Redox-Neutral 1,3-Diol Synthesis by Base-Promoted Diastereoselective Alcohol-Aldolization

Article abstract of DOI:10.1021/acs.orglett.0c02536

In order to prepare more efficiently key 1,3-diol fragments, we have devised a base-promoted redox-neutral condensation of ketones with alcohols. This diastereoselective alcohol-aldolization enables bypassing the classical oxidation and reduction steps necessary for the preparation of this crucial backbone by an overall redox-neutral formal borrowing hydrogen process. The starting alcohols constitute both the precursors of the in situ generated reactive aldehydes and the hydride source necessary for the chemoselective reduction of the aldol adduct intermediates.

Full text of DOI:10.1021/acs.orglett.0c02536

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Letter
Redox-Neutral 1,3-Diol Synthesis by Base-Promoted
Diastereoselective Alcohol−Aldolization
Na Shao, Jean Rodriguez, and Adrien Quintard*
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ABSTRACT: In order to prepare more efficiently key 1,3-diol fragments, we have devised a base-promoted redox-neutral
condensation of ketones with alcohols. This diastereoselective alcohol−aldolization enables bypassing the classical oxidation and
reduction steps necessary for the preparation of this crucial backbone by an overall redox-neutral formal borrowing hydrogen
process. The starting alcohols constitute both the precursors of the in situ generated reactive aldehydes and the hydride source
necessary for the chemoselective reduction of the aldol adduct intermediates.
Scheme 1. 1,3-Diol Synthetic Challenges and Proposed
Alcohol−Aldolization
n order to minimize steps and waste generation associated
Iwith the stereoselective elaboration of complex organic
scaffolds, the invention of redox-neutral approaches is crucial.1
These transformations, such as the popular borrowing hydro-
gen, have the power to avoid unnecessary operations and
stoichiometric reagents associated with stepwise oxidation and
reduction sequences, a step further toward eco-compatible
synthesis.2 The elaboration of 1,3-diols, a common motif found
in a wide variety of natural products and drugs (Scheme 1a), is a
classic example of a synthetic sequence often involving
successive undesired redox steps.3 This key architecture is
usually constructed via aldol reaction between a carbonyl and an
aldehyde (Scheme 1b). However, the starting aldehyde is often
prepared by oxidation of the corresponding alcohol, and the
aldol adduct must then be reduced to form the desired 1,3-diol.
As a result, such a sequence implies two undesired time- and
energy-consuming redox steps. In order to limit redox issues,
different alternatives have been proposed such as the aldol
Tishchenko-type disproportionation. However, this reaction
occurs from the aldehyde oxidation level and requires an
additional equivalent of aldehyde to promote the reduction of
the aldol product through intramolecular hydride transfer.4
Most interestingly, a broad range of elegant metal-catalyzed
redox-neutral couplings have been developed such as the
allylations of alcohols.5 While these strategies elegantly enable
constructing alcohols directly from the same oxidation state,
further derivatizations of the obtained alkenes through redox
manipulation is mandatory to obtain complex polyol scaffolds.
Given 1,3-diols oxidation state, in order to obtain the best
synthetic efficiency, their elaboration should imply a redox-neutral
cascade construction by aldol condensation directly between a ketone
and an alcohol. Inspired by the synthetic economies provided by
borrowing hydrogen approaches, we present a new conceptual
alcohol−aldolization for the direct construction of anti-1,3-diols
Received: July 30, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02536
© XXXX American Chemical Society
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involving a base-promoted overall redox-neutral process starting
from simple primary alcohols and functionalized ketones (Scheme
1c).
Key features for the design of a successful alcohol−
aldolization are the efficient reduction of the carbonyl
compound and its enolizable character, ensuring both the
aldolization step and a chemoselective final hydrogen transfer.
To meet these requirements, we initially selected α-difluorinated
acetophenone 1a6,7 and benzyl alcohol (2a) as model substrates
(Table 1).8,9 Besides representing a proof of concept for the
benzoic acid, providing strong evidence for our proposed metal-
free redox-neutral pathway (entry 2). In addition, the final
reduction step occurred with good diastereocontrol, providing
3a in 10:1 dr.
In order to accelerate the aldolization step and potentially
limit the competing reduction of 1a, we added 20 mol % of
tetrabutylammonium chloride (TABCl), improving the selec-
tivity to a 2.7:1 ratio between 3a and 4 (entry 3).13 In contrast,
using a substoichiometric amount of KOH (0.5 equiv, entry 4)
decreased the selectivity of the alcohol−aldolization, while with
a large excess of KOH (10 equiv, entry 5) only a minor amount
of the expected product was observed. In order to facilitate the
reaction through the initial formation of a small amount of
aldehyde (vide infra), 20 mol % of benzophenone (PhCOPh)
was added as sacrificial hydride acceptor.14 Performing the
reaction at 40 °C resulted in a significantly improved selectivity
in favor of 3a, isolated in 61% yield (99:1 dr, entry 6), while
TBAI was found to be optimum forming 3a in 68% isolated yield
(99:1 dr, entry 7). Finally, the role of the base is crucial for the
reaction since use of Al(Oi-Pr)3, an excellent Lewis acid catalyst
for the Meerwein−Ponndorf−Verley process, only rapidly
reduced 1a to 4 (entry 8).
With optimal conditions for the alcohol−aldolization in hand,
we next confirmed the generality of this method on other
substrates (Scheme 2). The reaction tolerated different starting
α-difluorinated acetophenones containing either electron-
donating groups 1b,c,h,i in the ortho-, meta-, or para-position
or electron-withdrawing halogen atoms 1d−f. All of the
corresponding 1,3-diols 3 could be isolated in 27−81% yield
and 4:1 to 13:1 dr. However, the sharp drop in electron density
with p-nitro acetophenone 2g resulted in its fast reduction, and
only a trace amount of 3g was observed.
Interestingly, starting from monofluorinated ketone 1j, anti-
1,3-diol 3j could be isolated in unoptimized 23% yield,
demonstrating the potential of this approach for other classes
of substrates. Starting from α-difluorinated acetophenone 1a, a
broad range of different primary alcohols 2b−o also reacted in
the process. Starting from benzylic alcohols containing para- or
ortho-electron-donating or electron-withdrawing substituents
afforded diastereoselectively 1,3-diols 3b−f,h,i,k in 45−72%
yield and 5:1 to >20:1 dr. Other classes of substrates such as
naphthalene, furan-, and thiophene-containing alcohols also
reacted well, providing 3l−n in 38−56% yield albeit with lower
diastereocontrol concerning the smaller rings (2:1 and 4:1 dr).
Interestingly, cinnamyl alcohol also provided diol 3o opening
access to other classes of compounds. In contrast, under those
conditions, the use of ethanol only provided partial reduction to
4.
In order to shed light on the mechanism of this alcohol−
aldolization, several control experiments were performed. First,
as mentioned during the optimization, the reaction of 1a with
benzyl alcohol (2a) formed the desired product 3a together with
only minor amounts of alcohol 4 and benzoic acid 5 as side
products (Scheme 3a). This indicates that the evolution of the
aldol intermediate by Tishchenko-type disproportionation with
the in situ formed aldehyde producing benzoic acid 5 represents
a minor pathway.
Table 1. Selected Optimization for the Alcohol−Aldolization
3a yield
3a/4
(%) (dr
a
b
b
c
entry
conditions
ratio
3a dr
isolated)
d
1
2
3
KOH (2 equiv), t-BuOH, 60 °C
KOH (2 equiv), toluene, 60 °C
KOH (2 equiv),TBACl
(20 mol %), toluene, 60 °C
1:1.4
1.9:1
2.7:1
7:1
10:1
8:1
nd
nd
nd
4
5
6
KOH (0.5 equiv), TBACl
1:1.7
1:4.2
4:1
nd
nd
nd
(20 mol %), 60 °C
KOH (10 equiv),TBACl
(20 mol %), toluene, 60 °C
KOH (2 equiv),TBACl
(20 mol %),), PhCOPh
(20 mol %), toluene, 40 °C
KOH (2 equiv), TBAI
(20 mol %), PhCOPh
(20 mol %), toluene, 40 °C
3.5:1
8:1
61 (99:1)
68(99:1)
nd
7
4.2:1
8:1
8
Al(Oi-Pr)3 (50 mol %), toluene
or THF, 60 °C
1:99
nd
a
Reactions performed using 0.1 mmol of 1a and 0.3 mmol of 2a
b
c
during 18−24 h. Determined by H and 19F NMR. Isolated yield
after purification by recrystallization. Formation of approximately 1
1
d
equiv of benzoic acid with respect to 3a.
alcohol−aldolization, such a condensation would provide
valuable fluorinated 1,3-diols possessing a key difluoro-
methylene unit of great biological interest.10
Our initial experiments involved application of an iron
complex to initiate the reversible hydrogen transfer;11 however,
control experiments revealed that the redox process was mostly
promoted by the base presumably through Meerwein−
Ponndorf−Verley-type hydride transfers (vide infra).12 As a
result, we focused our attention on the identification of
appropriate basic conditions for this reaction (Table 1).
In t-BuOH as protic solvent, using different bases (see the SI
for details), such as a 2-fold excess of KOH at 60 °C (entry 1),
anti-1,3-diol 3a was formed diastereoselectively (7:1 dr)
together with secondary alcohol 4 in a 1:1.4 ratio indicating a
large amount of undesired reduction of the starting difluoro
ketone 1a (entry 1). Moreover, under these conditions, a large
amount of benzoic acid was also observed, suggesting either
competing aerobic oxidation mechanism or a release from a
Tishchenko-type disproportionation. These preliminary obser-
vations revealed that to be efficient, the system should
outcompete undesired 1a reduction as well as Tishchenko
reduction all-consuming undesired amounts of 1a and 2a.
Turning to the use of toluene considerably improved the process
forming 3a as the major product with only minor formation of
A Meerwein−Ponndorf−Verley-type hydride transfer under
those conditions was further demonstrated by reducing ketone
1a to 4 with 29% conversion using 3 equiv of 2-propanol 6 as
hydride donor (Scheme 3b). In addition to providing evidence
for the proposed mechanism, this type of reactivity is also
interesting for a potential eco-compatible reduction of
B
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fluorinated ketones involving cheap and nonhazardous reagents.
The reduction of α-difluorinated acetophenones is also poorly
reversible since when 4 was treated with ketone 7 no hydride
transfer occurred (Scheme 3c). Similarly, a crossover experi-
ment treating 3a under the same conditions with another
benzylic alcohol confirmed the irreversibility of the final
reduction (see the SI). Finally, alcohol 2c irreversibly reduces
aldol product 8 to 1,3-diol 3a with good diastereocontrol
together with the formation of a small amount of alcohol 4
(Scheme 3d).15 This clearly indicates that a retro-aldol reaction
is partially competing with the direct reduction, which was
further confirmed when 8 was treated under the same conditions
without hydride donor (see the SI). Interestingly, in the reaction
of Scheme 3d, carboxylic acid 10 is formed together with
aldehyde 9. This suggests that the aldehyde able to accumulate
in this equation is partially oxidized through aerobic oxidation
and a competing Tishchenko reaction as confirmed through
control experiments (see the SI).
Scheme 2. Scope of the Alcohol−Aldolization
Altogether, these observations suggest that the major pathway
for this alcohol−aldolization follows the mechanism proposed in
Scheme 4a. The redox steps involve a base-promoted
Scheme 4. Mechanism of the Alcohol−Aldolization
Scheme 3. Mechanistic Experiments
Meerwein−Ponndorf−Verley-type hydride transfer from alco-
holates to carbonyls (Scheme 4b). From the primary alcohol,
hydride transfer to a sacrificial acceptor (fluorinated ketone or
benzophenone)16 initiates the reaction by generating a small
amount of reactive aldehyde. The propagation cycle occurs
through a fast and reversible base-promoted ketone addition
creating the aldol adduct intermediate. Its diastereoselective
reduction by hydrogen transfer from another molecule of
alcohol regenerates the aldehyde, thus closing the propagation
cycle. The final reduction is strongly irreversible, shifting the
equilibrium toward the desired 1,3-diol.
The diastereoselective reduction of the nonenolizable aldol
intermediate can be rationalized by formation of a hydrox-
ycarbonyl chelate as already observed in Meerwein−Ponndorf−
Verley hydride transfers.9a In addition, this behavior also argues
in favor of its chemoselective reduction in the presence of the
starting ketone, whose reduction is hampered by enolization in
basic media.
With these conditions, limitations can arise when the aldol
adduct is reduced too slowly by the alcohol. Under such
scenario, fast reduction of the starting ketone could result in
aldehyde accumulation and subsequent parasitic aerobic
C
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(Scheme 4a). As a result, future development in this chemistry
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To conclude, we have developed a new condensation of
fluorinated ketones with alcohols enabling the direct synthesis of
1,3-diols through a base-promoted redox-neutral process. This
transformation occurs through several Meerwein−Ponndorf−
Verley-type hydride transfers combined with an aldol con-
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alcohol as hydride source, this alcohol−aldolization provides
considerable synthetic economies (step, reagent, waste) and
enables bypassing the classical oxidation and reduction steps
necessary for the preparation of valuable 1,3-diol scaffolds. We
are convinced that the concept described here will serve as a
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condensations or related reactions using hydride transfer or
borrowing hydrogen metal catalysts.
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02536.
Additional experiments, protocols for the alcohol−
aldolization, product characterization, and spectra
(PDF)
FAIR data, including the primary NMR FID files, for
compounds 3a−3o (ZIP)
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AUTHOR INFORMATION
Corresponding Author
■
Adrien Quintard − Aix Marseille Univ, CNRS, Centrale
Marseille, iSm2, Marseille 13397, France; orcid.org/0000-
0003-0193-6524; Email: adrien.quintard@univ-amu.fr
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1988, 38, 19−40. (d) Sasaki, S.; Yamauchi, T.; Kubo, H.; Kanai, M.;
Ishii, A.; Higashiyama, K. Tetrahedron Lett. 2005, 46, 1497−1500.
(e) Sokeirik, Y. S.; Sato, K.; Omote, M.; Ando, A.; Kumadaki, I. J.
Fluorine Chem. 2006, 127, 150−152. (f) Mikami, K.; Murase, T.; Itoh,
Y. J. Am. Chem. Soc. 2007, 129, 11686−11687.
Authors
Na Shao − Aix Marseille Univ, CNRS, Centrale Marseille, iSm2,
Marseille 13397, France
Jean Rodriguez − Aix Marseille Univ, CNRS, Centrale Marseille,
iSm2, Marseille 13397, France
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02536
(8) For the use of fluorinated ketones in aldol−Tishchenko reactions,
́
see: (a) Xu, W.; Medebielle, M.; Bellance, M.-H.; Dolbier, W. R. Adv.
Synth. Catal. 2010, 352, 2787−2790. (b) Asano, T.; Kotani, S.;
Funding
Nakajima, M. Org. Lett. 2019, 21, 4192−4196.
(9) For other examples of preparation of bis-fluorinated 1,3-diols, see:
(a) Kuroboshi, M.; Ishihara, T. Bull. Chem. Soc. Jpn. 1990, 63, 1185−
1190. (b) Prakash, G. K.S.; Hu, J.; Mathew, T.; Olah, G. A. Angew.
Chem., Int. Ed. 2003, 42, 5216−2019. (c) Clarke, M. L.; France, M. B.;
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Angew. Chem., Int. Ed. 2014, 53, 9512−9516. (g) Doi, R.; Ohashi, M.;
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The Agence National de la Recherche (ANR-19-CE07-0033),
the Centre National de la Recherche Scientifique (CNRS), and
́
Aix-Marseille Universite are warmly acknowledged for financial
support. N.S. thanks the China Scholarship Council for a PhD
grant (no. 201908070004).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
All technical staff from Aix-Marseille Spectropole are acknowl-
edged for their support.
■
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(15) Reduction of 8 is also possible using 3 equiv of 2-propanol but
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Supporting Information for details.
(16) Given the same type of reactivity observed in the absence of
benzophenone resulting only in slightly decreased yield, we can rule out
a possible radical pathway. Benzophenone is believed to act as a hydride
acceptor facilitating the initiation step without consuming too much
starting ketone. The lower yield obtained in the redox-neutral
aldolization when performing the reaction under air indicates that
oxidation by oxygen is less likely to initiate the process. This is
confirmed by the absence of peroxide formation at the end of these
alcohol aldolizations.
E
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