3062 J . Org. Chem., Vol. 40, No. 21,1975
Brzechffa, Eberle, and Kahle
(55) J. Harley-Mason, Nature (London), 155, 515 (1945). (56)L. A. Kalutskii, A. F. Kolomiets, N. K. Bliznyuk, and S. L. Varshavskii, Russian Patent 191,543;Chem. Abstr., 68, 49298w (1968). (57)R. G. Jones and H. Gilman, Org. React., 6, 339 (1951). (58)G. Fraenkel, S. Dayagi, and S. Kobayashi, J. Phys. Chem., 72, 953 (1968);W. H. Glaze and A. C. Ranade, J. Org. Chem.. 36,3331 (1971). (59)S.C. Watson and J. F. Eastman, J. Organornet. Chem., 9, I65 (1967). (60)D. Seyferth and M. A. Weiner, J. Am. Chem. SOC.,83,3583 (1961). (61)H. Normant, Adv. Org. Chem., 2, l(1960). (62)D. Seyferth and L. G. Vaughan, J. Am. Chem. Soc., 86, 863 (1964);J. Organornet. Chem., I, 201 (!963). (63)H. Gilman and W. E. Catlin, Organic Syntheses”, Collect. Vol. I, Wiley, New York, N.Y., 1941,p 471,H. Gilman, E. A. Zoellner, and J. B. Dickey, J. Am. Chem. Soc., 51, 1575 (1929). (64)B. Mechin and N. Naulet, J. Organomet. Chem., 39, 229 (1972). (65)D. Seyferth and L. G. Vaughan, J. Organomet. Chem., 1, 138 (1963). (66)D. K. Wedegaertner, R . M. Kopchik, and J. A. Kampmeier, J. Am. Chem. SOC., 93, 6890 (1971).
(67)H. Gilman and R. D. Gorsich, J. Org. Chem., 23, 550 (1958). (68)S.Goldschmidt and E. Wurzschmitt, Ber. Dtsch. Chem Ges. 8,55, 3216 (1922). (69)G. Reddeiien, Ber. Dtsch. Chem. Ges., 46, 2718 (1913). (70)I. Ugi and R. Meyr, Org. Synth., 41, 101 (1961). (71)W. Hemillan and H. Silverstein, Ber. Dtsch. Chem. Ges., 17, 741 (1884). (72)W. Schlenk and E. Bergmann, Justus Liebigs Ann. Chem., 464, 1 (1928). (73)Prepared from benzhydryl chloride and lithium wire. (74)M. Protiva, J. 0. Jilek, 0. Exner, M. Borovicka, J. Pliml, V. Simak, and S. Sedlvy, Chem. Listy, 47, 1621 (1953);Chem. Abstr., 49,248i(1955), (75)Y. Minoura and S. Tsuboi, J. Org. Chem., 37, 2064 (1972). (76)H. Gilman and G. L. Schwebke, J. Org. Chem.. 27,4259(1962). (77)A. N. Nesmeyanov, A. E. Barlsov, and N. V. Novikova, Dokl. Akad. Nauk SSSR, 119, 712 (1958);Chem. Abstr., 52, 17161h(1958). (78)R. L. Shriner, R. C. Fuson, and D. Y. Curtin, “The Systematic Identification of Organic Compounds”, 5th ed, Wiley, New York, N.Y., 1964,p 299.
The Peripheral Synthesis of Medium-Ring Diaza Heterocycles via @-EliminationReactions Leszek Brzechffa, Marcel K. Eberle,* and Gerard G. Kahle Department of Research, Division of Sandoz, Inc., East Hanover, New Jersey 07936 Received M a y 6,1975 Compounds 4 a n d 7, respectively, obtained from t h e corresponding quinazolinones, were m e t h y l a t e d t o give 5 a n d 8 respectively. T r e a t m e n t with base l e d t o t h e m e d i u m - r i n g diaza compounds 6b a n d 9, respectively.
The peripheral synthesis of medium-ring azacycles as disclosed in the literature1 involves the selective cleavage of the central bond of a fused 1-azabicycloalkanone. This was achieved via quaternization of the nitrogen in the proximity of an activating substituent leading to the selective cleavage of one nitrogen-carbon bond. We have applied this concept to the formation of medium-ring diazacycles under nonreductive conditions. Similar to a Hofmann degradation,2 the nitrogen-carbon bond cleavage is induced by a tetraalkylammonium salt. An aniline was placed in a 1,3 position to the ammonium salt as depicted in structure C of Scheme I. The more basic terti-
Scheme I
0 A
B
I
R
R
C
D
ary nitrogen should guarantee the selective alkylation of B by an alkyl halide to give C. We expected ring enlargement to D to occur in the presence of a suitable base via p-elimination with abstraction of a proton from the secondary amine. The precursors for B are well documented in the literature3 and are readily prepared from o-anthranilic acid and an activated lactam, e.g., an imino ester, to give the fused quinazolinones of the general structure A. These can be reduced to the compounds of the general structure B in the presence of lithium aluminum h ~ d r i d e . ~
As our starting material we selected the known5 [1,4]diazepino[1,2-a]indol-l-one(1) (Scheme 11). The imino ester 2 was prepared with the aid of Meerwein’s salt following standard literature p r o ~ e d u r e s . ~This ~ , ~ activated lactam formed the novel pentacyclic quinazolinone 3 when heated with anthranilic acid in analogy to similar reactions described in the literature.38 Spectral and analytical data were found in agreement with the assigned structure 3. Treatment of this compound with lithium aluminum hydride in refluxing tetrahydrofuran resulted in the reduction of both functional groups4 of 3 to give 4. With dry hydrochloric acid, the base 4 was transformed into a bishydrochloride according to analytical data. While two of the three nitrogens present in 4 are basic
J. Org. Chem., Vol. 40, No. 21, 1975
Peripheral Synthesis of Medium-Ring Diaza Heterocycles enough to form salts with a strong acid, a selective monoalkylation was observed when 4 was allowed to react with methyl iodide. From the following reaction it may be concluded that methylation of 4 took place on the tertiary nitrogen to yield 5. The product obtained was treated with aqueous sodium hydroxide. A new crystalline substance was isolated which we assigned structure 6b for the following reasons. Both elemental analysis and mass spectral data were in agreement with the composition C20H21N3. The infrared spectrum of 6b gave an absorption at 1630 cm-l due to the C=N substructure. This assignment was confirmed by the NMR spectrum of 6b, which showed a singlet at 6 8.73 pprn that is typical of CH=N. Other singlets due to the methyl group, the benzylic methylene, and the proton in position 3 of the indole appeared at chemical shifts expected for these positions. We would like to draw attention to a 2 H triplet observed at 6 4.72 ppm. This was assigned to the methylene group attached to the indole nitrogen based on examples we published earlier. There we learned that such a methylene group gives rise to a triplet when the side chain of the indole possesses a certain degree of rotational freedom, as, e.g., in 9-(3-aminopropyl)1,2,3,4-tetrahydrocarbazoleand others? In the absence of this rotational freedom, e.g., 2,3,6,6a-tetrahydro-Ga-ethyllH-3a,lOb-dia~afluoranthen-4(5H)-one,~ no triplet could be observed for the corresponding methylene group. In the medium-sized ring of triazacycloundecine 6b enough rotational freedom is present to render the two protons magnetically equivalent as observed by the presence of the triplet. Conjugation between the two aromatic ring systems of 6b could also be observed in the ultraviolet spectrum of that compound with an absorption at 336 nm extending into the visible spectrum. When the medium-sized ring compound 6b was treated with hydriodic acid, the pentacyclic compound 5 was recovered. This change was accompanied by the loss of the longwave uv absorption. As indicated above the quinazoline 4 was converted to a bishydrochloride. This compound can exist in two tautomeric forms, one represented by the quinazoline 4, the other by the indolo[2,1-c][1,4,8]benzotriazacycloundecine 6a, or as an equilibrium of the two tautomeric forms. Our spectral data seems to indicate that the free base exists in the form of the quinazoline 4 while the hydrochloride exists at least to some degree if not exclusively in the mediumring form 6a. We were not able to obtain a NMR spectrum of the free base owing to low solubility. When 4 was dissolved in trifluoroacetic acid a singlet at 6 8.56 ppm was observed which we assigned to the CH of an imino double bond. Similar observations were made when the NMR spectrum of the bishydrochloride of 4 was recorded in Me2SO as solvent. We anticipated a singlet in the vicinity of 6 4.0 ppm7 corresponding to the bridgehead proton of 4. However, it seems more likely that the partial structure CH=N gives rise to an absorption which coincides with the signals associated with the aromatic protons. Similar conclusions were reached from the interpretation of the ir and uv spectra. In particular the salt form 6a showed an ir absorption at 1640 cm-l and a uv absorption at 348 nm both of which were absent in the respective spectra of the free base 4. In addition a direct comparison of the infrared and ultraviolet spectra of the salt with those of the mediumsized ring compound 6b seemed to confirm that the addition salt of 4 is present either in the medium-sized ring form itself or coexists in an equilibrium with the pentacyclic form 4. In order to explore this novel ring opening reaction further we decided to investigate the preparation of
3063
Scheme I11
7
CH 9
4,5,6,7,8,9-hexahydro-8-methyl-3H[ 1,8]benzodiazacycloundecine (9) (Scheme 111). Starting from the known 4,5,6,7-tetrahydro-3H-azepino[2,1-b]quinazolin-9-one,3a following the same sequence of reactions as described above for the medium-ring compound 6b, the novel compound 4,5,6,7,8,9-hexahydro-8-methyl-3 H-[1,8]benzodiazacycloundecine (9) was isolated and characterized as a liquid. In the NMR spectrum of 9 the proton on the newly generated double bond appeared as a triplet at S 7.68 ppm, compatible with the assigned structure 9. This compound was unstable at room temperature. Upon standing a nonvolatile substance was obtained which we did not investigate further. In contrast to 4,which formed a bishydrochloride, 9 gave only a monohydrochloride. Spectral data seems to indicate the presence of the medium-ring tautomer in 7 HCl. The NMR spectrum of this compound showed a signal at 6 8.9 ppm in agreement with the presence of a N=CH. This is also supported by the ir spectrum of 7 HC1 (see Experimental Section). Direct proof for the existence of the imino double bond in 9 stems from hydrogenation experiments. After uptake of 1 mol of hydrogen the octahydro-1H-[1,8]benzodiazacycloundecine 10 was isolated and characterized in the form of its bishydrochloride. Experimental Section Melting points were determined on a Thomas-Hoover capillary melting point apparatus and have not been corrected. Proton magnetic resonance spectra were obtained on a Varian Associates A-60 spectrometer and are recorded in hertz or 6 values (parts per million) relative to MeaSi (tetramethylsilane) as internal standard. Infrared spectra were recorded on a Perkin-Elmer spectrometer Model 457. Ultraviolet spectra were determined in 95% ethanol with a Carey recording spectrometer Model 15. Thin layer chromatography (TLC) was carried out on glass plates coated with silica gel HF-254, E. Mer& AG. Mass spectra were measured on a LKB 9000 mass spectrometer. l-Ethoxy-3,4-dihydro-5H-[ l,l]diazepino[ 1,2-a]indole (2). To a solution of 61.0 g (0.32 mol) of triethyloxonium fluoroborate”h in methylene chloride was added 45.0 g (0.275 mol) of lactam 15 dissolved in methylene chloride. After 2 hr at room temperature the mixture was poured on 500 ml of 2 N NazCOs and worked up the usual way to give 54.5 g of crude imino ester 2. This material was distilled in a Kugelrohr to give 35.3 g (57%) of 2: bp 140-160’ (0.3 mm); m / e 228 (M+); NMR (CDC13) 6 1.38 (t, 3, J = 7.1 Hz, CH3), 2.0-2.4 (m, 2, C H Z C H ~ C H ~3.4-3.7 ), (m, 2, C=NCH2) 4.17 (t, 2, J = 6.4 Hz, indole NCHz), 4.23 (q, 2, J = 7.1 Hz, OCHz), 6 96 (s, 1, indole C3H), 7.0-7.3 (m, 3, CfiHs), 7.4-7.7 (m, 1, CeHl); ir N ~ O (film) 1670, 1650, 1620 cm-‘. Anal. Calcd for C I ~ H ~ ~(228.28): C, 73.7; H, 7.1; N, 12.3. Found: C, 73.6; H, 7.1; N, 12.1. 7,8-Dihydro-GH-indol0[2’,1‘:3,4][1,4]diazepino[2,1- blquinazolin-IO(lOH)-one (3). A mixture of 12.6 g (0.055 mol) of imino ester 2 and 8.2 g (0.060 mol) of anthranilic acid in 100 ml of ethanol was heated t o reflux overnight. The product precipitated from the solution and was filtered off to give 11.0 g (66.5%) of 3, mp 215-216’. A sample recrystallized from methanol gave mp 215216’; m / e 301 (M+); NMR (CDCld 6 2.36 (m, 2, CH&H&HJ,
3064 J . Org. Chem., Vol. 40, No. 21, 1975 4.0-4.5 (m, 4, 2 NCHz), 7.0-8.0 (m, 8, aromatic H), 8.2-8.5 (m, 1, &HI); ir (CHzClZ) 1675 (C=O), 1610, 1590 cm-l; uv 218 nm ( e 35,420), 330 (26,460). Anal. Calcd for C1gH15N30 (301.37): C, 75.7; H, 5.0; N, 13.9, Found: C, 75.7; H, 5.0; N, 13.9. 7,8,15,15a-Tetrahydro-6H,lOH-indolo[2',L':3,4][ 1,4]diazepino[2,1-b]quinazoline (4). A solution of 6.5 g (0.022 mol) of the quinazolinone 3 in 300 ml of absolute T H F was added dropwise to a suspension of 2.6 g (0.07 mol) of LiAlH4 in 50 ml of absolute T H F under an atmosphere of nitrogen. The mixture was heated to reflux during 3 hr. The excess of reducing agent was destroyed by slowly adding water to obtain a white precipitate which was filtered and washed with ether. The filtrate was concentrated and a solid was obtained which was recrystallized from methanol to give 4.6 g (74%) of 4: mp 233-234'; m / e 289 (M+); NMR (CF3COOH) d 2.5-3.0 (broad, 2, CHzCHzCHz), 4.0-4.5 (m, 2, NCHz), 4.5-4.9 (m, 2, NCHz), 5.50 (9, 2, N C H Z C ~ H ~ 7.2-8.1 ), (m, 9, aromatic H), 8.56 (9, 1, CH=N); ir (CHC13) 3400 (NH), 1610, 1590 cm-I (weak); uv 220 nm ( E 35,600), 276 (10,600), 284 (10,500). Anal. Calcd for C19H19N3 (289.37): C, 78.9; H, 6.6; N, 14.5. Found: C, 78.8; H, 6.6; N, 14.4. A sample of 4 was suspended in methanol and treated with a stream of hydrogen chloride. The starting material dissolved and then precipitated as the yellow bishydrochloride: mp 229-231O (methanol-ether); NMR (MezSO-ds) 6 1.8-2.5 (broad, 2, CHzCHzCHz), 3.3-3.8 (m, 2, CHz), 3.9-5.1 (m, 4, 2 CHz), 6.37 (9, 1, indole C3H), 6.6-8.4 (m, -9, aromatic CH=N), below 8.5 (3, very broad, 3 NH); ir (Nujol) 3600-2400 (NH), 1640 (C=N), 1608 cm-I (aromatic); uv 270 nm ( t 14,200), 348 (3010). Anal. Calcd for C19H19N~2HCl(362.3): C, 63.0; H, 5.9; N,11.6; C1, 19.6. Found: C, 62.8; H, 6.1; N, 11.5; C1, 19.8. 7,8,9,10-Tetrahydro-9-methyl-6H-indole[2,l-c][ 1,4,8]benzotriazacycloundecine (6b). A mixture of 2.0 g (0.007 mol) of the amine 4 and 10.0 g (0.07 mol) of methyl iodide in 50 ml of chloroform was heated to reflux for 3 hr. The solid was filtered off to yield 2.8 g (94%) of 5 , mp 212-213O. When the same reaction was carried out in methanol the product obtained had mp 231-233'. The salt was suspended in ether and after addition of 2 N NaOH a clear solution was obtained. The organic phase was dried over K2C03 and evaporated to give 1.9 g (90%)of 6b as a yellow solid, mp 158-159O. Recrystallization from methanol-water gave 1.4 g (66%) of 6b: mp 161-162"; m / e 303 (M+); NMR (CDC13) 6 2.35 ( 8 , 3, CH3), 1.7-2.7 (m, 4, CHZCHZNCH~), 3.38 ( 8 , 2, CsH4CHz), 4.72 (t, 2, J = 7.0 Hz, indole NCHz), 7.0 (s, 1, indole C3H), 7.1-7.8 (m, 8, 2 CeH4), 8.73 (s, 1, CH=N); ir (CHzClZ) 1630 (C=N), 1610 (weak), 1590 cm-'; uv 265 nm ( t 11,050), 270 (11,200), 286 (8120), 298 (7040), 336 (9750). Anal. Calcd for C Z ~ H Z(303.44): ~ N ~ C, 79.2; H, 7.0; N, 13.9. Found: C, 78.8; H, 7.1; N, 13.9. A small sample of 6b in methanol was treated with a few drops of hydriodic acid. The solution was stirred at room temperature for 2 hr. The solvent was evaporated and the residue recrystallized from methanol-ether to give 5: mp 239-240'; uv 215 nm (E 52,8001, 272 (16,390). Anal. Calcd for CzoH21N3-HI (431.35): C, 55.7; H, 5.2; N, 9.7. Found: C, 55.8; H, 5.6; N, 9.7.
+
5,5a,6,7,8,9,10,12-0ctahydroazepino[2,1-b]quinazo~ine (7). To the suspension of 5.3 g (0.14 mol) of LiAlH4 in 50 ml of T H F a solution of 9.8 g (0.046 mol) of 6,7,8,9,10,12-hexahydroazepino[2,l-b]quinazolin-12-0ne~~ in 300 ml of T H F was added dropwise. When the addition was completed the mixture was heated to reflux for 3 hr and then worked up with the usual precautions to give 8.9 g (96%) of 7 as a liquid, ir (film) 3380 (NH), 1610,1590 cm-'. A sample was treated with dry hydrogen chloride to give 7 HCl: mp 199-200"; m / e 202 (M+); NMR (CFsCOOW 6 1.6-2.4 (m, 6, 3 CHz), 2.8-3.4 (m, 2, CHz), 3.9-4.5 (m, 2, NCHd, 5.63 (s, 2,
Brzechffa, Eberle, and Kahle CsHdCHzN), 7.4-8.0 (m, 4, C6H4), 8.9 (t, 1, J = 3 Hz, N=CH); ir (Nujol) 3200 (NH), 1610, 1598 cm-' (both weak); uv 242 nm (C 97001, 292 (2100). Anal. Calcd for C13HlsNz.HCl (238.8): C, 65.4; H, 8.0; N, 11.7. Found: C, 65.5; H, 7.9; N, 11.4. 4,5,6,7,8,9-Hexahydro-8-methyl-3H-[ 1,8] benzodiazacycloundecine (9). A solution of 20.2 g (0.1 mol) of the amine 7 in 500 ml of CHC13 was treated with 60.0 g (0.42 mol) of methyl iodide. After 10 min at room temperature a solid started to precipitate. The mixture was stirred overnight, and the solid was collected by filtration and washed with chloroform to give 8, mp 218220'. This was stirred vigorously with 80 ml of 2 N NaOH in the presence of 300 ml of water and 500 ml of methylene chloride for 30 min. The organic layer was separated and the aqueous phase was extracted with additional methylene chloride. The combined organic phases were washed with water, dried over KzC03, and concentrated to give 21.0 g of 9 as a liquid. Distillation of 17 g of the crude gave 11.5 g (64%) of pure 9: mle 216 (M+); NMR (CDC13) 6 1.3-2.0 (m, 6, 3 CHz), 2.12 (s, 3, NCHs), 2.2-2.7 (m, 4, 2 CHz), 3.40 (9, 2, C ~ H ~ C H Z 6.6-7.4 ), (m, 4, C,&,), 7.68 (t,1, J = 5.5 Hz, N=CHCHz); ir (CHzC12) 1668 cm-' (C=N); uv 244 nm ( B 10,340), 289 (2481). A sample of the base was treated with dry HC1 to form 9 HC1, mp 210-211'. Anal. Calcd for C14HZoNrHCl (252.8): C, 66.5; H, 8.4; N, 11.1; C1,14.0. Found: C, 66.7; H, 8.1; N, 11.0; C1,13.8. 2,3,4,5,6,7,8,9-0ctahydro-8-methyl-l H-[ l,d]benzodiazacycloundecine (10). A solution of 6.0 g (0.028 mol) of the amine 9 in 100 ml of ethanol was hydrogenated in a Parr apparatus in the presence of 1.0 g of Pd/C (10%). A crude product was filtered through a silica gel column with benzene to give 5.2 g (86%) of 10. A sample was treated with dry hydrogen chloride to give 10 2HC1: mp 203-205' (ethanol-ether); mle 218 (M+); NMR (CDC13 MezSO-ds) 6 1.1-2.0 (m, 9, 4 CHz NH), 2.74 (s, 3, CH3), 2.8-3.3 (m, 4, 2 NCHZ),4.44 (9, 2, J = 12 Hz, Au = 10.6 Hz, C ~ H ~ C H Z N ) , 6.6-7.5 (m, 4, C&), 8.4-8.9 (broad, 2, "2); ir (Nujol) 3200-2700 (NH), 1590 cm-I (weak); uv 255 nm ( B 11,5281, 313 (2530). Anal. Calcd for C14Hz~N2-2HCl(291.3): C, 57.7; H, 8.3; N, 9.6; C1, 24.3. Found: C, 57.8; H, 8.1; N, 9.4; C1, 24.9.
+
+
Acknowledgments. We would like to thank Dr. W. J. Houlihan for his interest and support and Dr. S. Barcza and his staff for recording the spectra. Registry No.-1, 26304-37-0; 2, 56404-31-0; 3, 56404-30-9; 4, 56404-29-6; 4 HCl, 56404-28-5; 5 , 56404-27-4; 6bp 56421-60-4; 7, 56404-26-3; 7 HCl, 56404-25-2; 8,56404-24-1; 9,56404-23-0; 9 HCl, 56404-22-9; 10 HC1, 55661-92-2; anthranilic acid, 118-92-3; methyl iodide, 74-88-4; hydriodic acid, 10034-85-2.
References and Notes (a)M. G. Reinecke and R. G. Daubert, J. Org. Chem., 38,3281 (1973); (b) M. G. Relnecke and I?. F. Francis, ibid., 37, 3494 (1972); (c) M. G. Reinecke, L. R. Kray, and R. F. Francis, ibid., 37, 3489 (1972), and references cited In these papers. A. C. Cope, and E. R. Trumbull, Org. React., 11, 317 (1960). (a) S . Peterson and E. Tietze. Justus Liebigs Ann. Chem., 623, 166 (1959); (b) H. Meerwein, W. Florlan, N. Schon, and G. Stopp, ibid,, 641, I (196 1).
(a) E. Spath, and N. Platzer, Cbem. Ber., 68, 2221 (1935); (b) J. S. Fitzgerald, S.R. Johns, J. A. Lamberton. and A. H. Redcliffe, Aust. J. Chem., 19, 151 (1966): (c) R. Landl-Vittory and F. Gatta, Gazz. Chim. Ita/., 99, 59 (1969). E. E. Reynolds and J. R. Carson, German Patent 1,923,726; Cbem. Abstr., 72, 55528v (1970): US. Patent 3,689,503; Cbem. Abstr., 77, 1522419 (1972). M. K. Eberle and G. G. Kahle, Tetrahedron, 29,4045 (1973). M. K. Eberle and G. G. Kahle, Tetrahedron,29, 4049 (1973).
