New cyclization route to the skeletons of lennoxamine and chilenine

Article abstract of DOI:10.1080/00397910802116575

A new cyclization route, triggered by epoxide opening, has been performed to provide the key intermediates for isoindolobenzapine alkaloids, lennoxamine and chilenine. The epoxide was prepared by the Stille reaction using vinyltributylstannane and the fol

Full text of DOI:10.1080/00397910802116575

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New Cyclization Route to the
Skeletons of Lennoxamine and
Chilenine
Guncheol Kim a , Ki Youn Lee a & Chul-Hwan Yoo a
a Department of Chemistry , College of Natural
Science, Chungnam National University , Taejon,
Korea
Published online: 12 Sep 2008.
To cite this article: Guncheol Kim , Ki Youn Lee & Chul-Hwan Yoo (2008) New
Cyclization Route to the Skeletons of Lennoxamine and Chilenine, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 38:19, 3251-3259, DOI: 10.1080/00397910802116575
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Synthetic Communications1, 38: 3251–3259, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802116575
New Cyclization Route to the Skeletons of
Lennoxamine and Chilenine
Guncheol Kim, Ki Youn Lee, and Chul-Hwan Yoo
Department of Chemistry, College of Natural Science, Chungnam National
University, Taejon, Korea
Abstract: A new cyclization route, triggered by epoxide opening, has been
performed to provide the key intermediates for isoindolobenzapine alkaloids,
lennoxamine and chilenine. The epoxide was prepared by the Stille reaction using
vinyltributylstannane and the following dioxirane treatment. Cyclization under
the treatment of BF3ꢀOEt2 provided an azepine moiety, and the oxidative cycliza-
tion toward the known precursor for the alkaloids has been achieved by reaction
with a stoichiometric amount of Pd(OAc)2. This formal synthesis suggests a new
route to the alkaloids.
Keywords: Chilenine, epoxide, lennoxamine, oxidative cyclization, palladium
acetate
INTRODUCTION
Isoindolobenzapine alkaloids, lennoxamine 1 and chilenine 2, have been
isolated from Chilean Berberis darwinii Hook and Berberis empetrifolia
Lam, respectively (Fig. 1).[1–3] Because of their unique tetracylic ring fea-
ture, many groups have shown interest in their syntheses and suggested
several attractive ways to the total synthesis as well as the ring system
synthesis.[4–14]
For a new approach to the ring skeleton, we wanted to arrange an
expedient formation of acyliminium intermediate A and figure out the
feature of the following transformation to the ring system (Scheme 1).
Recived December 28, 2007.
Address correspondence to Guncheol Kim, Department of Chemistry, College
of Natural Science, Chungnam National University, Taejon 305–764, Korea.
E-mail: guncheol@cnu.ac.kr
3251

3252
G. Kim, K. Y. Lee, and C.-H. Yoo
Figure 1. Structure of lennoxamine and chilenine.
As shown in the Scheme 1, the Friedel–Crafts reaction of A (path a)
would afford lennoxamine 1; on the other hand the elimination reaction
(path b) would provide compound 3.
RESULTS AND DISCUSSION
The requisite precursor for A, aldehyde 6, was prepared preliminarily
through a three-step sequence. Condensation of 3,4-methyenedioxyphe-
nethyl amine and 2,3-dimethoxybenzoic acid provided 4 (56%), Friedel–
Crafts alkylation of 4 with 2-methyl-3-buten-2-ol yielded 5 (75%), and
osmylation (65%) followed by oxidative cleavage using NaIO4 (62%)
afforded the aldehyde 6. For the transformation to A and the following
cyclization, 6 was treated with various acids in different solvents; however,
1
only a negligible amount of 3 has been detected in H NMR (Scheme 2).
To facilitate the cyclization and study the aspect of this reaction
under milder conditions, we designed an in situ process of cyclization.
We considered that epoxide 10 would rearrange to aldehyde 6 with
BF3ꢀOEt2 on the carbonyl group, which should expedite the subsequent
cyclization.[15] For the preparation of 10, we first coupled 7 with 2,3-
dimethoxybenzoic acid to provide 8 in 57% yield. Stille reaction of 8 with
vinyltributylstannane afforded the vinyl compound 9 in 82% yield,[16]
Scheme 1. Suggested cyclization pathways.

Skeletons of Lennoxamine and Chilenine
3253
Scheme 2. Initial pathway to aldehyde 6.
and its epoxidation with dimethyldioxirane provided the desired epoxide
10 in 61% yield.[17] Treatment of 10 with BF3ꢀOEt2 in benzene afforded
compound 3 as a mixture of ca. 2:1 conformers detected by NMR in 77%
Scheme 3. Synthesis of compound 11.

3254
G. Kim, K. Y. Lee, and C.-H. Yoo
yield. The reaction proceeded via only path b. We questioned which
vigorous conditions would enforce the equilibrium between A and 3 and
enable conversion to 1 (Scheme 1). Treatment of 3 with various acids under
high temperature in different solvents, however, resulted in only decompo-
sition. As the direct transformation to lennoxamine was not successful, we
decided to search for an alternative for the synthesis. We tried oxidative
ways to the known tetracyclic precursor 11 for the alkaloids from 3[18]
and found that heating 3 in acetic acid[19] in the presence of a stoichiometric
amount of Pd(OAc)2 was best, providing 11 in 49% yield (Scheme 3).
CONCLUSION
In conclusion, we have suggested a new way to isoindolobenzapine
alkaloids by making the azepine moiety through epoxide transformation
and the following oxidative cyclization, achieving a formal synthesis of
lennoxamine and chilenine, in a concise manner.
EXPERIMENTAL
All reactions were performed in oven-dried glassware with magnetic
stirring. Commercial-grade reagents and anhydrous solvents were used
without further purification. 3,4-Methylenedioxyphenethylamine hydro-
chloride, 2,3-dimethoxybenzoic acid, N-ethyl-N0-(3-dimethyldiaminopro-
pyl)-carbodiimide HCl (EDCI), 2-methyl-3-buten-2-ol, tributyl(vinyl)tin,
Pd2(dba)3, and AsPh3 were purchased from Aldrich Chemical Co. Silica
gel was purchased from Merck.
Nuclear magnetic resonance spectra were recorded on a Jeol-
JNM-AL400 instrument with Me4Si as the internal standard and CDCl3
as solvent. Chemical shifts are reported in parts per million (ppm). Mass
spectra were recorded on a Hewlett-Packard 5890A gas chromatograph=
Hewlett-Packard 5971A mass selective detector. Analytical thin-layer
chromatography (TLC) was performed on silica-gel 60F-254 plates and
visualized with UV light (254 nm) and=or anisaldehyde-H2SO4-AcOH
as detecting agent. Flash-column chromatography was performed on
silica gel (Kieselgel 60, EM Regents, 230–400 mesh).
Synthesis of Amide 4
2,3-Dimethoxybenzoic acid (0.580 g, 3.20 mmol), EDCI (0.940 g,
4.95 mmol), and 4-dimethylaminopyridine (DMAP) (15 mg, 0.12 mmol)
were added to a solution of 3,4-methylenedioxyphenethyl amine

Skeletons of Lennoxamine and Chilenine
3255
(0.410 g, 2.48 mmol) in 10 ml of THF. The mixture was stirred for 5 h at rt
and diluted with 50 mL of CH2Cl2, and the organic layer was washed
with water (10 mL ꢁ 3) and brine. After drying over MgSO4, filtering,
and concentrating, the crude product was purified by silica-gel column
chromatography (hexane–EtOAc ¼ 2:1) to afford 4 (0.450 g, 56%). MS
1
m=z¼ 329 (Mþ); H NMR (CDCl3, 400 MHz) d 8.01 (br s, 1H), 7.69
(dd, 1H, J ¼ 6.4, 8.0 Hz), 7.13 (t, 1H, J ¼ 8.0 Hz), 7.01 (d, 1H, J ¼ 6.4 Hz),
6.76–6.70 (m, 3H), 5.92 (s, 2H), 3.87 (s, 3H), 3.73–3.64 (m, 5H), 2.86 (t,
2H, J ¼ 6.8 Hz); 13C NMR (100 MHz, CDCl3) d 165.0, 152.4, 147.7,
147.3, 146.0, 132.7, 126.4, 124.2, 122.6, 121.5, 115.1, 108.9, 108.2,
100.7, 60.9, 55.9, 40.8, 35.0.
Synthesis of Amide 5
Concentrated H2SO4 (0.17 mL, 3.3 mmol) was added slowly to a solution
of 4 (1.0 g, 3.0 mmol) in 10 mL of CH2Cl2 containing 2-methyl-3-buten-2-
ol (3.1 mL, 30 mmol) at 0 ꢂC. The mixture was stirred for 3 h at rt.
Dilution of the mixture with 30 mL of CH2Cl2 was followed by washing
with water (10 mL) three times. The organic layer was dried over MgSO4,
filtered, and concentrated. The crude product was purified by silica-gel
column chromatography (hexane–EtOAc ¼ 3:1) to afford 5 (0.91 g,
1
75%). 2 MS m=z ¼ 397 (Mþ); H NMR (CDCl3, 400 MHz) d 8.90 (br
s, 1H), 7.69 (d, 1H, J ¼ 8.4 Hz), 7.14 (t, 1H, J ¼ 8.4 Hz), 7.02 (d, 1H,
J ¼ 8.4 Hz), 6.69 (s, 1H), 6.66 (s, 1H), 5.88 (s, 2H), 5.17 (br, 1H), 3.88
(s, 3H), 3.74 (s, 3H), 3.65 (q, 2H, J ¼ 6.4 Hz), 3.28 (d, 2H, J ¼ 6.8 Hz),
2.87 (t, 2H, J ¼ 4 Hz), 1.69 (s, 3H), 1.71 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 165.1, 152.4, 147.4, 146.1, 145.6, 133.3, 132.4, 129.6, 126.6,
124.3, 123.1, 122.7, 115.2, 109.6, 109.5, 100.6, 61.0, 56.0, 40.4, 36.3,
32.2, 25.6, 17.8.
Synthesis of Aldehyde 6
Osmium tetroxide (6.4 mg, 0.025 mmol) and 4-methylmorphorine
N-oxide (NMO) (76 mg, 0.64 mmol) were added to a solution of com-
pound 5 in 2 mL of H2O–acetone–acetonitrile (1:1:1). The mixture was
stirred for 1.5 h at rt, and 3 mL of distilled water were added. The mixture
was extracted with CH2Cl2 three times, and the organic layer was dried
over MgSO4. After filtration, concentration, and separation by silica-
gel column chromatography, a diol product was obtained in 65% yield.
1H NMR (CDCl3, 400 MHz) d 8.20 (br s, 1H), 7.65 (d, 1H,
J ¼ 6.4 Hz), 7.12 (t, 1H, J ¼ 8.0 Hz), 7.02 (d, 1H, J ¼ 6.4 Hz), 6.72 (s,
1H), 6.71 (s, 1H), 5.90 (s, 2H), 3.88–3.80 (m, 8H), 2.94–2.65 (m, 7H),

3256
G. Kim, K. Y. Lee, and C.-H. Yoo
1.31 (s, 3H), 1.30 (s, 3H); 13C NMR (100 MHz, CDCl3) d 165.6, 152.4,
147.3, 146.2, 146.1, 131, 130.4, 126.2, 124.4, 122.7, 115.4, 110.4, 109.5,
100.8, 79.5, 72.7, 61.1, 56, 41.1, 34.5, 32.5, 25.6, 24.4.
The diol product (0.210 g, 0.490 mmol) in 5 mL of CH2Cl2 was
treated with NaIO4 supported on silica gel (1.0 g) for 1.5 h at rt. After
addition of water to the solution, the reaction mixture was extracted with
CH2Cl2 (10 ml ꢁ 3). The organic layer was dried over MgSO4, filtered,
and concentrated. The crude product was purified on a silica-gel column
to afford aldehyde 6 (0.11 g, 60%). MS m=z ¼ 371 (Mþ); 1H NMR
(CDCl3, 400 MHz) d 9.72 (t, 1H, J ¼ 2.0 Hz), 8.10 (br s, 1H), 7.67 (d,
1H, J ¼ 6.4 Hz), 7.68 (d, 1H, J ¼ 6.4 Hz), 7.14 (t, 1H, J ¼ 6.4 Hz), 7.02
(s, 1H), 7.03 (s, 1H), 6.78 (s, 1H), 6.64 (s, 1H), 5.93 (s, 2H), 3.88 (s,
3H), 3.78 (s, 3H), 3.76 (d, 2H, J ¼ 1.6 Hz), 3.57 (dd, 2H, J ¼ 8.8,
20.8 Hz), 2.82 (t, 2H, J ¼ 7.2 Hz); 13C NMR (100 MHz, CDCl3) d
199.2, 165.4, 152.4, 147.4, 147.1, 146.5, 131.3, 126.2, 124.3, 123.4,
122.6, 115.3, 110.7, 109.9, 101, 61.1, 55.9, 47.7, 40.6, 32.5.
Synthesis of Iodo-amide 8
2,3-Dimethoxybenzoic acid (0.58 g, 3.2 mmol), EDCI (0.94 g, 4.95 mmol),
DMAP (15 mg, 0.12 mmol), and NaH (0.11 g, 4.95 mmol) were added to a
solution of 2-iodo-4,5-methylenedioxyphenethyl amine (0.722 g,
2.48 mmol). After the solution was stirred for 5 h at rt, the reaction mix-
ture was quenched by addition of water and extracted with CH2Cl2
(10 ml ꢁ 3 ). The organic layer was dried over MgSO4, filtered, concen-
trated, and separated by silica-gel column chromatography (hexane–
EtOAc ¼ 1:1) to afford compound 8 (0.654 g, 57%). MS m=z ¼ 455
(Mþ); 1H NMR (CDCl3, 400 MHz) d 8.03 (br s, 1H), 7.71 (d, 1H,
J ¼ 6.4 Hz), 7.26 (s, 1H), 7.16 (t, 1H, J ¼ 6.4 Hz), 7.04 (d, 1H, J ¼ 6.4 Hz)
6.81 (s, 1H), 5.94 ( s, 2H), 3.88 (s, 3H), 3.80 (s, 3H), 3.69–3.65 (t, 2H,
J ¼ 7.2 Hz), 3.00 (t, 2H, J ¼ 7.2 Hz); 13C NMR (100 MHz, CDCl3) d
166.1, 153.4, 148.5, 146.5, 145.9, 131.6, 125.3, 123.5, 121.9, 121.2,
114.8, 108.2, 100.1, 89.2, 60.2, 54.9, 41.8, 36.2.
Synthesis of Vinyl Amide 9
To a solution of compound 8 (0.500 g, 0.110 mmol) in 20 mL of DMF,
tributyl(vinyl)tin (0.38 mL, 0.140 mmol), Pd2(dba)3 (100 mg, 0.011 mmol)
mmol) and AsPh3 (0.270 g, 0.088 mmol) were added. The solution was
stirred for 12 h at 50 ꢂC under an N2 atmosphere. After cooling to rt,
the reaction mixture was quenched with saturated NH4Cl solution and
extracted with ethylacetate (20 mL ꢁ 3). The organic layer was washed

Skeletons of Lennoxamine and Chilenine
3257
with water (10 ml ꢁ 3 ), dried over MgSO4, and concentrated after
filtration. The crude product was purified by silica-gel column chromato-
graphy (hexane–EA ¼ 1:1) to afford compound 9 (0.340 g, 82%). MS
1
m=z ¼ 355 (Mþ); H NMR (CDCl3, 400 MHz) d 8.05 (br s, 1H), 7.71
(d, 1H, J ¼ 8.0 Hz), 7.16 (dd, 1H, J ¼ 8.0 Hz, J ¼ 8.0 Hz), 7.03–6.94 (m,
2H), 7.01 (s, 1H), 6.69 (s, 1H), 5.92 (s, 2H), 5.54 (d, 1H, J ¼ 16.8 Hz),
5.22 (d, 1H, J ¼ 11.2 Hz), 3.87 (s, 3H), 3.75 (s, 3H), 3.62 (bt, 2H), 2.96
(t, 2H, J ¼ 7.6 Hz); 13C NMR (100 MHz, CDCl3) d 165.0, 152.3, 147.3,
146.5, 133.4, 130.3, 130.2, 126.4, 124.0, 122.5, 115.1, 114.0, 109.5,
105.3, 100.8, 60.9, 55.8, 40.5, 32.5.
Synthesis of Epoxy Amide 10
Oxone (0.270 g, 0.442 mmol) was added to a solution of compound 9
(0.157 g, 0.442 mmol) in acetone=H2O (4 mL=2 mL) containing NaHCO3
(0.130 g, 1.55 mmol). The mixture was stirred for 10 min, and the same
amount of NaHCO3 and Oxone was added. The mixture was stirred
for 1.5 h at rt. The reaction mixture was diluted with ethylacetate
(30 mL) and washed with water (10 ml ꢁ 3 ). The organic layer was dried
over MgSO4, filtered, and concentrated. The crude product was purified
by silica-gel column chromatography (hexane–EA ¼ 1:2, and then 1:4) to
afford compound 10 (0.101 g, 61%). MS m=z ¼ 371 (Mþ); 1H NMR
(CDCl3, 400 MHz) d 8.19 (br s, 1H), 7.58 (d, 1H, J ¼ 8.0 Hz), 7.12 (dd,
1H, J ¼ 8.0 Hz, J ¼ 8.0 Hz), 7.02 (s, 1H), 7.01 (d, 1H, J ¼ 8.0 Hz), 6.66
(s, 1H), 5.12 (m, 1H), 3.86 (s, 3H), 3.51–3.70 (m, 4H), 2.96 (m, 1H),
2.81 (m, 1H); 13C NMR (100 MHz, CDCl3) d 165.6, 152.3, 147.3,
146.7, 146.4, 132.8, 129.3, 126.1, 124.2, 122.3, 115.3, 109.4, 106.9,
100.8, 77.3, 77.0, 76.6, 70.6, 67.6, 61.0, 55.8, 41.0, 32.1.
Synthesis of Azonin Amide 3
BF3ꢀOEt2 was added to a solution of epoxide 10 (0.748 g, 2.014 mmol) in
anhydrous benzene (25 mL). The reaction mixture was stirred at rt for
12 h, and the mixture was diluted with CH2Cl2 and washed with water.
The organic layer was washed with water and brine, dried over MgSO4,
filtered, and concentrated. The crude product was purified by silica-gel
column chromatography (hexane–EA ¼ 1:2, and then 1:4) to afford
compound 3 as a ca. 2:1 mixture of conformers (0.572 g, 77%). MS
1
m=z ¼ 353 (Mþ); minor conformer, H NMR (CDCl3, 400 MHz) d 7.43
(d, 1H, J ¼ 10.8 Hz), 7.12 (dd, 1H, J ¼ 8.0 Hz, J ¼ 8.0 Hz), 6.97 (d, 1H,
J ¼ 8.0 Hz), 6.85 (d, 1H, J ¼ 8.0 Hz), 6.70 (s, 1H), 6.50 (s, 1H), 5.91 (s,
2H), 5.75 (d, 1H, J ¼ 10.8 Hz), 3.89 (s, 3H), 3.85 (s, 3H), 3.75–4.25 (m,

3258
G. Kim, K. Y. Lee, and C.-H. Yoo
2H), 2.94 (m, 2H); major conformer, 1H NMR (CDCl3, 400 MHz) d 7.10
(dd, 1H, J ¼ 8.0 Hz, J ¼ 8.0 Hz), 6.97 (d, 1H, J ¼ 8.0 Hz), 6.84 (d, 1H,
J ¼ 8.0 Hz), 6.63 (s, 1H), 6.59 (s, 1H), 6.28 (d, 1H, J ¼ 10.8Hz), 5.91 (s,
2H), 5.34 (d, 1H, J ¼ 10.8 Hz), 3.89 (s, 3H), 3.85 (s, 3H), 3.75–4.25 (m,
2H), 3.04 (m, 2H).
Synthesis of Dehydrolennoxamine 11
Pd(OAc)2 (0.126 g, 0.56 mmol) was added to a solution of compound 3
(0.100 g, 0.28 mmol) in CH3COOH (10 mL), and the mixture was heated
to reflux for 6 h. After concentration, the crude product was diluted with
CH2Cl2, and the organic layer was washed with water twice, saturated
NaHCO3 solution, and brine. Drying over MgSO4 was followed by fil-
tration, concentration, and purification by silica-gel column chromato-
graphy (hexane–EA ¼ 1:2, and then 1:4) to afford compound 11
(0.049 g, 49%). The spectroscopic data of 11 (1H and 13C NMR, mp,
and mass) were identical to the reported values in Ref. 7 in the main text.
ACKNOWLEDGMENTS
This work was supported by a Korea Research Foundation Grant funded
by the Korea Government (MOEHRD, Basic Research Promotion
Fund) (KRF-2005-070-C00073), and we appreciate the Center for
Research Facilities, Chungnam National University, for the permission
to use the NMR facilities.
REFERENCES
1. Fajardo, V.; Elango, V.; Cassels, B. K.; Shamma, M. Chilenine: An isoindo-
lobenzazepine alkaloid. Tetrahedron Lett. 1982, 23, 39.
2. Valencia, E.; Weiss, I.; Firdous, S.; Freyer, A. J.; Shamma, M.; Urzua, A.;
Fajardo, V. The isoindolobenzazepine alkaloids. Tetrahedron 1984, 40, 3957.
3. Valencia, E.; Freyer, A. J.; Shamma, M.; Fajardo, V. (ꢃ)-Nuevamine, an
isoindoloisoquinoline alkaloid, and (ꢃ)-lennoxamine, an isoindolobenzaze-
pine. Tetrahedron Lett. 1984, 25, 599.
4. County, S.; Meyer, C.; Cossy, J. A short synthesis of lennoxamine via
ynamides. Tetrahedron Lett. 2006, 47, 767.
5. Taniguchi, T.; Iwasaki, K.; Uchiyama, M.; Tamura, O.; Ishibashi, H. A short
synthesis of lennoxamine using a radical cascade. Org. Lett. 2005, 7, 4389.
6. Comins, D. L.; Schilling, S.; Zhang, Y. Asymmetric synthesis of 3-substituted
isoindolinones: Application to the total synthesis of (þ)-lennoxamine. Org.
Lett. 2005, 7, 95.

Skeletons of Lennoxamine and Chilenine
3259
7. Sahakitpichan, P.; Ruchirawat, S. A practical and highly efficient synthesis of
lennoxamine and related isoindolobenzazepines. Tetrahedron 2004, 60, 4169.
8. Kim, G.; Kim, J. H.; Kim, W.-J.; Kim, Y. A. Intramolecular Heck reaction
of methylenephthalimidine derivatives: A simple route to lennoxamine and
chilenine. Tetrahedron Lett. 2003, 44, 8207.
9. Koseki, Y.; Katsura, S.; Kusano, S.; Sakata, H.; Sato, H.; Monzene, Y.;
Nagasaka, T. Total synthesis of lennoxamine and chilenine via ring-
expansion of isoindoloisoquinoline to isoindolobenzazepine. Heterocycles
2003, 59, 527.
10. Fuchs, J. R.; Funk, R. L. Total synthesis of (ꢃ)-lennoxamine and (ꢃ)-
aphanorphine by intramolecular electrophilic aromatic substitution reactions
of 2-amidoacroleins. Org. Lett. 2001, 3, 3923.
11. Ruchirawat, S.; Sahakitpichan, P. A novel synthesis of isoindolobenzazepine
alkaloids: Application to the synthesis of lennoxamine. Tetrahedron Lett.
2000, 41, 8007.
12. Couture, A.; Deniau, E.; Grandclaudon, P. Hoarau, C. A new approach to
isoindolobenzazepines: A simple synthesis of lennoxamine. Tetrahedron
2000, 56, 1491.
13. Koseki, Y.; Kusano, S.; Sakata, H.; Nagasaka, T. A new approach to isoin-
dolobenzazepines via a ring-expansion of isoindoloisoquinoline: Synthesis of
lennoxamine and chilenine. Tetrahedron Lett. 1999, 40, 2169.
14. Ishibashi, H.; Kawanami, H.; Ikeda, M. Sulfur-controlled 5-exo selective aryl
radical cyclization of N-vinylic 2-bromobenzamides: Synthesis of lennoxa-
mine and chilenine. J. Chem. Soc., Perkin Trans. 1 1997, 817.
15. Smith, J. G. Synthetically useful reactions of epoxides. Synthesis 1984, 629.
16. Littke, A. F.; Schwarz, L.; Fu, G. C. Pd=P(t-Bu)3: A mild and general cata-
lyst for stille reactions of aryl chlorides and aryl bromides. J. Am. Chem. Soc.
2002, 124, 6343.
17. Murray, R. W.; Jeyaraman, R. Dioxiranes: Synthesis and reactions of
methyldioxiranes. J. Org. Chem. 1985, 50, 2847.
18. Ishibashi, H.; Kawanami, H.; Iriyama, H.; Ikeda, M. Sulfur-directed 5-exo
selective aryl radical cyclization onto enamide: A simple route to chilenine.
Tetrahedron Lett. 1995, 36, 6733.
19. Kno¨lker, H. J.; Reddy, K. R. Indoloquinones, part 6: First palladium-
mediated oxidative cyclization of arylamino-1,2-benzoquinones to carbazole-
3,4-quinones. Application to the total synthesis of carbazoquinocin C and
(ꢃ)-carquinostatin A. Synlett. 1999, 596.