V. I. Handmann et al. ■Sila-Substitution of the Q-Amino Acid Proline
136
added dropwise at -5 °C within 4 h to a stirred solution of of the solvent under reduced pressure, the residue was pu-
bis(chloromethyl)dimethylsilane (2.79 g, 17.8 mmol) in rified by distillation (82 °C, 4 Torr) to give (/?)-6 in 77%
THF (80 ml). The resulting reaction mixture was allowed
to warm up to room temperature over a period of 13 h,
followed by addition of diethyl ether (150 ml) and water
yield (9.80 g, 46.2 mmol) as a colorless liquid. - 1H NMR
(300.1 MHz): 6 = 0.74 (SQ), 1.10 (<5T), 2.20 (<5N), 3.916
(SA), 3.921 (<5k), and 3.97 (SB) [2/(AB) = 20.4 Hz, 5/(AK)
(150 ml). The organic phase was separated and the aque- = 3.7 Hz, V(BK) = 3.8 Hz, 3/(KN) = 3.6 Hz, V(NQ)
ous layer extracted with diethyl ether (3 x 150 ml), and
the combined organic extracts were dried over anhydrous
Na2SC>4. The solvent was removed under reduced pres-
sure and the oily residue distilled in a Kugelrohr apparatus
(oven temperature 125 °C, 0.01 Torr). The distillate was
dissolved in /7-hexane (20 ml) and the resulting solution
kept undisturbed at -10 °C for 5 h (crystallization of the
by-product rac-S). After removal of the crystals by filtra-
= 6.9 Hz, 3/(NT) = 6.9 Hz, 10 H; CHAHB-N=C-CHK-
CHn(CHQ3)(CHT3)], 1.24 (Sx), 4.04 (6A), and 4.07 (6B)
[2/(AB) = 10.6 H z,3/(AX) = 7.2 Hz, 3/(BX) = 7.0 Hz, 5
H; 0-CHaHb-CHX3], 1.25 (6X), 4.06 (SA), and 4.16 (<$B)
[2/(AB) = 10.6 Hz, 3/(AX) = 7.2 Hz, 37(BX) = 7.0 Hz, 5
H; 0-CHaHb-CHX3]. - 13C NMR (75.5 MHz): 6 = 14.3
(2 C, OCH2CH3), 17.0 (CHCH3), 19.0 (CHCH3), 32.5
[CHCH(CH3)2], 46.8 (CCH2N), 60.7 (2 C, OCH2CH3),
tion, the solvent of the filtrate was removed under reduced 61.0 [CHCH(CH3)2], 161.8 (C=N), 164.3 (C=N). - MS,
m/z (%): 212 (7) [M+], 197 (3) [M+- CH3], 169 (86) [M+
mmol) as a colorless liquid. - ‘H NMR (300.1 MHz): 6 = - CH(CH3)2], 85 (100). CnH20N2O2 (212.3): Calcd. C
pressure at 25 °C to give rac-4 in 50% yield (2.59 g, 8.90
62.24, H 9.50, N 13.20. Found C 62.0, H 9.6, N 13.2%.
0.16 (s, 3 H; SiCH3), 0.17 (s, 3 H; SiCH3), 0.91 (<5A), 1.27
(<5b), 3.94 (<5l ), 3.96 (<5M), and 4.03 (<5K) [2/(AB) = 14.6
Hz, 3/(AK) = 10.7 Hz, 3/(BK) = 5.0 Hz, V(KL) = 4.2 Hz,
5/(KM) = 3.5 Hz, 2/(LM) = 20.2 Hz, 5 H; Si-CHAHB-
CHk-N=C-CHl Hm], 1-24 (<SX), 4.02 (6A), and 4.05 (<5B)
[2/(AB) = 10.6 Hz, V(AX) = 7.2 Hz, V(BX) = 7.1 Hz, 5
H; 0-CHaHb-CHx3], 1.25 (6X), 4.02 (<5A), and 4.10 (<5B)
[2/(AB) = 10.6 Hz, 3/(AX) = 7.1 Hz, 3/(BX) = 7.1 Hz,
5 h; 0-Chahb-ChX3], 2.82 (<SA) and 2.87 (<5B) [V(AB)
= 13.4 Hz, 2 H; Si-CHAHB-Cl], - 13C NMR (75.5 MHz):
6 = -3.91 (SiCH3), -3.86 (SiCH3), 14.2 (OCH2CH3),
14.3 (OCH2CH3), 20.3 (SiCH2CH), 31.2 (SiCH2Cl),
46.4 (CCH2N), 52.9 (SiCH2CH), 60.8 (OCH2CH3), 60.9
(OCH2CH3), 161.6(C=N), 165.7 (C=N ).-29Si NMR: 6 =
3.5. - MS, m/z (%): 290 (4) [M+], 275 (1) [M+- CH3], 261
(3) [M+- CH2CH3], 241 (9) [M+- CH2C1], 169 (100) [M+
- CH2Si(CH3)2CH2Cl]. C,2H23ClN20 2Si (290.9): Calcd.
C 49.55, H 7.97, N 9.63. Found C 49.3, H 7.8, N 9.5%.
(2R,5R)- and (2S,5R)-2-{[(Chloromethyl)dimethylsilyl]-
methyl}-3,6-diethoxy-5-isopropyl-2,5-dihydropyrazine
[(2R,5R)-1 and (2S,5R-1)]
A 2.5 M solution of rc-butyllithium in /7-hexane (2.0 ml,
5.00 mmol /z-BuLi) was added dropwise at -10 °C within
20 min to a stirred solution of (R)-6 (8.00 g, 37.7 mmol)
in THF (100 ml). After cooling the reaction mixture to
-70 °C, again a 2.5 M solution of n-butyllithium in n-
hexane (13.1 ml, 32.8 mmol n-BuLi) was added drop-
wise over a period of 1 h. The mixture was stirred at
-70 °C for 10 min, warmed up to -40 °C, and then added
dropwise at -5 °C within 4 h to a stirred solution of
bis(chloromethyl)dimethylsilane (5.92 g, 37.7 mmol) in
THF (110 ml). The resulting mixture was allowed to warm
up to room temperature within 2 h, followed by addition
of diethyl ether (300 ml) and water (300 ml). The organic
phase was separated and the aqueous layer extracted with
diethyl ether (3 x 250 ml), and the combined organic
extracts were dried over anhydrous Na2SC>4. The sol-
vent was removed under reduced pressure and the oily
residue distilled in a Kugelrohr apparatus (oven temper-
ature 125 °C, 0.01 Torr) to give 7.29 g (21.9 mmol, yield
58%) of a mixture consisting of (2/?,5/?)-7 and (25,5/?)-7
(molar ratio 85:15; GC and 'H NMR analysis). The di-
astereomerically pure compounds (2/?,5/?)-7 and (25,5/?)-
7 were obtained by liquid-chromatographic separation
(see below).
(R)-3,6-Diethoxy-2-isopropyl-2,5-dihydropyrazine
[(R)-67
This compound was synthesized in analogy to (R)-
3,6-dimethoxy-2-isopropyl-2,5-dihydropyrazine accord-
ing to ref. [18] (in this context, see also ref. [19]): A mix-
ture of (/?)-3-isopropylpiperazine-2,5-dione (9.40 g, 60.2
mmol) and triethyloxonium tetrafluoroborate (28.5 g,
150 mmol) in dichloromethane (200 ml) was stirred at
room temperature for 24 h. After addition of another por-
tion of triethyloxonium tetrafluoroborate (11.4 g, 60.0
mmol), the resulting mixture was stirred at room tem-
perature for 48 h, followed by addition of a solution
of NaH2P04-H20 (24.9 g, 180 mmol) and Na2HP04 •
7 H20 (161 g, 601 mmol) in water (500 ml). The organic
phase was separated and the aqueous layer extracted with
dichloromethane (3 x 150 ml). The combined organic ex-
tracts were dried over anhydrous Na2SC>4. After removal
Preparative liquid-chromatographic separation of the di-
astereomers (2R,5R)-1 and (2S,5R)-1
The diastereomers (2/?,5/?)-7 and (25,5/?)-7 were sep-
arated by liquid chromatography on silica gel (30-60
Baker, 7024). The experimental conditions were as fol-
lows: LC pump, Biichi Pump 688; detector, differential
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