Synthesis of pyrazine alcaloids from Botryllus leachi. diazines 43

Article abstract of DOI:10.1021/jo0478196

(Chemical Equation Presented) Regioselective metalation of pyrazines and cross-coupling reactions provides an easy access to botryllazines A and B and to an isomer of botryllazine A with good yields from chloropyrazine.

Full text of DOI:10.1021/jo0478196

Supporting information to:
SYNTHESIS OF PYRAZINES ALCALOIDS FROM
BOTRYLLUS LEACHI. DIAZINES 43.
Frederic Buron, Nelly Ple, Alain Turck*, Guy Queguiner
IRCOF, Laboratoire de Chimie Organique Fine et Hétérocyclique, UMR 6014, INSA, B.P.
0
8, 76131 Mont St Aignan Cedex, France.
Fax: (33)2 35 52 29 62, E-mail: alain.turck@insa-rouen.fr
Table of contents
1
2
3
4
5
6
7
8
. GENERAL INFORMATION........................................................................................................................S.2
. SYNTHESIS OF BOTRYLLAZINE B.........................................................................................................S.2
. METALATION OF KETAL DERIVATIVES ............................................................................................S.4
. NUCLEOPHILIC SUBSTITUTION ............................................................................................................S.7
. SYNTHESIS OF AN ANALOGUE OF BOTRYLLAZINE A ...................................................................S.9
. SYNTHESIS OF BOTRYLLAZINE A ......................................................................................................S.12
. SPECTRA .....................................................................................................................................................S.15
. REFERENCES .............................................................................................................................................S.67
S.1

1
. General Information
1
13
Melting points were determined on a Kofler hot-stage apparatus. The H, C NMR spectra
were recorded on Bruker instruments (AC 200 and Avance 300). Microanalyses were
performed on a Carlo Erba CHNOS 1160 apparatus. The IR spectra were obtained from
potassium bromide pellets with a Perkin-Elmer FTIR 1650 spectrophotometer.
All reagents were of commercial quality purchased from Aldrich Co. and Acros. Pd-catalyst
was prepared according to the literature.
Procedure A for direct lithiation by lithium 2,2,6,6-tetramethylpiperidide. A solution of n-
butyllithium (1.6M or 2.5M in hexane) was added to cold (-50°C), stirred and anhydrous THF
(
50 mL) under an atmosphere of dry nitrogen. Then 2,2,6,6-tetramethypiperidine (TMPH)
was added. The mixture was warmed to 0°C. After 20 min, the mixture was cooled to the
temperature θ and a solution of pyrazine dissolved in 8 mL of THF, added. After a time t at
, the electrophile was introduced and the stirring was continued for a time t at θ
Hydrolysis was then carried out at θ using a solution of ethanol and water (4 : 1). The
1
1
θ
1
2
2
.
2
mixture was evaporated and the residue was extracted with dichloromethane (3x20 mL), the
combined organic extracts were dried over magnesium sulfate and evaporated. The crude
product was purified by column chromatography on silica gel.
Procedure B for cross-coupling of arylboronic acids with halodiazines under Suzuki
conditions.
A mixure of halodiazine, arylboronic acid (n equiv.), Pd(PPh ) (0.1 equiv.), aqueous 2M
3
4
potassium carbonate (1 equiv.) and ethanol (1 mL) in degassed toluene (15 mL) was heated to
reflux under nitrogen for a time t. The reaction mixture was cooled, diluted with 20 mL of a
mixture of water and dichloromethane (1:1) and the organic layer separated. The aqueous
layer was extracted with dichloromethane (3x20 mL). The combined organic extracts were
dried over magnesium sulfate and evaporated. The crude product was purified by column
chromatography on silica gel.
2
2
. Synthesis of Botryllazine B
-chloro-6-tri-n-butylstannylpyrazine (4)
N
N
Cl
SnBu3
A solution of n-butyllithium 2.5M (3.15 equiv., 10.83 mL) was added to cold (-50°C), stirred
and anhydrous THF (75 mL) under an atmosphere of dry nitrogen. Then 2,2,6,6-
tetramethypiperidine (3.15 equiv., 4.69 mL) was added. The mixture was warmed to 0°C.
After 20 min, the mixture temperature was carried to -78°C. Chloropyrazine (1 g, 8.73 mmol)
was dissolved in 50 mL THF and tri-n-butyltin chloride (1 equiv., 2.63 mL) were
simultaneously introduced at -100°C into a solution containing the metalating agent (LTMP)
S.2

The mixture was then stirred for 2.5 h, during this time, temperature was slowly increased
from -100°C at -40°C. Hydrolysis was then carried out at -40°C using a solution of 35%
aqueous hydrochloric acid, ethanol and THF (1:4:5). At room temperature, the mixture was
made slightly basic with saturated sodium hydrogenocarbonate solution. The mixture was
evaporated and the residue was extracted with dichloromethane (3x20 mL). The combined
organic extracts were then dried over magnesium sulfate and evaporated. The crude product
was purified by column chromatography and gave after purification by column
chromatography (silica gel, eluent: dichloromethane) 3.13 g (89%) of (4) as a yellow liquid.
1
13
H NMR (CDCl
3
) : 8.36 (s, 1H, H
5
), 8.27 (m, 1H, H
3
), 1.53-0.77 (m, 27H, 3Bu); C NMR
), 28.9, 27.2, 10.0 (CH ), 13.5 (CH );
(
CDCl ) : 170.0 (C
3
6
), 151.2 (C ), 148.7 (C
2
5
), 142.7 (C
3
2
3
-
1
IR : 2953, 2925, 2871, 2852, 1489, 1463, 1404, 1376, 1169, 1150, 1001, 876 cm ; IC : 405
(
+
MH ), 371, 347.
2
-chloro-6-(1-oxo-[4-methoxyphenyl]methyl)pyrazine (6)
N
N
O
Cl
O
A solution of 4-methoxybenzoyl chloride (7.7 g, 3 equiv.), Pd(PPh
was heated to 80°C under a nitrogen atmosphere. 2-chloro-6-tri-n-butylstannylpyrazine (4)
6.1 g, 15.1 mmol) was added and the solution was refluxed for 12 h. After cooling, a mixture
3 4
) (0.1 equiv.) in toluene
(
of water (30 mL) and dichloromethane (30 mL) was added. The aqueous layer was extracted
with dichloromethane (3x20 mL). The combined organic extracts were then dried over
magnesium sulfate and evaporated. The crude product was purified by column
chromatography (silica gel, eluent : dichloromethane/cyclohexane (8:2)) and gave 2.63 g
1
(
H
70%) of (6) as a yellow solid, mp : 98°C. H NMR (CDCl
5
3
) : 9.08 (s, 1H, H
3
), 8.76 (s, 1H,
13
), 8.12 (d, 2H, J=8.7 Hz, HPh2,6), 6.97 (d, 2H, J=8.7 Hz, HPh3,5), 3.89 (s 3H, OCH
3
). C
(
(
1
CDCl ) : 188.7 (C ), 164.4 (C ), 149.8 (C ), 147.6 (C ), 146.7 (C ), 143.6 (C ), 133.7
3
7
Ph4
2
6
3
5
C
3
Ph2,6), 127.9 (CPh1), 114.0 (CPh3,5), 55.7 (OCH ). IR : 3048, 2984, 2939, 2844, 1651, 1594,
-
1
511, 1324, 1268, 1179, 1160, 1021, 961, 841, 774 cm . Anal. calcd for C12
9 2 2
H ClN O
(
248.67) : C, 57.96; H, 3.65; N, 11.27. Found: C, 57.90; H, 3.73; N, 10.90.
2
-(1-oxo-[4-methoxyphenyl]methyl)-6-(4’-methoxyphenyl)pyrazine (8)
N
N
O
O
O
Coupling of 4-methoxyphenylboronic acid (470 mg, 2 equiv.) with (6) (385 mg, 1.54 mmol)
according to the procedure B (t=8 h) gave after purification by column chromatography (silica
gel, eluent: cyclohexane/ethyl acetate (6:4)) 446 mg (90%) of (8) as a yellow solid, mp :
1
1
8
14°C. H NMR (CDCl
3
) : 9.14 (s, 1H, H
3
), 9.04 (s, 1H, H
5
), 8.24 (d, 2H, J=8.7 Hz, HPh2,6),
13
.21 (d, 2H, J=8.7 Hz, HPh’2,6), 7.03 (m, 4H, HPh3,5 and HPh’3,5), 3,90 (m, 6H, 2xOCH ). C
3
(
CDCl
3
) : 190.9 (C
7
2 6 3 5
), 164.1 (CPh4), 161.6 (CPh’4), 150.3 (C ), 149.6 (C ), 143.0 (C and C ),
1
33.8 (CPh2,6), 128.8 (CPh’1), 128.6 (CPh’2,6), 128.2 (CPh1), 114.8 (CPh’3,5), 113.8 (CPh3,5), 55.7
(
OCH ). IR : 3075, 2997, 2938, 2913, 2835, 1649, 1604, 1516, 1342, 1274, 1249, 1164, 1036,
3
S.3

-
1
9
52, 842, 829, 774 cm . Anal. calcd for C H N O (320.35) : C, 71.24; H, 5.03; N, 8.74.
1
9
16
2
3
Found: C, 70.91; H, 5.02; N, 8.72.
Botryllazine B (1)
N
O
N
HO
OH
Pyridine hydrochloride (10 g) was heated at 220°C for 15 min, and (8) (100 mg, 0.31 mmol)
was added. The mixture was maintained at this temperature for 1h, then poured on to ice . The
solution was extracted with ether (3x20 mL), the combined organic extracts were then dried
over magnesium sulfate and evaporated. The crude product was purified by column
chromatography (silica gel, eluent: cyclohexane/ethyl acetate (5:5)) and gave 83 mg (91%) of
1
(
1) as a yellow solid, mp >250°C. H NMR (CD
3
OD) : 9.19 (s, 1H, H
5
), 8.85 (s, 1H, H
3
),
8
.07 (d, 2H, J=8.7 Hz, HPh2,6), 8.00 (d, 2H, J=8.7 Hz, HPh’2,6), 6.92 (m, 4H, HPh3,5 and HPh’3,5).
1
3
C (CD OD) : 192.7 (C ), 165.0 (C ), 161.6 (C ), 152.7 (C ), 151.8 (C ), 143.9 (C ),
3
7
Ph4
Ph’4
6
2
5
1
3
43.1 (C ), 135.3 (CPh2,6), 130.2 (CPh’2,6), 128.9 (CPh1), 128.4 (CPh1’), 117.4 (CPh’3,5), 116.6
Ph3,5). IR : 3165, 1644, 1603, 1563, 1515, 1421, 1340, 1275, 1250, 1152, 946, 833, 774 cm
-
(
C
1
.
Anal. calcd for C H N O (292.30) : C, 69.86; H, 4.14; N, 9.58. Found: C, 69.88; H, 3.89;
1
7
12
2
3
N, 9.27.
3
2
. Metalation of ketal derivatives
-(2-(4-methoxyphenyl)-1,3-dioxolan-2-yl)-6-(4’-methoxyphenyl)pyrazine (9)
N
N
O
O
O
O
In a flask equipped with a dean stark apparatus, was placed a solution of (8) (843 mg, 2.63
mmol), glycol (10 equiv.) and APTS (0.1 equiv.) in toluene and heated under reflux for 12 h.
After cooling, a saturated solution of sodium bicarbonate (30 mL) and dichloromethane (30
mL) was added. The aqueous layer was extracted with dichloromethane (3x20 mL). The
combined organic extracts were then dried over magnesium sulfate and evaporated. The crude
product was purified by column chromatography (silica gel, eluent : dichloromethane) and
1
gave 939 mg (98%) of (9) as a colorless liquid. H NMR (CDCl
3
) : 8.87 (s, 1H, H
5
), 8.77 (s,
1
3
H, H ), 7.95 (d, 2H, J=8.7 Hz, HPh’2,6), 7.62 (d, 2H, J=8.7 Hz, HPh2,6), 6.98 (d, 2H, J=8.7 Hz,
HPh’3,5), 6.89 (d, 2H, J=8.7 Hz, H ), 4.18 (m, 4H, 2xCH ), 3.84 (s, 3H, OCH ), 3.78 ( s, 3H,
Ph3,5
2
3
1
3
OCH
3
). C (CDCl
3
) : 161.2 (CPh’4), 159.8 (CPh4), 154.8 (C
2
), 151.3 (C
6
3
), 140.4 (C ), 139.0
5
(C ), 132.9 (CPh1), 128.8 (CPh’1), 128.6 (CPh’2,6), 127.8 (CPh2,6), 114.4 (CPh’3,5), 113.6 (CPh3,5),
1
1
08.1 (C
7
), 65.5 (CH
2
), 55.5 (OCH
3
). IR : 2958, 2894, 2836, 1609, 1513, 1422, 1251, 1172,
O (364.40+1/2x18.02) : C, 67.55; H, 5.67;
-
1
032, 834 cm . Anal. calcd for C21
H
20
N
2
O
4
,
1/2
H
2
N, 7.50. Found: C, 67.65; H,5.84; N, 6.94.
S.4

2
-chloro-6-(2-[4-methoxyphenyl]-1,3-dioxolan-2-yl)pyrazine (12)
N
N
O
Cl
O
O
In a flask equipped with a Dean Stark apparatus, was placed a solution of (6) (740 mg, 2.98
mmol), glycol (10 equiv.) and APTS (0.1 equiv.) in toluene and heated to reflux for 8 h. After
cooling, a solution of saturated of sodium bicarbonate (30 mL) and dichloromethane (30 mL)
were added. The aqueous layer was extracted with dichloromethane (3x20 mL). The
combined organic extracts were then dried over magnesium sulfate and evaporated. The crude
product was purified by column chromatography (silica gel, eluent : dichloromethane) and
1
gave 854 mg (98%) of (12) as a yellow liquid. H NMR (CDCl
3
) : 8.79 (s, 1H, H
5
), 8.48 (s,
),
), 139.7
1
3
H, H
.78 ( s, 3H, OCH
3 2
), 7.52 (d, 2H, J=8,7Hz, HPh2,6), 6.87 (d, 2H, J=8.7 Hz, HPh3,5), 4.11 (m, 4H, 2xCH
1
3
3
). C (CDCl
3
) : 159.9 (CPh4), 155.9 (C
6
), 148.8 (C
2
), 144.0 (C
3
(
2
C ), 131.9 (C ), 127.6 (CPh2,6), 113.8 (CPh3,5), 107.2 (C ), 65.6 (CH ), 55.4 (OCH ). IR :
958, 2895, 2837, 1610, 1511, 1390, 1304, 1250, 1175, 1099, 1032, 966, 947, 835 cm . Anal.
5 Ph1 7 2 3
-
1
calcd for C H ClN O (292.72) : C, 57.45; H, 4.48; N, 9.57. Found: C, 57.49; H, 4.46; N,
1
4
13
2
3
9
.68.
3
-chloro-2-deutero-5-(2-[4-methoxyphenyl]-1,3-dioxolan-2-yl)pyrazine (13)
D
N
O
Cl
N
O
O
Metalation of (12) (710 mg, 2.43 mmol) according to procedure A with n-BuLi 1.6M (1.1
equiv., 1.70 mL), TMPH (1.2 equiv., 0.46 mL), t =30 min, θ =-78°C, followed by addition of
ethyl alcohol-d (5 equiv., 0.46 mL) t =5 min, θ =-78°C gave after purification by column
chromatography (silica gel, eluent : dichloromethane) 700 mg (98%) of (13) as a yellow
1
1
2
2
1
liquid. H NMR (CDCl
3
) : 8.78 (s, 1H, H
6
), 7.54 (d, J=8.7 Hz, 2H, HPh2,6), 6.88 (d, J=8.7
1
3
Hz, 2H, HPh3,5), 4.11 (m, 4H, 2xCH
55.9 (C
07.2 (C ), 65.5 (CH ), 55.3 (OCH ). IR : 2957, 2895, 2836, 1610, 1511, 1313, 1250, 1172,
2 3
135, 1099, 1033, 1015, 834, 810, 783, 458 cm . Anal. calcd for C14H12ClDN O (293.73) :
2
3 3
), 3.77 (s, 3H, OCH ). C NMR (CDCl ) : δ 159.9 (CPh4),
1
1
1
5 3 2 6
), 148.7 (C ), 143.9 (C ), 139.6 (C ), 131.8 (CPh1), 127.5 (CPh2,6), 113.7 (CPh3,5),
7
2
3
-
1
C, 57.25; H, 4.12; N, 9.54. Found : C, 57.16; H, 4.31; N, 9.56.
2
-deutero-3-(4’-methoxyphenyl)-5-(2-[4-methoxyphenyl]-1,3-dioxolan-2-yl)pyrazine (14)
S.5

D
N
N
O
O
O
O
Coupling of 4-methoxyphenylboronic acid (680 mg, 1.1 equiv.) with (13) (1.20 g, 4.08 mmol)
according to procedure B (t=8 h) gave after purification by column chromatography (silica
1
gel, eluent: dichloromethane) 1.34 g (90%) of (14) as a yellow liquid. H NMR (CDCl
3
) :
8
H
6
.79 (s, 1H, H ), 7.96 (d, J=8.7 Hz, 2H, HPh’2,6), 7.62 (d, J=8.7 Hz, 2H, HPh2,6), 6.90 (m, 4H,
1
3
Ph3,5 and HPh’3,5), 4.10 (m, 4H, 2xCH
) : δ 160.9 (CPh’4), 159.5 (CPh4), 154.5 (C
Ph1 and CPh1’), 128.2 (CPh2,6 and CPh’2,6), 114.1 (CPh3,5 and CPh’3,5), 107.8 (C
2
), 3.77 (s, 3H, OCH
3
), 3.72 (s, 3H, OCH
), 138.8 (C ), 132.6 (C
), 65.2 (CH
3
). IR : 2958, 2895, 2837, 1711, 1608, 1581, 1514, 1373, 1302, 1253, 1174, 1125,
3
). C NMR
), 128.4
),
(
(
CDCl
C
3
5
), 150.8 (C
3
6
2
7
2
5
1
5.1 (OCH
073, 834, 812 cm . Anal. calcd for C H DN O (365.41) : C, 69.03; H, 5.24; N, 7.67.
-
1
2
1
19
2
4
Found: C, 68.98; H, 5.22; N, 7.63.
2
-(1-hydroxy-[4’’-methoxyphenyl]methyl)-3-(4’-methoxyphenyl)-5-(2-[4-
methoxyphenyl]-1,3-dioxolan-2-yl)pyrazine (10) and 2-(1-hydroxy-[4’’-
methoxyphenyl]methyl)-3-(2-[4-methoxyphenyl]-1,3-dioxolan-2-yl)-5-(4’-
methoxyphenyl)pyrazine (11)
O
O
OH
N
N
O
N
N
O
HO
O
O
O O
O
O
1
0
11
Metalation of (9) or (14) (200 mg, 0.55 mmol) according to procedure A with n-BuLi 1.6M
3.1 equiv., 1.06 mL), TMPH (3.1 equiv., 0.29 mL), t =30 min, θ =-78°C, followed by
addition of p-anisaldehyde (3.1 equiv., 0.2 mL) in THF (10 mL) t =60 min, θ =-78°C gave
after purification by column chromatography (silica gel, eluent : cyclohexane/ethyl acetate
(
1
1
2
2
1
(
6:4)) 192 mg (70%) of (10) and (11) as yellow liquids. (10) H NMR (CDCl
3
) : 8.75 (s, 1H,
H ), 7.50 (d, 2H, J=8.7 Hz, HPh2,6), 7.20 (d, 2H, J=8.7 Hz, HPh’2,6), 6.90 (d, 2H, J=8.7 Hz,
6
H
Ph’’2,6), 6.78 (m, 6H, HPh3,5, HPh3,5 and HPh’3,5), 5.84 (d, 1H, JCH,OH=8.7 Hz, CH), 4.55 (d, 1H,
1
J
CH,OH=8.7 Hz, OH), 4.10 (m, 4H, 2xCH
.84 (s, 1H, H ), 7.90 (d, 2H, J=8.7 Hz, HPh2,6), 7.33 (d, 2H, J=8.7 Hz, HPh’2,6), 7.05 (d, 2H,
J=8.7 Hz, HPh’’2,6), 6.92 (m, 6H, HPh3,5 Ph’3,5 and HPh’3,5), 6.25 (d, 1H, JCH,OH=8.7 Hz, CH),
2 3 3
), 3.77 (m, 9H, OCH ).(11) H NMR (CDCl ) :
8
6
H
13
4
.35 (d, 1H, JCH,OH=8.7 Hz, OH), 4.10 (m, 4H, 2xCH ), 3.77 (m, 9H, OCH ). (10 and 11) C
2 3
NMR (CDCl ) : δ 160.6-159.9 (C , C
CPh’4 ), 154.3-152.3 (Cpyr), 138.6 (C6(10) and
6(11)), 136.2-129.1 (CPh1, CPh’1 and CPh’’1), 129.9-128.1 (CPh2,6,CPh’2,6 and CPh’’2,6), 114.1 (CPh3,5,
3
Ph4
Ph’4,
C
C
Ph3,5 and CPh’3,5), 108.1 (C
7
10)
7 2 3
and C (11)), 77.2 (CH), 65.7 (CH ), 55.7 (OCH ). IR : 3449,
(
3
002, 2957, 2934, 2897, 2836, 1609, 1512, 1463, 1379, 1308, 1251, 1174, 1096, 1033, 883
-
1
,
755 cm . HRMS (IC) calculated for C29
29 2 6
H N O : 501.2025. Found : 501.2061.
3
-chloro-2-trimethylsilyl-5-(2-[4-methoxyphenyl]-1,3-dioxolan-2-yl)pyrazine (15)
S.6

Si
N
N
O
Cl
O
O
Metalation of (12) (620 mg, 2.12 mmol) according to procedure A with n-BuLi 2.5M (1.1
equiv., 0.93 mL), TMPH (1.1 equiv., 0.42 mL), t =30 min, θ =-78°C, followed by addition of
1
1
trimethylsilyl chloride (1.1 equiv., 0.30 mL) t
2
=60 min, θ
2
=-78°C gave after purification by
column chromatography (silica gel, eluent : dichloromethane) 603 mg (78%) of (15) as
1
colorless liquid. H NMR (CDCl ) : 8.91 (s, 1H, H ), 7.55 (d, J=8.7 Hz, 2H, H ), 6.88 (d,
3
6
Ph2,6
13
J=8.7 Hz, 2H, HPh3,5), 4.11 (m, 4H, 2xCH
2
), 3.78 (s, 3H, OCH
3
3
), 0.39 (s, 9H, 3xCH ). C
NMR (CDCl
3
) : δ 161.8 (CPh4), 159.9 (C
2 3 5 6
), 154.5 (C and C ), 140.0 (C ), 132.2 (CPh1), 127.6
(
CPh2,6), 113.7 (CPh3,5), 107.2 (C ), 65.5 (CH ), 55.3 (OCH ), -1.6 (SiMe ). IR : 2956, 2898,
7
2
3
3
-
1
1
611, 1510, 1250, 1172, 1098, 1053, 1034, 845, 790, 587 cm . Anal. calcd for
Si (364.91) : C, 55.96; H, 5.80; N, 7.68. Found : C, 56.24; H, 6.12; N, 7.45.
17 2 3
C H21ClN O
2
-trimethylsilyl-3-(4’-methoxyphenyl)-5-(2-[4-methoxyphenyl]-1,3-dioxolan-2-
yl)pyrazine (16)
Si
N
N
O
O
O
O
Coupling of 4-methoxyphenylboronic acid (160 mg, 1.1 equiv.) with (15) (360 mg, 0.98
mmol) according to procedure B (t=12 h) gave after purification by column chromatography
1
(
silica gel, eluent: dichloromethane) 263 mg (61%) of (16) as a yellow solid, mp : 116°C. H
NMR (CDCl ) : 8.96 (s, 1H, H ), 7.60 (d, J=8.7 Hz, 2H, HPh2,6), 7.40 (d, J=8.7 Hz, 2H,
3
6
H
Ph’2,6), 6.94 (d, J=8.7 Hz, 2H, HPh’3,5), 6.88 (d, J=8.7 Hz, 2H, HPh3,5), 4.13 (m, 4H, 2xCH
2
),
13
3
1
1
:
.84 (s, 3H, OCH
58.9 (CPh’4, CPh4, C
27.7 (CPh2,6), 113.5 (CPh3,5 and CPh’3,5), 107.9 (C
3
), 3.78 (s, 3H, OCH
3
), 0.10 (s, 9H, 3xCH
), 139.7 (C
), 65.4 (CH
2957, 2884, 2840, 1608, 1507, 1464, 1364, 1300, 1252, 1170, 1077, 1031, 836 cm . Anal.
Si (436.59) : C, 66.03; H, 6.46; N, 6.42. Found: C, 65.83; H, 6.52; N,
). C NMR (CDCl ) : 160.3-
3 3
2
and C ), 152.4 (C
3
5
6
), 133.2 (CPh1 and CPh’1), 130.8 (CPh’2,6),
7
2 3 3
), 55.4 (OCH ), -0.2 (SiMe ). IR
-
1
28 2 4
calcd for C24H N O
6
.37.
4
2
. Nucleophilic substitution
-chloro-6-(4-methoxyphenyl)pyrazine (18)
N
N
Cl
O
Coupling of 4-methoxyphenylboronic acid (917 mg, 0.9 equiv.) with 2,6-dichloropyrazine (1
g, 6.71 mmol) according to procedure B (t=8 h) gave after purification by column
chromatography (silica gel, eluent: dichloromethane/cyclohexane (7:3)) 1.03 g (70%) of (18)
1
as a white solid, mp : 86°C. H NMR (CDCl ) : 8.82 (s,1H, H ), 8.40 (s, 1H, H ), 7.94 (d,
3
5
3
S.7

1
3
2
1
H, J=8.7 Hz, HPh2,6), 6.97 (d, 2H, J=8.7 Hz, HPh3,5), 3.84 (s, 3H, OCH ). C (CDCl ) :
3 3
61.7 (CPh4), 152.3 (C
6 2 3 5
), 148.8 (C ), 141.4 (C ), 138.7 (C ), 128.6 (CPh2,6), 127.2 (CPh1), 114.6
(
1
5
C
Ph3,5), 55.5 (OCH ). IR : 3058, 2971, 2928, 2835, 1605, 1519, 1326, 1260, 1163, 1150,
3
-
1
027, 929 cm . Anal. calcd for C11
9.58; H, 4.27; N, 12.64
9 2
H ClN O (220.66) : C, 59.88; H, 4.11; N, 12.70. Found: C,
3
-chloro-2-(1-hydroxy-4-methoxyphenylmethyl)-5-(4’-methoxyphenyl)pyrazine (19)
O
N
OH
N
Cl
O
Metalation of (18) (530 mg, 2.40 mmol) according to procedure A with n-BuLi 2.5M (1.1
equiv., 1.06 mL), TMPH (1.1 equiv., 0.46 mL), t =30 min, θ =-78°C, followed by addition of
p-anisaldehyde (1.2 equiv., 0.35 mL) in THF (10 mL) t =60 min, θ =-78°C gave after
purification by column chromatography (silica gel, eluent : cyclohexane/ethyl acetate (7:3))
1
1
2
2
1
7
3 6
28 mg (85%) of (19) as a yellow solid, mp : 100°C. H NMR (CDCl ) : 8.87 (s, 1H, H ),
7
6
.98 (d, J=8.7 Hz, 2H, HPh’2,6), 7.29 (d, J=8,7Hz, 2H, HPh2,6), 7.01 (d, J=8.7 Hz, 2H, HPh’3,5),
.85 (d, J=8.7 Hz, 2H, HPh3,5), 5.99 (d, JCH,OH=7.5 Hz, 1H, CH), 4.60 (d, JCH,OH=7.5 Hz, 1H,
1
3
OH), 3.87 (s, 3H, OCH
3
), 3.77 (s, 3H, OCH
3
). C NMR (CDCl
3
) : 161.8 (CPh’4), 159.6
), 133.2 (CPh1), 128.6 (CPh2,6 and CPh’2,6),
27.0 (CPh1’), 114.7 (CPh’3,5), 114.1 (CPh3,5), 71.7 (CH), 55.5 (OCH
(
C
Ph4), 151.7 (C
5
), 151.3 (C
2
), 146.6 (C ), 137.3 (C
3
6
1
1
3
); IR : 3360 , 2932, 2837,
608, 1579, 1520, 1437, 1418, 1303, 1280, 1256, 1174, 1158, 1042, 1027, 837, 801, 773, 552
-
1
cm . Anal. calcd for C H ClN O (356.81) : C, 63.96; H, 4.80; N, 7.85. Found : C, 63.82;
19
17
2
3
H, 4.88; N, 7.83.
3
-chloro-2-(1-oxo-4-methoxyphenylmethyl)-5-(4’-methoxyphenyl)pyrazine (20)
O
N
O
N
Cl
O
To a solution of (19) (450 mg, 1.26 mmol) in 50 mL of THF was added MnO (10 equiv.,
2
1
.09 g). The solution was stirred at room temperature for 8 h. The mixture was filtered
through celite, and the filtrate was evaporated. After purification by column chromatography
silica gel, eluent : cyclohexane/ethyl acetate (7:3)) 407 mg (91%) of (20) was obtained as a
(
1
white solid, mp : 202°C. H NMR (DMSO) : δ 9.32 (s, 1H, H
H
HPh’3,5), 3.87 (s, 6H, 2xOCH ). C NMR (DMSO) : δ 190.1 (C ), 164.8 (C ), 162.1 (CPh’4),
1
1
6
), 8.20 (d, J=8.7 Hz, 2H,
Ph2,6), 7.89 (d, J=8.7 Hz, 2H, HPh’2,6), 7.14 (d, J=8.7 Hz, 2H, HPh3,5), 7.10 (d, J=8.7 Hz, 2H,
1
3
3
7
Ph4
52.6 (C
5
), 147.3 (C
3 2 6
), 144.5 (C ), 139.1 (C ), 133.1 (CPh2,6), 129.4 (CPh’2,6), 127.8 (CPh1),
3
26.5 (CPh’1), 115.1 (CPh3,5 and CPh’3,5), 56.1 (OCH ). IR : 3015, 2974, 2935, 2840, 1667,
S.8

-
1
1
605, 1519, 1311, 1299, 1256, 1173, 1164, 1081, 1014, 936, 832, 795 cm . Anal. calcd for
(354.80) : C, 64.32; H, 4.26; N, 7.90. Found : C, 64.07; H, 4.34; N, 7.80.
19 2 3
C H15ClN O
3
-chloro-2-(1-hydroxy-t-butyldimethylsilyl-4-methoxyphenylmethyl)-5-(4’-
methoxyphenylmethyl)pyrazine (21)
O
N
N
O
Si
Cl
O
Imidazole (1.6 equiv., 280 mg) and tert-butyldimethylsilyl chloride (1.2 equiv., 460 mg) were
added to a solution of (19) (900 mg, 2.52 mmol) in 50 mL of CH Cl . The solution was stirred
2
2
at room temperature for 8 h, and then washed with 30mL of water. The aqueous layer was
extracted with dichloromethane (3x20 mL). The combined organic extracts were then dried
over magnesium sulfate and evaporated. The crude product was purified by column
chromatography (silica gel, eluent : dichloromethane) and gave 880 mg (74%) of (21) as a
1
yellow liquid. H NMR (CDCl
3
6
) : 8.88 (s, 1H, H ), 7.96 (d, J=8.7 Hz, 2H, HPh’2,6), 7.46 (d,
J=8.7 Hz, 2H, HPh2,6), 7.00 (d, J=8.7 Hz, 2H, HPh’3,5), 6.86 (d, J=8.7 Hz, 2H, HPh3,5), 6.32 (s,
1
H, CH), 3.86 (s, 3H, OCH ), 3.78 (s, 3H, OCH ), 0.92 (s, 9H, 3xCH ), 0.08 ( s, 3H, CH ),
3
3
3
3
1
3
0
.02 ( s, 3H, CH
), 138.9 (C
Ph3,5), 73.3 (CH), 55.5 (OCH
608, 1511, 1439, 1374, 1251, 1176, 1158, 864, 836, 778 cm . Anal. calcd for
C H ClN O Si (471.08) : C, 63.74; H, 6.63; N, 5.95. Found: C, 63.63; H, 6.28; N, 5.84.
3
). C (CDCl
3
) : 161.6 (CPh’4), 159.1 (CPh4), 152.7 (C
5
), 150.8 (C
2
), 146.2
(
(
C
C
3
6
), 133.9 (CPh1), 127.6 (CPh2,6 and CPh’2,6), 127.2 (CPh1’), 114.6 (CPh’3,5), 113.8
3 3 3
), 26.0 (CH ), 18.5 (C), -4.6 (CH ). IR : 2955, 2930, 2856,
-
1
1
25
31
2
3
5
. Synthesis of an analogue of Botryllazine A
3
2
-chloro-2-(1-hydroxy-4-methoxyphenylmethyl)-5-(2-[4’-methoxyphenyl]-1,3-dioxolan-
-yl)pyrazine (24)
O
N
N
O
HO
Cl
O
O
Metalation of (12) (820 mg, 2.80 mmol) according to procedure A with n-BuLi 1.6M (1.1
equiv., 1.95 mL), TMPH (1.1equiv., 0.54 mL), t =30 min, θ =-78°C, followed by addition of
1
1
p-anisaldehyde (1.1 equiv., 0.39 mL) t
2
=60 min, θ
2
=-78°C gave after purification by column
chromatography (silica gel, eluent : cyclohexane/ethyl acetate (5:5)) 985 mg (82%) of (24) as
1
yellow solid, mp : 106°C. H NMR (CDCl
3
) : δ 8.72 (s, 1H, H
6
), 7.46 (d, J=8.7 Hz, 2H,
S.9

HPh’2,6), 7.17 (d, J=8.7 Hz, 2H, HPh2,6), 6.77 (m, 4H, HPh3,5 and HPh’3,5), 5.87 (d, JCH,OH=7.5 Hz
,
3
(
1H, CH), 4.47 (d, JCH,OH=7.5 Hz, 1H, OH), 4.04 (m, 4H, CH
2
), 3.70 (s, 3H, OCH
3
), 3.68 (s,
13
H, OCH
3
); C NMR (CDCl
3
) : δ 160.3 (CPh’4), 159.9 (CPh4), 155.3 (C ), 154.1 (C
5
2
), 146.9
C ), 138.6 (C ), 132.9 (C ), 132.2 (CPh’1), 129.2 (CPh2,6), 127.9 (CPh’2,6), 114.2 (CPh3,5 and
3 6 Ph1
C
Ph’3,5), 107.5 (C
7
2 3
), 72.0 (CH), 65.9 (CH ), 55.6 (OCH ); IR : 3994, 2995, 2933, 2896, 2835,
-
1
1
611, 1510, 1250, 1154, 1092, 1031, 995, 826, 593 cm . Anal. calcd for C22
2 5
H21ClN O
(
428.88) : C, 61.61; H, 4.94; N, 6.53. Found : C, 61.55; H, 4.95; N, 6.46.
3
-chloro-2-(1-oxo-4-methoxyphenylmethyl)-5-(2-[4’-methoxyphenyl]-1,3-dioxolan-2-
yl)pyrazine (25)
O
N
N
O
O
Cl
O
O
To a solution of (24) (1.50 g, 3.50 mmol) in 50 mL of THF was added MnO (10 equiv., 3.00
2
g). The solution was stirred at room temperature for 8 h. The mixture was filtered through
celite, and the filtrate was evaporated. The crude product gave after purification by column
chromatography (silica gel, eluent : cyclohexane/ethyl acetate (5:5)) 1.36 g (91%) of (25) as a
1
yellow solid, mp : 124°C. H NMR (CDCl
3
) : δ 8.86 (s, 1H, H
6
), 7.78 (d, J=8.7 Hz, 2H,
),
), 164.8 (CPh4), 160.1
H
Ph2,6), 7.58 (d, J=8.7 Hz, 2H, HPh’2,6), 6.94 (m, 4H, HPh3,5 and HPh’3,5), 4.17 (m, 4H, CH
2
1
3
3
.87 (s, 3H, OCH
3
), 3.80 (s, 3H, OCH
3
). C NMR (CDCl
3
) : δ 189.8 (C
7
(
(
CPh’4), 156.6 (C ), 150.3 (C ), 145.7 (C ), 138.6 (C ), 132.9 (C ), 131.7 (C ), 127.8
5 2 3 6 Ph2,6 Ph1
C
Ph’1), 127.6 (CPh’2,6), 114.0 (CPh3,5 and CPh’3,5), 107.3 (C
8
), 65.7 (CH
2
3
), 55.6 (OCH ). IR :
3
003, 2963, 2936, 2838, 1666, 1575, 1320, 1256, 1177, 1103, 999, 937, 916, 832, 642, 549
-
1
cm . Anal. calcd for C22
H, 4.57; N, 6.46.
2
H19ClN O
5
(426.86) : C, 61.90; H, 4.49; N, 6.56. Found : C, 61.68;
2
-(1-oxo-4-methoxyphenylmethyl)-3-(4’-methoxyphenyl)-5-(2-[4’’-methoxyphenyl]-1,3-
dioxolan-2-yl)pyrazine (26)
O
N
N
O
O
O
O
O
Coupling of 4-methoxyphenylboronic acid (930 mg, 2 equiv.) with (25) (1.30 g, 3.04 mmol)
according to procedure B (t=8 h) gave after purification by column chromatography (silica
gel, eluent: cyclohexane/ethyl acetate (7:3)) 1.32 g (87%) of (26) as a white solid, mp : 68°C.
1
H NMR (CDCl
3
) : 8.83 (s, 1H, H
6
), 7.83 (d, 2H, J=8.7 Hz, HPh2,6), 7.64 (d, 2H, J=8.7 Hz,
and HPh’’3,5), 6.81 (d, 2H, J=8.7
HPh’’2,6), 7.54 (d, 2H, J=8.7 Hz, HPh’2,6), 6.83 (m, 4H, H
Hz, HPh’2,6), 4.21 (m, 4H, CH
Ph3,5
1
3
2
), 3.90-3.70 (m, 9H, OCH
3
). C (CDCl
3
) : 193.2 (C
7
), 164.3
S.10

(
(
C ), 160.9 (CPh’4), 159.9 (CPh’’4), 155.3 (C ), 151.5 (C ), 149.5 (C ), 137.5 (C ), 132.9
Ph4 5 3 2 6
C
Ph2,6), 132.5 (CPh1), 130.8 (CPh’2,6), 129.0 (CPh’1 and CPh’’1), 127.8 (CPh’’2,6), 114.1 (CPh3,5
,
C
1
(
Ph’3,5 and CPh’’3,5), 107.9 (C
8
), 65.6 (CH
510, 1376, 1306, 1256, 1175, 1150, 1094, 1029, 929, 839 cm . Anal. calcd for C29
498.54) : C, 69.87; H, 5.26; N, 5.62. Found: C, 69.85; H, 5.22; N, 5.61.
2
), 55.5 (OCH
3
). IR : 2958, 2985, 2838, 1664, 1598,
-
1
H
26
2
N O
6
2
,5-di-(1-oxo-4-methoxyphenylmethyl)-3-(4’-methoxyphenyl)pyrazine (27)
O
N
N
O
O
O
O
A solution of hydrochloric acid 6N (6 equiv., 2.8 mL) was added to a solution of (26) (1.30 g,
.61 mmol) in 50 mL of methanol. The solution was stirred at reflux for 2 h. After cooling, a
2
mixture of a saturated sodium hydrogenocarbonate solution (30 mL) and dichloromethane (30
mL) was added. The aqueous layer was extracted with dichloromethane (3x20 mL). The
combined organic extracts were then dried over magnesium sulfate and evaporated. The crude
product gave after purification by column chromatography (silica gel, eluent :
1
cyclohexane/ethyl acetate (6:4)) 1.04 g (88%) of (27) as a white solid, mp : 162°C. H NMR
(
7
CDCl
3
) : δ 9.09 (s, 1H, H
6
), 8.24 (d, 2H, J=8.7 Hz, HPh2,6), 7.90 (d, 2H, J=8.7 Hz, HPh’’2,6),
.64 (d, 2H, J=8.7 Hz, HPh’2,6), 6.97 (m, 6H, HPh3,5, Ph3,5 and HPh’’3,5), 3.92-3.79 (m, 9H,
H
1
3
OCH ). C (CDCl ) : 192.8 (C ), 190.3 (C ), 164.6 (C and CPh’’4), 161.3 (CPh’4), 151.8
3
3
7
8
Ph4
(
C
5
), 150.6 (C
3
), 149.8 (C
2 6
), 141.4 (C ), 133.8 (CPh2,6 and CPh’’2,6), 130.8 (CPh’2,6), 128.5 (CPh1,
CPh’1and CPh’’1), 114.3 (CPh3,5, CPh’3,5 andCPh’’3,5), 55.7 (OCH ). IR : 2961, 2933, 2837, 1661,
3
-
1
1
598, 1510, 1373, 1333, 1310, 1253, 1208, 1173, 1151, 1029, 921, 837, 760 cm . Anal.
calcd for C27 (454.49) : C, 71.36; H, 4.88; N, 6.16. Found : C, 71.11; H, 4.89; N,
.14.
22 2 5
H N O
6
Analogue
of
Botryllazine
A
:
2,5-di-(1-oxo-4-hydroxyphenylmethyl)-3-(4’-
methoxyphenyl)pyrazine (28)
OH
N
N
OH
O
O
HO
Pyridine hydrochloride (10 g) was heated to 220°C for 15 min, (27) (200 mg, 0.44 mmol) was
added, and the mixture was kept at this temperature for 1 h then poured into ice. The solution
was extracted with ether (3x20 mL), the combined organic extracts were then dried over
magnesium sulfate and evaporated. The crude product was purified by column
chromatography (silica gel, eluent: ether) and gave 163 mg (90%)of (28) as a yellow solid,
1
mp : 200°C. H NMR (CD
3 6
OD) : 8.96 (s, 1H, H ), 8.12 (d, 2H, J=8.7 Hz, HPh’’2,6), 7.75 (d,
2
H, J=8.7 Hz, HPh2,6), 7.52 (d, 2H, J=8.7 Hz, HPh’2,6), 6.86 (m, 6H, HPh3,5, HPh3,5 and HPh’3,5).
1
3
C (CD
51.8 (C
3
OD) : 194.5 (C
7 8 3
), 191.7 (C ), 165.1 (CPh4 and CPh4’’), 160.7 (CPh’4), 152.8 (C ),
1
2
and C ), 141.9 (C
5
6
), 134.5 (CPh2,6 and CPh’’2,6), 131.8 (CPh’2,6), 128.4 (CPh1,
CPh’1 and
S.11

CPh’’1), 116.5 (CPh3,5, CPh’’3,5 and CPh’3,5). IR : 3392, 2812, 2703, 1662, 1647, 1582, 1513, 1375,
-
1
1
6
251, 1209, 1157, 971, 845 cm . Anal. calcd for C24
.79. Found: C, 69.98; H, 3.83; N, 6.73.
16 2 5
H N O (412.41) : C, 69.90; H, 3.91; N,
6
2
. Synthesis of Botryllazine A
,3-Dichloropyrazine (29)
N
N
Cl
Cl
Metalation of chloropyrazine (1 g, 8.73 mmol) according to procedure A with n-BuLi 2.5M
1.1 equiv., 3.84 mL), TMPH (1.2 equiv., 1.65 mL), t =30 min, θ =-78°C, followed by
reaction with hexachloroethane (1.2 equiv., 2.8 g) in THF (10 mL) t =60 min, θ =-78°C gave
after purification by column chromatography (silica gel, eluent : dichloromethane) 1.17 g
(
1
1
2
2
1
13
(
(
90%) of (29) as a colorless liquid. H NMR (CDCl
CDCl ) : δ 147.9 (CCl); 141.8 (CH); IR : 1359, 1194, 1153, 1051, 865, 801, 485 cm . Anal.
Cl (148.98) : C, 32.25; H, 1.35; N, 18.80. Found : C, 32.26; H, 1.32; N,
3
) : δ 8.28 (s, 2H, H
5 6
and H ); C NMR
-
1
3
calcd for C
4
H
2
2 2
N
1
8.84.
2
,3-Dichloro-5-(1-hydroxy-4-methoxyphenylmethyl)pyrazine (30)
N
Cl
HO
N
Cl
O
Metalation of (29) (1 g, 6.71 mmol) according to procedure A with n-BuLi 2.5M (1.2 equiv.,
.03 mL), TMPH (1.2 equiv., 1.38 mL), t =30 min, θ =-78°C, followed by addition of p-
5
1
1
anisaldehyde (1.2 equiv., 1 mL) t =60 min, θ =-78°C gave after purification by column
2
2
chromatography (silica gel, eluent : cyclohexane/ethyl acetate (7:3)) 1.55 g (81%) of (30) as a
1
white solid, mp : 118°C. H NMR (CDCl
3
6
) : δ 8.26 (s, 1H, H ), 7.18 (d, J=8.7Hz, 2H, HPh2,6),
6
.78 (d, J=8.7Hz, 2H, H ), 5.70 (d, JCH,OH=3.4 Hz, 1H, CH), 3.70 (s, 3H, OCH ), 3.59 (d,
Ph3,5
1
3
3
JCH,OH=3.4 Hz, 1H, OH); C NMR (CDCl ) : δ 159.8 (C ), 156.1 (C ), 146.3 (C and C ),
3
Ph4
5
2
3
1
2
39.7 (C
968, 2879, 1609, 1511, 1461, 1388, 1155, 1025, 849, 786, 546 cm . Anal. calcd for
(285.13) : C, 50.55; H, 3.54; N, 9.82. Found : C, 50.52; H, 3.62; N, 9.79.
6 3
), 133.0 (CPh1), 128.2 (CPh2,6), 114.4 (CPh3,5), 73.7 (CH), 55.4 (OCH ); IR : 3309,
-
1
12 2 2 2
C H10Cl N O
2
,3-Dichloro-5,6-di-(1-oxo-4-methoxyphenylmethyl)pyrazine (32)
S.12

O
Cl
Cl
N
N
O
O
O
Metalation of (30) (1.7 g, 5.96 mmol) according to procedure A with n-BuLi 1.6M (4.1
equiv., 15.30 mL), TMPH (4.1 equiv., 4.20 mL), t =30 min, θ =-78°C, followed by addition
of p-anisaldehyde (1.2 equiv., 1 mL) t =60 min, θ =-78°C. the crude product was treated with
1
1
2
2
a solution of saturated sodium hydrogenosulfite. The mixture was filtrated and the precipitate
was washed with ether. The aqueous layer was extracted with ether (3x20 mL). The combined
organic extracts were then dried over magnesium sulfate and evaporated. The crude product
and 2 g of manganese oxide were added to 50 mL of THF. The solution was stirred at room
temperature for 12 h. The mixture was filtered through celite and the filtrate was then dried
over magnesium sulfate and evaporated. The crude product was purified by column
chromatography (silica gel, eluent : cyclohexane /ethyl acetate (7:3)) and gave 1.76 g (71%)
1
of (32) as a yellow solid, mp : 174°C. H NMR (CDCl ) : 7.96 (d, J=8.7Hz, 4H, 2xHPh2,6),
3
13
6
.97 (d, J=8.7Hz, 4H, 2xHPh3,5), 3.87 (s, 6H, 2xOCH
3 3 7
). C (CDCl ) : 188.3 (C ), 164.7
(
C ), 150.5 (C ), 146.4 (C ), 133.2 (C ), 127.7 (C ), 117.4 (C ), 55.7 (OCH ). IR :
Ph4
5
2
Ph2,6
Ph1
Ph3,5
3
2
7
985, 2941, 2841, 1656, 1592, 1508, 1315, 1253, 1174, 1129, 1024, 991, 937, 845, 811, 791,
69, 616, 552 cm . Anal. calcd for C20H14Cl N O (417.25) : C, 57.57; H, 3.38; N, 6.71.
2 2 4
-
1
Found: C, 57.93; H, 3.48; N, 6.67.
2
-chloro-3-(4’’-methoxyphenyl)-5,6-di-(1-oxo-4-methoxyphenylmethyl)pyrazine (33)
O
Cl
N
N
O
O
O
O
Coupling of 4-methoxyphenylboronic acid (430 mg, 0.9 equiv.) with (32) (1.30 g, 3.11 mmol)
according to procedure B (t=8 h) gave after purification by column chromatography (silica
gel, eluent: cyclohexane/ethyl acetate (7:3)) 1.07 g (70%) of (33) as a yellow solid, mp :
1
1
3
76°C. H NMR (CDCl ) : 8.21 (m, 6H, 3xHPh2,6), 7.14 (m, 6H, 3xHPh3,5), 4.05 (m, 9H,
3
1
3
xOCH
3
). C (CDCl
3
) : 190.1 (C
7
and C
8
), 164.4 (CPh4 and CPh’4), 161.6 (CPh’’4), 151.3 (C
), 133.4 (CPh2,6 and CPh’2,6), 131.8 (CPh’’2,6), 128.2 (CPh1 and
3
Ph’1), 127.3 (CPh’’1), 114.0 (CPh3,5, CPh’3,5 and CPh’’3,5), 55.7 (OCH ). IR : 3010, 2937, 2839,
5
and C
C
1
6
), 149.0 (C
3
), 144.8 (C
2
-
1
667, 1650, 1509, 1308, 1294, 1255, 1160, 1025, 975, 848, 828, 617 cm . Anal. calcd for
C H ClN O (488.93) : C, 66.33; H, 4.33; N, 5.73. Found: C, 66.57; H, 4.29; N, 5.65.
27
21
2
5
2
,3-di-(1-oxo-4-methoxyphenylmethyl)-5-(4’’-methoxyphenyl)pyrazine (34)
S.13

O
N
N
O
O
O
O
In a flask, was placed a solution of (33) (700 mg, 1.43 mmol), triethylamine (10 equiv, 2 mL),
formic acid (5 equiv, 0.28 mL) and Pd/C (10%) (0.1 equiv) in acetone and heated at reflux for
3
h. After cooling, a saturated sodium hydrogenocarbonate solution (30 mL) and
dichloromethane (30 mL) were added. The aqueous layer was extracted with dichloromethane
3x20 mL). The combined organic extracts were then dried over magnesium sulfate and
(
evaporated. The crude product was purified by column chromatography (silica gel, eluent :
1
dichloromethane) and gave 488 mg (75%) of (34) as a yellow solid, mp : 85°C. H NMR
(
CDCl
3
) : 9.09 (s, 1H, H
6
), 8.04 (m, 6H, HPh2,6, HPh’2,6 and HPh’’2,6), 7.01 (m, 6H, HPh3,5
,
1
3
H
Ph’3,5 and HPh’3,5), 3.88 (s, 9H, 3xOCH
3
). C (CDCl
), 150.9 (C ), 149.3 (C
and CPh’2,6), 129.1 (CPh’’2,6), 128.6 (CPh1 and CPh’1), 127.5 (CPh1’’), 114.8 (CPh’’3,5), 113.9 (CPh3,5
). IR : 2934, 2838, 1654, 1598, 1510, 1307, 1256, 1172, 1119, 1026,
3
) : 191.3-190.9 (C
7
and C
8
), 164.2
(
C
Ph4 and CPh’4), 162.1 (CPh4’’), 153.3 (C
5
3
2
), 139.1 (C ), 133.2 (CPh2,6
6
and CPh’3,5), 55.7 (OCH
3
-
1
9
58, 932, 841 cm . Anal. calcd for C27
H
22
N O
2 5
(454.49) : C, 71.36; H, 4.88; N, 6.16. Found:
C, 71.14; H, 4.98; N, 6.11.
Botryllazine A (2)
OH
N
O
O
N
HO
OH
Pyridine hydrochloride (10 g) was heated to 220°C for 15 min, (34) (200 mg, 0.44 mmol) was
added, and the mixture was kept at this temperature for 1h and then poured on to ice . The
solution was extracted with ether (3x20 mL), the combined organic extracts were then dried
over magnesium sulfate and evaporated. The crude product was purified by column
chromatography (silica gel, eluent: ether) and gave 163 mg (90%) of (2) as a yellow solid, mp
1
:
144°C. H NMR (CD OD) : 9.20 (s, 1H, H ), 8.07 (d, 2H, J=8.7 Hz, HPh’’2,6), 7.87 (d, 2H,
3
6
J=8.7 Hz, HPh’2,6), 7.85 (d, 2H, J=8.7 Hz, HPh2,6), 6.94 (d, 2H, J=8.7 Hz, HPh’’3,5), 6.85 (m, 4H,
1
3
HPh3,5 and HPh’3,5). C (CD OD) : 193.2 (C ), 192.7 (C ), 164.5 (C ), 164.3 (CPh’4), 161.7
3
7
8
Ph4
(
(
C
Ph’’4), 153.7 (C
3
), 152.8 (C
5
), 149.7 (C
2
6
), 140.5 (C ), 134.5 (CPh’2,6), 134.4 (CPh2,6), 130.2
C
Ph’’2,6), 128.6 (CPh’1), 128.5 (CPh1), 127.4 (CPh’’1), 117.1 (C-Ph’’3,5), 116.2 (CPh3,5 and CPh’3,5).
1
IR : 3274, 2926, 1648, 1590, 1259, 1165, 959, 846 cm . Anal. calcd for C24
412.41) : C, 69.90; H, 3.91; N, 6.79. Found: C, 69.84; H, 4.08; N, 6.71.
16 2 5
H N O
(
S.14

7
. Spectra
S.15

S.16

S.17

S.18

S.19

S.20

S.21

S.22

S.23

S.24

S.25

S.26

S.27

S.28

S.29

S.30