Copper-catalyzed tandem reaction of 2-bromobenzyl bromides with 1,3-dicarbonyl compounds leading to 4H-chromenes

Article abstract of DOI:10.1016/j.cclet.2012.08.005

A Cu(I)-catalyzed one-pot tandem reaction of 2-bromobenzyl bromides with 1,3-dicarbonyl compounds leading to 4H-chromene derivatives has been developed. This new approach toward 4H-chromenes combines several reactions in one pot and builds molecular complexity from readily available starting materials.

Full text of DOI:10.1016/j.cclet.2012.08.005

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 1129–1132
www.elsevier.com/locate/cclet
Copper-catalyzed tandem reaction of 2-bromobenzyl bromides
with 1,3-dicarbonyl compounds leading to 4H-chromenes
a
a
b
a
Xin Ying Zhang a, , Liang Liang Fang , Nan Liu , Hua Yue Wu , Xue Sen Fan
*
a School of Chemistry and Environmental Science, Key Laboratory for Yellow River and Huai River Water Environment and Pollution Control,
Ministry of Education, Henan Normal University, Xinxiang 453007, China
b College of Chemistry & Materials Engineering, Wenzhou University, Wenzhou 325027, China
Received 15 June 2012
Available online 23 September 2012
Abstract
A Cu(I)-catalyzed one-pot tandem reaction of 2-bromobenzyl bromides with 1,3-dicarbonyl compounds leading to 4H-
chromene derivatives has been developed. This new approach toward 4H-chromenes combines several reactions in one pot and
builds molecular complexity from readily available starting materials.
# 2012 Xin Ying Zhang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: One-pot tandem reaction; 4H-Chromenes; Copper catalysis
Tandem reactions are emerging as a powerful tool for organic chemists. Compared with classical organic synthesis
involving stepwise formation of individual bonds in the construction of a targeted molecule, tandem reactions combine
multiple transformations in one pot and allow rapid buildup of molecular complexity from relatively simple starting
materials. In addition, this kind of reaction not only saves time and energy, but also reduces the use of solvents in the
isolation and purification of intermediates [1].
Chromenes constitute a widespread structural motif in various biologically active compounds and naturally
occurring products [2]. Compounds bearing a 4H-chromene moiety have showed remarkable biological activities [3].
Due to their importance, several methods for the synthesis of 4H-chromenes have been developed [4–9]. Li et al. have
recently reported a synthesis of 4H-chromene derivatives starting from 2-bromobenzyl bromides and 1,3-dicarbonyl
compounds [10]. However, Li’s synthesis of 4H-chromenes combines two separate steps and the first step is
unfortunately very low yielding (Scheme 1) [11]. As a continuation of our research interest in tandem reactions [12],
we were interested in developing an efficient and practical approach to 4H-chromenes directly from 2-bromobenzyl
bromides and 1,3-dicarbonyl compounds via a one-pot tandem procedure (Scheme 1) [13].
Initially, we chose 2-bromobenzyl bromide (1a, 0.5 mmol) and cyclohexane-1,3-dione (2a, 1.0 mmol) as substrates
for surveying the reaction parameters. 1a and 2a were firstly treated with CuI and Cs2CO3 in dioxane in the presence of
N,N’-dimethyl ethylenediamine (DMEDA) at reflux for 12 h. From the reaction mixture, the expected 3a was isolated
but in a low yield (21%). The reaction was then tried under different conditions with regard to different bases, solvents,
* Corresponding author.
E-mail address: xinyingzhang@htu.cn (X.Y. Zhang).
1001-8417/$ – see front matter # 2012 Xin Ying Zhang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2012.08.005

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X.Y. Zhang et al. / Chinese Chemical Letters 23 (2012) 1129–1132
Proposed one-pot synthesis of 4H-chromenes
Br
O
O
Br
Br
O
Bu4NF/Bu4NI
THF/CHCl3
CuI, base
ligand
+
O
O
O
1
2
3
Li's synthesis of 4H-chromenes via a two-step procedure
Scheme 1. Li’s synthesis of 4H-chromenes via a two-step procedure.
and Cu sources. It turned out that K2CO3 was as effective as Cs2CO3. Next, we found the nature of solvent was
essential to influence the yield. Among the solvents studied (dioxane, i-PrOH, DMF, DMSO, THF), i-PrOH was
ineffective, whereas DMF gave the best results. Then, several ligands such as pipecolinic acid, N,N-dimethyl glycine
and L-proline were tried and they did not give better yields of 3a than DMEDA, which gave 3a in a yield of 57%. To
our surprise, a control experiment without using any ligand afforded 3a in a yield of 58%. However, when the amount
of 2a was reduced from 2 equiv to 1 equiv, the yield of 3a decreased dramatically, indicating that 2a may act as a ligand
in this tandem process. With regard to Cu source, CuBr, CuCl and CuCN were inferior to CuI in promoting this
reaction. The effect of catalyst loading was also examined. When the amount of CuI was increased to 20 mol% from
10 mol%, the yield of 3a did not improve substantially. Furthermore, the cascade reaction gave poor yields of 3a when
the temperature was below 100 8C. Based on the above results, the optimal conditions were identified as follows: 1a
(0.5 mmol), 2a (1.0 mmol), CuI (0.05 mmol), K2CO3 (1.5 mmol), in DMF at 100 8C for 12 h. Under such conditions,
3a was obtained in a yield of 58%.
With the optimized reaction conditions in hand, the scope of this one-pot synthesis of 4H-chromenes was studied.
For this purpose, several 5-alkyl or 5-aryl substituted cyclohexane-1,3-diones (2b–2f) were prepared and reacted
smoothly with 1a (Table 1, entries 2–6). Next, we found it was well compatible with 1-bromo-2-(bromomethyl)-
naphthalene (1b) (entries 7 and 8). In addition, reactions with 5-bromo-6-(bromomethyl)-benzo[d][1,3]dioxole (1c)
gave the corresponding 4H-chromenes in moderate yields (entries 9 and 10). Interestingly, in addition to cyclic 1,3-
diketones, an acyclic 1,3-diketone, 1,3-diphenylpropane-1,3-dione (2g), took part in this tandem process smoothly
(entries 11–13).
Table 1
Preparation of 4H-chromenes 3 a [14].
Entry
1
1
2
3
Yield (%)b
58
O
O
Br
Br
2a
3a
1a
O
O
O
O
2
3
1a
1a
54
58
2b
2c
3b
3c
O
O
CH3
O
CH3
O
O
O
CH3
CH3
CH3
CH3
O
O
4
5
1a
1a
45
41
2d
3d
O
O
Ph
O
O
Ph
O
Cl 2e
3e
3f
O
O
Cl
O
6
1a
46
CH3
2f
O
O
CH3

X.Y. Zhang et al. / Chinese Chemical Letters 23 (2012) 1129–1132
1131
Table 1 (Continued )
Entry
7
1
2
3
Yield (%)b
55
O
2a
1b
3g
O
Br Br
O
8
1b
2f
53
3h
O
CH3
O
Br
Br
9
2c
57
49
O
O
1c
3i
CH3
CH3
O
O
O
O
10
1c
2d
O
O
3j
O
Ph
O
11
12
1a
1b
45
44
O
O
Ph
O
2g
3k
Ph
Ph
O
Ph
2g
Ph
3l
O
Ph
O
13
14
1c
1a
2g
42
46
O
O
Ph
3m
3n
O
O
Ph
O
O
O
2h
O
CH3
HO
CH3
OH
O
15
16
a
1a
1a
37
38
O
2i
3o
O
O
O
O
O
Et
Et
N
N
3p
2j
O
CH3
HO
CH3
0.5 mmol of 1, 1.0 mmol of 2, 0.05 mmol of CuI, 1.5 mmol of K2CO3, 3 mL of DMF, 100 8C, 12 h.
Isolated yields.
b
Finally, the applicability of 4-hydroxy-6-methyl-2H-pyran-2-one (2h), 4-hydroxy-2H-chromen-2-one (2i), and 4-
hydroxy-6-methyl-pyridine-2(1H)-one (2j) for this tandem process was also studied. Under standard conditions, the
reactions of 2h–2j with 1a proceeded smoothly to give the corresponding products 3n, 3o, and 3p in 46%, 37%, and
38% yields, respectively (Table 1, entries 14–16), thus resulting a promising approach toward the biologically
interesting chromenopyranones and chromenopyridinones.
In summary, we have successfully developed a novel synthesis of 4H-chromene derivatives through CuI-catalyzed
one-pot tandem reaction of various 1,3-dicarbonyl compounds with 2-bromobenzyl bromides under ligand free
conditions. The choices of solvent and base are essential to the success of this tandem process. Compared with
literature methods, advantages of the present protocol include readily available starting materials, free of added
ligands, simple operation process, and reasonably good yields.
Acknowledgments
This work was financially supported by the National Natural Science Foundation of China (Nos. 20972042 and
21172057), and the Opening Foundation of Zhejiang Provincial Top Key Discipline.

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X.Y. Zhang et al. / Chinese Chemical Letters 23 (2012) 1129–1132
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[14] Typical procedure for the preparation of 3a: To a solution of 2-bromobenzyl bromide (1a, 0.5 mmol) and cyclohexane-1,3-dione (2a,
1.0 mmol) in DMF (3 mL) were added K2CO3 (1.5 mmol) and CuI (0.05 mmol). The mixture was stirred at 100 8C until a complete conversion.
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concentrated under vacuum. The crude product was purified by column chromatography eluting with ethyl acetate/hexane (10–20%) to give the
desired product 3a. Products 3b–3p were obtained in a similar manner. 3a: 1H NMR (400 MHz, CDCl3): d 2.00–2.06 (m, 2H), 2.44 (t, 2H,
J = 6.4 Hz), 2.53 (t, 2H, J = 6.4 Hz), 3.48 (s, 2H), 6.93 (d, 1H, J = 7.6 Hz), 7.03 (t, 1H, J = 6.8 Hz), 7.11–7.15 (m, 2H); 13C NMR (100 MHz,
CDCl3): d 20.6, 21.1, 27.7, 36.6, 109.9, 116.4, 120.8, 124.6, 127.6, 129.7, 149.7, 166.8, 198.1. MS: m/z 201 (MH)+. HRMS (FAB) Calcd. for
C
13H13O2: 201.0916 [M+H], found: 201.0919.