Stereospecific ring opening of cyclopropanes : a route tofunctionalized medium sized ringsCitation for published version (APA):Loozen, H. J. J. (1976). Stereospecific ring opening of cyclopropanes : a route to functionalized medium sizedrings. Technische Hogeschool Eindhoven. https://doi.org/10.6100/IR144464

DOI:10.6100/IR144464

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STEREOSPECIFIC

RING OPENING

OF CYCLOPROPANES

· A ROUTE TO FUNCTIONALIZED

MEDIUM SIZED RINGS

HUBERT LOOZEN

STEREOSPECIFIC RING OPENING OF CYCLOPROPANES

A ROUTE TO FUNCTIONALIZED MEDIUM

SIZED RINGS

PROEFSCHRIFT

TER VERKRIJGING VAN DE GRAAD VAN DOCTOR IN DE TECHNISCHE WETENSCHAPPEN AAN DE TECHNISCHE HOGESCHOOL EINDHOVEN, OP GEZAG VAN DE RECTOR MAGNIFICUS, PROF. DR. P.VAN DER LEEDEN, VOOR EEN COMMISSIE AANGEWEZEN DOOR HET COLLEGE VAN DEKANEN IN HET OPENBAAR TE VERDEDIGEN OP

DINSDAG 26 OKTOBER 1976 TE 16.00 UUR

DOOR

HUBERT LOOZEN

GEBOREN TE HEERLEN

DIT PROEFSCHRIFT IS GOEDGEKEURD DOOR

DE PROHOTOREN

PROF.DR. H.H. BUCK

EN

PROF.DR. TH.J. DE BOER

Aan mvn ouders Aan Fia

CONTENTS

In troduction

Chapter I

Chapter IJ

Ch-zpter JIJ

Solvolytic ring expansions I-1 Mechanistic backgrounds of the sal­

volysis of cyclopropyl derivatives I-2 Silver perchlorate promoted ring ex­

pansions of some geminal dibromo­

cyclopropanes I-3 Experimental sectien

References and notes

7

12

Non-solvolytic ring expansions 25

II-1 Silver tosylate promoted ring enlarge­

ment of geminal dibromocyclopropanes

II-2 Silver nitrate promoted ring expan­

sions of geminal dibrornocyclopropanes

II-3 Influences of nucleophilicity and

ring size in the aleoholysis of sorne

dibrornocyclopropanes

II-4 Structure assignments II-5 Experimental section

Raferences and notes

Stereosele~tive synthesis of gerninal endo­

iodo-exo-bromo-cyclopropanes

III-1 Introduetion

III-2 Iodination of endo-lithio-exo-bromo­

cyclopropanes

45

Chapter IV

Summary

Samenvatting

III-3 Silver fluoride as an effective catalyst in ring expansions of geminal dihalocyclopropanes

III-4 Experimental section

References and notes

Bishomoaromatic interaction in the disrota- 67 tory ring opening of cyclopropyl carbenoids

IV-1 Introduetion IV-2 Lithiation of geminal dibromocyclo­

propanes IV-3 Backgrounds of the ring opening of

cycloprópylidenes

IV-4 Behaviour of cyclopropylidenes attached to polyenes

IV-5 Experimental section References and notes

94

96

Curriculum Vitae 98

Dankwoord 99

INTRODUCTION

The important influence of steroids in the dynamics of the living organism has been accepted now for several decades. An important and fascinating achievement in chemistry was the elucidation of the metabolic pathway by which steroids are built up from the simple precursor acetic acid.

--N 3 y~~oP206-

Geranyl- ~ pyrophosphate ~

--- ----

""-, Farnesylpyrophosphate

Squalene

Lanosterol 7

In the biogenesis of steroids, especially the conversion of

squalene into the tetracyclic larrosterol constitutes a problem

of outstanding interest. In this polycyclization reaction only one tetracyclic product is formed from an a-chiral precursor.

It was assumed that an enzyme folds the squalene molecule in

such a conformation that the cyclization results in one stereo­

isomer only (the tetracyclic lanosterol). Experiments under

non-enzymatic conditions showed that the methyl substitution pattern in squalene determines the formation of carbenium

ion centers during the cyclization and therefore is respon­

sible for the formation of products having a five-membered

C-ring. This contrasts with the formation of a six-membered

C-ring exclusively in the enzymatle reaction. The stereo­

chemistry of larrosterol determines the mode of folding for

2,3-epoxysqualene (first product formed before the cyclization

to lanosterol). From model studies it can be deduced that a

chair-boat-chair folding must be involved (leading references

have been cited below 1- 4 ).

\::'-------- ~~ ....... ---·~ l,

'

0 ) ...... ,/'

In order to gain more insight in the influences of conformation

on the nature of the products originati~g from cyclization re­

actions, the synthesis of molecules which contain a part of the

squalene chain in a fixed conformation, was started.

8

n = 2,3 R:: H,C~

Preparatien of nine- or ten-membered rings (n=2 and 3 respec­

tively) containing two trans double bands and an unsaturated

C-5 side chain at an allylic position seemed to be an attrac­tive approach for the aims above. At this stage attention

was focused on the typical chemistry of medium sized rings.

In a relatively simple straight forward sequence such a molecule, containing a nine-membered basic skeleton, was

made accessible in the following way 5•

. H Br

c:x·~ AgClOt. ------5% aq. acetone

tosy !chloride ~H ~···oH

------pyridine, 0°

8r

- 5%-H:!SDt_-Clfs OH

Buli, THF;-1.5°

~H ~···oros

Br

2,1. ,l. -trimethyl­oxa-zoline, Buli,THF. -70"

9

However, several fundamental problems remained unclear in such an approach. Reduction of bramine from a trans double bond with retention of contiguration proved to be rather

cumbersome. Purthermare the control of stereochemistry was

lost completely in the reaction of the oxazoline with the

2-bromocyclonona-1,6-dien-3-yltosylate, whereas the eluci­

dation of the stereochemistry with the aid of pure spectros­copie techniques seemed to be hampered by the fact that we

are dealing with a rather scarcely explored area of these particular cyclic systems. Best outlook for the final achieve­

ment of a straight forward synthesis seemed to be incorpora­ted in the development of new synthetic methods in this field,

which allow the facile and stereocontrolled introduetion of interesting functionality and which provide a profound in­

sight in the elementary nature of reactivity in cyclic struc­tures.

JO

Rq-erences

1. W.S. JOHNSON, Acc. Chem. Res., l• 1 (1968)

2. E.E. van TAMELEN, Acc. Chem. Res., ~. 152 (1975)

3. D. ARIGONI, Pure Appl. Chem. (IUPAC), !l, 219 (1975)

4. E.E. van TAMELEN, Acc. Chem. Res., l• 111 (1968)

5. H.J.J. LOOZEN, unpublished results.

11

CHAPTER I

solvolytic nng expansions

I-1 Meohanistic backgrounds of the solvolysis of

cyclopropyl derivatives

One of the most used ways in constructing medium sized rings consists of rupture of the bond between the bridge-head

carbon atoms of bicyclic systems 1 • In this way cyclic structures containing n+3 carbon atoms can be obtained from bicyclo[ n. 1. O] al kanes.

The property of a variety of cyclopropyl systems to undergo

a- rapid solvolytic ring opening to allylic derivatives is

commonly used as the basic element of such ring expansions.

The presence of a good leaving group at Cn+ 3 of the cyclo­propane part of the molecule is a prerequisite. As such monohalo- and geminal dihalocyclopropanes represent

a favourite class of compounds for effecting such ring

expansions; the more so because they are readily accessible.

12

x

"'0<-~ . Rt. Solv

The arrangement of the substituents attached to the double bond is, of course, dependent upon the mode of ring opening of the cyclopropyl cation.

Since the announcement of Woodward and Hoffmann's rules of conservation of orbital symmetry 2

• 3 , several profound

investigations concerning the characteristic elements of the solvolytic ring opening of cyclopropane derivatives appeared

in the literature 4 13 , Solvolytic rate measurements of a

series of substituted cyclopropyl halides and cyclopropyl

tosylates were indicative for the following mechanistic

features.

1. Ring opening proceeds in a disrotatory manner, as can be

predicted from Woodward-Hoffmann rules for a two electron

system (cyclopropyl cation).

2. Substituents which are arranged cis to the leaving group

rotate inward and those which are trans to the leaving

group rotate outward. This latter condition implicates that the departure of the

leaving group and the ring opening praeeed concertedly and not as separate processes.

13

-x (exol ..!:)-k, :--1~

"A From these considerations it becomes clear that the ring expansion of ais-bicyclo[n.1.0lalkanes may lead to cyclic olefins, containing n+3 carbon atoms, exhibiting a cis or a trans geometry, depending on the original orientation of the leaving group.

-x ( endo) _______ ,_ Solv

~.,H ~Solv

_______ ,..,.. Solv

When the exo group is lost the final geometry will be trans. Endo leaving results in a cis arrangement. This solvolytic behaviour of cyclopropanes, annulated to cyclic structures, has received wide spread experimental support 1 ~- 28 •

It has been established quite recently 29 - 35 that silver perchlorate assisted solvolytic ring opening of geminal dibromocyclopropanes, annulated to seven-, eight- and nine membered rings, proceeds with loss of the more accessible exo bromine atom. The products arising from such reactions should necessarily have the trans geometry.

14

A further remarkable selectivity in this ring opening reaction results from the fact that the nucleophile enters concertedly

at the same side of the incipient allylic system from which the exo halogen atom is released, thus leading to one single

diastereoisomer only. This latter phenomenon has been observed

befare in the salvolysis studies performed by Parham et al·

on 1,1-dichloro-2,3-dipropylcyclopropanes 11• Schematically

this can be visualized as follows:

Ag+

r

2) Solv

It should be mentioned that the endo halogen atom is lost

preferentially in those compounds where the expanded ring would become too small to accommodate a trans double bond.

Then cis compounds are formed as a matter of course 36,

As an illustrative example the different rates of the

salvolysis of 7-endo-chloronorcarane, 7-exo-chloronorcarane and 7,7-dichloronorcarane are given:

~l ~\

H

k=1.4x1o-6 sec- 1 -7 1 k=4.5x10 sec

J,j

In order to elaborate a well-set up synthesis, leading to the target compounds, mentioned in the introduction, the develop­

ment of novel approaches for the introduetion of interesting functionality with control of stereochemistry was required.

As such an intensive examinatien of ring expansions in medium

sized rings seemed to be a logical beginning.

I-2 SiZveP pepchZorate promoted ring expansions of

some geminaZ dibromocycZopropanes

As substrates for the silver ion catalysed ring expansion

reactions the dibromides 1-4 were selected. They were readily

accessible by the reaction of the corresponding olefins with dibromocarbene according to the original procedure of Doering

and Hoffmann 37•

H Br

(j:' CD

H Br

~~ ®

r-~r CJ'~Br

These compounds, upon reaction with an excess of silver

perchlorate, according to the method of Reeseet aZ. 29 ,

afforded the trans allylic alcohols 5-8 as the main products.

cqc cq< . . ~" ~OH '()H -Br

H Br Br

G) (i) G)

16

Whereas the ring opening of 1 and 3 afforded only S and 7 in a smooth reaction, the ring opening of 2 and of 4 gave

besides the expected products 6 and 8 reproducible amounts of a side product (ca. 20% in both cases). These products

could be separated by column chromatography. Their micro­analyses proved to be consistent with those of the concomi

tantly formed trans alcohols. The possibility that these

by-products might be the trans isoroers 9 and 10 could be

ruled out easily. It has been established that both trans­

cyclonenene and trans-cyclodecene (which are optically active

molecules) are optically labile at room temperature 38 • 39 •

The explanation for this behaviour is based on the fact that

the olefinic hydragen can rotate through the loop of the ring

with a relatively low activation energy:

~ E "' 20 kcal/mol

(Yl ... oH

~ t:

E n.11kcal/mol

@) Br

From these values it can be seen that bath 6 and 8 exist at

room temperature as two rapidly equilibrating diastereoiso­mers. This intra molecular isomerization process can be re­

cognized by nmr. The 1H-nmr spectrum displays a double doublet

at ê 4.02 (J=11 and 4 Hz) and a multiplet at ê 4.54 for the

methine protons, and two double doublets at ê 6.03 (J=10 and

6 Hz) and at,ê 6.21 (J=10 and 7 Hz) for the olefinic proton.

For the equilibrium 8 t 10 the activation energy is so small

that at room temperature 8 and 10 are not distinguishable.

17

The spectrum displays only one double doublet for the methine proton at 6 4.17 10 and 5 Hz) and a triplet at 6 6.26 (J= 8 Hz) for the olefinic hydrogen. With all these conside­rations in mind the side products from the ring opening of 2 and of 4 must be the cis alcohols 11 and 12 respectively.

®

~OH

~Br

® From the back-ground hitherto known, there are two possibili­

ties to explain the formation of such cis products. The first possibility, an isomerization of the diastereoisomerie mixture of 6 and 8 under the reaction conditions, could be ruled out easily. Stirring of 6 and 8 with silver perchlorate in aqueous acetone did not yield 11 and 12 respectively. Another possibi­lity is based on mechanistic considerations. In case that besides the exo halogen also the endo halogen is expelled in 2 and 4, then 11 and 12 would be formed:

AgCl04 -----· 5o;. aq.acetone

This explanation seems, for the moment, not unrealistic, because it has been demonstrated that 9-endo-bromobicyclo­[6.1.0)nonane actually undergoes, though very slowly, ring opening with silver perchlorate 29 • As such the ring expansion of. 2 and 4 might be regarded as an ordinary competition of "exo leaving" VB. "endo leaving".

18

~

Table I

Salvolysis of geminal dibromocyclopropanes

with AgCl04 in 5% aqueous acetone1

Substroles Products' Mp, °C • 'field,% NMR dato (CDCI 3), 6 values

(j~· o::x 76 4,17 (dd, 1, methine H, J=9 and 6 Ez)

tlH 6 • 11 ( dd, 1 , o 1 e fin E, J = 11 and 5 Hz)

G) @ Sr

dZ~ OH

11: 4.75 (m, 1, methine Hl,

CQ< ~r 6.18 (t, 1, alefin H, J=11 Hz)

72-74 2 73 6: 4.02 (dd, methine H, J=8 and 4 Hz) H (cis) 4.55 (m, methine H)

0 @72 Br

@ 28 6.03 (dd, alefin H, J=10 and 6 Hz) 6.40 (dd, alefin H, J=10 and 7 Hz)

d Cq< 4.16 (dd, 1, methine H, J=10 and 5 Hz)

\ "Br

84-86' 65 5.37 (m, 2, alefin H) ' H

5.87 (t, 1, alefin H, J=7.5 Hz) @ cv Br

12: 4.82 (t, 1, methine H, J=8 Hz)

(\)( c::c 5.98 (dd, 1, alefin H, J=12 and 6 Hz) d Br 48-so• 71 8: 4.42 (dd, 1, methine H, J=9 and 4 Hz) (cis) 6.23 (t, 1, alefin H, J=7.5 Hz) OH

G) @77 Br

@ 23

l Reactions were carried out with initial 1 molar concentrations of silver perchlorate. 2) Crystallized from petroleum ether (60/80). 3) Crystallized from diisopropyl ether. 4) Yields arebasedon crude isolated rnatorials (purity > 95~). 5) Satisfactory analytica! data were obtained for the new products (~ 0.3~ for C and H).

I-3 Experimental seation

General. Starting materials 1-4 were prepared by a modification of the classica! procedure from the corresponding olefins and dibromocarbene• 0 • Cyclononene, required for the preparation of 4 was obtained from 2 by conversion with methyl­lithium in ether to the cyclonona-1,2-diene and subsequent reduction with sodium in ammonia- 1

• The solvolytic ring expan­sion reaction is exemplified with the salvolysis of 2 and 4. A survey of the products obtained in the salvolysis reactions of 1-4 is given in Table I.

2-Bromo-3-hydroxycyclonon-1-ene (6, 11) To a solution of 5.64 g (0.02 mol) of 2 in 50 ml of 5% aqueous acetone was added a solution of 5.36 g (0.026 mol) of silver perchlorate in 25 ml of 5% aqueous acetone. The mixture was stirred for 1 hr at ambient temperature and monitored with tlc. After addition of 50 ml of saturated sodium chloride solution stirring was prolonged for an additional 5 min. The precipitate was filtered. The filtrate was diluted with 200 ml of water and extracted with ether. Upon washing, drying and evaporation of the organic phase 3.19 g (73%) of the product was left as a colorless oil. The product consisted of two components. Chromatography (silica gel; chloroform-2% methanol as eluent) afforded 0.89 g of the cis alcohol 11 (Rf 0.29) and 2.29 g of the diastereoisomerie mixture of trans alcohols 6 and 9 (Rf 0.22). The cis alcohol was recrystallized from petroleum ether: mp 72-74°; nmr (CDC1 3) o 4.75 (m, 1, methine H), 6.18 (t, 1, olefin H, J= 11Hz). Anal. Calcd for C9H15Br0: C, 49.31; H, 6.84. Found: C, 49.29; H, 6.80.

2-Bromo-3-hydroxycyclodec-1-ene (8, 12) A solution of 5.92 g (0.02 mol) of 4 and 5.36 g (0.026 mol) of silver perchlorate in 75 ml of 5% aqueous acetone was stirred for 3 hr at room temperature. Work-up in a similar manner as described above afforded 3.21 g (71%) of the product.

20

Chromatography over silica gel (chloroform-2% methanol) as

eluent afforded 2.55 g of trans alcohol 8 (Rf 0.38) as a colourless oil: nmr (CDC1 3) ó 4.18 (dd, 1, methine H, J= 9

and 5 Hz), 6.24 (t, 1, alefin H, J= 9 Hz). The other com­ponent (0.75 g, Rf 0.44) was the cis alcohol 12 mp 48-50° (petroleum ether); nmr (CDC1 3) o 4.82 (t, 1, methine H, J= 8 Hz), 5.98 (dd, 1, alefin H, J= 12 and 6 Hz). Anal. Calcd for c10H17Br0: C, 51.50; H, 7.29. Found: C, 51.62; H, 7.31.

21

Re_[erences and notes

1. C.D. GUTSCHE and D. REDMORE, "Advances in Alicyclic Chemistry"; Carbocyclic Ring Expansion Reactions, Academie Press, New York, 1968

2. R.B. WOODWARD and R. HOFFMANN, J. Amer. Chem. Soc.,

8 ' 395 (1965) 3. R.B. WOODWARD and R. HOFFMANN, "The Conservation of

Orbital Symmetry", Verlag Chemie G.m.b.H., Weinheim, 1970

4. C.H. DE PUY, L.G. SNACK, J.W. HAUSSERand W. WIEDEMANN, J. Amer. Chem. Soc., JU, 400.6 (1965)

5. L. SKATTEB~L, J. Org. Chem., ll• 1554 (1966)

6. C.H. DE PUY, L.G. SNACK and J.W. HAUSSER, J. Amer. Chem. Soc., , 3343 (1966)

7. P.v.R. SCHLEYER, G.W. VAN DINE, U. SCHÖLLKOPF and J.PAUST,

J. Amer. Chem. Soc.,~. 2868 (1966) 8. J.W. HAUSSERand N.J. PINKOWSKI, J. Amer. Chem. Soc.,

~. 6981 (1967)

9. W.E. PARHAM, K.S .. YONG, J. Org. Chem., ~. 3947 (1968)

10. J.A. LANDGREBE and L.W. BECKER, J. Org. Chem., 33, 1173,

(1968)

11. W.E. PARHAM and K.S. YONG. J. Org. Chem., ~. 683 (1970)

12. P.v.R. SCHLEYER, W.F. SLIWINSKI, G.W. VAN DINE, U. SCHÖLLKOPF, J. PAUST, K. FELLENBERGER, J. Amer. Chem. Soc., Qi, 125 (1972)

13. W.F. SLIWINSKI, T.M. SU and P.v.R. SCHLEYER, J. Amer. Chem. Soc., 94, 133 (1972

14. S.J. CRISTOL, R.M. SEQUEIRA, C.H. DE PUY, J. Amer. Chem. Soc., !U_, 4007 (1972)

15. G.H. WHITHAM and M. WRIGHT, Chem. Comm., 294 (1967)

16. U. SCHÖLLKOPF, K. PELLENBERGERand M. PATSCH, Tetr. Lett.,

3639 (1967)

17. M.S. BAIRD and C.B. REESE, Tetr. Lett., 1379 (1967)

18. W. PARHAM and R.J. SPERLEY, J. Org. Chèm., ~. 924

(1967)

19. W.E. PARHAM and R.J. SPERLEY, J. Org. Chem., ~. 926

(1967)

20. C.W. JEFFORD and W. WOJNAROWSKI, Tetr. Lett., 199 (1968)

21. W.E. PARHAM, F.M. PARHAM, J.F. DOOLEY and M.K. MEILAHN, J. Org. Chem., ~. 3651 q968)

22. D.T. CLARK and G. SMALE, Chem. Comm., 868 (1969)

23. M.S. BAIRD and CrB. REESE, J. Chem. Soc. (C), 1808 (1969)

24. M.S. BAIRD, D.G. LINDSAY and C.B. REESE, J. Chem. Soc. (C), 1173 (1969)

25. D.B. LEDLIE and E.A. NELSON, Tetr. Lett., 1175 (1969)

26. S.R. SANDLER, J. Org. Chem. , ~. 3876 (1966)

27. S.R. SANDLER and P.S. SKELL, J. Amer. Chem. Soc., ~. 2024 (1958)

28. E.E. SCHWEIZER and W.E. PARHAM, J. Amer. Chem. Soc.,~. 4085 (1960)

29. C.B. REESE and A. SHAW, J. Amer. Chem. Soc., 2 2566

(1970)

30. C.B. REESE and A. SHAW, Chem. Comm., 1365 (1970)

31. C.B. REESE and A. SHAW, Chem. Comm., 1367 (1970)

32. D. DUFFIN and J.K. SUTHERLAND, Chem. Comm., 626 (1970)

33. M.S. BAIRD and C.B. REESE, Tetr. Lett., 4637 (1971)

34. G.H. WHITHAM and M. WRIGHT, J. Chem. Soc. (C), 1173

(1969)

35. C.B. REESE and A. SHAW, J. Chem. Soc., ( Perkin I) ' 2422 (1975)

36. P.M. WARNER, R.C. LA ROSE, R.F. PALMER, c. LEE, D.O. ROSS and J.C. CLARDY, J. Amer. Chem. Soc. , 9 7,

5507 (1975). See also references 1 2 ' 1 3' 1 4, 26' 27

and 28

2S

37. W.E. DOERING and A.K. HOFFMANN, J. Amer. Chem. Soc., ~. 6162 (1954)

38. A.C. COPE, K. BANHOLZER, H. KELLER, B.A. PAWSON, J.J. WHANG and H.J.S. WINKLER, J. Amer. Chem. Soc., !I, 3644 (1965)

39. G. BINSCH and J.D. ROBERTS, J. Amer. Chem. Soc., !I• 5157 (1965)

40. L. SKATTEB~L, Acta Chem. Scand., !l, 1683 (1963) 41. P.D. GARDNER and M. NARAYANA, J. Org. Chem., ~' 3518

(1961)

24

CHAPTER IJ

Non-solvolytic rzng expansions

II-1 SiZver tosyZate promoted ring enZargement of

geminaZ dibromoayaZopropanes

The reactions described in the preceding section are always performed by reacting halocyclopropanes, with or without silver salts, in solvents such as methanol, ethanol, aqueous acetone or acetic acid. Therefore they may be classi­fied as solvolytic ring opening reactions 1 • The role of the silver ion consists in facilitating the formation of a cyclopropyl cation by withdrawal of the halogen atom. Based on steric considerations it is self-evident that complexation will occur preferentially at the exo iite. The products ari­

sing from such solvolytic ring opening reactions are generally allyl ethers, allyl alcohols or allyl esters when these re­actions are carried out in alcohols, aqueous solvents or acids respectively. With regard to the synthesis of the target com­pounds the question was raised if the scope of this reaction could be extended such that interesting functionality could be introduced at the allylic position in one step and with control of stereochemistry. The use of silver tosylate in a neutral solvent seemed to be a good choice 2 -~. The silver ion

induces the ring opening whereby the intermediate allylic cation should be captured by the tosylate anion; thus giving a direct entry to allylic tosylates. The substrates 1-4 were used again as representative model compounds.

25

H Br

d'"' ~c ~IBr

CD 0 H Br

c:i"' . H Br

c:Jt:'Bc 0 0

Upon treatment of 1 and 3 with two equivalents of silver to­sylate in refluxing acetonitrile trans-2-bromo-3-tosyloxy­cyclooct-1-ene (13) and trans,ais-2-bromo-3-tosyloxycyclo­nona-1,6-diene (14) were formed respectively.

@ ®

The configurations of these tosylates could be confirmed easily by independent synthesis from the corresponding aleo­hals with tosyl chloride in pyridine. It is obvious that the

formation of 13 and 14 underlies the samebasic features as the solvolytic reactions outlined in Chapter I. Again the

ring expansion of 2 and 4 with silver tosylate afforded ring expanded tosylates. However, they proved to have cis double bands. Via synthesis from the corresponding alcohols they were identified as ais-2-bromo-3-tosyloxycyclonon-1-ene (15)

and ais-2-bromo-3-tosyloxycyclodec-1-ene (16) respectively. The formation of exclusively cis products from the ring

opening of 2 and 4 is rather curieus. They are nat formed by isomerization from the trans tosylates 17 and 18.

26

® This could be checked easily by control experiments. Formation of 15 and 16 by expelling the endo bramine atom from 2 and 4 is highly improbable, as there is no reason that complexing of the exo bramine would become unfavourable. Conclusive evidence is obtained from the fact that 9-endo­

bromobicyclo[6.1.0)nonane (19) is unreactive towards silver tosylate 5

•

Obviously the ring opening of 2 and 4 leads to a strained transient trans cation which isomerizes rapidly to a ~is cation befare reacting with the weakly nucleöphilic tosylate anion. In contrast, the ring opening of 1 and 3 leads ëxclu­sively to trans tosylates 13 and 14 because full development of a free trans cation would require a too unfavourable geometry. Therefore these reactions praeeed completely con­certed (a survey of the tosylates is given in Table II). The model description presented above seems to be quite "re­alistic, but it deserves to be supported by more experimen­tal evidence. Therefore a more profound investigation was undertaken.

27 '

Table II

React10n of gem,nal dibromoc_yclopropanes

with AgOTos m acetonitrile

Substroles Produels l Mp,°C Yîeld.~ó 2 NMR dol a I CDCt3 ,, b volues

Cl IBr 6.10 (dd, 1, alefin H, J=11 and 5 Hz)

a::;>( os

80-82 85 4.92 (t, 1, methine H, J=8 Hz) 2.42 (s, 3, CH 3)

CD @ Br 3

2i OT os 6.04 (t, 1, alefin H, J=8 Hz)

~IBr (j-Br 91-93 93 5.52 (dd, 1, methine H, J=10 and 5 Hz)

2.40 (s, 3,

® H Sr 5. 85 (t' 1, alefin H, J=8 Hz)

d/Br ccx 5.27 (m, 2, H cis double bond) 89-91 89 4.85 (dd, 1, methine H, J=10 and 6 Hz)

OTos 2.39 (s, 3,

0 @ Br

eX .. C::XOTos 5.75 (rn, 2, alefin IJ and methine Ü) 108-111 81 2.41 (s, 3, CH 3)

Br

0 ®

1) Satisfactory analytica! data were obtained (~ 0.3% for C and H).

2) Yields are hased upon isolated crude material (purity > 95%). ~

II-2 Bilver nitrate promoted ring expansions of

geminal dibromoeyelopropanes

The geminal dibromocyclopropanes 1-4 react rapidly with silver tosylate giving either trans or cis products. In order

to prove this tendency a series of ring enlargement reactions

with silver nitrate 6 • 7 was carried out under similar con­ditions as described for the silver tosylate promoted ring expansions. The substrates 1 and 3 gave the trans allylic nitrates 20 and 21 respectively.

The identity of 20 was proved by synthesis from the parent

alcohols with acetyl nitrate in acetic anhydride-methylene chloride mixture 8 • The structure of 21 could be established

by reduction with lithium aluminohydride in refluxing THF to

trans,eis-2-bromocyclonona-1,6-diene (22) 9,

10•

cq<" 0 cq<" AcN03 , 0 ... . "OH AcfJ CH2Ct2 "ON02

® Br @ Br

Q:,X" LiAlH4, THF Q:{<" . ... . "ON02

reflu x "H

@ Br @ Br

1 LiAIH4 ,0' ether

(9<" ' OT os

@ Br

29

Upon reaction of 2 with silver nitrate in acetonitrile ois-

2-bromocyclonon-1-en-3-ylnitrate (23) was formed as sole product. This could be confirmed by nitrating the cis alco­hol 11 .

The ring opening of 4 with silver nitrate seemed, according to tic, to afford a single isomer. However, the 1H-nmr spec­trum revealed a 1:1 mixture of ois-and tPans-2-bromocyclodec-1-en-3-ylnitrate 24 and 25 respectively.

The isomers 24 and 25 were not separable by chromatography

and could only be obtained by synthesis from their parent alcohols. The formation of both the trans and cis isomer 24 and 25 may be explained readily by assuming a competition between attack of the nitrate anion and isomerization of the trans cation into the cis cation. This contrasts with the re­

action of 4 with silver tosylate which leads exclusively to the cis tosylate 16. Apparently the nitrate anion is a better nucleophile than the tosylate anion. The formation of only a cis nitrate 23, in the ring opening of 2, is probably the result of such a severe strain in the intermediate cation that isomerization occurs far more rapidly than attack of the

nitrate anion. A survey is given in Table III.

~

Substrot es

d (Î)

~~ 0

cY: -~ w~

®

cY: ®

Table III

Reaction of geminal dibromocyclopropanes

with AgN03 in aceotonltrile

Praducts trotio)

~:02 @) Br

~NOz

~Br

@

~H ~~NO:z @) Br

WH @ 50 Br '6N0:2

cyç:o2

@ 65H

c:x::02 @so

dNOz @3S

l Yield,0/o Time,hr

71

78

62

83 3

72 0.5

NMR dato I CDCl3 I, 6 vol u es

6.37 (t, 1, alefin H, J•B Hz)

5. 76 (t, 1, mcthine H, J•B Hz]

6.33 (t, 1, alefin H, J=9 Hz) 5.86 (m, 1, methlne fl)

6.08 (dd, 1, olefln H, J•8 and 6 Hz]

5.35 (m, 2, cis double bond) 5.14 0•, 1, mcthine H]

~: 6.37 (t, 1, alefin H, J=8 Hz) 5. 21 (t, 1, methine H, J=7 Hz)

cis 5.82-6.32 (m, 2, alefin H and

methine H)

~: 4.72-5.28 (m, 1, methine H) 5.36-6.03 (m, 2, alefin H)

cis 5.20-6.08 (m, 3, methine H + alefin H) 13c (ppm downfield to external TMS)

trans: 86.8 methine C cis 82.9 mothine C

1) Yields were based on pure isolated products after chromatography.

2) Satisfactory analytical data were obtained (~ 0.3~ for C, ll and N).

With regard to the previously presented data it is clear that two factors control the cis or trans geometry of the products formed after ring opening, viz. the strain in the incipient trans cation (ring size) and the nucleophilicity of the anion. If the ring size imposes severe restrictions on the formation of a free transient trans cation, then the production of trans products is favoured, without regard to the nature of the nu­cleophile. Larger rings allow the formation of a transient

trans cation, which can isomerize to a more stabie cis cation, thus leading to cis products. The extent to which such an iso­merization takes place is clearly dependent on the nucleophili­city.

II-J InfZuenaee of nuaZeophiZiaity and ring eize in the

aZcoholysis of some dibromoaycZopropanee

It has become clear in the preceding section that the ring expansion products all originate from the same kind of a disrotatory ring opening of the cyclopropane ring. The extent to which cationic character may be ascribed to the transition state is clearly dependent on the ring size. The experiments carried out with a series of geminal dibromo­

cyclopropanes show that 9,9-dibromobicyclo[6.1 .Oinonane (2) is the smallest ring in the series which obviously possesses the property of undergoing ring opening in a semi-concerted way i.e. via a more or less free transient cation. There is no reason to assume why the solvolytic reactions should exhibit a different behaviour towards nucleophilicity than the reactions performed under non-solvolytic conditions. So, a series of solvolytic ring expansions was carried out with 2 which clearly demonstrate the effect of nucleophili­city on the cis/trans ratio of the products formed.

32

As typical reagents for such an experiment the following alcohols were chosen with decreasing nucleophilicity in the order methanol > ethanol > iso-propanol > t-butanol.

The reactions were carried out with initial concentrations

of lM of silver perchlorate at 40°. The results are summa­rized in Table IV.

Table IV

Aleoholysis of 9,9- dibromobicyclo[6.1.0]nonone

OR c:J-.,. ~ ~··~aR

@) Br

@

R Cis,% Trans,%

0 CH3 10 90

(§) C2H5 39 61

CS) iso-c3H7 53 47

@ i·C4Hg 64 36

S3

The results which are achieved with these solvolytic ring

expansions are self explanatory. A rather drastic increase

in cis products is observed with decreasing nucleophilicity

of the solvent. Obviously the influence of nucleophilicity

is in both solvolytic and non-solvolytic reactions an impor­tant factor in determining the cis/trans ratios. Alternative­

ly the ring opening reactions of 9,9-dibromobicyclo[6.1.0)

non-4-ene (3) and 8,8-dibromobicyclo[5.1.0)octane (1) should

give trans products exclusively, even if solvolyzed in the

solvent with the lowest nucleophilicity viz. t-butanol. Indeed, reaction of 1 and 3 with silver perchlorate in t-but­anol at 40° afforded only trans t-butyl ethers.

H Br

lj·~ CD

_____ ,.,.

. AgCl04-t-C4HgOH

40~ 10 min

H Br

~~, ----·

0

... (f;i'VH ~·''OH

pTSA, 0 Br

toluene

The configurational constitution of 28 and 29 was determined

readily by cleavage of the ether linkage by treatment with p-toluenesulfonic acid in refluxing toluene for 10 minutes.

This led to the formation of the known alcohols 5 and 7 (see

Chapter I). The formation of 5 from 28 was accompanied by

some isomerization to the cis alcohol, a phenomenon which is

not unusual if we consider the strain at the double bond.

34

The two isomers could be separated by application of column chromatography. The result obtained by alcoholysing 10,10-

dibromobicyclo(7.1.0ldecane (4) in t-butanol is in full agree­ment with the hypothesis that nucleophilicity and ring size determine the final cis/trans ratio. Upon treatment of 4 for 10 minutes at 40° with a 1M solution of silver perchlorate in

t-butanol, a mixture of two t-butoxy ethers was obtained, viz.

80% of the trans isomer (31) and 20% of the cis isomer (30).

The transient trans cation in the ten-membered ring is much less tained with strain and consequently the propensity to

isomerization is strongly diminished.

H Br

~' trans I eis N 80/20

The reaction of 9-exo-bromobicyclo[6.1.0lnonane (32) with

silver perchlorate in t-butanol affords in a very rapid re­

action mainly trans-3-t-butoxycyclonon-1-ene (33) which con­

tained about 10% of the related cis compound (34).

® trans/cis N 90/10

35

The considerable differences between the cis/trans ratios in the products arising from 9,9-dibromobicyclo[6.1.0lnonane (2)

and 9-exo-bromobicyclo[6.1 .Olnonane (32) at first glance seem

rather unexpected. Probably this discrepancy can be explained

in a quite simple way if we consider the stereochemistry of

the cation in question (Fig. I).

Figure I

The difference in transition state between the monobromo

derivative (32) and the dibromo derivative (2) is only the

presence of a bulky bromine atom in the cation formed in the

ring opening of 2. Apparently increased stability arising

from the interaction of the pn-electrons of the bromine atom

with the n-electrons of the allylic cation is of minor impar­tanee with respect to the steric influence of the bromine

atom in the transition state. Therefore the enhanced propen­sity to isomerization in the ring opening of 2 might be due

to a severe trans-annular interaction between the bramine

atom and the methylene hydragen at c7. Ring opening of 32 with silver nitrate, alternatively, gave a 2:1 mixture of trans

and cis nitrate 35 and 36 respectively. This observation fits

well with the hypothesis that the configuration of the product will be dependent on the relative nucleophilicity of the anion.

The influence of unfavourable steric interactions in the for­

mation of anomalous products has been observed earlier in the

dihalocarbene addition to norbornene 11 - 1 ~.

. H Br

~''" + ...

@ trans 1 cis cv 65/35

II-4 StPuctuPe assignments

The contiguration of products 26a-d and 27a-d arising

from the ring expansion of 2 were determined with the aid of

their 1H- and 13c- nmr spectra (see Table V). In the proton spectrum the trans products 27a-d exist as two rapidly equi­

librating diastereoisomers (rotation of the trans double bond

through the loop of the ring 15 •16

). Their spectra display

typical double doublets for the olefinic region. The methine

part of the spectrum shows a characteristic double doublet and a lower field multiplet. The corresponding cis structures

26a-d can be detected readily by their typical olefinic tri­

plet and by the signal of the methine proton; a multiplet which resonates always at lower field than the methine protons

of the trans diastereoisomers. These observations are in good

agreement with recently reported data for similar compounds 17 , 18 •

An additional and valuable methad of determining the contigu­

ration of the product consisted in comparison of the 13c-nmr

spectra. Of importance is the resonance of the allylic carbons.

One of these, to which the alkoxy subsituent is attached may readily be found.

37

For the cis isomer this latter allylic carbon resonates ge­nerally at 5-10 ppm upfield relative to the allylic signal

of the corresponding trans diastereoisomers 19,

In this way the mixtures 30/31 and 33/34, as well as the

mixtures of trans- and cis-cyclonon-1-en~3-ylnitrate (36 and 35) were analyzed unambiguously. The structural assign­

ments of the two trans compounds 28 and 29 were made in

accordance with their 1H-nmr spectra20 • The coupling con­stants were in good agreement with the values measured in analogous compounds.

Compound

26a, 27a

26b' 27b

26c, 27c

26d, 27d

29

28

30' 31

33, 34

Tabl e V

1H-nmr values

(CC1 4 solutions)

3.91 and 3.47 (m and dd,

methine H-3, trans, J~s and

10 Hz), 4.20 (rn, methine H-3,

cis)

3.62 and 4.02 (m and dd, methine

H-3, trans, J•S.S and 1 0 Hz),

4.35 (m, methine H-3, cis)

4.11 (rn, methine H-3, trans),

4.40 (rn, methine H-3, cis),

6.20 (t, J=9 Hz, olefin H-1, cis)

3.72 and 4.07 (rn and dd, trans t

J methine H-3, J=5 and 10 Hz),

4.41 (m, cis, methine H), 6.02

(t, alefin ll-1, J=9 Hz, cis)

5.78 (t. 1, H-1, J=8 Hz), 5.19 (m, 2. H-5 and ll-6). 3.84 (m, 1, rnethine H-3)

5.99 (dd, 1, H-1, J=11 and 4. 5

3.96 (t' 1, H-3 1 J=B Hz)

6.24 (t. J=8 Hz, trans·, H-1), 5.82 (dd, H-1, cis, J=12 and 6

4.49 (m, H- 3 ~ cis) ,

3.99 (m, H-3, trans)

3.59 (m, methine H, trans),

4.06 (m, methine H, cis)

5. 21 (m, olefin H)

Hz),

Hz),

13c-nmr, ppm downfield to

external TMS in c2Br2F4

56.9

85.9

, 79.2 (C-:i, cis),

87.2 (C-3, trans)

64.7 (CH3

-ç_H20), 77.4 (C-3,

cis), 84.1 and 85.4 (C-3, trans)

69.2 ( (CH 3 ) 2f.), 74.2 (C-3, cis), 81.3 and 82.7 (C-3, trans)

70.4 (C-3, cis), 74.7

( (CH3 ) 3

f_), 78.1 and 79.3

(C-3, trans)

75.1 (f_(CH3

)3), 78.7 (C-3,

trans)

69.2 (C-3, cis), 75.0 (f.(CH3) 3) 77.6 (C-3, trans)

68.9 (C-3, cis),

73.9 (f_(CH 3 ) 3), 75.9 (C-3, trans)

1) Only the most significant signals were tabulated, because in the methine region

the slgnals are often overlapped by alcoxy protons, whereas in the olefinic

region the protons of cis and trans structures coincide.

39

II-5 Experimental seation

General. The starting materials 1-4 were prepared

according to known procedures by the reaction o~ dibromocar­bene with the appropriate olefins 21 . 9-endo-Bromobicyclo[6.1.0]-

nonane (19) was obtained from reduction of 2 with tri-n-butyl­tinhydride22·23. The isomerie 9-exo-bromobicyclo[6.1.0]nonane (32) was synthesized from 2 by reduction of the dibromide 2 with dimsyl anion in DMS0 24 . Silver tosylate was prepared from silver oxide and p-toluenesulfonic acid, according to the pro­cedure of Kornblum et al. 25 . Cyclononene, required for the preparation of 4 was obtained from 9,9-dibromobicyèlo[6.1.0l­

nonane (2) by conversion to cyclonona-1,2-diene and subsequent reduction 26 . 1H-Nmr spectra were measured on a Varian T-60 spectrometer and 13c-nmr spectra were obtained on a Varian HA-100 apparatus at 25.12 Mc/s. A typical experimental procedure for the preparation of the tosylates is exemplified with the synthesis of 14. The ring expansion reaction with silver nitrate is illustrated with the preparation of 23. The aleoholysis reactions were performed at 40°, starting with an initial 1M concentration of silver per­chlorate. A typical experiment is illustrated by the preparation of 28.

2-Bromo-3-tosyloxycyclonona-trans,ais-1 ,5-diene (14) To a solution of 2.80 g (0.01 mol) of 3 in 10 ml of acetoni­trile was added a solution of 3.10 g (0.011 mol) of silver tosylate in 15 ml acetonitrile. The mixture was stirred with gentie reflux for 2 hr. After cooling and addition of an equal

vo~ume of ether the precipitate was filtered and the filtrate evaporated to dryness. The resulting gummy product was chroma­tographed through a short silica gel column and afforded 3.3 g (89%) of white crystalline tosylate 14. Recrystallization from

diisopropyl ether gave analytica! material; mp 89-91°. Anal.

Calcd for c 16H19Brü3S: C, 51.75; H, 5.12. Found: C, 51.64; H, 5.12.

40

cis-2-Bromocyclonon-1-en-3-ylnitrate (23)

A solution of 2.82 g (0.01 mol) of 9,9-dibromobicyclo[6.1.0l­

nonane (2) and 3.33 g (0.02 mol) of silver nitrate in 20 ml of acetonitrile was refluxed with stirring for 4 hr (progress

of the reaction was monitored by tlc). After cooling the re­

action mixture was poured onto 100 ml of saturated sodium chloride solution and 75 ml of ether. Stirring was continued

for 10 minutes and the mixture was filtered through Celite.

The organic layer was separated from some tlc immobile mate­

rial by chromatography through a short silica gel column,

using pentane as eluent. Upon bulb to bulb distillation 1.86

g (78%) of 23 was obtained as a colourless oil. Nmr data are presented in the Table; ir (neat) cm- 1 2930, 2860, 1630, 1460,

1440, 1360, 1320, 1290, 1270, 1160, 1020, 1005, 970, 962, 946,

920, 890, 845, 750. Anal. Calcd for c9H14N0 3Br: C, 40.91;

N, 5.30. Found: C, 40.99; H, 5.36; N, 5.19.

Product 23 was obtained also by nitration of cis-2-bromocyclo­

non-1-en-3-ol as follows. To 3 ml of acetic anhydride was added

265 mg (1.1 mmol) of Cu(N03) 2 .3H20.After the appearance of the

typical precipitate of cupric acetate the mixture was stirred

for an additional 15 minutes and then cooled to 0°. A solution

of 210 mg (1 mmol) of cis-2-bromocyclonon-1-en-3-ol (11) in 2 ml of methylene chloride was added in 1 minute. The mixture

was stirred for an additional 5 minutes and then poured on

20 ml of water. After neutralization with solid sodium bicar­

bonate the product was extracted with ether. The oil which

remained after evaporation of the organic phase was chromato­

graphed over a short silica gel column (pentane as eluent) and

afforded 240 mg (91%) of 23.

trans-2-Bromo-3-t-butoxycyclooct-1-ene (28)

Toa solution of 4.14 g (0.02 mol) of silver perchlorate in

20 ml of t-butanol c~ 15 g) was added at 40° with vigorous

stirring 2.68 g (0.01 mol) of 1. Precipitation of silver

bromide began immediately. After 20 minutes the starting

bromide had disappeared (as evidenced by the thin layer chro­

matogram; Merck silicagel plates, benzene as eluent). 41

Then 20 ml of saturated sodium chloride solution were added. The mixture was stirred for about 5 minutes and filtered

through Celite. After dilution with 100 ml of water the pro­duct was extracted twice with ether. Upon washing, drying

and evaporation of the solvent 2.16 g (83%) of pure 28 re­mained as a colourless oil. The nmr data are presented in

Table V. A solution of 1.3 g (0.005 mol) of 28 in 10 ml of toluene,

containing about 100 mg of p-toluenesulfonic acid was re­

fluxed for 10 minutes. The mixture was washed twice with 10% sodium bicarbonate solution and once with water. After drying

and evaporation of the organic phase 0.75 g (74%) of a 3:2

mixture of trans and cis alcohol was obtained. These two al­cohols were separated by column chromatography (silica gel

chloroform-2% methanol as eluent); Rf (cis alcohol) 0.35; Rf (trans alcohol) 0.29. Nmr (CDC1 3) for the trans alcohol 5:

ó 4.18 (dd, 1, methine H-3, J 10 and 5 Hz), 6.11 (dd, 1, ole­

fin H-1, J 10.5 and 4.5 Hz). Nmr (CDC1 3) for the cis isomer: ó 4.71 (dd, 1, methine H-3, J 10 and 5 Hz), 6.21 (t, 1, ole­fin H-1, J 8.5 Hz).

trans,ais-2-Bromocyclonona-1,6-diene (22) To a suspension of 0.8 g (0.021 mol) of lithium aluminohydride

in 10 ml of dry THF was added with stirring a solution of 2.62

g (0.01 mol) of 7 in 5 ml of THF. No reaction took place 27•

Then the mixture was refluxed for 0.5 hr. After work up in the

usual manner the resulting oil was chromatographed through a

short silica gel column, using pentarre as eluent. Upon bulb to

bulb distillation 0.7 g (35%) of 22 was obtained; bp 67-70°

(1 mm). Nmr (CDC1 3) ó 5.67 (m, 1, H-1 olefin), 5.37 (m, 2, H-6

and H-7 olefin).

This compound proved to be identical with an authentic sample prepared by reduction of the corresponding tosylate.

42

Rf!ferences and notes

1. A. STREITWIESER, Jr., "Solvolytic Displacement Reactions",

McGraw-Hill, Inc., New York 1962

2. N. KORNBLUM, W.J. JONES and G.J. ANDERSON, J. Amer. Chem.

Soc.,~. 4113 (1959)

3. W.D. EMMONS and H.F. FERRIS, J. Amer. Chem. Soc., 7

2257 (1953)

4. H.M.R. HOFFMANN, J. Chem. Soc., 6748 (1965)

5. The 9-exo-bromobicyclol6.1.0lnonane reacts within 5 minutes

completely with silver tosylate under the common reaction

conditions. Though a crude tosylate could be isolated, the

purification failed.

6. Y. POCKER and P.N. KEVILL, J. Amer. Chem. Soc.,~. 4760

(1965)

7. N. KORNBLUM and D.E. HARDIES, J. Amer. Chem. Soc.,~.

1707 (1966)

8. Acetylnitrate was prepared by modifying a known method;

T. SATO, T. AKIMAand K. UNO, J. Chem Soc. (C), 891 (1973)

9. The nitrate 21 could be prepared actually by reaction of

the parent alcohol with acetyl nitrate, but this reaction

suffers from giving a lot of side products, probably

arising from the addition of acetyl nitrate to the double

bondor from trans-annular reactions.

10. C.B. REESE and A. SHAW, Chem. Comm., 787 (1972)

11. W.R. MOORE, W.R. MOSER and J.E. LaPRADE, J. Org. Chem.,

' 2200 (1963)

12. R.C. DeSELMS and C.M. COMBS, J. Org. Chem., ~. 2206 (1963)

13. C.W. JEFFORD and R.T. MEDARY, Tetr., ~. 4123 (1967)

14. C.W. JEFFORD, S. MAHAJAN, J. WASLYN and B. WAEGEL, J. Amer.

Chem. Soc.,~. 345 (1965)

43

15. A.C. COPE, K. BANHOLZER, H. KELLER, B.A. PAWSON, J.J. WHANG and H.J.S. WINKLER, J. Amer. Chem. Soc., !I• 3644 (1965)

16. G. BINSCH and J.D. ROBERTS, J. Amer. Chem. Soc., !I• 5157 (1965)

17. C.B. REESE and A. SHAW, J. Chem. Soc., (Perkin I), 2422

(1975) 18. C.B. REESE and A. SHAW, Chem. Comm., 1365, 1367 (1970) 19. J.W. de HAAN and L.J.M. van de VEN, Org. Magn. Resonance,

~. 147 (1972) and references cited herein 20. The trans-2-bromo-3-t-butoxycyclooct-1-ene (28) isomerizes

spontaneously on standing for several days 21. L. SKATTEB~L, Acta Chem. Scand., 12, 1683 (1963) 22. M.S. BAIRD and C.B. REESE, J. Chem Soc. (C), 1808 (1969) 23. D. SEYFERTH, H. YAMAZAKI, D.L. ALLESTON, J. Org. Chem.,

~. 703 (1963) 24. C.L. OSBORN, T.C. SHIELDS, B.A. SHOULDERS, C.G. CARDENAS

and P.D. GARDNER, Chem. Ind., 766 (1965) 25. N. KORNBLUM, W.J. JONES and G.J. ANDERSON, J. Amer. Chem.

Soc., .§_1, 4113 (1959) 26. P.D. GARDNER and M. NARAYANA, J. Org. Chem., ~. 3518

( 1961) 27. Normally this reaction should afford the corresponding

alcohol. See: L.M. SOFFER, C.W. PAROTTA and J. DI DOMENICO, J. Amer. Chem. Soc., .z.!, 5301 (1952)

44

GRAPTER !//

stereoselective synthesis rif geminal endo-iodo-exo-bromo­cyc lopropanes

III-1 Introduetion

In the preceding chapter it has been discussed how the configuration of the product is determined by both ring size and nucleophilicity of the solvent (solvolytic ring expansion) or the anion (non-solvolytic ring expansion). The following

general rules are now available. 1. If the expanded ring would become too small to accommodate

a trans double bond, then the endo halogen atom is lost. This always leads to cis products via a disrotatory ring opening. Some representative examples are presented below.

H

Ckr ;

r

H

®

AgOAc-HOAc

re flux - Br- ( endo)

AgOAc-HOAc

re flux -Cl- (endo)

ö-OAc

Br

l {ref. 1) -

(ref. 2 I

45

2. In ring expansions leading to enlarged rings which can bear a trans double bond, but in which the geometry of the en­

larged system does not allow the existence of a free trans

cation, the exo halogen atom is lost. The nucleophile en­ters concertedly with the ring opening and the product formed

does have a trans geometry. These reactions display two-fold

stereospecificity. The r opening proceeds in a stereo-electronic controlled way 3 •~ and the attack of the nucleo­

phile at the incipient allylic centre implies an inversion

of configuration 5 • So only one diastereoisomer is formed. A representative example is given below.

H ~

~ ~a~.

H~H ~OH Br

------------

5°/o aq.acetone

3. Another important class of bicyclic systems actually exhi-

46

bits opening via free cationic intermediates. Now two

pathways exist for product formation. If the cation is

trapped immediately the products will have a trans geometry.

From molecular models it is obvious that the steric builcl-

up of such a cation will not allow the formation of both

diastereoisomers one would expect. As such, the final stereo­

selectivity of these reactions might be similar to the situ­

ation presented for the fully conceited reaction.

If the cation does not react immediately with the solvent or an anion then isomerization to a cis cation may occur.

Generally this occurs preferentially in the presence of

weak nucleophiles such as No;, t-C4H90H, TosO • The products will show now a cis double bond arrangement.

AgOTos

The formation of either cis or trans products is encountered only in two extreme cases. A reasonably stabilized trans cation reacting with a hard nucleophile leads to a trans

configuration, whereas a trans cation which exhibits strong propensity towards trans+cis isomerization reacts with a weak nucleophile under formation of a cis product.

In practice these extreme prerequisites will seldom be en­countered and in most cases hitherto known mixtures of cis

and trans products are formed. Representative examples are

e.g. the ring opening of 10,10-dibromobicyclo[7.1.0)decane (4) with silver nitrate and the t-butanolysis of 9,9-dibromo­bicyclo[6.1.0lnonane (2).

H Br

cj::~ d~r (R%" AgCI04 + !-C4HgOH - crt-c H - 4 9

0 @ Br 8 H Br

c:x~r AgN03 w:ON02 -~H + C~CN ~ ., Br

0 @ "'oNo2 ® Br

47

Only in the case of very weak nucleophilic anions like the tosylate anion, the ring expansion of 2 and 4 results in cis products exclusively.

III-2 Iodination of endo-Zithio-exo-bromocyaZopropanes

In a similar way the synthesis of a vinyl iodide has been described by ring opening of a geminal diiodocyclopro­pane precursor 6 (41, 42).

@

The examples of diiodocyclopropanes described in the litera­ture are scanty, because these compounds are in most cases too unstable to be isolated or disproportionate rapidly at room temperature. Some efforts directed towards the synthe­sis of functionalized nine-membered systems bearing a trans vinyl iodide moiety, were rewarded with very moderate success due to the extreme instability of the prerequisite geminal diiodocyclopropanes 7

• 8 • As it is to be expected that mixed dihalocyclopropanes are more stáble precursors than the corresponding diiodo derivatives different chemical routes for their preparatien will be discussed. Synthesis of these hitherto unknown substrates by stereoselective addition of iodobromocarbene to cyclic olefins seemed to be less promi­sing, with regard to the results of a variety of mixed car­bene additions to cyclic olefins 9 - 15 • Köbrich et aZ. 16 found that upon treatment of 7,7-dichloronorcarane with n-butyl­

lithium at -95° a reasonably stable mixture of endo- and exo isomers of 7-lithio-7-chloronorcarane was obtained.

48

Recently Hiyama et aZ. 11, showed that the corresponding 7,7-

dibromonorcarane could be lithiated stereoselectively at -95°

leading to 7-endo-lithio-7-exo-bromonorcarane. Subsequent addition of methyl iodide afforded the corresponding 7-endo­

methyl-7-exo-bromonorcarane (43).

1) Buli, THF, -95°

2lCH3I, -95° -H

CK, H

@)

Based on the above mentioned considerations it was to be ex­pected that iodination of such a lithiate would afford the

corresponding endo-iodo-exo-bromo derivative. This method had

been used for the precursor 9,9-dibromobicyclo[6.1.0lnonane (2). Treatment of 2 with one equivalent of n-butyllithium at -95° results indeed in the specific formation of 9-endo-lithio-9-exo-bromobicyclo[6.1.0lnonane. This was evidenced by a

quenching experiment with methyl iodide (see Chapter IV).

Upon treatment of this lithiate with iodine in THF at -95°

a single isomer was isolated which proved to be structure 44.

@

This compound displayed a typical 13c-nmr resonance at 4.1 ppm

downfield to TMS ( fBri, see Table VI). With the aid of simple silver ion promoted ring expansions the stereochemistry of 44

was determined as 9-endo-iodo-9-exo-bromobicyclo[6.1.0lnonane

(see Scheme I).

49

On treatment of 44 with a molar excess of silver perchlorate

in 10% aqueous acetone a mixture of the diastereoisomers of

trans-2-iodo-3-hydroxycyclonon-1-ene (45) and cis-2-iodo-3-hydroxycyclonon-1-ene (46) was obtained (approximate ratio

45/46 ~ 75/25). Close examination of the crude cis product

revealed the presence of about 20% of cis-2-bromo-3-hydroxy­

cyclonon-1-ene (11). The presence of this product may readily

be explained by assuming some competition of a mo4e of ring

opening in which the endo iodine atom is expelled. This side reaction is not unexpected since the endo site now holds a

much better leaving group 18 • The ring expansion of 44 with

silver tosylate gave, as expected, cis-2-iodo-3-tosyloxycyclo­

non-1-ene (47) only. lts identity could be established by

synthesis from the corresponding cis-2-iodo-3-hydroxycyclo­

non-1-ene (46).

Scheme I

H Br I

d~ Ag+ w H20 O::X" ---- .

' OH

@ @I

OT os ' OH

C)-1 TosO- w-1 HzO ... Cj-1 @ @

50

In a similar way as outlined for the preparation of 44 the compounds 1, 2, 37 and 48 were converted into their corres­

ponding geminal endo-iodo-exo-bromo derivatives 50, 44, 49

and 51 respectively (see Table VI).

Same final remarks should be made with regard to the iodina­tion of the lithiates. Attempts to synthesize 6-endo-iodo-6-

exo-bromobicyclo[3.1.0lhexane (53) from the corresponding dibromo derivative (52) met with failure. Presumably this

lithiate disproportionates at -95° via an intermediate

allene 19 • 20 •

d"Bc Buli, THF a·'" ... [0] -95°

...

@) + I ' '

~·'"' dimers

® Another interesting observation is the fact that 9,9-dibromo­

bicyclo[6.1.0]non-4-ene (3) could not be converted into the corresponding 9-endo-iodo-9-exo-bromobicyclo[6.1.0lnon-4-ene.

The lithiate derived from 3 proved to decompose instantaneous­

ly into the corresponding allene (54) even at -95° as evidenced by an attempt to quench this lithiate with water.

H Br

c}(·' 0

1)8uLi,-95° ------

~' 51

Table VI

GE>m1nal ~- bro mo- E>ndo- iodocyclopropanE>s

Substra!E>s Produc ts 1 YiE>ld,% Bp(mm].Mp{°C I spE>ctro ( ppm val u es

H Br d' èt'' I 77 69-72 (0.01) 10.0 (CBri), 29.4, 33.9, 35.0,

36.2

CD @ H Br

c!l C:X'Br H''I 82 77-79 (0.02) 4.3 (CBri), 27.9, 29.3, 31.4,

34.7

® @

ä H ar

'Br 0~1fi 102-103 2 2.3 (CBri), 27.2, 28.3, 32.8,

90 33.1, 34.2, 34.5, 81.7, 82.2, 0

-J---o''~~. -1- < H 108.4 "' 0 @

H

~' (tl.' 69 71-75 (0.05) 11.3 (CBri), 21.7, 25.5, 29.4 , 1 'ar

@H @)H

1) Satisfactory elemental analyses were obtained (~ 0.3\ for C and H) for all products. 2) Crystallized from 95% ethanol.

3) Spectra obtained from neat products; except 51 which was measured as a 30t salution in CDC1 3 • ~

This phenomenon is discussed in detail in the next Chapter.

The silver ion assisted salvolysis of 49 is worth recording

since 7,7-dihalobicyclo[4.1.0lheptanes are prone to undergo ring expansion by expelling the endo halogen atom 18 • Upon

heating 49 with silver acetate in acetic acid for several

hours only ais-2-bromo-3-acetoxycyclohept-1-ene (38) was isolated in 74\ yield.

This synthesis of endo-iodo-exo-bromocyclopropanes is a hither­

te unprecedented approach which permits the stereoselective

introduetion of the elements of iodobromocarbene into an ole­finic system via an indirect way. Finally it is noteworthy

to comment that in contrast to the diiodocyclopropanes, the

corresponding endo-iodo-exo-bromocyclopropanes show indeed a high stability. Even on standing at room temperature for seve­

ral weeks no disproportienation could be detected.

III-3 SiZver fluoride as an effeative oataZyst in ring

expansions of geminaZ dihaZooyaZopropanes

The ring expansions which have been presented in the

preceding section can be characterized as follows. If the ring size and the relative nucleophilicity of Nu

are known (either solvent or anion) it must be possible to

make rather accurate forecasts which products (and in which ratios) are formed (see Scheme II).

--X, Nu

coneerled

r-t~ , \/"'"~'\

y Nu

------·

' Nu Nu

--Y, Nu

isomerisation _ ~+ .. _, H H

y

One interesting set of experiments with silver fluoride is finally described. Treatment of 9,9-dibromobicyclo[6.1.0]non-

4-ene (3) with two equivalents 21 of silver fluoride gives via

a disrotatory ring opening with concomitant attack of the

fluoride anion at the incipient allylic centre trans,eis-2-

bromo-3-fluorocyclonona-1 ,6-diene (55). Details have been pre­

sented in Table VII.

54

AgF, CH3CN

reflux, 3hr - ~H ~~F tf?l Br ~

The 1H-nmr spectrum displayed a typical double doublet coup ling pattern for the allylic hydragen (J 10 and 6 Hz) and a

geminal F-H coupling of 46 Hz. The olefinic proton adjacent

to the bramine atom resonates as a lower field triplet (J 8

Hz). This is in good agreement with the observations made upon reaction of 3 and a number of nucleophiles under silver

ion assisted ring opening. The dibromides 2 and 4 gave mix­tures of cis and trans products upon reaction with silver

fluoride in acetonitrile.

H Br

c:z,~ F

AgF,CH3CN ~ ----=--- V-rBr eq; 0 @) Br

cis/trans C\l 60/40

cis/ trans C\l 20/80

The cis and trans products could be separated by column chroma­

tography in both cases. The less polar compounds proved to be

the trans isomers. Structure assignment of 56 and 57 can be made readily.

55

The trans isomer 57 displays at room temperature the typical pattern of two equilibrating diastereoisomers (57a, b)

~H ~-,,.F

Br

8 - ~F ~--.,H

Sr

The methine part consistsof a multiplet at ö 5.17 and a double doublet (J= 10 and 5 Hz) at ó 4.82 which are both split by

a characteristic geminal F-H coupling (J= 47Hz). The methine

part of the cis fluoride shows only a double doublet at ö 5.54

(J= 10 and 5 Hz; JFH= 47Hz). Further it is recognized that the methine proton of the cis fluoride (56) resonates at lower

field than the methine protons of the trans diastereoisomers

(57a, b). This is in agreement with similar observations made in numerous compounds. A comparison of the formation of cis

and trans fluorides (56, 57) with the results achieved under

non-solvolytic conditions with other silver salts shows that increasing nucleophilicity produces an increase in the per­centage of trans product (compare the silver fluoride cata­

lyzed ring expansions with the silver nitrate reaction).

The formation of mainly trans-2-bromo-3-fluorocyclodec-1-ene

(59) upon reacting 4 with silver fluoride is fully consistent with the postulates and deserves no further comments. The

structure assignment was based on the observation mentioned

earlier that the methine proton for 58 resonates at lower field than that in 59.

Attempts to synthesize 2-bromo-3-fluorocyclohept-1-ene (60) by the reaction of 7,7-dibromobicyclo[4.1.0]heptane (37) with

silver fluoride resulted in recovery of starting material, as

37 is a typical system which is prone to undergo ring opening

with release of the endo halogen atom.

56

It seemed much prom1s1ng to choose 7-endo-iodo-7-exo-bromobi­

cyclo[4.1.0]heptane (49) as a substrate, thereby favouring the ring expansion by a better leaving group at the endo site (I-). Upon refluxing of 49 for 6 hours with a two-fold molar excess of silver fluoride a ZOt yield of 60 was obtained.

AgF, CH3CN

-----''-----• 6 hr. reflux

1) AgPF5,

CH3CN, reflux 0.5 hr

2JH2D

®

As by-product the N-(2-bromocyclohept-1-en-3-yl)-acetamide

(61) was isolated, probably formed by a competitive Ritter reaction 22 • Upon using silver hexafluorophosphate (AgPF6) the amide 61 could even be obtained as a single product in

65% yield. The methad presented above constitutes a novel and facile approach in introducing fluorine stereospecifically in organic molecules with simultaneous ring enlargement. As such this con­stitutes not only an alternative approach for ring enlargement,

but also it is a valuable extension of the arsenal of methods to introduce fluorine in organic compounds 23 -

36• Under circum­

stances activatien of a cyclopropane unit by introduetion of

a better leaving group may be a useful technique.

57

Whereas 7,7-dibromobicyclo[4.1.0]heptane (37) displays only

moderate reactivity towards silver nitrate, the corresponding

7-endo-iodo-7-exo-bromobicyclo[4.1.0]heptane (49) could be

converted within 10 minutes to the 2-bromocyclohept-1-en-3-ylnitrate (62) in excellent yield.

58

AgN03 , CH3CN

10 mm. rel lux -

~

Substroles

d' 1/Br

H

CY:,, H 0 H Br

~tBr

H cy.;r '/I

H

@

Table VII

Reaction of gem•nol diholocyclopropanes

with AgF acetonilrile

Product s 3 [ra t1o )11

Yield,%1 Rt 2 NMR dato ! CDCt 3 I, Ó va lues

d-~ cqçH 36

@)4oBr 60

O:XH 33 F

@ Br

CÇ{H c:x: .. 41 ' Br ~

@so 20

F

(j-~ 20

@

56: 6.25 (t

0.29(c) (dd, 1'

0.33(t) JHF=47 57: 6.07 (d

4.82 an

0.16 55: 5.88 [t

5. 29 (m

4.80 (d

58: 6.07 (d 0.22(c) 5.59 (d

0.29(t) JHF=47 59: 6.37 (t

4. 90 (t

JHF=47

0.25 60: 6.46 (t

2 Hz),

4 7 Hz)

, 1, alefin H, J=9 llz], 5.

methine H, J=10 and 5 Hz],

Hz

d, J=10 and 6 Hz)

d 5.17 1, m and dd, J•10

Hz

, olcfin 11, J=8 Hz)

, 1 , olefin H5 and H6 )

d, 1, methine, 11, J=10 and

d, 1, olefin H, J•10.5 and

d, 1, mcthine !!, J=9 and 6

lz

, 1, alefin H, J=R Hz)

, methinc H, J=7 Hz

lz

, 1, alefin J=6 Hz,

5.11 (m, 1, methine H,

1) Yields are based on pure products, isolated after chromatography. 2) Rf values wcre measured on Merck

silicagel plates, using hexane as eluent. 3) Satisfactory analytica! data were obtained (! 0.3\ for C

and H). 4) Product ratlos were determined on the basis of isolated yields after chromatography and wcre consistent with ratios estimated from the nmr spectra of thc mixtures.

III-4 Experimental seation

GeneraZ. The dibromides 1-4 and 37 were prepared by

a documented method 37 • Cyclononene, required for the prepa­

ration of 4 was synthesized from 2 in a two-step sequence 38•

Silver fluoride was purchased from Merck A.G. (Darmstadt).

Silver hexafluorophosphate was obtained from Alfa Inorganics (Beverly, Mass.). 13C-Nmr spectra were measured on a Varian HA-100 apparatus at 25.12 Hc/s. Helting points are uncorrec­

ted. A typical experimental iodination procedure is outlined

for the preparation of 44 from 2. The preparation of the

fluorides is illustrated by the synthesis of 56 and 57.

9-endo-Iodo-9-exo-bromobicyclo[6.1.0]nonane (44)

To a salution of 2.82 g (0.01 mol) of 2 in 15 ml of THF

(freshly distilled from LiAlH4) was added dropwise with stir­

ring at -95° 5.4 ml (0.01 mol) of a 15% salution of butyl­lithium in hexane. After stirring for 10 minutes a salution

of 2.79 g (0.011 mol) of iodine in 5 ml of THF was intro­ducedat such a rate to maintain the temperature below -80°.

After stirring for an additional 10 minutes the mixture was

allowed to reach room temperature. Upon addition of 100 ml of water the product was extracted twice with 50 ml portions

of ether. After washing, drying and evaporation of the solvent the residual oil was chromatographed through a short silica gel column (hexane as eluent) and was finally distilled under reduced pressure. This afforded 2.69 g (82%) of 44; bp 77-79°

(0.02). 13c-Nmr data are presented in Table VI. Anal. Calcd

for C9H14Brl: C, 32.83; H, 4.25. Found: C, 33.09; H, 4.33.

60

2-Bromo-3-fluorcyclonon-1-ene (56, 57) To a salution of 2.82 g (Q.01 mol) of 2 in 20 ml of aceton­

itrile was added 2.52 g (0.02 mol) of silver fluoride. The mixture was stirred with gentie reflux, while monitoring the reaction by tlc. After 3 hours the reaction.mixture was caol­

ed and poured onto 100 ml of saturated NaCl solution. Then 50 ml ether were added and stirring was prolonged for 10

minutes. Upon removal of the silver salts by filtration, the organic layer was separated and washed twice with water. The

residue, which remained after drying and evaporation of the

solvent, was taken up in hexane and filtered through a short florisil column. This gave 795 mg (39%) of a mixture of ais­

and trans-2-bromo-3-fluorocyclonon-1-ene (56 and 57 respecti­vely). An analytica! sample was obtained from evaporative bulb to bulb distillation. Anal. Calcd for c9H14BrF: C, 48.87;

H, 6.33. Found: C, 48.57; H, 6.30. The individual isomers were obtained by chromatography through silicagel, using hexane as eluent (see Table VII).

trans-4,5-Dihydroxy-9,9-dibromo-ais-bicyclo[6.1.0Jnonane, acetonide (48) Toa stirred salution of 1.82 g (0.01 mol) of the acetonide of 1 ,2-trans-dihydroxycyclooct-5-ene 39 • 40 , 12.65 g (0.05 mol) of bromoform and ZOO mg of benzyldimethylcetylammonium chlo­ride was added at 50° 4 g of 50% aqueous NaOH (0.05 mol). The mixture was stirred for 24 hours at 55-60° and then di­

luted with 100 ml of water. The product was extracted twice

with ether. The residue which left after washing, drying and

evaporating of the solvent was treated with 95% ethanol at an ice bath. The white solid obtained was collected and once

recrystallized from 95% ethanol and gave 2.19 g (62%) of 48; mp 85-86°. Nmr (CDC1 3) ó 1.38 (s, 6, CH3), 3.40-4.20 (m, 2, C~(O)-C~(O)-). Anal. Calcd for c12H18 Br 2o2 : C, 40.67; H, 5.08. Found: C, 40.51; H, 5.09.

61

2-Iodo-3-hydroxycyclonon-1-ene (45a, b and 46)

To a solution of 830 mg (4 mmol) of silver perchlorate in 4 ml of 10% aqueous acetone was added with stirring 658 mg

(2 mmol) of 44. Precipitation of silver bromide started imme­diately. Stirring was prolonged for 1.5 hours while monotering

the reaction progress with tlc. Upon addition of 10 ml of sa­

turated· sodium chloride solution and 15 ml of ether the mix­

ture was stirred for additional 10 minutes. After removal of

the precipitates the organic phase was washed twice with

water. Upon drying and evaporation of the solvent a mixture of 45a, b and 46 (3:1, according to 1H-nmr) left as an oil. Chromatography (silica gel; chloroform as eluent) afforded

96 mg of cis-2-iodo-3-hydroxycyclonon-1-ene (46) Rf 0.35, mp (hexane) 66-68° and 325 mg of a diastereoisomerie mixture

of trans-2-iodo-3-hydroxycyclonon-1-ene (45a, b, Rf 0.31). Nmr (CDC1 3) for 46: o 0.85-2.40 (m, 12, ring methylene H),

1.87 (s, 1, OH), 4.04 (m, 1, methine H), 6.51 (t, 1, alefin

H). Nmr (CDC1 3) for 45a, b: o 0.75-2.60 (m, 12, methylene H), 2.36 (s, 1, OH), 3.49 and 4.67 (m, 1, methine H), 6.02 and

6.41 (tand m, 1, alefin H, J 8 Hz), Anal. Calcd for C9H15 ro (7): C, 40.60: H, 5.64. Found: C, 40.52; H, 5.71.

cis-2-Iodo-3-tosyloxycyclonon-1-ene (47) A salution of 658 mg (2 mmol) of 44 and 1.12 g (4 mmol) of silver tosylate in 4 ml of acetonitrile was refluxed for 15

minutes. To the caoled mixture was added with stirring 15 ml

of ether and 10 ml of saturated sodium chloride solution.

After filtratien of the precipitates the organic layer was separated and washed twice with water. The product obtained

was chromatographed through a short silica gel column (benzene I

as eluent). This gave 657 mg (78%) of tosylate 47 as a white

crystalline solid; mp (hexane) 59-60°. Anal. Calcd for

c16H21 ro 3s: C, 45.72; H, 5.04.

62

Found: C, 45.87; H, 5.09. Nmr (CDC1 3): ö 2.40 (s, 3, CH3), 5.02 (dd, 1, methine H, J 11 and 5 Hz), 6.40 (t, 1, alefin H, J 9 Hz). The product was identical with an authentic

sample of 47 prepared by tosylation of cis alcohol 46 with

p-toluenesulfonylchloride in pyridine.

cia-2-Bromo-3-acetoxycyclohept-1-ene (38)

A mixture of 301 mg (1 mmol) of 37, 334 mg (2 mmol) of silver

acetate and 2 ml of acetic acid was heated for 10 hours at

100°. The product was poured onto 20 ml of water and neutra­lized with portions of solid sodium bicarbonate. After ex­traction with ether, washing, drying and evaparatien the crude

38 left as an oil. Upon chromatography (Si02-CHC1 3) 184 mg

(78%) of pure 38 were isolated (identical with a sample pre­pared from 7,7-dibromobicyclo[4.1.0lheptane). Nmr (CDC1 3)

ö 2.10 (s, 3, CH 3), 5.57 (m, 1, methine H), 6.43 (t, 1, ale­fin H, J 7 Hz).

N-(2-bromocyclohept-1-en-3-yl)-acetamide (61)

A salution of 602 mg (2 mmol) of 49 and 1. 01 g ( 4 mmol) of

AgPF 6 in 5 ml of dry acetonitrile was refluxed with stirring

for 0.5 hour. The product was poured onto a stirred mixture

of 20 ml of saturated NaCl salution and 20 ml of ether. After 10 minutes the silver salts were filtered and the orga­

nic layer was separated. Upon washing, drying and evapora­

tien of the solvent a solid was obtained. Recrystallization

from benzene-pet.ether gave 300 mg (65%) of 61; mp 106-107°.

Anal. Calcd for c9H14BrNO: C, 46.55; H, 6.03; N, 6.03. Found: C, 46.55; H, 6.05; N, 5.90. Nmr (CDC1 3) ö 2.02 (5, 3, CH 3),

4.81 (m, 1, methine H), 6.30 (t, 1, alefin H, J 6 Hz), 6.77

(m, 1, NH); ir (KBr) vco 1650 cm- 1 .

63

Rejerences and notes

1. P.S. SKELL and S.R. SANDLER, J. Amer. Chem. Soc.,~. 2024 (1958)

2. S.J. CRISTOL, R.M. SEQUEIRA and C.H. DePUY, J. Amer.

Chem. Soc.,~. 4008 (1965) 3. R.B. WOODWARD and R. HOFFMANN, J. Amer. Chem. Soc.,

~. 395 (1965) 4. C.H. DePUY, R.G. SNACK and J.W. HAUSER, J. Amer. Chem.

Soc.,~. 3343 (1966) 5. C.B. REESE and A. SHAW, J. Chem. Soc. (Perkin I), 2422

(1975) 6. M.S. BAIRD, Chem. Comm., 197 (1974) 7. J.P. OLIVER and U.V. RAO, J. Org. Chem., ll, 2696 (1966) 8. P. WEYERSTAHL and R. MATHIAS, Angew. Chem., ~. 42 (1974) 9. P. WEYERSTAHL, R. MATHIAS and G. BLUME, Tetr. Lett., 611

(1973)

10. R.A. MOSS and F.G. PILKIEWICZ, Synth., 209 (1973)

11. D. SEYFERTH and S.P. HOPPER, J. Organomet. Chem., ~. 77 (1973)

12. D. SEYFERTH and C.K. HAAS, J. Organomet. Chem., ~. C-33 (1972)

13. H. DAHL, F. NERDELand P. WEYERSTAHL, Ann., 755, 40

(1972) 14. M. SCHLOSSER, G. HEINZ and LE VAN CHAN, Ber., 104, 1921

(1971) 15. T. ANDO, H. HOSAKA, H. YAMANAKA and W. FUNASAKA, Bull.

Chem. Soc. Jap., Q, 2013 (1969)

16. G. KÖBRICH and W. GOYERT, Tetr., ~. 4327 (1968) 17. K. KITATANI, T. HIYAMA and H. NOZAKI, J. Amer. Chem. Soc.,

~. 949 (1975)

64

18. W.F. SLIWINSKI, T.M. SU and P.v.R. SCHLEYER, J. Amer. Chem. Soc., 94, 133 (1972)

19. W.R. MOORE and W.R. MOSER, J. Amer. Chem. Soc., 5469 (1970)

ZO. L.A. PAQUETTE, G. ZON and R.T. TAYLOR, J. Org. Chem., 39, 2677 (1974)

21. For the interconversion of halogen with fluorine nor­mally an undesirable complex formation of the type AgF.AgX takes place. Therefore excess of silver fluoride is usually required. See: R.D. Chambers, "Fluorine in Organic Chemistry", Wiley and Sons, Inc., New York, 1973, pg 38.

22. The formation of an amide has been observed also in the silver tosylate promoted ring opening of 1-fluoro-1-iodo-2-phenylcyclopropane in acetonitrile. See: P. WEYERSTAHL, R. MATHIAS and G. BLUME, Tetr. Lett., 611 (1973).

23. G.A. OLAH, M. NOJIMA and I. KEREKES, Synth., 487, 779 and 786 ( 1973)

24. L.N. MARKOVSKIJ, V.E. PASHINNIK and A. V. KIRSANOV, Synth., 787 (1973)

25. G.A. OLAH and J. WELCH, Synth., 652 (1974) 26. D. LANOINI, F. MONTANARI and F. ROLLA, Synth., 428 (1974) 27. G. PARGES and A. KERGOMAROL, Bull. Soc. Chim. France,

3647 (1969) 28. G.L. GRADY, Synth., 255 (1971) 29. L.O. HALLand J.F. MANVILLE, Can. J. Chem., ±l• 361

(1969) 30. L.O. HALLand D.L. JONES, Can. J. Chem., ~. 2902 (1971) 31. G. BARTOLI, A. LATROFA, F. NASO and P.E. TOOESCO, J. Chem.

Soc. (Perkin I), 2671 (1972) 32. G.A. BOSWELL Jr., J. Org. Chem., 3699 (1968) 33. M. ZUPAN and A. POLAK, Chem. Comm., 845 (1973) 34. M.J. ROBINS and S.R. NAIK, Chem Comm., 18 (1972) 35. M. SCHLOSSER and G. HEINZ, Ber., 102, 1944 (1969)

65

36. A. BOWERS, P.G. HOLTON, E. DENOT, M.C. LOZA and R. URQUIZA, J. Amer. Chem. Soc.,~' 1050 (1962)

37. L. SKATTEB~L, Acta Chem. Scand., !I, 1683 (1963) 38. P.D. GARDNER and M. NARAYANA, J. Org. Chem., ~

3518 (1961)

39. P. YATES, C.G. LAVARS and P.H. McCABE, Can. J. Chem.,

~. 1548 (1972) 40. J.M. MciNTOSH, Can. J. Chem., ~. 2152 (1972)

CHAPTER IV

Bishomoaromatic interaction in the disrotatory rzng opening qJ cyclopropyl carbenoids

IV-1 Introduation

In the general introduction, presented at the outset of

this thesis target compounds have been presented.

n = 2, 3

R= H, CH3

In order to achieve the ultimate synthesis of these compounds several individual basic problems had to be solved befare a straight forward synthesis would become feasible. An answer

to a part of the questions raised at the beginning of this

work has been given in the preceding chapters.

A mechanistic reaction path has been outlined which prediets the stereochemistry of the products arising from ring expan­sion reactions with a variety of silver salts. In this way

it has become possible to synthesize interesting functiona­

lized precursors for the prerequisite model compounds.

Furthermore, an elegant route has been elaborated which per­

mits the stereospecific introduetion of iodine at olefinic

bonds, starting from stabie iodo precursors (endo-iodo-exo­

bromocyclopropanes).

67

These latter systems are of particular interest, since it is to be expected that they may be reduced under mild conditions

to the parent olefinic systems with retension of stereochemis­try. To convert stereoselectively a variety of the correspon­ding trans-2-bromo-3-hydroxycycloalk-1-enes to the trans-3-

hydroxycyc~oalk-1-enes proved to be rather cumbersome and was

always accompanied by extensive isomerization 1•

2•

So, on treatment of both ais-2-bromo-3-hydroxycyclonon-1-ene (11) and trans-2-bromo-3-hydroxycyclonon-1-ene (6) witheither

Li-NH3-t-C4H90H, Na-C 2H50H or Li-ethylenediamine always ais-3-

hydroxycyclonon-1-ene (63) was obtained.

frYH ~%H ® Br

dissolving metal

/

OH

Cj

Apparently the reduction proceeds through intermediate radi­

cals which, upon progress of the reaction, give the stable cis olefin.

68

~L-yH \../" Y "tJu

Br

~H ~ 0 OU --------

t

'

An alternative approach to trans-cycloalkenes (I) or trans-2-

methylcycloalkenes (II) would entail the ring opening of the corresponding ezo-bromobicycloalkanes (III) or the ezo-bromo­endo-methylbicycloalkanes (IV).

~r u ~'H @)

H Br Ag•

~"' _______ ,_

®

H

<;i.;> H H

~ H H

H

~Sol' ____ ,... H H

CH3

ÇJy.so\' .... H H

@

69

The approach presented above hings on the accessibility of the cyclopropane precursors. Therefore an investigation in

this typical area was obvious.

IV-2 Lithiation geminaZ dibromoayatopropanes

Geminal dihalo compounds have been shown to produce

carbenoid species on treatment with organo lithiums 3 •

In the specific instanee of 1,1-dibromocyclopropanes the

transient carbenes generally disproportionate readily. Host

commonly allenes are formed via a conrotatory ring opening

of the four-electron species~- 11 •

conrota t ory -------- , __ /

~-----,

An alternative, often competative, mode of reaction of the

carbenoid species is the insertion inC-H bonds 12 - 20 •

Though it is difficult to derive rules from literature, it

becomes clear that insertion reactions occur predominately

in highly substituted cyclopropylidenes with great preferenee

for tertiary C-H bonds. Illustrative is the following example 1 ~.

70

(80%)

+

120% I

It has been found quite recently that carbenoid species do have slight stability at very low temperatures. Under these

circumstances they behave like anions and are readily alky­latable21-23. In conneetion with the presented work aiming

at the synthesis of the model systems, this behaviour of

carbenoid species might be applied in an elegant way to

achieve an entry into methylated olefins. To this end the

recently described method of Hiyama et aZ. was employed,

which permits the stereoselective synthesis of endo-methyl­

exo-bromocyclopropanes by lithiation and subsequent methyl­ation of geminal dibromocyclopropanes.

R~1 R Br

, "' ' • Br H ::.

H

Buli

THF, -95°

R~1 Br

, _. '-' • "'L· H :. I

H

____ ,_ R~1 R Li

" ;.-' . B H ~ r H

71

The formation of the endo-lithio compounds is proposed to occur via an initia! e~o-lithio derivative which isomerizes to the more stabie endo-lithio derivative. The authors showed that these compounds are excellent precursors for specifically

substituted olefins.

~"' H ~ Br

H

AgOAc- HOAc --~----------,--

Treatment of 1-e~o-bromo-1-endo-methyl-trans-2-phenylcyclopro­

pane (64) with silver acetate in acetic acid leads to E-S­methylcinnamylacetate (65). With these considerations in mind the methad of Hiyama et aZ. was applied to 9,9-dibromobicyclo­[ 6.1.0lnonane (2) and to the acetonide of 4,5-trans-dihydroxy-9,9-dibromo-ais-bicyclo[6.1.0lnonane (48) as representative models.

Upon treatment of 2 with one equivalent of butyllithium in dry THF at -95° and after subsequent addition of excess of methyliodide at -95° one single isomer was obtained in essen­

tially quantitative yield. The 1H-nmr spectrum revealed a sharp singlet at o 1.63 (CDC1 3) forthemethyl group. Further­more this compound reacted within 5 minutes with an excess of silver tosylate, a reagent which is very sensitive towards e~o­

bromocyclopropanes (see Chapter I). With the help of the latter reaction the structure of the compound has tentatively

assigned as 9-e~o-bromo-9-endo-methyl-ais-bicyclo[6.1.0lnonane (66). In an identical way 48 was converted to the corres­ponding endo-methyl derivative 67 in 92% yield. The 1H-nmr

spectrum showed again the presence of one isomer, with a sharp singlet at o 1.63 (CDC1 3).

72

H Br

~''''Br o~H +o~@

------ (77%)

1) Buli, THF,-95°

2) CH3I ,-95°

(92 %)

However, on treatment of 9,9-dibromo-ais-bicyclo[6.1.0lnon-4-

ene (3) with butyllitium and methyliodide under identical con­ditions, the allene 54 was obtained as the sole product.This

was established unambiguously from its 1H-nmr and ir speetral data 2 ~- 26 •

1) Buli, THF,-95° -

It is worth recording here that a similar anomalous behaviour

of 3 has been observed in the reduction of this dibromide with

dimsyl anion in DMS0 27• The dibromides 2 and 48 can be reduced

easily to their corresponding exo-bromo derivatives 68 and 69

respectively. In contrast, reduction of 3 with this reagent

affords only the allene 54.

73

H Br

c::i"' --------

NoH - DMSO. room temperoture

---------------

These reduction reactions are believed to praeeed via carbe­

noid species. It is most likely that the presence of the double bond at c4 5 in 3 might be a crucial factor in this

' anomalous behaviour. In order to get more insight in this problem a related system was used which bare a cyclopropane

unit insteadof a double bond at c4 , 5 .

Treatment of i0,10-dibromo-cis,cis-tricyclo[7.1 .o.o 4' 6 Jdecane

(70) with butyllithium and methyliodide at -95° afforded the corresponding allene 71 and no trace of the methylated product.

H Br

H~''Br H,,~H

H H

@

Buli, CH3I

THF,-95°

H

-~ H

® It is interesting to note that the strained 9,9-dibromo-trans­

bicyclo[6.1.0]nonane (72) proved to be stable under the con­

ditions described above and could be converted smoothly to

9-methyl-9-bromo-trans-bicyclo[6.1.0]nonane (73) without allenic impurities.

74

q., Br

@

1)BuLi, THF,-95°

2)CH31 ,-95° -

Whereas allene formation may be regarcled as a common reaction at elevated temperatures (> -30°), its formation at such a low

temperature must be regarcled as rather surprising.

IV-J Backgrounds of the ring opening of oyolopropylidenea

Upon consiclering the ability of cyclopropyliclenes to undergo alkylation reactions, they can be regarcled as anions at such low ternperatures. The preferrecl mode of ring opening of such species, leading to allenes, will be conrotatory

basedon orbital symrnetry considerations 28 • 29 • This has been

confirmed by extended Hüokel 30 , ab initio 31 and MIND0/2 32

calculations. A representative exarnple would be the highly

stereospecific ring opening of 9-endo-deuterio-9-exo-chloro­

ois-bicyclo!6.1.0]nona-2,4,6-triene (74) with potassiurn in THF leading to oia,oia,oia,trana cyclononatetraenyl anion (75)33,34.

K, THF, -30° 0

-----------------

®

75

The stereochemistry of the anion 75 is indicative for the conrotatory nature of the ring opening. However, the deute­rium atom does exhibit pseudo-scrambling by topomerization. Upon warming, the more stable all cis anion is formed. Based

on steric considerations, the conrotatory mode of ring ope­

ning seems to be an unfavourable process at very low tempe­ratures for the carbenoids derived from 2, 3, 48 and 70, and even for 72 in which the cyclopropane unit is fused in a fa­vourable trans manner. The conrotatory mode of ring opening 72 at low temperatures is restricted, because the system has

to pass through an initially strained trans,trans allylic geometry. Th1s explanation, basedon steric considerations, can

be supported by an experiment carried out by Winatein et al.

and Paquette et aZ. 35-

40• Treatment of eis-bicyclol6.1.0]nona-

2,4,6-tri~ne (76) with potassium in glyme at -80° gave a non­classica! anion 77, whereas the corresponding trans-bicyclo-

6.1.0 nona-2,4,6-triene (78), upon treatment with potassium

under similar conditions, gave the classica! anion 79. The ring opening of 78 would lead to an unfavourable strained eia,trans­

cyclononatetraenyl radical anion.

d< ,,,,H

non- c lassi cal "H -

H

@ K , glyme, -80° ®

H H

0< classica! -H

H

@ ®

76

The ring opening of 2, 3, 48 and 70 by an alternative disro­tatory movement seems to be more attractive but in fact this is a forbidden process. Therefore it is most likely now that the rapid mode of ring opening of 3 and 70 is due to a bis­homoaromatic interaction between the cyclopropylidene moiety and the double bond or the WaZsh type orbitals of the cyclo­propane unit at c4 , 5 respectivelyq 0 • Extension of the elec­tronic system of the cyclopropylidene by two electrons in

this way leads to an aromatic transition state, favouring a disrotatory ring opening.

Br

Br

Further evidence for this explanation can be quoted from recent literature on bicyclo[3.2.1locta-2,6-diene systemsql-qq.

A particular example which is worth recording, and which by its nature has close similarity to the problem mentioned afore, is the base-catalyzed rearrangement of 3-bromobicyclo[3.2.1]­octa-2,6 diene (80) to endo-6-ethynylbicyclo[3.1.01hex-2-ene (81) 45 • In this reaction the intermediacy of a homoconjugated carbene has been suggested.

77

d:>-sr t- c,u..Jï- t:f:>_.---------._ - ~ '!I" • - - -· Br !-C4HgOH -------

------

I• f

The model for the rapid ring opening of the cyclopropylidenes derived from 3 and 70 suggests an interaction through space

over a relatively large distance. Therefore it was obvious that a further requirement might be some flexibility in the

bicyclo[6.1.0)nonane skeleton which allows bending of the

double bond (in 3) and of the cyclopropane (in 70) towards the cyclopropylidene system. An example in this series which

doesnotmeet this requirement is 9,9-dibromo-cis-bicyclo-

[ 6.1.0)nona-2,4,6-triene (82) in which the double bond at

c4,5 is tightly fixed.

1)Buli, THF,-95° -------------

78

Indeed, upon treatment of 82 with butylithium and methyl iodide at -95° only 9-endo-methyl-9-exo~bromo-cis-bicyclo [6.1.0lnona-2,4,6-triene 83 was formed. Some experiments carried out at higher temperatures showed that the lithiate

derived from 82 proved to be stable up to -45°. Above this temperature decomposition to an undefinable mixture of

products took place. The lithiate derived from 2 proved to

undergo ring opening at an appreciable rate at -40°, leading to the corresponding allene.

IV-4 Behaviour of cyclopropylidenes attached to polyenes

In the preceding section it has been shown that cyclo propylidenes disproportionate readily at temperatures above

-40° to allenes or insertion products. At very low temperature

(< -80°) the carbenoid species display a remarkable stability,

except in those cases where favourable electronic interactions facilitate the mode of ring opening (a suitably located double bondor a cyclopropane unit).

------·-

For these cases an "apparent" vialation of Woodward-Hoffmann

rules is observed. A prerequisite for such interactions seems

to be the close proximity and correct position of the double

bond. An example drawn from the literature is the reaction

of 9,9-dibromo-cis-bicyclo[6.1 .O]non-2-ene (84) with methyl­lithium. The product from this reaction is not the allene

but the insertion products arising from a relatively "stable"

carbenoid (85 and 86)46

79

H

Q{ 8 8 CH3Li. ether +

z -40° Br H

@ @ ®

It would be of special interest to see if interactions be-tween cyclopropylidenes and double bonds would be present in relatively flexible systems, viz. cyclopropylcarbenoids sub­stituted with a polyenic system. This attempt seemed not to be much proruising with regard to some literature data now available, but synthetically it seemed challenging enough to try. Compound 87 was chosen as a model and submitted to the action of butyllithium and methyl iodide at low temperature in order to see if an alkylation could be brought about, leading to 88.

Both 87 and 88 were not known in literature and preparation via selective cyclopropanation of the corresponding triene was considered as the most attractive approach. For the pre­paration of 87 as starting compound 2-methyl-3-buten-2-ol (89) was used (see Scheme III). Treatment of 89 with vinylethyl ether and a catalytic amount

of phosphoric acid for 3 hours at 160° led via a Claisen re­

arrangement to 5-methylhex-4-en-1-al (90)' 7 in 481 yield.

80

Co ....

(<oH

@)

+ ~0~

ÇU" @ ?-P~J· THF,-40°

çó @

cot. H3P04

160°

Cr03. 2 Pyr. HCI

CH2CI 2

q" r--MgBr

~ THF, -20°

@) ® I

CH ( OC2H5J3cH3 cot. c2H5COOH, 130°

' ço LiAIH4 WOC2Hs I ether, 0°

@) ®

Upon reacting this aldehyde with vinylmagnesium bromide at

-20° in dry THF a smooth conversion to 3-hydroxy-7-methylocta-

1,6-diene (91) was achieved in essentially quantitative yield.

The crude product was treated with ethyl orthoacetate and a

catalytic amount of propionic acid. This gave via an orthoes­

ter Claisen rearrangement the E-9-methyldeca-4,8-dienoic acid,

ethyl. ester (92) in 74% yield 4 8•

4 9• Reduction of this ester

with lithium aluminohydride gave quantitatively the corres­

ponding alcohol 93. Subsequent oxidation with pyridine chloro­

chromate50 in methylene chloride afforded the aldehyde E-9-

methyldeca-4,8-dienal (94) in 62% yield. Reaction of this

aldehyde with the ylide derived from isopropyltriphenylphos­

phonium iodide at -40° in THF gave the required 2,10-dimethyl­

dodeca-2,6,10-triene (95) as a colourless liquid in 82% yield.

The cyclopropanation was attempted with the aid of phase­

transfer catalysis 51 . As a catalyst S-hydroxyethyldimethyl­

benzylammonium hydroxide was chosen 52 . This catalyst has been

documented to give selectively mono adducts e.g. in the re­

action of cyclododecatriene with chloroform. Treatment of 95

with an excess of bramofarm and 50% aqueous sodium hydroxide

at 50° in the presence of the catalyst gave a mixture of mono­

and biscyclopropanated product 87 and 96 in a ratio of about

60/40. This ratio remained unaltered upon changing the reaction

conditions. The use of other catalysts, such as e.g. benzyl­

dimethylcetylammonium bromide, did nat imprave the result.

82

CHBr3 ,50% -NaOH

soa. :;N_.....oH +

Br

(',I J</··,,s, • LyV ar

@) ai=

Br

''''Br

mono/ bis rv 60/40

The two products could be separated by means of column chroma­

tography. The biscyclopropanated product proved to be only

terminally substituted. This result may, to all probability,

be ascribed to a strong steric factor. Treatment of 87 with

butyllithium and methyl iodide at -95° gave a mixture of two

isomerie methylated products to which the structures 88 and

97 have been assigned, based on the observation that an endo­

methyl group resonates at higher field than the corresponding

exo-methyl derivative 21•

··~ +

........ ':... ' , Br

The formation of bath the endo and the exo derivative may be

explained by the higher degree of substitution of the cyclo­

propane unit, which decreases the energy difference between the endo lithio and the exo-lithio derivative and thus gives

rise to the formation of product mixtures. It is self-evident

that there may still be a preferenee for the formation of 88.

From the experiment outlined above it is obvious that in an open-chain system like 87 there does not exist a strong in­

teraction between the cyclopropyl lithiate and the nearby

double bond. For such an interaction the presence of a double

bond in a transition state like arrangement seemes to be an

additional ite.

IV-5 Experimentat seotion

Generat. The starting dibromides 2 and 3 were prepared by reaction of the appropriate olefins with dibromocarbene 53

•

9,9-Dibromo-trans-bicyclo[6.1.0]nonane (72) was obtained from trans-cyclooctene 5 ~ by reaction with bromoform and potassium

t-butoxide in pentane 6• The preparatien of 9,9-dibromo-ois­

bicyclo[6.1.0]nona-2,4,6-triene (82) was brought about as indicated by VogeZ 55

• The preparatien of the dibromide 48 had been achieved as outlined in Chapter III. Compound 70 had been obtained in 58% yield by the reaction of bicyclo­[6.1.0]non-4-ene with dibromocarbene 56 ; bp 83-85° (0.01). Helting points were determined on a Mettier apparatus and are uncorrected. Nmr spectra were recorded on a Varian T-60 spectrometer, using TMS as an internal standard.

3~Hydroxy-ois-cyclonon-1-ene (63) To a solution of 200 mg of lithium in 10 ml of liquefied ammo­nia was added dropwise with stirring at -40°, a solution of 219 mg (1 mmol) of ois-2-bromo-3-hydroxycyclonon-1-ene (11) and of 200 mg of t-butanol in 2 ml of THF. The mixture was kept for 0.5 hour at -40° and the excess of lithium was de­stroyed with solid ammonium chloride. After evaporation of ·the ammonia, 10 ml of water and 10 ml of ether were added. The organic layer was separated and washed twice with water.

Upon drying and evaporation of the solvent 116 mg (83%) of 63 left as an oil. The product was identical in all respects with an authentical sample prepared from 9-endo-bromobicyclo­[6.1.0]nonane and silver perchlorate in 5% aqueous acetone 57

•

Nmr (CDC1 3) o 0.8-2.3 (m, 12, methylene H), 2.61 (s, 1, OH),

4.54 (m, 1, C!:!OH), 5.49 (m, 2, olefin H).

84

The same product was obtained by reduction of the tPana-2-

bromo-3-hydroxycyclonon-1-ene (6) under identical conditions.

9-exo-Bromo-9-endo-methyl-ais-bicyclo[6.1.0lnonane (66) To a solution of 2.80 g (0.01 mol) of 2 in 15 ml of dry THF (distilled from LiAlH 4) was added dropwise 4 ml of a 20\ solution of butyllithium in hexane at -95° (toluene-liquid nitrogen bath). After stirring for 10 minutes 1.5 ml of methyl

iodide was auded in one portion and after one hour the mixture was gradually warmed to 0°. Then 100 ml of water was added and the product was extracted with ether. Work-up and subsequent

distillation gave 1.5 g (70%) of 66; bp 118-121° (14). Nmr (CDC1 3) ö 1.63 (s, 3, CH 3), 1.60-2.20 (alifatic and cyclo­propane H). Anal. Calcd for c10 H17Br: C, 55.30; H, 7.83. Found: C, 55.31; H, 7.89.

4,5-tPana-Dihydroxy-9-exo-bromo-9-endo-methyl-aia-bicyclo­[~.1.0]nonane, acetonide (67) Toa solution of 1.7 g (0.005 mol) of 48 in 10 ml of dry THF

was added 2.2 ml of butyllithium salution and 0.7 ml of methyl iodide in a similar way as described for 2. Work-up afforded 1.22 g (92%) of 67 as a white solid; mp [ (i-Pr) 20J70-71°. Nmr (CDC1 3) ö 1.39 (s, 6, CH 3), 1.63 (s, 3, endo CH 3), 3.40-4.35 (m, 2, CH(O)-CH(O)-). Anal. Calcd for c13H21 Br0: C, 53.98; H, 7.27. Found: C, 54.04; H, 7.10.

Cyclonona-1,2,6-triene (54) Toa salution of 2.80 g (0.01 mol) of 3 were added 0.011 mol of butyllithium and excessof methyl iodide at -95°, as described for the synthesis of 66. Work-up gave an oil which, upon examination by tlc, proved to consist of one component

besides some tlc immobile material (silica gel; pentane as eluent). Chromatography gave 0.98 g (81\) of 54; identical with the compound prepared by other routes 2 ~• 25 •

85

Nmr (CDC13

) 6 5.20 (m, 2, allenic H), 5.55 (m, 2, alefin H), 1.25-2.60 (m, 8, other H); ir (neat) v 1958 cm- 1 (allene).

ois-Bicyclo[7.1.0]deca-4,5-diene (71) This compound was prepared in an identical way as described

for 54 from 2.94 g (0.01 mol) of 70. Work-up and chromato­

graphy over a short column (silicagel; pentane as eluent) provided 0.89 g (67%) of the allene 71, nmr (CDC1 3) 6 5.27

(m, 2, allenic H), 0.40-2.60 (m, 12, alifatic ringHand cyclopropyl H). Ir (neat) v 1960 cm- 1 (allene). This compound

proved to be thermolabile.

9-exo-Bromo-ois-bicyclo[6.1 .O]nonane (68) 27

To 20 ml of a 1M salution of dimsyl anion in DMSO was added

with stirring 2.8 g (0.01 mol) of 2 at such a rate as to

maintain the temperature at 25 30°. After stirring for an additional 2 hours, 150 ml of water was added and the product was extracted with ether. After washing, drying and evapo­

ration of the organic solvent the residue was distilled and

afforded 1.1 g (55%) of 68; bp 105-110° (18).

4,5-trans-Dihydroxy-9-exo-bromo-cis-bicyclo[6.1.0]nonane, acetonide (69)

A salution of dimsyl anion was prepared by dissolving 15 g (ca. 0.5 mol) of sodium hydride (80% dispersion in mineral

oil) in 500 ml of m1s0 (CaH2 dried). In half an hour was added dropwise with stirring at 20° a salution of 60 g (0.17

mol) of 48 in 100 ml of THF. The mixture was stirred for

about 2 hours and poured into 4 l of water. The product was

extracted with ether. The oil which remained after washing,

drying and evaporation of the solvent was treated with 95%

ethanol and afforded 21 g (45%) of 69; mp (95% ethanol) 66-67°.

86

Nmr (CDC1 3) ö 1.40 (s, 6, CH 3), 0.60-2.55 (alifatic and cyclo­propyl H), 3.42-4.40 (m, 2, -CH(O)-CH(O)-). Anal. Calcd for

c12 H19 Br0 2 : C, 53.36; H, 6.91. Found: C, 52.44; H, 7.06.

9-Hethyl-9-bromo-trans-bicyclo[6.1 .O]nonane (73) A salution of 2.82 g (0.01 mol) of 72 in 20 ml of THF was

treated at 95° with butyllithium and methyl iodide as de­

scribed for 66. Work-up afforded 1.93 g (89%) of 73; bp:

55-60° (0.1). Nmr (CDC1 3) o 1.68 (s, 3, CH3), 1.65-2.40 (other H's). Anal. Calcd for c10H17Br: C, 55.30; H, 7.83.

Found: C, 55.20; H, 7.81.

9-endo-Methyl-9-exo-bromo-cis-bicyclo[6.1.0]nona-2,4,6-triene ( 8 3)

A salution of 1.38 g (0.005 mol) of 82 in 10 ml of THF was

treated with butyllithium and methyl iodide as described for

66. Work-up in the usual way afforded an oil which upon sepa­ration of the compounds which had no tlc mobility (silica gel;

pet.ether as eluent), gave 0.89 g (84%) of 83. Nmr (CDC1 3) ö

1.61 (s, 3, endo CH 3), 2.09 (s, 2, cyclopropane CH), 5.62-6.05

(m, 6, olefin H). The compound proved to decompose upon dis-sa

tillation .

3-Hydroxy-7-methylocta-1 ,6-diene (91) To a salution of 2.24 g (0.02 mol) of 5-methylhex-4-en-1-al (90)- 7 in 25 ml of THF was added dropwise with stirring at

-20° a solution of 0.022 mol of vinylmagnesium bromide (pre­pared by dissolving 10 ml of a 2M salution of vinylmagnesium

bromide in 20 ml of THF). After additional stirring for 1

hour the mixture was poured onto 150 ~1 of 10% ammonium chloride solution and extracted with ether. Upon washing,

drying and evaporation 2.7 g (96%) of pure 91 leftas a colourless oil.

87

Nmr (CDC1 3) o 1.58 (s, 3, CH 3), 1.70 (s, 3, CH 3), 5.16 (m, 3, olefin H), 5.86 (m, 1, olefin H-2).

E~9-Methyldeca-4,8-dienoic acid, ethyl ester (92)

A mixture of 2.80 g (0.02 mol) of 91 and 23 g of ethyl ortho­

acetate c~ seven-fold molar excess) containing 300 mg of pro­pionic acid was treated at 130° for 1 hour with continuous

removal of ethanol. After evaporation of the orthoacetate under reduced pressure, the residue was distilled in vacuo

and gave 3.11 g (74%) of 92; bp 108-111°(0.5). Nmr (CDC1 3) o 1.23 (t, 3, CH 3), 1.60 (s, 3, CH 3), 1.69 (s, 3, CH 3), 4.10

(q, 2, CH 2), 5.11 (m, 1, olefin H-8). 5.46 (m, 2, olefin H-4 and H-5).

E-9-Methyldeca-4,8-dien-1-ol (93) Toa suspension of 4.18 g (0.11 mol) of lithium aluminohydride

in 350 ml of dry ether was added with stirring at 0-5° a so­

lution of 42.0 g (0.2 mol) of the ester 92 in 150 ml of ether. The mixture was refluxed for 15 minutes and worked up by subsequent addition of 4.2 ml of water, 4.2 ml of 10% sodium

hydroxide and 13 ml of water. Upon filtering the aluminates

over Celite the resulting clear solution was concentrated and the residue was distilled in vacuo. This afforded 30.5 g

(91%) of alcohol 93 as an oil; bp 88-92° (0.1). Nmr (CDC1 3)

o 1.60 (s, 3, CH3), 1.71 (s, 3, CH 3), 3.60 (t, 2, C!:!20H), 5.13 (m. 1, olefin H-8), 5.44 (m, 2, olefin H-4 and H-5).

E-9-Methyldeca-4,8-dien-1-al (94)

Toa suspension of 32.3 g (0.15 mol) of pyridinium chlorochro­

mate and 4.10 g (0.15 mol) of sodium acetate in 250 ml of

anhydrous methylene chloride was added with stirring 16.8 g

(0.1 mol) of the alcohol 93 in 30 ml of methylene chloride.

88

After 1 hour 200 ml of ether and 30 g of sodium sulfate were added. The mixture was stirred for an additional 15 minutes and filtered through a short Florisil column. After removal of the solvent the remaining residue was distilled and gave

10.3 g (62%) of 94, bp 82-86° (2). Nmr 1.59 (s, 3, CH3),

1.69 (s, 3, CH 3). 5.09 (m, 1, olefin H-8). 5.42 (m, 2, olefin H-4 and H-5). 9.72 (s, 1, CHO).

2,10-Dimethyldodeca-2,6,10-triene (95) To a suspension of 30.2 g (0.07 mol) of isopropyltriphenyl­phosphonium iodide in 200 ml of dry THF was added at 20°

under a nitrogen atmosphere 38.5 ml of a 15% solution of butyllithium in hexane. The deep red solution of the ylide

was added dropwise at -40° to a solution of 8.3 g (0.05 mol) of aldehyde 94 in 150 ml of ether, until persistenee of the

red colour. After additional stirring for 10 minutes, the mixture was warmed to room temperature and poured onto 750 ml of pentane. The precipitates were filtered and the solvent was removed in vacuo. The residue was chromatographed through a short Florisil column (pentane as eluent) and subsequently distilled. This gave 6.64 g (82%) of 95 as a colourless liquid, bp 135-136° (18). Nmr (CDC1 3) o 1.57 (s, 6, CH 3), 1.69 (s, 6, CH 3), 5.10 (m, 2, olefin H-3 and H-10). 5.41 (m, 2, olefin

H-6 and H-7).

1,1-Dibromo-2,2-dimethyl-3-(2-methyl-nona-2,6-dien-9-yl)­cyclopropane (87)

A mixture of 1.26 g (5 mmol) of bromoform, 400 mg of 50% aqueous sodium hydroxide (5 mmol), 168 mg (1 mmol) of triene 95 and 20 mg of 8-hydroxyethylbenzyldimethylammonium hydroxide

was stirred vigourously at 50° for 20 hours. The reaction

mixture was diluted with 10 ml of water and extracted twice with pentane.

89

The residue which remained upon washing, drying and evapora­

tion of the pentane, consisted besides starting material of 2

compounds (Rf 0.50 and 0.38; hexane-3% benzene as eluent). The less polar product proved to be the desired compound 87; 76 mg (21%). The more polar compound was assigned to be 96;

74 mg (14%). The ratio 87/96 ~ 60/40. Nmr for 87 (CDC1 3) 6

1.18 (s, 3, CH3), 1.33 (s, 3, CH 3), 1.58 (s, 3, CH3), 1.67

(s, 3, CH 3), 5.11 (m, 1, olefin H-3'), 5.43 (m, 2, olefin

H-6' and H-7'). Nmr for 96 (CDC1 3) 6 1.18 (s, 6, CH 3), 1.40

(s, 6, CH 3), 5.46 (m, 2, olefin H).

1-Bromo-1-methyl-2,2-dimethyl-3-(2-methyl-nona-2,6-dien-9-yl)­cyclopropane (88 and 97)

To a salution of 364 mg (1 mmol) of 87 in 3 ml of THF was

added at -95° a salution of 15% butyllithium in hexane (0.55

ml, ~ 1.1 mmol). Afteranaging period of 10 minutes an excess of methyl iodide (0.2 ml) was added and the mixture

was allowed to stirr for an additional 20 minutes at -95°.

Upon warming to room temperature 10 ml of water and 10 ml of

ether were added. The organic layer was separated, washed twice

and dried. Upon concentrating 252 mg of product (84%) left as

a colourless oil. The tlc showed two components (Rf 0.29 and 0.31, hexane as eluent). Attempts to isolate them by means of

chromatography failed due to decomposition. By means of nmr

the structures have been assigned as 88 and 97. Nmr (CDC13

)

6 endo (88) at 1.42; exo CH 3 (97) at 1.93. Ratio 88/97 ~ 2/1 .

90

RCferences and notes

1. H.J.J. LOOZEN, J. Th. RICHTER, unpublished results 2. D. DEVAPRABHAKARA, A. KUf\lAR and A. SINGH, Tetr. Lett.,

3343 (1975) 3. W. KIRMSE, "Carbene Chemistry", 2nd ed, Academie Press,

New York, N.Y., 1971 4. K. KLEVELAND and L. SKATTEB0L, Acta Chem. Scand. (B),

~. 191 (1975) 5. H.S. BAIRD, Chem. Comm., 1145 (1971) 6. A.C. COPE, W.R. HOORE, R.D. BACH and H.J.S. WINKLER,

J. Amer. Chem. Soc., 2, 1243 (1970) 7. E.T. HARQUIS and P.D. GARDNER, Tetr. Lett., 2793 (1966) 8. W.R. HOORE and H.R. WARD, J. Org. Chem., ?:.]_, 4179 (1962) 9. W.v.E. DOERING and P.M. La FLAMME, Tetr., 2, 75 (1958)

10. K.G. UNTCH, D.J. ~~RTIN and N.T. CASTELLUCCI, J. Org. Chem., 30, 1683 (1965)

11. P.D. GARDNER and M. NARAYN1A, J. Org. Chem., ~. 3518 (1961)

12. L.A. PAQUETTE, G. ZON and R.T. TAYLOR, J. Org. Chem., ~. 2677 (1974)

13. D.P.G. HAMHON and V.C. TRENERRY, Tetr. Lett., 1371 (1974) 14. R.B. REINARZ and G. PONKEN, Tetr. Lett., 441 (1974)

15. D.W. BROWN, M.E. HENDRICK and M. JONES, Tetr. Lett., 3951 (1973)

16. W.R. MOORE and J.B. HILL, Tetr. Lett., 4343 (1970) 17. W.R. MOORE and J.B. KING, J. Org. Chem., 36, 77 (1971) 18. W.R. MOORE and J.B. KING, J. Org. Chem~, 36, 1882 (1971) 19. L. SKATTEB0L, Tetr. Lett., 2361 (1970) 20. E.T. MARQUIS and P.D. GARDNER, Chem. Comm., 726 (1966)

21. K. KITATANI, T. HIYN~ and H. NOZAKI, J. Amer. Chem. Soc., Q.l., 949 (1975)

91

22. R.L. LAMBERT and D. SEYFERTH, J. Amer. Chem. Soc., 4, 9248 (1972)

23. E.J. COREY and G.H. POSNER, J. Amer. Chem Soc.,~. 5615 (1968)

24. M.S. BAIRD and C.B. REESE, J. Chem. Soc., (C), 1808 (1969) 25. L. SKATTEB~L, Tetr. Lett., 167 (1961) 26. J.H. WOTIZ and D.E. MANCUSO, J. Org. Chem., ~. 207 (1957) 27. C.L. OSBORN, T.C. SHIELDS, B.A. SHOULDERS, C.G. CARDENAS

and P.D. GARDNER, Chem. Ind., 766 (1965) 28. W.M. JONES and W.J. WILSON, Tetr. Lett., 1587 (1965) 29. W.M. JONES and D.L. KRAUSE, J. Amer. Chem. Soc., 93, 551

(1971) 30. R.B. WOODWARD and R. HOFF~~NN, J. Amer. Chem Soc.,~.

395 (1965) 31. P. MERLET, S.D. PEYERIMHOFF, R.J. BUENKER and S. SHIH

J. Amer. Chem. Soc., 96 959 (1974) 32. H.J.S. DEWAR and S. KIRSCHNER, J. Amer. Chem. Soc., 93,

4290 (1971) 33. G. BOCHE, D. ~~RTENS and W. DANZER, Angew. Chem., , 1003

(1969) 34. G. BOCHE, A. BIEBEREACH and H. WEBER, Angew. Chem., ~.

550 (1975) 35. ~1. OGLIARUSO, R. RIEKE and S. WINSTEIN, J. Amer. Chem. Soc.,

~. 4731 (1966) 36. M. OGLIARUSO, J. Amer. Chem Soc.,~· 7490 (1970) 37. G. MOSHUK, G. PETROWSKI and S. WINSTEIN, J. Amer. Chem.

Soc.,~. 2179 (1968) 38. L.B. ANDERSON, M.J. BROADHURST and L.A. PAQUETTE, J. Amer.

Chem. Soc., 95, 2198 (1973) 39. L.A. PAQUETTE, R.E. WINGARD Jr. and R.K. RUSSELL, J. Amer.

Chem. Soc., 2198 (1973) 40. For a review on the concept of homoaromatic interactions

see: S. WINSTEIN, Quart. Rev. Chem. Soc.,~. 141 (1969) 41. P.K. FREE~~N and T.A. HARDY, Tetr. Lett., 3939 (1971) 42. G.B. TRIMITSIS and A. TUNCAY, J. Amer. Chem. Soc., 7

7193 (1975)

92

43. J.t1. BROWN and L.J. OCCOLOWITZ, J. Chem. Soc. (B), 412 (1968)

44. S. WINSTEIN, M. OGLIARUSO, M. SAKAI and J.M. NICHOLSON, J. Amer. Chem. Soc.,~. 3656 (1967)

45. R.G. BERMAN and V.J. RAJADHYAKSHA, J. Amer. Chem. Soc.,

~. 2164 (1970) 46. C.G. CARDENAS, B.A. SHOULDERS and P.D. GARDNER, J. Org.

Chem., E• 1220 (1967) 47. R. HARBET and G. Saucy, Helv. Chim. Acta,~. 2095 (1967) 48. D.J. FAULKNER and M.R. PETERSEN, Tetr. Lett., 3243 (1969) 49. W.S. JOHNSON, R. WERTHEt~NN, W.R. BARTLETT, T.J. BROCKSOM,

T. LI, D.J. FAULKNER and M.R. PETERSEN, J. Amer. Chem. Soc., ~. 741 (1970)

50. E. J. COREY and W.J. SUGGS, Tetr. Lett., 2647 (1975) 51. E.V. DEHHLOV, Angew. Chem., 187 (1974) 52. T. HIYAMA, H. SAWADA, M. TSUKANAKA and H. NOZAKI, Tetr.

Lett., 3013 (1975) 53. L. SKATTEB0L, Acta Chem. Scand., lZ• 1683 (1963) 54. E. VEDEJS, K.A.J. SNOBLE and P.L. FUCHS, J. Org. Chem.,

~. 1178 (1973) 55. E. VOGEL, Angew. Chem., , 548 (1961) 56. D.I. SCHUSTER and F.T. LEE, Tetr. Lett., 4119 (1965) 57. C.B. REESE and A. SHAW, J. Chem. Soc. (Perkin I), 2422

(1975) 58. Bicyclo[6.1.0]nona-2,4,6-trienes have a very strong

tendency to rearrange upon warming; see S.W. STALEY and T.J. HENRY, J. Amer. Chem. Soc.,~. 1239 (1969) and references cited therein.

SUMMARY

In this thesis several new methods are described which

permit the synthesis of medium sized cycloalkanes with func­

tionality at the olefinic and allylic carbon atom, by ring expansions of geminal dihalocyclopropanes under non-solvo­lytic conditions. The synthesis of medium sized rings via

silver ion assisted ring expansions of geminal dihalocyclo­

propanes in solvents, such as acetic acid, aqueous acetone or methanol, proceeds with loss of the more accessible exo halo­gen atom and has been well documented. This reaction general­

ly leads to trans allylic products. The alternate approach, viz. ring expansions under non-solvolytic conditions, has not

been described before.

Treatment of a variety of geminal dibromobicyclo[n.1.0Jalkanes

(n= 5, 6, 7) with silver salts (AgX) in acetonitrile shows that the ring opening may lead to both cis and trans products.

The anion (X-) now replaces the role of the solvent in solvo­

lytic reactions. A hypothesis has been developed now that the

nature of the product is dependent on two main factors.

Products which can bear a trans double bond, but which are not able to accommodate a trans,trans allylic cation, are

formed in a reaction in which the nucleophile enters con­

comitantly with the ring opening at the same side of the in­cipient allylic system as where the exo halogen atom is lost.

If the product is actually able to accommodate a trans,trans allylic cation, then two possibilities exist: either attack

of the nucleophile at the transrtrans cation occurs immedi­ately (leading totrans products), or an isomerization toa

cis cation takes place (leading to cis products).

94

Furthermore, a synthesis of geminal endo-iodo-exo-bromocyclo­

propanes has been developed, based upon the ability of dibromo­cyclopropanes to undergo a stereoselective halogen-metal

interconversion with butyllithium at -95°, leading to endo­

lithio-exo-bromocyclopropanes. The compounds, obtained by iodination of such stereospecifically generated lithiates

proved to be excellently stable precursors for the stereo-

fic synthesis of cyclic systems hearing a vinyl iodide

moiety, along the lines indicated above. The lithiate derived from 9,9-dibromobicyclo[6.1.0]non-4 ene

is highly unstable, even at -95°, and disproportionates readily to an allene. Responsible for this anomalous behaviour is the presence of the favourably located double bond. A

strong bishomoaromatic interaction favours a rapid disrota­tory ring opening. As such this is one of the few examples,

hitherto known in the area of bicyclic systems, in which a

cyclopropyl anion exhibits an apparently forbidden mode of ring opening by homointeraction.

A further investigation shows that these interactions are not

present in cyclopropyl anions substituted with a polyenic

chain. Probably, the presence of a double bond in a transi­tion state like arrangement is a prerequisite.

~MEN~TnNG

In dit proefschrift worden enige nieuwe methoden be­

schreven om te komen tot gefunktionaliseerde middelgrote ring systemen, door middel van ring opening van geminale dihalo­

cyclopropanen onder niet-salvolytische omstandigheden. De synthese van middelgrote ringen met behulp van zilver zouten

onder salvolytische kondities, in oplosmiddelen zoals bijv.

azijnzuur, methanol of waterige systemen, geschiedt via het

afsplitsen van het meest toegankelijke exo halogeen atoom. Door middel van dit type reaktie worden als regel trans pro­

dukten verkregen. De ring openingsreaktie onder niet-solva­lytische omstandigheden was tot nu toe niet bestudeerd.

Tijdens de reaktie van geminale dibroombicyclo[n.1.0lalkanen

(n= 5, 6, 7) met zilver zouten (AgX) in acetonitril worden

zowel trans als cis produkten gevormd. Het anion (X-) vervult nu dezelfde rol als het oplosmiddel in de salvolytische reak­

tie. Vastgesteld is dat de aard van het produkt afhankelijk

is van een tweetal faktoren. Cyclische produkten, die een trans dubbele band kunnen bevatten, doch geen trans,trans kation, worden gevormd in een ring opening, waarbij het af­

splitsen van het exo halogeen atoom gelijktijdig plaatsvindt

met de aanval van het nucleofiel (X-) aan dezelfde kant van

het molecuul. Dit leidt tot trans produkten. Wanneer we te maken hebben met moleculen, die zowel een trans dubbele band

als een trans,trans kation kunnen bevatten, dan kan er ofwel

direkt aanval van het nucleofiel plaatsvinden, ofwel er treedt eerst een isomerisatie naar het cis kation op. In dit

laatste geval worden er cis produkten gevormd.

96

De mate waarin deze cis produkten worden gevormd, is afhanke­lijk van de spanning in het trans,trans kation (ring grootte) en van de nucleofiele eigenschappen van het anion. Verder wordt in dit proefschrift de synthese van geminale endo-iodo-exo-broomcyclopropanen beschreven. Deze synthese is gebaseerd op de mogelijkheid om stereoselektief endo-lithiö­exo-broomcyclopropanen te genereren uit de overeenkomstige dibroom verbindingen en deze vervolgens te joderen bij -95°. Met behulp van deze uitermate stabiele verbindingen kunnen op de wijze, zoals hierboven beschreven, stereospecifiek cyclische systemen worden bereid, die een vinyljodide fragment bevatten. Het lithium derivaat, verkregen uit 9,9-dibroombi­cycloi6.1.0Jnon-4-een, blijkt zeer instabiel te zijn, zelfs bij -95°. Dit is vermoedelijk het gevolg van een bishomoaro­matische interaktie van het cyclopropyl anion met de dubbele band, die een gemakkelijke disroterende ringopening tot gevolg heeft. Het produkt dat hierbij wordt gevormd is het alleen. Tot nu toe zijn van dit type interakties die een schijnbaar verboden ring opening tot gevolg hebben in bi­

cyclische systemen weinig voorbeelden bekend. Verder onder­zoek aan een cyclopropyl anion, gesubstitueerd met een poly­een doet vermoeden dat de aanwezigheid van een dubbele band in een transition-state achtige positie een voorwaarde is voor interaktie.

97

CURRICULUM VITAE

De auteur werd geboren op 24 augustus 1948 te Heerlen.

Na het behalen van het einddiploma HBS-b aan de HBS St.

Antonius Dr. te Kerkrade, werd in 1966 begonnen met de studie

scheikunde aan de Technische Hogeschool te Eindhoven. Het

kandidaatsexamen werd in 1969 afgelegd. In september 1971

behaalde hij met lof het Ingenieurs diploma, met als afstu­

deerrichting Organische Chemie.

Tot medio 1974 werkte hij op de afdeling Organische Chemie

van de Technische Hogeschool te Eindhoven, onder leiding van

Dr. E.P. Godefroi, aan de synthese van heterocyclische ver­

bindingen. Het onderzoek met betrekking tot de synthese van

modelstoffen voor biomimetische reakties, dat in dit proef­

schrift beschreven is, werd gestart medio 1974 onder leiding

van Prof. Dr. H.M. Buck.

In de periode dat hij werkzaam was op de afdeling Organische

Chemie verschenen van zijn hand een twaalftal wetenschappe­

lijke publikaties.

Sinds 1 september 1976 is hij werkzaam als research chemicus

op de Research and Development Laboratories van Organon

International B.V. te Oss.

98

DANKWOORD

Mijn erkentelijkheid zou ik willen uitspreken aan de

docenten Prof. Dr. H.M. Buck en Dr. E.F. Godefroi, die in zeer belangrijke mate hebben bijgedragen tot mijn weten­schappelijke vorming, welke de basis is geweest voor de

totstandkoming van dit proefschrift.

Ik zou mijn dank willen uitspreken tegenover Dr. J.W. de

Haan voor zijn bijdrage met betrekking tot de spectrosco­

pische aspekten van mijn werk.

Tenslotte zou ik alle leden van de Vakgroep Organische Chemie willen bedanken. Tijdens mijn werkzaamheden vormden

zij het inspirerende klimaat, waarin mijn wetenschappelijk

werk tot stand gekomen is.

99

STELLINGEN

I De conclusie van OZah et aZ., dat in 1,3-diarylcyclobutenyl

kationen geen homoconjugatie tussen de koolstofatomen c1 en c3 voorkomt, is aanvechtbaar.

G.A. Olah, J.S. Staral, R.J. Spearen G. Liang,

J. Amer. Chem. Soc.,~. 5489 (1975) A.E. van der Hout-Lodder, J.W. de Haan, L.J.M.

van de Ven en H.M. Buck,

Reel. Trav. Chim., ~. 1040 (1973)

2 De beschouwing van Seebaah et aZ., waarin het thioacroleine dianion wordt beschreven als synthon voor allyl carbeen,

is onjuist.

D. Seebach, K.H. Geiss en M. Pohmakotr,

Angew. Chem., ~. 449 (1976)

8 Het toekennen van de structuur van 2,6-exo,exo-dihydroxy­bicyclo[3.3.1]-9-thianonaan op grond van uitsluitend

infrarood gegevens, is zeer twijfelachtig.

E.D. Weil, K.J. Smith en R.J. Gruber,

J. Org. Chem., ll, 1669 (1966)

4 Het door Massoth en SaaPpieZZo gebruikte model voor re­ductie van Bi 2o3 met propeen, is onjuist.

F.E. Massoth en D.A. Scarpiello,

J. Cat., ~. 225 (1971)

S Het mechanisme dat door Hiyama et al. wordt voorgesteld voor de vorming van a,B-onverzadigde ketonen uit geminale

dichloorcyclopropanen, is te speculatief.

T. Hiyama, T. Mishima, K. Kitatani en H. Nozaki,

Te t r . Le tt. , 3 2 9 7 ( 19 7 4)

6 De veronderstelling, dat het meten van een optische

draaiing bij de reactie van chloroform met olefinen onder

phase-transfer condities is toe te schrijven aan chirale

inductie, berust op verkeerde interpretatie van de gege­

vens. T. Hiyama, H. Sawada, M. Tsukanaka en H. Nozaki, Tetr. Lett., 3013 (1975)

7 Het onderscheid dat Bril maakt tussen het substituant­effect in de B3o6

3- ring en een symmetrisch tri-gesubsti­

tueerde benzeen ring van het type c6H3x3 , is uit het oog­punt van mesomeria niet terecht.

T.W. Bril, Proefschrift, Technische Hogeschool Eindhoven

(1976)

8 Aan het gebruik van het voorvoegsel "bio" in wetenschap­

pelijke literatuur dient paal en perk te worden gesteld.

H.J.J. Loozen Eindhoven, 26 oktober 1976