Preparation of Aminoalkyl Chlorohydrin Hydrochlorides
J . Org. Chem., Vol. 61, No. 11, 1996 3643
d6, 100 MHz) δ 133.5, 133.3, 132.0, 131.2, 131.1, 71.3, 63.2,
58.2, 57.9, 47.3, 33.7, 27.4, 24.6, 22.9. MS (FAB) m/ z 346
(MH+). Anal. Calcd for C21H29Cl2NO: C, 65.96; H, 7.64; N,
3.66. Found: C, 65.60; H, 7.69; N, 3.69. A reference sample
of (2R,3R)-8d was prepared in the same manner starting from
D-leucinol and used for isomeric purity determinations: mp
system), 3.52(dd, J ) 11.4, 7.8 Hz, 1H, ABX system), 2.96
(broad m, 1H), 2.01 (m, 1H), 0.99 (d, J ) 6.9 Hz, 3H), 0.95 (d,
J ) 6.9 Hz, 3H). MS (FAB) m/ z 152 (MH+).
(S)-3-Am in o-(S)-2-h ydr oxy-5-m eth yl-1-ch lor oh exan e Hy-
d r och lor id e (9d ). Obtained in 91% yield as a white crystal-
line solid: mp 134-136 °C. [R]25 -34.6° (c 1, MeOH). IR
D
155-158 °C. [R]23D -1.4° (c 1, MeOH). Anal. Calcd for C21H29
-
(KBr) ν 3325, 1610, 1510 cm-1
.
1H NMR (DMSO-d6, 400 MHz)
Cl2NO: C, 65.96; H, 7.64; N, 3.66. Found: C, 65.73; H, 7.74;
N, 3.62. Samples of (2S,3S)-8d and (2R,3R)-8d were neutral-
ized with aqueous NaHCO3, extracted into hexane, and
analyzed by HPLC (Chiralcel OD column, 5% EtOH/hexane,
isocratic, 0.5 mL/min): tR (2R,3R)-8d , 10.8 min (0.06%). tR
(2S,3S)-8d , 11.8 min (98.1%).
δ 8.10 (broad s, 3H), 5.99 (d, J ) 5.4 Hz, 1H), 3.98 (broad m,
1H), 3.65 (dd, J ) 11.4, 6.0 Hz, 1H, ABX system), 3.58 (dd, J
) 11.2, 7.2 Hz, 1H, ABX system), 3.26 (dt, J ) 9.6, 3.3 Hz,
1H), 1.74 (m, 1H), 1.48 (ddd, J ) 14.1, 10.2, 4.2 Hz, 1H), 1.32
(ddd, J ) 16.2, 10.2, 3.8 Hz, 1H), 0.90 (d, J ) 6.6 Hz, 3H),
0.86 (d, J ) 6.6 Hz, 3H). 13C NMR (DMSO-d6, 50 MHz) δ 70.5,
50.8, 45.0, 35.4, 23.4, 21.4. MS(FAB) m/ z 166 (MH+). Anal.
Calcd for C7H17Cl2NO: C, 41.60; H, 8.48; N, 6.93. Found: C,
41.47; H, 8.61; N, 6.90.
N,N-Dib en zyl-(S)-3-a m in o-(S)-2-h yd r oxy-4-[4-(b en zy-
loxy)p h en yl]-1-ch lor obu ta n e Hyd r och lor id e (8e). Crude
epoxide 7e (12.32 g, 27.4 mmol) was dissolved in THF (30 mL),
and 6 N aqueous HCl (50 mL) was added. After stirring
overnight at 5 °C, a gummy residue was formed. The
supernatant was removed by decantation and the gum was
crystallized from hot MeOH. 8e was obtained as a beige-
colored solid that was collected and washed with 95:5 ether-
MeOH and then ether (5.59 g, 39% yield overall from 3e): mp
(S)-3-Am in o-(S)-2-h yd r oxy-4-(4-h ydr oxyph en yl)-1-ch lo-
r obu ta n e Hyd r och lor id e (9e). Obtained in 98% yield as a
white crystalline solid: mp 176-180 °C. [R]25 -39.9° (c 1,
D
MeOH). IR (KBr) ν 3380, 1610, 1590, 1580, 1415 cm-1
.
1H
NMR (DMSO-d6, 400 MHz) δ 9.42 (s, 1H), 8.17 (broad s, 3H),
7.10 (d, J ) 7.8 Hz, 2H), 6.75 (d, J ) 8.1 Hz, 2H), 6.08 (d, J )
5.4 Hz, 1H), 3.95 (broad m, 1H), 3.61 (dd, J ) 11.4, 4.9 Hz,
1H, ABX system), 3.48 (dd, J ) 11.1, 7.8 Hz, 1H, ABX system),
3.44 (m, 1H), 2.88 (dd, J ) 14.2, 6.5 Hz, 1H, ABX system),
2.56 (dd, J ) 14.2, 7.4 Hz, 1H, ABX system). 13C NMR
(DMSO-d6, 100 MHz) δ 156.4, 130.3, 126.3, 115.5, 70.3, 54.6,
178-180 °C. [R]23 +12.7° (c 1, MeOH). [R]23
+54.9° (c
D
Hg365
1, MeOH). IR (KBr) ν 3250, 2560, 1610, 1510, 1450, 1290 cm-1
.
1H NMR (MeOH-d4, 400 MHz) δ 7.55-7.27 (m, 15H), 7.04 (m,
2H), 6.91 (m, 2H), 5.07 (s, 2H), 4.98 (broad d, J ) 13.2 Hz,
1H, AB system), 4.70 (broad d, J ) 13.6 Hz, 1H, AB system),
4.53 (broad t, J ) 7.2 Hz, 1H), 4.47 (broad d, J ) 13.7 Hz, 1H,
AB system), 4.43 (broad d, J ) 13.6 Hz, 1H, AB system), 3.92
(broad m, 1H), 3.47 (dd, J ) 13.9, 10.0 Hz, 1H), 3.12 (m, 1H),
3.10 (dd, J ) 11.0, 6.6 Hz, 1H), 2.78 (dd, J ) 10.7, 8.1 Hz,
1H). 13C NMR (157.2, 136.9, 131.8, 131.2, 130.3, 130.1, 129.3,
128.6, 128.5, 128.3, 127.7, 127.6, 114.8, 69.1, 68.6, 62.7, 54.4,
45.5, 31.9. MS (FAB) m/ z 216 (MH+). Anal. Calcd for C10H15
-
Cl2NO2: C, 47.64; H, 6.00; N, 5.56. Found: C, 47.48; H, 6.12;
N, 5.54.
(2S,3S)-N-Boc-3-a m in o-1,2-ep oxy-4-p h en ylbu ta n e (2a ).
Di-tert-butyl dicarbonate (1320 g, 6.05 mol) and triethylamine
(1698 mL, 12.18 mol) were dissolved in reagent grade THF
(10.8 L), and the solution cooled in an ice bath. Solid amino
chlorohydrin hydrochloride 9a (1418 g, 6.00 mol) was added
in portions over 30 min. The cooling bath was removed and
the reaction mixture stirred 3.5 h at room temperature, after
which, RP-HPLC analysis indicated completion of the reaction.
The white slurry was cooled again in an ice bath, and a
solution of KOH (1344 g, 23.95 mol) in methanol (5.34 L) was
added over 15 min. The ice bath was removed and stirring
continued for an additional 75 min. TLC analysis (4:1 hexane/
EtOAc) indicated complete reaction. The reaction mixture was
poured into 60 L of water and the white precipitate collected
by suction filtration. The material was air-dried to constant
weight. 2a was obtained as a white crystalline solid (1530 g,
96% yield): mp 124-125 °C, lit.10a mp 122-124.5 °C. Rf 0.49
(4:1 hexane/EtOAc). [R]25 +6.9° (c 1, CHCl3), [R]23 -8.6° (c
45.9, 26.6. MS (FAB) m/ z 486 (MH+). Anal. Calcd for C31H33
-
Cl2NO2: C, 71.26; H, 6.37; N, 2.68. Found: C, 71.16; H, 6.36;
N, 2.65. HPLC (neutralization with NaHCO3, hexane extrac-
tion, Chiralcel OD, 5% EtOH/hexane, isocratic, 1 mL/min): tR
18.7 min (>97%).
(S)-3-Am in o Ch lor oh yd r in Hyd r och lor id es 9a -e. Gen -
er a l P r oced u r e. The N,N-dibenzylamino chlorohydrin hy-
drochloride 8a -e and 20% palladium hydroxide on charcoal (ca.
10% by weight) were suspended in MeOH, and the slurry was
stirred under 1 atm of hydrogen gas until completion (6-48
h). The catalyst was removed by filtration using MeOH for
washings, and volatiles were evaporated under reduced pres-
sure. The residue was triturated with ether, filtered, and dried
under vacuum.
(S)-3-Am in o-(S)-2-h ydr oxy-4-ph en yl-1-ch lor obu tan e Hy-
d r och lor id e (9a ). Obtained in 97% yield as a white crystal-
D
D
1, MeOH), lit.10a [R]20D -8.1° (c 1.0%, MeOH). IR (KBr) ν 3375,
line solid: mp 204-208 °C. [R]25 -42.5° (c 1, MeOH). IR
1625, 1595, 1425 cm-1 1H NMR (CDCl3, 400 MHz) δ 7.35-
.
D
(KBr) ν 3360, 1600, 1580, 1500 cm-1
.
1H NMR (DMSO-d6, 400
7.2 (m, 5H), 4.47 (broad s, 1H), 3.70 (broad s, 1H), 2.97 (dd, J
) 14.0, 5.1 Hz, 1H, ABX system), 2.91 (m, 1H), 2.85 (broad
dd, J ) 14.0, 7.6 Hz, 1H, ABX system), 2.79 (m, 1H), 2.75
(broad m, 1H), 1.39 (s, 9H).10a,g 13C NMR (CDCl3, 50 MHz) δ
155.3, 136.8, 129.4, 128.5, 126.7, 79.6, 53.2, 52.8, 46.8, 37.6,
MHz) δ 8.34 (broad s, 3H), 7.3-7.4 (m, 5H), 6.14 (broad d, J
) 5.4 Hz, 1H), 4.00 (m, 1H), 3.63 (dd, J ) 11.4, 5.4 Hz, 1H,
ABX system), 3.55 (m, 1H), 3.51 (dd, J ) 11.4, 7.8 Hz, 1H,
ABX system), 3.02 (dd, J ) 14.0, 7 Hz, 1H, ABX system), 2.92
(dd, J ) 14.3, 7.2 Hz, 1H, ABX system). 13C NMR (DMSO-d6,
100 MHz) δ 136.7, 129.3, 128.5, 126.8, 70.3, 54.3, 45.3, 32.7.
MS (CI-isooctane) m/ z 200 (MH+). Anal. (analytical sample
crystallized from ethanol) Calcd for C10H15Cl2NO: C, 50.86;
H, 6.40; N, 5.93. Found: C, 50.49; H, 6.43; N, 5.84.
28.3.10g MS (FAB) m/ z 264 (MH+). Anal. Calcd for C15H21
-
NO3: C, 68.41; H, 8.04; N, 5.32. Found: C, 68.33; H, 8.08; N,
5.19.
Deter m in a tion of th e Isom er ic P u r ity of 2a by HP LC
An a lysis on a Ch ir a l Colu m n . Authentic samples of all four
possible isomers of 2a were prepared by literature methods.9
All four isomers were resolved by isocratic, normal-phase
HPLC on a Chiralcel OD column using 5% EtOH in hexane
as eluant. Retention times at 0.5 mL/min flow rates: (2S,3R),
11.9 min; (2R,3S), 12.5 min; (2R,3R), 13.3 min; (2S,3S), 14.1
min. The isomeric purity of 2a was evaluated at >99.5%
(detection limit <0.5%).
(2S,3S)-N-Boc-3-a m in o-1,2-ep oxybu ta n e (2b). Di-tert-
butyl dicarbonate (2.80 g, 13 mmol) and triethylamine (3.62
g, 26 mmol) were dissolved in reagent grade THF (20 mL),
and 9b (2.00 g, 12.5 mmol) was added. The suspension was
stirred 2.5 h at room temperature. KOH (2.81 g, 50 mmol) in
MeOH (10 mL) was added and the mixture stirred an ad-
ditional 20 min at room temperature. TLC (2:1 hexane/EtOAc)
indicated complete conversion to the epoxide. The reaction
mixture was concentrated to 1/4 volume under reduced pres-
(S)-3-Am in o-(S)-2-h yd r oxy-1-ch lor obu ta n e Hyd r och lo-
r id e (9b). Obtained in 93% yield as a white crystalline solid:
mp 102-105 °C. [R]25 -12.4° (c 1, MeOH). IR (KBr) ν 3350,
D
3260, 1585, 1510,1505 cm-1
.
1H NMR (DMSO-d6, 400 MHz)
δ 8.18 (broad s, 3H), 5.98 (d, J ) 5.4 Hz, 1H), 3.93 (m, 1H),
3.64 (dd, J ) 11.1, 6.0 Hz, 1H, ABX system), 3.55 (dd, J )
11.1, 6.9 Hz, 1H, ABX system), 3.33 (m, 1H), 1.13 (d, J ) 6.9
Hz, 3H). 13C NMR (DMSO-d6, 100 MHz) δ 70.1, 48.2, 45.2,
11.7. MS (FAB) m/ z 124 (MH+). Anal. Calcd for C4H11Cl2-
NO: C, 30.02; H, 6.93; N, 8.75. Found: C, 30.09; H, 7.01; N,
8.57.
(S)-3-Am in o-(S)-2-h yd r oxy-4-m eth yl-1-ch lor op en ta n e
Hyd r och lor id e (9c). Obtained in 98% yield as an oil which
1
was used without purification: [R]25 -10.7° (c 1, MeOH). H
D
NMR (DMSO-d6, 400 MHz) δ 8.13 (broad s, 3H), 6.00 (broad
s, 1H), 3.96 (broad m, 1H), 3.81 (dd, J ) 11.4, 3.6 Hz, 1H, ABX