Sulfonylimination of Proline with Sulfonylazides Involving Aldehyde-Induced Decarboxylation Coupling

Article abstract of DOI:10.1021/acs.orglett.0c04187

In the presence of aldehyde, a facile method was developed to obtain N-sulfonyl amidines under metal- and oxidant-free conditions by the decarboxylative of proline. This transformation features a double C-N bond formation and allows for the green synthesis of the N-sulfonyl amidines on the basis of mild conditions.

Full text of DOI:10.1021/acs.orglett.0c04187

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Letter
Sulfonylimination of Proline with Sulfonylazides Involving
Aldehyde-Induced Decarboxylation Coupling
Hongyan Liu, Zengfen Pang,* Liqiang Hao, Jian Sun, Zheng Zhang, Fuqiang Wen, and Chengcai Xia*
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ABSTRACT: In the presence of aldehyde, a facile method was developed to obtain N-sulfonyl amidines under metal- and oxidant-
free conditions by the decarboxylative of proline. This transformation features a double C−N bond formation and allows for the
green synthesis of the N-sulfonyl amidines on the basis of mild conditions.
temperature, reaction time, amounts of raw materials, and
atmosphere. First, the screening of different solvents such as
tetrahydrofuran (THF), DMF, DCE, DMSO, acetone, MeOH,
EtOH, and EtOH/H2O (4:1) was tested (Table 1, entries 1−9),
and it worked best when EtOH was used as the solvent (Table 1,
entry 8). Next, the yield of 4a dropped to 59 and 69% when the
reaction time was shortened to 1 h and extended to 3 h (Table 1,
entries 10 and 11). When considering the effect of temperature
on the reaction, we noticed a slight decrease in yield when the
reaction temperature was reduced to 100 °C or increased to 120
°C (Table 1, entries 12 and 13). Here different amounts of the 4-
methylbenzenesulfonyl azide (1a) were examined (Table 1,
entries 14 and 15) bearing electron-withdrawing groups.
With the optimal conditions in hand, we attempted to
investigate the range of substrates for this reaction by examining
the various substituents on the benzene ring of the
benzenesulfonyl azide, and the results are shown in Table 2.
Substituents bore electron-donating groups, halogen groups,
and electron-withdrawing groups on the para substituents, such
as 4-Me (4a), 4-H (4b), 4-C(CH3)3 (4c), 4-OMe (4d), 4-F
(4e), 4-Cl (4f), 4-Br (4g), 4-CF3 (4h), and 4-NO2 (4i), to
provide the correlation products in excellent yield.
N-Sulfonyl amidines are ubiquitous in all aspects of the chemical
sciences and play critical roles in pharmaceuticals.1−11 Mean-
while, these compounds can still be employed as useful synthons
for the assembly of complex molecules and ligands in
coordination complexes.12−15 In recent decades, a range of
techniques have been developed to construct versatile amidines.
The most prevalent technique is the oxidation of the C−C bond
in tertiary amines (Scheme 1A).16−19 The Wan group has
worked out a practical CC bond decomposition reaction
developed for the synthesis of N-sulfonyl amidines in water
using enaminoesters and tosyl azides as starting materials for
initiation (Scheme 1B).20 Subsequently, Huang and Hu
reported the use of N-sulfonyl acetylketenimine as a highly
reactive intermediate to synthesize N-sulfonyl amidines
(Scheme 1C).21 In addition, Odell’s group carried out the
carbonylative/coupling of sulfonamides and substituted amides
(Scheme 1D).22 Conventionally, a direct condensation reaction
between formamides and sulfonamides in the presence of
Zn(OTf)2 to yield N-sulfonyl amidines was also possible
(Scheme 1E).23−25 Elsewhere, N-sulfonylcarboxamides are
regularly employed as the main product from the reaction of
benzoic acid with azide substrates (Scheme 1F).26 Therefore, a
metal-free catalytic strategy for the green synthesis of amidines
with readily available enamines as substrates is imminent.
Herein, inspired by these works and our continuing efforts
toward this tandem reaction,27−29 we have developed the
decarboxylation of proline with sulfonamides to furnish
substituted N-sulfonyl amidines (Scheme 1G).
Moreover, ortho substituents bearing electron-donating
character (2j), halogen substituents (4p, 4r), and electron-
Received: December 18, 2020
Published: February 9, 2021
With 4-Methylbenzenesulfonyl azide (1a), 2-pyrrolecarbal-
dehyde (2a), and proline (3a) selected as the model substrates,
the reaction conditions were optimized, including the solvent,
https://dx.doi.org/10.1021/acs.orglett.0c04187
© 2021 American Chemical Society
Org. Lett. 2021, 23, 1234−1238
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a b
,
Scheme 1. Synthesis Strategy of N-Sulfonyl Amidines
Table 1. Reaction Optimization
b
entry
solvent
T (°C)
time (h)
yield (%)
1
2
3
4
5
6
7
8
THF
DMF
DCE
DMSO
acetone
CH3CN
CH3OH
EtOH
EtOH/H2O (4:1)
EtOH
EtOH
EtOH
EtOH
110
110
110
110
110
110
110
110
110
110
130
80
2
2
2
2
2
2
2
2
2
1
4
2
2
2
2
2
40
23
37
18
nr
74
trace
80
nr
69
74
64
68
9
10
11
12
13
14
15
16
120
110
110
110
c
EtOH
EtOH
EtOH
77
73
trace
d
e f
,
a
Reaction conditions: 1a (0.2 mmol), 2 (0.3 mmol), 3 (0.3 mmol),
and solvent (2.0 mL) in a sealed tube with an air atmosphere stirred
b
c
for 2 h. Isolated yield. 1a (0.2 mmol), 2 (0.2 mmol), 3 (0.2 mmol).
d
e
f
1a (0.4 mmol), 2 (0.2 mmol), 3 (0.2 mmol). N2 O2.
Ortho substituents such as 2-Me (5j), 2-Br (5k), and 2-CF3 (5l),
afforded the corresponding products in good yield. By replacing
the proline with the piperidine-2-carboxylic acid, we isolated the
product (5m) in 60% yield. Regrettably, many substituted
pralines (5n−5q) and uncyclized N-alkyl α-carboxylic acids
(5r−5t) have been tested under the standard conditions, and
products have not been detected.
withdrawing character (4s) were well tolerated, but 2-Cl-
phenylsulfonylazide (4q) could not be converted into the
corresponding products. Similarly, meta substituents with
diverse electronics with many substituents such as methyl
(4j), halogen (4l, 4m), and trifluoromethyl (4n) in the para
position of 1 showed good compatibility to produce the
corresponding products in about 56−65% yields. The multiple-
substituted compounds 4t (2-CH3, 4-CH3) and 4u (2-CH3, 4-
CH3, 6-CH3) were furnished in slightly lower yields than those
with other substituents. In addition, thiophene-2-sulfonyl azide
gave a 46% yield of 4v. Considering the influence of 2-
pyrrolecarbaldehyde, 1-methyl-1H-pyrrole-2-carbaldehyde, thi-
ophene-2-carbaldehyde, and furan-2-carbaldehyde in the
addition of EtOH (2 mL), we subsequently observed a 58, 56,
and 59% yield (4w, 4x, 4y) of products, respectively.
Inspired by the above results, we investigated a range of
substrates for this reaction, and the range varied with the
substituents of the aromatic aldehyde (Table 3). A large role was
also played by para substituents with diverse electronics; the
electron-donating groups (5a−5c), halogen substituents (5d,
5e) and withdrawing character (2f) all provided N-sulfonyl
amidine in good yield. Furthermore, substrates with meta
substituents that bring electron-donating groups (2n), halogens
(2o), or electron-withdrawing groups (2p) were well tolerated.
To gain a plausible mechanism for this reaction, a set of
control experiments was carried out. Initially, we found that the
yield of the desired product 4a was slightly reduced when a free-
radical scavenger such as TEMPO (2,2,6,6-tetramethyl-1-
piperidinyloxy) was added to the reaction mixture (Scheme
2a). Alternatively, using pyrrolidine as feedstock, the reaction
proceeded under standard conditions (Scheme 2b), and the
desired product 4a was not isolated. It is suggested that the
carboxyl group of proline is essential for mediating this reaction.
Finally, we did not detect intermediate 6 (Scheme 2c) in the
absence of 1H-pyrrole-2-carbaldehyde, which clearly indicates
that the aldehyde plays a crucial part in the reaction.
Additionally, the reaction is affected by the atmosphere in
which it is located. For example, in an atmosphere of nitrogen or
oxygen, the reaction will be inhibited (Table 1, entry 16).
On the basis of the above experimental investigations and
several well-documented reports,16,17 a plausible mechanism is
proposed (Scheme 3). First, the condensation of aldehyde with
proline causes the formation of oxazolidin-5-one (A), a known
intermediate in the subsequent decarboxylative formation of the
azomethine ylide intermediate (B).30 Second, the dipole (B)
reacts with 1a and H+ to generate intermediate (C). Meanwhile,
a cascade reaction proceeds through a sequential nucleophilic
addition and denitrogenation reaction to give intermediate (D).
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a b
,
a b
,
Table 2. Scope for the Synthesis of 4a−4y
Table 3. Scope for the Synthesis of 5a−5t
a
Reaction conditions: 1 (0.2 mmol), 2a (0.3 mmol), 3 (0.3 mmol),
b
and EtOH (2.0 mL), air, sealed tube, 110 °C, 2 h. Isolated yield.
c
KOtBu (1.0 equiv) were added.
Scheme 2. Mechanistic Studies
a
Reaction conditions: 1a (0.2 mmol), 2 (0.3 mmol), 3 (0.3 mmol),
b
and EtOH (2.0 mL), air, sealed tube, 110 °C, 2 h.. Isolated yield.
Finally, the target product 4 or 5 is obtained by an elimination
reaction of intermediate (D).
Compound 5b exhibited well-defined antitumor activity
against MCF-7 and SH-SY5Y cells, as demonstrated by the
IC50 values of 18.5 1.2 and 62.5 1.1 μM in Table S2. This
indicates that compound 5b exhibited a preferential inhibitory
effect on tumor cells. Subsequently, the mechanism of the
antitumor activity of 5b on the MCF-7 cell line was further
investigated based on these experimental results. More detailed
experimental results are available in the Supporting Information.
In conclusion, we have developed an aldehyde-induced facile
synthesis of N-sulfonyl amidines through a one-pot approach
starting from benzenesulfonyl azide and proline. Furthermore,
the reactions proceed under convenient operation and have high
functional group tolerance. Moreover, this novel strategy allows
for the green synthesis of N-sulfonyl amidine 5b without the use
of any catalyst or additive and exhibited satisfactory anticancer
activity toward MCF-7 (IC50 = 18.5 1.2 μM) and SH-SY5Y
(IC50 = 62.5 1.1 μM) cells.
Accession Codes
CCDC 2042783 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
ASSOCIATED CONTENT
* Supporting Information
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AUTHOR INFORMATION
Corresponding Authors
■
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c04187.
Chengcai Xia − Pharmacy College, Institute of Pharmacology,
Shandong First Medical University & Shandong Academy of
Experimental procedures and spectral data (PDF)
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Medical Sciences, Taian 271016, China; orcid.org/0000-
0002-1943-5720; Email: xiachc@163.com
Zengfen Pang − Shandong Cancer Hospital and Institute,
Shandong First Medical University & Shandong Academy of
Medical Sciences, Jinan 250117, China; Email: pangzf0806@
163.com
Authors
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Liqiang Hao − Pharmacy College, Institute of Pharmacology,
Shandong First Medical University & Shandong Academy of
Medical Sciences, Taian 271016, China
Jian Sun − Pharmacy College, Institute of Pharmacology,
Shandong First Medical University & Shandong Academy of
Medical Sciences, Taian 271016, China
Zheng Zhang − Pharmacy College, Institute of Pharmacology,
Shandong First Medical University & Shandong Academy of
Medical Sciences, Taian 271016, China
Fuqiang Wen − Pharmacy College, Institute of Pharmacology,
Shandong First Medical University & Shandong Academy of
Medical Sciences, Taian 271016, China
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Novel indolin-2-one-based sulfonamides as carbonic anhydrase
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Complete contact information is available at:
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Notes
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synthesis of quinazolines through copper-catalyzed reaction of aniline-
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We thank the Academic promotion programme of Shandong
First Medical University(no. 2019LJ003) for financial support.
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