P. J. M. Taylor, S. D. Bull / Tetrahedron: Asymmetry 17 (2006) 1170–1178
1175
allowed to stir for 1 h. A solution of benzyl bromide
(1.3 equiv) in THF was then added dropwise and the reac-
tion mixture allowed to stir for a further 16 h whilst slowly
warming to room temperature. Aqueous potassium car-
bonate solution (pH >8) was then added and the reaction
extracted with Et2O (·3). The combined organic extracts
were dried over MgSO4 and concentrated in vacuo to
afford the corresponding (3S,6R)-[6-2H]-bis-lactim ethers
12a–f in >90% de that were then purified to >95% de via
column chromatography.
3.57 (3H, s, OMe), 3.64 (1H, d, J 3.4 Hz, H3), 3.66 (3H,
s, OMe), 6.80 (1H, ddd, J, 7.9, 6.4 and 2.6 Hz, ArH),
7.10–7.19 (2H, br m, ArH), 7.73 (1H, d, J 7.9 Hz, ArH);
dC (75 MHz, CHCl3) 15.5, 18.1, 30.4, 43.7, 51.5, 51.6,
59.5, 100.8, 126.7, 127.0, 130.0, 138.3, 140.2, 162.0, 162.8;
m/z (CI) 402 (MH+, 17%), 358 (M+ꢀi-Pr, 100%); HRMS
(FAB+) [MH+] for C16H202HIN2O2 requires 402.0783,
found 402.0783.
4.2.4.
(3S,6R)-[6-2H]-3-Isopropyl-6-(4-fluorobenzyl)-2,5-
dimethoxy-3,6-dihydropyrazine 12d. The reaction of (S)-
[6-2H2]-bis-lactim ether 6 (0.200 g, 1.08 mmol) in THF
(10 ml) with 2.36 M n-BuLi in hexanes (0.5 ml, 1.18 mmol)
and 4-fluorobenzyl bromide (0.265 g, 1.40 mmol) in THF
(2 ml) according to the general procedure afforded the title
4.2.1. (3S,6R)-[6-2H]-3-Isopropyl-6-benzyl-2,5-dimethoxy-
3,6-dihydropyrazine 12a.19 The reaction of (S)-[6-2H2]-
bis-lactim ether 6 (0.200 g, 1.08 mmol) in THF (10 ml) with
2.36 M n-BuLi in hexanes (0.5 ml, 1.18 mmol) and benzyl
bromide (0.240 g, 1.40 mmol) in THF (2 ml) according to
the general procedure gave the title compound 12a as a clear
compound 12d as a clear oil (0.225 g, 0.77 mmol) in 71%
25
yield and >95% de; ½aꢁD ¼ ꢀ62:4 (c 1.0, EtOAc); mmax
/
oil (0.238 g, 0.865 mmol) in 80% yield and >95% de;
cmꢀ1 1694 (C@N); dH (300 MHz, CDCl3) 0.53 (3H, d,
6.8 Hz, CH3(CH3)CH), 0.88 (3H, d, 6.8 Hz,
25
½aꢁD ¼ ꢀ41:2 (c 1.3, CH2Cl2) [lit.19 for (3R,6S)-12a, +40.4
J
J
(c 1.55, CH2Cl2)]; mmax/cmꢀ1 1681 (C@N); dH (300 MHz,
CDCl3) 0.53 (3H, d, J 6.8 Hz, CH3(CH3)CH), 0.87 (3H,
d, J 6.8 Hz, CH3(CH3)CH), 2.07 (1H, m, CH(CH3)2), 3.01
(2H, app s, CH2Ph), 3.18 (1H, d, J 3.2 Hz, H3), 3.61 (3H,
s, OMe), 3.65 (3H, s, OMe), 6.99–7.20 (5H, br m, ArH);
dC (75 MHz, MeOD) 16.8, 19.4, 31.5, 40.3, 52.5, 52.8,
60.6, 126.7, 128.2, 130.4, 137.7, 162.8, 164.4; m/z (CI)
276 (MH+, 100%); HRMS (FAB+) [MH+] for
C16H212HN2O2 requires 276.1817, found 276.1814.
CH3(CH3)CH), 2.08 (1H, m, CH(CH3)2), 2.98 (2H, app t,
J 14.0 Hz, CH2Ph), 3.25 (1H, d, J 3.0 Hz, H3), 3.59 (3H,
s, OMe), 3.63 (3H, s, OMe), 6.82 (2H, app t, J 8.1 Hz,
ArH), 6.97 (2H, dd, J 8.1, 5.8 Hz, ArH); dC (75 MHz,
MeOD) 16.8, 19.4, 31.6, 39.4, 52.5, 52.7, 60.7, 115.0 (d, J
10.5 Hz), 131.7 (d, J 3.8 Hz), 133.4, 162.6, 164.4;26 m/z
(CI) 294 (MH+, 32%), 278 (M+ꢀMe, 100%); HRMS
(FAB+) [MH+] for C16H202HFN2O2 requires 294.1723,
found 294.1721.
4.2.2.
(3S,6R)-[6-2H]-3-Isopropyl-6-(2-bromobenzyl)-2,5-
4.2.5.
(3S,6R)-[6-2H]-3-Isopropyl-6-(4-bromobenzyl)-2,5-
dimethoxy-3,6-dihydropyrazine 12b. The reaction of (S)-
[6-2H2]-bis-lactim ether 6 (0.200 g, 1.08 mmol) in THF
(10 ml) with 2.36 M n-BuLi in hexanes (0.5 ml, 1.18 mmol)
and 2-bromobenzyl bromide (0.358 g, 1.43 mmol) in THF
(2 ml) according to the general procedure afforded the title
dimethoxy-3,6-dihydropyrazine 12e.27 The reaction of
(S)-[6-2H2]-bis-lactim ether 6 (0.200 g, 1.08 mmol) in THF
(10 ml) with 2.36 M n-BuLi in hexanes (0.5 ml, 1.18 mmol)
and 4-bromobenzyl bromide (0.354 g, 1.42 mmol) in THF
(2 ml) according to the general procedure afforded the title
compound 12b as a clear oil (0.279 g, 0.79 mmol) in 73%
compound 12e as a amorphous solid (0.287 g, 0.81 mmol)
25
25
yield and >95% de; ½aꢁD ¼ ꢀ7:5 (c 1.0, EtOAc); mmax
/
in 75% yield and >95% de; mp = 58–64 ꢁC; ½aꢁD ¼ ꢀ5:2
cmꢀ1 1694 (C@N); dH (300 MHz, CDCl3) 0.58 (3H, d, J
6.8 Hz, CH3(CH3)CH), 0.94 (3H, d, J 6.8 Hz, CH3(CH3)-
CH), 2.14 (1H, m, CH(CH3)2), 2.86 (1H, d, J 14.0 Hz,
CHAHBPh), 3.39 (1H, d, J 14.0 Hz, CHAHBPh), 3.57
(3H, s, OMe), 3.59 (1H, d, J 3.6 Hz, H3), 3.66 (3H, s,
OMe), 6.99 (1H, ddd, J 9.0, 5.8 and 3.2 Hz, ArH), 7.06–
7.26 (2H, br m, ArH), 7.37–7.50 (1H, m, ArH); dC
(75 MHz, MeOD) 16.9, 19.5, 31.8, 40.6, 52.9, 56.3, 60.8,
125.8, 127.2, 128.3, 132.3, 133.0, 138.2, 163.5, 164.2; m/z
(CI) 356 (MBr81H+, 98%), 354 (100%, MBr79H+); HRMS
(FAB+) [MH+] for C16H202H79BrN2O2 requires 354.0921,
found 354.0922.
(c 1.0, EtOAc); mmax/cmꢀ11694 (C@N); dH (300 MHz,
CDCl3) 0.54 (3H, d, J 6.8 Hz, CH3(CH3)CH), 0.88 (3H,
d, J 6.8 Hz, CH3(CH3)CH), 2.08 (1H, m, CH(CH3)2),
2.96 (2H, app s, CH2Ph), 3.32 (1H, d, J 3.0 Hz, H3), 3.49
(3H, s, OMe), 3.63 (3H, s, OMe), 6.89 (2H, d, J 7.9 Hz,
ArH), 7.25 (2H, d, J 7.9 Hz, ArH); dC (75 MHz, CDCl3)
16.8, 19.4, 31.7, 39.6, 52.6, 56.7, 60.7, 120.7, 131.3, 132.0,
136.8, 162.5, 164.4; m/z (CI) 356 (M81BrH+, 33%), 354
(M79BrH+, 34%), 340 (M81Br+ꢀMe, 100%), 338
(M79Br+ꢀMe, 100%); HRMS (FAB+) [MH+] for
C16H202H79BrN2O2 requires 354.0921, found 354.0922.
4.2.6.
(3S,6R)-[6-2H]-3-Isopropyl-6-(4-trifluoromethyl-
4.2.3. (3S,6R)-[6-2H]-3-Isopropyl-6-(2-iodobenzyl)-2,5-di-
methoxy-3,6-dihydropyrazine 12c. The reaction of (S)-
[6-2H2]-bis-lactim ether 6 (0.200 g, 1.08 mmol) in THF
(10 ml) with 2.36 M n-BuLi in hexanes (0.50 ml,
1.18 mmol) and 2-iodobenzyl bromide (0.414 g, 1.40 mmol)
in THF (2 ml) according to the general procedure afforded
benzyl)-2,5-dimethoxy-3,6-dihydropyrazine 12f. The reaction
of (S)-[6-2H2]-bis-lactim ether 6 (0.200 g, 1.08 mmol) in
THF (10 ml) with 2.36 M n-BuLi in hexanes (0.5 ml,
1.18 mmol) and 4-trifluoromethylbenzyl bromide (0.330 g,
1.39 mmol) in THF (2 ml) according to the general proce-
dure afforded the title compound 12f as a crystalline solid
the title compound 12c as a clear oil (0.295 g, 0.74 mmol) in
(0.308 g, 0.90 mmol) in 83% yield and >95% de;
25
25
68% yield and >95% de; ½aꢁD ¼ ꢀ15:5 (c 1.0, EtOAc); mmax
/
mp = 57–58 ꢁC; ½aꢁD ¼ ꢀ20:7 (c 1.0, EtOAc); mmax/cmꢀ1
cmꢀ1 1692 (C@N); dH (300 MHz, CDCl3) 0.58 (3H, d, J
7.0 Hz, CH3(CH3)CH), 0.94 (3H, d, 7.0 Hz,
1694 (C@N); dH (300 MHz, CDCl3) 0.54 (3H, d, J 7.2 Hz,
CH3(CH3)CH), 0.87 (3H, d, J 7.2 Hz, CH3(CH3)CH),
J
CH3(CH3)CH), 2.15 (1H, m, CH(CH3)2), 2.86 (1H, d, J
13.6 Hz, CHAHBPh), 3.35 (1H, d, J 13.6 Hz, CHAHBPh),
2.08 (1H, m, CH(CH3)2), 2.99 (1H, d,
CHAHBPh), 3.11 (1H, d, J 13.2 Hz, CHAHBPh), 3.33 (1H,
J 13.2 Hz,