Metal-free direct: C -arylation of 1,3-dicarbonyl compounds and ethyl cyanoacetate: A platform to access diverse arrays of meta -functionalized phenols

Article abstract of DOI:10.1039/c8cc06235h

A base mediated, highly convenient strategy for the direct C-arylation of 1,3-dicarbonyls and cyanoacetate with various phenol derivatives as aryl partners is presented. The present work excels in forming a C-C bond at the meta-position of the phenols, which is traditionally challenging to functionalize. This protocol further leads the way to have scalable, straightforward access to phenol assimilated heterocycles which have powerful applications both in synthetic chemistry and medicinal research.

Full text of DOI:10.1039/c8cc06235h

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
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Metal-free direct C-arylation of 1,3-dicarbonyl compounds and
ethyl cyanoacetate: A platform to access diverse array of meta-
functionalized phenols
Received 00th January 20xx,
Accepted 00th January 20xx
Neha Taneja, Rama Krishna Peddinti*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
provide α-arylated products. If this is realised, it would pave a
Base mediated, highly convenient strategy for the direct C-
arylation of 1,3-dicarbonyls and cyanoacetate with various phenol way to highly prudent methodology to furnish meta-
derivatives as aryl partners is presented. The present work excel in
forming C–C bond at the meta-position of the phenols which is
traditionally challenging to functionalize. This protocol further
leads the way to have scalable, straightforward access to phenol
assimilated heterocycles which have powerful applications both in
synthetic chemistry and medicinal research.
functionalized phenols. The synthesis of meta-substituted
phenols possesses a significant challenge of bypassing the
normal ortho/para directing group effect of hydroxyl
functionality. Recent reported methods for meta-
functionalization are mainly based on transition metal catalysis
and template-based strategies.7 Although efficient, these
methods often require lengthy synthetic routes, high
temperature and prolonged reaction time.
C-arylation has drawn extensive and revolutionized attention
as one of the significant methods for the C–C bond formation,
which provides an easy access to complex organic frameworks
that manifest a wide range of pharmacological activities.1 The
chemistry of 1,3-diones is a cornerstone of organic synthesis
by virtue of their eloquent reactivity of functional group. The
enolate arylation of 1,3-dicarbonyl compounds and ethyl
cyanoacetate were usually carried out by transition metals2
but rarely by organocatalysts.3 Particularly, Stoltz4a et al.
isolated the small amount of C-arylation product during aryne
insertion reaction into the C–H σ−bond of 1,3-diones. Wang4b
Herein, we disclose our results on base-mediated C-
arylation of 1,3-diones and cyanoacetate with commercially
available, innocuous 2-methoxyphenols as aryl partners. These
phenols can be easily dearomatized to the corresponding
benzoquinone derivatives, also known as masked o-
benzoquinones (MOBs). Thus in situ generated conjugated
cyclohexadienones were then subjected to Michael attack by
C–H activated acids to access meta-selective C–H
functionalized products under very mild conditions. Further
remarkability of this approach has been proven by extending it
for the synthesis of various phenol functionalized N- and O-
heterocyclic scaffolds viz., pyrazole, isoxazole, coumarin, and
triazolone derivatives by utilizing β-diketones as essential
building blocks. Some of these heterocyclic compounds that
are counted among the most potent biologically active
scaffolds8–11 are shown in Figure 1.
et al. studied the α-arylation of dicarbonyls with CuBr-
trichloroacetic acid as a catalyst. Owning to the potential
application5 of 2-aryl 1,3-dicarbonyls,
practical and strategy for the direct
a
convenient and
α-arylation of 1,3-
dicarbonyl compounds and cyanoacetates is still challenging.
During our studies on dearomatization of phenols, we
found that the in situ generated reactive intermediates6
bearing rich functional groups could potentially participate in
various addition reactions. It occurred to us that the addition
of 1,3-dicarbonyl compounds and cyanoacetate to 2-methoxy-
phenols-derived ortho-benzoquinone monoketals would
OH
MeO
OH
O
OMe
N
O
O
N
H
P1
OH
H
N
O
N
MeO
MeO
O
OMe
O
N
N
N
H
HO Ph
BET inhibitor
MeO
OMe
OMe
CA4 analogue
OMe
anti-Alzheimer agent
TACE inhibitor
(antitumor agent)
(antitumor agent)
Fig. 1 Pharmaceutically active agents containing heterocyclic scaffolds
.
The feasibility of the enolate arylation reaction of 1,3-
diones is investigated by attempting the reaction between 4-
bromo-2-methoxyphenol (1a) and acetylacetone (3). In the
initial step, the dearomatization of 4-bromoguaiacol was
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Table 2 Reactions of substituted guaiacols with various 1,3-dicarbonyl compounds 3–8a
carried out with diacetoxyiodobenzene (DIB, 1.2 equiv) in
methanol to generate o-benzoquinone monoketal 2a. This
transformation then facilitated the Michael addition of C–H
activated acid
3 in the presence of Et3N (1 equiv) to enable the
synthesis of product 11a with desired substitution in 60% yield
(Table 1, entry 1). The base additive was found to be crucial for
the reaction (entry 2). Fortified by above results, other
reaction parameters such as the choice of base, solvent and
temperature were screened. It was observed that with most of
the commonly used bases such as Cs2CO3, K2CO3, NaOH,
KOtBu, DABCO, the reaction went on to completion
successfully (entries 3–7). Among these, Et3N was proved to be
efficient base for this enolate arylation. In order to circumvent
the nucleophilic attack of MeOH on MOB, after dearomati-
zation event, methanol was first removed from the reaction
mixture by rotatory evaporator in vacuo and the reaction was
continued by diluting the residue in another solvent followed
by the addition of base and dicarbonyl compound (entries 8–
11). To our delight, when the reaction was carried out in
toluene, the arylated product 11a was obtained in enhanced
yield of 62% (entry 11). An increment of the product yield was
observed by increasing the amount of Et3N to 2.0 equiv
(entries 12 and 13). However, increasing the stoichiometry of
acetylacetone also showed a positive effect on the yield
(entries 14 and 15). However, elevating the temperature has
no substantial effect on the reaction (entry 16).
1,3-dicarbonyl
compound
Entry
1
1
Time
3 h
Yield (%)b
Keto form
Enol form
O
O
1a
–
11a/72
3
O
O
2
3
1a
1a
12a/71c
3 h
5 h
OEt
4
O
O
O
13a/68
14a/80
–
–
–
EtO
Ph
OEt
OEt
5
O
4
5
1a
1a
6 h
3 h
6
15a/82
O
O
O
O
7
6
1a
16a/86
–
4 h
Table 1 Screening of reaction conditionsa
8
7
1c
1b
1c
1b
1b
1d
1d
1d
1d
1d
1e
1e
1e
1e
1e
1f
3
5
6
7
8
3
5
6
7
8
3
5
6
7
8
3
6
5
3 h
6 h
d11c/71
13b/65
d14c/76
–
–
8
–
9
5 h
–
10
11
12
13
14
15
16
17e
18e
19e
20e
21e
22
23
24
2 h
15b/80
3 h
16b/85
11d/78
13d/Traces
–
–
50 min
2 h
Acetylacetone
(equiv)
Base
(1 equiv)
Yieldb
(%)
Entry
Solvent
2 h
14d/80c
3 h
15d/85
–
–
1
2
1
1
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
DCM
Et3N
-
60
nr
4 h
16d/86
KOtBu
K2CO3
Cs2CO3
NaOH
DABCO
Et3N
61
58
63
nd
55
40
55
50
62
65
68
72
73
61
4 h
11e/60
13e/61
14e/62
–
–
3
1
7 h
–
4
1
6 h
–
15e/70
16e/76
–
5
1
5 h
6
1
5 h
–
7
1
4 h
11f/81
14f/74
8
1
1f
5 h
–
9
1
CAN
Et3N
1g
6 h
13g/52c
10
11
12 c
13 d
14 d
15 d
16d, e
1
THF
Et3N
a Reaction conditions: 1 (0.3 mmol), DIB (0.36 mmol), 1,3-dicarbonyl compound
1
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Et3N
b
1
Et3N
(3–6, 0.45 mmol), Et3N (0.67 mmol), solvent (3 mL) stirred at rt. Pure and
1
Et3N
isolated yields. c Combined yield of both keto and enols forms. d Michael addition
took place at C-5 of 4-iodo MOB 2c. e Reaction was performed at 80 oC.
1.2
2.0
1.2
Et3N
Et3N
Having established the optimum reaction conditions, we were
keen to study the generality of this protocol. A number of
acyclic and cyclic dicarbonyls were subjected to react with
variously substituted 2-methoxyphenols under these
Et3N
a Reaction conditions: 1a (0.30 mmol), DIB (0.36 mmol), acetylacetone (3, 0.45
mmol), base, solvent (3 mL) stirred at rt, in air for 3 h. b Pure and isolated yields.
nd: Not determined. nr: No reaction. c Performed with 1.5 equiv of Et3N at room
d
temperature for 24 h. Performed with 2.0 equiv of Et3N at room temperature
for 24 h. e Carried out with 1.5 equiv of Et3N at 80 oC.
conditions. Thus the reactions of dicarbonyls
3–8 and 2-
methoxyphenols 1a–1e furnished the arylated meta-
2 | J. Name., 2012, 00, 1-3
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functionalized phenols successfully in good to high yields the meta-substituted product 18a was obtained in 78%
revealing the validity of standard established reaction isolated yield. All the substrates reacted well under these
conditions for
the alicyclic 1,3-dicarbonyl compounds afforded the products derivatives (Scheme 2) in good yields.
11a e–14a in good to high yields. A minor drop in the yield of
compounds 13a arising from less acidic diethyl malonate
) may be noted. A dynamic equilibrium between keto and
α-arylation of 1,3-diones (Table 2). As shown, conditions and furnished the substituted ethyl cyanoacetate
O
O
-
-e
O
O
O
,b
,e
OH
OH
OH
9
PhI(OAc)2
OMe
OMe
R1
OH
(
5
R1
OMe
R1
OMe
MeOH, rt
10 min
Et3N, toluene
R2
R2
enol forms has been observed in case of compound 12a and
14d. Furthermore, the cyclohexadienone 2e derived from 2,3-
dimethoxyphenol (1e) is less reactive and hence the Michael
addition was performed at 80 oC (entries 17–21). Enthrallingly,
R2
3−5 h, rt
17a,b,d,e
2
isolated yield
78%
1
R1 = Br, R2 = H (17a)
R1= Cl, R2 = H (17b)
R1= CH3,R2 = H (17d)
R1= Br (a), Cl (b), Me (d), R2 = H
R1 = H, R2 = OMe (e)
75%
88%
R1 = OCH3, R2 = OCH3 (17e) 75%
cyclic 1,3-diketones
7 and 8 can also be employed in this base
Previous work
OMOM
mediated transformation to furnish the desired products
15a,b,d,e and 16a,b,d,e, respectively, in good to excellent
yields of 70–86%. The vanillin-derived acetal 1f worked equally
good and furnished 11f and 12f (entries 22 and 23). The
electron-withdrawing phenyl group in 1g resulted in the
formation of 13g in a reduced yield of 52% (entry 24). The
current protocol did not work with p-methoxy phenols.
It was envisioned that positions 3 and 5 of in situ generated
MOBs are susceptible for nucleophilic attack. Interestingly, the
site for Michael attack in this transformation is directed by the
substituent present on cyclohexadienone system. Unlike the
reaction of 4-bromo, 4-chloro, 4-methyl and 5-methoxy
guaiacol derivatives 1a,b,d,e, where the nucleophiles attacked
on C-3 of the corresponding MOBs, the reaction of 4-
iodoguaiacol (1c) proceeded via Michael attack on C-5 of its
oxidized species 2c to furnish the products 11c and 14c in good
yields.
MeO
MeO
O
O
MeO
MeO
O
O
B(OH)2
(i)
OH
(ii)
MeO
OH
OH
OH
OMe
OMOM
Prefunctionalized substartes
(i) Pb(OAc)4, Hg(OAc)2, CHCl3, 40 oC, overnight, (ii) Pyridine, CHCl3, 60 oC.
Scheme 1 Reactions of 2-methoxyphenol derivatives with 4-hydroxycoumarin.
It is worth mentioning here that the arylated ethyl cyanoacetates
worked as excellent starting materials to generate stable
quaternary stereocenter via C–C bond formation13
.
O
O
OEt
NC
OEt
OH
O
OH
PhI(OAc)2
NC
10
OMe
R1
R1
OMe
R1
OMe
MeOH, rt
10 min
Et3N, ACN
80 oC, 3−6 h
OMe
R1 = Br, 18a/78%
R1 = Cl, 18b/80%
R1 = Me, 18d/88%
1
2
R1= Br (a), Cl (b), Me (d)
Scheme 2 Reactions of guaiacol derivatives with ethyl cyanoacetate.
As 1,3-diketones are widely known to show commendable
keto-enol tautomerism, it is worth to mention the effect of
substituents on phenols and ketones on the tautomerism of
the corresponding products. Thus, the reaction of 2-methoxy-
Having successfully developed an efficient protocol for
meta-substituted phenols, we turned our focus on the utility of
these obtained compounds to access phenol functionalized
novel heterocyclic scaffolds in one-pot manner. Condensation
4-methylphenol (1d) with 6 and 9 under the optimal conditions
of α-arylated diketones with phenylhydrazine and
hydroxylamine in presence of iodine led to the formation of
furnished the products 14d and 17d as a 3:1 mixture of keto
and enol tautomers. It was observed that pronucleophiles such
corresponding pyrazoles 19
–
22 and isoxazole 23, respectively,
as diethyl malonate (5) provided products predominately in
in high yields (Scheme 3).
keto form, whereas ethyl acetoacetate (
product dominating enol form.
4) furnished the
R4
(iii) PhNHNH2
I2, EtOH, 80 o
5−6 h
N
C
Ph N
OH
Spurred by the great synthetic medicinal interest of
substituted coumarin, especially benzopyranocoumarins for
the treatment of neurodegenerative diseases such as
Alzheimer’s disease, the versatility of this approach was
R3
R1
OMe
OH
R2 = H
Isolated
yield
R1
R1
Br
R3 R4
CH3 CH3 (19) 78%
CH3 CH3 CH3 (20) 80%
Br CH3 OEt (21) 72%
CH3 Ph OEt (22) 75%
OMe
(i) PhI(OAc)2
MeOH, rt
R2
extended to the 4-hydroxycoumarin (
the reaction of substituted guaiacols with
established conditions. Delightfully, all the products 17a,b
9
). Thus, we carried out
under previously
d,e
(ii) Et3N
toluene, rt
O
O
9
R1 = H
R4
(iii) NH2OH
I2, EtOH
80 oC, 5 h
R3
,
N
O
OH
obtained in excellent yields of 75–88% (Scheme 1). These
compounds are quite similar to the precursors of
benzopyranocoumarins, worked as potent anti-Alzeimer
agents and were prepared through metal catalysis starting
from pre-functionalized substrates and in multi-step
processes12 (Scheme 1).
OMe
OMe
23 (81%)
Previous approach
R
Ar
N
N
After this, we stepped ahead to explore the reactivity of
PinB
PinB
O
O
N
Cross-coupling
Cycloaddition
160 oC, 24 h
N
N
ethyl cyanoacetate
(10). The initial attempts for meta-
XPhosPdG2 (10%)
Na2CO3, 80 oC, 16 h
DME : H2O (1:1)
N
Ar
substitution with optimized reaction conditions were
unsuccessful due to its low reactivity. However, when we
o
performed the reaction of 1a with 10 in acetonitrile at 80 C,
Ar
R
R
HO
OMe
Scheme 3 Synthesis of phenol substituted pyrazoles and oxazoles
.
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drugs, fabrics, plastics, lubricants and fertilizers.16 The cyano
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Acknowledgements
This work was generously supported by the Science and
Engineering Research Board (SERB, research grant no.
EMR/2017/000174). We thank DST-FIST program for the HRMS
facility. NT thanks MHRD for a research fellowship.
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