Redox-Neutral Arylations of Vinyl Cation Intermediates

Article abstract of DOI:10.1002/adsc.201600860

Herein we present a new unified concept for C?C bond formation under redox-neutral conditions. Our strategy hinges upon interception of a vinyl cation with a sulfoxide resulting in simultaneous C–C and C?O bond formation and arylation. A range of structurally diverse vinyl cations are generated in situ in the presence of a sulfoxide, resulting in hydrative arylation, direct arylation of enol triflates and interrupted Meyer–Schuster rearrangement. Mechanistic investigations showcase the crucial role played by the fleeting vinyl cation intermediate and structural features that lead to its stabilization. Applications of the reaction products to synthesis are also presented. (Figure presented.).

Full text of DOI:10.1002/adsc.201600860

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DOI: 10.1002/adsc.201600860
Very Important Publication
Redox-Neutral Arylations of Vinyl Cation Intermediates
Daniel Kaiser,a Luis F. Veiros,b and Nuno Maulidea,*
a
University of Vienna, Faculty of Chemistry, Institute of Organic Chemistry, Wꢀhringer Straße 38, 1090 Vienna, Austria
E-mail: nuno.maulide@univie.ac.at
Centro de Quꢁmica Estrutural, Complexo I; Instituto Superior Tꢂcnico, Universidade de Lisboa, Av. Rovisco Pais 1,
b
1049-001 Lisbon, Portugal
Received: August 3, 2016; Revised: September 30, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600860.
Abstract: Herein we present a new unified concept ment. Mechanistic investigations showcase the cru-
ꢀ
for C C bond formation under redox-neutral condi- cial role played by the fleeting vinyl cation inter-
tions. Our strategy hinges upon interception of mediate and structural features that lead to its stabi-
a vinyl cation with a sulfoxide resulting in simultane- lization. Applications of the reaction products to syn-
ꢀ
ous C–C and C O bond formation and arylation. A thesis are also presented.
range of structurally diverse vinyl cations are gener-
ated in situ in the presence of a sulfoxide, resulting Keywords: arylation; Meyer–Schuster rearrange-
in hydrative arylation, direct arylation of enol tri- ment; sigmatropic rearrangement; sulfoxides; vinyl
flates and interrupted Meyer–Schuster rearrange- cations
Introduction
nium-like) and nucleophilic (III, enolate-like) precur-
sors. While highly successful in the past,[2b,3d,e] this ap-
The Claisen rearrangement is ideally suited for crea- proach pays a price in atom-economy given the gener-
tion of molecular complexity from simple precursors, ation of wasteful by-products.
achieving this through skeletal reorganization.[1] In
An alternative analysis (b) of the same intermedi-
the context of a-arylation chemistry, our group[2] and ate I would suggest the possibility of adding a neutral
others[3] have exploited the opportunities presented sulfoxide V to a vinyl cation species IV. Given the in-
by [3,3]-sigmatropic Claisen-type rearrangements of stability and fleeting nature of vinyl cations, this ap-
intermediates of the general formula I (Scheme 1). pears to be a pathway fraught with pitfalls; can vinyl
Conventional analysis (a) of I suggests a disconnection cations be generated under conditions that enable
ꢀ
along the Y S bond, leading to electrophilic (II, sulfo- capture by a weak nucleophile and, if so, can redox-
neutral sequences be developed? In this article, we
report our endeavours in this field and the deploy-
ment of a family of redox-neutral arylations of vinyl
cation intermediates.[2f]
Results and Discussion
Hydrative Arylation of Alkynes
Initial attempts at intercepting intermittently generat-
ed vinyl cations were met with moderate success.
Treating a solution of phenylacetylene 1a and diphen-
yl sulfoxide 2a with various Brønsted acids resulted
only in trace amounts of the desired a-arylated
ketone 3a (TfOH, Table 1, entries 1–3), or failed to
deliver any product at all (AcOH, TFA). Due to
a high degree of apparent decomposition of the start-
Scheme 1. Approaches to the generation of crucial vinylsul-
fonium intermediate I.
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Table 1. Optimization of conditions for hydrative arylation
of alkyne 1a.
mation of a-arylated ketone 3a in a high yield with
either triflic acid (entry 4) or bis(trifluoromethane)-
sulfonimide (entry 5). While, once again, lowering the
apparent concentration of the nucleophile led to di-
minished product formation (entry 6), the use of sub-
stoichiometric amounts of triflic acid at 808C afforded
3a in 96% yield (Table 1, entry 7).
It is important to note that the high conversion and
pronounced polarity difference between product 3a
and sulfoxide 2a enabled an easy and quantitative
(99%) recovery of excess sulfoxide by chromatogra-
phy.[4]
Exploration of the generality and functional group
tolerance of this transformation included the investi-
gation of various alkynes and sulfoxides, with general-
ly good results obtained (selected results are shown in
Scheme 2; see ref.[2f] for the full scope).
En- Acid
2a
(equiv.)
Solvent T/t
Yield
[%][a]
try
(equiv.)
1
2
3
4
5
6
7
TfOH (0.5)
TfOH (0.5)
TfOH (0.1)
TfOH (1.0)
Tf2NH (0.5) 4.0
TfOH (1.0)
2.0
2.0
2.0
4.0
CH2Cl2 258C/21 h trace
MeCN
MeCN
neat
258C/16 h 13
258C/16 h
808C/2 h
808C/2 h
808C/2 h
808C/2 h
2
79
80
69
96[b]
neat
2.0
4.0
neat
TfOH (0.5)
neat
[a]
NMR yield using 1,3,5-trimethoxybenzene as internal
standard.
Isolated yield. 2.97 equiv. (99%) unreacted diphenyl sulf-
oxide (2a) recovered.
[b]
ing material, we suspected that failure to rapidly trap
The chemoselectivity and connectivity of the final
the high-energy protonation adduct with an appropri- product is governed by the stability of the intermit-
ate nucleophile (sulfoxide oxygen) opened up other tently formed vinyl cation. As shown by Hanack,[5]
reaction pathways, including oligomerization, poly- both aryl substituents and cyclopropyl moieties (as
merization and hydration. Therefore we opted to per- the ideal alkyl substituents) allow for high degrees of
form the reaction under solvent-free conditions, em- vinyl cation stabilization. In this context, while com-
ploying 4 equivalents of diphenyl sulfoxide as both pound 3h (Scheme 3) was isolated in moderate yield –
the nucleophile and the solvent. Satisfyingly, this in- owing to reduced ability of vinyl cation stabilization –
crease in nucleophile concentration enabled the for- hydrative arylation of cyclopropyl(pentyl)acetylene 1i
Scheme 2. Selected scope of alkynes and sulfoxides for the hydrative arylation of alkynes.[2f]
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argyl alcohols with triflic acid in the presence of aryl
sulfoxides was investigated. Herein, protonation of
the alcohol (and departure of water) leads to the in-
termittent generation of a propargyl cation, in reso-
nance with the corresponding allenic vinyl cation –
the classical pathway of the well-known Meyer–
Schuster rearrangement.[7] Ensuing nucleophilic
attack of the aryl sulfoxide, followed by [3,3]-sigma-
tropic rearrangement, was expected to afford a,b-un-
saturated, a-aryl carbonyl compounds. Nonetheless,
a more stringent limitation than in the prior study
was at play here: not only was the fleeting vinyl
cation intermediate to be intercepted by a sulfoxide,
but this was to occur in the presence of water as
a competing nucleophile.
Scheme 3. Hydrative arylation of alkyl-substituted alkynes.[6]
Initial experiments were conducted with propargyl
alcohol 8a and diphenyl sulfoxide 2a under solvent-
leads to the exclusive formation of cyclopropyl free reaction conditions, but led only to the formation
ketone 3i in good yield and with complete regiospeci- of low amounts of the desired product (not shown).
ficity.[6]
Anticipating a pronounced effect of the solvent and
Encouraged by these results, in support of the reac- reaction conditions on the feasibility of the desired re-
tion manifold laid forth in our original mechanistic action and the crucial suppression of the undesired
proposal (see Scheme 1), i.e., the successful nucleo- classical Meyer–Schuster pathway, our efforts focused
philic attack of a sulfoxide (V) on a vinyl cation (IV), on finding the best conditions for a variety of diverse-
we carried out additional experiments (Scheme 4).
ly substituted substrates (8a, 12a, Table 2, see the Sup-
porting Information for further details). Polar aprotic
solvents (entry 4) showed to be optimal, while weaker
acids than TfOH showed
a deleterious effect
(entry 5). It was found that a catalytic amount of trifl-
ic acid and mild heating provided the best results. In
the event, a 96% yield of the desired a-arylated, a,b-
unsaturated carbonyl compound, alongside 98% of re-
covered excess diphenyl sulfoxide were obtained
(entry 8).
With suitable reaction conditions in hand (see the
Supporting Information for a full optimization table),
the scope of propargyl alcohols was explored. Varia-
Table 2. Optimization of conditions for the interrupted
Meyer–Schuster rearrangement of propargyl alcohols 8a and
12a.
Scheme 4. Trapping solvolytically-generated vinyl cations.
Entry R1 Acid
(equiv.)
Solvent
(1M)
T
t
Yield
[8C] [h] [%][a]
Since thermal solvolysis of vinyl triflates and nona-
flates is possible in highly polar solvents,[5] the forma-
tion of 6 and 3a, from 5 and 7, respectively, by this
method provides further experimental evidence for
the intermediacy of vinyl cations. From a synthetic
viewpoint, the implicit retrosynthetic disconnection of
an a-aryl ketone being formed from a vinyl triflate is
interesting and non-obvious.
1
2
3
4
5
6
7
8
H
H
H
H
TfOH (0.2) DCE
TfOH (0.2) PhMe
TfOH (0.2) MeCN
TfOH (0.2) MeNO2
80
80
80
80
80
80
50
50
3
3
3
3
38, 13aa
43, 13aa
61, 13aa
75, 13aa
Ph TFA (1.0) MeNO2
Ph TfOH (0.5) MeNO2
Ph TfOH (0.1) MeNO2
Ph TfOH (0.2) MeNO2
18 trace, 9aa
4
4
4
86, 9aa
86, 9aa
96,[b] 9aa
[a]
NMR yield using 1,3,5-trimethoxybenzene as internal
standard.
Isolated yield. 2.94 equiv. (98%) unreacted diphenyl sulf-
oxide (2a) recovered. TfOH=trifluoromethanesulfonic
acid. TFA=trifluoroacetic acid.
Intercepted Meyer–Schuster Rearrangement
[b]
Intrigued by the possibility of expanding this transfor-
mation beyond classical alkynes, the reaction of prop-
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Scheme 5. Interrupted Meyer–Schuster rearrangement of various propargyl alcohols 8.
tions on the acetylenic moiety were well tolerated in electron-rich substrate 8b, additionally containing two
all cases (Scheme 5), giving high yields for a variety aryl substituents stabilizing the cationic intermediate,
of aromatic and aliphatic substituents (9aa–9ka). Sim- afforded 9ba under mild heating (308C), the electron-
ilarly, varying substitution on the fragment of the sub- poor substrate 8r required a higher temperature
strate containing the benzyl alcohol moiety gave ex- (1008C) in order for the reaction to proceed and yield
cellent yields (9la–9ta), with the exception of the 9ra. Analogously, substrates with a decreased capabil-
moderate yield of 9ra, reflecting the reduced stabiliza- ity of cation-stabilization, such as 8e (leading to 9ea)
tion of the intermittent carbocation, and the highly and 8t (the nitrogen being protonated under the reac-
electron-rich product 9sa. As shown in Scheme 5, the tion conditions, leading to 9ta) also required elevated
optimum reaction temperature varied considerably, reaction temperatures.
depending on the nature of the substrate. While the
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Scheme 6. Scope of products formed by interrupted rearrangement of various sulfoxides 2.
The use of a variety of aryl sulfoxides (Scheme 6) corresponding hydrated products 15a and 15e [Eq.
led to the desired products in consistently high yields. (1)].[9] This showcases the versatility of this method
In addition to internal alkynes 8a–t, derivatives further, expanding from the formation of a,b-unsatu-
containing either a primary propargyl alcohol (10) rated, a-aryl carbonyl compounds to a-arylated func-
(Scheme 7) or a terminal alkyne (12) (Scheme 8) tionalized carboxylic acid derivatives.
were also employed. The products of these transfor-
mations are, respectively, enones containing a terminal
olefin (11aa–11be) or (E)-configured enals (13aa–
13ae). Substrates containing protons in the b-position
to the alcohol afforded low yields due to competing
elimination (as observed by crude NMR analysis) and
conceivable side reactions, such as Rupe rearrange-
ment (see the Supporting Information for further de-
tails).[8]
To the best of our knowledge, this method consti-
tutes the first instance in which an arylative Meyer–
Schuster rearrangement is capable of yielding the cor- Mechanistic Considerations
responding aldehydes.
All reactions reported in this work furnished exclu- Owing to the highly reactive nature of the vinyl cat-
sively the (E)-isomer of the double bond (as proven ions at the centre of this transformation, as well as
by X-ray crystallographic analysis for 13ba, Scheme 8. the pronounced influence of the electronic properties
CCDC 1440462 contains the supplementary crystallo- of the employed aryl sulfoxides on the efficiency of
graphic data for this compound. These data can be the arylation, our interest turned towards mechanistic
obtained free of charge from The Cambridge Crystal- investigations.
lographic Data Centre via www.ccdc.cam.ac.uk/data_-
In order to probe the mechanism of the reaction,
DFT calculations were undertaken, as previously re-
request/cif).
The treatment of 3-(phenylthio)prop-2-yn-1-ol (14) ported.[2f,10] Herein, phenylacetylene (1a) and either
with aryl sulfoxides 2a and 2e interestingly yields the diphenyl sulfoxide (2a) or methyl phenyl sulfoxide
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A similar reaction pathway can be observed for the
reaction of 1a with methyl phenyl sulfoxide (2e) (see
Supporting Information, Figure S2). For both nucleo-
philic attack of the sulfoxide and rearomatization,
barrier differences of less than 2 kcalmolꢀ1 were
found. The [3,3]-sigmatropic rearrangement, however,
is 4.4 kcalmolꢀ1 higher in energy than for the respec-
tive reaction with 2a. This result is reflected in the ex-
perimental results shown above, requiring higher tem-
peratures when alkyl aryl sulfoxides are employed
(see Scheme 2 and Scheme 4).[11,12]
Turning to the protonation of propargyl alcohols
and the ensuing interrupted Meyer–Schuster rear-
rangement, we were intrigued by the possibility of
varying substitution – and with it stabilization of the
intermittent cation. The ease of the protonation-dehy-
dration step was further investigated. To this effect,
an initial qualitative NMR study was performed,
showcasing the differences of reactivity of substrates
8a, 10a and 12a at 258C, forming 9aa, 11aa and 13aa,
respectively (Figure 1).
These qualitative curves confirm the assumption
and experimental observation (cf. Scheme 6,
Scheme 7 and Scheme 8) that the reactivities of sub-
strates with varying substitution patterns differ great-
ly. While 8a is converted to 9aa smoothly, even at am-
bient temperature, the analogous reactions of 12a
(and, even more so, 10a) are sluggish.
These observations were further substantiated by
probing the stabilities of cations of type VI by DFT
calculations (Scheme 10).[10]
The free energy balances shown in Scheme 10 indi-
cate clearly that, under our conditions, the reaction
outcome directly mirrors the stability of the carbocat-
ion. Thus, in the case of R1 =R2 =Ph, the increased
extension of the p-conjugated system leads to a more
Scheme 7. Terminal a,b-unsaturated ketones formed via in-
terrupted rearrangement of primary propargyl alcohols.
(2e) were considered as the reactants. Scheme 9 effective delocalization of the positive charge, a more
shows the free energy profile of the reaction of 1a stable carbocation and a more effective reaction
with 2a (for the corresponding representation of the (product 9aa). The reaction outcome is further re-
reaction with 2e, see the Supporting Information).
flected by the charge distribution along the cation
Triflic acid-mediated protonation of phenylacety- and, particularly, in the two phenyl groups that ac-
lene (1a), A!B, has a barrier of 10.1 kcalmolꢀ1. As commodate more than 50% of the total charge with
can be easily rationalized with the well-established in- charges of CPh =0.21 and CPh =0.32 (NPA, see
stability of the formed vinyl cation, this step is ender- Figure 2).
gonic (DG=5.6 kcalmolꢀ1). Owing to this high reac-
Comparing the other two carbocations, for the case
tivity, the following step, namely O-nucleophilic of R1 =H and R2 =Ph (12a, leading to 13aa), cation
attack of the sulfoxide on the sp-hybridized carbocat- VI shows greater stability, displaying a better charge
ion, B!D, is exergonic (DG=ꢀ27.8 kcalmolꢀ1) and distribution along the p-system with a charge of CPh =
possesses an energetic barrier of only 2.0 kcalmolꢀ1. 0.46 in the phenyl moiety, compared to CPh =0.38 in
The final steps, involving [3,3]-sigmatropic rearrange- the case of the cation derived from 10a (R1 =Ph, R2 =
ment and triflate-promoted rearomatization (D!E! H). This is reflected in the reaction conditions neces-
F) appear to be facile in nature. The sigmatropic shift sary for the corresponding reactions, yielding 13aa
has a value of DG° =13.7 kcalmolꢀ1, a barrier easily and 11aa, respectively.
surpassed under the reaction conditions (vide supra).
Following the activation step, forming VI, O-nucle-
The overall process, being thermodynamically fav- ophilic attack of the aryl sulfoxide leads to an inter-
oured, displays a free energy balance of DG= mediate of type I, as illustrated in Scheme 1. The pro-
ꢀ65.0 kcalmolꢀ1.
gression of the reaction, including the aforementioned
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Scheme 8. a,b-Unsaturated aldehydes via rearrangements of terminal propargyl alcohols.
Figure 1. Reaction monitoring for the formation of 9aa, 11aa and 13aa at 258C. The reactions were performed in MeNO2-d3
(1M), using 4 equiv. of 2a and 0.2 equiv. of TfOH. Product formation was monitored by NMR, using 1,2-dibromoethane as
an internal standard.
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Scheme 9. Schematic profile calculated for the reaction of 1a with 2a (distances in ꢄ). Free energy values (kcalmolꢀ1) rela-
tive to the separated reactants. See the Supporting Information for details.
Product Elaboration
The products shown above can be easily functional-
ized due to the large number of synthetic handles
they contain.
Alkyl aryl sulfides can be chemoselectively coupled
Scheme 10. Free energy balance (kcalmolꢀ1) calculated for
the formation of carbocation VI.
with arylzinc reagents, affording biaryl-compounds,
even in the presence of carbonyls (Scheme 11).[13]
Treating alkyl aryl sulfides 4ce/ae/cf with arylzinc-lith-
nucleophilic attack, [3,3]-sigmatropic rearrangement ium chloride complexes and a palladium catalyst (Pd-
and rearomatization, proceeds analogously to the pre- PEPPSI-SIPr) afforded biphenyls 16a–d in high
viously described formation of product 3a (Scheme 9). yields.[2f]
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by the formation of imidazole 18 and diaryl-thioxo-
AHCTUNGTRENNUNG
imidazolidinone 19.[15,16] The formation of quinoxaline
20 can be achieved even more conveniently by com-
bined aerobic oxidation and condensation of 3a with
phenylenediamine.[17] It is noteworthy that 20 is
formed in only two steps from phenylacetylene, di-
phenyl sulfoxide and o-phenylenediamine, employing
only air and catalytic amounts of triflic acid and
DABCO as promoters. Quinoxaline cores related to
20 have been described in DNA-cleaving agents or
electroluminescent materials.[18]
Similarly, enones can be condensed to afford drug-
like heterocycles, as shown in Scheme 12b and c. Het-
erocycle formation was achieved by treatment of 9ae
with either guanidinium chloride, to afford pyrimi-
dine-amine 21 in moderate yield (Scheme 12b), or
methylhydrazine, which led to the formation of
a mixture of pyrazoline 22a and pyrazole 22b
(Scheme 12c).[19]
While reduction of the arylsulfanyl moiety has been
previously reported for similar substrates,[2d] the high
degree of functionalization of the arylated enones
renders reduction difficult to control (Scheme 13a).
Whereas treatment of 9le with Raney nickel and hy-
drogen in acetone led merely to hydrogenation of the
a,b-unsaturation (product 24), omitting hydrogen and
changing the solvent to ethanol afforded 23 as the
main product.[20] Additionally, chloride 9ia could be
converted to vinyltetrahydrofuran 25 in two simple
steps, involving Luche reduction and silver-mediated
SN2 ring closure (Scheme 13b).[21]
Figure 2. Charge distributions (NPA) along the C-atoms of
the carbocations VI.
Methyl thioether 9ae could be selectively converted
to benzothiophene 26 by treatment with N-bromosuc-
The newly formed carbonyl moieties lend them- cinimide (Scheme 14). The resulting structure consti-
selves to several forms of derivatization.[2f] Amongst tutes the core motif of the potent selective estrogen-
these, heterocycle formation plays a prominent role receptor modulator (SERM) raloxifene.[22]
and enables the facile formation of aryl-substituted
The inherent, albeit low, nucleophilicity of alkynes
heterocycles (Scheme 12a). The oxidation of 3a to di- enables the use of electrophiles other than protons.
ketone 17 can be achieved by copper-catalyzed oxida- Preliminary studies show the possibility of activation
tion.[14] This diketone, in turn, can be readily con- of 1a with N-bromosuccinimide, followed by trapping
densed with a variety of nucleophiles, as exemplified with diphenyl sulfoxide (2a). Subsequent rearrange-
Scheme 11. Palladium-catalyzed cross coupling of 4ce/ae/cf with an arylzinc reagent.
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Scheme 12. Facile oxidation and subsequent condensation of the products, leading to heterocycles.
ment and rearomatization leads to the formation of ylating agent. These reactions lead to the formation
the a-bromo ketone 27 [Eq. (2)].
of a-aryl ketones or E-configured a-aryl enones and
enals at will, and show a tolerance for a wide range of
functionality. The ortho- or ortho/meta-substitution
patterns on the aryl moiety, arising from [3,3]-sigma-
tropic rearrangement, are unprecedented in the 1,2-
difunctionalization of alkynes and propargyl alcohol-
s,[3g–i] and offer handles for further elaboration by pal-
ladium-catalyzed cross-coupling and conjugate addi-
tions. The procedures detailed herein benefit from the
use of highly stable and, in most cases, commercially
available starting materials, as well as operational
simplicity (atmospheric conditions, “wet” solvents,
Conclusions
In summary, we have developed a novel concept for facile purification) and the atom-economical nature
carbon-carbon bond formation via the interception of of the reactions, including quantitative recovery of
highly reactive vinyl cations with sulfoxides. The excess reagents. DFT calculations and mechanistic ex-
latter species function as both the nucleophile and ar- periments highlight the crucial role of the intermittent
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were dissolved in nitromethane (1 M). Trifluoromethanesul-
fonic acid (0.20 equiv.) was added in one portion and the re-
action mixture was stirred at the indicated temperature until
TLC analysis showed full consumption of the starting mate-
rial. Heating was ceased and the reaction was terminated by
addition of a saturated aqueous solution of sodium bicar-
bonate, followed by ethyl acetate. The phases were separat-
ed, the organic phase was dried over anhydrous sodium sul-
fate, the dried solution was filtered and the filtrate was con-
centrated under reduced pressure. Flash column chromatog-
raphy purification afforded the corresponding a-arylated
a,b-unsaturated carbonyl compound.
Phenyl(2-phenylbenzo[b]thiophen-3-yl)methanone
(26)
To a solution of (E)-2-[2-(methylthio)phenyl]-1,3-diphenyl-
prop-2-en-1-one (9ae, 19.9 mg, 0.0602 mmol, 1.00 equiv.) in
1,2-dichloroethane (3.00 mL, 0.02M), N-bromosuccinimide
(11.3 mg, 0.0632 mmol, 1.05 equiv.) was added and the reac-
tion mixture was heated at 408C. After 20 h, 1M hydrochlo-
ric acid (2 mL) was added and the resulting biphasic mixture
was extracted with dichloromethane (2ꢅ5 mL). The com-
bined organic phases were dried over anhydrous sodium sul-
fate, the dried solution was filtered and the filtrate was con-
centrated under reduced pressure. The crude residue was
purified by flash column chromatography on silica gel (hep-
tane/ethyl acetate 9/1) to afford of the title compound as
a light yellow oil; yield: 17 mg (90%).
Scheme 13. a) Raney-Ni catalyzed reduction of 9le and b)
synthesis of a cis-stilbene-substituted furan.
3-(4-Fluorophenyl)-2-[2-(methylthio)phenyl]-1-
phenylpropan-1-one (24)
An aqueous suspension of an excess of activated Raney
nickel was washed with anhydrous acetone (3ꢅ5 mL) under
an argon atmosphere and ultimately covered in acetone
(2.00 mL, 0.05M). To this suspension, (E)-3-(4-fluorophen-
yl)-2-[2-(methylthio)phenyl]-1-phenylprop-2-en-1-one (9le,
34.8 mg, 0.100 mmol, 1.00 equiv.) was added. The reaction
vessel was evacuated and back-filled with hydrogen gas
three times, after which the reaction mixture was stirred vig-
orously at 258C under a hydrogen atmosphere. After 15 h,
when TLC analysis indicated full consumption of the start-
ing material, the reaction mixture was filtered and the fil-
trate was concentrated under reduced pressure. The crude
residue was purified by flash column chromatography on
silica gel (heptane/ethyl acetate 6/1) to afford an inseparable
colourless oil (yield: 23 mg), containing a mixture of the
title compound (59%) and 3-(4-fluorophenyl)-1,2-diphenyl-
propan-1-one (23, 8%).
Scheme 14. Synthesis of the core motif 26 of the potent
pharmaceutical raloxifene.
vinyl cation and the subsequent arylative [3,3]-sigma-
tropic rearrangement of the pivotal sulfonium inter-
mediate.
(E)-2-{2-Phenyl-1-[2-(phenylthio)phenyl]vinyl}-
tetrahydrofuran (25)
To a solution of (E)-6-chloro-1-phenyl-2-[2-(phenylthio)phe-
nyl]hex-1-en-3-one (9ia, 30.0 mg, 0.0763 mmol, 1.00 equiv.)
in methanol (760 mL, 0.1 M), cerium(III) chloride heptahy-
drate (28.4 mg, 0.0763 mmol, 1.00 equiv.) was added and the
reaction mixture was stirred at 258C. After 15 min, sodium
borohydride (3.03 mg, 0.0802 mmol, 1.05 equiv.) was added
and stirring was continued at 258C. After 2 h, when TLC
analysis showed no remaining starting material, a saturated
aqueous solution of ammonium chloride (2 mL) was added
Experimental Section
General Procedure for Interrupted Meyer–Schuster
Rearrangement of Propargyl Alcohols
Under atmospheric conditions, the propargyl alcohol
(1.00 equiv.) and the corresponding sulfoxide (4.00 equiv.)
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and the resulting mixture was extracted with diethyl ether
(2ꢅ5 mL). The combined organic phases were dried over
anhydrous sodium sulfate, the dried solution was filtered
and the filtrate was concentrated under reduced pressure.
The crude residue was subsequently dissolved in tetrahydro-
furan (760 mL, 0.1M) and the solution was cooled to 08C.
At this temperature, silver(I) oxide (19.5 mg, 0.0839 mmol,
a saturated aqueous solution of sodium chloride (5 mL) and
subsequently dried over anhydrous sodium sulfate. The
dried solution was filtered and the filtrate was concentrated
under reduced pressure. The crude residue was purified by
flash column chromatography on silica gel (heptane/ethyl
acetate 3/1) to afford 22a as an off-white solid (yield: 62 mg,
71%) and 22b as an off-white solid (yield: 20.5 mg, 24%).
1.10 equiv.)
and
silver(I)
trifluoromethanesulfonate
(4.90 mg, 0.0191 mmol, 0.250 equiv.) were added and the re-
sulting suspension was warmed to 508C. After 24 h, the re-
action mixture was filtered through a pad of diatomaceous
earth with ethyl acetate. The filtrate was washed with a satu-
rated aqueous solution of sodium bicarbonate (10 mL) and
the washed solution was dried over anhydrous sodium sul-
fate, before being filtered and concentrated under reduced
pressure. The crude residue was purified by flash column
chromatography on silica gel (heptane/ethyl acetate 7/1) to
afford the title compound as a yellow oil; yield: 20 mg
(75%).
5-[2-(Methylthio)phenyl]-4,6-diphenylpyrimidin-2-
amine (21)
Under an atmosphere of air, a solution of (E)-2-[2-(methyl-
thio)phenyl]-1,3-diphenylprop-2-en-1-one (9ae, 30.0 mg,
0.0908 mmol, 1.00 equiv.), guanidinium chloride (17.3 mg,
0.182 mmol, 2.00 equiv.) and sodium hydroxide (18.2 mg,
0.454 mmol, 5.00 equiv.) in ethanol (454 mL, 0.2M) was
heated at 758C for 14 h. After this time, the base was
quenched by the addition of a saturated aqueous solution of
ammonium chloride (10 mL) and the resulting mixture was
extracted with ethyl acetate (2ꢅ7 mL). The combined or-
ganic phases were washed with a saturated aqueous solution
of sodium bicarbonate (5 mL) and subsequently dried over
anhydrous sodium sulfate. The dried solution was filtered
and the filtrate was concentrated under reduced pressure.
The crude residue was purified by flash column chromatog-
raphy on silica gel (heptane/ethyl acetate 1/1) to afford the
title compound as a yellow solid; yield: 10 mg (30%).
3-(4-Fluorophenyl)-1,2-diphenylpropan-1-one (23)
An aqueous suspension of an excess of activated Raney
nickel was washed with anhydrous ethanol (3ꢅ5 mL) under
an argon atmosphere and ultimately covered in ethanol
(1.50 mL, 0.07M). To this suspension, (E)-3-(4-fluorophen-
yl)-2-[2-(methylthio)phenyl]-1-phenylprop-2-en-1-one (9le,
34.8 mg, 0.100 mmol, 1.00 equiv.) was added and the reac-
tion mixture was stirred vigorously at 258C. After 1 h, when
TLC analysis indicated full consumption of the starting ma-
terial, the reaction mixture was filtered and the filtrate was
concentrated under reduced pressure. The resulting residue
was dissolved in dichloromethane (1.00 mL, 0.1M) and to
the resulting solution, Dess–Martin periodinane (DMP,
48.8 mg, 0.115 mmol, 1.15 equiv.) was added. After stirring
at 258C for 1 h, excess oxidant was quenched by the addi-
tion of a saturated aqueous solution of sodium sulfite
(1 mL) and the reaction mixture was neutralized by the ad-
dition of a saturated aqueous solution of sodium bicarbon-
ate (2 mL). The mixture was extracted with dichlorome-
thane (2ꢅ5 mL) and the combined organic phases were
dried over anhydrous sodium sulfate. The dried solution was
filtered and the filtrate was concentrated under reduced
pressure. The crude residue was purified by flash column
chromatography on silica gel (heptane/ethyl acetate 6/1) to
afford the title compound as a colourless solid; yield: 26 mg
(85%).
Acknowledgements
We are grateful to the ERC (StG FLATOUT), the DFG
(Grant MA 4861/4-1 and 4-2), the Austrian Academy of Sci-
ences (DOC award to D.K.) and the FCT (UID/QUI/00100/
2013) for financial support.
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generated from the fragmentation of such transiently
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Redox-Neutral Arylations of Vinyl Cation Intermediates
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Daniel Kaiser, Luis F. Veiros, Nuno Maulide*
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