Direct Transformation of Terminal Alkynes into Amidines by a Silver-Catalyzed Four-Component Reaction

Article abstract of DOI:10.1021/jacs.8b11039

An unprecedented conversion of terminal alkynes into N-sulfonimidamides (amidines) is reported by a silver-catalyzed, one-pot, four-component reaction with TMSN₃, sodium sulfinate, and sulfonyl azide. The reaction scope includes both aromatic and aliphatic alkynes. A possible cascade reaction mechanism, consisting of alkyne hydroazidation, sulfonyl radical addition, 1,3-dipolar cycloaddition by TMSN₃, and retro-1,3-dipolar cycloaddition, is proposed. TMSN₃ is found to play an essential role in each step of the reaction.

Full text of DOI:10.1021/jacs.8b11039

Article
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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Direct Transformation of Terminal Alkynes into Amidines by a
Silver-Catalyzed Four-Component Reaction
Binbin Liu,†,⊥ Yongquan Ning,†,⊥ Matteo Virelli,§ Giuseppe Zanoni,§ Edward A. Anderson,∥
and Xihe Bi*,†,‡
†Department of Chemistry, Northeast Normal University, Changchun 130024, China
‡State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
§Department of Chemistry, University of Pavia, Viale Taramelli 12, 27100, Pavia, Italy
∥Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom
S
* Supporting Information
ABSTRACT: An unprecedented conversion of terminal
alkynes into N-sulfonimidamides (amidines) is reported by
a silver-catalyzed, one-pot, four-component reaction with
TMSN3, sodium sulfinate, and sulfonyl azide. The reaction
scope includes both aromatic and aliphatic alkynes. A possible
cascade reaction mechanism, consisting of alkyne hydro-
azidation, sulfonyl radical addition, 1,3-dipolar cycloaddition
by TMSN3, and retro-1,3-dipolar cycloaddition, is proposed. TMSN3 is found to play an essential role in each step of the
reaction.
regulative role in the reaction of the in situ formed
aminotriazole intermediate: in the absence of TMSN3, the
anticipated triazole product was obtained, whereas in the
presence of TMSN3, an amidine was unexpectedly isolated as
the major product (Figure 1c). Numerous reactions to make
amidines from N-substituted enamines have been reported;
however, the amidination of free enamines with azides is
unknown,13 despite the importance of amidines in azahetero-
cycle synthesis,14 molecular recognition,15 and pharmaco-
phores in medicinal chemistry.16 Therefore, the development
of an efficient synthetic method for amidines, especially for the
iminyl-unprotected amidines, would be of great value.17 We
envisaged that a novel cleavage transformation of the carbon−
carbon triple bond functionality into an amidine group could
be achieved by a silver-catalyzed four-component reaction,
directly starting from terminal alkynes with TMSN3, sodium
sulfinate, and sulfonyl azide. Here, we report the results of this
investigation, which enables the synthesis of a wide range of N-
sulfonimidamides (Figure 1d).17b,18 To the best of our
knowledge, this is the first report of the direct transformation
of alkynes into amidines.19
INTRODUCTION
■
The development of novel functional group transformations of
commonly available chemicals is of great importance in the
development of general and readily applied synthetic method-
ologies.1 Alkynes are one example of a readily available
chemical class; however, the large dissociation energy required
for the complete cleavage of the CC triple bond (∼200 kcal
mol−1) poses a challenge to the transformation of this
functionality into other motifs.2 Most of the known examples
of alkyne cleavage processes are involved in the construction of
heterocycles and carbocycles.3,4 Far fewer strategies are
available for the transformation of CC triple bonds into
other functional groups such as ketones,5,3g carboxylic esters
and (thio)amides,6 olefins,7 alkynes,8 and nitriles9 (Figure 1a).
Nevertheless, these procedures often require the use of
activated alkynes or expensive and/or toxic transition
metals.5−9 The development of functional group trans-
formations starting from nonactivated alkynes remains highly
appealing.
Our group has recently developed a silver-catalyzed
hydroazidation of terminal alkynes, which provided a method
for the direct transformation of terminal alkynes to α-
substituted vinyl azides.10 We subsequently reported a silver-
catalyzed three-component reaction of terminal alkynes,
trimethylsilyl azide (TMSN3), and sodium sulfinate, which
enables the synthesis of β-sulfonyl enamines (Figure 1b).11
The efficient generation of these enamines from terminal
alkynes encouraged us to investigate their synthetic utility. One
of the most studied reactions of enamines is their cycloaddition
with sulfonyl azides, leading to triazoles.12 In the case of β-
sulfonyl enamines, TMSN3 was found to play a crucial
RESULTS AND DISCUSSION
■
In an initial study, p-tolylacetylene 1a, TMSN3, sodium
sulfinate 2a, tosyl azide 3a, and water were reacted in the
presence of Ag3PO4 catalyst in DMSO at 70 °C, giving 4-
methyl-N-tosylbenzimidamide 4a in 80% yield (Table 1, entry
1). This discovery prompted us to further optimize the
Received: October 19, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.8b11039
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
was obtained in a modest 43% yield (entries 8−11). Notably,
reducing or increasing the amount of Ag3PO4 resulted in lower
product yields. The conditions listed in entry 1 were therefore
optimal and are termed “standard conditions”.
With the optimized conditions in hand, we sought to
examine the reaction scope with respect to the alkyne substrate
(Scheme 1). Aryl alkynes with either electron-donating or
a
Scheme 1. Reaction Scope of Aromatic Terminal Alkynes
Figure 1. (a) Previous transformations of alkynes into other
functional groups. (b) Previous work from our group on alkyne
aminosulfonylation. (c) Transformation of β-sulfonyl enamine into an
amidine. (d) Reaction blueprint for the development of the direct
transformation of terminal alkynes into amidines.
a
Table 1. Optimization of the Reaction Conditions
b
entry
[M] cat.
amount (mol %)
solvent
DMSO
yield (%)
1
2
3
4
5
6
7
8
9
Ag3PO4
Ag2CO3
AgNO3
AgF
Pd(OAc)2
CuI
Au(PPh3)Cl
Ag3PO4
Ag3PO4
Ag3PO4
Ag3PO4
20
20
20
20
5
20
10
20
20
20
20
80
47
62
55
0
0
0
43
0
0
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
CH3CN
DCE
1,4-dioxane
a
Reaction conditions: 1 (0.5 mmol), TMSN3 (1.0 mmol), TolSO2Na
(0.75 mmol), TsN3 (0.75 mmol), and Ag3PO4 (0.1 mmol) in DMSO
(3 mL) at 70 °C under air for 10 h. Yields of isolated products.
electron-withdrawing groups on the para-position of the
phenyl ring proved to be competent for the CC triple
bond cleavage reaction, providing amidines 4a−4m in
uniformly good yields. A variety of functional groups, such as
alkoxy, halo, trifluoromethyl, cyano, ester, nitro, and formyl,
were well-tolerated. The structure of the amidine products was
further confirmed by X-ray crystallographic analysis of the
product 4m.20 The meta-substituted aryl alkynes as well as
substrates with two substituents on the phenyl ring also
afforded the desired products in 59−85% yield (4n−4s). A
phenol (4p) was also well-tolerated under the cleavage
reaction conditions. In addition, a naphthyl group was suitable
for the preparation of amidine 4t (59%). Heteroaryl alkynes,
such as 3-quinolinyl, 2- and 3-pyridyl, 2- and 3-thienyl, and
dibenzo[b,d]thiophene-4-yl, also participated in the reaction,
affording the desired products (4u−4z) in 55−79% yield. As
an example of the application to the late-stage modification of
more complex molecules, the methodology was successfully
applied to 4-methylumbelliferone and endofolliculina, afford-
10
11
0
a
Reaction conditions: 1a (0.5 mmol), TMSN3 (1.0 mmol), H2O (1.0
mmol), TolSO2Na 2a (0.75 mmol), TsN3 3a (0.75 mmol), catalyst
(5−20 mol %) in solvent (3 mL) at 70 °C under air for 10 h.
b
Isolated yields.
reaction conditions for this CC triple bond cleavage. In the
absence of any one of the three reagents (TMSN3, TolSO2Na,
and TsN3), no product was obtained. When Ag3PO4 was
replaced by other common silver salts such as Ag2CO3,
AgNO3, and AgF (entries 2−4), no improvement in yield was
recorded. Other transition-metal-based catalysts, such as
Pd(OAc)2, CuI, and Au(PPh3)Cl, did not show any activity
(entries 5−7). The reaction outcome proved highly solvent
dependent with no detection of the desired product in
CH3CN, DCE, or 1,4-dioxane, whereas in DMF, product 4a
B
DOI: 10.1021/jacs.8b11039
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Article
ing the corresponding amidine-modified derivatives in
moderate yield.
Table 2. Reaction Scope of Sodium Sulfinates and Sulfonyl
Azides
a
To test the large-scale applicability of this silver-catalyzed
transformation, an experiment was performed where 20 mmol
of 1a was subjected to the standard reaction conditions,
affording N-tosyl amidine 4a in a slightly reduced yield (73%),
which could be easily deprotected to amidine 4a′ in 84% yield
on treatment with NaOH.21
b
entry
R1 = R2
6 = 6′
yield (%)
1
2
3
4
5
6
4-MeOC6H4
Ph
4-MeOC6H4
Ph
6a
6b
6c
6d
6e
74
67
75
78
82
Our attention next turned to the reaction scope for aliphatic
alkynes. As illustrated in Scheme 2, this class of substrates also
4-ClC6H4
4-FC6H4
Oct
4-ClC6H4
4-FC6H4
Oct
a
Scheme 2. Reaction Scope of Aliphatic Terminal Alkynes
Me
Me
6f
85
b
b
entry
R1 ≠ R2
6
yield (%)
6’
yield (%)
7
8
Me
4-MeC6H4
4-MeC6H4
4-ClC6H4
6f
4a
0
0
4a
6c
80
75
a
Reaction conditions: 1 (0.5 mmol), TMSN3 (1.0 mmol), R1SO2Na 2
(0.75 mmol), R2SO2N3 3 (0.75 mmol), and Ag3PO4 (0.1 mmol) in
DMSO (3 mL) at 70 °C under air for 8−10 h. Yields of isolated
products.
b
alternative product. This finding demonstrates that the
sulfonamide unit in the product originates from the sulfonyl
azide rather than from the sulfinate, where the intermediate
sulfone group is presumably lost in the course of alkyne
cleavage.
Further experiments were carried out to gain a deeper
understanding of the mechanistic pathway (Scheme 3): (a)
Scheme 3. Mechanistic Investigations
a
Reaction conditions: 1 (0.5 mmol), TMSN3 (1.0 mmol), TolSO2Na
(0.75 mmol), and Ag3PO4 (0.1 mmol) in DMSO (2 mL) at 70 °C for
4 h, then TsN3 (0.75 mmol, dissolved in 1 mL of DMSO), at 70 °C
b
under air for another 4−6 h. Yield of isolated products. 2 equiv of
TolSO2Na was used.
underwent this transformation with similar efficiency, provid-
ing amidines in generally good yields. Terminal linear alkynes
of varying chain length gave comparable reaction outcomes
(5a−5d) as did the underivatized cycloalkylacetylenes (5e−
5g) of varying ring size. Substrates with a variety of functional
groups, such as ester, ether, thioether, phthalimide, and in
particular an internal alkyne, still afforded the corresponding
amidines (5h−5l) in 55−82% yield, thus demonstrating
chemoselectivity of this silver-catalyzed reaction for the
terminal alkyne. The amidination of terminal alkynes was
also effective with styryl acetylenes, leading to conjugated
products 5m and 5n in comparable yields. When 3-butyn-1-ol
was used as substrate, the unexpected sulfonylated amidine 5o
was obtained in 55% yield, possibly via a rarely described
dehydroxysulfonation of the primary alcohol,22 followed by the
amidination reaction.
The scope for sodium sulfinate and sulfonyl azide was
explored by testing the reaction of a small range of these
components with p-tolylacetylene 1a (Table 2). When the
sodium sulfinate and the sulfonyl azide featured the same
substituent (R1 = R2, aryl or alkyl), the target amidines (6a−
6f) were obtained in 67−85% yield. When we performed the
reaction with different groups on the sulfinate and sulfonate
azide (i.e., R1 ≠ R2), amidines 4a and 6c were obtained as the
sole products, with no detectable trace of the possible
Addition of the radical traps 2,2,6,6-(tetramethylpiperidin-1-
yl)oxyl (TEMPO) or butylated hydroxytoluene (BHT) to the
reaction under the optimized conditions led to the formation
of only a trace amount of product 4a, thus implying the
possible involvement of a radical process. (b) When terminal
alkyne 1a was replaced by vinyl azide 7, 4a was obtained in a
yield (82%) comparable to that in the analogous optimized
one-pot conditions (cf. Table 1, entry 1), thus suggesting the
vinyl azide as a potential initial reaction intermediate. (c)
When vinyl azide 7 was subjected to the optimized reaction
C
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conditions but in the absence of TsN3, the aminosulfonylated
product 8 was obtained in 83% yield and amidine 4a was not
detected. Moreover, no product 8 could be observed when the
reaction was carried out in the absence of either TolSO2Na or
TMSN3. (d) When 8 was subjected to the optimized
conditions (but in the absence of the sulfinate salt), 4a was
isolated in 56% yield, implying 8 also to be a reaction
intermediate. No reaction occurred without TMSN3, thus
confirming this reactant as essential for conversion to the
amidine. Moreover, the silver catalyst and water seemed to be
detrimental to this particular reaction, with an improved 78%
yield of 4a attained in their absence. (e) No reaction occurred
when treating 8 with TMSN3, whereas the cycloaddition of
enamine 8 with TsN3, but in the absence of TMSN3, led to
triazole product 9 in 86% yield. Further, no reaction was
observed on treatment of 9 with TMSN3, so 9 is not an
intermediate in the formation of amidine product.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.8b11039.
■
S
Experimental procedures, analytical data, and copies of
NMR spectra (PDF)
X-ray data for 4m (CIF)
AUTHOR INFORMATION
Corresponding Author
*bixh507@nenu.edu.cn
ORCID
Edward A. Anderson: 0000-0002-4149-0494
Xihe Bi: 0000-0002-6694-6742
■
Author Contributions
⊥B.L. and Y.N. contributed equally to this work.
Based on the above results and related precedent,12a,23
a
plausible mechanism for the amidination of tolylacetylene 1a is
outlined in Scheme 4. As demonstrated in Scheme 3c, tosyl
Notes
The authors declare no competing financial interest.
Scheme 4. Proposed Mechanism
ACKNOWLEDGMENTS
■
Financial support was provided by NSFC (21871043,
21522202, 21502017) and the Department of Science and
Technology of Jilin Province (20180101185JC,
20190701012GH). E.A.A. thanks the EPSRC for support
(EP/M019195/1).
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azide.11 1,3-Dipolar cycloaddition with TsN3 gives 1,2,3-
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CONCLUSION
■
In conclusion, we have developed an unprecedented silver-
catalyzed CC cleavage of terminal alkynes to amidines by a
one-pot four-component reaction. The reaction accommodates
a wide variety of aryl-, heteroaryl-, alkyl-, and alkenyl-
substituted terminal alkynes and tolerates a range of other
functional groups. From a mechanistic perspective, a cascade
sequence is proposed consisting of hydroazidation, sulfonyl
radical addition, 1,3-dipolar cycloaddition, and retro-1,3-
dipolar cycloaddition, resulting in the amidine product.
Given the importance of amidines in medicinal chemistry
research, this process offers a facile entry to this useful
functional group.
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