Phosgenation Reactions - Phosgenations - page 160

vacuo. Chromatography of the crude product on silica gel eluting with hexane/
ethyl acetate (6:1) afforded chloromethylarylcarbamate 555 as a colorless crystalline
solid (230 mg, 89%). A suspension of chloromethylarylcarbamate 555 (53 mg, 0.2
mmol) and cesium carbonate (163 mg, 0.5 mmol) in dichloromethane (5 mL) was
stirred for 40 h at 23 C. The reaction mixture was then filtered through a pad of
Celite and the solvent was evaporated in vacuo. Chromatography of the crude
product on silica gel eluting with hexane/ethyl acetate (6:1) gave 556 as a colorless,
crystalline solid (35 mg, 76%); mp 149-150 C.
The 9-fluorenylmethoxycarbonyl (Fmoc) group is exceptionally stable towards acid;
thus, carboxylic acids can be converted to acid chlorides with thionyl chloride or
tert-butyl esters using H 2 SO 4 and isobutene. Furthermore, Fmoc groups are unaf-
fected by HBr in HOAc or CF 3 COOH, thereby enabling the selective deprotection
of Z and Boc groups. On the debit side is the low solubility of many Fmoc-protected
amino acids in common organic solvents and the need for chromatographic sepa-
ration of the non-volatile by-products from the deprotection step. The use of the
Fmoc group in peptide synthesis has been extensively reviewed [392-394].
The 2,7-di-tert-butyl-9-fluorenylmethoxycarbonyl (Fmoc*) group has been developed
as a more soluble analogue of the 9-fluorenylmethoxycarbonyl (Fmoc) protecting
group [395]. Like Fmoc, the Fmoc* group is readily introduced as its chloroformate.
The chloroformate (Fmoc*-Cl ) 560 is prepared in three steps from fluorene 557.
The last of these is a slow chlorocarbonylation with phosgene [396].
Amines can be protected by treatment with Fmoc*-Cl in a biphasic mixture of di-
chloromethane and aqueous sodium carbonate [395, 397], and can be deprotected
with a 20% solution of piperidine in DMF [395].

Typical procedure for the Fmoc*-protection of an amine [395]. An ice-cooled, 250-mL,
three-necked, round-bottomed flask equipped with a nitrogen inlet adapter, a glass
stopper, a rubber septum, and a magnetic stirring bar was charged with 559
(6.75 g, 21.9 mmol), dichloromethane (20 mL), and a solution of phosgene (for a
safe source, see Chapter 7) in toluene (33.2 mL, 1.98 m, 65.7 mmol). The ice in the
ice bath was allowed to melt, and the reaction mixture was stirred for 72 h. Con-
centration of the mixture yielded 8.13 g (100%) of Fmoc*-Cl 560 as a light-brown
oil of su cient purity for its subsequent use. An analytical sample was obtained
as a white solid by adding a minimal amount of pentane, chilling to 78 C

under nitrogen until crystals formed, decanting the mother liquor, and removing
the residual pentane in vacuo; mp 63-65 C.
An ice-cooled, two-necked, round-bottomed flask equipped with a magnetic stir-
ring bar, nitrogen inlet adapter, and septum was charged with p-methoxybenzyl-
amine 561 (0.422 g, 3.07 mmol), dichloromethane (1.0 mL), and 10% aqueous
Na 2 CO 3 (8.3 mL). After 5 min, a solution of Fmoc*-Cl 560 (1.14 g, 3.07 mmol) in
dichloromethane (3.2 mL) was added over a period of 2 min. The ice bath was re-
moved, and the reaction mixture was stirred at room temperature for 2 h. It was
then diluted with dichloromethane (60 mL) and washed with 1 m HCl (60 mL).
The aqueous layer was extracted with dichloromethane (2 20 mL), and the com-

bined organic layers were dried over MgSO 4 , filtered, and concentrated to yield