1438 J. Org. Chem., Vol. 40, No. 10, 1975
Evens and Caluwe
Pyrido[2,3- dlpyrimidines. Latent 2-Aminonicotinaldehydes Georges Evens and Paul Caluwe* State University
of
New York, Polymer Research Center, College of Environmental Science and Forestry, Syracuse, New York 13210 Received October 21,1974
Friedlander condensation of 4-aminopyrimidine-5-carboxaldehydewith aromatic ketomethylenes resulted in the formation of 7- and 6,7-disubstituted pyrido[2,3-cl]pyrimidines.Facile ring opening of the pyrimidine moiety of this heterocyclic system gave substituted 2-aminonicotinaldehydes. Incorporation of the ortho amino aldehyde functional pair in aromatic substrates virtually ensures the successful construction of a variety of N-heterocyclic ring structures. However, utilization of this functional pair is severely limited by the difficult elaboration of the two functional groups in the required ortho position. I t is not surprising, therefore, that in the synthesis of quinolines the Pfitzinger modification is preferred instead of the more direct Friedlander condensation utilizing o -aminobenzaldehyde.l Methods available in the literature for the construction of the o-amino aldehyde functional pair are essentially twofold: nitration of a methyl aromatic compound and oxidation of the methyl group followed by reduction of the nitro function and generation of the aldehyde function from appropriate o -aminocarboxylic acid derivatives (e.g., McFayden-Stevens rearrangement of o -aminotosylhydrazides) .2a,b Both methods require separate elaboration of the functional groups and this generally results in lengthy synthetic procedures. The first method is generally successful in carbocyclic ring structures; the second has found limited application in heterocyclic systems. Neither method is readily adapted for the introduction of substituents in the aromatic or heterocyclic ring carrying the o-amino aldehyde functional pair. In earlier work we described a facile synthesis of 2-aminonicotinaldehyde from the readily available 2-(3'-pyridyl)pyrid0[2,3d]pyrimidine.~ In this synthesis both the aldehyde and amino functions, in the desired ortho positions, were formed in a single reaction step. Since the inaccessibility of ring-substituted o -amino aldehydes constitutes the main limitation for their synthetic utility, exploration of a similar sequence for the synthesis of 2-aminonicotinaldehydes substituted in the pyridine ring seemed desirable. This paper reports a general synthesis of 7- and 6,7-substituted pyrido[2,3-cl]pyrimidines and their acid-catalyzed conversion to substituted 2-aminonicotinaldehydes. Two general strategies for the synthesis of pyridopyrimidines can be envisioned: annelation of the pyridine nucleus to a pyrimidine ring already in being and formation of the pyrimidine moiety from appropriately functionalized pyridines. Previous experience in the annelation of pyridine rings via the Friedlander condensation prompted us to explore a similar sequence for the synthesis of the pyridine moiety of pyrido[2,3d]pyrimidine. This approach requires 4-aminopyrimidine-5-carboxaldehyde ( l ) ,readily obtained from 4-aminopyrimidine-5-carbonitrileby hydrogenolysis of the nitrile group.4 Base-catalyzed condensation of 1 with
1
2
3
aromatic ketomethylenes proceeded in high yield and resulted in the formation of 7- and 6,7-substituted pyrido[2,3cllpyrimidines (3) (Table I).
Inspection of Table I indicates that this condensation reaction is generally successful for the two types of aromatic ketomethylenes: ArC(=O)CHzR and ArCHzC(=O)R (R = alkyl, aryl). Aliphatic ketones (acetone, cyclohexanone), on the other hand, failed to react similarly, although they Apparcondense smoothly with 2-aminoni~otinaldehyde.~ ently 1 is less reactive towards ketomethylenes, supported by the fact that no condensations take place with piperidine as catalyst, although this is highly effective in promoting condensations with 2-aminoni~otinaldehyde.~ The pyrido[2,3-d]pyrimidinesobtained by the above reaction contain no oxo or amino substituents in their pyrimidine moiety, as is the case in most synthetic routes leading to this ring system.6 Acid-catalyzed hydrolysis of the substituted pyrido[2,3dlpyrimidines (3a-f) resulted in ring opening of the pyrimidine moiety with formation of the o-amino aldehyde functional pair in excellent yield (Table 11). The structures of the substituted 2-aminonicotinaldehydes (4a-f) are based upon their analytical and spectral data, which are in excellent agreement with their formulation. Their ir spectra
3
4
show particularly characteristic absorptions a t 3400, 3250, 3150 (NH2), and 1660 cm-l (C=O) and their NMR spectra show the proper absorptions and proper counts (see Table IV, supplementary material). Inspection of Table I1 indicates t h a t a variety of substituents can be incorporated into the 5 and 6 positions of the pyridine ring carrying the o -amino aldehyde functional pair. This choice of substituents is limited only by the necessity of utilizing aromatic ketomethylenes in the condensation with 1. Condensations with arylacetaldehydes which would lead to 5-aryl-2-aminonicotinaldehydeswere not carried out owing to the instability of the ketomethylenes under the basic reaction conditions employed for the formation of 3. The lower yield of 2-amino-5-phenyl-6methylnicotinaldehyde (4d) is probably due to self-condensation of this highly reactive compound under the acidic conditions of the hydrolysis reaction. The driving force for t h e transformation 3 4 is the acid-catalyzed covalent hydration of the pyrido[2,3d]pyrimidine system,s followed by irreversible ring opening of the pyrimidine moiety. Occurrence of covalent hydrations is well documented in similar N-heterocyclic systems such as pteridine, which on degradation is converted into 2-aminopyrazine-3-carboxaldeh~de.~ The pyrimidine moiety of the pyrido[2,3-d]pyrimidine system is thus employed as "latent" l o o-amino aldehyde functional pair, readily unmasked under mild reaction conditions. Phenomenologically the above reaction consists of the following transformation. -f
J.Org. Chem., Vol. 40,No. 10, 1975
1439
Table I
Pyrido[2,3-d]pyrimidines(3) Obtained from 4-Aminopyrimidine-j-carb~xaldehyde~ Compd
Registry no.
R
R'
Yield, % Mp, ' C
11,
Nmr, 6 '*
cm-lbpd
a
54595-53-8 C6H5 H 84 188.5 1600, 1580, 1530 9.63 (s, l), 9.51 (s, 1) 54595-54-9 C6H5 C,H, 75 157 1600, 1570, 1540 9.60 (s, l), 9.55 (s, 11, 8.33 (s, H-5) C 54595-55-0 CsH5 CH3 75 169 1600, 1580, 1524 9.48 (s, 11, 9.41 (s, 11, 2.58 (s, 3, CH,) d 54595-56-1 CH3 C6H, 80 203 1605, 1585, 1575, 1550 9.53 (s, l ) , 9.46 (s, l), 2.75 (s, 3, CH,) e 54595-57-2 2-Pyridyl H 85 200 1605, 1590, 1570, 1545 I 54595-58-3 2-Naphthyl H 82 272 1600, 1530 a Satisfactory analytical data (i0.270 for C, H, N) were reported for all compounds, b Nujol mull, c CDCls. d Full spectral data are given in supplementary pages; see paragraph a t end of paper.
b
Table I1 2-Aminonicotinaldehydes (4) Obtained from Pyrido[2,3-d]pyrimidinesa R
Compd
Registry no.
a
5298-01-1 54595-59-4 54595-80-7 54595-61-8 54595-62-9
b C
d
e
Yiefd,
R'
C6H5 C6H5 C6H5 CH, 2-Pyridyl
%
H C6H5 CH, C6H5 H
90 95 90 60 95
Mp, 'C
137 202 160 160 134
If,
1650, 1670, 1660, 1660, 1650,
c m - 1b*d
1600, 1605, 1610, 1610, 1640,
1575, 1580, 1580, 1535 1600,
Nmr,
1540 1525 1535 1570,
6c9d
9.85 (s, 1, CHO), 6.83 (br, 2, 10.03 ( s , 1, CHO) (DMSO-ds) 9.90 (s, 1, CHO), 6.75 (br, 2, 9.86 (s, 1, CHO), 7.00 (br, 2, 9.93 (s, 1, CHO), 6.86 (br, 2,
NH2)
NH2) NH,) NH,)
1520
f
54595 -63 -0 2 -Naphthyl H 90 181 1670, 1600, 1570, 1540 9.98 ( S , 1, CHO) ( D M s 0 - d ~ ) Satisfactory analytical data (*0.2% for C, H, N) were reported for all compounds. b Nujol mull; all spectra contained NHz and CH bands at 3400-3100 and 2700-2800 cm-1. c CDCls unless otherwise noted. d Full spectral data are given in supplementary pages; see paragraph at end of paper. a
Y$(Z - - gCHO "*
compounds which can be sublimed readily without decomposition. Spectroscopic data are collected in Table IV (supplementary material).
R
1
4
From this viewpoint the pyrimidine ring of 1 can be considered as a latent pyridine nucleus. I t is interesting t o note that during this transformation the functionality of the system remains the same; Le., the o-amino aldehyde pair is present in both 1 and 4 in the same relative positions. In conclusion we would like to emphasize that the synthesis of substituted aminonicotinaldehydes as described herein is of particular utility since the starting materials are readily available and a variety of substituents are therefore easily introduced. Furthermore, it seems to us t h a t the o-amino aldehydes thus obtained may serve as useful starting materials for functionalized pyridine derivatives via known functional group transformations. Experimental Section Melting points are uncorrected. Infrared spectra were recorded on a Perkin-Elmer Model 137 spectrophotometer. Nuclear magnetic resonance spectra (NMR) were measured with a Varian Associates A-60 spectrometer and chemical shifts (6) are reported in parts per million downfield from Me&. Mass spectra were observed in these laboratories with an Hitachi Perkin-Elmer instrument, Model RMUGE. Microanalyses were done by Galbraith Laboratories, Inc., Knoxville, Tenn. Generalized Procedure for the Preparation of Pyrido[2,3dlpyrimidine (3). To a refluxing solution of 4-aminopyrimidine5-carboxaldehyde (5 mmol) and the ketomethylene (5 mmol) in ethanol (25 ml) were added 5 drops of a 20% KOH solution in methanol. The mixture was refluxed for 12-48 hr; the precipitate was collected and recrystallized from a suitable solvent. The pyrido[2,3d]pyrimidines reported in Table I are colorless crystalline compounds. Their spectroscopic characteristics are collected in Table I11 (supplementary material). Generalized Procedure for the Preparation of 2-Aminonicotinaldehydes (4). The pyrido[2,3-d]pyrimidine (5 mmol) was refluxed in 2 N HC1 (500 ml) for 2-5 hr. The mixture was neutralized (NH40H) and the precipitate was collected and recrystallized from suitable solvents.11The 2-aminonicotinaldehydes are yellow
Acknowledgment. This research was sponsored by the
U. S. Army Research Office, Durham, N.C. We wish to express appreciation to Professor M. Szwarc, without whose help this investigation would not have been possible. We thank Mr. Kuen-Wai Chiu for carrying out some preliminary experiments. Registry No.-1, 16357-83-8; 2a, 98-86-2; 2b, 451-40-1; 2c, 9355-0; 2d, 103-79-7; 213, 1122-62-9; 2f, 93-08-3. Supplementary Material Available. Additional spectral data for compounds 3 and 4 will appear following these pages in the microfilm edition of this volume of the journal. Photocopies of the supplementary material from this paper only or microfiche (105 X 148 mm, 24X reduction, negatives) containing all of the supplementary material for the papers in this issue may be obtained from the Journals Department, American Chemical Society, 1155 16th St., N.W., Washington, D.C. 20036. Remit check or money order for $4.00 for photocopy or $2.50 for microfiche, referring to code number JOC-75-1438. References and Notes ( 1 ) L. A. Paquette, "Principles of Modern Heterocyclic Chemistry", W. A. Benjamin, New York, N.Y., 1968, pp 277-278. (2) (a) J. S. McFayden and T. S. Stevens, J. Chem. SOC.,584 (1936). (b) A. Albert and F. Reich, J. Chem. SOC.,1372 (1960). (3) T. G.Majewicz and P. Caluwe, J. Org. Chem., 39, 720 (1974). (4) H. Bredereck, G.Simchen, and H. Traut, Chem. Ber., 100, 3364 (1967). (5)E. M. Hawes and D. G. Wibberley, J. Chem. 5oc. C, 315 (1966). (6) For a review on the synthesis of pyridopyrimidines, see W. J. Irwin and D. G.Wlbberley, Adv. Heterocycl. Chem., I O , 149 (1969). (7) W. L. F. Armarego, J. Chem. SOC.,4094 (1962). (8) Review: A. Albert and W. L. F. Armarego, Adv. Heterocycl. Chem., 4, 1 (1965). (9) A. Albert and H. Yamamoto, J. Chem. SOC.,2289 (1968). (10) For a review on latent functionality, see D. Lednicer, Adv. Org. Chem., 8, 179-293 (1972). (11) Of all substituted 2-aminonicotinaldehydes reported herein, 2-amino-6phenylnicotinaldehyde (4a) had been prepared previously by McFaydenStevens rearrangement (see ref 5). The reported melting point (124125O) is significantly different from 137' reported in Table 11, obtained on samples recrystallized from EtOH. Superior analytical data and excellent spectral characterization indicate higher purity of our sample.
