C. Aus´ın et al. / Tetrahedron 66 (2010) 68–79
75
(41 mL, 0.51 mol) was added, portionwise through the condenser,
to the stirred aminoalcohol over a period of 5 min. The solution
was removed from the ice-bath and was heated to a reflux, which
was maintained for 1 h. The solution was then distilled at at-
mospheric pressure to remove the excess of ethyl formate. Re-
sidual ethyl formate was eliminated under high vacuum leaving
the desired product 125 as a colorless oil (23.6 g, 230 mmol, 67%).
7.53 (t, J¼7.4 Hz, 2H), 7.45 (t, J¼7.4 Hz, 2H), 4.67 (d, J¼6 Hz, 2H), 4.41
(t, J¼6 Hz, 1H), 4.18 (t, J¼5.2 Hz, 2H), 3.44 (t, J¼5.2 Hz, 2H). 13C NMR
(75 MHz, DMSO-d6):
d 161.3, 154.3, 143.2, 140.7, 127.6, 127.1, 124.8,
120.1, 68.5, 66.1, 46.2, 36.1. þESI-TOF MS: calcd for C18H17NO4
(MþH)þ 312.1236, found 312.1228.
3.1.6. 9-Fluorenylmethyl 2-(N-thioformylamino)ethyl carbonate (7).
9-Fluorenylmethyl 2-(N-formylamino)ethyl carbonate (6, 2.3 g,
7.4 mmol) and Lawesson reagent (1.49 g, 3.69 mmol) were dissolved
in THF (75 mL). The solution was stirred at w25 ꢀC for 10 min. Silica
gel (10 g) was added to the reaction mixture and the resulting sus-
pension was evaporated under reduced pressure. The material left
was loaded on the top of a column packed with silica gel (120 g). The
product7 eluted fromthe columnusingCH2Cl2 asthe eluent andwas
isolated in a yield of 79% (1.93 g, 5.89 mmol). 1H NMR (300 MHz,
1H NMR (300 MHz, DMSO-d6):
1H), 3.50 (d, J¼6.0 Hz, 2H), 3.22 (d, J¼6.0 Hz, 2H), 1.54 (t, J¼6.0 Hz,
2H). 13C NMR (75 MHz, DMSO-d6):
161.4, 58.5, 34.5, 32.3.
d 8.07 (s, 1H), 4.60 (s, 1H), 3.65 (s,
d
3.1.2. 3-(Methylamino)propan-1-ol (2). To a cold (0 ꢀC) stirred so-
lution of 3-(N-formyl-amino)propan-1-ol (1, 1.72 g, 17.0 mmol) in
THF (50 mL) was added 1 M borane/THF complex in THF (50 mL,
50 mmol), dropwise, overa period of 1 h. The solutionwas stirred for
an additional 5 h at w25 ꢀC and was then cooled to 0 ꢀC. NaOH (3 M,
15 mL) was added to the solution, which was allowed to stir for 12 h
at w25 ꢀC. The aqueous phase was saturated with K2CO3 and the
organic phase was collected. The aqueous phase was extracted with
Et2O (3ꢂ50 mL); the combined organic extracts were dried over
anhydrous Na2SO4 and evaporated to dryness under reduced pres-
sure. The crude aminoalcohol 225a (1.33 g, 15.0 mmol) was suffi-
ciently pure to be used without further purification in the synthesis
of 3-(N-formyl-N-methylamino)propan-1-ol (3).
DMSO-d6):
d
10.50 (br s, 1H), 9.39 (s, 1H), 7.98 (d, J¼7.2 Hz, 2H), 7.75
(d, J¼7.2 Hz, 2H), 7.52 (t, J¼7.2 Hz, 2H), 7.44 (t, J¼7.2 Hz, 2H), 4.66 (d,
J¼6.0 Hz, 2H), 4.40 (t, J¼6.0 Hz, 1H), 4.35 (t, J¼5.0 Hz, 2H), 3.88 (q,
J¼5.0 Hz, 2H). 13C NMR (75 MHz, DMSO-d6):
d 189.3, 154.2, 143.2,
140.7, 127.7, 127.1, 124.8, 120.0, 68.6, 64.6, 46.2, 41.4. þESI-TOF MS:
calcd for C18H17NO3S (MþH)þ 328.1007, found 328.1005.
3.1.7. 2-(N-Thioformylamino)ethan-1-ol (8). 9-Fluorenylmethyl 2-
(N-thioformylamino)ethyl carbonate (7, 1.93 g, 5.89 mmol) was
dissolved in a solution of 20% piperidine in DMF. The resulting so-
lution was stirred at w25 ꢀC for 30 min and was then poured into
water (75 mL). The aqueous solution was extracted with CH2Cl2
(2ꢂ50 mL). The organic extracts were dried over sodium sulfate and
filtered. The filtrate was evaporated under low pressure and the
material left was purified by chromatography on silica gel using
a gradientof MeOH (0/2%) in CH2Cl2. Pure 827 (523 mg, 4.98 mmol)
3.1.3. 3-(N-Formyl-N-methylamino)propan-1-ol (3). 3-(Methylami-
no)propan-1-ol (2, 1.33 g, 15.0 mmol) was placed in a flask con-
nected to a condenser and was cooled to 0 ꢀC. Ethyl formate (1.66 g,
22.5 mmol) was added, portionwise through the condenser, to the
cold aminoalcohol over a period of 5 min. The solution was re-
moved from the cold bath and was heated to a reflux, which was
continued for 1 h. The excess ethyl formate was distilled off at at-
mospheric pressure leaving the amido alcohol 3,25b which was used
without further purification in the synthesis of the deoxy-
ribonucleoside phosphoramidite 24.
was isolated in a yield of 84%. 1H NMR (300 MHz, DMSO-d6):
d 10.27
(br s, 1H), 9.27 (s, 1H), 4.90 (br s, 1H), 3.49 (t, J¼5.2 Hz, 2H), 3.36 (t,
J¼5.2 Hz, 2H). 13C NMR (75 MHz, DMSO-d6):
d 188.0, 57.6, 45.1.
3.1.8. 6-(Methylthio)hexan-1-ol (13). To a stirred aqueous solution
(25 mL) of sodium methylmercaptide (3.00 g, 42.8 mmol) was
added 6-chlorohexanol (5.08 g, 37.2 mmol). The solution was left
stirring at w25 ꢀC for 8 h and was then extracted with chloroform
(25 mL). The organic phase was collected and dried over anhydrous
K2CO3. Following filtration, the filtrate was evaporated under re-
duced pressure and the crude product was purified by chroma-
tography on silica gel using CH2Cl2/MeOH (95:5 v/v) as the eluent.
Pure 1328 was isolated as a light yellow oil (5.34 g, 36.0 mmol, 97%).
3.1.4. 2-(N-Formylamino)ethan-1-ol (5). Freshly distilled ethanol-
amine (2.00 g, 32.7 mmol) was placed in a flask connected to
a condenser and was cooled to w5 ꢀC by immersion in an ice-water
bath. Ethyl formate (3.64 g, 49.1 mmol) was added in portions of
1 mL, through the condenser, to the stirred ethanolamine over
a period of 5 min. The solution was removed from the ice-bath and
brought to a reflux, which was continued for 1 h. The excess ethyl
formate was removed by distillation at atmospheric pressure and
the crude product was purified by chromatography on silica gel
using a gradient of MeOH (0/5%) in CH2Cl2 to give 526 (2.02 g,
1H NMR (300 MHz, DMSO-d6):
J¼5.1, 5.8 Hz, 2H), 2.54 (t, J¼7.3 Hz, 2H), 2.12 (s, 3H), 1.7–1.2 (m, 8H).
13C NMR (75 MHz, DMSO-d6):
60.6, 33.3, 32.4, 28.7, 28.1, 25.1, 14.6.
d
4.41 (t, J¼5.1 Hz, 1H,), 3.48 (dt,
22.7 mmol) in a yield of 69%. 1H NMR (300 MHz, DMSO-d6):
d
8.09
d
(br s, 1H), 4.84 (t, J¼5.5 Hz, 1H), 3.51 (m, 2H), 3.25 (m, 2H). 13C NMR
(75 MHz, DMSO-d6):
d
161.7, 60.0, 40.3.
3.1.9. 5-Chloropentan-1-ol (14). To a stirred solution of methyl 5-
chlorovalerate (1.80 g, 11.9 mmol) in 40 mL of Et2O was added,
dropwise, a suspension of LiAlH4 (0.49 g, 13 mmol) in THF (13 mL).
The suspension was stirred for 1 h at 25 ꢀC, at which point, the
excess LiAlH4 was quenched by addition of ice-cold diluted sulfuric
acid. The white solid that was formed was removed by filtration.
The filtrate was extracted with Et2O (3ꢂ30 mL). The etheral extracts
were collected, dried over anhydrous Na2SO4, and filtered. The fil-
trate was evaporated under low pressure and the crude product
was purified by silica gel chromatography using hexane/EtOAc (9:1
v/v) as the eluent. The pure alcohol 1412 (850 mg, 6.93 mmol, 58%)
3.1.5. 9-Fluorenylmethyl 2-(N-formylamino)ethyl carbonate (6). A
solution of 2-(N-formylamino)ethan-1-ol (5, 1.00 g, 11.2 mmol) in
60 mL of pyridine was cooled to w5 ꢀC in an ice-water bath. 9-
Fluorenylmethoxycarbonyl chloride (3.49 g, 13.5 mmol) was added
to the solution, which was left stirring for 2 h at w5 ꢀC. The reaction
was quenched by adding ethanediol (2 mL); after 10 min, the re-
action mixture was evaporated to an oil under reduced pressure.
The crude material was dissolved in CH2Cl2 (100 mL) and was
washed with a saturated aqueous solution of NaHCO3 (50 mL). The
aqueous phase was collected and was extracted with CH2Cl2
(2ꢂ40 mL); the organic extracts were pooled together, dried over
sodium sulfate, and filtered. The filtrate was evaporated under low
pressure and the material left was purified by chromatography on
silica gel using a gradient of MeOH (0/2%) in CH2Cl2. Pure 6 (2.3 g,
7.4 mmol) was isolated in a yield of 66%. 1H NMR (300 MHz, DMSO-
was isolated as a colorless oil. 1H NMR (300 MHz, DMSO-d6):
d 4.37
(t, J¼5.2 Hz, 1H), 3.61 (t, J¼6.6 Hz, 2H), 3.39 (m, 2H), 1.71 (t,
J¼6.6 Hz, 2H), 1.43 (m, 4H). 13C NMR (75 MHz, DMSO-d6):
d 60.5,
45.3, 31.9, 31.6, 22.9.
3.1.10. 5-(Methylthio)pentan-1-ol (15). 5-Chloropentanol(14, 836 mg,
d6):
d
8.15 (br s, 1H), 8.00 (d, J¼7.4 Hz, 2H), 7.76 (d, J¼7.4 Hz, 2H),
6.82 mmol) was added to a stirred aqueous solution (5 mL) of sodium