A Simple and Efficient Access to Naphtho[b]furans by Claisen Rearrangement/Cyclization of Bromonaphthyl 3-Phenylallyl Ethers

Article abstract of DOI:10.1002/adsc.201500151

A transition-metal-free Claisen rearrangement/cyclization reaction was developed for the synthesis of naphthofuran derivatives from bromonaphthyl 3-phenylallyl ethers. The nature of the base employed in this reaction plays an important role in determining the ratio for the formation of naphthofuran and naphthol products. By using K₂CO₃ as base and DMF as solvent, we have synthesized a variety of functionalized naphthofurans in good to high yields (49-92 %) and with satisfactory selectivities.

Full text of DOI:10.1002/adsc.201500151

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DOI: 10.1002/adsc.201500151
A Simple and Efficient Access to Naphtho[b]furans by Claisen
Rearrangement/Cyclization of Bromonaphthyl 3-Phenylallyl
Ethers
Wei Wang,a Jin Huang,a Rong Zhou,b Zhi-Jie Jiang,a Hai-Yan Fu,a,*
Xue-Li Zheng,a Hua Chen,a and Rui-Xiang Lia,*
a
Key lab of Green Chemistry and Technology, Ministry of Education; College of Chemistry, Sichuan University, Chengdu
610064, Peopleꢀs Republic of China
Fax: (+86)-28-8541-2904; e-mail: liruixiang@scu.edu.cn or scufhy@scu.edu.cn
Chemical Engineering College, Xinjiang Agricultural University, Urumqi 830052, Peopleꢀs Republic of China
b
Received: February 13, 2015; Revised: May 21, 2015; Published online: July 14, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500151.
Abstract:
A
transition-metal-free Claisen rear-
naphthyl 2-propynyl ethers (Scheme 1a). Unfortu-
nately, expensive and highly hygroscopic CsF was
used as base to promote this reaction. More recently,
Rueping[13] and Yoshimi et al.[14] prepared a series of
naphtho[b]furans in good yields, utilizing a transition-
metal-free Heck-type cyclization/isomerization reac-
tion of halonaphthyl ethers (Scheme 1b). However,
these transformations required either highly basic
KOtBu or UV light, thus limiting their functional
group tolerance. Therefore, the development of
a simple, straightforward and cost-effective method to
synthesize naphtho[b]furans is highly desirable.
Herein, we report a transition metal-free process for
the synthesis of naphtho[b]furans from bromonaphth-
rangement/cyclization reaction was developed for
the synthesis of naphthofuran derivatives from bro-
monaphthyl 3-phenylallyl ethers. The nature of the
base employed in this reaction plays an important
role in determining the ratio for the formation of
naphthofuran and naphthol products. By using
K2CO3 as base and DMF as solvent, we have syn-
thesized a variety of functionalized naphthofurans
in good to high yields (49–92%) and with satisfac-
tory selectivities.
Keywords: bromonaphthyl ethers; Claisen rear-
rangement; cyclization; naphthofurans; transition-
metal-free
Naphtho[b]furans are important structural motifs that
find presence in many natural products[1] and pharma-
ceutical agents.[2] As a consequence, numerous effi-
cient synthetic strategies have been developed for the
construction of this structure. Among the protocols
reported to date, most involve the use of versatile
starting substrates[3] in combination with a suitable
transition-metal catalyst, such as Pd,[4] Pt,[5] In,[6] Ru,[7]
Au,[8] Ag,[9] Fe,[10] Cu.[11] Despite of their synthetic ver-
satility, the cost of transition-metal catalysts and the
difficulty associated with removing transition-metal
impurities from final products may restrict the practi-
cal applicability of these methods.
Not surprisingly, transition-metal-free approaches
to prepare naphthofurans have also been pursued.
For example, in 2012, Thomas et al.[12] reported that
naphtho[b]furans could be obtained in high yields by
Scheme 1. General strategies for the construction of the
naphtho[b]furan skeleton through a transition-metal-free
a facile microwave-assisted Claisen rearrangement of system.
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A Simple and Efficient Access to Naphtho[b]furans
Table 1. Effect of bases on this reaction[a]
Table 2. Effect of solvents on this reaction[a]
Entry K2CO3
[mmol]
Solvent Temp Yield of 2a Yield of
[8C]
[%][b]
3a [%][b]
1
2
0.5
0.5
toluene 100
n-buta- 100
nol
2
13
20
5
3
0.5
1,4-di- 100
oxane
1
2
Entry
Base
Yield of 2a [%][b]
Yield of 3a [%][b]
4
5
6
7
0.5
0.5
0.5
0.5
0.5
0.5
0.25
0.75
1.0
NMP
DMA
DMF
DMF
DMF
DMF
DMF
DMF
DMF
120
120
120
100
100
80
120
120
120
58
85
89
24
71
11
84
91
86
40
11
8
2
6
8
8
7
8
1
2
3
4
5
6
7
8
–
0
0
NaOAc
Li2CO3
Na2CO3
K2CO3
Cs2CO3
K3PO4
NaOH
LiOtBu
NaOtBu
KOtBu
23
28
45
85
68
66
22
62
4
43
49
47
11
24
27
49
27
93
46
8[c]
9[c]
10
11
12
[a]
9
10
11
Reaction conditions: 1a (0.25 mmol), under nitrogen, sol-
vent (1 mL), 8 h.
Yields are determined by HPLC.
24 h.
[b]
[c]
26
[a]
Reaction conditions: 1a (0.25 mmol), base (0.5 mmol),
DMA (1 mL), under nitrogen, 1208C, 24 h.
Yields are determined by HPLC.
[b]
(NMP) significantly decreased the yield (Table 2, en-
tries 1–4). Switching solvent to dimethylformamide
yl 3-phenylallyl ethers via a Claisen rearrangement/ (DMF) improved the reaction efficiency, and the de-
cyclization cascade event (Scheme 1c). This method sired naphtho[b]furan 2a was formed in 89% yield
requires K2CO3 as base and DMF as solvent, and pro- (Table 2, entry 6). Lowering the reaction temperature
vides various naphtho[b]furan compounds with di- had a deleterious effect on the reaction performance
verse substitution patterns.
(Table 2, entries 8 and 9). The amount of K2CO3 was
In our initial studies, 1-bromo-2-[[(2E)-3-phenyl-2- also briefly assessed. The best yield of 2a was ob-
propen-1-yl]oxy]naphthalene (1a) was chosen as served when 3 equiv of K2CO3 was employed
model substrate and dimethylacetamide (DMA) as (Table 2, entries 10–12). Based on these optimization
solvent (Table 1). However, no desired naphtho[2,1- studies, further reactions were performed in DMF at
b]furan 2a was detected after being heated at 1208C 1208C in the presence of 3 equiv of K2CO3.
for 24 h (Table 1, entry 1). Considering there is
To evaluate the substrate scope of this reaction, we
a formal loss of HBr during the product formation, subjected a wide range of bromonaphthyl 3-phenylall-
we envisioned that a base would be a good promoter yl ethers to the established conditions. First, different
for the reaction. As expected, the introduction of substituents on the 3-phenyl moiety were tested
bases like NaOAc, Li2CO3, or Na2CO3 induces this re- (Table 3). Among the different para-substituted
action to occur, and the desired product 2a was ob- phenyl derivatives screened, those bearing electron-
tained in acceptable yields (Table 1, entries 2–4). It is donating groups provided higher product yields than
noteworthy that under these conditions, a byproduct, those bearing electron-withdrawing groups (Table 3,
2-naphthol derivative 3a was also formed in signifi- 2b–2g). Furthermore, the yields of the byproducts 2-
cant amounts (43–49% yields), the structure of which naphthol 3c-3e decreased as the substituent became
was unambiguously confirmed by single-crystal X-ray more electron-donating. To our delight, meta- or steri-
diffraction.[15,16] Further screening of base showed cally demanding ortho-substituted phenyl derivatives
K2CO3 to be optimal, which not only suppressed the were also tolerated, furnishing the desired products
formation of 3a, but afforded 2a in 85% yield 2h–2l in good to excellent yields (79–88%). The
(Table 1, entries 5–11). Interestingly, the use of structure of compound 2k was further confirmed by
sodium tert-butoxide (NaOtBu) led to 3a as the major single-crystal X-ray diffraction.[17] Notably, the isomer-
product in 93% yield (Table 1, entry 10). These re- ic 2-bromonaphthyl ether (1a’) also participated in
sults suggest that the base exhibits a dramatic effect this reaction, and gave naphthofuran 2a’ in 53%
on both reaction selectivity and yield.
yield. Unexpectedly, for substrate 1m bearing a 2-CF3
Having identified the optimal base, we then group, a double bond isomerization occurred to give
screened different solvents (Table 2). The use of tolu- vinyl ether 1m’ in 50% yield,[18] and none of the de-
ene, n-butanol, 1,4-dioxane, or N-methylpyrrolidone sired product was observed.
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Wei Wang et al.
Table 3. Scope of the transition-metal-free Claisen rear-
rangement/cyclization reaction of 1-bromonaphthyl deriva-
tives.[a]
Table 4. Scope of the transition-metal-free Claisen rear-
rangement/cyclization reaction of 1,6-dibromonaphthyl de-
rivatives.[a]
[a]
Reaction conditions: 1 (0.25 mmol), K2CO3 (0.75 mmol),
DMF (1 mL). Yields of isolated products.
this reacting, resulted in 2x and 2y in good to excel-
lent yields. These results demonstrated the generality
and usefulness of this strategy.
[a]
Reaction conditions: 1 (0.25 mmol), K2CO3 (0.75 mmol),
DMF (1 mL). Yields of isolated products.
We have performed several experiments to eluci-
date the mechanism of this transformation (Table 5).
To rule out the possibility that this reaction was cata-
lyzed by the trace level of transition-metal contami-
nant,[20] we repeated our model reaction (1a to 2a,
Table 5, entry 1) using metal-free, high purity
[b]
1a’ was used.
We next explored the reactivity of 1,6-dibromo- (99.997%) K2CO3.[21] No reduction in rate or change
naphthyl ethers under the same reaction conditions in selectivity was observed in this case (Table 5,
(Table 4). To our delight, all the tested substrates 1n– entry 1).
1v could react smoothly, affording corresponding bro-
We then preformed this reaction in the presence of
minated naphtho[b]furans 2n–2v in up to 92% yield. air or radical inhibitor 2,2,6,6-tetramethyl-1-piperidi-
À
Interestingly, only one C Br bond was chemoselec- noxy (TEMPO). The reaction efficiency was not sig-
tively cleaved during the reaction, and the remaining nificantly inhibited under these conditions (Table 5,
aryl bromide functional group can serve as a versatile entries 2 and 3). Moreover, the reaction worked
handle for further manipulation. In case of substrate equally well when conducted in the dark (Table 5,
1w containing 2-CF3 group at 2-propenyl moiety, no entry 4). These results described above suggested that
desired product was formed. Like 1m it was again a radical mechanism[13,14] might not be operating in
prone to undergo double bond isomerization into the this process. Furthermore, chloro-substituted deriva-
vinyl ether compound 1w’.[19] These observations tive 1aa produced the desired product 2a only in 6%
could be explained by an intramolecular [1,3]-type H- yield under the present reaction conditions, whereas
shift.[10d,13] In addition, substrates bearing pharmaceut- the use of higher temperature afforded 2a in 36%
ically relevant quinoline rings could also be used in yield. (Y=Cl, Table 5, entries 5 and 6). Here, a plausi-
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A Simple and Efficient Access to Naphtho[b]furans
Table 5. Condition-controlled Claisen rearrangement/cycliza-
tion reaction of 1[a]
Entry Y Conditions
Yield of 2a Yield of 3a
[%][b]
86
[%][b]
8
1
Br K2CO3(99.997%,
Alfa), N2
Br air
2
73
67
89
6
17
31
7
Scheme 3. Proposed mechanism.
3
4
Br TEMPO, N2
Br no light, N2
Cl N2
5
5
6[c]
Cl N2
36
46
In conclusion, we have developed a simple and effi-
cient method for constructing various naphtho[b]fur-
ans from bromonaphthyl 3-phenylallyl ethers via
a transition-metal-free Claisen rearrangement and
cyclization reaction. Compared with the previous ap-
proaches, the present methodology has the advantag-
es of simple reaction system, operational ease, and
[a]
Reaction conditions: 1 (0.25 mmol), K2CO3 (0.75 mmol),
DMF (1 mL), 1208C, 8 h.
Yields are determined by HPLC.
1408C, 20 h.
[b]
[c]
ble explanation could be a lower compulsion of the broad applicability, and should be an attractive choice
chlorine to leave the naphthyl ring, which hinders the for the synthesis of naphtho[b]furan derivatives.
processes of Claisen rearrangement and cyclization.[13]
Additionally, it was found that 3a failed to give any
of the desired product 2a under the employed condi- Experimental Section
tions, so 3a was not the intermediate species to form
2a. Addition of Ag2CO3 led to the transformation of
3a to 2a in high yield (Scheme 2).
Representative procedure for 2a: K2CO3 (0.75 mmol) and
1a (0.5 mmol) were added into a dried Schlenk tube with
a magnetic bar, which was subjected to evacuation/flushing
with dry nitrogen five times, and then DMF (1.0 mL) was
added into it. The reaction mixture was heated at 1208C for
20 h with stirring. After cooling, water (3 mL) was added
into the mixture and subsequently the mixture was extracted
with ethyl acetate (3”3 mL). The combined organic extracts
were washed with brine (3”3 mL), dried with anhydrous
MgSO4, and concentrated under vacuum. The residue was
purified by silica gel chromatography (petroleum ether) to
give the product 2a (112 mg, 0.435 mmol, 87%).
On the basis of these results, a tentative mechanism
of this reaction is proposed in Scheme 3. Phenylallyl
ether 1a first undergoes a [3,3]-sigmatropic rearrange-
ment to give the dearomatized intermediate A. Base-
induced dehydrohalogenation of A then affords al-
kenyl ketone B, which then cyclizes to give the arom-
atized intermediate C.[12,22] The desired product 2a is
ultimately constructed via tautomerization of C,[12,14]
another aromatizing process. The byproduct naphthol
3a is possibly produced by direct reduction of the in-
termediate A by base or solvent.[23] Further study on
the formation of 3a is currently ongoing in our labo-
ratory and will be reported in due course.
Acknowledgements
We gratefully acknowledge the Natural Science Foundation
of China (No. 21202104).
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