Copper-Assisted Synthesis of 2-Hydroxyphenyl-1,2-diones from Phenols and 2-Oxoaldehydes

Article abstract of DOI:10.1002/ejoc.201501423

An efficient copper(II)-catalyzed protocol for the ortho-functionalization of phenols was developed. A wide variety of 2-oxoaldehydes and phenols were tolerated, and the corresponding 2-hydroxyphenyl-1,2-diones were afforded in appreciable yields.

Full text of DOI:10.1002/ejoc.201501423

DOI: 10.1002/ejoc.201501423
Communication
1,2-Diones
Copper-Assisted Synthesis of 2-Hydroxyphenyl-1,2-diones from
Phenols and 2-Oxoaldehydes
Narsaiah Battini,[a,b] Satyanarayana Battula,[a,b] and Qazi Naveed Ahmed*[a,b]
Abstract: An efficient copper(II)-catalyzed protocol for the or- sponding 2-hydroxyphenyl-1,2-diones were afforded in appreci-
tho-functionalization of phenols was developed. A wide variety
able yields.
of 2-oxoaldehydes and phenols were tolerated, and the corre-
Introduction
Derivatives of benzils, such as 2-hydroxyphenyl-1,2-diones
(HPDs), are widely distributed in nature.[1] These compounds
possess intriguing structures and exhibit important biological
activities such as anticancer,[1a,1b] antimicrobial,[1c] antioxid-
ant,[1d] antibacterial, and hypertensive[1e] activities, and they
also show inhibition of the enzymatic activity of carboxyl ester-
ases[2] (Figure 1). As a result, the development of new practical
methods for the synthesis of this scaffold is of considerable
interest. In this context, Thasana and co-workers developed a
method for the synthesis of HPDs through intramolecular cycli-
zation of anionic benzylic esters of aryl benzyl ethers in the
presence of a base followed by dioxirane oxidation.[3] This
Figure 1. Naturally occurring bioactive 2-hydroxyphenyl-1,2-diones.
Scheme 1. Various synthetic approaches to 2-hydroxyphenyl-1,2-diones.
method, however, suffers with limitations in terms of using
complex starting materials and the products are obtained in
low yields. Li et al. reported the synthesis of HPDs by FeII cata-
lyzed ortho-functionalization of phenols with α-hydroxy ket-
ones.[4] The yields were comparatively good, but longer reac-
tion times and an external oxidant were required. Our group
also established a synthetic strategy for the generation of HPDs
through an amine-catalyzed cross-coupling approach. In this
[a] Medicinal Chemistry Division, Indian Institute of Integrative Medicine
(IIIM/1871/2015),
Jammu 180001, India
E-mail: naqazi@iiim.ac.in
http://www.iiim.res.in
[b] Academy of Scientific and Innovative Research (AcSIR),
2-Rafi Marg, New Delhi, India
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201501423.
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case, the required product was produced in less than 40 % yield
(Scheme 1).[5]
Table 1. Optimization of the ortho-functionalization of phenol.[a]
Drawing from our recent CuII-catalyzed reactions of oxazoles
and/furanones[6] and in light of the importance of HPDs, we
succeeded in achieving a practical synthesis of HPDs in high
yields through the CuII-catalyzed reaction of 2-oxoaldehydes
with phenols.
Entry
Solvent
Catalyst
(mol-%)
T
[°C]
t
[h]
Yield[b]
[%]
1
2
3
4
5
6
7
8
toluene
toluene
toluene
toluene
toluene
toluene
toluene
MeOH
Cu(OAc)2·H2O (20)
CuCl2·H2O (20)
CuO (20)
r.t.
r.t.
r.t.
r.t.
45
60
80
60
60
60
60
60
60
60
60
60
60
24
24
24
24
12
12
5
5
5
5
5
5
5
5
5
5
5
25
trace
5
Results and Discussion
Our initial studies focused on developing an efficient catalytic
system to investigate the reaction of phenol (1a, 0.746 mmol)
with phenylglyoxal (2a, 0.746 mmol) as a model system. Upon
conducting this reaction with 20 mol-% Cu(OAc)2·H2O in tolu-
ene, to our delight we isolated product 3a in 25 % yield
(Table 1, entry 1). To improve the yield, initially we performed
a screening of the reaction in the presence of various CuI/CuII
catalysts at a loading of 20 mol-% (Table 1, entries 2–4). With
the exception of Cu(OAc)2·H2O, no catalyst gave an appreciable
yield of 3a. Next, the model reaction with Cu(OAc)2·H2O was
investigated at various temperatures/times (Table 1, entries 5–
7). We observed a better yield of desired product 3a at 60 °C
within 12 h (Table 1, entry 6). A further increase in the tempera-
ture did not have a significant effect on the reaction yield
(Table 1, entry 7). Further, to interpret the solvent effect, the
reaction was examined in various solvent systems (Table 1, en-
CuI (20)
–
Cu(OAc)2·H2O (20)
Cu(OAc)2·H2O (20)
Cu(OAc)2·H2O (20)
Cu(OAc)2·H2O (20)
Cu(OAc)2·H2O (20)
Cu(OAc)2·H2O (20)
Cu(OAc)2·H2O (20)
Cu(OAc)2·H2O (20)
Cu(OAc)2·H2O (20)
Cu(OAc)2·H2O (15)
Cu(OAc)2·H2O (25)
Cu(OAc)2·H2O (20)
Cu(OAc)2·H2O (20)
58
82
82
12
20
40
5
9
CH3CN
CH2Cl2
H2O
10
11
12
13
14
15
16[c]
17[d]
DMSO
–
toluene
toluene
toluene
toluene
toluene
82
76
82
86
10
[a] Reaction conditions: Phenol (1a, 0.746 mmol), phenylglyoxal (2a,
0.746 mmol), Cu catalyst (20 mol-%), solvent (1.5 mL), temp., 5 h. [b] Yield of
isolated product. [c] Under an O2 atmosphere (balloon). [d] Under an atmos-
phere of argon (balloon).
Table 2. Scope of the reaction with respect to phenols 1.[a]
[a] Reaction conditions: Substituted phenol 1 (0.746 mmol), phenylglyoxal (2a, 0.746 mmol), Cu catalyst (20 mol-%), solvent (1.5 mL), 60 °C, 5 h. [b] Yield of
isolated product.
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tries 8–12). Among them, toluene was found to be the best- low nucleophilicity. Moreover, the reaction with 4-phenylphenol
suited solvent for the reaction. A survey of the catalyst loading was also compatible with the reaction conditions and produced
was also conducted (Table 1, entries 13–15). Additionally, reac- product 3l in high yield.
tions performed under O2 and argon atmospheres were also
performed (Table 1, entries 16 and 17). These two experiments
undoubtedly emphasized the role of oxygen as a promoter of
the reaction. Finally, we observed that the best yield of 3a was
obtained if the model reaction was performed with 20 mol-%
Cu(OAc)2·H2O in toluene at 60 °C for 5 h (Table 1, entry 13).
With the optimized procedure in hand, to check the viability
of the reaction in terms of substituted phenols 1, we performed
a series of experiments between substituted phenols 1 and
phenylglyoxal (2a) to afford products 3a to 3l (Table 2). As ob-
served, all the reactions proceeded smoothly to the desired pro-
ducts, which were obtained in good to excellent yields (40–
Next, we extended the substrate scope of the reaction by
conducting various reactions between phenol (1a) and 2-oxo-
aldehydes 2 to afford products 3m–w (Table 3). This reaction
was very compatible with all varieties of 2-oxoaldehydes 2. It is
clear that the electronic environment of the phenyl ring in sub-
strate 2 has no appreciable effect on the reaction or the yield.
On the basis of our observations, substrates 2 bearing electron-
donating groups, for example, OMe (see products 3m–o) and
Me (see products 3p and 3q) groups, afforded slightly lower
yields than substrates 2 with electron-withdrawing groups, for
example, Cl (see product 3r) and CF3 (see product 3s) groups.
In addition, the reaction of hydroxy-substituted phenylgly-
90 %). More precisely, simple phenol (see product 3a) and oxal and a heterocyclic 2-oxoaldehyde with phenol also af-
phenols bearing electron-donating groups, namely, isopropyl forded desired products 3t and 3u in good yields. Along with
(see products 3b and 3c) and methyl (see products 3d and 3e) these results, we successfully obtained comparable yields of
groups, afforded the products in high yields. Phenol substituted corresponding desired products 3v and 3w in reactions with
with both isopropyl and methyl groups produced desired prod- α- and ꢀ-naphthylglyoxals. Finally, as presented in Table 4, we
uct 3f in an excellent yield, but phenols containing halogen generated products 3x–ab in good yields by performing reac-
atoms, that is, F, Cl, and Br atoms, produced products 3g–j in tions between various phenols 1 and substituted phenylglyox-
moderate yields, whereas the phenol containing the electron- als 2. In general, we can summarize that this protocol is applica-
withdrawing OCF3 group produced 3k in a low yield owing to ble to all sorts of substituted phenols 1 and glyoxals 2.
Table 3. Scope of the reaction with respect to 2-oxoaldehydes 2.[a]
[a] Reaction conditions: Phenol (1a, 0.746 mmol), substituted phenylglyoxal 2 (0.746 mmol), Cu catalyst (20 mol-%), solvent (1.5 mL), 60 °C, 5 h. [b] Yield of
isolated product.
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Table 4. Scope of the reaction of 1 with 2.[a]
[a] Reaction conditions: Phenol 1 (0.746 mmol), substituted phenylglyoxal 2 (0.746 mmol), Cu catalyst (20 mol-%), solvent (1.5 mL), 60 °C, 5 h. [b] Yield of
isolated product.
To interpret the reaction mechanism, we performed a few observed, even after 24 h. This clearly ruled out the direct oxid-
control experiments (Scheme 2). In experiment (1), upon sub- ation of 4 in the presence of the CuII/CuI system. In experi-
jecting substrate 4 to our reaction conditions, no product was ment (2), we performed a reaction between normal aldehyde
Scheme 2. Control experiments.
Scheme 3. Plausible reaction mechanism.
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1H NMR (400 MHz, CDCl3): δ = 11.38 (s, 1 H), 7.97 (d, J = 7.4 Hz, 2
H), 7.67 (t, J = 7.4 Hz, 1 H), 7.59–7.42 (m, 4 H), 7.07 (d, J = 8.5 Hz, 1
H), 6.88 (t, J = 7.5 Hz, 1 H) ppm. 13C NMR (126 MHz, CDCl3): δ =
199.35, 192.06, 163.38, 138.15, 135.26, 132.68, 132.45, 130.05,
5 and phenol (1a) under the standard reaction conditions. As
expected, the reaction failed to produce the corresponding or-
tho-functionalized product. This clearly indicated the role of the
glyoxals/2-oxoaldehydes under the reaction conditions. Eventu-
ally, from experiment (3), it became clear that 2-oxoacids were
ineffective under the reaction conditions.
129.18, 119.77, 118.72, 116.86 ppm. IR (CHCl3): ν = 3438, 3063, 2923,
˜
2852, 1726, 1678, 1631, 1615, 1451, 1578, 1598, 1205, 1155, 888,
756, 719 cm–1. GC–MS (EI): m/z (%) = 226.2 (6.57) [M]+, 209.2 (3.27),
181.2 (2.04), 121.2 (100), 105.3 (34.73), 93.1 (7.2), 77.1 (30.12), 51.1
(8.5).
On the basis of the above results and literature reports,[7]
a
plausible reaction mechanism for the Cu-catalyzed ortho-func-
tionalization of phenols 1 with glyoxals 2 is described in
Scheme 3. Initially, glyoxal 2 coordinates to CuII through its two
carbonyl groups. Its reaction with phenol results in ortho C–C
bond formation to generate adduct A. Adduct A tautomerizes
to intermediate B, which further undergoes oxidation to pro-
duce desired product 3 with elimination of CuI, which under-
goes air-assisted regeneration to CuII that ultimately re-enters
the catalytic system.[7c]
Acknowledgments
N. B. and S. B. thank the University Grants Commission (UGC),
New Delhi and the Council of Scientific and Industrial Research
(CSIR), New Delhi, respectively. The authors also thank the Ana-
lytical Department of IIIM for support. Finally, the University
Grants Commission (CSIR), New Delhi is gratefully thanked for
funding this work through the network project (BSC-0108).
Conclusions
Keywords: Synthetic methods · C–H activation · Copper ·
Phenols
In conclusion, we established an efficient strategy to perform
the copper-catalyzed ortho-functionalization of simple phenols
with 2-oxoaldehydes. By this technique, we achieved the syn-
thesis of biologically interesting 2′-hydroxyphenyl-1,2-dione
scaffolds in high yields. The mild reaction conditions and the
generality of the substrate scope are also attractive merits of
this reaction. Further, its application towards the synthesis of
various natural products is in progress.
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Experimental Section
General Procedure for the Synthesis of 3: A round-bottomed
flask equipped with a reflux condenser was charged with a mixture
of phenol 1 (0.746 mmol), arylglyoxal monohydrate 2 (0.746 mmol),
and Cu(OAc)2·H2O (20 mol-%). Toluene (1.5 mL) was added, and the
resulting mixture was stirred at 60 °C for 5 h. Upon completion of
the reaction, the mixture was cooled to room temperature and wa-
ter was added. The mixture was extracted with ethyl acetate (2 ×
5 mL). The organic layer was collected and dried with MgSO4. The
organic solvent was evaporated under reduced pressure to afford
the crude product, which was purified by column chromatography
(silica gel, 100–200#; petroleum ether/EtOAc, 10:1). Desired product
3a was produced as a white solid (138 mg, 82 %); m.p. 71–73 °C.
Received: November 10, 2015
Published Online: January 18, 2016
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662
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim