Nickel-catalyzed synthesis of benzocoumarins: Application to the total synthesis of arnottin I

Article abstract of DOI:10.1021/jo061477h

The ring-opening addition of methyl 2,3-dimethoxy-6-iodobenzoate to oxabenzonorbornadienes followed by cyclization in the presence of NiBr ₂(dppe) and Zn metal powder in acetonitrile at 80 °C to give the corresponding benzocoumarin derivatives

Full text of DOI:10.1021/jo061477h

Nickel-Catalyzed Synthesis of Benzocoumarins:
Application to the Total Synthesis of Arnottin I
Sachin Madan and Chien-Hong Cheng*
Department of Chemistry, National Tsing Hua UniVersity,
Hsinchu 30013, Taiwan
chcheng@mx.nthu.edu.tw
ReceiVed July 17, 2006
The ring-opening addition of methyl 2,3-dimethoxy-6-iodo-
benzoate to oxabenzonorbornadienes followed by cyclization
in the presence of NiBr2(dppe) and Zn metal powder in
acetonitrile at 80 °C to give the corresponding benzocou-
marin derivatives is described. This methodology was then
applied to the synthesis of natural product arnottin I, first
isolated from Xanthoxylum arnottianum Maxim, using pro-
tecting group chemistry. After deprotection and subsequent
ring closure, arnottin I was obtained in 21% overall yield
after six steps starting from catechol.
FIGURE 1. Structures of gilvocarcin-class antibiotics.
However, the coumarin-based natural product arnottin I, having
a 6H-benzo[d]naphtho[1,2-b]pyran-6-one skeleton found in
gilvocarcin-type antibiotics, has received less attention.6 Previ-
ously, it has been synthesized utilizing a 2-methylarenofuran
as a masked salicylaldehyde6a and also via the internal aryl-
aryl coupling reaction of aryl ortho-halobenzoate catalyzed by
palladium complexes.7
Gilvocarcins1 and other related compounds, such as ravido-
mycin2 and chrysomycins,3 are metabolites of certain Strepto-
myces species and belong to a class of aryl C-glycoside
antibiotics4 (Figure 1). These molecules, sharing a common
tetracyclic aromatic nucleus, 6H-benzo[d]naphtho[1,2-b]pyran-
6-one to which sugars are attached at the C-4 position, have
attracted great attention. Defucogilvocarcins5 having a similar
chromophore have also been extensively studied (Figure 1).
Our long and continued interest in nickel chemistry8,9 and
the coumarin10 synthesis encouraged us to investigate a new
(5) For isolation and structure of defucogilvocarcin V, see: (a) Misra,
R.; Tritch, H. R., III; Pandey, R. C. J. Antibiot. 1985, 38, 1280. (b)
Defucogilvocarcin M: Nakashima, T.; Fujii, T.; Sakai, K.; Sameshima, T.;
Kumagai, H.; Yoshioka, T. PCT Patent Appl. W098/22612 A1, 1998; Chem.
Abstr. 1998, 129, 49638. For the total synthesis of defucogilvocarcins, see:
(c) Macdonald, S. J. F.; McKenzie, T. C.; Hassen, W. D. J. Chem. Soc.,
Chem. Commun. 1987, 1528. (d) Patten, A. D.; Nguyen, N. H.; Danishefsky,
S. J. J. Org. Chem. 1988, 53, 1003. (e) Jung, M. E.; Jung, Y. H. Tetrahedron
Lett. 1988, 29, 2517. (f) McGee, L. R.; Confalone, P. N. J. Org. Chem.
1988, 53, 3695. (g) Hart, D. J.; Merriman, G. H. Tetrahedron Lett. 1989,
30, 5093. (h) Deshpande, P. P.; Martin O. R. Tetrahedron Lett. 1990, 2931,
6313. (i) Parker, K. A.; Coburn, C. A. J. Org. Chem. 1991, 56, 1666. (j)
Hua, D. H.; Saha, S.; Roche, D.; Maeng, J. C.; Iguchi, S.; Baldwin, C. J.
Org. Chem. 1992, 57, 399. (k) Takemura, I.; Imura, K.; Matsumoto, T.;
Suzuki, K. Org. Lett. 2004, 6, 2503.
(6) For isolation and structure determination of arnottin I, see: (a) Ishii,
H.; Ishikawa, T.; Murota, M.; Aoki, Y.; Harayama, T. J. Chem. Soc., Perkin
Trans. 1 1993, 1019. (b) Ishii, H.; Ishikawa, T.; Haginiwa, J. Yakugaku
Zasshi 1977, 97, 890.
(7) (a) Harayama, T.; Yasuda, H.; Akiyama, T.; Takeuchi, Y.; Abe, H.
Chem. Pharm. Bull. 2000, 48, 861. (b) Harayama, T.; Yasuda, H.
Heterocycles 1997, 46, 61.
(1) For isolation and structure elucidation of gilvocarcin V and M, see:
(a) Horii, S.; Fukase, H.; Mizuta, E.; Hatano, K.; Mizuno, K. Chem. Pharm.
Bull. 1980, 28, 3601. (b) Nakano, H.; Matsuda, Y.; Ito, K.; Ohkubo, S.;
Morimoto, M.; Tomita, F. J. Antibiot. 1981, 34, 266. (c) Takahashi, K.;
Yoshida, M.; Tomita, F.; Shirahata, K. J. Antibiot. 1981, 34, 266. (d)
Hirayama, N.; Takahashi, K.; Shirahata, K.; Ohashi, Y.; Sasada, Y. Bull.
Chem. Soc. Jpn. 1981, 54, 1338. (e) Balitz, D. M.; O’Herron, F. A.; Bush,
J.; Vyas, D. M.; Nettleton, D. E.; Grulich, R. E.; Bradner, W. T.; Doyle, T.
W.; Arnold, E.; Clardy, J. J. Antibiot. 1981, 34, 1544. (f) Jain, T. C.;
Simolike, G. C.; Jackman, L. M. Tetrahedron 1983, 39, 599. For the total
synthesis of gilvocarcin V and M, see: (g) Matsumoto, T.; Hosoya, T.;
Suzuki, K. J. Am. Chem. Soc. 1992, 114, 3568. (h) Hosoya, T.; Takashiro,
E.; Matsumoto, T.; Suzuki, K. J. Am. Chem. Soc. 1994, 116, 1004.
(2) For isolation and structure determination of ravidomycin, see: (a)
Findlay, J. A.; Liu, J.-S.; Radics, L.; Rakhit, S. Can. J. Chem. 1981, 59,
3018. (b) Findlay, J. A.; Liu, J.-S.; Radics, L. Can. J. Chem. 1983, 61,
323. (c) Narita, T.; Matsumoto, M.; Mogi, K.; Kukita, K.; Kawahara, R.;
Nakashima, T. J. Antibiot. 1989, 42, 347. For the total synthesis of
ravidomycin, see: (d) Futagami, S.; Ohashi, Y.; Imura, K.; Ohmori, K.;
Matsumoto, T.; Suzuki, K. Tetrahedron Lett. 2000, 41, 1063.
(8) (a) Rayabarapu, D. K.; Cheng, C.-H. J. Am. Chem. Soc. 2002, 124,
5630. (b) Huang, Y.-C.; Majumdar, K. K.; Cheng, C.-H. J. Org. Chem.
2002, 67, 1682. (c) Rayabarapu, D. K.; Cheng, C.-H. Chem. Commun. 2002,
942. (d) Shanmugasundaram, M.; Wu, M.-S.; Cheng, C.-H. Org. Lett. 2001,
3, 4233. (e) Hsiao, T.-Y.; Santhosh, K. C.; Liou, K.-F.; Cheng, C.-H. J.
Am. Chem. Soc. 1998, 120, 12232.
(3) For chrysomycin A and B, see: (a) Strelitz, F.; Flon, H.; Asheshov,
I. N. J. Bacteriol. 1955, 69, 280. (b) Weiss, U.; Yoshihira, K.; Highet, R.
J.; White, R. J.; Wei, T. T. J. Antibiot. 1982, 35, 1194.
(4) For an excellent review on aryl C-glycoside antibiotics, see: Hacksell,
U.; Daves, G. D., Jr. Prog. Med. Chem. 1985, 22, 1-65.
10.1021/jo061477h CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/13/2006
8312
J. Org. Chem. 2006, 71, 8312-8315

SCHEME 1. Retrosynthetic Analysis
method for the synthesis of arnottin I via a nickel-catalyzed
ring-opening addition of substituted o-iodobenzoate to oxaben-
zonorbornadienes. To the best of our knowledge, no nickel-
catalyzed synthesis of arnottin I has been reported in the
literature. Herein, we report the results of this study.
Initially the reaction was tested using commercially available
7-oxabenzonorbornadiene 1 and methyl 2,3-dimethoxy-6-iodo-
benzoate11 2. Under the standard reaction conditions,12 that is,
NiBr2(dppe) [dppe ) 1,2-bis(diphenylphosphino)ethane] and Zn
powder in CH3CN at 80 °C under N2 atmosphere for 12 h, the
desired annulated coumarin 3 was obtained in 75% isolated
yield (eq 1). Similarly, treatment of 2,3-dimethoxy-7-oxaben-
zonorbornadiene 4 with o-iodobenzoate 2 gave tetramethoxy-
substituted coumarin 5 in 68% isolated yield (eq 1). Starting
material 4 was prepared from 4,5-dibromoveratrole and furan
in the presence of nBuLi at -78 °C using Diels-Alder reaction,
while 2 was synthesized from 2,3-dimethoxybenzoic acid and
thallic trifluoroacetate (prepared in situ by refluxing Tl2O3 in
CF3COOH for 2 days).13
I. Further, no desired product was observed when nickel com-
plex systems, such as NiCl2(PPh3)2/Zn/Et3N, NiCl2(PPh3)2/Zn,
and NiCl2(PPh3)2/PPh3/Zn having PPh3 as the monodentate
ligand, were employed. Under these reaction conditions, major
product for the reaction of oxabenzonorbornadiene 6 with
o-iodobenzoate 2 is 7 instead of the expected product arnottin
I. Compound 7 is likely from the facile dehydroxylation
(-MOH) of reaction intermediate 8 due to the highly electron-
rich character of the 1,3-benzodioxolane group that can stabilize
an R-carbon cation intermediate or transition state during the
elimination of the MOH group in 8 to give 7 (Figure 2).
The above examples have successfully demonstrated the
utility of this nickel-catalyzed reaction in the synthesis of highly
functionalized benzocoumarin derivatives. We thus decided to
extend this methodology further for preparation of the coumarin-
based natural product arnottin I. As shown from retrosynthetic
analysis in Scheme 1, two approaches were tested for its syn-
thesis. Path a involved the reaction of 1,3-dioxolane-substituted
oxabenzonorbornadiene 6 with o-iodobenzoate 2. Compound 6
can be prepared via the Diels-Alder reaction of furan and the
benzyne generated from commercially available 1,2-dibromo-
4,5-methylenedioxybenzene and nBuLi. Unfortunately, the reac-
tion of 6 with 2 in the presence of NiBr2(dppe) and Zn powder
in CH3CN failed to give the desired natural product in decent
yield even after variation of temperature and change of solvent
for the reaction. Different nickel catalyst systems, such as NiBr2-
(dppe)/dppe/Zn, NiBr2(dppe)/Zn/Et3N, NiCl2(dppe)/Zn/Et3N,
NiBr2(dppb)/Zn/Et3N, NiBr2(dppp)/Zn/Et3N, and Ni(COD)2/
PPh3, gave only a trace amount of the desired product arnottin
FIGURE 2. Structures of 7 and 8.
We then turned our attention to the alternative route (Scheme
1, path b). Using protecting group methodology, benzyl-, allyl-,
and silyl-protected oxabenzonorbornadienes 9-11 were syn-
thesized in three steps starting from catechol. Treatment of
catechol with bromine in acetic acid gave 4,5-dibromocatechol
in 90% yield.14 Protection of the free hydroxyl groups as
benzyl-/allyl-substituted derivatives (NaH, THF, RX), followed
by the Diels-Alder reaction of the benzynes generated (nBuLi,
THF, -78 °C) with furan, gave the corresponding 2,3-dibenzyl-
and 2,3-diallyl-7-oxabenzonorbornadienes 9 and 10 in 52 and
46% yields, respectively (Scheme 2). Similarly, tert-butyldi-
methylsilyl was used as the protecting group (TBDMSCl,
(9) (a) Rayabarapu, D. K.; Yang, C.-H.; Cheng, C.-H. J. Org. Chem.
2003, 68, 6726. (b) Rayabarapu, D. K.; Cheng, C.-H. Chem.sEur. J. 2003,
9, 3164. (c) Rayabarapu, D. K.; Chiou, C.-F.; Cheng, C.-H. Org. Lett. 2002,
4, 1679. (d) Huang, D.-J.; Rayabarapu, D. K.; Li, L.-P.; Sambaiah, T.;
Cheng, C.-H. Chem.sEur. J. 2000, 6, 3706. (e) Sambaiah, T.; Huang, D.-J.;
Cheng, C.-H. New J. Chem. 1998, 22, 1147. (f) Shukla, P.; Cheng, C.-H.
Org. Lett. 2006, 8, 2867.
SCHEME 2. Preparation of Substituted
Oxabenzonorbornadienes 9-11
(10) (a) Murray, R. D. H.; Mendez, J.; Brown, S. A. The Natural
Coumarins: Occurrence, Chemistry, and Biochemistry; Wiley: New York,
1982. (b) Naser-Hijazi, B.; Stolze, B.; Zanker, K. S. Second Proceedings
of the International Society of Coumarin InVestigators; Springer: Berlin,
1994. (c) Hepworth, J. D. In ComprehensiVe Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Boulton, A. J., McKillop, A., Eds.; Pergamon
Press: Oxford, 1984; Vol. 3, Chapter 2.24, pp 799-810. (d) Staunton, J.
In ComprehensiVe Heterocyclic Chemistry; Barton, D. H. R., Ollis, W. D.,
Sammes, P. G., Eds.; Pergamon Press: Oxford, 1979; Vol. 4, Chapter 18.2,
pp 651-653.
(11) Dyke, S. F.; Tiley, E. P. Tetrahedron 1975, 31, 561.
(12) Rayabarapu, D. K.; Shukla, P.; Cheng, C.-H. Org. Lett. 2003, 5, 4903.
(13) Taylor, E. C.; Kienzle, F.; Robey, R.; McKillop, A. J. Am. Chem.
Soc. 1970, 92, 2175.
J. Org. Chem, Vol. 71, No. 21, 2006 8313

SCHEME 3. Synthesis of Dihydroxy Coumarin 15
SCHEME 4. Total Synthesis of Arnottin I
imidazole, DMF) for the free hydroxyl groups in 4,5-dibro-
mocatechol to prepare 1,2-bis(tert-butyldimethylsilyloxy)-4,5-
dibromobenzene. The Diels-Alder reaction of the corresponding
benzyne generated (nBuLi, THF, -78 °C) with furan then
afforded 1,2-bis(tert-butyldimethylsilyloxy)-7-oxabenzonorbor-
nadiene 11 in 44% yield over three steps (Scheme 2).
atives in good yields. The methodology was further extended to
the preparation of natural product arnottin I employing TBDMS-
protected oxabenzonorbornadiene 11 as the substrate for reaction
with 2. After removal of the TBDMS group under mild reaction
conditions and subsequent ring closure, the desired compound
arnottin I 16 was obtained in 21% overall yield after six steps.
With substituted oxabenzonorbornadienes 9-11 in hand, we
carried out the nickel-catalyzed coumarin synthesis reaction.
Hence, treatment of dibenzyl derivative 9 with o-iodobenzoate
2 under our standard reaction conditions furnished dibenzyl
coumarin 12 in 65% isolated yield (Scheme 3). Debenzylation
using H2/Pd-C gave the desired dihydroxy compound 15 but
only in 25% yield. Next, we used diallyl-substituted oxaben-
zonorbornadiene 10 as the substrate for reaction with 2 using
our standard protocol to furnish diallyl coumarin 13 in 69%
yield (Scheme 3). Deallylation with Pd(PPh3)4/morpholine15a
in degassed THF gave only a trace amount of dihydroxy
derivative 15. Even Corey’s modified Pd-catalyzed conditions15b
failed to give 15 in decent yield.
Finally, TBDMS-protected oxabenzonorbornadiene 11 was
employed as substrate for the reaction with o-iodobenzoate 2
to give the corresponding coumarin derivative 14 in 72% iso-
lated yield. The silyl groups were successfully removed by KF
(10.0 equiv) in a mixture of THF and CH3CN (1:1 by volume)
to give dihydroxy derivative 15 in 90% yield. Final ring closure
was carried out using triethylamine and CH2Br2 in CH3CN under
reflux for 15 h to furnish the title compound arnottin I 16 in
74% isolated yield (Scheme 4). The spectroscopic data of this
compound are consistent with those reported previously.6a
In summary, we have successfully demonstrated the use of
the nickel-catalyzed ring-opening addition reaction of methyl
2,3-dimethoxy-6-iodobenzoate 2 to substituted oxabenzonor-
bornadienes to give highly functionalized benzocoumarin deriv-
Experimental Section
4,5-Dibromocatechol and 1,2-bis(benzyloxy)-4,5-dibromoben-
zene were prepared according to the methods reported in the
literature.14,16,17
General Procedure for the Preparation of Benzocoumarins
3 and 5. A round-bottom sidearm flask (25 mL) containing the
corresponding bicyclic olefin 1 or 4 (1.5 mmol), methyl o-iodo-
benzoate 2 (1.0 mmol), NiBr2(dppe) (31 mg, 0.05 mmol, 5 mol
%), and Zn metal powder (2.75 mmol) was evacuated and purged
with nitrogen gas four times. Freshly distilled CH3CN (3.0 mL)
was added to the above mixture, and the reaction mixture was stirred
at 80 °C for 12 h. The reaction mixture was then cooled, diluted
with methylene chloride (15 mL), and stirred in the air for 15 min.
Then it was filtered through a short pad of Celite and silica gel. It
was then washed with CH2Cl2 several times. The filtrate was
concentrated in vacuo, and the crude product was purified by silica
gel column using a mixture of ethyl acetate and hexanes as eluent
to afford the corresponding benzocoumarin products 3 and 5.
7,8-Dimethoxy-6H-dibenzo[c,h]chromene-6-one (3): This com-
pound was obtained in 75% yield; 1H NMR (600 MHz, CDCl3) δ
3.93 (s, 3H), 3.99 (s, 3H), 7.37 (d, 1H, J ) 8.8 Hz), 7.51 (t, 1H,),
7.54 (t, 1H), 7.63 (d, 1H, J ) 8.8 Hz), 7.77 (d, 1H, J ) 8.0 Hz),
7.83 (d, 1H, J ) 8.8 Hz), 7.88 (d, 1H, J ) 8.8 Hz), 8.48 (d, 1H,
J ) 8.2 Hz); 13C NMR (150 MHz, CDCl3) δ 56.4, 61.6, 112.7,
115.6, 118.0, 119.1, 119.4, 122.1, 123.6, 124.1, 126.9, 127.4, 127.5,
129.3, 133.6, 146.1, 151.6, 153.3, 157.6; HRMS calcd for C19H14O4
306.0892, found 306.0891.
2,3,7,8-Tetramethoxy-6H-dibenzo[c,h]chromene-6-one (5): This
compound was obtained in 68% yield; 1H NMR (600 MHz, CDCl3)
δ 3.96 (s, 3H), 4.00 (s, 3H), 4.01 (s, 3H), 4.08 (s, 3H), 7.11 (s,
1H), 7.41 (d, 1H, J ) 8.8 Hz), 7.53 (d, 1H, J ) 8.7 Hz), 7.75
(14) Kohn, M. J. Am. Chem. Soc. 1951, 73, 480.
(15) (a) Eicher, T.; Ott, M.; Speicher, A. Synthesis 1996, 755. (b) Stoltz,
B. M.; Kano, T.; Corey, E. J. J. Am. Chem. Soc. 2000, 122, 9044.
8314 J. Org. Chem., Vol. 71, No. 21, 2006

(s, 1H), 7.81 (d, 1H, J ) 8.7 Hz), 7.85 (d, 1H, J ) 8.8 Hz); 13C
NMR (150 MHz, CDCl3) δ 55.9, 56.4, 56.5, 61.6, 101.0, 106.4,
111.7, 115.3, 117.5, 117.8, 118.8, 119.7, 122.6, 129.8, 129.9, 145.6,
150.2, 150.6, 151.7, 153.0, 157.9; HRMS calcd for C21H18O6
366.1103, found 366.1105.
General Procedure for the Preparation of Dibenzocoumarins
12-14. These compounds were prepared according to the procedure
already reported above for compounds 3 and 5.
2,3-Bis(benzyloxy)-7,8-dimethoxy-6H-dibenzo[c,h]chromene-
1
6-one (12): This compound was obtained in 65% yield; H NMR
(600 MHz, CDCl3) δ 3.92 (s, 3H), 4.02 (s, 3H), 5.24 (s, 2H), 5.31
(s, 2H), 7.14 (s, 1H), 7.28-7.57 (m, 12H), 7.68-7.73 (m, 2H),
7.85 (s, 1H); 13C NMR (150 MHz, CDCl3) δ 56.6, 61.5, 70.9, 71.0,
103.6, 109.4, 111.7, 115.4, 117.5, 117.6, 119.1, 119.9, 122.6, 126.4,
127.1, 127.2, 127.4, 127.8, 127.8, 128.5, 130.0, 130.0, 136.9, 145.6,
150.0, 150.3, 151.9, 153.0, 157.7; HRMS calcd for C33H26O6
518.1729, found 518.1730.
General Procedure for the Preparation of Oxabenzonorbor-
nadienes (6, 9-11). To a solution of appropriate dibromo com-
pound (4.0 mmol) and furan (3 mL) in dry THF (25 mL) at -78 °C
n
under N2 atmosphere was added BuLi (4.4 mmol, 2.5 M in hex-
anes) over a period of 1 h using a syringe pump. After the addition
was completed, the reaction mixture was allowed to attain room
temperature and was stirred overnight. It was quenched with brine
and extracted with diethyl ether (4 × 10 mL). The combined organic
layers were washed with brine and dried over MgSO4. After con-
centration, the crude product was purified by silica gel chroma-
tography using a mixture of ethyl acetate and hexanes as eluent
to afford the corresponding substituted 7-oxabenzonorbornadienes
(6, 9-11).
2,3-Bis(allyloxy)-7,8-dimethoxy-6H-dibenzo[c,h]chromene-6-
1
one (13): This compound was obtained in 69% yield; H NMR
(600 MHz, CDCl3) δ 3.95 (s, 3H), 4.01 (s, 3H), 4.71 (d, 2H, J )
5.2 Hz), 4.78 (d, 2H, J ) 5.2 Hz), 5.33 (m, 2H), 5.51 (m, 2H),
6.16 (m, 2H), 7.10 (s, 1H), 7.38 (d, 1H, J ) 8.8 Hz), 7.48 (d, 1H,
J ) 8.7 Hz), 7.75 (s, 1H), 7.76 (d, 1H, J ) 8.8 Hz), 7.81 (d, 1H,
J ) 8.9 Hz); 13C NMR (150 MHz, CDCl3) δ 56.5, 61.5, 69.5, 69.7,
102.5, 108.2, 111.6, 115.2, 117.4, 117.7, 118.0, 118.1, 118.8, 119.6,
122.6, 129.7, 129.9, 132.7, 132.8, 145.5, 149.4, 149.7, 151.6, 152.9,
157.8; HRMS calcd for C25H22O6 418.1416, found 418.1418.
2,3-Bis(t-butyldimethylsilyloxy)-7,8-dimethoxy-6H-dibenzo-
[c,h]chromene-6-one (14): This compound was obtained in 72%
2,3-Methylenedioxy-7-oxabenzonorbornadiene (6):18 This com-
pound was obtained in 45% yield; 1H NMR (600 MHz, CDCl3) δ
5.62 (s, 2H), 5.87 (s, 1H), 5.92 (s, 1H), 6.82 (s, 2H), 7.02 (s, 2H);
13C NMR (150 MHz, CDCl3) δ 82.4, 101.1, 103.8, 143.2, 143.3,
144.3; HRMS calcd for C11H8O3 188.0473, found 188.0475.
2,3-Bis(benzyloxy)-7-oxabenzonorbornadiene (9): This com-
pound was obtained in 52% yield; 1H NMR (600 MHz, CDCl3) δ
5.09 (s, 4H), 5.62 (s, 2H), 6.98 (s, 2H), 6.99 (s, 2H), 7.26-7.42
(m, 10H); 13C NMR (150 MHz, CDCl3) δ 72.3, 82.4, 110.7, 127.8,
128.0, 128.4, 137.4, 142.6, 143.1, 146.0; HRMS calcd for C24H20O3
356.1412, found 356.1414.
2,3-Bis(allyloxy)-7-oxabenzonorbornadiene (10): This com-
pound was obtained in 46% yield; 1H NMR (500 MHz, CDCl3) δ
4.53 (d, 4H, J ) 5.0 Hz), 5.22 (dd, 2H, J ) 1.5 and 10.5 Hz), 5.36
(dd, 2H, J ) 1.5 and 17.0 Hz), 5.62 (s, 2H), 6.03 (m, 2H), 6.94 (s,
2H), 6.99 (s, 2H); 13C NMR (150 MHz, CDCl3) δ 70.8, 82.4, 109.9,
117.4, 133.6, 142.1, 143.1, 145.5; HRMS calcd for C16H16O3
256.1099, found 256.1102.
1
yield; H NMR (600 MHz, CDCl3) δ 0.28 (s, 6H), 0.30 (s, 6H),
1.02 (s, 9H), 1.03 (s, 2H), 3.91 (s, 3H), 3.99 (s, 3H), 7.16 (s, 1H),
7.33 (d, 1H, J ) 8.8 Hz), 7.43 (d, 1H, J ) 8.8 Hz), 7.70 (d, 1H,
J ) 8.7 Hz), 7.76 (d, 1H, J ) 8.7 Hz), 7.84 (s, 1H); 13C NMR
(150 MHz, CDCl3) δ -4.1 (-CH3-Si), -4.1 (-CH3-Si), 18.5,
18.5, 25.9, 26.0, 56.4, 61.4, 110.7, 111.3, 115.3, 116.2, 117.3, 117.6,
119.4, 122.4, 129.8, 130.2, 145.3, 148.4, 148.9, 151.5, 152.8, 157.7;
HRMS calcd for C31H42O6Si2 566.2520, found 566.2524.
2,3-Dihydroxy-7,8-dimethoxy-6H-dibenzo[c,h]chromene-6-
one (15): To a solution of 14 (400 mg, 0.70 mmol) in THF:CH3-
CN (1:1, 8 mL) was added KF (406 mg, 7 mmol), and the reaction
mixture was stirred at room temperature for 15 h. The solid formed
in the reaction mixture was separated and washed several times
with diethyl ether. It was then dried under vacuum overnight to
furnish 215 mg of 15 (90%): 1H NMR (500 MHz, CD3CN) δ 3.78
(s, 3H), 3.85 (s, 3H), 6.82 (s, 1H), 7.19 (s, 1H); 7.31 (d, 1H, J )
8.8 Hz), 7.59 (d, 1H, J ) 9.0 Hz), 7.65 (d, 1H, J ) 8.9 Hz), 7.97
(d, 1H, J ) 9.0 Hz); 13C NMR (150 MHz, CD3CN) δ 56.9, 61.5,
100.8, 108.1, 109.1, 114.2, 115.2, 116.9, 118.7, 121.4, 122.6, 130.3,
130.8, 145.0, 150.9, 152.5, 153.8, 155.4, 158.4.
Preparation of Arnottin I (16). A mixture of 15 (200 mg, 0.60
mmol), methylene bromide (156 mg, 0.06 mL, 0.9 mmol), and
triethylamine (180 mg, 0.25 mL, 1.8 mmol) in CH3CN (10 mL)
was refluxed for 15 h. After removal of the solvent, the residue
was redissolved in CH2Cl2 (20 mL), washed with water and brine,
and dried over MgSO4. Column chromatographic purification (ethyl
acetate:hexanes, 1:5) gave 150 mg of the desired natural product
16 (74%): 1H NMR (600 MHz, CDCl3) δ 3.97 (s, 3H), 4.01 (s,
3H), 6.08 (s, 2H), 7.11 (s, 1H), 7.42 (d, 1H, J ) 8.4 Hz), 7.51 (d,
1H, J ) 9.0 Hz), 7.81 (d, 1H, J ) 9.0 Hz), 7.83 (s, 1H), 7.87 (d,
1H, J ) 9.0 Hz); 13C NMR (150 MHz, CDCl3) δ 56.6, 61.6, 99.1,
101.5, 104.0, 111.7, 117.7, 117.8, 119.7, 120.0, 123.2, 125.0, 129.8,
131.2, 135.2, 144.0, 145.4, 148.2, 151.8, 153.1, 157.7; HRMS calcd
for C20H14O6 350.0790, found 350.0791.
2,3-Bis(t-butyldimethylsilyloxy)-7-oxabenzonorbornadiene (11):
1
This compound was obtained in 57% yield; H NMR (600 MHz,
CDCl3) δ 0.16 (s, 6H), 0.17 (s, 6H), 0.97 (s, 18H), 5.59 (s, 2H),
6.78 (s, 2H), 6.95 (s, 2H); 13C NMR (150 MHz, CDCl3) δ -4.1
(CH3-Si), -4.1 (CH3-Si), 18.3, 25.9, 82.3, 114.9, 141.5, 142.8,
142.9; HRMS calcd for C22H36O3Si2 404.2203, found 404.2205.
Methyl 2,3-dimethoxy-6-(naphtho[2,3-d][1,3]dioxol-7-yl)ben-
zoate (7). A round-bottom sidearm flask (25 mL) containing 6 (280
mg, 1.5 mmol), o-iodobenzoate 2 (320 mg, 1.0 mmol), NiBr2(dppe)
(31 mg, 0.05 mmol, 5 mol %), and Zn metal powder (2.75 mmol)
was evacuated and purged with nitrogen gas four times. Freshly
distilled CH3CN (3.0 mL) was added to the above mixture, and
the reaction mixture was stirred at 80 °C for 12 h. The reaction
mixture was then cooled, diluted with methylene chloride (15 mL),
and stirred in air for 15 min. Then it was filtered through a short
pad of Celite silica gel and washed with CH2Cl2 several times. After
concentration in vacuo, the crude product was purified by silica
gel column (ethyl acetate: hexanes, 1:15) to afford 265 mg of the
title compound 7 in 73% yield: 1H NMR (600 MHz, CDCl3) δ
3.63 (s, 3H), 3.91 (s, 3H), 3.92 (s, 3H), 6.02 (s, 2H), 7.01 (d, 1H,
J ) 8.5 Hz), 7.09 (s, 1H), 7.10 (s, 1H), 7.16 (d, 1H, J ) 8.5 Hz),
7.32 (dd, 1H, J ) 1.8 and 8.3 Hz), 7.62 (s, 1H), 7.63 (d, 1H, J )
8.5 Hz); 13C NMR (150 MHz, CDCl3) δ 52.3, 56.0, 61.7, 101.0,
103.6, 104.0, 113.4, 124.8, 125.6, 126.1, 127.0, 128.8, 129.4, 130.3,
132.4, 135.6, 146.0, 147.6, 147.8, 151.7, 168.2; HRMS calcd for
C21H18O6 366.1103, found 366.1104.
Acknowledgment. The authors thank the National Science
Council of the Republic of China (NSC 93-2811-M-007-039)
for the financial support of this research.
Supporting Information Available: Copies of 1H NMR spectra
for all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(16) Hu, M.; Brasseur, N.; Yildiz, S. Z.; van Lier, J. E.; Leznoff, C. C.
J. Med. Chem. 1998, 41, 1789.
(17) Stringer, M. B.; Wege, D. Tetrahedron Lett. 1980, 21, 3831.
(18) Rayabarapu, D. K.; Sambaiah, T.; Cheng, C.-H. Angew. Chem., Int.
Ed. 2001, 40, 1286.
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