Journal of Molecular Structure, 214 (1992) 25%2’75 Elsevier Science Publishers B.V., Amsterdam

259

Conformational analysis of tricyclic systems including the N-C-O unit by molecular mechanics IV. Perhydrocycloalkane [e] pyrido[l,2-cl-1,3-oxazines

Luis Carballeira”, Berta Fern6ndezb and Adrian0 Miranda”

“Departamento Quimica Pura y Aplicada, Lab. Quimica Fisica, Facultad de Ciencias, Apdo. 874, Vigo (Spain) ‘Departamento Quimica Fisica, Facultad de Q&mica, Santiago de Compostela (Spain)

(Received 1 June 1992)

Abstract

A conformational analysis of the racemic isomers of decahydro-lH,6H-pyrido[1,2-c&1,3- benzoxazine and 5H-cyclopenta[e]pyrido[1,2-+1,3-oxazine and their lo-methylated deriva- tives, all of which contain an N-GO unit, was carried out using a modification of the MM235 force field of Tai and Allinger (J. Am. Chem. Sot., 110 (1966) 2050). The calculated relative energies and geometries were consistent with qualitative experimental estimates.

INTRODUCTION

In previous work [2] we adapted Tai and Allinger’s program ~~285 [l] for the study of linear and cyclic compounds containing N-C-O units. Struc- tural and energy data for a number of bicyclic compounds have been satisfactorily approximated using the new force field [2-51.

The chief problem in the conformational analysis of the tricyclic title compounds (Fig. 1) is the paucity of experimental data, which consist solely of qualitative stabilities estimated from IR and NMR spectra [6]. However, the availability of MM285 results for related bicyclic compounds [3] allows investigation of the structural consequences of adding the third ring. The results are interpreted in terms of the anomeric effect, i.e. the greater stability of the anti form of the chain Lp-X-C-Y, where Lp is a lone pair on X and C-Y is a polar bond [7,8].

Figure 1 shows all the possible diastereoisomers of the tricycles obtained by the fusion of a five- or six-carbon ring to the perhydropyrido[l,2-cl-1,3-

Correspondence to: Dr. L. Carballeira, Departamento Quimica Pura y Aplicada, Lab. Quimica Fisica, Facultad de Ciencias, Apdo. 674, Vigo, Spain.

0022-2860/92/$05.00 0 1992 Elsevier Science Publishers B.V. All rights reserved.

260 L. Carballeira et al./J. Mol. Struct., 274 (1992) 259-275

In

Fig. 1. Diastereoisomers of the compounds studied.

oxazine. In this work, for each diastereoisomer, the conformers are named by a letter indicating the relative orientation of the two heterocycles (A for trans, B for O-inside cis, C for O-outside cis, as in ref. 3 and, for the pentanes, a number indicating which of the two possible stable pentane conformations is present; for methylated derivatives, these denominations are followed by an indication in parentheses of whether the substituent is axial (A) or equatorial (E). (All possible starting configurations were optimized for the unsubstituted systems; 14 for the cyclohexane compounds and 76 for the cyclopentane ones (the twist (C,) form of cyclopentane has three distinct types of bond (with torsion angles of about lo,30 and 400), the fusion of each of which with the oxazine gave a different starting conforma- tion)). In this work, discussion is limited to conformers with energies within 8 kcal mall’ of the most stable, i.e. those making up a significant proportion (at least 0.01%) of the total population at 298 K. Note that none of the isomers complying with this condition has a central ring that can be considered as a boat or twist form. All the results presented were obtained using a dielectric constant of 1.5, preliminary calculations having shown that changing this to 2.25 (at the other extreme of the range for solvents used in expe~ental practice) gave rise to negligible alteration of the calculated energies and geometries.

As well as the unsubstituted molecules, we also studied their lo-methy- lated derivatives, the only members of this class for which at least qualita- tive experimental data are available [6]. The starting conformations used for these derivations were those of the conformers of the unsubstituted molecules with significant populations according to the criteria specified above.

L. Carballeira et al.lJ. Mol. Struct., 274 (1992) 25%275 261

RESULTS AND DISCUSSION

Decahydro-lH, GH-pyrido[l,2-cl-1,3-benzoxazines

Tables 1 and 2 list the chief results for the systems under study. Figure 2 shows those optimized conformations of diastereoisomer III, in which the methyl group is equatorial, and the numbering scheme used. Figure 3(a) shows the optimized conformers of the unsubstituted molecule belonging to diasterioisomers other than III.

I;R=H,n=2

In agreement with experimental estimates, IA and IB are much more stable than IC, which has a negligible population. IA is 3.7 kcal mall’ more stable than IB, whereas in the bicycle perhydropyrido[l,2-cl-1,3-oxazine, the more stable conformer is B because of the anomeric effect [3]. Although the similarity between the relevant parts of the geometries of the bicycle and the tricycle shows the anomeric effect to be of the same magnitude in both, repulsion from the hexane ring in conformer B is sufficient to alter the angles C-N-C, N-C-C (1X.2’), Cl&N-C-C% (by 10’) and LPN-C-O (by 5’), and as a result to invert the relative stabilities of A and B. In addition, the hexane ring of IB contains three gauche butane interactions against only two in IA [9].

The non-planarity h, of the N atom, defined as the distance between this atom and the plane formed by the three atoms to which it is bound, is less in IB than in IA. For conformer A it is the same as for the bicycle, whereas for B the N atom is more planar in the tricycle than the bicycle [3], evidently because repulsion between the two lateral cycles opens up the B conformer. Ring conformations were analysed .in terms of generalized puc- kering parameters [lo]: the puckering amplitude Q is a measure of the ring non-planarity, the angle 0 distinguishes between chair conformations (0 = 0 or 180’) and boat or twist conformations (0 = 900), and B distin- guishes boats (when 0 is an integer multiple of 60’) from twists (when o is an odd integer multiple of 30’). As in the bicycle, the pyrido-oxazine rings are flatter in A than in B, and the values of 6’ for IB indicate considerable distortion of all three chairs (Table 3).

II; R = H, n = 2

Like I, II has a type C conformer (which in this case has a central ring in the twist-boat form) that is much more unstable than its A and B conformers. Unlike I, II has B more stable than A (by 1.65 kcal molll); this is the same order as for the corresponding conformer of lH, GH-pyrido[l,2-

TA

BL

E

1

En

ergi

es

(kca

lmol

-I),

m

ain

ge

omet

rica

l fe

atu

res

(bon

d le

ngt

hs

in

A

and

angl

es

in

deg)

an

d pl

anar

itie

s at

th

e N

at

om

h,

(A)

of

lH,

GH

-dec

ahyd

ropy

rido

[l,2

-cl-

1,3-

ben

zoxa

zin

e (F

ig.

2)

Con

form

er

En

ergy

h

, N

-C

o-c

N-C

-0

LP

N-C

-O

Cl&

N-C

-C5

o-C

-c-C

l4

Cll

-C-C

-Cl4

IA

IB

IIA

IIB

IIIA

IIIB

IIIC

IVC

32.2

513

0.44

88

1.44

9 1.

412

111.

3 62

.9

178.

1

35.9

702

0.41

68

1.43

9 1.

432

113.

1 -

171.

2 -

81.5

30.9

601

0.44

33

1.44

8 1.

412

111.

0 61

.5

178.

5

29.3

068

0.43

74

1.44

0 1.

432

112.

9 -

175.

9 -

71.5

34.6

640

0.44

52

1.44

7 1.

412

111.

4 61

.1

179.

5

33.2

952

0.43

50

1.43

8 1.

432

113.

2 -

175.

7 -

71.0

34.6

884

0.42

36

1.44

6 1.

413

110.

5 -

60.7

17

9.6

34.5

301

0.42

34

1.44

7 1.

413

110.

6 -

59.8

17

8.9

- 68

.2

- 80

.2

- 17

8.4

179.

5

- 17

8.8

179.

0

68.8

177.

3

- 56

.6

- 60

.7

55.5

54.8

- 56

.6

- 57

.4

57.2

- 55

.9

TA

BL

E

2

En

ergi

es

(kca

l m

all’)

, m

ain

ge

omet

rica

l fe

atu

res

(bon

d le

ngt

hs

in A

an

d an

gles

in

deg

) an

d pl

anar

itie

s at

th

e N

ato

m

h,

(A)

of t

he

met

hyl

deri

vati

ve

of

lH,

GH

-dec

ahyd

ropy

rido

[1,2

-c]-

1,3-

ben

zoxa

zin

e (F

ig.

2)

Con

form

er

En

ergy

h

, N

-C

0-c

N-C

O

LP

N-C

O

Cl&

N-C

-C5

o-c-

c-c1

4 C

ll-C

-C-C

l4

WA

) W

E)

IWE

) II

A(A

)

IIA

(E)

IIB

(A)

IIB

(E)

IIIA

(A)

IIIA

( E

)

IIIB

(A)

IIIB

(E)

IIIC

(A)

IIIC

( E

)

IVC

(A)

IVC

(E)

36.6

510

0.42

28

1.45

0 1.

413

111.

6 61

.4

179.

8 34

.576

9 0.

4459

1.

452

1.41

2 11

2.0

63.3

17

8.2

38.8

002

0.41

32

1.44

1 1.

431

113.

3 -

172.

0 -

81.5

35

.149

0 0.

4175

1.

448

1.41

2 11

1.1

60.2

17

9.7

33.4

822

0.43

95

1.45

0 1.

410

111.

5 62

.9

177.

6 37

.358

2 0.

3867

1.

440

1.43

1 11

3.8

- 17

0.5

- 79

.7

31.7

872

0.43

50

1.44

1 1.

432

112.

9 -

176.

8 -

71.1

38

.812

6 0.

4182

1.

447

1.41

2 11

1.5

60.1

17

9.5

37.1

731

0.44

22

1.44

9 1.

410

111.

9 61

.9

179.

0 41

.534

8 0.

3836

1.

438

1.43

1 11

4.1

- 17

0.3

- 79

.2

35.7

940

0.43

19

1.43

9 1.

432

113.

3 -

176.

4 -

70.7

37

.594

5 0.

4211

1.

449

1.41

4 11

0.8

- 60

.2

179.

1 36

.556

2 0.

4178

1.

447

1.41

5 11

1.1

- 60

.2

177.

7 37

.528

6 0.

4209

1.

449

1.41

3 11

0.9

- 59

.4

178.

9

36.5

038

0.41

78

1.44

8 1.

414

110.

9 -

59.5

17

7.6

- 68

.6

- 68

.1

- 81

.6

- 17

7.7

- 17

7.8

178.

6

178.

7

- 17

8.8

- 17

8.5

178.

6

178.

6

69.0

68.4

177.

4

177.

1

- 56

.6

- 56

.5

- 61

.2

55.5

55.5

54.5

54.6

- 56

.0

- 55

.6

- 57

.5

- 57

.6

57.1

56.8

- 55

.7

- 55

.9

264 L. Carballeira et al.lJ. Mol. Struct., 274 (1992) 25.%275

IIINEI IIIBCE) IIIQE)

Fig. 2. Conformers of diastereoisomer III (R = Me, n = 2) and the numbering scheme used.

IA

IIA

Fig. 3. Conformers of diastereoisomers I, II and Iv: (a) R = H, n = 2; (b) R = H; n = 1.

TA

BL

E 3

Pu

cker

ing

coor

din

ates

(Q

, 0,

4)

for

th

e lH

,GH

-pyr

ido[

l,2-c

l-1,

3-be

nzo

xazi

nes

Con

form

er

Cyc

le l

-2%

ti-5

-6

Ql

01

41

Cyc

le

1+7%

8-S

-10

@

02

Cyc

le 4

-11-

12-1

3-14

-5

Q3

03

R=

H

IA

IB

IIA

II

B

IIIA

II

IB

IIIC

N

C

R =

M

e

IA(A

) IA

(E)

IB(E

) II

A(A

) II

A(E

) II

B(A

) II

B(E

) II

IA(A

) II

IA(E

) II

IB(A

) II

IB(E

) II

IC(A

) II

IC(E

) IV

C(A

) IV

C(E

)

0.57

1 3.

3 0.

542

11.6

0.

568

- 2.

3 0.

560

- 3.

0 0.

551

1.7

0.54

1 2.

8 0.

556

- 2.

5 0.

559

- 1.

5

0.569

4.3

0.57

0 4.

2 0.

545

10.7

0.

567

- 3.

5 0.

566

- 4.

5 0.

546

- 4.

8 0.

566

- 3.

0 0.

543

0.7

0.54

7 0.

4 0.

528

3.2

0.54

9 4.

3 0.

556

- 2.

0 0.

551

1.7

0.55

9 -

1.4

0.55

9 -

1.3

14.7

0.

573

- 2.

7 2.

8 0.

565

56.0

0.

535

6.9

83.9

0.

550

174.

9 0.

575

1.1

91.6

0.

587

114.

8 0.

567

- 0.

6 42

.4

0.59

0 14

4.2

0.57

4 -

1.5

68.4

0.

569

138.

7 0.

567

1.1

101.

3 0.

566

135.

5 0.

552

- 2.

8 3.

4 0.

568

129.

7 0.

550

- 2.

7 23

.4

0.58

6

0.5

0.56

6 -

3.7

25.5

0.

564

13.1

0.

576

- 3.

1 3.

6 0.

564

65.8

0.

541

7.0

84.3

0.

548

165.

6 0.

566

2.0

106.

4 0.

585

168.

4 0.

582

1.0

50.8

0.

586

117.

4 0.

552

- 7.

4 0.

5 0.

594

72.7

0.

571

- 0.

9 61

.7

0.59

1 84

.2

0.56

7 -

2.6

97.0

0.

570

96.5

0.

579

- 1.

2 69

.5

0.57

1 10

9.2

0.55

2 7.

1 17

4.8

0.56

6 15

8.4

0.57

1 1.

7 99

.5

0.56

6 13

1.9

0.54

1 -

2.5

36.0

0.

566

144.

2 0.

574

- 1.

5 68

.4

0.56

9 12

3.3

0.53

7 -

1.8

1.2

0.58

6 14

3.0

0.55

6 -

1.9

52.4

0.

586

- 2.

7 29

.0

- 11

.9

32.0

-

1.7

180.

0 -

2.8

162.

0 -

2.2

28.0

-

3.8

32.0

3.

5 16

8.0

- 1.

1 10

9.0

- 2.

8 28

.0

- 2.

7 29

.0

- 13

.0

32.0

-

1.4

170.

0 -

1.8

165.

0 -

3.6

157.

0 -

3.3

161.

0 -

2.3

42.0

-

1.8

31.0

-4

.1

33.0

-

4.2

28.0

3.

6 16

8.0

- 2.

2 28

.0

-1.1

11

6.0

- 1.

1 10

7.0

266 L. Carballeira et al./J. Mol. Struct., 274 (1992) 259-275

cl-1,3-oxazine [3], but inverts the experimentally estimated order [6]. Since interaction between the hexane and pyrido rings is minimal in IIA and IIB, the discrepancy is attributed, as in other molecules [3-51, to underestima- tion of the interaction between the Cl0 methylene group and the oxygen atom or overestimation of the anomeric effect.

The alkane ring fused trans to the bicycle causes hardly any alteration in the chief geometric parameters of the heterocycles or in the anomeric effect, but makes both A and B more planar, especially B, in which the pyrido ring is closer to the hexane ring than A (Fig. 3(a)). Since the N atom is already more planar in the B form of the bicycle than in the A form, this order is retained in the tricycle. Ring puckering Q is hardly altered by the third ring and the heterocycles remain almost perfect chairs; the new cyclohexane ring is likewise an almost perfect chair, and its Q value, 0.582, is strikingly similar to that of free cyclohexane.

111;R = H,n =.2

IIIB is 1.36 kcalmolll more stable than IIIA and IIIC, which have very similar energies. This again contradicts the experimental estimates and is attributed to the stabilizing anomeric effect, and to the above-mentioned underestimation of the interaction between the Cl0 methylene and the 0 atom. IIIA and IIIC have no significant van de Waals interactions and the rest of the contributions to their energies are very similar; the destabilizing effect of the three gauche butane interactions in IIIC is balanced in IIIA by the opening of the lateral ring wings to reduce mutual interaction.

The chief features of the geometry of these conformers are anomeric effects (widening of N-C-O and lengthening of C-O) . Addition of the alkane ring has little effect on the heterocycle geometry. The environment of the N atom is flattest in C and least flat in A. From the bicycle to the tricycle, both the valency and puckering coordinates are hardly altered; the planarity of the hexane ring is virtually the same in all three confor- mers and the values of 6’ reflect almost perfect chair forms.

IV; R = H, n = 2

The only conformer of diastereoisomer IV with a significant population is IVC. IVA and IVB both have twist-boat central rings with very high energies. The only conformer detected experimentally is IVC, in which all three rings are chairs. Comparison with the data for the corresponding lH,GH-pyrido[l,2-cl-1,3-oxazine [3] shows that the alkane ring hardly affects the geometries of the other two. The N atom is slightly more planar than in the bicycle due to repulsion between the hexane and pyrido rings. Heterocycle planarity is hardly altered by the alkane ring, which has the same Q value as free cyclohexane and a 8 value very close to 0’.

L. Carballeira et al./J. Mol. Struct., 274 (1992) 25S275 267

The IO-methylated derivatives

Table 2 lists the results obtained for the lo-methylated derivatives. The most stable conformers have equatorial methyl groups, in keeping with NMR data and with the analysis of the Bohlmann bands in the IR spectrum. The order of the A (axial methyl) conformers is affected by repulsion between methyl and the free pairs of the oxazine 0 atom, which increases the energies of IB(A), IIB(A) and IIIB(A). The energy of IB(A) is further increased by interaction between the methyl group and the hexane ring.

Comparison of the geometries of these derivatives with those of the unsubstituted conformers shows hardly any significant changes in bond lengths, torsion angles or the N-C-O angle, the only exceptions occurring for conformers in which the methyl group is oriented inwards. Specifically, there is a 7’ increase in ClO-N-C-G in IIB(A) and IIIB(A) due to repulsion between the methyl group and the nearby oxygen lone pairs, which opens up the molecule and flattens both the environment of the N atom (leaving IIB(A) and IIIB(A) with very similar h, values) and the heterocycles, especially the central ring (see Q values in Table 3). In addition, the t9 values show that the chair form of the pyrido ring becomes significantly distorted and that the distortion of the central ring similarly increases slightly, while the hexane ring is almost unaffected.

Decahydro-SH-cyclopentapyrido[l,2-c]-1,3-oxazine.s

The chief results for these molecules are listed in Tables 4 and 5. Figure 4 shows those optimized conformations of diastereoisomer III of the methy- lated derivatives in which the methyl group is equatorial, together with the numbering scheme used. Figure 3(b) shows the conformers of the unsub- stituted molecule belonging to diastereoisomers other than III. The number appended to A, B or C in the conformer names distinguishes between positive and negative values of Cl-C-C-C13. In these molecules, the pentane ring, like other five-membered rings, has only two puckering parameters [lo]: 6 distinguishes between the twist (C,) and envelope (C,) conformations of the pentane ring, with values that are integer multiples of 36’ for the former and odd integer multiples of 18’ for the latter, while Q becomes particularly large in envelope conformations in which the atom at the tip of the flap is very far from the plane of the other four atoms.

I;R = H,n=l

Conformer IC is unstable and, in keeping with experimental estimations, IA is more stable than IB-1 or IB-2. IB-1 is 0.88 kcal mall’ more stable than IB-2 due to Cl2 being placed further from the rest of the molecule in the former.

TA

BL

E

4

En

ergi

es

(kca

lmol

-‘),

mai

n

geom

etri

cal

feat

ure

s (b

ond

len

gth

s in

A

an

d an

gles

in

de

g)

and

plan

arit

ies

at

the

N

atom

h

, (A

) of

BW

cycl

open

ta[e

]pyr

ido[

l,2c

]-l,

-oxa

zin

e (F

ig.

4)

Con

form

er

En

ergy

h

, C

-N

c-o

N-G

O

Lp-

N-C

-O

Cl&

N-C

C5

cMX

X13

C

&C

-CC

13

IA

IB-1

IB-2

IIA

IIB

IIIA

-1

IIIA

-2

IIIB

-1

IIIB

-2

IIIC

IVC

36.0

308

0.44

64

1.44

8 1.

411

110.

7 60

.9

31.9

047

0.42

58

1.43

9 1.

430

112.

8 -

175.

9

38.1

784

0.42

38

1.44

1 1.

431

113.

1 -

173.

6

36.7

169

0.44

13

1.45

4 1.

417

111.

6 63

.6

35.5

630

0.43

61

1.44

6 1.

438

113.

9 -

174.

3

39.2

693

0.45

15

1.44

5 1.

411

111.

2 60

.1

39.4

115

0.45

28

1.44

5 1.

410

110.

7 58

.5

37.0

914

0.43

71

1.43

7 1.

429

112.

9 -

179.

5

37.2

574

0.43

52

1.43

7 1.

431

113.

3 -

177.

4

38.8

595

0.42

38

1.44

6 1.

412

110.

3 -

59.5

41.0

766

0.41

99

1.45

2 1.

418

111.

4 -

61.2

176.

8

- 80

.6

- 80

.1

179.

0

- 72

.1

178.

4

177.

7

- 71

.2

- 71

.1

- 17

8.8

179.

2

-739

15

.3

- 92

.5

- 24

.3

- 84

.5

31.2

- 17

0.3

- 16

.2

- 17

2.3

- 13

.7

167.

3 2.

2

162.

6 34

.3

159.

1 37

.6

165.

7 3.

4

74.1

-

19.5

169.

8 10

.5

TA

BL

E

5

En

ergi

es

(kca

l m

ol-I

),

mai

n

geom

etri

cal

feat

ure

s (b

ond

len

gth

s in

A a

nd

angl

es

in d

eg)

and

plan

arit

ies

at t

he

N a

tom

h

, (A

) of

th

e m

eth

yl

deri

vati

ve

of B

H-c

yclo

pen

ta[e

]pyr

ido[

l,2c

]-l,

&ox

azin

e (F

ig.

4)

Con

form

er

En

ergy

h

, C

-N

IA(A

) 40

.204

8 0.

4214

1.

448

IA(E

) 38

.341

0 0.

4444

1.

451

LB

-l(E

) 40

.398

0 0.

4224

1.

442

IB-2

(E)

41.3

559

0.42

08

1.44

3

IWA

) 40

.858

8 0.

4150

1.

454

IIA

(E)

38.9

992

0.43

85

1.45

6

IIB

(A)

43.5

627

0.38

51

1.44

7

IIB

(E)

38.1

434

0.43

28

1.44

8

IIIA

-l(A

) 43

.435

8 0.

4268

1.

445

IIIA

-l(E

) 41

.758

4 0.

4491

1.

448

IIIA

d(E

) 41

.906

3 0.

4501

1.

447

IIIB

-l(A

) 44

.630

0 0.

3865

1.

438

IIIB

-l(E

) 39

.293

6 0.

4336

1.

438

IIIB

-2(A

) 44

.754

8 0.

3864

1.

437

IIIB

-2(E

) 39

.378

7 0.

4341

1.

439

IIIC

(A)

41.7

675

0.42

14

1.44

9

IIIC

(E)

40.7

674

0.41

78

1.44

8

IVC

(A)

44.0

748

0.41

79

1.45

4

IVC

(E)

43.0

285

0.41

40

1.45

3

c-o

N-GO

LP

N-C

-O

Clw

SC

-c5

O-C

CC

13

1.41

2 11

0.9

59.3

1.41

1 11

1.4

61.3

1.43

0 11

2.9

- 17

6.5

1.43

1 11

3.2

- 17

4.4

1.41

7 11

1.8

61.5

1.41

6 11

2.3

63.8

1.43

7 11

4.7

- 16

8.9

1.43

9 11

4.0

- 17

4.8

1.41

2 11

1.3

57.7

1.41

1 11

1.9

60.1

1.41

0 11

1.5

58.9

1.42

8 11

4.0

- 17

4.1

1.42

9 11

2.9

179.

9

1.43

0 11

4.2

- 17

3.4

1.43

1 11

3.1

179.

4

1.41

3 11

0.6

- 59

.1

1.41

3 11

0.7

- 59

.6

1.41

8 11

1.7

- 60

.7

1.41

8 11

1.7

- 61

.1

178.

6

177.

0

- 80

.8

- 80

.1

- 17

8.8

179.

3

- 80

.3

- 72

.3

179.

8

178.

7

177.

8

- 79

.7

- 71

.3

- 79

.6

- 70

.7

- 17

9.1

179.

6

178.

8

178.

0

- 73

.9

- 73

.6

- 93

.7

- 86

.0

- 17

0.4

- 17

0.2

- 17

2.8

- 17

2.9

166.

2

167.

3

162.

8

157.

3

158.

4

161.

2

162.

4

74.0

73.8

169.

8

169.

6

14.4

17.2

- 25

.2

32.3

- 16

.2

- 14

.7

- 14

.3

- 16

.1

- 1.

5

1.3

34.3

38.7

37.6

- 8.

7

- 7.

1

- 17

.8

- 17

.7

11.2

11.7

270 L. Carballeira et al./J. Mol. Struct., 274 (1992) 259-275

IIIA-2(E)

IIIB-I(E)

/r

IIIB-e(E,

Fig. 4. Conformers of diastereoisomer III (R = Me, n = 1) and the numbering scheme used.

Addition of the pentane ring to the corresponding bicycles [3] hardly altered the geometry of the heterocycles. Like the IB conformer of the cyclohexane derivative, IB-1 and IB-2 have flatter N atoms than the B conformer of the parent bicycle, because of repulsion between the pyrido and alkane cycles. For the same reason, the heterocycles of IB-1 and IB-2 are all much flatter than those of the parent bicycle [3], whereas the heterocycle planarities in IA are very similar to those of the bicycle. According to the values of the puckering parameter 43, the pentane ring is an envelope in IA and IB-2, and an almost perfect twist in IB-1.

II; R = H, n = 1

As in the cyclohexane-containing molecules, the most stable of all the

L. Carballeira et al.lJ. Mol. Struct., 274 (1992) 259-275 271

coroners of the molecule is IIB. Again, inversion of the expe~entally estimated stability order of IIA and IIB is attributed to underestimation of the interaction between the Cl0 methylene group and the 0 atom. The geometrical parameters of the heterocycles hardly differ from those of the corresponding bicycles, but as usual for the tricycles in this work, adding the third ring flattens the enviro~ent of the N atom. The puckering amplitude of the oxazine ring is also less than in the bicycle, but not that of the pyrido ring, which again shows the minimal effect of the third ring in these conformers. The pentane ring, an almost perfect envelope, has very similar valency coordinates in IIA and IIB.

III; R = H, n = 1

Decahydro-5H-cyclopentapyrido[l,2-cl-1,3-oxazine has five stable dia- stereoisomer III conformers, because both IIIA and IIIB are stable for two forms of the pentane ring (Fig. 4). For the same reasons as in the case of the hexanes, the most stable calculated conformers are the IIIB forms.

All the internal coordinates of the heterocycles are very similar to those of the parent bicycles. IIIA-1 differs from IIIA-2, and IIIB-1 from IIIB-2, only in the torsion angle C4-C-GC13, which makes the pentane rings of IIIA-1 and IIIB-2 twist and those of the other two conformers envelope. The planarity of the N atom is virtually the same as for the parent bicycles and the corresponding cyclohexane derivatives. The puckering coordinates show flattening of the central ring, which is also distorted from its perfect chair conformation, especially in the conformers with envelope (IIIA-2 and IIIB-1) or twist (IIIA-1 and IIIB-2) pentane rings. The pentane ring of IIIC has a conformation intermediate between envelope and twist.

IV;R=H,n=l

As in the parent bicycle and for the same reasons, the only stable form is IVC (Fig. 3(b)), which is, in any case, the most unstable of all the compounds with n = 1, in agreement with experimental estimations. Its geometry is very similar to those of the parent bicycle and the cyclohexane derivatives, but the central ring is somewhat less flat and chairlike. The pentane ring is a distorted envelope.

The IO-methylated derivatives

Tables 5 and 6 list the results for the lo-methylatecl derivatives. As in the case of the cyclohexane derivatives and in keeping with experimental findings, in all the conformers the equatorial arrangement of the methyl group is favoured over the axial one. For the same reasons as in the

TA

BL

E 6

Pu

cker

ing

coor

din

ates

(Q

, 0,

4)

for

th

e U

+cy

clop

enta

[e]p

yrid

o[l,

2c]-

1,3-

oxaz

ines

Con

form

er

Cyc

le l

-2-3

-4-5

6

Q1

01

Cyc

le

1+7-

8910

Q2

02

Cyc

le 4

-11-

12-1

3-5

Q3

43

R=

H

L4

IB-1

IB

-2

IIA

II

B

IIIA

-1

IIIA

-2

IIIB

-1

IIIB

-2

IIIC

IV

C

R =

M

e

IA(A

) IA

(E)

IB-l

(E)

IB-2

(E)

IIA

(A)

IIA

(E)

IIB

(A)

IIB

(E)

IIIA

-l(A

) II

IA-l

(E)

IIIA

-2(E

)

0.54

5 -

4.2

147.

4 0.

576

0.50

6 -

16.0

13

7.9

0.54

0 0.

528

11.3

77

.3

0.52

8 0.

592

- 6.

4 96

.7

0.57

7 0.

581

- 5.

0 12

4.0

0.55

5 0.

521

- 6.

8 78

.7

0.57

9 0.

509

- 11

.3

89.4

0.

581

0.50

2 -

15.5

14

9.7

0.56

1 0.

516

9.0

151.

7 0.

563

0.53

6 -

5.5

81.7

0.

552

0.57

5 4.

2 68

.9

0.55

2

0.54

4 -

5.0

158.

8 0.

568

0.54

4 -

3.9

159.

5 0.

579

0.51

2 -

16.6

13

1.9

0.54

5 0.

533

11.2

87

.8

0.53

4 0.

588

- 6.

4 10

4.3

0.56

9 0.

590

- 6.

9 97

.7

0.58

1 0.

569

- 6.

4 13

2.8

0.54

0 0.

586

- 3.

5 12

9.5

0.55

8 0.

516

- 7.

9 89

.3

0.57

2 0.

519

- 6.

6 79

.8

0.58

3 0.

506

- 10

.7

92.1

0.

585

- 0.

3 54

.3

0.40

8 15

9.0

6.2

92.3

0.

406

109.

0 6.

6 64

.5

0.37

8 16

5.0

- 0.

8 97

.1

0.46

9 19

.0

2.7

126.

0 0.

480

19.0

-

0.7

110.

7 0.

395

176.

0 -

0.9

122.

9 0.

413

163.

0 2.

9 10

5.7

0.40

7 15

7.0

2.6

79.9

0.

385

148.

0 -

2.4

10.1

0.

410

8.0

- 2.

8 9.

9 0.

469

167.

0

- 1.

4 50

.9

0.40

8 16

0.0

- 0.

7 11

.8

0.40

9 15

6.0

6.5

95.0

0.

404

108.

0 6.

8 65

.3

0.37

5 16

2.0

- 1.

2 78

.6

0.47

0 19

.0

- 0.

3 63

.0

0.47

0 17

.0

9.0

159.

5 0.

484

18.0

2.

9 13

5.7

0.48

3 16

.0

- 1.

2 84

.7

0.39

1 17

7.0

- 0.

4 43

.4

0.39

7 17

8.0

- 0.

9 96

.3

0.41

5 16

4.0

L. Carballeira et al.lJ. Mol. Strut., 274 (1992) 25%275 273

274 L. Carballeira et al.lJ. Mol. Struct., 274 (1992) 25S275

cyclohexane derivatives, IIB(A), IIIB-l(A) and IIIB-2(A) are made relative- ly unstable by the methyl group (and IB-l(A) and IB-2(A) even more so). Conformers differing only in the form of the pentane ring differ little in energy, the only exception being that IIIA-2(A) is much more unstable than IIIA-l(A).

The geometries of these structures are very similar to those of the corres- ponding conformers of the unsubstituted molecule, except (for the same reasons as for the cyclohexane derivatives) for IIB(A), IIIB-l(A) and IIIB- 2(A); the only significant changes in the pentane ring concern the angle C&C-C-C13 in IIIB-2(A) and IIIB-B(E). Only in IIIB-l(A) and IIIB-l(E) is the environment of the N atom appreciably flatter (for the reasons men- tioned previously) than in the corresponding methylated bicycle [3]. The rings of IIB(A), IIIA-l(A), IIIB-l(A) and IIIB-2(A) are flatter than in the unmethylated molecules.

Only in the type II and type IV isomers is the central ring less flat and chairlike than in the parent bicycle, although in several other conformers the central ring is totally distorted. In most conformers the pentane ring is envelope, but in IB-1 (E), IIIA-l(A) and IIIA-l(E) it is twist.

CONCLUSIONS

Introducing the 5- or g-membered alkane ring into the parent bicycle causes minimal alteration of the valency coordinates of the heterocycles, but increases the planarity of both the heterocycles and the environment of the nitrogen N atom. For the unmethylated molecule, the order of stabilities among conformers is the same for the cyclopentane as for the cyclohexane derivatives. For the lo-methylated derivatives, conformers with the methyl group equatorial are more stable than those with the methyl group axial.

ACKNOWLEDGEMENTS

This work was supported by grants from the Spanish Interministerial Committee for Science and Technology and the Xunta de Galicia.

REFERENCES

1 J.C. Tai and N.L. Allinger, J. Am. Chem. Sot., 110 (1988) 2050. 2 B. Fernandez, M.A. Rios and L. Carballeira, J. Comput. Chem., 12 (1991) 78. 3 B. Fernandez, L. Carballeira and M.A. Rios, J. Mol. Struct., 245 (1991) 53. 4 B. Fernbndez, M.A. Rios and L. Carballeira, J. Mol. Struct., 246 (1991) 301. 5 B. Fernbndez, L. Carballeira and M.A. Rios, J. Mol. Struct., 263 (1991) 157. 6 (a) T.A. Crabb and E.R. Jones, Tetrahedron, 26 (1970) 1217. (b) T.A. Crabb and R.F.

Newton, Tetrahedron, 24 (1968) 4423. 7 L. Schafer, C. Van Aslenoy, J.O. Williams, J.N. Scarsdale and H.J. Geise, J. Mol. Struct.

L. Carballeira et al./J. Mol. Struct., 274 (1992) 259-275 275

(Theochem), 76 (1981) 349. 8 C. Romers, C. Altona, H.R. Boys and E. Harmga, Top. Stereochem., 4 (1969) 39. 9 I.D. Blackburne, A.R. Katritzky, D.M. Read, P.J. Chivers and T.A. Crabb, J. Chem. Sot.,

Perkin Trans. 2, (1976) 418. 10 D. Cremer and J.A. Pople, J. Am. Chem. Sot., 97 (1975) 13.54.