Synthesis of sulfones by iron-catalyzed decomposition of sulfonylhydrazones

Article abstract of DOI:10.1002/ejoc.201001492

The Fe-catalyzed decomposition of sulfonylhydrazones gives rise to sulfones. The reaction is quite general and allows the preparation of sulfones from a variety of aryl, alkyl, and α,β-unsaturated aldehydes and ketones. Crossover experiments reveal that the reaction is an intermolecular process, which may proceed by nucleophilic attack of the sulfinate anion on an iron carbene complex. Carbonyl compounds can be easily transformed into sulfones by Fe-catalyzed decomposition of the corresponding sulfonylhydrazones. The process most likely proceeds through an iron carbene complex and opens the door for the design of othernovel Fe-catalyzed reductive couplings. Copyright

Full text of DOI:10.1002/ejoc.201001492

FULL PAPER
DOI: 10.1002/ejoc.201001492
Synthesis of Sulfones by Iron-Catalyzed Decomposition of Sulfonylhydrazones
José Barluenga,*[a] María Tomás-Gamasa,[a] Fernando Aznar,[a] and Carlos Valdés*[a]
Keywords: Sulfur / Hydrazones / Iron / Cross-coupling / Diazo compounds / Carbenes
The Fe-catalyzed decomposition of sulfonylhydrazones gives
rise to sulfones. The reaction is quite general and allows the
preparation of sulfones from a variety of aryl, alkyl, and α,β-
unsaturated aldehydes and ketones. Crossover experiments
reveal that the reaction is an intermolecular process, which
may proceed by nucleophilic attack of the sulfinate anion on
an iron carbene complex.
of nitrogen from tosylhydrazones (Scheme 1, Equation d).
Taking into account the interest of sulfones both as syn-
thetic intermediates[6] and as structural units in pharmaceu-
ticals,[7] we optimized this background reaction and, thus,
identified conditions to carry out this transformation
through a Fe-catalyzed process. The formation of sulfones
from tosylhydrazones had been previously reported by Che
and co-workers by employing a Ru-based catalyst,[8] al-
though the reaction showed a very limited scope. However,
very recently, a similar transformation promoted by Cu
salts was reported by Yu and co-workers.[9] This report
prompted us to disclose our own results in this area.
The discovery of the Pd-catalyzed cross-coupling reac-
tion between tosylhydrazones and aryl halides that allows
the synthesis of polysubstituted olefins (Scheme 1, Equa-
tion a) triggered our interest in these types of reagents.
Since our initial contribution, our group and others have
developed different coupling reactions that employ tosylhy-
drazones and Pd catalysts. As a continuation of this study,
we investigated whether or not this reaction could be car-
ried out by employing other metal catalysts. Bolstered by
the growing interest and applications of iron catalysts[10]
and by the fact that iron is one of the most abundant,
cheapest, and environmentally friendly metals,[11] we fo-
cused on iron-based catalysts for the latter transformation.
Introduction
One of the main challenges of current organic chemistry
is the development of new sustainable processes to achieve
chemical transformations. Therefore, great efforts are being
paid to the discover of new methodologies that improve the
efficiency, selectivity, and availability of starting materials
and the environmental sustainability of synthetic pro-
cesses.[1] In this context, we have recently focused on tos-
ylhydrazones[2] as valuable and readily available reagents in
C–C and C–O bond-forming reactions through Pd-cata-
lyzed[3] and metal-free processes[4] (Scheme 1, Equations a–
c). Our group and others[5] have shown that the use of tos-
ylhydrazones represents a very convenient methodology for
the unconventional modification of carbonyl compounds.
Scheme 1. Equations a–c: recent applications of tosylhydrazones
for the unconventional elaboration of carbonyl compounds; equa-
tion d: this work.
Results and Discussion
We first turned our attention to couplings involving
Fe(acac)3 as the catalyst (30 mol-%). When tosylhydrazone
1a derived from 4-methylacetophenone was treated with 4-
bromotoluene (2) in the presence of LiOtBu in dioxane at
110 °C no cross-coupling reaction was observed (Scheme 2).
The only products obtained were those derived from the
evolution of the diazo compound generated from the hydraz-
one, Bamford–Stevens alkene 3, and homocoupling prod-
ucts 4 and 5.[12] Inclusion of FeCl3 in the same reaction also
failed to afford any cross-coupled product. However, under
these reaction conditions a significant amount of sulfone 6a
During our research, we observed that under certain re-
action conditions sulfones could be obtained by the loss
[a] Instituto Universitario de Química Organometálica
“Enrique Moles”, Universidad de Oviedo
c/ Julián Clavería 8, Oviedo 33006, Spain
Fax: +34-985103450
E-mail: barluenga@uniovi.es
acvg@uniovi.es
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001492.
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Sulfones through Fe-Catalyzed Decomposition of Sulfonylhydrazones
was isolated together with compounds 4 and 5. These and % of the iron salt was found to be optimal. When 5 mol-%
numerous other failed reactions with an assortment of iron of FeCl3 was used, 6a was formed in lower yield (Table 1,
salts inspired us to rethink how best to accomplish our goal Entry 10).
of developing an iron version of the previously developed
Table 1. Influence of the reaction conditions in the Fe-catalyzed
Pd-catalyzed cross-couplings.
thermal decomposition of tosylhydrazone 1a.[a]
Entry
Fe source
Base
Product ratio [%][b]
3
4
5
6
1
2
3
4
5
6
Fe(acac)3
FeCl3
Fe[Cp(CO)2]Cl
FeCl3
EtMgBr
EtMgBr
EtMgBr
LiOtBu
K2CO3
MeMgBr
EtMgBr
EtMgBr
EtMgBr
EtMgBr
–
8
15
4
0
14
0
18
17
3
0
83
0
8
5
16
15
31
21
8
4
4
23
0
36
18
0
58
33
68
51
35
71
10
10
3
29
2
62
34
5
26
47
12
34
20
8
64
69
90
48
15
2
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
–
7[c,f]
8[d,f]
9[e]
10[e,g]
11
Scheme 2. Unsuccessful attempts at an iron-catalyzed cross-cou-
pling between tosylhydrazones and aryl halides.
12
LiOtBu
EtMgBr
EtMgBr
EtMgBr
13[e,f,h]
14[e,f,i]
15[e,f,j]
FeCl3
FeCl3
FeCl3
29
27
7
19
68
19
In light of difficulties encountered when taking into ac-
count only the source of iron, we examined the impact of
base upon the reaction. We were specifically interested in
the use of Grignard reagents as bases, as their role in the
formation of low-valent iron–magnesium catalysts was well
8
66
[a] Reaction conditions: 1a (0.5 mmol), base (3 equiv.), Fe cat (30
mol-%), dioxane (2 mL). [b] Determined by GC–MS; total conver-
sion of 1a was observed in all cases. [c] Addition time of the tos-
established.[13] This preliminary survey showed that the ylhydrazone: 2 h. [d] Addition time of the tosylhydrazone: 8 h.
[e] Addition time of the tosylhydrazone: 4 h. [f] FeCl3 (10 mol-%)
catalytic systems being tested were not able to promote the
desired cross-coupling reaction; instead, sulfone 6a was
again formed under the selected reaction conditions. Given
at 90 °C.
the importance of sulfones as synthetic intermediates and
was employed. [g] FeCl3 (5 mol-%) was employed. [h] Carried out
at 80 °C. [i] Carried out in refluxing THF. [j] Carried out in toluene
also as members of a key structural motif in medicinal
In order to minimize the formation of alkene and homo-
chemistry, we investigated the feasibility of this reaction as coupling products, the rate of addition of the tosyl-
a synthetically useful transformation by which to obtain hydrazone was considered.[14] Delightfully, much better re-
sulfones from sulfonylhydrazones.
sults were obtained when the tosylhydrazone was added
Initial optimization efforts focused on the identification slowly by using a syringe pump. Thus, when a solution of
of the best iron source, base, solvent, and tosylhydrazone by tosylhydrazone 1a in dioxane was slowly added over the
using 1a as the model substrate. We found that formation of course of 4 h at 110 °C (at a rate of approximately
sulfone 6a took place to varying extents under a variety 0.250 mLh–1) to a solution of ethylmagnesium bromide
of reaction conditions; selected examples are included in (1 equiv.) and FeCl3 (10 mol-%), sulfone 6a was formed as
Table 1. Using dioxane as solvent, FeCl3 provided the best the major product with only small amounts of other side
results and afforded product 6a as the major component products being detectable.
of a mixture (Table 1, Entry 2). Comparison of the results
With this protocol in hand, we studied the scope of the
obtained with reactions using an assortment of bases indi- reaction (Table 2). The transformation seems to be general,
cated that ethylmagnesium bromide was the most effective as tosylhydrazones derived from ketones or aldehydes were
reagent for this transformation (Table 1, Entries 2 and 4–6). converted into corresponding compound 6 by using the
A control experiment in the absence of base confirmed that above-mentioned conditions. Electron-rich aromatic sys-
the iron salt showed some catalytic ability, as 6a was ob- tems (Table 2, Entries 1 and 6) as well as electron-poor de-
tained in low yield (Table 1, Entry 11). However, in the ab- rivatives (Table 2, Entries 3, 4 and 7) underwent the reac-
sence of the iron salt, the reaction failed to provide appreci- tion. Moreover, esters and nitriles were unaffected by these
able amounts of sulfone (Table 1, Entry 12). The reaction conditions. Halogen substitution of the aromatic rings was
was dependent on the nature of the solvent and on the tem- also tolerated (Table 2, Entries 3 and 13), enabling further
perature. Thus, better yields were achieved when the reac- derivatization through metal-catalyzed cross-coupling tech-
tion was carried out in dioxane at 110 °C. The use of other niques. The transformation was found to proceed in good
solvents (THF, toluene; Table 1, Entries 14 and 15) as well yields when heterocyclic derivatives were used (Table 2, En-
as lower reaction temperatures (Table 1, Entry 13) provided tries 11 and 12). Importantly, unlike the Cu-catalyzed pro-
poorer results. With respect to the catalyst loading, 10 mol- cess, the reaction is not limited to tosylhydrazones derived
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J. Barluenga, M. Tomás-Gamasa, F. Aznar, C. Valdés
FULL PAPER
Table 2. Iron-catalyzed synthesis of tolyl sulfones from tosylhydraz- from aromatic carbonyl compounds. Indeed, hydrazones
ones 1.[a]
derived from dialkyl ketones and alkyl aldehydes also par-
ticipated successfully in the reaction (Table 2, Entries 5 and
8). Moreover, allyl sulfones, important synthetic intermedi-
ates,[15] could be prepared from α,β-unsaturated cyclic or
acyclic tosylhydrazones (Table 2, Entries 9 and 10).
The reaction was also successfully conducted with mes-
ylhydrazones, giving rise to dialkyl sulfones (Scheme 3).
This is an interesting result, as the methyl sulfone group is
found in many therapeutic agents.
Scheme 3. Iron-catalyzed synthesis of methyl sulfones 8 from mes-
ylhydrazones 7. Reaction conditions: EtMgBr (1 equiv.), FeCl3 (10
mol-%), dioxane. A solution of hydrazone 7 (0.5 mmol) in dioxane
(1 mL) was added to the mixture of FeCl3 and the base in dioxane
(1 mL) at 110 °C over 3–10 h. Yields are those obtained for the
isolated product after column chromatography. For substrate 8b,
an additional amount of LiOtBu (2.4 equiv.) was needed to im-
prove the yield.
It is well known that N-tosylhydrazones in the presence
of base undergo thermal decomposition through the Bam-
ford–Stevens reaction to generate diazo compounds, which
may produce metal carbenes in the presence of a transition
metal.[2] The mechanisms previously proposed by the
groups of Che and Yu for the formation of sulfones from
sulfonylhydrazones are based on this reaction and comprise
the addition of the sulfinate, released upon decomposition
of the sulfonylhydrazone, to the metal-stabilized carbene
complex (Figure 1).
Figure 1. Proposed mechanism for the Fe-catalyzed C–S bond-
forming reaction.
To find additional support for this mechanistic proposal
and to eliminate the possibility of an intramolecular nitro-
[a] Reaction conditions: EtMgBr (1 equiv.), FeCl3 (10 mol-%), dioxane.
gen extrusion reaction, we carried out a crossover experi-
A solution of hydrazone 1 (0.5 mmol) in dioxane (1 mL) was added to
ment by employing two different sulfonylhydrazones. Thus,
tosylhydrazone 1b, derived from acetophenone, and mes-
the mixture of FeCl3 and the base in dioxane (1 mL) at 110 °C over a
period of 2 to 8 h. [b] Isolated yield after column chromatography.
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Sulfones through Fe-Catalyzed Decomposition of Sulfonylhydrazones
N-mesylhydrazones 7 derived from carbonyl compounds 4 were
prepared following a procedure described in the literature.[17] NMR
spectra were recorded at 400 or 300 MHz for 1H and 100 or
75 MHz for 13C, with the residual solvent signals as standard for
1H and 13C. The data are being as s = singlet, br. s = broad singlet,
d = doublet, t = triplet, q = quartet, dd = doublet of doublets, dt
= doublet of triplets, and m = multiplet or unresolved. Mass spec-
tra were obtained by EI (70 eV) with a Finnigan Mat 95 spectrome-
ter.
ylhydrazone 7c, derived from 4-methoxybenzaldehyde, were
used in the established procedure (Scheme 4). The reaction
afforded an equimolar mixture of the four different combi-
nations of the carbonyl and sulfonyl fragments – two methyl
sulfones and two tolyl sulfones – indicating that, indeed, the
intermolecular pathway and not an intramolecular ex-
trusion process takes place.
General Procedure for the Synthesis of Tolyl Sulfones from Tosyl-
hydrazones 1: A reaction tube under a nitrogen atmosphere was
charged with FeCl3 (4.87 mg, 10 mol-%, 0.03 mmol). After 1 min,
ethylmagnesium bromide (1.0 equiv.) and dioxane (1 mL) were
added. The system was heated at 110 °C with stirring, and the cor-
responding tosylhydrazone 1 (0.3 mmol) dissolved in dioxane
(1 mL) was added with a syringe pump over 2 to 8 h (0.500 to
0.125 mL/h). After addition, the reaction mixture was kept at
110 °C for an additional period of 24 h (GC–MS monitoring).
When the reaction was complete, the crude reaction mixture was
allowed to reach room temperature, the solvent was eliminated, and
1 m HCl and dichloromethane were added, and the layers were sep-
arated. The aqueous phase was extracted three times with dichloro-
methane. The combined organic layers were washed with two por-
tions of 1 m HCl and brine and then dried with MgSO4 and filtered.
Solvent was removed under reduced pressure. If necessary, the
products were purified by chromatography on silica gel.
Scheme 4. Study of the pathway of the iron-promoted synthesis of
sulfones through a crossover experiment.
Although mechanistic studies to shed light on this pro-
cess and establish the role of the metal catalyst are currently
underway, a plausible catalytic cycle involves an iron carb-
ene (Figure 1). Attack of the sulfinate group upon the iron
carbene[16] is envisioned to generate a metal–alkyl complex
that, upon protonolysis, affords the sulfone.
1-Methyl-4-[(1-p-tolylethyl)sulfonyl]benzene (6a): 4-Methyl-NЈ-(1-p-
tolylethylidene)benzenesulfonohydrazide (90.7 mg, 0.3 mmol) af-
forded 6a (51.0 mg, 62% yield) as a white solid (m.p. 131.0–
140.3 °C). Compound 6a was purified by flash chromatography on
silica gel (hexanes/ethyl acetate, 4:1). Rf (hexanes/ethyl acetate, 4:1)
Conclusions
1
3
= 0.31. H NMR (300 MHz, CDCl3): δ = 1.71 (d, JH,H = 7.2 Hz,
3 H, CHCH3), 2.32 (s, 3 H, CH3), 2.39 (s, 3 H, CH3), 4.18 (q, 3JH,H
In conclusion, we have developed a new iron-catalyzed
C–S bond-forming reaction. This transformation, catalyzed
by inexpensive and environmentally friendly FeCl3, pro-
vides efficient access to a great variety of sulfones, which
are highly useful organic products. Moreover, it is worth
noting that these reactions meet the requirements of sus-
tainable chemistry: (i) a nontoxic metal catalyst is employed
= 7.2 Hz, 1 H, CHCH3), 7.01–7.10 (m, 4 H, CHarom), 7.19 (d, 3JH,H
3
= 8.1 Hz, 2 H, CHarom), 7.43 (d, JH,H = 8.1 Hz, 2 H, CHarom
)
ppm. 13C NMR (75 MHz, CDCl3): δ = 14.2 (CH3), 21.1 (CH3),
21.5 (CH3), 65.6 (CH), 129.0 (2 CH), 129.2 (4 CH), 129.3 (2 CH),
130.7 (C), 134.0 (C), 138.5 (C), 144.3 (C) ppm. HRMS (EI): calcd.
for C16H18O2S 274.1028; found 274.1021.
and (ii) a carbonyl compound is transformed into a sulfone 1-Methyl-4-[(1-phenylethyl)sulfonyl]benzene (6b):[18] 4-Methyl-NЈ-
(1-phenylethylidene)benzenesulfonohydrazide (86.5 mg, 0.3 mmol)
afforded 6b (48.4 mg, 62% yield) as a yellow solid (m.p. 133.0–
138.0 °C). Compound 6b was purified by flash chromatography on
silica gel (hexanes/ethyl acetate, 4:1). Rf (hexanes/ethyl acetate, 4:1)
with H2O and N2 as the only byproducts. Furthermore, the
importance of the process lies in its intermolecular nature.
Thus, the reaction involves the introduction of a nucleo-
phile, the sulfinate group, and an electrophile, the proton, in
a sequential manner. Future work in this area will include
detailed mechanistic studies and the extension of the reac-
tion to other types of nucleophiles and electrophiles.
1
3
= 0.40. H NMR (300 MHz, CDCl3): δ = 1.77 (d, JH,H = 7.0 Hz,
3
3 H, CHCH3), 2.41 (s, 3 H, CH3), 4.23 (q, JH,H = 7.0 Hz, 1 H,
3
CHCH3), 7.12–7.34 (m, 7 H, CHarom), 7.43 (d, JH,H = 7.1 Hz, 2
H, CHarom) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.0 (CH3),
21.5 (CH3), 65.9 (CH), 128.2 (2 CH), 128.6 (CH), 129.0 (2 CH),
129.1 (2 CH), 129.3 (2 CH), 133.8 (2 C), 144.3 (C) ppm. HRMS
(EI): calcd. for C15H16O2S 260.0871; found 266.0880.
Experimental Section
General Methods: All reactions were carried out with a RR98030
12 place Carousel Reaction Station from Radleys Discovery Tech-
nologies, equipped with gas-tight threaded caps with a valve, cool-
ing reflux head system, and digital temperature controller. Dioxane
and dichloromethane were dried by standard procedures. Anhy-
drous FeCl3 was purchased from Aldrich Chemical Co. and used
without further purification and weighed in air. EtMgBr (1.0 m in
THF) was purchased from Aldrich Chemical Co. All carbonyl
compounds are commercially available from Aldrich Chemical Co.,
Acros Organics Chemical Co., and Alfa Aesar Chemical Co. and
were used without further purification. N-Tosylhydrazones 1 and
1-Chloro-4-[(1-p-tolylethyl)sulfonyl]benzene (6c): NЈ-[1-(4-Chlo-
rophenyl)ethylidene]-4-methylbenzenesulfonohydrazide (96.8 mg,
0.3 mmol) afforded 6c (66.3 mg, 75% yield) as a yellow oil. Com-
pound 6c was purified by flash chromatography on silica gel (hex-
anes/ethyl acetate, 2:1). Rf (hexanes/ethyl acetate, 2:1) = 0.37. 1H
3
NMR (300 MHz, CDCl3): δ = 1.73 (d, JH,H = 7.2 Hz, 3 H,
3
CHCH3), 2.42 (s, 3 H, CH3), 4.20 (q, JH,H = 7.2 Hz, 1 H,
3
CHCH3), 7.08 (d, JH,H = 8.7 Hz, 2 H, CHarom), 7.19–7.25 (m, 4
H, CHarom), 7.43 (d, 3JH,H = 8.7 Hz, 2 H, CHarom) ppm. 13C NMR
(75 MHz, CDCl3): δ = 14.2 (CH3), 21.6 (CH3), 65.3 (CH), 128.6 (2
CH), 129.2 (2 CH), 129.4 (2 CH), 130.7 (2 CH), 132.5 (C), 133.7
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J. Barluenga, M. Tomás-Gamasa, F. Aznar, C. Valdés
FULL PAPER
(C), 134.8 (C), 144.7 (C) ppm. HRMS (EI): calcd. for C15H15ClO2S
294.0481; found 294.0468.
3
3.03–3.12 (m, 2 H, CH2CH2CH2), 7.12 (d, JH,H = 7.2 Hz, 2 H,
3
CHarom), 7.18–7.28 (m, 3 H, CHarom), 7.37 (d, JH,H = 8.1 Hz, 2
H, CHarom), 7.79 (d, 3JH,H = 8.1 Hz, 2 H, CHarom) ppm. 13C NMR
(75 MHz, CDCl3): δ = 21.6 (CH3), 24.2 (CH2), 34.1 (CH2), 55.5
(CH2), 126.3 (CH), 128.0 (2 CH), 128.3 (2 CH), 128.5 (2 CH),
129.8 (2 CH), 136.1 (C), 139.9 (C), 144.6 (C) ppm. HRMS (EI):
calcd. for C16H18O2S 274.1028; found 274.1021.
Methyl 4-[(p-tolylsulfonyl)methyl]benzoate (6d):[19] Methyl 4-[(2-tos-
ylhydrazono)methyl]benzoate (60.8 mg, 0.3 mmol) afforded 6d
(44.3 mg, 40% yield) as a yellow solid (m.p. 179.0–198.5 °C, de-
composition). Compound 6d was purified by flash chromatography
on silica gel (hexanes/ethyl acetate, 3:1). Rf (hexanes/ethyl acetate,
1
3:1) = 0.53. H NMR (300 MHz, CDCl3): δ = 2.21 (s, 3 H, CH3),
1-(4,4-Dimethylcyclohex-2-enylsulfonyl)-4-methylbenzene (6i): NЈ-
(4,4-Dimethylcyclohex-2-enylidene)-4-methylbenzenesulfonohydraz-
ide (87.7 mg, 0.3 mmol) afforded 6i (39.7 mg, 50% yield) as a yel-
low oil. Compound 6i was purified by flash chromatography on
silica gel (hexanes/ethyl acetate, 3:1). Rf (hexanes/ethyl acetate, 3:1)
3
3.46 (s, 3 H, CH3), 3.82 (s, 2 H, CH2), 6.18 (d, JH,H = 6.8 Hz, 2
3
3
H, CHarom), 6.24 (d, JH,H = 6.8 Hz, 2 H, CHarom), 6.45 (d, JH,H
3
= 6.8 Hz, 2 H, CHarom), 6.81 (d, JH,H = 6.8 Hz, 2 H, CHarom
)
ppm. 13C NMR (75 MHz, CDCl3): δ = 21.5 (CH3), 52.2 (CH3),
62.6 (CH2), 128.5 (2 CH), 129.5 (2 CH), 129.6 (2 CH), 130.3 (C),
130.7 (2 CH), 133.2 (C), 134.7 (C), 144.9 (C), 166.5 (C) ppm.
HRMS (EI): calcd. for C16H16O4S 304.0769; found 304.0762.
1
= 0.50. H NMR (300 MHz, CDCl3): δ = 0.78 (s, 3 H, CH3), 0.93
(s, 3 H, CH3), 1.23–1.36 (m, 1 H, CCHHCH2), 1.42–1.52 (m, 1 H,
CCHHCH2), 1.85–2.01 (m, 2 H, CCH2CH2), 2.44 (s, 3 H, CH3),
3
3.64–3.71 (m, 1 H, CH), 5.65 (dd, JH,H = 3.0, 10.1 Hz, 1 H,
1-Methyl-4-(1-phenylpropan-2-ylsulfonyl)benzene (6e): 4-Methyl-NЈ-
3
3
CH=CH), 5.77 (d, JH,H = 10.1 Hz, 1 H, CH=CH), 7.33 (d, JH,H
(1-phenylpropan-2-ylidene)benzenesulfonohydrazide
(90.7 mg,
3
= 8.5 Hz, 2 H, CHarom), 7.74 (d, JH,H = 8.5 Hz, 2 H, CHarom
)
0.3 mmol) afforded 6e (47.7 mg, 58% yield) as a colorless oil. Com-
pound 6e was purified by flash chromatography on silica gel (hex-
anes/ethyl acetate, 3:1). Rf (hexanes/ethyl acetate, 3:1) = 0.34. 1H
ppm. 13C NMR (75 MHz, CDCl3): δ = 19.8 (CH2), 21.6 (CH3),
28.2 (CH3), 29.3 (CH3), 31.3 (C), 33.9 (CH2), 61.9 (CH), 116.2
(CH), 129.2 (2 CH), 129.4 (2 CH), 134.2 (C), 144.5 (C), 144.9 (CH)
ppm. HRMS (EI): calcd. for C15H20O2S 264.1184; found 264.1181.
3
NMR (300 MHz, CDCl3): δ = 1.14 (d, JH,H = 6.8 Hz, 3 H,
CH2CHCH3), 2.45–2.53 (m, 4 H, CH3, CHHCHCH3), 3.16–3.30
2
3
(m, 1 H, CH2CHCH3), 3.42 (dd, JH,H = 3.1, JH,H = 13.2 Hz, 1
H, CHHCHCH3), 7.07–7.12 (m, 2 H, CHarom), 7.20–7.30 (m, 3 H,
1-(Cinnamylsulfonyl)-4-methylbenzene (6j):[22] 4-Methyl-NЈ-[(E)-3-
phenylallylidene]benzenesulfonohydrazide (90.1 mg, 0.3 mmol) af-
forded 6j (54.7 mg, 67% yield) as a white solid. Compound 6j was
purified by flash chromatography on silica gel (hexanes/ethyl acet-
3
CHarom), 7.35–7.42 (m, 2 H, CHarom), 7.81 (d, JH,H = 8.3 Hz, 2
H, CHarom) ppm. 13C NMR (75 MHz, CDCl3): δ = 12.6 (CH3),
21.6 (CH3), 35.3 (CH2), 61.6 (CH), 126.8 (CH), 128.6 (2 CH), 128.9
(2 CH), 129.0 (2 CH), 129.7 (2 CH), 134.1 (C), 137.0(C), 144.6 (C)
ppm. HRMS (EI): calcd. for C15H16O3S 276.0808; found 276.0802.
ate, 3:1). Rf (hexanes/ethyl acetate, 3:1)
=
0.63. 1H NMR
(300 MHz, CDCl3): δ = 2.45 (s, 3 H, CH3), 3.93 (d, 3JH,H = 7.6 Hz,
3
2
H, CH=CHCH2), 6.10 (dt, JH,H
=
7.6, 16.1 Hz,
1
H,
1-Methoxy-4-[(p-tolylsulfonyl)methyl]benzene (6f):[20] NЈ-(4-Meth-
CH=CHCH2), 6.39 (d, 3JH,H = 16.1 Hz, 1 H, CH=CHCH2), 7.27–
7.35 (m, 7 H, CHarom), 7.76 (d, 3JH,H = 8.2 Hz, 2 H, CHarom) ppm.
13C NMR (75 MHz, CDCl3): δ = 21.5 (CH3), 60.5 (CH2), 115.3
(CH), 126.5 (CH), 128.3 (CH), 128.4 (2 CH), 128.6 (2 CH), 129.6
(2 CH), 135.5 (C), 135.7 (C), 138.9 (CH), 144.7 (C) ppm. HRMS
(EI): calcd. for C16H16O2S 272.00873; found 272.0871.
oxybenzylidene)-4-methylbenzenesulfonohydrazide
(91.3 mg,
0.3 mmol) afforded 6f (63.0 mg, 76% yield) as a white solid (m.p.
115.0–124.0 °C). Compound 6f was purified by flash chromatog-
raphy on silica gel (hexanes/ethyl acetate, 4:1). Rf (hexanes/ethyl
acetate, 4:1) = 0.32. 1H NMR (300 MHz, CDCl3): δ = 2.43 (s, 3 H,
3
CH3), 3.80 (s, 3 H, CH3), 4.24 (s, 2 H, CH2), 6.80 (d, JH,H
=
3
2-[(p-Tolylsulfonyl)methyl]furan (6k):[23] NЈ-(Furan-2-ylmethylene)-
4-methylbenzenesulfonohydrazide (79.3 mg, 0.3 mmol) afforded 6k
(43.2 mg, 61% yield) as a yellow oil. Compound 6k was purified
by flash chromatography on silica gel (hexanes/ethyl acetate, 2:1).
Rf (hexanes/ethyl acetate, 8:1) = 0.30. 1H NMR (300 MHz, CDCl3):
δ = 2.45 (s, 3 H, CH3), 4.18 (s, 2 H, CH2), 6.29–6.34 (br. s, 1 H,
8.3 Hz, 2 H, CHarom), 7.02 (d, JH,H = 8.3 Hz, 2 H, CHarom), 7.25
3
3
(d, JH,H = 8.3 Hz, 2 H, CHarom), 7. 52 (d, JH,H = 8.3 Hz, 2 H,
CHarom) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.5 (CH3), 55.1
(CH3), 62.1 (CH2), 113.9 (2 CH), 120.0 (C), 128.5 (2 CH), 129.4 (2
CH), 131.9 (2 CH), 135.0 (C), 144.4 (C), 159.8 (C) ppm. HRMS
(EI): calcd. for C15H16O3S 276.0808; found 276.0802.
3
CHarom), 7.21–7.25 (m, 1 H, CHarom), 7.29 (d, JH,H = 8.7 Hz, 2
4-[(p-Tolylsulfonyl)methyl]benzonitrile (6g): NЈ-(4-Cyanobenzyl-
idene)-4-methylbenzenesulfonohydrazide (89.8 mg, 0.3 mmol) af-
forded 6g (58.6 mg, 72% yield) as a yellow solid (m.p. 198.5–
208.0 °C, decomposition). Compound 6g was purified by flash
chromatography on silica gel (hexanes/ethyl acetate, 20:1). Rf (hex-
3
H, CHarom), 7.36–7.38 (m, 1 H, CHarom), 7.63 (d, JH,H = 7.5 Hz,
2 H, CHarom) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.6 (CH3),
53.4 (CH2), 112.5 (CH), 112.8 (C), 128.6 (2 CH), 129.6 (2 CH),
134.9 (C), 142.8 (CH), 143.4 (CH), 144.8 (C) ppm. HRMS (EI):
calcd. for C12H12O3S 236.0507; found 236.0496.
1
anes/ethyl acetate, 20:1) = 0.47. H NMR (300 MHz, CDCl3): δ =
3
2.43 (s, 3 H, CH3), 4.33 (s, 2 H, CH2), 7.23 (d, JH,H = 8.3 Hz, 2
2-[(p-Tolylsulfonyl)methyl]benzofuran (6l): NЈ-(Benzofuran-2-yl-
methylene)-4-methylbenzenesulfonohydrazide (94.3 mg, 0.3 mmol)
afforded 6l (60.1 mg, 70% yield) as a pale brown solid (m.p. 202.0–
205.8 °C, decomposition). Compound 6l was purified by flash
chromatography on silica gel (hexanes/ethyl acetate, 3:1). Rf (hex-
anes/ethyl acetate, 3:1) = 0.43. 1H NMR (300 MHz, CDCl3): δ =
2.45 (s, 3 H, CH3), 4.55 (s, 2 H, CH2), 6.69 (s, 1 H, CHarom), 7.20–
7.34 (m, 4 H, CHarom), 7.39 (d, 3JH,H = 7.4 Hz, 1 H, CHarom), 7.55
3
H, CHarom), 7.27 (d, JH,H = 8.3 Hz, 2 H), 7.51 (d, 3JH,H = 8.2 Hz,
3
2 H, CHarom), 7.57 (d, JH,H = 8.2 Hz, 2 H, CHarom) ppm. 13C
NMR (75 MHz, CDCl3): δ = 21.6 (CH3), 62.5 (CH2), 112.7 (C),
118.1 (C), 128.4 (2 CH), 129.7 (2 CH), 131.4 (2 CH), 132.2 (2 CH),
133.5 (C), 134.6 (C), 145.3 (C) ppm. HRMS (EI): calcd. for
C15H13NO2S 271.0667; found 271.0673.
1-Methyl-4-[(3-phenylpropyl)sulfonyl]benzene (6h):[21] 4-Methyl-NЈ-
3
3
(3-phenylpropylidene)benzenesulfonohydrazide
(90.7 mg,
(d, JH,H = 7.4 Hz, 1 H, CHarom), 7.67 (d, JH,H = 7.9 Hz, 2 H,
CHarom) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.6 (CH3), 53.4
(CH2), 108.8 (CH), 111.2 (CH), 121.1 (CH), 123.0 (CH), 124.8
(CH), 127.8 (C), 128.4 (2 CH), 129.7 (2 CH), 135.2 (C), 145.0 (C),
145.2 (C), 155.2 (C) ppm. HRMS (EI): calcd. for C16H14O3S
286.0700; found 286.0664.
0.3 mmol) afforded 6h (53.5 mg, 65% yield) as a yellow oil. Com-
pound 6h was purified by flash chromatography on silica gel (hex-
anes/ethyl acetate, 3:1). Rf (hexanes/ethyl acetate, 3:1) = 0.41. 1H
NMR (300 MHz, CDCl3): δ = 1.97–2.12 (m, 2 H, CH2CH2CH2),
3
2.47 (s, 3 H, CH3), 2.71 (t, JH,H = 7.6 Hz, 2 H, CH2CH2CH2),
1524
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1520–1526

Sulfones through Fe-Catalyzed Decomposition of Sulfonylhydrazones
1-Bromo-4-(p-tolylsulfonylmethyl)benzene (6m): NЈ-(4-Bromobenz-
ylidene)-4-methylbenzenesulfonohydrazide (106.0 mg, 0.3 mmol)
afforded 6m (55.4 mg, 57% yield) as a yellow solid (m.p. 162.0–
180.0 °C). Compound 6m was purified by flash chromatography on
alumina (hexanes/ethyl acetate, 2:1). Rf (hexanes/ethyl acetate, 2:1)
13C NMR (75 MHz, CDCl3): δ = 38.7 (CH3), 55.3 (CH3), 60.6
(CH2), 114.5 (2 CH), 120.0 (C), 131.6 (2 CH), 160.2 (C) ppm.
HRMS (EI): calcd. for C9H12O3S 200.0507; found 200.0509.
1-Bromo-3-[(methylsulfonyl)methyl]benzene (8d): NЈ-(3-Bromo-
benzylidene)methanesulfonohydrazide (83.1 mg, 0.3 mmol) af-
forded 8d (54.6 mg, 73% yield) as a yellow solid (m.p. 88.0–
103.0 °C). Compound 8d was purified by flash chromatography on
silica gel (hexanes/ethyl acetate, 1:1). Rf (hexanes/ethyl acetate, 1:1)
1
= 0.20. H NMR (300 MHz, CDCl3): δ = 2.45 (s, 3 H, CH3), 4.25
(s, 2 H, CH2), 6.98 (d, 3JH,H = 8.3 Hz, 2 H, CHarom), 7.28 (d, 3JH,H
3
= 8.3 Hz, 2 H, CHarom), 7.42 (d, JH,H = 8.3 Hz, 1 H, CHarom),
3
7.53 (d, JH,H = 8.3 Hz, 2 H, CHarom) ppm. 13C NMR (75 MHz,
1
= 0.57. H NMR (300 MHz, CDCl3): δ = 2.54 (s, 3 H, CH3), 3.71
CDCl3): δ = 21.6 (CH2), 62.1 (CH3), 123.1 (C), 127.3 (C), 128.5 (2
CH), 129.6 (2 CH), 131.7 (2 CH), 132.3 (2 CH), 134.7 (C), 144.9
(C) ppm. HRMS (EI): calcd. for C14H13BrO2S 323.9820; found
323.9814.
(s, 2 H, CH2), 6.24–6.31 (m, 1 H, CHarom), 6.33–6.37 (m, 1 H,
CHarom), 6.46–6.54 (m, 2 H, CHarom) ppm. 13C NMR (75 MHz,
CDCl3): δ = 39.3 (CH3), 60.5 (CH2), 123.0 (C), 129.1 (CH), 130.2
(C), 130.6 (CH), 132.3 (CH), 133.3 (CH) ppm. HRMS (EI): calcd.
for C8H9BrO2S 249.9486; found 249.9501.
General Procedure for the Synthesis of Methyl Sulfones from Mes-
ylhydrazones 7: A reaction tube under nitrogen atmosphere was
charged with FeCl3 (4.87 mg, 10 mol-%, 0.03 mmol). After 1 min,
ethylmagnesium bromide (1.0 equiv.) and dioxane (1 mL) were
added. The system was heated at 110 °C with stirring, and the cor-
responding mesylhydrazone 7 (0.3 mmol) dissolved in dioxane
(1 mL) was added with a syringe pump over 3 to 10 h (0.333 to
0.100 mL/h). After addition, the reaction mixture was kept at
110 °C for an additional 24 h (GC–MS monitoring). When the re-
action was complete, the crude reaction mixture was allowed to
reach room temperature, the solvent was eliminated, and 1 m HCl
and dichloromethane were added, and the layers were separated.
The aqueous phase was extracted three times with dichlorometh-
ane. The combined organic layers were washed with two portions
of 1 m HCl and brine and then dried with MgSO4, and filtered.
The solvent was removed under reduced pressure. If necessary, the
products were purified by chromatography on silica gel.
2-[(Methylsulfonyl)methyl]benzofuran (8e): NЈ-(Benzofuran-2-yl-
methylene)methanesulfonohydrazide (94.3 mg, 0.3 mmol) afforded
8e (44.8 mg, 71% yield) as a pale brown solid (m.p. 131.5–
138.5 °C). Compound 8e was purified by flash chromatography on
silica gel (hexanes/ethyl acetate, 1:1.5). Rf (hexanes/ethyl acetate,
1:1.5) = 0.10. 1H NMR (300 MHz, CDCl3): δ = 2.67 (s, 3 H, CH3),
3.93 (s, 2 H, CH2), 5.95–5.98 (m, 1 H, CHarom), 6.23–6.35 (m, 2 H,
3
3
CHarom), 6.45 (d, JH,H = 6.7 Hz, 1 H, CHarom), 6.54 (d, JH,H
=
6.7 Hz, 1 H, CHarom) ppm. 13C NMR (75 MHz, CDCl3): δ = 40.3
(CH3), 54.8 (CH2), 109.1 (CH), 111.3 (CH), 121.4 (CH), 123.4
(CH), 125.2 (CH), 127.9 (C), 145.1 (C), 155.3 (C) ppm. HRMS
(EI): calcd. for C10H10O3S 210.0351; found 210.0359.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H and 13C NMR spectra of compounds 6 and
8.
1-Methyl-4-[1-(methylsulfonyl)ethyl]benzene (8a): NЈ-(1-p-Tolyleth-
ylidene)methanesulfonohydrazide (67.9 mg, 0.3 mmol) afforded 8a
(31.5 mg, 53% yield) as a yellow solid (m.p. 80.6–83.6 °C). Com-
pound 8a was purified by flash chromatography on silica gel (hex-
anes/ethyl acetate, 1:1.5). Rf (hexanes/ethyl acetate, 1:1.5) = 0.13.
Acknowledgments
This work was financially support by Dirección General de In-
vestigación (DGI) of Spain (CTQ2007-61048/BQU) and Consejería
de Educación y Ciencia of Principado de Asturias (IB08-088). An
FPU predoctoral fellowship to M.T.-G. is gratefully acknowledged.
3
1H NMR (300 MHz, CDCl3): δ = 1.79 (d, JH,H = 7.2 Hz, 3 H,
3
CHCH3), 2.38 (s, 3 H, CH3), 2.65 (s, 3 H, CH3), 4.18 (q, JH,H
=
3
7.2 Hz, 1 H, CHCH3), 7.22 (d, JH,H = 7.8 Hz, 2 H, CHarom), 7.34
3
(d, JH,H = 7.8 Hz, 2 H, CHarom) ppm. 13C NMR (75 MHz,
CDCl3): δ = 13.5 (CH3), 21.0 (CH3), 37.6 (CH3), 64.4 (CH), 128.7
(2 CH), 129.6 (2 CH), 131.3 (C), 139.1 (C) ppm. HRMS (EI): calcd.
for C10H14O2S 198.0715; found 198.0715.
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1-Chloro-3-[1-(methylsulfonyl)ethyl]benzene (8b): NЈ-[1-(3-Chlo-
rophenyl)ethylidene]methanesulfonohydrazide (74.0 mg, 0.3 mmol)
afforded 8b (37.4 mg, 57% yield) as a yellow oil. Compound 8b
was purified by flash chromatography on silica gel (hexanes/ethyl
acetate, 1:1). Rf (hexanes/ethyl acetate, 1:1) = 0.43. 1H NMR
3
(300 MHz, CDCl3): δ = 1.77 (d, JH,H = 7.2 Hz, 3 H, CHCH3),
3
2.68 (s, 3 H, CH3), 4.15 (q, JH,H = 7.2 Hz, 1 H, CHCH3), 7.30–
7.39 (m, 3 H, CHarom), 7.42–7.48 (m, 1 H, CHarom) ppm. 13C NMR
(75 MHz, CDCl3): δ = 13.7 (CH3), 37.9 (CH3), 64.1 (CH), 127.1
(CH), 128.9 (CH), 129.3 (CH), 130.2 (CH), 134.9 (C), 136.3 (C)
ppm. HRMS (EI): calcd. for C9H11ClO2S 218.0168; found
218.0168.
1-Methoxy-4-[(methylsulfonyl)methyl]benzene (8c):[24] NЈ-(4-Meth-
oxybenzylidene)methanesulfonohydrazide (68.5 mg, 0.3 mmol) af-
forded 8c (45.1 mg, 75% yield) as a white solid (m.p. 108.0–
122.0 °C). Compound 8c was purified by flash chromatography on
silica gel (hexanes/ethyl acetate, 1:1.5). Rf (hexanes/ethyl acetate,
1:1.5) = 0.10. 1H NMR (300 MHz, CDCl3): δ = 2.76 (s, 3 H, CH3),
3
3.84 (s, 3 H, CH3), 4.19–4.22 (br. s, 2 H, CH2), 6.95 (d, JH,H
=
3
8.6 Hz, 2 H, CHarom), 7.35 (d, JH,H = 8.6 Hz, 2 H, CHarom) ppm.
Eur. J. Org. Chem. 2011, 1520–1526
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1525

J. Barluenga, M. Tomás-Gamasa, F. Aznar, C. Valdés
FULL PAPER
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Received: November 4, 2010
Published Online: January 31, 2011
1526
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1520–1526