Regioselective desymmetrization of diaryltetrahydrofurans via directed ortho-lithiation: An unexpected help from green chemistry

Article abstract of DOI:10.1039/c4cc03149k

An efficient functionalization of diaryltetrahydrofurans via a regioselective THF-directed ortho-lithiation is first described. This reaction can be successfully carried out in cyclopentyl methyl ether as a greener alternative to Et₂O, with better results in terms of yield and selectivity and, surprisingly, also in protic eutectic mixtures competitively with protonolysis.

Full text of DOI:10.1039/c4cc03149k

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Regioselective desymmetrization of
diaryltetrahydrofurans via directed ortho-lithiation:
an unexpected help from green chemistry†‡
Cite this: Chem. Commun., 2014,
50, 8655
Received 28th April 2014,
Accepted 20th May 2014
Valentina Mallardo, Ruggiero Rizzi, Francesca C. Sassone, Rosmara Mansueto,
Filippo M. Perna, Antonio Salomone and Vito Capriati*
DOI: 10.1039/c4cc03149k
www.rsc.org/chemcomm
An efficient functionalization of diaryltetrahydrofurans via a regio- environmentally friendly reaction media, thus unexpectedly opening
selective THF-directed ortho-lithiation is first described. This reac- up new avenues and possibilities for the organolithium field.
tion can be successfully carried out in cyclopentyl methyl ether as a
At the outset of our investigation, we selected 2,2-diphenyl-
‘‘greener’’ alternative to Et2O, with better results in terms of yield tetrahydrofuran 3a as our model substrate, taking into considera-
and selectivity and, surprisingly, also in protic eutectic mixtures tion the fact that a regioselective ortho-functionalization would
competitively with protonolysis.
create a chiral molecule via a desymmetrization reaction.
Compound 3a was straightforwardly prepared in 80% yield via
Substituted tetrahydrofuran (THF) derivatives are important struc- an intramolecular basic cyclization by reacting a THF solution of
tural features commonly encountered in many synthetic and natural the commercially available PhMgCl 2a (3 equiv.) with 4-chloro-1-
products with wide-ranging biological activity.1 Their lack of reac- phenylbutan-1-one 1a (1 equiv.) for 24 h (Scheme 1). When an
tivity, however, has discouraged their use as a starting material in Et2O solution of 3a (1 equiv.) was subjected to the conditions we
organic synthesis, which remains a challenging task. It’s only used for the ortho-lithiation of aryloxetanes (s-BuLi (1.4 equiv.),
recently that a few strategic THF ring elaborations have started to 0 1C, 10 min),8 followed by quenching with MeI, we were pleased
be documented; these include: direct functionalization reactions,2 to find that the desired ortho-methylated adduct 4a did indeed
a-zincation,3a a-alumination,3b a-lithiation,4 iron-catalysed ring- form in 65% yield (Table 1, entry 1), presumably through the
opening azidation and allylation,5 and N-heterocyclic carbene- putative ortho-lithiated intermediate 3a–Li. Using a two-fold
borane promoted tetrahydrofuran nucleophilic substitutions.6 As excess of the base led to an increase of the yield up to 80%
part of our program aimed at developing new aspects of reactivity of (Table 1, entry 2), whereas a longer lithiation time of 60 min, or
saturated oxygen-based heterocycles, we have recently discovered the presence of a bidentate ligand such as tetramethylethylene-
that an oxetane motif can act as an effective director of both diamine (TMEDA) (2 equiv.)10 resulted in the isolation of 4a in 75
a-lithiation7 and ortho-lithiation.8 Thus, we became interested in and 50% yields, respectively (Table 1, entries 3 and 4).
also studying the ability of the THF moiety to promote an ortho-
The employment of temperatures as low as À78 and À20 1C, as
lithiation process.9 Building on our recent findings, this paper well as different organolithium reagents such as n-BuLi and lithium
describes the first successful use of tetrahydrofuran as an effective diisopropylamide (LDA), failed to produce ortho-lithiation (Table 1,
direct metalation group (DMG) in the regioselective desymmetriza- entries 5–8). Other solvents, such as THF and toluene, proved to be
tion/functionalization of diaryltetrahydrofurans. In the course of our similarly ineffective (Table 1, entries 9 and 10). To our delight, the
investigation it was found that (a) cyclopentyl methyl ether proved to use of t-BuLi (1.9 equiv.) as a base in Et2O at 0 1C improved the
be a valid, greener alternative to Et2O, often providing better yields conversion considerably allowing the recovery of 4a in a nearly
and higher selectivity, and (b) organolithium reactions could also quantitative yield (498%) (Table 1, entry 11). Most probably, the
be successfully carried out in protic eutectic mixtures as more stronger basicity of t-BuLi compensates for the lower electron-donor
ability of tetrahydrofuran in coordinating the lithium compared to
that of an oxetane ring,8 thereby promoting more efficiently the
`
Dipartimento di Farmacia-Scienze del Farmaco, Universita di Bari ‘‘Aldo Moro’’,
Consorzio C.I.N.M.P.I.S., Via E. Orabona 4, Bari, I-70125, Italy.
E-mail: vito.capriati@uniba.it; Tel: +39 080 5442174
† Electronic supplementary information (ESI) available: Experimental proce-
dures, spectroscopic data, and copies of the 1H/13C NMR spectra of compounds
3b–d, 4a–x, and 5f. See DOI: 10.1039/c4cc03149k
‡ This communication is dedicated to Professor R. J. K. Taylor on the occasion of
his 65th birthday.
Scheme 1
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Table 1 Optimization of the regioselective ortho-lithiation–alkylation of
3a under different conditions
Table 2 Scope study for the directed ortho-lithiation of diaryltetrahydro-
furan derivatives 3a–da,b
Entry Base (equiv.) Time (min) T (1C) Solvent RI
4 yield (%)
1
2
3
4
5
6
7
8
s-BuLi (1.4)
s-BuLi (2)
s-BuLi (2)
s-BuLi (2)b
s-BuLi (2)
s-BuLi (2)
n-BuLi (2)
LDA (2)
s-BuLi (2)
s-BuLi (2)
t-BuLi (1.9)
t-BuLi (1.9)
t-BuLi (1.9)
10
10
60
10
10
10
10
10
10
10
10
10
10
0
0
0
0
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
THF
MeI 4a (65)a
MeI 4a (80)a
MeI 4a (75)a
MeI 4a (50)a
MeI 4a (0)
MeI 4a (o5)c
MeI 4a (0)
MeI 4a (0)
MeI 4a (0)
À78
À20
0
0
0
0
0
0
0
9
10
11
12
13
Toluene MeI 4a (20)a
Et2O
CPME
CPME
MeI 4a (498)a
MeI 4a (498)a
EtI 4b (80)a,d
a
a
b
Isolated yield after column chromatography. All reactions were conducted
Isolated yield after column chromatography. 2 equiv. of TMEDA.
c
d
Determined by 1H NMR of the crude reaction mixture. No reaction
with 1 mmol of substrate in 0.5 M concentration. All products are racemic
b
mixtures. Both compounds 4v and x derive from the reaction of 3d.
in Et2O.
c
d
Reaction run in CPME (0.5 M). Isolated as a mixture of two separable
e
diastereomers (60 : 40). This yield also refers to reactions in which an Et2O
solution was reacted with an acetone–water mixture (6 equiv. each) or with
neat acetone (6 equiv.). Isolated as a mixture of two inseparable diaster-
ortho-lithiation. Running the lithiation of 3a with up to 4 equiv. of
t-BuLi in Et2O, followed by quenching with MeI, however, did not
provide any bis-methylated adduct, but only 4a (498%). Thus, most
probably, an ortho-dilithiated intermediate could not be formed.
f
eomers (60 : 40).
With the optimized conditions in hand, a range of electro- –formylation sequences, all of them successfully furnished the
philes was screened and the results are reported in Table 2. As ortho-substituted products 4q–u in reasonable to very good yields
for heteroatom-based electrophiles, the reaction of 3a–Li with (60–85%). In the case of the unsymmetrical THF derivative 3d, a
Bu3SnCl, PhSSO2Ph, and Ph2PCl afforded the corresponding mixture of two separable regioisomers 4v and x in 55 and 30%
tin, sulphenyl, and phosphenyl derivatives 4c–e in good to high yields, respectively, was obtained upon deprotonation–formyla-
yields (60–90%). Both chlorination and fluorination could also tion (Table 2). The formation of adducts 4s–x also indicates that
be successfully accomplished using hexachloroethane and the tetrahydrofuran ring is more effective at directing ortho-
N-fluorobenzenesulfonimide as Cl+ and F+ synthetic equivalents, lithiation than a methoxy substituent. It is worth noting that
thus leading to adducts 4f and g in very good yields (85–90%). the above diaryltetrahydrofurans can also be adequate precursors
Trapping with both DMF and N,N-dimethylbenzamide delivered of the corresponding g-butyrolactones, which are common struc-
aldehyde 4h and the aromatic ketone 4i, respectively, both in tural motifs in many biologically active compounds and natural
90% yield. Remarkably, the reactions with 4-methylphenyl-1- products. Indeed, compounds 3a and 4f consistently produced
isocyanate and ethyl 2-(bromomethyl)acrylate as more reactive the corresponding lactones 5a and f both in 70% yield (Table 2)
electrophiles resulted in the formation of the amide 4j and the once subjected to the system composed of catalytic ruthenium(IV)
allylated product 4k bearing an ester moiety, both in good yield oxide and NaIO4 in CCl4–H2O.
(70%). Reactions with carbonyl compounds proceeded equally
Environmentally friendly reaction media are continuously
well with enolizable aliphatic aldehydes. Indeed, 3a–Li could being searched for by the chemical industry, with the aim of
be smoothly ortho-functionalized with acetaldehyde and cyclo- maximizing the sustainability and safety of chemical processes,
hexanone, affording the expected ortho-hydroxyalkylated deriva- in particular during scale-up work. Cyclopentyl methyl ether
tives 4l and m in good yield (70%). No reaction, however, was (CPME), which can be produced directly from cyclopentene,
detected with acetone (4n: 0%), and the addition to an aromatic has recently been promoted as a potential green alternative
ketone (benzophenone) and aldehyde (4-chlorobenzaldehyde) solvent for many organometallic reactions.11 Thus, we wondered
gave lower yielding reactions (4o and p: 40%).
whether it could represent a valid alternative to Et2O for carrying
We also evaluated the effects of substituents on the sensi- out the above ortho-lithiation reactions. We were delighted to
tivity of the reaction. To this end, symmetrically- and non- find that subjecting 3a to lithiation with t-BuLi (1.9 equiv., 0 1C)
symmetrically-disubstituted diaryltetrahydrofurans 3b–d, with in CPME, followed by quenching with MeI, provided the
fluorine and methoxy groups, were similarly prepared from the expected adduct 4a in an almost quantitative yield (498%)
corresponding commercially available chloroketones 1b and c, (Table 1, entry 12). We sought to capitalize on that by cross-
and Grignard reagents 2a–c, as outlined in Scheme 1. Once checking results for some representative reactions run in CPME.
subjected to deprotonation–methylation, –chlorination, and Pleasingly, quenching 3a–Li in CPME with both benzophenone
8656 | Chem. Commun., 2014, 50, 8655--8658
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Table 3 Regioselective preparation of intermediate 3a–Li and quenching
with electrophiles in ChCl-containing DES mixtures
and 4-chlorobenzaldehyde, which were shown to react sluggishly
in Et2O, furnished the corresponding hydroxyalkylated THF
derivatives 4o and p in 90% and 80% yields, respectively
(Table 2). Similarly, in the case of chlorodiphenylphosphine, a
better yield could be achieved for 4e in CPME (85% vs. 60% in
Et2O), whereas adducts 4v and x were isolated in 57 and 33%
yields, respectively, upon deprotonating 3d in CPME followed by
interception with DMF (Table 2).
Impressively, while no reaction was observed between 3a–Li
and EtI in Et2O, the desired ortho-ethylated adduct 4b formed
in 80% yield in CPME (Table 1, entry 13). The reaction of 3a–Li
with acetone (6 equiv.) in CPME took place as well, although the
expected hydroxyalkylated compound 4n formed in 30% yield
only (Table 2). Most probably, in the case of acetone, under the
above conditions, enolization still competes a lot with the
nucleophilic addition.
Entry
Solvent
DESa
Electrophile
4 yieldb (%)
1
2
3
4
5
6
Et2O
ChCl–Gly (1 : 2)
ChCl–Gly (1 : 2)
ChCl–urea (1 : 2)
ChCl–H2O (1 : 2)
ChCl–urea (1 : 2)
ChCl–Gly (1 : 2)
Acetone
4n (40)
4o (75)
4o (75)
4o (33)
4e (75)
4h (90)c,d
CPME
CPME
CPME
CPME
CPME
Benzophenone
Benzophenone
Benzophenone
Ph2PCl
DMF
a
b
DES: 2 g per 1 mmol of 3a. Isolated yield after column chromato-
c
graphy, the remaining being starting material only. t-BuLi (1.9 equiv.,
1.7 M) was added to a solution of 3a in DES. Reaction time 1 min.
d
(1 : 2) DES, the yield of 4o being only 33% (Table 3, entry 4).
A recent paper by Madsen and Holm has shown that in the Chlorodiphenylphosphine (2 equiv.) also readily underwent
presence of protic reagents such as water, the rate of carbonyl nucleophilic substitution in ChCl–urea (1 : 2) to give the corre-
addition from highly reactive Grignard reagents is comparable sponding adduct 4e in 75% yield (Table 3, entry 5). Finally, we
to that of protonation by the same reagents.12 In the case of the also investigated the formation of anion 3a–Li directly in the
more polar and basic organolithium reagents, one would expect protic DES mixture in the absence of an electrophile. To this
that protonation occurs almost instantaneously. However, once end, t-BuLi (1.9 equiv., 1.7 M) was added at 0 1C and under air
an Et2O solution of 3a–Li (0.45 M) was added over an acetone– to a solution of 3a (1 mmol previously solubilized in 2 mL of
water mixture (6 equiv. each) at room temperature, it was CPME) in the ChCl–Gly (1 : 2) eutectic mixture (2 g) under
somewhat surprising to find that the desired adduct 4n could vigorous stirring. After 1 min reaction time, the reaction
still be recovered in 30% yield (Table 2). In a subsequent mixture was quenched with neat DMF (2 equiv.), remarkably
experiment in which the above ethereal solution of 3a–Li was affording the expected adduct 4h in 90% yield (Table 3, entry 6).
added to acetone alone (6 equiv.) (neat conditions), product 4n It follows from the above that the formation of intermediate
again formed in 30% yield (Table 2). This result implies that 3a–Li from t-BuLi, surprisingly, takes place competitively with
the formation of 4n is unrelated to any ‘‘rate acceleration’’ the protonolysis of the latter.
promoted by water; instead, the key to success may be the
‘‘inverse addition’’.13 However, the apparent role as a ‘‘specta- ortho-lithiation/functionalization of diaryltetrahydrofurans in
tor’’ played by water in the above addition is intriguing.14
which the THF moiety acts as an effective DMG. ortho-
In summary, we have reported the first direct regioselective
A
perusal of the literature revealed that water can act as a polar Lithiation was found to proceed smoothly using t-BuLi as the
ligand towards lithium,15 successfully competing also with base at 0 1C both in Et2O and in CPME, the latter often providing
TMEDA.15b Thus, to further assess the potential impact of better yields and selectivity compared to Et2O. In addition, we
protic solvents on organolithium chemistry, we turned our noticed that both the generation of ortho-lithiated derivative
attention to the so-called deep eutectic solvents (DESs) which 3a–Li and its trapping reactions with electrophiles could also
were introduced by Abbott and co-workers in 200316a and be fruitfully performed at 0 1C or RT, and under open air
rapidly emerged as a new generation of promising green media. conditions in eutectic mixtures of ChCl and donor molecules,
They are the result of the right combination of a hydrogen-bond such as glycerol and urea, competitively with protonolysis. Our
donor and a hydrogen-bond acceptor that form a eutectic, with next aim is to set up an enantioselective desymmetrization of
a melting point much lower than either of the individual diaryltetrahydrofurans in the presence of chiral ligands as well
components, and are known to exhibit interesting and unusual as to deeply investigate the scope of protic DES mixtures as a new
solvent properties.16b,c
eco-friendly reaction media for organolithium reactions.
This work was financially supported by the Interuniversities
Once an Et2O solution of 3a–Li (1.9 equiv., 0.5 M) was added
to acetone (6 equiv.) in a choline chloride (ChCl)–glycerol (Gly) Consortium C.I.N.M.P.I.S. We also thank Professor Saverio
(1 : 2) eutectic mixture at room temperature (RT) and under air, Florio and Professor Dietmar Stalke for valuable discussions.
adduct 4n could be recovered with a yield of 40% (Table 3, entry
1). Similarly, the addition reaction of a CPME solution of 3a–Li
(1.9 equiv., 0.5 M) to benzophenone (2 equiv.) as the electro-
phile, run either in a ChCl–Gly (1 : 2) or ChCl–urea (1 : 2) DES
Notes and references
1 J. P. Wolfe and M. B. Hay, Tetrahedron, 2007, 63, 261.
mixture, smoothly afforded the desired ortho-hydroxyalkylated
product 4o in both cases in 75% yield (Table 3, entries 2 and 3).
A decrease in selectivity, however, was observed when the
addition to benzophenone was carried out in a ChCl–H2O
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