Ru(ii)-Catalysed synthesis of (1 H)-isothiochromenes by oxidative coupling of benzylthioethers with internal alkynes

Article abstract of DOI:10.1039/c8ob03201g

The synthesis of 1H-isothiochromenes by oxidative coupling of benzyl(tert-butyl)thioethers with internal alkynes, catalysed by Ru(ii), has been achieved. The reaction occurs by S-directed C-H activation at the ortho position of the aryl ring, promoted by ruthenium, migratory insertion of the alkyne, 1,2-thio-Wittig rearrangement of the tert-butyl group and reductive elimination by C-S coupling between the resulting anionic sulfide and the vinylic carbon.

Full text of DOI:10.1039/c8ob03201g

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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DOI: 10.1039/C8OB03201G
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Ru(II)-catalysed synthesis of (1H)-isothiochromenes by oxidative
coupling of benzylthioethers with internal alkynes
Esteban P. Urriolabeitia,*a and Sara Ruiz a
Received 00th January 20xx,
Accepted 00th January 20xx
The synthesis of 1H-isothiochromenes by oxidative coupling of benzyl(tert-butyl)thioethers with internal alkynes, catalysed
by Ru(II), has been achieved. The reaction occurs by S-directed C-H activation at the ortho position of the aryl ring, promoted
by ruthenium, migratory insertion of the alkyne, 1,2-thio-Wittig rearrangement of the tert-butyl group and reductive
elimination by C-S coupling between the resulting anionic sulfide and the vinylic carbon
DOI: 10.1039/x0xx00000x
www.rsc.org/
estrogen receptor modulators (SERMs),7a active compounds in
the osteoporosis treatment,7b and behave as analogs of
isocoumarins in the cancer treatment.7c According to the
retrosynthesis shown in Scheme 1c, the oxidative coupling
between a thioether and an internal alkyne through C-H
activation could be the shortest and most efficient synthetic
pathway to this class of compounds but, as far as we know, it is
still unknown.
Introduction
The transition metal-catalysed oxidative functionalization of C-
H bonds is at present a well consolidated synthetic tool in
organic chemistry.1,2 In particular, the synthesis of heterocycles
by oxidative coupling of arenes or heteroarenes with internal
alkynes has experienced an impressive development.3 Key
features of these processes are the use of catalytic amounts of
metals, mild reaction conditions and high regio- and stereo-
selectivity, achieved using directing groups (DG). In addition,
when the process is designed to incorporate the DG into the
target molecule, a complete atom economy can be attained,
minimizing synthetic steps and waste materials, and saving
time, resources and energy. Relevant examples are the
synthesis of isocoumarins or isoquinolines from coupling of
internal alkynes with, respectively, carboxylic acids (Scheme 1a)
and amines or imines (Scheme 1b).3
A detailed inspection of the literature in this area shows that O-
or N-based DGs are almost ubiquitous, while other heteroatoms
with good bonding ability are underrepresented. The use of S-
directing groups in the synthesis of S-heterocycles is a paradigm
of the latter statement, because few examples are known.
Probably, the high affinity of transition metals to bind to sulfur
is the responsible for this shortage of examples, because a
strong M-S bond would form stable complexes, promoting the
poisoning and deactivation of the catalyst.4
Scheme 1. Synthesis of isocoumarins (a) and isoquinolines (b) from carboxylic acids and
imines. Retrosynthesis of (1H)-isothiochromenes (c) and a representative example.
Previous work in metal-mediated synthesis of (1H)-
isothiochromenes by coupling of arenes and alkynes started
with the work of Pfeffer et al., where orthopalladated thiothers
were reacted with internal alkynes under harsh conditions to
give thiopyranes, thiepins and related species (Scheme 2a).8a-c
This method proved to be versatile, but consumed
stoichiometric amounts of Pd. The reaction of thiophthalic
anhydride with alkynes catalysed by Ni0 provides an additional
route (Scheme 2b), but needs harsh reaction conditions and
specific combinations of solvents and additives, otherwise
mixtures of compounds were obtained.8d The reaction of
internal alkynes with aryl rings containing S-directing groups,
such as phosphine sulfides,8e sulfoxides,8f or thioethers,8g gives
only ortho-alkenylated derivatives by hydroarylation, (Scheme
2c). Due to the interest of (1H)-isothiochromenes and the lack
of simple and efficient preparative routes,9 we have
The interest on sulfur heterocycles resides on their recognized
biological and pharmacological activity,5 their presence in
agrochemical compounds,5 in materials with useful optical and
electronic properties, or as valuable synthetic intermediates or
ligands.6 More specifically, the (1H)-isothiochromenes such as
the lasofoxifene and its analogues (Scheme 1c) are selective
a. Instituto de Síntesis Química y Catálisis Homogénea, ISQCH, CSIC-Universidad de
Zaragoza, Pedro Cerbuna 12, 50009 Zaragoza (Spain)
Electronic Supplementary Information (ESI) available: [Complete experimental investigated this area, following previous related research.8g We
section, characterization data and NMR spectra of all compounds; optimization of
compound 3aa]. See DOI: 10.1039/x0xx00000x.
report here the synthesis of (1H)-isothiochromenes by Ru-
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catalysed oxidative coupling of benzyl(tert-butyl) thioethers crystals of 3ba (from 1b and 2a, see Scheme 4 and ESI), which
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with internal alkynes (Scheme 2d).
were adequate for X-ray diffraction. TheDmOoI:le10c.u10la3r9/sCt8ruOcBt0u3r2e01oGf
3ba is shown in Figure 1, and shows an isothiochromene or
benzothiopyrane bicyclic molecule, that is, a phenyl ring fused
to a thiopyrane ring, which is substituted in positions 3 and 4 by
ethyl groups and in position 1 by the tert-butyl group. This
means that, in addition to the expected ortho-activation of the
thioether and migratory insertion of the alkyne, an unexpected
migration of the tert-butyl group from the sulfur to the C1 has
taken place, as well as the desired formation of the C-S bond.
The bond distances and angles of this structure are identical,
within experimental error, to those observed in the few
examples found in the literature.8a
Scheme 2. Previous and present work on synthesis of (1H)-isothiochromenes.
(b)
(a)
Results and discussion
We have selected as model substrate the benzyl(tert-butyl)
thioether 1a, because it showed an excellent reactivity in
hydroarylation reactions.8g Moreover, we expect that the tert-
butyl group could be eliminated as isobutene and H+,8a
generating a nucleophilic thiolate, more prone to give the C-S
coupling than the neutral thioether. Other thioethers 1a-1n
were prepared from tBuSH and the substituted benzylbromides,
using a phase transfer agent in basic medium (see ESI for
details).
Figure 1. Thermal ellipsoid plot of isothiochromene 3ba: (a) top view and (b) side view
We started the optimization of this reaction from the conditions
reported for hydroarylation of thioethers: 1 mmol thioether 1a,
2 mmol alkyne 2a, 10% mol Ru catalyst, 10% mol KPF6, 1 mmol
Cu(OAc)2, hexafluoroisopropanol (HFIP) as solvent, 100 °C, 24
h.8g Under these conditions, only the hydroarylation product
4aa was obtained (Scheme 3a). According to our previously
reported mechanism, after C-H bond activation of the thioether
and migratory insertion of the alkyne, a protodemetalation step
occurs due to the acetic acid generated after the C-H bond
activation.8g It seems sensible to assume that the removal of the
acid, performing the reaction in the presence of base, would
disfavour the protodemetalation allowing the C-S coupling. In
fact, when the reaction between 1a and 2a was performed at
100 °C in presence of 1 mmol of K2CO3 the formation of 4aa
decreased notably to a 36%, while the formation of a new
product 3aa in 57% yield was evident. The full details of the
optimization procedure are given in the ESI. Despite this initial
result, and after exhaustive screening of reaction conditions, we
found that a decrease of the reaction temperature to 60 °C
allowed the selective formation of 3aa, surprisingly without the
need of additional base. This suggests that the synthesis of 3aa
or 4aa from the same precursors is a problem of kinetic nature.
The complete characterization of 3aa and, in general, of
compounds type 3, required the combined use of spectroscopic
and diffraction techniques. We succeeded obtaining single
Scheme 3. Condensed optimization of the synthesis of 3aa
Once the reaction has optimized conditions, the scope of the
reaction was checked. Good isolated yields were achieved with
electron-rich alkynes, such as 3-hexyne, 2-butyne or 2-hexyne
(Scheme 4), obtaining the isothiochromenes 3aa, 3ab and 3ac
in 94%, 39% and 82% isolated yields, respectively. As for 3ab the
moderate yield was due to purification problems, because the
hydroarylation by-product 4ab (also obtained in this case) was
difficult to separate by column chromatography. In the case of
2-hexyne, 3ac was obtained as the mixture of the two
regioisomers. The reactivity of electron-poor alkynes is more
restricted, as alkynes containing ester groups showed to be
unreactive, while alkynes containing aryl groups gave low
conversions and the corresponding derivatives could not be
isolated in pure form.
The reaction shows a high tolerance to the presence of
functional groups on the benzyl fragment. First, we have
checked if poly-insertion of alkynes can occur, as observed in
hydroarylation reactions.8g The unsubstituted thioether 1b
reacts with 2a under the optimized conditions to give selectively
the mono-inserted derivative 3ba (Scheme 4) whose X-ray
crystal structure was determined (Figure 1). Even if the reaction
is performed using an excess of alkyne, the bis-insertion product
2 | J. Name., 2012, 00, 1-3
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was not detected. Therefore, this method is not restricted to electron-withdrawing ability of the substituent iVniecwreAartsicelesO, nflioner
the use of ortho-substituted precursors, allowing a wide instance when a 2-CF3 unit is employedD, OthI:e10i.s1o03th9/ioCc8hOrBo0m32e0n1Ge
prospect of starting materials. In addition, only the ortho- 3ka is still obtained, but the isolated yield drops to 37%. When
position of the benzyl ring was activated, meaning that the thioethers containing nitro groups as 1l or 1n were used (ESI),
reaction takes place regioselectively due to the S-directing only hydroarylation derivatives were obtained, while the
effect.
isothiochromenes were not detected. While the reaction
tolerates different substituents at the alkyne and the benzyl
fragment of the thioether, it seems quite selective with respect
to the S-substituent. In fact, when the starting benzylthioether
contains other bulky groups at the S atom (for instance iso-
propyl or cyclohexyl) instead of the tert-butyl group, the
formation of the isothiochromene was not detected and only
the hydroarylation reaction is observed.
From the mechanistic point of view, we propose tentatively that
the reaction starts by coordination of thioether 1a to Cu(OAc)2,
as previously described (Scheme 5).8g
Scheme 4. Scope of the synthesis of (1H)-isothochromenes
The thioether 1c, containing a methyl group at 3-position, gives
3ca with complete regioselectivity, showing that the less
sterically hindered 6-position was activated. It seems that the
activation of the 2-position in the thioether when a substituent
is present at 3-position is strongly inhibited. Thus, the reaction
of the 3,5-dimethyl substituted thioether 1d with 2a affords 3da
only as traces, because both positions (2 and 6) are hindered.
However, 1e, containing two methyl substituents at 2 and 4
positions, gives 3ea in good yield (89%) by selective activation
at the 6-position, while the 4-tBu substituted 1f affords 3fa in
83% yield.
Strongly electron-donating groups such as -OMe have a
beneficial effect for the synthesis of the isothiochromenes. The
reaction between the 4-OMe substituted thioether 1g with 2a
gives 3ga in an excellent 96% isolated yield. Moreover, the
reaction of the 3,5-dimethoxy thioether 1h with 2a gives 3ha in
a moderate 50% yield, meaning that the detrimental effect of
the steric hindrance can be counterbalanced by the activating
electronic effects exerted by strong electron-donating groups.
On the other hand, the substitution of the phenyl ring with
electron-withdrawing groups is also tolerated, although a slight
decrease in the reaction yield is observed. Thus, synthetically
useful groups such as iodide (3ia) and chloride (3ja) can be kept
during the reaction, giving the corresponding heterocycles in
yields around 53% (Scheme 4). It is remarkable that the
formation of the iodine derivative 3ia is totally regioselective,
obtaining the isomer with the iodine in 7-position. When the
Scheme 5. Proposed catalytic cycle for the synthesis of (1H)-isothiochromenes
From the Cu center, both the thioether and one acetate can be
transmetallated to Ru, where C-H activation at the ortho-
position of the aryl ring takes place giving cycloruthenated A.
Intermediate A can then follow two different pathways. In the
first one (lowest part of Scheme 5), bonding of the alkyne and
further migratory insertion affords vinyl intermediate B. Then,
reductive elimination from B does not explain the formation of
isothiochromenes 3, because a migration of the tert-butyl group
from the sulfur to the C has to take place. The migration of the
tert-butyl group from the sulfur to the alpha carbon can be
formally considered a 1,2-thio-Wittig rearrangement, a reaction
often found in ethers and thioethers, which occurs in the
presence of base and gives alcohols and thiols, respectively.10
The mechanism of the [1,2]-Wittig rearrangement has been
subject of extensive discussion, but it seems well-established
now that it takes place via a radical dissociation-recombination
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mechanism.10 Therefore, intermediate C is formed after the hydrogen atoms were refined with anisotropic displacement
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Wittig migration. From C, containing a nucleophilic sulphide, a parameters. The hydrogen atoms werDeOpI:l1a0c.1e0d39a/Ct8OidBe0a3l2iz0e1Gd
reductive elimination could take place, giving Ru(0) and positions and treated as riding atoms. Each H atom was
isothiochromenes 3. The Ru(II) species are regenerated by assigned an isotropic displacement parameter equal to 1.2
oxidation with Cu(II), closing the catalytic cycle. In the second times the equivalent isotropic displacement parameter of its
2
possibility (middle part, Scheme 5), intermediate A undergoes parent atom. The structures were refined to Fo and all
thio-Wittig rearrangement before alkyne insertion, affording reflections were used in the least-squares calculations.16
species D. Alkyne bonding to D and further migratory insertion Crystallographic data (including structure factors) for the
affords C, which evolves as discussed in the previous paragraph. structure of 3ba had been deposited with the Cambridge
The exact point of the catalytic cycle at which the thio-Wittig Crystallographic Data Centre as supplementary publication
rearrangment takes place (A or B) remains speculative. We number CCDC 1544460. Copies of the data can be obtained, free
know that it can't occur before the C-H activation step, that is, of charge, on application to CCDC, 12 Union Road, Cambridge
before the formation of species A, because the reactivity of CB2 1EZ, UK (fax: +44-(0)1223-336033 or e-mail:
thiolates with internal alkynes in the presence of Cu(OAc)2 has deposit@ccdc.cam.ac.uk).
been recently reported and follows a totally different pathway, Preparation and characterization of starting materials. General
not observed here.11 Thus, it can occur either after the C-H bond procedure for the synthesis of tert-butyl thioethers 1a-1n
activation in A, giving cycloruthenated D, which affords C by
migratory insertion of 2a, or in vinyl intermediate B to give C.
Attempts to isolate cycloruthenated A were not successful,
therefore details of the reactivity of A are not accessible.
Starting thioethers (1a-1n) were synthetized as follows. To a
mixture of the corresponding benzylbromide (2.5 mmol),
aliquat (50 mg, 0.12 mmol) and NaOH (225 mg, 5.6 mmol) in
toluene/water (2.5:2.5 mL), tert-butylthiol (2.5 mmol) was
added dropwise. The resulting mixture was stirred for 1 h at 25
C. After this time, the reaction was quenched by addition of
HCl 1M (10 mL), then extracted with Et2O (2×10mL). The organic
Experimental
General methods
phase was washed with brine (5×30 mL), dried over MgSO4 and
evaporated to dryness to yield the pure products as oils. The
characterization of 1a is shown here. The characterization of the
remaining compounds 1b-1n is given as ESI.
All reactions were carried out in Young's flasks, without
protecting atmosphere. Solvents were used as received from
commercial sources: they were not distilled nor subjected to
additional purification. Flash column liquid chromatographies
were performed on aluminium oxide 90 neutral (50-200 μm) or
silica gel (70-230 m). 1H and 13C NMR spectra were all recorded
in CDCl3 or acetone-d6 solutions at 25 oC on Bruker AV500,
AV400 or AV300 spectrometers (δ in ppm, J in Hz) at 1H
operating frequencies of 500.13, 400.13 or 300.13 MHz,
respectively, and were referenced using the solvent signal as
internal standard. HRMS and ESI (ESI+) mass spectra were
recorded using an MicroToF Q, API-Q-ToF ESI with a mass range
from 20 to 3000 m/z and mass resolution 15000 (FWHM). Some
products could not be adequately characterized by high-
resolution MS. In these cases, elemental analyses (CHNS) were
provided instead, which were performed on a PerkinElmer 2400
Series II microanalyser. The synthesis of [Ru(p-cymene)Cl2]2 has
been carried out following published procedures.12
1a (tert-butyl(2-methylbenzyl)sulfane): dark yellow oil (427 mg,
1
88 %). H NMR (400 MHz, CDCl3): δ = 7.16 (m, 1H, C6H4), 7.02
(m, 3H, C6H4), 3.63 (s, 2H, CH2), 2.30 (s, 3H, CH3), 1.29 (s, 9H,
C(CH3)3). 13C{1H} NMR (101 MHz, CDCl3): δ = 136.7 (C), 135.9 (C),
130.5 (CH), 129.9 (CH), 127.2 (CH), 126.1 (CH), 42.7 (C), 31.2
(CH2), 30.8 (CH3), 19.1 (CH3). Anal. Calcd for C12H18S: C, 74.17; H,
9.34; S, 16.50. Found: C, 73.95; H, 9.05; S, 16.80.
General procedure for the catalytic coupling of benzylthioethers 1
with alkynes 2
To a suspension of [RuCl2(p-cymene)]2 (61.2 mg, 0.1 mmol),
K[PF6] (18.7 mg, 0.1 mmol) and Cu(OAc)2 (181.6 mg, 1 mmol) in
HFIP (3 mL), the corresponding thioether 1 (1 mmol) and
internal alkyne 2 (2 mmol) were added. The reaction mixture
was stirred for 24 h at 60 °C. After the reaction time the solvent
was evaporated to dryness, the residue was dissolved in CH2Cl2
and purified by flash column chromatography using neutral
alumina as support and CH2Cl2 as eluent. The collected fraction
was evaporated to dryness and the oily residue was further
purified by column chromatography using silica gel as support
X-Ray crystallography. Crystal structure determination of 3ba
Crystals of compound 3ba of adequate quality for X-ray
measurements were grown from slow evaporation of a CHCl3
solution of the crude compound at room temperature. A single
crystal was mounted at the end of a quartz fiber in a random
orientation, covered with perfluorinated oil and placed under a
cold stream of N2 gas. The X-ray data collection was performed
on an Oxford Diffraction Xcalibur2 diffractometer using
graphite-monochromated Mo-Kα (λ = 0.71073 Å). A hemisphere
of data was collected based on ω-scan or φ-scan runs. The
diffraction frames were integrated using the program CrysAlis
RED13 and the integrated intensities were corrected for
absorption with SADABS.14 The structures were solved and
developed by Patterson and Fourier methods.15 All non-
and
a
mixture of Et2O/hexane as eluent, affording
isothiochromenes (3) as yellow oils, which solidifed on standing
in most of the cases. . The characterization of 3aa is shown here.
The characterization of the remaining isothiochromenes is
given in the ESI.
3aa (1-(tert-butyl)-3,4-diethyl-8-methyl-1H-isothiochromene):
yellow waxy solid (258 mg, 94 %). Purified by column
chromatography on silica gel, eluting with hexane/Et2O 99:1. 1H
NMR (300 MHz, acetone-d6): δ = 7.35 (m, 1 H, C6H3), 7.17 (m, 2
H, C6H3), 3.94 (s, 1H, CH), 2.68 (m, 3H, CH2CH3), 2.42 (s, 3H, CH3),
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2.17 (m, 1H, CH2CH3), 1.26 (t, 3H, CH2CH3, 3JHH = 7.5 Hz), 1.16 (t,
3
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3H, CH2CH3, JHH = 7.5 Hz), 0.93 (s, 9H, C-(CH3)3). 13C{1H} NMR
DOI: 10.1039/C8OB03201G
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Vasilyev, Chem. Rev. 2016, 116, 5894; (d) S. Ruiz, P. Villuendas
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(75 MHz, acetone-d6): δ = 135.6 (C), 135.1 (C), 131.7 (C), 130.5
(C), 129.3 (CH), 128.1 (C), 126.0 (CH), 121.5 (CH), 46.4 (CH), 39.4
(C), 27.1 (CH2), 26.8 (CH3), 21.4 (CH2), 20.5 (CH3), 13.5 (CH3).
HRMS (ESI-TOF) m/z: [M+Na+O]+ calcd for C18H26NaOS
313.1597, obtained 313.1588.
Conclusions
In conclusion, we have developed for the first time a catalytic
method for the synthesis of (1H)-isothiochromenes involving C-
C and C-S bond formation, providing a synthetic disconnection
not previously reported. The method is based on the oxidative
coupling of a benzylthioether with an internal alkyne, and takes
place in one pot through regioselective Ru-catalysed C-H
activation of the thioether, migratory insertion of the alkyne,
1,2-thio-Wittig rearrangement of the tert-butyl group and C-S
bond formation by reductive elimination. This method
represents a substantial improvement with respect to previous
methods, and provides a wide scope of application.
4
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Conflicts of interest
There are no conflicts to declare.
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Acknowledgements
E.P.U. thanks the European Cooperation in Science and
Technology (COST) program under CA15106 grant (CHAOS: CH
Activation in Organic Synthesis) and Gobierno de Aragón-FEDER
(Spain, research group E19_17R: Aminoácidos y Péptidos) for
financial support. S. R. thanks Gobierno de Aragón for a PhD
fellowship.
8
Notes and references
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