2-Lithiated-2-phenyloxetane: A new attractive synthon for the preparation of oxetane derivatives

Article abstract of DOI:10.1039/c1cc13670d

A valuable and direct method to access 2-substituted-2-phenyloxetanes by electrophilic quenching of the corresponding 2-lithiated derivative has, for the first time, been described. 2-Lithiated-2-phenyloxetane was found to be configurationally unstable. E

Full text of DOI:10.1039/c1cc13670d

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2-Lithiated-2-phenyloxetane: a new attractive synthon for the preparation
of oxetane derivativeswz
Donato Ivan Coppi, Antonio Salomone, Filippo Maria Perna and Vito Capriati*
Received 20th June 2011, Accepted 14th July 2011
DOI: 10.1039/c1cc13670d
A valuable and direct method to access 2-substituted-2-phenyl-
oxetanes by electrophilic quenching of the corresponding 2-lithiated
derivative has, for the first time, been described. 2-Lithiated-2-
phenyloxetane was found to be configurationally unstable. Evidence
is presented to show that electron-transfer processes are also
operative in the coupling reactions with electrophiles.
consideration for a proper tuning of their reactivity toward a
nucleophilic/electrophilic behavior.9 In the case of a-lithiated
styrene oxide, for example, its dichotomous reactivity could
successfully be tuned in THF by the concentration.10 Inspired
by the intensive interest in the field of a-lithiated oxiranes,11 we
became intrigued by the possibility both of generating an
a-lithiated oxetane chemically stable on the timescale of its
reactions and of investigating its reactivity. Herein, we report an
efficient route to 2-substituted phenyloxetanes obtained exploiting
the nucleophilic character of 2-lithio-2-phenyloxetane, 2-Li,
chosen as a model of a stabilised intermediate. Stereochemical
integrity of such a reactive species has also been tackled.
Oxetanes, the closest homologs to epoxides, are an important
group of four-membered cyclic ethers that can undergo a wide
range of chemical transformations and whose ring motif is also
found in many natural products that exhibit a range of biological
activities.1 The importance of oxetanes as versatile building
blocks in synthetic and medicinal chemistry as well as in material
and agrochemical sciences has dramatically increased over the
last ten years with the development of new and efficient methods
for their preparation.2 Despite recent advances, their reactivity
towards organometallic reagents has only been scarcely explored
compared to that of ethers and epoxides.3 A closer perusal of the
literature reveals that, to date, organolithium and organo-
magnesium reagents have been shown to be effective in triggering
Lewis acid-catalysed oxetane-ring-opening reactions only,
exploiting the strain of the four-membered ring.4
2-Phenyloxetane
2 (Scheme 1) was straightforwardly
prepared in 85% yield by basic cyclisation of 3-chloro-1-
phenyl-1-propanol 1, as similarly reported for other cases.4b
Treatment of a precooled (ꢀ78 1C) THF solution (0.2 M) of 2
(1 equiv.) with s-BuLi (1.4 equiv.) led to regioselective generation
of 2-Li through a clean hydrogen–lithium exchange. Quenching of
the reaction mixture after only 5 min with MeOD gave deuterated
oxetane [D]-2 (1H NMR analysis) (90% yield, 95% D). As for the
bases and the nature of the solvents, we ascertained that (a) both
lithium diisopropylamide (LDA) and n-BuLi were ineffective
(THF, ꢀ78 1C, 5 min) and also that (b) no deprotonation
occurred when rac-2 was treated with s-BuLi employing toluene
or hexane as the sole solvent.12 On the other hand, lithiation of 2
with s-BuLi in Et2O afforded, after MeOD quenching, [D]-2 with
only 10% D even after 15 min deprotonation time.
In the 1980s, the reactivity of 3,3-disubstituted oxetanes
towards alkyllithiums was first investigated by Klumpp and
coworkers:5 nucleophilic substitution at C-2 always competed
with a-lithiation. Quenching of the reaction mixture with a
deuterium source, however, provided no a-deuterated products.
Metalated oxetanes have also been shown to occur as inter-
mediates in the isomerisation of (E)-1-benzyloxy-2,3-epoxyalkanes
to unsaturated diols upon treatment with the superbasic mixture,
lithium diisopropylamide/potassium tert-butoxide.6 In the 1990s,
the carbenoid nature7 of a-lithiated ethers was unambiguously
proved by Boche and coworkers.8 In general, aggregation and
solvation of lithium carbenoids are crucial factors to be taken into
The chemical stability of 2-Li in THF was also checked at
longer reaction time: after 30 min stirring at ꢀ78 1C, followed
by quenching with MeOD, [D]-2 was recovered with the same
yield and deuterium content. The temperature proved to be
critical. Indeed, at a temperature higher than ꢀ78 1C, 2-Li
mainly underwent decomposition with the formation of a
complex reaction mixture of unidentified products. It is also
worth pointing out that even running the deprotonation of
oxetane 2 (1 equiv.) in THF with s-BuLi (1.4 equiv.) at ꢀ78 1C
`
Dipartimento Farmaco-Chimico, Universita di Bari ‘‘Aldo Moro’’,
Consorzio Interuniversitario Nazionale ‘‘Metodologie e Processi
Innovativi di Sintesi’’ C.I.N.M.P.I.S., via E. Orabona 4, I-70125 Bari,
Italy. E-mail: capriati@farmchim.uniba.it; Fax: +39 080 5442539;
Tel: +39 080 5442174
w This paper is dedicated to the memory of Professor Gernot Boche,
an outstanding scientist, whose pioneering contributions to the field of
lithium carbenoids continue to inspire.
z Electronic supplementary information (ESI) available: Experimental
procedures, spectroscopic data and copies of 1H/13C NMR spectra for
compounds 2c–l, 4 and 6. See DOI: 10.1039/c1cc13670d
Scheme 1 (i) t-BuOK/THF, 4 h, 25 1C. (ii) s-BuLi, THF, ꢀ78 1C,
5 min. (iii) MeOD.
c
9918 Chem. Commun., 2011, 47, 9918–9920
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Table 1 Synthesis of 2-substituted 2-phenyloxetanes 2a–l
Scheme 2 (i) t-BuOK/THF, 4 h, 25 1C. (ii) s-BuLi, THF, ꢀ78 1C,
Oxetanes 2a–l (Yield %)a
5 min. (iii) MeOD.
1
4
2
5
3
6
Scheme 3 (i) s-BuLi, THF/Et2O (3 : 2), ꢀ116 1C, Me3SiCl (in situ
quenching). (ii) s-BuLi/TMEDA, Et2O, ꢀ116 1C, Me3SiCl (in situ
quenching).
racemic [D]-2 (90% yield, 95% D) after a 5 min reaction time
(Scheme 2). Even an in situ trapping experiment with Me3SiCl
as the electrophile at ꢀ116 1C both in THF/Et2O (3: 2) (as the
sole solvent mixture) and Et2O in the presence of TMEDA
(1 equiv.)14 essentially gave racemic silane 2c in 95% and 10%
yield, respectively (Scheme 3). The configurational lability of
lithiated oxetane 2-Li in ethereal solvents was thereby revealed.
Additionally, in contrast to what was observed in the case of
lithiated styrene oxides,11c even the employment of hexane/
TMEDA was ineffective to hinder the racemisation of 2-Li.
Indeed, once such a reactive intermediate was generated by
treating (R)-2 with s-BuLi (1.4 equiv.) at ꢀ78 1C in the fore-
going solvent mixture (hexane/TMEDA), it similarly under-
went very quick racemisation to give, after in situ quenching
with Me3SiCl, again, completely racemic 2c (40% yield). In
previous work,13 we ascertained that a-lithiated styrene oxide is
either configurationally stable at ꢀ100 1C in THF or it reacts
with all electrophiles under strict stereoretention.10,13 One
possibility to explain the missing configurational stability
exhibited by 2-Li in polar solvents is that an enhanced stability
of the carbanion by resonance increases planarisation of the
carbanionic center and the formation of a solvent-separated ion
pair.15 In such a case, intra- and intermolecular dynamic
processes may promote racemisation, thereby facilitating the
migration of the lithium cation from one enantiotopic face to
the other. Lithiated oxetane 2-Li, however, as stated above,
undergoes racemisation in non-polar hydrocarbon solvents as
well. Thus, epimerisation also through a higher aggregate16
cannot be ruled out at least at present as we do not know the
aggregation state of 2-Li.15 Astonished by the completely
racemic substitution product 2c obtained upon an in situ
quenching of 2-Li with Me3SiCl (Scheme 3), we also wondered
whether a single-electron transfer (SET) mechanism competes
with a polar one. To determine if such a radical pathway was
also operational in the reaction with electrophiles, lithiated
oxetane 2-Li was reacted in THF at ꢀ98 1C with cyclopropyl-
methyl bromide 3, which is a very fast radical probe. The only
product isolated by column chromatography (40% yield)
(with almost 50% of the starting substrate remaining) was the
linear butenyl-substituted oxetane 4 resulting from coupling
with the more stable butenyl radical further to the radical
opening of the cyclopropyl ring (Scheme 4). The formation of
4 is consistent with an SET mechanism.17
7
8
9
10
11
12
a
b
Isolated yield after column chromatoghraphy. Overall isolated yields in
c
both diastereomers. Diastereomeric ratio = 2 : 1. Inseparable mixture
d
e
of diastereomers. Relative configuration has not been assigned.
f
g
Diastereomeric ratio = 1.2 : 1. Separable mixture of diastereomers.
in the presence of N,N,N0,N0-tetramethylethylenediamine
(TMEDA), followed by quenching with MeOD, led to both
minor yield (50%) and deuterium content (62% D) of [D]-2.13
With efficient reaction conditions in hand, we surveyed the
nucleophilicity of 2-Li towards representative, structurally diverse
electrophiles in order to prepare 2,2-disubstituted derivatives. The
reactions of 2-Li with alkyl halides (MeI, EtI) as well as with
Me3SiCl and n-Bu3SnCl proceeded efficiently, thereby giving the
desired substitution products 2a–d in excellent yields (86–95%)
(Table 1, entries 1–4). Similarly, 2-Li underwent efficient benzyla-
tion and benzoylation (60–70% yield) upon exposure to benzyl
chloride and N,N-dimethylbenzamide (Table 1, entries 5 and 6).
Aliphatic and aromatic aldehydes and ketones (pivalaldehyde,
p-chlorobenzaldehyde, acetaldehyde, acetone, isopropyl phenyl
ketone, and benzophenone) also reacted smoothly, thereby
affording the expected addition products 2g–l in very good yields
(70–82%) (Table 1, entries 7–12), albeit with poor diastereo-
selectivity (dr = 1.2–2 : 1) at the newly created stereogenic centres
(Table 1, entries 7–9 and 11). Of particular note, enolisation did
not appreciably complicate the additions, as reaction of 2-Li with
acetaldehyde, acetone and isopropyl phenyl ketone did furnish the
corresponding hydroxyalkylated products 2i–k in 75–82% yield,
respectively (Table 1, entries 9–11).
Attention was then turned towards investigating the
configurational stability of 2-Li. To this end, enantiomerically
enriched (R)-2 (er 99 : 1) was similarly prepared in 86% yield
by stereospecific basic cyclisation of commercially available
3-chloro-1-phenyl-1-propanol (R)-1 (er = 99 : 1) (Scheme 2).4b
The deprotonation of (R)-2 with s-BuLi (1.4 equiv.) in THF
at ꢀ78 1C, followed by quenching with MeOD, gave completely
c
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2 Oxetanes were found to improve key drug physicochemical proper-
ties and are also promising modules for drug discovery; for a
leading review, see: J. A. Burkhard, G. Wuitschik, M. Rogers-
Evans, K. Muller and E. M. Carreira, Angew. Chem., Int. Ed.,
¨
2010, 49, 9052 and references therein.
3 For dialkyl ethers, see: (a) A. Maercker and W. Demuth, Justus
Liebigs Ann. Chem., 1977, 11–12, 1909. For epoxides, see:
(b) F. Chemla and E. Vranken, in The Chemistry of Organolithium
Compounds, ed. Z. Rappoport and I. Marek, Wiley, New York,
2004, vol. 2, p. 1165; (c) V. Capriati, S. Florio and R. Luisi, Chem.
Rev., 2008, 108, 1918.
Scheme 4
4 (a) T. Bach and F. Eilers, Eur. J. Org. Chem., 1998, 10, 2161
and references therein. For regio- and stereoselective inter/
intramolecular openings of oxetanes with other nucleophiles, see:
(b) F. Bertolini, S. Crotti, V. Di Bussolo, F. Macchia and
M. J. Pineschi, J. Org. Chem., 2008, 73, 8998; (c) R. N. Loy and
E. N. Jacobsen, J. Am. Chem. Soc., 2009, 131, 2786.
5 M. Schakel, J. J. Vrielink and G. W. Klumpp, Tetrahedron Lett.,
1987, 28, 5747.
6 A. Thurner, F. Faigl, A. Mordini, A. Bigi, G. Reginato and
Scheme 5
To the best of our knowledge, such a mechanism is some-
times operative in the case of a-aminoorganolithiums but it
has never been observed, to date, for a-alkoxyorganolithiums.
The reactivity of 2-Li with tropylium tetrafluoroborate 5,
which is one of the most stable non-benzenoid aromatic carbo-
L. Toke, Tetrahedron, 1998, 54, 11597.
¨
7 Closs and Moss first suggested the appellation (as a noun) of
‘‘carbenoid’’ to those species capable of undergoing electrophilic
reactions without necessarily being free carbenes; see: G. L. Closs
and R. A. Moss, J. Am. Chem. Soc., 1964, 86, 4042.
8 G. Boche, F. Bosold, J. C. W. Lohrenz, A. Opel and P. Zulauf,
Chem. Ber., 1993, 126, 1873.
18
nium ions much less prone to undergo an SET process was
also investigated (Scheme 5). The occurrence of one-electron
transfer towards cation 5 would give rise to a tropyl radical
which is known to dimerise to ditropyl.18b,c However, the only
compound detected in the crude reaction mixture and isolated
(20% yield)19 was the covalently bonded a-tropylated adduct 6.
This ‘‘negative’’ result neither excludes nor confirms the inter-
vention of an SET process, since the rates of both the polar and
the radical coupling reactions have not been measured.17
In summary, we have shown for the first time that the regio-
selective a-deprotonation of 2-phenyloxetane is possible (s-BuLi,
THF, ꢀ78 1C) and that the carbanionic character of the corres-
ponding a-lithiated species obtained can be fruitfully exploited for
synthesising phenyl-substituted derivatives with a variety of
different electrophiles well-accommodated onto the oxetane core.20
Evidence for configurational instability (in both polar and non-
polar solvents) was also found for a-lithiated phenyloxetane, 2-Li,
with radical processes competing with polar enantiomerisation
mechanisms most likely in those reactions where either electrophiles
that are easily reduced (e.g. benzophenone) or ‘‘activated’’ halides
(e.g. benzyl chloride) are involved. Support for this came from the
isolation of the butenyl-coupled product 4 in the reaction of 2-Li
with the ‘‘activated’’ halide cyclopropylmethyl bromide 3.17
Expectations of considerable synthetic utility rest upon the control
of stereochemistry, which could be achieved particularly by
asymmetric substitution of chiral lithiated oxetanes that can
undergo dynamic equilibration. This issue is currently being
investigated in our laboratory.
9 For leading reviews on lithium carbenoids, see: (a) G. Boche and
J. C. W. Lohrenz, Chem. Rev., 2001, 101, 697; (b) M. Braun, in The
Chemistry of Organolithium Compounds, ed. Z. Rappoport and
I. Marek, Wiley, New York, 2004, vol. 2, ch. 13; (c) V. Capriati and
S. Florio, Chem.–Eur. J., 2010, 16, 4152.
10 Dilution (e.g. 0.05 M THF solution) favors the trisolvated monomeric
a lower carbene-like reactivity; see:
species which does have
V. Capriati, S. Florio, F. M. Perna, A. Salomone, A. Abbotto,
M. Amedjkouh and S. O. Nilsson Lill, Chem.–Eur. J., 2009, 15, 7958.
11 (a) V. Capriati, S. Florio and A. Salomone, in Stereochemical
Aspects of Organolithium Compounds: Oxiranyllithiums as Chiral
Synthons for Asymmetric Synthesis, ed. R. E. Gawley, Helvetica
Acta, Zurich, 2010, vol. 26, ch. 4, p. 135; (b) V. Capriati, S. Florio,
¨
F. M. Perna and A. Salomone, Chem.–Eur. J., 2010, 16, 9778;
(c) F. M. Perna, A. Salomone, M. Dammacco, S. Florio and
V. Capriati, Chem.–Eur. J., 2011, 17, 8216.
12 Oxetane 2 exhibits very poor solubility in hexane at a temperature
below ꢀ80 1C.
13 Conversely, TMEDA was shown to be necessary for successfully
preserving the chemical integrity of a-lithiated styrene oxide once
generated in THF; see: V. Capriati, S. Florio, R. Luisi and
A. Salomone, Org. Lett., 2002, 4, 2445.
14 Running the deprotonation of (R)-2 with s-BuLi at ꢀ116 1C in
Et2O in the absence of TMEDA, 2c formed in less than 5% yield
(1H NMR and GC-MS analysis); thus, its er could not be
determined.
15 A computational and multinuclear magnetic resonance investigation
on 2-Li is currently ongoing and results will be reported in due course.
16 For selected examples, see: (a) H. J. Reich, M. A. Medina and
M. D. Bowe, J. Am. Chem. Soc., 1992, 114, 11003; (b) D. Hoell,
C. Schnieders and K. Mullen, Angew. Chem., Int. Ed. Engl., 1983,
¨
22, 243; (c) V. Capriati, S. Florio, R. Luisi, F. M. Perna and
A. Spina, J. Org. Chem., 2008, 73, 9552.
17 (a) R. E. Gawley, E. Low, Q. Zhang and R. Harris, J. Am. Chem.
Soc., 2000, 122, 3344; (b) R. E. Gawley, in Topics in Stereo-
chemistry, Stereochemical Aspects of Organolithium Compounds,
ed. R. E. Gawley and J. S. Siegel, Wiley-VCH, Weinhem, 2010,
vol. 26, ch. 3, p. 93.
18 (a) M. R. Wasielewski and R. Breslow, J. Am. Chem. Soc., 1976,
98, 4222. For reviews, see: (b) G. D. Kolomnikova and
Z. N. Parnes, Russ. Chem. Rev., 1967, 36, 735; (c) F. Pietra, Chem.
Rev., 1973, 73, 293.
This work was financially supported by MIUR-FIRB
(Code: CINECA RBF12083M5N), the University of Bari,
and Interuniversities Consortium C.I.N.M.P.I.S. We are
especially grateful to Professor Saverio Florio for his sustained
interest and support in this study and to Prof. Robert E.
Gawley for valuable discussions.
19 The low yield of 6 is probably due to the poor solubility of 5 towards
THF and, consequently, to the longer reaction time required for
2-Li to react during which it mainly underwent decomposition.
20 Phenyl-oxetanyl derivatives have recently been patented by
Novartis: R. Albert, N. G. Cooke, F. Zecri and I. Lewis,
WO 2009068682, Novartis, 2009.
Notes and references
1 H. C. Hailes and J. M. Behrendt, in Comprehensive Heterocyclic
Chemistry III. Oxetanes and Oxetenes: Monocyclic, ed.
A. R. Katritzky, Pergamon, Oxford, 2008, vol. 2, ch. 2.05, p. 321.
c
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