Synthesis, enantiomeric conformations, and stereodynamics of aromatic orffto-substituted disulfones

Article abstract of DOI:10.1021/ol015804d

(equation presented) Aromatic ortho-disulfone derivatives are readily accessible from diiodide precursors by Cu(l)-mediated reactions with sodium sulfinate salts. The sulfone substituents adopt C₂-symmetric enantiomeric conformations (λ and δ)

Full text of DOI:10.1021/ol015804d

ORGANIC
LETTERS
2001
Vol. 3, No. 9
1407-1410
Synthesis, Enantiomeric Conformations,
and Stereodynamics of Aromatic
ortho-Substituted Disulfones
,†
Je´roˆme Lacour,* David Monchaud,† Ge´rald Bernardinelli,‡ and France Favarger†
De´partement de Chimie Organique, UniVersite´ de Gene`Ve, quai Ernest-Ansermet 30,
CH-1211 Gene`Ve 4, Switzerland, and Laboratoire de Cristallographie, UniVersite´ de
Gene`Ve, quai Ernest-Ansermet 24, CH-1211 Gene`Ve 4, Switzerland
jerome.lacour@chiorg.unige.ch
Received March 7, 2001
ABSTRACT
Aromatic ortho-disulfone derivatives are readily accessible from diiodide precursors by Cu(I)-mediated reactions with sodium sulfinate salts.
The sulfone substituents adopt C -symmetric enantiomeric conformations (λ and δ) as evidenced by X-ray structural analysis and 1H and 31
P
2
NMR on chiral bis(sulfonyl)veratrol derivatives and hexacoordinated tris(benzenediolato)phosphate anions. Slow dynamic conformational
‡
isomerism (∆G g 19.8 kcal mol-1) was detected in solution.
The octahedral geometry of pentavalent hexacoordinated
phosphorus allows the formation of chiral anionss∆ and Λ
enantiomerssby complexing the phosphorus with three
identical catecholate ligands.1 Recently, we reported that the
introduction of electron-withdrawing groups (chlorine atoms)
on the aromatic nuclei increases the configurational stability
of the resulting tris(tetrachlorobenzenediolato)phosphate(v)
(or TRISPHAT 1) derivative (Figure 1).
This anion, resolved by association with an enantiopure
ammonium cation, is an efficient NMR chiral shift reagent
for cationic and neutral molecules, a powerful resolving agent
for ruthenium(II) complexes, and chiral inducer onto iron(II)
tris(diimine) compounds.2 To extend the pool of chiral anions
for possible asymmetric applications, we decided to prepare
a hexacoordinated phosphate anion (2) derived from a new
catechol ligand substituted with stronger electron-withdraw-
ing p-toluenesulfonyl residues (SO2-pTol). In this letter, we
report that the introduction of ortho p-toluenesulfonyl groups
on the catechol rings of chiral phosphate anion 2 is not
asymmetrically innocent. The ortho sulfones adopt C2-
symmetric enantiomeric conformations (δ and λ) that inter-
convert slowly on the NMR time scale. This leads to mixtures
of diastereomeric hexacoordinated phosphate anions that can
be observed in 31P NMR. This unusual stereodynamic
† De´partement de Chimie Organique.
‡ Laboratoire de Cristallographie.
(1) Hellwinkel, D.; Wilfinger, H. J. Chem. Ber. 1970, 103, 1056-1064.
Allcock, H. R.; Bissell, E. C. J. Am. Chem. Soc. 1973, 95, 3154-3157.
Hellwinkel, D.; Krapp, W. Phosphorus 1976, 6, 91-93. Koenig, M.; Klaebe,
A.; Munoz, A.; Wolf, R. J. Chem. Soc., Perkin Trans. 2 1976, 955-958.
Koenig, M.; Klaebe, A.; Munoz, A.; Wolf, R. J. Chem. Soc., Perkin Trans.
2 1979, 40-44. Cavezzan, J.; Etemad-Moghadam, G.; Koenig, M.; Klaebe,
A. Tetrahedron Lett. 1979, 795-798. Lacour, J.; Ginglinger, C.; Grivet,
C.; Bernardinelli, G. Angew. Chem., Int. Ed. Engl. 1997, 36, 608-609.
Figure 1. Chiral hexacoordinated phosphate anions.
10.1021/ol015804d CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/06/2001

Scheme 1. Synthesis and Isolation of Phosphate Anion 2a
a (a) I2, H5IO6, MeOH, 70 °C, 4 (83%); (b) CuI, RSO2Na, DMF, 110 °C, 5a (R ) p-Tol, 88%), 5b (R ) (+)-camphor-10-, 85%); (c)
5a, BBr3 (5.0 equiv), CH2Cl2, 3 (R ) p-Tol, 93%); (d) PCl5 (0.33 equiv), CH2Cl2, then DMF, 25 °C; Bu3N, 25 °C, [Bu3NH][2]; (e)
malachite green chromatography (SiO2, CH2Cl2), [6][2] (two steps, 63%).
behavior was further proved by the synthesis of 4,5-bis((+)-
anions, while only one was expected. This result was
furthermore surprising as only one set of signals correspond-
ing to anion 2 could be observed in H NMR. Further
camphor-10-sulfonyl)veratrol, whereas the atropisomers can
1
1
be simply monitored by H NMR.3
4,5-Bis(p-toluenesulfonyl)catechol 3, necessary for the
making of anion 2, was prepared in three steps and good
overall yield (Scheme 1). From veratrol, diiodination with
I2/H5IO6 proceeded smoothly to give 4 (83%).4 Bis-sulfo-
nylation of 4 by a Cu(I)-mediated reaction with sodium
p-toluenesulfinate resulted,5 after optimization, in the syn-
characterization of salt [6][2] by mass spectrometry (ES-
MS) confirmed its structural integrity. The four signals in
31P NMR could not be explained by the presence of four
different chemical compounds and had to be solely attributed
to compound 2. It appeared to us that this situation for 2
was somewhat reminiscent of what is usually noticed for
tris(bidentate) octahedral complexes made of nonplanar
chelate rings, such as [Co(en)3]3+. As first noted by Corey
and Bailar,7 when chelate rings adopt chiral conformations
(δ and λ), four diastereomers, always appearing in enantio-
meric pairs, are generated as a result of the inherent chirality
of the octahedral complexes (∆ and Λ): ∆(δδδ)/Λ(λλλ),
∆(δδλ)/Λ(λλδ), ∆(δλλ)/Λ(λδδ), ∆(λλλ)/Λ(δδδ).8 However,
for 2, the planarity of the chelating catechol rings was not
compatible with such an explanation. If chiral conformations
were to be the source of the four signals observed in 31P
NMR, they would have to result from the spatial arrangement
of the sulfonyl substituents.
1
thesis of 5a (88%). H NMR analyses of 5a did not reveal
any particularity except a signal broadening, which could
only be understood in the course of this study. Deprotection
of 5a using classical conditions (BBr3, CH2Cl2) led to the
4,5-bis(p-toluenesulfonyl)catechol 3 in 93% yield.
Anion 2 was prepared by addition of 3 to PCl5 in CH2Cl2.
Concentration in vacuo and addition of DMF and then nBu3N
afforded the [nBu3NH][2] salt along with minor amounts of
degradation products (Scheme 1). Purification of the crude
reaction mixture was effected by the addition of malachite
green and subsequent chromatography (SiO2, CH2Cl2) to give
the bis(dimethylaminophenyl)phenylmethinium (6) salt, [6]-
[2], in 63% yield (two steps).6
It was indeed highly probable that, to minimize strong
dipolar interactions, the ortho sulfonyl groups would adopt
an “up-and-down” arrangement with regard to the aromatic
plane (Figure 3). This disposition of the sulfonyl groups
imparts a C2-symmetry and thus the adoption by the ortho
substituents of two enantiomeric helical conformations (δ
Characterization of salt [6][2] by 31P NMR was, at first
glance, puzzling. Four signals (DMSO-d6, δ -76.7, -77.3,
-77.5, and -78.2, Figure 2) were observed in the -80 ppm
region characteristic of the tris(benzenediolato)phosphate
(2) See Lacour et al. (last reference of footnote 1) and the following:
Lacour, J.; Jodry, J. J.; Ginglinger, C.; Torche-Haldimann, S. Angew. Chem.,
Int. Ed. Engl. 1998, 37, 2379-2380. Lacour, J.; Goujon-Ginglinger, C.;
Torche-Haldimann, S.; Jodry, J. J. Angew. Chem., Int. Ed. 2000, 39, 3695-
3697. Ratni, H.; Jodry, J. J.; Lacour, J.; Ku¨ndig, E. P. Organometallics
2000, 19, 3997-3999.
(3) For a general overview of atropisomerism, see: Eliel, E. L.; Wilen,
S. H. Stereochemistry of Organic Compounds; John Wiley & Sons: New
York, 1994; pp 1142-1155.
(4) Suzuki, H.; Nakamura, K.; Goto, R. Bull. Chem. Soc. Jpn. 1966, 39,
128-131.
(5) Suzuki, H.; Abe, H. Tetrahedron Lett. 1995, 36, 6239-6242.
(6) Lacour, J.; Barche´chath, S.; Jodry, J. J.; Ginglinger, C. Tetrahedron
Lett. 1998, 39, 567-570.
(7) Corey, E. J.; Bailar, J. C., Jr. J. Am. Chem. Soc. 1959, 81, 2620-
2629.
(8) Von Zelewsky, A. Stereochemistry of Coordination Compounds; John
Wiley & Sons: Chichester, U.K., 1996.
Figure 2. 31P NMR (DMSO-d6, 162 MHz, parts) of [6][2].
1408
Org. Lett., Vol. 3, No. 9, 2001

5a (Scheme 1). Sodium (+)-camphor-10-sulfinate salt 7 was
unstable and decomposed slowly at room temperature
(monitoring by IR) even under inert conditions (N2).11 A large
excess of 7 (25 equiv) was required for the Cu(I)-mediated
bis(sulfonylation) reaction to proceed with good yield (5b,
85%).
1H NMR analysis at room temperature of 5b revealed two
sets of signals, as could be expected from the introduction
of new stereogenic centers, corresponding to the diastereo-
meric δ and λ conformations. Diastereotopic protons H(10)
and the geminal methyl groups of the camphorsulfonyl units
were split, as well as the aromatic protons H(3′) (Figure 5)
Figure 3. Views of the conformations adopted by ortho sulfonyl
groups and configurational assignment (δ and λ); a‚‚‚‚‚a constitutes
the plane of the phenyl ring; b‚‚‚‚‚b is a line passing through the R
substituents.
and λ) depending on their left- or right-handed orientation,
respectively.9
The existence of these chiral conformations was first
confirmed by the X-ray structural analysis of 5a‚C6H12. The
molecular conformation observed in the solid state shows a
C2 axis passing through bonds C(1)-C(2) and C(4)-C(5)
of 5a (Figure 4). Both δ and λ configurations of 5a are
1
Figure 5. Variable temperature H NMR (400 MHz, DMSO-d6)
of 5b. Proton H(3′) of the major (M) and minor (m) diastereomeric
conformations. Coalescence temperature, 117 °C.
and the methoxy groups of the veratrol ring (Table 1). The
two diastereomeric δ and λ conformations in 5b are not
evenly populated as the integration of the respective signals
reveals a 2.25:1 diastereomeric ratio. The chiral (+)-
camphor-10-sulfonyl units lead not only to the magnetic
nonequivalency of the conformations but also to an asym-
metric induction in favor of one of the λ or δ configurations.12
Dynamic conformational isomerism was detected for 5b
1
in H NMR with a coalescence temperature of 117 °C for
the signals (400 MHz, Figure 5), demonstrating without
ambiguity the slow interconversion at room temperature
between diastereomeric δ and λ conformations of the ortho
Figure 4. Ortep view (ellipsoids at the 50% probability level) of
the crystal structure of 5a (δ configuration) showing the “up-and-
down” orientation of the p-tolyl substituents.
1
observed since the compound crystallizes in the centrosym-
metric space group P1h.10
Table 1. Chemical Shifts in H NMR (400 MHz, CDCl3) for
Selected Protons of the Major (M) and Minor (m)
The presence of these enantiomeric δ and λ conformations
was then confirmed in solution by preparing the 4,5-bis((+)-
camphor-10-sulfonyl)veratrol 5b, whose conformational
Diastereomeric Conformations of 5b
1
isomerism could be easily monitored by H NMR. The
synthesis of 5b turned out to be more challenging than of
(9) For an example of such chiral conformation in a highly twisted
hexasubstituted arene, see: Collard, D. M.; Sadri, M. J.; VanDerveer, D.;
Hagen, K. S. J. Chem. Soc., Chem. Commun. 1995, 1357-8.
(10) See the CIF file in the Supporting Information.
Org. Lett., Vol. 3, No. 9, 2001
1409

disulfones. The corresponding free energy of interconversion
is 19.8 kcal mol-1.13
In conclusion, aromatic ortho disulfone derivatives adopt
two precise C2-symmetric enantiomeric conformations, which
can be detected by the formation of chiral hexacoordinated
tris(benzenediolato) phosphate anions or by the synthesis of
enantiopure camphor-10-sulfonyl derivatives. The rate of
interconversion is slow on the NMR time scale and depends
on the nature of the sulfonyl side chains (∆G‡ g 19.8 kcal
mol-1).
Taking thus into account the existence, in the solid state
and in solution, of enantiomeric δ and λ conformations for
the ortho disulfones of each of the three chelating catechols,
four diastereomers, always appearing in enantiomeric pairs,
can be considered for anion 2: ∆(δδδ)/Λ(λλλ), ∆(δδλ)/
Λ(λλδ), ∆(δλλ)/Λ(λδδ), ∆(λλλ)/Λ(δδδ). Each of the signals
observed in the 31P NMR spectra can thus be assigned to
one of the diastereomers, considering that the rate of
interconversion of the p-toluenesulfonyl groups is slow
compared to the NMR time scale. A stereodynamic study
was attempted by variable temperature in 31P NMR. Within
the range of temperature studied (DMSO-d6, 25-147 °C,
162 MHz), no variation in the shape of the four signals was
observed, showing a very slow equilibration of the δ and λ
conformations of the ortho-p-toluenesulfonyl substituents.14
Acknowledgment. We are grateful for financial support
of this work by the Swiss National Science Foundation and
Federal Office for Education and Science (J.L., COST D11).
We thank Mr. A. Pinto, Mr. J.-P. Saulnier, Mr. W. Kloeti,
and Mrs. E. Sandmeyer for NMR and MS measurements.
1
Supporting Information Available: H, 13C, and/or 31
P
NMR spectra for compounds [6][2], 3 and 5a-5b and X-ray
crystallographic CIF file for 5a‚C6H12. This material is
available free of charge via the Internet at http://pubs.acs.org.
(11) Salt 7 was prepared following the directions found in Krauthausen,
E. In Organosulfur Compounds; fourth ed.; Klamann, D., Ed.; Georg Thieme
Verlag: Stuttgart, 1985; Vol. E11, p 619.
OL015804D
(12) No attempts have been made to determine which of the two
diastereomeric conformations is preferred.
(13) The relationship ∆G‡ ) RTc(22.96 + ln(Tc/∆ν)) was used to
determine the activation energy, ∆G‡, from the coalescence temperature,
Tc (K), and the frequency separation of the peaks, ∆ν (Hz).
(14) The activation energy ∆G‡ is higher than 21.4 kcal mol-1
,
considering a Tc g 147 °C and a minimum ∆ν value of 29 Hz (∆δ -77.35
to -77.53).
1410
Org. Lett., Vol. 3, No. 9, 2001