Vinyl sulfones

Article abstract of DOI:10.1107/S0108270108002692

Four neutral vinyl sulfones, two of which are paired with phosphonate groups, are described. The compounds are diisopropyl (2-phenyl-ethenylsulfonyl- meth-yl)phosphonate, C15H23O5PS, (I), diisopropyl {[2-(7-meth-oxy-1,3-benzodi- oxol-5-yl)ethenylsulfon-yl

Full text of DOI:10.1107/S0108270108002692

organic compounds
Acta Crystallographica Section C
Crystal Structure
Communications
of antivirals, with the possibility for covalent attachment
(Meadows & Gervay-Hague, 2006b; Meadows et al., 2007). As
part of these ongoing inhibition studies, we previously
reported the structures of the saturated phosphonate mono-
sulfone diisopropyl (diisopropoxyphosphorylmethylsulfonyl-
methyl)phosphonate (Wong, Olmstead & Gervay-Hague,
2007) and the disulfone diisopropyl (diisopropoxyphosphor-
ylmethylsulfonylmethylsulfonylmethyl)phosphonate (Wong,
Olmstead, Fettinger & Gervay-Hague, 2007) reagents, which
are the starting materials for the title compounds.
ISSN 0108-2701
Vinyl sulfones
Jessica H. Wong, Marilyn M. Olmstead,* James C.
Fettinger and Jacquelyn Gervay-Hague
Department of Chemistry, University of California, One Shields Avenue, Davis,
CA 95616, USA
Correspondence e-mail: olmstead@chem.ucdavis.edu
Received 23 January 2008
Accepted 24 January 2008
Online 9 February 2008
Four neutral vinyl sulfones, two of which are paired with
phosphonate groups, are described. The compounds are
diisopropyl (2-phenylethenylsulfonylmethyl)phosphonate,
C15H23O5PS, (I), diisopropyl {[2-(7-methoxy-1,3-benzodi
oxol-5-yl)ethenylsulfonyl]methylsulfonylmethyl}phosphonate,
C18H27O10PS2, (II), bis(trans-2-phenylethenyl) sulfone,
C16H14O2S, (III), and bis(trans-2-phenylethenylsulfonyl)
methane, C17H16O4S2, (IV). Their structures can be consid-
ered as highly functionalized mimics of mono-, di- and
triphosphates. These phosphate isosteres are currently of
interest as agents for enzyme inhibition in both cancer and
HIV therapy. All except one of the compounds has Z0 > 1. The
lone exception is (IV), a disulfone with twofold crystal-
lographic symmetry. Geometrically, the sulfone functionality
is found to be a good mimic for phosphate. The principal
effect of the vinyl group is to shorten the S—C(vinyl) distance
Selected bond lengths for (I)–(IV) are given in Tables 1–4,
and a summary of selected bond distances and angles in (I)–
(IV) is presented in Table 5. The bonds between the S and the
˚
vinyl C atoms are systematically shorter [average 1.741 (4) A]
than those between the S atom and a methylene bridging C
˚
relative to the S—CH2 distance by ca 0.05 A. The S—C—S
and S—C—P backbones resemble the P—O—P backbone but
are not identical because the S—C and P—C distances are
longer than the P—O distance and the S—C—S and S—C—P
angles are more acute than the P—O—P angle. No prior
crystal structures of comparable compounds have been
published.
Comment
Recent investigations have focused on the replacement of
phosphate backbones with phosphate mimics that possess
several desirable characteristics. For example, when the brid-
ging O atom of the phosphate is replaced with a methylene
unit, greater stability towards hydrolysis is achieved.
Replacement of the P atom with sulfur and oxidation to the
sulfone maintains metallophilicity, which is of potential
importance in inhibition that involves metalloenzymes. The
noncharged nature of the sulfone improves cellular penetra-
tion over ionizable mimics such as l-chicoric acid (Hadd et al.,
2001; Meadows et al., 2005; Meadows & Gervay-Hague,
2006a). The vinyl sulfone groups in the compounds reported in
this study, (I)–(IV), have been shown to be an important class
Figure 1
A view of (I), with displacement ellipsoids drawn at the 50% probability
level. H atoms have been drawn at an arbitrary size. The two molecules
are shown in projection down the vinyl group.
o132 # 2008 International Union of Crystallography
doi:10.1107/S0108270108002692
Acta Cryst. (2008). C64, o132–o136

organic compounds
˚
atom [average 1.780 (7) A]. Compound (I) has two molecules
2007). We selected 21 acyclic structures with R < 0.075. The
˚
average P—O distance is 1.603 (18) A, the P—O—P angle is
in the asymmetric unit, shown in Fig. 1 perpendicular to the
vinyl group plane in order to demonstrate the flexibility in the
backbone of the molecule. The S1ꢀ ꢀ ꢀP1 and S21ꢀ ꢀ ꢀP21
ꢁ
˚
133 (2) , the Pꢀ ꢀ ꢀP distance is 2.94 (3) A and the Oꢀ ꢀ ꢀO
˚
distance is 2.48 (4) A. As would be expected, the P—C and
˚
distances are 3.0262 (10) and 3.0065 (10) A, respectively.
S—C distances are longer than the P—O distance, and the S—
C—S and S—C—P angles are more acute than the P—O—P
angle. Additionally, although the tetrahedral geometry at S
and P is similar, the fact that S—C bonds are longer than P—O
bonds means that the repeat distance between bridging C
atoms is greater than the Cꢀ ꢀ ꢀO and Oꢀ ꢀ ꢀO distances. Thus, we
found that the vinyl sulfone or vinyl sulfone/phosphonate
backbone is lengthened relative to the polyphosphate back-
Compound (II) (Fig. 2) also has Z0 = 2. The intermolecular
˚
Sꢀ ꢀ ꢀP distances are 3.0274 (5) and 3.0304 (5) A; the Sꢀ ꢀ ꢀS
˚
distances are slightly longer at 3.0472 (5) and 3.0470 (5) A.
Compound (III) has Z0 = 3 (Fig. 3). One of the molecules is
disordered in the orientation of the set of atoms C49–C56.
Fig. 3 shows the three molecules in their relative orientations
in the structure. Again, there are obvious conformational
differences among the three molecules. In Table 5 the metric
data for the disordered molecule of (III) has been omitted.
Compound (IV) (Fig. 4) has a crystallographic twofold axis
passing through atom C9. The S1ꢀ ꢀ ꢀS1i separation is
˚
bone by ca 0.40 A per repeat. None of the structures (I)–(IV)
contains solvent molecules or possesses any strong inter-
molecular interactions. Since all of the crystals were obtained
from non-aqueous solvents, the corresponding structures in
hydrophillic environments may significantly differ. However,
it is clear that the backbones of these vinyl sulfones and mixed
sulfone/phosphonate compounds resemble those of polypho-
sphates, and replacement of the bridging O atom by a CH2
˚
3.0549 (6) A.
In order to compare (I)–(IV) with polyphosphates, average
values for P—O(bridging) distances, P—O—P angles and
Pꢀ ꢀ ꢀP distances can be compared with the P—C, S—C, S—
C—S and S—C—P distances and angles, as well as the Sꢀ ꢀ ꢀP
and Sꢀ ꢀ ꢀS distances in di- and triphosphates in the CSD
(Allen, 2002; ConQuest; Cambridge Structural Database,
Figure 3
A view of the three molecules of (III), showing displacement ellipsoids at
the 50% probability level. The disorder in one of the molecules has been
omitted for clarity. H atoms have been drawn at an arbitrary size. The
three molecules are shown in the relationship in which they exist in the
asymmetric unit.
Figure 2
A view of the two molecules of (II) in the asymmetric unit, showing
displacement ellipsoids at the 50% probability level. H atoms have been
drawn at an arbitrary size. The projection of the two molecules is
arbitrarily chosen to show the relationship between the two molecules
Figure 4
A view of (IV), showing displacement ellipsoids at the 50% probability
level. H atoms have been drawn at an arbitrary size. [Symmetry code: (A)
1
ꢃx + 1, y, ꢃz + .]
2
ꢂ
Acta Cryst. (2008). C64, o132–o136
Wong et al.
C15H23O5PS, C18H27O10PS2, C16H14O2S and C17H16O4S2 o133

organic compounds
Table 1
Selected bond lengths (A) for (I).
group preserves the rotational flexibility of the polyphosphate
structure.
˚
P1—O3
P1—O5
P1—O4
P1—C9
S1—O2
S1—O1
S1—C8
S1—C9
1.4794 (19)
1.5614 (19)
1.5901 (19)
1.805 (3)
1.4324 (18)
1.4480 (19)
1.741 (3)
P21—O23
P21—O25
P21—O24
P21—C29
S21—O22
S21—O21
S21—C28
S21—C29
1.442 (2)
1.5673 (19)
1.5792 (19)
1.813 (3)
1.4368 (19)
1.4539 (19)
1.750 (3)
Experimental
For the preparation of compound (I), the monosulfone reagent di-
isopropyl (diisopropoxyphosphorylmethylsulfonylmethyl)phosphon-
ate (Wong, Olmstead & Gervay-Hague, 2007) (600 mg, 1.42 mmol)
was dissolved in dry tetrahydrofuran (THF; 1.8 ml) at room
temperature under argon in a flame-dried flask. LiBr (180 mg,
2.13 mmol) was added with stirring until dissolved. At this point,
sodium hydride (51 mg, 2.13 mmol) was added until all bubbles
disappeared, and then benzaldehyde (75 mg, 0.71 mmol) was added.
The reaction mixture was stirred at room temperature for 3 h and
then quenched with a 1:1 solution of acetic acid and water (2 ml). The
solution was partitioned between ethyl acetate and water, and
extracted three times with ethyl acetate. The organic phase was
collected and dried over sodium sulfate. The solvent was evaporated
to yield a crude oil that was subjected to column chromatography
(80% hexane:20% ethyl acetate) and eventually crystallized in a test
tube to give compound (I) in 39% yield. 1H (400 MHz, CDCl3): ꢀ 7.63
(d, J = 15.2 Hz, 1H), 7.56–7.54 (m, 2H), 7.45–7.41 (m, 3H), 7.28 (d, J =
15.2 Hz, 1H), 4.87–4.82 (m, 2H), 3.67 (d, J = 16.8 Hz, 2H), 1.36 (d, J =
6.4 Hz, 12H). 13C (100 MHz, CDCl3): ꢀ 144.5, 132.3, 131.5, 129.2,
128.9, 126.2, 73.0, 72.9, 54.3 (d, J = 139.7 Hz), 24.3, 24.2, 24.0, 23.9.
LRMS (ESI): m/z calculated for C15H23O5PS (M + Na)+ 369.1, found
369.1.
1.790 (2)
1.765 (3)
Table 2
Selected bond lengths (A) for (II).
˚
P1—O10
P1—O8
P1—O9
P1—C9
S1—O4
S1—O5
S1—C7
S1—C8
S2—O7
S2—O6
S2—C9
S2—C8
1.4734 (10)
1.5623 (10)
1.5736 (10)
1.8156 (14)
1.4430 (10)
1.4431 (10)
1.7356 (13)
1.7877 (14)
1.4389 (11)
1.4420 (10)
1.7698 (13)
1.7816 (14)
P21—O30
P21—O28
P21—O29
P21—C29
S21—O24
S21—O25
S21—C27
S21—C28
S22—O27
S22—O26
S22—C29
S22—C28
1.4736 (10)
1.5623 (10)
1.5739 (10)
1.8167 (14)
1.4424 (10)
1.4452 (10)
1.7330 (13)
1.7891 (14)
1.4376 (11)
1.4420 (10)
1.7707 (13)
1.7795 (14)
Compound (I)
For the preparation of compound (II), the disulfone reagent di-
isopropyl (diisopropoxyphosphorylmethylsulfonylmethylsulfonyl-
methyl)phosphonate (Wong, Olmstead, Fettinger & Gervay-Hague,
2007) (224 mg, 0.44 mmol), 7-methoxy-1,3-benzodioxole-5-carbal-
dehyde (169 mg, 0.94 mmol) and LiBr (115 mg, 1.32 mmol) were
dissolved in 3–4 ml of dry THF in a flame-dried flask, and then
Hunig’s base (230 ml, 1.32 mmol) was added to the solution. After
stirring overnight, the reaction mixture was quenched by the addition
of 5% HCl until the pH was 3–4. The solution was partitioned
between ethyl acetate and water, and extracted three times. The
organic phase was collected and dried over sodium sulfate. The
solvent was evaporated to yield a crude solid material that was
subjected to column chromatography (30% ethyl acetate:70%
hexanes, RF = 0.21) to yield crystals of the mono-coupled product as a
minor component in a test tube.
Crystal data
C15H23O5PS
Mr = 346.36
Triclinic, P1
ꢄ = 63.533 (4)ꢁ
V = 1731.5 (10) A
Z = 4
Mo Kꢂ radiation
ꢅ = 0.30 mmꢃ1
T = 90 (2) K
0.55 ꢄ 0.53 ꢄ 0.38 mm
3
˚
˚
a = 8.933 (3) A
˚
b = 10.014 (3) A
˚
c = 22.059 (7) A
ꢂ = 79.769 (4)ꢁ
ꢃ = 89.938 (4)ꢁ
Data collection
Bruker SMART 1000
diffractometer
Absorption correction: multi-scan
(SADABS; Sheldrick, 2006)
Tmin = 0.853, Tmax = 0.895
15459 measured reflections
7911 independent reflections
7462 reflections with I > 2ꢆ(I)
Rint = 0.032
Compound (III) was the second product eluted from the column in
the preparation of (I). It also crystallized in a test tube in 33% yield.
For the preparation of compound (IV), the disulfone reagent
(Wong, Olmstead, Fettinger & Gervay-Hague, 2007) (103 mg,
0.21 mmol), benzaldehyde (0.07 ml, 0.68 mmol) and LiBr (60 mg,
0.069 mmol) were dissolved in 3–4 ml of dry THF, and then Hunig’s
base (91 ml, 0.069 mmol) was added to the solution. The reaction
mixture was stirred overnight before being quenched by the addition
of 5% HCl until pH 3–4 was attained. The solution was partitioned
between ethyl acetate (80 ml) and water (50 ml), and extracted three
times (50 ml). The organic phase was collected and dried over sodium
sulfate. After removal of the solvent, the crude material was
subjected to column chromatography (40% ethyl acetate:60%
hexanes, RF = 0.43) to yield 65 mg (88%) of (IV). 1H NMR (CDCl3,
400 MHz): ꢀ 4.68 (s, 2H), 7.21 (d, 2H, J = 15.6 Hz), 7.38–7.54 (m, 10H),
7.67 (d, 2H, J = 15.6 Hz). 13C NMR (CDCl3, 100 MHz): ꢀ 74.11,
124.38, 129.18, 129.31, 131.77, 132.09, 147.02. FT–IR (film): ꢁ 3060,
1612, 1448 (C C), 1323, 1124 (SO2 str), 976 (trans C C str).
Analysis calculated for C17H16O4S2: C 58.60, H 4.63%; found: C 58.21,
H 4.63%.
Refinement
R[F2 > 2ꢆ(F2)] = 0.041
wR(F2) = 0.104
S = 1.06
406 parameters
H-atom parameteꢃrs3 constrained
˚
Áꢇmax = 0.71 e A
ꢃ3
˚
7911 reflections
Áꢇmin = ꢃ0.43 e A
Compound (II)
Crystal data
C18H27O10PS2
Mr = 498.49
Triclinic, P1
a = 9.8656 (3) A
b = 15.1481 (5) A
˚
c = 15.9024 (5) A
ꢂ = 86.929 (3)ꢁ
ꢃ = 89.893 (3)ꢁ
ꢄ = 72.267 (3)ꢁ
V = 2260.11 (12) A
Z = 4
Mo Kꢂ radiation
ꢅ = 0.36 mmꢃ1
T = 90 (2) K
3
˚
˚
˚
0.49 ꢄ 0.08 ꢄ 0.07 mm
ꢂ
o134 Wong et al. C15H23O5PS, C18H27O10PS2, C16H14O2S and C17H16O4S2
Acta Cryst. (2008). C64, o132–o136

organic compounds
Table 3
Selected bond lengths (A) for (III).
Table 5
Summary of structural parameters for (I)–(IV) (A, ).
ꢁ
˚
˚
In square brackets, the average deviation from the mean value is followed by
the number of observations.
S1—O2
S1—O1
S1—C8
S1—C9
1.4422 (17)
1.4432 (16)
1.738 (2)
S21—O22
S21—O21
S21—C28
S21—C29
1.4415 (16)
1.4428 (15)
1.739 (2)
S—C( C) S—C
S
O
P
O
P—O
1.571
P—C
1.813
S—C—S S—C—P
1.751 (2)
1.742 (2)
1.741
[4,9]
1.780
[7,9]
1.443
[4,20]
1.467
[10,4]
117.23
[17,3]
114.9
[3,4]
[7,8]
[3,4]
Table 4
Selected bond lengths (A) for (IV).
˚
Data collection
S1—O2
S1—O1
1.4369 (9)
1.4502 (9)
S1—C8
S1—C9
1.7422 (12)
1.7896 (9)
Bruker SMART 1000
diffractometer
8747 measured reflections
2302 independent reflections
Absorption correction: multi-scan
(SADABS; Sheldrick, 2006)
Tmin = 0.865, Tmax = 0.928
1978 reflections with I > 2ꢆ(I)
Rint = 0.022
Data collection
Refinement
Bruker SMART APEXII
diffractometer
Absorption correction: multi-scan
(SADABS; Sheldrick, 2006)
Tmin = 0.845, Tmax = 0.976
25647 measured reflections
13151 independent reflections
11227 reflections with I > 2ꢆ(I)
Rint = 0.017
R[F2 > 2ꢆ(F2)] = 0.032
wR(F2) = 0.092
S = 1.11
137 parameters
All H-atom parameters refined
ꢃ3
˚
Áꢇmax = 0.42 e A
ꢃ3
˚
2302 reflections
Áꢇmin = ꢃ0.31 e A
In (I), all H atoms were treated as riding, with C—H distances in
˚
the range 0.95–1.00 A and Uiso(H) values of 1.2 (for primary and
Refinement
R[F2 > 2ꢆ(F2)] = 0.034
wR(F2) = 0.092
S = 1.03
13151 reflections
623 parameters
Only H-atom displacement para-
meters refined
secondary) or 1.5 (for tertiary) times the Ueq of the bonded C atom.
The structure was refined as a pseudo-merohedral twin. The twin law
was (100/110/001) and the twin parameter 0.4822 (10). In (II), H-atom
positional parameters were treated as for (I) and the displacement
parameters were refined. In (III), one of the three molecules in the
asymmetric unit is disordered in one-half of the molecule. Occu-
pancies for these two components were originally refined and
subsequently fixed at values of 0.57 and 0.43 for the major and minor
parts, respectively. H atoms were treated as in (I). In (IV), all atoms
ꢃ3
˚
Áꢇmax = 0.50 e A
Áꢇmin = ꢃ0.35 e A
ꢃ3
˚
Compound (III)
Crystal data
3
˚
V = 8262.5 (9) A
Z = 24
˚
were fully refined [C—H = 0.92 (2)–0.989 (19) A].
C16H14O2S
Mr = 270.33
Orthorhombic, Pbca
For all compounds, data collection: SMART (Bruker, 2002) for (I),
(III) and (IV), and APEX2 (Bruker, 2006) for (II); cell refinement:
SAINT (Version 7.23; Bruker, 2005) for (I), and SAINT (Version
7.16b; Bruker, 2004) for (II), (III) and (IV); data reduction: SAINT
(Version 7.23) for (I), and SAINT (Version 7.16b) for (II), (III) and
(IV); program(s) used to solve structure: SHELXS97 (Sheldrick,
2008); program(s) used to refine structure: SHELXL97 (Sheldrick,
2008); molecular graphics: SHELXTL (Sheldrick, 2008); software
used to prepare material for publication: SHELXL97.
Mo Kꢂ radiation
ꢅ = 0.23 mmꢃ1
T = 90 (2) K
0.51 ꢄ 0.09 ꢄ 0.06 mm
˚
a = 10.1632 (7) A
˚
b = 23.6753 (16) A
˚
c = 34.339 (2) A
Data collection
Bruker SMART 1000
diffractometer
Absorption correction: multi-scan
(SADABS; Sheldrick, 2006)
Tmin = 0.892, Tmax = 0.987
60803 measured reflections
9492 independent reflections
5497 reflections with I > 2ꢆ(I)
Rint = 0.085
We thank the University AIDS Research Program (grant
No. D02-D-400) and the Tobacco-Related Disease Research
Program (grant No. 12RT-0254H) for partial support of this
research. The Bruker SMART 1000 diffractometer was funded
in part by NSF instrumentation grant No. CHE-9808259.
Refinement
R[F2 > 2ꢆ(F2)] = 0.051
wR(F2) = 0.135
S = 1.09
562 parameters
H-atom parameteꢃrs3 constrained
˚
Áꢇmax = 0.61 e A
Áꢇmin = ꢃ1.01 e A
ꢃ3
˚
9492 reflections
Supplementary data for this paper are available from the IUCr electronic
archives (Reference: SK3201). Services for accessing these data are
described at the back of the journal.
Compound (IV)
Crystal data
3
˚
V = 1578.21 (10) A
Z = 4
C17H16O4S2
Mr = 348.42
References
Monoclinic, C2=c
Mo Kꢂ radiation
ꢅ = 0.35 mmꢃ1
T = 90 (2) K
0.29 ꢄ 0.24 ꢄ 0.20 mm
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a = 15.7551 (6) A
˚
b = 11.9609 (5) A
˚
c = 8.6212 (3) A
ꢃ = 103.728 (1)ꢁ
ꢂ
Acta Cryst. (2008). C64, o132–o136
Wong et al.
C15H23O5PS, C18H27O10PS2, C16H14O2S and C17H16O4S2 o135

organic compounds
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o136 Wong et al. C15H23O5PS, C18H27O10PS2, C16H14O2S and C17H16O4S2
Acta Cryst. (2008). C64, o132–o136