Synthetic Communications

ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20

Improved Syntheses of Peptide Coupling Reagents

Bop and PyBOP Using Triphosgene

I. A. Rivero , R. Somanathan & L. H. Hellberg

To cite this article: I. A. Rivero , R. Somanathan & L. H. Hellberg (1995) Improved Syntheses of
Peptide Coupling Reagents Bop and PyBOP Using Triphosgene, Synthetic Communications,
25:14, 2185-2188, DOI: 10.1080/00397919508015899

To link to this article: http://dx.doi.org/10.1080/00397919508015899

Published online: 23 Sep 2006.

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SYNTHETIC COMMUNICATIONS, 25(14), 2185-2188 (1995)

IMPROVED SYNTHESES OF PEPTIDE COUPLING REAGENTS

BOP AND PyBOP USING TRIPHOSGENE.

1. A. Rivero, R. Somanathan*, and L.H. Hellberg

Centro de Graduados e lnvestigacion del lnstituto

Tecnologico de Tijuana, Apdo. Postal 1166, 22000 Tijuana,
B.C. Mexico.

A B S T R A C T : Synthesis of Benzotriazolyloxy tris [dimethyl-

amino] phosphonium hexafluorophosphate (BOP) and
Benzotriazolyloxy tris [pyrrolidino] phosphonium
hexafluorophosphate (PyBOP), using triphosgene and
hydroxybenzotriazofe.

Castro and Co-workers reported the synthesis of

Benzotriazolyloxy tr i s [dimethylamino] Phosphonium
Hexafluorophosphate ( BOP Reagent) ( l ) , an excellent peptide
coupling reagent, by saturating HMPA with phosgene and
subsequently reacting this mixture with hydroxybenzotriazole
followed by KPF6. The peptide coupling is often carried out
in DMF in the presence of BOP and the reaction goes to
completion in 2 h 1,2,3,4.

Two modified inexpensive synthetic routes to BOP were

later reported by the same authors. One uses commercially
available phosgene in toluene (20%)/HMPA2> another
POCI3/HMPA3. Later, Castros and coworkers developed a new

*To whom correspondence should be addressed

2185

Copyright 0 1995 by Marcel Dekker, Inc.

2186 FUVERO, SOMANATHAN, AND HELLBERG

coupling agent PyBOP from tris [pyrrolidinol-phosphine oxide/

POC135, thus avoiding the toxic HMPA6,7.

We recently have reported the synthetic use of solid

triphosgene as a substitute for phosgene gas in a number of
reactions%g. Here we wish to report the use of this reagent in
the synthesis of BOP (1) and PyBOP (7),making this route
reasonably attractive when compared to the POC13/HMPA,
POCI3/Tris [pyrrolidino] phosphonium chloride methods.

(4)
(3)

(1)R l = R ~CH, BOP

(7) &=RF (CH2)4 PyBOP

Triphosgene was added to hexamethylphosphoric triamide

(HMPA) and the mixture was vigorously stirred at OOC. The
reaction was monitored by NMR by following the disappearance
of the HMPA doublet at 2.63 ppm and the appearance of a
doublet at 2.91 ppm (J=lOHz), and is completed after 3h. The
solvent was removed under reduced pressure and the residue
was treated with methylene chloride and hydroxy-
benzotriazole monohydrate. The resultant chloride was then
exchanged with KPF6 to give the desired BOP reagent. Using the
same technique tris(N,N-tetramethy1ene)phosphoric acid
BOP AND @BOP 2187

triamide was converted to PyBOP. NMR and IR spectra of both

products agreed with authenthic samples.

Although our method is complimentary to the one

reported by Castro and co-workers, the solid triphosgene has
several obvious advantages: easy to weigh out the required
amount, its shelf life is much longer, it is less moisture
sensitive compared to POCIS, and from the safety point of
view, it is much easier to handle.

EXPERIMENTAL: Melting points were obtained on a Gallenkamp

apparatus and are uncorrected. Infrared spectra were recorded
on a Perkin-Elmer FT-IR 1750 spectrophotometer. The proton
nuclear magnetic resonance spectra were recorded on a
Chemagnetic 200 MHz and Varian EM-360 60 MHz.

Preparation of Be nz ot r i a z o l y l - N - o x y t r i s
[dimethylamino] phosphonium Hexaphluorophosphate
(BOP):

To a vigorously stirred solution of HMPA (15.0 g, 83.7

mmol) was added triphosgene (1 1.28 g, 38.01 mmol) in
dichloromethane (15 mL) over a period of 40 min at 0%. The
ice bath was removed and the mixture was stirred at RT. At
various intervals small aliquots were taken to follow the
disappearance of the HMPA signal. After 3 h, the solvent was
removed (under reduced pressure) to give a residue. The
residue was redissolved in dry dichloromethane (40 mL) and
solid hydroxybenzotriazole monohydrate (12.76 g, 94.4 mmol)
was added with stirring . The solution was cooled to about
-5OC with an acetonehe bath and triethylamine (8.42 g, 83.4
mmol) was added over 15 min., stirring was continued for 4 h
at -5OC. The precipitate of triethylammonium chloride was
filtered and the filtrate was concentrated under reduced
pressure to give a solid which was triturated with ether (3x
50mL). The residue was dissolved in water (50mL) and mixed
with a filtered solution of potassium hexafluorophosphate
(16.68 g, 90.6 mmol) in water (120mL),to give BOP as a
crystalline solid (28.919, 78%), mp. 136-138OC. (litlo m p .
2188 RIVERO, SOMANATHAN, AND HELLBERG

138oC dec.). IR(K6r): 2965, 1493, 1323, 1178, 1072, 1019,

836, 770, 665 cm-1. 1H NMR (CDC13): 6 8.08(d,lH, Ar-H),
7.74(m,2H,Ar-H), 7.54(m,lH,Ar-H), 2.88(d,18H,J=10.7Hz, CH3-
N) PPm.

Be nzot r iazo Iy I oxy t r is [ p y r ro I i d i no] p hosp ho n i u m

hexafluoro-phosphate (PyBOP). Prepared as described for
BOP(5.31g, 85%), mp 155-157oC. ( l i t l o mp. 154-1560C dec.).
IR(KBr): 2965, 1615, 1470, 1395, 1357, 1220, 1156, 1108,
836, 910, 839, 556 em-’. I H NMR (CDC13): 6 8.1O(d,lH,Ar-H),
7.74( m,2H,Ar-H), 7.56(m, 1H,Ar-H), 3.46 (m ,12H ,CH2- N ) ,
1.96(m,12H,CH2-C-N) ppm.

Acknowledgement: We gratefully acknowledge support of

this project by CONACYT (GRANTS No. 1528-E9207 and No.
1502-E9201) and San Diego State University for Spectral Data.

REFERENCES

B. Castro, J.R. Dormoy, G. Evin and C. Selve, Tetrahedron

Lett.,&%, 1219 (1975).
B. Castro, G. Evin, C. Selve, R. Seyer, Synthesis, 413
(1 977).
B. Castro, J.R. Dormoy, 6. Dourtouglou, G. Evin, C. Selve,
J.C. Ziegler, Synthesis, 751 (1976).
J. Diago-Meseguer, A.L. Palomo-Coll, J.R. Fernandez-
Lizarbe and A. Zugaza-Bilbao, Synthesis, 547 (1980).
J. Coste, 0.Le-Nguyen and 6.Castro, Tetrahedron Letters,
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J.W. Lloyd, J. Am. Ind. Hva. Assoc., 25, 662 (1975).
L.D. Shott, A.B. Borkovee and W.A. Knapp, J. Toxicol. A p ~ l .
Pharmacol., B, 499 (1971).
I.A. Rivero, R. Somanathan and L.H. Hellberg, Ora. Prep.
Proced. Intl., 24, 363 (1992).
I.A. Rivero, R. Somanathan and L.H.Hellberg, Svnthetic
Communications, a, 71 1 (1993).
Aldrich Chemical Co., Inc., Milwaukee, Wisconsin, USA,
53201.

(Received in the USA 01 December 1994)