Phosgenation Reactions - Phosgenations - page 275

Typical procedure. N-Benzyl-N 0 -tetrahydrofurfurylurea 1027 [577]: To a stirred solu-
tion of S-methyl N-benzylthiocarbamate (for the synthesis, see Section 4.3.2 ''Car-
bamates'') (0.11 g, 0.63 mmol) in methanol (2 mL) was added tetrahydrofurfuryl-
amine (0.12 g, 1.1 mmol). After heating at 60 C for 24 h, the reaction mixture was
concentrated under reduced pressure to leave a crude solid. Recrystallization of
this solid from CHCl 3 /hexane gave N-benzyl-N 0 -tetrahydrofurfurylurea as colorless
crystals (0.14 g, 88%).

Phosgene
An enantioselective and stereospecific synthesis of the important vitamin (

)-
Biotin 1031, in 12 steps from l-cystine dimethyl ester, required the preparation of
bis(urea) 1030 [729].
The preparation was achieved in two steps by a sequence of: (1) treatment of
l-cystine dimethyl ester dihydrochloride 1028 suspended in refluxing toluene with
a slow stream of phosgene for 5 h (for the phosgene source, see Chapter 7) to af-
ford, after concentration, the corresponding diisocyanate 1029 in high yield; and
(2) reaction of this diisocyanate 1029 with a 10% excess of benzylamine in di-
chloromethane (0 C initially and then 23 C for 1 h) to give, after addition of
methanol (just enough to give a clear solution), dilution with petroleum ether, and
cooling at 4 C, the bis(urea) 1030; mp 166-167 C (91%).

þ

O

O

NH 2 C

COCl 2
toluene
reflux

BnNH 2
CH 2 Cl 2
0-23°C

N

H Ph

HN

2 (S

COOMe

2 (S

2 (S

COOMe

COOMe

*HCl

91%

91%

1028 1029 1030

O

N H

H N

COOH

S

1031

(+)-Biotin

Bis-4-(2,2-dimethyl-1,3-dioxolyl)methyl carbodiimide (BDDC) 1034, a useful re-
agent for racemization-free esterifications, peptide couplings, and dehydration, has
been prepared via the symmetrical urea 1033 by a reaction sequence involving an
amine phosgenation [758].

Typical procedure. N,N 0 -Bis-4-(2,2-dimethyl-1,3-dioxolyl)methyl urea 1033 [758]: A so-
lution of amine 1032 (149 g, 1.14 mol) in toluene (680 mL) was added to a solution
of NaHCO 3 (192 g, 200 mol%) in H 2 O (680 mL). This two-phase mixture was