J. Org. Chem. 1985, 50, 4865-4872
two br s, N(l)-H, N(3)-H, and amide NH, no assignments made), 7.86 (1 H, s, 7-H), 7.56-6.95 (5 H, complex m, phenyl), 2.11 (3 H, s, methyl of 6-acetamido group); IR (KBr) 3445, 3312,1733, 1696,1493,1396 cnT1; MS (El mode) mje 324 (M+), 282 (M+ HN=C=0). Anal. Calcd for C16H12N404-2.5H20: C, 52.03; H, 4.64; N, 15.16. Found: C, 51.94; H, 3.19; N, 15.02. The percentage of hydrogen is seen to deviate widely. 6-Amino-7-bromoquinazoline-2,4,5,8-(lif,3JJj-tetrone (10). A mixture of 0.107 g (0.43 mmol) of 1 and 1.0 mL of bromine in 20 mL of acetic acid was heated at reflux for 5 min. Upon cooling of the reaction to room temperature, the purple precipitate was filtered off and washed with diethyl ether: yield of 10 as an analytically pure purple microcrystalline solid 0.10 g (87%); mp dec pt >300 °C; TLC [butanol-acetic acid-H20 (5:2:3)] on silica gel, fyO.51; IR (KBr) 3174,1754,1710,1591,1502,1387 cm'1 MS (El mode) mje 287 (M+ + 2), 244 (M+ + 2 0=C=NH), 206 (M+ HBr). Anal. Calcd for C8H4BrN304: C, 33.58; H, 1.40; N, 14.67. Found: C, 33.50; H, 1.40; N, 14.57. pKa for N(l) proton dissociation is 5.62 ± 0.08. UV data Xmal, nm (e): (10) 286 (1 X 104), 326 (1.66 X 104), 508 (1200), (10") 274 (1.3 X 104), 350 (2.3 X 104), 480 (690).
C10H7N3O5-0.75H2O: C, 45.72; H, 3.26; N, 15.98. Found: C, 45.81;
H, 3.04; N, 15.77.
6-(Methylamino)-8-(methylimino)quinazoline-2,4,5(lfT,3H)-trione (3). Addition of 0.19 g (0.76 mmol) of 1 to 5
-
mL of 40% aqueous monomethylamine was followed by heating at reflux for 15 min. After the reaction mixture was chilled for 1 h, the red product was filtered off and washed with water and then methanol. Recrystallization from 4 N HC1 afforded fibrous red crystals: 0.10 g (56%); mp 220-250 °C with evolution of gas; TLC [butanol-acetic acid-H20 (5:3:2)] on silica gel, Rf 0.22 as a red spot; 'H NMR (trifluoroacetic acid-di with 1 drop of D20 against Me4Si) 5 6.00 (1 H, s, 7-H), 3.44 and 3.37 (6 H, two s, aminomethyl and iminomethyl, no assignments made); 13C NMR (trifluoroacetic acid-dj with 1 drop of D20, against Me4Si) 5 158.8, 145.8,138.0,137.2,136.6,136.1, 90.2, 72.1 (no assignments made), 16.1 and 14.7 (methyl groups); MS (El mode) mje 234 (M+), 203 (M+ CO), 190 (M+ HN=C=0), 178 (M+ HC=CNHCH3); IR (KBr) 3232,1641,1635,1596,1525,1499,1464,1413 cm'1. Anal. Calcd for C10H10N4O3-1.25H2O: C, 46.78; H, 4.90; N, 21.81. Found:
J. Org. Chem. 1985.50:4865-4872. Downloaded from pubs.acs.org by AUCKLAND UNIV OF TECHNOLOGY on 01/29/19. For personal use only.
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-
4865
*;
-
-
-
C, 46.75; H, 4.44; N, 21.44.
8-(Phenylimino)-6-acetamidoquinazoline-2,4,5-(lH,3H)trione (11). A mixture consisting of 200 mg (0.80 mmol) of 1, 2.0 g of aniline, and 10 mL of DMF was heated at reflux for 2 min. Upon cooling to room temperature, the volume of the reaction mixture was diluted to 50 mL with water. After chilling for 12 h, this mixture yielded red crystals that were filtered and recrystallized from ethanol: yield of copper-colored flakes 51.5 mg (20%); dec pt >250 °C; TLC [butanol-acetic acid-H20 (5:2:3)] on silica gel, Rf 0.51; XH NMR (Me2SO-d6) S 11.18 and 9.57 (3 H,
Acknowledgment. The research was supported by a Faculty Grant-in-aid from Arizona State University, a Cottrell Research Grant from the Research Corp., a grant from the Petroleum Research Foundation, and an award from the National Cancer Institute, Grant DHHS (PHS# 1 R01 CA 36876-01).
Proton-ionizable Crown Compounds. 2. Synthesis, Complexation Properties, and Structural Studies of Macrocyclic Polyether-Diester Ligands Containing a 4-Hydroxypyridine Subcyclic Unit11 S. Bradshaw,* Mary Lee Colter, Yohji Nakatsuji,1 Neil O. Spencer, Michael F. Brown,§ Reed M. Izatt,* Giuseppi Arena,1 Pui-Kwan Tse, Bruce E. Wilson, John D. Lamb, and
Jerald
N. Kent Dailey
Department of Chemistry, Institute for Thermochemical Studies, Brigham Young University, Provo, Utah 84602
Frederick G. Morin and David M. Grant* Department of Chemistry, University of Utah, Salt Lake City, Utah 84112 Received May 6, 1985
A series of macrocyclic polyether-diester ligands containing a proton-ionizable 4-hydroxypyridine subcyclic unit has been prepared. These new macrocyclic ligands form stable complexes with both alkylammonium perchlorate salts and with alkylamines. The crystal structure for one of these complexes with an alkylamine shows that the hydroxy proton has been donated to the amine with the resultant formation of a 4-pyridone unit. Chiral dimethyland diphenyl-substituted macrocycles containing the 4-hydroxypyridine subcyclic unit exhibit chiral recognition for the enantiomers of 2-(l-naphthyl)ethylamine and their hydrogen perchlorate salts.
We are interested in the design of host macrocycles which show selectivity toward guest molecules and ions, especially those with enantiomeric properties. An important aspect of such design is the creation of host molecules capable of exchanging protons on the host for
the guest ions of interest at membrane interfaces. Such capability could lead to the design of selectivity into an appropriate membrane system making continuous proton-coupled ion transport possible. The feasibility of proton-coupled transport of alkali metal cations by calixarenes has been shown,1 and selectivity for Cs+ over other alkali cations in mixtures of these has been demonstrated.2
Permanent address: Faculty of Engineering, Osaka University, Japan.
Permanent address: Department of Chemistry, University of Catania, Italy. 1
5 1
Deceased,
April
(1) Izatt, R. M.; Lamb, J. D.; Hawkins, R. T.; Brown, P. R.; Izatt, S. R.; Christensen, J. J. J. Am. Chem. Soc. 1983, 105, 1782. (2) Izatt, S. R.; Hawkins, R. T.; Christensen, J. J.; Izatt, R. M. J. Am. Chem. Soc. 1985, 107, 63.
14, 1985.
Contribution No. 363.
0022-3263/85/1950-4865$01.50/0
©
1985 American Chemical Society
4866
J. Org. Chem., Vol. 50, No. 24, 1985
Bradshaw et al. A.
Benzyl-Blocked, Eeter
B.
Tetrahydropyran-Blocked Eater
N-N
Ry0 ko
H
°YR ck
k^Ovk 1, R=H 2, R=CH,(S, S)
OCH,Ph I
.0
0
'o Cc
o
» c0 '0
0
3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14,
n=o, n=1, n=1, n=1, n=1, n=1, n=2, n=1, n=1, n=1,
n:2,
R,=PhCH2,R2=H R,=PhCH2, R2=H R,=THP, R2=H R,=PhCH2, R^CH, R,=PhCH2, R2=CH3(§, S) R,=PhCH2, R,=Ph (S, S) R,=PhCH2, R2=H R,, R2=H R,=H, R2=CH3(S, §) R,=H, R2=Ph (R. R) R,=R2=H
3
o
Figure
2.
Preparation of starting diester compounds.
Results and Discussion OCH jPh
10
Figure
1.
Structures of compounds.
We have prepared two new classes of proton-ionizable macrocycles based on the cyclic polyether structure in which the ionizable function is part of the macrocyclic ring. The synthesis, complexation properties, and structural studies of diester macrocycles from one of these classes which contains a proton-ionizable triazole subcyclic unit was reported recently by us3 (see compounds 1 and 2, Figure 1). The work of others which involves protonionizable crown compounds has been reviewed by us.3 The triazole-containing macrocycles complexed with amines in a manner that involved the transfer of the proton of the triazole ring to the amine. In fact, the complex of 1 with benzylamine was kinetically more stable than its complex with benzylammonium perchlorate.3 We now report the synthesis, some complexation reactions, and structural properties of a second class of diester crown compounds containing a proton-ionizable 4hydroxypyridine subcyclic unit (compounds 11-14, Figure 1). A preliminary publication describing compound 11 and its properties as compared to ligand 15, the non-ester analogue of 11, has been published.4 These new protonionizable ligands form stable complexes with both alkylamines and alkylammonium salts. The crystal structure of compound 11 shows the 4-hydroxypyridine structure which is unusual since 4-hydroxypyridine compounds in general have a 4-pyridone structure. The crystal structure of an amine complex shows that the proton has been transferred to the amine resulting in a 4-pyridone structure. The crystal structure also shows an uncomplexed ligand to be present in the 4-hydroxypyridine form. Compounds 12 and 13 exhibit chiral recognition for the enantiomers of 2-(l-naphthyl)ethylamine and their hydrogen perchlorate salts. (3) Bradshaw, J. S.; Chamberlin, D. A.; Harrison, P. E.; Wilson, B. E.; Arena, G.; Dailey, N. K.; Lamb, J. D.; Izatt, R. M.; Morin, F. G.; Grant, D. M. J. Org. Chem. 1985, 50, 3065. (4) Nakatauji, Y.; Bradshaw, J. S.; Tse, P-K.; Arena, G.; Wilson, B. E.; Dailey, N. K.; Izatt, R. M. J. Chem. Soc., Chem. Commun. 1985, 749.
Compounds 3-10 (Figure 1) were prepared by the reaction of dimethyl 4-(benzyloxy)-2,6-pyridinedicarboxylate (16) or its tetrahydropyranyl-blocked analogue (17) with the appropriate glycol in benzene using an alkali metal methoxide as the catalyst. The reaction was driven to OR
OR
Jk
.
I
LL ^-0
0CH3
0CH3
4-
o-
X
V°y;
X o-
r°
16, R-CH2Ph 1
°"i cr
7, R=THP
4, R=CH2Ph 5, R=THP
completion by removal of the methanol by its absorption into molecular sieves. Product yields ranged from 5% to 57 % for this reaction. The benzyl-blocked crowns were then reduced to the 4-hydroxypyridine-containing crowns 11, 12, and 14 in a Parr hydrogenator with palladium on carbon as a catalyst. Yields ranged from 30% to 78%. Crown 11 was also prepared by hydrolyzing THP-blocked macrocycle 5. Chiral crown 13 was prepared from THPblocked ester 17 as above, but the THP-blocked crown was hydrolyzed immediately to form 13. The structures proposed for the macrocyclic compounds are consistent with data obtained from IR and *H NMR spectra, combustion analyses, and molecular weight and crystal structure determinations. The starting dimethyl 4-(benzyloxy)-2,6-pyridinedicarboxylate (16) was prepared as shown in Figure 2A from commercially available chelidamic acid (18).5,6 Dimethyl 4-[(tetrahydro-2-pyranyl)oxy]-2,6-pyridinedicarboxylate (17) was also prepared from acid 18 as shown in Figure 2B. The new macrocyclic compounds formed complexes with various guest species. The benzyl-blocked ligands 4 and 7 formed complexes with alkylammonium salts while the (5) Bradshaw, J. S.; Maas, G. E.; Lamb, J. D.; Izatt, R. M.; Christensen, J. J. J. Am. Chem. Soc. 1980, 102, 467. (6) Bradshaw, J. S.; Spencer, N. 0.; Hansen, G. R.; Izatt, R. M.; Christensen, J. J. J. Heterocycl. Chem. 1983, 20, 353.
Proton-Ionizable Crown Compounds
J. Org. Chem., Vol. 50, No. 24, 1985
Table I. Carbon-Carbon Bond Lengths on the Pyridine Unit CA4-CA5 CA2-CA3 CA3-CA4 11
(Figure 3) methyl derivative of 11 (Hx = CH3) (Figure 4) benzyiamine complex of 11 (Figure 6) uncomplexed complexed benzylammonium perchlorate complex of 11 (Figure 5) 15
(ref 4)
CA5-C18
CA4-OA4
1.380 (3) 1.381 (3)
1.393 (4) 1.380 (4)
1.386 (3) 1.389 (4)
1.372 (3) 1.376 (3)
1.336 (3) 1.351 (3)
1.376 1.383 1.379 1.352
1.382 1.406 1.379 1.432
1.389 1.413 1.354 1.441
1.389 1.375 1.395 1.350
1.339 1.289 1.359 1.261
(7) (9) (8) (3)
(9) (11) (10) (3)
(9) (10)
(10) (3)
(7) (8) (9) (3)
Because there are two ligand units in the benzyiamine complex, the atoms of the pyridine unit in the complexed molecule C22, CA23, CA24, OAC4, CA25, and C38 in the atom list. “
ligands containing 4-hydroxypyridine moieties 11-13 formed complexes with both alkylamines and alkylammonium salts. The 18-membered ring ligands containing the 4-hydroxypyridine unit (11-13) also formed monohydrates. The p/f4 and pK2 values (valid in H20) for the consecutive removal of protons from the H2L+ form of 11 as determined by a calorimetric titration technique are estimated to be 1.70 and 8.49, respectively. These numbers differ appreciably from the pKx and pK2 values for the parent 4-hydroxypyridine (p/fj = 3.27 and pK2 = 11.09)7 and 4-pyridone ligand 15 (pA\ = 3.10 and p^ = 10.98).4 The significant difference between the pKn values of 11 and 15 together with the fact that the pKn values for 15 are similar to those for 4-pyridone suggests that compound 11 contains the 4-hydroxypyridine structure. Indeed, the reported X-ray structure of 15 was shown to contain the 4-pyridone unit4 while the X-ray structures reported here for the hydrate of 11 and the alkylammonium salt complex of 11 show a 4-hydroxypyridine unit. These latter data were obtained to clarify the structure of the pyridine ring of 11 in the indicated complexes. Four crystal structures were determined in order to establish whether 4-hydroxypyridine or 4-pyridone was present in 11 and to determine the type of complexation that occurs between 11 and an amine and an organic ammonium salt. The experimental details as well as a discussion of the X-ray structure solutions are given in the Experimental Section. Computer drawings of the four structures are shown in Figures 3-6. The pertinent structural features are summarized here. In Figure 3, it is seen that the hydrogen atom HOA4 is bonded to OA4 which establishes that the six-membered ring of 11-H20 exists as a 4-hydroxypyridine. This structural assignment was verified by the X-ray study of the benzyl amine complex of 11 (Figure 4). This structure is particularly informative as the asymmetric unit contains the complex of 11 and also an uncomplexed ligand. The presence of the hydrogen atom, HOA4, in the uncomplexed molecule confirms the presence of a 4-hydroxypyridine subunit. However, in the complex there was no hydrogen on OA24 and the six-atom ring is present as a 4-pyridone with a hydrogen being donated to the nitrogen of the amine. This will be discussed below. The hydrogen atom on OA4 in the benzylammonium perchlorate complex of 11 could not be located (Figure 5). This was likely due to the fact that the disorder of the C104~ affected the intensity data significantly. However, a pyridine subunit was present in this molecule. Aside from the presence of the hydroxy hydrogen, a pyridine can be distinguished from a pyridone by the presence of a longer C-0 interatomic distance (ca. 1.35 A for a hydroxy group vs. ca. 1.25 A for a carbonyl in the pyridone) and by the presence of (7) Christensen, J. J.; Hansen* L. D.; Izatt, R. M. “Handbook of Proton Ionization Heats and Related Thermodynamic Quantities”, Wiley-Interscience: New York, 1976.
4867
are
(7) (9) (8) (3)
labeled
