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31293 00904 58 1

This is to certify that the

dissertation entitled

Part I Studies of the Haznrov cyclieation courlod with
Cascade rearrangements.

Part II A study of 4-ironohutyldiphony]pUOSphiup oxide
as a synthon for cyclohutylidene derivatives.
presented by

April Cu Cruhn

has been accepted towards fulfillment
of the requirements for

mm. degree in Organic Chemistry

 

7mm

Major professor

Date ‘t/‘(/ 73

MSU is an Affirmative Action/Equal Opportunity Institution 0-12771

 

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Michigan State
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PART I
STUDIES OF THE NAZAROV CYCLIZATION COUPLED WITH
CASCADE REARRANGEMENTS
PART II
A STUDY OF 4-BROMOBUTYLDIPHENYLPHOSPHINE OXIDE

AS A SYNTHON FOR CYCLOBUTYLIDENE DERIVATIVES

By

April Gu Gruhn

A DISSERTATION

Submitted to

Michigan State University

in partial fulfillment of the requirements

for the degree of

DOCTOR OF PHILOSOPHY

Department of Chemistry

1 993

ABSTRACT

PARTI
STUDIES OF THE NAZAROV CYCLIZATION COUPLED WITH
CASCADE REARRANGEMENTS
PART"
A STUDY OF 4-BROMOBUTYLDIPHENYLPHOSPHINE OXIDE
AS A SYNTHON FOR CYCLOBUTYLIDENE DERIVATIVES
By

April Gu Gruhn

EARL]: The substrate 2-(2'-oxo-(E)-4'-phenyl-3'-butenylidene) spiro[3,5]nonane
(8) was synthesized in six steps in 51.5% overall yield. Methylenecyclohexane
was reacted with dichloroketene via [2+2] cycloaddition to give 1,1-
dichlorospiro[3,5]nonan-2-one (1). Dichloroketone (1) was elaborated to give 1-
spiro[3,5]-2'-nonanylidene-2-propanone (7), which then underwent aldol conden-
sation with benzaldehyde to give dienone (8). Acid-catalyzed reaction and
rearrangement of dienone (8) was studied by treatment with phosphoric acid,
hydrochloric acid, iodotrimethylsilane and tin (IV) chloride. Reaction of (8) with

phosphoric acid at room temperature gave dispiro[cyclohexane-1,1'-cyclobutane-

3',2'-6'-phenyldihydro-2'I-I-pyran-4'(3"H)-one] (11) in 31% yield. At 90 °C, this
reaction gave 5,7-dimethyltetralin (12) in 64% yield and 2-cyclohexenyI-1-methyl-
3-phenylbenzene (13) in 10% yield, the former by an initial retroaldol reaction
and the latter by a series of tautomerizations and electrocyclic reactions following
cation induced four-membered-ring cleavage. On treatment with hydrochloric
acid, (8) gave 2-chIoro-2-(2'-oxo-(E)-4'-phenyI-3'-butenyl) spiro[3,5]nonane (14)
quantitatively. Reflux of (8) with iodotrimethylsilane gave compound (13)
quantitatively. Reflux of (8) with one equivalent of tin (IV) chloride in chloroform
gave a kinetically controlled mixture of Nazarov rearrangement products:
spiro[cyclohexane-1,5'-3'—phenyl-3',4',5',6'-tetrahydropentalen-1'(2'H)-one] (1 5) ,
spiro[cyclohexane-1 ,5'-3'-phenyl-4',5',6',6'a-tetrahydropentalen-1 '(3'aH)-one] (16),
and spiro[cyclohexane-I ,5'-3'a-phenyI-4',5',6',6'a-tetrahydropentalen-1'(3'aH)-
one] (17) in 20.8%, 16.2% and 34.0% GC yields respectively. This mixture was
stable under the reaction conditions, but (15) was completely converted to (16)
on treatment with toluene sulfonic acid. Finally, a discussion of Nazarov

cyclization coupled with cascade rearrangements is presented.

3AM: 4-Bromobutyldiphenylphosphine oxide (1) was synthesized in 90%
yield by aqueous hydrolysis of commercially available 4-bromotriphenyl-
phosphonium bromide. Oxide (1) was reacted with two equivalents of
phenyllithium in tetrahydrofuran, and then with dicyclopropylketone to give (1'-
dicyclopropylhydroxymethylcyclobutyl)diphenylphosphinyl oxide (3) in 77%
overall yield. Oxide (3) was then reacted with sodium hydride in dimethyl
formamide at room temperature to give cyclobutylidenedicyclopropylmethane (4)
in 82% yield. Cyclobutylidenedicyclopropylmethane (4) was transformed into 2,2-
dicyclopropylpentanone (5) when it was exposed to air.

ACKNOWLEDGMENTS

To Dr. William Reusch for his guidance, insight, patience and

encouragement throughout the course of this work.

To Drs. John Stille, Ned Jackson, Donald Farnum and Michael Flathke

for their guidance and critical advice during my studies.

To Paul Weipert, Greg Cook, the Reusch group, especially Ed Bryant for

being good friends and great coworkers.
To Michigan State University for financial assistance.

And to Todd and my family, for their support and love throughout.

 

TABLE OF CONTENTS

Chapter ............................................................................................. Page
LIST OF SCHEMES vi
LIST OF FIGURES x
LIST OF TABLES xvi
LIST OF ABBREVIATIONS xvii
EABIJ 1
INTRODUCTION 2
SYNTHESIS 17
CYCLIZATION RESULTS AND DISCUSSIONS 26
CONCLUSION 47
EXPERIMENTAL 48
APPENDIX l: SPECTRAL PART I 63

BIBLIOGRAPHY 124

PART II

INTRODUCTION

RESULTS AND DISCUSSIONS

EXPERIMENTAL

APPENDIX ll: SPECTRAL PART II

BIBLIOGRAPHY

vi

128

129

130

137

142

163

LIST OF SCHEMES

Scheme .................................................................................................. Page

EABLI
Scheme 1. Arena-olefin Meta-photocycloaddition. 3
Scheme 2. Tandem Radical Reaction. 4
Scheme 3. Cascade Rearrangement. 5
Scheme 4. Rearrangements of [7,7-Dz]-Dispiranol. 7
Scheme 5. Nazarov Cyclization Mechanism. 8
Scheme 6. Secondary Cationic Rearrangement. 9
Scheme 7. Proposed Rearrangement of Dicyclobutylidene Acetone. 10
Scheme 8. a-Methyl Group Substituent Effect. 11
Scheme 9. Migratory Aptitude Effect. 12
Scheme 10. Substituent Effect. 13
Scheme 11. Proposed Retrosynthesis of lsocomene. 14
Scheme 12. Proposed Rearrangements of (8). 15

vii

Scheme 13.

Scheme 14.

Scheme 15.

Scheme 16.

Scheme 17.

Scheme 18.

Scheme 19.

Scheme 20.

Scheme 21.

Scheme 22.

Scheme 23.

Scheme 24.

Scheme 25.

Scheme 26.

Scheme 27.

Scheme 28.

Scheme 29.

Scheme 30.

Preparation of (2).

Dehalogenation of (1) in Acetic Acid.
Mechanism of Formations of (3) and (4).
Preparation of (7).

Aldol Condensation of (7) with Benzaldehyde.
Transformations of (9) and (1 0).

Reaction of (8) with Phosphoric Acid at 25 °C.
Mechanism of Formation of (11).

Reaction 01(8) with Phosphoric Acid.
Cyclobutyl Cation Equilibria.

Reaction of 2-VinyI-2,3,3-trialkylcyclobutanone.
Mechanism of Formation of (13).

Mechanism of Formation of (12).

Hydrochloric Acid Addition to (8).

Mechanism of Formation of (13).

Reaction of (8) with Tin(lV) Chloride.

Mechanism of Formation of (15), (16) and (17).

Acid-catalyzed lsomerization of (15) and (16).

viii

17

18

19

21

23

24

28

30

31

33

33

34

35

36

38

39

40

42

Scheme 31

EABLLI

Scheme 1.

Scheme 2.

Scheme 3.

Scheme 4.

Scheme 5.

Scheme 6.

Scheme 7.

. lsomerization of (17).

Preparation of (1).

Preparation of (4).
Retroalkylation of (3).

Reaction of (4).

Reaction of Bicyclopropylidene.

Mechanism of Formation of (5).

Reaction of Cycloprolidenedicyclopropylmethane.

43

130

131

132

133

133

134

136

LIST OF FIGURES

Figure ................................................ ' .................................................. Page
flBLI
Figure 1. Angular Triquinanes. 2
Figure 2. Spectroscopic Characteristics of (11). 29
Figure 3. Cyclopentanoids. 43
Figure 4. Spectroscopic Characteristics of (15). 44
Figure 5. Spectroscopic Characteristics of (16). 45
Figure 6. Spectroscopic Characteristics of (17). 46
Figure 7. 1H NMR Spectrum 01(1). 64
Figure 8. 130 NMR Spectrum of (1). 65
Figure 9. Infrared Spectrum of (1). 66
Figure 10. Mass Spectrum of (1). 67
Figure 11. 1H NMR Spectrum 01(2). 68
Figure 12. 13C NMR Spectrum of (2). 69

Figure 13.
Figure 14.
Figure 15.
Figure 16.
Figure 17.
Figure 18.
Figure 19.
Figure 20.
Figure 21.
Figure 22.
Figure 23.
Figure 24.
Figure 25.
Figure 26.
Figure 27.
Figure 28.
Figure 29.

Figure 30.

Infrared Spectrum of (2).

Mass Spectrum of (2).

1H NMR Spectrum of (3) and (4).

Mass Spectrum of (3).

1H NMR Spectrum of (5).
13c NMR Spectrum of (5).
Infrared Spectrum of (5).
Mass Spectrum of (5).

1H NMR Spectrum of (6).
130 NMR Spectrum of (6).
Infrared Spectrum of (6).
Mass Spectrum of (6).

1H NMR Spectrum of (7).
130 NMR Spectrum of (7).
Infrared Spectrum 01(7).
Mass Spectrum 01(7).

1H NMR Spectrum of (a).

130 NMR Spectrum of (3).

xi

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

Figure 31.
Figure 32.
Figure 33.
Figure 34.
Figure 35.
Figure 36.
Figure 37.
Figure 38.
Figure 39.
Figure 40.
Figure 41.
Figure 42.
Figure 43.
Figure 44.
Figure 45.
Figure 46.
Figure 47.

Figure 48.

Infrared Spectrum of (8).
Mass Spectrum of (8).

1H NMR Spectrum of (9).
130 NMR Spectrum 01(9).
Infrared Spectrum of (9).

Mass Spectrum of (9).

1H NMR Spectrum of (8) and (10).

Mass Spectrum of (10).

1H NMR Spectrum of (11).
13C NMR Spectrum of (11).
Infrared Spectrum of (11).
Mass Spectrum of (11).

‘H NMR Spectrum of (12).
130 NMR Spectrum of (12).
Infrared Spectrum of (12).
Mass Spectrum of (12).

1H NMR Spectrum of (13).

13C NMR Spectrum of (13).

xii

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

Figure 49.
Figure 50.
Figure 51.
Figure 52.
Figure 53.
Figure 54.
Figure 55.
Figure 56.
Figure 57.
Figure 58.
Figure 59.
Figure 60.
Figure 61.
Figure 62.
Figure 63.
Figure 64.
Figure 65.

Figure 66.

Infrared Spectrum of (13).
Mass Spectrum of (13).

1H NMR Spectrum of (14).

130 NMR Spectrum of (14).

Infrared Spectrum of (14).
Mass Spectrum of (14).

‘H NMR Spectrum of (15).

13C NMR Spectrum of (15).

Infrared Spectrum of (15).
Mass Spectrum of (15).

1H NMR Spectrum of (16).

130 NMR Spectrum of (16).

Infrared Spectrum of (16).
Mass Spectrum of (16).

1H NMR Spectrum of (17).

130 NMR Spectrum of (17).

Infrared Spectrum of (17).

Mass Spectrum of (17).

xiii

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

BABE!

Figure 1.
Figure 2.
Figure 3.
Figure 4.
Figure 5.
Figure 6.
Figure 7.
Figure 8.

Figure 9.

Figure 10
Figure 11
Figure 12
Figure 13
Figure 14
Figure 15

Figure 16

1H NMR Spectrum 01(1).
130 NMR Spectrum of (1).
Infrared Spectrum 01(1).
Mass Spectrum of (1).

1H NMR Spectrum of (2).
130 NMR Spectrum of (2).
Infrared Spectrum of (2).
Mass Spectrum of (2).

. 1H NMR Spectrum of (3).
. 130 NMR Spectrum of (3).
. Infrared Spectrum of (3).

. Mass Spectrum of (3).

. 1H NMR Spectrum 01(4).
. 130 NMR Spectrum of (4).

. Infrared Spectrum of (4).

xiv

Bisected Cyclopropylcarbinyl Cation.

135

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

Figure 17.
Figure 18.
Figure 19.
Figure 20.

Figure 21.

Mass Spectrum of (4).

1H NMR Spectrum of (5).

130 NMR Spectrum of (5).

Infrared Spectrum of (5).

Mass Spectrum of (5).

158

159

160

161

162

LIST OF TABLES

Table ..................................................................................................... Page
PART I

Table 1. 1H NMR Spectra of (2), (3) and (4). 15

Table 2. Reactions of (8) Monitored by 1H NMR. 22

Table 3. Products from Reactions of (8) with Phosphoric Acid. 26

Table 4. Products from Reactions of (8) with Tin(lV) Chloride. 33

Table 5. Acid Catalyzed lsomerization of (15). 35
BABE!

n-BuLi

mCPBA

DEPT

DMF

Et

5120

LDA

MeLi

Ph

PhLi

TEA

THF

TMS

TS

LIST OF ABBREVIATIONS

n-Butyllithium
meta-Chlorperbenzoic acid
Distortionless enhancement by polarization
tranfer

N, N-Dimethylformamide
Ethyl

Ether

Lithium diisopropylamide
Methyllithium

Phenyl

Phenyllithium
Triethylamine
Tetrahydrofuran
Tetramethylsilane

Toluenesulfonyl

xvii

PART I

STUDIES OF THE NAZAROV CYCLIZATION COUPLED WITH

CASCADE REARRANGEMENTS

NR TIN

Largely through the efforts of Bohlman and co-workers, a variety of
angular triquinanes has been isolated from natural sources over the past two
decades.1 This class of compounds, having a tricyclo[6.3.0.01-5]undecane ring
system, is represented by the hydrocarbons isocomene, pentalenene,

silphinene and Silphiperfolene (see Figure 1).

 

     

lsocomene Pentalenene Silphinene Silphiperfolene

Figure 1. Angular Triquinanes.

 

 

 

These biologically Significant condensed tricyclopentanoids, having
contiguous quaternary centers, have awakened a surge of interest in the
design and implementation of ingenious routes to their syntheses. These total

syntheses can be divided into two categories: the consecutive synthetic

 

 

._.—._.7

3

approach, and the convergent synthetic approach. The consecutive approach
involves stepwise application of classic or recently developed cyclopen-
tannulation reactions to construct the carbon skeleton one ring at a time.2
Regio- and stereocontrol here are achieved mainly by appropriate chain
elongation or functional group elaboration reactions, and in some cases by the
cyclopentannulation reactions themselves. The convergent approach is
achieved from precursors through a design in which several rings are
established Simultaneously, with regio- and stereospecificity. For example,
arena-olefin meta-photocycloadditions, tandem radical reactions, and cascade

rearrangements.

(a) Arene-olefin meta-Photocycloadditions. In one experiment by
Wender and co-workers,3 irradiation of an arena olefin substrate gave a 1:1
mixture of photoadducts in 70% yield. Reductive cleavage of a cyclopropane

bond gave silphinene and triquinane in 74% yield in a 9:1 ratio (Scheme 1).

 

 

Arene Olefin

Li, 0113qu

v

 

74%

 

Silphinene

Scheme 1. Arene-olefin meta-Photocycloadditon.

 

 

 

(b) Tandem Radical Reactions. In work by Curran and co-workers,4
treatment of a substrate with 1.1 equivalents of tri-n-butyltin hydride gave two

separable tricyclic products, which are formed in a 3 : 1 ratio (see Scheme 2).

 

 

Silphiperfolene

Scheme 2. Tandem Radical Reaction.

 

 

 

(c) Cascade Rearrangements. In a Study by Fitjer and co-worker,5 a
dispiranol was heated with an equimolar amount of p-toluenesulfonic acid in
benzene to give modehephene and isocomene via initial cyclobutane ring

enlargements and subsequent 1,2-shifts (see Scheme 3).

 

 

a) 62% 0%

b) 0% 27%

c) 0% 27%
Modehephene lsocomene

70 °C; a) 10min; b) 22 h; c) 76 h.

Scheme 3. Cascade Rearrangement.

 

 

 

These convergent syntheses built tricyclic Skeletons in one fell swoop
and demonstrated the relationship between reaction complexity and design

brevity.

The chemistry of Strained carbon rings has intrigued chemists6 Since
Baeyer first speculated about their stabilities over one hundred years ago.
Cyclobutanes are known to possess a considerable inherent ring strain energy
(about 25 kcanole).7 This angle strain provides a powerful thermodynamic
driving force for ring cleavage and ring expansion transformations. Such
compounds are often versatile and useful intermediates for organic syntheses;
and their applications were reviewed recently].8 with the previously described
work of Fitjer being a good example (Scheme 3). In this case, a
stereoelectronic effect favors migration of the cyclobutane bond trans to the C-6
hydroxyl group. The favorable alignment of the migrating cyclobutane bond
with respect to the leaving group at the developing cationic center, combined
with the relief of angle strain, helped facilitate the rearrangements. In Fitjer's
model study,9 (7,7-D2]-dispiranol gave an [8,8-D2]-propellane quantitatively.
This indicated that the rearrangements of [7,7-Dg]-dispiranol had proceeded
regiospecifically, initiated by an exclusive 1,2-Shift of that cyclobutane bond

having an antiperiplanar alignment with the leaving hydroxyl group (Scheme 4).

 

 

[7,7-Dz]-Dispiranol Antiperiplanar Alignment

 

   

[8,8-D2]-Propellane

Scheme 4. Rearrangements of [7,7-D2]-Dispiranol.

 

 

 

During the 1940's and 50's, studies by I. N. Nazarov and coworkers10
established the Nazarov reaction: a general synthesis of 2-cyclopentenone by
acid-induced cyclization of allyl vinyl ketones, divinyl ketones and dienynes. In
this dissertation, we propose that Nazarov cyclization can be used to initiate
cascade rearrangements of four-membered rings leading to a synthesis of
angular triquinanes. The Nazarov cyclization (see Scheme 5) is an
intramolecular electrocyclic reaction: the protonated dienone is treated as a

hydroxypentadienyl cation having four it-electrons.11 The thermal electrocyclic

reaction should therefore be conrotatory12 by the Woodward-Hoffmann rules for
the conservation of orbital symmetry. The cyclopentenone products of the
Nazarov cyclization may include isomers distinguished by different locations of
the double bond. Normally, the thermodynamically favored enone will
predominate, but appropriately silicone-substituted substrates may be used to

direct the initial enone to the less stable location.13

 

 

Scheme 5. Nazarov Cyclization Mechanism.

 

 

 

Although Nazarov cyclization is normally followed by proton loss to give
a cyclopentenone product, an intervening rearrangement may occur when
circumstances are favorable. One example,14 illustrated in Scheme 6,

involves a 1,2-methyl shift facilitated by an adjacent double bond.

 

 

9| I ”
(1%TsOI-I, 180°C,
40%)

 

Scheme 6. Secondary Cationic Rearrangement.

 

 

 

We expect a bis-cyclobutylidene substrate to give an angular tripen-
tanoid via the Nazarov cyclization and subsequent rearrangements (see
Scheme 7). In this case, the propellane tripentanoid should not be formed,

since the cationic center is destabilized by the adjacent carbonyl group.

10

 

 

 

 

 

-i-H+ L
'\ 2
Dicyclobutylidene Acetone Trans-
OH
—- * 0
— k
v

Propellane Tripentanoid

 

Angular Tripentanoid

Scheme 7. Proposed Rearrangement of Dicyclobutylidene Acetone.

 

 

11

In this sequence of rearrangements, an initial stereochemical factor is
absent, but substituent effects may exist. For example, substituents might

affect the course of rearrangement in the following ways:

(a) An ct-methyl group substituent might direct the initial rearrangement

by localization of charge (see Scheme 8).

 

   

alternative

Scheme 8. tat-Methyl Group Substituent Effect.

 

 

 

(b) Migratory aptitude might influence the course of rearrangement (see

Scheme 9).

12

 

OI'

 

alternatives

Scheme 9. Migratory Aptitude Effect.

 

 

 

(c) The previous effects might combine in a tandem fashion in

competition substrate (see Scheme 10).

13

 

   
  

 

l I +H+

. .\\R1 .
R2

 

 

alternatives

Scheme 10. Substituent Effect.

 

 

 

A possible retrosynthesis of isocomene, one of our target molecules,
can be formulated according to the proposed rearrangements as shown in

Scheme 11.

14

 

 

lsocomene R = CH3, CHZOR, COOCH3

Scheme 11. Proposed Retrosynthesis of lsocomene.

 

 

 

Because the bis-cyclobutylidene substrate described in Scheme 7 is not
readily available and would pose a challenging synthesis problem, the simpler
model, 2-(2'-oxo-(E)-4'-phenyl-3'-butenylidene) spiro[3,5]nonane (8), was
chosen for the initial study and designed to generate bicyclo[3.3.0]octane
products by subsequent ring enlargement of a spirocyclobutane intermediate.
This substrate should serve to address questions of whether a Nazarov
cyclization can initiate rearrangements of the kind proposed here and the
relative facility of ring expansion versus a 1,2-phenyl migration or a 1,2-

hydrogen Shift (see Scheme 12).

 

15

 

O HO+

 

 

 

(8)

 

 

Path (a)
0 Ph 0
Enlargement H . H H . . Ph
"H+ g & 5 E or S ’c
(16) (17)
Path (b)
Initial PIT-Shift Ph
or H-Shiit
-H’

 

 

Q
& . or
O

Scheme 12. Proposed Rearrangements of (8).

 

 

16

In the course of these studies, products characteristic of initial ring en-
largement, as in path (a) in Scheme 12, spiro[cyclohexane-1,5'-3'-phenyl-
3',4',5',6'-tetrahydropentaIen-1'(2'H)-one] (15), spiro[cyclohexane-1,5‘-3'-phe-
nyl-4',5',6',6'a-tetrahydropentalen-1'(3'aH)-one] (16), and spiro[cyclohexane-
1,5'-3'a-phenyI-4',5',6',6'a-tetrahydropentalen-1'(3'aH)-one] (17), were indeed
isolated. However, elucidation of the various products from dienone (8) under
different reaction conditions disclosed novel and unexpected transformations.
Information obtained during these studies should prove useful in future

applications of this synthetic strategy.

§YNTHE§I§

Synthesis of the Nazarov cyclization precursor, 2-(2'-oxo-(E)-4'-phenyl-
3'-butenylidene) spiro[3,5]nonane (8), was accomplished in Six steps from
methylenecyclohexane. The high yields and the ready availabilities of the

starting materials make this an especially attractive method.

Ultrasound promoted cycloadditon of methylenecyclohexane with i_n_sit_u-
generated dichloroketene gave15 1,1-dichIorospiro[3,5]nonan-2-one (1) via a
21: + 21c cycloaddition reaction. Reductive removal of the chlorine atoms from
dichloroketene (1) by treatment with zinc in a mixture of acetic acid and water

gave spiro[3,5]nonan-2-one (2)16 in 84.5% overall yield (see Scheme 13).

o o
c
. CbCOOCI. Zn Zn, CH3COOH-H20
E c 3

(1) (2)

 

 

 

Scheme 13. Preparation of (2).

 

 

 

17

18

An initial dehalogenation of dichloroketene (1) in neat acetic acid15(8)
generated ketone (2) plus 1-cyc|ohexenyl-2-propanone (3) and 1-
cyclohexylidene-2-propanone (4), two ring cleavage isomers of ketone (2), in
a 9: 5 : 1 molar ratio (see Scheme 14). Ketone (2), and a mixture of (3) and (4)

were isolated by flash chromatography.

0 o e O

3% Zn, CchOOH: + i +
O .... 0 O x
(4)

(1 ) (2) (3)
Molar ratio (GC): 9 : 5 : 1

 

 

Scheme 14. Dehalogenation of (1) in Acetic Acid.

 

 

 

Apparently, isomers (3) and (4) were formed because the reaction was
too acidic and the temperature was too high. The undesirable isomers (3) and
(4) can be avoided by conducting the dehalogenation reaction in a mixture of
acetic acid and water at room temperature. In this fashion, ketone (2) was
obtained exclusively. The mechanism of formation of isomers (3) and (4) can
be rationalized as an electrocyclic opening of an intermediate cyclobutene

derivative (see Scheme 15).

19

4 A» i te—

Cyclobutene

 

O ZnCI”

; . r f

Scheme 15. Mechanism of Formations of (3) and (4).

 

 

 

The structure of dichloroketone (1) was evident from its spectroscopic
characteristics. The mass spectrum Showed Signals at m/z 210, 208, 206,

which were indicative of two chlorine atoms in the molecular ion. A signal at 8
193.1 ppm in the 13C NMR and an infrared absorption at 1809 cm1 reflected

the presence of a cyclobutanone carbonyl group.

The structures of ketones (2), (3) and (4) were confirmed by comparing

their 1H NMR data with those reported in the Iiterature.16.17 (see Table 1)

20

Table 1. 1H NMR Spectra of (2), (3) and (4).

 

1H NMR (8) ppm

 

(2) reported‘ 6 2.68 (s, 4H), 1.8~1.3 (m, 10H)

 

(2) observed 2.70 (s. 4H), 1.61 ~1 .63 (d, J = 7.0 Hz, 4H), 1.41 ~1 .54 (broad s, 6H)

 

(3) reported‘ 7 5.55 (m41H), 2.94 (broad m, 2H), 2.07 (sgw, 1.3~2.2 (6H, broad,)

 

(3) observed 5.56 (m, 1H), 3.00 (m, 2H), 2.13 (m, 3H), 2.03 (m, 2H), 1.88~1.98 (m, 2H),

1.52.4 .63 (m, 4H)

 

(4) reported17 5.94 (1H, m),g.1 (3H, s),1.3~2.2 greed, 10H)

 

 

 

 

(4) observed 5.99 (m)

 

Wittig-Horner olefination18 of ketone (2) with the triethylphosphono-
acetate derived carbanion proceeded as anticipated; ethyl spiro[3,5]-2-
nonanylideneacetate (5) was isolated in 91.2% yield. Base hydrolysis of ester
(5) gave spiro[3,5]-2-nonanylideneacetic acid (6) in 84.9% yield. Acid (6) then
reacted with two equivalents of methyllithium19 to give 1-spiro[3,5]-2'-

nonanylidene-2-propanone (7) in 91% yield (see Scheme 16).

21

 

0 COOCHZCHa
(EtO)2POCHZCOOEI

. LDA, THF . 20% NaOH
. . CH30H~THF

(2) (5)

 

Scheme 16. Preparation of (7).

 

 

 

The spectroscopic characteristics of (5) supported its structure
assignment. The molecular ion was found at m/z 208 in the mass spectrum. An
infrared absorption at 1716 cm'1 and a 13C NMR signal at 6 166.5 ppm were
indicative of the carbonyl group. Signals at 8 163.5 and 114.2 ppm in the 13C
NMR and a Signal at 5 5.68~5.64 (m, 1H) in the 1H NMR were indicative of the
double bond. Finally, the ethoxy group was reflected by 13C NMR Signals at 5
59.5 and 14.4 ppm, and 1H NMR Signals at 8 4.14 (q, J = 7.2 Hz, 2H) and 1.27

(t, J = 7.2 Hz, 3H) ppm.

22

The molecular ion of acid (6) was found at m/z 180 in the mass spectrum.
The carboxyl group was characterized by infrared absorptions at 3350~2400
and 1688 cm'1, and a signal at 8 11.5 ppm in the 1H NMR.

The molecular ion of methyl ketone (7) was found at m/z 178 in the mass
spectrum. An infrared absorption at 1697 cm'1 and a signal at 8 197.8 ppm in

the 1("C NMR were indicative of the carbonyl group. A signal at 8 2.08 (s, 3H)
ppm in the 1H NMR was indicative of the methyl group.

Aldol condensation of methyl ketone (7) with benzaldehyde was more
difficult to accomplish than anticipated. Under conventional reaction
conditions,20 with one equivalent of benzaldehyde in a 1:1 mixture of aqueous
20% sodium hydroxide solution and 95% ethanol at room temperature, the
reaction gave benzoic acid and benzyl alcohol, products of the Cannizzaro
reaction,21 plus a small amount of starting material and an intractable product
mixture. Alternatively, when (7) was refluxed with ~one equivalent of
benzaldehyde and 0.43 molar equivalents of barium hydroxide22 in 95%
ethanol overnight, dienone (8) was isolated in about 15% yield. The
Cannizzaro reaction products of benzaldehyde were not observed, possibly
due to fact that the barium hydroxide was poorly soluble in ethanol.
Encouraged by this result, we lowered the reflux temperature by using
methanol instead of ethanol; thus, methyl ketone (7) was reacted with one
equivalent of benzaldehyde in methanol to give a mixture of dienone (8) (31.8%
yield based on 1H NMR integration) and 2-methoxyl-2-(2'-oxo-(E)-4'-phenyl-3'-
butenyl) spiro[3,5]nonane (9) (56.5% yield based on 1H NMR integration) (see

Scheme 17). This mixture of (8) and (9) was refluxed with a catalytic amount of

23

iodine in benzene to give (8) in 86.5% overall yield. 1,4-Addition of methanol to
the activated enone double bond of (8) is facilitated by angular strain relief,

Since the Sp3 B-carbon atom in (9) is less strained than the Sp2 B—carbon in (8).

 

COCH3

PhCHO, Ba(OH)2

. CHgOH ~ H20

(7)

 

   

(9)

Scheme 17. Aldol Condensation of (7) with Benzaldehyde.

 

 

 

The structure of (8) was confirmed by spectroscopic evidence. The
molecular ion was observed at m/z 266 in the mass spectrum. An infrared
absorption band at 1676 cm'1 and a Signal at 8189.3 ppm in the 13C NMR
indicated the carbonyl group. Infrared absorptions at 3060, 3025 cm“,
together with 13C NMR signals at 8 164.3, 141.9, 135.0 and 130.1 ppm and 1H
NMR signals at 8 7.55 (d, J = 16.1Hz, 1H), 6.79 (d, J = 16.1Hz, 1H) and 6.34 (m,
1H) ppm indicated the two double bonds.

The molecular ion of (9) was found at m/z 298 in the mass spectrum. A
signal at 8 3.18 (s, 3H) ppm in the 1H NMR was indicative of the methoxy group,
and an AB quartet in the 1H NMR at 8 1.94 ppm (J = 12.9 Hz, AvAB =19.3 Hz,

4H) was indicative of the two methylene groups on the cyclobutane ring.

24

About 3~14% compound (9) decomposed to 2-(2'-oxo-(E)-4'-phenyl-3'-
butenyl) spiro[3,5]nonane (10) and dienone (8) during flash chromatography.
When compound (9) or (10) was treated with a catalytic iodine23 in refluxing
benzene containing 4A° molecular sieves, it was converted to dienone (8)

quantitatively (see Scheme 18).

 

 

0
Flash Chromatography
(paltial transform) Ph
l2 , Phl-l,
Ph reflux
Flash Chromatography
(partial transform) 0

 

Scheme 18. Transformations of (9) and (10).

 

 

 

25

The molecular ion of (10) was found at m/z 266 in the mass spectrum.
Signals at 8 6.04 (m, 1H) ppm in the 1H NMR indicated a olefinic hydrogen in
the endocyclic double bond and signals at 8 2.84 (S, 2H), 2.45 (S, 2H) ppm in
the 1H NMR indicated methylene hydrogens adjacent to the carbonyl group and

methylene hydrogens in the cyclobutane ring.

The 5 : 1 product ratio of (3) and (4) (Scheme 14), and the isomerization
of (10) to (8) (Scheme 18) can be analyzed from a thermodynamic standpoint.
According to studies of Allinger,24 the differences of calculated MM2 energies
in kcanole (heats of formation, gas phase, 25 °C) (experimental values in
parentheses) for exo-endo ratios in Six- and four-membered rings are,
respectively, 3.29 (2.3) and 1.15 (0.9) kcal/mole. In the six-membered ring,
torsion strain of the eclipsing unit is greater than angle strain, and the
endocyclic double bond is favored. With the four-membered ring, on the other
hand, angle strain is greater than torsion, and the endocyclic double bond is
disfavored. Thus, dienone (8) (exocyclic bond) is more stable than dienone
(10) (endocyclic bond).

With the synthesis of dienone (8), we have achieved one of the
objectives of this work. We next proceeded to study the Nazarov reactions of

this compound.

MATIQN RE§ULT§ AND DI§§U§§IQN§

The Nazarov cyclization, a thermal conrotatory ring closure of divinyl
ketones in acidic medium, generally leads to cyclopentenones in excellent
yields.25 The most useful reagent for this purpose has been reported to be a
H3PO4/HCOOH mixture.26 Various other mineral acids or Lewis acids have
also been applied.27 Nazarov cyclization reactions are "temperamental" in that
a given set of reaction conditions will often not work as a general method. In
this dissertation, after an initial unsuccessful attempt to use ferric chloride, a
wide variety of acids and temperatures conducive to the desired cyclizations of
dienone (8) were screened by 1H NMR. The Nazarov reactions were then
carried out on a preparative scale. Among the reaction conditions investigated
for cyclization of dienone (8) were: a mixture of phosphoric acid and formic
acid; a mixture of phosphoric acid, formic acid and tetrahydrofuran; sulfuric
acid; hydrochloric acid; trifluoroacetic acid; iodomethylsilane; boron trifluoride

etherate and tin(lV) chloride.

An initial cyclization study of dienone (8), using ferric chloride in
methylene chloride solution (FeCI3/CH2CI2),13 gave a pale yellowish solid,
insoluble in most organic solvents and water, plus a poor yield of recovered
starting material. Broad Signals in the 1H NMR spectrum were not helpful for

product identification. Examination of the product mixture suggested that the

26

 

 

27

 

major loss of dienone was due to polymerization, oxidation or other degra-

dation, and this procedure was not studied further.

A survey of acidic catalyst effectiveness was made by 1H NMR (Table 2).

Solutions of (8) in deuterated chloroform were treated with two drops of a

catalyst solution. Initial 1H NMR spectra were taken immediately after mixing

(<15 minutes).

Table 2. Reactions of (8) Monitored by 1H NMR.

 

 

 

 

 

 

 

 

 

 

<15 minutes, 12 hours, 12 hours,
Em” cams” 25 °c 25 °c 40~45 °c
SMa + (14)°
c
1 com. HCI (12 : 13),: (14)
2 CFacOOH SW SW 8M8
3M8 + (17)d+ Unknown"
6 a
3 BF3 Ether SM SM (3:1)d
5M8 + (1nd+ Unknownb 8M3 + (17)d+ Unknownb
a
4 snc" SM (9 : SP (2 : 3)d

 

(a) SM indicated start'ng material.

(b) Unknown means broad unresolved signals in 1H NMR spectrum.

(6) Molar ratio was determined by 1H NMR integration of (14) compared to (8), oorrpound
(14) was isolated later.
(d) Molar ratios were determined by 1H NMR integration of the downfield signal of corrpound

(17) compared to (8), compound (17) was isolated later.

 

28

Larger scale reactions catalyzed by phosphoric acid, hydrochloric acid,
iodotrimethylsilane and tin(lV) chloride were then carried out, as described in

the following sections.

(1) Reaction at Room Temperature

Dienone (8) proved to be insoluble in 85% phosphoric acid, or a mixture
of 85% phosphoric acid and 88% formic acid; however, it gave a
homogeneous solution in a mixture of phosphoric acid, formic acid and
tetrahydrofuran. This resulting solution gave recovered starting material and
dispiro[cyclohexane-1 ,1 '-cyclobutane-3',2'-6'-phenyldihydro-2'H-pyran-4'(3' H
)-one] (11) (see Scheme 19). Compound (11) was isolated in 31% yield.

 

H3P04/ HCOOH/THF

 

= (3)+

Room Tenperature

   

(8) (11)

Scheme 19. Reaction of (8) with Phosphoric Acid at 25 °C.

 

 

 

29

The structure of (11) was assigned with the assistance of 1H NMR

decoupling experiments and DEPT in the 13C NMR (see Figure 2).

 

 

m/z 284 (1) (MS) molecular ion
1720 cm'1 (IR), 8 206.5 ppm (13C NMR) carbonyl group
a 4.68(t, J = 7.5 Hz, 1H), 2.52 (d, J = 7.5 Hz, 2H) ppm (1H NMR) ozH-C3H2
81.86 (m, 2H) ppm (1H NMR) C5H2
8 2.60 (AB, q, J = 13.8 Hz, AvAB = 37.4 Hz, 2H) and

8 2.06 (AB, q, J = 12.6 Hz, AvAB = 70.6 Hz, 2H) ppm(1H NMR) C7H2 and C14H2

Figure 2. Spectroscopic Characteristics of (11).

 

 

 

The structure of (11) was then confirmed by chemical reaction. Thus,
reflux of (11) with catalytic amounts of iodine and p-toluenesulfonic acid
monohydrate in benzene solution gave 58% dienone (8) plus recovered (11)

(determined by 1H NMR). This result leaves no doubt as to the identity of (11).

30

Formation of compound (11) can be rationalized (see Scheme 20) as an
acid catalyzed 1,4-addition of water to the activated enone double bond to give
an hydroxyl enone, which then cyclized by 1,4-addition to the conjugated

double bond. This process is, ofcouse, reversible.

 

 

Scheme 20. Mechanism of Formation of (11).

 

 

 

31

(2) Reactions at High Temperature

Reaction of dienone (8) with a mixture26 of 85% phosphoric acid and
88% formic acid at 90 °C gave 5,7-dimethyltetralin (12)28 and 2-cyclohexenyl-
1-methyI-3-phenylbenzene (13) in 64% and 10% isolated yield (see Scheme

21). No Starting material was recovered.

 

 

o
| HgPO4/HCOOH
. : +
70 °C or 90 °C . 6
(8) (12) (13)
Scheme 21. Reaction of (8) with Phosphoric Acid.

 

 

 

The molar ratios of these products at 70 °C or 90 °C were determined by
Gas Chromatography and are given in Table 3. The proportion of (12)

increased with reaction temperature.

32

Table 3. Products from Reactions of (8) with Phosphoric Acid.

 

 

 

Reaction Conditions Molar Ratio (GC) of Products
Entries (8). 85% H3P04. 88% HCOOH (12) : (13)
1 0.2 9.5 mL, 10 mL, 70 °C,3h 1 : 5
2 0.49 4L5 mL, 5 mL,90 °C, 3 h 6 : 1

 

 

 

 

 

We were initially puzzled by the unanticipated nature of these products
and at first assumed they were impurities from solvents. Eventually, the
structures of (12) and (13) were established by spectroscopic methods. The
structure of (12) was confirmed by comparing its spectra with those reported in
the literature.28 The structure of (13) was assigned on the following evidence.
A molecular ion at m/z 248 in the mass spectrum was consistent with the
C19H20 composition. Signals at 8 137.8, 137.4, 136.5, 134.8, 131.8, 129.9,
129.5, 128.7, 127.4, 126.7, 126.5, 123.8 ppm in the 13C NMR indicated twelve
distinct sp2 carbons. A signal at 8 2.42 (s, 3H) ppm in the 1H NMR was
assigned to the aryl methyl group, and Signals at 8 2.92~2.82 (m, 4H) and
2.00~1.81 (m, 4H) ppm in the 1H NMR resulted from the other aliphatic
hydrogens.

It is clear that the conversion of (8) to (12) and (13) must involve four-
membered ring cleavage at some stage. We attribute this unexpected result to
geminal-dialkylation on the distal carbon in the cyclobutylidene, which favors
the 3°-homoallyl cation component of the cyclobutyl cation contributor of the
conjugated acid of (8),29 as shown in Scheme 22. This, of course, diverts the

proposed Nazarov cyclization to other modes of reaction.

33

 

 

 

 

Ho DH
/ a' /R.
+ \
C R: T A +
H“ R

 

Scheme 22. Cyclobutyl Cation Equilibria.

 

 

 

A Similar substitution effect may be operating in the reported acid-
catalyzed reactions of 2-vinyl-2,3,3-trialkylcyclobutanone,3° as shown in
Scheme 23.

 

 

\
\O
O
I
m
to

RI CH3$03H

 

 

%
/

 

 

Scheme 23. Reactions of 2-VinyI-2,3,3-trialkylcyclobutanone

 

 

34

Formation of compound (13) can be rationalized as a cyclobutane ring
cleavage and tautomerism to a tetraenol, followed by an electrocyclic reaction,

[1,5] hydrogen Shift, and dehydration to give (13) (see Scheme 24) .

 

 

 

 

 

 

0 110+)
| 4+ J I
O ——» (9 ——~
0 O
(8)
OH
/
_'_H_: \ I Electrocycllc‘
O
Tetraenol
OH OH
O 0 [1,5]Hshift: O . +120
6 O O

(13)

Scheme 24. Mechanism of Formation of (13).

 

 

 

35

Formation of compound (12) may be rationalized in a Similar way,

assuming a prior retro-aldol fragmentation of (8) to give methyl ketone (7).

Protonated (7) may then experience an initial cyclobutane ring cleavage,

followed by tautomerism,

electrocyclic closure and dehydration to give

compound (12) (see Scheme 25).

 

Tautomerization

 

 

Scheme 25. Mechanism of Formation of (12).

/\

 

Trienol

6

(12)

[4

 

 

36

The above mechanism was supported by the fact that, under the same

reaction conditions, methyl ketone (7) gave compound (12) quantitatively.

From Table 3, we can see that the retroaldol condensation of dienone
(8) presumably increases with reaction temperature, as the proportion of

product (12) increases.

2. T rhlrIAl tlz Re tln.

Dienone (8) in methylene chloride solution was reacted with hydrochloric
acid11(d) at room temperature to give 2-chIoro-2-(2'-oxo-(E)-4'-phenyl-3'-
butenyl) spiro[3,5]nonane, (14), quantitatively (see Scheme 26) via 1,4-

addition to the activated enone double bond.

 

   

(8) (14)

Scheme 26. Hydrochloric Acid Addition to (8).

 

 

 

37

The molecular ion of (14) was found at m/z 302 in the mass spectrum.
An infrared absorption at 1698 cm'1 and a 13C NMR Signal at 8 198.1 ppm were
indicative of the carbonyl group. A signal at 8 3.02 (s, 2H) ppm in the 1H NMR
was generated by the methylene hydrogens adjacent to the carbonyl function.
A Signal at 8 2.44 (m, 4H) ppm in the 1H NMR reflects the methylene hydrogens

on the cyclobutane ring.

3, Inc lgggtrlmethylsllane Catalyzed Reaction,

When dienone (8) was reacted with chlorotrimethylsilane and sodium
iodide in dimethyl formamide,31 2-cyclohexenyI-1-methyl-3-phenylbenzene,

(13), was obtained in high yield.

We reasoned that iodotrimethylsilane might form an intermediate Silyl
enol ether iodide. This very reactive iodide could then initiate a series of
tautomeriZation and hydrogen shifts to give (13) (see Scheme 27), which is

similar as Scheme 24.

38

 

 

 

 

 

(13)

Scheme 27. Mechanism of Formation of (13).

 

 

 

 

Refluxing a solution of dienone (8) with one equivalent of tin (IV)
chloride27 in chloroform gave dicyclopentanoids (15), (16) and (17) in 20.8%,
16.2% and 34.0% 60 yields respectively using phenanthrene as an internal
standard (see Scheme 28). The superiority of tin(lV) chloride in effecting the

Nazarov cyclization of (8) is remarkable.

39

 

(3)

 

(15)

:22:

(15)

Scheme 28. Reaction of (8) with Tin (IV) Chloride.

(17)

 

 

‘ GC yields of (15), (16) and (17) are given in Table 4. Combined yields
of isolated (17) with a isolated mixture of (15) and (16) averaged 70%. The

proportion of (15), (16) and (17) in the product mixture varied Slightly with the

substrate to catalyst ratio, but in general was nearly equimolar.

Table 4. Products from Reactions of (8) with Tin(lV) Chloride.

 

 

 

 

 

Reaction Conditions 60 yield (%)

((8) : SnCLt) (15) (16) (IL
‘ 1:1I 24 hours, reflux 2f0.8 122 34.0

1:2, 24 hours, reflux 24.8 33.7 26.6

 

 

40

The mechanism may be rationalized (Scheme 29) as Nazarov cyclization
of (8) initially formed cyclopentenyl cation (A), which transformed to (8) via
enlargement of cyclobutane ring. Cation (B) converted subsequently to (15),

(16) via 1,2-hydrogen Shift, and (17) via a 1,2-phenyl shift.

 

 

 

   

 

 

 

 

 

 

OSnCIaCI OSnCIacI'
Initial Ring
SnCl4 Enlargement
Ph ———" —’ "'4, #7
CHCIa / H Ph
(8)
(A)
(OSnClacl'
Tautomerization omh—v
(15)
OSnCI3Cl‘ (OSnCI3Cl‘
00:) 0C8: on
(16)
(OSnCIacl‘
1.2-Ph Shift 0%
Eh
I 17)

Scheme 29. Mechanism of Formation of (15), (16) and (17).

 

 

41

Discussions about the mechanism:

(1) GO analysis indicated that treatment of each of the isomers (15),
(16) and (17) in turn under the reaction conditions gave essentially no
converision to the other two (< 3%). This suggests that the product mixture
obtained from the tin (IV) chloride-induced Nazarov reaction reflects the relative
rates at which (B) is converted to (15), (16) and (17), Le. kinetic product

control.

(2) When each of the isomers (15), (16) and (17) was refluxed
respectively with p-toluene-sulfonic acid monohydrate in chloroform solution,
and monitored by GC analysis. lsomer (15) was transformed to (16) within 24
hours (Table 5). For isomer (16), no transformations to either (15) or (17) were
observed during 48 hours period. For isomer (17), no transformation to (15)
and little transformation (< 3% SC yield) to (16) were observed during 48 hours

penod.

Table 5. Acid Catalyzed lsomerizations of (15).

 

 

 

 

 

Products: Products: Products: Products:
(15) : (16) : (17) (15) : (16) : (17) (15) : (16) : (17) (15) : (16) : (17)
(%) (%) (%) 4%)
Time (hours) 1 2 24 36 48
(15) 79.6 : 11.2 : 0.0 0.0 : 89.0: 1.6 0.0 : 75.8: 1.5 0.0 : 59.3 : 1.2

 

 

 

 

 

42

lsomerization of (15) to (16) indicated interconversion of (15) and (16)
may occur via their common unstable [Sq-unsaturated isomer (Bredt's rule) (see
Scheme 30). We expect that the fully conjugated isomer (16) iS

thermodynamically more stable and predominate at equilibrium.

 

 

O - OH OH1 O
cod—=— =oc§ no
(15) P“ P“ P“ (16) P"

 

 

lit-unsaturated ketone

Scheme 30. Acid Catalyzed lsomerization of (15), and (16).

 

The failure of (17) to isomerize indicated that the 1,2-phenyl shift would
not occur easily (Scheme 31), and we suggest this reflects a high barrier for the .
conversion of the oxyallyl conjugate acid cation (C) to the isolated cation (B), a
key Species in these reactions (Scheme 29). Apparently, if (B) were generated,
an equilibrium pathway would exist, and isomer (16) would presumably be the

favored component.

 

43

 

 

(15)
——;< >CE§ —* <16)
1 ,2-Ph
(17) (17)
(C) (3)

Scheme 31. lsomerization of 17).

 

(3) None of secondary rearrangement products in Scheme 12 (see
Figure 3) via an initial 1.2-hydrogen Shift or an initial 1,2-phenyl shift were
observed. We concluded that the cyclobutane enlargement predominated a

1.2-hydrogen shift or a 1,2-phenyl shift under the Nazarov reaction conditions.

 

Figure 3. Cyclopentanoids.

 

 

 

 

44

It is interesting to note that UV absorption spectroscopy nicely

distinguishes these isomers, the ir-rtt" max being Am 241 nm for (15), 289

nm for (16), and 217 nm for (17).

The structure of (15), spiro[cyclohexane-l,5'-3'-phenyl-3',4',5',6'-tetra-
hydropentalen-l'(2'H)-one], was assigned on the following evidence (see

Figure 4).

 

 

m/z 266 (100) (MS) molecular ion
1699 cm-1 (IR), 8 203.7 ppm (130 NMR) carbonyl group
8 3.19 (dd, J =19.5, 6.6 Hz, 1H) and
2.65 (dd, J = 19.5, 2.2 Hz, 1H) ppm (1H NMR) oZ'Hz
8 2.40215 (m, 4H) ppm (1H NMR) c4'H2 at 66'H2
6 3.00 (dd, J = 5.5 Hz, J = 9.9 Hz, 1H) ppm (1H NMR) 06‘8H

 

 

figure 4. Spectroscopic Characteristics of (15)-

45

The structure of (16), spiro[cyclohexane-1,5'-3'-phenyl-4',5',6',6'a-
tetrahydropentalen-1'(3'aH)-one], was assigned on the following evidence (see

Figure 5).

 

 

mlz 266 (39) (MS) molecular ion
1693 cm-1 (IR), 6 212.0 ppm (13C NMR) carbonyl group
3050 our1 (IR), 6 7.31 (s, 1H) ppm (1H NMR) CZ'H-c3'
8 3.80~3.78 (m, 1H), 3.12~3.03 (m,1H) ppm (1H NMR) 03'ch6'aH

Figure 5. Spectroscopic Characteristics of (16).

 

 

 

The structure of (17), spiro[cyclohexane-1,5'-3'a-phenyl-4',5',6',6'a-
tetrahydropentalen-1'(3'aH)-one] was assigned on the following evidence with

assistance of DEPT in the 13C NMR (see Figure 6).

 

46

 

 

 

m/z 266 (32) (MS)

1711 cm“ (IR), 6 213.5 ppm (13C NMR)

3050, 3015 cm-1 (IR), 6 7.64 (d, J = 5.5 Hz, 1H) and

6.00 (d, J = 5.5 Hz, 1H) ppm (1H NMR)

6 61.0 ppm (13C NMR)

6 2.11 (AB, q, J = 13.7 Hz, AVAB = 25.7 Hz, 2H) ppm (1H NMR)
6 1.96 (m, 2H) ppm (1H NMR)

63.00 (dd, J = 5.5 Hz, J = 6.9 Hz,1H) ppm (1H NMR) and

6 56.0 ppm (13C NMR)

Figure 6. Spectroscopic Characteristics of (17).

molecular ion

calbonyl group

CZ'H-c3'H
o3"!
C4'H2
CG'Hg

c6'aH

 

 

M

We have learned that additions of the activated double bond of the
cyclobutylidene substrate are competitive side reactions for the Nazarov
reactions. This complication can be avoided by not using nucleophilic acids,

such as: hydrochloric acid, hydrobromic acid or titanium (IV) chloride.32

The choice of substrate (8) for this study was made for ease of synthesis.
However, an unfortunate consequence of this selection was that the geminal-
dialkylation at the homoallylic position of the cyclobutylidene moiety served to
divert the reaction from the desired Nazarov course. Although our selection of
(8) as a substrate for this study introduced unnecessary complications, the tin
(IV) chloride procedure demonstrates that subsequent ring enlargement
rearangements may be effectively coupled to Nazarov ring closure to give fused

cyclopentane ring systems.

In summary, we have achieved some success in our strategy of using
the Nazarov cyclization coupled with cascade rearrangements to synthsize
fused cyclopentane ring systems. The synthesis and rearrangement of a
suitably functionalized dienones therefore gains credence as a new pathway to
angular triquinanes. And Nazarov reactions need to be studied in much greater

detail and their reaction conditions need to be optimized.

47

EXPERIMENTAL

m All reactions were conducted under a dry argon or nitrogen
atmosphere. All reagents were obtained from commercial suppliers and used
without further purification, unless otherwise indicated. 320 and THF were
freshly distilled under nitrogen from sodium/benzophenone ketyl. Benzene,
hexane, methylene chloride, and diisopropylamine were freshly distilled under
argon from calcium hydride. Magnetic stirrers were used for small scale
reactions, large scale reactions were agitated using paddle stirrers. Organic
extracts were dried over anhydrous sodium sulfate or magnesium sulfate. Thin
layer chromatography (TLC) analyses were performed using Merck Aluminum-
backed F254 Silica Gel plates. Ultraviolet light or a 5% sulfuric acid methanol
solution with subsequent heating served for visualization. Flash
chromatography was performed using Merck Silica Gel 60 (230~400 mesh,
ASTM, column diameter 10~50 mm), according to the method of Still.33 Gas
liquid chromatography was performed on a Hewlett Packard 5880A gas
chromatograph. Melting points were measured in glass capillaries on a
Thomas-Hoover melting point apparatus, or on glass Slides using a Reichert
hot-stage microscope and are uncorrected. 1H NMR spectra were obtained
using Gemini 300 (300 MHz), Varian VXR 300 (300 MHz) or Varian VXR 500
(500 MHz) spectrometers. Chemical shifts for proton resonances are reported
in parts per million (8) downfield from TMS (8 = 0 ppm) or relative to residual
chloroform (8 = 7.24 ppm) as internal standards. Signal patterns are indicated

as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br 5, bread singlet;

48

49

overlapping m, overlapping multiplet. Coupling constants (J) are given in Hertz.
13C NMR spectra were measured on Gemini 300 (75 MHz) or Varian VXR 300
(75 MHz) spectrometers. Chemical shifts for carbon resonances are reported in
parts per million (8) downfield from TMS (8 = 0 ppm) or deuterated chloroform
triplet Signal (8 = 77.0 ppm). Infrared (IR) spectra were obtained on a Nicolet
PC/IR Fourier Transform spectrometer, equipped with a Nicolet lR/42 optical
bench, using sodium chloride salt plates. Ultraviolet spectra were recorded on
a Shimadzu UV 160 spectrometer. Mass Spectra (MS) were obtained on a
Finnigan 4000 GC/MS mass spectrometer equipped with an Incos 4021 data
system or a TRIO-1 GC/MS mass Spectrometer, both operating at an ionization
energy of 70 ev. High resolution mass measurements were determined on a
JEOL HX 100 spectrometer at the Michigan State University, Department of
Biochemistry, Mass Spectroscopy Facility, East Lansing, Michigan.
Microanalyses were conducted by Spang Microanalytical Laboratory, Star Rt.
1, Box 142, Eagle Harbor, Michigan 49951. Ultrasonic activation was
accomplished by using a Bransonic Ultrasonic Laboratory cleaner (B-2200R-1,
117 volts, 50/60 Hz), partially filled with water at ambient temperature (15~20
°C).

Registry No. __ spiro[3,5]nonan-2-one (2), 29800-56-4; 1-
cyclohexenyI-2-propanone (3), 768-50-3; 1-cyclohexylidene—2-propanone (4),
874-68-0; 5,7-dimethyltetralin (12), 21693-54-90.

50
1WD). To a 250 mL three-"60k round

bottomed flask fitted with a rubber septum, an addition funnel and a reflux
condenser was added 2.00 g (20.8 mmol) methylenecyclohexane, 1.80 g (27.5
mmol) Zn dust and 100 mL of 820. To this suspension, agitated by an
ultrasonic bath (Branson 2200) and maintained at 20°C, was added 3.0 mL
(4.89 g, 26.9 mmol) of trichloroacetic chloride in 50 mL of Et20 dropwise over
thirty minutes. This mixture was sonicated for three hours. The solid was
removed by suction filtration through a Celite pad and washed with 8:20. The
ethereal extract was washed with saturated ammonium chloride, saturated
sodium bicarbonate, brine, then dried over anhydrous sodium sulfate.
Evaporation of solvent gave pale yellowish liquid 4.08 g (95.0% yield ) of
dichloroketone (1), and was used directly without further purification in the next
step. 1H NMR (300 MHz, CDCI3) 8 3.03 (s, 2H), 1.88~1.62 (m, 7H), 1.38~1.22
(m, 3H) ppm; 130 NMR (75 MHz, CDCla) 6 193.1, 93.2, 52.0, 46.1, 33.6, 25.0,
23.4 ppm; IR (NaCl) 2936, 2859, 1809, 1452, 990, 750 cm”; MS (EI) m/z
(relative intensity) 210 (0.03), 208 (0.12), 206 (M, 0.19), 171 (5), 164 (34), 93
(29), 81 (73), 68 (100), 55 (35).

Wag-113942), A stirred mixture of 3.00 g (14.5 mmol)
dichloroketone (1), 2.70 g (41.3 mmol) Zn dust, 60 mL of water and 40 mL of

acetic acid was reacted overnight at room temperature. Solids were removed
by suction filtration through a Celite pad and washed with hexane. The hexane
extract was washed with 2 N aqueous sodium hydroxide to pH 10, then
washed with brine and dried over anhydrous sodium sulfate. Evaporation of
solvent gave a pale yellow liquid 1.78 g (88.9 % yield) of ketone (2), and was

used directly without further purification in the next step. A small amount was

51

purified by flash chromatography using a 24:1 mixture of hexane and Eth to
give a colorless liquid. 1H NMR (300 MHz, CDCIa) 8 2.70 (S, 4H), 1.63~1.61
(m, 4H), 1.54~1.41 (bs, 6H) ppm; 13C NMR (75 MHz, CDCI3) 8 207.7, 57.1,
37.5, 30.5, 25.6, 24.0 ppm; IR (NaCl) 2934, 2853, 1782 cm'1; MS (EI) m/z
(relative intensity) 138 (M, 3), 110 (9), 96 (23), 61 (100), 67 (70), 55 (54).

Qahalaganatlgn af (1) In agetla aala. A stirred mixture of 2.00 g (9.6

mmol) dichloroketone (1), 1.6 g (24.5 mmol) Zn dust and 17 mL of acetic acid
was reacted at 90 °C overnight. Solids were removed by suction filtration
through a Celite pad and washed with hexane. The hexane extract was
washed with 2 N aqueous sodium hydroxide to pH 10, then washed with brine
and dried over anhydrous sodium sulfate. Evaporation of solvent gave a pale
yellow liquid 1.07 g (80.1% yield) mixture of ketone (2), 2-cyclohexenyl-2-
propanone (3) and 1-cyclohexenylidene-2-propanone (4) in a 9 : 5 : 1 molar
ratio (determined by Gas Chromatography). Ketone (2) and a mixture of
isomers (3) and (4) were isolated by flash chromatography using a 9 : 1 mixture

of hexane and diethyl ether.

1W3), 1H NMR (300 MHz, CDCI3) 8
5.56 (s, 1H), 3.00 (s, 2H), 2.13 (s, 3H), 2.03 (m, 2H), 1.94~1.88 (m, 2H),
1.63~1.52 (m, 4H) ppm. MS (EI) m/z (relative intensity) 139 (1.6), 138 (M, 14),
123 (3), 95 (45), 80 (19), 67 (32).

1fixalahaxylldana-Z-araaanana (4). (partial) 1H NMR (300 MHz,
CDCI3) 85.99 (5) ppm.

52

Ethyl apjra[3,§]-2-nananylIdanaaaatata (5). A solution of LDA was
prepared by reacting a cold (-78 °C) solution of 2.5 mL (1.81 g, 17.8 mmol) of

diisopropylamine and 20 mL of THF with 6.0 mL 2.5 M (15.0 mmol) of BuLi in a
7 : 3 mixture of hexane and Eth (added dropwise over 10 minutes). The this
was dropwise added a solution of 3.40 g (15.2 mmol) triethyl
phosphonoacetate, followed 10 minutes, later by a solution of 2.00 g (14.5
mmol) ketone (2) in 5 mL of THF was added (temperature maintained at - 78 °C
throughout). The cooling bath was removed and the resulting mixture was
stirred at room temperature for two hours and then poured into water. This
mixture was concentrated to a yellow slurry, hexane and brine were added.
The hexane extract was washed with brine and dried over anhydrous sodium
sulfate. Evaporation of solvent gave pale yellowish liquid 2.75 g (91.2% yield)
of ester (5), and was used directly without further purification in the next step. A
small amount was purified by flash chromatography using a 9 : 1 mixture of
hexane and Eth to give colorless liquid. 1H NMR (300 MHz, CDCI3) 8
5.68~5.64 (m, 1H), 4.14 (q, J = 7.2 Hz, 2H), 2.79 (S, 2H), 2.48 (s, 2H), 1.50 (m,
4H), 1.47~1.34 (m, 6H), 1.27 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (75 MHz,
CDCI3) 6 166.5, 163.5, 114.2, 59.5, 44.6, 43.3, 37.7, 36.9, 25.8, 23.3, 14.4 ppm;
IR (NaCl) 3050, 2934, 2926, 2853, 1716, 1678, 1199, 1186 cm°1; MS (El) m/z
(relative intensity) 208 (M, 85), 179 (32), 163 (59), 135 (100), 119 (53), 105
(51), 91 (63), 81 (77), 67 (43), 53 (33). High resolution MS, Cal., 208.1463 for
formula C13H2002; Found, 208.1499.

r - -n n n II n tl I 2.00 g (9.6 mmol) ester (5)
and 50 mL of 20% sodium hydroxide. 20 mL of methanol and 5 mL of THF were

mixed. After refluxing for two hours, this mixture was cooled to room

53

temperature, 40 mL of water was added. most of the methanol was evaporated
in a rotary evaporator. 15 mL of THF was added, methanol residue and
tetrahydrofuran were evaporated in a rotary evaporator. The mixture was
neutralized by 2 N hydrochloric acid and extracted with Etgo. The ethereal
extract was combined, washed with brine, then dried over sodium sulfate and
evaporated of solvent. The white residue was recrystalized from absolute
. ethanol, dried in vacuum at 70 °C overnight to give 1.47 (84.9% yield) of acid
(6), as. white square crystals. mp 102 °C; 1H NMR (300 MHz, CDCI3) 811.5
(s, 1H), 5.66 (m, 1H), 2.62 (s, 2H) 2.52 (s, 2H), 1.55~1.48 (m, 4H), 1.49~1.34 (m,
6H) ppm; 130 NMR (75 MHz, CDCIS) 8172.8, 166.3, 114.2, 45.1, 43.7, 37.7,
36.9, 25.8, 23.3 ppm; IR (NaCI) 3350~2400, 2926, 2849, 2631, 2550, 1688,
1655, 1449, 1433, 1408, 1292, 1259, 1240, 959, 938, 868, 845 cm'i; MS (EI)
m/z (relative intensity) 180 (M, 40), 162 (22), 135 (100), 121 (45), 98 (40), 81
(100), 67 (32), 55 (22).

1- - '- n n II n -2- r n n 7. Asolution of1.009 (5.5
mmol) acid (6), 60 mL of Eth was cooled to 0 °C. 8.1 mL 1.4 M (11.3 mmol) of
MeLi in 320 was added dropwise in 10 minutes. The resulting milk-white
suspension turned pale yellow and following a 2 h reaction period at 0 °C was
neutralized by 1 N hydrochloric acid and extracted with Eth. The ethereal
extract was washed with brine and dried over sodium sulfate. Evaporation of
solvent gave yellow liquid, which was purified by flash chromatography using a
9 : 1 mixture of hexane and Et20 to give colorless liquid 0.90 g (91.0% yield) of
methyl ketone (7). 1H NMR (300 MHz, CDCI3) 8 5.93 (m, 1H), 2.72 (S, 2H), 2.43
(S, 2H), 2.08 (s, 3H), 1.42 (d, J = 5.7 Hz, 4H), 1.40~1.25 (bs, 6H) ppm; 13C NMR
(75 MHz, CDCI3) 8 197.8, 162.2, 124.0, 45.0, 43.5, 37.5, 36.8, 29.9, 25.5, 23.0

54

ppm; IR (NaCl) 2924, 2852, 1697, 1671, 1637, 1449, 1360, 1254, 1198, 1184
cm“; MS (EI) m/z (relative intensity) 179 (2), 178 (M, 6), 163 (13), 149 (13),
135 (100), 121 (25), 105 (23), 96 (45), 81 (66), 66 (70), 55 (63). High resolution
MS, Cal., 178.1358 for formula C12H130; Found, 178.1340.

AI tl n f 7 . A 2.00 g (11.22 mmol) sample of methyl ketone
(7), was mixed with 1.20 g (11.32 mmol) freshly distilled benzaldehyde, 90 mL

of methanol, 0.82 g (4.79 mmol) barium hydroxide and 4 drops of water. This
mixture was refluxed for two hours. 150 mL of water was added, and most of
the methanol was removed by a rotary evaporator. 50 mL of THF was added;
residual methanol and THF were removed by a rotary evaporator. The solution
was gravity filtered and washed with Et20. The ethereal extract was washed
with saturated ammonium chloride, brine, then dried over anhydrous sodium
sulfate. Evaporation of diethyl ether gave 2.84 9 yellow oil mixture of 2-(2'-oxo-
(E)-4'-phenyl-3'-butenylidene) Spir0[3,5]nonane (8) (31.8% yield based on 1H
NMR integration) and 2-methoxyl-2-(2'-oxo-(E)-4'-phenyI-3'-butenyl) spiro[3,5]-
nonane (9) (56.5% yield based on 1H NMR integration). The mixture was
separated by flash chromatography, using a 9 : 1 mixture of hexane and 820,
to give 0.95 g (28.4% yield) of compound (9), 0.67 9 mixture of dienone (8)
(19.4% yield based on 1H NMR integration) and 2-(2'-oxo-(E)-4'-phenyI-3'-
butenyl) spiro[3,5]nonane 10) (3.0% yield based on 1H NMR integration). The
yields changed from 31.8% : 56.5% : 0% to 19.4% : 28.4% : 3% for compounds
(8), (9) and (10) indicated that during flash chromatography, (9) partially
decomposed to (8) or (10).

55
- '- - -4'-- :_ I- '-- tn :_- re 01:

(8). mp 44 °C; 1H NMR (300 MHz, CDCI3) 8 7.55 (d, J = 16.1 Hz, 1H), 7.51
(m, 2H), 7.36 (m, 3H), 6.79 (d, J = 16.1 Hz, 1H), 6.34 (m, 1H), 2.89 (m, 2H), 2.54
(m, 2H), 1.57~1.48 (m, 4H), 1.47~1.26 (m, 6H) ppm; 13C NMR (75 MHz,
CDCI3) 8 189.3, 164.3, 141.9, 135.0, 130.1, 128.8, 128.2, 127.1, 121.6, 45.6,
44.0, 37.6, 37.5, 25.7, 23.2 ppm; IR (NaCl) 3060, 3025, 2922, 2851, 1676,
1638, 1598, 1449, 1202, 694 cm'i; UV (95% ethanol) Amax 308 nm, emax
2.3x104, Am 227 nm, em 6.8x103; MS (EI) m/z (relative intensity) 266 (M, 5),
223 (9), 184 (17), 167 (11), 153 (8), 141 (10), 131 (88), 115 (20), 103 (70), 91
(63), 77(100), 67 (48), 55 (69). Elemental analysis, Cal., C, 85.66%; H, 8.33%
for formula C19H220; Found, C, 85.69%; H, 8.47%.

 

0209.19). 1H NMR (300 MHz, CDCI3) 6 7.51 (d, J = 16.2 Hz, 1H), 7.54~7.50
(m, 2H), 7.35~7.32 (m, 3H), 6.79 (d, J = 16.2 Hz, 1H), 3.18 (s, 3H), 2.89 (s, 2H),
1.94 (AB, q, J = 12.9 Hz, AvAB = 19.3 Hz, 4H), 1.49~1.30 (m, 10H) ppm; 13C
NMR (75 MHz, CDCI3) 8 198.0, 142.2, 134.5, 130.2, 128.7, 128.2, 126.4, 74.8,
49.7, 49.3, 42.3, 39.2, 38.9, 31.6, 25.6, 23.0, 22.5 ppm; IR (NaCl) 3090, 3060,
3030, 2924, 2851, 1682, 1640, 1607, 1576, 1440, 1332, 1201, 1148, 1064, 978,
743, 693 cm'l; MS (El) m/z (relative intensity) 298 (M, 2) 266 (5), 238 (2), 202
(22), 174 (100), 128 (12), 103 (100), 91 (16), 77 (90), 67 (28), 55 (28).

- '-0-x- -'---th l-'-- t l slo, no : :1l_
(partial) 1H NMR (300 MHz, CDCI3) 8 6.20 (d, J = 11.9 Hz, 1H), 6.04 (m, 1H),
2.84 (s, 2H), 2.45 (S, 2H) ppm; MS (EI) m/z (relative intensity) 266 (M, 27), 223
(28), 184 (40), 131 (100), 103 (60), 77 (45).

56
gamma), A solution of 0.95 g (3.34 mmol) compound (9) in

150 mL of benzene containing a catalytic amount iodine, 0.5 g 4A° molecular
sieves was refluxed for three hours. The reaction mixture was filtered and
washed with benzene. The benzene extract was washed with 20% sodium
bisulfite, brine, then dried over anhydrous sodium sulfate. Evaporation of

benzene gave 0.84 g (99% yield) of dienone (8).

MM A 0.67 9 mixture of dienone (8) and (10) (6 : 1 molar

ratio, based on 1H NMR integration) in 150 mL benznene contianing catalytic
amount iodine, 0.5 9 4A molecular sieves was refluxed for three hours. The
reaction mixture was filtered and washed benzene. The benzene extract was
washed with 20% sodium bisulfite, brine, then dried over anhydrous sodium

sulfate. Evaporation of benzene gave 0.66 g (98.5% yield) of dienone (8).

Raafilaa af (9) with ahaaaharla aala at raam tamaaratara, A solution
of 0.300 g (1.13 mmol) dienone (8), 15 mL of 85% phosphoric acid, 7.5 mL of

88% formic acid and 7.5 mL of THF was stirred at room temperature for two
hours and turned dark red. Benzene and water were added. The benzene
extract was washed with saturated sodium bicarbonate, brine, then dried over
anhydrous sodium sulfate. Evaporation of solvent gave 0.296 g pale yellowish
liquid of product mixture. 0.099 g (31% yield) compound (11) was separated by

flash chromatography, using a 9 : 1 mixture of hexane and ethyl acetate.

 

" - " " - 1H NMR (300 MHZ, CDCI3) 8 7.38~7.29 (m,

57

5H), 4.66 (t, J = 7.5 Hz, 1H), 2.60 (AB, q, J = 13.6 Hz, AVAB = 37.4 Hz, 2H), 2.52
(d, J = 7.5 Hz, 2H), 2.06 (AB, q, J = 12.6 Hz, AvAB = 70.6 Hz, 2H), 1.66 (s, 2H),
1.49~1.33 (m, 10H) ppm; 13C NMR (75 MHz, CDCI3) 8 206.5, 140.9, 128.5,
127.8, 125.7, 75.5, 73.0, 53.9, 49.1, 45.7, 42.0, 40.1, 38.4, 31.1, 25.6, 22.9, 22.6
ppm; IR (NaCl) 3090, 3070, 3050,2924, 2851, 1720, 1450, 1282, 1251, 1056.
989, 742, 698 cm'I; MS (EI) m/z ( relative intensity) 284 (M, 1), 266 (1), 131
(100), 104 (82), 94 (13), 81 (17), 67 (19), 56 (20), 41 (12). High resolution MS,
Cal., 284.1776 for formula C19H2402; Found, 284.1723.

MM), A 0.100 g (0.352 mmol) sample of compound (11) in 100
mL of benzene containing catalytic amounts of iodine and p-toluenesulfonic
acid monohydrate was refluxed for four hours. The reaction mixture was filtered
and washed with benzene The benzene extract was washed with 20% sodium
bisulfite twice, brine, then dried over sodium sulfate. Evaporation of solvent
gave a mixture of dienone (8) (58% yield, based on 1H NMR integration) and

recovered (11).

392W A 0.490 9 (1.84 mmol)

sample of dienone (8) was mixed with 5 mL each of 85% phosphoric acid and
88% formic acid, Then heated at 90 °C for three hours. The dark blue mixture
was diluted with 20 mL of water and heated an additional hour. Benzene and
water were then added to the cooled reddish brown mixture. The benzene
extract was washed with saturated sodium bicarbonate, brine, then dried over
anhydrous sodium sulfate. Evaporation of solvent gave 0.38 g pale yellowish

liquid of prduct mixture. 0.188 g (64% yield) of 5,7-dimethyltetralin (12) and

 

58

0.046 g (10% yield) of cyclohexenyI-1-methyI-3-phenylbenzene (13) were

isolated by flash chromatography using hexane.

W 1H NMR (300 MHz, CDCI3) 8 6.82 (m, 1H),
6.77 (m, 1H), 2.74 (t, J = 6.3 Hz, 2H), 2.59 ( t, J = 6.3 Hz, 2H), 2.26 (s, 3H), 2.18
(s, 3H), 1.89~1.71 (m, 4H) ppm; 13C NMR (75 MHz, CDCI3) 8 136.9, 136.5,
134.4, 132.4, 127.9, 127.4, 30.0, 26.3, 23.5, 23.0, 20.8, 19.4 ppm; IR (NaCl)
3004, 2928, 2859, 2838, 1614, 1580, 1481, 1451, 1437, 847, 823, 700 cm”;
MS (EI) m/z (relative intensity) 161 (5), 160 (M, 47), 145 (100), 132 (32), 117
(22), 105 (8), 91 (11), 77 (7), 65 (5).

- x --tl--hnlnzn1.1HNMR(300
MHz, CDCI3) 6 7.62 (m, 1H), 7.60 (m, 1H), 7.48~7.32 (m, 5H), 7.07~6.96 (m,
2H), 2.92~2.82 (m, 4H), 2.42 (s, 3H), 2.00~1.81 (m, 4H) ppm; 13C NMR (75
MHz, 00013) 8 137.8, 137.4, 136.5, 134.8, 131.8, 129.9, 129.5, 128.7, 127.4,
126.7, 126.5, 123.8, 30.1, 26.5, 23.5, 22.8, 21.0 ppm; IR (NaCl) 3010, 3058,
3025, 3007, 2928, 2856, 2838, 1601, 1576, 1495, 1466, 1.448, 1439, 1074,
1028, 960, 862, 752, 692 cm'1; MS (EI) m/z (relative intensity) 250 (2), 249 (16),
248 (M, 100), 233 (67), 220 (25), 205 (50), 191 (16), 170 (18), 155 (35), 141
(22), 128 (34), 115 (33), 108 (27), 91 (46), 89 (17), 77 (16), 65 (7), 55 (1). High
resolution MS, Cal., 248.1565 for formula C1gH20: Found, 248.1563.

Qanvaralan at (7) ta (12). A 0.100 g (0.56 mmol) sample of methyl ketone
(7) was added to a mixture of 4 mL each of 85% phosphoric acid and 88%
formic acid. This mixture was stirred at 85~90 °C for three hours. Benzene and

water were added to the dark red solution. The benzene extract was washed

59

with saturated sodium bicarbonate, brine, then dried over anhydrous sodium

sulfate. Evaporation of benzene gave 0.86 g (96% yield) of compound (12).

h hl rl l t . A 100 mL round bottomed flask

equipped with a reflux condenser and a magnetic stirrer was alternately
evacuated and filled with argon. 0.25 g (0.94 mmol) dienone (8), 30 mL of
methylene chloride and 30 drops of concentrated hydrochloric acid were
added. The mixture was stirred at room temperature for 24 hours and pured to
water. Methylene chloride was added. The methylene chloride extract was
washed with brine, then dried over sodium sulfate. 0.27 9 (yield 95%) liquid of

compound (14) was isolated.

 

(14), 1H NMR (300 MHz, CDCI3) 87.59~7.51 (m, 2H), 7.55 (d, J = 16.0 Hz,
1H), 7.41 ~7.35 (m, 3H), 6.77 (d, J = 16.0 Hz, 2H), 3.02 (s, 2H), 2.44 (s, 4H),
1.74~1.67 (m, 2H), 1.47~1.25 (m, 8H) ppm; 13C NMR (300 MHz, CDCI3) 8
196.4, 143.0, 134.3, 130.5, 128.9, 128.3, 126.5, 62.8, 54.6, 49.7, 39.3, 39.1,
33.6, 25.4, 23.1, 22.8, 22.5 ppm; IR (NaCl) 3070, 3040, 3030, 2924, 2851,
1698, 1669, 1638, 1609, 1448, 978, 756, 692 cm'l; MS (EI) m/z (relative
intensity) 302 (M, 2), 266 (16), 267 (66), 266 (48), 223 (41), 194 (47), 175 (21),
131 (100), 115 (22), 103 (95), 91 (57), 77 (91), 67 (36), 55 (44).

Baaatlan at (a) with laaatrlmathylallaaa. A solution of 0.100 g (0.376
mmol) dienone (8) and 0.563 g (3.76 mmol) sodium iodide in 2 mL of DMF was

treated with 0.48 mL (0.41 g, 3.77 mmol) of chlorotrimethylsilane. This mixture

60

was then stirred at 60 °C for 10 minutes, then raised to 110~120 °C for five
hours. The cooled mixture was diluted with water and 820. The ethereal
extract was washed with 20% sodium bisulfite, brine, then dried over sodium

sulfate to give 0.88 g (95% yield ) of compound (13).

Baaglan at (a) with tin(lV) ahlarlaa. (T able 4, Entry 1) A solution of 0.50

g (1.9 mmol) dienone (8) in 100 mL of dry chloroform was treated with 1.9 mL of
1 M (1.9 mmol) of tin(lV) chloride in methylene chloride. This solution was
refluxed for twenty-four hours, poured into water, filtered and diluted with
methylene chloride. The methylene chloride extract was washed with saturated
sodium bicarbonate, water, and then dried over sodium sulfate. The solvent
was removed in vacuum. A mixture of (15), (16) and (17) was obtained in
20.8%, 16.2% and 34.0% GC yields. GC yields were determined using
phenanthrene as a standard. Some of dicylopentanoid (15) and some of (16)
were isolated by successive flash chromatography using a 35% Et20~haxane
mixture. Compound (17) was isolated by flash chromatography, using a 8%
Et20~haxane mixture. Combined yields of isolated (17) and a isolated mixture

of (15) and (16) over several repetitions of this procedure averaged 70%.

 

mm 1H NMR (300 MHz, CDCI3) 6 7.36~7.21 (m, 3H),
7.12~7.08 (m, 2H), 3.96~3.90 (m, 1H), 3.16 (dd, J = 18.5, 6.6 Hz, 1H), 2.62 (dd, J
= 16.5, 2.2 Hz, 1H), 2.40~2.15 (m, 4H), 1.60~1.30 (m, 10H) ppm; 130 NMR (75
MHz, CDCI3) 6 203.7, 166.1, 147.2, 141.1, 128.9, 126.1, 50.4, 46.9, 44.1, 43.5,
36.6, 38.5, 37.5, 25.7, 23.1, 22.9 ppm; IR (NaCl) 3050, 2922,2649, 1699,
1642, 1453, 1223, 762 cm-1; uv (95% ethanol) Amax 241 nm, em, 7.7x103;

61
MS (El) m/z (relative intensity) 267 (21), 266 (M, 100), 238 (33), 209 (27), 186
(52), 171 (41), 141 (64), 115 (39), 91 (75), 77 (53). High resolution MS. Cal.,
266.1671 for formula C1gH220; Found, 266.1632.

 

MW mp 119 °C; 1H NMR (300 MHz, CDCI3) 8
7.68~7.58 (m, 2H), 7.55~7.40 (m, 3H), 7.31 (s, 1H), 3.80~3.78 (q, m, 1H),
3.12~3.03 (m, 1H), 2.12~1.95 (m, 2H), 1.52~1.15 (m, 12H) ppm; 130 NMR (75
MHz, CDCI3) 8 212.0, 177.1, 133.5, 131.0, 128.8, 127.7, 125.0, 51.1, 47.3,
46.0, 42.7, 38.8, 38.3, 36.3, 26.2, 23.6, 23.0 ppm; IR (NaCl) 3050, 2924, 2853,
1693, 1593, 1570, 1449, 1186, 768 cm'l; UV (95% ethanol) km 289 nm, em
1.3x104, Amax 220 nm, emax 6.2x103; MS (EI) m/z (relative intensity) 267 (9),
266 (M, 39), 170 (100), 158 (98), 141 (37), 115 (29), 91 (32), 77 (31). High
resolution MS, Cal., 266.1671 for formula C19H220; Found, 266.1646.

. - ‘ -
O O o

- ' ' 1H NMR (300 MHz, CDCI3) 8 7.64 (d, J = 5.5 Hz,
1H), 7.35~7.18 (m, 5H), 6.00 (d, J = 5.5 Hz, 1H), 3.00 (dd, J = 8.9 Hz, J = 5.5 Hz,
1H), 2.11 (AB, q, J = 13.7 Hz, AvAB = 25.7 Hz, 2H), 1.98 (m, 2H), 1.47~1.29 (m,
10H) ppm; 13C NMR (75 MHz, CDCI3) 8 213.5, 171.6, 145.3, 129.9, 128.7,
126.6, 125.9, 61.0, 58.0, 47.8, 46.4, 39.7, 37.3, 26.0, 23.7, 23.0 ppm; IR (NaCl)
3050, 3015, 2926, 2855, 1711, 1495, 1450, 761, 700 cm'1; UV (95% ethanol)
Jim” 217 nm, em 7.1x103; MS(EI) m/z (realative intensity) 267 (6), 266 (M,
32), 236(7), 224 (23), 170 (100), 158 (51), 141 (35), 126 (37), 115 (31), 91 (35),
77 (28), 67 (35), 55 (31). High resolution MS, Cal., 266.1671 for formula
C19H220; Found, 266.1680.

62

z rl f 1 n 17 . Isomers (15), (16)
and (17) were each refluxed in chloroform solution with an equivalent of p-
toluenesulfonic acid monohydrate. GC identifications and yields were
determined using phenanthrene as an internal Standard. lsomer (15) was
completely converted to (16) and a trace of (17) within 24 h (see Table 5);
however isomers (16) and (17) remained unchanged, saved for a little

decoposition, over a 48h period.

 

APPENDIX l

SPECTRAL PART I

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Paquette, L. A. Top. Curr. Chem, 1984, 119, 1.

Paquette, l. A.; Calemino, R. A. Jr.; Springer, J. P. J. Am. Chem. Soc,
1983, 105, 6975-6976.

Wender, P. A.; Ternansky, R. J. Tetrahedron Lett., 1985, 26, 2625-2628.
(a) Curran, D. P.; Kuo, S. C. J. Am. Chem. Soc, 1986, 108, 1106-1107.
(b) Curran, D. P.; Kuo, S. C. Tetrahedron, 1987, 43, 5653-5661.

Fitjer, L.; Kanschik, A.; Majewski, M. Tetrahedron Lett., 1988,29, 5525-
5528.

Vogel, E. Angew. Chem. Int. Ed. Engl., 1960, 72, 4-26.

Bellus, D.; Ernst, B. Angew. Chem. Int. Ed. Engl., 1988, 27, 797-827.
Wang, H. N. C.; Lau, K. L.; Tam, K. F. Top. Curr. Chem, 1986, 133, 83-
157.

Fitjer, L.; Majewski, M.; Kanschik, A. Tetrahedron Lett., 1988, 29,

1 263-1264.

124

10.

11.

12.

13.

14.

15.

125

Nazarov, I. N.; Zaretskaya, l. I. Izv. Akad. Nauk SSSR, Ser. Khim. 1943,

211 (C. A. 1943, 37, 6243). Nazarov, I. N. Usp. Khim. 1949, 18, 377 (C. A.

1951, 45, 6572); Usp. Khim. 1954, 20, 71 (C. A. 1954, 48, 611).

(a) Braude, E. A.; Coles, J. A. J. Chem. Soc, 1952, 1430.

(b) Shoppee, C. W.; Lack, R. E. J. Chem. Soc. [C], 1969, 1346.

(c) Shoppee, C. W.; Cooke, J. A. J. Chem. Soc. Perkin Trans. I,

1972, 2271.

(d) Shoppee, C. W.; Cooke, J. A. J. Chem. Soc. Perkin Trans. l,

1973, 1026-1030.

(a) Woodward, R. 8.; Hoffman, R. The Conservation of Orbital Symmetry,
Verlag Chemie, Weinheim, 1970, 58.

(b) Sorensen, T. S.; Rauk, A. Pericyclic Reactions, Vol. 2, Marchand, A. P.;
Lehr, R. E.; Eds., Academic Press, New York, 1977, 31.

Denmark, S. E.; Jones, T. K. J. Am. Chem. Soc, 1982, 104, 2642-3702.
Ohloff, G.; Schulte-Elte, K. H.; Demole, E. Helv. Chim. Acta, 1971, 54,
2913-2915.

(a) Bak, D. A.; Brady, W. T. J. Org. Chem, 1979, 44, 107-110.

(D) Mehta, G.; Rao, H. S. P. Syn. Comm, 1985, 15, 991-1000.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

126
Wenkert, E.; Davis, L. L; Mylari, B. L; Solomon, M. F.; Silva, R. R.;

Shulman, S.; Warnet, R. J. J. Org. Chem, 1982, 47, 3242-3247.
Yoshika, T.; Higashida, S.; Murayama, K. Bull. Chem. Soc. Jpn.,

1972, 45, 636-638.

Bougaty, J.; Thomas, R. Chem. Rev., 1974, 74, 87-99.

Bare, T. M.; House, H. 0. Organic Synthsis, 1969, 49, 81-85.

Bunce, S. C.; Dorsman, H. J.; Popp, F. D. J. Chem. Soc., 1963, 302-307.
Dhar, D. N.; Barton, D. The Chemistry of Chalcones and Related
Compounds, John Wiley 8 sons, New York, 1981, 8.

Sinisterra, J. V.; Garcia-Raso, A. Synthesis, 1984, 502-504.

Conant, J. B.; Tuttle, N. Organic Synthesis, 1941, Coll 1, 345-347.
Allinger, N. L.; Yuh, Y.; Sprague, J. T. J. Comput. Chem, 1980, 1, 30.
(a) Santelli-Rouvier, C.; Santelli, M. Synthesis, 1983, 429-442.

(D) Denmark, S.E. Comprehensive Organic Synthesis, Pergamon
Press, Inc., New York, 1991, Vol 5, 751-784.

Hirano, S.; Hiyama, T.; Nozaki, H. Tetrahedron Lett., 1974, 15, 1429-1430.
Marina, J. P.; Linderman, R. J. Org. Chem, 1981, 46, 3696-3702.

Baker, K. M.; Bell, K. H.; Davis, B. R. Aust. J. Chem, 1968, 21, 2945.

29.

30.

31.

32.

33.

127

(a) Hanack, M.; Schneider, H. J. Fortschr. Chem. Forsch. 1967, 8, 554.

(b) Hanack, M.; Schneider, H. J. Angew. Chem. Int. Ed. Engl. 1967, 6, 666-
677.

(c) Sarel, S.; Yovell, J.; Sarel-Imber, M. Angew. Chem. Int. Ed. Engl. 1968,
7, 577-588.

((1) Saunders, M.; Krause, N. J. Am. Chem. Soc. 1988, 110, 8050-8052.
Jackson, D. A.; Rey, M.; Dreiding, A. S. Helv. Chim. Acta 1983, 66, 2330-
2341; ibid., 1985, 68, 439-449.

Sakai, T.; Miyata, K.; Takeda, A. Chem. Lett., 1985, 1137-1138.

Titanium tetrachloride hes been found to be a poor choice in that
1.4-addition to the activated enone readily occurs; see Paquette, I. A.;
Fristad, W. E.; Dime, D. S.; Bailey, T. R. J. Org. Chem, 1980, 45, 3017.

Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem, 1978, 43, 2923-2925.

ART II

A STUDY OF 4-BROMOBUTYLDIPHENYLPHOSPHINE OXIDE

AS A SYNTHON FOR CYCLOBUTYLIDENE DERIVATIVES

128

Cyclobutanone is a potentially valuable building block in the synthesis of
cyclobutylidene substrates, but its use is hampered by its relatively high cost
and its low availability.1 A possible precursor of a cyclobutylidene ylide,
cyclobutyltriphenylphosphonium bromide, gave intractable mixtures of crude
products when it reacted with one equivalent of phenyllithium.2 This difficulty
was overcome by using 4-bromobutyldiphenylphosphine oxide (1), as a
precursor to an equivalent ylide reagent, cyclobutyldiphenylphosphine oxide
(2). Alternatively (2) may be prepared by aqueous alkaline hydrolysis3 of
cyclobutyltriphenylphosphonium bromide. The usefulness of reagent (1) was
demonstrated by its reaction with dicyclopropylketone to give cyclobutylidene-
dicyclopropylmethane, an interesting substrate for vinylcyclopropanecyclo-

pentene rearrangements (VCR)4 or singlet oxygen (O12) reactions.5

129

RE LT AND DI I N

A new synthon, 4-bromobutyldiphenylphosphine oxide (1 ), was
obtained in 90% yield by aqueous alkaline hydrolysis of commercially available

4-bromobutyltriphenylphosphonium bromide (see Scheme 1).

 

Br 20% NaOH ‘
Phap CH2CH20H20HzBI ' thPOCH2CH2CH20HzBr

(1)

 

Scheme 1. Preparation of (1).

 

 

 

The molecular ion of (1) was found at m/z 336 in the mass spectrum, and
an infrared absorption at 1184 cm“1 was indicative of the P=O group. The 1H

NMR and 13C NMR spectra were also consistent with the assigned structure.
Oxide (1) possesses the following advantages:

(a) Unlike the precursor phosphonium salt, it is soluble in tetrahydro-

furan. Reactions of oxide (1) can therefore proceed in homogeneous solutions.

130

131

(b) Hydroxyphosphine oxide adducts are normally crystalline and readily
purified. The by-product, sodium diphenylphosphinate, can be easily removed

by water.

Cyclobutylidene products were synthesized from (1) by reaction of the

cyclized ylide with an aldehyde or a ketone in a Wittig-Horner like reaction.

For example, oxide (1), on treatment with one equivalent of
phenyllithium in tetrahydrofuran at - 78 °C, gave cyclobutyldiphenylphosphine
oxide (2)3 in 92% yield. Reaction with a second equivalent of phenyllithium
followed by dicyclopropylketone gave (1'-dicyclopropylhydroxymethyl-
cyclobutyI)-diphenylphosphinyl oxide (3) in 84% yield. Finally oxide (3) was
reacted with sodium hydride in dimethyl formamide at room temperature6 to

give cyclobutylidenedicyclopropylmethane (4) in 82% yield (see Scheme 2).

 

POPh2
PhLi
thPOCH2CH20H2CHzBI 5
THF

 

(1) (2)

 

 

(4)

Scheme 2. Preparation of (4).

 

 

 

132
The solvent and temperature employed in the final condensation step are
critical. When (3) was refluxed7 with sodium hydride in tetrahydrofuran, it

decomposed to (2) quantitatively (see Scheme 3).

 

POPh2
NaH, THF, rent:

 

(3) (2)

Scheme 3. Retroalkylation of (3).

 

 

 

The structure of (2) was confirmed by comparing its 1H NMR data with

those in the literature.5

The molecular ion of (3) was found at m/z 366 in the mass spectrum. An
infrared signal at 3450~3150 cm", a signal at 8 73.9 ppm in the 130 NMR and

a signal at 5 4.68 (s, 1H) ppm in the 1H NMR were indicative of the hydroxyl
group.

The molecular ion of (4) was found at m/z 144 in the mass spectrum.
Signals at 8 134.9, 129.0 ppm in the 13C NMR were indicative of the double
bond.

On standing for a prolonged time exposed to air, alkene (4) underwent a

novel oxidative rearrangement to give 2,2-dicyclopropylpentanone (5). In

133

hexane solution, alkene (4) was transformed to (5) within 24 hours on

treatment with a stream of air (see Scheme 4).

 

 

O
standing 2 years In arr: ,..~\A
or hexane .
airbtbble24h

(4) (5)

Scheme 4. Reaction of (4).

 

 

 

The molecular ion of (5) was found at m/z 164 in the mass spectrum. An

infrared absorption at 1734 cm'1 and a signal at 8 221.6 ppm in the 13C NMR

were indicative of the carbonyl group.

This reaction of (4) is similar to the reported reaction8 of
bicyclopropylidene with singlet oxygen (see Scheme 5). However, only triplet

oxygen was involved in the reaction of (4).

 

102 O O
H >24 +62
3: 5

Scheme 5. Reaction of Bicyclopropylidene

 

 

 

134

A tentative mechanism for the conversion of (4) to (5) is proposed in
Scheme 6. Auto-oxidation9 of (4) should generate a peroxide, which may react
with catalytic acid to give a peroxide cation. This cation should then rearrange
to (5) with loss of HO+ cation. The HO+ would cause rearrangement of another

molecule of (4) and provide a proton for the acid-catalyzed conversion of

()2 Catalytic H“ ‘
CQ' \i
O-H

Peroxide

99—91

(5)

Ovfifi (5) + H“
H+

Scheme 6. Mechanism of Formation of (5).

another peroxide.

 

 

Peroxide Cation

 

(4) + HO+

 

 

 

The reactivity of (4) possibly results from a combination of cyclobutane

ring strain and cyclopropyl radical or charge delocalization.1o The cyclobutane

135

ring strain is relieved to some extent (sp2 carbon to sp3 carbon) when addition
of oxygen occurs. Regioselectivity is provided by the cyclopropyl substituents.
In the bisected cyclopropylcarbinyl cation,10(b) the carbonyl carbon (C4) and its
substituents lie in a plane that is perpendicular to the plane of the cyclopropane
ring and bisects C1 and the C2 - C3 bond (see Figure 1). The vacant p orbital at
C4 is parallel to the plane of the ring and to the C2 - C3 bond. By 1: overlap with
the C - C bonding orbitals of the cyclopropane rings, which, because of angle
strain, . have an abnormal amount of p character, the positive charge at C4 is

delocalized to all three ring carbons.

 

 

Figure 1. Bisected Cyclopropylcarbinyl Cation.

 

 

 

Frimer and co-worker5 attempted to prepare the epoxide derivative of
cyclopropylidenedicyclopropylmethane by reacting it with a peracid. Under this
condition the epoxide rearranged rapidly to an isomeric 2.2-dicyclopropyl-
cyclobutanone (see Scheme 7), consistent with our speculation that an
intermediate in the transformation from (4) to (5) may be an epoxide like

species.

136

 

 

mCPBA

 

 

 

_ J

Scheme 7. Reaction of Cyclopropylidenedicyclopropylmethane.

 

In summary, oxide (1) can be used as a precursor of cyclobutylidene

denvaflves.

 

EXPEBIMENTAL

Registry No. _ cyclobutyldiphenylphosphine oxide (2), 16958-47-7.

4- rm tllhnl hln xi 1. T020.009(41.8

mmol) of 4-br0mobutyltriphenylphosphonium bromide in a 500 mL round
bottom flask was added 200 mL of a 20% aqueous solution of sodium
hydroxide. This mixture was refluxed for fifteen minutes, allowed to cool to
room temperature, and the oily globules of product were extracted with
methylene chloride. The methylene chloride extracts were combined, washed
with water, dried over anhydrous sodium sulfate, and evaporated to near
dryness in a rotary evaporator. The gummy residue was recrystallized from a
1:1 mixture of ethyl acetate and hexane and dried overnight in vacuum at 56 °C
to give 12.8 g (90.1% yield) of oxide (1), as white needle crystals. mp 84 °C;
1H NMR (300 MHz, CDCI3) 5 7.79~7.71 (m, 4H), 7.54~7.46 (m, 6H), 3.38 (t, J =
6.6 Hz, 2H), 2.33~2.24 (m, 2H), 2.02~1.94 (m, 2H), 1.93~1.78 (m, 2H) ppm;
13C NMR (75 MHz, CDCI3) 8 133.5 (d, J = 95 Hz), 132.3, 131.2 (d, J = 9 Hz ),
129.2 (d, J = 12 Hz), 33.6 (d, J = 14 Hz), 32.7, 23.9 (d, J = 72 Hz), 20.4 (d, J = 4
Hz) ppm; IR (NaCI) 3300, 3060, 2960, 1437, 1134, 1120, 718, 696 cm-1; MS
(EI) m/z (relative intensity) 336 (M, 7), 257 (100), 229 (45), 215 (16), 201 (100),
155 (16), 91 (7), 77 (44). Elemental analysis, Cal., C, 56.97%; H, 5.38% for
formula C16H13BrOP; Found, C, 56.85%; H, 5.51%.

137

138

CyglgbutylgiphenylphgsphIne Qxlge (2). A 5.00 g (14.8 mmol)

sample of oxide (1) was dissolved in 50 mL of THF in a 250 mL three-neck
round bottomed flask and then theflask was immersed in a -78 °C isopropyl
alcohol-dry ice bath. The mixture was stirred for 20 minutes and 8.6 mL (15.5
mmol) 1.8 M of PhLi in a 7 : 3 mixture of cyclohexane and Etzo was added
dropwise over 20 minutes. The reaction mixture turned pale yellowish orange
and was stirred for an additional two hours at - 78°C. The dry ice bath was
removed, and the reaction mixture was allowed to warm to room temperature.
The mixture was then poured into water, neutralized by dilute hydrochloric acid
and extracted with Eth. The extracts were combined, washed with brine and
dried over anhydrous sodium sulfate. Evaporation of the solvent and
recrystallization from a 1 : 1 mixture of methylene chloride and diethyl ether and
dried overnight in vacuum gave 3.5 g (92.1% yield) of oxide (2), as white
needle crystals. mp 162 °C; 1H NMR (300 MHz, CDCI3) 8 7.75~7.65 (m, 4H),
7.58~7.4O (m, 6H), 3.40~3.25 (m, 1H), 2.63-2.45 (m, 2H), 2.24~1.98 (m, 4H)
ppm; 13C NMR (75 MHz, CDCI3) 6 133.0 (d, J = 96 Hz), 132.1 (d, J = 3 Hz),
131.5 (d, J = 9 Hz), 129.0 (d, J = 11 Hz), 32.7 (d, J = 73 Hz), 21.4 (d, J = 5 Hz),
20.3 (d, J = 16 Hz) ppm; IR (NaCl) 3052, 2951, 2936, 2855, 1437, 1183, 1117,
748, 719, 702 cm'1; MS (EI) m/z (relative intensity) 256 (M, 73), 227 (12), 202
(100), 183 (26), 155 (31), 77 (32).

1'-D I I r mthI- I-ihenlh-
W3), A 250 mL three-neck round bottomed flask equipped with a

rubber septum, an addition funnel, an argon inlet and a magnetic stirrer was

139

alternately evacuated and filled with argon. 3.00 g (11.7 mmol) oxide (2) and
50 mL of THF were added. Oxide (2) was dissolved, the flask was immersed in
a - 78 °C isopropyl alcohol-dry ice bath and the mixture was stirred for 20
minutes. 7.0 mL 1.8 M (12.6 mmol) of PhLi in a 7 : 3 mixture of cyclohexane and
Eth was added dropwise at - 78 °C over 15 minutes. The reaction mixture
turned dark red and was stirred for an additional 10 minutes, following which
1.5 mL (1.47 g, 13.3 mmol) of dicyclopropylketone was added at - 78 °C. The
resulting mixture was stirred at - 78 °C for two hours; The dry ice bath was
removed, and the reaction mixture was allowed to warm to room temperature.
The mixture was then poured into water and neutralized by dilute hydrochloric
acid. THF was removed on a rotary evaporator, and excess
dicyclopropylketone was removed by steam distillation. The aqueous residue
was extracted with methylene chloride. The methylene chloride extract was
washed with water and dried over anhydrous sodium sulfate. Evaporation of
solvent and recrystallization from a 1 : 1 mixture of methylene chloride and EtzO
gave 3.6 g (84.0% yield) of oxide (3), as white square crystals. mp 151 °C; 1H
NMR (300 MHz, CDCI3) 8 7.94~7.84 (m, 4H), 7.52~7.40 (m, 6H), 4.68 (s, 1H),
2.88~2.72 (m, 2H), 2.70~2.52 (m, 2H), 2.19-2.02 (m, 1H), 1.50-4.35 (m, 1H),
1.17-1.06 (m, 2H), 0.77~0.65 (m, 2H), 0.62~0.52 (m, 2H), 0.38~0.27 (m, 2H),
-0.18 ~ - 0.30 (m, 2H) ppm; 130 NMR (75 MHz, 00013) 5 134.9 (d, J = 94 Hz),
132.1 (d, J = 8 Hz), 131.6, 128.7 (d, J = 11 Hz), 73.9, 50.7 (d, J = 63 Hz), 25.4,
18.7 (d, J = 7 Hz), 17.8 ( d, J = 11 Hz), 2.4, 1.5 ppm; IR (NaCI) 3450~3150,
3050, 3009, 2980, 1437, 1152, 1111, 713, 697 cm'1; MS (EI) m/z (relative
intensity) 368 (14), 367 (52), 366 (M, 3), 349 (100), 255 (34), 201 (100), 147
(32), 91(57), 77 (46); Elemental analysis, Cal., C, 75.37%; H, 7.43% for formula
023H2702P; Found, C, 75.36%; H, 7.38%.

140

I tll n I I r Im th n 4 . A 250 mL three-neck
round bottomed flask equipped with an argon inlet and a magnetic stirrer was
alternately evacuated and filled with argon. 0.20 g (8.3 mmol) sodium hydride,
60 mL of DMF and 3.00 g (8.2 mmol) oxide (3) were added. The resulting
brownish foamy suspension was stirred at room temperature for 30 minutes.
The mixture was then poured over water. THF was removed and the residue
was extracted with hexane. The hexane extract was washed with water and
dried over anhydrous sodium sulfate. Evaporation of solvent gave 1.05 g
(86.0% yield) pale yellowish oil of compound (4). 1H NMR (300 MHz, CDCI3) 6
2.74 (t, J = 7.6 Hz, 4H), 1.89 (quintet, J = 7.6 Hz, 2H), 1.06 (quintet, J = 6.8 Hz,
2H), 0.50-0.43 (m, 8H) ppm; 13C NMR (75 MHz, CDCI3) 6 134.9, 129.0, 30.7,
16.9, 10.9, 3.6 ppm; IR (NaCl) 3088, 3011, 2959, 2928, 2874, 2856, 1458,
1427, 1379, 1018 cm'1; MS (EI) m/z (relative intensity) 148 (M, 90), 133 (27),
119 (39), 105 (94), 91 (100), 79 (55), 77 (35), 65 (13); High resolution MS, Cal.,
148.1252 for formula C11H16: found, 148.1265.

Retrgalkylatlgn gt (3). A 100 mL three-neck round bottomed flask
equipped with an argon inlet and a magnetic stirrer was alternately evacuated
and filled with argon. 0.50 g (20.8 mmol) sodium hydride, 0.54 g (1.5 mmol)
oxide (3) and 40 mL of THF were added. The resulting suspension was stirred
‘ at room temperature overnight and refluxed for 10 minutes. The mixture was
poured over water. Evaporation of THF gave yellowish slurry, which was

extracted with methylene chloride. The extracts were washed with water and

141

dried over anhydrous sodium sulfate. Evaporation of solvent gave 0.37 g
(98.0% yield) white solid oxide (2).

2.2-Digyglgprgpylgyglgpgntangne (5). Compound (4) was stored

without argon for two years to give compound (5) quantitatively. Compound (4)
was bubbled with air for 24 hours in hexane to give compound (5)
quantitatively. 1H NMR (300 MHz, 000;.) 6 2.14 (t, J = 7.0 Hz, 2H), 1.34
(quintet, J = 7.0 Hz, 2H), 1.47 (t, J = 7.0 Hz, 2H), 0.94-0.33 (m, 2H), 0.45-0.23
(m, 6H), 0.19~0.09 (m, 2H) ppm; 13C NMR (75 MHz, CDCI3) 6 221.6, 49.7,
39.1, 31.2, 19.0, 16.1, 1.0. 0.4 ppm; IR (NaCl) 3031, 3007,2961, 2333, 1734,
1464, 1406, 1149, 1018, 818 cm'1; MS (EI) m/z (relative intensity) 164 (M, 1),
136 (70), 121 (45), 103 (83), 93 (77), 79 (100), 67 (34), 55 (16); High resolution
MS, Cal., 164.1201 for formula C11H160; Found, 164.1203.

APPENDIX ll

SPECTRAL PART II

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(a) Trost, B. M; Vladuchick, W. C. Synthesis, 1978, 821, and references
cited.

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