How Reaction Conditions May Influence the Regioselectivity in the Synthesis of 2,3-Dihydro-1,4-benzoxathiine Derivatives

Article abstract of DOI:10.1021/acs.joc.8b02012

The exploration of different reaction conditions aiming to obtain both 2,3-dihydro-1,4-benzoxathiine-2-yl derivatives and 2,3-dihydro-1,4-benzoxathiine-3-yl ones is reported. The treatment of 1,2-mercaptophenol with an organic base and a specific 2-bromo acrylate results in a solvent- and substrate-dependent exclusive solvation of O- and S-anions, thus managing the regioselectivity.

Full text of DOI:10.1021/acs.joc.8b02012

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Article
How reaction conditions may influence the regioselectivity
in the synthesis of 2,3-dihydro-1,4-benzoxathiine derivatives
Andrea Casiraghi, Ermanno Valoti, Lorenzo Suigo, Angelica Artasensi, Erica Sorvillo, and Valentina Straniero
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02012 • Publication Date (Web): 28 Sep 2018
Downloaded from http://pubs.acs.org on September 28, 2018
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The Journal of Organic Chemistry
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“How reaction conditions may influence the regioselectivity in the synthesis of 2,3-dihydro-1,4-
benzoxathiine derivatives”
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Andrea Casiraghi, Ermanno Valoti, Lorenzo Suigo, Angelica Artasensi, Erica Sorvillo and
Valentina Straniero*
Prof. E. Valoti, orcid.org/0000-0002-5608-3875;
Dr. A. Casiraghi, orcid.org/0000-0002-6256-5694,
Dr. V. Straniero, orcid.org/0000-0002-5089-0879;
Department of Pharmaceutical Sciences;
Università degli Studi di Milano;
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via Mangiagalli 25, 20133 Milano, Italy;
valentina.straniero@unimi.it;
Abstract
The exploration of different reaction conditions aiming to obtain both 2,3-dihydro-1,4-
benzoxathiine-2-yl derivatives and 2,3-dihydro-1,4-benzoxathiine-3-yl ones is here reported.
The treatment of 1,2-mercaptophenol with an organic base and a specific 2-bromo acrylate results
in a solvent- and substrate- dependent exclusive solvation of O- and S- anions, thus managing the
regioselectivity.
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Introduction
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1,4-benzoxathiane is a common scaffold of a copious number of therapeutic agents, having
specific biological activities. The most significant and deeply studied derivatives are the ones
showing antihypertensive properties,1 by blocking α-1 and α -2 adrenoreceptor activity.2 Others
have been considered, due to their sweetness properties,3 and only recently 2,3-dihydro-1,4-
benzoxatins were examined and further evaluated as anticancer agents.4,5 Specifically, these
purine analogs act against the MCF-7 cancer cell line, showing activity towards several protein
kinases, as GP132, ERN1 or RAC1, and inducing apoptosis and then cancer cell death.
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Even if this scaffold is quite ubiquitous and of high pharmacological relevance, the chemistry of
the 1,4-benzoxathiane scaffold seems scarcely exploited. To the best of our knowledge, the few
existing synthetic procedures are dated, with harsh reaction conditions or troublesome work-up,
and almost exclusively directed to 2-substituted derivatives (Scheme 1). 6-13
The first synthetic work6 for the obtainment of this class of compounds concerns non-substituted
1,4-benzoxathianes (Scheme 1-A); Parham and coworkers used a strong-base catalysis, sodium
methoxide, and yielded the desired and unstable products with only poor yields.
This initial synthetic pathway was then fully overcome in the following years by one-pot
procedures7,8 (Scheme 1-B), in which suitably substituted cyclohexanones were treated with 1,2-
mercaptoethanol and a bromine source (NBS or CuBr2). Large amounts of bromine equivalents
were required, being responsible of thio-acetalization, ring expansion and aromatization. This
tandem reaction, even if quite convenient and versatile in several conditions, is limited by the
impossibility of usage in case of oxidative- or halogen- sensitive products.
Further additional studies involved the treatment of 1,2-mercaptophenol with α-halo Michael
acceptors9, methyl-4-bromobutenoate10 or 2,3-dibromopropyl derivatives11, in acetone and using
potassium carbonate as base (Scheme 1-C). In almost the totality of these works, the unique
reaction products revealed to be the 2-substituted 1,4-benzoxathianes. Such a result was
explained by the greater nucleophilicity of the sulfur as compared with oxygen and by the greater
acidity of thiophenol as compared to phenol.12,13 Sulfur atom is thus responsible for the initial
nucleophilic attack on the primary carbon atom of the suitable reactive. The consequent ring
closure, achieving the 2-substituted derivatives, proved to be mostly simultaneous, due to the high
reactivity of the reaction intermediate.
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Literature showed the sole obtainment of 3-substituted 1,4-benzoxathianes only when β-methyl
and β,β-dimethyl substituents were present in the α-halo Michael acceptors9 (Scheme 1-D).
Several alternative mechanisms were proposed in order to explain this opposite behavior;
nevertheless, no reaction intermediates could be isolated to support those hypotheses.
Furthermore, a few years later, Cocco and coworkers14 achieved 3-methyl or 3,3-dimethyl 2-
substituted 1,4-benzoxathianes in a similar manner, thus confusing the interesting result obtained
before.
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Besides, only in the latest decade, Campos and coworkers[4,5] (Scheme 1-E) reported the
obtainment of both 2,3-dihydro-1,4-benzoxathiine-2-yl and 3-yl methylpurines. These derivatives
were accomplished through an initial treatment of the 1,2-mercaptophenol with epichlorohydrin
and the consecutive Mitsunobu reaction, affording both the substituted derivatives, in different
percentages.
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In the first step, as already seen by Cabiddu,
the reaction of 1,2-mercaptophenol with
epichlorohydrins affords both the six-membered and the seven-membered rings, as a
consequence of the different nucleophilic attack by the phenoxide ion at the less or the more
hindered position of the epoxide. This was explained as a consequence of the larger atomic radius
of the sulfur atom versus the oxygen one, which causes primarily the attack at the secondary
carbon atom of the epoxide, thus affording the 1,5-benzoxathiepine derivative. Nevertheless, the
2-substituted six-membered ring was anyway accomplished, even if only in 20-30 % yields. The
second step, that is the microwave-assisted Mitsunobu coupling, brought, on one side, to the final
2,3-dihydro-1,4-benzoxathiin-2yl-methylpurine and, on the other, to the contraction of the 1,5-
benzoxathiepine into the six-membered 3- substituted 2,3-dihydro-1,4-benzoxathiine.
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SCHEME 1: Literature background
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NaOMe
1,2-dibromoethane
SH
OH
S
A)
B)
O
reflux
1,2-mercaptoethanol
NBS or CuBr2
R1
S
S
NBS or CuBr2
R1
NBS or CuBr2
R1
R1
S
O
DCM or diglyme
0°C or 100°C
DCM or diglyme
0°C or 100°C
DCM or diglyme
0°C or 100°C
O
O
O
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ethyl-2-bromo-acrylate or
2-chloroacrylonitrile
K2CO3
S
acetone
RT
O
R2
methyl-4-bromobutenoate
K2CO3
methyl-4-bromobutenoate
COOMe
K2CO3
S
SH
OH
S
C)
COOMe
acetone
reflux
acetone
reflux
OH
O
ethyl-
2,3-dibromopropionate
K2CO3
S
O
COOEt
acetone
reflux
methyl-2-bromo-3-methylacrylate or
methyl-2-bromo-3,3-dimethylacrylate
K2CO3
S
COOMe
acetone
reflux
R= H or CH3
O
R
SH
OH
D)
acetone
reflux
O
S
COOEt
R= H or CH3
R
ethyl-2,3-dibromo-butyrate or
ethyl-2,3-dibromo-3-methyl-butyrate
K2CO3
R3
N
N
S
R4
N
S
OH
O
NaOH
H2O
N
N
Suitable purine
Ph3P, DIAD
N
N
O
SH
OH
epichlorohydrin
O
S
E)
+
+
reflux
anhydrous THF
45°C, MW
10% aq. NaOH
reflux
R5
OH
O
R6
N
O
S
OH
S
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While working on the synthesis of innovative antibacterial agents,16,17 acting as FtsZ inhibitors, we
designed 2- and 3- substituted 2,3-dihydro-1,4-benzoxathiane scaffolds. After having considered
the lack of literature around the chemistry of this heterocycle, we decided to start from an
established synthetic method18, satisfactorily used for the obtainment of a large number of 1,4-
benzodioxane derivatives.19,20
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In particular, as reported in Scheme 2, the desired 1,4-benzodioxane carboxylate was
accomplished through condensation of the commercially available catechol with ethyl or methyl
2,3-dibromopropionate, obtained by bromination of the corresponding acrylate.
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The mechanism of this reaction was abundantly studied few decades ago firstly by Koo and
coworkers21 and later by Caputo’s research group.22 They strengthened the hypothesis of the
initial dehydrobromination of the 2,3-dibromopropionate, achieving the 2-bromoacrylate, and the
consecutive Michael addition of the cathecol anion on the primary carbon.
SCHEME 2: 1,4-benzodioxane scaffold synthesis
O
O
Br
O
K2CO3
K2CO3
K2CO3
Br
Br
O
O
O
OR
Br
RO
OR
RO
acetone
reflux
acetone
reflux
acetone
reflux
O
OH
Similarly, considering this simple procedure, we decided to apply it on 1,2-mercaptophenol
instead of catechol, treating the 2-hydroxythiophenol with methyl or ethyl 2,3-
dibromopropionate, in presence of triethylamine (TEA) as weak organic base.
We aimed at the obtainment of methyl or ethyl 1,4-benzoxathian-2- or 3- carboxylate, which could
easily undergo reduction of the estereal function and thus condensation with the suitable phenol,
achieving the desired compounds (Scheme 3).
SCHEME 3
K2CO3
3-hydroxy-2,6-
difluorobenzamide
CONH2
F
O
F
OH
SH
TEA
LiAlH4
O
O
S
O
S
Br
Br
O
RO
+
O
OH
OR
acetone
RT
THF
RT
DMF
80°C
S
R= Me/Et
R= Me/Et
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Results and discussion
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We planned to initially use acetone as reaction medium, as previously done for the 1,4-
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5
1
benzodioxane (Scheme 4); interestingly the H-NMR of the reaction crude revealed that methyl or
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ethyl 2,3-dihydro-1,4-benzoxathine-2-carboxylate (1 and 3) were almost the single reaction
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products.
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SCHEME 4: Synthetic pathway for the obtainment of compounds 1/3 and 2/4
O
O
O
TEA
O
Br2
1,2-mercaptophenol
Br
Br
O
S
S
+
RO
OR
OR
RO
acetone
RT
solvent*
RT
O
Ia (R= Me)
Ib (R= Et)
1 (R= Me)
3 (R= Et)
2 (R= Me)
4 (R= Et)
R= Me/Et
* The solvent used affects regioselectivity
The obtainment of 2- substituted regioisomers 1 and 3 as prevalent products prompted us to
outline a hypothetical reaction mechanism (Scheme 5). Thence, we started treating methyl and
ethyl dibromopropionate (Ia and Ib) in acetone with a single equivalent of TEA and we noticed the
instant dehydrobromination and the consequent obtainment of methyl or ethyl 2-bromoacrylate
1
(IIa and IIb). Both the derivatives were easily isolated from the reaction medium and their H-
NMR23 spectra confirmed the chemical structure. The second step, consisting in the reaction of IIa
and IIb with 1,2-mercaptophenol and a further equivalent of TEA, probably involves the initial
attack of the more nucleophilic thiolate on the β-position. This leads to the achievement of the
intermediates III, as the main product of the nucleophilic β-addition on the α,β-unsaturated
carbonyl function. Unfortunately, we did not succeed in the isolation of intermediates III and their
characterization, because they rapidly undergo the spontaneous ring closure. This consecutive
reaction should be managed by the nucleophilic phenate and further favored by the high
electrophilicity of the α-carbon atom, obtaining compounds 1 and 3 as the main regioisomers.
SCHEME 5: Proposed mechanism of reaction for the obtainment of compounds 1 and 3
O
O
1 eq TEA
O
1,2-mercaptophenol
1 eq TEA
O
S
Br
Br
OR
Br
RO
OR
1 (R= Me)
3 (R= Et)
Ia (R= Me)
Ib (R= Et)
IIa (R= Me)
IIb (R= Et)
O
O
OH
S
O
S
O
O
S
Br
OR
H
O
O
OR
S
OR
OR
Br
Br
1 (R= Me)
3 (R= Et)
III
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4
Evaluating how to achieve the regioisomers 2 and 4, we thought to work on modifying the
nucleophile characteristics, trying to avoid substantial changes in the synthetic pathway, as
previously we were forced to do for 1,4-benzodioxanes24, 25, 26 and for the pyrido-dioxanes.27, 28
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We therefore moved firstly varying the solvent, and secondly evaluating other reaction variables
(introduction of co-solvent, changes in reaction temperature and time), in order to understand if
the 3- substituted regioisomers could be somehow formed under specific conditions. We
highlighted how the solvent change directly affected the achieved regioisomer ratio. In addition, in
order to profoundly estimate the composition of each crude, we set up two peculiar HPLC method
(see Experimental section for column and methods), able to fully control the reaction conversion
and to correctly quantify the regioisomer content.
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The most interesting results, here summarized in Tables 1 and 2, highlighted several unexpected
features. Besides, we avoided including information on reaction times in the tables, because, after
a huge number of attempts, we assessed that the coupling required 72 hours for its completion.
No significant changes happened after that period and therefore time has no significant influence
on reaction regioselectivity.
Table 1: Regioisomer percentages of 1 and 2 (evaluated by HPLC), considering the main reaction parameters involved
% Regioisomer
O
O
O
S
S
Solvents
Ratio
Reaction
Temperature
OMe
OMe
Trial
Solvent
Co-solvent
O
1
2
a-1
b-1
c-1
d-1
e-1
f-1
DCM
Acetone
Acetone
ACN
/
/
/
/
/
/
/
/
/
100/0
100/0
100/0
100/0
100/0
100/0
100/0
100/0
100/0
RT
RT
47%
94%
96%
37%
16%
51%
47%
62%
86%
53%
6%
60°C
RT
4%
63%
84%
49%
53%
38%
14%
ACN
60°C
RT
DMF
g-1
h-1
i-1
DMF
60°C
RT
DMSO
DMSO
60°C
Conversely, we observed how the obtainment of the 2,3-dihydro-1,4-benzoxathiane-2-
carboxylates or the 3- substituted ones was completely solvent-dependent, moving from roughly
the totality of the 2-substituted regioisomers (1 and 3) to an high molar percentage of the 3-
substituted derivatives 2 and 4.
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We considered four additional solvents, chosen for their peculiar miscibility with water and for
their divergent polarity: dichloromethane (DCM), acetonitrile (ACN), N,N-dimethylformamide
(DMF) and dimethyl sulfoxide (DMSO).
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DCM was firstly used as single solvent and the couplings were performed at RT (a-1, a-2), the
results were soon significantly different: on one side, the ethyl derivative kept its preference for 2-
substitution, showing only 10% of 3- regioisomer. On the other side, the methyl derivative reacted
in an opposite way, moving its regioselectivity to an equal proportion of the both products.
The different polarity of methyl and ethyl 2-bromoacrylate prompted us to perform reaction b-2 in
an aqueous biphasic system, in the presence of tetrabutylammonium bromide (TBAB) as phase
transfer catalysis. In these conditions, the partial formation of the 3-substituted compound 2 was
revealed, and its relative abundance was calculated from HPLC analysis and resulted to be of 25%.
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Table 2: Regioisomer percentages of 3 and 4 (evaluated by HPLC), considering the main reaction parameters involved
% Regioisomer
O
O
O
Solvents
Ratio
Reaction
Temperature
OEt
S
Trial
Solvent
Co-solvent
OEt
S
O
3
4
a-2
b-2
c-2
d-2
e-2
f-2
DCM
DCM
/
100/0
50/50
100/0
100/0
100/0
100/0
50/50
20/80
100/0
100/0
100/0
50/50
20/80
100/0
100/0
100/0
50/50
20/80
RT
RT
90%
75%
94%
96%
76%
80%
60%
50%
70%
77%
100%
38%
40%
71%
71%
100%
38%
39%
10%
25%
6%
H2O(+TBAB)
Acetone
Acetone
ACN
/
RT
/
/
60°C
RT
4%
24%
20%
40%
50%
30%
23%
0%
ACN
/
60°C
RT
g-2
h-2
i-2
ACN
H2O
H2O
/
ACN
RT
DMF
RT
j-2
DMF
/
60°C
80-90°C
RT
k-2
l-2
DMF
/
DMF
H2O
H2O
/
62%
60%
29%
29%
0%
m-2
n-2
o-2
p-2
q-2
r-2
DMF
RT
DMSO
DMSO
DMSO
DMSO
DMSO
RT
/
60°C
80-90°C
RT
/
H2O
H2O
62%
61%
RT
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3
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The scarce results in the obtainment of the 3- substituted regioisomers forced us to consider other
solvents, moving to water-miscible ones and with a progressively increased polarity: ACN, DMF,
DMSO and water itself.
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Acetonitrile was used alone (d-1 and e-2) or with growing amounts of water for the ethyl
compounds, in order to enhance 3- regioisomer amounts (g-2, h-2). The results in Table 1 and
Table 2 confirmed that water is crucial in order to enhance the abundance of the 3-substituted
derivative and that the maximum reachable size was almost an equimolar ratio of 1/2 and 3/4.
Neither an extreme increase in the quantity of water (h-2) has a significant effect on the
regioisomer ratio.
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DMF afforded progressively upgraded results for ethyl derivatives, reaching almost 60% of
derivative 4 when water was added as co-solvent to the reaction medium (l-2 and m-2). A similar
outcome was achieved using DMSO, whose usage enabled conclusions similar to the DMF ones (h-
1, n-2, q-2 and r-2).
Furthermore, we evaluated how an increase in the reaction temperature could somehow affect
the regioisomer ratio. The results were quite clear for the ethyl derivatives (Table 2); in these
trials, the progressive heating of the reaction mixture always moved to an enhancement of the 2-
substituted regioisomers. We hypothesized this could be due to a thermo-dependent stabilization
of the intermediate III.
A different behavior was observed for the methyl compounds, which regioisomer preference at
high temperature was completely solvent-dependent.
The interesting results highlighted how the regioisomer balance was severely solvent-dependent,
and particularly how the more polar was the solvent used the more profuse was the amount of
the 3-substituted compound yielded. Indeed, the addition of water as co-solvent moved to a
strong redefinition of the balance between 3 and 4.
Unfortunately, the water insolubility of both the reagents and the reaction products prevented the
possibility of using pure water as the reaction solvent. This prompted us to consider other water-
soluble 1,2-dibromo-moieties and to deeply examine their influence on the regioselectivity
balance, while using the best reaction conditions seen by far.
We therefore moved to the application of the same synthetic procedure over two more polar
scaffolds, thus starting from 2,3-dibromopropionamide (IVa) and 2,3-dibromoproprionitrile (IVb),
following the same synthetic pathway of the two estereal series, starting from the commercial
acrylamide and acrylonitrile, as shown in Scheme 6.
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3
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5
6
7
The bromine addition on the acrylamide or the acrylonitrile afforded derivatives IV in good to
quantitative yields, and was followed by treatment with 1 equivalent of TEA, causing the complete
dehydrobromination and the obtainment of compounds Va and Vb that were isolated and fully
characterized.
8
SCHEME 6: Synthetic pathway for the obtainment of compounds 5/8
9
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
S
S
+
NH2
NH2
O
R
R
Br
Br
Br2
TEA
R
Br
1,2-mercaptophenol
5
7
6
8
MeOH or ACN
RT or reflux
30' or 2 hrs
diethyl ether or DCM
RT or reflux
8 hrs
solvent*
72 hrs
O
S
CN
S
CN
Va (R= CONH2)
Vb (R= CN)
R= CONH2
or CN
IVa (R= CONH2)
IVb (R= CN)
+
O
* The solvent used affects the regioselectivity
The modest to high solubility of compounds V in water let to accomplish the coupling reaction in
pure water (f-3 and f-4).
Interestingly and unexpectedly, working on the amide (f-3), operating at room temperature, and
stirring for 72 hours, as done before, we had the complete conversion and the obtainment of a
single derivative; 1H and C NMR confirmed its nature as the 3-substituted regioisomer 6. We did
13
not evaluated any trace of the 2-substituted compound 5, neither in TLC nor in NMR spectra and
in HPLC (see Experimental section for column and methods).
Here, the proposed reaction mechanism is similar to the one presented in Scheme 4, but in this
case, TEA mediates the initial deprotonation of the phenolic function (see Scheme 7). The resulting
phenate is the nucleophile directly responsible of the attack on the double bond and the
consecutive achievement of Intermediate VIa. Contrarily to what observed for Intermediate III, we
succeeded in the isolation of this derivative by blocking the reaction after a few hours.
Unfortunately, the chromatography required for its characterization was truly demanding and we
obtained Intermediate VIa in poor yield and slightly poisoned by the presence of 1,2-
mercaptophenol; nevertheless the H NMR confirmed its structure.29 In order to further verify its
1
identity, we successively treated isolated Intermediate VIa with a further equimolar amount of
TEA, leading to the complete conversion into the desired derivative 6.
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SCHEME 7: Proposed mechanism of reaction for the obtainment of compound 6
2
3
4
5
6
7
8
S
O
SH
O
O
O
Br
OH
SH
NH2
1 eq TEA
O
NH2
S
NH2
Br
VIa
O
6
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Here, the possibility to isolate Intermediate VIa could be explained on one hand by the lower
electrophilicity of the amide α-carbon atom, and on the other by the reduced basic properties in
the aqueous medium, slowing down the spontaneous ring closure, achieving the 3-substituted
benzoxathiine 6.
In addition to water, we evaluated the same solvents used before for the esters, starting from
Intermediate Va. Contrarily to what seen for esters 1/2 and 3/4, the condensation performed in
pure DCM (a-3) and using the reaction parameters set before (RT, 72 hours reaction time) let to
the obtainment of both 5 and 6. We quantified the regioisomer balance by HPLC and it resulted to
be of 34% 5 vs 66% 6, as reported in Table 3.
The use of acetone (b-3) or ACN (c-3) had a similar outcome, with a final almost equimolar amount
of 5 and 6. Furthermore, neither DMF nor DMSO revealed to be good solvents for these amides
because their use limited the 1,4-benzoxatine ring formation and the reaction mixture revealed to
be composed mainly of 1,2-mercaptophenol. Consequently, for these derivatives, the presence of
both the regioisomers suggested how both the substrate and the solvent polarities have a key role
in the reaction.
Table 3: Regioisomer percentages of 5 and 6 (evaluated by HPLC), considering the main reaction parameters involved
% Regioisomers
O
O
Solvents
Ratio
Reaction
O
S
S
SOLVENT
CO-SOLVENT
NH2
NH2
Temperature
O
5
6
a-3
b-3
c-3
d-3
e-3
f-3
DCM
Acetone
ACN
/
/
/
/
/
/
100/0
100/0
100/0
100/0
100/0
100/0
RT
RT
RT
RT
RT
RT
34%
42%
50%
nd
66%
58%
50%
nd
DMF
DMSO
H2O
nd
nd
0%
100%
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2
3
4
Differently, working in water on the 2-bromoacrylonitrile (f-4, Table 4), operating at room
temperature, and stirring for 72 hours, as done before, we did not have the complete conversion
of the 1,2-mercaptophenol into one or both the regioisomers.
5
6
7
8
9
Even if both 7 and 8 were partially achieved, a novel and structurally different derivative revealed
to be the main reaction product (reaching yields of 87% when performing the reaction in acetone
– b-3). We then isolated the compound by flash chromatography and analyzed it through NMR: 1H
and 13C spectra confirmed its nature as the 1,3-benzoxathiol-2-acetonitrile 9. The same derivative,
even if achieved with lower amounts, was the main product of all the reactions.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Here, we proposed a different reaction mechanism, coming from the results reached by Cabiddu
and coworkers a few decades ago30 (See Scheme 8).
SCHEME 8: Proposed mechanism of reaction for the obtainment of compound 9
2-bromo
OH
OH
SH
OH
S
O
S
acrylonitrile
CN
O
S
9
CN
S
CN
CN
Br
VII
Specifically, the 2-bromoacrylonitrile Vb underwent Michael reaction on the 1,2-mercaptophenol
followed by dehydroalogenation, achieving Intermediate VII. This intermediate was sequentially
deprotonated by TEA on its phenolic function.
The resulting phenate is directly responsible of the closure of the ring, achieving 9.
Table 4: Regioisomer percentages of 7 and 8 (evaluated by HPLC), considering the main reaction parameters involved.
(*The relative percentages do not consider the formation of the 1,3-benzoxathiol 9)
% Regioisomers
Solvents
Ratio
Reaction
O
S
CN
S
CN
SOLVENT
CO-SOLVENT
Temperature
O
7
8
a-4
b-4
c-4
d-4
e-4
f-4
DCM
Acetone
ACN
/
/
/
/
/
/
100/0
100/0
100/0
100/0
100/0
100/0
RT
RT
RT
RT
RT
RT
85%*
15%*
56%*
37%*
51%*
62%*
33%*
44%*
63%*
49%*
38%*
67%*
DMF
DMSO
H2O
Despite the interesting result of this unknown 5-membered ring, the presence of both the
regioisomers in all the tested solvents (a-4-e-4, Table 4) stressed once again the importance of
both the substrate and the solvent polarities in the regioisomer selection.
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The Journal of Organic Chemistry
1
2
3
4
5
6
7
Consequently, we decided to further enlarge the scope of this reaction, evaluating an additional
starting material that shows a substantial increase in lipophilicity: the tert-butyl acrylate. We
aimed at better understanding how such a lipophilic change could affect the regioisomer balance
when applying the previously set-up reaction conditions.
8
9
We therefore started quantitatively preparing the tert-butyl 2-bromoacrylate (IX) through the
formation of the intermediate tert-butyl 2,3-dibromopropionate VIII, as previously described for
the other derivatives. Both VIII and IX were isolated, fully characterized and compared with
literature data,31 in order to assess their structure identities (Scheme 9).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
SCHEME 9: Synthetic pathway for the obtainment of compounds 10/11
O
O
O
O
O
Br2
TEA
1,2-mercaptophenol
S
Br
Br
O
S
Br
O-tBu
O-tBu
+
O-tBu
O-tBu
O-tBu
DCM, RT
18 hrs
DCM, RT
16 hrs
solvent*
72 hrs
O
VIII
* The solvent used affects the regioselectivity
IX
10
11
The lipophilic properties of compound IX let to accomplish the coupling reaction in DCM, acetone,
ACN, DMF and DMSO, as done for the previous derivatives (a-5 to e-5 in Table 5), while its
insolubility in water required an aqueous biphasic system, as in b-2, by adding
tetrabutylammonium bromide (TBAB) as phase transfer catalysis.
Table 5: Regioisomer percentages of 10 and 11 (evaluated by HPLC), considering the main reaction parameters involved.
(*The relative percentages do not consider the formation of the tert-butyl-α-(2-hydroxyphenyl)thio-acrylate 12)
% Regioisomers
Solvents
Ratio
Reaction
O
O
SOLVENT
CO-SOLVENT
O
S
S
Temperature
OtBu
OtBu
O
10
11
a-5
b-5
c-5
d-5
e-5
f-5
DCM
Acetone
ACN
/
100/0
100/0
100/0
100/0
100/0
50/50
RT
RT
RT
RT
RT
RT
36%*
73%*
32%*
15%*
41%*
24%*
64%*
27%*
68%*
85%*
59%*
76%*
/
/
DMF
/
DMSO
H2O
/
DCM (+ TBAB)
Unexpectedly, working with the tert-butyl derivative at room temperature and stirring for 72
hours, as done before, we did not completely converted the 1,2-mercaptophenol into one or both
the regioisomers. Hence, together with the partial obtainment of both 10 and 11, we identified an
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3
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5
6
7
8
additional and unfamiliar reaction product, which was achieved with different yields (from traces
amounts in acetone- b-5 up to main product in ACN- c-5) depending on the solvent used.
As previously done for derivative 9, we isolated the novel compound by flash chromatography and
1
13
we analyzed it through NMR. H and C spectra helped us in defining its nature as the tert-butyl-
α-(2-hydroxyphenyl)thio-acrylate 12.
9
Starting from the structure of this novel compound, we hypothesized that, after the initial Michael
addition of the thiolate on the 2-bromo acrylate, an intramolecular cyclization to bromine-
solfonium salt X took place, driven by the steric hindrance of the tert-butyl group (Scheme 10).
Intermediate X is completely unstable and soon rearranged to the olefinic thio-derivative 12; a
similar outcome was already seen by Boucher and collaborators,32 while working on the synthesis
of differently hindered dienophilic olefins.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
SCHEME 10: Proposed mechanism of reaction for the obtainment of compound 12
OH
S
OH
S
O
OH
S
O-tBu
OH
S
Br
O-tBu
O
O-tBu
Br
O-tBu
O
Br
O
IX
X
12
The impressive and unpredictable results coming from the different substrates corroborated our
hypothesis in considering of equal importance in the regioisomer selection both the substrate and
the solvent features.
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The Journal of Organic Chemistry
1
2
Conclusion
3
4
5
6
In conclusion, we found a completely innovative and easy method for the obtainment of pure 2-,
pure 3- or a differently proportioned mixture of 2- and 3- substituted 2,3-dihydro-1,4-
benzoxathiine.
7
8
9
With the present work we demonstrated how the regioselectivity of this scaffold could be strongly
dependent on the polarity of the reaction medium as well as on the nature of the reagents
employed.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In particular, in our opinion, the negative charge, due to deprotonation, moves from phenol, in
polar solvents, to thiol, in non-polar ones. The whole molecule becomes more polar in the
presence of the phenolate; by contrast, in non-polar solvents the deprotonation is transferred to
the thiolate, making the complete molecule more lipophilic.
Furthermore, each single structural feature of the reactives, in particular the polarity, the water
solubility and the steric hindrance, have an exclusive, noteworthy and additive effect on the final
regioisomer balance.
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3
Experimental section:
General:
4
5
Ethyl acrylate, methyl acrylate, acrylonitrile, acrylamide and tert-butyl acrylate were purchased
6
7
8
9
from commercial suppliers and were used without further purification. The solvents, such as
1
acetone, DCM, DMF, DMSO, analytical grade ACN, were purchased from Sigma Aldrich. H and 13C
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NMR spectra were taken on Varian 300 Mercury NMR spectrometer operating at 300 MHz for H
NMR, and 75 MHz for 13C NMR. Chemical shifts (δ) are reported in ppm relative to residual solvent
as internal standard. Signal multiplicity is used according to the following abbreviations: s= singlet,
d= doublet, dd= doublet of doublets, t=triplet, td= triplet of doublets, q=quadruplet, m=multiplet,
sept= septuplet and bs= broad singlet. Elemental analyses of the new substances are within 0.40 %
of theoretical values. Silica gel F254 was used in analytical thin-layer chromatography (TLC), and
silica gel (particle size 40-63 µm, Merck) was used in flash chromatography; visualizations were
accomplished with UV light (λ 254 nm). Melting point were determined by DSC (TA INSTRUMENTS)
or Büchi Melting Point (B-540).
The regioisomer-separation analyses were performed on HPLC by using Elite LaChrom HPLC
system with diode array detector (190–400 nm) and a Water XBridgeTM C-18 column (5 µm,
4.6x150mm). The peculiar methods (A, B, C and D) are reported in the Supporting Information and
proved to be effective in separating all the regioisomeric pairs of the final compounds.
HPLC evaluation:
The HPLC methods were set up, using a Water XBridgeTM C-18 column, which was flushed with
freshly prepared acetate buffer (pH 4.7)/ACN (70:30, v/v) for 1/2, 5/6 and 7-9, acetate buffer (pH
4.7)/ACN (65:35, v/v) for 3/4 or acetate buffer (pH 4.7)/ACN (60:40, v/v) for 10-12, until column
pressure was stable.
All the investigated samples were prepared through dissolution either of the crude reaction
mixtures or of the purified products in the selected mobile phase, at the approximate
concentrations of 1 mg/mL, filtered through a 0.45 µm filter and analyzed. The injection volume
was 20 µL. Owing to the presence of the 1,4-benzoxathiane or the 1,3-benzoxathiol scaffold in
each compound, regioisomer contents were evaluated on chromatograms recorded at 290 nm.
Synthesis:
Methyl 2,3-dibromopropionate33 (Ia). Bromine (0.57 mL, 11.1 mmol) was added dropwise to a
solution of methyl acrylate (1.0 mL, 11.1 mmol) in acetone (10 mL), under reflux. Once added, the
reaction mixture was kept stirring at reflux for 30 minutes. The reaction mixture was then brought
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The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
to room temperature, quenched with aqueous 10% sodium thiosulfate solution, dried over
Na2SO4, filtered and concentrated under reduced pressure, affording Ia as a colourless oil. Yield:
2.42 g (89%). 1H NMR (300 MHz, CDCl3): δ= 4.45 (dd, J = 11.3, 4.4 Hz, 1H), 3.92 (dd, J = 11.3, 9.9 Hz,
1H), 3.84 (s, 3H), 3.68 ppm (dd, J =9.9, 4.4 Hz, 1H). Anal. Calcd for C4H6Br2O2: C, 19.54; H, 2.46; Br,
64.99; O, 13.01. Found: C, 19.12; H, 2.66; Br, 65.23; O, 12.98.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Methyl 2-bromoacrylate34 (IIa). TEA (1.13 mL, 8.13 mmol) was added dropwise to a solution of Ia
(2.0 g, 8.13 mmol) in acetone (10 mL), at room temperature. Once added, the reaction mixture
was stirred for 30 minutes at room temperature and filtered. The resulting solution was washed
with aqueous 10% HCl solution, dried over Na2SO4, filtered and concentrated, affording IIa as a
yellow oil. Yield: 1.34 g (99%). 1H NMR (300 MHz, CDCl3): δ= 6.97 (d, J = 1.6 Hz, 1H), 6.28 (d, J = 1.6
Hz, 1H), 3.85 ppm (s, 3H). Anal. Calcd for C4H5BrO2: C, 29.12; H, 3.05; Br, 48.43; O, 19.39. Found: C,
28.96; H, 3.08; Br, 48.78; O, 19.18.
General procedure for Methyl 1,4-benzoxathian-2-carboxylate (1) or Methyl 1,4-benzoxathian-3-
carboxylate (2): TEA (0.25 mL, 1.76 mmol) was added dropwise to a solution of Ia (0.22 g, 0.88
mmol) into the desired solvent (4 mL). Compound IIa was quantitatively accomplished after
stirring at room temperature for 30 min, therefore 1,2-mercaptophenol (0.11 g, 0.88 mmol) was
slowly added. The reaction mixture was stirred at RT or at 60°C for 72 hrs, then it was diluted with
diethyl ether and water, the organic phase was dried over Na2SO4, filtered and concentrated, to
give a yellow oil as residue. The crude was purified by flash chromatography on silica gel, using
cyclohexane/ethyl acetate 9/1 as elution solvent, the yielded ratio between the two regioisomers
1
was quantified by H NMR and HPLC data. Global yield: from 0.08 g (43%) to 0.15 g (80%),
depending on the solvents used.
1
Methyl 1,4-benzoxathian-2-carboxylate (1): yellowish oil, tr (Method A): 17.2 min. H NMR (300
MHz, CDCl3): δ= 7.05 (m, 2H), 6.97 (dd, J= 8.7, 1.2 Hz, 1H), 6.88 (dd, J= 7.4, 1.2 Hz, 1H), 5.03 (dd, J =
13
4.8, 3.9 Hz, 1H), 3.82 (s, 3H), 3.29 (d, J = 3.9 Hz, 1H), 3.28 ppm (d, J = 4.8 Hz, 1H). C NMR (75
MHz, CDCl3): δ=169.2, 150.2, 127.6, 126.3, 121.9, 118.5, 116.5, 72.7, 52.8, 26.7. Anal. Calcd for
C10H10O3S: C, 57.13; H, 4.79; O, 22.83; S, 15.25. Found: C, 57.41; H, 4.59; O, 22.63; S, 15.36.
1
Methyl 1,4-benzoxathian-3-carboxylate (2): colourless oil, tr (Method A): 18.2 min. H NMR (300
MHz, CDCl3): δ= 7.05 (m, 2H), 6.89 (m, 2H), 4.55 (dd, J = 11.5, 3.3 Hz, 1H), 4.49 (dd, J = 11.5, 5.9 Hz,
13
1H), 4.14 (dd, J = 5.9, 3.3 Hz, 1H), 3.81 ppm (s, 3H). C NMR (75 MHz, CDCl3): δ=169.0, 151.0,
127.0, 125.9, 122.1, 118.4, 116.6, 65.9, 53.1, 41.3. Anal. Calcd for C10H10O3S: C, 57.13; H, 4.79; O,
22.83; S, 15.25. Found: C, 57.39; H, 4.63; O, 22.68; S, 15.30.
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Ethyl 2,3-dibromopropionate35 (Ib). Bromine (0.51 mL, 10.0 mmol) was added dropwise to a
solution of ethyl acrylate (1.0 g, 10.0 mmol) in acetone (10 mL), under reflux. Once added, the
reaction mixture was kept stirring at reflux for 30 minutes. The reaction mixture was then brought
to room temperature, quenched with aqueous 10% sodium thiosulfate solution, dried over
Na2SO4, filtered and concentrated under reduced pressure, affording Ib as a yellowish oil. Yield:
2.60 g (100%). 1H NMR (300 MHz, CDCl3): δ= 4.42 (dd, J = 11.4, 4.4 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H),
3.92 (dd, J = 11.4, 9.9 Hz, 1H), 3.67 (dd, J = 9.9, 4.4 Hz, 1H), 1.32 ppm (t, J = 7.1 Hz, 3H). Anal. Calcd
for C5H8Br2O2: C, 23.10; H, 3.10; Br, 61.48; O, 12.31. Found: C, 22.92; H, 3.01; Br, 61.63; O, 12.44.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ethyl 2-bromoacrylate36 (IIb). TEA (0.18 mL, 1.27 mmol) was added dropwise to a solution of Ib
(0.3 g, 1.15 mmol) in acetone (3 mL), at room temperature. Once added, the reaction mixture was
stirred for 30 minutes at room temperature and filtered. The resulting solution was washed with
aqueous 10% HCl solution, dried over Na2SO4, filtered and concentrated to dryness, affording IIb
as a yellow oil. Yield: 0.20 g (97%). 1H NMR (300 MHz, CDCl3): δ= 6.95 (s, 1H), 6.26 (s, 1H), 4.29 (q,
J = 7.1 Hz, 2H), 1.34 ppm (t, J = 7.1 Hz, 3H). Anal. Calcd for C5H7BrO2: C, 33.55; H, 3.94; Br, 44.64; O,
17.88. Found: C, 33.36; H, 3.88; Br, 44.83; O, 17.92.
General procedure for Ethyl 1,4-benzoxathian-2-carboxylate (3) or Ethyl 1,4-benzoxathian-3-
carboxylate (4): 3 and 4 were accomplished starting from Ib (0.23 g, 0.88 mmol) and 1,2-
mercaptophenol (0.11 g, 0.88 mmol), following the same procedure described for 1 and 2, and
purifying the products by flash chromatography on silica gel, using cyclohexane/ethyl acetate 95/5
1
as elution solvent. The ratio between the two regioisomers was quantified by H NMR and HPLC
data; global yield: 0.11 g (54%) to 0.16 g (80%), depending on the solvent used.
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Ethyl 1,4-benzoxathian-2-carboxylate (3): yellow oil, tr (Method B): 22.3 min. H NMR (300 MHz,
CDCl3): δ= 7.04 (m, 2H), 6.96 (d, J= 7.7 Hz, 1H), 6.87 (t, J= 7.4 Hz, 1H), 4.99 (dd, J = 5.3, 3.8 Hz, 1H),
4.27 (q, J = 7.1 Hz, 2H), 3.29 (d, J = 3.8 Hz, 1H), 3.28 (d, J = 5.3 Hz, 1H), 1.28 ppm (t, J= 7.1 Hz, 3H).
13C NMR (75 MHz, CDCl3): δ=168.7, 150.3, 127.5, 126.2, 121.8, 118.5, 116.5, 72.5, 61.9, 26.7, 14.1.
Anal. Calcd for C11H12O3S: C, 58.91; H, 5.39; O, 21.40; S, 14.30. Found: C, 58.61; H, 5.59; O, 21.63; S,
14.17.
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Ethyl 1,4-benzoxathian-3-carboxylate (4): yellow oil, tr (Method B): 24.3 min. H NMR (300 MHz,
CDCl3): δ= 7.06 (m, 1H), 7.00 (dd, J= 7.6, 2.0 Hz, 1H), 6.88 (t, J= 7.4 Hz, 2H), 4.56 (dd, J = 11.5, 3.0
Hz, 1H), 4.46 (dd, J = 11.5, 6.5 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 4.12 (dd, J = 6.5, 3.0 Hz, 1H), 1.30
ppm (t, J= 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ=168.5, 151.1, 127.0, 125.9, 122.0, 118.4, 116.8,
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66.1, 62.2, 41.4, 14.1. Anal. Calcd for C11H12O3S: C, 58.91; H, 5.39; O, 21.40; S, 14.30. Found: C,
58.58; H, 5.71; O, 21.63; S, 14.08.
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2,3-dibromopropionamide37 (IVa). Bromine (1.44 mL, 28.14 mmol) was added dropwise to a
solution of acrylamide (2.0 g, 28.14 mmol) in methanol (12 mL), at room temperature. Once
added, the reaction mixture was refluxed for 30 minutes, until decoloration occurred, then
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concentrated to dryness, affording IVa as a white solid. Yield: 6.50 g (100%). MP= 111°C. H NMR
(300 MHz, CDCl3): δ= 6.12 (bs, 1H), 6.00 (bs, 1H), 4.49 (dd, J = 8.5, 4.6 Hz, 1H), 3.95 (dd, J = 10.4,
8.5 Hz, 1H), 3.81 ppm (dd, J = 10.4, 4.6 Hz, 1H). Anal. Calcd for C3H5Br2NO: C, 15.61; H, 2.18; Br,
69.22; N, 6.07; O, 6.93. Found: C, 15.75; H, 2.42; Br, 69.01; N, 6.13; O, 6.69.
2-bromoacrylamide38 (Va). TEA (2.41 mL, 17.32 mmol) was added dropwise to a solution of IVa
(4.0 g, 17.32 mmol) in diethyl ether (40 mL), at room temperature. Once added, the reaction
mixture was refluxed for 80 hrs, the resulting suspension was filtered and the filtrate concentrated
to dryness, affording Va as a yellowish wax. Yield: 2.35 g (90%).1H NMR (300 MHz, CDCl3): δ= 6.96
(s, 1H), 6.52 (bs, 1H), 6.06 ppm (s, 1H), 5.90 (bs, 1H). Anal. Calcd for C3H4BrNO: C, 24.03; H, 2.69;
Br, 53.28; N, 9.34; O, 10.67. Found: C, 24.14; H, 2.92; Br, 53.03; N, 9.07; O, 10.84.
General procedure for 1,4-benzoxathian-2-carboxamide (5) or 1,4-benzoxathian-3-carboxamide
(6): 5 and 4 were accomplished starting from IVa (0.20 g, 0.88 mmol) and 1,2-mercaptophenol
(0.11 g, 0.88 mmol), following the same procedure described for 1 and 2, and purifying the
products by flash chromatography on silica gel, using cyclohexane/ethyl acetate 1/1 as elution
1
solvent. The ratio between the two regioisomers was quantified by H NMR data; global yield:
0.012 g (7%) to 0.13 g (75%), depending on the solvent used.
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1,4-benzoxathian-2-carboxamide (5): yellow oil, tr (Method C): 7.6 min. H NMR (300 MHz,
CDCl3): δ= 7.12–6.97 (m, 2H), 6.89 (m, 2H), 6.61 (bs, 1H), 6.39 (bs, 1H), 4.73 (dd, J = 8.4, 2.5 Hz,
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1H), 3.36 (dd, J = 13.2, 2.5 Hz, 1H), 3.19 ppm (dd, J = 13.2, 8.4 Hz, 1H). C NMR (75 MHz, CDCl3):
δ= 171.3, 149.9, 127.8, 126.1, 122.4, 118.2, 117.9, 74.4, 27.1. Anal. Calcd for C9H9NO2S: C, 55.37;
H, 4.65; N, 7.17; O, 16.39; S, 16.42. Found: C, 55.61; H, 4.58; N, 6.97; O, 16.59; S, 16.25.
1,4-benzoxathian-3-carboxamide (6): white solid, MP:124°C, tr (Method C): 6.4 min. 1H NMR (300
MHz, CDCl3): δ= 7.05 (m, 2H), 6.91 (t, J = 8.2 Hz, 2H), 6.81 (bs, 1H), 6.24 (bs, 1H), 4.91 (dd, J = 11.4,
13
3.3 Hz, 1H), 4.21 (dd, J = 11.4, 2.0 Hz, 1H), 3.89 ppm (dd, J = 3.3, 2.0 Hz, 1H). C NMR (75 MHz,
CDCl3): δ= 171.1, 151.6, 127.0, 126.3, 122.4, 119.0, 115.1, 66.0, 42.6. Anal. Calcd for C9H9NO2S: C,
55.37; H, 4.65; N, 7.17; O, 16.39; S, 16.42. Found: C, 55.65; H, 4.51; N, 7.07; O, 16.50; S, 16.27.
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2,3-dibromopropionitrile39 (IVb). Bromine (0.96 mL, 18.8 mmol) was added dropwise to a solution
of acrylonitrile (1.0 g, 18.8 mmol) in ACN (10 mL), at 0-5 °C. Once added, the reaction mixture was
warmed to RT and stirred for 2 hours. The reaction mixture was then diluted with DCM (20 mL)
and quenched with aqueous 10% sodium thiosulfate solution, dried over Na2SO4, filtered and
concentrated under reduced pressure, affording IVb as a yellowish oil. Yield: 2.42 g (60%). 1H NMR
(300 MHz, CDCl3): δ= 4.54 (dd, J = 9.2, 6.3 Hz, 1H), 3.78 (d, J = 9.2 Hz, 1H), 3.78 ppm (d, J = 6.3 Hz,
1H). Anal. Calcd for C3H3Br2N: C, 16.93; H, 1.42; Br, 75.07; N, 6.58. Found: C, 16.72; H, 1.71; Br,
75.23; N, 6.34.
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2-bromoacrylonitrile39 (Vb). TEA (1.59 mL, 11.39 mmol) was added dropwise to a solution of IVb
(2.43 g, 11.39 mmol) in DCM (20 mL), at room temperature. Once added, the reaction mixture was
stirred for 3 hours at room temperature and filtered. The resulting solution was washed with
aqueous 10% HCl solution, dried over Na2SO4, filtered and concentrated to dryness, affording Vb
as a yellow oil. Yield: 1.19 g (78%). 1H NMR (300 MHz, CDCl3): δ= 6.72 (d, J = 2.4 Hz, 1H), 6.41 ppm
(d, J = 2.4 Hz, 1H). Anal. Calcd for C3H2BrN: C, 27.31; H, 1.53; Br, 60.55; N, 10.61. Found: C, 27.13;
H, 1.48; Br, 60.76; N, 10.63.
General procedure for 1,4-benzoxathian-2-carbonitrile (7) or 1,4-benzoxathian-3-carbonitrile (8):
7 and 8 were accomplished starting from IVb (0.19 g, 0.88 mmol) and 1,2-mercaptophenol (0.11 g,
0.88 mmol), following the same procedure described for 1 and 2, and purifying the products by
flash chromatography on silica gel, using cyclohexane/ethyl acetate 9/1 as elution solvent. The
1
ratio between the two regioisomers was quantified by H NMR and HPLC data; global yield: 0.020
g (13%) to 0.093 g (60%), depending on the solvent used.
1,4-benzoxathian-2-carbonitrile (7): yellow oil, tr (Method A): 17.2 min. 1H NMR (300 MHz, CDCl3):
δ= 7.08 (m, 2H), 6.94 (m, 2H), 5.33 (dd, J= 5.7, 2.9 Hz, 1H), 3.40 (dd, J = 13.6, 2.9 Hz, 1H), 3.28 ppm
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(dd, J = 13.6, 5.7 Hz, 1H). C NMR (75 MHz, CDCl3): δ= 148.6, 127.7, 126.6, 123.2, 118.9, 116.2,
115.7, 62.7, 27.9. Anal. Calcd for C9H7NOS: C, 60.99; H, 3.98; N, 7.90, O, 9.03; S, 18.09. Found: C,
61.27; H, 3.79; N, 7.82, O, 9.22; S, 17.89.
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1,4-benzoxathian-3-carbonitrile (8): white solid, MP: 68.5°C, tr (Method A): 13.6 min. H NMR
(300 MHz, CDCl3): δ= 7.09 (m, 2H), 6.96 (m, 2H), 4.69 (dd, J = 11.5, 4.1 Hz, 1H), 4.35 (dd, J = 11.5,
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2.2 Hz, 1H), 4.14 ppm (dd, J = 4.1, 2.2 Hz, 1H). C NMR (75 MHz, CDCl3): δ=150.2, 127.1, 127.0,
122.8, 119.0, 116.5, 113.7, 65.7, 26.8. Anal. Calcd for C9H7NOS: C, 60.99; H, 3.98; N, 7.90, O, 9.03;
S, 18.09. Found: C, 61.37; H, 3.75; N, 7.73, O, 9.21; S, 17.94.
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1,3-Benzoxathiol-2-yl-acetonitrile (9): yellow oil, tr (Method A): 13.2 min. H NMR (300 MHz,
CDCl3): δ= 7.18 (dd, J = 7.6, 1.5 Hz, 1H), 7.07 (m, 1H), 6.97 (d, J= 7.5, 1.3 Hz, 1H), 6.90 (m, 1H), 6.23
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(t, J= 5.7 Hz, 1H), 3.05 (dd, J = 16.8, 6.0 Hz, 1H), 2.96 ppm (dd, J = 16.8, 5.5 Hz, 1H). C NMR (75
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MHz, CDCl3): δ=154.1, 126.6, 123.6, 123.2, 122.3, 115.2, 111.0, 85.6, 27.1. Anal. Calcd for
C9H7NOS: C, 60.99; H, 3.98; N, 7.90, O, 9.03; S, 18.09. Found: C, 61.08; H, 3.89; N, 7.62, O, 9.02; S,
18.39.
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Tert-Butyl 2,3-dibromopropionate31 (VIII). Bromine (0.40 mL, 7.8 mmol) was added dropwise to a
solution of tert-butyl acrylate (1.14 mL, 7.8 mmol) in DCM (10 mL), at 0-5 °C. Once added, the
reaction mixture was warmed to RT and stirred for 18 hours. The reaction mixture was then
diluted with DCM (20 mL) and quenched with aqueous 10% sodium thiosulfate solution, dried over
Na2SO4, filtered and concentrated under reduced pressure, affording VIII as a colourless oil. Yield:
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2.25 g (quantitative). H NMR (300 MHz, CDCl3): δ= 4.33 (dd, J = 11.4, 4.4 Hz, 1H), 3.88 (dd, J =
11.4, 9.7 Hz, 1H), 3.64 (dd, J = 9.7, 4.4 Hz, 1H), 1.51 ppm (s, 9H). Anal. Calcd for C7H12Br2O2: C,
29.20; H, 4.20; Br, 55.49; O, 11.11. Found: C, 29.42; H, 4.07; Br, 55.37; O, 11.13.
Tert-Butyl 2-bromoacrylate31 (IX). TEA (1.09 mL, 7.80 mmol) was added dropwise to a solution of
VIII (2.25 g, 7.80 mmol) in DCM (20 mL), at room temperature. Once added, the reaction mixture
was stirred for 16 hours at room temperature and filtered. The resulting solution was washed with
aqueous 10% HCl solution, dried over Na2SO4, filtered and concentrated to dryness, affording IX as
a yellowish oil. Yield: 1.53 g (95%). 1H NMR (300 MHz, CDCl3): δ= 6.85 (d, J = 1.5 Hz, 1H), 6.21 (d, J
= 1.5 Hz, 1H), 1.51 ppm (s, 9H). Anal. Calcd for C7H11BrO2: C, 40.60; H, 5.35; Br, 38.59; O, 15.45.
Found: C, 40.79; H, 5.42; Br, 38.46; N, 15.33.
General procedure for tert-Butyl 1,4-benzoxathian-2-carboxylate (10) or tert-Butyl 1,4-
benzoxathian-3-carboxylate (11): 10 and 11 were accomplished starting from VIII (0.25 g, 0.88
mmol) and 1,2-mercaptophenol (0.11 g, 0.88 mmol), following the same procedure described for 1
and 2, and purifying the products by flash chromatography on silica gel, using cyclohexane/ethyl
1
acetate 98/2 as elution solvent. The ratio between the two regioisomers was quantified by H
NMR and HPLC data; global yield: 0.066 g (30%) to 0.18 g (80%), depending on the solvent used.
Tert-Butyl 1,4-benzoxathian-2-carboxylate (10): white wax, tr (Method D): 30.8 min. 1H NMR (300
MHz, CDCl3): δ= 7.04 (m, 2H), 6.95 (m, 1H), 6.86 (m, 1H), 4.93 (dd, J= 5.2, 3.2 Hz, 1H), 3.29 (dd, J =
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13.1, 3.2 Hz, 1H), 3.23 (dd, J = 13.1, 5.2 Hz, 1H), 1.47 ppm (s, 9H). C NMR (75 MHz, CDCl3): δ=
167.7, 150.3, 127.5, 126.2, 121.6, 118.4, 116.5, 82.8, 72.3, 27.9, 26.7. Anal. Calcd for C13H16O3S: C,
61.88; H, 6.39; O, 19.02; S, 12.71. Found: C, 61.57; H, 6.54; O, 19.22; S, 12.67.
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Tert-Butyl 1,4-benzoxathian-3-carboxylate (11): cream oil, tr (Method D): 38.2 min. H NMR (300
MHz, CDCl3): δ= 7.04 (m, 2H), 6.95 (m, 1H), 6.86 (m, 1H), 4.56 (dd, J= 11.5, 2.9 Hz, 1H), 4.39 (dd, J =
11.5, 6.9 Hz, 1H), 4.05 (dd, J = 6.9, 2.9 Hz, 1H), 1.48 ppm (s, 9H).13C NMR (75 MHz, CDCl3): δ=167.5,
151.1, 129.8, 127.0, 125.7, 121.9, 118.3, 83.0, 66.3, 42.3, 27.9. Anal. Calcd for C13H16O3S: C, 61.88;
H, 6.39; O, 19.02; S, 12.71. Found: C, 61.61; H, 6.51; O, 19.26; S, 12.61.
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Tert-Butyl α-(2-hydroxyphenyl)thio-acrylate (12): colourless oil, tr (Method D): 24.2 min. 1H NMR
(300 MHz, CDCl3): δ= 7.45 (dd, J= 7.7, 1.6 Hz, 1H), 7.37 (m, 1H), 7.06 (dd, J= 8.2, 1.3 Hz, 1H), 6.95
(dd, J= 7.7, 1.3 Hz, 1H), 6.51 (bs, 1H), 6.22 (s, 1H), 5.07 (s, 1H), 1.53 ppm (s, 9H).13C NMR (75 MHz,
CDCl3): δ=163.1, 157.2, 137.9, 136.7, 132.5, 121.6, 121.4, 115.8, 115.0, 83.0, 27.9. Anal. Calcd for
C13H16O3S: C, 61.88; H, 6.39; O, 19.02; S, 12.71. Found: C, 61.59; H, 6.60; O, 19.20; S, 12.60.
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Supporting information
1H NMR of all the compounds, 13C NMR spectra of the derivatives 1-12, COSY NMR of Intermediate
VIa (together with their nomenclature and their chemical structure) and HPLC methods.
References
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15 Cabiddu, S.; Melis, S.; Sotgiu, F.; Cerioni, G. Heterocyclic Compounds Studies, Synthesis of 1,5-
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Bolchi, C.; Fumagalli, L.; Moroni, B.; Pallavicini, M.; Valoti, E. A Short Entry to Enantiopure 2-
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21Koo, J.; Avakian, S.; Martin, G. J. Derivatives of 1,4-Benzodioxan. I. l,4-Benzodioxan-2-
Carboxamides, J. Am. Chem. Soc. 1955, 77, 5373-5375.
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