Synthesis, C-H bond functionalisation and cycloadditions of 6-styryl-1,2-oxathiine 2,2-dioxides

Article abstract of DOI:10.1039/d1ob01125a

A series of 6-styryl-1,2-oxathiine 2,2-dioxides have been efficiently obtained by a two-step protocol from readily available (1E,4E)-1-(dimethylamino)-5-arylpenta-1,4-dien-3-ones involving a regioselective sulfene addition and subsequent Cope elimination. Pd-Mediated direct C-H bond functionalisation of the 6-styryl-1,2-oxathiine 2,2-dioxides and a wider selection of 5,6-diaryl substituted 1,2-oxathiine 2,2-dioxides proceeded smoothly to afford C-3 (hetero)aryl substituted analogues and the results are contrasted with those of a complementary bromination - Suzuki cross-coupling sequence. Whilst the cycloaddition of benzyne, derived fromin situfluoride initiated decomposition of 2-(trimethylsilyl)phenyl trifluoromethanesulfonate, to the substituted 1,2-oxathiine 2,2-dioxides resulted in low yields of substituted naphthalenes, the addition of 4-phenyl-1,2,4-triazoline-3,5-dione to the 6-styryl-1,2-oxathiine 2,2-dioxides afforded novel 5,9-dihydro-1H-[1,2]oxathiino[5,6-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione 8,8-dioxides through a silica-mediated isomerisation of the initial [4 + 2] adducts.

Full text of DOI:10.1039/d1ob01125a

Organic &
Biomolecular Chemistry
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Synthesis, C–H bond functionalisation and
cycloadditions of 6-styryl-1,2-oxathiine 2,2-
dioxides†
Cite this: Org. Biomol. Chem., 2021,
19, 6431
Christopher D. Gabbutt,
and Dimitrios Zonidis
B. Mark Heron, * Thomas Lilly, Ochola W. Ogwang
*
A series of 6-styryl-1,2-oxathiine 2,2-dioxides have been efficiently obtained by a two-step protocol from
readily available (1E,4E)-1-(dimethylamino)-5-arylpenta-1,4-dien-3-ones involving regioselective
a
sulfene addition and subsequent Cope elimination. Pd-Mediated direct C–H bond functionalisation of the
6-styryl-1,2-oxathiine 2,2-dioxides and a wider selection of 5,6-diaryl substituted 1,2-oxathiine 2,2-diox-
ides proceeded smoothly to afford C-3 (hetero)aryl substituted analogues and the results are contrasted
with those of a complementary bromination – Suzuki cross-coupling sequence. Whilst the cycloaddition
of benzyne, derived from in situ fluoride initiated decomposition of 2-(trimethylsilyl)phenyl trifluoro-
methanesulfonate, to the substituted 1,2-oxathiine 2,2-dioxides resulted in low yields of substituted
naphthalenes, the addition of 4-phenyl-1,2,4-triazoline-3,5-dione to the 6-styryl-1,2-oxathiine 2,2-diox-
ides afforded novel 5,9-dihydro-1H-[1,2]oxathiino[5,6-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione
8,8-dioxides through a silica-mediated isomerisation of the initial [4 + 2] adducts.
Received 10th June 2021,
Accepted 29th June 2021
DOI: 10.1039/d1ob01125a
rsc.li/obc
route to diversely substituted 4-dialkylamino-3,4-dihydro-
1,2-oxathiine 2,2-dioxides and successfully eliminated the di-
Introduction
alkylamine moiety to afford a series of unsaturated mono-,
di- and tri-(hetero)aryl substituted 1,2-oxathiine 2,2-dioxides
(Scheme 1).13,19
The 1,2-oxathiine 2,2-dioxide unit is a useful but little studied
six-membered heterocyclic ring system.1–4 Transformation of
the 1,2-oxathiine 2,2-dioxide unit into five-membered hetero-
cyclic rings, pyrazoles and pyrroles, has been accomplished
upon condensation with hydrazines5 and 2,4-disubstituted
furans result from thermolysis.6 Indeed thermolysis of 4,6-
dimethyl-1,2-oxathiine 2,2-dioxide provides facile access to 2,4-
dimethylfuran from which the intricate side chain of mycolac-
tones A and B7 and the A and C ring moieties of taxol8 have
been obtained. Terphenylenes result from the cycloaddition of
acetylenes to 1,2-oxathiine 2,2-dioxides under forcing con-
ditions with the expulsion of SO3.9,10 Recently, the 1,2-
oxathiine 2,2-dioxide unit has attracted interest in materials
application including in energy storage/battery technology,11
as photoresists for high resolution lithography12 and as a core
unit in a photochromic dithienylethene.13 The synthesis,
chemistry and applications of 1,2-oxathiine 2,2-dioxides has
recently been reviewed.14
In this work we explore the selectivity of the addition of sul-
fenes to α,β-unsaturated enaminoketones derived from either
(E)-4-arylbut-3-en-2-ones or 4-phenylbut-3-yn-2-one to afford
unsaturated 1,2-oxathiine 2,2-dioxides bearing either a C-6
arylethenyl or arylethynyl moiety after Cope elimination of the
amine function from the intermediate 3,4-dihydro 1,2-
oxathiine 2,2-dioxides. Further functionalisation of the
oxathiine dioxide ring is examined by transition metal-
mediated cross-coupling and cycloaddition chemistry leading
to diversely substituted derivatives.
Results and discussion
Heating the (E)-4-(4-aryl)but-3-en-2-ones 1a–e in PhMe contain-
ing excess DMFDMA readily afforded the (1E,4E)-1-(dimethyl-
amino)-5-phenylpenta-1,4-dien-3-ones 2a–e in 51–93% yield.
The geometry of each CvC unit within the molecule was
readily established by 1H NMR spectroscopy with the styryl
moiety affording a doublet for 4-H at ca. δ 6.8 and for 5-H at
ca. δ 7.6 with J ∼ 15.8 Hz and the dimethylaminoethene unit
affording a doublet for 2-H at ca. δ 5.3 and for 1-H δ 7.8 with J
∼ 12.4 Hz. (E)-1-(Dimethylamino)-5-phenylpent-1-en-4-yn-3-one
We have previously reinvestigated the relatively scarcely
employed addition of sulfenes to enaminoketones15–18 as a
Department of Chemical Sciences, School of Applied Sciences, University of
Huddersfield, Queensgate, Huddersfield, HD1 3DH, UK. E-mail: m.heron@hud.ac.uk,
dimitrios.zonidis@hud.ac.uk
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
d1ob01125a
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Scheme 1
2f was obtained in a similar manner from 4-phenylbut-3-yn-2- dioxide 3g which was subsequently transformed into the
one 1f in 77% yield (Scheme 2). known 1,2-oxathiine 2,2-dioxide 4g in an overall yield of 81%
Generating phenylsulfene in situ using our established pro- (Scheme 3) which is comparable to that reported by Bisetty
1
tocol19 of the dropwise addition of excess phenylmethanesulfo- et al.20 The signal for 3-H in the H NMR spectrum of 4g (d6-
nyl chloride to a cold (−10–0 °C) stirred solution of the enami- DMSO) resonated at δ 7.26 and exhibited typical cis-alkene
noketone 1a–f, in anhydrous THF containing excess Et3N gave coupling with J3,4 = 10 Hz; 4-H appeared as a dd at δ 7.26 and
the 6-styryl, 3a–e, and 6-phenyethynyl, 3f, 4-dimethylamino- 5-H as a doublet (J4,5 = 6.7 Hz) at δ 6.31. The styryl group
3,4-dihydro-1,2-oxathiine 2,2-dioxides in 35–77% yield. In the exhibited the predicted doublets at δ 7.09 and 7.21 with J = 16
1H NMR spectra of 3a–f the alkene proton, 5-H, resonates at Hz.
ca. δ 5.6 and appears as a doublet (J4,5 ∼ 2.5 Hz), 4-H appears
As a consequence of the similarity between the key func-
at ca. δ 4.4 as a dd (J ∼ 2.5, 11.3 Hz) and 3-H, adjacent to the tional group of 4g (sultone) to 2H-pyrones and coumarins (lac-
SO2 moiety, appears as a doublet (J3,4 ∼ 11.3 Hz) at ca. δ 4.5. tones), we were inspired by direct C–H functionalisation strat-
The magnitude of the 3J coupling between 3-H and 4-H egies,21 in particular the work of Pereira et al., for the direct
suggests a trans-diaxial arrangement in accord with data C-3 arylation of coumarins.22 Thus, heating 4g in DMF con-
observed for simple 3,6-diaryl substituted 4-dimethylamino- taining AgOAc (1.1 eq.), Pd(PPh3)4 (10 mol%) and 4-iodobenzo-
3,4-dihydro-1,2-oxathiine 2,2-dioxides where J3,4 ∼ 11.3 Hz.19 trifluoride (3 eq.) overnight gave 4h in 82% yield.
The styryl moiety of 3a–f remains intact, since the sulfene
Encouraged by the success of this alternate strategy to func-
addition is regiospecific to the enaminoketone moiety, and tionalise C-3 of the 1,2-oxathiine 2,2-dioxide moiety we
affords the expected pair of doublets δ ∼6.6 and 7.1 with J = selected three mono- and bis-aryl substituted 1,2-oxathiine 2,2-
15.9 Hz.
dioxides prepared in our previous study.19 Employing the
Treatment of 3a–f with m-CPBA in cold DCM readily effected aforementioned direct C–H bond functionalisation reaction
the Cope elimination of the 4-dimethylamino function to afford conditions, a series of 3-aryl 1,2-oxathiine 2,2-dioxides were
4a–f in 84–93% yield, without any epoxidation of the styryl func- obtained (Table 1) in good to moderate, though as yet un-opti-
1
tion. In the H NMR spectra of 4a–f, 4-H, conjugated with the mised, yields. This ring functionalisation protocol is a useful
SO2 moiety, resonated further downfield (∼δ 6.9) than 5-H tool for the direct introduction of, in particular electron
(∼δ 6.2) and each appeared as a doublet with J4,5 = 6.6–7.4 Hz, deficient hetero(aryl) groups at C-3 which otherwise require
typical of a cis-diene unit. The styryl moiety of 4a–f predictably incorporation into the starting arylmethanesulfonyl chloride,
afforded a pair of doublets δ ∼6.6 and 7.3 with J = 15.8 Hz.
aryl sulfene precursor, of which there are relatively few avail-
In a complementary strategy to 3-aryl-6-styryl-1,2-oxathiine able inexpensive examples.
2,2-dioxides, the addition of sulfene, generated from MeSO2Cl
In a complementary exploration of C-3 functionalisation 5a
and Et3N, to 2a to afford the 3,4-dihydro-1,2-oxathiine 2,2- was brominated (Br2, CHCl3, 72 h, reflux) to afford 7 in 73%
Scheme 2 Reagents and conditions: (i) Either DMFDMA, reflux or DMFDMA, L-proline (10 mol%), reflux; (ii) Et3N, PhCH2SO2Cl, THF, 0 °C–rt; (iii)
m-CPBA, DCM, 0 °C–rt.
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Scheme 3 Reagents and conditions: (i) Et3N, MeSO2Cl, THF, 0 °C–rt; (ii) m-CPBA, DCM, 0 °C–rt; (iii) AgOAc (1.1 eq.), Pd(PPh3)4 (10 mol%),
4-I-C6H4CF3 (3 eq.), DMF, 80 °C, N2.
Table 1 Direct C–H bond arylation of 5a–c
homo-coupled oxathiine 10 (δ4,4′-H 7.56) was optimised to 51%.
From the present study it would appear that the 3-bromo-1,2-
oxathiine 2,2-dioxide unit is susceptible to homo-coupling.
Indeed, homo-coupling of aryl halides has been observed
during borylation reactions and utilised to good effect for
example in the total synthesis of Pusilatin A25 and biindolyls.26
Metz et al., have previously examined the cycloaddition of
acetylenic dienophiles e.g. DMAD ethyl propiolate and phenyl-
Yielda
(%)
acetylene27 to the fixed diene unit of 4,6-diaryl-1,2-oxathiine
Substrate R1
R2
Product Ar
2,2-dioxides and noted that the cycloaddition required forcing
conditions e.g. for DMAD either 150 °C (100 W microwave) for
30 min or 25 °C, 1300 MPa for 3 days.28 We were interested to
examine the cycloaddition of the reactive hetero dienophile,
4-phenyl-1,2,4-triazoline-3,5-dione (PTAD), to the di- and tri-
phenyl substituted oxathiine 2,2-dioxides 5a and 6a, respect-
ively and in particular the addition of PTAD to the series of 4a–
d, g and h in anticipation that the latter would readily add to
the diene unit comprised of the C5–C6 CvC unit and the
6-styryl substituent to afford a novel tricyclic ring system. PTAD
5a
5a
5a
5a
5b
5c
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
6a
6b
6c
6d
6e
Ph
39
4-MeOC6H4 26
4-CF3C6H4
4-Pyridyl
Ph
57
68
32
33b
4-MeOC6H4 4-MeOC6H4 6f
4-Pyridyl
a Yields are unoptimized. b Compound 6f is slightly air sensitive and
becomes red upon standing.
yield. Guided by reaction conditions employed by Wu et al., has attracted much interest over the years29,30 and there has
for the 3-arylation of 3-bromopyran-2-ones23 the Suzuki cross- been a resurgence in its use as a consequence of its excellent
coupling of 7 with arylboronic acids gave 6a (40%), 6b (58%) dienophile character31–34 and as a component in new electro-
and 6c (36%) (unoptimized yields); it is noteworthy that the philic substitution ‘click’ reactions.35
highest yield for the Suzuki cross-coupling reaction was
Prolonged heating of a mixture of PTAD and either 5a or 6a
recorded with the electron rich 4-methoxyphenylboronic acid in 1,2-DCE failed to afford any cycloadduct, confirming the
and complements the C–H bond functionalisation where the experimental observations by Metz et al.,27,28 that cycloaddi-
best yield was noted for electron deficient coupling partners. tions to the 1,2-oxathiine 2,2-dioxide ‘diene’ unit require
Bromination of 5b was marginally more effective, though did forcing conditions. Encouragingly, the wine-red colour of a
require the addition of pyridine (0.25 eq.) to assist with the solution of PTAD and the 6-styryl-1,2-oxathiine 2,2-dioxide 4a
elimination step, affording 8 in 87% yield. Suzuki cross-coup- in 1,2-DCE gradually discharged overnight suggestive of con-
1
ling of the latter afforded 6e in 27% together with 6,6′-diphe- sumption of the PTAD. Examination of the H NMR spectrum
nyl-[3,3′-bi(1,2-oxathiine)] 2,2,2′,2′-tetraoxide 9 (10%) as a con- of the resulting crude product indicated the formation of the
1
sequence of homo-coupling (Scheme 4). In the H NMR spec- expected [4 + 2] adduct, 5,10a-dihydro-1H-[1,2]oxathiino[5,6-c]
trum of 9 5,5′-H appears as a distinct doublet at δ 6.63 with J = [1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione 8,8-dioxide, 11a,
7.4 Hz; the signal for 4,4′-H was coincidental with the signal by the presence of three well separated signals at δ 5.37
for the aromatic ring protons.
(10a-H), δ 5.81 (5-H) and δ 6.31 (6-H) with the signal for 10-H
The one step direct C–H functionalisation protocol was coincidental with the aromatic signals. A pair of cross-peak
more effective for the preparation of 6a, 6c, and 6e whereas the contours between 5-H and 10a-H were also observed on the
bromination – Suzuki cross-coupling protocol afforded 6b in NOESY spectrum of 11a, pointing to a syn disposition between
better yield albeit requiring greater synthetic effort.
these two protons in agreement with the suprafacial fashion of
Attempts to effect a Suzuki–Miyaura borylation of 7 employ- the hetero Diels–Alder addition of PTAD. Rather unexpectedly,
24
ing B2Pin2 and Pd(dppf)Cl2 in order to afford a 3-borylated 11a rearranged upon a quick clean up by short column chrom-
adduct for exploitation in alternative Suzuki cross-coupling atography on silica to afford the isomeric 5,9-dihydro-1H-[1,2]
reactions with aryl halides were unsuccessful and whilst no oxathiino[5,6-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione
borylated product could be identified the formation of the 8,8-dioxide 12a in 60% yield (Scheme 5). The 1H NMR spec-
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Scheme 4 Reagents and conditions: (i) Br2, CHCl3, reflux, 72 h; (ii) Br2, pyridine (0.25 eq.), CHCl3, reflux; (iii) ArB(OH)2 (1.5 eq.), Pd(OAc)2 (5 mol%),
PCy3 (10 mol%) (K2HPO4·3H2O (3 eq.), DMAc/MeOH, N2; (iv) B2pin2, Pd(dppf)Cl2, KOAc, 1,4-dioxane, 80 °C, 1.5 h, N2; (v) PhB(OH)2 (1.5 eq.), Pd(OAc)2
(5 mol%), PCy3 (10 mol%), K2HPO4·3H2O (3 eq.), DMAc, N2.
trum of 12a presented four well-resolved signals at δ 5.48 (ddd, long-range correlation of this carbon with the adjacent proton
J = 0.8, 1.0, 3.6 Hz, 9-H), δ 5.96 (ddd, J = 0.5, 0.8, 6.1 Hz, 5-H), δ at δ 7.11 (10-H), as well as one with the aromatic protons at
6.14 (ddd, J = 1.0, 1.7, 6.1 Hz, 6-H) and δ 7.11 (ddd, J = 0.5, 1.7, circa δ 7.56; no such correlation was observed with either
3.6 Hz, 10-H) (see ESI†). Although no conformational infor- of the other protons of the tricyclic core [δ 5.96 (5-H) and
mation about these protons could be inferred via NOESY, their δ 6.14 (6-H)].
multiplicity and coupling constants (J = 1.7 Hz for 6-H and
The addition of PTAD proceeded in a similar manner with
10-H, J = 0.8 Hz for 5-H and 9-H) attested to 6-H and 10-H 4b and 4c to afford the analogous 5,9-dihydro-adducts 12b
being appended on the terminal positions of a diene fragment, and c, respectively. In each case a small amount of the crude
with 5-H and 9-H on their periphery and at a distance where adduct was purified by trituration and characterised to estab-
no long-range coupling can occur between them. The spectra lish the identity of the initial [4 + 2] adduct prior to rearrange-
of the initial isolated crude adduct 11a and rearranged isolated ment upon column chromatography silica. Indeed, stirring a
product 12a are presented in Fig. 1.
solution of 11c in EtOAc containing suspended chromato-
Additional NMR evidence for the proposed structure 12a graphy silica readily effected the rearrangement to afford 12c
was obtained via 2D-NMR experiments that provided more in quantitative yield in a matter of minutes. The trend of
information regarding the position of 9-H at δ 5.48. In particu- decreasing yield of adduct with increasing electron withdraw-
lar, the HSQC spectrum of 12a suggested that 9-H is situated ing power of the styryl unit was further confirmed by the
on a C atom that resonates at δ 63.07. Utilising this infor- failure of 4d, bearing a 4-nitrostyryl group, to afford any
mation, the HMBC spectrum of the compound presented a adduct. Interestingly, the addition of PTAD to 4h, in which
Scheme 5 Reagents and conditions: (i) 1,2-DCE, rt and or reflux; (ii) column chromatography on silica, CH2Cl2.
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Fig. 1 1H NMR spectra (selected chemical shift range) of initial adduct (11a) and isolated product (12a) after elution from silica.
the Ph and 4-CF3C6H4 groups are inverted relative to those in nylnaphthalene 16 (22%), 1-(4-methoxyphenyl)naphthalene 17
4c, proceeded to afford 12f in 18% yield, further supporting (8%) and 1,2,4-triphenylnaphthalene 18 (32%), respectively
the observation that the presence of electron withdrawing (Scheme 7). Unfortunately, addition of benzyne to 6-styryl-1,2-
substituents is detrimental to the efficiency of the addition oxathiines 4a,b gave a complex reaction product from which
process.
The addition of excess PTAD to 4g, in which the 1,2-
no pure compound could be isolated.
In summary, a small library of 3-aryl-1,2-oxathiine 2,2-diox-
oxathiine ring is unsubstituted at C-3, only gave the mono- ides with 6-arenyl and 6-arynyl substituents was constructed
adduct 12e in 70% after stirring in 1,2-DCE overnight followed starting from α-methyl ketones via our established 3-step pro-
1
by routine treatment with chromatography silica. The H NMR tocol, highlighting the suitability of these steps in furnishing
spectrum of 12e further supports the silica-mediated double 1,2-oxathiine 2,2-dioxides with unsaturated moieties on the
bond migration and affords a multiplet at δ 4.24 accounting 6-position. Attempts at coupling selected aryl substituted 1,2-
for the diastereotopic 9-H pair; 5-H and 6-H appear at δ 5.91 oxathiine 2,2-dioxides with aryl iodides in a C–H activation
and δ 6.08, respectively and 10-H at δ 6.96.
coupling reaction allowed the functionalisation of the 3-posi-
Continuing our initial survey of cycloadditions to the tion; the protocol also allowed for the introduction of a pyridyl
6-styryl substituted 1,2-oxathiines, a mixture of 4b and DMAD group, thus avoiding the use of an expensive sulfonyl halide
was heated overnight. Elution of the resulting dark, multi-com- precursor in
a potentially challenging sulfene addition.
ponent reaction mixture from silica gave the aromatised Bromination of selected aryl substituted 1,2-oxathiine 2,2-diox-
adduct 13 in 10% yield as the only identifiable product; provid- ides proceeded with moderate efficiency and the brominated
ing an alternative, albeit low yielding, de novo route to a analogues were coupled to aryl boronic acids in a Suzuki cross-
diversely substituted benzoxathiine 2,2-dioxide (Scheme 6).
coupling method to assess the efficiency of this method in
In a final exploration of the reactivity of the substituted 1,2- functionalising the 1,2-oxathiine ring scaffold. Interestingly,
oxathiine 2,2-dioxides, benzyne, generated in situ from the the two Pd-catalytic routes presented complimentary reactivity
action of excess CsF on 2-(trimethylsilyl)phenyl trifluorometha- profiles, with C–H activation coupling appearing to be more
nesulfonate,36 was added to 6e, 14 and 15 to afford 1,4-diphe- suitable for appending electron deficient aryl groups and the
Scheme 6
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Scheme 7 Reagents and conditions: (i) CsF, MeCN, rt.
Suzuki cross-coupling more compatible for incorporating elec- spectrophotometer equipped with a diamond ATR attachment
tron rich aryl groups. An additional aspect made apparent (neat sample). Flash column chromatography was performed
during these attempts was the unexpected ability of 1,2- on chromatography silica gel (Fluorochem, 40-63 micron par-
oxathiine 2,2-dioxides to undergo homo-coupling to give bis- ticle size distribution). All final compounds were homo-
heterocyclic analogues. Utilising the styryl analogues in geneous by TLC using a range of eluent systems of differing
cycloadditions proved to be of special interest in the case of polarity (Merck TLC aluminium sheets silica gel 60 F254 (cat.
PTAD, as the cycloadducts resulting from the addition of PTAD no. 105554)). High resolution mass spectra were recorded on
readily rearrange in the presence of silica towards dienic regio- an Agilent 6210 1200 SL TOF spectrometer within the IPOS
isomers, which presents an unusual case of structure altera- centre at the University of Huddersfield.
tion during purification. Finally, a preliminary exploration of
The following styrylketones and enaminoketones were
benzyne addition towards naphthalene derivatives met with obtained by standard procedures and possessed spectroscopic
limited success, with further work required to optimise the and physical data in agreement with literature data: (E)-4-(4-
reaction conditions and ascertain potential substitution methoxyphenyl)but-3-en-2-one,37 (E)-4-(4-nitrophenyl)but-3-en-
effects.
2-one,38
(E)-4-(4-(4-trifluoromethyl)phenyl)but-3-en-2-one,39
(E)-4-(2-bromophenyl)but-3-en-2-one40 and (1E,4E)-1-(dimethyl-
amino)-5-phenylpenta-1,4-dien-3-one.41
Experimental
Preparation of enaminoketones
Equipment and materials
(1E,4E)-1-(Dimethylamino)-5-phenylpenta-1,4-dien-3-one 2a.
Unless otherwise stated, reagents and solvents were purchased 4-Phenyl-3-buten-2-one (5.00 g, 34.2 mmol) was dissolved in
from major chemical catalogue companies and were used as DMFDMA (11.4 mL, 85.5 mmol, 2.5 eq.) under a N2 atmo-
supplied. Routine 1H NMR (400 MHz) and 13C NMR (100 MHz) sphere and heated to 80 °C, before the addition of L-proline
spectra were recorded on a Bruker Avance DPX400 in CDCl3. (0.39 g, 3.42 mmol, 10% mol). The reaction mixture was
Occasional 1H NMR spectra were also recorded on a Bruker stirred at 80 °C overnight and then cooled. The volatile com-
Avance 300 MHz instrument in CDCl3. Chemical shifts are pro- ponents were removed by rotary evaporation and the crude
vided in parts per million (ppm) using either the residual solid was triturated with Et2O to afford the title compound as
solvent peak or TMS as the internal reference. Coupling con- a pale yellow-brown solid (5.65 g, 82%); mp 90–95 °C (lit. mp
stants (J) are provided in Hz and where applicable, in order to 94–96 °C (ref. 41)); νmax (neat): 3020, 2916, 1639, 1616 (CvO),
resolve close signals and extract valuable coupling infor- 1577, 1549, 1496, 1484, 1432, 1365, 1345, 1275, 1219, 1200,
mation, the raw FID data was processed using a Gaussian mul- 1158, 1116, 1030 cm−1; δH (400 MHz, CDCl3) 2.88 (s, 3H,
tiplication in place of the more usual exponential multipli- N(CH3)2), 3.12 (s, 3H, N(CH3)2), 5.27 (d, J = 12.5 Hz, 1H,
cation. All FT-IR spectra were recorded on a Nicolet 380 FTIR OCCHvCHNMe2), 6.79 (d, J = 15.8 Hz, 1H, PhCHvCHCO),
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7.29–7.37 (m, 3H, Ar–H), 7.53–7.55 (m, 2H, Ar–H), 7.55 (d, J = Hz, 1H, 4-H), 7.58 (d, J = 15.9 Hz, 1H, 5-H), 7.65–7.68 (m, 2H,
15.7 Hz, 1H, PhCHvCHCO), 7.75 (d, J = 12.5 Hz, 1H, Ar–H), 7.80 (d, J = 12.2 Hz, 1H, 1-H), 8.20–8.22 (m, 2H, Ar–H);
OCCHvCHNMe2); δC (100 MHz, CDCl3) 37.27, 44.99, 96.39, δC (100 MHz, CDCl3) 37.35, 45.18, 96.54, 124.05, 128.31,
127.88, 128.31, 128.71, 129.23, 135.82, 138.49, 153.46, 186.32.
(1E,4E)-1-(Dimethylamino)-5-(4-methoxyphenyl)penta-1,4- = 247.1082, C13H14N2O3 requires [M + H]+ = 247.1080.
dien-3-one 2b. (E)-4-(4-Methoxyphenyl)but-3-en-2-one (6.93 g, (1E,4E)-1-(2-Bromophenyl)-5-(dimethylamino)penta-1,4-dien-
132.38, 135.54, 142.37, 147.79, 154.12, 184.94; found [M + H]+
39.3 mmol) was dissolved in PhMe (50 mL) and DMFDMA 3-one 2e. (E)-4-(2-Bromophenyl)but-3-en-2-one was dissolved in
(15.6 mL, 118.0 mmol, 3 eq.) and L-proline (0.45 g, 10% mol) DMFDMA (7.40 mL, 55.5 mmol, 2.5 eq.) under a N2 atmo-
under a N2 atmosphere. The mixture was refluxed for 5 d and sphere and the reaction mixture was heated to reflux overnight
then cooled to room temperature whereupon the volatile com- and then cooled to room temperature. The volatile com-
ponents were removed by rotary evaporation. The resulting ponents were removed by rotary evaporation to afford the
solid was triturated with Et2O to afford the product as a yellow product as a pale brown oil (5.77 g, 93%); νmax (neat): 2908,
solid (5.46 g, 60%); mp = 100–102 °C (lit. mp 99–101 °C (ref. 2803, 1654, 1610 (CvO), 1541, 1463, 1416, 1351, 1258, 1217,
42)); νmax (neat): 2996, 2909, 2837, 1653, 1610, 1597, 1573, 1199, 1082, 1020 cm−1; δH (400 MHz, CDCl3) 2.90 (s, 3H,
1531, 1509, 1434, 1417, 1405, 1355, 1300, 1269, 1247, 1170, NCH3), 3.14 (s, 3H, NCH3), 5.31 (d, J = 12.5 Hz, 1H, 2-H), 6.71
1144, 1084, 1026 cm−1; δH (400 MHz, CDCl3) 2.89 (br s, 3H, (d, J = 15.8 Hz, 1H, 4-H), 7.14–7.19 (m, 1H, Ar–H), 7.27–7.30
NCH3), 3.08 (br s, 3H, NCH3), 3.82 (s, 3H, CH3O), 5.25 (d, J = (m, 1H, Ar–H), 7.57–7.63 (m, 2H, Ar–H), 7.75 (d, J = 12.5 Hz,
12.5 Hz, 1H, 2-H), 6.67 (d, J = 15.9 Hz, 1H, 4-H), 6.87–6.89 (m, 1H, 1-H), 7.86 (d, J = 15.8 Hz, 1H, 5-H); δC (100 MHz, CDCl3)
2H, Ar–H), 7.48–7.50 (m, 2H, Ar–H), 7.53 (d, J = 15.9 Hz, 1H, 37.27, 45.08, 95.90, 125.26, 127.51, 127.62, 130.16, 131.42,
5-H), 7.73 (d, J = 12.5 Hz, 1H, 1-H); δC (100 MHz, CDCl3) 37.43, 133.27, 135.95, 136.83, 153.71, 186.03; found [M + H]+
=
44.90, 55.33, 96.40, 114.17, 126.16, 128.55, 129.40, 138.26, 280.0328, C13H1479BrNO requires [M + H]+ = 280.0331.
153.14, 160.61, 186.54; found [M + H]+ = 232.1334, C14H17NO2
requires [M + H]+ = 232.1335.
(E)-1-(Dimethylamino)-5-phenylpent-1-en-4-yn-3-one 2f.
4-Phenylbut-3-yn-2-one (3.03 mL, 20.8 mmol, 1.0 eq.) was dis-
(1E,4E)-1-(Dimethylamino)-5-(4-(trifluoromethyl)phenyl)penta- solved in PhMe (20 mL) and DMFDMA (4.15 mL, 31.2 mmol,
1,4-dien-3-one 2c. (E)-4-(4-(Trifluoromethyl)phenyl)but-3-en-2- 1.5 eq.) under a N2 atmosphere. The resulting mixture was
one was dissolved in DMFDMA (7.75 mL, 58.3 mmol, 2.5 eq.) heated at reflux overnight. Upon cooling the volatile com-
and PhMe (15 mL) under a N2 atmosphere. The mixture was ponents were removed under reduced pressure to afford a
heated to reflux overnight and then cooled to room tempera- viscous crude oil which upon trituration with Et2O afforded
ture whereupon the volatile components were removed by the title compound as a pale brown powder (3.18 g, 77%); mp
rotary evaporation. The obtained crude solid mass was = 80–82 °C, (lit. mp = 86–87 °C (ref. 43)); νmax (neat): 1621
crushed into a fine powder and triturated with 1 : 1 Et2O/P.E. (CvO), 1558, 1488, 1441, 1405, 1343, 1308, 1267, 1207, 1193,
to yield the product as a yellow solid (3.17 g, 51%); mp = 1178, 1115, 1025 cm−1; δH (400 MHz, CDCl3) 2.89 (s, 3H,
131–133 °C (lit. mp 133–134 °C (ref. 42)); νmax (neat): 3062, NCH3), 3.17 (s, 3H, NCH3), 5.33 (d, J = 12.6 Hz, 1H, COCH),
2916, 2803, 1653, 1613 (CvO), 1537, 1422, 1360, 1318, 1264, 7.33–7.41 (m, 3H, Ar–H), 7.54–7.57 (m, 2H, Ar–H), 7.74 (d, J =
1161, 1111, 1089, 1063, 1009 cm−1; δH (400 MHz, CDCl3) 2.91 12.6 Hz, 1H, CHNMe); δC (100 MHz, CDCl3) 37.36, 45.36,
(s, 3H, NCH3), 3.16 (s, 3H, NCH3), 5.28 (d, J = 12.4 Hz, 1H, 86.53, 87.79, 102.17, 121.38, 128.45, 129.55, 132.40, 158.22,
2-H), 6.85 (d, J = 15.7 Hz, 1H, 4-H), 7.58 (d, J = 15.7 Hz, 1H, 174.78; found [M + H]+ = 200.1068, C13H13NO requires [M +
5-H), 7.59–7.66 (m, 4H, Ar–H), 7.79 (d, J = 12.4 Hz, 1H, 1-H); δC H]+ = 200.1073.
(100 MHz, CDCl3) 37.29, 45.13, 96.42, 124.05 (q, J = 272 Hz),
125.65 (q, J = 3.8 Hz), 127.93, 130.63, 130.65 (q, J = 32.3 Hz),
Preparation of 3,4-dihydro-1,2-oxathiine 2,2-dioxides
136.61, 139.35, 153.86, 185.55; δF (376.5 MHz, CDCl3) −62.66;
(E)-4-(Dimethylamino)-3-phenyl-6-styryl-3,4-dihydro-1,2-
oxathiine 2,2-oxide 3a. A solution of phenylmethanesulfonyl
chloride (8.27 g, 43.4 mmol, 3.5 eq.) in anhydrous THF
found [M + H]+ = 270.1100, C14H14F3NO requires [M + H]+
270.1103.
=
(1E,4E)-1-(Dimethylamino)-5-(4-nitrophenyl)penta-1,4-dien-3- (35 mL) was added dropwise to a cold (−10 °C) stirred solution
one 2d. (E)-4-(4-Nitrophenyl)but-3-en-2-one (1.00 g, 5.2 mmol) of (1E,4E)-1-(dimethylamino)-5-phenylpenta-1,4-dien-3-one
was dissolved in PhMe (25 mL) and DMFDMA (1.73 mL, (2.5 g, 12.4 mmol) and Et3N (6.05 mL, 43.4 mmol, 3.5 eq.) in
13.0 mmol, 2.5 eq.) under a N2 atmosphere. The reaction anhydrous THF (35 mL) under nitrogen, over 10 min, with the
mixture was refluxed for 6h and then cooled to room tempera- rate of addition such that the temperature was maintained at
ture whereupon the volatile components were removed by or below 0 °C. Upon completion of the addition the reaction
rotary evaporation. The crude product was filtered through a mixture was warmed to room temperature overnight, before
silica column (neat CHCl3 to 5% MeOH/CHCl3) to afforded the being filtered to remove the precipitated Et3N·HCl. Removal of
title compound as an orange solid after trituration with Et2O the solvent gave the crude product which was purified by
(0.99 g, 77%); mp = 152–154 °C; νmax (neat): 3035, 2912, 1650, column chromatography (alumina, 20% to 30% EtOAc/hexane)
1614 (CvO), 1593, 1537, 1505, 1436, 1424, 1355, 1335, 1302, to yield the title product as a pale yellow solid (2.87 g, 65%);
1265, 1089 cm−1; δH (400 MHz, CDCl3) 2.91 (s, 3H, NCH3), 3.17 mp = 124–126 °C (from EtOAc/hexane); νmax (neat): 2830, 2793,
(s, 3H, NCH3), 5.28 (d, J = 12.2 Hz, 1H, 2-H), 6.89 (d, J = 15.9 1651, 1496, 1468, 1454, 1368 (O-SO2), 1315, 1268, 1228, 1191,
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1170 (O-SO2), 1073, 1039 cm−1; δH (400 MHz, CDCl3) 2.25 (s, Hz, 1H, CHvCHC–O), 7.45–7.46 (m, 3H, Ar–H), 7.53–7.55 (m,
6H, N(CH3)2), 4.38 (dd, J = 2.4, 11.2 Hz, 1H, 4-H), 4.53 (d, J = 4H, Ar–H), 7.61–7.63 (m, 2H, Ar–H); δC (100 MHz, CDCl3)
11.2 Hz, 1H, 3-H), 5.50 (d, J = 2.6 Hz, 1H, 5-H), 6.55 (d, J = 15.9 41.22, 63.35, 64.63, 109.77, 122.02, 124.04 (q, J = 270 Hz),
Hz, 1H, PhCHvCH), 7.04 (d, J = 15.9 Hz, 1H, PhCHvCH), 125.79 (q, J = 3.7 Hz), 127.17, 129.07, 129.27, 129.73, 129.85,
7.32–7.39 (m, 3H, Ar–H), 7.44–7.46 (m, 5H, Ar–H), 7.52–7.55 130.13, 130.34 (q, J = 32 Hz), 139.04, 149.16; δF (376.5 MHz,
(m, 2H, Ar–H); δC (100 MHz, CDCl3) 41.24, 63.35, 64.58, CDCl3) −62.64; found [M + H]+ = 424.1191, C21H20F3NO3S
108.09, 119.62, 127.06, 128.77, 128.83, 129.23, 129.26, 129.75, requires [M + H]+ = 424.1192.
129.76, 131.72, 135.59, 149.60; found [M + H]+ = 356.1323,
C20H21NO3S requires [M + H]+ = 356.1315.
(E)-4-(Dimethylamino)-6-(4-nitrostyryl)-3-phenyl-3,4-dihydro-
1,2-oxathiine 2,2-dioxide 3d. A solution of phenylmethanesul-
(E)-4-(Dimethylamino)-6-(4-methoxystyryl)-3-phenyl-3,4-dihydro- fonyl chloride (1.27 g, 6.7 mmol, 1.8 eq.) in anhydrous THF
1,2-oxathiine 2,2-dioxide 3b. A solution of phenylmethanesulfo- (15 mL) was added dropwise over 10 min to a cold (−10 °C)
nyl chloride (10.30 g, 54.0 mmol, 2.5 eq.) in anhydrous THF stirred solution of (1E,4E)-1-(dimethylamino)-5-(4-nitrophenyl)
(60 mL) and DCM (10 mL) was subsequently added dropwise penta-1,4-dien-3-one (0.92 g, 3.7 mmol) and Et3N (0.90 mL,
over 20 min to a cold (−5 °C) stirred solution of (1E,4E)-1- 6.7 mmol, 1.8 eq.) in anhydrous THF (15 mL) and DCM
(dimethylamino)-5-(4-methoxyphenyl)penta-1,4-dien-3-one (20 mL) under nitrogen. The resulting mixture was stirred at
(5.00 g, 21.6 mmol) and Et3N (7.53 mL, 54.0 mmol, 2.5 eq.) in −5 °C for 2 h and was warmed to room temperature over 2 h.
anhydrous THF (60 mL) and DCM (15 mL) under nitrogen. Removal of the solvent afforded a sticky solid mass which was
Upon completion of the addition, the reaction mixture was purified by column chromatography (basic alumina, 20%
stirred for 2 h at 0 °C, before warming to room temperature EtOAc/hexane to neat EtOAc) to afford the title product as a
overnight and then filtered to remove the precipitated pale yellow solid after trituration with Et2O (0.80 g, 54%); mp =
Et3N·HCl. Removal of the solvent gave the crude product 156–158 °C (from EtOAc/hexane); νmax (neat): 2787, 2359, 2341,
which was purified by column chromatography (alumina, 20% 1619, 1590, 1506, 1498, 1456, 1377 (O-SO2), 1335, 1267, 1226,
to 50% EtOAc/hexane) to afford the title compound as a yellow 1189, 1139 (O-SO2), 1107, 1072, 1053, 1038 cm−1; δH (400 MHz,
solid (6.39 g, 77%); mp = 125–127 °C (from EtOAc/hexane); CDCl3) 2.26 (s, 6H, N(CH3)2), 4.40 (dd, J = 2.5, 11.3 Hz, 1H,
νmax (neat): 2976, 2938, 2831, 2781, 1601, 1510, 1495, 1453, 4-H), 4.55 (d, J = 11.3 Hz, 1H, 3-H), 5.64 (d, J = 2.5 Hz, 1H,
1372 (O-SO2), 1319, 1251, 1226, 1169 (O-SO2), 1109, 1015 cm−1
;
5-H), 6.70 (d, J = 15.8 Hz, 1H, O2NC6H4CH), 7.07 (d, J = 15.8
δH (400 MHz, CDCl3) 2.25 (s, 6H, N(CH3)2), 3.83 (s, 3H, OCH3), Hz, 1H, CHvCHC–O), 7.45–7.54 (m, 5H, Ar–H), 7.58–7.60 (m,
4.39 (dd, J = 2.2, 11.1 Hz, 1H, 4-H), 4.52 (d, J = 11.1 Hz, 1H, 2H, Ar–H), 8.22–8.24 (m, 2H, Ar–H); δC (100 MHz, CDCl3)
3-H), 5.43 (d, J = 2.5 Hz, 1H, 5-H), 6.43 (d, J = 15.9 Hz, 1H, 41.25, 63.30, 64.69, 123.78, 124.22, 124.30, 127.56, 128.90,
HCvCHC–O), 6.88–6.91 (m, 2H, Ar–H), 6.99 (d, J = 15.9 Hz, 129.02, 129.24, 129.32, 129.70, 129.95, 141.92, 147.55; found
1H, AnCHvCH), 7.38–7.41 (m, 2H, Ar–H), 7.44–7.45 (m, 3H, [M + H]+ = 401.1168, C20H20N2O5S requires [M + H]+
Ar–H), 7.53–7.55 (m, 2H, Ar–H); δC (100 MHz, CDCl3) 41.18 (2 401.1169.
=
× C), 55.35, 63.32, 64.61, 106.79, 114.29, 117.42, 128.35,
(E)-6-(2-Bromostyryl)-4-(dimethylamino)-3-phenyl-3,4-dihydro-
128.44, 129.21, 129.36, 129.72, 129.74, 131.32, 149.89, 160.18; 1,2-oxathiine 2,2-dioxide 3e. A solution of phenylmethanesulfo-
found [M + H]+ = 386.1417, C21H23NO4S requires [M + H]+
386.1424.
=
nyl chloride (7.45 g, 39.2 mmol, 2.2 eq.) in anhydrous THF
(60 mL) was added dropwise over 15 min to a cold (−5 °C)
(E)-4-(Dimethylamino)-3-phenyl-6-(4-(trifluoromethyl)styryl)- stirred solution of (1E,4E)-1-(2-bromophenyl)-5-(dimethyl-
3,4-dihydro-1,2-oxathiine 2,2-dioxide 3c. A solution of phenyl- amino)penta-1,4-dien-3-one (5.00 g, 17.8 mmol) and Et3N
methanesulfonyl chloride (3.80 g, 20.0 mmol, 1.8 eq.) in anhy- (5.46 mL, 39.2 mmol, 2.2 eq.) in anhydrous THF (60 mL)
drous THF (50 mL) was added dropwise over 10 min to a cold under nitrogen. Upon completion of the addition the mixture
(−10 °C) stirred solution of (1E,4E)-1-(dimethylamino)-5-(4-(tri- was stirred for 2 h at −5 °C and then warmed to room tempera-
fluoromethyl)phenyl)penta-1,4-dien-3-one (3.00 g, 11.1 mmol) ture overnight and then filtered to remove the precipitated
and Et3N (2.77 mL, 20.0 mmol, 1.8 eq.) in anhydrous THF Et3N·HCl. Removal of the solvent gave the crude product
(50 mL) under nitrogen. The resulting mixture was stirred for which was purified by column chromatography (basic
2 h at −10 °C and was warmed to room temperature overnight alumina, 30% EtOAc/hexane) to afford the title product as a
and then filtered to remove the precipitated Et3N·HCl. pale-yellow powder after washing with Et2O (4.68 g, 61%); mp
Removal of the solvent gave the crude product which was puri- = 128–130 °C (from EtOAc/hexane); νmax (neat): 2978, 2936,
fied by column chromatography (basic alumina, 30% to 50% 2863, 2837, 2794, 2359, 2343, 1657, 1496, 1458, 1437, 1364
EtOAc/hexane) to afford the title compound as an off-white (O-SO2), 1337, 1310, 1280, 1259, 1207, 1186 (O-SO2), 1171,
powder after trituration with Et2O (3.40 g, 72%); mp = 1149, 1092, 1076, 1046, 1022 cm−1; δH (400 MHz, CDCl3) 2.26
128–129 °C (from EtOAc/hexane); νmax (neat): 2980, 2948, 2359, (s, 6H, N(CH3)2), 4.37 (dd, J = 2.4, 11.4 Hz, 1H, 4-H), 4.55 (d, J =
2341, 1652, 1613, 1496, 1455, 1414, 1376 (O-SO2), 1321, 1267, 11.4 Hz, 1H, 3-H), 5.55 (d, J = 2.4 Hz, 1H, 5-H), 6.50 (d, J = 15.4
1221, 1188, 1163 (O-SO2), 1105, 1063, 1044, 1013 cm−1; δH Hz, 1H, BrC6H4CH), 7.14–7.18 (m, 1H, Ar–H), 7.28–7.32 (m,
(400 MHz, CDCl3) 2.26 (s, 6H, N(CH3)2), 4.39 (dd, J = 2.7, 11.1 1H, Ar–H), 7.34 (d, J = 15.4 Hz, 1H, CHvCHC–O), 7.45–7.46
Hz, 1H, 4-H), 4.54 (d, J = 11.1 Hz, 1H, 3-H), 5.58 (d, J = 2.7 Hz, (m, 3H, Ar–H), 7.53–7.55 (m, 3H, Ar–H), 7.55–7.61 (m, 1H, Ar–
1H, 5-H), 6.63 (d, J = 15.9 Hz, 1H, F3CC6H4CH), 7.05 (d, J = 15.8 H); δC (100 MHz, CDCl3) 41.23, 63.33, 64.58, 109.35, 122.49,
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124.63, 126.95, 127.55, 129.21, 129.24, 129.75, 129.78, 129.80, pletion of the addition the reaction mixture was warmed to
130.35, 133.37, 135.68, 149.41; found [M + H]+ = 434.0421, room temperature over 2 h and then washed with H2O
C20H2079BrNO3S requires [M + H]+ = 434.0423.
(20 mL), aq. Na2SO3 (0.7 M, 2 × 15 mL), aq. NaOH(aq) (1 M,
4-(Dimethylamino)-3-phenyl-6-(phenylethynyl)-3,4-dihydro- 15 mL) and H2O (15 mL). The organic layer was dried over
1,2-oxathiine 2,2-dioxide 3f. A solution of phenylmethanesul- anhydrous Na2SO4 and the solvent was removed under
fonyl chloride (5.73 g, 30.0 mmol, 3.0 eq.) in anhydrous THF reduced pressure to afford the target compound as a bright
(30 mL) was added dropwise to a cold (−10 °C) stirred solution yellow solid (0.54 g, 89%); mp = 155–158 °C; νmax (neat): 3025,
of (E)-1-(dimethylamino)-5-phenylpent-1-en-4-yn-3-one (2.00 g, 1627, 1602, 1540, 1494, 1448, 1356 (O-SO2), 1291, 1263, 1199,
10.0 mmol) and Et3N (4.20 mL, 30.0 mmol, 3.0 eq.) in anhy- 1169 (O-SO2), 1069, 1032 cm−1; δH (400 MHz, CDCl3) 6.06 (d,
drous THF (30 mL). Upon completion of the addition the reac- J = 7.1 Hz, 1H, 5-H), 6.67 (d, J = 16.0 Hz, HCvCHC–O),
tion mixture was stirred at −10 °C for 2 h and warmed room 7.33–7.42 (m, 4H, Ar–H/PhHCvCH), 7.43–7.47 (m, 3H, Ar–H),
temperature overnight and then filtered to remove the precipi- 7.50–7.53 (m, 2H, Ar–H), 7.60–7.63 (m, 2H, Ar–H); δC
tated Et3N·HCl. Removal of the solvent gave the crude product (100 MHz, CDCl3) 105.45, 118.63, 127.57, 127.60, 128.98,
which was purified by column chromatography (alumina, 20% 129.00, 129.04, 129.64, 129.84, 130.25, 134.85, 135.18, 135.65,
EtOAc/petroleum spirit (40–60 °C)) to afford the title product 155.07; found [M + Na]+ = 333.0562, C18H14O3S requires [M +
as an off-white solid after trituration with Et2O (1.23 g, 35%); Na]+ = 333.0564.
mp = 128–130 °C (from EtOAc/petroleum spirit (40–60 °C));
(E)-6-(4-Methoxystyryl)-3-phenyl-1,2-oxathiine 2,2-dioxide 4b.
νmax (neat): 2779, 2214, 1647, 1488, 1455, 1442, 1366 (O-SO2), A suspension of m-CPBA (3.14 g, 12.7 mmol, 1.4 eq.) in DCM
1316, 1299, 1280, 1258, 1228, 1182 (O-SO2), 1168, 1108, 1071, (50 mL) was added dropwise over 15 min to a cold (0–5 °C)
1050, 1032 cm−1; δH (400 MHz, CDCl3) 2.27 (s, 6H, N(CH3)2), stirred solution of (E)-4-(dimethylamino)-6-(4-methoxystyryl)-3-
4.35 (dd, J = 2.7, 11.3 Hz, 1H, 4-H), 4.50 (d, J = 11.3 Hz, 1H, phenyl-3,4-dihydro-1,2-oxathiine 2,2-dioxide (3.50 g, 9.1 mmol)
3-H), 5.90 (d, J = 2.7 Hz, 1H, 5-H), 7.35–7.42 (m, 3H, Ar–H), in DCM (75 mL). Upon completion of the addition the reaction
7.44–7.45 (m, 3H, Ar–H), 7.51–7.53 (m, 4H, Ar–H); δC mixture was warmed to room temperature over 2 h and then
(100 MHz, CDCl3) 41.28, 63.53, 64.85, 80.78, 91.69, 114.60, washed with H2O (20 mL), aq. Na2SO3 (0.7 M, 2 × 15 mL), aq.
120.93, 128.54, 128.87, 129.24, 129.68, 129.71, 129.84, 131.92, NaOH(aq) (1 M, 15 mL) and H2O (15 mL). The organic layer was
135.18; found [M + H]+ = 354.1157, C20H19NO3S requires [M + dried over anhydrous Na2SO4 and the solvent was removed
H]+ = 354.1158.
under reduced pressure to afford the title compound as an
(E)-4-(Dimethylamino)-6-styryl-3,4-dihydro-1,2-oxathiine 2,2- orange solid (2.78 g, 90%); mp = 205–207 °C; νmax (neat): 2962,
dioxide 3g. A solution of methanesulfonyl chloride (4.7 mL, 1631, 1598, 1571, 1540, 1509, 1444, 1361 (O-SO2), 1311, 1298,
60.8 mmol) in anhydrous THF (35 mL) was added dropwise to 1251, 1171 (O-SO2), 1151, 1070, 1026 cm−1; δH (400 MHz,
a cold (−10 °C) stirred solution of (1E,4E)-1-(dimethylamino)-5- CDCl3) 3.85 (s, 3H, OCH3), 6.05 (d, J = 7.4 Hz, 1H, 5-H), 6.53 (d,
phenylpenta-1,4-dien-3-one (8.16 g, 40.5 mmol) and Et3N J = 15.8 Hz, 1H, HCvCHC–O), 6.87 (d, J = 7.4 Hz, 1H, 4-H),
(8.40 mL, 60.8 mmol) in anhydrous THF (100 mL) under nitro- 6.91–6.93 (m, 2H, Ar–H), 7.31 (d, J = 15.8 Hz, 1H, AnCHvCH),
gen, over 15 min, with the rate of addition such that the temp- 7.43–7.47 (m, 5H, Ar–H), 7.60–7.62 (m, 2H, Ar–H); δC
erature was maintained at or below 0 °C. Upon completion of (100 MHz, CDCl3) 55.42, 104.48, 114.46, 116.35, 127.51,
the addition the reaction mixture was warmed to room temp- 128.01, 129.01, 129.18, 129.23, 129.67, 130.38, 134.11, 135.40,
erature and stirred overnight, before being filtered to remove 155.52, 160.91; found [M]•+ = 340.0761, C19H16O4S requires
the precipitated Et3N·HCl. Removal of the solvent gave the [M]•+ = 340.0763.
crude product which was purified by column chromatography
(E)-3-Phenyl-6-(4-(trifluoromethyl)styryl)-1,2-oxathiine
2,2-
using 80% EtOAc in hexane produced a brown solid (9.40 g, dioxide 4c. A suspension of m-CPBA (1.64 g, 7.1 mmol, 1.5 eq.)
83%); mp = 132–134 °C; νmax (neat) 1364, 1347, 1167, 749, 686, in DCM (50 mL) was added dropwise over 10 min to a cold
632, 571, 529; δH (300 MHz, CDCl3) 2.35 (s, 6H, NMe2), 3.26 (0–5 °C) stirred solution of (E)-4-(dimethylamino)-3-phenyl-6-
(dd, J = 11.4, 13.3 Hz, 1H, 3-H), 3.50 (ddd, J = 1.0, 7.3, 13.3 Hz, (4-(trifluoromethyl)styryl)-3,4-dihydro-1,2-oxathiine 2,2-dioxide
1H, 3-H), 4.13 (dddd, J = 2.6, 7.16, 8.9, 10.3 Hz, 1H, 2-H), 5.36 (2.00 g, 4.7 mmol) in DCM (50 mL). Upon completion of the
(d, J = 2.6 Hz, 1H, 4-H), 6.49 (d, J = 15.9 Hz, 1H, PhCH), 7.00 addition the reaction mixture was warmed to room tempera-
(d, J = 15.9 Hz, 1H, CHvCHC–O), 7.30–7.45 (5H, m, Ar–H); δC ture over 2 h and then washed with H2O (75 mL), aq. Na2SO3
(100 MHz, CDCl3) 40.64, 43.07, 59.47, 108.59, 119.69, 127.04, (0.7 M, 2 × 50 mL), aq. NaOH(aq) (1 M, 50 mL) and H2O
128.80, 131.55, 135.53, 149.62; found [M + H]+ = 279.0923, (60 mL). The organic layer was dried over anhydrous Na2SO4
C14H17NO3S requires [M + H]+ = 279.0928.
and the solvent was removed under reduced pressure to afford
the title compound as pale yellow crystals (1.64 g, 92%); mp =
220–221 °C (from DCM); νmax (neat): 3039, 1631, 1610, 1542,
Preparation of 1,2-oxathiine 2,2-doxides
(E)-3-Phenyl-6-styryl-1,2-oxathiine 2,2-dioxide 4a. A suspen- 1514, 1492, 1359 (O-SO2), 1323, 1266, 1263, 1164 (O-SO2),
sion of m-CPBA (0.69 g, 2.76 mmol, 1.4 eq.) in DCM (15 mL) 1119, 1108, 1067, 1032, 1014 cm−1; δH (400 MHz, CDCl3) 6.12
was added dropwise to a cold (0–5 °C) stirred solution of (E)-4- (d, J = 7.1 Hz, 1H, 3-H), 6.73 (d, J = 15.6 Hz, 1H, F3CC6H4CH),
(dimethylamino)-3-phenyl-6-styryl-3,4-dihydro-1,2-oxathiine 6.88 (d, J = 6.1 Hz, 1H, 4-H), 7.35 (d, J = 15.6 Hz, 1H,
2,2-oxide (0.70 g, 1.97 mmol) in DCM (25 mL). Upon com- CHvCHC–O), 7.45–7.47 (m, 3H, Ar–H), 7.59–7.65 (m, 6H,
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Ar–H); δC (100 MHz, CDCl3) 106.65, 120.99, 123.92 (q, J = 271 organic layer was dried over anhydrous Na2SO4 and the solvent
Hz), 125.92 (q, J = 3.2 Hz), 127.62, 127.63, 128.63, 129.09, removed under reduced pressure gave the crude solid which
130.05, 130.06, 131.01 (q, J = 33 Hz), 133.62, 135.80, 138.53, was triturated with Et2O to afford the title compound as a
154.31; δF (376.5 MHz, CDCl3) −62.64; found [M]•+ = 378.0532, yellow solid (0.81 g, 84%); mp = 133–135 °C; νmax (neat): 2203,
C19H13F3O3S requires [M]•+ = 378.0537.
1622, 1546, 1488, 1441, 1361 (O-SO2), 1280, 1270, 1251, 1177
(E)-6-(4-Nitrostyryl)-3-phenyl-1,2-oxathiine 2,2-dioxide 4d. A (O-SO2), 1155, 1126, 1063, 1031 cm−1; δH (400 MHz, CDCl3)
solution of m-CPBA (0.52 g, 2.3 mmol, 1.5 eq.) in DCM (25 mL) 6.38 (d, J = 7.1 Hz, 1H, 5-H), 6.80 (d, J = 7.1 Hz, 1H, 4-H),
was added dropwise over 10 min to a cold (0–5 °C) stirred solu- 7.37–7.47 (m, 6H, Ar–H), 7.53–7.56 (m, 2H, Ar–H), 7.58–7.62
tion of (E)-4-(dimethylamino)-6-(4-nitrostyryl)-3-phenyl-3,4- (m, 2H, Ar–H); δC (100 MHz, CDCl3) 81.14, 98.52, 111.43,
dihydro-1,2-oxathiine 2,2-dioxide (0.60 g, 1.5 mmol) in DCM 120.50, 127.69, 128.02, 128.66, 129.09, 129.87, 130.23, 130.27,
(25 mL). Upon completion of the addition the reaction mixture 132.05, 137.37, 139.80; found [M]•+ = 308.0491, C18H12O3S
was warmed to room temperature overnight. Consecutive requires [M]•+ = 308.0502.
washes of the reaction mixture with H2O (60 mL), aq. Na2SO3
(E)-6-Styryl-1,2-oxathiine 2,2-dioxide 4g. A suspension of
(0.7 M, 2 × 50 mL), aq. NaOH (1 M, 50 mL) and H2O (50 mL) m-CPBA (10.31 g, 46.0 mmol, 77%) in DCM (75 mL) was added
afforded an organic layer which was dried over anhydrous dropwise to a cold (0–5 °C) stirred solution of (E)-4-(dimethyl-
Na2SO4. Removal of the solvent under reduced pressure gave amino)-6-styryl-3,4-dihydro-1,2-oxathiine 2,2-oxide (8.56 g,
the title compound as yellow crystals (0.49 g, 93%); mp = 30.67 mmol) in DCM (50 mL). Upon completion of the
230–232 °C; νmax (neat): 3060, 1607, 1590, 1514, 1446, 1339 addition the reaction mixture was warmed to room tempera-
(O-SO2), 1259, 1168 (O-SO2), 1104, 1060, 1034, 1009 cm−1; δH ture over 2 h and then washed with H2O (2 × 50 mL), aq.
(400 MHz, CDCl3) 6.18 (d, J = 7.2 Hz, 1H, 5-H), 6.80 (d, J = 15.8 Na2SO3 (0.7 M, 2 × 30 mL), aq. NaOH(aq) (1 M, 30 mL) and H2O
Hz, 1H, O2NC6H4CH), 6.90 (d, J = 7.2 Hz, 1H, 4-H), 7.37 (d, J = (50 mL). The organic layer was dried over anhydrous Na2SO4
15.8 Hz, 1H, CHvCHC–O), 7.46–7.48 (m, 3H, Ar–H), 7.61–7.66 and the solvent was removed under reduced pressure to afford
(m, 4H, Ar–H), 8.24–8.26 (m, 2H, Ar–H); δc (100 MHz, CDCl3) the target compound as a pale brown solid after trituration
107.58, 122.69, 124.31, 127.66, 128.00, 128.41, 129.13, 129.91, with Et2O/hexane (6.95 g, 97% yield); mp = 108–110 °C; νmax
130.22, 132.52, 136.45, 141.36, 147.90, 153.88; found [M]•+
355.0504, C18H13NO5S requires [M]•+ = 355.0514.
=
(neat) 1599, 1372, 1357, 1155, 846, 772, 669, 565, 504.9,
475 cm−1; δH (400 MHz, CDCl3) 5.95 (d, J = 6.8 Hz, 1H, 5-H),
(E)-6-(2-Bromostyryl)-3-phenyl-1,2-oxathiine 2,2-dioxide 4e. A 6.61 (dd, J = 10.4 Hz, 1H, 3-H), 6.62 (d, J = 15.6 Hz, 1H, PhCH),
suspension of m-CPBA (2.39 g, 10.4 mmol, 1.5 eq.) in DCM 6.87 (d, J = 6.8, 10.4, 1H, 4-H), 7.32–7.41 (4H, m, Ar–H,
(60 mL) was added dropwise over 15 min to a cold (0–5 °C) CHvCHCO), 7.48–7.51 (m, 2H, ArH); δC (100 MHz, CDCl3)
stirred solution of (E)-6-(2-bromostyryl)-4-(dimethylamino)-3- 103.80, 118.70, 119.22, 127.66, 128.99, 129.78, 134.47, 134.97,
phenyl-3,4-dihydro-1,2-oxathiine 2,2-dioxide (3.00 g, 6.9 mmol) 136.22, 156.35; found [M + H]+ = 234.0347. C12H10O3S requires
in DCM (60 mL). Upon completion of the addition the reaction [M + H]+ = 234.0352.
mixture was warmed to room temperature over
Consecutive washes of the reaction mixture with H2O (60 mL),
aq. Na2SO3 (0.7 M, 2 × 50 mL), aq. NaOH (1 M, 50 mL) and
2 h.
Preparation of bromo substituted 1,2-oxathiine 2,2-dioxides
3-Bromo-3,6-diphenyl-1,2-oxathiine 2,2-dioxide 7. A solution
H2O (50 mL) afforded an organic layer which was dried over of Br2 (2.81 mL, 17.6 mmol) in CHCl3 (50 mL) was added drop-
anhydrous Na2SO4. Removal of the solvent under reduced wise over 30 min to a stirred solution of 5,6-diphenyl-1,2-
pressure gave the title compound as yellow crystals (2.34 g, oxathiine 2,2-dioxide (5.00 g, 17.6 mmol) in CHCl3 (200 mL) at
87%); mp = 142–145 °C (from DCM); νmax (neat): 1627, 1539, room temperature. The resulting solution was stirred at 70 °C
1435, 1359 (O-SO2), 1304, 1252, 1174 (O-SO2), 1069, 1022 cm−1
;
for 72 h, before being cooled and diluted with CHCl3 (100 mL)
δH (400 MHz, CDCl3) 6.10 (d, J = 6.6 Hz, 1H, 5-H), 6.61 (d, J = and washed with an aq. Na2S2O3 solution (250 mL) and H2O (2
15.6 Hz, 1H, BrC6H4CH), 6.87 (d, J = 6.6 Hz, 1H, 4-H), × 150 mL). Removal of the dried (anhydrous Na2SO4) organic
7.19–7.20 (m, 1H, Ar–H), 7.30–7.32 (m, 1H, Ar–H), 7.44–7.47 layer gave the product after trituration with 9 : 1 Et2O/EtOAc as
(m, 3H, Ar–H), 7.57–7.68 (m, 5H, Ar–H/CHvCHC–O); δC an off-white solid (4.68 g, 73%); mp = 137–138 °C (from
(100 MHz, CDCl3) 106.29, 121.38, 125.17, 127.16, 127.63, EtOAc/hexane); νmax (neat): 3041, 1621, 1546, 1489, 1446, 1377
127.65, 128.75, 129.05, 129.94, 130.19, 130.50, 133.59, 133.77, (O-SO2), 1339, 1272, 1188 (O-SO2), 1157, 1124, 1108, 1008,
135.18, 135.47, 154.65; found [M]•+ = 387.9768, C18H1379BrO3S 1000 cm−1; δH (400 MHz, (CD3)2CO): δ 7.30–7.43 (m, 10H, Ar–
requires [M]•+ = 387.9769.
H), 7.62 (s, 1H, 4-H); δC (100 MHz, (CD3)2CO): 110.58, 119.64,
3-Phenyl-6-(phenylethynyl)-1,2-oxathiine 2,2-dioxide 4f. A 128.48, 128.56, 129.13, 129.19, 129.23, 130.68, 130.80, 134.54,
suspension of m-CPBA (1.00 g, 4.35 mmol, 1.4 eq.) in DCM 140.21, 152.09; found [M + Na]+ = 384.9500, C16H1179BrO3S
(15 mL) was added dropwise to a cold (0–5 °C) stirred solution requires [M + Na]+ = 384.9504.
of 4-(dimethylamino)-3-phenyl-6-(phenylethynyl)-3,4-dihydro-
3-Bromo-6-phenyl-1,2-oxathiine 2,2-dioxide 8. A solution of
1,2-oxathiine 2,2-dioxide (1.10 g, 3.10 mmol) in DCM (15 mL). Br2 (0.78 mL, 15.2 mmol, 1.1 eq.) in CHCl3 (50 mL) was added
The resulting reaction mixture was warmed to room tempera- dropwise over 20 min to a stirred solution of 6-phenyl-1,2-
ture overnight and then washed with H2O (40 mL), aq. Na2SO3 oxathiine 2,2-dioxide (2.87 g, 13.8 mmol) in CHCl3 (100 mL) at
(0.7 M, 40 mL), aq. NaOH (1 M, 30 mL) and H2O (30 mL). The room temperature. Upon completion of the addition the
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mixture the reaction mixture was set to reflux (70 °C) for 16 h 119.06, 122.15, 128.16, 128.27, 129.13, 129.16, 129.22 (2C),
before cooling to room temperature. Pyridine (0.28 mL, 130.09, 131.21, 132.26, 133.87, 135.98, 151.50, 161.03; found
3.5 mmol, 0.25 eq.) was added and the mixture was heated at [M + Na]+ = 413.0813, C23H18O4S requires [M + Na]+
reflux for 15 min. The reaction mixture was diluted with CHCl3 413.0824.
=
(100 mL) and washed with aq. Na2S2O3 solution (150 mL), aq.
5,6-Diphenyl-3-(4-trifluoromethylphenyl)-1,2-oxathiine
2,2
HCl (1 M, 100 mL) and H2O (100 mL). The obtained organic dioxide 6c. A solution of 3-bromo-5,6-diphenyl-1,2-oxathiine
layer was dried with anhydrous Na2SO4 and the solvent was 2,2-dioxide (0.40 g, 1.1 mmol, 1.0 eq.), 4-CF3C6H4B(OH)2
removed to afford the crude product, which was triturated with (0.31 g, 1.7 mmol, 1.5 eq.), Pd(OAc)2 (0.012 g, 0.06 mmol, 5%
8 : 2 petroleum ether : EtOAc to afford the title compound as mol), PCy3 (0.031 g, 0.11 mmol, 10% mol) and K2HPO4·3H2O
an off-white solid (3.43 g, 87%) mp = 130°–132 °C (from (0.75 g, 3.3 mmol, 3 eq.) in DMAc (7.5 mL) and MeOH (7.5 mL)
CHCl3); νmax (neat): 3037, 2918, 2849, 1626, 1542, 1494, 1447, under nitrogen was heated to 60 °C overnight. The cooled reac-
1365 (O-SO2), 1261, 1179 (O-SO2), 1070, 1035, 1006 cm−1; δH tion mixture was poured into H2O (20 mL) and extracted with
(400 MHz, CDCl3) 6.33 (d, J = 7.3 Hz, 1H, 4-H), 7.10 (d, J = 7.3 EtOAc (2 × 40 mL). The combined extracts were washed with
Hz, 1H, 5-H), 7.44–7.52 (m, 3H, Ar–H), 7.69–7.71 (m, 2H, Ar– aq. NaHCO3 (40 mL), brine (40 mL), dried over anhydrous
H); δC (100 MHz, CDCl3) 101.57, 110.98, 125.55, 129.12, Na2SO4 and the solvent was removed under reduced pressure.
130.07, 131.53, 135.09, 159.43; found [M + Na]+ = 308.9186, The crude solid was purified by a short column (silica, neat
C10H779BrO3S requires [M + Na]+ = 308.9191.
DCM) to afford the title compound as pale-yellow crystals
(0.17 g, 36%); mp = 160–162 °C (lit mp = 161–163 °C (ref. 19));
νmax (neat) 3062, 1616, 1574, 1555, 1487, 1444, 1366 (O-SO2),
Suzuki cross-coupling reactions
3,5,6-(Triphenyl)-1,2-oxathiine 2,2-dioxide 6a. A suspension 1351, 1322, 1277, 1172 (O-SO2), 1116, 1067, 1036, 1014,
of 3-bromo-5,6-diphenyl-1,2-oxathiine 2,2-dioxide (0.40 g, 1006 cm−1; δH ((CD3)2CO, 400 MHz) 7.33–7.43 (m, 10H, Ar–H),
1.1 mmol, 1.0 eq.), PhB(OH)2 (0.20 g, 1.65 mmol, 1.5 eq.), Pd 7.54 (s, 1H, 4-H), 7.88 (app. d, J = 8 Hz, 2H, Ar–H), 8.02 (app. d,
(OAc)2 (0.012 g, 0.06 mmol, 5% mol), PCy3 (0.031 g, J = 8 Hz, 2H, Ar–H); δC ((CD3)2CO, 100 MHz) 119.00, 123.75 (q,
0.11 mmol, 10% mol) and K2HPO4·3H2O (0.75 g, 3.3 mmol, J = 271 Hz), 126.04 (q, J = 3.8 Hz), 128.09, 128.33, 128.53,
3.0 eq.) in DMAc (10 mL) under nitrogen were heated to 75 °C 129.07, 129.32, 130.62, 130.83, 131.71 (q, J = 33 Hz), 132.64,
for 48 h. The solvent was removed azeotropically with consecu- 133.45, 135.42, 135.63, 153.04; δF (CDCl3, 376 MHz) −63.3.
tive portions of PhMe and the resulting crude was purified by
3,6-Diphenyl-1,2-oxathiine 2,2-dioxide 6e. A suspension of
short column chromatography (silica, neat DCM), to afford the 3-bromo-6-phenyl-1,2-oxathiine 2,2-dioxide (0.40 g, 1.4 mmol,
title compound as pale yellow microneedles (0.16 g, 40%); mp 1.0 eq.), PhB(OH)2 (0.25 g, 2.1 mmol, 1.5 eq.), Pd(OAc)2
= 158–160 °C (lit. mp = 159–160 °C (ref. 13)); νmax (neat) 3060, (0.015 g, 0.07 mmol, 5% mol), PCy3 (0.039 g, 0.14 mmol, 10%
1620, 1540, 1445, 1368 (O-SO2), 1350, 1187 (O-SO2), 1129, mol) and K2HPO4·3H2O (0.95 g, 4.2 mmol, 3.0 eq.) in DMAc
1012, 972, 852, 773, cm−1; δH (CDCl3, 400 MHz) 7.03 (s, 1H, (10 mL) under nitrogen was heated to 75 °C for 48 h. The
4-H), 7.26–7.39 (m, 10H, Ar–H), 7.47–7.51 (m, 3H, Ar–H), cooled reaction mixture was poured into H2O (40 mL) and
7.68–7.73 (m, 2H, Ar–H); δC (CDCl3, 100 MHz) 118.99, 127.75, extracted with EtOAc (5 × 20 mL). The organic extracts were
128.23, 128.38, 129.07, 129.14, 129.21, 129.29, 129.90, 129.96, washed with H2O (100 mL), brine (100 mL) and dried over
130.28, 131.12, 133.99, 134.13, 135.81, 152.12.
anhydrous Na2SO4. Removal of the solvent under reduced
3-(4-Methoxyphenyl)-5,6-diphenyl-1,2-oxathiine 2,2-dioxide pressure afforded the crude product which was subjected to
6b. 3-Bromo-5,6-diphenyl-1,2-oxathiine 2,2-dioxide (0.40 g, column chromatography (silica, 50% DCM/petroleum ether) to
1.1 mmol, 1.0 eq.), 4-MeOC6H4B(OH)2 (0.25 g, 1.7 mmol, 1.5 give fraction 1: 3,6-diphenyl-1,2-oxathiine 2,2-dioxide 6e
eq.), PCy3 (0.031 g, 0.11 mmol, 10% mol) and K2HPO4·3H2O (0.11 g, 27%) as a pale yellow solid mp 129–131 °C (lit. mp =
(0.75 g, 3.3 mmol, 3 eq.) were charged into a dried flask under 130–132 °C (ref. 19)); νmax (neat) 3063, 1632, 1558, 1494, 1448,
nitrogen. A suspension of Pd(OAc)2 (0.012 g, 0.06 mmol, 5% 1353 (O-SO2), 1335, 1264, 1173 (O-SO2), 1072, 1031, 1009 cm−1
;
mol) in DMAc (7.5 mL) and MeOH (7.5 mL) was added and the δH (CDCl3, 400 MHz) 6.58 (d, J = 7.1 Hz, 1H, 5-H), 6.96 (d, J =
reaction mixture was heated at 60 °C overnight. The cooled 7.1 Hz, 1H, 4-H), 7.50–7.47 (m, 6H, Ar–H), 7.67–7.64 (m, 2H,
reaction mixture was poured into H2O (15 mL) and the product Ar–H), 7.83–7.77 (m, 2H, Ar–H); δC (CDCl3, 100 MHz) 101.60,
was extracted with EtOAc (4 × 20 mL). The combined extracts 125.49, 127.66, 128.98, 129.01, 129.05, 129.87, 130.12, 130.65,
were washed with aq. NaHCO3 (40 mL) and brine (40 mL), 131.13, 134.48, 156.02.
dried over anhydrous Na2SO4 and the solvent was removed to
Fraction 2: 6,6′-diphenyl-[3,3′-bi(1,2-oxathiine)] 2,2,2′,2′-tet-
afford the crude product which was purified by a short column raoxide 9 (0.02 g, 10%) as an orange solid; mp = 227–230 °C;
(silica, neat DCM) to afford the title compound as a pale- νmax (neat): 1614, 1537, 1490, 1445, 1376 (O-SO2), 1340, 1309,
yellow solid after trituration with Et2O (0.25 g, 58%); mp = 1266, 1237, 1183 (O-SO2), 1064, 1032, 1004 cm−1; δH (CDCl3,
147–148 °C (from DCM); νmax (neat): 1604, 1510, 1444, 1364 400 MHz) 6.63 (d, J = 7.4 Hz, 2H, 5,5′-H), 7.47–7.51 (m, 8H, Ar–
(O-SO2), 1305, 1272, 1254, 1228, 1180 (O-SO2), 1127, 1035, H/4,4′-H), 7.76–7.77 (m, 2H, Ar–H); δC (CDCl3, 100 MHz)
1007 cm−1; δH (CDCl3, 400 MHz) 3.85 (s, 3H, OCH3), 6.91 (s, 102.06, 124.24, 125.81, 129.18, 130.04, 131.61, 131.90, 157.17;
1H, 4-H), 6.96–6.98 (m, 2H, An–H), 7.22–7.34 (m, 2H, Ar–H), found [M + Na]+ = 437.0126, C20H14O6S2 requires [M + Na]+ =
7.60–7.62 (m, 2H, An–H); δC (CDCl3, 100 MHz) 55.46, 114.54, 437.0132.
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CH-activated coupling protocol
1558, 1540, 1371 (O-SO2), 1181 (O-SO2), 1133, 1073 cm−1; δH
(CDCl3, 400 MHz) 7.25–7.29 (m, 4H, Ar–H), 7.33–7.38 (m, 6H,
Ar–H), 7.57–7.58 (m, 2H, 3,5-Py-H), 8.70–8.71 (m, 2H, 2,6-Py-
H); δC (CDCl3, 100 MHz) 118.95, 121.25, 128.33, 128.64,
129.05, 129.37 (2 × C), 130.68, 130.78, 131.38, 135.24, 136.76,
3,5,6-(Triphenyl)-1,2-oxathiine 2,2-dioxide 6a. 5,6-Diphenyl-
1,2-oxathiine 2,2-dioxide (0.40 g, 1.41 mmol, 1.0 eq.), Pd
(PPh3)4 (0.16 g, 0.14 mmol, 10% mol) and AcOAg (0.26 g,
1.6 mmol, 1,1 eq.) were charged into a flame dried flask under
N2. DMF (5 mL) was added, followed by PhI (0.47 mL,
4.22 mol, 3.0 eq.) and the resulting suspension was heated to
80 °C overnight. The cooled reaction mixture was poured into
H2O (10 mL) and extracted with EtOAc (4 × 15 mL). The com-
bined organic extracts were washed with H2O (50 mL), dried
over anhydrous Na2SO4 and the solvent was removed under
reduced pressure. The crude product was subjected to short
column chromatography (silica, neat DCM) to afford the title
compound after trituration with Et2O as a yellow solid (0.20 g,
39.2%). Physical and spectroscopic data were identical to pre-
viously prepared material.13
137.47, 150.55, 153.70; found [M
C21H15NO3S requires [M + H]+ = 362.0845.
+ = 362.0843,
H]+
5,6-Bis(4-methoxyphenyl)-3-(pyridin-4-yl)-1,2-oxathiine 2,2-
dioxide 6f. 5,6-Bis(4-methoxyphenyl)-1,2-oxathiine 2,2-dioxide
(0.50 g, 1.5 mmol), 4-iodopyridine (0.89 g, 4.4 mmol, 3.0 eq.)
and AgOAc (0.27 g, 1.6 mmol, 1.1 eq.) were charged into a
flame-dried flask under N2. DMF (5 mL) was added, followed
by Pd(PPh3)4 (0.17 g, 0.15 mmol, 10% mol) and the reaction
mixture was heated to 80 °C for 0.5 h. Upon cooling the reac-
tion mixture was filtered through celite and the celite was
washed with EtOAc (2 × 50 mL). Removal of the solvent gave a
crude mixture that was purified by column chromatography
(silica, neat EtOAc to 10% MeOH/EtOAc) to afford the title
compound after trituration with EtOAc as a pale red solid
which darkens upon standing (0.20 g, 33%); mp = 134–138 °C
(decomp.); vmax (neat): 1600, 1591, 1568, 1531, 1514, 1499,
1460, 1444, 1413, 1366 (O-SO2), 1302, 1292, 1251, 1173
(O-SO2), 1137, 1117, 1107, 1071, 1025, 1015 cm−1; δH (CDCl3,
400 MHz) 3.80 (s, 3H, OMe), 3.83 (s, 3H, OMe), 6.76–6.78 (m,
2H, Ar–H), 6.89–6.91 (m, 2H, Ar–H), 7.19 (s, 1H, 4-H),
7.19–7.21 (m, 2H, Ar–H), 7.30–7.32 (m, 2H, Ar–H), 7.57–7.58
(m, 2H, 3,5-Py-H), 8.69–8.71 (m, 2H, 2,6-Py-H); δC (CDCl3,
100 MHz) 55.36, 55.40, 113.83, 114.83, 117.21, 121.19, 123.08,
127.59, 130.06, 130.24, 131.07, 137.24, 137.98, 150.21, 153.61,
159.66, 161.40; found [M + H]+ = 422.1054, C23H19NO5S
requires [M + H]+ = 422.1060.
(E)-6-Styryl-3-(4-(trifluoromethyl)phenyl)-1,2-oxathiine 2,2-
dioxide 4h. (E)-6-Styryl-1,2-oxathiine 2,2-dioxide (0.50 g,
2.1 mmol), 4-CF3C6H4I (0.94 mL, 6.4 mmol, 3.0 eq.) and
AgOAc (0.39 g, 2.3 mmol, 1.1 eq.) were charged into a flame-
dried flask under N2. DMF (15 mL) was added followed by Pd
(PPh3)4 (0.24 g, 0.2 mmol, 10% mol) and the reaction mixture
was heated to 80 °C for 2 h. Upon cooling the reaction mixture
was filtered through celite and the celite was washed with
EtOAc (2 × 50 mL). Removal of the solvent gave a crude
mixture that was triturated with Et2O/DCM (1 : 1) to afford the
title compound as an orange solid (0.65 g, 82%); mp =
192–195 °C; vmax (neat): 1631, 1616, 1543, 1353, 1326 (O-SO2),
1263, 1195, 1170 (O-SO2), 1153, 1111, 1064, 1017 cm−1; δH
(CDCl3, 400 MHz) 6.10 (d, J = 7.1 Hz, 1H, 5-H), 6.68 (d, J = 15.9
Hz, 1H, PhCHvCH), 6.96 (d, J = 7.1 Hz, 1H, 4-H), 7.36–7.42
(m, 4H, ArH/PhCHvCH), 7.51–7.53 (m, 2H, ArH), 7.69–7.74
(m, 4H, ArH); δC (CDCl3, 100 MHz) 105.25, 118.38, 123.74 (q, J
= 272 Hz), 126.02 (q, J = 3.7 Hz), 127.72, 127.84, 129.03, 129.92,
130.64, 131.54 (q, J = 33 Hz), 133.23, 133.75, 134.97, 136.57,
155.93; δF (376.5 MHz, CDCl3) −62.90; found [M]•+ = 378.0530,
C19H13F3O3S requires [M]•+ = 378.0532.
3-(4-Methoxyphenyl)-5,6-diphenyl-1,2-oxathiine 2,2-dioxide
6b. 5,6-Diphenyl-1,2-oxathiine 2,2-dioxide (0.20 g, 0.7 mmol,
1.0 eq.), p-MeOC6H4I (0.49 g, 2.1 mmol, 3.0 eq.) and AcOAg
(0.13 g, 0.8 mmol, 1.1 eq.) were charged into a flame dried
flask under N2. After the addition of DMF (5 mL), Pd(PPh3)4
(0.08 g, 0.07 mmol, 10% mol) the reaction mixture was heated
to 80 °C overnight. Upon cooling the reaction mixture was
diluted with EtOAc (80 mL) and washed with H2O (60 mL) and
brine (60 mL). The organic layer was dried over anhydrous
Na2SO4 and the solvent was removed under reduced pressure.
The crude product was subjected to short column chromato-
graphy (silica, 20% EtOAc/petroleum ether) to afford the target
compound which was recrystallised from EtOAc/petroleum
ether as a yellow solid (0.07 g, 26%). Physical and spectro-
scopic data were identical to previously prepared material.
5,6-Diphenyl-3-((4-trifluoromethy)phenyl)-1,2-oxathiine 2,2
dioxide 6c. 5,6-Diphenyl-1,2-oxathiine 2,2-dioxide (0.20 g,
0.7 mmol), 4-CF3C6H4I (0.31 mL, 2.1 mmol, 3.0 eq.) and
AgOAc (0.13 g, 0.8 mmol, 1.1 eq.) were charged into a flame-
dried flask under N2. DMF (5 mL) and Pd(PPh3)4 (0.08 g,
0.07 mmol, 10% mol) were added and the reaction mixture
was heated to 80 °C for 2 h. Upon cooling the reaction mixture
was filtered through celite and the celite was washed with
EtOAc (2 × 50 mL). Removal of the solvent gave the crude
product which was triturated with Et2O to afford the title
product as a pale yellow solid (0.17 g, 57%). Physical and spec-
troscopic data were identical to previously prepared material.19
5,6-Diphenyl-3-(pyridin-4-yl)-1,2-oxathiine 2,2-dioxide 6d.
5,6-Diphenyl-1,2-oxathiine 2,2-dioxide (0.20 g, 0.7 mmol),
4-iodopyridine (0.43 g, 2.1 mmol, 3.0 eq.) and AgOAc (0.13 g,
0.8 mmol, 1.1 eq.) were charged into a flame-dried flask under
N2. DMF (10 mL) was added followed by Pd(PPh3)4 (0.08 g,
0.07 mmol, 10% mol) and the reaction mixture was heated to
80 °C for 1 h. Upon cooling the reaction mixture was filtered
through celite and the celite was washed with EtOAc (2 ×
50 mL). Removal of the solvent gave a crude mixture that was
purified by column chromatography (silica, 40% to 60%
EtOAc/petroleum ether) to yield the title compound as a pale
yellow solid (0.17 g, 68%); mp = 144–146 °C; vmax (neat): 1592,
3,6-Diphenyl-1,2-oxathiine 2,2-dioxide 6e. 6-Phenyl-1,2-
oxathiine 2,2-dioxide (0.21 g, 1.0 mmol), AcOAg (0.18 g,
1.1 mmol, 1.1 eq.) and PhI (0.33 mL, 3.0 mmol, 3.0 eq.) were
charged into a flame dried flask under N2. After the addition
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of DMF (5 mL) and Pd(PPh3)4 (0.12 g, 0.1 mmol, 10% mol) the
5-(4-Methoxyphenyl)-2,9-diphenyl-5,9-dihydro-1H-[1,2]
reaction mixture was heated to 80 °C overnight. Upon cooling oxathiino[5,6-c][1,2,4]triazolo[1,2-a] pyridazine-1,3(2H)-dione
the reaction mixture was poured into H2O (10 mL) and 8,8-dioxide 12b. A solution of PTAD (0.33 g, 1.9 mmol, 1.6 eq.)
extracted with EtOAc (5 × 20 mL). The combined organic in 1,2-DCE (15 mL) was added dropwise to a stirred solution of
extracts were washed with H2O (80 mL), dried over anhydrous (E)-6-(4-methoxystyryl)-3-phenyl-1,2-oxathiine
2,2-dioxide
Na2SO4 and the solvent was removed under reduced pressure. (0.40 g, 1.2 mmol) in 1,2-DCE (25 mL) at room temperature
The crude product was subjected to short column chromato- and the resulting reaction mixture was stirred at room temp-
graphy (silica, 20% to 50% EtOAc in petroleum ether) to afford erature overnight and then heated at reflux for 1.5 h. Removal
the title compound after recrystallisation from EtOAc/pet- of the solvent gave the crude product which was eluted
roleum ether as a pale yellow solid (0.09 g, 32%). Physical and through a short column (silica, neat DCM) and the resulting
spectroscopic data were identical to previously prepared solid was triturated with Et2O to afford the title product as a
material.19
pale pink solid (0.40 g, 67%); mp = 158–160 °C (from DCM);
vmax (neat): 3063, 1770, 1712, 1608, 1512, 1504, 1491, 1442,
1401, 1381 (O-SO2), 1307, 1262, 1240, 1170 (O-SO2), 1144,
Attempted Suzuki–Miyaura borylation
5,5′,6,6′-Tetraphenyl-[3,3′-bi(1,2-oxathiine)] 2,2,2′,2′-tetraox- 1103, 1089, 1020 cm−1; δH (CDCl3, 400 MHz) 3.82 (s, 3H, OMe),
ide 10. A suspension of 3-bromo-3,6-diphenyl-1,2-oxathiine 5.48 (dd, J = 1.1, 3.5 Hz, 1H, 9-H), 5.92 (dd, J = 0.5, 6.1 Hz, 1H,
2,2-dioxide (0.5 g, 1.38 mmol), B2pin2 (0.16 g, 0.7 mmol, 0.5 5-H), 6.14 (ddd, J = 1.1, 1.6, 6.1 Hz, 1H, 6-H), 6.94–6.96 (m, 2H,
eq.), KOAc (0.34 g, 3.5 mmol, 2.5 eq.), Pd(dppf)Cl2 (0.12 g, ArH), 7.06–7.09 (ddd, J = 0.5, 1.6, 3.5 Hz, 1H, 10-H), 7.34–7.55
0.14 mmol, 10% mol) in degassed 1,4-dioxane (20 mL) under a (m, 12H, ArH); δC (CDCl3, 100 MHz) 55.37, 55.64, 63.09,
N2 atmosphere was stirred at 80 °C for 1.5 h. Upon cooling the 106.73, 112.53, 114.59, 114.60, 125.14, 125.52, 126.67, 128.70,
mixture was diluted with H2O (30 mL) and the biphasic 129.22, 129.33, 129.42, 129.92, 130.04, 130.25 (2 × C), 142.12,
mixture extracted with EtOAc (5 × 50 mL) and the combined 148.20, 149.12, 160.76; HRMS: Found [M]•+ = 515.1148,
extracts washed with brine (2 × 50 mL), dried over anhydrous C27H21N3O6S requires [M]•+ = 515.1151.
Na2SO4. Removal of the solvent gave a crude product which
2,9-Diphenyl-5-(4-(trifluoromethyl)phenyl)-5,9-dihydro-1H-
was purified by column chromatography (silica, neat DCM) to [1,2]oxathiino[5,6-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-
afford the title compound as a yellow-orange solid (0.20 g, dione 8,8-dioxide 12c. A solution of PTAD (0.28 g, 1.6 mmol,
51%); mp = 190 °C (darkening and decomp); vmax (neat): 3062, 2.0 eq.) in 1,2-DCE (8 mL) was added dropwise to a stirred
1609, 1533, 1486, 1442, 1364 (O-SO2), 1329, 1317, 1284, 1191 solution
of
(E)-3-phenyl-6-(4-(trifluoromethyl)styryl)-1,2-
(O-SO2), 1154, 1126, 1102, 1073, 1035, 1008 cm−1; δH (CDCl3, oxathiine 2,2-dioxide (0.30 g, 0.8 mmol) in 1,2-DCE (8 mL) at
400 MHz) 7.23–7.38 (m, 20H, ArH), 7.56 (s, 2H, 2 × 4-H); δH room temperature and then the resulting mixture was heated
(CDCl3, 400 MHz) 119.69, 123.78, 128.33, 128.67, 129.10, at 50 °C overnight. Removal of the solvent gave the crude
129.36, 129.45, 130.55, 130.89, 134.83, 136.75, 153.46; found product which was purified by column chromatography (silica,
[M + Na]+ = 589.0749, C32H22O6S2 requires [M + Na]+ = 589.0758. 20% to 30% EtOAc/petroleum spirit) to afford the title com-
pound after trituration with Et2O as colourless crystals (0.17 g,
Preparation of phenyltriazolinedione adducts
39%); mp = 173–176 °C (EtOAc/P.E.); vmax (neat): 1776, 1709,
2,5,9-Triphenyl-5,9-dihydro-1H-[1,2]oxathiino[5,6-c][1,2,4] 1620, 1599, 1495, 1405, 1388, 1323 (O-SO2), 1166 (O-SO2),
triazolo[1,2-a]pyridazine-1,3(2H)-dione 8,8-dioxide 12a. A solu- 1115, 1067, 1018 cm−1; δH (CDCl3, 400 MHz) 5.49 (dd, J = 1.0,
tion of PTAD (0.32 g, 1.6 mmol, 1.2 eq.) in 1,2-DCE (10 mL) 3.6 Hz, 1H, 9-H), 6.01 (dd, J = 0.5, 6.2 Hz, 1H, 5-H), 6.14 (ddd, J
was added dropwise to a stirred solution of (E)-3-phenyl-6- = 1.0, 1.5, 6.2 Hz, 1H, 6-H), 7.14 (ddd, J = 0.5, 1.5, 3.6 Hz, 1H,
styryl-1,2-oxathiine 2,2-dioxide (0.4 g, 1.3 mmol) in 1,2-DCE 10-H), 7.35–7.54 (m, 10H, ArH), 7.63–7.74 (m, 4H, ArH); δC
(10 mL) and the resulting reaction mixture was stirred over- (CDCl3, 100 MHz) 55.30, 63.11, 107.66, 111.34, 123.65 (q, J =
night at room temperature. Removal of the solvent gave the 273 Hz), 125.46, 126.41 (q, J = 3.5 Hz), 127.93, 128.90, 128.98,
crude product which was eluted through a short column 129.12, 129.32, 129.40, 129.90, 130.00, 130.38, 132.13 (q, J = 33
(silica, neat DCM) and the resulting pale yellow solid was tritu- Hz), 137.18, 142.68, 148.07, 148.85; δF (376.5 MHz, CDCl3)
rated with Et2O afford the product (0.38 g, 60%) as an off- −62.89 (s, 3F); HRMS: Found [M
white solid; mp = 146–147 °C (from DCM); vmax (neat): 3073, C27H18F3N3O5S requires [M + Na]+ = 576.0819.
1768, 1712, 1620, 1494, 1455, 1412, 1384 (O-SO2), 1304, 1220, 2,5-Diphenyl-5,9-dihydro-1H-[1,2]oxathiino[5,6-c][1,2,4]tri-
+ = 576.0815,
Na]+
1165 (O-SO2), 1148, 1103, 1030 cm−1; δH (CDCl3, 400 MHz) azolo[1,2-a]pyridazine-1,3(2H)-dione 8,8-dioxide 12e. A solu-
5.48 (ddd, J = 0.8, 1.0, 3.6 Hz, 1H, 9-H), 5.96 (ddd, J = 0.5, 0.8, tion of PTAD (0.25 g, 1.4 mmol, 1.1 eq.) in 1,2-DCE (10 mL)
6.1 Hz, 1H, 5-H), 6.14 (ddd, J = 1.0, 1.7, 6.1 Hz, 1H, 6-H), 7.11 was added dropwise to a stirred solution of (E)-6-styryl-1,2-
(ddd, J = 0.5, 1.7, 3.6 Hz, 1H, 10-H), 7.33–7.57 (m, 15H, ArH); oxathiine 2,2-dioxide (0.30 g, 1.3 mmol) in 1,2-DCE (15 mL) at
δC (100 MHz, CDCl3) 56.05, 63.07, 106.93, 112.26, 125.53, room temperature overnight. Further PTAD (0.23 g, 1.3 mmol)
126.60, 128.53, 128.75, 129.25, 129.35 (2 × C), 129.39, 129.92, was added with stirring at room temperature continued for 3 h
130.01, 130.20, 130.28, 133.31, 142.17, 148.20, 148.95; HRMS: and then the mixture was stirred at 50 °C for a further 2 h.
Found [M + H]+ = 486.1121, C26H19N3O5S requires [M + H]+ = Removal of the solvent gave a crude product which was puri-
486.1125.
fied by a short column (silica, 0% to 10% EtOAc/DCM) to
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afford a solid that was triturated with Et2O to yield the title com- 149.99, 154.64, 160.58; HRMS: Found [M − H]− = 514.1062,
pound as an off-white solid (0.37 g, 70%); mp = 196–198 °C C27H21N3O6S requires [M − H]− = 514.1067.
(EtOAc/DCM); vmax (neat): 1762, 1704, 1621, 1497, 1458, 1402,
Isolation of 2,9-diphenyl-5-(4-(trifluoromethyl)phenyl)-5,10a-
1384 (O-SO2), 1305, 1291, 1272, 1182, 1172 (O-SO2), 1157, 1142, dihydro-1H-[1,2]oxathiino [5,6-c][1,2,4]triazolo [1,2-a]pyrida-
1102, 1086, 1032 cm−1; δH (CDCl3, 400 MHz) 4.24 (ddd, J = 0.7, zine-1,3(2H)-dione 8,8-dioxide 11c. A solution of PTAD (0.20 g,
4.7, 17.6 Hz, 1H, syn-9-H), 4.28 (ddd, J = 0.7, 5.5, 17.6 Hz, 1H, 1.2 mmol, 1.1 eq.) in 1,2-DCE (8 mL) was added dropwise to a
anti-9-H), 5.93 (d, J = 6.0 Hz, 1H, 5-H), 6.10 (ddd, J = 0.7, 1.7, 6.0 stirred solution of (E)-3-phenyl-6-(4-(trifluoromethyl)styryl)-1,2-
Hz, 1H, 6-H), 6.98 (ddd, J = 1.7, 4.7, 5.5 Hz, 1H, 10-H), 7.36–7.46 oxathiine 2,2-dioxide (0.40 g, 1.1 mmol) in 1,2-DCE (10 mL) at
(m, 10H, ArH); δC (CDCl3, 100 MHz) 46.92, 56.05, 101.24, room temperature and the mixture was stirred at room tempera-
112.35, 125.58, 126.08, 128.42, 128.76, 129.26, 129.27, 129.94, ture overnight. Removal of the solvent gave a solid which was tri-
130.20, 133.37, 142.09, 148.26, 148.83; HRMS: Found [M + H]+ = turated with AcMe and n-pentane to afford the title compound
410.0800, C20H15N3O5S requires [M + H]+ = 410.0802.
as a white powder; mp = 169–172 °C; vmax (neat): 1780, 1721,
2,5-Diphenyl-9-(4-(trifluoromethyl)phenyl)-5,9-dihydro-1H- 1495, 1411, 1377, 1325 (O-SO2), 1256, 1182, 1141 (O-SO2), 1111,
[1,2]oxathiino[5,6-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)- 1090, 1058, 1021 cm−1; δH (CDCl3, 400 MHz) 5.40 (q, J = 2.3 Hz,
dione 8,8-dioxide 12f. A solution of PTAD (0.11 g, 0.6 mmol, 1H, 10a-H), 5.88 (dd, J = 5.0, 2.3 Hz, 1H, 5-H), 6.33 (dd, J = 5.0,
1.1 eq.) in 1,2-DCE (7 mL) was added dropwise to a solution 2.0 Hz, 1H, 6-H), 7.35–7.55 (m, 9H, ArH/10-H), 7.63–7.70 (m, 6H,
of (E)-6-styryl-3-(4-(trifluoromethyl)phenyl)-1,2-oxathiine 2,2- ArH); δC (CDCl3, 100 MHz) 54.54, 54.59, 115.72, 123.72 (q, J =
dioxide (0.20 g, 0.5 mmol) in 1,2-DCE (10 mL) at room temp- 272 Hz, CF3), 125.18, 126.16 (q, J = 3.6 Hz, o-ArC-CF3), 126.55,
erature. After stirring overnight at room temperature, a further 128.12, 128.75, 129.11, 129.27, 129.28, 129.40, 130.17, 130.95,
portion of PTAD (0.05 g, 0.3 mmol) was added and the reaction 131.92 (q, J = 33 Hz, C-CF3), 137.54, 141.76, 142.67, 149.85,
mixture was heated at 50 °C for 72 h. Removal of the solvent 154.50; δF (376.5 MHz, CDCl3) −62.90 (s, 3F); HRMS: Found [M
gave the crude product which was purified by column chrom- − H]− = 552.0846, C27H18F3N3O5S requires [M − H]− = 552.0843.
atography (silica, 20% EtOAc/petroleum spirit) to afford an off-
Dimethyl 7-(4-methoxyphenyl)-3-phenylbenzo[e][1,2]oxathiine-
white solid that was triturated with Et2O to yield the title 5,6-dicarboxylate 2,2-dioxide 13. A mixture of DMAD (0.12 mL,
product as a white powder (0.09 g, 18%); mp = 156–157 °C 0.97 mmol, 1.1 eq.) and (E)-6-(4-methoxystyryl)-3-phenyl-1,2-
(EtOAc/petroleum spirit); vmax (neat): 1770, 1715, 1410, 1388 oxathiine 2,2-dioxide (0.30 g, 0.88 mmol, 1.0 eq.) was heated to
(O-SO2), 1328, 1184, 1167 (O-SO2), 1133, 1103, 1069 cm−1; δH reflux overnight. Upon cooling the complex reaction mixture
(CDCl3, 400 MHz) 5.53 (dd, J = 1.0, 3.5 Hz, 1H, 9-H), 5.98 (dd, J was subjected to flash column chromatography (using DCM,
= 0.5, 5.9 Hz, 1H, 5-H), 6.20 (ddd, J = 1.0, 1.5, 5.9 Hz, 1H, 6-H), 0% to 10% MeOH in DCM). The fractions with an Rf = 0.9
7.08 (ddd, J = 0.5, 1.5, 3.5 Hz, 1H, 10-H), 7.33–7.51 (m, 10H, (10% MeOH/DCM) were combined to afford the title product
ArH), 7.69–7.71 (m, 2H, ArH), 7.75–7.77 (m, 2H, ArH); δC after trituration from petroleum spirit/Et2O 8 : 2 as an off-white
(CDCl3, 100 MHz) 56.06, 62.56, 105.71, 112.91, 123.64 (q, J = solid (0.04 g, 10.0%) mp = 214–216 °C; νmax (neat): 2953, 1747,
274 Hz), 125.50, 126.32 (q, J = 3.7 Hz), 126.98, 128.48, 128.82, 1728 (CvO), 1719 (CvO), 1609, 1516, 1491, 1438, 1387, 1373
129.27, 129.39, 130.10, 130.13, 130.41, 132.62 (q, J = 33 Hz), (O-SO2), 1329, 1275, 1247, 1217, 1180 (O-SO2), 1152, 1112,
133.14, 133.47, 141.98, 148.20, 148.89; δF (376.5 MHz, CDCl3) 1021 cm−1; δH (CDCl3, 400 MHz) 3.65 (s, 3H, CH3O), 3.86 (s,
−62.94 (s, 3F); HRMS: Found [M
+
H]+
=
554.0994, 3H, CO2CH3), 3.93 (s, 3H, CO2CH3), 6.96–6.98 (m, 2H, Ar–H),
7.28–7.30 (m, 2H, Ar–H), 7.41 (s, 1H, 8-H), 7.50–7.51 (m, 3H,
C27H18F3N3O5S requires [M + H]+ = 554.0996.
PTAD addition reactions to 6-styryl-1,2-oxathiine 2,2-dioxides Ar–H), 7.63 (s, 1H, 4-H), 7.67–7.69 (m, 2H, Ar–H); δC (CDCl3,
for purpose of characterization of the silica sensitive initial 100 MHz) 52.70, 53.38, 55.37, 114.23, 117.62, 122.12, 127.18,
adducts – isolation of 5-(4-methoxyphenyl)-2,9-diphenyl-5,10a- 129.15, 129.32, 129.91, 130.27, 130.53, 130.76, 131.58, 138.58,
dihydro-1H-[1,2]oxathiino[5,6-c][1,2,4]
triazolo[1,2-a]pyrida- 144.08, 151.29, 160.18, 165.94, 167.71; HRMS: Found [M + Na]+ =
zine-1,3(2H)-dione 8,8-dioxide 11b. A solution of PTAD (0.19 g, 503.0770, C25H20O8S requires [M + Na]+ = 503.0777.
1.1 mmol, 1.2 eq.) in 1,2-DCE (5 mL) was added dropwise
to a stirred solution of (E)-6-(4-methoxystyryl)-3-phenyl-1,2-
Addition of benzyne to substituted 1,2-oxathiine 2,2-dioxides
oxathiine 2,2-dioxide (0.30 g, 0.9 mmol) in 1,2-DCE (10 mL) at
1,4-Diphenylnaphthalene 16. A solution of 2-(trimethylsilyl)
room temperature and the mixture was stirred at room temp- phenyl trifluoromethanesulfonate (0.48 mL, 2.0 mmol, 1.1 eq.)
erature overnight. Removal of the solvent and trituration of the in anhydrous MeCN (5 mL) was added dropwise to a stirred
resulting solid with AcMe afforded the title compound as a suspension of 3,6-diphenyl-1,2-oxathiine 2,2-dioxide (0.5 g,
white powder; mp = 164–168 °C; vmax (neat): 1717, 1599, 1503, 1.8 mmol) and CsF (0.68 g, 4.5 mmol, 2.5 eq.) in anhydrous
1409, 1372 (O-SO2), 1256, 1180 (O-SO2), 1139, 1089, 1026 cm−1
;
MeCN (25 mL) at room temperature under a N2 atmosphere.
δH (CDCl3, 400 MHz) 5.36 (q, J = 2.3 Hz, 1H, 10a-H), 5.78 (dd, Upon completion of the addition the reaction mixture was
J = 2.2, 5.1 Hz, 1H, 5-H), 6.31 (dd, J = 2.2, 5.1 Hz, 1H, 6-H), stirred at room temperature for 2 h and then heated to reflux
6.88–6.91 (m, 2H, ArH), 7.35–7.50 (m, 11H, ArH/10-H), for 1 h. The cooled mixture was diluted with H2O (50 mL) and
7.68–7.71 (m, 2H, ArH); δC (CDCl3, 100 MHz) 54.45, 54.86, extracted with EtOAc (2 × 25 mL). The combined organic
55.31, 114.35, 116.66, 125.24, 125.86, 126.96, 128.16, 128.55, extracts were washed with brine (30 mL), dried over anhydrous
129.20, 129.21, 129.31, 130.39, 130.40, 130.81, 141.45, 141.85, Na2SO4 and the solvent removed. The resulting crude product
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was purified by column chromatography (silica, 0% to 3%
EtOAc/petroleum spirit), to afford a pale-yellow solid that was
triturated with n-pentane to afford the title compound as an
off-white solid (0.11 g, 22%); mp = 126–129 °C [lit. mp =
132–133 °C (ref. 44)]; vmax (neat): 3052, 1598, 1573, 1512, 1488,
1469, 1446, 1384, 1238, 1154, 1071, 1028 cm−1; δH (CDCl3,
400 MHz) 7.43–7.57 (m, 14H, ArH), 7.96–8.00 (m, 2H, ArH); δC
(CDCl3, 100 MHz) 125.87, 126.41, 126.48, 127.29, 128.32,
130.17, 131.92, 139.84, 140.83.
Notes and references
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2 M. Sainsbury, Chapter 40: Compounds containing a Six-
membered Ring having two Hetero-atoms from Group VIB
of the Periodic Table: Dioxanes, Oxathianes and Dithianes,
in Rodd’s Chemistry of Carbon Compounds, 2nd edn, 1964,
vol. IV, pp. 375–426.
3 M. J. Cook, Chapter 2.26: Six-membered Rings with More
than One Oxygen or Sulfur Atom, in Comprehensive
Heterocyclic Chemistry, ed. A. J. Boulton and A. McKillop,
1984, vol. 3, pp. 943–994.
4 E. Kleinpeter, Chapter 8.10: 1,2-Dioxins, Oxathiins,
Dithiins, and their Benzo Derivatives, in Comprehensive
Heterocyclic Chemistry III, ed. A. Aitken, 2008, vol. 8, pp.
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5 K. A. Ali, A. Jäger and P. Metz, ARKIVOC, 2016, iii,
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6 Th. Morel and P. E. Verkade, Recl. Trav. Chim. Pays-Bas,
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1-(4-Methoxyphenyl)naphthalene
17.
2-(Trimethylsilyl)
phenyl trifluoromethanesulfonate (0.56 mL, 2.3 mmol, 1.1 eq.)
was added dropwise via syringe to a stirred suspension of 6-(4-
methoxyphenyl)-1,2-oxathiine 2,2-dioxide (0.5 g, 2.1 mmol)
and CsF (0.51 g, 3.4 mmol, 1.6 eq.) in anhydrous MeCN
(25 mL) at room temperature under a N2 atmosphere and the
mixture was stirred at room temperature overnight. The reac-
tion mixture was diluted with H2O (50 mL) and extracted with
EtOAc (2 × 25 mL). The combined organic extracts were
washed with brine (30 mL), dried over anhydrous Na2SO4 and
the solvent removed to afford the crude product which was
eluted from silica with 10% EtOAc/petroleum spirit to afford
the title adduct after trituration with n-pentane as an off-white
solid (0.04 g, 8%); mp = 111–114 °C [lit. mp = 112–113 °C (ref.
45)]; vmax (neat): 2991, 2954, 2831, 1607, 1513, 1504, 1461,
1451, 1437, 1422, 1393, 1282, 1239, 1207, 1173, 1143, 1107,
1057, 1030 cm−1; δH (CDCl3, 400 MHz) 3.89 (s, 3H, OMe),
7.02–7.04 (m, 2H, ArH), 7.39–7.53 (m, 6H, ArH), 7.83–7.85 (m,
1H, ArH), 7.89–7.93 (m, 2H, ArH); δC (CDCl3, 100 MHz) 55.38, 10 J. Gaitzsch, V. Rogachev and P. Metz, Synthesis, 2014, 46,
113.72, 125.42, 125.72, 125.94, 126.08, 126.92, 127.35, 128.27,
131.13, 131.83, 133.13, 133.84, 139.91, 158.94.
0531–0536.
11 M. Zhang and C. Han, US Patent, US20180294483A1, 2018;
K. Hatta, N. Shimosaka, M. Machida, M. Aoki and
M. Miyamoto, PCT Int. Appl, WO2015107910A1, 2015.
1,2,4-Triphenylnaphthalene 18.
phenyl)-1,2-oxathiine 2,2-dioxide (0.50 g, 1.4 mmol) and 2-(tri-
methylsilyl)phenyl trifluoromethanesulfonate (0.36
A solution of 3,5,6-(tri-
mL, 12 J. H. Ko, Y. J. Ha, C. H. Lee, Y. M. Lim and J. A. Ahn,
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Republic of Korea Patent, KR2009084547A, 2009; T. Aoai and
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extracts were washed with brine (30 mL) dried over anhydrous 14 O. D. C. C. de Azevedo, B. M. Heron and D. Zonidis,
Na2SO4 and the solvents removed under reduced pressure. The
crude product was eluted from silica with 10% Et2O/petroleum
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159–161 °C (ref. 46)]; vmax (neat): 3053, 3019, 1599, 1573, 1491, 3, 754–755.
1439, 1419, 1379, 1251, 1209, 1141, 1070, 1056, 1032 cm−1; δH 16 W. E. Truce, D. J. Abraham and P. Son, J. Org. Chem., 1967,
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Sci. Synth., 2004, 27, 123–134.
19 S. Aiken, K. Anozie, O. D. C. C. de Azevedo, L. Cowen,
R. J. L. Edgar, C. D. Gabbutt, B. M. Heron, P. A. Lawrence,
A. J. Mills, C. R. Rice, M. W. J. Urquhart and D. Zonidis,
Org. Biomol. Chem., 2019, 17, 9585–9604.
Conflicts of interest
There are no conflicts to declare.
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