E
Y. Ichikawa et al.
Paper
Synthesis
mmHg, water bath temperature 50 °C) to afford a yellow solid, which
was dissolved in CH2Cl2 (300 mL). The solution was transferred into a
1-L Erlenmeyer flask and cooled to 0 °C in an ice bath. Aqueous NaOH
(2.5 M, 90 mL) was added, and the biphasic layer was stirred vigor-
ously for 30 minutes. This process removed most of the phenol and
hydrolyzed the excess phenyl carbamate. Note: longer reaction times
led to partial hydrolysis of the produced carbamate 8. The organic lay-
er was separated with a 1-L separately funnel, and the aqueous layer
was extracted with CH2Cl2 (2 × 100 mL). The combined organic ex-
tracts were washed with brine (150 mL), dried over anhydrous
MgSO4, filtered and concentrated under reduced pressure (200 mmHg,
40 °C) to afford cinnamyl carbamate 8 as a pale-yellow solid (14.08–
14.62 g). The crude product was dissolved in a minimal amount of hot
EtOAc (30 mL). The crystals formed upon cooling at r.t. were collected,
washed with EtOAc/n-hexane (v/v 1:1, 20 mL) and air-dried to furnish
8 (11.57–11.13 g, 65.3–62.8 mmol, 87.6–84.3%) as white needles. The
mother liquor was concentrated with a rotary evaporator (15 mmHg,
25 °C) and recrystallized from hot EtOAc (5 mL) and washed with
EtOAc/n-hexane (v/v 1:1, 5 mL) to yield a second crop of 8 (0.50–1.01
g, 2.8–5.7 mmol, 3.8–7.7%, a combined yield: 12.07–12.14 g, 68.1–
68.5 mmol, 91–92%).
water layers were combined and extracted with CH2Cl2 (2 × 100 mL).
The combined organic layers were transferred to a 1-L separating fun-
nel and washed with aqueous saturated NaHCO3 (150 mL) and brine
(150 mL). The organic layer was transferred into a 1-L recovery flask,
and concentrated under reduced pressure (200 mmHg, 40 °C). The
residue was dissolved in Et2O (300 mL), and the solution was trans-
ferred into a 1-L Erlenmeyer flask with a stirring bar and saturated
aqueous NaHCO3 (150 mL). The biphasic layer was stirred vigorously
for 30 minutes (gentle evolution of gas was observed) and transferred
to a 1-L separating funnel. The aqueous layer was separated, and the
organic layer was transferred into a 1-L Erlenmeyer flask with a stir-
ring bar and saturated aqueous NaHCO3 (150 mL). Similar operation of
stirring with saturated aqueous NaHCO3 and separation of aqueous
layer was repeated once more. The organic layer was washed with
brine (150 mL) and dried over anhydrous MgSO4. Concentration un-
der reduced pressure (200 mmHg, water bath temperature 40 °C)
gave crude products (17.52–18.78 g) as brown semisolids. The crude
product was dissolved in a minimal amount of eluent and charged
on a column (4.5 × 33 cm) of 170 g of silica gel and eluted with
n-hexane/EtOAc (v/v 6:1). Fraction collection (100-mL fractions) was
begun, and the desired product was obtained in fractions 7–16. The
combined fractions were concentrated by evaporation (25 °C, 15
mmHg), and dried under vacuum (0.15 mmHg) to afford benzyl
1-phenylallylcarbamate (11) as a white solid (14.62–14.90 g, 54.7–
55.7 mmol, 80–82%).
Mp 122–123 °C.
IR (NaCl): 3420, 3332, 1686 cm–1
.
1H NMR (500 MHz, CDCL3): = 4.72–4.80 (2 H), 4.76 (d, J = 6.5 Hz,
2 H), 6.30 (dt, J = 15.5, 6.5 Hz, 1 H), 6.66 (d, J = 15.5 Hz, 1 H), 7.23–7.42
(5 H).
13C NMR (125 MHz, CDCl3): = 65.6, 123.45, 126.50, 127.9, 128.50,
128.54, 133.7, 136.1, 156.9.
Mp 50–51 °C.
IR (NaCl): 3324, 1682, 1536 cm–1
.
1H NMR (500 MHz, CDCl3): = 5.08–5.14 (2 H), 5.23 (d, J = 17.5 Hz,
1 H), 5.24 (d, J = 10.5 Hz, 1 H), 5.36 (br, 1 H), 6.00 (ddd, J = 17.5, 10.5,
5.5 Hz, 1 H), 7.26–7.37 (10 H).
1H NMR (500 MHz, CD3OD): = 5.03–5.10 (2 H), 5.15 (d, J = 10.0 Hz,
1 H), 5.16 (d, J = 17.5 Hz, 1 H), 5.25 (d, J = 5.5 Hz, 1 H), 5.15 (d, J =
10.0 Hz, 1 H), 5.99 (ddd, J = 17.5, 10.0, 5.5 Hz, 1 H), 7.20–7.35 (10 H).
HRMS (ESI): m/z [M+ Na]+ calcd for C10H11NO2: 200.0688; found:
200.0685.
Anal. Calcd for C10H11NO2: C, 67.78; H, 6.26; N, 7.90. Found: C, 67.85;
H, 6.27; N, 8.05.
13C NMR (125 MHz, CDCl3): = 56.9, 66.7, 115.6, 126.9, 127.5, 127.6,
128.0, 128.3, 128.5, 136.2, 137.4, 140.5, 155.4.
Benzyl 1-Phenylallylcarbamate (11)
An oven-dried 1-L, three-necked, round-bottomed flask equipped
with a stirring bar, an adapter fitted with a thermometer, an inlet
adapter with three-way stopcock fitted with an argon-filled balloon
and a rubber septum was charged with cinnamyl carbamate (8)
(dried overnight in a desiccator over P2O5 in vacuum (ca. 20 mmHg)
prior to use, 12.07 g, 68.1 mmol), Et3N (29 mL, 208 mmol, 3.1 equiv)
and CH2Cl2 (260 mL). The flask was cooled with an ice bath (internal
temperature 1–2 °C). Trifluoroacetic anhydride (11.4 mL, 81.7 mmol,
1.2 equiv) was added via syringe through the septum over the course
of 15 minutes, maintaining the internal temperature below 5 °C. After
stirring at 1–2 °C (internal temperature) for 20 minutes, the reaction
mixture turned to a clear yellow solution. After monitoring the disap-
pearance of carbamate 8 by TLC analysis using 1:1 EtOAc/n-hexane as
eluent (Rf carbamate = 0.50), benzyl alcohol (35 mL, 0.35 mol, 5.1
equiv) and Et3N (30 mL, 0.20 mol) were added. The cooling bath was
removed, and stirring was continued at r.t. for 5 h to afford a brown
solution. TLC analysis using 4:1 n-hexane/EtOAc as eluent showed the
formation of Cbz-carbamate 11 (Rf Cbz-carbamate 11 = 0.43, Rf benzyl
alcohol = 0.25). Succinic anhydride (51 g, 0.51 mol) was added, and
stirring was continued at r.t. overnight (ca. 16 h) to obtain a dark-
black solution. This process transformed the excess benzyl alcohol
into the corresponding half ester 12. TLC analysis showed the forma-
tion of half ester (4:1 n-hexane/ EtOAc as eluent: Rf half ester = base-
line; 1:1 EtOAc/n-hexane as eluent: Rf half ester = 0.40). The reaction
mixture was transferred to a 1-L separating funnel and washed with
aqueous KHSO4 (1 N, 150 mL) and water (2 × 100 mL). The KHSO4 and
HRMS (ESI): m/z [M+ H]+ calcd for C17H18NO2: 268.1338; found:
268.1340.
Anal. Calcd for C17H18NO2: C, 76.38; H, 6.41; N, 5.24. Found: C, 76.49;
H, 6.44; N, 5.52.
Tin-Catalyzed Transcarbamoylation Using Methyl Carbamate; Typ-
ical Procedure
Dodecyl Carbamate (13b)
A solution of dodecanol (13a; 300 mg, 1.6 mmol), methyl carbamate
(480 mg, 6.4 mmol) and dibutyltin maleate (35 mg, 0.1 mmol) in tolu-
ene (13 mL) was heated at reflux for 3 h. The reaction mixture was
cooled to r.t. and diluted with H2O and EtOAc. The separated aqueous
layer was extracted with EtOAc and the combined organic layers were
washed with water and brine, dried over Na2SO4 and concentrated
under reduced pressure. The crude product (422 mg) was purified by
silica gel chromatography (1:5 EtOAc/n-hexane) to afford dodecyl car-
bamate (13b; 357 mg, 97%).
Mp 81–82 °C.
IR (KBr): 3421, 3332, 3265, 3217, 1683, 1620 cm–1
.
1H NMR (CDCl3, 400 MHz): =0.85 (t, J = 6.3 Hz, 3 H), 1.23 (br s, 18 H),
1.55–1.63 (m, 2 H), 4.03 (t, J = 6.8 Hz, 2 H), 4.62 (br s, 2 H).
13C NMR (CDCl3, 100 MHz): = 14.1, 22.7, 25.8, 28.9, 29.26, 29.32,
29.51, 29.55, 29.60, 29.62, 31.9, 65.3, 157.3.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–F