synthesis of a pyrrolo[1,4]benzodiazepinequinone ricardo a. tapia,cesar r. centella and jaime a....

7/29/2019 Synthesis of a Pyrrolo[1,4]Benzodiazepinequinone Ricardo a. Tapia,Cesar r. Centella and Jaime a. Valderrama

1/6

SYNTHETIC COMMUNICATIONS, 29(12), 2163-2168 (1999)

SYNTHESIS OF A PYRROLO[1,4]BENZODIAZEPINEQUINONE

Ricardo A. Tapia*, Cesar R. Centella, and Jaime A . ValderramaFacultad de Quim ica, Pontificia Universidad Catolica de Chile.Casilla 306. Santiago-22, Chile.

Abs t r ac t : Condensation of 3,6-dimethoxy-2-nitrobenzoyl chloride withL-proline methyl ester afforded amide 4, which underwent reductivecycl izat ion wi th i ron(1l) sul fate and ammonium hydroxide to yieldpyrrolobenzodiazepine 5. Oxidation of 5 with ammonium cerium(lV) nitrateled to the new heterocyclic quinone 6 in 53% overa ll yield.

There are many naturally occurring and synthetic compounds having aheterocyclic ring fused to a quinone moiety that exhibit antitumor activity.It has been shown that both the quinone and heterocyclic ring are essentialfor the biological activity.2 In connection with our studies on the synthesisof he teroc ycl ic quinones,a we became interested in com bining aheterocyclic seven mem ber ring with a quinone ring as another example ofamalgamating two biologically active ring systems, in a search for novelanti-cance r activity.Considering that a number of pyrrolo[2,1 -c][l,4]be nzo diaz ep ines areknown for their antitumor activity,4 our objective was the synthesis of apyr ro lo [ 1,4]ben~odiazepinequinone.~n this work we describe thesynthesis of that new class of heterocyclic quinone from 3,6-dimethoxy-2-nitrobenzoic acid 3.

* To whom correspondence should be addressed.2163

Copyright 0 999 by Marcel Dekker, Inc. w w w .dekker .corn

Downlo

adedby[UniversityofReg

ina]at08:0808September2013


2/6

2164 TAPIA, CENTELL A, AND VALDERRAMAOxidation of 2,5-dimethoxyacetophenone 1 with commercial sodiumhypochlorite solution followed by reaction with nitric acid at 0 pC gave amixture of nitro isomers,6 which were separated by recrystallization fromethanol affording nitrocompound3 in 71Yooverall yield.

OH __j_N03 @OH + O 2 v O HNO2OMe OMe OMe

2 3Treatment of 3 with thionyl chloride and subsequent reaction of theresulting acid chloride with L-proline methyl ester furnished the amide 4,as a 1 :1 mixture of syn and anti rotamers, in 81Yo ield.7

OMe 0 O M e O C 02 M e OM e 0p H % Q p $ + y - - - -NO2 NO2

OMe OMe OM eH 03 4 5

6

a) SOC12; b) L-proline methyl ester, Et3N; c) FeS04; d) (NH4)2Ce(N03)6

Downlo




3/6

PYRROLO[ 1,4]BENZODIAZEPINEQUINONE 2165Reductive cyclization of compound 4 with iron(l1) sulfate and ammoniumhydroxide yielded the pyrrolobenzodiazepine 5 (86%). Then oxidativedemethylat ion of 5 with ammonium cerium(lV) nitrate (CAN)8 usingacetonitrile as solvent afforded the pyrrolobenzodiazepinequinone 6 in75% yield. Th e presence of two doublets at 6 6.92 and 7.05 ppm with acoupling constant of 10.2 Hz for quinone protons and the appearance oftwo signals at 6 183.5 and 184.8 ppm for carbonyl groups in the 1H and13C-NMR spectra respectively confirmed the structure of heterocyclicq u i n o n e 6 . Fur ther s tud ies on the b io log ica l ac t iv i ty o fpyrrolobenzodiazepinequinone6 are in progress.

EXPERIMENTAL

Melting points were determined with a Kofler hot-stage apparatus andwere not corrected. IR spectra were obtained on a Perkin-Elmer Model1310 spectrophotometer. 1H and 1% NMR spectra were recorded inCD CI3 on a Bruk er AM-200 spectrometer, using tetramethylsilane asinternal reference, and coupling constants are given in Hz. Columnchromatography was performed on Merck sil ica gel 60 (70-23 0 m esh).Elem ental analyses were obtained with a FISONS EA 1108 C H N S -0analyzer. Op tical rotations ([a] ) at the N a-D line were m easured on aPerkin-Elmer 241 MC polarimeter.

25

2,5Dimethoxybenzoic acid 2Oxidat ion of 2,5-dimethoxyacetophenone 1 (2.0g, 11.1 mrnoles) with9commercial sodium hypochlorite solution according to th e l i terature,yielded compound 2 (1.88 g, 93%); m.p. 76-78 gC (Lit.'' 76-77 %).3,6-Dimethoxy-2-nitrobenzoic acid 32,5-Dimethoxybenzoic acid 2 (4.0 g, 22 mmoles) was nitrated by a knownprocedure to give a mixture of nitro isomers. Fractional crystallizationfrom ethanol gave 3 (3.8 g, 76%); m.p. 192-193 % (Lit.

11,1211 193-194 %)

Downlo




4/6

2166 TAPIA, CENTELLA, AND VALDERRAMAMethy I (2S)-N- (3,6 d met ho x y -2-n t ro benz o y I)py r r o I d ne-2-carboxylate4To a solution of L-proline methyl ester hydrochloride (2.18 g, 13.2

mmoles) in tetrahydrofuran (50 mL) cooled at 0 T , triethylamine (3.7 mL,26.3 mmoles) was added dropwise. After stirring for 5 min, 3,6-dimethoxy-2-nitrobenzoyl chloride solution, prepared from 3,6-dimethoxy-2-nitrobenzoic acid 3 (3.0 , 13.2 mmoles) and thionyl chloride (10 mL), intetrahydrofuran (50 mL) was added. The reaction mixture was then stirredat room temperature fo r 12h. The resulting triethylarnine hydrochloridewas filtered and the filtrate was evaporated under reduced pressure. Theresidue was purified by column chromatography on silica gel with ethylacetate as eluent to give 4 (3.62 g, 81%), as a 1 1 mixture of syn and antirotamers; m.p. 116-117Vc;tR (KBrv,,,): 1760, 1630, 1530, 1430, 1450,1430, 1360, 1290 cm-1; IH-NMR 6 : 1.8-2.4 (m, 4H, 2xCH2), 3.2-3.5 (m,2H, CHz), 3.73 (s, 3H, OCH3), 3.84 (s , 6H, 2xOCH3), 4.60 (dd, 1 H, J = 3.4and 8.6 Hz, CH), 6.98 (d, lH , J = 9.5 Hz, ArH), 7.05 (d, lH , J = 9.5 Hz,ArH); 13C-NMR 6: 24.4 (24.6), 29.6, 30.3 (30.9), 47.7, 52.2, 58.6, 60.7,114.6 (114.9), 115.1 (115.9), 120.8 (121.8), 138.4 (138.8), 145.0 (145.4),148.6 (149.2), 162.0 (162.8), 171.7 (172.1); [a] D - 76 (C 2.0, CHC13);5Anal. Calc. for C15H18N207 : C, 53.25; H, 5.36; N, 8.28. Found: C, 53.28;H, .33; N, 8.33.(11as)-2,3,5,10,11,11 a-Hexahydro-6,9-dimethoxy-lHpyrrolo[2,1-c][l ,4] benzodiazepin-5,l -dione 5To a solution of iron (11) sulfate heptahydrate (18.0 g , 64.7 mmoles) andammonium hydroxide (6.5 mL) in water (80 mL), a solution of 4 ( 2.0 g , 6mmoles) in ethanol (80 mL) was added. The reaction mixture was heatedunder reflux for 6h, and after cooling the resultant suspension was filtered.The filtrate was evaporated under reduced pressure and the residue wasextracted with ethyl acetate (2x25 mL) and dried (MgS04). Removal of thesolvent left a residue which was purified by column chromatography onsilica gel with ethyl acetate- methylene chloride (1O:l) as eluent to yield 5(1.4 g, 86%); m.p. 213-214 *C; IR (KBr vmax): 3220, 2960, 1680, 1630,1310, 1260 cm-I; 1H-NMR 6: 1.8-2.8 (m , 4H, 2xCH2), 3.3-3.8 (m, H,CH2), 3.80 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 4.07 (m, l H , CH), 6.67 (d,l H , J = 9 . O H z , A r H ) , 6 . 8 5 ( d , l H , J = 9 . 0 H z , A r H ) , 7 . 8 1 (s,lH,NH);13C-

Downlo




5/6

PYRROLO[1,4]BENZODIAZEPINEQUINONE 2167NMR 6: 23.1, 26.0, 46.2, 56.2, 56.8, 56.9, 107.8, 112.3, 112.9, 117.8,25126.0, 152.6, 162.5, 171.4 ppm; [a] + 103 (c 2.0, CHCI,); Ana l. Calc.for C14H16N204: C , 60.86; H, 5.84; N, 10.14. Found: C, 61.03; H, 5.95; N,10.35.

(11aS)-2,3,5,10,11,1 a-Hexahydro-6,9-dimethoxy-lHpyrrolo[2,1-c] [l ,4] benzodiatepin-5,6,9,1 -tetraone 6To a stirred solution of 5 (100 mg, 0.36 mmoles) in acetonitrile (3 mL)cooled to 0 *C a solution of ammonium cerium (IV) nitrate (250 mg, 0.46mmoles) in water (2 mL) was added. After stirring for 30 min at roomtemperature the reaction mixture was quenched with water and thenextracted with ethyl acetate (2x10 mL). Removal of the solvent, andpurification of the residue by column chromatography on silica gel withethyl acetate as eluent gave 6 (60 mg, 75 %); m.p. 150 QC dec.); IR (KBrvmax):3435, 1720, 1670, 1625 cm-'; 1H-NMR 6: 1.8-2.8 (m , 4H, 2xCH2),3.3-3.8 (m , 2H, CH2), 4.60 (dd, I H , J= 1.7 and 6.1 Hz, CH), 6.92 (d , l H , J29.0, 47.2, 58.3, 121.0, 134.9, 137.5, 139.7, 160.7, 170.9, 183.5, 184.8ppm; [a] + 377 (c 2.0, CHC13); Anal. Calc. for C12H ioN204: C, 58.54;H, 4.09; N, 11.38. Found : C, 58.81; H, 4.27; N, 11.21.

= 10.2 Hz), 7.05 (d, l H , J = 10.2 Hz), 8.95 ( s , I H , NH); '3C-NMR 6:26.9,25

ACKNOWLEDGEMENTSThe authors acknowledge FONDECYT, Research Grant 2950045 and8980003.

REFERENCES AND NOTES1. Remers, W. A., "The Chemistry of Antitumor Antibiotics", Wiley, N.

Y., 1979, pp. 221-276. b) Berdy, J. "CRC Handbook of AntibioticCompounds" Vo l Ill, CRC Press, Florida, 1980, pp. 315-341. c)Giorgi-Renault , S.; Renault, J.; Gebel-Servolles, P.; Baron, M.;Paoletti, C.; Cros, S.; Bissery, M-C.; Lavelle, F. and Ghanem, A. J.Med. Chem. 1991, 34, 38. d) Tao, X.L.; Cheng, J-F.; Nishiyama, S .and Yamamura, S. Tetrahedron,1994, 50, 2017. e) Rao, K.V. andRock, C.P. J. Heterocycl. Chem. 1996, 33, 447.

Downlo




6/6

2168 TAPIA, CENTELLA, A N D VALDERRAMA2.3.

4.5.

6.

7.

8.9.10.11.

Yasuda, M. and Boger, D. L., J. Heterocycl. Chem. 1987, 24, 1253;and references therein.a) Tapia, R. A.; Garate, M. C.; Valderrama, J. A.; Jenkins, P. R.;Fawcett, J. and Russell, D. R. Tetrahedron Left. 1997, 38, 153. b)Zuloaga, F.; Tapia, R. A. and Quintanar, C. J. Chem. SOC.PerkinTrans. 2, 1995, 939. c) Tapia, R. A.; Valderrama, J. A. andQuintanar, C. Heterocycles,1994, 38, 1797.a) Hurley, L. H., J. Antibiot. 1977,30, 349. b)Needham-VanDevanter,D. R. Ace. Chem. Res.1986, 19,230.F o r a recent rev iew on the syn thes is of pyrrolo[2,1-c][l,4]benzodiazepines, see: Thurston, D. E.; Bose, D. S., Chem.Rev. 1994, 94, 433.a) Azadi-Ardakani, M. and Wallace, T. W. Tetrahedron Lett. 1983,24, 1829. b) Villani, F. J. and Lang, J. J. Am. Chem. SOC.1950, 72,2301.Two singlets at 6 4.63 and 4.67 ppm, in aproximately 1 1 ratio, were

obtained for the me thine proton after irradiation of the mu ltiplet at 61.8-2.4 ppm. The above signals colapsed to one singlet when thesample is heated at 60 *C .Kitahara, Y.; Nagatsu, M.; Shibano, Y. and K ubo, A. Chem. Pharm.Bull. 1997, 45, 1697.Vogel, A."Textbook of Practical Organic Synthesis" 4th Ed. Longrnan,New York, 1978, pp. 477.Bost, R. W. and. Howe, C. A. J. Amer. Chem. SOC.1951, 73,5864.Azadi-Ardakani, M. and W allace, T. W. Tetrahedron Lett. 1983, 24,1829.

12. Howe, C. A.; Howe, A.; Harnel, C. R.; Gibson, H. W. and Flynn, R. R.J. Chem. SOC. 965,795.

( R e c e i v e d i n t h e USA TO Novembe r 1998)Downlo



synthesis of a pyrrolo[1,4]benzodiazepinequinone ricardo a. tapia,cesar r. centella and jaime a....

Documents