Lewis Base Catalyzed Intramolecular Reduction of Salicylaldehydes by Pinacol-Derived Chlorohydrosilane

Article abstract of DOI:10.1002/ejoc.201800544

A newly developed stable chlorohydrosilane derived from pinacol is herein described. This was successfully used in the reduction of salicylaldehydes in reasonable to excellent yields (51–97 %). The ability of the hydrosilane to react as a reducing agent is increased upon the in situ formation of a trialkoxyhydrosilane and activation with a Lewis base, as further indicated by density functional theory studies. 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) was identified to be a suitable catalyst for this metal-free reduction, promoting the regio- and chemoselective reduction of aldehydes in ortho-position to phenols, despite the presence of vicinal ketones. The performance of pinacol-derived chlorohydrosilane in the reduction of salicylaldehydes was further observed to be superior to that of well-established commercially available chlorohydrosilanes.

Full text of DOI:10.1002/ejoc.201800544

DOI: 10.1002/ejoc.201800544
Full Paper
Selective Reduction
Lewis Base Catalyzed Intramolecular Reduction of
Salicylaldehydes by Pinacol-Derived Chlorohydrosilane
Benedicta Assoah,*[a] João R. Vale,[a,b] Elina Kalenius,[c] Luis F. Veiros,[d] and
Nuno R. Candeias*[a]
Abstract: A newly developed stable chlorohydrosilane derived be a suitable catalyst for this metal-free reduction, promoting
from pinacol is herein described. This was successfully used in the regio- and chemoselective reduction of aldehydes in ortho-
the reduction of salicylaldehydes in reasonable to excellent position to phenols, despite the presence of vicinal ketones.
yields (51–97 %). The ability of the hydrosilane to react as a The performance of pinacol-derived chlorohydrosilane in the
reducing agent is increased upon the in situ formation of a reduction of salicylaldehydes was further observed to be supe-
trialkoxyhydrosilane and activation with a Lewis base, as further rior to that of well-established commercially available chloro-
indicated by density functional theory studies. 1,3-Dimethyl- hydrosilanes.
3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) was identified to
Introduction
along with catalysts[2a,4] such as Lewis acids,[5] Lewis bases[6] or
transition metal complexes.[7] Despite the notable progresses
made in transition metal catalyzed hydrosilylations,[3c,8] the
metal-free version of such reductions has received tremendous
importance in recent research endeavors;[3a] as they benefit
from the absence of costly and often toxic metal catalysts and
the need to remove any metal impurities particularly relevant
for pharmaceutical products.[9]
The reduction of carbon-heteroatom unsaturated organic com-
pounds remains one of the most essential transformations in
synthetic organic chemistry for both academic and industrial
applications. An array of catalytic protocols such as hydrogen-
ation reactions, electron transfer and hydride transfer reduc-
tions have been explored extensively with carbon-heteroatom
multiple bond reductions.[1]
Mild reductions of carbonyl groups to the corresponding al-
cohol functionality by metal-free hydrosilylation methods have
been largely accomplished through use of acid and bases as
catalysts.[2a,6b] Despite the rather low Si–H bond energy of
hydrosilanes when compared with C–H bond, employing hydro-
silanes in metal-free carbonyl reduction requires either carbonyl
activation by complexation with Brønsted or Lewis acids or acti-
vation of the hydrosilane, in which B(C6F5)3 has been exten-
sively explored.[10] Both alcohols or hydrocarbons[5,11] can be
obtained, depending on the reaction conditions and the hydro-
silane used. One of the approaches explored in the activation
of hydrosilanes has been the expansion of tetrahedral silicon
to a pentavalent anion intermediate upon complexation with
nucleophilic species.[12] Silicon valence expansion leads to a re-
distribution of the electronic density, polarizing the covalent
bonds around silicon, decreasing silicon electron density and
increasing the electron density of the silicon substituents. Over-
all, these results in a higher hydride donating ability of the
pentavalent complex when compared with its tetracoordinate
counterpart.[13] Mitsuo and co-workers reported an in situ for-
mation of pentacoordinate bis(diolato)hydridosilicates from tri-
chlorosilane and catechol or 2,2′-dihydroxybiphenyl for the
reduction of carbonyl compounds. However, pentacoordinate
hydridosilicates from aliphatic diols such as 1,2-ethanediol and
In recent years, catalytic hydrosilylation has made significant
progress and is being used as a major tool in the reduction of
organic substrates, serving as a convenient alternative to the
use of hydrogenation and metal hydrides.[2] Since the electronic
and steric properties of hydrosilanes can be tuned by interac-
tion with unreactive functional groups in the substrate or with
external chemical agents, these reagents have found their way
in the reduction toolbox of synthetic chemists, as they can be
used to perform a large variety of chemoselective reductions
under mild conditions.[3] Specifically, their reducing properties
towards carbonyl can be controlled by the silicon substituents
[a] Laboratory of Chemistry and Bioengineering,
Tampere University of Technology,
Korkeakoulunkatu 8, 33101 Tampere, Finland
E-mail: benedicta.assoah@tut.fi
nuno.rafaelcandeias@tut.fi
http://www.tut.fi/syn
[b] Instituto de Investigação do Medicamento (iMed.ULisboa),
Faculdade de Farmácia, Universidade de Lisboa,
Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal
[c] University of Jyväskylä, Department of Chemistry, Nanoscience Center,
Jyväskylä, Finland
[d] Centro de Química Estrutural, Instituto Superior Técnico,
Universidade de Lisboa,
Av. Rovisco Pais No. 1, 1049-001 Lisboa, Portugal
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201800544.
pinacol proved to be less effective as reducing agents.[14]
[3a,15]
Cs2CO3
TBAF,[16] tBuOK,[17] CsF, and KF[6a] have been re-
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Scheme 1. Intramolecular hydrosilylation of hydroxy carbonyl compounds.
ported as active catalysts or activators in the chemoselective would form.[23] Such an event would activate a Lewis basic site
hydrosilylation of aldehydes and ketones, while being tolerant such as oxygen of a carbonyl, and simultaneously decrease the
to other functional groups. Hypervalent Cl3SiH-DMF silicate was Si–H bond strength.
described by Kobayashi et al. to be an effective reducing agent
in the reduction of aldehydes, imines and in the reductive amin-
ation of aldehydes.[18]
In order to verify these assumptions a novel chlorohydro-
silane was prepared and its reactivity tested in the Lewis base
catalyzed hydrosilylation of salicylaldehyde derivatives, which
The intramolecular hydrosilylation of carbonyl compounds we used in several instances in multicomponent Petasis
has been explored as a way to achieve stereoselective reduc- borono-Mannich reaction.[24] Notably, despite the widely avail-
tions due to more constrained cyclic transition states able methods for reduction of salicylaldehyde,[25] as far as our
(Scheme 1). Davis and co-workers achieved moderate to excel- knowledge goes its Lewis base-catalyzed hydrosilylation has
lent stereoselectivities on the intramolecular hydrosilylation of never been reported.
ꢀ-hydroxyketones using Lewis acid catalysis (Scheme 1a),[19]
while intramolecular hydrosilylation of ꢀ-hydroxyesters was
better accomplished with catalytic amounts of fluoride.[20]
Pentacoordinate hydrosilanes, activated by an internal N–Si
Results and Discussion
Our initial attempts on the preparation of five-membered
chlorohydrosilane derived from ethylene glycol with HSiCl3 in
presence of different amines resulted in complex mixtures due
to disproportionation and formation of silicon-amine ad-
ducts.[26] Questioning the putative high reactivity of the five-
membered chlorohydrosilane formed under such conditions,
the ethylene glycol was replaced by pinacol aiming at increas-
ing the stability of the chlorohydrosilane. Gladly, treatment of
pinacol with an excess amount of trichlorosilane and pyridine
in diethyl ether under inert atmosphere yielded the desired
pinacol-derived chlorohydrosilane (PCS) in nearly quantitative
yield after filtration and solvent removal (Scheme 2). Just as
many chlorosilanes, PCS is an air and moisture sensitive clear
colorless liquid that can be stored for at least 6 months at
–20 °C under inert atmosphere without any change in reactivity.
The ability of PCS to serve as a reducing agent was tested in
bond have been successfully used in the same kind of trans-
formation (Scheme 1b).[21] More recently, O'Neil and co-
workers[6b,6c] reported a cooperative Lewis base-mediated
intramolecular carbonyl hydrosilylation of ꢀ-hydroxyketones
(Scheme 1c). The hydrosilyl ether formed upon reaction of the
hydroxyl group with diphenylchlorosilane, in presence of a terti-
ary base, could undergo an intramolecular hydride delivery pro-
moted by imidazole. However, the system was not rendered
catalytic and the use of superstoichiometric amounts of imid-
azole and diphenylchlorosilane were required.
Considering that the hydride character of hydrosilanes is
highly dependent on the silicon substituents, we envisioned
that alkoxy derived hydrosilanes would be highly reactive under
certain constrains (Scheme 1d). The hydride character would be
further increased by constraining the silicon atom within a ring,
as known that 4- and five-membered silacycles have higher
Lewis acid character than their acyclic counterparts, due to the hydrosilylation of salicylaldehyde in dichloromethane
strain release.[22] Cyclic structures derived from silicon could (Table 1), for which the corresponding salicyl alcohol was ob-
have their Lewis acid character further increased upon com- tained in 24 % yield after 72 h in dichloromethane in absence
plexation with a Lewis base, as a pentavalent silicon complex of base (entry 1). Gratifyingly, the same alcohol was obtained
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aldehydes were generally reduced more efficiently affording 3
and 4 in excellent yields, while 5-halogen derivatives were ob-
tained in slightly lower yields as for 5 and 6. 5-Nitrosalicyalde-
hydes could be efficiently reduced in less than 2 h, affording 8
and 9 in up to 54 % yield. Notably, despite the vicinity of ether
groups to the hydroxyl substituent of salicylaldehyde, no reduc-
tion of 3-alkoxy substituents was observed, as only the corre-
sponding salicyl alcohols 7 and 9 were obtained. The procedure
was further expanded to the reduction of 3,5-dihalogens result-
ing in formation of 10–12 in up to 72 % yield. As a continuation
of our work on preparation of hydroquinone from quinic
acid,[29] we also performed the reduction of readily available
formyl-hydroquinone.[30] The reduced product 13 was obtained
in 70 % yield by changing the solvent from dichloromethane to
acetonitrile without increasing the amount of PCS.
Scheme 2. Preparation of pinacol-derived chlorohydrosilane (PCS).
in 70 % after 3 h when using triethylamine as a hydrochloric
acid sequester (entry 2). When diminishing the amount of base
to 20 mol-%, reduction was rather incomplete as judged by
TLC, and the product was formed in only 29 %, indicating the
dual role of the amine as a catalyst and HCl sequester (entry 3).
Screening of other bases prone for HCl sequestering and Lewis
base catalysis, such as pyridine and Hünig's base, led to product
formation in lower yields (entries 4 and 5). Use of DMF as reac-
tion solvent, in absence of any additive, resulted in salicyl alco-
hol formation in 68 % likely due to the Lewis base character
of DMF.[27] Although the promoter role of triethylamine was
notoriously visible, a more effective Lewis base was searched to
be used in combination with the amine HCl sequester. Moder-
ate yields were observed when using PPh3, pyridine N-oxide
and HMPA, for which presence of triethylamine had a negligible
effect (entries 7–9). Gladly, when using 20 mol-% of DMPU, an
environmentally benign substitute to HMPA,[28] the desired
product was obtained in excellent 94 % yield after 3 h (entry
10), for which the presence of triethylamine showed a negligi-
ble effect other than HCl trapping.
Table 1. Lewis base-catalyzed reduction of salicylaldehyde with PCS.
Entry[a]
Base [equiv.]
Cat.
Yield [%][b]
1
2
3
–
–
–
Et3N
24[c]
70
29
Et3N (1.2)
–
4
5
6
DIPEA (1.2)
pyridine (1.2)
DMF[d]
–
–
–
51
58
68
7
8
9
10
Et3N (1.0)
Et3N (1.0)
Et3N (1.0)
Et3N (1.0)
PPh3
pyridine N-oxide
HMPA
58 (57)[e]
70 (56)[e]
64 (64)[e]
94 (97)[e]
DMPU
[a] PCS (0.65 mmol) in DCM (1 mL) was added over 5 min to a mixture of
salicylaldehyde (0.54 mmol), base and catalyst in DCM (1.5 mL) at 0 °C. After
20 min, mixture was left reacting at room temperature for 3 h and then
treated with TBAF (1
M in THF, 0.75 mmol). [b] Isolated yield. [c] Reaction
conducted for 72 h. [d] DMF used as solvent. [e] Reaction yield in absence
of TEA in parenthesis.
After optimization of the reaction conditions, the reduction
of different substituted salicylaldehydes was performed
(Scheme 3). Reaction times varied between 0.5 h and 8 h, af-
fording the desired salicyl alcohols in reasonable to excellent
yields (51–97 %). 5-Alkyl-substituted salicylaldehydes were
promptly reduced to afford 1 and 2 after desilylation with TBAF.
Scheme 3. Scope of Lewis base-promoted reduction of salicylaldehydes with
PCS.
Considering the observed dual role of triethylamine in the
Despite the presence of nitro and halogen substituents suscep- reduction of salicylaldehyde, as the use of 1.2 equiv. allowed
tible to reduction, the salicylaldehydes efficiently undergo re- formation of the desired product in 70 % yield (Table 1, entry
duction of the carbonyl group. 3-Halogen substituted salicyl- 2), we have optimized the reaction conditions as this could ren-
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der a more practical use of PCS as reducing agent. Gratefully,
salicyl alcohol could be obtained in 94 % isolated yield in aceto-
nitrile after 3 h and further treatment with TBAF (Scheme 4).
Nevertheless, a superior catalytic role of DMPU was observed,
as the use of 20 mol-% in DCM led to formation of salicyl alco-
hol in 97 % yield in the absence of any HCl sequester (Table 1,
entry 10).
Scheme 4. Optimization for dual use of Et3N in reduction of salicylaldehyde
with PCS.
In order to attest the superiority of PCS for salicylaldehyde
reduction, commercially available chlorohydrosilanes were
tested using the optimized procedures. When using diphenyl-
chlorosilane with dichloromethane as solvent and DMPU as
catalyst in presence of stoichiometric amount of triethylamine,
salicylic alcohol was obtained in only 31 % yield after 72 h
(Scheme 5). Chlorodimethylsilane and chlorodiisopropylsilane
failed in providing the reduced product under the same condi-
tions.
Scheme 6. Regioselective and chemoselective DMPU-catalyzed reduction of
salicylaldehydes with PCS.
In order to expand the suitability of this system to the reduc-
tion of carbon-heteroatom unsaturated bonds, PCS was tested
as a reducing agent in the reductive amination of a salicylalde-
hyde-derived iminium (Scheme 7). After condensation of salicyl-
aldehyde and indoline for 6 h in refluxing dichloromethane,
the in situ formed iminium was reduced by PCS, affording the
corresponding tertiary amine 22 in 72 % yield. Delightfully, de-
spite the high propensity of PCS towards hydrolysis, the use of
molecular sieves was enough to trap the water formed in the
condensation process. Optimization of this process and its ex-
pansion to other amines is under way and will be reported in
due course.
Scheme 5. Reduction of salicylaldehyde with diphenylchlorosilane.
The several attempts to reduce benzaldehyde with PCS using
the optimized protocol proved futile, even when increasing the
reaction time to 24 h or the reaction temperature. The lack of
reactivity of benzaldehyde towards PCS indicate the required
formation of a trialkoxyhydrosilane as well as the intramolecular
reduction process. Furthermore, the reduction of O-methyl
salicylaldehyde 15 was not accomplished with the reaction con-
ditions as only starting material was visible after 24 h
(Scheme 6a). Despite the rather high reactivity of PCS, its ability
to reduce aryl ketones is notoriously low, as confirmed by for-
mation of 17 in only 47 % yield after 4 h (Scheme 6b). With
such information in hand, we also examined the chemo- and
regioselectivity of the reduction process (Scheme 6c and d).
Gratifyingly, our system allowed the regioselective reduction of
5-formyl salicylaldehyde 18, resulting in exclusive reduction of
the aldehyde group in the ortho-phenol position in 55 % yield.
In order to test the chemoselectivity of the system, 20 was
synthesized and submitted to the same reduction conditions.
Scheme 7. DMPU-catalyzed reductive amination of salicylaldehyde-derived
iminium with PCS.
The mechanism of aldehyde reduction with PCS was studied
by means of DFT calculations[31] using salicylaldehyde as sub-
strate. The calculations starting point is the trialkoxyhydrosilane
that results from HCl loss from the initial hydrosilane, and the
free energy profile obtained is depicted in Figure 1.
In the first step of the mechanism, from A to B, there is
Despite the previously observed reduction of the ketone in 16, coordination of the base, DMPU, to the Si-atom in the trialkoxy-
the chemoselective reduction of the aldehyde functionality of hydrosilane. In the corresponding transition state, TSAB, the
20 was observed, rendering product 21 exclusively in 49 % new Si–O bond is only incipient with a distance of 2.56 Å, still
yield after 3 h.
0.58 Å longer than its final value, in B. This is a very facile step
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Figure 1. Free energy profile for the reduction of salicylaldehyde with PCS catalyzed by DMPU. Free energy values [kcal/mol] relative to the pair of reactants,
DMPU plus the trialkoxyhydrosilane (A). Distances in Å.
with a negligible barrier of only 1.0 kcal/mol and the resulting
intermediate (B) is only 0.4 kcal/mol more stable than the rea-
gents. From B, there is rotation around the Si–Ophenol bond that
leads to another conformer, B′. In the following step, from B′
to C, there is hydride attack into the carbonyl C-atom and coor-
dination of the corresponding O-atom to silicon. In the transi-
tion state, TSB′C, formation of the new C–H bond is practically
accomplished with a bond length only 0.03 Å longer than the
one existing in C, while the Si–O bond is only beginning to
form with a distance of 4.09 Å, indicating a non-synchronous
process in which C–H bond formation precedes the C–O coun-
terpart. The barrier associated with this step is the highest of
all path, TSB′C being 20.0 kcal/mol less stable than the reactants,
but the process is clearly exergonic with ΔG = –32.2 kcal/mol.
In the last step of the mechanism, there is liberation of the
catalyst, DMPU, and formation of the final product, salicyl alco-
hol. In the corresponding transition state, TSCD, the process of
Si–ODMPU bond breaking is well advanced, with distance of
2.37 Å, already 0.55 Å longer than the one present in intermedi-
ate C. This is a fairly easy step with a barrier of only 2.2 kcal/
mol, and overall the reaction is thermodynamically favorable,
with a free energy balance of ΔG = –33.0 kcal/mol.
The mechanism of salicylaldehyde reduction in the absence
of catalyst was also investigated by DFT calculations, for com-
parison purposes. The free energy profile obtained is repre-
sented in Figure 2.
Figure 2. Free energy profile for the reduction of salicylaldehyde with PCS in
the absence of catalyst. Free energy values [kcal/mol] relative to the trialkoxy-
hydrosilane (E).
1.87 Å, respectively. Significantly, the reaction has an associated
barrier of 33.3 kcal/mol, and the overall process is very fa-
vorable with ΔG = –34.4 kcal/mol. The comparison of the two
mechanism shows the role of DMPU as catalyst, lowering
12.9 kcal/mol the total barrier of the reaction.
The reaction starts with coordination of the carbonyl O-atom
to silicon, from E to F. From F, there is hydride transfer from
silicon to the CC=O-atom, through transition state TSFG. In the
Conclusions
transition state the process of Si–H bond breaking and C–H Herein we report the easy preparation of a novel chlorohydro-
bond formation is halfway through with distances of 1.61 and silane derived from pinacol that can be easily isolated by simple
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solution of PCS (0.65 mmol) in dichloromethane (1 mL) was added
dropwise via syringe pump to the reaction mixture over 5 min and
the resulting solution stirred at this temperature for 20 min and
then warmed to room temperature. After consumption of salicyl-
aldehyde, as judged by TLC, the reaction was treated with a solution
filtration to remove the pyridinium chloride salt. Its Lewis base
promoted and metal-free reduction of salicylaldehydes enables
the preparation of several substituted salicyl alcohols in reason-
able to excellent yields. Despite the high reactivity of the devel-
oped system, we demonstrated its ability to perform the de-
sired reductions in a regio- and chemoselective manner due
to the in situ formation of a trialkoxyhydrosilane followed by
intramolecular hydride delivery promoted by a Lewis base.
From screening of several Lewis bases, DMPU was identified as
of TBAF in 1
M THF (0.75 mL, 0.75 mmol) and stirred for 30 min.
The mixture was then quenched with saturated NH4Cl (15 mL) and
extracted with CH2Cl2 (3 × 10 mL). The combined organic layer was
dried with MgSO4, filtered out and solvent removed under reduced
pressure. The crude product obtained was purified by flash column
the best base in promoting the intramolecular hydride delivery, chromatography. NMR spectra of compounds 1–2, 4–9, 11–13, 17,
19 and 22 are consistent with previously reported.[32]
and its catalytic role was further verified by DFT calculations.
1
Nevertheless, a more practical procedure using small excess of
common triethylamine is also reported. The potential use of
pinacol-derived chlorohydrosilane has been preliminarily dem-
onstrated through its ability to perform the reductive amination
of a salicylaldehyde-derived iminium.
3: Yield 97 % (83 mg, 0.52 mmol). H NMR (300 MHz, CDCl3, 25 °C,
TMS): δ = 2.45 (br. s., 1 H; CH2OH) 4.79 (s, 2 H, ArCH2) 6.71 (br. s., 1
H; ArOH) 6.82 (t, J = 8.2 Hz, 1 H; ArH) 7.09 (d, J = 8.2 Hz, 1 H; ArH)
7.28 (dd, J = 6.4, 1.8 Hz, 1 H; ArH) ppm. 13C NMR (75 MHz, CDCl3):
δ = 62.7, 120.4, 120.8, 127.0, 127.4, 128.8, 150.2 ppm. MS (ESI) m/z
calculated for C7H7ClO2Na+ [M + Na]+ 181.0027, found 181.0034.
10: Yield 59 % (119 mg, 0.32 mmol). 1H NMR (300 MHz, CDCl3, 25 °C,
TMS): δ = 2.28–2.56 (br.s., 1 H; CH2OH) 4.76 (s, 2 H, ArCH2) 7.27–
7.33 (br.s., 1 H; ArOH) 7.36–7.41 (m, 1 H, ArH) 7.91 (d, J = 1.8 Hz, 1
H; ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = ppm, 63.1, 82.5, 86.9,
Experimental Section
All syntheses were carried out in oven-dried glassware under inert
atmosphere. Dichloromethane was dried by distillation under argon
with calcium hydride. Triethylamine, pyridine and DMF were puri-
fied and dried before use. Reactions were monitored through thin-
layer chromatography (TLC) with commercial silica gel plates (Merck
silica gel, 60 F254). Visualization of the developed plates was per-
formed under UV lights at 254 nm and by staining with cerium
ammonium molybdate. Flash column chromatography was per-
formed on silica gel 60 (40–63 μm) as stationary phase. 1H NMR
spectra were recorded at 300 MHz, and 13C NMR spectra were re-
corded at 75 MHz in a 300 MHz Varian Mercury spectrometer, using
CDCl3 as solvent. 29Si NMR was recorded at 99 MHz in a Jeol ECZR
500. Chemical shifts (δ) are reported in ppm referenced to the CDCl3
residual peak (δ = 7.26 ppm) or TMS peak (δ = 0.00 ppm) for 1H
NMR, to CDCl3 (δ = 77.16 ppm) for 13C NMR and to TMS for 29Si
NMR (δ = 0.00 ppm). The following abbreviations were used to
describe peak splitting patterns: s = singlet, d = doublet, t = triplet,
m = multiplet. Coupling constants, J, were reported in Hertz [Hz].
High-resolution mass spectra were recorded on a Waters ESI-TOF
MS spectrometer or on ABSciex QSTAR Elite ESI-Q-TOF.
+
127.7, 136.8, 145.3, 154.2 ppm. MS (ESI) m/z calculated for C7H6I2O2
[M]+ 376.8452, found 376.8455.
Preparation of 3-Acetyl-5-(tert-butyl)salicylaldehyde (20) and
Reduction by PCS: 4-tert-Butyl-2,6-diformylphenol (300 mg,
1.45 mmol, 1 equiv.) was dissolved in 5 mL of dry DCM in a round-
bottomed flask under Argon. Triethylamine (252 μL, 1.81 mmol,
1.25 equiv.) and DMAP were added (18 mg, 0.15 mmol, 0.1 equiv.).
Then, tert-butyldimethylsilyl chloride (264 mg, 1.75 mmol,
1.2 equiv.) was added. The solution was stirred at room temperature
for three hours. The reaction was quenched with 5 mL of saturated
aqueous NH4Cl solution and the layers separated. The organic
phase was collected and the aqueous phase extracted with DCM
(2 × 5 mL). The organic phases were combined, dried with MgSO4,
filtered, and the solvent evaporated under vacuum. Purification by
flash chromatography (Hex/DCM, 1:1) gave 20a in 75 % yield
(349 mg, 1.09 mmol) as a white solid. 1H NMR (300 MHz, CDCl3,
25 °C, TMS): δ = ppm 0.17 [s, 6 H, Si(CH3)2] 1.09 (s, 9 H, tBu) 1.34 (s,
9 H, tBu) 8.10 (s, 2 H, ArH) 10.35 (s, 2 H, CHO) ppm. 13C NMR
(75 MHz, CDCl3): δ = ppm –4.4, 18.6, 25.8, 31.2, 34.8, 128.8, 131.8,
145.9, 158.9, 189.0 ppm.
Synthesis of the Pinacol-Derived Chlorohydrosilane (PCS): A so-
lution of trichlorosilane (22.3 g, 166 mmol) in diethyl ether (150 mL)
in a round-bottomed flask fitted with a dropping funnel under
argon was cooled to 0 °C in an ice bath. A mixture of pinacol (6.5 g,
55 mmol) and pyridine (9 mL, 111 mmol) in diethyl ether (100 mL)
was transferred to the dropping funnel via a syringe and added
slowly to the reaction mixture for about an hour. After complete
addition, the mixture was warmed up to room temperature and
stirred for 48 h. The pyridinium chloride salt was then filtered out
and the solvents evaporated under reduced pressure affording PCS
in 95 % yield (9.8 g, 54.5 mmol), that was used without further
20a: (376 mg, 1.17 mmol, 1 equiv.) was dissolved in 13 mL of dry
THF in a round-bottomed flask under argon. The solution was
cooled to –78 °C and MeLi (1.17 mL of 1.6
M solution, 1.17 mmol,
1 equiv.) was added dropwise. After addition, the solution was
warmed to room temperature for 10 min. The reaction was
quenched with 15 mL of saturated aqueous NH4Cl solution and the
layers separated. The organic phase was collected and the aqueous
phase extracted with Et2O (2 × 15 mL). The organic phases were
combined, dried with MgSO4, filtered, and the solvent evaporated
under reduced pressure. Purification by flash chromatography (Hex/
DCM, 4:1) gave 20b in 61 % yield (241 mg, 0.72 mmol) as a white
solid. 1H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = –0.01 (s, 3 H, SiCH3)
0.07 (s, 3 H, SiCH3) 0.92 (s, 9 H, tBu) 1.33 (s, 9 H, tBu) 1.41 (d, J =
6.4 Hz, 3 H; CH3CH) 5.23 (q, J = 6.1 Hz, 1 H; CHOTBDMS) 7.40 (d, J =
2.3 Hz, 1 H; ArH) 7.90 (d, J = 2.3 Hz, 1 H; ArH) 9.89 (s, 1 H, CHO)
11.08 (s, 1 H, ArOH) ppm. 13C NMR (75 MHz, CDCl3): δ = –4.8, –4.8,
18.4, 25.3, 26.0, 31.4, 34.4, 65.0, 128.1, 131.7, 135.0, 142.6, 155.6,
197.1 ppm.
1
purification. H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 1.45 (s, 12
H, CH3) 5.69 (s, 1 H, SiH) ppm. 13C NMR (75 MHz, CDCl3): δ = 24.9,
84.6 ppm. 29Si NMR (99 MHz, CDCl3, 25 °C, TMS): δ = –37.5
(d, JSi-H = 354 Hz) ppm. HR-MS (ESI+): calculated for C6H15O3Si+ [M
– Cl + H2O]+ 163.0785, found 163.0786. For [C6H13O+] calculated
101.0961, found 101.0961.
General Procedure for DMPU-Catalyzed Hydrosilylation of
Salicylaldehyde: DMPU (14 mg, 0.11 mmol) followed by triethyl-
amine (66 mg, 0.54 mmol) were added to a stirred solution of
salicylaldehyde (0.54 mmol) in dichloromethane (1.5 mL) at 0 °C. A
20b: (201 mg, 0.6 mmol, 1 equiv.) was dissolved in 5 mL of THF.
The solution was cooled to 0 °C and TBAF (1.2 mL of 1
M solution,
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1.2 mmol, 2 equiv.) was added. The reaction was then warmed to
room temperature for 30 min. The solution was diluted with 15 mL
of Et2O and washed with saturated NaHCO3 aqueous solution (3 ×
15 mL). The organic layer was collected, dried with MgSO4, filtered
and the solvent evaporated to give 20c as a colorless oil in quantita-
tive yield (0.6 mmol, 137 mg), which was used directly in the next
step. 1H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 1.33 (s, 9 H, tBu)
1.55 (d, J = 6.4 Hz, 3 H; CH3CH) 5.17 (q, J = 6.8 Hz, 1 H; CHOH) 7.44
(d, J = 2.9 Hz, 1 H; ArH) 7.69 (d, J = 2.3 Hz, 1 H; ArH) 9.90 (s, 1 H,
CHO) ppm. 13C NMR (75 MHz, CDCl3): δ = 23.1, 31.4, 34.4, 66.3,
120.0, 128.8, 131.4, 133.3, 142.9, 156.7, 197.2 ppm.
Keywords: Hydrosilylation · Aldehydes · Alcohols · Lewis
bases · Homogeneous catalysis
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21: 49 % yield (20 mg), following general procedure, starting from
1
0.182 mmol (40 mg) of 20. H NMR (300 MHz, CDCl3, 25 °C, TMS):
δ = 1.32 (s, 12 H, tBu) 2.51–2.56 (br.s., 1 H, CH2OH) 2.66 (s, 3 H, CH3)
4.74 (s, 2 H, ArCH2) 7.56 (d, J = 2.3 Hz, 1 H; ArH) 7.64 (d, J = 2.3 Hz,
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Reductive Amination of Salicylaldehyde and Indoline-Derived
Iminium: A mixture of salicylaldehyde (0.54 mmol), indoline
(64.4 mg, 0.54 mmol) and molecular sieves (3 Å, 255 mg) in di-
chloromethane (1 mL) was refluxed for 5 h under argon. The mix-
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added in one portion followed by dropwise addition of a solution
of PCS (0.65 mmol) in dichloromethane (1 mL) via a syringe pump
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M THF (0.75 mL, 0.75 mmol) and stirred for
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Acknowledgments
The Academy of Finland is acknowledged for the financial
support to N. R. C. (Decisions No. 287954 and 294067). L. F. V.
and J. R. V. acknowledge Fundação para
a Ciência e
Tecnologia (UID/QUI/00100/2013, SFRH/BD/120119/2016). CSC-
IT Center for Science Ltd, Finland, is acknowledged for the allo-
cation of computational resources.
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Received: April 5, 2018
Published Online: ■
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Selective Reduction
B. Assoah,* J. R. Vale, E. Kalenius,
L. F. Veiros, N. R. Candeias* ............ 1–9
Lewis Base Catalyzed Intramolecular
Reduction of Salicylaldehydes by
Pinacol-Derived Chlorohydrosilane
Help your neighbor: A new chloro- method was observed to be regio- and
hydrosilane can reduce aromatic alde- chemoselective as other carbonyl
hydes when assisted by an ortho- functionalities in the same molecule
phenol moiety and upon activation by are not reduced.
a Lewis base. This metal-free reductive
DOI: 10.1002/ejoc.201800544
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