Chapter 2 100

CHAPTER 2

STEREOCHEMISTRY OF

QUINOLIZINES BY DYNAMIC NMR SPECTRAL STUDIES

2.1 Synthesis and stereochemistry of cyclopentaquinolizines

In the first chapter, we described reductive amination of various I , 5-diketones

to generate six-membered nitrogen heterocycles. Subsequently, we extended this work

towards the synthesis and stereochemistry of cyclopentaquinolizine 1-4 and

perhydropyrido[3,2,1-ijlquinoline derivative 5-6 (Fig. 2.1) from 1,5,9-triketones 7a and

7b via molecular stitching of carbonyl carbons through reductive amination-cyclization

procedure.

- - A A

RO OMe OMe OMe

l : R = O M e 2: R = OMe 5 3. R = OCH,Ph 4: R = OCH,Ph

Fig. 2.1

Perhydroquinolizine (quinolizidine) are readily recognizable structural entities

in a-shhizozygol 8,' Vallesamidine 9,' callichiline 10,' 10,10,

methylenebis(no~al1esamidine) 11,' stermpeliopine 12: andrangine 1 3 , ~ and

criophylline 14' (Fig. 2.2).

Chapter 2 101

OMe

Fig. 2.2

Aryl groups bonded to peri positions of a planar framework, like 1,s-

disubstituted naphthalene, adopt a face to face (stacked) arrangement and display

restricted rotation about the aryl naphthalene bond that, in particular cases, might have a

suffic:ently high barrier as to produce configurationally stable cis and trans isomers."

number of barriers for the interconversion of these types of isomers have been

reported.' When the aryl substituents are not sufficiently large, stereolabile isomers

(conformers) have often been observed and the corresponding interconversion barriers

determined by variable temperature NMR spectroscopy.'0 Heterocycl~c rings bonded to

the 1,8 positions of naphthalene displayed analogous features." Barriers of this type

were also determined in the case of aryl groups bonded, in a stacked arrangement, into

other ngid kameworks like anthracene,12 cyclobutane," and acenaphthene."

Chapter 2 102

Chart 2.1 I

Presently, we observed a quite peculiar situation where two aryl rings are

bonded to the less rigid framework of perhydrocyclopentaquinolizine'5 (see compounds

1. 2 of Chart 2.1, where methoxy groups in the para position of the aryl rings serve to

a~inplify NMR spectra). Thus, in addition to the rotation process involving these anisole

substituents attached to a more flexible ling system, the inversion processes occuning

within the perhydrocyclopentaquinolizine moiety should also be observed.

In the perhydroquinolizine (quinolizidine) framework a nitrogen atom replaces

the carbon C-4a of cis- or trans-decalins (perhydronaphthalenes), as displayed in

Scheme 2.1. The framework of trans-decalin is locked, as it cannot invert to an

alternative chair-chair system unless carbon-carbon bonds are broken and then

r ~ ~ o i n e d ; ' ~ on the contrary, cis-decalin can interconvert between two chair-chair

conformations, even at ambient temperature. As shown in Scheme 2.1, and in contrast

to the conformational rigidity of

Scheme 2.1

rfiin-decalin, the trana-quinolizidine can interconvert from one chair-chair

;onformat~on to other chair-chair conformat~on via CIS-quinolizid~ne. This i\ possible

tince nitrogen Inverts its configuration and. k i n g th~s process faster than chair-to-chair

c~chanpe in piperidines ", it is likely that trans-quinol~zidines Interconvert rapidly 10

mother form at ambient temperature.'x Equilibration o f chair conformations In

i~u~mlizidines can be prevented by adding n br~dging ring such as that o f

c~clopenta[r,j]quinolizidines 1 and 2 in Chart 2.1, or hy hlocking nltrogen inversion by

crln\erslon of the molecule to the corresponding ammonium salt. in effect making the

\y\trm more similar to rrans- decalin\.

Dynamic NMR spectroscopic can be wed to evaluate the conformational

change> involving, possibly, nitrogen inversion, ring inversion and restricted rotation o f

Ihe aryl r~ngs in quinolizidines o f the type 1 and 2. Since the hapic

cyc'lopenta[r,j]quinolizidine structural motif is encountered in the structure o f a number

ol complex alkalo~ds, studies o f the conformational dynamics involved in such systems

idn be quite useful from the point o f view o f structure activity relationships.

2.1.1 Synthesis and characterizations of quinolizines

The 1,5,9- triketones 7a-c were synthesized according to established procedure

.ic\eloped procedure in our laboratory (Scheme 2.21.'' Thus, Mannich bases 15a, b

xcre heated under microwave irradiation in the presence of triethyl amine to provide

1.5.9-triketones.

Chapter 2 104

Scheme 2.2

1 5 a : X = O M e Y = H 16:n.l 18a. X = OMe, Y = H, n = 1 15b: X = OCH,Ph, Y = H 17: n = 2 1 8 b ' X = O M e , Y = H , n = Z

18c X = OCH,Ph, Y = H, n = 1

7a: X = OMe, Y = H, n = 1 7b. X = OMe, Y = H, n = 2 7c. X = OCH2Ph, Y = H, n = l

1 Reagents and conditions: i) EtlN, PEG-200, MU', 370 W, 1 min. --

Earlier in our laboratory,2u the 1,5,9-triketone 19 was subjected to reductive

amination-cyclization with ammonium formate in PEG-200 under microwave

Irradiation at 370 W power to provide a diastereolnenc mixture of 3,s-

d~phenylperhydrocyclopenta

[r,]quinolizines 20 and 21 in 87% yield in the ratio of 2:l (Scheme 2.3).Is The

diastereomeric mixture of amines 20 and 21 were separated and characterized.

Scheme 2.3

19 20 21

Reagents and conditions: i) HCOONH4, PEG-200, MW, 370 W. 1 min.

Chapter 2 105

Spthesis of quinolizidines 1-6 fits into overall ongoing research activity

wherein we identitied quinolizidine based crown ethers as our synthetic targets. We

reasoned that crown ethers of the type 23 could show selective aff~nity towards

aromatic amino acids. In this plan, 7a and 7b were to be transferred into his-phenol 22

before the preparation of crown ethers 23 (Scheme 2.4).

Scheme 2.4 -

For the present research, we repeated the reductive amination-cyclization

reaction on 2,5-di[3-(4-methoxn,henyl)-3-oxopropyl]-l-cycopentanone 7a and 2 3 -

d1{'-[4-(benzyloxy)phenyl]-3-oxopropyl)-l-cyclopentanone 7c individually. Under

microwave irradiation triketone 7a reacted with ammonium foimate, in PEG-200 to

furnish three products namely a diasteromeric mixture of

perhydrocyclopenta[ijlquinolizines 1, 2 and I-(4-methoxypheny1)-3-[2-(4-

Chapter 2 106

methoxyphenyl)-6,7-dihydro-5H-cyclopenta[b]pn-7-yl]-I-propanone 24 the ratio

of 1:2.4 the in total 62% of yield (Scheme 2.5). The three products were separated by

column chromatography and were characterized separately.

Scheme 2.5

I

24 R = OMe 25: R = OCH2Ph

1 Reagents and conditions: i ) HCOONh, PEG-200, pv, 370 W, I min. 1

The 'H NMR spectra of the major product -(4-methoxypheny1)-3-[2-(4-

methoxyphenyl)-6,7-dihydro-5H-cyclopenta[b]pdin-7-yl]-l-propanone 24 shows

four doublets located at 6 8.02 (J = 7.0 Hz), 7.96 (J = 7.0 Hz), 7.48 (J = 7.9 Hz) and

7.41 (J= 7.9 Hz) ppm indication of the pyridine ring. A multiplet located between at 6

2.98-2.78 ppm was accounted to COCH2. The "C NMR spectrum of 24 shows only five

s i ~ a l s for aliphatic carbons. A low intensity signal 6 199 ppm was assigned for the

Chapter 2 107

keto group. The IR spechum revealed presence a band for keto group at v 1669 cm".

IR, 'H NMR and I3c NMR spectra of the hvo diastermmers of 1 and 2 matched with

unsubstituted derivatives available in our laboratory.

Similarly the reductive amination cyclization was repeated on OCH2Ph

substituted triketone 7c, the reaction gives diastereomeric mixture of isomers 3,s-di[4-

(benzyloxy)phenyl]perhydrocyclopenta[ljlquinolizine 3, 4 and 1-14-

(benzyloxy)phenyl]-3-{2-[4-(benzyloxy)phenyl]-6,7-dihydro-5H-cyclopenta[b]pfldin-

7-ylj-I-propanone 25 in the ratio of 1:2. The major compound 25 spectral data was

similar to the 24.

From the above results we are getting undesired aromatized pyridine compound

24 and 25 in more than 50% yield. We concluded that Leuckart-Wollach reaction is not

a good choice to obtain perhydrocyclopenta[ij]quinolizine 1-4. In the earlier unit we

have demonstrated the reductive cyclization protocol for the synthes~s of

perhydrocyclopena[h]pfldines and decahydroquinolines from corresponding 1,5-

diketones by using NaBH4/AcOH in THF at 70 O C . In continuation of this results we

used Na(OAc)3BH as a reducing agent for the reduction of enamine, intermediates

generated by reaction with ammonium acetate. When we subjected the rrductive

anination of 1,5,9-triketone 7a two diastereomeric products 1, 2 were obtained in good

yield, and there is no trace of the cyclopenta[h]pyridine t p e compounds (Scheme 2.6).

Scheme 2.6 1 -

\

OMe OMe

- --

- 39

OMe Me0 OMe Me0

I 7a 1 2 ' Reagents and conditions: i) Na(OAc),BH, N h O A c , AcOH, THF, 60 "C, Ih. 80% 1

Chapter 2 I 08

The 'H NMR spectra (Fig. 2.3) of the major product 1 shows characteristic

triplet at 6 2.86 ppm with J value of 4.5 Hz for H9b indicating pseudo-equatorial

orientation of aryl groups. The spectrum also display in aliphatic region doublet of

doublet at 6 3.22 ppm with Jvalue of 6.0 Hz and 4.6 Hz for H3, H5 protons and S 1.98-

2.06 multiplet for H9a, H7a protons. In aromatic region multiplet at 6 6.35-6.38 ppm

was assigned for ortho-0Me attached CH (H12) and broad singlet at 6 6.76 ppln was

assigned for CH (HI 1). The "C NMR spectrum (Fig. 2.3) of 1 revealed six signals for

aliphatic carbons and one for OMe and four signals for aromatic carbons, which also

point to existence of pseudo- mirror plane symmetry in the molecule.

The sterwchemistry of the ring junction was investigated by ID NOE

experiments (Fig. 2.4) and was found to correspond to a cis, cis ring junction at

perhydrocyclopentaquinolizine moiety. Irradiation of the triplet of H9b (at 2.88 ppm)

yields NOE effects on the pair of hydrogens 3,5 (at 3.24 ppm), on the pair of hydrogens

7a,9a (at 2.28 ppm) and on the hydrogens 1,7 (at 1.71 and 1.55 ppm).

Chapter 2 109

, . - a r t .

"-,.,.*" -, u.. -L.-. - .~,.~..".., +I

3 n.r n i t .% l," : I., - ,! 7 ?, .=""..,.. - rL .. ,>.,>,* - 1, ',,/ '7

"- -*- I

* - -> ...,, - I ".,me " .# "3 M

".a" , > > M > Ii i 1~

,".. .. " .,",, ' ,

Me0 bhi.14 3 3 , 3 2 0 2 .9 , pp,

I

r / , l i , - I . - . . J . ... .. . - -- -- -- ,I .--- . .--.. . . . . ~ . ------

7 0 6 % L . 0 l 5 1.0 ( I '0 I 5 I 0 1 1 1 0 c w > m,c,.

P P

-,.,,A. -a.

m." --. .>w .. ..~. <a,*,, W P r,. c 8. 8 . I / I , - I .I. - .- "-. .- ",- .,om 0.0.. ." 1 ,,,.,-. 2 " ,a. -. .

.,> ,w .c>.*, w . ?-.., "3 S" ... 2. ,

,- .. - * , "*.< -2 - > < > ,> 2

k. < 2 * . ..".,>A. ," 5,. ..>. 5 ),,. ". a , , . . < * .

--sf - 6 .,." ,>, L, ., Y ~

...$. ,. -,"m . .,-, ". ,. ,*, *. . .," ". ., ,,. ... ..." -.," . . ., ,.. 3s ," , ,

. , I . I . -.._I>... a .,,. ,,,, ,, *. .. . ". " .,, r. 8 , ,,v 32, ,> 4 , ., s ! ,. .... ". ..*. ... s. .,>a u. 3e .s . 3 . J >. ,,.,", r . . s . ,*

~

I

Fig. 2.3 'H NMR spectrum (top) and "C NMR spectrum (bottom) of (3SR,SSR,7aRS, 9aSR)-3,5-di(4-methox~henyl)perhydrocyciopenta[i~]qnolizine 1

Chapter 2 110

H.Lo&

Hgs

H 2 6 .

H,,

-d . . - - -h--- Il

I I I

I

V - T T

6 9 3 6 3.0 1 4 1.0 ppm

Fig. 2.4 NOE experiment (600 MHz in CDzCI2) obtained by irradiating the signals of the hydrogen in position 9b (top trace) and of the two hydrogens in position 3,5 (midile trace) in compound 1. These two signals experience a strong reciprocal NOE enhancement since their averaged relative distance is computed to be quite short (2.7 A). Irradiation of the H9b signal does not yield enhancement of the aromatic signals.

On the contrary NOE was not observed on H8,H9 (1.84 and 2.02 ppm) nor on

the aromatic hydrogens. These results were further confirmed by the irradiation of the

H3, H5 triplet. The detail NOE correlations are given in the (Fig. 2.5) and complete

structure was assigned on the basis of HMBC, HMQC and COSY experiments.

Fig. 2.5 Selected NOE correlations for (3SR,SSR.7aRS,9aSR)-3.5-Dit4-methoxy phenyl)perhydrocyclopenta[~j]qu~nol~zine 1

The 'H NMR spectra (Fig. 2.6) of the mlnor product 2 show> tuu charactenrtic

~riplel at 6 2.86 ppm with J value o f 4.5 Hz for HYh In aliphatic region indicat~ng

p,cudo-equatorial orientation of aryl groups, doublet of doublet at 6 3.22 ppm w ~ t h J

ialur of 6.0 Hz and 4.6 Hz for H3. H5 proton\ and 6 I .YE-2.06 multiplet for H9a. H7a

proton?. In aromatic region multiplet at 6 6.35-6.38 ppm wa\ a\r~gned for ortho-OMe

dtt~ched CH (HI2 ) and broad singlet at 6 6 76 ppm was awgned for CH ( H I I ) The "C

NMR rpectrum (Fig. 2.6) of 2 revealed six signals for al~phnt~c carbon> and one for

OMe and four signals for aromatic carbons, which also polnr to exl\tence 01' pieudo-

nllrror plane symmetry in the molecule. The slructure of the iwmeric compound 2 war

~ l s o ohtained by means of NOE experi~nenti that ~nd~cate the \ame type of I I J . ci.!

lunctlon for the perhydrocyclopentaquinolizine moiety since, ar in the case of 1.

irrdd~ation of the H9b triplet enhances the signal of the hydrogens in positions 7a.Ya

1 Fig. 2.7).

Chapter 2 112

I I

Fig. 2.6 'H NMR spectrum (top) and "C NMR spectrum (bottom) of (3R$SRS,7aRIi,9aSR)-3,5-di(4-methox).phenyl)perhyocyclopenla[i~]quinoizine 2

Chapter 2 - - 113

Fig. 2.7 NOE experiment (600 MHz in CD2C1z) obtained by irradiating the signals of the hydrogen in position 9b (top trace) and of the two hydrogens in position 3,5 (middle trace) in compound 2. These two signals experiences a weak reciprocal NOE enhancement since their averaged relative distance is computed to be quite large (3.82 A). Contrary to the case of 1 (See Fig. 2.4), irradiation of the H9b signal yields a large enhancement (as large as that due to the irradiation of the H3,5 signal) of the aromatic hydrogens meta to OMe (i.e HI 1).

Chapter 2 114

Here the two aryl groups are anti to the five-membered ring (i.e, in a dynamlr

,l,eudo axial position) since irradiation of the H9b triplet enhances the aromatic

hydrogens in position meta to the OMe group (position I I ) whereas yields a very small

~ f fec t on the signals of H3, H5, contrary to the case of 1 (Fig. 2.3). The deta~l NOE

~orrelat~ons are glven in the (Fig. 2.8) and complete structure was awgned on the basi\

,,i HMBC, HMQC and COSY expenmen(\.

Fig. 2.8. Selected KOE correlations for (3RS.SR.Y.7aRS.9ltVR~-3,S-d1(4-methoxyphenyl) perhydrocyclopenta[~jlquinolizine 2

2.1.2 Chair to boat interconversion and face to face interactions i n isomeric a ~ l

cllbstituted perhydrocyclopenkaquinolizines 1 and 2

4 complete conformational search for 1 and 2 was carrled out by molecular niechal~~cs

N M F F force field) measurements." and the two most \table conlbrmers were

~ubsequently mlnimired by Dm computations2' In Figure 2.9 1s di\played the preferred

conformation (its energy is 1.9 kcal mot" lower than that of the second most stahle form

where both the six membered rings are chair,), where one of the two \ix-membered

nngs is a chair whereas the other is a twisted boat." Such a \latic conformer exlsts a\

IU'O enantiomeric forms that interconvert rapidly at amblent temperature yielding a

d!.narnic C, symmetry which accounts for the equivalence of the pairs o f the "C lines In

I112 corresponding spectrum at t25 "C.'

1 o* temperature dynam~c NMR studied and lhcorcltcal calculallon wrrr supponcd h) Prof Luna?fl'\ '"lup In Univers~ty of Bologna. Italy

Chapter 2 115

Fig. 2.9 DFT-computed structure of the preferred conformer of 1 (arhltrar~ly \elected a\ 3SR. 5RS. 7aRS. 9aSR). The exchange with its mlrror Image y~elds a dynamic C , \ymmetry.

The D R computed dihedral angler H-C9h-C9a-H and H-CYh-C7a-H are 46 and

38': when introduced in the Karpius equation2" they yield vicinal J couplingr of 3.7 and

4 9 Hz. Due to [he mentioned rapid interconver\ion at amb~cnt temperature, the

dvcraged J hecome\ 4.3 Hz. We also calculated these vicinal J couplings hy making

dlreot use o f the DFT approach?' (including the Fertni contact contribution), thus

dvoidlng the application of the empirical Karplu\ equation: the values obtained in this

w'ay were found 4.6 and 5.6 Hz. yieldlng an averaged J coupl~ng of 5.2 Hz. By taklng

Into account the two theoret~cal approaches (that define a range of 4.3-5.2 Hz) a value

of 4.7 r .5 Hz can be predicted for this J coupling (Tahle 2. I). wh~uh fits well the

cxper~mental value (4.5 Hz).

Chapter 2 116

Table 2.1. Experimental Values and Computed Ranges for the Vicinal J Couplings

(Hz) Involving the Hydrogen in Position 9b.

The "C spectrum of 1 (150.8 MHz in CD2CI2) shows a broad s~gnal (ca. 129.5

ppm) for the CH carbons in the meta position to OMe (CI 1 ). on lowermg the

temperature (Fig. 2.10) this signal broadens further and eventually splits into a palr o l

equally Intense integrated lines (the same occurs for C12 line, ortho to the OMe group.

although with a lower shift separation).

Compound

1

2

1-Hi

Vicinal JHCCH

Experimental

4.5

8.4

4.4

Vicinal J ! i ~ r l (

Computed

4.7 i 0.5

8 . 6 1 1.5

4.411.3

Experimental

9.0

Computed

11.5 i 0.1

Chapter 2 - 117

Fig. 2.10 Left: Temperature dependence of the "C signal (150.8 MHL 1nCD2C12) ofthe aromatic carbons meta to the OMe group @osition 1 I ) of compound 1. Right: Computer simulation with the rate constants reported.

This process is due to the restricted rotation of the aryl rings, and from the rate

constants obtained by line shape simulation a AG' value of 12.55 kcal moll was

derived2' (Table 2.2).

Chapter 2 118

TABLE 2.2. Experimental and DFT computed barriers (kcal mol-I) for 1 and 2

Compd. Aryl Rotation

12.55

I I j Aryl B: 2. I I I I

"See text

On further lowering the temperature, almost ail of the "C lines broaden, and at - 100 'C, they split into pairs; in particular the aromatic carbons at position I I, which

y~elded two lines at -36 'C, as shown in Fig. 2.1 1, exhibit four lines at -100 "C, as do the

aromatic carbons at position 12.

Fig. 2.11 "C NMR signals (150.8 MHz in CD2C12) of the aromatic CH carbons in position meta ('2-11) and ortho (C-12) to the OMe moiety of compound 1. Each of the tow single lines observed at 1 2 5 "C splits into four at -100 OC because the aryl rotatlon and the ring inversion processes are both frozen.

Chapter 2 119

As an example, the trace of Fig. 2.12 displays the splitting of the line due to the

par of carbons at positions 3, 5, where as the single line of the carbon at posltion 9b,

obv~ously, does not split. This process is due to the slow inversion of the SIX-membered

rings, which has a free energy of activation of 8.6 kcal mol-1 (Table 2), as obtait~ed

from the rate constants reported in the simulated spectra.

Fig. 2.12 Temperature dependence of the "C signals (150.8 MHz in CD2C12) of the aliphatic carbons in positions 3,5 and 9b (65.5 and 62.8 ppm at -35"C, respectively) of compound 1 (left). The line of the single carbon in position 9b is not sensitive to the internal motion and, therefore, was not included in the simulation (right).

Chapter 2 120

In order to better understand the nature of this invers~on process, a %arch for the

corresponding transition state was carried out by mean\ of DFT computations. This

dructure (Fig. 2.13) has a computed energy 9.6 kcal mol ' higher that that of the pound

\tare of Fig. 2.9.

Compound l

DFT computed R ~ n g lnverslon transltlon state (TS)

E = 9.6 kcal mol '

DFT computed Arql rotatlon transillon \late iTS)

E = 14.2 kcal mol-'

Fig.2.13 Representation of the DFT computed traniitiona states for the inversion of :he perhydrocyclopentaquinolizine ring (top) and for the rolation of the aryl groups 'bottom). The energies are relative to the ground state of Figure 2.9.

Chapter 2 I21

Such a value is in fair agreement with that the measured barnsr. The

experimental rate constants are relative to the motion of both the six-membered rings,

thus the motion of a single ring corresponds to half the rate constants reponed. It is thus

the AG* obmned from '/2 k values that should, in principle, be compared to the

theoretical value of 9.6 kcal mol-I. The AG* obtained In this way (8.9 kcal mol.') is in

even better agreement with the theory.26 It indicates that the transition state corresponds

to the transfonation of the twist-boat six-membered ring into a chair and vice bersa."

This process does not correspond to the typical chair to chair inversion (where the ax~al

substituents become equatorial) since here the twist-boat becomes a chair and vrre

wrsa. This process, apparently, does not involve a significant inversion of the nitrogen

atom; the latter, in fact, has essentially the same degree of pyramidal~zation." The

degree of pyamidalization is defined as 360"-ZRNR and cover the range 40" (for a

nearly perfect pyramidal nitrogen, as that of NH,) to 0" (for a perfectly planar n~trogen).

In the case of acyclic three-alkyl amines (like NMe,) this degree is about 27" aid it is

somewhat lower in the case of cyclic three-alkyl amines In the ground and in thc

transition states, with these values being 23.4 and 22 .4 , respectively L ike~ i se , wc used

DFT calculations to identify the transition state that accounts for the rotation of thc aryl

rings. The structure for the corresponding transition state was found to have a computed

energy 14.2 kcal mol" (Table 2.2) higher than that of the ground state, again in

satisfatory agreement with the experimental bamer. These calculations ind~cate that, In

order to make sufficient space to accomplish the rotation of the aromatlc rings, a

flattening of the nitrogen atom is also required. In this transition state, in fact, the latter

is computed to be almost planar, its degree of pyn'midalization2%eing 5.2" (Fig.2.13).

The structure of the isomeric compound 2 was also obtained by means of NOE

experiments that indicate the same type of cis, cis junction for the perhydrocyclopenta-

quinolizine moiety. The two most stable conformers of the above stnrcture were

identified by DFT computations. Actually there is also a computed minimum with an

energy 0.4 kcal mof l higher than that of the ground state, but this corresponds to a

conformer having the same arrangement for the three fused rings shown in Fig.2.9 and

differing solely by the torsion angles of the two q l groups (62" and 54' rather than 13"

and 52') Fig. 2.14.

Chapter 2

Fig. 2.14 DFT- computed structure of the preferred conformer of 2 (arbitrarily selected J\ 3RS. 5SR, 7aRS, 9aSR). The exchange with its mirror Image )irlds a dynamic C, (yrnmetry

The preferred conformation is displayed (its energy belng 1 . 1 kcal mol ' lower

than the hecond most stable form where both the \ix rnemhered rings are chair.;). A\ ~t

dppears in Fig. 2.14, the two six-membered rings of the ftatic conlormer are dlffrrcnt.

hecause one is a chair, whereas the other is essent~allq a boat. Accord~ngly, the

perhydrocyclopentaquinolizine moiety ha\ a different shape than in the ca\e of 1. and

lor this reason the corresponding dihedral angles H-C9b-C9a-H and H-C9b-C7a-H are

\~gnificantly smaller ( i t 31" and 3.5"). From the Karplu\ equation." the related J

o ~ u p l i n p become 5.9 and 8.2 Hz, re6pectively and the averaged value, refulting from

the fast inversion process, is thus 7.05 Hz. The direct DFT drterminatiun of the\e

~ouplings yields an average value of 10.1 Hz (resuit~ng from 8.4 and 11.8 Hz). By

Idhlng into account the two theoretical approache\ (that define a range of 7.05 - 10.1

Hz). a vicinal J coupling of 8.6 ? 1.5 Hz i \ predicted (Table 2.1). in agreement with the

experimental value of 8.4 Hz.

Therefore, the structures proposed for 1 and 2 on the basis of the NOE

c\periments, also account for the observation of a vicinal J coupling larger in 2 with

lL'fpect to 1, although both compounds have the same type of C I A , ci.1 ring junction.

Like in the cace of 1, also the "C signals of 2 broaden on cooling and eventually

!~cld a greater number of sharp lines, owing to the restriction of the internal motions.

an example, in Fig. 2.15 is reported the temperature dependence of the signals of the

Chapter 2 I23

quaternary aromatic carbon in para position to OMe (C10) and of the aromatic CH

carbon in meta position to OMe (CI1). The carbons in position 10 have the

corresponding signal insensitive to the aryl rotation because they lie on the rotation axis

of the aryl moiety, thus the observed 1:l splitting must be attributed solely to the

restriction of ring inversion, the corresponding banier, obtained from the rate constants

of Fig.2.15, being 7.0 kcal mol". The carbons in position I I, on the other hand, have

the corresponding signal sensitive to both rotation and inversion processes, and should

y~eld, in principle, two doublets (as observed for compound 1).

Fig. 2.15 The "C signal (150.8 MHz in CHF2C11CHFC12) of the aromatic quaternary carbons para to the OMe group (position 10) of compound 2 splits into a doublet at - 141 OC, whereas that of the aromatic CH carbon meta to the OMe group (Position 11) splits into three lines at the same temperature. The simulations were obtained with the rate constants reported.

Chapter 2 124

Contrary to the case of 1, however, only three lines, with a l:2: I intensity ratio,

are observed below -140°C (Fig. 2.151, suggesting that the rotation process of one of

the two aryl groups is frozen at this temperature, whereas the other is not. This was

confirmed by the observation that also the '2-12 signal splits into three lines with the

same 1 :2: 1 intensity pattern.

The first and the third lines of C11 in Fig.2.15 (130.3 and 127.4 ppm,

respectively) are those of the two diastereotopic carbons of the aryl group wh~ch does

not rotate anymore, whereas the twice intense central line (129.5 ppm) is that of the two

equivalent carbons of the aryl group which is still in the fast rotation mode. The line

shape simulation of these three lines was obtained without a direct exchange rate

between the first and third line (i.e. the rate corresponding to the aryl rotation): their

exchange occurred through the intermediacy of the ring inversion rate, as shown by the

fact that the same values of the rate constants, used to simulate the exchange of the C10

Ilnes, were also employed. This situation, therefore, corresponds to that observed in the

cases of exchange processes that, in spite of the presence of a hlgher barner, are

ne\,ertheless NMR invisible until a second process, with a lower barrier, is also frozen.

Such a situation, for instance, has been encountered in some aliphatic amines where the

larger C-N rotation barrier is NMR invisible until the N-inversion, which has a lower

barrier.3u,3' In this case the rotation of one of the two aryl groups has a barrier higher

than ring inversion, but can be observed only when the latter process (which is the rate

limiting process) is also frozen: this means that the high rotation barrier cannot be

cxperimentally determined. The lower rotation barrier of the other aryl group, on the

other hand, cannot be determined for a different reason, i.e, because its value is too low

for a NMR measurement. The following computational results help in understanding

this type of stereodynamics.

The DFT computed transition state for the ring inversion process indicates that,

In order to transform the boat into a chair (and vice-versa), a concomitant nitrogen

Inversion is also required; in the course of this process, in fact, the nitrogen atom inverts

through an essentially planar state having a degree of ~yramidalization of 2.2' (see

Fig.2.15). The energy for this transition state, computed with respect to the ground state,

1s 5.6 kcal mol.', a value lower than that computed (9.6 kcal mol.') in the case of 1. T h ~ s

2iult parallels the experimental determination, which yields an inversion hamier for 2

, w e r than for 1 (i.e. 7.0 vs. 8.6 kcal rnol", a\ in Table 2.2).

In the static conformation of 2 ( h g . 2.14) the two iuyl poups (labelled A and B )

.ire In very d~fferent posttions, contrary to the c a r of 1: the rotation transition state o f

one of them (aryl A in Fig. 2.16) is computed to have an energy of about 13.3 Lcal mol.'

1.e \irnilar to that of 1) whllst that ofthe other (aryl B ) I\ o i ~ l y ?.I kcal rnol '. Thc latter

I, too low for a NMR deterrn~nation. thuf one of the two aryl group\ wil l alway\

di*play. at any attainahlc temperature, a \~nplc l ~ n e for the corresponding carhonr In

po\itlon I I. as experimentally observed

pig. 2.16: Representation of the DFT computed transit~ons l a t e for the invers~on of the "erhydrocyclopenaquinolizine ring (top) and for the rotiltlon o f the aryl group A hottorn left) an of the aryl group B (hottom right).

Chapter 2 126

Since the inversion banier of the perhydrocyclopentaquinolizine ring is

computed (and measured) to be much lower than 13.3 kcal mol-I, the aryl group A, with

the higher rotation barrier, exchanges rapidly its position with the aryl B (which has the

2.1 kcal mol-I rotation barrier). When this rapld A to B exchange has occurred, the

rotation of the former aryl A becomes also very fast and for this reason cannot display

the shift differences for its C11 lines: this will only occur when the ring inversion

process, which restores the identity of the aryl A, IS also frozen. The klnetlc IS

controlled, m practice, by the process with the lower of the two bamers (1.e. ring

Inversion), so that the higher bamer, for the rotation of aryl A, cannot be determined by

NMR (Table 2.2).

2.1.3 Stereochemistry of quinolidne salts I-H' and 2-H'

When treated with 1 equiv of CF3COOH. compound 1 yelds the corresponding

ammonium salt (I-H') (Scheme 2.7). The 'H NMR spectrum (Fig 2.17) displays

essentially the same vicinal coupling (J = 4.4 Hz) as that 01' 1 for the hydrog& in

positlon 9b, the latter being, In addition, coupled w ~ t h the NH' hydrogen (J = 8.7

HZ)."C NMR spectra (Fig 2.17) shows the upfield sh~Aed In al~phatic region.

Scheme 2.7 - -

(-+a> 4 GN.J

I - - N* J

" /?, -5 - 2 'c, r - .==.

M e 0 OMe M e 0 OMe

Chapter 2 127

<- 8 rn

->,>.," - -. -- .<* "1- ->

f,\ - *., ,., ,. * ,,-. ,., -. ..- .,,, . ., - c8 "% t.>S." -. ",S".. k'-'f'"l l\,.,=:$/

" .~ * , s , ,.

(j 2;:; I ! I hIcO OSLr,, i - - . . - . .

I -H- , .I I .o p,.

2.- - r.7.-, . w 1

1

I I

I I ' I-/< ' . ~ .? 1 -

.L La a ' . L . I . P I .

.- -' . "-., , * --, -.. ..-- .,,., .,,- ." - ,. , ,. . . -, , - , . , - .,... ,..,, - :- mmw. ." m. ..3 , . ," .. . -" .,, ,,, ">,.>, ., , ,..>,,.. ,,.*, ..

., *, ,,., ,. -. , ,.... ,,, ," .,, , , -. ,, . . ,,.., .., ,,* >,< ., , - ,".". , -. , ".x ", ., ,,, ,. , ..&" ,. -..- . ",,.,..,'.. , . . ..%, .., $. ,,, ,. -* --. .. . ",, .., ,, .,> . , , .-,., .,,,. ~. .," " ....,., , . . .,,*" "," ,.. - .,- 1, .,

., .,.... ,,... . , ,,,,,..,.. . ., ,,..,,, . . , , s ,.. , , ,.'. ,,. ,. ... , . ,, ,"..<,..,,, , ,, ..".,.,..,. , . .

ill i* I,( ,,1 I,. la. it* 1-1 *I * I 70 $0 I I 0 I* PP.

Fig. 2.17 'H NMR spectrum (top) and "C NMR spectrum (bottom) of 3SR,5SR,7aRIi,9aSR)-3,S-di(4-methoxqphenyI)perhydrocyclop~]quinolizine trifluoruacetate I-@

Chapter 2 128

Also the patterns of the NOE (Fig. 2.18) parallel those of 1. The NOE expenments were carried out at -10°C since the spectrum d~splays a better

resolution than at ambient temperature.

Fig 2.18 a) 'H spectrum (600 MHz in CD2C12 at -10 'C) of the CF,COO- ammontum salt 1-Hi showing two signals (Av = 620 Hz) for the diastereotopic hydrogens mcta to OMe (psition 11). b) NOE due to irradiation of the signals of the hydrogens in positions 3.5. c) NOE due to irradiation of the signals of the hydrogen in posltion 9b. d) XOE due to irradiation of the signal of the NH' hydrogen.

Chapter 2 129

This depends on the fact that in a CD2C12 solution the salt 1-H' appears to

experience an exchange process with a form which is present in such a small amount

(less than 1%) as to be NMR invisible (possibly the form where the N-Hi bond is

synclinal, rather than antiperiplanar, to the H-C9b bond). At -10 "C the rate of this

process becomes sufficiently slow as to make the lines of the salt sharper than at -125

,C. This is the well known effect occurring when there is an exchange process between

~ i i o very biased partners. The hypothesis of two forms for such a type of ammonium

sa11 will be better clarified in the case of the ammonium salt 2-H' (see further). The

ialue of the vicinal J coupling and the NOE results thus indicate that the salt has the

sane type of structure as the free m i n e 1, i.e. the two aryl groups, in a pseudo

equatorial position, are syn to the five-membered ring.

This structure is confirmed by the single crystal X-ray diffraction of 1-H*

(Flg.2.19, top) that displays a cis, cis junction at the prrhydrocyclopentaquinolizirie

Iiioiety, with the N H hydrogen antiperiplanar to the hydrogen in position 9b. The solid

slate conformation of the salt 1-Hi shows that both the six-membered nngs adopt a

chair d~sposition, whereas the DFT calculations indicate that this corresponds to the

wand most stable conformer, the preferred one (with a 1.4 kcal mol" lower energy)

hc~ng that which has one ring as a chair and the other as a twisted boat, l ~ k e amine 1. It

15 not unusual to encounter such differences between the conformations in solid and in

bolution, that depend on the fact that the crystals privilege the conformation which fits

bctrcr the crystal cell.'" j4

The conformation adopted in solution, on the other hand, corresponds to that

predicted by calculations, as proved by low temperature NMR spectra. Below +S°C the

'H signals of the aromatic hydrogens meta to OMe (position 11) decoalesce into a pair

c:' signals, as shown in Fig.2.18 (trace a). The aryl rotation barrier responsible for this

efkct was found to be 12.25 kcal m0l.l (Table 2.3), a value essentially equal, within the

errors (M.15 kcal mol"), to that determined for the m i n e 1.

I hapter 2

Computed (E = 0.0) Computed (E = I . A )

Fig. 2.19. (a) & (b) Single-crystal X-ray diffract~on structure of the ammonium salt I-H'. Underneath Ic) & (d) are reported the two mo\t stable D F I computed conformer\. a ~ t h the relative energies ( E ) ~n kcal mo l l . In the computations, the presence o f the CF,COO' an~on ha3 been neglected.

On funher lowering the temperature, a number of aliphauc 'H and "C signals

hruaden and eventually decoalesce at -130°C. due to the freezing of the ring inversion

i'roce\s. as an example the splitting\ of the CH carbons in positions 7a. 9a and CH2

~ ~ r h o n ~ in positions 2.6 are displayed in Rg. 2.20. This feature prove3 that In I-H' the

wu stx-membered rings are different, as predicted by calculations (i.e. a twisted boat

m d a chair), and not equal (two chairs) a5 in the crystalline state.

Chapter 2 131

Fig.2.20 Temperature dependence of the "C slgnals of the CH and CH2 carbons of the a ~ ~ m o n i u m salt 1-H' at position 7a, 9a and 2,6.

Furthennore, since a N-inversion process cannot occur in the ammonium salt,

this find~ng supports the theoretical prediction that also the ring lnversion pathway

(char to twisted-boat and vice versa) in m i n e 1 does not involve appreciable N-

~nversion. The value of the barrier measured for the ring inversion In I-H' (7.7 kcal

moi", as in Table 2.3) is quite close to that of the analogous process occumng in 1, the

difference being only 0.9 kcal mol'l.

Chapter 2 132

'TABLE 23 . Experimental and DFT Computed Barriers (kcal mor l ) for the

~ m m o n i u m Salts 1-Hi and 2-H'.

I I

I I Aryl B: 5.5 Aryl B: 7.3 I l

Compound

1-H'

2-H' (major form)

a) In these computations the anion CFlCOO has not been ~ncluded. b' See text

Also the m i n e 2 yields the corresponding ammonlum salt 2-Hi when treated

i i ~ t h one equivalent of CFlCOOH (Scheme 2.8). The 'H NMR spectrum ( F I ~ 2.21)

displays essentially the same vicinal coupling (J = 5.0 Hz) as that of 2 for the hydrogel1

in posit~on 9b, the latter being, in addition, coupled w ~ t h the NH* hydrogen ( J = 8.7

Hz).'c NMR spectra (Fig 2.21) shows the upfield shifted In aliphatic region.

k n g Invers~on Aryl Rotation

-p

Scheme 2.8 !

7 7

I 0 15

Me0 OMe

2 2-H'

Reagents and conditions: i) CFICOOH, CD2C12

8 9 12 25

1 5 0 4 q l ~ n o t m e a s u r a b l e ~ ' A r y l ~

19 4

166

Chapter 2 133

Fig. 2.21 'H Nh4R spectrum (top) and "C NMR spectrum (bottom) of (3RS,5R$7aRS,9~R)-3,5di(4-methox~henyl)perhy~ocyclop~~[ij]quinolizine hfluoroacetate 2Hi

The corresponding room temperature spectrum o f 2-H* shows the presence o f

,,,o forms at the equilibrium: there are, in fact two specual traces. with very different

-~lenslty, having the line widths hroadened by a mutual exchange process. When cooled

I -10 "C, in fact, these lines become sharper so that the signal o f the minor form could

bc ~ntegrated, indicating that its proponlon I S 3 * 0.3% (Fig. 2.22).

l'ig.2.22 'H spectrum of the CF3COOe ammonium salt (2H') of the amine 2, where the :cd line\ indicatr some of the signals o f the minor form (3%) and the green \tar\ the "C ,.itelliter of the major form (trace a). The NOE effect on the NH' signal due to -rad~ation of the Hi,5 major signal (trace b) is much smaller that that due to irradiat~on f the Hqb major signal (trace c). This is opposlte to what observed In I-H', indicating

"ur the relationship between the N-H' and H-C9b bonds is synclinal in the major form f 2-H' hut antiperiplmar in I-HI, in agreement with the DFT computations.

Chapter 2 135

The sharpening of the lines at lower temperatures is an effect analogous to that

observed3* in I-Hi (the NOE experiments were carried out at -lO°C since the specuum

d~splays a better resolution than at ambient temperature. This depends on the fact that in

a CD2C12 solution the salt I-H' appears to experience an exchange process with a form

which is present in such a small amount (less than I%) as to be NMR invisible @ossibly

the form where the N-H' bond is synclinal, rather than antiperiplanar, to the H-C9b

bund). At -10 'C the rate of this process becomes sufficiently slow as to make the llnea

of the salt sharper than at +25 OC. This is the well known effect occurring when there is

a11 exchange process behveen two very biased partners); in the present case, however,

the signals of minor form, although quite small, are clearly visible. The exchange

between the two forms of the salt can take place because the Hi of the N-H' bond 1s

quite mobile in solution, so the corresponding bond can bc broken at m b ~ e n t

temperature making possible for H' to be l~nked to the nitrogen atom in two opposite

positions, yielding, as a consequence, a pair of isomeric ammonium salts having thr

pyramidal nitrogen inverted.

We suggest that the structure of the major form should be that where the N-HA

bond IS In a synclinal relationsh~p to the H-C bond In position 9b, whereas the mlnor

form should correspond to the structure where the N-HI bond is antipenplanar to thc H-

C9b bond. The DFT computed structures (Fig.2.23) indicate, in fact, that the Ibrmer

structure (synclinal) is about 6 kcal mol-l more stable than the latter (antipenplanar).

The DFT computations were performed, for convenience, on the free cation w~thout

including the presence of the anlon CF,COO-. This might account for the computed

energy difference (6 kcal mol-') being larger than the AGO value (1.9 kcal mol"),

corresponding to the experimental ratio measured at -10 OC.

Fig 2.23 Top left: X-ray diffraction structure o f 2-H' sh(iw~ng that the conformilt~on in !he solid state is asymmetric. Bottom: DFT computed structures [energy (El In kcal mol ' I for the two t y p s of the ammonium salt 2-H' ob\erved in the NMR spectrum at ambient temperature. The asymmetr~c form (CI point group) on the left. where the N-H' hond is synclinal to the H-C bond in position 9h. IS computed to he more stable (hy 6.0 lcal m o l l ) than the more symmetric (C, point group, i f the OMe groups are not considered) on the right, where the N-H* and the H-C9b bonds are in an ant~periplanar ~rlationsh~p. The more stable computed structure o f 2-H' (hottom left) is essent~ally equal to the X-ray structure (top left) and is also quite similar to the ground \rate dructure computed for the corresponding amine 2.

Experimentdl support to thl\ d\slgnment wac obtained by medm o f NOE

experiments. In particular, irradiation of the H9b signal (this signal appeilrs a\ a

multiplet at 6 3.6 ppm with J = 9.2 Hz. due to the coupling with the two equivalent H7a.

Chapter 2 137

ti9a hydrogens, and J = 4.9 Hz, due to the coupling with the N-H' hydrogen. In the

rnlnor form these Jvalues are quite different, being 5.0 and 11.7 Hz, respectively) of the

major form yields a very large enhancement of the NH' signal at S 10 ppm (Fig.2.22)

since the average interproton distance is computed to be as low as 2.1 A. On the other

hand, Irradiation of the signal of the two equivalent H3, H5 hydrogens (Fig.2.22) yields

3 much lower enhancement of the NH- signal: the corresponding averaged interproton

dlstance is computed to be 2.64 A, thus enlaling a NOE effect smaller by a factor of

about four with respect to the previous one. Such a result (i.e. the wend of thc

enhancement of the NH' signal) is opposite to that observed for I-H' (Fig. 2.18, traces

b and c), thus reinforcing the conclusion that in the major form of 2-H' the N-Hi and

the H-C9b bonds adopt a synclinal, rather than an antipenplanar relationship, as in 1-

H*.

Independent support to this assignment is also obtained by the analysis of the

vlcinal J coupling constants (Table 2.1). The vicinal Jcoup l~ng between H9b and H7a.

H9a, measured in the major fonn, was found larger (9.2 Hz) than that (5.0 Hz)

measured in the minor form of 2-Ht According to DFT computations the corresponding

d~hedral angles of the major asymmetric form of Fig. 2.23 (left) 6.6' and 31°,

respectively: when inserted m the Karplus equatlon they yield a J value of 7.0 Hz

(resulting from the average of 8.1 and 5.9 Hz, respectively). The angles of the more

symmetric minor form, as in Fig. 2.23 (right), are both equal to 47', providing a

computed J value of 3.6 Hz. The direct DFT computation of these viclnal J coupl~nys

(which include the contribution of the Fermi contact) provides values of 10.6 Hz

(average of 13.0 and 8.2 Hz) for the major and 6.9 Hz for the minor form. By

co~nb~ning the two theoretical approaches, the computed coupling of the major fonn is

expected to lie in a 7.0-10.6 Hz range and the mlnor in a 3.6-6.9 Hz. Thus the major IS

predicted to have a vicinal Jcoupling (8.8 1 1.8 Hz) larger than that (5.2 11.7 Hz) of the

minor form, in agreement with the trend of the experimental values of 9.2 and 5.0 Hz,

respectively (Table 2.1). Also the vicinal H-N-C-H couplings between NH' and H9b

(1.9 and 11.7 H z for the major and minor form can be rationalized on the basis of the

appropriate Karplus equation

The corresponding computed dihedral angles for the major (38.5") and the minor

180") form yield J values of 4.9 and 11.6 Hz. respectively and the direct DFT

.,imputations predict 6.9 and 12.0 Hz, respectively. Thus the H-N-C-H coupling of the

~illijor 15 expected to lie in a 4.9-6.9 Hz range and that o f the minor form in a 1 1.6-12.0

H I . These values (i.e. 5.9+1 and 1 1 3 d . 2 Hz, at in Table 2.1) are agatn In good

~greement u i th the experimental data and further \upport the proposed atsignment The

lrlalor form (970) o f 2-Ht displays a J = 9.2 Hz for the vicinal coupllng 36 hetween

IiYh and the pair H7a. H9a (Tahle ?.I ), i.e. a value close 10 that (8.4 Hz) measured in

the corresponding amlne 2 Thi5 huggests. therefore, that the halt and the amtne have the

ran]? type o f structure. i.e, a CIA, 1.1, junct~on for the perhydrocyclopentaquinol~ztne

tn~oiety. wtth the two aryl groups ant1 to the five-memhered rlng in a pseudo axial

po+ltlon, Indeed the DFT computed structure o f [he lower energy form o f 2-H'

lFtg.2.23, left) is quite 51mllar to the computed structure of the corresponding amine 2.

The soltd state structure o f 2-Hi iFtg. 2.24). ohta~ncd hy singlr crystal X-ray

d~ffraction. I\ essentially equal to that proposed for the major form in solut~on (Fig.

2.23). thus confirming that the N-H' and the H-CYh hands are In a tynclinal relationsh~p

.!nd also that one of the two +ix memhered ring5 is a chair and the orhcr a hoclt.

Fig. 2.24 X-ray crystal structure of i3RS.5RS.7aRS,9aSR)-3,5-di(4-ethoxyphenyl) perhydrocyclopenta[ij]qu~nol~zine trifluoroacetate 2-H'

Chapter 2 139

On lowering the temperature the single 'H signal of the two OMe groups of the

major (97 %) form broadens and splits into a pair of equally lntense lines at -93 "C, as

In Fig. 2.25 (the same occurs for the signal of the hydrogens in positions 3 and 5).

OMe T ("c)

Fig. 2.25 Temperature dependence (left) of the hydrogen signal of the OMe group due to the restricted chair to boat ring inversion of the ammonium salt 2-H+. On the right IS

shown the simulation obtained with the rate constants reported.

Since the signals of these hydrogens are insensitive to the effect of the aryl

rotation, the observed dynamic process must be attributed to the restriction of ring

inversion. This agrees with the computations that show how the two

Chapter 2 140

perhydroquinolizine rings have different shapes in the major form, one being a chair the

other a boat (Fig. 2.23).

The boat to chair mterconversion is fast at ambient temperature (making

isochronous the signals of the OMe as well of the H3,HS hydrogens and carbons) but

becomes slow below -9OoC, thus rendenng these hydrogens diastereotopic. L ~ n e shape

s~mulat~on yields a barrier of 10.151 0.15 kcal mol- l (Table 2.3) for the cha r to boat

nng inversion. This value is larger than that measured in the corresponding amlne 2,

suggesting that in the ammonium salt the structure 1s more rigid. This trend is opposite

to that observed for the barriers of nng invers~un processes in the m i n e 1 and in ~ t s

ammonium salt I-Hi. The latter, In fact, has a structure quite different from that of 2-

H'. thus making ~ t s shape inore flexible than that of the corresponding m i n e I .

On the contrary, the OMe signal of the minor (3%) form of 2-H' remalns a

s~ngle line in the same temperature range. T h ~ s behaviour is In keeping with the

structure pred~cted by Dm colnputatlons for the minor conformer, where the two

perhydroquinolizine rings are equal (both have the shape of a chalr as in Fig.2.23, thus

In t h ~ s form the two aryl nngs cannot become diastereoloplc.

In the same temperature range the major form also d~splays dynam~c e f i c t s fur

each of the aromatic doublet signals of the hydrogens in the ortho and meta posltlons to

the methoxy substituents (HI2 and HI I , respectively). Both signals eventually split into

three doublets with a l:1:2 ~ntens~ty ratlo (Fig.2.22) Indicating that, in addition lo the

restncted chair to boat interconversion, the rotation of unz of the two aryl groups IS also

restncted at -93 "C whereas the other is not. This dynam~c process is essent~ally the

same as that described above for the corresponding m i n e 2. The line shape simulation

of (F1g.2.22) was obtained using the very same rate constants denved from the

simulation of the OMe signal (i.e. the rates correspond~ng to the chair to boat ring

~nversion). Furthermore, in order to obtain a good simulation, the rates for the direct

exchange between the two downfield signals with a 1: 1 intensity could not be included,

provlng that these signals exchange vla the intermediacy of the third signal (that upfield

w ~ t h a double intensity). As discussed In the case of the m i n e 2 this proves that the

observed motion does not allow the measurement of the rotation barrier but rather the

barrier for ring inversion. Accordingly, the higher rotation barrier of one aryl group

Chapter 2 141

(labelled A in Fig. 2.23) is not measurable, because the related effects are detectable

only when also the faster ring inversion is frozen. On the other hand the rotation barrier

of the second aryl group (labelled B) must be lower than that for the ring inversion.

A demonstration of the correctness of such interpretation is obtained by

txamining the I3c spechum (at 150.8 MHz) in CHF2CI. At about -100 'C, In fact, the

iarbons in position 11 display, as do the corresponding CH hydrogens of Fig.2.26, three

ripals (one of which is again twice as intense as the other hvo), but on further cooling,

[he twice intense signal broadens significantly and eventually splits into two 1:1 l~nes,

separated approximately by 500 Hz at -152 "C.

chapter 2 142

pig. 2.26 Left: aromatic \pectral region of the ammontum salt 2-H*. where each of. the douhlet signals of H-I I (red) and H-I2 (blue) split\, at -93°C. Into three I :I :2 doublet\. hght: line shape simulat~on obtained with the same rate constants derived from those of [he OMe line In Fig.2.25 (see text).

At t h i temperature, therefore, the rotatlon of the second aryl group B I S also

Itoren and the corresponding barrier (5 .5 t 0.3 kcal mol ' ) 1s lower, a\ anticipaled, than

!hat meaured for the ring tnversion. The trend of the computed Dm values for 2-Hi

Table 2.3) agrees with this interpretation since the high and low aryl rotatlon barriers

,ire 16.6 and 7.3 kcal mol", respectively and the chair to boat nng inversion barrier has

Chapter 2 143

an intermediate value (15.0 kcal mol-'). The computed barriers of Table 2.3 are all

o~erestimated although their sequence does parallel the experimental trend. The main

source of approximations in these computations is the consequence of not having

~onsidered the presence of the CF~COO- anion (in order to reduce the computational

tune), thus treating 1-Hi and 2-Hi as '.naked cations.

2.1.4 Synthetic efforts towards quinolizine based crown ethers

In continuation of efforts towards quinolizine based crown ethers, we have

dsprotected the hydroxyl group 1 with 40% HBr In acetic acid to obtain h~s-phenonl

~ 2 . ' ~ Similarly hydrogenation of 3 with (10%) PdlC on hydrogen provided his-phenol in

quantitative yield (Scheme 2.9).

Scheme 2.9 ~ - - -

\ , N 4 I -

Me0 OMe HO OH PhH,CO OCH,Ph

1 22 3

Reagents and conditions: i) 40% HBr in AcOH, 10 h, 84%; i i ) 10% PdlC, Hz. EtOH, rt,

Structure of the his-phenol 22was confirmed by the presence of strong band at

3378 cm.' In 'H NMR specuwn a signal for OMe was completely absent. "C NMR

spectnun showed absence of signal at 6 55.9 pprn for OMe resonances. Due to

solubility problem of the 22 we prepared the benzoyl derivative 26 and character~sed it

(Scheme 2.10).

Chapter 2 1 44

I Scheme 2.10 -

I . i+ \ / N u 2

-=-, m, < h, ;;i

PhOCO OCOPh

I Reagents and conditions: i) Benzyl chloride, I5%NaOH, I

I 0 "C + n, 83%.

Further we have tried for making quinolizine based crown ethers but the

reactions conducted so for did not gives satisfactory results. Funher research work is

need to achieve target molecule.

The suuctures and conformations of the cyclic mines 1 and 2 were determined

by means of NOE experiments, analysis of vicinal J coupling constants and DFT

computations. Both display a cis, cis junction at the perhydrocyclopentaquinolizine

molety: in the case of 1 the hvo six-membered rings adopt the shape oi'a chair and of a

tw~sted boat (with the stacked aryl groups displaying a dynamic pseudo-equatorial

d~sposltion), whereas in the case of 2 the two six-membered nngs adopt the shape of a

chair and of a boat (with the stacked aryl groups displaying a dynamic pseudo-axlal

disposition). The barriers for the ring inversion (8.6 and 7.0 kcal mol-I for 1 and 2.

respectively) and aryl rotation have been determined by dynamic NMR spectroscopy,

with values in fair agreement wlth the theoret~cal predictions. The corresponding

ammomum salts (1-Ht and 2-H') exhibit the same type of structure as well as

analogous conformations. The ring inversion barriers were also determined: in the case

of I-Hi it was found (7.7 kcal mar') lower than that of its amine 1, whereas in the case

of 2-Hi it was found higher (10.15 kcal mol") than that of its m i n e 2. The structures of

the two ammonium salts in the solid state were also obtained by single crystal X-ray

diffraction.

Chapter 2 145

2.2 Synthesis and stereochemistry of cyclyoheaaquinolizines

Similar to cyclopentquinolizines 1 and 2, basic structural features of

~~clohexaquinolizine 5, 6 (hexahyrogjulolidines) can be rzcognised as segments of

several alkaloids of biological interest such as matrine 27" and matridine 28'' (Fig.

2.27).

Me0 OMe

5, 6 27 28

Fig. 2.27

The review of stereochemical models of cyclohexaquinolizlnes had revealed that

Ihs stable ABC ring fusion could have three type of configurat~ons In 29-32 (Fig.

? . 2 ~ ) . ' ~ Due to three sterogenic centers, in 29-32 there is a possibility of bur

diastereomers of which 30 and 31 are equ~valent.

Fig. 2.28

lntroducing two more stereogenic centers at 3,5 pos~tion as seen in 5 and 6 there

1s a possibility of 16 diasteromers as given in the Fig. 2.29.

Chapter 2 146

Ckr' Ar Ar Ar Ar 'Y" Ar Ar Ar Ar

Fig. 2.29

Synthesis and stereochemistry of quinolizldine in general and

hexahydroquinilizidine in particular have been focus of intere~t.~' Kartritzky and

coworkers studied the conformational equilibrium between cis and trans quinolizines as

~ncorporated into cyclohexaquinolizidine structure. They found the free energy

difference between two was about 4.4 kcalimol and trans quinolizidine structure 1s

more stable."

Chapter 2 147

Since two aryl groups in the present study are same the structures E-H is are

cnatiomenc with I-L, similarly, structure C-D and 0 - P are also enantiomeric pairs. cis,

(runs Cyclohexaquinolizidine of the type 30 (E-L) can be readily distinguished from

tbpe 29 (A-D and M-P) by IR spectnnn. Isomers 30 exhibit weak Bohlmann bands In

the 2800-2700 cm-' region, where as other two isomers exhibit strong Bohlmann bands.

c i ~ , cis lsomers to the type 29 were distinguished from col~espondinp trans.

o-un~ isomers type 31 by conversion to corresponding quaternary ammonium salt with

ilel. The cis, cis isomer posses a nitrogen lone pair of electron shielded from the

reagent (MeI) by the C ring and accordingly it reacts more slowly." The cis, cis and

irorrs, t r u ~ u isomers distinguished readily by 'H NMR spectroscopy, where in, for truns,

irolls isomer, ClObH appears as a tnplet with a coupling constant value of 10 Hz, where

In ci5, cis Isomer ClObH appeared as a triplet with a coupling consstant of 1-3 Hz.

Recently Kravchenko and coworkers reported the reductive amination of I ,5,9-

t r i k e t o n e - 2 , 6 - b i s [ ( 2 - o x o c y c 1 o h e x y l ) m e t h y o n e 33 by Leuckat? reaction

ionditions (Scheme 2 . l1 ) . '~ A mlxture of seven diasteromers of

iyclohexaquinolizidines 34 were obtained. Each diastereomer was separated and

punfied for characterization. The stereochemistry of diastereomers were determ~ned by

extensive analysis of 'H and "C NMR data. We have now utilized this data to

determine structure and stereochemistry of 5 and 6

Scheme 2.11

k e n t s and conditions: i) HlNCHO, HCOOH, 160 'C, 80 min. 85% I I

For synthesis of 3,5di(4-methox~henyl)perhydrop).Tido[3,2,l-1j]qunoline 5

and 6 we have selected alicyclic 1,5,9 triketone 7b as the precursor. The triketone 7b

was prepared from Mannich base 1Sa and cyclohexanone 17. Diastereomeric mixture as

Chapter 2 148

such was subjected to MW mediated reductive amination-cyclisation with ammonlum

formate in PEG-200 to transform withln 1 min into a diastereomeric mixture of 3-(3-

methoxqphenyl)-5-(4-methoxphenyl)perhy~do[3,2,1-ij]quinoline 5 and 6 in 68%

ycld in the ratio of 3:l (Scheme 2.12). lnspite of best efforts the diastereomenc

rnlxtures of amines 5 and 6 could not be separated by different chromatographic

~cchniques. The isomers, were therefore, characterized as a mixture.

Scheme 2.12 ~

OMe OMe

A

"\ ( 7 7 L '7

Me0 OMe Me0 OMe

Reagents and conditions: I ) HCOONH4, PEG-200, MW, 370 W, 1 min. 68%. ~ The major compound (54%) was distinguished in the mixture NMR spectra and

ahsigned structure 5. The Cz symmetric nature of 5 and 6 could be recognized from ' H

and I3c NMR spectra. In the 'H NMR spectrum C3H, C5H appeared as a triplet wlth

coupling constant 6.0 Hz which showed its equatorial disposition and consequently

axlal disposition of the C3, C5 aryl groups. The ClObH appeared as a triplet w~th

coupllng constant 4.4 Hz, which indicated its equatorial disposition and trans, [runs

relationship between AC, BC rings. In the "C NMR spectrum this Isomer C3,5 and

ClOb carbons appeared at 6 66.66, 63.99 ppm respectively, and C7a,lOa carbons

appeared at 40.7 ppm.

The minor Isomer (45%) 6 showed doublet of doublet centered at 6 3.3 ppm ( J =

10.4, 3.4 Hz) in the mixture 'H NMR spectrum indicating its axial d~sposltion,

consequently aryl groups are equatorial. The ClObH appeared as a broad singlet in 'H

NMR spectra, which on careful examination appeared as a triplet. Nature of the peak

clearly delineated the stereochemistry of AC and BC rings as truns, trans. The "C

Chapter 2 149

hMR spectrum of the mixture showed required seven peaks for 6 in the aliphatic region

out of which those located at 6 70.6, 65.4 ppm were for C3.5 and ClOb respectively.

C7a, ClOa carbons appeared at 6 38.9 ppm.

Similar to those found in cyclopentaquinolizidines as discussed in the earlier

unit C2' and C6' hydrogen in 5 as well as appeared as broad doublet rather than sharp

doublets, possibility due to restricted rotation around aryl rings. In order to relieve steric

interaction between prominate aromatic ring. The molecule could adopt twisted chair or

boat conformation. The NOESY spectrum of both 5 and 6 exhibited cross peaks

between C3H and C5H and ClObH. Although, cross peak between C3H and C6H to

ClObH in the case of isomer 6 is expected, it was indeed surprising to find such low

intensity cross peak in the case of Isomer 5. Thls result can be explained by assuming

CIA-decaline type of conformat~on. Further work 1s required to separate the isomer 5 and

6 and charactenzation them independently.

2.3 Experimental Section

NhlR Spectroscopy

'H NMR and "C NMR spectra were recorded un CDCIJ, CD*CI* or CClj

mixture with JEOL 400 MHz, Bmcker 300,400, 500 MHz NMR and Varian 600 MHz

spectrometers using TMS (0 ppm) and the centerline of the chloforn-d triplet (77.0

ppm) as the Internal standard, respectively. Low temperature experiments were

conductd at 600 MHz for 'H and 150.8 MHz for "c. Full assignments of the ' H and

"C signals were obtained by bi-dimensional experiments (g-COSY, e d i t e d - g ~ s ~ ~ ~ '

and ~HMBC" sequences). The NOE experiments were obtained by means of the

DPFGSE-NOE~' sequence. To selectively irradiate the deslred signal, a 50 Hz wide

shaped pulse was calculated with a refocusing-SNOB shape and a pulse width of 37 ms.

'dixing time was set to 0.75 i 1.1 s. The samples for obtaining spectra at temperatures

lower than -100 "C were prepared by connecting to a vacuum line the NMR tubes

containing the compound and a small amount of CaDs (for locking purpose), and

condensing therein the gaseous CHF2CI and CHFCll (4:l vlv) under cooling with liquid

nitrogen. The tubes were subsequently sealed in vacuo and introduced Into the pre-

cooled probe of the spectrometer. Low temperature ''c spectra were acquired with a 5

mm dual probe, without spinning, with a sweep width of 38000 Hz, a pulse width of 4.9

Chapter 2 I SO

ps (70' tip angle), and a delay time of 2.0 s. Proton decoupling was achieved with the

standard Waltz-16 sequence. A line broadening function of 1-5 Hz was applied to the

FlDs before Fourier transformation. Usually 512 to I024 scans were acquired.

Temperature calibrations were performed immediately before the experiments, using a

CutNi thermocouple immersed in a dummy sample tube filled with isopentane, and

under conditions as nearly identical as possible. The uncertainty in the temperatures was

cstimated from the calibration curve to be * 1.0 "C. The line shape simulations were

performed by means of a PC version of the QCPE program DNMR 6 no 633, lnd~ana

University, Bloommgton, IN.

Calculations

Computations were carried out at the B3LYPl6-31G(d) level by means of the

Gaussian 03 series of programs, the standard Berny algorithm In redundant internal

coordinates and default criteria of convergence were employed. The reported energy

ialues are not ZPE corrected. Hamonic vibrational frequenc~es were calculated for all

the stationary points. For each optimized ground state the frequency analysis showed

the absence of imaginary frequencies, whereas each transltlon state showed a slngle

llnaglnary frequency. Visual inspection of the corresponding normal mode was used to

confirm that the correct transition state had been found. NMR chemical shift

calculations were obtained with the GlAO method at the B3LYP16-

31 1++G(2d,p)I/B3LYPI6-31G(d) level. TMS, calculated at the same level of theory.

x u used as reference to scale the absolutr. shield~ng value. J-coupling calculations were

ubtained at the B3LYPl6-31 I+tG(2d,p)l/B3LYPi6-31G(d) Level using the program

optlon that includes the Fermi contact contribution.

General procedure for the reaction of substituted !3-dimethylaminopropiophenone

under microwave irradiation

Synthesis of 2-[3-(4-methoxyphenyI)-3-oxopropyl~-l-cycopentanone 18a and 2,s-

di[3-(4-methox~henyI)-3-oxopropyl]-l-cyclopentanone 7a

~Dimethylaminopropiophenone hydrochloride (5 g, 20.5 mmol) was taken in a

beaker and the minimum amount of water (10 mL) was added to dissolve the salt. The

beaker was kept in an ice bath and 20% aqueous sodium hydroxide was added drop

wise while periodically checking pH using pH paper. As neutralization proceeded the

Chapter 2 151

slution became hubid. The addition of sodium hydroxide was continued until the pH

reached 10, at which point an oily layer of base was visible. This oily layer was extracted

ulth dichloromethane and conceneated to give P-dimethylamiopmpiophone 1Sa (4.2 g,

20.3 mmol), to which were added cyclopentanone 16 (853 mg, 10 mmol). tnethylamlne

(2.81 mL, 20.28 mmol) and PEG-200 (10 mL) in a 50 mL conical flask. The result~ng

mixnue was irradiated, al atmospheric pressure, in a domestic microwave oven (BPL-

Sanyo, India; mono-made, multi-power; power source 230V, 50 Hz, mlcro\r;i\c

iiequency: 2450 MHz) at 370 W for 2 min. The reaction mixture was cooled to rc>utli

temperature, diluted with 60 mL of dichloromethane, and poured over ~ce-cooled water;

!he organic layer was separated, washed again with water (2 x 50 mL) and saturated

aqueous NaCl (50 mL), and dried (Na2S04). The solvent was removed under reduced

pressure and the crude mixture separated by column chromatography (s~llca gel 100-200

mesh, hexanelethyl acetate 90:10 to 80: 20) to give 2-[3-(4-methox~~l i~t iyI) -3-

oxopropyl]-I-cyclopentanone 18a 1.34 g (26% ) and 2.5-di[3-(4-methoxyphcnyl)-3-

oxopropyl]-I-cyclopentanone 7a 4.92 g (58%).15

Synthesis of 2-3- [4-(benzyloxy)phenyl]-3-oxopropyl-l-cyclohexanone lflc and 2.5-

dij3-~4-(benzyloxy)phenyl]-3-owopropyl)--cyclopentanone 7c

Following the general procedure described above, the reaction of 1-14.

(benzyloxv)phenyl]-3-(dimethylamino)-I-propanone 1Sb (I0 g, 35.3 mmol), cyclopenta

none 16 (1.48 g, 17.6 mmol), tricthylamine (3.6 mL, 35.3 mmol), and PEG-200 (8 mL) 111

a conical flask for 2 min, 300 W resulted the mixture of 2-3-[4-(bmzyloxy)phcnyl]-3-

oxopropyl-I-cyclohexanone 18c and 2,5-di{3-[4-@enzyloxy)phenyl]-3-oxopropyI I - I -

cyclopentanone 7c which were purified by column chromatography (slltca gel 100-200

mesh, 5-15% EtOAcihexanes).

2-3-[~(Benzyloxy)phenyl]-3-oxopropyl-l-eyclopentanone 18c:

Yield 3.5 g (31%); mp 86-88 OC; R/= 0.46 (15% 0

EtOAcihexanes); IR (KBr) u 3065,2953,2868, 1730, ,A+

I

1680, i597. 1450, 1102, 1261, 1157, l105. IOOI. 833, c f * O -

742, 690, 655 cm'l; 'H NMR ( 30t) MHz, CDCI,) 8 ph-o

7.95 (d , J = 7.0 Hz, 2H), 7.44-7.33(m, 6H), 7.01-6.99 (4J= 7.9 HZ,

IH), 5.12 (s, OCH2,2H), 3.08-3.03 (m, ZH), 2.33-1.90 (m, 6H), 1.89-1.68 (ma 2H),

Chapter 2 152

(m P P ~ ; "C NMR (75 MHz, CDCI,) 6 130.36, 128.67, 128.21, 127.45, 114.57,

70.12, 48.26, 38.1 1, 35.13, 29.90, 24.50, 20.64 ppm; Anal. Calcd for CZ~H2?O3: C.

78.23; H, 6.88. Found: C, 77.64; H, 6.02.

2,5-Dl(% [4-(benzyloxy)phenyl]-3-oropropyl}-l-cyclopentone 7c:

Yield 9.1 g (46%); mp 131-133 'C; Rf= 0.43 (15%

EtOAchexmes); IR (KE3r) IJ 3027, 2981, 1724, 1678,

1602, 1510, 1255, 1178, 1028, 837 cm"; 'H NMR ( 300

MHz, CDCI,) 8 7.96-7.92 (d, J = 7.0 Hz, 4Hj, 7.41-7.25

(m, 12H), 7.02-6.97 (d, J = 7.9 Hz, 2H), 5.12 (s, OCH.,

4H), 3.05-3.03 (m, 6H), 2.33-1.90 (m, 4H), 1.55-1.89 (m, OCHzPh OCHzPh

2H), 1.40-1.25 (m, 2H) ppm; '?c NMR (75 MHz, CDCI3j 6 198.39, 162.55, 130.33,

130.07, 128.4, 128.65, 128.26, 128.18, 127.42, 114.55, 70.09, 48.50, 35.70, 27.77, 24.8

ppm; Anal. Calcd for C37H3605: C, 79.26; H, 6.47. Found: C, 79.28, H, 6.43.

Synthesis of 2-(3-(4-methoxyphenyl)-3-oxopropyll-l-cyclobexanone 18b and 2.6-

dill-(4-methoxyphenylbf oxopropylJ-1-cyclohexanone 7b

Following the general procedure described above, the reaction ol' 3-

(dimethylaminoj-I-(4-methoxypheny1)-1-propanone 15b (6 g, 28.9 mmol), cyclohexo

none 17 (1.4 mL, 14.4 mmol), triethylamine (2.9 mL, 28.2 mmol), and PEG-200 (10

mL) in a conical flask for 2 min, 300 W resulted the 2-[3-(4-methoxqpheny1)-3-

oxopropyl]-I-cyclohexanone 18b 1.9 g (26%) and 2,6-di[3-(4-methoxn,henyl)-3-

oxopr~pyl]-l-c~clohexanone'~~ 7b 3.9 g (32%) after purification by column

chromatography (silica gel 100-200 mesh, 5-1 5% EtOAchexanes).

Representative procedure for reductive amination-cyclization of mixture of c b and

Runs- 1,5,9-triketones: Synthesis of (3SR,5SR,7aRS,9aSR)-3,5-di(4-methoxyphenyl)

perhydrocyclopenta[ijlquinolizine 1, (3RS,SRS,7aRS,9aSR)-3,5-di(4-methoxy

~henyl)perhydrocyclopenta[ijlquinolizine 2 and 1-(4-methoxypheny1)-3-12-(4-

methoxyphenyl)-6,7-dihydro-5H-cyclopentIblpyridin-7-yl]-l-propanone 24

Method A

To a stirred solution of NaBH(OAc)] (738 mg, 3.67 mml) in dry THF (10 mL)

were added 2,5-di[3-(4methox~henyl)-3-oxopmpyl]-l-cyclopentanone 7a (500 mg.

1.22 mmol), ammonium acetate (471 mg, 6.31 mmol), and acetic acid (0.5 mL), in

Chapter 2 153

sequence, at room temperature under a blanket of dry nitrogen. The resulting reaction

mixture was stirred and placed m a preheated oil bath at 60 T for 1 h. The mlxture was

then cooled to ambient temperature, and the pH was adjusted to 7.5 with 20% NaOH

(about 8 mL). To the resulting b~phasic mixture were added dichloromethane (DCM, 20

mL) and water (5 "C, 25 mL), and the organic layer was separated. The aqueous layer

was extracted with dichloromethane ( I0 mL x 2). The combined organic layer was

washed with water (2 x 50 mL) and brine (20 niL) and dried over anhydrous Na2S04.

The solvent was removed under reduced pressure and the crude mixture subjected 10

column chromatography (silica gel 100-200 mesh, hexanetethyl acetate 97:3 to 90: 10)

to obtain mlxture of 3,5-di(4-methoxyphenyl)perhydrocyclopenta[]quinolizine 1 and 2

In 80% (369 mg) yeld and in a 7:3 ratlo.

Method B

A mixture of cis- and rruns-2,5-di[3-(4-methoxyphenyl)-3-oxopropyl]-l-

cyclopentanone 7a (700 mg, 1.71), ammonlurn formate (929 mg, 14.7 mmol) and PEG-

200 were taken in a conical flask and the resulting mixture was Irradiated in a domestlc

microwave oven at 370 W for 1 min. The mixture was cooled to room temperature,

d~luted with 30 mL dichloromethane and and poured over ice-cooled water, the organic

layer was separated and washed again with water (2 * 30 mL), saturated aqucous

sod~um chloride (25 mL) and dried over anhydrous NalS04. The solvent was removed

under reduced pressure and the crude reaction mixture was separated by column

~.hromoatography (silica gel 100-200 mesh. 3-10% EtOAc-hexanes) furnished mixture

of 3,5-di(4-methoxqphenyl)perhydrocyclopenta[]quinolizine 1, 2 and 1-(4-

methox).phenyl)-3-[2-(4-methoxqpheny1)-6,7-dihydro-5cyclopenta[b]pidin-7-y]- I - propanone 24 in the ratio of 1: 2.5%.

(3SR,5SR,7aRS,9aSR)-3,5-Di(4-methox~henyl)perhydrocyclopenta[~~quinolizine

1.

Yield 223 mg (26%) mp 90-93 "C; Rf = 0.52 (3% -

LtOAchaanes); IR (KBr) v 3039. 2911. 2765, I606 1479, 965. & 845, 785 cm -' 'H-NMR (600 MHz, CD2Ci2, 25 OC, TMS) G 6.76

C N ~

(br s, 2H), 6.38-6.35 (m, 2H), 3.63 (s, OMe, 6H), 3.22 (dd, J = 6.0, (p oJ 4.6, H3, H5, 2H), 2.86(t, J = 4.5 Hz,H9b, lH), 2.21-2.14 (m, 2H),

Me0 OMe

Chapter 2 154

2.06-1.98 (m. 2H,), 1.86-1.79 (m, 2H), 1.73-1.65 (m, 4H), 1.58-1.51 (m, 4 ~ ) ppm; 1 ' ~

NMR (150.8 MHz, CD2Ch9 25 "C, TMS) S 158.3 (q), 138.8 (q). 130.2 (CH, br), I 12.8

ICH), 67.4 (CH, C3 and C5), 64.7 (CH, C9b), 55.9 (CHI, OMe), 41.6 (CH, C7a and

C9a). 31.5 (CHI), 30.7 (CH2), 24.7 (CH2) ppm; HRMS (El): d z calcd for C:IHIINOZ:

377.235479; found: 377.2354.

( 3 ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ) - 3 , ~ - D i ( ~ - m e t h 0 ~ ~ p h e n ~ l ) ~ e r h ~ d r o c ~ c l o ~ e n t a [ i j ~ ~ u i n o 1 i ~ n e

1:

Yield 154 mg (18%) mp 102-105 'C; R, = 0.40 (3% H

EtOAchexanes); IR (KBr) v 2931, 2816. 1483. 1440, 1129. 761. (-:'! 707 cm -I; 'H-NMR (600 MHz. CD?CI:, 25°C TMS) 6 7.28 (m, < 'C ?H),6.76(m,2H),3.87(t,J=6.8Hz.2H),3.73(s,OMr,6H),3.31 < ?

\.! ' '&., ;" (L, J = 8.4 Hz, IH), 2.10-1.91 (m, 4H), 1.80-1.74 (m, 2H), 1.68.1.58 ,

Me0 OMe (m. 4H), 1.50-1.43 (m, 2H). 1.42-1.34 (m, 2H) p p m ; " ~ h'MR

(150.8 MHz, CDICII, 25"C, TMS) 6 158.9 (q), 139.0 (a,), 129.3 (C'H), 113.8 (CH), 60.4

(CH, C3 and C5), 56.1 (CH, C9b), 55.9 (OMe), 39.1 (CH, C7a and C9a), 31.2 (CH:),

30.0 (CHI), 27.4 (CHI) ppm; HRMS (EI): miz calcd for C21H31N02: 377.235479:

found: 377.2355.

1-(4-Methoxyphenyl)-3-[2-(4-methoxphenyl)-6,7-dihydro-SH-

c)clopenta[b]pyridin-7-yll-1-propanone 24:

l'ield 412 mg (48%); mp 114-1 16 "C; R, = 0.33 <7>+\

(15% EtOAchexanes); IR (KBr) u 2931.2833, 1674, 15 10, iJ 1247, 1174, 1029, 812 cm-'; 'H NMR (400 MHz, CDCI,) 6

Me0 8.02 (d, J = 7.0 Hz, 2H), 7.96 (d, J = 7.0 Hz, 2H), 7.48 (d, J

= 7.9 Hz, lH), 7.41 (d, J = 7.9 Hz, IH), 6.96 (d, J = 7.0 Hz, .Po 6- >HI, 6.87 (d, J = 7.0 Hz, 2H), 3.82 (s, 3H), 3.81 (s, 3H),

Me0 3.37-3.15 (m, 3H), 2.98-2.78 (m, IH), 1.87-1.75 (m, IH)

ppm; "C NMR (100 MHz, CDCI,) S 199.46, 167.32, 163.37, 161.4, 155.19, 134.64,

132.70, 130.58, 130.31, 128.04, 117.43, 114.03, 113.72, 55.43, 55.35, 44.83 (CH),

36.43 (CH2), 30.60 (CHI), 29.14 (CH*), 28.85 (CH2) ppm; HRMS. Calcd for

GsHI~NO, for 387.476, found 387.468; Anal. Calcd for CISH~SNO~: C, 77.50; H, 6.50.

N, 3.61.Found: C, 77.24, H, 6.38, N, 3.52..

Chapter 2 155

Synthesis of (3SR,SSR,7aRS,9aSR~3,5-di(4-benzylox~henyl)perhydro

cyclopental@lquinolidne 3, (3RS,5RS,7aRS,9aSR~3,5-di(4-benzylox~phenyl)per

hydrocyclopento(~~quinolizine 4 and 1-[4-(Be~loxy)phenyl~-3-{2-[4~benqloxy)

pbenyll-6,7-dihydro-5H~yclopentalb~pyrin-7-yl)-l-propanone 25

Following the general procedure of method B a mixture of cis- and fruri-2,s-

di(3-[4-(benzyloxy)phenyl]-3-oxopropyl)-l-cyclopentanone 7c (500 mg, 0.9 mtiiol).

ammonium formate (562 mg, 9 mmol) and PEG-200 were taken (3mL) in a conical

flask and the resulting mixture was irradiated in a domestic microwave oven at 370 W

for 1 min, resulted the mixture 3,5di[4-(benzyloxy)phsnyl]perhydrocyclopenta[~j]

qurnolizine 3, 4 and 1-[4-(benzyloxy)pheny1]-3-(2-[4-(benzyloxy)phenyl]-6,7-dihyd1~~~-

5H-cyclopenta[b]pyri&r~-7-yl)-I-propanone 25 in the ratio of 1: I :2.

(3SR,5SR,7aRS,9aSR)-3,5Di(4-enzyloxyphenyl)pe1hyd1ocyc1openta[~~quinolizine

3:

Yield 98 mg (22%); mp 73-75 "C; R, = 0.68 (3% H

EtOAcI hexanes); IR (KBr) u 3012, 2988, 2761, 1608, 1412, ,-,+ ',~ ' 903, 818, 780 cm.'; 'H NMR (400 MHz. CDCI;) 6 7.39-7.29

im, 8H), 6.85-6.70 (br s, 2H), 6.51-6.43 (d, 8H), 4.90 (s, 4H, -,- \ /+- ; ' 1

OCHZ), 3.21 (t, J = 6.0, 4.6 Hz,JH, H3, H5), 2.86 (t, J = 4.5 'Y . Hz, 1H. H9b), 2.25-2.12 (m, 2H), 2.08-1.96 (m, 2H), I .88- PhH,CO OCH,Ph

1.79 (m, 2H), 1.78-1.63 (m, 4H), 1.64-1.5 1 (m, 4H) ppm; "C NMR (1 00 MHz, CDCI?)

8 156.89 (q), 138.39 (C), 137.58 (C), 129.49 (CH), 128.51 (CH), 127.75 (CH), 127.36

(CHI, 113.25 (CH), 70.11 (OCHI), 66.77 (CH, C3, and C5), 64.06 (CH, C9b), 40.85

(CH, C7a and C9a), 30.74 (CHI), 29.97 (CHI), 24.05 (CHI) ppm; HRMS calcd tbr

C:7H,9Nq 529.720, found 528.643; Anal. Calcd for C;~H,~NOI: C, 83.89; H, 7.42. N.

2.64.Found: C, 83.87, H, 7.44, N, 2.63.

(3RS,5RS,7aRS,9aSR)-3,SDi(4-benzyloxy - ~henyl)perhydrocyclopenta[@~quinoliine 4:

Yield 89 mg (20%); mp 104-106 'C; Rf= 0.66 (3% &-

EtOAcihexanes); IR (KBr) u 2932, 2864, 1491, 1451, 1126, iNi, 759, 699 im.'; 'H NMR (400 MHz, CDCI,) 6 7.36-7.23 (m, 9 '4 ]OH), 6.79-6.75 (d, 4H), 6.50-6.41 (d, 4H), 4.94 (s, 4H, PhH,CO OCH,Ph

Chapter 2 156

OCHl), 3.32-3.11 (m, J = 6.0, 4.6 HZ, 2H, H3, H5), 2.91 (dd, J = 4.5 Hz, IH, H9b).

2.25-2.12 (m, 2H), 2.24-2.08 (m, 2H), 1.88-1.53 (m, 6H), 1.49-1.34 (m, 2H), 1.3?-1.?1

(m 2H) P P ~ ; "C NMR (100 MHz, CDCII) s 156.93 (q), 138.65 (c). 137.76 (c). 130.05 (CH), 128.76 (CH), 127.98 (CH), 127.63 (CH), 114.03 (CH), 70.91 (OCHZ),

71.65 (CH, C3, and C5), 70.44, (CH, C9b), 42.58 (CH, C7a and C9a), 39.28 (CH:),

31.70 (CHI), 27.75 (CHI) ppm; Anal. Calcd for CnH3uN&: C, 83.89: H, 7.42. N.

2.64.Found: C, 83.86, H, 7.44,N, 2.65.

I - [ 4 - ~ n z y l o x y ) p h e n y l l - 3 - ~ 2 - I 4 - @ e n z y l ~ x ~ c y c 1 o p e n t a l h l

pyridin-7-$1-1-propanone 25:

Yield 173 mg (39%); mp 118-120 "C; R, = 0.30 I, ' : , - . .

(15% EtOAcihexanes); IR (KBr) u 3035, 2943, 2876, N 1 ; 1 1600, 1508, 1439, 1241, 1171, 1015, 823 cm-'; 'H P~CH,O* -

NMR (400 MHz, CDCI,) S 7.98 (d, J = 7.0 Hz, 2H), 0

7.90 (d, J = 7.0 Hz, 2H), 7.48 -7.41 (m, 12H), 6.98-

6.88 (m, 4H), 5.08 (s, 2H), 5.07 (s, 2H), 3.30-3.18 (m, PhCH,

3H),2.93-2.84(m,2H), 2.14-2.37(m, 1H),2.19-2.14(m,ZH), 1.86-1.79(m, I l i ) p p ~ n :

"cNMR (100 MHz, CDCII)S 198.62, 167.35, 162.37, 159.31, 155.24, 137 02. 130.37.

134.3. 132.82, 132.54, 130.66, 130.59, 128.69, 128.60, 128.18, 128.10, 127.96, 117.33.

114.89. 114.48, 69.76 (OCHI), 44.74 (CH), 36.13 (CH*), 30.61 (CH:), 28.95 (C'1-11).

28.81 (CHI) ppm; Anal. Calcd for C,,H3~NO1: C, 82,35: H, 6.16. N, 2.60.Found. (',

82.14,H,6.10,N,2.91.

Synthesis of 3,5-di(~methoxyphenyI)perhydropyrido[3,2,l-ij)quinollne 5 and 3.5-

~(4-methox~henyl)perhydropyrrdo[3,2,1-1~]quinoline 6:

Followmg the general procedure of method B a mlxture of

as- and trans-2,6-d1[3-(4-methox~henyl)-3-oxopropy]-I- 1 cyclohexanone 7b (400 mg, 0 9 mmol), ammonlum formate (597 )' , mg, 9 4 mmol) and PEG-200 were taken (2 mL) in a conlcd flask ,&\ h'

and the resulting mlxture was i r rdated m a dornestlc nucrowave )' ' M e 0 OMe

oven at 370 W for 1 mm resulted the mlxture 3,s-6(4-

methoxyphenyl)perhydropyndo[3,2, I-i~]qunolne 5, 6 m 2 18 mg (68%) After

punficat~on by column chromatography m 2 1 ratlo Y~eld 256 mg (54%), mp 90-93 C ,

Chapter 2 157

R/ = 0.52 (97:3 hexaned EtOAc); 1R (KBr) u 756, 827, 1034, 1176, 1242. 1461. 1508.

1609, 2058, 2859, 2930 cm'l; 'H NMR (400 MHz, CDCI,) 6 6.71-6.6 (m, 4H). 6 38.

6.31 (m, 4H), 3.81-3.73 (m, IH), 3.64 (s, 6H), 3.20 (t, J = 6.0 Hz, 1H). 3.04 (dd. .i =

10.4, 3.6 HG IH), 2.86 (t, J = 4.4 Hz, IHz), 2.55 (br s, IH), 2.20-2.18 (m, 3H), 2.0-1.9

(m, 2H), 1.87-1.25 (m, 13H) ppm; "C NMR (100 MHz, CDC12) 6 24.0 (CH:), 2 0 . 5 2

(CH2), 27.26 (CHt), 29.92 (CHI), 30.36 (CHI), 30.66 (CHI), 33.34 (CH:), 38.87 (CH).

40.74 (CH), 55.14 (OCHI), 55.17 (CHI), 63.94 (CH), 65.40 (CH), 66.60 (CH), 70.55

(CHI, 112.12 (CH), 112.45, 129.28, 138.01, 139.69, 156.93, 157.42 ppm: Anal. C,ilcd

for C ~ ~ H I I N O ~ : C, 79.76; H, 8.49. N, 3.58.Found: C, 79.84, H, 8.23, N, 3.23.

Synthesis of (3SR,SSR,7eRT,9aSR)-4-[5-(4-hydronyphen?I

In a round bottom flask equipped with a reflux condenser H

(3SR.5SR,7aRS,9aSR)-3,5-di(4-metho~yphenyI)perhydro~y~~openta[i~ f 1 N

qu~nolizine 1 (100 mg, 0.26 mmol) was treated wlth 3 mL of 48%

aqueous HBr The solutlon was heated to reflux for I0 h cooled to rt,

dlluted wtth 20 mL of dlchlromethane and water (I0 mL) and slowly HO OH

neutral~zed with 2 lg of NaHCOl After belng stirred for 15 mln, the

layers allowed to separate and the aqueous layer was extracted w~th CHCI, (3 * 15 mL).

The following washing with brine and drying (Na2S04), the combined organic cxtracts

removed and purified by column chromatography by using 40-509' EtOAc'hcxmcs to

obtained ( 3 S R , 5 S R , 7 a R S , 9 a S R ) - 4 - [ 5 - ( 4 - h y d r o x y p h e n y l ) p e ~ ]

quinolizin-3-yllphenol 22. Yield 78 mg (84%); mp 161-162 "c; R, = 0.30 (40'k)

EtOAchexanes); IR (KBr) u 3378, 2927, 1600, 1506, 1456. 1362, 1231, 767 cm ; ' H

NMR (400 MHz, DMSO+CDC13) 6 7.89 (br s, 2H), 6.9 (d, J = 8.8 Hz, 2H), 6.74 id. . I=

8.0Hz. 2H), 6.69 (d, J = 8.4-Hz, 4H), 4.9-5.1 (br s 2H), 3.72 (m, J = 6.0, 4.6. H3, 1-15,

2H), 3.57 (t, J = 4 . 5 Hz, H9h, IH), 3.11 (d, J = 6 . 8 Hz, 2 ~ ) , 2.23-2.11 (m,?H). 1.75-

1.62 (m, 2H), 1.60-1.33 (m, 6H) ppm; "C NMR (I00 MHz, CDCI,) 6 155.90 136 17,

132.41, 128.54, 127.18, 114.67, 60.71, 59.85, 45.21, 34.68, 25.73 ppm; Anal. Calcd for

C23H27N02: C, 79.05; H, 7.79. N, 4.0l.Found: C, 79.06, H, 7.76, N, 4.03.

Chapter 2 158

Synthesis of ~(5-~4-@enzoyloxy)pbenyl~perhydrocyclopenta[~~quinoliAn-3-~l)

pbenyl benzoate 26:

To a s t d soluhon of (3SR,SSR,?aRS,9aSR)-4-[5-(4- -

hy&oxyphenyl)pehydrocyclopenta[D]qu1noliz1n-3-yl]phenol -\J" 22 (25 mg, 0 l mmol) In 30% aqueous NaOH (3 mL) was \ N

sttrred at 0 OC and slowly added benzoyl chlonde (0 18 mL, r-7 - 0 15 mmol) and conhnued the stlmng for 30 min AAer \- - compleuon of the reactlon (TLC) react~on mixture was cooled PhCOO OOCPh

to rt and a brown color solid was formed, filtered the solid and washed with cooled

water and recrystallized with mcthanol!diethyl ether to obtained 4-15-[4-

(benzoyloxy)phenyl]perhydrocyclopenta[ij]quinolizin-3-yl]pheny benzoate 26. Yield

34 mg (83%); mp 139-141 OC; R,= 0.64 (30% EtOAchzxanes); IR (KBr) u 2934.2859,

1735, 1598, 1503, 1451, 1267, 1200, 1172, 1061, 876 cm-'; ' H NMR (400 MHI,

CDCII) 6 8.23-8.19 (m, 4H), 7.66-7.49 (m, 4H), 7.16-7.05 (m, SH), 3.87 (d, J = 3 HI,

IH), 3.51-3.38 (m, IH), 3.20 (dd, J = 10.2 Hz, 3Hz, IH), 2.29-2.04 (m, 5H), 183-1 48

(m, 9H) ppm; I3c NMR (100 MHz, CDCI,) 6 155.90 136.17, 132.41, 128.54, 127.18,

114.67, 60.71, 59.85, 45.21, 34.68, 25.73 ppm: Anal. Calcd for C ~ ~ H I ~ N O ~ . C, 70.69;

H,6.33.N,2.51.Found: C, 79.64,H, 6.31,N,2.54.

trifluoroacetate 1-Hi:

'H-NMR (600 MHz, CDIC12, -10 'C, TMS) 6 1004 (br s,

NH, IH), 7 57 (br s, 2H), 6 54 (br s, 2H), 6 34 (br s, 4H), 3 79 (ddd, H

J = 1 0 3 Hz, 8 2 Hz, 2 9 H z , 2 H ) , 361 (s,OMe, 6H), 347 (dt, J =

8 7 Hz, 4 4 Hz, H9b, IH), 2 81-2 72 (m, 2H), 2 53-2 45 (m, 2H) c L.

H

2 36-2 26 (m, 2H), 1 98-1 83 (m, 6H) 1 67-1 60 (m. 2H) ppm, 'k C-

NMR (150 8 MHz, CDICII, -10 "C, TMS) 6 159 7 (q), 131 4 (CH, r' ' M e 0 OMe

br), 114 3 (CH), 130 6 (q), 75 9 (CH, Cgb), 73 0 (CH, C3 and C5),

55 9 (CH3, OMe), 41 2 (CH, C7a and C9a), 27 1 (CHI), 3 1 6 (CHI). 24 9 (CH?) ppm.

MS (ESII) mlz 378 [M-CFCOO)', loo%], MS(ES1-) miz 113 [CF3COO, 100Do]

3RS5RS,7nRS,9aSR)-35-di(4-methoxyphenyl)p~ydmyclopnh[~]quinoli~ne

trifluomaeetato 2-H':

'H-NMR (600 MHz, CD2CI:. -10°C. TMS) 6 7.46 (hr \. -

3H). 9.95 (hr s. NH, IH), 6.90 (d. J = 8.2 Hz, 4H), 6.41 (minor

tom, d, J = 8.9 Hz). 4.80 (minor form. hr m. H3.H5). 4.43 (minor

furm,dt. J = 11.6. 5.0Hz. H9h, IHJ. 4.17(hrm. H3. H5. 2H). 3.77 rb ,\. OMe, 6H), 3.63 (minor OMe). 3 57 (dt. J = 9.2. 4.9 Hz. H9h. \ I . IH). 2.48 (hrs ,2H), 2.32-2.21 (m. 2H1.2.15-2.02im. JH). 1.76(hr

Me0 OMe \ . ?H). 1.57-1.44 (m, 4H) p p m : " ~ NMR (150.8 MHz. CD2CI:.

t?S'C. TMS) 6 161.2 (q) , 130.8 (CH, br). 128.4 ( q ) , 115.1 (CHI. 63.6 iCH. CYh). 58.6

ICH, C3.C5). 56.1 (CHI. OMe). 36.0 (CH. C7a and C9a). 31.0 (CH:). 26.5 (CH:).

15 9(CH2, br) ppm.

('rystal Data for 1-H'

Crystals obtained from CHCI;, molecular formula. ~ C ~ ~ H ~ ~ N O ~ . ~ C ~ F J O ~ . ~ C H C I I . Mr

= 1221.81. monoclinic, spacr group P2,Ic (No. 14). u = 16.6403i 16), h = 13.4738(13). c

= 25.472(3) A, P = 95.429(2), V = 5685.4( 10) A', T = ?98(2) K, Z = 4, p, = 1.427 g c m ~

'. F(000) = 2544. graphite-monochromated Mona radiation th = 0.71073 A). p(Mon,) =

0.377 mm-I, colourless brick (0.5 x 0 4 x 0.2 mm'). empirical absorpt~on correction

~ l t h SADABS (transmission factors: 0.9284 - 0.8338). 2400 frames, exposure time 10

,. 1.61 5 0 5 26.00. -205 h 5 20. -16 d k 5 16. -31 5 15 31.57235 reflections collected.

. 'hapter 2 160

I 172 independent reflections (R,., = 0.0327). solution hy direct methods (SHELXS97*)

,nd subsequent Fourier syntheses, full-matrix least-squares on F,.! (SHELXY7).

~ydrogen atoms refined with a riding model except for the two ammonium hydrogens,

:ha1 were experimentally located. data I restraints I parameters = 1 1 1721 174 1 822. s ( P )

; 1.103, R(F) = 0.0904 and WR(PJ = 0.2098 on all data. R(FJ = 0.0634 and NR(~') =

i i 1956 for 7514 reflections with I > 20111, weight~ng \theme w, = l l jo:(~,, ') + ( 0 1167~) ' + 1.646P3 where P = (F,,' + ?~,:)13, large\t difference peal. and hole 0.41h

.ind -0.610 e k' The unit cell contains two indcpendcnt catlons, and two independent

.~n~ons (both disordered). Two CHCI? molecules (one of which disordered) are a lw part

~f the independent unit. Crystallographic data (excluding \tructurr factors) for thc

,tructure reported in this p a p r have been deposited with the Camhrldpc

Crystallographic Data Centre as supplementary puhlicatlon no. CCDC-66628 I . Copies

i l l the data can be obtained on application lo CCDC. I? linlon Road. Cu ih r~dge

CB2IEZ. L'K ( fax: (+44) 1221-336-033; e-mail. de~oslt@>ccdc cam.ac.uk).

Crystal Data for 2-H'

Cry%tals obtained from CHCI,, molecular formula: ~ C ~ ~ H ~ ~ N O : . ~ C ~ F I O ~ . C : H F I O : . M,

= 1097.10, tnclinic, space group P- l (No. 2), u = 11.3651(10), h = 16.3126( 14). I . =

17.2339(15) A, a = 110.3030(10). /3= 98.6520(10), y = 107.6590(10J, V = 2735.8(4)

4'. T = 298(2) K, Z = 2, p, = 1.332 g cm-'. F(000) = 1152, graphile-monochromaled

L ~ O K ~ radiation (h = 0.71073 A). p(MoKa) = 0.1 1 l mm ', colourless brick (0.2 x 0.2 x

Chapter 2 161

0.1 mm3), empirical absorption correction with SADABS (transmission factors: 0.9890

- 0.9782), 2400 frames, exposure time 20 s, 1.44 5 8 Ir 25.49, -135 h < 13, -19 < k Ir 19, -20 5 1 5 20, 27537 reflections collected, I0142 independent reflections (R,,, =

0.0328), solution by direct methods (SHELXS97') and subsequent Fourier syntheses,

full-matrix least-squares on F: (SHELX97), hydrogen atoms refined with a riding

model except for the two ammonium hydrogens, that were experimentally located, data

, restraints 1 parameters = 101421 55 1 739, s ( P ) = 1.039, R(FJ = 0.1354 and M R ( ~ ) =

0.2462 on all data, R(FJ = 0.0707 and I L R ( ~ ) = 0.2000 for 5004 reflections with I >

20(1), weighting scheme w = l l [ c r 2 ( ~ ~ ) + (0.1 1 6 9 ~ ) ~ + 0.574Pl where P = (F,' +

2~,')13, largest difference peak and hole 0.628 and 4 .348 e A-'. The unit cell contains

two independent cations, and two independent anions (one of which is disordered). A

molecule of CF,COOH is also present. Crystallographic data (excluding structure

factors) for the structure reported in this paper have been deposited with the Cambridge

Crystallographic Data Centre as supplementary publication no. CCDC-666282. Copies

of the data can be obtained on application to CCDC, 12 Union Road, Cambridge

CB21EZ, UK (fax: (+44) 1223-336-033; e-mail: dmositiu~ccdc.cam.ac.uk~.

2.4 References

I Remer, U. N. J. Nur. Prod, 1964,27,406-408.

' Dickman, D. A,; Heathcock, D. A. J. Am. Chem. Soc. 1989, I l l , 1528-1530.

' McPhail, a. T.; Poisson, J. Tetrahedron 1983, 39, 3629-3637.

' Mehri, H.; Basassou, S.; Plat, M. ' Nat. Prod. 1991, 54, 372-379.

Josef, H.; Jan, T. Collect. Czech. Chem. Commun. 1986,Sl. 1731.

' rune ton, J.; Bouquet, A,; Cave, A. Phytochemistry 1974, 13, 1963-1967.

Cave, A,; Bruneton, J.; Ahond, A,; Bui, A,-M.: Husson, H. -P.; Kan, c.; Lukacs, G.;

Potier, P. Tetrahedron Len. 1973, 14, 5081-5084.

' Clough, J. D.; Roberts, J. D. J. Am. Chem. Soc. 1976,98, 101 8-1 020.

a) Cozzi, F.; Cinquini, M.; Annunziata, R.; Dwyer, T.; Siegel, I. S. J. Am. Chem. Soc.

1992, 114, 5729-5723; b) Cozzi, F.; Cinquini, M.; Annunziata, R.; Siegel, I. S. Am.

Chem. Soc. 1993,115,5330-5331; c ) Tumambac, G. E.; Wolf, C. Org. Chem. 2005,

70.2930-2938.

Chapter 2 162

lo a)House, H.O.; Campbell, W. J.; Gil, M. J Org. Chem. 1970,35, 18 15-1 8 19; b)

Anderson, J. E.; Cooksey, C. J. Chem. Comm. 1975,942-943; c) Cosmo, R.; Sternhell,

S. Aust. J Chem. 1987,40, 1107-1 126; d) Cozzi, F.; Ponzini, F.; Annunziata, R.;

Cinquini, M.; Siege], J. S. Angew. Chem. Int. Ed. Engl. 1995, 34, 1019-1020; e) Thirsk,

C.; Hawkes, G. E.; Kroemer, R. T.; Liedl, K. R.; Loerting, T.; Nasser, R.; Pritchard, R.

G.; Steele, M.; Warren, J. E.; Whiting, A. J. Chem. Soc. Perkin Trans 2,2002, 15 10-

1519.

'la)Zoltewicz, J. A,; Maier, N.M.; Fabian, W.M.F. J Org. Chem. 2006, 71, 7018-7021;

b) Wolf, C.; Ghebremariam, B. T. Tetrahedron Asymmetry 2002.13, 1153-1 156; c)

Zoltewicz, J. A,; Maier, N . M.; Fabian, W. M. F. Tetruhedron 1996, 52, 8703-8706; d)

Nakagawa, Y.; Honda, K.; Nakanishi, H. Mugn. Reson Chem. 1996,34, 78-82.

I' Lunazzi, L.; Mancinelli, M.; Mazzanti, A. J Org. Chem. 2007, 72, 5391-5394.

l 3 Ben-Efraim, D. A,; Arad-Yellin, R. J Chem. Soc. Perkin Trans 2 1994,853-860.

" Lai, Y.-H.; Chen, P. J Chem. Soc. Perkin Trans. 2 1989, 1665-1670.

" Rao, H. S. P.; Jeyalakshmi, K.; Senthilkumar, S. P. Tetrahedron 2002,58,2189-

2199.

l6 Eliel, E. L.; Wilen. S. H.; Mander, L. N. Stereochemistry of Orgunic Compucind~;

Wiley-Interscience: Kundli, 2003, pp 776 - 777.

a) Rubiralta, M.; Giralt, E.; Diez, A. Piperidine: Structrrrr, Preparution, Reac1ivit.v

und Synthetic Applications ofpiperidine and its Der~vutives; Elsevier: Amsterdam,

1991; h) Anet, S. A. L.; Yavari, I. J Am. Chem. Soc. 1977,YY, 2794-2796.

I X a) Moyneh, T. M.; Schofield, K.; Jones, R. A,; Katntzky, A. R. J Chem. SOL. 1962,

2637-39; b) Sugiura, M.; Sasaki, Y, Chem. Pharn~. Bull. 1976, 22,2988-92; c) Lalonde,

R. T.; Donvito, T. N. Can. J. Chem. 1974,52,3778-3783; d) Slough, G. A,; Han, F.;

Lee, B. H. Tetrahedron Lett. 1999,40,3851-3854.

a) Gill, N. S.; James, K. B.; Lions, F.; Potts, K. T. J Am. Chem. Soc. 1952, 74,4923-

4928; b) Rao, H. S. P.; Poonguzhali, E.; Senthilkumar, S. P. Synth. Commun. 2008,38,

937-942.

'' Senthil Kumar, S . P. Ph.D. thesis submitted to the Pundicherry Universiry.

Puducherry, 2003.

Chapter 2 163

-- -

* ' MMFF force field, as implemented in Titan 1.0.5, Wavefunction Inc., Irvine, CA. A

Montecarlo algorithm (version 1.0.3) was used for locating the global minima.

'* Program Gaussian 03, Revision D.O1, Frisch, M. J. et 01. Gaussian, Inc., Wallingford

CT, 2004

*' a) Bushweller, C. H. J. Am. Chem. Soc. 1969, 91,6019-6024; b) Weiser, 1.; Golan,

0. ; Fitjer, L.; Biali, S. E. J. Org. Chem. 1996, 61, 8277-8284; c) Gill, G.; Pawar, D. M.;

Noe, E. A. J. Org. Chem. 2005, 70, 10726-10731; d) Thanikasalam,K.; Jeyaraman, R.;

Panchanatheswaran, K.; Low, J. N.; Glidwell, C. Actu C~sr t . 2006, C62,324-327.

?' Karplus, M.J. Am. Chrm. Soc. 1963,85, 2870-2871.

'' a) Dondoni, .4.; Lunazzi, L.; Giorgianni, P.; Macciantelli, D. J. Org. Chem. 1975, 40,

2979-2980; b) D. Hoogosian, S.; Bushweller, C. H.; Anderson, W. G.; Kigsley, G. J.

Phys. Chem. 1976,80,643-648; c) Lunazzi, L.; Cerioni, G.; Ingold, K. U. J. Am. Cheni.

Soc. 1976, 98, 7484-7488; d) Lunazzi, L.; Dondoni, A,; Barbaro, G.; Macciantelli, D.

Tetrahedron Lett. 1977, 18, 1079-1080; e) Forlani, L.; Lunazzi L.; Medici, A.

Tetrahedron Lett. 1977, 18,4525-4526; i ) Bemardi, F.; Lunazzi, L.; Zanirato, P.;

Cerioni, G. Tetrahedron 1977,33, 1337-1343; g) Cremonini, M. A,; Lunazzi, L.;

Placucci, G.; Okazaki, R.; Yamamoto, G. J. Am. Chem. Soc. 1990, 112,2915-2921; i)

Anderson, J. E.; Tocher, D. A.; Casanni, D.; Lunazzi, L. J. Org. Chem. 1991, 56, 1731-

1739; h) Gribble, G. W.; Olson, E. R.; Brown, J . H.; Bushweller, C. H. J. Org. Chen~.

1993, 58, 1631-1634; i) Borghi, R.; Lunazzi, L.; Placucci, G.; Cerioni, G.; Foresti, E.;

Plumitallo, A. J. Org. Chem. 1997, 62,4924-4927; j) Garcia, M. B.; Grilli, S.; Lunazzi,

L.; Mazzanti, A,; Orelli, L. R. J. Org. Chem. 2001,66,6679-6684; k ) Garcia, M.B.;

Grilli, S.; Lunazzi, L.; Mazzanti, A,; Orelli, L. R. Eur. J Org. Chem. 2002, 24,4018-

4023; 1) Anderson, J. E.; de Meijere, A,; Kozhushkov, S. I.; Lunazzi, L.; Mazzant~, A. J.

Anz. Chem. Soc. 2002, 124,6706-6713; m) Casarini, D.; Rosini, C.; Grilli, S; Lunazzi.

L.; Mazzanti, A. Org. Chem. 2003, 68, 18 15-1820; n) Casarini, D.; Grilli, S.;

Lunazzi, L.; Mazzanti, A. J. Org. Chem. 2004, 69, 345-351; o) Bartoli, G.; Lunazzi, L.;

Massacesi, M.; Mazzanti, A. J. Org. Chem. 2004, 69,821-825; p) Casarini, D.;

Coluccini, C.; Lunazzi, L.; Mazzanti, A,; Rompieni, R. J, Org. Chem. 2004, 69, 5746-

5748.

Chapter 2 1 64

26 Lunazzi, L.; Mazzanti, A.; Minzoni, M. J. Org. Chem. 2007, 72, 2501-2507.

" Kolossovary, I.; Guisa, W. J. Am. Chem. Soc. 1993,115,2107-21 19.

'%anguly, B.; Freed, D. A.; Kozlowski, M. C.' Org Chem. 2001, 66, 1103-1 108.

"a) Moqneh, T. M.; Schofield, K.; Jones, R. A.; Kabitzky, A. R. J. Chem. Soc. 1962,

2637-2639; b) Sugiura, M.; Sasaki, Y. Chem. Pharm. Bull. 1976,22,2988-2992; c)

Lalonde, R. T.; Donvito, T. N. Can. J. Chem. 1974,52,3778-3783; d) Slough, G. A,;

Han, F.; Lee, B. H. Tetrahedron Len. 1999,40,3851-3854.

l o Jackson, W.R.; Jennings, W.B. Tetrahedron Lett. 1974,15, 1837-1838.

" a) Anderson, J. E.; Casarini, D.; ljeh, A. J.; Lunazzi, L. Am. Chen~. Soc. 1997, 119,

8050-8057; b) Casarini, D.; Lunazzi, L.; Mazzanti, A,; Foresti, E. Org. Chem. 1998,

63,4746-4754; c) Lunazzi, L.; Mazzanti, A.; ~ l v a r e z Muioz, A. JOrg Chem. 2000, 65,

3200-3206.

j2 a) Anet, F. A. L.; Basus, V. J. J Magn. Resort. 1978, 32, 339-343; b) Okazawa, N.;

Sorensen, T. S. Can J. Chem. 1978, 56,2737-2742; c ) Lunazzi, L.; Mazzanti, A,;

Casarini, D.; De Lucchi, 0 . ; Fabris, F. J. Org. Chem. 2000, 65, 883-888.

'' a) Johansen, J. T.; Vallee, B. L. Proc. nhf. Acad. Sci. USA 1971, 68,2532-2535; b).

Kessler, H. Fresenius Z. Anal. Chem. 1987, 327, 66-67; c) Burke, L. P.; DeBellis, A.

D.; Fuhrer, H.; Meier, H.; Pastor, S. D.; Rihs, G.; Rist, G.; Rodebaugh, R. K.; P. Shum,

S. P. J. Am. Chem. Soc. 1997,119, 8313-8323; d) Paulus, E. F.; Kun, M.; Matter, H.;

Vertesy. L. Am. Chem. Soc. 1998, 120, 8209-8221; e) Coluccini, C.; Grilli, S.;

Lunazzi, L.; Mazzanti, A. J.Org. Chem. 2003, 68,7266-7273; f) Perry, N. B.; Blunt, J.

W.; Munro, M. H. Magn. Reson. Chem. 2005,27,624-627.

l4 Lunazzi, L.: Mazzanti, A,; Minzoni, M.; Anderson, J. E. Org. Lert. 2005, 7, 1291-

1294.

" a) Anet, F. A. L.; Basus, V. J. J. Magn. Reson. 1978,32,339-343; b) Okazawa, N. ;

Sorensen, T. S. Can J. Chem. 1978,56,2737-2742; c) Lunazzi, L.; Mazzanti, A.;

Casarini, D.; De Lucchi, 0 . ; Fabris, F. J. Org. Chem. 2000,65,883-888.

36 Mayers, A. 1.; Elworthy, T. R.; J, Org. Chem. 1992,57,4732-4740.

" Mandell, L.; Singh, K. P.; Gresham, J. T.; Freeman, W. Am. Chrm. Soc., 1963,85,

2682-2683.

Chapter 2 165

Mandal, L.; Singh, K. P. ibid., 1961,83, 1766-1769.

l9 a) Saeki, S. Chem. Phann. Bull. Jun. 1961,9,226-233; b) Crabb, T. A,; Newton, R.

F.; Jackson, D. Chem. Rev. 1971, 71, 109-126; c) Cai, B.; Pan, Y.; Dewas, J. C.; Wink,

D. J.; Murphy, R. B.; Schuster, D. I. Tetrahedron Lett. 1993, 34,2067-2070.

Crabb, T. A.; Newton, R. F.; Jackson, D. Chem. Rev. 1971, 71, 109-126.

4' Johnson, C. D.; Jones, R. A. Y.; Katritzky, A. R.; Palmer, C. R. Schofield, K.; Wells,

R. J. J Chem. Soc., 1965,6797.

4' &imova, T. 1.; Kravchenko, N. S.; Denisenko, V. A. Telruhedron 2008,64,4204-

4208.

" a) Bradley, S. A,; Krishnamurthy, K. Magn. Reson. Chem. 2005,43, 117-123; b)

Willker, W.; Leibfritz, D.; Kersebaum, R.; Bermel, W. Magn. Rrson. Chem. 1993, 31,

287-290.

44 Hurd, R. E.; John, B. K. J. Magn. Reson. 1991,91,648-653.

41 a) Stott, K.; Stonehouse, J.; Keeler, 1.; Hwand, T.-L.; Shaka, A. J. J. Ant. Chem. SOC.

1995, 11 7,4199-4120; b) Stott, K.; Keeler, J.; Van, Q. N.; Shaka, A. J. J. Mugn. Reson.

1997,125,302-324; c ) Van, Q. N.; Smith, E. M.; Shaka, A. J . J Magn Reson. 1999,

141, 191-194; d) See also: Claridge, T. D. W. High Resolurion NMR Techniques rrt

Organic Chemistry; Pergamon: Amsterdam, 1999.