Simple and efficient copper-catalyzed cascade synthesis of naphthols containing multifunctional groups under mild conditions

Article abstract of DOI:10.1039/c0cc01544j

A simple and efficient copper-catalyzed method for synthesis of naphthols containing multifunctional groups has been developed under mild conditions (room temperature to 60 °C), and it can tolerate various functional groups.

Full text of DOI:10.1039/c0cc01544j

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Simple and efficient copper-catalyzed cascade synthesis of naphthols
containing multifunctional groups under mild conditionsw
Hao Xu,ab Shangfu Li,b Hongxia Liu,b Hua Fu*a and Yuyang Jiang*b
Received 24th May 2010, Accepted 31st August 2010
DOI: 10.1039/c0cc01544j
A simple and efficient copper-catalyzed method for synthesis of
naphthols containing multifunctional groups has been developed
under mild conditions (room temperature to 60 1C), and it can
tolerate various functional groups.
Table 1 Copper-catalyzed cascade synthesis of dimethyl 4-hydroxy-
2-methylnaphthalene-1,3-dicarboxylate (3a) via coupling of methyl
3-(2-bromophenyl)-3-oxopropanoate (1a) with methyl 3-oxobutanoate
(2a): optimization of conditionsa
The demand for functionalized aromatic compounds is
growing rapidly in many research fields.1 In the aromatic
compounds, naphthalene derivatives show wide applications
in academic lab and industry,2,3 and they often occur as the
basic skeletons of natural products and pharmaceuticals.4
Therefore, it is very desired to develop practical and efficient
methods for the synthesis of naphthalenes with various func-
tional groups.5 In the previous methods, aromatic electrophilic
substitution is a common strategy, however, it is often difficult
to control substitution sites regioselectively with this reaction.
The direct construction of naphthalene rings presents a potential
advantage from monocyclic precursors in which substituents
are arranged at predetermined positions.6 Recently, copper-
catalyzed coupling reactions have made great progress,7 and
the cross-coupling strategy has been used to make heterocycles.8
In continuation of our endeavors to develop copper-catalyzed
coupling reactions,9 herein, we report a simple and efficient
copper-catalyzed synthesis of naphthols containing multi-
functional groups under mild conditions.
Yield of
3ab (%)
Yield of
4ab (%)
Entry
Cu Cat.
Base
Solvent
1
2
3
4
5
6
7
8
CuI
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K3PO4
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
Dioxane
THF
82
80
90
16
5
30
5
Trace
82
69
63
5
Trace
Trace
Trace
Trace
0
Trace
0
0
Trace
Trace
Trace
0
CuBr
CuCl
Cu2O
CuO
Cu(OAc)2
Cu
—
9
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
10
11
12
13
14c
15e
7
0
DMF
DMF
60 (73d)
62
Trace
Trace
a
Reaction condition: methyl 3-(2-bromophenyl)-3-oxopropanoate
(1a) (0.5 mmol), methyl 3-oxobutanoate (2a) (0.6 mmol), catalyst
(0.05 mmol), base (1 mmol), solvent (2 mL), room temperature
Initially, methyl 3-(2-bromophenyl)-3-oxopropanoate (1a)
and methyl 3-oxobutanoate (2a) were chosen as the model
substrates to optimize reaction conditions including the
catalysts, bases and solvents under nitrogen atmosphere. As
shown in Table 1, seven copper catalysts (0.1 equiv.) were
tested at room temperature by using 2 equiv. of Cs2CO3 as the
base (relative to amount of 1a) in DMF (entries 1–7), CuCl
showed the highest activity, and the target product (3a) was
obtained in 90% yield with trace amounts of dimer (4a) from
1a appearing (entry 3). The reaction could not be carried out
in the absence of copper catalyst (entry 8). The effect of bases
was investigated (compare entries 3, 9 and 10), and the results
showed that Cs2CO3 was the best choice (entry 3). We
attempted various solvents (compare entries 3, 11–13), and
DMF provided the highest yield. When CuCl was reduced
b
(B25 1C) under nitrogen atmosphere, reaction time (1 h). Isolated
yield. 0.025 mol of CuCl was used. Reaction time (4 h). Reaction
c
d
e
temperature (60 1C).
to 5 mol% from 10 mol% in entry 3, a 60% yield was provided,
and the cascade reaction also gave higher yield (73%) as time
elongated (entry 14). The yield decreased because of hydrolysis
of a small amount of ester bonds in 2a and 3a when tempera-
ture was raised to 60 1C (entry 15). Interestingly, the reaction
did not need an additional ligand or additive, and the result
implies that the substrates (methyl 3-(2-bromophenyl)-3-oxo-
propanoate and methyl 3-oxobutanoate) containing b-keto
ester group can act as ligands (see reaction mechanism in
Scheme 2), and similar copper-catalyst ligands, b-diketone10
and b-keto ester,11 were reported in the previous researches.
The scope of copper-catalyzed cascade synthesis of
naphthol derivatives was investigated under the optimized
condition (10 mol% CuCl as the catalyst, 2 equiv. of Cs2CO3
as the base, DMF as the solvent). As shown in Table 2, most
of the substrates examined provided moderate to good
yields under very mild conditions. For the substituted methyl
3-(2-bromophenyl)-3-oxopropanoates (entries 1–17) and
3-(2-bromo-5-chlorophenyl)-3-oxopropanenitrile (entries 18–20),
the reactions were carried out at room temperature (B25 1C)
(except entry 6). Methyl 3-(2-chlorophenyl)-3-oxopropanoate
a Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical
Biology (Ministry of Education), Department of Chemistry,
Tsinghua University, Beijing 100084, P. R. China.
E-mail: fuhua@mail.tsinghua.edu.cn; Fax: +86 10 62781695;
Tel: +86 10 62797186
b Key Laboratory of Chemical Biology (Guangdong Province),
Graduate School of Shenzhen, Tsinghua University,
Shenzhen 518057, P. R. China
w Electronic supplementary information (ESI) available: General
procedure for synthesis of compounds 3a–t, characterization data
for compounds 3a–t, and 1H and 13C NMR spectra of compounds
3a–t. See DOI: 10.1039/c0cc01544j
c
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 7617–7619 7617

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Table 2 Copper-catalyzed synthesis of naphthol derivativesa
Table 2 (continued )
Entry
1
2
Time/h
8
3
Yieldb (%)
12
1a
83
13
14
1b 2a
1
1
84
68
1b 2c
Entry
1
1
2
Time/h
1
3
Yieldb (%)
1a
90
15
16
17
1b 2e
1b 2k
1b 2l
1
6
2
74
62
68
2
3
1a
1a
1
1
66
75
4
5
6
7
1a
1a
1a
1a
1
1
8
4
95
68
90
95
18
1c 2c
5
58
19
20
1c 2e
5
5
55
77
1c 2l
21
22
23
1d 2a
1d 2i
1d 2j
12
12
12
3a
3i
3j
52
58
41
8
9
1a
1a
2
2
61
66
a
Reaction condition: under nitrogen atmosphere, 1 (0.5 mmol), 2
(0.6 mmol), catalyst (0.05 mmol), base (1 mmol), DMF (2 mL),
reaction temperature (B25 1C for entries 1–5 and 7–20, 40 1C for
b
entry 6, 60 1C for entries 21–23). Isolated yield.
(1d) did not work at this temperature, fortunately, it also
afforded the corresponding target products in the reasonable
yields when the temperature was raised to 60 1C (entries
21–23). In fact, aryl chlorides were very weak substrates in
the previous copper-catalyzed Ullmann-type couplings.7 For
b-keto esters, ethyl 3-oxo-3-phenylpropanoate showed slightly
weaker reactivity than the others, so the reaction needed
10
11
1a
1a
8
6
64
63
c
7618 Chem. Commun., 2010, 46, 7617–7619
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higher temperature (40 1C) (entry 6). Reaction of acetyl-
acetone with methyl 3-(2-bromophenyl)-3-oxopropanoate
(1a) gave the target product (3g) in an excellent yield (95%)
(entry 7). Alkyl 2-cyanoacetates, 3-oxo-3-phenylpropanenitrile
and malononitrile also showed higher reaction activity
(entries 8–12). Interestingly, reaction of substituted methyl
3-(2-bromophenyl)-3-oxopropanoate (1a) with 3-oxo-3-phenyl-
propanenitrile (2k) afforded product 3k not 3k0, and the result
exhibited that nucleophilic attack of a-C of b-keto ester in
intermediate IV selectively occurred on the carbonyl rather
than on the cyano group as shown in Scheme 1, which is
attributed in higher electrophilicity of carbonyl than cyano in
3-oxo-3-phenylpropanenitrile.
b-keto ester acts as the ligand.10,11 Coupling of the free
substrate (1) with 2 under catalysis of CuLCl provides
C-arylation product (II). Intramolecular nucleophilic addition
of a-C–H to CN in II gives intermediate III, and isomerization
of III provides the desired target product (3).
In summary, we have developed a simple and highly efficient
copper-catalyzed method for synthesis of naphthols containing
multifunctional groups under mild conditions. The protocol
uses readily available substrates as the starting materials, and
the target products containing various substituents, such as
hydroxyl, amino, ester, cyano, and carbonyl groups, were
obtained in moderate to good yields. The present method
can tolerate various functional groups, and shows economical
and practical advantages over the previous methods, so it will
provide opportunity for construction of diverse and useful
molecules in organic chemistry and medicinal chemistry.
Financial support was provided by the National Natural
Science Foundation of China (Grant No. 20972083), Chinese
863 Project (Grant No. 2007AA02Z160) and the Key Subject
Foundation from Beijing Department of Education
(XK100030514).
We attempted the reaction of 3-(2-bromo-5-chlorophenyl)-
3-oxopropanenitrile (1c) with malononitrile (2l) without the
addition of an extra ligand, the copper-catalyzed cascade
reaction provided the corresponding target product (3t) in
77% yield (entry 20), and the result indicated that 1c or/and 2l
could act as ligand(s). The nitrile as a ligand was reported
in the previous research.12 The copper-catalyzed cascade
synthesis of naphthol derivatives above could tolerate various
functional groups including ester (entries 1–19, 21–23), carbonyl
(entry 7), C–Cl bond (entries 13–20), and cyano group (entries 11,
12, 16–20) in the substrates.
Notes and references
1 For a comprehensive review, see: Modern Arene Chemistry, ed.
D. Astruc, Wiley-VCH, Weinheim, 2002.
2 R. T. Mason, M. Talukder and C. R. Kates, in Kirk-Othmer
Encyclopedia of Chemical Technology, ed. R. E. Kirk, Wiley,
New York, 4th ed., 1995, vol. 16, pp. 963–1017.
A possible mechanism for synthesis of naphthol derivatives
was proposed in Scheme 2 according to the results above
(herein, reaction of substituted methyl 3-(2-halophenyl)-3-
oxopropanoate (1) with the substrate (2) containing cyano
group was chosen as an example). Coordination of b-keto
ester (1) with CuCl forms complex CuLCl (I), so part of
3 (a) P. E. Georghiou, Z. Li, M. Ashram, S. Chowdhury, S. Mizyed,
A. H. Tran, H. Al-Saraierh and D. O. Miller, Synlett, 2005, 879;
´
(b) M. Medarde, A. B. S. Maya and C. Perez-Melero, J. Enzyme
Inhib. Med. Chem., 2004, 19, 521.
4 (a) T. Kometani, Y. Takeuchi and E. Yoshii, J. Org. Chem., 1983,
48, 2630; (b) W. Lester, Annu. Rev. Microbiol., 1972, 26, 85;
(c) K. L. Rinehart, Jr, Acc. Chem. Res., 1972, 5, 57.
5 (a) C. B. de Koning, A. L. Rousseau and W. A. L. van Otterlo,
Tetrahedron, 2003, 59, 7; (b) M. Brasholz, S. Sorgel, C. Azap and
¨
H.-U. Reibig, Eur. J. Org. Chem., 2007, 3801; (c) K. Tsubaki, Org.
Biomol. Chem., 2007, 5, 2179.
6 G. Chai, Z. Lu, C. Fu and S. Ma, Chem.–Eur. J., 2009, 15, 11083.
7 For recent reviews on copper-catalyzed cross couplings, see:
(a) D. Ma and Q. Cai, Acc. Chem. Res., 2008, 41, 1450;
(b) K. Kunz, U. Scholz and D. Ganzer, Synlett, 2003, 2428;
(c) S. V. Ley and A. W. Thomas, Angew. Chem., Int. Ed., 2003,
42, 5400; (d) I. P. Beletskaya and A. V. Cheprakov, Coord. Chem.
Rev., 2004, 248, 2337; (e) G. Evano, N. Blanchard and M. Toumi,
Chem. Rev., 2008, 108, 3054; (f) F. Monnier and M. Taillefer,
Angew. Chem., Int. Ed., 2009, 48, 6954 and references cited therein.
8 (a) R. Martin, M. R. Rivero and S. L. Buchwald, Angew. Chem.,
Int. Ed., 2006, 45, 7079; (b) G. Evindar and R. A. Batey, J. Org.
Chem., 2006, 71, 1802; (c) F. Bonnaterre, M. Bois-Choussy and
J. Zhu, Org. Lett., 2006, 8, 4351; (d) B. Zou, Q. Yuan and D. Ma,
Angew. Chem., Int. Ed., 2007, 46, 2598.
Scheme 1 Reaction mechanism of substituted methyl 3-(2-bromo-
phenyl)-3-oxopropanoate (1a) with 3-oxo-3-phenylpropanenitrile (2k).
9 Selected papers for copper-catalyzed cross couplings, see:
(a) D. Jiang, H. Fu, Y. Jiang and Y. Zhao, J. Org. Chem., 2007,
72, 672; (b) H. Rao, Y. Jin, H. Fu, Y. Jiang and Y. Zhao,
Chem.–Eur. J., 2006, 12, 3636; (c) H. Rao, H. Fu, Y. Jiang and
Y. Zhao, Angew. Chem., Int. Ed., 2009, 48, 1114; (d) X. Liu, H. Fu,
Y. Jiang and Y. Zhao, Angew. Chem., Int. Ed., 2009, 48, 348.
10 S. Shafir and S. L. Buchwald, J. Am. Chem. Soc., 2006, 128, 8742.
11 X. Lv and W. Bao, J. Org. Chem., 2007, 72, 3863.
12 R. Zhu, L. Xing, X. Wang, C. Cheng, D. Su and Y. Hu, Adv.
Synth. Catal., 2008, 350, 1253.
Scheme 2 Possible mechanism for synthesis of naphthol derivatives.
c
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 7617–7619 7619