Synthesis of spiro[2,3-dihydrofuran-3,3′-oxindole] derivatives: Via a multi-component cascade reaction of α-diazo esters, water, isatins and malononitrile/ethyl cyanoacetate

Article abstract of DOI:10.1039/c9gc01751h

We report a green synthesis of spiro[2,3-dihydrofuran-3,3′-oxindole] derivatives which are of potential value in medicinal chemistry. We are able to access spiro[2,3-dihydrofuran-3,3′-oxindole] derivatives via a Cu(OTf)₂-catalyzed or Cu(OTf)₂/Rh₂(OAc)₄-cocatalyzed multi-component cascade reaction of α-diazo esters, water, isatins and malononitrile/ethyl cyanoacetate. The reaction can be accomplished in good to excellent yields (60-99%), and the structure of products 6a and 6k was supported by X-ray crystallography. The catalyst Cu(OTf)₂ can be recycled 4 times without a sharp loss of the yield of 6a. 6q can be easily synthesized in gram scale. In brief, the reaction is characterized by step economy, a harmless solvent, and a recyclable catalyst.

Full text of DOI:10.1039/c9gc01751h

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DOI: 10.1039/C9GC01751H
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Green Chemistry
Journal Name
RSCPublishing
COMMUNICATION
Synthesis of spiro[2,3-dihydrofuran-3,3′-oxindole] via
a multi-component cascade reaction of α-diazo esters,
water, isatins and malononitrile/ethyl cyanoacetate
Cite this: DOI: 10.1039/x0xx00000x
Taoda Shi†a, Shenghan Teng†a, Yajie Wei a, Xin Guoc and Wenhao Hu*b
Received 00th March 2019,
Accepted 00th March 2019
DOI: 10.1039/x0xx00000x
www.rsc.org/
Molecules bearing spirooxindole backbone
We reported a green synthesis of spiro[2,3-dihydrofuran-
3,3 -oxindole] derivatives which are of potential value in
medicinal chemistry. We are able to access the spiro[2,3-
dihydrofuran-3,3 -oxindole] derivatives via a Cu(OTf)2-
Me
′
N
Et
NH
Me
Me
N
OMe
H
X
O
O
O
′
N
CO2Me
N
HO
N
H
H
H
catalyzed or Cu(OTf)2/Rh2(OAc)4-cocatalyzed multi-
component cascade reaction of α-diazo ester, water, isatins
and malononitrile/ethyl cyanoacetate. The reaction can be
accomplished in good to excellent yields (60-99%) and the
structure of products 6a and 6k were supported by X-ray
crystallography. The catalyst Cu(OTf)2 can be recycled 4
times without a sharp loss of the yield of 6a. 6q can be easily
synthesized in gram-scale. Shortly, the reaction is
characterized with step-economy, harmless solvent, and
recyclable catalyst.
(+)-elacomine (III)
horsfiline, (I) X=MeO
coerulescine, (II) X=H
rhynchophylline (IV)
O
Me
N
Me
H
OH
OH
N
O
O
O
O
O
N
OH
H
O
O
O
O
N
O
N
N
H
n-pent
alkyl
alkaloid (VI) produced by
Neosartorya siamensis
alkaloids aspergillines A, B (VII)
XEN907(V): blocker of hNav 1.7
Our hypothesis
H2N
N
Green chemical process requires chemists to produce
valuable chemicals with least amount of energy, time, and
waste 1
. Multi-component reactions (MCR), which arrange the
EWG
CN
O
OH
EWG
EWG
EWG'
O
EWG'
H2O
+
O
O
N
H
N
N
H
EWG'
N2
H
majority of atoms from more than two starting materials into the final
product in a single step without releasing pollutant, are an ideal
strategy for green chemistry.2 MCR are known to possess the
following features:2d 1) MCR are designed to maximize the
incorporation of all starting materials into the final product; 2) MCR
are designed to access the final product in fewest number of steps; 3)
MCR furnish products with structural complexity and diversity via
combinatorial method. Therefore, development of novel MCR is one
of the efficient methods of fulfilling principles of green chemistry.
Furthermore, for the sake of environment, MCR with mild and
harmless conditions are highly recommended. Practically,
environmentally detrimental solvents like halogenated solvents
should be replaced with more favourable solvents such as H2O,
alcohols, esters, etc. On the other hand, recycling the materials of
MCR is expected to reduce cost and waste. We are guided by these
principles to design reactions to generate functionally interesting
molecules.
EWG
CN
H2N
EWG'
O
+
H2O
O
N
H
Fig. 1 Biologically active compounds bearing spirooxindole scaffold (top) and
our hypothesis of synthesizing spirooxindole (bottom).
Spirooxindole scaffold is widely found in natural products and
pharmaceutical molecules.3 For example, coerulescine (II), (+)-
elacomine (III), rhynchophylline (IV), alkaloids (VI) produced by
Neosartorya siamensis and alkaloids aspergillines A, B (VII) are
natural products with interesting bioactivities.4 Horsfiline (I) and
XEN907 (V) identified as analgesic and inhibitor of hNa1.7 are
promising drug candidates (Fig. 1, top).5 Due to their biological
significance, spirooxindole building block has triggered wide interest
in organic synthesis community.6 In recent years, our group and others
have documented multi-component reactions using isatin as the one
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of the starting materials.7 But a straightforward approach to generating
spirooxindoles from isatin remains rare.8 We envision a multi-
component cascade reaction, in which isatylidene malononitrile/2-
cyanoacetate is employed to trap the protic oxonium ylide and
in 5 mL water over one hour via syringe pump at 80 ℃. b Isolated yield. c d.r.
1
e
ratio was determined by H NMR. d EtOAc/H2O = 1/1 was used as solvent.
Pure H2O was used as solvent. f Pure EtOAc was used as solvent.
subsequently undergo intramolecular cyclization,
affording
Next, we seek to make this reaction greener by replacing DCM
with more environmentally friendly solvents. Interestingly, ethyl
acetate (EtOAc) could give even higher yield than DCM (Table 1,
entry 11). According to the GSK’s solvent selection guide, EtOAc is
considered to be a priority in the chemical process.9 It should be noted
that the reactivity dropped surprisingly when pure EtOAc or pure
water is used as the solvent (table 1, entries 12-13), indicating the
increased solubility of catalysts and starting material in the mixture of
water and EtOAc contributed to the reactivity.
With the establishment of the optimal conditions, we next
examined the scope of substrates. Firstly, a variety of isatins were
investigated with 1a as a standard substrate. Isatin derivatives bearing
both electron-donating and electron-withdrawing substituents at 5-
position gave high to excellent yields of the corresponding products
(Table 2, 6b-6g). The structure of cis-6a was supported by X-ray
crystallography (Table 2, 6a, CCDC No.: 1899658). For 4, 6, and 7-
chloro-substituted isatins, the reaction proceeded smoothly as well,
furnishing products in 90-94% yields (Table 2, 6h-6j). However,
when 4a was replaced by ethyl cyanoacetate (4b), the yield of the
desired product is unsatisfactory in the copper-catalyzed reaction due
to the weaker electrophilicity of isatylidene cyanoacetate compared to
5a. Reassuringly, when Cu(OTf)2/Rh2(OAc)4 cocatalyst was applied
to the system, the reaction finished smoothly affording 6k and 6l with
96% and 60% yields, respectively. The structure of trans-6k was
supported by X-ray crystallography (Table 2, 6k, CCDC No.:
1941034). The lower yield of 6l than 6k may be due to the decrease
in electrophilicity of the isatylidene cyanoacetate 5l which is bearing
electron-donating group at 5-position.
Then different diazo esters were explored with 3a and 4a as the
standard substrates. Under the optimal conditions, α-alkyl substituted
diazo esters could not be decomposed smoothly by Cu(OTf)2. Gladly,
if Rh2(OAc)4 was used as a cocatalyst, the reaction proceeded
smoothly with high efficiency, providing 6 in 78%-83% yields. (Table
3, 6m-6o). Methyl phenyldiazoacetate showed good reactivity as well,
furnishing 6p in 52% yield. The variance of R3 group of diazoaceate
was allowed, providing products 6q and 6r in excellent yields.
Notably, the gram-scale reaction was successfully conducted to afford
11 grams of 6q in 80% yield. Albeit the diastereoselectivities of the
products are almost equal to 50:50, these diastereomers could be
easily isolated with flash chromatography. For the sake of building
compound library for drug discovery, the reaction can facilitate the
building up library with stereo-diversity and render a rapid access to
the future study on the relationship between stereochemistry and
potential functions.
spirooxindole in one pot (Fig. 1, bottom). The method represents one
of the examples that use environmentally friendly solvents and recycle
the material of the reaction, shedding the light upon the green
chemistry-oriented reaction development.
At the outset, we conducted the Rh2(OAc)4-catalyzed multi-
component reaction of in situ-generated ethyl diazoacetate (EDA) (2a)
from glycine ethyl ester hydrochloride (1a), water and in situ-
generated isatylidene malononitrile (5a) from isatin (3a) and
malononitrile (4a) in the two-phase solvent of water and
dichloromethane (DCM). As depicted in Fig. 1 bottom, Michael-type
adduct of hydroxyl oxonium ylide and the isatylidene malononitrile
underwent intramolecular ring-closure smoothly to afford 6a as the
final product in 87% yield with 50:50 diastereoselectivity (Table 1,
entry 1). Then the reaction was set as the template to screen a series
of other metal catalysts. All the catalysts could furnish 6a in high to
excellent yields (81-96%, Table 1, entries 2-8) with 50:50 dr values,
except Fe (ClO4)3·xH2O and Cu(ClO4)2·xH2O (Table 1, entries 9-10),
Cu(OTf)2 was the optimal catalyst affording 6a in 96% yield (Table
1, entry 6).
a
Table 1 Optimization of reaction conditions.
H2
N
O
NaNO2 (1.0 eq)
NC
NH3
Cl
H2SO4 (10 mol%)
CO2Et
CO2Et
N2
solvent, -5 o
C
O
H
CO2Et
1a
N
2a
H
trans-6a
+
catalyst
+
solvent, 80 o
C
O
NC
H2
N
CN
O
O
+
NC
CN
O
solvent, 80 o
C
NC
N
CO2Et
H
N
O
H
5a
3a
4a
N
H
cis-6a
Entry
Catalyst (mol%)
Rh2(OAc)4 (1)
[Ir(cod)Cl]2 (1)
Yield (%)b
trans-6a/cis-6ac
50:50
1
2
3
4
5
87
83
80
81
90
50:50
[PdCl(ŋ3-C3H5)]2(1)
Pd(CH3CN)2Cl2 (1)
CuI (5)
50:50
50:50
50:50
6
7
Cu(OTf)2 (5)
96
87
92
20
<5
98
<5
<5
50:50
50:50
50:50
50:50
-
CuSO4 (5)
8
Cu(CH3CN)4PF6 (5)
Cu(ClO4)2·xH2O (5)
Fe (ClO4)3·xH2O (5)
9
10
11 d
12e
13f
Cu(OTf)2 (5)
Cu(OTf)2 (5)
Cu(OTf)2 (5)
45:55
-
Table 2 Scope of functional isatylidene malononitrile/cyanoacetate in multi-
component cascade reactions of 1a, 3 and 4 in water and EtOAc.a
-
a Reaction conditions: Unless otherwise noted, the reaction was carried out in
a 0.5 mmol scale. To a mixture of glycine ethyl ester hydrochloride (1a) and
sodium nitrite in 5 mL solvent and 5 mL water, was added H2SO4 dropwise at
-5 ℃. Then the organic layer was syringed to the mixture of in situ-generated
isatylidene malononitriles 5a (0.5 mmol) from 3a and 4a at 80 ℃, and Cu(OTf)2
2 | J. Name., 2019, 00, 1-3
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COMMUNICATION
NaNO2 (1.0 eq)
NH
3 Cl
Water, acting as a reactant and solvent in the reaction, not only
increased the reactivity, but also facilitated the recycling of catalyst
Cu(OTf)2. 1a, 3a and 4a were chosen as substrates to conduct the
catalyst-recycling experiment. The aqueous phase of catalyst was
directly used in the next batch after the simple separation of EtOAc
and water. The results remained excellent even after catalyst-
recycling for four times (table 4, entries 1-4). However, the yield
started to drop to 75% in the 5th batch (table 4, entry 5), and it further
reduced to 51% even with longer reaction time (table 4, entry 6). 2a
could not be decomposed in the 7th batch (table 4, entry 7).
H2SO4 (10 mol%)
CO2Et
N2
H
CO2Et
EtOAc/H2O, -5 o
C
H2
N
2a
1a
O
EWG
Cu(OTf)2 (5 mol%)
+
CO2Et
EWG
R1
O
O
EtOAc/H2O
80 o
C
CN
O
N
H
R1
+
NC
O
EWG
6, 60-96%b
42:58-70:30 drc
,
EtOAc/H2
80 o
O
R1
N
H
C
N
H
5
3
4
H2
N
O
NC
CO2Et
O
N
H
6a, 98%
trans:cis = 45:55
cis-6a
H2
N
H2
N
H2N
O
O
O
Table 4 Catalyst recycling in multi-component cascade reactions of 1a, 3a and 4a
NC
NC
NC
Me
MeO
F
CO2Et
CO2Et
CO2Et
in water and EtOAc.a
O
O
O
N
N
N
H
H
H
NaNO2 (1.0 eq)
6b, 90%
trans:cis = 44:56
6c, 88%
trans:cis = 42:58
6d, 93%
trans:cis =48:52
NH3
Cl
H2SO4 (10 mol%)
CO2Et
N2
H2
N
H2
N
H2N
H2
N
H
CO2Et
1a
EtOAc/H2O, -5 o
C
2a
O
O
O
O
NC
NC
NC
NC
Br
O2N
Cl
CO2Et
CO2Et
CO2Et
CO2Et
Cu(OTf)2 (5 mol%)
EtOAc/H2O,
+
O
O
O
O
N
N
H
N
O
NC
H
H
N
CN
O
80 o
C
6f, 92%
trans:cis = 48:52
H
6g, 91%
trans:cis = 49: 51
H2
6e, 92%
trans:cis = 50:50
6a
+
NC
CN
O
N
EtOAc/H2O,
80 o
N
H2
N
C
H
O
H2
NC
N
N
NC
O
H
5a
O
NC
CO2Et
3a
4a
Cl
CO2Et
O
CO2Et
O
O
N
H
Batch
Time (min)
Yield (%)b
trans-6a/cis-6ac
45:55
N
H
Cl
Cl
NH
6h, 90%
trans:cis = 50:50
6j, 94%
trans:cis = 46:54
6i, 93%
trans:cis = 46:54
1
2
3
4
5
6
7
60
60
98
94
92
92
75
51
0
H2
N
H2N
O
O
45:55
EtO2
C
EtO2C
MeO
CO2Et
CO2Et
O
O
60
45:55
N
N
H
H
6kd, 96%
trans:cis = 60:40
6ld, 60%
trans:cis = 70:30
trans-6k
60
45:55
a
Reaction conditions: Unless otherwise noted, the reaction was carried out in a
80
45:55
0.5 mmol scale. A mixture of glycine ethyl ester hydrochloride (1a) and sodium
nitrite in 5 mL EtOAc and 5 mL water, was added H2SO4 dropwise at -5 ℃. Then
the EtOAc layer was syringed to the mixture of in situ-generated isatylidene
malononitriles 5 (0.5 mmol) from 3 and 4 at 80 ℃, and Cu(OTf)2 in 5 mL water
120
120
45:55
-
a Unless otherwise noted, the reaction was carried out in a 0.5 mmol scale. A mixture
of glycine ethyl ester hydrochloride (1a) and sodium nitrite in 5 mL EtOAc and 5
mL water, was added H2SO4 dropwise at -5 ℃. Then the EtOAc layer was syringed
to the mixture of in situ-generated isatylidene malononitriles 5a (0.5 mmol) from 3a
and 4a at 80 ℃, and Cu(OTf)2 in 5 mL water over one hour via syringe pump at
80 ℃. b Isolated yield. c d.r. ratio was determined by 1H NMR.
over one hour via syringe pump at 80 ℃. Isolated yield. cd.r. ratio was
b
determined by 1H NMR. d 1 mol% Rh2(OAc)4 was used as co-catalyst.
Table 3 Scope of diazo esters in multi-component cascade reactions of 1, 3a and
4a in water and EtOAc.a
N2
H2
N
R2
CO2R3
O
NC
O
2
R2
CO2R3
CN
O
NC
Cu(OTf)2 (5 mol%)
The possible mechanism of the multi-component cascade reaction
was elaborated in the Scheme 1. To begin with, carbenoid A was
generated in the process of the decomposition of α-diazo ester 2
catalyzed by Cu(OTf)2 or Rh2(OAc)4. Then A reacted with H2O to
form oxonium ylides, which existed in the form of B1, B2 and B3.10 If
not being trapped by active electrophile, B2 was easily transformed
into alcohols 7 via 1,2-H shift. When the electrophile 5 was added, the
highly active intermediate B2 was trapped to produce a Michael-type
adduct C, which underwent delayed proton transfer to form D. Then
intermediate E was formed via intramolecular nucleophilic addition
to the nitrile with hydroxy group. Finally, product 6 were furnished
through tautomerization from E.
O
+
NC
CN
EtOAc/H2
80 o
O
O
EtOAc/H2
80 o
O
N
H
C
N
C
N
H
H
5a
6, 79-99%b
42:58-48:52 drc
,
3a
4a
H2
N
H2
N
H2
N
O
O
Bun
O
Me
CO2Et
NC
NC
Et
NC
CO2Et
CO2Et
O
O
O
N
N
H
N
H
H
6md, 82%
6od, 78%
trans:cis = 42:58
H2
6nd, 83%
trans:cis = 44:56
H2
trans:cis = 45:55
H2
N
N
N
O
O
O
Ph
NC
NC
NC
CO2Me
CO2But
O
CO2Me
O
O
N
N
N
H
H
H
6pd, 52%
6q, 99% (80%)e
trans:cis =48:52
6r, 92%
trans:cis = 42:58
trans:cis = 48:52
a Reaction conditions: Unless otherwise noted, the reaction was carried out in a 0.5
mmol scale. A mixture of diazo ester 2 (2 mmol) in 5 mL EtOAc was syringed to
the mixture of in situ-generated isatylidene malononitrile 5a (0.5 mmol) from 3a
and 4a at 80 ℃, and Cu(OTf)2 in 5 mL water over one hour via syringe pump at 80
℃. b Isolated yield. c d.r. ratio was determined by 1H NMR. d 1 mol% Rh2(OAc)4
was used as co-catalyst. e Reaction was conducted in gram scale.
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COMMUNICATION
Journal Name
HN
O
N
Procedure for the scale-up synthesis of 6q from glycine methyl
ester hydrochloride.
C
OH
R4
R1
CO2R2
R4
R1
cyclization
CO2R2
R3
O
R3
O
N
N
H
To the 400 mL aqueous solution of 1q (154 mmol) and sodium
H
D
E
N2
nitrite, was added 100 mL EtOAc and 100 mL water. Then 1 M
intramolecular H-shift
R1
CO2R2
o
tautomerization
sulfuric acid (1.54 mmol) was added dropwise with funnel at -5 C.
2
M (II)
The resulting yellow EtOAc solution was washed with NaHCO3 to
eliminate the remaining acid. In the other 1000 mL flask, 200 mL
EtOAc/H2O mixture with isatin 3a (38.60 mmol) was mixed with 200
mL EtOAc/H2O mixture with malononitrile 4a at 80 oC for 1 h. Then
the in situ-generated methyl diazoacetate 2q was added slowly to the
solution of isatylidene malononitrile 5a with 20 mol% Cu(OTf)2 in
400 mL water. After all the methyl diazoacetate added within 2 h, the
crude product in organic phase was separated with a funnel and the
aqueous phase was extracted with EtOAc (50 mL×3). The combined
organic phases were washed with Na2CO3, and then brine. Then
anhydrous Na2SO4 (50 g) was added to the final product solution.
After filtration, the solvent was removed to afford solid crude product,
which then underwent recrystallization in the mixture of EtOAc and
petroleum ether. Eventually, 6q was obtained (11.4 g, 80% yield) as
yellowish white solid.
Cu(II)
N
H2N
R4
M = Cu(OTf)2
or Rh2(OAc)4
O
C
R1
OH2
R1
CO2R2
O
R4
CO2R2
O
M(II)
R3
R3
N
OH
N
H
R1
CO2R2
H2O
H
A
6
C
R1
CO2R2
7
1,2-H shift
R4
Cu(II)
N
C
OH2
CO2R2
OH2
H2O
R1
OM(II)
OR2
O
R1
R3
R1
CO2R2
M(II)
N
H
B1
5
B2
B3
Scheme 1 Proposed mechanism of the multi-component cascade reaction.
Conclusions
In conclusion, a Cu(OTf)2-catalyzed or Cu(OTf)2/Rh2(OAc)4-
cocatalyzed reaction of α-diazo ester, water, isatin and
malononitrile/cyanoacetate in one pot was disclosed. This report
exhibited a green approach to spiro[2,3-dihydrofuran-3,3′-oxindole]
analogues in 60-99% yields. Water plays dual roles in the reaction,
acting as a reactant providing hydroxyl source for the final product,
and as solvent increasing the reactivity and facilitating the recycling
of the catalyst. The catalyst Cu(OTf)2 was reused for 4 times without
loss of the yield of 6a. Notably, the reaction could be scaled up to
gram scale by using in situ generated methyl diazoacetate and
Acknowledgements
NSFC 21332003 (WH). The Program for Guangdong Introducing
Innovative and Entrepreneurial Teams 2016ZT06Y337 (WH). China
Scholarship Council (TS).
Notes and references
aShanghai Engineering Research Center of Molecular Therapeutics and
New Drug Development, School of Chemistry and Chemical Engineering,
East China Normal University, Shanghai, China, 200062.
bGuangdong Chiral Drug Engineering Laboratory, School of Pharmaceutical
Sciences, Sun Yat-sen University, Guangzhou, China, 510006.
cSchool of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou,
Zhejiang Province, China, 325035.
isatylidene malononitrile, resulting in 11 g of 6q after crystallization.
Atom economy, which quantifies the use efficiency of atoms in
the staring materials in the chemical process, is a pivotal concept of
green chemistry principles. The reactions we reported here have atom
economy ranging from 91-93%.11 And the rest of 7-9% atoms from
the starting materials go to the air as the form of innocent nitrogen
gas. The application of this method in the synthesis of biologically
interesting molecules and identification of bioactivity of the products
is ongoing in our lab.
†These authors contribute equally.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/c000000x/
1
(a) B. M. Trost, Science. 1991, 254, 1471; (b) Green Chemistry:
Frontiers in Benign Chemical Syntheses and Processes. P. Anastas,
T. C. Williamson, Oxford Science Publications: New York, 1998; (c)
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General procedure for the synthesis of 6.
To a mixture of glycine ethyl ester hydrochloride (1a) and sodium
nitrite in 5 mL EtOAc and 5 mL water, was added H2SO4 dropwise at
-5 ℃. Then the EtOAc layer was syringed to the mixture of in situ-
generated isatylidene malononitriles 5 (0.5 mmol) from 3 and 4 at 80
℃, and Cu(OTf)2 in 5 mL water over one hour via syringe pump at 80
℃. When the reaction was complete as monitored by TLC, the
reaction mixture was separated with a funnel, then the aqueous phase
was extracted with ethyl acetate (5 mL×3). The combined organic
layers were dried with Na2SO4. After filtration, the crude product was
purified by flash chromatography on silica gel (petroleum ether: ethyl
acetate = 3:1 to 1:1) to provide the corresponding products trans-6 (Rf
= 0.25 when PE: EA=1:1) and cis-6 (Rf = 0.2 when PE: EA=1:1).
2
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DOI: 10.1039/C9GC01751H
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This journal is © The Royal Society of Chemistry 2019
J. Name., 2019, 00, 1-3 | 5

Green Chemistry
Page 6 of 6
View Article Online
DOI: 10.1039/C9GC01751H
Graphical Abstract
Synthesis of spiro[2,3-dihydrofuran-3,3′-oxindole] via a
multi-component cascade reaction of α-diazo esters, water,
isatins and malononitrile/ethyl cyanoacetate
Taoda Shi†, Shenghan Teng†, Yajie Wei, Yin Guo and Wenhao Hu*
R2
NaNO2 (1.0 eq)
NH
3 Cl
H2SO4 (10 mol%)
N2
CO2R3
H2N
R2
CO2R3
EtOAc/H2O, -5 o
R2 = H
C
O
1
2
EWG
R2
[Cu]
or [Cu]/[Rh]
CO2R3
O
+
R1
EtOAc/H2O, 80 o
C
O
EWG
N
CN
O
19 examples
up to 99% yield
6
H
R1
O
+
EWG
CN
R1 = H, 5-OMe, 5-Br, 5-NO2, 5-
Me, 5-F, 5-Cl, 4-Cl, 6-Cl, 7-Cl
R2 = H, alkyl, phenyl
R1
EtOAc/H2O
N
H
80 o
C
N
H
3
4
5
* High atom economy * Benign solvent R3 = Me, Et,But
* Recyclable catalyst * Safe scalability
EWG = CN, CO2Et