Chemistry Reference
In-Depth Information
The synthesis of benzotriazolyloxy tris(dimethylamino)phosphonium hexafluoro-
phosphate 1317 (BOP), an excellent peptide coupling reagent, has been tradition-
ally performed by saturating hexamethylphosphoric triamide (HMPA) 1313 (R
1
¼
R
2
Me) with phosgene and subsequently treating this mixture first with hydroxy-
benzotriazole 1315 and then with KPF
6
. Peptide coupling is often carried out in
DMF in the presence of BOP, whereby the reaction goes to completion within 2 h
[991-994].
Two modified inexpensive synthetic routes to BOP were later reported by the
same authors. One uses commercially available phosgene in toluene (20%)/HPPA
[992], the other POCl
3
/HMPA [993]. More recently, a new coupling agent, PyBOP,
derived from tris(pyrrolidino)phosphine oxide/POCl
3
, has been developed [995],
which avoids the use of toxic HMPA.
Triphosgene (less moisture-sensitive than POCl
3
) has been successfully used in
the synthesis of BOP (1317,R
1
¼
(CH
2
)
4
),
making the route reasonably attractive when compared to the POCl
3
/HMPA or
POCl
3
/tris(pyrrolidino)phosphonium chloride methods [996].
¼
R
2
¼
Me) and PyBOP (1317,R
1
¼
R
2
¼
(CCl
3
O)
2
CO
O
P(NR
1
R
2
)
3
Cl
P(NR
1
R
2
)
3
Cl
1313
1314
OH
N
N
Et
3
N
1315
OP(NR
1
R
2
)
3
PF
6
Cl
OP(NR
1
R
2
)
3
KPF
6
N
N
N
N
N
N
1317
1316
BOP
R
1
= R
2
= Me
PyBOP
R
1
= R
2
= (CH
2
)
4
Typical procedure. Benzotriazolyl-N-oxytris(dimethylamino)phosphonium hexafluorophos-
phate (1317, BOP) [996]: To vigorously stirred HMPA (15.0 g, 83.7 mmol) at 0
C,
a solution of triphosgene (11.28 g, 38.01 mmol) in dichloromethane (15 mL) was
added over a period of 40 min. The ice bath was then removed and the mixture was
stirred at room temperature. At various intervals, small aliquots were removed in
order to follow the disappearance of the HMPA spectroscopically. After 3 h, the
solvent was removed under reduced pressure to leave a residue. This residue was
redissolved in dry dichloromethane (40 mL) and solid hydroxybenzotriazole mono-
hydrate (12.76 g, 94.4 mmol) was added with stirring. The resulting solution was
cooled to about
5
C with an acetone/ice bath, whereupon triethylamine (8.42 g,
83.4 mmol) was added over a period of 15 min and stirring was continued at
5
C
