Consecutive C1-Homologation / Displacement Strategy for Converting Thiosulfonates into O,S-Oxothioacetals

Article abstract of DOI:10.1002/adsc.202000919

A conceptually intuitive synthesis of oxothioacetals is reported starting from thiosulfonates as electrophilic sulfur donors. The installation of a reactive CH₂Cl motif with a homologating carbenoid reagent, followed by the immediate nucleophilic displacement with alcoholic groups [(hetero)-aromatic, aliphatic] offer a convenient access to the title compounds. Genuine chemoselectivity is uniformly observed in the case of multi-functionalized systems. (Figure presented.).

Full text of DOI:10.1002/adsc.202000919

Title: Consecutive C1-Homologation / Displacement Strategy for
Converting Thiosulfonates into O,S-Oxothioacetals
Authors: Laura Ielo, Veronica Pillari, Margherita Miele, Wolfgang
Holzer, and Vittorio Pace
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10.1002/adsc.202000919
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Consecutive C1-Homologation / Displacement Strategy for
Converting Thiosulfonates into O,S-Oxothioacetals
Laura Ielo,a Veronica Pillari,a Margherita Miele,a Wolfgang Holzera and Vittorio Pacea,b*
a
University of Vienna, Department of Pharmaceutical Chemistry, Althanstrasse 14 – 1090 Vienna (Austria). Tel. +43-1-
4277-55035. http://drugsynthesis.univie.ac.at/ - e-mail: vittorio.pace@univie.ac.at
University of Turin, Department of Chemistry, Via P. Giuria 7 – 10125 Turin (Italy) – e-mail; vittorio.pace@unito.it
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
the pure homologation leading through an internal
displacement of the X element - carried out with
Abstract.
A
conceptually intuitive synthesis of
oxothioacetals is reported starting from thiosulfonates as
electrophilic sulfur donors. The installation of a reactive an internal nucleophilic species (e.g. Nuint) – to the
CH2Cl motif with a homologating carbenoid reagent,
followed by the immediate nucleophilic displacement with
alcoholic groups [(hetero)-aromatic, aliphatic] offer a
convenient access to the title compounds. Genuine
chemoselectivity is uniformly observed in the case of multi-
functionalized systems.
homologue, as illustrated by the (aza)-carbonyl
homologation to aziridines and epoxides[7] or by
the elegant Matteson-type boronic esters
homologation.[8] Motivated by the interest towards
such chemistry, we designed selective processes
characterized by the triggering of molecular
rearrangements once the initial homologation was
accomplished, e.g. fully α-substituted aldehydes
from vinyl ketones[9] or, aziridines via telescoped
homologations of TFAICs.[10] To the best of our
knowledge, classical manifolds for conducting the
C1-insertions have been restricted to X-Y systems
(X, Y = carbon-carbon, carbon-heteroatom,
heteroatom 1 – heteroatom 2)[11] whereas,
analogous operations on homo-dimeric materials
(X-X, X = heteroatom) are much less developed.
In this context, in 2016 we reported a direct
procedure for converting disulfides and
diselenides into symmetrical dithioacetals and
diselenoacetals, respectively (Scheme 1c).[12] This
transformation, regarded as elusive for decades,[13]
was successfully conducted with the highly
nucleophilic LiCH2Br, which by attacking the di-
chalcogen link furnished an intermediate α-halo
thio- or seleno-ether.[12] The subsequent internal
nucleophilic displacement – with the anion
released during the homologation (RS- or RSe-) –
yielded the final homologated products. We
wondered if an externally added (second) oxygen-
centered nucleophile could be analogously
employed and thus, diversifying the strategy for a
modular synthesis of oxothioacetal (Scheme 1d).
The following critical points had to be properly
addressed during the protocol design: 1) to be
Keywords: Homologation; Carbenoids; Oxothioacetals;
Sequential processes; Sulfur.
Introduction
Homologation chemistry represents a valid tactic
for selectively introducing a methylene group (-
CH2) into a given array.[1] This operation
underpins significant modifications of the organic
skeleton, thus modulating important physical-
chemical parameters such as the lipophilicity and
the overall chemical reactivity, inter alia.[2]
Ideally, the homologation event would precisely
deliver the methylene fragment between a
preformed R-Y linkage (Scheme 1a). Among the
plethora of reagents developed to this end (e.g.
diazomethane, ylides),[3] carbenoid reagents
constitute important players for the release of the
methylene under tuneable nucleophilic or
electrophilic regime governed (mainly) by the
nature of the metal.[4] Two main – intimately
connected (Scheme 1b) - mechanistic pathways
can be devised for the reaction of a metal
carbenoid (e.g. LiCH2X – usually nucleophilic)
with an electrophilic manifold (R-Y):[5] i) the
interrupted homologation in which upon forming
the new
R-CH2X bond, the X defining element
productive, the expulsed leaving group (
Y
) on the
remains constitutively in the final scaffold;[6] ii)
1
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10.1002/adsc.202000919
Advanced Synthesis & Catalysis
sulfur electrophile should manifest (almost) no
°C or increasing up to 0 °C resulted in no reactivity
nucleophilic behaviour to ensure no competitive (entries 5-6). In order to tame the nucleophilicity
phenomena with the external nucleophile; 2) the of the Y leaving group, as well as, to enhance the
same
Y
group should impart a strong electrophilic
sulfur electrophilicity, we focused on different
behaviour to the RS- platform to ensure the attack sulfenylating agents fulfilling these requirements.
of the nucleophilic carbenoid; 3) the oxygen-type Accordingly, chloro-, cyano-phenylsulfide and N-
reagent used for activating the displacement phenylthiophtalimide (entries 7-9) were effective
should be compatible with the adopted lithiating in suppressing the formation of the symmetrical
conditions, ideally ensuring wide flexibility of the
substituents incorporated on the alcoholic partner.
dithioacetal 2a, though chemical yields did not
exceed 55% even in the presence of significant
loadings of both carbenoid and second nucleophile
(entry 10). Collectively, these initial experiements
suggested that taming the nucleophilicity of the Y
group had to be adequately complemented by a
strong sulfur electrophilicity enhancing element.
Thus, we turned our attention towards a S-
thiosulfonate ester[15] which, pleasingly under the
homologation /displacement conditions was
transformed into the desired compound
2 in 78%
isolated yield and excellent selectivity (entry 11).
Moreover, the Finkelstein reaction with the phenol
benefited from the addition of catalytic amount of
NaI (0.1 equiv), thus delivering
yield (entry 12). From
2
a
in a 86% isolated
practical and
environmental perspective the use of the S-
thiosulfonate is attractive because of the good
manipulability and the avoiding of common
drawbacks affecting sulfurating chemicals (odor,
toxicity, instability).[16] It should be noted that the
overall process was positively influenced by the
basic conditions – due to the organolithium – of
the mixture: by quenching the reaction with
stoichiometric HCl (1N) after realizing the
homologation and, then adding the phenol, the full
recovery of the α-halothioether 1a was obtained
(entry 13).
Scheme 1. General context of the presented work.
Results and Discussion
As the model substrates we selected diphenyl
disulfide (Y = SPh) and the ester substituted
phenol 1b as the attacking nucleophile to gather
initial information on the chemoselectivity. This
was motivated by the innate reactivity of
carbenoids towards carboxylic derivatives which
may result in poor chemocontrol (Table 1).[7b, 14]
Introducing the C1 unit in the form of LiCH2Br
leaded to almost exclusive formation of the
dithioacetal 2a, probably because of the higher
nucleophilicity of the released mercapto anion
compared to the EWG-substituted phenol (entry
1). No improvement was noticed when LiCH2I –
affording a more reactive methylene-iodide bond
– was used (entry 2), while a detectable amount of
the desired product
2 was formed in the presence
of LiCH2Cl (entry 3). By solubilizing 1b in a polar
solvent such as DMF prior to the addition to the
homologation mixture benefited the reaction,
providing a detectable amount of the desired
product
2 (entry 4). Raising the temperature from
-78 °C to rt was pivotal for activating the
phenoxide attack, since keeping the mixture at -78
2
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10.1002/adsc.202000919
Advanced Synthesis & Catalysis
Table 1. Reaction optimization.a)
state is fully compatible with the methodology, as
indicated by the somehow reluctant (to
organolithium carbenoids)[17] nitro compound
9.
With much of our delight, o-aminophenol was
exclusively alkylated at the oxygen, thus leaving
untouched the per se nucleophilic amino group
Entry
Y group
LiCH2X
Solv. a
Ratio
2/2ab
Yield
of
(X,
equiv)
Homologation
Nu
Substitution
(10). 2-Naphtol- (12) and the sterically demanding
2
(%)c
2,6-diphenylphenol- (13) derivatives additionally
illustrates the versatility of the method. Moreover,
the installation of a sensitive element such as a
terminal olefin – a cyclopropane manifold[18] – is
tolerated (14). The different acidity between a
phenol and a benzylic alcohol enabled to
selectively functionalize the aromatic alcohol, thus
preparing the hydroxymethyl-containing scaffold
15. The protocol was flexible to prepare S-alkyl
1
2
PhS
PhS
(Br, 1.8)
(I, 1.8)
THF
THF
>1:99
>1:99
7:93
-
-
3
PhS
(Cl, 1.8)
(Cl, 1.8)
(Cl, 1.8)
(Cl, 1.8)
(Cl, 1.8)
(Cl, 1.8)
(Cl, 1.8)
(Cl, 2.8)
(Cl, 1.8)
(Cl, 1.8)
(Cl, 1.8)
THF
4
7
-
4
PhS
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
11:88
1:99
5d
6e
7
PhS
type
oxothioacetals
starting
from
the
PhS
2:98
-
corresponding thiosulfonates. With comparable
efficiency we could synthesize under full
Cl
>99:1 25
>99:1 39
>99:1 48
>99:1 55
>99:1 78
>99:1 86
chemocontrol
aforementioned sensitive functionalities on the
aromatic nucleus such as bromo (16), chloro (17
18) and even the highly reactive iodo compound
analogues
embodying
the
8
CN
-
9
PhN-Phth
PhN-Phth
SO2Ph
SO2Ph
SO2Ph
(
(
19). Polyaromatic (20) or encumbered systems
21 efficiently promoted the nucleophilic
10f
11
12g
13h
)
substitution upon completion of the homologation.
In analogy to aromatic thiosulfonates, carboxylic
(22), carbonyl (23) and alkenyl (24) oxothioacetals
were assembled without compromising the
chemical integrity of these reactive handles. The
chemoselectively profile was further maintained
when a nitrile-substituted phenol was used (11):
this is particularly interesting because of the well-
established chemistry dealing with the addition of
carbanion-like reagents to the CN group en route
-
-
Carbenoids were formed in Barbier-type conditions using a dihalomethane (2.0 equiv)
as precursors: i.e. ICH2Br (LiCH2Br), ICH2I (LiCH2I), ICH2Cl (LiCH2Cl)
–
respectively - and MeLi-LiBr (Et2O solution 1.5 M, 1.8 equiv) in THF at -78 °C.
a Otherwise stated after the addition of the phenol (1.3 equiv) at -78 °C, the cooling
b
bath was removed and the mixture was allowed to reach rt. The ratio has been
calculated by 1H-NMR analysis using 1,3,5-trimethylbenzene as an internal standard.
c Isolated yield. d Reaction kept at -78 °C for 12 h. e Reaction kept at 0 °C for 8 h after
f
the addition of the nucleophile and removing of the cooling bath. 4-EtCO2C6H4OH
to ketones.[19] Notably, also
thiosulfonate smoothly underwent the sequential
homologation/displacement giving 25
a
benzylic
(3.0 equiv) were used. g NaI (0.1 equiv) was added. h 1a was obtained in 89% isolated
yield.
.
With the optimized condition in hand, we then
studied the scope of the reaction (Scheme 2). The
high chemocontrol of the sequential process was
not only evident in the case of an ester-substituted
phenol (
(towards carbenoids) ketone-substituted system
) presenting the benzoyl group in the phenol
2) but, also in the case of a more reactive
(3
ortho position. The X-ray analysis of this
derivative gave useful structural information on
the oxothioacetal motif. The O1-C1 bond (1.421
Å) is significantly shorter than the S1-C1 bond
(1.819 Å), whereas the distance between the
heteroatoms (O1-S1) is 2.736 Å and the dihedral
angle S1-C1 O1-C1 is 114.68 °. The presence of
potentially exchangeable halogen on the core of
the phenol did not minimally affect the
transformation, as evidenced in the cases of bromo
(4
) or chloro (
5-8) derivatives. The employment of
nitrogen-substituted phenol at different oxidation
3
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10.1002/adsc.202000919
Advanced Synthesis & Catalysis
accessed. As showcased by the challenging poly-
nitrogenated requested for synthesizing the
pyrimidinyl- (28) and the 1,3,4-thiodiazolyl- (29
)
analogues, no alkylating effect was displayed by
chloroiodomethane, thus allowing the correct
genesis of the carbenoid.
Scheme 3. Thiosulfonate homologation / nucleophilic
displacement with aliphatic alcohol derivatives.
Finally, selective manipulations on particular
synthesized skeletons were realized for briefly
screening their reactivity profile (Scheme 4). The
iodo-substituted derivative 18 underwent a smooth
I/SH interchange under Chae’s Cu-catalyzed
conditions[20] with 1,2-ethanedithiol as the mercapto
source, yielding the oxothioacetal 32 presenting a free
thiol group (path a). The selective deprotonation of the
oxothioacetal methylene of 30 with n-BuLi furnished
an intermediate oxo-thio geminal lithium anion which
was intercepted with a Weinreb amide en route to a
mixed oxo-thio ketone 33, thus complementing our
previous achievements on the synthesis of α-
substituted ketones (path b).[6h, 21] Finally, we were
pleased in using a bis-disulfide-containing diphenol as
the displacing alcohol for the tandem protocol: upon
completing the carbenoid homologation, the
nucleophilic substitution could be executed on only
one of the phenolic groups with full retention of the
labile S-S bond (34 – path c).
Scheme 2. Scope of the thiosulfonate homologation /
nucleophilic displacement with aromatic alcohols.
To gain full advantage of the methodology the
employment of aliphatic alcohols was also studied
(Scheme 3). Based on the above seen evidence that
a benzylic alcohol (15) was not alkylated under the
reaction conditions, we found that by pre-treating
the hydroxyl-derivative with stoichiometric
Cs2CO3 in DMF at 0 °C – i.e. forming a caesium
alkoxide – enabled to address the shortcoming.
Thus, analogues 26 (from a ortho-substituted
benzylic
alcohol)
and
27
(from
3-
pyridinylmethanol) were easily prepared in high
yield. Similarly, upon the formation of caesium
methoxide,
oxothioacetals
a
series
28 30
of
O-methylated
(
-
)
could be smoothly
4
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10.1002/adsc.202000919
Advanced Synthesis & Catalysis
compounds were purified as reported below
through column chromatography.
The crystal structure of compound 3 is available at
http://www.ccdc.cam.ac.uk/conts/retrieving.html
with the CCDC code 2016779.
Acknowledgements
We thank the University of Vienna, the University of Turin
and Fondazione Ri.Med (Palermo, Italy) for generous support.
V. Pillari acknowledges the university of Vienna for a
Uni:docs doctoral fellowship. M. Miele is grateful to the
OEAD for a Blau grant. We thank A. Roller and N. Gajic for
X-ray analysis and D. Dobusch for HRMS data.
Scheme 4. Selective functionalizations of dithioacetals.
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thiosulfonate ester to asymmetric dithioacetals
The S-thiosulfonate ester (RSSO2R, 1.0 equiv) was
dissolved in dry THF under Argon and cooled
down to -78 °C. Chloroiodomethane (2.0 equiv)
was added and, after 5 min, MeLi-LiBr (2.2 M
solution in Et2O, 1.8 equiv) was added via syringe
pump (rate 0.2 mL/min) and then, the resulting
mixture was stirred for 1 h. After increasing the
temperature up to 0 °C, a solution of alcohol
(R1OH, 1.3 equiv) and NaI (0.1 equiv) in dry DMF
was added dropwise. Upon reaching room
temperature, the reaction mixture was further
stirred for 6 h and, subsequently was quenched
with aqueous saturated NH4Cl solution. The
resulting organic phase was extracted 3 times with
Et2O, washed with brine, dried over anhydrous
Na2SO4 and concentrated in vacuo. The crude
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10.1002/adsc.202000919
Advanced Synthesis & Catalysis
FULL PAPER
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Adv. Synth. Catal. Year, Volume, Page – Page
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