An efficient amide-forming reaction using tributyltrichloromethylphosphonium chloride

Article abstract of DOI:10.1081/SCC-100000572

An efficient and expeditious amide-forming reaction is described via a combination of tributylphosphine and carbon tetrachloride (in situ generation of tributyltrichloromethylphosphonium chloride) in the absence of tertiary amines.

Full text of DOI:10.1081/SCC-100000572

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AN EFFICIENT AMIDE-FORMING REACTION USING
TRIBUTYLTRICHLOROMETHYLPHOSPHONIUM
CHLORIDE
Miguel Lorca a & Michio Kurosu b
a Department of Chemistry , The Florida State University , Tallahassee, Florida, 32306,
U.S.A.
b Department of Chemistry , The Florida State University , Tallahassee, Florida, 32306,
U.S.A.
Published online: 16 Aug 2006.
To cite this article: Miguel Lorca & Michio Kurosu (2001) AN EFFICIENT AMIDE-FORMING REACTION USING
TRIBUTYLTRICHLOROMETHYLPHOSPHONIUM CHLORIDE, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 31:4, 469-473, DOI: 10.1081/SCC-100000572
To link to this article: http://dx.doi.org/10.1081/SCC-100000572
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SYNTHETIC COMMUNICATIONS, 31(4), 469–473 (2001)
AN EFFICIENT AMIDE-FORMING
REACTION USING TRIBUTYLTRICHLORO-
METHYLPHOSPHONIUM CHLORIDE
Miguel Lorca and Michio Kurosu∗
Department of Chemistry, The Florida State University,
Tallahassee, Florida 32306, U.S.A.
ABSTRACT
An efficient and expeditious amide-forming reaction is de-
scribed via a combination of tributylphosphine and carbon tetra-
chloride (in situ generation of tributyltrichloromethylphosphonium
chloride) in the absence of tertiary amines.
A number of additives in peptide coupling reactions, such as HOBt (1),
HOOBt (2), and HOAt, have been developed in order to enhance the reaction rate
of peptide formation when used either in combination with a carbodiimide, or an-
other coupling reagent in the presence of tertiary amines. HOAt incorporates both
tertiary amine and HOBt elements within a single molecule. However, the DCC-
HOAt promoted coupling in the presence of NMM requires usually several hours
in the reaction time (3). Since racemization during coupling is a base-catalyzed
process, it is judicious to develop conditions that exclude the tertiary amine from
the reaction mixture. This communication discloses a practical amide-forming re-
action using a combination of tributylphosphine and carbon tetrachloride in DMF
in the absence of tertiary amines.
∗Corresponding author.
469
Copyright ꢀ 2001 by Marcel Dekker, Inc.
www.dekker.com
C

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LORCA AND KUROSU
It was observed in our laboratory that the addition of base was not neces-
sary in the coupling reaction of N-protected amino acid chlorides with C-blocked
amino acid hydrochloride salts when using DMF as a solvent. The coupling
reaction of N-protected amino acid chloride (synthesized from the correspond-
ing amino acid via 1-chloro- N,N,2-trimethylpropenylamine (4)) and C-protected
amino acid hydrochloride salt in DMF in the absence of tertiary amine afforded
the corresponding peptide in good to excellent yield. Therefore, DMF can ade-
quately dissociate the amine hydrochloride to the free amine and its acid and act as
a buffer in the reaction. However, both preparation and application of amino acid
chlorides remain fairly limited; the generation of acid chlorides in situ from the
corresponding N-protected amino acids in the presence of an amino acid accep-
tor in DMF has not been successful. On the other hand, the ordinary carboxylic
acids (non-amino acids) can be converted into the acid chlorides under neutral
conditions by treatment with triphenylphosphine in carbon tetrachloride (5,6). N-
methoxyamide synthesis using CBr4-Ph3P in CH2Cl2 in the presence of Et3N was
reported (6). When this transformations was applied to Fmoc-L-Phe-OH (1) in
DMF, the rate limiting step for the formation of the acid chloride proved to be
the attack of chloride anion onto the acyloxyphosphonium intermediate (i), which
is stable under the conditions. No acid chloride formation was observed at room
temperature. Nonetheless, this intermediate (i) was polarized enough to react with
C-protected amino acid hydrochlorides. For example, the aminolysis of i with
HCl·H-L-Phe-OMe (2) afforded dipeptide (3) in 55% yield together with triph-
enylphosphine oxide as a by-product (Scheme 1). More conveniently, the desired
dideptide 3 was formed in 60 min by addition of Ph3P into a mixture of 1, 2 and
CCl4 in DMF.
In order to accelerate the reaction rate and facilitate separation from Ph3PO,
triphenylphosphinewasreplacedbytributylphosphine. Thesamecouplingreaction
of 1 and 2 with nBu3P afforded 3 within 10 min in 75% yield without detectable
racemization by 1H-NMR. The abbreviations for amino acids follow the IUPAC-
IUB Joint Commission on Biochemistry Nomenclature. The utility of this rapid
and simple method for the formation of peptide bonds under mild conditions was
verified and is summarized in Table 1. The rate difference between the conditions
of Ph3P-CCl4 and nBu3P-CCl4 will be attributable not only to the reactivity of
Ph
Ph
Ph
O
PPh3-CCl4
DMF
.
H
HCl H-L-Phe-OMe (2)
.
OH
O
PPh3 Cl
N
FmocHN
FmocHN
OMe
FmocHN
O
O
O
1
i
3
+
Ph3PO
Ph
Scheme 1.

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471
Table 1. The CCl4-nBu3P Promoted Dipeptide Formations∗
Acceptor Product
Donor
Yield (%)
Fmoc-L-Phe-OH
Fmoc-L-Val-OH
Z-L-Phe-OH
HCl·H-L-Phe-OMe Fmoc-L-Phe-L-Phe-OMe
HCl·H-L-Phe-OMe Fmoc-L-val-L-Phe-OMe
HCl·H-L-Phe-OMe Z-L-Phe-L-Phe-OMe
HCl·H-L-Phe-OMe Boc-L-Pro-L-Phe-OMe
75
70
80
70
70
75
Boc-L-Pro-OH
Fmoc-L-Asp(Tr)-OH HCl·H-L-Phe-OMe Fmoc-L-Asp(Tr)-L-Phe-OMe
Alloc-L-Phe-OH
HCl·H-L-Pro-OMe Alloc-L-Phe-L-Pro-OMe
∗All reactions were carried out at room temperature with a donor:acceptor:CCl4:nBu3P =
1:1.5:5:3 molar ratio.
tributyl or triphenyltrichloromethylphosphonium chloride (R3PCCl3 · Cl) toward
the carboxylic acid, but also to more basic nature of tributyphosphine, which reacts
with the amino acid hydrochlorides to generate the free amines.
This protocol was also applied with success to piperazic acid derivative 4,
which is known to show poor reactivity under conventional peptide-forming con-
ditions such as DCC and BOP (Scheme 2). In order to examine the extent of racem-
ization, a diastereomixture of Boc-DL-Tyr(Me)-L-Phe-OMe was synthesized using
CCl4-nBu3P. ComparisonofthismixturewithBoc-L-Tyr(Me)-L-Phe-OMe, synthe-
sized in the same manner, using 1H-NMR revealed that no detectable racemization
occurred. All of the dipeptides synthesized showed a single diastereomer by 1H-
NMR. However, two limitations were observed for the CCl4-PBu3 promoted pep-
tide-forming reaction: (1) N-protected β-hydroxy amino acids, (e.g., threonine),
form dehydroamino acids; and (2) N-acyl protected amino acids give unsatisfactory
results.
In conclusion, it has been demonstrated that the conditions described here
will be a valuable asset for coupling with urethane-protected amino acids. This
method is rapid and convenient, and generates an easily separable by-product,
tributylphosphine oxide.
Ph
O
O
HN NZ
MeO
OH
MeO
Ph
nBu3P -CCl4
DMF
+
FmocHN
H
O
N
NZ
H
75%
1
4
O
FmocHN
Scheme 2.

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LORCA AND KUROSU
EXPERIMENTAL
General
Dry N,N-dimethylformamide (DMF) was purchased from Aldrich. Infrared
spectra (IR) were obtained on a Perkin-Elmer 1320 infrared spectrometer. 1HNMR
spectra were recorded at 300 MHz. Chemical shifts are reported in parts per million
(ppm). The residual solvent peak was used as an internal reference. Low-resolution
mass spectra (LRMS) and high-resolution mass spectra (HRMS) were recorded in
a Finnigan 90/MAT using positive chemical ionization.
General Procedure for Fmoc-L-Phe-L-Phe-Ome (3)
To a stirred solution of Fmoc-L-Phe-OH (130 mg, 0.336 mmol), HCl·H-L-
Phe-OMe (195 mg, 0.504 mmol), and CCl4 (162 µL, 1.68 mmol) in DMF (2 mL)
was added nBu3P (6) (270 µL, 1.08 mmol). After 10 min at room temperature, the
reaction was concentrated in vacuo. The crude dipeptide was purified by silica gel
chromatography (2:1:1, Hexanes:EtOAc:CH2Cl2) to afford Fmoc-L-Phe-L-Phe-
OMe (126 mg, 0.252 mmol, 75%). (The slow addition of nBu3P increases the
product yield slightly.)
1
3 H NMR (300 MHz, CDCL3): 3.09 (m, 4H), 3.61 (s, 3H), 4.15 (t, 1H),
4.23 (m, 2H), 4.35 (m, 1H), 4.79 (q, 1H), 5.31 (d, 1H), 6.23 (d, 1H), 6.95–7.75
(m, 18H). HRMS (CI): calcd for C34H32O5N2 549.2389, found m/z = 549.2440
(M+H)+. IR: 3299.7, 3061.9, 2923.0, 1739.0, 1685.4, 1659.0, 1536.3. [α]D
+15.5◦ (c 0.5, CHCl3).
=
5 1H NMR (300 MHz, CDCL3): 1.17 (t, 2H), 1.59 (s, 2H), 2.02 (s, 3H), 3.42
(m, 1H), 4.17 (m, 3H), 4.23 (m, 2H), 4.41 (m, 3H), 5.20 (m, 1H), 5.22 (s, 2H), 7.30
(m, 8H), 7.58 (t, 1H), 7.77 (m, 1H), 7.86 (t, 2H), 8.03 (t, 2H), 8.22 (d, 2H), 8.41
(d, 2H). LRMS (CI): calcd for C38H37O7N3 648.2710, found m/z = 649 (M+H)+.
IR: 3325.4, 3058.3, 2922.7, 2854.1, 1810.9, 1718.6, 1518.8. [α]D = +24.3◦ (c 0.3,
CHCl3).
ABBREVIATIONS
Abbreviationsused:HOBt=1-hydroxybenzotriazole;HOOBt=3-hydroxy-1,2,3-
benzotriazin-4(3H)-one; HOAt = 1-hydroxy-7-azabenzotriazol; NMM = N-
methylmorpholine; Fmoc = 9-fluorenylmethoxycarbonyl; Z = benzyoxycarbonyl;
Boc = tert-butoxycarbonyl; DCC = dicyclohexylcarbodiimide; BOP = bezotri-
azole-yloxytris(dimethylamino)phosphonium hexafluorophosphate; Alloc
allyloxycarbonyl.
=

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473
ACKNOWLEDGMENT
This work was supported by The Florida State University.
REFERENCES
1. Ko¨nig, W.; Geiger, R. Ber. Desch. Chem. Ges. 1970, 103, 788.
2. Fan, C.; Hao, X.; Ye, Y. Synth. Commun. 1996, 26, 1455.
3. Carpino, L.A. J. Am. Chem. Soc. 1993, 115, 4397.
4. B. Haveaux, A.; Deckoker, M.; Pens, A.; Sidani, J.; Toye, J.; Ghosez, L. Org.
Synt. Coll. Vol. VI, 282.
5. Lee, J.B. J. Am. Chem. Soc. 1966, 88, 3440.
6. Einhorn, J.; Einhorn, C.; Luche, J.-C. Synth. Commun. 1990, 20, 1105.
7. Hale, K.J.; Cai, J.; Delisser, V.; Manaviazar, S.; Peak, S.A.; Bhatia, G.S. Tetra-
hedron 1998, 54, 4413.
Received in the USA May 29, 2000

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