
Assignments were based on the off-
resonance coupled spectra.
The resonances for carbon atoms
3 and 5 were not distinguished.
However, if the y-effect
of the substituents on the methyl derivative on the 2-position
is significant, one would expect a slight upfield shift for
carbon atoms 3 relative to carbon 5.
The assignments of
carbon atoms 3 and 5 in Table 1 were based on this assumption.
Nevertheless, it is not inconceivable that in the case of
compounds 4a, 4b, 4d and 4e, the inductive effect through
53
cn
CO
oo
CN
00
rCM
00
A
00
-p
o
oo r00 CN
rH
w
g
0
4J
d
1
u
CN
00
CN
sh
a)
•
•
<d
w
CD
a
0
c
fd
JH
>i
04
|
H
w
CQ
C
E-*
<
'd
c
fd
r-
cn
rH
1
1
u
rH
1
I
a\
rH
VD
•
*
1
CTs
•
C\
rH
rH
O
00
I
K
a
CN
CN
CN
•
•
i—1
m
VD
in
•
•
•
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rH
in
VD
in
in
m
r»
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CTi
VD
00
VD
I
u
rI
00
VD
00
•
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•
•
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m
in
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in
in
rH
in
rH
CN
VD
i—1
o
VD
rH
in
VD
rH
<T>
CN
r-
00
rH
CJ
Q
U
LO
I
o
w
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M-4
•H
-a
cn
rH
cd
o
•H
e
(U
x:
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00
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u
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w
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a
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fcn
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<T\
S3
W
>
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a
VD
•
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VD
rH
rH
VD
rH
rH
VD
rH
rH
oo
VD
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•
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•
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00
rrH
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rrH
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t>
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00
rrH
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m
rH
rH
i-3
O
w
w
u
53
W
VD
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CO
I
U
•
rH
rH
•
•
rH
rH
in
rH
rH
00
a\
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rH
ON
•
•
•
•
•
•
VD
rH
rH
00
rH
rH
VD
rH
«—1
rH
H
CN
rH
i—1
00
rH
rH
O
O
VD
w
§
CN
I
u
-p
o
3
T3
0
U
VD
CN
•
•
•
•
•
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00
VO
rH
O
vd
rH
VD
i—1
VD
VD
rH
m
VD
rH
CT>
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i—1
<d
&
O
Q)
MH
<5*
<Ti
54
space of the chloro substituents on carbon atom 3 is significant enough to reverse the order of assignment in the table.
13
A
C-NMR measurement on the concentrated crude reac-
tion mixture revealed a triplet at 48.6 p.p.m. in the offresonance coupled spectrum, and the infrared spectrum did
not reveal a carbonyl band near 16 55 or 1660 cm"1 suggesting
the structure for the original cycloadduct as the dihydropyran, 3_, shown above.
Also, the infrared spectrum did not
show any absorptions in the 1800 cm - 1 region suggesting the
absence of any (2+2) cycloaddition product.
All the 4-pyranones are solids at room temperature
except 4a and 4b which are liquids, and had to be purified
by distillation.
The compounds, 4a^ and 4b, were also observed
to undergo some decomposition as the compounds turned dark
after standing at room temperature for five hours or more.
Elemental analyses were obtained for both compounds, but a
less satisfactory result was obtained for 4a.
The original cycloadduct 3^ must undergo an elimination,
which apparently occurs on heating to yield the carbonyl
compound 5_. Danishefsky and Walker observed the same elimination pattern in their reports (1,16).
It is likely com-
pound 5^ undergoes the facile allylic rearrangement subsequent
to the elimination reaction.
This allylic rearrangement
is analogous to that described by Scarpati and coworkers
55
0-Si (CH,)
OR
X
for the cycloadduct resulting from the 1,4-cycloaddition of
diphenylketene to acylketene acetal (17).
in acidic meth-
anol, 3_ is probably hydrolyzed to 5_' which subsequently
undergoes elimination to give 5_. The experimental observations of Danishefsky et al
0-H
1
0-Si(CH 3 ) 3
X
6-
MEQH/HCl
„1
0RJ
X
(3)
X
(18) support this viewpoint.
2y
0
LI
V
'OR1
(5 •)
+ R 1 0H
r
,R2
2'
X
o'
(5)
The (4+2)-cycloaddition reactions described are likely
occurring in two steps through a dipolar intermediate.
It
would appear that the electron-donating substituents on the
conjugated diene, being capable of stabilizing the positive
charge in the dipolar intermediate, provides a favorable
stepwise pathway.
A nucleophilic attack of the conjugated
diene through the most electronically charged carbon atom
4 (5,6) on the electrophilic sp-hybridized central atom of
the ketene molecule yields a resonance stabilized dipolar
intermediate.
The interesting feature of this cycloaddition
56
X
X
2
/
c
v5
\
F
J^°-Si(CH3)3
II
0
2'
R
^
1
OR
0-Si(CH 3 )3
0-Si(CH 3 )3
rS
V
X
X
O-Si(CH 3 ) 3
I
2 ^ C ' ' Q ^ ° OR 1
LR"
2y
OR
X
(3)
is that the second ring closing occurs from the oxy anion,
thus yielding cycloaddition across the carbon-oxygen
double bond of the ketene rather than ring closure from
the carbanion which would lead to the cyclohexenone
derivative, 3'.
Diphenylketene reacted in a similar fashion with dienes
lc and Id to give the 4+2 cycloaddi tion product, 6_.
How-
ever, the methanolic hydrolysis of this original cycloaddition product yielded the dihydro-2-pyranone, 1_.
Chloro- and
dichloroketenes, generated in situ by the dehydrochlorination
57
R~
OR
I
/
H2C=C-CH=C
\ 2
OR
lc
Ph 2 C=C=0
(2c)
R 1 =Me, R 2 =(Si(CH 3 ) 3 ,
R 3 = OMe
Id
R 1 =R 2 =Si(CH 3 ) 3 , R 3 =Me
R"
OR
Ph
2C^N)-
OR 2
(6)
I
P h
2
C
^ 0 ^ °
(7c-d)
of the corresponding acetyl chloride, reacted with 1,3dimethoxy-l-trimethylsiloxy-1,3-butadiene, lc, to give the
acyclic product, 9_, as well as the dihydropyran, 6.
The
products, 6^ and 9_, were hydrolysed by using methanol and a
few drops of concentrated hydrochloric acid to give the
58
OMe
I
H2C=C-CH=C
X
OMe
OSi(CH3)3
X
v
2
c=c=o
/
2a X1=C1, X 2 =H
(lc)
2b X 1 =X 2 =C1
OMe
!
V
x1
v
X"
-OMe
0
X
0
OMe
OMe
il
I
/
„ CH-C-CH=C-CK=C
X
\
OSi(CH3)3
OSi(CH3)3
(6)
(9)
MeOH/HCl
OMe
X'
v
0
OMe
0
II
I
||
CH-C-CH=C-CHA0-C-OMe
/
X
2 > ^
0
^ °
X*
7a X^Cl, X2=H
10a X1=C1, X 2 =H
7b X 1 =X 2 =C1
10b X 1 =X 2 =C1
dihydro-2-pyranone, 7_, and the ester, 10_.
Separation of 7
and 10^ was achieved by column chromatography.
The acyclic
product, 9_, is the result of the apparent competing reaction
59
between the diene and the chlorinated acetyl chloride from
which the chloroketenes were generated.
This was demon-
strated by the reaction of chloroacetyl and dichloroacetyl
chlorides with l£ to yield the acyclic product.
A similar
reaction of this type of diene with acetyl chloride has
*
X
1
\
9
II
CH-C-C1
X
+
lc
>
2
X
\
0
OMe
OSi (CH-,)
II
I
/
CH-C-CH=C-CH=C
2
'
\
v
X
OMe
(9)
X
0
OMe
0
N II
I
II
. CHC-CH=C-CH„-C-OMe
X
(10)
previously been observed.
Brownbridge and Chan (19) reported
the reaction of 1,3-bis(trimethylsiloxy)-1-methoxy-l,3butadiene with acetyl chloride to give the poly-3-carbonyl
compound.
(H
3 C ) 3 S l *?
OMe
I
/
H C=C C :=C
2 ~ j v
H
OSi(CH3)3
, „TT
+
CH3
°
"
C C1
~
o
-78°
9
^
9
v
Q
-QMe
60
The use of a 10% excess of triethylamine to generate
the ketenes resulted in the isolation of the 2-pyranones
from the reaction mixture after hydrolysis and chromatography .
The carbonyl absorptions for compounds 7a—d appeared
in the range of 1710 to 1740 cm
. The two carbon-carbon
double bonds appear in the range of 1600 to 1640 cm -1 .
The protons on the nucleus of the compounds, 7a
through 7d_ exhibited singlets for the olefinic protons in
the range of 5.03 to 5.66 p.p.m., and the resonances for
the methylene hydrogens showed up within 3.08 to 3.40 ppm.
Both the infrared and nmr spectral data are consistent with
literature reports on the spectral characteristics of dihydro-2-pyranones (17,20,21,22).
13
The completely decoupled
C spectrum, Table 2, revealed five resonances for the
nucleus carbons with the characteristic carbonyl carbon (23)
signal appearing around 170 p.p.m. except for compound 7d
whose resonance appeared at 161.6 p.p.m. Most revealing in
13
the
C-data were the resonances for the phenyl groups in
compounds lc_ and 7d.
With equivalent phenyl groups, one
would expect only four signals.
However, a look at the
molecular models for these compounds reveals steric congestion between the ortho hydrogens of the phenyl groups, and
as a result, the phenyls are forced out of a co—planar
61
1
ro
I* *
co
CO
T5
FD
R-
!H
CD
to
•P
O
CD
C
0
C
(G
M
>1
OU
1
CM
I
O
&
u
U
CN
X
£
O-I
a.
M
O
4-F
W
a
PQ
C
+W>
A
CD
E
C
TN
*H
CO
CO
<
CN
/ \
H
U
Q
A
*0
C
FTI
+>
MH
•H
X:
to
&
0
"H
£
CD
U
ro
T—!
1
U
Ct\ R -
VD
I
O
R- R-
CN CN
ro C N
<T\ R H 0 0
C N• K D•
0 0 KO
C N C N CN
CT\ 00
ro CN
rH r—1
h
» * i
RH H
LO
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VD
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<£>
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CN
—
i 1
•
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r^•
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ro
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ro
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rrro
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o rro C N
CN CN
S
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o
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•
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<3*
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co
CD
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CD
ro
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CM
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00
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CT•i
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3
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FT
rd
r^
62
relationship.
Hence the non—equivalence of these groups and
the resulting increase in the carbon resonances displayed.
The structures of the acyclic products, 10a-b, were
determined by their IR and NMR spectral data.
The infrared
spectra showed absorptions at 1595, 1690 and 1740 cm"1 for
10b, and at 1590, 1680 and 1735 cm
1
for 10a.
The C-13
spectral data and assignments for these compounds are
indicated on their respective structures.
The assignments
were based on the off-resonance coupled spectrum.
43
-6 o ^ o c h ; 8
O 51-4
J
II +
I
II
C1CH 9 - C - CH — C — CH 0 — C -OCH,
3
189.8
t
168.4
3S\*
J0 :>
(10a)
\
169.6
94,0 56,4
70.7
51 8
0
OCHo
O
*
3
2
l l i i ||
CI CH - C - CH — C - CH 2 - C "OCH 3
185.4 168.2^
172.7
39.0
(10b)
The facile allylic rearrangement observed in the formation of 4-pyranones did not readily take place with the
dihydro-2-pyranones.
Refluxing the dihydropyranone overnight
in benzene did not result in conversion to the 2—pyranone.
Evidently, the carbonyl group is necessary to promote the
allylic rearrangement through the added inherent acidity of
63
the methylene hydrogens.
However, a trace of triethylamine
at room temperature resulted in the quantitative conversion
of 7 to 8.
R
R
C Hc/Et,N
6 6 3
X1
->
xJ
\ CHX
o
2/
X
h
x
7a-d
0
8a-d
The infrared spectra for compounds 8a-e exhibited characteristic absorptions (21,24) between 1719 and 1730 cm - 1 for
the carbonyl, and in the range of 1600 to 1665 cm 1 for the
olefinic bonds.
The ^ - n m r spectral data are consistent
with the structures.
The C-13 spectral data, shown in
Table 3, showed a signal for the carbonyl and four reson2
ances for the sp -hydridized ring carbons.
The number of
resonances for the phenyl carbons in compounds 8£ and 8d
attest to the equivalence of the phenyl groups in each of the
compounds.
All assignments were made on the basis of off-
resonance coupled spectrum and literature reports (23).
The
chemical shift difference between the methoxy carbon and the
carbon of diphenylmethyl substituent in compound 8c is too small
64
*•
•»
r-
U)
E
0
-P
VD
«
•
00
CN
rH
00
CN
rH
CD
O
•
rd
•
00
CN
rH
1
u
G\
CN
rH
<
<D
oo
I
-P
o
rd
CO
w
rH
Q)
V£>
in
•
•
in
in
m
rH
CN
H
CN
u
CN
U
0
PQ
C
00
•
ro
CN
•
«
•
•
VD
in
in
in
in
in
vo
o
MH
W
in
•
Ml
0
>i
&1
1
CN
H
H
H
•
ch rro cn
rH »—1
•
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a
0)
e
c
Cn
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a
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rd
CN 00
cri m
* i»
00 f^
rO CN
iH rH
CD
e
a
a*
H
r-
<sO
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U
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in
•
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CN
CN
KO
KD
H
i—1
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rH
rH
V£>
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•—i
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ro
fi
rd
w
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MH
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a>
in
CN
in
in
•
•
•
•
•
l
U
rH
O
rH
o
o
rH
CN
O
rH
rH
rH
rH
H
rH
in
CN
r-
CN
•
•
•
•
•
I
u
00
in
rH
rin
rH
m
in
rH
in
in
rH
o
CN
J2
w
iH
rd
0
*H
s
CD
x:
u
00
«H
i
u
r4J
a
<D
>
i—I
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w
H
ro
CO
I
O
CD
O
a
cd
CD
4H
CD
CN
I
o
-P
O
3
T3
0
u
01
•
•
«
•
•
r00
00
o
rH
VJD
O
rH
cr»
00
O
CN
•
•
o>
00
o
in
•
o
rrH
0>I
rd
00
•
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in
KD
rH
KD
rH
rH
X)
O
00
00
TS
00
0)
00
KD
rH
O
65
to allow a definite assignment for these carbons.
While it
might appear that the off—resonance coupled spectrum should
allow a definite assignment of these carbons, the peaks are
considerably overlapped to allow for unambiguous assignment.
However, it appears the methoxy carbon is relatively downfield at 55.8 ppm.
Dichloroketene reacted with 3-methyl-l,1-bis(trimethylsiloxy) -1, 3-butadiene, Id, to yield a (4+2) and a (2+2) cycloadduct.
The use of an excess of triethylamine to generate
CH_J
OSi(CH_)_
I
/
3 3
H0£C=C-CH=C\
OSi (CH3) 3
CH.
1)
2)
2b
MeOH/HCl '
ci2CHx\o-^O
CI,
,0
+
CH.
:O2H
(Id)
(8e)
(11)
dichloroketene resulted in the isolation of 8e and 11 after
methanolic hydrolysis in 31% and 55% respectively.
All
efforts to isolate the dihydro-2-pyranone by varying the
amount of triethylamine relative to the acid halide failed.
While it is conceivable that the 2-pyranone, 8e, may arise
from the original (2+2) cycloadduct, this adduct did not
rearrange to the 2-pyranone upon refluxing in benzene for
4 8 hours, or heating in ortho dichlorobenzene for 36 hours.
66
The structure of the acid, 11, was established by its
spectroscopic data.
at 1805, 1710 cm
3660 cm 1 .
1
The infrared spectrum showed absorptions
and the OH band in the range of 3010 to
The proton-nmr spectrum was consistent with
structure revealing significant coupling between the geminal
hydrogens on the ring; a doublet centered at 2.89 ppm and
another centered at 3.42 ppm («HH»=17 Hz).
The C-13
spectrum exhibited resonances as indicated.
All assignments
were based on the off-resonance coupled spectrum, and the
192.3 '
92.1
41.0
54 .4
23.1
0H
176.7
(CDCl^ - 77.0 ppm)
(11)
distinction between the two methylenes were deducted from
the known fact that rings have a shielding effect on the
3
sp -hybridized carbons in the rings.
The cycloaddition of 1,1-bis(trimethylsiloxy)-1,3butadiene, le, with dichloro— and diphenylketenes resulted
in only the (2+2) cycloaddition products.
The cyclobutanone
67
from diphenylketene was hydrolyzed and derivatized to the
corresponding anilide for characterization.
However, all
efforts to purify the cyclobutanone and derivatives
from dichloroketene and le^ failed.
X,1
\
OR
H„C=CH-CH=C
+
C=C=0
2/
X
\
OR
le R=Si(CH3)3
lb
X 1 =X 2 =C1
lc
X1=X2=Ph
->
MeOH/HCl
X
XJ
CO2H
S0C1.
Aniline
78.1
49.7
h
31.5
/208.8
¥0.4
Ph-NH-C
169 .4 0
(12)
(CDCl^ - 77.0 ppm)
68
The IR spectrum of compound 12 exhibited typical absorptions in the range of 3200-3500 cm -1 , and at 1765, 1650 cm -1 .
The proton-nmr showed a doublet centered at 2.32 ppm
corresponding to the methylene hydrogens on Carbon 2.
methine proton showed up as a quintet at 3.90 ppm.
The
The ring
methylene hydrogens resonated in the range of 2.80 to 3.60 ppm
as a multiplet.
The C-13 spectral data, indicated on the
structure, are consistent with the structure.
The phenyl
carbons resonated at 140.2, 139.0, 137.5, 128.9, 128.5,
127.9, 127.4, 127.1, 124.6, 124.3, and 120.0 ppm.
The most reasonable explanation accounting for the
above described products is in the stepwise pathway; the
initial formation of a dipolar intermediate from the nucleophilic attack of the conjugated diene on the electrophilic
sp-hybridized carbon atom of the ketene molecule.
A con-
sideration of the conformations of the dipolar intermediate
which would lead to a (4+2) cycloaddition product reveals
that the steric interaction between the ketene substituents
and the substituents in the 1-position of the diene in conformer 11 prevents ring-closure to yield the cyclohexenone
derivative, i.e., the rotation around the a,b or b,c bond is
much faster than the ring-closing step.
The steric conges-
tion in I is minimized and cyclization occurs readily to
give the dihydropyran.
Conformer III would be expected to
be the precursor to the (2+2) cycloaddition product, the
69
X1 ©
(I)
(II)
/'
(III)
X
v
V
X2
X1
0
R
R~
R20
favored when
R =Me, OMe, OSi(CH3)3
exception:
1 2
^
When X =X =C1, and R =Me
(4+2) and (2+2) cycloadducts isolated,
favored when
R 3 =H
70
cyclobutanone.
Apparently, a substituent in the 3-position
of the diene as well as the substituent on the ketene exerts
a strong influence on the second ring-closing step.
Diphenyl-
ketene undergoes (4+2) cycloaddition with all four of the
3-substituted dienes studied, but a (2+2) cycloaddition with
the unsubstituted diene, le.
Dichloroketene underwent a
(4+2)-cycloaddition when the 3-substituent was a siloxy or
methoxy substituent, a mixture of (4+2)- and (2+2)-cycloaddition with the 3-methyl derivative and only (2+2)cycloaddition when the 3-position was unsubstituted.
The
above rationale is consistent with the few literature
results on the reaction of ketenes with activated dienes
(25,26,27).
The readiness of the studied reactions of the activated
dienes with ketenes, and the reports of Schenone et al on
the cycloaddition of ketenes to N,N-disubstituted vinyl
ketones (28,29,30) prompted an investigation of the reaction
of ketenes with $-methoxy-a,6-unsaturated ketones.
Although
the activated ketones are 4ir-electron systems like the
dienes, they are less reactive ketenophiles.
The activated
ketones could be thought of as precursors of the siloxy
dienes.
In fact, l-methoxy-3-trimethylsiloxy-l,3-butadiene,
la, was derived from 4-methoxy-3-buten-2-one, If.
71
Dichloro- and phenylchloroketenes were generated in
situ in the presence of 4-methoxy-3-buten-2-one, If, by the
dehVdrochlorination of the corresponding
chlorinated acid
chlorides by the use of triethylamine in refluxing hexane.
The original cycloadducts, 13, were not isolated, but treated
with excess zinc in moist acetic acid to afford the 2—pyra—
nones, 14a and 14b in 28 and 26 per cent yield respectively.
OMe
0
li
X
CH,OtCH=CH-C-CH,
+
N
3
X
(If)
c=c=o
2'
2b X 1 =X 2 =C1
(13)
2d X X =C1, X2=Ph
Zn/AcOH, H O
H
3C
•0
14a X =C1
14b X =Ph
72
In an attempt to improve the yield, the reaction was run
in refluxing benzene, THF and ether but compound 14 was not
isolated.
The infrared on the concentrated crude polymeric
mixture of the addition product of ketene and the activated
ketone did not reveal the characteristic absorptions for
T
he addition of triethylamine to a solution of the acid
chloride and If gave a relatively clean reaction.
However,
on concentration of the reaction mixture, the residue turned
dark green.
All efforts to isolate and elucidate the struc-
ture failed.
It was observed however, that lf_ reacted with
the acid chlorides over a six—hour period to give polymeric
material.
The infrared spectra for compounds 14a-b revealed
absorptions at 1700 and 1620 cm""1 for the carbonyl and
olefinic bonds.
The methyl protons of compounds 14a-b resonated at
about 2.20 ppm showing up as
broad peaks due to slight
coupling with the olefinic proton in the 5-position.
13
The
C-spectral data are consistent with the structures and
the assignments were based on off—resonance coupled spectra.
The chemical shifts and assignments of the resonances are
shown on the respective structures.
Carbon atoms 1 and 6
resonated within three or less parts per million of each
other and hence, makes their assignments arbitrary.
The
73
140 .2
140.6
103.0
118 .4
18 .a
10 3.7
124 .0
19 .3
HoC
158.4 161.0
161.4 161.7
(14a)
(14b)
phenyl carbons of 14b exhibited signals at 134.5, 127.9,
127.8 and 127.7 ppm.
Diphenylketene, 2c, reacted with If to give 13c in
good yield.
OMe
0
ii
82 + 5 C
Ph.
CH 3 0-CH=CH-C-CH 3 + Ph 2 C=C=0
H,C \
(If)
0
^0
(13c)
The infrared spectrum for 13c revealed absorptions at
1750 and 1700 cm
1
corresponding to the carbonyl and olefinic
double bonds.
The 1H-nmr spectrum of 13c exhibited fine allylic
coupling with the proton in the 4-position showing up as a
doublet (4.36 ppm) and the one in the 5-position as a double
doublet (5.43 ppm).
The C-13 data are consistent with
structure and the assignments are shown on the structure.
74
The signals for the phenyl carbons showed up at 139.2, 130.2,
128.3, 127.9, 127.5, 127.2, and 126.7 ppm.
102.3
18.1
H
57.0
OMe
Ph
60.2
77. \
Ph
^<0
3C
-0
151.1 169.4
(13c)
(Z)—2—Methoxymethylenecyclohexanone, lg, underwent a
similar (4+2)-cycloaddition reaction with dichloro- and
phenylchloroketenes to give 15a-b which on treatment with
zinc in moist acetic acid gave 16a and 16b in 56 and 4 7 per
cent yield respectively.
Treatment of the concentrated
crude reaction mixture with dry ether led to the precipitation and isolation of 15b in 68 per cent yield.
Compound 15b,
a stereospecific product, was found to be stable to triethylamine in refluxing benzene, and hence leads one to believe
(15b)
that the isomeric form produced might be the one shown above
75
0
OMe
OMe
X
\
X
c=c=o
L
1/
2b X1=X2=C1
(ig)
{15a-b)
2d X1=C1, X2=Ph
Zn/AcOH, H 2 0
16a X =C1
16b X =Ph
Diphenylketene reacted with lg at 82+5°C to give the
3,4-dihydro-2-pyranone, 15c, in 90 per cent yield.
O
OMe
OMe
82 + 5
+
(lg)
Ph2C=C=0
(15c)
76
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77
The C-13 data, Table 4, for compounds 15 and 16 are
consistent with structures revealing resonances of the
pyranone carbonyl in the range of 158 to 169 ppm.
The
assignments for carbons 5 through 8 are arbitrary.
The reaction of diphenylketene with lg was monitored
with infrared at varied conditions by following the disappearance of the ketene band at 2100 cm -1 .
When the reac-
tion was carried out at 82 + 5°C, it was over in two to
three hours.
In refluxing hexane, the reaction was over
in five to six hours to afford the (4+2)-cycloadduct,
15£, in about the same yield as at 8 2 + 5°C.
However, the
reaction at room temperature, in hexane after two days,
showed the ketene band, and in fact, there was no noticeable
trace of 15c.
The same was observed when the reaction was
done without a solvent at room temperature.
The reaction of
lg with diphenylketene in acetonitrile was over in five hours
to give 17 in about 32 per cent yield.
CH 3 CN
Ph2CH'
0
OMe
lg + Ph2C=C=0
0 C, 5 hrs
(17)
78
The structure of 17 was established by its spectral
properties:
m.p., 69-79°C; nmr, 6, 1.64 (quartet, -CH2~),
2.11-2.42 (m, -CH2-CH2-)# 3.26 (s, 3 H) , 5.13 (s,l H),
5.29 (t, 1 H), 5.44 (Br, 1 H), 7.20-7.49 (m, 10 H).
57.1
The
fi
59.7
Ph CH
2 170.i?
OMe
110.3,
113
* 6 f^44 Tsf^ 1 4 1 * 9
22.5
21.4
C-13 spectral data agree with structure, and the chemical
shifts and assignments are shown on the structure.
all efforts to reproduce this result failed.
However,
Instead, the
cyclic product, 15c, was isolated.
DiphenyIketene reacted with B—methoxymethylene-ottetralone at 82 +_ 5 C to give _18^ in good yield.
The same
product was isolated in about the same yield when the
reaction was carried out in acetonitrile.
o
OMe
+ Ph2C=C=0
82 + 5 C
or
CH^CN, r.t.,
(lh)
2-3 hrs
(18)
79
Phenylethylketene, 2f, underwent (4 + 2)-cycloaddition
with lh to give one isomeric form of 19.
C=C=0
(lh)
82 + 5 C
(2f)
(19)
Gompper (31) noticed a similar solvent effect on rate
in the reaction of diphenylketene with 2-ethoxymethylenecyclohexanone.
It should, however, be mentioned that the
calculated kinetic parameters (AH^ = 10 kcal mole -1 ;
= -47 eu) could be interpreted in terms of either a
one or a two step reaction.
On the basis of the observed solvent effect on the
rate of the cycloaddition reaction, it is tempting to
think of these (4+2) ketene cycloadditions as occurring
through a stepwise pathway; the initial attack of the
80
keteneophile on the electrophilic sp-hybridized carbon of
the ketene to give the 1,4-dipolar intermediate which then
cyclises to give 15c.
MeO
MeO
CPh„
V
(15c)
The isolated stereospecific products from the cycloaddition reactions of lg with phenylchloroketene and lh
with phenylethylketene do not allow for the elimination
of synchronous cycloaddition.
However, the stereochemical
course in a stepwise pathway depends on the relative rates
of ring closure and of the possible internal rotations in
the dipole.
There are examples of two-step cycloaddition
reaction that proceed with stereospecificity and/or
stereoselectivity (43,44 ,45,46,47) .
81
The described (4+2) cycloaddition reaction of ketenes
found ready application in the synthesis of Goumarin derivatives.
Coumarins are naturally occurring compounds that
continue to be of great interest to synthetic organic
chemists because of their diverse and varied use as medicinals (32,33,34), laser and fabric dyes (35,36,37) fluorescent whiteners (38,39) and photographic sensitizers (40).
The generation of dichloro-, methylchloro-, and phenylchloroketenes from the corresponding chlorinated acetyl
chlorides by the use of triethylamine in the presence of
3-methoxymethylene-a-tetralone, 111, in refluxing hexane
resulted in the 3,4-dihydro-2-pyranone, 20_. The dihydropyranone was not isolated, but was treated with zinc in
moist acetic acid or triethylamine in refluxing benzene to
OMe
CI
X
R
(lh)
8
CH-C-Cl
/
2b R=C1
2d R=Ph
2e R=CH.
Et3N
hexane
reflux
(20)
82
give the 5,6-dihydrobenzocoumarins, 21a-e, in respectable
yields.
However, the product from the triethylamine
treatment of the original cycloadduct from the reaction of
methylchloroketene with lh could not be isolated.
OMe
(20>
reflux
overnight
21a R=C1
(20)
21b R=Ph
2Id R=C1
21e R=Ph
21c R=CH.
The C-13 spectral data for the dihydrobenzocoumarins
are shown in Table 5.
The assignments of the observed
chemical shifts were based on the off-resonance coupled
spectrum and literature reports (41) . The assignments of
carbon atoms 5, 6, 7 and 8 are all arbitrary, and in the
case of compounds 21b and 21e, the chemical shift for
carbon atom 7 could not be distinguished at all because of
the number and overlapping of peaks in the spectral phenyl
region for these compounds.
83
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An attempted oxidation of 21a with 2,3-dichloro-5,6dicyano-1,4-benzoquinone (DDQ) in refluxing benzene failed.
Refluxing over a long period of time (5 days), somewhat
surprisingly, did not convert any of 21a to 22a.
However,
chloro substituents are known to deactivate systems toward
DDQ (42) .
Happily, the treatment of 21a with N-bromosuccinimide
(NBS) in refluxing carbon tetrachloride for 18 hours resulted
in good yield of the 7,8-benzocoumarin.
Similarly, com-
pounds 21b, 21d, and 21e underwent the same reaction to give
the substituted 7, 8-benzocoumarins,. 22.
NBS
CCl^, reflux
18 hrs
22a R=C1, R 1 =H
21b
22b R=Ph, R 1 =H
II
21a R=C1, R X =H
R X =H
21e
22 e
pd
II
tr
22d R=C1, R1=OMe
R1=OMe
II
05
2 Id R=C1, R1=OMe
R1=OMe
86
Compound 21c readily underwent oxidation on treatment
with DDQ in refluxing benzene to provide 22c in 68% yield
DDQ, C-H
6 6
reflux 18 hrs
(21c)
(22c)
after chromatography over alumina.
1
The
H-nmr spectra for the benzocoumarins revealed
multiplets in the aromatic region, and the C-13 chemical
shifts, shown in Table 6, were not assigned because of the
considerable crowdedness and overlapping of the peaks around
the aromatic region.
In conclusion, chloro-, dichloro- and diphenylketenes
readily undergo (4+2) cycloaddition reactions with electronrich alkoxy and/or siloxy conjugated dienes to give dihydropyrans which are easily hydrolyzed to 4- or 2-pyranones
depending on the substitutions in the ketenes and dienes.
Substitution in the 3-position of the diene, and to a less
extent the substitution in the ketenes, play a significant
role in the ring-closing step of the dipolar intermediate.
87
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Kt •
00 CN
• •
00 ^
CN rH
rH rH
•
I/)
-P
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•H
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ld
• •
r- rH
CM CN
rH rH
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rCN
rH
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o
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•
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** CN
00 •
• CT\
CN rH
CO rH
rH
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rH O
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CN (T\
00 rH
rH rH
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• •
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rH rH
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rH rH
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88
The balance between the substituents in the reactants determines whether (4+2) or (2+2) cycloaddition occurs.
Diphenylketene and the studied halogenated ketenes
react with 6-methoxy-a,3-unsaturated ketones in a (4+2)
fashion to give 3,4-dihydro-2-pyranones which are easily
converted to the 2-pyranones.
The described (4+2) cycloaddition reactions of ketenes
do not only represent new and versatile synthetic route to
pyranones, the reactions should add to the available synthetic methods of potential use in the total synthesis of
natural and industrial products.
The demonstrated applica-
tion of (4+2) ketene cycloaddition reaction in the convenient and efficient synthesis of 7,8—benzocoumarins, derivatives of naturally occuring coumarins, underscores the
significance of these reactions in potential synthesis.
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