The direct substitutions of 9H-xanthen-9-ol with indoles in a room temperature ionic liquid medium BmimBF4

Article abstract of DOI:10.1016/j.tetlet.2011.08.085

A simple, atom economical, highly efficient and green protocol has been developed for the S_N1-type substitutions of 9H-xanthen-9-ol with indoles or other nucleophiles (such as diketone and pyrrole). This approach provides the substitution products in high or excellent yields in the BmimBF₄ media at room temperature.

Full text of DOI:10.1016/j.tetlet.2011.08.085

Tetrahedron Letters 52 (2011) 5636–5639
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
The direct substitutions of 9H-xanthen-9-ol with indoles in a room
temperature ionic liquid medium BmimBF4
⇑
⇑
Ling-yan Liu , Bing Wang, Hong-mei Yang, Wei-xing Chang, Jing Li
State Key Laboratory and Research Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 June 2011
Revised 26 July 2011
Accepted 16 August 2011
Available online 22 August 2011
A simple, atom economical, highly efficient and green protocol has been developed for the SN1-type sub-
stitutions of 9H-xanthen-9-ol with indoles or other nucleophiles (such as diketone and pyrrole). This
approach provides the substitution products in high or excellent yields in the BmimBF4 media at room
temperature.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Xanthen-9-ol
Indoles
Nucleophiles
Ionic liquid
Introduction
Many of these procedures involved strong acidic conditions, low
yields of products, and complex handling. For this reason, superior
With the rapid development in chemistry industry and academic,
green chemistry has been promoted worldwide by an increasing
number of research groups because it provides transformations that
are environmentally benign.1,2 As a result, ionic liquids have
received recognition as green media in organic synthesis, because
they display many advantages over common organic solvents, such
as low flammability, low volatility, low toxicity, wide liquid range
and thermal stability and so on.3 A more attractive feature of ILs is
the possibility to recycle them and to easily recover the product
(by simple extraction procedures). It is immiscible with many
organic solvents, and possesses good solvating properties for both
inorganic and organic compounds.4,5 A lot of organic,4 organometal-
lic,4,5 and biocatalyzed reactions5,6 have been investigated in ionic
liquids. Moreover, it is found that many reactions could smoothly
proceed in ionic liquid but not in organic solvents. Of course, the
ionic liquid is not omnipotent. Some reactions can only proceed in
organic solvents but not run in ionic liquid media. In addition, the
isolation of reaction products is also often simple. Thus, ionic liquids
have been widely used as environmentally benign solvents to
replace the common organic reaction media.7
catalyst systems, which are cheap, easy to access, and in stable air,
are desirable. Shun-jun Ji has recently found that indium tris(dode-
cyl Sulfonate) (In(DS)3), a strong Lewis acidic surfactant, efficiently
catalyzes 9H-xanthen-9-ol with various indoles in water.10 Pier
Giorgio Cozzi reported the direct substitution of alcohol ‘on water’
without added Bronsted or Lewis acid is possible.11 But this ‘on
water’ reaction must be carried out at 80 °C. Recently, Jianji Wang
reported this direct nucleophilic substitution of alcohols mediated
by a zinc-based ionic liquid.12 In fact, this zinc-based IL is still an
organic metal Lewis acid catalyst in organic synthesis. In addition,
the indole moiety represents the main structural feature of a variety
of unnatural and natural bioactive products, such as the indole alka-
loids.13,14 Since the 3-position of indole is the preferred site for the
electrophilic substitution, the SN1-type substitution of 9H-xanthen-
9-ol with various indoles is feasible without any catalyst.
With these in our mind and as part of our ongoing research
work on ionic liquid,15 we reported herein that ionic liquids could
be used as an efficient reaction media in the SN1-type substitution
of 9H-xanthen-9-ol with various indoles (Scheme 1). To the best of
For the nucleophilic substitution of alcohols, a number of meth-
ods have been reported in organic solvents.8 In previous articles, the
reactions of xanthen-9-ol with nucleophilic reagents such as thiol,
imide, indoles, and thiophene are promoted by acids or BF3ꢀEt2O.9
HN
R
OH
ionic liquid
+
R
N
O
rt, overnight
O
H
1
⇑
2
Corresponding authors.
E-mail addresses: liulingyan@nankai.edu.cn (L.-y. Liu), lijing@nankai.edu.cn
3
(J. Li).
Scheme 1. The reaction of xanthen-9-ol with indoles.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.085

L.-y. Liu et al. / Tetrahedron Letters 52 (2011) 5636–5639
5637
Table 1
Table 2
The solvent effect on reaction of xanthen-9-ol 1 with indole 2aa
Reactions of xanthen-9-ol 1 with indoles 2a–m in the BmimBF4 mediaa
HN
HN
R
OH
OH
BmimBF4
r.t
+
R
+
N
O
rt, overnight
N
O
O
O
H
H
1
2
3a
3
1
2a
Entry
1
Indole
Product
HN
Yieldb (%)
Entry
Solvent
t (h)
Yieldb (%)
1
2
3
4
5
6
7
THF
72
48
72
72
24
24
4 d
32
40
—
CH2Cl2
DMSO
DMF
BmimBF4
BmimPF6
H2O
N
H
2a
92
—
3a
3b
92
61
—
O
HN
Me
Me
N
H
a
2
3
2b
93
97
The reaction was carried out at room temperature for the given time in the
table.
b
Isolated yields.
O
Me
HN
Me
our knowledge, there are no examples on the ionic liquids
employed in the substitution of 9H-xanthen-9-ol.
N
H
2c
3c
Initially, we investigated the substitution of 9H-xanthen-9-ol
and indole 2a at room temperature in different reaction media,
and the results were illustrated in Table 1. Surprisingly, we found
that this reaction could be efficiently performed in 1-butyl-3-
methylimidazolium tetrafluoroborate (BmimBF4), 1-butyl-3-
methylimidazolium hexafluorophosphate (BmimPF6) for over-
night without the use of any additional catalyst in moderate or
high yields (Table 1, entries 5 and 6). The reaction of 9H-xan-
then-9-ol with indole 2a in organic solvent (THF, CH2Cl2) gave
lower conversions even when the reaction time was prolonged
to 72 h (Table 1, entries 1 and 2). However, in the strong polar
solvent of DMSO or DMF, the reaction of xanthen-9-ol with in-
dole 2a could not run at all at room temperature even prolonging
the reaction time for 72 h (entries 3 and 4). Additionally, this
reaction could not proceed in water at room temperature even
prolonging for 4 days (Table 1, entry 7). Therefore, BmimBF4
was chosen as the reaction media for other indoles and other
nucleophiles without the use of any promoter.
To evaluate the generality of this reaction, using an optimized
protocol, we performed the SN1-type substitution of xanthen-9-ol
1 with various indoles 2a–k in a room temperature ionic liquid
BmimBF4 (Table 2). As can be seen from the summarized results,
all other substituted indoles could be substituted smoothly to give
the corresponding 3-(9-H-xanthen-9-yl)-1H-indole derivatives
with moderate or high yields. Not only 4-substituted or 5-substi-
tuted indoles but also 6- or 7-substituted indoles showed high
reactivity in our methodology. Upon closer inspection of the data
in Table 2, except for the 4-acetoxy indole, we noticed that indoles
with electronic-withdrawing substituted group (Table 2, entries
5–7 and 9–10) gave lower yields than those with electronic-donat-
ing substituted indoles (Table 2, entries 2–3, 8 and 11). Moreover,
for the 4-methyl indole, the corresponding product could be affor-
ded with high up to 97% yield (Table 2, entry 3). In addition, we
also examined other nucleophiles under standard procedure. For
example, pyrrole and acetylacetone, both of them could smoothly
proceed in our protocol and obtained the corresponding products
with high yields (Table 2, entries 12 and 13). But unfortunately,
changing the xanthen-9-ol to the benzhydrol, the nucleophilic
substitution with indole was hardly run in this media at room
temperature even prolonging for 72 h. Nevertheless, when this
reaction of benzhydrol with indole was heated to 60 °C, the
corresponding substitution product could be obtained with 45%
yield (Scheme 2).
O
O
O
CH3
O
HN
HN
O
O
CH3
O
4
5
64
85
N
H
3d
2d
Cl
Cl
N
H
2e
3e
Cl
HN
Cl
Br
N
H
6
7
8
76
69
92
2f
3f
O
Br
HN
N
H
2g
3g
O
MeO
HN
OMe
Cl
N
H
2h
2i
3h
O
HN
N
H
Cl
Br
9
73
75
3i
O
Br
HN
N
H
2j
10
3j
O
Me
HN
N
H
2k
Me
11
93
3k
O
(continued on next page)

5638
L.-y. Liu et al. / Tetrahedron Letters 52 (2011) 5636–5639
HN
Table 2 (continued)
OH
Entry
Indole
Product
Yieldb (%)
BmimBF4
+
O
N
H
NH
O
rt, overnight
N
H
O
2l
12
92
1
2a
3a
3l
O
Scheme 3. Reusing of ionic liquid in subsequent substitution. Run 1, 92%; Run 2,
O
O
O
90%; Run 3, 91%; Run 4, 92%; Run 5, 90%.
2m
13
94
Table 3
3m
The pH values of ionic liquidsa
O
a
Entry
Object
pH value
Reaction condition: the reaction was carried out with xanthen-9-ol (40 mg,
0.2 mmol) and indole 2a (23 mg, 0.2 mmol) in BmimBF4 (0.5 mL) at room temper-
ature for the given time in the Table. After completion, the reaction mixture was
extracted with ethyl ether (20 mL ꢂ 3). The organic phase was combined and fol-
lowed by concentrating in vacuum, and the residue was isolated by silica gel col-
umn chromatography to obtain the pure product.
1
2
3
H2O
BmimBF4
BmimPF6
7.00
6.35
6.86
a
All pH values are determined by pH meter.
b
Isolated yields.
HN
OH
BmimBF4
60oC, overnight
+
N
H
Yield 45%
Scheme 2. The reaction of benzhydrol with indole in BmimBF4.
Next, we investigated the recycling of the ionic liquid in this SN-
1 type substitution of xanthen-9-ol with indole 2a (Scheme 3). It
was found that the ionic liquid (BmimBF4) was reused for five runs
without any appreciable loss of activity.
In general, water is inevitable in BmimBF4 ionic liquid because
it is hydrophilic, even after a moderate drying procedure.16
BmimPF6 may generate traces of HF when it is in touch with mois-
ture or heated at high temperature.17 In order to investigate if the
ionic liquids synthesized by us has a certain acidic property, we
preliminarily determined the acidity of the used ionic liquids by
pH meter (Table 3).18 As shown in the Table 3, it was found that
the BmimBF4 showed weak acidity. It may be due to the hydrolysis
Figure 1. FT-IR spectra of (a) pure pyridine; (b) pyridine + BmimBF4; (c) pyri-
dine + BmimPF6 (pyridine/ionic liquid = 1:4 by weight in (b) and (c)).
for the pH value determination of aqueous solution. As to the reac-
tion mechanism of this direct substitution of xanthen-9-ol with in-
doles, we believe the acidity of ionic liquid is not dominant. The
mechanism of catalysis in ionic liquids is currently still in its infancy.
Ionic liquids are composed only of ions, such ionic nature can affect
the course of the reactions. It can be conjectured that the strong elec-
trostatic field possessed by the dialkyl imidazolium cation mediated
with the counterion, may play an important role in initiating the de-
sired reaction and a traditional acid or base catalytic mechanismwas
not involved.
In summary, we report that the SN-1 type substitution of xan-
then-9-ol with indoles carried out in an ionic liquid which is a con-
venient and efficient reaction media. The title reactions proceeded
smoothly in BmimBF4 without the use of any additional catalyst.
And by this method, a series of indole derivatives are produced
in high or excellent yields. More importantly, this reaction condi-
tion is mild and carried out at room temperature. Furthermore,
the product can be easily separated from the reaction system by
simply extracting with the ethyl ether and the left ionic liquid
which can be continuously used for the next reaction. Obviously,
the advantages of this method include using recyclable ionic liquid
as the reaction media and high yields, simple operations and it is
environmentally benign. Further applications of ionic liquids in
green synthesis are ongoing in our group.
ꢁ
of BF4 anion in the presence of trace water from air. And the
BmimPF6 was nearly neutral. Simultaneously, Prof. Chen’s research
group has reported the pKa values of various 1,3-dialkylimidazoli-
um ionic liquids.19 The pKa value of BmimBF4 is 22.6 for the 2-
hydrogen of imdazolium cation moiety in nonprotic solvent DMSO
media. It could be concluded that the acidity of 2-hydrogen in the
imidazolium moiety is very weak.
In addition, according to the previously reported literature,20c the
Lewis and Brønsted acidity of the ionic liquid was also examined by
using pyridine as a probe molecule by monitoring the bands in the
range of 1400–1700 cmꢁ1 arising from its ring vibration modes.20
The presenceof a band near 1450 cmꢁ1 is indicative of pyridine coor-
dinated to Lewis acid sites, while a band near 1540 cmꢁ1 is an indi-
cation of the formation of pyridinium ions resulting from the
presence of Brønsted acidic sites. Based on this, we paid more atten-
tion to these two bands. In Figure 1, the FT-IR spectra of pure pyri-
dine showed a band at 1437 cmꢁ1 (Fig. 1a). When mixing pyridine
with ionic liquid BmimBF4 or BmimPF6 synthesized by our group,
we observed that the spectra of the two cases showed no band near
1450 or 1540 cmꢁ1 (Fig. 1b and c). Based on these results, both the
BmimBF4 and BmimPF6 were neutral ionic liquids. Consequently,
this was a little different from the above pH values determined by
the PH meter. It may be due to the pH meter used generally suitable

L.-y. Liu et al. / Tetrahedron Letters 52 (2011) 5636–5639
5639
Plaquevent, J. C.; Levillain, J.; Guillen, F.; Malhiac, C.; Gaumont, A. C. Chem. Rev.
2008, 108, 5035–5060; (g) Sebesta, R.; Kmentová, I.; Toma, S. Green Chem. 2008,
10, 484–496; (h)Ionic Liquids in Synthesis; Wasserscheid, P., Welton, T., Eds.;
Wiley-VCH: Weinheim, 2007; (i) Prvulescu, V. I.; Hardacre, C. Chem. Rev. 2007,
107, 2615–2665; (j) van Rantwijk, F.; Sheldon, R. A. Chem. Rev. 2007, 107, 2757–
2785; (k) Welton, T.; Smith, P. J. Adv. Organomet. Chem. 2004, 51, 251–284; (l)
Gu, Y. L.; Peng, J. J.; Qiao, K.; Yang, H. Z.; Shi, F.; Deng, Y. Q. Prog. Chem. 2003, 15,
222–241; (m) Dupont, J.; De Souza, R. F.; Suarez, P. A. Z. Chem. Rev. 2002, 102,
3667–3691.
Acknowledgments
We are grateful for financial support from the National Natural
Science Foundation of China (Grants 20372033). And we also thank
for the support from the Fundamental Research Funds for the Cen-
tral Universities.
6. Sheldon, R. A.; Lau, R. M.; Sorgedrager, M. J.; van Rantwijk, F.; Seddon, K. R.
Green Chem. 2002, 4, 147–151.
Supplementary data
7. Bonhote, P.; Dias, A. P.; Papageorgiou, N.; Kalyanasundaram, K.; Gratzel, M.
Inorg. Chem. 1996, 35, 1168–1178.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.08.085.
8. For recent reports of catalyzed C–C, C–N, and C–O bond formation through
direct substitution of allylic or propargylic alcohols with nucleophiles, see: (a)
Terrasson, V.; Marque, S.; Georgy, M.; Campagne, J. M.; Prim, D. Adv. Synth.
Catal. 2006, 348, 2063–2067; (b) Zhan, Z.; Wang, W.; Yang, R.; Yu, J.; Li, J.; Liu,
H. Chem. Commun. 2006, 3352–3353; (c) Nishibayashi, Y.; Shinoda, A.; Miyake,
Y.; Matsuzawa, H.; Sato, M. Angew. Chem. 2006, 118, 4953–4957. Angew. Chem.,
Int. Ed. 2006, 45, 4835–4839; (d) Motokura, K.; Fujita, N.; Mori, K.; Mizugaki, T.;
Ebitani, K.; Kaneda, K. Angew. Chem. 2006, 118, 2667–2671. Angew. Chem., Int.
Ed. 2006, 45, 2605–2609; (e) Qin, H.; Yamaginawa, N.; Matsunaga, S.; Shibasaki,
M. Angew. Chem. 2007, 119, 413–417. Angew. Chem., Int. Ed. 2007, 46, 409–413;
(f) Yasuda, M.; Somyo, T.; Baba, A. Angew. Chem. 2006, 118, 807–810. Angew.
Chem. Int. Ed. 2006, 45, 793–796; (g) Sanz, R.; Miguel, D.; MartMnez, A.;
Nlvarez-GutiOrrez, J. M.; RodrPguez, F. Org. Lett. 2007, 9, 2027–2030; (h)
Shirakawa, S.; Kobayashi, S. Org. Lett. 2007, 9, 311–314.
9. (a) Hargittai, B.; Barany, G. J. Peptide Res. 1999, 54, 468–479; (b) Phillips, P.; Pitt,
B. M. J. Am. Chem. Soc. 1943, 65, 1355–1357; (c) Bond, L. J. Am. Pharm. Assoc.
1954, 43, 32–33; (d) Deschner, R.; Pindur, U. J. Heterocycl. Chem. 1984, 21,
1485–1488; (e) Pindur, U.; Deschner, R. Zur. Arch. Pharm. 1988, 321, 427–428;
(f) Bratton, L. D.; Roth, B. D.; Trivedi, B. K.; Unangst, P. C. J. Heterocycl. Chem.
2000, 37, 1103–1108; (g) Ancizar-Sordo, B. Helv. Chim. Acta 1931, 14, 141–153.
10. Wang, S. Y.; Ji, S. J. Synthetic Commun. 2008, 38, 465–472.
11. (a) Cozzi, P. G.; Zoli, L. Green Chem. 2007, 9, 1292–1295; (b) Cozzi, P. G.;
Vicennati, P. Eur. J. Org. Chem. 2007, 2248–2253; (c) Cozzi, P. G.; Zoli, L. Angew.
Chem., Int. Ed. 2008, 47, 4162–4166.
References and notes
1. (a) C. Baird, Environmental Chemistry, New York, 1999; (b) Anastas, P.; Heine,
L. G.; Williamson, T. C. In Green Chemical Syntheses and Processes; Oxford
University Press: New York, 2000; (c) Lancaster, M. In Green Chemistry: An
Introductory Text; Royal Society of Chemistry: Cambridge, UK, 2002.
2. (a) Lancaster, M. In Handbook of Green Chemistry and Technology; Clark, J. H.,
Macquarrie, D. J., Eds.; Blackwell Publishing: Abingdon, 2002; (b) Bruckmann,
A.; Krebs, A.; Bolm, C. Green Chem. 2008, 10, 1131–1141; (c) Horv0ath, I. T. Green
Chem. 2008, 10, 1024–1028.
3. (a) Garcia, M. T.; Gathergood, N.; Scammells, P. J. Green. Chem. 2005, 7, 9–14;
(b)Chem. Commun. 2001, 2399–2407; (c) Wilkes, J. S. J. Mol. Catal. A: Chem.
2004, 214, 11–17; (d) Wasserscheid, P.; Keim, W. Angew. Chem., Int. Ed. 2000,
39, 3772–3789; (e) Shen, H.-Y.; Mao, H.-L.; Ying, L.-Y.; Xia, Q.-H. J. Mol. Catal. A:
Chem. 2007, 276, 73–79; (f) Shen, H.-Y.; Judeh, Z. M. A.; Ching, C.-B. Tetrahedron
Lett. 2003, 44, 981–983; (g) Wasserscheid, P.; Hal, R.; Bosmann, A. Green Chem.
2002, 4, 400–404.
4. (a) Dupont, J.; de Souza, R. F.; Suarez, P. A. Z. Chem. Rev. 2002, 102, 3667–3691;
(b) Welton, T. Coord. Chem. Rev. 2004, 248, 2459–2477; (c) Pinkert, A.; Marsh, K.
N.; Pang, S. S.; Staiger, M. P. Chem. Rev. 2009, 109, 6712–6728; (d) Green, M. D.;
Lomg, T. E. Polym. Rev. 2009, 49, 291–314; (e) Sowmiah, S.; Srinivasadesikan, V.;
Chu, Y. H. Molecules 2009, 14, 3780–3813; (f) Luo, S.; hang, L. Z.; Cheng, J. P.
Chem. Asian J. 2009, 4, 1184–1195; (g) Giunta, D.; Solinas, M. Curr. Org. Chem.
2009, 13, 1300–1321; (h) Borodin, O. J. Phys. Chem. B 2009, 113, 11463–11478;
(i) Han, S.; Li, J.; Zhu, S.; Chen, R.; Wu, Y.; Zhang, X.; Yu, Z. Bioresources 2009, 4,
825–834; (j) Wang, Y.; Tian, M.; Bi, W.; Row, K. H. Int. J. Mol. Sci. 2009, 10,
2591–2610; (k) Gu, Y.; Li, G. Adv. Synth. Catal. 2009, 351, 817–847; (l) Lu, J.; Yan,
F.; Texter, J. Prog. Polym. Sci. 2009, 34, 431–448; (m) Li, Z.; Jia, Z.; Luan, Y.; Mu, T.
Curr. Opin. Solid State Mater. Sci. 2009, 12, 1–8; (n) Roth, M. J. Chromatogr., A
2009, 1216, 1861–1880; (o) Wu, B.; Liu, W.; Zhang, Y.; Wang, H. Chem. Eur. J.
2009, 15, 1804–1810.
12. Zhu, A. L.; Li, L. J.; Wang, J. J.; Zhuo, K. L. Green Chem. 2011. doi:10.1039/
c0gc00763c.
13. Saxton, J. E. Nat. Prod. Rep. 1997, 14, 559–590.
14. Toyota, M.; Ihara, N. Nat. Prod. Rep. 1998, 15, 327–340.
15. Tang, L.; Ding, L.; Chang, W. X.; Li, J. Tetrahedron Lett. 2006, 47, 303–306.
16. Kosmulski, M.; Gustafsson, J.; Rosenholm, J. B. Thermochim. Acta 2004, 412, 47–
53.
17. Shen, H.; Judeh, Z. M. A.; Ching, C. B. Tetrahedron Lett. 2003, 44, 981–983.
18. Cui, X. J.; Zhang, S. G.; Shi, F.; Zhang, Q. H.; Ma, X. Y.; Lu, L. J.; Deng, Y. Q.
ChemSusChem 2010, 3, 1043–1047.
19. Chu, Y.; Deng, H.; Chen, J. P. J. Org. Chem. 2007, 72, 7790–7793.
20. (a) Parry, E. P. J. Catal. 1963, 2, 371–379; (b) Yang, Y.; Kou, Y. Chem. Comm.
2004, 226–227; (c) Duan, Z. Y.; Gu, Y. L.; Deng, Y. Q. J. Mol. Catal. A: Chem 2006,
246, 70–75.
5. (a) Plechkova, N. V.; Seddon, K. R. Chem. Soc. Rev. 2008, 37, 123–150; (b) Ledz, P.
S.; Mauduit, M.; Grela, K. Chem. Soc. Rev. 2008, 37, 2433–2442; (c) Greaves, T.
L.; Drummond, C. J. Chem. Rev. 2008, 108, 206–237; (d) Haumann, M.; Riisager,
A. Chem. Rev. 2008, 108, 1474–1498; (e) Martins, M. A. P.; Frizzo, C. P.; Moreira,
D. N.; Zanatta, N.; Bonacorso, H. G. Chem. Rev. 2008, 108, 2015–2050; (f)