Synthesis and Structure of Functionalized Derivatives of the Cleft-Shaped Molecule Dithiosalicylide

Full text of DOI:10.1021/jo971349g

J . Org. Chem. 1997, 62, 9361-9364
9361
tion, we present the crystal structures of two dithiosali-
cylides that show that the compounds form discrete, self-
included dimers and that interactions between the
dimers give rise to interesting supramolecular structures.
Syn th esis a n d Str u ctu r e of F u n ction a lized
Der iva tives of th e Cleft-Sh a p ed Molecu le
Dith iosa licylid e
Kaushik Mitra,† Melissa E. Pohl,†
Leonard R. MacGillivray,† Charles L. Barnes,† and
Kent S. Gates*,†,‡
Resu lts a n d Discu ssion
The 3H-1,2-benzodithiol-3-ones (5) used in these stud-
ies were prepared by conversion of the appropriately
substituted anthranilic acid derivatives (6) to the corre-
sponding thiosalicylic acid analogs (7),15 followed by
cyclization using thiolacetic acid in sulfuric acid (Scheme
2).16 In each case, treatment of 5 with triphenylphos-
phine in methylene chloride at room temperature affords
good yields of the corresponding dithiosalicylide analogs
(8) (Scheme 2). Consistent with the notion (Scheme 1)
of negative charge developing on sulfur in the transition
state of the triphenylphosphine-mediated dimerization
reaction, we observe that 5b reacts more rapidly than
either 5a or 2.
With the aim of preparing functionalizable dithiosali-
cylides, we sought to brominate the methyl positions of
8a . Accordingly, treatment of 8a with N-bromosuccin-
imide (NBS) in carbon tetrachloride yields a mixture of
brominated analogs that are separable by careful silica
gel column chromatography and recrystallization. With
careful control of conditions, it is possible to obtain the
monobrominated cleft (9) and the dibrominated cleft (10)
in 30% and 27% recovered yields respectively (Scheme
3).
Because the dithiosalicylide-forming reaction described
here (Scheme 1) involves dimerization of triphenylphos-
phine-activated 3H-1,2-benzodithiol-3-ones, it is possible
to prepare assymetrically functionalized clefts by this
method. For example, treatment of a 1:1 mixture of 5b
and 5c with triphenylphosphine in methlylene chloride
at 24 °C affords 11, 8b, and 8c in approximately equal
yields. These products are separable by careful column
chromatography. Using this approach, the asymmetric
clefts 11-14 were prepared.
Departments of Chemistry and Biochemistry, University of
Missouri-Columbia, Columbia, Missouri 65211
Received J uly 22, 1997
In tr od u ction
Conformationally rigid molecules whose structures
define cavities and clefts have potential uses as
receptors,1-3 catalysts,4,5 and as molecular building blocks
in the construction of new materials.6 Dithiosalicylides
are a class of conformationally well-defined, cleft-shaped
molecules.7,8 NMR7 and X-ray crystallographic8 studies
have shown that dithiosalicylide (1) adopts a boat con-
formation where the aromatic rings form a shallow “v-
shaped” pocket in which the dihedral angle between the
aromatic rings is approximately 65 °.8 Although dithiosal-
icylides are not conformationally locked, as is the case
for the structurally related Kagan’s ether1,2 and Troeger’s
base3 compounds, the inversion barrier between the
enantiomeric boat conformations is quite high (∼25 kcal/
mol).7
As part of investigations9-11 into the chemistry of 3H-
1,2-benzodithiol-3-one 1-oxide and related compounds, we
recently developed a simple preparation of dithiosali-
cylide from 3H-1,2-benzodithiol-3-one (2).12,13 Treatment
of 2 with triphenylphosphine provides good yields of 1,
presumably via dimerization of a benzothietan-2-one (3)
or ketene (4) intermediate (Scheme 1).14 We describe
here the application of this protocol to the preparation
of dithiosalicylide analogs that present larger cavities
than the parent compound and to several analogs that
may be amenable to further functionalization. In addi-
Crystals of dithiosalicylides 8c and 11 suitable for
X-ray analysis were obtained by dissolving each com-
pound in a mixed solvent system (ethyl acetate:hexane
for 11 and chloroform:ethanol for 8c) and allowing slow
evaporation to dryness. As shown in Figure 1, each
molecule contains a well-defined v-shaped pocket with
dihedral angles between the planes of their aromatic
units of 56.6° (8c) and 62.2° (11), similar to the parent
dibenzo derivative 1.8 Notably, elaboration of 1 has
increased the size of each cleft such that the entrance to
each pocket approaches nanometer dimensions as dem-
onstrated by “upper rim” H‚‚‚H (8.29 Å) and H‚‚‚Br (8.16
Å) separations for 8c and 11, respectively, which are
greater than those H‚‚‚H separations (6.43 and 6.69 Å)
of 1.
Views depicting the crystal structures of 8c and 11 are
shown in Figure 1c,d. Both molecules assemble such that
they form self-included dimers held together by offset
face-to-face [plane-to-plane distances: 3.36 (8c), 3.43 Å
(11)] and tilted T edge-to-face π-π interactions [ring
center-ring center distances: 5.37 (8c), 5.37 Å (11)].17
The self-inclusion exhibited by the unsymmetric cleft 11
* To whom correspondence should be addressed. Phone: (573) 882-
6763. Fax: (573) 882-2754. E-mail: chemkent@showme.missouri.edu.
† Department of Chemistry.
‡ Department of Biochemistry.
(1) Harmata, M.; Barnes, C. L. J . Am. Chem. Soc. 1990, 112, 5655.
(2) Harmata, M.; Barnes, C. L.; Karra, S. R.; Elahmad, S. J . Am.
Chem. Soc. 1994, 116, 8392.
(3) Adrian, J . C. J .; Wilcox, C. S. J . Am. Chem. Soc. 1991, 113, 678-
680.
(4) Breslow, R. Acc. Chem. Res. 1995, 28, 146-153.
(5) Wintner, E. A.; Conn, M. M.; Rebek, J . J . Acc. Chem. Res. 1994,
27, 198-203.
(6) Mallouk, T. E. Nature 1997, 387, 350-351.
(7) Guise, G. B.; Ollis, D. W.; Peacock, J . A.; Stephanatou, J . S.;
Stoddart, J . F. J . Chem. Soc., Perkin Trans. 1 1982, 1637.
(8) Medard, J .-M.; Rodier, N.; Reynaud, P.; Brion, J . D.; Xuong, N.
T. Acta Crystallogr. 1983, C39, 1136.
(9) Behroozi, S. B.; Kim, W.; Gates, K. S. J . Org. Chem. 1995, 60,
3964-3966.
(10) Behroozi, S. J .; Kim, W.; Dannaldson, J .; Gates, K. S. Biochem-
istry 1996, 35, 1768-1774.
(11) Kim, W.; Dannaldson, J .; Gates, K. S. Tetrahedron Lett. 1996,
37, 5337-5340.
(12) Mitra, K.; Gates, K. S. Tetrahedron Lett. 1995, 36, 1391-1394.
(13) For other syntheses of 1, see: (a) Elkaschef, M. A. F.; Abdel-
Megeid, F. M. E.; Elbarbary, A. A. Tetrahedron 1974, 30, 4113. (b)
Fanning, A. T., J r.; Bickford, G. R.; Roberts, T. D. J . Am. Chem. Soc.
1972, 94, 8505. (c) Tsuge, O.; Tashiro, M.; Kanemasa, S.; Takasaki,
K. Chem. Lett. 1972, 9, 827. (d) Chapman, O. L.; McIntosh, C. L. J .
Am. Chem. Soc. 1970, 92, 7001. (e) Baker, W.; El Nawawy, A. S.; Ollis,
W. D. J . Chem. Soc. 1952, 3163.
(15) Allen, C. F. H.; MacKay, D. D. Organic Syntheses; Wiley: New
York, 1943; Collect. Vol. II, pp 580-583.
(16) Iyer, R. P.; Phillips, L. R.; Egan, W.; Regan, J . B.; Beaucage, S.
L. J . Org. Chem. 1990, 55, 4693-4699.
(14) For examples of such intermediates, see: (a) Wentrup, C.;
Bender, H.; Gross, G., J . Org. Chem. 1987, 52, 3838. (b) Goerdeler, J .;
Kohler, K.-H. Tetrahedron Lett. 1976, 34, 2961.
S0022-3263(97)01349-2 CCC: $14.00 © 1997 American Chemical Society

9362 J . Org. Chem., Vol. 62, No. 26, 1997
Notes
Sch em e 1
Sch em e 2a
Å (8c), 3.62 and 3.67 Å (11)], which give rise to infinite
supramolecular layered arrays.
Exp er im en ta l Section
Chemicals were purchased from the following suppliers:
absolute ethanol, McCormick Distilling Co.; NaOH, NaHCO3,
Na2SO4, H2SO4, HCl, Fisher Chemical Company; 3-amino-2-
naphthoic acid, Fluka Chemical Co. All other chemicals were
purchased from Aldrich Chemical Co. Thin-layer chromatog-
raphy was performed on silica gel plates, 0.25 mm, with F254
fluorophore (Aldrich), and visualization of compounds was
achieved with UV light at 254 or 360 nm. Column chromatog-
raphy was performed using 230-400 mesh silica gel (Merck) with
technical-grade solvents that were distilled prior to use. High
resolution mass spectrometry was performed at the Midwest
Centre for Mass Spectrometry (University of Nebraska-
Lincoln), and elemental analysis was performed at M-H-W
Laboratories (Phoenix, AZ). Intensity data for crystallographic
studies were collected on Enraf-Nonius CAD-4 diffractometers
at 298 K. All crystallographic calculations were conducted using
the NRCVAX program package18 locally implemented on an
IBM-compatible pentium-based PC. Packing diagrams were
constructed with the aid of RES2INS.19
a
Reagents: (a) NaNO2-HCl, Na2S; (b) Zn, HOAc, reflux 8 h;
Gen er a l P r oced u r e for th e Syn th esis of Su bstitu ted 3H-
1,2-Ben zod ith iol-3-on es (5). To a stirred suspension of the
appropriate anthranilic acid derivative (165 mmol) in water (85
mL) and concd HCl (33 mL) at 5 °C was added dropwise a
solution of NaNO2 (11.4 g, 165 mmol) in water (45 mL) and the
solution maintained at 5 °C. Crushed ice was added to the
reaction mixture periodically during addition to keep the tem-
perature below 5 °C. Meanwhile, Na2S‚9H2O (43.7 g, 182 mmol)
and sublimed sulfur (5.8 g, 181 mmol) were dissolved in water
(48 mL) by heating and made alkaline by addition of 10 M NaOH
(17 mL), and the resulting alkaline disulfide solution was cooled
to 5 °C in an ice bath. The cold diazo solution was added to the
alkaline disulfide solution dropwise with crushed ice added
periodically to maintain the temperature below 5 °C. Following
addition of the diazo solution, the mixture was stirred at 24 °C
until evolution of N2 gas stopped. Concentrated HCl was added
to the solution until precipitation of the crude product as a yellow
solid was complete. The precipitate was collected and boiled in
a saturated solution of NaHCO3 (400 mL). After being boiled
for 15 min, the mixture was filtered to remove the insoluble
material, and concd HCl was added to the filtrate until the crude
product precipitated out as a yellow solid. Excess concd HCl
was added to the mixture until precipitation was complete, and
the precipitate was isolated by filtration. This material was
boiled in absolute EtOH (150 mL) for 15 min and filtered and
the filtrate concentrated under reduced pressure to yield the 2,2′-
dithiosalicylic acid derivative (approximately 90% pure).
The 2,2′-dithiosalicylic acid derivative was mixed with Zn dust
(10 g) in glacial CH3COOH (150 mL) and refluxed for 48 h. The
mixture was then cooled and filtered. The solid collected in this
manner was boiled in 5 M NaOH (300 mL). After being boiled
for 30 min, the undissolved solid was removed by filtration and
the clear filtrate acidified with concd HCl until the crude product
precipitated out as a yellow solid. Concentrated HCl was added
to the mixture until the precipitation was complete. The
precipitate was collected and boiled in EtOH (125 mL) and
(c) H2SO4, CH3COSH 60 °C; (d) Ph3P.
Sch em e 3
displays selectivity, with the naphthyl, rather than the
bromo, substituent residing within the cleft. Neighboring
dimers in both structures interact via offset face-to-face
π-π interactions [plane-to-plane distances: 3.48 and 3.60
(18) Gabe, E. J .; Le Page, Y.; Charland, J .-P.; Lee, F. L.; White, P.
S. J . Appl. Crystallogr. 1989, 22, 384.
(17) J orgensen, W. L.; Severence, D. L. J . Am. Chem. Soc. 1990,
112, 4768.
(19) Barbour, L. J . University of Missouri-Columbia, unpublished
program.

Notes
J . Org. Chem., Vol. 62, No. 26, 1997 9363
stirred in CH2Cl2 (30 mL) under N2 at 24 °C. When TLC
indicated that the reaction was nearly complete (∼160 h), the
turbid yellow mixture was evaporated to dryness under reduced
pressure to obtain the crude product. Reaction times can be
decreased with use of excess triphenylphosphine. Because the
triphenylphosphine sulfide byproduct of this reaction migrates
close to the dithiosalicylide products on silica gel, it was desirable
to convert the triphenylphosphine sulfide to the more polar
triphenylphosphine oxide prior to column chromatography.
Accordingly, glycidol (2.6 mL, 38.6 mmol) and CF3COOH (3.0
mL, 39 mmol) were added to a solution of the crude reaction
product in benzene (25 mL), and the mixture was heated at 55
°C until all triphenylphosphine sulfide was converted to triph-
enylphosphine oxide20 as indicated by TLC. This workup
procedure does not affect the yield of the desired product. The
solution was then cooled, diluted with EtOAc (30 mL), and
extracted with saturated NaHCO3 (2 × 50 mL) and water (2 ×
50 mL). The organic phase was dried over Na2SO4 and concen-
trated under reduced pressure to yield a thick oil that was
subsequently purified by column chromatography.
6H,12H-Diben zo[b,f][1,5]d ith iocin -6,12-d ion e (1). Flash
chromatography on silica gel eluted with hexane-EtOAc (8:1)
provided 1 as a white solid (74%). This material was recrystal-
lized from CH2Cl2-hexane to give white crystals: mp 174-
176°C, °C (lit.10e mp 175-176 °C); 1H NMR (500 MHz, CDCl3) δ
7.35 (m, 4H), 7.25 (m, 4H); 13C NMR (500 MHz, CDCl3) δ 197.3,
142.5, 135.6, 131.2, 131.0, 126.5, 125.2 (corresponds with
literature data11a).
2,8-Dim eth yl-6H,12H-d iben zo[b,f][1,5]-d ith iocin -6,12-d i-
on e (8a ). Flash chromatography on silica gel eluted with
hexane-EtOAc (8:1) provided 8a as a white solid (74%). This
material was recrystallized from EtOAc-hexane to give white
crystals: mp 188-189 °C; 1H NMR (500 MHz, CDCl3) δ 2.28 (s,
6H), 7.04 (m, 4H), 7.21 (m, 2H); 13C NMR (500 MHz, CDCl3) δ
21.2, 122.1, 127.2, 131.8, 135.6, 142.0, 142.6, 198.3; HRMS (EI)
m/ z calcd for C16H12O2S2 300.0279, found 300.0280. Anal.
Calcd for C16H12O2S2: C, 63.99; H, 4.03. Found: C, 63.74; H,
4.27.
2,8-Dib r om o-6H,12H-d ib en zo[b,f][1,5]d it h iocin -6,12-d i-
on e (8b). Compound 8b was prepared as described above,
except the reaction was complete at ∼140 h. Flash chromatog-
raphy on silica gel eluted with hexane-EtOAc (8:1) provided
8b as a white solid (72%). This material was recrystallized from
EtOAc-hexane to give colorless crystals: mp 223-224 °C; 1H
NMR (500 MHz, CDCl3) δ 7.23 (s, 1H), 7.26 (s, 1H), 7.39-7.47
(m, 4H); 13C NMR (500 MHz, CDCl3) δ 123.9, 126.2, 129.7, 134.5,
137.1, 143.6, 194.7; HRMS (EI) m/ z calcd for C14H6O2S2Br2
427.8176, found 427.8171.
Din a p h t h o[2,3-c:2′,3′-g][1,5]d it h iocin -7,15-d ion e (8c).
Flash chromatography on silica gel eluted with EtOAc provided
8c as a white solid (48%). This material was recrystallized from
EtOH-CHCl3-hexane to give colorless cubic crystals: mp 324-
325 °C; 1H NMR (500 MHz, CDCl3) δ 7.48 (m, 4H), 7.65 (m, 2H),
7.77 (m, 2H), 7.80 (s, 2H), 7.88 (s, 2H); 13C NMR (500 MHz,
CDCl3) δ 120.9, 127.4, 128.1, 128.5, 128.6, 128.6, 133.1, 133.6,
136.8, 139.8, 197.9; HRMS (EI) m/ z calcd C22H12O2S2 372.0279,
found 372.0267. Anal. Calcd for C22H12O2S2: C, 70.96; H, 3.25.
Found: C, 68.23; H, 3.47. Single crystals for X-ray diffraction
studies were obtained by slowly evaporating to dryness (∼3 days)
a 10:10:1 solution of EtOH-CHCl3-hexane containing analyti-
cally pure crystallized 8c (10 mg). Crystal data for 8c: triclinic,
space group P-1, a ) 9.851(2) Å, b ) 9.899(2) Å, c ) 10.212(2)
Å, R ) 78.300(2)°, â ) 85.990(2)°, γ ) 63.940(2)°, U ) 875.8(3)
Å3, Fcalcd ) 1.41 g cm-3, 2θmax ) 120°, Cu KR radiation (λ )
1.540 60 Å) for Z ) 2. Least-squares refinement based on 2377
reflections with Inet > 2.0σ(Inet) (out of 2591 unique reflections)
and 235 parameters on convergence gave a final value of R )
0.038 (refinement based on F).21
F igu r e 1.
filtered and the filtrate concentrated under reduced pressure to
yield the thiosalicylic acid derivative (7) contaminated with a
small amount of elemental sulfur. This material was directly
carried on to the next step.
To a stirred suspension of the thiosalicylic acid derivative (7,
11.9 mmol) in concd H2SO4 (25 mL) at 24 °C under N2 was added
thiolacetic acid (1.87 mL, 26.2 mmol) over a period of 10 min.
The mixture was placed in an oil bath preheated to 60 °C and
stirred for 4 h. The dark mixture was then poured over crushed
ice and allowed to stand at 24 °C for 30 min. The precipitate so
obtained was triturated with boiling CHCl3 (2 × 100 mL), the
resulting CHCl3 solution filtered, and the filtrate extracted with
saturated NaHCO3 (2 × 100 mL) and water (2 × 100 mL). The
organic layer was dried over Na2SO4 and the solvent removed
under reduced pressure to yield the crude product (5), which
was subsequently purified by column chromatography.
5-Meth yl-3H-1,2-ben zod ith iol-3-on e (5a ). The yellow solid
was purified by flash chromatography on silica gel with hexane-
EtOAc (6:1) to yield 5a as a yellow solid (64% yield from
5-methylanthranilic acid). This material was recrystallized from
EtOAc-hexane to form fine yellow needles: mp 78 °C; 1H NMR
(500 MHz, CDCl3) δ 2.46 (s, 3H), 7.52-7.46 (m, 2H), 7.75 (s,
1H), 13C NMR (500 MHz, CDCl3) δ 20.7, 124.1, 126.9, 129.3,
134.9, 135.9, 145.4, 193.6; IR (CHCl3) 3032, 1675, 1221 cm-1
HRMS (EI) m/ z calcd for C8H6OS2 181.9860, found 181.9863.
Anal. Calcd for C8H6O2S: C, 52.72; H, 3.32. Found: C, 52.90;
H, 3.49.
;
5-Br om o-3H-1,2-ben zod ith iol-3-on e (5b). The yellow solid
was purified by flash chromatography on silica gel with with
hexane-EtOAc (8:1) to yield 5b as a yellow solid (38% yield from
5-bromoanthranilic acid). This material was recrystallized from
EtOAc-hexane to form light yellow needles: mp 114-115 °C;
1H NMR (500 MHz, CDCl3) δ 7.50 (d, J ) 8.6 Hz, 1H), 7.73 (dd,
J ) 1.9 Hz, 8.6 Hz, 1H), 8.08 (d, J ) 1.9 Hz, 1H); 13C NMR (500
MHz, CDCl3) 119.7, 125.7, 129.9, 131.0, 136.3, 146.9, 191.9;
HRMS (EI) m/ z calcd for C7H3OS2Br 245.8808, found 245.8813.
Anal. Calcd for C7H3OS2Br: C, 34.16; H, 1.23. Found: C, 34.30;
H, 1.32.
3H-1,2-Na p h th od ith iola n -3-on e (5c). The reddish yellow
powder (prepared as described above except stirred for only 45
min in the thiolacetic acid reaction) was purified by flash
chromatography on silica gel with hexane-EtOAc (6:1) to yield
5c as a reddish yellow solid (48% yield from 3-amino-2-naphthoic
acid). This material was recrystallized from EtOAc-hexane to
form reddish yellow crystals: mp 147-148 °C; 1H NMR (500
MHz, CDCl3) δ 7.54 (m, 1H), 7.65 (t, J ) 7.6 Hz, 1H), 7.84 (d, J
) 8.4 Hz, 1H), 8.02 (d, J ) 8.4 Hz, 1H), 8.04 (s, 1H), 8.54 (s,
1H); 13C NMR (500 MHz, CDCl3) δ 122.5, 126.7, 127.0, 127.2,
128.3, 129.9, 130.2, 130.5, 135.8, 140.0, 194.0; HRMS (EI) m/ z
calcd for C11H6OS2 217.986, found 217.9853. Anal. Calcd for
Gen er a l P r oced u r e for th e Syn th esis of Un sym m etr ica l
Dith iosa licylid es 11-14. Equal portions of two 3H-1,2-ben-
zodithiol-3-ones (0.83 mmol of each) and triphenylphosphine (477
(20) Chan, T. H.; Finkenbine, J . R. J . Am. Chem. Soc. 1972, 94,
2880-2882.
(21) The author has deposited atomic coordinates for 8c and 11 with
the Cambridge Crystallographic Data Centre. The coordinates can be
obtained, on request, from the Director, Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.
C
11H6OS2: C, 60.55; H, 2.77. Found: C, 60.70; H, 2.59.
Gen er a l P r oced u r e for th e Syn th esis of Dith iosa li-
cylid es 1 a n d 8. The appropriate 3H-1,2-benzodithiol-3-one
(3.84 mmol) and triphenylphosphine (1.01 g, 3.84 mmol) were

9364 J . Org. Chem., Vol. 62, No. 26, 1997
Notes
mg, 1.8 mmol) were stirred in CH2Cl2 (20 mL) under N2 at 24
°C. When all starting material was consumed as indicated by
TLC, the turbid yellow mixture was evaporated to dryness under
reduced pressure to yield the crude product. Glycidol (550 µL,
8.3 mmol) and CF3COOH (639 µL, 8.3 mmol) were added to a
solution of the crude reaction product in benzene (10 mL), and
the mixture was heated at 55 °C until all triphenylphosphine
sulfide was converted to triphenylphosphine oxide as indicated
by TLC. The solution was cooled, diluted with EtOAc (25 mL),
and extracted with saturated NaHCO3 (2 × 25 mL) and water
(2 × 25 mL). The organic phase was dried over Na2SO4 and
concentrated under reduced pressure to yield a thick oil that
was subsequently purified by column chromatography.
13C NMR (500 MHz, CDCl3) δ 120.8, 123.7, 125.8, 127.5, 128.2,
128.7, 128.9, 129.0, 129.6, 133.2, 133.5, 134.3, 136.9, 137.1, 139.0,
144.4, 196.3, 196.4; HRMS (EI) m/ zcalcd for
C18H9O2S2Br
399.9227, found 399.9234. Single crystals for X-ray diffraction
studies were obtained by slowly evaporating to dryness (∼3 days)
a 10:1 solution of CHCl3-hexane containing analytically pure
crystallized 11 (10 mg). Crystal data for 11: triclinic, space
group P-1, a ) 8.974(2) Å, b ) 9.776(5) Å, c ) 10.029(5) Å, R )
89.19(3)°, â ) 89.13(3)°, γ ) 67.33(3)°, U ) 811.7(6) Å3, Fcalcd
)
1.64 g cm-3, 2θmax ) 46°, Mo KR radiation (λ ) 0.710 69 Å) for
Z ) 2. Least-squares refinement based on 1674 reflections with
Inet > 2.0σ(Inet) (out of 2250 unique reflections) and 208 param-
eters on convergence gave a final value of R ) 0.066 (refinement
based on F).21
2-Met h yl-6H ,12H -d ib en zo[b,f][1,5]d it h iocin -6,12-d ion e
(12). Flash chromatography on silica gel eluted with hexane-
EtOAc (10:1) provided 12 as a yellow-white solid (28%). Com-
2-(Br om om e t h yl)-8-m e t h yl-6H ,12H -d ib e n zo[b,f][1,5]-
d ith iocin -6,12-d ion e (9) a n d 2,8-Bis(br om om eth yl)-6H,12H-
d iben zo[b,f][1,5]d ith iocin -6,12-d ion e (10). Compound 8a
(300 mg, 1.0 mmol) and NBS (crystallized from EtOAc, 356 mg,
1.9 mmol) were dissolved in CCl4 (20 mL) and heated to reflux.
When the solution reached reflux, a catalytic amount of AIBN
was added and refluxing was continued for 8 h under N2. The
solution was then cooled and evaporated to dryness under
reduced pressure. The resulting yellowish-white solid was
dissolved in CHCl3 (20 mL) and extracted with water (2 × 30
mL). The organic phase was dried over Na2SO4, solvent removed
under reduced pressure, and the yellow solid purified by flash
chromatography on silica gel with 12:1 hexane EtOAc to isolate
10, which elutes first off the column (recovered yield: 30%) and
9 (recovered yield: 27%). Both were recrystallized from EtOAc-
hexane to give white crystals. Compound 9: mp 129-130 °C;
1H NMR (500 MHz, CDCl3) δ 2.29 (s, 3H), 4.31-4.36 (m, 2H),
7.05 (m, 2H), 7.22 (m, 1H), 7.25 (m, 2H), 7.31 (m, 1H) ; 13C NMR
(500 MHz, CDCl3) δ 21.2, 30.8, 121.8, 125.3, 127.0, 127.2, 131.2,
132.0, 135.6, 136.1, 141.3, 142.2, 143.2, 197.2, 197.5; HRMS (EI)
m/ z calcd for C16H11O2S2Br 377.9384, found 377.9398. Com-
pound 10: mp 165-166 °C; 1H NMR (500 MHz, CDCl3) δ 4.30-
4.36 (m, 4H), 7.24 (m, 2H), 7.26 (m, 2H), 7.31 (s, 1H), 7.33 (s,
1H); 13C NMR (500 MHz, CDCl3) δ 30.7, 125.1, 127.0, 131.4,
136.2, 141.6, 142.8, 196.4; HRMS (EI) m/ z calcd for C16H10O2S2-
Br2 455.8489, found 455.8492. Anal. Calcd for C16H10O2S2Br2:
C, 42.12; H, 2.21. Found: C, 42.12; H, 2.01.
pounds 8a and
1 were obtained in 24% and 26% yields,
respectively. This material was recrystallized from EtOAc-
hexane to give white crystals: mp 139-140 °C; 1H NMR (500
MHz, CDCl3) δ 2.27 (s, 3H), 7.03 (m, 2H), 7.20 (d, J ) 7.6 Hz,
1H), 7.25 (m 2H), 7.35 (m, 2H); 13C NMR (500 MHz, CDCl3) δ
21.2, 122.0, 125.4, 126.6, 127.2, 131.0, 131.2, 131.8, 135.6, 135.7,
142.1, 142.4, 142.8, 197.7, 198.0; HRMS (EI) m/ z calcd C15H10O2S2
286.0122, found 286.0121. Anal. Calcd for C15H10O2S2: C,
62.93; H, 3.52. Found: C, 63.00; H, 3.45.
2-Br om o-6H ,12H -d ib en zo[b,f][1,5]d it h iocin -6,12-d ion e
(13). Flash chromatography on silica gel eluted with hexane-
EtOAc (10:1) provided 13 as a white solid (35%). Compounds
8b and 1 were obtained in 26% and 23% yields, respectively.
This material was recrystallized from EtOH-hexane to give
1
white crystals: mp 198-199 °C; H NMR (500 MHz, CDCl3) δ
7.2 (d, J ) 7.6 Hz, 1H), 7.25 (m, 1H), 7.32 (m, 1H), 7.37-7.42
(m, 4H); 13C NMR (500 MHz, CDCl3) δ 124.3, 124.8, 125.6, 126.6,
129.4, 131.4, 131.5, 134.0, 135.8, 136.8, 142.3, 143.7, 195.6, 196.3;
HRMS (EI) m/ z calcd for C14H7O2S2Br 349.9071, found 349.9079.
Anal. Calcd for C14H7O2S2Br: C, 48.01; H, 2.02. Found: C,
48.20; H, 2.18.
2-Br om o-8-m eth yl-6H,12H-d iben zo[b,f][1,5]d ith iocin -6,-
12-d ion e (14). Flash chromatography on silica gel eluted with
hexane-EtOAc (12:1) provided pure 14 as a white solid (25%).
Compounds 8a and 8b were also obtained in 28% and 24%
yields, respectively. This material was recrystallized from
EtOH-hexane to give white crystals: mp 215-216 °C; 1H NMR
(500 MHz, CDCl3) δ 2.31 (s, 3H), 7.06 (s, 1H), 7.11 (m, 1H), 7.21
(m, 1H), 7.24 (s, 1H), 7.38 (m, 2H); 13C NMR (500 MHz, CDCl3)
δ 21.2, 121.5, 124.4, 125.7, 127.3, 129.6, 132.2, 134.0, 135.7,
136.9, 142.2, 142.5, 144.0, 196.3, 196.7; HRMS (EI) m/ z calcd
for C15H9O2S2Br 363.9227, found 363.9231. Anal. Calcd for
Ack n ow led gm en t. We are grateful to the National
Science Foundation for support in the form of a summer
research fellowship to M.E.P. and for support of the
NMR facilities at the University of Missouri-Columbia
(Grant Nos. 9221835 and 8908304). We thank the
University of Missouri-Columbia for financial support.
C
15H9O2S2Br: C, 49.46; H, 2.49. Found: C, 49.60; H, 2.32.
2-Br om o-6H,12H-n a p h th oben zo[b,f][1,5]d ith iocin -6,12-
Su p p or tin g In for m a tion Ava ila ble: Complete X-ray
data and methods for 8c and 11 (10 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
d ion e (11). Flash chromatography on silica gel eluted with
hexane-EtOAc (12:1) provided 11 as a white solid (22%).
Compounds 8b and 8c were also obtained in 33 and 30% yields,
respectively. This material was recrystallized from CHCl3-
1
hexane to give white crystals: mp 284 °C; H NMR (500 MHz,
CDCl3) δ 7.20 (d, J ) 8.3 Hz, 1H), 7.27 (m, 1H) 7.41 (d, J ) 2.1
Hz, 1H), 7.60 (m, 2H), 7.78 (m, 2H), 7.83 (m, 1H), 7.91 (s, 1H);
J O971349G