Simple route to synthesize (E)-3-propyl-4-oxo-2-butenoic acid esters through the Z isomer

Article abstract of DOI:10.1080/00397911.2017.1390587

Esters of 3-alkyl-4-oxo-2-butenoic acid, which are very important synthons, are not equally accessible in both E and Z configurations. The (Z)-isomers can be easily obtained from 3-alkyl-4-hydroxybutenolides, in turn prepared by aminoalkylation of aliphatic aldehydes with glyoxylic acid. The (E)-isomers, on the contrary, result from laborious procedures: the condensation of aldehydes with glyoxylic acid, followed by separation from γ-hydroxybutenolide by-product and esterification, or of aldehyde enamines with glyoxylic esters, followed by Z ester by-product conversion into γ-aminobutenolide and purification. Here, we describe a straightforward route to the title compounds, applied to methyl (E)-3-propyl-4-oxo-2-butenoate, avoiding any problematic by-product or isomer chromatographic separation: pentanal and glyoxylic acid are condensed to 3-propyl-4-hydroxybutenolide, which is converted to methyl (Z)-3-propyl-4-oxo-2-butenoate and then isomerized to E ester under acidic conditions.

Full text of DOI:10.1080/00397911.2017.1390587

Synthetic Communications
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A simple route to synthesize (E)-3 propyl-4-oxo-2-
butenoic acid esters through the Z isomer
Cristiano Bolchi, Gabriella Roda & Marco Pallavicini
To cite this article: Cristiano Bolchi, Gabriella Roda & Marco Pallavicini (2017): A simple
route to synthesize (E)-3 propyl-4-oxo-2-butenoic acid esters through the Z isomer, Synthetic
Communications, DOI: 10.1080/00397911.2017.1390587
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Date: 12 November 2017, At: 11:43

A simple route to synthesize (E)-3 propyl-4-oxo-2-butenoic
acid esters through the Z isomer
Cristiano Bolchi*
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Milano, Italia
Gabriella Roda
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Milano, Italia
Marco Pallavicini
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Milano, Italia
Address correspondence to Cristiano Bolchi. E-mail: cristiano.bolchi@unimi.i
ABSTRACT
Esters of 3-alkyl-2-oxo-2-butenoic acid, which are very important synthons, are not equally
accessible in both E and Z configuration. The Z isomers can be easily obtained from 3-alkyl-4-
hydroxybutenolides, in turn prepared by aminoalkylation of aliphatic aldehydes with glyoxylic
acid. The E isomers, on the contrary, result from laborious procedures: the condensation of
aldehydes with glyoxylic acid, followed by separation from -hydroxybutenolide by-product and
esterification, or of aldehydes enamines with glyoxylic esters, followed by Z ester by-product
conversion into -aminobutenolide and purification. Here, we describe a straightforward route to
the title compounds, applied to methyl (E)-3-propyl-4-oxo-2-butenoate, avoiding any problematic
1

by-product or isomer chromatographic separation: pentanal and glyoxylic acid are condensed to
3-propyl-4-hydroxybutenolide, which is converted to methyl (Z)-3-propyl-4-oxo-2-butenoate and
then isomerized to the E ester under acidic conditions.
GRAPHICAL ABSTRACT
KEYWORDS: 3-alkyl-4-hydroxybutenolide, 3-alkyl-4-oxobutenoic acid ester, 3-
alkylbutenolide, e configuration, isomerization, z configuration
Introduction
Esters of (E)- and (Z)-3-alkyl-4-oxo-2-butenoic acid (1 and 2) and 3-alkyl substituted
butenolides (3) are very useful intermediates in organic synthesis, in particular as dienophiles and
α,β-unsaturated substrates of conjugate reduction or addition reactions giving access to either
racemic or enantiomerically enriched saturated derivatives (Figure 1).[1–6] α,β-Unsaturated--
lactones, chiral -lactones possessing a β-stereocenter and -hydroxybutenolids are constituents of
a wide number of naturally occurring and/or biologically active compounds.[3,7,8]
A vast literature has focused on the preparation of 3 and great attention has been devoted
to a condensation/reduction strategy to make it ready available.[3,9–11] Aldol condensation of
glyoxylic acid with aliphatic and cyclic ketones provides α-hydroxy--oxo carboxylic acids and -
oxo-α,β-unsaturated carboxylic acids,[12] but it is virtually unsuccessful with aliphatic aldehydes
2

mainly because of self-aldolization. On the other hand, G.G. Wermuth has reported that Mannich-
type aminoalkylation of enolizable aldehydes with equimolar glyoxylic acid and morpholine
hydrochloride, namely under acidic conditions, directly affords -hydroxybutenolides 4 in high
yields suggesting a mechanism involving the spontaneous elimination of morpholine from the
corresponding α-morpholino--hydroxybutanolides (Figure 2).[13] As more recently reported,
piperidine hydrochloride can be used in place of morpholine hydrochloride.[3,13]
-Hydroxybutenolides 4 are easily converted into 3 by reduction with sodium
borohydride[3,14,15] or into Z methyl or ethyl esters 2 by treatment with a base and methyl iodide or
triethyloxonium tetrafluoborate respectively.[6,16]
More problematic is to obtain E esters 1. Indeed, aldol condensation of glyoxylic acid with
an aliphatic aldehyde in basic medium gives the corresponding E α,β-unsaturated -oxo carboxylic
acid, but besides the undesired -hydroxy butenolide 4 and, as previously underlined, large amount
of self-condensed aldehyde.[17] Therefore, although the E acid can be isolated from the other
products and easy converted into ester 1, the procedure is inefficient. However, according to A.
Guingant, formation of 4 and self-aldolization can be avoided by condensation of glyoxylic esters
with aliphatic aldehydes morpholinenamine, followed by acid treatment.[17] The resulting mixtures
of E and Z esters, with 1 as a major component and 2 as a minor component, are not resolvable by
chromatography and neither by distillation, as elsewhere reported.[18] Nevertheless, if neutral,
instead of acidic, conditions are adopted for the final hydrolysis, the Z isomers are quantitatively
converted into -morpholinobutenolides and the unchanged E isomers can be recovered from the
(E)-1/morpholinobutenolide mixture by chromatography.
Results and Discussion
3

It is evident that the reported routes to esters 1 or to their acid precursors are penalised by
the side formation of 4 or of 2, which has to be converted into butenolides to allow the separation
from 1. Therefore, we planned an alternative strategy to obtain 1, relying on the isomerization of
readily accessible 2 to 1 rather than on its discharge as an undesired by-product through conversion
into butenolides. Such Z to E isomerization is not described for the 4-oxo-2-butenoic acid esters
having an alkyl substituent at C(3). Instead, it is reported for the unsubstituted 4-oxo-2-butenoic
acid ester: maleinaldehydic acid methyl ester is quickly and quantitatively converted to
fumaraldehydic acid methyl ester by light exposure in the presence of traces of iodine or by acidic
catalysis.[19] We thus decided to verify whether 2, in particular the methyl ester of (Z)-3-propyl-4-
oxo-2-butenoic acid 2a, can be quantitatively isomerized to 1a (Alk = n-propyl). If so, a unique
straightforward way would be followed to prepare all the three compounds, butenolide and E and
Z -oxo-α,β-unsaturated esters. From glyoxylic acid and pentanal we would be able to prepare, in
the order, 4a, 3a, 2a and, above all, 1a (Scheme 1).
The condensation of glyoxylic acid with valeraldehyde was accomplished by treatment
with little more than stoichiometric piperidine hydrochloride in boiling dioxane/water. At variance
with literature reports, simple extraction procedures allowed pure -hydroxybutenolide 4a to be
recovered in 55% yield without chromatographic separation. In fact, by-products were removed
by washing the reaction mixture, previously diluted with 2 M aqueous HCl, with diisopropyl ether
and 4a was successively extracted with dichloromethane. The subsequent reduction of 4a with
sodium borohydride in methanol afforded 3a in quantitative yield, while 2a was obtained from 4a
by treatment with NaH and CH3I in HMPA in 82% yield after chromatographic purification. The
same reaction, accomplished with NaH and CH3I in DMSO, quantitatively afforded a 7/5 mixture
of 2a and 1a, which was directly converted into pure 1a by stirring in dichloromethane at room
4

temperature for 1 hour in the presence of few millilitres of 4 M HCl dioxane solution. No
conversion into 1a was observed by light exposure in the presence of iodine. The isomerization of
2a to 1a could be easy monitored by TLC, where 2a gives, under 1/1 cyclohexane/DCM elution,
a slow running spot, completely separated from the faster running spot of 1a. Furthermore, the two
isomers could be clearly distinguished and relatively quantified, when in mixture, by H NMR
spectroscopy on the basis of the aldehyde proton resonance. Consistently with what is reported in
the literature for the Z and E isomers of the analogous 3-methyl, 3-ethyl and 3-isopropyl substituted
4-oxo-2-butenoates,[17,20] the Z aldehyde proton resonance appears, as expected, downfield relative
to the resonance frequency of the E isomer. In particular, the chemical shifts of the aldehyde proton
singlet of 2a (10.56 δ) and of 1a (9.50 δ) are the same reported, respectively, for the Z and E isomer
of the 3-isopropyl substituted analogue.[17]
The acid catalysed isomerization in dichloromethane successfully completed the synthetic
sequence opening a direct and simple route to esters 2, otherwise poorly available and through
laborious procedures. Furthermore, the esterification in DMSO allowed us not only to avoid the
use of HMPA but also to accomplish the Z to E isomerization on a mixture containing a
considerable percentage of E isomer in advance. In case of large-scale preparation of 2 from 4,
HMPA must be obviously replaced by another solvent, which will be selected depending on the
3-alkyl substituent and the chosen esterifying R group. Conversion of -hydroxybutenolides into
Z esters under conditions different for reagents and solvent is fairly exemplified in literature.[6,8,21–
24] Trimethyloxonium tetrafluoborate and NaH in THF under anhydrous conditions are not the only
alternative; iodomethane and bases, such as DIPEA or potassium carbonate, in dipolar aprotic
solvents, such as DMSO, DMF or aceton, are widely used. Furthermore, for the other reactions,
undesirable solvents, such as dioxane, DCM and di-isopropyl ether, whose substitution is advisable
5

or requested, could be replaced by ‘green’ ethers (MeTHF, TAME, CPME) according to the
continuously updated suggestions of the current solvent selection guides.
Conclusions
In summary, we have developed a straightforward route from ready available glyoxylic
acid and pentanal to both the E and Z isomers of 3-propyl-4-oxobutenoic acid methyl ester, which
are very useful synthetic intermediates. In order to avoid laborious and inefficient isomers
separations, we exploited the much easier accessibility of the Z isomer of this kind of esters from
the corresponding 4-hydroxybutenolides and tried subsequent isomerization to E form. According
to such an approach, we first prepared methyl (Z)-3-propyl-4-oxobutenoate and then quantitatively
isomerized it to E butenoate. By this simple way, we succeeded in making the E isomer, otherwise
arduous to synthesize, as available as the Z isomer.
Experimental
3-Propyl-4-hydroxybutenolide (4a)
Glyoxilic acid monohydrate (4.55 g, 49.42 mmol) and piperidine hydrochloride (6.30 g,
51.80 mmol) were added to a solution of pentanal (5 mL, 47.02 mmol) in 7/1 dioxane/water (25
mL) under nitrogen. The mixture was heated at reflux for 18 h and, after cooling to room
temperature, diluted with 2 M HCl (100 mL) and extracted with diisopropyl ether (330 mL). The
first extract was discharged, while the other two were combined and extracted with 2 M HCl (330
mL). These three acidic extracts were combined with the reaction mixture, which had been
previously diluted 2 M HCl and washed with diisopropyl ether, and the whole aqueous layer was
extracted with DCM (380 mL). The DCM were concentrated to give 4a (3.68 g, 55%) as an oil.
6

1H NMR (300 MHz, CDCl3) δ 6.00 (s, 1H), 5.84 (t, J = 1.8 Hz, 1H), 4.65 (bs, 1H, exchange with
D2O), 2.25-2.52 (m, 2H), 1.52-1.77 (m, 2H), 1.00 (t, J = 7.6 Hz, 3H). 13C NMR (75 MHz, CDCl3)
δ 172.3, 170.3, 117.2, 99.4, 29.6, 19.9, 13.7. Anal. Calcd for C7H10O3: C, 59.14; H, 7.09. Found:
C, 58.98; H, 7.13.
3-Propylbutenolide (3a)
Sodium borohydride (2.0 g, 52.86 mmol) was portionwise added to a solution of 4a (3.62
g, 25.47 mmol) in methanol (50 mL). After stirring at room temperature for 1 h, the reaction
mixture was concentrated and 2 M HCl (100 mL) was added. The aqueous phase was extracted
with DCM (40 mL). The organic extract was dried over Na2SO4 and concentrated to give 3a in
quantitative yield as an oil. 1H NMR (300 MHz, CDCl3) δ 5.83 (s, 1H), 4.73 (s, 2H), 2.38 (t, J =
13
7.6 Hz, 2H), 1.55-1.70 (m, 2H), 1.00 (t, J = 7.0 Hz, 3H). C NMR (75 MHz, CDCl3) δ 172.3,
170.3, 117.2, 99.4, 29.6, 19.9, 13.7. Anal. Calcd for C7H10O2: C, 66.65; H, 7.99. Found: C, 66.48;
H, 8.03.
Methyl (Z)-3-propyl-4-oxo-2-butenoate (2a)
A solution of 4a (10 g, 70.35 mmol) in HMPA (40 mL) was added dropwise to a suspension
of sodium hydride (1.69 g, 70.35 mmol) in HMPA (40 mL) at 0 °C. After stirring at 0 °C for 1 h,
iodomethane (6.6 mL, 105.53 mmol) was added dropwise. The mixture was stirred at room
temperature for 15 min and then cooled to 0 °C again. Water (100 mL) was slowly added and the
resulting solution was extracted with diethyl ether (380 mL). The organic extracts were dried
over Na2SO4 and concentrated. The resultant residue was purified by chromatography on silica gel
(petroleum ether/ethyl acetate 95/5) to give 2a (8.96 g, 82%) as an oil. 1H NMR (300 MHz, CDCl3)
δ 10.56 (s, 1H), 6.47 (t, J = 1.2 Hz, 1H), 3.80 (s, 3H), 2.30 (td, J = 7.6, 1.2 Hz, 2H), 1.47 (sextet,
7

J = 7.6 Hz, 2H), 0.93 (t, J = 7.6 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 193.0, 165.3, 154.0, 129.2,
52.1, 32.4, 21.3, 13.7. Anal. Calcd for C8H12O3: C, 61.52; H, 7.74. Found: C, 61.40; H, 7.78. The
above procedure was repeated by replacing HMPA with DMSO: 4a (10 g, 70.35 mmol) was
converted into a 7/5 mixture (10.64 g, 97%) of 2a and 1a, which was directly used in the
subsequent isomerization step without chromatographic purification.
Methyl (E)-3-propyl-4-oxo-2-butenoate (1a)
A 4 M solution of HCl in dioxane (5 mL) was added to a solution of a 7/5 mixture of 2a/1a
(10.64 g, 68.12 mmol) in DCM (80 mL). After stirring for 70 min, DCM (70 mL) was added and
two washings were performed with saturated aqueous Na2CO3 solution (250 mL). The organic
phase was dried over Na2SO4 and concentrated. The residue was distilled in a Kugelrohr apparatus
(60 °C, 0.3 mbar) to give 1a (7.86 g, 74%) as an oil. 1H NMR (300 MHz, CDCl3) δ 9.50 (s, 1H),
6.46 (s, 1H), 3.81 (s, 3H), 2.66 (t, J = 7.6 Hz, 2H), 1.44 (sextet, J = 7.6 Hz, 2H), 0.92 (t, J = 7.6
Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 194.4, 165.7, 154.8, 134.9, 51.9, 26.6, 22.1, 14.1. Anal.
Calcd for C8H12O3: C, 61.52; H, 7.74. Found: C, 61.39; H, 7.77.
1
Supporting Information: H and 13C NMR spectra. This material can be found via the
“Supplementary Content„ section of this article’s webpage.
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Figure 1. 3-Alkyl substituted 4-oxobutenoic acid esters and butenolides.
10

Figure 2. Reaction pathway proposed for the glyoxylic acid-aliphatic aldehyde condensation to 4
in the presence of morpholine under acidic conditions.
11

Scheme 1. Reaction conditions: (a) piperidine hydrochloride, dioxane/water, reflux, 18 h; (b)
NaBH4, methanol, rt, 1 h; (c) NaH, CH3I, HMPA, rt, 15 min; (d) HCl in dioxane/DCM, rt, 70
min (from 2a prepared in DMSO rather than in HMPA).
12