PREPARATION OF N-SUBSTITUTED HYDROXXLAMINES

FROM OXAZIRIDINES

APPROVED:

£,1 Major Professor

Minor Professor

\j/M/PVOf sC-p^rector of the Department of Chemistry

| ( / i K A , ^ Dean of the Graduate School

PREPARATION OF N-SUBSTITUTED HYDROXY!AMINES

FROM OXAZIRIDINES

THESIS

Presented to the Graduate Council of the

North Texas State University in Partial

Fulfillment of the Requirements

For the Degree of

MASTER OF SCIENCE

By

Sharon G. Truitt, B. S,

Denton, Texas

January, 1963

TABLE OF CONTENTS

Chapter Page

I. INTRODUCTION . . l

II. EXPERIMENTAL PROCEDURE 11

III. DISCUSSION 23

BIBLIOGRAPHY 27

i n

CHAPTER I

INTRODUCTION

Ethylenediamine derivatives exhibit antihistamine activ-

ity (34). Heterocyclic analogues of pyranisamine (2-C(2-dimethyl-

aminoethyl)(p-methoxybenzyl)amino]pyridine) are some of the

most effective and least toxic antihistamines (4,14,16). A

similar compound, tripelennamine (2-[benzyl('2-dimethylamino-

ethyl)amino]pyridene), (19), is a widely prescribed drug for

hay fever and other allergies.

> In many series of compounds, intensity of biological

activity and chemical reactivity are proportional. Generally

whenever an alkyl group replaces a reactive hydrogen atom, as

would be the case for an N-substituted hydroxylamine as com-

pared to hydroxylamine, the over-all biological activity of

the resulting compound is lower than that of its nonalkylated

analogue (6). Since toxicity and physiological activity are

not proportional, this comparison can only suggest possible

types of derivatives to prepare and test.

Hydroxylamine affects the central nervous system and pro-

duces cortical convulsions (Id). Unfortunately, N-substituted

hydroxylamine derivatives tested to date have been toxic to

man.

1

The known physiological activities of ethylenediamine

derivatives and N-substituted hydroxylamine derivatives

suggested that N,N'-dihydroxylethylenediamine (I),

(HONHCHgCHgNHOH), might have useful medicinal properties or

properties that might indicate potentially fruitful areas

for further research.

1,2-Bis(aminooxy)ethane, (H2NOCH2CH2ONH2), has been

prepared (1), but the N-substituted isomer, (I), has not

been reported.

Emmons (7) has indicated that the acid hydrolysis of

oxaziridines to form N-substituted hydroxylamines is an

improvement over previously reported preparative routes.

Since only a few N-substituted hydroxylamines have been

reported as having been produced from the acid hydrolysis of

oxaziridines (8), synthesis of (I) serves as a test of the

generality and practicality of synthesizing N-substituted

hydroxylamines from oxaziridines.

A wide variety of oxaziridines have been prepared by

oxidation of imines with peracetic acid (7,16,19) and with

m-chloroperbenzoic acid (26) to form the oxaziridines (II)

directly. m-Chloroperbenzoic acid is especially applicable

£§-O-O-H 0 __

R-C=N-R" » R-C-N-R" R"= -CH 3 or -<£))

R R' CI

H

for the synthesis of oxaziridines which are easily hydrolyzed

by the acidic conditions of the reaction because the

m-chlorobanzoic acid produced precipitates from the reaction

mixture. Oxaziridines can also be prepared from imines

using 90 per cent hydrogen peroxide (14) to form an a-hydro-

peroxide (III) which is then refluxed in an inert solvent

such as benzene to form the oxaziridine.

R-C=N-R* — H S ° 2 — » R-C-N-R" R' R' &

HI

__ - H 20 A * m s » R-C-N-R

k

Oxaziridines have been produced through ultraviolet

irradiation of nitrones (IV) (32), and by the action of

9.. h V ?- . R-C=N-R » R-C-N-R R' R'

Q

4

hydroxylamine-O-sulfonic acids or chloramine on aldehydes or

ketones in alkaline solution (29,30). The latter preparatory

0 OH* p

R-C-R + H-N-OSOoH > R-C-N-R* L'< A' R R

method has been extended to acylation of the unsubstituted

oxaziridine in situ with acid chlorides and isocyanates to

give 2-acyloxaziridines (30).

Ozonization of olefins (19) in the presence of primary

amines at -20° in carbon tetrachloride forms a-hydroperoxy-

amines that lose water to yield the corresponding oxaziridine,

0, / R-NHP 0-0-H ^ O b ̂ i if

R-CZCC > R-C-N-R I l < i

R' R H

OO-H -HoO 0

R-C-N-R » R-C-N-R

R H

Although numerous methods of preparing N-substituted

hydroxylamines have been reported, the literature reveals

5 .

no general synthetic route. Various reduction methods have

been developed, such as the following:

1. Treatment with water of the reduction products of zinc alkyls or zinc or magnesium alkyl halides on alkyl nitrites, nitro-paraffins (2,3), and diphenyl nitrosoamines (21).

2. Catalytic reduction of aromatic nitro compounds (5).

3. Catalytic hydrogenation of aliphatic and alicyclic ketoximes to produce the corresponding N-mono-substituted hydroxylamines (34,37,39).

4. Reduction of aromatic nitro compounds with zinc dust and ammonium chloride (25).

5. Electrolytic reduction (2$) of primary and secondary nitroalkanes (27,22).

6. Reduction of alkyl and aryl aldoximes to yield N,N-disubstituted hydroxylamines (3&).

7. Diborane reduction of oximes (11) and nitro salts (10)

8. Action of nitric oxide on magnesium alkyl iodides in ether solution, followed by reduction (40).

9. Oxidation of dialkylamines to produce N,N-dialkyl-hydroxylamines (24,23).

Since acid hydrolysis of an oxaziridine appeared to be

a suitable synthetic route to N-substituted hydroxylamines,

two appropriate oxaziridines, 3>3'-di(pentamethylene)-2,2'-

ethylenedioxaziridine (7) and 3,3,-di(p-tolyl)-2,2t-

ethylenedioxaziridine (VI) were prepared by a modified

method of Krimm (20).

CH3^^-A-CH 2CH z-N-C-^>-CH

¥1

For the synthesis of (V), N,NT-bis(cyclohexylidene)-

ethylenediamine was first formed at 0° to 5° by condensing

in ether solution stoichiometric amounts of ethylenediamine

and cyclohexanone in the presence of calcium carbonate.

The imine was then oxidized at -20° to -10° with essen-

tially anhydrous peracetic acid to form the oxaziridine (V).

Preparation of (VI) differed from that of (V) only in

that the appropriate imine, N,Nf-bis(p-methylbenzylidene)-

ethylenediamine (12), was oxidized at room temperature to

form the corresponding oxaziridine.

Synthesis of (V) was attempted using 90 per cent hy-

drogen peroxide to oxidize the imine, followed by refluxing

in benzene. However, the ̂ -hydroperoxide did not appear to

be very stable, and refluxing it in benzene produced no

oxaziridine. Since this method did not initially prove

fruitful, no attempt was made to prepare (VI) in this

manner.

7

Using a modification of Emmon's method (9), the oxaziridines

were hydrolyzed by-methanolic sulfuric acid to N,Nf-dihydroxyl-

ethylenediammonium sulfate (VII).

0 ^ 2 HjCT +

R-C-N-CHOCHO'N-C-R • RHO-N-CHoCHiN-OHl sol R' R ' $0% " 2

/ l #—\

R-R' =» (CH^s or R = - C O > C H 3 r'= H

CHAPTER BIBLIOGRAPHY

1. Bauer, L., and K. S. Suresh, J. Org. Chem., 28, 1604 (1963)

2. Bewad, J., Chem, Ber., 40, 3065 (1907).

3. Bewand, I., J. Prakt. Chem., 2 , 94, 193 (1901).

4. Bovet, D., R: Horclois, and F. Walthert, Compt. Rend. Soc. Biol., 13 99 (1944); Alfred Burger, Ed., "Medicinal Chemistry," 2nd ed, Interscience Publishers Ltd., London, I960, p. 526.

5. Brand, K., and J. Steiner, Chem. Ber. , 55JB? $75-8$7 (1922).

6. Burger, Alfred, Ed., "Medicinal Chemistry," 2nd ed,

Interscience Publishers Ltd., London, I960, p. 526.

7. Emmons, W. D., J. Am. Chem. Soc., 7$, 6208 (1956).

8. Emmons, W. D., ibid., 79, 5741 (1957).

9. Emmons, W. D., ibid., 79, 5750 (1957). 10. Feuer, H.', B. F. Vincent, Jr., and R. S. Anderson, J. Org.

Chem., 30, 2880 (1965). —

11. Feuer, H., B. R. Vincent, Jr., and R. S. Bartlett, ibid., 30, '2887 (1965).

12. Frost, A. E., and H. H. Freedman, ibid., 24, 1905 (1959).

13. Halpern, B. N., and F. Walthert, Compt. Rend. Soc. Biol., l̂ j?, 402 (1945); Alfred Burger, Ed., "Medicinal Chem-istry," 2nd ed, Interscience Publishers Ltd., London, I960, p. 526.

14. Hoft, E., and A. Rieche, Angew. Chem. Internat. Edit., 4 (6), 524 (1965). r v

15. Horclois, R. J., U. S. Pat. 2,502,151 (1950).

16. Horner, L., and E. Jurgens, Chem. Ber., 90 2184 (1957).

8

17. Hurd, C. D., and H. J. Brownstein, J. Am. Chem. Soc., 47, 67 (1925). ^

Id. Hutter, C. P., C. Djerassi, W. L. Beears, R. L. Mayer, and C. R. Scholz, ibid., 63, 1999 (1946).

— ffs*J '

19. Krimm, H., Chem. Ber., 91, 1057-1068 (1953).

•20. Krimm, H., ibid., 91, 1065 (1953). — , , ,,

21. Lachman, A., ibid., 33, 1022 (1900).

22. Leeds, M. W., and G. B. L. Smith, J. Electrochem. Soc.,

93, 129 (1951).

23. List, H., U. S. Patent 2,795,611 (1957).

24. "Mamlock. L., and R. Wolffenstein, Chem. Ber., 34, 2499 (1901). ~

25. Marvel, C. S., and 0. Kamm, J. Am. Chem. Soc., 41, 277

(1919). ^

26. Pews, R. G., J. Org. Chem., 32, 1623 (1967).

27. Pierron, P., Bull. Soc. Chim Fr., 21, 730 (1399). 23. Richter, V., "Organic Chemistry," P. Blankiston's Sons

& Co., Philadelphia (1919), p. 171.

29. Schmitz, E., R. Ohme, and S. Schramm, Chem. Ber., '97, 2521-2526 (1964); Chem. Abstr., 61, 13179e (1964).

30. Schmitz, E., R. Ohme, and S. Schramm, - Tetrahedron Lett., 23, 1357-62 (1965); Chem. Abstr., 63, 6933g (1965).

31. Schulz, M., D, Becker, and A. Ricche, Angew. Chem. Internat. Edit., 4 (6), 525-6 (1965).

"1 • " 1 " 1

32. Splitter, J., and M. Calvin, J. Org. Chem., 23, 651 (1953). 1 •' 1

33. Staub, A. M., Ann. Inst. Pasteur, 400, 420, 435 (1939); Alfred Burger, Ed., "Medicinal Chemistry," 2nd ed., Interscience Publishers, Ltd., London, I960, p. 254-

34* Vavon, G., and P. Anziani, Bull. Soc. Chim., 41, 1642 (1927). ~

,35. Vavon, G., and A. L. Berton, ibid., 37,'301 (1925).

10

36. Vavon, G., and A. Callier, ibid., 41, 361, 674 (1927).

37* Vavon, G., and J. Flurer, ibid., 45, 756 (1929). fmsa . .

3$. ,Vavon, G., and Krajoinovic, ibid., 43, 231 (192$).

39. Vavon, G., and V. M. Mitchovitch, ibid., 41, 964 (1927)

40. Wieland, H., Chem. Ber., 36, 2315 (1903).

CHAPTER II

EXPERIMENTAL PROCEDURE

N, N'-Bis(cyclohexylidene)ethylenediamine

The following reaction was carried out in a 500-ml,

2-necked, round-bottomed flask fitted with a thermometer

and stirrer. A solution'of 16.7 ml (0.25 mole) of freshly

distilled ethylenediamine in 50 ml of ether was dropped into

a stirred mixture of 51.7 ml (0.50 mole) of cyclohexanone,

100 ml of ether, and 35 g of anhydrous calcium carbonate.

The rate of addition was adjusted to maintain the temperature

between 0° and 5°»

The reaction was allowed to warm to room temperature and

was stirred for 3 hr. The calcium carbonate was then removed

by filtration. The filtrate was evaporated overnight in a

rotary evaporator.

The clear, yellow, viscous liquid was distilled at re-

duced pressure. The fraction which distilled at 90° to 95°

(0.45 mm) was collected. The product solidified (10$.4 g,

49*4 per cent, mp 143-144°* with decomposition) and slowly

decomposed when allowed to stand at room temperature.

*A11 melting point determinations were made with a calibrated Thomas-Hoover Capillary Melting Point Apparatus.

11

12

Decomposition was rapid when redistillation was attempted.

The imine showed a characteristic C=N band at 1660 cm""'".

Peracetic Acid

A 125-ml flask was charged with 25 ml of ether and one

drop of sulfuric acid. The solution was cooled in an ice

bath, and 5-05 ml (0.165 mole) of 90 per cent hydrogen

peroxide was added dropwise. Twenty-one ml (0.19 mole) of

acetic anhydride were dropped into the ice-cold, rapidly

stirred hydrogen peroxide solution at a rate of about one

drop per second. The mixture was stirred 15 min in the ice

bath and 1 hr at room temperature.

Note: 1. Too rapid an addition of acetic anydride produces delayed splashing.

2. Plastic gloves, apron, and eye protection should be worn at all times. Reactions should routinely be conducted behind a protective shield.

3,3*-Di(pentamethylene)-2,2'-ethylenedioxaziridine

Trial 1 '

A 125-ml, 1-necked flask in an ice bath was charged with

13.0 g (0.060 mole) N,N?-bis(cyclohexylidene)ethylenediamine

and 75 ml ether. The solution was cooled, and 1.70 ml (0.0625

mole) 90 per cent hydrogen peroxide was stirred into the mix-

ture. The while solid that formed immediately was filtered

from the reaction mixture.

13

The product yellowed after exposure to air for a few

minutes. Attempts to recystallize the product from chloro-

form were unsuccessful.

Attempts to convert the supposed bis-hydroperoxide to

the corresponding dioxaziridine by refluxing in benzene also

resulted in no usable product.

• Trial 2

The following reaction was conducted in a 500-ml,

3-necked, round-bottomed flask fitted with a thermometer

and dropping funnel. The reaction flask was partially

submerged in an acetone-dry ice bath. (Prior cooling of

reactants and solvents allowed the reaction to be conducted

more rapidly.)

A peracetic acid solution containing about 0.6 mole

peracid was dropped into a cooled solution of 66.0 g (0.30

mole) N,NT-bis(cyclohexylidene)ethylenediamine. The peracetic

acid additon was regulated so that the temperature of the

stirred solution remained between -20° and -10°. Part of the

reaction mixture froze, and manual stirring was required to

maintain efficient mixing.

Soon after the peracid addition began, an off-white solid

formed which later became a viscous liquid. This white solid

contained active oxygen, as was shown by the formation of *

iodine when potassium iodide was added to a glacial acetic

acid suspension of the solid. When a sample of the crude

14

product was removed from the reaction medium and left at

room temperature, it decomposed into a brown substance.

The dry ice was allowed to sublime, and the reaction

mixture was left at room temperature over night. By morning

the entire product had decomposed. It did not contain active

oxygen and did not have a characteristic infrared spectrum

for an oxaziridine.

Trial 2

The apparatus used in this trial was the same as that

used in Trial 2. An ethereal solution containing essentially

1.1 mole peracetic acid in 25 ml ether was dropped into a

cooled, stirred solution of 110 g (0.50 mole) N,Nr-bis(cyclo-

hexylidene)ethylenediamine. The reaction mixture was kept

below -10° with an acetope-dry ice bath.

Again, a white solid was formed that contained active

oxygen. The reaction mixture was left in a freezer (-30°)

over night.

The white solid was filtered and washed with dilute

aqueous sodium carbonate and dilute aqueous sodium sulfate

solutions and finally with cold ether. The white crystal-

line product melted at 103°. After recrystallization the

flat white crystals (31.1 g> 2&.1+ per cent) melted 105-106°

(lit. (3), mp 106-107°).

15

Evaporation'of the ethereal filtrates produced an addi-

tional 2.0 g of product (mp 102-103°). The total yield was

30.0 per cent.

The oxaziridine was soluble in hot methanol and precip-

itated from solution at room temperature. At room temperature

it was soluble in ethanol, very soluble in dichloromethane,

and insoluble in' 10 per cent sulfuric acid and in glacial

acetic acid.

Subsequent trials showed that decomposition produced a

yellowed product when the reaction temperature was allowed to

rise to about -3°. This product may have been due to acid

hydrolysis of the oxaziridine.

During one preparation of 3>3,-di(penta^lethylene)-2,2,-

ethylenedioxaziridine, the ether in the filtrate from the

filtration of the solid product was removed on a rotary

evaporator. The resulting solution, open to the air, was

set aside. Within a few minutes the viscous, yellow solu-

tion exploded, producing a black liquid.

It is interesting to note that when the combined sodium

sulfate and sodium carbonate washings were heated on a steam

bath, the solution turned from orange to green. The solu-

tion returned to its original color when left at room

temperature overnight.

16

Trial

The apparatus used was the same as that in Trial 2,

except that.a 1-liter, rather than a 500-ml, flask was

employed.

A cooled solution of 27.5 g (0.125 mole) of unpurified

NjN'-bislcyclohexylideneJethylenediamine in 100 ml ether was

poured into the filtrate from a previous preparation of the

oxaziridine. The filtrate contained about 0.35 mole each of

peracetic acid and I^N'-bisCcyclohexylideneJethylenediamine

and 200 ml ether.

A solution of about 0.50 mole peracetic acid in 100 ml

ether was dropped into the stirred imine solution at such a

rate that the temperature remained below -20°. The reaction

mixture, which contained a fine, white solid, was left at

-30° overnight.

The product was filtered and washed with dilute sodium

sulfate and sodium carbonate solutions. The white product

(61.7 g> 51.6 per cent) contained active oxygen and melted

at 104 -106°.

Anal. Calc. for C-^H^NgOg: C, 66.63; H, 9.57; N, 11.10.

Found: C, 66.6; H, 10.92; N, 11.09. The ir spectrum showed

a characteristic oxaziridine band (1) at 1190 cm"1 and lacked

the C=N band at 1660 cm"1. The nmr spectrum (CDCl^) showed

a quartet at 3.27-3.21 (ethylene protons), a multiplet at

1*92 (_-methylene protons on cyclohexyl rings), and a multiplet

17

at 1.71 (other methylene protons on cyclohexyl rings). The

peak area ratio was 4:&:12.

N,N'-Bis(p-methylbenzylidene)ethylenediamine

A 500-ml, 1-necked, round-bottomed flask was charged

with 59.0 ml (0.50 mole) p-tolualdehyde and 50 ml ether. A

solution of 16.7 ml (0.25 mole) ethylenediamine in 50 ml

ether was dropped into the stirred aldehyde solution at room

temperature. Because the exothermic reaction evaporated most

of the ether, 50 ml of ether were added when the addition was

complete.

The reaction mixture was filtered and washed with cold

ether. The white solid (59-6 g, 100 per cent) melted at

153-154° (lit. (2), 153-160°).

Anal. Calc. for C^H^Ng: G, Sl.g; H, 7-6; N, 10.6.

Found: 0,30.6; H, 7-57; N, 10.4- The ir spectrum showed

a characteristic C=N band at 1635 cm--1-. The nmr spectrum

(CDCl^) showed a quartet at 7.72-7.14 (phenyl ring protons)

and multiplets at 3.9$ (ethylene protons), 2.39 (methyl

protons), and 1.80 (imine carbon protons). The peak area

ratios were 4*2:3:1.

3,3'-di(p-tolyl)-2,2rethylenedioxaziridine

The following reaction was performed in a 1-liter,

2-necked, round-bottomed flask fitted with a thermometer,

dropping funnel, and magnetic stirrer. A 0.20 mole solution

of peracetic acid was dropped at a rate of about 2 drops per

id

second into a suspension of 23.8 g (0.10 mole) N,NT-bis-

(p-methylbenzylidene)ethylenediamine in 300 ml ether pre-

viously cooled to -30°. The reaction mixture was stirred

at room temperature for 3•5 hr, then left at -30° overnight.

The white solid was filtered and then washed with dilute

sodium sulfate and sodium carbonate solutions. The product

(10.63 g, 39.4 per cent) melted at 119-120° and contained

active oxygen.

Anal. Calc. for C^H^NgOg: C, 71.17; H, 6.72; N, 10.3d.

Found: C, 73.5; H, 6.75; N, 9.4$. The ir spectrum lacked

the characteristic imine band at 1635 cm--'- and showed the

* 1

oxaziridine band at 1166 cm" . The nmr spectrum showed mul-

tiplets at 7.27 (phenyl protons), 4^62 (oxaziridine carbon

protons), 3*25 (ethylene protons), and 2 . 3 6 (methyl protons).

The peak area ratios were 4:1:2:3.

N,N1-Dihydroxyethylenediammonium sulfate

Trial 1

The following reaction was conducted in a 125-ml, 1-necked

distillation flask. An ethereal solution of 1.60 g (0.00625'

mole) 3>3,-(dipentamethylene)-2,2'-ethylenedioxaziridine was

dropped into an ice-cold, stirred mixture of 0.60 ml water,

6.25 ml methanol, and 0.40 ml concentrated sulfuric acid

(specific gravity, 1.S3).

The ice was allowed to melt, and the stirring was con-

tinued overnight at room temperature. An off-white solid which

19

contained active oxygen, indicating it was unreacted oxa-

ziridine, was filtered from the reddish-brown liquid. The

filtrate was diluted with 50 ml water and extracted with five

20-ml portions of ether. The combined ether extractions were

dried over magnesium sulfate. The ether layer contained

cyclohexanone (2,4-dinitrophenylhydrazone, mp 160°; lit.,

mp 162°).

The aqueous acid portion was partially dried by remaining

in a closed system while in the presence of concentrated sul-

furic acid.

No precipitate formed when 5 N soidium hydroxide solution

was used to neutralize the aqueous acid portion. The aqueous

solution was then extracted with chloroform, and the chloro-

form extractions were dried over magnesium sulfate.

An infrared spectrum of the chloroform solution, using

matched cells with the solvent as reference solution, lacked

sufficient resolution to show any product of interest.

Trial 2

One-hundred-fifty ml of ethanol, 2.52 ml (0.14 mole)

water, and 7.4$ nil (0.14 mole) concentrated sulfuric acid

(specific gravity, 1.83) were placed in a 500-ml, 1-necked

flask fitted with a dropping funnel. A solution of 17.6 g

(0.07 mole) 3,3'-di(pentamethylene)-2,2t-ethylenedioxaziridine

in 100 ml dichloromethane was dropped at a rate of about

20

2 drops per second into the rapidly stirred, ice-cold

alcohol—water—acid mixture.

The ice was allowed to melt after the addition was com-

pleted and stirring continued until a sample of the reaction

mixture no longer contained active oxygen.

The dark reddish-brown liquid was decanted from the

similarly colored, very thick oil that had formed. The oil

was cooled and triturated with ether until it solidified.

Water was carefully added to the solid until the discoloring

material dissolved, leaving a white solid, which was removed

by filtration. The white product (6.&5 g, 51.5 per cent) was

also soluble in water and melted at 110-113° (with decompo-

sition) .

Anal. Calc. for CgH^NgOg: G, 12.64; H, 5-31; N, 14-75.

Found: C, 12.2; H, 6.97; N, 14.26.

Trial 2

The same apparatus was used for Trial 3 as for Trial 2.

A solution of 7.11 g (0.0264 mole) 3>3'-di(p-methyl-

benzylidene)ethylene -2,2'-ethylenedioxaziridine in 100 ml

dichloromethane was dropped into a cold, stirred solution of

0.95 ml (0.053 mole) water, 2.33 ml (0.053 mole) concentrated

sulfuric acid (specific gravity, 1.83), and 150 ml ethanol.

The reaction mixture was stirred overnight at room temperature,

The white solid that formed was filtered from the reac-

tion mixture. The water-soluble product (3«70 g, 74 per cent)

melted at 102-103°.

21

Anal. Calc. for C2H10N202: C, 12.64; H, 5.31; N, 14-75.

Found: C, 12.33; H, 5.39; N, 15.3$. The ir spectrum showed

bands at 3390 cm-1 (OH and NH), 1350-1110 cm"1, 1350-110 cm-1

(OH and SO^"), cm"1 (NH), and 756 cm""1 (NH). The

presence of sulfur was indicated using a sodium fusion test.

CHAPTER BIBLIOGRAPHY

1. Chakravarty, J., submitted for publication in Can. J. Chem.

2. Frost, A. E.j and H. H. Freedman, J. Org. Chem., 24, , 1905 (1959).

3. Krimm, H., Chem. Ber., 91, 1065 (1953).

22

CHAPTER III

DISCUSSION

NjN'-dihydroxyethylenediammonium sulfate was found to

be more easily prepared from 3>3,-•di(p~tolyl)-2,2,-

ethylenedioxaziridine than from 3,3,-di(pentamethylene)-

2 , 2 ' -ethylenedioxaziridine. One reason for this is that

the latter oxaziridine and its corresponding imine are much

more readily prepared. The imine was a solid that could be

easily synthesized in quantitative yields. It is readily

purified from ethanol and has the stability expected of a

Schiff base. The oxaziridine was produced in 40 per cent

yield at room temperature without darkening of the product.

In contrast, N,N'-bis(cyclohexylidene)ethylenediamine

was not produced quantitatively. Because of its instability,

it could not be satisfactorily purified or analyzed (ather

than infrared analysis). Synthesis of 3,3,-di(pentamethylene)'

2,2f-ethylenedioxaziridine required very low temperatures

and careful procedures to prevent decomposition. Generally

the yields were 20 to 30 per cent.

Krimm's method for preparing 3,3,-di(pentamethylene)-

2,2'-ethylenedioxaziridine had to be modified. Allowing the •

reaction mixture to be stirred at room temperature produced

23

24

total decomposition. It was found that the temperature of

the reaction mixture must remain below -3° to prevent exces-

sive decomposition. Also, the product was washed with dilute

sodium sulfate and dilute sodium carbonate solutions to remove

any remaining peracetic acid.

Although Krimm reported a 39 per cent yield, this was

not obtained in any trial using his method. A 51.6 per cent

yield was obtained when the filtrate from a previous trial

was used in a subsequent trial.

In the acid hydrolysis of 3,3'-di(p-tolyl)-2,2'-ethylene~

dioxaziridine to form N,N'-dihydroxylethylenediammonium sulfate,

a 74 per cent yield was obtained as a white solid directly

from the reaction mixture. In contrast, acid hydrolysis of

3,3'-di(pentamethylene)-2,2'-ethylenedioxaziridine produced

51.5 per cent of the hydroxylamine salt as a brown solid..

The white product was obtained by carefully dissolving the

discoloring material in water. .

The N-substituted hydroxylamine sulfate was prepared

using a modification of Emmons' method. Emmons used a large

excess of water during the hydrolysis and subsequent extrac-

tion of the hydroxylamine salt. Only when a stoichiometric

amount of water was used in the acid hydrolysis of 3,3'-

di(pentamethylene)-2,2'-ethylenedioxaziridine> could the

N-substituted hydroxylamine salt be recovered. Also, de-

pending upon which oxaziridine was used, when no excess

25

water was used, a 51.5 per cent to 74 per cent yield of the

product precipitated from the reaction mixture, eliminating

the necessity of extraction procedures other than to improve

the yield.

It should be mentioned again that an explosion occurred

during the preparation of 3>3'-di(pentamethylene)-2,2'-

ethylenedioxaziridine and that explosions in connection with

oxaziridines have been reported in the literature. Reactions

involving oxaziridines should be routinely carried out behind

a protective shield. Plastic gloves and an apron and pro-

tective goggles should be worn at all times while working

with 90 per cent hydrogen peroxide, peracetic acid, and

oxaziridines.

This work substantiated that acid hydrolysis of oxaziri-

dines is a satisfactory and general method of preparing N-

substituted hydroxylamines. It should be noted that the

oxaziridine employed should be selected with care, since *

the per cent yield and the ease of conversion to N-substituted

hydroxylamine and its initial purity apparently depend upon

the oxaziridine hydrolyzed.

CHAPTER BIBLIOGRAPHY

1. Chakravarty,• J . , submitted for publication in Can. J. Chem. ;

26

BIBLIOGRAPHY

Books

Burger, Alfred, Ed., "Medicinal Chemistry," 2nd ed, Inter-science Publishers Ltd., London, I960, p. 526.

Richter, V., "Organic Chemistry," P. B^ankiston's Sons & Co., Philadelphia (1919), p. 171.

Articles

Bauer, L., and K. S. Suresh, J. Org. Chem., 28, 1604 (1963).

Bewad, J., Chem. Ber., 40, 3065 (1907).

Pewand, I., J. Prakt. Chem., 63 2 , 94)-, 193 (1901).

Bovet, D., R. Horclois, and F. Walthert, Compt. Rend. Soc. ar, Ed. , "Medic: iblishers Ltd.,

j y U • J i t • n U X U X U l b j d l i U . a • VVdJL w l l t i l O | U i l i [ J Kj

Biol., 99 (1944); Alfred Burger, Ed., "Medicinal Chemistry," 2nd. ed, Interscience Publishe: London, I960, p. 526.

Brand, K., and J. Steiner, Chem. Ber., 875-887 (1922).

Chakravarty, J., submitted for publication in Can. J. Chem.

Emmons, W. D., J. Am. Chem. Soc., 78, 6208 (1956).

Emmons, W. D., ibid., 79, 5741 (1957). '

Emmons, W. D., ibid., 79, 5750,(1957).

Feuer,- H., B. F. Vincent, Jr., and R. S, Anderson, J. Org. : Chem., 30, 2880 (1965).

Feuer, H., B. R. Vincent, Jr., guid R. S, Bartlett, ibid. ,'30, 2887 (1965). ' ^

Frost, A. E,, and H. H. Freedman, ibid., 24, 1905 (1959). * / W

27

28

Halpern, B. N.. and F. Walthert, Compt,'Rend. Soc. Biol., 139, 402 (l945); Alfred Burger, Ed., "Medicinal Chem-istry," 2nd ed, Interscience Publishers Ltd., London, I960, p. 526.

Hoft,E., and' A. Rieche, Angew, Chem. Internat. Edit., 4 (6), 524 (1965).

Horclois, R. J«, U. S. Pat. 2,502,151 (1950).

Horner, L., and E. Jurgens, Chem. Ber., 90, 2184 (1957).

Hurd, C. D., and H. J. Brownstein, J. Am. Chem. Soc., 47, 67 (1925).

Hutter, C. P., C. Djerassi, W, L. Beears, R. Mayer, and C. R. Scholz, ibid., 68, 1999 (1946)*

Krimm, H. , Chem. Ber., 91, 1057,"1068 (J958).

Krimm, H., ibid., 91, 1065 (1958).

Lachman, A., ibid., 33, 1022 (1900).

Leeds, M. and G. B. L. Smith, J. Electrochem. Soc., 98, 129 (1951).

List, H., U. S. Patent 2,795,611 (1957).

Mamlock, L. , and R. Wolffenst&in, Chem^ Ber., 3/̂ , 2499 (1901)

Marvel, C. S., and 0. Kamm, Jt';Am. Chenu Soc., 41, 277 (1919)

Pews, R. G. , J. Org. Chem., 32| 162$ (^967).

fierron, P., Bull. Soc. Chim. ̂Fr., 21,,780 (1899).

Schmitz, E., R. Ohme, and S. Schramm, Qhem. Ber., 97, 2521-2526 (1964); Chem. Abstr., 61, 13l79e. (1964).

Schmitz-, E., R. Ohme, and S. Schramm, Tetrahedron Lett., 2^, 1857-62 (1965); Chem. Abstr., 6^, 6983g U9&5).

Schulz, M., D. Becker, and A. Ricche, Anpew. Chem. Internat. Edit., 4 (6), 525-6 (1965). "" ^ f

Splitter, J . , and M. Calvin, Jt Org. Chep., 23, 651 (1958).

29

Staub, A. M., Ann. Inst. Pasteur, 6j, 400, 420, 4^5 (1939); Alfred Burger, Ed., "Medicinal Chemistry," 2nd ed, Interscience Publishers Ltd., London, 19o0, p. 524.

Vavon, G., and P. Anziani, Bull. Soc. Chim., ̂ 1, 1642 (1927)

Vavon, G., and A. L. Berton, ibid., 2J> 301 (1925).

Vavon, G., and A. Callier, ibid., ̂ 1, 361, 674 (1927).

Vavon, G., and J. Flurer, ibid., 45> 756 (1929).

Vavon, G., and Kra.ioinovic, ibid., 43, 231 (192S).

Vavon, G., and V. M. Mitchovitch, ibid,, 41, 964 (1927).

Wieland, H., Chem. Ber., 36, 2315 (1903|.