NOVEMBER, 1964
NOTES
3407
mental results of other studies concerned with hydrogen bonds between hydroxyl and nitrogen. l 1
has been described previously, as have various 3-substituted3 and 4,4-disubstituted4derivatives, but for the proposed syntheses a simple, direct route was required. Experimental Using the reductive cyclization route to quinolizine derivatives described in earlier papers of this series, we cis-l,2-CyclopentanediolEster of 8-Quinolineboronic Acid.8-Quinolineboronic acid'2 (0.519g.) and cis-l,2-~yclopentanediol~~ have established a very convenient synthesis of 3 and, (0.306 9 . ) were refluxed with benzene (50 ml.) for 2 hr. in a because of the potential usefulness of this reaction Dean-Stark apparatus. The benzene was then distilled until sequence in related areas, these results are reported in the volume of solution was 10 ml. Pentane (40 ml.) was added this communication. to the residue and the resulting solution was cooled at 0-5' for Lithium aluminum hydride reduction of 1- [2-(324 hr. The white crystalline product which formed was filtered rapidly and dried in a vacuum desiccator over P205, yielding indolyl)-2-oxoethyl]pyridiniumsalts50r1-[2-(3-indolyl)0.545 g. (76y0),m.p. 120-121". ethyllpyridinium salts6 has recently been shown to be a Anal. Calcd. for C14H14BN02: C, 70.4; H , 5.90; N, 5.86. means of obtaining indolo [2,3-a]quinolizinederivatives Found: C, 69.10"; H, 5.93; N, 6.03. in satisfactory yield. Application of this procedure to cis-1,2-Cyclopentanediol Ester of Benzeneboronic Acid.The procedure of Sugihara and Bowmanl5 was followed: b.p. the synthesis of the desired ketone (3) was found to be 83-84' (1 mm.), m.p. about 17". possible by the choice of an appropriate pyridinium czs-1,2-Cyclopentanediol Ester of 2-(2-Boronophenyl)benziderivative. The use of a 4-alkoxy-1- [2-(3-indolyl)-2midazole.-2-(2-Boronophenyl)ben~imidazole4 (0.5 g.) was disoxoethyl]pyridinium salt in the reduction gave the solved in 3 ml. of cis-1,2-cyclopentanediol. Benzene (30ml.) was quinolizine (2) which, being an enol ether, under the added to the solution, which was then refluxed with continuous removal of water for 4 hr. Pentane (50ml.) was then added and the acid reaction work-up conditions readily yielded the solution was cooled for 1 week at 0-5". The white powder ketone. In this way, 4-ethoxy-1- [2-(3-indolyl)-2-0~0(0.24g.) which formed was filtered, washed with pentane, and ethyllpyridinium bromide (1) gave 1,2,3,4,6,7,12,12bdried. hfter recrystallization from carbon tetrachloride it was octahydro-2-oxoindolo [2,3-a]quinolizine (3) in 48% obtained as felted needles, m.p. 130-134'. yield. Anal. Cnlcd. for ClsH17BN20: C, 71.1; H , 5.61; N , 9.22. Found: C, 68.3514;H, 5.75; ir;, 9.47. The pyridinium salts were readily prepared either Infrared Spectra .-Spectra reproduced in Fig. 1 were obtained from 4-ethoxy- or 4-methoxypyridine and 3-indolyl on a Perkin-Elmer Model 421 grating spectrophotometer using bromomethyl ketone or 3-indolyl methyl ketone and 1-cm. Pyrocell near-infrared cells. Spectra shown in Fig. 2 iodine, the former method resulting in better yields. were obtained on a Beckman D K - 2 Arecording spectrophotometer using silica cells. Carbon tetrachloride was dried over PzO, Exchange of the anion for the perchlorate or picrate ion and distilled. Wet carbon tetrachloride was prepared by shaking gave highly crystalline salts, all of which showed strong purified carbon tetrachloride with either H20 or D20. hydrogen bonding characteristics in their infrared spectra, and salts prepared by both methods yielded an Acknowledgment.-This work was supported by the identical perchlorate, thus confirming the structural National Science Foundation a t Northwestern Univerassignments. Their ultraviolet absorption spectra sity. Acknowledgment is made to the donors of The were similar to those of other 3-acyl indole systems and Petroleum Research Fund, administered by the Amerjcan Chemical Society, for partial support of this research these data are reported in the Experimental. Reaction at Wake Forest College, and to Professor Harry S. of 4-ethoxypyridine with 2-(3-indolyl)ethyl bromide' hlosher for providing laboratory space and a grating gave the salt 5 which, though crystalline, does not have spectrophotometer so that some experiments could be conducted while J. D. SI. was a National Science Foundation Postdoctoral Fellow a t Stanford University. (11) H. H. Freedman, J . A m . Chem. Soc., 83,2900 (1961). (12) R . L. Letsinger and S. H. Dandegaonker, {bid., 81, 498 (1959). (13) L. N. Owen and P. N. Smith, J . Chem. Soc., 4026 (1952). (14) Carbon analyses for many B-N compounds are low.5 (15) J. M. Sugihara and C. A. Bowman, J . A m . Chem. SOC.,80, 2443 (1958).
bR
OEt
1
2
.1 A Synthesis of 1,2,3,4,6,7,12,12b-Octahydro2-oxoindolo[2,3-a]qiiinolizine1 K. T. P o n s
AND
I. D. NASRI
Department of Chemistry, University of Louisville, Louisville, Kentucky Received June 1, 1.964
As part of a study of the synthesis of various types of indole alkaloids, one of the approaches envisaged utilized the tetracyclic intermediate (3). This ketone (1) (a) Part V in the series, Synthetic Experiments Related to the Indole Alkaloids; (b) Part I V : K . T . Potts and D . H. Liljegren, J. Ore. Chem., 28, 3202 (1963); (c) support of this work by Grant HE-06475, National Heart Institute, Public Health Service, is gratefully acknowledged. ~~
OEt 5
4
3
(2) (a) L. H. Groves and G A. Swan, J . Chem. Soc., 650 (1952); (b) G . B. Kline, J. A m . Chem. Soc., 81, 2251 (1959). (3) c. Szantay and L. Toke, Tetrahedron Letters, 251 (1963); H . T. Openshaw and N . Whittsker, J . Chem. Soc., 1452 (1963). (4) R . N. Schut. U. S. Patent 3,087,930 (1963); Chem. Abstr., 69, 11,4976 (1963). (5) K . T. Potts and D . R . Liljegren, J . Ore. Chem., 28, 3066 (1963). (6) E. Wenkert, R. A. Massy-Westropp, and R . G. Lewis, J. A m . Chem. Soc., 84, 3732 (1962). (7) The recent synthesis of 2-(3-indolyl)ethanol from ethyl 3-indolylglyoxylate. and lithium aluminum hydride [T. Nogrady and T . W . Doyle, Can. J. Chem., 42, 485 (1964)] now makes this bromo compound readily available.
NOTES
3408
VOL. 29
which time it became solid. After cooling to room temperature, the desirable solubility and physlcal characteristics of the dark brown solid was triturated with absolute ethanol (20 the corresponding salts 1. ml.), and the crude bromide was obtained as a cream, crystalline The interesting solvent effects obtained in the lithium powder. It crystallized from water as long, colorless needles, aluminum hydride reductions reported in our earlier 12.5 g. (78%), m.p. 215-217' dec. Anal. Calcd. for CnHl7I3rN2O2:C, 56.5; H, 4.7; N, 7.75. work were also obtained in the reductions of these pyriFound: C, 56.3; H, 5.0; N, 7.6. dine derivatives. Reduction of 4-ethoxy-1- [2-(3-inInfrared data (Nujol): UNH 3401 cm.-', VC-o 1661 cm.-l; dolyl)-2-oxoethyl]pyridinium bromide with lithium 303, 257 (sh), 245 mp (log e 4.13, ultraviolet data (CHIOH): A,, aluminum hydride in tetrahydrofuran solution gave 275, 226 mp (log e 3.84, 3.92). 4.26, 4.32); A,, 1,2,3,4,6,7,12,12b-octahydro-2-oxoindolo [2,3- alquinoThe corresponding perchlorate (1, R = E t ; X = C104)was prepared by the addition of aqueous (50%) perchloric acid to a lizine in 48y0 yield. The identity of this product was hot aqueous solution of the bromide. It crystallized from water established by analytical and spectral data and by as small, colorless needles, m.p. 212-214" dec. direct comparison with an authentic specimen.* I n Anal. Calcd. for C17H1iC1N2Os: C, 53.6; H, 4.5; N, 7.35. ether solution the reduction gave a 21% yield of the Found: C, 53.7; H,4.8; N, 7.6. Infrared data (Kujol): U N H 3257 cm.-l, YC-o 1661 cm.-'; ketoquinolizine (3) and a n 11% yield of the uncyclized product, 1-[2-(3-indolyl)ethyl]-1,2,3,4,5,6-hexahydro-4-ultraviolet data (CHaOH): Amax 303, 257 (sh), 246 mp (log c 4.06, 4.18, 4.23); A m i n 274, 226 mp (log e 3.75,3.81). oxopyridine (4). The identity of this latter product The picrate (1, R = Et; X = CsH2NSO7) was prepared in was established by analytical data and spectral charethanol and crystallized from this solvent as long, yellow needles, acteristics, and the presence of an unsubstituted 2m.p. 203-205". Anal. Calcd. for CztHiBNbOB: C, 54.2; H , 3.8; N, 13.8. indole position was confirmed by a positive Ehrlich's Found: C, 54.3; H,3.75; N, 13.5. test. It was not possible to confirm the presence of the Infrared data (Nujol): UNH 3268 cm.-l, UC-o 1631 cm.-l; indole 2-proton in the n.ni.r. spectrum of the uncyclized ultraviolet data (CHIOH): ,A, 309, 244 mp (log e 4.28, 4.46); ketone. I n view of the recent workgin the indole series Amin 276, 227 mp (log e 3.99, 4.34). 4-Ethoxy-1- [2-(3-indolyl)-2-oxoethyl] pyridinium Iodide (1, that has shown the positions of both the indole 2- and R = Et; X = I).-A mixture of 3-indolyl methyl ketone (1.6 g., 3-protons to be concentration and solvent dependent, 0.01 mole) and 4-ethoxypyridine (2.6 g., 0.02 mole) was warmed it is most likely that this proton is undistinguishable gently until dissolution of the ketone was complete. Iodine (2.5 from the other aromatic protons in this particular g., 0.01 mole) was then added to the solution, and the mixture spectrum. The use of a mixture of lithium aluminum was heated on the steam bath for 45 min., with occasional stirring. A dark brown solid separated over this period. After cooling to hydride and aluminum chloride in tetrahydrofuran soluroom temperature, the solid was triturated with absolute ethanol tion gave a mixture of products from which the keto(10 ml.) and the crude iodide separated as a tan, crystalline quinolizine (3) was isolated in 31% yield and the unpowder. Recrystallization from water (charcoal) finally afforded cyclized 4-oxopyridine was obtained in 16y0yield. the iodide as fine, colorless needles, 2.3 g. (56%), m.p. 199-200" dec . It was of interest to contrast the yields obtained in Anal. Calcd. for C1iH171N202: C, 50.0; H , 4.2; N, 6.9. this reductive cyclization when using the [2-(3-indolyl)Found: C, 50.0; H,4.05; N,6.8. 2-oxoethyl]pyridinium salts with those obtained with Infrared data (Nujol): UNH 3344 cm.?, vc-o 1653 cm.-l; the oxygen-free system, the 1-[2-(8indolyl)ethyl]pyri- ultraviolet data (CHIOH):, , ,A 302, 257 (sh), 244 mp (log e 4.19, 4.32, 4.38); A,i,275, 231 mp (loge3.88, 4.29). dinium salts. In tetrahydrofuran solution, the ketoConversion of this iodide into the corresponding perchlorate quinolizine (3) was obtained in 35% yield, whereas salt gave a product that was identical in all respects with that when the reduction was carried out in ether solution, prepared from the bromide obtained when 3-indolyl bromomethyl the ketoquinolizine (31%) was associated with 8% of ketone was the starting material. the 4-oxopyridine (4). 4-Methoxy-1- [2-(3-indolyl)-2-oxoethyl]pyridinium Bromide ( 1 , R = Me; X = Br).-Using 4-methoxypyridine in the condensaThis route to ketoquinolizines should be capable of tion with 3-indolyl bromomethyl ketone gave the corresponding adaptation to the synthesis of other fused ketoquinosalt in 56y0 yield as yellow, irregular prisms, m.p. 201-203" dec. lizine ring systems, particularly the benz [alquinolizine Anal. Calcd. for CleH15BrN202:C, 55.3; H , 4.3; N, 8.1. system of interest in alkaloid studies. Found: C, 55.3; H,4.1; N, 8.05. Experimental'" 4-Ethoxy-1- [2-(3-indolyl)-2-oxoethyl] pyridinium Bromide (1, R = Et; X = Br).-3-Indolyl bromomethyl ketone" (10.5 g., 0.044 mole) was added to 4-ethoxypyridine12 (6.0 g., 0.048 mole) and the mixture was warmed on the steam bath for 5 min., during (8) The authors are indebted t o Dr. G. A. Swan for the gift of a sample of the ketoquinolizine prepared by his method.% (9) M.G. Reinecke, H. W. Johnson, Jr., and J. F. Sebastian, Chem. I n d . (London), 151 (1964); R. Jardine and R. Brown, Can. J . Chem., 41, 2067 (1963); M. G. Reinecke, H. W. Johnson, and J. F. Sebastian, Tetrahedron Letters, 1183 (1963). (10) All evaporations were carried out under reduced pressure on the steam bath and petroleum ether refers t o the fraction, b.p. 60-80°. Ultraviolet spectra were recorded on a Beckman DK-2 spectrophotometer and infrared spectra on a Baird recording spectrophotometer and a PerkinElmer 421 spectrophotometer. N.m.r. spectra were measured on a Varian V-4302 dual purpose, 60 Mc., n.m.r. spectrometer, and chemical shift values are reported in r-units, using tetramethylsilane as internal standard. We are indebted t o Mr. S. Thomas for determining these spectre. Chromatography was best carried out on Woelm neutral alumina, activity 4. Microanalyses are by Galbraith Laboratories, Inc., Knoxville. Tenn. (11) K . Bodendorf and A. Walk, Arch. Pharm., 194, 484 (1961). (12) H.J. Den Hertog and R. P. Cornbe, Rec. trau. chim., T O , 581 (1951); E. Ochiai. J . Pharm. Soe. Japan, 63, 265 (1943): J . Ore. Chem., 18, 534 (1953): see also F. Krohnke and H. Schafer, Chem. Ber., 96, 1098 (1962).
Infrared data (Nujol): YNH 3390, 3205 cm.?; YC-o1623 cm.-l; ultraviolet data (CHIOH): Amax 303, 257 (sh), 245 mp (log e 4.12, 4.30, 4.32); Ami, 275, 227 mp (log e 3.80, 3.95). 4-Ethoxy-l-[2-(3-indolyl)ethyl] pyridinium Bromide (5).-2-(31ndolyl)ethyl bromide (1.0 g., 0.0044 mole) was dissolved in 4ethoxypyridine (0.5 g., 0.0044 mole), and the mixture was heated on the steam bath for 10 min. On cooling to room temperature, the reaction mixture became gummy and light brown. After 12 hr. a t room temperature, the product had crystallized. Trituration with acetone ( 5 ml.) yielded a colorless, crystalline product which crystallized from ethanol-ether as small, colorless prisms, 1.0 g. (667,), m.p. 188-189" dec. Anal. Calcd. for C17H10BrN20:C, 58.8; H , 5.5; N, 8.1. Found: C, 58.8; H, 5.3; N, 8.0. Infrared data (Nujol): YNH 3106 em.?, YC-c 1639 cm.3; ultraviolet data (CH,OH): A,, 290, 281, 246 mp (log e 3.70, 3.76, 4.18); Amin 287, 267, 232 mp (log e 3.66, 3.72, 3.97). The corresponding perchlorate crystallized from ethanolether as fine, colorless needles, m.p. 156-157". Anal. Calcd. for C ~ ~ H ~ & I N ZC,O ~ 55.7; : H, 5.2; N, 7.6. Found: C, 55.5; H , 5.4; N, 7.45. Infrared data (Xujol): U N H 3279 cm.-', uc-c 1642 cm.?; 290, 280, 246 mp (log e 3.79, ultraviolet data (CHIOH): A,, 3.86, 4.26); X m i n 287, 267, 233 (log e 4.77, 3.81, 4.07). 1,2,3,4,6,7,12,12b-Octahydro-2-oxoindolo [2,3-a] quinolizine. Reduction of 4-Ethoxy-l-[2-(3-indolyl)-2-oxoethyl]pyridinium
NOVEMBER, 1964
NOTES
3409
Bromide. A. With Lithium Aluminum Hydride in TetrahydroFurther development of the column with benzene (500 ml.), a furan Solution .-The finely powdered 4-ethoxy-l-[2-(3-indolyl)- mixture of 1: 1 benzene-ether, ether, chloroform, and methanol gave a yellow, oily product (0.1 9.) which would not be char2-oxoethyl]pyridinium bromide (6.0 g., 0.016 mole) was added portionwise, with good stirring and in an atmosphere of dry nitroacterized. C. Lithium Aluminum Hydride and Aluminum Chloride in gen, to a solution of lithium aluminum hydride (3.6 g., 0.096 Tetrahydrofuran Solution.-The bromide (2.0 g., 0.004 mole) was mole) in anhydrous tetrahydrofuran (300 ml.). An intense green added portionwise, with vigorous stirring and in an atmosphere of fluorescence was observed immediately. The mixture was heated dry nitrogen, to a solution of lithium aluminum hydride (1.1 g., under reflux for 4 hr., and then cooled in an ice bath. Water (20 0.03 mole) and aluminum chloride (1.3 g., 0.01 mole) in anhyml.) was added dropwise to decompose the excess lithium aludrous tetrahydrofuran (250 ml.). The mixture was heated under minum hydride, resulting in the total disappearance of the fluoresreflux for 4 hr., a green fluorescence being observed after the first cence and the formation of a colorless precipitate. Addition of few minutes of heating. After reaction work-up as described 12% hydrochloric acid (100 ml.) dissolved the solid, the solution above and isolation of a crude product (2.0 g.) by chloroform exbecoming dark orange (pH 1-2). After standing overnight at traction, chromatography as described in the previous experiroom temperature, the tetrahydrofuran was removed from the ments (alumina, 55 g.) was used for purification of the product. solution by evaporation under reduced pressure, and the residual, Elution with benzene (100 ml.) yielded a yellow, solid material dark red oil did not crystallize on standing. This oil was separated by decantation from the aqueous phase and the latter was (A), 0.8 g. An Ehrlich test on A indicated the presence of some of the uncyclized product (4). The column was further developed neutralized with a saturated, aqueous solution of sodium bicarwith solvents of increasing polarity and yielded only a few millibonate. Filtration of the yellow precipitate (P)left a pale yellow grams of yellow, oily material which could not be characterized. filtrate ( F ) . A was dissolved in hot benzene (10 ml.) and rechromatographed The oil was dissolved in hot water (100 ml.) and the solution on neutral alumina (50 g.). Elution with benzene (100 ml.) afwas neutralized with sodium bicarbonate. A yellow precipitate forded as a yellow, crystalline material, 1,2,3,4,6,7,12,12b-octa(Pl) was formed, from which a pale yellow filtrate (F1) was obhydro-2-oxoindolo[2,3-a]quinolizine whcih crystallized from bentained. zene as small, yellow prisms, 0.3 g. (31%), m.p. 181-182". FurFractions P and PI were combined and continuously extracted ther development with benzene (200 ml.) gave 1-[2-(3-indolyl)]in a Soxhlet apparatus for 72 hr. with benzene. Drying of the 1,2,3,4,5,6-hexahydro-4-oxopyridinewhich crystallized from yellow benzene extract over anhydrous magnesium sulfate and benzene-petroleum ether as small, colorless needles, 0.15 g. evaporation of the benzene under reduced pressure gave a yellow, (16%), m.p. 134-136'. crystalline product (1.3 g.). Reduction of 4-Ethoxy-1[2-(3-indolyl)ethyl]pyridinium Bromide Fractions F and F1 were also combined and continuously exwith Lithium Aluminum Hydride. A . In Ether Solution.-The tracted with chloroform for 72 hr. After drying and removal of pyridinium bromide (2.0 g., 0.0057 mole) was added portionwise the solvent as above, a dark yellow oil was obtained (2 g.). It to a solution of lithium aluminum hydride (1.7 g., 0.045 mole) in crystallized on standing. anhydrous ether (250 ml.) and the mixture was heated under The crude 1,2,3,4,6,7,12,12b-octahydro-2-oxoindolo[2,3-u]-reflux in an atmosphere of dry nitrogen for 4 hr. Water (10 ml.) quinolizine crystallized from benzene (charcoal) as small, yellow was added dropwise to decompose the excess lithium aluminum prisms, 1.8 g. (457,), m.p. 181-182" (lit.2m.p. 18&180.5"). hydride and the colorless, inorganic material was dissolved by Anal. Calcd. for C15H16X20: C, 75.0; H , 6.7; PI', 11.65. addition of 18% hydrochloric acid (100 ml.). The solution beFound: C,75.15; H , 6 . 9 ; N , 11.5. came yellow in color. The next day the ether was removed by This product had an infrared spectrum identical with that of an heating the solution on a steam bath and, on neutralization of the authentic specimen kindly provided by Dr. G. A. Swan and no aqueous phase with sodium bicarbonate, a pink precipitate was depression in melting point on admixture of the two samples was obtained. The pale yellow filtrate was continuously extracted observed. with chloroform, and the yellow chloroform extract was dried Infrared data (CHCl,): YNH 3356 cm.-', YC-o 1701 cm.-l; over anhydrous magnesium sulfate and evaporated to dryness ultraviolet data (CHaOH): hmn, 290, 283 (sh) mp (log e 3.82, under reduced pressure, affording a dark orange oil (1.1 g . ) . The 3.90); Xmln 288, 246 mp (log e 3.80, 3.35); n.m.r. spectrum pink precipitate was also continuously extracted with chloroform, (CDCl3): methylenes, multiplet highest peak 7 7.34; aromatic and the chloroform extract yielded a red oil (0.6 g.). protons, highest peak 2.83; NH, 1.71. These assignments were The two oily fractions were combined and chromatographed on confirmed by the n.m.r. spectrum of the deuterated derivative a column of Woelm neutral alumina (60 g.), using the technique that was prepared by dissolving the ketoquinolizine (about 50 described above, and elution with benzene (100 ml.) afforded a mg.) in dioxane (2 ml.), diluting with 99.570 deuterium oxide (2 red, crystalline solid (A), 0.9 g. Further development of the ml.), and evaporating the solution to dryness in a desiccator column with benzene (200 ml.) gave a mixture of a yellow solid several times; n.m.r. spectrum (CDCla): methylenes, mukiplet and an oily material (0.4 g.). It crystallized from benzene-petrohighest peak 7 7.34; aromatic protons, highest peak 2.83. leum ether as irregular, yellow prisms, m.p. 15%183", and was a B. Lithium Aluminum Hydride in Ether Solution.-The mixture of the two ketones. The column was then developed pyridinium bromide (2.0 g., 0.004 mole) was added portionwise with benzene, ether, chloroform, and methanol, affording only and with good stirring to a solution of lithium aluminum hydride a few milligrams of a yellow, oily material which could not be (1.4 g., 0.038 mole) in anhydrous ether (280 ml.). The green characterized. fluorescence was less intense than that observed during the reProduct A was dissolved in hot benzene (12 ml.), and the soluduction of the bromide in tetrahydrofuran solution. The mixtion was transferred to another column of alumina (60 g , ) . After ture was then heated under reflux in an atmosphere of dry nitroelution with benzene (100 ml.), a yellow, solid product was obgen for 6 hr. and then worked up essentially as described above. [2,3-a]tained. This 1,2,3,4,6,7,12,12b-octahydro-2-oxoindolo The crude product (0.5 g.) isolated by chloroform extraction was quinolizine crystallized from benzene as small, yellow prisms, 0.4 dissolved in chloroform (few ml.), absorbed onto neutral Woelm g. (31%), m.p. 180-182". When the column was further eluted alumina (activity grade IT, 8 g.), and then transferred to a with benzene (200 nil.), a yellow, solid material was obtained. column of neutral alumina (50 g.) of the same activity. Elution The crude 1-[2-(3-indolyl)]-1,2,3,4,5,6-hexahydro-4-oxopyridine with benzene (100 ml.) yielded 1,2,3,4,6,7,12,12b-octahydro-2- crystallized from benzene-petroleum ether as small, cream neeoxoindolo[2,3-a]quinolizine(0.2 g., 21%) as yellow crystals. I t dles, 0.1 g. (8%),m.p. 134-135'. crystallized from benzene as small, irregular yellow prisms, m.p. Infrared absorption of the keto quinolizine: YNH 3322 cm.-l, 18G182". Further elution with benzene (100 ml.) yielded long, YC-o 1715 cm.?; infrared absorption of the keto hexahydrocolorless needles, (0.1 g . , 11%) of 1-[2-(3-indolyl)ethyl]-1,2,3,4,pyridine: YNH 3436 cm.?, YC-o 1712 cm.-'. 5,6-hexahydro-4-oxopyridine. I t crystallized from benzeneB. In Tetrahydrofuran Solution.-The reduction of the pyripetroleum ether as fine, colorless needles, m.p. 134-135". dinium bromide ( 5 ) in freshly distilled, anhydrous tetrahydroAnal. Calcd. for CISHIRN\;PO:C, 74.35; H , 7.5; N, 11.6. furan Rolution was carried out on the same scale and in the manner Found: C, 74.5; H , 7.7; N , 11.6. described above for the reduction in anhydrous ether solution. During the reaction, the mixture became blue-green in color, but Infrared data (CHC13): YNH 3425 cm.?, Y C - o 1709 cm.-l; no fluorescence was observed. Reaction work-up was essentially ultraviolet data (CHIOH): Amax 290, 282, 275 (sh) mp (log e as described above with the crude, oily product (1.2 9.) being 288, 245 mp (log e 3.59, 3.09); n.m.r. 3.62, 3.69, 3.66); A,, chromatographed on a column of alumina ( 5 5 g.). Elution with spectrum (CDCL): methylenes, multiplets centered at r 6.82, benzene (300 ml.) gave a yellow, crystalline product which crys6.93, 7.19; aromatic protons, highest peak 2.82.
NOTES
3410
tallized from benzene as small, yellow prisms, 0.45 g., m.p. 180181’. The yield of 1,2,3,4,6,7,12,12b-octahydro-2-oxoindolo[2,3-a]quinolizinewas 357,. The column was further developed with ether, chloroform, and methanol, but the few milligrams of oily product obtained could not be characterized.
VOL. 29
P
Synthesis of 5-Alkyl-5,lO-dihydro-lOphenylphenophosphazine
R
R
A
I
*
I
GEORGEBAUM,HELENA. LLOYD, AND CHRIST TAMBORSKI
b
T h e Polymer Branch, A‘onmetallic Materials Division, Air Force Materials Laboratory, Wright-Patterson A i r Force Base, Ohio Received M a y 1 , 1964
phenylamine could be used as the intermediate, (2) whether the secondary amine could be alkylated to the Few references to a 5,lO-dihydrophenophosphazine’ tertiary amine by more convenient synthetic procering systeni (I) appear in the literature. Michaelis dures, and (3) whether a di-Grignard of the N-alkyl-2,2’and Schenk2in 1890 reported a compound corresponddihalodiphenylamine could be prepared. ing to CI2HloNOPobtained by hydrolysis of the reacThe 2,2‘-dichlorodiphenylainine was prepared by the tion product of phosphorous trichloride and diphenylChapman rearrangement in the manner described in amine. Sergeev and KudryashovS later proposed that the literatures for the 2,2’-dibromodiphenylamine. the material was 5,lO-dihydro-10-hydroxyphenophos- The physical properties for the intermediates are rephazine (11),but Haring4 has assigned structure I11 on ported in the Experimental section. the basis of its infrared spectra. Jones and Mann5 Jones and Mann5 were unsuccessful in their attempts to alkylate the 2,2’-dibromodiphenylamine. Gilman and Zuech’ successfully affected alkylation by a hydrogen-metal interchange of the secondary amine with methyllithium followed by treatment of the organolithiuni intermediate with dimethyl or diethyl sulfate. In I our studies we were successful in alkylating either the A-1-1 0” ‘H H dichloro or dibromodiphenylaniine by a method which I I1 rn involves metalation with sodium hydrideg followed by were unable to obtain 5,lO-dihydrophenophosphazine alkylation of the sodium intermediate with an alkyl iodide. The yields and physical properties of the comderivative from 2,2’-dilithiodiphenylamine and phenylpounds prepared are reported in the Experimental secdichlorophosphine and instead obtained a viscous tion. orange liquid of unknown composition.6 It seemed, Preparations of the X-alkyl-2,2’-dilithiodiphenyltherefore, in order to obtain the desired phenophosphaamine were attempted on both the dibromo and dichloro zine derivative, a tertiary amine, N-alkyl-2,2’-dihalointermediates. The N-methyldibromodiphenylaniine diphenylamine, would be required. Recently Gilman yielded t.he dilithio intermediate which reacted readily and Zuech,’ who have further developed this cyclization with phenyldichlorophosphine to yield the desired prodreaction and have shown its versatility, synthesized the uct, 5-niethyl-lO-phenyl-5,lO-dihydrophenophosphazine, Si, Ge, and Pb analogs of this heterocyclic system. in 58.0% yield. However, the N-alkyl-2,2’-dichloroSimilar organometallic reaction schemes have been the diphenylamine would not form the desired 2,2‘-dilithio subject of several patents.8 intermediate.10 The di-Grignard of S-ethyl-2,2’-diWe now wish to report our observations in the synbromodiphenylamine likewise formed readily and carthesis of some substituted 5,lO-dihydrophenophosphabonation of this organometallic yielded the acid Nzine compounds via a cyclization reaction of diorganoethyl-2,S’-dicarboxydiphenylaniine in 55.8% crude metallic conipounds with difunctional phosphorus comyield. React,ion between the di-Grignard and phenylpounds. It was of interest in our studies to determine dichlorophosphine, however, yielded the cyclic 5,lO(1) whether the inore readily available 2,2’-dichlorodidihydrophenophosphazine in only 28% yield. Prepa(1) The nomenclature employed herein on the 5,10-dihydrophenophosration of the di-Grignard reagent from the S-alkyl-2,2’phazine ring system was recommended by the editorial staff of Chemical dichlorodiphenylaniine was considerably inore difficult. Abstracts. (2) A . Michaelis and K . Schenk, Ann., 260, 1 (1890). In ether or tetrahydrofuran, the reaction could not be (3) P. G. Sergeev and D. G. Kudryashov, J . Cen. Chem. U S S R , 8 , 266 initiated by iodine, ethyl bromide, ethyl iodide, or (1938). ethylene dibromide. The di-Grignard was finally pro(4) M. Haring, H e l u . Chim. Acta, IS, 1826 (1960). ( 5 ) E. R. H . Jones and F. G. Mann, J . Chem. Soc., 786 (1956). duced in small yield by a modification of the Blues and (6) T h e difficulty encountered by Jones and Mann was attributed t o the Bryce-Smith procedure” (see Experimental section). use of a secondary amine, 2,2’-dihromodiphenylamine,with its multiplicity
B
IT
B
o k D aNs aN$) a*
of reaction possibilities when treated with butyllithium and phenyldichlarophosphine. (7) (a) H. Gilman and E. A. Zuech, Chem. Ind. (London), 1227 (1958); 82, 2522 (1960); ( 0 ) (b) H . Gilman and E. A. Zuech, J . A m . Chem. SOC., H. Gilman and E. A. Zuech, J. Org. Chem., 26, 2013 (1961). (8) (a) R . E. Jones and D. Wasserman, U. S. Patent 3,065,251(1962); (b) J . Kollonitsch, U. S. Patent 3,120,565 (1964).
(9) Sodium hydride dispersion, 50% in mineral oil, was used; Metal Hydrides, Inc., Beverly, Mass. (10) Aromatic chlorine compounds seldom undergo a metal-halogen interchange: H . Gilman and 9. LM.Spats, J . A m . Chem. Soc., 63,1553 (1941); H. Gilman and F. W. Moore, ibid.,62, 1843 (1940). (11) E. T. Blues and D. Bryce-Smith, Chem. Ind. (London), 1533 (1960).
