Catalyst-free hydroarylation of in situ generated ortho-quinone methide (o-QM) with electron rich arenes in water

Article abstract of DOI:10.1039/c2gc35741k

We report the first C-H hydroarylation of in situ generated ortho-quinone methides with electron-rich arenes. The reaction takes place in water without any catalyst, and is highly regioselective. Ionic and non-ionic additives provide an increase in reaction rate, yield, and regioselectivity.

Full text of DOI:10.1039/c2gc35741k

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Catalyst-free hydroarylation of in situ generated ortho-Quinone methide
(o-QM) with electron rich arenes in water
Atul Kumar,* Mukesh Kumar and Maneesh Kumar Gupta
Received (in XXX, XXX) Xth XXXXXXXXX 200X, Accepted Xth XXXXXXXXX 200X
First published on the web Xth XXXXXXXXX 200X
DOI: 10.1039/b000000x
5
We report the first C-H hydroarylation of in situ generated
Intramolecular hydroarylation with electron rich arene like tertiary aromatic amine
ortho-quinone methides with electron-rich arenes. The reaction
takes place in water without any catalyst, and is highly
10 regioselective. Ionic and non-ionic additives provide an increase
in reaction rate, yield, and regioselectivity.
Et2N
O
O
Et2N
O
H
O
cat. Au(III)
Ethanol
Ph
Ph
Quinone methides are used ubiquitously as reactive
intermediates1 for the synthesis of complex natural products,2
morden materials,3 fine chemicals, and pharmaceuticals.4 In
15 particular, oꢀquinone methides (oꢀQMs) are involved in 1,4
Michaelꢀtype additions,5 azaꢀMichael reactions,6 DielsꢀAlder,
Michael type hydroarylation with electron deficient alkene
R
PdCl2
AcOH
R
NO2
NO2
Ar4Sn
Ar
Intermolecular Michael type hydroarylation of in situ generated
ortho-Quinone methides (o-QMs) with tertiary aromatic amines
and heteroꢀDielsꢀAlder cycloadditions.7
A
number of
O
O
N
biologically active natural products are also synthesized via in
situ generated oꢀQMs.8 Recently, furan annulated heterocycles
20 like furocoumarins and furoquinolones have been synthesized
via [4+1] cycloaddition of in situ generated oꢀQMs and
isocyanides.9 oꢀQMs derived from 4ꢀhydroxycoumarin
undergo [4+2] cycloaddition reaction with pentafulvenes to
afford pyranocoumarin and pyranopyrone.10
O
OH
N
H
CH2O
OH
Catalyst free, water
O
O
O
O
rt
Ortho-Quinone methides (o-QMs)
50
Fig. 1 Hydroarylation of alkene and alkyne
25 Hydroarylation involves direct addition of electron rich aryl
CꢀH bonds to alkenes and alkynes in intermolecular or
intramolecular manner and has been considered as one of the
most fundamental strategies for the construction of CꢀC
bonds.11 In Michaelꢀtype hydroarylations,12 electronꢀpoor
30 alkenes such as nitroalkenes and α, βꢀunsaturated carbonyl
compounds react with electronꢀrich arenes so that a CꢀH bond
is converted into a CꢀC bond (Fig. 1). However, these
reactions require expensive metal catalysts or strong acids in
organic solvents. Hence, it is desirable to develop catalystꢀ
35 free alternatives. Moreover, to the best of our knowledge, the
direct CꢀH hydroarylation of in situ generated oꢀQMs with
electron rich arenes like tertꢀaryl amines is still unknown.
In continuation of our work on green trasformation,13 herein
we highlight the direct hydroarylation of bioactive
40 heterocycles such as 4ꢀhydroxycoumarins, 4ꢀhydroxypyrones
and 2ꢀphenylindoles with N,Nꢀdialkylaminoarenes via in situ
generated oꢀquinone methides in water under catalystꢀfree
conditions (Scheme 1).
55
Scheme 1. Synthesis of 3ꢀSubstituted 4ꢀhydroxycoumarin
The heterocycles such as coumarins, pyrones and indoles
60 are key structural units in many natural products, and wide
range of pharmaceuticals14 like Warfarin,15 Phenprocoumon,
16 5ꢀMeOꢀDMT,17 and PNUꢀ96988.18
Various methods have been reported for the preparation of 3ꢀ
substituted coumarin, pyrone and 2ꢀphenylindole using
65 several metal, Lewis and Brønsted acid catalysts.19 Recently,
G. Palmisano et al. have reported Ultrasoundꢀenhanced
synthesis of 3ꢀArylcoumarin via sequential Knoevenagelꢀ
a Medicinal and Process Chemistry Division, Central Drug Research
Institute, CSIR, Lucknow India.
45 Fax: 91-522 2623405; Tel: 91-522-2612411,
E-mail: dratulsax@gmail.com /dratulkumarlab@gmail.com
† Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
reductive
Michael
addition
with
Hantzsch
1,4ꢀ
dihydropyridine.20
70
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We have interested to develop 3ꢀsubstituted heterocycles via 35 transformation was performed in aqueous medium under
direct hydroarylation with electronꢀrich arenes. In the
preliminary study, various catalysts and solvents were tested
for the CꢀH hydroarylation of in situ generated oꢀquinone
methides (oꢀQMs) derived from 4ꢀhydroxycoumarin and
catalystꢀfree condition (Table 1, entry 15).
Water was thus chosen for further investigations since it is
readily available, environmentally benign, safe, cheap, nonꢀ
flammable and non toxic. Furthermore, water displays unique
5
formaldehyde with tertiary aryl amines at room temperature. 40 reactivity21 and selectivity22 that cannot be obtained in
The results of optimization of reaction conditions are shown
in Table 1.
conventional organic solvents.
Table 2 Study of hydrophobic effect of ionic and nonꢀionic additives on
intermolecular hydroarylation of oꢀQMs with arenes in watera
Table 1 Optimization of the reaction conditionsa
Entry
Solvent
Time (h)
Yield
Yield 5a
Entry
Catalyst
(20 mol %)
Solvent
Yield
Yield
4a (%)c
(%)c
4a (%)e
5a (%)e
1
2
3
4
5
6
7
8
Acetic acid
Boric acid
PTSA
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
85
70
84
85
76
71
74
76
1
2b
3
H2O
6
72
50
74
78
79
81
40
74
20
40
10
5
H2O
4
1 M aq. LiCl
1.5 M aq. LiCl
2 M aq. LiCl
2.5 M aq. LiCl
2.5 M aq. LiCl
0.5 M aq. Glucose
3.5
2.2
1.5
1.2
1.0
4.5
TFA
4
ZnCl2
5
traces
ꢀ
CuSO4
6
7b
Copper triflate
Zinc triflate
50
10
8
9
10
11b
12c
LꢀProline
Catalyst free
Ethanol
Ethanol
25
40
70
60
9
10
11
1 M aq. Glucose
2.5 M aq. Glucose
2.5 M aq. NaCl
3
3
4.5
76
75
70
10
12
22
Catalyst free
Catalyst free
Ethanol
CH3CN
20
10
70
80
12
2 M aq. Urea
7
60
35
a
13c
14c
15d
Catalyst free
Catalyst free
Catalyst free
DCM
THF
Trace
Trace
72
90
85
20
Reaction conditions: 4ꢀhydroxycoumarin (1 mmol), formaldehyde (2
45 mmol) and N,Nꢀdialkylaniline, (1 mmol) in 5 mL of solvent at room
temperature. b Refluxed. c Isolated yields.
Water
a
10 Reaction conditions: 4ꢀhydroxycoumarin (1 mmol), formaldehyde (2
mmol) and N,Nꢀdialkylaniline (1 mmol) in 5 mL of solvent at room
temperature for 8 h. b Refluxed. c At room temperature for 12 h. d At room
temperture for 6 h. e Isolated yields.
We carried out the same reaction in water using ionic and
nonꢀionic additives to study the effect of hydrophobicity on
50 the reaction. The yield of the desired product 4a increased
significantly when reaction was carried out in water in the
presence of proꢀhydrophobic additives like LiCl, glucose and
NaCl.23 The use of different concentrations of proꢀ
hydrophobic additives have been studied and results are given
55 in Table 2.
Increasing the concentration of LiCl resulted in increased
yield of the desired products 4a.The best result was obtained
using a 2.5 M aq. solution of LiCl, with an exclusive
formation of 4a (Table 2, entry 6). Likewise, aq. glucose
60 (nonꢀionic hydrophobic additive) afforded better results at
high concentrations, ranging from 0.5 M to 2.5 M24 (Table 2,
entries 8, 9 and 10). No significant improvement was gained
in the yield of 4a when we employed 2.5 M aq. NaCl as well
as 2.0 M aq. urea solution (Table 2, entries 11 and 12
65 respectively). The reaction was also performed at various
temperatures and best results were obtained at room
temperature, as dimerized product 5a prevailed under reflux
(Table 2, entry 7).
15 Firstly, the reaction was carried out in ethanol at room
temperature in the presence of catalytic amounts of some
Brønsted acids: acetic acid, pꢀtoluenesulfonic acid (PTSA),
boric acid, and trifluoroacetic acid (TFA). Unfortunately,
under these conditions the major isolated product was dimer
20 5a instead of the desired product 4a (Table 1, entries 1 to 4).
The same result was obtained using Lewis acids such as
ZnCl2, CuSO4, copper triflate, and zinc triflate (Table 1,
entries 5 to 8).
We also screened organocatalysts such as Lꢀproline, which
25 gave only 25% yield for the desired 4a (Table 1, entry 9). It is
surprising that an enhanced yield of 4a was observed under
catalystꢀfree condition (Table 1, entry 10). On the contrary,
decreased yield of 4a was obtained under reflux without any
catalyst (Table 1, entry 11). When reactions were performed
30 in different solvents such as acetonitrile, dichloromethane,
and tetrahydrofuran under catalystꢀfree conditions, the
reaction was completed in 12 h with prevalent formation of
5a. (Table 1, entries 12, 13 and 14). On the contrary,
compound 4a was formed in good yield when the
To explore the scope and limitations of this protocol, we
70 investigated the reaction of 4ꢀhydroxycoumarin with
formaldehyde and tertiary aromatic amines 4a-h under
optimized reaction conditions (Table 3).
2
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Table 3 Intermolecular Hydroarylation of coumarins oꢀQMs with tertiary
Table 5 Hydroarylation of in situ generated 3ꢀmethyleneꢀ2ꢀphenylꢀ3Hꢀ
aromatic amines a,b
20 indolium with tertꢀaryl amines a,b
5
a Reaction conditions: 4ꢀhydroxycoumarin (1 mmol), formaldehyde (2
mmol) and N,Nꢀdialkylaniline (1 mmol) in 5 mL of 2.5 M aq. solution of
LiCl at room temperature under catalystꢀfree condition. bIsolated yield.
a Reaction conditions: 2ꢀphenylindole (1 mmol), formaldehyde (2 mmol)
and N, Nꢀdialkylaniline (1 mmol) in 5 mL of 2.5 M aq. solution of LiCl
25 at room temperature under catalystꢀfree condition. bIsolated yield.
We also synthesized a chemical library of C3ꢀalkylated 4ꢀ
hydroxypyrones 7a-d and C3ꢀalkylated 2ꢀphenylindoles 9a-f
One of the possibly reason of regioselectivity is the steric
hindrance of Nꢀalkyl group and ortho hydrogen of N,Nꢀ
dialkylanilines, which provides para selectivity. Similar
results were reported by Jørgensen et.al for the synthesis of
30 optically active aromatic mandelic acid esters by the reaction
of glyoxylate with N,Nꢀdialkylanilines.25
10 in good to excellent yields (Table 4 and 5). It is notable that in
all the cases we obtained exclusively para substituted
products.
Table 4 Synthesis of Cꢀ3ꢀalkylated 4ꢀhydroxypyrone derivatives a,b
Conclusions
In summary, we have developed a novel green process for
intermolecular hydroarylation of in situ generated oꢀquinone
35 methides (oꢀQMs) with electron rich arenes in aqueous
medium under catalystꢀfree condition at room temperature.
The reaction is efficient and highly regioselective. We hope
this protocol will be beneficial for the green synthesis of other
bioactive agents.
40 Experimental
General procedure for the preparation of C3-alkylated 4-
hydroxycoumarins (4a-h). 4ꢀHydroxycoumarin (1 mmol),
formaldehyde (2 mmol) and N,Nꢀdimethylaniline (1 mmol) in
5 mL of 2.5 M aq. solution of LiCl were taken in a roundꢀ
45 bottom flask equipped with a magnetic stirrer. The reaction
mixture was then stirred at room temperature for an
appropriate time as given in Table 3 and the progress of the
reaction was monitored by TLC. After completion of the
reaction, the reaction mixture was extracted with ethyl
50 acetate. Evaporation of the solvent gave a crude product
15
a
Reaction conditions: 4ꢀhydroxypyrone (1 mmol), formaldehyde (2
mmol) and N, Nꢀdialkylaniline (1 mmol) in 5 mL of 2.5 M aq. solution of
LiCl at room temperature under catalystꢀfree condition. b Isolated yield.
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60
Quinone Methides., Wiley Series of Reactive Intermediates in
Chemistry and Biology; John Wiley& Sons, Inc.; NJ,
Hoboken, 2009, Vol.1, p 180.
which was purified by column chromatography (silica gel,
ethyl acetate:hexane).
General procedure for the synthesis of C3-alkylated 4-
hydroxypyrones (7a-d). 4ꢀHydroxypyrone (1 mmol),
formaldehyde (2 mmol) and N,Nꢀdimethylaniline (1 mmol) in
5 mL of 2.5 M aq. solution of LiCl were taken in a roundꢀ
bottom flask equipped with a magnetic stirrer. The reaction
mixture was then stirred at room temperature for an
appropriate time as given in Table 4 and the progress of the
10 reaction was monitored by TLC. After completion of the
reaction, the reaction mixture was extracted with ethyl
acetate. Evaporation of the solvent gave a crude product
which was purified by column chromatography (silica gel,
ethyl acetate:hexane).
15 General procedure for the preparation of C3-alkylated 2-
phenylindole (9a-f). 2ꢀphenylindole (1 mmol), formaldehyde
(2 mmol) and N,Nꢀdimethylaniline (1 mmol) in 5 mL of 2.5 M
aq. solution of LiCl were taken in a roundꢀbottom flask
equipped with a magnetic stirrer. The reaction mixture was
20 then stirred at room temperature for an appropriate time as
given in Table 5 and the progress of the reaction was
monitored by TLC. After completion of the reaction, the
reaction mixture was extracted with ethyl acetate. Evaporation
of the solvent gave a crude product which was purified by
25 column chromatography (silica gel, ethyl acetate:hexane).
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Authors (MK and MKG) are thankful to CSIR UGC New
Delhi for the award of SRF. We also gratefully acknowledge
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Graphical Abstract
Catalyst-free hydroarylation of in situ generated ortho-Quinone methide (o-QM) with electron
rich arenes in water
Atul Kumar,* Mukesh Kumar and Maneesh Kumar Gupta
We report the first C-H hydroarylation of in situ generated ortho-quinone methides with electron-rich
arenes. The reaction takes place in water without any catalyst, and is highly regioselective. Ionic and non-
ionic additives provide an increase in reaction rate, yield, and regioselectivity.