Base-mediated benzannulation of α-cyanocrotonates with ynones: Facile synthesis of benzonitriles and fluorenes

Article abstract of DOI:10.1039/d0gc00608d

Here, we have demonstrated a strategic rapid approach for the synthesis of benzonitriles and cyanofluorenes via the [3 + 3] benzannulation of readily available alkynones and α-cyanocrotonates, a protocol par excellence for aryl nitriles. This decarboxylat

Full text of DOI:10.1039/d0gc00608d

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DOI: 10.1039/D0GC00608D
COMMUNICATION
Base Mediated Benzannulation of α-Cyano Crotonates
with Ynones: Facile Synthesis of Benzonitriles and
Fluorenes
Received 00th January 20xx,
Accepted 00th January 20xx
Maneesh Kumar Reddy Singamǁab, Attunuri Nagireddyǁab and Maddi Sridhar Reddy*ab
DOI: 10.1039/x0xx00000x
www.rsc.org/
We demonstrate here in
a strategic rapid approach for On the other hand, fluorenes, as the methylene-bridged arenes, are
benzonitriles and cyanofluorenes via [3 + 3] benzannulation of considered as privileged structures in materials because of their
readily available alkynones and α-cyanocrotonates, a protocol par easily modifiable nature which help in tuning the physical &
excellence for aryl nitriles. This decarboxylative annulation is chemical properties and thereby the optical and electrical features.9
assisted solely by a base without the need of any catalyst. The Consequently, enormous efforts have been made to find
only by-product is EtOH (and CO2) and the product is cleanly manufacturing approaches for the construction of this interesting
filtered off the contents after reaction at ambient temperature.
structure.10
R2
Benzannulation is a powerful strategy to rapidly construct the
benzene derivatives from acyclic precursors. Appropriately
functionalized acyclic precursors give highly and selectively
substituted adducts avoiding the linear tedious processes.1 While
reducing the chemical wastage, it imparts high convergence in the
approach. Conjugated carbonyls are often the feedstock in these
annulations where Michael addition usually triggers the annulation
and thus renders it a high regioselectivity.
O
R3
R1
(a)
NHC catalyst
oxidant
R2
R1
R3
Ar
O
+
base
Me
H
Ar
CN
O
R2
R1
NHC catalyst
NC
Me
R2
Within the realm of organic chemistry, aryl nitriles are fascinating
molecules to synthesis due to their perpetual utility as key
structural motifs in a wide array of medicinal agents, natural
products and functional materials.2 The highness of nitrile in aryl
nitriles is further explored by the transformations to comprehensive
range of functional groups such as amides, amines, aldehydes and
carboxylic acids.3 For structural diversification standpoint aryl
nitriles are highly sought by chemical community. Indeed, over the
decades there has been meteoric development in synthesis of aryl
nitriles. Canonical methods were devoted to TM catalyzed synthesis
which in general requires metal (metalloid) CN source and led to
heavy metal wastage. Even though some nonmetallic CN sources
have been developed, such sources are in its infancy stage.6 In this
regard, most recently, the groups of Wang et al. and Ye et al.
Ar
O
oxidant
+
base
R1
H
(b)
Ar
this work
O
CN
NC
O
R2
OEt
R2
base
+
R1
(c)
Greener Way R1
No catalyst/oxidant
Friendly (EtOH/CO2) byproducts
No column
Scheme 1. Benzannulation of conjugated carbonyls with crotonates.
(Scheme 1b) simultaneously came up with an NHC catalyzed The emergence of ynone as operable cycloaddition and annulation
synthesis of aryl nitriles following a protocol developed by Chi et al. partner is frequently witnessed in the recent literature. The ynones
for substituted benzenes (Scheme 1a).4 The success of these are arguably the most reactive substrates which can be
transformations eventually depends on NHC catalytic system. Not conveniently used as 2, 3 or 4 component partner to access
surprisingly, these findings have created a void to prosper protocol diversified molecular structures.5 In continuation of our interest in
which is environmentally more conscious and economically further finding new reactivities of functionalized alkyes,7 we recently
viable.
reported various novel annulations of ynones.5i, 7i-j We envisioned a
more promising and generic approach for aryl nitriles by further
exploring ynone. We thus report herein
a decarboxylative
annulation of ynones with α-cyano conjugated esters8 for the direct
access to multisubstituted aryl nitriles and fluorenes (Scheme 1c).
This methodology not only avoids requirement of special catalysts
and oxidants (to be the greener approach) but also produces
aDepartment of OSPC, CSIR-Indian Institute of Chemical Technology, Habsiguda,
Hyderabad 500007, India. E-mail: msreddy@iict.res.in
bAcademy of Scientific and Innovative Research, New Delhi 110001, India.
†Electronic
Supplementary
Information
(ESI)
available:
See
DOI: 10.1039/x0xx00000x
ǁ Contributed equally.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2012, 00, 1-3 | 1
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COMMUNICATION
Journal Name
complementary substitution patterns in products compared to substituted phenyl ynones (1n-q) were cleanly transformed to the
View Article Online
DOI: 10.1039/D0GC00608D
earlier protocols (Schemes 1a-b). An interesting mechanism corresponding adducts (3na-qa) in 77-85% yields. o-Brominated
involving an adjacent hydroxyl assisted decarboxylation is ynones (1r-s) suffered no impact of steric repulsion and produced
suggested.
the desired adducts in 63-67% yields. Terminal alkyne function in
3sa was successfully survived the reaction. Diynone 1t cleanly gave
the desired benzonitrile 3ta with ortho alkynyl function for further
modifications.
We began our investigation with ynone 1a and α-cyanocrotonate 2a
to optimize the conditions (Table 1). No product was observed
when the organic bases like DBU or DABCO and Brønsted base
NaOH were used in MeCN (entries 1-3). Pleasingly, the desired Table 2. Scope of ynones in benzannulation.
product was isolated in 20% yield with Cs2CO3. Other bases like
CN
O
NaOtBu and NaOEt produced 3a but in low yields (entries 5-7)
Ph
KtOBu (2 equiv)
Ph
O
NC
whereas KOtBu gave it in decent yield of 50% (entry 8). A thorough
screening of solvents with this base revealed that the best yield
(90%) was obtained in n-BuOH. The product was cleanly isolated by
filtering the contents through a small silica bed. No workup and
additional purification was required.
OEt
CH3
+
Ph
n-butanol, rt
R1
Ph
3aa-ma
1a-m
CN
2a
R1
60-90 min
CN
CN
Ph
Ph
Ph
Ph
R= H,
Ph
Ph
F
b
3aa
, 90% (83%)
Table 1. Optimization studies
3ba
R= Me,
R= Ph,
, 88%
, 81%
CN
O
3ca
3da
Ph
Ph
t
O
R= Bu,
, 82%
NC
OEt
CH3
3ea
R= ethylphenyl,
, 72%
3fa
+
Ph
Br
3ga
Ph
, 78%
CN
R
, 77%
CN
Ph
entry
1a
2a
3aa
Ph
CN
CN
yield(3aa)b
Ph
Ph
Ph
Ph
Ph
Ph
base
solvent
temp
Ph
Ph
--
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
DBU
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
1
--
DABCO
NaOH
Cs2CO3
NaOtBu
NaOEt
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
2
X
--
3
3ja
X= cyclohexyl,
, 66%
20
35
40
60
35
55
68
70
90
50
4
3ka
X= cyclopentyl,
, 58%
S
, 79%
MeO
OMe
5
3ha
3ia
, 70%
,83%
3ma
3la
X= butyl,
, 52%
6
aReaction conditions: 1 (0.5mmol), 2 (0.6 mmol), KOtBu (2 equiv) in n-BuOH,
at rt, open air. b yield in gram scale.
7
8
Expanding the scope, ynones with heteroaryls including indole,
furan and thiofuran were transformed well under standard
conditions to get hetero-arylated benzonitriles (3ua-wa) in 70-73%
yields.
EtOH
9
iPrOH
tBuOH
n-BuOH
THF
10
11
12
13
Table 3. Scope of ynones in benzannulation.
Reaction conditions: a(0.5 mmol) of , (0.6 mmol) of
1mmol of base in 3 mL solvent. bIsolated yields.
using
1a
2a
CN
O
R1
Ph
O
KtOBu (2 equiv)
n-butanol, rt
60-90 min
NC
Ph
R1
OEt
CH3
+
Ph
After establishing an optimized set of reaction conditons, we were
keen to explore the generality of this new benzannulation. We
initially headed to assess the scope of the alkyne terminal of ynone
(Table 2). Substrates containing phenyl group with alkyl (Me, Bu and
phenethyl) and phenyl substitution (1b-e) cleanly furnished the
desired adducts in 72-88% yields. Halo aryl (1f-g) and alkoxy (1h)
ynones also smoothly benzannulated with 2a to deliver the
expected products (3fa-ha) in 77-83% yields. Cyclohexenyl
benzonitrile 3ia was obtained in 70% yield from enynone 1i. Alkyl
(cyclohexyl, cyclopentyl and butyl) ynones (1j-l) were not
discriminated from aryl ynones in this benzannulation although the
products were obtained in slightly lower yields (52-66%).
Thiophenylated benzonitrile was 3ma similarly obtained from
corresponding ynone 1m in 79% yield. 3aa was obtained in 83%
yield when the reaction was conducted in a gram scale. We then
verified the reaction with substitution variation at carbonyl terminal
of ynone (Table 3). Alkyl (Me), alkoxy (OMe), halo (F and Cl)
1n-w
2
3na-3wa
Ph
R
CN
OMe
CN
CN
Ph
MeO
Ph
Br
Ph
3na
R= Me,
,83%
Br
3oa
, 85%
R= OMe,
R= F,
Ph
3pa
, 79%
, 77%
3ra
, 67%
Ph
Ph
3qa
R= Cl,
3sa
, 63%
Ph
CN
I
Ph
CN
Ph
CN
Ph
N
H
Ph
X
3ua
, 71%
3ta
,79%
3va
X= O,
X= S,
, 70%
3wa
, 73%
aReaction conditions: 1 (0.5mmol), 2 (0.6 mmol), KOtBu (2 equiv) in n-BuOH,
at rt, open air.
2 | J. Name., 2012, 00, 1-3
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COMMUNICATION
We next headed to test the reaction with variation of substitution
in α-cyanocrotonates (Table 4). Initially the β-aryl was subjected to
the change. Substrates with electron deficient cyano phenyl, chloro
phenyl and pi extended phenyl-phenyl group showed no resistance
to the transformation and produced the expected triaryl
benzonitriles (3ab-ad) in 72-82% yields. The products (3ae-ah) with
alkoxy groups (OPh, OMe, di-OMe, and -OCH2O-) were obtained in
excellent yields irrespective of the number or position of the
functions. Pyridyl group was successfully installed at C2 of
benzonitrile 3ai using β-pyridocrotonate 2i. Interestingly, 2-
ferrocenyl benzonitrile 3aj was obtained cleanly in 76% yield from
the corresponding starting material 2j.
α-cyanocrotonate system 4 so as to obtain highly interesting and
useful fluorenes (Table 5). Thus, treating 4a with ynone 1a under
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DOI: 10.1039/D0GC00608D
standard conditions cleanly resulted the cyanofluorene 5a in 71%
yield. Substrate scope for this new tricyclic system was then
studied. Different aryl/heteroaryl groups with varied substitution
were thus installed at C2 and C4 to get a wide range of
cyanofluorenes (5b-g) in good to excellent yields. Further, noncyclic
methyl crotonate 4h cleanly gave the tetrasubstituted benzonitrile
5h in 71% yield (Scheme 2).
Scheme 2. Tetrasubstitutedbenzonitrile through benzannulation.
O
CN
O
NC
Ph
Ph
Ph
KtOBu (2 equiv)
OEt
+
Ph
Table 4. Scope of α-CyanoCrotonates in benzannulation.
CH3
Et
n-butanol, rt
Ph
CN
O
Ph
75 min
O
4h
1a
Ph
R
NC
KtOBu (2 equiv)
5h
, 71%
OEt
+
Ph
A tentative mechanism for the title benzannulation is depicted in
Scheme 3. A base mediated Michael addition of crotonate on ynone
triggered the annulation (A). The Michael adduct underwent a
selective vinylogous addition on ketone than on ester due to high
n-butanol, rt
R
R
Me
2b-i
Ph
1a
60-90 min
Ph
3ab-aj
OMe
CN
CN
CN
Ph
Ph
Ph
, 78%
OMe
electron deficiency. The resulted cycle
B
underwent
a
3ab
R= Cl,
OMe
3af
decarboxylation using the assistance of neighboring hydroxy group
(C) to afford the final product 3&5.
3ac
R= CN,
R= Ph,
, 72%
, 82%
3ag
, 85%
Ph
Ph
, 80%
3ad
Ph
3ae
R= OPh,
, 84%
Scheme 3. Mechanistic Proposal.
CN
O
CN
N
CN
Ph
O
O
Ph
Ph
O
Fe
NC
Ar1
OEt
Ar1 OH
O
base
Ph
3ai
, 75%
3ah
, 80%
R1
Ar
Ph
3aj
Ph
, 76%
OEt
R
CN
Ar
aReaction conditions: 1 (0.5mmol), 2 (0.6 mmol), KOtBu (2 equiv) in n-BuOH,
O
H
R1
A
at rt, open air.
Ar1
O
B
R
R1
1
Finally, to further expand the scope of the reaction, impact of
substitution at the methyl group of crotonate was studied. We
initially chose indanone based
EtOH
O
CN
Ar
Table 5. Synthesis of Cynofluorenes.
Ar1
O
HC
OEt
NC
O
R1
R
NC
O
CN
Ar
KtOBu (2 equiv)
OEt
Ar1
R1
R1
+
base
CN
n-butanol, rt
R2
1
CN
Ar
R
C
4
R2
5a-h
30-45 min
Ar
H2C
O
NC
NC
NC
R1
Ph
Ph
CO2
OEt
Ph
R
2
4
R
3
or
5
or
To demonstrate the utility of this novel benzannulation, some of
the obtained products were derivatized to interesting adducts
(Scheme 4). Nitrile 3ba was converted to carboximidamide2e 6 in
72% yield using hydroxylamine hydrate in EtOH. Indolylbenzonitrile
7 using Cs2CO3. Further,
cyanofluorene 4c was oxidized to fluorenone9e 8 using NaH/air.
Ph
5b
, 70%
NC
5c
5a
, 73%
MeO
, 71%
NC
OMe
Br
Ph
Cl
X
3ua was cyclized to amidine2f
NC
Scheme 4. Derivatization of title compounds.
Ph
Ph
5d
X = O, , 62%
5e
X = S, , 60%
Ph
5g
, 67%
5f
, 69%
aReaction conditions: 1 (0.5mmol), 2 (0.6 mmol), KOtBu (2 equiv) in n-BuOH,
at rt, open air.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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COMMUNICATION
Journal Name
Ph
Lett., 2016, 18, 2212-2215; (c) C.-L. Zhang, Z.-H. Gao, Z.-Q.
NH2
N
Ph
Liang, and S. Ye, Adv. Synth. Catal., 2016, 358, 2V8ie6w2-A2rt8ic6le6O.nline
DOI: 10.1039/D0GC00608D
CN
Ph
NH2OH.H2O (2 equiv)
EtOH, 70 o
5
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OH
Ph
C
3ba
6
, 72%
H3C
H3C
NH
I
NC
Ph
Ph
Ph
Cs2CO3 (1.2 equiv)
THF, 60 o
N
C
N
H
3ua
Ph
7
, 85%
Ph
I
Ph
CN
CN
NaH (2 equiv)
THF, air, rt
MeO
MeO
O
4c
OMe
OMe
8
, 80%
6
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In conclusion, we demonstrated a most feasible assembly of highly
and selectively substituted benzonitriles and cyanofluorenes from
readily available ynones and cyanocrotonates under extremely
greener conditions. A four point diversity was successfully shown to
get a wide spectrum of the substituted adducts. A plausible
mechanism
through
a
neighboring
hydroxyl
assisted
decarboxylation is suggested. Synthetic applicability of the title
compounds has been accomplished successfully.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
MKRS thank CSIR and AN thank UGC for the fellowships. We thank
analytical division CSIR-IICT for the analytical support. We gratefully
acknowledge the financial support by DST (EMR/2017/0002413).
We thank Director CSIR-IICT for the constant encouragement and
support (IICT/Pubs./2020/083)
7
Notes and references
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Green Chemistry
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Journal Name
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DOI: 10.1039/D0GC00608D
COMMUNICATION
Base Mediated Benzannulation of α-Cyano Crotonates with Ynones:
Facile Synthesis of Benzonitriles and Fluorenes
Maneesh Kumar Reddy Singam, Attunuri Nagireddy and Maddi Sridhar Reddy*
O
CN
NC
O
R2
OEt
KOtBu
R2
+
R1
n-butanol
rt
1 40 examples
R
No catalyst/oxidant
Friendly (EtOH/CO2) byproducts
No column
Benzonitriles and cyanofluorenes are rapidly obtained via [3 + 3] benzannulation of readily available alkynones and α-
cyanocrotonates using KOtBu as the only reagent where EtOH (and CO2) is the only by-product.
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