Nucleophilic Iododifluoromethylation of Carbonyl Compounds Using Difluoromethyl 2-Pyridyl Sulfone

Article abstract of DOI:10.1021/acs.orglett.6b01258

A new, efficient method for iododifluoromethylation of carbonyl compounds utilizing difluoromethyl 2-pyridyl sulfone (2-PySO₂CF₂H) is described. This transformation is achieved by a nucleophilic addition of 2-PySO₂CF₂

Full text of DOI:10.1021/acs.orglett.6b01258

Letter
pubs.acs.org/OrgLett
Nucleophilic Iododifluoromethylation of Carbonyl Compounds Using
Difluoromethyl 2‑Pyridyl Sulfone
Wenjun Miao, Chuanfa Ni, Yanchuan Zhao, and Jinbo Hu*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling
Road, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: A new, efficient method for iododifluoromethylation of carbonyl compounds utilizing difluoromethyl 2-pyridyl
sulfone (2-PySO2CF2H) is described. This transformation is achieved by a nucleophilic addition of 2-PySO2CF2H with carbonyl
compounds and a subsequent iodination of sulfinate, which is generated in situ by a novel zinc-mediated depyridination reaction.
The method employs mild reaction conditions, exhibits excellent functional-group tolerance, and can be used in the synthesis of
various iododifluoromethylated carbinols.
Scheme 1. Strategies for Preparation of
Iododifluoromethylated Carbinols
rganofluorine compounds play significant roles in the
1
Ofields of pharmaceuticals, agrochemicals, and materials.
It is well established that selective introduction of fluorinated
moieties into organic molecules can often lead to profound
effects on the lipophilicity and metabolic stability of organic
molecules compared to their nonfluorinated counterparts.2
Among various fluorine-containing fragments, the iododifluoro-
methyl group (−CF2I) is an intriguing structural motif with
great potential, which can be exploited for the synthesis of
various difluoromethylenated products,3 as well as candidates
for investigating halogen bonding used in crystal engineering.4
Consequently, these applications have stimulated researchers to
develop efficient methods for incorporation of the CF2I group
into organic molecules under mild conditions. Existing methods
for the synthesis of compounds with the CF2I group mainly
involve modifications of CF2I-containing substances5 or
iodination of the difluoromethylene-containing molecules.6
However, the synthesis of iododifluoromethylated carbinols is
less studied because they are still challenging to access.7
Furthermore, direct iododifluoromethylation of ketones with
Me3SiCF2X (X = I or Br) has not been achieved, probably as a
result of their lower electrophilicity. In our previous protocol, 2-
PySO2CF2H and carbonyl compounds condense in the
presence of a base to afford an adduct, which quickly undergoes
Smiles rearrangement, giving the difluoromethylene-containing
sulfinate.7,10 Iodo- and bromodifluoromethylated products were
obtained by halogenating the sulfinate intermediate, followed
by deprotection (Scheme 1a). Further investigation indicates
that the removal of the pyridinoxyl group proceeds through a
carbenium intermediate, and therefore, it is difficult to remove
the pyridioxyl group on the substrates bearing electron-
withdrawing substituents.11 Moreover, this method is not
compatible with the aliphatic system,11 where multiple reaction
In 2012, utilizing difluoromethyl 2-pyridyl sulfone (1, 2-
PySO2CF2H) as a nucleophilic fluoroalkylation reagent, our
group had achieved a formal nucleophilic iododifluoro-
methylation of carbonyl compounds via halogenation of the
Julia−Kocienski intermediates and subsequent deprotection
(Scheme 1a).7 Recently, Dilman and co-workers reported a
method for direct nucleophilic iododifluoromethylation of
aldehydes using Me3SiCF2X (X = I or Br), which is based on
the generation of a transient halodifluoromethyl carbanion from
difluorocarbene and a halide anion (Scheme 1b).8 Although the
products were obtained in excellent yields, the scope of this
method is limited to nonenolizable aldehydes. Enolizable
aldehydes are not suitable substrates because difluorocarbene,
generated from Me3SiCF2X (X = I or Br), readily undergoes a
[2 + 1] cycloaddition with the enol form of aldehydes.9
Received: April 29, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01258
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Letter
pathways from the carbenium ion intermediate, such as
rearrangement and elimination, are possible. We were also
aware that Smiles rearrangement is sensitive to the steric
hindrance of the substrate such that the formation of sulfinate
intermediate is not efficient with diaryl ketones.12 To address
these problems, we herein report a new approach to achieve
nucleophilic iododifluoromethylation of carbonyl compounds
with 2-PySO2CF2H (Scheme 1c). In this strategy, Smiles
rearrangement is avoided, and we have developed an efficient
zinc-mediated depyridination reaction for the preparation of
sulfinate intermediates.
In the nucleophilic addition reaction between 2-PySO2CF2H
and carbonyl compounds, it was found that the S−O Smiles
rearrangement of the alcoholate anions took place readily. We
speculated that the Smiles rearrangement could be hampered
by decreasing both the reaction temperature and the polarity of
the solvent. Our research commenced with the nucleophilic
addition of 2-PySO2CF2H 1 to carbonyl compounds 2,
according to the previous report.12 We modified the reaction
conditions, and the products 3 were obtained in good to
excellent yields (Scheme 2; for details, see Supporting
Table 1. Survey of Reaction Conditions for Synthesis of
Sulfinate 6 by Reductive Depyridination
a
b
entry
solvent
reductant (equiv)
6, yield (%)
1
2
3
4
5
6
7
DMSO/AcOH (5:1)
MeOH/AcOH (10:1)
AcOH
Zn (15.0)
Zn (4.0)
Zn (4.0)
Zn (4.0)
−
90
95
85
0
MeOH
MeOH/AcOH (10:1)
MeOH/AcOH (10:1)
MeOH/AcOH (10:1)
0
Mg (4.0)
trace
0
Fe (4.0)
a
Reaction conditions: 3a (0.3 mmol, 1.0 equiv), solvent (3.0 mL), rt, 6
b
h. Yields were determined by 19F NMR.
in 95% yield when 4.0 equiv of Zn was used in CH3OH/AcOH
(entry 2). Control experiments demonstrated that the
depyridination required both AcOH and Zn (entries 3−5),
and in the absence of any of these components, the conversion
into the desired sulfinate was not observed. In addition,
magnesium and iron metal were found to be ineffective (entries
6−7). The in situ generated sulfinate underwent iodination by
treatment of I2 at 60 °C, affording the corresponding product
7a in 90% yield (Scheme 4).
Scheme 2. Nucleophilic Addition of (2-Py)SO2CF2H to
Carbonyls
Scheme 4. One-Pot Synthesis of Iododifluoromethylated
Carbinols 7a from 3a
Information (SI)). With a series of the (2-pyridylsulfonyl)-
difluoromethylated carbinols 3 in hand, converting diverse (2-
pyridylsulfonyl)difluoromethylated carbinols 3 to the corre-
sponding sulfinates became a key step to achieve our goal. In
recent years, several methods have been developed for the
efficient synthesis of fluoroalkanesulfinates by removing the
heteroaryl group in fluoroalkyl heteroaryl sulfones.13 We tested
3a using the EtSNa/EtSH system,13a and product 4 was formed
in 87% yield, while the S−O Smiles rearrangement byproduct 5
was obtained in 12% yield (Scheme 3); this side reaction could
Having established an efficient route to 7a, we assessed the
scope of the method with regard to the carbonyl compounds
(Scheme 5). This reaction exhibits a broad substrate scope. In
addition to benzaldehyde (7a) and 2-naphthaldehyde (7b),
aromatic aldehydes containing the electron-donating (7c, 7d)
and electron-withdrawing substituents (7e−7i) were well
tolerated. Various functional groups, such as methoxyl,
dimethylamino, cyanide, trifluoromethyl, bromide, chloride,
and ester, were found to be compatible with the reaction
conditions. The structure of 7e was confirmed by X-ray crystal
structure analysis (see SI).15 Beyond phenyl derivatives,
heterocyclic substrates such as benzothiophene work equally
well (7j). Aliphatic aldehydes with acidic α-protons gave
iododifluoromethylation product 7k in 47% yield. Cinnamalde-
hyde afforded product 7l in good yield. It is noteworthy that
ketones are also suitable substrates, while, in Dilman’s recent
work, nucleophilic iododifluoromethylation of carbonyl com-
pounds was only limited to aldehydes. Aromatic ketones such
as acetophenone (7m, 7n), acetothienone (7o), and some
other substituted aromatic ketones (7p, 7q) could be employed
with our method. Aromatic ketones bearing a CC double
bond (7r) and CC triple bond (7s) were also amenable to
this reaction. It is noteworthy that sterically hindered ketones,
such as benzophenone, were also reactive, providing product 7t
in satisfactory yield. Additionally, when aliphatic ketones were
used as substrates (7u−7w), the iododifluoromethylation
products were obtained in good yields.
Scheme 3. Preparation of Difluoroalkylsulfonates from 3a
not be eliminated. Furthermore, this method is not operation-
ally and environmentally friendly because EtSH has a strongly
disagreeable odor. The formation of 5 indicates that 3a is
readily deprotonated under basic conditions, which results in
the undesired S−O Smiles rearrangement.
Given these disadvantages, we set out to develop a new and
efficient method to prepare fluorinated sulfinates. Inspired by a
preparation of sulfinates through a reduction of the electron-
withdrawing heterocyclic sulfone by treatment with Zn/
EtOH−AcOH,14 we attempted to conduct the preparation of
fluorinated sulfinates under similar reaction conditions. With 3a
as a model compound, the desired fluorinated sulfinate 6 was
obtained in 90% yield through the depyridination using a large
excess of Zn in DMSO/AcOH (Table 1, entry 1). We found
that the depyridination proceeded smoothly to give sulfinate 6
B
DOI: 10.1021/acs.orglett.6b01258
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sought to apply our method to furnish iododifluoromethylated
imines. Compound 9 participated in the removal of the pyridyl
group by reduction, and subsequent iodination afforded the
amine 10 in 76% yield (Scheme 7). Bromodifluoromethylated
Scheme 5. Iododifluoromethylation of Various Carbonyl
Compounds 2
a b
,
Scheme 7. Nucleophilic Iododifluoromethylation of Imine
carbinols were also evaluated according to a one-pot procedure,
whereas no product 11 was detected (Scheme 8a). Never-
theless, when the hydroxyl was protected, bromodifluoro-
methylated product 13 was achieved in 52% yield (Scheme 8b).
Scheme 8. Bromodifluoromethylation of Carbonyl
Compounds
In conclusion, we have developed an efficient method for
nucleophilic iododifluoromethylation of aldehydes and ketones
using 2-PySO2CF2H. In this synthetic strategy, nucleophilic
addition of 2-PySO2CF2H with carbonyl compounds has been
achieved and the use of a Smiles rearrangement to produce a
sulfinate intermediate is avoided. A novel zinc-mediated
depyridination reaction for the preparation of sulfinate is
reported. The method is mild and tolerant of a variety of
functional groups. It thus serves as a new approach to prepare
diverse iododifluoromethylated carbinols.
a
Reaction conditions: 3 (1.0 mmol, 1.0 equiv), Zn (4.0 equiv), I2 (4.0
b
c
equiv), MeOH (4.0 mL), AcOH (0.4 mL). Isolated yield. Condition
A: LiHMDS (1.5 equiv), THF/HMPA (10:1), −98 °C, 0.5 h.
d
Condition B: t-BuOK (1.5 equiv), THF, −78 °C, 0.5 h.
As a demonstration of the importance of this protocol, in
addition to the simple molecules, we applied this strategy to
complex molecules. As shown in Scheme 6, the (2-pyridyl-
ASSOCIATED CONTENT
* Supporting Information
■
Scheme 6. Iododifluoromethylation of 3x and 3y
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01258.
Experimental procedures and characterization data for
products (PDF)
Crystallographic data for compounds 7e (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jinbohu@sioc.ac.cn.
Notes
sulfonyl)difluoromethylated carbinols 3x and 3y could be
achieved from steroids in excellent yields. It should be
mentioned that the depyridination reactions of carbinols 3x
and 3y proceeded slowly, and a longer reaction time was
needed. By a combination of depyridination and iodination,
products 7x and 7y were prepared in one pot in 66% and 63%
yield, respectively (Scheme 6). In 2014, a method for direct
halodifluoromethylation of iminium ions with Me3SiCF2Br has
been described by Dilman’s group,16 but halodifluoro-
methylation of imines has not been reported to date. We
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Basic Research
Program of China (2015CB931900, 2012CB821600), the
National Natural Science Foundation of China (21372246,
21421002, 21472221), Shanghai Science and Technology
program (15XD1504400), Youth Innovation Promotion
C
DOI: 10.1021/acs.orglett.6b01258
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Organic Letters
Letter
(16) Tsymbal, A. V.; Kosobokov, M. D.; Levin, V. V.; Struchkova, M.
I.; Dilman, A. D. J. Org. Chem. 2014, 79, 7831.
Association CAS (2014231), and Chinese Academy of
Sciences.
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DOI: 10.1021/acs.orglett.6b01258
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