Visible light-promoted copper catalyzed regioselective acetamidation of terminal alkynes by arylamines

Article abstract of DOI:10.1039/c9gc03608c

Herein, we describe a copper photoredox catalyzed synthesis of acetamide via regioselective C-N coupling of arylamines with terminal alkynes using molecular oxygen (O₂) as an oxidant at room temperature under visible light irradiation (47 examples). Unique simultaneous formation of both amide and ester functionalities occurs via intramolecular cyclization in a single-step reaction in the case of anthranilic acids using inexpensive copper as a catalyst and eco-friendly O₂ as an oxidant and reagent. Different substrates undergo different reaction pathways to generate similar acetamide products, as evidenced by ¹⁸O₂ labelling experiments. The current protocol was also applied for the rapid, few step preparation of biologically active inhibitors (BACE-1 and PDE4). This process can be readily scaled up to a gram scale, and calculations of green metrics suggest the economic feasibility and eco-friendly nature of the current photoredox approach.

Full text of DOI:10.1039/c9gc03608c

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Visible light-promoted copper catalyzed
regioselective acetamidation of terminal
Cite this: DOI: 10.1039/c9gc03608c
alkynes by arylamines†
V. Kishore Kumar Pampana,
Arunachalam Sagadevan,
Ayyakkannu Ragupathi and Kuo Chu Hwang
*
Herein, we describe a copper photoredox catalyzed synthesis of acetamide via regioselective C–N coup-
ling of arylamines with terminal alkynes using molecular oxygen (O2) as an oxidant at room temperature
under visible light irradiation (47 examples). Unique simultaneous formation of both amide and ester func-
tionalities occurs via intramolecular cyclization in a single-step reaction in the case of anthranilic acids
using inexpensive copper as a catalyst and eco-friendly O2 as an oxidant and reagent. Different substrates
undergo different reaction pathways to generate similar acetamide products, as evidenced by 18O2 label-
ling experiments. The current protocol was also applied for the rapid, few step preparation of biologically
active inhibitors (BACE-1 and PDE4). This process can be readily scaled up to a gram scale, and calcu-
lations of green metrics suggest the economic feasibility and eco-friendly nature of the current photo-
redox approach.
Received 20th October 2019,
Accepted 19th November 2019
DOI: 10.1039/c9gc03608c
rsc.li/greenchem
transformations necessitate the use of stoichiometric unstable
azides (e.g., TsN3 or TMSN3) as coupling partners with term-
Introduction
Amide functionalities are important and ubiquitous structural inal/internal alkynes for amide bond formation. Moreover,
motifs found in natural products, pharmaceutical drugs, and several other methods have been developed including amida-
polymeric materials, and they represent important synthetic tion of alcohols at high temperature using expensive Ru/Rh-
intermediates that can be utilized for further construction of catalysts.8 As such, the development of a new method for
complex molecules.1 Traditional methods for the synthesis of amide bond construction using commercially available stable
amides include; (i) condensation of amines with carboxylic arylamines to couple with terminal alkynes using inexpensive
acids at high temperatures,2 (ii) nucleophilic addition of catalysts (e.g., copper) under low energy visible light irradiation
amines to activated carbonyl moieties, such as water-sensitive would be a desirable goal in contemporary organic synthesis.
acyl chlorides and anhydrides,3 (Scheme 1a), and (iii) coupling
In recent years, photoredox catalysis has enabled the
reaction of acids and amines using stoichiometric coupling development of a wide range of challenging chemical trans-
reagents (typically used in excess)4 (Scheme 1b). Transition- formations via outer-sphere single electron transfer (SET)
metal-catalysis has emerged as a powerful and alternative processes.9 Unlike expensive photoredox catalysts (Ru- and Ir-
attractive approach for amide bond construction.5 In this complexes),9b Earth-abundant cheaper copper-based photo-
regard, Chang et al. reported that inexpensive copper catalysis redox catalysts can be much more feasible in various trans-
has successfully facilitated amide bond formation, wherein formations10 via an outer-sphere10a,b or inner-coordination-
terminal alkynes and TsN3 were employed as coupling part- sphere mechanism.10c,d
ners (Scheme 1c).6 Consequently, Jiao et al. recently reported
Herein, we report the first visible light-induced acetamida-
Au/Ag-co-catalyzed nitrogenation of alkynes via Csp2–Csp clea- tion of terminal alkynes by arylamines and molecular O2 using
vage at elevated temperatures to synthesize amides using copper as a catalyst that opens a new synthetic route to aceta-
TMSN3 (Scheme 1d).7 Despite indisputable advances, these mides.11 The reaction proceeds at room temperature using an
inexpensive catalyst (5 mol% CuCl), K2CO3 as a base, and O2
as an oxidant, without the use of additional oxidants and
Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan,
ligands (Scheme 1e). Notably, the current work represents the
Republic of China. E-mail: kchwang@mx.nthu.edu.tw; Fax: (+886) 35711082
first literature method for mono-ketonation/amidation of term-
†Electronic supplementary information (ESI) available. CCDC 1893991–1893993.
inal alkynes by arylamines, which is complementary to the
For ESI and crystallographic data in CIF or other electronic format see DOI:
reported copper-catalyzed process for diketonation/amidation
10.1039/c9gc03608c
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Scheme 1 Different synthetic approaches for amide formation.
Table 1 Optimization of the reaction conditionsa
of terminal alkynes.11,12 The notable key features of the
current method include: (a) avoiding the use of protecting
groups in the cases of 2-aminophenol and anthranilic acid to
synthesize acetamide, which would be an important task in
organic synthesis,13a (b) simultaneous single-step formation of
amide and ester functionalities in the case of anthranilic
acids, which are not possible by using previously reported lit-
erature methods,13b and (c) as compared to the previous
unstable azide (Ts-N3 or TMS-N3) protocol,6 the current
method achieves mono-ketonization/amidation using simple
anilines and eco-friendly O2 (as an oxidant and reagent) in a
clean manner under sustainable conditions.
Entry
Cu [catalyst]
Base
Solvent
[Yield %]b
1
2
3
4
CuCl
CuCl
Other Cu-salts
CuCl
CuCl
CuCl
None
CuCl (dark)
CuCl
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
None
K2CO3
K2CO3
K2CO3
CH3CN–MeOH
CH3CN–MeOH
CH3CN–MeOH
ACN or ACN–DMF
CH3CN–MeOH
CH3CN–MeOH
CH3CN–MeOH
CH3CN–MeOH
CH3CN–MeOH
68
82
<65
0
78
0
n.r.
0
5c
6d
7e
8f
9g
0
a Unless otherwise noted, the reaction conditions are as follows; 1a
(0.50 mmol), 2a (0.7 mmol), base (1.1 equiv.), [Cu]-catalyst (5 mol%),
and solvents (8 mL) in 1 : 1 v/v. The reaction mixture was irradiated
with blue LEDs (40 mW cm−2 at 460 nm) for 12 h under O2 (1 atm).
b Yield of the isolated product. c Under 1 atm. air. d In absence of a
base. e In absence of a copper catalyst. f Under dark conditions at
70 °C. g Under a N2 atm. n.r = no reaction.
Results and discussion
Inspired by our previous work where α-ketoamides were
obtained by C–N coupling of anilines and terminal alkynes
under neutral conditions,11c,14 we were delighted to find that
the presence of an inorganic base drives the reaction to a
different pathway, leading to the formation of acetamides,
instead of α-ketoamides, as dominant products (for mechanis-
tic comparison, please see Scheme S6 in the ESI†). Although light, O2, or [Cu]-catalyst all resulted in no product formation
the current reaction conditions (the presence of an additional (entries 6–9) (for detailed optimization, please see Table S1,
base) are only slightly different from our previous work,11c the ESI†).
chemistry (i.e., mono-ketonation amidation), reaction mecha-
Under the optimized conditions, the scope of this reaction
nisms, and products are totally different from our previous with various arylamines 1 and terminal alkynes 2 was explored
diketonation/amidation reaction under neutral conditions.11c (Table 2). Arylamines containing electron-donating groups, in
Visible light irradiation of 4-methoxyaniline 1a and phenyl- general, facilitate the transformation to afford their corres-
acetylene 2a in the presence of Cs2CO3 (1.1 equiv.) with ponding acetamides in high yields (3a–3e). In addition, a gram
5 mol% CuCl in CH3CN–MeOH (1 : 1 v/v) afforded acetamide scale reaction of 1a with 2a generates acetamide 3a in 77%
3a in 68% yield (Table 1, entry 1) with yield being improved to yield. Notably, when 2-aminophenol 1b was used to couple
82% when K2CO3 was used as a base (entry 2). After screening with 2a (affording 3b in 74%), there was no need of pre-protec-
different solvents, CH3CN : CH3OH (1 : 1 v/v) turned out to give tion and deprotection of the phenolic OH group. However,
the best yields, whilst alternative Cu-salts (CuBr & CuCl2) were electron poor anilines fail to produce acetamides, probably
scrutinized and showed inferior results. A series of control due to their weaker nucleophilic nature and thus poor inter-
experiments were then carried out. Exclusion of either base, action with Cu(II)-phenylacetylide. Consequently, the C–N
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Table 2 Substrate scope of aryl amines and terminal alkynesa
Table 3 Substrate scope of anthranilic acids and terminal alkynesa
a Standard reaction conditions. Isolated yields after purification by
column chromatography on silica gel. b Reaction performed on the
10.0 mmol scale.
a Standard reaction conditions. Isolated yields after purification by
column chromatography on silica gel. b ACN–EtOH was used as a co-
solvent. When longer chain alcohols, such as propanol and butanol,
were used to mix with ACN as a co-solvent, no product was observed.
bond formation step might be very slow or difficult to achieve.
As compared to anilines, aliphatic amines and 2° aryl, alkyl-
amines do not work in the current protocol, probably due to
their stronger tendency to compete with alkynes and form
complexes with the Cu(I) ion, forbidding the formation of the
key Cu(I)-phenylacetylide photoredox light absorbing species.15 and halogen substituents (F, Cl & Br) react well with 2a to
Next, the scope of terminal alkynes in the current oxidative furnish the corresponding acetamides (5a–5e & 5f–5h) in good
C–N coupling reactions was explored. Aryl alkynes bearing to moderate yields. In addition, amino naphthoic acid couples
butyl, ethyl, and methoxy groups performed well (3f–3i, with 2a effectively to afford 5i in 78% yield. However, no
79–85% yields, Table 2). Moreover, a diverse array of electron desired products were obtained when anthranilamide, 2-ami-
withdrawing phenylacetylenes (–NO2, di-CF3, and acyl) was nobenzenesulfonamide and orthanilic acids were used as start-
found to be competent substrates with 1b (3j–3l, 68%–71% ing materials, instead of anthranilic acid. Finally, a wide range
yields). 1,3- and 1,4-Di-alkynes work well to generate the of terminal alkynes including electron-rich and electron with-
corresponding acetamides (3m & 3n). Bulky 1-ethynylnaphtha- drawing groups were employed to react with 2-aminobenzoic
lene also showed good reactivity with 1b to generate 3o in 70% acid 4a, furnishing their acetamides in good yields (Table 3).
yield. Notably, heterocyclic alkynes, such as ethynylthiophenes Aryl alkynes bearing –Me, –OMe, halogen substituents (F, Cl,
(2p & 2q) and carbazole alkynes (2r) which are usually sensitive Br & I), an electron withdrawing group (–CF3), and naphthyl
to oxidative conditions, however, reacted smoothly in the alkyne showed excellent tolerance in the current transform-
current protocol to generate the desired acetamides in good ation (5j–5s) in 69% to 87% yields. Notably, acetamides
yields (3p–3r).
bearing halogen substituents can be used in late-stage
Furthermore, 2-aminobenzoic acid 4a could react with functionalization. Furthermore, aliphatic terminal alkynes
phenylacetylene 2a to produce 5a in 83% yield (Table 3), were also successfully employed in this photoredox transform-
demonstrating a single step simultaneous formation of amide ation. Long-chain terminal alkynes, such as hexyne, heptyne
and ester functionalities from the co-solvent methanol. and octyne, performed well. Linear-chain terminal alkynes
Anthranilic acids bearing electron-rich groups (–OMe & –Me) bearing a benzyl group, electron withdrawing groups (–CN and
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–Cl), and branched aliphatic alkyne smoothly underwent the zation of 3o, which evades the use of unwanted protection and
reaction to furnish the corresponding acetamides (5t–5z) de-protection steps,16 demonstrating the practical application
without having any side reactions. Structurally labile tetrahy- of the current protocol. The PDE4 phosphodiesterase inhibitor
dro-2H pyran type alkyne underwent regioselective C–N coup- 5zb was synthesized via simultaneous formation of ester and
ling with 4a to produce acetamide 5za in 76% yield without amide bonds in a single-step reaction, which is unprecedented
having oxidation at the α-methyne/methylene C–H bonds. (see Schemes S3 and S4, ESI†). Furthermore, 3p and 3q are
Additionally, we found that there is a dramatic decrease in the potential anti-tubercular agents.17 We further evaluated the
yield of product 5a to 18% when methanol was replaced by calculations of green metrics for the synthesis of 3oa and
ethanol and used as a co-solvent. When methanol was made a comparison with those obtained from the existing lit-
replaced by other longer-chain alcohols (i.e. propanol, butanol, erature methods. Our current photoredox process to synthesize
and isopropyl alcohol), no product formation was detected. 3oa (overall yield of 63%) with an overall E-factor of 48.6, atom-
Methanol is a less hindered, better nucleophile as compared economy of 94.5% and 84.2% in two steps, and with a 100%
to ethanol and other long-chain alcohols (bulky hindered overall carbon efficiency is better in comparison with thermal
nucleophiles). Thus, a methoxide anion (MeO−) would attack literature procedures that involve multistep processes (4 steps)
more easily on the six-membered cyclic anhydride type inter- to synthesize 3oa (overall yield of 41%) (see the detailed green
mediate 15 (see, the proposed mechanism in Scheme 4) than metric calculations in the ESI†).
other longer-chain counterparts, which leads to higher
product yields. The structures of 3b, 3o and 3q were confirmed were carried out (Scheme 3, eqn (1)–(6)). First, pre-synthesised
by single crystal X-ray diffraction (Fig. S5–S7, ESI†). Cu(I) phenylacetylide 2a′ was used as a stoichiometric starting
To gain mechanistic insight, several control experiments
Finally, the current methodology can be applied to syn- material in the absence of CuCl to react with 1a, which
thesize pharmacologically active drugs, such as BACE-1 3oa13a afforded 3a in 63% yield after 30 h irradiation (see eqn (1)),
and PDE4 5zb (Scheme 2).13b The BACE-1β-secretase inhibitor suggesting that in situ generated Cu(I) phenylacetylide is most
3oa was successfully synthesized via late-stage functionali- probably the key light-absorbing photocatalyst.11b,c Next, when
the reaction of 1a with 2a was carried out in the presence of a
radical scavenger TEMPO (1.0 equiv.), the formation of acet-
amide product 3a was completely inhibited (see eqn (2)),
which is in line with the radical intermediate nature of the
transformation. Thereafter, we carried out the reaction of 4a
and 2a using deuterated methanol solvents (CD3OD and
CH3OD) under standard conditions (see eqn (3) & (4)), which
successfully afforded deuterated products 5a-D5 and 5a-D2.
Physical mixing of acetamide 5a with CD3OD or in the pres-
ence of K2CO3 does not lead to H/D exchange at the methylene
protons. These control experiments suggest that the source of
the methylene protons is H+/D+ from water, which undergoes
H/D exchange with deuterated methanol. When o-amino-
phenol was used as a substrate, instead of 4a, in eqn (4),
Scheme 2 Synthesis of pharmacologically active inhibitors.
similar deuteration at the methylene protons was also
Scheme 3 Mechanistic control studies.
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observed for product 3b-D2 (for details, see the ESI†). Finally, (Fig. S1, ESI†).11c A superoxide radical anion eventually
we carried out the reaction using 1b and 4a under a labelled becomes H2O2, and then H2O via metal ion induced decompo-
18O2 (98%) atmosphere (see eqn (5) & (6)). Mass spectra sition of H2O2.11c,18 In the next step, nucleophilic addition by
measurements show that 92% of 18O2 was incorporated into anilines, either 1b or 4a, with 8 (at the α C-site of terminal
acetamide 3b, but only 2% of 18O2 was incorporated into alkynes), followed by electron transfer to molecular oxygen
product 5a (Schemes S7 and S8, ESI†). Thus, these results generated an amine-Cu(III)-phenylacetylide species (not shown
reveal that the carbonyl oxygen in acetamide 5a originates in the mechanism cycle, as we already showed this step in our
from the ortho-carboxylic acid group via intra-molecular previous studies, ref. 11c). Coordination of amine to Cu(II)-phe-
nucleophilic addition of a carboxylic anion to imine carbon, nylacetylide could facilitate the oxidative conversion of the
followed by the addition of methanol (see the mechanism in Cu(II)-phenylacetylide to the Cu(III) state.19 Subsequent reduc-
Scheme 4). Note that in the reaction with aniline substrates tive elimination of amine-Cu(III)-phenylacetylide leads to the
bearing the o-carboxylic acid moiety, molecular O2 does not formation of highly reactive Cu(I)-π coordinated ynamine inter-
get incorporated into the final products, but simply acts as an mediates 9 and 13, in which the ortho group i.e., the carboxylic
electron acceptor to initiate the reaction via a SET process. group would be in chelation with the Cu(I) ion.11c,20
More precisely, aniline derivatives bearing o-hydroxy/-carboyx- Acetamides 3 and 5 were formed from different pathways A
lic acid moieties undergo different reaction pathways to gene- and B, respectively. In the presence of a base, a hydroxyl anion
rate similar acetamide products. Furthermore, the reduction will be formed and it would attack the electron deficient imine
potential of photo-excited copper(I)-phenyl acetylide 2a′ is carbon centre 10 to form Cu(I)-coordinated hydroxyl intermedi-
−2.048 VSCE in CH3CN, which is sufficiently higher than that ate 11, which abstracts a H+/D+ from water to form the amide
of O2 (E1/2 = +0.98 VSCE). Therefore, the SET process from the carbonyl (CvO) bond 12, and finally affords the desired
triplet excited state 2a′ to O2 is exothermic and occurs product 3 acetamide and regenerates the CuCl catalyst. In path
spontaneously.11c
Based on the above results and our previous studies,11 we by a subsequent intramolecular nucleophilic attack of the car-
propose reaction mechanism (Scheme 4) as below. boxylic anion on the electrophilic imine carbon centre 14,
Photoexcitation of in situ formed Cu(I)-phenylacetylide (λabs resulting in the formation of a six-membered cyclic intermedi-
B, a carboxylic acid proton was abstracted by a base, followed
a
=
476 nm) by visible light generates a long-lived triplet excited ate 15. Further nucleophilic attack by the methoxy group (from
state Cu(I)-phenylacetylide 7,11a which then undergoes a facile methanol solvent) on the carbonyl carbon of 15 leads to the
SET event with O2 to generate Cu(II)-phenylacetylide 8 and a transfer of acid oxygen to ketone and the formation of
superoxide radical anion, as evidenced by EPR measurements acetamide 5 with concomitant regeneration of CuCl. Notably,
Scheme 4 Plausible reaction mechanisms.
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path B allows a simultaneous formation of both ester (C–OMe)
and amide carbonyl (CvO) functionalities, which is not
possible using previously reported literature methods.13b The
18O2 experiment confirms that the carbonyl oxygen in 5 is
from the o-carboxylic acid (CO–OH) group, instead of mole-
cular O2 (see eqn (6)).
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Conclusion
In summary, we report the first literature example of photo-
redox copper catalyzed regioselective acetamidation, including
both mono-ketonization and amidation, of terminal alkynes
by arylamines using molecular O2 as a sustainable oxidant at
room temperature (47 examples) which can be readily scaled
up to a gram scale. The presence of an inorganic base drives a
subtle change in the reaction pathway from diketonization–
amidation (under neutral conditions)11c to mono ketoniza-
tion–amidation (under basic conditions) of terminal alkynes
under visible light irradiation. The current method achieves
unprecedented single-step formation of both ester and amide
functionalities which are not possible using previously
reported literature thermal methods, and evades the need of
pre-protection and de-protection of ortho-hydroxyl/-carboxylic
acid groups in the synthesis of acetamides. The photoredox
chemistry reported here was never disclosed by any previous
literature work. Mechanistic studies illustrated that different
8 (a) A. O. Gálvez, C. P. Schaack, H. Noda and J. W. Bode,
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undergo different reaction mechanisms to produce the same
acetamide core structure. The current protocol was applied to
synthesize two biologically active inhibitors with fewer steps
(2 steps for BACE-1 inhibitor 3oa and 1 step for PDE-4 inhibitor
5zb) without using water-sensitive (SOCl2) reagents, and is more
practicable than the literature reported thermal methods.
(b) A. C. Hernandez-Perez and S. K. Collins, Acc. Chem. Res.,
2016, 49(8), 1557; (c) J. M. Ahn, T. S. Ratani, K. I. Hannoun,
G. C. Fu and J. C. Peters, J. Am. Chem. Soc., 2017, 139, 12716;
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O. Reiser, Science, 2019, 364, eaav9713; (f) R. Kancherla,
K. Muralirajan, A. Sagadevan and M. Rueping, Trends Chem.,
2019, 1, 510.
11 (a) A. Sagadevan, A. Ragupathi and K. C. Hwang, Angew.
Chem., Int. Ed., 2015, 54, 13896; (b) A. Sagadevan,
V. P. Charpe, A. Ragupathi and K. C. Hwang, J. Am. Chem.
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C.-C. Lin, J. R. Hwu and K. C. Hwang, Green Chem., 2015,
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This work was supported by the Ministry of Science &
Technology, Taiwan.
12 C. Zhang and N. Jiao, J. Am. Chem. Soc., 2010, 132, 28.
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