Merging α-Lithiation and Aldol-Tishchenko Reaction to Construct Polyols from Benzyl Ethers

Article abstract of DOI:10.1021/acs.orglett.0c03014

α-Lithiobenzyl ethers, generated by selective α-lithiation, undergo an aldol-Tishchenko reaction upon treatment with carboxylic esters and paraformaldehyde. The reaction of the organolithium with the carboxylate generates an intermediate enolate that, after formaldehyde addition, affords 1,2,3-triol derivatives in a straightforward and one-pot manner. These products are obtained as single diastereoisomers bearing a quaternary stereocenter. The complete diastereocontrol of the aldol-Tishchenko process is attributed to stereoelectronic preferences in the transition state.

Full text of DOI:10.1021/acs.orglett.0c03014

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Letter
Merging α‑Lithiation and Aldol-Tishchenko Reaction to Construct
Polyols from Benzyl Ethers
́
Carlos Sedano, Rocío Velasco, Samuel Suarez-Pantiga, and Roberto Sanz*
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ABSTRACT: α-Lithiobenzyl ethers, generated by selective α-lithiation,
undergo an aldol-Tishchenko reaction upon treatment with carboxylic
esters and paraformaldehyde. The reaction of the organolithium with
the carboxylate generates an intermediate enolate that, after form-
aldehyde addition, affords 1,2,3-triol derivatives in a straightforward and
one-pot manner. These products are obtained as single diastereoisomers
bearing a quaternary stereocenter. The complete diastereocontrol of the
aldol-Tishchenko process is attributed to stereoelectronic preferences in the transition state.
α-Lithiated oxygen-substituted compounds,1 though carbe-
noids in nature,2 are useful reagents for accessing function-
alized oxygenated compounds. Although α-lithiated benzyl
ethers can be easily accessed by deprotonation with highly
basic alkyllithiums3 or by Sn−Li exchange,4 their synthetic
usefulness is limited by competitive processes like eliminations
or Wittig rearrangements.5 Following our interest in the
preparation and applications of oxygen-functionalized organo-
lithiums,6 we have reported that aryl α-lithiobenzyl ethers,
generated from α-lithiation with t-BuLi at low temperatures,
can be functionalized with electrophilic reagents avoiding the
previously described [1,2]-Wittig rearrangement (Scheme 1,
eq 1).7 In the study of the reactivity of these α-oxygenated
organolithiums, we found that their reactions with aromatic
carboxylic esters gave rise to ketones rather than the expected
tertiary alcohols. This behavior was likely due to the in situ
formation of an enolate, by the fast deprotonation of the
ketone with the ethoxide byproduct (Scheme 1, eq 2).8
On the contrary, the classical aldol-Tishchenko reaction
leads to the trimerization of an enolizable aldehyde, under
basic conditions, affording a 1,3-anti-diol monoester.9 In
particular, ketone enolates react with an excess of aldehyde
to form 1,3-anti-diol monoesters in a hetero-aldol-Tishchenko
reaction that is a powerful, one-step methodology for creating
up to three contiguous stereocenters, even in an enantiose-
lective way in the presence of chiral catalysts (Scheme 1, eq
3).10 Nevertheless, very few examples of acyclic ketones with a
tertiary stereocenter at the α-position, thus leading to the
construction of quaternary stereocenter, have been reported.11
A related transformation is the aldol condensation of aliphatic
aldehydes with formaldehyde followed by a crossed Canni-
zzaro reaction to give gem-dihydroxymethyl derivatives
(Scheme 1, eq 4).12 However, with related ketones, form-
aldehyde typically affords hydroxymethylated products.13 It is
also noteworthy that formaldehyde is one of the most
important C1 electrophiles in organic synthesis.14
Scheme 1. Previous Results in the Reaction of Aryl α-
Lithiobenzyl Ethers with Carboxylates and the Work
Presented Here
Received: September 9, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03014
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Considering an enolate as a plausible and potentially useful
intermediate from the reactions of α-lithiobenzyl ethers with
carboxylates,8 we envisaged that its treatment with an
aldehyde15 could trigger an aldol-Tishchenko reaction, though
the diastereoselectivity of the process could not be clearly
predicted due to the generation of a quaternary stereocenter
(Scheme 1, eq 5). Herein, we report how the α-lithiation of
simple benzyl ethers could be merged with the powerful aldol-
Tishchenko reaction, allowing access to interesting triol
derivatives in a complete diastereoselective manner in one
operational step.16
Scheme 2. Stereochemical Assignment of 3aa and Synthesis
of 1,3-Dioxane 4a
With an efficient protocol in place to obtain a triol derivative
like 3aa, we surveyed the scope of this reaction with a selection
of easily available aryl benzyl ethers 1 and different esters
(Table 2). Using benzyl phenyl ether 1a, a wide variety of
We selected benzyl phenyl ether 1a as model substrate, and
as we had previously reported, its α-lithiation with a slight
excess of t-BuLi and further reaction with ethyl benzoate gives
rise after hydrolysis to α-phenoxy ketone 2aa (Table 1, entry
Table 2. Reactions of α-Lithiated Aryl Benzyl Ethers 1 with
a
(Hetero)aromatic Carboxylates and Formaldehyde
Table 1. Conditions for the Reaction of α-Lithiated 1a with
a
Benzoates and Formaldehyde
b
entry ether
Ar
R
product yield (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
70
61
75
60
72
70
75
73
67
25
66
80
74
65
67
64
61
62
1-naphthyl
4-(MeO)C6H4
2-(MeO)C6H4
4-FC6H4
4-BrC6H4
2-ClC6H4
3-ClC6H4
2-thienyl
i-Pr
4-FC6H4
4-FC6H4
4-FC6H4
4-FC6H4
4-FC6H4
Ph
b
c
entry
R
x
product
yield (%)
1
2
3
4
5
6
7
8
Et
Et
Et
Et
Me
i-Pr
Bn
Ph
0
1.1
2
2.5
2.5
2.5
2.5
2.5
2aa
3aa
3aa
3aa
3aa
3aa
3aa
79 (73)
(21)
(58)
74 (70)
70
39
53
−
9
10
11
12
13
14
15
16
17
18
3aj
d
−
4-(MeO)C6H4
4-ClC6H4
4-(t-Bu)C6H4
4-PhC6H4
3-(CF3)C6H4
2-(i-Pr)C6H4
2-(MeO)C6H4
2-naphthyl
3be
3ce
3de
3ee
3fe
3ga
3ha
3ie
a
Reaction conditions: 1a (0.5 mmol), t-BuLi (0.65 mmol, 30 min),
PhCO2R (0.65 mmol, 1 h), (HCHO)n (x equiv, 2 h);
b
paraformaldehyde used as the HCHO source. Equivalents of
c
paraformaldehyde referenced to 1a. NMR yield using 1,3,5-
trimethoxybenzene as an internal standard. Isolated yield in
1g
1h
1i
d
parentheses. Decomposition was observed without any identified
Ph
4-FC6H4
product.
a
Reaction conditions: 1 (0.5−1 mmol), t-BuLi (1.3 equiv, 30 min),
b
RCO2Et (1.3 equiv mmol, 1 h), (HCHO)n (2.5 equiv, 2 h). Isolated
1). When paraformaldehyde (1.1 equiv) was added before the
hydrolysis, a different compound was observed, although
significant decomposition was also detected (entry 2). This
compound was initially assigned to triol derivative 3aa, arising
from an aldol-Tishchenko reaction. Remarkably, it was
generated as a single diastereoisomer. Looking to improve its
formation, we found a larger amount of paraformaldehyde to
be required (entries 3 and 4). Under the optimal conditions
(entry 4), we decided to test other benzoates as electrophiles
to determine if the lithium alkoxide, released from the reaction
of 1a-Li with the ester, plays a non-innocent role in the
formation of the intermediate enolate from ketone 2aa.
Whereas methyl benzoate afforded a similar result (entry 5),
isopropyl and benzyl benzoates provide lower yields of 3aa
(entries 6 and 7, respectively), and phenyl benzoate led to only
decomposition (entry 8). Thus, methyl and ethyl carboxylates
were selected as the optimal partners.
yield referenced to starting ether 1.
(hetero)aromatic carboxylates was evaluated to demonstrate
the applicability of this strategy for accessing functionalized 2-
phenoxy-1,3-diol derivatives 3 (entries 1−9). Aromatic esters
bearing electron-donating or electron-withdrawing groups at
different positions, as well as a heteroaromatic ester, gave rise
to the corresponding triol derivatives 3aa−ai in good yields.
The use of an aliphatic ester, such as ethyl isobutyrate, led to
the corresponding product 3aj in a lower yield, along with
starting ether 1a, likely due to competitive α-proton
abstraction, and some unidentified side products (entry 10).
Other functionalized aryl benzyl ethers 1b−i, possessing
different groups at the ortho, meta, or para positions of the
aryl moiety, also showed the same reactivity as the parent ether
1a affording, after α-lithiation and reaction with ethyl p-
fluorobenzoate or ethyl benzoate and formaldehyde, the
corresponding 2-aryloxy-1,3-diol derivatives 3 also in high
yields (entries 11−18). In this way, we were able to prepare
triol derivatives 3 being functionalized in both aromatic rings.
Azzena and co-workers had described the direct metalation
of methyl and methoxymethyl benzyl ethers 5 and 6, showing
The complete characterization and stereochemical assign-
ment of 3aa were carried out by its transformation into ketal
derivative 4a through reaction with an acetone equivalent
under acid catalysis (Scheme 2). The NMR analysis of 4a
supports the proposed aldol-Tishchenko product and lets us
know the relative configuration of the stereocenters in 3aa.
B
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that the corresponding α-alkoxy-substituted benzyllithium
derivatives could be reacted with electrophiles prior to undergo
Wittig rearrangement.17 To minimize the amount of the
carboxylic ester employed as an electrophile, which is
influenced by the excess of the base required for the
metalation, a revision of the reaction conditions initially
reported for the α-lithiation of both alkyl benzyl ethers 5 and 6
was carried out (see the Supporting Information). Gratifyingly,
treatment of the α-lithiobenzyl ethers derived from 5 and 6,
under the same conditions previously described for 1, led to
the expected aldol-Tishchenko products, 2-alkoxy-1,3-diols 7
and 8, respectively, as single diastereoisomers (Table 3, entries
Scheme 3. Synthesis of 1,3-Dioxanes 4b and 4c
Scheme 4. Mechanistic Proposal
Table 3. Synthesis of 2-Alkoxy and 2-Hydroxy 1,3-Diol
a
Derivatives 7−9 from Alkoxy Benzyl Ethers 5 and 6
b
entry
starting ether
Ar
product
yield (%)
1
2
3
4
5
6
7
8
5
5
5
5
5
6
6
6
6
6
6
6
6
6
6
6
Ph
7a
7b
7c
7d
7e
8a
8b
8c
8d
8e
8f
8g
8h
9b
9c
9e
69
57
49
50
58
55
60
68
50
60
75
61
63
52
62
56
1-naphthyl
4-FC6H4
4-BrC6H4
2-ClC6H4
Ph
1-naphthyl
4-FC6H4
4-BrC6H4
2-ClC6H4
3-ClC6H4
2-FC6H4
4-CF3C6H4
1-naphthyl
4-FC6H4
2-ClC6H4
transfer via transition state IV. The relative stereochemistry of
the triol derivatives corresponds to an arrangement in which
the C-2 alkoxy or aryloxy group is located in an axial position.
This fact could be attributed to a stereoelectronic preference
for the conformation in which the oxygenated substituent, the
best donor lone pair or bond, is antiperiplanar to the best
acceptor bond, the ketone group. In addition, we have carried
out the reaction of 1a using paraformaldehyde-d2 isolating
trideuterated 3aa-d3, thus further supporting our proposal
(Scheme 4).
9
10
11
12
13
14
15
c
Then, we turned our attention to the use of diethyl
carbonate, which can be easily accessed from CO2,18 as a C1
synthon carboxylate partner19 for the methodology reported
herein. First, we found that its reaction with the α-lithiobenzyl
ethers generated from 1a, 5, and 6 led, after hydrolysis, to
bis(α-alkoxy)benzyl ketones 10, which were obtained as
variable mixtures of diastereoisomers that could be isolated
independently (Scheme 5). Their formation was also explained
c
c
16
a
Reaction conditions: 5 or 6 (1 mmol), t-BuLi (1.2 mmol, 30 min),
b
ArCO2Et (1.2 mmol, 1 h), (HCHO)n (2.5 mmol, 2 h). Yield of the
isolated product referenced to starting ether 5 or 6. Corresponding
crude products 8 were treated with PTSA (1 equiv) in EtOH at 60 °C
for 4 h.
c
Scheme 5. Reactions of α-Lithiated Benzyl Ethers with
Diethyl Carbonate and Synthesis of Ketones 10 and Tetraol
Derivatives 11
1−13). A selection of aromatic carboxylates was assayed with
both alkyl benzyl ethers giving rise to triol derivatives 7 and 8
in moderate to good yields, although mainly from 5 lower
yields were obtained compared to those from aryl benzyl ethers
1. Moreover, if crude 2-methoxymethyloxy-1,3-diol derivatives
8 are treated with acid, the corresponding 1,2,3-triol products
9 can be easily obtained (entries 14−16). The relative
stereochemistry of the obtained 1,3-diols 7 and 8 was found
to be the same as that of 1,3-diols 3, as shown by NMR
analysis of 1,3-dioxanes 4b and 4c (Scheme 3).
Our mechanistic proposal to account for the formation of
triol derivatives 3, 7, and 8 from α-lithiobenzyl ethers I is
shown in Scheme 4. According to our previous results, a
ketone 2 is generated after the reaction of I with the
carboxylate, which undergoes in situ deprotonation with the
alkoxide byproduct leading to enolate II. Its reaction with two
molecules of formaldehyde affords intermediate hemiacetal III
that evolves to the final products by intramolecular hydride
C
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by assuming that the generation of corresponding enolates II′
is faster than the third addition of the organolithium that
would give rise to the tertiary alcohol. Then, when form-
aldehyde was added prior to hydrolysis, tetraol derivatives 11
were obtained in moderate to good yields as mixtures of
diastereoisomers, though 11b and 11c with remarkable
selectivity. In accordance with our mechanistic proposal, the
relative stereochemistry of C-2 and C-3 in the 2,4-
diphenylbutane-1,3-diols 11 is completely controlled by
aldol-Tishchenko transition state IV′ (Scheme 5).
Tishchenko reaction. Remarkably, the triol derivatives
obtained in a diastereoselective manner are excellent building
blocks for the synthesis of valuable compounds, such as
functionalized oxetanes that can be obtained in only two
operational steps from simple starting materials.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03014.
Due to the interest of the oxetane motif in medicinal
chemistry as a surrogate for lipophilic gem-dimethyl or labile
carbonyl groups as well as its potential usefulness for further
synthetic transformations,20 we planned to synthesize function-
alized oxetanes from the prepared 1,3-diol derivatives. As the
intramolecular Williamson etherification is one of the most
general strategies for the synthesis of oxetanes,21 first, we
prepared primary monotosylate 12a from 1,3-diol derivative 7a
(Scheme 6). Then, we attempted to synthesize oxetane 13a by
Full experimental procedures, characterization data, and
copies of NMR spectra (PDF)
FAIR data, including the primary NMR FID files, for
compounds 3aa, 3aa-d3, 3ab, 3ac, 3ad, 3ae, 3af, 3ag,
3ah, 3ai, 3be, 3ce, 3de, 3ee, 3fe, 3ga, 3ha, 3ie, 4a, 4b,
4c, 5-d, 6-d, 7a, 7b, 7c, 7d, 7e, 8a, 8b, 8c, 8d, 8e, 8f, 8g,
8h, 9b, 9c, 9e, 10a-diast1, 10a-diast2, 10b-diast1, 10b-
diast2, 10c-diast1, 10c-diast2, 11a, 11b, 11c, 12a, 13a,
13b, 13c, 13d, and 14 (ZIP)
Scheme 6. Synthesis of Oxetanes 13 from Triol Derivatives
7
AUTHOR INFORMATION
Corresponding Author
■
́
́
́
Roberto Sanz − Area de Quimica Organica, Departamento de
́
Quimica, Facultad de Ciencias, Universidad de Burgos, 09001
Burgos, Spain; orcid.org/0000-0003-2830-0892;
Email: rsd@ubu.es
Authors
́
́
́
Carlos Sedano − Area de Quimica Organica, Departamento de
́
Quimica, Facultad de Ciencias, Universidad de Burgos, 09001
Burgos, Spain
́
́
́
Rocío Velasco − Area de Quimica Organica, Departamento de
its treatment with n-BuLi.21a However, a very low yield of the
desired oxetane was obtained. Looking for a suitable, as well as
one-pot procedure, process, we found that the reaction of a
variety of 1,3-diols 7 with an excess of tosyl chloride in the
presence of base led to the desired oxetanes 13 in moderate to
good yields, presumably via an initial sulfonation of the
primary alcohol with subsequent alkylation of the secondary
hydroxy group (Scheme 6).22 In addition, the relative
stereochemistry of the final oxetanes further supports that
proposed from 1,3-dioxane derivatives 4.
́
Quimica, Facultad de Ciencias, Universidad de Burgos, 09001
Burgos, Spain
́
́
́
́
Samuel Suarez-Pantiga − Area de Quimica Organica,
́
Departamento de Quimica, Facultad de Ciencias, Universidad
de Burgos, 09001 Burgos, Spain; orcid.org/0000-0002-
4249-7807
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03014
Notes
In summary, we have described an efficient highly
diastereoselective protocol to synthesize polyol derivatives in
one operational step from simple and easily available benzyl
ethers involving α-lithiation, carboxylate addition, and aldol-
Tishchenko reaction. The C−H bond functionalization of the
benzyl ethers takes place selectively through α-lithiation at low
temperatures, thus avoiding the expected [1,2]-Wittig
rearrangement. After a fine-tuning of the reaction conditions,
the α-lithiobenzyl ethers generated were successfully engaged
in addition to carboxylates. Then the in situ-produced enolate
evolves through a second C−C bond-forming reaction to the
desired polyols after aldol-Tishchenko reaction upon addition
of formaldehyde. This method has been revealed to be efficient
for obtaining challenging quaternary carbons, which are found
to commonly participate in retro-aldol reaction. Under the
established reaction conditions, no noticeable retro-aldol
reaction was observed. Interestingly, diethyl carbonate was
also demonstrated to act as carboxylate equivalent in the
process allowing the addition of 2 equiv of α-lithiobenzyl
ethers providing access to tetraol derivatives after aldol-
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors gratefully acknowledge Ministerio de Ciencia e
■
́
Innovacion and FEDER (CTQ2016-75023-C2-1-P) and Junta
́
de Castilla y Leon and FEDER (BU291P18) for financial
́
support. S.S.-P. thanks Junta de Castilla y Leon and FEDER for
́
a postdoctoral contract. C.S. thanks Ministerio de Educacion
for an FPU predoctoral contract.
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(15) After a brief initial screening that formaldehyde was the only
aldehyde that provides good results in the proposed sequence. The
use of an aromatic aldehyde like p-chlorobenzaldehyde leads to the
intermediate ketone, what indicates that no reaction occurs between
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E
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Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
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(22) The preparation of the corresponding oxetanes from 3 was not
possible due to competitive Grob fragmentation of the intermediate
into an aldehyde and an enol ether 14 (see the Supporting
Information for further details).
F
https://dx.doi.org/10.1021/acs.orglett.0c03014
Org. Lett. XXXX, XXX, XXX−XXX