Efficient synthesis of novel 9H-xanthen-9-yl derivatives of bidentate heterocyclic nucleophiles by Fe(HSO4)3 as a catalyst

Article abstract of DOI:10.1016/j.cclet.2012.08.010

We have demonstrated the direct substitution of 9H-xanthen-9-ol with different nucleophilic reagents such as thiazoles, triazoles, tetrazoles, hydrazines and hydrazinecarboxamides in good to high yields. This reaction catalyzed by ferric hydrogensulfate a

Full text of DOI:10.1016/j.cclet.2012.08.010

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 1153–1156
www.elsevier.com/locate/cclet
Efficient synthesis of novel 9H-xanthen-9-yl derivatives of bidentate
heterocyclic nucleophiles by Fe(HSO4)3 as a catalyst
*
Hossein Eshghi , Mehdi Bakavoli, Javad Abedini-Torghabeh, Mohammad Rahimizadeh
Department of Chemistry, School of Sciences, Ferdowsi University of Mashhad, P.O. Box 91775-1436, Mashhad, Iran
Received 26 June 2012
Available online 21 September 2012
Abstract
We have demonstrated the direct substitution of 9H-xanthen-9-ol with different nucleophilic reagents such as thiazoles,
triazoles, tetrazoles, hydrazines and hydrazinecarboxamides in good to high yields. This reaction catalyzed by ferric hydro-
gensulfate as a heterogeneous acid catalyst in ethanol through SN1 type reaction of pyrylium with a nucleophilic reagent afforded
the heterocycle- and aromatic-N-substituted xanthene derivatives as simple marked molecules in short reaction times.
# 2012 Hossein Eshghi. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Xanthen; Ferric hydrogensulfate; Nucleophilic reagents; SN1 type
9H-Xanthen-9-ol falls in the group of non-specific reagents since it reacts with various natural products, urea,
amino acids, ribonuclease and cytochrome [1], 9H-xanthen-9-ol and numerous derivatives are being intensively
investigated as chemotherapeutic agents, insecticides, pesticides [2,3], photodynamic therapy [4], anti-inflammatory
effects [5], and anti viral activity [6]. Several sulfa drugs were tried with 9H-xanthen-9-ol and were found to give
suitable derivatives [7].
Recently, the reactions of 9H-xanthen-9-ol with nucleophilic reagents such as thiol [8], imide [9], indoles [10,11], and
thiophene [12] promoted by acidsor BF3ꢀEt2O [11] have been reported. The reaction of xanthene derivatives with indoles
and pyrrole catalyzed by CAN through SN1 reaction of pyrillium with a nucleophilic reagent afforded the corresponding
indole- and pyrrole-substitutedxanthenederivatives [13]. We have previously reported that Fe(HSO4)3 as an efficientand
recyclable catalyst for the one-pot synthesis of 14-aryl- or alkyl-14H-dibenzo[a,j]-xanthene derivatives and 1,3-diaryl-
3H-benzo[f]chromenes [14,15]. This catalyst has emerged as a promising solid acid catalyst for acid catalyzed reactions,
such as Friedel–Crafts acylation [16,17], Schmidt reaction [18], Mannich reaction [19], and functional group protections
[20,21]. Herein, we report that Fe(HSO4)3, effectively catalyzes the reactions of 9H-xanthen-9-ol 1 with different
nucleophilic reagents 2a–j in ethanol to give 9H-xanthen-9-yl derivatives in good to high yields (Scheme 1).
We decided to explore the regioselectivity of heterocyclic systems with different nucleophilic centers (such as 2g)
using a simple marker, 9H-xanthen-9-ol 1. The results of this investigation which lead to the synthesis of N-marked
product 3g in the presence of ferric hydrogensulfate catalyst in ethanol reflux conditions. N-Alkylation is more
favorable than S-alkylation of nucleophile or O-alkylation of solvent (Scheme 2).
* Corresponding author.
E-mail address: heshghi@ferdowsi.um.ac.ir (H. Eshghi).
1001-8417/$ – see front matter # 2012 Hossein Eshghi. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2012.08.010

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H. Eshghi et al. / Chinese Chemical Letters 23 (2012) 1153–1156
Fe(HSO4)3
O
O
10 mol%
NH2 - Het -XH
EtOH / Reflux
X : NH, S
2a-j
HN
OH
Het
XH
3a-j
1
Scheme 1. The reactions of 9H-xanthen-9-ol 1 with different nucleophilic reagents 2a–j.
Table 1
Reaction of nucleophilic reagents 2a–j with 9H-xanthen-9-ol 1 catalyzed by Fe(HSO4)3 in ethanol.
Entry Reagent 2
Product 3
Time Yield Entry Reagent 2
(h)
Product 3
Time Yield
(%)
(h)
(%)
a
1
89
f
0.5
92
O
O
N
S
NH2
HN
N
S
N
NH2
S
NH
NH
N
N
CH3
HN
S
N
CH3
b
2
85
g
2
85
O
H
O
N
S
N
H
S
N
NH
N
O
N
S
NH2
S
HN
c
0.5
95
h
2
95
NHNH2
N N
O
N
NH2
Cl
HN
NH
O
NH
Cl
N
N
N
d
0.5
92
i
1
89
O
SH
NHCONHNH2
N
N
N
NH2
N H N H
NHCONHNH
NHNH2
N
H2N
N
N
HS
e
0.5
96
j
0.5
95
N
O
NH2
O
N
N
NH2
N
H
HN
NH
NH
NH
O
N
N
N
NH2

H. Eshghi et al. / Chinese Chemical Letters 23 (2012) 1153–1156
1155
Fe(HSO4)3
H
O
N
O
10 mol%
N
S
EtOH / Reflux
N
H
OH
1
2g
3g
S
N
H
Scheme 2. The reactions of 9H-xanthen-9-ol 1 with imidazolidine-2-thione 2g.
The solvent (EtOH) does not compete with nucleophile in this condition. Various nucleophilic reagents 2a–j
employed in this reaction. Fe(HSO4)3, effectively catalyzes the reactions of 9H-xanthen-9-ol 1 with different
nucleophilic reagents 2a–j in ethanol to give 9H-xanthen-9-yl derivatives which exclusively N-alkylated in good to
high yields. The results are listed in Table 1. Primary amines are reacted efficiently over secondary or strickted amines.
The structures of compounds 3a–j were characterized by 1H NMR and IR spectrometry [22]. The 1H NMR spectrum
of 3a showed signals for NH group (d 4.85 ppm) and methine (d 5.45, 6.85 and 7.24 ppm), together with multiplet for
the aromatic region (6.90–7.36 ppm) protons. IR spectra of compound 3a show strong absorption bands at 3273 cmꢁ1
for the NH group and 3097, 1624, 1515, 1478, 1259, 761, 750 moieties. As a suggested mechanism, Fe(HSO4)3
promoted the cleavage of the hydroxyl group in compound 1 to give the intermediate pyrylium species it was then
attacked by the nucleophilic reagents 2a–j regioselectively to give the desired product, in competition with
nucleophilic solvent without any side products. The pyrylium cation is a conjugated polyaromatic system with one
carbon atom replaced by a positively charged oxygen atom. These high nucleophilic selectivities are due to stability of
pyrylium cation and new C–N bond formation.
Melting points were determined in open capillary tubes in an Electrothermal IA 9000 melting point apparatus. IR
1
spectra were recorded on an Avatar 370 FT-IR Thermo Nicolet Infrared spectrophotometer. H NMR spectra were
recorded on a Bruker-100 MHz instrument using tetramethylsilane (TMS) as an internal standard. Elemental analyses
were obtained on a Thermo Finnigan Flash EA microanalyzer. Ferric hydrogensulfate was prepared according to
previously reported procedure [18].
In conclusion, the present protocol provides a novel, convenient method and highly efficient procedure for the
synthesis of novel 9H-xanthen-9-yl derivatives of nitrogen contain heterocyclic nucleophiles, through the Fe(HSO4)3
mediated SN1 reaction. The simplicity, together with the use of inexpensive, recyclable and environmentally benign
nature of catalyst, is other remarkable features of the procedure.
Acknowledgment
We are grateful to Department of Chemistry, Ferdowsi University of Mashhad, for financial support (49-P-24-01-
89).
References
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H. Eshghi et al. / Chinese Chemical Letters 23 (2012) 1153–1156
[14] H. Eshghi, M. Bakavoli, H. Moradi, Chin. Chem. Lett. 19 (2008) 1423.
[15] H. Eshghi, G.H. Zohuri, S. Damavandi, M. Vakili, Chin. Chem. Lett. 21 (2010) 1423.
[16] P. Salehi, M.M. Khodaei, M.A. Zolfigol, S. Zeinoldini, Synth. Commun. 33 (2003) 1367.
[17] K.P. Boroujeni, Chin. Chem. Lett. 21 (2010) 1395.
[18] H. Eshghi, J. Chin. Chem. Soc. 53 (2006) 987.
[19] C. Wang, L.J. Zhang, Z. Zhang, Z.J. Quan, Chin. Chem. Lett. 23 (2012) 423.
[20] F. Shirini, M.A. Zolfigol, P. Salehi, M. Abedini, Curr. Org. Chem. 12 (2008) 183.
[21] H. Eshghi, M. Rahimizadeh, S. Saberi, Catal. Commun. 9 (2008) 2460.
[22] General procedure: a mixture of 9H-xanthen-9-ol (0.198 g, 1 mmol), nucleophilic reagents 2a–j (1 mmol), and Fe(HSO4)3. (0.035 g,
0.1 mmol) in ethanol (5 mL) was stirred at reflux for appropriate time according to Table 1. The progress of the reaction was monitored
by TLC. After the completion, the reaction mixture was filtered and the organic solvent was cooled and concentrated to afford crude product.
The crystalline pure product was obtained by further recrystallization from ethanol. Data for new compounds: N-(9H-Xanthen-9-yl)-1, 3-
thiazol-2-amine (3a): Yellow powder, yield: 0.249 g (89%). mp 188–189 8C, Anal. calcd. for C16H12N2OS (280.34): C, 68.55; H, 4.31; N,
9.99%. Found: C, 68.53; H, 4.29; N, 9.97%. 1H NMR (100 MHz, CDCl3): d 4.85 (br, s, 1H, NH), 5.45 (s, 1H, CH), 6.85 (d, 1H, CH), 7.24 (d,
1H, CH), 6.90–7.36 (m, 8H). IR (KBr, cmꢁ1) n: 3273 (NH), 3097, 1624, 1515, 1478, 1259, 761, 750. N-(9H-Xanthen-9-yl)-1, 3-benzothiazol-
2-amine (3b): Yellow powder, yield: 0.281 g (85%). mp 230–231 8C, Anal. calcd. for C20H14N2OS (330.40): C, 72.70; H, 4.27; N, 8.48%.
Found: C, 72.68; H, 4.25; N, 8.49%. 1H NMR (100 MHz, CDCl3): d5.81 (br, s, 1H, NH), 5.62 (s, 1H, CH), 7.15–7.76 (m, 12H). IR (KBr, cmꢁ1
)
n: 3162 (NH), 2976, 1594, 1568, 1536, 1481, 1255, 749. N-(9H-Xanthen-9-yl)-4H-1, 2, 4-triazol-4-amine (3c): White powder, yield: 0.251 g
(95%). mp 236–238 8C, Anal. calcd. for C15H12N4O (264.28): C, 68.17; H, 4.58; N, 21.20%. Found: C, 68.14; H, 4.60; N, 21.22%. 1H NMR
(100 MHz, CDCl3): d5.40 (d, 1H, NH), 5.55 (d, 1H, CH), 7.08–7.58 (m, 10H). IR (KBr, cmꢁ1) n: 3217 (NH), 3125, 1481, 1260, 1064, 775, 756,
632. 4-Amino-5-[2-(9H-xanthen-9-yl) hydrazinyl]-4H-1, 2, 4-triazole-3-thiol (3d): White powder, yield: 0.300 g (92%). mp 216–218 8C,
Anal. calcd. for C15H14N6OS (326.38): C, 55.20; H, 4.32; N, 25.75%. Found: C, 55.21; H, 4.30; N, 25.70%. 1H NMR (100 MHz, CDCl3): d 2.15
(br, s, 1H, NH), 4.25 (br, s, 1H, NH), 5.55 (s, 1H, CH), 5.77 (s, 2H, NH2), 7.05–7.45 (m, 8H), 13.26 (s, 1H, SH). IR (KBr, cmꢁ1) n: 3346, 3268
(NH), 3212 (NH2), 1645, 1601, 1481, 1260, 754. N-(9H-Xanthen-9-yl)-1H-tetrazol-5-amine (3e): White powder, yield: 0.255 g (96%). mp
235–236 8C, Anal. calcd. for C14H11N5O (265.27): C, 63.39; H, 4.18; N, 26.40%. Found: C, 63.36; H, 4.15; N, 26.36%. 1H NMR (100 MHz,
CDCl3): d 4.75 (d, 1H, NH), 4.65 (s, 1H, NH), 6.05 (d, 1H, CH), 6.87–7.58 (m, 8H). IR (KBr, cmꢁ1) n: 3396 (NH), 1576, 1483, 1258, 754. 5-
Methyl-4-(9H-xanthen-9-ylamino)-2, 4-dihydro-3H-1,2,4-triazole-3-thione (3f): White powder, yield: 0.285 g (92%). mp 201–203 8C, Anal.
calcd. for C16H14N4OS (310.37): C, 61.92; H, 4.55; N, 18.05%. Found: C, 61.90; H, 4.50; N, 18.01%. 1H NMR (100 MHz, CDCl3): d 1.29 (s,
3H, CH3), 5.27 (d, 1H, NH), 6.23 (d, 1H, CH), 7.11–7.65 (m, 8H), 10.90 (br, s, 1H, NH). IR (KBr, cmꢁ1) n: 3252 (NH), 3048, 1578, 1481, 1458,
1258, 756. 2-(9H-Xanthen-9-ylsulfanyl)-4, 5-dihydro-1H-imidazole (3g): White powder, yield: 0.240 g (85%). mp 178–179 8C, Anal. calcd.
for C16H14N2OS (282.36): C, 68.06; H, 5.00; N, 9.92%. Found: C, 68.10; H, 5.06; N, 9.90%. 1H NMR (100 MHz, CDCl3): d 3.15–3.36 (m, 2H,
CH2), 3.42–3.66 (m, 2H, CH2), 5.81 (br, s, 1H, NH), 7.10 (s, 1H, CH), 7.15–7.68 (m, 8H). IR (KBr, cmꢁ1) n: 3224 (NH), 2872, 1497, 1479,
1450, 1253, 759. 1-(4-Chlorophenyl)-2-(9H-xanthen-9-yl) hydrazine (3h): White powder, yield: 0.307 g (95%). mp 196–197 8C, Anal. calcd.
for C19H15ClN2O (322.79): C, 70.70; H, 4.68; N, 8.68%. Found: C, 70.67; H, 4.65; N, 8.65%. 1H NMR (100 MHz, CDCl3): d 5.05–5.21 (m, 2H,
NH-NH), 5.30 (d, 1H, CH), 7.04–7.72 (m, 12H). IR (KBr, cmꢁ1) n: 3256, 3157 (NH), 2966, 1622, 1566, 1263, 756. N-Phenyl-2-(9H-xanthen-
9-yl)hydrazinecarboxamide (3i): White powder, yield: 0.295 g (89%). mp 234–235 8C, Anal. calcd. for C20H17N3O2 (331.17): C, 72.49; H,
5.17; N, 12.68%. Found: C, 72.45; H, 5.15; N, 12.65%.1H NMR (100 MHz, DMSO): d 5.15 (s, 1H, CH), 5.45 (br, s, 1H, NH), 6.75 (br, s, 1H,
NH), 8.15 (br, s, 1H, NH), 7.10–7.70 (m, 13H). IR (KBr, cmꢁ1) n: 3334, 3249, 3240 (NH), 1658, 1537, 1481, 1261, 761. N4, N40-Di (9H-
xanthen-9-yl)-[1,10-biphenyl]-4, 4’-diamine (3j): White powder, yield: 0.517 g (95%). mp 267–268 8C, Anal. calcd. for C38H28N2O2 (544.64):
C, 83.80; H, 5.18; N, 5.14%. Found: C, 83.75; H, 5.15; N, 5.10%. 1H NMR (100 MHz, DMSO): d 3.65 (br, s, 2H, 2NH), 5.48 (s, 1H, CH), 6.75
(d, 4H, CH ortho), 6.91 (m, 20H). IR (KBr, cmꢁ1) n: 3468, 3374 (NH), 1625, 1498, 1477, 1445, 1249, 750.