Copper-catalyzed synthesis of α-naphthols from enol esters

Article abstract of DOI:10.1002/adsc.201300503

An unprecedented synthesis of α-naphthol derivatives from the reactions of two molecular equivalents of enol esters in the presence of a copper catalyst is described. This protocol is mild and tolerates various functional groups.

Full text of DOI:10.1002/adsc.201300503

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DOI: 10.1002/adsc.201300503
Copper-Catalyzed Synthesis of a-Naphthols from Enol Esters
Niranjan Panda,a,* Raghavender Mothkuri,a Arpan Pal,a and Alok R. Paitalb
a
Department of Chemistry, National Institute of Technology, Rourkela – 769008, Odisha, India
Fax : (+91)-661-246-2651; phone: (+91)-661-246-2653; e-mail: npanda@nitrkl.ac.in
Salt and Marine Division, CMCRI, Bhavnagar, Gujuarat – 364021, India
b
Received: June 8, 2013; Revised: August 5, 2013; Published online: October 9, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300503.
Abstract: An unprecedented synthesis of a-naph-
thol derivatives from the reactions of two molecular
equivalents of enol esters in the presence of
a copper catalyst is described. This protocol is mild
and tolerates various functional groups.
naphthols from the intramolecular formal diazo
ꢀ
carbon insertion of tosyl hydrazones to keto C C
bonds.[6] Besides, Wirth,[7] Jiang[8] and Yoan[9] inde-
pendently made significant advances for the synthesis
of a-naphthol derivatives from the intramolecular
cyclization of their monocyclic b-keto ester precur-
sors. As part of our continued interest on transition
Keywords: copper catalysts; enol esters; ethyl pro-
piolate; ortho-halobenzoic acids; a-naphthols
ꢀ
ꢀ
metal-catalyzed C C and C N bond forming pro-
AHCTUNGTRENNUNG
protocol involving two molecular equivalents of enol
esters to produce substituted a-naphthols under mild
reaction conditions.
Naphthalene derivatives are found abundantly in vari-
Our work initiated with a serendipitous discovery:
ous natural and synthetic products with important on treatment of (E)-2-(ethoxycarbonyl)vinyl 2-iodo-
biological properties such as antimalarial, anti-HIV benzoate (1aa) in the presence of a copper salt and
and anticancer activities.[1] They also exhibit applica- base, an intramolecular cyclization to isocoumarin de-
tions in agrochemical and dye preparations.[2] Apart rivative 3 did not occur, rather a new product with
from this, naphthols, the most important naphthalene a molecular weight of 288 (as shown by the ESI-MS)
derivatives, serve as versatile chiral ligands in synthet- was produced predominantly (Scheme 1). The product
ic organic chemistry.[3] The profound usage of naph- was purified and an attempt was made to characterize
thalene derivatives stimulates the development of it by NMR spectroscopy. The NMR data shows a phe-
new and complementary methods for their synthesis. nolic proton giving a singlet at 12.52 ppm, which grad-
Stepwise electrophilic aromatic substitution to a naph- ually disappears on treatment with D2O by deuterium
thalene ring is recognized as a conventional method exchange. The appearance of distinguishing signals
to access polysubstituted naphthalenes by functionali- for ethyl groups indicates the presence of two ethyl
ꢀ
ꢀ
ꢀ
zation of aromatic C H bonds to C C and C -N/O ester substituents in the new product. In consideration
1
bonds. Complex reaction conditions and frequent for- of the H and 13C NMR spectra, we anticipated the
mation of regioisomeric mixtures are the inevitable structure to be that of diethyl 4-hydroxynaphthalene-
drawbacks associated with the above process.[4] Thus,
a number of eminent methods including the Diels–
Alder reaction, Hauser phthalide annulations, rear-
rangement of cyclopropanes or cyclobutanes, and
acid-catalyzed cyclization reactions have been devel-
oped.[5] Numerous transition metal catalysts encom-
passing Cr, Mn, Pd, Rh, and Cu were also successfully
employed for the construction of naphthalene rings
from their monocyclic precursors owing to their ad-
vantages over the regioselectivity problem.[5] In con-
trast, the regioselective synthesis of naphthols with
predetermined substituents is less well endowed with
literature precedents. Very recently, Wang and co-
workers developed an efficient method to achieve naphthols.
Scheme 1. Cu-catalyzed reaction enol esters to afford a-
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Niranjan Panda et al.
Table 1. Optimization of the reaction conditions.[a]
COMMUNICATIONS
Entry Catalyst
Base
Solvent
Yield [%] of 2a
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
–
Cs2CO3 DMSO
K2CO3 DMSO
62
0
0
48
82
0
n. r.
33
58
0
43
0
62
0
0
n.r.
KOAc
DMSO
t-BuOK DMSO
K3PO4
K3PO4
–
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
THF
1,4-dioxane
toluene
ClCH2CH2Cl n.r.
methanol
CuI
CuBr
K3PO4
9
CuACHTNUGTERN(NUNG OAc)2 K3PO4
10
11
12
13
14
15
16
17
18
Cu(OTf)2 K3PO4
ACHTUNGTRENNUNG
CuCl
CuO
CuI
CuI
CuI
CuI
CuI
CuI
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
Figure 1. ORTEP drawing of 2a.[12]
0
[a]
1,3-dicarboxylate (2a). The exact structure of 2a was
further confirmed from X-ray crystallography
(Figure 1).[11] This result is completely unprecedented,
although encouraging. Thus, efforts have been made
to study the feasibility of this novel coupling reaction
to access multisubstituted a-naphthols.
Reaction conditions: 1aa (100 mg, 0.29 mmol), catalyst
(10 mol%), base (2 equiv.), of solvent (3 mL), 508C for
5 h; n.r. represents no reaction.
tantly, this reaction protocol required neither an an-
To test the feasibility of the process, a number of hydrous atmosphere nor extra pure solvent to pro-
enol esters (1) were prepared by the reaction of alkyl duce multisubstituted naphthols 2a in good yield.
propiolates with ortho-halobenzoic acids following the
Having the optimum reaction conditions (10 mol%
similar procedure reported earlier[13] (see the Support- CuI, 2 equiv. of K3PO4, DMSO), the scope of the
ing Information for details). Recently, a vast number copper-catalyzed transformation of enol esters to a-
of reports invoked the potential of copper catalysts in naphthols was investigated (Table 2).[15] When the
cross-coupling reactions.[14] Thus, having in hand (E)-2-(ethoxycarbonyl)vinyl 2-bromobenzoate (1ba)
a pool of enol esters, the cyclization reaction was at- was treated under similar reaction conditions, no
tempted in the presence of copper catalysts. The re- trace of product was identified (from TLC) even on
sults are summarized in Table 1.
prolonged heating at 508C. However, on raising the
It was observed that, among the tested solvents, the reaction temperature to 908C, 1ba gave the target
reaction only proceeds in the presence of DMSO and naphthol (2a) over a period of 12 h, albeit in lower
DMF, whereas no naphthol 2a was isolated in other yield (44%). Similarly, as expected, the less reactive
solvents such as ClCH2CH2Cl, THF, methanol, 1,4-di- (E)-2-(ethoxycarbonyl)vinyl 2-chlorobenzoate (1ca)
oxane and toluene (entries 14–18). The reactivities of requires an even higher temperature (i.e., 1508C) to
different copper catalysts and bases were also investi- give 2a in 30% yield over a period of 24 h. To our de-
gated. It was observed that CuI (10 mol%) served as light, reactions of other enol esters having variable
the best catalyst to provide 2a in optimum yield chain lengths as well as substituents on the aromatic
(82%).[15] A decrease in CuI concentration from ring produced the substituted a-naphthols in moder-
10 mol% to 5 mol% afforded the naphthol in poor ate to good yield (55–82%).[17]
yield (62%), whereas an increase in catalyst concen-
To gain an insight into the copper-catalyzed cycliza-
tration to 20 mol% did not produce better results tion of enol esters several controlled experiments, as
(75%). Among the tested bases (Cs2CO3, K2CO3, presented in Scheme 2, were performed to elucidate
KOAc, t-BuOK and K3PO4), K3PO4 provided 2a in the mechanism. Initially, the involvement of
the highest yield in DMSO at 508C. The concentra- a [2+2+2]cycloaddition of benzyne with the generat-
tion of base is also revealed to be important. Two ed enol (Scheme 2a) derived from the hydrolysis step
equivalents of base were needed to produce the naph- was considered. However, a trapping experiment with
thol in a maximum yield. Lowering the temperature furan was unsuccessful, implying that benzyne is not
from 508C to room temperature or increasing the involved as an intermediate for this reaction. Further-
temperature to 908C afforded 2a with nearly the more, no radical intermediate was trapped by the rad-
same yield within 24 h and 2 h, respectively.[16] Impor- ical scavenger TEMPO (2,2,6,6-tetramethylpiperidin-
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Copper-Catalyzed Synthesis of a-Naphthols from Enol Esters
Table 2. Cu-catalyzed synthesis of a-naphthols.[a]
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Niranjan Panda et al.
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Table 2. (Continued)
[a]
Reaction conditions: enol ester 1 (100 mg), CuI (10 mol%), K3PO4 (2 equiv.) in 3 mL of DMSO,
508C.
[b]
[c]
[d]
[e]
Reaction was carried out at 908C.
Reaction was carried out at 1508C.
Reaction was carried out at room temperature.
Reaction was carried out at room temperature and resulted in the incomplete conversion of enol
ester 1aj.
1-yl oxyl), which ruled out the possibility of a radical the absence of CuI, ether[18] 4 (34%) as well as benzo-
pathway to achieve 2a (Scheme 2b). Next, when 1aa ic acid (from the acidification of the corresponding
was treated under the optimum reaction conditions in aqueous extract) were produced (Scheme 2c). This
suggests that the first step of the reaction may be the
hydrolysis step. Indeed, the presence of two ester
groups in the naphthol product 2a, indicates the in-
volvement of two equivalents of enol esters (e.g., 1aa)
to produce one equivalent of 2a. Notably, when an
equimolar mixture of different enol esters (1aa and
5a) was treated under the optimum reaction condi-
tions, an inseparable mixture of naphthols (from
NMR spectra) was obtained (Scheme 2d). Moreover,
the similar experimentation in the presence of
1 equiv. of 5b, resulted in 2a in higher yield (68%
with regard to 1 equiv. of 1aa); which further proves
the involvement of enolate (e.g., A or B) intermedi-
ate in the tandem annulation process. Based on the
above observations, thus, a plausible pathway for the
regioselective synthesis of a-naphthol (2a) is outlined
in Scheme 3. Initially, enol ester 1aa undergoes hy-
drolysis to enolate A, which on tautomerization leads
to the intermediate B.
Presumably, the intermediate B, thus formed reacts
with another molecule of 1aa to produce C. In the
presence of CuI and base in DMSO, intermolecular
C-arylation[19] may take place to produce D. Next, the
annulated intermediate E forms through the intramo-
lecular 1,2-addition reaction of D. Subsequently, E un-
dergoes rearrangement, followed by aromatization
(E!F!G!2a) to afford the desired product 2a.
In conclusion, a novel method for the synthesis of
polysubstituted a-naphthols from simple monocyclic
Scheme 2. Control experiments for insights into the mecha-
nism.
enol esters has been demonstrated. The reaction con-
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Copper-Catalyzed Synthesis of a-Naphthols from Enol Esters
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ditions are mild and do not require any anhydrous
medium or expensive catalytic protocol to access such
products in good yield. Further investigations to
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mechanistic studies are currently underway in our lab-
oratory.
Experimental Section
Typical Procedure for the Synthesis of 2a
A mixture of enol ester 1aa (100 mg, 0.29 mol), CuI (3 mg,
10 mol%), K3PO4 (122 mg, 0.58 mmol) in 3 mL of DMSO
was stirred at 508C. The progress of the reaction was moni-
tored by TLC. After 5 h the reaction mixture was quenched
with 1N HCl solution and then extracted with ethyl acetate.
The solvent was removed under reduced pressure and the
crude reaction mixture was purified by column chromatog-
raphy to yield diethyl 4-hydroxynaphthalene-1,3-dicarboxy-
late (2a) as a white crystalline solid; yield: 82%.
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Acknowledgements
This work was financially supported in part by DST, New
Delhi (No. SR-S1/OC-60/2011), and BRNS (No. 2012/37C/3/
BRNS), DAE, Government of India. DST, New Delhi (No.
SR/FST/CS1-018/2010) is also acknowledged for providing
the MS facility at NIT Rourkela. ARP (solved the crystal
structure of 2a) is thankful to the analytical division of
CMCRI for HR-MS data.
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