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SYNTHESIS or SOME DIALKILAHINOPROPYL
BETA-Emu ETHERS

By

Mildred B. Em

I. THESIS

mitt“ to the School of Graduate studio. of 1110111311:
State College of Agriculture and Applied 501ch
in partial “1111.13.“ of tho requirement.
for the degree of

METER at EIEHCE

Damn-ant of Chemistry

1953

M! é- Lc-J

ACW

The author nobo- to oxpmo hor
appreciation to Dr. Robert H . Herb-t
for his guidnnoo and encouragement
during tho oouflo of this mrk.

W
W
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337985

comma
PAM
WHOI...................................................... 1
”MAL...“.................................................. 2
Wanna"................................................ 6
Mil-“unuuun........................................ 12

Mn“.COO-00000000000000.0000.ooooooooooooo00.000.000.000! 12
Propmtion or i-oW-bomomnltommm..........n 12
Prop-"Mon of 1-oh1m-2-(2-nqhthoxflpropm. .. .. . ......... 15
W‘tion Of 1-(2-Wh‘hov)-2wpmlo o o 0.. o. .0 o 00 00000000 16
Propontion o: 2-oh1m-1-(2-n-phtmnmopm. . . . . . . . . . . . . .. 17
Preparation of l-norpholitw1-2-(2-uphtthy)pr09m . . . . . . . . . . 19
Propantion o: 2- R-nlphtbxygolwpiporidylprm . . . . . . . . . . . . 21
Prop-ration of 2- 2-mphthozw -1-pyrrolidy1propm. . .. . . . . . .. 22
Preparation 9: lcdiothylnino-2-(2-uphthozy) pm. . . . . . . . . 23
h'anltion of 1-dinothy1uino-2~(2-uphthoxy propul- . . . . . . . . 2h
Notation or 2-uorpho11w1-1-( 2-whthon)propm . . . . . . . . . . ‘25
Preparation of 1-22-nuphthoxyb2-pipuidy1pmpano. . . . . . . . . . . . 26
MMtion Of 1. 2’mmm"2dpm°11d’1pmm o o o o o o o o o o o 38
Mutation of 2-diothy1.ino-1-( 2-nnphthoq) . . . . . . . . . 29

Mutation of MWbu-mm m........ )0
WOOOOOOOOOOOOOOOOOOO60.00000000.0000IOOOIOOOQIOOOIOOI0.0000. n
"win...00000000000000...-OOOOOOOOOOOOQOOOOO0.00000000-ooa‘000 33

maomrxou

MRODUCTION

Many biologically active compounds have been found to have the
general atrueture (I) in which I represents a hetero ate- (1).

44-0-11: C‘OH,OCH,CH.KR.
(I) (II)

flex-bet and Johneon (2) prepared eeverel diallryl-ineethyl
naphtth ether-a (II) ahioh were found to poeeeae aarked local ahea-
thetie action.

Thie theaie deaoribee the preparation or two gronpa or iacaerie
dialkylnimproml fl-naphthyl ethere (III ,IV) . Beth groupe of in-
am pone" the dialkylalinoethyl other atruetnre but differ in that
a methyl group ie attached to one or the other of the car-hone of the
ethyl residue.

{Hz $1003.33“- fi-Cuflvoggc’fifi.
(m) (n)

Teate have not yet been carried out to determine whether theee
coapounde have local aneethetio or other pharmacological actions or
to «spare their activity, it any , with that of the ooapounda prepared
by Berbet and Johneon.

HISTORIC“-

HISPORICAL

Aa mentioned in the introduction, the object of thie aork me the
preparation of diaJchlminOpz-Opyl fl-naphthyl ethere having the
formlae cun,oca.cn(ca.)m. and cwa,oc3(cn.)cn.un. in which the group
an. aae (a) lorpholinyl, (b) piperidyl, (c) pyrrolidyl, (d) cumi-
anino, or (e) dinethylanino.

Inorr (3) haa prepared dinethylminoethyl phenyl ether by reaction
of phenol and the hydrochloride of dinethylminoethyl chloride in
eodiua ethylate . Application of thie

cape. + (ca,).uca.camm1 --o c.n.ocn.cn.u(cn,).
procedure to the preeent problem would have required the preparation
of ten different dialkyl-inOprOpyl chloridea (n;-ca(ca.)ca.01 and
a.n-ca.cn(ca,)cn . A procedure which would reguire fever different
intemediatea would be preferable .

Wright and Moore (t) have prepared og-naphtkvl alkaline ethera by
refluxing diethyluinopropyl chloride with naphthol in alcoholic
potaeaiun hydroxide. Thin method ia an application of lnorr'a procedure
and would liked" entail the preparation of many different minopmpyl
chloridee aa internediatee .

film and Eotlauf (5) prepared dimethylaninoetlyl /s.ncpnnw1
other by the thermal elimination of carbon dioxide from ,3 onaphthyl .
dietwlaninoethyl carbonate . The letter on prepared by interaction
of [3 -naphthyl chlorocarbonate and diethylninoethanolt

(1) p-c‘onm 4 can, —-e {a-cwawcom

(2) p-cwamoci e- (0.3.),mnpnpnafi-cwawcoocafingmfi).

(3) p-ccoacocoocwnwcafi.)e—a fi'cioavocHeCHe'(°eHe)a + CO.

Here again a large group of different animalcohole (mucngcnpn
and n,nca.cn(cn.)oa) would be required as intenediates 1: this nethod
Iere applied to the problem described in this thesis.

Harbat and Johnaon (2) prepared a umber of d-and p -naphthyl
ethera of the type c1oa,oca.ca.ua. in which the group JR. me
(e) lorpholinyl, (b) piperidyl, (c) diothylaaino, or (d) dilethylamino.
Their procedure involved the fometion of oh and p-naphthyl bro-oethyl
ethera hy the interaction of ethylene dibrolide and the naphthol in the
preeence of sediun hydroxide . subsequent treataent of the bro-oathyl
ether with various secondary aninee in‘beneene or toluene solution gave
the desired dialkylalinoethyl ethera . ,

(1) cue-,0“ e 03.310114» ——e cpamnpmr
(2) ctoawchapar + 3.1m -—> c;&,mapn.m.

ipplication.of an analogous procedure to the preparation of the
ieeaeric brouopropyl naphthyl ethera was not practical . Although
propylene dibraide is readily available , ite reaction with /3 -naphthol
would lead to a mixture of isomeric broncpropyl ethera Ihoae separation
would be difficult and time consuming at best.

c‘m e (33.93.33.31- ———> 0,98,oqmn.3r + cIoE-IOCHfiHBr
Br CH. CH.

Two alternative proceduree were available for the preparation of
chloroallquethera, each of which could be expected to give only one of

the anticipated isomers .

Ola-o and Perkin (6) had described the synthesis of chloroethyl
p-toluenesulfonate fro- ethylene chlorohydrin and potoluenesulfowl
chloride. They further showed that interaction of fl-naphthol and the
chloroetharl p-tolueneeulfo nate led to the for-nation of fi-naphthyl
chloroethyl ether. I'oldi (7,8) had sheen that a siailar sequence of
reactions could be carried out starting with benzenesulfonyl chloride
and ethylene chlorohydrin.

(1) 0.3.80.6]. e accupapi—r apnea ,ca,ca.c1 9 m1

(2) 6,8,80,03,6le + irate -—-> ”0011.03.61 e 0.3.80,“

The second alternative, studied by Kirner and Richter (9) , involved
the treatnent of a phenol in alkaline nediun vith ethylene chlorohvdrin.
The resulting hydroxyethyl ether on treatment With thionyl chloride was
converted into the chloroethyl ether.

(1) Na + CEBICHfiH —-> irocnpapn e an

(2) ”confined e 3631. -——>Armh,dH,Cl + 33. 4- m1

lone of these aethods have been applied to the synthesis of chloro-
or broeopmpyl naphthyl ethera .

A nuaber of techniques have been described for the preparation of
aryl dialkylninoalkyl others from the corresponding haloalkyl ethera.

Aralflfiflfil e m. --e irocnpnann,
ale-c and Perkin (S) and Knorr and Both (10) both described nethods
for carrying out the reaction of the halide with a secondary nine in
sealed tubes. This technique appeared to be particularly applicable
to reactions involving diaethylanine and diethyluine . Cromwell and
Fitsgibbon (11), Herbst end Sinonian (12), end Eerbst end Johnson (2)

used nethods in which the secondary mine and the halide were refluxed
in a suitable solvent. This procedure was employed primarily with the
less volatile secondary nines . l

DIES-U 8810!

DI$USSION

Both groups of isomeric dialkyluinopropyl fi-naphthyl ethers can
be prepared tro- p-naphthol and propylene chlorohydrin. li‘he use of
these readily available chemicals, however, necessitates tso different
sets of reactions to obtain the two different sets of isomeric products.

An adaptation of the Oleno and Perkin (6) technique should lead
to a chloroieopropyl naphthyl ether in which the carbon ato- carrying
the Iva-owl group in the propylene chlorohydrin was involved in the
etherlinkage. This technique would require the preparation of a
chloroisopropyl beraenesultonate and its subsequent interaction with
lg-naphthol as outlined in Schene I.

ache-e I

(a) cupmnpl e 0.3.so.c1——e c.n.so.cmn.ci
m on.
(b) 64.5039333131 e down-yon —-+ fi-Ctougma-Cflfil
ca. on.
(c) [a-c‘a-ficmngn + 3.33....) p-c,°e,comn,sa.
. on, on.

in isoaeric chlorOprOpyl naphthyl ether would result by application
or the sequence or reactions described by Iirner and Richter (9). By
interaction of propylene chlorohydrin and [B-naphthol an ether linkage
would be tor-ed involving the carbon ato- carrying the halogen in the
chlorohydrin . The resulting hadronalkyl other would be converted into
the chloroallql other on treatment with thionyl chloride as outlined in
ache-e II .

Scheme 11
(e) 011,353.01 + fl-cwawne ~—-e [s-cma,ocn.cuoa
on,

(b) a-c‘awcapnon e can, -——> p-cmnwcngmi
on. on,

(3) M‘fimagml * 3,1111 "—9 {S‘Caoavocflaqme
on. on,

A nodification or the procedure used for the preparation of n-butyl
p-toluenesultonate (13) sas applied to the synthesis of the chloro-
isopropyl bensenesuli'cnate (reaction I-a) . Very alas addition of
aqueous sodiu- lnrdroxide solution to the reactants and 100$ excess of
propylene chlorohydrin vere found to be essential to obtain a saline
yield . is low a pressure as possible was needed to distill the chloro-
isopropyl benssnesuli'onate vithout decomposition. Using matest care,
homer, only approxiaately 110$ yields were obtainable.

Imerous difficulties were encountered in the reaction or the
chloroiscpropyl bensenesulronate with fl-nephthol (reaction lob) .

A solid, Ihich ses later found to be l-(2-naphthozy)-2-propanol
(c,,a,ccn.cn(oa)cn.) , gradually precipitated m- the chloroisopmpyl
naphthyl ether (Gun-,OCMCBJCEfil) . This alcohol could arise in either
of two “is. It could be the product of a side reaction of the

p .mphthel men prepylene chlorohydrin forced by hydrolysis of the
ehlorcisopropyl beneenesulfonate in the alkaline reaction aediun .

(1) 6.3.80.9map1 1292, when,“ e cmgmam
ca. _ n

(2) Gunman e p—ctaqoue—a fl-c,oe,ocn.caon
on ca,

It could also be a product of hydrolysis and rearrangement (or vice
versa) of the chlorosthcr.

CH, rearrangement 3 CH.

Puson and Icehnshs (lb) had observed an analogous rearrangement when
l—Ivdroxy—( 2-pr0pyl) phenyl sulfide was treated with thiowl chloride .
The product was Zochloro-(l-opropyl)phenyl sulfide . Whether such a
rearrangement :

I'c cocoa 8001 C can m1
“fins ““9" '3' 'EH.

cf hydroay ethsre would occur has not been deter-iced, nor has the
hydrolysis of sinilu- chloroalkyl sulfides or ethers been studied .
However, it is not inconceivable that such rearrange-lent could take
place during the hydrolysis of the chloroelkyl sulfides and others.

Hydrolysis of a salple of the chloroisOprOpyl fi-naphtlvl
ether sinned no concrete evidence of a rearrangement. Consequently, it
would appear that the alcohol present in the product was forced by the
first of the two possible routes .

Repeated distillation of this chloroether nay have caused sons
dehydrohalogenation. A slaple which was thought to be free of the
alcohol gave low halogen and high carbon and hydrogen analyses. The
sue sasple decolcrised bromine in chlorofors, indicating that it was
unsaturated.

These various side reactions, of course, lower the yield of the
desired product. This is shown from the fact that epprometaly 1151 of
sclewhat contestinated chlorocther was about the best yield obtainable.

Powell (15) made Y-hydromn-propyl phenyl ether by dissolving
phenol in dilute alkali, adding trinethylone chlorohydrin, and reflux:-
ing for one-half hour. A technique essentially the sue as his was
found to proceed very smoothly for the preparation of the hydroxypropyl
[B-naphttvl ether (reaction II-a) . Yields of approxinately 801 were
obtained when 100% causes prepylene chlorohydrin as used.

For the Daraens reaction (reaction Ila-b) the procedure of Herbst
and Sherman (12) in which a chlorofora solution of thionyl chloride
is added to e chloroform solution of the alcohol in the absence of
pyridine was found to produce the best results.

Gerrard (16) and ten-i (11) have independently concluded that the
neoheniee of the Daraens reaction involves the for-ation of an inter-
sediate sulfinyl chloride which decomposes that-sally to produce the
chloride and a molecule of sulfur dioxide.

non e ooc1.——> 305061 A» an e so.

The existence of the intersediate sulfirql chloride is verified
by the work described in this thesis . On attempting to deccnpcse' the
eeoeee thicxwl chloride in the reaction mixture with methanol a white
solid was obtained which nslted at his-55% . after recrystallisation
fro: bemene and ligroin. carbon, hydrogen, and sulfur analyses agreed
remnably well with the theoretical counts of these eleaents present
in the aethyl ester of the sulfinic acid related to the intemediate
sulfinyl chloride ('1) .

10

flnlwmmaoe + 3001.——-> [s-cmepcnacaosom + an
on. on,

y. (Y)
,Q-cloneocuzqaosowcfi.) p—C;&vmfie9ml * 302
on. . ca

('1)

Apparently the internediate sulfinyl chloride (1) formed in this
reaction is relatively etable to heat since it had to be heated to
approxisately 110°C . before the evolution of sulfur dioxide could be
detected. Deconposition of this intermediate was found to be best
accomplished by heating at 125-th00. under reduced pressure. Such a
procedure netted a 66% yield of the chloropropyl ether.

Ithe tertiary nines were formed in rather poor yield on refluxing
the various secondary amines sith the chloropropyl ethera in benzene ,
toluene, or xylene solution. Bearer, when an eznesa of the secondary
amines was used as solvent the reaction gave satisfactory results.

The secondary and tertiary amines were separated free any unreacted
chloropropyl ether by precipitation of the hydrochlorides fru an iso-
propyl other solution of the products . Regeneration of the amines was
accomplished by dissolving the hydrochlorides in water and leaking the
solution basic Iith sedit- carbonate . After extraction of the snines
with bensene , they were easily separated by distillation since the
compactively low boiling secondary amines were quite completely ruoved
Ilth the solvent. The tertiary amines all appeared as high boiling
Maude.

Certain sodifieations of procedure were necessary due to the
different properties of the various secondary nines used. Reactions

ll

involving very volatile amines such as diethyl- and dinethylanine were
carried out in sealed tubes. In the case of the dimethylnnine, which
is a gas at room temperature, an aqueous-diam solution of the anine
III used.

The hydrochlorides were prepared by passing twdro gen chloride
through an isopropyl ether solution of the amine .

EXPERIHENTAL

EXPERM'TAL

Reagents
Propylene chlorohydrim Obtained from the Dow Chemical compare'

and Distillation Products Industries, division of East-an Kodak Company.
Pyrrolidines Obtained fru Electrochemicals Dcpartnent of E. I.
duPont de Honours and Company.
. Hydrogen chlorides Prepared by adding concentrated hydrochloric
acid to concentrated sulfuric acid through a capillary tube.
The following reagents were obtained free Dietillation Products
Industries, division of Eastman Kodak Coupanyc
Benzenesulfonyl chloride
(ac-naphtha '
Thiowl chloride
Methyl-inc as a 335 aquews solution
earphones ‘
Pyridine
Diethylsnine

Pro tion of l-chloro-z-bemenesulfono no one

- 30.0mm).
on,

Into a three necked flask fitted with stirrer, thernoeeter, and

 

separatory funnel was placed 95 g. (86 1131., l nole) of propylene

13

chlorohydrin and Mi 3. (32 n1., 0.25 mole) of benseneeulfonyl chloride.
While cooling in an ice-water bath 80 ml. of S I codiun hydroxide were
added dropuise with stirring at such a rate as to aaintain the tuperature
at . 10-15% .

When the sodim hydroxide solution had all been added a second
portion of 12 ill. (0.25 sole} or beneeneeulfonyl chloride was added to
the reaction mixture and another 80 I1. portion or 5 l sodiun hydroxide
see added drcpwise with stirring as before. m total addition time
required for both portions of sodium hydroxide was 15-20 hours.

Stirring was centimed for several hours after the addition was couplete.
it the end of the reaction the layers were separated and beam
us added to the organic layer until it would float on water. This
bensene solution was washed with 10$ sodiun hydroxide solution and with
inter. After drying ever potassius carbonate the solvent was reeeved
and the product was distilled under reduced presnre. A total of h? g.
(M) of saterial boiling at 1119-155" 0 . (uncorr.) \mel‘ 3.5 an.
pressure and having a refractive index of 1.5210 at 18°C. was obtained.
mum-f Calc'd. for cannon. 01, 15.1; s, 13.6.
found: Cl, 15.2, 15.1» 8, 13.5, 13.5.

A series of experisents was done to deter-inc the optimal preporticns
of propylene chlorohydrin and beneenesulfonyl chloride. The reactions
were all carried out as described above. The results are sunarised in
Table I.

 

*inalyses accept for the nitrogen and chlorine analyses of the
nine hydrochlorides were done by liicro-‘l‘ech laboratories at
Bkckie , nlincie.

 

2 S m. o 8 o. a «an 8n

 

2 cm m. o 8 . 2.4 m3 0mm
3 . 3 m6 8 m4 3." cow
3 5 m6 3 o; ma 8."
an on m6 8 who a. om
33?... grudges; €33“? ”mug
omega

 

1H

ghomggamgmlwlog GA 8 Ion—“gamma
ME. «on Nag gamma mama an. no 5%”an ME

H H548

15

much of l-chloro-Zeflzi-naphthogmropane

./ ‘ \ . $33.01
| on.
\ /

To to g. (0.3 mole) of IB-naphthcl in s three-necked flask fitted
with c stirrer, reflux condenser, and dropping funnel was added a solu-
tion of 50 g. of sodium hydroxide in 100 ml. inter. This mixture was
bested on a steam bath and stirred until the naphthol dissolved. With
continued heating and stirring 59 g. (0.25 mole) of l—chloro-a-bersene-
sulfonewpropane was added dropwise from the dropping funnel. Heating
and stirring were continued for one hour after the addition was complete.
the reaction sisters was poured into ice water and stirred until the
ice dissolved. a yellowish oil separated. The oil II taken up in
bensene. After drying the benzene solution over potassiua carbonate
the solvent was removed by distillation. Upon vacuum distillation of
the produce two fractions were obtained. The first boiled at 158.66%.
(uncorr.) under 6-8 as. pressure and had a refractive index of 1.5966
at 19°C. The second boiled at 166-170°c. (uncorr.) under 6 on. pressure
and m a refractive index of 1.5953 at 19°C . The ccnbined yield was
25 3. (Mi) .

It was found to be ilpossible to obtain a sample which was completely
free of contaminants and which would give satisfactory analytical re-u
cults. However, since the tertiary nine derivatives gave satisfactory
analyses it is probable that this compound was correctly formulated.

16

Preparation of l-(2-naphthoq) -2 ~propenol

’0 h, R,QHOH
O on,

To a solution of 72. g. (0.5 mole) of l3~naphthol in 500 m1. 10$
aqueous sodius hydroxide was added 95 g. (86 311., 1 mole) of prepylene
chlorolrzdrin. This solution was heated to boiling under a reflux con-
denser. In a few sinutee an oil be gen to separate free the solution.
Refluxing was continued for about 1.5 minutes. it the end of this tine
the reaction mixture was allowed to cool, Inherenpon the oil solidified.
Stirring while cooling in an ice bath was found to be helpful to keep
the oil from solidifying as a hard coating on the sides of the flask.
The white solid was filtered, washed tilice with outer, and then dis.
solved in benzene . After the email amount of residual water in the
solid was separated free the benzene solution, ligroin was added until
the solution use Just cloudy. The solution was then allowed to stand
until crystallisation was complete. a yield of 82 g. (811) of product
melting at 83-8h°c . was obtained.

He malysis was carried out on this compound since an entirely
independent synthesis by catalytic reduction of fl ~naphthoiqeeetone was
reported by Kurd and Perlets (18). they observed a selting point of
82-83% .

Since it me anticipated that part of the propylene chlorohydrin
sight be ludrolysed in the alkaline reaction sedim, experiments were
done with different proportions of fi-mphthol and propylene chlorohydrin

17

to determine the Optimum conditions . The results are summarised in
Table II.

monomer 2whlcrwl-LZ-naphtmm

0O . Raquel
j . OHa

Into a three necked flask fitted with stirrer, reflux condenser,
and drOpping humel were placed 51 g. (0.25 mole) of l-(bnaphtlwnd-
2~pr0panol and 100 ml . chloroform. The mixture was stirred until the
alcohol was completely or nearly completely dissolved. While stirring
143 g. (26 1111., 0.14 mole) of thionyl chloride dissolved in 50 ll. chloro-
fors was added dropwiee at noon temperature over a period of about two
hours. Stirring Ias continued overnight. The solvent and emcee thiomrl
chloride were rmvod by dietillation while applying suction free! the
aspirator, after which heating was continued for four hours at 125-th .
to liberate the sulfur dioxide from the intermediate sulfinyl chloride .
The product was then vacuum distilled to yield 36 g. (665) of chloro-
ether which boiled at 138-1h9.5°c. (mm-r.) under 3 m. pressure and
had a refractive index of 1.6059 at 20.5%. This slightly yellow oil
slowly solidified on standing. after two recrystallisations from ethanol
3 white solid neltinz at 39-14% . ms obtained.

Analysis. Calc'd. for GuHuClO: c, 70.8; B, 5.9; Cl, 16.1.

Found: C, 71.1, 70.91 8, 6.0, 6.1) 01, 16.2, 16.1.

18

 

 

 

 

E. 2. m6 2. m4 SH 8a

3 mm m.o 2. 0.“ mm 8a

mo mo m . o 2. E... o :. om

3 S m.o a. We 2 o

280 2m .55 3H0: .55 33x 3.5 383.520
33» afififia-Q signage going .83
gasp—om
538%.? Sagas... YA

mo Bpafimm man. man H29”:— nHmBmomQEo ”mug ma ho ECHABSEQ mm.“
NH ah

19

In neural emporium en nttempt nu nude to dour-0y the excess
thionyl chloride in the reaction nature by nddition of nethlnol .
A crude product with I tide nelting point range was obtained. On
{notional equalization tron benzene and lizroin lane emu-c.1-
(2-uphthoxy)propnm and me white 0011:! uniting at Sis-55°C. are ob-
tnined. The carbon, hydrogen, and chlorine amines for the compound
Inning at 516500 . corresponded remahly with the theoretic-a mount.-
a: thou elements wasn‘t in the nettvl um“. of the mum acid re-
lnted to the intemdim “111ml chloride .

Andy-in. Cele'd. for 6,330.3: c, 60.0; I, 5.73 8, ll.h.

round: 6, 60.53 H, 5.93 3, 11.2.

Wtion of lmpoliqloaiz-mphthom

93.33%
‘CHfiH.’

tn.

 

A mean or 0.1 :01. (22 g.) o: 1-oh1m-2-(2-uphthou)propm
and 0.3 ml. (26 3., 26 .1.) or Iorpholine no name! for 2h hours.
the mention unsure III tuneful-red to n lager flux and diluted with
inopmpyl other. alum hydrogen chloride m bubbled into the eolutien
to precipitate the w'drechloridel of the secondary and tonic: min“.
The “pennant liquid m donated end the inapmpyl other m moved
by diltflhuon, luring u, residue of 5 g. of mounted ehloroether.
The Inn-m yield of product, therefore, would be 77$.

20

The hydrochloric!“ were clinched in enter. The weter eolution he
nede belie with eodinn eerbonete to liberete the eninee , ehioh vex-e
extruted eith three portione of benzene. After drying over “drierite'
the beneene I. removed by dietilletion end the reeidue Iee moon
' dietilled to give 16 z. (605) of product boiling et 18h-l92°C. (uncouth)
under 3 .. preeeure end heving e refractive index of 1.5818 et 205°C. .

The distilled mine tee dieeolved in dry ieopnopyl ether. Anhydrous
hydrogen chloride on bubbled into the solution to pmipitete the hydro-
chloride, ehioh nee reeryetellieed tron eoetone, teem-owl alcohol, end
inept-owl ether. Oryetele nelting et 160.5-161.5°0., 139411190” end
131432 .S°c . em ieoleted.

Anelyeie. Celo'd. {or cannula“ Cl, 11.91 ll, L6.

Cmtele nelting et 160.5461 5°C..
rm. (21:12.0; I,“ L9.

Cryetele melting et 139—1h1°c .e
Pounds Cl, 11.9.

Cmtele nelting et 131-132 5%..
Found: 01, 11.9.

* Chlorine enelyeee for thie end to: eubeeqnent compounde eere done

by the leJene nethod in e 75$ ethenol eolntion «in; diohlmtluoreeoein
ee indieetor (19) .

” Nitrogen enelyeee for thin end for eubeequent ouponnde vet-e done
by the Holden-mania; lethod Iith the emeption of piperidyl derivetivee ,
for Mei: the (Jeldehl-Oonningbirnold lethod he need (20) .

21

Pregeretion or Z-S fighting) -l-piperidfl.2r_oge_n£

Pascal
warm; on.
da. ‘ca,cn.’

 

 
 

A mixture of 0.1 role (2: g.) of l-ohloroofl-(2-nephthoxy)pr0pene
end 0.3 nole (25.5 3., 30 ml.) of piperidine wee refluxed for 2h ham-e.
The nation nixtnre tee treneterred to e lerger flak, diluted with
ioopropyl ether, end the ivdroohloridee or the miner em precipitated
with gueone hydmgen chloride . The inepmpyl ether lolntion we de—
oented end eveporeted to give e reeidue of 5.7 g. or enreeeted chloro-
ether. The nexinnn extent of reaction I! therefore 7M.

The hydrochloric!“ were dieeolved in teeter end eodinn eerbonete
eel edded to liberete the free miner. The minor were extreoted eith
three portione or beam . “ter drying over 'drierite' the eolvent
end emu piperidine were renorod by dietilletion. . The product nee
dietilled under menu. A yield of 16.1; g. (611) or enine boiling et
lhO-lh8°c. (worn) under 3.5 In. present-e end hering e reflective
index of 1.5800 at 195°C. eee obteined.

The eeine flee dieeolved in dry ieoprOpyl ether end the hydro-
chloride nee precipiteted vith enlwdrone hydrOgen chloride. The hydro-
chloride m reoryetellieed tron eoetene, ieoprOpyl eleohol, end
ieopropyl ether. The yield of hydrochloride wee 90$. The melting
point on 182-183°c .

Andyeie. Celo'd. :or eunucno: Cl, 11.9, n, h.6.

Pound: Cl, 11.93 ll, LS. ‘

22

generation of 2-(2-nnpht mgL-l-pyrrolidzlgrogene

// /\ girlie???
w *e 0 :5 e

A mixture of 0.1 mole (22 g.) of 1-0h10ro-2-(2-nephthoxy)propene
and 0.3 mole (21 3,, 25 ll.) of pyrrolidine uoo refluxed for 2h boom.
The reaction mixture nee diluted with ieOprOpyl other end hydrogen
chloride gee wee bubbled through the eolution to precipitete the hydro-
chloridee of the eninee . The inepropyl ether eolution wee decanted
from the eticky precipitate end evepcreted to leeve 3.5 g . of unreected
chloroether, indicating e nexinun reeotion to the extent of 8M. - O

The hydrochloridee Vere diuolvod in outer end eodiun oerbonete .o.
edded to liberate the free mince. The eminee were extreoted Iith three
portione of beneene. The beneene solution vee dried over 'drieriteJ'
The drying egent wee filtered off, the eolvent end exceee pyrrolidine
were removed by dietilletion, end the product no dietilled under
vecnnn. A total of 18 .5 a. (73%) of product boiling et lSh-16h°6.
(uncorr.) under 2.5 we. preeeure end heving e refreotiee index of
1.5900 et 19°C. eel obteined.

The wine we dieeolved in (amt-one ieopropyl ether end the hydro-
chloride wee precipiteted with geeeoue hydrogen chloride. The hydro-
chloride wee recryetellieed by dieeolving it in eoetone end ieopmpyl
eloo hol end edding iloprOpyl ether until the eolution nee elightly
cloudy. A 98‘ yield of hydrochloride, which melted et 153 .5-157 5°C.,
nee obteined. Thin product no epperently e nixture of cryetel foree,

23

eince on further recrystallization it yielded cryetele melting et 139-
11.0%., 163-165"C., end 178 .5-179°C. The enelyeee were cerried out on
the product melting It 153 .5-157 5° C.
inelyeie. Celc'd. for Cnaucmo: 01, 12.53 N, h.8.
Found: CI, 12.3: H, 5.0.

rropmtion or l-diethzlenino-Z-g2-Lephthog)m

03,08.
-. ma
ca. 03.03,

 

\

  

I

A nixture of 0.1 role (22 g.) of lochlomd-(I-nephthoxybmpw
end 0.3 role (22 3., 31 .1.) of diethyl-eine eee heeted in e eeeled tube
et loo-105°C . for he been . The oontente of the tube were mead out
with ieOprOpyl other end the inrdrochlcridee were precipiteted with geeeoue
hydrogen chloride. After dimlwing the hydrochloridee in weter, the
leyere eere eepereted. The equecue hy‘r eee weehed once with ieopropyl
ether. The combined ieopropyl ether leyere were dried over 'drierite.‘
hovel of the eolvent end dietilletion gewe 11.5 g. of unreeoted
chloroether, indieeting e nerd-n- reection to the extent of 1:81.

The nter eolntion m nede beeic with eodiu cerbonete to liberete
the aim, which were extrected 1th four portione of beneene. After
the beneene eolution wee dried over 'drierite ," the eolwent end eeneee
diethyluine were removed , end the product wee wecuun dietilled. A totel
of 9.7 e. (385) of neteriel boiling et 150.35%. (uncorr.) et 3.5 1-.
prenure end hewing e refrectiwe index of 1.5635 et 195°C. the obteined.

2h

The hydrochloride wee produced by peeeing dry hydrogen chloride gee
through en ieopropyl ether eolution of the enine. Two recryetellieetione
from ecetone, ieopropyl eloohol, end ieoprOpyl ether gewe e hydro-
chloride meh melted et 129 .5-131°c . ’

Anelyeie. Celc'd. for 6,78,431110: Cl, 12th I, 13.8.

Found: 01, 12.!” II, 5.1, h.9.

etion of l-dine lenino-i'u 2- hth ) ene

fine
‘03,

 

A wixture of 0.05 mole (11 e.) of l-chloro-Zou-nephthoxyhropene
end 0.2 hole (33 e1.) of 331 ecu-cue eolution of dinerthylaine end 20 e1.
dionne no heeted in e eeeled tube et loo-105°C . for 1.8 houre. After
the contente of the tube were eeehed out with ieopropyl ether, the
hydrochloride. were forced with geeeoue hydrogen chloride, whereupon
they dieeolwed in the equeoue leyer. lore nter wee edded to dieeolwe
the twdrochloridee coupletely. The leyere were repented. The equeone
leyer wee weehed once with inpropyl ether. The cabined ieopropyl
ether leyere were dried over 'drierite," then ewepcreted to leewe 2.7 g.
of nnreected chloroether, indieeting e neeinue reeetion to the extent
of 75‘.

The miner were libereted by letting the equeone eolution of the
hydrochloridee beeio with eediun eerbonete. The product ne extrected
with four portione of beneene. After drying over ”drierite' the eolrent
wee renewed end the product wee dietilled under reduced preeeure to give

25

6.5 g. (57;) of coin. boiling et 1h9-152°C. (enact-r.) et 3.5 not. end
heving e refrectiwe index of 1.5752 It 19°C .

The hydrochloride wee propered by dieeolwing the enine in dry ieoo
propyl other end peeeing in enhydroue hydrogen chloride. After recryetel-
1ieetion from eoetone end ethyl eoetete e 921 yield of hydrochloride wee
obteined . Cryetele melting et lid-120°C . end 160-161°c . were ieoleted.
Reoryetellieetion of the product melting et 118-120°C. frol the use
eolwente yielded cryetele nelting et 135.5-136.S°C. ipperently the
compound on eeiet in three different oryetel tome.

hilly-1e. Celo'd. for cuedzleo. 01, 13.8; I, 5.3.

Cryetele eating et loo-161%..
Found: Cl, 13.6) I, 5.5, 5.3.

Cryetele melting et 135.5-136.5°c..
Found: I, 5.3.

groperetion of g-norpholinyl-lzg aflhthogngpene

a
.‘, demonic 'w‘o

I ‘ce,cu.’
ca,

 

 

A eizture of 0.1 eole (22 e.) of 2-chloro-1-(2-nephthoxy)pr0pene
end 0.3 hole (20 3., 26 .1.) of lorpholine wee refluad for 2h houre.
The reection nixture wee then treneferred to e lerger fleck end diluted
with ieopropyl ether. Hydrogen chloride gee wee bubbled into thie
eolution to precipitete the hydrochloridee . The hydrochloridee ‘eere
dieeolred in weter to {Oomute their leperetion from the ilopmpyl

t

26

ether eolution of the eterting neteriel. After eeperetion of the leyere
the equeoue leyer wee weehed once with inepmpyl ether. Thie weehing
wee added to the impropyl ether leyer, which he then dried over
'drieriteJ' After maul of the eolvent 2.3 g. of unreeoted ohloroether
were recovered. The Ieximul percentage reection wee therefore 90.

The weter leyer ue wede heeic with eodiue cerhonete to liberete
the mince, which were eepereted by three extrectione with heneene.
After ch-ying over 'drierite' the beneene end exceee norpholine were
removed by dietilletion end the product wee vacuu- dietilled. i pele
yellow oil boiling et 182-1890. (worn) under 3 we. preeeure end
hem; e zen-entire index of 1.5877 et 19°C. eee ohteined. the yield
wee 21.5 e. (791).

The nine wee dieeolved in dry iSOpropyl ether end the Wehloride
he precipiteted with enhydrone hydrogen chloride. The twdrochloride
thine ohteined wee dieeelved in eeetone end ieOpropyl eloohol. Ieogropyl
ether wee edded to produce e elightly turbid eolution free which the
Mdrechloride cryetellieed on etending. in 863 yield of hydrochloride,
thich eelted et 163.5-16h°c. efter e eecond recryetellieetion, wee
ohteined.

enelyeie. Gelc'd. for c,,n,.cmo,a Cl, 11.9, H, 11.6.

Found: 0)., 12.0) I, h.7.

Pre etionofl 2- htho ~2 ieri 1r

,ca 3,

“4302,9341 '0 ca,
_ . 4' ca, cups;

27

A mixture of 0.1 role (22 g.) of 2-chlom-lc-(2-nephthoxy)pr0pene
end 0.3 male (26 g., 30 ml.) of piperidine wee refluxed for 2h houre.
The reaction mixture wee diluted with ieOprOPyl other end hydro gen
chloride gee was bubbled through the eolution to precipitete the hydro-
chloridee of the mince. The hydrochloridee were dieeolved in water
end the leyere were eepereted. The equeoue leyer wee weehed once with
ieopropyl ether. The ieOprOpyl ether leyere were entwined end dried
over 'drierite.‘ The eolwent wee removed from the dried ether eolution
end 10 .S g. of unreected chloroether use recovered, indicating thet
521 bed reected.

The equeoue luer wee cede beeic with eodinw cerhonete to libel-etc
the nine, which m then extrected three tieee with beneene end dried
over 'drierite.' The benzene end emcee piperidine were renewed frm
the product by dietilletion. The tertiery line we dietilled under
3 en. preeeure to give 11 3. (hot) of product boiling et 170-173°0.
(decor-r). The retjrectiwe index fie 1.5838 et 19.508.

To propere the lvdrechloride the nine wee dieeolwed in dry ice--
propyl ether end dry hydrogen chloride gee wee peeeed tin-ouch the eolu-
tion. The wdrochloride fie recryetellieed Ira ecetone, ieepropyl
elcohol, end impropyl ether. A 973 yield of the hydrochloride wee
obteined. Two oryetel tom. eeltihg et lat-165.500 . end 190-19o.s°c .
were ieeleted. The ten eeltinz et 1611-65 5°C could be wede to re-
eolidiry into needlee which eelted et 190.190.5°c. The enelyeee were
perfumed on the eryetel {one ulting et 190-190 .560 .

Anelyeie. Gelo'd. for eunucme 01, 11.91 I, h.6.

Found! 01, 11.83 I, 11.6.

28

eretion of 1- 2- htho -2 Ii 1 no ene
m 3"?“
/ (in, trace,

A wixture of 0.1 eole (22 g.) of 2-chlor0-1-(2-nephthozy)pr0pene
md 0.3 eole (21 3., 25 ll.) of pyrrolidine wee refluxed for 2h houre.
The reeotion eixture wee diluted with ieopropyl other end the hydro-
chloridee of the mince were precipiteted with geeeoue hydrogen y
chloride. The hydrochloridee were dieeolwed in weter end the other
leyer wee eepereted. The equeoue leyer wee weehed once with ieopropyl
ether. The oowbined ether leyere were dried over “drierite' end then
ewepereted to give 3.? g. of enroected chlercether, thue indiceting
83$ reaction. ‘

The equeoue eolution of the hydrochloric!” wee wede beeic with
eodiu oerbonete to liberete the mince, which were extreoted with
three portione of beneene . After drying ever 'drierite' the beneene
end exceee pyrrclidine were renewed by dietilletion end the tertiery
eeine wee dietilled under 3 In. preeeure to give 21 7.. (83!) of product
which boiled et 167-173°O. (uncut-r.) end hed e‘refrective irdex of
1.58112 et 20°C.

In order to propere the hydrochloride the enine wee dieeolved in
dry ieopropyl other end enhydrone hydrogen chloride wee bubbled through
the eolntion. The hydrochloride wee recryetellieed free ecetone, ieo-
propyl elcohol, end ieopropyl other. in 88% yield of hydrochloride
melting et 169—170.5°C . he obteined. 0n recryetellieetion of thie

29

pmdect for e eecond tine fro- the eene eclrente e ulting point of
155-155 .500. no charred) epperently the product ney cmtelliee in
two fer-e. The enelyeee were «flied out on the cryetele nelting et
155455.506.
inelyeie. Celc'd. tor eunucmou 01, 12.53 I, 14.8.
rounds c1, 12.2, 12.3; I, n.9, hJ.

much of 2-dietglelinc-l-s 2-gghthog2mgg

 

In eeeh or ten eeeled tuhee wee pleced 0.1 nele (22 g.) or 2-ehloro-
1-(2-nephthozy)propene end 0.3 ncle (22 ¢.. 31 :1.) er uuwmm.
the» were then heeted et 100-105°c . for 72 More . The contente e: the
tubee were nehed out with inapropyl ether end outlined . Oeeeoue
hydrogen chloride wee bubbled through the eolnticn to precipitete the
hydrochloridee, which were then dieeclved in weter. the legere were
eepereted, the emcee luer ue weehed with iecprepyl ether, end the
combined ether leyere were dried over 'drierite.' After the eolvent wee
reloved a. the dried ieopropyl ether eclntien the reeidue of meeeted
chlercether wee dietilled. A totel of 3h 3. of chloroether m recovered,
indiceting e Iain. reection e! 221.

the emcee mer wee nede belie with ecdim eerbonete to liberete
the uinee, which were extreeted with {our portione o: heneene. the
beneene ecluticn wee dried over "drierite ," exter edaich the drying egent
wee filtered err, the 'eolwent end eeceee diethyleeine were renowd, end

30

the product wee dietilled. it e preeenre or 3-3.5 In. the mine boiled
et 153-161°C. (morn) end weighed 6 g. (121) . the refrective index
wee 1.5712 n 20°c.

The nine wee dillolwed in dry impropyl ether to precipitate the
lnrdroohloride by the eddition of dry hydrogen chloride gel. The oily
twdrochloride would not cryetelliee tro- eny of the eolvente or eolwent
lint-urn tried, but elweye me out ee en oil. Attempte to obtein e
cmtelline «Hecate , beneyl chloride, or ethiodide eleo teiled .
Coneeqnently, the mine wee regenereted end redietilled. A nitrogen
enelyeie wee eel-tied out on thie redietilled nine.

inelyeie. Celc'd. (or enhance l, 5.1;.

Pound: I, 5.1.

Pro etion of 2-dinet lenim-l 2- htho re

 

e eixture of 0.05 eolee (ll 8,) of 2—chlorcal-(2onephthoxy)propene,

0.2 nole (33 :1.) of 33: «been: eolution or dilethyleeine, end 20 e1.
dioxene m heeted in e eeeled tube et IOU-105°C . for he honre. After
the tube wee opened, the contente were nehed out with ieopropyl ether.
The hydrochloridee were toreed with geeeone hydrogen chloride, where-
upon they dieeolwed in the equeoue leyer. Here weter wee edded to
dieeolwe the hydrochloric!» completely . The leyere were lepereted end
the wet-er leyer no weehed with inepropyl other . The leopropyl other

31

layers were dried over "drierite' and evaporated to give 1.3 g. of un-
reectod chloroether, indiceting 88$ mention.

The equeoue lever wee Iede beeic with eodime oerbonete to liberete
the mince, which were extreoted with four portion or beneene. The
benzene eolution wee dried over 'drierite .' After removel of the
benzene by dietilletion the product no distilled under wecnm to give
9 g. (785) of product boiling et 180-182°c. (morn) under 1; mm.
preeeure.

The deroohloride wae prepered by passing enhydrone hydrogen
chloride into en ieopropyl ether eolution of the eeine end recryetellie-
ing from ecetone, ieopropyl elcohol, end ieoprooyl ether. i 95% yield
of hydrochloride wee obteined. . The white cryetele melted eherply et
139-lh0°0. efter e eeoond reoryetellieetion.

inelyeie. Oelc'd. for cumfimos 01, 13.83 I, 5.3.

Found: Cl, 13.7; I, 5.1»-

WI

1. 1-Chloro-2-(2-nephthoxy)propene wee propered by interection c:
l-ohlerowa-beneeneeultonomropene end fi-nephthol in en eqmone elkeline
wediu . The l-ohloro-Z—beneeneeultonnypropene wee prepered by treeting
propylene chlorohydrin with beneeneeulfonyl chloride in the preeence of
I eodiul hydroxide .

2. 2-Cb1cro-1-(2-cepbtbcxymcpm wee eyntheeieed rm 2-Way»
1-(2-nepbtbeaq)prcpene by treetnent with thionyl chloride. The 241qu-
l-(z-nephthoxy)propene wee prepered by intereetion of propylene chloro-
hydrinend fi-nephtholinenelkelinenodim.

3 . Tertiery ewino deriwetiwee c: lochloro-Z-(Z-nephthoxy)pmpene
end 2-chlerccl-(2-nephthoxybropene were prepered by hating the chloro-
elkyl ethere with earpholine, piperidine, pyrrolidine, diethyluine,
end dieethyluine. All or the ,tertiery uinee emcee-ed ee high boiling
liquide .

h. The hydrochloridee or the tertiery ninee were prepered.
Bowerel of the Indrochloridee eppeeredte exiet inecre then one eryetel

tore.

RQEREECES

33

.REFERENCES

1. Burger, 1., Hedicinel Chemist , Vol. 1., New Iork end London:
InteneWfiFE'eWfiS’fl, pp . 31114-5, nu .

2. Rerbet, a. 14. end Johann, 2.. J. Org. Chem, 11. 693-7 (1952).

3. Know, 1... 3a.. 2g. nus-9 (1905).

1.. Wright, 3. a. mum", n. 3.. J. An. cm. 800., 1;, 2281-3 (1951).

5.31m, 1. end mm, 1... mm, fig, 256-8 (1911).

6. 61.0, G. 3. end Perm, w. 3., J. Chem. 506., 151., 6.2-9 (1922).

7. 18m, 2.. Ber. 53,, 1836-9 (1920). '

8. 131cm, z., Ber. 52, 1810.7 (1920).

9. time? U.)R. md Richter, G. 3., J. Am. Chen. 800., 2, 31:09-18
1929 e

10. Inert, 1.. end Roth, P., Ben, 12, 11423-1; (1906).

11. Geo-1e11, l. H. end litegibbon, V. 8., J. AI. Chem. 300., 19,
387-9 (191.8) .

12. Herbet, R. 1!. end W. J. V... J. Org. Chem... 11. 595-99 (1952) .
13. 011311, 8., editor, Oriana mtheeie, Coll. Vol. 1, 2nd ed.,
lee tax-k0 John ey end ne, ., 19116, pp. 1115-7.
11.. mean, a. c. end mum, J. 3., J. Org. one... 9.- 706-11 (191.9).
15. Poe-11, s. 0.. J. 1-. on... 800., 1.2, 2708-11 (1923). '
16. Gerrard, w.. J. cm. 801%., 99-103 (1939): 213-30 (191.0).
17. cups, 2., am. Boo. cm. knee, 5;, 1075-81. (1933).
18. am, a. n. u: Perlete, 2., J. 1-. Chen. soc. 90;. 38.1.0 (19h6).

19. Bubeoh, I. end Rider, ‘1‘. 3., Ind. Eng. Che-”A1111. 3d,, 1, 165-6

 

 

(1935).

20. Lepper, K. In, editor, Official end Tentative 110th of the
Aeeooietion of Of! c (2 ur C late, 6th ed.,
Weehington, . .1 nos 11 a or 31-1611le

Chant. ’ 1915, P e 27 e

 

 

 

 

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