Application of dearomatization strategy on the synthesis of furoquinolinone and angelicin derivatives

Article abstract of DOI:10.1021/ol300648t

The oxidative dearomatization of 3-(3-alkynyl-4-hydroxyphenyl)propanoic acid is combined with a cascade transition-metal catalyzed cyclization/addition/ aromatization/lactamization sequence, which provides a novel approach to prepare furoquinolinone and angelicin derivatives in a convergent and efficient manner.

Full text of DOI:10.1021/ol300648t

ORGANIC
LETTERS
2012
Vol. 14, No. 8
2114–2117
Application of Dearomatization Strategy
on the Synthesis of Furoquinolinone and
Angelicin Derivatives
Yang Ye, Li Zhang, and Renhua Fan*
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai, 200433,
China
rhfan@fudan.edu.cn
Received March 13, 2012
ABSTRACT
The oxidative dearomatization of 3-(3-alkynyl-4-hydroxyphenyl)propanoic acid is combined with a cascade transition-metal catalyzed cyclization/
addition/aromatization/lactamization sequence, which provides a novel approach to prepare furoquinolinone and angelicin derivatives in a
convergent and efficient manner.
Furoquinolinones (Figure 1), the bioisosters of angelicin,1
are potential photochemotherapeutic agents.2 For example,
1,4,6,8-tetramethylfuro[2,3-h]quinolin-2(1H)-one (FQ) shows
strong antiproliferative activity against tumor cell lines upon
UVA (Ultraviolet Radiation A) irradiation, without inducing
interstrand cross-links (ISC).3 The general synthetic route of
furoquinolinones starts from m-phenylenediamines and in-
volves multistep procedures and relatively harsh reaction
conditions (Scheme 1).4 With the aim to find more effective
and less toxic antitumor compounds, the design and synthesis
of new furoquinolinone derivatives with high efficiency is
highly desirable.
Dearomatization of aromatic compounds is one of
the most sustainable and straightforward methods for
accessing complex molecules.5 The fascination of such
an approach has drawn significant attention in recent
decades.6,7 As part of an effort to extend the power of
the dearomatization reaction,8 we originally conceived
that the scaffold of furoquinolinones could be readily
constructed from (3-alkynyl-4-hydroxyphenyl)propanoic
acids 1 with a dearomatization strategy. As shown in
Scheme 2, compound 1 can be conveniently prepared from
3-(4-hydroxyphenyl)propanoic acid via an iodination and
a Sonogashira coupling reaction. Under oxidizing condi-
tions, dearomatization of compound 1 would provide
(1) (a) Wang, X.; Wang, Y.; Yuan, J.; Sun, Q.; Liu, J.; Zheng, C.
J. Chromatogr. A 2004, 1055, 135. (b) Gambari, R.; Lampronti, I.; Bianchi,
N.; Zuccato, C.; Viola, G.; Vedaldi, D.; Dall’Acqua, F. Top. Heterocycl.
Chem. 2007, 9, 265. (c) Zhang, B.-L.; Fan, C.-Q.; Dong, L.; Wang, F.-D.;
Yue, J.-M. Eur. J. Med. Chem. 2010, 45, 5258.
(2) (a) Rodighiero, P.; Guiotto, A.; Chilin, A.; Bordin, F.; Baccichetti,
F.; Carlassare, F.; Vedaldi, D.; Caffieri, S.; Pozzan, A.; Dall’Acqua,
F. J. Med. Chem. 1996, 39, 1293. (b) Chilin, A.; Marzano, C.; Guiotto, A.;
Manzini, P.; Baccichetti, F.; Carlassare, F.; Bordin, F. J. Med. Chem.
1999, 42, 2936. (c) Chilin, A.; Marzano, C.; Guiotto, A.; Baccichetti, F.;
Carlassare, F.; Bordin, F. J. Med. Chem. 2002, 45, 1146. (d) Marzano, C.;
Chilin, A.; Bordin, F.; Baccichetti, F.; Guiotto, A. Bioorg. Med. Chem.
2002, 10, 2835. (e) Chilin, A.; Marzano, C.; Baccichetti, F.; Simonato, M.;
Guiotto, A. Bioorg. Med. Chem. 2003, 11, 1311. (f) Marzano, C.; Chilin,
A.; Baccichetti, F.; Bettio, F.; Guiotto, A.; Miolo, G.; Bordin, F. Eur. J.
Med. Chem. 2004, 39, 411. (g) Chilin, A.; Dodoni, G.; Frezza, C.; Guiotto,
A.; Barbieri, V.; Lisa, F. D.; Canton, M. J. Med. Chem. 2005, 48, 192.
(h) Xie, L.; Qian, X.; Cui, J.; Xiao, Y.; Wang, K.; Wu, P.; Cong, L. Bioorg.
Med. Chem. 2008, 16, 8713.
(3) (a) Bordin, F.; Marzano, C.; Carlassare, F.; Rodighiero, P.;
Guiotto, A.; Caffieri, S.; Baccichetti, F. J. Photochem. Photobiol., B:
Biol. 1996, 34, 159. (b) Bordin, F.; Baccichetti, F.; Marzano, C.;
Carlassare, F.; Miolo, G.; Chilin, A.; Guiotto, A. Photochem. Photobiol.
2000, 71, 254. (c) Marzano, C.; Baccichetti, F.; Carlassare, F.; Chilin, A.;
Lora, S.; Bordin, F. Photochem. Photobiol. 2000, 71, 263.
(4) Chilin, A.; Rodighiero, P.; Pastorini, G.; Guiotto, A. J. Org.
Chem. 1991, 56, 980.
(5) For reviews, see: (a) Bach, T. Angew. Chem., Int. Ed. 1996, 35,
ꢀ
729. (b) Quideau, S.; Pouysegu, L. Org. Prep. Proced. Int. 1999, 31, 617.
€
(c) Pape, A. R.; Kaliappan, K. P.; Kundig, E. P. Chem. Rev. 2000, 100,
2917. (d) Magdziak, D.; Meek, S. J.; Pettus, T. R. R. Chem. Rev. 2004,
104, 1383. (e) Keane, J. M.; Harman, W. D. Organometallics 2005, 24,
ꢀ
ꢀ
ꢀ
ꢀ
1786. (f) Lopez Ortiz, F.; Iglesias, M. J.; Fernandez, I.; Andujar Sanchez,
ꢀ
C. M.; Gomez, G. R. Chem. Rev. 2007, 107, 1580. (g) Quideau, S.;
ꢀ
ꢀ
Pouysegu, L.; Deffieux, D. Synlett 2008, 467. (h) Pouysegu, L.; Deffieux,
D.; Quideau, S. Tetrahedron 2010, 66, 2235. (i) Roche, S. P.; Porco, J. A.,
Jr. Angew. Chem., Int. Ed. 2011, 50, 4068.
r
10.1021/ol300648t
Published on Web 04/05/2012
2012 American Chemical Society

2-alkynyl cyclohexadienone 2 as the intermediate. With a
transition metal as the catalyst, intermediate 2 could react
with an amine via a cascade cyclization/addition/aromati-
zation/lactamization process9 to afford 3,4-dihydrofuro-
[2,3-h]quinolin-2(1H)-one 4. After an oxidation, the
scaffold of furoquinolinone could be formed.
Scheme 1. General Synthetic Route of Furoquinolinones
Scheme 2. Synthesis of Furoquinolinones from 3-(4-
Hydroxyphenyl)propanoic Acid with a Dearomatization
Strategy
Figure 1. Structures of furoquinolinones and angelicin.
To implement this strategy, the first step was the realiza-
tion of a rapid oxidative dearomatization of the phenol
(6) For recent examples, see: (a) Mejorado, L. H.; Pettus, T. R. R.
J. Am. Chem. Soc. 2006, 128, 15625. (b) Dohi, T.; Maruyama, A.;
Takenaga, N.; Senami, K.; Minamitsuji, Y.; Fujioka, H.; Caemmerer,
ꢀ
S. B.; Kita, Y. Angew. Chem., Int. Ed. 2008, 47, 3787. (c) Pouysegu, L.
Chassaing, S.; Dejugnac, D.; Lamidey, A.-M.; Miqueu, K.; Sotiropoulos,
J.-M.; Quideau, S. Angew. Chem., Int. Ed. 2008, 47, 3552. (d) Quideau, S.
Lyvinec, G.; Marguerit, M.; Bathany, K.; Ozanne-Beaudenon, A.;
ꢀ
ꢀ
Buffeteau, T.; Cavagnat, D.; Chenede, A. Angew. Chem., Int. Ed.
2009, 48, 4605. (e) Li, F.; Tartakoff, S. S.; Castle, S. L. J. Am. Chem.
Soc. 2009, 131, 6674. (f) Gaich,T.;Mulzer, J.J. Am. Chem. Soc. 2009, 131,
ꢀ
452. (g) Guerard, K. C.; Sabot, C.; Racicot, L.; Canesi, S. J. J. Org. Chem.
2009, 74, 2039. (h) Snyder, S. A.; Kontes, F. J. Am. Chem. Soc. 2009, 131,
1745. (i) Dong, S.; Hamel, E.; Bai, R.; Covell, D. G.; Beutler, J. A.; Porco,
J. A., Jr. Angew. Chem., Int. Ed. 2009, 48, 1494. (j) Mitasev, B.; Porco Jr.
Org. Lett. 2009, 11, 2285. (k) Qi, J.; Beeler, A. B.; Zhang, Q.; Porco, J. A., Jr.
J. Am. Chem. Soc. 2010, 132, 13642. (l) Frie, J. L.; Jeffrey, C. S.; Sorensen,
E. J. Org. Lett. 2010, 12, 5394. (m) Trzupek, J. D.; Lee, D.; Crowley, B. M.;
Marathias, V. M.; Danishefsky, S. J. J. Am. Chem. Soc. 2010, 132, 8506. (n)
Liang, H.; Ciufolini, M. A. Org. Lett. 2010, 12, 1760. (o) Lian, Y.; Davies,
H. M. L. J. Am. Chem. Soc. 2010, 132, 440. (p) Uyanik, M.; Yasui, T.;
Ishihara, K. Angew. Chem., Int. Ed. 2010, 49, 2175. (q) Rudolph, A.; Bos,
P. H.; Meetsma, A.; Minnaard, A. J.; Feringa, B. L. Angew. Chem., Int. Ed.
2011, 50, 5834.
(7) For recent examples, see: (a) Imbos, R.; Minnaard, A. J.; Feringa,
B. L. J. Am. Chem. Soc. 2002, 124, 184. (b) Hayashi, Y.; Gotoh, H.;
Tamura, T.; Yamaguchi, H.; Masui, R.; Shoji, M. J. Am. Chem. Soc.
2005, 127, 16028. (c) Ladziata, U.; Koposov, A. Y.; Lo, K. Y.; Willging,
J.; Nemykin, V. N.; Zhdankin, V. V. Angew. Chem., Int. Ed. 2005, 44,
7127. (d) Liu, Q.; Rovis, T. J. Am. Chem. Soc. 2006, 128, 2552. (e) Vo,
N. T.; Pace, R. D. M.; O0Hara, F.; Gaunt, M. J. J. Am. Chem. Soc. 2008,
130, 404. (f) Lu, S.; Xu, Z.; Bao, M.; Yamamoto, Y. Angew. Chem., Int.
Scheme 3. Oxidative Dearomatization of 3-(4-Hydroxy-3-(2-
phenylethynyl)phenyl)propanoic Acid 1a
Ed. 2008, 47, 4366. (g) Garcıa-Fortanet, J.; Kessler, F.; Buchwald, S. L.
´
J. Am. Chem. Soc. 2009, 131, 6676. (h) Gu, Q.; Rong, Z.-Q.; Zheng, C.;
You, S.-L. J. Am. Chem. Soc. 2010, 132, 4056. (i) Wu, Q.-F.; Liu, W.-B.;
Zhuo, C.-X.; Rong, Z.-Q.; Ye, K.-Y.; You, S.-L. Angew. Chem., Int. Ed.
2011, 50, 4455.
(8) (a) Fan, R.; Li, W.; Ye, Y.; Wang, L. Adv. Synth. Catal. 2008, 350,
1531. (b) Wang, L.; Han, Z.; Fan, R. Adv. Synth. Catal. 2010, 352, 3230.
(c) Ye, Y.; Wang, H.; Fan, R. Synlett 2011, 923. (d) Ye, Y.; Fan, R.
Chem. Commun. 2011, 47, 5626.
(9) (a) Yao, T.; Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2004,
126, 11164. (b) Yao, T.; Zhang, X.; Larock, R. C. J. Org. Chem. 2005, 70,
7679. (c) Patll, N. T.; Wu, H.; Yamamoto, Y. J. Org. Chem. 2005, 70,
4531.
ring of compound 1 without affecting the sensitive alkynyl
function.10 The screening of oxidants and solventsrevealed
that PhIO was the best oxidant11 and CF3CH2OH was the
best solvent for the dearomatization. Treatment of com-
pound 1a with 1 equiv of PhIO in CF3CH2OH at 50 °C for
(10) Dohi, T.; Maruyama, A.; Yoshimura, M.; Morimoto, K.;
Tohma, H.; Kita, Y. Angew. Chem., Int. Ed. 2005, 44, 6193.
Org. Lett., Vol. 14, No. 8, 2012
2115

2 min provided 2-phenylethynyl cyclohexadienone 2a in
81% isolated yield (Scheme 3). The 1H NMR spectroscopy
of compound 2a showed that the hydrogen atom at the C-3
position has a higher chemical shift than that of the
hydrogen atom at the C-5 position. It indicates that the
nucleophilic addition might prefer to occur at the C-3
position.
AuCl (10 mol %), and the desired product 4aa was isolated
in 48% yield (Table 1, entry 1). The structure of compound
4aa was confirmed by its single-crystal diffraction analysis
(Figure 2). Encouraged by this result, various metal salts
were examined as catalysts (Table 1, entries 2ꢀ12). Pd-
(PPh3)2Cl2 proved to be the best catalyst for the generation
of compound 4aa (Table 1, entry 6). We then started to
optimize the reaction conditions to improve the chemical
yield. With ClCH2CH2Cl as the reaction media, the yield
of 4aa was increased to 72% (Table 1, entry 18). The lower
temperature or the reduced loading of Pd(PPh3)2Cl2 re-
sulted in the lower yield (Table 1, entries 20ꢀ22). The best
ratio of substrate 1a, p-toluidine 2a, and Pd(PPh3)2Cl2 for
the reaction was 1:1.5:0.1, increasing the yield of 4aa to
79% (Table 1, entry 23). Although p-toluidine 3a is an
electron-rich aromatic compound, the C-addition of the
aryl ring of p-toluidine to compound 2a was not observed
in all cases.
Table 1. Evaluation of Catalyst and Conditionsa
4aa
entry
catalyst
conditions
(%)b
1
AuCl (0.1 equiv)
CH3CN, reflux
CH3CN, reflux
CH3CN, reflux
CH3CN, reflux
CH3CN, reflux
CH3CN, reflux
CH3CN, reflux
CH3CN, reflux
CH3CN, reflux
CH3CN, reflux
CH3CN, reflux
CH3CN, reflux
CF3CH2OH, reflux
DMF, 90 °C
48
37
35
43
0
2
AuCl3 (0.1 equiv)
3
CuBr (0.1 equiv)
4
PtCl2 (0.1 equiv)
5
Rh(PPh3)3Cl (0.1 equiv)
Pd(PPh3)2Cl2 (0.1 equiv)
Pd(OAc)2 (0.1 equiv)
AgOTf (0.1 equiv)
6
57
32
35
19
16
<5
<5
23
59
56
48
<5
72
16
69
68
63
79
7
8
9
Cu(OTf)2 (0.1 equiv)
Bi(OTf)3 (0.1 equiv)
10
11
12
13
14
15
16
17
18
19
20
21
22
23c
In(OTf)3 (0.1 equiv)
Ni(OTf)2 (0.1 equiv)
Pd(PPh3)2Cl2 (0.1 equiv)
Pd(PPh3)2Cl2 (0.1 equiv)
Pd(PPh3)2Cl2 (0.1 equiv)
Pd(PPh3)2Cl2 (0.1 equiv)
Pd(PPh3)2Cl2 (0.1 equiv)
Pd(PPh3)2Cl2 (0.1 equiv)
Pd(PPh3)2Cl2 (0.1 equiv)
Pd(PPh3)2Cl2 (0.1 equiv)
Pd(PPh3)2Cl2 (0.05 equiv)
Pd(PPh3)2Cl2 (0.02 equiv)
Pd(PPh3)2Cl2 (0.1 equiv)
toluene, 90 °C
1,4-dioxane, 90 °C
DMSO, 90 °C
ClCH2CH2Cl, reflux
H2O, 90 °C
ClCH2CH2Cl, 70 °C
ClCH2CH2Cl, reflux
ClCH2CH2Cl, reflux
ClCH2CH2Cl, reflux
Figure 2. X-ray diffraction structure of compound 4aa.
To simplify the reaction procedure, the crude oxidative
dearomatization product was treated with p-toluidine 3a
without purification. Under the optimized conditions, this
two-step reaction provided compound 4aa in 62% yield
based on substrate 1a (Table 2, entry 1). As shown in
Table 2, a variety of aromatic amines were suitable reac-
tion partners (Table 2, entries 2ꢀ10). Reactions of amines
bearing an electron-donating substituent delivered the
corresponding products in higher yields compared with
those bearing an electron-withdrawing substituent. Two
kinds of heteroaromatic amines were also examined
(Table 2, entries 22 and 23). The reaction of 5-amino-1,3-
dimethyl-1H-pyrazole gave rise to product 4ep in 61%
yield, but the reaction of 4-amino-pyridine was very com-
plex. When benzylamine, butylamine, benzyl carbamate,
tert-butyl carbamate, or 4-methylbenzenesulfonamide was
employed, the formation of the desired product was not
observed (Table 2, entries 11ꢀ15). For the reaction with
tert-butyl carbamate as the reaction partner, all metal salts
listed in Table 1 were examined as catalysts, but all failed.
a Reaction conditions: substrate 1a (0.1 mmol), 4-CH3C6H4NH2
(0.2 mmol), solvent (2 mL), unless noted. b Isolated yield based on
substrate 1a. c 1.5 equiv of 4-CH3C6H4NH2 was used.
Our further investigations were focused on examining
the feasibility of the designed cascade reaction between
compound 2a with p-toluidine 3a. We were pleased to
observe that the reaction proceeded well in the presence of
(11) For reviews on the chemistry of hypervalent iodine, see: (a)
Zhdankin, V. V.; Stang, P. J. In Chemistry of Hypervalent Compounds;
Akiba, K., Ed.; VCH Publishers: New York, 1999; Vol. 11, p 327. (b)
Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2002, 102, 2523. (c) Wirth, T.
Hypervalent Iodine Chemistry: Modern Developments in Organic
Synthesis. Topics in Current Chemistry; Springer: 2003; Vol. 224.
(d) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299.
(12) (a) Wulff, W. D.; McCallum, J. S.; Kunng, F. A. J. Am. Chem.
Soc. 1988, 110, 7419. (b) Vangveravong, S.; Zhang, Z.; Taylor, M.;
Bearden, M.; Xu, J.; Cui, J.; Wang, W.; Luedtke, R. R.; Mach, R. H.
Bioorg. Med. Chem. 2011, 19, 3502. (c) Kraus, J. M.; Tatipaka, H. B.;
McGuffin, S. A.; Chennamaneni, N. K.; Karimi, M.; Arif, J.; Verlinde,
C. L. M. J.; Buckner, F. S.; Gelb, M. H. J. Med. Chem. 2010, 53, 3887.
2116
Org. Lett., Vol. 14, No. 8, 2012

process with water as a nucleophile (Scheme 4). In these
cases, N,N-dimethylpyridin-4-amine (DMAP) and dicy-
clohexylcarbodiimide (DCC) were added to promote the
lactonization.
Table 2. Reaction Scope Investigation
Scheme 4. Synthesis of 3,4-Dihydrofuro[2,3-h]chromen-2-one
entry
R1
R2
4 (%)a
1
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4-CH3C6H4
C6H5
4aa (62)
4ab (63)
4ac (62)
4ad (61)
4ae (67)
4af (64)
4ag (38)
4ah (59)
4ai (53)
4aj (63)
4ak (0)
2
3
4-CH3OC6H4
4-BrC6H4
4
5
4-ClC6H4
6
4-FC6H4
7
4-CF3C6H4
1-naphthalen
2,4,6-(CH3)3C6H2
3,5-(CH3)2C6H3
C6H5CH2
8b
9b
10
11
12
13
14
15
16
17
18
19
20
21
22
Treatment of compound 4aa or 5a with 2,3-dichloro-
5,6-dicyano-1,4-benzoquinone (DDQ)12 led to the corre-
sponding furoquinolinone derivative 6aa or angelicin
derivative 7a, respectively (Scheme 5).
CH3CH2CH2CH2
CbzNH2
4al (0)
4am (0)
4an (0)
4ao (0)
BocNH2
TsNH2
4-CH3C6H4
4-ClC6H4
CH3CH2CH2CH2
(CH3)3C
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3OC6H4
4-ClC6H4
4ba (62)
4ca (36)
4da (82)
4ea (91)
4ec (85)
4ee (90)
4ep (61)
Scheme 5
(CH3)3C
(CH3)3C
(CH3)3C
1,3-(CH3)2-1H-
pyrazol-5-yl
4-pyridyl
23
24
25
26
27c
(CH3)3C
cyclopropyl
TMS
4eq (00)
4fa (63)
4ga (0)
4ha (0)
4ea (87)
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
In conclusion, we have developed a new strategy for
accessing furoquinolinone and angelicin derivatives. This
method involves the oxidative dearomatization of 3-(3-
alkynyl-4-hydroxyphenyl)propanoic acids and the subse-
quential transition-metal catalyzed cascade cyclization/
addition/aromatization/lactamization sequence. Current
dedication has also been made to extend its scope, to
explore its reaction mechanism and possible synthetic
applications, and these results will be reported in due
course.
H
(CH3)3C
b
a Isolated yield based on substrate 1. DCC (1 equiv) and DMAP
(0.1 equiv) were added to promote the lactamization. c The reaction was
conducted at a 2 mmol scale.
A substituent at the alkyne moiety of compound 1 also
affectedthe reaction. For example, compound1bbearing a
4-methylphenyl group was a better substrate than com-
pound 1c bearing a 4-chlorophenyl group (Table 2, entries
16 and 17). When the R1 group was an n-butyl or a tert-
butyl group, the reactions gave rise to the corresponding
products in good to excellent yields (Table 2, entries
18ꢀ21). When the R1 group was a cyclopropyl group, a
moderate yield was obtained (Table 2, entry 24). Complex
reactions were observed when the R1 group was a trimethyl-
silyl group or a hydrogen (Table 2, entries 25 and 26). When
the reaction was conducted at a larger scale (2 mmol), a
slightly low yield was obtained (Table 2, entry 27).
Acknowledgment. Financial support from National
Natural Science Foundation of China (No. 21072033) is
gratefully acknowledged.
Supporting Information Available. Experimental pro-
cedures, characterization data, copies of 1H and 13C
NMR of new compounds, and crystallographic data of
compound 4aa (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
Moreover, the precursor of angelicin, 3,4-dihydrofuro-
[2,3-h]chromen-2-one 5 could also be prepared via a similar
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 8, 2012
2117