An efficient catalytic method for regioselective sulfenylation of electron-rich aza-aromatics at room temperature

Article abstract of DOI:10.1002/ejoc.201201100

Electron-rich aza-aromatic compounds such as indoles and pyrroles are structures of particular interest and importance in organic chemistry. A useful methodology for the regioselective introduction of the sulfenyl group into electron-rich aza-aromatics using S-alkyl- and S-arylthiophthalimides as sulfenylating agents is described. Catalytic amounts of CeCl₃· 7H₂O/NaI are crucial to the promotion of this regioselective carbon-sulfur-bond-forming electrophilic aromatic substitution reaction. The reaction occurred under mild conditions, and the products were obtained in good to excellent yields. The method represents an efficient preparation of sulfenyl aza-aromatics, which are useful intermediates for important organic transformations, due to the great importance of functionalized indoles among natural compounds and pharmaceutical products. A useful method for the regioselective introduction of the sulfenyl group into electron-rich aza-aromatics using S-alkyl- and S-arylthiophthalimides as sulfenylating agents is described. Catalytic amounts of CeCl₃·7H₂O/NaI are crucial to the promotion of this regioselective carbon-sulfur-bond-forming electrophilic aromatic substitution reaction. Copyright

Full text of DOI:10.1002/ejoc.201201100

FULL PAPER
DOI: 10.1002/ejoc.201201100
An Efficient Catalytic Method for Regioselective Sulfenylation of
Electron-Rich Aza-Aromatics at Room Temperature
Enrico Marcantoni,*[a] Roberto Cipolletti,[a] Laura Marsili,[a] Stefano Menichetti,*[b]
Roberta Properzi,[a] and Caterina Viglianisi[b]
Dedicated to Professor Alfredo Ricci on the occasion of his retirement
Keywords: Synthetic methods / Heterogeneous catalysis / Cerium / Regioselectivity / Nitrogen heterocycles / Sulfur / Lewis
acids
Electron-rich aza-aromatic compounds such as indoles and
pyrroles are structures of particular interest and importance
in organic chemistry. A useful methodology for the regiose-
lective introduction of the sulfenyl group into electron-rich
aza-aromatics using S-alkyl- and S-arylthiophthalimides as
sulfenylating agents is described. Catalytic amounts of
CeCl3·7H2O/NaI are crucial to the promotion of this regiose-
lective carbon–sulfur-bond-forming electrophilic aromatic
substitution reaction. The reaction occurred under mild con-
ditions, and the products were obtained in good to excellent
yields. The method represents an efficient preparation of
sulfenyl aza-aromatics, which are useful intermediates for
important organic transformations, due to the great impor-
tance of functionalized indoles among natural compounds
and pharmaceutical products.
dramatically in the presence of an iodide source, such as
NaI.[5] In recent years, the 3-sulfenylation of indoles with
disulfides catalyzed by copper(I) and iron(III) salts have
been shown to give similarly excellent improvements over
existing Friedel–Crafts-type reactions.[6] Among the numer-
ous aza-aromatic derivatives known, 3-thioindoles have re-
cently attracted considerable attention from both industry
and academia, due to their therapeutic value against a vari-
ety of diseases.[7] In the public domain, examples of com-
plex small molecules (Figure 1) containing 3-thioindole
moieties include MK-886 (A), an inhibitor of 5-lipoxygen-
ase,[8] and 3-(arylsulfenyl)indole B, an inhibitor of tubulin
polymerization that is also capable of inhibiting the growth
of human breast cancer cells.[9] 3-Thioindole derivatives are
also often used as synthetic intermediates in the preparation
of heterocyclic compounds of higher complexity, such as L-
737,126 (C), which is known to have potent anti-HIV prop-
erties.[10] Considering the synthetic utility of 3-thioindoles,
methods to insert sulfide moieties into polyfunctionalized
aza-aromatic molecules[11] are important, and the develop-
ment of new procedures that can also be used for this pur-
pose would be desirable.
Introduction
The Friedel–Crafts reaction is one of the most important
reactions in organic synthesis, and it provides a useful
method for the direct introduction of a functional group
into heteroarene compounds.[1] The Friedel–Crafts reaction
of electron-rich aza-aromatic rings such as indoles and pyr-
roles is an interesting challenge in organic chemistry, due to
the strong tendency of these compounds to polymerize.[2]
Thus, useful modifications in bond-forming Friedel–Crafts-
type reactions for the preparation of heterocyclic polyfunc-
tionalized molecules have been realized.[3] Recent studies by
us and by others have shown that cerium(III) chloride also
promotes the reaction of indoles and pyrroles with several
electrophiles, and new reactions for the formation of car-
bon–nitrogen, carbon–oxygen, and carbon–carbon bonds
have been developed.[4] CeCl3 has emerged as a cheap, non-
toxic, and water-tolerant Lewis acidic promoter, and the re-
activity of commercially available CeCl3·7H2O increases
[a] School of Science and Technology, Chemistry Division,
University of Camerino,
Via S. Agostino 1, 62032 Camerino, Italy
Fax: +39-0737-402297
Many strategies have been developed for the 3-sulf-
enylation of electron-rich heterocycles, and sulfenylating
agents such as thiols,[12] sulfenyl halides,[13] and quinone
mono-O,S-acetals[14] have been used. However, these meth-
ods are very difficult to use because of the severe reaction
conditions required together with the limited stability of the
E-mail: enrico.marcantoni@unicam.it
Homepage: http://www.chimica.unicam.it/marcantoni
[b] Department of Chemistry “Ugo Schiff”, University of Firenze,
Via della Lastruccia 13, 50019 Firenze, Italy
E-mail: stefano.menichetti@unifi.it
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201100.
132
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Sulfenylation of Electron-Rich Aza-Aromatics
sis seemed an attractive proposition. Indeed, our efforts
have allowed us to develop a new general procedure that
proceeds under mild catalytic reaction conditions, and un-
like the method reported by Tudge et al.,[25] we have devel-
oped a sulfenylation protocol that proceeds at room tem-
perature.
Results and Discussion
First, the reaction of indole (1a) with S-arylthiophthal-
imide 2a was carried out using CeCl3·7H2O (1 equiv.) and
NaI (1 equiv.) as promoter, in acetonitrile at room tempera-
ture, the desired 3-sulfenylindole (i.e., 3aa) was produced in
75% yield after 24 h (Table 1, entry 1). Changing the tem-
perature to 70 °C, only traces of the desired product were
recovered, along with several by-products (Table 1, entry 2).
Figure 1. Examples of biologically active 3-thioindole derivatives.
reagents, and the observed yields are relatively low. Further-
more, some of the catalysts used are expensive, toxic, and
air/moisture sensitive. Thus, a mild and efficient general
method for the sulfenylation of aza-aromatics is still neces-
sary. Given that some of us have experience in electrophilic
sulfur-transfers, we focused our attention on N-thiophthal-
imides. It is well known that these reagents are useful sulfur-
transfer reagents that have been used for many years for the
formation of new sulfur–sulfur[15] and sulfur–nitrogen[16]
bonds. In particular, they have been used in the synthesis
of complex natural products, such as in the introduction the
methyl trisulfide moiety into the calicheamicin skeleton.[17]
Generally, N-thiophthalimides are commonly prepared by
reacting potassium phthalimide with the appropriate sulf-
enyl halide.[18] However, this procedure suffers from several
limitations due to the high reactivity, low stability, and diffi-
culties in storing and handling of many sulfenyl halides. We
have developed an optimized procedure in which phthal-
imidesulfenyl chloride (PhtNSCl, Pht = Phthaloyl), a crys-
talline solid that can be easily prepared and stored for
months without decomposition, reacts with nucleophiles,
such as alkynes,[19] enolizable ketones,[20] phenols,[21] and
other electron-rich arenes,[22] to form a variety of N-thio-
phthalimides as potential sulfur-transfer reagents useful for
the formation of carbon–sulfur bonds.[19–23] For all these
reasons, we report in this paper the results of a study on the
potential of different substituted S-aryl- and S-alkylthio-
Table 1. Sulfenylation of indole 1a under different reaction condi-
tions.[a]
Entry CeCl3·7H2O NaI
Conditions/time
CH3CN, r. t./4 h
Yields [%][b]
75
[equiv.]
[equiv.]
1
2
3
4
5
6
1.00
1.00
1.00
0.30
0.30
–
1.00
1.00
1.00
0.30
–
CH3CN, reflux/2 h trace[c]
SiO2, r. t./2 h
trace[c]
95
CH3CN, r. t./4 h
CH3CN, r. t./4 h
CH3CN, r. t./4 h
trace[d]
trace[d]
0.30
[a] All reactions were carried out by stirring mixtures of 1a
(2 mmol), N-thiophthalimide 2a (2 mmol), and catalyst for the re-
action times shown. [b] Yields of products isolated by column
chromatography. [c] Complex reaction mixture analyzed by GC/
MS. [d] Starting material recovered after reaction.
Then we moved to a solvent-free approach, which we had
phthalimides as sulfur-transfer reagents towards indoles used previously in the development of a new strategy for
and pyrroles, a reaction of particular interest bearing in the Michael reaction,[26] but this strategy was unsuccessful,
mind the biological relevance of the products obtained. In and only traces of 3-sulfenylindole 3aa were recovered
this context, recently, Silveira et al. have found that 3-sulf- (Table 1, entry 3). In general, an equimolar ratio of cerium
enyl indoles are obtained by using N-thiophthalimides and trichloride and NaI in acetonitrile was found to give the
dry CeCl3 in DMF at 80 °C.[24] We have repeated the reac- best results, and in optimizing the reaction conditions, we
tion without CeCl3, and the corresponding 3-sulfenyl indole tested several different stoichiometries of CeCl3·7H2O/NaI
was recovered in similar yield (72%). The same formation relative to the starting materials, while keeping these two
of indole dimer or trimer by-products, whose separation reagents in an equimolar ratio. Our results in Table 1 indi-
from the desired product by liquid chromatography is very cate that 0.3 equiv. cerium salt and 0.3 equiv. NaI were the
difficult, was also observed. This result provides evidence most appropriate for this type of reaction. Hence in this
that the CeCl3 is not necessary in Silveira’s conditions. process, the CeCl3·7H2O/NaI system works as a catalyst
Thus, a general electrophilic aromatic substitution reaction rather than a stoichiometric promoter of this sulfenylating
of indoles and pyrroles with this type of sulfur electrophile reaction. Undoubtedly, the presence of NaI is essential for
reagents under mild conditions of CeCl3·7H2O/NaI cataly- the efficient preparation of 3-sulfenylindole 3aa by our
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methodology, but all previous efforts to structurally charac-
In the light of this, and due to the great importance of
terize our CeCl3·7H2O/NaI system have been unsuccessful. functionalized indoles[30] among natural compounds and
For a possible understanding of the mechanistic role of pharmaceutical products, we used our methodology for the
NaI, we analyzed the interaction between CeCl3·7H2O and synthesis of a heterocyclic compound with five fused rings
NaI by X-ray Photoelectron Spectroscopy (XPS).[27] The (i.e., 3ha) (Table 2, entry 13). The optimized reaction condi-
CeCl3·7H2O/NaI system was treated with acetonitrile for tions were successfully applied to tert-butyl 1H-indole-2-
4 h at room temperature, and then the solvent was removed carboxylate 1h too. This compound was easily prepared
by rotary evaporation and the resulting mixture was ana- from the corresponding 2-carboxylic acid indole,[31] and
lyzed. From this study, it may be inferred that the introduc- then, after reaction with arylthiophthalimide 2a, we iso-
tion of the NaI into the system does not alter the degree of lated the corresponding oxathiepinoindole (i.e., 3ha) in
the hybridization of the f states with the conduction states. good yield, and with none of the 3-sulfenylindole adduct
This suggests that there is no direct interaction between the isolated. We believe that the formation of the lactone moi-
CeIII center and the iodide ion. Given that it is known that ety in 3ha could occur through intramolecular transesterifi-
the activity of CeCl3·7H2O/NaI system is mainly exerted in cation arising from the selective deprotection of a tert-butyl
the heterogeneous phase, we believe that a chloride-bridged ester catalyzed by the CeCl3·7H2O/NaI system.[32] It is also
oligomeric structure of CeCl3·7H2O[28] could be broken by noteworthy that an ethyl ester does not undergo deprotec-
donor species such as iodide ion, and that the resulting mo- tion (Table 2, entry 4), and although we cannot exclude an
nomeric CeCl3·7H2O/NaI complex would be a more active interaction of the CeIII Lewis acid with the β-keto ester
Lewis acid catalyst. After optimization of the amounts of moiety[33] of 2c, this is neither productive nor an obstacle
CeCl3·7H2O and NaI used in the reaction, we also observed to the sulfenylation reaction.
that neither CeCl3·7H2O (Table 1, entry 5) nor NaI
The results show that the combination of NaI and CeCl3
(Table 1, entry 6) alone could accomplish the sulfenylation is essential for the sulfenylation, and the fact that the ad-
reaction, even after 1 week. It is also worth noting that the ducts (i.e., 3) were obtained in high yields without forma-
sulfenylation is not catalyzed by water alone: no trace of 3- tion of any of the oligomeric by-products normally ob-
sulfenyl indole was observed following the simple addition served under the influence of strong acids[34] excludes the
of water to a mixture of indole (1a) and N-thiophthalimide possibility that sites may contain simultaneously Brønsted
2a.
and Lewis acidic sites.[35] To confirm this, following Spen-
A variety of solvents were examined, and the efficiency cer’s approach,[36] we found that the reaction worked well in
based on the yields of 3aa showed that acetonitrile was the the presence of a strongly hindered base, 2,6-di-tert-butyl-4-
solvent of choice. In fact, the order, in terms of efficiency, methylpyridine, which only binds to protons and is unable
was as follows (yields in parentheses): acetonitrile (95%), to coordinate to the cerium center, due to the bulky tert-
EtOH (64%), THF (60%), DMF (55%), CH2Cl2 (45%), butyl groups.[37] Analogously, we also obtained high yields
and Et2O (40%). Then we examined several substrates of the desired products in the presence of a radical inhibitor
using a variety of functionalized indoles and S-alkyl- and such as 2,6-di-tert-butyl-4-methylphenol,[38] which demon-
S-arylthiophthalimides. The results are shown in Table 2. strates that the reaction has not occurred following an elec-
The substitution on the indole nucleus occurred exclusively tron-transfer pathway. Finally, we also carried out the reac-
at the 3-position, and the indole nitrogen did not require tion with other cerium salts such as CAN [Cerium(IV) am-
prior protection. Under our conditions, the indole moieties monium nitrate], Ce(OTf)3, and Ce(NO3)3. Among these,
are reactive substrates, and even indolyl rings bearing elec- CeCl3 was found to be the most effective reagent, and gave
tron-withdrawing groups gave the corresponding 3-sulf- the best results. The reactivity observed in all cases indicates
enylindoles in satisfactory yields (Table 2, entries 5, 7, 8, that the reaction was being catalyzed by Lewis acidic ce-
and 11). We also investigated the electronic effects of sub- rium rather than the counter-ion in CeCl3.[25] Thus, even
stituents on the nitrogen of the indole ring, and here, the though it would be premature to speculate on the exact na-
presence of an electron-donating group (in 1d) resulted in ture of the mechanism, our findings can be rationalized by
the formation of the corresponding product 3da in a shorter assuming that under these conditions,[19c,22b] an initial coor-
reaction time than when an electron-withdrawing group was dination of a cerium(III) Lewis acid species occurs at the
present (in 1f) (Table 2, entries 6 and 10, respectively). It oxygen of the imidic group (Scheme 1).
can, therefore, safely be asserted that the reaction proceeded
Unfortunately, it was impossible to follow the course of
in good yield, even for less reactive indoles, and, interest- the reaction by NMR spectroscopy,[39] owing to the pres-
ingly, also for an indole derivative containing a hydroxy ence of paramagnetic CeIII species.[40] In fact, when we tried
group (i.e., 1b). It is known that direct Lewis-acid-promoted to study the complexation of reagents with CeCl3 by 13C
reactions of hydroxyindole substrates are generally prob- NMR spectroscopy, the signals observed were very broad,
lematic, and normally result in low yields due to the interac- and no identifiable species could be discerned from the
tion of the indolyl hydroxy group with the Lewis acid cata- spectra. An attempt to study the process in the more ex-
lyst.[29] With our system, this problem with hydroxyindoles pensive [D3]acetonitrile (rather than CDCl3 or CD3OD)
was much reduced (Table 2, entries 2 and 3). In short, the gave more complicated results. Therefore, we propose that
conditions of our methodology are such that they provide a nucleophilic substitution of the indole C-3 at the sulfur
high compatibility with a wide range of functional groups.
of the sulfenyl group moiety gave intermediates 4 and 5.
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Sulfenylation of Electron-Rich Aza-Aromatics
Table 2. 3-Sulfenylation of indoles 1 catalyzed by CeCl3·7H2O/NaI in acetonitrile at room temp.[a]
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Table 2. (continued)
[a] All products were identified by their IR, NMR, and mass spectra. [b] Regioselectivity estimated from 1H NMR spectroscopic analysis.
[c] Yields of products after isolation by flash chromatography. [d] Only the product of cyclization was isolated. TBDMS = tert-butyldi-
methylsilyl.
Scheme 1. Proposed reaction mechanism.
Finally aromatization of 4 to reform the indole ring (in 3) experiments, seem to suggest that the actual sulfur-transfer
occurs by deprotonation of 4 by the nitrogen atom of 5, species is a Lewis-acid-activated N-thiophthalimide, as
releasing the catalyst and resulting in the formation of shown in Scheme 1, and not a sulfenyl iodide. Further con-
phthalimide 6 and sulfenyl indole target 3. Of course, vari- firmation of such a mechanism comes from the fact that no
ous other mechanistic hypothesis have been proposed to ex- diaryl disulfide was observed when S-arylthiophthalimide
plain the formation of the 3-sulfonylindoles in other sulf- 2a was treated with CeCl3·7H2O/NaI system without the
enylation reaction systems.[4,41] However, all these interpret- addition of indole (1a).
ations are ruled out in our system by some unequivocal
Pyrroles, like indoles, are heteroaromatic structural mo-
experimental evidence. We observed that our CeCl3·7H2O/ tifs present in a vast number of natural products,[43] and
NaI system failed to promote some intramolecular electro- they are frequently used as building blocks in the construc-
philic cyclizations of N-thiophthalimides that occur using, tion of more complex heterocycles in medicinal and phar-
for example, AlCl3 as Lewis acid. It is difficult to rationalize maceutical chemistry.[44] The importance of sulfenyl pyr-
how these reactions could fail if a very reactive sulfenyl iod- roles as valuable building blocks for the assembly of bioac-
ide was formed as intermediate. Certainly, we cannot defi- tive agents with a broad range of pharmacological ac-
nitely rule out the possibility of the formation of a transient tivity[45] prompted us to evaluate whether our Lewis-acid-
sulfenyl iodide as the actual sulfur-transfer reagent, as in catalyzed sulfenylation reaction could also be used on pyr-
the mechanism described by Tudge.[25] However, the high role substrates.[46] We tested the optimized reaction condi-
lability of sulfenyl iodides, compared to those of other hal- tions, and 2-sulfenylpyrroles were obtained in good yields,
ides,[42] and their fast disproportionation to give disulfides, in short reaction times, and with complete regioselectivity
which were never isolated or observed as by-products in our for C-2-sulfenylation (Table 3).
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Sulfenylation of Electron-Rich Aza-Aromatics
Table 3. Sulfenylation of pyrroles 7 with thiophthalimides 2 catalyzed by CeCl3·7H2O/NaI at room temp.[a]
[a] All products were identified by their IR, NMR, and mass spectra. [b] Regioselectivity estimated from 1H NMR spectroscopic analysis.
[c] Yields of products after isolation by flash chromatography. [d] The regioisomeric ratio was estimated by GC/MS analysis of the crude
of reaction mixture. It was not possible to separate the C-3-substituted by-product by column chromatography.
imides, already regarded as useful compounds, being devel-
Conclusions
oped further. New schemes of synthesis for the preparation
In summary, we have reported a Lewis-acid-catalyzed
of other biologically important substances are in progress
sulfenylation of electron-rich aza-aromatic compounds with
good functional group tolerance, using a CeCl3·7H2O/NaI
system. The simplicity of our approach, the low cost of the
in our laboratories, and the results will be reported sub-
sequently.
reagents, and the fact that no particular precautions to ex-
clude moisture or oxygen from the reaction system need to
Experimental Section
be taken suggest to us that the CeCl3·7H2O/NaI combina-
General Remarks: Commercially available reagents were used
throughout without purification unless otherwise stated. Solvents
(EtOAc and hexanes) for flash chromatography were distilled. Ana-
lytical thin-layer chromatography was carried out on pre-coated
glass-backed plates (Merck Kieselgel 60 F254), which were visual-
ized under UV light at 254 nm and/or by dipping the plates into
iodine vapour and Von’s reagent [ceric sulfate (1.0 g) and ammo-
nium molybdate (24.0 g) in sulfuric acid (31 mL) and water
(470 mL)]. Solutions were evaporated under reduced pressure with
a rotary evaporator, and the residue was purified by chromatog-
raphy on silica gel 60 (230–400 mesh).
tion could be useful in further reactions for the formation
of new heterocycles. In particular, the procedure studied
represents an efficient method for the preparation of sulf-
enyl aza-aromatic compounds, which are of profound im-
portance in organic chemistry. It is clear that the simplicity
of this approach represents another example of the attract-
iveness of CeCl3·7H2O/NaI as catalyst for new bond-form-
ing reactions. Even if the exact nature of the intermediate
obtained by the interaction of the reagents with the
CeCl3·7H2O/NaI catalyst is not yet known, we believe that
this method will find many useful applications in organic
synthesis and in medicinal chemistry.[47] The mild reaction
conditions described in this paper also suggest that new ap-
plications of this sulfenylation method in synthesis should
Fully characterized compounds were chromatographically homo-
geneous. Infrared spectra were recorded with a Perkin–Elmer FTIR
Paragon 500 spectrometer as thin films on NaCl plates. Only the
characteristic peaks are quoted. NMR spectra were recorded at
be possible, which will result in the utility of N-thiophthal- 400 MHz (1H) or 100 MHz (13C). Chemical shifts are quoted in
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1
ppm, and were referenced to residual H in the deuterated solvent
as the internal standard. J values are quoted in Hz. Mass spectra
were obtained both using electron ionization (EI) at 70 eV, and
electrospray ionization (ESI). Fragment ions were separated with a
quadrupolar mass analyzer. High-resolution mass-spectra (HRMS)
analysis was carried out using ESI, analyzed by time-of-flight
(TOF). X-ray Photoelectron Spectroscopy was performed with an
A1 anode (A1 Kα: 1487.7 eV). A surface area of 700ϫ300 nm was
analyzed at a take-off angle of 90°. The analyzer was a VG-Clam
4 hemisperical analyzer, which provided on overall resolution of
0.7 eV for a constant pass energy of 22 eV. All measurements were
performed below 10–9 Torr.
70:30) gave product 3ac in 79% isolated yield as a brown oil. H
NMR (CDCl3): δ = 1.23 (t, J = 6.4 Hz, 3 H), 1.35 (t, J = 6.4 Hz,
3 H), 2.35 (s, 3 H), 2.57 (s, 3 H), 4.16–4.22 (dd, J = 6.8, JЈ =
14.1 Hz, 2 H), 4.24–4.29 (dd, J = 6.8, JЈ = 14.1 Hz, 2 H), 7.20–
7.23 (m, 2 H), 7.34–7.37 (m, 2 H), 7.41 (s, 1 H), 7.75–7.76 (m, 4
H), 7.86–7.87 (m, 3 H), 8.26 (br. s, 1 H), 8.51 (br. s, 1 H) ppm. 13C
NMR ([D6]DMSO): δ = 13.6, 26.8, 61.7, 62.9, 118.2, 120.4, 122.5,
123.2, 132.4, 133.3, 134.3, 134.4, 168.7, 205.5 ppm. IR (neat): ν =
˜
3406, 2496, 1772, 1413 cm–1. ESI-MS: positive ion mode: m/z =
300 [M + Na]+. HRMS: calcd. for C14H16NO3S [M + H]+
278.0851; found 278.0849.
3,5-Dimethoxy-2-(5-nitro-1H-indol-3-ylthio)phenol (3cd): Column
chromatography on silica gel (eluent: cyclohexane/ethyl acetate =
70:30) gave product 3cd in 75% isolated yield as a green solid, m.p.
Typical Procedure for the CeCl3·7H2O/NaI-Catalyzed Sulfenylation
Reaction of 1-(1H-Indol-3-ylthio)naphthalen-2-ol (3aa): CeCl3·7H2O
(0.26 g, 0.72 mmol) and NaI (0.1 g, 0.72 mmol) were added to a
mixture of indole (1a; 0.28 g, 2.4 mmol) and 2-(2-hydroxynaph-
thalen-1-ylthio)isoindoline-1,3-dione (2a; 0.76 g, 2.4 mmol) in
CH3CN (25 mL) at room temperature. The reaction mixture was
stirred at room temperature for 4 h. After the reaction was com-
plete, as indicated by TLC, the mixture was treated with a solution
of CH3COOH (10% in dist. H2O; 10 mL) and extracted with
CH2Cl2 (50 mL). The extract was washed with a saturated solution
of NaHCO3 (10 mL) and dried with anhydrous Na2SO4. The sol-
vent was evaporated under reduced pressure, and the residue was
purified by chromatography on silica gel (eluent: cyclohexane/ethyl
acetate = 75:25) to afford 3-sulfenylindole 3aa (0.66 g, 95%) as a
1
129–132 °C (ethanol). H NMR (CD3OD): δ = 3.30 (s, 3 H), 4.86
(s, 3 H), 6.69 (d, J = 3.40 Hz, 1 H), 7.44–7.49 (m, 1 H), 7.77–7.83
(m, 2 H), 8.01–8.04 (dd, J = 2.14, JЈ = 8.97 Hz, 1 H), 8.55 (d, J =
2.11 Hz, 1 H) ppm. 13C NMR (CDCl3): δ = 105.2, 105.2, 111.3,
111.3, 112.0, 117.8, 118.2, 119.2, 123.8, 127.6, 127.7, 134.6, 138.2,
142.6, 168.3 ppm. IR (neat): ν = 3104, 2479, 1558, 1413, 1321 cm–1.
˜
ESI-MS: positive ion mode: m/z = 347 [M + H]+. HRMS: calcd.
for C16H15N2O5S [M + H]+ 347.0702; found 347.0700.
1-(1-Methyl-1H-indol-3-ylthio)naphthalen-2-ol
(3da):
Column
chromatography on silica gel (eluent: cyclohexane/ethyl acetate =
1
89:20) gave product 3da in 90% isolated yield as a brown solid. H
NMR (CD3OD): δ = 3.71 (s, 3 H), 6.99 (t, J = 7.3 Hz, 1 H), 7.09–
7.17 (m, 2 H), 7.26–7.29 (m, 2 H), 7.41 (s, 1 H), 7.49 (t, J = 7.7 Hz,
1 H), 7.66–7.73 (m, 3 H), 8.71 (d, J = 8.5 Hz, 1 H) ppm. 13C NMR
(CDCl3): δ = 33.2, 103.3, 109.8, 112.5, 116.9, 119.3, 120.4, 122.5,
123.6, 125.1, 127.5, 128.7, 128.7, 129.6, 131.7, 132.7, 135.2, 137.1,
1
brown oil. H NMR (CD3OD): δ = 6.94 (t, J = 8.1 Hz, 1 H), 7.04
(t, J = 8.1 Hz, 1 H), 7.16 (d, J = 8.9 Hz, 1 H), 7.26–7.28 (m, 2 H),
7.46–7.50 (m, 2 H), 7.64 (d, J = 7.7 Hz, 1 H), 7.69–7.72 (m, 2 H),
8.72 (d, J = 8.5 Hz, 1 H) ppm. 13C NMR (CD3OD): δ = 106.0,
112.7, 112.8, 114.1, 118.6, 120.1, 120.7, 124.1, 124.3, 126.2, 128.0,
155.8 ppm. IR (neat): ν = 3362, 1241, 1508 cm–1. ESI-MS: positive
˜
129.5, 130.3, 132.2, 135.4, 136.9, 137.9, 157.7 ppm. IR (neat): ν =
˜
ion mode: m/z = 306 [M + H]+, 308 [M + Na]+; negative ion mode:
m/z = 304 [M – H]–. HRMS: calcd. for C19H16NOS [M + H]+
306.0953; found 306.0949.
3424, 3056, 1593 cm–1. ESI-MS: positive ion mode: m/z = 292 [M
+ H]+, 314 [M + Na]+; negative ion mode: m/z = 290 [M – H]–,
326 [M + Cl]–. HRMS: calcd. for C18H14NOS [M + H]+ 292.0796;
found 292.0790.
3-(2-Hydroxynaphthalen-1-ylthio)-1H-indole-5-carbonitrile
(3ea):
Column chromatography on silica gel (eluent: cyclohexane/ethyl
3-(2,4-Dimethoxyphenylthio)-1H-indol-5-ol (3bb): Column chroma-
tography on silica gel (eluent: cyclohexane/ethyl acetate = 75:25)
gave product 3bb in 78% isolated yield as a yellow oil. 1H NMR
(CDCl3): δ = 3.75 (d, J = 3.1 Hz, 3 H), 3.92 (d, J = 8.5 Hz, 3 H),
5.02 (br. s, 1 H), 6.23–6.26 (m, 1 H), 6.45 (d, J = 2.1 Hz, 1 H), 6.62
(d, J = 8.5 Hz, 1 H), 6.80–6.83 (m, 2 H), 6.99 (s, 1 H), 7.42 (d, J
= 2.6 Hz, 1 H), 8.37 (br. s, 1 H) ppm. 13C NMR (CDCl3): δ = 55.7,
56.1, 98.9, 101.7, 104.3, 105.2, 112.6, 112.9, 127.7, 129.9, 130.6,
acetate = 70:30) gave product 3ea in 70% isolated yield as a yellow
1
oil. H NMR (CD3OD): δ = 7.18 (d, J = 8.97 Hz, 1 H), 7.26–7.32
(m, 2 H), 7.40 (d, J = 8.55 Hz, 1 H), 7.49–7.53 (m, 1 H), 7.66 (s, 1
H), 7.70–7.75 (m, 2 H), 8.11 (s, 1 H), 8.70 (d, J = 8.55 Hz, 1 H)
ppm. 13C NMR (CDCl3): δ = 28.5, 29.9, 112.7, 117.1, 123.9, 124.5,
124.6, 124.9, 126.0, 127.9, 128.9, 128.9, 132.4, 132.4, 135.2 ppm.
IR (neat): ν = 3447, 2225, 1462 cm–1. ESI-MS: negative ion mode:
˜
m/z = 315 [M – H]–. HRMS: calcd. for C19H13N2OS [M + H]+
131.8, 131.9, 150.8, 156.6, 158.9 ppm. IR (neat): ν = 3391, 1582,
˜
317.0749; found 317.0745.
1410 cm–1. ESI-MS: positive ion mode: m/z = 302 [M + H]+, 324
[M + Na]+; negative ion mode: m/z = 300 [M – H]–, 335 [M +
Cl]–. HRMS: calcd. for C16H16NO3S [M + H]+ 302.0851; found
302.0847.
1-(5-Nitro-1H-indol-3-ylthio)naphthalen-2-ol
(3ca):
Column
chromatography on silica gel (eluent: cyclohexane/ethyl acetate =
1
70:30) gave product 3ca in 73% isolated yield as an orange oil. H
NMR (CD3OD): δ = 6.68 (d, J = 3.42 Hz, 1 H), 7.44–7.49 (m, 2
H), 7.78–7.84 (m, 5 H), 8.01–8.04 (dd, J = 2.60, JЈ = 9.00 Hz, 1
H), 8.55 (d, J = 2.14 Hz, 1 H) ppm. 13C NMR (CD3OD): δ =
105.1, 112.4, 117.8, 118.5, 124.2, 125.9, 127.9, 128.8, 129.5, 130.9,
3-(2-Hydroxynaphthalen-1-ylthio)-1H-indol-5-ol (3ba): Column
chromatography on silica gel (eluent: cyclohexane/ethyl acetate =
70:30) gave product 3ba in 76% isolated yield as a yellow oil. 1H
NMR (CD3OD): δ = 6.61–6.64 (m, 1 H), 7.07–7.17 (m, 3 H), 7.25
(t, J = 8.1 Hz, 1 H), 7.43 (s, 1 H), 7.48 (t, J = 7.3 Hz, 1 H), 7.68–
7.71 (m, 2 H), 8.71 (d, J = 8.5 Hz, 1 H) ppm. 13C NMR (CD3OD):
δ = 106.0, 112.7, 119.5, 120.1, 120.7, 123.0, 124.3, 126.2, 128.0,
129.5, 130.1, 130.9, 132.1, 135.3, 136.9, 137.9, 157.7 ppm. IR
131.0, 132.0, 133.1, 134.4, 135.5, 171.1 ppm. IR (neat): ν = 3627,
˜
3095, 1602, 1561, 1330 cm–1. ESI-MS: negative ion mode: m/z =
335 [M – H]–. HRMS: calcd. for C18H13N2O3S [M + H]+ 337.0647;
found 337.0644.
(neat): ν = 3457, 1303, 1508 cm–1. ESI-MS: positive ion mode: m/z
˜
2-(1H-Indol-3-ylthio)-4-methoxyphenol (3ae): Column chromatog-
raphy on silica gel (eluent: cyclohexane/ethyl acetate = 80:20) gave
product 3af in 82% isolated yield as a yellow oil. 1H NMR
(CD3OD): δ = 3.63 (s, 3 H), 6.18 (d, J = 3.00 Hz, 1 H), 6.43–6.46
(m, 1 H), 6.67 (d, J = 8.55 Hz, 1 H), 7.04–7.9 (m, 1 H), 7.44–7.47
(t, J = 7.26 Hz, 1 H), 7.51 (s, 1 H) 7.75–7.82 (m, 2 H) ppm. 13C
= 308 [M + H]+, 330 [M + Na]+; negative ion mode: m/z = 307
[M – H]–, 342 [M + Cl]–. HRMS: calcd. for C18H14NO2S [M + H]
+
308.0745; found 308.0744.
Ethyl
2-(1H-Indol-3-ylthio)-3-oxobutanoate
(3ac):
Column
chromatography on silica gel (eluent: cyclohexane/ethyl acetate =
138
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 132–140

Sulfenylation of Electron-Rich Aza-Aromatics
NMR (CD3OD): δ = 55.9, 101.6, 111.6, 113.1, 113.7, 115.3, 115.6,
MS: m/z (%) = 221 (100) [M]+, 188, 126. HRMS: calcd. for
115.2, 117.1, 121.1, 130.6, 132.8, 138.7, 148.4, 154.9 ppm. IR
C11H12NO2S [M + H]+ 222.0589; found 222.0588.
(neat): ν = 3660, 3457, 1604 cm–1. ESI-MS: negative ion mode: m/z
˜
4-Methoxy-2-(1-methyl-1H-pyrrol-2-ylthio)phenol (8be): Column
chromatography on silica gel (eluent: cyclohexane/ethyl acetate =
90:10) gave product 8be in 80% isolated yield as a brown oil. 1H
NMR (CDCl3): δ = 3.58 (s, 3 H), 3.64 (s, 3 H), 6.25–6.17 (m, 1 H),
6.46 (d, J = 3 Hz, 1 H), 6.54–6.56 (m, 1 H), 6.61–6.64 (m, 1 H),
6.77 (s, 1 H), 6.79–6.81 (m, 1 H), 8.4 (br. s, 1 H) ppm. 13C NMR
(CDCl3): δ = 34.5, 55.9, 108.7, 114.8, 116.2, 116.5, 118.9, 123.8,
= 270 [M – H]–. HRMS: calcd. for C15H14NO2S [M + H]+
272.0745; found 272.0743.
1-[1-(Phenylsulfonyl)-1H-indol-3-ylthio]naphthalen-2-ol (3fa): Col-
umn chromatography on silica gel (eluent: toluene/cyclohexane/
ethyl acetate = 60:35:5) gave product 3fa in 85% isolated yield as
1
a yellow oil. H NMR (CD3OD): δ = 6.25 (d, J = 10.26 Hz, 1 H),
6.91 (s, 1 H), 7.30–7.32 (m, 1 H), 7.36–7.39 (m, 3 H), 7.44–7.46 (m,
1 H), 7.46–7.54 (m, 5 H), 7.57 (d, J = 10.26 Hz, 1 H), 7.76 (d, J =
9.00 Hz, 1 H), 7.88 (d, J = 8.12 Hz, 1 H), 7.98 (d, J = 6.83 Hz, 1
H) ppm. 13C NMR (200 MHz, CDCl3, Me4Si): δ = 111.2, 121.3,
123.1, 124.0, 124.8, 127.1, 127.9, 128.5, 128.5, 129.2, 130.1, 130.2,
126.5, 134.5, 148.8, 153.8 ppm. IR (neat): ν = 3452, 1410,
˜
1260 cm–1. EI-MS: m/z (%) = 235 [M]+, 202, 126, 81 (100). HRMS:
calcd. for C12H14NO2S [M + H]+ 236.0745; found 236.0745.
3-(5-Nitro-1H-pyrrol-2-ylthio)naphthalen-2-ol
(8ca):
Column
chromatography on silica gel (eluent: cyclohexane/ethyl acetate =
95:5) gave product 8ca in 84% isolated yield as a brown solid, m.p.
96–98 °C (petroleum ether). 1H NMR (CDCl3): δ = 6.28 (d, J =
10.3 Hz, 1 H), 6.60 (br. s, 1 H), 7.34–7.49 (m, 3 H), 7.51–7.58 (m,
2 H), 7.73–7.77 (m, 1 H), 7.81–7.83 (m, 1 H), 8.16–8.2 (d, J =
8.5 Hz, 1 H) ppm. 13C NMR (CDCl3): δ = 121.3, 123.1, 124.1,
124.8, 127.1, 128.0, 128.5, 130.4, 130.5, 131.8, 135.6, 111.4, 152.5,
130.4, 120.5, 131.8, 134.6, 141.4, 152.4, 187.2 ppm. IR (neat): ν =
˜
3062, 2906, 1668, 1214 cm–1. HRMS: calcd. for C24H18NO3S2 [M
+ H]+ 432.0728; found 432.0724.
5-Bromo-3-(2,4-dimethoxyphenylthio)-1H-indole (3gb): Column
chromatography on silica gel (eluent: cyclohexane/ethyl acetate =
80:20) gave product 3gb in 88% isolated yield as a white solid, m.p.
138–140 °C (ethanol). 1H NMR (CDCl3): δ = 3.73 (s, 3 H), 3.92 (s,
3 H), 6.25–6.28 (dd, J = 1.7, JЈ = 8.55 Hz, 1 H), 6.46 (d, J =
2.14 Hz, 1 H), 6.65 (d, J = 8.55 Hz, 1 H), 7.29 (d, J = 1.28 Hz, 1
H), 7.45 (d, J = 2.12 Hz, 1 H), 7.73–7.78 (m, 1 H), 7.84–7.86 (m,
1 H), 8.81 (br. s, 1 H) ppm. 13C NMR (CDCl3): δ = 55.7, 56.1,
99.1, 102.9, 105.3, 113.2, 114.5, 118.1, 122.6, 123.8, 126.1, 128.4,
187.2 ppm. IR (neat): ν = 3436, 2855, 1552 cm–1. HRMS: calcd.
˜
for C14H11N2O3S [M + H]+ 287.0490; found 287.0488.
4-(tert-Butyldimethylsilyloxy)-2,3-dimethyl-6-(1H-pyrrol-2-ylthio)-
phenol (8af): Column chromatography on silica gel (eluent: cyclo-
hexane/ethyl acetate = 90:10) gave product 8ag in 90% isolated
1
yield as a brown oil. H NMR (CDCl3): δ = 0.12 (s, 6 H) 0.98 (s,
131.4, 132.1, 132.8, 134.6 ppm. IR (neat): ν = 3677, 1508,
˜
9 H), 2.1 (s, 3 H), 2.16 (s, 3 H), 6.07 (s, 1 H), 6.17–6.19 (m, 1 H),
6.44–6.46 (br. s, 1 H), 6.66 (s, 1 H), 6.78–6.80 (dd, J = 1.2, JЈ =
2.5 Hz, 1 H), 8.07–8.11 (br. s, 1 H) ppm. 13C NMR (CDCl3): δ =
13.1, 13.3, 18.4, 26.0, 29.9, 40.1, 40.0, 110.0, 116.1, 117.5, 117.7,
1303 cm–1. ESI-MS: positive ion mode: m/z = 265 [M + H]+; nega-
tive ion mode: m/z = 263 [M – H]–, 399 [M + Cl]–. HRMS: calcd.
for C16H15BrNO2S [M + H]+ 364.0007; found 364.0005.
4-(tert-Butyldimethylsilyloxy)-6-(1H-indol-3-ylthio)-2,3-dimethyl-
phenol (3af): Column chromatography on silica gel (eluent: cyclo-
hexane/ethyl acetate = 80:20) gave product 3af in 77% isolated yield
119.9, 121.2, 123.6, 124.8, 130.1, 137.0, 147.9 ppm. IR (neat): ν =
˜
3410, 2930, 1600, 1549, 1332 cm–1. EI-MS: m/z (%) = 349 [M]+,
225, 198 (100), 73. HRMS: calcd. for C18H28NO2SSi [M + H]+
350.1610; found 350.1609.
1
as a yellow oil. H NMR (CDCl3): δ = 0.05 (s, 6 H), 0.96 (s, 9 H),
2.08 (s, 3 H), 2.18 (s, 3 H), 7.17–7.24 (m, 2 H), 6.80 (s, 1 H), 7.30–
7.32 (m, 2 H) 7.73 (d, J = 7.7 Hz, 1 H), 8.26 (br. s, 2 H) ppm. 13C
NMR (CDCl3): δ = 13.2, 18.4, 26.1, 105.4, 111.8, 117.2, 119.5,
120.4, 121.0, 123.2, 124.3, 128.6, 128.7, 130.0, 136.5, 146.9,
Supporting Information (see footnote on the first page of this arti-
cle): IR, EI and ESI mass, 1H and 13C NMR spectra of 3-sulf-
enylindoles and 2-sulfenylpyrrole products.
148.1 ppm. IR (neat): ν = 3600, 3500, 1453 cm–1. ESI-MS: positive
˜
ion mode: m/z = 400 [M + H]+; negative ion mode: m/z = 398 [M –
H]–. HRMS: calcd. for C22H30NO2SSi [M + H]+ 400.1767; found
400.1767.
Acknowledgments
The authors thank the University of Camerino and the University
of Firenze. This work was carried out under the framework of the
National Project “Dynamic study of photochemical processes in
the gas phase on systems of environmental and biological interest”
supported by the Ministero dell’Università e della Ricerca (MIUR)
(PRIN 2009). The authors thank Pfizer Ascoli Piceno Plant for
funding a doctoral fellowship for R. P. and CARIPLO Milano for
a grant to C. V. The authors are grateful to the Interdepartmental
Center of the University of Camerino for performing XPS mea-
surements.
Naphtho[2Ј,1Ј:2,3][1,4]oxathiepino[6,5-b]indol-8(9H)-one (3ha): Col-
umn chromatography on silica gel (eluent: cyclohexane/ethyl acet-
ate = 80:20) gave product 3ha in 80% isolated yield as an orange
1
oil. H NMR (C6D6): δ = 5.95 (d, J = 9.8 Hz, 1 H), 6.45 (d, J =
10.9 Hz, 1 H), 6.68 (d, J = 7.3 Hz, 1 H), 6.86–6.97 (m, 2 H), 7.18–
7.26 (m, 1 H), 7.29–7.31 (m, 1 H), 7.45 (d, J = 8.1 Hz, 1 H), 7.57
(d, J = 7.7 Hz, 1 H), 8.08 (d, J = 8.1 Hz, 1 H) ppm. 13C NMR
(C6D6): δ = 121.8, 123.6, 124.4, 125.0, 127.4, 128.1, 128.2, 128.4,
128.6, 128.8, 128.9, 130.1, 130.2, 130.4, 132.5, 136.3, 140.9, 153.2,
186.6 ppm. IR (neat): ν = 3046, 1675, 1507, 1456 cm–1. ESI-MS:
˜
negative ion mode: m/z = 317 [M – H]–. HRMS: calcd. for
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Eur. J. Org. Chem. 2013, 132–140
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
139

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Received: August 13, 2012
Published Online: November 19, 2012
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