Atropisomerism at C - S bonds: Asymmetric synthesis of diaryl sulfones by dynamic resolution under thermodynamic control

Full text of DOI:10.1002/anie.200901718

Communications
DOI: 10.1002/anie.200901718
Atropisomeric Sulfur Compounds
À
Atropisomerism at C S Bonds: Asymmetric Synthesis of Diaryl
Sulfones by Dynamic Resolution Under Thermodynamic Control**
Jonathan Clayden,* James Senior, and Madeleine Helliwell
Dedicated to Professor Marc Julia on the occasion of his 87th birthday
The family of atropisomeric compounds—those containing a
bond about which the rotation is sufficiently slow that
conformers are separable—includes numerous natural prod-
ucts[1] and valuable ligands.[2] Atropisomerism is associated
principally with single bonds joining two planar substituents.[3]
The most common of these are the biaryls,[4] but the last
15 years have seen non-biaryl atropisomers[5] based on the C
À
[5b]
CO bond of amides,[5a] the C N bond of anilides or urea
À
Scheme 1. Diaryl sulfides, sulfones, and sulfoxides by copper-catalyzed
derivatives,[5c] and the C O bond of ethers[6] come forward as
À
coupling. a) Br2, Fe, CHCl3, 08C, 4 h (55%); b) 1. tBuLi, THF, À788C,
5 min.; 2. I2, À788C, 2 h (87%); c) 1. tBuLi, THF, À788C, 5 min;
2. Me2S2, À788C, 2 h (93%); d) tBuSNa (5 equiv), DMF, reflux, 16 h
(93%); e) CuI (1 equiv); K2CO3 (2 equiv); ethylene glycol (2 equiv),
tert-amyl alcohol, 1208C, 16 h (79%); f) mCPBA (1 equiv), CH2Cl2, RT,
1.5 h (80%); g) mCPBA (4 equiv), CH2Cl2, RT, 16 h (quant.).
compounds with interesting and valuable structural,[5d]
dynamic,[5e] mechanistic,[5f] catalytic/synthetic,[5g] and biolog-
ical[5h] properties. The separation of atropisomers due to slow
À
rotation about C S bonds has however never been reported,
and in this Communication we show for the first time that
À
compounds made chiral by virtue of an atropisomeric C S
bond—in particular diaryl sulfides and sulfones—may be
a) resolved and b) made in an enantioselective manner.
Heavily substituted diaryl ethers are known to be atropi-
someric.[6] NMR data suggest that bond rotations in diaryl
sulfides 1 are slightly faster than in related diaryl ethers,[7] but
with four ortho substituents diaryl sulfides 1 and sulfones 3 are
potentially atropisomeric at 258C.[8] In 2002, Buchwald and
Kwong reported the synthesis of diaryl sulfides 1 by copper-
catalyzed arylation of thiophenols.[9] By adapting their con-
ditions, we found that even the heavily encumbered aryl iodide
6 and thiophenol 7 (both obtained from arene 4 via bromide 5)
gave sulfide 1a in good yield provided a stoichiometric amount
of CuI was employed (Scheme 1). Sulfide 1a was oxidized to
sulfoxide 2a or sulfone 3a with mCPBA.
The stereochemical properties of sulfoxide 2a were
immediately evident from its 1H NMR spectrum. Slow
À
rotation about the two Ar S bonds, combined with the
resulting pseudoasymmetric center at sulfur, causes the two
rings to occupy diastereomeric environments. A separate set
of peaks is accordingly observed for each of the two aromatic
rings and their substituents. Compounds 1a, 2a, and 3a
(Figure 1a) were furthermore separable into enantiomers by
HPLC on a chiral stationary phase, though close to ambient
[*] Prof. J. Clayden, J. Senior, Dr. M. Helliwell
School of Chemistry, University of Manchester
Oxford Rd., Manchester M139PL (UK)
Fax: (+44)161-275-4939
http://clor2.ch.man.ac.uk/home.htm
E-mail: clayden@man.ac.uk
Figure 1. Structure and configuration of sulfide 1a, sulfoxide 2a, and
sulfone 3a. a) Structural formulae; b) X-ray crystal structures; c) HPLC
traces on a chiral stationary phase (Chiralpak AD-H; 1a and 3a: 258C;
2a: 178C).
[**] We are grateful to the EPSRC for support of this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200901718.
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temperature sulfoxide 2a showed the broadened peak shape
characteristic of a compound racemizing on the timescale of
the HPLC elution (Figure 1c).[10]
in its 1H NMR spectrum at 258C in CDCl3, indicating that the
À
sulfinyl substituent exerts only weak control over the C S
axis.[17] In sulfinyl sulfones 13 and 14 only a single conformer is
Barriers to racemization of all three compounds were
determined,[11] and are shown in Table 1. Sulfone 3a race-
mizes some ten times slower than its sulfide analogue 1a,
evident, indicating that the interaction between the sulfinyl
À
substituent and the C SO2 bond leads to population of one of
the diastereomeric conformers with > 20:1 selectivity.
The X-ray crystal structure analysis of 13 and 14
(Figure 2a, b) indicates that the molecules adopt (R,M)
conformations in the solid state,[12] which we assume is also
the favored conformation in solution. This conformation may
result from an electrostatic interaction between the sulfoxide
S atom and the pro-S sulfone O atom (leading to a near-linear
Table 1: Structural parameters for 1a, 2a and 3a.
Sulfide 1a
Sulfoxide 2a Sulfone 3a
DG° [kJmolÀ1 [a]
t1/2
]
100.8 (408C) 86.3 (178C)
106.5 (508C)
6 days
180.8
rac [b]
14 h
70 s
[c]
À
C S bond length [pm]
179.4
182.0
Osulfone–Ssulfoxide–Osulfoxide arrangement and close Osulfone–Ssulfoxide
À
approach, as shown in Figure 2c). Since a similar attraction to
the pro-R oxygen atom would incur encumbrance between
the two rings (Figure 2c), a conformational preference is
[a] Barrier to C S bond rotation. [b] Estimated half life for racemization
(258C), assuming DS° =0. [c] Determined from crystallographic data.
À
imposed upon the C S bonds of both the sulfone and the
though sulfoxide 2a racemizes at least three orders of
magnitude faster than either 1a or 3a. Crystal structures of
the three compounds were obtained (Figure 1b):[12] the
enantiomeric instability of 2a may be related to its longer
sulfoxide. Consistent with this dipole-driven rationalization of
the conformational preference are the lower selectivity with
sulfide 12 and the fact that 14 showed lower levels of
conformational selectivity in the more polar solvents DMSO
or MeOH.[18]
À
C S bond, with steric hindrance contributing to the enantio-
À À
meric stability of 3a.
We expected that a fourth substituent ortho to the C S C
axis would give rise to atropisomeric structures. Bromide 15
Having demonstrated for the first time atropisomerism in
diaryl sulfides and sulfones, we set out to synthesize them in
enantiomerically enriched form. Dynamic resolution under
thermodynamic control (dynamic thermodynamic resolu-
tion)[13] is particularly well suited to the asymmetric synthesis
of atropisomers[14] because an enantiomerically pure auxiliary
substituent placed adjacent to the potentially atropisomeric
axis can lead to a conformational bias in favor of one of the
two diastereomeric axial conformers. The most effective
controlling auxiliaries employed for this strategy have been
sulfoxides.[5b,6b,14a] In order to evaluate the effectiveness of an
À
adjacent sulfinyl substituent in the control of a C S axis, we
made the sulfoxides 12–14 by lithiating[15] 8–10 and quenching
with (1S,2R,5S)-(+)-menthyl-(RS)-p-toluenesulfinate (+)-11
(Scheme 2).[16]
Derivatives 12–14 are only tri-orthosubstituted about the
C S C axis, and so presumably[6,7] cannot exist as atropisom-
À À
ers. Sulfinyl sulfide 12 showed two conformers in a ratio of 3:1
Figure 2. X-ray crystal structures of a) 13 and b) 14, both showing the
favored (R,M) conformation. c) Presumed governing SO2–SO dipole/
Ar–Ar steric interaction, with values of d (distance between sulfone
pro-S O atom and sulfoxide S atom) and q (angle formed by sulfone
pro-S O, sulfoxide S, and sulfoxide O atoms) for 13, 14, 21, and 22.
X-ray crystal structures of d) 21 and e) 22,[12] both showing the favored
(S,P) conformation.
Scheme 2. Synthesis and conformational preference of sulfinyl sulfides
and sulfinyl sulfones. a) nBuLi, THF, À788C, 1 min, then (+)-11;
b) sBuLi, THF, À788C, 30 min, then (+)-11.
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gave the diastereomeric sulfinyl sulfides 16 (Scheme 3), and
two conformers were evident by 1H NMR spectroscopy
(258C, CDCl3) in a 1:1 mixture. Chromatographic separation
of the atropisomeric diastereomers was possible, but equili-
bration in solution was complete within 16 h at ambient
temperature, and two-dimensional thin-layer chromatogra-
phy demonstrated interconversion within minutes. The bar-
À
rier to C S bond rotation for both diastereomers of 16 was
thus estimated to be less than 95 kJmolÀ1.
More-hindered tetra-orthosubstituted sulfinyl sulfones 21
and 22 were made by sequential double ortholithiation[15] of
bis(2-isopropylphenyl)sulfone (17). A sulfinyl substituent was
introduced by two alternative strategies: addition to (À)-11[16]
gave (S)-21 in 75% yield, while addition to dimethyldisulfide
and asymmetric oxidation of the resulting sulfide 19 with
oxaziridine 20[19] gave S-22 with an e.r. greater than 94:6.
The equilibrated (unchanged on heating for 48 h at 508C
in CDCl3) conformational ratio of toluenesulfinyl sulfone 21
was 6:1. The methylsulfinyl sulfone 22 was however essen-
tially conformationally pure (NMR: > 20:1 conformational
selectivity in CDCl3). X-ray crystal structure analysis of 21
and (Æ )-22[12] (Figure 2d, e) suggested that a dipole inter-
action (Figure 2c) similar to that in 13 and 14 was at the origin
of the conformational preference. The greater selectivity with
the methylsulfinyl group may be due to stronger dipole
attraction (Figure 2c) in a less hindered system.
Scheme 3. Conformational preference in a pair of atropisomeric sulfi-
nyl sulfides.
The stereogenic centers of the two sulfinyl
sulfones 21 and 22 were removed by the oxidation
to bissulfones (P)-23 and (P)-24[20], respectively, in
CHCl3 to maximize the conformational ratio, and
at 08C to minimize racemization of the products.
Bissulfones 23 and 24 were obtained with enan-
tiomeric ratios which reflected the product of
conformational and enantiomeric ratios of the
starting sulfinyl sulfones (Scheme 4). Half-lives
À
for racemization and barriers to C S bond rota-
tion are given in Scheme 4.[11]
In conclusion, we have demonstrated that
hindered diaryl sulfides and diaryl sulfones may
exist as resolvable atropisomeric compounds. A
dipole interaction between the sulfone and an
adjacent sulfinyl group may be exploited to
À
impose a preferred conformation on a C SO2
bond. Conversion of the sulfinyl group by oxida-
tion to a second sulfone substituent constitutes the
first asymmetric synthesis of an atropisomeric
compound whose axial chirality derives from a
À
rotationally restricted C S bond. We are currently
seeking to extend this methodology to compounds
with higher barriers to provide a new class of
ligands suitable for use in asymmetric catalysis.
Received: March 30, 2009
Revised: June 9, 2009
Published online: July 16, 2009
Keywords: atropisomerism · dynamic resolution ·
.
Angew. Chem. Int. Ed. 2009, 48, 6270 –6273
Scheme 4. Asymmetric synthesis of diaryl sulfones; e.r.=enantiomeric ratio.
rotational barriers · sulfones · sulfoxides
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[17] The configuration of the major conformer of 12 is unknown and
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[18] In DMSO, coalescences at ca. 608C confirmed that the
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