Gated access to α-lithiated phenyltetrahydrofuran: Functionalisation via direct lithiation of the parent oxygen heterocycle

Article abstract of DOI:10.1039/c3cc45499a

Cycloreversion of α-lithiated phenyltetrahydrofuran was successfully tamed at -78 °C in a non-coordinating solvent in the presence of TMEDA. This anion showed excellent nucleophilicity and could be intercepted with a variety of structurally different electrophiles to give 2,2-disubstituted derivatives which can be further elaborated to γ-butyrolactones. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc45499a

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Gated access to a-lithiated phenyltetrahydrofuran:
functionalisation via direct lithiation of the parent
oxygen heterocycle†‡
Cite this: Chem. Commun., 2013,
49, 10160
Received 19th July 2013,
Accepted 2nd September 2013
Rosmara Mansueto, Valentina Mallardo, Filippo Maria Perna, Antonio Salomone
and Vito Capriati*
DOI: 10.1039/c3cc45499a
www.rsc.org/chemcomm
Cycloreversion of a-lithiated phenyltetrahydrofuran was success- This reaction is known to proceed via a radical intermediate
fully tamed at À78 8C in a non-coordinating solvent in the presence (formed in the rate-determining step) as a precursor to the
of TMEDA. This anion showed excellent nucleophilicity and could be anion. 2-Lithiotetrahydrofurans in particular were trapped by
intercepted with a variety of structurally different electrophiles to only PhCHO to give adducts as pairs of threo and erythro
give 2,2-disubstituted derivatives which can be further elaborated isomers. A major breakthrough recently came by the work of
to c-butyrolactones.
Mulvey and co-workers who reported the discovery that bases
containing two different metals could indeed reduce the reac-
Among the saturated oxygen heterocycles, substituted tetra- tivity of the THF a-anion, thus preventing ring fragmentation
hydrofuran (THF) derivatives are important scaffolds in a broad reactions; the reactivity towards electrophiles in C–C bond-
array of biologically active natural compounds, such as lignans, forming reactions still remains, however, the major challenge.8
polyether antibiotics, and marine macrolides.1 However, while As part of our programme aimed at developing new regio- and
increasing attention has recently been paid to the regio- and stereoselective functionalisation reactions of oxygen-bearing
stereoselective construction of these ring motifs2 and the dis- lithium compounds,9 we became particularly keen to see whether
covery of new reactivity,3 direct functionalisation processes remain our success with the synthesis of 2-substituted-2-phenyloxetanes
extremely rare.4 Conventional strong organolithium bases are long by electrophilic quenching of the corresponding 2-lithiated
known to smoothly cleave tetrahydrofurans, yielding alkenes derivative9b could be translated into an equivalent transforma-
and lithium enolates of aldehydes by means of a reverse [3+2] tion for 2-phenyltetrahydrofuran, selected as a model substrate.
cycloaddition.5 Clayden and co-workers recently provided evidence In this communication, we wish to report an efficient protocol
that the presence of additives (e.g., TMEDA, (À)-sparteine, and for the direct lithiation-electrophile trapping of the latter hetero-
HMPA) can also trigger competitive THF decomposition pathways cycle and its elaboration for the installment of a lactone func-
initiated by deprotonation of THF at both C-2 and C-3.6 The tionality. Stereochemical aspects will also be discussed.
occurrence of these many fragmentation reactions has most
2-Phenyltetrahydrofuran 3 was conveniently prepared in two
likely discouraged the use of THF derivatives as starting materials steps by reduction of commercially available 4-chloro-1-phenyl-
in organic synthesis. This provokes the question of whether there 1-butanone 1 to give 4-chloro-1-phenyl-1-butanol 2 (90% yield)10
exists any way to reduce the reactivity of THF-derived anions, followed by basic intramolecular cyclisation using t-BuOK–THF
thereby keeping their cycloanionic structure intact.
(>98% yield) (Scheme 1).11
The pioneering work of Cohen and co-workers showed that
Letsinger and Pollart previously noted that although the
the preparation of non-transient a-lithio derivatives of cyclic a-position of THF was activated by a phenyl group, 3 cleaves
medium-sized ethers can be achieved from the corresponding much faster than THF itself upon treatment with organolithium
a-(phenylthio)ethers by reductive lithiation of C–S bonds performed reagents, acetophenone being the sole product isolated after
in THF at À78 1C with lithium 1-(dimethylamino)naphthalenide.7 hydrolysis as the result of a [3+2] cycloreversion.12 Subjecting 3
to the conditions we used to generate 2-lithio-2-phenyloxetane
(s-BuLi (1.4 equiv.), THF, À78 1C),9b followed by quenching with
`
Dipartimento di Farmacia – Scienze del Farmaco, Universita di Bari ‘‘Aldo Moro’’,
Consorzio C.I.N.M.P.I.S, via E. Orabona 4, I-70125 Bari, Italy.
E-mail: vito.capriati@uniba.it; Fax: +39 080 5442539; Tel: +39 080 5442174
† This communication is dedicated to Professor Leonardo Di Nunno on the
occasion of his retirement.
‡ Electronic supplementary information (ESI) available: Experimental procedures,
spectroscopic data and copies of 1H/13C NMR spectra of compounds [D]-3 and 5a–k.
See DOI: 10.1039/c3cc45499a
Scheme 1 (i) NaBH4, MeOH, 0 1C. (ii) t-BuOK, THF, RT.
c
10160 Chem. Commun., 2013, 49, 10160--10162
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Table 1 Optimisation of the lithiation/deuteration reaction of 3 under different
Table 2 Scope of the study for 2,2-disubstituted THF derivatives formationa
conditions
Time
[D]-3 Da 4 Yielda,b
Entry (min) T (1C) Solvent
Co-solvent (%)
(%)
1
2
3
4
5
6
7
8
9
2
À78
À98
"
À78
À98
"
THF
"
"
"
—
—
—
TMEDA
"
—
TMEDA
"
"
90c
40
50
—
5
20
—
5
—
—
—
"
30
10
"
50d
70e
40
"
"
"
Et2O
"
Hexane
Toluene
20d
13
90
"
2
À90
"
À78
>98
a
b
Calculated by 1H NMR of the crude reaction mixture. % D was in all
c
d
examined cases around 70%. Chemical yield: 50%. Chemical yield:
95%. Chemical yield: 80%.
e
MeOD after 2 min, deuterated [D]-3 was obtained with 90%
deuterium incorporation (1H NMR analysis), albeit as an equi-
molar mixture with deuterated acetophenone 4 (50% yield,
70% D) (Table 1, entry 1). Further experimentation in THF
established that (a) a temperature as low as À98 1C precluded
cycloreversion, but led to lower deuterium incorporation into 3
(40% D) (Table 1, entry 2) which increased only up to 50% with
a longer reaction time (30 min) (Table 1, entry 3) and (b) the
presence of TMEDA (1.4 equiv.) at À78 1C slowed down both
cycloreversion of 3-Li (4: 20% yield) and metalation of 3 ([D]-3:
70% D) (Table 1, entry 4 compared with entry 1), whereas
a
Isolated yield after column chromatography. All the reactions were
carried out on a 0.5 mmol scale and using a ratio of 3/s-BuLi/TMEDA
1 : 1.4 : 1.4. Conversion established on the basis of 1H NMR spectra.
b
c
d
Overall isolated yields in both diastereomers. Isolated as a mixture
of two inseparable diastereomers (60 : 40).
lowering the temperature to À98 1C again proved to be detri- be excellent toward both heteroatom- and carbon-based halides.
mental to deuterium incorporation into 3 (Table 1, entry 5). Alkylation, including allylation and benzylation, all proceeded to
Deprotonation carried out in Et2O with and without TMEDA did give the corresponding 2,2-disubstituted tetrahydrofurans 5a–c
not lead to greater than 20% deuterium incorporation into 3 in reasonable yields (40–74%). Silylation, stannylation, and
(Table 1, entries 6 and 7). Much to our delight, upon switching to sulphenylation proved to be equally viable providing compounds
a non-polar solvent, lithiation of 3 with s-BuLi–TMEDA afforded, 5d–f in moderate to good yields (40–85%). As for reactions with
after MeOD quenching, [D]-3 as the sole product with 90% D in carbonyl electrophiles, anion 3-Li reacted smoothly with both
hexane at À90 1C (Table 1, entry 8), and with >98% D after 4-chlorobenzaldehyde and enolisable carbonyl partners (acetone
running the reaction in toluene at À78 1C (Table 1, entry 9); the and acetaldehyde) to afford the hydroxyalkylated derivatives 5g–i
reaction time was 2 min in both cases. Surprisingly, under the in 45–80% yield. The use of DMF as a quenching reagent
latter conditions, anion 3-Li also proved to be chemically stable allowed the introduction of the formyl moiety at the a-position
up to 30 min. On the other hand, no deprotonation occurred (90% yield) to give 5j, whereas the treatment of 3-Li with chloro-
with s-BuLi in hexane (or toluene) without TMEDA, even when diphenylphosphine furnished the functionalised phosphine 5k
using an excess of this base, and the n-BuLi–TMEDA mixture (65% yield).14
proved to be similarly ineffective (toluene, À78 1C, 5 min).
As an application of this methodology, we wondered whether the
Thus, remarkably, the joint employment of s-BuLi–TMEDA above-synthesised tetrahydrofurans 5 could be used as adequate
retarded both cycloreversion of 3-Li and metalation of 3 in precursors of the corresponding g-butyrolactones, which are
coordinating solvents (e.g., THF), whereas only the latter pro- present as substructures in a large variety of natural products
cess was selectively privileged in non-coordinating solvents and biologically active compounds. Chiral phenyldihydrofuranone
(e.g., toluene).13
derivatives, in particular, have also recently come to the fore as
With the optimal conditions in hand, we set out to evaluate selective phosphodiesterase IV inhibitors.15 In their pioneering
the scope of this methodology with a variety of electrophiles to study on RuO4 as a multipurpose oxidant, Berkowitz and
prepare more functionalised derivatives. As is evident from the Rylander first reported the conversion of tetrahydrofuran to
results shown in Table 2, the nucleophilicity of 3-Li proved to g-butyrolactone.16 Aromatic systems, however, are notoriously
c
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This work was financially supported by MIUR-FIRB (Code:
CINECA RBF12083M5N) and the Interuniversities Consortium
C.I.N.M.P.I.S.
Scheme 2
Notes and references
1 Reviews: (a) J. P. Wolfe and M. B. Hay, Tetrahedron, 2007, 63, 261;
(b) A. Lorente, J. Lamariano-Merketegi, F. Albericio and M. Alvarez,
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`
2 Selected recent examples: (a) G. Jalce, X. Franck and B. Figadere,
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3 Chemoselective copper(II)-catalysed intermolecular activation and
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Scheme 3
4 For C–H arylation/alkylation at the a-position of cyclic aliphatic
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known to be labile to RuO4. By reacting phenyloxetanes with
NaIO4 in the presence of a catalytic amount of ruthenium(III)
chloride, oxetan-2-carboxylic acids can, indeed, be synthesised
in excellent yields.17 g-Ethyl-g-phenylbutyrolactone (6a) is a
synthetic oral anticonvulsant and hypnotic agent.18 After some
trials, we were pleased to find that upon exposure of tetra-
hydrofuran 5a to the system composed of catalytic ruthenium(IV)
oxide and NaIO4,19 lactone 6a was straightforwardly formed in
remarkable yield (70%) (Scheme 2).
6 J. Clayden and S. A. Yasin, New J. Chem., 2002, 26, 191.
7 T. Cohen and M.-T. Lin, J. Am. Chem. Soc., 1984, 106, 1130.
8 (a) A. R. Kennedy, J. Klett, R. E. Mulvey and D. S. Wright, Science,
´
´
2009, 326, 706; (b) E. Crosbie, P. Garcıa-Alvarez, A. R. Kennedy,
J. Klett, R. E. Mulvey and S. D. Robertson, Angew. Chem., Int. Ed.,
2010, 49, 9388.
Next, we questioned the possibility of enantioselective con-
struction of 2,2-disubstituted tetrahydrofurans. We began our
study exploring the configurational stability of 3-Li on the
reaction time scale generated by deprotonation of the corre-
sponding enantio-enriched parent substrate. Optically active
(R)-3 (er 90 : 10) was stereospecifically prepared by subjecting
(R)-2-phenyloxetane9b to a ring-expansion reaction with dimethyl-
sulphoxonium methylide, as reported.20 Exposing (R)-3 to s-BuLi
(1.4 equiv.)–TMEDA (1.4 equiv.) (or (À)-sparteine (1.4 equiv.)),21
both in toluene at À78 1C and in hexane at À90 1C, followed by
deuteration with MeOD, caused, however, complete racemisa-
9 For a-lithiated aryloxiranes, see: (a) V. Capriati, S. Florio and
A. Salomone, in Topics in Stereochemistry, Stereochemical Aspects of
Organolithium Compounds, ed. R. E. Gawley and J. S. Siegel, Wiley-
VCH, Weinheim, 2010, vol. 26, ch. 4, p. 135; (b) For lithiated aryl-
oxetanes, see: D. I. Coppi, A. Salomone, F. M. Perna and V. Capriati,
Chem. Commun., 2011, 47, 9918; (c) D. I. Coppi, A. Salomone,
F. M. Perna and V. Capriati, Angew. Chem., Int. Ed., 2012, 51,
7532.
10 (a) M. P. Gamble, A. R. C. Smith and M. Wills, J. Org. Chem., 1998,
63, 6068; (b) J. W. Hulshof, P. Casarosa, W. M. P. B. Menge, L. M. S.
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11 T. H. Chan and P. Pellon, J. Am. Chem. Soc., 1989, 111, 8737.
12 R. L. Letsinger and D. F. Pollart, J. Am. Chem. Soc., 1956, 78, 6079.
tion of [D]-3 (>98% D (toluene), 90% D (hexane), er 50 : 50), with 13 At present, we can only speculate that a more reactive ternary pre-
lithiation complex among tetrameric s-BuLi, 2-phenyltetrahydro-
furan 3 and TMEDA, similarly to that envisaged in the case of
arylepoxides, might be involved in non-coordinating solvents on the
way to lithiation; see: F. M. Perna, A. Salomone, M. Dammacco,
S. Florio and V. Capriati, Chem.–Eur. J., 2011, 17, 8216.
reaction times of 2 and 1 min, respectively (Scheme 3). Even an
in situ trapping experiment with TMEDA (or (À)-sparteine) as
the diamine and Me3SiCl as the electrophile (Me3SiCl) run both
in toluene and THF at À78 1C yielded compound 5d (70% yield)
as a racemate (Scheme 3). These results indicate configurational
lability of the organolithium intermediate 3-Li in both polar and
nonpolar solvents even at a low temperature.
14 Ether–phosphine ruthenium(II) complexes have proven to be
´
efficient catalysts; see: S. Sabata, J. Vcelak and J. Hetflejs, Collect.
Czech. Chem. Commun., 1995, 60, 127.
15 H. Laurent, P. Esperling, K. Hamp, H. Schneider and H. Wachtel,
US pat., 006011060A, 2000.
16 L. M. Berkowitz and P. N. Rylander, J. Am. Chem. Soc., 1958, 80, 6682.
In conclusion, we have reported the first direct functionalisa-
tion of 2-phenyltetrahydrofuran by a-deprotonation-electrophilic 17 S. Albert, S. Robin and G. Rousseau, Tetrahedron Lett., 2001, 42,
2477.
quenching. Under optimised conditions (s-BuLi–TMEDA, À78 1C,
´
18 (a) F. Vega-Dıaz and F. Vega-Rasgado, Ann. Esc. Nal. Cien. Biol., 1991,
toluene), the typical reverse [3+2] cycloaddition that occurs
in the presence of strong organolithium bases can be gently
slowed down, and a variety of different electrophiles can be
regioselectively incorporated into the tetrahydrofuranyl ring in
moderate to excellent yields. This method also sets the scene for
obtaining functionalised 4,4-disubstituted-g-butyrolactones, which
are of pharmaceutical interest. Work is currently underway to
determine the full extension of this reaction aimed at preparing
chiral non-racemic disubstituted THF derivatives by asymmetric
substitution, in the presence of different chiral ligands, under
dynamic resolution.
´
´
34, 23; (b) F. Vega-Dıaz, S. Garcıa and F. Vega-Rasgado, Ann. Esc. Nal.
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19 W. F. Berkowitz, A. S. Amarasekara and J. J. Perumattan, J. Org.
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21 TMEDA has been found to hamper the progress of racemisation of
optically active a-lithiated aryloxiranes (see: (a) R. Mansueto,
F. M. Perna, A. Salomone, S. Florio and V. Capriati, Chem. Commun.,
2013, 49, 4911) and to enhance the configurational stability of
N-Boc-2-lithio-2-phenylpyrrolidine (see: (b) N. S. Sheikh, D. Leonori,
G. Barker, J. D. Firth, K. R. Campos, A. J. H. M. Meijer, P. O’Brien and
I. Coldham, J. Am. Chem. Soc., 2012, 134, 5300; (c) T. K. Beng, J. S. Woo
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c
10162 Chem. Commun., 2013, 49, 10160--10162
This journal is The Royal Society of Chemistry 2013