Novel reaction of indoles and pyrrole with pyrillium catalyzed by ceric ammonium nitrate (CAN)

Article abstract of DOI:10.1055/s-2007-985590

The reaction of xanthene derivatives with indoles and pyrrole catalyzed by CAN in methanol through S_N1 reaction of pyrillium with a nucleophilic reagent afforded the corresponding indole- and pyrrole-substituted xanthene derivatives in high yields, respectively. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-985590

2222
LETTER
Novel Reaction of Indoles and Pyrrole with Pyrillium Catalyzed by Ceric
Ammonium Nitrate (CAN)
R
eaction of In
h
doles and
P
y
u
rrole with Py
n
rillium -Yi Wang, Shun-Jun Ji*
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry and Chemical Engineering, Suzhou (Soochow) University,
Renai Road, Suzhou Industrial Park, Suzhou 215123, P. R. of China
Fax +86(512)65880307; E-mail: chemjsj@suda.edu.cn
Received 6 May 2007
We have previously reported that ceric ammonium nitrate
Abstract: The reaction of xanthene derivatives with indoles and
(CAN) efficiently catalyzes the Michael addition of in-
pyrrole catalyzed by CAN in methanol through SN1 reaction of
dole to a,b-unsaturated ketones under ultrasonic irradia-
tion to afford the corresponding adducts in excellent
yields.9 As an extension of this study, we decided to inves-
tigate the Michael addition of indole 2a with a,b-unsatur-
ated compounds like 1a (Scheme 1). These homologues
were expected to provide 1-oxo-(3-indolyl)-13c-methyl-
oxy-1,2,3,13c-dihydrodibenzo[a,kl]-xanthene (3a) as the
target product.10 However, as discussed herein, when
compounds 1a and 2a were mixed together in the
presence of 5 mol% CAN in methanol under ultrasonic
conditions, an unexpected product 1-oxo-13c-(3-indolyl)-
1,13c-dihydrodibenzo[a,kl]-xanthene (4a) was obtained
with high regioselectivity.
pyrillium with a nucleophilic reagent afforded the corresponding
indole- and pyrrole-substituted xanthene derivatives in high yields,
respectively.
Key words: CAN, indole, pyrrole, xanthen, pyrillium
The xanthenes and benzoxanthenes are natural or synthet-
ically important compounds, which were used as dyes,
fluorescent materials for visualization of biomolecules
and in laser technologies due to their useful spectroscopic
properties.1 Among these compounds, santalin pigments,
as they are known, have been isolated from a number of
plant species.2 Xanthene-based compounds have also
been investigated for agricultural bactericidal activity,3
photodynamic therapy,4 anti-inflammatory effects,5 anti-
viral activity,6 and for antagonism of the paralyzing action
of zoxazolamine.7 However, few literature procedures are
available concerning the synthesis and reaction of 1-oxo-
13c-alkyloxy-1,13c-dihydrodibenzo[a,kl]-xanthene from
1,1¢-bi-2-naphthol.8
First, the reaction of 1-oxo-13c-methoxy-1,13c-dihydro-
dibenzo[a,kl]-xanthene (1a) with 2a (1.0 equiv) was stud-
ied. The reaction was catalyzed by CAN under ultrasonic
irradiation. It was found that reaction of 1a with 2a in
methanol proceeded smoothly under sonic waves to give
the unexpected product 4a in 95% yield after 3 hours
(Table 1, entry 1).11 When the amount of 2a was changed
HN
O
OR
O
5 mol% CAN
3a (not obtained)
O
+
OMe
O
N
MeOH
H
HN
1a
2a
O
O
4a
Scheme 1 Reaction of 1a with indole
SYNLETT 2007, No. 14, pp 2222–2226
0
3
.0
9
.2
0
0
7
Advanced online publication: 14.08.2007
DOI: 10.1055/s-2007-985590; Art ID: W08907ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Reaction of Indoles and Pyrrole with Pyrillium
2223
from 1.0 to 2.0 equivalents, the reaction still furnished
compound 4a as the sole product in high yield without fur-
ther Michael addition of the indole to the cyclohexenone
(Table 1, entry 2). The structure of compound 4 was con-
firmed by NMR and IR spectroscopy.
Table 1 Reactions of 1a–d with Indole 2aa
HN
O
O
5 mol% CAN
MeOH
+
OR
O
N
H
Figure 1 X-ray structure of compound 4e
O
Table 2 Reactions of 1a with Indoles 2a–k Catalyzed by CANa
1a–1d
2a
4a
Entry
R (Subst.)
Me
Time (h)
Yield (%)b
Entry
1
Indoles
Product Time
(h)
Yield
(%)b
1
2
3
4
5
1a
3
3
2
2
2
95 (88)c
95d
2a
2b
4a
3
95
Me
1a
1b
1c
1d
N
H
Et
95
i-Bu
n-Bu
82
2
3
4b
4
89
82
N
a The reactions were carried out under sonication conditions.
b Isolated yields.
Me
2c
4c
3
95
Me
Me
c The reaction was carried out without ultrasound irridiation.
d 2.0 Equiv of 2a was used under the identical conditions.
N
H
4
5
2d
2e
4d
4e
6
4
87
84
When compounds 1b–d were used as the starting materi-
als in the reactions under the identical conditions using
CAN as the catalyst, the same product 4a was obtained in
good yields (Table 1, entries 3–5).
N
H
A variety of indoles 2b–j were then tested (Table 2).
Compound 1a reacted smoothly with various substituted
indoles 2b–f in the presence of a catalytic amount of CAN
under sonic waves to afford 1-oxo-13c-(3-indolyl)-1,13c-
dihydrodibenzo[a,kl]-xanthenes 4b–f in high yields
(Table 2, entries 2–6). However, reactions of 1a with
2g–i did not give the desirable products, which might be
due to steric restriction (Table 2, entries 7–9). The less
reactive nitroindole derivate 2j also did not react under the
same reaction conditions (Table 2, entry 10). In addition,
the structure of the product 4e was ascertained by spectro-
scopic methods, and the conclusive proof of the assigned
structure was confirmed by single-crystal X-ray analysis
(Figure 1).12
N
H
Me
6
2f
4f
5
80
O2N
N
H
7
8
9
2g
2h
2i
–
–
–
5
5
5
n.r.
n.r.
n.r.
N
H
Me
N
H
Ph
Me
The reaction occurred predominantly at 2-position of
pyrrole 5, while the regioisomeric 3-substituted adduct
could hardly be detected by NMR analysis of the final
reaction mixture. The reaction of 1a and 5 was examined
to generate the desired product 6 in 90% yield under sonic
conditions (Scheme 2).
N
H
10
2j
–
5
n.r.
N
H
NO2
A possible mechanism of the reaction was shown in
Scheme 3. First, CAN promoted the cleavage of the
alkoxy group in compound 1 to give the intermediate
a All reactions were performed under sonication conditions.
b Isolated yields.
Synlett 2007, No. 14, 2222–2226 © Thieme Stuttgart · New York

2224
S.-Y. Wang, S.-J. Ji
LETTER
1
products. All products were characterized by H NMR,
IR, and mass spectrometry and also by comparison with
values reported in literature.14
HN
O
5 mol% CAN
O
OMe
+
N
H
O
MeOH
)))
For pyrrole 5, the alkylation reaction occurred predomi-
nantly at 2-position, while the 3-substituted adduct could
not be detected by NMR analysis of the product mixture.
Hence, the desired product 2-(9H-xanthen-9-yl)-1H-
pyrrole (9) was formed in 88% yield in the presence of
5 mol% CAN (Scheme 5).
O
1a
5
6
Scheme 2 Reaction of 1a with pyrrole 5 catalyzed by CAN
In conclusion, we have described a novel and convenient
method for the alkylation of indoles and pyrrole through
the CAN-mediated SN1 reaction. This method offers sev-
eral advantages including high product yields, clean reac-
tion profiles, higher selectivity, and simple experimental/
product isolation procedures, which makes it a useful and
attractive strategy for the synthesis of indoles and pyrroles
bearing xanthen substituents.
pyrillium species, it was then attacked by the nucleophilic
indole and pyrrole regioselectively to give the desired
product.
Considering the structural similarities between 1a and
9H-xanthen-9-ol (7), we also tried reactions of compound
7 with indole or pyrrole catalyzed by CAN under similar
conditions.13 It was found that the reaction of 7 with in-
dole 2a in the presence of anhydrous MeOH proceeded
smoothly at room temperature, giving 8a in 90% yield
even without ultrasound irradiation (Scheme 4).
As shown in Table 3, xanthen-9-ol 7 reacted well with
various substituted indoles such as 2c, 2d, and 2g, and the
desired 3-(9H-xanthen-9-yl)-1H-indole derivatives were
formed in good yields (Table 3, entries 3, 4, and 7). It was
interesting to note that the reaction of the passivated in-
dole derivate 2f could also be perform under the same
conditions to give the desired product 8f in 90% yield
(Table 3, entry 6). The migration of groups from the 3- to
the 2-position of indole was also observed in the alkyla-
tion of 3-substituted indoles. By analogy, reaction of 7
with indole 2i proceeded smoothly at the 2-position giving
the 3-indolyl-3-(3-methyl-1H-indol-2-yl)indolin-2-one 8i
in 96% yield under identical conditions (Table 3, entry 9).
In all cases, the reactions proceeded smoothly at ambient
temperature to give the desired products in good to excel-
lent yields with high regioselectivity without any side
OH
O
CAN/MeOH
+
0.5 h
N
H
O
NH
88%
7
5
9
Scheme 5 Reaction of 7 with 5 catalyzed by CAN
Acknowledgment
This work was supported in part by Natural Science Foundation
of Jiangsu Province (No.BK2006048), Nature Science Key Basic
Research of Jiangsu Province for Higher Education (No.
06KJA15007), and the National Natural Science Foundation of
China (No. 20472062, 20672079) as well as a Research Grant from
the Innovation Project for Graduate Student of Jiangsu Province.
HN
CAN
O
CAN
MeO-
O
OMe
O
O
O
O
Scheme 3 Proposed reaction mechanism
OH
O
CAN, MeOH
+
R
N
R
O
H
N
H
7
2
8
Scheme 4 Reaction of 7 with 2 catalyzed by CAN
Synlett 2007, No. 14, 2222–2226 © Thieme Stuttgart · New York

LETTER
Reaction of Indoles and Pyrrole with Pyrillium
2225
Table 3 Reactions of Indoles 2a–k with 7 Catalyzed by CANa
Entry
1
Indoles
Productc
Time (h)
1
Yield (%)b
90 (93)d
2a
2b
8a
8b
X
X
N
H
N
H
2
0.5
75
N
N
Me
Me
3
4
5
2c
2d
2e
8c
8d
8e
0.5
3
76
80
91
X
X
Me
Me
N
H
N
H
N
H
Me
N
H
Me
0.5
X
N
H
N
H
Me
Me
6
7
2f
2g
2h
2i
8f
8g
8h
8i
0.5
0.7
1
90
88
90
96
95
X
O2N
O2N
N
N
H
H
X
N
H
Me
N
H
Me
X
8
N
H
Ph
N
H
Ph
9
1
Me
Me
N
H
N
H
X
X
10
2j
8j
0.5
N
H
N
H
NO2
OBn
NO2
OBn
11
2k
8k
1
76
X
N
H
N
H
a All reactions were carried out using a catalytic amount of CAN (5 mol%) at r.t.
b Isolated yields.
c X = 9-xanthenyl.
d The reaction was carried out under sonication conditions.
Synlett 2007, No. 14, 2222–2226 © Thieme Stuttgart · New York

2226
S.-Y. Wang, S.-J. Ji
LETTER
1-Oxo-13c-3-indoly-1,13c-dihydro-dibenzo[a,kl]-
References and Notes
xanthene (4a)
(1) (a) Menchen, S. M.; Benson, S. C.; Lam, J. Y. L.; Zhen, W.;
Sun, D.; Rosenblum, B. B.; Khan, S. H.; Taing, M. US
6583168, 2003. (b) Banerjee, A.; Mukherjee, A. K. Stain
Technol. 1981, 56, 83. (c) Reynolds, G. A.; Tuccio, S. A.;
Peterson, O. G.; Specht, D. P. DE 2109040, 1971.
(2) (a) Arnone, A.; Merlini, L.; Nasini, G. Tetrahedron Lett.
1972, 13, 3503. (b) Ravindranath, B.; Seshadri, T. R.
Phytochemistry 1973, 12, 2781. (c) Gurudutt, K. N.;
Seshadri, T. R. Phytochemistry 1974, 13, 2845. (d) Kumar,
N.; Seshadri, T. R. Curr. Sci. 1974, 43, 611. (e) Arnone, A.;
Camarda, L.; Merlini, L.; Nasini, G.; Taylor, D. A. H.
J. Chem. Soc., Perkin Trans. 1 1977, 2116.
Kelly needles (chartreuse, acicular crystals) mp 192–194 °C.
IR (KBr): n = 3465, 3056, 1697 (C=O), 1458, 1227, 1026,
810, 740 cm–1. 1H NMR (400 MHz, CDCl3): d = 6.43 (d,
1 H, J = 9.6 Hz), 6.84–6.88 (m, 2 H), 6.97–7.21 (m, 4 H),
7.78–7.81 (m, 7 H), 7.35–7.40 (m, 3 H), 7.65 (d, 1 H, J = 8.0
Hz), 7.75 (d, 1 H, J = 8.8 Hz), 7.89 (d, 1 H, J = 8.0 Hz), 8.08
(br, s, 1 H, NH). 13C NMR (100 MHz, DMSO-d6): d = 50.1,
111.8, 112.8, 115.8, 117.3, 117.4, 117.9, 118.8, 120.8,
122.2, 123.2, 123.6, 124.4, 124.5, 125.5, 127.4, 127.7,
128.0, 129.0, 130.6, 130.9, 132.3, 132.4, 135.3, 138.3,
147.6, 148.6, 201.0. HRMS: m/z calcd for C28H17NO2:
399.1259; found: 399.1240 [M+].
(3) Hideo, T. Jpn. Tokkyo Koho JP 56005480, 1981.
(4) (a) Carreon, J. R.; Roberts, M. A.; Wittenhagen, L. M.;
Kelley, S. O. Org. Lett. 2005, 7, 99. (b) Ion, R.-M.;
Albulescu, C.; Sirkecioglu, O.; Talinli, N. http://
www.photobiology.com/photobiology2000/rodica2/
index.htm, The Third Internet Photochemistry and
Photobiology Conference, 2000.
(5) Poupelin, J. P.; Saint-Ruf, G.; Foussard-Blanpin, O.;
Narcisse, G.; Uchida-Ernouf, G.; Lacroix, R. Eur. J. Med.
Chem. 1978, 13, 67.
(6) Lambert, R. W.; Martin, J. A.; Merrett, J. H.; Parkes, K. E.
B.; Thomas, G. J. WO 9706178, 1997.
(7) Buu-Hoi, N. P.; Saint-Ruf, G.; De, A.; Hieu, H. T. Bull.
Chim. Ther. 1972, 7, 83.
(8) (a) Rieche, A.; Kirschke, K.; Schule, M. Justus Liebigs Ann.
Chem. 1968, 711, 103. (b) Schneider, H. P.; Streich, E.;
Schurr, K. Chem. Ber. 1984, 117, 2660. (c) Tan, D.-M.; Li,
H.-H.; Wang, B.; Liu, H.-B.; Xu, Z.-L. Chin. J. Chem. 2001,
19, 91.
(12) Crystallographic data for the structural analysis have been
deposited with the Cambridge Crystallographic Data Centre,
CCDC No. 268046 for compound 4e. Copies of this
information may be obtained free of charge from The
Director, CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK
[e-mail: linstead@ccdc.cam.ac.uk or
deposit@ccdc.cam.ac.uk; fax: +44 (1223)336033]. Crystal
data for 4e·C3H6O: C29H19NO2·C3H6O, Mr = 471.53,
triclinic, space group P–1, a = 9.7116(16) Å,
b = 10.9061(18) Å, c = 11.572(2) Å, a = 95.996(5)°,
b = 101.305(5)°, g = 96.887(5)°, V = 1182.8(4) Å3, Z = 2,
Dcalc = 1.324 g cm–3, (MoKa) = 0.085 mm–1; 11701
reflections collected, 4286 unique reflections, R = 0.0196.
(13) In the last 20 years, reactions of xanthen-9-ol with indole,
promoted by AcOH and BF3·OEt2, have been reported. See:
(a) Deschner, R.; Pindur, U. J. Heterocycl. Chem. 1984, 21,
1485. (b) Pindur, U.; Deschner, R. Arch. Pharm. 1988, 321,
427. (c) Bratton, L. D.; Roth, B. D.; Trivedi, B. K.; Unangst,
P. C. J. Heterocycl. Chem. 2000, 37, 1103.
(9) Ji, S.-J.; Wang, S.-Y. Synlett 2003, 2074.
(14) General Experimental Procedure
(10) Compound 1a with 3.0 equiv morpholine proceeded
smoothly under sonic waves to give the 3¢ after 3 h under
neat conditions.
A mixture of indole 2a (0.059 g, 0.5 mmol), 7 (0.099 g, 0.5
mmol), CAN (0.014 g, 0.025 mmol), and anhyd MeOH (2
mL) was stirred in flask at r.t. until 2a was completely
consumed (1 h, checked by TLC). After standing 0.5 h, the
reaction mixture was washed with cold H2O (3 × 15 mL).
The crude mixture was purified by flash chromatography to
afford the pure product 3a (0.134 g, yield: 90%).
(11) General Procedure for the Reaction of Indoles with 1-
Oxo-13c-alkyloxy-1,13c-dihydro-dibenzo[a,kl]-xanthene
A mixture of 1-oxo-13c-methoxy-1,13c-dihydro-
dibenzo[a,kl]-xanthene (1a, 0.157 g, 0.5 mmol), indole 2a
(0.059 g, 0.5 mmol), CAN (0.014 g, 5 mol%), and anhyd
MeOH (2 mL) was irradiated with ultrasound in an open
vessel at r.t. until the indole was completely consumed (3 h,
monitored by TLC). Then the reaction mixture was washed
with cold H2O (3 × 15 mL) and cold EtOH (3 × 0.5 mL),
respectively. The crude mixture was purified by flash
chromatography to afford the pure product 4a (0.190 g,
yield: 95%).
3-(9H-Xanthen-9-yl)-1H-indole (8a)
Mp 143–145 °C (lit.13a 145 °C). IR (KBr): n = 3429 (NH),
3051, 2920, 2850, 1254, 749 cm–1. 1H NMR (400 MHz,
CDCl3): d = 5.55 (s, 1 H, CH), 6.90–7.36 (m, 13 H), 8.02 (br,
s, 1 H, NH). 13C NMR (100 MHz, CDCl3): d = 59.8, 111.2,
116.3, 119.6, 119.6, 120.3, 122.1, 122.8, 123.1, 124.4,
125.8, 127.7, 129.4, 136.7, 151.3. HRMS: m/z calcd for
C21H15NO: 297.1154; found: 297.1157 [M+].
Synlett 2007, No. 14, 2222–2226 © Thieme Stuttgart · New York

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