RSS-Feed abonnieren
DOI: 10.1055/s-0029-1219544
Efficient One-Pot Synthesis of 6-Arylpyrrolo[3,2-d]pyrimidines from 6-Arylethynyl-5-nitropyrimidines
Publikationsverlauf
Publikationsdatum:
23. Februar 2010 (online)

Abstract
A highly concise one-pot synthesis of 6-arylpyrrolo[3,2-d]pyrimidines via conjugative addition reaction of secondary amines to 6-arylethynyl-5-nitropyrimidines and subsequent reduction is described.
Key words
pyrrolo[3,2-d]pyrimidines - 6-arylethynyl-5-nitropyrimidines - enamines - cyclization
- 1a
Farutin V.Masterson L.Andricopulo AD.Cheng J.Riley B.Hakimi R.Frazer JW.Cordes EH. J. Med. Chem. 1999, 42: 2422Reference Ris Wihthout Link - 1b
Evans GB.Furneaux RH.Gainsford GJ.Hanson JC.Kicska GA.Sauve AA.Schramm VL.Tyler PC. J. Med. Chem. 2003, 46: 155Reference Ris Wihthout Link - 2a
Gangjee A.Li W.Yang J.Kisliuk RL. J. Med. Chem. 2008, 51: 68Reference Ris Wihthout Link - 2b
Bavetsias V.Jackman AL. Curr. Med. Chem. 1998, 5: 265Reference Ris Wihthout Link - 3
Norman MH.Chen N.Chen Z.Fotsch C.Hale C.Han N.Hurt R.Jenkins T.Kincaid J.Liu L.Lu Y.Moreno O.Santora VJ.Sonnenberg JD.Karbon W.
J. Med. Chem. 1994, 37: 1526 ; and ref. 16-19 therein - 4a
Fredholm BB.Zerman AP.Jacobson KA.Koltz K.-N.Luiden J. Pharmacol. Rev. 2001, 53: 527Reference Ris Wihthout Link - 4b
Grahner B.Winiwarter S.Lanzner W.Muller CE. J. Med. Chem. 2000, 43: 4288Reference Ris Wihthout Link - 4c
Stefanachi A.Nicolotti O.Leonetti F.Cellamare S.Campagna F.Loza MI.Brea JM.Mazza F.Gavuzzo E.Carotti A. Bioorg. Med. Chem. 2008, 16: 9780Reference Ris Wihthout Link - 5a
Pfleiderer M. Chem. Ber. 1957, 90: 738Reference Ris Wihthout Link - 5b
Kawahara N.Nakajima T.Itoh T.Ogura H. Chem. Pharm. Bull. 1985, 33: 4740Reference Ris Wihthout Link - 5c
Sizova OS.Glushkov RG. Pharm. Chem. J. 1984, 18: 420Reference Ris Wihthout Link - 5d
Brahta M.Daves GD.
J. Chem. Soc., Perkin Trans. 1 1992, 1883Reference Ris Wihthout Link - 5e
Majumdar KC.Das U.Jana NK. J. Org. Chem. 1998, 63: 3550Reference Ris Wihthout Link - 5f
De Jong RL.Davidso JG.Dozeman GJ.Fiore PJ.Giri P.Kelly ME.Puls TP.Seamans RE. Org. Process Res. Dev. 2001, 5: 216Reference Ris Wihthout Link - 5g
Majumdar KC.Mondal S. Tetrahedron 2009, 65: 9604Reference Ris Wihthout Link - 5h
Song JJ.Tan Z.Reeves JT.Fandrick DR.Lee H.Yee NK.Senanayake CH. Tetrahedron Lett. 2009, 50: 3952Reference Ris Wihthout Link - 6a
Cupps TL.Wise DS.Townsend LB. J. Org. Chem. 1983, 48: 1060Reference Ris Wihthout Link - 6b
Cupps TL.Wise DS.Townsend LB. Tetrahedron Lett. 1982, 23: 4759Reference Ris Wihthout Link - 6c
Otmar M.Masojidkova M.Budesinsky M.Holy A. Tetrahedron 1998, 54: 2931Reference Ris Wihthout Link - 6d
Evans GB.Furneaux RH.Hutchison TL.Kezar HD.Morris PE.Schramm LT.Tyler PC. J. Org. Chem. 2001, 66: 5723Reference Ris Wihthout Link - 7a
Rodriguez AL.Koradin C.Dohle N.Knochel P. Angew. Chem. Int. Ed. 2000, 39: 2488Reference Ris Wihthout Link - 7b
Susvilo I.Brukstus A.Tumkevicius S. Synlett 2003, 1151Reference Ris Wihthout Link - 7c
Cikotiene I.Pudziuvelyte E.Brukstus A. J. Heterocycl. Chem. 2008, 45: 1615Reference Ris Wihthout Link - 8a
Muller TE.Beller M. Chem. Rev. 1998, 98: 675Reference Ris Wihthout Link - 8b
Beller M.Riermeier TH. In Transition Metals for Organic Synthesis Wiley-VCH; Weinheim: 1998.Reference Ris Wihthout Link - 8c
Teles JH.Brode S.Chabanas M. Angew. Chem. 1998, 110: 1478Reference Ris Wihthout Link - 8d
Koradin C.Dohle W.Rodriguez AL.Schmid B.Knochel P. Tetrahedron 2003, 59: 1571Reference Ris Wihthout Link - 9a
Cikotiene I.Morkunas M.Motiejaitis D.Rudys S.Brukstus A. Synlett 2008, 1693Reference Ris Wihthout Link - 9b
Cikotiene I.Kairys V.Buksnaitiene R.Morkunas M.Motiejaitis D.Rudys S.Brukstus A.Fernandes MX. Tetrahedron 2009, 65: 5752Reference Ris Wihthout Link - 9c
Cikotiene I.Morkunas M. Synlett 2009, 284Reference Ris Wihthout Link - 9d
Cikotiene I.Morkunas M.Rudys S.Buksnaitiene R.Brukstus A. Synlett 2008, 2799Reference Ris Wihthout Link - 10
Cikotiene I.Pudziuvelyte E.Brukstus A.Tumkevicius S. Tetrahedron 2007, 63: 8145
References and Notes
Typical Procedure
for the Preparation of 2,4-Disubstituted 6-Arylpyrrolo[3,2-
d
]pyrimidines
4a-o
To a solution of the corresponding 6-arylethynyl-5-nitro-pyrimidine 1a-p (0.3
mmol) in MeOH (5 mL) freshly distilled Et2NH (21,9 mg,
0.3 mmol) was added. The resulting reaction mixture was refluxed
for 15 min, then deeply red solution was cooled to r.t., 10% Pd/C
(0.33 mg, 0.03 mmol) was added, and the resulted mixture was stirred under
H2 atmosphere for 2 h. After the completion of the reaction,
the catalyst was filtered off, the mother liquid was evaporated
under reduced pressure, the residue washed with H2O,
filtered, and recrystallized to give compounds 4a-p.
4-Amino-6-phenylpyrrolo[3,2-
d
]pyrimidine
(4a)
Yield 98%; mp 226-227 ˚C
(from DMF-H2O). IR (KBr): νmax = 3444,
3441, 3396 (NH, NH2) cm-¹. ¹H
NMR (300 MHz, DMSO-d
6): δ = 6.81
(br s, 2 H, NH2), 6.86 (s, 1 H, C7H), 7.38 (t, J = 7.5 Hz,
1 H, ArH), 7.51 (t, J = 7.5
Hz, 2 H, ArH), 7.87 (d, J = 7.5
Hz, 2 H, ArH), 8.11 (s, 1 H, C2H), 11.64 (br s, 1 H, NH) ppm. ¹³C
NMR (75 Hz, DMSO-d
6): δ = 98.6,
114.7, 125.1, 128.3, 129.0, 131.1, 131.4, 139.4, 150.2, 150.7 ppm.
Anal. Calcd for C12H10N4: C, 68.56;
H, 4.79; N, 26.65. Found: C, 68.37; H, 4.51; N, 26.88.
4-Amino-2-methylthio-6-phenylpyrrolo[3,2-
d
]pyrimi-dine
(4e)
Yield 82%; mp 235-237 ˚C
(from DMF-H2O). IR (KBr): νmax = 3446,
3443, 3398 (NH, NH2) cm-¹. ¹H
NMR (300 MHz, DMSO-d
6): δ = 2.45
(s, 3 H, SCH3), 6.77 (s, 1 H, C7H), 7.14 (br s, 2 H,
NH2), 7.36 (t, J = 7.5
Hz, 1 H, ArH), 7.49 (t, J = 7.5
Hz, 2 H, ArH), 7.91 (d, J = 7.5
Hz, 2 H, ArH), 12.19 (br s, 1 H, NH) ppm. ¹³C
NMR (75 Hz, DMSO-d
6): δ = 13.4,
98.8, 112.9, 125.2, 127.4, 128.1, 131.5, 139.5, 148.8, 150.3, 160.6
ppm. Anal. Calcd for C13H12N4S:
C, 60.91; H, 4.72; N, 21.86. Found: C, 60.77; H, 4.66; N, 21.99.
4-Morpholino-6-phenylpyrrolo[3,2-
d
]pyrimidine
(4p)
Yield 88%; mp >230 ˚C
(dec.; from MeOH). IR (KBr): νmax = 3341
(NH) cm-¹. ¹H NMR
(300 MHz, CDCl3): δ = 3.87
(br s, 8 H, morpholino), 6.86 (s, 1 H, C7H), 7.41-7.48
(m, 3 H, ArH), 7.72 (d, J = 7.2
Hz, 2 H, ArH), 8.52 (s, 1 H, C2H), 9.23 (br s, 1 H, NH) ppm. ¹³C
NMR (75 Hz, CDCl3): δ = 46.8,
66.6, 100.9, 116.4, 125.9, 129.1, 129.2, 131.2, 142.1, 150.8, 150.9,
151.4 ppm. Anal. Calcd for C16H16N4O:
C, 68.55; H, 5.75; N, 19.99. Found: C, 68.50; H, 5.66; N, 20.08.
Compounds 4b-d,f-o and 5a were also fully characterized by IR, ¹H NMR, ¹³C NMR spectroscopic and microanalytical data.