Synthetic Approaches to Heterocyclic Bicyclo[2.1.0]Pentanes

Home , Azide, Aziridine, Cyclobutene, Phenyl azide

SYNTHETIC APPROACHES TO HETEROCYCLIC BICYCLO[2.1.0]PENTANES

Rabah N. Alsulami

A THESIS

Submitted to the Graduate College of Bowling Green State University in partial fulfillment of The requirements for the degree of

MASTER OF SCIENCE

August 2011

Committee:

Thomas H. Kinstle (Advisor)

Marshall Wilson

Alexander N. Tarnovsky

ABSTRACT

Thomas H. Kinstle, Advisor

Bicyclic systems such as bicyclo[2.1.0]pentanes and 5-oxabicyclo[2.1.0]pentanes are known to display a variety of unique chemical properties associated with their high strain energy. To the best of our knowledge, there were no reports regarding synthesis and investigation of 5- azabicyclo[2.1.0]pentanes.

Therefore, the initial goal of this research was synthesis of 5-azabicyclo[2.1.0]pentane and investigation of its chemical properties. The cycloaddition reaction of azides (58, 59, 61) to olefins (54, 55) with further elimination of nitrogen was chosen as a synthetic method in order to obtain the compounds of interest. Starting olefins (3,3-dimethyl-1-cyclobutene-1-carboxylic acid

(54) and methyl 3,3-dimethyl-1-cyclobutene-1-carboxylate (55) and azides phenyl azide (58), p- toluenesulfonyl azide (59), and picryl azide (61) were successfully synthesized and characterized by NMR spectroscopy and GCMS spectrometry. The addition reaction between azides and olefins was performed under various conditions, such as different solvents and temperature; however, according to NMR spectroscopy and GCMS spectrometry, olefins (54, 55) do not undergo cycloaddition reaction with azides (58, 59, 61). In order to investigate that behavior, cycloaddition reactions of more reactive olefins (66, 68) with azides (58, 59, 61) were performed under a variety of conditions. The reaction of endo-bicycloheptene-2,3-dicarboxylic anhydride

(68) with phenyl azide (58) in toluene at 80 0C resulted in successful formation of triazoline.

Additionally, triazoline was formed in the reaction between norbornene (66) and picryl azide

(61) in chloroform at room temperature.

ACKNOWLEDGMENTS

In this acknowledgement I would like to express my gratitude to all those people who helped me during this period. I thank my advisor, Dr. Thomas H. Kinstle, for giving me the opportunity and the challenge to study of organic chemistry. Thanks to Dr. Wilson and Dr.

Tarnovsky for patiently waiting on my draft and being on my committee. Special thanks to my husband Nawaf, my family, and my friend Valentina, for without their love, support, encouragement, none of this would have been possible.

TABLE OF CONTENTS

Page

INTRODUCTION ………………………………………………………………………...... 1

1.1. Strained Monocyclic Systems ………………………………………………..….… 1

1.1.1 Cyclopropanes …….………………………………………………..….….... 1

1.1.2 Cyclobutenes ……………………..……………………………….………… 2

1.1.3 Heterocycles ……………………………………………………..………….. 2

1.2 Highly Strained Carbobicyclic Systems ……………………………………………. 3

1.3 Bicyclic Systems Containing Oxygen Heteroatom…………………………………. 5

1.4 Aziridines …………………………………………….…………………………….. 9

RESULTS AND DISCUSSION ………………..………….……..………………….……… 15

2.1 Synthesis of Requisite Cyclobutenes ……………………...…………………….….. 15

2.2 Cycloaddition of Azides to Form Triazolines …………………….………………… 18

2.3 Azide Cycloaddition to Norbornenes …………………..……………….…….…….. 22

EXPERIMENTAL SECTION …………………………………………………………...…… 23

3.1 General ……………………………………………………………………….……… 23

3.2 Synthesis of 1-(2-methylprop-1-enyl) piperidine …………………..…..…………… 23

3.3 Synthesis of 3,3-dimethyl-1-cyclobutene-1-carboxylic acid ………….…..………… 23

3.4 Synthesis of nitrosomethyl urea …………………………………………..………… 24

3.5 Synthesis of diazomethane ………………………………………………..……...…. 25

3.6 Synthesis of methyl 3,3-dimethyl-1-cyclobutene-1-carboxylate ……….……..….… 25

3.7 Synthesis of phenyl azide ………………………………………………….…….…. 25

3.8 Synthesis p-toluenesulfonylazide …………………………………………..……..… 25 3.9 Synthesis of o-nitrophenylazide ………………………………………………… 26

3.10 Synthesis of picryl azide ……………………………………………………..… 26

3.11 Synthesis of compound (49) general procedure for preparation of triazoline …. 27

3.12 Picryl azide addition to norbornene ……………………………………….…… 27

3.13 Phenyl azide addition to endo-bicycloheptene -2, 3-dicarboxylic anhydride… 27

4-REFERENCES……………………………………………………………………. 28

5- FUTURE WORK………………………………………………………………… 29

LIST OF SCHEMES

Page

1.1 Scheme 1. Structures of small strained rings and their strain energy ……… 1

1.2 Scheme 2. Rates of solvolysis reaction …………………………………….. 4

1.3 Scheme 3.Thermal decomposition of bicyclo [2.1.0] pentane ………….…... 5

1.4 Scheme 4. Reaction of cyclohexane epoxide using acid catalysis ………..... 5

1.5 Scheme 5. Thermolysis of exo-bicyclo [3.2.0]hept-6-ene oxide …………... 6

1.6 Scheme 6. Pyrolysis of 5-oxabicyclic[2.1.0]pentanes …………………….... 7

1.7 Scheme 7. Epoxides thermal ring opening …………………………...……... 8

1.8 Scheme 8 .Disallowed “disrotatory” ring opening ………………………….. 9

1.9 Scheme 9. Naturally occurring aziridines ………………………………..… 10

1.10 Scheme 10. Synthetic aziridines ………………..……………...... ….10

1.11 Scheme 11.The ring opening reaction of aziridines ………………….…... 11

1.12 Scheme 12. Aziridines thermal ring opening ……………………..……… 12

1.13 Scheme 13. Synthesis of aziridines …………………………………….... 13

1.14 Scheme 14. Singlet and triplet aziridine formation ………..…………….. 14

1.15 Scheme 15. Cycloaddition of azides to alkenes …….……………………. 15

1.16 Scheme 16. Synthesis of compounds 52, 53, 54, and 55 …..………….... 17

1.17 Scheme 17. Proposed synthesis of 5-azabicyclo [2.1.0]pentanes ……… 21

1.18 Scheme 18. Successful synthesis of triazoline cycloadducts …………... 22 1-INTRODUCTION

The study of ring strained organic compounds has been a popular area of research since

1885 when the first small ring compound was reported by Aldolf von Baeyer. From simple monocycles such as cyclopropane 1, cyclobutane 2, epoxide 3, aziridine 4 to literally hundreds of examples of bicyclic and polycyclic ring systems have been reported and studied. Of particular relevance to this thesis are bicyclo[2.1.0]pentanes 5 and their heterocyclic analogues: 5-oxabicyclo[2.1.0]pentanes 6 and 5-azabicyclo[2.1.0]pentanes 7. While substituted examples of 5 and 6 have been investigated rather thoroughly, to the best of our knowledge there have been no reports in the literature regarding synthesis and properties of 5-azabicyclo[2.1.0]pentanes 7.

Therefore, the purpose of our research is to synthesize and compare the chemical properties of 5- azabicyclo [2.1.0]pentanes 7 with the previously reported and studied analogous systems, such as bicyclo[2.1.0]pentanes and 5- oxabicyclo[2.1.0]pentanes.

H O N O N R 1 2 3 4 5 6 7 Cyclopropane Epoxide Aziridine Cyclobutane Bicyclo[2.1.0]pentane 5-oxabicyclo[2.1.0]pentane 5-azabicyclo[2.1.0]pentane about 27 K/cal 56 K/cal ?

Scheme 1. Structures of small strained rings and their strain energy

1.1 Strained Monocyclic Systems

1.1.1 Cyclopropanes

Cyclopropane (1) is a saturated three-membered ring with an endocyclic angle of 600.

Therefore, valence angles are significantly distorted and valence bonds exist in a “banana” shape

(so called bent bonds). This distortion leads to the high ring strain energy (27 kcal/mol) in cyclopropane,1 which is the highest strain energy in monocyclic rings. Therefore, in

1 cyclopropane the cleavage of a C-C bond proceeds even easier than in ethylene oxide. The C-C bonds in cyclopropane posses a high degree of sp2 character, therefore, it exhibits behavior similar to the double bond in olefins.2 Cyclopropanes undergo electrophilic addition reactions, such as addition of HX (X = Halogen), that obey Markovnikov’s rule and result in ring opened products reaction. Likewise, bromination leads to the formation of 1, 3-dibromopropane 3 and thermolysis at 450-5000 C leads to the formation of propene.4 These ring bond cleavage reactions proceed even easier than those in ethylene oxide.

1.1.2 Cyclobutanes

Cyclobutane is a saturated four-membered ring, which possesses high strain energy (26 kcal/mol) similar to cyclopropane again due to its endocyclic angle distortion from 1090 (sp3) to

0 90 . However, unlike cyclopropane cyclobutane is not planar and has an angle between planes of

350.5 As a result of lower strain energy, the ring opening by pyrolysis proceeds at higher temperatures compared to cyclopropane ring opening. Also, cyclobutane shows less reactivity than cyclopropane in addition reactions, such as bromination and hydrogenation.

1.1.3 Heterocycles

Ethylene oxide (2), also known as an epoxide or oxirane, is a saturated three-membered oxygen-containing heterocycle with an endocyclic bond angle of 600. Ethylene oxide possesses ring strain energy of about 27 kcal/mol. Ring opening of ethylene oxide occurs under basic or neutral condition, and by acid catalyzed reaction with even weak nucleophiles.6

Aziridine (3), also known as ethyleneimine, is a saturated three-membered nitrogen- containing heterocycle. Again, valence angles are significantly distorted and bonds exist in a

“banana” shape. This distortion makes the ring strain energy about 27 kcal/mol in this molecule.7

Therefore, easy cleavage of the C-N bond occurs upon nucleophilic attack. Usually, this cleavage proceeds with high stereoselectivity and regioselectivity, which makes this strained ring system a valuable synthetic intermediate.

1.2 Highly Strained Carbobicyclic Systems

Bicyclic systems have gained much attention since 1957 due to high ring strain energies

(up to 56 kcal/mol) that they posess.8 Therefore, they display greater reactivity and less stability than their monocyclic analogues. It has been shown that cyclopropyl rings are able to stabilize adjacent ionic centers. The particular structure of the reactive cationic intermediate determines the change in the reactivity in reactions with nucleophiles. According to Schleyer and Van Dine solvolysis rates dramatically increase in case of carbinyl carbon being adjacent to the strained bridging bond (Scheme 2).9 For example, the more strained bicyclic structure 12 reacts with nucleophile 1.3 times faster than the monocyclic structure 8. But, when the reaction center is attached to the bridge bond (structure 14) the reaction rate raises from 1.3 (structure 12) to 40000

(structure14). This drastic increase in the reaction rate can be explained by the ability of the bridging bond to participate in the stabilization of the carbocation formed form structure 14. The cleavage of the bridging bond leads to release of the high strain energy of the molecule.

Scheme 2. Rates of solvolysis reaction

According to Criegee and Rimmelin small bicyclic ring systems such as bicyclo[2.1.0] pentanes can be converted to the diradical species by thermal decomposition.10 Thermal decomposition of bicyclo[2.1.0]pentanes at temperatures higher than 250 0C leads to the formation of cyclopentenes10 and 1,4–pentadienes11 (Scheme 3).The formation of cyclopentene is explained by migration of hydrogen from C-2 in the cyclopentane 1,3-diradical intermediate, and

formation of 1,4 -pentadienes results from ring opening cleavage of the C4-C5 bond in the 1,3- diradical species.

4 products, such as 24. For example, Garin has shown the following result (Scheme 5). This is similar to the thermal behavior of simple epoxides.13

O ∆ O H

Scheme 5. Thermolysis of exo-bicyclo[3.2.0]hept-6-ene oxide

However, when either or both R1 and R2 are charge supporting, an apparent heterolytic cleavage of the C1-C4 bond of 5-oxabicyclo[2.1.0]pentanes occurs to produce the resonance delocalized carbonyl yield species 16, which has been trapped by dipolarophlies such as 17 to

13 produce adducts such as 18. An alternate homolytic cleavage of the C1-C4 bond which would generate biradical 20 cannot be ruled out. When 5-oxabicyclo[2.1.0]pentanes (R1=COOCH3; R2=

H) is subjected to Flash Vacuum Pyrolysis conditions, compound 19 is isolated in good yield.

The mechanism suggested by Hazlett involves the formation of 16 (or 20), followed by an orbital symmetry allowed suprafacial [1,4]-hydrogen shift in the 6-electron π-system.14

6 R1

Heterolytic cleavage R2 Homolytic cleavage 1300 Homolytic cleavage R1 R1 R1 R1 O O O O R R2 16 21 2 R2

H C O O 3 R2 FVP 20 H R1 O O CH3 17 R1 H

H O O O CH O H R2 3 22 R1 O CH3 R2 19 O H R1 R1 O H R2 18 OH O H H R2 R2 24 23

Scheme 6. Pyrolysis of 5-oxabicylic [2.1.0] pentanes

Thermal ring opening reactions of simple epoxides containing charge stabilizing substituents have also been reported. Huisgen studied the thermal behavior of cis and trans cyanostilbene oxide by trapping the ring opened carbonyl ylides with dimethyfumarate. The ring opening should be a conrotatory process, and trapping should lead to two distinct steresisomeric products from each of the cyanostilbene oxide isomers. However, the cis-cyanostilbene oxide

7 produced all four stereisomeric cycloadducts 29-32 in these experiments. This requires either (a) isomerization of the less stable carbonyl ylide 27 to the more stable 28 one prior to trapping, or

(b) direct “disallowed” disrotatory ring opening (Scheme 7). 15

O O H Ph H CN Ph CN 26 Ph 25 Ph

D is ro ta to Conrotatory Conrotatory ry

Ph O Ph Ph O CN isomerization H CN Ph H 28 27

R R R=CO2CH3 R R

O H Ph H O Ph H O CN H O CN Ph CN Ph CN Ph Ph Ph Ph R R R R R R R R 29 30 31 32

Scheme 7. Epoxides thermal ring opening

8 Other examples of this “disallowed” opening include: 16, 17

Scheme 8. Disallowed “disrotatory” ring opening

The reason for this apparent violation of orbital symmetry requirement is not clear.

1.4 Aziridines

Our interests are in developing new and comparative chemistry of aziridines. Aziridines were first synthesized in 1888 by Gabriel.18 These compounds are saturated heterocyclic three- membered rings that contain one nitrogen and two carbon atoms. The high strain energy in aziridines can lead to facile cleavage reactions of the C-N bond that proceed with high stereoselectivity and regioselectivity, making aziridines valuable synthetic intermediates.

Both natural and synthetic aziridines were shown to display biological activity. Naturally occurring aziridines (Scheme 9)21 display biological activity as antitumor drugs. For example, mitomycins A, B, C, and porfiromycin B represent an important class of naturally occurring mitosanes, isolated from the soil.21 Mitomycin C, is one of the most important antitumor agents in clinical chemotherapy for stomach and lung cancer. The aziridine ring in mitosanes is 9 essential for the anti-tumor activity of mitomycins. Several synthetic aziridines also show biological activity (Scheme 10). For example, 2-(4-amino-4-carboxybutyl)aziridine-2-carboxylic acid 33 behaves as an inhibitor of the bacterial enzyme diaminopimelic acid epimerase22a and 2-

(3-carboxypropyl)aziridine-2-carboxylic acid 34 is an inhibitor of glutamate racemase. 22b

O O NH2 X O YO NZ N

O Mitomycin A; X=OMe, Y=Me, Z=H Mitomycin B; X=OMe, Y=H, Z=Me Mitomycin C; X=NH2, Y=Me, Z=H Porfiromycin B; X=NH2 , Y=Me, Z=Me

Antitumor agents

Scheme 9. Naturally occurring aziridines

HO2C CO2H CO2H HO2C

HN NH2 HN 33 34

Scheme 10. Synthetic aziridines

The ring opening reaction mechanism for aziridines is shown in Scheme 11. This reaction proceeds via protonation of aziridine nitrogen followed by nucleophilic attack on the adjacent carbon atom which could lead to the formation of four products.19 However, the reaction

proceeds through clean SN2 attack of nucleophile, on the stable cationic ammonium salt intermediate. Therefore, only two products are formed (upper pathway). When strong nucleophiles are used the reaction proceeds by direct SN2 reaction formation of ammonium salt.

Aziridine ring opening reactions can lead to the formation of nitrogen containing compounds such as α and β −amino acids, 1, 2- diamines, β-lactam antibiotics, amino alcohols, etc.20

Scheme 11. The ring opening reaction of aziridines 15

Aziridines can also undergo thermal ring opening to yield azomethines (Scheme 12).23

Huisgen has extensively studied the thermal heterolytic cleavage of the bond bridge in aziridines which leads to the formation of the 1,3-dipolar resonance stabilized intermediate 36 or 37. This azomethine ylide 37 can be captured by dipolarophiles to produce cycloadduct compound 39.

According to Woodward Hoffmann rules for orbital symmetry controlled reactions, the isomerization of cyclopropyl anion to allyl anion is a conrotatory process thermally allowed and is a disrotatory process photochemically allowed.24 The stereospecificity of the ring opening was shown to be conrotatory by the formation of trans-dimethyl-2,5-pyrolidine-dicarboxylate from the cis-aziridine, and the formation of the cis-pyrolidine from the trans-aziridine.

Scheme 12. Aziridines thermal ring opening

As started earlier, aziridines are important intermediates in organic synthesis. However, the number of stereoselective methods to produce aziridines of specific stereochemistry is reduced compared to epoxide analogs. For example, stereospecific epoxidation of olefins with peroxyacids proceeds in the presence of metal catalysts [Ti (IV),V(V),Mo(VI)]; however, stereospecific aziridination of olefins does not occur under analogous conditions.19

12 Therefore, numerous synthetic routes for aziridine formation have been studied. In general, aziridines can be synthesized by ring closing cyclization or by direct cycloaddition methodology (Scheme 13).25 Overall, there are three cyclization pathways, which include 1,2- aminoalcohol cyclization, 1,2-azidoalcohol ring closing reaction, and epoxide transformation into aziridines using triphenylphosphine and metal azides. In general, there are two cycloaddition pathways: complexed nitrene (or nitrene equivalent) addition to alkenes and carbene (or carbene equivalent) addition to imines.

Scheme 13. Synthesis of aziridines

Direct addition of nitrene to olefins can proceed mechanistically in two ways (Scheme 14).19 One is the addition of singlet nitrene to olefins by synchronous bond formation to form aziridines.

Alternatively, the addition of triplet nitrene to olefins proceeds in a two step process via diradical formation that produces aziridines in a nonstereospecific manner. Usually, stereosoecifc addition occurs with nitrenes and metallonitrenes. Photolysis or high temperature thermolysis of alkoxycarbonyl azides produce acylnitrenes in both singlet and triplet excited states. Therefore, the reaction results in formation of a mixture cis and trans isomers.

Scheme 14. Singlet and triplet aziridine formation

Finally, aziridines can be synthesized by nitrogen (N2) elimination from triazoline

(Scheme 15) which are formed by cycloaddition of azides to alkenes. Further discussion of this method will be found in the Results and Discussion section.

Scheme 15. Cycloaddition of azides to alkenes 14

2-RESULTS AND DISCUSSION

2.1 Synthesis of Requisite Cyclobutenes

The initial goal of this research was the synthesis of a 5-azabicyclo[2.1.0]pentanes in order to investigate the chemical and physical properties of such compounds. Comparison of 5- azabicyclo[2.1.0]pentanes with the corresponding 5-oxabicyclo[2.1.0]pentanes was of particular interest. Our planned synthetic route required the availability of cyclobutene precursor 54 and

55, so our synthetic efforts began with the synthesis of these compounds. For this we followed a known synthetic procedure with some modification.

Starting materials isobutyraldehyde, piperidine, methyl acrylate and methyl-p- toluenesulfonate were purchased from Sigma-Aldrich. Isobutyraldehyde (50) and piperidine were purified by distillation; the remaining compounds were used as delivered.

All the compounds were characterized by NMR, IR (Infrared) spectroscopy, and GCMS spectrometry. NMR spectra of previously reported compounds matched these reported in the literature.

Intermediate 51 (1-isobutenylpiperidine) was synthesized by a previously reported procedure.22 Isobutyraldehyde (50) and piperidine in a 1:2 ratio were heated under reflux in the presence of potassium carbonate for 24 h (Scheme 16). The crude product was purified by vacuum distillation to yield colorless (51) in 78 % yield. This yield is 23 % higher than the reported one (55 %). The enhancement of reaction yield can be attributed to the extension of refluxing time compared to the reported one (4 h). Therefore, we have succeeded in optimizing the synthesis of (51).

A procedure for utilizing 51 in a stepwise thermal 2π+2π cycloaddition to produce a cyclobutane adduct was then undertaken .26 Intermediate 51 was refluxed with methyl acrylate (2 equivalents) in acetonitrile in the presence of hydroquinone for 9 h (Scheme 16). Distillation of crude product under reduced pressure resulted in the isolation of 3,3-dimethyl-2-piperidinyl cyclobutane (52) as a yellow liquid in 82 % yield ,which is 10% higher than previously reported.

This increase in yield compared to the literature can also explained by the extension of reflux time from 2 hours up to 9 hours.

Conversion of the cyclobutane adduct 52 to 3,3 dimethyl-1-cyclobutene-1- carboxylic acid 54 has been done elsewhere.26 Thus, a mixture of intermediate 52 and commercially available methyl-p-toluenesulfonate in a 1:1 ratio was heated on the steam bath for 7 hours to form the quaternary ammonium salt 53 which was then subjected to treatment with a hot solution of sodium hydroxide to effect elimination to the unsaturated acid 54. Isolation and purification resulted in crystalline 54 in a yield (80%) (Scheme 16) similar to the reported value.

The synthetic procedure of preparation of ester 55 (3,3-dimethyl-1-cyclobutene-1- carboxylate) was previously reported. In order to obtain ester 55, diazomethane was synthesized in four steps following a literature procedure.27 Compound 55 was prepared by dropwise addition of diazomethane to previously synthesized 54. The excess of reagents and solvent were removed under reduced pressure provide to a 54 % yield of liquid upon cooling.

The 1H NMR OF 54 consisted of four sharp singlets; a six-proton singlet at δ 1.23 due to the germinal methyl protons, a two-proton signal at δ 2.43 due to the methylene protons, a three- proton absorption caused by the ester proton at δ 3.73 and the vinyl hydrogen resonance at δ

6.84. This was identical to a previously reported spectrum of this ester.

H a N b N O O O H

50 51 52

O HO

O O e d N O O

55 54 53

Scheme 16. Synthesis of compounds 52, 53, 54, and 55

Reagents and Conditions: (a) Piperidine, K2CO3, reflux for 24 h; (b) MeCN, hydroquinone, reflux for 9 h, methylacrylate;(c) heated in steam bath for 7 h, methyl p-toluenesulfonate;(d) KOH, extraction with ether, conc HCL; (e) CH2N2 (35).

Many attempts were then made to convert this ester into a triazoline such as 56 and 57, a precedent structure precursor to aziridine.

2.2 Cycloaddition of Azides to Form Triazolines

The cycloaddition reaction of alkyl and aryl azides to variety of olefins was first discovered by Wolff in 1912 and resulted in the formation of 1, 2, 3-∆2-triazolines. 1, 2, 3-∆2- triazolines derived from phenyl azides display stability; however, They decompose when they are derived from p-toluenesulfonyl azide.31,33 After that the reaction was widely discussed in literature and numerous olefins that display high reactivity as well as non-reactive alkenes were reported. The reaction can proceed at mild conditions; however, in some cases hard conditions, such as high pressure and temperature are required.32 For example, Malpass and co-worker reported successful quantitative addition of phenyl azide to derivatives of 2- azabicyclo[2.2.1]hept-5-ene at mild conditions, and 2-azabicyclo[2.2.2]oct-5-en-3-one, 2- azabicyclo[2.2.1]hept-5-en-3-one at harsh conditions.32

The addition reaction of aryl and acyl azides to olefins was studied in details by Bailey and White.33 Overall, picryl azide displayed the best reactivity compare to phenyl and p- toluenesulfonyl azide in the addition reaction with olefins due to efficient stabilization of negative charge in the transition state by nitro groups. Also, it has been shown that the rate of the addition reaction of phenyl azide to norbornene is not affected by the nature of the solvent. On the other hand, the nature of the solvent in addition reaction of picryl azide to norbornene showed the influence on the reaction rate. Best results were obtained when halogen-containing solvents such as chloroform were used. 33 Additionally, it has been shown that solvents have little influence on the rate of the addition reaction of p-toluenesulfonyl azide to olefins. The considerable numbe of olefins that failed in the reaction with picryl azide, such as ethyl cinnamate , cinnamaldehyde , trans-stilbene, tetracynanoethylene , ethyl acrylate, hex-3-yne ,

mesityl oxide, and p-benzoquinone, was reported.33 It has been shown that the rate of the reaction of strained olefins was affected by subsitituents which were not directly attached to the

C=C bond. For example, endo-bicycloheptene-2, 3-dicarboxylic anhydride showed less reactivity than norbornene. Also, the rate of the reaction can be decreased by substituents directly attached to the C=C bond in the olefins.

A number of different reagents and numerous methods were explored in the study. For example Table 1 summarizes the attempted addition reaction of highly strained olefins with substituent at double bond (electron withdrawing) 54 and 55 to organic azide such as phenyl azide, p-toluenesulfonyl azide, and picryl azide. All attempts to react either 54 acid or 55 ester with azides failed. According to H1 NMR, IR spectroscopy, GCMS spectrometry, TLC (thin layer chromatography) the reaction does not preceed and original signals from starting materials were observed. In over attempts to accomplish the addition reaction we changed the conditions such as, solvent, temperature, and time as shown in Table 1.

Table 1

Addition olefin to azide in variety conditions

Olefin Azide Solvent Temperature Time Observation

0 Cyclobutene acid Phenyl azide CCl4 25 C 5 Days - 50 0C 1 Day - DCM 25 0C 5 Days - 50 0C 1 Day - ACN 25 0C 5 Days - 50 0C 1 Day -

0 p-toluenesulfonyl CCl4 25 C 5 Days - azide ACN + Tol 25 0C 5 Days -

0 Picryl Azide CHCl3 25 C 5 Days -

0 Cyclobutene ester Phenyl azide CCl4 25 C 5 Days - 50 0C 1 Day -

0 p-toluenesulfonyl CCl4 25 C 5 Days - azide 50 0C 1 Day -

In order to synthesis compound (5-azabicyclo[2.1.0]pentanes) the compound 54 and 55 were treated with variety kind of solvent like phenyl azide, picryl azide ,and p-toluenesulfonyl azide at room temperature in the dark for 5 days to yield compounds 62 and 64 (Scheme 15).

N R O O N N R O O R-N N 3 O hv or ∆ O

54 62 63

N R R HO N N OH OH N O O R-N3 O hv or ∆

55 64 65

Scheme 17. Proposed synthesis of 5-azabicyclo[2.1.0]pentanes

o 0 Reagents and conditions: (a) PhN3, CCl4 , 25 C; (b) picryl azide, CHCl3, 25 C ; (c) P- 0 toluensulfonate azide, CCl4, 25 C;(d) hv

Since the formation of triazoline 62 and 64 was unsuccessful, their conversion to the desired 5-azabicyclo[2.1.0]pentanes was not possible, so the proposed synthetic scheme described in (scheme 17) was not accomplished.

In order to make available some triazoline which we could use to develop procedures and techniques for aziridine formation, we reacted our synthetic azides with some strained alkenes previously shown to be reactive with azides, namely endo-bicycloheptene-2, 3-dicarboxylic anhydride and norbornene itself. The positive results of these efforts listed in Table 2 and

Scheme 18.

Table 2

Olefin Azide Solvent Temperature Time Observation

Norbornene anhydride 0 Phenyl azide CHCl3 25 C 5 Day - Tol 80 0C 1 Day +

Norbornene anhydride 0 Picryl azide CHCl3 25 C 1 Day - 5 Day -

80 0C 1 Day -

0 Norbornene Picryl azide CHCl3 25 C 1 Day +

2.3 Azide Cycloadditions to Norbornenes

N N N N N O2N O2N NO2 N +

NO2

O2N NO2 66 61 67

N O N N N N O + N O O

O O

68 58 69

Scheme 18. Successful synthesis of triazoline cycloadducts.

EXPERIMENTAL SECTION

General: All solvents were purchased from commercial sources. Piperidine, isobutyralaldehyde, methyl p-toluene sulfonate, and methyl acyrlate were purchased from commercial sources and distilled prior to use. NMR spectra were recorded at room temperature in 5 mm tubes using a Bruker spectrometer operating at 300 MHz for 1H, 75.5 MHz for 13C.

Chemical shifts were measured relative to tetramethylsilane as internal references. Mass spectra were recorded using a Shimadzu model QP5050A (GC-MS) spectrometer equipped with direct probe and electron impact ionization.

Synthesis of 1-(2-methylprop-1-enyl)piperidine (51) 26 Isobutyralaldehyde, 144 g, (2 mol) and piperidine, 340 g, (4mol) were refluxed in the presence of K2CO3, 74.99 g, (0.54 mol) for 24 hours. Excess of piperidine was removed under reduced pressure and the resulting crude product was purified by distillation under reduced pressure to yield 78% (218 g, 2 mol) of 1-(2-

1 methylprop-1-en-1-yl) piperidine (51). H NMR (CDCl3): δ 1.49-1.65 (t, 12H, J=8Hz), δ 2.47-

2.54 (d, 4H, br, J=5.4Hz), δ 5.33 (s, 1H, br); mass spectrum m/e 139, 138, 124, 110, 96, 82.

Synthesis of 3, 3-dimethyl-1-cyclobutene-1-carboxylic acid (54) 261-(2-methylprop-1- en-1-yl) piperidine (51), 218 g, (1.56 mol) and methyl acrylate, 280.96 mL, (3.12 mol) were refluxed in 200 mL of acetonitrile in the presence of catalytic amount of hydroquinone for 9 hours. The solvent was removed by distillation. The resulting crude product was purified by distillation under reduced pressure to yield 82% 101.28 g, (1.56 mol) of methyl 3,3-dimethyl-2-

1 piperidinocyclobutanecarboxylate (52). H NMR (CDCl3): δ 1.08-1.13 (6H, s), δ 1.40-1.42

(3H), δ 1.40-1.55( 6H), δ 2.37-2.40(2H), δ 2.51-2.5 9(2H), δ 2.64-2.67(1H), δ 2.77-2.83(1H), δ

3.66-3.68(2H). Compound (52) 101.28 g, (0.44 mol) and methyl p-toluenesulfonate 81.84 g,

(0.44 mol) were heated in steam bath for 7 hours, and cooled to the room temperature. The 24

yellow solid product which was formed. (20 g) was dissolved in a solution of 6.8 g of potassium hydroxide in 9 mL of water, and heated on a steam bath for 30 minutes. The mixture was cooled, extracted with ether, acidified with concentrated hydrochloric acid, and dried with magnesium sulfate. The solvent was removed under reduced pressure to yield 40% 8 g (0.0662 mol) of 3,3-

1 dimethyl-1-cycobutene-1-carboxylic acid (54): H NMR (CDCl3) : δ 1.24 (6H, s), δ 2.45 (2H, s), δ 7.00 (1H, s), δ 9.31 (1H, s, br): mass spectrum m/e 126, 111, 84, 79, 65, 41.

Synthesis of nitrosomethyl urea (56)27 To a solution of 120 g of 40 % methylamine in water (200 mL) concentrated hydrochloric acid was added dropwise until the solution became acidic. Then water was added until the weight of the reaction mixture reached 500 g. Urea 300g

(5mol) was added to the reaction mixture, and the solution was refluxed for 3 hours; and refluxed vigorously for about 15 more minutes. The solution was cooled and 110 g (1.5 mol) of potassium

0 nitrite was added, and the whole content was cooled to 0 C. A mixture of ice, 125 g, and concentrated sulfuric acid, 15 g, was taken in a beaker and cooled to 0 0C. The cooled solution of methyl urea and potassium nitrite was added to the cooled beaker containing sulfuric acid dropwise with stirring at a rate that avoided overheating and NO2 evolution. Nitrosomethyl urea rose to the surface as a crystalline foamy precipitate, which was filtered by suction filtration and dried at room temperature to yield 90.76 g, (1.5 mol) of nitrosomethyl urea (42).

Synthesis of diazomethane (57)27 A solution of 50% potassium hydroxide in water and

200 cc ether was cooled to 5 0C and 20 g of nitrosomethyl urea was added, and the reaction mixture was heated in water bath. A yellow solution of diazomethane in ether distilled and was collected in a receiver cooled to 0 0C.

Synthesis of methyl3,3-dimethyl-1-cyclobutene-1-carboxylate (55) 3,3-Dimethyl-1- cyclobutene-1-carboxylic acid 8 g (0.0662 mol) was dissolved in 4 mL of ether, and diazomethane was added dropwise until the evolution of gas ceased. The excess of reagents and solvent were removed under reduced pressure to yield 53% 5 g (0.0662 mol) of methyl 3,3-

1 dimethyl-1-cyclobutene-1-carboxylate. H NMR (CDCl3): δ 1.23 (6H, s) δ 2.43 (2H, s), δ 3.73

(3H, s) δ 6.84 (1H, s); mass spectrum m/e 140, 125, 109, 108, 97, 81, 80, 79 .

Synthesis of phenyl azide (58)28 A solution of 25 % hydrochloric acid (18.5 mL) in water (100 mL) was cooled to 0 0C, and phenyl hydrazine 11.8 g was added dropwise to the reaction mixture. White crystals of phenylhydrazine hydrochloric acid precipitated from the solution, when 33 mL of ether were added. A solution of sodium nitrite 8 g in 10 mL of water was added dropwise at such a rate that the temperature of reaction mixture never rose above 5

0C. The crude product was steam distilled, the organic layer was separated and the water layer was extracted once with 25 mL of ether. The organic layers were combined and washed with sodium hydroxide (2N) until no phenol could be detected by ferric chloride test. The solvent was removed under reduce pressure to yield 53% 7 g, (0.11 mol) of phenyl azide. 1H NMR (300

-1 MHz, CDCl3): δ 7.06 (2H, J=9 HZ), δ 7.16 (1H, J=6 HZ), δ 7.37 (2H, J=9 HZ); IR (Cm ) 2412

Synthesis p-toluenesulfonylazide (59)29. A solution of 15g, (0.076 mol) of p- toluensulfonylchloride in 80 mL of acetone was heated to 45 0C and added dropwise with stirring to a solution of 7.6 g, (0.11 mol) of sodium azide in 20 mL of water and 40 mL of acetone.

During this addition sodium chloride was separated and the reaction mixture turned light brown color. The mixture was stirred at room temperature for 2.5 hours, the solvent was removed under reduce pressure at 35 0C. The residue was mixed with 120 mL of water in a separatory funnel

and the oil p-toluensulfonyl azide was separated. These oily crystals were washed with two 10 mL portions of water and dried over anhydrous sodium sulfate, filtered to yield 48% 7.3 g,

1 (0.076 mol) of p-toluenesulfonyl azide (59). H NMR (300 MHz, CDCl3): δ 2.50 (3H, s), δ 7.42

(2H, J=9Hz, d), δ 7.86 (2H, J=9Hz, d).

Synthesis of o-nitrophenyl azide (60) 30 A mixture of o-nitroaniline (14g, 0.1 mol) was dissolved in 40 ml of water and concentrated HCl 23 mL, (0.27 mol). The reaction was stirred

0 and cooled to 0 C, and NaNO2 7.25 g, (0.11 mol) in water 25 mL was added dropwise. After 1

0 hour stirring at 0 C the yellow solution was filtered from insoluble impurities and then NaN3 6.5 g, (0.1 mol) in water (25mL) was added dropwise to the reaction mixture. During this addition a light cream colored product began to precipitate. This product was filtered and dried at room

1 temperature to yield 13.5 g of o-nitrophenyl azide. H NMR (300 MHz, CDCl3):

δ 7.93(1Η, J=8Hz, d), δ 7.64(1H, J=8, d), δ 7.35(1Η, J=8, d), δ 7.27 (1Η, J=8, d).

Synthesis of picryl azide (61) 31A mixture of 25 mL of fuming nitric acid and 25 mL of concentrated sulfuric acid, were stirred and cooled to 0 0C, then 5 g of o-nitrophenyl azide was added dropwise at such a rate that the temperature of the solution never rose above 5 0C. After stirring at 0 0C for 1 hour, the reaction mixture was poured on ice, the solid was filtered by suction filtration and dried at room temperature .Rapid recrystallization from methanol yielded

1 70% 3.5 g of picryl azide. H NMR (300M, CDCl3): δ 8.93(2Η ,s): mass spectrum m/e 254,

226,196,120.

Synthesis of compound (62,64) general procedure for preparation of triazoline 31

The olefin (54, 55) was treated with azide (58, 59, 61) in solution of carbon tetrachloride in a 1:2 ratio for 5 days in the dark at room temperature. 27

Synthesis of compound (67) by addition of Picryl azide to norbornene 30 Norbornene

(100 mg, 1.04 mmol) was added dropwise into a solution of picryl azide (240 mg, 0.945 mmol) in chloroform (5 mL) and the reaction mixture was kept in the dark for 1 day at room temperature. Crude 1H-NMR showed formation of a single product.

Synthesis of compound (69) by addition of Phenyl azide to endo-bicycloheptene-2,3- dicarboxylic anhydride 30 endo-bicycloheptene-2,3-dicarboxylic anhydride (100 mg, 1.04 mmol) was added dropwise into a solution of phenyl azide (240 mg, 0.945 mmol) in toluene (5 mL) and the reaction mixture was kept in the dark for 1day at 800 C. Crude 1H-NMR showed formation of a single product.

FUTURE WORK

In experiment currently in progress the direct synthesis of 5-azabicyclo[2.1.0]pentanes by addition of nitrenes to the cyclobutene ring system (54, 55) is being studied. We are using a literature based procedure for the generation of the phthalimide nitrene by lead tetraacetate oxidation of N-aminophthalamide illustrated Scheme 19. If successful, the chemistry described in Scheme 20 will produce first example of a 5-azabicyclo[2.1.0]pentanes.35

O O Pht Pht Pb(OAc) R N 4 R + N R N NH2 N N H H O O

Scheme 19. Synthesis of N-phthalamidoaziridines

RO Pht OH O N O O

Pb(OAc)4 N NH2 + RT, 10 min O

Scheme 20. Synthesis of 5-azabicyclo[2.1.0]pentane by addition of N-aminophthalamide

An alternate path for the synthesis of 5-azabicyclo[2.1.0]pentane employs the ethylazidoformate, a well known precursor to nitrene, to react with of 3,3-dimethyl-1-cyclobutene-1-carboxylic acid

(54) and methyl 3,3-dimethyl-1-cyclobutene-1-carboxylate (55).36 Thesis experiments are also underway.

RO CO2CH2CH3 OR N O O O hv + CH3CH2OCN3 -N2

Scheme 21. Synthesis of 5-azabicyclo[2.1.0]pentane by addition of ethoxy carbonyl nitrene

REFERENCES:

1. Liebman, J. F.; Greenberg, A. Chem. Rev. 1976, 76, 311-312. 2. Weigert, F. J.; Roberts, J. D. J. J. Am. Chem. Soc. 1967, 89, 5962-5963. 3. Ogg Jr, R. A.; Priest, W. J. J. Am. Chem. Soc. 1983, 60, 217-218. 4. For a review of the pyrolysis of three and four-membered rings, see Frey, H.M.Adv.Phys.Org. Chem. 1966, 4,147. 5. Wiberg, K .B. Acc. Chem. Res. 1996, 29, 229-234. 6. Parker, R. E.; Isaacs, N. S. Chem. Rev. 1959, 59, 737-749. 7. Pellissier, H. Tetrahedron 2010, 66, 1509-1555. 8. Chang, S-J.; McNally, D.; Shary-Tehhrany, S.; Hickey, S. M. J.; Boyd, R. H. J. Am. Chem. Soc. 1970, 92, 3109-3118. 9. Schleyer, P. V. R.; Van Dine, G. W. J. Am. Chem. Soc. 1966, 88, 2321-2322. 10. Crigee, R.; Rimmelin, A. Chem.Ber. 1957, 90, 414. 11. Tanner, D. Angew.Chem.Int.Ed.Engl. 1994, 33, 599. 12. Shaborov, Yu S.; Blagodatskikh, S. A.; Fedotov, A. N.; Vestn. Mosk.Univ .Khim. 1976, 17(3), 354-357.CA; 86(5)29539u. 13. Grain, D. L. J. Org .Chem. 1969, 34, 2355-2358. 14. Hazlett, D. E. Ph.D.Thesis, Univeristy of Toledo, 1983, 1-14. 15. Huisgen, R.; Markowski, V. J.C.S.Chem.Comm. 1977, 440-442. 16. Markowski, V.; Huisgen, R. J.C.S.Chem.Comm. 1977, 439. 17. Arnold, D. R.; Chang, Y. C. J. Heterocycl. Chem. 1971, 8, 1097. 18. Gabriel, S. Chem Ber. 1888, 21, 1049. 19. Atkinson, R. S. Tetrahedron 1999, 55, 1519-1559. 20. a -Deyrup, J. A. In The Chemistry of Heterocyclic Compounds Ed.Hassner, A., Wiley, New York, 1983,42, 1. b-Padawa, A.; Woolhouse, A. D. Aziridines,Azirines and Fused Ring Derivatives in Comprehensive Heterocyclic Chemistry ,Ed. Lwowski, w.; Pergamon, Oxford, 1984,7,47. C-Osborn, H. M. l; Sweeney, J. Tetrahedron:Asym. 1997,8,1693. 21. Kasai, M.; Kono, M. Synlett. 1992,778-790.

22. a- Gerhart, F.; Higgins, W.; Tardif, C.; Ducep, J. J.Med.Chem. 1990, 33, 2157- 2162.b- Tanner, M. E.; Maio, S. Tetrahedron Lett 1994, 35, 4073-4076. 23. Huisgen, R.; Scheer, W. Huber, H. J. Am .Chem. Soc. 1967, 89, 1753-1755. 24. Woodward, R. B.; Hoffmann, R. J.Am.Chem.Soc. 1965, 87,395-397. 25. Watson, L. G.; Yu, L.; Yudin, A. K. Acc.Chem.Res. 2006, 39, 194-206. 26. Brannock, K. C.; Bell, A.; Burpitt, R. D.; Kelly, C. A. J.Org.Chem. 1964, 29, 801- 808. 27. Hudlicky, M. J. Org .Chem. 1980, 45, 5378; 28. Lindsay, R. O.; Allen, C. F. H. Org. Synth. 1942, 22, 96.b- Lindsay, R. O.; Allen, C.F.H. Org. Synth. 1955, 3, 710. 29. Guiver, M. D.; Roberston, G. P. Macromolecules 1995, 28,294-301. 30. Shea, K. J.; Kim, J. S. J. Am. Chem. Soc. 1992, 114, 4846–4855. 31. Wolff, L. Liebigs Ann.Chem.1912, 394, 23. 32. Malpass, J.; Belkacemi, D.; Griffith, G.; Robertson, M. Arkivoc. 2002(vi) 164- 33. Bailey, A. S.; White, J. E. J.Chem.Soc. (B) 1966, 819-821. 34. Huisgen, R.;Szeimies, G. und Mobius, L. Chem.Ber. 1966, 99,475-490. 35. Anderson, D. J.; Gilchrist, T. L.; Horwell, D. C.; Rees, C. W. J. Chem. Soc. (C) 1970, 576-580. 36. Hafner, K.; Konig, C.Angew. Chem. Internat. Edit. 1963, 2, 96.

APPENDIX

N N N

S N N N O

N N N

O2N NO2

NO2

N N O

N O

N N O2N N

NO2 O2N