Stereochemical studies—971a. Saturated heterocycles—991b

F. Ffnop er al.

2346 iodide

salt

iodine,

the

thioether

proved

the

analogous

ditions, and g.

of

which

2 and 4 with

iodide

formed.

substance

However,

!, gave

on slight

containing

under

no ionic

identical

a 3~7 mixture

of

concompounds

heating,

could be transformed 2 and 6 were obtained in good yields

derivatives

methyl

2.

derivative

mixture,

2-methylthio

pounds

thiolcarbamate

trans-thioxo

Compound $ in this

The desired

1, but a water-insoluble

to be the

iodide

in the presence

of

-CiS

I

-cis:

2

-6 -cis:

trans: -_

8

trans: -_

4

trans:

a base

binding

to a. from com-

the hydrogen

X=Br:

2

6

2

x = Cl:

&E,

Scheme 1 In the

reaction

113 formation of the corresponding Z-__ with methyl iodide, methylthio derivative was supposed 14 and the correct structure 12g ___ of the reaction 17 product was later determined . An analogous finding was made for the oxazine 15 18,19 17 homologues . On the basis of earlier literature data , Clapp --et al. assumed that the 4,4-dimethyl substitution exerts a stabilizing effect in the reaction of of

4,4-dimethyloxazolidinethione

S 6;;

s I-CT$-(C&+,-NW-SCT+S

-

-r

methyl

ring-opened

n = 1

119 -___ gig

n = 2

amine hydrobromide19 As the

above

has not

been

nations

are

reaction

seemed

vative

2.

After

with

the

reagents

detailed

proving

that

its

a short

standing

iodide

to give

on the action

bromoethyl-

different. methyl

of

studies, and contradictory results 17-19 , we performed investigations step

in the

reaction takes

iodide

by adding

quantitative

was achieved

reaction

of

deri-

thione

The ring-opening

the hydrogen

of

was obtained

S-substituted with

the

Formation

from 4,4-dimethyl-2-oxazolidineare

IR

iodide

and explaon the

generalizability.

the first iodide.

12.

vative

in the two reactions

ring-opening

of

structure

the corresponding

on the subject

hydrogen

in nearly

hydrogen

129

aim of

likely of

mechanism

was formed

n = 2

surprising

on the.action

this

&ZZe

subject

the

formation

step, of

the

n = 1

, 1.~.

to be found

with

It the

However, the intense -1 at 1646 cm rather indicates

band’g

Go

with

iodide.

formed hydrogen

(Scheme iodide

at room temperature, yield.

The trans

the ring-opened

urea

is S-methylation, place 1). to

the isomer

with

in the following Unambiguous

the

proof

2-methylthio

deri-

ring-opened

product

6,

reacted

derivative

however, fl only

2

on slight

heating. The cis chloride

compound

derivatives

2 and Je could

oxazolidinethione the of

4,4-dimethyl the bromide In contrast

cis-

2 underwent

at room temperature, relative

no reaction

be isolated. to that

substitution

with

but on refluxing of

hydrogen

bromide

in ethanolic the stability

Thus,

P-bromoethylamine

as assumed earlier

“,

but

or hydrogen

solution of

the halogen

4,4-dimethyl-2-

hydrobromide

is

to the

nucleophilicity

lower

due not

anion. to

the

reactions

of

2 and f,

ethanol

at room temperature

opening,

but the expected

to yield 2-thioether

not

their

structural reacted

and trans-l,S-perhydrobenzoxazine-2-thiones, the

hydrogen

isomers12

with

methyl

iodomethylthiolCaTt)aA5’tas iodide

salts

(12,’

16).

and

iodide

13, in

by ringThe

to

F. 1FoL(kCI al. Tebla

1.

Selected

Com-

IR and

‘H NHR date

IR bands

pound

on compounds

j-&Q,

12 and 16’

,.hemical

shifts

(bppm)

Coupling

constants Jag,

(Hz)

?NH

3c=o

SC=N

42-H

bz- H

10-H

Jbtz, b&

-

-

1615

4.21

4.06

3.59

-10.4

3.4

4.5

-

-

1650

4.19

3.90

2.91

-10.2

4.4

10.8

5

5

‘bg,

3300

1630

3.22

2.98

4.39

-9.9

6.0

8.5

3280

1630

-

3.41

3.05

3.60

-9.6

2.9

9.6

3200

1625

-

3.42

3.19

4.40

-10.2

6.5

8.1

3150

1630

-

3.54

3.32

4.40

-11.0

6.6

7.1

-

-

1620

3.51

3.31

4.44

-15.7

5.3

2.6

-

-

1615

3.49

3.04

3.84

-15.6

5.0

11.1

and trans

(A@)

a For ease of comparability of the spectroscopic data on the compounds investigated, the following numbering has been used:

distortion

in the heterorings

compounds

were identified

compound 15, O-inside --

analogously

firm

to

predominates

Table

2.

of

compounds. with

the P-thioxo (Fig.

The &

earlier

(12)

NMR parameters9.

derivatives

In the -cis earlier ‘1, the

investigated

1).

13C NMRchemical

shifts

of

compounds

13C NMRchemical

Compound

these

by comparison

shifts

Z-JP,

12 and iaa

(6ppm) c-9

c-10

21.3

32.3

52.3

13.5

25.3

34.1

58.5

13.5

C-2

C-b

C-5

C-6

C-l

c-e

z

156.5

10.5

32.3

2b.lb

2b.2b

6_

157.2

71.6

38.0

27.3

25.3

SCH,

I

167.6

0.7

43.1

21.1

24.1

21.0

30.5

50.6

12.2

B

167.3

11.5

45.2

32.3

25.3b

25.0b

33.5

54.9

12.2

P

167.1

35.8

42.7

26.1

24.0

20.9

30.4

49.6

12.2

lP

167.5

46.15

42.7

25.1

24.0

20.9

30.3

40.9

12.1

12

157.2

49.6

32.5

25.2

23.9

19.9

29.8

74.7

13.2

16

157.7

50.4

37.6

28.2

23.9

24.9

31.1

79.7

13.2

is

possible.

a See Table

1.

b Reversed

assignment

also

EXPERIMENTAL The ‘H and “C on a Sruker meter, spectra data

NHR spectra

YM-250 spectrometer

respectively, were

recorded

and the

synthesis

were

recorded

and at 20.14

in COC13 solution,

with

in

5 and 10 mm tubes UP-80

TMS as internal

standard.

on a SPECORO 75 IR spectrometer methods

are

given

in

at

MHz on a Bruker

Table

3.

in KBr pellets.

250.13

MHz

SY spectroThe

IR

The physical

s~8-.saturatalhetcrocycka-99 Reaction

of

2 - or 4 _ with

Thioxo methyl

compound

iodide

reaction

of

Thioxo ml) with product of

wes

methyl was

the

iodide extracts,

H.p.

30% thioether

in

3.

(OC)

5

oil

6

6

oil

B

presence

which,

of

of

the

conditions,

on refluxing

water ml).

for

on compounds

C

H

N

8)

5X methanolic

KOH (20

(20 ml) vas added

After

drying as

>-1Q, - -_

Found (X)

(X1

in

2 or $ was obtained

data

Yield

KOH (Method

gl was stirred (3x30

thioether

Analytical

ml> and

(30

Under similar

salt,

evaporation,

extraction

the

Method

pound

the

0.85

After

(1 ill.

chloroform

5 hr and evaporation

was obtained.

(1)

iodide

by ether

Table

Corn-

methyl

for

in

compound e.

2 or 4 (5 mmole,

isolated

combined

about into

converted

compound

standing

product

compound fl with

A)

g> was dissolved

After

edded.

2_ or 4_ with

(Method

0.85

a crystalline

was completely

Reaction

iodide

2 (5 mmole,

(1 ml)

mixture,

compound 4 gave 3 hr,

methyl

2349

and the

and evaporation a pale-yellow

oil.

12 and IQ

Calculated

Formula

(Xl

c

H

‘N

89 82

50.59 58.25

0.46 8.25

7.99 7.97

C9N15NOS

50.34

8.16

7.56

97 78 L$

34.72 34.47

5.32 5.32

4.97 4.22

C9H161NOS

34.51

5.15

4.47

I

116-117a

;

!!

127-12Sb

;

P

SO-8Sb

C

61

40.94

6.74

5.05

CqH166rNOS

40.60

6.06

5.26

19

50-55c

C

63

40.06

7.81

6.61

C9H16C1NOS

40.74

7.27

6.32

lZd

112-114’

A A

95 93

34.27 34.11

5.40 5.12

4.66 4.92

C9H161NOS

34.51

5.15

4.47

Jhd

170-172a

a From EtOH. b From EtOAc. Reaction

of

2 (0.5 stand

5 - or 6 - with

cc.

salt

6 underwent

HEr or cc.

Attempted

12 (0.5

il could

lit.9

of

thioether for

Al and &B1’. m.p.

was refluxed by

185.5-186 of

residue

extracts,

was obtained,

epimerizetion

be detected

the

was refluxed

oil

oxazinones ‘C,

Attempted

gl

of

d Hydrogen

(Method (15 ml)

salts

for

6 hr.

3 hr.

was extracted

with

crystalline

products

12 and 16 (Method (25 ml>.

‘H NMR spectrum

Under similar ‘C).

of

conditions,

was allowed The trans

After

thioether

evaporation

chloroform. (I-lQ> _ __

and

After

were obtained.

01

On evaporation,

which

to

The ring-opening

HI (1 ml).

HI for

S hr in ethanol the

salt.

and the solution

40X aqueous with

iodide

C)

out by refluxing

on refluxing

10% NaOH, the

ring-opening

crystallizing

with

HCl was carried

and evaporation

186-187

halides

in ethanol

ring-opening

with

neutralization

of

hydrogen

g) was dissolved

with

ture

From I-hexane.

1 hr at room temperature

for

drying

’

suggested

16 __ gave

a slowlya 3:l

18 __ (67X,

mixm.p.

11

for R hr in ethanol 1 H NMR spectroscopy;

(20 ml)

with

4gX aqueous

70% unchanged

HI (1 ml).

&I was recovered.

No ia

F. Ftkdr er al.

2350 References la

Part for

96:

Gy.

Argay,

publication;

A. Kalman,

lb

Part

submitted ’ 1.

Kanetani,

for

Heterocycles,

12,

735

J.

Simon,

Szabb,

G. BernBth, L.

Fodor,

2.

&.

accepted

Struct.,

E. Szfics,

G. BernBth,

P.

Sohar,

publication.

K. Kigasawa,

’ A. V. Bogatskii,

L.

98:

M. Hiigari,

K. Yakisaka,

H. Sugi,

K.

lanigera,

(1979).

N. G. Lukianenko,

1.

I.

Kirichenko,

-.

E.

Soed _*,

1%@,

723. 4

K. T. 29,

Potts,

1677

’ P.

Richter,

6 I.

Lantos,

0.

E.

K. G. Bordeaux,

Y. R. Knehuling,

R. L.

Salsbuny,

2.

m.

m.,

(1965). D. Horgenstern, P.

E.

Griswold,

Pharmazie,

Bender, 0.

T.

22,

’ F.

Fulop,

G. BernBth,

P.

* F.

Fiilop,

G. Bernath,

Gy.

2.

Med. u.,

SohBr,

I.

(1984).

B. H. Sutton,

K. A. Razgaitis, Walz,

301 21,

Pelcter,

. s.

2.

A. KBlmtin, P. SohBr,

Argay,

M.

J.

Oi Hartino,

72 (1984). Perkin

I,

Tetrahedron,

C!Nj, ip,

2043.

2053

(19B4). 9 G. BernBth, lo

Gy.

GtindBs, K. Kovks,

A. E.

G. StBjer,

Szabb,

F.

P. Sohar,

Fulop,

Tetrahedron,

G. Bernath,

P.

20,

Sohar,

981

(1973).

Heterocvcles,

13,

1191

(1982).

l1 F. Fiilijp, l2

G. Bernath, A. E.

G. Sttijer, Tetrahedron,

13

14

P. SohBr,

22,

1829

G. Bernath,

A. F. McKay,

M.

1’

T. Hukaiyama,

l6

F.

Csirinyi,

Gy.

Sohar, F.

Tetrahedron,

a.

m.

Kuwajima, J.

Reson.,

Can.

2.

2o 0.

M. Grant, F.

22 F. W. Wehrli, London,

1978,

8. V. Cheney,

Fiiliip, pp.

for

A. KBlmBn,

22-48.

159 49,

publication. Gy.

Argay,

P. SohBr,

2.

A. Szabb,

G. BernBth,

3. fi.

&.

a.

Interpretation

a.

(1963).

Chem.,

21,

-Can. a.

2.

@.,

Q,

1982, 1149. _-__ 2, 107 (196B).

m., 24,

m.,

Reson.,

of

32 (1966).

Synthesis,

Heterocyclic

%.,

w.

(1973). 205

K. Hikui,

G. Bernath,

T. Wirthlin,

2,

Chem.,

L. Long, J., ” R. C. Clapp, F. H. Bissett, 18 H. Skulski, 0. L. Garmaise, A. F. McKay, 19 R. C. Clapp, L. Long, T. Hasselstrom, J. 21 P. SohBr,

accepted

G. BernBth,

FiilBp,

(19B3).

E. Kreling,

I.

FulSp,

P.

Szabb,

za, 5315 22,

Carbon-13

815

1308

(1956).

(1963).

(1967). 527

(1984).

NMR

spectra,

Heyden

Ltd,