Starting from aliphatic y-orr: 11-halonitriles and a-bromoesters,
w -halo-~-ketoesters, 2-substituted ~1 -pyrrolines or 2-substituted
~ 1-piperideines, were obtained. Some of the chemical and spectroscopic
properties of the prepared compounds are described

L. Arsenijević

V. Arsenijević

English

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CCA-528 C R 0 AT I C A CHE MIC A A C TA 41 (1969) 1 547.743.1 :547.822.3.07 Original Scientific Paper The Reformatsky Reaction with Aliphatic Y- and b-Halonitriles. The Synthesis of Some 2-Substituted ~1 -Pyrrolines and ~1 -Piperideines* L. Arsenijevic and V. Arsenijevic Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia, Yugoslavia Received July 19, 1968 Starting from aliphatic y-orr: 11-halonitriles and a-bromoesters, w-halo-~-ketoesters, 2-substituted ~1-pyrrolines or 2-substituted ~1-piperideines, were obtained. Some of the chemical and spectro-scopic properties of the prepared compounds are described. The reaction of a-bromoesters containing a tertiary (III), a secondary (IV) or a primary (V) bromine atom with aliphatic y or b-halonitriles (I and II) in the presence of zinc was investigated. Different products were obtained de-pending on reaction conditions. If the reaction was carried out in ether, tet-rahydrofurane or benzene, the main product was the corresponding w-halo--B-ketoester (VI, VII VIII and IX), but if anisole was employed as solvent, 2-substituted LV-pyrroline (XI) or 2-substituted LV-piperideines (XIII and XIV) were obtained. In both cases the reaction probably occurred as in the Grignard reaction with the same halonitriles.1- 6 Consequently, the preparation of these compounds was performed according to the reactions Scheme. Some chemical transformations of the primarily obtained compounds (VII, XI and XIV) are also described in this paper. Thus, the w-halo-B-ketoester (VII) was submitted to ketonic hydrolysis giving the corresponding w-chloroketone (X). The esters XI, XIII and XIV were decarbalkoxylated by heat1ng with 10 N sulphuric acid, giving 2-isopropyl 1\1-pyrroline (XII) and 2-isopropyl ~1-piperideine (XV), respectively. The hy-drogenation of the later gave 2-isopropylpiperidine (XVI). The structure of compound XI was confirmed by elemental analysis and by spectroscopic examination. In the infrared the compound XI has no band in NH region, but at 1639 cm.-1 it has ain intense absorption band chara-cteristic for the nonconjugated C = N group . . If this azomethiine group is pro-tonated by preparation of the picrolonate or the perchlorate, it causes in the infrared a hypsochromic 41 cm.-1 shift, also observed by other authors.7 The IR spectrum of perchlorate (hexachlorobutadiene mull) gives three peaks (im-monium band) at 1900-2200 cm.-1, while the ammonium band is absent. The absence of this band may be attributed to the intramolecular hydrogen bond * The paper was presented at the 2nd Yugoslav Conference for Pure and Applied Chemistry, Belgrade, June 1966. R' R R' I Zn ""/ X-(CH2)n-CN + R-C-COOR" -X-(CH2)u-C-C-COOR" I 11 Br N-ZnBr I n=3; X=Br III R=R'=CH3; R"=Et II n=4; X=Cl IV R=CHs; R' =H; R"=Et I H+ V R=R'=H; R"=CH3 R R' "'-/ X-(CH2)11-CO-C-COOR" SCHEME -Zn(Br)X / ""' VI R=R'=CH3; R"=Et; n=3; X=Br H+ -----VII R=R'=CHs; R"=Et; n=4; X=Cl l VIII R=CH3; R' ~=H; R"=Et ; n=4; X=Cl Cl-(CH2)4-CO-CH(CHsh x IX R=R'=H; R"=CHs; n=4; X=CI CH3 Od-cooEt I CHs XI CHs 06-cooR" I CH3 XIII R"=CHs XIV R"=Et H+ H+ CH3 Q~H-CHa XII CHa ·01 N"' CH-CHa xv H2, Pt02 OcH(CHah I H XVI !:\!)- r > !:d Ul M z H '-' M < H ("} > z tJ ~ > !:d Ul M z H '-' M < H (') THE REFORMATSKY REACTION 3 between the carbonyl of ester and the hydrogen of C = NH group.* The presence of this intramolecular hydrogen bond is confirmed by the fact that in the spectrum of perchlorate of XI the carbonyl of ester gives absorption at 1680 cm.-1, while this group in unprotonised compound XI absorbs at the normal position (1735 cm.-1). In the IR spectrum of picrolonate of XI both the am-monium and the immonium bands are very weak (KBr pellets and hexachloro-butadiene mull), which has been observed in some LV-pyrrolines.i' In the NMR spectrum of XI, the vinyl proton was absent; the spectrum showes a triplet centered at 't = 6.3 (Ha'), a triplet centered at r = 7.61 (HB) and a multiplet centered at 't = 8.18 (HB') which is consistent with the presence of a i\ 1-pyrroline ring. That the pyrroline ring was not changed during the decarbalkoxylation of XI in strong acidic medium, can be shown by the following** : a) The IR spectrum of XII has no band in the NH region, either, while at 1648 cm.-1 iit gives absorption for the C = N group. The spectrum of its hy-drochloride (hexachlorobutadiene mull) showes a strong ammonium band at 2550 cm.-1, three peaks (immonium band) at 1900-2200 cm.-1 and a strong band at 1683 cm.-1 (protonated azomethine group). In contrast to this, in the spectrum of its picrate these bands are very weak.9 The NMR spectrum of XII showes a triplet centered at 't = 6.36 (Ha'), a multiplet centered at • = 7.66 (H B and H tert.) and a multiplet centered at r = 8.21 (H B') while the vinyl proton is absent. b) Compound XII prepared directly, i.e . by reaction between y-bromo-butyronitrile and isopropylmagnesium bromide in boiling xylene, was identical (IR spectra and mixed m. p. of picrates) with the compound obtained by decar-balkoxylation of XI. The Grignard synthesis was carried out as it was described for preparation of 2-ethyl i\1-pyrroline.4 The structure of the compound XIV was proved by its IR spectrum as well as by its conversion into known substances XV and XVI. Our conclusion about the i\1-position of the double bond in the pyrroline and piperideine ring in our compounds is in agreement with the results obtained by other authors 11 usiing different methods. EXPERIMENTAL Melting points were determined on a Kofler heating microscope. The IR spectra were recorded on a Perkin-Elmer spectrophotometer model 237. The NMR spectra were recorded on a Varian A-60 spectrometer with tetramethylsilane as internal standard. Carbon tetrachloride was used as solvent. Ethyl 6-bromo-2,2-dimethyl-3-oxohexanoa.te (VI) A mixture of halonitrile I (14.8 g., 0.1 mole), zinc wool (7.8 g., 0.12 at.), a-bromoe-ster III (23.4 g., 0.12 mo.le), a few mg. of mercuric chloride and 70 ml. of dry ether was stirred and heated. After a while the reaction started and if it became too vigo-rous the flask had to be cooled in cold water. When the reaction rate decreased, the mixture was refluxed and stirred for 3 hours; a white precipitate was formed and most of the zinc was disolved. The reaction mixture was then cooled and decomposed * In a similar example,8 the absence of the ammonium band is attributed to the strong intramolecular hydrogen bonding. ** Resistance of the 2-substituted ~ 1-pyrroline ring to acids was earlier ob-served.10 4 L. ARSENIJEVIC AND V. ARSENIJEVIC by stirring with 100/o ice-cooled sulphuric acid (300 ml.) for 30 minutes. The aqueous layer was separated and extracted with ether. The combined ethereal layers were shaken with sodium bicarbonate sOilution, and water and dried with MgS04. The solvent was removed and the res'idue distilled in vacuo, b.p. 148f'/14 mm. Ylield 9.2 g. (350/o). IR spectrum (Hqu~d film): 1718 s (ketone CO), 1745 s (ester CO) cm.-1• Anal. C10H 17Br03 (265.23) calc'd.: C 45.34; H 6.45°/o found: C 45.53; H 6.500/o Ethyl 7-chloro-2 ,2-dimethyl-3-oxoheptanoate (VII) Prepared as before from halonitrile II (23.4 g., 0.2 mole), zinc (15.6 g., 0.24 at.) and a-bromoester III (47 g., 0.24 mole) in 200 ml. of dry benzene. The haloketoester VII has, b.p. 150°/9 mm. Yield 23 g. (480/o). IR spectrum (liquid film): 1710 s (ketone CO), 174:.; s (ester CO) cm.-1• Anal. C11H19Cl08 (234.65) calc'd.: C 56.40 ; H 8.12% found: C 56.41; H 8.370/o Ethyl 7 -chloro-2-methy l-3-oxoheptanoate (VIII) Prepared as before from halonitrile II (11.7 g., 0.1 mole), zinc (13 g., 0.2 at.) and a-bromoester IV (36.2 g., 0.2 mole) in 100 ml. of dry benzene. Haloketoester VIII has b. p. 150-151°/12 mm_ Yield 8.5 g. (380/o). IR spectrum (liquid film): 1714 s (ketone CO), 1740 s (ester CO) cm.-1• Anal. C10H11Cl03 (220.68) calc'd.: C 54.39; H 7.760/o found: C 54.42; H 7.720/o Methyl 7-chloro-3-oxoheptanoate (IX) Halonitrile II (11.7 g., 0.1 mole), zinc (13 g., 0.2 at.), mercuric chloride (O.l g.) and 50 ml. of dry tetrahydTofuraine were placed in a flask aind the mixture was heated to boiling where upon a solution of a-bromoester V (30.6 g., 0.2 mole) in 50 ml. of tetrahydrofurane was added dropwise,12 over a period of 40-50 minutes. The boiling was continued for 2 hours. The solvent was removed by distillation, at atmospheric pressure and finally in vacuo. Then 100 ml. of benzene was added and the solution was treated in the same way as VI. Haloketoester IX has b. p. 154°/17 mm. Yield 6.2 g. (400/o). IR spectrum (liquid film): 1720 s (ketone CO), 1750 s (ester CO) cm.-1• Anal. C8H13Cl03 (192.63) calc'd.: C 50.00; H 6.61% found: C 50.38; H 6.61% 7-Chloro-2-methyl-3-heptanone (X) Haloketoester VII (4 g.), p-toluenesulphonic acid (2 g.) and 80°/o. acetic acid (12 ml.) were heated under reflux for 3 hours. The reaction mixture was cooled, neutralized with potassium carbonate solution and extracted with ether. The organic layer was washed with water and dried with MgS04. The ether was removed and the residue was distilled, b. p. 109°/15 mm. Yield 2 g. (700/o). Anal. C8H15Cl0 (162.66) calc'd.: C 59.04; H 9.320/o found: C 59.30; H 9.540/o 2,4-D in it r op hen y l hydra zone: m. p. 370 (ethanol). Anal. C14H19ClN404 (342.77) calc'd.: N 16.340/o found : N 16.370/o Ethyl 2-methyl-2(!'l1-pyrrolinyl-2)-propionate (XI) Halonitrile I (7.4 g., 0.05 mole), zinc (3.9 g., 0.06 at.), mercuric chloride (0.1 g.) a-bromoester III (12 g., 0.06 mole) and dry anisole (25 ml.) were heated carefully to initiate the reaction. When the reaction rate decreased, the mixture was refluxed for further 30 minutes. After cooling, 80 ml. of ice-cooled 100/o sulphuric acid was THE REFORMATSKY REACTION 5 added and the mixture was stirred 15 minutes. The aqueous layer was washed twice with ether, cooled to o0, made strong alkaline with potassium hydroxide (pellets) and the base was extracted with ether. The combined ethereal extract was shaken with saturated sodium chloride solution and dried with potassium hydroxide. Ether was removed and the residue distilled in vacuo, b. p. 108-110°/16 mm. Yield 4.8 g. (55%). Anal. C10H11N02 (183.24) calc'd.: C 65.54; H 9.35; N 7.64°/o found : C 65.48; H 9.49; N 7.710/o Pi c r o 1 on ate: m. p. 189-1900 (from ethanol). IR spectrum (KBr Pellet.): 1680 m + (C = NH), cm.-1• Anal. C20H2sNs01 (447.44) calc'd.: N 15.65°/o found: N 15.790/o 2-Isopropyl-t-..1-pyrroline (XII) Ester XI (10 g.) and 10 N sulphuric acid (50 ml.)" were refluxed* for 30 minutes. To the ice-cooled solution potassium hydroxide (pellets) was added (pH about 12) and extracted with ether. The ethereal extract was washed with saturated sodium chloride solution and dr.ied with potassium hydroxide. Ether was removed and the amine distilled, b. p. 138°1740 mm. Yield 5 g. (820/o). Pi crate: m . p. 114° (from ethanol). Anal. C18H 16N407 (340.29) calc'd.: C 45.88; H 4.74; N 16.47°/o found: C 45:57; H 4.70; N 16.50°/o Preparation of XII by the Grignard Reaction To a Grignard reagent [from magnesium turnings (2.9 g.) isopropyl bromide (14.3 g.) in dry ether (50 ml.) by refluxing during one hour] a solution of halonitrile I (5. g.) in dry ether (15 ml.) was added with stirring and ice-cooling for 15 minutes. The reaction mixture was then refluxed for 30 minutes, ether removed by distil-lation and replaced by dry xylene (30 ml.). After boiling for 30 minutes and cooling to 0°, the mixture was treated with saturated ammonium chloride solution. The organic layer, was separated and extracted with diluted hydrochloric acid. The acidic aqueous layer was washed with ether, made strong alkaline by adding potas.-sium hydroxide (pellets) and extracted three tim es with ether. 'I1he combined ethereal layers were washed with saturated sodium chloride solution and dried with potassium hydroxide. Ether was removed, the residue distilled a nd transformed into picrate, m . p . 114°. Yield : 1.1 g. Methyl 2-meth y l-2( l'l 1-piperideiny l-2 )-propionate (XIII) Prepared as compound XI, from halonitrile II (19.9 g., 0.17 mole), zinc (13 g., 0.2 at.) and methyl a-broimoisobutyrate (36.2 g., 0.2 mole) rn 80 ml. of dry anisole. The crude product (15 g.) was isolated by continuous extraction of alkaline aqueous layer and distilled through a short fractionating column under reduced pressure. The fraction boiling at 107°/ U mm. was collected. Yield 6-7 g. (33-38 O/o). This com-pound has a tendency to polymerize on standing. Anal. C10H11N02 (183.24) calc'd.: C 65.54; H 9.35; N 7.64-0/o found: C 65.35; H 9.32; N 7.820/o Ethyl 2-methyl-2(N-piperideinyl-2)-propionate (XIV) Prepared as before from halonitrile II (19.9 g., 0.17 mole), zinc (13 g., 0.2 at.) and ethyl a-bromoisobutyrate (39 g., 0.2 mole) in anisole (80 ml.). The crude product (15.5 g.) was fractionated, b. p. 132°/23 mm. IR spectrum (liquid film): 1728 s (ester CO), 1661 s (C = N) cm.-1• * We have recently employed this method of decarbalkoxylation in the isoqui-noline series.16 6 L. ARSENIJEVIC AN:D V. ARSENIJEVIC Anal. C11H 19N02 (197.27) calc'd.: C 66.97; H 9.71; N 7.100/o found: C 66.61; H 9.55; N 6.860/o + Pi c r o 1 on a t e: m. p. 180° (from ethanol). IR spectrum (KBr Pellet.): 1695 s (C = NH), 1930 vw (immonium band) cm.-1 Anal. C21H2sNs01 (459.45) calc'd.: C 54.89; H 5.48; N 15.240/o found: C 54.47; H 5.73; N 15.170/o 2-Isopropyl-l°'>.1-piperideine (XV) Ester XIV (2 g.) and 10 N sulphuric acid (10 ml.) were refluxed for 30 minutes. To the ice-cooled solution potas,s.ium hydroxide was added to make the solution strongly alkaline and the amine was isolated by continuous extraction with ether. The ethereal extract was washed with saturated sodium chloride solution and dried with »Drierite«. Ether was removed and the residue (1.2 g., 880/o) was distilled in a micro-apparatus. Picrate: m. p. 120--1210 (from ethanol). Lit.13 •14 m. p. 118-119°. IH + spectrum of picrate (KBr pellet): 1690 m (C = NH) cm.-1. 2-Isopropylpiperidine (XVI) A solution of compound XV (1.1 g.) in glacial acetic acid (10 ml.) containing platinum oxide (0.2 g.) was hydrogenated at atmospheric pressure of hydrogen. The uptake of 1 mole equivalent of hydrogen required 40-45 minutes. The catalyst was removed by suction and the solvent was distilled at .atmospheric pressure over a Vigreux column. The residue was treated with a solution of picric acid in ether. The picrate has m. p. 137-138° (from ethanol). Lit.13 •15 m. p. 137-138°. Hydrochloride: m. p. 215° (from ethanol-acetone). Lit.13 •14 m. p. 210-216°. Acknowledgments. The authors whish to thank Dr. D. Jeremie (Institute orf Che-mistry, Technology and Metallurgy, Beograd) who kindly determined and interpreted the NMR spectra. REFERENCES 1. J. B. C 1 o k e, J. A.m. Chem. Soc. 51 (1929) 1174. 2. J. B. C 1 o k e and 0. Ayers, J. Am. Chem. Soc. 56 (1934) 2144. 3. J. V. Murr a y and J. B. C 1 o k e, .1. Am. Chem. Soc. 68 (1946) 126. 4. L. C. Craig, H. Bu 1 bro ck, and M. Hixon, J. Am. Chem. Soc. 53 (1931) 1831. 5. J. G. Ki 'r ch n er and J . B. Johns, J. Am. Chem. Soc. 62 (1940) 2183. 6. J. H. Burck ha 1 t er and J . H. Short, J. Org. Chem. 23 (1958) 1281. 7. M. F. Grundon and B. E. Reynolds, J. Chem. Soc. 1964, :~445; R . Bon-net, V. M. Clark, A. G :iddey, and Sir A. Todd, J. Chem. Soc. 1959, 2087; B. Witkop, J. Am. Chem. Soc. 76 (1954) 5597, 78 (1956) 2873; M. C. Koetz el, J. L. P .inc us, and R. M. wash burn, J. Am. Chem. Soc. 79 (1957) 4222. 8. K. Nakanishi, Infrared Absorption Spectroscopy-Practical, Holden-Day, Inc., San Frandsco, 1962, p. 193. 9. P. J. A . Demo en and P. A. J. Janssen, J. Am. Chem. Soc. 81 (1959) 6281. 10. W. Koller and P. Schlack, Chem. Ber. 96 (1963) 93; W. Giel en, Z. Physiol. Chem. 348 (1967) 329. 11. H. Wedkamp and F. Korte, Chem. Ber. 95 (1962) 2896; K. H. Buch el and F. Korte, Chem. Ber. 95 (1962) 2460; H. Booth, A. W. Johnson, and F. Johnson, J. Chem. Soc. 1962, 98. 12. H. B. Kagan and Y-H en g Suen, Bull. Soc. Chim. France 1966, 1817. 13. W. Sobe c kd, Ber. 41 (1908) 4108. 14. A. Laden burg, Ber. 20 (1887) 1646. 15. A. Lad en burg, Ann. 247 (1888) 73. 16. L. Ar sen i j e vi c and V. Ar s en i j e vi c, Bull. Soc. Chim. France 1968, 3408. THE REFORMATSKY REACTION 7 IZVOD Reakcija Reformatskog na alifatiCne y- i ll-halogen-nitrile. Dobijanje 2-supstituisanih L\1-pirolina i N-piperideina L. Arsenijevic i V. Arsenijevic Proucavana je reakcija a-brom-estara i cinka sa y i ll-halogen-nitrilima sa ci-ljem da se sintetiziraju N-heterocikliena jedinjenja. Ako se reakcija izvodi u nisko-kljueajucim rastvaracima npr. u etru, tetrahidrofuranu i1i benzolu, dobijaju se w-halo-gen-~-keto-estri, dok u anizolu nastaje 2-karbetoksi-alkil-~1-pirolin, odnosno 2-kar-betoksi-alkil-~1-piperidein. Ova poslednja jedinjenja Iako gube karbetoksi-grupu za-grevanjem sa 10 N sumpornom kiselinom uz nastajanje 2-alkil-N-pirolina, odnosno 2-alkil-~1-piperideina. ~1-Polofaj dvogube veze u pirolinskom i piperideinskom prstenu potvrden je odsustvom vibracije NH-grupe u IR spektrima a struktura 2-supstituisanih ~1-piro­lina potvrdena je i pomoeu NMR spektara. ZA VOD ZA ORGANSKU HEMIJU FARMACEUTSKIFAKULTET Prlmljeno 19. srpnja 1968. BEOGRAD 

The Reformatsky Reaction with Aliphatic Y- and b-Halonitriles. The Synthesis of Some 2-Substituted D 1 -Pyrrolines and D -1 -Piperideines

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