Propanephosphonic acid anhydride-mediated cyclodehydration of maleic acid monoamides

Article abstract of DOI:10.1080/00397911.2012.727060

Propanephosphonic acid anhydride (T3P) has been proposed as a novel reagent for the preparation of maleic acid isoimides from the corresponding monoamides. A series of substituted aromatic and aliphatic isoimides have been prepared in good yields. The mai

Full text of DOI:10.1080/00397911.2012.727060

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Propanephosphonic Acid Anhydride-Mediated
Cyclodehydration of Maleic Acid Monoamides
Eduards Bakis a , Anda Priksane a & Igors Klimenkovs a
a Faculty of Chemistry, University of Latvia, Riga, Latvia
Accepted author version posted online: 05 Apr 2013.
To cite this article: Eduards Bakis , Anda Priksane & Igors Klimenkovs (2013): Propanephosphonic Acid Anhydride-Mediated
Cyclodehydration of Maleic Acid Monoamides, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, DOI:10.1080/00397911.2012.727060
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PROPANEPHOSPHONIC ACID ANHYDRIDE-MEDIATED
CYCLODEHYDRATION OF MALEIC ACID MONOAMIDES
Eduards Bakis1, Anda Priksane1, Igors Klimenkovs1,*
1Faculty of Chemistry, University of Latvia, Riga, Latvia
University of Latvia, Faculty of Chemistry, 48 Kr. Valdemara street, Riga, LV-1013
Latvia, E-mail: igors.klimenkovs@lu.lv
Abstract
Propanephosphonic acid anhydride (T3P) has been proposed as a novel reagent for the
preparation of maleic acid isoimides from the corresponding monoamides. A series of
substituted aromatic and aliphatic isoimides have been prepared in good yield. The main
advantage of this synthetic method is the use of environmentally benign, cost-efficient
reagents and solvents, which are also safer to handle than the ones employed previously.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications® to view the free supplemental file.
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INTRODUCTION
Propanephosphonic acid anhydride (T3P, Figure 1) has been recently used for a
wide variety of dehydration reactions. Its use for large scale processes has been
extensively promoted by scientists at several pharmaceutical companies, as it is
considered a cost-efficient and environmentally benign reagent.[1,2]
T3P has been employed for the synthesis of amides from carboxylic acids[1,3,4] as
well as for dehydration of amides to yield nitriles.[5] Several heterocyclic compounds
have also been prepared in T3P-mediated reactions.[7-9] In many reactions a new carbon –
nitrogen bond has been formed, or bond order has been increased.[7]Our aim was to
explore the possibilities of expanding the use of this versatile reagent, so as to include
cyclodehydration of maleic acid monoamides (1). This reaction may proceed to yield
either the thermodynamically preferred maleic acid imides or the somewhat labile
isoimides.[10] While both compounds are of great interest in organic chemistry, the higher
reactivity of maleic acid isoimides (2) makes them especially appealing as reactive
intermediates in many synthetic sequences that lead to polyamides,[11]polymerizable
surfactants,[12,13] and -lactams,[14] to name just a few (Scheme 1).
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The reagents currently used for the synthesis of isoimides 2 are
cyclohexylcarbodiimide[15,16] and ethyl chloroformate,[16] and they both are highly
undesirable because of serious safety concerns. In recognition of this problem, some
other reagents have been suggested recently, including cyanuric chloride[17] and 2-chloro-
1,3-dimethylimidazolinium chloride.[18] However, probably because of somewhat limited
utility of these reagents for other similar transformations, their advantages in
cyclodehydration of monoamides 1 have not been widely recognized.
T3P could in this case be an excellent alternative, as it is already widely employed
in organic synthesis, it is user-friendly and in dehydration reactions produces only
innocuous by-products.[1]The reagentused to prepare isoimides 2 has to be able to effect
dehydration of monoamides 1 at temperatures low enough to suppress thermal
isomerization of isoimides to imides, and the reaction medium must be devoid of
chemical species able to promote catalytic isomerization. We proposed that T3P
corresponds to these two requirements: it is an efficient and gentle dehydrating reagent.
RESULTS AND DISCUSSION
The requisite monoamides 1 were prepared by simple acylation of the corresponding
amines with maleic anhydride.[19] As our aim was to determine the scope and
applicability of T3P-mediated cyclodehydration of monoamides 1, we decided to explore
this reaction for structurally different monoamides 1: substituted aromatic, simple
aliphatic, as well as - and -branched aliphatic (Scheme 2, Table 1).
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We initially carried out dehydration of monoamides 1 under conditions described
earlier to work well for other T3P-mediated reactions. T3P is usually available as a
solution in different solvents. Previously isoimides 2 have almost invariably been
synthesized in dichloromethane solution,[15,20] and even up to date it still remains the
solvent of choice.[17,18] As we wished to develop an environmentally benign synthetic
method for the preparation of isoimides 2, we replaced dichloromethane with ethyl
acetate. Two equivalents of a tertiary amine have to be used in most reactions employing
T3P, presumably to convert the carboxylic acid group in the substratesto the more
nucleophilic carboxylate anion and to prevent the reaction medium from becoming
acidic, as propanephosphonic acid is liberated in the course of reaction. N-
Methylmorpholine(NMM) has been suggested as a good choice.[21] It has already been
noted that the tertiary amine has to be added before T3P to avoid possible side
reactions.[5] We observed that this order of addition also helped to achieve homogeneous
reaction medium, as several monoamides 1 were poorly soluble in ethyl acetate. In a few
cases when a clear solution could not be obtained, it turned out to be advantageous to
reflux the solution for a few minutes before addition of T3P, so as to ensure that
monoamides 1 were completely converted to the corresponding NMM salts. The solution
of T3P was added at -15…-20°C, and the reaction was left to proceed at +4°C. Under
these conditions the reaction was complete over night, the only exceptionbeing
preparation of bis-isoimide 2l that went to completion only at room temperature. As usual
for T3P-mediated reactions, reaction by-products could be successfully removed by
extraction with water.[22] Even though isoimides 2 are rather susceptible to hydrolysis,[23]
extraction with water to remove reaction by-products did not present a significant
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problem in this case. Further purification of the obtained isoimides 2 was achieved by
dissolution in dry diethyl ether and removal of the unreacted monoamides by filtration.
Crystallization or chromatographic purification were not required, and indeed were better
avoided to prevent isomerization of isoimidesto imides.
The yields of isoimides 2 were generally high and in the same range as obtained
by both the classical and the recently developed methods(Table 1). A lower yield was
obtained for tert-butyl isoimide 2d, yet it can be readily accounted for by unfavorable
sterical interaction during the reaction. The lowest reactivity was exhibited by bis-
monoamide 2l, as has already been observed with other dehydrating reagents. A detailed
comparison with the recently introduced methods is not possible, since 2-chloro-1,3-
dimethylimidazolinium chloride has been used for the synthesis of only
threeisoimides,[18] while cyanuric chloride has been used mainly for the synthesis of
aromatic isoimides.[17]
In conclusion, we have developed a novel method for the preparation of isoimides
2 that is similar to published methods in terms of yield, but is clearly advantageous from
the environmental point of view. We have also broadened the applicability of T3P–a
newly introduced dehydrating reagent, and validated that this reagent combines
efficiency and gentleness, necessary to convert monoamides 1 into isoimides 2.
EXPERIMENTAL
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All reagents and solvents were purchased from Merck and used as received. T3P
was also obtained from Merck as a 50% solution in ethyl acetate. Monoamides 1 were
prepared as described before.[19] NMR spectra were recorded on a Varian 400 MHz
instrument. Chemical shifts are referenced to the NMR solvent. IR spectra were obtained
using a Perkin Elmer Frontier spectrometer. Elemental analysis was performed using a
PerkinElmer2400Series II instrument.
General Procedure For The Synthesis Of Maleic Acid Isoimides (2)
Maleic acid monoamide 1(1.70 mmol or 0.85 mmolbis-monoamide 1l) was
dissolved or suspended in dry ethyl acetate and NMM(0.37 mL, 3.4 mmol) was added. In
case the monoamide did not dissolve completely, the solution was heated 1-2 min to
reflux. The solution was cooled to -15…-20°C, and a 10% solution of T3P in ethyl
acetate (5.4 g of solution, 1.7 mmol) was added dropwise with stirring over 10 min. With
continued stirring, the solution was allowed to reach +4°C over 1 h and was left at this
temperature over night (cyclodehydration of bis-monoamide 1l was effected at room
temperature). The solution was extracted twice with water (2×15 mL) and once with
brine (15 mL). The organic layer was collected, dried with 4 Å molecular sieves and
concentratedinvacuo at room temperature. The residue was taken up in dry diethyl ether
(40 mL), filtered and concentrated again to yield pure isoimide 2.
SUPPORTING INFORMATION
Analytical data, including full previously unreported spectroscopic data for isoimides 2a,
2g and 2l, and 1H and 13C NMR spectra of isoimides 2a, 2g, 2l and 2k (the only new
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compound) can be found via the “Supplementary Content” section of this article’s
Webpage.
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Table 1. Synthesis of maleic acid isoimides 2 using T3P and other reagents
Yield (%)
Mp (°C)
Found Lit.
Entry
Product
2
T3P
Lit.
1
2a
80%
85%
88%
a 74[24]
oil
oil
oil
a 77[24]
a 60[23]
a 52[16]
c 79[16]
2
3
2b
2c
a 85[23]
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a 97[23]
a 82[20]
4
2d
51%
30-32
30-32.5[23]
5
2e
81%
a 87[23]
50.0-51.7 45-46.5[23]
a 87[23]
c 88[23]
6
7
2f
75%
85%
42.1-43.8
37.2-38.8
42-44[23]
36-38[20]
O
c 72[20]
d 53[18]
O
2g
N
a 91[23]
a 40[20]
c 79[23]
49.5-50[23]
oil[20]
8
2h
70%
49.0-50.0
b 93[17]
a 90[25]
a 85[23]
c 98[23]
a 72[23]
a 60[26]
b 91[17]
100-
103[17]
9
2i
2j
85%
96%
94.6-96.5
74.0-75.9
96-98[25]
96-97[23]
77-79[23]
75[26]
10
75[17]
11
12
2k
2l
93%
51%
59.8-61.4
93.0-94.5
a 65[20]
a 52[16]
95-96[2]
94-96[16]
Dehydrating agent used:
a Dicyclohexylcarbodiimide
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b Cyanuric chloride/triethylamine
c Ethylchloroformate/triethylamine
d 2-Chloro-1,3-dimethylimidazolinium chloride/triethylamine
Scheme 1. Synthetic utility of maleic acid isoimides 2
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Scheme 2. Synthesis of isoimides 2
Fig. 1. Propanephosphonic acid anhydride (T3P)
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