Accepted Manuscript

One-pot Synthesis of 12H-Benzo[b]xanthen-12-ones and Naphtha[2,3-b]furansfrom Non-naphthalene Substrates

Yan He, Shenghai Guo, Xuesen Fan, Chenhao Guo, Xinying Zhang

PII: S0040-4039(14)01166-6DOI: http://dx.doi.org/10.1016/j.tetlet.2014.07.025Reference: TETL 44868

To appear in: Tetrahedron Letters

Received Date: 10 May 2014Revised Date: 28 June 2014Accepted Date: 7 July 2014

Please cite this article as: He, Y., Guo, S., Fan, X., Guo, C., Zhang, X., One-pot Synthesis of 12H-Benzo[b]xanthen-12-ones and Naphtha[2,3-b]furans from Non-naphthalene Substrates, Tetrahedron Letters (2014),doi: http://dx.doi.org/10.1016/j.tetlet.2014.07.025

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Tetrahedron Letters jo urn al h om e pa ge: w w w.els evi er . com

One-pot Synthesis of 12H-Benzo[b]xanthen-12-ones and Naphtha[2,3-b]furans from

Non-naphthalene Substrates

Yan He, Shenghai Guo, Xuesen Fan,∗ Chenhao Guo, and Xinying Zhang*

School of Environment, School of Chemistry and Chemical Engineering, Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine

Chemicals, Henan Key Laboratory for Environmental Control, Henan Normal University, Xinxiang, Henan 453007, P. R. China

———

∗ Corresponding author. Tel.: +0-86-373-3329261; fax: +0-86-373-3329275; e-mail: xuesen.fan@htu.cn; xinyingzhang@htu.cn

In a recent study, we have revealed an oxidation initiated and

Et3N promoted synthesis of 3-acyl-2-naphthol (A, Scheme 1)

from 2-(4-hydroxy-but-1-ynyl)benzaldehyde.1 Meanwhile, it

was observed that xanthone derivatives could be synthesized via

base-promoted intramolecular O-arylation of (2-hydroxyaryl)(2-haloaryl)methanones,

1,2 and the benzofuran scaffolds were

usually constructed through condensation of (o-hydroxyaryl)

ketones with α-halocarbonyl compounds,3 respectively. As one-

pot tandem reactions have remarkable advantages over stepwise

synthesis, we envisioned a one-pot preparation of 12H-benzo[b]

xanthen-12-one (2a) directly from non-naphthalene substrates

via Jones reagent initiated and base (stronger than Et3N)

promoted cascade reaction of 2-(4-(2-bromoaryl)-4-hydroxybut-

1-ynyl)benzaldehyde (1a), as well as a new route toward 3-

phenylnaphtho[2,3-b]furan-2-carbonitrile (5a) via Jones reagent

initiated and base promoted cascade reaction of 2-(4-hydroxy-

but-1-ynyl)benzaldehyde (3a) with 2-bromo acetonitrile (4a) as shown in Scheme 1.

Xanthone unit constitutes the core of numerous naturally

occurring compounds.4 Moreover, xanthone and its derivatives

have shown antibacterial,5 anticancer,

4a,6 cytotoxic,

7 anti-HIV,

8

antimalarial,9 and antihypertensive activities.

10 Although several

reliable protocols for the preparation of xanthone derivatives

have been developed,11-17

new methods featured with a practical

and straightforward nature are still highly desirable.

Scheme 1. Proposed one-pot synthetic pathways toward 2a and 5a from the tandem reaction of non-naphthalene substrates.

Thus, 2-(4-(2-bromophenyl)-4-hydroxybut-1-ynyl)benzal-

dehyde (1a) was firstly treated with Jones reagent at 60 oC in

CH3CN for 10 min. Then, 1 equiv of Na2CO3 were added and

the resulting mixture was stirred under reflux for 4 h. To our

pleasure, the expected tandem process as shown in Scheme

1 occurred smoothly to give the desired 12H-benzo[b]xan-

then-12-one (2a) in 40% yield (Table 1, entry 1). Promisingly,

when Na2CO3 was replaced by K2CO3, the yield raised to

55% (entry 2). Further studies showed that a stronger base,

ARTIC LE INFO ABSTRACT

Article history:

Received

Received in revised form

Accepted

Available online

An efficient one-pot synthesis of 12H-benzo[b]xanthen-12-ones via an oxidant initiated and

base promoted tandem reaction of 2-(4-(2-haloaryl)-4-hydroxybut-1-ynyl)benzaldehydes has

been developed. By using similar strategy, a one-pot synthesis of naphtha[2,3-b]furans from

the cascade reaction of 2-(4-hydroxy-but-1-ynyl)benzaldehydes with 2-bromoacetonitrile or α-

bromocarbonyl compounds has also been achieved.

2009 Elsevier Ltd. All rights reserved.

Keywords:

12H-Benzo[b]xanthen-12-ones

Naphtha[2,3-b]furans

One-pot Synthesis

2

NaOH, or some weaker bases, such as NaHCO3 and KHCO3,

were much less effective than K2CO3 (entries 3-5). It was

also observed that the amount of base affected the yield of 2a

significantly and 2 equiv of K2CO3 gave the best yield

(entries 6-9). Subsequently, the effect of different

temperatures on this reaction was also studied (entries 10-12)

and a yield of 75% was obtained when the reaction was run in

refluxing CH3CN for 4 h (entry 12).

Table 1 Optimization study for the synthesis of 2a

a

Entry Base (equiv) T (°C) t (h) Yield (%) b

1 Na2CO3 (1) 60 4 40

2 K2CO3 (1) 60 4 55

3 NaOH (1) 60 4 20

4 NaHCO3 (1) 60 6 trace

5 KHCO3 (1) 60 6 trace

6 K2CO3 (0.2) 60 6 26

7 K2CO3 (0.5) 60 6 48

8 K2CO3 (2) 60 4 61

9 K2CO3 (3) 60 4 60

10 K2CO3 (2) r.t. 8 trace

11 K2CO3 (2) 40 6 43

12 K2CO3 (2) reflux 4 75 a Reaction conditions: 1a (0.5 mmol), Jones reagent (0.35 mmol), CH3CN (5 mL), 60 ºC, 10 min, then, base. b Isolated yield.

In the next stage, the scope and generality of this tandem

reaction was explored. It was firstly found that in addition to

2-bromo substituted substrate, 2-fluoro or 2-chloro derivative

could also take part in this reaction (Table 2, entries 2-3).

Among them, fluoro substituted substrate reacted faster than

bromo or chloro derivative. This is mostly likely due to

fluoride’s enormous inductive effect which accelerates the

rate-determining nucleophilic aromatic substitution step. On

the other hand, bromo substituted substrate was more reactive

than 2-chloro derivative since Br- is a better leaving group than

Cl- but has similar inductive effect as Cl-. Furthermore, the R1

Table 2

Scope of the reaction leading to 2a

Entry 1 2 Yield

(%)d

1

1a

2a

75

2

1a'

2a

74b

3

1a''

2a

70c

4

1b

3b

77

5

1c

2c

65

6

1d

2d

70

7

1e

2e

60

8

1f

2f

77

9

1g

2g

78

10

1h

2h

62

11

1i

2i

60

12

1j

2j

74

13

1k

2k

80

14

1l

2l

85

15

1m

2m

78

a Reaction conditions: 1 (0.5 mmol), Jones reagent (0.35 mmol),

CH3CN (5 mL), 60 ºC, 10 min, then, K2CO3 (1.0 mmol), reflux, 4 h. b 1 h. c 12 h. d Isolated yield.

Table 3

Scope of the reaction leading to substituted naphtho[2,3-b]furan 5a

Entry 3 4 5 Yield (%)b

1

3a

4a

5a

86

2

3b

4a

5b

87

3

3c

4a

5c

72

4

3d

4b

5d

72

5

3e

4b

5e

73

6

3c

4b

5f

70

7

3b

4c

5g

80

8

3f

4c

5h

83

9

3g

4c

5i

84

10

3b

4c

5j

88

11

3h

4c

5k

75

12

3i 4d

5l

73

13

3j 4e

5m

90

a Reaction conditions: 3 (0.5 mmol), Jones reagent (0.35 mmol), CH

3CN (5 mL), 60 ºC, 10 min; then, K

2CO

3 (2.0 mmol), 4 (0.6 mmol), reflux, 10 h.

b Isolated yield.

4unit of 1 could be either an electron-rich or an electron-deficient

group (entries 6-15). Meanwhile, the aromatic aldehyde moiety

with different substituents (R2) on the aryl ring could afford the

corresponding products in an almost equally efficient manner. As

a result, xanthones with different substitution patterns were

obtained efficiently and conveniently from this reaction.

On the other hand, literature searching revealed that naphtha-

[2,3-b]furan derivatives such as naphtho[2,3-b]furan-4,9-diones

were found in many naturally occurring products and were well

known for their biological activities.18 Therefore, the

development of novel methods for the preparation of naphtha

[2,3-b]furans scaffold is an important task in both synthetic and

medicinal arena. This promoted us to further explore the reaction

of 2-(4-hydroxy-but-1-ynyl)benzaldehyde in order to develop a

one-pot procedure for the preparation of naphtho[2,3-b]furan as

shown in Scheme 1.

For this purpose, 2 equiv of K2CO3 and 1.2 equiv of 2-bromo

acetonitrile (4a) were added to the mixture resulting from the

oxidation of 2-(4-hydroxy-4-phenylbut-1-ynyl)benzaldehyde (3a)

with Jones reagent in CH3CN. It was then stirred under reflux for

4 h. Promisingly, the expected 3-phenylnaphtho[2,3-b]furan-2-

carbonitrile (5a) was obtained in a yield of 47%. When the

amount of K2CO3 increased from 2 equiv to 4 equiv and the

reaction period prolonged from 4 h to 10 h, the yield of 5a

improved to 86%, thus resulting a highly efficient and

straightforward protocol for the preparation of naphtho[2,3-b]

furan from substrate without a naphthalene scaffold. Encouraged

by this result, other 2-(4-hydroxy-4-phenylbut-1-ynyl)benz-

aldehydes and α-halocarbonyl compounds were also tested and

the results were listed in Table 3. We were pleased to find that

this new method could be applied to substrates possessing

various functional groups on the benzene ring (Table 3, entries 1-

13). Halogen atoms, trifluoromethyl and methoxy groups were

well tolerated under the reaction conditions. It was notable that in

addition to phenyl unit, the R1 section of 3 could also be a

naphthyl or thienyl unit (entries 11-13). Thankfully, not only 2-

bromoacetonitrile (entries 1-3) but also ethyl 2-bromoacetate

(entries 4-6) and 2-bromo-1-arylethanone (entries 7-13)

participated in this reaction smoothly to afford the corresponding

naphtho[2,3-b]furans (5a-5m) in good to excellent yields.

Finally, on the basis of the above observations and previous

reports,1-3 plausible mechanisms for the formation of 2a and 5a

are proposed in Scheme 2. Initially, through the tandem reaction

of 1a or 3a, 3-acyl-2-naphthol (A) as a key intermediate is

formed and it should be simultaneously transformed into anion B

in the presence of K2CO3. When the X unit in B is a bromo group,

an intramolecular O-arylation occurs to give 2a with C as a

possible intermediate. On the other hand, when X is H and in the

presence of 2-bromoacetonitrile (4a), anion B undertakes a

nucleophilic substitution reaction with 4a to give intermediate D.

Subsequent intramolecular aldol type reaction of D under the

promotion of base affords 5a as the final product.

In summary, we have developed a straightforward and efficient

one-pot protocol for the preparation of benzo[b]xanthen-12-ones

via Jones reagent initiated and K2CO3 promoted tandem reaction

of the readily obtainable 2-(4-(2-haloaryl)-4-hydroxybut-1-

ynyl)benzaldehydes. Moreover, with 2-(4-hydroxy-but-1-ynyl)

benzaldehydes as the substrates and in the presence of 2-

bromoacetonitrile or α-bromocarbonyl compounds, a more

sophisticated process could be realized to afford naphtha[2,3-b]

furans with high efficiency. Compared with literature procedures,

the strategies developed in this paper showed remarkable

advantages such as readily available starting materials, simple

synthetic procedure and high efficiency.

O

2a

O

O

OBr

OCN

OH

CHO

X

1) oxidant

2) base

O

X

O

X

O

B

O O

D

OH

O

Br OC

X = Br

NCCH2Br (4a)X = H

CN

O

O CN

base

5a

base

1a: X = Br

3a: X = H

A

Scheme 2. Proposed pathways for the formation of 2a and 5a.

Acknowledgments

This work was financially supported by the National Natural

Science Foundation of China (NSFC) (grant numbers 21172057,

21272058), the Research Fund for the Doctoral Program of Higher Education (RFDP) (grant number 20114104110005), and

the Program for Changjiang Scholars and Innovative Research

Team in University (PCSIRT) (IRT 1061) for financial support.

Supplementary data

Supplementary data associated with this article can be found,

in the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.

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19. Typical procedure for the preparation of 12H-benzo[b]xanthen-12-one

(2a): To a flask containing 2-(4-(2-bromophenyl)-4-hydroxybut-1-

ynyl) benzaldehyde (1a, 164 mg, 0.5 mmol) in CH3CN (5 mL) was

added Jones reagent (0.35 mmol, 0.13 mL) dropwisely with stirring at

60 oC. Then, the stirring continued for another 10 min. At this stage,

K2CO3 (1 mmol, 138 mg) was added and the resulting mixture was stirred under reflux for 4 h. Upon completion, the reaction was

quenched by addition of isopropanol. The mixture was filtered and the

filtrates were concentrated under vacuum. The residue was purified by column chromatography on silica gel to give 12H-benzo[b]xanthen-12-

one (2a). Eluent: petroleum ether-ethyl acetate (20:1); solid (92 mg,

75%), mp 209-211 oC (214-215 oC)17; 1H NMR (400 MHz, CDCl3) δ:

7.34 (t, J = 7.6 Hz, 1H), 7.44-7.48 (m, 2H), 7.58 (t, J = 7.2 Hz, 1H),

7.69-7.73 (m, 1H), 7.82 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 8.02 (d, J =

8.0 Hz, 1H), 8.32-8.35 (m, 1H), 8.88 (s, 1H); 13C NMR (100 MHz,

CDCl3) δ: 113.6, 117.9, 121.1, 121.3, 123.5, 125.5, 126.97, 127.05, 128.4, 129.1, 129.5, 129.8, 135.3, 136.7, 152.2, 156.7, 178.0; MS: m/z

247 [MH]+. Other benzo[b]xanthen-12-ones (2b-2m) were obtained in

a similar manner. 20. Typical procedure for the preparation of 3-phenylnaphtho[2,3-b]furan-

2-carbonitrile (5a): To a flask containing 2-(4-hydroxy-4-phenylbut-1-

ynyl)benzaldehyde (3a, 125 mg, 0.5 mmol) in CH3CN (5 mL) was

added Jones reagent (0.35 mmol, 0.13 mL) dropwisely with stirring at 60 oC. Then, the stirring continued for another 10 min. At this stage,

K2CO3 (2 mmol, 276 mg) and 2-bromoacetonitrile (4a, 71 mg, 0.6

mmol) were added and the resulting mixture was stirred under reflux for 10 h. Upon completion, the reaction was quenched by addition of

isopropanol. The mixture was filtered and the filtrate was concentrated

under vacuum. The residue were purified by column chromatography on silica gel to give 3-phenylnaphtho[2,3-b]furan-2-carbonitrile (5a).

Eluent: petroleum ether-ethyl acetate (20:1); solid (116 mg, 86%), mp

133-135 oC; 1H NMR (400 MHz, CDCl3) δ: 7.50-7.65 (m, 5H), 7.84-

7.86 (m, 2H), 7.98 (d, J = 8.0 Hz, 3H), 8.33 (s, 1H); 13

C NMR (100 MHz, CDCl3) δ: 108.0, 121.1, 125.1, 125.7, 126.9, 127.9, 128.5, 128.7,

129.5, 129.8, 131.0, 133.4, 153.6; MS: m/z 270 [MH]+; HRMS (ESI)

calcd for C19H12NO: 270.0919 [M+H], found: 270.0923. Other naphtha [2,3-b]furans (5b-5m) were obtained in a similar manner.

6

Graphical Abstract

One-pot Synthesis of 12H-Benzo[b]xanthen-

12-ones and Naphtha[2,3-b]furans from Non-

naphthalene Substrates

Yan He, Shenghai Guo, Xuesen Fan,* Chenhao Guo, and Xinying Zhang*

Leave this area blank for abstract info.