The C=C Bond Decomposition Initiated by Enamine-Azide Cycloaddition for Catalyst- and Additive-Free Synthesis of N-Sulfonyl Amidines

Article abstract of DOI:10.1002/adsc.201901054

The chemo-selective synthesis of N-sulfonyl amidines is realized via the decomposition of the enamine C=C bond of enaminoesters through an in situ generated triazoline intermediate. Control experiments prove that the electron withdrawing ester group in the enamine component is crucial in inducing the chemo-selective formation of amidines. The method is featured with high efficiency and sustainability by employing pure water as medium without requiring any catalyst or additive.

Full text of DOI:10.1002/adsc.201901054

Title: The C=C Double Bond Decomposition Initiated by Enamine-
Azide Cycloaddition for Catalyst- and Additive-Free Synthesis of
N-Sulfonyl Amidines
Authors: Xixi Zheng and Jie-Ping Wan
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901054
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10.1002/adsc.201901054
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
The C=C Bond Decomposition Initiated by Enamine-Azide
Cycloaddition for Catalyst- and Additive-Free Synthesis of N-
Sulfonyl Amidines
Xixi Zhenga and Jie-Ping Wana*
a
College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330022, P. R. China
Tel:/Fax: +86 791 8812 0380; Email: wanjieping@jxnu.edu.cn
In memory of Professor Dieter Enders
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. The chemo-selective synthesis of N-sulfonyl formation of amidines. The method is featured with high
amidines is realized via the decomposition of the enamine efficiency and sustainability by employing pure water as
C=C bond of enaminoesters through an in situ generated medium without requiring any catalyst or additive.
triazoline intermediate. Control experiments prove that the
electron withdrawing ester group in the enamine component
is crucial in inducing the chemo-selective
Keywords: Enaminoester; C=C bond functionalization;
Catalyst-free; Amidine; In water
substrates wherein the reactive C=C bond is prior fixed.
However, most known works using stable enamines
such as enaminones as substrates usually suffer from
narrow substrate scope and/or low efficiency.[11] In
other cases, the reactions of enaminone with azide
substrates tend to chemo-selectively provide 1,2,3-
triazoles as the major products (Scheme 1B).[12]
Therefore, searching for efficient methods enabling
the selective synthesis of amidines with easily
available enamine substrates and environmentally
benign catalytic conditions is highly valuable work.
Stable enamines such as enaminones and
enaminoesters have in recent years exhibited
tremendously widespread application in the synthesis
of various organic molecules,[13] which demonstrates
the possibility to establish more efficient synthetic
methods to amidines with improved selectivity by
transformation their C=C
Amidines are valuable chemicals for a variety of
sophisticated organic syntheses by acting as main
building blocks.[1] In addition, amidine structure has
also been well documented as crucial fragment in
numerous biologically relevant molecules.[2] While the
classical condensation of amines with amide acetals
resulting from the treatment of amides with SOCl2,
POCl3 etc used to be frequently employed for amidine
synthesis in early years,[3] the driving force of
developing environmentally benign synthetic methods
has triggered the occurrence of many important new
tactics providing amidine products. For example, the
reactions involving direct activation of amides,[4] the
reactions involving decomposition of the in situ
generation 1,2,3-triazole ring given by copper-
catalyzed
azide-alkyne
cycloaddition,[5]
the
condensation of C=S bond with amine precursors,[6]
three-component protocols involving the coupling of
amine or precursors with amides and electrophiles,[7]
the Ag-catalyzed activation of alkyne C≡C triple
bond,[8] the reactions involving nitrone/isocyanate
[3+2] cycloaddition.[9] And most prevalently, the
oxidative imidation of the C-C bond on tertiary
amines.[10] Besides employing oxidant, one major
issue in method of tertiary amine oxidation is the
generation of isomeric products when tertiary amine
with different N-substitution is used (Scheme 1A).
Alternatively, a potential tactic which may be able to
overcome these problems is employing enamine as
1
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10.1002/adsc.201901054
Advanced Synthesis & Catalysis
T
Yield
(%)b
69
Entry Solvent
EWG
(oC)
50
50
1
H2O
CO2Et
CO2Et
2c
H2O/EtOH
H2O/1,4-
dioxane
H2O/DMF
EtOH
61
3c
CO2Et
50
59
4c
5
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
50
50
50
50
50
25
40
60
40
40
40
44
49
53
65
40
46
72
61
24
52
trace
45
6
7
8
1,4-dioxane
toluene
DMF
9
H2O
10
11
12d
13e
14f
15
H2O
H2O
H2O
H2O
H2O
H2O
Scheme
1
Different reaction pathways between
enamines/enamine precursors and azide
CO2Me 40
bond. On the basis of our longstanding interest in
organic synthesis with electron deficient enamines,[14]
we have recently identified the synthesis of N-sulfonyl
amidines with excellent chemo-selectivity by simply
modifying the enamine structure to enaminoesters, and
the reactions take place with high efficiency using pure
water as the sole medium[15] without any catalyst or
additive (Scheme 1C),[16] disclosing further the
promising application of stable enamines in the
designation of green and sustainable synthetic
methods towards diverse products.
CO2Bu-
t
COPh
COMe
16
H2O
40
41
17
18
H2O
H2O
40
40
trace
trace
aGeneral conditions: enaminoester/enaminone 1 (0.2 mmol),
tosyl azide 2a (0.5 mmol), stirred for 17 h in 2.0 mL solvent.
bYield of isolated products based on 1. The ratio of water
c
to organic solvent was 3:1. eIn the presence of I2 (0.1 mmol).
eIn the presence of TBHP (0.1 mmol). In the presence of
f
Et3N (0.1 mmol).
To start the investigation, the reaction of
enaminoester 1a (R = CO2Et) and tosyl azide was
To illustrate the application scope of this protocol of
amidine synthesis, a series of enaminoesters 1 and
sulfonyl azides 2 were then employed under the
catalyst- and additive-free conditions, respectively.
According to the acquired data (Scheme 2), this
synthetic method exhibited general application to the
synthesis of N-sulfonyl amidines 3 by tolerating
available substrates 1 and 2. First, when tosyl azide
was fixed to react with different enaminoesters, the
enaminoesters containing diverse secondary amino
substructures, including cyclic secondary amino (3a
and 3f, Scheme 2), dialkyl amino (3b-3e, Scheme 2),
o
conducted by heating at 50 C in water. We were
delighted that the target product 3a was provided with
69% yield from the experiment (entry 1, Table 1). The
parallel experiments using mixed water/organic
solvent (entries 2-4, Table 1) as well as pure organic
solvent such as EtOH, dioxane, toluene and DMF
(entries 5-8, Table 1) both gave this product with
evidently lower yield, suggesting the specific
promotion effect of water to this transformation. By
performing the reaction at different temperatures,
further increased yield was afforded by heating at 40
oC (entries 9-11, Table 1). However, attempts on
employing additive such as I2, TBHP, or Et3N didn’t
show positive effect to the reaction (entries 12-14,
Table 1). As much more significant work, the effect of
the electron withdrawing group (EWG) in 1 to the
titled reaction was then examined. Varying EWG to
other ester groups such as CO2Me and CO2Bu-t gave
product 3a with lower yields (entries 15-16, Table 1).
On the other hand, only trace 3a was observed when
EWG as alternated with ketone fragment such as
COPh and COMe (entries 17-18, Table 1). These
results confirmed the particularly important function
of the ester fragment in the enamine substrate for this
reaction involving C=C bond decomposition.
Table 1 Optimization on reaction parametersa
2
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10.1002/adsc.201901054
Advanced Synthesis & Catalysis
synthesis of amidines, the diethyl 2-amino fumarates 4
were also employed to react with tosyl azide 2a. To
our delight, corresponding amidine products 5 were
obtained with fine tolerance to the amino group in 4.
Albeit the low yields of products 5, it was the first time
that such ester functionalized amidines could be
synthesized from simple 2-amino fumarates (Scheme
3).
Scheme 3 Synthesis of C-substituted sulfonyl amidines
Based on the in hand results and the many reports
on tertiary amine-based synthesis of N-sulfonyl
amidines,[10] the possible mechanism for the reaction
is proposed (Scheme 4). First, the [3 + 2] cycloaddition
of the enaminone C=C bond and sulfonyl azide gives
rise to the 1,2,3-triazoline intermediate 6. The
decomposition of this intermediate then provides the
amidine products 3 and 5 by releasing ethyl
diazoacetate. When stronger electron withdrawing
group such as ketone (COR instead of CO2R) presents
in the enamine, the relatively more potent acidity of
the α-C-H bond induces the selective amine
elimination from 6 to give 1,2,3-triazoles as found in
previous reports.[12] Therefore, the combination of the
ester group as well
Scheme 2 Scope on the synthesis of N-sulfonyl amidines
using β-enaminoester
dibenzyl amino (3g, Scheme 2) and aryl alkyl amino
(3h, Scheme 2) participated the synthesis with fair to
excellent product yield. On the other hand, aryl
sulfonyl azides containing electron donating (3i, 3i, 3p
and 3s, Scheme 2) and withdrawing groups (3j-3k,
3m-3o, 3q-3r and 3x, Scheme 2) displayed identically
satisfactory tolerance to the reaction. In addition, fused
aryl (3t, Scheme 2) and heteroaryl (3u, Scheme 2)
functionalized sulfonyl azides could also take part in
the synthesis of corresponding aryl sulfonyl amidines.
More notably, alkyl sulfonyl azides such as benzyl
sulfonyl azide and ethyl sulfonyl azide reacted with 1a
to give alkylated sulfonyl amidine with good to
excellent yield (3v-3w, Scheme 2). Meanwhile,
independently employing phenyl azide and benzyl
azide to reaction with enaminoester 1a didn’t provide
the expected amidine products. In addition, when the
readily available NH2 and NH-functionalized
enaminoesters were used to react with tosyl azide,
respectively, the expected formation of amidine was
not observed, either (Scheme 2).
Scheme 4 The plausible reaction mechanism
as the fixed C=C bond in the enaminoester is the ideal
option enabling this chemo-selective and green
amidine synthesis.
In conclusion, we have developed a practical C=C
bond decomposition reaction for the synthesis of N-
sulfonyl amidines by employing enaminoesters and
tosyl azides as starting materials. The reactions
proceed practically in pure water without employing
any catalyst or additive. In addition, primary
investigation reveals the feasibility of synthesizing
ester functionalized N-sulfonyl amidines by similar
transformation. The method provides hitherto the only
route to N-sulfonyl amidines without using any
In the journey to disclosing even more individual
application of the present C=C cleavage in the
3
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10.1002/adsc.201901054
Advanced Synthesis & Catalysis
catalyst or additive for green synthesis of N-sulfonyl
K. Han, J. Am. Soc. Chem. 2006, 128, 12366; d) Y. Feng,
W. Zhou, G. Sun, P. Liao, X. Bi, X. Li, Synthesis 2017,
49, 1371; e) F. Yi.; Q. Sun, J.; Sun, C. Fu, W. Yi, J. Org.
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amidines.
Experimental Section
General procedure for the synthesis of N-sulfonyl
amidines 3 and 5. To a 25 mL round-bottom flask were
charged with enaminoester 1 or 4 (0.2 mmol), sulfonyl azide
2 (0.5 mmol) and water (2 mL). The resulting mixture was
stirred at 40 oC for 17 h (TLC) under air atmosphere. After
cooling down to room temperature, the suspension was
extracted with ethyl acetate (3 × 8 mL). The combined
organic solution was washed with small amount of water,
and dried with anhydrous Na2SO4. After filtration, the
solvent in the acquired solution was removed under reduced
pressure. The resulting residue was subjected to flash silica
gel column chromatography to provide pure products with
the elution of mixed petroleum ether/ethyl acetate (v/v =
2:1).
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This work is financially supported by National Natural Science
Foundation of China (no. 21562025; 21861019) and Education
Department of Jiangxi Province (GJJ170213).
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Advanced Synthesis & Catalysis
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5
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10.1002/adsc.201901054
Advanced Synthesis & Catalysis
UPDATE
The C=C Bond Decomposition Initiated by
Enamine-Azide Cycloaddition for Catalyst- and
Additive-Free Synthesis of N-Sulfonyl Amidines
Adv. Synth. Catal. Year, Volume, Page – Page
Xixi Zheng, Jie-Ping Wan*
6
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