Synthesis and characterization of thermodynamically unstable polycyclic aromatic hydrocarbon episulfides and episulfoxides

Full text of DOI:10.1021/jo000086e

J . Org. Chem. 2000, 65, 8083-8085
8083
Sch em e 1
Syn th esis a n d Ch a r a cter iza tion of
Th er m od yn a m ica lly Un sta ble P olycyclic
Ar om a tic Hyd r oca r bon Ep isu lfid es a n d
Ep isu lfoxid es
Uri Zoller* and Fa-Pu Chen
Department of Science Education-Chemistry,
Haifa University-Oranim, Kiryat Tivon 36006, Israel
uriz@research.haifa.ac.il
Received J anuary 21, 2000
In tr od u ction
in the formation of the corresponding DNA adducts.9 On
the other hand, the higher polarizability of the sulfur
atom, the weaker strength of the sulfur-carbon bond
compared to the strength of the oxygen-carbon bond, and
consequently, the better leaving capacity of the sulfur
atom compared to that of the oxygen may make the PAH-
episulfides better electrophiles toward the nucleophilic
sites of the DNA than their epoxide counterparts.
We reported previously on a highly efficient method
for the conversion of bay-region benzylic PAH epoxides
to the corresponding episulfides with N,N-dimethylthio-
formamide (DMTF) in the presence of the Lewis acid
catalyst BF3‚Et2O at low temperature.5 We now report
the synthesis and characterization of the hitherto un-
known polycyclic aromatic hydrocarbon episulfide 3
without the use of the Lewis-type catalyst and the
identification/characterization of the first, thus far il-
lusive, corresponding episulfoxide 4, as well as arene
episulfide 5. In view of the surprising hydrolytic stability
of the previously prepared PAH-episulfides,5 the rela-
tively more electrophilic episulfoxide 4 (compared to
sulfide 3) may result in a hydrolysis rate similar to that
of the corresponding epoxide. This has bearing on the
formation of the corresponding DNA adducts.
Polycyclic arene epoxides have been established as the
primary metabolites of the carcinogenic polycyclic aro-
matic hydrocarbons (PAHs),1-3 leading, eventually, to the
ultimate carcinogenic PAH-diol epoxides (DEs). The first
sulfur analogues 1a ,b and 2c,d of the parent epoxides
and DEs (saturated A-ring) have been just recently
prepared,4,5 while the syntheses of selected polycyclic
arene episulfides have been previously attempted6 and
their thermodynamic stability theoretically studied.6,7
These episulfides were found to be, thermodynamically,
significantly less stable than the corresponding epoxides
toward elimination of sulfur and oxygen, respectively.
Their relative stability can be deduced from the degree
of the aromatic character of the rings that do not carry
the heteroatom.7
Resu lts a n d Discu ssion
Our synthesis of episulfide 3 is given in Scheme 1. The
preparation of the key 1,2,3,4-tetrahydrophenanthrene-
3,4-oxide (8)10 was first achieved by means of J erina’s
procedure (using for the hydrolysis step an ion-exchange
resin in a hydroxy anion form).11 Thus, a 60% yield of 8
was obtained from the racemic 3-bromo-1,2,3,4-tetrahy-
dro-4-hydroxyphenanthrene (7). Since benzylic epoxides
can undergo both acid- and base-catalyzed solvolysis to
the corresponding hydroxy compounds,5,12,13 various bases,
i.e., DBN, sodium methoxide, sodium hydroxide, sodium
carbonate, and sodium bicarbonate in different solvent
Polycyclic aromatic hydrocarbon episulfides are highly
interesting. On one hand, they maintain the basic
requirement of the PAH carcinogenicity8 and the par-
ticular steric, electronic, and electrophilic requirements
(1) Harvey, R. G. Polycyclic Aromatic Hydrocarbons: Chemistry and
Carcinogenicity; Cambridge University Press: Cambridge, England,
1991.
(2) Thakker, D. R.; Yagi, H.; Levin, W.; Wood, A. W.; Conney, A.
H.; J erina, D. M. Bioact. Foreign Comp. 1985, 7, 177.
(3) Harvey, R. G.; Geacintov, N. E. Acc. Chem. Res. 1988, 21, 66.
(4) Shalom, Y.; Kogan, V.; Badriah, Y.; Harvey, R. G.; Blum, J . J
Heterocycl. Chem. 1996, 33, 53.
(9) Whalen, D. L.; Islam, N. B.; Gupta, S. C.; Sayer, J . M.; J erina,
D. M. In PAH 11: Measurements, Means and Metabolism; Battelle
Press: Columbus, OH; 1991.
(5) Yagi, H.; Vepachedu, S.; Sayer, J . M.; Chang, R.; Cui, X. X.;
Zoller, U.; J erina, D. M. Polycyclic Aromat. Compd. 1999, 17, 85.
(6) Zoller, U.; Shakkour, E.; Pastersky, I. Phosphorus, Sulfur Silicon
1994, 95-96, 453.
(10) For reviews on the synthesis of PAH arene oxides, see: Harvey,
R. G. Synthesis 1986, 605. However, no spectral characterization of 8
is available in the literature.
(11) Boyd, D. R.; Greene, R. M. E.; Neill, J . D.; Stubbs, M. E.; Yagi,
H.; J erina, D. M. J . Chem. Soc., Perkin Trans. 1 1981, 1477.
(12) Lin, B.; Islam, N.; Friedman, S.; Yagi, H.; J erina, D. M.; Whalen,
D. L. J . Am. Chem. Soc. 1998, 120, 4327.
(7) Zoller, U.; Shakkour, E.; Pastersky, I.; Sklenak, S.; Apeloig, Y.
Tetrahedron 1998, 54, 14283.
(8) Dipple, A.; Moschel, R. C.; Bigger, C. A. H. In Chemical
Carcinogens, 2nd ed.; Searle, C. E., Ed.; ACS Monograph 182, American
Chemical Society: Washington, DC, 1984; Vol. 1, pp 41-163.
(13) Blumenstein, J .; Ukachukwu, V. C.; Mohan, R. S.; Whalen, D.
L. J . Am. Chem. Soc. 1993, 58, 924.
10.1021/jo000086e CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/21/2000

8084 J . Org. Chem., Vol. 65, No. 23, 2000
Notes
systems, were used to optimize the transformation from
7 to 8. We have found that sodium carbonate/water/THF
was the best system for this purpose, giving the highest
yield (83%) of epoxide 8. Although many polycyclic arene
epoxides were prepared via direct epoxidation of the
corresponding alkenes with m-CPBA,14-18 the direct
epoxidation of 6 with this reagent failed, whereas using
methyl (trifluromethyl) dioxirane19 afforded 8 in too low
yield to facilitate purification by recrystallization. The
epoxidation of 6 using the DCC/H2O2 system20 also did
not afford 8.
In our hands, the direct preparation of the bromo-
hydrin 7 from 6 using NBS proved to be the method of
choice (92% yield), compared to an initial bromination
of 6 to give 3,4-dibromo-1,2,3,4-tetrahydrophenanthrene
(9), followed by the hydrolysis of the latter to afford 7 in
72% yield (i.e., from 6 to 7 via 9).21
acid and BF3‚Et2O. We have found that excess of DMTF
or 3-methylbenzothiazole-2-thione (10 equiv) could trans-
form 8 and 10 into the corresponding episulfides 3 and
5, respectively, at low temperature in the absence of any
catalyst. At these same temperatures, the same trans-
formations can also be achieved using only 2 equiv of
DMTF or 3-methylbenzothiazole-2-thione in the presence
1
of catalytic BF3‚Et2O. In an H NMR spectroscopic study
of the transformation of 10 to 5 using DMTF as the sulfur
transfer agent, neither the resulting DMF nor the start-
ing 10 (4.55 ppm, s) showed any peaks at the 3.4-4.0
ppm range. The new peaks at 3.51 and 3.67 ppm were
assigned to the oxothiolane intermediate (12).
We propose the following mechanism (eq 2) for the
transformation of epoxide 10 to the episulfide 5, which
On the basis of our previously developed synthetic
methodology for an efficient highly stereoselective con-
version of epoxides to the corresponding episulfides in
the PAH series,5 8 and 10 have been treated with DMTF
without any catalyst at -78 to 0 °C to afford the
episulfide 3 (in 80% isolated yield) and the decomposition
products of episulfide 5, respectively. Significantly, the
1H NMR (CDCl3) of H3 and H4 in 3 (3.77 and 4.64, J 3,4
)
6.6 Hz) is in full accord with that reported for the
corresponding H3 and H4 in 1a (3.92 and 4.98 J 3,4 ) 6.5
Hz).4 It was previously found experimentally4,5 and
theoretically, via molecular orbital calculations,6,7 that
K-region PAH-episulfides are, thermodynamically, more
stable toward sulfur extrusion than their bay-region
isomers. This, together with the relatively higher ther-
modynamic stability of the episulfides with the higher
aromatic character of the ring system,7 is in accord with
the instability of 3. The thus far elusive 54 was previously
detected by us via 1H NMR spectroscopy (CDCl3, 3.98,
s)6,7 in accordance with the previously reported data for
the corresponding episulfide ring protons in 1b (3.92 and
4.44).4 However, it is too unstable to be isolated. Instead,
its decomposition products, elemental sulfur (72%) and
phenanthrene (11) (74%), respectively, were isolated (eq
1).
is in accord with the accepted mechanism for transforma-
tions of epoxides to the corresponding episulfides induced
by sulfur transfer agents.24
Oxidation of episulfide 3 with m-CPBA afforded the
corresponding episulfoxide 4, which lost SO very fast at
room temperature to give 6, so that the isolation of 4 was
not possible. However, the IR spectrum of the reaction
mixture showed a strong absorption at 1065 cm-1, which
is characteristic for the sulfur-oxygen (SdO) stretching
frequency of thiirane oxides.25 The EI-MS of 4 showed a
base peak of m/z 180 (M+ - SO). Regardless whether the
sulfoxide group was eliminated following an initial
ionization by the electron impact on 4 or that thermal
decomposition is responsible for this elimination,25 the
base peak of m/z 180 and the expected absence of peak
at m/z 212 strongly suggest that the expected episulfoxide
4 has been formed. The formation of the latter is further
corroborated via the low-temperature NMR studies of 4
in which H4 and C3 were detected at 6.07 and 53.3 ppm,
respectively. To our best knowledge, 4 is the first detected
PAH benzylic episulfoxide.
These results point to a good yield for the transforma-
tion of 10 to 5 while the ∼1:1 sulfur:phenanthrene ratio
is in accord with the intermediacy of 5. Traditionally,
conversions of oxiranes to the corresponding thiiranes by
sulfur transfer agents such as DMTF22 and 3-methyl-
benzothiazole-2-thione23 were achieved only in the pres-
ence of an acid or Lewis-type catalyst, e.g., trifluoroacetic
We are currently further exploring the possibilities of
preparing both benzylic polycyclic aromatic hydrocarbon
episulfide and episulfoxide systems that are more ther-
modynamically stable than 5 and 4 to facilitate study of
their chemistry and biological activity.
(14) Yagi, H.; Thakker, D. R.; Hernandez, O.; Koreeda, M.; J erina,
D. M. J . Am. Chem. Soc. 1977, 99, 1604.
(15) Yagi, H.; Hernandez, O.; J erina, D. M. J . Am. Chem. Soc. 1975,
97, 6881.
(16) Wu, Y.-S.; Lai, J .-S.; Fu, P. P. J . Org. Chem. 1993, 58, 7283.
(17) Zhang, F.-J .; Harvey, R. G. J . Org. Chem. 1998, 63, 1168.
(18) Zhang, F.-J .; Harvey, R. G. J . Org. Chem. 1998, 63, 2771.
(19) Yang, D.; Wong, M.-K.; Yip, Y.-C. J . Org. Chem. 1995, 60, 3887.
(20) Murray, R. W.; Lyanar, K. J . Org. Chem. 1998, 63, 1730.
(21) Yagi, H.; J erina, D. M. J . Am. Chem. Soc. 1975, 97, 3185.
(22) Takido, T.; Kobayashi, Y.; Itabashi, K. Synthesis 1986, 779.
(23) Calo, V.; Lopez, L.; Marchese, L.; Pesce, G. J . Chem. Soc., Chem.
Commun. 1975, 621.
(24) Zoller, U. In Small Ring Heterocycles; Hassner, A., Ed.; Inter-
science: New York, 1983; pp 340-353.
(25) Zoller, U. In Synthesis of Sulphones, Sulphoxides and Cyclic
Sulphides; Patai, S., Rappoport, Z., Eds.; J ohn Wiley & Sons: Chich-
ester, 1994; pp 403-408.

Notes
J . Org. Chem., Vol. 65, No. 23, 2000 8085
stored in the freezer at - 75 °C. IR (CH2Cl2) 2963, 1530, 665
cm-1; 1H NMR (CDCl3, rt) δ 2.24 (m, 1H, H2), 2.52 (m, 1H, H2′),
2.69 (dd, 1H, H1), 2.91 (m, 1H, H1′, J 1,2 ) 5.9 Hz), 3.77 (m, 1H,
H3, J 2,3 ) 3.3 Hz), 4.64 (d, 1H, H4, J 3,4 ) 6.6 Hz), 7.16 (d, 1H,
H10, J 9,10 ) 8.3 Hz), 7.44 (m, 1H, H7), 7.56 (m, 1H, H6), 7.65 (d,
1H, H9), 7.80 (d, 1H, H8), 8.25 (d, 1H, H5, J 5,6 ) 8.6 Hz); HRMS
calcd for C14H12S 212.0660 (M+), found 212.0626; calcd for (M+-
S) 180.0939, found 180.0932 (base peak).
Exp er im en ta l Section
Gen er a l. Melting points were recorded on a Buchi 510
apparatus and are uncorrected. 1H and 13C NMR spectra were
recorded at 200 and 50.33 MHz, respectively. Mass spectra were
determined at an ionization voltage of 70 eV. Column chroma-
tography was performed with silica gel (70-230 mesh). Ether,
THF, and toluene were distilled over sodium; 10 was prepared
according to the literature procedure.26 All commercially avail-
able reagents were used directly as obtained.
Syn th esis a n d Detection of 1,2,3,4-Tetr a h yd r op h en a n -
th r en e-3,4-ep isu lfoxid e (4). Into a solution of 3 (190 mg, 0.895
mmol) in dichloromethane (7 mL) was added dropwise during 5
min at -65 °C m-CPBA (185 mg, 1.07 mmol) in dichloromethane
(10 mL). Stirring was continued for 40 min, and the temperature
1,2-Dih yd r op h en a n th r en e (6). By a modified procedure,21
a mixture of 1-hydroxy-1,2,3,4-tetrahydrophenanthrene (4.95 g,
25 mmol), p-toluenesulfonic acid monohydrate (0.7 g, 3.7 mmol),
and benzene (140 mL) was refluxed for 45 min. After cooling to
room temperature, the reaction mixture was washed with water,
3% sodium carbonate, and then water again and dried (Na2SO4),
and the solvent was evaporated to leave 6 (4.53 g, 100%) as a
colorless oil that solidified at about 0 °C and had a blue
fluorescence.
3-Br om o-1,2,3,4-tetr a h yd r o-4-h yd r oxyp h en a n th r en e (7).
A 50 mL flask was charged with 6 (1.56 g, 8.65 mmol), sodium
acetate (0.66 g), water (8 mL), and DMSO (40 mL) and cooled
to 0 °C. NBS (3.05 g, 17.1 mmol) was added during 3 min into
the above solution with vigorous stirring. Stirring was continued
at 0 °C for 1 h. Ethyl acetate (180 mL) was then added followed
by water (380 mL). The organic layer was washed several times
with water. The solvent was then removed to give a slightly
yellow solid. Recrystallization from a mixture of hexane (16 mL)/
ethyl acetate (8 mL) afforded 7 (2.2 g, 92%) as a white solid, mp
156-157 °C (lit.21 mp 157-158 °C).
1,2,3,4-Tetr a h yd r op h en a n th r en e-3,4-oxid e (8). A mixture
of 7 (132 mg, 0.476 mmol), sodium carbonate monohydrate (344
mg, 2.77 mmol), water (5 mL), and THF (17 mL) was stirred at
room temperature for 2 days under N2. The THF was removed
in vacuo, and the residue was extracted by ether. The organic
layer was washed several times with water. The solvent was
removed to give a white solid. Recrystallization from hexane
gave racemic 8 (77 mg, 83%) as colorless prisms, mp 58-60 °C:
1H NMR (CD2Cl2) δ 1.84 (m, 1H, H2), 2.48 (m, 1H, H2′), 2.76 (m,
2H, H1), 3.88 (m, 1H, H3), 4.71 (d, 1H, H4), 7.29 (d, 1H, H10, J 9,10
) 8.3 Hz), 7.57 (m, 2H, H6, H7), 7.79 (d, 1H, H9), 7.89 (d, 1H,
H8), 8.33 (d, 1H, H5, J 5,6 ) 8.4 Hz); 13C NMR (CD2Cl2) δ 20.90
(C2), 24.89 (C1), 47.05 (C3), 55.53 (C4), 121-134.69 (C5-C12); MS
m/z (EI) 196 (M+), 180 (M+ - O) (base peak), CI (Isobutane)
197.1 (MH+), 181.2 (MH+ - O).
1,2,3,4-Tetr a h yd r op h en a n th r en e-3,4-ep isu lfid e (3). Into
a solution of 8 (221 mg, 1.12 mmol) in dichloromethane (7 mL)
was syringed DMTF (190 µL, 2.23 mmol) at -65 °C followed by
a catalytic amount (2 µL) of BF3‚Et2O. The mixture was stirred
until the entire oxide was consumed (4 h, as indicated by TLC
on silica gel with a 5:1:0.05 mixture of hexane/ethyl acetate/
triethylamine as eluent). The solvent was then evaporated under
reduced pressure at -20 °C, and the residue was chromato-
graphed through a short silica gel column with a 10:1:0.05
mixture of hexane/ethyl acetate/triethylamine as quickly as
possible. The product obtained, episufide 3, is a colorless solid
(190 mg, 80%). It completely lost elemental sulfur when left to
stand at room temperature for a day. It did not deteriorate when
o
was allowed to rise to - 20 C. The consumption of the peracid
and 4 was checked via a moist iodine-starch paper and TLC
(developed with a 10:1:0.05 mixture of hexane/ethyl acetate/
triethylamine, Rf for 6 ) 0.9, Rf for 3 ) 0.5, Rf for 4 ) 0.3). The
reaction mixture was washed with cold 5% sodium carbonate,
and the solvent was removed in vacuo at - 20 °C to give a white
solid, the IR and MS of which was immediately taken. IR (CH2-
Cl2) 1065 cm-1; MS m/z 180 (M+ - SO). The sulfoxide 4 lost SO
quickly to give the blue fluorescent 6 at room temperature. It
slowly lost SO even when stored in the freezer at -75 °C and
could not be detected by IR (1065 cm-1) when stored for more
than a month at this temperature.
A solution of epoxide 8 (11 mg, 0.056 mmol) in CD2Cl2 (0.5
mL) in an NMR tube was cooled to -40 °C in an NMR
instrument. After 1H and 13C NMR were recorded, the tube was
further cooled to -50 °C and DMTF (9.5 µL, 0.11 mmol) followed
by BF3‚Et2O (1 µL) were syringed into it at this temperature.
The mixture was then monitored by 1H NMR at -40 °C. The
entire 8 was consumed after 2 h. Episulfide 3: 1H NMR δ 4.52
(1H, H4); 13C NMR δ 21.88 (C2), 24.02 (C1), 42.07 (C3), 69.00 (C4).
m-CPBA (29 mg, 0.166 mmol) was then added portionwise at
-40 °C ,and the mixture was allowed to warm to -30 °C to avoid
solidification of the solution. Mixture: 1H NMR δ 6.07 (m, H4 of
the episulfoxide 4); DEPT 13C NMR δ 53.3 (C3 of the episulfoxide
4).
Syn th esis a n d 1H NMR Stu d y of P h en a n th r en e-9,10-
ep isu lfid e (5). Epoxide 10 (10 mg, 0.0515 mmol) and CDCl3
(0.4 mL) were loaded into an NMR tube. The solution was
1
monitored by H NMR spectroscopy at -55 °C before and after
the addition of DMTF (60 µL, 0.70 mmol).
To a 50 mL flask was added 10 (130 mg, 0.67 mmol) together
with dichloromethane (40 mL). The solution was cooled to -78
°C. DMTF (1 mL, 11.7 mmol) was then syringed into the flask,
and the stirring was continued for an additional 5 min, allowing
the temperature to rise to 0 °C. The solvent was removed in
vacuo, and water (8 mL) was added to extract the residue (yellow
oil). Removal of the water was followed by further washing of
the resulting yellow solid with water. Recrystallization from
ethanol (7 mL) afforded 15 mg (0.48 mmol, 72%) of sulfur as a
yellow solid, which was identical in its physical and chemical
properties with an authentic sample of elemental sulfur. Water
(8 mL) was then added into the mother ethanolic solution to
deposit the phenanthrene (88 mg, 0.50 mmol, 75%) as an off
white solid, which was identical in all respects (mp, mixed mp,
IR, TLC) with an authentic sample of phenanthrene.
(26) Harvey, R. G.; Cortez, C. Org. Synth., Collect. Vol. 6, 1988, 887.
J O000086E