Expedient synthesis of highly substituted 3,4-dihydro-1,2-oxathiine 2,2-dioxides and 1,2-oxathiine 2,2-dioxides: revisiting sulfene additions to enaminoketones

Article abstract of DOI:10.1039/c9ob01657k

Diversely substituted 1,2-oxathiine 2,2-dioxides, including 3,5,6-triaryl-, 3,6-diaryl-, 3,5-diaryl-, 5,6-diaryl- and selected fused heterocyclic analogues, have been efficiently obtained by the application of a mild Cope elimination of a 4-amino moiety from the requisite 4-amino-3,4-dihydro-1,2-oxathiine 2,2-dioxides, which themselves were readily obtained by the addition of sulfenes to enaminoketones.

Full text of DOI:10.1039/c9ob01657k

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Expedient synthesis of highly substituted
3,4-dihydro-1,2-oxathiine 2,2-dioxides and
1,2-oxathiine 2,2-dioxides: revisiting sulfene
additions to enaminoketones†
Cite this: Org. Biomol. Chem., 2019,
17, 9585
a
Stuart Aiken, a Kelechi Anozie, a Orlando D. C. C. de Azevedo,
a
Lewis Cowen, a Ross J. L. Edgar, a Christopher D. Gabbutt,
B. Mark Heron, *a Philippa A. Lawrence, a Abby J. Mills, a Craig R. Rice,
a
Mike W. J. Urquhart b and Dimitrios Zonidis
*
a
Received 26th July 2019,
Accepted 31st October 2019
Diversely substituted 1,2-oxathiine 2,2-dioxides, including 3,5,6-triaryl-, 3,6-diaryl-, 3,5-diaryl-, 5,6-
diaryl- and selected fused heterocyclic analogues, have been efficiently obtained by the application of a
mild Cope elimination of a 4-amino moiety from the requisite 4-amino-3,4-dihydro-1,2-oxathiine 2,2-
dioxides, which themselves were readily obtained by the addition of sulfenes to enaminoketones.
DOI: 10.1039/c9ob01657k
rsc.li/obc
ketones.5 4,6-Diaryl substituted compounds result from either
sulfonation of acetophenones6 or arylacetylenes7 though one
Introduction
1,2-Oxathiine 2,2-dioxides (Fig. 1), historically referred to as drawback of this sulfonation approach is that the 4- and 6-aryl
δ-sultones, are the relatively scarcely studied isomers in the substituents are identical. Unexpected syntheses of the 1,2-
homologous series of sultones.1 Indeed the 1,2-oxathiine ring oxathiine 2,2-dioxide ring have been noted from the sulfuric acid
is the lesser explored isomer of the six-membered heterocyclic mediated acetolysis of methyl 5,6-di-O-acetyl-2,3-O-isopropyl-
systems which contain one sulfur and one oxygen atom.2 idene-β-L-gulofuranoside,8 from the oxidative ring expansion of
However, there has been recent interest in the 1,2-oxathiine 2,5,9,12-tetra(tert-butyl)diacenaphtho[1,2-b:1′,2′-d]thiophene9
2,2-dioxide unit in energy storage/battery technology3 and as and via tri-n-butylstannyl radical rearrangement of but-3-ynyl are-
photoresists for high resolution lithography.4
nesulfonates.10 Recent interest in the synthesis of benzofused
There are relatively few synthetic routes to this fully unsatu- δ-sultones has been stimulated by the Rh(III)-catalyzed oxidative
rated ring system, simple alkyl substituted analogues can be coupling of arylsulfonic acids with internal alkynes.11 In spite of
obtained by sulfonation of either α,β- or β,γ-unsaturated the lack of general and versatile synthetic routes to 1,2-oxathiine
2,2-dioxides their chemistry offers potential with photolysis
affording ketosulfonic esters12 and thermolysis providing an
efficient and frequently exploited route to 2,4-dimethylfuran13
which serves as a useful building block for the A and C ring sub-
units of taxol14 and the complex side chain of mycolactones A
and B.15 The addition of hydrazines to 1,2-oxathiine 2,2-dioxides
affords both pyrroles and pyrazoles16 and cycloaddition with
acetylenes under forcing conditions results in overall expulsion
Fig. 1 Structure and numbering for the 1,2-oxathiine 2,2-dioxide ring
of SO3 to afford a useful array of terphenylene derivatives.17
system.
A relatively scarcely explored route to the 1,2-oxathiine
system involves the addition of sulfenes to enaminoketones.18,19
aDepartment 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
bGlaxoSmithKline Research and Development Limited, Medicines Research Centre,
Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK
†Electronic supplementary information (ESI) available. CCDC 1913653–1913658.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c9ob01657k
Examination of the literature revealed that Schenone and co-
workers had exploited the addition of sulfenes20–24 to a selec-
tion of enaminoketones to afford 3,4-dihydro-1,2-oxathiine 2,2-
dioxides. Interestingly, the amino function was retained in each
of these sulfene addition reactions affording 3,4-dihydro-1,2-
oxathiine 2,2-dioxide rather than undergoing a facile elimin-
ation to produce the conjugated 1,2-oxathiine 2,2-dioxide
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Fig. 2 Previous attempts to obtain the 1,2-oxathiine 2,2-dioxide from substituted dihydro-1,2-oxathiine 2,2-dioxides.
system.21–23 Notably, when chlorosulfene was added to a series oxathiine 2,2-dioxides from preformed 3,4-dihydro analogues
of enaminoketones 1 the elimination of HCl was accomplished (Fig. 2) we commenced our exploration of the addition of aryl-
from the adducts 2 upon subsequent treatment with DBN to sulfenes to a diverse series of enaminoketones with a view to
afford the substituted amino-1,2-oxathiine 2,2-dioxides 3, but widening access to 3,4-dihydro-1,2-oxathiine 2,2-dioxides and
not the unsubstituted alkene, in good yield (Fig. 2).24 In a examining their transformation into new unsaturated 1,2-
related study the dehydrogenation of sulfene adduct 4 (NR2
=
oxathiine 2,2-dioxides.
NMe2) with DDQ in refluxing benzene for 10 h gave the
oxathiine 5a in 27% yield and a similar treatment of 4 (NR2 =
morpholine) with a 24 h reflux gave 5b in 17% yield (Fig. 2).25
In the foregoing study the authors noted the variably of their
Results and discussion
DDQ aromatization protocol which failed to dehydrogenate the A range of enaminoketones 9a–k were efficiently prepared by
1,2-oxathiine ring of the furan analogue 4 X = O and instead treatment of the requisite α-methylene ketones in N,N-di-
gave 6.26 We have previously examined the synthesis of a novel methylformamide dimethylacetal (DMFDMA) according to lit-
dithienylethene photochromic system in which the ethene erature procedures. Of note was the influence of the reaction
bridge forms part of a 1,2-oxathiine 2,2-dioxide ring.27 In the medium and conditions on the outcome of the reaction
latter work the oxathiine unit was introduced by (phenyl) of 3-oxo-3-phenylpropanenitrile (benzoylacetonitrile) with
sulfene addition to a series of thienyl substituted enaminoke- DMFDMA to afford 9f; here crystalline salts 9f′ and 9f″ were
tones with the intermediate 3,4-dihydro-1,2-oxathiine 2,2-diox- isolated as minor by-products and have been characterised by
ides 7 undergoing a facile, room temperature Cope elimination X-ray crystallography (see ESI Fig. 1–3†).
of the dimethylamine function to afford the unsaturated 1,2-
oxathiine 2,2-dioxide moiety 8 in good yield (Fig. 2).
Arylsulfenes, readily generated in situ from the base
mediated elimination of HCl from the requisite arylmethane-
Given the success of our Cope elimination protocol coupled sulfonyl chlorides, underwent efficient addition to the acyclic
with the limited literature reports for the formation of 1,2- enaminoketones 9a–d to afford the 3,5,6-triaryl-4-amino-3,4-
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dihydro-1,2-oxathiines 2,2-dioxides 10a–e in generally high yield angle = 153°) in a half-chair conformation. The magnitude of
(48–96%). Enaminoketone 9d which possesses an additional 1H NMR coupling constant, J3,4 = 8.0 Hz, in 10a is somewhat
electron withdrawing group (X = Bz) required an extended reac- diminished for such an arrangement viz. the typically larger
tion time in order to afford the desired oxathiine adduct 10e. trans-diaxial coupling in cyclohexane rings,28 though in this
However, no oxathiines could be observed from the prolonged instance the O–C6–C5–C4–C3 unit of the oxathiine ring is near
reaction of either 9e or 9f and the enaminoketone precursors planar. The J3,4 coupling constants for the other 3,5,6-triaryl
were recovered (Scheme 1). The enaminoketones 9g−9k, derived substituted dihydro-1,2-oxathiines are comparable with that of
from ‘acetophenones’, similarly underwent smooth arylsulfene 10a with 10b, J3,4 = 8.8 Hz and 10c, J3,4 = 7.6 Hz. Interestingly,
addition to afford 3,6-diaryl-4-amino-3,4-dihydro-1,2-oxathiines the J3,4 coupling constants for the remaining 3,5,6-trisubsti-
2,2-dioxides 10f–j in generally good yield (52–83%) with the tuted oxathiines were larger with 10d1, J3,4 = 9.4 Hz and 10e,
exception of the pyridyl example 10i (10%) where work-up was J3,4 = 10.3 Hz. For the minor isomer 10d2 the smaller J3,4 coup-
protracted due to the presence of the basic pyridyl function. ling of 6.3 Hz results from the interaction between axial and
In a limited number of instances, the isolated crude 3,5,6- equatorial disposed protons.
trisubstituted 4-dimethylamino-3,4-dihydro-1,2-oxathiines 10
In contrast, J3,4 for the 3,6-diaryl substituted oxathiines
were obtained as an unequal mixture of diastereoisomers as (unsubstituted at C-5) (10f–10j) were again larger for those of
indicted from their NMR spectra. For example, the 1H NMR 10a–e typically of the order of 11.2 Hz. Clearly the presence of
spectrum of crude 10a revealed doublets at δ 4.96 (4-H) and δ an aryl ring at C-5 in 10a–e modifies the conformation of the
4.49 (3-H) with J3,4 = 8.0 Hz for the major isomer and doublets dihydro-1,2-oxathiine ring and thus the coupling constants (Fig. 4).
1
at δ 4.89 (4-H) and δ 4.73 (3-H) with J3,4 = 5.9 Hz for the minor
Examination of the H NMR spectra of the adducts 12a, b
isomer (Fig. 4), with the isomer ratio determined as 4 : 1. which resulted from the addition of sulfene to enaminoke-
Similarly, crude 10d displayed doublets at δ 4.76 (4-H) and δ tones 9a, b (Scheme 3) revealed J3,4 coupling constants of 7.4
4.51 (3-H) with J3,4 = 9.4 Hz for the major isomer (10d1) and Hz and 9.1 Hz (12a) and 6.3 Hz and 11.4 Hz (12b), respectively
doublets at δ 4.81 (4-H) and δ 4.69 (3-H) with J3,4 = 6.3 Hz for and which are indicative of the 4-dimethylamino substituent
the minor isomer (10d2), with an isomer ratio of 1.6 : 1. The occupying an equatorial site of the half-chair conformer. Of
1
major diastereoisomer 10d1 could be obtained in 48% yield by note in the H NMR spectrum of 12b was a long-range coup-
flash chromatography and crystallization. Additionally, a small ling of 1.0 Hz between 5-H and the equatorially disposed 3-H.
amount of the minor isomer 10d2 was isolated (25%) and fully Interestingly, a second component was isolated from the reac-
characterized. Interestingly, recording the 1H NMR spectrum tion between sulfene and 9b which was characterized as the
of a CDCl3 solution of 10d2 over 6 days revealed the gradual oxathiine-2,2-dioxide 13b (50%) on the basis of the chemical
epimerisation of 10d2 into the original major isomer 10d1 shift of 3-H (δ 6.57, d, J = 10.0 Hz), 4-H (δ 6.91, dd, J = 10.0, 6.8
(Fig. 3). We suspect that this epimerisation of 10d2 may be Hz) and 5-H (δ 6.30, d, J = 6.8 Hz) and which presumably
facilitated by protonation of the enol moiety (at C-5) which forms by the facile elimination of dimethylamine from the
enables the 4-NMe2 group to adopt a less hindered orientation isomer in which the dimethylamine group and a 3-H are trans-
that leads to
arrangement of the 4-NMe2 and 3-Ph substituents in the major data is presented in Fig. 4 for a series of 3,5,6-triphenyl-, 3,6-
a
proposed transoid equatorial–equatorial disposed (anti-peri-planar arrangement). Selected 1H NMR
isomer 10d1 (Scheme 5 insert).
diphenyl- and 5,6-diphenyl-1,2-oxathiine 2,2-dioxides.
The geometry of 10a was established by X-ray crystallogra-
In order to extend the structural diversity of the dihydro-
phy (CCDC 1913655†), (Fig. 5 and ESI†) which revealed a trans- 1,2-oxathiines, by substrate variation, sulfene additions to
diaxial arrangement of 3-H and 4-H (H3–C3–C4–H4 torsion enaminoketones 15 and 18, derived from arylmethyleneketone
Fig. 3 Time resolved 1H NMR spectra (δ 3.0–5.0) showing epimerisation of 10d2 into 10d1 over 6 days in CDCl3 solution.
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be facile e.g. 12b → 13b and 22 → 23, presumably from an
isomer where 3-H is suitably disposed to the 4-dimethylamino
function. Thus, treatment of a PhMe solution of 10a with a
catalytic amount of 4-TsOH and stirring at either room temp-
erature or under reflux failed to afford any 11a. Indeed,
increasing the amount of 4-TsOH up to a 10-fold molar excess
of 10a and heating the solution under reflux overnight resulted
in darkening of the reaction mixture together with the for-
mation of decomposition products as indicated by the pres-
ence of several very minor components observed by TLC
together with some unchanged major component. Given the
conformation depicted in Fig. 5, a Cope elimination protocol29
was explored. Treatment of a cooled CH2Cl2 solution of 10a
with a slight excess of m-CPBA and stirring at room tempera-
ture for 18 h resulted in the efficient elimination of the di-
methylamine unit to afford 11a in 71% isolated yield. A singlet
Fig. 4 Selected 1H NMR data (CDCl3) for 3,5,6-triphenyl-, 3,6-diphenyl-,
3,5-diphenyl- and 5,6-diphenyl- (3,4-dihydro) 1,2-oxathiine 2,2-dioxides.
14 and 2-tetralone, respectively and sulfene addition to the
enaminoaldehyde 21 were explored (Scheme 4). Phenylsulfene
addition to 15 proceeded smoothly to afford 16 in 79% yield.
As a consequence of restricted rotation of the o-fluorophenyl
unit due to steric congestion with the adjacent methyl and di-
methylamino groups the 1H NMR spectrum of 16 was
complex. Indeed recording the spectrum at 233 K revealed a
mixture of two rotamers (ESI) which coalesce upon recording
the spectrum at 323 K. A small variation in J3,4 was observed
with the rotamers affording couplings of 9.7 and 9.9 Hz
(233 K) and the thermally averaged compound giving J3,4 = 9.5
Hz (323 K). The 1,2,5,6-tetrahydronaphtho[1,2-e][1,2]oxathiine
3,3-dioxide 19 (from 18) was isolated in 65% yield and exhibi-
ted J3,4 = 8.9 Hz. In contrast to the foregoing reactions of
enaminoketones, the enaminoaldehyde derivative 21 afforded a
complex crude product from which two new pure components
22 (5%) and 23 (2.9%) were isolated. The dihydro-1,2-oxathiine
22 exhibited a doublet with allylic coupling of 1.5 Hz, at δ 6.66
for 6-H and a doublet at δ 4.66 for 3-H with the typical J3,4 value
of 9.7 Hz. The introduction of the CvC bond in 23 resulted in
Fig. 5 Crystal structure of 10a (thermal ellipsoids shown at 50% prob-
ability level).
1
the presence of a pair of doublets (δ 7.07, 7.03) in the H NMR
spectrum with a coupling constant of 2.1 Hz (Fig. 4).
With a series of 4-dimethylamino-3,4-dihydro-1,2-oxathiine
2,2-dioxides to hand (10a–j, 12a, 12b, 16 and 19) the introduc-
tion of the C-3–C-4 oxathiine ring double bond by the elimin-
ation of dimethylamine was examined. From our earlier obser-
Fig. 6 Crystal structure of 11a (thermal ellipsoids shown at 50% prob-
vations it is clear that the elimination of dimethylamine can ability level).
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was observed at δ 7.03 for 4-H confirming the elimination of 5,6-disubstituted analogue 13a (Fig. 4). The foregoing trend in
the amine and a single crystal structure (CCDC 1913656†), the magnitude of the coupling constants was consistent for
(Fig. 6) confirmed the successful elimination protocol. The the mono-aryl substituted oxathiine 13b with J3,4 = 10.0 Hz
Cope reaction sequence was then carried out on the remaining and J4,5 = 6.8 Hz.
4-dimethylamino substituted 1,2-oxathiine 2,2-dioxides to
In an extension of the foregoing elimination study, we
afford 11b–j, 13a, 13b, 17 and 20 in good to excellent yields examined the acid-catalysed elimination of dimethylamine
(68–96%) (Schemes 1 and 2). Interestingly for the 3,6-diaryl from the isolated minor isomer 10d2 in which 4-NMe2 group
substituted 1,2-oxathiines (11f–j) J4,5 was ca. 6.8–7.2 Hz, is in an anti-peri-planar arrangement with 3-H. Thus, heating
whereas J3,4 = 10.2 Hz was typical of cis-alkene coupling for the 10d2 in toluene containing 4-TsOH (20 mol%) gave a multi-
Scheme 1 Synthesis of 3,5,6-trisubstituted 1,2-oxathiines 2,2-dioxides 11. Reagents and conditions: (i) Ar2CH2SO2Cl, Et3N, THF 0 °C–rt;
(ii) m-CPBA (1.2 eq), CH2Cl2, 0 °C–rt.
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Scheme 2 Synthesis of 3,6-disubstituted 1,2-oxathiine 2,2-dioxides 11. Reagents and conditons: (i) Ar2CH2SO2Cl, Et3N, THF 0 °C–rt; (ii) m-CPBA
(1.2 eq), CH2Cl2, 0 °C–rt.
Scheme 3 Synthesis of 5,6-diaryl- and 6-aryl-1,2-oxathiine 2,2-dioxides. Reagents and conditions: (i) MeSO2Cl, Et3N, THF 0 °C–rt; (ii) m-CPBA (1.2
eq.), CH2Cl2, 0 °C–rt.
component reaction mixture from which the major com-
With efficient methodology developed for the addition of
ponent, the 1,2-oxathiine 2,2-dioxide 11d, was isolated in low sulfenes to the series of enaminoketones and the subsequent
yield (15%) (Scheme 5).
elimination of the dimethylamino function from the 3,4-
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Scheme 4 Synthesis of substituted 1,2-oxathiine 2,2-dioxides 17, 20 and 23. Reagents and conditions: (i) DMFDMA, reflux; (ii) PhCH2SO2Cl, Et3N,
THF 0 °C–rt; (iii) m-CPBA, CH2Cl2, 0 °C–rt.
Scheme 5 Elimination reactions to afford 11d. Reagents and conditions: (i) m-CPBA (1.2 eq.), CH2Cl2, 0 °C–rt; (ii) 4-TsOH (20 mol%), PhMe, reflux.
dihydro-1,2-oxathine 2,2-dioxides to afford a diverse series of O is near planar with the SO2 unit out of plane and that H-3
novel 1,2-oxathine 2,2-dioxides the synthesis of some con- and H-4 are in a trans-diaxial arrangement with a H3–C3–C4–
1
densed
heterocyclic
ring
systems
was
examined. H4 torsion angle of ca. 162°. The H NMR spectrum of crude
3-Hydroxymethylene substituted chroman-24 and thiochro- 29 also indicated the presence of a minor isomer (ratio minor :
man-4-ones 25 were readily obtained by literature major = 3 : 50 with J3,4 = 4.5 Hz). The 1H NMR spectrum of
protocols.30,31 Allowing a dry PhMe solution of either 24 or 25 the major isomer showed similar features to that of 28 with
containing pyrrolidine to stand overnight over anhyd. Na2SO4 δ3-H 4.91 and δ4-H 4.61, however J3,4 is now smaller at 5.2 Hz
resulted in the efficient formation of the enaminoketones 26 which suggests that the presence of the larger sulfur atom
(82%) and 27 (95%), respectively. Using our standard pro- exerts an influence on the geometry of the fused oxathiine
cedure, the reaction of phenylsulfene, generated in situ, with dioxide ring.
26 and 27 was undertaken and afforded the fused dihydro-1,2-
The Cope elimination reaction proceeded smoothly with 28
oxathiines 28 (54%) and 29 (43%) (Scheme 6). The 1H NMR to afford 30 in 49% yield. An excess of m-CPBA was used for
spectrum of crude 28 indicated the presence of a minor the Cope reaction of 29, as a consequence of the possibility of
isomer (ratio minor : major = 3 : 20) with J3,4 = 5.1 Hz (δ3-H oxidation of the thiochroman ring heteroatom, and resulted in
4.65, δ4-H 4.25) which was readily removed upon recrystalliza- a mixture of the S-oxidised analogues 31a (32%) and 31b
tion to leave the major diastereoisomer which exhibited δ3-H (50%) (Scheme 6). The chemical shift of the oxathiine ring
4.94 and δ4-H 4.61 with J3,4 = 7.6 Hz. The X-ray crystal structure proton (4-H) for the series 30, 31a and 31b appeared in the
of 28 (CCDC 1913658†), (Fig. 7) revealed that the C3–C4–C5–C6– narrow range δ 6.75–6.97 and the gem-methyl groups (C-5) are
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Scheme 6 Synthesis of fused benzo(thio)pyrano 1,2-oxathiines 30 and 31. Reagents and conditions: (i) pyrrolidine, PhMe (anhyd.), rt; (ii)
PhCH2SO2Cl, Et3N, THF 0 °C–rt; (iii) m-CPBA (1.2–3.0 eq.), CH2Cl2, 0 °C–rt.
3.75; δvCH 7.99) in 86% yield after crystallisation.
Phenylsulfene addition proceeded smoothly to afford 34 in
74% yield, after routine flash column chromatography.
Compound 34 was isolated as an inseparable mixture of dia-
stereoisomers in a ratio 1.7 : 1.0 based on relative integrals of
1
the H NMR signals for 3-H and for 4-H in each isomer which
appear at (major)δ3-H 4.79 (J3,4 = 10.5 Hz) and (minor)δ3-H 4.88
(J3,4 = 6.4 Hz) and (major)δ4-H 4.59 and (minor)δ4-H 4.65. Cope
elimination of the NMe2 function using a 7.25-fold excess of
m-CPBA afforded the tricyclic tetraoxide 35 in 76% yield
1
(Scheme 7). In the H NMR spectrum of 35 4-H and the 6-CH2
unit appear as singlets at δ 7.54 and δ 5.00, respectively.
Notably the signal for the equivalent 6-CH2 protons in 35 is
shifted downfield relative to that in 34, in which the non-equi-
valent protons resonate as doublets [major diastereoisomer δ
3.56, δ 4.15 (J = 14.2 Hz) and minor diastereoisomer δ 3.75, δ
4.07 (J = 14.2 Hz)] as a consequence of the oxidation of the S
atom during the Cope elimination protocol. The structure of
35 (Fig. 8) was confirmed by X-ray crystallography (CCDC
Fig. 7 Crystal structure of 28 (thermal ellipsoids shown at 50% prob-
ability level).
non-equivalent in 31b (δMe = 1.46, 1.71) and equivalent in 30 1913657†) which revealed that the SO2 unit of each hetero-ring
(δMe = 1.65) and 31a (δMe = 1.68).
lies out of the main ring plane.
Isothiochromanone 32 was readily prepared by the Friedel–
Given the preliminary success concerning the synthesis of
Crafts cyclisation of commercial S-benzylthioacetic acid the oxathiines 11a–j, 13a, 13b, 17, 20, 23 and fused oxathiines
according to the procedure described by Aiken et al.32 Reaction 30, 31a,b and 35 we briefly examined the reaction of (E)-N-((di-
of 32 with DMFDMA afforded the enaminoketone 33 (δ1-H methylamino)methylene)-4-methylbenzamide 36, derived from
Scheme 7 Preparation of 3-phenyl-6H-isothiochromeno[3,4-e][1,2]oxathiine 2,2,5,5-tetraoxide 35. Reagents and conditions: (i) DMFDMA, reflux;
(ii) PhCH2SO2Cl, Et3N, THF 0 °C–rt; (iii) m-CPBA (7.25 eq.), CH2Cl2, 0 °C–rt.
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addition of in situ produced MeOH to the formed 39.
Repeating the reaction with DMFDMA but with removal of the
produced methanol from the reaction by distillation resulted
in the smooth formation of 39. Bis-dimethylaminomethylene
39 has been previously obtained in 90% yield by the reaction
of bis(dimethylamino)-t-butoxymethane (Bredereck’s reagent)
with 2-phenylacetamide34 though the present method
affording 39 in 63% yield is advantageous as a consequence of
the readily available and inexpensive DMFDMA. The gene-
ration of phenylsulfene in the presence of 39 unexpectedly
afforded the oxathiine dioxide 42 directly in 9% yield after
aqueous washings, column chromatography and recrystalliza-
tions; the anticipated 3,4-dihydro adduct 40 was not observed.
Fig. 8 Crystal structure of 35 (thermal ellipsoids shown at 50% prob-
ability level).
p-toluamide and DMFDMA, with a view to obtaining the 3,4-
dihydro-1,2,5-oxathiazine 2,2-dioxide 37 (Scheme 8).
Conclusions
Unfortunately, 37 could not be detected from the reaction of (E)-2,4-Dicyano-1,5-dioxo-1,5-diphenylpent-3-en-2-ide,
a new
36 with phenylsulfene and instead the N-formylbenzamide 38 extensively delocalised carbanion, has been isolated and struc-
(62%) was the major product isolated after aqueous work-up. turally characterised from the preparation of (E)-2-benzoyl-3-
The hydrolysis of N-((dimethylamino)methylene)benzamides (dimethylamino)acrylonitrile from benzoylacetonitrile. The
has been previously reported as
a
useful route to nature of the accompanying cation was dictated by the reaction
N-formylbenzamides.33
conditions; with DMFDMA diluted with PhMe at RT the N-((di-
We sought to capitalise on the foregoing observation and methylamino)methylene)-N-methylmethanaminium counter-
examined the reaction of the unsymmetrical bis-dimethyl- ion was preferred whereas neat DMFDMA favoured the for-
aminomethylene 39 with phenylsulfene in order to obtain the mation of the tetramethylammonium counterion.
N-formyl protected 6-amino substituted 3,4-dihydrooxathiine
The addition of various sulfenes, generated in situ from the
dioxide 33 (Scheme 9). Our initial attempt to prepare precursor (aryl)alkylsulfonyl chlorides and Et3N, to an extensive series of
39 upon refluxing a solution of 2-phenylacetamide was unsuc- enaminoketones proceeded smoothly to afford diversely sub-
cessful with the 1H NMR spectrum of the crude reaction stituted 4-amino-3,4-dihydro-1,2-oxathiine 2,2-dioxides, includ-
product indicating two singlets at δ 3.02 and δ 2.95 each ing 3,5,6-triaryl-, 3,6-diaryl-, 3,5-diaryl- and 5,6-diaryl- ana-
accounting for 6H and lower field singlet at δ 3.74 accounting logues, in good yield. A transoid (di-equatorial) relationship
for 3H. Column chromatography of the mixture gave the pure between the 3-aryl substituent and the 4-amino function for
formimidate 41 (39%) as a consequence of adventitious the isolated major isomers was established by X-ray crystallo-
Scheme 8 Formation of N-formylbenzamide 38. Reagents and conditions: (i) PhCH2SO2Cl, Et3N, THF 0 °C–rt.
Scheme 9 Formation of N-protected 6-amino 1,2-oxathine 42. Reagents and conditions: (i) DMFDMA, reflux; (ii) DMFDMA, reflux, MeOH removal;
(iii) PhCH2SO2Cl, Et3N, THF 0 °C–rt.
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graphy and NMR spectroscopy for the adducts derived from an with a graphite monochromated Cu(Kα) radiation source and a
aryl methanesulfonyl chloride. In CDCl3 solution, a sample of cold stream of N2 gas.
an isolated pure minor isomer (10d2) was observed by 1H
The following enamino-carbonyl compounds: (E)-3-(di-
NMR spectroscopy to epimerise to afford the major isomer in methylamino)-1,2-diphenylprop-2-en-1-one35 (9a), (E)-3-(di-
ca. 6 days.
methylamino)-1,2-bis(4-methoxyphenyl)prop-2-en-1-one36 (9b),
The 4-amino-3-aryl-3,4-dihydro-1,2-oxathiine 2,2-dioxide (E)-3-(dimethylamino)-1-(4-methoxyphenyl)prop-2-en-1-one37
(10a) resisted attempts to effect an acid-catalysed elimination (9h), (E)-3-(dimethylamino)-1-(2-nitrophenyl)prop-2-en-1-one38
of the 4-amino function. However, the isolated minor isomer (9k), (E)-3-(dimethylamino)-1-(4-(trifluoromethyl)phenyl)-prop-
(10d2) underwent a reluctant acid acid-catalysed elimination 2-en-1-one39 (9i), 2-((dimethylamino)methylene)-1,3-diphenyl-
to afford the 1,2-oxathiine 2,2-dioxide 11d. Application of Cope propane-1,3-dione40 (9d), methyl 2-benzoyl-3-(dimethylamino)
methodology resulted in the efficient, smooth elimination of acrylate41 (9e), 1-((dimethylamino)methylene)-3,4-dihydro-
the 4-amino function from 10a–j and 10d1 to afford the unsa- naphthalen-2(1H)-one42 (18), 3-(dimethylamino)-2-phenylacryl-
turated 1,2-oxathiine 2,2-dioxides series 11 in high yield. This aldehyde43 (21), (E)-3-(dimethylamino)-1-phenylprop-2-en-1-
simple protocol constitutes an efficient route to a series of one44 (9g) and (E)-N-((dimethylamino)methylene)-4-methyl-
novel, structurally diverse 1,2-oxathiine 2,2-dioxides and in benzamide45 (36) were obtained by refluxing the requisite
particular describes a new condensed heterocyclic ring system, α-methylene carbonyl compound or amide in neat N,N-di-
the 6H-isothiochromeno[3,4-e][1,2]oxathiine. It is noteworthy methylformamide dimethylacetal (DMFDMA) (2.5 equivalents)
that previously reported direct routes to 1,2-oxathiine 2,2-diox- until TLC examination of the reaction mixture indicated that
ides cannot provide the structural diversity afforded by the no starting α-methylene carbonyl compound remained. (Z)-3-
two-step protocol described herein. Attempts to extend our (Hydroxymethylene)-2,2-dimethylchroman-4-one30 (24) and
sulfene addition–elimination protocol to N-((dimethylamino) (Z)-3-(hydroxymethylene)-2,2,6-trimethylthiochroman-4-one31
methylene)benzamides to obtain 1,2,5-oxathiazine 2,2-dioxides was (25) and isothiochromanone32 (32) were prepared according to
unsuccessful and resulted in a new route to N-formylbenzamides.
previously reported procedures. 4-(Dimethylamino)-3-(2-fluoro-
Our studies concerning both the reactivity and the appli- phenyl)but-3-en-2-one (15) was prepared according to the pro-
cation of the 1,2-oxathiine 2,2-dioxide moiety as a scaffold for cedure described by Kozmin et al., for the preparation of 4-(di-
materials applications are ongoing.
methylamino)-3-phenylbut-3-en-2-one.46 (E)-4-(Dimethylamino)-
1,3-diphenylbut-3-en-2-one47 (9c) was prepared by heating
1,3-diphenylacetone in toluene containing DMFDMA.
3-(Dimethylamino)-1-(4-pyridyl)-2-propen-1-one (9j) was obtained
by heating 4-acetylpyridine in DMFDMA containing 10 mol%
Equipment and materials
Unless otherwise stated, reagents and solvents were purchased L-proline.44
from major chemical catalogue companies and were used as
supplied. Routine 1H NMR (400 MHz) and 13C NMR (100 MHz)
spectra were recorded on a Bruker Avance DPX400 instrument
Preparation of enaminoketones
Preparation of (E)-2-benzoyl-3-(dimethylamino)acrylonitrile 9f
in CDCl3. Variable Temperature 1H NMR (500 MHz) and
13C NMR (125 MHz) spectra were recorded on a Bruker Avance
I 500 MHz NMR instrument in CDCl3. Chemical shifts are pro- A solution of benzoylacetonitrile (12.0 g, 82.7 mmol) in N,N-di-
vided in parts per million (ppm) using either the residual methylformamide dimethylacetal (27.4 mL, 207 mmol, 2.5 eq.)
solvent peak or TMS as the internal reference. Coupling con- under nitrogen was heated under reflux overnight. Upon
stants (J) are provided in Hz and where applicable, in order to cooling the excess N,N-dimethylformamide dimethylacetal and
resolve close signals and extract valuable coupling infor- other volatiles were removed and the resulting crude product
mation, the raw FID data was processed using a Gaussian mul- was eluted from silica using 4% to 10% MeOH in DCM to
tiplication in place of the more usual exponential multipli- afford two fractions:
cation. All FT-IR spectra were recorded on a Nicolet 380 FTIR
Fraction 1, (E)-2-Benzoyl-3-(dimethylamino)acrylonitrile 9f
spectrophotometer equipped with a diamond ATR attachment as an off-white solid (9.36 g, 57%); mp 111–113 °C (lit. mp
(neat sample). Flash column chromatography was performed 113–114 °C (ref. 48)); νmax (neat) 2924, 2191, 1640, 1586, 1568,
on chromatography silica gel (Fluorochem, 40–63 micron par- 1444, 1426, 1412, 1318, 1300, 1229, 1180, 1135, 1095, 1070,
ticle size distribution). All final compounds were homo- 1056, 1027 cm−1; δH (CDCl3, 400 MHz) 3.38 (3H, s, NMe), 3.47
geneous by TLC using a range of eluent systems of differing (3H, s, NMe), 7.45–7.41 (2H, m, Ar–H), 7.52–7.48 (1H, m,
polarity (Merck TLC aluminium sheets silica gel 60 F254 (Cat. Ar–H), 7.69–7.67 (2H, m, Ar–H), 7.88 (s, 1H, alkene-H); δC
No. 105554)) when visualised with a dual lamp (254 and (CDCl3, 100 MHz) 39.0, 48.3, 79.7, 120.3, 128.1, 128.2, 131.5,
365 nm) Spectroline 8 W hand held TLC inspection lamp. 138.5, 159.4, 190.3; found [M + H]+ = 201.1027, C12H12N2O
High resolution mass spectra were recorded on an Agilent requires [M + H]+ = 201.1022.
6210 1200 SL TOF spectrometer within the IPOS centre at the
Fraction 2, Tetramethylammonium (E)-2,4-dicyano-1,5-dioxo-
University of Huddersfield. Single crystal X-ray diffraction data 1,5-diphenylpent-3-en-2-ide 9f′ as yellow crystals (2.15 g, 14%);
was collected on a Bruker Venture diffractometer equipped mp 250 °C (decomp.); νmax (neat) 3031, 2199, 2186, 1612, 1596,
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1574, 1483, 1448, 1316, 1295, 1241, 1176, 1109, 1074, 1026, dimethylchroman-4-one 24 (10.0 g, 49 mmol) in anhydrous
1002 cm−1; δH (DMSO-d6, 400 MHz) 3.09 (12H, s, N+Me4), toluene (150 mL) at room temperature. The resulting yellow
7.51–7.39 (10H, m, Ar–H), 8.02 (1H, s, alkene-H); δC (DMSO-d6, solution was stirred at room temperature overnight and the
100 MHz) 54.38 (t, J = 4.0 Hz), 86.68, 118.62, 127.75, 127.96, resulting mixture was dried with anhydrous sodium sulphate
130.21, 139.76, 152.52, 190.04; found [M − NMe4]− = 299.0825, and the toluene and excess pyrrolidine were removed by rotary
C23H23N3O2 requires [M − NMe4]− = 299.0821.
evaporation to afford the crude product as a bright orange/
yellow solid which was recrystallized from EtOAc/hexane to
afford the pure pyrrolidinomethylene compound 26 as a bright
yellow solid (10.40 g, 82%); mp 105–108 °C; νmax (neat) 2976,
Alternative preparation of (E)-2-benzoyl-3-(dimethylamino)
acrylonitrile 9f
A solution of benzoylacetonitrile (2.00 g, 13.8 mmol) in PhMe 2844, 1652, 1589, 1538, 1455, 1250, 1212, 1177, 985, 837, 823,
(50 mL) containing N,N-dimethylformamide dimethylacetal 758, 536 cm−1; δH (CDCl3, 400 MHz) 1.58 (6H, s, 2-Me),
(2.02 mL, 15.2 mmol, 1.1 eq.) was stirred overnight at room 1.90–1.93 (4H, m, (CH2)2), 3.36 (4H, bs, N(CH2)2), 6.82, (1H, s,
temperature whereupon the volatiles were removed in vacuo. alkene-H), 6.83 (1H, d, J = 8.3 Hz, 8-H), 6.93 (1H, app. t, J =
Recrystallization from EtOH gave two fractions:
7.5 Hz, 6-H), 7.31–7.36 (1H, m, 7-H), 7.89 (1H, dd, J = 7.8,
Fraction 1, (E)-2-Benzoyl-3-(dimethylamino)acrylonitrile 9f 1.6 Hz, 5-H); δC (CDCl3, 100 MHz) 25.5, 28.9, 53.7, 81.5,
from the room temperature crystallization as yellow filaments 107.0, 117.4, 120.3, 123.5, 126.2, 133.7, 144.3, 158.1, 179.1;
(2.34 g, 85%) mp 110–112 °C (lit. mp 113–114 °C (ref. 48)) with found [M + H]+ = 258.1485, C16H19NO2 requires [M + H]+
=
spectroscopic data identical to that obtained previously.
Fraction 2, N-((Dimethylamino)methylene)-N-methyl-
methanaminium (E)-2,4-dicyano-1,5-dioxo-1,5-diphenylpent-3-
en-2-ide 9f″ from cooling the filtrate as an off-white solid
258.1489.
Preparation of (Z)-2,2,6-trimethyl-3-(pyrrolidin-1-ylmethylene)
thiochroman-4-one 27
(0.090 g, 3.5%); mp 146–147 °C; νmax (neat) 3044, 2203, 2195, Pyrrolidine (1.36 mL, 16.6 mmol) was added dropwise over
1698, 1605, 1574, 1495, 1442, 1423, 1413, 1369, 1337, 1250, 5 minutes to a stirred solution of (Z)-3-(hydroxymethylene)-
1168, 1114, 1066, 1025, 1001 cm−1; δH (CDCl3, 400 MHz) 3.29 2,2,6-trimethylthiochroman-4-one 25 (3.70 g, 16 mmol) in
(6H, s, NMe2), 3.32 (6H, s, NMe2), 7.26–7.40 (6H, m, Ar–H), anhydrous toluene (70 mL) at room temperature. The resulting
7.56–7.58 (4H, m, Ar–H), 8.04 (1H, s, alkene-H), 8.16 (1H, s, yellow solution was stirred at room temperature for 48 h and
Me2NCHv); δC (CDCl3, 100 MHz) 39.35, 46.51, 87.86, 120.09, then the mixture was dried with anhydrous sodium sulfate
128.12, 128.32, 130.51, 139.77, 154.69, 157.49, 192.16; found and the toluene and excess pyrrolidine were removed by rotary
[M − Me2NvCHNMe2]− = 299.0824, C24H24N4O2 requires evaporation to afford the crude product as a bright orange/
[M − Me2NvCHNMe2]− = 299.0826.
yellow solid which was recrystallized from EtOAc/hexane to
afford the pure pyrrolidinomethylene 27 as a bright yellow
solid (4.38 g, 95%); mp 128–131 °C; νmax (neat) 2944, 2866,
1625, 1598, 1538, 1463, 1372, 1335, 1266, 1215, 1159, 1133,
Preparation of 4-(dimethylamino)-3-(2-fluorophenyl)but-3-en-
2-one 15
A solution of 1-(2-fluorophenyl)propan-2-one (5.0 g, 33 mmol) 928, 827, 782, 671, 523 cm−1; δH (CDCl3, 400 MHz) 1.63 (6H, s,
in N,N-dimethylformamide dimethylacetal (10.9 mL, 2-Me), 1.89–1.92 (4H, m, (CH2)2), 2.35 (3H, s, 6-Me), 3.20 (4H,
82.1 mmol) was heated under reflux for 48 h. Upon cooling bs, N(CH2)2), 6.89 (1H, s, alkene-H), 7.09–7.16 (2H, m, 7-H,
the excess N,N-dimethylformamide dimethylacetal and other 8-H), 8.04 (1H, bs, 5-H); δC (CDCl3, 100 MHz) 21.0, 25.5, 29.7,
volatiles were removed by vacuum distillation to leave 4-(di- 47.5, 53.4, 109.7, 127.4, 128.6, 132.2, 132.7, 134.3, 135.9, 142.7,
methylamino)-3-(2-fluorophenyl)but-3-en-2-one 15 as a pale 182.4; found [M + H]+ = 288.1412, C17H21NOS requires
brown viscous oil (4.80 g, 71%) which was used directly; νmax [M + H]+ = 288.1417.
(neat) 3034, 2923, 1651, 1614, 1557, 1492, 1423, 1384, 1351,
Preparation of (Z)-3-((dimethylamino)methylene)
isothiochroman-4-one 33
1288, 1213, 1087, 956, 754, 635 cm−1; δH (CDCl3, 400 MHz)
1.87 (3H, s, Me), 2.62 (6H, vbs, NMe2), 6.92–6.97 (1H, m, Ar–
H), 6.99–7.03 (1H, m, Ar–H), 7.06–7.10 (1H, m, Ar–H), A solution of isothiochroman-4-one 32 (5.0 g, 30 mmol) in
7.15–7.20 (1H, m, Ar–H), 7.58 (1H, s, alkene-H); δC (CDCl3, N,N-dimethylformamide dimethylacetal (10.5 mL, 76 mmol)
100 MHz) 26.89, 42.50 (broad), 103.34, 115.11 (d, J = 22.8 Hz), was heated under reflux for 18 h. Upon cooling the excess N,N-
123.56 (d, J = 3.6 Hz), 125.59 (d, J = 17.3 Hz), 129.01 (d, J = 7.9 dimethylformamide dimethylacetal and other volatiles were
Hz), 134.25 (d, J = 2.8 Hz), 150.29, 161.02 (d, J = 241.5 Hz), removed by rotary evaporation to afford an orange-brown solid
195.33; found [M + H]+ = 208.1132, C12H14FNO requires which was recrystallized from hexane/EtOAc to afford the title
[M + H]+ = 208.1138. A sample of 15 was used directly for the compound 33 as orange needles (5.75 g, 86%); mp 107–109 °C;
preparation of the dihydro-1,2-oxathiine 2,2-dioxide 16.
νmax (neat) 1633, 1595, 1539, 1402, 1319, 1293, 1255, 1131,
1092, 1051, 1031, 963, 946, 913, 896, 867, 780, 760, 728, 707,
685, 646, 573, 533, 484, 416 cm−1; δH (CDCl3, 400 MHz) 3.25
(6H, s, N(CH2)2), 3.75 (2H, s, 1-H), 7.10–7.12 (1H, m, 8-H),
Preparation of (Z)-2,2-dimethyl-3-(pyrrolidin-1-ylmethylene)
chroman-4-one 26
Pyrrolidine (4.22 mL, 51.4 mmol) was added dropwise over 7.32–7.39 (2H, m, 6-H, 7-H), 7.99 (1H, s, alkene-H), 8.00–8.02
5 minutes to a stirred solution of (Z)-3-(hydroxymethylene)-2,2- (1H, m, 5-H); δC (CDCl3, 100 MHz) 31.8, 43.6, 94.6, 125.8,
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127.5, 128.8, 131.1, 134.7, 139.8, 149.7, 183.9; found [M + H]+ = ((CD3)2CO, 100 MHz) 40.13, 61.90, 70.88, 124.2 (q, J =
220.0792, C12H13NOS requires [M + H]+ = 220.0791.
270.0 Hz, CF3), 123.58, 125.84 (q, J = 4.0 Hz, o-ArC-CF3),
127.65, 127.97, 128.07, 129.04, 130.06, 130.76 (q, J = 32.0 Hz,
ArC-CF3), 131.05, 133.29, 136.66, 137.03, 147.83; δF ((CD3)2CO,
376 MHz) −63.13; found [M + H]+ = 473.1260, C25H22F3NO3S
requires [M + H]+ = 473.1272.
4-(Dimethylamino)-5,6-bis(4-methoxyphenyl)-3-phenyl-3,4-
dihydro-1,2-oxathiine 2,2-dioxide 10c from 9b (16.1 mmol) as
off-white microcrystals (5.10 g, 68%) from EtOAc/hexane; mp
Preparation of 1,2-oxathiine
2,2-dioxides
General method for the preparation of dihydro-1,2-oxathiine
2,2-dioxides from arylmethanesulfonyl chlorides
A solution of the arylmethanesulfonyl chloride (1.1 eq.) [phe- = 120–121 °C; νmax (neat) 2945, 2836, 2793, 1604, 1509, 1371,
nylmethanesulfonyl chloride unless otherwise indicated] in 1354 (SO2–O), 1240, 1171 (SO2–O), 1063, 965, 839, 728 cm−1
;
anhydrous THF (50 mL) under a nitrogen atmosphere was δH (CDCl3, 400 MHz)‡ 2.23 (6H, s, NMe2), 3.76 (3H, s, OMe),
added dropwise over 15 minutes to an ice cold (0–5 °C) vigor- 3.79 (3H, s, OMe), 4.39 (1H, d, J = 7.6 Hz, 4-H), 4.92 (1H, d, J =
ously stirred solution of the enaminoketone (1.0 eq.) and tri- 7.6 Hz, 3-H), 6.67–6.72 (2H, m, Ar–H), 6.77–6.80 (2H, m, Ar–
ethylamine (1.125 eq.) in anhydrous THF (60 mL for a typical H), 7.14–7.17 (2H, m, Ar–H), 7.21–7.25 (2H, m, Ar–H),
20 mmol scale reaction) under nitrogen. Upon completion of 7.40–7.45 (3H, m, Ar–H), 7.57–7.59 (2H, m, Ar–H); δC (CDCl3,
the addition the ice-water bath was removed and the resulting 100 MHz) 40.59, 55.16, 55.26, 62.23, 71.93, 113.29, 113.70,
solution was stirred until TLC examination of the reaction 120.79, 125.31, 127.10, 128.06, 129.20, 129.39, 129.76, 129.89,
mixture indicated that no starting enaminoketone remained 130.57, 130.82, 131.14, 132.03, 148.01, 158.98, 159.84; found
(typically stirred overnight). The reaction mixture was filtered [M + H]+ = 466.1684, C26H27NO5S requires [M + H]+
=
through a sinter containing chromatography silica (ca. 20 mm 466.1688. ‡The 1H NMR spectrum of the crude isolated
depth) with further THF (ca. 200 mL) used to wash any remain- product indicated a mixture of diastereoisomers in a ca. 5 : 1
ing product from the silica. The THF and excess triethylamine ratio.
were removed from the filtrate by rotary evaporation to afford
6-Benzyl-4-(dimethylamino)-3,5-diphenyl-3,4-dihydro-1,2-
the crude product which was then suspended in EtOAc (ca. oxathiine 2,2-dioxide 10d1 and 10d2 from 9c (18.8 mmol)
100 mL) and washed with water (3 × 50 mL) and brine (50 mL). after elution from silica using 10% to 30% EtOAc/hexane
The EtOAc layer was dried (anhyd. Na2SO4) and then evapor- and crystallization from EtOAc/hexane. Fraction 1: 10d1 as
ated to give the crude product which was purified by either colourless microcrystals (3.78 g, 48%), mp = 133–136 °C;
column chromatography or crystallization. The following 3,4- νmax (neat) 2935, 2834, 2788, 2010, 1667, 1600, 1495, 1454,
dihydro-1,2-oxathiine 2,2-dioxides were obtained in this 1442, 1428, 1361 (SO2–O), 1313, 1223, 1182 (SO2–O), 1119,
manner:
1091, 1067, 1031 cm−1; δH (CDCl3, 400 MHz)‡ 2.07 (6H, s,
4-(Dimethylamino)-3,5,6-triphenyl-3,4-dihydro-1,2-oxathiine NMe2), 3.48 (1H, d, J = 15.3 Hz, PhCH), 3.56 (1H, d, J = 15.3
2,2-dioxide 10a from 9a (19.9 mmol) as off-white microcrystals Hz, PhCH), 4.51 (1H, d, J = 9.4 Hz, 4-H), 4.76 (1H, d, J = 9.4
(7.40 g, 92%) from EtOAc/hexane; mp = 152–154 °C; νmax (neat) Hz, 3-H), 7.18–7.45 (13H, m, Ar–H), 7.57–7.60 (2H, m, Ar–
3063, 2938, 1644, 1455, 1365 (SO2–O), 1182 (SO2–O), 1036, 925, H); δC (CDCl3, 100 MHz) 30.97, 37.89, 40.82, 62.59, 70.51,
692, 508 cm−1; δH (CDCl3, 400 MHz)‡ 2.23 (6H, s, NMe2), 4.49 122.86, 126.84, 127.88, 128.42, 128.57, 128.69, 129.06,
(1H, d, J = 8.0 Hz, 4-H), 4.96 (1H, d, J = 8.0 Hz, 3-H), 7.15–7.32 129.18, 129.53, 129.80, 131.03, 135.84, 137.10, 148.67;
(10H, m, Ar–H), 7.42–7.47 (3H, m, Ar–H), 7.60–7.62 (2H, m, found [M + H]+ = 420.1627, C25H25NO3S requires [M + H]+ =
Ar–H); δC (CDCl3, 100 MHz) 40.64, 62.36, 71.75, 122.78, 127.72, 420.1628.
127.85, 128.22, 129.02, 129.14, 129.24, 129.49, 129.88, 129.95,
Fraction 2: 10d2 as a white solid (1.94 g, 25%), mp =
131.75, 132.84, 137.27, 148.30; found [M + H]+ = 406.1471, 101–102 °C; νmax (neat) 2863, 2796, 1657, 1600, 1493, 1453,
‡
1
C24H23NO3S requires [M + H]+ = 406.1471. The H NMR spec- 1362 (O–SO2), 1290, 1247, 1187, 1163 (O–SO2), 1102, 1071,
trum of the crude isolated product indicated a mixture of dia- 1041 cm−1; δH (CDCl3, 400 MHz) 2.06 (6H, s, N(CH3)2), 3.52
stereoisomers in a ca. 4 : 1 ratio (see ESI for spectrum†).
(1H, d, J = 15.3 Hz, PhCH), 3.68 (1H, d, J = 15.3 Hz, PhCH),
4-(Dimethylamino)-5,6-diphenyl-3-(4-(trifluoromethyl) 4.67 (1H, d, J = 6.3 Hz, 4-H), 4.79 (1H, d, J = 6.3 Hz, 3-H),
phenyl)-3,4-dihydro-1,2-oxathiine 2,2 dioxide 10b from 9a 7.21–7.41 (13H, m, ArH), 7.55–7.57 (2H, m, ArH); δC (CDCl3,
(15.5 mmol) and 4-trifluoromethylphenylmethanesulfonyl 100 MHz) 37.80, 42.03, 64.76, 68.09, 120.74, 126.88, 127.89,
chloride (4.50 g, 17.4 mmol) as colourless microcrystals 128.29, 128.61, 128.64, 128.78, 129.33, 129.44, 129.79, 130.58,
(4.40 g, 60%) from EtOAc/hexane; mp = 125–128 °C; νmax (neat) 136.18, 136.90, 148.37; found [M
+ = 420.1627,
H]+
2833, 2794, 2248, 2222, 2179, 2159, 2041, 2028, 2005, 1978, C25H25NO3S requires [M + H]+ = 420.1631.
1
1955, 1662, 1620, 1491, 1446, 1421, 1371, 1364 (SO2–O), 1323,
‡The H NMR spectrum of the crude isolated product indi-
1223, 1186, 1162 (SO2–O), 1114, 1098, 1069, 1049, 1035, 1018, cated a mixture of diastereoisomers in a ca. 1.6 : 1 ratio.
1000 cm−1; δH ((CD3)2CO, 400 MHz) 2.22 (6H, s, NMe2), 4.79
(4-(Dimethylamino)-2,2-dioxido-3,6-diphenyl-3,4-dihydro-
(1H, d, J = 8.8 Hz, 4-H), 5.42 (1H, d, J = 8.8 Hz, 3-H), 7.22–7.27 1,2-oxathiin-5-yl)(phenyl)methanone 10e from 9d (17.9 mmol)
(8H, m, Ar–H), 7.35–7.38 (2H, m, Ar–H), 7.86 (2H, app. d, J = as a waxy solid (7.40 g, 96%) after filtration through silica
8.2 Hz, Ar–H), 8.06 (2H, app. d, J = 8.2 Hz, (Ar–H); δC using CH2Cl2 as eluent. Crystallization of a small sample from
9596 | Org. Biomol. Chem., 2019, 17, 9585–9604
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EtOAc/hexane gave off-white microcrystals; mp = 146–148 °C; 1220, 1178 (SO2–O), 1117, 1099, 1072, 1056, 1040 cm−1; δH
νmax (neat) 1655, 1613, 1596, 1448, 1371 (SO2–O), 1242, 1185, (CDCl3, 400 MHz) 2.29 (6H, s, NMe2), 4.45 (1H, dd, J = 11.2, 2.6
1160 (SO2–O), 1072, 883, 711, 670, 684, 513 cm−1; δH (CDCl3, Hz, 4-H), 4.61 (1H, d, J = 11.2 Hz, 3-H), 6.17 (1H, d, J = 2.6 Hz,
400 MHz) 2.06 (6H, s, NMe2), 4.83 (1H, d, J = 10.3 Hz, 4-H), 5-H), 7.46–7.51 (5H, m, Ar–H), 7.54–7.56 (2H, m, Py–H),
4.87 (1H, d, J = 10.3 Hz, 3-H), 7.27–7.31 (3H, m, Ar–H), 8.68–8.70 (2H, m, Py–H); δC (CDCl3, 100 MHz) 41.35, 63.20,
7.43–7.48 (5H, m, Ar–H), 7.52–7.56 (3H, m, Ar–H), 7.60–7.62 64.62, 108.46, 118.70, 128.82, 129.34, 129.71, 129.97, 138.99,
(2H, m, Ar–H), 7.94 (2H, app. d, J = 7.3 Hz, Bz–H); δC (CDCl3, 148.14, 150.49; found [M + H]+ = 331.1117, C17H18N2O3S
100 MHz) 40.68, 62.14, 69.03, 123.01, 128.29, 128.65, 128.83, requires [M + H]+ = 331.1111.
128.87, 129.41, 129.65, 129.74, 130.01, 130.35, 131.39, 133.29,
136.45, 149.84, 193.25; found [M 434.1428, 1,2-oxathiine 2,2-dioxide 10j from 9k (22.7 mmol) as off-white
H]+
C25H23NO4S requires [M + H]+ = 434.1421.
microcrystals (6.40 g, 75%) from EtOAc/hexane; mp
4-(Dimethylamino)-6-(2-nitrophenyl)-3-phenyl-3,4-dihydro-
+
=
=
4-(Dimethylamino)-3,6-diphenyl-3,4-dihydro-1,2-oxathiine 125–127 °C; νmax (neat) 2950, 2835, 2778, 1530, 1471, 1356
2,2 dioxide 10f from 9g (28.5 mmol) as colourless microcrys- (SO2–O), 1182 (SO2–O), 1109, 1034, 985, 902, 848, 805, 705,
tals (4.96 g, 52%) from EtOH; mp = 144–146 °C; νmax (neat) 569 cm−1; δH (CDCl3, 400 MHz) 2.28 (6H, s, NMe2), 4.40 (1H,
3388, 2831, 2783, 1659, 1575, 1494, 1469, 1452, 1367 (SO2– dd, J = 11.3, 2.1 Hz, 4-H), 4.63 (1H, d, J = 11.3 Hz, 3-H), 5.63
O), 1313, 1272, 1222, 1178 (SO2–O), 1117, 1105, 1072, (1H, d, J = 2.1 Hz, 5-H), 7.45–7.47 (3H, m, Ar–H), 7.55–7.57
1039 cm−1; δH (CDCl3, 400 MHz) 2.29 (6H, s, NMe2), 4.43 (2H, m, Ar–H), 7.60–7.63 (2H, m, Ar–H), 7.67–7.70 (1H, m,
(1H, dd, J = 11.2, 2.6 Hz, 4-H), 4.58 (1H, d, J = 11.2 Hz, 3-H), Ar–H), 7.98 (1H, d, J = 7.9 Hz, Ar–H); δC (CDCl3, 100 MHz)
5.92 (1H, d, J = 2.6 Hz, 5-H), 7.51–7.37 (6H, m, Ar–H), 41.24, 63.29, 64.54, 109.08, 124.55, 127.68, 128.90, 129.27,
7.60–7.51 (2H, m, Ar–H), 7.69–7.60 (2H, m, Ar–H); δC 129.77, 129.85, 130.94, 131.39, 133.13, 147.39, 148.04; found
((CD3)2CO, 100 MHz) 41.27, 63.08, 64.60, 104.38, 125.02, [M + H]+ = 375.1008, C18H18N2O5S requires [M + H]+
128.69, 129.24, 129.36, 129.76 (×2), 129.86, 131.81, 150.51; 375.1015.
=
found [M + H]+ = 330.1140, C18H19NO3S requires [M + H]+ =
330.1158.
4-(Dimethylamino)-5-(2-fluorophenyl)-6-methyl-3-phenyl-
3,4-dihydro-1,2-oxathiine 2,2-dioxide 16 from 15 (23.1 mmol)
4-(Dimethylamino)-6-(4-methoxyphenyl)-3-phenyl-3,4- as off-white microcrystals (6.62 g, 79%) from EtOAc/hexane;
dihydro-1,2-oxathiine 2,2-dioxide 10g from 9h (24.4 mmol) as mp = 130–132 °C; νmax (neat) 2919, 2833, 2785, 1612, 1487,
off-white microcrystals (7.30 g, 83%) from EtOAc/hexane; mp = 1359 (SO2–O), 1230, 1159 (SO2–O), 1143, 1106, 1037, 934, 853,
123–124 °C; νmax (neat) 2943, 2798, 1662, 1606, 1509, 1359 829, 742, 618, 553 cm−1; δH (CDCl3, 400 MHz, 295 K) 1.92 (3H,
(SO2–O), 1250, 1172 (SO2–O), 1045, 984, 903, 818, 790, 698, s, 6-Me), 2.04 (6H, s, NMe2), 4.61 (1H, bs, 4-H), 4.78 (1H, d, J =
592 cm−1; δH (CDCl3, 400 MHz) 2.28 (6H, s, NMe2), 3.85 (3H, s, 9.5 Hz, 3-H), 7.10–7.20 (2H, m, Ar–H), 7.28–7.36 (2H, m, Ar–H),
OMe), 4.41 (1H, dd, J = 11.1, 2.6 Hz, 4-H), 4.55 (1H, d, J = 7.44–7.49 (3H, m, Ar–H), 7.62–7.64 (2H, m, Ar–H); δF (CDCl3,
11.1 Hz, 3-H), 5.79 (1H, d, J = 2.5 Hz, 5-H), 6.92 (2H, app. d, J = 376 MHz) −114.5 to −112.7; δC (CDCl3, 100 MHz) 18.58, 40.69,
8.9 Hz, Ar–H), 7.44–7.46 (3H, m, Ar–H), 7.54–7.57 (4H, m, Ar– 62.47, 68.93, 69.59, 115.66, 115.89, 116.19,† 123.99, 124.66,
H); δC (CDCl3, 100 MHz) 41.24, 55.42, 63.04, 64.60, 102.36, 124.81, 127.26, 128.14, 129.30, 129.35, 129.43, 129.58, 129.89,
114.04, 124.36, 126.54, 129.21, 129.49, 129.70, 129.76, 150.37, 130.08, 130.57, 130.80, 131.04,† 133.75, 148.32, 158.94, 161.38.
160.86; found [M + H]+ = 360.1264, C19H21NO4S requires
[M + H]+ = 360.1264.
1-(Dimethylamino)-2-phenyl-1,2,5,6-tetrahydronaphtho[1,2-e]
[1,2]oxathiine 3,3-dioxide 19 from 18 (61.4 mmol) as off-
4-(Dimethylamino)-6-(4-trifluoromethylphenyl)-3-phenyl- white microcrystals (14.18 g, 65%) from EtOAc/hexane; mp =
3,4-dihydro-1,2-oxathiine 2,2-dioxide 10h from 9i (14.4 mmol) 154–156 °C; νmax (neat) 2946, 2832, 2788, 1666, 1467, 1363
as off-white microcrystals (3.67 g, 64%) from EtOAc/hexane; (SO2–O), 1169 (SO2–O), 1139, 1026, 937, 829, 805, 765, 698,
mp = 125–127 °C; νmax (neat) 2981, 1615, 1497, 1455, 1375 571 cm−1; δH (CDCl3, 400 MHz) 2.14 (6H, s, NMe2), 2.48 (1H,
(SO2–O), 1322, 1167 (SO2–O), 1114, 1066, 990, 903, 785, 733, ddd, J = 2.4, 7.0, 17.1, 5-H), 2.65–2.75 (1H, m, 5-H), 2.86 (1H,
698, 566, 500 cm−1; δH (CDCl3, 400 MHz) 2.29 (6H, s, NMe2), ddd, J = 2.5, 6.3, 17.1 Hz, 6-H), 3.00–3.09 (1H, m, 6-H), 4.80
4.46 (1H, dd, J = 11.2, 2.4 Hz, 4-H), 4.62 (1H, d, J = 11.2 Hz, (1H, dd, J = 3.0, 8.9 Hz, 1-H), 4.90 (1H, d, J = 8.9 Hz, 2-H),
3-H), 6.06 (1H, d, J = 2.4 Hz, 5-H), 7.45–7.47 (3H, Ar–H), 7.16–7.27 (4H, m, Ar–H), 7.43–7.50 (3H, m, Ar–H), 7.62–7.65
7.54–7.57 (2H, m, Ar–H), 7.67 (2H, app d, J = 8.4 Hz, Ar–H), (2H, m, Ar–H); δC (CDCl3, 100 MHz) 27.71, 28.26, 40.10, 61.34,
7.75 (2H, app d, J = 8.4 Hz, Ar–H); δC (CDCl3, 100 MHz) 41.29, 65.47, 115.60, 125.17, 126.34, 126.80, 127.34, 129.35, 129.71,
63.05, 64.67, 106.77, 123.77 (q, J = 272 Hz), 125.31, 125.74 (q, 129.98, 131.32, 132.00, 133.88, 151.02; found [M + H]+
J = 3.8 Hz), 128.99, 129.33, 129.73, 129.94, 131.66 (q, J = 32.9 356.1314, C20H21NO3S requires [M + H]+ = 356.1320.
=
Hz), 135.09, 149.23; δF (CDCl3, 376 MHz) −62.80; found
δH (CDCl3, 500 MHz, 233 K)* 1.89 (3H, app. t, J = 1.5 Hz,
[M + H]+ = 398.1033, C19H18F3NO3S requires [M + H]+ = 398.1032. 6-Me), 1.97 (3H, d, J = 1.7 Hz, 6-Me), 2.01 (12H, bs, NMe2), 4.52
4-(Dimethylamino)-3-phenyl-6-(pyridin-4-yl)-3,4-dihydro- (1H, ddd, J = 1.5, 3.5, 9.7 Hz, 4-H), 4.76 (1H, ddd, J = 1.7, 3.5,
1,2-oxathiine 2,2-dioxide 10i from 9j (29 mmol) as orange- 9.9 Hz, 4-H), 4.80 (1H, d, J = 9.7 Hz, 3-H), 4.87 (1H, d, J = 9.9
yellow microcrystals (0.95 g, 10%) from 2 × EtOAc; mp = Hz, 3-H), 7.07–7.39 (8H, m, Ar–H), 7.43–7.52 (6H, m, Ar–H),
124–126 °C; νmax (neat) 3046, 2979, 2942, 2800, 2359, 1651, 7.60–7.68 (4H, m, Ar–H); δC (CDCl3, 126 MHz) 18.84, 19.07,
1594, 1548, 1495, 1474, 1454, 1410, 1368 (SO2–O), 1315, 1278, 40.62, 61.55, 61.84, 67.69, 69.73, 114.63, 115.71, 115.88,
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115.98, 116.16, 117.39, 124.03, 124.05, 124.30, 124.33, 124.45, hexane, mp = 86–88 °C; νmax (neat) 1603, 1547, 1507, 1345
124.65, 124.78, 129.46, 129.52, 129.61, 129.67, 129.90, 129.97, (SO2–O), 1173 (SO2–O), 1022, 920, 759, 708, 646, 530 cm−1
130.33, 131.92, 148.24, 148.53, 158.77, 159.32, 160.71, 161.28. δH (CDCl3, 400 MHz) 3.86 (3H, s, MeO), 6.31 (1H, d, J = 6.8 Hz,
;
δH (CDCl3, 500 MHz, 323 K) 1.89 (3H, dd, J = 0.8, 1.8 Hz, 5-H), 6.58 (1H, d, J = 10.0 Hz, 3-H), 6.91 (1H, dd, J = 10.0, 6.8
6-Me), 2.04 (6H, s, NMe2), 4.55 (1H, app. d, J = 9.5 Hz, 4-H), Hz, 4-H), 6.93–6.96 (2H, m, Ar–H), 7.64–7.67 (2H, m, Ar–H);
4.73 (1H, d, J = 9.5 Hz, 3-H), 7.05–7.17 (2H, m, Ar–H), δC (CDCl3, 100 MHz) 55.52, 98.43, 114.45, 117.60, 123.11,
7.22–7.32 (2H, m, Ar–H), 7.37–7.45 (3H, m, Ar–H), 7.56–7.63 127.52, 134.87, 157.58, 162.18; found [M + H]+ = 239.0375,
(2H, m, Ar–H); δC (CDCl3, 126 MHz) 18.43, 40.58, 62.80, 69.30, C11H10O4S requires [M + H]+ = 239.0373.
115.64, 115.82, 123.91, 123.94, 124.78, 124.90, 129.08, 129.46,
Fraction 2: 4-(dimethylamino)-6-(4-methoxyphenyl)-3,4-
129.50, 129.56, 129.87, 131.01, 148.35, 159.25, 161.21; found dihydro-1,2-oxathiine 2,2-dioxide 12b as off-white microcrys-
[M + H]+ = 362.1215, C19H20FNO3S requires [M + H]+
362.1226.
=
tals (2.28 g, 40%) from EtOAc/hexane, mp = 104–105 °C; νmax
(neat) 2928, 2831, 2780, 1613, 1486, 1355 (SO2–O), 1317, 1259,
*At this temperature there are two rotamers present in solu- 1246, 1171 (SO2–O), 1110, 1028, 989, 967, 843, 831, 818, 766,
tion. †Very broad signal and approximate position is given.
570, 549 cm−1; δH (CDCl3, 400 MHz) 2.37 (6H, s, NMe2), 3.25
(1H, dd, J = 13.3, 11.4 Hz, 3-H), 3.50 (1H, ddd, J = 13.3, 6.3, 1.0
Hz, 3-H), 3.83 (3H, s, OMe), 4.15 (1H, ddd, J = 11.4, 6.3, 2.6 Hz,
4-H), 5.65 (1H, dd, J = 2.6, 1.0 Hz, 5-H), 6.88–6.92 (2H, m, Ar–
General method for the preparation of dihydro-1,2-oxathiine
2,2-dioxides from methanesulfonyl chloride
A solution of methanesulfonyl chloride (1.1 eq.) in anhydrous H), 7.48–7.52 (2H, m, Ar–H); δC (CDCl3, 100 MHz) 40.64, 42.75,
THF (50 mL) under a nitrogen atmosphere was added dropwise 55.40, 59.46, 103.00, 114.02, 124.30, 126.45, 150.45, 160.85;
over 15 minutes to an ice cold (0–5 °C) vigorously stirred found [M + H]+ = 284.0956, C13H17NO4S requires [M + H]+
solution of the enaminoketone (1.0 eq.) and triethylamine 284.0951.
=
(1.125 eq.) in anhydrous THF (60 mL for a typical 20 mmol
scale reaction) under nitrogen. Upon completion of the addition
the ice-water bath was removed and the resulting solution was
Method for the addition of phenylsulfene to
3-(dimethylamino)-2-phenylacrylaldehyde 21
stirred until TLC examination of the reaction mixture indicated
A solution of phenylmethanesulfonyl chloride (7.07 g,
that no starting enaminoketone remained (typically stirred over- 37.1 mmol) in anhydrous THF (70 mL) under a nitrogen atmo-
night). The reaction mixture was filtered through a sinter con- sphere was added dropwise over 15 minutes to an ice cold
taining chromatography silica (ca. 20 mm depth) with further (0–5 °C) vigorously stirred solution of the crude 3-(dimethyl-
THF (ca. 200 mL) used to wash any remaining product from the amino)-2-phenylacrylaldehyde 21 (5.0 g, 28 mmol) and triethyl-
silica. The THF and excess triethylamine were removed from the amine (5.4 mL, 38 mmol) in anhydrous THF (100 mL) under
filtrate by rotary evaporation to afford the crude product which nitrogen. Upon completion of the addition the ice-water bath
was then suspended in EtOAc (ca. 100 mL) and washed with was removed and the resulting solution was stirred until TLC
water (3 × 50 mL) and brine (50 mL). The EtOAc layer was dried examination of the reaction mixture indicated that no starting
(anhyd. Na2SO4) and then evaporated to give the crude product enaminoketone remained (30 h). The reaction mixture was fil-
which was purified by either column chromatography or crystal- tered through a sinter containing chromatography silica (ca.
lization. The following dihydro-1,2-oxathiine 2,2-dioxides were 20 mm depth) with further THF (ca. 100 mL) used to wash any
obtained in this manner:
remaining product from the silica. The THF and excess tri-
4-(Dimethylamino)-5,6-diphenyl-3,4-dihydro-1,2-oxathiine ethylamine were removed from the filtrate by rotary evapor-
2,2-dioxide 12a from 9a (27.4 mmol) as off-white microcrys- ation to give the crude product as a multicomponent viscous
tals (10.03 g, 53%) from EtOAc/hexane; mp = 157–159 °C; brown sludge which was chromatographed on silica using
νmax (neat) 3398, 2830, 2781, 1658, 1493, 1443, 1370 (SO2–O), CH2Cl2 (5–100% in hexanes) to MeOH (2% in CH2Cl2) gradient
1339, 1280, 1260, 1225, 1192, 1173 (SO2–O), 1149, 1114, as eluent. The fractions eluting at Rf values of 0.15 and 0.38
1101, 1072, 1045, 1004 cm−1; δH ((CD3)2CO, 400 MHz) 2.30 (TLC eluent CH2Cl2 40% in hexanes) were collected. The band
(6H, s, NMe2), 3.78 (1H, dd, J = 9.1, 14.0 Hz, 3-H), 3.95 (1H, with Rf = 0.38 was further chromatographed on silica using
dd, J = 7.4, 14.0 Hz, 3-H), 4.46 (1H, dd, J = 7.4, 9.1 Hz, 4-H), CH2Cl2 (40% in hexanes) as eluent and the solvent removed
7.14–7.23 (10H, m, ArH); δC (CDCl3, 100 MHz) 40.13, 42.63, under reduced pressure. The residue was crystallised from hot
63.92, 121.71, 127.66, 127.82, 128.14, 128.99, 129.15, 129.90, toluene/hexanes to give 3,5-diphenyl-1,2-oxathiine 2,2-dioxide
132.94, 136.38, 148.47; found [M
C
+
H]+
=
330.1155, 23 (0.71 g, 9%) as a cream powder. The solvent was reduced to
18H19NO3S requires [M + H]+ = 330.1158.
give a second crop (0.24 g, 3%) as a pale-yellow powder; mp =
6-(4-Methoxyphenyl)-1,2-oxathiine 2,2-dioxide 13b and 4-(di- 90–91 °C; νmax (neat) 2989, 2932, 2850, 1634, 1496, 1454, 1362
methylamino)-6-(4-methoxyphenyl)-3,4-dihydro-1,2-oxathiine 2,2- (SO2–O), 1174 (SO2–O), 1108, 1082, 1048, 955, 841, 765, 759,
dioxide 12b from 9b (19.9 mmol) after elution from silica with 732, 697, 620, 570, 540, 474 cm−1; δH (CDCl3, 400 MHz) 7.07
50% EtOAc in hexanes increasing to 80% EtOAc in hexanes after (1H, d, J = 2.1 Hz, 6-H‡), 7.23 (1H, d, J = 2.1 Hz, 4-H‡),
elution of fraction 1.
7.54–7.40 (8H, m, Ar–H), 7.70–7.63 (2H, m, Ar–H); δC (CDCl3,
Fraction 1: 6-(4-Methoxyphenyl)-1,2-oxathiine 2,2-dioxide 100 MHz) 122.37, 126.43, 127.95, 128.89, 129.11, 129.26,
13b as off-white microneedles (2.38 g, 50%) from EtOAc/ 129.95, 130.25, 130.34, 133.45, 136.07, 142.11; found
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[M + NH4]+ = 302.0850, C16H12O3S requires [M + NH4]+
302.0845.
=
100 MHz) 118.99, 123.74 (q, J = 270.0 Hz), 126.02 (q, J = 3.7
Hz), 128.07, 128.30, 128.55, 129.08, 129.32, 130.60, 130.82,
131.68 (q, J = 33 Hz), 132.62, 133.44, 135.41, 135.61,
‡ 1H NMR assignments may be reversed.
The fraction with Rf = 0.15 was crystallised from chloro- 153.03; δF (CDCl3, 376 MHz) −63.32; found [M + NH4]+
=
form/hexanes to give 4-(dimethylamino)-3,5-diphenyl-3,4- 428.0707, C23H15F3O3S requires [M + NH4]+ = 428.0694.
dihydro-1,2-oxathiine 2,2-dioxide 22 (0.27 g, 3%) as a cream 5,6-Bis(4-methoxyphenyl)-3-phenyl-1,2-oxathiine 2,2-dioxide
powder. The solvent was reduced to give a second crop (0.20 g, 11c from 10c (9.13 mmol) as bright yellow microcrystals
2%) as a pale orange powder; mp = 145–150 °C (dec.); νmax (3.60 g, 94%) from EtOAc/hexane; mp = 129–131 °C; νmax (neat)
(neat) 2953, 2839, 1556, 1494, 1449, 1359 (SO2–O), 1285, 1175 3006, 2935, 2838, 1604, 1506, 1462, 1354 (SO2–O), 1256, 1243,
(SO2–O), 1131, 1002, 974, 688, 664, 643, 622, 595, 582, 560, 1171 (SO2–O), 1130, 1106, 1032, 972, 835, 788, 697, 589 cm−1
;
512, 459 cm−1; δH (CDCl3, 400 MHz) 2.08 (6H, s, NMe2), 4.77 δH (CDCl3, 400 MHz) 3.80 (3H, s, OMe), 3.82 (3H, s, OMe),
(1H, dd, J = 9.7, 1.5 Hz, 4-H), 4.66 (1H, d, J = 9.7 Hz, 3-H), 6.66 6.75–6.77 (2H, m, Ar–H), 6.87–6.89 (2H, m, Ar–H), 6.98 (1H, s,
(1H, d, J = 1.5 Hz, 6-H), 7.32–7.42 (5H, m, Ar–H), 7.45–7.52 4-H), 7.18–7.21 (2H, m, Ar–H), 7.29–7.31 (2H, s, Ar–H),
(3H, m, Ar–H), 7.62–7.69 (2H, m, Ar–H); δC (CDCl3, 100 MHz) 7.43–7.46 (3H, m, Ar–H), 7.64–7.67 (2H, m, Ar–H); δC (CDCl3,
40.55, 62.52, 67.44, 127.11, 127.52, 128.09, 128.38, 129.30, 100 MHz) 55.32, 55.34, 113.68, 114.65, 117.22, 123.60, 127.64,
129.76, 129.90, 130.63, 135.48, 138.12; found [M + H]+
330.1178, C18H19NO3S requires [M + H]+ = 330.1158.
=
128.21, 129.00, 129.71, 130.11, 130.28, 130.57, 130.88, 133.08,
134.56, 151.92, 159.45, 160.94; found [M + NH4]+ = 438.1370,
C24H20O5S requires [M + NH4]+ = 438.1370.
(6-Benzyl-3,5-diphenyl-1,2-oxathiine 2,2-dioxide 11d from
10d1 (4.8 mmol) as colourless microcrystals (1.21 g, 68%) from
General method for the preparation of 1,2-oxathiine
2,2-dioxides
A solution of 3-chloroperoxybenzoic acid (1.2 eq., ca. 77%) in EtOAc/hexane; mp = 110–111 °C; νmax (neat) 3062, 3026, 1634,
dichloromethane (40 mL) was added dropwise over 15 minutes 1601, 1576, 1557, 1493, 1454, 1444, 1421, 1365 (SO2–O), 1349,
to an ice cold (ca. 0–5 °C) vigorously stirred solution of the 3,4- 1286, 1264, 1224, 1175 (SO2–O), 1155, 1105, 1072, 1031,
dihydro-1,2-oxathiine 2,2-dioxide (1.0 eq.) in dichloromethane 1002 cm−1; δH (CDCl3, 400 MHz) 3.78 (2H, s, CH2), 6.85 (1H, s,
(70 mL for a typical 12 mmol scale reaction). Upon completion 4-H), 7.21–7.47 (13H, m, Ar–H), 7.59–7.62 (2H, m, Ar–H); δC
of the addition the cooling bath was removed and the resulting (CDCl3, 100 MHz) 37.52, 119.73, 127.18, 127.74, 128.59,
solution was stirred until TLC indicated that no starting 3,4- 128.68, 128.82, 128.88, 129.00, 129.07, 129.88, 129.91, 132.65,
dihydro-1,2-oxathiine 2,2-dioxide remained (ca. 24 h). The 133.89, 135.11, 135.32, 154.48; found [M + NH4]+ = 392.1315,
mixture was transferred into a separating funnel and diluted C23H18O3S requires [M + NH4]+ = 392.1315.
with dichloromethane (50 mL). The mixture was washed with
(2,2-Dioxido-3,6-diphenyl-1,2-oxathiin-5-yl)(phenyl)metha-
aq. sodium thiosulfate solution (5 × 100 mL, 10% aq.) followed none 11e from 10e (9.2 mmol) as pale yellow microcrystals
by washing with dilute NaOH (3 × 50 mL, 1 M aq.) solution (2.64 g, 74%) after elution from silica CH2Cl2 (60–100% gradi-
and finally with water (100 mL). The dichloromethane solution ent) in hexanes and crystallization from EtOAc/hexanes; mp =
was dried with anhydrous Na2SO4 and then the solvent was 129–130 °C; νmax (neat) 1655, 1612, 1558, 1369 (SO2–O), 1256,
removed by rotary evaporation to afford the crude product 1242, 1175 (SO2–O), 1090, 922, 882, 711, 684, 544 cm−1; δH
which was further purified by crystallization from EtOAc/ (CDCl3, 400 MHz) 7.21–7.31 (6H, m, Ar–H, s, 4-H), 7.35–7.39
hexane. The following compounds were obtained by this (1H, m, Ar–H), 7.48–7.49 (5H, m, Ar–H), 7.68–7.71 (2H, m,
protocol:
Ar–H), 7.73–7.76 (2H, m, Ar–H); δC (CDCl3, 100 MHz) 117.60,
3,5,6-Triphenyl-1,2-oxathiine 2,2-dioxide 11a from 10a 127.88, 128.51, 128.54, 129.13, 129.42, 129.64, 129.68, 130.23,
(12.3 mmol) as pale yellow microcrystals (3.15 g, 71%) from 130.44, 132.03, 133.75, 134.78, 136.03, 157.77, 193.27; found
EtOAc/hexane; mp = 159–160 °C; νmax (neat) 3060, 1621, 1540, [M + NH4]+ = 406.1112, C23H16O4S requires [M + NH4]+
1444, 1368 (SO2–O), 1349, 1186 (SO2–O), 1130, 1011, 972, 851, 406.1108.
=
771, 697, 605, 524 cm−1; δH (CDCl3, 400 MHz) 7.03 (1H, s,
3,6-Diphenyl-1,2-oxathiine 2,2-dioxide 11f from 10f
4-H), 7.25–7.39 (10H, m, Ar–H), 7.46–7.50 (3H, m, Ar–H), (1.52 mmol) as pale yellow microcrystals (0.34 g, 79%) from
7.67–7.71 (2H, m, Ar–H); δC (CDCl3, 100 MHz) 118.99, 127.74, CH2Cl2; mp = 130–132 °C; νmax (neat) 3063, 1633, 1559, 1493,
128.21, 128.35, 129.05, 129.13, 129.20, 129.28, 129.90, 129.95, 1447, 1353 (SO2–O), 1336, 1264, 1173 (SO2–O), 1071, 1031,
130.27, 131.11, 133.99, 134.11, 135.80, 152.14; found [M + NH4]+ 1010 cm−1; δH (CDCl3, 400 MHz) 6.58 (1H, d, J = 7.1 Hz, 5-H),
= 378.1158, C22H16O3S requires [M + NH4]+ = 378.1158.
6.96 (1H, d, J = 7.1 Hz, 4-H), 7.50–7.47 (6H, m, Ar–H),
5,6-Diphenyl-3-(4-(trifluoromethyl)phenyl)-1,2-oxathiine 7.67–7.64 (2H, m, Ar–H), 7.83–7.77 (2H, m, Ar–H); δC (CDCl3,
2,2-dioxide 11b from 10b (4.2 mmol) as pale yellow micro- 100 MHz) 101.60, 125.49, 127.66, 128.98, 129.01, 129.05,
crystals (1.38 g, 73%) from EtOH; mp = 161–163 °C; νmax 129.87, 130.12, 130.65, 131.13, 134.48, 156.02; found [M + H]+
(neat) 3060, 1617, 1576, 1557, 1488, 1446, 1415, 1365 = 284.0511, C16H12O3S requires [M + H]+ = 284.0507.
(SO2–O), 1350, 1324, 1275, 1170 (SO2–O), 1116, 1068, 1035,
6-(4-Methoxyphenyl)-3-phenyl-1,2-oxathiine 2,2-dioxide 11g
1016, 1008 cm−1; δH ((CD3)2CO, 400 MHz) 7.32–7.44 (10H, from 10g (11.8 mmol) as yellow microcrystals (3.00 g, 81%)
m, Ar–H), 7.54 (1H, s, 4-H), 7.89 (2H, app. d, J = 8 Hz, from EtOAc/hexane; mp = 173–174 °C; νmax (neat) 2984, 2939,
Ar–H), 8.02 (2H, app. d, J = 8 Hz, Ar–H); δC ((CD3)2CO, 2842, 1626, 1604, 1547, 1507, 1456, 1361 (SO2–O), 1253, 1182,
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1168 (SO2–O), 1117, 999, 815, 787, 695, 569 cm−1; δH (CDCl3, (4.20 g, 96%) from EtOAc/hexane; mp = 126–128 °C; νmax (neat)
400 MHz) 3.89 (3H, s, OMe), 6.44 (1H, d, J = 7.2 Hz, 5-H), 6.93 2889, 1634, 1583, 1364 (SO2–O), 1184, 1171 (SO2–O), 1158,
(1H, d, J = 7.2 Hz, 4-H), 6.97–7.01 (2H, m, Ar–H), 7.44–7.50 1090, 973, 925, 778, 755, 734, 690, 557 cm−1; δH (CDCl3,
(3H, m, Ar–H), 7.652–7.65 (2H, m, Ar–H), 7.71–7.74 (2H, m, 400 MHz) 2.81 (2H, t, J = 8.0 Hz, 6-H), 3.06 (2H, t, J = 8.0 Hz,
Ar–H); δC (CDCl3, 100 MHz) 55.52, 99.88, 114.47, 123.17, 5-H), 7.21–7.34 (5H, m, Ar–H, 1-H), 7.45–7.48 (3H, m, Ar–H),
127.31, 127.56, 129.00, 129.41, 129.62, 130.31, 133.21, 156.19, 7.63–7.65 (2H, m, Ar–H); δC (CDCl3, 100 MHz) 26.82, 27.88,
162.03; found [M + NH4]+ = 332.0953, C17H14O4S requires [M + 113.35, 122.87, 127.34, 127.75, 127.86, 127.89, 128.25, 129.07,
NH4]+ = 332.0951.
6-(4-Trifluoromethylphenyl)-3-phenyl-1,2-oxathiine 2,2-dioxide NH4]+ = 328.1002, C18H14O3S requires [M + NH4]+ = 328.1002.
11h from 10h (4.3 mmol) as yellow microcrystals (1.09 g, 72%) 5,6-Diphenyl-1,2-oxathiine 2,2-dioxide 13a from 12a
129.91, 130.37, 130.49, 132.99, 135.00, 155.91; found [M +
from EtOAc/hexane; mp = 139–140 °C; νmax (neat) 3049, 1629, (6.6 mmol) as off-white microcrystals (1.87 g, 72%) from
1615, 1366 (SO2–O), 1328, 1301, 1177 (SO2–O), 1116, 1065, 957, EtOAc/hexane; mp = 154–155 °C; νmax (neat) 3079, 1616, 1574,
870, 757, 690, 581 cm−1; δH (CDCl3, 400 MHz) 6.64 (1H, d, J = 7.1 1545, 1487, 1444, 1372, 1356 (SO2–O), 1294, 1237, 1182 (SO2–
Hz, 5-H), 6.95 (1H, d, J = 7.1 Hz, 4-H), 7.46–7.49 (3H, m, Ar–H), O), 1164, 1149, 1093, 1069, 1033, 1005 cm−1; δH (CDCl3,
7.61–7.66 (2H, m, Ar–H), 7.72 (2H, app d, J = 8.3 Hz, Ar–H), 7.87 400 MHz) 6.73 (1H, d, J = 10.2 Hz, 3-H), 7.03 (1H, d, J = 10.2
(2H, app d, J = 8.3 Hz, Ar–H); δC (CDCl3, 100 MHz) 103.36, 123.61 Hz, 1H, 4-H), 7.18–7.34 (10H, m, Ar–H); δC (CDCl3, 100 MHz)
(q, J = 272 Hz), 125.65, 126.02 (q, J = 3.8 Hz), 127.72, 128.40, 117.49, 118.83, 128.20, 128.33, 129.00, 129.18, 129.46, 130.45,
129.13, 129.76, 130.21, 132.54 (q, J = 33 Hz), 133.93 (q, J = 1.4 131.10, 135.29, 139.32, 153.63; found [M + H]+ = 285.0587,
Hz), 135.82, 154.23; δF (CDCl3, 376 MHz) −62.96; found [M + C16H12O3S requires [M + H]+ = 285.0580.
NH4]+ = 370.0723, C17H11F3O3S requires [M + NH4]+ = 370.0719.
6-(4-Methoxyphenyl)-1,2-oxathiine 2,2-dioxide 13b from 12b
3-Phenyl-6-(pyridin-4-yl)-1,2-oxathiine 2,2-dioxide 11i from (10.6 mmol) as pale fawn microneedles (2.02 g, 80%) by tri-
10i (1.82 mmol) as pale-yellow microcrystals (0.37 g, 72%) turation from Et2O; mp = 86–88 °C; νmax (neat) 1603, 1547,
from EtOAc/hexane; mp = 141–143 °C; νmax (neat) 3053, 1637, 1507, 1345 (SO2–O), 1173 (SO2–O), 1022, 920, 759, 708, 646,
1594, 1550, 1492, 1447, 1410, 1352 (SO2–O), 1326, 1267, 1250, 530 cm−1; δH (CDCl3, 400 MHz) 3.86 (3H, s, MeO), 6.31 (1H, d,
1222, 1175 (SO2–O), 1067, 1023 cm−1; δH (CDCl3, 400 MHz) J = 6.8 Hz, 5-H), 6.58 (1H, d, J = 10.0 Hz, 3-H), 6.91 (1H, dd, J =
6.74 (1H, d, J = 6.9 Hz, 4-H), 6.95 (1H, d, J = 6.9 Hz, 5-H), 10.0, 6.8 Hz, 4-H), 6.93–6.96 (2H, m, Ar–H), 7.64–7.67 (2H, m,
7.48–7.63 (7H, m, Ar–H, Py–H), 8.74–8.76 (2H, m, Py–H); δC Ar–H); δC (CDCl3, 100 MHz) 55.52, 98.43, 114.45, 117.60,
(CDCl3, 100 MHz) 104.47, 118.63, 127.79, 127.91, 129.18, 123.11, 127.52, 134.87, 157.58, 162.18; found [M + H]+
129.59, 130.43, 136.99, 137.81, 150.74, 153.14; found [M + H]+ 239.0375 C11H10O4S requires [M + H]+ = 239.0373.
= 286.0533, C15H11NO3S requires [M + H]+ = 286.0532.
=
Acid-catalysed dehydration of 10d2: alternative preparation of
6-(2-Nitrophenyl)-3-phenyl-1,2-oxathiine 2,2-dioxide 11j
(6-benzyl-3,5-diphenyl-1,2-oxathiine 2,2-dioxide 11d
from 10j (2.67 mmol) as pale-yellow microcrystals (0.76 g,
86%) from EtOAc/hexane; mp = 208–210 °C; νmax (neat) 2914, 4-(Dimethylamino)-3,5,6-triphenyl-3,4-dihydro-1,2-oxathiine
2842, 1642, 1568, 1519, 1368 (SO2–O), 1178 (SO2–O), 1061, 2,2 dioxide 10d2 (0.50 g, 1.2 mmol) was dissolved in PhMe
1030, 788, 550 cm−1; δH (DMSO-d6, 400 MHz) 6.86 (1H, d, J = (60 mL) and mixed with 4-TsOH (0.046 g, 0.24 mmol,
7.2 Hz, 5-H), 7.41 (1H, d, J = 7.2 Hz, 4-H), 7.51–7.55 (3H, m, 20 mol%) at room temperature. The reaction mixture was
Ar–H), 7.62–7.67 (2H, m, Ar–H), 7.80–7.90 (3H, m, Ar–H), 8.10 heated under reflux overnight, with the colour of the mixture
(1H, d, J = 7.9 Hz, Ar–H); δC (DMSO-d6, 100 MHz) 106.99, gradually turning orange. Upon full consumption of the start-
125.02, 128.00, 129.67, 129.71, 130.64, 131.83, 133.07, 134.11, ing material, as confirmed by TLC, the solvent was removed
134.14, 147.86, 152.65; found [M
+
NH4]+
=
347.0693, under reduced pressure. Purification of the crude product by
column chromatography (neutral alumina, dry loading, 10%
C16H11NO5S requires [M + NH4]+ = 347.0696.
5-(2-Fluorophenyl)-6-methyl-3-phenyl-1,2-oxathiine 2,2- EtOAc in petroleum ether (bp 60–80 °C)) gave 6-benzyl-3,5-
dioxide 17 from 16 (5.1 mmol†) as colourless needles (1.25 g, diphenyl-1,2-oxathiine 2,2-dioxide 11d as colourless microcrys-
78%) from EtOAc/hexane; mp = 98–99 °C; νmax (neat) 1651, tals in 15% yield which was identical to material previously
1579, 1491, 1359 (SO2–O), 1264, 1155 (SO2–O), 971, 782, 719, obtained by the Cope elimination reaction on 10d1.
568 cm−1; δH (CDCl3, 400 MHz) 2.15 (3H, s, 6-Me), 6.76 (1H, s,
Addition of phenylsulfene to (Z)-2,2-dimethyl-3-(pyrrolidin-
4-H), 7.15–7.31 (3H, m, Ar–H), 7.37–7.43 (4H, m, Ar–H),
1-ylmethylene)chroman-4-one 26
7.59–7.62 (2H, m, Ar–H); δC (CDCl3, 100 MHz) 18.65, 112.69,
116.30 (d, J = 21.7 Hz), 122.82 (d, J = 15.2 Hz), 124.63 (d, J = 3.7
A solution of phenylmethanesulfonyl chloride (1.17 g,
Hz), 127.73, 128.99, 129.83, 129.87, 130.68 (d, J = 8.1 Hz), 6.12 mmol) in anhydrous THF (15 mL) under a nitrogen atmo-
131.25 (d, J = 2.6 Hz), 132.21, 133.26, 155.18, 159.67 (d, J = sphere was added dropwise over 10 minutes to an ice cold
246.6 Hz); found [M + NH4]+ = 334.0911, C17H13FO3S requires (−10 to 0 °C) vigorously stirred solution of the pyrrolidino-
†
[M + NH4]+ = 334.0908. An additional 0.2 eq. of m-CPBA with methylenechromanone 26 (1.5 g, 5.8 mmol) and triethylamine
an additional 24 h reaction time was required.
(0.90 mL, 6.4 mmol) in anhydrous THF (25 mL) under nitro-
2-Phenyl-5,6-dihydronaphtho[1,2-e][1,2]oxathiine
3,3- gen. The resulting solution was stirred and allowed to warm
dioxide 20 from 19 (14.1 mmol) as off-white microcrystals room temperature over ca. 4 hours. The mixture was filtered
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through a sinter containing a little chromatography silica vigorously stirred solution of (Z)-3-((dimethylamino)methyl-
(1 cm depth) and then the THF and excess Et3N were removed ene)isothiochroman-4-one 33 (2.80 g, 12.8 mmol) and excess
by rotary evaporation to afford the crude product which was Et3N (2.14 mL, 15.3 mmol) in anhydrous THF (50 mL) under
further purified by recrystallization from ethyl acetate and nitrogen. The resulting yellow suspension was then allowed to
hexane to afford 5,5-dimethyl-3-phenyl-4-(pyrrolidin-1-yl)-4,5- warm to room temperature and stirred. After the reaction was
dihydro-3H-[1,2]oxathiino[5,6-c]chromene 2,2-dioxide 28 as a judged to be complete by TLC examination (7 h) the mixture
yellow solid (1.29 g, 54%); mp 134–136 °C; νmax (neat) 2980, was filtered through a sinter containing chromatography silica
2932, 2823, 1660, 1485, 1456, 1372 (SO2–O), 1184 (SO2–O), (30 mm depth) and the volatiles were removed by rotary evap-
1034, 935, 880, 830, 768, 702, 516, 508 cm−1; δH (CDCl3, oration to afford the crude product as a yellow solid which was
400 MHz)‡ 1.46 (3H, s, 5-Me), 1.56–1.70 (7H, m, (CH2)2, s, recrystallized from EtOAc/hexanes to afford the 4-(dimethyl-
5-Me), 2.47 (2H, bs, NCH2), 2.59–2.64 (2H, m, NCH2), 4.61 (1H, amino)-3-phenyl-4,6-dihydro-3H-isothiochromeno[3,4-e][1,2]
d, J = 7.6 Hz, 4-H), 4.94 (1H, d, J = 7.6 Hz, 3-H), 6.86 (1H, d, J = oxathiine 2,2-dioxide 34 as yellow microcrystals (3.55 g,
8.1 Hz, 7-H), 6.95–6.99 (1H, m, 9-H), 7.22–7.27 (1H, m, 8-H), 74.4%); mp 173–176 °C; νmax (neat) 2981, 2875, 2796, 1490,
7.40 (1H, dd, J = 7.7, 1.4 Hz, 10-H), 7.42–7.48 (3H, m, Ar–H), 1448, 1364 (SO2–O), 1183 (SO2–O), 1161, 1008, 983, 947, 839,
7.53–7.56 (2H, m, Ar–H); δC (CDCl3, 100 MHz) 23.6, 25.4, 26.4, 792, 776, 697, 573, 533 cm−1; δH (CDCl3, 400 MHz)† 2.16 (6H,
47.6, 61.9, 62.0, 79.8, 116.6, 117.9, 121.2, 122.3, 129.4, 129.69, s, NMe2(maj)), 2.18 (6H, s, NMe2(min)), 3.56 (1H, d, J = 14.2
129.73, 131.0, 131.7, 153.4; found [M
+
H]+ 412.1575, Hz, 6-H (maj)), 3.75 (1H, d, J = 14.2 Hz, 6-H(min)), 4.07 (1H, d,
C23H25NO4S requires [M + H]+ 412.1577. ‡The 1H NMR spec- J = 14.2 Hz, 6-H(min)), 4.15 (1H, d, J = 14.2 Hz, 6-H(maj)), 4.59
trum of the crude isolated product indicated a mixture of dia- (1H, d, J = 10.5 Hz, 4-H(maj)), 4.65 (1H, d, J = 6.4, 4-H(min)),
stereoisomers in a ca. 20 : 3 ratio.
4.79 (1H, d, J = 10.5 Hz, 3-H(maj)), 4.88 (1H, d, J = 6.4, 3-H
(min)), 7.15–7.21 (2H, m, Ar–H), 7.29–7.49 (11H, m, Ar–H),
7.57–7.63 (4H, m, Ar–H), 7.64–7.69 (1H, m, Ar–H(min)); δC
(CDCl3, 100 MHz) 30.71, 30.85, 40.99, 41.57, 62.67, 63.49,
Addition of phenylsulfene to (Z)-2,2,6-trimethyl-3-(pyrrolidin-
1-ylmethylene)thiochroman-4-one 27
A
solution of phenylmethanesulfonyl chloride (1.14 g, 66.53, 68.74, 118.74, 120.18, 122.51, 122.58, 126.56, 126.58,
5.98 mmol) in anhydrous THF (15 mL) under a nitrogen atmo- 127.52, 127.79, 128.33, 128.53, 129.17, 129.41, 129.75, 129.79,
sphere was added dropwise over 10 minutes to an ice cold 129.89, 129.98, 130.01, 130.44, 130.65, 131.11, 140.60, 141.28;
(−10 to 0 °C) vigorously stirred solution of the pyrrolidino- found [M + H]+ 374.0876, C19H19NO3S2 requires [M + H]+
methylenethiochromanone 27 (1.53 g, 5.32 mmol) and excess 374.0879. †Sample present as an inseparable mixture of dia-
Et3N (0.87 mL, 6.2 mmol) in anhydrous THF (25 mL) under stereoisomers by routine flash chromatography (ratio 1.7 : 1.0
1
nitrogen. The resulting yellow solution was then allowed to based on relative integrals of H NMR signals) where possible
warm to room temperature and stirred. After the reaction was signals from the major (maj) and minor (min) isomer have
judged to be complete by TLC examination (5 h) the mixture been identified.
was filtered through a sinter containing chromatography silica
(1 cm depth) and the THF and triethylamine were removed by
rotary evaporation to afford the crude product which was
Preparation of 5,5-dimethyl-3-phenyl-5H-[1,2]oxathiino[5,6-c]
chromene 2,2-dioxide 30
further purified by elution from silica with 20% EtOAc A solution of 3-chloroperoxybenzoic acid (ca. 77%, 1.64 g,
in n-hexanes to afford the 5,5,9-trimethyl-3-phenyl-4-(pyrroli- 6.69 mmol) in dichloromethane (20 mL) was added dropwise
din-1-yl)-4,5-dihydro-3H-thiochromeno[3,4-e][1,2]oxathiine 2,2- over 15 minutes to an ice cold vigorously stirred solution of
dioxide 29 as a yellow solid (1.00 g, 43%); mp 146–148 °C; νmax 5,5-dimethyl-3-phenyl-4-(pyrrolidin-1-yl)-4,5-dihydro-3H-[1,2]
(neat) 2939, 2865, 1626, 1598, 1537, 1462, 1372 (SO2–O), 1266, oxathiino[5,6-c]chromene 2,2-dioxide 20 (2.5 g, 6.1 mmol) in
1160 (SO2–O), 1133, 827, 782, 403 cm−1; δH (CDCl3, 400 MHz) dichloromethane (50 mL). The orange solution was allowed to
1.55 (3H, s, 5-Me), 1.62 (3H, s, 5-Me), 1.68–1.75 (4H, m, warm to room temperature and stirred for 48 hours. The
(CH2)2), 2.35 (3H, s, 9-Me), 2.61–2.65 (4H, m, N(CH2)2), 4.61 mixture was then diluted with water and the CH2Cl2 layer was
(1H, d, J = 5.2 Hz, 4-H), 4.91 (1H, d, J = 5.2 Hz, 3-H), 7.08 (1H, separated. The CH2Cl2 layer was washed with aqueous sodium
dd, J = 7.9, 1.0 Hz, 8-H), 7.19 (1H, d, J = 7.9 Hz, 7-H), 7.42–7.47 thiosulfate (2 × 50 mL), washed with dilute aqueous sodium
(4H, m, Ar–H, 10-H), 7.52–7.54 (2H, m, Ar–H); δC (CDCl3, bicarbonate (4 × 50 mL) and then with water (50 mL). The
100 MHz) 21.2, 23.8, 26.9, 27.5, 43.9, 47.0, 62.4, 63.2, 122.2, orange solution was then dried with anhydrous sodium sul-
124.9, 126.9, 127.4, 129.37, 129.39, 129.8, 130.4, 133.2, 135.4, phate and the solvent was removed by rotary evaporation to
145.6; found [M + H]+ 442.1500, C24H27NO3S2 requires [M + afford the crude product which was further purified by column
H]+ 442.1505.
chromatography with 25% EtOAc in n-hexanes to afford the
title product 30 as a pale yellow solid (1.02 g, 49%); mp
98–100 °C; νmax (neat) 2976, 1633, 1549, 1482, 1362 (SO2–O),
1352, 1170 (SO2–O), 1053, 950, 833, 778, 695, 682, 563,
Addition of phenylsulfene to (Z)-3-((dimethylamino)
methylene)isothiochroman-4-one 33
A
solution of phenylmethanesulfonyl chloride (2.80 g, 525 cm−1; δH (CDCl3, 400 MHz) 1.65 (6H, s, 5-Me), 6.75 (1H, s,
14.7 mmol) in anhydrous THF (50 mL) under a nitrogen atmo- 4-H), 6.88 (1H, dd, J = 8.2, 0.4 Hz, 7-H), 7.00–7.04 (1H, m, 9-H),
sphere was added dropwise over 10 minutes to a cold (∼0 °C) 7.30–7.35 (1H, m, 8-H), 7.44–7.48 (3H, m, Ar–H), 7.55 (1H, dd,
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J = 7.7, 1.5 Hz, 10-H), 7.62–7.64 (2H, m, Ar–H); δC (CDCl3, 34 (3.0 g, 8.0 mmol) in dichloromethane (150 mL). The yellow
100 MHz) 27.3, 78.6, 114.7, 115.8, 117.1, 121.8, 122.9, 127.3, suspension was allowed to warm to room temperature and
127.7, 129.1, 130.0, 130.3, 132.9, 134.8, 146.9, 154.0; found stirred for 6 days. The mixture was then diluted with water
[M + H]+ 341.0843, C19H16O4S requires [M + H]+ 341.0842.
(200 mL) and the CH2Cl2 layer was separated. The CH2Cl2 layer
was washed with aqueous sodium sulfite solution (6 × 50 mL),
washed with dilute aqueous sodium bicarbonate (5 × 50 mL)
and then with water (100 mL). The yellow solution was then
Oxidation of 5,5,9-trimethyl-3-phenyl-4-(pyrrolidin-1-yl)-4,5-
dihydro-3H-thiochromeno[3,4-e][1,2]oxathiine 2,2-dioxide 29
A solution of 3-chloroperoxybenzoic acid (ca. 77%, 4.59 g, dried with anhydrous sodium sulphate and the solvent was
18.7 mmol) in dichloromethane (35 mL) was added dropwise removed by rotary evaporation to afford the crude product
over 15 minutes to an ice cold vigorously stirred solution of which was recrystallized from acetone/MeOH to afford the title
5,5,9-trimethyl-3-phenyl-4-(pyrrolidin-1-yl)-4,5-dihydro-3H-thio- product 35 as a pale yellow solid (2.21 g, 76%); mp 215–216 °C;
chromeno[3,4-e][1,2]oxathiine 2,2-dioxide 29 (2.5 g, 5.7 mmol) νmax (neat) 1610, 1381 (SO2–O), 1307, 1155 (SO2–O), 1053, 752,
in dichloromethane (50 mL). The cloudy orange/yellow solu- 684, 612, 543, 442 cm−1 1H NMR ((CD3)2CO, 400 MHz) 5.00
;
tion was allowed to warm to room temperature and stirred (2H, s, 6-H), 7.54 (1H, s, 4-H), 7.61–7.63 (3H, m, Ar–H),
until TLC examination of the reaction mixture indicated that 7.70–7.77 (3H, m, Ar–H), 7.79–7.83 (2H, m, Ar–H), 8.03–8.07
no starting material remained (ca. 48 hours). The mixture was (1H, m, 10-H); 13C NMR ((CD3)2CO, 100 MHz) 54.3, 118.7,
then diluted with water (200 mL) and the dichloromethane 122.4, 124.8, 126.3, 128.0, 129.1, 129.3, 129.7, 130.2, 130.6,
layer was separated. The CH2Cl2 layer was washed with 130.8, 133.4, 136.0, 154.6; found [M
aqueous sodium thiosulfate solution (2 × 50 mL), washed with C17H12O5S2 requires [M + K]+ = 398.9758.
dilute aqueous sodium bicarbonate solution (3 × 50 mL) and
+ = 398.9771
K]+
Attempted preparation of 4-(dimethylamino)-3-phenyl-6-
(p-tolyl)-3,4-dihydro-1,2,5-oxathiazine 2,2-dioxide 37
(Preparation of N-formyl-4-methylbenzamide 38)
finally with water (100 mL). The orange/yellow solution was
then dried with anhydrous sodium sulfate and solvent was
removed by rotary evaporation to afford the crude product
which was further purified by column chromatography using
A
solution of phenylmethanesulfonyl chloride (3.98 g,
40% EtOAc in n-hexanes to afford two fractions. Fraction 1, 20.9 mmol) in anhydrous THF (40 mL) was added dropwise to
5,5,9-trimethyl-3-phenyl-5H-thiochromeno[3,4-e][1,2]oxathiine a cold (−5 °C) stirred solution of (E)-N-((dimethylamino)
2,2,6,6-tetraoxide 31a as a yellow solid (0.79 g, 32%); mp methylene)-4-methylbenzamide (3.79 g, 19.9 mmol) and tri-
161–163 °C; νmax (neat) 2973, 1633, 1549, 1481, 1455, 1362 ethylamine (3.05 mL, 21.9 mmol) in anhydrous THF (50 mL)
(SO2–O), 1267 (SO2), 1168 (SO2–O), 1138 (SO2), 946, 760, 697, under nitrogen. The solution was allowed to warm to room
562 cm−1; δH (CDCl3, 400 MHz) 1.68 (6H, s, 5-Me), 2.53 (3H, s, temperature and stirred for 24 hours. Following TLC analysis,
9-Me), 6.95 (1H, s, 4-H), 7.48–7.50 (4H, m, Ar–H, 8-H), further triethylamine (3.05 mL, 21.9 mmol) was added to the
7.61–7.64 (2H, m, Ar–H), 7.76 (1H, s, 10-H), 7.96 (1H, d, J = 7.9 reaction mixture which was cooled to −5 °C and a solution of
Hz, 7-H); δC (CDCl3, 100 MHz) 20.1, 21.8, 58.1, 119.8, 125.5, phenylmethanesulfonyl chloride (3.98 g, 20.9 mL) in anhy-
126.6, 126.7, 127.0, 127.8, 129.3, 129.5, 130.4, 130.7, 132.6, drous THF (40 mL) was added dropwise to the reaction
137.3, 145.2, 146.5; found [M + H]+ 403.0669, C20H18O5S2 mixture. The reaction mixture was allowed to warm to room
requires [M + H]+ 403.0668.
temperature stirred for 6 days. The reaction mixture was fil-
Fraction 2, 5,5,9-trimethyl-3-phenyl-5H-thiochromeno[3,4-re] tered through Celite and the solvent removed under vacuum.
[1,2]oxathiine 2,2,6-trioxide 31b as a yellow solid (1.19 g, 50%); The resulting residue was purified by column chromatography
mp 70–73 °C; νmax (neat) 2976, 1633, 1548, 1455, 1363 (SO2– (1% methanol in dichloromethane) to afford N-formyl-4-
O), 1172 (SO2–O), 1298, 1267, 1124, 1083, 1036 (SO), 953, 901, methylbenzamide 38 as the major fraction (2.00 g, 62%) as col-
759, 734, 696, 564 cm−1; δH (CDCl3, 400 MHz) 1.46 (3H, s, ourless needles; mp = 128–130 °C (lit. mp = 130–132 °C49);
5-Me), 1.71 (3H, s, 5-Me), 2.49 (3H, s, 9-Me), 6.97 (1H, s, 4-H), νmax 1668, 1609, 1443, 1363, 1204, 1182, 11223, 1067, 1036,
7.44 (1H, d, J = 7.9 Hz, 8-H), 7.48–7.51 (3H, m, Ar–H), 834, 726, 677, 640, 608, 563, 471 cm−1 1H NMR (400 MHz,
;
7.61–7.64 (2H, m, Ar–H), 7.70–7.72 (2H, app. d, J = 7.6 Hz, CDCl3) δH 10.1 (1H, bd, J = 8.2 Hz, NH), 9.38 (1H, d, J = 9.7 Hz,
7-H, 10-H); δC (CDCl3, 100 MHz) 20.03, 21.62, 22.49, CHO), 7.89–7.87 (2H, m, Ar–H), 7.35–7.26 (2H, m Ar–H), 2.44
55.27, 116.07, 124.53, 126.51, 127.78, 127.91, 129.20, 129.77, (3H, s, Ar–Me).
129.81, 130.40, 132.74, 132.91, 136.61, 143.51, 148.28;
Preparation of (E)-3-(dimethylamino)-N-((E)-(dimethylamino)
methylene)-2-phenylacrylamide 39
found [M + H]+ 387.0716, C20H18O4S2 requires [M + H]+
387.0719.
A stirred solution of 2-phenylacetamide (2.0 g, 15 mmol) in
DMF·DMA (10 mL, 83 mmol) was heated in a distillation set
up such that the produced MeOH was removed. After 4 h the
Preparation of 3-phenyl-6H-isothiochromeno[3,4-e][1,2]
oxathiine 2,2,5,5-tetraoxide 35
A solution of 3-chloroperoxybenzoic acid (ca. 77%, 13.05 g, reaction mixture was cooled to room temperature and the
58.23 mmol) was added portionwise over 15 minutes to an ice volume reduced under pressure. The crude yellow product was
cold vigorously stirred solution of 4-(dimethylamino)-3-phenyl- washed with hexane containing a little EtOAc and filtered to
4,6-dihydro-3H-isothiochromeno[3,4-e][1,2]oxathiine 2,2-dioxide yield the title compound 39 (2.3 g, 63%) as pale yellow crystals;
9602 | Org. Biomol. Chem., 2019, 17, 9585–9604
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mp 115–116 °C (lit. mp 112 °C37); νmax (neat) 1601, 1553, 1495,
Conflicts of interest
1435, 1421, 1384, 1328, 1283, 1266, 1204, 1172, 1087, 1063,
981, 947, 920, 890, 798, 738, 728, 700, 634, 568, 546 cm−1; δH There are no conflicts to declare.
(CDCl3, 400 MHz) 2.69 (6H, s, vCH-NM
3.05 (3H, s, NMe), 7.15–7.28 (5H, m, Ar–H), 8.13 (1H, s, vCH
NMe2), 8.42 (1H, s, NvCH-NMe2); δC (CDCl3, 100 MHz) 34.77,
40.90, 43.22, 107.60, 125.69, 127.12, 132.17, 138.28, 150.28,
158.39, 179.26; found [M + H]+ = 246.1604 C14H19N3O requires
[M + H]+ = 246.1601.
̲e2̲ ), 3.02 (3H, s, NMe),
̲-
̲
References
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A stirred solution of 2-phenylacetamide (10.1 g, 75 mmol) in
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