Highly efficient synthesis of 9-aminoxanthenes via the tandem reaction of arynes with salicyl N-tosylimines

Article abstract of DOI:10.1016/j.cclet.2012.11.008

A cascade insertion-nucleophilic annulation reaction of salicyl N-tosylimines with aryne generated in situ from 2-(trimethylsilyl) aryl triflate and KF-18-crown-6 has been developed, providing 9-aminoxanthenes efficiently in one step.

Full text of DOI:10.1016/j.cclet.2012.11.008

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 1359–1362
www.elsevier.com/locate/cclet
Highly efficient synthesis of 9-aminoxanthenes via the tandem
reaction of arynes with salicyl N-tosylimines
*
Lin He , Ji Xin Pian, Jing Zhang, Yuan Zhen Li
Key Laboratory for Green Processing of Chemical Engineering of Xinjiang Bingtuan and School of Chemistry and
Chemical Engineering, Shihezi University, Shihezi 832000, China
Received 15 August 2012
Available online 30 November 2012
Abstract
A cascade insertion–nucleophilic annulation reaction of salicyl N-tosylimines with aryne generated in situ from 2-(trimethyl-
silyl) aryl triflate and KF-18-crown-6 has been developed, providing 9-aminoxanthenes efficiently in one step.
# 2012 Lin He. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Salicyl N-tosylimines; Aryne; 9-Aminoxanthene
Arynes are highly reactive intermediate those have been applied widely in organic chemistry [1]. About 30 years
ago, the group of Kobayashi demonstrated that arynes can be generated in situ through the fluoride induced 1,2-
elimination of 2-(trimethylsilyl) aryl triflates under mild conditions [2]. These findings led to a dramatic growth in
aryne chemistry and a variety of important transformations have been developed, such as pericyclic reactions,
insertion reactions, multicomponent reactions and others [3]. On the other hand, owing to the biological and
pharmaceutical activity, xanthenes and their derivatives have attracted considerable attention over the past decade [4].
Several methods for the preparation of xanthenes have been established and usually involve the Friedel–Crafts
reaction to construct the central heterocyclic ring [5]. However, the multistep reaction, complicated manipulation and
hash reaction conditions restrain their potential application. Therefore, it is still meaningful to develop more simple
and efficient method for the synthesis of this type of compounds.
Recently, Okuma [6], Larock [7] and Huang [8] developed a tandem insertion–nucleophilic cyclization strategy to
access xanthenes independently. Through this strategy, arynes coupled with different intramolecular bifunctional (Nu-
E) substrates such as 2-substituted benzoates, salicylaldehydes and ortho-hydroxychalcones smoothly to give
xanthones, 9-hydroxyxanthenes and 9-alkylxanthenes respectively (Scheme 1). In line with our continuing interest of
the reaction of organosilicon reagents [9], we envisioned that under the promotion of fluoride, 2-(trimethylsilyl)aryl
triflates may proceed a cascade insertion–cyclization reaction with ortho-substituted imines to give 9-
aminoxanthenes. To the best of our knowledge, no straightforward methodology for the synthesis of this type of
xanthene derivatives has been reported. Herein, we would like to disclose our preliminary results on the coupling of
arynes with salicyl N-tosylimines to give 9-aminoxanthenes under very mild conditions.
At the outset, the tandem reaction of salicyl N-tosylimine 2a with aryne precursor 1a was selected as the model
reaction. To our delight, we found that in the presence of 3.0 equiv. CsF, the cascade reaction proceeded smoothly
* Corresponding author.
E-mail address: helin@shzu.edu.cn (L. He).
1001-8417/$ – see front matter # 2012 Lin He. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2012.11.008

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L. He et al. / Chinese Chemical Letters 23 (2012) 1359–1362
O
R
R
R
TMS
CO2R
CsF
+
+
(a)
(b)
Ref7a, 7b
OTf
OH
O
OH
H
R
TMS
CHO
OH
CsF
Ref6
OTf
O
E
E
TMS
OTf
CsF
Ref7c, 8
+
+
(c)
(d)
O
OH
NTs
NHTs
R
TMS
OTf
R
KF-18-crown-6
this work
OH
O
3
2
1
Scheme 1. Fluoride promoted nucleophilic cyclization of arynes to xanthenes.
under mild conditions, to give 9-aminoxanthene 3a in 70% isolated yield (Table 1, entry 1). With these fruitful result in
hand, other fluorides such as KF, Bu4NF and KF/Al2O3 [10] were also tested for the reaction, but only obtained the
desired product in very low yield (Table 1, entries 2–4). Conducted the reaction in CH3CN/Et2O mixed solvent or
added 2.0 equiv. carbonate to the reaction, no improvement of the yield was observed (Table 1, entries 5–7).
Fortunately, when 2.0 equiv. 18-crown-6 was added as co-additive with 3.0 equiv. KF, the reaction could be converted
quantitatively within 1 h (Table 1, entry 8). To our surprise, either increased the amount of 18-crown-6 to 3.0 equiv. or
reduced to 1.0 equiv., the reaction yield decreased obviously (Table 1, entries 9 and 10).
Other reaction media such as THF, toluene, ether and dichloromethane were also evaluated briefly, the experiments
indicated that acetonitrilewas the best choice with respect to yield (Table 1, entries 11–14). Lowered the amount of KF to
2.0 equiv. and 1.0 equiv., respectively, the yield of the reaction also decreased steply (Table 1, entries 15 and 16). Finally,
control experiment showed that the reaction cannot occur in the absence of fluoride (Table 1, entry 17).
With the optimal reaction conditions in hand (3.0 equiv. KF, 2.0 equiv. 18-crown-6, CH3CN, room temperature), the
generality of the cascade reaction was evaluated and the results were summarized in Table 2 [11]. For salicyl
Table 1
Evaluation of conditions for the tandem reaction.a
Entry
Additives
Solvent
Time (h)
Yield (%)b
1
CsF 3.0 equiv.
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN/Et2O
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
12
12
12
12
12
12
12
1
70
<10
22
2
KF 3.0 equiv.
3
Bu4NF 3.0 equiv.
4
KF/Al2O3 3.0 equiv.
<10
<10
18
5
KF 3.0 equiv.
6
KF(3.0 equiv.) + Cs2CO3(2.0 equiv.)
KF(3.0 equiv.) + K2CO3(2.0 equiv.)
KF(3.0 equiv.) + 18-crown-6(2.0 equiv.)
KF(3.0 equiv.) + 18-crown-6(3.0 equiv.)
KF(3.0 equiv.) + 18-crown-6(1.0 equiv.)
KF(3.0 equiv.) + 18-crown-6(2.0 equiv.)
KF(3.0 equiv.) + 18-crown-6(2.0 equiv.)
KF(3.0 equiv.) + 18-crown-6(2.0 equiv.)
KF(3.0 equiv.) + 18-crown-6(2.0 equiv.)
KF(2.0 equiv.) + 18-crown-6(1.3 equiv.)
KF(1.0 equiv.) + 18-crown-6(0.6 equiv.)
No additives
7
<10
99
8
9
1
71
10
11
12
13
14
15
16
17
1
69
1
8
Et2O
1
6
Toluene
CH2Cl2
CH3CN
CH3CN
CH3CN
1
9
1
57
6
85
6
39
6
0
a
Reaction conditions: 1 (1.5 equiv.) and 2a (0.1 mol/L, 1.0 equiv.), room temperature.
Isolated yield.
b

L. He et al. / Chinese Chemical Letters 23 (2012) 1359–1362
1361
N-tosylimines, substitution of an electron-donating or electron-withdrawing group on the aromatic ring resulted in no
obvious effect on the yield (Table 2, entries 1–4). Additionally, different positions of the substituted groups on the
aromatic ring were all tolerated and the desired products were obtained in excellent yield (Table 2, entries 5–7). More
interestingly, N-tosyliminederivedfrom2-hydroxy-1-naphthaldehydewasalsoprovedtobegoodreactantforthetandem
reaction, afforded compound3 h in98%yield(Table 2, entry8). On the otherhand, the substituted aryneprecursor 1bcan
also react with salicyl N-tosylimine to provide 9-aminoxanthene in high yield (Table 2, entry 9).
Based on the experiments results and the pioneering work on fluoride promoted insertion–cyclization reactions of
arynes, a plausible mechanism was proposed and depicted in Scheme 2. Fluoride ion attacks 2-(trimethylsilyl)aryl
triflate 1 to afford aryne, while the free KF complexed with salicyl imine to form intermediate I, which undergo
insertion reaction with aryne to give intermediate II, and after nucleophilic cyclization to provide 9-aminoxanthene.
In summary, we have demonstrated a fluoride promoted insertion–nucleophilic annulation of aryne and salicyl
tosylimine. The very mild conditions, simple procedure provides a highly efficient approach for the construction of 9-
aminoxanthenes. Further exploration and application of this protocol are ongoing in our laboratory.
Table 2
Preliminary scope of the insertion–nucleophilic cyclization reaction.
Entry
1
Aryne precursor
Salicyl tosylimine
Product
Yield (%)b
99
NTs
TMS
NHTs
OTf
1a
2a
3a
OH
O
NTs
NHTs
2
3
4
5
1a
1a
1a
1a
96
93
92
95
MeO
H3CO
2b
O
3b
OH
NTs
NHTs
Cl
Br
Cl
Br
OH
2c
3c
O
NTs
NHTs
OH 2d
3d
O
NTs
OH
NHTs
O
OC2H5
OC2H5
2e
3e
NHTs
NTs
6
7
1a
1a
95
95
H
3
CO
OH
H
3
CO
O
2f
3f
NHTs
NTs
OH
O
F
F
2g
3g
8
1a
98
84
NHTs
NTs
OH 2h
O
3h
Me
Me
TMS
OTf
NHTs
O
NTs
9
Me
Me
1b
OH
3i
a
Reaction conditions: 1 (0.45 mmol), 2 (0.3 mmol), KF (0.9 mmol), 18-crown-6 (0.6 mmol), anhydrous acetonitrile 3.0 mL, room temperature.
b
Isolated yield.

1362
L. He et al. / Chinese Chemical Letters 23 (2012) 1359–1362
O
O
O
O
O
TMS
TfO
F
K
O
+
+ TMSF
Ts
K
N
NTs
Ts
F
N
+
KF
K
F
O
H
O
H
OH
(I)
(II)
NTs
NHTs
O
O
H
(III)
Scheme 2. Proposed reaction mechanism.
Acknowledgments
We appreciate the National Natural Science Foundation of China (No. 21162022) and the Team Innovation Project
of Shihezi University (No. 2011ZRKETD-04) for financial support.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/
j.cclet.2012.11.008.
References
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[11] General procedure: a solution of 2-(trimethylsilyl) aryl triflate (110 mL, 0.45 mmol), salicyl N-tosylimine 2a (83 mg, 0.3 mmol), KF (54 mg,
0.9 mmol), 18-crown-6 (159 mg, 0.6 mmol) in 3.0 mL anhydrous acetonitrile was stirred for 1 h at room temperature, then, the reaction mixture was
diluted with 15 mL ethylacetate and filtered through a pad of silica gel. The solvent was concentrated in vacuum and the residue was purified by flash
chromatography (silica gel, Pe–EtOAc 5:1–3:1) to give 3a as pure product. Data for 3a: White solid, mp 191.2–191.8 8C; Yield: 99%; IR (KBr, cmÀ1
)
(3324, 2962, 1599, 1573, 1481, 1454, 1425, 1325, 1263, 1155, 1088, 1022, 884, 817, 744, 662, 557; 1H NMR (400 MHz, CDCl3): d 7.72 (d, 2H,
J = 8.16 Hz), 7.25 (d, 2H, J = 8.16 Hz), 7.22–7.14 (m, 2H), 7.10–6.86 (m, 6H), 5.68 (d, 1H, J = 8.6 Hz), 4.86 (d, 1H, J = 8.6 Hz), 2.39 (s, 3H); 13
C
NMR (100 MHz, CDCl3): d 150.19, 142.56, 137.52, 128.78, 128.41, 126.09, 122.54 119.32, 115.67, 48.10, 20.57.