Interception of amide ylides with sulfonamides: Synthesis of (: E)- N -sulfonyl amidines catalyzed by Zn(OTf)2

Article abstract of DOI:10.1039/c7cc07364j

Through the interception of amide ylides with sulfonamides, we herein report the first general example of an intermolecular condensation reaction between sulfonamides and amides. Beyond formamides, this approach was successfully applied to a variety of lactams and linear amides, giving rise to a broad array of (E)-N-sulfonyl amidines.

Full text of DOI:10.1039/c7cc07364j

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DOI: 10.1039/C7CC07364J
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Interception of Amide Ylides with Sulfonamides: Synthesis of (E)-
N-Sulfonyl Amidines Catalyzed by Zn(OTf)2
Received 00th January 20xx,
Accepted 00th January 20xx
Jijun Chen, Wenhao Long, Shangwen Fan, Yonggang Yang,* and Xiaobing Wan*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Through the interception of amide ylides with sulfonamides, we condensation reactions has largely been limited to those with
herein report the first general example of intermolecular activated methylene moieties to construct C=C double bonds,8
condensation reaction between sulfonamides and amides. Beyond whereas condensation with other nucleophiles has found far
formamides, this approach was successfully applied to a variety of less success. One example of the latter case is the
lactams and linear amides, giving rise to a broad array of (E)-N- condensation
reaction between formamides and
sulfonyl amidines.
sulfonamides,9 whose synthetic utility is impaired by its
requirement of hazardous reagents and harsh conditions
(Scheme 1a).
Amidine-based compounds are ubiquitous in nature and play
critical roles in pharmaceutical and agrochemical industries.1
Amidine often serves as a key scaffold in drug discovery, a
useful building block for heterocyclic construction, and a
common coordinating ligand of transition metals.2
Unfortunately, conventional synthetic approaches that
produce amidines from substrates such as thioamides,3a
isonitriles3b and aldoximes3c often have inadequate reaction
efficiency and rely on precursors that themselves are not
readily available and thus need to be prepared beforehand.
The development of new, efficient and sustainable methods
for the generation of amidine-containing molecules has always
been a focus of synthetic chemistry.4 Recently, several
excellent strategies have been reported, including one that
involves Cu-catalyzed three-component coupling via
a
ketenimine intermediate5 and another that features oxidative
dehydrogenation of tertiary amines coupled with a tandem
reaction with sulfonyl azides.6 In theory, the condensation of
amides and amines represents the most direct and atom-
economical method to synthesize amidines.
Condensation of reactive carbonyl compounds, including
aldehydes, ketones and esters, with various nucleophiles is
one of the most critical tools in synthetic chemistry for
building molecular complexity from simple and readily
available substrates.7 In contrast, amides are generally
considered unsuitable for these transformations due to their
poor electrophilicity. In fact, current research on amide
Scheme 1 Condensation of sulfonamides and amides.
Recently, we described the NaI-catalyzed direct
condensation of sulfonamides and formamides based on the in
situ generation of TsN•NaI.10 Although this approach was a
significant improvement over earlier methods of N-sulfonyl
formamidine synthesis, it required the use of formamide as
solvent to ensure satisfactory yields. Another well-known
obstacle lies in the accomplishment of intermolecular
condensation between sulfonamides and common amides,
a.Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry,
Chemical Engineering and Materials Science, Soochow University, Suzhou 215123,
China. E-mail: wanxb@suda.edu.cn
†Electronic Supplementary Information (ESI) available: Experimental procedures,
characterization data of the products. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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, and 5c). Several sulfonamide-containing VietwhAerrtiaclpeeOunltinice
4x
though successful intramolecular reactions have been
reported.11. To simultaneously address both challenges, we
drew inspiration from the well-established methodology, in
which an amide is first activated by a transition-metal
carbene12 to generate a reactive ylide intermediate, which
then underwent classical [3+2] cycloadditions with alkynes or
alkenes for synthesizing heterocyclic compounds.13 We reason
that the interception of amide ylides with sulfonamides would
generate the desired amidine products in a mechanistically
distinct manner (Scheme 1c). This methodology is compatible
with a wide range of lactams and linear amides carrying
diverse functional groups, thereby creating infusive
opportunities for the late-stage functionalization of drug
molecules.
compounds, including zonisamide, celecoxib and topiramate,
DOI: 10.1039/C7CC07364J
were found to be amenable to condensation with 1-phenyl-2-
pyrrolidinone 1a to produce the target amidines in good yields
5a-5c), which highlighted the utility of our method for
(
generating novel and potentially bioactive drug derivatives.
The exact (E)-configuration of the lactam amidine product was
unequivocally confirmed by single-crystal X-ray analysis of 4a
(For details, see ESI). To demonstrate the scalability and
operational simplicity of the condensation method, we
successfully synthesized 6.2 g of N-sulfonyl amidine 4a in
almost quantitative yield from 3.22 g of 1a and 3.42 g of 2a in
just 20 mL of C6H12 (Scheme 3).
Given the abundance of lactam-based natural products, we
began our study by exploring the condensation between 1-
phenyl-2-pyrrolidinone 1a and p-toluenesulfonamide 2a using
commercially available EDA (ethyl diazoacetate) 3a as additive.
The key to success is finding a suitable transition-metal
catalyst that favors the formation of the desired amidine
product 4a, over the competing N−H insertion of 2a into 3a 14
.
Gratifyingly, we detected a trace amount of the desired
product 4a when Cu(OAc)2 was used as catalyst (Table S1,
entry 1, see ESI). As expected, increasing the EDA loading
enhanced the reaction efficiency (Table S1, entries 2-3).
Encouraged by the result, we then optimized the reaction by
screening a panel of different transition-metal catalysts with
varying degrees of success (Table S1, entries 4-8). In particular,
we discovered that 4a was generated in nearly quantitatively
yield under the catalysis of Zn(OTf)2 (Table S1, entry 9). The
choice of solvent was also found to have a critical impact
(Table S1, entries 10-15). As expected, the condensation was
largely abolished in the absence of either Zn(OTf)2 or EDA 3a
(Table S1, entries 16 and 17). Screening of different diazo
reagents (Table S1, entries 18-22) revealed that ethyl
phenyldiazoacetate 3d and trimethylsilyldiazomethane 3f had
considerably poorer catalytic performance than 3a (Table S1,
entries 20 and 22), whereas dimethyl 2-diazomalonate 3e
bearing two electron-withdrawing substituents failed
completely (Table S1, entry 21). Notably, the reaction was not
sensitive to moisture or oxygen, and therefore can be set up
under atmospheric conditions.
Scheme 2 Variation of the sulfonamide. Conditions: 1a (0.2 mmol),
mmol), 3a (0.4 mmol), Zn(OTf)2 (10 mol%) in C6H12 was stirred under reflux
for 12 h under air.
2 (0.2
We next explored the substrate scope of our reaction by
screening different sulfonamides (Scheme 2). A variety of
synthetically useful functionalities with diverse electronic
Scheme 3 Gram-scale reaction.
properties, such as halides (4c, 4e, 4f, 4i, 4m and 4o), ester (4k)
and nitryl (4l and 4n), were well tolerated and intactly
preserved, opening up the possibility for further derivatization.
Furthermore, the position of the substituent on the phenyl
ring showed no apparent negative effect on the reaction
efficiency (4a−4o). Heteroaryl sulfonamides, such as those
bearing a quinolone or a thiophene moiety, were shown to be
suitable substrates and furnished medicinally important
We also tested various lactam substrates (Scheme 4) and
found an electronically diverse set of substituents, including
the strongly electron-withdrawing cyano (6f) and nitryl groups
(
6m), to be well tolerated on the N-phenyl ring.
Polysubstituted aryl lactams were shown to be compatible
with the condensation reaction (6p 6r). The phenyl group in
1a could also be replaced with naphthyl (6s), thiophene (6t
−
,
heterocyclic amidines (4q
and benzyl sulfonamides, the corresponding N-sulfonyl
amidines were still obtained in remarkable yields (4s 4v).
Challengingly, oxy-sulfamide and azo-sulfamide could also be
−4r) in satisfactory yields. For alkyl
6u), or even an alkyl moiety such as alkyl (7f−7h), cyclohexyl (7i
or benzyl (7j), without significant decline in reaction efficiency.
On the other hand, our method could accommodate other
cyclic amides, including a proline derivative (7a), strained β-
)
−
installed to generate the desired products in good yields (4w
,
lactams (7c
-
7e) and spiro-amide compound (7b).
2 | J. Name., 2012, 00, 1-3
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and furnished the corresponding amidine VpierwoAdruticcletsOnliinne
moderate to high yields. CondensationDoOfI: 1a0m.10id3e9/Cc7oCnCt0a7in36in4gJ
proline structure with 2a resulted in the formation of 8j with
the preservation of the stereo configuration at the chiral
center. The exact (E)-configuration of the linear amidine
product was confirmed by single crystal X-ray analysis of 8d
(For details, see ESI). Unfortunately, both primary and
secondary amides were poor substrates for this
transformation under the optimized reaction conditions.
Finally, despite not being the main focus of the current
study, we showed that formamide derivatives could also serve
as suitable substrates (Scheme 6). It was especially noteworthy
that the nitrogen atom in the formamide could be
functionalized with two a bulky isopropyl groups (9d) or be
part of a heterocycle (9e−9f).
Scheme 6 Variation of the formamide. Conditions:
mmol), 3a (0.4 mmol), Zn(OTf)2 (10 mol%) in C6H12 was stirred at reflux for
12 h under air.
1 (0.2 mmol), 2a (0.2
Scheme 4 Variation of the lactam. aConditions:
1 (0.2 mmol), 2 (0.2 mmol),
3a (0.4 mmol), Zn(OTf)2 (10 mol%) in C6H12 was stirred at reflux for 12 h
under air. b3a (0.6 mmol), Zn(OTf)2 (30 mol%).
To probe the mechanism of the zinc-catalyzed condensation
reaction, 4-tert-butylstyrene, which was proven to be an
efficient carbene trap, was added to the model reaction of 1a
and 2a. The cyclopropanation product 10 was detected by GC-
MS, confirming the involvement of a carbene intermediate
(Scheme S1a). On the other hand, the reaction of 1a with
compound 11, which could be seen as derived from the N−H
insertion of TsNH2 into EDA, produced no amidine produce 4a
and therefore provided counterevidence against the
alternative N−H insertion/condensation pathway (Scheme S1b).
Substitution of H2O for TsNH2 led to the formation of
compound 12 based on HRMS detection (Scheme S1c).
Moreover, when H2O18 was used, [18O]-1a was observed by
HRMS (Scheme S1d). Taken together, these experiment data
indicated that an amide ylide intermediate was generated in
situ and subsequently trapped with a nucleophile. 1H NMR
study of the model reaction suggested that EDA was converted
to 2,2'-oxydiacetate 14 (Figure S1). This was further
corroborated by the observation that ethyl glycolate 13 could
undergo O−H insertion into 3a to generate 14 in the presence
of Zn(OTf)2.
Scheme 5 Variation of the linear amide. aConditions:
1 (0.2 mmol), 2a (0.2
mmol), 3a (0.4 mmol), Zn(OTf)2 (10 mol%) in C6H12 was stirred at reflux for
12 h under air. b3a (0.6 mmol), Zn(OTf)2 (30 mol%).
Based on the abovementioned investigations and recently
published studies,
described in Scheme 7. The catalytic cycle begins with
formation of an electrophilic carbenoid species from the Zn-
promoted decomposition of EDA.17 Subsequently, the amide
substrate performs a nucleophilic attack on and leads to the
generation of an ylide intermediate , which is in equilibrium
a tentative reaction mechanism was
We next demonstrated that the scope of our protocol could
be extended to include linear amides as substrates, which have
shown to be prevalent in a series of marketed drugs.15
A
Remarkably, sterically demanding amides (8b, 8c, and 8h),
A
which were generally incompatible with several previously
B
described condensation reactions,9,10,16 readily reacted with 2a
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with imine C 13,18
Trapping of
Journal Name
Zhu, F. Xiao, F. Chen, B. Fu and Z. Zhang, Angew. Chem. Int.
.
B
or
C
with sulfonamide furnishes
and the Zn
Ed., 2017, 56, 4320; (c) J. Cesar, K. Nadrah and VMiew. SA.rtiDcleoOlennlince,
DOI: 10.1039/C7CC07364J
intermediate , which then decomposes into
catalyst.19 Finally,
undergoes elimination to afford the
desired amidine product and ethyl glycolate 13, the latter of
which is immediately trapped by and results in the
generation of 2,2'-oxydiacetate 14 through O−H insertion.13a
The detection of by HRMS (For details, see see ESI) provided
D
E
Tetrahedron Lett., 2004, 45, 7445.
E
4
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D. Xu, Org. Lett., 2015, 17, 5598.
A
E
the most convincing evidence in support of our proposed
mechanism.
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8
9
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Scheme 7 Proposed mechanism.
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In conclusion, we herein reported the first intermolecular
condensation reaction of common amides and sulfamides,
leading to a broad array of (E)-N-sulfonyl amidines in good
yields and with excellent stereoselectivity. The wide substrate
scope, exceptional functional group tolerance, operational
simplicity and neutral reaction conditions would make this
mechanistically novel method particularly well suited for
preparing various amidine compounds. Future efforts will
focus on the discovery of condensation reaction of amides and
other nucleophiles, which triggered by the amide ylides.
A
Project Funded by the Priority Academic Program
Development of Jiangsu Higher Education Institutions (PAPD),
NSFC (21572148, 51673141).
Notes and references
1
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,
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Interception of Amide Ylides with Sulfonamides: Synthesis of (E)-N-Sulfonyl Amidines Catalyzed by
Zn(OTf)2
Jijun Chen, Wenhao Long, Shangwen Fan, Yonggang Yang, and Xiaobing Wan
Chem. Chem., 2017, Volume, Page – Page
DOI: 10.1039/b000000x
Through the interception of amide ylides with sulfonamides, we herein report an intermolecular
condensation reaction between sulfonamides and common amides.