ELSEVIER

Journal of

Journal of Molecular Structure 377 (1996) 277-288

MOLECULAR STRUCTURE

Synthesis, structure and conformational analysis of imidazo-thiazines

Pi1 PerjCsia, Pi1 SohBrby *, Zsolt Bijcskei”, GBbor Magyarfalvib, odiin Farkasd, Marianna Mike

‘Department of Medical Chemistry, University Medical School, P.O.B. 99, H-7601 Pees, Hungary bDepartment of General and Inorganic Chemistry, Lorand Eiitvds University, P.O.B. 32, H-1518 Budapest, Hungary

‘CHINOIN Pharmaceuticals, P.O.B. 110. H-1325 Budapest, Hungary ‘Department of Organic Chemistry, Lordnd Eiitviis University. P.O.B. 32, H-1518, Budapest, Hungary

‘Cenlrat Research Institute of Chemistry, Hungarian Academy of Sciemes, P.O.B. 17, H-1525 Budapest, Hungary

Received 3 August 1995; accepted in final form 25 September 1995

Abstract

BFs .OEtz-catalyzed reaction of chalcones (2) with imidazolidine-2-thione (1) yielded 2,3-dihydro-5,7-diaryl-7% imidazo[2,1-b][l,3]thiazines (3). The structure of the compounds was confirmed by MS, X-ray and NMR studies. Ab initio and semiempirical theoretical calculations were carried out to corroborate experimental findings concerning the possible conformations of the products.

Keywords: Conformational isomerism; Synthesis; Imidazo-thiazines

1. Introduction 2. Results and discussion

Earlier we reported that the BFs . OEt,- catalyzed reaction of imidazolidine-2-thione (1) with 2-benzylidene-cycloalkanones is a versatile route for synthesis of tricyclic condensed skele- ton heterocycles with imidazo[2,1-6][ 1,3]thiazine moiety [I]. As the rather rare ring system is of interest from both biological [2] and synthetic [3] aspects, we investigated the similar reaction of chalcones 2a-h with 1, which was expected to yield bicyclic 1,34hiazines 3a-h.

* Corresponding author.

Compound 1 was treated with chalcones 2a-h in absolute CHCls solution in the presence of BFs . OEt, as catalyst. In these reactions only one of the possible structural isomers was formed as a. racemic mixture, which was confirmed by TLC and ‘H NMR investigation of the crude reaction products. The compounds obtained were charac- terized as hydrochloride salts (3a-h). From 3a-c the corresponding bases 4a-c were liberated for spectroscopic investigations. The liberated bases showed the same physical and spectroscopic charac- teristics (m.p., IR, ‘H and t3C NMR) as the respective 4a-c obtained by direct crystallization from the crude products.

0022-2860/96/$15.00 0 1996 Elsevier Science B.V. All rights reserved SSDI 0022-2860(95)09123-8

218 P. Perjhi et al./Journal of Molecular Structure 377 (1996) 277-288

I: s

c -+I@ + I. BW(Wd2

NH 2. NH, 3. HCI

1 2a - h

NH3

3a - h 43-C

Scheme 1.

Based on the investigation of the reaction of 1 with 2-benzylidenecyclanones [l], reaction of 1 with chalcones 2a-h was expected to furnish compounds 3a-h with a As double bond. Since isomerization of the primary products under the reaction conditions cannot be excluded, MS, X-ray and NMR investigations were performed to corroborate the structure of the compounds.

The electron ionization mass spectra of 3a-c (the hydrochloride salts) displayed abundant peaks of molecular ions of the base components (4a-c). Exact mass measurements revealed their expected elemental compositions. The main and common primary fragmentation route of the compounds is

Table 1 Partial metastable daughter ion mass spectra of [M+--721 ions of 3a-c

Processes

[M+-721

[M+-721

3a

-C&l,CN $

-C&H&N,

3b

100

-

3c

100 38

8 100

the loss of CHzNCS to form the most abundant fragment ions, [M+-721. This feature, which was also observed for the above mentioned tricyclic analogues [l], reflects the presence of a common heterocyclic skeleton for the compounds. The lower parts of the mass spectra showed significant differences, and on this basis the isomeric struc- tures 3b and 3c were easily distinguishable. The metastable daughter ion spectra of the [M+-721 ions provided a firm basis to differentiate between the C(5) and C(7) substituents. Metastable decom- position of the [M+--721 ions of both 3a and 3b is very selective, consisting mainly from C6H&N losses, while that of 3c fragments by highly selective loss of ClC6H4CN (Table 1). This clearly indicates that it is 3c which has the 4-Cl-phenyl substituent in C(5) position. Thus, the orientation (mechan- ism) of the ring closures is the same as was observed earlier [ 11.

In order to determine the position of the double bond in the reaction products a crystal structure analysis of 4a was performed. The struc- ture of the molecule is shown in Fig. 1 by an ORTEP

P. Perjhi et al./Journal of Molecular Struclure 377 (1996) 277-288 279

Fig. I. Crystal structure of 4a. Selected bond distances (A) and angles (“): S(8)-C(9) 1.740(3), S(S)-C(7) 1.834(4), N(4)-C(5) 1.393(4), C(5)-C(6) 1.337(5), C(6)-C(7) 1.496(5), C(7)-S(8)-C(9) 98.8(2), N(4)-C(5)-C(6) 122.7(3), C(5)-C(6)-C(7) 124.3(2), C(6)-C(7)-S(8) I11.4(3), C(6)-C(7)-C(16) 114.1(l)“.

drawing using 50% probability thermal motion ellipsoids. The S(8)-C(9) bond length is 1.740(3) A, significantly shorter than a normal single C(sp*)-S bond, which indicates some kind of delocalization of the lone pair of S(8) toward the C(9) atom. The lone pair of the N(4) atom is also delocalized towards both of its sp* neighbor carbons [C(5) and C(9)]. The C(5)-C(6) bond can be identified as a pure double bond, while the C(6)-C(7) is a single bond and even the H-atom bonded to the C(7) can be clearly seen in the difference Fourier map.

The six-membered ring is in a half-chair con- formation and the sulfur atom is 0.32 A above, while C(7) is 0.55 A below the general plane of the remaining seven atoms of the two rings. The two phenyl rings form angles of 62.5” [that con- taining the C(lO)-C(15) atoms] and 100.0” [that

containing the C(16)-C(21) atoms] with the plane mentioned above. The interplanar angle of the two phenyl rings is 60”. (See Table 6 for further details.)

The ‘H and 13C NMR data proving the struc- tures of 3a-h and 4a-c are given in Tables 2 and 3. The assignments were supported by DNOE [4,5], 2D-HSC (heteronuclear shift correlation) [6], and DEPT [7,8] measurements. An interesting and characteristic difference was observed between the ‘H NMR spectra of the same base or salt regis- tered in CDC13 and DMSO-&. Especially, the values of vicinal proton-proton coupling constant J[H(6),H(7)] in the two solvents differ significantly; in CDCl, they are 4.7 Hz (salts) and 4.5-4.8 Hz (bases) while 6.6 f 0.1 Hz (salts) and 5.8 Hz (base) in DMSO-L&. Such a high difference in vicinal coupling constants cannot be interpreted merely by solvent effect [12].

Table

2

Char

acte

ristic

IR

fre

quen

cies

(in c

m-‘)

in

KBr

disc

s and

‘H

NMR

data

(ch

emica

l sh

ifts

(6)

in pp

m,

coup

ling

cons

tant

s in

Hz,

& M

s = 0

ppm

) in

CDCl

s or

DM

SO-d

s so

lution

a at

250

.15

MHz

b

Com

poun

d

3a*

vNH

-r&H

band

(p

-disu

bst.)

693

H(6

)

5.47

H(7)

J&

,7)

C&(2

) C&

(3)

d(l

W

d(1

HI

m (

2 H)

m

(2 H

) a L

5.44

4.

7 -4

.1

?,j;

3100

-210

0 75

5

-4.1

%

s 1

3.8-

4.8

3

3.75

F h

3.84

2 2

3.75

5

3a

3b

3e

3d

3e

3f w 3hj

4a*

705

704

695

705

694

704

694

705

5.74

5.

62

6.6

5.74

5.

62

6.7

5.52

5.

4 4.

7 5.

72

5.60

6.

7 5.

16

5.68

6.

6 5.

13

5.61

6.

7 5.

50

5.40

4.

7 5.

67

5.57

6.

4 5.

13

4.99

4.

7

3.9-

4.15

3.

95-4

.15

3100

-210

0 82

5 75

8 31

00-2

100

822

754

3 100

-220

0 82

2 75

8 31

00-2

100

826

761

3100

-220

0 83

7 77

2 3 1

00-2

200

811

747

3 100

-220

0 80

9 76

8 -

-

3.9-

4.1

3.9-

4.15

3.

9-4.

15

3.9-

4.1

3.4-

3.6

774,

746

707,

695

4a

4b*

5.19

5.

09

5.15

5.

8 3.

40

3.55

4.

95

4.8

3.53

83

4 75

9 70

6

- 82

4 -3

.90

2 %

167

692

5.20

’ 5.

15

4.99

4.

5 3.

40

3.62

-3

.55

4b

442 a C

DCls

* so

lvent

for

3c,

g an

d 4c

, DM

SO-d

, fo

r 3b

,d-f

h, b

oth

CDCl

s* a

nd D

MSO

-d,

for

3a a

nd 4

a,b.

b Ass

ignm

ents

wer

e pr

oved

by

DNOE

an

d ZD

-HSC

mea

sure

men

ts in

CDC

ls (

4a,b)

an

d DM

SO-d

6 (4a

). ’ I

nten

sity:

10

H fo

r 3a

and

4a,

9 H

for

3b-h

an

d 4b

,c, r

espe

ctive

ly.

dssk

Inte

nsity

: 5

H/2

H/l

H.

’ 7-P

heny

l gr

oup.

r S

inglet

-like

signa

l. ’ J

(A,

B) =

8.5

(3d,e

), 8.

1 Hz

(3h

) fo

r th

e AA

’BB’

sp

in sy

stem

of t

he 1

,4-d

isubs

titut

ed

arom

atic

ring.

i T

riplet

-like

sig

nal (

2 H)

of t

he a

rom

atic

hydr

ogen

s vic

inal

to

the

fluor

ine

subs

titue

nt:

3Jo”

ho(H

, H)

z3 J

(F,

H):

8.7

Hz.

) 6 C

Hs 2

.33

ppm

(s,

3 H)

.

P

P

Comp

ound

N+

H Ar

H (F

’os.

5,7)

P:

br (1

H)

2. 1-

3 sig

nal(s

)c 2 $

3a*

-13.1

7.3

-7.5d

7.4

5 d-e

J 2 g

3a

-12.2

7.3

5-7.6

5 z

3b

7.45-

7.65

\ 2

3c

-13.1

7.3

-7.5d

” 7.

42g

7.4g

g %

3d

-11.9

7.4

-7.7

7.45g

th 7.6

3gvh

E

3e

4 -1

2.5

7.3%

7.55d

.C

7.6e

h 7.7

2gTh

5

-12.2

7.

27’

7.5-7

.65

9

g*

-13.0

7.

14’

2 7.3

-7.6

3hj

7.23

gh

7.35g

.h 7.4

-7.6d

5

4af

z -

7.2-7

.4 ;;: :

4a

- -7

.3L

7.35-

7.5

T 4h

* -

-7.29

-7

.37d

z 3 4b

7.3

-7.6

h,

4c

7.3-7

.4 7 E

282 P. Perjhi et aLlJournal of Molecular Structure 377 (1996) 277-288

P. Perjhi et al./Journal of Molecular Structure 377 (1996) 277-288 283

Ph

I

H

Ph

Ph

Ph

H E

Fig. 2. Skeletal structures of the conformers of 4a. E and A are the pseudo-equatorial and the pseudo-axial forms, T is the transition state structure connecting them.

The possibility that the tautomeric equilib- rium is shifted towards the A6-structure in CDC&, while the preferred tautomer is the A5- form in DMSO-d6 can be ruled out. In the case of,a tautomeric equilibrium the protons on C(5) and C(7) should be exchangeable by adding D20 to the solution of the compounds investigated. However, exchange was not observable. We tried to check this hypothesis by INEPT [9] and COLOC [lo, 1 l] measurements proving the 3J(C,H) interaction between the C(3) methylene hydrogens and C(5) of sp3 (A6) or sp2 (As) charac- ter for 4a and 4b. However, it was not possible to identify different tautomeric structures in the different solvents.

An alternative explanation is the solvent dependence of the conformations. Assuming the A5-structure proved by X-ray measurement, two relatively stable conformations are to be consid- ered. Both involve a half-chair type arrangement for the six-membered ring. In the conforma- tion found in the solid state (A) the aryl substituent

on C(7) is in a quasi-axial position, in the other conformation (E) in a quasi-equatorial position. As the H-C(6)-C(7)-H dihedral angle is expect- edly about 25” in A and about 90” in E, the respec- tive coupling constants must differ widely, the value in A being smaller.

We have performed a theoretical conforma- tion study to assess the feasibility of the hypo- thesis. An ab initio HF study was carried out for the unsubstituted skeleton of this mol- ecule (2,3-dihydro-7H-imidazo[2,1-b][ 1,3]thiazine). In this case the analogues of A and E are two enantiomeric half-chair type structures, which are interconverted by a ring inversion. The geo- metry obtained for the conformers reproduces the geometry found in the solid state (for 4a) well, i.e. most bond lengths in the ring differ less than 0.01 A, the shortening of the S(8)-C(9) bond and the planarization of N(4) can be observed. In the transition state of the inversion the ring system is close to planarity. The energy barrier is 6.54 kJ mol-‘. Thus the inversion should be virtually free at room temperature.

To estimate the energy difference between the two conformers semiempirical calculations (AM 1 [13]) were carried out for 4a. Two minima were found on the potential energy surface corres- ponding to A and E. The former is more stable by 5.27 kJ mol-‘. The calculated structures were less acceptable in this case compared with the struc- ture determined as rather large quantitative and qualitative differences were found. For example, the arrangement around N(4) was pyramidal, instead of being planar, thus rendering the struc- tures boat-like. The energy of the transition state is 4.3 and 10.6 kJ mol-’ higher than the energy of A and E, respectively.

We can assume the predominance of E in CDC13 based on the crude energy estimate. The measured J-values were 4.65 (in CDC13) and 5.8 Hz (in DMSO-de). This fact implies that form A has a significant contribution to the con- formational equilibrium in DMSO-ds. The stability of A in DMSO requires explanation. The calcu- lations show very small difference in the dipole moments of the two forms. However, in the A form the S-8 atom is more easily accessible because of the quasi-axial position of the vicinal 7-aryl

284 P. Perjki et al./Jownal of Molecular Structure 377 (1996) 277-288

group, thus enabling better interaction with the solvent molecules. This interaction expectedly is not dipolar, but a sulfur-oxygen nonbonded inter- action with the sulfoxide oxygens of the DMSO molecules. Similar arguments may be used to explain the solid state conformation, since the A form can improve packing and enhance intermole- cular interaction. Indeed the nonbonded distance between S(8) and N(1) is 3.70 A.

3. Experimental

Melting points (uncorrected): Boetius apparatus; IR: Bruker IFS-113~; MS: AEI MS-902 (70 eV, 100 PA, 8 kV, direct inlet, 190°C source tempera- ture); ‘H and 13C NMR: Bruker WM-250; Thin- layer chromatography (TLC): Ready-to-use plates with silica gel 60 F2s4 (Merck); Elemental analyses: Department of Organic Chemistry, Lorand Eotvos University, Budapest; Chalcones [ 141 and imidazolidine-2-thione [ 151 were synthe- sized by literature methods.

3.1. General procedure

Imidazoline-2-thione (0.02 mol) was suspended in 100 ml of absolute CHC13 solution of chalcone 2a-h (0.02 mol). The mixture was cooled to 0°C and BF3. OEt, (0.04 mol) was added dropwise with stirring during l/2 h. It was stirred with cool- ing for an additional 2 h, then the stirring was continued at room temperature. After completion of the reaction (lo-14 days) the mixture was cooled and made alkaline with 25% NH3 solu- tion. The aqueous solution was separated, extracted with CHC13 (2 x 50 ml), and the com- bined organic layers were washed with water (3 x 50 ml), dried (NazSO& and evaporated. The oily residue was dissolved in ethanol, cooled to O”C, treated with dry HCl, and the separated colorless solid was crystallized from ethanol/ ether (Method A), or the oily residue was dissolved in Et,0 and kept in refrigerator over- night (Method B) to obtain 3a-h and 4a-c, respec- tively. Liberation of 4a-c from the respective 3a-c was performed at 0°C using 25% NH3 solution.

3.1.1. 2,3-Dihydro-.5,7-diphenyl-7H-imidazo[Z,l-b] [1,3]-thiazine hydrochloride (3a)

Yield: 5.7 g (87%; Method A), m.p. 21 l-214°C (decomp.); MS, m/z (%): 292.054 (100) [M+‘, C1sHi6N2S], 259 (18) (M+-SH], 220 (76) [M+-721, 208 (32), 207 (35) 117 (41), 102 (26), 91 (62), 77 (35); C1sHi7C1N2S, (328.9): calcd. C 65.74, H 5.21, S 9.75, Cl 10.78; found C 65.58, H 5.28, S 9.67, Cl 10.94.

3.1.2. 2,3-Dihydro-5,7-diphenyl-7H-imidazo[2,1-b] [ I,3 Jthiazine (4a)

Yield: 3.6 g (62%; Method B), m.p. 103-105°C (diethyl ether); C1sHi6N2S (292.4): calcd. C 73.94, H 5.52, S 10.97; found C 73.78, H 5.45, S 10.61.

3.1.3. 2,3-Dihydro-5-phenyI-7-(4-chlorophenyl)-7H- imidazo[2,1-b][l,3 jthiazine hydrochloride (3b)

Yield: 6.2 g (85%; Method A), m.p. 239-242°C (decomp.); MS, m/z (%): 326.063 (100) [M+‘, C,sH&IN2S], 293 (13) (M+-SH], 254 (73) [M+-721, 151 (19), 91 (66); C1sH&12N2S (363.3): calcd. C 59.51, H 4.40, N 7.71, Cl 19.52; found C 59.21, H 4.39, N 7.41, Cl 19.74.

3.1.4. 2,3-Dihydro-5-phenyl-7-(I-chlorophenyl)- 7H-imidazo[2,1-6][1,3Jthiazine (46)

Yield: 4.9 g (75%; Method B), m.p.: 152-154°C (benzene-petroleum ether); C1sH&1N2S (326.9): calcd. C 66.15, H 4.63, S 9.81; found C 66.24, H 4.57, S 9.74.

3.1.5. 2,3-Dihdydro-5-(I-chlorophenyl)-7-phenyl- 7H-imidazo[2,1-b][l,3]thiazine hydrochloride (3~)

Yield: 5.8 g (80%; Method A), m.p. 200-203°C (decomp.); MS, m/z (%): 326.064 (100) [M+‘, C,sH,sC1N2S], 293 (14) [M+-SH], 254 (79) [M+-721, 152 (14), 125 (30), 117 (52), 91 (27), 86 (18); C1sH&12N2S (363.3): calcd. C 59.51, H 4.40, N 7.71, Cl 19.52; found C 59.22, H 4.47, N 7.77, Cl 19.32.

3.1.6. 2,3-Dihdydro-5-(I-chlorophenyl)-7-phenyl- 7H-imidazo[2,1-b][l,3]thiazine (4~)

Yield: 4.1 g (63%; Method B), m.p.: 104-106°C (petroleum ether); C1sH&1N2S (326.9): calcd. C 66.15, H 4.63, S 9.81; found C 65.97, H 4.78, S 9.67.

P. Perjki et al./Journal of Molecular Structure 377 (1996) 277-288 285

3.1.7. 2,3-DihydroJ-phenyl-7-(I-bromophenyl)- 7H-imidazo[2,1-b][l ,J]thiazine hydrochloride (W

Yield: 6.9 g (85%; Method A), m.p. 248-251°C (decomp.); CtsHt6BrC1N2S (407.8): calcd. C 53.02, H 3.96, N 6.87, Cl’, 17.39; found C 53.18, H 4.25, N 6.69, Cl’ 17.24.

3.1.8. 2,3-Dihydro-5-(Cbromophenyl)-7-phenyl- 7H-imidazo[2,1-b ][1,3 Jthiazine hydrochloride (3e)

Yield: 6.6 g (81%; Method A), m.p. 198-201°C (decomp.); C1sHr6BrClN2S (407.8): calcd. C 53.02, H 3.96, N 6.87, Cl’ 17.39; found C 53.02, H 4.05, N 6.87, Cl’ 17.16.

3.1.9. 2,3-Dihydro-S-Phenyl-7-(I-Jluorophenyl)- 7H-imidazo[2,1-b][l,3]thiazine hydrochloride (3f)

Yield: 5.8 g (84%; Method A), m.p. 234-237°C (decomp.); C1sHt6FC1N2S (346.9): calcd. C 62.33, H 4.65, N 8.08, Cl 10.22; found C 62.14, H 4.73, N 8.21, Cl 10.07.

3.1.10. 2,3-Dihydro-5-(I-j?uorophenyl)-7-phenyl- 7H-imidazo[2,1-b][l,3]thiazine hydrochloride (3g)

Yield: 5.6 g (81%; Method A), m.p. 226-229°C (decomp.); C1sHr6FC1N2S (346.9): calcd. C 62.33, H 4.65, N 8.08, Cl 10.22; found C 62.45, H 4.54, N 7.91, Cl 9.96.

3.1.11. 2,3-Dihydro-5-phenyl-7-(I-methylphenyl)- 7H-imidazo[2,1-b][l,3]thiazine hydrochloride (3h)

Yield: 5.7 g (83%; Method A), m.p. 231-234°C (decomp.); C19H1&1N2S (342.9): calcd. C 66.55, H 5.59, N 8.17, Cl 10.34; found C 66.61, H 5.47, N 8.04, Cl 10.56.

3.2. X-ray structure analysis of 4a

A single crystal (0.70 x 0.50 x 0.20 mm) of 4a grown from ethanol was mounted on a Rigaku AFC6S diffractometer equipped with a graphite monochromator. Cell constants (Table 4) were determined by least-squares refinement of diffract- ometer angles for 25 reflections collected in the 20” < 0 < 27” range. A total of 3154 data were collected in the w-28 scan mode of which 2991

’ The whole halogen content is expressed as chlorine.

Table 4 Crystal data for 4a0

Empirical formula Formula weight Crystal system Sp?ce group a (4 b 6) c (A) P(“) Volume (A3) Z D, (8 cmm3) W%) p (mm-t) (abs. coeff.) Temperature (K) 8 range for data collection (“) Data/restraints/parameters S (goodness-of-fit on F) R [I > 3.00(I)] JL A/u pmnr and Pmin (e A-‘)

CISHI~NZS 292.4 Monoclinic p&/a I I.71 l(2) lO.l81(2) 12.786(4) 97.08(2) 1512.8(2) 4 1.284 I.5418 I.84 298 2.5-75.0 2235/O/207 5.31 0.053 0.067 0.078 0.21 and -0.32

n Further details of the crystal structure investigation are avail- able on request from the Fachinformationszentrum Karlsruhe, Gesellschaft fur wissenschaftlich-technische Information mbH, D-75 I4 Eggenstein-Leopoldshafen 2, on quoting the depository number CSD-58686, the names of the authors, and the journal citation.

were unique. The structure was solved by direct methods and expanded using Fourier techniques, refinement by full matrix least squares: H atoms were generated, kept fixed but the isotropic thermal motion parameters were refined, all non- hydrogen atoms were refined anisotropically (see also Table 5). After isotropic refinement an empirical absorption correction (using the DIFABS program [ 161, min/max transmission 0.70/ 1.22), as applied to all reflections while after anisotropic refinement a secondary extinction correction was applied. All calculations were done using the teXsan [ 171 program package on a Silicon Graphics R3000 workstation. Lists of structure factors and anisotropic displacement parameters are available from one of the authors (Zs. B.) on request.

3.3. NMR measuremeks

The NMR spectra were recorded in CDCls or DMSO-d, solutions in 5 mm tubes at room

286

Table 5

P. Perjtki et al./Journal of Molecular Structure 377 (1996) 277-288

Atomic coordinates and B, for 4s with e.s.d.‘s in parentheses

Atom s Y z Neq)

S(8) N(l) N(4) C(2) C(3) C(5) C(6) C(7) C(9) C(‘O) C(“) C(12) C(l3) C(l4) CC’3 CC161 C(l7) CC’S) CC’9 WO) C(21) I-WA) WW WA) HP) H(6) H(7) W”) W2) Wl3) Wl4) H(‘5) Wl7) W8) ‘-I(‘% HP4 HP)

0.68261(S) 0.4558(3) 0.5385(2) 0.3642(3) 0.4162(3) 0.6268(3) 0.7264(3) 0.751 l(3) 0.5480(3) 0.6042(3) 0.6152(3) 0.5938(4) 0.5631(3) 0.5535(3) 0.5734(3) 0.7210(3) 0.6200(4) 0.5918(4) 0.6629(4) 0.7646(4) 0.7934(3) 0.2985 0.3341 0.3836 0.3996 0.7884 0.8348 0.6392 0.6010 0.5436 0.5301 0.5672 0.5653 0.5181 0.6407 0.8148 0.8688

0.16685(g) 0.1510(3)

-0.0396(3) 0.0504(3)

-0.0724(4) -0.1146(3) -0.0622(3)

0.0819(4) 0.0923(3)

-0.2586(3) -0.3161(4) -0.4484(4) -0.5242(4) -0.4694(4) -0.3354(4)

0.1478(3) 0.1177(4) 0.1819(5) 0.2770(5) 0.3070(4) 0.2420(4) 0.0801 0.0308

-0.0888 -0.1491 -0.1218

0.0944 -0.2612 -0.4885 -0.6147 -0.5229 -0.2960

0.0520 0.1647 0.3199 0.3750 0.2618

0.88967(7) 0X855(2) 0.8409(2) 0.8721(3) 0.8294(3) 0X078(3) 0.7869(3) 0.7871(3) 0.8689(2) 0.7944(3) 0.6986(3) 0.6822(4) 0.763 l(4) 0.8589(4) 0.8758(3) 0.6804(3) 0.6167(3) 0.5216(3) 0.4894(3) 0.5514(3) 0.6462(3) 0.8242 0.9384 0.7581 0.8704 0.7730 0.8075 0.6416 0.6117 0.7491 0.9169 0.9447 0.6386 0.4777 0.4209 0.5304 0.6894

4.51(4) 4.3(l) 3.8(l) 4.4(2) 4.8(2) 3.8(l) 4.5(2) 4.4(2) 3.7(l) 3.7(l) 5.0(2) 6.0(2) 5.3(2) 5.3(2) 4.4(2) 4.1(2) 5.6(2) 6.5(2) 6.0(2) 5.8(2) 4.8(2) 5.4(9) 3.4(7) 7(l) 7(l) 6(l) 3.9(7) 7(l) 8(l) 8(l) 8(l) 7(l) 7(l) 8(l) %‘I 90) 6(l)

temperature on a Bruker WM-250 FT spectro- meter controlled by an Aspect 2000 computer at 250 (‘H) and 63 (13C) MHz, with the 2H signal of the solvent as the lock and TMS as internal stand- ard. The most important measuring parameters were as follows: spectral width 5 and 18.5 kHz, pulse width 1.0 (‘H) and 7.0 (13C) ms (~20” and N 90” flip angle, respectively), acquisition time 1.64 and 0.40 s, number of scans 16 (‘H) and 256-3.5 K (13C), computer memory 16 K, Lorentzian expo- nential multiplication for signal-to-noise enhance- ment (line width 0.7 or 1.0 Hz), and complete

proton noise decoupling (ca. 0.5 W) for the 13C NMR spectrum. The standard Bruker micro- program DNOEMULT.AU was used to generate NOE with a selective pre-irradiation time of 5 s and a decoupling power (CW mode) of ca. 3- 40 mW. The 2D-HSC spectra were obtained by using the standard Bruker pulse program XHCORRD.AU. Data points: 4 K (13C domain), increments: 64-256, digital resolution (‘H domain): better than 5 Hz/point, transients: 256, relaxation delay: 3 s. All C-H correlations were found by using J(C, H) = 135 Hz, for calculation

P. Perjhi et al./Jownal of Molccdar Strctcrctre 377 (1996) 277-288 281

Table 6 Bond lengths (A), angles (“) and selected torsion angles (“) with e.s.d.‘s in parentheses

Bond lengths

Atom Atom Distance Atom Atom Distance

SW C(7) S(8) C(9) N(l) C(2) N(l) C(9) N(4) C(3) N(4) C(5) N(4) C(9) C(2) C(3) C(5) (36) C(5) C(lO) C(6) C(7) C(7) (316)

Bond angles

I .834(4) I .740(3) I .478(4) I .274(4) I .462(4) I .393(4) 1.391(4) 1.521(S) I .337(S) I .496(5) I .496(S) I .522(5)

C(lO) C(lO) cc1 1) C(W C(l3) C(l4) ‘716) C(l6) C(l7) C(18) C(l9) WO)

C(ll) C(l5) C(W C(l3) C(l4) C(l5) C(l7) WI) C(l8) C(l9) WO) WI)

I .377(5) 1.384(5) I .379(5) 1.371(6) I .362(6) I .395(5) 1.384(5) 1.386(5) I .383(6) I .369(6) 1.381(6) 1.385(5)

Atom Atom Atom Angle Atom Atom Atom Angle

C(7) S(8) WI N(1) C(3) N(4) C(3) N(4) C(5) N(4) N(l) C(2) N(4) C(3) N(4) C(5) N(4) C(5) (36) C(5) C(5) (36) SW C(7) W4 C(7) C(6) C(7) W-0 C(9) S(8) C(9) N(l) C(9)

Selected torsion angles

C(9) C(9) C(5) C(9) C(9) C(3) C(2) (26) C(10) C(10) C(7) C(6) CC161 CC161 N(l) N(4) N(4)

98.8(2) 105.8(3) 126.9(3) 107.0(3) 124.6(3) 107.2(3) 101.9(3) 122.7(3) I 16.3(3) 121.0(3) 124.2(3) I I I .3(3) I I I .2(2) I l4.1(3) 122.7(3) 120.1(3) I I7.0(3)

C(5) C(5) cc1 1) C(10) C(ll) C(l2) C(l3) C(lO) C(7) C(7) C(17) C(l6) C(l7) C(18) C(l9) CC161

C(lO) C(lO) C(10) cc1 1) C(W C(13) C(l4) C(l5) C(l6) ‘716) C(l6) C(l7) C(l8) C(l9) WO) WI)

C(11) C(15) C(15) C(l2) C(l3) C(l4) C(15) C(l4) C(l7) WI) WI) C(l8) C(l9) WN Wl) WO)

I l9.0(3) 121.9(3) ll9.2(3) 120.9(4) ll9.8(4) 120.1(4) 120.6(4) ll9.4(4) l21.1(3) 120.4(3) Il8.5(4) 120.5(4) 120.6(4) ll9.8(4) ll9.6(4) 12 1.0(4)

(1) (2) (3) (4) Angle (1)

W C(7) (76) C(5) 35.7(5) (36) C(7) W C(9) -44.8(3) S(8) C(7) (36) C(l7) -84.4(4) (36) C(5) C(lO) C(ll) -54.7(5) C(7) C(6) C(5) C(10) 173.2(3) ‘36) C(7) C(16) C(l7) 42.4(5) N(l) C(9) W-3) C(7) - 148.7(3) C(9) SW C(7) C(16) 83.5(3) N(4) C(5) (36) C(7) -5.8(6) C(3) N(4) C(5) (36) 156.0(4)

N(4) C(5) C(10) C(l5) -56.1(4) C(3) N(4) C(5) C(lO) -23.0(5) N(4) C(9) S(8) C(7) 36.5(3) C(5) (36) C(7) W6) -91.0(5)

288 P. Perjhi et al./Joumal of Molecular Structure 377 (1996) 277-258

of the delay. DEPT spectra [7] were run in a standard way [8], using only the 0 = 135” pulse to separate the CH/CHs and CH, lines phased up and down, respectively. Selective INEPT experi- ments (INAPT) were performed according to the literature [9], using a modified version of the Bruker microprogram INEPTRD. The polariza- tion transfer delays were set to 36 ms, correspond- ing to J(C, H) = 7 Hz, and the pulse width of the soft pulse (go”, ‘H decoupler) was set to 10 ms. The COLOC spectra were recorded employ- ing the standard Bruker software COLOC.AU. Typical conditions included acquisition time 0.4 s, digital resolution 4-8 Hz/point and 512 cycles within 12 h. Delay parameters were opti- mized for the detection of 3-7 Hz heteronuclear couplings.

3.4. Calculational details

Geometry optimizations and transition state localization was performed by using a modified GDIIS [ 18,191 gradient minimizer with natural internal coordinates [20] built into the MOPAC 5.5 program (which is a modified version of MOPAC 5.00 [21]). Energy and gradients were calculated by the program package TX90 [22] using the 3-21G* basis set [23].

Acknowledgements

This work was supported by EGIS Pharma- ceuticals (Budapest, Hungary) and the Hungarian Ministry of Welfare. We are indebted to Dr. I. Kdvesdi for help in measuring the selective INEPT and COLOC spectra.

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