Bromomethyllithium-mediated chemoselective homologation of disulfides to dithioacetals

Article abstract of DOI:10.1039/c5cc10280d

An efficient, chemoselective homologation of disulfides and diselenides to the corresponding dithio- and diselenoacetals has been developed via the addition of bromomethyllithium. Chemoselectivity is fully preserved in the presence of concomitant electrophilic sites decorating the substrates. The synthetic potential of selected dithioacetals has been evaluated in Feringa-Fa?anas-Mastral-type Pd-catalyzed coupling with an organolithium and in the unusual 1,4-addition to a Weinreb amide.

Full text of DOI:10.1039/c5cc10280d

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Bromomethyllithium-Mediated Chemoselective
Homologation of Disulfides to Dithioacetals
Cite this: DOI: 10.1039/x0xx00000x
Vittorio Pace,a* Azzurra Pelosi,a,b Daniele Antermite,a Ornelio Rosati,b Massimo
Curinib and Wolfgang Holzera
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
of the halide with subsequent formation of valuable scaffolds such as
epoxydes14 or aziridines.9h,15
An efficient, chemoselective homologation of disulfides and
diselenides to the corresponding dithio- and diselenoacetals
has been developed via the addition of bromomethyllithium.
Chemoselectivity is fully preserved in the presence of
concomitant electrophilic sites decorating the substrates. The
synthetic potential of selected dithioacetals has been
evaluated in Feringa-Fañanas-Mastral-type Pd-catalyzed
coupling with an organolithium and in the unusual 1,4-
addition to a Weinreb amide.
Pioneering work by Field in the 1970s documented the insertion of
electrophilic zinc carbenoids into disulfides to access in low yields
dithioacetals.16 Analogous limited success was observed in the
reaction of (nucleophilic) sulfur ylides17 with disulfides, being the
desired homologated products only the minor components of
complex reaction mixtures.18 Interestingly, also diazomethane
proved to be not efficient for accomplishing the process, as deducted
by Schill.19 Taking into account these precedents, we wondered if
the increase of the nucleophilicity of the homologating reagent
would benefit the overall transformation. Additionally, at the outset
of our investigations we were cognizant of the good reactivity that
disulfides show in reactions with polar organometallic reagents.20
The concept of homologation plays a pivotal role across the
chemical sciences ranging from preparative to pharmaceutical
chemistry (e.g. the different biological activity reported
hexamethonium vs. decamethonium towards nicotinic receptors).1
From a synthetic perspective, homologation reactions constitute a
fundamental tool for elongating a given fragment through the formal
insertion of a constant unit usually represented by a methylene group
(CH2).2 Accordingly, two different tactics can be envisioned for the
homologation mechanism: a) the addition of a nucleophilic CH2 unit
- whose prototype may be considered the diazomethane-based
Arndt-Eistert reaction3 - and, b) the insertion of an electrophilic CH2
fragment simplified by Simmons-Smith cyclopropanation-type
processes.4 In this scenario, metal halocarbenoids – due to their
intrinsic ambiphilicity - are highly valuable reagents able to perform
homologations according both routes.5 The nature of the metal and
the temperature are key factors for establishing the reactivity profile
of the carbenoids.5a Thus, lithium5b,6 and magnesium7 carbenoids of
type MCH2Hal do manifest predominantly nucleophilic properties8
suitable to homologate a plethora of electrophiles encompassing
carbonyl-type derivatives,9 boron,10 zirconium,11 germanium or
silicon-containing12 substrates. On the other hand, in the case of zinc
carbenoids the electrophilic behavior is largely predominant.13
Noteworthy, in certain cases the simple and straightforward addition
of a carbanionic halomethyl unit may be followed by the expulsion
Scheme 1. Context of presented work.
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10b
2.5 (X = Br)c
2.5 (X = I)c
THF
THF
-
-
95
We reasoned that performing the disulfide homologation with a
LiCH2X species would provide the target scaffolds via the addition
of the nucleophilic halomethyl group followed by the halide
elimination. Herein, we present our investigations on the
11b
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DOI: 10.1039/C5CC10280D
LiCH2X were generated from ICH2Cl, ICH2Br or CH2I2 and MeLi-LiBr.
Reactions were quenched with NH4Cl (aq.). Yields refer to pure isolated
compounds.
homologation
of
disulfides
and
diselenides
with
bromomethyllithium to dithioacetals and diselenoacetals,
respectively.
a Reaction quenched after 2 h at -78 °C. b Reaction run 2 h at -78 °C followed
c
by additional stirring at rt for 1 hour and then quenched. TMSCl (2.0
equiv.) used an additive.
The model substrate diphenyl disulfide 1a was subjected to reaction
with LiCH2Cl according to our previously established conditions in
the case of carbon-electrophiles (Barbier-type generation, -78 °C, Once the optimal conditions had been established, we next focused
THF),9a-f resulting in full conversion of the starting material. The 1H-
on the scope of the method. The protocol resulted of wide
NMR of the crude indicated the presence of a mixture of two applicability as shown in Scheme 2. Thus, diaryl disulfides
presenting substituents with different electronic behavior provided
chloromethylphenylsulfide 2a. The displacement of the halogen (on the corresponding dithioacetals in high yields (3a-l), although in the
case of a strong EDG such as 4-methoxy, reaction resulted in lower
compounds:
the
desired
dithioacetal
3a
and
2a) by the thiophenoxyde anion proved to be the critical step of the
overall process: increasing the loading of chloro carbenoid up to 2.5 conversion. The presence of halogens – known to be easily
exchanged with organolithiums21 – did not interfere at all with the
equiv had a beneficial effect (entries 1- 7). Analogously, the solvent
polarity proved to be critical in order to maximize the rate of the process (3d-h). Of particular significance was the chemoselectivity
observed in the cases of ester 3i which did not compete with the
general theory of nucleophilic substitutions, a more polar medium disulfide for the attack of the carbenoid and, of a secondary amide
functionality (3j) – in which no deleterious effect was played by the
(entries 2-4). Allowing reaction to reach room temperature and acidic NH- proton.9f,22 Pleasingly, even the less reactive dibenzyl
halogen displacement by the thiophenoxyde: in agreement with the
such as THF gave better results compared to toluene or diethyl ether
disulfide or the asymmetric benzyl-phenyl one were homologated
continuing the stirring for additional 2 h, substantially increased the
with success, delivering structures 3k and 3l, respectively.
yield of 3a compared to 2a, thus indicating the displacement of the
halogen from 2a, takes place at a later stage of the reaction. Further Heteroaromatic disulfides were excellent substrates for the
transformation (3m-o). It is worth mentioning the dependence of
of TMSCl which presumably might facilitate the halogen reaction outcome’s from the position of nitrogen in pyridinyl-type
disulfides: the 2-pyridinyl analogue smoothly undergoes
bromomethyllithium (LiCH2Br) – which per se incorporates a better homologation furnishing dithioacetal 3o, while the regioisomer 4-
pyridinyl does not react at all. This behavior parallels a similar effect
obtained in an excellent 95% isolated yield (entry 10). Surprisingly, observed by Savoia and co-workers during studies on the
homologation of pyridine-nuclei containing imines, in which only
improvement was noticed by performing the reaction in the presence
displacement. When the homologation was realized with
leaving group than LiCH2Cl, the desired dithioacetal 3a was
by employing the even more reactive iodomethyllithium (LiCH2I,
entry 11) reaction did work equally but, along with dithioacetal 3a, the 2-pyridinyl systems – because of the possibility to coordinate
with the approaching carbenoid – were found amenable to react.23
various impurities were formed as judged by 1H-NMR thus,
indicating LiCH2Br as the best homologating agent.
Table 1. Reaction optimization.
Entry LiCH2X (equiv) Solvent Yield of 2a (%) Yield of 3a (%)
1a
2 a
3 a
4 a
5 a
6 a
7 a
8b
1.5 (X = Cl)
2.0 (X = Cl)
2.0 (X = Cl)
2.0 (X = Cl)
2.5 (X = Cl)
2.5 (X = Cl)
2.5 (X = Cl)
2.5 (X = Cl)
2.5 (X = Cl)c
THF
THF
53
61
72
59
68
74
47
26
12
28
33
14
10
21
31
48
67
78
Toluene
Et2O
THF
THF
THF
THF
9b
THF
2 | J. Name., 2012, 00, 1‐3
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DOI: 10.1039/C5CC10280D
Scheme 3. Exploration of the reactivity of dithioacetals in Pd-catalyzed
cross-coupling with RLi and in 1,4-addition to Weinreb amides.
By employing a different chalcogenide such as selenium, the
procedure could be extended to synthesize the corresponding
diselenoacetals (Scheme 4). As such, under the above established
optimized reaction conditions, compounds 7a and 7b could be
accessed analogously in high yields.
Scheme 2. Scope of the method.
Scheme 4. Homologation of diselenides to diselenoacetals.
Taking into account the versatility of the synthesized structures, we
evaluated their reactivity in unexplored routes dealing with the use
of organolithium methods (Scheme 3). In particular, the presence of
a reactive bromine in 3g opened up the field to evaluate the Pd-
catalyzed coupling of an aryl bromide-containing substrate with an
organolithium reagent (2-thienyllithium), elegantly reported by
Feringa-Fañanas-Mastral and co-workers in 2012 as an effective
method for generating C-C bonds with lithium carbanions.24 We
were delighted in observing the applicability of this robust method to
a dithioacetal, thus accessing the previously non-reported 2-
In conclusion, an efficient chemoselective access to dithioacetals and
diselenoacetals has been disclosed. Pivotal for the positive outcome
of the transformation was individuating the good nucleophilicity of
bromomethyllithium as the homologating agent. The protocol
showcases an excellent scope and chemoselectivity is fully
maintained in the presence of additional sensitive functionalities
towards organolithium such as aryl halides, heterocycles, ester and
amide. Importantly, the procedure could be employed for
homologating an asymmetric disulfide and diselenides. Of particular
significance is the use of bromo-containing diarylthiodiacetals in Pd-
catalyzed Feringa-Fañanas-Mastral cross couplings with an
organolithiums or the addition of the corresponding lithiated
dithioacetal in Michael fashion to a Weinreb amide.
thienylphenyl compound 4. On the other hand,
a lithiated
dithioacetal generated from deprotonation of 3 with n-BuLi reacted
through a 1,4-attack on the acryl-type Weinreb amide.25
Notes and references
a
University of Vienna - Department of Pharmaceutical Chemistry.
Althanstrasse, 14. A-1090, Vienna, Austria. *vittorio.pace@univie.ac.at
b University of Perugia – Department of Pharmaceutical Sciences. Via del
Liceo, 1. 06123 Perugia, Italy.
The University of Vienna is gratefully acknowledged for generous
support. One of the authors (A. P.) thanks the University of Perugia
(Italy) for a visiting professor grant.
Electronic Supplementary Information (ESI) available.
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