Application of carbon-13 nuclear magnetic resonance to the configurational analysis of stereoisomeric N,-methyl-Ng-acetylphlegmarines

ANDRZEJ LENIEWSKI' AND DAVID B. MACLEAN Department of Chemistry, McMaster University, Hamilton, Ont., Canada L8S 4Ml

AND

JOHN K. SAUNDERS Dipartement de chimie, Universiti de Sherbrooke, Sherbrooke (Qui.) , Canada J1 K 2RI

Received April 10, 1981

ANDRZH LENIEWSKI, DAVID B. MACLEAN, and JOHN K. SAUNDERS. Can. J. Chem. 59,2695 (1981). The carbon-13 chemical shifts of isomeric phlegmarines and analogues are presented. The chemical shifts at C-7 and C-9 confirm

the assignment of the stereochemistry at C-5. The stereochemistry at C-2' of the isomeric phlegmarines was assigned by comparing the observed shifts with those predicted from conformer populations and conformer shifts for the various conformers obtained by rotation about the (C-5, C-11) and (C-11, C-2') bonds. In particular it is possible to assign the relative configuration l b to the naturally occuning Nu-methyl-No-acetylphlegmarine.

ANDRZEJ LENIEWSKI, DAVID B. MACLEAN et JOHN K. SAUNDERS. Can. J. Chem. 59, 2695 (1981). On presente les deplacements chimiques du "C des phlegmarines isomeres et de leurs analogues. Les deplacements chimiques

des carbones en positions 7 et 9 confirment la stereochimie attribuee au carbone en position 5. On adeduit la stereochimie du carbone en position 2' des phlegmarines isomkres en comparant les deplacements observes i ceux attendus a partir des populations des conformkres et aux deplacements de divers conformkres obtenus par la rotation autour des liaisons (C-5, C-1 I) et (C-1 I, C-2'). En particulier il est possible d'attribuer la configuration relative l b i la Nu-methyl Ng-acCtylphlegmarine naturelle.

[Traduit par le journal]

We have recently reported a synthesis of (f )- N,-methyl-ND-acetylphlegmarine (1) that has es- tablished that the compound has the relative stereo- chemistry shown in structure l a or l b . Here we report an analysis of the 13C spectra of racemic l a and l b that has enabled us to derive the relative stereochemistry at C-2' in the two compounds and thereby to establish the relative stereochemistry of all five centres of the naturally-occurring alkaloid (2). The configurational assignment is based upon an approach recently developed by Beierbeck and Saunders (3). In the course of this work we also examined the 13C spectra of two other diastereom- ers of the alkaloid, 2a and 2b, and several interme- diates prepared in the synthetic work. The model compounds, trans -7-methyldecahydroquinolines 3, trans-N-acetyl-7-methyldecahydroquinoline 4, and the 2,2,5-trideutero derivatives of each were also prepared and examined to aid in the interpretation of the spectra. The data for all compounds are collected in Table 1.

7-Methyldecahydroquinoline was prepared by lithium aluminum hydride reduction of the tosyl hydrazone of ketolactam 5 according to an estab- lished procedure (4). Besides 3 the reduction mix-

'Present address: Institute of Fundamental Problems of Chemistry, Warsaw University, Pasteura 1, 02-093 Warsaw, Poland.

ture contained ca. 1% of monounsaturated product, probably the A5*l0 or Ass6 derivative of 3 or a mixture of the two. The trideutero derivative was prepared by reduction with lithium aluminium deuteride. The acetyl compounds, 4, and 4-d3, were prepared in the conventional manner.

In the spectrum of 3 the signals of the C-methyl and of the three methine carbon atoms were differentiated from the rest in the off-resonance spectrum. The methine carbon signals at 61.7,42.8, and 32.1 were assigned to C-9, C-10, and C-7, respectively, based on substituent effects. Of the six signals associated with methylene carbon atoms the signal at lowest field, 47.2, is assigned to C-2. (This signal is absent in the spectrum of the deuterated analogue.) The signal at 32.4 has been assigned to C-5. Not only does it undergo the expected isotopic shift (5) but it also appears as a triplet in the noise decoupled spectrum and is reduced in intensity because of deuteration. As- signments at C-3, C-4, C-6, and C-8 were made by comparison with the published spectra of trans- decahydroquinolines (6) and by calculation accord- ing to the approach of Beierbeck et al. (7). The observed and calculated spectra were in good agreement with the exception of the signal attrib- uted to the C-Me group.

In the N-acetyl compound 4 the signals at C-2, C-3, C-4, C-8, and C-10 are shielded with respect to

0008-4042/81/182695-08$01 .MI0 01981 National Research Council of Canada/Conseil national de recherches du Canada

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2696 CAN. J . CHEM. VOL. 59. 1981

the corresponding signals of 3 with the largest effect apparent at C-2. These assignments were made by comparison of the spectrum of 4 with that of 4-d,. The signals attributed to C-2 and C-5 are directly affected by deuteration while the signals at C-3, C-6, and C-10 show isotopic shifts. The signals at C-7 and C-9 were easily differentiated from the signals of the methylene carbon atoms in the off-resonance spectrum and were assigned by com- parison with the spectrum of 3. The assignment of signals to C-4 and C-8 was also made by compari- son with the spectrum of 3.

The spectrum of the trans-ketolactam 5 was also analysed and assignments were made by compari- son with the published spectra of cis-ketolactam 6 (8)2 and Zpiperidine (9).3 The assignments of signals to C-3 and C-4 were made by comparison with the spectrum of Zpiperidone and those to C-2

21n the published spectrum of 6 the assignments at C-8 and C-3 should be reversed.

'2-Pipendone: C-2 (173.1); C-3 (31.5); C-4 (21.9); C-5 (22.3); C-6 (42.0).

and C-5 as a consequence of their carbonyl charac- ter. The signals assigned to C-7, C-9, and C-10 are differentiated from the rest in the off-resonance spectrum and assignments made to each on the basis of substituent parameters. Of the two remain- ing signals, that at lower field is assigned to C-6 because of the proximity to the carbonyl group.

The assignment of signals in the spectra of 7 ,8 ,9 , 10, and 11 was made by off-resonance studies and by comparison with the spectra of 5 ,3 , a-picoline, and vinyl pyridine (10). The differences observed for the signals in the carbocyclic ring between 8 and 9 on the one hand and 10 and 11 on the other reflect the equatorial and axial character of the substit- uents at C-5 in the two pairs of isomers and are in accord with predictions (see ref. 5, p. 29).

The assignments made in the spectra of the isomeric pairs l a , 16 and 2u, 26 are based on comparison with the spectra of 4 and 1 ,Zdimethyl- piperidine (12).4 Again it is possible to differentiate the axial from the equatorial isomers at C-5, i.e. l a and l b from 2u and 26, on the basis of the chemical shifts of the carbon atoms at C-7 and C-9 of the carbocyclic ring. The distinction between l a and l b and between 2a and 26 is not as straightforward. However, inspection of the data in Table 1 reveals that in each series, C-5, C-6, C-11, C-2', and C-3' are more shielded in one molecule than in the other. There follows a detailed study of the assignments

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TABLE 1. Carbon-13 chemical shifts of isomeric phlegmarines and model compoundsa

Carbon

Compound

5 3 (obs)

3 (calcd) 34 4

4 - 4 7 8 9

10 11 lan lb" 2nn ?.b '

-

OAll samoles were run in solution in CDCI,: values are accurate to f 0.1 oom from internal TMS.

~ ~ h ; & c a l shifloiii;bonyl carbon atom = 169.8 (in 4-4 = 169.9ppm). OA gated decoupl~ng experiment showed that the doublet centered at 124.9 ppm did not have an addilional

differentiated from those at 124.3 and 121.5 ppm where an additlonal7 Hz coupling was observed coupling of ca. 7 Hz characteristic of "mero ' spin interactions In this way this signal was

~ ~

'C-6 and C-8 may be reversed. 'C-6, C-8, and C-l l may be interchanged. OC-3 and C-4' as well as C-4 and C-5' mav be reversed. "COMe and N-Me may be reversed

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2698 CAN. J . CHEM. VOL. 59, 1981

FIG. 1. Various conformations about the (C-5, C-11) bond in 2. FIG. 2. Conformation about the (C-11, C-2') bond in 2u.

of 2a and 2b in which the substituent at C-5 occupies the equatorial orientation.

The difference between 2a and 2b rests in the stereochemistry at C-2'. If one chooses as a refer- ence that enantiomer in which C-5, C-7, C-9, and C-10 have the R configuration it is then necessary to determine which isomer, 2a or 2b, has the R and which the S configuration at C-2'. This can be accomplished by using the method reported for acyclic hydrocarbons (3). Basically the method consists of determining conformer shifts for each orientation and using the sum of conformer popula- tion multiplied by conformer shifts to obtain the predicted shift for each carbon atom in the mole- cule. For the molecules of interest, rotation is possible about the (C-5, C-11) and the (C-11, C-2') bonds. Rotamer energies were estimated by con- sidering the number of gauche butane interactions (referred to as y interactions) and the number of 6 syn interactions. The y interaction is evaluated at 3.8kJmol and the 6 interaction at 15.4kJImol (13, 14).

There are three possible orientations about the (C-5, C-11) bond and these are shown in Fig. 1. Fortunately two, I1 and 111, can be neglected since these involve more severe steric interactions than those in I. For I1 the (C-11, C-2') bond is gauche with respect both to the (C-5, C-6) and the (C-5, C-10) bonds. For 111, the piperidine ring is syn with respect to the nitrogen containing ring and it is impossible for either stereoisomer to possess rot- amers without severe steric interactions. Thus only

conformers which have the rotamer denoted I about the (C-5, C- 11) bond need be considered. The three rotamers about the (C-1 1, C-2') bond for both the R and S stereoisomers are shown in Figs. 2 and 3, respectively.

For the R stereoisomer, conformer 1-1 has three y interactions, one between the N-CH, and C-11, one between C-3' and C-5, and one between C-6 and C-2'. The energy is thus evaluated at 11.4 kJ/mol. In conformer 1-2, there is an E interaction between the N-CH, and C-6 which is an extremely severe interaction and this rotamer can be neglected. For 1-3, there is a 6 syn interaction between C-6 and C-3', and y interactions between the nitrogen and C-5 and between the N-CH, and C-11. The relative energy of this conformer is thus evaluated at 23.4 kJ/mol which is significantly higher than that for conformer 1-1 and can be neglected. We can therefore conclude that the R stereoisomer exists predominantly as conformer I- 1.

For the S stereoisomer conformer 1-1 has a 6 interaction between C-3' and C-6 and a y interac- tion between the N-CH, and C-11 which gives an estimated energy for this conformer of 19.2 kJ/mol. For conformer 1-2, the relative energy is estimated to be 19.2 kJ/mol as this conformer has a 6 interac- tions between the N-CH, and C-5 and a y inter- action between C-6 and C-2'. The N-CH, could also exist in the axial orientation, conformer I-2',

SThe same energy value is estimated for a CH, placed on nitrogen as for a CH, on a carbon.

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LENIEWSKI ET AL. 2699

I- J

I FIG. 3. Conformations about the (C-1 I, C-2') bond in 2b.

which would alleviate the severe 6 interaction. The energy would then be estimated at 19.0kJlmol since there are 5 y interactions involved; N-CH3 with C-3', C-5', and C-11; C-6 with C-2'; and the nitrogen with C-5. The final conformer 1-3 has an estimated energy value of 26.8 kJ/mol (1 6 and 3 y interactions) which is significantly higher than that

for 1-1 or 1-2 and can therefore be neglected. We would thus predict that the S stereoisomer exists as a 1 : 1 : 1 mixture of I-1,I-2, and 1-2'.

From the predicted conformer populations for the two stereoisomers, the predicted chemical shifts for each conformer were calculated. This was accomplished by using the method (7) which takes a reference shift for each carbon atom and takes account of the number of 1,3 diaxial H,H interactions, the number of gauche C,C (or C,N) interactions, and the number of 6 syn interactions present in the molecule which are absent in the reference. The reference shifts for C-5 and C-6 are the corresponding shifts in 4, for C-11 the shift of the CH2 of propane, and for the C-atoms of the piperidine ring the corresponding shifts in 1,2- dimethylpiperidine. For C-5, an a shift is also necessary. Each time a 1,3-diaxial H,H interaction (henceforth referred to as an HC interaction) is present in the molecule of interest which was absent in the reference, an increment of +4.5 ppm is added. For each gauche interaction present in the molecule which was absent in the reference, a shift of 1.80 ppm is added to the italicized carbon

atom, and finally for each 6 interaction introduced a shift of 2.6ppm is added. The predicted shifts for each carbon atom in 1-1 in which C-2' has been assigned the R configuration are as follows

C-5 32.5 (reference) 6.0 (introduction of C-11)

-2.7 (replacement of H-4, H-5 interaction in reference by (C-4, C-lo), (C-5, C-11) gauche interaction)

1.8 gauche, ((C-2', C- 1 1), (C-5, C-6) interaction) - 37.6

C-6 35.1 (reference) 4.5 (HC interaction between H- 11 and H-6a) -

39.6

C- 1 1 17.6 (reference) 9.0 (HC interactions between H- 1 1 and H-6a and H- lOa) 4.5 (HC interactions between H-11 and H-3'a) 4.0 (HN interaction between nitrogen lone pair and H-11) 1.8 gauche, (C-6, C-5), (C-11, C-2') 1.8 gauche, (C-3', C-2'), (C-1 1, C-5) -

38.7

C-2' 59.4 (reference) 1.8 gauche, (C-5, C-11), (C-2', C-3') -

61.2

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2700 CAN. 1. CHEM. VOL. 59. 1981

C-3' 34.9 (reference) -4.5 (HC interaction between H-11 and H-3'e removed) - 30.4

For the S stereoisomer, the predicted shifts are

Rotamer I- 1 Rotamer 1-2 C-5 32.5 (reference) 32.5 (reference)

6.0 ( o r ) 6.0 (a) -2.7 (see R isomer above) -2.7 (see R isomer above)

4.5 (H-2' with H-5) 1.8 gauche, (C-2', C-11), (C-5, C-6) 1.8 gauche, (C-2', C-11), 2.6 (6 syn)

(C-5, C-6) - - 42.1 40.2

C-6 35.1 (reference) 35.1 (reference) 4.5 (H-11 with H-6a) 4.5 (H-11 with H-6) 2.6 (6 syn) - -

42.2 39.6

C- 1 1 17.6 (reference) 17.6 (reference) 9.0 (H-11 with H-10 9.0 (H-1 1 with H-10 and H-6)

and H-6) 4.5 (H-11 with H-3') 9.0 (2 x H-11 with 2 x H-3') 4.0 (H-11 with N) 4.0 (H-11 with N) 1.8 gauche, (C-3', C-2'), 1.2 gauche, (N-l', C-27, (C-11, C-5)

(C- 1 1 , C-5) 1.8 gauche (C-6, C-5), 1.8 gauche, (C-6, C-5), (C-1 1 , C-2')

(C- 11, c-2') - - 38.7 42.6

C-2' 59.4 59.4 4.5 (H-2' with H-5) 1.2 gauche, (C-5, C-11), (C-2', N-1') 1.8 gauche, (C-5, C-11),

(C-2', C-3') - - 65.7 60.6

C-3' 34.9 34.9 -4.5 (removal of H-3' with H-11)

2.6 (6 syn)

The differences between 1-2 and 1-2' are the following: for C-5 the 6 interaction is absent, C-6 is unchanged, for C- 11 the H-1 1 with N interaction is absent, for C-2' the HC interaction is replaced by a CC interaction, and for C-3' the H-3' with N interaction is removed. The predicted shifts for 1-2' are therefore: C-5,37.6; C-6,39.6; C-ll,38.6; C-2', 57.9; C-3', 30.9.

If we assume that the S isomer exists as a 1 : 1 : 1 mixture of I-1,I-2, and 1-2' then the predicted shift for C-5 is 40.0ppm, for C-6 is 40.5, for C-11 is 40.0ppm, for C-2' is 61.4, and for C-3',is 32.9ppm. The predicted shifts for all the carbons in the S

isomer are more deshielded than in the R stereo- isomer and we can therefore assign configuration. The results are summarized in Table 2.

The neglect of less highly populated conforma- tions will affect the absolute values of the predicted chemical shifts but will not change the sign of the difference between the two configurations.

The difference for the N-CH, group between the two stereoisomers is relatively small and for this reason it was not included in the analysis. In the R stereoisomer, it should appear at the same position as in 1,2-dimethylpiperidine, which it does. For the S stereoisomer, one would predict,

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iKI ET AL. 2701

TABLE 2. Observed and predicted chemical shifts for 2a and 2b

R S (2b)

I Observed Predicted Observed Predicted

' C-5 38.2 37.6 40.3 40.0 I C-6 41.4 39.6 43.0 40.5 I C-11 36.3 38.7 38.1 40.0 " C-2' 61.4 61.2 62.5 61.4

C-3' 30.6 30.4 32.6 32.9

TABLE 3. Observed and predicted chemical shifts for l a and l b

R (la) s (lb)

Observed Predicted Observed Predicted

C-5 36.9 34.7 35.2 32.2 C-6 40.2 37.8 38.4 36.9 C-1 l 30.3 30.8 28.3 29.5 C-2' 63.5 61.4 62.0 61.2 C-3' 32.0 33.4 30.4 30.6

relative to 1,2-dimethylpiperidine, an increment of i zero for conformer 1-1, an increment of 2.6 ppm (6

interaction) for 1-2, and an increment of -9.0ppm for conformer 1-2'. Thus this carbon is predicted to

I be shielded by 2.1 ppm in the S relative to the R , stereoisomer. Again the predicted sign of the I

difference between the two stereoisomers for these carbons corresponds to that observed.

; The assignment of stereochemistry for the ax- ially substituted compounds l a and 16 follows in a logical fashion since the same conformers are present. The R stereoisomer of 1 is the mirror image of the S for 2 with respect to the chiral centres at C-5 and C-2' and it is this compound which has the more deshielded carbons at 5 , 6 , 11, 2', and 3'. The analysis of the stereoisomers of 1 is summarized in Table 3.

The same situation is present with respect to the N-CH, group in the axial isomers, l a and 16, as that already discussed for the equatorial isomers, 241 and 26.

The analysis of the carbon-13 chemical shifts has permitted the assignment of the relative stereo- chemistry at the fifth asymmetric centre of the four molecules examined and has confirmed the assign- ment at other centres. It should be emphasized that both stereoisomers at C-2' were necessary to assign the stereochemistry at this carbon since it is the differences which are important rather than the absolute values.

In the previous paper on the phlegmarines (1) it was shown that 16 and N,-methyl-Np-acetylphleg- marine derived from nature had common physical properties in solution including the same Rf value

in several solvent systems. This study has there- fore resolved the relative stereochemistry of the alkaloid.

Experimental Apparatus, Methods, and Materials

The reader is referred to ref. 1 for complete details.

trans-(7H, IOH), trans-(9H, IOH-7-Methylde~ahydro~uinoline 3 and its 2,2,5-Trideutero Deriuatiue, 3-d3

Tosylhydrazone of 5 To a solution of trans-ketolactam 5 (905 mg, 5.0mmol) in

warm methanol (16mL), p-toluenesulphonylhydrazide (98%, 950 mg, 5.1 mmol) was added and the mixture kept at 5WC for 2 h. The precipitated product was filtered off when the solution had cooled. The tosylhydrazone (1.50g, yield 86%) melted at 199-200°C; ir v,,, (cm-I): 3405,3245 and 3180 (NH), 3080, 1605 (aromatic), 1675 (C=N), 1658, 1648 (C=O), 1352,1169 (S02N); 'H nmr SBoMHz (ppm): 1.04 (3H, d, J = 5.6Hz, CH-CH,), 2.44 (3H, s, phenyl-CH,), 5.9 (2H, br. s , NH), 7.3 and 7.8 (4H, AA'BB' system, aromatic protons).

Hydride (Deuteride) Reduction of Tosylhydrazone of 5 To a suspension of LAH (300 mg, -8 mmol) in T H F (40mL),

solid hydrazone (1.05 g, 3.0mmol) was added at room tempera- ture and the solution heated under reflux for 20 h. After cooling the mixture, water (8mL) and ether (60mL) were added. A white precipitate was filtered off and from the filtrate 135 mg of a colorless volatile slightly impure (tlc) solid were obtained. The white precipitate was treated with aqueous sodium hydroxide solution and the mixture steam distilled. The distillate (50mL) was collected and extracted with ether to give 134mg of the same product isolated above.

By the same procedure but using LAD instead of LAH 312 mg of deuterated compounds were obtained.

Pure 3 and 3-d, were obtained by transformation of the crude products to their N-acetyl derivatives, that were purified by chromatographic separation on alumina, and then hydrolysed in 20% H2S04.

N-Acetylation of 3 and 3-d, The same procedure was used in both cases. Crude 3 (135 mg)

was dissolved in absolute pyridine (4mL) and treated with acetyl chloride (0.3 mL) at WC. When the mixture reached room temperature, water was added (50 mL) and most of the pyridine was evaporated at reduced pressure. To the residue 10% aqueous HCI (5 mL) was added and the solution extracted with chloroform. The collected extracts were washed with water and dried over anhydrous MgSO,; 164mg of undeuterated and 160mg of deuterated amides were obtained as oils. Column chromatography on neutral alumina (activity 3, log) gave 138mg of the N-acetyl derivative of 3, and 130mg of the N-acetyl derivative of I d , , respectively, and 2mg of N-acetyl- 5,lO- or 5,6)-dehydro derivatives of each or a mixture of both were also obtained.

Compound 4: colorless oil, solidifying at temperatures below 0°C; 'H nmr 890MHz (ppm): 0.91 (3H, d, J = 6 Hz, CHCH,), 2.06 (3H, s,COCH,), 3.1 (IH, m, H-2a), 3.30(1H, m, H-9),3.70(lH, m, H-2e); ms: 195 (M+, 30), 180 (12), 152 (9), 138 (65), 136 (9), 96 (loo), 83 (I]), 82 (lo), 67 (8), 55 (15%).

Compound Qd,: colorless oil, solidifying at temperatures below WC; ms: 198 (M+, 47), 183 (8), 154 (6), 141 (74), 140 (6), 139 (9), 127 (2), 125 (2), 99 (loo), 86 (4), 84 (4%). N-acetyl-5,10(6)-dehydro-2-d2 derivative, colorless oil; ms:

196 (26), 195 (82), 180 (63), 166 (6), 153 (23), 152 (38), 138 (loo), 136 (36), 124 (39%).

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2702 CAN. J. CHEM. VOL. 59. 1981

Hydrolysis of N-Acetyl3 and N-Acetyl 3-d3 Portions (100mg) of the pure undeuterated and deuterated

acetamides were refluxed separately with 20% aqueous H,SO, (5 mL) for 6 h, 30% aqueous NaOH was carefully added to the cooled solution and the mixture extracted with chloroform yielding 3 and 3 d 3 as colorless, volatile solids. Compound 3 (68 mg, yield 87%), mp47-48°C; 'H nmr890MHz (ppm): 0.90(d, J = 6Hz, CHCH,), 2.12 (lH, m, H-9), 2.32 (lH, br s, NH), 2.64 (lH,td,J=11and4.5Hz,H-2a),3.10(lH,dofq,J=11.5and ~ H z , H-2e); 890MHz (C6D6) (ppm): 0.88 (d, J = ~ H z , CHCH,), 1.93 (lH, m, H-9), 2.48 (lH, m, H-2a), 2.92 ( lH, d of q, J = 12 and 3Hz, H-2e); ms: 153 (M+, 14), 152 (12), 138 (3), 136 (31, 125 (31, 124 (3), 112 (7), 110 (4), 96 (loo), 83 (91, 82 (81, 69 (6), 55 (12%). Exact Mass calcd. for C,,H,,N: 153.152; found (hrms): 153.153. Compound 3-d, (66mg, yield 84%), mp 47.5- 48°C; 'H I l m r 8 9 0 ~ ~ z (C6D6) (ppm): 0.90 (d, J = ~ H z , CHCH,), 1.90 (lH, br s, NH), 2.12 (IH, m, H-9); (C6D6) (ppm): 0.89(d, J = 6Hz, CHCH,), 1.94(lH, t ofd, J = 9and4Hz, H-9); ms: 156 (M+, 16), 155 (7), 99 (loo), 98 (5), 85 (7), 84 (7), 58 ( 9 , 56 (3), 55 (4%). Exact Mass calcd. for CloH16D3N: 156.170; found (hrms): 156.170.

Acknowledgements Financial support from the Natural Sciences and

Engineering Research Council of Canada is grate- fully acknowledged.

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