Toward Customized Tetrahydropyran Derivatives through Regioselective α-Lithiation and Functionalization of 2-Phenyltetrahydropyran

Article abstract of DOI:10.1002/ejoc.201600365

In this contribution, the first direct and efficient functionalization of the preformed 2-phenyltetrahydropyran (2-PhTHP) nucleus by electrophilic interception of the corresponding α-lithiated derivative by employing sBuLi as the base and THF as the solvent at –78 °C was explored. The presence of N,N,N′,N′-tetramethylethylenediamine (TMEDA) proved to be critical to governing reaction feasibility both in polar and apolar solvents and for improving the yield of the reaction. Both carbon- and heteroatom-based halides were found to be competent electrophiles for this transformation, as well as aliphatic and aromatic aldehydes and ketones, isocyanates, and carboxylic acid derivatives. The combination of hexane/TMEDA lowered the rate of racemization of α-lithiated optically active 2-PhTHP, which thereby enabled calculation of its barrier to inversion at –78 °C.

Full text of DOI:10.1002/ejoc.201600365

DOI: 10.1002/ejoc.201600365
Communication
Lithiation Chemistry
Toward Customized Tetrahydropyran Derivatives through
Regioselective α-Lithiation and Functionalization of 2-
Phenyltetrahydropyran
Luciana Cicco,[a] Valeria Addante,[a] Andrea Temperini*[b] Carsten Adam Donau,[c]
Konstantin Karaghiosoff,[c] Filippo Maria Perna*[a] and Vito Capriati*[a]
Dedicated to Professor Achille Umani-Ronchi on the occasion of his 80th birthday
Abstract: In this contribution, the first direct and efficient func- carbon- and heteroatom-based halides were found to be com-
tionalization of the preformed 2-phenyltetrahydropyran (2- petent electrophiles for this transformation, as well as aliphatic
PhTHP) nucleus by electrophilic interception of the correspond- and aromatic aldehydes and ketones, isocyanates, and carb-
ing α-lithiated derivative by employing sBuLi as the base and oxylic acid derivatives. The combination of hexane/TMEDA low-
THF as the solvent at –78 °C was explored. The presence of ered the rate of racemization of α-lithiated optically active 2-
N,N,N′,N′-tetramethylethylenediamine (TMEDA) proved to be PhTHP, which thereby enabled calculation of its barrier to inver-
critical to governing reaction feasibility both in polar and apolar sion at –78 °C.
solvents and for improving the yield of the reaction. Both
Introduction
of both cyclic and acyclic ethers with electron-deficient hetero-
arenes (Scheme 1, a).[7] Liu and co-workers showed that the
reactivity of the trityl ion can be successfully tuned to promote
chemoselective C–H functionalization of various cyclic ethers
Saturated oxygen heterocycles, such as functionalized tetra-
hydropyran (THP) rings, are common structural motifs that are
widely distributed across bioactive natural compounds and are
also representative of the skeleton of new synthetic therapeutic
agents.[1] Given the wealth of THP-containing products, it is not
surprising that several efficient methodologies for the stereo-
selective construction of variously substituted THPs have been
developed throughout the years.[2] Recent examples also in-
clude (organo)catalytic methodologies[3,4] and 6-exo-tet cycliza-
tions of phenylseleno alcohols.[5a] A novel one-pot multistep
synthetic procedure for isochromane derivatives, on the basis
of the addition of ortho-lithiated aryloxiranes to enaminones,
was also reported.[6] However, despite advances in synthetic
methodologies, direct functionalization processes of pre-exist-
ing THP nuclei remain challenging and rare. In this context,
significant success was recently achieved by MacMillan and Jin,
who developed an efficient photoredox-mediated α-arylation
[a] Dipartimento di Farmacia-Scienze del Farmaco,
Università di Bari “Aldo Moro”, Consorzio C.I.N.M.P.I.S.,
Via E. Orabona 4, 70125 Bari, Italy
E-mail: filippo.perna@uniba.it
vito.capriati@uniba.it
http://www.farmacia.uniba.it
[b] Dipartimento di Scienze Farmaceutiche, Università di Perugia,
Via del Liceo 1, 06123 Perugia, Italy
E-mail: andrea.temperini@unipg.it
[c] Department Chemie, Ludwig-Maximilians-Universität München,
Butenandtstrasse 5–13, Haus F, 81377 München, Germany
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201600365.
Scheme 1. Direct functionalization of THP derivatives; TFA = trifluoroacetic
acid.
Eur. J. Org. Chem. 0000, 0–0
1
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
(Scheme 1, b)[8a] and also disclosed effective, oxidative cross- ment with sodium phenyl selenolate (obtained from in situ re-
dehydrogenative coupling protocols for chromenes, benzylic duction of diphenyl diselenide by the addition of sodium),[20]
ethers, and benzopyran.[8b–8d] An efficient palladium-catalyzed underwent clean nucleophilic alkyl–oxygen bond cleavage with
stereoselective arylation protocol at the unactivated 3-position concomitant loss of CO2 to afford straightforwardly δ-phenyl-
of THP was recently described by Affron and Bull (Scheme 1, seleno ketone 3 in an overall yield of 56 %. The reduction of 3
c).[9]
Organolithium compounds (RLi) are known to react with
by using NaBH4 in THF/MeOH furnished the expected δ-phenyl-
seleno alcohol 4 in 90 % yield. Finally, oxidation of 4 with an
excess amount of m-chloroperoxybenzoic acid (m-CPBA) and
dipotassium hydrogen phosphate occurred smoothly at room
temperature to give the corresponding phenylselenone inter-
mediate 5, which cyclized in the presence of powdered KOH
according to a 6-exo-tet ring pattern to deliver the desired
2-PhTHP 6 in 80 % yield (Scheme 2).
ethers to promote either “protophilic” (i.e., proton abstraction
at the α- or ꢀ-carbon atom of the ether) or “nucleophilic” (i.e.,
replacement of an alkoxy group) fission reactions. The rate of
these processes is dependent on the nature of the RLi and that
of the ether and on the temperature.[10] In addition, α-lithiated
ethers are typical Li/OR carbenoids that are able to exhibit
carbanionic/carbene-like behavior.[11]
The burgeoning field of oxygen heterocycles has seen signifi-
cant breakthroughs over the last 10 years, because of the devel-
opment of new lithiation methodologies for the preparation
of more functionalized derivatives.[12] In particular, as for cyclic
ethers, both protophilic and nucleophilic fissions have been ob-
served quite frequently with oxiranes, oxetanes, and tetrahydro-
furans.[10,13–15] THP is more resistant than THF to both proto-
philic and nucleophilic fissions: for example, the half-life of
nBuLi in THF is 1.78 h versus 21.0 h in THP at +20 °C.[14] By
treating sBuLi with THP at –20 °C, a ring-opening reaction fol-
lowed by polymerization was assumed to take place.[14,16] Most
likely, the first stage of such “protophilic ether cleavage” is α-
metalation rather than ꢀ-metalation; the latter is instead typical
of larger rings (e.g., oxepane) that can easily assume the re-
quired conformation for an E2 elimination reaction.[13] This
statement is consistent with the recent isolation and characteri-
zation of a crystalline α-zinc-substituted THP adduct by Mulvey
and co-workers.[17] α-Lithiation of 2-(phenylsulfonyl)tetrahydro-
pyran was reported to be feasible with nBuLi at –78 °C in THF,
although spontaneous ꢀ-elimination of phenylsulfinic acid oc-
curred, which thereby afforded the corresponding α,ꢀ-unsatu-
rated adducts as the final products.[18] The reductive lithiation
of both α-phenylthioTHF and THP derivatives set up by Cohen
and Lin in the 1980s represented the first general method for
the preparation of nontransient α-lithio cyclic ethers from
carbon radicals (as precursors to the anions) formed in the rate-
determining step.[19]
Scheme 2. Reagents and conditions: (i) 1. LDA, THF, –70 °C; 2. PhCOCl;
(ii) PhSeNa, DMF, 110 °C; (iii) NaBH4, THF/MeOH; (iv) m-CPBA, K2HPO4, MeCN,
rt., 2 h; (v) KOH, r.t.
Such a compound was then subjected to the action of vari-
ous organolithium bases, with or without N,N,N′,N′-tetramethyl-
ethylenediamine (TMEDA), with varying solvents and tempera-
tures to find the best conditions for α-lithiation. The first sur-
prise was that subjecting 6 to the conditions reported to be
effective to metalate 2-PhTHF quantitatively and that precluded
at the same time its spontaneous cycloreversion (sBuLi/TMEDA,
toluene, –78 °C),[12f] followed by quenching of the putative 6-
Li with MeOD after 5 min, afforded deuterated [D]-6 with only
53 % deuterium incorporation (1H NMR spectroscopic analysis)
(Table 1, entry 1). This percentage dramatically dropped down
to 4 % in the absence of such a ligand (Table 1, entry 2). The
replacement of toluene by other apolar solvents such as hexane
and cyclopentyl methyl ether (CPME) did not lead to any im-
provement, and deuterium was incorporated into 6 at –78 °C
in up to 42 or in 16 % in the presence or absence of TMEDA,
respectively (Table 1, entries 3–6).
The above findings are in line with recent studies reported
by Capriati and co-workers on the lithiation of aryloxiranes,
which showed that α-deprotonation did take place in hexane
with sBuLi in the presence of TMEDA only, most likely thanks to
the formation of more reactive ternary prelithiation complexes
among tetrameric sBuLi, epoxides, and TMEDA.[21] Thus, it can-
not be ruled out that such complexes may also play a key role
in promoting deprotonation of 6. We were pleased to find that
Herein we wish to report the first successful direct α-lithi-
ation of 2-PhTHP as a means to obtain 2,2-disubstituted THP
derivatives with a quaternary stereogenic center (Scheme 1, d).
An assessment of the configurational stability of the α-lithiated
THP intermediate was also undertaken.
Results and Discussion
We began our study by conducting a large series of experi- upon switching to a more polar solvent such as THF, lithiation
ments on 2-PhTHP 6, which was prepared according to a new of 6 with sBuLi/TMEDA afforded, after MeOD quenching, [D]-6
attractive route that is complementary to the others already with 84 % D at –78 °C, whereas the absence of TMEDA again
described for arylTHPs[5a] and arylTHFs.[5b] Commercially avail- led to minor deuterium content (46 % D) of [D]-1 (Table 1, en-
able δ-valerolactone (1) was first α-deprotonated with lithium tries 7 and 8). The employment of 2-MeTHF promoted a clean
diisopropylamide (LDA; 2 equiv., THF, –70 °C) and then treated hydrogen–lithium exchange on 6 with sBuLi, although this fur-
with benzoyl chloride (1 equiv.) to give ꢀ-ketolactone 2, which nished [D]-6 with 26 or 4 % D in the presence or absence of
was used without further purification. The latter, upon treat- TMEDA, respectively (Table 1, entries 9 and 10). Remarkably, a
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
2
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
Table 1. Optimization of the regioselective α-lithiation/deuteration of 6.
and allylation with allyl bromide afforded the expected α-sub-
stituted derivatives 7a and 7b in reasonable yields (52–78 %,
Scheme 3). The reaction of 6-Li with Me3SiCl, Bu3SnCl, and
(PhS)2 provided the desired silyl, tin, and sulfenyl derivatives
7c–e in yields of 47–80 %. Direct iodation was also successfully
accomplished with I2, which thus furnished the corresponding
α-iodated adduct 7f in high yield (91 %). The use of N,N-
dimethylformamide (DMF) as a quenching agent delivered
aldehyde 7g in essentially quantitative yield (98 %), whereas
trapping with 4-methylphenyl-1-isocyanate, as a more reactive
electrophile, produced amide 7h in 49 % yield.
Entry Base
(equiv.)
T
[°C]
Solvent
Co-solvent
(equiv.)
D[a]
[%]
1
2
3
4
5
6
7
8
sBuLi (2)
sBuLi (2)
sBuLi (2)
sBuLi (2)
sBuLi (2)
sBuLi (2)
sBuLi (2)
sBuLi (2)
sBuLi (2)
sBuLi (2)
sBuLi (3)
sBuLi (3)
sBuLi (3)
sBuLi (3)
nBuLi (3)
Me(CH2)5Li (3)
tBuLi (3)
–78
–78
–78
–78
–78
–78
–78
–78
–78
–78
–78
–78
–98
0
toluene
toluene
CPME
CPME
hexane
hexane
THF
TMEDA (2)
–
TMEDA (2)
–
TMEDA (2)
–
TMEDA (2)
–
53
4
42
16
40
0
84
46
26
4
80
94
0
THF
9
2-MeTHF
2-MeTHF
Et2O
THF
THF
THF
THF
THF
THF
TMEDA (2)
–
10
11
12
13
14
15
16
17
TMEDA (3)
TMEDA (3)
TMEDA (3)
TMEDA (3)
TMEDA (3)
TMEDA (3)
TMEDA (3)
47[b]
20
0
–78
–78
–78
88
[a] Deuterium incorporation as calculated by analysis of the crude reaction
mixture by 1H NMR spectroscopy; no other products were detected. [b] A
complex mixture of unidentified products was detected in the crude mixture
along with the starting material.
threefold excess amount of both sBuLi and TMEDA allowed an
increase in the amount of deuterium incorporated into 1 to up
to 80 and even to 94 % at –78 °C in Et2O and THF, respectively
(Table 1, entries 11 and 12). Further experimentation in THF
established that a temperature as low as –98 °C precluded lithi-
ation of 6 (Table 1, entry 13), whereas a temperature as high as
0 °C was detrimental to the chemical stability of 6-Li, as [D]-6
formed with 47 % D but with considerable decomposition
(Table 1, entry 14). As for other bases, we found that metalation
of 6 with nBuLi/TMEDA in THF at –78 °C did not lead to greater
than 20 % deuterium incorporation (Table 1, entry 15), and sur-
prisingly, the combination of Me(CH2)5Li/TMEDA in THF proved
to be totally ineffective (Table 1, entry 16). Finally, the use of a
stronger base such as tBuLi jointly with TMEDA in THF at –78 °C
afforded [D]-6 with 88 % D (Table 1, entry 17).
Scheme 3. Scope of electrophiles for the trapping reactions of 6-Li. All reac-
tions gave full conversion, yields refer to isolated products after column chro-
matography. Adducts 7i–k were isolated as separable mixtures of diastereo-
mers (see the Supporting Information).
As for reactions with carbonyl compounds, both an aromatic
TMEDA is a commonly used ligand to modify the behavior enolizable ketone such as acetophenone and aromatic and ali-
of RLi species.[22] Such a ligand is known to have the most phatic aldehydes (e.g., 4-chlorobenzaldehyde and acetalde-
pronounced effects on organolithium aggregates and, thus, on hyde) were competent electrophilic partners, and they afforded
their reactivity in the absence of strong donor solvents, whereas the expected hydroxyalkylated derivatives 7i–k in good yields
the relative affinities of TMEDA and THF for lithium seem to (64–73 %, Scheme 3).
be highly substrate dependent.[22,23] Thus, in contrast to that
We were also interested in establishing whether the present
observed in the case of other cyclic ethers,[12b,12f,24] the appar-
protocol could be further expanded to obtain optically active
ent beneficial influence of this ligand in all of the above-de-
scribed metalations, both in polar and apolar solvents, is in-
triguing and deserves further consideration.[25]
derivatives. To this end, we explored the configuration stability
of 6-Li generated by deprotonation of the corresponding opti-
cally active (S)-6. The latter was prepared by preliminarily sub-
Having established the optimal conditions for efficient α- jecting prochiral δ-phenylseleno ketone 3 to enantioselective
lithiation of 6 (Table 1, entry 12), we next focused on evaluating reduction by using borane and the chiral Corey–Bakshi–Shibata
the scope and generality of this methodology for the prepara- (CBS) oxazaborolidine catalyst [(S)-MeCBS],[26] which afforded
tion of more functionalized derivatives by reaction with a broad (S)-4 in 84 % yield with an enantiomeric ratio (er) of 98:2. Final
range of structurally varied electrophiles. Alkylation with MeI oxidation of (S)-4 with m-CPBA followed by cyclization of the
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
3
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
putative selenone intermediate with powdered KOH under the Conclusions
above-described conditions stereospecifically delivered (S)-6 in
In summary, we showed for the first time that under optimized
conditions and in the presence of TMEDA, regioselective and
efficient functionalization of 2-PhTHP (6) could be successfully
accomplished through a direct α-lithiation reaction performed
in THF at –78 °C by using sBuLi as the base, followed by trap-
ping with several electrophiles. This reaction has a broad elec-
trophile scope and 2,2-disubstituted THP derivatives 7 can be
isolated in yields up to 98 %. Optically active α-lithiated inter-
mediate (S)-6-Li was found to be configurationally labile in THF
but underwent slower racemization in hexane/TMEDA. The cal-
culated barrier to inversion of 13.5 kcal mol–1 at –78 °C encour-
ages investigation of the preparation of more functionalized
optically active arylTHP derivatives, also exploiting asymmetric
substitution of chiral lithiated racemic substrates that can un-
dergo dynamic equilibration in the presence of a chiral ligand.
an overall yield of 80 % with an er value of 98:2 (Scheme 4).
Scheme 4. Reagents and conditions: (i) BH3·Me2S, (S)-MeCBS, THF, 0 °C; (ii) m-
CPBA, K2HPO4, MeCN, r.t., 2 h; (iii) KOH, r.t.
Exposing a 0.2
M
solution of (S)-6 to sBuLi (3 equiv.)/TMEDA
(3 equiv.) in THF, followed by quenching with MeOD, essentially
gave racemic [D]-6 (60–94 % D, er 50:50) after a reaction time
of either 5 min or 30 s at –78 °C (Table 2, entries 1 and 2).
Interestingly, upon changing the solvent from THF to hexane,
the rate of racemization slowed down and (S)-[D]-6 was recov-
ered with an encouraging er value of 60:40 (92 % D; Table 2,
entry 3). Of note, a progressive increase of the er value up to
86:14 was observed upon aging enantiomerically enriched (S)-
6-Li for shorter reaction times up to 10 s (Table 2, entries 4–6).
Experimental Section
Preparation of THP Derivative 7a as a Typical Procedure: A solu-
tion of 2-PhTHP (6; 50 mg, 0.31 mmol) and TMEDA (0.14 mL,
0.93 mmol) in dry THF (2.5 mL) was cooled to –78 °C and treated
with sBuLi (1.25
M in cyclohexane, 0.74 mL, 0.93 mmol). The result-
ing red mixture was stirred for 5 min at this temperature before it
was quenched with MeI (0.58 mL, 0.93 mmol). The mixture was kept
at –78 °C for an additional 5 min. After this time, the mixture was
slowly warmed to room temperature, and a saturated aqueous
NH4Cl solution (5 mL) was added. Then, the mixture was extracted
with Et2O (3 × 10 mL), the organic layers were combined and dried
with anhydrous Na2SO4, and the solvent was removed under re-
duced pressure to leave a crude oil, which was purified by flash
chromatography (silica gel; hexane/Et2O, 20:1) to afford THP deriva-
Table 2. Lithiation/deuteration of 2-PhTHP (S)-6 with different solvents.
Entry
Solvent
t [s]
D [%][a]
er[b]
1
tive 7a (42 mg, 78 %) as an oil. H NMR (400 MHz, CDCl3): δ = 1.39
1
2
3
4
5
6
THF
THF
hexane
hexane
hexane
hexane
300
30
300
120
30
94
60
92
95
95
55
50:50
50:50
60:40
70:30
79:21
86:14
(s, 3 H), 1.55–1.86 (m, 5 H), 2.29–2.33 (m, 1 H), 3.47–3.52 (m, 1 H),
3.72–3.75 (m, 1 H), 7.22–7.26 (m, 1 H), 7.33–7.43 ppm (m, 4 H). 13C
NMR (100 MHz, CDCl3): δ = 20.1, 26.0, 32.7, 34.6, 62.8, 75.9, 125.9,
126.5, 128.4, 145.4 ppm. FTIR (neat): ν = 2937, 1492, 1446, 1057,
˜
758, 701 cm–1. GC–MS (70 eV): m/z (%) = 176 (1) [M]+, 161 (100),
105 (82), 77 (20). HRMS (ESI-TOF): calcd. for C12H17O 177.1279 [M +
H]+; found 177.1283.
10
[a] Calculated by analysis of the crude reaction mixture by 1H NMR spectro-
scopy and corrected for the percentage deuterium found. [b] Determined by
chiral stationary phase HPLC (see the Supporting Information).
Supporting Information (see footnote on the first page of this
article): Experimental procedures, spectroscopic data, and copies of
1
the H NMR and 13C NMR spectra of compounds 3, 4, 6, and 7a–k.
On the basis of these results, the barrier to enantiomerization
of (S)-6-Li could be then calculated. The first-order plot ob-
tained (R2 = 0.9898) indicated a racemization half-life (t1/2) of
2.8 min at –78 °C. Application of the Eyring equation to
the estimated rate of enantiomerization (kenant; calculated as
the rate of racemization divided by two, i.e., krac/2) for
Acknowledgments
This work was financially supported by Ministero dell'Università
e della Ricerca (MIUR) and the Interuniversities Consortium
C.I.N.M.P.I.S. through the project “Sintesi di nuove molecole
come farmaci per malattie rare” (code: CMPT148470). The au-
thors would like to acknowledge Dr. Francesca Sassone for her
contribution to the Experimental Section.
(S)-6-Li furnished
a
barrier to inversion [ΔG≠(enant)] of
13.5 0.1 kcal mol–1 at –78 °C in hexane (see the Supporting
Information).[27]
Thus, the stereochemistry of chiral nonracemic α-lithiated 2-
PhTHP could be controlled in nonpolar solvents in the presence
of TMEDA in line with α-lithiated styrene oxides,[21] whereas
optically active α-lithiated phenyloxetane[12b] and PhTHF[12f]
proved to be configurationally unstable in both polar and non-
polar solvents and underwent very fast racemization.
Keywords: Synthetic methods · Carbanions · Lithium ·
Oxygen heterocycles · Regioselectivity
[1] a) E. Alvarez, M. L. Candenas, R. Perez, J. L. Ravelo, M. J. Delgado, Chem.
Rev. 1995, 95, 1953–1980; b) K.-S. Lee, G. Li, S. H. Kim, C.-S. Lee, M.-H.
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
4
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
Woo, S.-H. Lee, Y.-D. Jhang, J.-K. Son, J. Nat. Prod. 2002, 65, 1707–1708;
c) T. Nakata, Chem. Rev. 2005, 105, 4314–4347; d) E. J. Kang, E. Lee, Chem.
Rev. 2005, 105, 4348–4378; e) J. E. Aho, P. M. Pinko, T. K. Rissa, Chem. Rev.
2005, 105, 4406–4440; f) S. D. Roughley, A. M. Jordan, J. Med. Chem.
2011, 54, 3451–3479; g) F. Xu, M. J. Zacuto, Y. Kohmura, J. Rosen, A. Gibb,
M. Alam, J. Scott, D. Tschaen, Org. Lett. 2014, 16, 5422–5425.
[2] For selected reviews, see: a) T. L. B. Boivin, Tetrahedron 1987, 43, 3309–
3362; b) L. E. Titze, G. Kettschau, Top. Curr. Chem. 1997, 189, 1–120; c)
P. A. Clarke, S. Santos, Eur. J. Org. Chem. 2006, 2045–2053; d) I. Larrosa,
P. Romea, F. Urpí, Tetrahedron 2008, 64, 2683–2723; e) N. M. Nasir, K.
Ermanis, P. A. Clarke, Org. Biomol. Chem. 2014, 12, 3323–3335; f) M. A.
Perry, S. D. Rychnovsky, N. Sizemore, Top. Heterocycl. Chem. 2014, 35, 43–
95.
reviews, see: h) F. M. Perna, A. Salomone, V. Capriati, Oxygen-Bearing
Lithium Compounds in Modern Synthesis, in: Lithium Compounds in Or-
ganic Synthesis – From Fundamentals to Applications (Eds.: R. Luisi, V.
Capriati), Wiley-VCH, Weinheim, Germany, 2014, p. 153–189; i) F. M.
Perna, A. Salomone, V. Capriati, Recent Developments in the Lithiation
Reactions of Oxygen Heterocycles, in: Advances in Heterocyclic Chemistry
(Eds.: E. F. V. Scriven, C. A. Ramsden), Elsevier/Academic Press, Cambridge,
MA, 2016, vol. 118, p. 91–127.
[13] R. B. Bates, L. M. Kroposki, D. E. Potter, J. Org. Chem. 1972, 37, 560–562.
[14] P. Stanetty, M. D. Mihovilovic, J. Org. Chem. 1997, 62, 1514–1515.
[15] R. L. Letsinger, D. F. Pollart, J. Am. Chem. Soc. 1956, 78, 6079–6085.
[16] J. Langer, M. Köhler, R. Fischer, F. Dündar, H. Görls, M. Westerhausen,
Organometallics 2012, 31, 6172–6182.
[3] M. G. Núñez, P. García, R. F. Moro, D. Díez, Tetrahedron 2010, 66, 2089–
2109.
[17] A. R. Kennedy, J. Klett, R. E. Mulvey, D. S. Wright, Science 2009, 326, 706–
708.
[18] S. V. Ley, B. Lygo, A. Wonnacott, Tetrahedron Lett. 1985, 26, 535–538.
[19] T. Cohen, M.-T. Lin, J. Am. Chem. Soc. 1984, 106, 1130–1131.
[20] Previous examples of the in situ preparation of PhSeNa by reduction of
diphenyl diselenide employed NaBH4 in DMF at 110–120 °C or Na in
THF/hexamethylphosphoric triamide (HMPA) at reflux; see: a) R. N. Scar-
borough Jr., A. B. Smith III, Tetrahedron Lett. 1977, 18, 4361–4364; b) D.
Liotta, H. Santiesteban, Tetrahedron Lett. 1977, 18, 4369–4372.
[21] F. M. Perna, A. Salomone, M. Dammacco, S. Florio, V. Capriati, Chem. Eur.
J. 2011, 17, 8216–8225.
[4] R. Guo, J. Huang, H. Huang, X. Zhao, Org. Lett. 2016, 18, 505–507.
[5] a) A. Temperini, A. Barattucci, P. M. Bonaccorsi, O. Rosati, L. Minuti, J. Org.
Chem. 2015, 80, 8102–8112; b) L. Minuti, A. Barattucci, P. M. Bonaccorsi,
M. L. Di Gioia, A. Leggio, C. Siciliano, A. Temperini, Org. Lett. 2013, 15,
3906–3909.
[6] A. Salomone, F. M. Perna, F. C. Sassone, A. Falcicchio, J. Bezenšek, J. Svete,
B. Stanovnik, S. Florio, V. Capriati, J. Org. Chem. 2013, 78, 11059–11065.
[7] J. Jin, D. W. C. MacMillan, Angew. Chem. Int. Ed. 2015, 54, 1565–1569;
Angew. Chem. 2015, 127, 1585–1589.
[22] a) D. B. Collum, Acc. Chem. Res. 1992, 25, 448–454; b) B. L. Lucht, D. B.
Collum, J. Am. Chem. Soc. 1995, 117, 9863–9874; c) B. L. Lucht, M. P.
Bernstein, J. F. Remenar, D. B. Collum, J. Am. Chem. Soc. 1996, 118,
10707–10718; d) D. B. Collum, D. Hoffmann, J. Am. Chem. Soc. 1998, 120,
5810–5811.
[23] a) H. J. Reich, W. S. Goldenberg, A. W. Sanders, K. L. Jantzi, C. C.
Tzschucke, J. Am. Chem. Soc. 2003, 125, 3509–3521; b) H. J. Reich, W. S.
Goldenberg, A. W. Sanders, ARKIVOC 2004, xiii, 97–129.
[8] a) M. Wan, Z. Meng, H. Lou, L. Liu, Angew. Chem. Int. Ed. 2014, 53, 13845–
13849; Angew. Chem. 2014, 126, 14065–14069; b) Z. Meng, S. Sun, H.
Yuan, H. Lou, L. Liu, Angew. Chem. Int. Ed. 2014, 53, 543–547; Angew.
Chem. 2014, 126, 553–557; c) W. Chen, Z. Xie, H. Zheng, H. Lou, L. Liu,
Org. Lett. 2014, 16, 5988–5991; d) F. Li, Z. Meng, J. Hua, W. Li, H. Lou, L.
Liu, Org. Biomol. Chem. 2015, 13, 5710–5715.
[9] D. P. Affron, J. A. Bull, Eur. J. Org. Chem. 2016, 136–149.
[10] a) G. Köbrich, A. Baumann, Angew. Chem. Int. Ed. Engl. 1973, 12, 856–
858; Angew. Chem. 1973, 85, 916–918; b) A. Maercker, Angew. Chem. Int.
Ed. Engl. 1987, 26, 972–989; Angew. Chem. 1987, 99, 1002–1019.
[11] For reviews on lithium carbenoids, see: a) G. Boche, J. C. W. Lohrenz,
Chem. Rev. 2001, 101, 697–756; b) V. Capriati, S. Florio, Chem. Eur. J.
2010, 16, 4152–4162, and references cited therein; c) V. Capriati, Modern
Lithium Carbenoid Chemistry, in: Contemporary Carbene Chemistry (Eds.:
R. A. Moss, M. P. Doyle), Wiley, Hoboken, NJ, 2013, p. 327–362.
[12] For α-lithiated aryloxiranes, see: a) V. Capriati, S. Florio, A. Salomone, Top.
Stereochem. 2010, 26, 135–164; for lithiated oxetanes, see: b) D. I. Coppi,
A. Salomone, F. M. Perna, V. Capriati, Chem. Commun. 2011, 47, 9918–
9920; c) D. I. Coppi, A. Salomone, F. M. Perna, V. Capriati, Angew. Chem.
Int. Ed. 2012, 51, 7532–7536; Angew. Chem. 2012, 124, 7650–7654; d)
J. V. Geden, B. O. Beasley, G. J. Clarkson, M. Shipman, J. Org. Chem. 2013,
78, 12243–12250; e) K. F. Morgan, I. A. Hollingsworth, J. A. Bull, Chem.
Commun. 2014, 50, 5203–5205; for lithiated aryltetrahydrofurans, see: f)
R. Rosmara, V. Mallardo, F. M. Perna, A. Salomone, V. Capriati, Chem. Com-
mun. 2013, 49, 10160–10162; g) F. C. Sassone, F. M. Perna, A. Salomone,
S. Florio, V. Capriati, Chem. Commun. 2015, 51, 9459–9462; for recent
[24] TMEDA was also shown to be necessary to preserve the chemical integ-
rity of α-lithiated styrene oxide once generated in THF and to mitigate
its carbene-like reactivity, see: a) V. Capriati, S. Florio, R. Luisi, A. Salom-
one, Org. Lett. 2002, 4, 2445–2448; b) V. Capriati, S. Florio, F. M. Perna, A.
Salomone, A. Abbotto, M. Amedjkouh, S. O. Nilsson Lill, Chem. Eur. J.
2009, 15, 7958–7979.
[25] Solution and solid structure investigation of 6-Li are underway and re-
sults will be reported in due course.
[26] E. J. Corey, R. K. Bakshi, S. Shibata, J. Am. Chem. Soc. 1987, 109, 5551–
5553.
[27] Activation free energy for the enantiomerization (ΔG≠enant, kcal mol–1
)
was calculated by application of the Eyring equation, in which T is the
absolute temperature and kenant is the rate constant [s–1] (kenant = krac
2): ΔG≠
= 4.574 T [10.318 + log10(T kenant)]: H. Eyring, Chem. Rev.
/
enant
1935, 17, 65–77.
Received: March 23, 2016
Published Online: ■
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
5
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
Lithiation Chemistry
L. Cicco, V. Addante, A. Temperini,*
C. A. Donau, K. Karaghiosoff,
F. M. Perna,* V. Capriati* ................. 1–6
Toward Customized Tetrahydro-
pyran Derivatives through Regiose-
lective α-Lithiation and Functionali-
zation of 2-Phenyltetrahydropyran
2-Phenyltetrahydropyran is easily func- the optically active intermediate is
tionalized in up to 98 % yield in THF slowed down in hexane/TMEDA, which
by using a sBuLi-mediated lithiation- thereby paves the way for the prepara-
trapping method in the presence of tion of enantiomerically enriched
N,N,N′,N′-tetramethylethylenediamine tetrahydropyran derivatives.
(TMEDA). The rate of racemization of
DOI: 10.1002/ejoc.201600365
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
6
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim