Derivatives of Alpha, Alpha-Dimethyl-Beta-Phenethylamine

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PURDUE UNIVERSITY

THIS IS TO CERTIFY THAT THE THESIS PREPARED UNDER MY SUPERVISION

5Z______ fcerard 0. Platan entitled

________

Derivatives of alpha,

— ----- ----

alpha—Dimethffl-beta*»

________phenethylamine.__________________________ COMPLIES WITH THE UNIVERSITY REGULATIONS ON GRADUATION THESES

AND IS APPROVED BY ME AS FULFILLING THIS PART OF THE REQUIREMENTS

FOR THE DEGREE OF

Doctor

1 obotdIiv

of

P

r o f e s s o r in

Charge

of

T h e s is

4 H

3 /

TO

19

ead o f

S

chool, o r

D epartm ent

J

THE LIBRARIAN:------

is vxo'tr THIS THESIS IS NOT TO BE REGARDED AS CONFIDENTIAL.

PROFESS OB

GRAD. SCHOOL FORM 0—3 - 4 9 —1M

rsr

CHARGE

DERIVATIVES OF ALPHA, ALPHA-DIMETHÏL-BETA-PHENETHrLAllINE A Thesis Submitted to the Faculty of Purdue University by Gerard 0. Flatau In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy June, 1950

ProQuest Number: 27714145

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ACKNOWLEDGMENT

This work was begun under Dr. H. B. Hass; but the major portion of this work was directed by Dr. G. B. Bachman to whom the author is indebted for many helpful suggestions and for stimulating enthusiasm given during the course of the research. The author wishes to acknowledge assistance received from Abbott Research Laboratories and the Purdue Research Foundation which made this investigation possible.

TABIE OF GOSTENTS Page A B S T R A C T ..................................................

i

INTRODUCTION..............................................

1

D I S C U S S I O N ..............................................

.

7

EXPERIMENTAL................................................ 2? Preparation of

...........

p-Nitro b enzy 1Chloride

Preparation of 2,U-DinitrobenzylChloride

. . . . . . . . .

Preparation of o-Nitrob enzyl Chloride Action of Chlorine on o—Nitrotoluene

27 27

......... ....

.....

28

Action of Sodium Hypochlorite on ^-Nitrotoluene • » • • •

28

Oxidation of o-Nitroto luene to o-Nitroben zaldehyde

29

...

Reduction of o-Nitrobenzaldehyde to o-Nitrobenzyl Alcohol . . . . . . . . . . . . . . . . . . . . . .

30

Conversion of o-Nit robenzyl Alcohol to o-Nitrob enzyl Chloride . . . . .. .. ... . . . . . .

30

Formation of Anthranilic Acid in an Attempted Brominatinn of o-Nitroto luene . . . . . . . . . . . . .

. 31

Preparation of 1-(g-Nitrophe nyl)-2—methyl-2nitropropane . . . . . . . . . . . . . . . . . . . . . . .

32

Preparation of 1-(2*,U 1—Dinitropheny^-2-methyl-2nitropropane . . . . .

32

Preparation of 1-( o-Nitrophenyl )-2-methyl-2nitropropane.........

33

Preparation of 1—(g-iAniinophenyl )-2-methy1-2propyl amine Hydrochloride . . . . . . . . . . . . . . .

3U

Preparation of l-( o-Aminophenyl )-2-methyl- 2......... propylardne Hydrochloride

35

Preparation of 1-( p-Aminophenyl )-2-methyl-2nitropropane.........

36

Page Preparation of 1—(2 1,L*-Diamincphenyl )—2-me thyl- 2propylamLne Tril^drochl oidude.........................

37

Preparation of l-(2 1-Nitro-U1-aminophenyl)-2iaethyl-2-nitropropane ................. . Selective Reduction .

...................

38

Proof of Structure by Deamination.............

. .

38

Preparation of l-(Chlorophenyl)-2-methyl-2-propylamine ............... . 39 hydrochloride . . . . . Preparation of 1- (o-Chlorophenyl )-2— metlryl- 2propylamine hydrochloride . . . . . . . . . . . .

UO

Preparation of l-(]>-Hydroxyphenyl)-2-methyl-2— ................... propylamine Hydrochloride

IpL

Preparation of l-t^-Methoxyphenyl)-2-methyl-2proiylamine hydrochloride . . . . . ..........

1*2

Preparation of l-( 2 ^Nitro-U^hydroxyphenyl)-2methy1- 2 -nitropropane . . . . . .. . . . . ........... 1*3 Preparation of l-( 2 1-Amino-U1-hyclrcccyphenyl )-2methyl-2-propylamine Dihydr och loride ........... • • •

1*1*

Attempted preparation of 1 -(£-Fluorophenyl )-2methy1- 2- propylandn e ........... Action of KLuoboric A c i d ...... • • • • ............. 1*5 Action of Anhydrous hydrofluoric A c i d .............. 1*6 Preparation of Ch-Nitrobenzyl Bromide...............

1*7

Reaction of o-Hitrobenzyl Bromide and the Sodium Salt of 2-Witropr opane . . . . . . . . . . . . .

1*8

....

SUMMARY.................................................... U9 BIBLIOGRAPHY.............................................. $Q V I T A ....................................................

LIST OF FI GORES Figure I II

III

Page Reactions of Nitrobenzyl Chlorides and the Sodium Salt of 2-Nitropropane.......................

•

Reduction of l-(o- or ]>-Nitrophenyl )-2-methyl- 2— nitropropane and of 1- (2 *,U 1-Dinitro phenyl )-2iaethyl-2-nitropropane ......... Selective Diazotizations of l-(o- and £- Amino— phe ryl )- 2 -met hyl- 2-pro pylamine ..........

U

5 5 8

IV and V

Synthesis of a Series of Derivatives of alpha, alpha-Dimetbyl-beta-phenethylamine and oftheir Intermediates ...... . . . . . . . . . .

VI

Preparation of o-Nitrobenzyl Chloride from 0-Nitrotoluene by Oxidation, Reduction and Chlorination .............................

11

Preparation and Proof of Structure of 1-( 2 *-Nitro-IV - aminophenyl )-2-methyl-2nitropropane.........

17

Preparation of l-(o- and p-Chloro phenyl )-2me thyl- 2-propylamine..........................

19

Preparation of 1~(£~hYdroxyphenyl)-2-methyl-2propylamine .............

20

Preparation of 1-(jo-Methoxyphenyl )-2-methyl-2....................... propylanriLne

21

Preparation of l-( 2 *-Nitro-U1-hydr oxyphenyl )2-methyl— 2—nitropropane and reduction of the product to the corresponding diamine• • • • • • .

23

VII

VIII IX X XI

9

LISTS OF TABLES AND GRAPHS last of Tables I II

New Intermediates Isolated in the Investigation

Page ..21*

Derivatives of alpha, alpha-Dimethyl—betaphenethylaznine Hydrochloride .........

26

List of Graphs I

Selective Reduction of 1 - (p-Nitro phenyl )- 2metly1 -2-nitropr opane . . . . . . . . . . . . .

16

(Contribution from the Purdue Research Foundation and the Department of Chemistry of Purdue University)

DERIVATIVES OF ALPHA, ALPIiA-DIMETHYL-BETA-PHENETHYIAIlINE^*

(1)

An abstract of a thesis by Gerard 0* Platan, submitted to the Faculty of PuÈdue University in partial fulfillment of the requirements for the degree of Doctor of Philosophy, June, 1950.

By G. Bryant Bachman, H e m y B. Hass**, and Gerard 0. Flatau^

(2)

Present address: N.Y.

General Ainiline and Film Corp., New York,

(3)

Abbott Laboratories Research Fellow, 19U8-50.

AN ABSTRACT Derivatives of beta-phenethylamine with the amino group on a tertiary alkyl carbon have received little attention.

They

are especially interesting since they should strongly resist the enzymatic deamination reaction shown to limit the duration of sympathomimetic activity.

They cannot be deaminated by living

organisms in the usual manner, that is, by oxidation to the corresponding imine followed by hydrolysis, since there is no tydrogen on the carbon atom to which the amino group is attached. This investigation deals with the synthesis of a series of

il

derivatives of alpha, alpha-dlmetlçrl-beta^-phenetlxylamine -with various substituents in the phenyl ring.

A convenient approach

to their synthesis was suggested by the work of Hass, Berry and in these Laboratories, who investigated the carbon

(U)

Hass, Berry and Bender, This Journal, 71, 2290 (19U9)*

(5)

Bass and Bender, This Journal. 71» 3k82 (19k9).

alkylation of nitro parrafin salts with ortho- and para-nitroben^rl chloride. It was found that reduction of nitrophenyl nitroalkanes, obtained from nitrobenzyl halides and 2—nitropropane, produced aminophenylalkylamines having the desired structure. CH2 C1 gh3

no2 ch3

GHo I * CH. - C - CH-a

GHg — C — CHj m 2

OgN

NO, 2

O Jk?

Hp — Ni

>

nh2

I

3

üi

In this manner l-( o-aminophenyl)-2-meth^l-2-propylajm.ne, l-(£eoninophei^rl)-2-meth5rl-2 -propy*lainine and l-( 2 *,li.1-diaiainepheiyl )2-methcrl-2-propyland.ne vrere prepared by low pressure (5 atm.)

hydrogenation at 100°C. with Raney nickel.

These amines were

concerted to the water soluble hydroc hloride salts for physiological testing purposes.

The para-nitro group in l-( 2f,U'-dinitrophenyl)-

2-methyl- 2-nitropr opane was selectively reduced by ammonium, poly-

sulfide prepared in situ#

The structure of the product was

proven b y deamination to 1 -( o-nitrophenyl )-2-methyl-2-nitrojaropane.

CH2 - G - CHj 0 2N

-K.

no2 ( N % ) 2Sx

Eton no2

OgN

o nh2

gh3 I CHg - C - CH3

XV

The aromatic amino group in the various reduction products was also replaced hy other functional groups after diazotlzatlon. This work was facilitated by the investigations of Kcrrblum and Iffland^ at Purdue University who found that in a sufficiently

(6 ) Korriblum and Iffland, This Journal, 71* 2337 (19li9 )•

acidic medium

(pH = 3 or less) an aryl amino group can be selectively

diazotized and then eliminated b y treatment with hypophosphorous even in the presence of an aliphatic amino group*

We have new

found that in the same fashion an aromatic amino group can b e replaced ty chlorine, hydroxy and methojy groups without affecting the aliphatic amino group, e.g. CH. I ' CHg — C — CH3

H2N

O

CH. I " CH-

hh 2 (1)HC1, NaH02 pH = 3 (2 ) Cu2Cl2

C - CH3 NH2

C1

C - CH

(1) HgSO^, NaW02 ________ p H — 3

(2)

H20

V

In this manner water-soluble hydrochloride salts of l-(o-chloropheEyl)2-methyl- 2-propyl anine , l-( g- chlor opheny])-2-methyl- 2-propyl amine,

1-(£-hydix)xyphenyl )-2-methyl-2-propylamine and l-Cp-methoxyphenyl )2-methyl-2—propylamine were prepared*

l-( 2 *-Nitro-U1-aminophenyl )-2-metty1-2—nitr opropane was converted to l-( 2 1-nitro-U1-lydr oxyphenyl )-2—me thyl-2-nitr opr opane by diazotization and hydrolysis*

The nitro group in the phenyl

ring stabilizes the diazonium salt and consequently slows its decomposition to a considerable degree, thus facilitating its coupling with the phenolic product as soon as any of the latter is formed and producing an azo dye*

This dye formation was

suppressed to some extent by carlying out the hydrolysis in a dilute sulfuric acid solution beneath a layer of xylene*

The

xylene soluble product was isolated and then reduced to l-(2 1amino-U,-ehydroxyphenyl)-2—methyl-2—propylamine; the product was isolated as its water-soluble hydrochloride salt* Table I summarizes all of the final products isolated in this investigation.

Pharmacological Testing* -

According to tests conducted by the

Abbott Research Laboratories, l—(£—aminophenyl)-2—methyl—2—propyl­ amine dihydrochloride showed seme pressor activity* compounds were inactive.

The other

TABLE I

DERIVATIVES OF ALPHA, ALPHA-DTMETHrL-BETA-PHENETHTLAMINE HYDROCHLORIDE

Substituents X T

Yield %

Me Pe

°c.

Analyses, % Nitrogen Calcde Found

H

NH3CI

82

233

11.3

11.5

HH3CI

H

80

315

11.8

12.0

NH3CI

NH3CI

72

211

1U .5

Ht .5

H

Cl

hh

181

6.36

6.16

Cl

H

50

231

6.36

6.U5

OH

H a

33

208

6.93

6.90

OCH3

H

56

162

6.51

6.65

OH

NH3CI

65

18U

9.69 b

9.73

(a)

R e Ward claims the preparation of the corresponding sulfate salt. Doctoral Thesis, Purdue University, 19U 8*

(b)

Calculated for the dihydratee

vil

Acknowledgment.. —

The authors wish to express their appreciation

to the Abbott Research Laboratories and the Purdue Research Foundar» tion for the financial support which made this investigation possible.

vüi

EXPERIMENTAL?

(7)

All melting points are corrected; Galbraith.

-Nitrobenayl Halides.

-

micro analyses by Dr. H.

Although j^nitrobenzyl chloride {33%

yield) and 2 ,U-dinitrobenzy1 chloride {70% yield) are readily available from the nitration of benzyl chloride with mixed acid or fuming nitric and fuming sulfuric acids respectively; the onitrobenzyl chloride, formed at the same time as £~nitrobenzyl chloride when mixed acid is employed, is not isolable from the reaction mixture by practical procedures.

We have investigated

its preparation and that of its brcmo analogue by other methods employing o-nitrotoluene as the starting material with the following results: (a)

Direct chlorination^ at 120-130° for 96 hours with

(8 ) Vanino, “Handbuch der Preparativen Ghemie”, Edwards Bros., Inc., Ann Arbor, Michigan, 19U3* Vol. II, p. It59.

S2 CI2 as catalyst gave low yields (lt.0 % theory). (b)

Chlorination with hypohalite ion in strongly basic

aqueous solution at zero degrees gave no reaction. (c)

Direct bromination at 11*5° under strong illumination

gave anthranilic acid (details in a later publication) ♦

ix

(d)

(9)

Bromination with N-bromosuccinimide^^^ in the presence

Ziegler, Ann», 551, 80 (19U2).

of dibenzoyl peroxide at 78 ° for 12 hours gave a h6% yield. The best procedure found for the preparation of o-nitrobenzyl chloride was:

(a)

oxidation of o-nitrotoluene to o-

nitrobenzal . diacetate with chromium trioxide^-0 (23% yield).

(10) Blatt, “Organic Synthesis’1, John Wiley and Sons, Inc., New York, N.Y., 19Wl, Vol. XXIV, p. 75.

(b)

hydrolysis to the aldehyde with 15 N sulfuric acid {70% yield),

(c)

reduction to o-nitrobenzyl alcohol with Al( i-OC^Hy )^ {90%

yield) and (d)

conversion to the desired halide with P d £ in

CHCI3 at zero degrees (80$ yield).

2-Nitrobenzyl-2-nitropropane s. -

Overall yield 11.6$.

The condensations of nitrobenzyl

chlorides with 2 -nitropropane were carried out by somewhat modifying the procedures of Hass et al^*^.

The yields ($) obtained were the

same as those reported by the latter.

Unfortunately the readily

prepared o-nitrobenzyl bromide gave oxygen-alkylation only and no carbon-alkylation product could be isolated.

X

Preparation of l-(2 *,U 1-Diaminopheiyl )-2 -methy1 - 2-propylamine Trilydro chloride . -

1 - (2 *,U 1-Dinitrophenyl )- 2- methyl- 2-nitropropane^

(3*00 ge, *011 mole), Raney nickel (0.5 g. ) and 60 ml. of ethanol were placed in a glass pressure bottle enclosed in a steam, jacket. The reaction mixture was subjected to hydrogenation at 70 p.s.i. for six hours at 100°C.

The catalyst was filtered from the

mixture, ethanol was removed under reduced pressure, and the residual oil was taken up in ether, treated with tiforit and dried. Addition of anhydrous hydrogen chloride to the ether extract followed by further purification (dissolution in water, addition of base, extraction with ether, and addition of dry hydrogen chloride gas) gave l-(2 1,ij.1-diaminophenyl)-2-methyl-2-propylamine trihydro­ chloride; yield 2.25 g. {72% theory); m.p. 2H°C. (d). Anal. Calcd. for

•3HC1 $ N, Ui.5 . Founds

N, lii.5.

Preparation of l-( 2 1-Nitro-U *aminophenyl )-2-methyl- 2-nitropr opane. (a)

Reduction. -

l-( 2 1,U *-Dinitrophenyl )- 2-methyl-2-nitropro p ane^

(HieO g., 0 .0 5 2 mole), ethanol (8 0 ml.), ammonium chloride (1 9 .6 g., 0 .3 7 2 mole) and U ml. of 28 % ammonium hydroxide were heated to

75°C. While stirring NagS"?!^ (11.2 g., 0.172 mole) and 2 g. of sulfur were added, and the reaction mixture was refluxed for one hour.

The mixture was cooled, filtered and the filtrate was

evaporated to dryness under reduced pressure.

The residue was

dissolved in anhydrous ether and filtered; the ether solution was decolorized by passage through a nine inch Norit column.

The

xi

ether was removed under reduced pressure and the residue was recrystallized from ethanol.

1- (2 T-Nitro-U1- aminophenyl )-2-

methyl-2-nitropropane was obtained; yield lu2 ge (3h% theory); m.p. 97°C. Anal. Calcd. for ci o % 3 % 0U s Cb)

17»57*

Proof of Structure by Deamination. -

Found:

N, 17*62.

l-(2 1-Nitro-U'-aminopheryl)-

2-methyl“ 2-nitropropane (2 .0 g., 0 .0 0 8 mole) was dissolved in 50^

hypophosphorous a d d (2 0 g., 0.15 mole) and 15 ml. of water. Sodium nitrite (0.70 g., 0.010 mole) dissolved in 3 ml. of water was added dropwise with stirring at 5°C.

The solution was placed

in a refrigerator for three hours and then kqpt at room temperature for twenty-four hours.

The suspension was extracted with ether;

the ether extract was washed with 20 $ sodium tydroxide, dried over potassium carbonate, and the ether removed under reduced pressure.

The residue was reerystallized from petroleum ether

(35-37°).

1- (o-Nitropheryl )-2-methy1-2-nitropropane was obtained;

yield 0.9 g* (50$ theory); m.p. 5U°C.; lit. m.p. 51+-55°C.^

Preparation of 1- (]£-Chloropheryl )-2-inethyl-2—propylamine I^ndrochloride . — 1-(^-Aminophenyl)-2-methyl-2-propjrlaniine^ (U.O g., 0.021; mole) was dissolved in 9 ml. of 37 $ hydrochloric acid (0 .1 0 mole) and h0 ml. of water.

Sodium nitrite (2.0 g., 0.030 mole) dissolved in 20 ml.

of water was added dropvd.se with stirring at 5°C.

The cold

diazonium solution was rapidly added at 0°C. to a well-stirred

acidic solution of freshly prepared cuprous chloride (3 * 0 g*, 0*030 mole)*

The cold solution was slowly allowed to reach room

temperature and finally was heated to 60°C*

The suspension was

made somewhat basic and extracted with ether* was treated with Norit and dried*

The ether extract

Addition of anhydrous hydrogen

chloride to the ether extract followed by further purification (dissolution in water, addition of base, extraction with ether, and addition of dry hydrogen chloride gas) gave 1-(£-chloropheryl)-2 metbyl-2-propylamine hydro chloride; yield 2 * 6 g. (50 $ theory); m*p* 231°C* Anal* Calcd* for CinHi)tNCl*ECl:

N, 6 *3 6 . Found:

N, 6*U5.

Preparation of 1-( o-Chloropheuyl)-2-methyl-2-propylamLne iydrochloride♦ This salt was prepared from l-(o-aminophenyl )-2-methyl-2-propylaznine in the same manner as its para isomer* Anal* Calcd* for Cin^i)!NC1*EC1:

Yield

m*p* 181°C*

N, 6 .3 6 . Found:

N, 6.16*

Preparation of 1-(p-Ijydroxyphenyl)-2-methyl-2-propylamine Hydrochloride* 1-(^-Aminopheryl)-2-methyl-2-propylamineU (3*0 g*, 0*018 mole) was dissolved in 350 ml* of water containing ii*l ml* of 96 $ sulfuric acid (0.072 mole)*

Sodium nitrite (1*U g*, 0*020 mole) dissolved

in 20 ml* of water was added dropwise with stirring at 5°C*

The

cold diazonium solution was slowly added below the surface of a well-stirred boiling solution of 3 ml* of 96 $ sulfuric acid in

3CÜi

200 ml. of water*

The reaction mixture was made sli^itly basic

after cooling, and then exactly neutralized with carbon dioxide* The aqueous suspension was repeatedly extracted with ether, the ether extract was treated with Norit and dried*

Addition of

anhydrous hydrogen chloride to the ether extract followed by further purification (dissolution in a neutral aqueous medium, extraction with ether, and addition of dry hydrogen chloride gas) gave 1 - (]>-hydroxyphenyl )-2-methyl-2 -propylanine hydrochloride; yield 1*2 g. (33# theory); m*p* 208°C* Anal* Calcd* for Ci q H ^ N 0*HC1:

N, 6*93*

Found:

N, 6.90*

Preparation of 1-(|>-Methoxyphenyl )-2-methyl-2-propylanriLne hydrochloride* 1-(]>-Aminophelyl)-2-methyl-2-propylaminek (h.O g*, 0.02U mole) was dissolved in 100 ml* of methanol and 9 ml* of 37 # hydrochloric acid (0*10 mole).

Sodium, nitrite (2*0 g*, 0.030 mole) dissolved

in 3 ml* of water was added dropwise with stirring at 5>°C*

After

two hours the mixture was allowed to reach room toaperattire and was then refluxed for three more hours*

The material was cooled,

filtered, and the methanol was removed under reduced pressure. The residue was dissolved in water, made somewhat alkaline and extracted with ether. and dried.

The ether extract was treated with Norit

Addition of anhydrous hydrogen chloride to the ether

solution followed by further purification (dissolution in water, addition of base, extraction with ether, and addition of dry

hydrogen chloride gas) gave 1 —(^-methoxypheryl)—2—met-ly1 — 2—propyl­ amine hydrochloride; yield 2.8 g. (56^ theory); m.p. 162°C. Anal. Calcd. for C-n

yNOHCl:

N, 6.51*

Found:

N, 6.65.

Preparation of l-( 2 1-Nitro-U1-hydroxyphenyl )-2-methyl-2-nitropropane. l-( 2 1-Nitro-U*-aminopheryl )-2-methyl-2-nitropropane (6.0 g., 0.025 mole) was added to a boiling solution of 12 ml* of 37 # hydrochloric acid (0.1Ü5 mole) and 38 ml* of water*

When complete dissolution

was accomplished, the solution was cooled to 5°C.

Sodium nitrite

(2 .0 g*, 0 *0 3 0 mole) dissolved in 10 ml* of water was added dropwise with stirring at 5°C.

The cold diaz onium solution was slowly

added to the bottom of a solution of 3 ml* of 96 # sulfuric acid in 200 ml* of water covered with a layer of xylene.

The solution

was stirred intermittently, the temperature being maintained at 95°C*

The xylene layer was separated and extracted with 5#

sodium hydroxide* with ether.

The alkaline solution was acidified and extracted

The ether extract was treated with Norit, dried,

and evaporated under reduced pressure.

The residue was recrystallized

from benzene-petroleum ether (60 -70 °) giving l-( 2 *-nitro-U1hydroxypheryl)— 2-methyl-2~n±tropropane;

yield 2 *0 g. (33 # theoiy);

m.p* 75-76°C. Anal. Calcd. for C1 oIS.2N2°5$

11*62.

Found:

N, 11.68.

3V

Preparation of l-( 2 ^Amino^li1-hydroxypheanyl )-2-methyl-»?~propylamlne Dihydrochlorlde» -

l-( 2 1-Nitro-U1-hydroxyphenyl )-2-methyl-2-

nitropropane (2,0 g», 0,008 mole) was reduced with Raney nickel and hydrogen as described above. hydrochloride salt.

The diamine was converted to its

This salt is extremely hygroscopic and was

dried at 80°C, under vacuum; heating to higher temperatures caused decomposition of the material zation were retained.

Yield 1,U g, (65% theory); m,p, 18U°C,

Anal, Calcd, for N, 9.13*

Two molecules of water of crystalli­

2HC1*2 H 2O "

9,69,

Found:

SUMMARY

The synthesis of a series of new drivatives of alpha, alpha-dimetlyl-beta-phenethylamine hydrochloride with various substituents in the phenyl ring is described.

These compounds

were tested as pressor amines but only showed slight activity.

Lafayette, Indiana

DERIVATIVES OF ALPHA, ALPHA-DTMETHYL-DETA-PHEMETHyLAMTME

2

INTRODUCTION

A series of medicinally and pharmacologically Important compounds may be regarded as being derived from beta-phenehtylamine» These organic medicinal agents have the property of stimulating the sympathetic nervous system, and for this reason have been called sympathomimetic drugs.

They also have been called pressor

drugs because many of them increase the blood pressure. This series of amines provides one of the best known cor­ relations of the effect of chemical structures on physiological activity.

Three definite conclusions can be drawn (ll)(lU).

First of all, the optimum activity is found in those compounds in which the aromatic ring and the amino group are attached to adjacent carbon atoms (i.e. beta-phenetbylamines)•

On the other

hand alpha- and gamma- phenylalkylamines have very little activity. Secondly, primary amines are more active and less toxic than the corresponding methylated, secondaiy amines.

Further alkylation

of the amino group, such as conversion into tertiary amines or increasing the size of the alkyl in the secondary amines, increases the toxicity and decreases the pressor activity. Thirdly, compounds with the amino group attached to a secondary alpha carbon atom as in benzedrine,

CHgCHNHg,

are much more active on the circulation after oral administration than are the homologs with the amino group on a primary alpha

3

carbon atom, as in betar-phenethylamine,

CHgCHgNHg. This

phenomenon may be explained by the fact that the amino-oxidase in living organisms deaminates much more readily and rapidly those compounds in which the amino group is attached to a primary carbon atom (2 ), This reasoning suggests that a beta-phenylalkylamine with the amino group placed on a tertiary alkyl carbon should resist even more the enzymatic deamination believed to limit the duration of the sympathomimetic activity of the phenylalkylamines*

However,

such derivatives of beta-pherylalkylamine seem to have received little attention up to now, even though their physiological nature and action may be especially interesting* B eta-pherylalkylamines of the type

CHg CHNHgR where K

is larger than methyl have been found to possess no sympathomimetic activity.

Therefore it seemed most interesting to prepare a

series of derivatives of alpha, alpha-dimethyl-beta-phenethylaioine with various substituents in the phenyl ring, e.g* CHo CHg

I J

p — CH3

u

A convenient approach to the synthesis of these new compounds was suggested by the work of E* J. Berry and M. Bender (12)(13), who investigated the reaction of sodium salts of secondary nitro paraffins with various benzyl chlorides.

They found that only

with ortho and para nitrobenzyl chloride is the carbon alkylation product of the nitro paraffins obtained.

All other substituted

benzyl chlorides yield ketones as products.

CH2C1

G - CH

CHi 'x C = HOg-Ha* CH,

ortho or para^

^ortho or para^J

CHo I3 C - CHo I 3 NOo

CH■C = NO2~Na

NO,

NO, Fig. I

The nitrophenyl nitroalkanes obtained from this reaction can be reduced to aminopherylalkylamines having the desired tertiary alpha carbon atom.

5 CH» I3 CHg *• C - CH. 2

CH' CHg - C - CHh2

Raney nickel NHg ^ortho or para ) çh3 CE C - CH-

[ crtho or para \

NO, Raney nickel N02 Fig. II

NHg

The aromatic amino group can be replaced by various other groups after selective diazotization•

C - CH

C - CH 2

(1 ) HCl, HaM02 _______ t»H = 3 (2) CUgCl2

CH, (1) H2 S0tl, NaNOg _____ pH - 3

NH,

H20 OH Fig. n i

6

This was facilitated by D. C. Iffland (15) "who found that in a sufficiently acidic solution (pH - 3 or less), an aryl amino group can be selectively diaaotized without altering an alkyl amino group*

Iffland in his work selectively deaminated diamines

containing both an aromatic and an aliphatic amino group. This investigation deals with the synthesis of eight new derivatives of alpha, alpha-dimethy1-beta-phenethylamine and the synthesis of their intermediates. The amines or their salts were submitted to the Abbott Research Laboratories for physio­ logical testing.

7

DISCUSSION

The synthesis of the desired derivatives of alpha, alphadimethyl-beta-phenethylamine was accomplished by conducting the series of reactions outlined on the following two pages.

All of

the starred structures were new compounds whose identity was established beyond doubt by group tests, preparation of derivatives, elemental

analyses, and the manner of their synthesis.

The synthesis of two of the starting materials, jg-nitrobensyl chloride and 2,U-dinitrobenzyl chloride was quite simple and straightforward; however, considerable difficulty was encountered in the preparation of o-nitrobenzyl chloride. £-Nitrobenzyl chloride may be prepared by the nitration of benzyl chloride at 10-C • using mixed acid.

An overall, yield of

63% of ortho- and para-nitrobenzyl chloride is obtained, with the para and ortho isomers being formed in a ratio of 5*2.

Somewhat

more than half of the reaction product fractionally crystallized from water as pure ip—nitrobenzyl chloride, leaving behind an oil, an eutectic mixture of the para and ortho is oners, containing 60 per cent of the ortho isomer (19).

g-Nitrob enzyl chloride

can also be purchased from the Eastman Kodak Co. 2 ,U—Dinitrobenzyl chloride is easily obtained by nitrating

nitrobenzyl chloride at 60°C. with a- mixture of fuming nitric and fuming sulfuric acids.

The procedure used was essentially

8

n

CsHd‘H08H

o' CM

CM

d

CM

O

CM

CM

Og o-c!)-

O

CM

CM

h « CM CM

o

o

o o

CM

9

CM

O O

CM

% 2 * O OCM CM

O

CM

CM

CM

O O

O

I

S

CM

CM

g

CM

O

o

to1 3 Î2î

g* ti

a

10

that of Friedlaender ani Cohn (9) and gave a yield of 69 per cent» The preparation of o-nitrobenayl chloride, on the other hand, is extremely difficult, there being no really satisfactory method#

The only procedure mentioned in the literature (18)

involves the chlorination of o-nitrotoluene at 120 -130 °C. in the presence of sulfur and illumination. The reaction is extremely time consuming and gives at best a 6 .7 per cent yield of o-nitro­ benzyl chloride, which must serve as a starting material for a long series of reactions* H. C • Brown and Kharasch (8 ) found that chlorination of o-nitrotoluene with sulfuryl chloride in the presence of benzoyl peroxide gives no chlorinated product, possibly because the oxygen of the nitro group stops the free radical chain reaction by combining with the chlorine free radicals.

Ziegler (23) has

shown U-chloro compounds (e.g. N-chioroac etamine ) are unsatis­ factory in replacing allylie hydrogen atoms with chlorine atoms in contrast to similar brominations with N-bromo amides. Since nitromethane can be chlorinated at 0°C. with sodium hypochlorite, it seemed interesting to determine the action of sodium hypochlorite on o-nitrotoluene, a vinylog of nitromethane. However, an attempt to carry out this reaction gave no indication that any chlorination of o-nitrotoluene had taken place.

11

As pointed out above, nitration of benzyl chloride yields only pure para-nitrobenzyl chloride and a difficultly separable eutectic mixture of the ortho and para isomer. The only expedient method of preparing o-nitrob enzyl chloride in fair yields was found to be as follows :

CHCOCOCH^Jg T"N02 (ch3 co)2o

ÇHO

û

o

H0 2

CH-OH

mo2

Al[pCH(CH3 )2l 3

CH2 C3. pci5 CHCI3

Fig. VI

Û

no2

12

o-Nitrobenz aldehyde was prepared from o-nit-rotoluene in yields equal to those cited in the literature (17 per cent) (6 ),

The

aldehyde was reduced with aluminum isopropoxide in a yield of 90 per cent according to the recommended directions for aluminum

alkoxide reductions (21).

The alcohol was then converted to

o-nitrobenzyl chloride in an 80 per cent yield by treating it with phosphorus pentachloride in chloroform at 0°C.

The use of

thionyl chloride instead of phosphorus pentachloride proved to be very unsatisfactory • Xt is quite true that o-nitrobenzyl bromide can be and was prepared from. £-n±trotoluene in fair yield (k6 per cent; conversion 27 per cent), by following Ziegler1s (23) procedure for side chain broraination using N-bromosuccinimide. However, it was found that in the next step, the reaction of o-nitrobenzyl bromide and 2-nitropropane in sodium ethoxide, oxygen alkylation occurs predominantly and very little if any carbon alkylation, A very interesting observation was made quite incidentally when an attempt was made to prepare o-nitrobenzyl bromide by the bromination of o-nitrotoluene. It is reported in the literature (10) that bromination of o-nitrotoluene at 175°C. yields a brominated anthranilic acid which Yabroff (22 ) Identified to be 2-amino-3 , 5—dibromobenzoic acid.

It appears that under the conditions of

the reaction, internal oxidation—reduction of the o—nitro toluene occurs first, followed by bromination of the resulting anthranilic acid.

The experiment in this work was carried out employing

13

essentially the same experimental conditions (5 ) as are used for the bromination of p-nitrotoluene (light, no catalyst, high tem­ perature, lli50 C»), a reaction that yields p-nitrobenzyl bromide• However, instead of obtaining brominated anthranilic acid, un­ substituted anthranilic acid, melting at lU5°Ce, was isolated in fair yields. o-Nitrobenzyl chloride, p-nitrobenzyl chloride and 2 ,U~ dinitrobenzyl chloride were alkylated with the sodium salt of 2 -nitropropane in yields of U2 per cent, 78 per cent and 30 per

cent respectively.

In the case of the o-nitrobenzy1 chloride and

2 ,It-dinitrobenzyl chloride some modifications and improvements

were made in the experimental procedures given by Bender (13), especially in the mode of isolation of the desired products, thus cutting down considerably the time consumed in running the reaction.

Details will be found in the experimental section.

The 2-nitropropane used was obtained from the Commercial Solvents Company and purified by fractional distillation through a two

foot column packed with glass helices. The three alkylated products thus obtained were subjected to several reduction studies.

l-(o-Mitropheiyl)— 2-methyl-2—

nitropropane was reduced to the corresponding diamine.

l-(p-

Nitrophenyl)-2-methyl-2-nitropropane was reduced to the correspond­ ing diamine and also selectively reduced to l-(p-aminopheiyl)2—methyl— 2—nitropropan e.

1 - (2 1,U 1—Dinitrophenyl )— 2-methyl— 2 —

nitropropane was reduced to the corresponding triamine and also

lU

selectively reduced to 1 — (2 1—nitro—U 1—amnopheny 1 )— 2 —mettyl— 2— nitr opr cpane, whose structure was established beyond doubt (see page 17). Dinitro compounds, having the same general structure as those obtained in this research, have heretofore only been reduced at high pressures (100-200 atmospheres) (12).

It was found,

however, that the reduction of 1 —(o-nitrophenyl)-2 -metlyl-2nitropropane and l-(p~nitropheryl)-2-methyl~2~nitropropane to the corresponding diamines proceeds very satisfactorily at 100°C. and a pressure of five atmospheres, using freshly prepared Raney nickel as the catalyst.

As this work by necessity had to

be carried out with small quantities, reduction at low pressures proved to be a distinct advantage.

In this manner l-(£-aminophenyl)-

2-methyl-2-propylamine was obtained in an 80 per cent yield and 1-( o-aminophenyl )-2-methyl-2-propylamine was obtained in an 82

per cent yield.

Both diamines, derivatives of alpha, alpha-diniettyl-

beta-phenethylamine, were converted to the corresponding watersoluble dihydrochloride salts by treating their dry etheral solutions with dry hydrogen chloride gas. G. R. Ward in his Ph.D. thesis (20) describes an attempt to reduce selectively the aromatic nitro group in 1- (p-nitropheryl)— 2-methyl- 2-nitropr op ane. However, as Ward only reports his product as a low melting brown sulfate salt and gives no analysis, it seemed advisable to reinvestigate this reaction.

Repeating

the reaction under the conditions given by Ward gave mixtures of

15

various melting points*

As it is known that the catalytic activity

of platinum and nickel at times inhibit each other (U), it was decided to employ as catalyst a mixture of U.O.P nickel pellets, platinum oxide and Raney nickel# Using the mixed catalyst at a temperature of 23°C# and a pressure of three atmospheres at the outset, it was found that after hydrogen sufficient to reduce one nitro group had been absorbed, further uptake of hydrogen practically ceased (see graph) # The desired monoamine was isolated as its sulfate salt (nup. 300°C# ) in a 75 per cent yield# nor diamine was recovered#

No dinitro compound

From the salt the free anine was

obtained in crystalline fora, it melted sharply, analyzed exactly for the monoamine and was diown to be an aromatic amine by diazo­ tization and coupling with beta-naphthol#

Therefore a satisfactory

method for the selective catalytic reduction of an aromatic nitro group in the presence of an aliphatic nitro group has been developed# 1-

(2 *,1**-Dinitr ophenyl )- 2-methyl- 2-ni tropropane was

readily reduced in ethyl alcohol to the corresponding triamine at 100°C# and a pressure of five atmospheres, using freshly prepared Raney nickel as the catalyst#

The free triamine,

another new derivative of alpha, alpha-dimethy1—beta—phenethylamin e, was not very stable and so was converted to its stable, white, water-soluble trihydrochloride salt in the usual manner# elemental analysis checked well#

The

16

o

■u\ e n o c\» D— Ox trx i—l t '­ _ v o CM r * - 1—i _ , _ _ O O H H C M C M C M C M C M C sJ es i

co CM

XA O

O

O 1A 1A U X O 1A O

- ~ Î O s - = f O v O f A CM CM H H CA ( A CM CM CM CM CM CM

iH

O

H

CM o 'X - r îV W Q o - c o

Time (hours)

vo O

H

♦H

CO

O ,h' -Dinitrophenyl )-2-methyl- 2-nitropropane (lU g», 0*052 mole) was dissolved in 80 ml* of ethyl alcohol. Ammonium chloride (19*6 g*, 0*372 mole) and 28^ ammonium hydroxide (3.6 g*) were added and the reaction mixture was heated to 75°C*

Sodium

sulfide containing nine molecules of water of crystallization (lfU2 g*, 0.172 mole) and sulfur (2 g. ) were added with stirring. The reaction mixture was refluxed for one hour and was then allowed to stand overnight*

The product was filtered and the

organic filtrate was evaporated to dryness under reduced pressure. The residue was dissolved in anhydrous ether and filtered, removing any sulfur and inorganic salts that had not been previously removed. The ether solution was passed through a nine inch Norit column* The ether was evaporated under reduced pressure and the residue was recryst alliz ed frcm ethyl alcohol.

Four and two tenths grams

of 1-( 21-nitro-U1-aminopheryl)-2~metIy1-2—nitropropane was obtained; yield 3h%; m.p. 97°C. Analysis Calcd. : N, 17.57%.

Founds

N, 17.62%.

Proof of Structure by Deamination. l-( 21-Nitro-U1-aminopheryl)-2-methyl-2-nitropropane (2 g., 0.008 mole) was dissolved in 50% hypophosphorous acid (20 g. ) and 15 ml. of water.

Sodium nitrite (0.70 g., 0*010 mole) dissolved

in 3 ml. of water was added dropwise with stirring at 5°C.

The

solution was placed in a refrigerator for three hours and then

39

kept at room temperature for twenty-four hours» was extracted several times with ether.

The suspension

The ether extract was

washed with a 20% solution of sodium Igrdroxide, dried over potassium carbonate, and the ether was removed under reduced pressure* The residue was recrystallized from petroleum ether (35-37°)♦ Nine-tenths grams of 1—(o-nitropheiyl )-2-metlyl-2-nitropropane was obtained; yield 50%; m.p. 5U°G.

The melting points for the

two possible products are as follows: methyl-2-nitropropane - 5U-55°C. nitropropane - 65-66°C.

1-(o-nitropheryl)-2-

1-(j^nitropheryl)--2-methy1-2-

Therefore the structure of the selectively

reduced product is l-(2‘-nitro-U*-aminophenyl)-2-methyl-2-nitropropane.

Preparation of 1- (p- Chloropheryl )-2-methyl-2-pr opyl amine fÿrdrochloride 1-(£-Aminopheryl)-2-methyl-2-propylamine (U#0 g., 0.02U mole) was dissolved in 9 ml. of 37% hydrochloric acid (0*10 mole) and 1*0 ml. of water.

Sodium nitrite (2.00 g., 0.030 mole) dissolved

in 20 blL. of water was added dropvd.se with stirring at 5°C. mixture was stirred for fifteen minutes.

The

Cuprous chloride (3*0 g.,

0.030 mole) was freshly prepared according to the directions given in the literature (3) and was dissolved in 8 ml. of 37% hydrochloric acid and 10 ml. of water • The cold diazonium solution was rapidly added at 0°C. to the well-stirred cuprous chloride solution.

The

hO

cold solution was slowly allowed to reach room temperature and

finally was heated to 60°C, and extracted with ether.

The suspension was made somewhat basic The ether extract was treated with Norit

and dried over potassium sulfate.

Addition of anhydrous lydrogen

chloride to the ether* extract yielded the desired salt.

The product

was further purified by solution in water, addition of base, extraction with ether, and adddition of dry hydrogen chloride gas. Two and six-tenths grams of l-(]^ chior ophenyl )-2-mettyl~2-propylamine hydrochloride was obtained; yield $0%i m.p. 231°C. Analysis Calcd.î N, 6.36%. Found:

N, 6.!j5$6.

Preparation of 1- (o- Chlorophenyl )-2-methyl-2-propylamin e Hydr ochloride 1-(o-Aminopheny1 )-2-methy1-2-propylamine (3.0 g., 0.018 mole) was dissolved in 7 ml. of 37% hydrochloric a d d (0.08 mole) and 30 ml. of water.

Sodium nitrite (1.5 g., 0.022 mole) dissolved

in 15 ml. of water was added dropwise with stirring at 5°C. mixture was stirred for fifteen minutes.

The

Freshly prepared cuprous

chloride (2.25 g., 0.022 mole) was dissolved in 6 ml. of 37% hydrochloric acid and 8 ml. of water.

The cold diazcnium solution

was rapidly added at 0°C. to the well-stirred cuprous chloride solution.

The cold solution was slowly allowed to reach room

temperature and finally was heated to 60°C. made somewhat basic and extracted with ether.

The suspension was The ether extract

la

■was treated iwith Norit and dried over potassium, sulfate.

Addition

of anhydrous hydrogen chloride to the ether extract yielded the desired salt*

The product was further purified ty solution in

water, addition of base, extraction with ether, and addition of dry hydrogen chloride gas.

One and seven-tenths grans of l-(o-

chlorophenyl)-2—methyl-2-propylamine hydrochloride was obtained; yield hh%> m.p. l8l°C# Analysis Calcd. : N, 6 .3 6 $. Found:

N, 6.16#.

Preparation of l-(g-I^ydro3yphenyl )-2-methyl-2-propylamine lydr ocîilori de 1-(g-Aminophenyl)-2-methyl-2-propylamine (3.0 g., 0.018 mole) was dissolved in 150 ml. of water and lul ml. of 9 6 # sulfuric acid (O.O72 moles).

The reaction mixture was placed in an ice bath.

Sodium nitrite (1.4 g., 0.020 mole) dissolved in 20 ml. of water was added dropwise with stirring at 5°C.

The cold diazonium

solution was slowly added below the surface of a well-stirred boiling solution of 3 ml. of 96 # sulfuric a d d in 200 ml. of water.

The mixture was heated for fifteen more minutes and then

allowed to cool to room temperature.

The reaction mixture was

made slightly basic and was then exactly neutralized with carbon dioxide.

The aqueous suspension was repeatedly extracted with

ether; the ether extract was treated with Norit and dried over magnesium sulfate.

Some of the ether solution was evaporated to

U2

dryness xmder reduced pressure.

The residue was reciyshaXLised

from petroleum ether (60-70°).

The 1- (p-hydroxypheny1 )-2-methyl-

2-propyl amine thus obtained melted at 131-13 2° C. Analysis Calcd.:

8.1*8$. Found:

N, 8.1*2$.

The major portion of the ether solution was treated with anhydrous hydrogen chloride.

The salt produced was further purified by

dissolution in a neutral aqueous medium, extraction with ether, and addition of hydrogen chloride gas.

One and two-tenths gram of

1- (p-hydrosjyphenyl )-2-m ethyl-2-pro pylamine hydroc KL ori de was obtained; yield 33$5 m.p. 208°C. Analysis Calcd. : N,

6.93$. Found:

N, 6.90$.

Preparation of 1-( p-Mebhoxyphenyl)-2-methyl-2-propylamine Ifydrochloride 1- (p-Aminophery1 )- 2-methyl- 2-propylamin e (1*.0 g.,0.021* was dissolved in 100 ml. of chloric acid (0.10 mole).

mole)

methyl alcohol and 9 ml. of 37$hydro­ Sodium nitrite (2.0 g., 0.030 mole)

dissolved in 3 ml. of water was added dropwise with stirring at 5°C.

The reaction mixture was maintained at 5°C. for two hours,

it was then allowed to reach room temperature and was finally refluxed for three hours.

The material was cooled, filtered from

the inorganic salts, and the methanol was removed under reduced pressure.

The residue was dissolved in water, made somewhat

alkaline and extracted with ether.

The ether extract was treated

U3

m t h Norit anri dried over magnesium, sulfate.

Addition of anhydrous

hydrogen chloride to ihe ether solution yielded the desired product, which was further purified by dissolution in water, addition of base, extraction with ether, and addition of diy hydrogen chloride gas.

Two and eight-tenths grams of 1- (g-methoxyphenyl )-2-met hyl-2-

propylamine hydrochloride was obtained; yield 56/S; m.p. l62°C. Analysis Calcd.:

N, 6.512»*

Found:

N, 6.65^ *

Preparation of l-( 2 1Nitro-U1-hydroxyphenyl )-2-met hyl-2- nitr opropane 1-(21-Nitro-U1-aminopheryl)-2-methyl-2-nitropropane (6.0 g., 0.025 mole) was added to a boiling solution of 12 ml. of 37% hydro­ chloric acid (0.11j5 mole) and 38 ml. of water.

When complete

dissolution was accomplish ed, the solution was cooled to 5°C. Sodium nitrite (2.0 g., 0.030 mole) dissolved in 10 m l . of water was added dropwise with stirring at 5°C.

The cold diazonium

solution was slowly added to the bottom of a solution of 3 ml. of 96% sulfuric acid and 200 ml. of water with a layer of xylene on the surface.

The solution was stirred intermittently, the

temperature being maintained at 95°C.

The xylene l^rer was

separated and extracted with 5% sodium tydr oxide. solution was acidified and extracted with ether.

The alkaline The ether

extract was treated with Norit, dried over potassium, sulfate, and evaporated under reduced pressure.

The residue was recrystal—

Mt

lized from benzene-petroleum ether (60-70°) giving two grams of l-( 2 »-nitro-U1-hydrostyphenyl )-2-methyl- 2-nitro pr opane; yield 33%} m*p. 75-76°G. Analysis Calcd»:

N, 11 »62%»

Founds

N, 11 *68^.

Preparation of 1—(21-Amino-U1-hydro^yphenyl )2-methyl— 2-propylamine Dihydrochloride l-( 21-Nitro-U1-hydr axyphecyl )-2-methyl-2 -nitro propane (2*0 g#, 0,008 mole) was dissolved in 20 ml, of absolute ethyl alcohol.

The solution was placed in a 350 ml. glass pressure bottle

enclosed in a steam jacket and 0.5 g. of Raney nickel catalyst was added.

The reaction mixture was subjected to hydrogen at 60 p.s.i.

for "three hours at 100°C.

The product was freed from the Raney

nickel by filtration and the ethanol was evaporated under reduced pressure.

The resulting amine, which was insoluble in ether, was

converted to its hydrochloride salt.

The latter could only be recrys-

talii zed from dilute hydrochloric acid.

The salt, which was found

to be extremely hygroscopic, was dried at 80°C. under vacuum; further heating to higher temperatures only caused decomposition of ihe material.

The elemental analysis indicated that two molecules

of water of crystallization were retained.

One and four-tenths

grams of the desired product was obtained; yield 6%%} m.p. 181|°C. Analysis Calcd.:

N, 9.69#. Found:

N, 9.73#.

kS

MISCELLANEOUS

Atteiqpted. Preparation of 1- (£- Fluorophei^rl)- 2-met

2-pro pylamine

Action of Fluoborlc A d d * l-(£-•Ann.nophenyl)-2-mettyl--2-p2?opylamine (U«0 g., 0.02L mole) was dissolved in 9 ml. of 37# hydrochloric acid (0.10 mole) and UO ml. of water.

Sodium nitrite (2.0 g., 0.030 mole) dissolved

in 8 ml. of water was added dropwise with stirring at 5°C. mixture was stirred for fifteen minutes.

The

An ice-cold solution

of li5# fluoborlc acid (0.050 mole) was added to the solution of the diazonium salt at 0°C. thirty minutes.

The reaction mixture was stirred for

The solution was subjected to a vacuum evaporation.

The resulting crystalline diazonium fluoborate salt was washed with 10 ml. of iced w&ter, 10 ml. of methaiol and lO ml. of ether. The salt was then dried in a vacuum desiccator over 96# sulfuric acid.

The salt was heated gently at one point near its surface

with a small flame until decomposition began.

Heating was

continued from time to time until no more fumes of boron trifluoride were evolved.

In spite of all the care taken in the decomposition

of the diazonium fluoborate salt, considerable carbonization occurred. The residue was extracted with water, and the aqueous extract was treated with base, precipitating a small amount of brown black

h6

material.

This material was insoluble in the usual organic sol­

vents and was only soluble in 5% hydrochloric acid.

The material

could not be identified satisfactorily. Action of Anhydrous Hydrofluoric Acid. 1-

(g-Aminoph enyl )-2-methyl-2-propylamine (3.0 g., 0.019

mole) was placed in an iron container and h ml. of anhydrous hydrofluoric acid was added at 0°G.

Solid anhydrous sodium

nitrite (1.5 g., 0.023 mole) was added while stirring.

After two

hours the reaction mixture was slowly allowed to reach room temperature and finally was warmed to U0°C. to complete the decomposition of the addition compound.

The mixture was allowed

to stand over night to remove all the hydrofluoric acid by evaporation.

The procedure up to this point is based on a German

patent (1 6 ) for the preparation of fluorobenzene from aniline. The residue remaining on evaporation was dissolved in water. brown precipitate was obtained on addition of base.

A

This material

was soluble in acid, but insoluble in organic solvents.

The

nature of the product leads one to believe that possibly ammonia is split out in the aliphatic side chain which is followed by polymerization in the presence of hydrogen fbcttide. The product1s solubility in acid may be due to the aromatic amino group which may never have been attacked by the sodium nitrite. An attempt to prepare the desired 1-(p-fluorophenyl)-2methy1— 2—pr opylamine by the action of fluoboric acid on the

h7

diazonium salt of 1- (£- aminopherçrl )-2-met ryl-2-nitroprop ane followed b y reduction was likewise unsuccessful.

A yellow oil

was obtained from the diazotization r eaction which could not be crystallized and vhi ch did not absorb hydrogen*

This oil could

not be identified*

Preparation of o-Nitrob enzyl Bromide N-Bromosu ccinimide (98*0 g* , 0*550 mole ), o-nit rotoluene (98*0 g*, 0.715 mole) and dibenzoyl peroxide (0.75 g#5 0.003 mole) were added to 200 ml* of carbon tetrachloride, and the mixture was refluxed for twelve hours with stirring.

The reaction mixture

was cooled to 5°C*, and the precipitated succinimide and unreacted bromo— succinimide was removed by filtration*

The carbon tetra­

chloride was removed under reduced pressure, and the residue was washed successively with 2.5% aqueous sodium bisulfite, water, 15^ aqueous ferrous sulfate and water *

The unreacted o-nitro-

toluene was removed under a vacuum of 2 mm*, using steam as the heating source in order to avoid over-heating the o-nitrob enzyl bromide remaining in ihe distillation flask.

The residue after

distillation was repeatedly extracted with petroleum ether (30-60°)3 on cooling o-nitrob enzyl bromide crystallized out. grams of o-nitrobengr 1 bromide was obtained; yield 27^; m.p. U5~U6.50 C. Ziegler (23).

Thirty-one conversion

This is essentially the procedure of

U8

Reaction of o-Nitroben^y 1 Bromide and the Sodium. Salt of 2-Nit ropropane Sodium (U*6 g«, 0.20 mole) was dissolved in 2 50 ml. of absolute ethyl alcohol.

2-Nitropropane (17.8 g., 0.20 mole) and

o-nitrobenzyl bromide (Ip..5 g., 0.19 mole) were added.

The

reaction mixture was shaken intermittently* at room temperature for eighteen hours. filtration*

The precipitated sodium brcmide was removed ty

The filtrate was concentrated at atmospheric pressure

and the residue was dissolved in ether.

The ether solution was

stirred for two hours with a saturated aqueous solution of sodium, bisulfite, and the resulting sodium bisulfite addition product of o-nitrob enzaldehyde was removed by filtration.

The etheral layer

was separated, washed with water, dried and evaporated under reduced pressure.

There was hardly ary residue left; no carbon

alkylation product could be isolated.

U9

SUMMAET

In the search for superior sympathomimetic drugs, it was of great interest to prepare a series of derivatives of alpha, alpha-dimetl^yl-beta-phenethylamine with various substituents in the phenyl ring. These new substances were successfully synthesized^ but tests indicated that only 1- (p-aminophenyl )-2-methy1-2-propylamine dihydrochloride has seme activity.

50

BIBLIOGRAPHY

1.

AnschueLz and HeusCLer, Ber.> 19> 2161 (1886).

2.

Beyer and Lee, J. Pharmacol.^ 7U, 155 (19U2).

3*

Blatt, 11Organic Syntheses”, John Y/iley and Sons, Inc., Hew York, N.Y., 19U6, Coll. Vol. I, p. 170.

U.

Blatt, ibid, p. U69.

5.

Blatt, ibid.. Coll. Vol. II, p. 1^3•

6.

Blatt, ibid., 19iiU, Vol. XXIV, p. 75

7.

Blatt, ibid., 19U5, Vol. XXV, p. 5.

8.

Brown, H. C. and Kharasch, J. Am. Chem. Soc., 61, 21U2 (1939)•

9.

Friedlaender and Cohn, Ber., 35, 1266 (1902).

10.

Greiff, Ber., 13, 288 (1880).

11.

Hartimg, Ind. Eng. Chem., 37, 126 (19U5).

12.

Hass, Berry and Bender, J. Am. Chem. Soc., 71, 2290 (19U9)•

13.

Hass and Bender, J. Am. Chem. Soc., 71, 3U82 (19U9) •

lit.

Jenkins and Hartung, ”Chemistry of Organic Medicinal Products”, 3rd Edition, John Wiley and Sons, Inc., New York, N.Y., 19U9, p. 363.

15 •

Korriblum and Iffland, J. Am. Chem. Soc., 71, 2137 (19U9)*

16.

Osswald and Scherer, (to I. G. Farben Ind.,) •B.R.P. 600706, (July 30, 193U).

17.

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18.

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19.

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51

20.

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21*

Wilds, "Organic Reactions”, John Wiley and Sons, Inc., New York, N.Y., 19Ut, Vol. II, p. 198.

22.

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VITA

Gerard 0* Platan was born June 29, 1926 at Potsdam, Germany, the son of Dr. and Mrs. Martin Platan.

He attended George Washing­

ton High School in New York City, graduating in June, 19U2.

In

June, 19^6, he received the degree of Bachelor of Arts from Brooklyn College.

In the fall of 19U6 he entered the Graduate School of

Purdue University and was employed as a graduate teaching assistant. He was given the Abbott Research Laboratories Fellowship for the two years, 19U8-1950.

He was awarded the degree of Master of

Science, February, 19U8, and the degree of Doctor of Philosophy, June, 1950.

He is a member of Phi Lambda Upsilon and Sigma Xi

fratemiti es .