Efficient synthesis of aryl methyl sulfide derivatives using (methylthio)trimethylsilane as methylthiolation reagent

Article abstract of DOI:10.1080/00397910903531664

The synthesis of various aryl methyl sulfides has been achieved by treatment of nitroarenes with a combination of (methylthio)trimethylsilane and cesium carbonate in dimethylsulfoxide. This reaction gives access to aryl methyl sulfide derivatives in high yields. Copyright

Full text of DOI:10.1080/00397910903531664

Synthetic Communications1, 40: 3691–3698, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903531664
EFFICIENT SYNTHESIS OF ARYL METHYL SULFIDE
DERIVATIVES USING
(METHYLTHIO)TRIMETHYLSILANE AS
METHYLTHIOLATION REAGENT
Qi Qiao, Romyr Dominique, Achyutharao Sidduri,
Jianping Lou, and Robert A. Goodnow, Jr.
Roche Research Center, Hoffmann-La Roche Inc., Nutley, New Jersey, USA
The synthesis of various aryl methyl sulfides has been achieved by treatment of nitroarenes
with a combination of (methylthio)trimethylsilane and cesium carbonate in dimethylsulfox-
ide. This reaction gives access to aryl methyl sulfide derivatives in high yields.
Keywords: Aryl methyl sulfides; methylthiolation; (methylthio)trimethylsilane; nitroarenes; nucleophilic
displacement
Aryl methyl sulfides and aryl methyl sulfones are found in many pharmaceutically
important molecules.[1] Consequently, they are frequently incorporated as building
blocks in structure-activity relationship (SAR) development of medicinal entities.
Several synthetic methods have been reported for the formation of aryl-sulfur bonds.
The most common methods include lithium exchange of aryl halides and subsequent
quenching with an alkyldisulfide or elemental sulfur,[2] metal-catalyzed (Cu, Ni, Pd)
cross-coupling reactions of aryl halides and triflates with sulfides or sulfinic acid
salts[3] and substitution reactions of thiolate anions on activated aryl halides.[4]
However, these reactions are often not compatible with substrates having sensitive
functional groups.
During the course of our SAR exploration, we were interested in preparing aryl
methyl sulfide and aryl methylsulfone derivatives. Oshima et al.[5] recently reported
the nucleophilic aromatic substitution reaction (SNAr) of nitroarenes bearing strong
electron-withdrawing groups (EWG) with alkyl and aryl thiols under the mediation
of cesium carbonate. However, the use of methanethiol has not been reported to
date, perhaps due to practical handling considerations (e.g., methanethiol is a toxic,
malodorous gas at room temperature). We envisioned that such a method could be
adapted for the preparation of various aryl methyl sulfide derivatives if a non-
volatile chemical equivalent of methanethiol could be identified. We anticipated that
Received August 17, 2009.
Address correspondence to Dr. Romyr Dominique, Roche Research Center, 340 Kingsland Street,
Nutley, NJ 07110, USA. E-mail: romyr.dominique@roche.com
3691

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Q. QIAO ET AL.
Scheme 1. General method for the preparation of aryl methyl sulfide derivatives.
commercially available (methylthio)trimethylsilane (TMSSMe)[6] would generate
methanethiolate in situ when treated with a base (Scheme 1).
TMSSMe has been previously reported in literature as a reagent for thioketa-
lization[7] reactions, methyl ether cleavage,[8a] preparation of thioesters,[8b] prep-
aration of methylthio-substituted sugars[8c] and also for the preparation of aryl
methyl sulfide by the reaction with arenediazonium tetrafluoroborates.[9] In the last
case, this methodology was reported only with arenediazonium salts thus it would be
advantageous to be able to perform the same type of transformation by direct
replacement of aromatic nitro groups which are known to be common precursors
to arenediazonium salts through aniline derivatives, thereby, reducing the number
of steps in a synthetic scheme. To the best of our knowledge, TMSSMe has never
been reported as methylthiolation reagent for the nucleophilic displacement of aro-
matic nitro groups. Herein, we report an efficient and convenient method which uses
the combination of TMSSMe and Cs2CO3 in DMSO as a methylthiolation reagent
for the preparation of aryl methyl sulfide derivatives; the scope of the reaction is also
described.
In order to investigate the utility of this new methodology, we set out to com-
pare the substitution reactions of 1-iodo-3,5-dinitrobenzene with sodium thiometh-
oxide (NaSMe), which has often been reported to perform the same type of
nucleophilic displacement on nitroarenes.[10] However, in our hands, the reaction
with NaSMe gave unsatisfactory results, resulting in decomposition or lower yields
depending on the amount of NaSMe used. On the other hand, performing the same
reaction with TMSSMe gave an excellent yield when 1.4 equiv. of TMSSMe and 1.6
equiv. of cesium carbonate were used. Under these conditions, 1-iodo-3-methylsulfa-
nyl-5-nitro-benzene (2) was obtained in 97% yield (Scheme 2).
Once the best conditions were established, a variety of aryl methyl sulfide deri-
vatives were synthesized in good to excellent yields from commercially available
nitroarenes. The mild reaction conditions are compatible with diverse functional
groups such as esters, cyanides and methyl ketones as shown in Table 1 (e.g., entries
Scheme 2. a) NaSMe, DMSO, r.t., 16 h; b) TMSSMe, Cs2CO3, DMSO, r.t., 16 h.

ARYL METHYL SULFIDE DERIVATIVES
3693
Table 1. Results for the reaction of nitroarenes with TMSSMe=Cs2CO3
(Continued )

3694
Q. QIAO ET AL.
Table 1. Continued
1, 2, 3, and 14). As anticipated, it was also found that the best yields were obtained
for substrates containing an electron-withdrawing group in the ortho or para
position on nitroarenes. The presence of an electron-withdrawing group at those
positions activates the nitro group and increase its propensity for displacement.
The reaction of 1,2-dinitrobenzene proceeds almost quantitatively (e.g., entry 11).
All other electron-withdrawing substituted phenyl substrates such as those para-
substituted with esters, ketones, trifluoromethyl and nitro groups underwent
nucleophilic displacement with good to excellent yields (Table 1, entries 1–5). With
4-nitrobiphenyl no reaction was observed, probably due to the fact that the phenyl
moiety did not activate the nitro group sufficiently for the nucleophilic displace-
ment to occur (entry 16). All para-halonitrobenzenes provided the unanticipated
para-methylthionitrobenzenes (7) where the halogen atom was displaced by the

ARYL METHYL SULFIDE DERIVATIVES
3695
methanethiolate anion while leaving the nitro group in place (e.g., entries 6–9). The
identification of (7) was also confirmed by observing that the reaction with 1,4-dini-
trobenzene and TMSSMe afforded an identical product. We rationalized that the
displacement of the halogen substituent could perhaps be favored since the halogen
substituent was activated by the stronger electron-withdrawing capacity and charge
stabilizing effect of the nitro group, thus displaced exclusively by TMSSMe.
To expand the scope of this methodology, we explored the nucleophilic dis-
placement of the nitro group on disubstitued nitroarenes. It is worth to mention that
the presence of an ortho-methoxy group did not impede the replacement of the acti-
vated iodide located in the para position with respect to the nitro group (entry 10).
All meta substituted nitrobenzenes proceeded in poor yield under the same
conditions (Table 1, entries 12–14). However, the disubstituted nitroarenes in Entry
15 and the example shown in Scheme 2 produced the desired aryl methyl sulfides in
high yields. In those examples, the halogen is located on the meta-position and is not
activated, and only the nitro group is displaced, giving access to interesting disubsti-
tuted aryl methyl sulfide derivatives.At this time, the mechanism of this reaction is
not fully understood. Although, we could believe that the reaction proceeds through
a nucleophilic aromatic substitution,[5] some of our results such as the formation of
compound 2 might be better rationalized by radical anion chemistry through a single
electron transer (SET) mechanism. Further work would be needed to investigate the
mechanism of this reaction.
In summary, the combination of (methylthio)trimethylsilane (TMSSMe) and
Cs2CO3 in DMSO at room temperature was found to be efficient as a methylthiola-
tion reagent in accomplishing the nucleophilic displacement of aromatic nitro
groups. High chemical yields, combined with operationally convenient conditions,
render this method practically useful for the preparation of aryl methyl sulfide
derivatives.
EXPERIMENTAL
All chemicals and solvents were of commercial quality and used without
further purification. Compounds were characterized either by 1H-NMR using a
Varian Inova 400 MHz NMR Spectrometer or a Varian Mercury 300 MHz NMR
Spectrometer as well as by high resolution mass spectrometry using a Bruker Apex-II
high-resolution 4.7 T FT-Mass Spectrometer. All products were purified by flash-
column chromatography using pre-packed silica gel columns (RediSep) eluted with
a CombiFlash system.
Representative Procedure for the Synthesis of Aryl Methyl Sulfides:
Synthesis of 1-Iodo-3-methylsulfanyl-5-nitro-benzene (2)
To a solution of 1-iodo-3,5-dinitrobenzene (891 mg, 3.03 mmol) in DMSO
(5 ml) was added Cs2CO3 (1.58 g, 4.84 mmol) and the mixture was stirred for 2 min.
TMSSMe (0.6 ml, 4.23 mmol) was added to give a dark purple solution. The reaction
mixture was then stirred at room temperature overnight. The reaction mixture was
diluted with water (25 ml) and extracted with EtOAc (50 ml). The organic layer

3696
Q. QIAO ET AL.
was washed with brine, dried with anhydrous sodium sulfate, filtered, and concen-
trated under reduced pressure to provide a solid as the crude product. Purification
using flash column chromatography (10% EtOAc=Hexanes) afforded the compound
1
as a yellow powder (868 mg, 97%). H NMR (400 MHz, CDCl3) d: 8.27 (1H, s, Ph),
7.99 (1H, s, Ph), 7.81 (1H, s, Ph), 2.54 (3H, s, CH3). 13C NMR (100 MHz, CDCl3) d:
148.5, 143.6, 139.5, 128.2, 119.4, 93.5, 15.4. HR-MS m=z calcd. for C7H6NO2SI:
294.9164; found: 294.9165.
4-Methylsulfanyl-benzoic Acid Methyl Ester (3)
1H NMR (400 MHz, DMSO) d: 7.85 (2H, m, Ph), 7.34 (2H, m, Ph), 3.81 (3H, s,
OCH3), 2.51 (3H, s, SCH3). 13C NMR (100 MHz, CDCl3) d: 166.6, 145.3, 129.7,
126.1, 124.7, 52.0, 14.8. HR-MS m=z calcd. For C9H10O2S: 182.0402; found:
182.0402.
1-Methylsulfanyl-4-trifluoromethyl-benzene (6)
1H NMR (400 MHz, CDCl3) d: 7.56 (2H, d, Ph), 7.30 (2H, d, Ph), 2.54 (3H, s,
CH3). 13C NMR (100 MHz, CDCl3) d: 143.7, 126.9, 126.5, 125.5, 122.9, 15.1. HR-EI
m=z calcd. for C8H7SF3: 192.0221; found: 192.0221.
2-Methoxy-1-methylsulfanyl-4-nitro-benzene (8)
1H NMR (400 MHz, CDCl3) d: 7.88 (1H, d, Ph), 7.65 (1H, s, Ph), 7.11 (1H, d,
Ph); 4.12 (3H, s, OMe); 2.51 (3H, s, CH3). 13C NMR (100 MHz, CDCl3) d: 155.0,
146.2; 138.4; 122.3; 116.5; 104.8; 56.3; 15.6. HR-EI m=z calcd. for C8H9NO3S:
199.0306; found: 199.0303.
1-Methylsulfanyl-2-nitro-benzene (9)
1H NMR (400 MHz, CDCl3) d: 8.22 (1H, d, Ph), 7.60 (1H, t, Ph), 7.39 (1H, d,
Ph), 7.23 (1H, t, Ph), 2.54 (3H, s, CH3). 13C NMR (100 MHz, CDCl3) d: 145.3,
139.2, 133.6, 126.1, 125.5, 124.1, 16.0. HR-EI m=z calcd. for C7H7NO2S:
169.0198; found: 169.0197.
1-Methoxy-3-methylsulfanyl-5-nitro-benzene (11)
1H NMR (300 MHz, CDCl3) d: 7.66 (1H, s, Ph), 7.47 (1H, s, Ph), 7.05 (1H, s,
Ph), 3.88 (s, 3H, OMe), 2.54 (s, 3H, CH3). HR-EI m=z calcd. for C8H9NO3S:
199.0294; found: 199.0303.
3-Methylsulfanyl-5-nitro-benzoic Acid Methyl Ester (12)
1H NMR (300 MHz, CDCl3) d: 8.56 (1H, s, Ph), 8.20 (1H, s, Ph), 8.17 (1H, s,
Ph), 3.98 (s, 3H, OMe), 2.60 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3) d: 164.6,
148.5, 142.6, 131.9, 131.8, 123.6, 120.3, 52.9, 15.4. HR-MS m=z calcd. for
C9H9NO4S: 227.0252; found: 227.0252.

ARYL METHYL SULFIDE DERIVATIVES
3697
ACKNOWLEDGMENTS
The authors are grateful to Paul Gillespie and Jeff Tilley for critical reading of
this manuscript.
REFERENCES
1. (a) The World Drug Index contains over 300 reports of aryl methyl sulfides and aryl
methyl sulfones; (b) Jarvest, R. L.; Berge, J. M.; Brown, M. J.; Brown, P.; Elder, J. S.;
Forrest, A. K.; Houge-Frydrych, C. S. V.; O’Hanlon, P. J.; McNair, D. J.; Rittenhouse,
S.; Sheppard, R. J. Optimisation of aryl substitution leading to potent methionyl tRNA
synthetase inhibitors with excellent gram-Positive antibacterial activity. Bioorg. Med.
Chem. Lett. 2003, 13, 665–668; (c) Conlon, D. A.; Drahus-Paone, A.; Ho, G.-J.; Pipik,
B.; Helmy, R.; McNamara, J. M.; Shi, Y.-J.; Williams, J. M.; Macdonald, D.; Descheˆ nes,
D.; Gallant, M.; Mastracchio, A.; Roy, B.; Scheigetz, J. Process Development and
Large-Scale Synthesis of a PDE4 Inhibitor. Org. Process Res. Dev. 2006, 10, 36–45; (d)
Lu, W.; Chen, P.; Lin, G. New stereoselective synthesis of thiamphenicol and florfenicol
from enantiomerically pure cyanohydrin: A chemo-enzymatic approach. Tetrahedron
2008, 64, 7822–7827; (e) Caturla, F.; Amat, M.; Reinoso, R. F.; Cordoba, M.; Warrellow,
´
G. Racemic and chiral sulfoxides as potential prodrugs of the COX-2 inhibitors Vioxx and
Arcoxia. Bioorg. Med. Chem. Lett. 2006, 16, 3209–3212; (f) Morrow, R. J.; Millership, J.
S.; Collier, P. S. Facile syntheses of the three major metabolites of thioridazine. Helv.
Chim. Acta 2005, 88, 962–967; (g) Vernon, M. W.; Heel, R. C.; Brogden, R. N. Enoxi-
mone. A review of its pharmacological properties and therapeutic potential. Drugs
1991, 42, 997–1017.
2. (a) Cremlyn, R. J. An Introduction to Organosulfur Chemistry; Wiley: New York, 1996; (b)
Seebach, D.; Neumann, H. Bromine-lithium exchange in vinyl and aryl bromides with
tert-butylithium. Ring enlargement via dibromocarbene adducts. Chem. Ber., 1974, 107,
847–853; (c) Perlow, D. S.; Kuo, M. S. Moritz, H. M.; Wai, J. S. Egbertson, M.S. Practical
synthesis of 4-fluoro-2-(methylthio)benzylamine and the corresponding sulfone and sulfo-
namide. Synth. Commun. 2007, 37, 1887–1897; (d) Ham, J.; Yang, I.; Kang, H. A facile
one-pot synthesis of alkyl aryl sulfides from aryl bromides. J. Org. Chem. 2004, 69,
3236–3239.
3. (a) Migita, T.; Shimizu, T.; Asami, Y.; Shiobara, J.; Kato, Y.; Kosugi, M. The palladium
catalyzed nucleophilic substitution of aryl halides by thiolate anions. Bull. Chem. Soc. Jpn.
1980, 53, 1385–1389; (b) Kondo, T.; Mitsudo, T. Metal-catalyzed carbon-sulfur bond
formation. Chem. Rev. 2000, 100, 3205–3220; (c) Zheng, N.; McWilliams, J. C.; Fleitz,
F. J.; Armstrong III, J. D.; Volante, R. P. Palladium-catalyzed synthesis of aryl sulfides
from aryl triflates. J. Org. Chem. 1998, 63, 9606–9607; (d) Kwong, F. Y.; Buchwald, S.
L. A general, efficient, and inexpensive catalyst system for the coupling of aryl iodides
and thiols. Org. Lett. 2002, 4, 3517–3520; (e) Itoh, T.; Mase, T.
A general
palladium-catalyzed coupling of aryl bromides=triflates and thiols. Org. Lett. 2004, 6,
4587–4590; (f) Fernandez-Rodriguez, M. A.; Shen, Q.; Hartwig, J. F. A general and
long-lived catalyst for the palladium-catalyzed coupling of aryl halides with thiols.
J. Am. Chem. Soc. 2006, 128, 2180–2181; (g) Baskin, J. M.; Wang, Z. An efficient copper
catalyst for the formation of sulfones from sulfinic acid salts and aryl iodides. Org. Lett.
2002, 4, 4423–4425.
4. (a) Montanari, S.; Paradisi, C.; Scorrano, G. Influence of ion pairing, steric effects, and
other specific interactions on the reactivity of thioanions with chloronitrobenzenes.
Nucleophilic aromatic substitution vs. reduction. J. Org. Chem. 1991, 56, 4274–4279;

3698
Q. QIAO ET AL.
(b) Capkova, K.; Yoneda, Y.; Dickerson, T. J.; Janda, K. D. Synthesis and structure-
activity relationships of second-generation hydroxamate botulinum neurotoxin A pro-
tease inhibitors. Bioorg. Med. Chem. Lett. 2007, 17, 6463–6466; (c) Johnson, N. W.;
Semones, M.; Adams, J. L.; Hansbury, M.; Winkler, J. Optimization of triarylimidazoles
for Tie2: Influence of conformation on potency. Bioorg. Med. Chem. Lett. 2007, 17,
5514–5517.
5. Kondoh, A.; Yorimitsu, H.; Oshima, K. Nucleophilic aromatic substitution reaction of
nitroarenes with alkyl- or arylthio groups in dimethyl sulfoxide by means of cesium
carbonate. Tetrahedron 2006, 62, 2357–2360.
6. Groutas, W. C.; Felker, D. Synthetic applications of cyanotrimethylsilane, iodotrimethyl-
silane, azidotrimethylsilane, and methylthiotrimethylsilane. Synthesis. 1980, 861–868.
7. (a) Evans, D. A.; Truesdale, L. K.; Grimm, K. G.; Nesbitt, S. L. Thiosilanes, a promising
class of reagents for selective carbonyl protection. J. Am. Chem. Soc. 1977, 99, 5009–5017;
(b) Mantus, E. K.; Clardy, J. The synthesis of dithyreanitrile. Tetrahedron Lett. 1993, 34,
1085–1086.
8. (a) Hanessian, S.; Guindon, Y. Cleavage of methyl and benzyl ethers with thiotrimethyl-
silanes. Tetrahedron Lett. 1980, 21, 2305–2308; (b) Howell, G. P.; Fletcher, S. P.; Geurts,
K.; ter Horst, B.; Feringa, B. L. Catalytic Asymmetric Synthesis of Acyclic Arrays by
Tandem 1,4-Addition-Aldol Reactions. J. Am. Chem. Soc. 2006, 128, 14977–14985; (c)
Kanemitsu, T.; Wong, C.-H.; Kanie, O. Solid-Phase Synthesis of Oligosaccharides and
On-Resin Quantitative Monitoring Using Gated Decoupling 13C NMR. J. Am. Chem.
Soc. 2002, 124, 3591–3599.
9. Prakash, G. K. S.; Hoole, D.; Ha, D. S. Wilkinson, J.; Olah, G. A. Convenient prep-
aration of aryl methyl and aryl phenyl sulfides from arenediazonium tetrafluoroborates
and trimethyl(methylthio)- and trimethyl(phenylthio)silanes. Arkivoc, 2002, 13, 50–54.
10. (a) Pang, Y.-P.; Xu, K.; Kollmeyer, T. M.; Perola, E.; McGrath, W. J.; Green, D. T.;
Mangel, W. F. Discovery of a new inhibitor lead of adenovirus proteinase: Steps toward
selective, irreversible inhibitors of cysteine proteinases. FEBS Lett. 2001, 502, 93–97; (b)
Kornblum, N.; Cheng, L.; Kerber, R. C.; Kestner, M. M.; Newton, B. N.; Pinnick, H.
W.; Smith, R. G.; Wade, P. A. Displacement of the nitro group of substituted
nitrobenzenes-a synthetically useful process. J. Org. Chem. 1976, 41, 1560–1564; (c) Beck,
J. R. Nucleophilic displacement of aromatic nitro groups. Tetrahedron 1978, 34,
2057–2068.
11. McBee, E. T.; Graham, P. J. Alkylthio(trifluoromethyl)benzenes. J. Am. Chem. Soc. 1950,
72, 4235–4237.
12. Pilgram, K.; Korte, F. Thermolysis of O,O-dialkyl-S-arylthiophosphates. Tetrahedron
1965, 21, 1999–2013.
13. Allaire, F. S.; Lyga, J. W. Nonaqueous diazotization of arylamines in the presence of
dimethyldisulfide; the convenient synthesis of arylmethylsulfides from anilines. Synth.
Commun. 2001, 1857–1861.

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