A Highly Regioselective Palladium-Catalyzed O,S Rearrangement of Cyclic Thiocarbonates

Article abstract of DOI:10.1002/ejoc.201701181

This work describes an operationally simple catalytic synthesis of cyclic S-thiocarbonates with predictable regioselectivity in good yields. The reaction utilizes substrates derived from ubiquitous 1,2-diols in an atom economical intramolecular rearrangement, catalysed by an inexpensive and simple catalyst–ligand system. A crystal structure is presented that clearly confirms the regioselectivity of the reaction.

Full text of DOI:10.1002/ejoc.201701181

A Journal of
Accepted Article
Title: A Highly Regioselective Palladium Catalyzed O,S
Rearrangement of Cyclic Thiocarbonates
Authors: William Mahy, Sinéad Cabezas-Hayes, Gabriele Kociok-
Köhn, and Christopher Frost
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701181
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10.1002/ejoc.201701181
European Journal of Organic Chemistry
COMMUNICATION
A Highly Regioselective Palladium Catalyzed O,S Rearrangement
of Cyclic Thiocarbonates
William Mahy,[a] Sinéad Cabezas-Hayes,[a] Gabriele Kociok-Köhn,[b] and Christopher G. Frost*[a]
Abstract: This work describes an operationally simple catalytic
synthesis of cyclic S-thiocarbonates with predictable regioselectivity
in good yields. A crystal structure is presented that clearly confirms
the regioselectivity of the reaction.
has an additional level of complexity due to the possibility of the
formation of two regioisomers. The following study was focused
not only on the efficiency of rearrangement, but also the
generation of a highly predictive and regioselective catalytic
system.
Introduction
Sulfur containing chemicals are prevalent starting materials
for the synthesis of highly functionalized, high value molecules.
Sulfur is renowned for its importance in the pharmaceutical
industry, where roughly 20% of the Top 200 US pharmaceuticals
in 2011 contained sulfur.[1] O-thiocarbamates have demonstrated
synthetic utility in N- to C- aryl migrations allowing for the
synthesis of highly functionalized thiols.[2] They have also proven
useful intermediates for the Barton-McCombie reaction,[3] and
their use in thermal Newman-Kwart rearrangements,[4] as well as
catalytic variants,[5] has allowed for the efficient synthesis of aryl
sulfides via an O- to S- aryl migration. Our group recently
developed the synthetic utility of O-thiocarbamates, accessing the
previously unreported O- to S- alkyl migration by employing a
ruthenium catalyst to generate thiooxazolidinones.[6] These
reactions, however, are constrained to thiocarbamates, thus
limiting the generality of the reactions.
We envisioned that by tuning the catalytic system, we could
exploit the reactivity of thiocarbonyls towards rearrangement of an
O-thiocarbonate system, thus allowing access to 1,3-oxathiolane-
2-ones. The ring-opening of these structures could in turn provide
Figure 1. O to S alkyl migrations.
access to β-hydroxythiols,[7]
a sub-class of organosulfur
For this purpose, 4-phenyl-1,3-dioxolane-2-thione (1) was
readily synthesized as a model substrate for the investigation of a
metal-catalyzed rearrangement. [RuCl2(p-cymene)]2 was initially
employed to probe the efficacy of the transformation due to the
excellent reactivity observed in previous studies. In the presence
of 5 mol% catalyst (10 mol% [Ru]) (table 1, entry 1) we achieved
products (2a and 2ab) and a small (6%) amount of the
desulfurized carbonate 2ac.
compounds which have been used in the synthesis of high value
starting materials.[8] Generally, the synthesis towards β-
hydroxythiols involves oxidative addition of sulfur across an
alkene, however the regioselectivity tends to yield the anti-
Markovnikov product, and therefore the less-substituted thiol.[9]
There are scant literature examples of O- to S- rearrangements
1,3-dioxolane-2-thiones, and the products have largely been
reported as byproducts in low yields.[10] As such, attempts to direct
the exclusive formation of 1,3-oxathiolane-2-ones using catalysis
remains, to the best of our knowledge, underexplored.
Encouraged by this result, a number of different transition
metals were investigated (table 1, entries 2-5). Cu, Ni, and Fe
catalysts (see supporting information) gave consistently poor
conversions and selectivities, however late transition group
metals proved promising. RuCl2(phen)3•H2O gave improved
overall conversion but reduced regioselectivity, and a large
proportion of 2-phenylthiirane formation was also observed (table
1, entry 2). It was believed the phenanthroline ligand was
Results and Discussion
Based on our previous findings, we investigated the
rearrangement of cyclic thiocarbonates towards the generation of
masked β-hydroxythiols. The rearrangement of thiocarbonates
responsible for nucleophilic attack of 2a, resulting in
a
decarboxylative ring contraction. Palladium catalysts showed the
highest propensity for the formation of the desired regioisomer,
exhibiting superior selectivity, however, significant levels of
desulfurization were observed. Importantly, no rearrangement or
desulfurization products were observed in the absence of catalyst
(table 1, entry 6). Rigorous exclusion of moisture and oxygen
when employing palladium catalysts proved effective in
eliminating the formation of the desulfurized byproduct (table 1,
[a]
[b]
Department of Chemistry, University of Bath, Bath, BA2 7AY, UK
E-mail: c.g.frost@bath.ac.uk
http://www.bath.ac.uk/chemistry/contacts/academics/chris_frost/
Chemical Characterisation and Analysis Facility, University of Bath,
Bath, BA2 7AY, UK
Supporting information for this article is given via a link at the end of
the document
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10.1002/ejoc.201701181
European Journal of Organic Chemistry
COMMUNICATION
entry 7), leading to high conversion (99%) and selectivity for 2a
over 2ab (>20:1).
(table 1, entries 12,13) resulted in improved conversion whilst
maintaining high regioselectivity. The comparable results of PPh3
to the more expensive Buchwald-type ligand SPhos led us to
select PPh3 as our additive ligand. An excess of phosphine was
believed to improve product liberation and hence catalyst
turnover. Despite being able to achieve quantitative conversion of
1a in only 3 hours in the absence of ligands, addition of PPh3 at
higher catalyst loadings was retained to form general conditions
that would perform well for both facile and more challenging
substrates. Varying reaction concentration had negligible effect
on conversion, and as such a higher working concentration was
employed for the optimized conditions (table 1, entry 14).
Table 1. Selected screening results[a]
Conversion[b]
Table 2. Synthesis of secondary 1,3-oxothiolane-2-ones
Entry
Catalyst
Ligand
-
2a
2ab
2ac
1[c]
[RuCl2(p-cymene)]2
50
10
6
2[c]
RuCl2(phen)3.H2O
Ni(PPh3)Cl2
[Rh(OAc)]2
Pd(PPh3)4
-
-
-
-
-
-
-
-
31 (42)[d]
21
5
0
1
0
1
1
5
4
0
0
0
0
0
7
0
31
0
3
0
7
0
0
0
1
1
3[c]
6
4[c]
0
5[c]
36
6[c]
0
7
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
95
8[e]
33
9[e],[f]
10[e], [g]
11[e],[g]
12[e], [f]
13[e], [f]
14[h]
DMAP
18 (12) [d]
DPPF
BINOL
SPhos
PPh3
32
24
45
44
99
PPh3
Reaction conditions: 1 (1 mmol), Pd(PPh3)4 (0.1 mmol), PPh3 (0.2 mmol) in
toluene (5 mL) under argon at 100 °C for 3 h. Isolated yields.
[a]Standard reaction conditions: substrate (0.25 mmol), catalyst (10
[b]
mol%), toluene (0.1 M), 100 °C, 3 h
Conversion calculated by
After the optimal conditions were established, we focused
our attention on investigating the scope and limitations of the
catalytic rearrangement. A number of cyclic thiocarbonates were
prepared from commercially available 1,2-diols (or readily
[c]
[d]
[e]
crude 1H NMR
Under air
Conversion to 2-phenylthiirane
Pd(PPh3)4 (2 mol%), 1 h [f] Ligand (4 mol%) [g] (2 mol%) [h] PPh3 20
mol%), toluene (0.2 M)
The addition of ligands was investigated in the presence of
Pd(PPh3)4 to ascertain if properties of the catalytic system could
be enhanced by prevention of catalyst deactivation and
poisoning. Due to the already excellent conversion at 10 mol%
catalyst, the catalyst loading was reduced to 2 mol% for 1 h for
these studies (table 1, entry 8). DMAP (table 1, entry 9) exhibited
increased total conversion over the control reaction, however, the
use of pyridine based ligands (see supporting information)
resulted in reduced regioselectivity and 2-phenylthiirane
formation, consistent with the observed reactivity with the use of
RuCl2(phen)3•H2O. Bi-dentate ligands (table 1, entries 10, 11)
gave no enhancement of reactivity, or proved detrimental to both
conversion and regioselectivity, whereas mono-dentate ligands
accessible through commercially available alkenes via
a
dihydroxylation strategy or Grignard addition to hydroxyacetone),
and by treatment of the 1,2-diols with thiophosgene (see
supporting information). Electron-rich and electron-deficient aryl
secondary 1,3-dioxolane-2-thiones (table 2) were subjected to the
reaction conditions, and the system proved tolerant of a number
of functionalities resulting in good conversions and high
regioselectivity.
Although substrates demonstrated high conversion in all
cases, isolated yields were significantly lower due to the poor UV
visibility and staining with TLC indicators. Despite the inclusion of
an aryl bromide in the reaction, no proto-dehalogenation was
observed in the case of the para-bromo substituted substrate (2c),
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10.1002/ejoc.201701181
European Journal of Organic Chemistry
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however erosion of regioselectivity was observed. The reaction
was also tolerant of cinnamyl ester derivative, giving the single
regioisomer 2e. Interestingly, this is the opposite selectivity than
the rearrangement reported by Ko with the use of catalytic
bromide.[11] Additionally, only a single pair of diastereomers was
isolated, with no evidence of racemization of the benzylic position
in crude 1H NMR spectroscopy.
In this more highly substituted system (table 3), neither yield
nor regioselectivity significantly fluctuated with electronics, as
both electron-donating and electron-withdrawing substituents
were well tolerated. In the case of the secondary substrates (table
2), increasing electron-withdrawing character resulted in lower
isolated yields. We believe mechanistic parallels can be drawn
between this and our previous work,[5] with the transformation
occurring through a possible radical pathway, however the
possibility of an ionic intermediate has not been ruled out. As we
did not observe any erosion of stereochemical information in 2e,
it is likely that the reaction does not proceed via a planar
intermediate, or that any planar intermediate formed is short-lived.
Upon the introduction of any non-benzylic substituents (2f,
2g), the reaction proved unviable, where high levels of
desulfurization were witnessed, but no conversion to desired
product.
Table 3. Synthesis of tertiary 1,3-oxothiolane-2-ones[a]
Figure 2. Crystal structure of 4e CCDC 1557205 (ellipsoids drawn at the 50%
level)
Conclusions
We have developed a novel catalytic rearrangement
procedure towards the installation of benzylic thiols. The reaction
utilizes substrates derived from ubiquitous 1,2-diols in an atom
economical intramolecular rearrangement, catalysed by an
inexpensive and simple catalyst-ligand system. This process
exhibits highly predictable regioselectivity, with excellent retention
of stereochemical information to form secondary and tertiary
masked thiol building blocks, 1,3-oxathiolane-2-ones, which could
prove to be versatile intermediates in the synthesis of a number
of sulfur containing molecules.
[a] Reaction conditions: 1 (1 mmol), Pd(PPh3)4 (0.1 mmol), PPh3 (0.2 mmol) in
toluene (5 mL) under argon at 120 °C for 20 h. Isolated yields.
Tertiary 4-methyl-4-aryl-1,3-dioxolane-2-thiones (Table 3)
were also investigated. The observed reactivity was significantly
slower under the standard reaction conditions, however elevating
the temperature and extending the reaction time (120 °C, 20 h)
proved sufficient in improving conversion. The use of tertiary
substrates also resulted in the formation of the more highly
substituted regioisomer in all cases, and their identity was
confirmed absolutely through the crystal structure of 4e (Figure
2). High conversions were observed, however the prolonged
reaction times, and hence exposure to sub-stoichiometric
quantities of phosphine, led to competitive Corey-Winters
olefination, as indicated by the presence of styrene derivatives by
crude 1H NMR spectroscopy. Two particularly interesting
examples were ortho-methoxy (4h) and naphthyl (4i) derivatives,
as the congestion around the quaternary center gives no apparent
reduction in reactivity and allows highly substituted sulfur
compounds to be synthesized.
Experimental Section
General Procedure: Pd(PPh3)4 (0.1 mmol) and PPh3 (0.2 mmol)
was charged into an oven-dried carousel tube, sealed and the
contents of the reaction vessel were purged with argon, before a
solution of 1,3-dioxolane-2-thione (1.0 mmol) in dry, degassed
toluene (5 mL) was added via septum. The solution was heated
to 100 oC for 3 h (or 120 °C for 20 h). After this time the reaction
was cooled to room temperature and concentrated under reduced
pressure. The crude material was purified via flash silica gel
chromatography.
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Acknowledgements
[11] S. Y. Ko, J. Org. Chem. 1995, 60, 6250.
We are grateful to the University of Bath (S.C-H), and University
of Bath CSCT for funding (W.M).
Keywords: alkyl migrations • thiocarbonates • homogeneous
catalysis • Newman-Kwart
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
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Catalytic O,S rearrangements
William Mahy, Sinead Cabezas-Hayes,
Gabriele Kociok-Köhn, Christopher G.
Frost*
Page No. – Page No.
Text for Table of Contents
Title
This work describes an operationally simple synthesis of cyclic S-thiocarbonates with predictable
regioselectivity in good yields. A crystal structure has clearly confirmed the regioselectivity of the
reaction.
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