A Protocol to Transform Sulfones into Nitrones and Aldehydes

Article abstract of DOI:10.1021/acs.orglett.8b02483

A simple method to transform sulfones into nitrones and therefore into the corresponding carbonyl derivatives has been developed. Some examples demonstrate that it is a new reliable and versatile reaction in the toolbox of sulfones that has great synthetic potential. NMR and computational studies were used to elucidate the mechanism.

Full text of DOI:10.1021/acs.orglett.8b02483

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
A Protocol To Transform Sulfones into Nitrones and Aldehydes
́
́
Eduardo Rodrigo, Ines Alonso, and M. Belen Cid*
́
Department of Organic Chemistry, Universidad Autonoma de Madrid, Cantoblanco 28049, Madrid, Spain
́
Institute for Advanced Research in Chemical Sciences (IAdChem), Universidad Autonoma de Madrid, Madrid 28049, Spain
S
* Supporting Information
ABSTRACT: A simple method to transform sulfones into
nitrones and therefore into the corresponding carbonyl
derivatives has been developed. Some examples demonstrate
that it is a new reliable and versatile reaction in the toolbox of
sulfones that has great synthetic potential. NMR and
computational studies were used to elucidate the mechanism.
Scheme 1. Initial Hypothesis of Work
ulfones are very useful functional groups, not only from a
1
Ssynthetic point of view but also due to their biological
activity2 and their utility in bioconjugation and immobiliza-
tion.3 Thanks to its electron-withdrawing ability, the sulfone
moiety allows the formation of α-sulfonyl carbanions, which
are versatile nucleophiles,1 as well as the activation of double
bonds providing very powerful electrophiles, dienophiles, or
dipolarophiles.4 The most common transformations of alkyl
arylsulfones carbanions are alkylations, reactions with
aldehydes to undergo traditional Julia olefination in two
steps,5 reductive desulfonylation or β-elimination to give
olefins.6 A very useful transformation but with severe
limitations and far from being general is the conversion of
sulfones into a carbonyl moiety via oxidative desulfonylation
(see below). This fact is in contrast to other electron-
withdrawing groups such as the nitro group, which can be
transformed straightforwardly into carbonyl moieties (Nef
reaction).7 Therefore, it would be highly desirable to develop a
robust and reliable protocol for this transformation.
primary alkyl phenyl sulfones into carboxylic acids under an
oxygen atmosphere.
All the approaches to accomplish oxidative desulfonylation
of alkyl arylsulfones are based on the idea of introducing an
oxygen (or a nitrogen) atom at the α-position that pushes out
the sulfonyl group to generate the carbonyl (or imine) moiety
(Scheme 1a). One of the limitations relies on the used
reactants, which are toxic, expensive, or explosive. Some of
them are MoOPH (MoO5 Py, HMPA), a strong and expensive
oxidant,8 or difficult to prepare and explosive like bis-
(trimethylsilyl)peroxide.9 Other safer peroxides such as tert-
butyl trimethylsilyl peroxide (TBTSP)10 have also been
employed. For particular examples, Ni(II) complexes in the
presence of oxygen11 and oxaziridines as a source of
electrophilic nitrogen to form an imine12 have also been
used. Another described process implied several steps such as
transformation of the preformed sulfonyl carbanion into a
boronate ester and subsequent oxidation with m-CPBA to
afford the carbonyl moiety.13 More recently, the group of
Murphree14 published a method for the transformation of
Heteroaryl alkyl sulfones are particularly interesting and
deserve special mention because they are able to undergo
Julia−Kocienski olefination15 affording double bonds in a one-
pot process (Scheme 1b) and their electron-withdrawing
properties provide high electrophilicity to double bonds.16
However, it is important to note that, apart from the Julia−
Kocienski olefination, some of the classical transformations for
alkyl aryl sulfones have been scarcely studied with heteroaryl
sulfones.17
Looking into the assumed mechanism of the Julia−
Kocienski olefination that uses carbonyl compounds as
electrophiles (C=O bond) and where SO2 and the heterocycle
are removed from the initial sulfone (Scheme 1b), we
hypothesized that the analogous reaction with a nitroso
derivative (N=O bond) could follow the same pathway
Received: August 3, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02483
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Letter
(Scheme 1c). This could be a potential method for the
formation of imines, which could be later hydrolyzed to give
the desired carbonyl moiety.
Table 1. Optimization of the Formation of the Nitrone
With the objective of developing a new useful and reliable
transformation of heteroaryl sulfones, we performed the first
experiments using sulfone 1a and 2-methyl-2-nitrosopropane
under the typical Julia−Kocienski conditions. Nevertheless, we
did not observe the imine, but the nitrone 2a was isolated in
50% yield after purification (Scheme 2).
conv
(%)
yield
(%)
entry
R
solvent
base (equiv)
time
5 h
2 h
1
2
3
4
5
6
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
THF
DMF
Cs2CO3 (2)
Cs2CO3 (2)
>95
>95
>95
8
−
>95
50
63
41
n.d.
−
CH3CN Cs2CO3 (2)
toluene
DMF
6 h
Scheme 2. Reaction of Heteroaryl Sulfone 1a with t-BuNO
Cs2CO3 (2)
DBU (1.2)
LiHMDS
(1.2)
20 h
20 h
0.5 h
DMF
67
7
8
9
Ph
Ph
Ph
DMF
DMF
DMF
Cs2CO3 (2)
Cs2CO3 (2)
LiHMDS
(1.2)
0.5 h
1 h
10 min
>95
>95
>95
81
62
62
a
Therefore, in spite of the presence of the strongly
electrophilic center at the heterocycle, the reaction did not
follow the Julia−Kocienski type mechanism. At this point, we
performed a basic DFT calculation that interestingly indicated
that the formation of the imine was thermodynamically more
favored than that of the nitrone.18 Moreover, a thorough
search in the literature led us to a particular analogue
transformation in which nitrosobenzene reacted with the
carbanion of a fluorenyl phenyl sulfone to provide the
corresponding nitrone.19 Despite the great potential of this
transformation, the only precedent seemed to be restricted to a
particular type of sulfones and had a very limited synthetic
impact. Similar reactions of nitroso derivatives using other
groups able to stabilize anions and acting as leaving groups
such as pyridinium salts, sulfur ylides, or silanes have also been
described.20 The result of Scheme 2 altered our expectations,
but opened up a new pathway to develop a general oxidative
desulfonylation method and an alternative approach to prepare
nitrones, versatile intermediates in synthesis,21 and attractive
therapeutic agents22 due to its free radical trapping properties
that reduce damage in biological systems.23
a
Employing 1.1 equiv of nitrosobenzene.
also be obtained in a one-pot process from sulfone 1a in 78%
yield (Scheme 3).
Scheme 3. One-Pot Transformation to the Corresponding
Aldehyde
We extended the study of the reaction to different sulfones
containing both aryl and heteroaryl substituents (Scheme 4).
First, we tested several heterocycles such as BT, TBT, and Py
(compounds 1b−d), which afforded good yields in all cases,
especially in the case of sulfone 1b with the BT heterocycle
(88% yield). The fact that pyridine undergoes this reaction is
an important point as it has been used as a directing group in
many interesting transformations.24 Aromatic sulfones (1e−f)
For this reason, we decided to optimize the reaction, extend
it to other types of sulfones, determine the scope of the
transformation, and study the mechanism by NMR experi-
ments and DFT calculations. First, using sulfone 1a as a model,
we performed a screening of solvents, bases, and nitroso
derivatives (Table 1).
Scheme 4. Scope of Sulfones and Benzylic Substituents
Using 2 equiv of 2-methyl-2-nitrosopropane, the reaction
proceeded well in polar solvents such as THF, CH3CN, or
DMF (entries 1−3). Nonpolar solvents such as toluene led to
very low conversion (entry 4). DMF proved to be the best
solvent in terms of both yield and reaction rate, affording
nitrone 2a in 63% yield after 2 h (entry 2). The use of DBU
afforded a complex reaction mixture (entry 5). LiHMDS, a
common base to form the anion in the Julia−Kocienski
olefination, was also used under Barbier-type conditions to
afford the final nitrone in similar yield to the one obtained with
Cs2CO3 (entries 6 and 2). Nitrosobenzene yielded nitrone 3a
in higher yield after 0.5 h (81%, entry 7). A reduction in the
amount of nitroso compound from 2 to 1.1 equiv led to a
decrease of the reaction rate and yield (entry 8), and the use of
LiHMDS (entry 9) did not appear to be as effective as
Cs2CO3.
The hydrolysis of nitrone 3 using HCl at 50 °C for 1 h
provided p-bromobenzaldehyde 4a in 95% yield, which could
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also undergo the process, although the yields of the aldehyde
were slightly lower (71−74%). A CF3 substituent (1g) turned
out to be an outstanding substrate for this reaction, likely due
to its excellent properties as a leaving group. The reaction was
not only general to any class of sulfone but also independent
from the nature of the aromatic or heteroaromatic ring and the
electronic features of its substituents (1h−n). Although we
performed the one-pot process to obtain the aldehydes, the
isolation of the intermediate nitrone would be possible.
The more interesting and challenging reaction with alkyl
sulfones required further optimization. The treatment of
sulfone 5a (R = PT) with nitrosobenzene and Cs2CO3 in
DMF as solvent (the best conditions found for benzylic
compounds, entry 7, Table 1) led to a complex reaction
mixture probably due to the lower acidity of the α-proton and
the lower stability of the aliphatic nitrones as compared with
the aromatic ones. Therefore, a new study of the substituents
of the sulfone and nitroso derivative, base, counterion, solvent,
and temperature had to be performed.25
After considerable experimentation, we could obtain nitrone
6 by performing the reaction at lower temperature, using a
higher excess of t-BuNO instead of PhNO, and employing
stronger bases such as amidures and potassium as a counterion.
Although it was possible to isolate the aliphatic nitrone 6, it
could not be purified using silica gel due to decomposition.
Therefore, it was directly transformed into the aldehyde 7,
which was obtained in moderate yield, by treatment with acidic
media. Once the reaction had been optimized, we tried
different sulfones 5a−c. In this case, sulfone 5c (R = CF3)
yielded slightly better results (Scheme 5), while aromatic
sulfones (p-Tol) provided poor yields.
representative substrates (Scheme 7). The highly electrophilic
heteroaryl vinyl sulfone 9 and sulfone 5g had been previously
Scheme 7. Illustration of the Usefulness of the
Transformation
described by us in the context of the enantioselective
organocatalytic Michael addition via enamine activation.16d
The epoxy sulfone 5h has been recently prepared by Baran17a
by addition to the same sulfone 916f,17 of the corresponding
radical formed from the olefin moiety of limonene 1,2-epoxide.
Both PT-sulfones 5g−h could be transformed into the
corresponding nitrones and carbonyl compounds. Then,
using this protocol the heteroaryl vinyl sulfone 9 can be
considered a versatile synthetic equivalent of an α-electrophilic
acetaldehyde.
The reaction also worked with secondary dibenzylic
heteroarylsulfones. Using nitrosobenzene under the conditions
that we optimized for the benzylic substituent (Scheme 4),
sulfone 10a was transformed into the nitrone 11a in 89% yield
after 2 h. The reaction was also possible for different
diaromatic nitrones (Scheme 8). Interestingly, the reaction
Scheme 5. Reaction of Alkyl Aryl Sulfones with t-BuNO
Scheme 8. Preparation of Diarylnitrones
We proved that these conditions could be used in the
presence of representative functional groups such as imides,
esters, or ethers to provide the aldehydes 8d−f (Scheme 6).
Scheme 6. Scope of Aliphatic Substituents
using 2-methyl-2-nitrosopropane as an electrophile directly
afforded the corresponding ketones.25 When we tried to
expand the scope of this reaction to secondary alkyl heteroaryl
sulfones, we found some unexpected results and a mixture of
different products.25
At this point, we decided to study the mechanism of the
developed transformation. Based on a previous computational
study of the Julia−Kocienski reaction,26 we tried to optimize
the structure of the possible addition products between the
model anion I and t-BuNO.25 However, all attempts to localize
these adducts were unsuccessful, and nitrone was usually
observed regardless of the initial conformation or basis set used
in the calculation. Thus, we decided to search for the
corresponding transition states. In this case, we considered
several relative approaches between the nucleophile and the
electrophile (Si−Re, Si−Si, Re−Re, and Re−Si respectively).
Nevertheless, the reaction with allylic substituents led to
complex mixtures. Although the intrinsic instability of aliphatic
nitrones prevents their purification, their isolation was possible
in all the cases.
To demonstrate the synthetic potential of this trans-
formation, we performed the reaction with 5g and 5h as
C
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The energy profile for this addition step from the starting
model structures, considering the most stable transition state
Si−Re, is shown in Figure 1. For comparative purposes, we also
studied the equivalent transition state27 and product for the
reaction with pivalaldehyde, for which the usual reactivity
should be expected.
obtained, and oxaziridine 12 was recovered unaltered without
observing nitrone 13. When we monitored the reaction by
NMR we did not detect any intermediate which, along with
DFT calculations, suggests a concerted mechanism.25
In conclusion, we have developed a general and straightfor-
ward protocol to transform sulfones into nitrones, and
therefore carbonyl compounds, through reaction of the
corresponding α-sulfonyl carbanions with nitroso derivatives.
The great potential of the method was proved with some
transformations that were difficult to perform in a different
way. Since no experimental or theoretical intermediates have
been observed, this very favorable and direct process seems to
take place in a concerted fashion from the reaction of the
starting materials.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02483.
Figure 1. Comparative free energy profile for the addition step
between anion I and t-BuNO or t-BuCHO. Optimized structures in
THF (wB97xd/TZVP, CPCM model). Relative G values at 298 K
(kcal·mol−1). Relevant distances in TS (Å) are also indicated.
Full experimental procedures, spectroscopic character-
izations, computational data, and NMR spectra (PDF)
AUTHOR INFORMATION
According to the results collected in Figure 1, the energy
barrier to overcome for the reaction to take place would be
similar for both electrophiles, nitroso or aldehyde derivatives.
The IRC analysis starting from TSSi−ReCHO confirmed this
geometry for the transition state of the conversion of the
starting structures into the adduct intermediate III. Never-
theless, from TSSi−ReNO, it was not possible to localize any
intermediate, as nitrone was directly formed. According to
their structures, TSSi−ReCHO is an earlier transition state, with
a longer distance for the bond being formed for C1−C3. By
contrast, in the case of TSSi−ReNO the new bond is shorter and
the C1−S bond, which is going to be broken in the final
product, is slightly longer. The NBO analysis indicates that the
origin of the different evolution of these TSs could be related
to the different electronic features of the electrophile.28
Additionally, a slightly shortened C1−C2 distance is observed
in the latter case because of an increase of conjugation, which
completely agrees with the shape of the HOMO orbital.25
According to the literature, an oxaziridine intermediate
could be operative.19 Scheme 9 shows the two possible
■
Corresponding Author
*E-mail: belen.cid@uam.es.
ORCID
́
M. Belen Cid: 0000-0001-7713-3715
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the Spanish Government (CTQ-2012-35957,
CTQ2016-78779-R) for financial support, Dr. A. Garcıa-
Rubia (Centro de Investigaciones Biologicas (CSIC), Madrid,
■
́
́
Spain) for the preparation of some starting materials, and Dr. J.
́ ́ ́
L. Acena (Departamento de Quımica Organica y Quımica
̃
́
́
Inorganica, Facultad de Farmacia, Universidad de Alcala,
́
Alcala de Henares, 28871 Madrid, Spain) for useful
́
discussions. We also thank the Centro de Computacion
́
Cientıfica (UAM) for generous allocation of computer time.
REFERENCES
■
Scheme 9. Nitrone Formation in the Presence of an
Oxaziridine
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E
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