PRACTICAL SYNTHETIC PROCEDURES
One-Pot Curtius Rearrangement
1939
poured into cold H2O (400 mL) and stirred for 15 min. The two lay-
ers were separated and the aqueous layer was extracted with EtOAc
(2 ꢀ 350 mL). The combined organic layers were washed with brine
(350 mL), dried (Na2SO4), filtered, and concentrated at 40 °C by ro-
tary evaporation. The resulting oil was placed on a high vacuum
pump for 24 h to remove the residual solvent traces affording the
crude title product as a clear pale yellow oil, which was used in the
next step without further purification; Rf = 0.38 (10% EtOAc–hex-
anes).
hexanes) afforded 6.75 g (70%) of the pure protected amino acid 4
as a colorless oil; Rf = 0.28 (10% EtOAc–hexanes).
IR (neat): 3425, 3265, 2978, 2932, 1704, 1495, 1365, 1252, 1163,
1055, 1028, 698 cm–1.
1H NMR (400 MHz, C6D6, 70 °C): d = 7.11–6.99 (m, 11 H), 5.32
(br s, 1 H), 3.86 (q, J = 7 Hz, 2 H), 2.63–2.47 (m, 2 H), 2.44–2.37
(m, 1 H), 2.10–2.03 (m, 1 H), 1.52 (s, 3 H), 1.40 (s, 9 H), 0.89 (t,
J = 7 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 174.3, 154.1, 141.3, 128.3, 128.2,
125.9, 79.3, 61.5, 59.4, 38.4, 30.6, 28.3, 23.6, 14.1.
HMRS (ESI): m/z calcd for C18H27NO4 + Na [M + Na]+: 344.1832;
found: 344.1817.
IR (neat): 2981, 1729, 1455, 1258, 1182, 1105, 1027, 700 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.30–7.27 (m, 2 H), 7.20–7.18 (m,
3 H), 4.19 (q, J = 7 Hz, 4 H), 2.60–2.56 (m, 2 H), 2.19–2.15 (m, 2
H), 1.50 (s, 3 H), 1.26 (t, J = 7 Hz, 6 H).
13C NMR (100 MHz, CDCl3): d = 172.2, 141.5, 128.37, 128.34,
125.9, 61.2, 53.6, 37.5, 30.8, 20.0, 14.1.
Anal. Calcd for C18H27NO4: C, 67.26; H, 8.47; N, 4.36; O, 19.91.
Found: C, 67.24; H, 8.44; N, 4.46; O, 19.88.
HMRS (ESI): m/z calcd for C16H23NO4 [M + H]+: 279.1591; found:
279.1588.
Benzyl 2-Iodophenylcarbamate (6); Procedure 3
To a solution of 2-iodobenzoic acid (5; 7.44 g, 30.0 mmol), NaN3
(2.92 g, 45.0 mmol), t-BuONa (231 mg, 2.40 mmol) in DME (100
mL) was added dropwise benzyl chloroformate12 (4.71 mL, 33.0
mmol) over 15 min at 25 °C. The resulting reaction mixture was
then stirred at 75 °C for 16 h. The mixture was cooled to r.t. and
quenched with aq 10% NaNO2 (50 mL). The biphasic mixture was
stirred 30 min at r.t.. The two layers were separated, and the organic
layer was washed successively with sat. aq NH4Cl (75 mL), brine
(75 mL), and dried ( Na2SO4). The organic solution was filtered and
concentrated at 40 °C by rotary evaporation to afford an orange oil.
The solvent was removed under reduced pressure. The desired anil-
ide 6 (9.74 g, 92%) was obtained as a white solid after flash chro-
matography (3% EtOAc–hexanes); mp 49 °C; Rf = 0.57 (20%
EtOAc–hexanes).
Anal. Calcd for C16H22NO4: C, 69.04; H, 7.97; O, 22.99. Found: C,
69.03; H, 8.26; O, 22.48.
2-(Ethoxycarbonyl)-2-methyl-4-phenylbutanoic Acid (3)
To a solution of diethyl 2-methyl-2-phenethylmalonate (16.7 g,
60.0 mmol) in EtOH (150 mL) at 50 °C was added dropwise over
15 min a solution of KOH (3.40 g, 60.6 mmol) in a H2O (15 mL)–
EtOH (25 mL) mixture. The colorless homogeneous solution was
then allowed to stir under argon at 50 °C for 64 h. The reaction mix-
ture was then cooled to r.t., and concentrated at 50 °C by rotary
evaporation. The resulting white solid was dissolved in H2O (250
mL), and the resulting aqueous layer was washed with EtOAc (350
mL). The aqueous solution was then acidified with concd HCl (8
mL), and extracted with EtOAc (2 ꢀ 350 mL). The combined organ-
ic layers were washed with brine (250 mL), dried (Na2SO4), and
concentrated at 40 °C by rotary evaporation. The resulting colorless
oil was dried under vacuum, which smoothly crystallized at r.t. to
afford 9.3 g (62%) of the monoester of malonic acid 3 as a white
crystalline solid; mp 80 °C; Rf = 0.49 (10% MeOH–CH2Cl2).
IR (neat): 3383, 3031, 2953, 1732, 1586, 1514, 1432, 1201, 1036,
741 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.10 (d, J = 8 Hz, 1 H), 7.77 (d,
J = 8 Hz, 1 H), 7.46–7.33 (m, 6 H), 7.05 (br s, 1 H), 6.81 (t, J = 8
Hz, 1 H), 5.24 (s, 2 H).
13C NMR (100 MHz, CDCl3): d = 153.2, 151.4, 138.8, 138.2, 135.7,
129.2, 128.6, 128.3, 125.1, 120.3, 88.8, 67.2.
IR (neat): 2966, 2941, 1744, 1701, 1453, 1280, 1179, 1066, 933,
751, 696 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.30–7.27 (m, 2 H), 7.21–7.18 (m,
3 H), 4.23 (q, J = 7 Hz, 2 H), 2.63–2.59 (m, 2 H), 2.27–2.14 (m, 2
H), 1.55 (s, 3 H), 1.29 (t, J = 7 Hz, 3 H).
HMRS (ESI): m/z calcd for C14H12INO2 [M + H]+: 353.9985; found:
353.9982.
1,3-Diphenylurea (8); Procedure 4
13C NMR (100 MHz, CDCl3): d = 177.9, 172.2, 141.1, 128.4, 128.3,
To a solution of benzoic acid (7, 3.66 g, 30.0 mmol), NaN3 (2.92 g,
45.0 mmol), t-BuONa (231 mg, 2.40 mmol) in DME (100 mL) was
added phenyl chloroformate15 (4.14 mL, 33.0 mmol) over 15 min at
25 °C. The resulting reaction mixture was then stirred at 75 °C dur-
ing 8 h, then aniline (4.10 mL, 45.0 mmol) was added and the mix-
ture was stirred at 75 °C for 16 h. The mixture was cooled to r.t. and
diluted with hexanes (70 mL). The solution was then cooled to 0 °C
(ice bath) with continuous stirring; H2O (10 mL) was added and the
stirring maintained for 25 min at 0 °C. The solid was filtered and
triturated with Et2O (40 mL). The desired urea 8 (4.45 g, 70%) was
obtained as a white solid; Rf = 0.51 (40% EtOAc–hexanes); mp
219 °C.
126.1, 61.8, 53.6, 37.7, 30.9, 20.3, 14.6.
HMRS (ESI): m/z calcd for C14H18O4 + Na [M + Na]+: 273.1097;
found: 273.1094.
Anal. Calcd for C14H18O4: C, 67.18; H, 7.25. Found: C, 67.18; H,
7.25.
N-tert-Butyl 2-(Ethoxycarbonyl)-4-phenylbutan-2-ylcarbamate
(4); Procedure 2
To a solution of 2-(ethoxycarbonyl)-2-methyl-4-phenylbutanoic
acid (3; 7.51 g, 30.0 mmol), NaN3 (3.90 g, 60.0 mmol), TBAB
(0.870 g, 2.70 mmol), and zinc triflate (220 mg, 0.600 mmol) in
THF (150 mL) was added warm di-tert-butyl dicarbonate (7.60 mL,
33.0 mmol) via a syringe over 10 sec. The reaction mixture was
stirred with a mechanical stirrer under argon at 50 °C for 50 h. The
mixture was cooled to r.t. and quenched with aq 10% NaNO2 (50
mL). The biphasic mixture was stirred for 30 min at r.t. and the two
layers were separated, and the organic layer was washed succes-
sively with sat. aq NH4Cl (75 mL), brine (75 mL), and dried
(Na2SO4, 50 g). The organic layer was filtered and concentrated at
40 °C by rotary evaporation to afford an orange oil. Purification by
column chromatography (2% EtOAc–hexanes, then 5% EtOAc–
IR (neat): 3281, 3036, 1646, 1592, 1538, 1496, 1439, 1230, 893,
751 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.24 (br s, 2 H), 7.45 (d, J = 8 Hz,
4 H), 7.27 (t, J = 8 Hz, 4 H), 6.96 (t, J = 7 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 152.4, 139.6, 128.7, 121.7, 118.1.
HMRS (ESI): m/z calcd for C13H12N2O + Na [M + Na]+: 235.0842;
found: 235.0843.
Synthesis 2009, No. 11, 1935–1940 © Thieme Stuttgart · New York