Terification of maleamic acids without double bond isomerization

Article abstract of DOI:10.1002/ejoc.200901365

Activation of the carboxylic acid group of a maleamic acid by treatment with an arenesulfonyl chloride followed by addition of an alcohol affords a fumaramate or a maleamate, depending on the reaction conditions. The E isomer is obtained when the acid is treated with nearly equimolar amounts of 2,4,6-triisopropylbenzenesulfonyl chloride and an alcohol in pyridine. Replacement of pyridine by 2-picoline and use of a larger excess of activating agent (mesitylenesulfonyl chloride) and alcohol affords the Z isomer. In both cases, high diastereomeric excesses and yields are achieved.

Full text of DOI:10.1002/ejoc.200901365

FULL PAPER
DOI: 10.1002/ejoc.200901365
Esterification of Maleamic Acids without Double Bond Isomerization
Albert Sánchez,[a] Enrique Pedroso,[a] and Anna Grandas*[a]
Keywords: Isomerization / Carboxylic acids / Acylation / Maleamates
Activation of the carboxylic acid group of a maleamic acid
by treatment with an arenesulfonyl chloride followed by ad- alcohol in pyridine. Replacement of pyridine by 2-picoline
dition of an alcohol affords a fumaramate or a maleamate, and use of a larger excess of activating agent (mesitylene-
depending on the reaction conditions. The E isomer is ob- sulfonyl chloride) and alcohol affords the Z isomer. In both
amounts of 2,4,6-triisopropylbenzenesulfonyl chloride and an
tained when the acid is treated with nearly equimolar
cases, high diastereomeric excesses and yields are achieved.
acyl-chloride-forming reagents promotes Z to E isomeriza-
tion (a),[9] whereas other reagents such as ethyl chloro-
formate yield maleic or fumaric acid derivatives, or mix-
tures of both, depending on the reaction conditions and, in
particular, on temperature (b).[10] The carboxylic acid group
of a maleic acid monoester can be activated with a carbodi-
imide to provide the unsymmetrical diester (c), but carbodi-
imide activation of maleamic acids (d) yields iso-
maleimides, maleimides or mixtures of both, depending on
the substituents.[11] Treatment of maleamate salts with alkyl
halides would seem a good alternative, but when we pre-
pared the cesium salt of N-benzylmaleamic acid (1) and
treated it with benzyl bromide the benzyl ester was not ob-
tained (data not shown). This result deserves further investi-
gation, but that is beyond the scope of this work.
Introduction
Maleic and fumaric acid esters are simple, versatile mole-
cules that may undergo a variety of reactions, such as an-
ionic or radical polymerization, hydrolysis under acid or ba-
sic conditions, Michael-type conjugate additions and Diels–
Alder cycloadditions.
Over the years, maleic and fumaric acid derivatives have
found application in many different areas. Their use in the
field of polymers dates from long ago, but the synthesis of
monomers and polymers with improved properties is still a
subject of research.[1] They have also been used, for in-
stance, in the preparation of prodrugs and drug delivery
systems,[2] or to assess the properties of dual-acting drugs
and to provide information on how spatial arrangement af-
fects binding to a receptor.[3] The interconversion between
Z and E isomers has been exploited in the preparation of
mechanically interlocked molecules capable of responding
to external signals (molecular shuttles),[4] or to induce water
gelation by transforming microspheres into gel fibres.[5] Ma-
leic and fumaric acid derivatives are common substrates for
heat- and light-promoted [4+2] and [2+2] cycloadditions,
which have been combined and exploited in the design of
molecular switches,[6] and have also been used in [3+2] and
1,3-dipolar cycloadditions.[7] Quite recently, reactivity and
structural studies of complexes involving maleates and
maleamates as ligands have also been undertaken.[8]
Derivatization of fumaric acid is essentially straightfor-
ward, the main possible difficulty being the selective func-
tionalization of one of the two carboxylic acid groups.
However, the synthesis of maleic acid derivatives is usually
accompanied by side reactions (Scheme 1). Treatment with Scheme 1. Reactions taking place upon activation of butenedioic
acids or monosubstituted derivatives: a) double bond isomerization
promoted by acyl-chloride-forming reagents; b) activation of the
[a] Department of Organic Chemistry, IBUB, Universitat de Barce-
carboxylic acid group of a maleamate by treatment of a maleamic
lona,
acid with ethyl chloroformate, TEA and an amine yield a mixture
Martí i Franquès 1–11, 08028 Barcelona, Spain
of maleamide and fumaramide derivatives; c) activation of maleic
Fax: +34-93-339-7878
E-mail: anna.grandas@ub.edu
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901365.
acid monoesters with carbodiimides does not promote isomeriza-
tion; d) treatment of maleamic acids with carbodiimides yields mix-
tures of isomaleimides and maleimides.
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Esterification of Maleamic Acids
Few maleamate syntheses have been reported. The most arylsulfonyl chloride in the presence of pyridine both as sol-
commonly synthesized derivatives, methyl esters, have usu-
ally been preparated either by adid-catalysed esterification
or by treatment with diazomethane.[11b,12] However, Fischer
esterification, which can furnish esters other than methyl
esters, does not allow phenyl esters to be obtained,[13] and
use of strong acid catalysts is not compatible with sub-
strates containing acid-labile groups. In this manuscript we
wish to describe a study on the use of reagents that yield
mixed carboxylic sulfonic anhydrides for the esterification
of maleamic acids. We first looked for conditions that
would allow the preparation of maleamates with high dia-
stereomeric excesses, and final optimization provided high
synthesis yields.
vent and nucleophilic catalyst. Methanol was then added
and the reaction was allowed to proceed overnight. 2,4,6-
Triisopropylbenzenesulfonyl chloride (TipbsCl) and mesit-
ylenesulfonyl chloride (MessCl) were used in most of the
experiments. 1-Mesitylenesulfonyl-3-nitro-1H-1,2,4-triazole
was also tested, but its use is not recommended because the
nitrotriazolide anion liberated upon formation of the mixed
anhydride reacts with the double bond to afford a succin-
amate rather than a maleamate derivative.
The first experiment, involving nearly equimolar
amounts of maleamic acid, arylsulfonyl chloride and
alcohol (Table 1, Entry 1), afforded methyl N-benzylfumar-
amate (90% de) and a very small amount of methyl N-benz-
ylmaleamate. It is worth pointing out here that NMR
characterization may not be unequivocal with only one of
the two isomers available, because the CH=CH coupling
constants of the Z and E isomers are very similar[12b] (in
our case, 13 and 15 Hz, respectively). The 2D ROESY spec-
tra provided the key to the identification of the two com-
pounds, because only maleamates exhibit the diagnostic
cross peak (quick inspection of NOESY spectra may sug-
gest that olefinic protons are coupled both in maleamates
and in fumaramates). In addition to differences in chemical
shifts (the NH and the olefinic protons of the Z isomer
were downfield and upfield, respectively, from those of the
E isomer), it was observed that the positions of the two
doublets of the CH=CH system and the NH of the E iso-
mer varied depending on the concentration of the sample,
in contrast with the signals of the Z isomer, which did not.
A plausible explanation for this behaviour is that the NH
moiety in the Z isomer may form an intramolecular H bond
Results and Discussion
Experiments designed to establish suitable esterification
conditions were carried out with N-benzylmaleamic acid,
obtained from benzylamine and maleic anhydride as shown
in Scheme 2, a). A sample of methyl maleamate was ob-
tained through acid-catalysed esterification [Scheme 2, b)].
Scheme 2. Syntheses of a) N-benzylmaleamic acid, and b) the cor-
responding methyl ester under Fischer esterification conditions.
Arylsulfonyl-chloride-mediated esterification was devised with the CO component of the ester,[14] whereas in the case
as a one-pot procedure consisting of two sequential steps. of the E isomer the association is intermolecular and thus
In the first, the acid was activated by treatment with the concentration-sensitive (Figure 1).
Table 1. Results of the first esterification experiments: Z/E ratios.
[a] When the catalyst is not used as solvent, the molar fold excess of catalyst with respect to the acid is indicated in brackets. [b] Determined
1
by H NMR analysis of the crude product. [c] Room temp. (ca. 20 °C).
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A. Sánchez, E. Pedroso, A. Grandas
FULL PAPER
on the ratio of diastereomers (cf. Entries 8 to 10 and 9 to
11). Replacement of pyridine by 2-picoline gave very high
Z/E ratios (Entries 12–13). The 2-picoline methyl group re-
duced pyridine’s nucleophilicity, and hence the extent of
isomerization. Further experiments with 2-picoline as both
catalyst and solvent (Entries 14–17) confirmed that the
highest levels of isomerization are found with use of low
molar ratios of alcohol. Surprisingly, NMR spectroscopic
analysis showed that the higher the excess of methanol the
more homogeneous the crude reaction product, which sug-
gests the use of at least 5 equiv. of alcohol.
Our second concern was the reaction yield, which was
below 25% in all the experiments that had given the male-
amate in high diastereomeric excess. Because poor conver-
sion of acid into ester was possibly due to steric hindrance
around the sulfonyl group, less hindered reagents such as
MessCl, 2-methylbenzenesulfonyl chloride (oMbsCl) and
TsCl were tested (Table 2, Entries 18–20). Replacement of
TipbsCl by MessCl gave a better esterification yield, with
no change in the stereochemical outcome of the reaction.
We have no explanation for the fact that MessCl performed
better than oMbsCl and TsCl. Adjustments in the molar
ratios of acid, MessCl and methanol (Table 2, Entries 21–
26) allowed for high esterification yields, with isomerization
being kept within satisfactory limits.
Figure 1. Plausible formation of H-bonds in intra- and intermo-
lecular association of maleamates and fumaramates.
Olefin isomerization can be induced by light or radical
initiators, or by totally different mechanisms such as in Pd/
Bu3SnH-mediated reactions.[15] The isomerization of double
bonds, however, is most often accounted for by ionic inter-
mediates. Conjugate addition of a nucleophile allows the
CH–CH bond to rotate, and this is followed by a retro-
Michael reaction.[16] Hydrogen halides and primary and
secondary amines have been reported to promote Z-to-E
isomerizations of maleic acid and maleates,[17] as has N-
methylimidazole.[18]
In an experiment carried out with a larger excess of
methanol, the two isomers were found in the reaction mix-
ture in similar proportions (Table 1, Entry 2). This was the
first evidence that the presence of an excess of alcohol could
modify the outcome of the reaction. As can be seen in En-
tries 1–6, increasing amounts of methanol reversed the Z/E
ratio when activation was effected either at room temp. or
at 0 °C.
The two isomers have very similar Rf values and are diffi-
cult to separate, so the decision as to which are the best
Methyl N-benzylmaleamate was not altered by methanol, esterification conditions is not obvious. If the goal is the
pyridine, pyridinium hydrochloride or aqueous workup. isolation of pure maleamate, the conditions of Entry 22
This suggested that isomerization was occurring prior to may be optimal. The esterification yield is not the highest,
ester formation, in one of the precursor activated species but the extent of isomerization is virtually nil. Should con-
(mixed carboxylic sulfonic anhydride or acyl pyridinium de- tamination with a small amount of the E isomer not be
rivative), through a reaction between this species and a nu- important, the conditions of Entry 24 (or 25 if the alcohol
cleophile. This assumption was consistent with the effect of is not too valuable and can be easily separated) may be
using large amounts of MeOH, which should increase the preferable.
rate of the reaction between the activated species and
MeOH and thus reduce the risk of isomerization.
The conditions that allowed essentially isomerization-
free esterification (Table 2, Entry 22) were used for the syn-
Experiments with smaller amounts of pyridine gave bet- thesis of some other maleamates (Scheme 3, a). Different
ter but still unsatisfactory results (Table 1, Entries 7–9), and esters of N-benzylmaleamic acid were obtained after treat-
shortening the activation time had no significant influence ment with primary and secondary alcohols [methanol, 2-
Table 2. Results of the second group of esterification experiments: maleamate yield.
[a] Determined by 1H NMR analysis of the crude product. [b] Entry 17 is repeated for purposes of comparison, so subsequent experiments
are numbered consecutively.
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Esterification of Maleamic Acids
cyanoethanol, (2-methoxyethoxy)ethanol, 2-propanol, (–)- containing compound, in very good yields and in particular
1
menthol] and phenol. In all cases H NMR analysis of the with high diastereomeric excesses. To the best of our knowl-
crude products showed the proportion of diastereomers to edge, isomerization-free activation of maleamic acid carb-
be the same as that found for the methyl ester in the prelimi- oxylic acid groups has not previously been reported. Un-
nary experiment (Table 2, Entry 2), or even lower. Treat- der the reaction conditions studied here – activation of the
ment of N-phenyl- and N-tert-butylmaleamic acids (synthe- maleamic acid carboxylic acid group with an arylsulfonyl
sized as shown in Scheme 2, a) with secondary alcohols chloride and treatment with an alcohol at room tempera-
[propan-2-ol, (–)-menthol] and other phenols also furnished ture – the relative proportions of reagents required to afford
the corresponding esters satisfactorily. Although this meth- the best yields of maleamates are substantially different
odology allowed different esters to be synthesized in good from those needed to give fumaramates. The excess of
to very good yields (from 64 to 95%), the need to use a alcohol has a strong influence on the degrees of isomeriza-
considerable excess of alcohol or phenol may be a problem tion, but the key point for prevention of isomerization is
if this is a valuable compound. Moreover, it proved not to substitution of 2-picoline for pyridine. The described meth-
be suitable for the preparation of esters of tertiary alcohols. odology allows maleamic acids to be esterified with primary
A signal with the m/z ratio expected for tert-butyl N-benzyl- and secondary alcohols, as well as the synthesis of phenyl
maleamate was detected in the ESI-MS spectrum of the re- maleamates, which cannot be prepared by acid-catalysed
action mixture, but analysis of the 1H NMR spectrum Fischer esterification.
showed that the ester had been formed in less than 15%
yield. Hence, with the exception of the tert-butyl ester, ma-
leamates were obtained in fairly good to high yields irre-
spective of the amic acid N-substituent.
Experimental Section
Syntheses of Maleamic Acids
N-Benzylmaleamic Acid (1): Maleic anhydride (2.63 g, 26.8 mmol)
was dissolved in anhydrous THF (40 mL), and benzylamine
(2.7 mL, 24.4 mmol) was subsequently added. The mixture was
stirred for 2 h at room temp., and the solvent was eliminated in
vacuo. The resulting crude product was dissolved in CH2Cl2
(25 mL) and extracted with aqueous citric acid (10%, 3ϫ50 mL)
and water (1ϫ50 mL). The organic phase was dried with anhy-
drous MgSO4. Solvent removal by rotary evaporation afforded pure
N-benzylmaleamic acid. White crystals; quantitative yield; m.p.
137–138 °C; Rf 0.47 (CH2Cl2/MeOH/AcOH, 88:10:2). 1H NMR
(400 MHz, CDCl3): δ = 7.57–7.43 (m, 5 H, Ar), 7.19 (br. s, 1 H,
3
3
NH), 6.51 (d, JH,H = 12.9 Hz, 1 H, NCOCH), 6.44 (d, JH,H
=
3
12.9 Hz, 1 H, CHCOO), 4.73 (d, JH,H = 5.9 Hz, 2 H, CH2) ppm.
13C NMR (100 MHz, CDCl3): δ = 165.8, 165.0, 136.9, 135.8, 130.7,
129.1, 128.3, 128.2, 44.6 ppm. HRMS (ESI+): calcd. for
C11H12NO3 [M + H]+ 206.0811; found 206.0821; calcd. for
C11H11NNaO3 [M + Na]+ 228.0631; found 228.0633; calcd. for
C22H22N2NaO6 [2M + Na]+ 433.1370; found 433.1366.
N-Phenylmaleamic Acid (3): Maleic anhydride (593 mg, 6.04 mmol)
was dissolved in anhydrous CH2Cl2 (15 mL), and aniline (0.5 mL,
5.49 mmol) was subsequently added. The mixture was stirred for
1 h at room temp. (precipitation of the acid was observed after a
few minutes). The pure solid was obtained by filtration and wash-
ing with CH2Cl2. White powder; quantitative yield; m.p. 193–
194 °C; Rf = 0.26 (CH2Cl2/MeOH/AcOH, 88:10:2). 1H NMR
(400 MHz, [D6]DMSO): δ = 13.12 (s, 1 H, COOH), 10.38 (s, 1 H,
NH), 7.62 (m, 2 H, Ar), 7.33 (m, 2 H, Ar), 7.09 (m, 1 H, Ar), 6.48
(d, 3JH,H = 12.2 Hz, 1 H, NCOCH), 6.31 (d, 3JH,H = 12.2 Hz, 1 H,
CHCOO) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 166.7,
163.1, 138.4, 131.6, 130.3, 128.7, 123.8, 119.4 ppm. HRMS (ESI+):
calcd. for C10H10NO3 [M + H]+ 192.0655; found 192.0656.
Scheme 3. Preparation of a) different maleamates and b) fumar-
amates.
The conditions that afforded the E isomers (Table 1,
Entry 1) were used to prepare some fumaramates
(Scheme 3, b), which were obtained with high yields and
diastereoselectivities.
N-tert-Butylmaleamic Acid (4): The synthesis procedure was the
same as for compound 1 (see above). White powder; quantitative
yield; m.p. 152–153 °C; Rf 0.45 (CH2Cl2/MeOH/AcOH, 88:10:2).
1H NMR (400 MHz, [D6]DMSO): δ = 8.74 (s, 1 H, NH), 6.42 (d,
Conclusions
3
3JH,H = 12.6 Hz, 1 H, NCOCH), 6.20 (d, JH,H = 12.6 Hz, 1 H,
In summary, fine-tuning of the esterification conditions
allowed a maleamic acid to be transformed into either a
CHCOO), 1.32 (s, 9 H, CH3) ppm. 13C NMR (100 MHz, [D6]-
maleamate or a fumaramate on treatment with a hydroxy- DMSO): δ = 165.4, 165.0, 132.7, 132.7, 51.5, 27.9 ppm. HRMS
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A. Sánchez, E. Pedroso, A. Grandas
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(ESI+): calcd. for C8H14NO3 [M + H]+ 172.0968; found 172.0970;
H, NCOCH), 6.36 (d, JH,H = 12.9 Hz, 1 H, CHCOO), 4.51 (d,
3JH,H = 5.7 Hz, 2 H, CH2) ppm. 13C NMR (100 MHz, CDCl3): δ
= 164.7, 163.7, 150.0, 139.0, 129.6, 128.7, 128.6, 127.8, 127.5, 126.4,
125.0, 122.0, 43.8 ppm. HRMS (ESI+): calcd. for C17H16NO3 [M
+ H]+ 282.1125; found 282.1120; calcd. for C17H15NNaO3 [M +
Na]+ 304.0944; found 304.0939; calcd. for C34H30N2NaO6 [2M +
Na]+ 585.1996; found 585.1992.
3
calcd. for C8H13NNaO3 [M + Na]+ 194.0798; found 194.0796.
Acid-Catalysed Esterification
Methyl N-Benzylmaleamate (2): Concd. H2SO4 (500 µL) was added
to a solution of N-benzylmaleamic acid (500 mg) in anhydrous
MeOH. The mixture was stirred for 4 h at room temp. and the
solvent was removed by rotary evaporation. The resulting crude
product was dissolved in CH2Cl2 (25 mL), and washed with aq.
NaHCO3 (10%, 3ϫ50 mL) and brine (1ϫ50 mL). The organic
phase was dried with MgSO4. Elimination of the solvent under
reduced pressure afforded pure methyl N-benzylmaleamate as a
colourless oil in quantitative yield. Rf 0.40 (CH2Cl2/EtOAc, 75:25).
1H NMR (400 MHz, CDCl3): δ = 8.46 (br. s, 1 H, NH), 7.37–7.27
2-(2-Methoxyethoxy)ethyl N-Benzylmaleamate (7): Colourless oil;
yield 70%; Rf 0.19 (CH2Cl2/EtOAc, 7:3). 1H NMR (400 MHz,
CDCl3): δ = 8.46 (br. s, 1 H, NH), 7.36–7.26 (m, 5 H, Ar), 6.37 (d,
3
3JH,H = 12.5 Hz, 1 H, NCOCH), 6.15 (d, JH,H = 12.5 Hz, 1 H,
3
3
CHCOO), 4.53 (d, JH,H = 5.6 Hz, 2 H, CH2), 4.32 (t, JH,H
=
3
4.8 Hz, 2 H, COOCH2CH2O), 3.72 (t, JH,H = 4.8 Hz, 2 H, CO-
OCH2CH2O), 3.64–3.62 (m, 2 H, OCH2CH2O), 3.54–3.52 (m, 2
H, OCH2CH2O), 3.36 (s, 3 H, OCH3) ppm. 13C NMR (100 MHz,
CDCl3): δ = 166.0, 163.9, 138.6, 137.8, 128.6, 127.8, 127.4, 125.0,
71.8, 70.5, 68.7, 64.5, 59.0, 43.7 ppm. HRMS (ESI+): calcd. for
C16H22NO5 [M + H]+ 308.1492; found 308.1488; calcd. for
C16H21NNaO5 [M + Na]+ 330.1312; found 330.1307.
3
(m, 5 H, Ar), 6.38 (d, JH,H = 13.1 Hz, 1 H, NCOCH), 6.15 (d,
3JH,H = 13.1 Hz, 1 H, CHCOO), 4.54 (d, JH,H = 5.7 Hz, 2 H,
3
CH2), 3.76 (s, 3 H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ =
166.6, 163.8, 138.5, 137.8, 128.7, 127.8, 127.5, 125.0, 52.4,
43.8 ppm. HRMS (ESI+): calcd. for C12H14NO3 [M + H]+
220.0968; found 220.0972; calcd. for C12H13NNaO3 [M + Na]+
242.0787; found 242.0791; calcd. for C24H26N2NaO6 [2M + Na]+
461.1683; found 461.1686.
Isopropyl N-Benzylmaleamate (8): Yellow oil; yield 72%; Rf 0.58
(Et2O). 1H NMR (400 MHz, CDCl3): δ = 8.73 (br. s, 1 H, NH),
3
7.36–7.24 (m, 5 H, Ar), 6.33 (d, JH,H = 13.0 Hz, 1 H, NCOCH),
Synthesis of Maleamates. General Procedure: The N-substituted
maleamic acid (200 mg) and MessCl (5 equiv.) were dissolved in
anhydrous 2-picoline. The mixture was stirred under Ar at room
temp. for 30 min, after which the required alcohol (or phenol,
25 equiv.) was added. After 12–15 h stirring at room temp., the sol-
vent was eliminated by rotary evaporation. The resulting crude
product was dissolved in CH2Cl2 (25 mL), and washed with aq.
citric acid (10%, 3ϫ50 mL), aq. NaHCO3 (10%, 2ϫ50 mL) and
brine (1ϫ50 mL). The organic phase was dried with MgSO4 and
the solvent was removed under vacuum. Esters were purified by
silica gel column chromatography. In the case of 2, 5, 6 and 7,
elution was carried out with CH2Cl2 and increasing amounts of
EtOAc (up to 30%). Esters 8–10, 12 and 13 were purified by elution
with hexanes and increasing amounts of Et2O (up to 30%). Finally,
esters 11, 14 and 15 were purified by elution with hexanes and
increasing amounts of EtOAc (up to 30%).
6.10 (d, 3JH,H = 13.0 Hz, 1 H, CHCOO), 5.06 (sept, 3JH,H = 6.2 Hz,
3
3
1 H, CH), 4.53 (d, JH,H = 5.5 Hz, 2 H, CH2), 1.27 (d, JH,H
=
6.2 Hz, 6 H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 165.6,
163.9, 137.9, 137.8, 128.5, 127.7, 127.3, 126.0, 69.3, 43.6, 21.6 ppm.
HRMS (ESI+): calcd. for C14H18NO3 [M + H]+ 248.1281; found
248.1285; calcd. for C14H17NNaO3 [M + Na]+ 270.1101; found
270.1101; calcd. for C28H34N2NaO6 [2M + Na]+ 517.2309; found
517.2309.
Menthyl N-Benzylmaleamate (9): Pale yellow solid; yield 64%; Rf
1
0.80 (Et2O); m.p. 68–70 °C. H NMR (400 MHz, CDCl3): δ = 8.92
3
(br. s, 1 H, NH), 7.34–7.27 (m, 5 H, Ar), 6.36 (d, JH,H = 13.2 Hz,
3
1 H, NCOCH), 6.13 (d, JH,H = 13.2 Hz, 1 H, CHCOO), 4.74 (dt,
3JH,H = 4.5, JH,H = 10.8 Hz, 1 H, COOCH menthyl), 4.54 (d,
3
3JH,H = 5.6 Hz, 2 H, ArCH2), 2.02–1.97 (m, 1 H, CH menthyl),
3
3
1.82 (dsept, JH,H = 2.5, JH,H = 6.9 Hz, 1 H, CHCH3 menthyl),
1.70–1.67 (m, 3 H, CH menthyl), 1.54–1.45 (m, 1 H, CH menthyl),
1.44–1.36 (m, 2 H, CH menthyl), 1.08–1.04 (m, 1 H, CH menthyl),
0.91 (d, 3JH,H = 6.6 Hz, 3 H, CH3 menthyl), 0.89 (d, 3JH,H = 6.9 Hz,
Methyl N-Benzylmaleamate (2): Colourless oil; yield 71%; Rf 0.41
1
(CH2Cl2/EtOAc, 7:3). H NMR (400 MHz, CDCl3): δ = 8.47 (br.
3
3
s, 1 H, NH), 7.37–7.26 (m, 5 H, Ar), 6.38 (d, JH,H = 13.1 Hz, 1
3 H, CH3 menthyl), 0.74 (d, JH,H = 6.9 Hz, 3 H, CH3 men-
3
thyl) ppm. 13C NMR (100 MHz, CDCl3): δ = 165.9, 164.0, 138.7,
137.9, 128.6, 127.7, 127.3, 125.7, 75.9, 46.8, 43.7, 40.6, 34.1, 31.4,
26.2, 23.4, 21.9, 20.7, 16.3 ppm. HRMS (ESI+): calcd. for
C21H30NO3 [M + H]+ 344.2220; found 344.2232; calcd. for
C21H29NNaO3 [M + Na]+ 366.2040; found 366.2042; calcd. for
C42H59N2O6 [2M + H]+ 687.4368; found 687.4365; calcd. for
C42H58N2NaO6 [2M + Na]+ 709.4187; found 709.4185.
H, NCOCH), 6.15 (d, JH,H = 13.1 Hz, 1 H, CHCOO), 4.54 (d,
3JH,H = 5.7 Hz, 2 H, CH2), 3.76 (s, 3 H, CH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 166.8, 163.9, 137.7, 137.4, 128.5, 127.7,
127.3, 125.3, 52.2, 43.5 ppm. HRMS (ESI+): calcd. for C12H14NO3
[M + H]+ 220.0968; found 220.0967; calcd. for C12H13NNaO3 [M
+ Na]+ 242.0788; found 242.0790; calcd. for C24H26N2NaO6 [2M
+ Na]+ 461.1683; found 461.1679.
2-Cyanoethyl N-Benzylmaleamate (5): Pale yellow oil; yield 68%;
Isopropyl N-Phenylmaleamate (10): Yellow oil; yield 78%; Rf 0.21
(hexanes/Et2O 1:1). H NMR (400 MHz, CDCl3): δ = 10.97 (br. s,
Rf 0.33 (CH2Cl2/EtOAc, 7:3). 1H NMR (400 MHz, CDCl3): δ =
1
3
7.59 (br. s, 1 H, NH), 7.36–7.26 (m, 5 H, Ar), 6.37 (d, JH,H
=
1 H, NH), 7.66 (m, 2 H, Ar), 7.33 (m, 2 H, Ar), 7.11 (m, 1 H, Ar),
3
3
3
12.5 Hz, 1 H, NCOCH), 6.15 (d, JH,H = 12.5 Hz, 1 H, CHCOO),
6.40 (d, JH,H = 13.3 Hz, 1 H, NCOCH), 6.16 (d, JH,H = 13.3 Hz,
1 H, CHCOO), 5.13 (sept, 3JH,H = 6.3 Hz, 1 H, CH), 1.31 (d, 3JH,H
= 6.3 Hz, 6 H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 166.3,
161.6, 140.0, 137.9, 128.9, 125.9, 124.4, 120.0, 69.9, 21.6 ppm.
HRMS (ESI+): calcd. for C13H16NO3 [M + H]+ 234.1125; found
234.1122; calcd. for C13H15NNaO3 [M + Na]+ 256.0944; found
256.0940; calcd. for C26H30N2NaO6 [2M + Na]+: 489.1994; found
489.1994.
3
3
4.49 (d, JH,H = 5.7 Hz, 2 H, Ar-CH2), 4.33 (t, JH,H = 6.4 Hz, 2
H, OCH2), 2.70 (t, JH,H = 6.4 Hz, 2 H, CH2CN) ppm. 13C NMR
3
(100 MHz, CDCl3): δ = 165.4, 163.7, 137.5, 128.7, 127.9, 127.6,
125.1, 116.5, 59.4, 43.8, 17.7 ppm. HRMS (ESI+): calcd. for
C14H15N2O3 [M + H]+ 259.1077; found 259.1073; calcd. for
C14H14N2NaO3 [M + Na]+ 281.0897; found 281.0892; calcd. for
C28H28N4NaO6 [2M + Na]+ 539.1901; found 539.1900.
Phenyl N-Benzylmaleamate (6): Colourless oil; yield 70%; Rf 0.66
4-Methoxyphenyl N-Phenylmaleamate (11): Yellow oil; yield 71%;
Rf 0.21 (hexanes/EtOAc, 3:2). 1H NMR (400 MHz, CDCl3): δ =
1
(CH2Cl2/EtOAc, 7:3). H NMR (400 MHz, CDCl3): δ = 7.98 (br.
3
s, 1 H, NH), 7.42–7.11 (m, 10 H, Ar), 6.50 (d, JH,H = 12.9 Hz, 1 10.34 (br. s, 1 H, NH), 7.62 (m, 2 H, Ar), 7.31 (m, 2 H, Ar), 7.11
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Eur. J. Org. Chem. 2010, 2600–2606

Esterification of Maleamic Acids
3
3
(m, 1 H, Ar), 7.09 (d, JH,H = 9.0 Hz, 2 H, CHar,α), 6.92 (d, JH,H CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 165.9, 163.3, 137.3,
3
= 9.0 Hz, 2 H, CHar,β), 6.58 (d, JH,H = 13.1 Hz, 1 H, NCOCH), 136.1, 130.5, 128.9, 127.9, 127.9, 52.2, 44.1 ppm. HRMS (ESI+):
6.43 (d, 3JH,H = 13.1 Hz, 1 H, CHCOO), 3.81 (s, 3 H, OCH3) ppm.
calcd. for C12H14NO3 [M + H]+ 220.0968; found 220.0965; calcd.
13C NMR (100 MHz, CDCl3): δ = 165.7, 161.3, 157.8, 143.4, 141.0, for C12H13NNaO3 [M + Na]+ 242.0788; found 242.0784; calcd. for
137.5, 134.2, 128.9, 124.8, 122.0, 120.2, 114.6, 55.6 ppm. HRMS
C24H26N2NaO6 [2M + Na]+ 461.1683; found 461.1693.
(ESI+): calcd. for C17H16NO4 [M + H]+ 298.1074; found 298.1081.
Cyanoethyl N-Benzylfumaramate (17): White solid; yield 80%; Rf
1
0.86 (CH2Cl2/EtOAc, 7:3); m.p. 126–127 °C. H NMR (400 MHz,
Methyl N-tert-Butylmaleamate (12): White powder; yield 95%; m.p.
61–62 °C; Rf 0.16 (hexanes/Et2O 1:1). 1H NMR (400 MHz,
CDCl3): δ = 7.75 (br. s, 1 H, NH), 6.24 (d, JH,H = 13.1 Hz, 1 H,
CDCl3): δ = 7.37–7.28 (m, 5 H, Ar), 6.97 (d, 3JH,H = 15.3 Hz, 1 H,
NCOCH), 6.87 (d, JH,H = 15.3 Hz, 1 H, CHCOO), 6.24 (br. s, 1
3
3
H, NH), 4.54 (d, 3JH,H = 5.6 Hz, 2 H, CH2), 4.37 (t, 3JH,H = 6.2 Hz,
2 H, OCH2), 2.74 (t, 3JH,H = 6.4 Hz, 2 H, CH2CN) ppm. 13C NMR
(100 MHz, CDCl3): δ = 164.714, 162.920, 137.335, 137.204,
129.394, 128.871, 127.962, 127.893, 116.473, 59.236, 44.114,
17.970 ppm. HRMS (ESI+): calcd. for C14H15N2O3 [M + H]+
259.1077; found 259.1077; calcd. for C14H14N2NaO3 [M + Na]+
281.0896; found 281.0901; calcd. for C28H28N4NaO6 [2M + Na]+
539.1901; found 539.1903.
3
NCOCH), 6.02 (d, JH,H = 13.1 Hz, 1 H, CHCOO), 3.76 (s, 3 H,
OCH3), 1.38 (s, 9 H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ
= 166.5, 163.2, 140.2, 123.6, 52.2, 51.4, 28.4 ppm. HRMS (ESI+):
calcd. for C9H16NO3 [M + H]+ 186.1125; found 182.1122.
2-Propyl N-tert-Butylmaleamate (13): Yellow oil; yield 94%; Rf 0.29
(hexanes/Et2O 1:1). H NMR (400 MHz, CDCl3): δ = 8.16 (br. s,
1 H, NH), 6.20 (d, JH,H = 13.1 Hz, 1 H, NCOCH), 5.99 (d, JH,H
1
3
3
3
= 13.1 Hz, 1 H, CHCOO), 5.07 (sept, JH,H = 6.5 Hz, 1 H, CH),
1.39 (s, 9 H, CH3), 1.28 (d, JH,H = 6.5 Hz, 6 H, CH3) ppm. 13C
3
Phenyl N-Benzylfumaramate (18): White solid; yield 83%; Rf 0.86
(CH2Cl2/EtOAc, 7:3); m.p. 143–144 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.41–7.03 (m, 12 H, Ar), 6.28 (br. s, 1 H, NH), 4.54
(d, 3JH,H = 5.8 Hz, 2 H, CH2) ppm. 13C NMR (100 MHz, CDCl3):
δ = 164.0, 163.1, 150.3, 137.7, 137.3, 130.0, 129.5, 128.8, 127.9,
127.8, 126.2, 121.3, 44.1 ppm. HRMS (ESI+): calcd. for
C17H16NO3 [M + H]+ 282.1124; found 282.1127; calcd. for
C17H15NNaO3 [M + Na]+ 304.0944; found 304.0951; calcd. for
C34H31N2O6 [2M + H]+ 563.2176; found 563.2185; calcd. for
C34H30N2NaO6 [2M + Na]+ 585.1996; found 585.2011.
NMR (100 MHz, CDCl3): δ = 165.8, 163.2, 140.1, 124.7, 69.1, 51.4,
28.4, 21.7 ppm. HRMS (ESI+): calcd. for C11H20NO3 [M +
H]+ 214.1438; found 214.1434; calcd. for C11H19NNaO3 [M +
Na]+ 236.1257; found 236.1254; calcd. for C22H38N2NaO6 [2M +
Na]+ 449.2622; found 449.2612.
4-Methoxyphenyl N-tert-Butylmaleamate (14): Yellow oil; yield
81%; Rf 0.35 (hexanes/EtOAc, 1:1). H NMR (400 MHz, CDCl3):
δ = 7.33 (br. s, 1 H, NH), 7.04 (d, JH,H = 9.0 Hz, 2 H, CHar,α),
1
3
3
3
6.88 (d, JH,H = 9.0 Hz, 2 H, CHar,β), 6.37 (d, JH,H = 12.7 Hz, 1
3
(2-Methoxyethoxy)ethyl N-Benzylfumaramate (19): White solid;
H, NCOCH), 6.21 (d, JH,H = 12.7 Hz, 1 H, CHCOO), 3.77 (s, 3
1
H, OCH3), 1.35 (s, 9 H, CH3) ppm. 13C NMR (100 MHz, CDCl3):
δ = 164.8, 163.1, 157.4, 143.5, 140.4, 123.6, 122.1, 114.4, 55.4, 51.6,
28.4 ppm. HRMS (ESI+): calcd. for C15H20NO4 [M + H]+
278.1387; found 278.1385; calcd. for C15H19NO4Na [M + Na]+
300.1206; found 300.1206; calcd. for C30H38N2NaO8 [2M + Na]+
577.2520; found 577.2518.
yield 83%; Rf 0.30 (CH2Cl2/EtOAc, 7:3); m.p. 42–43 °C. H NMR
3
(400 MHz, CDCl3): δ = 7.34–7.23 (m, 5 H, Ar), 6.98 (d, JH,H
=
=
3
15.3 Hz, 1 H, NCOCH), 6.95 (br. s, 1 H, NH), 6.82 (d, JH,H
3
15.3 Hz, 1 H, CHCOO), 4.49 (d, JH,H = 5.8 Hz, 2 H, CH2), 4.24
3
3
(t, JH,H = 4.8 Hz, 2 H, COOCH2CH2O), 3.68 (t, JH,H = 4.8 Hz,
2 H, COOCH2CH2O), 3.64–3.61 (m, 2 H, OCH2CH2O), 3.54–3.52
(m, 2 H, OCH2CH2O), 3.35 (s, 3 H, OCH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 165.5, 163.5, 137.4, 136.8, 129.9, 128.6,
127.8, 127.6, 71.8, 70.4, 68.9, 64.2, 58.9, 43.8 ppm. HRMS (ESI+):
calcd. for C16H22NO5 [M + H]+ 308.1492; found 308.1495; calcd.
for C16H21NO5Na [M + Na]+ 330.1311; found 330.1324; calcd. for
C32H43N2O10 [2M + H]+ 615.2912; found 615.2920; calcd. for
C32H42N2NaO10 [2M + Na]+ 637.2731; found 637.2735.
4-Bromophenyl N-tert-Butylmaleamate (15): Yellow oil; yield 87%;
Rf 0.35 (hexanes/EtOAc, 1:1). 1H NMR (400 MHz, CDCl3): δ =
7.51 (d, JH,H = 8.8 Hz, 2 H, CHar,β), 7.05 (d, JH,H = 9.0 Hz, 2 H,
CHar,α), 6.97 (br. s, 1 H, NH), 6.41 (d, JH,H = 12.6 Hz, 1 H,
NCOCH), 6.22 (d, JH,H = 12.6 Hz, 1 H, CHCOO), 1.37 (s, 9 H,
3
3
3
3
CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 164.1, 163.0, 149.1,
140.3, 132.5, 123.5, 123.2, 119.3, 51.7, 28.5 ppm. HRMS (ESI+):
calcd. for C14H17BrNO3 [M + H]+ 326.0386; found 326.0383; calcd.
for C14H16BrNNaO3 [M + Na]+ 348.0206; found 348.0202; calcd.
for C28H32Br2N2NaO6 [2M + Na]+ 673.0519; found 673.0519.
Supporting Information (see also the footnote on the first page of
1
this article): H and 13C NMR spectra.
Acknowledgments
Synthesis of Fumaramates. General Procedure: N-Benzylmaleamic
acid (200 mg) and TipbsCl (1.5 equiv.) were dissolved in anhydrous
pyridine. The mixture was stirred under Ar at room temp. for
30 min, after which the required alcohol (or phenol, 1.1 equiv.) was
added. After 12–15 h stirring at room temp., the solvent was elimin-
ated by rotary evaporation. The resulting crude product was dis-
solved in CH2Cl2 (25 mL) and washed with aq. citric acid (10%,
3ϫ50 mL) and brine (1ϫ50 mL). The organic phase was dried
with MgSO4 and the solvent was removed under vacuum. The es-
ters (16–19) were purified by silica gel column chromatography by
elution with CH2Cl2 and increasing amounts of EtOAc (up to
30%).
This work was supported by funds from the Ministerio de Ciencia
e Innovación (MICINN) (CTQ2007-68014-C02-01), and the Gene-
ralitat de Catalunya (XRB, 2009SGR208). Albert Sánchez is a re-
cipient fellow of the Generalitat de Catalunya. Technical support
from the MS and NMR facilities of the Serveis Científico Tècnics
de la Universitat de Barcelona is also acknowledged.
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Eur. J. Org. Chem. 2010, 2600–2606
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2605

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Received: November 25, 2009
Published Online: March 17, 2010
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Eur. J. Org. Chem. 2010, 2600–2606