Preparation of carboxamides via carboxylic-phosphoric anhydrides

Article abstract of DOI:10.1021/op980205g

A number of reagents used to prepare carboxamides via a carboxylic-phosphoric anhydride intermediate have been reexamined. It was found that a simple carboxylic-phosphoric anhydride prepared from a carboxylic acid and commercially available diethyl chlorophosphate provided several significant advantages over more complex intermediates in many cases.

Full text of DOI:10.1021/op980205g

Organic Process Research & Development 1999, 3, 92−93
Preparation of Carboxamides via Carboxylic-Phosphoric Anhydrides
Bruce Gaede
Chemical and Agricultural Products DiVision, Abbott Laboratories, North Chicago, Illinois 60064
Scheme 1
Abstract:
A number of reagents used to prepare carboxamides via a
carboxylic-phosphoric anhydride intermediate have been re-
examined. It was found that a simple carboxylic-phosphoric
anhydride prepared from a carboxylic acid and commercially
available diethyl chlorophosphate provided several significant
advantages over more complex intermediates in many cases.
Introduction
The formation of a carboxamide from a carboxylic acid
and an amine is a common operation in organic processes.
The classical approach involving conversion of the carboxylic
acid to an acid chloride followed by reaction with the amine
in the presence of a base often gives rise to problems of
selectivity due to the highly reactive reagents employed and
the highly reactive nature of carboxylic acid chlorides. An
array of alternative reagents have been developed to activate
the carboxylic acid in the formation of amides, and each
offers particular advantages of selectivity or ease of purifica-
tion that make the selection of the correct reagent the key to
a successful chemical process.
On a laboratory scale, it is often convenient to employ a
carbodiimide reagent for this purpose since these reagents
are readily available and give good selectivity while main-
taining high reactivity. Carbodiimide reagents are often
expensive, however, and they are inconvenient to use on a
large scale due to toxicology and waste handling issues. In
the course of investigating alternatives to the carbodiimide
coupling for the formation of amides, it was found that mixed
carboxylic-phosphoric anhydrides are convenient activated
intermediates for reaction with amines. Furthermore, it was
found that a simple reaction procedure was often just as
effective in carrying out the transformation as more elaborate
reactions using exotic reagents. This procedure may provide
a useful alternative to other methods which cannot be used
due to considerations of selectivity, or where patent consid-
erations prevent the use of more commonly encountered
reagents.
it is not clear if the auxiliary reagent plays any role in the
formation of the anhydride.5 Other approaches to the
anhydride intermediate include the use of dialkyl phosphites,6
dialkylphosphoric acids,7,8 and their salts.9 The few cases
where dialkylphosphorus halides have been used directly do
not involve direct formation of the mixed anhydride. One
account uses reaction of dialkylphosphorus halide with the
sodium salt of a carboxylic acid.10 Dialkylphosphorus halide
is used with N-hydroxybenzotriazole (HOBT), another acyl-
transfer reagent, but there is some confusion as to whether
this reagent serves to form the phosphorus anhydride of the
carboxylic acid11 or to form the HOBT ester.12 Yet another
account uses a dialkyl chlorophosphite.13
Results
Selected examples prepared by some of these methods
have been repeated using the simple reaction sequence shown
in Scheme 2. A carboxylic acid (1) is reacted with the
inexpensive reagent diethyl chlorophosphate (2) in tetrahy-
drofuran in the presence of triethylamine. The resulting
carboxylic-phosphoric anhydride (3) is reacted in situ with
Some reagents used in the preparation of carboxylic-
phosphoric anhydrides are shown in Scheme 1. These
reagents are often derived from dialkylphosphoryl halides1-3
or are diarylphosphoryl halides.4 Dialkylphosphoryl halide
is used in conjunction with an acyl-transfer reagent, although
(5) Ohta, A.; et al. Heterocycles 1984, 22, 2369.
(6) Ma, X.-b.; Zhao, Y.-f. J. Org. Chem. 1989, 54, 4005.
(7) Edmundson, R. S.; et al. J. Chem. Soc. (C) 1971, 2452.
(8) Bentley, R. J. Am. Chem. Soc. 1948, 70, 2183.
(9) Sheehan, F. J. Am. Chem. Soc. 1950, 72, 1312.
(10) Lambie, A. J. Tetrahedron Lett. 1966, 3709.
(11) Kim, S.; Chang, H.; Ko, Y. K. Tetrahedron Lett. 1985, 26, 1341.
(12) Kim, S.; Chang, H.; Ko, Y. K. Bull. Korean Chem. Soc. 1987, 8, 471.
(13) Anderson, G. W.; Young, R. W. J. Am. Chem. Soc. 1952, 74, 5307. Young,
R. W.; et al. J. Am. Chem. Soc. 1956, 78, 2126.
(14) Brown, R. F. C.; et al. Aust. J. Chem. 1977, 30, 179.
(15) Fuhrer, W.; Gschwend, H. W. J. Org. Chem. 1979, 44, 1133.
(1) Shiori, T.; et al. Tetrahedron 1976, 32, 2211.
(2) Rosowsky, A.; et al. J. Med. Chem. 1982, 25, 960.
(3) Cramer, F.; Gaertner, K.-G. Chem. Ber. 1958, 91, 704; 1562.
(4) (a) Grosz, H.; Katzwinke, S.; Gloede, J. Chem. Ber. 1966, 99, 2631. (b)
Wakselman, M.; Acher, F. Tetrahedron Lett. 1980, 21, 2705.
92
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10.1021/op980205g CCC: $18.00 © 1999 American Chemical Society and Royal Society of Chemistry
Published on Web 01/07/1999

Table 1
Table 2
recrystallization
solvent
mpa
lit. mp
yield
(%)
literature method
reagent (ref)
diethyl
chlorophosphate
product
(°C)
(°C)
yield method yieldb
5a
5b
5c
5d
5e
5f
5g
5h
5i
EtOH/H2O
EtOH
147-147.5 151-1521
114-115
80
60
68
66
53c
36
93
60
86
R
R′
product (%)
(%)
118-1191
1463
EtOAc/heptane 142-147
Diethyl Cyanophosphate1,2
c-Hex
Ph
EtOAc/heptane 100-104b
823
Ph
PhCH2
5a
5b
97
83
80
60
EtOH/H2O
PhCH3/heptane
EtOH
86-89
56-58
103
1013
614b
104-1054b
118-1194b
164-1655
Diethyl R-Ethoxy-â-carboxyethylvinyl phosphate3
EtOAc/heptane 105-106
EtOH
PhCH3
Heptane
Cbz-NH-CH2
Cbz-NH-CH2
Cbz-NHCH-
Ph
5c
5d
5e
62
74
63
68c
66
53
161-162
105-107
117-121
CH2CO2Et
CH2CO2Et
5j
5l
1158 (108-109d)14 52
118-12015
87
(CH2CH(CH3)2)
2-Chloro-2-oxo-1,3,2-benzodioxaphosphole4
1
a Uncorrected. b Higher mp unexplained. H NMR consistent with expected
structure. c Compound 5e: [R]25 ) -20.8° (lit.3 -27°). d From benzene.
CH3
Ph
CH2Ph
CH2Ph
CH2Ph
CH2CO2Et
5f
84
42
63
76
36
93
D
5g
5h
5d
Cbz-NH-CH2
Cbz-NH-CH2
60c
66
Conclusion
It has been shown that mixed carboxylic-phosphoric
Diethyl Chlorophosphate + 3,6-Diethyl-2-hydroxypyrazine5
anhydrides can be easily prepared from a carboxylic acid
and diethyl chlorophosphate, and that these intermediates can
be reacted with amines to form amides in one-pot procedure.
This simple procedure replaces a number of elaborate
methods using exotic reagents which have appeared in the
literature for generating the activated intermediates. This
gives the process chemist another viable choice for carrying
out the transformation of a carboxylic acid and an amine to
a carboxamide.
Ph
Ph
Ph
CH2Ph
5i
5g
81
83
86
93
2-Benzoyloxy-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane7
Ph
Ph
Acetyldibenzylphosphate8
Ph 5j
5i
90
86
CH3
a
52
Diethylchlorophosphate + Na Salt of Acid10
CF3
t-Bu
Ph
Ph
5k
5l
a
a
d
87
Diethylchlorophosphate + HOBT11,12
Experimental Section
Ph
c-Hex
Ph
CH2Ph
Ph
5a
5b
5f
93
96
92
96
80
60
36
86
Starting materials, reagents, and solvents were obtained
from Aldrich Chemical Co., Milwaukee, WI, and were used
as received.
PhCH2
CH3
Ph
5i
CAUTION: Diethyl chlorophosphate is highly toxic,
paticularly by absorption through the skin. Personal protec-
tiVe equipment should be eValuated for suitability for use
with this compound.
a No yield given. b Recrystallized yields. c Product somewhat impure by NMR.
d Intractable mixture.
Scheme 2
General Procedure. A mixture of 1.00 equiv of the
carboxylic acid component and 2.20 equiv of triethylamine
is dissolved in tetrahydrofuran (1000 mL/mol). To this
mixture is added 1.05 equiv of diethyl chlorophosphate with
stirring and cooling over 5-10 min at 15-20 °C. The
resulting white suspension is stirred 3 h at ambient temper-
ature. To this mixture is added a solution of 1 equiv of amine
in tetrahydrofuran (200 mL/mol) at 20-25 °C. The reaction
is stirred for 1 h, whereupon TLC analysis shows that acid
and amine have been consumed. The reaction is transferred
to a separatory funnel with ethyl acetate (1200 mL/mol) and
water (500 mL/mol). The layers are separated, and the
organic layer is washed with 500 mL/mol portions of 1 N
hydrochloric acid, saturated sodium bicarbonate solution
(2×), and brine. The organic layer is dried over anhydrous
magnesium sulfate, filtered, and evaporated. The crude
amines are recrystallized and dried. Recrystallization sol-
vents, melting points, and yields for the various amides are
the amine component (4) to form the amide (5). The results
are shown in Table 1.
In most cases, the amides 5 are formed using the diethyl
chlorophosphate reagent in yields comparable to those which
are observed using the reagents shown in Scheme 1.
Exceptions are the acetamides 5f and 5j, which are difficult
to recrystallize efficiently, and the trifluoroacetamide 5k,
which gives predominately the phosphoramide resulting from
attack of the amine on the phosphorus side of the mixed
anhydride 3 (R ) CF3).
Often an optically active component is included in the
examples to determine if the amidation method is mild
enough to avoid racemization of the asymmetric component
or product. Example 5e is included to determine if the
phosphoric anhydride method is compatible with optically
active components. The resulting Cbz-leucylglycine ethyl
ester (5e) retains 77% optical purity. This indicates that, by
adjusting reaction conditions, it may be possible to preserve
optical activity during this reaction.
1
shown in Table 2. In addition, H NMR spectra have been
obtained for each amide. The spectra are consistent with the
structure or match published spectra for each compound.
Received for review May 21, 1998.
OP980205G
Vol. 3, No. 2, 1999 / Organic Process Research & Development
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