Modified coumarins. II. Mannichreaction of substituted 4-phenylcoumarins

Article abstract of DOI:10.1023/A:1002835422747

Aminomethylation of 5-hydroxy- and 7-hydroxy-4-phenylcoumarins by substituted 1,1-diaminomethanes is studied. Mannich condensation of amino acids and their esters with 7-hydroxy-4-phenylcoumarin gives a series of 8-aminoacylmethylcoumarins and 4-phenyl-9,

Full text of DOI:10.1023/A:1002835422747

Chemistry of Natural Compounds, Vol. 36, No. 5, 2000
MODIFIED COUMARINS. II. MANNICH REACTION
OF SUBSTITUTED 4-PHENYLCOUMARINS
M. M. Garazd,1 Ya. L. Garazd,2
S. V. Shilin,2 and V. P. Khilya2
UDC 547.9:582.89
Aminomethylation of 5-hydroxy- and 7-hydroxy-4-phenylcoumarins by substituted 1,1-diaminomethanes is
studied. Mannich condensation of amino acids and their esters with 7-hydroxy-4-phenylcoumarin gives a
series of 8-aminoacylmethylcoumarins and 4-phenyl-9,10-dihydro-2H,8H-chromeno[8,7-e][1,3]oxazin-2-
ones.
Key words:
5-hydroxy- and 7-hydroxy-4-phenylcoumarins, 8-dialkylaminomethyl-4-phenylcoumarins, 6-
dialkylaminomethyl-4-phenylcoumarins, 8-aminoacylmethyl-7-hydroxy-4-phenylcoumarins, synthesis.
Chemical modification of natural bioregulators is one of the most promising methods of synthesizing new biologically
active compounds. The bioregulators exhibit high biological activity owing to the presence of several pharmacophoric centers.
Neoflavones, which are based on the 4-phenylcoumarin core, are widely distributed in the plant kingdom and possess various
pharmacological properties. The Mannich reaction is one method for chemical modification that introduces a basic function
into a molecule. Converting it to the ammonium salt makes the molecule soluble in aqueous solutions. Most aminomethyl
derivatives of coumarins act as central-nervous-system stimulants and barbiturate antagonists [1-4].
We synthesized Mannich bases from 5-hydroxy- and 7-hydroxy-4-phenylcoumarins. The required 4-phenylcoumarins
1-6 were prepared by Pechmann condensation of polyphenols and ethylbenzoylacetate in the presence of trifluoroacetic acid
(TFA). It should be noted that using resorcinol, 2-methylresorcinol, 4-chloro-, and 4-alkylresorcinols in this reaction produces
the corresponding 7-hydroxy-4-phenylcoumarins. Using orcinol produces the 5-hydroxy derivative of 4-phenylcoumarin [5].
The classical conditions of the Mannich reaction for hydroxy compounds based on benzopyran provide for the reaction
of substrate, amine, and formaldehyde in alcohol with prolonged heating [6]. In our opinion, the use of substituted 1,1-
diaminomethanes is more convenient for introducing an aminomethyl into a benzopyran system because the rate of such a
reaction is high and side products are not formed.
According to the literature, the position
to the hydroxyl is most preferred for attack in a Mannich reaction for
ortho
all phenolic derivatives. This is explained by the reaction mechanism, according to which a H-bond is formed first between the
Mannich reagent and the substrate. This is followed by attack at the position [6].
ortho
The C-aminomethylation reaction was performed by boiling 4-phenylcoumarins with substituted 1,1-diaminomethanes
in absolute dioxane. The aminomethyl group occupies the 8-position of the coumarin system in the reaction of 1-4. For 5 and
6, it occupies the 6-position according to PMR spectroscopy results.
According to the experimental results, 7-hydroxy-4-phenylcoumarin (1) is the most active substrate in the
aminomethylation reaction. The reaction occurs in 30-60 min. If 6-substituted 7-hydroxy-4-phenylcoumarins 2-4 are used,
longer heating (2-4 h) is required. In our opinion, the fact that even longer heating (10-20 h) is required to carry out the
Mannich reaction with 8-methyl-7-hydroxy-4-phenylcoumarin (5) proves that the 6-position is unreactive toward
aminomethylation. The reactivity of the 6-position increases sharply if a OH is introduced in the 5-position. The reaction takes
1-3 h for 7-methyl-5-hydroxy-4-phenylcoumarin (6).
1) Institute of Bioorganic and Petroleum Chemistry, National Academy of Sciences, Ukraine, 02094, Kiev, ul.
Murmanskaya, 1; 2) Taras Shevchenko Kiev National University, 01033, Kiev, ul. Vladimirskaya, 64. Translated from Khimiya
Prirodnykh Soedinenii, No. 5, pp. 383-388, September-October, 2000. Original article submitted November 6, 2000.
0009-3130/00/3605-0485$25.00 ©2001 Plenum Publishing Corporation
485

N
N
N
N
H
HO
Cl
O
O
HO
R
O
O
O
O
O
HO
R
O
O
R
10. R=H; 11. R=Cl; 12. R=Et
9
7. R=H; 8. R=Cl
17. R=H; 18. R=Cl
HO
O
O
N
N
R
HO
R
O
O
HO
Cl
O
O
1. R=H; 2. R=Cl;
3. R=Et; 4.R=Pr
13. R=H; 14. R=Cl
15. R=Et; 16. R=Pr
23
O
N
N
N
N
HO
R
O
O
HO
R
O
O
HO
O
O
R
24. R=H; 25. R=Cl;
26. R=Et; 27. R=Pr
19. R=H; 20. R=Cl
21. R=Et; 22. R=Pr
28. R=H; 29. R=Cl;
30. R=Et; 31. R=Pr
HO
O
O
HO
N
O
O
HO
N
O
O
N
33
32
34
HO
O
O
HO
O
O
HO
O
O
N
N
N
35
39
5
HO
O
O
HO
N
O
O
HO
N
O
O
N
O
38
37
36
486

TABLE 1. Properties of 8-Dialkylaminomethyl-4-phenylcoumarins 7-31
PMR spectrum, , ppm, SSCC (J, Hz), CDCl3 solvent
coumarin ring protons
3-H, 4-Ph, 5-H, d, 6-H, d,
Com-
Empirical
formula
Yield, mp,
pound
%
C
dialkylamino protons
7-OH, 8-CH2,
s
m
J = 8.0
J = 8.0
s
s
7
8
9
C18H17NO3
C18H16ClNO3
C20H20ClNO3
81
88
72
174
229
177
6.15
6.14
6.11
7.52
7.50
7.50
7.29
6.69
-(Cl)
-(Cl)
11.05
11.08
11.00
4.08
4.15
4.26
2.52 (6H, s, CH3)
2.52 (6H, CH3)
7.39 (s)
7.37 (s)
2.86 (4H, q, CH2),
1.25 (6H, t, CH3)
10
11
12
13
14
15
16
17
18
19
20
21
22
C20H19NO3
C20H18NO3
C22H23NO3
C21H21NO3
C21H20ClNO3
C23H25NO3
C24H27NO3
C22H23NO3
C22H22ClNO3
C22H23NO3
C22H22ClNO3
C24H27NO3
C25H29NO3
74
79
71
82
89
79
64
69
72
74
76
68
65
156
198
172
178
196
176
118
131
163
196
204
128
118
6.07
6.11
6.12
6.12
6.15
6.11
6.12
6.15
6.12
6.13
6.12
6.12
6.12
7.48
7.50
7.50
7.47
7.50
7.49
7.50
7.51
7.49
7.48
7.50
7.50
7.50
7.24
6.67
-(Cl)
10.99
9.00
4.25
4.33
4.25
4.08
4.19
4.09
4.09
4.04
4.19
4.09
4.17
4.10
4.09
2.78 (4H, m, CH2),
1.91 (4H, m, CH2)
7.38 (s)
7.12 (s)
7.23
2.93 (4H, m, CH2),
2.00 (4H, m, CH2)
2.57 (q, 2H);
1.14 (t, 3H) (Et)
6.66
11.44
9.57
2.77 (4H, m, CH2),
1.91 (4H, m, CH2)
2.63 (4H, m, CH2),
1.64 (6H, m, CH2)
7.39 (s)
7.11 (s)
-(Cl)
11.43
11.08
2.80 (4H, m, CH2),
1.78 (6H, m, CH2)
2.60 (q, 2H); 1.13
(t, 3H) (Et)
2.60 (4H, m, CH2),
1.68 (6H, m, CH2)
7.09 (s) 2.54 (t, 2H); 1.53 (m, 10.64
3H); 0.92 (t, 3H) (Pr)
2.60 (4H, m, CH2),
1.66 (6H, m, CH2)
7.28
6.68
-(Cl)
6.65
-(Cl)
10.10
10.30
10.17
11.57
9.30
3.09 (2H, m), 2.27 (2H, m),
1.1-1.8 (5H, m), 0.89 (3H, d)
3.06 (2H, m), 2.33 (2H, m),
1.1-1.8 (5H, m), 0.93 (3H, d)
3.05 (2H, m), 2.27 (2H, m),
1.1-1.8 (5H, m), 0.95 (3H, d)
3.14 (2H, m), 2.42 (2H, m),
1.1-1.8 (5H, m), 0.98 (3H, d)
3.05 (2H, m), 2.30 (2H, m),
1.1-1.8 (5H, m), 0.98 (3H, d)
3.02 (2H, m), 2.28 (2H, m),
1.1-1.8 (5H, m), 0.94 (3H, d)
7.38 (s)
7.24
7.37 (s)
7.10 (s)
2.57 (q, 2H); 1.13
(t, 3H) (Et)
7.08 (s) 2.54 (t, 2H); 1.53 (m, 9.83
3H); 0.92 (t, 3H)
(Pr)
23
24
25
26
27
28
29
30
31
C23H24ClNO3
C20H19NO4
62
75
79
71
62
79
86
73
75
181
226
217
156
112
208
211
129
113
6.07
6.16
6.20
6.14
6.13
6.14
6.18
6.13
6.13
7.49
7.48
7.50
7.50
7.50
7.48
7.50
7.50
7.50
7.39 (s)
7.29
-(Cl)
6.68
-(Cl)
12.00 4.14; 4.50*
3.20 (2H, m), 2.52 (1H, m),
1.4-2.0 (8H, m), 1.00 (3H, t)
3.80 (4H, m, CH2),
2.69 (4H, m, CH2 ),
3.82 (4H, m, CH2),
2.75 (4H, m, CH2 ),
3.80 (4H, m, CH2),
2.69 (4H, m, CH2 ),
3.80 (4H, m, CH2),
2.68 (4H, m, CH2 ),
2.74 (4H, m), 2.59 (4H, m), 2.33
(3H, s)
9.01
8.90
7.90
4.12
4.14
4.13
4.09
4.12
4.16
4.13
4.13
C20H18ClNO4
C22H23NO4
7.39 (s)
7.14 (s)
2.58 (q, 2H); 1.13
(t, 3H) (Et)
C23H25NO4
7.10 (s) 2.52 (t, 2H); 1.54 (m, 9.20
3H); 0.90 (t, 3H) (Pr)
C21H22N2O3
C21H21ClN2O3
C23H26N2O3
C23H26N2O3
7.27
6.67
8.06
7.90
8.40
7.39 (s)
7.13 (s)
-(Cl)
2.78 (4H, m), 2.59 (4H, m), 2.34
(3H, s)
2.59 (q, 2H); 1.13
(t, 3H) (Et)
2.70 (4H, m), 2.59 (4H, m), 2.33
(3H, s)
7.10 (s) 2.53 (t, 2H); 1.55 (m, 8.20
3H); 0.92 (t, 3H) (Pr)
2.72 (4H, m), 2.53 (4H, m), 2.33
(3H, s)
______
*Protons of the methylene group are diastereotopic and resonate as two doublets with SSCC 15 Hz.
487

TABLE 2. Properties of 6-Dialkylaminomethyl-4-phenylcoumarins 32-46
PMR spectrum, , ppm, SSCC (J, Hz), CDCl3 solvent
Com- Empirical Yield mp,
coumarin ring protons
pound formula
%
C
dialkylamino protons
H-3, s 4-Ph, m 5-R, s 6-CH2, s 7-R, s
8-R, s
32
33
34
35
36
37
38
39
40
41
42
43
44
45
C21H21NO3 83
C21H23NO3 64
C21H21NO3 69
C22H23NO3 72
C23H25NO3 70
C24H27NO3 61
C21H21NO4 75
C22H24N2O3 86
C19H19NO3 81
C21H21NO3 69
C22H23NO3 77
C23H25NO3 70
C24H27NO3 61
C21H21NO4 84
C22H24N2O3 88
156
122
143
154
135
148
173
158
176
178
189
162
151
207
192
6.13
6.14
6.13
6.13
6.13
6.12
6.15
6.15
6.06
6.05
6.06
6.06
6.06
6.07
6.06
7.48
7.48
7.48
7.48
7.48
7.47
7.48
7.48
7.38
7.39
7.39
7.39
7.37
7.39
7.38
6.90(H)
6.90(H)
3.79
3.75
3.79
3.63
3.64
10.00(OH) 2.34(CH3)
9.50(OH) 2.35(CH3)
10.00(OH) 2.34(CH3)
10.00(OH) 2.34(CH3)
8.93(OH) 2.34(CH3)
10.00(OH) 2.33(CH3)
10.00(OH) 2.34(CH3)
8.40(OH) 2.35(CH3)
2.31(CH3) 6.69(H)
2.30(CH3) 6.68(H)
2.29(CH3) 6.68(H)
2.29(CH3) 6.68(H)
2.28(CH3) 6.66(H)
2.31(CH3) 6.72(H)
2.27(CH3) 6.69(H)
2.62 (4H, m, CH2 ), 1.85 (4H, m, CH2 )
2.62 (4H, q, CH2 ), 1.11 (6H, t, CH3 )
2.62 (4H, m, CH2 ), 1.85 (4H, m, CH2 )
2.50 (4H, m, CH2 ), 1.58 (6H, m, CH2 )
6.90(H)
6.89(H)
6.90(H)
2.94 (2H, m), 2.10 (2H, m) ,
1.1-1.8(5H, m), 0.95 (3H, d)
6.88(H)
3.58;
4.12*
3.68
2.73 (2H, m), 2.28 (1H, m) ,
1.1-1.8(8H, m), 0.85 (3H, t)
6.93(H)
3.76 (4H, m, CH2 ), 2.56 (4H, m, CH2 )
6.93(H)
3.68
3.65
3.79
3.64
3.65
2.70 (4H, m ), 2.59 (4H, m ), 2.32 (3H, s )
2.35 (6H, CH3)
10.00(OH)
8.43(OH)
8.38(OH)
9.19(OH)
8.80(OH)
8.90(OH)
9.20(OH)
2.59 (4H, m, CH2 ), 1.78 (4H, m, CH2 )
2.47 (4H, m, CH2 ), 1.53 (6H, m, CH2 )
2.88 (2H, m ), 2.07 (2H, m ),
1.1-1.8(5H, m), 0.91 (3H, d)
3.55;
4.01*
3.68
2.78 (2H, m), 2.30 (1H, m) ,
1.1-1.8(8H, m), 0.86 (3H, t)
3.62 (4H, m, CH2 ), 2.51 (4H, m, CH2 )
46
3.67
2.63 (4H, m ), 2.45 (4H, m ), 2.30 (3H, s )
______
*Protons of the methylene group are diastereotopic and resonate as two doublets with SSCC 15 Hz.
Aminals of dimethylamine, diethylamine, pyrrolidine, piperidine, 2-ethylpiperidine, 3-methylpiperidine, 4-
methylpiperidine, morpholine, and 1-methylpiperazine underwent the Mannich reaction. The most reactive of the 1,1-
diaminomethanes was bis(dimethylamino)methane. Use of the other aminals requires longer heating.
The structures of the resulting Mannich bases were confirmed by quantitative elemental analysis and PMR
spectroscopy. The PMR spectra of 7-31 lack signals at 6.7-6.8 ppm for H-8 of the coumarin system. The spectrum is simplified
as a result. Protons in the 5- and 6-positions resonate as doublets with SSCC 8 Hz at 7.2 and 6.8 ppm, respectively (for
compounds 7, 10, 13, 17, 19, 24, 28). For compounds 8, 9, 11, 12, 14-16, 18, 20-23, 25-27, and 29-31, which contain a
substituent in the 6-position, H-5 resonates at 7.1-7.4 ppm as a 1H singlet. The spectra of compounds 32-46 lack a signal for
H-6 of the benzopyran ring. Proton H-8 appears as a singlet at 6.6-6.7 ppm (for compounds 32-39). For compounds 40-46, H-5
is observed at 6.9 ppm. The spectra of compounds 7-46 also contain signals for a methylene at 4.1-4.2 ppm and signals
characteristic for aminoalkyl substituents. It is interesting that the methylene protons in Mannich bases 23, 37, and 44 are
diasterotopic and, therefore, appear as two doublets with SSCC 15 Hz. The hydroxyl protons of 7-OH and 5-OH resonate at
weak field (9-11 ppm) because they are involved in an intramolecular H-bond with the N of the dialkylaminomethyl group. The
properties of Mannich bases 7-46 are listed in Tables 1 and 2.
488

O
O
O
O
O
O
OH
OH
OH
N
N
N
40
42
41
O
O
O
O
O
O
OH
N
OH
OH
N
44
6
43
O
O
O
O
OH
N
OH
N
N
O
45
46
We also studied the Mannich reaction of 7-hydroxy-4-phenylcoumarin with amino acids and their derivatives. It was
found that prolonged heating of a mixture of 7-hydroxy-4-phenylcoumarin, the corresponding amino acid, and an equivalent
amount of formalin produces 7-hydroxy-8-(N-aminoacyl)methyl-4-phenylcoumarins (47-53). This reaction produced derivatives
of alanine (47), 2-aminobutanoic acid (48), norvaline (49), leucine (50), isoleucine (51), norleucine (52), and phenylalanine
(53).
O
R
HO
HO
O
O
NH
H NCHRCOOH
HO
O
O
2
CH O
2
1
47-53
1. R1=R2=R3=R4=H
2. R1=R2=R4=H; R3=OH
3. R1=H; R2=R3=OH; R4=C6H5CO
4. R1=R4=H; R2=R3=OH
5. R1=R2=R3=OH; R4=H
The structures of the resulting 8-aminoacylmethyl derivatives of 4-phenylcoumarin were confirmed by quantitative
elemental analysis and PMR spectroscopy. The PMR spectra of compounds 47-53, which were recorded in TFA, are simplified
in the aromatic region of the coumarin system because coupling with H-8 is avoided. The aromatic protons H-5 and H-6
resonate as doublets with SSCC 9 Hz at 7.8 and 7.2 ppm, respectively. The PMR spectra of the resulting Mannich bases also
exhibit signals for the amino acid. A 2H signal for the methylene appears at 5.0 ppm. The physicochemical properties of
compounds 47-53 are listed in Table 3.
489

TABLE 3. Properties of 8-Aminoacylmethyl-7-hydroxy-4-phenylcoumarins 47-53
PMR spectrum, , ppm, TFA solvent
Com- Empirical Yield,
mp, C
coumarin ring protons
amino-acid fragment
pound
formula
%
CH2, m
H-3, s
6.61
Ph-4, m
H-5, d
778
H-6, d
7.20
CH, m
R
47
48
49
50
51
52
53
C19H17NO5 49
C20H19NO5 61
C21H21NO5 55
C22H23NO5 51
C22H23NO5 56
C22H23NO5 65
C25H21NO5 72
305
287
292
284
276
295
288
7.50-7.60
4.91
4.98
4.90
4.93
4.95
4.94
4.87
4.42
4.45
4.38
4.41
4.40
4.41
4.47
-CH3
1.51
6.61
6.62
6.60
6.61
6.61
6.60
7.52-7.62
7.50-7.60
7.50-7.60
7.50-7.60
7.50-7.60
7.50-7.60
7.82
7.79
7.80
7.78
7.83
7.75
7.19
7.18
7.15
7.19
7.18
7.18
-CH2, -CH3
2.37; 1.26
-CH2 -CH2 -CH3
2.29; 1.57; 1.25
-CH2 -CH -(CH3)2
2.31; 1.69; 1.21
-CH(CH3) CH2 -CH3
2.45; 1.25; 1.51; 1.19
-CH2 -CH2 -CH2 -CH3
2.36; 1.68; 1.39; 1.26
-CH2 -Ph
3.27; 7.20-7.30
It is known that several products are formed if primary amines are used in the Mannich reaction [6]. In particular,
aminomethylation of 7-hydroxy-4-methylcoumarin by primary amines showed that different products are formed depending on
the formaldehyde equivalent. If one equivalent is used, 7-hydroxy-8-aminomethyl-4-methylcoumarins is formed. For two
equivalents, dihydrobenzoxazines are produced [7]. Dihydrobenzoxazines are known to be intermediates in the synthesis of
bis-(2-hydroxybenzyl)amines and secondary Mannich bases [6]. It is also known that dihydrobenzoxazines based on coumarins
are antifungal and antitumor agents [8].
Condensation of 7-hydroxy-4-phenylcoumarin, a double equivalent of formalin solution (35%) and valine benzyl ester,
phenylalanine isopropyl ester, or phenylalanine benzyl ester in dioxane at 100 C produces dihydrooxazino[7,8-e]coumarins (54-
56).
Me
O
O
Me
O
O
N9
N
HO
O
O
10
O1
O
O
O
O
Me
O
O
7 O
Me
O
O
3
NH
NH
2
2
4
5
2CH O
2CH O
2
2
1
54
55
O
Me
Me
2CH O
2
O
NH
2
O
O
Me
Me
O
N
O
O
56
490

The structures of the resulting 4-phenyl-9,10-dihydro-2H,8H-chromeno[8,7-e][1,3]oxazin-2-ones were confirmed by
quantitative elemental analysis and PMR spectroscopy. Thus, the PMR spectra of compounds 54-56 exhibit the following
differences from the spectrum of the starting coumarin. Instead of signals for OH-7 and H-8 of the coumarin, the corresponding
signals for the amino acid and methylenes of the dihydrooxazine ring appear at 4.3-4.5 and 4.7-5.0 ppm. It is interesting that
the methylene protons are diastereotopic, appearing as two doublets with the corresponding constants.
EXPERIMENTAL
The course of the reactions and the purity of the products were monitored by TLC on Silufol UV-254 plates. The
eluents were mixtures of CHCl and CH OH (9:1 and 95:5). PMR spectra were recorded on a Varian VXR-300 instrument in
3
3
TFA and CDCl (TMS internal standard).
3
Starting coumarins 1-6 were prepared according to the literature [5].
General Synthesis of Mannich Bases 7-46. A solution or suspension of coumarin 1-6 (4 mmol) in absolute dioxane
(25-30 ml) was treated with the appropriate 1,1-diaminomethane (4.5 mmol). The reaction was heated (100 C) for 0.5-20 h
(completion of the reaction was determined by TLC). The solvent was removed under vaccum when the reaction was completed.
The solid or oil was crystallized from hexane—diethylether (1:1). Yields and properties of synthesized Mannich bases 7-46
are listed in Tables 1 and 2.
General Synthesis of 8-Aminoacylmethyl-7-hydroxy-4-phenylcoumarins 47-53. A warm solution of 7-hydroxy-4-
phenylcoumarin (1.19 g, 5 mmol) in ethanol (30 ml) was treated with the appropriate amino acid (5 mmol) in water (20 ml)
and formalin (35%, 0.45 ml, 5 mmol). The reaction mixture was heated (80-90 C) for 6-8 h. The resulting precipitate was
filtered off and crystallized from ethanol (50%). Yields and properties of compounds 47-53 are listed in Table 3.
General Synthesis of Dihydrooxazino[7,8-e]coumarins 54-56. A suspension of the hydrochloride of the appropriate
amino-acid alkyl ester (4 mmol) in absolute dioxane (20 ml) was cooled (0 C), stirred vigorously, and treated with freshly
distilled triethylamine (0.56 ml, 5 mmol). The mixture was stirred for 30 min. The resulting precipitate (triethylammonium
chloride) was filtered off. The filtrate was treated with formalin (35%, 0.72 ml, 8 mmol). The resulting mixture was held at
room temperature, stirred for 4 h, treated with 7-hydroxy-4-phenylcoumarin (0.95 g, 4 mmol), and heated at 90-100 C for
1-2 h (completion of the reaction was determined by TLC). Dioxane was evaporated under vacuum. The oil was crystallized
by treatment with diethylether—hexane (1:1).
2-(2-Oxo-4-phenyl-9,10-dihydro-2H,8H-chromeno[8,7-e][1,3]oxazin-9-yl)-3-phenylpropanoic acid isopropyl ester
(54): Yield 69%, mp 111 C, C29H27NO5. PMR spectrum (300 MHz, CDCl ): 0.89, 1.06 (two doublets, J = 6.3 Hz, 6H,
3
isopropyl methyls), 3.12 (d, J = 7.8 Hz, 2H, phenylalanine CH ), 3.81 (t, 1H, phenylalanine CH), 4.41, 4.49 (two doublets,
2
J = 17.4 Hz, 2H, CH -10), 4.76 (m, 1H, isopropyl CH), 5.00, 5.06 (two doublets, J = 12.9 Hz, 2H, CH -8), 6.21 (s, 1H, H-3),
2
2
6.68 (d, J = 9 Hz, 1H, H-6), 7.20 (m, 5H, phenylalanine phenyl), 7.26 (d, J = 9 Hz, 1H, H-5), 7.45 (m, 5H, Ph-4).
2-(2-Oxo-4-phenyl-9,10-dihydro-2H,8H-chromeno[8,7-e][1,3]oxazin-9-yl)-3-phenylpropanoic acid benzyl ester
(55): Yield 76%, mp 104 C, C33H27NO5. PMR spectrum (300 MHz, CDCl ): 3.17 (m, 2H, phenylalanine CH ), 3.91 (t, 1H,
3
2
phenylalanine CH), 4.43, 4.51 (two doublets, J = 17.4 Hz, 2H, CH -10), 4.77, 4.83 (two doublets, J = 13 Hz, 2H, CH -8), 5.03
2
2
(s, 2H, benzyl CH ), 6.18 (s, 1H, H-3), 6.66 (d, J = 8.4 Hz, 1H, H-6), 7.00-7.20 (m, 10H, benzyl and phenylalanine phenyls),
2
7.26 (d, J = 8.4 Hz, 1H, H-5), 7.45 (m, 5H, Ph-4).
3-Methyl-2-(2-oxo-4-phenyl-9,10-dihydro-2H,8H-chromeno[8,7-e][1,3]oxazin-9-yl)butanoic acid benzyl ester (56):
Yield 73%, mp 133 C, C29H27NO5. PMR spectrum (300 MHz, CDCl ): 0.93, 1.06 (two doublets, J = 6.6 Hz, 6H, valine
3
methyls), 2.27 (m, 1H, valine CH), 3.17 (d, J = 10.5 Hz, 1H, valine -CH), 4.32, 4.49 (two doublets, J = 17.4 Hz, 2H, CH -10),
2
4.71, 4.87 (two doublets, J = 12.6 Hz, 2H, CH -8), 5.01 (s, 2H, benzyl CH ), 6.15 (s, 1H, H-3), 6.64 (d, J = 9 Hz, 1H, H-6), 7.20
2
2
(m, 5H, benzyl phenyl), 7.25 (d, J = 9 Hz, 1H, H-5), 7.45 (m, 5H, Ph-4).
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492