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BENZOCYCLOBUTYL-DIHYDROOXEPINS VIA INTRAMOLECULAR CYCLOADDITIONS OF ENYNE [3]CUMULENALS

A THESIS

SUBMITTED TO THE FACULTY OF CLARK ATLANTA UNIVERSITY

IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR

THE DEGREE OF MASTER OF SCIENCE

BY

TAWFEQ ABDUL-RAHEEM KAIMARI

DEPARTMENT OF CHEMISTRY

ATLANTA, GEORGIA

JULY 1996 (c) 1996 TAWFEQ A. KAIMARI All Rights Reserved ABSTRACT

CHEMISTRY

KAIMARI, TAWFEQ A. B.A., CITY UNIVERSITY OF NEW YORK, 1994

BENZOCY CLOBUTYL-DIHYDROOXEPINS VIA INTRAMOLECULAR CYCLOADDITIONS OF ENYNE r31CUMULENALS

Advisor: Dr. Augusto Rodriguez

Thesis dated: July, 1996

The synthesis of 2-(3-phenyl-l-trimethylsilanyl-9H-8-oxa-benzo[a]cyclobuta[d]cyclohepten-2- ylidene)propionaldehyde (171) is described. Our laboratories have an interest in developing new methods for the construction of complex oxygen heterocycles. In this context, we describe the intramolecular [2+2] cycloaddition of enyne cumulenal 168 to produce benzofused dihydrooxepin 171. The synthesis of 168 was accomplished in four steps from the commercially available starting material, o-hydroxybenzophenone (164). Treatment of o- hydroxybenzophenone with 3-bromo-l-(trimethylsilyl)-l- in the presence of potassium carbonate/potassium iodide mixture in refluxing 2-butanone afforded pheny[2-3- trimethylsilanyl-prop-2-ynyloxy)phenyl]-methanone (165) in 88% yield. Addition of the lithio anion of 2-methyl-3- gave 4-methyl-1-phenyl-l-[2-(3-trimethylsilanyl-prop-2-ynyloxy)-

1 phenyl]-pent-4-en-2-yn-l-ol (166) in 70% yield. Epoxidation of 166 with m- chloroperoxybenzoic acid gave 3-(2-methyl-oxiran-2-yl)-l-phenyl-l-[2(3-trimethylsilanyl- prop-2-ynyloxy)-phenyl]-prop-2-yn-lol (167) in 92% yield. Rearrangement of 167 with boron trifluoride (at -78°C) gave a 1:1 mixture of E/Z 2-methyl-5-phenyl-[2-(3-trimethyl-5-[2-(3- trimethylsilanyl-prop-2-ynloxy)-phenyl]-penta-2,3,4-trienal (168) in 80% yield. Attempts to disilyate

168 using potassium carbonate and methanol gave a complex mixture of 4- methoxy-2-methyl-5-phenyl-5-[2-(prop-2-ynyloxy)-phenyl]-penta-2,4-dienal (169) in 61% yield. Heating the mixture of E/Z 168 afforded a mixture of E/Z 2-(3-phenyl-l- trimethylsilanyl-9H-8-oxa-benzo[a]cyclobuta[d]cyclohepten-2-ylidene)propionaldehyde (171) in 86% yield. Theoretical calculations on [2+2] intramolecular cumulene cycloadditions are in agreement with the experimental findings.

2 ACKNOWLEDGMENTS

First and foremost, I would like to thank my father, Abdul-Raheem Kaimari, who has taught me that through curiosity, careful reasoning, honesty, persistence, and faith all things in life are possible and my mother, Mukarram Maswadeh, who has been the inspirational force behind all of my accomplishments.

I would also like to thank my research advisor, Professor Augusto Rodriguez. He allowed considerable latitude to conduct this research project, generously gave moral and intellectual support, as well as guidance and prudent advice. I would also like to express my appreciation to the members of my committee: Dr. Issifu Harruna, Dr. Ishrat Khan, and Dr.

Reynold Verret. Funding of this work through the U.S. Army’s Edgewood Research

Development and Engineering Center (Grant No. DAAA15-94-K0004) is appreciated.

In addition, I would like to express my gratitude to Dr. Gabriel Garcia, for his great friendship, philosophical discussions, and deep discussions about the meaning of chemistry in relation to everyday life and to Ms. Pauline Pugh, for bringing much happiness to the group through her lively character. I would also like to thank my fellow lab mates for their friendship.

I would also like to express my sincere appreciation for my friends outside of CAU, especially my mentor, Dr. Charles Meredith, who introduced me to CAU and gave me technical advice and encouragement. I wish to also thank Ms. Janet Waymer, who always placed others before herself, welcomed me into her home, gave me her encouragement, and helped me reach my goals. Finally, I thank Ms. Amy Ferdinand, whose friendship has made the good times great and the rough times tolerable. She truly is the “super woman”. TABLE OF CONTENTS

Page

ACKNOWLEDGMENTS ü

LIST OF TABLES vi

LIST OF FIGURES vü

I. STATEMENT OF THE PROBLEM 1

H. LITERATURE REVIEW OF [3]CUMULENES 2

2.1 STRUCTURE AND PROPERTIES 2

2.2 PREPARATIONS 4

2.2.1. Elimination Routes 5

2.2.1.1. Dihalides 5

2.2.1.2. Cyclopropyl Dihalides 5

2.2.2. Reduction-Elimination Routes 8

2.2.2.I. Dihalides 8

22.2.2. Diols 8

2.2.2.3. Other Reduction-Elimination 9

2.2.3. Wittig Routes 10

2.2.4. Metal Catalyzed Dimerization Routes 12

2.2.5. Miscellaneous Preparations14

iii 2.3 REACTIONS 17

2.3.1. Hydrogenations 17

2.3.2. Halogénations 18

2.3.3. Isomerizations 18

2.3.4. Oxidations and Reductions 19

2.3.5. Additions 20

2.3.6. Inter-Molecular Cyclizations 20

2.3.6.1. Metal Catalyzed Dimerizations 20

2.3.6.2. Thermally and Photochemically Induced Dimerization 21

2.3.6.3. Diels-Alder 22

2.3.7. Intra-Molecular Cyclizations 22

2.3.7.1. Benzocycloaromatizations 22

2.3.7.1.1. Acyclic Systems 22

2.3.7.1.2. Cyclic Systems 24

2.3.7.2. [2+2] Cycloadditions 24

HI. LITERATURE REVIEW ON OXEPINS 26

3.1. STRUCTURE AND PROPERTIES 26

3.2. PREPARATIONS 27

IV. RESULTS AND DISCUSSION 35

V. EXPERIMENTAL SECTION 67

VI. CONCLUSION 74

IV VH. APPENDIX 76 vm. REFERENCES 77

v LIST OF TABLES

Table Page

I. O-Alkylation of 2-Hydroxybenzophenone 38

H. Reaction enthalpies (kcal/mole) for the [2+2] cyclization of [3]cumulenal 156 68

vi LIST OF FIGURES

Figure Page

5.1 Proton NMR spectra for Pheny-[2-3-trimethylsilanyl-prop-2yynyloxy)phenyl]-

methanone (153) 39

5.2 Infrared spectra for Pheny-[2-3-trimethylsilanyl-prop-2yynyloxy)phenyl]-

methanone (153) 40

5.3 13C NMR spectra for Pheny-[2-3-trimethylsilanyl-prop-2yynyloxy)phenyl]-

methanone (153) 41

5.4 Proton NMR spectra for 4-Methyl-l-phenyl-l-[2-(3-trimethylsilanyl-prop-2-ynyloxy)-

phenyl]-pent-4-en-2-yn-l-ol (154) 43

5.5 Infrared spectra for 4-Methyl-1-phenyl-l-[2-(3-trimethylsilanyl-prop-2-ynyloxy)-

phenyl]-pent-4-en-2-yn-l-ol (154) 44

5.6 l3C NMR spectra for 4-Methyl-1-phenyl- l-[2-(3-trimethylsilanyl-prop-2-ynyloxy)-

phenyl]-pent-4-en-2-yn-l-ol (154) 45

5.7 Proton NMR spectra for 3-(2-methyl-oxiran-2-yl)-l-phenyl-l-[2(3-trimethylsilanyl-

prop-2-ynyloxy)-phenyl]-prop-2-yn-lol (155) 47

5.8 Proton NMR spectra for the diastereomers protons of 3-(2-methyl-oxiran-2-yl)-

1 -phenyl-1 -[2(3-trimethylsilanyl-prop-2-ynyloxy)-phenyI]-prop-2-yn-1 ol (155) 48

vii 5.9 Infrared spectra for 3-(2-methyl-oxiran-2-yl)-1 -phenyl- l-[2(3-trimethylsilanyl-prop-2-

ynyloxy)-phenyl]-prop-2-yn-lol (155) 49

5.10 l3C NMR spectra for 3-(2-methyl-oxiran-2-yl)-1-phenyl- l-[2(3-trimethylsilanyl-prop-2-

ynyloxy)-phenyl]-prop-2-yn-lol (155) 50

5.11 Proton NMR spectra for 2-Methyl-5-phenyl-[2-(3-trimethyl-5-[2-(3-trimethylsilanyl-

prop-2-ynIoxy)-phenyl]-penta-2,3,4-trienal (156) 52

5.12 Infrared spectra for 2-Methyl-5-phenyl-[2-(3-trimethyl-5-[2-(3-trimethylsilanyl-prop-2-

loxy)-phenyl]-penta-2,3,4-trienal (156) 53

5.13 13C NMR spectra for 2-Methyl-5-phenyl-[2-(3-trimethyl-5-[2-(3-trimethylsilanyl-prop-

2-ynloxy)-phenyl]-penta-2,3,4-trienal (156) 54

5.14 Proton NMR spectra for 4-Methoxy-2-methyl-5-phenyl-5-[2-(prop-2-ynyloxy)-

phenyl]-penta-2,4-dienal (157) 56

5.15 Infrared spectra for 4-Methoxy-2-methyl-5-phenyl-5-[2-(prop-2-ynyloxy)-phenyl]-

penta-2,4-dienaI (157) 57

5.16 13C NMR spectra for 4-Methoxy-2-methyl-5-phenyl-5-[2-(prop-2-ynyloxy)-phenyl]-

penta-2,4-dienal (157) 58

5.17 Proton NMR spectra for 2-(3-phenyl-l-trimethylsilanyl-9H-8-oxa-benzo[a]cyclobuta

[d]cyclohepten-2-ylidene)propionaldehyde (160) 60

5.18 Infrared spectra for 2-(3-phenyl-l-trimethylsilanyl-9H-8-oxa-benzo[a]cyclobuta / [d]cyclohepten-2-ylidene)propionaldehyde (160) 61

5.19 13C NMR spectra for 2-(3-phenyl-l-trimethylsilanyl-9H-8-oxa-benzo[a]cyclobuta

viii

J [d]cyclohepten-2-ylidene)propionaldehyde (160) 62

5.20 13C/dept90 NMR spectra for 2-(3-phenyl-l-trimethylsilanyl-9H-8-oxa-benzo[a]

cyclobuta[d]cyclohepten-2-ylidene)propionaldehyde (160) 63

5.21 Expanded region between 120-135 ppm of figure 5.20 64

5.22 The orbital distribution for acetelyne and cumulene 66

IX I. STATEMENT OF THE PROBLEM

Cycloaddition reactions of [3]cumulenes have not yet been fully explored. Of particular interest are intramolecular cycloadditions of [3]cumulenes because these reactions are expected to render unsaturated fused rings. We have devised a strategy for the construction of a fused oxepin- ring using a [2+2] intramolecular cycloaddition approach. New methods for the construction of oxepin rings are in demand because these rings are found in many biologically active molecules. In this work, we will test this strategy.

156 160 II. LITERATURE REVIEW ON [3JCUMULENES

2.1. STRUCTURE AND PROPERTIES

Cumulenes are compounds with sequential double bonds which are of considerable theoretical, structural, and synthetic interest.1 Cumulenes can be defined as compounds

which contain a unit of n carbon atoms with (n-1) double bonds between them and n

having a value of greater than 2.2 Members of this family include propadienes (aliénés),

butatrienes ([3]cumulenes), pentatetraenes ([4]cumulenes), and hexapentaene

([5]cumulenes).

The stability of cumulenes is decreased if one or more of the four substituents are

replaced by hydrogen atoms. Thus, butatriene 1 can only be obtained by a very careful

process of isolation, and is extremely labile.3

PhCH=HC CH=CHPh

1

According to van’t Hoffs theory,4 cumulene 2 containing an even number of

double bonds must have four substituents in two perpendicular planes; whereas cumulene 3

containing an odd number of double bonds, the substituents are contained in the same

plane. This theory predicts that cumulene 3 with an odd number of double bonds should be

capable of exhibiting E-Z isomerism. Cumulenes containing an even number of double

2 R|\ yRl Rl\ y^A ^EZZ^IZi^Z ■ ^ • * " ■ *

X R2 R3 R2 R3

2 3

bonds occur in optically active forms if Rj ^ R2 and R3 * R4 and provided that free rotation

about the double bonds is sufficiently blocked. Cumulenes with an odd number of double bonds (butatrienes, and hexapentaenes) exist as E, Z .

The enthalpy of activation for the interconversion of 4E to 4Z is AH* =31.0 Kcal

mol'1.5 This is comparable to the enthalpy of interconversion of cis to trans

alkenes, which is AH*= 65.0 Kcal mol'1.6 The low barriers to isomerization are

H. H XCH3 y AH = _ :C=C: > 3Î KcalVnole_l CH3 H3C H3C

4Z 4E

presumably due to a significant contribution of zwitterionic or biradical resonance

structures to the overall structure of the cumulene system (figure 2.1). It is, therefore, not

suprising that the cis-trans interconversion occurs readily, either photochemically (in

diffuse daylight) or thermally (at 160 °C).

The electronic structure of cumulenes suggests that the central exhibits

some triple bond character.8 It has been shown that the middle double bond of

3 Figure 2.1 Stereoisomerism in cumulenes. cumulene 6 is shorter than that of the two terminal double bonds.9

1.28 A

5 6

The double bonds in aliéné 5 are considerably shorter than the double bond in (1.34 Â). This double-bond contraction has also been observed in ketenes.10

2.2. PREPARATIONS

Most known [3]cumulenes are multi-alkoxy or phenyl substituted because of better stability compared to their counterparts. Preparative methods for the synthesis of alkyl substituted [3]cumulenes are rare.

Whereas numerous derivatives of the aliénés have been prepared and investigated," in the butatriene series only very few derivatives have been reported.12 Most of the synthetic methods for [3]cumulenes involve eliminations, reduction-eliminations, Wittig type reactions, metal catalyzed, and miscellaneous preparations.

4 2.2.1. Elimination Routes

2.2.1.1. Dihalides

The elimination of dihalides has been employed for the preparation of acyclic

[3]cumulenes. For example, the dihalo 7 is converted to 8 with KOH in ethanol.13

KOH m Ph2CH C=C CHPh2 Ph C= C=C=CPh EtOH 2 2 Br Br

7 8

This method has also been applied to the synthesis of symmetric tetraaryl- and tetrapheny lbutatrienes.14‘16

2.2.I.2. Cyclopropyl Dihalides

In contrast to the aliénés, very little is known about the structure and chemistry of cyclic [3]cumulenes.17 Alkyl-substituted [3]cumulenes known to date have been obtained by methods that involve ring opening of dihalocyclo propanes, a method known as the

Doering-Moore-Skattebol method (DMS).18 The DMS method consists of the addition of dichloro- or dibromo- to double bonds yielding 1,1-dihalogenocyclopropenes 10, which are converted into 11 by treatment with lithium .

9 10 11

5 The DMS procedure has been used to synthesize 4-methyl-1,2,3-pentatriene,19,20 4-methyl-

1,2,3-hexatriene,20 cis- and trans- 1,4-dimethylbutatriene21 and tetramethylbutatriene.22 The starting materials in all cases have been prepared by dibromocarbene addition to the corresponding aliéné.

Another method dealing with the carbene chemistry for the synthesis of

[3]cumulene is the reaction of olefins 12 with dichlorocarbene to give gem- dichlorocyclopropanes 13.23

-2HCI R,R2C=CH CHR3R4 R1R2C—-CH—CHR3R4 alkoxide in cr'ci

12 13 14

The dichlorocarbene was generated from the reaction of ethyl trichloroacetate with sodium methoxide,24 or chloroform with aqueous sodium hydroxide solution (50 %) in the presence of catalytic amounts benzyltriéthylammonium chloride.25

A facile method for the preparation of cyclic [3]cumulenes involves the double elimination and ring opening of cyclopropyl dihalides. As an example, treatment of 1,2- cyclononadiene (15) with one equivelent of phenyl(tribromomethyl)mercury in refluxing followed by removal of phenylmercuric bromide and the solvent gave 16.26

Treatment of 15 with methyllithium in at -80 °C followed by warming to 0 °C gave

17.26

6 A stable example of simple cyclic [3]cumulenes reported is 1,2,3-cyclodecatriene

20, which was prepared by Moore and Ozretich in 1965.27 This compound is an air

A recent facile synthesis of alkyl and aryl substituted [3]cumulenes was reported by

Chow et al. via tetrabutylammonium fluoride (TBAF) induced 1,4-elimination of 1-

acetoxy-4-(trimethylsilyl)-2-butynes.28 Similar conditions were applied to the most recent

report by Wang et al. concerning a facile synthesis of [3]cumulene via 1,4-elimination.29

[3]Cumulene 22 was obtained by sequential treatment of 21 with n-butyllithium,

methanesulfonyl chloride, and TBAF.

1. nBuLi 2. MsCl 3. TBAF MejSi

21 22

7 2.2.2. Reduction-Elimination Routes

2.2.2.I. Dihalides

Arens, Brandsma and coworkers developed a general procedure for the synthesis of

aliphatic [3]cumulene 24. Reduction of 1,4-dichloro-2- 23 with zinc dust in

dimethylsulfoxide takes place at 80 °C leading to [3]cumulenes 24.30

7.n 80‘Y; DMSO

ci

23 24

Zinc powder has been used for the reduction of vicinal dihalides into the

corresponding [3]cumulenes. Synthesis of diphenyl-dimethyl [3]cumulene 27 can be

achieved by reduction of the dihalides precursor 26 with zinc powder.31 Alkyl-lithium

reagents can also be used to affect the dihalo-elimination.31

25 26 27

2.2.2.2. Diols

Propargylic rearrangements of acetylenic and polyacetylenic diols and their

derivatives have been used to synthesize higher cumulenes. The procedure is restricted to

cumulenes with an uneven number of double bonds.32

8 The preferred method for synthesis of aromatic [3]cumulenes 29 consists of reduction diols 28 with stannous chloride, hydrochloric acid and pottasium iodide in ethanol-sulphuric acid solvent mixture.33

.Ar Ar\ .Ar / Reducing ' / c=c—c c—c=c=c. /\ Agent J \ HO Ar Ar Ar

28 29

A similar reduction of 1,4-butyne-diols affording [3]cumulenes has been acomplished by using phosphorous iodide as the reducing agent. For example, diol 30

34 gives cumulene 31 in 67% when reacted with P2LI-

Ph Ph

30 31

2.2.2.3. Other Reduction-Elimination

Conjugated enynols have been used as substrates for the synthesis of conjugated cumulenic and . For example, 5-methyl-5-hydroxy-l-methoxy-l--

3-yne (32) under carefully controlled acidic conditions yields 10-15% of 5-methyl-2,3,4- hexatrienal (33).35

9 M' Me2p C=C CH=CHOMe V / OH Me CHO

32 33

Similarly, various phenyl-substituted cumulenic ketones are obtained by treatment of the corresponding conjugated enynols under acidic conditions.36'37 Conjugated cumulenic 35 can be obtained in 74% yield from the dehydration reaction of a-allenic alcohol 34.38 These conditions involve treatment of the a-allenic alcohol with p- toluenesulfonylchloride in triethylamine at low temperature.

-Ph p-MeCftHjStCOCl, NEh -78 "C Ph

34 35

2.2.3. Wittig Routes

The Wittig reaction has been used to provide a synthetic entry to cumulenes. It allows the conversion of into C-cumulenes by carbonyl olefination.39

Especially interesting are phosphacumulene ylides 36 and diylides because of their rich chemistry and usefulness as versatile reagents in organic synthesis.40

Ph3p=[:=]cR2

36

10 Phosphacumulene ylides are usually prepared by the reaction of the appropriate

cumulene phosphonium salts with such bases as Et3N and in CH3CN or PhLi in ether.41

Substituted [3]cumulenes can be prepared via the Homer-Emmons reaction of allenyldiphenylphosphine oxides in a similar way 42 For example, when aliéné 37 is reacted

with KN(TMS)2 at low temperatures in the presence of a carbonyl compound, cumulene 38 is formed.

37 38

Annulated benzene rings and aryl substituted [3]cumulenes can be obtained via

Wittig phosphacumulene sequence.43 Of particular importance is the reaction of the phospha cumulene 39 with carbonyl compounds affording cumulene 40.

11 Bromo-[3]cumulene was prepared from the phosphonium salt and 6-methyl-5- hepten-2-one by a Wittig condensation 44 A facile preparation of chloro-[3]cumulene was also reported via Wittig reaction,45 as was cumulene 43, prepared from the bis-ylide 42.46

emeu + 2 n-BuLi Ph F=C=C =PPh 2ArCHO -78 "C 3 3 ArCH=C=C =CHAr CH2CI2. -78 °C

41 42 43

The monocyclohexyl derivative of butatrienes is formed in low yield when

triphenylpropargylphosphonium bromide is converted by n-Butyllithium treatment into a

Wittig reagent (presumably allenyl triphenyl phosphorane), and the latter condensed with

cyclohexylcarboxaldehyde.47

A bicyclic cumulatriene 45 was also obtained via an intramolecular Wittig-type

olefinations.48

2.2.4. Metal Catalyzed Dimerization Routes

In an interesting catalytic reaction, t-butylacetylene is dimerized to cis- and trans-

2,2,7,7-tetramethyl-3,4,5-octatriene, with dihydrocarbonyltris(triphenylphosphine)-

12 ruthenium serving as catalyst.49 Another useful dimerization reaction involves carbene formation of a dibromo compound followed by Cu catalyzed dimerization. For instance,

TMS-protected dibromo-olefin 46 produces the corresponding [3]cumulene 47 when

50 treated with BuLi/Et20 followed by CuI.PBu3.

BuLi / Et2<^ CuI.PBuj

46 47 Other dimerizations have been investigated using copper51 and transition metal

catalysts.52 Two other reports have discussed the preparation of substituted [3]cumulene

by metal-initiated coupling of alkynes.53'54 Wakatsuki observed that the dimerization of 48

with 49 as hydride catalyst led to Z-[3]cumulene 50.55

tBuC=CH RuH2(CO)(PPh3)l

48 49 50

Cumulene 52 was obtained by the cleavage of the enyny 1-rhodium bond in 51 by

56 CF3C02H in or benzene.

51 52

13 2.2.5. Miscellaneous Preparations a. Substituted [3]cumulenes are prepared by a vinylogous propargylic rearrangement.

An illustrative example is the reaction of the ene-yne ether 53 with alkyl-lithium reagents at

low temperature, producing 4-alkyl substituted [3]cumulenes of the type 54.57'58

Ijle

xMe Eth er RLi + H2zC=C C=C C OBu , , - R-CH2CH=C= \ | low temp. Me Me

53 54

b. A novel method for the synthesis of [3]cumulene 58 (R=H) is starting from 1,4-

dihalo- or 1,4-bis-tosyl-2-butyne via 4-vinylidene-l,3-dithiolane-2-thione 57.59 The

subsequent Corey-Winter desulfurization to butatriene 58 (R=H) was accomplished with

the phosphorous base 1,3-dimethy 1-2-phenyl-1,3,2-diazaphospholidine at 0 °C with good

yield of 90%.60

Compared with the conventional method of Schubert et al.61 and Brandsma et al.62

for the synthesis of [3]cumulene, this method gave higher yields. For substituted

[3]cumulene, Raney nickel63 was an excellent desulfurization agent.

14 c. Cumulene 61 is formed when the diol 59 is dehydrated by acids. The reaction occurs via the divinylacetylene intermediate 60, which dimerizes under the reaction conditions.64,65

Aryl-substituted bis[3]cumulenes in which the triene linkages are separated by an aromatic

ring or an ethano group66 have likewise been prepared from acetylenic diols.67

d. Szeimies has reported the successful generation and trapping of 1,2,3-

cycloheptatriene (63) from rearrangement of a bridged bicyclo[1.1.0] (62).68

62 63

e. Substituted [3]cumulenes 65 have been prepared by reaction of 3-bromoalk-3-en-l-

yne (64) with organocopper(I) species.69 Substituted [3]cumulenes have also been

prepared by reaction of enynyl epoxide with organosilver(I) compound.70

64 65

15 f. Recently, a boron trifluoride rearrangement-dehydration of epoxy-alkynols

affording the corresponding [3]cumulenals has been reported. This methodology is particularly effective for a 1,1-diaryl [3]cumulenals, and involves treatment of the desired

epoxy-alcohol 66 with BFj.etherate in tetrahydrofuran at low temperature, yielding

[3]cumulenal 67.71

HO /CH3 Bfi-Et 2.0». KlNc Ri *2 ^CHO CH3 R2

66 67

g. Hirama72 and Bruckner73 have recently reported synthesis of [3]cumulene -

triggered vinylogous propargylic rearrangement (SN2’ reaction).

h. A simple and facile method of preparing silyl cumulene 52 is by heating

hexa[trimethyl silyl]-1,3- (70) at 650 °C under reduced pressure.74

Me3Si SiMe; Heat (Me3Si)3C“ -C(SiMe,)3 MejSi SiMe;

70 71

16 i. Retro-Diels-Alder reaction was found to be an excellent synthesis route for the preparation of 1,2,3-butatriene.75’76

2.3. REACTIONS

The chemistry of functionalized cumulenes (i.e. , carboxylic acids ,

and ) constitute an essentially unexplored area of organic chemistry. There are only

a handful of papers that describe the synthesis and reactivity of functionalized cumulenes.2

Of particular importance are hydrogenations, halogénations, isomerizations, oxidations,

carbene additions, metal catalyzed dimerizations and more recently intramolecular

cyclizations.

2.3.1. Hydrogenations

[3]Cumulenes can be partially and completely hydrogenated by catalytic

hydrogenation. In the presence of Raney nickel, butatrienes take up three moles of

hydrogen leading to the corresponding 72.77 A palladium catalyst poisoned with

lead78 affords a specific partial hydrogenation of butatrienes to give conjugated

73.79-80

)c=c=c=<

\ / CH2 CHj -CH / \ > "\

72 73

17 2.3.2. Halogénations

[3]Cumulenes take up halogen in the 2- and 3-positions and furnish the corresponding 2,3-dihalo-1,3-butadienes. For instance, tetraarylbutatrienes of the type 74 yield the corresponding vicinal dihalo compounds 75. The yields of these reactions tend to

increase when dibenzoylperoxide is used as a catalyst.81

Ar, ,Ar \ AT, .Ar =C=C= Br2 \ / c=c—c= AT Ar (PhCOOfe Ar'/ I I Ar Br Br

74 75

The addition of iodine to cumulene 76 gave diiodide 77 along with minor amounts

of several unidentified compounds.82

76 77

2.3.3. Isomerizations

Tetrasubstituted butatrienes are resistant toward basic reagents. However, when a

hydrogen atom is attached at the butatriene chain terminus as in 78, basic conditions cause

a retro-propargylic rearrangement producing the corresponding butenynes (vinylacetylenes)

79.83

18 Ph2c c—c CH—CH=CPh2 _KOH^ Ph2C=CH—c=C CH=cPh>

78 79

2.3.4. Oxidations and Reductions

Oxidation cleaves butatrienes into the corresponding carbonyl units.84 This reaction serves to establish the structure of higher cumulenes. For example, oxidation (with reagents such as chromic acid, permanganate, and ozone) of 80 produces 2 equivalents of

C02 and the corresponding ketones 81 and 82.

R R r RK / 3 . l\ > 3

C=C=C^=C Oxidatioy C=0 + 2 COj + 0=CN X N R X R2 R4 2 1*4

80 81 82

Ozonolysis has been shown to be the best cleaving procedure.85 Ozonolysis of 83,

employing oxygen-free ozone in ether-methylene chloride at -80 °C followed by oxidation

with hydrogen peroxide-acetic acid and esterification with methanol-sulfuric acid gave

dimethyl suberate 84.86 LJ H3C C tHJ C CH3 L J6

83 84

Reduction of 80 with an excess of sodium in liquid ammonia occurred rapidly to ( give cis and trans- in a ratio of 61 to 1; in the presence of tert-butyl alcohol,

19 the ratio was lowered to 9.3 to 1. Reduction of excess 83 with sodium in liquid ammonia

(to enable isolation of intermediate reduction products) gave cis,cis-l,3-cyclodecadiene.87

2.3.5. Carbene Additions

[3]Cumulenes react with carbenes at the internal double bond affording the

corresponding derivative. For instance, cumulene 85 upon treatment with

the carbene derived from 86 affords the corresponding [3]radialenes 87.88

85 86 87

2.3.6. Inter-Molecular Cyclizations

2.3.6.I. Metal Catalyzed Dimerizations

Cumulenes are prone dimerization. This process can be catalyzed using transition

metals.2 Symmetric [4]radialene 89 can be prepared from a metal catalyzed dimerization

reaction of 88.89

20 Silyl-, stannyl- and germyl substituted cumulene do not undergo metal catalyzed.90

The reason for this difference in behavior between the tetratrienes and the metal substituted cumulenes might be due to electron transfer facilitated by the metallic substituent.91

SnR'i R Sn-H^ R C=C=C= / R2C=C : =c: 3 2 s H

90 91

2.3.6.2. Thermally and Photochemically Induced Dimerizations

Two reports describing thermal dimerization of cumulene derivatives to

[4]radialenes had to be corrected after an X-ray structural analysis of the products was

carried out.92 Thus, the cumulene 9293 (on irradiation in the solid state) and 9493

(thermally) do not dimerize via central double bond, but by way of their terminal double

bond to provide a head-to-tail dimer 93 and a head-to-head dimer 95.

21 Heat ►

94 95

2.3.6.3. Diels-Alder

The structure of the (unstable) cumulene 96 follows from spectroscopic data,94 and from [2+4] cycloaddition reactions with cyclopentadiene which yields the (stable) propadienyl sulfonium salts 97.

96 97

2.3.7. Intra-Molecular Cyclizations.

2.3.7.1. Benzocycloaromatization

2.3.7.1.1. Acyclic systems

Several models have been developed to correlate the structure of ene-yne-cumulene with its reactivity. It is essential that the two atoms between which the new bond is formed

22 are sp-hybridized. Hirama’s group has shown that an acyclic ene-yne-[3]cumulene 98 is capable of cycloaromatization producing diradical intermediates.95

Compound 100 when heated in deoxygenated 1,4-cyclohexadiene furnishes a derivative 101 through Bergman-type cyclization.

80 oC, Ar O

H

100 101

Moreover, the corresponding TMS-deprotected [3]cumulenal 102 undergoes a

“Myers” type of benzocyclo-aromatization yielding the corresponding derivative 103.96

23 Two different groups, namely Myers and Saito,97’8 reported on the cyclization of conjugated cumulene-ene-ynes to benzene derivatives.

104 105

2.3.7.I.2. Cyclic Systems

[3]Cumulenes have been shown to undergo facile cycloaromatization when

constrained in a nine- or ten- membered ring. For example, l,6-dehydro[10]

(106) completely aromatizes to naphthalene 107 whith in 50 min. at -51°C."

HzSr H

106

23.1.2. [2+2] Cycloadditions

Recently new types of intramolecular cyclization of [3]cumulenes have been

reported,100’101 they involve [2+2] cycloaddition with acetylenic functionalities. Cumulene

108 when heated gave the corresponding [2+2] cycloadduct derivative 109.102 The

cycloaddition takes place between the internal cumulenic insaturation and the triple bond

forming a bis-ylidenecyclobutene system.

24 TMS

109

cycloaddition in which the terminal cumulenic insaturation reacts with the triple bond forming a cyclobutene fused to a benzene ring 106.

25 III. LITERATURE REVIEW ON OXEPINS

3.1. STRUCTURE AND PROPERTIES

Oxepins are hetrocyclic compounds containing an oxygen atom in which every ring carbon atom is sp2- hybridized and carries a C-C double bond. A vast amount of literature

on oxygen-containing seven-membered heterocycles has appeared since the 1970’s,105 and

many improved experimental methods for the synthesis and detection of new oxepins have

been developed.106 Much of the interest in oxepins has been based upon: a) attempts to

verify theoretical predictions concerning their antiaromatic character; b) the establishment

of an obligatory role for oxepin-arene oxide intermediates in the metabolism of aromatic

substrates in plants, animals and microorganisms; and c) the synthesis of seven-membered

oxygen heterocycles in the quest for useful chemotherapeutic properties of the type found

in nitrogen-containing analogues.107

Because of their unusual topology and electronic structures, these compounds have

aroused the interest of both preparative chemists and theoreticians. The theoretical impetus

for these efforts was first supplied by the qualitative observations108 that 112 can be

regarded as an analog of in the same sense that furan is an analog of

benzene. The possibility of such an electronic relationship was supported by molecular

orbital calculations suggesting that 112 might possess a certain amount of aromatic

character, despite the fact that it appears to violate the (4n + 2) requirements for

aromaticity.109 The parent structure, oxepin 112, exists in a state of spontaneous

equilibration with the valence bond isomer benzene oxide 113 at ambient temperature.108

26 0 O #O

112 113

NMR spectral studies have been used to investigate the oxepin-benzene oxide equilibrium.109 The ‘H-NMR spectrum of 112 at ambient temperature consisted of three

multiplets of equal intensity centered at Ô 6.1 (Ha), 5.65 (Hp) and 5.2 (HY) ppm. At lower

temperatures (-127 °C, CF3Br/), the rate of isomerization decreased until individual signals for the oxepin tautomer 112 were observed.

Ultra-violet spectroscopy has been particularly valuable in the study of the oxepin- benzene oxide equilibration. The oxepin isomer showed absorption at 305 nm, while benzene oxide absorbed at 271 nm.110

3.2. PREPARATIONS

The first successful synthesis of the unsubstituted parent compound oxepin 116 was reported in 1964 by Vogel, Schubart, and Boell.111 1,2-Dibromo-4,5-epoxycyclohexane

(114) was treated with l,5-diazabicyclo[3.4.0]non-5-ene (DBN). The formation of 116 was postulated to occur via thermal reorganization of transient epoxydiene 115. Vogel and co-workers also reported the conversion of 114 into 116, with sodium methoxide in refluxing ether, and indicated that 116 and 115 were both present in solution and underwent rapid interconversion at ordinary temperatures.112

27 Br

The Vogel synthetic approach had actually been explored several years earlier by

Meinwald and Nazaki,113 in which y-collidine or the sodium salt of ethylene glycol were used as dehydrohalogenating agents. The reaction conditions employed by Meinwald and

Nazaki were too strenuous. Thus, phenol was the only isolated product. This outcome can be understood readily since 116 undergoes facile thermal rearrangement to phenol at temperatures above 70 °C.114

Substitution at the 2-position by a group capable of entering into conjugation with the oxepin ring produces a stabilizing effect.115 This was demonstrated by the synthesis of

2-acetyloxepin 118 from 1 -acetyl- l,2-epoxy-4,5-dibromocyclohexane 117.

Dehydrobromination was effected smoothly in the presence of DBN. Unlike 2- methyloxepin 120, which is in equilibrium with a significant proportion of its “valence tautomer” at ordinary temperatures, 118 shows no evidence of being in equilibrium with the corresponding epoxide form.

28 Perhaps the most elegant and direct method devised to date for the synthesis of oxepins was reported in 1967 by Van Tamelen and Carty.116 Epoxidation of bicyclo[2.2.0]hexa-2,5-diene (122) “” with MCPBA afforded a 75% yield of 2,3-epoxybicyclo[2.2.0]hex-5-ene (123),117 which was transformed into oxepin 124 upon irradiation or heating.

Although substituted oxepins have not been prepared by this approach as of yet, it would seem reasonable to suppose that a great variety of such compounds could be obtained from the corresponding benzene derivatives, and that these compounds would be of interest in study the electronics factors governing the valance tautomerization of 120 to

121. An intemuclear cyclization reaction of an aromatic sulfonyl chloride occurred upon heating in the presence of a (I) chloride catalyst to yield tribenz[W,/]oxepin

(126).1,8

29 125 126

3-Benzoxepin (127) has been synthesized from phthalaldehyde and a bis- phosphonium salt by a double Wittig condensation reaction. 119

NaOMe

0= CH HC=0

BrPPh3^'V'o'/'S''Ph3PBr

The key step in the synthesis of oxepin-benzene oxide (130) is the dehydrohalogenation of a dibromoepoxide precursor. 120

Br. Br NaOMe or DBM v\

128 129 130

The photochemically induced isomerization of a series of 7-oxanorbornadienes to the corresponding 3-oxaquadricyclanes followed by a thermal rearrangement provides a relatively short and convenient route to the parent oxepin (133)121 and a range of substituted oxepins.

30 Heat

131 132 133

A major goal of study described in this work involves an intramolecular [2+2] cycloaddition of an acetylenic unit with a [3]cumulene. This method represents a simple and novel methodology for the preparation of oxepins and oxepin derivatives.

Three of the isomers of dihydrooxepin have been prepared. Attempts to prepare

the symmetrical 2,7-dihydrooxepin 136 have only led to the isolation of 134. It has been

suggested that 134 may be more stable than 136 because conjugation between the oxygen

atom and the diene system can be achieved in 134, but not in 136.122

134 135 136 137

Successful syntheses of 134 were reported simultaneously in 1960 by two

independent groups. In one approach, Meinwald and co-workers 123 converted 2,3,6,7-

tetrahydrooxepin (138) in stepwise fashion into trans-4,5-dibromo-2,3,4,5,6,7-

hexahydrooxepin (139), 4-(N,N-dimethylamino)-2,3,4,7-tetrahydrooxepin (140), and the

N-oxide 141. Pyrolysis of crude 141 at 80-100 °C (5mm) gave a 55% yield of 142. The

formation of 142 from 141 is considered to involve direct 1,4-elimination during the

31 pyrolysis step, rather than the alternative possibility of initial cis-elimination to 2,7- dihydrooxepin 136 and thermal isomerization of 136 to 134 in a separate step.

138 139 140 141 142

An ingenious method of ring closure used recently124 for the preparation of dibenz[£>,e]oxepin involves treatment of l-bromo-2-(2-bromobenzyloxy)-benzene 143 with n-butyllithium, and condensation of the resulting organolithium intermadiate with ethyl y-

(N,N-dimethylamino)butyrate to give N,N-dimethyldibenz[b,e]oxepin 145.

11-Alkylidene derivatives of the dibenz[b,e]oxepin ring system such as 145 have attracted considerable attention because of their potential value as psychopharmacodynamic agents. Initially, these compounds were synthesized by reaction of various 3-(N,N-dialkylamino)-l-propyl magnesium chlorides with dibenz[b,e]oxepin- ll(6H)-ones (147).125126 Alcohol 148 obtained in this fashion was dehydrated to oxepin mixture of E/Z 149 with HC1. Only the E isomer proved to be a much more potent antidepressant drug than the Z isomer.127

32 146 147 148 149

Another approach to the synthesis of 1 l(6H)-alkylidenedibenz[b,e]oxepins from the corresponding 1 l(6H)-ketones was described recently in a patent.128 This method involves a Wittig reaction between a triphenylphosphine N,N-dialkylaminoalkylene ylide and a dibenz[b,e]oxepin-l l(6H)-one.

The presence of the oxepin nucleus in a number of natural products of biological interest such as metabolites of Psammaplysin purpurea, which contain a spirocyclic dihydrooxepin nucleus,129 has spurred the development of synthetic strategies for preparing this ring system. Aranotin acetate 150 is a fungal metabolite exhibiting antiviral activity and containing two 4,5-dihydrooxepin nuclei that are identical in their functionality.130 One possible retro-synthetic analysis of this molecule, involving a disconnection of the epidithiapiperazinedione moiety, leads to the advanced intermediate 151, which could also be used as an intermediate for a number of other structurally related fungal metabolites.131

33 A practical synthetic approach towards the dihydrooxepin nucleus has emerged from the laboratories of J. D. White where the Cope rearrangement of divinyl has been shown to be a facile and effective route for the preparation of several dihydrooxepin derivatives.132 Other methods for the construction of oxepins nucleus include the intramolecular cyclization of o-(aryloxy)phenylalkynes to form benzofused oxepins,133 and via rearrangement of arene oxides.134

34 IV. RESULTS AND DISCUSSION

To accomplish our objective of studying [2+2] intramolecular cycloadditions, we devised a synthesis of cumulene 156. Cumulene 156 was selected because diaryl

[3]cumulenals have been shown to be stable towards polymerization and towards reaction with molecular oxygen, two of the common pathways that [3]cumulenes are decomposed.135 Furthermore, the trimethylsilyl group in 156 has been shown to direct the

[2+2] cycloaddition towards the internal double bond of a cumulene.136

The synthesis of cumulenal 156 starts with the O-alkylation of commercially available 2-hydroxybenzophenone (152), Table I.

35 TABLE I: O-Alkylation of 2-Hydroxybenzophenone

Trial Conditions Yield of Product

1 NaH, dry THF 24%

2 K2CO3, acetone 32%

3 K2CO3, dry acetone 48%

4 [(Me3Si)2NLi, Me3SiCl -

5 [(Me3Si)2NLi, THF S.M

6 K2CO3/KI, 2-butanone 88%

S.M = Starting Material

The conditions employed in trial 5 of Table I proved to be the best O-alkylating methodology. Thus, treatment of 2-hydroxybenzophenone with 3-bromo-l-

(trimethylsilyl)-l-propyne in the presence of potassium carbonate/potassium iodide mixture in refluxing 2-butanone afforded ether 153 in 88% yield. The structure of this new compound was established by proton NMR (figure 5.1) shows a singlet for the corresponding two methylene protons at 5 4.44 ppm and another singlet for nine protons at

8 0.04 for the TMS (Trimethylsilane) group. The Infrared spectra (figure 5.2) shows the characterestic stretching frequencey at 2189 cm'1. 13C-NMR (figure 5.3) shows

the chemical shifts of the carbonyl at 8 196.59 and for acetylene carbons are 8 100.03 and

93.50 ppm.

36

U>

Figure 5.1 Proton NMR spectra for Pheny-[2-3-trimethylsilanyl-prop-2yynyloxy)phenyl]- methanone (153) Figure 5.2 Infrared spectra for Pheny-[2-3-trimethylsilanyl-prop-2yynyloxy)phenyl]- methanone (153) 13 Figure 5.3 C NMR spectra for Pheny-[2-3-trimethylsilanyl-prop-2yynyloxy)phenyl]- methanone (153)

39 Addition of 2-methyl-buten-3-ynyllithium (freshly prepared by adding equimolar amounts of n-butyllithium to a -78 °C solution of 2-methylbuten-3-yne in dry tetrahydrofuran) gave alcohol 154 in 74% yield. The 'H-NMR (figure 5.4) of this compound, which is obtained as a racemic mixture of 154(R), 154(S), shows the diastereotopic hydrogens of the propargylic group at 5 4.36 ppm. Similar remote effects

have also been observed in related systems.137 Infrared spectra (figure 5.5) shows a

stretching frequency for the corresponding alcohol at 3539 cm'1. The l3C-NMR of 154

(figure 5.6) clearly shows two resonances for the methyl at 5 23.79 and 23.62 ppm, and

each acetylene carbon at 5 100.05, 99.89 and 93.69, 93.51 ppm.

A key step in the synthesis of [3]cumulenal 168 is the epoxidation of the conjugated

double bond functionality. A reported methodology utilizes freshly prepared

dimethyldioxirane to epoxidize the double bond.138 Epoxide 155 was prepared in 71%

yield following this methodology. Epoxidation could be accomplished with MCPBA in

92% yield. Upon working up the epoxide immediately after the reaction is completed.

A detailed study of the MCPBA epoxidation of 154 was performed following the

reaction progress by NMR spectroscopy. The disappearance of the vinylic methyl proton

40 TMS

1 n-i-T-r TT | T T II II I IT]' r~r j 1-I~T~ r-i 11 rrpm-rrn-T-i *j* : ppm 7 6 5 43;' Figure 5.4 Proton NMR spectra for 4-Methyl-1 -phenyl-1 -[2-(3-trimethylsilanyl-prop-2- ynyloxy)-phenyl]-pent-4-en-2-yn-1 -ol (154) Figure 5.5 Infrared spectra for 4-Methyl-1-phenyl-l-[2-(3-trimethylsilanyl-prop-2-ynyloxy)- phenyl]-pent-4-en-2-yn-l-ol (154) phenyl]-pent-4-en-2-yn-l-ol (154) 0.337 0.061 0.418 14.501 -0.221 23.793 23.620 41.447 57.472 90.400 88.480 78.361 77.773 77.457 77.138 74.766 57.979 93.690 93.514 ppm -122.564 -122.015 -121.871 -114.668 -114.326 -114.023 -127.969 -126.889 -126.738 -125.900 -133.284 -130.268 -130.196 -129.560 -128.801 -128.629 -128.580 -128.325 -127.828 -155.798 -155.682 -144.753 -134.017 -132.058 26.195 -VV^i00.050 -V'- 99.696 signal at 8 1.76 ppm in relation to the epoxide (methyl) proton signals at 5 1.63 and 1.61 ppm showed the reaction was complete within 162 minutes.

Epoxide 155 was obtained as a mixture of 4 diastereomers. A second chiral center is formed during the epoxidation step in addition to the one already present at the hydroxyl-carbon.

In the ‘H NMR spectroscopic data (figure 5.8), one of the epoxide protons of one

pair of diastereomers shows a doublet of chemical shift at 5 2.65 ppm, whereas the other

pair of diastereomers have a chemical shift of 5 2.58 ppm (figure 5.7). The same is true for

the methyl signals: one diastereomeric pair at 5 1.63 ppm, the other pair at 8 1.61 ppm.

Rearrangement of the hydroxy-epoxide 155 with boron trifluoride in a dry-

tetrahydrofuran solution (THF) gave a 1:1 mixture of E/Z cumulenal 156 in 80% yield. In

addition to this product, poly THF is also formed, which is removed upon purification via

flash column chromatography. Tetrahydrofuran as a solvent is necessary to obtain good

44 r (

Figure 5.7 Proton NMR spectra for 3-(2-methyl-oxiran-2-yl)-l-phenyl-l-[2(3- trimethylsilanyl-prop-2-ynyloxy)-phenyl]-prop-2-yn-lol (155) O H2/« CH3

-P- ON

1 ~ 1 ' I 1 J ppl* 26 2-5 2.4 2.3 7z Figure 5.8 Proton NMR spectra for the diastereomers epoxide protons of 3-(2-methyl-oxiran- 2-yJ)-1 -phenyl-1 -[2(3-trimethylsilanyl-prop-2-ynyloxy)-phenyl]-prop-2-yn-1 ol (155) Figure 5.9 Infrared spectra for 3-(2-methyl-oxiran-2-yl)-l-phenyl-l-[2(3-trimethylsiIanyl- prop-2-ynyloxy)-phenyI]-prop-2-yn-1 ol (155) prop-2-ynyloxy)-pheny]]-prop-2-yn-loi (155) Figure 5.10 l3C NMR spectra for 3-(2-methyl-oxiran-2-yl)-1 -phenyl-1-[2(3-trimethylsüanyl- 7 81 yields of 156. In methylene chloride, for instance, the reaction of 155 with BF3/Et20 does not give a complete conversion, and other unidentified products are formed.

156 E 156 Z

Attempts at separating 156 E and 156 Z by chromatographic techniques were not

successful. The stereoisomers can be distinguished upon examination of the proton NMR

of the mixture. Two sets of signals are observed for the mixture. Thus, two methyl

protons appear at 5 1.91 and 6 1.97 ppm, two methylene protons at 5 4.47 and Ô 4.46 ppm,

and two protons at 5 9.39 ppm and ô 9.56 ppm (figure 5.11). The l3C-NMR

signals are also paired. For instance, the carbonyl show up at 5 189.61, 189.33, methylene

5 56.97, 56.89 and methyl carbon signals show up at 5 14.35, and 14.08 ppm (figure 5.13).

Assignments of these signals cannot be unequivocally established at this time. However, it

is postulated that the aldehyde proton at 5 9.56 ppm corresponds to the 156 Z isomer. The

aldehyde proton is in close proximity to the deshielding zone of the and therefore is

expected to be further downfield than the aldehyde proton in 156 E (figure 5.11). The

Infrared spectrum shows the characteristic cumulene stretching frequency at 2051 cm'1

(figure 5.12).

49 / \ o—CH2- TMS <.CHO Ph CH3

U\o

|i()m Figure 5.11 Proton NMR spectra for 2-Methyl-5-phenyl-[2-(3-trimethyl-5-[2-(3 trimethylsilanyl-prop-2-ynloxy)-phenyl]-penta-2,3,4-trienaI (156) f W TMS

70

65

60

55

50

45

40

35

30

25

20

15

10

5

0

igure 5.12 Infrared spectra for 2-MethyI-5-phenyl-[2-(3-trimethyl-5-[2-(3-trimethylsilanyl- rop-2-ynloxy)-phenyl]-penta-2,3,4-trienal (156) / w TMS

Figure 5.13 l3C NMR spectra for 2-Methyl-5-phenyl-[2-(3-trimethyl-5-[2-(3-trirnethylsilanyl- prop-2-ynIoxy)-phenyl]-penta-2,3,4-trienal (156) Cumulene 156 has steric constraints imposed by the bulky trimethylsilyl group. In order to probe the intramolecular cycloaddition in the absence of these steric constraints, we attempted to disilyate 156 using potassium carbonate and methanol. Under these conditions, cumulene 156 gave a complex mixture of diene isomer 157. It is still uncertain

as to what position the methoxy is added (a or b). The GC-MS shows the incorporation

of a methanolic sub-unit. ‘H-NMR (figure 5.14) is consistant with the structure of only two

stereoisomers of the four possible isomers. The chemical shift of the aldehyde protons

show at Ô 9.69 and 9.52 ppm, vinylic protons appear at 5 6.51 and 6.31 ppm, propargylic

methylene protons show at 8 4.49 and 4.48 ppm, the methoxy functionality appear at 8

3.88 and 3.86 ppm, the acetylenic protons show as one signal at 8 2.38 ppm (due to the

fact that this proton is away from the stereocenters), and the absorbs at 8

1.53 and 1.50 ppm. Infrared spectra (figure 5.15) of 157 shows the charactarestic

frequencies for the acetylene at 2263 cm'1, H-C (sp) bond absorbs at 3309 cm'1, and the

carbonyl absorbtion band at 1651 cm'1. 13C-NMR spectra (figure 5.16) is consistant with

compound 157. The carbonyl absorbtion can be seen at 8 192.1 and 192.0 ppm, methoxy

group at 8 76.3 ppm, the methyne at 8 75.4 ppm, propargylic methylene absorb at 8 56.2

and 55.9 ppm, and the methyl group absorb at 8 7.18 and 7.04 ppm (figure 5.16). Under

the conditions employed for the disilylation, the cumulene suffers nucleophilic attack by

methanol to render diene 157.

53 ^—i—i—i—|—i—i—i—i—i—i—i—■ i i ' ' T ' i ■ 1 1 1 i r T 1 1 1—i— i 1 1 r 1 ' ' | i ' ' 1 I 10 0 9 0 0.0 7.0 6.0 5.0 4.0 3.0 2.0 Figure 5.14 Proton NMR spectra for 4-Methoxy-2-methyl-5-phenyl-5-[2-(prop-2-ynyloxy)- phenyl]-penta-2,4-dienal (157) Figure 5.15 Infrared spectra for 4-Methoxy-2-methyl-5-phenyl-5-[2-(prop-2-ynyloxy)- phenyl]-penta-2,4-dienal (157) CD in in m

a G. \ T

■ i " T — —, 1 I r <>00 150 100 50 0 -so PPM Figure 5.16 13C NMR spectra for 4-Methoxy-2-methyl-5-phenyl-5-[2-(prop-2-ynyloxy)- phenyl]-penta-2,4-dienal (157) This effect was also observed in the reduction of cumulene 158 which yielded zwitterion that was protonated at the vinylic carbanion in the presence of moisture. This reduction was initiated at the central double bond by the attack of triphenylphosphane.

Elimination of triphenylphosphane oxide and a second protonation afforded 159.139

R = TIPS

Heating a sample of 156 E : 156 Z (1:1 mixture) in o-dichlorobenzene (in an ampule and vacuum sealed at 180 °C) for 35 hours produced a mixture of E and Z dihydrooxepin 160. Careful separation via preparative thin layer chromatography gave pure 160 E in 59% yield and 160 Z in 27% yield. Upon standing, 160 Z was slowly converted to 160 E suggesting that 160 E is the thermodynamic product.

57 TMS 35.272

Figure 5.17 Proton NMR spectra for 2-(3-phenyl-l-trimethylsilanyl-9H-8-oxa- benzo[a]cyclobiita[d]cyclohepten-2-ylidene)propionaldehyde (160) Figure 5.18 Infrared spectra for 2-(3-phenyl-l-trimethylsilanyl-9H-8-oxa- benzo[a]cyclobuta[d]cyclohepten-2-ylidene)propionaldehyde (160) Figure 5.19 13C NMR spectra for 2-(3-phenyl-l-trimethylsilanyl-9H-8-oxa- benzo[a]cyclobuta[d]cyclohepten-2-ylidene)propionaldehyde (160) -«rmcMcv'vonojnfnoDr^r^oo n^OCDIM'HOOlCDlûOCDlDI'l^ ni w -H o en en g» en en eu r» "» j, n n nnn(nc\jf\JOJC\J(\Jt\iwruryruw V TMS

.

1 « > r— ‘—1—1 1 r_-T r > 1 > • 100 75 50 25 0 Don» 200 175 150 125 Figure 5.20 l3C/dept90 NMR spectra for 2-(3-phenyl-l-trimethylsilanyl-9H-8-oxa- benzo[a]cyclobuta[d]cyclohepten-2-ylidene)propionaldehyde (160) ppra ppra Figure 5.21Expandedregion between120-135ppmoffigure5.20 -, r—-^J— 132 130 ~~r~ 128 126 T~ 124 156 160 Z 160 E

The structural assignments of these isomers were unequivocally established with the aid of a NOE difference experiment. Irradiation of the trimethylsilyl peak of 160 E shows an enhancement of the methyl signal at Ô 1.86 ppm, thus establishing the E configuration about the double bond. The structural assignment is also consistent with the results of a

DEPT experiment (figure 5.20-5.21) which reveals the presence of 8 methine signals and 9 quaternary carbon signals. An observation in ‘H-NMR (figure 5.17) of an unusual upfield chemical shift at Ô 8 ppm for the aldehyde proton, undoubtedly due to the proximity of the shielding zone of the neighboring . The 13C-NMR (figure 5.19) is also in agreement with the proposed structure. The 6 conjugated carbon signals by 13C (400

MHz) NMR (cyclobutene system with the 2 exo ene functionalities) show at 5 173.01,

163.08, 158.41, 149.913, 144.25, and 140.16 ppm.

Previous reports on related intramolecular [2+2] cycloaddition reactions with

[3]cumulenes indicate that cycloaddition can occur at the terminal or the internal double bond of the cumulene system.44'47 If cycloaddition of 156 was to proceed at the terminal double bonds, then either aliéné 161 or 162 would be formed.

63 From an intuitive standpoint, reactions at the internal bond using the shaded orbitals would preserve the conjugation between the terminal double bonds.

Figure 5.22 The orbital distribution for acetelyne and cumulene.

In this study, cycloaddition takes place exclusively at the internal double bond to give 160. As a complement to our experimental findings, calculations were performed on various cycloaddition modes. (Table II). Semiempirical PM348 calculations were performed either with the MOPAC 6.0 program49 and the Insight II graphical interface

64 produced by Biosym (Biosym Technologies of San Diego, CA) on a Silicon Graphics

Indigo 2 workstation, or with MOPAC 7.0 on an IBM 370 or 590 workstation. All PM3

geometry optimizations were performed in Cartesian coordinates without symmetry

constraints, using the PRECISE keyword, which improves the convergence criteria by the

factor of one hundred. Both open and closed shell molecules were optimized using the

unrestricted Hartree-Fock (UHF) method to allow a direct comparison of the energies of

opened and closed shell systems.

For each cycloaddition, the TMS (trimethylsilane) group raised the reaction energy

by 5-7 kcal/mole because of steric hindrance. The cycloaddition of the middle bond is

thermodynamically favored over the others by 15-20 kcal/mole. The calculation clearly

demonstrates that in the absence of kinetic effects, [2+2] intramolecular cycloadditions of

156 will be made across the internal double bond exclusively.

65 TABLE II: Reaction enthalpies (kcal/mole) for the [2+2] cyclization of [3]cumulenal 168

Ri R2 AH, AH2 AH3

H CH3 -18.3 -36.0 -11.8

H CHO (Z) -19.1“ -37. r -12.8b

H CHO (E) -19.2“ -37.0a -

TMS CH3 -13.0 -32.5 -7.58

TMS CHO (Z) -12.6 -31.3 -5.34b

TMS CHO (E) -12.6 -32.4 -

a. E -reactant to Z-product because of change in atom priority.

b. Two product isomers become enantiomers by a single bond rotation and oxygen inversion.

Most stable isomer is reported.

TMS = Trimethylsilane

66 V. EXPERIMENTAL SECTION

General. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. Tetrahydrofuran (THF) was distilled under nitrogen from sodium/benzophenone. Acetone was distilled from celite and collected over molecular sieves. Reactions were monitored by thin-layer chromatography

(TLC) using precoated glass plates of 250-|im thickness silica gel with a fluorescent

indicator. Flash chromatography was carried out by using silica gel (35-70 p.m, 60-A pore)

or Florisil (100-200 mesh, Fisher Scientific). IR spectra was recorded on a Nicolet Impact

400 FT-IR. Elemental analyses were obtained from Atlantic Micro Lab, Inc. (Norcross,

GA) and are within ± 0.5 of the theoretical values. Mass spectral data were obtained on a

Hewlett Packard GC/MS Model HP 5890 at 70 eV. ‘H NMR spectra were recorded as

solutions in CDC13 on a Bruker 250 MHz or Bruker 400 MHz Spectrometer. Chemical

shifts are expressed in parts per million (5 units) relative to internal tetramethylsilane (0.0

8) or CHCI3 (7.26 8). Data is reported as follows: chemical shift, multiplicity (s = singlet,

d = doublet, t = triplet, q = quartet, m = multiplet), coupling constant (s), and integration.

13 C NMR spectra were determined as solutions in CDC13 on a Bruker 250 MHz or Bruker

400 MHz Spectrometer, and chemical shifts are reported in parts per million (8 units)

relative to the center peak of CDC13 (77.0 8). High-resolution mass spectra (El) were

performed at the Emory University microanalytical laboratory.

67 Pheny-[2-3-trimethyIsiIanyl-prop-2yynyloxy)phenyl]-methanone (153)

A reaction mixture containing 2-hydroxybenzophenone (3.96 g, 20 mmol), potassium carbonate (4.1 g, 30 mmol), potassium iodide (4.98 g, 30 mmol) and 2-butanone

(25 mL) was stirred at room temperature for 20 minutes. 3-bromo-l-(trimethylsilyl)-l- propyne (4.2 g, 22 mmol) was then added, and the resulting mixture was heated to reflux for 8 hours. The reaction mixture was then poured into 100 mL of water and extracted with ether (3 X 25 mL). The combined organic layers were washed with brine (15 mL), diluted sodium hydroxide (10%) (3 X 20) and dried over magnesium sulfate. The organic solvents were removed on a rotatory evaporator affording a pale yellow oil which was purified via silica gel chromatography using : ethyl acetate (15:1) as eluents, obtaining 153 in 88% yield as a pale yellow oil: IR (neat, cm'1 ) 3067, 2968, 2190, 1677;

'H NMR (400 MHz, CDC13) 5 7.68 (dd, J = 1.25 Hz, J = 7.82 Hz, 2H); 7.41 (t, J = 7.39

Hz, 1H); 7.33 (dt, J = 7.73 Hz, 1H); 7.28 (t, J = 7.68 Hz, 3H); 7.01 (d, J = 8.37 Hz, 1H);

6.96 (t, J = 7.51, 1H); 4.44 (s,2H); 0.04 (s,9H). 13C NMR (8, CDC13) 196.59, 155.79,

138.21, 133.28, 132.06, 130.26, 130.18, 129.99, 128.57, 121.86, 114.01, 100.03, 93.50,

57.46, 0.05. UV (hexane) X.max = 285.50 nm. Anal, calcd. for Ci9H2o02Si : C, 73.99; H,

6.54, found: C, 73.74, H, 6.63; HRMS : Calcd. mass, 308.1232, observed mass, 308.1249.

68 4-Methyl-l-phenyI-l-[2-(3-trimethylsilanyl-prop-2-ynyIoxy)-phenyl]-pent-4-en-2-yn- l-ol (154)

A solution containing 50 mL of dry THF and 2-methyl-l-buten-3-yne (0.7 g. 11

mmol) was cooled to -78 °C by means of an external dry ice/acetone bath. This solution

was then treated with 6.0 mL of a 2 M nBuLi solution. The reaction was kept at -78°C for

10 minutes. A solution of 154 (5.4 g, 11 mmol) in 50 mL of THF was then added

dropwise via syringe. Stirring was continued at -78°C for 20 minutes. The reaction

mixture was slowly allowed to warm to 25 °C for one hour. The resulting solution was

concentrated on a rotatory evaporator, and the residue was diluted with 60 mL of ether

and then washed with brine. The organic layer was dried over magnesium sulfate. The

solvent was removed on a rotatory evaporator recovering 3.8 g of crude product. This

material was purified by flash chromatography giving pure 154 in 70% yield. ‘H NMR

(400 MHz, CDC13, ppm) 5 7.38 (d, 7=7.38 Hz, 2H); 7.26 (d, 7=7.65 Hz, 1H); 7.17 - 7.08

(m,4H); 6.83 (t, 7=7.49 Hz, 2H); 5.19 (s,lH); 5.07 (s,lH); 4.36 (s, 7=8.75 Hz, 2H); 1.76

(s,3H; 0.04 (s, 9H). IR (neat, cm'1) 3539, 3065, 2960, 2368, 2184, 1953, 1743, 1677,

1604. 13C NMR (400 MHz, CDChppm) 6 155.80, 155.68, 144.75, 134.02, 132.06,

129.66, 128.63, 128.58, 127.97, 127.83, 122.02, 114.67, 100.05, 99.89, 93.51, 90.40,

88.48, 57.98, 57.47, 23.79, 23.62, 0.34. HRMS : Calcd. mass 374.1702, found 374.1702.

69 3-(2-Methyl-oxiran-2-yI)-l-phenyl-l-[2(3-trimethylsilanyl-prop-2-ynyloxy)-phenyI]- prop-2-yn-lol (155)

Over a 20 minute period, a dichloromethane solution of 154 (1.12g, 3.13mmol) was added dropwise to a solution of metachloroperbenzoic acid (MCPBA) (1.08g,

6.26mmol). The reaction was completed after 2 hours. To this mixture, 10 mL of cold water was added. The organic layer was separated and washed with a 5% NaOH solution

(50 mL); 10% NaHC03, and with water. The organic layer was dried over magnesium

sulfate, and the solvent was removed on a rotavaporator. The crude product was purified

via silica gel chromatography using hexane/ethylacetate (8:1) as eluent affording pure 155

(1.12g, 92% yield): *H NMR (400 MHz, CDC13, ppm) 5 7.65 (d, 7=7.48 Hz, 4H); 7.53 (dt,

7=7.74 Hz, 7=1.7 Hz, 2H); 7.05 (dt, 7=6.90 Hz, 7=1.05 Hz, 4H), 6.96 (dt, 7=7.32 Hz,

7=0.85 Hz, 2H), 6.87 (t, 7=7.74 Hz, 2H, 6.67 (t, 7=7.48 Hz, 2H), 6.56 (d, 7=8.11 Hz, 2H);

4.57 (s, 7=8.75 Hz, 2H); 2.65 (d, 7=5.70 Hz, 1H); 2.58 (d, 7=5.68 Hz, 1H); 2.11 (d,

7=5.73 Hz, 1H); 2.09 (d, 7=5.80 Hz, 1H), 1.63 (s, 3H), 1.61 (s, 3H), 0.20 (s, 18H).; IR

1 13 (neat, cm' ) 3532, 3064, 2971, 2257, 2189, 1605; C NMR (400 MHz, CDC13, ppm) 6

155.13, 143.71, 133.13, 129.20, 127.95, 127.79, 127.72, 127.11, 126.19, 121.51, 113.82,

99.37, 93.25, 85.87, 83.86, 73.76, 57.16, 55.21, 47.14, 22.79, 22.72, 0.02. HRMS :

Calcd. mass 390.1651, found 390.1661.

70 2-Methyl-5-phenyl-[2-(3-trimethyl-5-[2-(3-trimethylsilanyl-prop-2-ynIoxy)-phenyI]- penta-2,3,4-trienal (156)

A solution containing epoxide 155 (0.57 g, 1.46 mmol) and dry THF (15 mL) was

cooled to -78°C. Boron trifluoride etherate (0.17 mL, 1.3 mmol) was added to this

solution by means of a syringe. The mixture was stirred for 3 hours at this temperature and

the cooling bath was then removed. The reaction was kept at room temperature for 15

hours. The resulting mixture was diluted with 50 mL of ether, washed with water, brine

and organic layer, and was dried over magnesium sulfate. The residue was purified via

flash chromatography (hexane: ethylacetate 6:1) giving 425 mg of 156 as a 1:1 mixture of

E and Z isomers, (80% yield) of 156 an orange yellow oil: IR (neat, cm'1) 3065, 3026,

2960, 2927, 2855, 2177, 2052, 1743, 1670, 1611, 1512, 1223; ‘H NMR (400 MHz,

CDC13> ppm) Ô 9.57 (s, 1H), 9.39 (s, 1H), 7.41 - 7.37 (m, 4H), 7.28 - 7.24 (m, 2H), 7.24 -

7.21 (m, 8H), 6.99 (t, 2H, 7=7.3 Hz), 6.93 (q, 2H, 7=14.5 Hz), 4.47 (s, 2H), 4.46 (s, 2H),

13 1.98 (s, 3H, 1.91 (s, 3H), 0.04 (s, 18H); C NMR (400 MHz, CDC13, ppm) 5 189.61,

189.33, 170.96, 155.66, 155.60, 153.12, 152.83, 137.94, 137.63, 131.49, 130.46, 130.43,

129.41, 129.32, 129.01, 128.69, 128.50, 128.36, 128.34, 126.92, 126.91, 121.51, 121.43,

117.12, 117.02, 113.52, 99.64, 99.55, 92.94, 92.83, 56.97, 56.89, 14.35, 14.08, 0.41,

0.40; MS 372(M+), 57(100%). HRMS : Calcd. mass 372.1545, found 372.1522

71 2-(3-Phenyl-l-trimethylsilanyl-9H-8-oxa-benzo[a]cyclobuta[d]cydohepten-2- ylidene)propionaIdehyde (160)

A solution containing cumulenal 156 (80 mg, , 0.21 mmol) and 20 mL of freshly distilled o-dichlorobenzene was added to a thick wall thermolysis tube. The tube was purged and evacuated with nitrogen and sealed under vacuum. The tube was heated in an oil bath at 170 °C for 40 hours. The contents of the tube were poured in a 250 mL flask, then concentrated. The residue was purified via preparative TLC recovering 47 mg of 160

E (59%) and 22 mg of 160 Z (27% yield) 160 E IR (neat, cm'1) 3069, 2964, 2362, 2251,

2183, 1673, 1606, 1489, 1446, 1267; 'H NMR (400 MHz, CDC13) 6 8.05 (s, 1H), 7.46

(dd, 2H, 7y=2.08 Hz, 72=7.3 Hz), 7.35 - 7.28 (m, 3H), 7.25 - 7.21 (m, 2H), 7.02 (dt, 1H,

7/=1.83 Hz, 72=8.06 HZ), 6.89 (dd, 1H, 7,=1.46 Hz, 72=7.83 Hz), 5.1 (s, 2H), 1.86 (s, 3H),

13 0.33 (s, 9H); C NMR (400 MHz, CDC13) ô 192.69, 173.02, 158.97, 157.86, 150.52,

142.57, 139.12, 133.13, 131.94, 130.63, 128.84, 128.71, 128.63, 124.48, 124.33, 122.91,

120.02, 71.06, 12.45, 0.19; GC-MS 372(M+), 73(100%).

160 Z 'H NMR (400 MHz, CDC13) 5 9.77 (s, 1H), 7.31-7.22 (m, 2H), 7.16-7.15 (m, 3H),

7.08-6.99 (m, 2H), 6.84 (dt, 1H, 7,=2.52 Hz, 72=9.01 Hz); 6.66(dd, 1H, 7;=1.04 Hz,

1 72=8.2 Hz), IR (neat, cm' ) 3078.6, 2961.2, 2927.2, 2874.6, 1732.7, 1632.7

4-Methoxy-2-methyl-5-phenyl-5-[2-(prop-2-ynyloxy)-phenyl]-penta-2,4-dienal (157)

A solution containing 156 (300 mg, 0.806 mmol) in MeOH (15 mL) was stirred at room temperature. To this solution was added A catalytic amount of potassium carbonate was added to this solution. Complete conversion occurred in 1 hour (by TLC). The

72 reaction mixture was then quenched with ice-cold water and allowed to warm to room temperature. The resulting solution was concentrated on a rotatory evaporator. The residue was diluted with ether (60 mL), washed with brine, and dried over magnesium sulfate. The solvent was removed on a rotatory evaporator affording the crude product

(239 mg). This material was purified by flash chromatography using (Hexane : EtOAc,

8:1) as eluent giving pure 11 (164 mg, 61%). 157 IR (neat, cm'1) 3308, 2947, 2263, 2124,

1723, 1651, 1606, 1495, 1456, 1306; ‘H NMR (400 MHz, CDC13, ppm) 5 9.68 (s, 1H),

9.52 (s, 1H), 7.30 - 7.11 (m, 12H), 7.04 -6.90 (m, 6H), 6.51 (d, 1H, 7=1.4 Hz), 6.30 (d,

1H, 7=1.5 Hz), 4.47 (s, 2H), 4.46 (s, 2H), 3.87 (s, 3H), 3.85 (s, 3H), 1.52 (s, 3H), 1.46 (s,

13 3H); C NMR (400 MHz, CDC13, ppm) 8 192.13, 191.96, 131.14, 130.75, 129.58,

129.51, 128.53, 128.46, 128.27, 128.04, 127.57, 127.27, 121.54, 121.43, 119.54, 118.33,

113.36, 112.52, 78.19, 75.37, 56.37, 56.12, 56.02, 55.72, 7.18, 7.04; GC-MS 332(M+),

207(100%).

73 VI. CONCLUSION

Intramolecular [2+2] cycloadditions of [3]cumulenal 156 gave the oxepin 160 in

86% yield as a mixture of E/Z isomers. In this study, cycloaddition takes place exclusively at the internal double bond to give 160. As a complement to our experimental findings, theoritical calculations were performed and clearly demonstrates that in the absence of kinetic effects, [2+2] intramolecular cycloadditions of 156 will be made across the internal double bond exclusively. This new method for the construction of oxepin rings is in demand because these rings are found in many biologically active molecules.

Deprotection of [3]cumulenal 168 under basic conditions (methanolic potassium carbonate) did not give the expected product, but afforded a Michael type of addition occurred into the central unsaturation of the cumulene functionality by a

157.

74 VII. APPENDIX

Assigning R and S for aliénés

For axial chirality, as illustrated by an elongated tetrahedron, it is not necessary that

all four substituents be different. However, one must still be able to assign a unique

priority to each substituent. Since it is immaterial from which end of the chiral axis one

views such a structure when assigning (R) or (S), it is required that near groups (with

respect to the observer) are assigned a higher priority than far group. This ditinguishes

equivalent groups because when one of a pair of equivalent groups is near, the other one of

the pair will always be far. If this is not the case, the structure is not chiral.

Assignment of axial chirality is carried out in two steps. First, one chooses one end

of the chiral axis to look down to assign proiorities a > b > c > d.

75 Second, one views the model from the side opposite that of the lowest priority substituent, d, and traces a course from groups a to b to c. A clockwise course means the model is

(R). A counterclockwise course means it is (S).

Therefore, compound (1) is (S)

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