3 30 P. H . Benders et al. J 1,3-Dipolar cycloadditions to alkyldicyanamides

100 111) at 37°C for 2 h. HPLC analysis (systems I and 11) showed complete conversion of all oligomers 23-25 into the expected products. Data are collected in Table V.

h. Takadiastase T i : 10 pI of the stock solution was incubated with Takadiastase T, (Aspergillus oryzae, Boehringer, 2 pg) in 0.01 M Tris-HCI buffer (pH 7.5, 100 pl) containing 1 mM EDTA, at 37OC for 2 h. The products were analyzed by HPLC (system 111, Fig. 4). Quantitative data are given in Table V.

c. Venom phosphodiesterase (VPD): 10 pl of the stock solution was incubated with snake-venom phosphodiesterase (Crotalis terr. terr., Boehringer, 4 pg) in a buffer (100 pI) containing 25 mM Tris-HCI (pH 9.0) and 5 mM MgCI, at 37OC for 2 h. HPLC analysis (systems I and 11) showed complete conversion of oligomers 23-25 into the expected products. Data are given in Table V.

Yields of the purified lyophilized oligomers 23-25 (in the sodium form) were determined as follows. A portion ( 1 .O mg) of the oligo- mer was dissolved in water (50 pl) and the UV absorption of an appropriate dilution of this stock solution was measured. The E~~~ value for the oligomer was calculated by addition of the E valuesz6 for the mononucleotides and nucleosides and subse- quent correction for the hypochromicity of the oligomer. From the resulting E~~~ value the quantity of the pure nucleotide product in the lyophilized material was calculated. Yields of

23-25 are given in Table 111. Hypochromicities were determined by relating the quantity of the oligomers to the amount of the nucleotides released by venom phosphodiesterase (VPD) di- gestion, taking guanosine 3’-phosphate (Gp) as an internal standard. To a solution of the oligomer in venom buffer (100 pl, see c), a solution of G p (2 mg/ml, 20 pl) was added. After HPLC analysis (system 11). venom phosphodiesterase (VPD) was added, the mixture incubated at 37OC for 2 h and the products analyzed using HPLC (system I ) . Hypochromicities of 23-25 are given in Table 111. The conditions for the automatized sequence analysis of oligomers 24 and 25 by HPLC analysis of the monomers released by VPD digestion of the oligonucleotides were exactly as previously describedz9. The results for the hexamer 24 are given in Fig. 5. The results for the determination of part of the sequence of nonamer 25 are given in Fig. 6.

Acknowledgement

We thank Mr. C. Erkelens and Drs. A . J . Hartel, J . R. Mellema, P . P. Lankhorst and J. Doornbos for recording the NMR spectra.

1,3-Dipolar cycloadditions to alkyldicyanamides ’ * ’

P. H. Benders* and D. N. Reinhoudt

Laboratory of Organic Chemistry

and

D. M. W. van den Ham

Laboratory of Chemical Physics

Twente University of Technology, P. 0. Box 21 7 , 7500 A E Enschede, The Netherlands (Received February I l t h , 1981)

Abstract. The 1,3-dipoles 2,4,6-trimethylbenzonitrile oxide and benzyl azide react with alkyl- dicyanamides (1) to give the 3,5-disubstituted 1,2,4-oxadiazoles 2 and the 1,5-disubstituted tetra- zole 4, respectively, by (3 + 2)-cycloaddition. The structure of 4 has been determined by a single crystal X-ray analysis.

Introduction

In previous c o m m ~ n i c a t i o n s ~ ~ ~ on the chemistry of alkyl- dicyanamides (1) we have reported on the addition of various nucleophiles to one of the cyano groups of 1. The results led us to conclude that alkyldicyanamides belong to a class of activated cyano compounds such as perfluoro- and perchloro-alkyl cyanides, cyanates, sulfonyl cyanides, cyanoformates and cyanogen. Activated cyano compounds generally show enhanced reactivity towards 1,3-dipoles when compared with unsubstituted aliphatic nit rile^'-^ and in this paper we report on the reactions of methyl- and ethyl-dicyanamide with the 1,3-dipolar reagents 2,4,6-tri- methylbenzonitrile oxide and benzyl azide. Nitrile oxides add to the carbon nitrogen triple bond of various classes of cyano compounds, including not only the aforementioned activated ones, but also such compounds as aromatic and heterocyclic nitriles, cyanoguanidines,

’ Chemistry of alkyldicyanamides V; for part IV see ref. 4. P. H. Benders, Alkyldicyanamides. Synthesis and reactions with nucleophiles, Ph.D. Thesis, Twente University of Tech- nology, Enschede, The Netherlands, 1977. P. H. Benders, Recl. Trav. Chim. Pays-Bas 95, 217 (1976). P. H. Benders and P. A. E. van Erkelens, Synthesis 775 (1978).

’ R. Huisgen, Angew. Chem. 75, 604 (1963). ’ A . I . Meyers and J . C. Sircar, in “The Chemistry of the

Cyano Group”, 2. Rappoport editor, Interscience Publishers, London, 1970, p. 341.

’* E. Grigaf and R. Putter, Angew. Chem. 79, 219 (1967).

M . Hedayatullah, Bull. SOC. Chim. Fr. 1572 (1968). D. Martin and R. Bacaloglu, “Organische Synthesen mit Cyansaureestern”, Akademie-Verlag, Berlin 1980, p. 142. A . M. van Leusen and J . C. Jaqt. Tetrahedron Lett. 971 (1970). J . C. Jagf, Sulfonyl cyanides. Reactions with nucleophiles, dienes and 1,3-dipoles, Ph. D. Thesis, Groningen University, Groningen, The Netherlands, 1973.

‘D. Martin, Z. Chem. 7, 123 (1967).

Recueil, Journal of the Royal Netherlunds Chemical Society, l00/9, September 1981 331

etc. ' O-' '. Even simple, non-activated, aliphatic nitriles can participate in this reaction13 without the presence of a Lewis acid catalyst, as had been claimed earlier (see refs. 6 and 10). The reaction products are invariably 3,5-di- substituted 1,2,4-0xadiazoles '~-~~. In contrast to the number of reported cycloaddition reac- tions of cyan0 compounds with nitrile oxides, few examples of the corresponding reaction with organic azides can be found in the literature. The reactions of perfluoro- and perchloro-alkyl cyanides with alkyl and phenyl azideI4 are the only examples of nitriles undergoing cycloaddition with organic azides. Aryl cyanates failed to react with phenyl or tosyl azide" as did tosyl cyanide with tosyl azide','. How- ever, on refluxing in benzene with henzyl azide as the 1,3- -dipole, sulfonyl cyanides afforded the cycloadducts in high yields'. Cycloaddition of phenyl azide to tosyl cyanide re- quired more drastic conditions and the product was obtain- ed only in low yield'. Finally, the successful addition of or- ganic azides to ethyl cyanoformate has been reported but without details5. I". The reaction products were identified as 1,5-disubstituted tetrazoles. From the foregoing, two conclusions can be drawn. Firstly, organic azides are apparently much less powerful 1,3- dipoles than nitrile oxides with respect to a carbon nitrogen triplc hond. An analogou:, picture arises from kinetic studies of the reactions of benzonitrile oxide and phenyl azide with styrene and with phenylacetylene as dipolaro- philes'7.1x. Secondly. the 1.3-dipolar reactivity of organic azides is very dependent 011 thi: nature of the substituent present. Ih l s statement .I !,: I:,;- v , ~ l h tlic icaulL , , ! c . . ~ dition reactions of azidc., LO alet'inic doubh: bond:;, ~ ~ p i c , ~ l - ly in enaminesIX. In this context it should be einphabwd that on studying cycloaddition reactions of azides with tosyl cyanide, vuii Lcu.scn and Jug/" observed a difference in the reactivity ofthe 1,3-dipoles similar to that found by Huisgen and coworkers in reactions of azides with electron deficient alkenesI8. In both cases benzyl azide proved to be the most reactive 1,3-dipole.

Results

We found that methyl-(1, R = CH,) and ethyl-dicyanamide (1, R = C,H,)" react with 2,4,6-trimethylbenzonitrile oxide at room temperature to give 5-(N-alkyl-N-cyanami- no)-3-(2,4,6-trimethylphenyl)- 1,2,4-oxadiazoles (2) in al- most quantitative yields.

e

. N ' C z N

1 CH3 CH3

2 3 Mass spectrometry and elemental analysis clearly showed that the reaction products were 1 : 1 adducts. By analogy with previous results the orientation of addition can be assumed to be as shown, resulting in the formation of the 1,2,4-oxadiazole 2. This structure is supported by the presence of a strong fragment in the mass spectra at mje 159 corresponding to the ion 3. This fragmentation pattern has been previously observed in the mass spectra of 5-alkyl-3- aryl- 1,2,4-oxadiazoles l 3 and of 1,2,4-oxadiazoles with elec- tron releasing groups in the 5-positionZo-*'. The alternative fragmentation pattern of 3,Sdiaryl- 1,2,4-oxadiazoles has been shown to involve a formal retro 1,3-dipolar cyclo- addition". The required fragments for such fragmentation at m/e 161 and/or 81 or 95 in the spectra of 2 are of low intensity (< 5 z). The IR, 'H and I3C N M R spectra of 2 are in agreement with the assigned structure.

For reactions of alkyldicyanamides with organic azides we selected benzyl azide, because this has been found to be the most reactive I ,3-dipole with respect to electron deficient dipolarophiles (vide supra). Methyldicyanamide (1, R = CH,) was heated for 70 hours at ca. 120°C in a 4.6 M benzyl azide solution in chloroform to give l-benzyl-5- (N-cyano-N-methy1amino)tetrazole (4) in 60x, yield.

4

The reaction product was shown to be a 1 : 1 adduct by mass spectrometry and by elemental analysis. The regioselective formation of 1,s- rather than of 3,S-disubstituted tetrazoles from the reaction of perhaloalkyl cyanides with organic azides has been established by an independent synthesis of the reaction productsI4. In the case of cycloadducts of sulfonyl cyanides, evidence for the structure of a 1,5-di- substituted tetrazole was based only on the presence of a singlet (rather than a broad multiplet) for the phenyl protons in the 'H NMR spectrum of the reaction product of tosyl cyanide with phenyl azide'. Since we were not able to differentiate between the two possible structures for the 1 : 1 adduct of methyldicyanamide with benzyl azide on the basis of IR, 'Fi dtid 'C N"i< s w L ~ ~ z i , wr c " i icc i out an X-ray analysis pi dvide dellnite strucl urL p1.c)oi'. 1.1.g. i 1:: 2 sure0 plot" showing the mol~ .u la r :truotilre. 8;'rici lengths and angles are given in Table 1.

Experimental

Melting points were determined using a Mettler FPI instrument; values are given uncorrected. 1R spectra were recorded on a Perkin-Elmer 257 spectrophotometer and NMR spectra on a

l o Reviews: C. Grundmann, Synthesis 344 (1970). ' C. Grundmann and P. Grunanger, "The Nitrile Oxides",

Springer-Verlag, Berlin 1971, p. 130. K. Bast, M. Christl, R. Huisgen and W. Mack, Chem. Ber. 105, 2825 (1972).

I Z a G. Remharz, E. Fischer and F. Tittelhuch, J. Prakt. Chem. 313, 1065 (1971).

' C . Remharz, E. Fischrr and R. Behm, J. Prakt. Chem. 318. 479 (1976).

l 3 P. Beltrame, G. Gelli and A. Loi, J. Chem. Res. (S), 420 (1978). l 4 W. R. Carpenter, J. Org. Chem. 27, 2085 (1962); in this paper

cycloaddition of n-octyl azide to the C=N triple bond of 5-cyano-2-methyltetrazole is also reported. In addition. the intramolecular cyclization of 2-azido-2'-cyanobiphenyl has been described (see ref. 6). D. Martin and A . Weire, Chem. Ber. 99, 317 (1966).

l 6 The adducts from ethyl cyanoformate with phenyl azide (m.p. 84-85°C) and with p-nitrophenyl azide (m.p. 120- 121OC) were isolated in yields of 17 and 3%. respectively. R. Huisgen and L. Miihius, private communication.

l 7 Ref. lob, p. 92. l a R. Hui.rgen, G. S2eimie.r and L. Mlihius, Chem. Ber. 100, 2494

( I 967). l 9 C.A. names: Cyanomethylcyanamide [35840-- 17-61 and

Cyanoethylcyanamide [35687-57-11, 2 o L. B. Clapp, in "Advances in Heterocyclic Chemistry",

Vol. 20, 65, A . R. Katritzky and A. J . Boulton editors, Aca- demic Press, New York, 1976. A . J. Wittrueen, W. P. Trompen and J. Th. Hackmunn, Recl. Trav. Chim. Pays-Bas 89, 121 (1970).

2 2 C. K. Johnson, ORTEP, Report ORNL-3794. Oak Ridge National Laboratory, Oak Ridge, Tennessee (1965).

3 32 P. H . Benders et al. I,-l-Dipolar cycloadditions to alkyldicyanamides

Table I Bond lengths

I Atoms Distance I Atoms Distance

CI-C2 CI-C6 CI-H4 C2-C3 C2-H5 c 3 - c 4 C3-H6 c 4 - c 5 c 4 - c 7

1.365 (.011) 1.377 (.01 I ) 1.065 (.071) 1.364 (.010) 1.198 (.086) 1.377 (.014) ,807 (.054)

1.404 (.014) 1.498 (.009)

Bond unyles (")".

Atoms

C2-Cl-C6 C2-Cl-H4 C6-Cl-H4 CI - c 2 - c 3 Cl-C2-H5 C3-C2-H5 c2 -c3 -c4 C2-C3-H6 C4-C3- H6 c3 -c4 -c5 c3 -c4 -c7 c5 -c4 -c7 C4-CS-C6 C4-CS-H7 C6-C5-H7

Angle

119.1 (1.0) 115.9 (5.3) 124.9 (6.7) 120.4 (1.0) 115.4 (5.5) 124.3 (6.9)

121.5 (6.2) 116.4 (5.5) 117.3 (0.9) 123.1 (0.9) 119.5 (0.9)

114.3 (5.8) 125.3 (7.4)

122.0 (1.0)

120.2 (1 .O)

C5-C6 C5-H7 C6-H8 C7-N8 C7-H9 C7-H 10 N8-N9 N8-C 12 N9-N 10

1.368 (.011) .905 (.069)

1.008 (.078) 1.487 (.014) .967 (.067)

1.086 (.051) 1.361 (.009) 1.335 (.010) 1.283 (.014)

Atoms Distance

NlO-NIL 1.364 (.006) Nll-C12 1.312 (.013) C12-N 13 1.368 (.007) N13-Cl4 1.482 (.013) N13-Cl5 1.349 (.014) C14-HI 1.036 (. 126) C14-H2 ,885 (.062) C14-H3 ,829 (.068) C15-NI6 1.134 (.014)

Atoms Angle

C1 -C6-C5 Cl-C6-H8 C5-C6-H8 C4-C7-N8 C4-C7-H9 C4-C7-H10 N8-C7-H9 N8-C7-H10 H9-C7-H10 C7-N8-N9 C7-N8-C 12 N9-N8-C12 N8-N9-N10 N9-N 10-N 11

121.0(1.1) 118.0 (6.6) 120.4 (6.6) 113.2 (0.9) 106.2 (4.7)

107.6 (4.6) 105.0 (3.1) 115.0 (6.3) 118.1 (0.8) 134.2 (1.1) 107.7 (0.8) 106.2 (0.8) 1 1 1.5 (0.8)

110.0 (3.4)

a Estimated standard deviations are given in parentheses and refer to the last digits.

Atoms Angle I NlO-NlI-Cl2 N8-C 12-N 11 N8-CI2-Nl3 Nl l -CI2 -Nl3 C12-N 13-C14 C12-Nl3-Cl5 C14-N 13-C15 N13-C14-H 1 N13-C14-H2 N 13-C14-H3 H1 -C 14-H2 H1 -C l4-H3 H2-C l4-H3 N13-C15-N 16

105.1 (0.8) 109.6 (0.7) 127.9 (0.9) 122.5 (0.9) 118.5 (0.8) 123.5 (1.1) 1 1 5.9 (0.8) I 13.5 (9.2) 102.9 (4.5) 1 1 1.4 (5.9) 116.7 (1 1.0) 93.7 (8.0)

119.0 (9.8) 175.3 (1.0)

Fig. I.

Varian XL-100 with tetramethylsilane (6 = 0 ppm) as internal standard, Mass spectra were obtained using a CEC 21-1 10B spectrometer. Elemental analyses were carried out in the Institute for Organic Chemistry TNO, Utrecht, The Netherlands, under the supervision of Mr. W . J. Buis. The alkyldicyanamides ( l ) were prepared as described previ-

Stereo plot of 1 -benzyl-5- (N-cyano-N-methylami no) tetrazole (4)

Reactions of methyl- and ethyl-dicyanamide with 2,4,6-trimethyl- benzonitrile oxide

A solution of 1.61 g (10 mmol) of 2,4,6-trimethylbenzonitrile oxide24 in 10 ml of methylene chloride was added to 10 mmol of the alkyldicyanamide (1) dissolved in 10 ml of the same solvent. After stirring for 5 h at room temperature the solvent was re- moved under reduced pressure (temp. C20"C). The residue

2 3 P . H. Benders and J . Th. Hackmann, Recl. Trav. Chim. consisted of nearly pure cycloadduct 2. The analytical samples were obtained by recrystallization from ethyl acetate (2, R =

*4 C. Grundmann and J . M . Dean, J. Org. Chem. 30, 2809 CH,) and from petroleum ether (60-80"C)lbenzene (2, R = C, H 5)r respectively.

ously2JJ.

Pays-Bas 91, 343 (1972).

( 1965).

Recueil, Journal of the Royal Netherlands Chemical Society, 10019, September 1981 333

5 - [ N- Cyano-N-merhylamino) -3- (2,4,6-trimethylphenyl) - 1.2.4- oxadiazok (2, R = CH,): m.p. 138-139"C (dec.). IR (KBr): 2265 cm- ' (C=N), 1630, 1615, 1605 cm- ' (C=N)*'. ' H NMR (CDCI,): 6 2.21 ppm (s, 6H, o-CH,), 6 2.31 ppm (s, 3H, p-CH,), 6 3.56 ppm (s, 3H. CH,N), 6 6.94 pprn (s, 2H, ArH). 13C N M R (CDCI,): 6 20.0 pprn (q, o-CH,), 6 21.1 ppm (q, p-CH,), 6 38.4 ppm (q, CH,N), 6 108.3 ppm (s, C=N), 6 122.7 ppm (s, Arc) , 6 128.4 ppm (d, ArC-3,5), 6 137.5, 140.1 ppm (s, Arc). 6 166.8, 169.3 ppm (s, C-3jC-5). MS (70 ev) m/e ( I%, fragment): 242.1 12 (97, M .), 159.093 (79, Mt-C,H,N,O.). C,,H,,N,O (242.28): calcd. C, 64.45; H, 5.82; N, 23.13; 0, 6.60; found C, 64.51; H, 5.86; N, 23.07; 0, 6.64.

5 - (N-Cyano-N-erhylamino) -3- (2,4,6-trimeth,vlphenjl)-l,2,4-o.~a- diazole (2, R = C,H,): m.p. 113.5--1 14.5" (dec.). IR (KBr): 2250 cm- ' (C=N), 1610, 1600 c m - ' (C=N)". ' H N M R (CDCI,): 6 1.51 ppm (t, 3H, CH,), 6 2.22 ppm (s, 6H, o-CH,), 6 2.31 ppm (s, 3H, p-CH,), 6 3.93 ppm (q, 2H, CH,), 6 6.95 ppm (s. 2H, ArH). "C NMR (CDCI,): 6 12.7 ppm (9. CH,), 6 20.0 ppm (q. o-CH,), 6 21.1 ppm (q, p-CH,). 647.4 ppm (1. CH,), 6 107.3 pprn (s, C=N), 6 122.7 ppm (s, Arc), 6 128.4 ppm (d, ArC-3,5), 6 137.5, 140.0 ppm (s, Arc) , 6 166.5, 169.2 ppm (s, C-3/C-5). MS (70 ev) m/e (:<, fragment): 256.130 (63, M:), 159.091 (58, Mt-C,H,N,O'). C,,H,,N,O (256.31): calcd. C, 65.61; H, 6.29; N, 21.86; 0, 6.24; found C, 65.65; H. 6.21; N, 21.68; 0, 6.25.

Reacrion of meihyldicjanamide with hmz.vl azide

A solution of benzyl azide in chloroform was prepared by slightly modifying the procedure of Curfius and Ehrhart26. The reaction mixture was poured into 80 ml of water. The separated oily benzyl azide was washed with 30 and with 15 ml of water resp., taken up in chloroform (ca. 13 ml) and dried over anhydrous calcium chloride. The approximate concentration of benzyl azide was estimated by means of ' H N M R spectrometry. A mixture of 2.43 g (30 mmol) of methyldicyanamide and 7 ml of a 4.6 M benzyl azide solution in chloroform was refluxed for 70 h in an oil bath at cu. 120°C. After removal of the solvent the residue was treated with a little ethanol. The solid was isolated by filtration with suction and washed thoroughly four times with ethanol. Yield 60 7;. Recrystallization from ethanol afforded the analytically pure I-benzyl-5-(N-cyano-N-methylamino)tetrazole (4). m.p. 101-102'C. IR (KBr): 2240 cm- ' (C=N). ' H N M R (CDCI,): 6 3.48 ppm (s, 3H, CH,), 6 5.67 ppm (s, 2H, CH,), 6 7.34 ppm (s, 5H, ArH). I3C NMR (CDCI,): 6 40.5 ppm (q, CH,). 6 51.1 ppm (t, CH,), 6 109.8 ppm (s, C=N), 6 127.7, 128.9 ppm (d, Arc) , 6 132.5 ppm (s, Arc-I ) , 6 150.1 ppm (s, C-5). MS (70 ev) m/e ( x , fragment): 214.096 (16, M f ) , 91.055 (100, C7H7') . C l o H l o N , (214.23): calcd. C, 56.07; H, 4.71; N. 39.23; found C. 56.16; H, 4.86; N. 39.07.

X-ray structure analysis

Cell constants and intensity data were obtained at ambient tem- perature using a single-crystal diffractometer (Philips P W I 100) and graphite monochromated Mo K, radiation, h = 0.7107 A. Crystal data C,,HloN,: monoclinic, P2,, a = 11.827(4), h =

D, = 1.337 g cm- , . For data collection the 0-28 scan mode was applied. The scan speed was 0.025' s - I , scan width 1.8'. 8 values ranged from 2 to 30". The data set contained 1257 reflections of which 896 had intensities greater than the standard deviation. These reflections were used for refinement. The structure was solved with the aid of the Multanz8 programme and the refinement was carried out using a local version of ORFLSZ9. The parameters varied in the last cycle of refinement were: positional parameters of all atoms, anisotropic thermal parameters of the non-H atoms, isotropic thermal parameters of the H atoms and the scale factor. The weighted R value was 0.041.

6.138(1), c = 7.611(2) A, p = 105.69(2)", V = 531.9 A,. Z = 2,

Acknowledgements

Our thanks are due to Mr. P . G. J . de Boer for his contribu- tion to the experimental work and to Dr. R. Vissrr for discussion of the spectroscopic properties of the new compounds.

2 5 The IR spectra of 1,2,4-oxadiazoles show absorption from the C=N group between 1560 and 1590 cm- ' which is shifted to a higher wavenumber (1660 c m - ' ) in the spectrum of 5- amino-3-phenyl- 1 ,2,4-oxadiazole2". T. Curtiuc. and G. Ehrhart. Ber. Dtsch. Chem. Ges. 55, 1559 (1922). The benzyl azide was distilled (b.p. 82.5"C/16.5 mmHg) by these authors, but it has also been mentioned as being a particularly heat-sensitive explosive oilz7. We therefore used the crude azide in solution.

2 7 L. Eretherick, Handbook of Reactive Chemical Hazards, second edition, Butterworths, London 1979, p. 634.

2 x G. Germain, P. Main and M . M . Woolfj-on, Acta Crystallogr. Sect. A 27, 368 (1971).

") W. R. Busing, K . 0. Martin and H . A . Lecy. ORFLS, Report ORNL-TM-305, Oak Ridge National Laboratory. Oak Ridge, Tennessee (1962).

2 h

An efficient synthesis of 3-arylpiperidines

H. J. J. LooZen* and F. T. L. Brands

Organon Scientific Development Group, P.O. B0.r 20, 5340 BH Oss, The iVrther1and.s (Receitred March 6th. 1981)

Abstract. An alternative route to 3-arylpiperidines is described, thereby circumventing traditional Michael addition of substituted phenylacetonitriles to methyl acrylate. Treatment of (3-methoxy- pheny1)acetonitrile (2) with the THP ether of 3-bromo- I-propanol, followed by chromic acid oxidation and saponification provided 2-( 3-methoxyphenyl)glutaric acid (6). Treatment of the corresponding anhydride 7 with alkyl- and arylalkylamines provided the imides 8a-c. Replacement of the methoxy group by a benzyloxy group, followed by LiAIH, reduction and a catalytic reduction provided 1, 12 and 13.

I' M. Julia, E. Millet and J. Boqoi. Bull. SOC. Chim. Fr. 987 ( 1968). M. Julia, 0. Siff&-r and J. Bugor, Bull. SOC. Chim. Fr. 1000 (1968). ' H. Kugita, H. Inoue, T. Oine, G . Huyushi and S. Nurimoio,

J. Med. Chem. 7, 298 (1964).

Introduction

3-Arylpiperidines have received major attention in phar- macochemical literature as bearing potent analgesic pro- perties'"-c. Recently attention was focussed on this class of