A Micellar Catalysis Strategy for Amidation of Alkynyl Bromides: Synthesis of Ynamides in Water

Article abstract of DOI:10.1002/ejoc.201801601

Copper-catalyzed amidation of alkynyl bromides can be carried out in water for the first time, which is made possible by a micellar catalysis strategy using rosin-based surfactant APGS-550-M. The surfactant can be easily prepared from natural abundant biomass, resin acids. Studies as to substrate scope and reaction aqueous medium recycling showcase the ease and sustainability of this technology.

Full text of DOI:10.1002/ejoc.201801601

DOI: 10.1002/ejoc.201801601
Full Paper
Micellar Catalysis
A Micellar Catalysis Strategy for Amidation of Alkynyl
Bromides: Synthesis of Ynamides in Water
Yunqin Yang,[a] Xiangtai Meng,[a] Baolong Zhu,[a] Ying Jia,[a] Xiaoji Cao,[b] and
Shenlin Huang*[a]
Abstract: Copper-catalyzed amidation of alkynyl bromides can abundant biomass, resin acids. Studies as to substrate scope
be carried out in water for the first time, which is made possible and reaction aqueous medium recycling showcase the ease and
by a micellar catalysis strategy using rosin-based surfactant sustainability of this technology.
APGS-550-M. The surfactant can be easily prepared from natural
Introduction
(Scheme 1b);[10] (iii) hydration of ynamides at high temperature
(Scheme 1c).[11] Moreover, Skrydstrup reported that the pres-
ence of water, even a small amount of hydrates in potassium
phosphate, could dramatically lower the yield in Hsung's
ynamide synthesis.[12] As a part of our continuous efforts to
explore sustainable synthetic methodology in water,[13] herein,
we overcome these challenges employing micellar catalysis,[14]
enabled by a rosin-based surfactant.
Ynamides, displaying an optimal balance of stability and reac-
tivity, have become a privileged building blocks for the synthe-
sis of highly versatile nitrogen-containing molecules including
bioactive agents and natural products.[1,2] Accordingly, many
synthetic strategies for ynamides have been developed since
the first synthesis by Viehe in 1972.[3] Among all of these known
methods,[4] arguably one of the best routes to ynamides was
the copper-catalyzed amidation of alkynyl bromides by
Hsung.[5] However, this strategy, as well as others, tends to re-
quire dry organic solvents (e.g., toluene, DMF, DMSO, DCM) and
relatively high temperatures. Issues such as waste disposal,
health, safety, and catalyst recyclability remain.[6] Therefore, the
development of environmentally friendly and sustainable meth-
ods for ynamide synthesis is of significant importance.
Water could be an ideal solvent for ynamide synthesis as it
is abundant, cheap, nontoxic, nonflammable, and renewable.[7,8]
The amidation of bromoalkynes is compatible with a catalytic
amount of water as CuSO4·5H2O is usually used as the catalyst.
However, amidation of bromoalkynes in water still presents im-
plicit challenges with possible side reactions (i) homocoupling
to 1,3-diynes prior to cross-coupling (Scheme 1a);[9] (ii) hydra-
tion of homocoupled 1,3-diynes to 2,5-disubstituted furans
Scheme 1. Challenges in amidation of alkynyl bromides in water.
Rosin,[15] the major product from exudates of pines, is a re-
newable natural feedstock with one million metric tons annual
production. Rosin mainly consists of various resin acids (abietic
acid and its isomers), which are a class of hydrocarbon-rich bio-
mass with bulky hydrophobic hydrophenanthrene rings. Fur-
thermore, rosin-derived esters are biocompatible and are fre-
quently used as food additives in chewing gum and beverages.
Thus, we envisioned that the rosin-based amphiphile like APGS-
550-M (Table 1) would be complementary to the well-known
TPGS-750-M,[16] FI-750-M,[17] and others[18] used in micellar ca-
talysis.
[a] Jiangsu Provincial Key Lab for the Chemistry and Utilization of
Agro-Forest Biomass, College of Chemical Engineering, Jiangsu Key Lab of
Biomass-Based Green Fuels and Chemicals, Jiangsu Co-Innovation Center
of Efficient Processing and Utilization of Forest Resources, Nanjing Forestry
University,
Nanjing, 210037, P. R. China
E-mail: shuang@njfu.edu.cn
[b] College of Chemical Engineering, Zhejiang University of Technology,
Zhejiang 310014, P.R. China
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201801601.
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Table 1. Optimization of the reaction conditions.[a]
anthroline or K2CO3 (Table 1, entries 13–15). Furthermore, reac-
tion efficiency was reduced upon reducing the loading of K2CO3
(Table 1, entry 16). Additionally, various surfactants were also
examined (Table 1, entries 17–20 & Table S1). It is noteworthy
that Lipshutz's TPGS-750-M also led to the desired ynamide 1c
in a good yield, while others resulted in moderate yields. A
further comparison between TPGS-750-M and APGS-550-M with
other substrates revealed that APGS-550-M was the surfactant
of choice (See the Supporting Information, Table S3). Finally,
the control reaction in the absence of APGS-550-M did not led
to synthetically useful results (Table 1, entry 21), documenting
that the reaction might be mainly taking place within the
nanomicellar core.
Entry
[Cu]
Surfactant
Yield[b]
1
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
CuI
CuCN
Cu(OTf)2
Cu(OAc)2
Cu(NO3)2·3H2O
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
APGS-550-M
APGS-550-M
APGS-550-M
APGS-550-M
APGS-550-M
APGS-550-M
APGS-550-M
APGS-550-M
APGS-550-M
APGS-550-M
APGS-550-M
APGS-550-M
APGS-550-M
APGS-550-M
APGS-550-M
APGS-550-M
TPGS-750-M
TWEEN 80
Brij L23
88 %
11 %
69 %
70 %
58 %
72 %
29 %
77 %
66 %
58 %
35 %
15 %
0
With the optimal conditions in hand, the scope with respect
to the bromoalkynes was examined (Table 2). To our delight, a
variety of arylethynyl bromides with electron-withdrawing
groups (EWG) and electron-donating groups (EDG) were all well
accommodated at the para position, affording the desired
ynamides in good to excellent yields (Table 2, 1c–5c). When we
changed the substituents' location from the para to the meta
or the ortho positions, excellent yields were obtained (Table 2,
6c–8c). Gratifyingly, alkynyl bromides bearing strong EWG such
as aldehyde and nitro were also participated in this reaction,
providing products 9c and 10c in high yields. Importantly, het-
erocyclic aryl groups such as pyridine could also be tolerated
2[c]
3[d]
4[e]
5
6
7
8
9
10[f]
11[g]
12[h]
13[i]
14[j]
15[k]
16[l]
17
0
0
67 %
82 %
75 %
67 %
39 %
55 %
Table 2. Substrate scope with respect to bromoalkynes.[a,b]
18
19
20
21
Nok
None
[a] Condition: 1a (0.12 mmol), 1b (0.1 mmol), CuSO4·5H2O (10 mol-%), 1,10-
phenanthroline (20 mol-%), K2CO3 (0.2 mmol), solvent (0.2 mL), at 50 °C for
26 h. [b] Determined by HPLC using diphenyl disulfide as the internal stan-
dard. [c] Cs2CO3 instead of K2CO3. [d] K3PO4 instead of K2CO3. [e] Et3N instead
of K2CO3. [f] TMEDA instead of 1,10-phenanthroline. [g] DMEDA instead of
1,10-phenanthroline. [h] T = 40 °C. [i] T = 30 °C. [j] Without ligand. [k] Without
base. [l] K2CO3 (0.15 mmol). TMEDA: N,N,N′,N′-tetramethylethylenediamine,
DMEDA: N,N′-dimethyl-1,2-ethanediamine, Nok: ꢀ-sitosterol methoxypoly-
ethyleneglycol succinate (SPGS-550-M).
Results and Discussion
Our optimization studies focused on the coupling reaction of
1-(bromoethynyl)-4-(tert-butyl)benzene (1a) with N-benzyl p-
toluenesulfonamide (1b) (Table 1). To our delight, the desired
ynamide product 1c was formed in 88 % HPLC yield after a 26 h
reaction that employed 10 mol-% CuSO4·5H2O as the catalyst,
20 mol-% 1,10-phenanthroline as the ligand, 2 equivalents of
K2CO3 as the base, and 2 wt.-% APGS-550-M/H2O as the solvent
at 50 °C (Table 1, entry 1). Attempts to replace K2CO3 with other
bases, such as Cs2CO3, K3PO4 or Et3N, led to either no catalyst
turnover or a much lower yield (Table 1, entries 2–4). Inferior
reaction performance was also observed when other copper
catalysts such as CuI, CuCN, Cu(OTf)2, Cu(OAc)2, or Cu(NO3)2·
3H2O or other ligands such as TMEDA or DMEDA were used
(Table 1, entries 5–11 & Table S2). Upon lowering the reaction
temperature to 40 °C, the yield was dramatically decreased to
15 % (Table 1, entry 12). Not surprisingly, the coupling reaction
did not occur at 30 °C or in the absence of either 1,10-phen-
[a] Conditions: a (0.12 mmol), 1b (0.1 mmol), CuSO4·5H2O (10 mol-%), 1,10-
phenanthroline (20 mol-%), K2CO3 (0.2 mmol) in 2 wt.-% APGS-550-M/H2O
(0.2 mL) at 50 °C for 26 h. [b] Isolated yields. [c] At 60 °C.
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(Table 2, 12c). Alkyl-substituted bromoalkynes, including linear electron-donating groups (MeO and tBu) and electron-with-
and cyclic alkyl groups (Table 2, 13c–15c), underwent the de- drawing group NO2 on the phenyl ring were compatible under
sired coupling reaction in good yields. Furthermore, (bromo- the reaction conditions (28c–33c). In addition, oxazolidinones
ethynyl)triisopropylsilane is competent in this transformation, as well as N-phenyl methanesulfonamide were coupled in good
giving the desired ynamide 16c in 62 % yield. Notably, complex yields (34c–38c).
natural product-derived substrates such as estrone analogue
17c and ꢀ-sitosterol analogue 18c were also successful.
Finally, the recyclability of copper catalyst and reaction me-
dium was investigated in the amidation of (bromoethynyl)-
Encouraged by these results, we next evaluated the scope benzene 11a with N-benzyl p-toluenesulfonamide 1b
with respect to the amides (Table 3). Various N-benzyl-substi- (Scheme 2a). After full conversion of 1b, the desired ynamide
tuted p-toluenesulfonamides underwent the desired coupling 11c was extracted with a minimal amount of ethyl acetate. The
in good to excellent yields (Table 3, 19c–22c). N-(furan-2-yl- resulting reaction medium as well as copper sulfate and 1,10-
methyl) p-toluenesulfonamide was also reacted without diffi- phenanthroline could be reused in the first recycle, providing
culty, affording ynamide 23c in 81 % yield. Moreover, N-alkyl- ynamide 11c in 85 % yield. Unfortunately, the yield was
substituted p-toluenesulfonamides bearing methyl (24c), n- dropped to 58 % yield in the second recycle. Gratifyingly, the
butyl (25c), and cyclopropyl (26c) were also compatible with yield could be improved to 96 % with additional copper catalyst
the standard reaction conditions. The N-phenyl p-toluene- and ligand. These results suggest that the reaction medium can
sulfonamide was a good substrate for ynamide synthesis (27c), be fully recycled, with partial copper and ligand recycling.
employing DMEDA as the ligand. Other arylsulfonamides with Moreover, the E factor[19] for these amidation reactions is as low
as 5. Notably, phenylethynyl bromide also reacted smoothly
with N-benzyl p-toluenesulfonamide 1b in gram-scale to afford
the corresponding ynamide 11c in 92 % yield (Scheme 2b).
Table 3. Substrate scope with respect to amides.[a,b]
Scheme 2. Recycle studies and gram-scale reaction.
Conclusions
In summary, copper-catalyzed amidation of alkynyl bromides
can now be performed in water enabled by a rosin-based sur-
factant, APGS-550-M. The surfactant can be easily accessed
from renewable biomass and be recycled along with the aque-
ous solution. The associated E Factor for the ynamide synthesis
is very low, documenting its sustainable reaction conditions.
Experimental Section
General Procedure for the Synthesis of Ynamides in Water:
[a] Conditions: a (0.12 mmol), b (0.1 mmol), CuSO4·5H2O (10 mol-%), 1,10-
phenanthroline (20 mol-%), K2CO3 (0.2 mmol) in 2 wt.-% APGS-550-M/H2O
(0.2 mL) at 50 °C for 26 h. [b] Isolated yields. [c] DMEDA as the Ligand.
Bromo alkyne (0.24 mmol, 1.2 equiv) was added to a solution
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Acknowledgments
Financial support provided by the Natural Science Foundation
of China (21502094 and 21602200), and the Natural Science
Foundation of the Jiangsu Higher Education Institutions of
China (17KJA220003) is warmly acknowledged. We are also
grateful for support by the Top-notch Academic Programs
Project of Jiangsu Higher Education Institutions (TAPP
PPZY2015C221), the Priority Academic Program Development
of Jiangsu Higher Education Institutions (PAPD), and advanced
analysis and testing center of Nanjing Forestry University.
Keywords: Ynamides · Rosin · Micellar catalysis · Alkynyl
bromides · Water chemistry
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Received: October 28, 2018
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Micellar Catalysis
Y. Yang, X. Meng, B. Zhu, Y. Jia,
X. Cao, S. Huang* ............................... 1–5
A Micellar Catalysis Strategy for
Amidation of Alkynyl Bromides:
Synthesis of Ynamides in Water
The synthesis of ynamides in water APGS-550-M, which can be easily pre-
was achieved by a micellar catalysis pared from natural abundant biomass.
strategy using rosin-based surfactant
DOI: 10.1002/ejoc.201801601
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