Double C-N bond cleavages of: N-alkyl 4-oxopiperidinium salts: Access to unsymmetrical tertiary sulfonamides

Article abstract of DOI:10.1039/c9ob02107h

In this paper, regiospecific, double intraannular C-N bond cleavages of N-alkyl 4-oxopiperidinium salts are presented. The reaction sequence involves a charge-transfer complex, in situ formed between sulfonyl chloride and N-methylmorpholine, which induces S-Cl bond homolysis of sulfonyl chloride, yielding a reactive sulfonyl radical that further induces the double C-N bond cleavages of N-alkyl 4-oxopiperidinium salt. The secondary amine thus produced was trapped by sulfonyl chloride to yield the desired sulfonamide product. The key feature of this protocol is that two intraannular C-N bonds of the 4-oxopiperidine ring are cleaved in one step under metal- A nd oxidant-free conditions.

Full text of DOI:10.1039/c9ob02107h

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Double C–N bond cleavages of N-alkyl
4
-oxopiperidinium salts: access to unsymmetrical
Cite this: Org. Biomol. Chem., 2019,
7, 10172
1
tertiary sulfonamides†
a
a
a
b
a
Ying Fu, * Ming-Peng Li, Chun-Zhao Shi, Fang-Rong Li, Zhengyin Du * and
a
Congde Huo
*
In this paper, regiospecific, double intraannular C–N bond cleavages of N-alkyl 4-oxopiperidinium salts
are presented. The reaction sequence involves a charge-transfer complex, in situ formed between
sulfonyl chloride and N-methylmorpholine, which induces S–Cl bond homolysis of sulfonyl chloride,
yielding a reactive sulfonyl radical that further induces the double C–N bond cleavages of N-alkyl 4-oxo-
piperidinium salt. The secondary amine thus produced was trapped by sulfonyl chloride to yield the
desired sulfonamide product. The key feature of this protocol is that two intraannular C–N bonds of the
4-oxopiperidine ring are cleaved in one step under metal- and oxidant-free conditions.
Received 29th September 2019,
Accepted 11th November 2019
DOI: 10.1039/c9ob02107h
rsc.li/obc
efficiency in aliphatic C–N bond activation (Scheme 1(b)).
Furthermore, C–N bonds of aliphatic amines could also be
Introduction
Considering the fact that aliphatic tertiary amines are relatively activated by the neighboring functionalities. In this respect,
1
9
stable and widely present in nature, selective transformations the presence of the α-amino group in aminals, the phenyl
3
10
of C(sp )–N bonds of simple aliphatic tertiary amines into group in benzylamines and the CvC double bond in allyl-
their corresponding nitrogen-containing molecules are of sub- amines all have significant impacts on adjacent C–N bond
stantial interest for organic synthetic chemists, especially
1
1
those who are working in the area of pharmaceutical chemistry
and materials sciences. However, due to thermodynamic stabi-
lity and relatively high bond dissociation energies (ca. 80 kcal
−
1
3
mol ), the selective cleavage of inert C(sp )–N bonds of ter-
2
tiary amines remains a challenging task. Among the various
established methods for C(sp )–N bond activation, the conver-
sion of electron-rich C(sp )–N bonds of amines into electron-
3
3
deficient ammonium salts is the most efficient strategy. Since
1
988, pioneered by the work of Wenkert et al., aryltrimethyl-
3
4
ammonium salts,
ammonium salts, propargylic ammonium salts etc. have
N-alkylpyridinium salts,
benzylic
5
6
been extensively developed which, under transition metal cata-
+
lysis, are promising C equivalents and can be cross-coupled
with various nucleophiles, e.g., organometallics, boronic acids,
alkynes, alkenes etc. to form C–C bonds (Scheme 1(a)). In
addition, a charge-transfer complex (CTC) formed between
7
8
2 2
aliphatic amines and electrophiles (I , ArSO Cl ) has shown
a
College of Chemistry and Chemical Engineering, Northwest Normal University,
Lanzhou, 730070, China. E-mail: fu_yingmail@126.com,
zhengyin_du@nwnu.edu.cn, huocongde@nwnu.edu.cn
b
Pharmacy Department, Gansu University of Traditional Chinese Medicine, 743000,
China
†
Electronic supplementary information (ESI) available. See DOI: 10.1039/
c9ob02107h
Scheme 1 Strategies for C–N bond activation.
10172 | Org. Biomol. Chem., 2019, 17, 10172–10177
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a
energy and thus various kinds of valuable compounds were Table 1 Optimization of the reaction conditions
prepared. Despite these important advances, most of the
known C–N bond dissociation protocols are only effective
when using expensive transition metal catalysts and commonly
demand a larger excess amount of oxidants.
Recently, we reported an interesting CTC promoted sulfony-
b
Entry
Base
Solvent
T (°C)
Yield (%)
8
a
lation of tertiary ethylene-1,2-diamines. In these reactions,
c
3
1
2
3
4
5
6
7
8
9
Et N
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
80
80
80
80
80
80
80
80
80
80
40
60
110
80
80
35
C(sp )–N bonds were greatly attenuated by CTC, in situ formed
3
Et
3
N
55
between the two reactants, i.e. sulfonyl chloride and tertiary
,2-ethylenediamine. Thus, a large variety of synthetically
d
TMEDA
DBU
TBUP
Trace
1
Trace
0
0
0
0
useful N,N-disubstituted sulfonamides were easily prepared in
good to high yields. In continuation of our studies on C–N
bond activation and search for new synthetic procedures for
pharmaceutically important N,N-disubstituted sulfonamides,
our interest shifted to 4-oxopiperidinium salts as in these com-
K
2
CO
Cs CO
CaH2
3
2
3
NaOMe
NMM
NMM
NMM
NMM
NMM
NMM
Trace
1
1
0
1
76 e
CH Cl
2 2
n.r.
pounds, C–N bonds are doubly activated with ammonium 12
THF
Toluene
DMF
Trace
30
Trace
1
1
1
3
4
5
cations and γ-carbonyls. We thus anticipated that under basic
conditions, 4-oxopiperidinium salts could first undergo a
Hoffmann type elimination to yield an unsaturated tertiary
amine which could further react with sulfonyl chloride and
again undergo a Hoffman type elimination, yielding an N,N-di-
f
MeCN
72
a
Reaction conditions: 1a (0.5 mmol), base (1.5 mmol), 2a (0.6 mmol),
solvent (2.0 mL), air, 4 h. Isolated yield. 1.0 mmol Et N was
employed. TsNMe (yield: 72%) was isolated as the sole product. n.r. =
2
b
c
3
d
e
f
substituted tertiary sulfonamide (Scheme 1c). Although N,N-di- no reaction. Experiment was performed with 1a (5 mmol, 1.19 g) and
2a (6 mmol, 1.14 g) yielded 1.11 g of 3a (72%).
substituted sulfonamides could be easily prepared via cross-
1
2
coupling of sulfonyl chlorides with secondary amines, this
protocol has clear limitations as most functionalized second-
ary amines are unstable in air and are not commercially avail- delivering 3a in 76% yield (Table 1, entry 10). Further screen-
able. Alternatively, N-substituted sulfonamides could be pre- ing of the solvents and temperature indicated that MeCN and
1
3
pared via N-alkylation of sulfonamides with alkyl halides or 80 °C were the optimal reaction conditions (Table 1, entries
1
4
alcohols; however, limitations such as harsh reaction con- 10–14). Consequently, the best reaction conditions were
ditions, requirement of expensive catalysts, narrow substrate selected as indicated in entry 10. A gram-scale synthesis per-
scope etc. still exist. Here, we report a metal- and oxidant-free, formed under these conditions gave a 72% isolated yield of 3a
remote carbonyl group controlled, CTC facilitated regiospecific (Table 1, entry 15).
double C–N bond cleavages of N-substituted 4-oxopiperidi-
With the optimized reaction conditions in hand, the scope
nium salts whereby N,N-disubstituted sulfonamides were con- of this cascade reaction of double C–N bond cleavage method-
veniently prepared.
ology was evaluated over a wide array of sulfonyl chlorides
using 2a as a standard substrate (Table 2). First, benzenesulfo-
nyl chlorides bearing a variety of substituents were screened to
evaluate the general applicability of this transformation
Results and discussion
(
3a–m). In this respect, functionalities such as alkyl (3c & 3d),
(3f) and halogens (3h–k) were tolerant to
In our previous studies involving reactions of sulfonyl chlor- alkoxyl (3d & 3e), CF
3
8
a
ides with tertiary ethylene-1,2-diamines, Et N was demon- these optimized reaction conditions, delivering the corres-
3
strated to be an inert amine species towards sulfonyl chlorides. ponding sulfonamides in 41–80% yields. Remarkably, the
Thus it was selected as a base to promote the reaction between highly sterically constrained 2,4,6-triisopropylbenzenesulfonyl
TsCl 1a and N-(4-chlorobenzyl)-N-methyl-4-oxopiperidin-1-ium chloride (3c) and 2,2,4,6,7-pentamethyl-2,3-dihydrobenzo-
chloride 2a. First, when only 2 equivalents of Et
3
N were intro- furan-5-sulfonyl chloride (3d) were compatible with this reac-
duced, this reaction proceeded in MeCN at 80 °C and sulfona- tion system, indicating the broad feasibility of this approach.
mide 3a was formed in 35% isolated yield (Table 1, entry 1). Generally, benzenesulfonyl chlorides bearing an electron-
Gratifyingly, when 3 equivalents of Et
the yield of 3a increased to 55%. An attempt to replace Et
3
N (1.5 mmol) were used, donating group exhibit better efficiency than those with elec-
tron-withdrawing groups and the highest yield of sulfonamide
3
N
with N,N,N′,N′-tetramethylethylenediamine (TMEDA) delivered was obtained from 4-methoxybenzenesulfonyl chloride
N,N-dimethyltolylsulfonamide (TsNMe2, 72% yield) as the (3e, 80%). When 2-trifluoromethoxybenzenesulfonyl chloride
1
5
main product (entry 3). Other bases screened such as 1,8-dia- was employed, a relatively low yield of 3g (41%) was obtained,
zabicyclo[5.4.0]undec-7-ene (DBU),
tri-n-butylphosphine partially due to the steric effect of 2-OCF . Notably, in this
TBUP), K CO , Cs CO , CaH
, and NaOMe all failed to give cascade three-bond transformation reaction, an overall 41%
the desired product 3a (Table 1, entries 4–9). The best result yield is comparable to a 74% yield of a single-bond transform-
was obtained by using N-methylmorpholine (NMM) as a base, ation reaction; thus it is also satisfactory result.
3
(
2
3
2
3
2
a
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a,b
a,b
Table 2 Scope of sulfonyl chlorides
Table 3 Scope of 4-oxopiperidinium salts
a
Reaction conditions: (1). 4 (0.6 mmol), 6 (0.6 mmol), MeCN (2 mL),
0 °C, overnight and (2) 1 (0.5 mmol), NMM (1.5 mmol), CH CN
5
3
b
(
2 mL), 80 °C, 4 h. Isolated yield.
a
Reaction conditions: 1 (0.5 mmol), 2a (0.6 mmol), NMM (1.5 mmol),
b
3
CH CN (2 mL), 80 °C, 4 h. Isolated yield.
chloride (1c), 2-naphthalenesulfonyl chloride (1d) and methyl
-(chlorosulfonyl)thiophene-2-carboxylate (1e) were then
screened and they all participated in this transformation
3
Unexpectedly, when a strong electro-withdrawing NO2 group smoothly to give the desired compounds in moderate yields
was installed on benzenesulfonyl chloride at either the para or (5j–5n). Unexpectedly, aliphatic cyclopropanesulfonyl chloride
ortho position, only trace amounts of the desired sulfonamide was able to react with N-methyl-4-oxo-1-(2-oxo-2-phenylethyl)
products could be observed (3l & 3m). Both of the nitro- piperidinium bromide, in situ formed via the reaction of
benzene sulfonyl chlorides decomposed quickly under this N-methylpiperidinone and 2-bromoacetophenone, to yield sul-
reaction system. As expected, reactions involving quinoline-3- fonamide 5o in 46% isolated yield.
sulfonyl chloride and 2-thiophenesulfonyl chlorides proceeded
To elucidate the selectivity dependence of ring-opening
quite well, delivering the corresponding products 3n–p in pathways on the structure of the aza rings, some control
moderate yields. Aliphatic sulfonyl chlorides screened, e.g. experiments were conducted (Scheme 2). First, when N-(4-
trifluoromethylsulfonyl chloride, methanesulfonyl chloride chlorobenzyl)-N-methylpiperidinium chloride 7, instead of 2a,
and n-octyl sulfonyl chloride, could not participate in these was added to the standard reaction systems to react with TsCl
reactions, possibly because of the instability of these alkylsul- for the synthesis of 3a, no coupling reaction took place, and as
1
6
fonyl chlorides under the basic reaction conditions.
a result, the formation of 3a was not detected. Other attempts
To test the versatility of this double C–N bond cleavage pro- to replace the 4-oxopiperidine ring in 2a with morpholine (8)
tocol, a two-step one-pot procedure was then carried out and 4-hydroxypiperidine (9) also failed to give 3a
(
(
Table 3). At first, N-methyl-4-piperidone was converted by EtI (Scheme 2(a)–(c)), implying that the presence of the 4-oxo
1.2 equiv.) into its ammonium salt. Then TsCl (1.2 equiv.) moiety on the piperidine ring was indispensable. Furthermore,
and NMM (3.0 equiv.) were added and after stirring the when two equivalents of 2,2,6,6-tetramethylpiperidinooxy
mixture at 80 °C for 4 h, sulfonamide 5a was obtained in 76% (TEMPO) as a radical scavenger were added to the standard
isolated yield. Encouraged by this achievement, N-methyl, reaction systems for the synthesis of 3a, the yield dramatically
N-ethyl, N-propyl, and N-benzyl 4-piperidones (4) were first decreased to 7%, indicating that these reactions should follow
treated respectively with aliphatic halides 6, i.e. allyl bromide, a radical pathway. HRMS studies of the reaction mixture
ethyl bromoacetate and 2-bromoacetophenone etc. to convert showed that compounds 10 and 11 (42% isolated yield) were
them into their corresponding ammonium salts. Then, TsCl formed, indicating that a pent-1-en-3-one-5-yl radical and a
(
1a) was introduced and the reactions were performed under sulfonyl radical were formed during the formation of 3a, poss-
the optimized conditions to obtain the desired sulfonamides ibly because of the radical homolysis of the S–Cl bond in sulfo-
1
7
(
4
5b–5i) in 30–76% isolated yields. Without any hesitation, nyl chloride (Scheme 2(d)). This assumption was further con-
-methoxybenzenesulfonyl chloride (1b), benzenesulfonyl firmed by the control reactions listed in Scheme 3(e) where
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Fig. 1 (A) Photographs of 1a (TsCl), NMM, and 1a + NMM in MeCN
(
(
0.01 M). (B) UV-Vis absorption spectra of 1a (0.01 M), NMM (0.01 M), 2a
0.01 M) and their mixtures: 1a + NMM (0.01 M), 1a + 2a (0.01 M), and 1a
+
2a + NMM (0.01 M) in MeCN.
tion of TsCl (1a) in MeCN (0.01 M) at room temperature, the
color immediately changed from colorless to brownish
(
(
Fig. 1A). Furthermore, the UV-Vis absorption spectra of 1a
0.1 M), ammonium salt 2a and NMM (0.1 M) were measured
separately and combined (Fig. 1B). When 1a (0.1 M) and NMM
0.1 M) were mixed, a new band ranging from 350 to 450 nm
(
appeared (Fig. 1B), which is attributed to the charge transfer
complex arising from the charge transfer from NMM to 1a.
On the basis of the above results, especially due to the fact
that these reactions occurred only when pyrolysis of sulfonyl
chlorides began, that is, when compound 12 was detected, a
plausible mechanism accounting for the formation of 3a is
proposed (Scheme 3). Initially, a charge-transfer complex invol-
ving TsCl and NMM (N-methylmorpholine) was formed. Under
heating and activation by a CT-complex, slight pyrolysis of the
Scheme 2 Control experiments.
•
S–Cl bond in TsCl occurred, delivering a chlorine radical (Cl )
•
19
•
and a tosyl radical (Ts ). Radical Ts is not stable which, after
•
SO extrusion, delivers a tolyl radical (Tol ) and reacts with TsCl
2
to yield the byproduct 12. The main reaction was initiated via
radical abstraction of a hydrogen atom from 2a with a chlorine
•
•
radical or a tosyl radical (Cl or Ts ). The yielded carbon radical
ammonium I initiated the first C–N bond cleavage to produce
the tertiary amine radical cation II. Intramolecular hydrogen
transfer in II gave the carbon radical ammonium (III). Again, C–
N bond cleavage in III occurred and a secondary amine cation
radical IV was generated. Single electron transfer (SET) between
NMM and IV produced the secondary amine V and the
N-methylmorpholine radical cation VI which then abstracted a
hydrogen atom from 2a to regenerate radical I, completing the
full reaction cycle. Finally, amine V, a key reaction intermediate,
was captured and reacted with TsCl to form sulfonamide 3a.
Scheme 3 Proposed mechanism for the formation of 3a.
TsCl alone was stable at 80 °C and gradually decomposed to
p-tolyl 4-methylbenzenesulfinate 12 in the presence of NMM,
Conclusions
demonstrating the key role of tertiary amines in the pyrolysis We have established an efficient method to realize regiospeci-
of sulfonyl chloride and the presence of both p-tolylsulfonyl fic double C–N bond cleavages in unstrained N-substituted
1
8
and p-tolyl radicals in the reaction system.
4-oxopiperidium salts via a self-promoted radical pathway.
To understand the reason why a tertiary amine could acti- From these reactions, synthetically useful sulfonamides were
vate the S–Cl bond in sulfonyl chloride, a UV test was per- conveniently prepared. In general, these novel oxidant- and
formed. When NMM in MeCN (0.01 M) was added to a solu- metal-free transformations, accomplished under mild con-
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ditions and showing good tolerance toward a variety of func-
tional groups, are promising complements to previously
reported synthetic strategies, especially to those for which sec-
ondary amines are not easily available. Further studies on the
utility of this reaction protocol in synthetic chemistry and its
detailed mechanism are currently underway in our laboratory.
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(
0.5 mmol), N-(4-chlorobenzyl)-N-methyl-4-oxopiperidin-1-ium
chloride (165 mg, 0.6 mmol), N-methylmorpholine (165 mg,
.5 mmol) and acetonitrile (2.0 mL). The reaction mixture was
3
1
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and sulfonyl chloride (0.5 mmol) were added and the reaction
mixture was heated to 80 °C under air for 4 h. After cooling to
ambient temperature, the reaction mixture was dissolved
in ethyl acetate (10 mL) and washed successively with water
4
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8
further extracted with ethyl acetate (10 mL) and washed as
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over Na SO and concentrated. Purification by silica gel column
2 4
(
–
chromatography gave the desired sulfonamide products.
5
Conflicts of interest
2
There are no conflicts to declare.
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