Dealkylative intercepted rearrangement reactions of sulfur ylides

Article abstract of DOI:10.1039/C8CC08821G

Sulfur ylides are well-known to undergo sigmatropic rearrangement reaction. Herein, we describe a novel reactivity of sulfur ylides, which provides access to the product of a formal functional group metathesis upon dealkylative interception of the rearrangement process. Using a simple iron catalyst and in situ generated diazoalkanes this method provides access to α-mercaptoacetonitrile derivatives.

Full text of DOI:10.1039/C8CC08821G

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Dealkylative intercepted rearrangement reactions
of sulfur ylides†
Cite this: Chem. Commun., 2019,
55, 338
Claire Empel,
Katharina J. Hock
and Rene M. Koenigs
*
Received 5th November 2018,
Accepted 2nd December 2018
DOI: 10.1039/c8cc08821g
rsc.li/chemcomm
Sulfur ylides are well-known to undergo sigmatropic rearrangement products that cannot be obtained by traditional reaction path-
reaction. Herein, we describe a novel reactivity of sulfur ylides, which ways. Recently, the interruption of sigmatropic rearrangement
provides access to the product of a formal functional group metathesis reactions received significant interest,4–8 and meanwhile,
upon dealkylative interception of the rearrangement process. Using a different approaches towards interrupted Pummerer,5 Baeyer–
simple iron catalyst and in situ generated diazoalkanes this method Villiger,6 Dimroth7 or Pinacol8 rearrangement reactions have
provides access to a-mercaptoacetonitrile derivatives.
been described. Intercepted, sigmatropic rearrangement reac-
tions of sulfur ylides are much less investigated, and to the best
Rearrangement reactions are important transformations that of our knowledge, there are only limited examples dating back
proceed under the migration of the skeletal carbon framework to 1981 and 1988, when Garanti et al. and Moody et al. reported
with a high degree of stereocontrol and thus allow the rapid on the thermal decomposition reactions of cyclic sulfur ylides
assembly of complex molecular frameworks.1–3 In particular, followed by dealkylation reaction though limited to single
the course of the sigmatropic rearrangement of sulfur ylides examples and to intramolecular processes.9
can be distinguished by three predominant reaction pathways.1b,c
Sulfur ylides can be readily accessed by the reaction of
First, the Doyle–Kirmse reaction describes the [2,3]-sigmatropic diazoalkanes with sulfides in the presence of various metal
rearrangement of allylic sulfides;2 second, the Sommelet–Hauser catalysts.1b,c The in situ generation of diazoalkanes10,11 and in
reaction involves the [2,3]-sigmatropic rearrangement of benzylic particular of hazardous diazoacetonitrile11–13 allows safe and
sulfides;3 and third, the Stevens rearrangement is characterized by scalable access to small, reactive compounds that are valuable
a [1,2]-sigmatropic rearrangement (Scheme 1).3
precursors in the synthesis of functional molecules. As part of
The interruption or interception of the migration step with a our ongoing interest in highly reactive diazoalkanes and ylide
suitable electro- or nucleophile opens up avenues towards chemistry,11,14 we became intrigued by the reaction of benzyl
phenyl sulfide (1a) with in situ generated diazoacetonitrile
using earth abundant iron catalysts,15 which should undergo
either Sommelet–Hauser or Stevens rearrangement, similar
to ethyl diazoacetate (2).3a Unexpectedly, we observed the
formation of a-mercaptonitrile 6a and benzyl chloride 7a,
which arise from a formal exchange or metathesis reaction of
two aliphatic groups (Scheme 1). Not even trace amounts of
conventional Stevens or Sommelet–Hauser rearrangement
could be observed. This intriguing observation sheds new light
on the reactivity of sulfur ylides and now opens up a pathway
for the direct interconversion of alkyl groups.16
Inspired by this unexpected intercepted, debenzylative rear-
rangement, we studied the influence of different catalysts and
other reaction parameters to alter the chemoselectivity of this
Scheme 1 Rearrangement reactions of sulphur ylides.
reaction and to gain access to classic rearrangement products.
However, the catalyst had no influence on the chemoselectivity
RWTH Aachen University, Institute of Organic Chemistry, Landoltweg 1, D-52074
Aachen, Germany. E-mail: rene.koenigs@rwth-aachen.de
of this transformation, and in all cases a-mercaptonitrile 6a
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c8cc08821g
was obtained as the only product. The solvent had only little
338 | Chem. Commun., 2019, 55, 338--341
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Table 1 Reaction optimization under aqueous conditions
Table 2 Scope of the interrupted rearrangement/debenzylation reaction
Entry Catalyst
Solvent Addition time [min] T [1C] Yield [%]
Entry
Starting material
Product, yield
Yield [%]
1a
FeTPPCl
FePc
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
THF
CHCl3
Toluene 240
Acetone 240
DMSO
EtOH
H2O
30
30
30
30
30
30
30
30
30
120
240
600
240
240
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
0
17
39
44
27
41
26
40
13
61
68
81
55
80
94
73
71
2a
3a
FePcCl
TBA[Fe]
Hemin
Rh2OAc4
CoTPP
CoPc
FePc
FePc
FePc
FePc
FePc
FePc
FePc
FePc
FePc
FePc
FePc
1
2
3
4
5
6
7
8
9
1a, R = Ph
1b, R = 4-Et-Ph
1c, R = 4-tBu-Ph
1d, R = 4-F-Ph
1e, R = 4-Cl-Ph
1f, R = 2-Me-Ph
1g, R = 2-MeO-Ph
1h, R = –CH2–CH2-Ph
1i, R = –(CH2)3-Ph
1j, R = –CH2–CH2-OPh
6a, R = Ph
6b, R = 4-Et-Ph
6c, R = 4-tBu-Ph
6d, R = 4-F-Ph
6e, R = 4-Cl-Ph
6f, R = 2-Me-Ph
6g, R = 2-MeO-Ph
6h, R = –CH2–CH2-Ph
6i, R = –(CH2)3-Ph
6j, R = –CH2–CH2-OPh
94
91
74
76
89
95
95
91
57
62
4a
5a
6a
7a
8a
9b
10b
11b
12b
13b
14b
15b
16b
17b
18b
19b
20b
21
10
11
12
1k
1l
6k + traces of 8
8 + traces of 6l
69
81
240
240
240
240
240
240
240
82
90
76
No catalyst CHCl3
No reaction
FePc
FePc
FePc
CHCl3
CHCl3
CHCl3
92
60
51
22
23
60
80
Reaction conditions: 0.4 mmol sulfides (1a–1l), 1 mol% FePc, and 4.0 eq. 5
were dissolved in 100 mL CHCl3 and 1.0 mL H2O at 40 1C. A solution of
4.8 eq. NaNO2 in 1.0 mL H2O was added over a period of 240 min.
a
Reaction conditions: 0.4 mmol 1, 1 mol% catalyst, and 2.0 eq. 5 were
dissolved in 100 mL DCM and 500 mL H2O at 40 1C. A solution of 2.4 eq.
b
NaNO2 in 500 mL H2O was added over a period of 30 min. Reaction
conditions: 0.4 mmol 1, 1 mol% catalyst, and 4.0 eq. 5 were dissolved in
100 mL solvent and 1.0 mL H2O at 40 1C. A solution of 4.8 eq. NaNO2 in
1.0 mL H2O was added.
electron-donating and -withdrawing groups. Remarkably, while
electron-donating or halogen substituents had only a little
effect on the course of the reaction (Table 3, entries 1 and 2),
electron-withdrawing substituents (Table 3, entries 4 and 5) led
influence on this transformation, and in all cases the inter- to the formation of the Sommelet–Hauser reaction product in
cepted rearrangement product was obtained in high isolated low to moderate yields, though still the intercepted rearrange-
yield. Further experiments focused on the addition time of ment reaction was observed. Cyclic substrates did not undergo
sodium nitrite, concentration and reaction temperature, and the intercepted rearrangement process, but underwent Stevens
under optimized conditions (Table 1, entry 14) the debenzylation rearrangement to form tetracyclic system 4q. Thioanisole (1r)
product could be isolated in excellent yield (94%). Notably, no also underwent the same intercepted rearrangement reaction
reaction was observed in the absence of an iron catalyst, indicating and the a-mercaptoacetonitrile 6a was obtained in moderate
that a carbene transfer reaction is a key mechanistic step.
yield. Consequently, we investigated this demethylation reaction
We next investigated the influence of aromatic benzylic and were delighted to observe that methyl and ethyl thioethers
thioethers. Different substitution patterns were well tolerated smoothly underwent the intercepted rearrangement reaction
and the products of the intercepted rearrangement process and the corresponding a-mercaptoacetonitrile derivatives were
were obtained in good to excellent yields, exclusively (Table 2, obtained in moderate to good yields (Table 3, entries 7–12).
entries 1–7). Similarly, aliphatic benzyl thioethers smoothly
Finally, we also tested the compatibility of the intercepted
underwent a highly chemoselective intercepted rearrangement rearrangement with different acceptor-only diazoalkanes that
process and the debenzylation products were obtained in good were also generated in situ. The corresponding reaction products
yield (Table 2, entries 8–10). For benzyl(hexyl)sulfane (1k), the 10a–c were isolated in moderate to good yields (Scheme 2). In all
expected product 6k was accompanied by trace amounts of the cases only the product of the intercepted rearrangement was
second product 8, which results from a dealkylation rather than a observed, which is surprising, as the reaction of benzyl phenyl
debenzylation. This observation was even further pronounced in the thioethers with ethyl diazoacetate was reported to undergo Stevens
case of the branched aliphatic thioethers, benzyl(cyclohexyl)sulfane rearrangement.3a
1l, which almost exclusively reacted in a dealkylation reaction under
the formation of 8.
We were struck by the exclusive formation of the a-mercapto-
acetonitrile 6, and hypothesize this observation to result from
This unexpected formal dealkylation reaction prompted us the in situ formation of diazoacetonitrile. Water from the
to further investigate the influence of the aliphatic substituent reaction mixture may act as a proton source to protonate the
of the thioether and the generality of this transformation. In basic intermediate ylide under the formation of a sulfonium
the first step, we thus studied benzylic thioethers with different salt. The latter undergoes a subsequent nucleophilic substitution
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Table 3 Influence of the aliphatic substituent on the intercepted rear-
rangement reaction
Entry
Substrate
Product
Yield [%]
1
2
1m, R = 4-methoxy
1n, R = 4-bromo
6a
6a
62
65
3
4
1o, R = 4-nitro
1p, R = 4-cyano
4o
4p + 6a
26
53 + 24
Scheme 3 Postulated reaction mechanism and control experiments.
reaction of 1a with a solution of ethyl diazoacetate 2 provided
the product of the metathesis reaction in similar yield, Stevens
rearrangement was reported to occur without additional chloride
ions (Scheme 3b).3a When using sulfide 1a and chloroacetonitrile,
which should give an alternative metal-free pathway to the inter-
mediate sulfonium chloride salt, no reaction was observed, which
underlines the importance of the in situ generation of diazoalkanes
to drive this formal metathesis reaction (Scheme 3c).
In summary, we herein describe an interception of a rear-
rangement process that provides access to a formal functional
group metathesis reaction via dealkylation of sulfur ylides and
formation of a novel thioether. A cheap and readily available
iron catalyst and in situ generated diazoalkanes can be used in
this double exchange reaction of aliphatic groups, yielding a
range of different a-mercaptoacetonitrile derivatives in up to 95%
yield, and now opens up new reaction pathways of sulfur ylides.
This work was funded by the Deutsche Forschungsge-
meinschaft (DFG, German Research Foundation) – project no.
408033718. RMK gratefully thanks the Fonds der Chemischen
Industrie for generous support (Sachkostenbeihilfe).
5
33
6
7
1r, R = methyl
1s, R = ethyl
6a
6a
42
48
8
9
10
11
12
1t, R = 4-methyl
1u, R = 4-methoxy
1v, R = 4-chloro
1w, R = 4-bromo
1x, R = 2-bromo
6t, R = 4-methyl
6u, R = 4-methoxy
6e, R = 4-chloro
6w, R = 4-bromo
6x, R = 2-bromo
59
67
51
59
29
Reaction conditions: 0.4 mmol sulfides (1m–1x), 1 mol% FePc, and 4.0
eq. 5 were dissolved in 100 mL CHCl3 and 1.0 mL H2O at 40 1C. A solution
of 4.8 eq. NaNO2 in 1.0 mL H2O was added over a period of 240 min.
Scheme 2 Scope intercepted rearrangement with different in situ gen-
erated diazoalkanes. Reaction conditions: 0.4 mmol 1a, 1 mol% FePc, and
4.0 eq. amine hydrochlorides (9a–c) were dissolved in 100 mL CHCl3 and
1.0 mL H2O at 40 1C. 4.8 eq. NaNO2 in 1.0 mL H2O was slowly added using
a syringe pump over a period of 240 min.
Conflicts of interest
There are no conflicts to declare.
Notes and references
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the a-mercaptoacetonitrile 6 and benzyl chloride 7a, which could
be confirmed by NMR spectroscopy and GCMS of the crude
reaction mixture (Scheme 3a).17,18 The interception of the migra-
tion step by chloride ions is thus a key step to enable this
functional group metathesis reactions.
To understand if the diazocomponent and chloride are
mandatory in this transformation, we conducted a series of
control experiments. While additional sodium chloride19 in the
340 | Chem. Commun., 2019, 55, 338--341
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