Ring Size Effects on the Pinacol Rearrangement by Ramanujan Srinivasa a Thesis Submitted in Partial Fulfillment of the Requireme

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Ring size effects on the pinacol rearrangement by Ramanujan Srinivasa A thesis submitted in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY in Chemistry Montana State University © Copyright by Ramanujan Srinivasa (1979) Abstract: The pinacol rearrangement of 1.1'-bicycloalkyl diols, symmetrical and unsymmetrical, under acidic conditions is discussed. The present study has attempted to probe some very controversial aspects such as whether carbonium ion stability or product stability is the driving force for the ring size effects on the course of the rearrangement. The results of the present study point out the importance of the reaction conditions. When evaluating the ring size effects on the course of the pinacol rearrangement it is essential that the reaction conditions be well defined for otherwise interpretation of results may lead to erroneous conclusions. For instance, the rear-arangement of cyclopentyl cyclohexane-1,1'-diol with concentrated sulfuric acid at 0° yields mainly Spiro [4,6] undecan-6-one as the primary rearrangement product reflecting carbonium ion stability as the chief factor in the course of the rearrangement. On the other hand, the rearrangement with dilute sulfuric acid at reflux produces mainly Spiro [5,5] undecan-7-one, the thermodynamically more stable product. This is consistent with the secondary skeletal rearrangement of the initially formed product. Further, it was attempted to study the possibilities of the rearrangement occurring under non-acidic conditions. It was found that certain sulfur transfer reagents, such as N,N'-thiobisbenzi-midazole, could affect the rearrangement of 1,2-glycols. To

My Parents RING SIZE EFFECTS ON THE PINACOL REARRANGEMENT

RAMANUJAN'SRINIVASA

A thesis submitted in partial fulfillm ent of the requirements for the degree

o f

DOCTOR OF PHILOSOPHY

Chemistry

Approved:

Head, Major Department

Graduate Bean

MONTANA STATE UNIVERSITY

Bozeman, Montana

August, 1979 iv

Acknowledgement

A number of people have been responsible for incessant

success in my life and in my educational career. I am deeply

indebted, firs t of a ll, to my parents, brothers and sisters

for their unfathomable love, affection and encouragement, and

to my teachers whose tremendous influence has enabled me.to

develop a personality arid boldly face the challenges of life .

My special thanks are due to Dr. Bradford P. Mundy, my advisor,

for his valuable guidance, help, and for making me a chemist.

My sincere thanks are extended to professors A.P. Krapcho,

University of Vermont and D.N. Harpp, McGill University, for

their generous donations of spiroketones and thiobisbenzimidazole reagent. I am also thankful to all my friends for

their encouragement and kind sentiments. TABLE OF CONTENTS

Dedication i T i t l e in- V ita i i i Acknowledgement iv Table of Contents v List of Tables vi List of Charts vtii List of Figures xi Abstract xii ,Quotation xiii

P art I . RING SIZE EFFECTS ON PI NACOL REARRANGEMENT Introduction I Results and Discussion 18 Summary , 5 5

Part I I . PINACOL REARRANGEMENT WITH SULFUR TRANSFER REAGENTS Introduction 65 Results and Discussion 71 Summary 81 Experimental Section I 82 Experimental Section II 100 Experimental Section I I I 115 Experimental Part IIr 122 Appendix I 126 Appendix II 133 Appendix I I I 138 Appendix IV 142 References and Notes. 148 vi

LIST OF TABLES

I . Symmetrical pinacol condensation...... , . . . 2 3 II. Mixed pinacol condensation...... 24. III. Yields of pinacols normalized to 100%.,...... 25 IV . R elative yields(% ) o f combined aikene and pinacol...... 2 6 V. Temperature effects on product composition...... 27 ■VI. Mass spectral data comparison...... 2 8 V II. R elative abundance of the major p o s itiv e ly charged species in the mass spectral cleavage of pinacols...... 29 V I I I . T i(III)-In d u c e d reaction products...... 31 IX. Rearrangement of symmetrical pinacols under different acidic conditions ...... 34 X. A comparison of the results of the rearrangement of pinacol (16) with those reported by Christo! et a l ...... ; ...... 37 XI. Effect of temperature on the rearrangement of pinacol (Tj6) with 25% H2SO4 ...... 41 XII. Effect of acid concentration on the rearrangement of cyclopentyl cyclohexane-1,1'-diol (16)...... 4 6 X III. Effect of acid concentration on product composi tion for the pinacol rearrangement of cyclo pen tylcyclohexane-1,I '-diol (1 6 )...... 47 XIV. Effect of acid concentration on the rearrange ment of cyclopentyl cycloheptane-1,1'-diol (21)...50

XV. Comparison o f ra te o f aceto lysis o f cyclo a lk y l to s y la te s ...... 57 vi i

XVI. Sulfur transfer reagents ...... 66 XVII. A comparison of results of the reaction of unsymmetrical pinacols with N1N1-Thiobis- benzimidazole ...... 81 v i i i LIST OF CHARTS 1. The Pinacol Rearrangement, ...... ,I 2. Mechanism o f Pinacol Rearrangement ...... 2 3. Pinacol Rearrangement of 01*3-1,2- and trans-1,2- dim ethylcyclo h exan e-1,2-d io ls...... 3 4. Interconversion of 2 ,2-dimethyl cyclohexanone and I -acetyl-I -methyl eye I opentane ...... 7 5. Pinacol Rearrangement of cis-1,2- and trans-1,2- dimethyl cyclopentane-1,2-diols...... 8 6. Pinacol Rearrangement of I -phenyl-4-t-butyl- cy c lo h e x a n e -1 ,2 -d io l...... 9 7. Pinacol Rearrangement of alkyl group substituted monocycloalkyl pinacols...... 10 8. Pinacol Rearrangement of cyclopentylcyclopentane-1,1 '-d io l...11 9. Pinacol Rearrangement of cyclopentylcyclohexane-1,1 '-diol (Sands and B otteron) ...... 11 10. Pinacol Rearrangement of phenyl group substituted mono cycloethylene glycol (Botteron and Wood) ...... 12 11. Pinacol Rearrangement of cyclopentylcycloheptane-1,1 '-d io l...14 12. Effect of variation of reaction conditions on the product composition in the rearrangement of cyclopentylcyclohexane-1,1 1 -d io l ...... 15 13. Rearrangement of cis- and trans-perhydroindan-8,9-diols ...... 16 14. Rearrangement of symmetrical pinacols ...... 3 3 15. Rearrangement of cyclopentylcyclohexane-1,1 '-d io l ...... 36 16. Rearrangement of cyclopentylcycloheptane-1,1'-d io l ...... 38 17. Rearrangement of cyclohexylcycloheptane-1,1 '-d io l ...... 39 18. Rationalization.of the results from temperature effects on the rearrangement of pinacol (Tj5) ...... 42 19. Secondary rearrangement of spiroketones (18) and (19) ...... 4 3 ix 20. Secondary rearrangement of spiroketone (18^) with concentrated H2SO4 a t 0 ° ...... 4 4 21. Secondary rearrangement of spiroketone products of pinacol (16) rearrangement ...... 44 22. Rationalization of the secondary skeletal rearrangement of spiranone (18) ...... 45 23. Synthesis of traris-perhydrobenzocycloheptane-lOJl-diol ...... 52 24. Pinacol rearrangement of trans-perhydrobenzocyclo- h e p ta h e -1 0 ,ll-d io l...... 53 25. Rationalization of the pinacol rearrangement of trans- perhydrobenzocycl oheptane-10,11 -d io l ...... 54 26. Hydroboration, oxymercuration, and pinacol rearrangement studies o f other analogous systems...... ; .58 27. A scheme for the synthesis of spirocompounds...... 60 28. Typical natural spirocompounds...... 62 29. A model synthesis o f A x is o n itriI e -3 ...... 63 30. Pinacol rearrangement of 1,1,2-triphenyl ethylene-glycol...... 6 5 31. Rearrangement of Benzylic alcohols ...... 67 32. General mechanism of reaction with sulfur transfer reagents...67 33. Reaction of pinacol (40) with N,N'-thiobisbenzi- midazple ( Harpp and co-w orkers) ...... 68 34. Reaction of pinacol (42) with N1N1-Ihiobisbenzi- midazole ( Harpp and co-w orkers) ...... 69 35. Reaction of cyclohexylcyclohexane-1,1 '-diol. with N1N1 -Thiobisbenzimidazole ...... 71 36. Reaction of the pinacol rearrangement of cyclo hexyl cyclohexane- I ,1 '-diol with N 1Nl-Thiobisbensimidazole..,..73 37. Reaction of cycloheptylcycloheptane-1,1'-diol with . . N1N'-Thiobisbenzimidazole ...... 74 X

38. Rearrangement of cyclopentyl cyclohexane-1,1 '-diol with N5N1-ThiobisbenzimTdazole...... 77 39. Rearrangement of cyclopentyl cycloheptane-1,1 '-diol with NsNlThiobisbenzimidazole...... ,78 40. Rearrangement of cyclohexylcycloheptane-1,1 '-diol with N,N'-Thiobisbenzimidazole ...... 79 xi

LIST OF FIGURES

1. General structure of fused bicyclic-1,2-dtols (Mundy and Otzenberger) ...... 15 2. Symmetrical pinacol condensation...... 2 1 3. Mixed pinacol condensation...... 22 4. Mass spectral cleavage of pinacols...... ,29

5. Graphs o f % acid versus % product...... 48 6. Trans-perhydrobenzocycloheptane-10,11-d io l ...... 51 xi i. Abstract

The pinacol rearrangement of I , I '-bicycloalkyl diols, symmet rical and unsymmetrica I , under acidic conditions is discussed. The present study has attempted to probe some very controversial aspects such as whether carbonium ion stability or product stability is the driving force for the ring size effects on the course of the rear rangement. The results of the present study point out the importance of the reaction conditions. When evaluating the ring size effects on the course of the pinacol rearrangement it is essential that the reaction conditions be well defined for otherwise interpretation of results may lead to erroneous conclusions. For instance, the rear- arangement of cyclopentyl cyclohexane-1,1'-diol with concentrated sulfuric acid at 0° yields mainly Spiro [4,6] undecan-6-one as the primary rearrangement product reflecting carbonium ion stability as the chief factor in the course of the rearrangement. On the other hand, the rearrangement with dilute sulfuric acid at reflux produces mainly Spiro [5,5] undecan-7-one, the thermodynamically more stable product. This is consistent with the secondary skeletal rearrange ment of the in itia lly formed product. Further, it was attempted to study the possibilities of the rearrangement occurring under non-acidic conditions. It was found that certain sulfur transfer reagents, such as N,N'-thiobisbenzimidazole, could affect the rearrangement of 1,2-glycols. Pleasure is frail like a dew drop,

while it laughs it dies.

Rabindranath Tagore. INTRODUCTION

Perhaps the most fam iliar among the molecular rearrangements is the so-called "Pinacolie Rearrangement" of 1,2- glycols. Following the discovery by Fittig in 1859-1860 that tetramethyl ethylene gly col (Pinacol) rearranged to form methyl t-butyl ketone (Pinacolone) in concentrated sulfuric acid (Chart I), abundant literature concern ing many aspects.of the rearrangement has accumulated over the past 32 33 34 decades and excellent discussions of this topic have appeared. ’ 5

HO OH O i I Il C H g-C----- C-CHg CH3-C- -C-CH, 3 1 I 3 CH3 CH3

Pinacol Pinacolone

Chart I. The Pinacol Rearrangement

In general, the pinacol may be represented by the structure (I).

HO OH 11 I 2 3 RR1C-CR^Rd

I 1 2 3 (R, R , R , and R are hydrogen, alkyl, aryl or any combination of th ese.)

Besides sulfuric acid, many other agents such as phosphoric, ox^ 2 alic, perchloric, and formic acids are known to catalyze the rear- arangement. In certain instances,30, 35,36 certain Lewis acids such as A l2O3, BFg, POClg, e t c . , a t high temperatures have been e ffe c tiv e .

From a mechanistic view, the pinacol rearrangement can be re garded as a special case of a Wagner-Meerwein rearrangement involving 33 1,2- shifts. The generally accepted mechanism in concurrence with 37 the re s u lts of the k in e tic , oxygen exchange, and tra c e r studies fo r the pinacol rearrangement of tetramethyl ethylene glycol is outlined in Chart 2.

HO OH H9O I I K . 2I Me2C— CMe2 + H Me2C-

Slow, k2

OH OH I Me C— CMp < k3 Me2C U- 13 + fast W fa s t OH /\ 0 Me2C— CMe2 Il Me 3C— CMe + H

Chart 2. Mechanism of Pinacol Rearrangement. 3

The k in e tic equation consistent w ith the A -I mechanism as sug- 38 gested by Duncan and Lynn is ,

<2k3ho [Glycol] Rate (k_2 + kg)

From this it follows that,

K k g k g h 0 exp (k_2 + kg) where kexp is the experimental rate constant, h0 is the antilog of the

Hammett acidity function, Hq, and K is the thermodynamic equilibrium 39 constant. Smith and co-workers, based on their isotope kinetic data and those of Ley and Vernon,36 showed that the term kg/(k g + kg) is constant. On the other hand, plots of log k versus Hn and of Tog kQvlV(H + ) versus (H+ ) have been found to be lin e a r .38 . GXp Supporting evidence for the carbonium ion intermediate stems from the works of many other investigators.40’^ ’4^ Further, oxygen ex- 37 change studies have shown th a t the ra te of rearrangement in low a c id itie s is 25-30% w ith 70-75% of the carbonium ion re v e rtin g to pin - acol and the pinacol/pinacolone ratio decreases linearly with decrease in the activity of water (a^ 0). The formation and subsequent hydrol ysis of the epoxide to provide the carbonium ion intermediate could merely be an alternate path for the reaction. Although reports in sup 4 port of the pinacol rearrangement involving the epoxide intermediate 4? 43 for open chain pinacols have appeared in the lieterature, 9 such an intermediate does not seem to be possible for hindered glycols, especially the I ,1'-bicycloalkyl pinacols. No epoxide could be de tected during the rearrangement of cis-1,2- and trans-1,2- diols (2J

AA and (5^).. Similar results have been reported for the rearrangement 56 of cis- and trans-perhydroindan-8,9-diols.

The pinacolic rearrangement has been looked upon from several points of view. The "migratory aptitudes" of the substituents, the direction of the rearrangement, glycol stereochemistry, the stability of the products themselves under reaction conditions, the effect of reaction media, etc., are a few to mention. In cyclic systems, the direction of rearrangement and the "migratory aptitudes" are probably reflected by ring expansioh/contraction trends.

A considerable attempt has been made to study the steric course 45 of the rearrangement of cyclic glycols., Thus, Bartlett and PockeT studied the rearrangement of the cis-1,2- and the trans-1,2- dimethyl- cyclohexane-1,2- diols with 20% sulfuric acid under reflux and reported the following results (Chart 3): 5

CO (7 4 % )

(78% )

Chart 3. Pinacol Rearrangement of cis-1,2- and trans-1,2- dimethyl-

cyclohexane-1,2-diols.

2,2-Dimethyl cyclohexanone (4) and I- acetyl- I -methyl cyclopen

tane (7 ) were characterized as semiearhaZones■;i.n774%..and: 7;8% y ie ld s ,

respectively. These reactions were carried out during the time when

the very concept of the "free carboni urn ion" was s till in its infancy.

The argument offered, however, to explain the rearrangement was on the

AC basis of the "open.sectet theory" as put forth by Whitmore and it was always the. group being trans to the carbon atom, from which the

hydroxyl group was removed, that migrated. Thus different products were produced for the 1,2-diols.

Bunton and C a rr ^ studied the k in e tic s o f the rearrangement of 6 c is -1 ,2 - and tra n s -1 ;2 - dim ethylcyclohexane-1,2-diols in aqueous perr chloric acid solutions at various temperatures and found from the var

iation of the rate with acidity, the solvent deuterium isotope effect, and the Arrhenius parameters that both the diols produced the same-

ketone (7) in 91-98% yield via a common carbonium ion intermediate, in 45 contrast to the. above results. This then suggested that the cis- diol would firs t isomerize to the trans-diol via the carbonium ion

intermediate and thus contribute equally to the ring contraction pro duct. Bunton and Carr also noted th a t the proportion o f the 2 ,2 -d i methyl cyclohexanone (4) increased slightly with the increasing temper

ature and that a common intermediate such as (8) could account for the

interconversion of the ketones (Chart 4). They further noted that the

rate of formation of the carbonium ion from the trans-diol relative to

that of the cis-diol was approximately 2, but the rates of the reverse

reactions were almost the same. The interpretation was that in water

the cis-form was thermodynamically more stable. Mundy and Otzenberger

^ have offered similar arguments on the rearrangement of the cis-

and trans-diols to show that the work of Bartlett and PockeT^ was in

correct., 7

Chart 4.. Interconversion o f 2 , 2-dim ethylcyc lohexanone and I -a c e ty l-

I -methyl cyclopentane.

Contrary to these results are those obtained from the rearrange ment of cis-1,2- and trans-1,2-dimethyl cyclopentane-1,2-diols in 44 aqueous p erch loric acid . The major rearrangement product is 2 ,2 -d i methyl cyclopentanone (11_) in both the cases (Chart 5), indicating iso m erization of the tra n s - to the c is -d io l. The oxygen exchange studies have shown that the rate of exchange for the trans-diol is five times faster than the rearrangement. That the cis-diol does not exchange, but rearranges to the trans-diol, suggests that two non-interconvert- 44 ible intermediates are involved in these reactions. 8

Chart 5. Pinacol Rearrangement of cis-1,2- and trans-1,2-dimethyl- cyclopentane-1,2-diols.

Whether or not such cis-trans isomerizations occur in all 1,2- glycols is s till an open question. 47 The work of Barili and co-workers on the rearrangement of I - phenyl-4-t-butyI cyclohexane-1,2-diol (1_3) supports the "common car- bo ni urn ion intermediate" hypothesis in that a species such as this, once formed, loses all its memory of the previous stereochemistry of the 1,2-glycols. Their results obtained with the four diastereoiso- mers of (1_3) are presented in Chart 6. They concluded from their data th a t the stereochem istry a t the benzylic carbon was of no consequence to the products. 9

(Reaction conditions: BFZ3Et2O in benzene.)

Chart 6. Pinacol Rearrangement of I -phenyl-4-t-butylcyclohexane-

1 ,2 -d io l.

From what has been quoted from earlier investigations thus far, it appears that the stereochemistry of 1,2-glycols may not be the key factor in directing the rearrangement. 10

Many earlier workers have also attempted to look at the rearrange ment from the standpoint of the ring expansion trends in 1,2-diols. 49 Thus, Meerwein from his rearrangement studies on a series of 1,2- diols (Chart 7) found that the cyclopentane ring gave more expansion than the corresponding cyclohexane ring. Similar results have also been reported for the deamination of amines and amino-alcohols of anal ogous structures.^

R= Me Or Et

Chart 7. Pinacol Rearrangement of alkyl group substituted monocyclo alkyl pinacols.

The acid-catalyzed rearrangement of cyclopentyl cyclopentane-1,1 '- diol (40) to Spiro [4,5] decan-6-one (530 seems to be the firs t re port to appear on the pinacolic rearrnagement of 1,1'-bicycloalkyl diols6^ (Chart 8). 11

HO OH CHD 4 0 53

Chart 8. Pinacol Rearrangement of cyclopentylcyclopentane-1,1'-d io l.

Sands and Botteron^ observed that for the rearrangement of cyclopentylcyclohexane-1,11-diol (Iji) in 25% sulfuric acid at reflux, more of Spiro [5,5] undecan-7-one (1_9) than of Spiro [4,6] undecan-

6-one (Tjl) was formed; the major product was cyclopent-l-enyl- cyclohex-1'-ene (1_7), (Chart 9). They noted that the ketones (18) and (1_9) were produced in yields inconsistent with either ease of formation or stabilities of the carbonium ions.

19 16 17 18 802% 2 6% 17- 2%

Chart 9. Pinacol Rearrangement of cyclopentylcyclohexane-1,1 '-d io l.

(Sands and B o ttern).

Realizing that these results could not be rationalized in terms of the !-Strain Theory,5^ Botteron and Wood6 attempted to tackle the 12 problem from the "ring strain" standpoint. They carried out the re arrangement of a series of 1,2-glycols with concentrated sulfuric acid at 0° (Chart 10). In all these cases the major product was the ke tone (20) and again the cyclopentane ring gave more expansion. The interpretation was that there results a release in strain of about 52 10 K cal in the tra n s itio n s ta te when the C5-H n g expands and th is causes an acceleration in the rate of the reaction. Conversely, there occurs a retardation in the rate for the expansion of the C5-Hng be cause i t involves a strained seven-membered tra n s itio n s ta te .

HO OH PD O Ph O Z " " * \ l I ' ( ) Rh - I c - P h + ^ 2 n .C— CR + Vn + I OM' ph~ C X r R

n = 5 or 6

R = H or Me

Chart 10. Pinacol Rearrangement of phenyl group substituted monocyclo ethylene glycol ( Botteron and Wood).

The other side of the arguments which Botteron and Wood have over looked is that the carbonium ion next to a phenyl group is more stable and this not only accounts for the observed ring expansions, but re flects the relative stabilities of the carbonium ions as well. In sup port of this is the rearrangement of the diol (1_3) (Chart 6). That the 13 carbonium ion stability is the chief factor in the course of the pinacolic rearrangement of 1,1'-bicycloalkyl diols is discussed in the next section. (Also see references 53 and 54.)

Sands^ studied the rearrangement of cyclopentylcycloheptane-1,1 diol (21_) with 25% sulfuric acid at reflux and obtained the following results (Chart 11). His rationalization to account for the product distribution was on the basis of ring expansion trends as reflected in the relative strains of (25) and (26). He further argued that the carbonium ion on the five-membered ring is only slightly favored over th a t on the seven-membered and th a t the more strained ion ( 26) was more prone to form the product than reverting to the diol. However, the relative reactivities of cycloalkyl tosylates to acetolysis have de monstrated that the ease of formation of carbonium ion for the rings 55 is Cy> Cg>Cg and this perhaps offers a better explanation of the re s u lts . 14

HO OH

Chart 11. Pinacol Rearrangement of cyclopentylcycloheptane-1,1 '-diol

(Sands).

The importance of the reaction conditions as a factor in the on course of pinacolic rearrangement has also been demonstrated. The rearrangement of cyclopentylcyclohexane-1,1 '-diol (Tj6) has been studied under a variety of reaction conditions and the results obtianed are i l lustrated in Chart 12. 15

OO o D d Reaction Condition IZ 18 19

1) POCl3ZC5H5N, 6 hr. re flu x 100 - -

2) 20% H2SO4, 3 hr. reflux 76 3.9 20.1

3) 50% H2SO4, 2 hr. 25° 76.3 8.6 15.1

4) Cone. H 2SO4, h hr. O0 - 56.6 43.4

5) BF3ZEt2O-AcOH, 2 hr. 25° 60.0 20.5 19.5

6) BF3ZEt2O, 2hr. 25° 78.3 21.7

Chart 12. Effect of variation of reaction conditions on the product compostion in the rearrangement of cyclopentyl cyclohexane-1,1'-d io l.

With a view to assessing the ring size effects only on the rear rangement of cyclic 1,2-diols, Mundy and Otzenberger ’ selected a

1,2-glycol system of the general structure (27) for which the direction of the rearrangement, relative stabilities of the carbonium ions, and the migratory aptitudes are unimportant. (Figure I) 16

Ic h 2L 4 (CH2L-4 v S /

m=6, n=5, (R ef. 56, 57); m=6, n=6 (R ef. 58, 59); m=7, n=6 (R e f.60)

Figure I .

The treatm ent of the c is - and the tra n s - glycols (27J, m=6, n=5) with concentrated sulfuric acid produced exclusively the Spiro [4,4] nonan-

6-one (28) and neither the epoxide (29) nor the spiroketone (30) was detected.

Chart 13. Rearrangement of cis- and trans- perhydroindan-8,9-diols;-

These results, therefore, failed to throw any light on the effects of the ring size and the glycol stereochemistry. The conclusion arrived at was that the product stability was probably the determining factor in the rearrangement.

It is, therefore, seen that the mode of the pinacolic rearrange ment is s till not well understood. The scattered and fragmentary re ports on glycol stereochemistry, carbonium ion stability, product stability, and the reaction conditions do not seem to pinpoint in pre cise terms the course of the rearrangement and a general approach to the problem is lacking. Moreover, the interpretations of the results in many cases (for instance, see references 6 and 45) are questionable.

Also, in a few in vestig atio n s conclusions have been drawn on results 4 5 obtained from the reactions performed with impure glycols. 5

In order that the course of the pinacolic rearrangement be prop erly defined for alicyclic pinacols, it is necessary.to consider, in a more rational way, two fundamental questions: .

1. Is carbonium ion stability or product stability the prime fac

tor reflecting the ring size effects in the course of the re

arrangement?

2. How important are the reaction conditions in determining which

of the two factors predominantly controls the course of the

rearrangement?

An attempt is made in the following section in order to unravel these problems from a broader perspective. For this purpose, a series of 1,1'-bicyclo alkyl pinacols, both symmetrical and unsymmetrical, was chosen as the reaction systems and the course o f the rearrangement was studied under standard reaction conditions. 18

RESULTS AND DISCUSSION

SECTION I

1,1 '-BICYCLOALKYL DIOLS

In.this section the discussion of the 1,1'-bicycloalkyl diols,

(pinacols) is made under the following captions:

1. Preparation of the symmetrical and unsymmetricaI I ,1 '-bicy-

cloalkyl diols.

2. Effect of temperature on Pinacol Condensation.

3. A comment on the mass spectra of the unsymmetricaI 1,1'-

bicycloalkyl diols.

4. Titanium (III) - Induced carbonyl coupling.

I . Preparation of the symmetrical and unsymmetrical 1,1 '-bicycloalkyl diolfr.

The I , I '-bicycloalkyl diols (pinacols) used in the study of their rearrangements were prepared by the reductive coupling reactions of ketones in presence of titanium tetrachloride (TiCl4) and magnesium amalgam using tetrahydrofuran (THE) as so lven t. The reactio n was carried out at -IO0 under nitrogen atmosphere. In the preparation of mixed pinacols equal molar q u a n titie s o f two ketones were used. Gas- liquid chromatographic (glc) analysis of the reaction mixtures obtained for three different series revealed the formation of two products for the reactions leading to symmetrical pinacols and.six products for the 19

reactions leading to mixed pinacols (equations I and 2).

HOm u uOH n (I) 2 (^m^C=0 — -

m = 5.6 .or 7

+ >

I- m = 5 . n = 6 G ^=cC™) + 0 ^= c 0 + 0 : = < 7 ) 2. m = 5. n =7 3- m =6. n= 7 35

HO OH HO OH HO OH & < D 36 37 I S sJ C

Very few investigators1'6 have attempted the preparation of mixed pinacols. The first report on mixed reductive coupling of carbonyl compounds in equal molar amounts appeared in I9 6 0 .3 Sands4 and Sands and Botteron5 were able to carry out mixed reductive coupling of cyclic ketones in equal molar q u a n titie s using aluminum dust and mercuric chloride in benzene. In each case, three pinacols besides the alkenes were formed. However, the reported yields (as determined by weighing 20 the glc chromatogram peak areas) of the pinacols were very low (av erage 23%). Also, the pinacol mixtures proved to be inseparable.

7 Recently, McMurray and Krepski have carried out titan iu m (0 )- induced mixed carbonyl coupling of ketones and acetone which give rise to high yields of unsymmetric olefins with isopropylidene functional ity. They have postulated a two-step pathway involving the initial dimerization of the carbonyl compounds to a pinacol, thus upholding the 9 generally accepted anion- radical mechanism. While reporting the formation of three possible pinacols, they have claimed that these are produced in "a nearly statistical ratio." However, in these reac tions one o f the carbonyl compounds was acetone and th is was used in a four-fold excess. g Corey and co-workers have successfully coupled acetone with other 2+ ketones in the presence of low valent titanium (Ti ), which was gen erated in s itu from titan iu m te tra c h lo rid e and magnesium amalgam.

They used a thre-fold excess of acetone. A mechanism for the titanium

(II) - catalyzed formation of the pinacols has been proposed by these workers.

The reaction m ixtures obtained in .v a rio u s mixed coupling reactions which were carried out in our laboratory were firs t analyzed by glc before they were separated by column chromatography. The individual compounds were characterized by mass and infrared spectral analyses.

The products obtained in the coupling reactions are shown in Figures 2 21 and 3.

HO OH O = C

O = O + oO CU I 39 4 0

Cyclopentanone CycIo pentyli dene- Cyclopentyl - cyclopentane cyclopentane I ,1 '-diol

O HO OH Ii 2 o — • OO + OO 41 42

Cyclohexanone Cyclohexylidine- Cyclohexyl- cyclohexane cyclohexane- 1 ,1 '-diol

9 HO OH

= O -— OO +OO 4 3 4 4 Cycloheptanone Cycloheptyl i dene- Cyclohepty- cycloheptane cycloheptane 1,1 '-diol

Figure 3. Symmetrical Pinacol Condensation Figure 3. Mixed Pinacol Condensation. 23

The results obtained in the symmetrical pinacol condensation reactions are shown in Table I.

Table I

Symmetrical Pinacol Condensation

% PRODUCT RATIO

Yield of HO OH 2 ( ^ > 0 ( 2 > = < 2 > Products

m = 5 91.1 28.2 71.8

m = 6 86.9 33.4 66.6

m = 7 93.7 4.8 95.2

The results of three independent runs of each of the mixed pinacol condensations are summarized in Table I I ; the mean and the standard deviation are reported. Table I I

Mixed Pinacol Condensation

% Yield PRODUCT RATIO. Products Series # (jnjC = 0 + 0 = c 0 33 . 34 35 36 37 38

I m = 3 n = 6 . 85.5 10.2 14.0 4.1 11.4 42.0 18.2

. -ZA -0,4 1.6 0,6 0.3 2.4 3.8 PO -P=* 2 . m = 5 n = 7 85.3 8.0 4.2 16.7 27.8 33.9 10.8

-1,3 -3.7 2,9 4,7 4.3 1.6 3,7

3 m - 6 n = 7 84.6 1.8 7,2 4.8 28,7 48.8 8.7

-0.9 -1.0 5,5 5,9 6,5 3.6 6,4 25

Prima facie it appears that the pinacols are not formed in a statistical ratio. Even when the pinacols are normalize^ to 100%, the distribution (Table III) is not found in a statistical ratio.

Table I I I

Yields of Pinacols.Normalized to 100%

Series 36 : 37 : 38

I 16 59 25

2 38 47 15

3 33 57 10

I f one looks at the data in another way, i . e . , comparing the yields of (33^ + 36), (34 + 37J, and (.35 + 38) it is seen again that a statistical distribution is lacking although series I results show some indication (Table IV). 26

Table IV

Relative Yields (%) of .Combined Alkene and Pinacol

Series 34 + 36 34 + 37 35 + 38

1 22 56 22

2 35 38 27

3 31 56 14

On the other hand, the above results seem to reveal some inter esting features concerning the relative reactivities of the cyclic ke tones. Thus, in Series I , cyclopentanone and cyclohexanone seem to have comparable reactivities. In Series 2, the contribution of cyclo pentanone to products is 1.4 times more than that of cycloheptanone.

The Series 3 results also demonstrate that cyclohexanone is found .!in.. ' the products 1.4 times more frequently than cycloheptanone. However, a quantitative assertion of such conclusions demand more experimental evidence.

2. Effect of Temperature, on Pihacol Condensation

On one occasion where the experimental temperature was not care fu lly maintained, i t was found that the product composition was not significantly different from that obtained for reactions run at a main tained temperature of -10°. The observation provoked some interest and 27 therefore an attempt, was made to study the effect of temperature on the carbonyl coupling reaction. For this purpose, the coupling of cyclopentanone and cyclohexanone was chosen. The results of the three separate reaction's run at -10°, 22° (room temperature), and at reflux

(THF) are presented in Table V.

Table V .

Temperature Effects on Product Composition

Temperature ______Composition {%)

33 34 35 36 37 38

-10°. 10.2 14.0 4.1 11.4 42.0 18.2

22 10.5 18.2 8.4 13.9 33.2 15.9

Reflux . 7.8 20.6 14.9 8.8 26.4 21.5

From these results, i t is seen that the temperature has v irtu a lly no effect on the composition of symmetric alkenes and pinacols; but a decreasing trend in the yield of the unsymmetric pinacol (37) with increasing temperature and a corresponding increasing trend in the yield of the unsymmetric alkene (34) are notable. The observed trend for this series could be a unique rather than a general trend. The is 28

sue was not probed any further since the main object of the research

project was to pursue the study of the ring size effects on the pinacolic rearrangement of bicyclo alkyl-1 ,V -d io ls .

3. A Comment on the Mass Spectra of the Unsymmetric Pinacols

The mass spectra of the unsymmetric pinacols present some in te r- . esting features. The nature of the parent ion peak and the base peak

(Tables VI and VII) observed is as predicted from the pinacol struc ture. For instance, the relative abundance of the parent ion peak in each case is much less than observed for a monohydric alcohol. This is probably because addition of a hydroxyl group lowers the ionization potential and hence the increased decomposition.^’^7 Furthermore, the pinacols follow the same cleavage pattern (Figure 4) as evident from the positions of their base peaks.

Table VI

Mass Spectral Data Comparison

Pinacol M Peak (m/e) Base Peak (m/e)

C5 - C5 (40) 170 .8.5

C6 - C6 (42) .1 9 8 99

C7 - C7 (41) 226 113

C5 - C6 (Jl) . 184 99

C5 - C7 (H_) 198 113

C6 - C7 (48) 212 113 29

Table VII

Relative Abundances (%) of the major positively charged species in the mass spectral cleavage of pinacols

Pinacol O 6h =OH

(m/e 85) (m/e 85 + CH2) (m/e 85 + 2CH2)

(a) (b) (c)

C5 - C5 (40) 100

C5 - C5 (42) 100

C7 - C7 (44) 100

26.3 100 C5 " C6 ^ C5 - C7 (21) 25.0 100

C6 - C7 (48) 96.6 100

HO OH

I m = 5, n = 6 m/e 99 HO >OH m = 5, n = 7 m/3 113 m y,- + Base Peak m = 6, n = 7 m/3 113

Figure 4. Mass Spectral Cleavage of Pinacols. 30

It is seen from the Table VII that the major positively charged

species formed preferentially in the case of unsymmetrical pinacols

corresponds to the larger of the two rings. In the case of the Cg -

pinacol, the relative abundance at m/e 99 corresponding to the ion (b)

is notable. This probably points out the similar stabilities for this

species and (c); the species (a) being the least stable.

4. Titanium ( I I I ) - Induced Carbonyl Coupling

The reductive coupling of ketones with titanium tetrachloride and magnesium amalgam in tetrahydrofuran leading to pinacols is presumed

to be effected by a low valent titanium, T i ( I I ) , species generated 8 7 during the reduction. McMurray and Krepski, on the other hand, have

shown that the carbonyl coupling could be readily accomplished with

titanium trichloride (TiCT3) and an alkali metal to generate olefins with isopropylidene functionality. They believed that T i(III) was

probably f ir s t reduced by the alkali metal to Ti(O) which then induced

the coupling. However, the possibility of T i(II) or even T i(III) as

such without further reduction cannot be ruled out.

Encouraged by McMurry's hypothesis of the in itia l pinacol forma

tion during the coupling on one hand and by the fact that T i(III), 62 being more stable than T i ( I I ) , is a powerful reducing agent on the

other, the task of running the reaction with titanium trichloride alone

was undertaken. Cyclopentanone and cyclohexanone were chosen for this . purpose and surprisingly enough, the coupling did occur to give rise to 31 six products. These were identified by comparison with the compounds that had been obtained before by the Ti(II)-induced method for the ■ same reaction. The results are summarized in Table V III.

Table V III

T i(III)-Indu ced Reaction Products

PRODUCT (5)*

39 45 £L 40 16 42

%Yield 11.3 35.3 24.8 10.2 13.1 5.3

(* Product composition normalized to 100%.)

Although the overall yield of the products relative to that of the recovered starting materials was only 18%, the very fact that pinacol condensation did occur with TiC l3 alone is noteworthy. Since

TiClg could not be dissolved in THF, its poor so lu b ility was probably the reason for the observed low yields. However, at this point i t is d iffic u lt to say whether or not TiC l 3 is effective in other ketone coupling reactions. Perhaps it calls for a convenient solvent. One other comment about the formation of the pinacols besides the alkenes is that the former compounds were formed probably because of the ab sence of the alkali metal. 32

SECTION 2

THE ACID-CATALYSED REARRANGEMENT OF BICYCLOALKYL-1 ,T-DIOLS (PINACOLS)

In this section the results of the rearrangement of various pinacols are discussed under the following captions:

1. Rearrangement of symmetrical pinacols.

2. Rearrangement of unsymmetrical pinacols.

3. The effects of reaction conditions on the stabilities of pro

ducts of pinacol rearrangement.

4. The effects of acid concentration on product composition in the

rearrangement reaction at constant temperature.

5. Rearrangement of trans-perhydrobenzocycloheptane-10,ll-diol.

All the reactions were performed with pure pinacols. This was, however, not the case with the earlier investigations.^5^ Thus, there was no room for ambiguity in the identification or quantification of rearrangement products. The pinacols studied were considered as very representative of cyclic systems so that the conclusions reached for the experimental pinacols could apply as well to cyclic-!,2 glycols in general. . .

I . Rearrangement of Symmetrical Bicycloalk y l-I,I'-d io ls with Concen- -

trated H2SO4 at 0°.

The rearrangement of the pinacols (40), (42), and (44) with con 33 centrated sulfuric acid at 0° yielded almost exclusively the corres ponding spiroketones (53), (55), and (5 7 ) (Chart 14).

Chart 14. Rearrangement of Symmetrical Pinacols.

In dilute sulfuric acid solutions and other acidic conditions, the yields of spiroketones were substantially decreased. The results of such rearrangements as reported by e a rlie r workers are compiled in Table IX. TABLE IX

Rearrangement of Symmetrical Pinacols under

different acidic conditions

Pinacol Conditions Spiroketone Yield (%) References

I. Cyclobutylcyclobutane 10% H2SO4 Spiro [3,5]- 56-70 63,64,65 l .T - d i o l octane-5-one

2. CyclopentyleyeIopentane 20-50% H2SO4 Spiro [4 ,5 ]- I ,1‘-diol (40) . decan-6-0he (53) 70-98 61,28,29,30 * £ 11,66-77 Cone. H9SOzl 0° Il 100 30

33% Oxalic Acid Il 98 30

,Alum (anhydrous) Il 85-90 11

3. Cyclohexylcyclohexane 20-50% H2SO4 Spiro [5 ,6 ]- 10-30 30 1,1'-diol (42) dodecan^7-one(55)

33% oxalic acid Il 20 30

. DMSO; 60° Il 4 . 78

Cone. HgSO2; 0° H 100 30 TABLE IX

con't .

4. Cycloheptyl eycloheptane 20% H2SO4 Spiro [6,7]- 32 30 1,1 '-diol tetradecan- 8-one (57)

20-33% oxalic U 36 30 acid

Cone. H9SOzl; M 93 30,79,80 O0

5. Cyclooctyl cyclooctane 33% oxalic Spiro [7 ,8 ]- 15 80 I , T -diol acid hexadecan- 9-one 36

As the data in Table IX imply, the major competing reaction in

the pinacol rearrangement is a double dehydration yielding diene.

Also, the spiranone/diene product ratio seems to be very dependent

upon the acidity and the acid catalyst used.30

2. Rearrangement of Unsymmetrical Bicycloalkyl-1,1 'diol with Concen

trated Sulfuric Acid at 0°.

The reaction of cyclopentyl cyclohexane-1,1'-diol (16) with con centrated sulfuric acid at 0° gave the spiroketones (18) and (19);

neither the epoxide (60) nor the diene (17) was produced (Chart 15).

Chart 15. Rearrangement of Cyclopentylcyclohexane-1,1 '-d io l.

Christol, Krapcho, and Pietrasanta30 carried out the rearrange ments under two different conditions and obtained only the spiro- 37 i ■ ' . ketones (18) and (19,). A. comparison of the results is shown in

Table X.

TABLE X

A Comparison of the Results of the Rearrangement of on Pinacol (16) with those reported by Christo! et a l.

% Yield of Spiranones

Conditions 18 19. References

Cone. HgSO^, O0 62.0 - 8.7 38.0 - 8.7 Present study

Cone. HgSO^, 0° 56 43 30

BF3ZEt2O 78 22 30

The results in Table X show that at O0 the major rearrangement . product is invariably the spiroketone (18). It is further noted that

' the spiroketone (18)/spiroketone (19.) product ratio seems to reflect

the relative strains of the carbonium ion intermediates (58) and (59).

Cyclopentyl cycloheptane-1,1'-diol (2]_) on treatment with con

centrated sulfuric acid at 0° was found to rearrange to spiro[4,7]-

dodecan-6-one (23) and spiro[5,6]dodecan-8-one (24). Again, the epox

ide (61_) and the diene (22) were not formed (Chart 16). 38

O a O 62 O-O6/.

23 24 0 0% 3-5% 96-5%t

Chart 16. Rearrangement of Cyclopentylcycloheptane-I,I'-d io l.

As seen from the product distribution, the predominant ketone is

(24). This probably indicates that the carbonium ion on a seven-membered ring, (63) is more favored than on the five-membered ring, (62).

Consequently, the C5-Mng gives more expansion than the C 7-Mng.

The interpretation is that a stable six-membered ring is formed for

the expansion of cyclopentane ring whereas a strained eight-membered

ring is formed when cycloheptane ring expands. I t should be noted,

however, that Sands5 who studied the reaction offered just the oppo

site rationalization of his results.

The other unsymmetric pincacol that was selected for study was 39 cyclohexyl cycloheptane-1,1'-diol (48). This on treatment with con centrated sulfuric acid at O0 yielded only the spranone (51_) and the diene (49). Again, there was no epoxide (64) (Chart 17).

HO OH

Chart 17. Rearrangement of Cyclohexylcycloheptane-1,1'-d io l.

The results show that since (5]_) is the only spiroketone produced, the carbonium ion intermediate (66) must be more preferred. This is consistent with the notion that a carbonium ion on a seven-membered ring is more stable, for reasons of release in ring strain, than that on a six-membered ring, in which case the strain is added. On the other hand, for the ion (65), rearrangement would result in the expan sion of a strained seven-membered ring to a more strained eight-mem- 40 bered ring. Both the rings in (66) are stable and therefore this path way constitutes the major course for the reaction. The formation of the diene (49) is probably due to the reason that since in the ion

(65) both the rings are under strain, dehydration seems to be the only alternative course for the reaction. No earlier report on the rear rangement of the pinacol (48) is available.

3. Effects of Reaction Conditions on the S ta b ilitie s of Products of

Pinacol Rearrangement.

I t has been demonstrated by e a rlie r investigators^’ 5,30 that for the rearrangement of pinacols the product composition is greatly in fluenced by the reaction conditions (for instance, see Tables IX and

X ). From the data presented in Tables IX and X, i t appears that pina col rearrangement mostly depends upon the acidity and the temperature rather than the acid catalyst. However, proper rationalization of the results to account for the observed trends in product composition does not seem to have been offered. This was probably due to random reac tion condition used for any series of pinacols studied by previous workers.

Therefore, in order to ascertain the effects of acidity and temp erature separately on product composition, it was realized in the pre sent study that one of the factors should be maintained constant during the rearrangement. Thus, using 25% sulfuric acid the rearrangement of. 41 cyclbpantylcyclohexane-1,1-diol (16) was selected as a representative system and the reaction was carried out at O0 and at reflux (96°).

The results reported in Table XI are the average values of two indepen dent analyses in each case.

TABLE XI

Effect of Temperature on the Rearrangement of Pinacol (16)

With 25% H2SO4

Temperature Product Composition (%)*

I Z 18. 19

0°; 2hr. 92.35 - 3.5 0.725 - 0.675 6.95 - 2.65

96° (reflux); 43.5 - 1.7 6.55 - 0.45 49.95 - 1,25 2 hr.

*The yields reported are normalized to 100%. The overall reaction at 0° was poor ( ~ 20%). The reaction at 96° was 100%.

The results of the rearrangement at 0° seem to suggest that water 37 probably has a significant role at low acidity favoring dehydration.

At higher temperatures this effect is offset at least partially to fa c ilit a te the rearrangement. Although enough experimental data are not available at this writing, in light of the fact, however, that the spiro-ketone (18) is the major product at 0° with concentrated sulfuric 81 acid, the above results could, perhaps, be rationalized as follows 42

(Chart 18).

Chart 18. Rationalization of the results of temperature effects on

the Rearrangement of Pinacol (16).

Aside from the fact that the dehydration competes with rearrange ment in low acidities at higher temperatures, the above results tend to reveal one other feature. That is, between the two rearrangement products the spiroketone (!Si) predominates. This, no doubt, suggests that the ketone (1_9) is more stable at higher temperatures, thus indi cating that thermodynamic control is probably operative. 43

In order to further examine this observation, the two spiroketones (T_8) and (29) were separately refluxed with 25% sulfuric acid for two hours and i t was found that only the spiroketone (28) underwent

100% conversion to the symmetrical ketone (29) (Chart 19).

XJ + OO % 25% IS 13

REFLUX 0 0 % 1 0 0 %

2 5 % ^ 504 0 -0 % REFLUX 1 0 0%

Chart 19. Secondary Rearrangemnt of Spiroketones (28) and (29).

When the spiroketone (28) was treated with 92% sulfuric acid at

O0, no secondary rearrangement occurred (Chart 20). 44

9 2 % h 2S04 r x O x

c b 0” ' u V j d c 18 18 19

1 0 0 % 00%

Chart 20. Secondary Rearrangement of Spiroketone (18J with Concen trated H2SO4 at 0°.

On the other hand, when the whole reaction mixture obtained in the reaction of the pinacol (Tj5) with concentrated sulfuric acid at

O0 was refluxed with 25% sulfuric acid for three hours, the two spiroketones were obtained in a 50:50 ratio. Further, refluxing of the product mixture with 50% sulfuric acid for four hours produced the spiroketone (1_9) in 100% yield (Chart 21).

HO OH CONIC. % H2SO4 W W reflux ,3h CUQ 0° '6 IS 19 6&2% 31.8%

0XX, /f 50% H2SO4 % OO REFLUX.4h do LB 19 18 LS 5 0 8% 49.2% 00% 100%

Chart 21. Secondary Rearrangement of Spiroketone Products of Pinacol (16) Rearrangement. 45

The probable rationalization of the results of secondary rear rangement of the spiroketone (18J could be the following (Chart 22).

Chart 22. Rationalization of the Secondary Skeletal Rearrangement of Spironone (18).

4. The Effects of Acid Concentration on Product Distribution in the

Pinacol Rearrangement at Constant Temperature.

With a view to probing the influence of acid concentration alone on pinacol rearrangement, the pinacol (1_6) was again the f ir s t choice for the study. The reaction was carried out at 0° with sulfuric acid of d ifferen t concentrations ranging from 8% to 100% (by weight). The reaction time was two hours. The results obtained from two independent 46 determinations in each case are summarized in Tables X II and X IIL

TABLE X II

Effect of Acid Concentration on the Rearrangement of

Cyclopentyl cyclohexane-1,11-diol (16)

H2SO4W Pinacol (16) Yield (%)* (by weight) Recovered 17 18 19

8 97.95 - 0.05 1.55 - 0.15 0.15 - 0.05 0.35 - 0.05

20 98.45 - 0.25 1.15 - 0.15 0.15 - 0.05 0.25 - 0.05

40 97.05 - 0.35 2.05 - 0.35 0.3 - 0.0 0.6 - 0.0

52 93.3 - 0.8 2.6 - 0.5 0.3 - 0.1 0.8 - 0,2

60 86.05 - 1.05 12.75 - 1.15 0.2 - 0.1 I .0 - 0.0

80 19.9 - 1.4 71.05 - 1.95 2.45 - 0.05 6.6 - 0.5

92 0.05 - 0.05 68.15 - 3.75 10.9 - I .4 20.9 - 2.4

100 0.0 0.0 62.0 - 6.2 38.0 - 6.2

* (Values shown are the average of two independent analyses.) 47

TABLE X III

Effect of Acid Concentration on Product Composition for the Pinacol Rearrangement of Cyclopentylcyclohexane-1,1 1-d io l(16).

H2$04% Yield (%)* (by weight) (17) (18) (19)

. 8 76.75 + 0.5 6.5 ± I .8 16.8 ± 1.9

20 . 73.9 " 2.3 8.4 ± 1.9 17.8 ± 0.4

40 68.6 ± 3.5 10.4 ± 1.2 21.1 ± 2.2

52 71.6 ± 1.5 8.0 ± 0.2 ■ 20.4 ± 1.4 O C +1 60 91.3 ± 2.2 7.1 ± 0.9

80 88.7 ± 1.3 3.1 ± 0.2 8.3 ± I .1

92 68.15 ± 3.75 11.45 ±1.85 20.9 ± 2.4

100 0.0 62.0 ± 6.2 38.0 ± 6.2

*(Values shown are the average of two independent analyses and nor malized to 100%).

The plots of % acid versus % product corresponding to the Tables

XII and XIII are shown in Figure 5. Tl UD -sC (X>

U l o IOO O

CO O m % P R O D U C T

0 50 IOO VoH2SO4 % ^ s o 4 49

Graphs A and B show the influence of acid concentration on the

reaction profile and product composition, respectively. It is seen

that at low acidities (up to— 50%) negligible reaction occurs. At

higher acid concentrations the diene (1_7) is the predominantly formed

product and water probably facilitates the dehydration. Above 90%

acid concentration the yield of the diene drops down and that of the

spiroketones correspondingly increases, ultimately reaching 100% for

100% acid. Also, in agreement with the results presented e a rlie r, (19)

is the major spiroketone at all acid concentrations except concentrated

sulfuric acid where the spiroketone (1^) predominates.

In order to verify the above results, the effects of acid concen

tration were also studied on one other pinacol, namely, cyclopentyl-

cycloheptane-1,1'-diol (21_). The reaction was carried out under sim

ila r conditions using 25%, 45%, 75%, and 100% sulfuric acid (by weight). The results are presented in Table XIV. 50

TABLE XIV

Effects of Acid Concentration on the Rearrangement

of Cyclopentyleye!oheptane-i,1'-diol (21).

H2S0^(%) Product Composition {%)*

(by weight) 22 23 24

25 29.9 0.8 69.3

45 18.9 1.0 80.1

75 0.0 3.6 96.4

100 0.0 5.2 94.8

*(Yields reported are normalized to 100%)

As seen from the data in Table XIV, the trends observed for the products at increasing acid concentration are similar to those ob served for the pinacol (16) reaction. Although at lower acidities appreciable amount of the diene (22) is formed, the major product in variably is the spiroketone (24). This suggests that the carbonium ion on a seven-membered ring is preferred to that on a five-membered ring.

Thus, i t is the cyclopentane ring that gives more expansion.

From the above experiments, i t is evident that the course of the pinacol rearrangement is very dependent on the reaction conditions. At

0° in concentrated sulfuric acid the major course of the reaction for

the pinacol (Te) is the kinetically controlled formation of the spiro- 51 ketone (T_8), reflecting the ease of formation of carbonium ion in ring systems. At higher temperatures the thermodynamically stable spiroketone (19) is the ultimate product of rearrangement.

I t is , therefore, necessary to exercise caution when dealing with rationalizations based on carbonium ion s ta b ility or product s ta b ility and it is essential that the reaction conditions be well defined in order that they may be meaningful.

As a further test and in order to clarify the implications of the pinacol rearrangement from a broader perspective, a d ifferen t pinacol system, namely, trans-perhydrobenzocycloheptane-10,11-diol (75) was chosen for the study (Figure 6).

Figure 6. trans-perhydrobenzocycloheptane-10,1I-d io l.

This bicyclic pinacol was prepared from benzosuberone (67) by a multi-step reaction sequence (Chart 23). (See experimental section

III for details.) Incidentally, it is interesting to note the isomer ization of (72) to (7J_) during the lithium-amine (Benkeser) reduction of the Birch reduction products. 52

L i / NH3 EI2O 68 ( 20%) 6 5 ( 100 %) (78-7%)

C2H5NH2 + C3H7NH2 ,

L i; Et2O Tl 72

(I-O0Zo) ( 20-3%)

Tl Z2

(573% ) DlL AC I D MCP B CHCI3 (100 %)

Chart 23. Synthesis of trans-perhydrobenzocycloheptane-lOJI-dio). 53

Treatment of the diol (75) with concentrated sulfuric acid at O0

produced the spiroketones (18] and (1_9) w ithout undergoing any second ary rearrangement.56,57’58,59 (Chart 24).

-cb*do £> 19 OH 18 75 (7 5 .7 %) ( 2 4 .3 %)

Chart 24. Pinacol Rearrangement of trans-perhydrobenzocycloheptane- 10,11-diol.

The major product formed was (18] as expected from the standpoint of carbonium ion stability. The possible rationalization is shown in

Chart 25. 54

Chart 25. Rationalization of the Pinacol Rearrangement of trans- perhydrobenzocycloheptane-10,11-d io l.

The product composition seems to suggest that the major course for the rearrangement follows the path involving the more stable carboniurn ion (77). From this it follows that a carbonium ion on a seven-membered ring is favored over th a t on a six-membered ring in 55 accord with the previous conclusion.

Analogous results for the pinacol rearrangement of the cis-quaiol 82 (81) to s p iro terpenoids have been reported.

Summary

The results of the rearrangement of the representative pinacols discussed in the preceding section definitely point out the importance of the reaction conditions. When evaluating the ring size effects on the course of the pinacol rearrangement in terms of carbonium ion stability or product stability, it is highly proper to define the re action conditions for otherwise interpretation of results may lead to erroneous conclusions. In the earlier investigations, not only were the results misinterpreted, but also the pinacols used in the reactions were not pure. In addition, random reaction conditions that were used led to many complications and therefore, meaningful conclusions could not be reached.

In the present study of the effects of ring size on pinacol rearrangement, pure pinacols were used. The reaction conditions em- 56 ployed were such that secondary skeletal reorganizations of products did not occur. Also, since the experiments were conducted in dupli cate, the statistical validity of the results was ensured.

The important feature of the present study is that the primary rearrangement products obtained at 0° with concentrated sulfuric acid reflect the carbonium ion stability as the chief factor in the course of the rearrangement. This accordingly explains the observed ring expansions. Thus, for the unsymmetrical pinacols (16), (21), and (48) studied, the major spiroketones produced are (18), (24), and (51) respectively, suggesting the following ring expansion trends:

Cg Cy > Cg -—e» Cg; Cg -—$s- Cg %> Cy — > Cg. ;

C6 o Cy %> Cy Cs" Cg

83 The observed trends actually conform to the ring strain data, according to which the order of increasing strain is Cg Cy Cg

C0. In this connection it should be noted that the preferred formation of (19) under condition of 25% sulfuric acid at reflux is consistent with secondary rearrangement to the thermodynamically more stable 4 product.

In support of the conslusions reached from the present study, it can be noted that the relative reactivities of cycloalkyl tosylates to 55 acetoylsis reflect the ease of formation of carbonium ion in the 57

order Cy Cg %> Cg (Table XV).

TABLE XV

Comparison of Rate of Acetoylsis of Cycloalkyltosylates

Rate of Acetolysis (d)

m = 6 0.88

m = 7 27(b)

(a) The tosylates were treated w ith CHgCOOH a t 6 0 °C .

(b) At 5 0 ° C .

Similar relative reactivities have been observed for cyclic 84 ketones during th e ir reduction by sodium bprohydride. 85 Furthermore, DeBernardis working in our laboratory, observed some interesting results for hydroboration and oxymercuration of the alkene (82) and pinacol rearrangement of the 1,2-glycol (85) (Chart 26) 58

2. OXIDATION

89% 11% (cis)

85% 15% ( t r a s )

Chart 26. Hydroboration, oxymercuration, and pinacol rearrangement Studies of other Analogous Systems.

The firs t two reactions abide by anti-Markownikoff and Markowni- koff hydration techniques respectively. No doubt the three reactions follow different mechanisms, but they all appear similar in one res pect. That is, the positive charge shown at the carbon atom in the in termediate (86) is more stable. This further reinforces the notion 59 that carborn*urn ion formation from pinacol, not product stability or alcohol basicity is the driving force in the course of the pinacol re arrangement at 0° with concentrated sulfuric acid. 60

SCOPE AND LIMIT OF THE STUDY

The present study provides a basis from which one should be able to predict the course of pinacolic rearrangement of 1,2-glycols for a given set of reaction conditions. The primary characteristic that has been demonstrated to be a useful probe to the mechanistic mysteries of the rearrangement seems to be none other than the well used concept of "carbonium ion stability". As is seen from the experimental data presented throughout the discussion, this concept has succeeded in ex plaining the observed results.

From a practical viewpoint, since the rearrangement of bicyclic

1,2-glycols leads to formation of spiranones, the study offers a simple but elegant way of synthesizing many naturalIy occuring spiro com pounds. A few reviews on the methodologies, including the pinacolic rearrangement of 1,2-glycols, for the synthesis of spiroketones have 86 appeared recently. The following scheme for the synthesis of spiro compounds could probably be suggested (Cahrt 27).

Ketone I + Ketone 2 — Pinacol condensation ------► PI NACOL (Same or different)

Rearrange ment I . Reduction SPIRO COMPOUNDS ------SPIROKETONES ------2. Modification Chart 27. A Scheme for the Synthesis of Spiro Compounds. 61

By devising the reaction conditions suitably for the rearrange ment step it should be possible to obtain the desired spiroketone, exclusively.

In view of their biological activities, the spiro compounds have been of much interest to chemists. Many of the naturally occurring ones have been successfully isolated and their synthetic strategies are explored. It is appropriate, at this juncture, to lis t a representative sampling of naturally-occuring spirane compounds

(Chart 28). By retrosynthetic analysis, syntheses of these or their precursors by a pinacol rearrangement can be devised. Representative of this is the synthesis of Axisonitrile-3, outlined in Chart 29. .

It is of interest to.note that the requiste precursors to the diol are available by well-established, general synthetic procedures. 62

Lubimin Axisonitrile-3

(Antifungal metabolite From "Axinella Canna- isolated from "Solanaceae") bina" Tetrahedron, 32, J. Chem. Soc., Chem. Commn. 473 (1976) 1975, 431.

/? -Vetivone CX-Alaskene J. Org. Chem., 35, 192 (1970) Tet L e t t ., 1970, 2277

H1CO

Pronuciferine (belongs to Proaporphine alkaloids series) Chem. Revs., 68, 321 (1968)

Chart 28 Typical natural spirocompounds. 63

Chart 29. A model synthesis of AxisonitriI e-3. 64

Despite the fact that the present work has attempted to unravel some very intricate issues concerning pinacol rearrangement, it is limited in its scope in that it pertains only to the chemistry of un substituted bicyclic pinacols. Complications are likely to arise with substituted pinacols for then the migratory aptitudes, steric re quirements, etc., probably become operative. However, investigations on these lines were not pursued and therefore the area is s till open for future work. 65

PART I I

PINACOL rearrangement w ith sulfur transfer reagents

Introduction

The study of pinacolic rearrangement under conditions other than

the acid catlaysts has not received much attention. Perhaps the

rearrangement of 1,1,2-triphenyl ethylene glycol (111) to diphyenyl- methyl phenyl ketone(112) at its melting temperature could be noted

as the e a r lie s t re p o rt.

HO (?H . M Ph-C--^-Ph —=• H-C-C-Ph

Ph H Ph

111 112

Chart 30. Pinacol Rearrangement of 1,1,2-triphenyl ethylene glycol.

O O O Q Recently, Harpp and co-workers ’ have developed a number of

sulfur transfer reagents (Table XVI) that are useful in the formation

of sulfur-containing cyclic and chain polymers. A salient feature

of these reagents is that they contain a common nitrogen heterocyclic moiety as a leaving group and therefore are capable of reacting with

necleophiles. Thus, compounds with identical bifunctionality have been

found to react with these reagents to form sulfur-containing hetero 66 c y c lic systems (Equation 3 ).

TABLE XVI

Sulfur Transfer Reagents

N- X N-S-N PKa90 of the X conjugate acid

I N1N1-Thiobisimidazole N N - 6 .9 5 W 2 N,N'-Dithiobisimidazole

I N1N' -Thiobisbenzimidazole 5.53 00 2 N1N1-Dithiobisbenzimidazole

I N1N1-Thiobis-1,2,4-triazole N ^ N - 2.27 W 2 N1N1-Dithiobis-1,2,4-triazole I N1N1-Thiobis-I,2,4-benzotriazole 1 .6 QO 2 N1N'-Dithiobis-I,2,4-benzotriazole

(CH2 )n N - S 5rN (CH2)n X

X= I

n = 2 , 3 , Or 4 Z= S, NH ,0 , Or NR equation 3

With benzylic alcohols of the type (113) and (114), the corres

ponding sultines (115) and (116) are formed (Chart 31). 67

OH SIR OH

113 115

HO OH O-S d>-

(SIR = Sulfur Transfer Reagent)

Chart 31. Rearrangement of benzylic alcohols.

The mechanism that has been postulated for these reactions in volves an in itial protonation of the reagent, followed by the displace 88 ment of the heterocyclic moiety by the nucleophile (Chart 32). ..HVN N----S ----N+M N—H R-X R - ALKYL OR ARYL CROUP

X = O , NH, S , OR NR

-S-X-R + W W"

Chart 32. General mechanism of reaction w ith Sulfur Transfer Reagents 68

The reactivities of the sulfur transfer reagents are found to follow the same order as found for the dissociation of their conjugate acids (117)^ (also see Table XVI). Accordingly, the imidazole rea gents have proved to be the most re a c tiv e .

The u tility of the sulfur transfer reagents has been extended to 89 the study of 1,2-glycols. Thus, the reaction of cyclopentylcyclopentane-1,11-diol (40) with N.N'-thiobisbenzimidazole (TBBI) in carbontetrachloride at reflux for five days has been reported to yield two products, namely, the spiroketone (53) and the sulfoxylate exter (88).

The sulfoxylate ester, however, proved to be unstable and inseparable and therefore it could not be characterized. The olefins (39), (52), and (87J as well as the sulfite {8 9 ) and the thionosulfite (90) were not produced (Chart 33).

HO OH // O-^O —> O=O + 0 -0 + O=O G o 40 ' 3 9 52 87 53

-CuO 9 0

Chart 33. Reaction of Pinacol (40) with Thiobisbenzimidazole (Harpp and co-workers). 69

On the other hand, the reaction of cyclohexylcyclohexane-1 ,V - diol, (42) with the reagent under similar conditions has been reported 89 to give a number of products of which the thionosulfite (94) was the major product. No spiroketone (55) was detected. The yields of the other products have not been reported (Chart 34).

HO OH CuO 5 Oz3O+O-O 4_L cy, Reflux, 5 days 25

* c y - d b 55

A A X * cm *0-0 + OO 52 33 94 Chart 34. Reaction of Pinacol 42 with Thiobisbenzimidazole (Harpp and co-workers).

During the time when the study of the acid-catalyzed pinacol rearrangement was progressing in our laboratory, it was interesting to note the above results, particularly the formation of the spiro ketone (53) in the reaction of the pinacol (40) with N,N'-thiobis- 70 benzimidazole. The preliminary reports of Harpp and co-workers^ on the subject provided incentive to further explore in our laboratory the u tility of this reagent (TBBI) in effecting pinacol rearrangement.

Therefore, in continuation of the previous study, an attempt was also made to look into the possibilities of pinacolic rearrangement occurring under . honacidic conditions. In this study the same series of pinacols was used and a discussion of the results obtained is presented in the section to follow. 71

RESULTS AND DISCUSSION

The reaction of the cyclohexyl cyclohexane-1,1'-d io l, (42J with

N,N'-th iobisbenzimidazole in carbontetrachloride at reflux yielded

several products of which the thionosulfite (94) constituted a larger

proportion (Chart 35).

HO OH CUO OK31 + CHD * CHD

0A 0 P

2 3 2 4

Chart 35. Reaction of Cyclohexylcyclohexane-I,11-d io l, with N,N'-Thiobisbenzimidazole.

From the results reported, it is seen that although the thiono

sulfite (94) is the major product as has been the case with the earlier 89 study, the formation of the spiroketone (55) is significant. This 72 ketone has not been reported previously. The low y ie ld o f the ketone is probably attributable to the fact that under the reaction conditions the intermediate formed involves a carbonium ion on a six-membered ring which is unfavorable to ring expansion (see Part I). The alternative course for the reaction is therefore to undergo either dehydration to yield olefins or form the thionosulfite (94). An interesting feature of the reaction is that the olefin (41_) is, however, not formed in the corresponding acid-catalyzed reaction of the pinacol. The diene (91) 89 whose formation has been reported by earlier workers was not de tected .

Harpp and co-workers*^ have proposed a scheme to provide a ra tio n ale for the observed products of this reaction and therefore the following rationalization could be suggested on the same lines to account for the rearrangement (Chart 36).

On re flu x in g cyclo h ep tylcyclo h ep tah e-1,1'-d io l (44;) w ith the ben zimidazole reagent in CCl^, the same products as observed for the cor responding acid-catalyzed reaction except the alkene (43J were produced

(Chart 37). 73

n d \

\ C H D -O jO -SO2 I - OO OO 5 4 OO SI

Chart 36. Rationalization of the Pinacol Rearrangement of Cyclohexyl - cyclohexane-1,11-diol with N,N'-Thiobisbenzimidazole. 74

Chart 37. Reaction of Cycloheptylcycloheptane-I,1'-diol with N,N1-Thiobisbenzimidazole.

The results show that the pinacol (44) has undergone substantial

rearrangement, even though the major product is the diene (56). The diene (95) was not formed probably because it is less stable than (56).

It is surprising, however, to note that no thionosulfite (98) was

formed for this pinacol. The preferred formation of the olefins to the

thionosulfite (98), sulfite (97), or sulfoxy!ate ester (96), is prob

ably because of steric factors involved in the sulfur-containing struc

tures. However, it is difficult to offer proper explanations without

substantial experimental evidence. It should be noted, on the other 75

Band, that the analogous sulfite and thionosulfite have not been ob- on taihed for the pinacol (40) reaction.

The reactions o f un symmetrica I pinacols (1_6), (2 1 ), and (48) w ith the benzimidazole reagent under similar conditions yielded several products in each case (Charts 38, 39, and 40). A comparison of the product compositions for the three series is presented in Table XVII.

The results indicate the following trends:

1. Dehydration constitutes the major course for the reaction.

Generally, the dienes are favored over mdnoalkenes as has been

the case with acid-catalyzed reactions (see Part I). Also, the

symmetrical dienes predominate over the unsymmetrical ones.

2. All these reactions have suffered pinacol rearrangement. Except

for the pinacol (21_), the yields of spiroketones for the pinacols

(16) and (48) parallel those of the corresponding sulfur deriva

tives. These results seem to point out that benzimidazole can

affect rearrangement.

3. In each series, the predominantly formed spiroketone is the one

expected in light of the conclusions reached in the previous

study. The most favored spiroketone for the three series is (24)

and again the interpretation is that the carbonium ion on a

seven-membered ring is more favorable and th a t the C5-H n g ex

pands to the C5-Hng, thus adding more stability to the product. 76

A possible explanation of the oefinic products formed preferen tially is that, in view of the rationalization suggested above (Chart

37), higher temperature probably favors decomposition of the sulfur derivatives that formed firs t. 77

HO QH -»CKO+ cyo + o o + co 4 5 17 99 18

A X X cm cm OO 102 I^ Q IQl

Chart 38. Rearrangement of cyclopentylcyclohexane-IJ'-diol (16) with N1N1-Thiobisbenzimidazole. 78

HO OH

O O

Chart 39. Rearrangement of cyclopentyl cycloheptane-1,1'-diol (21) with N,N1-Thiobisbenzimidazole. 79

HO OH + +

47 107 4 3

4 3 . 5 0 5!

A. o< +

108 109 UO

Chart 40. Rearrangement of cyclohexylcycloheptane-1,I'-d io l (48) with N,N'-Thiobisbenzimidazole. TABLE XVII

A Comparison of the Results of the Reaction of Unsymmetrical

Pinacols with N,N'-Thiobisbenzimidazole

MIXED PINACOL PRODUCT RATIO (%)

16 45 17 99 18 19 100 101 102 % Y ield 46.5 37.9 0.0 0.6 6.5 3.6 2.8 2.1

21 46 22 103 23 24 104 105 . 106

% Y ield 9.5 45.1 8 .5 4.1 31.7 0.6 0.4 '0.1

48 47 49 107 50 51 108 109 n o

% Y ield 7 .0 58.2 8 .4 2.6 9.6 0.7 7.2 6.3 81

SUMMARY

Although the results discussed in the preceding section certainly demonstrate that the sulfur transfer reagents, such as benzimidazole, are capable of effecting pinacol rearrangement, the main course of the reaction seems to be in the direction of olefins. This is probably because of higher temperature conditions which are likely to facilitate secondary rearrangements of the in itia lly formed products. That this is so has been demonstrated for the acid-catalyzed reactions (Part I).

However, many aspects of these reactions s till remain obscure at the present writing. For instance, whether or not the reactions proceed via a concerted or a non-concerted mechanism is not yet known, although there is indication of the former course. Also, it is d iffi cult to arrive at any broader conclusions merely based on examining the reactions with only, one set of reaction conditions. Perhaps lower temperature and longer reaction time would favor rearrangement and formation of sulfur derivatives.

Therefore, any generalizations to be made in this regard should probably await more experimental evidence, particularly the kinetic

I and other physical data. Thus this study, being incomplete, offers a wider opportunity for future endeavors. 82

EXPERIMENTAL SECTION I

PINACOLS

Instrumentation

The mass spectra were obtained w ith a CH-5 mass spectrometer a t

70 ev. The in fra re d spectra were obtained w ith a Beckman-IRSA in fr a 

red spectrophotometer. The melting points of the pinacols were deter mined on a Fischer-Johns apparatus and the reported values are uncor

rected. The yields of the pinacols and al.kenes were calculated from

the glc peak areas as determined with an Autolab Minigrator and are

normalized to T00%.

M aterials

. Pure magnesium turnings (J. T. Baker) were.used. Tetrahydrofuran

(THF) was used as the solvent and was purified before use by firs t

drying it over potassium hydroxide pellets for thirty minutes and then

d is t illin g i t from lith iu m aluminum hydride under nitrogen atmos-

OC phere. The solvent was stored under nitrogen in a paraffin-sealed

brown bottle, the ketones were pre-distilled and their purity was

checked by glc prior to their use. The titaniumtetrachloride (TiCl4)

used was 99.5% pure. Unless otherwise mentioned, all the reactions

were carried out at -IO0C. 83

General Procedure for Preparing Symmetric pinacols (40), (42) and (44)

The method adopted to prepare the symmetric pinacols was th a t re ported recently by E. J. Corey and co-workers.8 Since the reactions were carried out under nitrogen atmosphere, the arrangement of the ap paratus consisted of a flame-dried three-necked flask (250 ml) fitted with a mercury-sealed mechanical stirrer, a thermometer, and a con denser, with one neck le ft free. Adapters were used to accomplish this arrangement. The top of the condenser was connected to the nitrogen source via a mercury trap which in turn was connected to a suction pump. A drierite guard tube was connected between the nitrogen source and mercury trap to free the gas of any moisture. The flask was charged with magnesium turnings (5.9g; 240mmol) and mercuric chloride

(1.74g; 6..4mmol) through the open neck and the la t t e r was then closed w ith a rubber septum. The fla s k was evacuated with the suction pump and flushed with nitrogen. The process of evacuation followed by . flushing of the flask was repeated three or four times. Dry THF

(20 ml) was injected into the flask and the mixture was stirred under nitrogen for twenty minutes. The gray turbid supernatant liquid was withdrawn by a disposable plastic syringe with a long needle (6";

No. 1 8 ). The remaining amalgam was washed three times w ith 20 ml por tions of fresh THF and the supernatant liquid was withdrawn each time before the next portion of solvent was added. More THF ( l50 ml) was added and the reaction flask was cooled in a dry-ice, isopropyl alcohol 84

bath a t -10°C. Small amounts o f d ry -ic e were p e rio d ic a lly added to

m aintain the tem perature. The use o f an ic e -s a lt cooling system proved

to be inconvenient to monitor the temperature over the long duration of

the reaction. TiCl^ (13.2 ml; 12OmmoI was now introduced drop-

wise by syringe while stirring the amaIgam-THF mixture continuously.

At this stage, the reaction mixture gradually turned to a greenish- yellow slurry. A solution of the ketone (SO mmol) in 10 ml THF was

slowly added while allowing the temperature to gradually rise to O0C.

During this period the reaction mixture turned dark purple. Stirring was continued a t O0 fo r two hours and the reaction was quenched with

a saturated aqueous solution (2 ml) o f potassium carbonate followed by

continuance of stirring for an additional twenty minutes. Ether

(50 ml) was then added and after brief stirring, the reaction mixture was filtered through a Whatman No. 41 filte r paper on which a layer of

Hyflo Super Cell was placed. The dark purple filtra te was extracted

with ether and, after washing the ether solution with saturated NaCl

solution, it was dried over anhydrous MgSO^. The ether solvent was

removed at reduced pressure to give a semi-solid crude mixture.

Reaction Reactant Weight o f Crude

A Cyclopentanone (C5) 5.40 g

B Cyclohexanone (C6 ) 5.58 g

C Cycloheptanone (C7) 7.33 g 85

Analyses of the Reaction Mixtures

. When the reaction mixtures were subjected to glc analysis on a

10% SE-SO-Anakram (70/80) column 8 ' x 1 /8 " , two peaks fo r the products were observed in each case besides a peak for the unreacted ketone.

The glc data are shown below.

Reaction A: glc at 170° and 30 psi helium

Peak # Retention Time (S ec.) Y ield (%)

1 59

2 233 28.2

3 673 71.8

CycTopentanone 60

Reaction B: glc at 170° and 30 psi helium

Peak # Retention Time (S ec.) Y ield (%)

1 78

2 482 33.4

3 1752 66.6

Cyclohexanone 84 86 Reaction C: glc at 200° and 40 psi helium

Peak # Retention Time (S e c .) Y ield (%)

2 398 4 .8

3 1314 95.2

Cyeloheptanone 66

Separation of Reaction A Mixtures: The reaction mixture obtained in

Reaction A was separated on a silica gel column with diethyl ether as the eluant. The first eluate corresponded to a liquid mixture of two compounds and one o f them was id e n tifie d by glc to be the unreacted cyclopentanone. The other compound was separated as an oil by prepara tive glc using an SE-30 column and characterized by GC/MS and IR spec tral analyses to be the alkene (39), corresponding to a mass, m/e

136(M+) and containing%>C=C

The second component eluted was a colorless so lid which on re - crystallization from ether-petroleum ether (35-60°) gave colorless, shiny platelets, yield 4.80g (71.4%). Mass and infrared spectral anal yses showed a mass, m/e 170 (Appendix I) and the presence of -OH

-I group (3379cm" , strong) respectively. Thus, the compound corresponded to the pinacol (40). The observed m.p. was 108-109° (literature m.p.

109-111°,28 111-112,8 and 11.4-112.429). 87

Separation of Reaction B mixture: The reaction mixture obtained in

Reaction B was separated on a silica gel column with petroleum ether

(35-60°)-ether mixture (50:50) as the eluant. The first eluate yielded a mixture of two products of which one was identified by glc to be the unreacted cyclohexanone. The other compound was separated as a solid by preparative glc and mass determination showed a mass, m/e 164(M+)

(Appendix II). The IR spectrum contained a weak absorption band at

1666cm""^ corresponding to%>C=C

The second compound eluted was a colorless solid and r e c r y s ta lli zation from petroleum ether (35-60°)-ether mixture gave colorless puffy long needle-shaped crystals; yield 5.2g (65.7%). Mass determination showed a molecular ion peak at m/e 198 (Appendix I) and IR spectrum

-I contained a strong absorption for -OH group (3375cm ). Thus, the compound was characterized as the plnacol (42), m.p. 126-127° (lite ra ture m.p. 124-125°8 and 124.5-126.5°28).

Separation of the Reaction C mixture: The reaction mixture of Reaction

C was separated by column chromatography using silica gel column and . petroleum ether (60-110°)-ether (75:25) as the eluant. The first fraction obtained was evaporated to give an oil which by glc was found to contain two products. One of them was identified to be the un reacted cycloheptanone. The other product was separated as an oil by

i 88

preparative glc and mass determination showed a molecular ion peak

at m/e 192 (Appendix I). the IR spectrum contained a very weak absorp- -l tion band at 1664-1645cnT indicating the presence of a Z>C=C

group. By comparison of its mass spectral datum with tha reported for cycloheptylidenecycloheptane, the compound was characterized to

be the alkene (43).

The second fra c tio n was evaporated to give a colorless solid which on recrystallization from petroleum ether (60-110°) formed colorless shiny platelets; yield, 8,55g (94.4%). MS, m/e 226(M+) (Appendix I); -I IR, 3356cm" , strong (-0H group). These data were consistent with pinacol (44), m.p. 73-73.5°.

Preparation of the Unsymmetric Pjnacols (16), (21), and (48).

The reactions for preparing the unsymmetric pinacols were carried out as described in the general procedure for preparing the symmetric pinacols except for the following:

1. A larger reaction flask (500 ml) was used.

2. Two different ketones and other materials in quantities as"men

tioned below were used.

Ketones, 0.2 mole each; Magnesium turnings, 1,0 mole equiv.;

Mercuric chloride, 44.2 mmol; TiCl 45 50 ml (455mmol ) ; THF,

300 ml; Potassium carbonate (aqueous saturated), 10.0 ml. 89

The three reactions leading to the unsymmetric pinacols were the following:

Reaction Ketones Used

D • Cyclopentanone + Cyclohexanone

E Cyclopentanone + Cycloheptanone

F Cyclohexanone + Cycloheptanone

Each reaction was run three times and the reaction mixture analyzed by glc. The products were separated by column chromato graphy and characterized by the methods as described below. Glc analysis of the Reaction D mixture:

Run #1: 5% SE-30i-Chromsorb G (60/80) column (6 ' x 1 /8 ") Temperature: 140°C:; Helium pressure* 30 psi.

Peak# I 2 3 4 5 6 7 8 C5 - Rt (Sec) 23 33 101 156 242 317 626 1021 23

% Y ield — — 9.9 15.9 4 .2 11.4 44,8 13.8 - -

Run #2: 10% SE--30-Anakram (70/80) column (10' x 1 /8 " ); Temperature, 150°; H e !iurn pressure , 30 p s i.

Peak # I 2 3 4 5 6 ' 7 8 C5 - Rt (Sec) 65 91 279 425 647 763 1457 2531 62

% Y ield — — 10.7 13.3 4.1 n j I 40.4 20.3

Run #3: 10% SE--30-Anakram (70/80) column (10' x 1 /8 " ); Temperature, 150°; H e !iurn pressure , 32 p s i.

Peak # I 2 3 4 5 6 7 8 C5

Rt (Sec) 55 77 233 353 535 629 1203 2077 53

% Yield ■— ■■ ■ “ 10.1 12.9 3.9 11.7 40.8 20.6 91

Separa tio n .O f the Products

The separation of the products in each case was accomplished by column chromatography using s ilic a gel (60-200 Mesh) as the statio n ary phase and petroleum ether (60-100°) and ether mixture as the eluant in varying proportions at different stages of the separation.

Separation of Reaction D mixture: The order of elution for the Reaction

D mixture was as follows:

Eluant Fraction Composition

Petroleum ether (100%) I Starting ketones and three products corres ponding to peaks 3 ,4 , and 5.

Pet. ether - Ether (80:20) II Only one product corres ponding to peak 5.

Pet. ether -' Ether(50:50) III One product correspond ing to peak 8.

IV One product correspond ing to peak 7.

V One product correspond ing to peak 6.

Ge peaks 3, 4* and 5 were id e n tifie d w ith "a u th e n tic samples as well as by mass spectral analysis to be the alkenes (39), (45), and (41).

Fractions corresponding to gc peaks 6, 7, and 8 were identified as the pinacols (40), (42), and (16J, respectively by mass spectral

(Appendix I) and infrared (-0H group of pinacol at 3322cnf^, strong) analyses. Recrystallization of the pinacol (%6) from petroleum ether 92

(35-60°) yielded puffy long needle-shaped colorless crystals, m.p.

90-91° (literature m.p. 91°30).

Analysis of Reaction E mixture:

The reaction mixture obtained in each run was analyzed by glc and the data are shown below. Glc analysis of the Reaction E mixture:

Run #1: 5% SE-30-Anakram (70/80)column (6' x 1/8"); Temperature, 200°; helium pressure, 40 psi.

Peak # I 2 3 4 5 6 7 8

Rt (Sec) 23 33 58 88 124 174 242 552

% Y ield — 4 .5 25.9 6,9 21.3 33.8 12.1

Run #2: 10% SE-30-Anakram (70/80)column (8' x 1 /8 ") Temperature, 200°; helium pressure. , 40 p s i.

Peak# I 2 3 4 5 6 7 8

Rt (Sec) 26 43 61 124 136 260 338 807

% Y ield ' ----- 7 .7 24.8 4.6 16.9 32.3 13.7

Run #3: 10% SE-30-Anakram (70/80); Temperature 170°; helium pressure. 30 p s i.

Peak# I 2 3 4 5 6 7 8

Rt (Sec) 56 108 178 422 716 1004 1304 3528

% Y ield 11.9 32.8 1.2 11.9 35.5 6.7 94 Separation of Reaction E mixture:

The following products were eluted with petroleum ether (60-100°)- ether mixture in the order shown below.

Eluant Fraction Composition

Petroleum, ether (100%) I Starting ketones plus pro ducts corresponding to gc peaks 3 , 4 , and 5.

Petroleum ether-Ether II One product corresponding (75:25.) to gc peak 8.

III One product corresponding to gc peak 7.

IV One product corresponding to gc peak 6.

The products corresponding to the gc peaks 3, 4, and 5 were id en t ified with authentic samples by glc to be.the alkenes (39), (46), and

(43), respectively. The products corresponding to gc peaks 6, 7, and

8 were characterized as the pinacols (40), (21), and (44) by mass I ' (Appendix II) and infrared (-0H group, at 3311 cm" , strong for the pinacol (21)) spectral analyses. Recrystallization of the pinacol (21) from petroleum ether (35-60°) gave colorless shiny platelets, m.p.

63.0-63.5°.

Analysis of the Reaction F mixture:

The glc data of the three runs are as follows. Glc analysis of the Reaction F mixtures:

Run #1: 5% SE-30-Anakram (70/80)column (6 ‘ x 1 /8 " ); Temperature, ISO0C ; Helium i pressure, 40 psi.

Peak# I 2 3 4 5 6 7 8 V Rt (Sec) 24 33 106 142 230 310 558 863 24 34

% Y ield — 2.3 1.0 1.8 27.4 51.7 15.8 — --

Run #2: 5% SE-30-Anakram (70/80)column (6I' x 1 /8 " ); Temperature, 200°C ; Helium i pressure, 40 psi.

Peak# I 2 3 4 5 6 7 8 Cy-Ketone

Rt (Sec) 18 29 74 94 118 151 241 360 18 30

% Y ield — 0.7 9.2 1.0 35.8 49.9 3 .4

Run #3: 10% SE-30-Anakram (70/80)column (8' x 1/8"); Temperature, 170°C ; Hel i urni pressure, 30 psi. .

Peak# I 2 3 4 5 6 7 8 V - 7 - Rt (Sec) 68 106 360 582 980 1234 2204 3412 68 105

% Y ield 2.5 11.4 11.6 23.0 44.7 6.8 96

Separation of the Reaction F mixture:

The reaction m ixture was separated by column chromatography using silica gel and ether-petroleum ether mixture of the eluant. The order of elution was as follows •

ETuant Fraction Composition

100% petroleum ether I Unreacted ketones and products corresponding to gc peaks 3 ,4 , and 5.

Ether-petroleum ether(35-60) II . One product correspond (25:75) ing to gc peak 6.

III One product correspond ing to gc peak 7.

IV One product correspond ing to gc peak 8.

The products corresponding to peaks 3, 4, and 5 were recognized with known samples (obtained in earlier reactions) as the alkenes (41),

(47), and (43), respectively, The compounds corresponding to the gc peaks 6, 7, and 8 were characterized by mass (See Appendix I) and in- , frared spectral analyses to be the respective pinacols (42), (48) and

(44). The pinacol (48) was recrystallized from petroleum ether

(35-60°) to yield colorless crystals, m.p. 99-9915°; IR, -OH absorption a t 3290cm"^.

Reductive Coupling of Cyclopentanone and Cyclohexanone at Room Temper ature and at Reflux (THF)

The procedure followed in these reactions was the same as des 97 cribed for preparing the symmetric pinacols except that the reaction flask was kept immersed in a water-bath (22°C) for the reaction at room temperature and the flask was heated with a heating mantle for the reaction at reflux. Also, smaller quantities of the materials as men tioned below were used.

Materials: Ketones (20 mmol each); magnesium turnings (160 immolj ;

mercuric chloride (4.42 mmol); TiCl 4 (8 .8 ml; 120

mmol); THF (200 m l); aqueous saturated potassium car

bonate solution (2,0 ml).

In each case, the reaction mixture was analyzed by glc and mass spectroscopy. The resu lts obtained are shown below.

Products (39) (45) (41) (40) (16) (42)

% Yield (22°) 10.5 18.2 8 .4 13.9 33.2 15.9

% Yield (Reflux) 7.8 20.6 14.9 8 .8 26.4 21.5

Reductive Coupling of Cyclopentanone and Cyclohexanone with TiCl? 92 To a suspension of TiClg in THF kept under nitrogen and cooled to -10° was added slowly a solution of cyclopentanone (0.84g; 10 mmol) and cyclohexanone (0.93g; 10 mmol) in 10 ml THF and the mixture was stirred for two hours while allowing the temperature to gradually rise to 0°. The dark purple-colored mixture was then treated with a sat urated solution of potassium carbonate (2.0 ml) and stirring was con tinued for further thirty minutes. Ether (25 ml) was added and after 98 brief stirring, the reaction mixture was filtered to remove the undis ol ved TiClg. The filtra te was extracted with water and ether; and the organic layer, after it had been washed with saturated NaCl solution, was dried (MgSO4) , and concentrated at reduced pressure. The resultant residual mixture was subjected to glc analysis using a 15% carbowax column (10' x 1/8") at 200° and 40 psi of helium. The results are sum marized below.

Product Ratio

39 45 41 40 16 42

Rt (Sec) 334 419 554 638 1215 2014

% Y ie ld * 11.3 35.3 24.8 10.2 13.1 5.3

( * The y ie ld s reported are based on the glc peak areas as determined by an autolab minigrator.)

The six products were identified by comparison of their retention times with those of the compounds which were obtianed in a previous reac tio n . 99 aqueous m ixture was extracted w ith ether and the ether solution was washed f i r s t w ith NaHCO3 and then with saturated NaCl solution. After drying over magnesium sulfate, the ether solution was concentrated at reduced pressure at room temperature and the residual mixture was sub jected to glc analysis.

Rearrangement of Cyclopentyl Cyclopentane-1,1'-d io l, (40) with Con- centrated H 3SO^ at 0°C.

The reaction was carried out as described in the general proce dure. Glc analysis of the reaction mixture gave the following results:

Column: 5% SE-30-Chromsorb G 60/80; 6' x 1/8"

Temperature: I SO0C

Helium pressure: 40 psi

Products -

Diene Spiroketone Unreacted Pinacol(40) Pure Pinacol(40)

Rt (Sec) 114 — 179

— % Y ield 0 .0 99.03 0.97

Mass spectrum: A mass at m/e 152 corresponding to the moelcular ion

peak (see Appendix II) was observed for the spiroketo.ne. The 2,4-di-

mitrophenyl hydrazone derivative of the spirandne was prepared (orange

crystals, m.p. 114-115°; literature m.p. IlG -Il?0;10 lll-112o11). Thus

the spiroketone was characterized to be spiro [4,5] decani-one, (53), 100

EXPERIMENTAL SECTION I I

PINACOL REARRANGEMENT

Instrumentation

The products from the pinacol rearrangement of pinacols were analyzed by glc and characterized by mass and infrared spectroscopic techniques. Also, the spiroketones formed in the rearrangement reac tions were compared w ith known samples. The m elting points reported for the 2,4-dinitrophenyl hydrazone derivatives of the spiroketones are uncorrected. The yields of products reported are normalized to

100% unless otherwise mentioned.

M aterials

Concentrated sulfuric acid (Baker, 96,3%) was used.

Acid-Catalyzed Rearrangement of Pinacols to Spiroketones

General procedure: The procedure followed for the rearrangement of pinacols was. that of Botteron and Wood.6 In a flame-dried Erlen- meyer flask was taken concentrated sulfuric acid (25 ml) in which a thermometer was suspended. The fla s k was immersed in an ice-bath and the acid was kept stirred slowly by a magnetic stirrer. When the temp erature of the acid dropped down to 0°, the pinacol ( I.O^mmol) was added at such a rate that the temperature-did not change. The reaction m ixture was s tirre d fo r two hours and poured into ice (5 0 .0 g ). . 101

The compound was further confirmed by comparing its retention time with

1 2 ' that of the known spiroketone.

Rearrangement of Cyclohexyl cyclohexane-1,1'-d iol, (42) with Concen- tarted HgSO^ at 0°C.

Following the general procedure described above, a 100% rearrange ment was realized for the pinacol (42). Analysis of the reaction mix ture by glc showed the formation of only one product for which a mass at m/e ISO(M+) (see Appendix II) was observed. 2,4-dinitrophenyl hydrazone derivative of the spiranone was prepared (reddish-brown cry stals, m.p. 115-117°; literature m.p. IU -IlS 0^3). Thus, the compound was characterized to be spiro [5,6] dodecan-7-one, (55).

Glc: 5% SE-30; 200°C; 40 psi of helium

Products

Diene Spiroketone Unreacted Pinacol(42) Pure Pinacol(42)

Rt (Sec) ~ 91 154

% Yield — 100 0.0 —

Rearrangement of Cycloheptyl- cycloheptane-1,T1-diol (44) with concentrated H2SO^ at O0C.

The reaction was carried out as described in the general proce dure. Glc analysis of the reaction mixture using a 5% SE-30-Chromsorb

G (60/80)coTumn(6l x 1/8") at a temperature of 200°C and 28 psi of 102 helium pressure gave the following results.

Products

Diene Spiroketone Unreacted Pinacol(44) Pure Pinacol(44)

Rt (Sec) 103 246 384

% Y ield 4.3 95.7 0.0

The two products were separated by preparative glc and character ized individually by mass spectoscopy (diene, m/e 190 (M+)); spiroke tone, m/e 208(M+); (see Appendix II) to be cyclohept-1-enyl-cyclohept-

I'-ene (56) and spiro [6,7] tetradecan-8-one, (57) respectively. The

2 ,4 -dim'trophenylhydrazone derivative of the spiroketone was prepared

(brown c ry s ta ls , m.p. 181-182°).

Rearrangement of Cyclopentyl cyclohexane-1,1'-did!, (16) with Concen- tra te d HgSO^at 0°C.

The general procedure was followed in this reaction. The glc re sults of the two runs are given below.

glc: 15% carbowax-Chromsorb-G (60/80); temperature 180° and 35 psi of helium. 103

, ; 12 Products Known Spironories

I 2 3 18 19 Rt (Sec) -- 734 821 723 813

Run #1

% Y ield 0 .0 55.8 44.2 -- —

Rt (Sec) -- 727 807 723 813

Run #2

% Y ield 0.0 68.2 31.8 — —

By comparison of retention times, the compounds corresponding to the gc peaks 2 and 3 were identified to be spiro[4,6] undecan-6-one,

(18) and spiro[5,5] undecan-7-one,. (19), respectively. These two com ponents were further characterized by mass spectroscopy (see Appen dix II) and their 2,4-dinitrophenylhydrazone derivatives. For these purposes the sp.iranones were separated by preparative glc. The spiroketone (Tj3) was a colorless liquid and the spiroketone (1_9) a solid 10 colorless crystal, m.p. 46-47° (literature m.p, 47° ). The m.p. of

.the 2.4-dinitrophenylhydrazone derivative (brown crystals) of (18^) was

119-120°C.^ The m.p. of the 2.4-dimitrophenylhydrazone derivative

(bright yellow crystals) of (Tj9) was 122-122.5° (literature m.p. 123-

124°10). 104

Rearrangement of Cyclopentylcycloheptane-I, I ' - d i o l , (21) with Concen- trated HgSO^ at 0°C.

The rearrangement was affected by following the general procedure

as described above. The re s u lts o f three runs are summarized below.

Products

I 2 .3

Run #1: 5% SE-30; Rt (Sec) 42 56 91 200°; He, 40 psi % Yield 1.8 5.2 93.0

Run #2: 5% SE-30; Rt (Sec) 145 283 314 170°; He, 40 psi % Yield 2.5 1.7 95.8

Run #3: 15% carbowax; Rt (Sec) mm ■ 1153 1595 O CO O He, 35 psi % Y ield 0.0 5.2 94.8

The products corresponding to gc peaks I, 2, and 3 were separated

by preparative glc and characterized by mass determination and com- 12 pari son with known samples. Thus peak I was found to correspond to

cyclopent-l-enyl-cyclohept-11-ene, (22); m/e 162 (Appendix II). The

peaks 2 and 3 were identified as spiro [4,7] dodecan-6-one, (23) and

spiro [5,6] dodecan-8-one (24J, respectively (see Appendix II). The

m.p. of the 2.4-dinitrophenylhydrazones of (23) and (24) were

129-130° (bright yellow crystals; literature^ 97-98°) and 125-126°

brown crystals), respectively. V

105

Rearrangement of Cyclohexylcycloheptahe-I,1 '-d io r(48) with Concen- tra te d H 2SO4 a t 0° C.

The re s u lt o f th is rearrangement are summarized below. A 15% carbowax column a t 200°C and 40 psi Helium was used.

Products (50)

I 2 3 (Standard^2)

Run #1 Rt (Sec) 419 1056 1202 1061

' % Yield 27.3 0.1 72.6 - -

Run #2 Rt (Sec) 417 1038 1202 1043

% Yield 9.5 0.1 90.4

The products corresponding to the glc peaks 1 ,2 , and 3 were sep arated by preparative glc and characterized by mass determination (Ap pendix II) and comparison with known compounds. Then they were found correspondent to cyclohex-l-enyl-cyclohept-11-ene, (49), spiro [5,7] tridecan-7-one, (50), and spiro [6,6] tridecan-8-one, (51J respective ly. 2,4-dinitrophenylhydrazones 0f (50) and (51_) were prepared. The observed melting points were 130-130.5° and 185-186°, respectively.

Rearrangement of Cyclopentylcyclohexane-T,1 '-d io l, (16) with 25% H 2SO4 a t 0° C.

10 ml of 25% sulfuric acid (by volume) were cooled in ice to 0° and 0.1 g of the pinacol (1_6) was slowly added, while stirring, to the 106 acid. The mixture was stirred until the solid had dissolved (two hours). The reaction mixture was poured into a separatory funnel and extracted with ether. The ether extract was washed with NaCHO 3 and saturated NaCl solutions followed by drying (MgSO^). After the sol vent had been stripped at reduced pressure at room teperature, the crude residual mixture was subjected to glc analysis using a 15% carbowax column at 200° C and 40 psi of helium. The results obtained are tabulated below. Products

Diene (16) Spiranone (18) Spiranone (19)

Rt (Sec) 257 447 496

% Y ield 89.0 1.4 9.6

Rearrangement of cyclopentyl cyclohexane-1,1'-diol (16) with concentrated HgSO^ at reflux.

A mixture of 0.1 g of the pinacol (16) and concentrated sulfuric acid (20 ml) was refluxed for 1^, hours and after the usual work up,

the reaction mixture was subjected to glc analysis. No characteristic

peaks corresponding to the usual rearranement products were observed.

This was probably due to dehydration products that were produced and

these could not be characterized. 107 Rearrangement of cyclopentylcyclohexane-1 ■>!’- d io l, (16) with 25% HgSO^ a t Reflux.

A mixture of the pinacol (0.18 g; 0.9 mmol) and 25% sulfuric

acid (25 ml) was refluxed for two hours according to Sand's^ procedure.

After the usual workup of the reaction mixture with ether followed by

evaporation of the solvent at reduced pressure, the crude product mix

ture was subjected to glc on a 15% carbowax column at 180° C and

35 psi o f he!ium.

Products

Diene (16) Spiranone (18) Spiranone (19)

Rt (Sec) 388 718 808

% Y ield 41.8 7 .0 51.2

Reaction of Spiro [5,5] undecan-7-one, (19) with 25% HgSO^ at. Reflux,

A mixture of (0.05 g; 0.3 mmol) the spirpketone (19) and 25%

sulfuric acid (10 ml) was refluxed for. two hours. After the usual

workup o f the reaction m ixture w ith ether followed by evaporation of

the solvent, the residual crude mixture was subjected to glc analysis

using a 15% carbowax column a t 180° C and 35 psi o f helium. Only one

peak corresponding to the starting ketone was observed and thus there

was no. rearrangement. 108 Rearrangement of Spiro [4 .6 ] undecan-6-one, (18) with 25% HgSO^ a t 0°C.

0.05 g (0.3 mmol) of the spiroketone { 2 2 ) was stirred with 25% ■ sulfuric acid (10 ml) at O0 for two hours. The reaction mixture was quenched w ith NaHGOg .. and extracted w ith e th e r. The ether solution was washed w ith saturated NaCl solution and dried (MgSO^) . The solvent was removed at reduced pressure and the resultant crude was subjected to glc analysis using a 15% carbowax column a t 200°C and 40 psi he lium. The results obtained are tabulated below.

Products

Diene (16) Spiranone (18) Spiranone (19)

Rt (Sec) - - 434 476

% Yield 0.0 93.3 6.7

Thus, no appreciable rearrangement was observed.

Reaction of Sprio [4.6] undecan-6-one, (18) with 92% HgSO^ at O0 C.

The reaction of the spiroketone (22) was carried out as described in its reaction with 25% sulfuric acid at 0° C except that 92% sulfuric acid was used in the present case. The glc analysis of the reaction mixture showed only one peak corresponding to the starting compound.

Thus, no rearrangement of the spiranone was observed. 109 Rearrangement of Spiro [4,6] undecan-6-one, (18) with Concentrated HgSO^ a t R eflux.

0.05 g (0.3 mmol) of the spiranone (18) was refluxed with concen trated H2SO4 (10 ml) for two hours in a hot water-bath (96° C). The reaction m ixture was cooled to room temperature and was quenched with

NaHCO0. It was then extracted with ether and the ehter solution, after i t had been washed w ith saturated NaCl s o lu tio n , was dried (MgSO^) and evaporated at reduced pressure to give a crude which was subjected to glc analysis. Only one peak corresponding to the spiroketodie (19) was observed. The results showed 100% conversion of (18) to (19).

15% carbowax Spiranone Spiranone 200°C; 40. psi He (18) ( I i )

Rt (Sec), before reflux 452 --

% Yield 100 0.0

Rt (Sec), after reflux — 478

% Y ield 0.0 100

Treatment of the Reaction Mixture of the Rearrangement at Q0 C of the Pinacol (16.). with 25% H2SO4 at Reflux.

The reaction mixture obtained in the rearrangement of the pinacol

(16). with concentrated sulfuric acid at 0° contained 57.9% of the 15 spiroketorie (22) and 42.1% of the spiroket.one (23).. The mixture n o

(O.lg) was refluxed with 25% sulfuric acid (10 ml) for three hours and

the reaction mixture, after the usual workup with ether followed by

evaporation of the latter at reduced pressure, was subjected to glc

an alysis.

g lc : 15%.carbowax; 200° C; 10 psi He.

Diene (16) Spiranone (18) Spiranone (19)

Rt (Sec) -- 423 471

% Y ield 0.0 50.8 49.2

O riginal mix 0.0 57.9 42.1

The reaction m ixture was further refluxed with 50% sulfuric acid

(10 ml) and glc analysis of the reaction mixture gave the following

re s u lts .

15% carbowax; 180° C; 32 psi He.

Diene (16) Spiranone (18) Spiranone (19)

Rt (Sec) — — 800 881

% Yield 0.0 0.0 100

Thus, there was 100% conversion of spiranone (18) to spira-

none (1 9 ). m

Rearrangement of the cyclopentyl cyclohexane-1,T'-diol (16) with suT-. fu r ic acid o f concentrations 8%, 20%, 40%, 52%, 60%, 80%, and 92% by weight) at 0° C.

With 8% HgSO ^: To 3 .0 ml o f 8% sulfuric acid cooled to 0° C was added

0.03 g (0.18 mmol) 0f the pinacol (16) and the mixture was stirred for

two hours. The reaction m ixture was then quenched w ith NaHCOg and

extracted with ether. The ether layer was washed with saturated NaCl

solution, dried over anlydrous magnesium sulfate, and evaporated at

reduced pressure. The residual mixture was subjected to glc using a

15% carbowax column at 200° and 40 psi of helium.

The reaction of the pinacol (T6) w ith 20%, 40%, 52%, 60%, 80%,

and 92% s u lfu ric acid was carried out in the same way and the reaction mixture obtained in each case was analyzed by glc. The resu lts of two

runs of these reactions are summarized below.

8% H9SOyi Products Pinacol c 4 17 18 19 16

Run #1 Rt (Sec) 233 418 460 1748

% Yield 1.4 0.2 0.3 98.1

Run #2 Rt (Sec) 233 417 459 1809

% Yield 1.7 0.1 0.4 97.8 112

20%.H2SO4 Products Pinacol

17, 18 19 16.

Run #1 Rt (Sec) 240 425 472 1920

% Y ield 1.0 0.1 0.2 98.7

Run #2 Rt (Sec) 242 431 472 1927

% Y ield ■ 1.3 0.2 0.3 98.2

40% H2SO4 Products Pinacol

17. 18 19 16

Run #1 Rt (Sec) ... 238 427 469 1812

% Y ield 2.4 0.3 0.6 96.7

Run #2 Rt (Sec) 239 429 474 1834

% Y ield 1.7 0.3 0.6 97.4

52% H2SO4 Products Pinacol

IZ 18 19. 16.

Run #1 Rt (Sec) 233 421 464 1732

% Y ield 3.1 0.4 1.0 95.5

Run #2 Rt (Sec) 234 419 462 1746

' %' Y ield 2.1 0.2 0.6 97.1 113

60% H2SO4 Products Pinacol

U J l I l 16

Run #1 Rt (Sec) 236 428 472 1861

% Y ield 11.6 0.3 1.0 87.1

Run #2 Rt (Sec) 230 415 458 1770

% Yield 13.9 0.1 1.0 85.0

80% H2SO4 Products Pinacol

IZ I l J l J l

Run #1 Rt (Sec) 237 413 458 1706

% Y ield 73.0 2.4 6.1 18.5

Run #2 Rt (Sec) 246 427 458 1766

% Y ield 69.1 2.5 7.1 21.3

92% H2SO4 Products Pinacol

17 I l I l J l

Run #1 Rt (Sec) .231 417 462 —

% Y ield 64.4 12.3 23.3 0.0

Run #2 Rt (Sec) 235 421 466 1700

% Y ield 71.9 9.5 18.5 0.1 1-14

Rearanqement of Cyclopentylcycloheptane-I,1 '-d io l, (21) with 25%, 45%, and 75% H2SO4 a t O0 C.

These reactions were carried out as follows: To the stirred

sulfuric acid solutions (10 ml in each case) at O0 was slowly added

0.1 g (0.5 mmol) of the pinacol (21) and the stirring continued for

IJg hours, when a clear solution was obtained. The reaction mixture

was extracted with ether; and the ether layer, after it had been washed w ith NaHCOg and NaCl so lu tio n s, was dried (MgSO^) follow ed by its evap

oration at reduced pressure. The resultant crude mixture obtained in

each reaction was subjected to glc using a 15% carbowax column a t

200° C and 40 psi of helium. The results of these reactions are tab

ulated below.

Products Pinacol

22 . 23 24 21_

25% H2SO4 R^(Sec) 317 690 843 - —

% Yield 29.9 0.8 69.3 0.0

45% H2SO4 Rt (Sec) 321 664 866 - -

% Yield 18.9 1.0 80.1 0.0

75% H2SO4 . Rt (Sec) „ 657 858

% Y ield 0.0 3.6 96.4 0.0 115

EXPERIMENTAL SECTION I I I

Reaction I 18 Huang-Mlnlon reduction of l-benzosuberone, (67): A mixture of benzosuberone (2.0 g; 0.0.125 mmo1) , hydrazine (1.44 g; 4.5 equiv alents), diethylene glycol (40 ml), and potassium hydroxide pellets

(2.25 g; 3.56 equivalents)^ was refluxed for 2 hours to form the hydrazone. Water and excess hydrazone were distilled until the temp erature raised to a point (195-200° C) that was favorable for the de composition of the hydrazone. The residual liquid mixture was refluxed for a further four hours, cooled to room temperature, diluted with water (25 ml), and poured into 6N HCl (20 ml) solution. The mixture was extracted with CHgClg and the extract after it was washed with saturated NaCl solution, was dried (MgSO^). The solvent was removed at reduced pressure to give a crude mixture which was subjected to glc analysis. The distillate was extracted with CHgClg and the organic la y e r was worked up in the same way as before. The concentrated re sidual liquid was analyzed. It was found that only the distillate con tained the reduced product (i .e., berizosuberane) that was formed in

100% y i e l d . .

The liquid product was purified by distillation and characterized by mass, NMR and IR spectral analyses. 116 Mass spectrum (see Appendix III): molecular ion peak at m/3.146

M + I peak, a t m/3 147

base peak a t m/e 146

NMR: 1.75 £ (6H); 2.75 & (4H); 6.93 B (4H).

IR: Absence o f carbonyl absorption. Aromatic C-H stretch a t -I .2959 cm

Reaction 2: 20 Reduction of Benzosuberane, (68) by the Wilds and Nelson method.

Benzosuberane (I .Og; 6.8 mmol and 50.0 ml of ether (previously dried over sodium) were taken in a three-necked flask (500 ml), the latter was fitte r with a mechanical stirrer, an air condenser, and an inlet glass tube. The flask was immersed in a dry ice-2-propanol bath, and liquid ammonia was distilled from sodium directly into the reaction flask through the inlet tube. Thus, about .200 ml of liquid ammonia were c o lle c te d . Lithium metal! (0 .5 g ; 0.07 equivalent) was added in small pieces over a period of fifteen-twenty minutes while stirring the mixture continuously. As the metal dissolved (two minutes), the solu tio n turned deep blue. The s tir r in g was continued fo r one hour and ab solute methanol was added drop-wise taking all care to avoid foaming.

When the blue color had disappeared, more of lithium (0.2g; 0.028 !equiv alent) was added followed by the addition of methanol to the blue so lution until the color disappeared. Further addition of the lithium metal was not necessary as found from a trial reaction. More ether

3 117

(25 ml) was now added and the ammonia was allowed to evaporate. Water

(25 ml) was carefully added and the reaction mixture, after it had been stirred briefly, was transferred into a separatory funnel. The upper ether layer that separated was removed and the aqueous layer was ex tracted with two 20 ml portions of ether. The combined ether layers were washed with saturated NaCl solution, dried (MgSO^), and concen trated at reduced pressure. The residual mixture was subjected to glc analysis using a 15% carbowax-Chromsab G column ( I O1 x 1/8") at 200° C and 40 psi of helium. The results obtained are shown below.

Products______Original Compound I 2 3 : 4 Rt (Sec) 122 285 192 252 250

% Yield 5.1 1.2 19.7 74.0 —

The glc peak 4 was identified as the unreacted benzosuberane, (68)

The products corresponding to the glc peaks I , 21, and 3 were separated on a small scale by preparative glc for the purpose of mass spectral analysis and the observed masses were m/e 150, m/e 150, and m/e 148, respectively (Appendix I I I ) . Thus, the products were characterized to

be (72), (71), and (69). The diene could be (70) instead of the diene

(69). No attempt was made to characterize the diene any further as it was of no consequence to the reaction carried out subsequently. 118

Reaction 3 : 22 Benkeser Reduction of the products of Reaction 2:

This reduction was carried out with the reaction mixture obtained in the Wilds and Nelson reduction (Reaction 2). Freshly distilled n- propylamine (20.ml) was taken in a three-necked flask fitte d with a condenser and an in le t glass tube, thus leaving one neck free. A mag netic spin bar was placed for stirrin g the contents of the flask. The flask was immersed in a dry-ice-2-propanol bath. While a slow stream of nitrogen was passing through, ethyl amine was d is tille d from po tassium hydroxide pellets d irectly into the flask via the in le t tube.

When su fficient amount of anhydrous ethyl amine (40 ml) was collected, the d is tilla tio n was stopped, the d is tilla tio n unit was disconnected, and the open end of the in le t tube was closed with a screw clamp. The mixture obtained in the previous reaction was introduced into the flask. Lithium metal (0.Sg; 0.043 equivalent) was added in small pieces and the contents were stirred while bubbling the nitrogen gas through the mixture. The metal dissolved to give a blue solution in 23 about fifte e n minutes. S tirring was continued for twenty-one hours.

After four hours the blue solution disappeared and therefore more L i thium (0.2g) had to be added in order to restore the color. During this period the temperature was allowed to rise gradually to 0°. The reaction mixture was now treated cautiously with NH4Cl (2.0g) and the amines were allowed to evaporate. Water (25 ml) was added slowly and 119

the reaction mixture was extracted with ether. The ether solution'was

washed with saturated NaCI solution, dried (MgSO4),. and concentrated

at reduced pressure. The residual yellow-brown liquid mixture was sub

jected to glc analysis using a 15% carbowax column (10* x 1/8") at

200° C and 40 psi of Helium. Only two peaks were observed as shown in

the following table.

Products Original Mixture

I 2 68 69 Z l 72

Rt (Sec) 121 146 248 191 146 121

% Yield 42.7 57.3 mm M mm ■

Thus, the glc peaks I and 2 corresponded ttir, the alkene (72) arid

(71), respectively. The higher yield of (Tl) indicates that (72) has

isomerized (see the results of Reaction 2). Also, no completely re- 22 duced product (80) was formed. The olefins (Tl) and (72) were sep

arated by preparative glc for further reaction.

Reaction 4 :

Epoxidation2,^ of the alkene (71)

A two-necked flask equipped with a reflux condenser and a drop

ping funnel was charged with the alkene (0.5 g; 6.4mmol ). A solution

of m-chloroperbenzoic acid (1.0 g; 6.4 mmol) in chloroform (25 ml) was

added drop-wise to the flask while stirring the contents vigorously

. over a period of one hour. The mixture was heated to reflux for two 120 hours and then was kept undisturbed overnight. The white precipi- tate of m-chloropenzoic acid that had formed was filtered and the f i l trate transferred to a separatory funnel to be treated with NaHSO0 j (20% aqueous) solution, NaHCO3 solid ( a pinch), and saturated NaCl solution in the order mentioned. The organic layer was removed, dried

(MgSO^)1 and concentrated at reduced pressure. Glc analysis of the residual reaction mixture showed a predominant peak corresponding to the epoxide (73) in 100% yield . Mass determination showed a mass at -I m/e 166 (see Appendix I I I ) ; IR, 1250 cm" (oxirane rin g ).

Reaction 5:

Transhydroxylation of the epoxide (73)

The epoxide (73_) was stirred with a very dilute solution of sul furic acid solution for I^ hours. After the usual workup with ether followed by evaporation of the solvent at reduced pressure at room temperature, the reaction mixture was subjected to glc analysis using a 15% carbowax column (10' x 1/8") at 200° C and 40 psi of Helium.

Only one predominant peak was observed and the product corresponding to this product was separated as a viscous solid by column chromato graphy with petroleum ether (35-60°)-ether mixture (60:40) on the eluant. Mass determination showed a mass at m/e 184 corresponding to the parent ion (see Appendix I I I ) . The product was thus recognized as the trans-Q, -glycol (75) (NMR: 3.394», quartet, two-OH protons). Re- c ry s ta llization of the viscous solid was d iffic u lt and hence the 121

melting point could not be properly determined.

Reaction 6 :

Pinacol Rearrangement of the trans-ct -glycol (75)

The glycol (75) was stirred with concentrated HgSO^ at O0 for

two hours. After the usual workup with ether followed by concentra

tion of the ether solution at reduced pressure at room temperature,

the residual liquid mixture was analyzed by glc using a 15% carbowax column (10' x 1/8") at 200° C and 40 psi of Helium. The results ob

tained are summarized below.

Products Spiranone . Spiranone

I 2 18 19

Rt (Sec) 394 435 393 436

% Yield . 75.7 24.3 --

The compounds corresponding to the glc peaks I and 2 were recog

nized as the spiroketones (18) and (19), respectively, by comparing

their retention times with known samples. 122

PART I I

. EXPERIMENTAL

General Procedure for the Reaction o f.Plnacols with N9N1-Thiobis- benzimidazole (TBBI)9^

A mixture of- N,N'-thiobisbenzimidazole (0.002 mol) and the pinacol

(0.001 mol) was. refluxed in carbontetrachloride (25.0 ml) for five days. The reaction mixture was filtered to remove the precipitated benzimidazole and the filtra te concentrated at reduced pressure at room temperature. The residual crude mixture was subjected to glc analysis using a 15% carbowax column (10' x 1/8") at 200° C and 40 psi of He lium.

In each Case, the products were separated by preparative glc and identified by mass and infrared analyses as well as by comparison with authentic samples. For solid products, the melting points were determined on a Fischer-Johns melting point apparatus and the reported melting points are uncorrected. The yields of products reported are normalized to 100%.

I . Reaction of cyclohexylcyclohexane-1,1'-djol ,(42) with TBBI 123

glc analysis of the reaction mixture:

Products

. 41_ 54 91 55 92 93 94

Rt (Sec) 75 129 504 — — — 1697

% Yield 17.8 29.7 0.0 9.9 0.0 0,0 45,6

The alkene (41_), (54), and (91) were characterized by determining th eir masses (see Appendixes I and I I ) and comparison with authentic samples. Similarly, the spiroketone (55) was characterized by compar ison with the known compound and by mass spectral analysis (see Ap pendix II). The thionosulfite (94) was obtained as colorless crystals; m.p. (CHCl3) 96-98° (lite ra tu re m.p. IOO-IOlo89). IR: 1130 cm"1 characteristic of O-S-O stretch. Mass determination showed a mass at m/e 260 (M+) (see Appendix IV).

2. Reaction of cyclopentyl cyclohexane-1,1'-diol (16) with TBBI

glc analysis of the reaction mixture:

Products.

45 T7 99 18_ 19 100 101 102

Rt (Sec) 112 201 — 359 398 2316 2334 2699

% Yield 46.5 37.9 0.0 0.6 6.5 3.6 2.8 2.1

The products were characterized by mass spectral analysis and by comparison with known samples. (See Appendixes I , I I , and IV for mass spectral data.) 124

3. Reaction of cyclopentylcycloheptane-l,1'-diol, (21) with TBBI

glc analysis of the reaction mixture:

Products

46 22- 103 23 24 104 105 106

Rt (Sec) 173 269 389 554 709 1907 2373 2916

% Yield 9.5 45.1 8.5 4.1 31.7 0.6 0.4 0.1

(See Appendixes I , I I , and IV for mass spectral data of the products.)

4. Reaction of cyclohexylcycloheptane^-l ,1 1-d io l, (48) with TBBI

glc analysis of the reaction mixture:

Products

47 49 107 50 51 108 109 n o

Rt (Sec) 226 331 396 841 935 1648 2096 3427

% Yield 7.0 58.2 Si 4 2.6 9.6 0.7 7.2 6.3

(See Appendixes I , I I , and IV for mass spectral data of the

products.) 125 .

5. Reaction of cycloheptycycToheptane-1,11-diol, (44) with TBBI

glc analysis of the reaction mixture:

Products

43 56 95 57 96 97 98

Rt (Sec) 474 1048 — 1449 — — —

% Yield . 23.7 42.9 0.0 33.4 0.0 0.0 0.0

(See Appendixes I and I I for mass spectral data.) MASS SPECTRAL DATA

Appendix I

Relative Abundance (R.A.) Data

Alkene (39) m/e R.A.(%) m/e R.A. (56) m/e R.A.(%) m/e R.A.(56)

39 62.1 66 78.9 91 78.9 119 24.2

40 97.9 67 100 92 25.3 121 71,6

41 78.9 68 83.2 93 89.5 134 75.8 (M+)

44 28.4 69 25.3 94 .68.4 136 8.4 (M + I)

51 22.1 77 50.5 95 98.9 137

53 30.5 . 78 25.3 105 27.4

55 37.0 79 89.5 106 30.5

57 20.0 80 35.8 107 48.4

65 31.6 87 22.1 108 22.1 127

Alkene (41) m/e R.A. (0Z) m/e R.A.(%) m/e R.A. {%) m/e R.A.(%)

39 60.0 54 41.1 79 63.2 97 17.8

40 95.7 55 87.0 80 47.6 T 05 9.7

41 78.4 56 9.7 81 74.6 107 20.0

42 16.7 65 20.5 82 84.3 108 12.4

43 20.5 66 15.1 83 64,2 109 10.8

44 51.9 67 . 100 91 27.6 121 19.5

50 8.6 68 43.2 93 33.5 122 13.0

51 20.0 69 16.2 94 22.7 135 10.3

52 18.4 ; 77 35.1 95 24.8 164 41.1 (M+)

53 44.3 78 17.3 96 22.2 165 5.9 (M + 128

Alkene (43) m/e R.A.(%) m/e R.A.(%) m/e R.A. (0Z) m/e R.A.(%)

39 23.3 79 60.3 105 15,0 135 35.6

41 68.5 80 23,3 107 24.7 136 15.0

53 23.3 81 98.6 108 27.4 147 11.0

54 20.5 82 56.2 109 22.0 148 26.0

55 79.5 91 31.5 n o 13,7 163 9.6

65 12.3 93 47.9 111 17.8 164 13,7

67 100 94 30.0 121 45.2 190 . 23.3

68 34,2 95 95.9 122 16.4 192 90.4 (M+)

69 24.7 96 87.7 123 11.0 193 15.0 (M +

77 27.4 97 43.8 133 9.6

Pinacol (40) m/e R.A.(%) m/e R.A.(%) m/e R.A.(%)

39 7.0 67 43.7 95 22.2

40 9.3 68 20.5 111 8,1

41 44.4 84 50.0 113 31.9

55 43.7 85 100 152 2.2

57 33.0 86 24.6 170 0.7 (M+) 129

Pinacol (42) m/e R.A.(%) m/e R.A.(%) m/e R.A. (0Z)

39 10.0 70 7.5 99 100

41 28.8 77 3.8 n o 2.5

43 25.0 79 6.3 111 , 3.1

53 10.0 81 . 51.3 137 3.1

55 31.3 82 6.3 162 1.3

57 10.0 83 3.8 180 2.5 .

67 8.8 91 1.3 198 1.3 (M+)

69 7.5 98 58.8

Pinacol (44) m/e R.A.(%) m/e R.A.(%) m/e R.A.(%)

39 5.0 67 12.4 96 6.9

41 21.6 ,68 9.1 112 33.9

43 14.2 69 12.8 113 100

53 .4.1 81 . 6.9 114, Tl. 5

55 22.1 84 7.3 150 . 2.7

57 6.9 95 42.2 208 3.2

226 1.8 (M+) 130

Alkene (45) m/e R.A.(%) m/e R.A.(%) m/e ■R.A.(55)

40 70.8 82 70.8 100 58.3

43 58.3 91 25.0 117 95.8

44 62.5 93 37.5 119 95.8

47 37.5 94 29.2 121 62.5

55 29.2 95 20.8 136 25.0

79 29.2 98 45.8 150 100 (M+)

81 41,7 99 41.7 151 12.5 (M + I)

Alkene (46) m/e R.A.(SI5) m/e R.A. (55 j m/e R.A. (55)

39 . 27.3 77 20.0 96 38.6

41 59.1 79 54.5 97 11.8

.53 22,7 80 20.0 108 13.6

54 20.0 81 . 59.1 109 11.8

55 41.0 82 34.1 121 12.7

65 15.5 83 18.2 135 9,1

66 18.2 91 18.2 136 9.2

67 100 93 . 31,8 162 6.8

68 36.4 94 27.3 164 20,0 (M+)

69 15.9 . 95 50.0 131

Alkene (47)

m/e R.A.(%) m/e R.A.(%) m/e 'R.A. (35)

39 17.7 81 86.0 125 88.5

41 43.8 82 25.5 132 20.8

53 15.1 83 15.6 133 13.0

54 16.1 94 32.8 136 17.7

55 45.3 95 32.8 162 71.9

67 80.2 96 ■ 48.4 178 IOO(M+)

68 20.3 97 . 18.7 179 12.0 (M + I)

69 13.5 98 18.2

79 19.8 109 60.9

80 18.2 112 23.4

Pinacol (16) m/e R.A. (%) m/e R.A. (35)

55 25.2 98 48.4

57 12.6 99 100

67 15.8 148 20.0

81 44.2 166 8.4

84 18.9 184 0.1 (M+)

85 26.3 132

Pinacol (21) m/e R.A.(%) m/e R.A (%) m/e R.A.(%)

41 40.0 70 20 7 112 28.0 .

43 35.3 . 71 21 3 113 100

55 38.7 83 12, 0 149 70.0 ■

57 37.3 . 84 20 0 166 31.3

67 22.0 85 25, 0 180 0.3

69 17.3 95 32 7 194 4.0

198 0.7 (M+)

Pinacol (48) m/e R.A.(%) . m/e R.A .(%) m/e R.A.(%)

41 48.3 67 24 .1 99 96.6

42 17.2 68 13 .8 112 24.1

43 34.5 69 24 .1 113 100

53 17.2 79 ,13 .8 137 3.4

55 58.6 81 65 .5 151 2.6

56 10.3 95 41 .4 176 1.7

57 20.7 98 31 .0 194 3.4

212 1.7 (M+) 133

Appendix I I

Relative Abundance (R,A.) Data

Spiroketone (53) m/e R-A-(X) m/e R-A-(X) m/e R.A.(X) .m/e R.A.(X)

39 44.9 68 31.9 91 9.7 112 20.2

41 56.2 77 11.9 93 33.0 123 20.5

53 27.6 79 24.3 95 74.0 124 7.0

54 24.3 80 14.0 108 75.1 134 7.6

55 45.4 81 46.5 109 12.4 152 63.2 (M+)

66 14.0 82 33.0 HO 17.3 153 6.5 (M + I)

67 78.9 83 10.3 111 100

Spiroketone (55) m/e ■ R.A.(X) m/e R.A.(X) m/e R-. A. (X) m/e R.A.(X)

39 30.5 55 66.7 81 74.3 98 12.8

40 22.0 67 100 82 30.0 108 31.7

41 65.5 68 27.7 83 13.3. 112 12.0

42 17.3 69 18.8 94 22.5 125 26.5

43 17.7 77 10.8 95 25.3 162 12.4

53 24.5 79 18.9 96 36.9 ' 180 14.0 (M+)

54 26.5 80 18.9 97 13.6 181 2.8 (M + I) 134

Spiroketone (57) m/e R.A.(%) m/e R.A(%) m/e R.A.(%) m/e R.A.(%)

39 27.3 56 22.7 91 22.7 n o 36.4

40 18.2 57 18.2 93 13.6 111 18.2

41 91.0 67 ■ 81.8 94 18.2 123 27.3

42 18.2 68 27.3 95 63.6 149 22.7

43 27.3 .69 31.8 96 54.5 190 13.6

44 18.2 79 22.7 97 18.2 208 18.2 (M+>

53 27.3 81 100 98 45.5 209 4.5 (M +

54 31.8 82 63.6 108 18.2

55 91.0 83 . 27.3 109 22.7

Alkene (17)

m/e R.A.(%) m/e R.A.(%) m/e ■R.A. (%) m/e R.A.(0Z)

36 46.9 65 27.2 81 29.6 107 42.0

38 16.0 66 24.7 91 91.4 119 37.0

39 38.3 67 51.9 92 44.4 120 27.2

41 51.9 77 4.0 93 35.8 134 34.6

51 19.6 78 37.0 94 13.6 148 100 (M+)

53 22.2 79 85.2 105 48.0 149 14.8 (M + I)

55 13.6 80 84.0 106 23.0 135

Spiroketone (18) m/e R.A. {%) m/e R.A.(%) m/e R.A.(%)

36 48.4 80 37.0 148 32.3

41 56.5 81 43.5 166 53.2 (M+)

44 43.5 82 45.2 167 6.5 (M +. I)

55 43.5 96 79.0

67 100 125 79.0

Spiroketdne.(19)

m/e R.A. {%) m/e ' R.A.(%) m/e R.A.(%)

36 47.4 95 34.8 125 21.5

41 42.2 98 42.2 148 11.9

55 37.8 111 100 166 45.2 (M+)

67 63.0 122 26.0 167 6.0 (M + I)

81 54.0 124 . 22.2

Spiroketone (23)

m/e R.A.(%) m/e R.A.(%) m/e R.A.(%)

41 58.6 81 38.0 180 33.3 (M+)

55 43.7 82 70.0 181 5.7 (M +. I)

67 100 95 82.8

80 40.2 162 33.3 136

Alkene (22) i. m/e R.A.(%) m/e R.A.(%) m/e R.A. {%) m/e R.A.(%)

42 32.8 67 53.7 82 22.4 111 25.4

43 23.9. 68 41.8 84 17.9 112 8.9

44 34.3 69 23.9 . 91 26.8 119 10.4

53 26.9 . 77 18.7 93 23.9 134 11.2

54 22.4 79 32.8 94 14.9 135 8.2

55 100 80 28.4 95 31.3 148 4.5

56 29.9 81 37.3 98 23.3 162 13.4 (M'

Spiroketone (24)

m/e R.A.(%) m/e R.A.(%) m/e R.A.(%)

39 24.7 68 30.1 125 21.5

41 57.0 81 51.6 136 25.8

44 ■ 21.5 82 29.0 . 162 19.4 .

54 21.5 95 48.4 180 50.5 (M+)

55 53.8 98 80.6 181 7.5 (M + D

67 62.4 111 100 137

Spiroketone (51) m/e R.A.(%) m/e R.A,(%) m/e R.A. (35.) m/e R.A. (0Z)

39 29.0 67 82.3. 95 50.0 120 16.1

41 83.9 68 29.0 96 38.7 148 - 11.3

53 22.6 69 27.4 n o 21.0 152 12.9

54 29.0 81 100 112 46.8 172 19.4

55 87.1 82 46.8 118 24.2 1.94 29.0 (M+)

195 . 4.8 (M +1)

Alkene (49) m/e R.A. (%) m/e R.A.(%) m/e R.A. (35) m/e R.A.(35)

39 20.4 79 63.5 105 59.2 121 . 30.4

41 3,8.1 80 47.3 106 20.8 133 73.8

53 19.6 81 52.3 107 46,2 134 61.2

55 25.4 91 ■ 76.2 108 26.2 . 135 19.2

65 18.5 92 30.4 117 13.8 146 74.2

67 38.5 93 55.0 118 55.4 147 73.5

77 38.1 ,94 72.7 119 25.4 160 16.9

78 22.3 95 52.3 120 ' 17.3 176 100 (M+)

177 27.3 (M + I) 138

Appendix I I I

Relative Abundance (R.A.) Data

Benzosuberane (68) m/e R.A. (%). m/e ■ R.A,(%) m/e R.A.(%) m/e R.A.(%)

39 57.6 54 13.5 79 . 11.2 116 17.1

41 28.2 63 22.4 91 74.1 . 117 76.5

44 30.6 • 64 16.5 92 28.2 118 . 44.7

50 . 14.1 65 24.7 103 19.4 131 44.7

51 35.9 68 11.2 104 83.5 • 145 11.8

52 12.4 77 28.2 105 57.6 146 100 (M+)

53 12.4 78 : 25.3 115 31.8 147 11.2 (M + I)

Diene (69) m/e R.A.(°/) m/e R.A.(%) m/e R.A.(0Z) m/e . R.A.(%)

39 31.3 66 1.4,7- 105 . 38.0 133 6.7

.41. 38.0 77 .j 18.7 106 Tl. 3 146 17.7

44 34.0 78 26.0 111 8.0 148 22.7 (M+)

51 14.0 .79 25.3 113 13.3 149 3.7 (M + I)

53 . 10.0 91 100 114 7.3

55 12.7 92 54.7 115 7.3

57 8,7 104 16.7 131 8.0 ■■■ 139

Alkene (72) m/e R.A.(%) m/e R.A.(%) m/e R.A.(%) m/e R.A.(%)

39 57.4 54 7.4 79 72.8 105 9.5

40 14.7 55 44.9 80 28.7 107 27.2

41 98.5 57 12.5 81 57.3 . 108 25.7

42 13.2 65 19.1 82 26.5 109 16.9

43 24.2 66 14.0 83 11.1 121 20.6

44 40.4 67 100 92 27.2 122 13.2

45 11.0 . 68 34.6 93 39.0 135 14.7

51 16.2 ■ 69 14.6 94 47.0 150 25.7 (M+)

52 11.8 77 30.9 95 22.0 151 3.7 (M +1)

53 31.6 78 15.4 96 11.8

Alkene (71) m/e R.A.(%) m/e R.A.(0Z) m/e R.A.(%) m/e R.A.(%)

39 14.2 . 67 29.9 96 14.2 109 20.1

40 25.4 . 68 13.4 98 22.4 122 32.1

41 23.9 77 11.9 99 30.6 123 20.1

44 26.6 79 29.1 100 15.7 135 39.6

53 9.0 .80 11.9 10.1 9.7 150 100 (M+)

54 8.2 81 27.6 107 34.3 151 15.7 (M +-I)

55 14.9 82 12.7 108 29.9 . 140

Epoxide (73) m/e . R.A.(%) m/e R.A. (%■) m/e R.A.(%) m/e R.A.(%)

39 41.0 68 15.8 92 25.3 123 22.1

40 26.3 69 34.7 93 24.2 133 15.8

41 80.0 77 23.2 94 20.0 137 75.8

44 26.3 78 13.7 95 86.3 148 34.7

53 23.2 79 40.0 . 97 17.9 166 22.1 (M+)

54 13.7 80 17.9 105 25.3 167 3.2 (M +

55 45.3 81 100 107 13.7

65 13.7 82 .14.7 HO 13.7

67 58.9 91 46.3 122 14.7 141

Trans-diol (75) m/e R.A(%) m/e R.A.(%) m/e R.A.(%) m/e R.A.(%)

39 78.8 67 73.5 93 39,4 122 44.7

40 36.5 68 31.8 94 30.0 123 14.7 .

41 79.4 69 32.3 95 41.2 124 14.7

42 38.2 70 37.0 96 22.4 133 10.6

43 70.6 71 18.3 97 26.5 134 13.5

44 26.5 77 38.2 98 51.8 135 24.7

51 22.9 78 20.6 99 17.6 136 14.7

52 17.0 79 75.9 . 105 17.0 137 10.0

53 44.7 80 31.2 107 30.6 139 11.2

54 25.3 81 57.0 108 29.4 ■ 148 8.8

55 100 82 20.3 109 16.5 149 7.6

56 23.5 . 83 33.5 TlO 15.9 164 32.9

57 31.1 84 54.1 111 11.8 166 11.2

58 15.3 85 21.8 112 10.0 180 4.1

65 24.1 91 44.1 120 13.5 182 5.3

66 19.4 92 17.6 121 22.4 184 2.9 (M+) 142

Appendix IV

Relative Abundance (R.A.) Data

Thionosulfite (94) m/e R.A.(%) m/e R-. A. (SK) m/e R.A, (SK) m/e R.A.(SK)

39 33.0 67 . 48.2 91 . 9.4 162 15.3

41 62.4 ■ 68 10.6 93 9.4 163 71 .8

42 58.9 69 35.3 94 8.2 164 27.1

43 20.0 70 23.5 95 29.4 178 2.4

44 10.6 76 16.5 96 9.4 180 3.5

48 7.0 . 77 9.4 97 10.6 196 5.9

53 15.3 79 22.4 .98 51.8 228 2.4

54 16.5 80 21.2 99 20.0 260 2.4 (M+)

55 100 81 82.4 ■ 107 8.2 261 V.W

56 11.8 82 36.5 109 9.4 262 V.W

64 18.8 83 25.9 121 10.6 143

Sulfoxylate (100) m /e' R.A.(*) m/e R.A.CO m/e R.-A-(JK)

36 90,3 55 100 111 12.5

38 33.3 67 36.1 148 12.5 (M-64) SO2

39 30.6 69 20.8 166 5.6 (M-48) SO

41 56.9 87 20.8 214 (M+) not observed

42 43.0 98 20.8

Sulfite (101) m/e R.A.(%) m/e R.A.(JK) m/e R.A. (JK)

40 86.7 67 93.3 148 66.7

45 60.0 82 100 166 13.3 (M-64)

59 80.0 109 40.0 230 (M+) not observed

■ Thionosulfite i(102) m/e R.A .(JK) m/e R.A.(SK) m/e R.A.(JK)

40 70 80 35 148 .30

41 75 81 40 166 . 15

55 100 91 30 182 (M-64) not observed

67 60 98 30 246 (M+) not observed 144

Diene ( 103) m/e R.A.(%) m/e R.A.(%) m/e R.A.(%)

39 35.6 91 96,9 118 57.5

41 53.1 92 38.7 132 70,6

65 30.0 93 70.0 133 56.9

67 48.1 94 31.2 146 25.6

77 50.6 105 48.1 162 100 (M+)

79 72.5 108 30.0 163 15.6 (M + I)

80 55.6

Sulfoxylate (104) m/e R.A.(%) m/e R.A.(%) m/e R.A.(%)

39 44.8 67 46.6 95 19.0

41 82.7 68 32.7 98 19.0 O C O 42 37.9 79 ■ 24.1 111

55 100 81 24.1 112 32.7

56 41.4 84 36.2 162 31.0

66 34.5 91 31.0 180 13.8 (M-48)

228 (M+) not observed 145

Sulfite (105) m/e R.A.(%) m/e R.A. (%) m/e R.A.(%)

39 46.3 67 46. 3 162 28.4

41 85.1 84 35. 8 180 16.4 (NI-64)

42 37.3 91 25, 4 244 (M+) not observed

55 100 m ; 26. 9

66 37.3 112 23. 9

Thionosulfite (106) m/e R.A.(%) m/e R.A. (%) m/e R.A.(0Z)

39 46.3 67 40. 2 112 24.4 ■

41 82.9 68 • 25. 6 162 26.8

42 36.6 79 24. 4 180 20.7

55 100 84 35. 4 196 1.2 (M-64)

56 40.2 91' 26. 8 260 (M+) not observed

66 36.8 m 24. 4 I

146

Diene (107) m/e R.A. W m/e R.A. (0Z) m/e R.A.OO

39 44.7 77 47.4 94 52.6 .

41 76.3 79 84.2 105 36.8

53 31.6 81 39.5 132 36.8

55 39.5 91 100 176 .50,0 (M+)

67 44.7 93 39.5

Sulfite (109) m/e R.A. {%) m/e R.A.(%) m/e R.A.(%) .

39 41.4 67 34.5 98 37.9

41 58.6 68 27.6 124 10.3

42 72.4 79 17.2 133 8.6

55 100 81 22.4 162 20.7

65 24.1 91 17.2 . 194 6.9 (M-64)

258 (M+) not observed 9

147

Sulfoxylate (108) m/e R.A .(0Z) m/e R.A.(%) m/e R.A,(%)

39 41.4 67 34.5 98 37,9

41 58.6 68 27,6 124 10.3

42 72.4 79 17.2 133 8.6

55 100 81 22.4 162 20.7 '

65 24.1 91 17.2 194 6.9 (M-48)

242 (M+) not observed

Thionosulfite (HO) m/e R.A.(%) m/e R.A.(%) m/e R.A. (0Z)

39 . 46.2 69 34.6 ' 133 20.5

41 82.1 79 38.5 176 35.8 (M-96)

42 56.4 81 33.3 194 9.0

55 100 91 35.8 . 206 5.0

67 35.8 94 35.8 274 (M+) not observed

68 41.0 112 25.6 REFERENCES AND NOTES

1. J. Wiemann, C.R. Hebd. Seances Acad. Sci., 212, 764 (1941).

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19. ( i ) Benzosuberone ( 9 9 % ) was purchased from Aldrich Chemical Company.

( i i ) Hydrazine was 8 5 % pure. (iii) Diethylene glycol (2,21-Oxydiethahol) was purchased from Baker. 20. A.L. Wilds and N.A. Nelson, Amer. Chem. Soc., 75, 5360 (1953). 21. C.K. Mann and K.K. Barnes, "Electro Cmeical Reactions in Non- agueous Systems", 1970,.Marcel Deckker, New York, pp 453, Table 14-5. 22. R.A. Benkeser, R.E. Robinson, D.M.Sauye, and O.H. Thomas, J. Amer.. Chem. Soc., 77, 3230 (1955). ' E.M. Kaiser, "A Comparison of Methods using Lithium/Amine and Birch Reduction Sustems, Synthesis, 39.1 (1972), a Review. 23. At the end of 21 hr, a small sample of the reaction mixture was withdrawn and afte r the work up as described in the proce dure i t was subjected to glc analysis. The chromatogram showed the absence of the reactants and the formation of two products. Thus, the reaction time was less than 24 hr which is usually recommended in amine/lithium reductions. 24. Organic Synthesis, 49, pp 62 (1969). 25. A.J. Gordon and R.A. Ford, "The Chemists' Companion", 1972, John Wiley and Sons, In c ., New York, pp 436. 26. Since titanium tetrachloride fumes extensively in a ir , the bottle containing i t was kept sealed with rubber septum in view of its frequent use. Every time i t was used, the material was withdrawn by a plastic syringe. 27. J.E. McMurry, M.P. Fleming, K.L. Kees, and L.R. Krepski, J. Or£. Chem., 43,3255 (1978). 28. C.R. Walter, J_. Amer. Chem. Soc., 74, 5185 (1952). 29. P.A. Naro and J.A. Dixon, J. Amer. Chem. Soc., 81, 1681 (1959). 150 30. H. Christo!, A.P. Krapcho, and F. Pietrasanta, Bull. Soc. Chim., 11, 4059-62 (1969). 31. R. F ittig , Ann, TJO5 U. (1859); ibid, 114, 54 (1860). 32. G.W. Wheland, "Advanced Organic Chemistry11, 3rd ed. , John Wiley, New York, 1960, Chapter 12. 33. C.J. Collins, Quart. Revs. (London), 14, 357 (1960). 34. "Molecular Rearrangements", Part I , Edited by Paul De Mayo, Interscience (Wiley), New York, 1963, pp 1-25. 35. Danilov, Russ. Phys. Che. , Soc., 61 , 723 (1929). 36. J.B. Ley and C.A. Vernon, Chem. & Ind. (London), 146 (1956). 37. C.A. Bunton, I . Hadwick, D.R. Llewellyn, and Y. Pocker, Chem. & Ind. (London) , 547, (1956); J . Chem. Soc (London), 403 (1958). 38. J.F. Duncan and K.R. Lynn, Jv Chem. Soc., 3512 (1956). 39. W.B. Smith, R.E. Bowman, and T.J. Kmet, J^. Amer. Chem. Soc., 81, 997 (1959). 40. T.S. Rothrock and A. Fry, I . Amer. Chem. Soc., 80, 4349 (1958) 41. N.C. Deno and D.J. Perizzolo, Jv Org. Chem., 22, 836 (1957). 42. K. Matsumoto, Tetrahedron, 24, 6851-6862 (1968). 43. Y. Pocker and B.P. Ronald, J_. Amer. Chem. Soc., 92, 3385 (1970) . 44. C.A. Bunton and M.D. Carr, J_. Chem. Soc., 5854 (1963); ibid., 5861 (1963). 45. P.D. B a rtlett and I Pockel, J. Amer. Chem. Soc., 59, 820 (1937).

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69. R.T. Conley and B.E. Nowak, Jv Orq. Chem., 26, 692 (1961), 70. J.W. Rowe, A. Melera, D. Arlgoni, 0. Jeger, and L. Ruzicka, Helv. Chem. Acta., 40;, I (1957). 71. A.P. Krapcho and R. Donn, J . Orq. Chem. , 30, 641 (1965). 72. E.J. Corey, J. Amer. Chem. Soc., 75, 2301 (1953), 73; N .I. Shuikin, 1.1. Voznesenskaya, B u ll. Acad, S c i., USSR, 1997 (1966). 74. O.H. Wheeler and E.G. De Rodriguez, Org. Chem. , 29, 718 (1964). 75. R.Yv Levina, V.R. Skvarchenko and O.Y. Oklobystin, J . Gen. Chem. USSR, 25, 1411 (1955). 76. N.D. Zelinsky and N .I. Shuikin, Ber., 62, 2180 (1929).. 77. N.D. Zelinsky and N.V. Elagina, Chem. Abstx, 40, 6058 (1946), 78. V.J. Traynelis, W.L. Hegenrother, H.T. Hanson, and J.A. Val ic e n ti, J_. Oirg. Chem. , 29, 123, (1964). 79. M.M. Godchot and G. Canquil, C.R. Acad. Sci., 186, 767 (1928). 80. A.P. Krapcho and J.E. McCullough, Org. Che., 32, 2453 (19.67). 81. C.H. Rochester, "Acidity Functions", 1970, Academic Press, New York, pp 157-164. 82. Nadgouda, S.A., Trivedi, G.K., and Bhattacharya, S.C., Indian iL Chem. , Sect. B 1976, 14 B (4), 249-51. 83. E.L. E liel, N.L. Al linger, S.J. Angyal, and G.A. Morrison, "Conformation Analysis". Interscience, 1967, New York, pp 193. 84. H.C. Brown and K. Ichikawa, Tetrahedron, ]_, 221 (1957). 85. A.R. DeBernardis, "Synthetic Routes to Perhydroazulenes studied with oxygenated models", Master's Thesis, 1971, Montana State University, Bozeman, Montana 59715. 86. A.P. Krapcho, Synthesis, 383 (1974); ibid. , 425 (1976); ibid., 77 (1978). 87. Danilov, J. Russ. Phy. Chem. Soc., 61 , 723 (1929). 153

88. David N. Harpp, Kosta Steliou, and T.H. Chan, J. Airier. Chem. Soc., 100, 1222 (1978). 89. Kosta Steliou,Ph.D Thesis^ McGill University (Canada), 1977. 90. D. Perrin, "Dissociation Constants of Organic Bases in Aqueous Solution", Butterworths, London, 1965, Supplement,1972. 91. The preliminary results on Pinacol Rearrangement of symmetrical pinacols with Sulfur Transfer Reagents were kindly supplied by Dr. Harpp of McGill University (Canada). Also, the Thiobis- benzimidazole reagent was generously donated by Dr. Harpp. 92. Titanium trichloride being sensitive to atmospheric oxygen was mixed with THF in a glove bag in an atmosphere of nitrogen. Owing to the low solubility of the material, only a suspension was obtained. This was stored in a brown bottle sealed with a rubber septum. The material was withdrawn by a syringe when i t was used in the experiment. »

U 31 Srinivasa, Ramanujan S r 34 Ring s iz e e ffe c ts on cop. 2 the pinacol rearrange ment

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