Selective amidation by a photocatalyzed umpolung reaction

Article abstract of DOI:10.1039/c9cc01079c

A metal-catalyzed organic transformation merged with another organophotocatalyst has been developed under mild conditions for production of α-ketoamides. CuI-catalyzed highly selective and rapid COCH₂-amidation in the presence of electrophilic C_αO bonds, which is synchronized by an eosin Y (EY)-photocatalyst, furnishes a wide range of labile α-ketoamides, unsymmetrical oxalamides and chiral analogues on the treatment of 1,3-dicarbonyls with amines, PhIO and LED light at room temperature. The current strategy opens up a new avenue to making photocatalysis a common synthetic tool for large-scale production in academia and industry.

Full text of DOI:10.1039/c9cc01079c

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DOI: 10.1039/C9CC01079C
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Selective amidation by a photocatalyzed umpolung reaction
Debasish Ghosh,a Rajesh Nandi,a Saikat Khamarui,b Sukla Ghosh,c and Dilip K. Maiti*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Scheme 1. Synthesis of -ketoamides and amides
A metal-catalyzed organic transformation merged with another
organophotocatalyst has been developed under mild conditions
for production of -ketoamides. CuI-catalyzed highly selective and
rapid COCH2-amidation in the presence of electrophilic C=O
bonds, which is synchronized by an eosin Y (EY)-photocatalysis to
furnish a wide range of labile -ketoamides, unsymmetrical
oxalamides and chiral analogues on the treatment of 1,3-
dicarbonyls with amines, PhIO and LED light at room temperature.
The current strategy opens up a new avenue to photocatalysis for
making it a common synthetic tool for the large-scale production
in academia and industry.
The photocatalytic organic synthesis emerged as an active area, and
several methods were introduced in the synthetic chemistry
utilizing Ultra Violet (stronger energy), abundant sunlight, light
emitting diode (LED) and other light sources.1 However, the light-
activated photocatalysis is not viable for large-scale and industrial
processes mainly because of their critically unsafe nature due to the
generation of large quantity of accident-prone radical
intermediates,2 and inability to access labile and/or chiral
compounds. The dual photocatalysis is encouraging, such as CuI-FeII
for CO2-reduction,3a IrII-NiII for C-C cross-coupling,3b NiII/CuII-
organophotocatalyst for hydroxylation,3d halofunctionalization,3c
and decarboxylative olefination.3e Herein, we have attempted a
dual photocatalysis-assisted direct amidation of –CO-CH2-, which is
unknown in the literature. Despite the conventional perception of
the radical mechanism of λ3-hypervalent iodanes4a,d mediated
reactions; we4b,c and others4e,f observed that these Lewis acid like
oxidants are also capable of switching between radical to ionic
mechanism depending on reaction conditions, electronic demands
and/or the presence of catalyst. -Ketoamides were synthesized
using pre-functionalized aryl acetylene amines, Ph2SO, and AuCl-
AgSbF6 catalysts (eq. i, Scheme 1),5a and through coupling of
ketomethyl-amine (eq. ii) with iodine and TBHP (excess).5b It is
challenging to perform amidation of a CH2-moiety with an amine-
nucleophile in the presence of electrophilic C=O centers, which is
more susceptible for amidation. For instance, Kirsch and co-workers
utilized (nBu4N)N3 and I2 for coupling of RNH2 to –CO-CH-CO-, and
amidation occurred to both the carbonyl groups (eq. iii).5c The
discovery of
a
general metal-catalysis merged with
organophotocatalytic reaction under mild conditions is displayed in
eq. iv, which rapidly produced -ketoamides, unsymmetrical
oxalamides, and chiral analogues.
-Ketoamides, chiral analogues, and oxalamides are widely
distributed in Nature, and are found as invaluable lead drugs, a
photoaffinity label, intermediates, pharmaceuticals, antiepileptic
drugs, anti-HIV agents, MR2B antagonists, Caspase inhibitors, useful
ligands and synthons.6-10 The widely used -ketoamide syntheses
include coupling of amines with -ketoacids or acyl halides,
oxidation of -hydroxyamides and -aminoamides, dual
carbonylative amidation, oxidative amination, and Henry cascade
and oxygenative alkyne-amine coupling.6a,b,8 Oxalamides were
synthesized through condensation of amines to activated -amido
carboxylic acids, oxidative carbonylation, coupling of the
a.Department of Chemistry, University of Calcutta, 92 A. P. C. Road, Kolkata-
700009, India.
b.Department of Chemistry, Government General Degree College at Kalna-1,
Burdwan-713405, India.
c. Department of Chemistry, Women's College, Calcutta, P-29, Kshirode Vidyavinode
Avenue, Kolkata -700003, India.
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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isocyanides with carboxamide lithium or trichloroacetic anhydride- marginal improvement of yield (30%, entry 5), and low valent Ir(I)
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DOI: 10.1039/C9CC01079C
amine,
and
transamination
of
2,2,2-trifluoroethyl was inefficient (entry 6). Relatively inexpensive CuBr produced 4a
chlorooxoacetate.10
with a modest yield (40%, entry 7). The yield and reaction rate (2 h)
The initial attempts for photocatalytic reaction between 1- were magnificently enhanced (80%) on improving the power of the
phenyl butane-1,3-dione (1a) with benzylamine (2a) was studied LED from 5 W to 30 W (entry 8). PhI(OAc)2, TBHP, K2S2O8 and,
utilizing 5 mol% of commonly used metallaphoto-catalyst of higher mCPBA did not improve the yield (entries 9-12). The rose bengal,
and moderate oxidation state, such as Cu(II), Ru(III) or Au(III) along synthesized Phe-PDI-Phe or Trp-PDI-Trp was not useful (entries 13-
with organophotocatalyst eosin Y under LED light (5 W), and 15). The combination of metal-catalyst and metallaphotocatalyst3a,b
product N-benzyl-2-oxo-2-phenylacetamide (4a, entries 1-3, Table such as CuBr-Ir(PPy)3, and CuBr-Ir(tpy)(bpy)Cl was not effective
1) was not detected.
(entries 16, 17). The yield and reaction rate was drastically reduced
in the absence of organic photocatalyst eosin Y or active LED source
(entries 18, 19). These observations indicate the metal-organic dual
photocatalytic system is essential for CO-CH2 amidation with C-C
cleavage. The photocatalysis was completely arrested on carrying
out the reaction without any CuBr or PhIO (entries 20, 21). The
photocatalysis was examined in water, methanol, MeCN, THF and
PhCH3 (entries 22-26) without improvement in yield. CuBr is found
as a smart catalyst over other Cu(I) salts (entries 27-29). We
screened visible light and blue LED of 475 nm was found as the
best for the dual catalysis (Figure 1S).
Table 1. Survey for developing selective-amidation photocatalysisa
Metal
Time
(h)
4a,Yield
(%)f
Entry
Reagentc
Photocatalystd
Solvente
Catalystb
1
2
Cu(OTf)2
RuCl3
PhIO
PhIO
eosin Yg
eosin Yg
CH2Cl2
CH2Cl2
24
24
ndh
nd
3
4
AuCl3
PhIO
PhIO
eosin Yg
eosin Yg
CH2Cl2
CH2Cl2
24
24
nd
25
The general scope of the combo-photocatalytic reaction among
1,3-diketones (1) with different aliphatic primary amines (2) was
investigated to synthesize labile α-ketoamides (4) under mild
conditions (Scheme 2). Interestingly, 1,3-diketones (1) smoothly
proceeded to a large number of structurally diverse -ketoamides
(4a-l) through C-C cleaved-coupling of amines (2) and sacrificed its
acyl, trifluoroacyl and benzoyl residues. The phenyl (4a, c, d, k, l),
substituted phenyl (4g, h, i), aromatic heterocyclic (4e, j), naphthyl
Scheme 2. Synthesis of substituted -ketoamides
AgOTf
5
AuCl
PhIO
eosin Yg
eosin Yg
eosin Yg
CH2Cl2
24
30
6
7
Ir(cod)Cl
CuBr
PhIO
PhIO
CH2Cl2
CH2Cl2
24
24
nd
40
8
CuBr
PhIO
eosin Y
CH2Cl2
02
80
9
CuBr
PhI(OAc)2
eosin Y
CH2Cl2
02
50
10
11
CuBr
CuBr
TBHP
eosin Y
eosin Y
CH2Cl2
CH2Cl2
02
02
45
30
K2S2O8
12
CuBr
mCPBA
eosin Y
CH2Cl2
02
50
13
14
CuBr
CuBr
PhIO
PhIO
rose bengal
CH2Cl2
CH2Cl2
12
24
30
nd
Phe-PDI-Phe
15
16
17
CuBr
CuBr
CuBr
PhIO
PhIO
PhIO
Trp-PDI-Trp
Ir(PPy)3
CH2Cl2
CH2Cl2
CH2Cl2
24
24
24
32
55
52
Ir(tpy)(bpy)Cl
18
19
CuBr
CuBr
PhIO
PhIO
-
CH2Cl2
CH2Cl2
24
24
15
15
eosin Yi
20
21
-
PhIO
-
eosin Y
eosin Y
CH2Cl2
CH2Cl2
24
24
nd
nd
CuBr
22
23
CuBr
CuBr
PhIO
PhIO
eosin Y
eosin Y
H2O
24
24
nd
10
CH3OH
24
CuBr
PhIO
eosin Y
CH3CN
24
52
25
26
CuBr
CuBr
PhIO
PhIO
eosin Y
eosin Y
THF
24
24
60
68
PhCH3
27
28
CuCl
CuI
PhIO
PhIO
eosin Y
eosin Y
CH2Cl2
CH2Cl2
24
02
48
70
29
CuCN
PhIO
eosin Y
CH2Cl2
24
65
1a (1 mmol) and 2a (1 mmol).aBlue LED (30 W, 475 nm).b5mol%.c(3.5
f
mmol).d1mol%.e5 mL, Purified by column chromatography. g5 W LED light
source. hNot detected. iNo LED light.
(4f) and aliphatic (4b) substituents are sustainable under this the
reaction conditions. Introduction of electron withdrawing
substituent into the aromatic residue slightly reduced the yield of
the corresponding products (4g, h). Almost all types of aliphatic
amines were structurally fit to do this job, and aromatic amines
were in vain probably due to their oxidation in the presence of
To our delight, using relatively lower oxidation state Ag(I)-eosin Y
combined photocatalysis furnished the desired product (4a) in low
yield (25%) at ambient temperature using neutral oxidant PhIO
(entry 4). Replacement of the metal catalyst by AuCl led to the
2 | J. Name., 2012, 00, 1-3
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hypervalent iodine. Simple aliphatic amine possessing hydrocarbon it is very difficult to control condensation with two different
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DOI: 10.1039/C9CC01079C
chain, aromatic residue and ester functionality were tolerated to amines.10
Scheme 4. Synthesis of unsymmetrical oxalamides
achieve desired products (4a-l) in high yield (62-80%) and shorter
reaction time (2-3.0 h). All the synthesized new compounds were
fully characterized and the structural skeletal of 4h was confirmed
with the help of single crystal XRD data analyses.11
The bio-utilities and other application of chiral -ketoamides
analogues (5) led us to target their synthesis utilizing readily
available chiral amines and -aminoacid esters (3, Scheme 3).
Optically pure -methyl benzylamines (3a,b) furnished
corresponding pure enantiomer of α-ketoamides (5a-d). A variety of
L-aminoacid esters (3c-i) was successfully utilized to produce rapidly
(2.5-4.5 h) amino acid-based chiral -ketoamides (5e-n) with good
yield (68-78%) under the unchanged conditions. Existence of pure
enantiomer (5) was verified using a semipreparative chiral HPLC
column and also by recording the optical rotation of all products
including a known compound (5b).6a
Scheme 3. Asymmetric synthesis of -ketoamides
Apart from normal aliphatic amines (2a,b,d), long chain (2e) and
ethyl glycinate (2f) were adequate for this purpose. The diversity of
the mild photocatalysis was validated through synthesis of optically
pure (-)-(S)-N1-phenyl-N2-(1-phenylethyl)oxalamide (8f) using chiral
amine (S)-1-phenylethylamine (3b). The overall yield of the
synthesized oxalamides (8a-f) is quite high (65-78%) and obtained in
shorter reaction time (3-4.5 h).
In order to shed light on regioselectivity we performed two
separate control experiments; one with electron withdrawing
chlorine substituent containing 1-(4-chlorophenyl)-3-phenyl-1,3-
propanedione (eq. i, Scheme 5) and another with electron donating
methyl substituent containing 1-(4-methylphenyl)-3-phenyl-1,3-
propanedione (eq. ii). In both the cases, we got a mixture of
products with unequal proportions. For the first reaction, the ratio
of 4a and 4g is 5:2 whereas in the second case, the ratio of 4a and
4m is 3:4 which is a clear indication that the presence of electron
withdrawing group in the phenyl residue allows its carbonyl portion
to get oxidize easily as compared to it is a counterpart. The
possibility of transforming -CH2- or/and C=O to amide of 1,3-
dicarbonyl substrate was confirmed utilizing C13-labelled 1,3-
diphenyl-propane-1,3-dione (C13-1c, eq. i, Scheme 5). The ESI-MS
analyses of the reaction mixture revealed a larger symbolic peak at
241.1053 (M+H+) for C13-4a relative to 240.1058 (M+H+) of 4a (ESI).
The source of the ‘O'-atom in the amide functionality is PhIO, which
was confirmed by formation of the O18-4a (e/m 242.1067), using
PhIO18 (eq. ii). Thus, amidation occurred selectively at CO-CH2
utilizing oxygen of PhIO. The reaction was failed to produce the
desired product 11 on using CH2-blocked cyclopropane substrate
(10, eq. iii).12 Quenching the reaction in the middle, we found the
traces of 12 (eq. vi, Scheme 5), which might be generated due to
the coupling of amine (3a). Benzoic acid (14a) was isolated and fully
characterized (ESI) from the reaction between 1a and 2a (eq. viii).
Right now, exact mechanism is unknown to us and a proposed path
for the umpolung (step 2) and ionic mechanism (step 1 and 3) is
depicted in Scheme 6 on the basis of experiments performed.
Next, we turned out attention to expand the scope of the
metal-organic synergic-photocatalytic approach for the synthesis of
valuable oxalamide derivatives (8, Scheme 4) from 1,3-ketoamide
substrates (6). Gratifyingly, an important observation was
experienced in this connection as labile oxalamides (8a-f) were
efficiently obtained in the presence of external amine 2 or 3 under
the unchanged conditions. Amide functionality of acetoacetalinide
did not hamper the progress of the dual photocatalysis process,
which addressed the chemoselective nature of the reaction. Herein,
the unsymmetrically substituted amides were constructed very
easily. The reported synthetic methods to oxalamides are
conventionally produced symmetrical compounds because most of
them were derived from activated oxalic acid or oxalal chloride and
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Scheme 5. Control experiments
fellowship to DG and JRF-UGC to RN, are gratefully
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DOI: 10.1039/C9CC01079C
acknowledged.
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Conflicts of interest
“There are no conflicts to declare”.
Acknowledgements
11 CCDC of 4h: 1862562.
Financial support from Government of India through SERB 12 J. P. Celerier, M. Haddad, D. Jacoby, G. Lhommet,
Tetrahedron Lett., 1987, 28, 6597.
project (No. EMR/2017/5018) and SRF-CSIR research
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