A convenient method for the conversion of a carboxy group into a 4,6-dimethoxy-1,3,5-triazine group: Application to N-benzylpyroglutamic acids

Article abstract of DOI:10.1055/s-2006-942519

Reaction of an activated form of carboxylic acids with a stoichiometric amount of zinc dimethyl imidodicarbonimidate (in CH₂Cl ₂-pyridine with molecular sieves), led to 4,6-dimethoxy-1,3,5- triazines in high yields. This method has b

Full text of DOI:10.1055/s-2006-942519

PAPER
2845
A Convenient Method for the Conversion of a Carboxy Group into a 4,6-Di-
methoxy-1,3,5-triazine Group: Application to N-Benzylpyroglutamic Acids
C
onversion of
o
a
C
arboxy G
u
roup into a
4
h
,6-Dimethox
i
y-1,3,5
l
-triaz
i
aG
roup Oudir,a Benoît Rigo,a Jean-Pierre Hénichart,b Philippe Gautret*a
a
Groupe de Recherche sur l’Inhibition de la Prolifération Cellulaire, EA 2692, Ecole des Hautes Etudes d’Ingénieur, 13 rue de Toul,
59046 Lille, France
b
Groupe de Recherche sur l’Inhibition de la Prolifération Cellulaire, EA 2692, Institut de Chimie Pharmaceutique Albert Lespagnol,
Université de Lille, 2 rue du Professeur Laguesse, 59006 Lille, France
Fax +33(3)28384804; E-mail: philippe.gautret@hei.fr
Received 22 March 2006; revised 3 May 2006
Under similar experimental conditions, stoichiometric
amounts of acid chloride 6a were reacted with zinc salt 5
to give the corresponding triazine 3a in a moderate 53%
yield (Table 1, entry 1). We also observed the formation
Abstract: Reaction of an activated form of carboxylic acids with a
stoichiometric amount of zinc dimethyl imidodicarbonimidate (in
CH2Cl2–pyridine with molecular sieves), led to 4,6-dimethoxy-
1,3,5-triazines in high yields. This method has been applied to N-
benzylpyroglutamic acids, in the preparation of potential antifungal of N-benzylpyroglutamic acid (4, R = H) as an important
products.
side-product of the reaction.
Key words: pyroglutamic derivatives, lactams, imidodicarbonimi-
date zinc salt, heterocycles, triazines
Formation of N-benzylpyroglutamic acid (4, R = H) was
presumably due to the hydrolysis of N-benzylpyroglutam-
ic chloride 6a by water formed during the reaction. In or-
der to avoid this hydrolysis, we thought to trap the water
We have reported earlier that several N-benzylpyrrolidi-
nones such as 11 and 22 exhibit antifungal activity. Some
2,4,6-triheteroalkyl-1,3,5-triazines show similar biologi-
cal properties.3 These results prompted us to investigate
the biostatic activity of products 3, which possess an N-
benzylpyrrolidinone group linked to a 4,6-dimethoxy-
1,3,5-triazine group at the 5-position (Figure 1).
by using 4 Å molecular sieves. We also studied the effect
of pyridine as co-solvent. The various conditions exam-
ined are listed in Table 1.
Higher yields were obtained when acid chloride 6a was
condensed with salt 5 in the presence of 4 Å molecular
sieves and pyridine as co-solvent (Table 1, entry 4). Thus,
these conditions were used as a standard procedure to syn-
thesize various triazinyl pyrrolidinones 3a–e in high
yields (Table 2).
OMe
N
N
N
N
N
As shown in Table 3, this method also succeeded with
some functionalized acid chlorides and anhydrides.
O
X
Y
O
R
O
N
O
N
N
OMe
In summary, we have developed an easy conversion of
carboxylic acids to 4,6-dimethoxy-1,3,5-triazines. The
method is very simple and, compared to the syntheses pre-
viously reported, the rate of conversion of the carboxy
group is very high.
R
R1
R2
1 R = H, X = CN
4 X = CO2H
2
3 R1, R2 = H, Me, Cl
Figure 1 N-Benzylpyrrolidinones 1–4
Melting points were determined using an Electrothermal apparatus
1
and are uncorrected. H and 13C NMR spectra were obtained on a
In order to obtain triazine derivatives 3a–e, we considered
a one-step synthesis from N-benzylpyroglutamic acids (2-
pyrrolidone-5-carboxylic acids) 4.4 Previously, a proce-
dure had described5 the reaction of activated carboxy
groups (acid chlorides, anhydrides, acylimidazolides)
with zinc dimethyl imidodicarbonimidate (5), giving 6-
substituted 2,4-dimethoxy-1,3,5-triazines. In this method,
the conversion rate of the activated carboxy group was
low, and good yields were only obtained when a very
large excess of the carboxylic acid derivative was used.
Varian Gemini 2000 at 200 MHz and 50 MHz, respectively. IR
spectra were obtained in ATR mode on an FTIR Bruker Tensor 27
spectrometer. Microanalyses were performed by the ‘Service Cen-
tral de Microanalyses’ of CNRS in Vernaison, France. Zinc dimeth-
yl imidodicarbonimidate (5),5a N-benzylpyroglutamic acid
chlorides 6a–e4 and dibromoacetyl chloride (7d)6 were prepared ac-
cording to literature methods.
N-Benzylpyroglutamic Acid Chlorides 6a–e4; General Proce-
dure
Under N2, a stirred mixture of acid 44 (4 mmol) and SOCl2 (952 mg,
8 mmol) in CH2Cl2 (4 mL) was refluxed for 4 h. The residue ob-
tained upon evaporation was heated at 40 °C under high vacuum
(< 0.1 mmHg) for 4 h in order to remove all traces of SOCl2.
SYNTHESIS 2006, No. 17, pp 2845–2848
x
x.
x
x
.
2
0
0
6
Advanced online publication: 25.07.2006
DOI: 10.1055/s-2006-942519; Art ID: P03806SS
© Georg Thieme Verlag Stuttgart · New York

2846
S. Oudir et al.
PAPER
Table 1 Condensation of Acid Chlorides 6a with Zinc Salt 5
MeO
NH
OMe
N
Zn
MeO
(0.5 equiv)
N
N
N
NH
O
COCl
O
N
N
5
OMe
1/2 ZnCl2
+
H2O
+
6a
3a
Entry
Conditionsa
CH2Cl2
Yield (%)b
1
2
3
4
53
63
72
91
CH2Cl2, 4 Å molecular sieves
CH2Cl2–pyridine
CH2Cl2–pyridine, 4 Å molecular sieves
a All reactions were performed at r.t. for 30 min.
b Determined by 1H NMR spectroscopy.
Table 2 Condensation of Acid Chlorides 6a–e with Salt 5
Table 3 Condensation of Acid Chlorides 7a–d and Anhydrides 7e,f
with Salt 5
OMe
OMe
N
O
N
OMe
R2
N
O
COCl
O
N
N
R
N
N
R
X
N
OMe
7a–f
R1
8a–f
X
R2
R1
6a–e
3a–e
Reactant
R
Time (h) Product Yield (%)a
Reactant R1
R2
H
Time (h) Product
Yield (%)a
91 (87)
83 (78)
85 (82)
99 (95)
80 (75)
7a
7b
7c
7d
7e
7f
CO2Me
CO2Et
CHCl2
CHBr2
Cl
Cl
Cl
Cl
1.5
1
8a
8b
8c
8d
8e
8f
93 (87)
92 (90)
94 (74)
90 (74)
86 (81)
84 (75)
6a
6b
6c
6d
6e
H
0.5
1.5
2
3a
3b
3c
3d
3e
Me
H
H
0.5
0.5
2
Me
H
Cl
H
0.5
2
CH(OMe)2 O(CO)CF3
CH(OEt)2 O(CO)CF3
Cl
2
a Determined by 1H NMR spectroscopy. Isolated yields are given in
parentheses.
a Determined by 1H NMR spectroscopy. Isolated yields are given in
parentheses.
Dimethoxyacetic Trifluoroacetic Anhydride
Diethoxyacetic Trifluoroacetic Anhydride
To a solution of potassium trimethylsilanolate (2.87 g, 22.4 mmol)
in THF (45 mL), was added methyl dimethoxyacetate (2.5 g, 18.6
mmol). The mixture was stirred at r.t. for 48 h and the solvent was
removed in vacuo. The residual crude potassium dimethoxyacetate
was dissolved in CH2Cl2 (100 mL) and trifluoroacetic anhydride
(2.7 mL, 19.4 mmol) was added dropwise at –20 °C under N2. The
mixture was stirred at r.t. for 1 h, and the solvent was evaporated at
reduced pressure to give crude dimethoxyacetic trifluoroacetic an-
hydride in 44% yield (1H NMR) as an orange oil that was used with-
out further purification in the next step.
This compound, obtained as an orange oil in 54% yield, was pre-
pared by the same procedure as described for dimethoxyacetic tri-
fluoroacetic anhydride using ethyl diethoxyacetate as starting
material.
1H NMR (200 MHz, CDCl3): d = 1.27 (t, J = 7.3 Hz, 6 H), 3.62–
3.80 (m, 4 H), 5.05 (s, 1 H).
4,6-Dimethoxy-1,3,5-triazines 3 and 8; General Procedure
Under N2, a solution of acid chloride 6a–e,4 7a–c, 7d6 or anhydride
7e,f (4.0 mmol) in anhyd CH2Cl2 (10 mL) was added dropwise (30
min) to a stirred mixture of salt 55a (651 mg, 2.0 mmol) and pow-
dered 4 Å molecular sieves (4 g) in distilled pyridine (15 mL). After
the addition was complete, the mixture was stirred at r.t. for the pe-
1H NMR (200 MHz, CDCl3): d = 3.46 (s, 6 H), 4.96 (s, 1 H).
Synthesis 2006, No. 17, 2845–2848 © Thieme Stuttgart · New York

PAPER
Conversion of a Carboxy Group into a 4,6-Dimethoxy-1,3,5-triazine Group
IR: 1684, 1553, 1494, 1449, 1362, 1104 cm–1.
2847
riod indicated in Tables 2 or 3. The mixture was filtered upon com-
pletion of the reaction, the solid was washed with CH2Cl2 and the
filtrate was concentrated (rotary evaporation). The residue was co-
evaporated with toluene (3 × 5 mL) in order to remove pyridine.
The remaining slurry was dissolved in CH2Cl2 (10 mL), washed
with 1 N HCl (3 × 10 mL), and then with aq sat. NaHCO3 solution
(10 mL). The residue obtained upon evaporation was crystallized,
then recrystallized from appropriate solvent or distilled.
1H NMR (200 MHz, CDCl3): d = 2.04–2.20 (m, 1 H), 2.29–2.55 (m,
2 H), 2.61–2.80 (m, 1 H), 4.02 (d, J = 14.9 Hz, 1 H), 4.03 (s, 6 H),
4.43 (dd, J = 8.7, 2.9 Hz, 1 H), 4.86 (d, J = 14.9 Hz, 1 H), 7.17 (dd,
J = 24.1, 8.3 Hz, 4 H).
13C NMR (50 MHz, CDCl3): d = 24.7, 29.7, 45.0, 55.5, 62.3, 128.6,
130.0, 133.4, 134.8, 172.8, 175.6, 181.6.
Anal. Calcd for C16H17ClN4O3: C, 55.10; H, 4.91; N, 16.06. Found:
C, 54.83; H, 4.81; N, 16.03.
1-Benzyl-5-(4,6-dimethoxy-1,3,5-triazin-2-yl)pyrrolidin-2-one
(3a)
Colorless oil.
IR: 1688, 1549, 1502, 1462, 1354, 1106 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.01–2.17 (m, 1 H), 2.29–2.80 (m,
3 H), 4.02 (s, 6 H), 4.02 (d, J = 14.6 Hz, 1 H), 4.46 (dd, J = 8.4, 2.6
Hz, 1 H), 4.92 (d, J = 14.6 Hz, 1 H), 7.14–7.31 (m, 5 H).
Methyl 4,6-Dimethoxy-1,3,5-triazine-2-carboxylate (8a)
White solid; mp 149–150 °C (MeOH).
IR: 1746, 1542, 1251, 1100 cm–1.
1H NMR (200 MHz, CDCl3): d = 4.01 (s, 3 H), 4.13 (s, 6 H).
13C NMR (50 MHz, CDCl3): d = 53.5, 55.8, 162.6, 167.1, 173.3.
13C NMR (50 MHz, CDCl3): d = 24.5, 29.6, 45.5, 55.3, 62.1, 127.4,
128.3, 128.4, 136.1, 172.6, 175.4, 181.6.
Anal. Calcd for C7H9N3O4: C, 42.21; H, 4.55; N, 21.10. Found: C,
42.52; H, 4.78; N, 20.90.
Anal. Calcd for C16H18N4O3: C, 61.14; H, 5.77; N, 17.82. Found: C,
61.34; H, 5.80; N, 17.88.
Ethyl 4,6-Dimethoxy-1,3,5-triazine-2-carboxylate (8b)
White solid; mp 50-51 °C (cyclohexane).
IR: 1747, 1549, 1356, 1212, 1039 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.36 (t, J = 7.2 Hz, 3 H), 4.06 (s,
6 H), 4.41 (q, J = 7.2 Hz, 2 H).
13C NMR (50 MHz, CDCl3): d = 14.0, 55.7, 62.9, 162.2, 167.5,
173.3.
5-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-1-(2-methylbenzyl)pyrro-
lidin-2-one (3b)
White solid; mp 94–95 °C (cyclohexane–Et2O).
IR: 1689, 1551, 1498, 1452, 1352, 1101 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.98–2.13 (m, 1 H), 2.26 (s, 3 H),
2.33–2.80 (m, 3 H), 4.02 (s, 6 H), 4.09 (d, J = 14.7 Hz, 1 H), 4.37
(dd, J = 8.8, 2.6 Hz, 1 H), 4.93 (d, J = 14.7 Hz, 1 H), 6.97–7.19 (m,
4 H).
Anal. Calcd for C8H11N3O4: C, 45.07; H, 5.20; N, 19.71. Found: C,
45.38; H, 5.45; N, 19.82.
13C NMR (50 MHz, CDCl3): d = 19.2, 24.9, 29.7, 43.8, 55.4, 62.2,
2-(Dichloromethyl)-4,6-dimethoxy-1,3,5-triazine (8c)7,8
Colorless oil; bp 86–88 °C/0.045 mmHg (Lit.7 bp 86–88 °C/0.045
mmHg, Lit.8 bp 90–93 °C/0.06 mmHg).
125.9, 127.9, 129.6, 130.4, 133.7, 137.0, 172.8, 175.3, 182.0.
Anal. Calcd for C17H20N4O3: C, 62.18; H, 6.14; N, 17.06. Found: C,
62.21; H, 6.51; N, 16.96.
IR: 1545, 1507, 1466, 1353, 1197, 1104 cm–1.
1H NMR (200 MHz, CDCl3): d = 4.13 (s, 6 H), 6.47 (s, 1 H).
13C NMR (50 MHz, CDCl3): d = 54.8, 68.2, 172.3, 175.4.
5-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-1-(4-methylbenzyl)pyrro-
lidin-2-one (3c)
Colorless oil.
IR: 1682, 1550, 1499, 1457, 1354, 1096 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.07 (m, 1 H), 2.27–2.78 (m, 3 H),
2.30 (s, 3 H), 3.96 (d, J = 14.8 Hz, 1 H), 4.02 (s, 6 H), 4.44 (dd,
J = 8.3, 2.8 Hz, 1 H), 4.90 (d, J = 14.8 Hz, 1 H), 7.06 (s, 4 H).
13C NMR (50 MHz, CDCl3): d = 21.0, 24.7, 29.7, 45.3, 55.4, 62.1,
128.5, 129.1, 133.0, 137.2, 172.7, 175.4, 181.8.
Anal. Calcd for C6H7Cl2N3O2: C, 32.17; H, 3.15; N, 18.75. Found:
C, 32.13; H, 3.55; N, 19.00.
2-(Dibromomethyl)-4,6-dimethoxy-1,3,5-triazine (8d)7
Colorless oil; bp 77–79 °C/0.01 mmHg (Lit.7 bp 112–118 °C/
0.017–0.027 mmHg).
IR: 1543, 1506, 1466, 1353, 1187, 1103 cm–1.
1H NMR (200 MHz, CDCl3): d = 4.11 (s, 6 H), 6.35 (s, 1 H).
13C NMR (50 MHz, CDCl3): d = 38.8, 55.8, 173.0, 177.0.
Anal. Calcd for C17H20N4O3: C, 62.18; H, 6.14; N, 17.06. Found: C,
62.32; H, 6.05; N, 16.95.
Anal. Calcd for C6H7Br2N3O2: C, 23.03; H, 2.25; N, 13.43. Found:
C, 22.66; H, 2.02; N, 13.05.
1-(2-Chlorobenzyl)-5-(4,6-dimethoxy-1,3,5-triazin-2-yl)pyrroli-
din-2-one (3d)
Yellowish solid; mp 137 °C (cyclohexane–Et2O).
IR: 1694, 1552, 1503, 1464, 1359, 1106 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.02–2.20 (m, 1 H), 2.34–2.79 (m,
3 H), 4.02 (s, 6 H), 4.28 (d, J = 15.5 Hz, 1 H), 4.50 (dd, J = 8.6, 2.7
Hz, 1 H), 5.00 (d, J = 15.5 Hz, 1 H), 7.14–7.34 (m, 4 H).
2-(Dimethoxymethyl)-4,6-dimethoxy-1,3,5-triazine (8e)9
White solid; mp 40–41 °C (cyclohexane) (Lit.9 mp 40–41 °C).
IR: 1550, 1504, 1462, 1354, 1193, 1059 cm–1.
1H NMR (200 MHz, CDCl3): d = 3.51 (s, 6 H), 4.08 (s, 6 H), 5.19
(s, 1 H).
13C NMR (50 MHz, CDCl3): d = 24.9, 29.4, 43.1, 55.4, 62.4, 126.9,
128.9, 129.4, 130.4, 133.7, 133.8, 172.7, 175.7, 181.7.
13C NMR (50 MHz, CDCl3): d = 54.4, 55.4, 102.7, 172.9, 176.5.
Anal. Calcd for C8H13N3O4: C, 44.65; H, 6.09; N, 19.53. Found: C,
44.34; H, 6.49; N, 19.81.
Anal. Calcd for C16H17ClN4O3: C, 55.10; H, 4.91; N, 16.06. Found:
C, 55.10; H, 5.21; N, 16.12.
2-(Diethoxymethyl)-4,6-dimethoxy-1,3,5-triazine (8f)
Colorless oil.
IR: 1549, 1356, 1058 cm–1.
1-(4-Chlorobenzyl)-5-(4,6-dimethoxy-1,3,5-triazin-2-yl)pyrroli-
din-2-one (3e)
Yellowish solid; mp 98–99 °C (Et2O).
Synthesis 2006, No. 17, 2845–2848 © Thieme Stuttgart · New York

2848
S. Oudir et al.
PAPER
1H NMR (200 MHz, CDCl3): d = 1.27 (t, J = 7.2 Hz, 6 H), 3.62–
(4) Rigo, B.; Kolocouris, N. J. Heterocycl. Chem. 1983, 20, 893.
(5) (a) Rembarz, G.; Fischer, E.; Roeber, K. Ch.; Ohff, R.;
Crahmer, H. J. Prakt. Chem. 1969, 311, 889. (b) Chiang, G.
C. US Patent 4933450 A, 1990; Chem. Abstr. 1990, 113,
231414. (c) Gates, P. S.; Jones, G. P.; Saunders, D. E. PCT
Int. Appl. WO 9309099 A2, 1993; Chem. Abstr. 1993, 119,
180810. (d) Voss, O.; Dudfield, P. J.; Bauer, K.; Bieringer,
H.; Rosinger, C.; Ford, M. J.; Green, D. Ger. Offen.
19521355 A1, 1996; Chem. Abstr. 1997, 126, 144293.
(e) Weiss, S.; Krommer, H. US Patent 6342600 B1, 2002;
Chem. Abstr. 2002, 136, 134795.
(6) Sen, A. B.; Joshi, K. C. J. Indian Chem. Soc. 1948, 25, 483.
(7) (a) Grundmann, C.; Kober, E. J. Am. Chem. Soc. 1957, 79,
944. (b) Grundmann, C.; Kober, E. US Patent 3022303,
1962; Chem. Abstr. 1962, 57, 56334.
(8) (a) Kober, E. J. Org. Chem. 1961, 26, 2270. (b) Kober, E.
H. US Patent 3226386, 1965; Chem. Abstr. 1966, 64, 67883.
(9) Kober, E.; Grundmann, C. J. Am. Chem. Soc. 1958, 80,
5547.
3.90 (m, 4 H), 4.07 (s, 6 H), 5.29 (s, 1 H).
13C NMR (50 MHz, CDCl3): d = 14.8, 55.0, 62.7, 101.0, 172.6,
177.0.
Anal. Calcd for C8H13N3O4: C, 44.65; H, 6.09; N, 19.53. Found: C,
44.80; H, 6.29; N, 19.83.
References
(1) (a) Rigo, B.; Lespagnol, C.; Pauly, M. J. Heterocycl. Chem.
1986, 23, 183. (b) Laboratoires Pauly M., EP 135144, 1985;
Chem. Abstr. 1985, 103, 123914.
(2) Caulier, P.; Couturier, D.; Rigo, B.; Fasseur, D.; Halama, P.
J. Heterocycl. Chem. 1993, 30, 921.
(3) (a) Fanelli, C.; Fabbri, A. A.; Monti, S.; Menicagli, R.; Pini,
D.; Rapaccini, S. M.; Samaritani, S.; Salvadori, P. 7th
International Congress of Plant Pathology; Edinburgh:
Scotland, 1998. (b) Samaritani, S.; Fabbri, A. A.; Fanelli, C.;
Menicagli, R.; Salvadori, P. XXV Convegno Nazionale della
Divisione di Chimica Organica; Folgaria: Italy, 1998.
(c) Ricelli, A.; Fabbri, A. A.; Fanelli, C.; Menicagli, R.;
Samaritani, S.; Pini, D.; Rapaccini, S. M.; Salvadori, P.
Restaurator 1999, 97.
Synthesis 2006, No. 17, 2845–2848 © Thieme Stuttgart · New York