CHAPTER 5

Attempted Synthesis of 12-phenyl-8-Azasteroids

5.1 Introduction

In animal kingdom steroid plays an important role as

hormones. Many of the biological functions in higher animals

such as growth, sex determination and reproduction are controlled

by steroidal molecules.' The golden age of steroidal chemistry may be taken as during 6th and 7th decades of this century.

However steroids continue to be actively studied particularly

with regard to modulating gene expre~sions.~ Azasteroids

form a distinct class in this group, in which one or more

Figure 5.1

carbon atoms in the steroid molecule is replaced by nitrogen

atoms. Azasteroids show various biological activities%uch

as antiviral: local anae~thetic,~ antiinflammatoryd and antico cer

(f;'7.'9 methyl group at C,, position ore referred as gonones 3,pnd

this ring system is relevant to the present study.

5.2 Retrosynthetic Analysis

Retrosynthetic analysis of 1 2-phenyl-8-azagoncl-1 ,3,5(10)-

triene 4 and D-homo-1 2-phenyl-8-azagono-l ,3,5(10)-triene

Ph Ph

&)n a x@)n ( ' 6 n = l ;

4 . " - 1 x - Y

x - H Oti 7 n - 2; 70. n - 2 5 . " - 2 5 0 . n - 1 0 X - H X = OCH, X - H X = OCHJ

X ' 11. dh+ X = H 100, &is&)fi n = 1: X ' 8 0 = 1 1 1 0 . x = OCH, lob . n - 1: X - H

9 . " - 2 9 a . n - 2 X * H X - OCH,

Scheme 5.1

137

systems 5 is given in Scheme 5.1. Chalcones 11, 1 l o were identified as starting materials, contributing ring A and C,;

phenyl. The ring D was to come from cyclopentanone 1 Oa

or cyclohexanone l o b . Nitrogen in C,-position was thought

to be introduced by reductive amination cyclisation pathway. The two carbon bridge forming ring B was planned to be introduced at the end of the synthetic efforts.

5.3 Attempted Synthesis of D-Homo-1 2-phenyl-8-azagona-

1,3,5(10)-triene

Michael addition of cyclohexanone l o b to chalcone

11 using activated Ba(OH), as baselo resulted in 2(3-0x0-

1 ,3-diphenylpropyl)cyclohexanone 9. The 1,5-diketone 9 was characterised on the basis of IR and 'H NMR spectra.

IR spectrum showed absorption ot 1730 and 1680cm.l for

the cyclic and aromatic ketones respectively. Initially the

diketone 9 was treated with NH,OH.HCI and CH,COONa in MeOH at rt with the intention of preparing, corresponding

mono oxime which in turn was desired to be converted to

de~ahydro~uinoline system by reduction and subsquent cyclisation.

However a white crystalline solid which resulted from the

reaction mixture was found to be trans-1 -methoxy-3,5-di~henyl-

2-oxabicycla[d.4.0]dec-3-ene 12 (Scheme 5.2). This compound

was characterised on the basis of IR, 'H, 13C and mass spectra. 'H NMR showed characteristic signal at 3.32ppm for methoxy

i) EtOH, Ba(OH),, rt. i i ) MeOH, NH,OH.HCI,

CH,COONa, rt

Scheme 5.2

group. On careful literature survey it was found that this

compound 12 was made earlier from 1,s-diketone 9 under

acidic condition in methanol medium."'" The 'H NMR of

2-oxabicyclodecene 12 matches with the reported values.

The I3C NMR spectral data of 2-oxabicyclodecene 12 has been reported for the first time in this chapter and this data

also confirms the structure.

When oxime preparation was conducted at methanol

reflux, this resulted in 60% yield of an unwanted 2,4-diphenyl- 5,6,7,8-tetrahydr~~uinoline 13 (Scheme 5.3). This compound

was prepared earlier via dioxime derived from the 1,5-diketone

9.13 The ~xab ic~c lodecene 12 was also converted to

tetrahydroquinoline 13 on heating with NH,OH.HCI and

CH,COONa in methanol reflux in 70% yield. The yield of tetrahydroquinoline improved dramatically to over 90% when

the reaction was conducted in CH,CN reflux. The

tetrahydroquinoline 13 con also be obtained over 85% yield

on reaction with CH,COONH, and CH,COOH in n-butanol

refulx.14

i) MeOH, NH,OH.HCI,CH,COONa, reflux.

Scheme 5.3

Leuckart reactioni5 on the 1,5-diketone 9 with HCOONH,

in PEG-200 reflux resulted in high yield of a mixture of 2,4-

diphenyldecahydroquinoline from which the major compound

was isolated and purified (Scheme 5.4). This compound

was found to be the required cis-2,d-diphenyl-trans-

decahydroquinioline 14. The relative stereochemistry of

the two phenyl rings was fixed as diequatorial and 1,3 cis from the splitting pattern of the C2-H and C,-H. The C2-H

appeared as dd at 3.82ppm with coupling constont valhes

10.6 and 2.64Hz indicating its axial orientation.'

i ] PEG-200, HCOONH,, reflux.

Scheme 5.4

the C,-phenyl group is present in the equatorial position.

The resonance at 2.38ppm appeared as triple doublet for

C,-H with coupling constant values 11.4 and 4.2Hz indi-

cating two equal diaxiol coupling with C,,mx.H and C,ox-H

and one equatorial-axial coupling with C,eq-H. This data

reveals that C,-H is in axial position and hence C,-Ph i s in

equatorial position. Thus the two phenyl rings present in

equatorial positions are in 1,3 cis configuration. The stereochemistry

of ring junction in the bicycle is fixed as trans ring fusion

based on the following argument. Reductive cyclisation

can potentially lead to cis- and trans-de~ah~droquinoline.

In the case of trans-decahydroquinoline isomer the C;H is

supposed to appear as a triple doublet with two equal diaxial

and one axial-equatorial coupling. Indeed, the C;H of 2,A-

diphenyldecahydroquinoline 14 appeared at 2.45ppm as

tripledoublet with a coupling constant 9.4 and 2.OHz indicating,

two diaxial and one axial-equatorialcou lin s which reveals cRB.j,y that C;H is present in the axial posit ioyas expected for the

trans-de~ohydroquinoline.~~~~~ In the same way, C1;H appeared

Fig. 5.3 'H and 13C NMR spectral vaules of 14

at 1.9ppm os quartet doublet with coupling constant 10.0

and 3.2Hz with three equal axial-axial couplings and an

axial-equatorial coupling. Eliel et 01, have done poineering work in analysing configuration of o k and trans-de~ahydro~uinoline

on the basis of 13C NMR spectral data.l6.l8 In case of N-

substituted trans-decahydroquinoline the C,, C,, C, and C,

carbon atoms appear at 33.1,25.9,25.8 and 30.74ppm1'(Fig

5.6) whereas in the case of cis-de~ohydro~uinoline they appear

e+ upfield at 31.6, 20.9, 25.7 and 15.6ppm.18 The I3C

NMR spectrum of decahydroquinoline 14 shows signals at

Figure 5.6

33.64,26.06,25.29 and 29.23ppm for C,, C,, C, and C,

carbon atoms lfic~e5.5) which match with 13C NMR spectra of trans-de~ahydro~uinoline 1 A. Hence, decahydroquinoline 14 has been assigned trans ring fusion.

The decahydroquinoline 14 was next alkylated on the

nitrogen atom with bromoethanol to result in N-(2'-hydroxyethyl)-

cis-2,4-diphenyl-trans-de~ahydro~uinoline 15 (Schem 5.5). C~'9.S.~3

The 13C NMR spectrum of this compound 15,showed two

add~tional signal for ethanol arnlne portion. The rest of the

13C NMR spectrum matched well with the parent compound.

The N-(2'-hydroxyethyl)-de~ahydro~uinoline 15 was also obtained

from reductive amination cyclisation of the 1,s-diketone 9

with ethanol amine and subsequent NaBH, reduction.20 This

reduction actually resulted in two isolable products (Scheme

5.5). One, trans decahydroquinoline 15 obtained earlier

was the maior ~ roduc t and the other was a minor

compound 16 whose structure was assigned as trans -2,4-

i) BrCH,CH,OH, K,CO,, reflux. ii) MeOH, HOCH,CH,NH,, reflux, NaBH,.

Scheme 5.5

diphenyl-cis-decahydroquinoline. The 1,3 trans orientation of the two phenyl rings of 16 were derived from 'H NMR

CP8.F 11) spectrum. In 'H NMR the C,-H appear as triplet at 3.90pprn

equatorial position with C,eph group at the axial postion.

The CA-H appeared at 2.52ppm as muhiplet indicates the

presence of the CA-H in axial position and C,-ph in the equatorial

position. The presence of cis ring fusion was elucidated by

the following arguments. As mentioned earlier the I3C NMR

Chemical Shifts of C,, C,, C,, C, Carbons can be taken as

diagnostic tool for assigning the stereochemistry of ring junction.

Generally the cis-decahydroquinoline can exist or can potentially

I I I 1 ! 1 , l l i rn " ' rn 1 / ' 1 R , , 1 1 1

? L SC

'lg 5 8 ''C NMR (DEPT) spectrum of N-(2-hydroxyethylJ-cis-

2 , 4 - d ~ p h e n y l - t r o n s - d e ~ ~ h Y d r ~ q ~ ~ n ~ ~ ~ n e (15)

Fig 5.9. 'H and I3C NMR spectrla values of 15

stabilise in any one of the two conformational isomers 17A and 17B as shown in Fig. 5.1 3. These two isomers can be recognised on the basis of the chemical shifts of C, and C, carbon atoms of the carbocylic ring. If the conformer is

Fig. 5.1 0 'H and I3C NMR spectral vaules of 16

2. present in type$ @form, the C, and C, carbons appear at

about 2 6 and 19ppm respectively, whereas they wil l app

at about 21 and 16ppm respectively in the case of type

conformotional i ~ o m e r . ' ~ In I3C NMR of decahydroquinolirte ( H a r 14

1 4 p k C, and C, appeared at 2 76 and 18 41 ppm indicating C ; 7 8 , ,

the predominance of type I conformat~on of the molecule.

Fig. 5.13

Next, various attempts were made for the cyclisation

via dehydration of the hydroxy group with the aromat~c ring

in N-(2'-hydroxy ethyl)-cis-2,~-diphenyl-trans-de~ohydro~uinoline

15 with intention of making D-homo-1 2-phenyl-8-azagonane

5 . The N-substituted decahydroquinoline 1 5 was treated

wi th Lewis acids such BF,.Et,O (neat) 2 ' TiCIA/CH2CIi or

CH2CICH2C1,2' H3B0,2' and AICI, (benzene)23. In all these

cases except that of BF3.Et20, the starting material was recovered

unchanged. In the case of BF3.Eti0 reaction, surprisingly,

on ethyl ether of the alcohol 1 8 was obtained as the sole

product (Scheme 5.6). The 'H NMR of ether derivative of

the d e ~ a h y d r o ~ u i n o l i n e 1 8 showed characteristic triplet at

OCH2CH, OH OOCCH,

18 15 19

i ) BF,.Et,O, neat i i ) CH,COOH, HBr

Scheme 5.6

1.05ppm and quartert at 3.1 5ppm for CH,, CH, confirming

the structure obtained for the mpjx$d Cyclisation wos

also attempted with HBr in CH,C00H,:2A This reaction resulted

I Fig. 5.17 "CNMR (DEPT] spectrum of ocevl derivative of N.12- I hydrovethyl)-cia~2,4-diphenyl-tranr-decohydroquioalioe I

119)

in 0-acetylated product 19 which was confirmed by the

appearance of singlet for methyl group at 1.95ppm in 'H < F l j 5 IL? NMR,pnd a sln I t at 170.85ppm for carbonyl carbon atom

hl 3 7 7 in 13C NMR. Further, cyclisation was also attempted with strong acids like CF,SO,H in toluene,25 con. H,S0,26 and

P20, in benzene or toluenez7. The starting material was

recovered unchanged in all these cases.

5.4 Attempted Synthesis of 1 2-Phenyl-8-ozagonane

In the case of Michael addition of cyclopentanone 100

to cholcone 1 1 in the resence of activated Ba(OH), resulted (Schemes R

in two products. The less polar compound was the expected

2(3-0x0-1 ,3-di~henylpropyl)cyclo pentanone 8. There was another more product formed in 30% yield. The structure

dh + "& i d e n t ~ f i e d p r o d u c t / /

i) EtOH, Ba(OH),, rt.

Scheme 5.7

156

of this compound is yet to be finalised. Interestingly the

1,5-diketone 8 failed to give 0x0 bicyclo compound anolo@s to the one found forNtb$i&?tone 9 derived from ~~clohexanone, on treatment withTin methanol. But the 1,s-diketone 8 on treatment with NH,OH.HCI and CH,COONo i n methanol

reflux resulted in known 2,4-diphenyl-6,7-dihydro-5H-1 -pyrindine

2 0 . 2 1 The 1,5-diketone 8 underwent reductive omination and cyclisation with ethanol amine in methanol20 to yield a

mixture of N-(2'-hydroxyethyl)-2,4-diphenylperhydro -pyrindine SLhzhlC 5 . 9 )

in over 75% yield. However, attempts to separate them

from the mixture by column c h r o r n ~ t o g r a p h ~ afforded only

i) MeOH, NH,OH.HCI and CH,COONo

Scheme 5.8

one pure N-substituted 2,4-diphenylperhydro-l -pyindine compound

21 and the other isomers were obtoined as mixture of two

i ) MeOH, HOCH,CH,NH,, NaBH,, reflux.

Scheme 5.9

isomers. Repeated efforts to separate them failed. The

pure compound perhydropyrindine 21 obtained was found

to be cis-24-diphenyl with trans ring fusion. The double

doublet appeared at 3.45ppm in 'H NMR indicates that C; H is present in equatorial postion and hence the C;ph is

present in the axial orientation. The appearance of a triplet

doublet at 2.55ppm for C4-H with J = 9.28 and 6.27Hz

indicates that it is present in the axial position with C4-ph in t h a t

the equatorial position. This also indicates-the C,;H i s

present in axial position. Another triple double; at 2.67ppm

with coupling constant 9.77 and 5.4Hz assigned to C;H

shows that it is also present in the axial position. So, it i s

concluded that there is trans ring fusion in the case of compound

Fig.5.20 'H and 13C NMR spectral value of 21

21 . This compound 21 yielded ether derivative of perhydropyridine 22 instead of 8-azagonane 4 when cyclisation was tried

with BF3.Et,02'( .~cheme5.10,).

i. BF,Et,O, neat.

Scheme 5.1 0

. - - -- ? - a ; ; 1 p 1

: d C i r . . 2 = 1 : i i 5: 0 I

. o , i. $ 6 1

, : I

i ;; i 1.- 2;

t 5 : ; gz I' , * : 3 : ~

I i 1

Thus, the efforts taken to cyclise N-substituted decahydroquinoline 14 and perhydropyridine 21 with various

reagents failed to give the target molecule 8-azasteroid.

5.5. Experimental Section

To a stirred solution of Ba(OH), (0.4009, 2 mmol) in 20 mL absolute alcohol was added dropwise cyclohexanone (0.989, 10 rnmol) at rt, and stirring was continued for 10 minutes. Chalcone 1 1 (2.089, 10 mmol) was added portionwise

to the reaction mixture and it was stirred for 4 h at rt to

afford a white solid. It was chr~moto~raphed on silica gel using CHCI, to yield 2.999 (98%) as a white solid. In

the case of cyclopentanone addition a mixture of 8 and 20

were obtained which were separated on a silica column using 10% ethyl accetate in hexane afford 55% of 8 and 45%.

Yield = 98 %; mp = 1 41°C; IR 3060, 2900, 1730, 1680,

1595, 1490, 1445, 1300cm.l; 'H NMR 90 MHz 61.20 - 2.00 (m, 7H), 2.2 - 2 . 9 (rn, 2H), 3.1 - 3 . 9 (m, 3H),7.1 - 8.0 (m. 1 OH, Ar-H).

Yield = 60%; mp = 670C; IR 3060, 291 0, 1730, 1680, 1450, 1200crn.l; 'H NMR 60 MHz 61.10 - 2.10 (m, SH), 2.3 . 3.15(m,2H),3.1 -3 .85(m,3H) ,7 .1 -8 .O(m. lOH,Ar -H) .

Unidentified product

Yield = 30%; mp = 204OC; IR 3450, 3050, 2950, 1660

(br), 1600, 1500, 1450, 1300, 1250, 1200cm-'; 'H NMR 200MHz 1.2 - 1 .7 (m, 4H), 1.96 (m. 1 HI, 2.9 (m, 1 H), 3.3 (dd, 1 H), 4.00 (dd, 1 H), 4.1 (dd, 1 H),4.2 (d, 1 HI, 4.3 (t, 1 H), 4.65 ( s , 1 H), 6.9 - 7.4 (m. 1 OH, Ar-H); 13C NMR 200 MHz 21.08, 33.61, 42.42, 43.20,48.37, 48.70, 55.02, 55.30, 80.94, 127.48, 127.85, 128.29, 128.62, 128.84,

132.20, 138.06, 139.41, 149.11, 144.66, 202.68.

Yield = 95%; mp = 1350C; IR 2950, 171 0, 1670, 2450,

1 120cm.l; 'H NMR 90 MHz 1.42-2.1 (m, 7H), 2.1 -2.9 (m,

2H), 3.1 -4.1 (m, 6H), 6.82 (dd, 2H, Ar-H), 7.2-7.4 (m, 7H,

Ar-H).

trans-1 -methoxy-3,5-diphenyl-2-oxobicycla[4.4.0]dec-3- ene (1 2):

To a solution of 1,5-diketones 9 (0.61 29, 2 mmol) in methanol (1 5mL) was added NH,OH.HCI (0.2809, 4mmol)

and CH,COONa (0.829, 1 rnrnol). Then reaction mixture was stirred for 2 h at rt. A white solid separated out was filtered and dried to afford 12 (0.3529, 55%).

trans-1 -methoxy-3,5-diphenyl-2-oxabicycla[4.4.0]dec-3- ene (1 2):

Yield = 55%; rnp = 171 oC; IR 2960, 1645, 1600, 1490, 1450, 1 150, 1085, 1025, 920 cm-'; 'H NMR 6 1.14-1.75 (m, 8H), 2.40 (dd, 1 H), 3.32(s, 3H, OCfil,), 3.35 (dd, 1 H, J = 11.2, 2.44), 5.47 (d, lH , J = 2.44), 7.28 (m, 8H, Ar- H), 7.64 (dd, 2H, Ar-H); 13C NMR 22.67 (t), 25.53 (t), 26.82 (t), 31.25 (t), 41.65 (d), 46.82 (d), 48.1 9 (q), 99.59 (s), 103.84 (d), 124.48 (d), 126.50 (d), 127.90 (d), 128.23 (d ) , 128.37 (d), 128.73 (d), 133.67 (s), 144.33 (s ) , 147.08 (5); MS m/z 320 ('1 01, 288 (25), 259 (1 O), 201 ( l o ) , 125 (1 5), 1 1 2 ( 1 00), 1 10 (40), 105 (22), 97 (1 8), 91 (1 0), 77 (1 8); Anal. calcd for C,,H,,O,: C, 83.82; H, 7.52; obsd: C,

82.46; H, 7.55;

To a stirred solution of 1,5-diketone (0.61 29, 2 mmol) in 10 rnL of MeOH was added NH,OH.HCI (0.28g,4mmol) and CH,COONa (0.0829, 1 rnmolj and the reoction mixture was heated at reflux overnight. The solution was cooled to rt, concentrated, and diluted with 25 mL of CHCI,. After the solution was washed with H,O (20 mL) and brine (10

rnl), the organic solvent were dried (Na,SO,) and concentrated. The residue was chromatographed using 5% EtOAc in hexane

yielded 13 (0.342 g, 60%) of tetr~h~droquinoline as a white solid.

Yield = 60%; mp = 1 0 2 - ~ o C ; IR 3065, 3060, 2950, 2940, 2870, 1585, 1570, 1490, 1450, 1380, 1025, 920 cm'; 'H NMR 400 MHz 6 1.74 (m, 2H), 1.93 (m, 2H), 2.65 ( t ,

2H, J = 6.351, 3.05 (t, 2H, J = 6.35), 7.25-7.45 (rn. 9H),

7.95 (d, 2H); I3C NMR 6 23.06 (t), 23.12 (t), 27.29 (t),

33.36 (t), 1 19.1 1 (d), 126.87 (d), 127.73 (d), 128.32 (dl,

128.43 (d), 128.55 (d), 128.6 (d), 139.74 ( s ) , 139.77 (s ) , 150.24 (s) , 154.31 (s), 157.63 ( 5 ) .

Yield = 70%; rnp = 143°C; IR 3065, 3060, 2950, 2940,

2870, 1585, 1490, 1450,1380, 1025,920 cm-'; 'H NMR 90 MHz 6 2.12 (m, 2H), 3.04 (m, 2H), 3.12 (t, 2H, J = 6.81, 7.25-7.45 (m. 8H), 7.95 (d, 2H); I3C NMR 6 23.47 (t), 30.59, 34.76 (t), 1 18.06 (d), 1 27.06 (dl, 1 28.53 (d), 128.71 (d), 133.1 2 (s), 137.1 8 (s), 140.1 2 (s), 146.01 ( s ) ,

156.59 (s), 166.89 (s); Anal. calcd for C,,H,,N: C, 88.1 1 ; N, 5.79; H , 6.18; Obsd: C, 88.52; N, 5.16; H, 6.31.

To a stirred solution of 1,s-diketone 6 (0.3069, 10 mmol)

in 15 mL of PEG-200 was added HCOONH, (3.159, 50 mmol) and was heated at reflux overnight. The solution was cooled to rt, diluted with 50 ml of CHCI,. The solution was washed with H,O and brine (1 5 mL), the organic solvent

were dried over Na,SO, and concentrated to give a dark brown liquid. The dark brown liquid was subjected to column

chrorilatography on silica using CHCI, yielded 1.849 (65%)

Yield = 65%; IR (neat) 3070, 3040, 2930, 2860, 1670 (br),

1600,1490, 1450, 1240, 1 120,1030,780 cm '; 'H NMR

2 0 0 M H z 6 0 . 8 (qd, l H ) , 1.00-1.84(m, lOH), 1 .9 (qd , l H ,

J=lO, 3.2Hz), 2.38 (td, 1 H, J = 11.4, 4.2Hz, C,-H), 2.45

(td, lH,J=11.4,2.2Hz,C,ox-H),3.82(dd,lH,10.6,2.64H~,

CzOx-H), 7.1-7.4 (m, 1 OH, Ar-H); "C NMR 200 MHz 6 26.06,

29.23, 33.64,43.59,46.76,50.18,61.95,62.29, 126.12, 126.71, 127.12, 127.71, 128.41, 144.71.

To a stirred solution of 1,5-diketone 9 (3.069, 10 mmol)

was added ethanolamine (0.6759, 11 mmol)and the mixture

was heated at reflux overnight. The solution was cooled to

rt and NaBH, (1.8059, 10 mmol) was added portionwise

for 6 h. Everytime after adding NaBH,, the reaction mixture

was stirred at rt for 10 minutes, heated at reflux for 1 O minutes,

and was cooled to rt before adding next portion. Finally

the reaction mixture was cooled to rt, concentrated, and diluted

with 1 OOml of CHCI,. After the solution was washed with

H,O and brine (1 5 ml), the organic layer was dried over Na,SO, and concentrated. The residue was subiected to

column chromatography on silica gel using 10% EtOAc in

hexane ~ i e l d e d 1.509 (45%) of 15 and 0.6509 (20%) of

16.

1455,1030,760, 700 crn.'; 'H NMR 400 MHz 6 0.85 (qd, l H ) , 1.12 (rn, lH) , 1.26 (rn, 2H), 1.45 (br, d, lH) , 1.56 (rn,

3H), 1.85 (dt, 1 H), 1.95 (q, 1 H), 2.1 6 (rn, 1 H), 2.26 (tt, lH) ,2 .38( td , lH,J=l1.6,4.12Hz), 2.65(rn,2H),3.12(rn, l H ) , 3.25 (rn, l H ) , 3.6 (dd, l H , J = 11.4, 3.OHz), 7.1-7.4 (rn, 1 OH, Ar-H); 13C NMR (DEPT) 25.76 (CH?), 25.82 (CH,),

30.32 (CH,), 32.36 (CH,), 43.49 (CH,), 46.30 (CH), 49.40 (CH), 52.16 (CH,), 60.64 (CH,), 68.50 (CH), 69.49 (CH), 126.15, 127.27, 127.53, 127.90, 128.35, 128.42 (Ar- CH), 144.62, 144.64 (Ar-c) ; Ms rn/z (M') colcd for C,,H,,NO 335.2249, obsd. 331.221 6 .

Yield = 20%; rnp = 1260C; IR 3025, 2944, 1596, 1488, 1456, 1401, 1372, 1145, 1062, 1030, 1017, 905, 700

crn.l. , 1 H N M R 4 0 0 MHz 6 0 . 9 2 (t, 2H), 1.1 -1.4 (rn, 3H), 1.5 (rn, 1 H), 1.6-2.0 (rn, 4H), 2.34 (br, s, 1 H), 2.52 (rn,

l H ) , 2.66 (rn, 2H), 3.15 (rn, 2H), 3.54 (rn, l H ) , 3.65 (t,

l H , J = 6.47Hz), 3.90 (t, lH , J = 7.10Hz), 7.2-7.4 (m, 10H, Ar-H); 13C NMR (DEPT) 61 8.39 (CH,), 20.76 (CH,),

25.85 (CH,), 28.05 (CH,), 39.72 (CH), 41.04 (CH), 44.38

(CH,), 49.01 (CH,), 57.84 (CH,), 58.04 (CHI, 61.34 (CH),

126.18, 127.24, 127.43, 127.80, 128.44, 128.48,143.57,

144.36.

N-(2-Hydroxyethyl]-cis-2(4-methoxy)-4-phenyl-trons-l - decohydroquinoline (70):

Yield = 35%;mp = 1252; IR 2950,2880,1600,151 0,1455cm- ' ; 'H N M R 4 0 0 M H z 6 0 . 8 (m, lH ) , 1.1-1.8 (m, lOH), 2.1- 2.4 (m, 3H1, 2.6 (m, 2H), 3.0-3.2 (m, 2H), 3.55 (dd, J = 10.1, 3.8Hz, 1 HI, 6.65-6.85 (m, 2H, Ar-H), 7.00-7.4 (m, 7H, Ar-HI.

Yield = 25%; IR (neat) 3020, 2944, 2864, 1600, 1488, 1429, 1380, 1240, 1 149, 1 105, 695cm-'; 'H NMR 400 MHz 1.2 (m, l H ) , 1.5-2.05 (m, 6H), 2.25-2.40 (m, 3H), 2.55 ( td, l H,J=9.2, 6.27Hz), 2.7 (td, 1 H , J = ~ . ~ , ~ . ~ H Z , C , ~ ~ J , 2.95 (br, s, lH ) , 3.13 (m, l H , J = 9.76, 2.93Hz, C,ox-H), 3.25 (dt, lH , J = 8.78, 3.421, 3.45 (dd, 1H J = 10.34, ~ H z ) , 7.1 0-7.40 (m, 1 OH, Ar-H). 13C NMR 21.49 (t), 22.83

(t), 3 1 . 8 l (t), 34.85 (t), 41 .22 (dl, 47.17 (dl, 55.36 (t),

59.95 (t), 68.1 8 (dl, 70.09 (dl, 125.86, 126.83, 127.47, 127.88, 1 28.08, 128.35 (d, Ar-C), 144.29 (s, Ar-C).

Cyclisation with BF,.Et,O

To a solution of N-substituted trans-decahyrdoquinoline

15 (0.1 659, 0.5 mmol) dissolved in 5 m l of freshly distilled BF,.Et,O was heated at reflux for 4 h under nitrogen atmosphere. The reaction mixture was cooled to rt, diluted with 50 mL of CHCI,. After the solution was washed with H,O and brine (1 0 mi), the or anic layer was dried over Na,SO, and concentrated. ,? ,m The residue-was subiected to column chromotogrophy on alumina using CH,CI, yielded 0.1549 (85%) of 18 as a dark brown liquid.

Ether derivative of N-(2-hydroxy ethyl)-trans-2,4-diphenyl- c is -de~ahydro~u ino l ine (1 8):

Yield = 90%; IR (neat) 3024, 2928, 2864, 2768, 1725,

1597, 1491, 1450,1110,752,701 crn-'; 'H NMR 400 MHz

6 0.89 (rn, 1 H), 1.09 (t, 3H, -CH,), 1.13-1.69 (rn, 5H), 1.75- 1.89 (m, 3H), 2.32 (m, 2H), 2.6 (m, l H ) , 2.80 (rn, lH) , 3.22-3.36 (m, 4H), 3.62 (dd, lH , J = 11.4, 3.OHz), 7.1-

7 .4 (rn, 1 OH, Ar-H); I3C NMR (DEPT) 6 15.1 7 (CH3), 25.86 (C,, (CH,), 30.35 (CH,), 31.77 (CH,), 44.65 (CH,), 46.93 (CHI, 49.35 (CH), 49.58 (CH,), 66.1 0 (CH,), 67.30 (CH,),

68.21 (CHI, 68.55 (CH), 126.07, 126.91, 127.59, 127.89, 128.30, 128.54 (Ar-CH), 144.62, 144.64 (Ar-C).

Ether derivative of N-(2-hydroxy ethyl)-cis-2,4-diphenyl-

trans-perhydro-1 hpyrindine (22) :

Yield = 85%; IR (neat) 3020, 2950, 2860, 2760, 1600, 1500, 1450, 1380, 1240, 1030, 760, 700 cm-'; 'H NMR

6 1.05 (t, 3H, Ctj,), 1.08-1.16 (m, lH) , 1.5-2.00 (m, 6H), 2.16 (qd, 1 H), 2.28 (m, 1 H), 2.54 (dddd, 1 H), 2.65 (dddd, lH) , 3.05 (dd, IH, J = 9.27, 5.86Hz), 3.08 (t, l H , J = 5.86),3.16-3.28(m,4H),3.52(dd,lHJ=l1.23,2.93Hz), 7.10-7.40 (m, 1 OH, Ar-H). I3C NMR 400MHz 6 15.16(9), 21.71, 22.73 (t), 30.35, 31.76 (t), 35.66 (t), 41.39 (d), 47.35 (dl, 51.56(t), 63.95 (t-), 66.64 (dl, 68.48 (dl, 68.80 (t), 125.78, 126.83, 127.47, 127.88, 128.08, 128.35 (d, Ar-C), 144.79, 145.42 (s, Ar-C).

Cyclisation with HBr

To a solution of trans-de~ah~droquinoline 15 (0.1 659, 0.5 rnrnol) dissolved in 10 r n L of glacial AcOH at rt was

added 0.2 mL Con. HBr and the reaction mixture was heated at reflux for 5 h under nitrogen atmosphere. The reaction mixture was cooled to rt, diluted with 50 mL of CHCI,. After

the solution was washed with 5% KOH solution and brine

(1 0 mL), the organic layer was dried over Na,SO, and concentrated. The residue was subiected to column chromatography on

alumina using CH2C12 yielded 170mg (85%) of acetyl derivative

of 15 as a white solid.

Acetyl derivative of N-(2-Hydroxy ethyl)-cis-2,4-diphenyl-

trans-decahydroquinoline (1 9):

Yield = 95%; mp = 10l0C; IR 3020, 2950, 2860, 2760,

1730, 1600, 1500, 1450, 1380, 1240, 1030, 760, 700 c m - ~ . , 1 H NMR 400 MHz 6 0.85 (qd, 1 H), 1 .12 (m, 1 H),

I .25 (m, 2H), 1.40 (m, 2H), 1.85 (m, 4H), 1.95 (s, 3H), 2.22 (m, l H ) , 2.32 (m, 3H lH) , 2.38 (td, l H ) 2.65 (m,

lH ) , 2.92 (m, lH) , 3.26 (m, lH ) , 3.64 (dd, lH , J = 11.0,

2.6.OHz), 3.9 (m, lH ) , 4.01 (m, lH ] , 7.1-7.42 (m, lOH,

Ar-H); 13C NMR 400 MHz (DEPT) 6 20.94 (CH,), 25.68 (CH,),

25.77 (CH,), 30.20 (CH,), 31.50 (CH,), 44.57 (CH,), 46.55

(CHI, 47.91 (CH), 49.38 (CH), 62.01 (CH,), 66.99 (CH,),

68.21 (CH), 126.08, 127.04, 127.50, 127.54, 127.72,

128.29, 128.35 (Ar-CHI, 144.48, 144.64 (s, Ar-C), 170.89

(5, G O ) .

5.6 References:

1. a. Brown, G. D.; Mckane, I. M.; Biology: Exploring life, John Wiley and sons: 1988, p. 58. b. Villee, C. A.; Solomon, E. P.; Davies,P. W. Biology, Holt. Sounders International

Editions, 1985, p. 53.

2. a. Power, R. F.; Mani, S. K.; Codina, J.; Conneely, 0 . M.; 0'-Malley, B. W.Science, 1991, 254, 1636. b. Swaneck,

G. E.; Fishrnan, J. Proc. Not/. Acad.Sci. U. S. A. 1988, 85, 7831. c. Spelsberg, T. C.; Ruh, T.; Ruh, M.; Goldberg,

A.; Horton, M.; Horo, J.; Singh, R. J. Steroid Biochem. 1988, 31, 579.

3. a.Dolle, R. E.; Allaudeen, H. S.; Kruse, L. I. J. Med. Chem. 1990,33,877. b. Huisman, H. 0 . Angnew. Chem. 1971, 10, 450. c . Akhrom, A. A,; Lakhivich, F. A,; Lis, I. G.; Pshenichnyi, V. N. Zh. Org. Khim. 1979, 15, 1396. b. Taylor, e.C.; Lenard, K. Chem. Commun. 1967, 97.

4. a.Chorvat, R. J.; Poppo, R. Tetrahedron Lett. 1975, 623. b. Chorvat, .R. J.; Pappo, R. I . Org. Chem. 1976, 4 1 , 2864.

5. a.Jager, 0.; Wehrli, H. U. Swiss Pat. 1973, 538,51 1;

Chern.Abstr. 1973, 79, 137385. b. Jager, 0.; Wehrli, H U.Swiss Pat. 1973, 537948; Chem. Abstr. 1973, 79,

137387.

6. Isomura, K.; Yamazaki, T.; Nagata, M.; Matoba, K. Japan kokai, 1975,7505400; Chem. Abstr., 1975,83, 10596b.

7 . a. Pitak, D. M.; Dorfman, R. I.; Tibbetts, D.; Cops, E. J. Med. Chem.1964, 7, 590. b. Lettre, M.; Knof, I. Ger.

Offen, 1959, 1,l 18,197; Chem. Abstr., 1962, 56, 10252.

8. Miyairi, S.; Ichikawa, T.; Nambara, T. Tetrahedron let!. 1991, 32, 1213.

9. a.Rasmusson, G. H.; Reynolds G. F; Steinberg, N . G.;

Walton, E.; Patel, G. F.; Liang, T.; Cascieri, M. A.; Cheug, A . H.; Brooks, J. R.; Berman, C. J. Med. Chem, 1986, 29, 2298. b. Rasmusson, G. H.; Reynolds, G. F.; Utne,

T.; Jobson, R. B.; Primka, R. 1.; Berman, C.; Brooks, J. R.

J. Med. Chem. 1984, 27, 1690.

1O.Garcia-Raso, A,; Garcia-Raso, J.; Campaner, B.; Mestres,

R.; Sinisterra, J. V. Synthesis, 1982, 1037.

11 .Vlosova, L. V.; Tyrina, T. I.; Klimenko, S. K.; Kharchenko, V. G. Khim. Getero. Soedin, 1979, 470.

12.Evtushenk0, I. Yo.; Klimenko, S . K.; Kharchenko, V. G.; lonin, B. I. Zh. Org. Khim. 1976, 12, 1807.

13.Sanmour, A,; Raouf, A,; Elkasaky, M.; Ibrohim, M . A.

Acfa. Chim.(Budapest), 1973, 78, 399.

14.Weiss M. J. Am. Chem. Soc. 1952, 74, 200

15.c1.de Bemmeville, P. L.; Macartney, J. H. J. Am. Chem. Soc. 1950, 72, 3073. b. More, M. I. Org. Reaction, 1949, 5, 301.

16.a.Vierhapper, F. W.; Eliel, E. 1. J. Org. Chem. 1979, 44,1081. b. Vierhapper, F. W.; Eliel, E. L. J. Org. Chem. 1977, 42, 51. c . Vierhapper, F. W.; Eliel, E.L. 1. AM. Chem. Soc. 1975, 97, 2424. d. Vierhapper, F. W.; Eliel, E. L. J . Org. Chem. 1977, 42, 51.

17.Grishin0, G. V.; Potapov, V. M. Khim. Gefero. Soedin.

1989, 579.

18. Eliel, E. L.; Vierhapper, F. W. I . Org. Chem. 1976, 4 1, 199.

19. a. Kriven'ko, A. P.; Boreko, E. I.; Vladyko, G. V.; Reshetov, P. V.; Kharchenko, V. G.; Khim. Farm. Zh. 1990, 24,

27. b. Booth, H.; Griffiths, V. D.; J. Chem. Soc. Perkin Trans. 11, 1975, 11 1. b. Booth, H.; Griffiths, V. D.; J. Chem. Soc. Perkin Trans. 11, 1972, 61 5 . d. Booth, H.; Bostock, A. H. Chem. Commun. 1967, 177.

20. Gertsev. V. V. Romanov, Yu. A. Khim. Getero. Soedin. 1989, 1483.

21. Jackson, A. K.; Naidoo, B.; Smith, P. Tetrahedron, 1968,

24, 61 19.

22. a.Di Roddo, P.; Harvey, R . G. Tetrahedron lett. 1988,

29, 3885. b. Olah, G. A,; Kobayoshi, S.; Tashiro, M. J.

Am. Chem. Soc. 1972, 9 4, 7448.

23. a. Richter, H. J. Org. Syn. Coll. 1963,4, 482. b. Tsukervanik,

I. P.; Bogdanova, N. I. J. Gen. Chem. U. S. S. R. 1953, 22, 410.

24. a.Canonne, P.; Holm, P.; Leitch, L. C.; Can. J. Chem.

1967, 45, 2151. b. Bradsher, C. K. Chem. Rev. 1946, 38, 447.

25. Barluenga, J.; Tomas, M.; Suorez-sobrino, A.; Rubio, E. J. Org. Chem. 1993, 58, 700.

26. a.Kholaf, A. A. Roberts, R. M. J. Org. Chem. 1972,

37, 4227. b. Robinson,R.O.; Davidson, D.; Bogert, M. T.J. Am. Chem. Soc. 1935, 57, 151.

27. a. .Masuda, Y.; Kagowa, R. Chem. Pham Bull. Japan, 1972, 20,2736. b. Morrison, G. C.; Cetenko, W.; Shovel,

Jr, J. J. Org. Chem. 29, 2771.