Exploration of the Differences between Amine and Thiolate Addition to Acetylenedicarboxylates

Article abstract of DOI:10.1021/acs.joc.9b01392

Nucleophilic addition of thiolates to diethyl acetylenedicarboxylate in chloroform at room temperature affords solely the meso dithioaddition product, whereas the addition of amines in ethanol gives only the corresponding (Z)-enamine, as confirmed by X-ra

Full text of DOI:10.1021/acs.joc.9b01392

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Article
Exploration of the Differences Between Amine
and Thiolate Addition to Acetylenedicarboxylates
Robyn L Crumbie, Gareth Chalmers, Mohan Bhadbhade, and Renate Griffith
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01392 • Publication Date (Web): 16 Oct 2019
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Exploration of the Differences Between Amine and Thiolate Addition to
Acetylenedicarboxylates
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Robyn L. Crumbie*§, Gareth Chalmers§, Mohan Bhadbhade ∫ and Renate Griffith*∫
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§
School of Science and Health, Western Sydney University, Locked Bag 1797, Penrith
NSW 2751, Australia
R.Crumbie@bigpond.com
∫ School of Chemistry, UNSW Australia, Sydney NSW 2052, Australia
R.Griffith@unsw.edu.au
Table of Contents/Abstract Graphic
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Abstract
Nucleophilic addition of thiolates to diethyl acetylenedicarboxylate in chloroform at
room temperature affords solely the meso dithioaddition product, whereas the addition of
amines in ethanol gives only the corresponding (Z)-enamine, as confirmed by X-ray
crystal analysis. The monoaddition product of thiolate addition, prepared and isolated at
lower temperatures, also exhibited (Z)-stereochemistry. The accompanying
computational study on simplified model systems explains the reasons for the observed
stereochemistry and why the acetylene dicarboxylate readily undergoes two addition
reactions with thiolate nucleophiles, whereas the (Z)-enamine is much less reactive
towards addition of thiolate or amine nucleophiles.
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Introduction
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The conjugate addition of primary amine and thiolate nucleophiles to diesters of
acetylene dicarboxylic acid has been known for many years.1,2 The reaction has
occasionally been used in the synthesis of amino3,4 and thio1 heterocycles but has to our
knowledge not been used as the first step in the synthesis of multifunctional acyclic
compounds.
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This reaction was potentially useful in the synthesis of some complex targets in which we
were interested, however several questions needed to be addressed. The first was
stereochemistry. The addition of one equivalent of nucleophile affords an alkene.
Reactions described in the earlier literature usually reported mixtures of isomers and
there was considerable discussion regarding the mechanism of addition and why mixtures
were obtained.5 The stereochemistry of the products was determined by IR,6 dipole
moment7 and by 1H NMR.8,9 However, the only stereochemically significant signal in the
NMR spectra was the single alkene singlet, so that if reaction conditions could be chosen
such that a single stereoisomer were obtained, stereochemical determination by routine
NMR alone would be more difficult. Therefore, we wished to confirm the
stereochemistry of the monoaddition and diaddition products by X-ray crystal structure. It
should be noted that the earlier literature is pre-Z,E nomenclature, and although Huisgen
defined cis and trans for his trisubstituted alkenes,7 it is not at all clear that the authors of
some subsequent papers were aware of this definition. It was clear, however, that the
nature of the product(s) was dependant on the reaction conditions, particularly the
solvent,10,11 and Sarrafini and co-workers12 have more recently reported the stereospecific
addition of thiols and secondary amines in water in the presence of potassium carbonate.
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Unfortunately, their attempted reaction with primary amines “did not give satisfactory
results”. Solvent-free reaction of primary amines with DEAD (diethyl
acetylenedicarboxylate) was found to often give the (Z)-isomer, but not in all cases.13
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The second issue needing clarification was the reaction pathway. To our knowledge,
there is only one example in the literature of addition of two equivalents of amine to the
acetylene dicarboxylate.14 The paper gives a general experimental method, and there are
no stated changes to the general reaction procedure for this one purported example of
diaddition. By contrast, the addition of two equivalents of thiolate in chloroform15 leads
to diaddition, although recent examples carried out in water use one equivalent and give
monoaddition only.12
Results and Discussion
Experimental Results
Diethyl acetylenedicarboxylate (DEAD) was treated with thiols15 and amines14 under
literature conditions. In each case a single stereoisomer was isolated, usually in good
yield (1–7, 9, 10). The exception was diethyl 2,3-bis(4’-hydroxyphenylthio)succinate 8,
which was obtained in only 24% yield. We suggest that the low yield may be due partly
to the presence of other nucleophilic sites in the reactant, but probably mostly to the
insolubility of the product in both chloroform and water, the solvents used in our general
method. This meant that the product, a white solid, was suspended in both the aqueous
and organic layers during the initial extraction, and although it was subsequently
extracted from the aqueous phase with ethyl acetate, product was certainly lost. Since
enough of the product was obtained for our subsequent investigations, the reaction was
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not repeated with a different workup procedure. The reaction conditions and yields for
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the synthesis of compounds 1-11 are summarised in Figure 1.
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Figure 1. Reaction conditions and yields for
the synthesis of 1-11.
1
The H NMR spectra of the diaddition products from reactions using the thiolate
nucleophile (1-8) were as expected. The methylene ester protons in the benzylic adducts
2, 4 and 7 were seen to be non-equivalent and the methyne protons adjacent to the
carbonyl groups and sulphur lay in the range of  3.51 to  4.00, dependant on the
sulphide substituent. All products gave good high resolution mass spectra for [M+H]+ or
[M+Na]+.
Monoaddition of the thiolate was achieved by conducting the reaction at -40oC with
subsequent workup at 0oC (Figure 1, conditions and yield for 11). Reactions at higher
temperatures gave mixtures of starting materials and diaddition product, with very little if
any monoaddition product by 1H NMR spectroscopy. The signal from the vinyl proton of
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the chlorobenzythiofumarate 11 was found at  6.36, analogous to the thiofumarates
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prepared by Sarrifini.12
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As described in the literature (with the single exception mentioned previously), reaction
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with the amine nucleophiles afforded only the monoaddition products (Figure 1,
conditions and yields for
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and 10). The 1H NMR spectrum of the
bromophenylaminofumarate 10 was in accord with the published literature,13,16 and that
of the chlorophenylaminofumarate 9 was analogous to the data published for the dimethyl
ester analogue.7 The three monoaddition products 9, 10 and 11 also gave good high
resolution mass spectra for [M+H]+.
Stereochemistry
X-ray crystal structures were obtained for diethyl 2-(4’-chlorobenzythio)fumarate 11 and
diethyl 2-(4’-chlorophenylamino)fumarate 9 as representatives of the monoaddition
products. Both products had (Z)-stereochemistry, with the ester functional groups trans
to each other. An x-ray crystal structure was also obtained for diethyl 2,3-bis(4’-
methylphenylthio)succinate 5 as representative of the dithioaddition products. The
compound was found to have meso (RS)-stereochemistry with the two sulphide groups
anti to each other. Thermal ellipsoid plots of the crystal structures are provided in the
supporting information.
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Reaction Pathways
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Amines and thiolates are both good nucleophiles so the difference in their reactivity with
acetylene dicarboxylates under standard conditions was intriguing. The difference in the
reactivity of amino and thiolate nucleophiles with the alkene intermediates was
investigated experimentally by varying the reaction conditions as shown in Table 1. It is
to be noted that in reactions with amines, more forcing conditions gave more degradation
and lower recovery of the monoaddition product. The fact that the thiolate did not react
with the enamine or the amine with the thioalkene was unexpected.
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Table 1: Attempted Synthesis of Diamino and Mixed Diaddition Products
Temperature
(oC)
Result
Time
(days)
Alkene
Nucleophile
Solvent
4-bromo
benzenethiolate
CHCl3 with
TEA
no reaction
no reaction
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0
0
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2
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CHCl3 with
TEA
4-bromoaniline
4-bromoaniline
4-bromoaniline
4-bromoaniline
starting material +
degradation only
THF
reflux
reflux
0
starting material +
degradation only
toluene
CHCl3 with
TEA
no reaction
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Computational Study and Discussion
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Simplified model compounds were investigated. Phenyl thiolate was used as the sulphur
nucleophile and aniline as the nitrogen containing nucleophile. Dimethyl
acetylenedicarboxylate (DMAD) was used. Cis and trans nomenclature is used for clarity
and refers to the relative position of the ester groups.
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Unless otherwise indicated, energy values are Gibbs free energy values (Go in kcalmol-1)
obtained after a final geometry optimisation at DFT level (ωB97X-D/6-31G*)17 in a C-
PCM implicit solvent model18,19, followed by calculation of the IR spectra and
thermodynamic quantities as implemented in the Spartan software (wavefun.com). These
values are provided in the supporting information.
As expected, all transition states show a high intensity imaginary frequency which, when
animated, resonates along the proposed reaction coordinate.
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Table 2: Imaginary Frequencies in Model Compounds
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Relative
Intensity
Compound
-ʋ (cm-1)
N transition state 1
N transition state 2
meso di-N product
S transition state 1
284 i
257 i
15 i
1.00
1.00
>0.50 x 10-5
0.48
218 i
182 i
25 i
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S transition state 2
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S dianion
cis mixed diproduct
mixed dianion
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7 i
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193 i
37 i
1.00
mixed transition state 2
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0.33 x 10-2
27 i
Table 2 provides these transition state imaginary frequencies, as well as a number of
additional, unexpected imaginary frequencies. We were not able to change the geometries
of these structures to avoid those extra imaginary frequencies. However, they are in all
cases small in terms of wavenumber (<40 cm-1) and intensity. These problems occur in
three sulphur containing compounds, and in one of the two largest nitrogen containing
compounds and in two sulphur containing transition states more than one imaginary
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frequency is observed. We propose that they are not physical but rather are the result of
numerical inaccuracies as suggested in the user manual of the Spartan software.
Kleingeld et al.20 investigated numerical accuracy of different DFT methods including
ωB97X-D/6-31G(d) for coordination complexes of fullerene and proposed that the very
small imaginary frequencies obtained (<17 cm-1) could be the result of small numerical
errors.
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Stereochemistry
Our computational studies showed that the lowest energy conformers did not have both
carbonyl groups coplanar with the S substituted alkene in either diastereomer. Structures
A and B in Figure 2 show the two thioalkene diastereomers in the lowest energy
conformations that were identified. The cis isomer was 6.7 kcalmol-1 higher in energy.
This modest difference together with a variety of low energy conformers with various
combinations of π–bond overlap with no substantial energy differences, add evidence that
the observed sole formation of the trans product (11) is due to a trans addition mechanism
rather than thermodynamic considerations. The lowest energy conformation in the trans
thioalkene came closest to having both carbonyl groups coplanar with the alkene whilst
the cis thioalkene was severely twisted, with the two carbonyl groups perpendicular.
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A
B
Figure 2: The lowest energy conformations of the model compounds of the cis (A) and
trans (B) thiolate monoaddition products. Elements are colour-coded: C-grey, O-red, S-
yellow and H-white.
A
B
Figure 3: The lowest energy conformations of the model compounds of the meso (A) and
(RR) (B) thiolate diaddition products. Elements are colour-coded: C-grey, O-red, S-
yellow and H-white.
The second trans addition of the thiolate could lead to the racemic mixture [(RR) and
(SS) diastereomers] or solely the meso (RS) product. Computations showed that the (RR)
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diastereomer exhibited substantial electronic repulsion in all conformations, whereas the
lowest energy conformation of the meso diastereomer showed the two sulphide groups
anti to each other (Figure 3). Despite this, the meso form is only 3.1 kcalmol-1 lower in
energy. However, this difference in energy for our model compounds appears to be
enough to account for the sole formation of the all trans meso product we observed for
the more complex compound 5.
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Our calculations indicated the two enamines were of similar energy and again, none of
the lowest energy conformations had the alkene coplanar with both carbonyl groups. The
trans isomer exhibited different modes of hydrogen bonding in all its lowest energy
conformations with resultant stabilising 5- and 6-membered rings (Figure 4 A). The
lowest energy conformations of the cis isomer contained no hydrogen bonds and hence
no resultant ring structures (Figure 4 B). Despite the hydrogen bonding, the trans isomer
was only 3.1 kcalmol-1 lower in energy. Again, this adds evidence that the observed sole
formation of the trans products (9 and 10) is due to a trans addition mechanism rather
than thermodynamic considerations.
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A
B
Figure 4: The lowest energy conformations of the model compounds of the trans (A) and
cis (B) enamine products. Elements are colour-coded: C-grey, O-red, N-blue and H-
white. The green dashed line in A indicates a hydrogen bond.
The aniline diaddition products were never formed in our hands, and it is interesting to
note that the (RR) product was more stable than the meso product by 3.5 kcalmol-1. This
can probably be attributed to favourable electronic interactions (distorted hydrogen
bonds), which have been indicated by green lines in Figure 5 A.
A putative mixed addition product resulting from attack of a thiolate on the enamine
(which was also not observed), also showed a more stable cis configuration (by 1.7
kcalmol-1), which can again be attributed to favourable electronic interactions (Figure 5
B).
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A
B
Figure 5: The lowest energy conformation of the model compounds of the putative (RR)
aniline diaddition product (A) and of the mixed addition product (B). Elements are
colour-coded: C-grey, O-red, N-blue S-yellow and H-white. The green lines indicate
favourable electronic interactions, with the distances provided in Å.
Reaction Pathways
Previous workers have stated that the thioalkene is formed by trans addition of the
thiolate nucleophile, and the dithio product formed from a second trans addition.5 The
idea that the enamine resulting from monoaddition of amine to DEAD is formed via cis
addition to afford initially the (E) product (ester groups cis), but this product
subsequently rearranges to the (Z) product (ester groups trans) is unusual,5 and we did not
find any experimental evidence for the (E) product. As described in the previous section,
the energies differences between cis and trans adducts were moderate to small, thus
adding evidence for trans addition. We therefore modelled all additions as trans additions
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and were able to construct all transition states with satisfactory geometries. The transition
states for the two monoadditions are shown in Figure 6. The aniline transition state is
stabilized by a hydrogen bond.
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Figure 6: Monoaddition transition states. Colours and symbols as in previous figures.
Newly formed bonds indicated by thin, black lines.
The monoaddition of aniline to DMAD is summarized on the left in Scheme 1. This is the
same, stepwise reaction mechanism via a zwitterionic intermediate as proposed by Gurjar
et al.21 for the addition of dimethylamine, pyrrolidine, and benzylamine to DMAD. Our
calculations show a zwitterionic product from a trans attack of aniline that was only 11
kcalmol-1 lower in energy than the transition state, and a barrier of 20 kcalmol-1 between
the reactants and the transition state. The trans enamine product was 43 kcalmol-1 lower
in Gibbs free energy than the starting materials. We propose that the zwitterion will
quickly rearrange to the final trans enamine, which is 52 kcalmol-1 more stable than the
zwitterion.
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Gurjar et al. report activation energies of around 13 kcalmol-1 in toluene and exothermic
ΔH0 values of 29 to 44 kcalmol-1. Table 3 provides our H0 values for comparison. These
were obtained in an implicit polar solvent model to mimic our reaction conditions
(ethanol as a solvent). The activation energy for our model reaction is 7 kcalmol-1, and
the exothermic ΔH0 is 58 kcalmol-1. These values are in excellent agreement with the
values obtained by Gurjar et al., considering the different solvent conditions and different
amines modelled.
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Table 3. H0 values for selected model compounds
-1
o
Compound
DMAD
-H (kcalmol )
334320
aniline
180340
N transition state 1
zwitterion 1
trans enamine
514653
514665
514718
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Scheme 1: The monoaddition reactions of aniline and the thiolate anion to DMAD. All
energies are Gibbs free energy (Go) values.
The monoaddition of the phenyl thiolate nucleophile to DMAD is also summarized in
Scheme 1. Our calculations show the alkene anion product 12 kcalmol-1 lower in energy
than the transition state with a barrier of only 7 kcalmol-1 and the final uncharged trans
alkene product 40 kcalmol-1 lower than the starting materials. The reaction conditions
(catalytic amounts of triethylamine in dry, ethanol-free chloroform) allow for the
presence of the much more nucleophilic thiolate, which we have used in the calculations,
despite its higher energy (by 295 kcalmol-1). The alkene anion is 329 kcalmol-1 higher in
energy than the uncharged, trans alkene and we suggest that it will quickly pick up a
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proton. The proposed diaddition reactions are summarized in Scheme 2 and the proposed
transition states are shown in Figure 7.
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A
B
C
Figure 7: Proposed diaddition transition states. Colours and symbols as in previous
figures.
Modelling of the attack of aniline to the enamine showed a barrier of 32 kcalmol-1. We
propose that this barrier is higher than the one for the rearrangement of the intermediate
zwitterion to the uncharged product and that this high barrier explains why the addition of
an amine nucleophile to an enamine never proceeded in our hands. In addition, the
calculated reaction would be only just exothermic with G0 of 0.8 kcalmol-1 overall and
the energy of the product anion (zwitterion 2) is only 1.3 kcalmol-1 lower than the
transition state.
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Scheme 2: Diaddition reactions. All energies are Gibbs free energy (Go) values.
The reaction depicted on the right of Scheme 2 was also attempted. Our calculations
predicted a high barrier of 29 kcalmol-1 and an overall endothermic reaction, explaining
why this reaction did also not proceed in our hands.
The addition of further phenyl thiolate nucleophile to the alkene 2 is summarized in the
middle of Scheme 2. This is the only diaddition reaction we observed, and it proceeded
rapidly in our hands. This reaction has a modest barrier of only 16 kcalmol-1, although the
energy difference between the transition state and the initial product formed in this
reaction sequence, i.e. the diadduct anion, was only 4 kcalmol-1. Again, we propose that
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the anion will easily be able to pick up a proton to form the final product. The overall
reaction was predicted to be exothermic (by 7 kcalmol-1).
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The frontier orbitals (HOMO and LUMO) of the trans alkenes were also examined. As
shown in Table 4, the HOMO and the LUMO of the enamine were higher in energy,
which is consistent with the lower reactivity of this compound towards nucleophiles.
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Table 4: Frontier orbital details for the model alkenes.
E LUMO
(eV)
E HOMO
(eV)
Bandgap
(eV)
Compound
enamine
0.19
0.01
-7.75
-8.35
7.94
8.36
thioalkene
The LUMO maps, where the absolute LUMO values are mapped onto the electron
density surface, also show small differences between the two alkenes (Figure 8). The
LUMO value on the carbon to be attacked by a nucleophile (right hand carbon) is higher
for the thioalkene (Figure 8 A; 0.0300 versus 0.0254).
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A
B
Figure 8: LUMO maps of the thioalkene (A) and the enamine (B). Absolute LUMO
values are mapped onto electron density surfaces and colour coded from red (low)
through orange, yellow and green to aqua and blue (high).
Conclusions
The molecular modelling calculations are able to explain the observed trans and meso
stereochemistry of the products. The trans and meso forms of the observed products are
always lower in energy than cis or racemic products. However, the differences are not
large and for the monoadditions this strongly suggests a trans addition mechanism.
The calculations provide plausible explanations for the facile diaddition of thiolate
nucleophiles to acetylenedicarboxylates and for the failure of amines and thiolates to add
to the enamine monoaddition products: the enamine is less reactive (lower LUMO
coefficient; less stable LUMO) than the thioalkene and the barriers for the addition of the
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second nucleophile to the enamine are much higher than for a second addition to the
thioalkene.
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Experimental
General Procedures
All solvents used were of AR grade and, where appropriate, were dried by the following
techniques: THF, benzene and toluene were heated under reflux over sodium metal for 1
hour and were then distilled. Ethanol-free chloroform was obtained by washing
commercially available chloroform with water and drying over barium oxide or passing
the solvent though a neutral alumina column, then distillation. All amines and thiols
were purified by recrystallization or distillation before use, except
4
hydroxybenzenethiol, which was supplied by the manufacturer as 90%. We were unable
1
to determine the nature of the impurities from the manufacturer’s website or H NMR
spectroscopy. TEA was dried over barium oxide and used without further purification.
Melting points were measured in capillary tubes and are uncorrected. High resolution
mass spectra were obtained using a Qtof spectrometer in ESI mode. Prior to analysis
instrument was externally calibrated with a solution of 1 mg/mL cesium iodide (CsI) over
the m/z acquisition range. 100-1000.
General Procedure for the Synthesis of Diethyl 2,3-Bis(phenylthio)succinate and
Analogous Compounds 1-815
Diethyl acetylenedicarboxylate (0.5 g, 2.94 mmol) was added over 30 min to a cooled
stirred solution of the selected thiol (5.88 mmol) in dry, ethanol-free chloroform (10 mL)
containing 2 drops of triethylamine at -10 oC. After addition, the solution was stirred at -
20 oC for 48 h. The solvent was removed under reduced pressure at 0 oC. The residue was
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washed with ether at 0 C to yield the desired product. A sample was then recrystallised
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from ethanol for spectral analysis.
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Diethyl 2,3-Bisphenylthiosuccinate 1
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The product was washed with ether to yield white prisms (0.90 g, 78%), mp 76-77 oC. 1H
NMR (300 MHz, CDCl3):  1.18 (t, 6H, J = 7.1); 3.92 (s, 2H); 4.16 (q, 4H); 7.40 (m,
10H). 13C NMR {1H} (75 MHz, CDCl3):  14.0;  52.0;  61.5;  128.9;  129.0; 
131.9;  134.2;  169.2. HRMS (ESI) calcd for [M+H]+ C20H23O4S2 391.1038, found
391.1057.
Diethyl 2,3-Bis(phenylmethanethio)succinate 2
o
The product was washed with ether to yield white prisms (0.98 g, 80%), mp 113 C
o
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(range < 1 C). H NMR (300 MHz, CDCl3):  1.23 (t, 6H, J = 7.0);  3.60 (s, 2H); A
13
3.87, B 3.84 (qAB, 4H, J = 12.8);  4.15 (m, 4H);  7.28 (m, 10H). C NMR {1H} (75
MHz, CDCl3):  14.0;  36.6;  47.3;  61.5;  127.4 ; 128.5 ;  129.2 ;  136.8 ; 
169.8. HRMS (ESI) calcd for [M+H]+ C22H27O4S2419.1351, found 419.1354.
Diethyl 2,3-Bis(4’-methoxyphenylthio)succinate 3
The product was washed with ether to yield white prisms (1.04 g, 79%), mp 109oC (range
o
1
< 1 C). H NMR (300 MHz, CDCl3):  1.25 (t, 6H, J = 7.0);  3.72 (s, 2H,);  3.79 (s,
6H);  4.19 q, 4H); A 6.82, B 7.37 (qAB, 8H, J = 9.0). 13C NMR {1H} (75 MHz,
CDCl3):  14.0;  51.8;  55.3;  61.4;  114.5;  121.5;  137.23;  160.7;  169.2.
HRMS (ESI) calcd for [M+Na]+ C22H26O6NaS2 473.1069, found 473.1084.
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Diethyl 2,3-Bis(4’-methoxyphenylmethanethio)succinate 4
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The product was washed with ether to yield white prisms (1.03 g, 73%), mp 122-123oC.
1H NMR (300 MHz, CDCl3):  1.25 (t, 6H, J = 7.1);  3.59 (s, 2H);  3.78 (s, 6H); A
3.80, B 3.84 (qAB, 4H, J = 12.6);  4.17 (m, 4H,); A 6.82, B 7.19 (qAB, 8H, J = 8.8).
13C NMR {1H} (75 MHz, CDCl3):  13.8;  35.8;  47.1;  55.0;  61.2;  113.6; 
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128.5;  130.1;  158.6;  169.7. HRMS (ESI) calcd for [M+H]+ C24H31O6S2 479.1562,
found 479.1571. HRMS (ESI) calcd for [M+Na]+ C24H30O6NaS2 501.1382, found
501.1402.
Diethyl 2,3-Bis(4’-methylphenylthio)succinate 5
The product was washed with ether to yield white prisms (0.96 g, 78%), mp 110-111oC.
1H NMR (300 MHz, CDCl3):  1.21 (t, 6H, J = 7.1);  2.32 (s, 6H);  3.81 (s, 2H); 
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4.17(m, 4H); A 7.10, B 7.33 (qAB, 8H, J = 7.8). C NMR {1H} (75 MHz, CDCl3): 
14.0;  21.3;  51.9;  61.4;  127.9;  129.8;  134.8;  139.3;  169.2. HRMS (ESI)
calcd for [M+H]+ C22H27O4S2 419.1351, found 419.1344.
Diethyl 2,3-Bis(4’-chlorophenylthio)succinate 6
The product was washed with ether to yield white prisms (0.92 g, 68%), mp 120-121oC.
1H NMR (300 MHz, CDCl3):  1.23 (t, 6H, J = 7.1);  3.82 (s, 2H); 4.18 (m, 4H); A
7.23, B 7.44 (qAB, 8H, J = 8.6). 13C NMR {1H} (75 MHz, CDCl3):  14.1;  51.9; 
61.8;  129.3;  130.1;  135.5;  135.7;  169.0. HRMS (ESI) calcd for [M+Na]+
C20H20O4NaS2Cl2 481.0073, found 481.0078.
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Diethyl 2,3-Bis(4’-chlorophenylmethanethio)succinate 7
5
6
7
8
The product was washed with ether to yield white prisms (0.79 g, 55%), mp 98-100oC.
1H NMR (300 MHz, CDCl3):  1.24 (t, 6H, J = 7.2);  3.51 (s, 2H,); A 3.78, B 3.81 (m,
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4H, J = 13.17);  4.14 (m, 4H); A 7.20, B 7.26 (qAB, 8H, J = 8.3). C NMR {1H} (75
MHz, CDCl3):  14.0;  36.0;  47.1;  61.6;  128.7;  130.5;  133.2;  135.5;  169.7.
HRMS (ESI) calcd for [M+H]+ C22H24O4S2Cl2 487.0571, found 487.0557.
Synthesis of Diethyl 2,3-Bis(4’-hydroxyphenylthio)succinate 8
This reaction was carried out using the general procedure given above, using 4’-
hydroxybenzenethiol (90%, 6.60 mmol). The product mixture, containing a heavy
precipitate, was diluted with water, the precipitate remaining largely suspended in the
aqueous phase. The chloroform phase was removed, and the aqueous phase extracted
with ethyl acetate (3x100mL). The ethyl acetate solution was dried (MgSO4) and the
solvent removed under reduced pressure. The crude product was washed with ether to
yield white needles, (0.3 g, 24%). mp 213-215oC. H NMR (300 MHz, d6DMSO):  1.68
1
(t, 6H, J = 7.2);  4.0 (s, 2H);  4.62 (q, 4H, J = 6.9); A 7.26, B 7.70 (qAB, 8H, J = 6.9),
13
10.4 (s, 2H) ppm. C NMR {1H} (75 MHz, CDCl3): 14.0;  52.0;  61.5;  128.9; 
129.0;  132.2;  131.9;  134.2;  169.2ppm. HRMS (ESI) calcd for [M+Na]+
C20H22O6NaS2 445.0756, found 445.0739.
Synthesis of Diethyl 2-(4’-Chlorobenzythio)fumarate 11
A solution of diethyl acetylenedicarboxylate (2.14 g, 12.56 mmol) in chloroform (5 ml)
was cooled to -40º. (4-Chlorophenyl)methanethiol (2 g, 12.56 mmol) and TEA (5 drops)
were dissolved in chloroform (5 mL) and then added drop wise to the DEAD solution.
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The reaction was left for a further 6h at -40º and then left overnight at -10º. The solution
was washed 3 times with sulfuric acid (0.01 M, 10 mL). The aqueous layers were
combined and extracted with chloroform twice (10 mL). The organic layers were then
combined and dried over anhydrous MgSO4. The mixture was evaporated at room
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temperature under pressure (2.31 g, 56%). H NMR spectroscopy showed the product to
be a 7:3 mixture of Z:E diastereomers. The Z isomer was obtained after column
chromatography on alumina (95:5, hexane: benzene) (1.55g, 39%). A sample for spectral
analysis was further purified by recrystallization from ethanol. (mp 62 oC, range < 1 oC).
1H NMR (300MHz, CDCl3):  1.26 (t, 3H, J = 7.1);  1.28 (t, 3H, J = 7.1);  4.08 (s, 2H);
 4.19 (q, 2H);  4.20 (q, 2H);  6.36 (s, 1H);  7.24-  7.26 (m, 4H). 13C NMR {1H} (75
MHz, CDCl3): 14.0; 14.2;  36.1;  60.8;  62.4;  120.7;  128.7;  130.5;  133.3; 
135.0;  147.6;  164.0;  165.1. HRMS (ESI) calcd for [M+H]+ C15H18O4SCl 329.0614,
found 329.0626.
General Method for the Synthesis of Diethyl 2-(Phenylamino)fumarate
Analogues 9 and 1014
A solution of the selected amine (2.94 mmol) in ethanol was added to a solution of
diethyl acetylenedicarboxylate (0.5 g, 2.94 mmol) in ethanol. The reaction mixture was
stirred for 24 h at room temperature. H2SO4 (1-2 drops, 0.1 M) was added and the
solution stirred for 1 h. The solution was neutralised with NaOH (10 mL, 0.2 M). The
aqueous phase was extracted with chloroform (3 x 50 mL) and the combined organic
phases washed with brine, dried (MgSO4) and the solvent removed under reduced
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pressure to yield the desired compound. A sample was then recrystallised from ethanol
for spectral analysis.
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Diethyl 2-(4’-Chlorophenylamino)fumarate 9
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The product precipitated from solution when the reaction mixture was neutralised,
yielding yellow crystals of high purity and yield (0.65 g, 74%) mp 55 oC (range < 1 oC).
1H NMR (300 MHz, CDCl3):  1.14 (t, 3H, J = 7.3),  1.30 (t, 3H, J = 7.3),  4.17 (q,
4H),  4.19 (q, 4H),  5.43 (s, 1H), A 6.83, B 7.22 (qAB, 4H, J = 8.8),  11.11 (s, 1H,
NH). 13C NMR {1H} (75 MHz, CDCl3):  13.7;  14.3;  60.1;  62.2;  94.9; 110.0; 
122.2;  129.1;  139.0;  147.8;  164.0;  169.5. HRMS (ESI) calcd for [M+H]+
C14H17NO4Cl 298.0846, found 298.0849.
Diethyl 2-(4’-Bromophenylamino)fumarate 10
The product precipitated from solution when the reaction mixture was neutralised,
yielding yellow crystals of high purity and yield (0.85 g, 85%) mp 47-48o C, lit. 16 49.5-
1
51.5oC. H NMR (300 MHz, CDCl3):  1.14 (t, 3H, J = 7.2);  1.30 (t, 3H, J = 7.2); 
4.17 (q, 2H);  4.19 (q, 2H);  5.43 (s, 1H); A 6.77, B 7.37 (qAB, 4H, J = 8.8);  9.60 (s,
13
1H, NH). C NMR {1H} (75 MHz, CDCl3):  13.7;  14.3;  60.1;  62.2;  95.0; 
117.0;  122.5;  132.0;  139.6;  147.7;  164.0;  169.5. HRMS (ESI) calcd for
[M+H]+ C14H17NO4Br 342.0341, found 342.0355.
Attempted Synthesis of Diamino and Mixed Diaddition Products
Experiments aimed at synthesising the diamino or aminothioaddition product from the
alkene intermediate are summarised in Table 1. After the stated times, the solutions were
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evaporated, and the products examined by H NMR spectroscopy. The spectra showed
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unreacted substrates with small amounts of polymeric degradation products.
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X-ray crystallography
Crystals of compounds 5, 9 and 11 were prepared by recrystallisation from ethanol.
Suitable single crystals were selected under the polarizing microscope (Leica M165Z),
mounted on a MicroMount (MiTeGen, USA) consisting of a thin polymer tip with a
wicking aperture. The X-ray diffraction measurements were carried out on a Bruker
kappa-II CCD diffractometer at 150 K by using graphite monochromated Mo-Kα
radiation (λ = 0.710723 Å). The single crystal, mounted on the goniometer using cryo
loops for intensity measurements, was coated with paraffin oil and then quickly
transferred to the cold stream using an Oxford Cryo stream attachment. Symmetry related
absorption corrections using the Bruker program SADABS were applied and the data
were corrected for Lorentz and polarisation effects using Bruker APEX2 software. The
structure was solved by Direct methods and the full-matrix least-square refinement was
carried out using SHELX22. The non-hydrogen atoms were refined anisotropically.
The three crystal structures were deposited at the Cambridge Crystallographic Data
Centre and were assigned to the following deposition numbers: CCDC 1552250-
1552252.
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Computations
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The Spartan software was used for all calculations (wavefunction.com), the Discovery
Studio visualizer and ChemDraw were used to prepare figures and schemes.
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Default parameters were used for geometry optimisations, except for the number of
cycles which had to be increased in some cases to 5000 to achieve convergence,
particularly for sulphur-containing transition states. The default convergence criteria
include a maximum gradient component of 3x10-4 Hartrees/Bohr and a maximum change
in bond length of 1.2x10-3 Å. If there was no Hessian matrix from previous calculations,
the default was MMFF molecular mechanics for geometry optimization and PM3
semiempirical for transition state optimisation. Final geometry optimisations were
performed at DFT level (ωb97X-D/6-31G*)17 in a C-PCM implicit solvent model18,19
,
followed by single point energy calculation of a Hessian matrix and of the IR spectra and
thermodynamic quantities as implemented in the Spartan software at the same level as the
final geometry optimisation (including implicit solvent). In some cases, this last Hessian
matrix was used to improve the final geometry optimisation and calculation of IR spectra
and thermodynamic quantities. Two variants of the implicit solvent model were used to
mimic the reaction conditions: a “polar” (dimethylformamide, dielectric constant of
37.22) solvent for aniline and a “nonpolar” (tetrahydrofuran, dielectric constant of 7.43)
solvent for thiophenolate reactions.
Racemic products were drawn as the (RR) diastereomer. All modelling was done using
the analogous dimethyl esters and aniline and the thiophenolate anion as the nucleophiles.
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