Exploiting the lithiation-directing ability of oxetane for the regioselective preparation of functionalized 2-aryloxetane scaffolds under mild conditions

Article abstract of DOI:10.1002/anie.201109113

Oxetane nudges in the DoM direction! Regioselective ortho-lithiation induced by an oxetane ring has been achieved. The reaction provides easy access to ortho-functionalized 2-aryloxetanes also through a lithiation/borylation Suzuki-Miyaura cross-coupling. The lithiation-directing ability of oxetane and the proton transfer mechanism have been investigated by competitive metalation and kinetic isotope effect studies. Copyright

Full text of DOI:10.1002/anie.201109113

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DOI: 10.1002/anie.201109113
Lithiation Chemistry
Exploiting the Lithiation-Directing Ability of Oxetane for the
Regioselective Preparation of Functionalized 2-Aryloxetane Scaffolds
under Mild Conditions**
Donato Ivan Coppi, Antonio Salomone, Filippo Maria Perna, and Vito Capriati*
Dedicated to Professor Saverio Florio on the occasion of his retirement
More than seventy years ago, Gilman[1] and Wittig[2] inde-
pendently observed that the lithiation of an aromatic ring
could be achieved ortho to a substituent, and hence opened up
new horizons for obtaining differently functionalized organo-
lithium derivatives through what is today known as the
directed ortho metalation (DoM) reaction. Since then, and
particularly thanks to seminal contributions from the groups
of Hauser, Meyers, Gschwend, Beak, Snieckus, and others,[3]
DoM methodology, which strikingly complements traditional
electrophilic aromatic substitution, has received an extra-
ordinary level of attention in the field of organometallic
chemistry.[4] The reaction is proposed to proceed by the
involvement of a direct metalation group (DMG) whose
ability to effect the ortho metalation process has generally
been interpreted in terms of an interplay of inductive and
complexation effects. The mechanistic rationalization for the
DoM reaction, however, still remains elusive and controver-
sial.[5]
Despite the broad range of hetero- and carbon-linked
substituents available to synthetic chemists for performing
hydrogen/metal permutation processes, saturated ring hetero-
cycles have surprisingly received much less attention as
potential DMGs.[6] The oxetane ring motif is an important
structural component of several naturally occurring com-
pounds, and oxetane derivatives have received increasing
exposure over the years as attractive and versatile modules
for both drug discovery and organic synthesis.[7] Herein, we
report the first successful use of oxetane as an effective DMG
in the regioselective preparation of functionalized 2-arylox-
etane scaffolds and explore the scope of such a methodology.
On the basis of intra- and intermolecular competition experi-
ments and kinetic evidence, we rank the lithiation-promoting
power of oxetane as being equal to that of an aminomethyl
group, and support a complex-induced proximity effect
(CIPE) as the main mechanism responsible for modulating
À
the ortho C H acidity.
Recently, the search for a new way to access 2-substituted-
2-phenyloxetanes has led to the discovery that sBuLi in THF
at À788C is the base of choice to perform a clean a-lithiation/
functionalization of 2-phenyloxetane.[8] As for saturated
cyclic ethers, it is also known that the electron-donor ability
of the oxygen atom is dependent upon the size of the ring, the
basicity being in the order four- > five- > six- > three-mem-
bered ring.[9] Thus, the intrinsic basicity of an oxetane ring is
not only higher than that of an epoxide, but also higher
compared with that of tetrahydrofuran. Inspired by this
observation, we became intrigued by the possibility that an
oxetane ring, in view of its remarkable basicity, could behave
as an ortho-directing group in the absence of a benzylic
proton. Thus, 2-Methyl-2-phenyloxetane 1 was chosen as
a model substrate. It was straightforwardly prepared in 90%
yield by the reaction of acetophenone with dimethylsulfoxo-
nium methylide (508C, 3 days) through a double methylene
transfer reaction.[10]
We were pleased to find that treatment of an Et2O
solution (0.2m) of 1 (1 equiv) at 08C with sBuLi (1.4 equiv),
followed by quenching of the reaction mixture after 10 min
with MeI, led to the ortho-methylated product 2a in 98%
yield, probably through the putative ortho-lithiated inter-
mediate 1-Li, which proved to be chemically stable for up to
30 min at 08C and for up to 10 min even at room temperature
(Scheme 1).
[*] Dr. D. I. Coppi, Dr. A. Salomone, Dr. F. M. Perna, Prof. V. Capriati
Dipartimento Farmaco-Chimico, Universitꢀ di Bari “A. Moro”
Consorzio Interuniversitario Nazionale Metodologie e Processi
Innovativi di Sintesi C.I.N.M.P.I.S.
Scheme 1. Synthesis of ortho-methylated 2-phenyloxetanes 2a and 5,
and of homoallylic alcohol 3. LIDAKOR=iPr2NLi/tBuOK.
Via E. Orabona, 4, 70125 Bari (Italy)
E-mail: capriati@farmchim.uniba.it
[**] This work was financially supported by MIUR-FIRB (CINECA
RBF12083M5N), the University of Bari, and Interuniversities
Consortium C.I.N.M.P.I.S. We would like to acknowledge Dr.
Francesca Sassone for her contribution to the Experimental Section.
As for the bases, we also ascertained that nBuLi, lithium
diisopropylamide (LDA), and lithium 2,2,6,6-tetramethylpi-
peridide (LTMP) were ineffective (08C, Et2O, 10 min),
whereas employing sBuLi in THF at 08C, followed by
quenching with MeI, afforded only an 80% yield of 2a after
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201109113.
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10 min. This observation can be attributed to the fact that
THF partially replaces the activating substituent (the oxetane
ring) in coordinating to lithium, thereby reducing its influence
in triggering the ortho-lithiation.[11] The role of precoordina-
tion in such a reaction also becomes apparent by changing the
coordination potential of the base: treatment of 1 with
a strong non-coordinating base such as LIDAKOR (iPr2NLi/
tBuOK) in THF at 08C (or at À788C) does not promote the
ortho-lithiation; instead, it results in the formation of
homoallylic alcohol 3 in 60% yield, the remaining 40%
being starting material only. This may be the result of a
b-elimination reaction involving the methyl group and the
oxetane ring oxygen (Scheme 1).[12] In Et2O, there is no
reaction.
Lithiation proceeds even when the a-position of
2-phenyloxetane is blocked by groups other than methyl:
treatment of 2-ethyl-2-phenyloxetane 4 with sBuLi in Et2O at
08C, followed by quenching with MeI, gave the ortho-
methylated compound 5 almost quantitatively (98% yield;
Scheme 1).
With the optimal conditions in hand, and in order to test
the generality of this new synthetic methodology, the lithiated
intermediate 1-Li was then trapped with a variety of
À
representative electrophiles. Gratifyingly, ortho C H func-
tionalization of 1 was also effective with electrophiles such as
Me3SiCl, Bu3SnCl, 1,2-dibromoethane, and hexachloro-
ethane, which gave the desired substitution products 2b–
e in high yields (70–90%; Scheme 2). Similarly, the reaction
worked well both with aromatic and aliphatic aldehydes and
ketones. Enolization, as in the case of acetaldehyde or
acetone, did not constitute a problem (Scheme 2); in fact,
the expected oxetanyl carbinols 2 f–j all formed in good yields
(50–85%; Scheme 2). A functionalized aryl ketone 2k could
also be obtained by this DoM method in 70% yield by
reacting 1-Li with N,N-dimethylbenzamide (Scheme 2).
Because the quest for biaryl structures is widely pursued
today,[13] we next explored the possibility of performing a one-
pot DoM-Suzuki–Miyaura cross-coupling reaction combining
Scheme 2. Preparation of ortho-substituted 2-methyl-2-phenyloxetanes
2b–k from 2-methyl-2-phenyloxetane 1. All yields shown are of prod-
ucts isolated by flash chromatography on silica gel. [a] Overall yield of
isolated product for both diastereomers. [b] Diastereomeric
ratio=1.5:1. [c] Separable mixture of diastereomers. [d] Relative config-
uration has not been assigned. [e] Diastereomeric ratio=1.2:1.
[f] Inseparable mixture of diastereomers. [g] Diastereomeric ratio=2:1.
Table 1: One-pot DoM-Suzuki–Miyaura reactions.
Entry
1
(Het)ArBr 7
Product 8
Yield [%][a]
50[b]
À
the oxetane-assisted ortho C H bond activation with a direct
Li–B exchange. To the best of our knowledge, the only
examples thus far of such one-pot procedures have been
reported by Snieckus and co-workers for pyridine deriva-
tives[14] and aryl sulfonamides.[15]
To expand on these precedents, ortho-lithiated 2-phenyl-
oxetane 1-Li was first quenched with the boropinacolate
iPrOBpin, as an electrophilic boron source, and then reacted
with ethyl p-bromobenzoate 7a under the optimized con-
ditions that we had recently determined for the assembly of
two aromatic epoxide residues onto a central diborylated
phenylene core.[16] To our delight, the putative boronate 6
cleanly underwent cross-coupling, regioselectively giving the
desired biaryl 8a in 50% overall yield (Table 1, entry 1).
Under the same conditions, p-bromoanisole 7b, bearing an
electron-rich group at the para position, also efficiently
participated in the coupling process, furnishing the expected
oxetanyl-substituted biaryl 8b in 50% overall yield (Table 1,
entry 2). Bromothiazole 7c could also be successfully part-
nered to afford the corresponding coupled product 8c in 45%
overall yield (Table 1, entry 3). Interestingly, all of the above
2
3
50[b]
45[b]
[a] Overall yield of isolated product after flash chromatography on silica
gel. [b] Substrate conversions: 66% (8a), 55% (8b), 50% (8c).
Dppf=1,1’-bis(diphenylphosphino)ferrocene, Pin=pinacol.
cross-couplings took place while leaving the oxetanyl ring
intact.
We also wondered whether a ring closure (cyclization)
promoted by an oxetanyl carbinol of the type 2 f–j might be
conceivable as a means to forge new heterocyclic systems.[17]
To this end, ortho-hydroxyalkylated phenyl oxetane (Æ)-2i,
2
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prepared from (Æ)-1, was selected as a prototypical substrate.
Activation of the Lewis basic oxetane oxygen with BF3·Et2O
in Et2O at À308C successfully induced an almost quantitative
(95% yield) 5-exo cyclization at the phenyl-substituted
carbon atom to give 1,3-dihydrobenzo[c]furan (phthalan,
(Æ)-9; Scheme 3).[18] In the case of (R)-(+)-2i, prepared from
enantiomerically enriched oxetane (R)-(+)-1 (e.r. 96:4; see
ortho positions to give [D1]-2l (60% D; regioselectivity
C6/C2 = 0:10; Table 2, entry 4).
We then turned our attention to investigating the lith-
iation of para-disubstituted derivatives. Both p-(trifluoro-
methyl) and p-(phenylthio)[21] phenyloxetanes 2n,p undergo
highly regioselective ortho-lithiation at the site nearest the
oxetanyl group to give deuterated and methylated derivatives
[D1]-2n (70% D) and 11 (90% yield) upon quenching with
MeOD and MeI, respectively (Table 2, entries 5 and 6). On
the other hand, lithiation of sulfone 2q[21] with sBuLi at 08C in
THF (this substrate proved to be poorly soluble in Et2O)
occurred only at the ortho and ortho’ positions (C3 and C2’)
nearest to the sulfonyl group (see the Supporting Informa-
tion) to give [D1]-2q (70% D as an equimolar mixture of
C3/C2’ regioisomers) upon quenching with MeOD (Table 2,
entry 7).
Scheme 3. Synthesis of phthalan 9 by intramolecular cyclization of
ortho-hydroxyalkylated 2-methyl-2-phenyloxetane 2i.
Finally, to assess the relative activation abilities of both
aminomethyl groups and alkoxides with respect to the
oxetane ring, two intermolecular competition experiments
were also performed.[22] Equimolar amounts of 2-methyl-2-
phenyloxetane 1 and substituted aromatics such as anisole
(12a) and N,N-dimethylbenzylamine (12b) were allowed to
compete with 0.9 equiv of sBuLi in Et2O. The lithio salts were
then trapped by the addition of MeI, and the relative ratios of
the corresponding methylated compounds 13a,b were deter-
mined (Table 3). These results suggest that the oxetane ring is
the Supporting Information),[19] intramolecular cyclization
proceeds with complete preservation of the starting optical
purity (e.r. 96:4) at the newly formed quaternary stereogenic
center. The high stereochemical fidelity observed in the
formation of (À)-9 is consistent with a stereospecific cycliza-
tion (Scheme 3). We assume that an SN2-type mechanism
(inversion of configuration) is followed.[20]
The effect of phenyl ring substitution on the regioselec-
tivity of proton abstraction was also investigated. When
ortho-chlorophenyloxetane 2e is treated with sBuLi, it
smoothly undergoes successive ortho-lithiation to give [D1]-
2e (98% D) and ortho-disubstituted product 10 (98% yield)
upon quenching with MeOD and MeI, respectively (Table 2,
entries 1 and 2).
Table 3: Intermolecular competition between 1 and 12a,b for deficient
amounts of sBuLi.
meta-Trifluoromethyl-substituted oxetane 2l could be
primarily deprotonated/deuterated at the site ortho to the
oxetanyl substituent to give [D1]-2l (90% D) instead, despite
the cooperative effect of the trifluoromethyl and the oxetanyl
groups promoting lithiation between these functional groups
(regioselectivity C6/C2 = 9:1; Table 2, entry 3). However,
when chlorine is meta to the oxetanyl group, as in 2m,
metalation/deuteration exclusively occurred in their mutual
Starting Material
Yield [%][a]
Methylated Product
Yield [%][a]
X
1
40
69
12
97
58
2a
60
31
13
3
42
OMe
CH2NMe2
1
[a] Yield determined by H NMR spectroscopy of the crude reaction
mixture.
Table 2: Substituent effects on the regioselectivity of lithiation.
more effective at directing ortho lithiation than a methoxy
substituent (moderate DMG),[3] and almost as strong as the
dimethylaminomethyl substituent, which is among one of the
most powerful non-acidifying functional groups, with regards
to directing ability.[3]
To verify that the above methylated products 13a,b result
from a direct metalation and not from an anion translocation
reaction, two crossover experiments were also performed.
Anisole 12a was ortho-lithiated in Et2O at 08C to give 12a-Li,
then treated with oxetane 1, and finally quenched with MeI;
compound 13a was the only methylated product detected in
the crude reaction mixture (38% yield; Scheme 4). In a similar
experiment, when ortho-lithiated oxetane 1-Li was reacted
with benzylamine 12b along with a deficiency of sBuLi
(0.9 equiv), again no translocation occurred and 2a was the
only product formed upon quenching with MeI (60%
conversion; Scheme 4).
[a]
Entry
2
R
E
Product
Yield [%]
C6/C2
1
2
3
4
5
6
7
2e
2e
2l
2m
2n
2p
2q
Cl (C6)
Cl (C6)
D
Me
D
D
D
[D1]-2e
10
[D1]-2l
[D1]-2m
[D1]-2n
11
98[b]
–
–
9:1
0:10
–
98[c]
CF3 (C3)
Cl (C3)
CF3 (C4)
PhS (C4)
PhSO2 (C4)
90[b]
60[b,d]
70[b,d]
90[c]
Me
D
–
–
[D1]-2q
70[b,e,f]
[a] Regioisomeric ratio. [b] Deuteration percentage determined by
1H NMR spectroscopy. [c] Yield of isolated product after flash chroma-
tography on silica gel. [d] Reaction performed at À788C. [e] THF solvent.
[f] Regioselectivity C3/C2’ =1:1 (see box).
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competition experiments ascertained that an oxetanyl ring is
a directing group that is: 1) weaker than those exerting strong
acidifying and coordination effects (such as sulfones),
2) stronger than chlorine, trifluoromethyl, phenylthio, and
methoxy groups, and 3) as strong as the dimethylaminomethyl
group, with respect to directing ability. Comparative KIE
studies, together with the screening of bases and solvents,
suggest the intervention of a two-step CIPE process rather
Scheme 4. Crossover experiments between 12a-Li and 1-Li with
oxetane 1 and benzylamine 12b, respectively.
À
than a single-step mechanism for the ortho C H lithiation.
What adds value to the method described above is the fact
that oxetane 1) is a strained small-ring heterocycle trans-
formable to useful targets (such as stereodefined
phthlans),[7,17] and 2) does not suffer from attack by the
lithiating agent (except in the presence of Lewis acids, the
only case in which it becomes vulnerable to nucleophiles).[17]
We are confident that in the near future a proper combination
of a- and ortho-lithiation protocols, together with the control
of stereochemistry, will allow for the design of new stereo-
selective and targeted transformations, which still remain
unexplored for aryloxetanes.
To gain further insight into the number of steps involved,
the intra- and intermolecular kinetic isotopic effects (KIEs)
were also determined.[5,23] Treatment of [D1]-1 (98% D) or an
equimolar mixture of 1 and [D2]-1 (98% D) with sBuLi in
Et2O at 08C, followed by quenching with MeI, furnished 2a
and [D1]-2a (Scheme 5).
Received: December 23, 2011
Revised: March 15, 2012
Published online: && &&, &&&&
Keywords: cross-coupling · isotope effects · ortho-lithiation ·
.
oxetanes · phthalans
Scheme 5. Determination of inter- and intramolecular KIEs.
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[2] G. Wittig, G. Fuhrmann, Chem. Ber. 1940, 73, 1197 – 1218.
[3] V. Snieckus, Chem. Rev. 1990, 90, 879 – 933.
[4] a) J. Clayden in Chemistry of Organolithium Compounds, Vol. 1
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Transformations: Applications in Organic Synthesis (Ed.: G.
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[5] M. C. Whisler, S. MacNeil, V. Snieckus, P. Beak, Angew. Chem.
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[6] a) G. W. Klumpp, Recl. Trav. Chim. Pays-Bas 1986, 105, 1 – 21;
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An apparent intermolecular KIE of 2 Æ 1 was obtained
from 1 and [D2]-1 at 08C, whereas the intramolecular KIE
calculated from [D1]-1 at 08C was 4.0 Æ 0.5 (see the Support-
ing Information). The fact that two small but measurable
values are observed, which are also roughly equal within
experimental error, is consistent with a rate-determining
proton transfer. Thus, two mechanistic pathways can be
suggested: 1) a one-step mechanism via a single transition
state arising from simultaneous complexation and proton
transfer, or 2) the intervention of a pre-equilibrium complex
between the substrate and the organolithium base followed by
slow deprotonation (CIPE effect). In light of the effects
exerted by solvents (for example, THF) and by noncoordi-
nating bases (for example, LIDAKOR) on the efficacy of
deprotonation (see above) and noting that a coordination-
driven lithiation pathway has also recently found support in
the deprotonation of other small-ring heterocycles, such as
epoxides[24] and aziridines,[25] we believe complexation to be
the more reasonable pathway.
In conclusion, 2-phenyloxetane is effective in directing
both a-lithiation and ortho-lithiation, the latter occurring in
the absence of benzylic protons.[26] Herein, we have described
the first direct ortho-lithiation/functionalization of 2-methyl-
2-phenyloxetane 1 with a variety of structurally different
electrophiles, including aryl and heteroaryl bromides, through
a one-pot DoM-Suzuki–Miyaura method. Ortho-lithiation
proceeds under mild conditions (sBuLi in Et2O at 08C or
room temperature) and without the need for the addition of
co-solvents, such as TMEDA.[27] Intra- and intermolecular
[11] Interestingly, while alkyllithiums commonly decompose THF,
the use of bimetallic bases promotes the selective a-metalation
of both THF and tetrahydrothiophene while retaining their
cycloanionic structures; see: E. Crosbie, P. Garcꢁa-ꢂlvarez,
A. R. Kennedy, J. Klett, R. E. Mulvey, S. D. Robertson, Angew.
Chem. 2010, 122, 9578 – 9581; Angew. Chem. Int. Ed. 2010, 49,
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[12] F. M. Perna, V. Capriati, S. Florio, R. Luisi, J. Org. Chem. 2002,
67, 8351 – 8359. In contrast to oxetanes, the treatment of a-
methylstyrene oxide with sBuLi in Et2O at 08C mainly led to the
formation of 1,3-dimethyl-1-phenylpent-1-ene, most likely by
4
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alkylative reduction of b-lithiated styrene oxide; see also
Ref. [24].
[13] J. Hassan, M. Sevignon, C. Gozzi, E. Schulz, M. Lemaire, Chem.
Rev. 2002, 102, 1359 – 1469.
[14] M. Alessi, A. L. Larkin, K. A. Ogilvie, L. A. Green, S. Lai, S.
Lopez, V. Snieckus, J. Org. Chem. 2007, 72, 1588 – 1594.
[15] C. Schneider, E. Broda, V. Snieckus, Org. Lett. 2011, 13, 3588 –
3591.
[16] A. Salomone, M. Petrera, D. I. Coppi, F. M. Perna, S. Florio, V.
Capriati, Synlett 2011, 12, 1761 – 1765.
[17] The intramolecular ring-opening of oxetanes has been scarcely
investigated to date; see: a) T. Bach, K. Kather, O. Krꢃmer, J.
Org. Chem. 1998, 63, 1910 – 1918; b) F. Bertolini, S. Crotti, V.
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[18] Phthalans are a well-known class of compounds with fascinating
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[20] For the related intramolecular cyclization of ortho-hydroxyalky-
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Perna, A. Salomone, J. Org. Chem. 2006, 71, 3984 – 3987.
[21] Oxetanes 2p and 2q were prepared from 2-(4-bromophenyl)-2-
methyloxetane 2o; see the Supporting Information for details.
[22] For other examples of intermolecular competition studies, see:
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[23] D. R. Anderson, N. C. Faibish, P. Beak, J. Am. Chem. Soc. 1999,
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Amedjkouh, S. O. Nilsson Lill, Chem. Eur. J. 2009, 15, 7958 –
7979, and references therein.
[25] F. Affortunato, S. Florio, R. Luisi, B. Musio, J. Org. Chem. 2008,
73, 9214 – 9220.
[26] A referee has suggested that this special type of metalation may
alternatively be considered as a new example of a directed
remote metalation, from the standpoint of the oxetane.
[27] For the effects of solvent and TMEDA on the configurational
stability of chiral lithiated aryloxiranes, see: a) V. Capriati, S.
Florio, F. M. Perna, A. Salomone, Chem. Eur. J. 2010, 16, 9778 –
9788; b) F. M. Perna, A. Salomone, M. Dammacco, S. Florio, V.
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Communications
Lithiation Chemistry
Oxetane nudges in the DoM direction!
Regioselective ortho-lithiation induced by
an oxetane ring has been achieved. The
reaction provides easy access to ortho-
functionalized 2-aryloxetanes also
D. I. Coppi, A. Salomone, F. M. Perna,
V. Capriati*
&&&& — &&&&
Exploiting the Lithiation-Directing Ability
of Oxetane for the Regioselective
Preparation of Functionalized 2-
Aryloxetane Scaffolds under Mild
Conditions
through a lithiation/borylation Suzuki–
Miyaura cross-coupling. The lithiation-
directing ability of oxetane and the proton
transfer mechanism have been investi-
gated by competitive metalation and
kinetic isotope effect studies.
6
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ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
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