Synthesis of novel tetracyclo-isocoumarins via AcOH-catalyzed cascade reaction of heterocyclic ketene aminals with 2,2-dihydroxy-2H-indene-1,3-dione

Article abstract of DOI:10.1016/j.tetlet.2010.11.100

A facile synthesis of tetracyclo-isocoumarins based on the AcOH-catalyzed cyclocondensation and rearrangement reaction between heterocyclic ketene aminals and 2,2-dihydroxy-2H-indene-1,3-dione is described. This method provides direct access to tetacyclo-

Full text of DOI:10.1016/j.tetlet.2010.11.100

Tetrahedron Letters 52 (2011) 465–467
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of novel tetracyclo-isocoumarins via AcOH-catalyzed
cascade reaction of heterocyclic ketene aminals with
2,2-dihydroxy-2H-indene-1,3-dione
⇑
Sheng-jiao Yan , Yu-lan Chen , Lin Liu, Ya-juan Tang, Jun Lin
Key Laboratory of Medicinal Chemistry for Natural Resources (Yunnan University), Ministry of Education, School of Chemical Science and Technology, Yunnan University,
Kunming 650091, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 July 2010
Revised 9 November 2010
Accepted 19 November 2010
Available online 24 November 2010
A facile synthesis of tetracyclo-isocoumarins based on the AcOH-catalyzed cyclocondensation and rear-
rangement reaction between heterocyclic ketene aminals and 2,2-dihydroxy-2H-indene-1,3-dione is
described. This method provides direct access to tetacyclo-isocoumarins, a class of compounds with
potential broad spectrum biological activities.
Ó 2010 Elsevier Ltd. All rights reserved.
Isocoumarins are an important class of natural lactones that
exhibit a broad range of biological activities1 including antitumor2
(e.g., Reticulol2a), anti-HIV-1 (Coriandrin),3 anti-HSV-1 (6,8-dihy-
droxy-3-hydroxymethyliso-coumarin),4 anti-allergic (such as
Thunberginool A and B),5 anticoagulants,6 antifungal,7 antimicro-
bial,8 anti-inflammatory,9 antimalarial,10 herbicidal,11 immuno-
modulatory,12 cytotoxic activity,13 DNA helicase inhibition
(heliquinomycin),14 b-amyloid eptide production inhibition15 and
protease inhibitory properties,15,16 among others.17 Due to their
broad range of biological activities and their use as synthetic precur-
sors in the synthesis of a variety of important pharmaceutical com-
pounds, such as the anticancer agents nitidine18 and ( )-O-methyl
PD 116740,19 the antibiotic heliquinomycin20 and pretetramide,21
isocoumarins have received increasing interest for many year-
s.1a,22–35 Recently, several methods have been reported for the
synthesis of isocoumarins 1 (Fig. 1).1a,22–35 The main synthetic
routes are transition metal (Ag, AgI, CuCl, CuBr) or proton acid
(TFA, PTSA) catalyzed reactions based on 2-ethynylbenzoic acid
derivatives 222 and the transition-catalyzed coupling and hetero-
cyclization reaction of alkyl 2-iodobenzoates 323 with alkynes or al-
lenyltributyltins. In addition, there are many other procedures
which have been used in the synthesis of isocoumarins22–35 and
among them, many substrates have been widely used, including
substituted 3,4-dihydroisochromen-1-ones 4,24 enol ethers 5,25
enamines 6,26 isobenzofuran-1(3H)-one derivatives 7,27 phthalic
synthesis of simple isocoumarins, these methods have not been used
in preparing the cyclo-fused isocoumarins. In a word, the synthesis
of cyclo-fused isocoumarins is challenging work which often re-
quires multistep reactions and complex experimental processes.
The procedures available for preparing highly functional, diverse,
cyclic fused isocoumarins are limited. Therefore, a general and con-
cise approach for producing this class of cyclo-fused isocoumarins
that tolerates a wide variety of functional groups is highly desirable.
In order to develop an isocoumarin synthesis method which
avoids the use of substrates 2–14, and in the process to expand
O
COOR''
R
COOR''
I
R'
R'
O
R'
R
3
2
Y
COOMe
O
O
Y=H, Br, I, etc
R'
1
R'
R
MeOOC
OMe
4
5
COOMe
R'
R'
O
O
COOH
R'
COOR''
Me2N
R
8
7
6
CHO
X
COOH
acid or esters 8,28
a
-(o-haloaryl)-substituted ketones 9,29 2-for-
R'
myl-benzoic acids 10,30 ketoaldehydes 11,31 aromatic keto acids
12,32 2-iodobenzoic acids 13,33 and alkyl 2-ynyl-benzoates 14,34
and so on.35 Although some of these methods are effective for the
CHO
R
O
11
R
O
10
9
COOH
O
COOH
I
COOR'
R
R'
12
R'
⇑
Corresponding author. Tel./fax: +86 0871 5033215.
E-mail address: linjun@ynu.edu.cn (J. Lin).
13
14
R
These authors contributed equally to this paper.
Figure 1. The substrates for synthesis of isocoumarins 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.100

466
S. Yan et al. / Tetrahedron Letters 52 (2011) 465–467
Table 2
COOEt
O
O
Synthesis of tetracyclo-isocoumarins 17
NH
Solvent
reflux
OH
OH
COOEt
HN
Yielda (%)
N
Entry
15
n
R
17
N
H
O
1
2
3
4
5
6
7
8
9
15a
15b
15c
15d
15e
15f
15g
15h
15i
1
1
1
2
2
2
2
3
3
3
3
COOEt
17a
17b
17c
17d
17e
17f
17g
17h
17i
81
73
70
79
75
71
74
89
88
84
78
O
15a
16
p-MeOC6H4CO
p-MeC6H4CO
p-MeOC6H4CO
p-MeC6H4CO
C6H4CO
p-ClC6H4CO
p-MeOC6H4CO
p-MeC6H4CO
C6H4CO
17a
Scheme 1. Synthesis of tetracyclo-isocoumarine 17a.
Table 1
Optimizing the reaction conditions for synthesis of 17a
10
11
15j
15k
17j
17k
Entry
Solvent
Catalyst
T (°C)
Time (h)
Yield/%a
p-ClC6H4CO
1
2
3
4
5
6
7
8
9
10
11
12
14
15
16
17
18
19
20
CH3CN
DMF
—
—
—
—
Reflux
Reflux
140
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
—
—
—
—
47
—
50
21
15
—
—
—
—
Trance
81
23
35
Trance
31
a
Isolated yield by silica gel column chromatograph.
DMSO
Dioxane
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
DMF
DMF
DMF
DMF
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
AcOH
TFA
HClO4ÁSiO2
H3PW14O40
ZnCl2
AcOH
TFA
HClO4ÁSiO2
H3PW14O40
ZnCl2
AcOH
TFA
HClO4ÁSiO2
H3PW14O40
ZnCl2
a
Isolated yield.
R
N
O
H
N
Figure 2. X-ray crystal structure of 17h.
R
OH
HOAc
HN
n
OH dioxane
reflux, 6 h
N
O
n
H
O
O
H
15
16
17
R
N
O
n=1~3
OH
aza-ene
n
R=COOEt, ArCO
OH
OH
N
H
addition
H
OH
Scheme 2. Synthesis of tetracyclo-isocoumarins 17.
OH
O
16
15
O
18
R
H
H
R
H
HO
HO
N
imine-enamine
tautomerization
N
the pool of suitable starting materials which allow access to cyclic
derivatives, we focused on the one-pot synthesis of tetracyclo-
isocoumarin derivatives 17 based upon the cyclocondensation
reaction of heterocyclic ketene aminals (HKAs) 15 and 2,2-
dihydroxy-2H-indene-1,3-dione 16 catalyzed by acetic acid.
To explore the practicality of the projected synthetic route, we
first evaluated the cascade reaction of ethyl 2-(imidazolidin-2-yli-
dene)acetate 15a and 2,2-dihydroxy-2H-indene-1,3-dione 16. The
mixture, which was composed of a 1:1.1 ratio of 15a to 16, was
treated under various conditions (Scheme 1) (Table 1, entries
1–11). We found that the reactions could not proceed in different
solvents such as acetonitrile, DMF, DMSO, and 1,4-dioxane under
catalyst-free conditions (Table 1, entries 1–4), while the catalysts
AcOH, H3PW14O40, ZnCl2, and TFA promoted the reactions.
The results demonstrated that the best reaction conditions for
the synthesis of tetracyclo-isocoumarins were dioxane as a solvent
and acetic acid as a catalyst under reflux for 6 h with an isolated
product of a good yield (81%) (Table 1, entry 16). The use of acetic
acid as a catalyst can promote the cyclocondensation of HKAs 15a
with 2,2-dihydroxy-2H-indene-1,3-dione 16 and the rearrange-
ment reaction of the intermediates (Table 1, entries 5 and 16).
Removing the acids prevented the cyclocondensation of HKAs
(Table 1, entries 1–4). This result indicated that this reaction is
catalyzed by protic acids.
OH
N
N
n
-H2O
OH2
OH n
OH
O
19
20
R
H
R
H
HO
N
H2O
N
-H2O
N
OH
N
O
n
n
21
HO
22
OH
R
R
NH
-H
HN
N
n
N
O
n
O
O
HO
23
17
Scheme 3. The proposed mechanism for cascade reaction.
Encouraged by this result, we examined the scope and limita-
tions of the cascade reactions involving various HKAs 15 with
2,2-dihydroxy-2H-indene-1,3-dione 16 (Scheme 2) (Table 2, en-
tries 1–11). The results demonstrated that HKAs with various sub-
stituents were all good substrates for the cascade reaction (Table 2,
entries 1–11). The reactions usually took ca. 6 h at reflux in 1,4-
dioxane in the presence of AcOH and gave the target compounds
with moderate to good yields.

S. Yan et al. / Tetrahedron Letters 52 (2011) 465–467
467
7. (a) Hussain, H.; Akhtar, N.; Draeger, S.; Schulz, B.; Pescitelli, G.; Salvadori, P.;
Antus, S.; Tibor Kurtán, T.; Krohn, K. Eur. J. Org. Chem. 2009, 749; (b) Zhang, W.;
Krohn, K.; Draeger, S.; Schulz, B. J. Nat. Prod. 2008, 71, 1078; (c) Engelmeier, D.;
Hadacek, F.; Hofer, O.; Lutz-Kutschera, G.; Nagl, M.; Wurz, G.; Greger, H. J. Nat.
Prod. 2004, 67, 19; (d) Nozawa, K.; Yamada, M.; Tsuda, Y.; Kawai, K.; Nakajima,
S. Chem. Pharm. Bull. 1981, 29, 2689.
8. Yoshikawa, M.; Harada, E.; Naitoh, Y.; Inoue, K.; Matsuda, H.; Shimoda, H.;
Yamahara, J.; Murakami, N. Chem. Pharm. Bull. 1994, 42, 2225.
9. Matsuda, H.; Shimoda, H.; Yoshikawa, M. Bioorg. Med. Chem. 1999, 7, 1445.
10. Chinworrungsee, M.; Kittakoop, P.; Isaka, M.; Chanphen, R.; Tanticharoen, M.;
Thebtaranonth, Y. J. Chem. Soc., Perkin Trans. 1 2002, 2473.
11. (a) Kurume, A.; Kamata, Y.; Yamashita, M.; Wang, Q.; Matsuda, H.; Yoshikawa,
M.; Kawasaki, I.; Ohta, S. Chem. Pharm. Bull. 2008, 56, 1264; (b) Matsuda, H.;
Wang, Q.; Matsuhira, K.; Nakamura, S.; Yuan, D.; Yoshikawa, M. Phytomedicine
2008, 15, 177.
12. (a) Matsuda, H.; Shimoda, H.; Yamahara, J.; Yoshikawa, M. Bioorg. Med. Chem.
Lett. 1998, 8, 215; (b) Shimoda, H.; Matsuda, H.; Yamahara, J.; Yoshikawa, M.
Biol. Pharm. Bull. 1998, 21, 809.
13. Hussain, M. T.; Rama, N. H.; Malik, A. Indian J. Chem., Sect B 2001, 40, 372.
14. Chino, M.; Nishikawa, K.; Yamada, A.; Ohsono, M.; Sawa, T.; Hanaoka, F.;
Ishizuka, M.; Takeuchi, T. J. Antibiot. 1998, 51, 480.
15. Bihel, F.; Quéléver, G.; Lelouard, H.; Petit, A.; da Costa, C. A.; Pourquié, O.; Checler,
F.; Thellend, A.; Pierree, P.; Krausa, J.-L. Bioorg. Med. Chem. 2003, 11, 3141.
16. Harper, J. W.; Powers, J. C. J. Am. Chem. Soc. 1984, 106, 7618.
17. (a) Heynekamp, J. J.; Hunsaker, L. A.; Vander Jagt, T. A.; Royer, R. E.; Decka, L.
M.; Vander Jagt, D. L. Bioorg. Med. Chem. 2008, 16, 5285; (b) Kam, C.-M.;
Kerrigan, J. E.; Plaskon, R. R.; Duffy, E. J.; Lollar, P.; Suddath, F. L.; Powers, J. C. J.
Med. Chem. 1994, 37, 1298.
The results in Table 2 demonstrate that HKAs, with various sub-
stituents (15a–k), were all good substrates for the reaction. The
substituents of the HKAs 15 had slight influence on the reactivity
and product yield. The yields of all substrates are all similar
(Table 2, entries 1–11).
Additionally, in terms of the ring sizes of the HKAs 15, the yields
of the seven-membered HKAs was superior to that of the five-mem-
bered and the six-membered HKAs (entries 8–11 vs 1–3 and 4–7).
All new compounds 17 were fully characterized on the basis of
their 1H, 13C NMR spectra, and high resolution mass spectra,36
which indicated that the HKAs reacted with 2,2-dihydroxy-2H-
indene-1,3-dione in a 1:1 ratio, affording novel kinds of tetracy-
clo-isocoumarins.
To verify the structure of the tetracyclo-isocoumarin products,
17h was selected as a representative compound and characterized
by X-ray crystallography, as shown in Figure 2 (CCDC 781822).37
A proposed mechanism of the acetic acid-catalyzed cascade
reaction is depicted in Scheme 3. Firstly, carbonyl group of 2,2-
dihydroxy-2H-indene-1,3-dione 16 accepted one proton of to form
18. Then the reaction of HKAs 15, due to the strongly electron-
withdrawing groups at the
a-position of the ketene N,N-acetals
acted as heteroene components, with 18 proceeded via an aza-
ene addition to afford 19. The intermediate 19 was followed by
imine–enamine tautomerization, intramolecular cyclization, and
dehydration to get 20. The adjacent OH undergoes intramolecular
attack on the carbonyl group to obtain a hydroxy epoxide interme-
diate 21, which through proton transfer is able to produce 22. Sub-
sequently ring-enlargement reaction occurs through opening of
the epoxide ring with losing a molecule of H2O to get 23. Finally,
23 loses proton to result in the target product 17.
In conclusion, we developed a procedure for the simple synthe-
sis of a variety of potential, biologically active tetracyclo-iso-
coumarins. Using this method, a molecularly diverse tetracyclo-
isocoumarin library was rapidly constructed with good yields by
simply refluxing a reaction mixture of HKAs and 2,2-dihydroxy-
2H-indene-1,3-dione, catalyzed by AcOH.
18. Minami, T.; Nishimoto, A.; Hanaoka, M. Tetrahedron Lett. 1995, 36, 9505.
19. Hauser, F. M.; Dorsch, W. A.; Mal, D. Org. Lett. 2002, 4, 2237.
20. Venkatesh, C.; Reissig, H.-U. Synthesis 2008, 3605.
21. Harris, T. M.; Harris, C. M.; Oster, T. A.; Brown, L. E., Jr.; Lee, J. Y. C. J. Am. Chem.
Soc. 1988, 110, 6180.
22. (a) Uchiyama, M.; Ozawa, H.; Takuma, K.; Matsumoto, Y.; Yonehara, M.; Hiroya,
K.; Sakamoto, T. Org. Lett. 2006, 8, 5517; (b) Hellal, M.; Bourguignon, J.-J.; Bihel,
F. J. Tetrahedron Lett. 2008, 49, 62.
23. (a) Ueura, K.; Satoh, T.; Miura, M. J. Org. Chem. 2007, 72, 5362; (b) Subramanian,
V.; Batchu, V. R.; Barange, D.; Pal, M. J. Org. Chem. 2005, 70, 4778; (c) Cherry, K.;
Parrain, J. L.; Thibonnet, J.; Duchene, A.; Abarbri, M. J. Org. Chem. 2005, 70,
6669; (d) Larock, R. C.; Doty, M.; Han, X.-J. J. Org. Chem. 1999, 64, 8770; (e)
Bellina, F.; Ciucci, D.; Vergamini, P.; Rossi, R. Tetrahedron 2000, 56, 2533.
24. Kinder, M. A.; Margaretha, P. Org. Lett. 2000, 2, 4253.
25. (a) Brasholz, M.; Reissig, H.-U. Synlett 2004, 15, 2736; (b) Waters, S. P.;
Kozlowski, M. C. Tetrahedron Lett. 2001, 42, 3567.
26. Woon, E. C. Y.; Dhami, A.; Mahon, M. F.; Threadgill, M. D. Tetrahedron 2006, 62,
4829.
27. Larock, R. C.; Varaprath, S.; Lau, H. H.; Fellows, C. A. J. Am. Chem. Soc. 1984, 106,
5274.
28. (a) Özcan, S.; Sahin, E.; Balci, M. Tetrahedron Lett. 2007, 48, 2151; (b) Özcan, S.;
Balci, M. Tetrahedron 2008, 64, 5531.
29. Tadd, A. C.; Fielding, M. R.; Willis, M. C. Chem. Commun. 2009, 6744.
30. Nakamura, Y.; Ukita, T. Org. Lett. 2002, 4, 2317.
31. Suzuki, T.; Yamada, T.; Watanabe, K.; Katoh, T. Bioorg. Med. Chem. Lett. 2005, 15,
2583.
32. Hauser, F. M.; Baghdanov, V. M. J. Org. Chem. 1988, 53, 4676.
33. Chakravarty, M.; Swamy, K. C. K. J. Org. Chem. 2006, 71, 9128.
34. (a) Peuchmaur, M.; Lisowski, V.; Gandreuil, C.; Maillard, L. T.; Martinez, J.;
Hernandez, J.-F. J. Org. Chem. 2009, 74, 4158; (b) Yao, T.; Larock, R. C.
Tetrahedron Lett. 2002, 43, 7401.
Acknowledgments
The authors acknowledge the financial support in the form of
grants from NSFCs (Nos. 30860342 and 20762013) and NSFYNs
(Nos. 2009cc017 and 2008cd063).
Supplementary data
35. (a) Opatz, T.; Ferenc, D. Eur. J. Org. Chem. 2005, 817; (b) Mal, D.;
Bandyopadhyay, M.; Ghorai, S. K.; Datta, K. Tetrahedron Lett. 2000, 41, 3677.
36. General procedure for the synthesis of compounds 17. HKAs 15 (2.5 mmol),
2,2-dihydroxy-2H-indene-1,3-dione 16 (2.75 mmol), and 1,4-dioxane (15 mL)
were charged into a 50 mL round-bottomed flask, then acetic acid (3 mL) was
added to the mixture and the mixture was refluxed. The resulting solution was
stirred for 4–6 h until the HKAs 15 were completely consumed. The mixture
was cooled to room temperature, neutralized with a saturated solution of
Na2CO3 to pH 8–9, and then EtOAc (50 mL Â 2) was added. The organic phase
was washed with water (10 mL), dried over Na2SO4, concentrated, and purified
by flash column chromatography to afford tetracyclo-isocoumarins 17 in a
71À89% yield. Compound 17a: yellow solid; 81% mp: 140–144 °C. IR (KBr):
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.11.100.
References and notes
1. (a) Barry, R. P. Chem. Rev. 1964, 64, 229; (b) Murray, R. D. H.; Mendez, J.; Brown,
S. A. The Natural Coumarins: Occurrence, Chemistry, and Biochemistry; J. Wiley:
New York, 1982; (c) Mali, R. S.; Babu, K. N. J. Org. Chem. 1998, 63, 2488.
2. (a) Kawano, T.; Agata, N.; Kharbanda, S.; Avigan, D.; Kufe, D. Cancer Chemother.
Pharmacol. 2007, 59, 329; (b) Agata, N.; Nogi, H.; Milhollen, M.; Kharbanda, S.;
Kufe, D. Cancer Res. 2004, 64, 8512; (c) Lim, D.-S.; Kwak, Y.-S.; Kim, J.-H.; Ko, S.-
H.; Yoon, W.-H.; Kim, C.-H. Chemotherapy 2003, 49, 146; (d) Qabaja, G.;
Perchellet, E. M.; Perchellet, J.-P.; Jones, G. B. Tetrahedron Lett. 2000, 41, 3007;
(e) Kumagai, H.; Masuda, T.; Ishizuka, M.; Takeuchi, T. J. Antibiot. 1995, 48, 175.
3. Hudson, J. B.; Graham, E. A.; Harris, L.; Ashwood-Smith, M. J. Photochem.
Photobiol. 1903, 57, 491.
3437, 2979, 1723, 1678, 1600, 1455, 1320, 1130, 765 cmÀ1 1H NMR (500 MHz,
.
CDCl3): d = 1.41 (t, J = 7.0 Hz, 3H, CH3), 4.09 (t, J = 7.5 Hz, 2H, NCH2), 4.21 (t,
J = 7.5 Hz, 2H, NCH2), 4.34 (t, J = 7.0 Hz, 2H, OCH2), 4.94 (s, 1H, NH), 7.31 (t,
J = 7.3 Hz, 1H, ArH), 7.70 (t, J = 7.3 Hz, 1H, ArH), 8.27 (d, J = 7.9 Hz, 1H, ArH),
9.01 (d, J = 7.9 Hz, 1H, ArH). 13C HMR (125 MHz, CDCl3): d = 15.2, 43.8, 49.2,
60.0, 84.5, 99.6, 117.4, 125.3, 125.5, 131.3, 135.6, 137.0, 150.1, 161.6, 164.9,
196.2. HRMS (TOF ES+): m/z calcd for C16H14N2NaO4 [(M+Na)+], 321.0846;
found, 321.0840.
4. Kornsakulkarn, J.; Thongpanchang, C.; Lapanun, S.; Srichomthong, K. J. Nat.
Prod. 2009, 72, 1341.
5. Furuta, T.; Fukuyama, Y.; Asakawa, Y. Phytochemistry 1986, 25, 517.
6. Kam, C. M.; Fujikawa, K.; Powers, J. C. Biochemistry 1988, 27, 2547.
37. CCDC 781822 contains the supplementary crystallographic data for compound
17h. These data can be obtained free of charge from The Cambridge
Crystallographic Data Center via www.ccdc.cam.ac.uk/data_request/cif.