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This is to certify that the

dissertation entitled

Divinylcyclobutane Cope
Rearrangements of Aromatic Substrates

presented by
Kenneth Rehder

has been accepted towards fulfillment
of the requirements for

JHD degree in (Ihemj 51:12.)!

 

Major professor

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DIVINYLCYCLOBUTANE COPE REARRANGEMENTS OF

AROMATIC SUBSTRATES

By

Ken Steven Rehder

A DISSERTATION

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

DOCTOR OF PHILOSOPHY

Department of Chemistry

1990

ABSTRACT

DIVINYLCYCLOBUTANE COPE REARRANGEMENTS OF
AROMATIC SUBSTRATES

By

Ken Steven Rehder

The use of the divinylcyclobutane C0pe rearrangement is a
powerful method for the stereocontrolled construction of
cyclooctanoid natural products and other structurally novel
compounds. However, there have been relatively few examples of
this method being used where one or more of the vinyl groups are
incorporated into an aromatic substrate. The synthesis of a number
of aromatic divinylcyclobutane Cope rearrangement precursors will
be described, and their behavior under a wide variety of Cope
rearrangement conditions will be discussed. In the cases studied, an
alternative mechanistic pathway to the Cope rearrangement appears
to be operative, involving the potential intermediacy of a 1,4
diradical resulting from homolytic scission of the cyclobutane bond.
Attempts to prove the intermediacy of this diradical will also be
examined.

To my high school chemistry teacher, Roger Palmer, who showed
me that science must be taught and learned with a sense of humor.

iii

ACKNOMEDGEWI‘S

To Dr. William Reusch, whose guidance, insight, and patience with

my reconstructed anterior cruciate ligament made all this possible.

To Drs. Stephen Tanis, John Stille, Ned Jackson, and Donald
Farnum for their critical comments and advice during Tuesday night
group meetings. I learned more on those nights than during all of
my classes combined.

To Paul Weipert, Mark McMills, Guy Laidig, Wuyi Wang, and John
Zepp for their listening ears, alternative ideas, and non-academic
distractions during my times of indecision, frustration, and doubt.

To NMR specialists Kermit Johnson and Dr. Long Le for providing
technical assistance and indulging me during my moments of
spectroscopic fancy.

To Michigan State University for financial assistance.

And to my parents, for their support and love throughout.

iv

TABLE OF CONTENTS

LIST OF TABLES
LIST OF FIGURES
INTRODUCTION

SYNTHESIS
Base Catalyzed Isomerization
Payne Rearrangement
Reductive Elimination

COPE REARRANGEMENTS
Anionic Oxy-Cope Rearrangement
Palladium Catalyzed Cope Rearrangement
Solution Thermolysis
Flash Thermolysis

MECHANISTIC INVESTIGATION
Derivative Synthesis and Thermolysis
Trapping Studies

CONCLUSION
APPENDIX

BIBLIOGRAPHY

vi

vii

12
16

22
22
27
31
33

37
37
43

46

67

168

LIST OF TABLES

Table 1. Selected Coupling Constants (and dihedral angles) of
21 and Derivatives. 26

Table 2. Thermolysis Experiments. 34

Table 3. Thermolysis of Cyclobutane Derivatives with added
Tributyltin hydride 44

vi

Figure
Figure
Figure
Figure
Figure

Figure

Figure
Figure
Figure
Figure
Figure

Figure

Figure
Figure
Figure
Figure
Figure

Figure

9MP?!"

>’

10.
ll.
12.

l3.
14.
15.
l6.
17.
18.

LIST OF FIGURES

The Cope Rearrangement.

The Oxy-Cope Rearrangement.

The Oxy-Anionic Cope Rearrangement.

The Palladium Catalyzed Cope Rearrangement.
The Divinylcyclobutane Cope Rearrangement.

Proposed Cope Rearrangement of Aromatic
Substrate 5.

Eight-membered Carbocyclic Ring Natural Products.

Cycloalkene to Endo Vinylcyclobutanol Synthesis.

Base Catalyzed Isomerization.
Payne Rearrangement.
NOE's of Vinyl Esters 8a and 8b.

Cyclobutyl Epoxy Alcohol-Epoxy Cyclobutanol
Manifold.

Allylic Alcohol Transposition.

Reductive Elimination.

Structural Proof of Geminal Methyl Aldehyde.
Possible Mechanism of Formation of 13.
Synthesis of Exo Vinylcyclobutanol 19.

Anionic Oxy-Cope Rearrangement.

vii

«#UJNN

LII

11
13
14

15
16
17
18
20
21
23

Figure

Figure
Figure

Figure

Figure

Figure
Figure

Figure
Figure

Figure
Figure

Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure

Figure

19.

20.
21.
22.

23.
24.

25.

26.
27.
28.

29.

30.
31.
32.
33.
34.
35.
36.
37.
38.

Conformations of Cyclohexanone 21 with
calculated Molecular Mechanics Energies.

Cyclization Induced Rearrangement Mechanism.

Palladium Catalyzed Cope Rearrangement.

Thermal Solvated Rearrangements of
Vinylcyclobutanols.

Diradical Intermediates.

Synthesis and Thermolysis of Exo and Endo
Vinylcyclobutyl Acetates 30 and 31.

Synthesis and Thermolysis of
Exo Methylcyclobutanol 34.

Synthetic Approach to Endo Vinylcyclobutane 35.

25
28
3O

32
36

38

39
39

Attempted Synthesis of Endo Vinylcyclobutane 35. 40

Synthesis and Thermolysis of Exo Vinyl Silyl Ether

41 and Exo Phenylcyclobutanol 42.

Synthesis and Thermolysis of
Cyclopropylcyclobutanol 45.

1H NMR Spectrum of l.
13"C NMR Spectrum of 1.
Infrared Spectrum of 1.
Mass Spectrum of l.

1H NMR Spectrum of 2.
13C NMR Spectrum of 2.
Infrared Spectrum of 2.
Mass Spectrum of 2.

1H NMR Spectrum of 3.

viii

42

43
67
68
69
7O
71
72
73
74
75

Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure

Figure

39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.

13C NMR Spectrum of 3.
Mass Spectrum of 3.
1H NMR Spectrum of 4.
Mass Spectrum of 4.
1H NMR Spectrum of 5.
13C NMR Spectrum of 5.

Infrared Spectrum of 5.

Mass Spectrum of Endo 5.

1H NMR Spectrum of 6.
13C NMR Spectrum of 6.
Mass Spectrum of 6.

1H NMR Spectrum of 7.
Mass Spectrum of 7.

1H NMR Spectrum of 8a.
13C NMR Spectrum of 8a.
Infrared Spectrum of 83.
Mass Spectrum of 8a.
1H NMR Spectrum of 8b.

13C NMR Spectrum of 8b.
Infrared Spectrum of 8b.

Mass Spectrum of 8b.

1H NMR Spectrum of 9.
13C vam Spectrum of 9.
Infrared Spectrum of 9.

ix

76
77
78
79
8O
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99

Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure

Figure

63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.

Mass Spectrum of 9.

1H NMR Spectrum of 103.

13C NMR Spectrum of 103.

Infrared Spectrum of 103.

Mass Spectrum of 103.

1H NMR Spectrum of 10b.

13C NMR Spectrum of 10b.

Infrared Spectrum of 10b.

Mass Spectrum of 10b.
1H NMR Spectrum of 123.

13C NMR Spectrum of 123.

Infrared Spectrum of 123.

Mass Spectrum of 123.

1H NMR Spectrum of 12b.

13C NMR Spectrum of 12b.

1H NMR Spectrum of 13.
Mass Spectrum of 13.
1H NMR Spectrum of 14.
Mass Spectrum of 14.
1H NMR Spectrum of 19.
13C NMR Spectrum of 19.
Infrared Spectrum of 19.
Mass Spectrum of 19.
1H NMR Spectrum of 21.

X

100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123

Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure

Figure

87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
99.

100.
101.
102.
103.

105.
106.
107.
108.
109.
110.

13C NMR Spectrum of 21.
Infrared Spectrum of 21.
Mass Spectrum of 21.

1H NMR Spectrum of 233.
Mass Spectrum of 233.
1H NMR Spectrum of 24.

Mass Spectrum of 24.

1H NMR Spectrum of Mixture of 25/26/27/28.

1H NMR Spectrum of 27.
13C NMR Spectrum of 27.
1H NMR Spectrum of 29.
13C NMR Spectrum of 29.
1H NMR Spectrum of 30.
13C NMR Spectrum of 30.
Infrared Spectrum of 30.
Mass Spectrum of 30.

1H NMR Spectrum of 31.
1H NMR Spectrum of 32.
Mass Spectrum of 32.

1H NMR Spectrum of 33.
13C NMR Spectrum of 33.
Infrared Spectrum of 33.
Mass Spectrum of 33.

1H NMR Spectrum of 36.

xi

124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147

Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure

Figure

111.
112.
113.
114.
115.
11.6.
117.
118.
119.
120.
121.
122.
123.
124.
125.
126.
127.
128.
129.
130.

13C NMR Spectrum of 36.

Infrared Spectrum of 36.

Mass Spectrum of 36.

1H NMR Spectrum of 38.

13C NMR Spectrum of 38.

Infrared Spectrum of 38.

Mass Spectrum of 38.
1H NMR Spectrum of 39.
1H NMR Spectrum of 40.
Mass Spectrum of 40.

1H NMR Spectrum of 41.

13C NMR Spectrum of 41.

Infrared Spectrum of 41.

1H NMR Spectrum of 42.

13C NMR Spectrum of 42.

Infrared Spectrum of 42.

1H NMR Spectrum of 45.

13C NMR Spectrum of 45.

Infrared Spectrum of 45.

Mass Spectrum of 45.

xii

148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167

Cyclobutanes are known to possess a considerable inherent ring
strain energy (approximately 26 kcal/mole),l which serves to
introduce or enhance reactivity in suitably constructed organic
substrates, permitting entry into systems which otherwise might be
inaccessible. An interesting and synthetically useful application of
cyclobutanes in organic chemistry occurs as a central component in

[3,3] sigmatropic shifts such as the Cope rearrangement (see Figure
1).2

02 C2
C3/ §C1 03/ \C1
—>
1 c ‘— c I
C \ ¢ 6 4% /C6
Cs Cs

Figure l. The Cope Rearrangement.

The concerted nature of the Cope rearrangement, with a well
ordered and predictable transition state, gives products in excellent
stereoselectivity and yield, even in highly functionalized systems.
Unfortunately, the Cope rearrangement of a 1,5 hexadiene requires
temperatures in excess of 200 °C, is reversible, and generally favors
the more substituted diene system. In order to alleviate some of
these difficulties, 3 number of modifications have been developed.

2

One of the most widely used modifications of the Cope
rearrangement is the oxy-Cope rearrangement (see Figure 2).3 In
this variant, 3 hydroxyl group has been introduced at the C3 position
of the rearranging framework. The initial rearrangement generates
an enol, which can then tautomerize to the more stable ketone. Since
ketones are in general around 15 kcal/mole lower in energy than the
corresponding enol, this modification effectively eliminates the
reverse rearrangement and allows for isolation of the desired
rearranged product.

HO HO 0

Figure 2. The Oxy-Cope Rearrangement.

Another variant is the anionic oxy-Cope rearrangement (see
Figure 3).4 This rearrangement has essentially the same structural
framework as the oxy-Cope, but has an oxygen anion at the 3
position rather than a hydroxyl group. There is a dramatic rate
enhancement of 1010 to 1017 over the simple oxy-Cope
rearrangement when the counterion present is potassium, which
allows for considerably lower reaction temperatures and shorter
reaction times. In addition, the initial rearrangement product is an
enolate rather than an enol, and can be subsequently manipulated
using standard enolate chemistry. These two advantages have led to
the widespread use of the anionic oxy-Cope rearrangement in natural
product syntheses.

Figure 3. The Anionic Oxy-Cope Rearrangement.

Another modification is the palladium-catalyzed Cope
rearrangement (see Figure 4).5 This modification has a different
mechanism than the previously discussed Cope rearrangements, and
has been termed a "cyclization-induced rearrangement catalysis"
mechanism. Like the anionic oxy-Cope, dramatically reduced
reaction temperatures and times can be used. The main drawback is
the apparent necessity for the rearranging 1,5 hexadiene framework
to be substituted at C5 and unsubstituted at C2, thereby limiting the
scope of this reaction. These limitations are thought to be due to the
need for both a sterically undemanding palladium coordination site
at C2 and a cation-stabilizing center at C5.

Pd("an

-I-P(I(")Ln -Pd(")Ln /

Figure 4. The Palladium Catalyzed Cope Rearrangement.

Finally, a powerful but specialized modification is found in the
divinylcyclobutane Cope rearrangement (see Figure 5).6 By

4

incorporating a strained cyclobutane ring into the rearranging
framework, the reaction can be driven in the forward direction by
the release of ring strain energy of approximately 26 kcal/mole,
forming a less strained cyclooctadiene as the product.

\
/

#
h
I

Figure 5. The Divinylcyclobutane Cope Rearrangement.

The Cope rearrangement and the modified Cope rearrangements
have been utilized to good advantage in a wide variety of synthetic
applications. One area where these reactions have not been
extensively used, however, is in the rearrangement of aromatic
substrates.7 Despite the obvious synthetic utility of this type of
rearrangement, the high energy cost of disrupting an aromatic ring
incorporated in the rearranging framework has made this route
unattractive. This is in contrast to the analogous but successfully
used aromatic Claisen rearrangement.3 Procedures which could
circumvent this limitation would be a valuable addition to Cope
rearrangement synthetic methodology.

In this dissertation the proposal that the Cope rearrangement of
an aromatic substrate can be achieved if the rearranging framework
is suitably constructed will be examined. In particular, the concept
of using the release of ring strain energy of a cyclobutane ring to
help overcome the loss of resonance energy due to disruption of an
aromatic ring system during a Cope rearrangement will be explored.
In order to probe this idea, the aromatic divinylcyclobutanol 5 was
proposed as an initial synthetic target and Cope rearrangement
precursor (see Figure 6). This compound contains many of the

5

features necessary to test the above proposal, including the presence
of a hydroxyl group in the C3 position of the 1,5-hexadiene
framework to form an oxy-Cope system, a divinylcyclobutane Cope
system, and an aromatic ring in the form of a substituted
naphthalene. Cope rearrangement of this compound must
necessarily proceed via a boat transition state, with cleavage of one
of the cyclobutane bonds and disruption of resonance in the
naphthalene ring system. This will form a cyclooctadienol, which can
then tautomerize to a cyclooctenone. Use of the oxy-anionic or
palladium-catalyzed Cope rearrangement modifications is also
possible for this appropriately substituted divinylcyclobutanol
system.

OH
I

30 3%: 3%

5

Figure 6. Proposed Cope Rearrangement of Aromatic Substrate 5.

By analyzing the bond energy differences between the starting
divinylcyclobutanol and the product cyclooctenone. the validity of
the above proposal from a thermodynamic standpoint can be probed.
Of particular interest is knowing whether the product of the Cope
rearrangement is substantially lower in energy than the starting
material. The key terms to consider are the cyclobutane bond
cleavage energy, the naphthalene bond resonance energy, the strain
in the cyclooctadiene structure. Two methods can be used for this

6

analysis. Simple use of bond energy tables can give a rough estimate
of the difference in energy between the product and the precursor.
Molecular mechanics can also be used to give a more accurate
analysis of the reaction energetics. Note, however, that these
analyses will yield no information regarding the activation energy of
this transformation.

Simple use of bond dissociation energy tables9 shows that the
product is substantially lower in energy than the precursor.
Cyclobutane ring strain energy has been estimated at 26 kcal/mole.
The cost of energy for disrupting the aromatic naphthalene ring can
be estimated by subtracting the resonance energy of benzene from
the resonance energy of naphthalene, giving 61 kcal/mole minus 36
kcal/mole, or 25 kcal/mole. The difference in energy between a
ketone and the enol form has been estimated at 15 kcal/mole,
favoring of the ketone. Thus the total amount of energy in favor of
the product is approximately 16 kcal/mole. This simple analysis
may not be fully accounting for a number of other potentially
important energy terms, including the strain of the intermediate
cyclooctadiene, the presence of a trans double bond in the product,
and the inevitable transannular interactions, but the magnitude of
the difference seems to favor the desired product.

Use of molecular mechanics can help to eliminate some the
uncertainty which is inevitable in simple bond energy calculations.
Molecular mechanicslo calculations predict a total energy of 63
kcal/mole for the starting material while in a conformation suitable
for rearrangement, a total energy of 71 kcal/mole for the initial enol
product, and a total energy for the final ketone. product of 49
kcal/mole. Thus the energy difference is 14 kcal/mole in favor of
the final product. Note that the energy difference between the
starting material and product corresponds nicely with those found
during the simple bond energy calculations. Another interesting
feature of this rearrangement was found during molecular mechanics
calculations. They show that the final ketone product can exist in
two different conformations, one with the ketone carbonyl moiety
"up", or pointing away from the naphthalene rings, and another with
the carbonyl "down", or pointing towards the naphthalene rings.

7

These two conformations differ in energy by about 3 kcal/mole in
favor of the "down" conformer. This difference in energy should
permit the isolation of these isomers if the desired Cope
rearrangement product is formed.

Examination of the product of this Cope rearrangement is
interesting for other reasons. The substituted m-cyclooctenone
may possess unusual or enhanced reactivity due to torsional strain,
transannular interactions, and the densely packed variety of
functional groups present. This might permit further useful
elaboration or isomerization. In addition, there is a growing
theoretical, medicinal, and synthetic interest in eight-membered
carbocyclic ring compounds such as ophiobolin A,11 dactylol,12
pleuromutilin,13 and stegnanacin14 (see Figure 7). The Cope
rearrangement of aromatic divinylcyclobutanes offers a general
entry to such eight-membered ring structures. Information obtained
during this study may prove useful for synthetic efforts directed
toward these and other natural products.

 

Figure 7. Eight-membered Carbocyclic Ring Natural Products.

Win

The initial attempt to synthesize the necessary endo
Vinylcyclobutanol Cope rearrangement precursor was essentially a
modification of a procedure initially outlined these laboratories”
(see Figure 8). Cycloaddition of dichloroketene16 to a cyclic olefin
generated a cis-bicyclo[n.2.0]dichloroketone, and subsequent
reductive removal of the chlorines provided the requisite fused ring
cyclobutanone.17 Reaction with the appropriate Wittig reagent gave
the ethylidene derivative. There is an inherent steric bias in this
system, which favors the approach of reagents from the less
hindered exo face (cis to the bridgehead hydrogens). Thus
epoxidation from the exo face, followed by base catalyzed
isomerization,18 was expected to give the desired endo
Vinylcyclobutanol.

OI - d.» °
1
d”‘\ ~ OI «—

Figure 8. Cycloalkene to Endo Vinylcyclobutanol Synthesis.

10

In the event, ultrasound promoted [2 + 2] cycloaddition of
acenaphthylene with main-generated dichloroketene, followed by
dechlorination of the crude dichlorocyclobutanone 1 gave the known
cyclobutanone 2 in 85% yield.overall (see Figure 9). Wittig reaction
gave the ethylidene cyclobutanes 3 as a 1 : 1 mixture (1H NMR) of
inseparable stereoisomers in 37% unoptimized yield. Epoxidation of
this mixture gave the spiro ethylidene oxides 4 as a 10 : 1 mixture of 4
stereoisomers about the epoxide center in 99% yield. Subjecting the
major epoxide isomers (presumably exo due to the folded nature of
the substrate and the relative inaccessibility of the endo face) to base
catalyzed rearrangement conditions did not give the expected endo
Vinylcyclobutanol 5, but rather the substituted acenaphthylene
derivative 6 in 83% yield. Modifications of the reaction conditions
and changes in the base used gave similar results. Base catalyzed
opening of the epoxide ring in 4 by initial removal of the endocyclic
benzylic proton rather than the desired primary one, and subsequent
electrocyclic opening of the resultant cyclobutene explain this result.
Structural elucidation of the diene was effected by Diels-Alder
reaction with dimethylacetylene dicarboxylate to give an adduct in
70% yield, whose properties were consistent with the expected 7.

L

 

H
O

 

Figure 9. Base Catalyzed Isomerization

l2

Earlier workersl9 had shown that in the base catalyzed
isomerization of certain spiro alkylidene oxide systems similar to this
one, endocyclic proton removal can be the preferred pathway,
especially if there is an available low energy syn coplanar transition
state.20 Examination of models shows that the epoxide oxygen and
the benzylic hydrogen in 4 are suitably aligned for such a
transformation. The enhanced acidity of the benzylic proton, a factor
not present in the previous work,15 may also be an important reason
for this divergence in behavior.

Went

A revised approach to the Cope precursor (see Figure 10) included
Horner-Emmons olefination21 of the cyclobutanone 2, reduction of
the a,B-unsaturated ester 8, epoxidation of the resulting allylic
alcohol 9 from the less hindered exo face, and Payne
rearrangement22 of the spiro epoxy alcohol 10 to the epoxy
cyclobutanol 11. Conversion of this epoxide to the corresponding
alkene would generate the desired endo Vinylcyclobutanol 5.
Although this Payne rearrangement (10 to 11) proceeds contrary to
previously observed substituent effects, the angle strain of the spiro
epoxide might override these tendencies, thus favoring, in this case,
the less substituted epoxide. This expectation was supported by
molecular mechanics calculations, which showed the spiro epoxide
10 to be approximately 10 kcal higher in energy than the
monosubstituted epoxide 11.

13

; 0 : COzEt :/ CHZOH
‘ —» ‘ —~ 30

 

 

Figure 10. Payne Rearrangement.

In the event, reaction of cyclobutanone 2 with the anion of
triethylphosphonoacetate gave the a, B-unsaturated ester 8 as a 10 :
1 mixture of stereoisomers (1H NMR) in 72% yield. The
stereochemistry of the major isomer 83 and the minor isomer 8b
were assigned through use of NOE experiments (see Figure 11).
Reduction of the major isomer 83 gave the allylic alcohol 93 in 61%
yield, and epoxidation yielded the spiro epoxy alcohol 10 as a 2 : 1
mixture of stereoisomers (1H NMR) in 99% yield. The major isomer
103, again presumably exo, was subjected to Payne rearrangement
conditions, but failed to give any rearranged product; only starting
material was recovered. Application of more forcing conditions gave

14

identical results. Attempted rearrangement of the minor isomer 10b
also gave only recovered starting material.

 

Major Vinyl Ester 83 Minor Vinyl Ester 8b

Figure 11. NOE's of Vinyl Esters 83 and 8b.

There are two main questions concerning the course of this
reaction which must be addressed. Is true Payne rearrangement
equilibrium between the two different epoxy alcohols actually being
achieved? If so, why does the equilibrium favor the calculated
higher energy isomer? In order to fully answer these questions,
synthesis of all eight of the possible spiro epoxy alcohol and epoxy
cyclobutanol isomers and examination of the rearrangement
capabilities of each might be necessary. The relationship between
these various isomers is shown in Figure 12. As stated earlier,
reduction of the major a,B-unsatur3ted ester isomer 83 gave 93, and
epoxidation furnished 103 and 10b. Similar treatment of the minor
isomer of 8b to yield 10c and 10d was not attempted. Obtaining the
Payne rearrangement equilibrium isomers from the opposite
direction should be possible by epoxidation of endo
Vinylcyclobutanol 5 to yield 113 and 11b, and epoxidation of exo
Vinylcyclobutanol 19 should yield 203 and 20b. However, efforts to

15

obtain 113, 11b, 203, and 20b through either standard or modified
epoxidation procedures gave only poor yields of recovered starting
materials. This surprising and frustrating result has not been
explained, and further attempts to synthesize these compounds were
abandoned.

o
i>m-CH:—OH “:fHH ()0

1 0 3
CHZOH /
moi-{20H
IIIIO
‘—
93 10b

 

o
E(\CH20H fiCHLOH
—-.-
9b

\

CHZOH

—>
«

"IIO

 

10d

Figure 12. Cyclobutyl Epoxy Alcohol-Epoxy Cyclobutanol Manifold.

16

Failure of the Payne rearrangement prompted modification of the
synthetic approach to the Cope rearrangement precursor 5. Already
having the allylic alcohol 9 (and the epoxy alcohol 10) in hand,
utilization of a known procedure for allylic alcohol transposition was
next attempted (see Figure 13).23 This procedure involves
epoxidation of the double bond and conversion of the hydroxyl
moiety to a methane sulfonate ester (mesylate). Treatment of this
mesylate with a suitable reducing agent effects concomitant mesylate
removal and epoxide opening to afford the transposed allylic alcohol.

epoxidation

O
meSYIaIion

reducfion

O
HOV <— \>\/OSOZCH3

. Figure 13. Allylic Alcohol Transposition.

In the event, mesylation of the spiro epoxy alcohol 10 mixture
gave the spiro epoxy mesylate 12, as a 2 : 1 mixture (1H NMR) in
98% yield (see Figure 14). Treatment of the major isomer 123 with
sodium naphthalide24 gave, in 42% yield, not the expected endo
Vinylcyclobutanol 5, but rather a compound whose spectral
properties, especially the high field 1H NMR signals, indicated a single
spiro cyclopropanol 13 with unspecified stereochemistry at both the

l7

carbinol and the quaternary cyclobutane carbon. Partial structural
elucidation of 13 included decoupling experiments and conversion to
a geminal methyl aldehyde l4.

-’ O

13

l . l

<— CO CO

15 14

 

 

Figure 14. Reductive Elimination

18

Further structural proof was planned by an independent
synthesis of 14 (see Figure 15). Wittig reaction of cyclobutanone 2
with the ylide derived from methoxymethyl triphenylphosphonium
bromide should give the cyclobutyl enol ether 16. Hydrolysis would
yield the aldehyde 17, and enolate formation followed by capture
with methyl iodide should yield the exomethylcyclobutyl aldehyde
18, assuming approach of the alkylating agent from the less
hindered exo face. This compound should either be identical with
14, or differ in configuration about the quaternary center (i.e. the
endomethylcyclobutyl aldehyde). Unfortunately, attempts to
synthesize 16 were unsuccessful, so the the stereochemistry of 14
remains unspecified.

I O - ecu, ' CH0
60 —~ 30 —~

2 16 17

l

I

Figure 15. Structural Proof of Geminal Methyl Aldehyde.

||| "

 

 

 

 

18

19

The presumed mechanism24 of reductive elimination in the 1,3
allylic alcohol transposition outlined in Figure 13 involves electron
transfer by the reducing agent to the mesylate group followed by
cleavage of what was the carbinol carbon to oxygen bond. The alkyl
radical is then reduced further to the carbanion, then opens the

epoxide to yield the allylic alkoxide. However, due to the
naphthalene ring system present in 12, a different reaction pathway
could be envisioned (see Figure 16). The standard oxidation

potentials25 (in DME vs. SCE) of sodium naphthalene (NaNp, 2.60 V)
and sodium acenaphthylene (NaAc, 1.65V), which can be used as a
rough model for 12, are substantially different, with NaAc being
more easily reduced. Thus treatment of 12 with NaNp might first
involve electron transfer from N aNp to generate the radical anion of
12. This then might intramolecularly attack the epoxide either as
the anion or the radical to give a strained cyclopropane, which could
be reduced further, either at the naphthalene ring or at the
cyclopropane ring. This reduction would cause cyclopropane bond
cleavage followed by mesylate expulsion to yield the cyclopropanol
13. Use of the minor mesylate isomer (derived from 8b) should
yield a eyelopropanol which differs in configuration only about the
hydroxyl center. The course of the reaction of the minor epoxy
mesylate isomer 12b (and its isomer derived from 8b) with
reducing agents was not determined.

20

..«CH20MS ““CHZOMs

 

Figure 16. Possible Mechanism of Formation of 13.

In a modification of the reductive elimination protocol, the major
spiro epoxy mesylate isomer 123 was treated with sodium iodide to
generate the intermediate spiro epoxy iodide 15, which was
converted 111.5111; to the desired endo Vinylcyclobutanol 5 (see Figure
14) in 41% yield. This result supports the earlier assumption that
the major spiro epoxy alcohol 103 had the assigned configuration, as
only this isomer should eventually give rise to the endo
Vinylcyclobutanol 5. Further support for this assumption comes
from the conversion of the minor (endo) spiro epoxy mesylate 12b
to the exo Vinylcyclobutanol 19, which was obtainable by an
independent route, namely addition of vinyl magnesium bromide to
cyclobutanone 2 to give 19 in 67% yield (see Figure 17).

21

,CI-Izosozel-ia

O
/

    

. vinyl reductive
Gngnard elimination
_., <—

2 1 9 1 2b

Figure 17. Synthesis of Exo Vinylcyclobutanol 19.

W

With both the "correct", stereoproximal endo Vinylcyclobutanol 5
necessary for the [3,3] sigmatropic Cope rearrangement, and the
"incorrect", stereodistal exo Vinylcyclobutanol 19 in hand, the
rearrangement properties of these two divinylcyclobutane systems
could be studied. Molecular mechanics calculations had shown that
the stereoproximal isomer was able to align itself in a low energy
conformation to allow both termini of the [3,3] system to approach
each other at distance amenable to rearrangement. Further
calculations showed that the ultimate product, a trans-cyclooctenone,
after passing through a high energy intermediate enol, was
substantially lower in energy than the starting material, primarily
through relief of strain in the cyclobutane bond cleavage. In
addition, the possibility that the stereodistal isomer might rearrange
also existed, as other studies26 of divinylcyclobutane systems have
shown that some stereodistal isomers can, under certain reaction
conditions, isomerize to the stereoproximal isomer, followed by Cope
rearrangement. A

1"0-CE

The initial attempt at rearrangement made use of the rate
accelerated anionic oxy-Cope rearrangement protocol.4 Treatment of
endo Vinylcyclobutanol 5 by the recommended basic conditions gave
a single compound in 59% yield. The spectral properties of this
compound suggested a cyclohexanone such as 21 or 22 (see Figure
18). Differentiation between these two fragmentation-recombination
possibilities (path a to 21, or path b to 22) was achieved by
exhaustive deuteration of the carbons a to the carbonyl to give either

233 (from 21) or 23b (from 22) in 86% yield. Thus cyclohexanone

22

23
21, with four a-hydrogens, will incorporate four deuteriums, while
cyclohexanone 22 will only incorporate three. Analysis of 23,
especially by the 1H NMR integration values and mass spectrum,

indicated the tetradeuterated derivative 233, thus implying that the
rearrangement product was 21, not 22.

 

OH
5
O
. 0 “30+ \3 \)
22
1“”
j 02 O 02 0
. ° °2 0 ‘— .
D
23b 233 21

Figure 18. Anionic Oxy-Cope Rearrangement.

24

The stereochemistry of the ring fusion in 21 was assigned
through decoupling experiments and conformational analyses of 21,
233, and the ethylene dithioketal derivative of 21(24). Molecular
mechanics calculations showed that the lowest energy conformers of
cis-21 were the exo-boat form 213 and the endo-boat form 21b,
present in roughly equivalent amounts (See Figure 19). The cis-21
exo- and endo-chair forms were calculated to be almost 3 kcal higher
in energy; as such they should be present in less than 1%, and thus
were ignored for the purpose of this analysis. Selected dihedral
angles and calculated coupling constants for the two cis boat
conformers 213 and 21b and for trans-fused 21c are shown in
Table 1, along with some of the observed coupling constants for 21,
233, and 24. The NMR spectrum of 21 showed Hx and Hy as clearly
resolved doublets of doublets (Jax = 6.4 Hz, Jay = 7.0 Hz, ny = 15.6
Hz), and the spectrum of 233 also displayed Hm and Hn, as doublets
of doublets (me = 5.6 Hz, an = 7.0 Hz, Jmn = 14.1 Hz).

25

cis exo boat 213
37.9 km!

 

quuu

cis endo boat 21 b
38.0 kcal

 

trans chair 21c
42.3 kcal

    

Immm

Figure 19. Conformations of Cyclohexanone 21 with calculated
Molecular Mechanics Energies.

26

Although the observed coupling constants match the calculated
cis-boat values better than the trans values, the decisive factor in
choosing the cis stereochemistry for 21 proved to be couplings
observed in the thioketal derivative 24. If 21 were trans, there
would be little change in the observed couplings, as the unavoidable
conformational rigidity of both the ketone and the thioketal would
result in similar dihedral angles for Ha, Hx, and Hy, If21 were cis,
however, there should be an increased population of the exo
conformer, as the endo conformer has a serious 1,3 diaxial
interaction between a sulfur atom of the thioketal moiety and the
naphthalene ring system. This equilibrium shift should result in
slightly increased In values and more dramatically increased Jay
values. This is in fact observed: In changes very little (actually
drops from 6.4 to 6.0 Hz), and Jay shows a more substantial change
(increases from 7.0 to 10.6 Hz). On the basis of these accumulated
observations, the cis stereochemistry for the cyclohexanone 21 was
decided upon.

Table 1. Selected Coupling Constants (and dihedral angles) of 21
and Derivatives. The first four entries represent MM2 derived
values, while the last three entries represent actual observed
values.

 

    

Swtctm

   

 

 

 

 

cis endo boat 21b 3.9 (54°) 2.3 (63°) 4.4 (52°) 2.2 (64°)
cis exo boat 213 4.6 (49°) 11.8 (108°) 4.4 (50°) 11.8 (167°)
trans chair 21c 2.7 (60°) 12.4 (179°) 2.4 (62°) 12.4 (178°)
averaged cis boat 4.3 7.4 4.4 7.3
cyclohexanone 21 6.4 7 .0
d4-cyclohexanone 23 5.6 7.0
thioketal 24 6.0 10.6

 

 

 

27

The formation of 21 from 5 was not entirely unexpected, as
earlier work27 had shown that the oxy-anionic rearrangement of a 1-
Vinylcyclobutanol system with an anionic stabilizing thiophenyl
group in the 2 position gave cyclohexanones of this type, although in
that case a mixture of cis and trans isomers was formed. The
mechanism of this transformation was presumed to occur by
conversion of the oxy-anionic Vinylcyclobutane to a ring-opened
vinyl ketone-stabilized anion, followed by intramolecular Michael
reaction. Under similar conditions the isomeric exo Vinylcyclobutanol
19 also gave cyclohexanone 21 in 56% yield In neither case was the
isomeric Vinylcyclobutanol or the trans cyclohexanone observed
among the products.

WWW

Having unsuccessfully attempted the anionic oxy-Cope
rearrangement, we next turned to transition metal catalysts,
specifically palladium(II). Palladium dichloride has been used
successfully as a catalyst for various types of [3,3] sigmatropic
shifts,5 including the oxy-Cope variant, and we hoped that the mild
reaction conditions used would help to minimize undesirable
byproducts. One possible mechanistic pathway for this
transformation is what has been called a "cyclization induced
rearrangement catalysis" (see Figure 20). The most pronounced
trend favoring this mechanism is the generally observed
requirement for a hydrogen substituent at C2 of the 1,5-hexadiene
unit, and a non-hydrogen substituent at C5. C2 must be relatively
unencumbered to allow the bulky palladium electrophile (E’t) to
attach itself at that site, and stabilization of the intermediate
cyclohexenyl carbocation at C5 will be facilitated by suitable electron
donating substituents in that position. Both 5 and 19 appear to
meet both of these requirements, being unsubstituted at C2 and able

28

to achieve benzylic carbocation resonance stabilization at C5. Note,
however, that the mechanistic picture of the palladium(II) catalyzed
Cope rearrangement of cis 1,2-divinylcyclobutanes is somewhat
unclear.28 Products are sometimes obtained other than those of the
analogous thermal Cope reaction, thus this type of transformation for
this class of compounds must be considered a special case. This is
probably due to the strain of the four membered ring and the
necessarily constricted boat conformation of intermediates or
transition states whose appearance may involve various degrees of
concertedness in the bond cleavage and formation.

’2 IV \
e> oh 3
0O 00 f—= 0Q

Figure 20. Cyclization Induced Rearrangement Mechanism.

In the event, treatment of endo Vinylcyclobutanol 5 with bis
(acetonitrile) palladium dichloride yielded a mixture of
cyclopentanones in 61% yield (25:26:27:28=1:l:14:4), but no desired
Cope product (see Figure 21). Treatment of exo Vinylcyclobutanol 19
with the same catalyst gave a similar mixture of cyclopentanones in
68% yield (25:26:27 :28=1:7:22:3). These results can be explained by
initial coordination of the palladium species to the vinyl group,
followed by electrophilic addition to the double bond. Migration of a
cyclobutane bond to the electron deficient center followed by B-
hydride elimination yields the (at-methylene cyclopentanone 25.
Readdition of the expelled metal hydride species then forms an a-

29

palladocyclopentanone. This can then B-hydride eliminate the same

hydrogen to give back 25 or, if the palladium added from the less
hindered exo face, it can eliminate the syn coplanar benzylic
hydrogen to yield the a,B-unsaturated cyclopentenone 26. If the
palladium species remains attached to the cyclopentanone rather
than eliminates, then reductive removal during workup will afford
the a-methyl cyclopentanones 27 and 28. The stereochemistry of
the methyl group is dependent on the direction of the initial attack of
metal hydride on the tat-methylene cyclopentanone 25, assuming
there was no epimerization of this center. Products of this type have
been observed previously.29 However, in those cases there was a
marked preference for the the endocyclic a,B-unsaturated ketone.
The considerable strain of the analogous product in our case,
compound 26, may explain this divergence.

   

+0” " PdClzL ° PdClL
0” PdClng 2
J\J _-.L_. . .H
<——
5 or 1 9 - HPdCll-z H
(B-hydride
elimination)
O
+ 0' 0
2 5
j j \PdCILz (B hydride
elimination)
O O
2 7 2 8

Figure 21. Palladium Catalyzed Cope Rearrangement

31

51.11111].

Thermal rearrangement of the vinylcyclobutanols in hydrocarbon
solvents was next attempted. No reaction was observed for either
isomer in refluxing benzene or toluene; however, a solution of endo
vinylcyclobutanol 5 in refluxing o-xylene yielded, after 48 hours, a 2

1 mixture of cyclohexanone 21 and the previously unobserved
vinyl ketone 29 (see Figure 22). Interestingly, subjecting exo
vinylcyclobutanol 19 to the same conditions gave identical results: a
2 : 1 mixture of 21 and 29. In neither case was the isomeric
vinylcyclobutanol or desired Cope product observed. Previous work
in this area30 has shown that cis 1,2-divinyl cyclobutane systems,
such as 5, generally undergo a [3,3] sigmatropic shift to cyclooctenes,
while the trans isomers, such as 19, rearrange predominantly
through a [1,3] sigmatropic shift to form 4-vinyl cyclohexenes. An
alternative pathway, the retro-ene ring opening,31 is available when
a hydroxyl substituent is present. Also known as a B-hydroxy olefin
cleavage, this reaction is essentially a [1,5] hydrogen shift yielding a
y,8-unsaturated vinyl ketone. Any or all of these processes, as well
as various radical intermediates, might be involved in these
examples . Obviously, either isomer could undergo the [1,3] shift to
eventually form 21 after passing through the enol. Although 5 and
19 are geometrically constrained to pass through, respectively, the
[3,3] and [1,5] rearrangement manifolds, the possibility of an initial
isomerization exists; therefore, all of these pathways must be
considered viable alternatives for both isomers. Additionally, one
final mode of rearrangement might be possible. Assuming the Cope
rearrangement and ketonization of the cyclooctadienol to have taken
place via either 5 or 19, a 1,5 hydrogen shift of the a-hydrogen of
the transcyclooctene product could occur (intramolecular ene
reaction),32 yielding the vinyl ketone 29, or a [1,3] alkyl shift giving
cyclohexanone 21.

32

 

3,3 Cope! 1,5 Bchydroxy
ketonization olefin cleavage
,3 alkyl shift

0 O

1,51ntramolecular . 1 3 h d an shift
ene reaction 0O £9; 0

29

/
/

 

Figure 22. Thermal Solvated Rearrangements of Vinylcyclobutanols.

33

W

One possible explanation for the absence of the expected [3,3]
Cope product or [1,5] retro-ene B-hydroxy olefin cleavage product in
the previous studies is the severity and/or duration of the reaction
conditions. Extended heating in refluxing o-xylene (bp 165 °C) might
allow the undoubtedly thermally labile [1,5] product to rearomatize
to form 29, the trans cyclooctene [3,3] product to rearrange to the
less strained 21, or allow the intramolecular ene reaction to take
place. To circumvent these possibilities, the use a flash thermolysis
system was explored. Minimization of the total contact time of the
substrates with heated surfaces was desired, thereby improving
chances of isolating one or more of these unstable intermediates. A
detailed description of this system can be found in the Experimental
Section. Basically this system consisted of a glass column filled with
Pyrex glass beads and heated with a ceramic jacket. A solution of
the sample was introduced by an addition funnel, carried through
the column in an Argon stream, collected in a dry-ice cooled vessel,
and the condensate analyzed. Note that this was not a Flash Vacuum
Pyrolysis (FVP) system. The results of these experiments are
presented in Table 2.

34

Table 2. Thermolysis Experiments. The product column
indicates the amount of acenaphthalene, vinyl ketone 29, and
cyclohexanone 21 obtained.

Entry Compound AdditionTemp. Starting , Product 8
time hrs ° aterial m s m s
5 2.0 300 10.3 3/3/4

 

 

 

 

 

 

 

 

1

2 5 1.5 300 14.1 2/3/5
3 19 3.0 300 100.0 15/12/18
4 19 1.0 300 100.0 4/6/11
5 19 2.2 300 100.0 13/13/20
6 l 9 2.2 245 100.0 0/12/15
7 21 2.5 300 17.6 0/0/12
8 29 2.0 300 13.7 0/7/0

 

The first two entries show the results of the thermolysis of the
endo vinylcyclobutanol 5. Heating this compound at 300 °C yielded
essentially 3 equal mixture of acenaphthylene, vinyl ketone 29, and
cyclohexanone 21. Entries 3-5 show that the same reaction for exo
vinylcyclobutanol 19 gave virtually the same results. Note that the
mass balance in these and other thermolyses is disappointingly low.
This is probably due to the deposition of intractable polymeric
material at the top of the thermolysis column, this being clearly
visible after the reaction was completed and the apparatus cooled
and dismantled. The manner in which this material is produced is
not known. Entry 6 shows the result of lowering the reaction
temperature. Only 21 and 29 were formed, paralleling the
previously observed result of refluxing o-xylene thermolysis,
indicating that perhaps the pathway for formation of acenaphthylene
may involve a higher energy intermediate or transition state than
that for formation of 21 or 29. Entries 7 and 8 show that 21 and 29
are probably not interconverting to other products during the course

35

of the reaction (although the low mass balances preclude any
definitive conclusions regarding this result).

The similar results obtained for the thermolysis of 5 and 19 in all
our thermolysis studies seem to indicate the existence of some
common intermediate during these transformations. The formation
of acenaphthylene at higher temperatures also needs to be accounted
for. Both of these experimental results can be rationalized by
invoking the intermediacy of a diradical (See Scheme 23).33 Scission
of the cyclobutane bond not only relieves considerable strain, but
also forms a highly stabilized benzyl-allyl diradical. This diradical
could recombine to form an enol which would then ketonize to yield
21. Abstraction of the hydroxyl proton would form the vinyl ketone
29. Finally, a Norrish type II cleavage reaction34 could account for
the formation of acenaphthylene; obviously methyl vinyl ketone
would be a by-product of this process.

36

O

OH OH H
5 or 1 9 1
OH OH
v1.9

1 l 1

0‘0 \

29 21

h dro n
cleavage labgtragion

Figure 23. Diradical Intermediates.

MW

Rationalization of the thermoyses results by postulation of a
diradical intermediate is tempting. Although proving the existence
of such intermediates in these flash thermolyses will be difficult, this
may be possible in the solution thermolyses. Addition of known
radical trapping agents to reaction mixture (such as tributyltin
hydride) may may lead to new products indicative of radical
intermediates. Alternatively, a structural subunit known to give a
characteristic transformation when in proximity to a radical site
might be incorporated into the substrate undergoing pyrolysis. An
example of this approach would be the conversion of the vinyl group
in 5 or 19 to a cyclopropyl group. If a 1,4 diradical species was
formed from these substrates, 3 cyclopropylmethyl radical would
then be present. This would create a cyclobutyl-cyclopropylmethyl-
homoallyl radical manifold, which might give rise to rearranged
products indicative of radical intermediates.

11"Sl'lIl1'

The initial strategy in synthesizing derivatives of the parent
cyclobutane system was to attempt selective suppression of the
various rearrangement pathways available to the intermediate 1,4-
diradical. The first implementation of this idea was to convert both
the exo vinylcyclobutanol 19 and the endo vinylcyclobutanol 5 into
their corresponding acetates, the exo Vinylcyclobutyl acetate 30 and
the endo Vinylcyclobutyl acetate 31 (see Figure 24). With non-
abstractable groups present on the oxygen, we anticipated that upon
thermolysis these derivatives would undergo only the recombination
mode of rearrangement to give the cyclohexyl enol acetate 32.
Accordingly, 30 and 31 were synthesized in 89% and 87% yield by

37

38

acetylation of 19 and 5, respectively. Unfortunately, solution
thermolysis under the standard conditions of refluxing o-xylene for
48 hours of both 30 and 31 gave only recovered starting material,
with no observed 32 or epimerization to the isomeric acetate.
Interestingly, 32 was produced in 41% yield by use of our flash
thermolysis system with 30 at 250 °C. The structure of 32 was
confirmed by examination of the 1H NMR spectrum and by acidic
hydrolysis to the previously observed cyclohexanone 21.

 

02cm3

OH
11» A j” n
5 3 1

Figure 24. Synthesis and Thermolysis of Exo and Endo Vinylclobutyl
Acetates 30 and 31.

The exo methylcyclobutanol 33 was next synthesized in 81% yield
by direct addition of methyllithium to the cyclobutanone 2 (see
Figure 25). With the vinyl group absent, the only mode of
rearrangement for the diradical is the hydrogen abstraction pathway.
Once again, however, thermolysis gave only recovered starting
material and no observed methyl ketone 34.

39

O
0 CH3
IIIIIOH
—> —)(—>
3 4

Figure 25. Synthesis and Thermolysis of Exo Methylcyclobutanol 34.

The next synthetic target was the endo Vinylcyclobutane 35 (see
Figure 26). The proposed approach to this compound involved
reduction of the allylic alcohol 9 by catalytic hydrogenation from the
less. hindered exo face to give primary alcohol 36, followed by
dehydration to give 35. Thermolysis of 35, with only the
recombination mode of rearrangement available, should give the
cyclohexene 37 .

/ °" °“ \ o
——>- ——> —-.
9 36 35 37

Figure 26. Synthetic Approach to Endo Vinylcyclobutane 35.

In the event, catalytic hydrogenation of 9 gave alcohol 36 in
essentially quantitative yield (see Figure 27). Mesylation of 3 6
proceeded in 90% to give 38. Treatment with DBU surprisingly gave
no reaction, even under forcing conditions. Changing the base to
potassium t-butoxide gave roughly equal amounts of the t-butoxy

40

ether 39 and the previously observed ethylidene derivative 3 as a
1:1 mixture (1H NMR) of stereoisomers in 78% yield. In a
modification of this elimination strategy, the xanthate ester 40 was
synthesized in 89% yield by sequential treatment of alcohol 36 with
sodium hydride, carbon disulfide, and methyl iodide. Flash
thermolysis of 40 at 250 °C or in refluxing o-dichlorobenzene
resulted in complete destruction of the starting material with no
observable products. No further attempts to synthesize 35 have
been made.

OH 03020113
m mfl
l +
0C820H3 +>ésK\ mocm'fila

Figure 27. Attempted Synthesis of Endo Vinylcyclobutane 35 .

40

The lack of observed rearrangement products in the solution
thermolyses of the Vinylcyclobutyl acetates 30, 31, and the exo
methylcyclobutanol 33 may be due to a destabilizing influence of the
substituents present in these compounds on the formation of the 1,4-
diradical, relative to the vinylcyclobutanols 19 and 5. The acetoxy
groups are less effective at stabilizing radicals than the hydroxyl and

41

vinyl groups. For instance, an allylic radical is generally estimated to
be around 10 kcal/mole9 more stable than the analogous alkyl
radical. The important structural dependence of this rearrangement
forced consideration of only synthetic targets whose radical
stabilizing characteristics upon thermolysis would closely resemble
that of 19 and 5.

The next synthetic targets were the exo vinyl t-butyldimethylsilyl
ether 41 and the exo phenylcyclobutanol 44 (see Figure 28). The
siloxy group in 41 should have similar radical stabilizing properties
as the hydroxyl group, but will allow only the recombination mode of
rearrangement to the silyl enol ether 43. Likewise, the phenyl group
should approximate the vinyl group in radical stabilizing ability, but
only the hydrogen abstraction mode of rearrangement should be
available, leading to phenyl ketone 44. Synthesis of both targets was
straightforward. Silylation of exo vinylcyclobutanol 19 with t-
butyldimethylsilyl chloride gave the silyl ether 41 in 92% yield.
Addition of phenyllithium to cyclobutanone 2 gave the exo
phenylcyclobutanol 42 in 78% yield. With these two compounds in
hand, examination of their thermolysis behavior was now possible.

Standard thermolysis of 41 gave a 3:1 mixture of cyclohexanone
21 and recovered starting material. Although the expected silyl enol
ether 43 was not observed, it is not unreasonable to assume that 43
was formed, but under the reaction conditions was converted to 21.
These results indicate that selective suppression of the hydrogen
abstraction process is possible, while allowing the recombination
process to occur unimpeded. The recovered starting material,
however, emphasizes the critical structural dependence of this
rearrangement, as both 19 or 5 are completely consumed under
these reaction conditions. Thermolysis of 42 was unfortunately not
as informative, as only recovered starting material was found, with
no evidence of phenyl ketone 44. This result is somewhat
surprising, considering the known radical stabilizing properties of the
phenyl group. One possible explanation for this lack of reactivity is
that the phenyl group is unable to attain a low energy conformation
where the p orbitals present in the aromatic ring can effectively
overlap with the incipient radical orbital.

42

 

 

'oraoMs' o
O _, O
- 43 - 21
o

 

Figure 28. Synthesis and Thermolysis of Exo Vinyl Silyl Ether 41 and
Exo Phenylcyclobutanol 42.

The final structural modification was introduction of a cyclopropyl
group into the latent 1,4-diradical system (see Figure 29). Addition
of cyclopropyl magnesium bromide to cyclobutanone 2 gave the
cyclopropylcyclobutanol 45 in 41% yield, along with recovered
starting material. If thermolysis of this compound forms an
intermediate diradical, products derived from cleavage and
rearrangement of the cyclopropylcarbinyl radical may be observed.
The possibility of formation of the cycloheptanone 46 was of
particular interest. This could arise by rearrangement of the
methylcyclopropyl radical to the homoallyl radical, followed by
capture of the benzylic radical. In addition, formation of cyclopropyl
ketone 47 via the hydrogen abstraction process may also occur. In
the event, thermolysis of 45 primarily recovered starting material

43

and a small amount (<10%) of unidentified side products. No further
attempts to demonstrate the existence of an intermediate diradical
by internal diversion through structural modification have been
conducted.

g M
if 12%?

Figure 29. Synthesis and Thermolysis of Cyclopropylcyclobutanol 45.
I . S 1'

Failure of structural modifications to yield conclusive evidence
regarding the existence of the proposed 1,4-diradical prompted the
development of an alternative approach to capture this elusive
intermediate. Specifically, a hydrogen atom donor, known to react
rapidly with radical species, might intercept the diradical
intermediate and yield products characteristic of that species.
Towards this goal, a number of solution thermolyses were performed

44

under standard reaction conditions with addition of tributyltin
hydride as a hydrogen atom donor. The results of these experiments
summarized in Table 3.

Table 3. Thermolysis of Cyclobutane Derivatives with added
Tributyltin hydride. Products include cyclohexanone 21 (CH),
acenaphthylene (ACE), starting material (SM), and vinyl
ketone 29 (VK). NR indicates no reaction.

 

Time Yield Products

      
 
    

Entry Compound Equiv.

 

   

 

 

 

 

 

 

 

1 . CH/ACE (5:1)

2 l 9 4.6 16.0 64 CH/ACE (6:1)

3 4 1 5.0 16.0 81 CH/ACE (2:1)

4 3 0 4.7 28.5 NR _

5 4 5 5.0 28.5 NR _

6 l 9 5.2 1.0 79 CH/ACE/SM (20:6:1)
7 4 1 6.2 1.0 72 CH/ACE/SM (5:1:1)
8 l 9 0.0 1.0 57 CH/VK/SM (4:1:30)
9 4 2 2.3 1.0 NR ..

 

Entries 1 and 2 show that the thermolysis of exo
vinylcyclobutanol 19 with added tributyltin hydride gives different
product ratios than those obtained without the hydrogen atom donor.
Vinyl ketone 29 is no longer formed, and instead only cyclohexanone
21 and acenaphthylene are observed. This is also the case with the
exo vinyl silyl ether 41 (entry 3). These are the first cases where
acenaphthylene has been observed during the lower temperature
solution thermolyses of our cyclobutane derivatives. Thermolysis of
exo vinyl acetate 30 or cyclopropylcyclobutanol 45 (entries 6 and 7)
under these conditions gave no reaction, identical to their failure to
react in the absence tributyltin hydride. Further experiments with
19 and 41 (entries 6 and 7) show that this alternative reaction

45

pathway occurs at dramatically reduced reaction times. The control
experiment using 19 with no added tributyltin hydride (entry 8)
confirms that these rearrangements are occurring at an accelerated
rate and are giving different product ratios than those previously
observed. Entry 9 shows that the exo phenylcyclobutanol 42 does
not react under these modified rearrangement conditions, paralleling
its' behavior in the absence of tributyltin hydride.

The results of these tributyltin hydride radical trapping
experiments are difficult to interpret. The tributyltin hydride
appears to be accelerating the reaction of 19 and 41 in a manner
slightly different from the previously observed rearrangements, but
a rationalization for this acceleration is not apparent. One aspect of
these results is irrefutable: no products corresponding to a hydrogen
atom trapped intermediate 1,4-diradical has been observed in any of
these reactions. Thus, the goal of proving the intermediacy of the
diradical has not been achieved.

W

This dissertation describes the synthesis of exo- and endo
vinylcyclobutanols 19 and 5, and efforts to effect a
divinylcyclobutane oxy-Cope rearrangement of the latter to generate
a unusually bridged acenaphthylene system. Central to this proposal
was the idea that the strain energy inherent in the four-membered
ring would help to overcome the energy cost of disrupting aromatic
resonance as this reaction proceeded to rearranged products.

Calculations and models supported the expectation that 5 could
achieve the correct geometry for reaction, and that the rearranged
product was thermodynamically more stable. Successful application
of this proposal would be useful both as 3 addition to existing Cope
rearrangement synthetic methodology and as an entry to the study
of novel bridged naphthalenes.

Despite these expectations, no Cope rearrangement products were
isolated or observed under the wide variety of reaction conditions
applied. The key tetrasubstituted cyclobutane bond, with certain
substitution patterns, appears to be susceptible to a number of
alternative transformations, whose activation energies may be lower
than that of the desired Cope rearrangement pathway. The anionic
oxy-Cope gave cyclohexanone 21 by a formal [1,3] shift, which may
proceed by heterolytic fragmentation of the cyclobutane bond to the
benzylic anion followed by Michael reaction. The palladium
catalyzed Cope gave cyclopentanones 25 -28 by migration of the
cyclobutane bond to an electrophilic center. The thermal Cope gave
cyclohexanone 21, vinyl ketone 29, and acenaphthylene, presumably
by homolytic cleavage of the cyclobutane bond to a diradical,
followed by recombination (to give 21), hydrogen abstraction (to
give 29), and Norrish type II cleavage (to give acenaphthylene).

The structural restrictions on homolysis to this presumed
diradical were studied extensively, and appear to be quite severe.
Products characteristic of the diradical appear to be formed only
when the substituents on the key cyclobutane bond are good radical

46

47

stabilizers, although this was not invariably the case. There may also
be a steric and/or stereoelectronic effect on the formation of this
reactive intermediate.

Attempts to prove the existence of the diradical by structural
modification or addition of radical traps were unsuccessful. This was
perhaps not unexpected, considering the undoubtedly short lifetime
of this intermediate. During the course of these investigations 3
mechanistically unusual transformation was uncovered involving
tributyltin hydride; future investigation into this reaction may shed
light on the critical structural dependency on formation of the
diradical during the thermolysis experiments.

Despite the failure to induce the desired Cope rearrangement, the
results of this dissertation should be useful to future investigators in
this field. The divinylcyclobutane Cope rearrangement has been
shown to have limitations under certain substitution patterns, with
diradical formation via homolytic cyclobutane bond scission
appearing to be the primary alternative pathway in the cases
studied. In addition, if the diradical could be efficiently and reliably
formed, it could be used as a reactive intermediate to effect further
synthetic transformations.

EXEERIMENIAL

mm. All reaction sensitive to oxygen or moisture were
performed using oven dried glassware under an argon atmosphere.
1H spectra were obtained on a Varian VXR 300 (300 MHz), Varian
VXR (500 MHz), or Bruker 250 (250 MHz) spectrometer. Chemical
shifts for proton resonances are reported in parts per million (8)
downfield from tetramethylsilane (8 = 0 ppm) or residual chloroform
(8 = 7.24 ppm) as an internal standard. Signal patterns are indicated
as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s, broad
singlet; overlapping m, overlapping multiplet. Coupling constants (J)
are given in hertz. 13C NMR spectra were obtained on a Varian VXR

300 (75 MHz) or Bruker 250 (69.8 MHz). Chemical shifts for carbon
resonances are reported in parts per million (8) downfield from the

deuterated solvent signal (8 = 77.0 ppm). Infrared (IR) spectra were
obtained on a Nicolet PC/IR Fourier transform spectrometer system
equipped with a Nicolet IR/42 optical bench. Mass spectra (M8)
were obtained on a Finnegan 4000 mass spectrometer equipped with
a Incos 4021 data system. Melting points were measured in glass
capillary tubes on a Hoover-Thomas melting point apparatus and are
uncorrected. Thin layer chromatography (TLC) analyses were
performed using Merck aluminum-backed F254 silica gel plates, using
ultraviolet light and either 30% aqueous sulfuric acid or ammonium
molybdate in 10% aqueous sulfuric acid as a visualization reagent.
Flash chromatography was performed using Merck Silica Gel 60
(230-400 mesh, ASTM, column diameter 10-40 mm) according to the
method of Still.35 Elemental analyses were conducted by Spang
Microanalytical Laboratory, Eagle Harbor, MI. All reagents were
obtained from commercial suppliers and used without purification,
unless otherwise indicated. Diethyl ether and tetrahydrofuran were
freshly distilled under nitrogen from sodium/benzophenone ketyl.

48

Tol
hex
diis
argt
hea

49

Toluene, o-xylene, benzene, hexane, methylene chloride,
hexamethylphosphoramide, dimethylformamide, triethylamine,
diisopropylamine, and dimethylsulfoxide were freshly distilled under
argon or nitrogen from calcium hydride. Sodium iodide was dried by
heating in a round bottomed flask (ca. 150 °C, 0.1 Torr) for 4-6 h.

Wanna—(1).. Jud—M h A: To a 500 mL 3-neck

round bottomed flask equipped with a reflux condenser, addition
funnel, Argon inlet, and rubber septa was charged acenaphthylene
(7.00 g, 46.0 mmol), zinc dust (10.10 g, 154.5 mmol), and ether (200
mL). The entire apparatus was suspended approximately 1 cm from
the bottom of a laboratory ultrasonic cleaner (Branson 2200) and
immersed in 0 °C water. Sonication was initiated, and to the agitated
solution was added over 1 hr. 3 solution of trichloroacetylchloride
(17.0 mL, 152.3 mmol) in ether (100 mL). The solution was
sonicated an additional 3 hrs., filtered through a Celite pad, then
washed with 1N HCl, water, sat'd NaHCO3, and brine to give a crude
dark brown oil, which was used directly without further purification
in the next step.

W: A 500 mL 3-neck round bottomed flask was equipped
with a reflux condenser, addition funnel, Argon inlet, and an
ultrasonic processor (S & M, Inc. VC500, 500W, 20 kHz; 40%
continuous output) fitted with a 1/2" extended horn was charged and
the reaction run and worked up as above. Again, the crude product
was used directly for the next step, but a small amount was
chromatographed (2:1 hexanes to ether) to give
dichlorocyclobutanone l, which was crystallized from hexanes to
give off white crystals, mp115 °C: 1H NMR (250 MHz, CDC13) 87.8-7.2
(m, 6 H), 5.51 (d, J = 7.3 Hz, 1 H), 4.91 (d, J = 7.3 Hz, 1 H); 13C NMR
(62.5 MHz, CDC13)8 191.5, 139.3, 138.5, 136.2, 131.8, 128.4, 128.1,
125.3, 124.8, 124.3, 121.1, 87.0, 67.1, 57.9; IR(CH2C12) 1807 cm '1; MS
(EI) m/z (rel. int.) 262 (3), 199 (100), 163 (31), 152 (29).

C3
dichlor

saturate
mmol).
refluxe
solven
ether.
NaHC
temov
gel, 2
acena
white
H), 5
1.83
146 .‘.
120.1
m/z

eth]
(10

of
adc

OVI

St:
at

II

50
W42; To a 0 °C solution of crude

dichlorocyclobutanone 1 (11.4 g 43.4 mmol) in ammonium chloride
saturated methanol (200 mL) was added zinc powder (11.0 g, 168.3
mmol). The solution was stirred 30 min. at 0 °C, 30 min. at 25 °C, and,
refluxed 8 hrs. The solution was filtered through a Celite pad, the
solvent removed in vacuo, and the brownish residue taken up in
ether. The organic phase was washed with 1N HCl, water, sat'd
NaHCO3, and brine, then dried over sodium sulfate. The solvent was
removed in vacuo, and the crude material chromatographed (silica
gel, 2:1 hexanes to ether) to yield cyclobutanone 2 (6.69 g, 84% from
acenaphthylene), which was crystallized from hexanes to give off-
white needles, mp 78 °C: 1H NMR (250 MHz, CDC13) 8 7.8-7.2 (m, 6
H), 5.18 (m, 1 H), 4.25 (m, 1 H), 3.61 (ddd, J = 18.3, 9.5, 3.7 Hz, 1 H),
2.83 (ddd, J = 18.3, 4.4, 3.7 Hz); 13C NMR (75 MHz, CDC13) 8 205.31,
146.23, 139.13, 137.91, 131.91, 128.53, 128.25, 124.09, 123.80,
120.60, 120.15, 71.94, 52.61, 34.63; IR (CH2C12) 1780 cm'l; MS (EI)
m/z (rel. int.) 194 (7), 165 (28), 154 (100).

Ethxlidgng Cyclobutane (3). To a 25 °C solution of
ethyltriphenylphosphonium bromide (6.40 g, 17.2 mmol) in toluene

(10.0 mL) was added 0.91 M potassium t-amyloxide in toluene (19.0
mL, 17.3 mmol). The solution was refluxed 45 min., then a solution
of cyclobutanone 2 (0.50 g, 2.57 mmol) in toluene (15.0 mL) was
added in one portion. The solution was refluxed 1 hr., then cooled
over 15 min. to 25 °C. The solution was washed with water, sat'd
NaHCO3, and brine. The organic phase was dried over sodium
sulfate, then removed in vacuo to give a crude product, which was
chromatographed (silica gel, hexanes) to yield ethylidene cyclobutane
3 as a yellow oil (0.20 g, 37%) in a 1:1 mixture (1H NMR) of
inseparable stereoisomers: 1H NMR (250 MHz, CDC13) 8 7.8-7.2 (m,
12 H), 5.42 (m, 1 H), 5.20 (m, 1 H), 4.88 (m, 1 H), 4.74 (m, 1 H), 4.19
(m, 2 H), 3.26 (m, 2 H), 2.45 (m, 2 H), 1.76 (m, 3 H), 1.41 (m, 3 H); 13C
NMR (75 MHz, CDC13)8 148.78, 147.12, 146.10, 141.06, 139.93,
139.91, 132.17, 132.08, 128.15, 128.00, 127.95, 123.39, 122.83,
122.79, 122.72, 122.68, 122.63, 119.97, 119.11, 119.04, 119.00.

118
13.!

I
'-—- 4‘ r1. -1 (It -__ (I)

51

118.73, 118.69, 118.52, 53.48, 52.34, 40.32, 40.20, 36.95, 34.95,
13.94, 13.28; MS (EI) m/z (rel. int.) 206(6), 191(5), 152(6), 40 (100).

W. To a 25 °C solution of alkenes 3
(124.3 mg, 0.60 mmol) in methylene chloride (2.00 mL) was added

over 1 hr. 3 25 °C solution of metachloroperbenzoic acid (129.0 mg,
0.75 mmol) in methylene chloride (5.00 mL). After addition was
complete, the solution was washed with sat'd sodium bisulfite, sat'd
NaHCO 3, and brine. The organic phase was dried over magnesium
sulfate and the solvent removed in vacuo to yield spiro ethylidene
oxides 4 as a yellow oil (133.6 mg, 99%) in a 10:10:1:1 mixture (1H
NMR) of stereoisomers : 1H NMR (250 MHz, CDC13) 8 7.8-7.2 Hz (m, 6
H), 4.55 (d, J = 6.5 Hz, 1 H), 4.40 (d, J = 6.5 Hz, 1 H), 4.1 (overlapping
m, l H), 2.8 (overlapping m, 2 H), 2.2 (overlapping m, 1 H), 1.38 (d, J
= 5.5 Hz, 3 H), 1.21 (d, J = 5.5, 3 H), 1.15 (d, J = 5.5 Hz, 3 H), 0.77 (d, J
= 5.5 Hz, 3 H); MS (EI) m/z (rel. int.) 222 (8), 207 (2), 193 (1), 178
(17), 165 (100), 152 (64).

WW. To a 25 °C solution of the major

spiro epoxy mesylate isomer 123 (36.0 mg, 0.99 mmol) in acetone
(25.0 mL) was added sodium iodide (2.00 g, 13.34 mmol). The
solution was refluxed 72 hrs., then the solvent removed in vacuo.
The solid residue was taken up in ether, washed with water, and
dried over sodium sulfate. The solvent was removed in vacuo to
yield a crude product which was chromatographed (silica gel, 2:1
hexanes to ether) to yield spiro epoxy iodide 15 (45.0 mg, 13%),
starting spiro epoxy mesylate 123 (38.0 mg, 11%), and endo
vinylcyclobutanol 5 (89.2 mg, 41%) as an off white solid, mp 87 °C:
1H NMR (250 MHz, CDC13) 8 7.8-7.2 (m, 6 H), 5.43 (dd, J = 17.4, 10.7
Hz, 1 H), 4.92 (dd, J = 17.4, 1.2 Hz, 1 H), 4.72 (dd, J = 10.7, 1.2 Hz, 1
H), 4.20 (m, 2 H), 2.63 (ddd, J = 12.7, 9.2, 2.7 Hz, 1 H), 2.42 (br s, 1 H),
2.09 (dd, J = 12.7, 5.2 Hz, 1 H); 13C NMR (62.5 MHz, CDC13) 8 148.7,
143.0, 141.5, 140.2, 131.9, 127.9, 127.8, 123.2, 122.8, 121.4, 118.9,
112.3, 78.3, 58.6, 41.7, 37.1; IR (CH2C12) 3685, 3056, 1605, 1179 cm-

1; M
152

vinyf
reill
chro

cycl
27%

lithi
porl

W35

5 2

;MS (EI) m/z (rel. int.) 222 (3), 205 (1), 193 (17),178 (7),165 (36),
152 (53), 55 (100). W: A solution of endo
vinylcyclobutanol 5 (44.2 mg, 0.20 mmol) in o-xylene (15.0 mL) was
refluxed 48 hrs., the solvent removed, and the residue
chromatographed (silica gel, 2:1 hexanes to ether) to yield
cyclohexanone 21 (18.9 mg, 43%) and vinyl ketone 29 (12.0 mg,
27%).

M. To a 0 °C 1 M solution (5:1 hexanes to ether) of
lithium diisopropylamide (0.30 mL, 0.30 mmol) was added in one
portion a solution of the major isomers of epoxide 4 (50.2 mg, 0.23
mmol) in ether (3.00 mL). The solution was stirred 30 min., then
washed with 1N HCl, water, sat'd NaHCO3, and brine. The organic
phase was dried over magnesium sulfate, and the solvent removed in
vacuo to give a crude product which was chromatographed (silica gel,
methylene chloride) to yield diene 6 as a pale yellow oil (41.7 mg,
83%): 1H NMR (250 MHz, CDC13) 8 7.8-7.3 (m , 6 H), 7.08 (s, 1 H),
5.69 (s, 1 H), 5.61 (s, 1 H), 4.92 (q, I = 8.3 Hz, 1 H), 1.85 (br s, 1 H),
1.49 (d, J = 8.3 Hz, 3 H), 13C NMR (62.5 MHz, CDC13) 8 147.8, 140.8,
139.0, 129.0, 128.2, 127.8, 127.5, 127.0, 125.3, 124.4, 123.8, 112.7,
77.5, 77.0, 76.5, 69.7, 23.0; MS (EI) m/z (rel. int.) 222 (4), 178 (9),
152 (72), 43 (100).

W A solution of diene 6 (15.0 mg.
0.07 mmol) and dimethylacetylene dicarboxylate (0.02 mL, 0.16
mmol) was refluxed 44 hrs. The crude product was

chromatographed (silica gel, 4:1 hexanes to ether) to yield Diels-
Alder cycloadduct 7 (17.3 mg, 70%): 1H NMR (250 MHz, CDC13) 8 7.8-
7.3 (m, 6 H), 5.48 (q, I = 8.3 Hz, 1 H), 4.08 (dd, J = 7.9, 5.0 Hz, 1 H),
3.92 (s, 3 H), 3.63 (s, 3 H), 3.32 (dd, J = 17.5, 7.9 Hz, 1 H), 2.30 (br s, 1
H), 1.44 (d, J = 8.3 Hz, 3 H); MS (EI) m/z (rel. int.) 364 (3), 332 (8),
315 (6), 304 (26), 287 (12), 273 (23), 261 (30), 229 (93), 217 (41),
202 (100).

53

W. To a 25 °C solution of sodium hydride (1.20 g,
48.5 mmol) in benzene (50.0 mL) was added over 25 min. a solution
of triethylphosphonoacetate (10.0 mL, 50.4 mmol) in benzene (25.0
mL). The solution was stirred 20 min., then a 25 °C solution of
cyclobutanone 2 (7.30 g, 37.6 mmol) in benzene (50.0 mL) was
added over 1 hr. The solution was stirred an additional 45 min., then
quenched with 1N HCl. The organic layer was washed with water,
sat'd NaHCO3, and brine, then dried over sodium sulfate. The solvent
was removed in vacuo, and the crude product chromatographed
(silica gel, 2:1 hexanes to ether) to yield vinyl esters 8 as a pale
yellow oil (7.17 g, 72%) in a 10:1 mixture (1H NMR) of stereoisomers.
Rechromatography (silica gel, 4:1 hexanes to ether) allowed for
isolation of each isomer, both a pale yellow oils: W
1H NMR (250 MHz, CDC13)87..8-72(m, 6H), 5.83 (dd,J=4.,6 2.8Hz,
1 H), 4.74 (br s, 1 H), 4.16 (m, 1 H), 4.00 (q,J = 7.0 Hz, 2 H), 3.65
(dddd, J = 18.9, 9.2, 2.8, 1.2 Hz, 1 H), 2.91 (ddd, J = 18.9, 4.6, 4.0 Hz, 1
H), 1.12 (t, J = 7.0 Hz, 3 H); 13C NMR (62.5 MHz, CDC13) 8 166.3, 166.2,
147.4, 144.1, 139.7, 132.0, 128.2, 123.6, 123.1, 119.4, 119.3, 115.1,
59.7, 54.3, 41.6, 39.7, 14.2; IR (CH2C12) 1709, 1265 cm'l; MS (EI) m/z
(rel. int.) 264 (39), 249 (2), 235 (16), 218 (24), 205 (6), 189 (57), 179
(24), 165 (19), 152 (100). W: 1H NMR (250 MHz,
CDC13) 8 7.8-7.2 (m, 6 H), 5.62 (dd, J = 4.3, 2.1 Hz, 1 H), 5.39 (br s, 1
H), 4.27 (q, overlapping m, 3 H), 3.36 (ddt, J = 9.0, 8.0, 2.1 Hz, 1 H),
2.64 (dm, J = 18.0 Hz, 1 H), 1.34 (t, J = 7.0 Hz, 3 H); 13C NMR (62.5
«MHz, CDC13)8 166.0, 165.0, 148.7, 144.5, 139.6, 132.0, 128.4, 127.8,
123.5, 123.1, 121.9, 118.8, 114.1, 59.8, 55.4, 41.2, 38.8, 14.4; IR
(CH2C12) 1711, 1201, 1097, 787 cm'l; MS (EI) m/z (rel. int.) 264 (30),
249 (l), 235 (10), 218 (16), 205 (4), 189 (34), 179 (12), 165 (27),
152 (100).

MW. To a 0 °C 1N solution of diisobutyl
aluminum hydride in hexane (15.0 mL, 15.0 mmol) was added over

30 min. a 25 °C solution of major vinyl ester isomer 83 (3.00 g, 11.4
mmol) in ether (25.0 mL). The solution was stirred 30 min. at 0 °C,
then 20 hrs at 25 °C. The reaction was quenched with 1N HCl, and

54

the organic phase washed with water, sat'd NaHCO3, and brine, then
dried over sodium sulfate. The solvent was removed in vacuo, and
the crude product chromatographed (silica gel, 2:1 hexanes to other)
to yield unreacted vinyl ester 83 (0.97 g, 32%) and allylic alcohol 9
(1.54 g, 61%), which was crystallized from hexanes to give off-white
needles, mp 75-76 °C: 1H NMR (250 MHz, CDC13) 8 7.8-7.2 (m, 6 H),
5.41 (m, l H), 4.62 (br s, 1 H), 4.05 (m, 1 H), 3.67 (t, J = 5.5 Hz, 2 H),
3.17 (ddt, J = 16.5, 9.5, 1.4 Hz, 1 H), 2.37 (ddt, J = 16.5, 5.8, 3.1 Hz, 1
H), 1.82 (br s, 1 H); 13C NMR (62.5 MHz, CDC13)8148.1, 144.9, 139.7,
131.9, 128.1, 128.0, 123.0, 122.9, 122.5, 119.5, 119.1, 118.9, 59.2,
53.4, 40.5, 35.2; IR (CH2C12) 3605, 3055, 2927, 2876, 1603 cm‘l; MS
(EI) m/z (rel. int.) 222 (18), 203 (50), 191 (26), 178 (33), 165 (20),
152 (100).

W. To a 25 °C solution of allylic alcohol
9 (876 mg, 3.94 mmol) in methylene chloride (10.0 mL) was added

over 30 min. a 25 °C solution of metachloroperbenzoic acid (880 mg,
5.11 mmol) in methylene chloride (15.0 mL). The solution was
stirred 5 min., then washed with sat'd sodium bisulfite and brine,
and the organic phase dried over sodium sulfate. The solvent was
removed in vacuo to yield spiro epoxy alcohol 10 (940 mg, 99%) as a
2:1 mixture (1H NMR) of stereoisomers. Chromatography (silica gel,
2:1 ether to hexanes) yielded both isomers as off white pastes: Major
W: 1H NMR (250 MHz, CDC13) 8 7.8-7.2 (m, 6 H), 4.47 (br
d, J = 7.0 Hz, 1 H), 4.21 (m, 1 H), 3.40 (br d, J = 12.8 Hz, 1 H), 3.10 (m,
l H), 2.95 (m, 2 H), 2.24 (ddd, J = 14.0, 4.0, 1.5 Hz, 1 H), 2.10 (br s, 1
H); 13C NMR (62.5 MHz, CDC13)8 147.1, 143.2, 143.1, 131.8, 128.1,
128.0, 123.5, 123.3, 119.7, 119.6, 67.7, 61.2, 58.6, 54.13,. 37.7, 34.3; IR
(CH2C12) 3601, 3055,2938,1605,1493 cm'l; MS (EI) m/z (rel. int.)
238(10), 219(3), 207(8), 191(5), 178(27), 165(85),152(100); Minor,
13.521119141111111 1H NMR (250 MHz, CDC13)8 7..8-72 (m, 6 H), 4.50 (d, J
= 5.8 Hz, 1 H), 3.98 (dt, J = 8.8, 5.8 Hz, 1 H), 3.75 (dd, J = 12.2, 3.5 Hz,
1 H), 3.49 (dd, J = 12.2, 5.2 Hz, 1 H), 3.25 (dd, J = 5.2, 3.5 Hz, 1 H),
2.97 (ddd, J = 14.0, 9.0, 1.5 Hz, 1 H), 2.13 (dd, J = 14.0, 4.9 Hz, 1 H),
2.37 (br s, 1 H); 13C NMR (62.5 MHz, CDC13) 8 148.3, 141.7, 140.0,

131
37.

of

ch
an

“’1

ll

\. 4.1. (. f1. .

55

132.1, 128.0, 127.9, 123.4, 123.1, 121.4, 118.6, 64.1, 61.6, 61.2, 53.1,
37.7, 35.5; IR (CH2C12) 3698, 3601, 3057, 2940, 1604 cm'l; MS (EI)
m/z (rel. int.) 238(23), 219(7), 207(27), 178(33), 165(93), 152(100).

WM. To a 0 °C solution of a 2:1 mixture
of epoxy alcohols 103/10b (529 mg, 2.21 mmol) in methylene

chloride (10.0 mL) was added triethylamine (0.45 mL, 3.23 mmol)
and methanesulfonyl chloride (0.20 mL, 2.58 mmol). The solution
was stirred 30 min., then quenched with 1N HCl. The organic phase
was washed with water, sat'd NaHCO3, and brine, then dried over
sodium sulfate. The solvent was removed in vacuo to yield spiro
epoxy mesylates 12 (689 mg, 98%) as a 2:1 mixture (1H NMR) of
stereoisomers. Chromatography (silica gel, 2:1 ether to hexanes)
yielded both isomers as unstable pale yellow oils which were used

immediately in subsequent steps: W: 1H NMR (250
MHz, CDC13) 8 7.8-7.2 (m, 6 H), 4.46 (d, J = 7.0 Hz, 1 H), 4.19 (m, 1 H),

3.89 (dd, J = 11.9, 3.7 Hz, 1 H), 3.68 (dd, J = 11.9, 7.0 Hz, 1 H), 3.01
(m, 2 H), 2.60 (s, 3 H), 2.22 (ddd, J = 13.9, 3.7, 1.5 Hz, 1 H); 13C NMR
(62.5 MHz, CDC13)8 146.6, 142.6, 139.4, 131.9, 128.1, 123.8, 123.5,
120.0, 119.6, 689, 68.,1 67.,7 54.,8 53.,9 376, 33.9, IR (CH2C12) 3059,
1604, 1361, 1178, 956 cm'l; MS (EI) m/z (rel. int.) 316 (6), 219 (3),
207 (3), 191 (9), 178 (35), 165 (100), 152 (88). W:
1H NMR (250 MHz, CDC13)87.8—7.,2(m 6H), 4.,60(brd J=5.8 Hz 1
H), 4.39.(dd, J = 11.9, 4.0 Hz, 1_ H), 4.06 (m, 2 H), 3.45 (dd, J =4 6.4,.4,3
Hz, 1 H), 3.04 (m, '1 H), 3.02 (overlapping s, 3 ,H), 2.19 (ddd,_J = 14.0,
5.,2 1.2 Hz, 1 H); 13C NMR (62.5 MHz, CDC13)8 147.8"1411.,2 139.8,
132.,0 1280, 123.,6 123.,2 121.,5 1187, 69.,0 57.5 52.,9 37.6, 37.,5
34.9.

W11. indium—Wilde; To a 25 °C
solution of naphthalene (2.05 g, 16.0 mmol) in tetrahydrofuran (50.0
mL) was added sodium metal (0.34 g, ' 14.8 mmol). The solution
turned dark green after 20 min., and was stirred a total of 2 hrs.
before use in the next step.

R;
(1.10
soluti
mmol
min.,
The
with
sulfa
ehrm
cyclc
(m, 1
H2.
11).
(rel.

(12‘
mn
hrs

.5,?

56

Reduction; To the 25 °C 0.30 M solution of sodium naphthalide
(1.10 mL, 0.33 mmol) prepared above was added over 5 min. a 25 °C
solution of major spiro epoxy mesylate isomer 123 (16.6 mg, 0.05
mmol) in tetrahydrofuran (5.00 mL). The solution was stirred 2
min., then quenched with sat'd aqueous ammonium chloride solution.
The organic phase was separated, and the aqueous phase extracted
with ether. The combined organic phases were dried over sodium
sulfate, the solvent removed in vacuo, and the crude product
chromatographed (silica gel, 2:1 hexanes to ether) to yield spiro
cyclopropanol 13 (4.9 mg, 42%): 1H NMR (250 MHz, CDC13) 8 7.8-7.2
(m, 6 H), 4.30 (m, 1 H), 4.02 (d, J = 5.8 Hz, 1 H), 3.53 (dd, J = 6.9, 3.4
Hz, 1 H), 2.97 (dd, J = 12.2, 9.6 Hz, 1 H), 1.87 (dd, J = 12.2, 4.4 Hz, 1
H), 0.76 (t, 6.9 Hz, 1 H), 0.09 (dd, J = 6.9, 3.4 Hz, 1 H); MS (EI) m/z
(rel. int.) 222 (8), 203 (3), 193 (11), 178 (20), 165 (26), 152 (100).

W- To a 25 °C 093 M solution

(1:1 methanol to water) of potassium hydroxide (2.00 mL, 1.86
mmol) was added cyclopropanol 13 (17.6 mg, 0.079 mmol). After 2
hrs., no reaction was observable by TLC, so an additional 2.0 mLs of
methanol was added to help increase solubility. After 6 hrs., there
was still no observable reaction, and 2.0 mLs of tetrahydrofuran was
added. The reaction was stirred an additional 14 hrs., then refluxed
8 hrs. The solution was cooled and poured into ether, then washed
with 1N HCl, water, sat'd NaHCO3, and brine. The solvent was dried
over sodium sulfate, then removed in vacuo to give a crude product
which was chromatographed (silica gel, 2:1 ether to hexanes) to yield
geminal methyl aldehyde 14 (6.4 mg, 36%): 1H NMR (250 MHz,
CDC13) 8 9.40 (s, 1 H), 7.8-7.2 (m, 6 H), 4.47 (d, J = 7.9 Hz, 1 H), 4.08
(m, 1 H), 3.05 (ddd, J = 13.3, 10.8, 0.8 Hz, 1 H), 1.66 (dd, J = 13.3, 10.8
Hz, 1 H), 0.88 (s, 3 H); MS (EI) m/z (rel. int.) 222(5), 193(4), 178(9),
165(38), 152(100).

WM. To a 25 °C solution of magnesium
tumings (1.70 g, 70.0 mmol) in tetrahydrofuran (5.0 mL) was added

over
tetr:
hr.,
imc
25

tetr
stir
org
iii
the

57

over 1 hr. 3 25 °C solution of vinyl bromide (5.00 mL, 70.9 mmol) in
tetrahydrofuran (45.0 mL). The solution was stirred an additional 1
hr., then 5.00 mL (1.42 M, 7.09 mmol) was transferred by syringe
into a separate reaction vessel. The solution was cooled to 0 °C, and a
25 °C solution of cyclobutanone 2 (840 mg, 4.32 mmol) in
tetrahydrofuran (20.0 mL) was added over 50 min. The solution was
stirred an additional 20 min., then quenched with 1N HCl. The
organic phase was washed with water, sat'd NaHCO3, and brine, then
dried over sodium sulfate. The solvent was removed in vacuo, and
the crude product chromatographed (silica gel, methylene chloride)
to yield exo vinylcyclobutanol 15 (629 mg, 67 %), which was
crystallized from hexanes to give off-white needles, mp: 82-83 °C:
1H NMR (250 MHz, CDC13) 8 7.8-7.2 (m, 6 H), 6.37 (d, J = 17.7, 10.4 Hz,
1 H), 5.47 (d, J =17.7 Hz, 1 H), 5.23 (d, 10.4 Hz, 1 H), 4.41 (br (1, J = 6.1
Hz, 1 H), 3.84 (dt, J = 8.5, 6.1 Hz, 1 H), 2.97 (ddd, J = 12.8, 8.5, 2.4 Hz,
1 H), 1.96 (br s, 1 1H), 1.88 (dd, 12.8, 6.1 Hz, 1 H); 13C NMR (62.5 MHz,
CDC13)8 149.6, 143.0, 141.4, 140.6, 132.1, 127.9, 127.7, 123.7, 122.5,
122.2, 118.4, 111.3, 73.2, 57.4, 43.5, 34.9; IR (CH2C12) 3572, 3053,
1604, 1363, 1221, 1009 cm-1; MS (EI) m/z (rel. int.) 222 (6), 167
(15) 152 (100). W: A solution of exo vinylcyclobutanol 19
(0.296 g, 1.33 mmol) in o-xylene (20.0 mL) was refluxed 48 hrs., the
solvent removed, and the residue chromatographed (silica gel, 2:1
hexanes to ether) to yield cyclohexanone 21 (0.135 g, 46%) and vinyl
ketone 29 (0.075 g, 25%).

W. To a -15 °C solution of potassium hydride
(1.67 g, 40.00 mmol) in tetrahydrofuran (10.0 mL) was added

hexamethylphosphoramide (8.00 mL, 46.00 mmol) and exo
vinylcyclobutanol 19 (197 mg, 0.89 mmol). The solution was stirred
1 hr. at -15 °C, 1 hr. at 0 °C, and 30 min at 25 °C, then poured into a 0
°C solution of a 1:1 mixture of aqueous acetic acid and pentane. The
aqueous layer was extracted with pentane, and the combined organic
layers washed with water, sat'd NaHCO3, and brine. The organic
phase was dried over sodium sulfate, then the solvent removed in
vacuo to yield a crude product which was chromatographed (silica

gel,

whicl
mp 1
11), 3
Hz, ‘.
(62.5
43.0.

(131)

eyc‘.
ml.‘
oxit
was
phe
V at
he:
86‘

H2

1.1

r--)

. 1‘" n.) f"

58

gel, methylene Ochloride) to yield cyclohexanone 21 (111 mg, 56%),
which was crystallized from hexanes to give clear colorless needles,
mp 113 °C: 1H NMR (250 MHz, CDC13) 8 7.8-7.2 (m, 6 H), 4.04 (m, 1
H), 3.91 (m, 1 H), 2.91 (dd, J = 15.6, 6.4 Hz, 1 H), 2.66 (dd, J = 15.6, 7.0
Hz, 1 H), 2.5-2.3 (m, 1 H), 2.3-2.1 (m, 1 H), 2.1-1.9 (m, 2 H); 13C NMR
(62.5 MHZ, CDC13)8 212.1, 131.3, 128.2, 123.2, 123.1, 119.1, 119.0,
43.0, 41.8, 40.9, 36.9, 26.5; IR (CH2C12) 3055, 1715, 1605, cm'l; MS
(EI) m/z (rel. int.) 222 (40), 193 (3), 179 (18), 165 (100), 152 (20).

Wane—12.3.3.1. To a solution of
cyclohexanone 21 (12.6 mg, 0.06 mmol) in dimethylformamide (1.00

mL) was added triethylamine (0.05 mL, 0.36 mmol) and deuterium
oxide (0.10 mL, 5.53 mmol). The solution was refluxed 24 hrs., then
washed with l N HCl, water, sat'd NaHCO3, and brine. The organic
phase was dried over sodium sulfate, and the solvent removed in
vacuo and the crude product chromatographed (silica gel, 2:1
hexanes to ether) to yield tetradeuteriocyclohexanone 233 (11.0 mg,
86%): 1H NMR (250 MHz, CDC13) 8 7.8-7.2 (m, 6 H), 4.07 (m, 1 H),
3.96 (m, 1 H), 2.42 (dd, J = 14.1, 5.6 Hz, 1 H), 2.03 (dd, J = 14.1, 7.0
Hz, 1 H); MS (EI) m/z (rel. int.) 226(92), 181(31), 165(100), 152(32).

W. To a 25 °C solution of cyclohexanone 21 (1.30 g,
4.50 mmol) in methylene chloride (20.0 mL) was added dithioethane
(1.50 mL, 17.2 mmol) and boron trifluoride etherate (0.50 mL, 4.07
mmol). The solution was stirred 20 min., then quenched with water.
The organic layer was separated and dried over sodium sulfate, then
the solvent was removed in vacuo to give a crude product.
Chromatography (silica gel, 1:1 hexanes to ether) yielded thioketal
24 (1.26 g, 94%) as a yellow oil: 2 H NMR (250 MHz,, CDC13) 8 7.8-7.2
(m, 6 H), 3.68 (m, 1 H), 3.53 (m, 1 H), 3.15 (m, 4 H), 2.39 (ddd, J =
13.6, 6.0, 0.9 Hz, 1 H), 2.15 (m, 2 H), 1.95 (m, 2 H), 1.71 (dd, J = 13.6,
10.7 Hz, 1 H); MS (EI) m/z (rel. int.) 298 (25), 281 (3), 269 (5), 237
(7), 205 (100), 165 (77), 152 (56).

Vin)
mL)

pad
ethe

V111!
C111
6X1

59

W. To a 25 °C solution of endo
vinylcyclobutanol 5 (20.3 mg, 0.09 mmol) in tetrahydrofuran (3.00

mL) was added bis(acetonitrile) palladium dichloride (2.6 mg, 0.01
mmol). The reaction was stirred for 24 hrs., filtered through a Celite
pad, and the residue chromatographed (silica gel, 1:1 hexanes to
ether) to give a mixture of cyclopentanes 25-28 (12.3 mg, 61%) as a

l:1:l4:4 mixture (1H ' NMR). Similar treatment of exo
vinylcyclobutanol 19 gave a similar mixture (1:7:22z3). Repeated
chromatography allowed for isolation of the

exomethylcyclopentanone 27 and for partial spectral assignment of

26-28. W: 1H NMR (250 MHz,
CDC13) 8 7.8-7.2 (m, 6 H), 6.16 (d, J = 1 Hz, 1 H), 5.78 (d, J = 1 Hz, 1 H),

4.88 (m, 1 H), 4.30 (m, l H), 3.13 (dd, J = 19.2, 9.6 Hz, 1 H), 2.67 (dd, J
= 19.2, 4.4 Hz, 1 H); WM: 1H NMR (250 MHz,
CDC13) 8 7.8-7.2 (m, 6 H), 4.71 (m, l H), 3.21 (dd, J = 18.0, 7.6 Hz, 1 H),
2.71 (dd, J = 18.0, 5.8 Hz, 1 H), 2.08 (d, J = 2.4 Hz, 3 H); w
W: 1H NMR (250 MHz, CDC13) 8 7.8-7.2 (m,
6 H), 4.17 (m, 1 H), 3.68 (t, J = 8.4 Hz, 1 H), 2.86 (dd, J = 18.8, 10.5 Hz,
1 H), 2.56 (ddd, J = 18.8, 5.5, 1.8 Hz, 1 H), 2.06 (m, 1 H), 1.25 (d, J =
7.3 Hz, 3 H). 13C NMR (75 MHz, CDC13) 8 219.39, 147.69, 147.64,
137.53, 131.80, 128.34, 128.19, 123.41, 123.35, 119.64, 118.92,
52.85, 50.03, 42.36, 42.08, 14.26; WM:
1 H NNIR (250 MHz, CDC13) CI 7.8-7.2 (m, 6 H), 4.6 (m, l H), 1.10 (d, J =
7.3 Hz, 3 H).

W. A solution of endo vinylcyclobutanol 5
(44.2 mg, 0.20 mmol) in o-xylene (15.0 mL) was refluxed 48 hrs, the

solvent removed, and the residue chromatographed (silica gel, 2:1
ether to hexanes) to yield cyclohexanone 21 (18.9 mg, 43%) and
vinyl ketone 29 (12.0 mg, 27%) as a colorless oil: 1H NMR (250 MHz,
CDC13) 8 7.8-7.2 (m, 6 H), 6.37 (dd, J = 17.7, 10.2 Hz, ‘1 H), 6.17 (d, J =
17.7 Hz, 1 H), 5.80 (d, J =10.2 Hz, 1 H), 4.15 (m, 1 H), 3.69 (dd, J =
17.4, 8.1 Hz, 1 H), 3.13 (dd, J: 17.4, 5.2 Hz, 1 H), 2.89 (m, 2 H); 13C
NMR (250 MHz, CDC13)8 199.6, 144.0, 138.4, 136.8, 128.5, 128.0,
127.8, 123.1, 122.4, 119.4, 118.9, 114.7, 46.7, 38.4, 38.3.

60

Wit—£2111. To a 25 °C solution of exo
vinylcyclobutanol 19 (84.0 mg, 11.3 mmol) in benzene (2.00 mL)

was added triethylamine (0.15 mL, 1.08 mmol), acetic anhydride
(7.00 mL, 74.0 mmol), and a few crystals of dimethylaminopyridine.
The solution was stirred 3 hrs., then washed with 10% HCl, water,
sat'd NaHCO3, and brine. The organic phase was dried over sodium
sulfate, then removed in vacuo to give a crude product, which was
chromatographed (silica gel, 2:1 ether to hexanes) to yield exo
Vinylcyclobutyl acetate 30 (89.3 mg, 89%) as a yellow oil: 1H NMR
(250 MHz, CDC13) 8 7.8-7.2 (m, 6 H), 6.40 (dd, J = 17.4, 10.7 Hz, 1 H),
5.38 (d, J = 17.4 Hz, 1 H), 5.25 (d, J = 10.7 Hz, 1 H), 4.53 (dd, J = 5.5,
2.4 Hz, 1 H), 3.77 (m, l H), 2.89 (ddd, J = 12.8, 8.4, 3.1 Hz, 1 H), 2.04
(dd, J = 12.8, 7.3 Hz, 1 H), 1.74 (s, 3 H); 13C NMR (250 MHz, CDC13) 8
169.9, 148.8, 142.2, 140.8, 132.3, 127.9, 127.7, 123.7, 122.9, 122.8,
118.2, 113.6, 79.5, 55.8, 41.7, 37.3, 21.2; IR (CH2C12) 1738, 1368,
1252, 1223, 824, 789 cm‘l; MS (EI) m/z (rel. int.) 264 (2), 222 (4),
193 (3), 178 (l), 165 (18), 152 (100). 11111311911515: A solution of exo
Vinylcyclobutyl acetate 30 (0.023 g, 0.09 mmol) in o-xylene (15.0
mL) was refluxed 48 hrs. and the solvent removed. The residue was
chromatographed (silica gel, 2:1 hexanes to ether) to yield only
recovered starting material.

Wan—(3.1).. To a 25 °C solution of
endo vinylcyclobutanol 5 (11.8 mg, 0.05 mmol) in benzene (2.00 mL)

was added triethylamine (0.02 mL, 0.14 mmol), acetic anhydride
(1.00 mL, 10.6 mmol), and a few crystals of dimethylaminopyridine.
The solution was stirred 2.5 hrs., then washed with 5% HCl, water,
sat'd NaHCO3, and brine. The solvent was dried over sodium sulfate,
then removed in vacuo to yield a crude product which was
chromatographed (silica gel, 2:1 ether to hexanes) to yield endo
Vinylcyclobutyl acetate 31 (12.0 mg, 87%): 1H NMR (250 MHz, CDC13)
8 7.8-7.2 (m, 6 H), 5.52 (dd, J = 17.4, 11.0 Hz, 1 H), 4.64 (d, J = 11.0
Hz, 1 H), 4.57 (d, J = 17.4 Hz, 1 H), 4.49 (d, J = 7.0, l H), 4.11 (m, l H),

2.96

ace:
4%

(sill
maz

of
Th
wi‘.

Th

51

61

2.96 (ddd, J = 13.7, 10.1, 1.8 Hz, 1 H), 2.29 (ddd, J = 13.7, 4.6, 1.2 Hz,
1 H), 2.10 (s, 3 H). W: A solution of endo Vinylcyclobutyl
acetate 31 (0.012 g, 0.05 mmol) in o-xylene (15.0 mL) was refluxed
48 hrs. and the solvent removed. The residue was chromatographed
(silica gel, 2:1 hexanes to ether) to yield only recovered starting
material.

WM. Mormons}: The results

of the flash thermolysis experiments are tabulated in Table 2,
Thermolysis Experiments. A representative experimental procedure
will be outlined for the thermolysis of exo vinylcylobutyl acetate 31:
The flash thermolysis system used consisted of a 125 mL pressure
equalizing addition funnel, which was placed above a glass column
filled with glass beads. The column was heated to the appropriate
temperature by use of an external ceramic jacket, and the
temperature monitored by a thermocouple placed between the jacket
and the column. The bottom of the column was attached to a 250 mL
round bottomed flask, which was partially filled with
tetrahydrofuran cooled to -78 °C in order to trap the effluent. An
argon stream was used to carry the solution through the system. A
solution of the sample to be thermolyzed in 50.0 mL of
tetrahydrofuran was added over a period of 1-3 hrs. The solvent
was then removed in vacuo and the condensate analyzed. W
W: A solution of exo Vinylcyclobutyl acetate 30 (77 .0
mg, 0.292 mmol) in tetrahydrofuran (50.0 mL) was thermolyzed
using the flash thermolysis system outlined above. Addition time
was 1 hr., and the column temperature was 250 °C. Removal of the
solvent and chromatography (silica gel, 2:1 hexanes to ether) of the
residue yielded recovered starting material (10.0 mg, 13%) and
cyclohexyl enol acetate 32 (31.2 mg, 41%): 1H NMR (250 MHz, CDC13)
8 7.8-7.2 (m, 6 H), 6.45 (t, J = 6.6 Hz, 1 H), 4.01 (q, J = 7.2 Hz, 1 H),
3.83 (q, J = 5.9, 1 H), 2.78 (m, 2 H), 2.30 (m, 2 H), 2.01 (s, 3 H); MS(EI)
m/z (rel.int.) 264(8), 222(7), 193(2), 178(2), 164(14), 152(100).

l4:

(3(
re:
yi:

62
W. To a 25 °C solution of 1.50 M

methyllithium (2.00 mL, 3.00 mmol) in hexanes was added over 8.5
min. a solution of cyclobutanone 2 (0.130 g, 0.67 mmol) in ether
(10.0 mL). The solution was stirred 10 additional minutes, then
quenched with water. The organic phase was washed with water,
the aqueous phase back-extracted with ether, and the combined
organic phases combined and dried over sodium sulfate. The solvent
was removed in vacuo and the crude product chromatographed
(silica gel, methylene chloride) to yield exo methylcyclobutanol 33
(0.115 g, 81%), which was crystallized from hexanes to give white
needles, mp 115 °C: 1H NMR (250 MHz, CDC13) 8 7.8-7.2 (m, 6 H), 4.12
(m, 1 H), 3.63 (m, 1 H), 2.60 (m, 1 H), 1.80 (br s, 1 H), 1.55 (m,
overlapping s, 4 H); 13C NMR (75 MHz, CDC13) 8 150.01, 142.06,
140.55, 132.32, 128.04, 127.82, 123.78, 122.58, 122.25, 118.44,
71.40, 58.95, 45.70, 34.75, 28.92; IR(CH2C12) 3574, 3053, 2974, 2932,
1604 cm'l; MS(EI) m/z (rel.int.) 210(17), 167(27), 152(100).
Thermolysis: A solution of exo methylcyclobutanol 33 in o-xylene
(20.0 mL) was refluxed 48 hrs. and the solvent removed. The
residue was chromatographed (silica gel, 2:1 hexanes to ether) to
yield only recovered starting material.

W. To a 25 °C solution of allylic alcohol 9
(0.100 g, 0.45 mmol) in 95% ethanol (20.0 mL) was added 10%

palladium on charcoal (0.02 g). The solution was stirred under a
hydrogen atmosphere for four hours, then filtered and the solvent
‘ removed to yield primary alcohol 36 (0.109 g, 100%) as a pale
yellow oil: 1H NMR (250 MHz, CDC13) 8 7.8—7.2 (m, 6 H), 4.22 (m, 1 H),
3.97 (m, 1 H), 3.31 (t, 2 H), 2.91 (m, 1 H), 2.70 (m, l H), 2.42 (br s, 1
H), 1.53 (m, 1 H), 1.40 (m, 1 H), 1.01 (m, 1 H); 13C NMR (75 MHz,
CDC13)8 150.60, 144.97, 140.97, 132.05, 127.80, 127.54, 122.71,
122.32, 121.10, 117.89, 60.63, 47.55, 40.83, 35.85, 34.08, 32.57;
IR(CH2C12) 3617, 3055, 2968, 2934, 1603, 1366, 1046 cm'l; MS(EI)
m/z (rel.int.) 224(5), 208 (1), 189(2), 178(5), 165(10), 152(100).

36

triei
(0.3
will
ove
mes

ove
.\'.\‘
127
33.
MS

Art-In”

63

W. To a 25 °C solution of primary alcohol
36 (0.745 g, 3.33 mmol) in methylene chloride (25.0 mL) was added

triethylamine (0.70 mL, 5.02 mmol) and methanesulfonyl chloride
(0.30 mL, 3.58 mmol). The solution was stirred 48 hrs., then washed
with 10% BC], water, sat'd NaHCOg, and brine. The solvent was dried
over sodium sulfate, then removed in vacuo to yield primary
mesylate 38 (0.901 g, 90%) as a yellow oil: 1H NMR (250 MHz, CDC13)
8 7.8-7.2 (m, 6 H), 4.30 (m, 1 H), 4.02 (m, 1 H), 3.00 (m, 3 H), 2.83 (m,
overlapping s, 4 H), 1.74 (m, 1 H), 1.41 (m, 1 H), 1.19 (m,1 H); 13C
NMR (75 MHz, CDC13)8 150.06, 144.15, 140.67, 131.90, 127.77,
127.44, 122.81, 122.28, 120.96, 117.96, 68.13, 47.01, 40.50, 36.78,
33.59, 31.97; IR(CH2C12) 3055, 1358, 1337, 1177, 972, 943 cm'l;
MS(EI) m/z (rel.int.) 302(1), 205(1), 191(2), 178(5), 165(11),
152(100).

W321. To a 25 °C solution of
primary mesylate 38 (37.0 mg, 0.12 mmol) in DMSO (10.0 mL) was

added potassium t-butoxide (20.0 mg, 0.19 mmol). The solution was
refluxed for 48 hrs., quenched with water, then extracted with ether.
The organic phase was dried over sodium sulfate, then removed in
vacuo to give crude product. This was chromatographed (silica gel,
2:1 hexanes to ether) to yield ethylidene cyclobutanes 3 (9.2 mg,
37%) as a 1:1 mixture of stereoisomers (1H NMR) and
(cyclobutyl)ethyl t-butyl ether 39 (14.1 mg, 41%): 1H NMR (250
MHz, CDC13) 8 7.8-7.2 (m, 6 H), 4.27 (m, J = 1 H), 4.02 (m, 1 H), 3.11 (t,
J = 7.3, 2 H), 2.99 (m, 1 H), 2.69 (m, 1 H), 2.00 (br s, 1 H), 1.72 (m, 1
H), 1.36 (m, 1 H), 1.0 (m, overlapping s, 10 H).

W. To a 25 °C solution of sodium hydride
(14.5 mg, 0.61 mmol) in ether (10.0 mL) was added a solution of

primary alcohol 36 (83.0 mg, 0.37 mmol) in ether (8.00 mL) in one
portion. The solution was refluxed 8.5 hrs., then a solution of carbon
disulfide (2.00 mL, 3.33 mmol) in ether (10.0 mL) was added in one
portion. The solution was stirred 2.5 hrs., then a 0.32 M solution of

64

methyl iodide (1.00 mL, 0.32 mmol) in ether was added in one
portion. The solution was refluxed 11 hrs., then quenched with
water and extracted with ether. The organic phase was dried over
sodium sulfate, the removed in vacuo to yield xanthate ester 40
(116.6 mg, 96%): 1H NMR (250 MHz, CDC13) 8 7.8-7.2 (m, 6 H), 4.42 (t,
2 H), 4.29 (m,1 H), 4.05 (m, 1 H), 2.98 (m, 1 H), 2.76 (m, 1 H), 2.45 (s,
3 H), 1.80 (m, 1 H), 1.3 (m, 2 H); MS(EI) m/z (rel.int.) 314(2), 267(2),
207(4), 191(3), 178(6), 165(16), 152(100).

WM. To a 25 °c
solution of exo vinylcyclobutanol 19 (0.254 g, 1.142 mmol) in
dimethylformamide (50.0 mL) was added imidizole (0.700 g, 10.28
mmol) and t-butyldimethylsilyl chloride (1.700 g, 11.28 mmol). The
reaction was stirred 96 hrs., then quenched with sat'd NH4C1. The
organic phase was separated and washed with 1N HCl, water, sat'd
NaHCOg, and brine, then dried over sodium sulfate. The solvent was
removed in vacuo, and the crude product chromatographed (silica
gel, 2:1 hexanes to ether) to yield exovinyl t-butyldimethylsilyl ether
41 (0.197 g, 51%) as a pale yellow oil: 1H NMR (300 MHz, CDC13) 8
7.8-7.2 (m, 6 H), 6.36 (dd, J = 17.4, 10.8 Hz, 1 H), 5.45 (d, J = 17.4 Hz,
1 H), 5.20 (d, J = 10.8 Hz, 1 H), 4.28 (d, J = 2.7 Hz, 1 H), 3.77 (dt, J =
8.4, 6.0 Hz, 1 H), 2.96 (ddd, J = 12.3, 8.4, 2.7 Hz, 1 H), 2.00 (dd, J =
12.3, 6.0 Hz, 1 H), 0.64 (s, 9 H), -0.12 (s, 3 H), -0.57 (s, 3 H); 13C NMR
(75 MHz, CDC13)8 149.85, 145.38, 143.19, 140.90, 132.10, 127.67,
127.41, 123.24, 122.90, 122.61, 117.76, 110.70, 58.34, 42.44, 35.83,
25.56, 17.90, -2.93, -3.69; IR(CH2C12) 2957, 2930, 1256, 1250, 1127
cm'l. W1 A solution of exovinyl t-butyldimethylsilyl ether
41 (62.9 mg, 0.187 mmol) in o-xylene (10.0 mL) was refluxed for 48
hrs., the solvent removed, and the residue chromatographed (silica
gel, 2:1 hexanes to ether) to yield cyclohexanone 21 (18.9 mg, 45%)
and recovered starting material (9.7 mg, 15%).

Wand—1.4.2.1.. To a -78 °C solution of
cyclobutanone 2 (80.1 mg, 0.41 mmol) in tetrahydrofuran (50.0 mL)

65

was added in one portion a solution of 1.8M phenyllithium (0.50 mL,
0.90 mmol) in 7:3 hexanes to ether. The dry ice bath was removed,
and the reaction was allowed to warm to room temperature over 1
hour. The reaction was quenched with ice cold sat'd NH4C1, and the
organic phase was separated and washed with 1N HCl, water, sat'd
N aHC O3, and brine. The solution was dried over sodium sulfate, then
the solvent was removed in vacuo to yield crude product. The
residue was chromatographed (silica gel, 3:1 hexanes to ether) to
give exo phenylcyclobutanol 42 (85.1 mg, 76%) as a white solid, mp
97 °C: 1H NMR (300 MHz, CDC13) 8 7.8-7.2 (m, 11 H), 4.63 (d, J = 6.6
Hz, 1 H), 4.00 (dt, J = 9.3, 6.0 Hz, 1 H), 3.27 (ddd, J = 13.2, 9.3, 1.8 Hz,
1 H), 2.14 (s, 1 H), 2.13 (dd, J = 13.2, 6.0 Hz, 1 H); 13C NMR (75 MHz,
CDC13)8 149.75, 146.93, 141.50, 140.85, 132.39, 128.50, 128.30.
127.98, 127.06, 124.63, 124.14, 122.90, 122.35, 118.89, 74.95, 59.57,
45.49, 36.00; IR(CH2C12) 3568, 3052, 2974, 2932, 1603 1495, 1449
cm‘l. Thermolysis: A solution of exo phenylcyclobutanol 42 (29.2
mg, 0.107 mmol) in o-xylene (10.0 mL) was refluxed for 48 hrs., and
the solvent removed. The residue was chromatographed (silica gel,
2:1 hexanes to ether) to yield recovered starting material.

minimum—(Ail. To a -78 °C solution of
cyclobutanone 2 (50.0 mg, 0.25 mmol) in tetrahydrofuran (50.0 mL)

was added a 1 M solution of cyclopropyl magnesium bromide (0.50
mL, 0.50 mmol). The solution was allowed to warm to room
temperature over 1 hr., then quenched with sat'd NH4C1. The organic
phase was washed with 1N HCl, water, sat'd NaHCOa, and brine, then
dried over sodium sulfate. The solvent was removed in vacuo, and
the residue chromatographed (silica gel, 2:1 hexanes to ether) to
yield cyclopropylcyclobutanol 45 (48.0 mg, 79%) as a yellowish solid,
mp 74 °C: 1H NMR (300 MHz, CDC13) 8 7.8-7.2 (m, 6 H), 4.23 (dd, J =
6.6, 0.9 Hz, 1 H), 3.69 (dt, J = 9.0, 6.0 Hz, 1 H), 2,62 (ddd, J = 12.6, 5.7,
2.1 Hz, 1 H), 1.72 (s, 1 H), 1.66 (dd, J = 12.6, 6.0 Hz, 1 H); 13C NMR (75
MHz, CDC13)8 150.11, 142.00, 140.73, 132.33, 128.10, 127.89, 123.77,
122.67, 122.02, 118.55, 73.74, 56.49, 41.82. 35.70, 20.11, 1.06, 0.74;
IR(CH2C12) 3574, 3053, 2978, 1605, 1221, 1107, 1020 cm'l; MS(EI)

66

m/z (rel. int.) 236(24), 167(23), 152(100). W: A solution
of cyclopropylcyclobutanol 45 (111.1 mg, 0.470 mmol) in o-xylene
(20.0 mL) was refluxed for 48 hrs., and the solvent removed. The
residue was chromatographed (silica gel, 2:1 hexanes to ether) to
yield recovered starting material (97.6 mg, 88%) and a small amount
of unidentified side product (10.2 mg).

W: The results of

these experiments are tabulated in Table 3, Thermolysis of
Cyclobutane Derivatives with added Tributyltin hydride. A
representative experimental procedure will be outlined for the
thermolysis of exovinyl t-butyldimethylsilyl ether 41, entry 7: A
solution of exovinyl t-butyldimethylsilyl ether 41 (20.3 mg, 0.060
mmol) and tributyltin hydride (0.10 mL, 0.371 mmol) in o-xylene
(10.0 mL) was refluxed for 1 hr., and the solvent removed. The
residue was chromatographed (silica gel, 2:1 hexanes to ether) to
yield acenaphthylene (1.1 mg, 12%), recovered starting material (2.0
mg, 10%) and cyclohexanone (6.7 mg, 50%).

APPENDIX

67

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