A Serendipitous One-Pot Cyanation/Hydrolysis/Enamide Formation: Direct Access to 3-Methyleneisoindolin-1-ones

Article abstract of DOI:10.1002/chem.202003209

A direct, one-pot conversion of 2’-haloacetophenones to 3-methyleneisoindolin-1-one scaffolds using CuCN as the sole reagent without the need for moisture-free or anaerobic conditions is reported. This serendipitously discovered transformation with a broa

Full text of DOI:10.1002/chem.202003209

Accepted Article
Accepted Article
Title: A Serendipitous One-Pot Cyanation/Hydrolysis/Enamide
Formation: Direct Access to 3-methyleneisoindolin-1-ones
Authors: Krishna Pillai Kaliappan and Trisha Banik
This manuscript has been accepted after peer review and appears as an
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To be cited as: Chem. Eur. J. 10.1002/chem.202003209
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01/2020

10.1002/chem.202003209
Chemistry - A European Journal
RESEARCH ARTICLE
A Serendipitous One-Pot Cyanation/Hydrolysis/Enamide Formation:
Direct Access to 3-methyleneisoindolin-1-ones
Trisha Banik,[a] and Krishna P. Kaliappan*[a]
[a] Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai-400076
Abstract: A direct, one pot conversion of 2’-haloacetophenones to
3-methyleneisoindolin-1-one scaffolds using CuCN as the sole
reagent without the need for moisture-free or anaerobic conditions is
reported. This serendipitously discovered transformation with a
broad substrate scope provides a significantly different route towards
these important scaffolds. The scope of the method has also been
further extended towards the synthesis of three special scaffolds,
which are analogous to various bio-active drugs.
With this serendipitous observation, an exhaustive literature
survey indicated that a direct one-pot transformation from 2’-
bromoacetophenones to 3-methyleneisoindolin-1-ones was
indeed a useful transformation and holds immense potential. It
was realized that among heterocyclic scaffolds, isoindolin-1-one
ring systems are privileged units with applications in medicinal
chemistry in the form of homo-N-nucleoside derivatives to assist
in DNA recognition studies.5 Isoindolinone on dimerization forms
isoindigo, whose derivatives have been utilized as high
performance polymers showing excellent photo-physical and
electrochemical properties.6
Introduction
OMe
O
OMe
O
MeO
MeO
N
NH
The development of efficient synthetic methods for the formation
of heterocyclic rings is one of the most extensively studied
research areas in organic chemistry.1 Among the various
methods for the synthesis of heterocycles, one-pot reactions
continue to attract synthetic community due to its potential in
assembling complex molecular architectures quickly.2 These
transformations contribute towards implementing step economy
and atom economy to complex processes, which are considered
to be major criteria for a reaction to be efficient.3 Owing to the
fact that most of the biologically important molecules contain a
variety of heterocyclic scaffolds, it is important to continue to
develop newer methods towards the synthesis of novel
scaffolds.
O
O
O
O
Me2N
4
5
Fumaridine
Lenoxammin
O
OH
N
O
N
MeO
O
MeO
MeO
6
7
Aristoyagonine
AKS-186
Figure 1: Pharmaceutically relevant compounds
During the course of one of the ongoing projects in our
laboratory,4 we were in need of several 2‘-acetyl substituted
benzonitriles. While preparing this from 2’-bromoacetophenone
(1) and CuCN under standard conditions for cyanation, to our
surprise, in addition to the desired product 3 in 42% yield, a new
compound, identified as 3-methyleneisoindolin-1-one (2), after
NMR and HRMS analysis, was obtained in substantial quantity
(Scheme 1). Once the new compound was identified and fully
characterized, it was deduced that cyanation, followed by
unexpected hydrolysis of the resulting nitrile and subsequent
enamide formation could have possibly produced this
unexpected scaffold. It was also postulated that the hydrolysis
had probably been facilitated by the presence of Cu(I) and trace
amounts of moisture in commercial grade DMF, which was used
The 3-methyleneisoindolin-1-one moiety also exists in natural
products like aristolactams and piperolactams, which exhibit
inhibitory activities against platelet aggregation induced by
collagen and arachidonic acid (Figure 1).7 Apart from these, a
variety of other biologically active natural products contain a 3-
methyleneisoindolinone scaffold and owing to this, several
protocols for the synthesis of this class of compounds have been
developed.8
The earlier methods for the construction of this unique class of
heterocyclic moieties include the Horner–Wadsworth–Emmons
type of condensation,9 photolytic or electrolytic addition and
condensation of phthalimides,10 5-exo-dig cyclization of pre-
formed o-(alkynyl)benzamides through electrophilic activation of
triple bonds.11 Base triggered direct nucleophilic attacks on o-
substituted triple bonds by amides12 or nitriles13 have also been
explored. In 2013, Kobayashi and co-workers synthesized 2,3-
dihydro-3-methylidene-1H-isoindol-1-ones, by the reaction of 2-
for the reaction.
O
CuCN (1.2 eq)
DMF, 170 o
(Expected)
C
CN
O
3
formylbenzonitriles
with
dimethyloxosulfoniummethylide,
Br
generated from trimethylsulfoxonium iodide and NaH.14
However, these methods have been either associated with poor
regioselectivity in case of unsymmetrical substrates or required
a number of additional synthetic steps. In order to overcome
these drawbacks, various groups resorted to using transition
metal catalyzed reactions such as Heck–Suzuki–Miyaura
O
1
CuCN (1.2 eq)
NH
DMF, 170 o
(Observed)
C
+
CN
O
2
3
; (42%)
; (21%)
Scheme 1: Serendipitous formation of 3-methyleneisoindolin-1-one
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10.1002/chem.202003209
Chemistry - A European Journal
RESEARCH ARTICLE
domino sequences involving ynamides [Scheme 2(a)],15
Sonogashira coupling-carbonylation–hydroamination of ortho-
dihaloarenes [Scheme 2(b)]12b,16 and domino coupling-
hydroamination of ortho-halobenzamides (Scheme 2(c)).17
clear indication that this is indeed the intermediate in this
transformation, possibly formed by a Rosenmund-von Braun
type cyanation on the aromatic halide.22 However, the lack of
formation of 3-methyleneisoindolin-1-one confirmed the
requirement of moisture in the medium for hydrolysis and
subsequent enamide formation.
(a) Cossy and co-orkers (2004) :15
O
O
O
R
Pd(OAc)2, PPh3
DMF, 80 o
ArB(OH)2
R
N
N
N
R
C
X
So, in order to facilitate the hydrolysis of the intermediate nitrile
3, water and acetic acid were added as additives, which
marginally increased the yield (Entries 3, 4). The use of non-
polar solvent toluene and polar aprotic solvent DMSO didn’t give
either of the products. However, NMP gave a mixutre of 2 and 3
in only moderate yield. On the other hand, switching to polar
protic solvents like MeOH and t-BuOH at 80 °C, only the nitrile
9
10
8
XL2Pd
Ar
(b) Alper and co-worlers (2008) :16
O
Br
PdCl2(PPh3)2/ CuI
R'
+
RNH2
N
R
+
DBU, [P+][Br-]
110 oC, 36 h, CO (1 atm)
I
13
12
14
11
R'
(c) Ma and co-workers (2009) :17
O
O
N
10 mol% CuI
30 mol% L-proline
R
N
intermediate
3 was obtained with 43% and 39% yields
H
R
R'
+
i-PrOH, K2CO3
85 oC - 110 o
Br
respectively (Entries 8, 9). Nonetheless, when i-PrOH was used
at 80 °C, significant amount of the product 2 was formed along
12
15
14
C
R'
(d) This work
O
with
3 and some unreacted starting material. Improved
CuCN
conversion of the nitrile into 2 was observed upon further
heating up to 120 °C to afford 82% of the cyclized product (Entry
10). In order to reduce the reaction time, combination of solvents
was then attempted. When a mixture of DMF and i-PrOH was
used, the yield of the cyclized product was dropped to 43%,
while the use of DMF and t-BuOH gave only 2 exclusively in
78% yield (Entry 12). The yield was further improved to 92%,
when water was used as a co-solvent (Entry 13).
NH
Solvent, ꢀ
X
O
2
1a
Scheme 2: Reported methods for synthesis of 3-methyleneisoindolin-1-one
scaffolds
Later in 2014, the groups of Lee18a and Patel18b utilized alkynyl
carboxylic acids to synthesize 3-methyleneisoindolin-1-one
derivatives via decarboxylative coupling with nitrogen donors.
Perhaps the most widely used tool for the synthesis of this
scaffold has been directing group assisted C-H activation,19,20
though most of these methods employ the use of expensive
transition metals, coupled with stoichiometric amounts of metal
based oxidants and highly activated olefinic reactants like
acrylates,19a-h vinyl sulfones,19h,i styrenes,19j,k difluoroalkenes,19l
or even alkynes.20 Although these one-pot routes are attractive
methods to construct this scaffold of interest, they either require
a multistep preparation of the starting materials or involve multi
component transformations, which often tend to suffer from the
formation of side products.
Table 1. Optimizationa
O
O
X
CuCN (1.2 eq)
NH
+
Solvent, Temperature
Time
CN
O
2
3
1a
Temp.
(oC)
Time
(h)
Yield
(2)
Yield
(3)
Entry
Solvent
1.
2.
DMF
DMF (dry)
DMF
170
130
150
150
110
120
110
80
24
48
6
21%
-
42%
56%
-
3.b
59%
37%
-
Thus in order to address these limitations, and in line with our
long-standing interest in the synthesis of various biologically
important heterocyclic scaffolds21, we sought to pursue this
serendipitously discovered one-pot transformation towards the
synthesis of 3-methyleneisoindolin-1-ones [Scheme 2(d)]. We
realized that efficient optimization of this transformation using
operationally simple conditions could provide a highly useful
synthetic methodology.
4.c
DMF
24
24
24
6
-
5.b
Toluene
NMP
-
6.b
24%
-
31%
-
7.b
DMSO
MeOH
t-BuOH
i-PrOH
8.b
48
12
48
24
24
20
24
18
-
39%
43%
Traces
25%
Traces
-
9.b
80
-
10.b
11.b
12.b
13.
14.d
15.e
120
110
110
110
110
110
82%
43%
75%
92%
78%
54%
DMF:i-PrOH (1:1)
Results and Discussion
DMF:t-BuOH (1:1)
DMF:t-BuOH:H2O (3:3:2)
DMF:t-BuOH:H2O (3:3:2)
DMF:t-BuOH:H2O (3:3:2)
Having already observed the product formation with
commercially available LR-grade DMF (Table 1, Entry 1), it was
important to confirm whether the trace amounts of moisture was
indeed driving the product formation. To this end, 2’-
bromoacetophenone was chosen as the test substrate for
optimization and it was reacted with CuCN in dry DMF (Entry 2).
The formation of 2-acetylbenzonitrile 3 as the sole product was a
18%
36%
a: X = Br, unless otherwise mentioned; all yields represent isolated yields; b: 1
drop of H2O was added as additive; c: Acetic acid was added as additive; d: X =
I; e:TBAI (cat. amount)
2
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10.1002/chem.202003209
Chemistry - A European Journal
RESEARCH ARTICLE
Among the aromatic halides, it was observed that bromides
(Entry 13) produced better yield than iodides (Entry 14), while
Disubstituted aromatic rings connected
to
the
2’-
haloacetophenones also yielded very good results (27-31). As a
heteroaromatic variant, the reaction was attempted on a pyridine
based scaffold to obtain a moderate yield (61%) of the cyclized
product 32. Finally when acetophenone derivatives were
replaced with other ketones, the products containing substituted
exocyclic double bonds were furnished in good to excellent
yields (34-40). It is worth mentioning that the formation of
substrate 35 was achieved in 89% yield when the reaction was
done at greater than 1 g scale. This further showcases the
scalability of our transformation (Scheme 3).
the use of
a
catalytic amount of TBAI with 2’-
bromoacetophenone only decreased the yield of the product
(Entry 15). So, the aromatic bromides were identified as the best
starting materials for exploring the substrate scope of our
transformation, except for a few substrates, where the iodinated
compounds were more easily accessible.
With the optimized reaction condition in hand (Table 1, Entry
13), the substrate scope of this domino transformation was
examined next. Very good functional group tolerance was
observed at each end of the electronic spectrum. To our delight,
both –NO2 (17) and –NMe2 (19) substituents furnished the
corresponding products in very good yields. Free amine groups
(–NH2), which generally hinder transition metal mediated
reactions, also worked efficiently under these reaction conditions
(18, 26). Amines derivatized as bis(sulfonamide) (20),
dibenzylamine (21) and benzanilide (22) also proved to be highly
tolerant to the reaction conditions. Surprisingly, the N,N-
dibenzoyl derivative upon treatment under the standard reaction
conditions, provided the monobenzoyl derivative (22) (See
Supporting Information). It may be reasoned that the one oft he
benzoyl groups was hydrolyzed under the reaction condition.
The presence of an extra fluoride on the aromatic ring was well
tolerated (23, 37, 38).
Having
successfully
syntheiszed
a
variety
of
3-
methyleneisoindolin-1-ones, we looked at extending this
methodology to synthesize another closely related class of
compounds, benzo[cd]indol-2(1H)-ones, which are frequently
found in a wide range of pharmaceuticals, dyes and natural
products.23 They also exhibit antitumor,24 anti-inflammatory,25
and antiplatelet activities.26 Compounds 41-44 (Scheme 4)
represent some members of this unique class of heterocycles,
which show important biological activities.23d,27
O
O
O
N
NH
NH
N
O
HN
N
MeO
OMe
O
S
O
HN
S
41
NH
44
O
O
Antitumor agent
for leukemia P388
& lung cancer A549
cell lines27a
Aristolactam
anticancer,
anti-inflammatory &
neuroprotective agent27c,d
O
Scheme 3: Substrate scopea
Cl
Br
42
43
Naphthostyril core
inhibitor for receptor
tyrosine protein kinase
(IC50 = 4.2 ꢁM
Aromatic variants:
BET inhibitor
for cancer &
inflammations23d
O
CuCN (1.2 eq)
for FGFR1)27b
NH
R
R
:
:
DMF t-BuOH H2O
110 °C
X
O
1a
X = Br, I
2a
O
O
NH
Br
O
NH
CuCN (1.2 eqv)
tBuOH:DMF:H2O
R
aromatization
R
NH
NH
NH
O
O
OMe
O
OMe
45
NH2
16; R = H (92%)
17; R = NO2 (93%)
R
OMe
46
47; (86%)
26; (74%)
27; R = Phenyl (88%)
28; R = 4-Fluorophenyl (89%)
R = 4-Methoxyphenyl
R = 2-Methoxyphenyl
R = 1-Naphthyl
18;
19;
20;
(73%)
(79%)
(87%)
R = NH2
R = NMe2
R = NTs2
29;
30;
31;
(59%)
(51%)
(63%)
Scheme 4: Synthesis of benzo[cd]indol-2(1H)-one based drug analogue
21; R = NBn2 (84%)
22; R = NHBz (40%); (51%)b
23;
24;
25;
(79%)
(46%)
R = F
R = I
O
O
NH
NH
(78%)
R = OMe
N
However, synthetic routes to access this scaffold have often
been inefficient and limited in scope. Traditionally,
benzo[cd]indol-2(1H)-ones have been prepared from the
reaction of 1,8-naphthalic anhydride with hydroxylamine
hydrochloride employing very harsh conditions , while exhibiting
a very narrow substrate scope.23c,d, 27a,b, 28 However, there have
been more recent methods which have managed to overcome
these obvious shortcomings including base mediated
benzannulation,29 reductive cyclization,30 aminocyclization on
triple bonds,31 and transition metal catalyzed carbonylative C-H
activation.32 To this end, we envisaged that our CuCN mediated
transformation may be easily employed to address some of the
drawbacks of the aforementioned methods in the synthesis of
benzo[cd]indol-2(1H)-one derivatives. In order to probe the
feasibility of this hypothesis, the tetralone 45 was treated under
O
O
33; (88%)
32; (61%)
Ketone variants:
R1
O
R2
R2
CuCN (1.2 eq)
R
NH
R
R1
:
:
DMF t-BuOH H2O
110 °C
X
1b
X = Br, I
O
2b
R2
R2
R1
NH
R2
R1
NH
R1
NH
MeO
F
MeO
O
O
O
34; R1 = R2 = Me (77%)
35; (89%) *(g scale)
37;
(73%)
39;
(65%)
R1 = R2 = H
R1 = R2 = Me
38; R1 = H, R2 = n-Hex (66%)
R1 = H, R2 = Ph
36; R1 = H, R2 = CH2Ph (96%)
40; R1 = H, R2 = n-Hex (70%)
a: All yields represent isolated yields; b: Obtained starting from N,N-
dibenzoylated compound (see SI)
our
standardised
conditions
to
obtain
the
3-
methyleneisoindolinone intermediate 46, wherein the newly
3
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10.1002/chem.202003209
Chemistry - A European Journal
RESEARCH ARTICLE
double bond of prostacyclin (PGI2) (Scheme 6).35 In order to
further extend our current methodology, we wanted to
synthesize the 3-benzylideneisoindolinone analogue (52) of
AKS-186.To this end, the free N-H of the substrate 35 was
converted to its corresponding PMB-derivative. Upon
subsequent treatment with BBr3, demethylation was achieved to
obtain the lower analogue of AKS-186 (52) in 86% yield
(Scheme 6). SAR studies on 3-methyleneisoindolinones have
led to the conclusion that the geometry of the exocyclic double
bond has little bearing on the biological activity of the
compounds.34
formed exocyclic double bond was part of the ring. Interestingly,
this underwent concomitant aromatization to furnish
benzo[cd]indol-2(1H)-one 47 in 86% yield, which illustrates the
potential application of our methodology (Scheme 4).
When the benzophenone derivative 48 lacking an α-hydrogen on
the ketone was reacted, the corresponding aminol 49 was
obtained. Interestingly, this aminol was a direct analogue of
chlorthalidone (50), which is very commonly used as an anti-
hypertensive drug33 (Scheme 5).
HO
O
In order to probe further into the mechanism of this unexpected
transformation, a couple of experiments were carried out.
Treatment of 2’-fluoroacetophenone (1a’) under the standard
reaction conditions left the starting material untouched. This
suggested that the mechanism for cyanation might not be SNAr
type, thereby indicating a Rosenmund-von Braun type cyanation
process. In order to further establish this idea, an alternative
cyanide source like Zn(CN)2 was used, which too, failed to react
with 2’-bromoacetophenone. This further confirmed that CuCN
was indispensible for our purpose and Cu was probably playing
a key role in the cyanation process (Scheme 7).
CuCN (1.2 eqv)
NH
tBuOH:DMF:H2O
I
O
49; (64%)
48
Cl
SO2NH2
HO
NH
O
50
Chlorthalidone
(antihypertensive drug)
O
Scheme 5: Synthesis of chlorthalidone analogue
CuCN (1.2 eq)
NH
optimized condition
Among the 3-methyleneisoindolin-1-one based compounds in
Figure 1, a lot of synthetic as well as biological studies have
been devoted towards AKS-186 (7). AKS-186, belonging to the
family of 3-(2-phenylethylidene)isoindolinone compounds (36), is
known to inhibit U-46619-induced vasoconstriction of pig
coronary artery with an impressive IC50 value of 0.6 µM.34 In this
regard, the compound 36 is a direct precursor for AKS-186 as
well as other derivatives of the same, each of which have
impressive biological profiles. Structure-activity relationship
studies on this class of pharmaceutically important compounds
have indicated that the one carbon lower analogues of AKS-186
(35) also show inhibitory activity towards the type of
vasoconstriction mentioned above, albeit to a lesser extent.
F
1a'
O
2
O
Zn(CN)2 (1.2 eq)
NH
optimized condition
Br
2
O
1
Scheme 7: Mechanistic studies
The observation of the formation of 2-acetylbenzonitrile (3) was
strong indication that the mechanism for this one-pot
a
transformation proceeds initially via a Rosenmund-von Braun
type cyanation in the presence of CuCN at high temperatures,
followed by Cu-assisted concomitant hydrolysis of the nitrile to
the amide 55.36 Subsequently, the amide nitrogen undergoes a
5-exo-trig cyclization with the ketone to generate the aminol 56,
which dehydrates to form the transient iminium ion 57. Finally
the iminium ion undergoes deprotonation to form our desired 3-
methyleneisoindolin-1-one (2) to complete the transformation.
(Scheme 8).
OH
OMe
Ph
Ph
Ph
NaH, PMBCl
DMF
0 oC - RT
BBr3, DCM
N
N
NH
-78 oC - RT
(86%)
52
(91%)
O
O
O
51
35
Structural analogy with prostacyclin:
1
1
1
COOH
2
3
2
2
3
3
4
O
O
O
4
4
6
H
N
H
O
N
5
5
5
O
O
ꢀ
CuCN,
H2O
O
6
6
O
NH2
H
N
X
NH
H2O
Cu(I)
O
55
HO
(I)Cu
1a
3
54
X = Br, I
36
35
3-(2-phenylethylidene)
isoindolinone derivative
*(precursor for vasoconstriction
inhibiting agents)
(3-benzylideneisoindolinone
derivative)
53:
Prostacyclin
H
H
HO
NH
N
NH
H
Scheme 6: Synthesis of one carbon lower analogue of AKS-186
O
56
O
O
2
57
As a matter of further interest, the exocyclic olefin in this class of
compounds have also been considered equivalent to the 5,6-
Scheme 8: Probable mechanism for the one-pot transformation
4
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10.1002/chem.202003209
Chemistry - A European Journal
RESEARCH ARTICLE
10.
11.
a) C. Sanchez-Sanchez, E. Perez-Inestrosa, R. Garcia-Segura, R.
Suau, Tetrahedron 2002, 58, 7267; b) F. Hatoum, J. Engler, C. Zelmer,
J. Wissen, C. A. Motti, J. Lex, M. Oelgemçller, Tetrahedron Lett. 2012,
53, 5573; c) N. Kise, S. Isemoto, T. Sakurai, Tetrahedron 2012, 68,
8805.
Isolation of the substrate 49 (as shown in Scheme 5) was
conclusive evidence for an aminol intermediacy in our
transformation.
a) N. G. Kundu, M. W. Khan, R. Mukhopadhyay, Tetrahedron 1999, 55,
12361; b) C. Koradin, W. Dohle, A. L. Rodriguez, B. Schmid, P.
Knochel, Tetrahedron 2003, 59, 1571; c) T. Yao, R. C. Larock, J. Org.
Chem. 2005, 70, 1432;
Conclusion
12.
13.
a) N. G. Kundu, M. W. Khan, Tetrahedron 2000, 56, 4777; b) C.
Kanazawa, M. Terada, Chem. –Asian J. 2009, 4, 1668.
In summary, we herein report a serendipitous obervation of an
one-pot transformation of 2’-haloacetophenones to 3-
methyleneisoindolin-1-ones, an important class of heterocycles.
This reaction was carefully optimized further to synthesize a
wide range of derivatives in good to excellent yields, exhibiting
good scalability under a set of simple reaction conditions. This
method has also been successfully extrapolated towards the
synthesis of three drug analogues, including the one carbon
a) M. J. Wu, L. J. Chang, L. M. Wei, C. F. Lin, Tetrahedron 1999, 55,
13193; b) W. D. Lu, C. F. Lin, C. J. Wang, S. J. Wang, M. J. Wu,
Tetrahedron 2002, 58, 7315.
14.
15.
K. Kobayashi, K. Matsumoto, D. Nakamura, S. Fukamachi, H. Konishi,
Helv. Chim. Acta. 2010, 93, 1048.
a) S. Couty, B. Liegault, C. Meyer, J. Cossy, Org. Lett. 2004, 6, 2511;
b) S. Couty, B. Liegault, C. Meyer, J. Cossy, Tetrahedron 2006, 62,
3882.
lower analogue of AKS-186, which is
a
well known
16.
17.
H. Cao, L. McNamee, H. Alper, Org. Lett. 2008, 10, 5281.
vasoconstriction inhibitor. The fact that moisture-free or
anaerobic conditions are not necessary and only CuCN is
enough to achieve this transformation makes it one of the
efficient methods for the construction of these biologically
important scaffolds.
a) L. Li, M. Wang, X. Zhang, Y. Jiang, D. Ma, Org. Lett. 2009, 11, 1309;
b) M. Hellal, G. D. Cuny, Tetrahedron Lett. 2011, 52, 5508.; c) A.
Bubar, P. Estey, M. Lawson, S. Eisler, J. Org. Chem. 2012, 77, 1572.
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Acknowledgements
K.P.K gratefully acknowledges SERB (EMR/2017/000578) for
the financial support. T.B acknowledges IIT Bombay for
fellowship. The instrumental facility of IIT Bombay is gratefully
acknowledged.
Keywords: 3-methyleneisoindolin-1-one • Heterocycles •
Cyanation • Enamide formation • One-pot transformation
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Entry for the Table of Contents
CuCN
.
.
.
.
.
High Atom Economy
Single Reagent Used
27 New Substrates
Upto 96% Yield
O
NH
O
X
X = Br, I
One-Pot
Drug Analogues
CuCN does it alone: A direct one-pot transformation of 2’haloacetophenones to 3-methyleneisoindolin-1-ones has been described.
CuCN mediates the 4-step transformation under highly robust conditions, accompanied by high yields and efficient atom economy.
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