Surprising fenchone induced cyclization: Synthesis of the new chiral diol biphenyl-2,2′-sulfone-3,3′-bisfenchol (BISFOL)

Article abstract of DOI:10.1016/j.tet.2005.08.089

The new chiral diol BISFOL (biphenyl-2,2′-sulfone-3,3′- bisfenchol) is surprisingly formed by cyclization of diphenylsulfone after treatment with n-buthyllithium at -78°C and subsequent addition of (-)-fenchone. Formation of fenchyl alcohol as byproduct points to a Meisenheimer intermediate as primary cyclization product, which transfers lithium hydride yielding the cyclic sulfone. As a chiral and chelating ligand, BISFOL catalyzes enantioselective diorganozinc additions to aldehydes and forms with dimethylzinc an unprecedented, macrocyclic, dimeric methylzinc complex.

Full text of DOI:10.1016/j.tet.2005.08.089

Tetrahedron 61 (2005) 10449–10453
Surprising fenchone induced cyclization: synthesis of the new
chiral diol biphenyl-2,20-sulfone-3,30-bisfenchol (BISFOL)
*
¨ ¨
Francis Soki, Jorg M. Neudorfl and Bernd Goldfuss
¨
¨
¨
¨
Institut fur Organische Chemie, Universitat zu Koln, Greinstrasse 4, D-50939 Koln, Germany
Received 4 July 2005; revised 4 August 2005; accepted 17 August 2005
Available online 19 September 2005
Abstract—The new chiral diol BISFOL (biphenyl-2,20-sulfone-3,30-bisfenchol) is surprisingly formed by cyclization of diphenylsulfone
after treatment with n-buthyllithium at K78 8C and subsequent addition of (K)-fenchone. Formation of fenchyl alcohol as byproduct points
to a Meisenheimer intermediate as primary cyclization product, which transfers lithium hydride yielding the cyclic sulfone. As a chiral and
chelating ligand, BISFOL catalyzes enantioselective diorganozinc additions to aldehydes and forms with dimethylzinc an unprecedented,
macrocyclic, dimeric methylzinc complex.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
in enantioselective additions of organozincs to aldehydes,5 in
enantiopure organolithiums reagents,6 and in fenchyl phos-
phinites for Pd-catalyzed allylic alkylations.7 Herein, we
present the surprising formation of the new fenchyl alcohol
BISFOL(2, biphenyl-2,20-sulfone-3,30-bisfenchol; Scheme 2)
via an unprecedented fenchone induced cyclization.
Additions of organolithium reagents to chiral ketones are
fundamental synthetic methods for syntheses of chiral
diols.1 Chelating diols such as BINOLs2 and TADDOLs3
play as chiral ligands an eminent role in enantioselective
synthesis. We recently reported the synthesis and the X-ray
crystal structure of (M)-BIFOL (1 biphenyl-2,20-bisfenchol,
Scheme 1), which exhibits, as BINOLs, a flexible, chiral
biaryl axis with minus (M) conformation induced by the
hydrogen bonded fenchol moieties, and sterically crowded
aliphatic alcohol functions, as TADDOLs.4
2. Results and discussion
ortho-Lithiation8 of diphenylsulfone (3) with n-butyllithium
in diethylether–tetrahydrofuran (1:1) at K78 8C followed
by reaction with (K)-fenchone, hydrolytic work up and
recrystallization from ethanol/dichloromethane afforded
colorless crystals of BISFOL (2) in 20% yield. However,
the expected open bisfenchol sulfone 4 could not be
detected. Besides BISFOL, fenchol, the reduction product
of fenchone, was detected (Scheme 3).
The structure of BISFOL (2) was confirmed by single-
crystal X-ray diffraction (Fig. 1). BISFOL exhibits
intramolecular hydrogen bonds between the hydroxy groups
of the fenchyl moieties and the oxygen atoms of the sulfone
Scheme 1. BIFOL (biphenyl-2,20-bisfenchol) with minus (M)-biaryl
conformation.
˚
˚
group (O1–H1–O2: 2.17 A, O1–O2: 2.69 A, O3–H2–O4:
˚
2.24 A, O3–O4: 2.72 A, Fig. 1).
˚
Modular chiral chelating fenchols (Scheme 2), accessible
via short synthetic routes, were applied recently as catalysts
To explore this unexpected fenchone induced cyclization,
several carbonyl compounds were employed as electrophiles
besides fenchone (Table 1, Scheme 3). Treatment of
dilithiodiphenylsulfone with benzophenone or fluorenone
gave, after hydrolytic work up, exclusively the non-cyclized,
open products (Table 1). Reductions of benzophenone and
fluorenone to the corresponding alcohols were not observed,
Keywords: Lithiations; Cyclizations; Diphenylsulfone; Catalysis; Zinc-
complexes.
*
Corresponding author. Tel.: C49 221 470 5729; fax: C49 221 470 5057;
e-mail addresses: goldfuss@uni-koeln.de;
URL:http://www.uni-koeln.de/goldfuss
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.08.089

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F. Soki et al. / Tetrahedron 61 (2005) 10449–10453
Scheme 2. From fenchone, modular fenchols are efficiently accessible.
Scheme 3. Surprising formation of BISFOL (2) via attempted synthesis of
the open bisfenchol sulfone 4.
yet an other difference to the reaction with fenchone.
Camphor or benzaldehyde gave under the same reaction
conditions neither cyclic nor acyclic products, enolization
or reduction were dominating (Table 1). Hence, among the
employed carbonyl compounds, only fenchone yields the
cyclized diol 2. The isolation of endo- and exo-fenchols
as byproducts point to the formation of lithium hydride
during the reaction. This supports, as a possible mechanistic
Figure 1. X-ray crystal structure of BISFOL (2).
scenario, a cyclization through nucleophilic aromatic
substitution of the lithiated diphenylsulfone (3) via an
addition–elimination sequence (Scheme 4).
Table 1. Treatment of dilithiodiphenylsulfone with different carbonyl compounds (cf. Scheme 3) yielding open or cyclic products
Producta
Carbonyl-compound
Open (%)b
27
Cyclic (%)c
—
Byproduct (%)d
—
Educt (%)e
70
Educt (%)e
67
6
—
—
—
–
55
64
38
30
—
—
—
20
—
endo/exo fencholf
60
42
60
17
23
a ‘R’ represents the substituent of the carbonyl group.
b No cyclization.
c Cyclization.
d Reduction product of the employed carbonyl compound during the reaction.
e Recovered educt.
f
The alcohols were identified by gas-chromatography by comparing with the authentic material.

F. Soki et al. / Tetrahedron 61 (2005) 10449–10453
10451
Scheme 4. Proposed reaction mechanism via nucleophilic aromatic substitution.
According to this suggested sequence, ortho-lithiation of
diphenylsulfone (3) yields an aryllithium unit, which adds to
the second phenyl group forming a Meisenheimer inter-
mediate being stabilized by the sulfone group. The aryl unit
is rearomatized by elimination of lithium hydride, which
reduces fenchone to the endo- and exo- fenchol byproducts
(Scheme 4, Table 1). Indeed, Brinon et al. postulated a
similar elimination of lithium hydride during an analogue
cyclization of diphenylsulfone with n-buthyllithium, yield-
ing dibenzothiophene 5, while no cyclic sulfone 6 was
observed (Scheme 5).9
Reetz et al. in the reduction of fenchone with potassium
hydride.10 Hellwinkel et al. have reported unexpected
formations of heterocyclic systems from sulfonamides due
to rearrangement by the reaction with organolithium
compounds.11 Due to its rigid chiral structure, BISFOL 2
is a promising ligand for enantioselective transformations,
for example, catalyzed diorganozinc additions to alde-
hydes.12 However, only up to 19% ee were achieved with
3 mol% of 2 in diethylzinc additions to benzaldehyde to
give 1-phenylpropanol. The low enantioselectivity and
especially the low reactivity of 2 as pre-catalyst in
diethylzinc additions might arise from formation of rather
stable dimeric and hence passive catalysts.5 Indeed, reaction
of dimethylzinc with a toluene solution of 2 at 0 8C and
recrystallization from toluene yields a macrocyclic C2-
symmetrical dimer with two, rather than only one, four-
membered, dimer-building Zn2O2 rings (Scheme 6, Fig. 2).
Fenchone seems to be particularly suitable for hydride
transfer due to steric reasons, as it was demonstrated by
3. Conclusions
The surprising, fenchone induced cyclization of ortho-
lithiated bisphenylsulfone can be explained by a nucleo-
philic aromatic substitution sequence. Besides the new
chiral BISFOL fenchole is formed via lithium hydride
elimination. The unique propensity of fenchone to support
Scheme 5. Brinon’s cyclization via lithiation of 3 yielding dibenzothio-
phene 5.
Scheme 6. Homochiral methylzinc dimers based on fencholes. While reactive dimmers (7) easily dissociate into active monomeric catalysts, the macrocycle in
8 inhibits active catalyst formation.

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F. Soki et al. / Tetrahedron 61 (2005) 10449–10453
s), 1.26 (3H, s), 1.43–2.38 (6H, m), 3.05 (1H, s), 5.31 (1H,
s), 7.52 (1H, t), 7.70 (2H, d); 13C NMR (CDCl3, 75 MHz)
145.87, 137.76, 132.87, 132.38, 131.13, 119.49, 86.42,
54.86, 49.24, 48.12, 43.10, 34.01, 29.94, 24.33, 21.60,
18.01; [a]2D0 K253 (c 0.3, toluene); EI-MS: 520 (MC), 504
(MCKO), 502 (MCKH2O); IR KBr, cmK1) 3556 (OH, s),
2989–2800 (Calkyl–H, m), 1300 (C–SO2, s), 1140 (C–SO2,
s). X-ray crystal data of 2: C32H40O4S; MZ520.70; space
˚
˚
group P212121; aZ11.4739(4) A, bZ14.8690(5) A, cZ
3
˚
˚
16.2201(3) A, VZ2767.24(1) A ; ZZ4; TZ100(2) K; mZ
0.152 mmK1; reflections total: 22,011, unique: 6037,
observed: 4905 (IO2s (I)); parameters refined: 494; R1Z
0.0347, wR2Z0.0623; GOFZ1.026.
4.2. Synthesis and X-ray analysis of Me2Zn–BISFOL 8
A solution of dimethylzinc (0.5 mmol, 2 M, 0.25 ml) in
toluene was added at room temperature to a solution of
0.5 mmol (260 mg) of 2 in 1 ml of toluene. The mixture was
stirred for 30 min. After cooling the solution to K78 8C and
thawing three times, the precipitate formed was dissolved in
hot toluene. Slow cooling to room temperature yielded the
homochiral dimer as colorless crystals. X-ray crystal data of
8: C34H44O4SZn2; MZ679.49; space group I222; aZ
Figure 2. X-ray crystal structure of 8, the dimeric, macrocyclic zincmethyl
complex of BISFOL. Hydrogen atoms are omitted for clarity.
this cyclization is evident from comparisons with other
carbonyl compounds. The low reactivity and enantioselec-
tivity of BISFOL in diorganozinc additions to benzaldehyde
is explained by the high stability of the macrocyclic alkylzinc
complex. Anyhow, as rigid, chelating and C2-symmetric diol,
BISFOL has promising potentials as building block in
enantioselective reagents and catalysts.
˚
˚
˚
10.848(1) A, bZ17.585(1) A, cZ18.632(1) A, VZ
3
3554.3(4) A ; ZZ4; TZ293(2) K; mZ1.441 mmK1; reflec-
˚
tions total: 10,367, unique: 3847, observed: 2359 (IO2s
(I)); parameters refined: 189; R1Z0.0817, wR2Z0.2013;
GOFZ1.064.
4.3. Catalytic ZnEt2-additions to benzaldehyde
4. Experimental
0.12 mmol (3 mol% with respect to benzaldehyde) of 2 was
treated with 4.52 ml (4.07 mmol, 0.9 M) of diethylzinc in
hexane at 0 8C for 15 min. Benzaldehyde (0.40 ml,
3.84 mmol) was added and this mixture was kept for 24 h
at K30 8C. After quenching with water and hydrolyzing
with hydrochloric acid, the organic layer was separated,
neutralized (NaHCO3) and dried (Na2SO4). The enantio-
meric excess was analyzed by GC (Chiraldex G-TA
column).
All reactions were carried out under argon atmosphere using
Schlenk-tube techniques. Solvents were dried by standard
methods and distilled under argon prior to use.
4.1. Synthesis of biphenyl-2,20-sulfone-3,30-bisfenchol
(BISFOL 2)
To a stirred solution of 6.55 g diphenylsulfone (30 mmol) in
45 ml THF and 45 ml Et2O, which was cooled on a dry ice/
alcohol bath (K78 8C), was added 39 ml (1.6 M, 60 mmol)
of a solution of n-butyllithium in hexane. After the addition
was complete, the solution was stirred 10 h by K78 8C.
After stirring the solution at room temperature, 9.72 ml
(60 mmol) (K)-fenchone were added to the mixture at
K78 8C. Hydrolysis was performed with 200 ml H2O. After
separation of the ether layer, the water layer was extracted
with 100 ml Et2O. The combined organic layers were dried
over anhydrous Na2SO4. Filtration and distillation of the
solvents left a yellow oil, to which 100 ml pentane was
added. Cooling at K78 8C during 2 h in a dry ice/alcohol
bath resulted in the precipitation of a solid, which was isolated
by filtration of the mixture. This procedure was repeated,
giving a total yield of compound 2 of 1.31 g (20%). After
recrystallization from dichloromethane/ethanol the
decomposition point was 283 8C.
Acknowledgements
We are grateful to the Fonds der Chemischen Industrie for
financial support as well as for a Dozenten-Stipendium to
B.G. We also thank the Deutsche Forschungsgemeinschaft
(DFG) for support (GO-930/9, GO-930/7 and GO-930/3).
We are grateful to the Bayer AG, the BASF AG, the Wacker
AG, the Degussa AG, the Raschig GmbH, the Solvay GmbH
and the OMG AG for generous gifts of laboratory
equipments and chemicals.
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