Double Carbonylation Using Glyoxal (HCOCOH): A Practical Copper-Promoted Synthesis of Isatins from Primary and Secondary Anilines

Article abstract of DOI:10.1002/adsc.201700583

A novel double carbonylation process has been demonstrated with easily available HCOCOH (glyoxal) as the double carbonylation reagent. Simple CuCl₂?2H₂O (copper(II) chloride dihydrate) was used as the oxidant for this transformation. Under optimized reaction conditions, various primary and secondary anilines were double-carbonylated to afford their corresponding isatins (26 examples, up to 80% yields). (Figure presented.).

Full text of DOI:10.1002/adsc.201700583

Title: Double Carbonylation Using Glyoxal (HCOCOH): A Practical
Copper-Promoted Synthesis of Isatins from Primary and
Secondary Anilines
Authors: Suzie Hui Chin Kuan, Wei Sun, Lu Wang, Chungu Xia, Meng
Guan Tay, and Chao Liu
This manuscript has been accepted after peer review and appears as an
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700583
Link to VoR: http://dx.doi.org/10.1002/adsc.201700583

10.1002/adsc.201700583
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Double Carbonylation Using Glyoxal (HCOCOH): A Practical
Copper-Promoted Synthesis of Isatins from Primary and
Secondary Anilines
†
†
Suzie Hui Chin Kuan,a,b, Wei Sun,a, Lu Wang,a Chungu Xia,a Meng Guan Tay,b and
Chao Liu, a,*
a
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Suzhou Research Institute of LICP, Lanzhou
Institute of Chemical Physics (LICP), Chinese Academy of Sciences, Lanzhou 730000, P. R. China. E-mail:
chaoliu@licp.cas.cn.
Department of Chemistry, Faculty of Resource Science and Technology, Universiti Malaysia Sarawak, 94300 Kota
b
Samarahan, Sarawak, Malaysia.
These authors contributed equally to this work
†
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))
di-carbonylation
sources.
Inspired
by
the
Abstract. A novel double carbonylation process has
been demonstrated with easily available HCOCOH
(glyoxal) as the double carbonylation reagent. Simple
CuCl2·2H2O (copper(II) chloride dihydrate) was used
as the oxidant for this transformation. Under optimized
reaction conditions, various primary and secondary
anilines were double-carbonylated to afford their
corresponding isatins (26 examples, up to 80% yields).
mono-carbonylation with HCHO,[5] we assumed that
whether HCOCOH could be used as the di-carbonyl
source to achieve di-carbonylation compounds,
because of that glyoxal is a widely available basic
chemical feedstock in industry. Moreover, it is much
easier to handle than CO gas. However, scarce
examples have been reported by utilizing glyoxal as
the
di-carbonylation
reagent
in
synthetic
community.[6] Herein, we demonstrated the first
copper promoted practical synthesis of isatins from
primary and secondary anilines by using glyoxal as
the double-carbonyl source (Scheme 1, approach c).
Keywords: Double Carbonylation; Glyoxal; Isatin
Synthesis; Anilines
Transition-metal-catalysed carbonylation is the
fundamental transformation for introducing carbonyls
into various organic molecules.[1] CO (carbon
monoxide) was majorly utilized as the carbonyl
source.[2] In recent years, due to its toxicity and
uneasy handling, increasing attention has been
focused on developing other chemical feedstocks,
such as HCHO (formaldehyde), CO2 (carbon dioxide),
formic acid and its derivatives, as the COgens to
replace CO gas as the carbonylative reagents.[3] Up to
date, most of the efforts were focused on the
mono-carbonylation processes. While the double
carbonylation with introducing two adjacent
carbonyls into organic molecules has been less
explored and CO gas was the majorly applied
carbonyl source.[4] Organic compounds with two
adjacent carbonyls are usually important molecules.
However, using CO as the double carbonylation
source usually has the challenge on controlling the
selectivity between mono- and di- carbonylation,
which restrict the development of di-carbonylation
with CO. Therefore, it is highly desirable to find new,
cheap, widely available and easy-handling
Scheme 1. Synthesis of isatins from anilines derivatives.
Isatin and its derivatives widely exist in nature
products and many of them are bioactive compounds
and pharmaceuticals.[7] Therefore, it has drawn much
attention to develop novel and practical methods for
the synthesis of isatins. Although many synthetic
methods have been reported for their synthesis, most
of
the
methods
suffers
from
substrate
pre-functionalization and inaccessible starting
1
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10.1002/adsc.201700583
Advanced Synthesis & Catalysis
materials.[8] An ideal approach would be the direct
double carbonylation of simple aniline derivatives.
Very early synthesis involves oxalyl chloride or
diethyl ketomalonate as the di-carbonylation reagent.
Recently, Fu et al. has used ethyl glyoxalate as the
double carbonyl source and Lei et al. has used carbon
monoxide as carbonyl source for the double
carbonylation of anilines (Scheme 1, approaches a
and b).[9] While both approaches were limited to
secondary anilines. Here, a double carbonylation of
both primary and secondary anilines by utilizing
glyoxal aqueous solution as the double carbonylation
reagent was demonstrated with Cu(II) as the oxidant
(Scheme 1, approach c).
Table 1. Reaction Parameters of Conversion Aniline to
Isatin.[a]
Entry
[Cu]
Additive
Yield[%][b]
1
2
3
4
5
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
-
Cs2CO3/TFA
Cs2CO3
89(80)[f]
59
25
20
64
78
50
0
65
TFA
-
CF3COOCs
CF3COOCs/TFA
CF3COOCs/Cs2CO3
Cs2CO3/TFA
Cs2CO3/TFA
Cs2CO3/TFA
6
7[c]
8
We started our research by applying
N-methyl-4-methylaniline (1a) and glyoxal in a
model reaction to test different reaction conditions.
From the chemical equation, it can be seen that
oxidant is required for this oxidative cross-coupling.
After considerable efforts, the transformation was
achieved by using the following optimal conditions: 2
equivalents of glyoxal, 4 equivalents of CuCl22H2O
as the oxidant, Cs2CO3 (1.3 equiv) and CF3COOH
(1.0 equiv) as the additives in MeTHF
9[d]
10[e]
CuCl2·2H2O
CuCl2·2H2O
0/0/0
Reaction conditions: [a] 1a (0.5 mmol), Glyoxal (1.0 mmol,
glyoxal solution 30% w/w in water), CuCl22H2O (2.0
mmol), Cs2CO3 (0.65 mmol), CF3COOCs (1.0 mmol),
o
CF3COOH (0.5 mmol), MeTHF (1.5 mL), 70 C, 5 hours.
[b]
The yield was determined by GC analysis using
naphthalene as an internal standard. [c] 0.5 mmol Cs2CO3.
[d]
[e]
Under oxygen atmosphere. 10 mol% of [Cu] with O2
[f]
o
or Na2S2O8 or TBHP as the terminal oxidant. Isolated
yield.
(2-methyltetrahydrofuran) at 70 C to react for 5
hours under N2 atmosphere (Table 1, Entry 1), in
which 80% of 2a was isolated. Variation from the
standard conditions is listed in Table 1.[10] In the
absence of CF3COOH, the yield of 2a decreased to
59% (Table 1, Entry 2). The yield of 2a decreased
dramatically in the absence of Cs2CO3 (Table 1,
Entry 2), indicating the importance of base in this
transformation. In the absence of both CF3COOH and
Cs2CO3, only 20% of 2a was obtained (Table 1, Entry
3). The reaction between Cs2CO3 and CF3COOH will
generate CF3COOCs, therefore, CF3COOCs was used
instead of Cs2CO3/CF3COOH. As a result, 64% of 2a
was obtained (Table 1, Entry 5). When the reaction
was performed with CF3COOCs in the presence of
CF3COOH, 78% of 2a was obtained (Table 1, Entry
6), showing that an acidic condition is also suitable
for this transformation. A combination of CF3COOCs
and Cs2CO3 resulted in a lower yield of 2a (50%)
(Table 1, Entry 7), which is similar to that of using
single Cs2CO3 as the additive in Entry 2. Overall,
along with the reaction proceeded, the system will be
more acidic due to the formation of HCl. Cs2CO3 may
be used to keep the reaction not to be too acidic. In
the absence of the oxidant CuCl22H2O, no 2a was
observed (Table 1, Entry 8). When the reaction was
performed under O2 atmosphere, a relatively lower
yield of 2a was obtained (Table 1, Entry 9). We also
tried to lower the amount of CuCl22H2O to be 1.0,
2.0 or 3.0 equivalents. However, decreased yields
were observed (see Table S1 in the Supporting
Information). Therefore, 4.0 equivalents of
CuCl22H2O was necessary in this transformation.
Attempt to utilize catalytic amount of CuCl22H2O
with O2, tert-butyl hydroperoxide or Na2S2O8 as the
terminal oxidant failed to deliver any desired 2a
(Table 1, Entry 10).
Scheme 2. Substrate scope of secondary anilines. Reaction
conditions:
1
(0.5 mmol), Glyoxal (1.0 mmol),
2
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10.1002/adsc.201700583
Advanced Synthesis & Catalysis
CuCl22H2O (2.0 mmol), Cs2CO3 (0.65 mmol), CF3COOH
moderate yields (2u-2z). 1-Naphthylamine and
2-naphthylamine afforded their corresponding isatins
2u and 2v in 40% and 47% yields, respectively.
Usually, the 1-position of naphthalene cycle has
higher reactivity towards electrophilic substitution.
The last cyclization step of Sandmeyer isatin
synthesis is generally believed to occur via an
electrophilic substation on the phenyl ring.
Meanwhile, 2-naphthylamine has been demonstrated
to selectively occur on its 1-position in Sandmeyer
isatin synthesis. [12] The result of 2v supports that the
formation of isatin in this transformation may occur
o
(0.5 mmol), MeTHF (1.5 mL), 70 C, 5 h. Isolated yields.
[a]
CF3COOCs (1.0 mmol) instead of Cs2CO3 (0.65 mmol)
[b]
and CF3COOH (0.5 mmol).
CF3COOCs (1.0 mmol)
instead of Cs2CO3. [c] 24h. [d] 40 h. [e] 8 h.
With the optimized condition in hand, a series of
secondary anilines were first tested as the substrates
in this transformation (Scheme 2). N-alkyl anilines
such as N-Me, N-Et and N-nBu afforded their
corresponding isatins 2b-2d in moderate yields.
N-Benzyl aniline solely generated the isatin product
2e without any observation of the reaction on benzyl
group. N-allyl group and N-propargyl were also
tolerated, afforded the desired products 2f and 2g in
moderate yields. Diaryl amines are usually less
reactive than alkylanilines. In this transformation,
with di-p-tolylamine as the substrate, the desired
isatin 2h could be obtained in a 55% yield when
prolonging the reaction time to 40 hours. p-iPr, p-tBu,
3,5-dimethyl and p-Ph substituted N-Me anilines all
proceeded well to give their desired isatins in good
yields (2i, 2j, 2k, 2l). It was worth to note that carbon
halogen bonds such as C-F, C-Cl and C-Br were well
tolerated, which allows further functionalization to
achieve complex molecule synthesis. In the case of
C-Cl and C-Br substrates, the reaction temperature
via
an
electrophilic
substitution
process.
3,5-Dimethylaniline and p-toluidine were also
successfully double-carbonylated to give their isatins
in moderate yields (2x-2y). o-Toluidine gave a 31%
yield of its corresponding isatin 2y. When
meta-substituted primary anilines were applied as the
substrates, the two different reactive sites on the
phenyl ring resulted in two isomers with a 4:3 ratio
(2z/2z’).
o
was raised up to 100 C and the reaction time was
prolonged to 24 hours (2n, 2o). Furthermore, those
halogen-containing isatins are usually precursors of
highly active anticancer therapeutic agents and
antioxidant agents.[11] Electron-withdrawing group
substituted anilines have not been used in those
carbonylation with CO or ethyl glyoxalate strategies.
However, the electron-withdrawing p-COOMe group
was tolerated and the corresponding isatin 2p was
obtained in a 38% isolated yield. An o-Me substituted
N-methylaniline afforded no desired 2q, indicating
that this transformation may not be compatible with
ortho-substituted secondary anilines. We have also
tested heteroaromatic aniline such as methyl
4-aminopyridine, while no desired isatin 2r was
observed. When meta-substituted N-Me anilines were
applied as the substrates, the two different reactive
sites on the phenyl ring resulted in two isomers with a
1:1 ratio (2s/2s’, 2t/2t’).
The Sandmeyer procedure, the Stolle procedure
and the Martinet procedure are the classical methods
for the conversion of primary anilines to their
corresponding isatins. The recently developed Fu
procedure and Lei procedure only limited to
secondary anilines. Therefore, we want to know that
whether this reaction condition is suitable for
converting primary anilines to their corresponding
isatins. To our delight, a series of primary anilines
were successfully converted to their desired isatins in
Scheme 3. Double carbonylation of primary anilines with
glyoxal. Reaction conditions: 1 (0.5 mmol), Glyoxal (1.0
mmol), CuCl22H2O (2.0 mmol), Cs2CO3 (0.65 mmol),
o
CF3COOH (0.5 mmol), MeTHF (1.5 mL), 70 C, 5 hours.
[a]
Isolated yields.
CF3COOCs (1.0 mmol) instead of
Cs2CO3 (0.65 mmol) and CF3COOH (0.5 mmol).
Mechanistically, mixing amine with aldehyde
initially forms a gem-aminoalcohol which can be
easily oxidized by [CuII] species. [13] Moreover, in the
reaction mixture, yellow deposition was observed at
the end of the reaction and no copper mirror was
observed, indicating that the resulting Cu species was
most likely to be Cu(I). From the reaction equation,
transferring one molecular aniline to its
corresponding isatin requires four electrons. Thus, 4
equivalents of [CuII] is required for the
transformation to proceed. Based on those
information, a tentative reaction pathway is proposed
in Scheme 4. Initially, aniline 1 reacts with glyoxal to
generate intermediate I. The oxidation of I by [CuII]
affords intermediate II. Then, an intramolecular
3
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10.1002/adsc.201700583
Advanced Synthesis & Catalysis
Friedel-Crafts alkylation of II generates III.[8a, 8k] In
this case, Cu(II) acts as a Lewis acid to promote this
transformation in the beginning of the reaction. Then,
the oxidation of III with [CuII] as the oxidant affords
the final product 2. As demonstrated above, the
reaction mixture will be more and more acidic due to
the formation of HCl. Cs2CO3 may be used to keep
the mixture to be a buffer solution.
To further demonstrate the practicality of this
transformation, a gram-scale transformation of 1a
was carried out (eq. 5). As a result, 1.35 g of 2a was
obtained (77% isolated yield), indicating the easy
scale up of this transformation. Furthermore, a simple
condensation of 2o with 4-chloroaniline generates a
compound 3 which has been shown to have better
anticonvulsant activity than the standard drugs
phenytoin, carbamazepine and valproic acid (eq.
6).[17]
Scheme 4. Proposed mechanism
Intermediate II was synthesized according to
[14]
literature report
and it was subjected to the
reaction condition to support this reaction mechanism.
As a result, 57% of 2a was obtained under the
standard condition (eq. 1), indicating the possible
involvement of intermediate II in this double
carbonylation process. Actually, other possible
mechanisms have also been considered during the
investigation of this transformation. For example,
Di-imine (IV) is usually easy to be formed when
mixing aniline with glyoxal. Therefore, it was
prepared to subject to the reaction condition, yet no
desired product was detected (eq. 2), indicating that
di-imine is not the intermediate in this transformation.
In another aspect, glyoxal is easy to be oxidized to
2-oxoacetic acid. Then, it was subjected to react with
aniline 1a to test whether the reaction proceeded via
the generation of 2-oxoacetic acid under the standard
conditions, as a result, only trace amount of 2a was
detected (eq. 3), indicating the less possibility of
involving 2-oxoacetic acid as an intermediate.
In conclusions, we have demonstrated a novel
double carbonylation reagent glyoxal for the direct
double carbonylation of primary and secondary
anilines, in which various isatins were generated.
Simple CuCl22H2O was used as the oxidant for this
transformation.
[15]
Furthermore, a Cannizzaro type reaction
of
intermediate I may generate compound V. To test the
feasibility of this compound as an intermediate in this
[16]
transformation, V was synthesized
and was
subjected to the standard conditions (eq. 4). As a
result, no desired 2a was observed and only V was
recovered. Thus, it illuminated that the reaction did
not proceed via the generation of V. Finally, the
reaction pathway proposed in Scheme 4 is most likely
the mechanism for this double carbonylation of
anilines with glyoxal.
Experimental Section
In a 25 mL Schlenk tube, cesium carbonate (211.8 mg,
0.65 mmol) and CuCl2·2H2O (341.0 mg, 2.0 mmol) were
added and charged with N2 three times. Then, anhydrous
MeTHF (1.5 mL) was added followed by trifluoroacetic
acid (57.0 mg, 0.5 mmol), aniline 1 (0.5 mmol) and
4
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10.1002/adsc.201700583
Advanced Synthesis & Catalysis
glyoxal solution 30% w/w in water (153 L, 1.0 mmol).
The mixture was allowed to stir at 70 °C for 5 hours. After
completion of the reaction (monitored by TLC), water was
added, and the mixture was extracted with ethyl acetate.
The organic layer was separated and combined, dried over
Na2SO4 and concentrated in vacuo. The crude product was
purified by flash column chromatography on silica gel
(EtOAc/petroleum ether) to give the pure product.
[8] a) Y. Zheng, J. Li, X. Yu, S. Lv, L. Hai, Y. Wu,
Tetrahedron Lett. 2016, 57, 39-42; b) Y. Wang, W. Li,
X. Cheng, Z. Zhan, X. Ma, L. Guo, H. Jin, Y. Wu,
Tetrahedron 2016, 72, 3193-3197; c) S. R. Laursen, M.
T. Jensen, A. T. Lindhardt, M. F. Jacobsen, T.
Skrydstrup, Eur. J. Org. Chem. 2016, 2016, 1881-1885;
d) G. Satish, A. Polu, T. Ramar, A. Ilangovan, J. Org.
Chem. 2015, 80, 5167-5175; e) P. Sai Prathima, R.
Bikshapathi, V. J. Rao, Tetrahedron Lett. 2015, 56,
6385-6388; f) J. Li, Y. Zheng, X. Yu, S. Lv, Q. Wang,
L. Hai, Y. Wu, RSC Adv. 2015, 5, 103280-103283; g)
Y. Zi, Z. J. Cai, S. Y. Wang, S. J. Ji, Org. Lett. 2014,
16, 3094-3097; h) M. Raghavender Reddy, N.
Nageswara Rao, K. Ramakrishna, H. M. Meshram,
Tetrahedron Lett. 2014, 55, 4758-4762; i) A. Ilangovan,
G. Satish, J. Org. Chem. 2014, 79, 4984-4991; j) J.
Huang, T. Mao, Q. Zhu, Eur. J. Org. Chem. 2014, 2014,
2878-2882; k) Q. Gui, F. Dai, J. Liu, P. Chen, Z. Yang,
X. Chen, Z. Tan, Org. Biomol. Chem. 2014, 12,
3349-3353; l) J. Sun, B. Liu, B. Xu, RSC Adv. 2013, 3,
5824; m) A. Ilangovan, G. Satish, Org. Lett. 2013, 15,
5726-5729; n) B. X. Tang, R. J. Song, C. Y. Wu, Y.
Liu, M. B. Zhou, W. T. Wei, G. B. Deng, D. L. Yin, J.
H. Li, J. Am. Chem. Soc. 2010, 132, 8900-8902.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (21673261, 21603245, and 21633013). We
also gratefully thank the State Key Laboratory for Oxo Synthesis
and Selective Oxidation (OSSO), Lanzhou Institute of Chemical
Physics (LICP), Chinese Academy of Sciences for generous
financial support. Support from CAS Interdisciplinary Innovation
Team and Young Elite Scientist Sponsorship Program by CAST
were also acknowledged. MGT and SHCK thank to Malaysian
Toray Science Foundation (MTSF) for research financial support
under grant number of GL(F07)/MTSF/2014(14).
References
[9] a) T. Liu, H. Yang, Y. Jiang, H. Fu, Adv. Synth. Catal.
2013, 355, 1169-1176; b) W. Li, Z. Duan, X. Zhang, H.
Zhang, M. Wang, R. Jiang, H. Zeng, C. Liu, A. Lei,
Angew. Chem., Int. Ed. 2015, 54, 1893-1896.
[1] a) H. M. Colquhoun, D. J. Thompson, M. V. Twigg,
Carbonylation
:
direct synthesis of carbonyl
compounds, Plenum Press, New York, 1991; b) M.
Beller, Catalytic carbonylation reactions, Springer,
Berlin ; New York, 2006; c) L. Kollꢀr, Modern
carbonylation methods, Wiley-VCH, Weinheim, 2008.
[10] Detailed condition screening was listed in the
supporting information.
[11] P. Pakravan, S. Kashanian, M. M. Khodaei, F. J.
[2] a) Q. Liu, H. Zhang, A. Lei, Angew. Chem., Int. Ed.
2011, 50, 10788-10799; b) X.-F. Wu, H. Neumann, M.
Beller, Chem. Soc. Rev. 2011, 40, 4986-5009; c) X.-F.
Wu, H. Neumann, M. Beller, Chem. Rev. 2013, 113,
1-35.
Harding, Pharmacol. Rep. 2013, 65, 313-335.
[12] A. S. Karpenko, M. O. Shibinskaya, N. M. Zholobak,
Z. M. Olevinskaya, S. A. Lyakhov, L. A. Litvinova, M.
Y. Spivak, S. A. Andronati, Pharm. Chem. J. 2006, 40,
595-602.
[3] a) J. Cao, Z.-J. Zheng, Z. Xu, L.-W. Xu, Coord. Chem.
Rev. 2017, 336, 43-53; b) S. D. Friis, A. T. Lindhardt,
T. Skrydstrup, Acc. Chem. Res. 2016, 49, 594-605.
[13] H. Yi, G. Zhang, J. Xin, Y. Deng, J. T. Miller, A. J.
Kropf, E. E. Bunel, X. Qi, Y. Lan, J.-F. Lee, A. Lei,
Chem. Commun. 2016, 52, 6914-6917.
[4] a) Y.-S. Lin, A. Yamamoto, in Handbook of
Organopalladium Chemistry for Organic Synthesis,
John Wiley & Sons, Inc., 2003, pp. 2399-2423; b) H.
des Abbayes, J.-Y. Salaun, Dalton Trans. 2003,
1041-1052.
[14] M. Miller, J. C. Vogel, W. Tsang, A. Merrit, D. J.
Procter, Org. Biomol. Chem. 2009, 7, 589-597.
[15] P. Wang, W.-J. Tao, X.-L. Sun, S. Liao, Y. Tang, J.
Am. Chem. Soc. 2013, 135, 16849-16852.
[5] a) K. Fuji, T. Morimoto, K. Tsutsumi, K. Kakiuchi,
Angew. Chem., Int. Ed. 2003, 42, 2409-2411; b) Q. Liu,
K. Yuan, P.-B. Arockiam, R. Franke, H. Doucet, R.
Jackstell, M. Beller, Angew. Chem., Int. Ed. 2015, 54,
4493-4497.
[16] Z.-S. Li, W.-X. Wang, J.-D. Yang, Y.-W. Wu, W.
Zhang, Org. Lett. 2013, 15, 3820-3823.
[17] M. Verma, S. N. Pandeya, K. N. Singh, J. P. Stables,
Acta Pharm. 2004, 54, 49-56.
[6] a) S. Gobec, U. Urleb, Sci. Synth. 2004, 16, 845-911; b)
D.-L. Yang, J.-R. Li, H.-Y. Lu, P. Zhang, D.-X. Shi, J.
Chem. Res. 2014, 38, 625-626.
[7] G. S. Singh, Z. Y. Desta, Chem. Rev. 2012, 112,
6104-6155.
5
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10.1002/adsc.201700583
Advanced Synthesis & Catalysis
COMMUNICATION
Double Carbonylation Using Glyoxal (HCOCOH):
A Practical Copper-Promoted Synthesis of Isatins
from Primary and Secondary Anilines
Adv. Synth. Catal. Year, Volume, Page – Page
†
†
Suzie Hui Chin Kuan,a,b, Wei Sun,a, Lu Wang,a
Chungu Xia,a Meng Guan Tay,b and Chao Liu,*a
6
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