Metal-free C(sp3)-H bond sulfonyloxylation of 2-alkylpyridines and alkylnitrones

Article abstract of DOI:10.1039/c8ob01075g

Pyridin-2-ylmethyl tosylate derivatives are obtained in high yields from 2-alkylpyridine 1-oxides via a [3,3]-sigmatropic rearrangement of the adduct between 2-alkylpridine 1-oxides with benzenesulfonyl chlorides. Moreover, alkylnitrones also undergo [3,3]-sigmatropic rearrangement to give α-tosylated ketones after hydrolysis. Substitution reactions with nucleophiles then lead to diverse useful functionalizations for the synthesis of pincer ligands.

Full text of DOI:10.1039/c8ob01075g

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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Metal-Free C(sp3)–H Bond Sulfonyloxylation of 2-Alkylpyridines
and Alkylnitrones
Received 00th January 20xx,
Accepted 00th January 20xx
Chang-Sheng Wang, Pierre H. Dixneuf, Jean-François Soulé*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Pyridin-2-ylmethyl tosylate derivatives are obtained in high yields phosphorylation of 2-alkylpyridine and nitrone derivatives via
from 2-alkylpyridine 1-oxides via
[3,3]-sigmatropic a similar [3,3]-sigmatropic rearrangement (Figure 1c).5
a
rearrangement of the adduct between 2-alkylpridine 1-oxides To the best of our knowledge, there is no example of [3,3]-
with benzenesylfonyl chlorides. Moreover, alkylnitrones also sigmatropic rearrangement of 2-alkylpyridine 1-oxides with
undergo [3,3]-sigmatropic rearrangement to give α-tosylated benzenesulfonyl chlorides, although it could provide an
ketones after hydrolysis. Substitution reactions with nucleophiles efficient synthetic method to pyridin-2-ylmethyl tosylate
then lead to diverse useful functionalizations for the synthesis of derivatives.
We decided to tackle this challenge by
pincer ligands.
investigating the reactivity of 2-alkylpyridine 1-oxides in the
presence of benzenesulfonyl chlorides (Figure 1d).
Alkyl sulfonates, such as alkyl tosylates, are typical substrates
for SN2 reactions. Compared to alkyl halides, they often
display higher thermal/light stability and resistance to radical-
triggered side reactions. They are generally synthetized from
alcohols by condensation reactions with benzenesulfonyl
chlorides.
A
more straightforward access to these
synthetically useful synthons would involve the direct
transformation of inert C(sp3)–H bond into C–OSO2R bond.1 In
2015, Dong and co-workers reported an elegant approach for
the synthesis of β-sulfonyloxylated alcohols through
C(sp3)–H
a
palladium-catalyzed regioselective bond
functionalizations of masked alcohols bearing 8-
formylquinoline-derived oxime as directing group (Figure 1a).2
The reaction has employed p-toluenesulfonic acid as
sulfonyloxation agent and N-fluorobenzenesulfonimide (NFSI)
as the oxidant. Pyridin-2-ylmethyl tosylate derivatives, which
are important building blocks for the preparation of metal
pincer complexes,3 are generally prepared from pyridin-2-
ylmethanol derivatives. In 2017, our group has succeeded the
C(sp3)–H bond benzoxylation of 2-alkylpyridine derivatives
through copper-catalyzed oxidative esterification of 2-
alkylpyridine 1-oxides with aldehydes followed by [3,3]-
sigmatropic rearrangement (Figure 1b).4 The same year, Chen,
Fu and co-workers reported metal-free conditions for the
Figure 1. Previous C(sp3)–H Bond Sulfonyloxylation and Functionation of 2-Alkyl
Pyridines via [3,3]-Sigmatropic Rearrangements
We selected 2,6-dimethylpyridine 1-oxide and tosyl chloride as
model substrates to study the formal C(sp3)–H bond
sulfonyloxylation through a [3,3]-rearrangement. Surprisingly,
the expected product
1
was not formed in the presence of
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potassium carbamate (K2CO3) as base in acetonitrile (CH3CN), sulfonyl bridged bis-heterocycle
Org. Biomol. Chem.
7
in 54% yield. Similar bridged
although those reaction conditions have been employed by structures exhibit important biological activities and are
the Sledeski’ group for the C(sp3)–H bond sulfonyloxylation of pharmaceutical drug precursors.7
2-methylquinoline 1-oxide (Table 1, entry 1).6 No reaction
occurred in CH2Cl2 when K2CO3 and KOH were employed as
base, whereas in the presence of 2 equivalents of organic base
such as triethylamine (Et3N), the sulfonyloxylated product
1
was obtained in 12% yield (Table 1, entries 2-4). Then, we
investigated the influence of nature of other solvents. The
reaction is not operative in CH3CN, dichloroethane (DCE) and
ethanol (Table 1, entries 4-7). However, in THF the desired
product
8). The use of 1.5 equivalents of tosyl chloride allowed to
improve the yield of the sulfonyloxylated product to 82%
1 was obtained in a high yield of 72% (Table 1, entry
1
yield and even better (87%) using 2.5 equivalents of base
(Table 1, entries 9 and 10).
Scheme 1. Scope of Benzenesulfonly Chloride in C(sp3)–H Bond Sulfonyloxylation of 2,6-
Table 1. Optimization of the Reaction Conditions
Dimethylpyridine 1-Oxide
Next, we investigated the reactivity of a set of 2-alkylpyridine
1-oxides in the presence of tosyl chloride (Scheme 2). 2-
Methyl pyridine 1-oxide underwent selectively C(sp3)–H bond
tosyloxylation to afford 8 in 75% yields, without the formation
of C(sp2)–H tosyloxylated product.8 This reaction is successful
Entry x / y
Base (z equiv.)
K2CO3 (2)
Solvent
CH3CN
Yield in 1 (%)
1
1:1.1
0
for the formation of tertiary carbons, as from 2-ethylpyridine
2
3
4
5
6
7
8
1:1.1
1:1.1
1:1.1
1:1.1
1:1.1
1:1.1
1:1.1
K2CO3 (2)
KOH (2)
Et3N (2)
Et3N (2)
Et3N (2)
Et3N (2)
Et3N (2)
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
DCE
0
0
1-oxide the tosyloxylated product
9 is obtained in 55% yield.
The reaction tolerated a bromo or an ester substituent on the
2-methylpyridine 1-oxide partner allowing the formation of 10
and 11 in good yield, respectively. We also succeeded in the
desymmetrization of one methyl group of 2,4,6-collidine 1-
oxide with the formation of mono-tosyloxylated product 12 in
69% yield. Finally, 2-methylquinoline 1-oxide nicely reacted
under these reaction conditions to deliver 13 in good yield.
12
0
0
EtOH
THF
0
72
9
1:1.5
1:1.5
Et3N (2)
THF
THF
82
10
Et3N (2.5)
87 (81)
[a] Determined by GC-MS analysis using n-dodecane as internal standard, isolated
yield is shown in parentheses
With the best conditions in hands, namely 2.5 equivalents of
Et3N as base in THF at room temperature, we turn our
attention to the scope of the reaction. First, we examined the
reactivity of other substituted benzenesulfonyl chlorides with
2,6-dimethylpyridine
Phenylbenzenesulfonyl chloride displays a low reactivity, as
the (6-methylpyridin-2-yl)methyl benzenesulfonate is
1-oxide
(Scheme
1).
2
isolated in only 23% yield. When benzenesulfonyl chloride is
substituted by an electron-donating group such as tBu or OMe
at the para-position, the sulfonyloxylated products
3 and 4 are
obtained in 62% and 78% yield, respectively. Benzenesulfonyl
Scheme 2. Scope of 2-Alkylpyridine 1-Oxides in Tosyloxylation with Tosyl Chlorides
chlorides bearing an electron-withdrawing group at meta
position such
F
displayed good reactivity, allowing the
in 53% yield. The reaction is
Next, we investigated the reactivity of nitrones, derived from
the in-situ condensation of acetophenones with 1-
methylhydroxylamine hydrochloride, in the presence of tosyl
chloride (Scheme 3). We are pleased to find that using only 1
equivalent of Et3N, the nitrone reacts with tosyl chloride
followed by [3,3] sigmatropic rearrangement and then by in
situ hydrolysis to yield α-keto tosylate 14 in 76% yield.
Interestingly, this reaction sequence for the α-tosyloxylation of
formation of desired product
5
not sensitive to the steric hindrance, as from 2,4,6-
triisopropylbenzenesulfonyl chloride, the sulfonyloxylated
products
6 is isolated in an excellent yield. Heteroarylsulfonly
chloride such as methyl 3-(chlorosulfonyl)thiophene-2-
carboxylate can be also employed under this reaction
conditions with 2,6-dimethylpyridine 1-oxide to prepare the
2 | Org. Biomol Chem., 2018, 00, 1-3
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enolizable ketones tolerates halo substituents (e.g., X = F, Br, I)
on the aryl group of the acetophenone derivatives allowing the
formation of the tosylates 16-18 in high yields. Noteworthy,
only a limited number of synthetic methods toward α-keto
tosylates have been reported.9 Most of them employed a two-
step procedure or required the use of stoichiometric amount
of a strong oxidant. In contrast, our method based on [3,3]-
rearrangement of nitrone-tosylate adducts has some
advantages, as it takes place under mild reaction conditions,
with user-friendly procedure and the reactants are available at
an affordable cost.
Figure 2. Proposed Mechanistic Pathways: a) for the Sulfonyloxylation of 2-
Alkylpyridine 1-Oxides; b) for the Sulfonyloxylation of Nitrone Derivatives
Finally, we performed leaving group-based strategy to late-
stage diversification of tosyloxylated pyridine
The C(sp3)−H tosyloxylation of 2,6-dimethylpyridine 1-oxide
has been performed on gram scale to afford in a similar yield
1 (Scheme 4).
1
(73%, 2 g), which serves as a common intermediate for the
diversification. The subsequent SN2 reactions rapidly prepared
a variety of pyridines derivatives through forming C−C, C−N,
and C−P bonds. In particular, 19 and 22 are important
intermediates for the preparation of PNN Milstein-type pincer
ligands,11 which are very useful catalysts for the activation of
small molecules.
N
a
N3
(
)
2
v
i
N
N
e
u
q
q
u
e
i
v
D
0
)
M
1
(
N3
NEt2
F
,
2
Scheme 3. [3,3] Rearrangement Reaction of Nitrone with Tosyl or Benzenesulfonyl
H
8
h
h
2
N
0
t2
1
º
C
1
E
20 73%
,
t
19 75%
r
Chlorides
,
F
H
T
N
)
Based on the previous Boekelheide rearrangements between
2-alkyl 1-oxide pyridine and acyl chloride,10 we proposed a
mechanistic pathway (Figure 2). The reaction is expected to
start with a nucleophilic addition−eliminaꢀon between 2-
v
i
P
u
h2
º
q
e
P
OTs
K
2
(
T
)
1
H
N
1
:
1
(
2
F
,
C
a
0
4
h
r
N
e
,
C
º
t
C
a
h
t
o
w
/
1
F
9
r
t
M
N
D
N
0
PPh2
CN
21 92%
O
methyl pyridine 1-oxide
formation of positively charged intermediate
the chloride anion. Et3N deprotonates the acidic C(sp3)–H
bond of , giving neutral intermediate with the formation of
Et3NHCl salt. Then, the intermediate spontaneous
undergoes [3,3]-rearrangement leading to the formation of
sulfonyloxylated pyridine The driving force of this [3,3]-
A and arylsulfonyl chloride to give the
22 57%
B
associated to Scheme 4. Diversification of Tosyloxylated Pyridine 1 via Leaving Group Strategy
B
C
C
Conclusions
In summary, the present study provides a convenient and
efficient approach for the diverse functionalization of alkyl
pyridines and aryl alkyl ketones through the direct
replacement of an C(sp3)−H bond with a good leaving group
(OTs). The formation of sulfonyloxylated pyridines is based on
[3,3] rearrangement of sulfonated pyridinium intermediate,
whereas the α-keto sulfonated are also obtained by a [3,3]
rearrangement of sulfonated nitrone intermediate. Both
rearrangements operate under very mild conditions in the
presence of only triethylamine and did not required the use of
oxidant.
D
.
rearrangement is the rearomatization of the pyridine unit. We
proposed a similar pathway with nitrone (Figure 2b). The
addition−eliminaꢀon of 2-methyl nitrone
chloride affords , which undergoes deprotonation of its acidic
C(sp3)–H bond followed [3,3]-rearrangement to afford the
imine . In the presence of water the imine is hydrolyzed to
the sulfonyloxylated ketone
E to arylsulfonyl
F
H
H
I.
Acknowledgements
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Org. Biomol. Chem.
C.-S.W. acknowledges the China Scholarship Council (CSC) fora
PhD grant.
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Conflicts of interest
“There are no conflicts to declare”.
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