'-

 

This is to certify that the

thesis entitled

APPROACHES TO THE SYNTHESIS
OF 3, 5-BIS( 5-METHINYLPYRRO-
LIDIN-ONYL)PYRAZOLE

presented by
ALAN C . BROWN

has been accepted towards fulfillment
of the requirements for

CHEMISTRY

 

MS degree in

 

/

ARY

Mic mhigan Stain
Urnvmxty

 

{QMW

Major professJV

Date 22- ‘)“f/V 4??”

031639

 

a‘u‘i‘i‘t-s:

- ‘ “u '11/ "
7 i ‘t‘q‘\‘:,lf’-- I"

  
     

 

v v .-.. « 1“
\' '1 « -
«yrf’u .(J‘ ,‘4: .

 

 

UVCKWI. rmc):
25¢ per day per item
RETURNING LIBRARY MATERIALS:

Place in book return to move
charge from circulation records

 

 

 

 

 

APPROACHES TO THE SYNTHESIS OF
3,5-BIS(5—METHINYLPYRROLIDIN-Z-ONYL)PYRAZOLE

By

Alan Curtis Brown

A THESIS
Submitted to
Michigan State University
in partial fulfillment of the requirements
for the degree of

MASTER OF SCIENCE

Department of Chemistry
1980

ABSTRACT
APPROACHES TO THE SYNTHESIS OF
3,5-BIS(S-METHINYLPYRROLIDIN-2—ONYL)PYRAZOLE

By

Alan Curtis Brown

The partial synthesis of 3,5-bis(5-methinylpyrrolidin-

1 is described.

2-onyl)pyrazole, by the Stevens method
Utilizing isoxazole technology, the bis-cycloaddition of the
nitrile oxide derived from methyl u-nitrobutyrate to 1,4-
pentadiene gave 3,3'-bis[5-(2-carbomethoxyethyl)isoxazolinyl]
methane. This was aromatized by N-bromosuccinimide (NBS)
bromination and dehydrobromination to the 3,3'-bis-[5-(2-
carbomethoxyethyl)isoxazololemethane. The two isoxazole
rings were hydrogenolysed to the bis-g-ketovinylogous

amine - using Adam's catalyst (PtOZ) - which consequently
ring closed to the bis-lactam by reaction of the amino

groups with esters. The remaining B-diketones did not re-
act with hydrazine to form the pyrazole ring of the target

molecule.

1Stevens, R. v., Tetrahedron, 2g, 1599 (1976).

To my wife, Regina, and my new
daughter, Megan, without whose support
this would not have been possible.

ii

ACKNOWLEDGMENTS
I would like to thank the Department of Chemistry for
providing me with financial support. I would also like to
express my gratitude to Dr Eugene LeGoff for his guidance
and his group for making my stay at MSU enjoyable.

iii

TABLE OF CONTENTS

Section

LIST OF FIGURES . . . . . . . . . . . . . . .
INTRODUCTION . . . . . . . . . . . . . . . . .
DISCUSSION AND RESULTS . . . . . . . . . . . .

EXPERINENTAL I I I I I I I I I I I I I I I I I

GENERAL PROCEDURE . . . . . . . . . . . .
1,4-pentadiyne. . . . . . . . . . . . . .
3-hydroxyh1,§epentadiyne . . . . . . . .
3-acetoxy-1,4—pentadiyne . . . . . . . .

Cycloaddition of the nitrile oxide to the
diynes I I I I I I I I I I I I I I I I I

Methyl 4-nitrobutyrate . . . . . . . . .

3.3'-biS[5-(2-carbomethoxyethyl)isoxazo-
linyfl methwe (6d . I I I I I I I I I I

3,3'-bis[5-(2-carbomethoxyethyl)isoxazo-
loyllmethane (Z) . . . . . . . . . . .

B-keto bis-vinylogous lactam (2) . . . .

Attempts to synthesis target molecule (3)

BIBLIOGRAPHY . . . . . . . . . . . . . . . .
APPENDIX I I I I I I I I I I I I I I I I I I I

iv

10
10
10
10
11

LIST OF FIGURES

Figure

1.
2.
3.
4.

11.

13.
11+I

15.
16.
17.
is,
19.

The proposed platyrin . . . . . . . .
L9GOff’Cheng methOd o o I o o o o o 0
Stevens method . . . . . . . . . . .

Hydrogenolysis of bis-isoxazole . . .

Target molecule: 3,5-bis(5-methinlpyrrolidin-

2-onyl)pyrazole . . . . . . . . . . .

Attempted cycloaddition to 1,4-pentadiynes

PMR of 3-hydroxy-1,4-pentadiyne . . .

IR (4000-1250 cm‘l) of 3-hydroxy-1,4-pentadiyne

IR (1250-650 cm'l) of 3-hydroxy-1,4-pentadiyne.

PMR of 3-acetoxy-1,4-pentadiyne . . .

IR(4000-1250 cm'l) of methyl A-nitrobutyrate

IR (1250-650 cm'l) of methyl u-nitrobutyrate

PMR (60 MHz) of bis-isoxazoline (é) . . . .

PMR (250 MHz) of bis-isoxazoline (Q) . . .

IR (40000-1250 cm'i) of bis-isoxazole (Z)

IR (1250-650 cm'l) of bis-isoxazole .
PMR (60 MHz) of bis-isoxazole (Z) . .

Mass spectrum of bis-isoxazole (Z) . . . . . .

Mass spectrum of fl-keto bis-vinylogous lactam.

18
19
2o
21
22
23
24
25
26
27
28
29
29

LIST OF FIGURES (continued)

Figure Page

20.

21.

22.

IR (4000-1250 cm-l) of B-keto bis-vinylo-
gous lactam C2) . . . . . . . . . . . . . . . . 30

IR (1250-650 cm-l) of B-keto bis-vinylogous
13.th (a) I I I I I I I I I I I I I I I I I I 31

PMR (60 MHz) of B-keto bis-vinylogous lactam £2) 32

vi

INTRODUCTION

Although intense interest in porphyrins has resulted in

an abundance of scientific literature,1

very few expanded
porphyrins (platyrins) have been synthesized.2 The syn-
thesis and study of the platyrin in Figure 1. would be a

unique model.

 

Figure 1. Proposed platyrin

This platyrin should be of interest because of its ability
to complex one or two metal atoms. There are potentially
interesting electron tranfer and catalytic properties in the
use of this molecule. The synthesis of the proposed com-
pound by conventional porphyrin techniques was unsuccess-
ful,3 and an alternative synthesis was envisioned using the
Stevens method.u
The object of this project was to construct an inter-

mediate molecule which could be transformed into a bis-

pyrrole and eventually cyclized into the proposed molecule

by the LeGoff-Cheng method.5

\ \ .-\ \ HBr \ .
\ ~HN==N N\\ +CH20 ETOH7 Figure-l.

Figure 2. LeGoff-Cheng method

 

The strategy of the Stevens method involves the manipu-
lation of the isoxazole moiety. The isoxazole has been use-
ful in functional group interchange6 and the synthesis of

7

B-furanones and porphyrins.8 The general chemical scheme
involves the placement of reactive functionalities on either

side of the 3 and 5 positions on the isoxazole, as in 1.

These functions are typically esters or ketones. When
the isoxazole ring is hydrogenolysed, the fi-functionality

formed can be used in the formation of the pyrrole rings.

Figure 3. Stevens method

The scheme necessary to synthesize one half of the
platyrin would require the use of two isoxazole moietiescr

to each other as in compound 2.

N— O—N
A // \\' B 3,

The isoxazole ring is most easily made by the cycloaddition
of nitrile oxides to alkynes.9 Thus, the synthesis of com-
pound 3 would necessitate the bis-cycloaddition of an ali-
phatic nitrile oxide to 1,4-pentadiyne or possibly a 3-sub-
stituted 1,4-pentadiyne. This procedure has been done with
stabilized nitrile oxides,10 however, it has been found that
most aliphatic nitrile oxides tend to dimerize instead of
forming the bis-adduct. A convenient solution to the prob-
lem lies in the ability of olefins to react 102-103 times
faster with nitrile oxides. Subsequent dehydrogenation11
of the resulting isoxazolines should give the desired
isoxazoles.

The hydrogenolysis of the isoxazole ring system has

12

been accomplished by a variety of methods. The cleavage

of the bis-adduct yields a masked a-tetraketone as an inter-

mediate.

N‘O 0-” [H] A N220 OH NH’ZB
/’

Ix/C\\5/1[\5;x\c/Jé§>jk\\,;::E;—é /’

Figure A. Hydrogenolysis of the bis-isoxazole

Although not utilized previously in the Stevens type
synthesis, these masked fi-tetraketones, after acid hydrol-

ysis, form various phenols13 via aldol condensations. Left

4
unhydrolysed, if A and B are esters, then the bis-vinylogous

lactam 2 will form.

O ./H H O
N 0"H‘o \N 3
\\ // . F“

The reaction of the above compound with hydrazine forms

pyrazole 3, the target compound of this project.

0 hi N_E‘ Ho

5 4
‘\ ./’ z’ "“

Figure 5. Target molecule: 3,5-bis(5-methinyl-
pyrrolidin-Z-onyl)pyrazole

DISCUSSION AND RESULTS

The first step in the synthesis of the target molecule
3 was a cycloaddition. As mentioned previously, the cyclo-
addition of aliphatic nitrile oxides to alkynes is not as
favorable as nitrile oxide dimerization. Several attempts
to add the necessary nitrile oxide derived from methyl
4-nitrobutyrate to both 1,4-pentadiyne and 3-acetoxy-1,u-
pentadiyne resulted in 5-10% of the adduct and 70-80% of the
nitrile oxide dimer. Yields were estimated by PMR compari-

son of the aromatic proton to those of the ester.

R 9
/\g +2 OZN-(CHzl3-C-OCH3 2.
R-H,-OAc '
o
‘th
COW—WOCH
E1 N H3 0 3
@3230 0 70-80}.
girl ' N—O O—N
+ HBCO // R \\ OCH3
O 5-on 0

Figure 6. The attempted cycloaddition
to the 1,4-pentadiynes

6

We found that substitution of 1,4-pentadiene for the
diyne overcame the low yields of the adduct and the diffi-
culty in the synthesis of the diynes. The cycloaddition of
two equivalents of the nitrile oxide to the diene yielded
55-60% of a stable white solid that had the correct parent
ion in the mass spectrum. Since there is the possibility of
thggg and erythro isomers in the 3 positions of both rings,
it is reasonable that the melting point was a rather broad
96-9° . The splitting in the bridging methylene, 3 and A
position protons was indicative of diastereomers, but sep-

aration and characterization of these isomers was not in-

vestigated.
2
N—o O—y .
id C;C)\Nz’T\cx’4LV/¥g\s/{L\,;X\¢/C‘Tr’C)C34 é»
3 ‘54HH 3

O O

The aromatization of compound 6 was attempted using
several recent techniques. Heterogeneous dehydrogenation

21A and Ni0215 proved fruitless. Although

with both Mn0
small amounts of the mono- and bis-aromatic were isolated,
the majority of the 6 was found to be complexed to the met-
als. Under these conditions, the reaction did not proceed.
Although 2,3 dichloro-5,6-dicyano-1,A-benzoquinone (DDQ) has
been shown to dehydrogenate 3-methyl-5-propyl isoxazoline in

16

good yields in both benzene and dioxane, no yields greater

than 2% (estimated by PMR) resulted when starting with

7
compound 6. Bromination and dehydrobromination using NBS
and triethylamine was successful in moderate yields of #0-
50%.
The bromine atom can be attached at the 3 or 4 posi-

17

tions on each ring of compound 6 and therefore, the thin
layer chromatogram (TLC) of the dibrominated material was
quite complex. Dehydrobromination with the mild base tri-
ethylamine, seemed to give the best results. When 1,5-di-
azabicycloES.4.0]undec-5-ene (DBU), a stronger base, was
used a more complex mixture was produced and led to appre-
ciably lower yields. The product mixture was separated by
Still's18 flash chromatography technique to one spot.

Although the off-white solid gave a good parent ion and
degradation pattern in the mass spectrum, the melting point
was broad and the PMR had an extraneous absorption at 5 =
3.70. The material showed a single spot on the TLC and the
decision was made to continue the synthesis with this mat-
erial.

The hydrogenolysis of the bis-aromatic Z was best ac-
complished by Adam's catalyst in 2% triethylaminesethylace-
tate. The oily solid that resulted was not characterized
extensively except for PMR and mass spectral data. The com-
pound was not stable to air due to spontaneous cyclization
to the amide. It was immediately placed into methanol with
a catalytic amount of base (triethylamine) and refluxed un-

der nitrogen until the bis-cyclization was complete.

Upon cooling the yellow methanolic solution, a

8
precipitate of fine yellow solid was obtained. Crystalliza-
tion from methanol gave a 35% yield of 8 with a melting
point of 179-80° . In accordance with it's structure, a
parent ion of mass 262 was obtained in the mass spectrum.

The PMR exhibited two multiplets centered about 6 = 2.52 and

N -O O -N H2, Pigg-
H3C0 / \ -

/ \ OCH3 ETOAC

(CFi ,, f1 (3 ,

o O fizo-HpHso 0 MW
2 ———>

\ / / N2,A

6 = 2.90 which would account for the protons on the lactam

ring. The B-diketone exhibited keto-enol tautomerization as
seen by a singlet at 6 = 3.52 for the keto and two singlets
at 6

5.04 and 6 = 5.20 for the E and Z vinyl enol protons.
The enol -0H exhibited an absorption as a broad singlet at
6 = 9.97. The amide N-H was further downfield at 6 = 10.7
as a broad singlet. The infrared spectrum (IR) showed the

N-H stretch at 3225 cm'1

1

superimposed on a broad absorption

to 3500 cm'l. The ketones and lactam car-

bonyls exhibited absorptions at 1720 and 1630 cm"1 respec-

from 2200 cm-

tively. The yellow-gold solid was sparingly soluble in most
organic solvents and exhibited a rather large tailing spot

on the TLC (Rf = 0.75) when eluted on a silica gel plate

9
with 1:1 ethylacetate/hexane.

The reaction of hydrazine with the B-ketones of com-
pound 2 failed. Varied reaction conditions were attempted;
slightly alkaline to slightly acidic, several solvents
and different temperatures. The products obtained were
usually viscous hygroscopic oils which were complex mixtures.
The mass spectrum of these showed minor amounts of mass 258
for the product, but mainly consisted of starting material
and various other components which were not explicable.

The reason for the lack of reaction and side products is
probably the abstraction of a proton to form the stabilized
enolate. This could further react as a nucleophile or just
be very sluggish in its reaction with the hydrazine. The
replacement of the acidic hydrogen with an alkyl group to
form the enol ether would probably be the answer, but in

this project it was not investigated.

 

 

ii 1 D

 

 

 

 

 

EXPERIMENTAL

GENERAL PROCEDURE

The melting points were determined on a Thomas Hoover
Uni-melt melting_point apparatus and are uncorrected.

The infrared spectra were recorded on a Perkin-Elmer
Model 237B or 137 spectrometer. The PMR spectra were ob-
tained on a Varian T-60 or a Bruker 180 or 250 spectrometers
with chemical shifts reported in 6 (ppm) measured from
tetramethylsilane as the internal standard. The 13CMR were
obtained on a Varian CFT-20 spectrometer with chemical
shifts reported in 6 (PPm) from CDCl3 as the internal stand-
ard. The UV and visible spectra were recorded on a Unicam
SP-800 spectrometer using lcm quartz cells. A Finnigan

#000 mass spectrometer was used to obtain mass spectra.

1,4:pentadiyne

The literature procedure was followed18 except the mat-
erial was not distilled due to its instability at higher
temperatures. The purity was estimated by PMR and used
in the cycloaddition.
3-hyroxy-1,4-pentadiyne

The literature19 procedure was followed except that the
product was not distilled. The crude oil isolated was

multiply extracted with boiling petroleum ether (BP 35-60°)

and a white solid was collected upon cooling. Yields were

10

11
typically 20-25%, melting point 51-2° .

3;acetoxy-1,4-pentadiyne
Again the literature procedure was followed20 and the
yields were typically 85-90% without distillation and 45-50%

with distillation.

Cycloaddition of the nitrile oxide to the above diynes
Typical procedure: In 50 ml dry benzene was placed 14
mmol of the diyne, 29 mmol (4.26 g) methyl 4-nitrobutyrate,
60 mmol (6.5 ml) phenyl isocyanate and 0.25 ml triethylamine.
The solution becomes heterogeneous after about 40 minutes
and gradually becomes thicker as the reaction proceeds.
After stirring for a total of 15-17 hours at room tempera-
ture, the solid was collected by filtration and washed with
fresh benzene. The solvents were removed in vacuo, leaving
a viscous dark brown oil (5.5-6.0 g) which could not be pur-
ified. By PMR analysis, yields of isoxazole (mono- and bis-
adduct combined) were estimated at 5-10% while the dimer of
the nitrile oxide made up 70-80% of the product. This was
done by comparison of the aromatic proton at 6 = 5.95 to the

methyl ester protons at 6 = 3.65.

Methyl 4-nitrobutyrate (5)

In a 1000 ml three necked flask fitted with a condenser;
Teflon stirrer and addition funnel with pressure equaliza-
tion sidearm with a nitrogen bleed was placed 500 ml (9.32
mol) nitromethane and 25 ml triethylamine. The solution was

heated to 90° and 130 ml (1.44 mol) of methyl acrylate was

12
added over a one hour period at reflux. The dark mixture
was refluxed for 24 hours and cooled. Instead of the usual
extractive work up, the mixture was stripped of nitromethane
in vacuo and the residue distilled under vacuum through a 5"
Vigreaux column. The boiling point was 84-85° at 1 mm. A
yield of 55-65 g or 27-31% was obtained: IR (neat): 2950,
1745, 1550, 1460 and 1340 em‘1; PMR (00013). 5 1.58 (d,
impurity), 2.0-2.61 (m, 4H, MeC-Cfiz-Cfiz), 3.61 (s, 3H,
-00g3), 4.38 (t, 2H, -C§2N02): mass spectrum. m/e 147

(parent): n30: 1.4532.

3,3Lbis-L5;(2-carbomethoxyethyl) isoxazolinyllmethane (6)

 

In a 250 ml three necked round bottom flask fitted with
a Teflon stirrer, an addition funnel with a pressure equali-
zation sidearm, a condenser and a nitrogen bleed was placed
10 ml (97 mmol) 1,4-pentadiene, 100 ml dry C014, 10 ml (72
mmol) triethylamine and 44 ml (0.194 mol) phenylisocyanate
at 0° . To the stirred solution was added dropwise 28.5 g
(0.194 mol) of methyl 4-nitrobutyrate in 60 ml dry C014 over
a 5-7 hour period, maintaining the temperature at 0-5° .
The thick mixture was stirred an additional 18-20 hours,
then cooled to 0°, filtered and the solid washed with 25 ml
dry 0014. The brown liquors were placed back into the flask
with 24 ml (0.220 mol) phenylisocyanate and 8.0 g (55 mmol)
more nitro ester in 15 ml 0C1“ was added over a 1-2 hour
period at 00 . After stirring overnight again, the mixture

was cooled and filtered. The solid cakes were combined and

13
dried. The solid was slurried in 150 ml 0112012 and filtered
to separate the product from the sym-diphenylurea. The
liquors were stripped to dryness, crushed to a fine powder
and slurried in 150 ml isopropanol to remove the last traces
of the urea. The solid was filtered and dried. A yield of
20.6 g or 65% was obtained. Recrystallization from C014
gave 18.9 g of a white solid: melting point 96-99° (s 95°);
PMR (CDCIB): 6 1.80 (overlapping t, 2H, -Cfi2-), 2.29-3.21
(m, 4H, 4 position), 2.59 (bs, 8H, -Cg2-Cfi2-), 3.60 (s, 6H,
-0C§3), 4.33-4.82 (overlapping q, 2H, 3 position): IR
(nujol): 2870, 1740, 1560 and 1200 cm'lg mass spectrum:

m/e 326 (parent).
3,3'bis-L5:(2-carb0methoxyethyl) isoxazoyljmethane (Z)

In a dry 250 ml three necked flask fitted with a thermo-
meter, a reflux condenser and a serum cap was placed 125 ml
dry 0014, 2.0 g (6.1 mmol) compound 6, 4.4 g (24.6 mmol) NBS
(recrystallized from H20) and 0.10 g (catalytic) benzoyl
peroxide. The mixture was refluxed with a subsurface nitro-
gen bleed for 1.25-1.50 hours until the starting material
(Rf = 0.34) and monobrominated material (Rf = 0.42) were
gone. The TLC silica gel plate was developed with 3:2
ethylacetate/hexane. The reddish mixture was cooled to 20°
and the succinimide was filtered off. The 0014 liquors were
washed with dilute bisulfite, then with NaHCOB, and dried
with MgSOu. After removal of the solvent in vacuo, approxi-

mately 3.0 g of a red oil was obtained with a TLC containing

14

4-5 spots with Rf values greater than 0.5. The oil was
placed in 25 ml dry THF and 10 ml Et3N and then refluxed for
24 hours under nitrogen. After cooling to 20°, the brown
solid was filtered and washed with fresh THF. A black oily
solid (2.5 g) was obtained after removal of the solvent.

The TLC showed two spots: Rf = 0.49 (product) and Rf = 0.53
(impurity). After removing the color on an alumina column
eluting with ethyl acetate, these were separated on a 5 cm

Still's flash chromatography column.21

This yielded 0.9 g
(45.6%) of an off-white solid: melting point 78-81°: PMR
(00013): a 2.47-3.15 (m, 8H, -cg2-0§2-), 3.60 (s, 6H,
-0Cfl3), 3.70 (s, impurity), 4.10 (s, 2H, -Cfl2-), 5.92 (s,
2H, isoxazole): IR (nujol): 3120, 2950, 1730, 1607, 1180

1

cm' 3 mass spectrum: m/e 322 (parent): UV: 245, 273nm.

a-keto bis-vinylogous lactam (3)

In a 250 ml Paar flask was placed 100 ml dry ethylace-

tate, 1.3 g (4 mmol) compound 2, 2 ml Et N and 0.13 g (cata-

3
lytic) Pt02 (Adam's catalyst). The light yellow mixture was

hydrogenated at 45 psi for 5-7 hours at room temperature.

The light green solution showed one spot by TLC (same solvent
system as for compound 2) at Rf = 0.1. After filtration and

removal of the solvent, a PMR and a mass spectrum were

taken: PMR (00013): 5 2.47 (t, 8H, -0§ -0g2-), 3.16 (s, 2H,

2
C-CflZCO), 3.60 (s, 6H, -0Cfi3), 4.95 (s, 2H, vinyl), 6.40
(vbs, 2H, Nfiz), 9.55 (vbs, 2H, enol -0H); mass spectrum:

m/e 326 (parent).

15

The above yellow-green oil was dissolved in 25 ml meth-
anol containing 1 ml Et3N and refluxed under nitrogen until
cyclization was complete (usually 4-5 hours). Upon cooling
a yellow solid precipitated out and was filtered off. The
solid was recrystalized from methanol and cooled slowly to
yield 0.37 g (35% yield based on bis-isoxazole) of bright
yellow-gold needles: melting point 178-9°(dec 184°): IR
(nujol): 3225, 1720, 1630, 1300, 1165 and 1125 cm‘1; PMR

(00013):5 2.48-2.54 (m,4H,-0g 0H200), 2.86-2.93 (m, 4H,

2
-CH2C§ZCO), 3.52 (s,1H, keto), 5.04 (s, 0.3H, enol), 5.20
(s, 0.2H, enol), 5.56 (s, 2H, vinylogous amide), 9.97

(broad s, 0.5H, enol -0H), 10.7 (broad s, 2H, -Nfl): mass

spectrum: m/e 262 (parent); UV: 297, 362, 392 and 402 um.

Attempts to synthesis target molecule (4Q

Compound (2) 0.02 mmol was dissolved in MeOH or THF
and 0.02 mmol of a hydrazine salt (sulfate or dihydrochlor-
ide) with enough base (EtBN, K2003 or KHCOB) to neutralize
the amine salt added. The mixture was heated to reflux
for 1-12 hours and cooled.The solids were removed by fil-
tration and the solvents removed in vacuo. A dark brown
viscous oil remained. The mass spectrum showed little or
nnee-0fxm£e;258 (parent);butnmestly starting material and
other ions not matching the hydrazone or identifiable pro-
ducts. The TLC (same system as above) showed many spots

which could not be separated by chromatography.

BI BLI OGRAPHY

10.

11.

12.

13.

BIBLIOGRAPHY

D. Dolphin, The Porphyrins, (New York:Academic Press,
1978): F.R. Longo, Porphyrin Chemistry Advances, (Ann
Arbor: Ann Arbor SciEnce, 1979).

R.A. Berger, Ph.D. tgesis, Michigan State University,
1978é)R.A. Berger and E. LeGoff, Tet Lett., 44,4425
197 .

J.Eé MacDonald, MS thesis, Michigan State University,
197 .

R.V. Stevens, C.G. Christensen, W. Edmonson, M. Kaplan,
E.B. Reid and M. Wentland, g. Amer. Chem. Soc., 93, 6629,
6637 (1971); R.V. Stevens, Tet. Lett.,22, 2793 (1974).

 

E. LeGoff and 0.0. Cheng, ibid, 1469 (1977).

G. Buchi and J.C. Vederas, g. Amer. Chem. Soc., 94,
9128 (1972).

 

G. Casnati, P.V. Finzi, A. Ricca and A. Quilico, Tet.
Lett., 233 (1966).

R.V. Stevens, Tetrahedron, 32, 1599 (1976).

G. Grundann and P. Grunanger, The Nitrile Oxides,
(Berlin: Springer, 1971).

A . Ricca, A. Quilico, G. Casnati and P. Vita-Fini,
Chimica g Industia, 42, 993 (1965);Gazz. Chim. Ital.,
96, 1064 (1966): Tet. Lett., 233 (19665.

A. Ricca and S.Auriccho, Gazz. Chim. Ital., 103, 37
1973 .

G. Shaw and G. Sugdowdz, g. 9. §., 665 (1954): A.
Quilico and A. Ricca, Gazz. Chim. Ital.,ggd 47 (1961):
P. Pino, F. Piacenti and G. Fatti, ibid, 99,356 (1960).
A. Ricca, S. Auriccho and S. Morrocchi, Tet. Lett.,23,

2793 (1974)-

16

14.

15.

16.

17.
18I

19.
20.

21.

17

A. Barco, S. Bennetti, G. Pollini and P. G. Baraldi,
SynthesiS. 837 (1977)-

A. I. Meyers, D. K. Minster, U. Jordis, S. M. Hecht and
A. L. Mazzu, Synthesis, 44, 497 (1979).

G.Bianchi and M. DeAmici, Synthesis, 837 (1979).
G. Bianchi and P. Grunanger, Tetrahedron, 21, 817 (1965).

W. C. Still, M. Kahn and A. Mitra, J. Org. Chem., 42,
2923 (1978)-

D. Verruijsse and M. Hassler, Synthesis, 4? 292 (1979).

E. R. Jones, J. B. Jones, L. Skattebol and M. C. Whiting,
J. Chem. Soc., 3489 (1960).

H. Baier and S. Heinrich, Angw. Chem., 8Z,743 (1975).

APPENDI X

0.0 .

-. It 0.-

 

 

 

 

 

 

 

 

 

 

  
  

 

 

 

 

 

 

18

 

 

 

[.1

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

l
l

-..
I

- ... ...
I. I 15 N ‘5 II ‘1 ‘ Il ‘1 I 5‘ 5‘ J 1 5‘ ll‘
4 -— . . 1‘l [J ‘11 q 5.1) id 51! m d 1 1m
..u . . .l‘) u . . —i . m . .
. . . m . _
Ill: 8...." Lavzgi 7...... n .- . . .. - .-
. \ a a
ll rl.,.:--..||I.. {UN-1141 lib‘ 4 (41 1.1
3141 a .11 .. . . I
._ . _ _ I . . H
II: fur»...- l ...... .. .....i.- . ..... ... . ..--I
. .. . . . H m
, . . m .
.n-...1...l (I. . ... . l-.i: w.-. a. _. _
. . _ . _. _ U . w
. . . . .
_ . . . .r M I. ..II- .5-
. ., . a “ 3?.nvw.
...-a 57..- - l. -I- .5-.-. . .w .
I . “ ...... {...-...... . . .
- . ...tt .. . .. ...... - ...... ...: I. .
. I ;m m m u .
. . . . . .
. . . . . . . m
. .

 

 

 

 

 

 

 

“(--.—.--...

l
I .

. . 5
. ...—..--cr ...—1....-—.o..— ...--.«
.. ' . u
. . r
. .

I
1 n
..-—:.—-...4_--....

 

)
"Mam:

 

 

 

p

p
D

1:4. :JVVV , 1x5- --.:4}. i - - .u I .v n
. U . . . . H .. .. . . a .
a. . .iii-m t ..n -.3 . . . . I
.. . . llw ,-......:.- .1- .14..” ....llnl :31... ... \ .-. 4 l .- l: l.- . ! -. .-: .... - . n. . . ..q 1..-...
: . . .. . .. ...r 2 . . _ . 2 m .
, . . . . ... . . .. . : a . u _ N ,. .
.7. :- -... .... in 11.....l n...J-. - w. ..-.l i 1... l 113..-... ..o-o 15.12.7111 ..5- o... 1...: o: . ... .
As: , .. .r .34.. W... U ...... v....... “3, _ . . .... W 1 .
.A . . . , , . ., . , . . . ”
... .h-,., ..- .- .. ll: Onl- F.-- l .. i l.- q...lm u , III 110-50: .ll -1 .... z:- _ ... . .00“ .. - y .. . . . ..
... . _. ,1 .. , N ”n+2” .. «$2.... S. .. L. . + M a . .
. W... . .L .. .L.I... .. ..... —. . 2 . . h . . r P .
P .— p P

 

 

 

 

 

 

 

 

 

Figure 7. PMR of 3-hydroxy-1,4-pentadiyne

19

81)
100
80
60
40
20

1500

6&)

4.0 MlCRONS 5.0
2900

2500

1&5

3000

31)

3500

 

215

100 "5
4000

_:. O o O O 0
co '0 V N
(%)33NV11|WSNVHI

Figure 8. IR (4000-1250 cm'l) 0f 3-hydr0xy-
1,4-pentadiyne

20

Hi0

8.0 M'CRONS 10.0 11012.0

71)

6!)

(%)3:>Nv111wsr~1v211

Figure 9. IR (1250-650 cm-l) of 3-hydroxy-
1,4-pentadiyne

 

1600 I400 1200 1000 800

1800

21

 

Figure 10. PMR of 3-acetoxy-1,4-pentad1yne

4.0 MICRONS 5.0"

22

81)
100
80

. 60
40
20

1500

61)

  

2000

2500

115

3000

31)

3500

2 -w+“¢~
ON !
‘ 1

...........+.......

.-.. . - m‘-—.—:.u~— ----31—-

1 ‘ '
.-.L.-. . -----.1 .-..-.
1

In .
‘V :3 c> c> c> c> c>
.— co ~O V N
(°/.)33Nv111w3Nv211

4000

Figure 11. IR (4000-1250 cm'l) of methyl 4-nitro-
butyrate

 

23

com coo. oom— oov. o

coo- oom. coon

.

._

    
 

8 em
I.
“a
2. .- o- w
S
w
H
I.
V
8 8 N
D
a
%
8 8
8. 8.

90— /\ ON— 6.: od— wZOmU_<< 0d .1 OK 0.0 ..\ O6

Figure 12. IR (1250-650 cm'l) of methyl 4-nitr0-
butyrate

1

 

 

.Ea

t‘.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

24

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

fl..— ..-.-L 1.‘

 

 

 

 

 

 

 

 

......ctqu.
. . H

.
.

 

 

 

 

 

 

   

 

. ..
._

O

;

 

 

 

 

 

 

 

 

 

 

(,é.)

ine

l

 
 

lS-lsovaO

 

 

 

 

 

7~~ - >~. ..-—...-

 

 

 

     

 

.95..
..

 

Figure 13. PMR (60 MHz) of b

 

25

 

 

 

 

 

 

 

3. 60 PP’“

 

Figure 14. PMR (250 MHz) of bis-isoxazoline (é)

26

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

I.‘/.) 3‘\Mw1 unuomwul

0 00m.— 000m 000m . 00m. 0000 00m..-
...:L: 5.27.... . H I...
. a J .1 1 r . n N I 1 . . .4“ a a 1,. n
_ u 1 u l u u . u . . H . I . .... 1 a 1 w 1 .
--. -4_1.---.1 ----.: 1+- .--;n - -- -:- . 1..-.a -. ....... - -. 1- 1-.-- --.--r.-. -.-
_U _ _ T m I M 1 m _ m . U . .gw. . .1 . m. a _ 1 r
. . . . . . . - . . . . . . .. . . . . . . . . .
. . . . . _ . . . H _ . u . . _ . . a H
m I 11. - L . w . s m _ . q 1 a .m . I . I. u . .Vm
cm . . L.- . . .111.-. -.- ..- .. 1 1 -L -.., 1.. 4 H 1.1.1 11- 111.1 9..
h . ... . w I _ . l . U a _ I . . .... . _ I.“
u 1.. ... .. ._ . -., . I I H n . . h n n . ,. . ..h.. ...
I . _ _ . ... u . I _ l n u I , a ,. . I I u . .
w . 1. 1T : 1.. . u L. . a u _ . .. h , . . n L . m .
-..1 11- 1 . .. ..-- - .- 151 _ 1.- 4 1.1, 1.- 1” - a 1. .. 11 1 ..1. I... 1.-.. .i 1111.1...-
" .. a _ . l . H _ . . r ... . H _ . n H m n . n _
. ... ..r . ..... . . . . u . _ .. W a q. . -. h. . . p...... n
._ I ._ :1 L . . . u _ . _ . i . . .. I ..n . H
. N. Z. . t . . . . . W . 1 I n . I . , . I . u
e. -..... a- ...-W... .- _ -.-- e .e :9 .2 -. 4. n- I 111.--- a _ m e.
......“ __ 1,. _ . . .. ., . W .. . .1 H .. _.. a .
5.; . _.: . _ 1 . H _ m w r ._ c r a r _ a a
......” «- -...» r1.-. 1 -.T .. 1.1- 11.. i..- - r .m 1. - L1. 1.. --.... -1. -1 11.11. - ...: 1 . .-,.11.1 ._1--
EW- 1;. w . a m . M m m I H m . M m . a m
#14 .1. . - _ W m m . a 1 - a m ._n..m ... w-“
. ”L ,h . r I u . H . h I . .. . .1 . .. _ .. n h . .
h 1.. ..vil . .1 .1 ~ . O F 1:11 A 1&1 11m 1. 1._ 1 1h. 1 1h 1 11s. .1 11.”. ..91 1 b. ~1hl l 1 011 v1 1 ~11 .1h11 II 5 9' m 1 - 1 t 1.:1W1 v11ln: L
00 1% m ..M w . I . r l u H . ... M H. 1 . H," 00
_ r .H 1. ... ._ _ . . _ u. . . n h . . . . h . _ n . . . . .
1.1 3 1...... . _ u m m . n a ma. . .11.. u 1 . _ m.”
rig-1:.Wrett+-i1a-T-n 1:0 L-Y-+fi-,;-11ct. “.1 11--«15111
. U. “1.: . _ I . _ n u u .. 1 ... . h.. H . 1 I
l _. . _ . . . . _ . . T _ . . _ . .
1 . .. . .\ w. . u . . . . n m .1 1.... 1 {.11. 5.1111.- - _ . . V1-11.“
. . . r, l . . _ . . . _ . . _ 11.-1.1.1. _
. M _ V . L h . . . u H .-. . H . H . . . a ..
Om . - 11.- \1 - .1. 1 114-111-1121;». -- 1.- , 1.1, .m 1.1 1.- 1- 1.-- 11--1..-.-1, “1 1.11.11.41.11om
.1 a . n _ u H N n , . 5 u . I _ . . . a
_ . . . . . . . . . . . . _ . .
n u H I a a 1L1. 1h -1 n .1 “- 1- n U . .. I _ . ,. . _
W W w . m _ m . . . h u a I H M . . .. . .
- 1.1 .1 1- 11: --.-1 .- li-tn. . a - .- 1“. .. - 1. -.1 1 1L ...- - 1 a .h -- -1 ..1 , -1 1 1-
. u 1“ . . I. ”1 . H 1 q , n _ _ r H . .- N u . 1. .1
_ w L 1 I W M a .. _ w m _ . . u _ m . _ .
00— PM 1+ 11.£-1.;-;11 a 1.: .. -H-n-:+.J- .4.t --z.-z-- .. -9 1:. W- -
- 4 - 14 . _ . 2 _ _ . _ L _ fl 4 . . D L _ q 4 n u _ _ _ -

 

 

 

on 205:2 0.-

 

 

lS-lSOX-

15. IR (4000-1250 cm-l) of b
azole (29

Figure

27

.. << .1 > 42.2382

000 000 _ 00m. 00: 000— 000— 000m

on 18

O
‘3

0V1

 

 

l

I
O
‘0

1

 

(Cc-\a‘wmwl chmwuu

.—

0

co

1 "7

1 .
|
I -
I

O

O)

8..-: .. ., . . -_.--.. ‘. w L m : . A 1......oo.
3: of Q: 3: 955.2 3 ox 0.0

0.
1n

lS-lSOX-

Figure 16. IR (1250—650 cm'l) of b

azole (7)

M

28

 

f s g

bun—9 % div—Ia
r F + J
b P 1 ‘ ‘
_ r 1; fi ‘
r L— { -—J ‘
—' «nu-n3
’ 1

p

?' 4
L __9 i ‘

 

70

L

.g!

D + 1 4
-L
:—
b ’ 4 J
F
P 1
r— . _1
b L 4
, 1
> d
+- 1—4
p F .
1
n _§ .1
I
. + .
’ _'—-—-'"" u. dam—4. - _ ' 4 .
M - o . s..-.‘r A: ... —- 9 ‘ —‘-
b ’ \ 4
i—i-
1
' !— “W
' 1
> 1
r ‘ ‘
D d
p
1
p
q
> fl
F * ‘
bun-l.
v—i
. V '
1
b 4
’ '4
1

‘0

"M is)

V

Y r r Y

Cl)

1
l
401)

D
p ‘1 1
'—" .l {—12
. fin
L 1
. f ‘ ‘
r ‘
P 4' ‘
. t ‘
b
h.
D {—13
, r
..2 3 ‘
b 4‘ { d J

 

 

 

 

 

 

Figure 17. PMR (60 MHz) of bis-isoxazole (l)

29

 

 

 

P h b P
W.
..bI II II I I I I I I I I, IIIIIM
5v
3 m.
H A...”
aL .VwJ I : I
o “...”: . I . -
O r
N\ w
_ firs... III.
0 /\ ... III I
f. a
, ...

‘1
'Tfir—W—rfi I v

 

/ f.I IIIIoI III II I I II II I I I
)‘ I \II
N I” v
Y
v
0 1 f
.0“. I .I I
.I. I
O V
b . T
I‘
3 v
H r
V
.3
.bIIlde . I I I
II. I . r
v.
4 r
5"" I'llilbx
...lal Iunlfl IwIIII’IIIIIII In If I II T
.. 1
.. I I
. 1
Y
.1.
.”.II Y...
Til
.4 I v
..4. I I I .I!
7:: II- x .I. r
5 w
T
T r
on. Y
319 - I - f.
... I! I l I
fl. I a 1 I ‘ d II IId:v I Q d . <.
....u .U
.M. .I...
...

--I.I, III» II III—

0.
> 0
7” n V
( IN.
c ,/

e ,
.IO* 0 ha»
2 v
a m \
x d
0 _

.

S
i
.0
f

O

m 3.... _ III-I-.-.!I.I:I- . :Ii- IIIII.1..II I uI I I
u -

r

t

c

e

p

S

S

S

a ...

M" u
8

1...

e
0W H... . a . r um. I
F m. 7....

«a

rI I I I I
..
...I-L
._

.4.
a
..
. I
a-
nu
.4-
..,.III I

[Y'TwI

Y
I

r—r.

 

T T‘r
0 '.

M

Figure 19.Mass spectrum of B-keto bis-vinylogous lactam (3)

30

0m

0?.

oo .-

om I-

oo—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

od nZDszz o.v

 

I. . . _ . e I . I I .I. I - . u n _ . u u
a . _ _ g _ _ m H n _ . . h u h \I L. . w . m M w . . u n n
H 3.4 m.7<~u m m _.I I I I m I I IUI. W m .m M m
: IT :._.-- r... ..m.: -..: H .... 1 - 7:: 1”... ..I L. :I-_I .- -1 1_ : .114“---..-11.M-
I . n u 3 h m u m . “ I q . I m H . n n h n
:.-.wr » m... I m I I . ”I“ u H .. .+. I m I m m m
. ....H n . .n H H M . M y H _ . . .. ... . _ . I . u w I" _ h
L: :11? I » Ire-1-1+: I 4. a .. 1 ..T L.-. :..:L I“: . III-1.1 - L . -”:: WI .-IHI--;T--
3 I ” u. m _ n . m I H . .. .. . . w _ m _ . . I n U
.. .. . _ g _ a . . . ‘ I v . . _ . . _ . . . .
3.; -fi 2. . n _ a . I _ .u I I. ..w I m u . H. w ”
...h H . . l _ w _ . . . . .. _ I n \ . _ ” . . . u
H u .I I “L. 1,— 2 w . . I m a . H h u . H I T. u m _ . _
III111.v.. .. n . . . . .11L11Y1 .n . +24 1w : -.:1 I.“ c .n IJI he I. . . ..HII- III ‘ u. p ..I 1Im.l.'l.»: :0 ..I I ”I I
Ii”. 0 If“ u m I. I _ H . I W I\ r. M _ _ _ ..1:
“ft..e+¢.m w m . o‘ggp M a x. . /,\. x m u. .vr1u
“ .I H .. :.. .I _ , H __ _ _ h . . I . n 11./I ...I- u _
1-1..1L.1+1.-I“ 11”.. L- . m ..1... -r - :.. ... -n. ... 1 :.- I .1 - .- -L:: -L- 1. . ..-.-.:..IH\. - -h :IWIIIH: :
. I .mmm . . _ w I I . u . . H . WI I I” u
. m. \ _ h .w. M h M M u _ H m M I H .I . m m * h m-.. m.

w H m .. ._ . I . p H n r u . » “I I u .. M I I w m
...-...-IL-.< :1. .-- u- :..-......I.---.: - .I- 1--.. 1m:- I :..-T:-
u r m H h m . m I I m I H . H~.;

_ m a h m . m u ” “Lx. m .n I a m a m w _
1--w +-;--:-f 9-.-.. . .be--.1 - : 1-1.::t.; :-1+1L-111.
. _ . n I . u I. . s I H . a . m m . . . . n
_ . r — _ _ m _ _ 9.1 . . _ . . . .
u a N . w . \L \I I f I . w H I. m . _ . q
. . . . . . . . . . I I . . . . I
h u » . . H . . . H . I . . u n _ I
.I A: 11 1.1:. -- - -. ”I- -H 911.- . m : m. .. :.- -.. $1.11qu --.WI- IH11MIr1
w m m _ *I _ W u xx . m . . . . _ q * M H H _ w w
..FI . h . :r -.. 7 £71..- :. 1r- 1: ,II: I” .I 11 1: LIV-“ “-..I: II: . r .I u 1:
n u w m a a m a -1 I . U H n . m _ _ . _ . fl h
u. ”m.“ I I _ M . m I_- f... _._. I m,
u: w “ ~ “ _ u . H U _ n . w n H _ . m m . n H
-. IV IL- M 7. m D .. .I- h 1..- I" I- .. I- 1- - ..W: ,W .“I {L -L--:-L:-::W- -
“ u h _ m _ .I _ . . . .. U m . I. _ n * a
m -m-~.“ “r. M m I _. M I. W . w ...;;;M
. I m n “71.. m _ _ .“m I . h ._ m ... m
¢III-I-I:1m-Iaw .L_ ... .1 - - mm I“... _. u: a u. u .._ .4 «ix H. 4::4 r. _ W:
I . _ - _
.1: . . H1. . . :1. a.
00 nm em _

.:ON

0
v

{CM II'ENVI chmvm

O
‘0

0m

- oo.

logous lactam £2)

gure 20. IR (4000-1250 cm-l) of fi-keto bis-
Vlny

O
1
*

F

31

000.

 

(%I33NV11|WSNV81

W

logous lactam (3)

.IR (1250-650 cm‘l) of fi-keto bis-
Vlny

gure 21

F1

32

 

 

 

 

 

1 Y

 

 

 

 

on so m. “I 40 ; '10 20

70

90

 

A A
P L gLA A

 

Figure 22. PMR (60 MHz) of fi-keto
vinylogous lactam £2)

bis-