Межі застосування частково ненасичених сультамів як дієнофілів і дієнів у реакції [4+2] циклоприєднання Дільса-Альдера
This study explores the reactivity of five- and six-membered sultams as both dienes and dienophiles in Diels-Alder reactions. As dienes in [4+2] cycloaddition, vinyl sultam bearing an additional endocyclic C=C double bond reacted with highly electron-poor alkenes, namely with maleimide, revealing th...
Збережено в:
| Дата: | 2025 |
|---|---|
| Автори: | , , , , , |
| Формат: | Стаття |
| Мова: | Англійська |
| Опубліковано: |
V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine
2025
|
| Теми: | |
| Онлайн доступ: | https://bioorganica.com.ua/index.php/journal/article/view/93 |
| Теги: |
Додати тег
Немає тегів, Будьте першим, хто поставить тег для цього запису!
|
| Назва журналу: | Ukrainica Bioorganica Acta |
| Завантажити файл: |  |
Репозитарії
Ukrainica Bioorganica Acta| _version_ | 1871193618772918272 |
|---|---|
| author | Borodin, Illia O. Zaika, Yevhen O. Brovarets, Volodymyr S. Doroshenko, Illia O. Grygorenko, Oleksandr O. Vashchenko, Bohdan V. |
| author_facet | Borodin, Illia O. Zaika, Yevhen O. Brovarets, Volodymyr S. Doroshenko, Illia O. Grygorenko, Oleksandr O. Vashchenko, Bohdan V. |
| author_institution_txt_mv | [
{
"author": "Illia O. Borodin",
"institution": "Taras Shevchenko National University of Kyiv, Kyiv, Ukraine; Enamine Ltd, Kyiv, Ukraine"
},
{
"author": "Yevhen O. Zaika",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine; Enamine Ltd., Kyiv, Ukraine"
},
{
"author": "Volodymyr S. Brovarets",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Illia O. Doroshenko",
"institution": "Taras Shevchenko National University of Kyiv, Kyiv, Ukraine; Enamine Ltd, Kyiv, Ukraine"
},
{
"author": "Oleksandr O. Grygorenko",
"institution": "Taras Shevchenko National University of Kyiv, Kyiv, Ukraine; Enamine Ltd, Kyiv, Ukraine"
},
{
"author": "Bohdan V. Vashchenko",
"institution": "Taras Shevchenko National University of Kyiv, Kyiv, Ukraine; Enamine Ltd, Kyiv, Ukraine"
}
] |
| author_sort | Borodin, Illia O. |
| baseUrl_str | https://bioorganica.com.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-19T14:56:55Z |
| description | This study explores the reactivity of five- and six-membered sultams as both dienes and dienophiles in Diels-Alder reactions. As dienes in [4+2] cycloaddition, vinyl sultam bearing an additional endocyclic C=C double bond reacted with highly electron-poor alkenes, namely with maleimide, revealing that successful cycloadduct formation occurred only under aqueous reflux conditions. Alternative conditions, including organic solvents and Lewis acid catalysis, were unsuccessful in promoting the reaction. Other dienophiles, such as acrylates and acetylene carboxylates, were ineffective, with sultam undergoing self-cycloaddition in moderate yields. As a dienophile, the partially unsaturated sultam reacted selectively only with electron-enriched Danishefsky’s diene, forming a fused sultam with an enone moiety. Other dienes, ranging from electron-enriched to electron-poor derivatives, did not react under the applied conditions, leaving the starting material unaltered. These results demonstrate the highly selective reactivity of sultams, influenced by their electronic properties, and provide valuable insights into their utility in synthetic organic chemistry |
| doi_str_mv | 10.15407/bioorganica2025.01.003 |
| first_indexed | 2025-07-17T12:20:06Z |
| format | Article |
| fulltext |
ISSN 1814-9758. Ukr. Bioorg. Acta, 2025, Vol. 20, N 1
UDC 547.853
DOI: https://doi.org/10.15407/bioorganica2025.01.003
3
RESEARCH ARTICLE
Scope and limitations of the use of partially unsaturated sultams as
dienophiles and dienes in [4+2] Diels-Alder reaction
Illia O. Borodin1,2, Yevhen O. Zaika1,3, Illia O. Doroshenko1,2, Volodymyr S. Brovarets3,
Oleksandr O. Grygorenko1,2, Bohdan V. Vashchenko1,2*
1 Enamine Ltd. (www.enamine.net), Kyiv, Ukraine
2 Taras Shevchenko National University of Kyiv, Kyiv, Ukraine
3 V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine
Abstract: This study explores the reactivity of five- and six-membered sultams as both dienes and dienophiles in Diels-Alder reactions.
As dienes in [4+2] cycloaddition, vinyl sultam bearing an additional endocyclic C=C double bond reacted with highly electron-poor
alkenes, namely with maleimide, revealing that successful cycloadduct formation occurred only under aqueous reflux conditions.
Alternative conditions, including organic solvents and Lewis acid catalysis, were unsuccessful in promoting the reaction. Other
dienophiles, such as acrylates and acetylene carboxylates, were ineffective, with sultam undergoing self-cycloaddition in moderate yields.
As a dienophile, the partially unsaturated sultam reacted selectively only with electron-enriched Danishefsky’s diene, forming a fused
sultam with an enone moiety. Other dienes, ranging from electron-enriched to electron-poor derivatives, did not react under the applied
conditions, leaving the starting material unaltered. These results demonstrate the highly selective reactivity of sultams, influenced by their
electronic properties, and provide valuable insights into their utility in synthetic organic chemistry.
Keywords: sultams; sulfonamides; dienes; dienophiles; Diels-Alder reaction; cycloaddition.
Introduction
Despite being recognized by the Nobel committee in
1950 as a prominent reaction, the Diels-Alder cycloaddition
[1] now serves as an important and rapid tool to construct
six-membered rings in a regio- and diastereoselective
manner with high tolerance to many functional groups [2-
6]. Current research demonstrates that the biosynthesis of
many natural products involves pericyclic reactions,
including the Diels-Alder reaction [7-9]. Modern synthetic
chemists often use common approaches for the
development of new promising compounds, which could be
the case with sultams [10]. A lot of important derivatives
contain a six-membered fused ring alongside the sultam
core (Figure 1) [11].
Received:
Revised:
Accepted:
Published online:
10.03.2025
24.03.2025
31.03.2025
30.06.2025
Corresponding author. Tel.: +380-44-239-3315;
e-mail: vashchenko@knu.ua (B.V. Vashchenko)
ORCID: 0000-0003-4575-2065
Figure 1. Pharmaceutically relevant examples of fused sultams.
© Zaika Ye.O. et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use,
distribution, and reproduction in any medium, provided the original author and source are credited.
Ukrainica Bioorganica Acta
w w w.b io or gani c a.o rg .ua
mailto:vashchenko@knu.
https://orcid.org/0000-0003-4575-2065
ISSN 1814-9758. Ukr. Bioorg. Acta, 2025, Vol. 20, N 1
4
In contrast to [2+2], and [3+2] cycloadditions [11], the
limited use of the [4+2] reaction for the preparation of
bicyclic sultams [12-16] could be addressed to the lack of
information on the synthesis and reactivity of sultams as
dienes and dienophiles for the preparation of bicyclic
derivatives. Therefore, in this work we have aimed at the
study of the reactivity of model sultams as both dienes and
dienophiles in the [4+2] cycloaddition reaction with
common reagents under various conditions.
Specifically, the study evaluates the model sultam
bearing two exo- and endocyclic C=C bonds as a diene in
[4+2] cycloaddition reactions with common dienophiles,
exploring the influence of electron-accepting groups and
reaction conditions on the outcome. Additionally, the
research examines the behavior of the sultam as a
dienophile when reacted with a range of dienes, aiming to
identify the electronic and structural factors critical for
successful cycloaddition and to expand the synthetic utility
of sultams in cycloaddition chemistry.
Results and Discussion
Sultams as dienes
First, we have aimed at the evaluation of the reactivity of
a model vinyl sultam 1 as diene (synthesized from
commercially available materials via enyne metathesis
reaction) in the [4+2] cycloaddition reaction (Diels-Alder
reaction) with maleimide 2a as a common dienophile
(Scheme 1).
Scheme 1. a) Synthesis of 1. b) The Diels-Alder reaction of a
model vinyl sultam 1 with maleimide 2a (relative configuration is
shown). c) Chemical shifts and correlations of main cross peaks
found in the NOE and HMBC spectra of compound 3 (PMP =
p-methoxyphenyl).
The cycloaddition reaction proved to be extremely
sensitive to the selection of solvent and conditions. Of the
five different attempts tried, the reaction was successful for
refluxing in an aqueous mixture (Table 1, entry 5),
providing cycloadduct 3 in moderate to good yield
depending on the reaction time.
At the same time, other common conditions, including
heating in toluene (Table 1, entries 1 and 2) or in CHCl3 in
the presence of Lewis acids (Table 1, entries 3 and 4), were
not successful in achieving the cycloaddition process.
A NOE experiment was performed to determine the
relative configuration of 3 after all the CHx protons were
matched by the HMBC method, which established no
interaction between the protons C(8a) at 3.90 and C(8b) at
4.23 ppm, indicating their relative trans-configuration.
Table 1. Reaction conditions and yields of the Diels-Alder
reaction of a vinyl sultam 1 with maleimide 2a (Scheme 1).
Entry Conditions Yield, %
1 PhMe, 100 °C 0
2 PhMe, 150 °C 0
3 Ti(Oi-Pr)4, CHCl3, 60 °C 0
4 Et2AlCl, CHCl3, 60 °C 0
5 H2O, 100 °C 37-70
Scheme 2. a) The Diels-Alder reaction of 1 as both diene and
dienophile to form product 4 (relative configuration is shown).
b) Chemical shifts and correlations of main cross peaks found in
the NOE correlation spectra of compound 4.
B.V. Vashchenko, O.O. Grygorenko et al.
5
Next, we have studied other common dienophiles, i.e.
acrylate 2b, acetylene carboxylate 2c, unsaturated sultam
2d, and azodicarboxylate 2e (Scheme 2).
It was envisaged, that the presence of a strong electron-
accepting sulfonamide fragment could have a negative
impact on the successful use of diene in the common Diels-
Alder reaction, which was confirmed by experiments with
alkenes bearing one electron-withdrawing group (EWG),
i.e. acrylate or acetylene carboxylate. In all cases, diene 1
reacted by a self-cycloaddition with the second equivalent
of 1 acting as a dienophile (Scheme 2). Product 4 was
formed in moderate yields, the structure and the relative
configuration of stereocenters were confirmed by a series of
NMR experiments including HMBC to match CHx carbons
and protons by chemical shifts, followed by a series of NOE
experiments to determine proton spatial interactions and
confirm the relative configuration. The relative confi-
guration of 4 was determined using NOE experiment based
on the interactions between protons C(6) at 1.85, C(7) at
3.03, C(7a) at 3.87 ppm, which proves that the protons at
3.03 and 3.87 ppm are on the same side of the formed ring.
In turn, only when the second EWG is present (e.g.
maleimide 2a), the dienophile has become activated enough
to react with diene 1, thus providing the corresponding
cycloadduct. Nevertheless, the reaction with diethyl azo-
dicarboxylate (DEAD) 2e was not fruitful in our hands.
Considering the electron-poor nature of diene 1, we have
tested the inverse electron-demand Diels-Alder reaction
with vinyl ether 2f, or dihydropyrrole 2g. To our surprise,
this approach was not successful in achieving the cross-
cycloadducts, and only product 4 was obtained.
Sultams as dienophiles
The model six-membered sultam 6 as a conjugated
alkene was subjected to the Diels-Alder reaction with model
dienes 7, ranging from the electron-enriched Danishefsky’s
diene 7a, dienamine 7b, alkyl-substituted derivative 7c,
N-Boc-protected pyrrole 7d to electron-poor carboxylate
derivative 7e (Scheme 3).
Only Danishefsky’s diene 7a (see Scheme 4) was a
suitable reagent for the preparation of fused sultam 8a
decorated with enone moiety in 45% yield (obtained as a ca.
4:1 mixture of trans- and cis-diastereomeric fused
derivatives; the structure was studied via a series of NMR
experiments; the key factor was the NOE interaction
between the bridgehead C(4a,8a) CHx protons of the formed
bicyclic system). In this case, the reaction proceeded by
heating the reaction mixture in toluene media over 12 h.
In all other cases and applied conditions (Table 2), no
reaction was observed, and the starting sultam remained
intact.
Reactions of sultam carboxylates 9 with electron-
enriched dienes 7 was not fruitful for the preparation of
cycloadducts 10 or 11 (Scheme 5). Sultam 12 bearing an
additional methoxymethylene group also did not react as a
dienophile, and the formation of two plausible
regioisomeric cycloadducts 13 and 14 was not observed.
These limited experimental results encouraged us to
study deeply the problem of the Diels-Alder reaction of
sultams. As is widely known, the reaction could proceed
through two primary frontier molecular orbital (FMO)
interactions. The normal electron demand type includes the
reaction between the HOMO (highest occupied molecular
orbital) of the diene and the LUMO (lowest unoccupied
molecular orbital) of the alkene, Alternatively, the inverse
electron demand is observed if the HOMO of the alkene
reacts with the LUMO of the diene. The pathway realized in
[4+2]
NBn
S
OO
COOH
6
N
N
Boc
7b 7c 7d 7e
O
TMSO
7a
7be
cross-cycloadduct
(not observed
in all experiments)
[diene][dienophile]
R
conditions
(Table 2)
R
NBn
S
OO
8
Scheme 3. The Diels-Alder reaction of sultam 6 with dienes 7.
Scheme 4. a) The Diels-Alder reaction of sultam 6 with Danishef-
sky’s diene 7a (relative configuration is shown). b) Chemical
shifts and correlations of main cross peaks found in the NOE
correlation spectra of compound 8a.
Table 2. Reaction conditions and yields of the Diels-Alder
reaction of dienophile 6.
Entry Conditions Yield, %
1 PhMe, 100 °C 0
2 Ti(Oi-Pr)4, CHCl3, 60 °C 0
3 Et2AlCl, CHCl3, 60 °C 0
4 H2O, 100 °C 0
5 TFA (cat), H2O, 100 °C 0
ISSN 1814-9758. Ukr. Bioorg. Acta, 2025, Vol. 20, N 1
6
Scheme 5. Attempted reactions of sultam carboxylates.
a given case depends predominantly on the relative orbital
energies. In turn, two major criteria are required for a
successful [4+2] cycloaddition: orbital symmetry
compatibility and a sufficiently small energy gap between
the interacting orbitals - generally no more than 11 eV.
Larger gaps typically require harsh conditions or may
render the reaction unfeasible.
Computational Methods
To estimate the orbital energies, we performed quantum
chemical calculations using ORCA 6.0.0. The MP2 method
with the def2-SVP basis set was employed, since it typically
provides more reliable energy estimations than standard
DFT methods, especially for frontier orbital analysis.
2-Benzyl-3,4-dihydro-2H-1,2-thiazine 1,1-dioxide (6)
has a LUMO at 3.00 eV and a HOMO at -10.81 eV. Thus,
the HOMO-LUMO gap exceeds the 11 eV threshold,
making cycloaddition unlikely under standard or even
moderately forcing conditions [17-19]. However, highly
electron-rich dienes i.e. Danishefsky’s diene (HOMO = -
7.90 eV) might react, given the calculated orbital gap (Δ =
10.9 eV) lying within the reactive range.
2-Benzyl-4-vinyl-2,3-dihydroisothiazole 1,1-dioxide (1)
has a LUMO of 1.74 eV and a HOMO of -9.83 eV. When
analyzing the exocyclic double C=C bond, it exhibits a
HOMO at -9.83 eV and a LUMO at 5.48 eV. Thus, dienes
with HOMO energies lower than -9.83 eV would
preferentially undergo dimerization via the direct pathway,
as the inverse pathway would involve a prohibitive orbital
gap (Δ = 15.4 eV). To assess the feasibility of
intermolecular cycloadditions versus diene dimerization, the
energy gap between the diene’s LUMO and the alkene’s
HOMO was calculated. The predicted pathway with the
smaller HOMO-LUMO gap is expected to dominate.
Table 3. Computational pathways of the Diels-Alder reac-
tion of sultams.
Alkene HOMO, eV Δ, eV[a]
Pathway
predicted
Product
observed
2e -13.30 3.47 dimerization dimer
2c -11.67 1.84 dimerization dimer
2b -10.72 0.89 dimerization dimer
2d -10.15 0.32 dimerization dimer
2g -9.40 -0.43 cross-cycloadduct dimer
2f -9.19 -0.64 cross-cycloadduct dimer
2a -9.11 -0.72 cross-cycloadduct cross-cycloadduct
[a] a gap between HOMO and LUMO
As found, two cases where theoretical predictions
diverge from experimental outcomes, when dimerization
was observed experimentally. This discrepancy may
indicate the influence of additional factors, e.g. aggregation,
solvent effects, or conformational constraints, which could
tip the balance toward dimerization even when the
B.V. Vashchenko, O.O. Grygorenko et al.
7
calculated energy advantage for product formation is up to
~0.7 eV.
Conclusions
The study highlights the selective reactivity of sultams as
both dienes and dienophiles in Diels-Alder reactions under
specific conditions, including heating in different solvents
i.e. PhMe, H2O or CHCl3 with or without addition of Lewis
acid catalyst.
The model sultam 1 demonstrated limited reactivity as a
diene, with successful cycloaddition occurring only under
aqueous reflux conditions with maleimide 2a, yielding
cycloadduct 3, and self-cycloaddition reaction to form
product 4. This suggests that the strong electron-accepting
nature of the sulfonamide fragment significantly influences
the reactivity and limits the scope of applicable dienophiles.
As a dienophile, the model sultam exhibited selective
reactivity with the electron-rich Danishefsky diene,
producing fused sultam 8. Other tested dienes failed to react
under the studied conditions, leaving the starting sultam
unchanged.
The analysis of frontier molecular orbital energies offers
valuable insight into the likely course of Diels-Alder
reactions involving heterocyclic dienes, i.e. 2-benzyl-3,4-
dihydro-2H-1,2-thiazine 1,1-dioxide and 2-benzyl-4-vinyl-
2,3-dihydroisothiazole 1,1-dioxide. In most cases, reactions
involving the selected dienes proceed via dimerization, even
when orbital energy gaps predict the possibility of
productive cycloaddition with certain electron-poor alkenes.
This suggests that factors beyond simple orbital energetics
are in action.
Experimental section
The solvents were purified according to the standard
procedures. All starting materials were available from
Enamine Ltd. or purchased from other commercial sources.
Melting points were measured on MPA100 OptiMelt
automated melting point system. Column chromatography
was performed using Kieselgel Merck 60 (230-400 mesh)
as the stationary phase. 1H, 13C and 19F NMR spectra were
recorded on a Agilent ProPulse 600 spectrometer (at
600 MHz for 1H NMR, 151 MHz for 13C NMR), Bruker
170 Avance 500 spectrometer (at 500 MHz for 1H NMR,
126 MHz for 13C NMR and 470 MHz for 19F NMR) and
Varian Unity Plus 400 spectrometer (at 400 MHz for 1H
NMR, 101 MHz for 13C NMR and 376 MHz for 19F NMR).
NMR chemical shifts are reported in ppm (δ scale)
downfield from TMS as an internal standard and are
referenced using residual NMR solvent peaks at 7.26 and
77.16 ppm for 1H and 13C in CDCl3, 2.50 and 39.52 ppm for
1H and 13C in DMSO-d6. Coupling constants (J) are given in
Hz. Spectra are reported as follows: chemical shift (δ, ppm),
multiplicity, integration, coupling constants (Hz). Elemental
analyses were performed at the Laboratory of Organic
Analysis, Department of Chemistry, Taras Shevchenko
National University of Kyiv. Mass spectra were recorded on
an Agilent 1100 LCMSD SL instrument (chemical
ionization (CI)) and Agilent 5890 Series II 5972 GCMS
instrument (electron impact ionization (EI)).
2-(4-Methoxybenzyl)-4-vinyl-2,3-dihydroisothiazole 1,1-
dioxide (1).
N-(4-methoxybenzyl)-N-(prop-2-yn-1-yl)ethenesulfona-
mide (20.0 g, 75.4 mmol) was dissolved in CH2Cl2 (500
mL), and Hoveyda-Grubbs II catalyst (2.36 g, 5mol%) was
added. Ethylene gas was bubbled through the solution and
reaction mixture was heated to 40 °C for 1 h. The resulting
mixture was concentrated under reduced pressure and
purified by column chromatography using EtOAc-hexanes
mixture (1:1, v/v). Colorless liquid. Yield 10.1 g (50%). 1H
NMR (500 MHz, CDCl3) δ 7.32 (d, J = 8.7 Hz, 2H), 6.89
(d, J = 8.7 Hz, 2H), 6.53 (s, 1H), 6.48 (dd, J = 17.7, 10.9
Hz, 1H), 5.51 (d, J = 10.8 Hz, 1H), 5.45 (d, J = 17.6 Hz,
1H), 4.30 (d, J = 2.4 Hz, 2H), 3.86 (s, 2H), 3.81 (s, 3H).
13C NMR (126 MHz, CDCl3) δ 159.1, 143.7, 129.4, 128.2,
126.5, 122.2, 121.8, 113.6, 54.7, 49.6, 46.7. GC/MS (EI):
m/z = 265 [M]+
. Anal. calcd. for C13H15NO3S: C 58.85; H
5.70; N 5.28; S 12.08. Found: C 58.80; H 5.74; N 5.60; S
11.94.
Rac-(5aR,8aS,8bS)-7-benzyl-2-(4-methoxybenzyl)-2,3,5,
5a,8a,8b-hexahydro-6H-isothiazolo[5,4-e]isoindole-6,8-
(7H)-di-one 1,1-dioxide (3).
Diene 1 (0.100 g, 0.400 mmol) was heated in water with
alkene 2a (75.0 mg, 0.400 mmol) at 100 °C for 16 hours.
After that, the solution was evaporated, and purification was
performed by HPLC. The target grey-colored product was
obtained in 52.0 mg (30%) yield. 1H NMR (600 MHz,
DMSO-d6) δ 7.24-7.19 (m, 5H), 7.18-7.13 (m, 2H), 6.85 (d,
J = 8.6 Hz, 2H), 5.93-5.87 (m, 1H), 4.55 (d, J = 15.0 Hz,
1H), 4.43 (d, J = 15.0 Hz, 1H), 4.26-4.21 (m, 1H), 4.16 (d, J
= 14.1 Hz, 1H), 3.98 (d, J = 14.1 Hz, 1H), 3.90 (t, J = 8.7
Hz, 1H), 3.71 (s, 3H), 3.57-3.53 (m, 1H), 3.49-3.46 (m,
1H), 3.41-3.38 (m, 1H), 2.61 (dd, J = 16.3, 7.1 Hz, 1H),
2.19-2.13 (m, 1H). 13C{H} NMR (151 MHz, DMSO-d6) δ
178.5, 174.4, 159.2, 136.3, 130.1, 128.7, 128.6, 127.8,
127.7, 127.6, 123.0, 114.3, 55.7, 55.5, 49.2, 47.5, 42.3,
39.9, 38.7, 22.6. LC/MS (ES-API): m/z = 451 [M–H]. Anal.
calcd. for C24H24N2O5S: C 63.70; H 5.35; N 6.19; S 7.08.
Found: C 64.00; H 5.26; N 6.43; S 6.84.
Rac-(7S,7aR)-2-(4-methoxybenzyl)-7-(2-(4-methoxyben-
zyl)-1,1-dioxido-2,3-dihydroisothiazol-4-yl)-2,3,5,6,7,7a-
he-xahydro-benzo[d]isothiazole 1,1-dioxide (4).
Diene 1 (1.00 g) was heated in water at 100 °C for 16
hours. After that, the solution was evaporated, and
purification was performed by HPLC. The target grey-
colored product was obtained in 0.601 g (60%) yield. 1H
NMR (600 MHz, CDCl3) δ 7.32 (d, J = 8.4 Hz, 2H), 7.22
(d, J = 8.4 Hz, 2H), 6.91-6.84 (m, 4H), 6.61 (s, 1H), 5.95-
5.88 (m, 1H), 4.36 (d, J = 14.3 Hz, 1H), 4.27 (d, J = 14.3
Hz, 1H), 4.22 (d, J = 14.3 Hz, 1H), 4.04-3.95 (m, 2H), 3.90-
3.84 (m, 1H), 3.82-3.75 (m, 7H), 3.61-3.54 (m, 2H), 3.08-
2.99 (m, 1H), 2.28-2.20 (m, 1H), 2.19-2.12 (m, 1H), 1.94-
1.88 (m, 1H), 1.87-1.83 (m, 1H). 13C{H} NMR (151 MHz,
ISSN 1814-9758. Ukr. Bioorg. Acta, 2025, Vol. 20, N 1
8
CDCl3) δ 159.5, 159.4, 147.7, 130.1, 129.9, 127.3, 127.0,
126.8, 125.0, 123.5, 114.3, 114.2, 59.7, 55.4, 54.3, 50.6,
47.6, 47.5, 34.1, 24.1, 22.2. LC/MS (ES-API): m/z = 529
[M–H]–. Anal. calcd. for C26H30N2O6S2: C 58.85; H 5.70; N
5.28; S 12.08. Found: C 59.05; H 5.33; N 4.91; S 12.44.
2-Benzyl-3,4,4a,8a-tetrahydro-2H-benzo[e][1,2]thiazin-
6(5H)-one 1,1-dioxide (8).
Obtained as a ca. 4:1 trans:cis mixture of diastereomers.
A mixture of the alkene (0.100 g, 0.450 mmol) and
Danishefsky diene (77.0 mg, 0.450 mmol) was heated in
toluene (1 mL) for 16 hours. After that, the solution was
cooled and evaporated under reduced pressure. Without
further analysis, a 1M HCl aq. solution was added over 1 h.
The resulting mixture was evaporated and purified by
HPLC. The target compound was obtained in 48.0 mg
(37%) yield. 1H NMR (500 MHz, CDCl3, mixture of
diastereomers) δ 7.67-7.17 (m, 8H), 7.16 (dd, J = 10.3, 1.9
Hz, 0.8H), 7.06 (dd, J = 10.3, 3.1 Hz, 0.2H), 6.36-6.16 (m,
1H), 5.84-5.64 (m, 1H), 4.43 (d, J = 14.3 Hz, 0.8H), 4.39-
4.26 (m, 2.2H), 4.12-4.07 (m, 0.2H), 3.82-3.69 (m, 2.8H),
3.54 (td, J = 13.5, 3.1 Hz, 0.8H), 3.35 (ddd, J = 13.5, 9.8,
3.4 Hz, 0.2H), 3.22 (dt, J = 14.2, 4.7 Hz, 0.2H), 3.19-3.04
(m, 1H), 2.94-2.79 (m, 0.8H), 2.75 (dd, J = 16.8, 6.0 Hz,
0.2H), 2.65-2.46 (m, 1H), 2.29 (dd, J = 16.8, 13.9 Hz,
0.8H), 1.76-1.57 (m, 2H). 13C{H} NMR (126 MHz, CDCl3)
δ 196.3, 195.7, 138.9, 138.8, 135.5, 135.4, 135.3, 133.1,
132.6, 128.8, 128.8, 128.7, 128.5, 128.5, 128.3, 128.2,
128.1, 128.0, 124.5, 119.6, 61.9, 58.1, 51.4, 50.9, 50.5,
49.7, 47.2, 46.8, 45.5, 43.1, 41.8, 38.8, 35.3, 28.9, 23.3.
LC/MS (ES-API): m/z = 290 [M–H]-. Anal. calcd. for
C15H17NO3S: C 61.83; H 5.88; N 4.81; S 11.00. Found: C
62.08; H 5.66; N 4.61; S 10.65.
Methyl 2-(tert-butyl)-4-methoxy-2,3-dihydroisothiazole-
5-carboxylate 1,1-dioxide (9).
Compound 15 (20 g, 80.2 mmol) was dissolved in
trimethyl orthoformate (100 mL) and stirred and 100 °C for
12 h. After the reaction was complete, excessive trimethyl
orthoformate was evaporated under reduced pressure. The
resulting solid residue was triturated in a hexane-t-BuOMe
(7:3) system to give pure compound 9. Yellow powder.
Yield 17.9 g (85%). 1H NMR (400 MHz, CDCl3) δ 4.04 (s,
3H), 4.00 (s, 2H), 3.81 (s, 3H), 1.45 (s, 9H). 13C NMR (101
MHz, CDCl3) δ 168.3, 158.9, 58.9, 57.0, 52.3, 45.2, 27.7.
LC/MS (ES-API): m/z = 206 [M–t-Bu]-. Anal. calcd. for
C10H17NO5S: C 45.62; H 6.51; N 5.32; S 12.18. Found:
C 45.26; H 6.59; N 5.29; S 11.97.
Methyl 2-(tert-butyl)-4-hydroxy-2,3-dihydroisothiazole-
5-carboxylate 1,1-dioxide (15).
Methyl tert-butylglycinate (70.0 g, 0.482 mol) was
dissolved in CH2Cl2 (1 L), Et3N (97.6 g, 0.964 mol)
was added, the solution was cooled to -10 °C. At this
temperature, methyl 2-(chlorosulfonyl)acetate (87.4 g,
0.506 mol) was added dropwise. The reaction mixture was
washed with water (1 L), 1 M HCl aqueous solution (1 L),
brine (500 mL), and evaporated under reduced pressure to
give 102 g of 14 (75% yield). To a single-neck flask, 14
(100 g, 0.355 mol) was added and dissolved in 1 L of
MeOH, followed by the addition of MeONa (38.4 g, 0.710
mol). The solution was stirred at 80 °C for 16 h. Then,
MeOH was evaporated, and the resulting precipitate was
washed with THF and evaporated under reduced pressure.
The compound was used in the next step immediately after
the preparation without additional purification. Pale yellow
solid. Yield 45.8 g (52%). 1H NMR (400 MHz, DMSO-d6)
δ 3.96 (s, 2H), 3.69 (s, 3H), 1.34 (s, 9H).
Notes
Acknowledgments and finances. The work was funded
by Enamine Ltd. The authors thank Prof. Andriy O.
Tolmachov for his encouragement and support, and all the
brave defenders of Ukraine that stood against the russian
full-scale invasion and made this research possible.
The authors declare no conflict of interest.
Author contributions. I.O.B.: synthesis of compounds,
calculations. Ye.O.Z.: conceptualization, synthesis of com-
pounds, formal analysis. I.O.D.: formal analysis, writing of
the manuscript. V.S.B.: conceptualization, supervision.
O.O.G.: conceptualization, supervision, writing of the
manuscript. B.V.V.: conceptualization, supervision, writing
of the manuscript.
Supporting information
Copies of NMR spectra for all key compounds.
References
1. Norton, J.A. The Diels-Alder Diene Synthesis. Chem. Rev. 1942, 31,
319-523.
2. Gregoritza, M.; Brandl, F.P. The Diels-Alder Reaction: A Powerful
Tool for the Design of Drug Delivery Systems and Biomaterials. Eur.
J. Pharm. Biopharm. 2015, 97, 438-453.
3. Yang, B.; Gao, S. Recent Advances in the Application of Diels-Alder
Reactions Involving o-Quinodimethanes, Aza-o-Quinone Methides
and o-Quinone Methides in Natural Product Total Synthesis. Chem.
Soc. Rev. 2018, 47, 7926-7953.
4. Nicolaou, K.C.; Snyder, S.A.; Montagnon, T.; Vassilikogiannakis, G.
The Diels-Alder Reaction in Total Synthesis. Angew. Chem., Int. Ed.
Engl. 2002, 41, 1668-1698.
5. Sara, A.A.; Um-e-Farwa, U.-F.; Saeed, A.; Kalesse, M. Recent
Applications of the Diels-Alder Reaction in the Synthesis of Natural
Products (2017-2020). Synthesis (Stuttg) 2022, 54, 975-998.
6. C. Bouchez, L.; Rusch, M.; Larraufie, M.-H. Diels-Alder
Cycloaddition in Medicinal Chemistry. Curr. Org. Chem. 2016, 20,
2358-2378.
7. Gao, L.; Ding, Q.; Lei, X. Hunting for the Intermolecular Diels–
Alderase. Acc. Chem. Res. 2024, 57, 2166-2183.
8. Stocking, E.M.; Williams, R.M. Chemistry and Biology of
Biosynthetic Diels-Alder Reactions. Angew. Chem., Int. Ed. Engl.
2003, 42, 3078-3115.
9. Watanabe, K. Discovery and Investigation of Natural Diels-
Alderases. J. Nat. Med. 2021, 75, 434-447.
10. Chong, Y.K.; Ong, Y.S.; Yeong, K.Y. Unveiling Sultam in Drug
Discovery: Spotlight on the Underexplored Scaffold. RSC Med.
Chem. 2024, 15, 1798-1827.
11. Grygorenko, O.O.; Vashchenko, B. V.; Blahun, O.P.; Zhersh, S.
Saturated Bicyclic Sultams. Eur. J. Org. Chem. 2020, 2020, 5787-
5800.
B.V. Vashchenko, O.O. Grygorenko et al.
9
12. Tornus, I.; Schaumann, E. Novel Applications of N-Sulfonyl-
Alkylamines in [2+4] Cycloadditions. Tetrahedron 1996, 52, 725-
732.
13. Dibchak, D.; Shcherbacova, V.; Denisenko, A.V.; Mykhailiuk, P.K.
Convenient Access to Conformationally Rigid Sultams. Org Lett
2019, 21, 8909-8914.
14. Greig, I.R.; Tozer, M.J.; Wright, P.T. Synthesis of Cyclic
Sulfonamides through Intramolecular Diels-Alder Reactions. Org.
Lett. 2001, 3, 369-371.
15. Ho, K.F.; Fung, D.C.W.; Wong, W.Y.; Chan, W.H.; Lee, A.W.M.
Synthesis and Diels-Alder Reactions of α,β-Unsaturated-γ-Sultams.
Tetrahedron Lett 2001, 42, 3121-3124.
16. Alonso, D.A.; Babrowski, A.; Fuensanta, M.; Nájera, C.; Varea, M.
3,5-Bis-(Trifluoromethyl)Phenyl Sulfones in the Synthesis of 3,5-
Disubstituted Cyclopent-2-Enones. Arkivoc 2007, 2007, 243-262.
17. Sarkar, S.; Bekyarova, E.; Haddon, R.C. Chemistry at the Dirac
Point: Diels-Alder Reactivity of Graphene. Acc. Chem. Res. 2012,
45, 673-682.
18. Dumont, E.; Chaquin, P. Diels-Alder Reaction: A Theoretical
Comprehensive Study of Substituent Effects Using the ‘H* Method.’
J. Mol. Struct. (Theochem) 2006, 758, 161-167.
19. Sauer, J.; Sustmann, R. Mechanistic Aspects of Diels‐Alder
Reactions: A Critical Survey. Angew. Chem., Int. Ed. Engl. 1980, 19,
779-807.
Межі застосування частково ненасичених сультамів як дієнофілів і дієнів у реакції
[4+2] циклоприєднання Дільса-Альдера
І.О. Бородін1,2, Є.О. Заїка1,3, І.О. Дорошенко1,2, В.С. Броварець3, О.О. Григоренко1,2, Б.В. Ващенко1,2*
1ТОВ НВП «Енамін», Київ, Україна
2Київський національний університет імені Тараса Шевченка, Київ, Україна
3Інститут біоорганічної хімії та нафтохімії ім. В.П. Кухаря НАН України, Київ, Україна
Резюме: У цій роботі досліджується реакційна здатність п’яти- та шестичленних сультамів як дієнів і дієнофілів у реакціях Дільса-Альдера. Як
дієн в [4+2] циклоприєднанні, вінілсультам, що містить додатковий ендоциклічний подвійний зв’язок C=C, прореагував з алкенами, збідненими
електронами, а саме з малеімідом, показуючи, що успішне утворення циклоадукту відбувалося лише за умов кип’ятіння у воді. Аль тернативні
умови, включаючи органічні розчинники та каталіз кислотою Льюїса, не сприяли реакції. Інші дієнофіли, такі як акрилати та
ацетиленкарбоксилати, були неефективними, а сультам піддавався самоциклоприєднанню з помірними виходами. Як дієнофіл, частков о
ненасичений сультам реагував вибірково лише зі збагаченим електронами дієном Данішефського, утворюючи конденсований сультам із
еноновою частиною. Інші дієни, починаючи від похідних, збагачених електронами, і закінчуючи похідними, збідненими електронами , не
вступали в реакцію за умов, що застосовувались, залишаючи вихідні речовини незмінним. Ці результати демонструють високоселективну
реакційну здатність сультамів, що залежить від їх електронних властивостей, і дають цінну інформацію про корисність таких сполук у
синтетичній органічній хімії.
Ключові слова: сультами; сульфаніламіди; дієни; дієнофіли; реакція Дільса-Альдера; циклоприєднання.
|
| id | oai:ojs2.bioorganica.com.ua:article-93 |
| institution | Ukrainica Bioorganica Acta |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-20T01:01:35Z |
| publishDate | 2025 |
| publisher | V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine |
| record_format | ojs |
| resource_txt_mv | bioorganicacomua/49/ddff8e63f8d24e936cdd49208b965c49.pdf |
| spelling | oai:ojs2.bioorganica.com.ua:article-932026-07-19T14:56:55Z Scope and limitations of the use of partially unsaturated sultams as dienophiles and dienes in [4+2] Diels-Alder reaction Межі застосування частково ненасичених сультамів як дієнофілів і дієнів у реакції [4+2] циклоприєднання Дільса-Альдера Borodin, Illia O. Zaika, Yevhen O. Brovarets, Volodymyr S. Doroshenko, Illia O. Grygorenko, Oleksandr O. Vashchenko, Bohdan V. sultams sulfonamides dienes dienophiles Diels-Alder cycloaddition сультами сульфаніламіди дієни дієнофіли Дільс-Альдер циклоприєднання This study explores the reactivity of five- and six-membered sultams as both dienes and dienophiles in Diels-Alder reactions. As dienes in [4+2] cycloaddition, vinyl sultam bearing an additional endocyclic C=C double bond reacted with highly electron-poor alkenes, namely with maleimide, revealing that successful cycloadduct formation occurred only under aqueous reflux conditions. Alternative conditions, including organic solvents and Lewis acid catalysis, were unsuccessful in promoting the reaction. Other dienophiles, such as acrylates and acetylene carboxylates, were ineffective, with sultam undergoing self-cycloaddition in moderate yields. As a dienophile, the partially unsaturated sultam reacted selectively only with electron-enriched Danishefsky’s diene, forming a fused sultam with an enone moiety. Other dienes, ranging from electron-enriched to electron-poor derivatives, did not react under the applied conditions, leaving the starting material unaltered. These results demonstrate the highly selective reactivity of sultams, influenced by their electronic properties, and provide valuable insights into their utility in synthetic organic chemistry У цій роботі досліджується реакційна здатність п’яти- та шестичленних сультамів як дієнів і дієнофілів у реакціях Дільса-Альдера. Як дієн в [4+2] циклоприєднанні, вінілсультам, що містить додатковий ендоциклічний подвійний зв’язок C=C, прореагував з алкенами, збідненими електронами, а саме з малеімідом, показуючи, що успішне утворення циклоадукту відбувалося лише за умов кип’ятіння у воді. Альтернативні умови, включаючи органічні розчинники та каталіз кислотою Льюїса, не сприяли реакції. Інші дієнофіли, такі як акрилати та ацетиленкарбоксилати, були неефективними, а сультам піддавався самоциклоприєднанню з помірними виходами. Як дієнофіл, частково ненасичений сультам реагував вибірково лише зі збагаченим електронами дієном Данішефського, утворюючи конденсований сультам із еноновою частиною. Інші дієни, починаючи від похідних, збагачених електронами, і закінчуючи похідними, збідненими електронами, не вступали в реакцію за умов, що застосовувались, залишаючи вихідні речовини незмінним. Ці результати демонструють високоселективну реакційну здатність сультамів, що залежить від їх електронних властивостей, і дають цінну інформацію про корисність таких сполук у синтетичній органічній хімії V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine 2025-06-30 Article Article application/pdf application/pdf https://bioorganica.com.ua/index.php/journal/article/view/93 10.15407/bioorganica2025.01.003 Ukrainica Bioorganica Acta; Vol. 20 No. 1 (2025): Ukrainica Bioorganica Acta; 3-9 Ukrainica Bioorganica Acta; Том 20 № 1 (2025): Ukrainica Bioorganica Acta; 3-9 1814-9766 1814-9758 10.15407/bioorganica2025.01 en https://bioorganica.com.ua/index.php/journal/article/view/93/90 https://bioorganica.com.ua/index.php/journal/article/view/93/91 Copyright (c) 2025 Illia O. Borodin, Yevhen O. Zaika, Volodymyr S. Brovarets, Illia O. Doroshenko, Oleksandr O. Grygorenko, Bohdan V. Vashchenko https://creativecommons.org/licenses/by/4.0 |
| spellingShingle | сультами сульфаніламіди дієни дієнофіли Дільс-Альдер циклоприєднання Borodin, Illia O. Zaika, Yevhen O. Brovarets, Volodymyr S. Doroshenko, Illia O. Grygorenko, Oleksandr O. Vashchenko, Bohdan V. Межі застосування частково ненасичених сультамів як дієнофілів і дієнів у реакції [4+2] циклоприєднання Дільса-Альдера |
| title | Межі застосування частково ненасичених сультамів як дієнофілів і дієнів у реакції [4+2] циклоприєднання Дільса-Альдера |
| title_alt | Scope and limitations of the use of partially unsaturated sultams as dienophiles and dienes in [4+2] Diels-Alder reaction |
| title_full | Межі застосування частково ненасичених сультамів як дієнофілів і дієнів у реакції [4+2] циклоприєднання Дільса-Альдера |
| title_fullStr | Межі застосування частково ненасичених сультамів як дієнофілів і дієнів у реакції [4+2] циклоприєднання Дільса-Альдера |
| title_full_unstemmed | Межі застосування частково ненасичених сультамів як дієнофілів і дієнів у реакції [4+2] циклоприєднання Дільса-Альдера |
| title_short | Межі застосування частково ненасичених сультамів як дієнофілів і дієнів у реакції [4+2] циклоприєднання Дільса-Альдера |
| title_sort | межі застосування частково ненасичених сультамів як дієнофілів і дієнів у реакції [4+2] циклоприєднання дільса-альдера |
| topic | сультами сульфаніламіди дієни дієнофіли Дільс-Альдер циклоприєднання |
| topic_facet | sultams sulfonamides dienes dienophiles Diels-Alder cycloaddition сультами сульфаніламіди дієни дієнофіли Дільс-Альдер циклоприєднання |
| url | https://bioorganica.com.ua/index.php/journal/article/view/93 |
| work_keys_str_mv | AT borodinilliao scopeandlimitationsoftheuseofpartiallyunsaturatedsultamsasdienophilesanddienesin42dielsalderreaction AT zaikayevheno scopeandlimitationsoftheuseofpartiallyunsaturatedsultamsasdienophilesanddienesin42dielsalderreaction AT brovaretsvolodymyrs scopeandlimitationsoftheuseofpartiallyunsaturatedsultamsasdienophilesanddienesin42dielsalderreaction AT doroshenkoilliao scopeandlimitationsoftheuseofpartiallyunsaturatedsultamsasdienophilesanddienesin42dielsalderreaction AT grygorenkooleksandro scopeandlimitationsoftheuseofpartiallyunsaturatedsultamsasdienophilesanddienesin42dielsalderreaction AT vashchenkobohdanv scopeandlimitationsoftheuseofpartiallyunsaturatedsultamsasdienophilesanddienesin42dielsalderreaction AT borodinilliao mežízastosuvannâčastkovonenasičenihsulʹtamívâkdíênofílívídíênívureakcíí42ciklopriêdnannâdílʹsaalʹdera AT zaikayevheno mežízastosuvannâčastkovonenasičenihsulʹtamívâkdíênofílívídíênívureakcíí42ciklopriêdnannâdílʹsaalʹdera AT brovaretsvolodymyrs mežízastosuvannâčastkovonenasičenihsulʹtamívâkdíênofílívídíênívureakcíí42ciklopriêdnannâdílʹsaalʹdera AT doroshenkoilliao mežízastosuvannâčastkovonenasičenihsulʹtamívâkdíênofílívídíênívureakcíí42ciklopriêdnannâdílʹsaalʹdera AT grygorenkooleksandro mežízastosuvannâčastkovonenasičenihsulʹtamívâkdíênofílívídíênívureakcíí42ciklopriêdnannâdílʹsaalʹdera AT vashchenkobohdanv mežízastosuvannâčastkovonenasičenihsulʹtamívâkdíênofílívídíênívureakcíí42ciklopriêdnannâdílʹsaalʹdera |