Selective Metal-Free Deoxygenation of Unsymmetrical 1,2-Dicarbonyl Compounds by Chlorotrimethylsilane and Sodium Iodide

Article abstract of DOI:10.1021/acs.orglett.6b01491

For the first time, the combination of chlorotrimethylsilane with NaI is used as a selective reducting system toward 1,2-diketones. This combination is successfully evaluated with several unsymmetrically benzil derivatives, which are reduced in good yield

Full text of DOI:10.1021/acs.orglett.6b01491

Letter
pubs.acs.org/OrgLett
Selective Metal-Free Deoxygenation of Unsymmetrical 1,2-
Dicarbonyl Compounds by Chlorotrimethylsilane and Sodium Iodide
Ling-Zhi Yuan,‡ Dolor Renko,‡ Ilhem Khelifi, Olivier Provot,* Jean-Daniel Brion, Abdallah Hamze,
and Mouad Alami*
BioCIS, Universite
France
́ ́ ́ ́ ̂
Paris-Sud, CNRS, equipe labellisee Ligue Contre le Cancer, Universite Paris-Saclay, 92290 Chatenay-Malabry,
S
* Supporting Information
ABSTRACT: For the first time, the combination of
chlorotrimethylsilane with NaI is used as a selective reducting
system toward 1,2-diketones. This combination is successfully
evaluated with several unsymmetrically benzil derivatives,
which are reduced in good yields and with a total α-
regioselectivity at room temperature. Identification of benzoin
intermediates is achieved, and a mechanistic radical process is
proposed.
t is well-established that trimethylsilyl iodide (TMSI), in
issues), which limit their application in polyfunctionalized
Iwhich the silicon atom acts as a hard acid and iodide as a soft substrates. Therefore, the availability of a mild, simple, safe,
base, is a useful and powerful reagent in organic synthesis.1 TMSI
chemoselective, and easy-to-handle reducing agent is of special
interest because it allows the formation of complex organic target
molecules without the need for wasteful protection/deprotection
steps. Herein, we report a highly efficient regioselective reduction
of 1,2-diarylketone derivatives using the couple chlorotrime-
thylsilane (TMSCl)/NaI in methylene chloride.
Initially, we had to investigate the ether cleavage of benzil
derivative 1a in CH2Cl2 using an excess of TMSCl/NaI
combination at room temperature (Scheme 1). Contrary to
reacts with oxygen-containing compounds to form a strong
silicon−oxygen bond. The iodide then acts as a strong
nucleophile in a subsequent displacement step, thus resulting
in cleavage of carbon−oxygen bonds. Typical applications of this
reagent are the cleavage of ethers or carboxylic esters and
conversion of ketals into carbonyl compounds and alcohols into
iodide derivatives. Most of these transformations occurred
through an ionic mechanism. Although ketones readily react with
TMSI to provide enol silyl ethers,2 to our knowledge, except
deoxygenation of sulfoxides into sulfides,3 nothing is known
about the ability of TMSI to act as a reducing agent with carbonyl
compounds.
Scheme 1. Regioselective Reduction of 1a by TMSCl/NaI in
CH2Cl2 at rt
Carbonyl reduction is among the most important and
prevalent reactions in organic synthesis, and both industry as
well as academia place special emphasis on this transformation
due to its versatility for the generation of a wide range of
products.4 In this context, the deoxygenation of ketones to
methylene derivatives is also an essential process in organic
chemistry.5 Although relatively uncommon in process chemistry,
the reductive mono-deoxygenation of 1,2-dicarbonyl com-
pounds into monoketone derivatives has also been reported,
but preparative methods that may drive these reactions
selectively have been seldom optimized in the past. To
accomplish this transformation, the use of catalytic hydro-
genation in the presence of Ni(0) complexes6 and metal-based
reducing agents (TiCl4/Zn, SmI2)7 comprises most examples,
but metal-free procedures (HI/AcOH and H2S/py)8 have also
been reported. From a large-scale preparative point of view, these
protocols suffer from many drawbacks, including the use of
flammable gas (H2 or H2S), the frequent need for specialized
equipment, the requirement of harsh reaction conditions, and
low functional group tolerance (chemo- and regioselectivity
our expectations, the reaction did not afford the desired phenol
derivative. We serendipitously discovered that, under these mild
conditions, if the 4-MeO group remained unchanged, one of the
two carbonyl functions (Cα = O) of benzil 1a was totally reduced
to produce the α-deoxybenzoin (DOB) α-2a9 as a single product
(97%)10 with a total α-regioselectivity. A similar yield of α-2a
(95%) was obtained when this reaction was achieved under
anhydrous conditions (oven-dried NaI and distillation of TMSCl
and CH2Cl2 over CaH2 prior to use). This result suggests that
traces of HCl in technical TMSCl or traces of moisture in the
solvent have no influence on the outcome of the reducing
properties of the TMSCl/NaI combination. To understand this
unexpected selective reduction, we initially investigated the
Received: May 23, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01491
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Letter
a
reaction of 1a in CH2Cl2 with different combinations of silicon
species and salts. First, we observed that the reduction process of
1a did not occur with TMSCl alone; 1a was recovered
unchanged even when the reaction was achieved at 40 °C.
Replacing the TMSCl/NaI combination by TMSI allows the
reaction to occur to provide α-2a, but with a lower yield of 65%.
Next, we focused our attention on the sources of silicon species in
the presence of NaI in this process. With TMSOTf, no reaction
occurred, whereas SiCl4 led to α-2a in a modest 65% yield along
with unidentified byproducts. However, we were pleased to
observe that the regioselective reduction of 1a was still efficient
using Ph3SiCl (97%) or (EtO)3SiCl (87%) in place of TMSCl
but required 10 equiv of the (EtO)3SiCl/NaI combination. The
nature of the additive salt was also studied, and no reduction of 1a
occurred when NaI was replaced by NaBr, clearly indicating that
the iodide counterion is important in this reaction. Because
TMSI fumes in air and should be prepared freshly, distilled, and
immediately used, contrary to TMSCl, we have chosen to take
advantage of this easy to handle and inexpensive TMSCl/NaI
combination to reduce benzil derivatives 1. Screening with
respect to the solvents was next carried out. No reduction
reaction occurred in protic polar solvents (e.g., MeOH, EtOH or
iPrOH) at rt, and 1a was recovered unchanged. The use of
aprotic polar solvent (e.g., CH3CN) resulted in a sluggish
reaction, and 2a was isolated with a modest 50% yield after 18 h
of reaction. Among the solvents studied, CHCl3, CCl4, or toluene
have been proven to be effective as CH2Cl2, providing α-2a with
nearly quantitative yields. Several control experiments were
achieved, as suggested by the reviewers, to prove that the
TMSCl/NaI combination is the reducing system rather than
small amounts of HI8a−c formed between TMSCl/NaI and traces
of water present in the solvent. Thus, when the reduction of 1a
was performed in CH2Cl2 at rt for 24 h with 0.5, 2, or 10 equiv of
aqueous HI (wt 57%), no reduction occurred. Increasing the
amount of HI to 15 equiv resulted in a mixture in which the
expected α-2a was formed in less than 15%.11 All of these results
strongly confirm that the novel reducing agent TMSCl/NaI is
responsible for this transformation, discarding definitively the HI
hypothesis.
After the experimental conditions with 1a and TMSCl/NaI
combination (5 equiv) in CH2Cl2 were optimized, the scope of
this reduction reaction was explored with several other benzils
1b−y. As shown in Table 1, a variety of functional groups was
well tolerated to give rise to the desired α-DOBs 2 with good to
excellent yields. Examination of the results showed that a total α-
regioselectivity was observed for several benzils having an
electron-donating group (EDG) on the ortho- and para-
positions. This regioselective reduction was also effective with
a para free-phenol derivative providing DOB α-2h with a high
89% yield. It should be noted that α-2h was also obtained from
other benzil derivatives bearing on the 4-position a −OMOM (α-
2h, 50%), −OTBS (α-2h, 84%), −OBn (α-2h, 67%), and −OAc
(α-2h, 80%) function. For p-ethoxycarbonylbenzil substrate, the
reactivity of the diketone significantly decreased, leading to a
complex mixture with no trace of DOB 2l. However, push−pull
benzil derivatives were successfully and regioselectively reduced
into the desired α-DOBs 2m−t with excellent yields. An example
of reduction of a push−push α-diketone is described, and as
expected, DOB 2y was obtained as a regioisomeric mixture of
monoketones (α-2y/β-2y = 84/16), indicating that the
reduction takes place preferentially on the carbon atom proximal
to the more electron-rich ring. To propose a plausible
mechanism of this regioselective reduction process of α-
Table 1. Functional Group Tolerance
Ar1
Ar2
α-2
yield (%)
98
2-MeOPh
3-MeOPh
4-MePh
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
α-2b
α-2c
α-2d
α-2e
α-2f
b
nd
c
78
4-MeSPh
95
d
4-(4′MeOPh)Ph
4-(4′t-BuPh)Ph
4-HOPh
83
d
α-2g
α-2h
α-2i
79
89
97
61
79
0
4-iPrOPh
4-H2NPh
α-2j
4-AcNHPh
4-MeO2CPh
4-MeOPh
4-MeOPh
4-MeOPh
4-MeOPh
4-MeOPh
4-MeOPh
4-MeOPh
4-MeOPh
4-MeOPh
4-MeOPh
4-MeOPh
4-MeOPh
4-MeOPh
α-2k
α-2l
4-O2NPh
4-EtO2CPh
4-BrPh
α-2m
α-2n
α-2o
α-2p
α-2q
α-2r
α-2s
α-2t
α-2u
α-2v
α-2w
α-2x
α-2y
80
96
97
73
88
57
95
4-IPh
4-FPh
2-IPh
4-F3CPh
2-FPh
d
98
3-CO2EtPh
3-NCPh
2-naphtyl
3-quinolyl
4-MePh
96
60
d
d
f
,e
80
95
98
a
Typical reaction conditions: a mixture of benzil 1 (1 mmol) and NaI
(5 mmol) was stirred in CH2Cl2 for 5 min. Then, 5 mmol of TMSCl
was added to the solution, which was stirred until completion (judged
by TLC). nd: not determined. Obtained as an inseparable mixture of
α-2d/β-2d = 88:12. Experiment was achieved in refluxing CHCl3.
b
c
d
e
f
Obtained as a separable mixture of α-2w/β-2w = 90:10. Obtained as
an inseparable mixture of α-2y/β-2y = 84:16.
diketones, we next isolated the benzoin intermediates by
quenching the reaction with H2O after reduced reaction times
and/or temperature (Scheme 2). The reduction of benzils 1a and
1b was achieved at −40 °C for 15 min, whereas the reduction of
quinoline derivative 1x required 2.5 h of reaction at rt.
In all cases, and to our surprise, the reduction of these benzils
proceeded overwhelmingly on the Cβ of diketones studied to
furnish mainly β-benzoins 3a and 3b and exclusively β-3x with
good to excellent yields.12
Scheme 2. Synthesis of DOBs 2 via Their Benzoin
Intermediates 3
a
For 1a and 1b the reaction was achieved at -40 °C for 15 min; for 1x
the reaction was carried out at rt for 2.5 h.
B
DOI: 10.1021/acs.orglett.6b01491
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Letter
Scheme 3. Plausible Mechanism for the Regioselective Reduction of Benzil 1a into DOB α-2a Using TMSCl/NaI Combination in
CH2Cl2
One can note that a less marked β-regioselectivity has been
previously reported with very few examples of unsymmetrical
benzils using other reducing agents such as alkylphosphines,13
baker’s yeast,14 and NADH models.15 Next, the reduction of
benzoins 3a,b and β-3x was attempted under the conditions
previously reported in Table 1. To our delight, a “reverse” Cα-
reduction occurred invariably to furnish the previously obtained
α-DOBs 2a,b and α-2x in good yields and with no trace of β-
DOB regioisomers.
species VI, thus explaining the regioselectivity of this reducing
process. All of our attempts to isolate TMSOTMS were
unsuccessful; however, when Ph3SiCl was used instead of
TMSCl, Ph3SiOSiPh3 was successfully isolated after hydrolysis,
reinforcing our ideas on this mechanism. A subsequent iodide
atom addition on VI would give the alkenyl intermediate VII.
After hydrolysis, the resulting enol VIII would react with NaI to
provide α-iodoketone IX, which was reduced to 2a by an
iodide.1b,18 To support this mechanistic hypothesis, incorpo-
ration of deuterium atoms into 2a in separate experiments was
tried. No D2-labeled 2a was observed when CD2Cl2 or TMSCl-d9
was used. On the contrary, when 1a was reacted with TMSCl/
NaI in CH2Cl2, hydrolysis with D2O allowed incorporation of
two deuterium atoms on Cα of 2a. To confirm that this selective
transformation proceeded through a radical process rather than
an anionic mechanism,19 1z having an o-allyl substituent, in
which the terminal olefin would trap radical species, was reacted
with TMSCl/NaI in CH2Cl2 (Scheme 4). Accordingly, a cyclized
We next studied the spectroscopic data of the TMSCl/NaI
1
combination via H and 13C NMR in CD2Cl2. Under argon, a
solution of equimolar proportions of NaI and TMSCl in CD2Cl2
furnished a colorless solution with absorptions at δ 1H 0.37 ppm
and δ 13C 1.34 ppm, rigorously identical with those of TMSCl
alone (see Figure 1 in the Supporting Information). On the
contrary, TMSI in CD2Cl2 led to a pink-purple solution with
different absorptions at 0.73 and 3.73 ppm. These observations
strongly suggest that TMSI is not formed in methylene chloride
by the combination of TMSCl with NaI, in agreement with
Olah’s report.1b
Scheme 4. Reaction of 1z with TMSCl/NaI Combination in
CH2Cl2 at rt
To explain this unusual regioselective reduction of benzils 1 by
the TMSCl/NaI combination in CH2Cl2, a plausible radical
mechanism is proposed in Scheme 3. The reductive process
begins probably by a coordination between oxygen atoms of 1a
with TMSCl followed by a nucleophilic addition of NaI on the
carbonyl functions giving intermediates α-I and β-I. Then a
radical fragmentation occurred on I to give siloxy ketone radical
of types α-II and β-II or their mesomeric forms α-III and β-III.
Further reaction of III in the presence of TMSCl and NaI would
furnish the intermediate IV and I2, which colored the methylene
chloride solution in brown.16 Next, an additional equivalent of
TMSCl would coordinate on the oxygen atom proximal to the
electron-rich ring. The resulting intermediate V can lose
TMSOTMS17 with the help of the MeO substituent to furnish
product 4 was isolated after hydrolysis in 21% yield, together
with unidentified byproducts. This result strongly supports the
radical mechanism20 depicted in Scheme 3.
Because deoxybenzoins are important structural moieties that
occur in bioactive molecules,21 it is now possible to have a rapid
and efficient access to the corresponding α- and β-DOBs 2
starting from a single diarylalkyne using two different pathways
C
DOI: 10.1021/acs.orglett.6b01491
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(Scheme 5). As an illustration, diarylalkynes 5a−c were
successfully transformed into β-2g, β-2n, and β-2p after a
Council for Ph.D. funding. Our laboratory is a member of the
laboratory of excellence LERMIT supported by a grant from
ANR (ANR-10-LABX-33).
Scheme 5. Regioselective Access to α-DOBs 2g, 2n, or 2p or β-
DOBs 2g, 2n, or 2p from Diarylalkynes 5a−c
REFERENCES
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In summary, we have demonstrated for the first time that the
TMSCl/NaI combination in CH2Cl2 is a highly efficient
reducing system of unsymmetrical benzil derivatives. The easy
to handle protocol developed herein provides a facile, rapid, and
regioselective access to DOBs α-2 at rt with no need for
hazardous reagents or expensive metals. The reduction takes
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rich aromatic ring. Since sustainable development is now a real
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indicating that a demethylation occurred to provide a phenolic species.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01491.
■
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(17) Ho, T. S. Synth. Commun. 1979, 9, 665.
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inhibited the reducing process of the benzil derivative 1a.
(20) Since a radical mechanism was supported by the transformation of
1z into 4, we discarded the formation of intermediate IV through a
reaction of α-I or β-I with an iodine atom.
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Experimental procedure, NMR spectra, and analytical data
for all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: olivier.provot@u-psud.fr.
*E-mail: mouad.alami@u-psud.fr.
Author Contributions
‡L.-Z.Y. and D.R. contributed equally.
Notes
(22) Le Bras, G.; Provot, O.; Peyrat, J.-F.; Alami, M.; Brion, J.-D.
Tetrahedron Lett. 2006, 47, 5497.
(23) Mousset, C.; Provot, O.; Hamze, A.; Bignon, J.; Brion, J.-D.;
Alami, M. Tetrahedron 2008, 64, 4287.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Dr. Philippe Renaud, University of Bern, is greatly thanked for
helpful mechanism discussions. We gratefully acknowledge
■
support of this project by CNRS, Universite
La Ligue Nationale Contre le Cancer through an Equipe
Labellisee 2014 grant. L.-Z.Y. thanks the Chinese Scholarship
́
Paris-Sud, and by
́
D
DOI: 10.1021/acs.orglett.6b01491
Org. Lett. XXXX, XXX, XXX−XXX