Iron-catalyzed cascade arene-aldehyde addition/cyclizations for the highly efficient synthesis of xanthenes and its analogous: Observation of a C-C bond cleavage in indole-based triarylmethanes

Article abstract of DOI:10.1021/jo9012354

(Chemical Equation Presented) An efficient, general, and one-pot procedure for the synthesis of multisubstituted xanthene derivatives through Fe(III)-catalyzed reactions of 2-aryloxybenzaldehydes with electron-rich arenes has been developed. This method offers several advantages such as high selectivities, mild reaction conditions, and easily accessible starting materials. A mechanistic study revealed that a C-C bond cleavage of a triarylmethane intermediate might be involved in the domino process.

Full text of DOI:10.1021/jo9012354

pubs.acs.org/joc
Iron-Catalyzed Cascade Arene-Aldehyde Addition/Cyclizations for the
Highly Efficient Synthesis of Xanthenes and Its Analogous: Observation
of a C-C Bond Cleavage in Indole-Based Triarylmethanes
Hongfeng Li,†,‡ Jingyu Yang,†,‡ Yuanhong Liu,*,† and Yanzhong Li*,‡
†State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, People’s Republic of China, and
‡Department of Chemistry, East China Normal University, 3663 North Zhongshan Road, Shanghai,
200062, People’s Republic of China
yhliu@mail.sioc.ac.cn
Received June 10, 2009
An efficient, general, and one-pot procedure for the synthesis of multisubstituted xanthene
derivatives through Fe(III)-catalyzed reactions of 2-aryloxybenzaldehydes with electron-rich arenes
has been developed. This method offers several advantages such as high selectivities, mild reaction
conditions, and easily accessible starting materials. A mechanistic study revealed that a C-C bond
cleavage of a triarylmethane intermediate might be involved in the domino process.
Introduction
bonds has emerged as a rapid and efficient access to a variety
of arenes and heteroarenes, which are highly useful synthetic
intermediates in the fields of organic and organometallic
chemistry.2 In this regard, Lewis acid-catalyzed addition of
electron-rich arenes to aldehydes or imines via a double
Friedel-Crafts process represents a valuable and atom
economic protocol for the construction of triarylmethanes.3
The development of sustainable, environmentally benign
C-C bond-forming processes is one of the fundamental
goals in organic chemistry. As a result, iron-catalyzed reac-
tions have received considerable attention due to the unique
properties of iron and its complexes, such as having a low
price and being nontoxic and easy to synthesize.1 On the
other hand, transition metal- or Lewis acid-catalyzed direct
functionalization of aromatic C-H bonds to form C-C
Various catalytic systems such as AuCl3,3a Cu(OTf)2,3b,c
3e-g
Sc(OTf)3,3b [Ir(COD)Cl]2-SnCl4,3d and FeCl3
are able
to catalyze these types of reactions under mild reaction
conditions. Meanwhile, the synthesis of unsymmetrical
*To whom correspondence should be addressed. Fax: (+86) 021-
64166128.
(1) For reviews, see: (a) Bolm, C.; Legros, J.; Paih, J. L.; Zani, L. Chem.
(3) (a) Nair, V.; Abhilash, K. G.; Vidya, N. Org. Lett. 2005, 7, 5857. (b)
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Esquivias, J.; Arrayas, R. G.; Carretero, J. C. Angew. Chem., Int. Ed. 2006,
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Rev. 2004, 104, 6217. (b) Dıaz, D. D.; Miranda, P. O.; Padron, J. I.; Martın,
V. S. Curr. Org. Chem. 2006, 10, 457.
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45, 629. (c) Alonso, I.; Esquivias, J.; Gomez-Arrayas, R.; Carretero, J. C. J.
Org. Chem. 2008, 73, 6401. (d) Podder, S.; Choudhury, J.; Roy, U. K.; Roy,
S. J. Org. Chem. 2007, 72, 3100. (e) Schaarschmidt, A.; Hermann, L.;
Szemzo, B. Ber. 1925, 58, 1914. (f) Ji, S.-J.; Zhou, M.-F.; Gu, D.-G.; Jiang,
Z.-Q.; Loh, T.-P. Eur. J. Org. Chem. 2004, 1584. (g) Li, Z.; Duan, Z.; Kang,
J.; Wang, H.; Yu, L.; Wu, Y. Tetrahedron 2008, 64, 1924. (h) Kodomari, M.;
Nagamatsu, M.; Akaike, M.; Aoyama, T. Tetrahedron Lett. 2008, 49, 2537.
(i) Temelli, B.; Unaleroglu, C. Tetrahedron Lett. 2005, 46, 7941. (j) Ke, B.;
Qin, Y.; He, Q.; Huang, Z.; Wang, F. Tetrahedron Lett. 2005, 46, 1751. (k)
Ramesh, C.; Banerjee, J.; Pal, R.; Das, B. Adv. Synth. Catal. 2003, 345, 557.
(l) Yadav, J. S.; Reddy, B. V. S.; Sunitha, S. Adv. Synth. Catal. 2003, 345, 349.
(m) Yadav, J. S.; Reddy, B. V. S.; Murthy, C. V. S. R.; Kumar, G. M.;
Madan, C. Synlett 2001, 783. (n) Lee, H. J.; Seong, M. R.; Song, H. N.; Kim,
J. N. Bull. Korean Chem. Soc. 1999, 20, 267. (o) Alvaro, M.; Garcıa, H.;
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Chung, K.-Y. Angew. Chem. 2000, 112, 3582 ; Angew. Chem., Int. Ed. 2000,
39, 3440 . (b) Bandini, M.; Melloni, A.; Umani-Ronchi, A. Angew. Chem.
2004, 116, 560 ; Angew. Chem., Int. Ed. 2004, 43, 550 . (c) Thalji, R. K.;
Ahrendt, K. A.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2001, 123,
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Fukuyama, T.; Kakiuchi, F.; Murai, S. J. Am. Chem. Soc. 1996, 118, 493. (g)
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2003, 5, 3607.
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Sanjuan, A.; Espla, M Appl. Catal., A 1998, 175, 105.
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DOI: 10.1021/jo9012354
r
Published on Web 07/30/2009
J. Org. Chem. 2009, 74, 6797–6801 6797
2009 American Chemical Society

Li et al.
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TABLE 1. Optimization Studies for the Metal-Catalyzed Xanthene Formation Reactions
entry
catalyst
solvent
time
yield (%) of 2aa
yield (%) of 3aa
1
2
3
4
5
6
7
8
9
10
11
12
13
14
5 mol % of AuCl3
10 mol % of FeCl3 6H2O
toluene
toluene
DCE
toluene
toluene
toluene
DCE
toluene
toluene
toluene
toluene
toluene
toluene
toluene
3 h
3 h
5 h
3 h
12 h
2 h
1 h
14 h
12 h
1 h
1 h
1 h
25
84
72
74
NRb
72
73
51
40
79
84
75
77
32
3
10 mol % of FeCl3 6H2O
10 mol % of FeCl3
3
20 mol % of BF3 Et2O
3
20 mol % of BF3 Et2O
3
5 mol % of AgOTf
10 mol % of ZnCl2
10 mol % of TfOH
5 mol % of TfOH
36
10 mol % of TsOH H2O
3
5 mol % of TsOH H2O
3
1.5 h
6 h
10 mol % of HClc
49d
a Isolated yields. b NR is no reaction. c HCl was used as a 3.08 M solution in Et2O. d 32% 1a was recovered.
iron-catalyzed C-C bond cleavage reactions are quite rare,6
and there are also no reports by applying the Fe-catalyzed C-C
bond cleavage reaction for the construction of valuable cyclic
compounds, to the best of our knowledge.
SCHEME 1
Results and Discussion
The substrates of 2-aryloxybenzaldehydes 1 were easily
prepared through nucleophilic aromatic substitution of 2-
fluorobenzaldehydes with phenols.7 We initiated our studies
by reacting 2-(4-methoxyphenoxy)benzaldehyde 1a with
1,2-dimethyl-1H-indole in the presence of 5 mol % of AuCl3
in toluene at 50 °C (Table 1, entry 1). It was found that
the desired 9-indolylxanthene 2a was formed in 25% yield
after 3 h, along with 32% yield of 1-aryl-1,1-bis(1H-indol-
triarylmethanes with three different arenes has also been
developed3b,g,4 (Scheme 1, eq 1). Generally, the literature
reports concentrated on the intermolecular reactions to
generate noncyclized triarylmethanes; there are rare reports
for the construction of cyclic derivatives by these attractive
methodologies. During our ongoing research program on
acid-catalyzed Friedel-Crafts reactions for the synthesis of
polycyclic aromatic compounds under extreme mild condi-
tions,5 we found that iron salts could catalyze a new domino
process of inter- and intramolecular Friedel-Crafts alkyla-
tion of arenes. In this paper, we report a highly efficient
approach for the synthesis of functionalized xanthenes through
iron-catalyzed annulation of arenes with 2-aryloxybenz-
aldehydes; we would like also to describe our discovery and
investigation of a novel C-C bond cleavage in the indole-based
triaylmethane intermediates (Scheme 1, eq 2). It is notable that
3-yl)methane 3a. Advantageously, the use of FeCl3 6H2O8
3
afforded the xanthene 2a in 84% yield (entry 2). Monitor
ing the reaction process by TLC revealed that the bis(1H-
indol-3-yl)methane 3a was also formed as an intermediate;
however, it could be completely consumed after 3 h. Chang-
ing the solvent to DCE also afforded 72% yield of 2a with
a longer reaction time (5 h, entry 3). When FeCl3 was used
as catalyst, the desired product 2a was formed in 74%
yield (entry 4). Without any catalyst, no reaction occurred
(entry 5), suggesting that these results correspond to a iron-
catalyzed double alkylation process. Further studies revealed
that BF3 Et2O was also a good catalyst for inducing cyclization
3
reactions, although a higher catalyst loading of 20% was
needed to achieve the better yield (entries 6 and 7). Other Lewis
acids such as AgOTf and ZnCl2 showed morderate activity for
this reaction (entries 8 and 9). Brønsted acids such as TfOH and
(4) (a) Das, S. K.; Shagufta, P. G. Tetrahedron Lett. 2005, 46, 3097. (b)
Burmester, A.; Stegmann, H. B. Synthesis 1981, 125. (c) Pratt, E. F.; Green,
L. Q. J. Am. Chem. Soc. 1953, 75, 275. (d) Katrizky, A. R.; Toader, D. J. Org.
Chem. 1997, 62, 4137. (e) Katrizky, A. R.; Gupta, V.; Garot, C.; Stevens, C.
V.; Gordeev, M. F. Heterocycles 1994, 38. (f) Katrizky, A. R.; Lan, X.; Lam,
J. M. Chem. Ber. 1991, 124, 1809.
(5) (a) Li, G.; Zhou, S.; Su, G.; Liu, Y.; Wang, P. G. J. Org. Chem. 2007,
72, 9830. (b) Liu, Y.; Zhou, S.; Li, G.; Yan, B.; Guo, S.; Zhou, Y.; Zhang, H.;
Wang, P. G. Adv. Synth. Catal. 2008, 350, 797. (c) Li, G.; Wang, E.; Chen, H.;
Li, H.; Liu, Y.; Wang, P. G. Tetrahedron 2008, 64, 9033. (d) Guo, S.; Liu, Y.
Org. Biomol. Chem. 2008, 6, 2064.
TsOH H2O also catalyze the reaction, in which the products
3
were formed in 75-84% yields (entries 10-13). The structure
(7) (a) Yeager, G. W.; Schissel, D. N. Synthesis 1995, 28. (b) Wang, J. Q.;
Harvey, R. G. Tetrahedron 2002, 58, 5927.
ꢀ
(6) (a) Benisvy, L.; Chottard, J. -C.; Li, J. M. Y. Eur. J. Inorg. Chem. 2005,
999. (b) Dhakshinamoorthy, A.; Pitchumani, K. Tetrahedron 2006, 62, 9911.
(c) Nakazawa, H.; Itazaki, M.; Kamata, K.; Ueda, K. Chem. Asian J. 2007, 2,
882. (d) Paine, T. K.; England, J.; Que, L. Jr. Chem.;Eur. J. 2007, 13, 6073.
(8) For iron-catalyzed arylation of benzyl alcohols and benzyl carbox-
ylates with electron-rich arenes, see: Iovel, I.; Mertins, K.; Kischel, J.; Zapf,
A.; Beller, M. Angew. Chem., Int. Ed. 2005, 44, 3913.
6798 J. Org. Chem. Vol. 74, No. 17, 2009

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TABLE 2. Iron-Catalyzed Domino Process to Substituted Xanthenes
SCHEME 2
anti-inflammatory16 activities. However, most of the known
methods required harsh reaction conditions and multistep
procedures.17 Thus the development of a general and efficient
synthesis of xanthenes is highly attractive.
We chose FeCl3 6H2O as catalyst for the following reac-
3
tions. The present method could be applied successfully to
various 2-aryloxybenzaldehydes (Table 2). In general, the
reactions are rapid at 50 °C and the corresponding xanthenes
2b-h were formed in 61-94% yield within 1-4 h. For
example, the reactions of 1a with 2-methylindole afforded
xanthene 2b smoothly in 87% yield (entry 1). The Ar2 ring
with phenyl- or 2-naphthyl group resulted in the formation
of 2c and 2d in high yields of 82% and 79%, respectively
(entries 2 and 3). However, Ar2 ring substituted with a -NMe2
group, namely, 2-(4-(dimethylamino)phenoxy)benzaldehyde
(1d), resulted in no reaction with 2-methylindole. Substitution
on the Ar1 ring with a chlorine or a -NO2 group gave rise to the
substituted xanthenes 2e and 2f in 94% and 76% yields,
respectively (entries 4 and 5). C-2-phenyl-substituted indole
could also be used in this reaction, furnishing 2g in 73% yield
(entry 6). When N-methylindole was employed, a higher reac-
tion temperature (100 °C) and higher catalyst loading (50%)
were required; under these conditions, the desired xanthene 2h
was obtained in a satisfactory yield of 61% (entry 7).
Several reaction pathways might be involved in the reaction.
To elucidate the reaction mechanism, the reaction of 1a and
1,2-dimethyl-1H-indole was quenched at 30 min. Interestingly,
it was found that the bis(1H-indol-3-yl)methane 3a was
obtained as a major product in 36% yield along with 10%
xanthene 2a and 27% of unreacted starting aldehyde 1a. The
results indicated that the xanthene derivative 2a might be
formed through iron-catalyzed transformation of the triaryl-
methane 3a. It puzzled us, however, since if it is true, a C-C
bond cleavage reaction in 3a must occur, and the released
indole could also be reused as substrate to enter the addition
sequence with aldehyde. As a matter of fact, only 1.2 equiv of
indole derivatives were sufficient in our reaction. We then
carried out the reaction of 3a in the presence of 10 mol % of
a Isolated yield. Unless noted, all the reactions were carried out at 50
°C for 1 h with 10 mol % of FeCl3 6H2O as catalyst and 1.2 equiv of
3
b
c
arenes in toluene. 50 °C, 4 h. 2.0 equiv of indole and 50 mol % of
FeCl3 6H2O were used, and the reaction temperature was 100 °C.
3
of xanthenes was confirmed by X-ray crystallographic analysis
of 2c (see Table 2, entry 2).9 Xanthene derivatives are of
significant synthetic interests since they can be applied as
luminescent dyes,10 photochromic and thermochromic
agents,11 laser dyes,12 as well as fluorescent materials for vis-
ualization of protease activities13 etc. They also exhibit a variety
of biological activities such as antibacterial,14 antiviral,15 and
(9) CCDC-727316 (compound 2c) and CCDC-727317 (compound 2k)
contain the supplementary crystallographic data for this paper. These data
can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html
(or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB2 1EZ, UK; fax (þ44) 1223-336-033; or deposit@ccdc.cam.ac.uk).
(10) (a) Rys, P.; Zollinger, H. In Fundamentals of the Chemistry and
Application of Dyes; Wiley-Interscience: NewYork, 1972. (b) Muthyala, R. In
Chemistry and Applications of Leuco Dyes; Katrizky, A. R., Sabongi, G. J., Eds.;
Plenum: New York, 1997.
(11) (a) Aldag, R. Photochromism Based on Dissociation Processes. In
Photochromism: Molecules and Systems; D€urr, H., Bouas-Laurent, H., Eds.;
Elsevier: London, UK, 1990. (b) Sanguinet, L.; Twieg, R. J.; Wiggers, G.; Mao,
G.; Singer, K. D.; Petschek, R. G. Tetrahedron Lett. 2005, 46, 5121. (c) Noack,
A.; Hartmann, H. Chem. Lett. 2002, 644.
FeCl3 6H2O; to our delight, it was found that the same
3
xanthene 2a was isolated in 76% yield, and the 1,2-dimethyl-
1H-indole was also produced in 64% yield (Scheme 2). The
results strongly supported our assumption that 2a was formed
through Fe(III)-catalyzed C-C bond cleavage of 3a and
subsequent cyclization in the one-pot procedure.
The fragmentation of triarylmethanes has been ob-
served in several reports.18 As known, the acid-catalyzed
Friedel-Crafts alkylation of arenes with aromatic
(12) (a) Sirkeeioglu, O.; Talinli, N.; Akar, A. J. Chem. Res., Synop. 1995,
502. (b) Ahmad, M.; King, T. A.; Ko, D. K.; Cha, B. H.; Lee, J. J. Phys. D:
Appl. Phys. 2002, 35, 1473.
(13) (a) Knight, C. G.; Stephens, T. Biochem. J. 1989, 258, 683. (b) Li, J.;
Yao, S. Q. Org. Lett. 2009, 11, 405.
(14) Lambert, R. W.;Martin, J.A.;Merrett, J. H.;Parkes, K. E. B.;Thomas,
G. J. PCT Int. Appl. WO9706178, 1997; Chem. Abstr 1997, 126, 212377 .
(15) Hideo, T. Jpn. Kokai Tokkyo Koho JP 56005480, 1981; Chem.
Abstr. 1981, 95, 80922.
(16) Poupelin, J. P.; Saint-Rut, G.; Foussard-Blanpin, O.; Narcisse, G.;
Uchida-Ernouf, G.; Lacroix, R. Eur. J. Med. Chem. 1978, 13, 67.
(17) (a) Wang, J.-Q.; Harvey, R. G. Tetrahedron 2002, 58, 5927. (b) Yang, Y.;
Escobedo, J. O.; Wong, A.; Schowalter, C. M.; Touchy, M. C.; Jiao, L.; Crowe,
W. E.; Fronczek, F. R.; Strongin, R. M. J. Org. Chem. 2005, 70, 6907. (c) Su, W.;
Yang, D.; Jin, C.; Zhang, B. Tetrahedron Lett. 2008, 49, 3391. (d) Caruso, A. J.;
Lee, J. L. J. Org. Chem. 1997, 62, 1058. (e) Agbaria, K.; Biali, S. E. J. Org. Chem.
2001, 66, 5482. (f) Zhao, J.;Larock, R. C.J. Org. Chem. 2007, 72, 583. (g) Okuma,
K.; Nojima, A.; Matsunaga, N.; Shioji, K. Org. Lett. 2009, 11, 169.
(18) (a) Roberts, R. M.; El-Khawaga, A. M.; Sweeney, K. M.; El-Zohry,
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M. F. J. Org. Chem. 1987, 52, 1591. (b) Alvara, M.; Garcıa, H.; Sanjuan, A.;
Espla, M. Appl. Catal. A 1998, 175, 105. (c) De Vries, T. S.; Vedejs, E.
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Organometallics 2007, 26, 3079.
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TABLE 3. Iron-Catalyzed Domino Process to Substituted Xanthenes and Its Analogues
a Isolated yield. Unless noted, all the reactions were carried out at 50 °C for 1 h with 10 mol % of FeCl3 6H2O, 4.0 equiv Ac2O, and 1.2 equiv of arenes
in toluene. b Mesitylene was used as solvent. c 2.0 equiv of arene was used. d DCE was used as solvent in a sealed tube at 120 °C, and 30 mol % of
FeCl3 6H2O was used. e CH2Cl2 was used as solvent in a sealed tube. f 50 mol % of FeCl3 6H2O was used.
3
3
aldehydes has been known for a long time.19 The earlier
studies have shown that the Lewis acids such as AlCl3-
promoted reactions usually afford several products such as
triarylmethanes, diarylmethanes, triarylmethanol, and an-
thracenes which have received a little attention. In a deep
study, Roberts pointed out that excess AlCl3 or Brønsted
acids are able to induce the dealkylations and realkylations
of triarylmethane intermediates that lead to mixed diaryl-
methanes and triarylmethanes in the reactions of aromatic
aldehydes with arenes.18a Recently, a C-C bond cleavage
has also been observed in the electrophilic activation of a
(19) (a) Griepentrog, H. Ber. Dtsch. Chem. Ges. 1886, 19, 1876. (b) Saito,
S.; Ohwada, T.; Shudo, K. J. Am. Chem. Soc. 1995, 117, 11081. (c) Olah, G.
A.; Rasul, G.; York, C.; Prakash, G. K. S. J. Am. Chem. Soc. 1995, 117,
11211.
borane complex Et3N BH3 with trityl tetrakis(penta-
3
fluorophenyl)borate.18c A mechanism involving electrophilic
substitution at an ipso carbon followed by fragmentation
6800 J. Org. Chem. Vol. 74, No. 17, 2009

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JOCArticle
SCHEME 3
extended to the synthesis of xanthene analogues. For example,
biologically interesting thioxanthene 9 and a 7-membered
oxacycle 11 have been prepared in 88% and 48% yields,
respectively (entries 8 and 9).23 The mechanism for most of
these reactions might be different from that for indoles.24 It
may proceed through the first formation of diacetate followed
by inter- and intramolecular Friedel-Crafts reactions to
afford the desired products.3g
Conclusion
In summary, we have succeeded in developing an efficient,
general, and one-pot procedure for the synthesis of multi-
substituted xanthene derivatives through Fe(III)-catalyzed
reaction of 2-aryloxybenzaldehydes with electron-rich arenes.
This method offers several advantages such as high selectivities,
mild reaction conditions, and easily accessible starting materi-
als. Interestingly, a mechanistic study revealed that a novel
C-C bond cleavage of a triarylmethane intermediate might be
involved in the domino process. Further studies to elucidate the
reaction mechanism and to extend the scope and synthetic
utility are in progress in our laboratory.
to Ph2CHþ was proposed. Borane complex was also suggested
to act as an electrophile, which may contribute to the C-C
bond cleavage. On the basis of the above results and the
known chemistry of triarylmethane, we tentatively propose a
mechanism for this tandem sequence as depicted in Scheme 3.
The reaction is initiated by Fe(III)-assisted double Friedel-
Crafts alkylations to afford 1-arylbis(1H-indol-3-yl)methane
3, then an electrophilic aromatic substitution occurs on the
indole ring by attack of C-3 to yield an ionic intermediate 4, this
is followed by C-C bond cleavage to generate dibenzylic cation
6, which undergoes intramolecular Friedel-Crafts reaction to
give the product 2. Protonation of the iron-adduct 5 would
produce indoles for reuse.
Experimental Section
A Typical Procedure for the FeCl3 6H2O-Catalyzed One-Pot
3
Synthesis of Xanthenes from the Reactions of Arenes with
2-Aryloxybenzaldehydes. A mixture of 2-(4-methoxyphenoxy)-
benzaldehyde 1a (57 mg, 0.25 mmol), 1,2-dimethyl-1H-indole
(44 mg, 0.3 mmol), and FeCl3 6H2O (6.7 mg, 10 mol %) in
3
toluene (3 mL) was stirred at 50 °C for 3 h. Then the reaction
mixture was quenched with saturated NaHCO3 solution and
extracted with ethyl acetate. The organic layer was washed with
brine and dried over anhydrous Na2SO4. After removal of the
solvent, the residue was purified by column chromatography on
silica gel (eluent: petroleum ether/ethyl acetate = 10:1) to afford
3-(2-methoxy-9H-xanthen-9-yl)-1,2-dimethyl-1H-indole 2a as a
white solid in 84% isolated yield. Alternatively, after the reaction
was complete, the solvent was removed under reduced pressure,
and the residue was purified by column chromatography on silica
gel to afford the desired products. Mp 65-67 °C. 1H NMR
(400 MHz, d6-DMSO, Me4Si) δ 2.45 (s, 3H), 3.50 (s, H), 3.60 (s,
3H), 5.61 (s, 1 H), 6.38 (d, J = 2.4 Hz, 1H), 6.68 (t, J = 7.2 Hz,
1H), 6.74 (dd, J = 9.0, 2.8 Hz, 1H), 6.82-6.93 (m, 4H), 7.05-7.11
(m, 3H), 7.26 (d, J = 8.0 Hz, 1H); 13C NMR (100.6 MHz,
d6-DMSO, Me4Si) δ 9.9, 29.3, 33.6, 55.1, 109.0, 112.8, 114.2,
114.6, 115.7, 116.5, 117.7, 118.4, 120.1, 122.8, 123.6, 125.0, 125.5,
127.5, 129.5, 133.9, 136.5, 144.5, 150.6, 154.8. HRMS (EI) for
C24H21NO2 [Mþ] calcd 355.1572, found 355.1573.
Encouraged by these results, we proceeded to explore the
cyclization reactions of aldehyde 2 with other arenes and
heteroarenes. The results are shown in Table 3. It should be
noted that in all of cases, the addition of 4.0 equiv of Ac2O
were needed.20,21 Under the appropriate reaction conditions,
a variety of 2-aryloxybenzaldehydes and arenes could be
used in this domino reaction, furnishing the corresponding
xanthenes 2i-o in moderate to high yields of 54-95%
(Table 3, entries 1-7).22 Electron-rich arenes such as mesi-
tylene, 1,4-dimethoxybenzene, and 1-methoxynaphthalene
are all compatible with the reaction conditions. The regio-
selectivity of 2k has been confirmed by X-ray crystallographic
analysis.9 The heteroarenes of 2-methylfuran and 2,5-di-
methylfuran afforded xanthenes 2l and 2m successfully in
61% and 69% yields, respectively (entries 4 and 5). Note that
a higher temperature of 120 °C and 30 mol % of iron catalyst
were required to achieve a good yield in the case of
2-mehylfuran. When the reaction was carried out at 50 °C in
Acknowledgment. We thank the National Natural Science
Foundation of China (Grant Nos. 20872163, 20872037, and
20732008), the Chinese Academy of Science, Science and Tech-
nology Commission of Shanghai Municipality (Grant No.
07JC14063), and the Major State Basic Research Development
Program (Grant No. 2006CB806105) for financial support.
the presence of 10 mol % of FeCl3 6H2O, the bis-
3 0
(5-methylfuran-2-yl)methane, namely, 5,5 -((2-chloro-6-(4-
methoxyphenoxy)phenyl)methylene)bis(2-methylfuran) 7 was
obtained in 78% yield as a major product (2 equiv of
2-methylfuran was used). The C-C bond cleavage in 7 could
also be observed by the reaction of 7 with 30 mol % of
Supporting Information Available: Experimental details,
spectroscopic characterization of all new compounds, and
X-ray crystallography of compounds 2c and 2k. This material
is available free of charge via the Internet at http://pubs.acs.org.
FeCl3 6H2O at 120 °C, in which the same xanthene 2l was
3
isolated in 55% yield. The efficiency of iron catalysis has been
(20) For the effect of additives, see refs 3g and 3h.
(21) We have reported that benzyl acetates are better substrates com-
pared with that of benzyl alcohols in various acid-catalyzed Friedel-Crafts
reactions, see refs 5a-c.
(23) According to 1H NMR spectra, compounds 2n and 2o have
diastereotopic methyl groups, while compound 11 appears not to, and
compound 9 has broad methyls.
(24) In most cases with the use of Ac2O, we did not observe the
intermediates of triarylmethane.
(22) For entry 3, we also tried the reaction using 5% TsOH H2O in the
3
presence or absence of Ac2O; however, no desired product was observed, and
most of the starting material remained.
J. Org. Chem. Vol. 74, No. 17, 2009 6801