958 J. Comb. Chem.

2005, 7, 958-967

A Concise and Diversity-Oriented Strategy for the Synthesis of

Benzofurans and Indoles via Ugi and Diels-Alder Reactions
Kui Lu,† Tuoping Luo,† Zheng Xiang,† Zejin You,† Reza Fathi,*,‡ Jiahua Chen,*,† and
Zhen Yang*,†,‡
Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education,
College of Chemistry, State Key Laboratory of Natural and Biomimetic Drugs,
School of Pharmaceutical Science, and Laboratory of Chemical Genomics, Shenzhen Graduate School,
Peking UniVersity, Beijing, 100871, and ViVoQuest, Inc., 711 ExecutiVe BouleVard,
Valley Cottage, New York 10989

ReceiVed August 5, 2005

A one-pot synthesis of diverse benzofurans and indoles from readily available starting materials was achieved
via the sequential Ugi four-component reaction, intramolecular Diels-Alder reaction, and oxidative
aromatization.

Introduction
Benzofuran1 and indole2 are the basic units among a wide
variety of naturally occurring products, and represent the
most important structural classes in drug discovery. For
example, both (+)-duocarmycin SA (1)3a and ellipticine (2)3b
(Figure 1) are natural products with exceptionally potent
antitumor activities. The naturally occurring khellinone (3)3c
is an important lead compound for the development of
voltage-gated potassium channel Kv1.3 blocker. Benzofuroyl
pyrroloquinolone (4)3d is a potent and selective PDE5
inhibitor.
Over the past 10 years, diversity-oriented synthesis (DOS)4 Figure 1. Biologically active indoles and benzofurans.
has acquired increasing attention in biomedical research.
Therefore, development of efficient strategies to rapidly subsequent IMDA reaction to build up the desired frame-
prepare structurally diverse small molecules, such as benzo- works, demonstrating the efficiency and multiplicative effect
furans and indoles, are imperative. of Ugi-4CR.
To date, syntheses of benzofurans and indoles generally Despite recent advances in Ugi-4CR and IMDA reaction
require multiple-step synthesis and purification.5 As a result, in complex molecules,10 there is no report that associates
the construction of a diversity-oriented benzofuran or indole the syntheses of tricyclic-based benzofurans and indoles with
library is challenging. The domino process, which addresses Ugi-4CR and IMDA reaction. Herein, we report our recent
issues of synthetic efficiency and reaction processing, efforts to achieve a sequential reaction process of Ugi-4CR,
provides an alternative route to the existing conventional IMDA reaction, and oxidative aromatization to construct
syntheses.6 Recently, we have directed considerable efforts heterotricyclic molecules in a one-pot operation, thereby
at developing a DOS platform to make natural product-like providing an efficient approach to access a collection of small
compounds by domino reactions.7 molecules having benzofuran and indole scaffolds with
The Ugi four-component reaction (Ugi-4CR)8 is an defined coordinates in chemical space.11
example of a domino reaction which has been widely
employed to construct complex structural frameworks with Results and Discussion
high efficiency. Therefore, as part of our strategy, we aimed In this new scenario (Figure 2), intermediate F is expected
to develop an approach that integrates Ugi-4CR and the to derive from its precursor E through an IMDA reaction,
intramolecular Diels-Alder (IMDA) reaction into a single and E could be derived from A, B, C, and D by Ugi-4CR.
synthetic process to construct benzofurans and indoles. We We assumed intermediate F could easily undergo an H-shift
hoped that, on the basis of our rational design, the intermedi- to form the conjugated aromatic furan G, which would then
ate derived from Ugi-4CR could simultaneously undergo undergo oxidative aromatization to afford product H. Syn-
thetically, this proposed synthetic process could potentially
* To whom correspondence should be addressed. zyang@pku.edu.cn.
† Peking University. be performed in the same reaction vessel, providing a format
‡ VivoQuest. amenable for application in combinatorial synthesis.
10.1021/cc050099b CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/11/2005
Ugi and Diels-Alder Benzofuran, Indole Synthesis Journal of Combinatorial Chemistry, 2005, Vol. 7, No. 6 959

Table 1. Synthesis of Benzofuran-Based Heterocycles

Figure 2. Synthetic analysis.

Scheme 1. Synthesis of Tricyclic Benzofuran 7

Initially, we chose a simple model to test the feasibility

to synthesize benzofuran (Scheme 1). Hence, the com-
mercially available propiolic acid 1, arylamine 2, furano-
aldehyde 3, and tert-butyl isonitrile 4 were mixed in methanol
to give Ugi product 5 in 95% yield.7b Compound 5 was then
heated to 80 °C in benzene; however, the expected IMDA
reaction did not occur. Under forcing conditions, however,
two new UV-active spots were observed on a TLC plate after
heating at 140 °C in xylene for 10 h, which were later
identified as 6 and 7 in 65% combined yield with a ratio of
4/1, respectively. The forcing conditions required for the
IMDA reactions are somewhat surprising and are presumably
due to the furan’s aromaticity.12 The formation of 7 under
the thermal conditions reflects the feasibility of a direct
synthesis of 7 from 5. To this end, 5 was refluxed in toluene
in the presence of activated carbon under positive oxygen
pressure for 12 h,13 and 7 was, indeed, obtained in 66% yield.
To achieve a one-pot reaction procedure, upon the
termination of Ugi-4CR, the methanol was removed, and the
residue was dissolved in xylene, then heated to 140 °C in
the presence of positive oxygen pressure for 12 h. In this
way, 7 was eventually obtained in 66% yield from simple
substrates 1, 2, 3, and 4.
To assess the generality of this one-pot synthetic reaction,
a Isolated yield based on DDQ oxidative aromatization. b Isolated
particularly in regard to the anticipated combinatorial library
construction, 13 additional benzofurans were synthesized. yields based on activated carbon-mediated oxidative aromatization.
To determine the efficiency profile, several commercially
available arylamines, propiolic acids, and three types of we subsequently showed that DDQ was a better oxidant in
isonitriles listed in Table 1 were screened to evaluate the the oxidative aromatization and gave better yields. The final
scope of the reaction. Optimum yields were obtained by yields of the benzofuran derivatives after silica gel column
performing the reaction with an equal amount of amine, chromatography are reported in Table 1, and the overall
aldehyde, acid, and isocyanide. yields range from 45 to 80%, reflecting the chemical
In the initial experiments, most oxidative aromatizations efficiency of each of the reactions involved (at least three
were achieved by the active carbon/oxygen system. However, reactions, >75% average yield).
960 Journal of Combinatorial Chemistry, 2005, Vol. 7, No. 6 Lu et al.

Table 2. Synthesis of Indole-Based Heterocycles Table 3. Synthesis of Polycyclic Heterocycles

a Isolated yield based on DDQ oxidative aromatization. b Isolated

yields based on activated carbon-mediated oxidative aromatization.

hydes substituted with benzene or indoles were employed

as substrates, two novel types of polycyclic heterocycles (see
entries 3 and 4) were accomplished. Interestingly, the
a Isolated yield based on DDQ oxidative aromatization. b Isolated symmetrical benzofuran 10e and indole 10f (entries 5-6)
yields based on activated carbon-mediated oxidative aromatization. could be obtained when 1,4-phenyldiamine was selected as
the amine fragment, thus providing a convenient approach
To assemble indole-based heterocycles, pyrrole aldehydes to the synthesis of benzofuran- or indole-based dimeric
were substituted for this one-pot reaction. Thus, under molecules.15
conditions identical to that of the benzofuran synthesis as
In conclusion, we have developed a novel and efficient
listed in Table 1, an array of indole-based heterocycles were
synthetic approach to construct heterocycles of benzofuran
obtained in good yields. The results are listed in Table 2.
and indole by using a sequential Ugi reaction, IMDA
We selected N-methyl-substituted pyrrole aldehydes in the
reaction, and oxidative aromatization from simple and
reaction to prevent its potential decomposition at the oxida-
commercially available precursors. The synthetic protocol
tive aromatization step. It is worthwhile to point out that as
embodies a domino process and is accomplished in a one-
in the case for 8h synthesis (see entry 8 in Table 1), the two
pot process according to the chemical efficiency paradigm.
benzylamine-based Ugi products (see entries 8-9 in Table
We anticipate that this method may have interesting implica-
2) gave low yields when DDQ was employed as an oxidative
tions in the construction of diversified heterocyclic molecules
agent, presumably due to the oxidative debenzylation of
and will find an application in the fields of combinatorial
N-benzylamines by DDQ during the process of oxidative
chemistry, diversity-oriented synthesis, and drug discovery.
aromatization.14 Therefore, to obtain the high yielding
products corresponding to 9h and 9i, we used active carbon/
Experimental Section
oxygen to carry out aromatization.
Having established the synthetic route to achieve the General Procedure for Ugi Reaction. To a solution of
desired structures, we then proceeded to further expand the arylamine (1.0 mmol) in methanol (1.0 mL) was added
scope of this one-pot synthetic procedure by synthesizing aldehyde (1.0 mmol), and the reaction mixture was stirred
six additional polycyclic molecules, as illustrated in Table at room temperature for 10 min. To this solution was added
3. Two thiazole-based heterocylces (entries 1 and 2) were acetylenic acid (1.0 mmol), and the reaction mixture was
obtained in acceptable yields. When R,β-unsaturated alde- stirred for 5 min, then isocyanide (1.0 mmol) was added,
Ugi and Diels-Alder Benzofuran, Indole Synthesis Journal of Combinatorial Chemistry, 2005, Vol. 7, No. 6 961

and the reaction mixture was stirred for an additional 5 h to 12 h. The reaction mixture was cooled first, diluted with
completion. EtOAc (30 mL), and then washed with NaOH solution (1
4-Furan-2-yl-2(propynoyl-p-tolylamino)-but-3-enoic Acid M, 10 mL), followed by brine (10 mL). The aqueous layer
tert-Butylamide (5). After Ugi-4CR, the solvent was re- was extracted with dichloromethane (10 mL × 3), and the
moved under vacuum, and the residue was then purified by combined organic layer was washed with brine (5 mL) and
flash chromatography (EtOAc/CH2Cl2/petroleum ether ) 1:8: then dried over Na2SO4. The solvent was removed under
8) to give product 5 (346 mg, 95% yield). 1H NMR (300 vacuum, and the residue was purified by flash chromatog-
MHz, CDCl3): 1.36 (s, 9H), 2.38 (s, 3H), 2.84 (s, 1H), 5.21- raphy (EtOAc/CH2Cl2/petroleum ether ) 1:12:12) to give
5.24 (d, J ) 9.0 Hz, 1H), 6.00 (s, 1H), 6.08-6.17 (dd, J ) product 8a (473 mg, 86% yield). 1H NMR (300 MHz,
9.0, 15.9 Hz, 1H), 6.29-6.30 (d, J ) 3.3 Hz, 1H), 6.36- CDCl3): 1.27 (s, 9H), 5.55 (s, 1H), 6.05 (br, 1H), 6.83 (d,
6.38 (dd, J ) 1.8, 3.6 Hz, 1H,), 5.42-5.47 (d, J ) 15.9 Hz, J ) 2.1 Hz, 1H), 7.04-7.09 (m, 1H), 7.38-7.49 (m, 5H),
1H), 7.17-7.24 (m, 4H), 7.34 (s, 1H). 13C NMR (75 MHz, 7.60-7.63 (m, 2H), 7.72-7.73 (d, J ) 2.1 Hz, 1H), 7.79 (s,
CDCl3): δ 21.2, 28.6, 51.7, 64.3, 76.0, 80.5, 109.5, 111.4, 1H), 7.91-7.94 (d, J ) 8.1 Hz, 1H). 13C NMR (75 MHz,
120.1, 124.6, 129.4, 129.7, 136.7, 138.9, 142.7, 151.4, 153.5, CDCl3): δ 28.6, 52.0, 66.1, 98.7, 105.1, 106.9, 127.7, 128.1,
167.4. LRMS (EI), 364 (M+). HRMS (EI) calcd forC22H24- 129.1, 129.4, 129.8, 130.2, 134.3, 135.5, 139.3, 140.1, 146.8,
N2O3 (M+), 364.1787; found, 364.1799. 157.1, 166.9, 168.0. LRMS (EI): 550 (M+). HRMS (EI)
5-Oxo-6-p-tolyl-6,7,7a,8-tetrahydro-5H-1-oxa-6-aza-s- calcd for C27H23N2O3I (M+), 550.0753; found, 550.0752.
indacene-7-carboxylic Acid tert-Butylamide (6). After Ugi- 6-(4-Methoxyphenyl)-4-methyl-5-oxo-6,7-dihydro-5H-
4CR, the solvent was removed under vacuum, xylene (30 1-oxa-6-aza-s-indacene-7-carboxylic Acid tert-Butylamide
mL) was added, and the mixture was stirred for 2 h at 140 (8b). After Ugi-4CR, the solvent was removed under
°C under nitrogen. The solvent was removed under vacuum, vacuum, and the residue was dissolved in dichloromethane
and the residue was purified by flash chromatography (1 mL) and diluted with benzene (25 mL). After stirring at
(EtOAc/CH2Cl2/petroleum ether ) 1:8:8) to give product 6 50 °C for 4 h under nitrogen, the mixture was cooled to
(182 mg, 50% yield as a pair of diastereoisomers) and room temperature, DDQ (227 mg, 1.0 mmol) was added,
product 7 (43 mg, 12% yield). The spectroscopic data for 6: and the mixture was refluxed under nitrogen for another 12
1 h. After cooling again to room temperature, the reaction
H NMR (300 MHz, CDCl3): 1.12 (s, 5.8H), 1.32 (s, 3.7H),
2.25 (m, 3.7H), 3.32-3.45 (m, 2H), 4.29-4.31 (m, 1H), 5.76 mixture was diluted with EtOAc (30 mL) and then washed
(s, 1H), 6.43 (d, J ) 1.5 Hz, 1H), 7.23-7.29 (m, 3.4H), with NaOH solution (1 M, 10 mL), followed by brine (10
7.36-7.39 (m, 2.6H), 7.52-7.55 (m, 0.7H). 13C NMR (75 mL). The aqueous layer was extracted with dichloromethane
MHz, CDCl3): δ 20.8, 24.2, 27.0, 28.2, 29.6, 35.8, 38.8, (10 mL × 3), and the combined organic layer was washed
51.3, 51.9, 65.0, 67.0, 108.7, 117.9, 118.2, 120.0, 120.8, with brine (5 mL) and dried over Na2SO4. The solvent was
123.2, 123.5, 129.5, 129.6, 135.0, 135.2, 135.5, 136.1, 142.7, removed under vacuum, and the residue was purified by flash
153.8, 153.9, 166.2, 166.3, 167.5, 168.8. chromatography (EtOAc/CH2Cl2/petroleum ether ) 1:1:5)
5-Oxo-6-p-tolyl-6,7-dihydro-5H-1-oxa-6-aza-s-indacene- to give product 8b (208 mg, 53% yield). 1H NMR (300 MHz,
7-carboxylic Acid tert-Butylamide (7). After Ugi-4CR, the CDCl3): 1.13 (s, 9H), 2.91 (s, 3H), 3.84 (s, 3H), 5.46 (d, J
solvent was removed under vacuum, the residue was mixed ) 0.9 Hz, 1H), 5.56 (s, 1H), 6.92-6.93 (m, 1H), 6.96-6.99
with activated carbon (200 mg) and xylene (30 mL), and (dd, J ) 2.4, 7.2 Hz, 2H), 7.64-7.67 (dd, J ) 2.4, 7.2 Hz,
the reaction mixture was heated at 140 °C for 2 h under a 2H),7.72 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 13.8, 28.3,
balloon pressure of oxygen. The activated carbon was filtered 51.5, 55.4, 65.1, 103.6, 105.6, 114.5, 122.2, 129.6, 131.1,
off, the filtrate was concentrated under vacuum, and the 132.3, 137.6, 146.1, 156.7, 156.9, 167.3, 168.8. LRMS
residue was purified by flash chromatography (EtOAc/ (EI): 392 (M+). HRMS (EI) calcd for C23H24N2O4 (M+),
CH2Cl2/petroleum ether ) 1:8:8) to give product 7 (239 mg, 392.1736; found, 392.1732.
66% yield). 1H NMR (300 MHz, CDCl3): 1.12 (s, 9H), 2.37 5-Oxo-4-phenyl-6-p-tolyl-6,7-dihydro-5H-1-oxa-6-aza-
(s, 3H), 5.54 (s, 1H), 5.62 (s, 1H), 6.87-6.88 (d, J ) 2.4 s-indacene-7-carboxylic Acid Cyclohexylamide (8c). After
Hz, 1H), 7.23-7.26 (d, J ) 8.4 Hz, 2H), 7.66-7.69 (d, J ) Ugi-4CR, the solvent was removed under vacuum, and the
8.4 Hz, 2H), 7.73-7.74 (d, J ) 2.1 Hz, 1H), 7.88 (s, 1H), residue was dissolved in dichloromethane (1 mL), then
8.07 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 20.9, 28.2, 51.6, diluted with benzene (25 mL). After stirring at 50 °C for 4
65.5, 106.0, 107.1, 117.4, 120.2, 126.2, 129.0, 129.9, 135.0, h under nitrogen, the mixture was cooled to room temper-
135.5, 136.9, 146.9, 157.7, 167.0, 167.9. LRMS (EI): 362 ature, DDQ (227 mg, 1.0 mmol) was added, and then the
(M+). HRMS (EI): calcd for C22H22N2O3 (M+), 362.1630; mixture was refluxed under nitrogen for another 12 h. After
found, 362.1648. cooling again to room temperature, the mixture was diluted
6-(2-Iodophenyl)-5-oxo-4-phenyl-6,7-dihydro-5H-1-oxa- with EtOAc (30 mL) and then washed with NaOH solution
6-aza-s-indacene-7-carboxylic Acid tert-Butylamide (8a). (1 M, 10 mL), followed by brine (10 mL). The aqueous phase
After Ugi-4CR, the solvent was removed under vacuum, and was extracted with dichloromethane (10 mL × 3), and the
the residue was dissolved in dichloromethane (1 mL) and combined organic layer was washed with brine (5 mL) and
then diluted with benzene (25 mL). After stirring at 50 °C dried over Na2SO4. The solvent was removed under vacuum,
for 4 h under nitrogen atmosphere, the mixture was cooled and the residue was purified by flash chromatography
to room temperature, DDQ (227 mg, 1.0 mmol) was added, (EtOAc/CH2Cl2/petroleum ether ) 1:1:6) to give product 8c
and the mixture was refluxed under nitrogen for an additional (380 mg, 82% yield). 1H NMR (300 MHz, CDCl3): 0.79-
962 Journal of Combinatorial Chemistry, 2005, Vol. 7, No. 6 Lu et al.

0.80 (m, 2H), 0.97-1.06 (m, 1H), 1.13-1.26 (m, 2H), 1.47- HRMS (EI): calcd for C27H23N2O3Cl (M+), 458.1397; found,
1.63 (m, 5H), 2.31 (s, 3H), 3.62-3.65 (m, 1H), 5.64 (s, 1H), 458.1393.
5.85 (s, 1H), 6.71-6.72 (d, J ) 1.2 Hz, 1H), 7.14-7.17 (d, 5-Oxo-4-phenyl-6-(4-trifluoromethylphenyl)-6,7-dihy-
J ) 8.4 Hz, 2H) 7.42-7.54 (m, 4H), 7.58-7.61 (d, J ) 8.4 dro-5H-1-oxa-6-aza-s-indacene-7-carboxylic Acid Cyclo-
Hz, 2H), 7.65-7.66 (d, J ) 1.2 Hz, 1H), 7.81 (s, 1H). 13C hexylamide (8f). After Ugi-4CR, the solvent was removed
NMR (75 MHz, CDCl3): δ 20.8, 24.2, 24.3, 25.1, 32.2, 32.3, under vacuum, and the residue was first dissolved in
48.3, 63.8, 105.3, 106.7, 120.3, 121.4, 127.8, 128.2, 129.5, dichloromethane (1 mL) and then diluted with benzene (25
129.7, 129.9, 134.5, 134.8, 135.0, 135.3, 137.9, 146.8, 156.9, mL). After stirring at 50 °C for 4 h under nitrogen, the
167.1, 167.3. LRMS (EI): 464 (M+). HRMS (EI): calcd mixture was cooled to room temperature, DDQ (227 mg,
forC30H28N2O3 (M+), 464.2100; found, 464.2087. 1.0 mmol) was added, and then the mixture was refluxed
4-Methyl-5-oxo-6-p-tolyl-6,7-dihydro-5H-1-oxa-6-aza- under nitrogen for an additional 12 h. After cooling again
s-indacene-7-carboxylic Acid tert-Butylamide (8d). After to room temperature, the mixture was diluted with EtOAc
Ugi-4CR, the solvent was removed under vacuum, and the (30 mL) and washed with NaOH solution (1 M, 10 mL),
residue was dissolved in dichloromethane (1 mL) and then followed by brine (10 mL). The aqueous layer was extracted
diluted with benzene (25 mL). After stirring at 50 °C for 4 with dichloromethane (10 mL × 3), and the combined
h under nitrogen, the mixture was cooled to room temper- organic layer was washed with brine (5 mL) and then was
ature, DDQ (227 mg, 1.0 mmol) was added, and the mixture dried over Na2SO4. The solvent was removed under vacuum,
was then refluxed under nitrogen for another 12 h. After and the residue was purified by flash chromatography
cooling again to room temperature, the mixture was diluted (EtOAc/CH2Cl2/petroleum ether ) 1:1:6) to give product 8f
with EtOAc (30 mL) and then washed with NaOH solution (321 mg, 62% yield). 1H NMR (300 MHz, CDCl3): 0.73-
(1 M, 10 mL), followed by brine (10 mL). The aqueous phase 0.91 (m, 2H), 0.98-1.06 (m, 1H), 1.15-1.29 (m, 2H), 1.47-
1.65 (m, 5H), 3.63-3.69 (m, 1H), 5.55-5.57(d, J ) 8.1 Hz,
was extracted with dichloromethane (10 mL × 3), and the
1H), 5.69 (d, J ) 0.9 Hz,1H), 6.76-6.77 (dd, J ) 2.1, 0.9
combined organic layer was washed with brine (5 mL) and
Hz, 1H), 7.47-7.65 (m, 6H), 7.72-7.73 (d, J ) 2.4 Hz,
then dried over Na2SO4. The solvent was removed under
1H), 7.87-7.88 (d, J ) 2.4 Hz, 1H), 7.39-7.96 (d, J ) 8.7
vacuum, the and residue was purified by flash chromatog-
Hz, 2H), 7.81 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 24.3,
raphy (EtOAc/CH2Cl2/petroleum ether ) 1:10:10) to give
24.4, 25.1, 32.3, 48.5, 63.8, 105.3, 106.7, 106.8, 119.3, 120.4,
product 8d (175 mg, 46% yield). 1H NMR (300 MHz,
126.4, 126.8, 127.9, 128.4, 129.9, 134.4, 135.6, 137.6, 141.1,
CDCl3): 1.13 (s, 9H), 2.36 (s, 3H), 2.84 (s, 3H), 5.46 (d, J
147.1, 157.2, 166.6, 167.6. LRMS (EI): 518 (M+). HRMS
) 0.3 Hz, 1H), 5.68 (s, 1H), 6.89-6.90 (dd, J ) 0.9, 2.1
(EI): calcd for C30H25N2O3F3 (M+), 518.1817; found,
Hz, 1H), 7.20-7.23 (d, J ) 8.4 Hz, 2H), 7.63-7.66 (d, J ) 518.1834.
8.4 Hz, 2H), 7.70-7.71 (m, 2H). 13C NMR (75 MHz,
6-Benzyl-5-oxo-4-phenyl-6,7-dihydro-5H-1-oxa-6-aza-
CDCl3): δ 13.8, 20.8, 28.2, 51.5, 64.9, 103.5, 105.6, 120.3,
s-indacene-7-carboxylic Acid tert-Butylamide (8g). After
122.4, 129.6, 132.3, 134.7, 135.6, 137.6, 146.0, 156.8, 167.3,
Ugi-4CR, the solvent was removed under vacuum, and the
168.8. LRMS (EI): 376 (M+). HRMS (EI): calcd for
residue was dissolved in dichloromethane (1 mL) and then
C23H24N2O3 (M+), 376.1787; found, 376.1777.
diluted with benzene (25 mL). After stirring at 50 °C for 4
6-(4-Chlorophenyl)-5-oxo-4-phenyl-6,7-dihydro-5H-1- h under nitrogen, the mixture was first cooled to room
oxa-6-aza-s-indacene-7-carboxylic Acid tert-Butylamide temperature, DDQ (227 mg, 1.0 mmol) was added, and the
(8e). After Ugi-4CR, the solvent was removed under vacuum, mixture was then refluxed under nitrogen for an additional
and the residue was first dissolved in dichloromethane (1 12 h. After cooling again to room temperature, the reaction
mL) and then diluted with benzene (25 mL). After stirring mixture was diluted with EtOAc (30 mL) and then washed
at 50 °C for 4 h under nitrogen, the mixture was cooled to with NaOH solution (1 M, 10 mL), followed by brine (10
room temperature, DDQ (227 mg, 1.0 mmol) was added, mL). The aqueous layer was extracted with dichloromethane
and the mixture was then refluxed under nitrogen for an (10 × 3), and the combined organic layer was washed with
additional 12 h. After cooling again to room temperature, brine (5 mL) and then dried over Na2SO4. The solvent was
the reaction mixture was diluted with EtOAc (30 mL) and removed under vacuum, and the residue was purified by flash
then washed with NaOH solution (1 M, 10 mL), followed chromatography (EtOAc/CH2Cl2/petroleum ether ) 1:10:10)
by brine (10 mL). The aqueous phase was extracted with to give product 8g (320 mg, 73% yield). 1H NMR (300 MHz,
dichloromethane (10 mL × 3), and the combined organic CDCl3): 1.18 (s, 9H), 4.41-4.56 (d, J ) 14.7 Hz, 1H), 4.79
layer was washed with brine (5 mL) and then dried over (s, 1H), 4.99-5.04 (d, J ) 14.7 Hz, 1H), 5.53 (s, 1H), 6.76-
Na2SO4. The solvent was removed under vacuum, and the 6.77 (d, J ) 2.1 Hz, 1H), 7.26-7.34 (m, 5H), 7.47-7.62
residue was purified by flash chromatography (CH2Cl2) to (m, 4H), 7.67-7.68 (d, J ) 2.1 Hz, 1H), 7.72 (s, 1H). 13C
give product 8e (380 mg, 87% yield). 1H NMR (300 MHz, NMR (75 MHz, CDCl3): δ 28.1, 46.2, 51.2, 64.0, 104.8,
CDCl3): 1.14 (s, 9H), 5.42 (s, 1H), 5.54 (s, 1H), 6.77-6.78 106.6, 120.8, 127.5, 127.7, 128.0, 128.5, 128.7, 129.0, 129.9,
(dd, J ) 2.4, 0.9 Hz, 1H), 7.34-7.38 (d, J ) 9.3 Hz, 2H), 134.4, 136.5, 139.1, 146.4, 156.5, 166.9, 168.9. LRMS
7.50-7.57 (m, 5H), 7.73-7.77 (m, 3H), 7.89 (s, 1H). 13C (ESI): 439 (M + H+).
NMR (75 MHz, CDCl3): δ 28.3, 51.7, 64.5, 105.1, 106.6, 6-(4-Methoxybenzyl)-5-oxo-4-phenyl-6,7-dihydro-5H-1-
121.2, 127.9, 128.4, 129.3, 129.8, 130.0, 134.5, 135.4, 136.8, oxa-6-aza-s-indacene-7-carboxylic Acid tert-Butylamide
137.8, 147.0, 157.2, 166.8, 167.3. LRMS (EI): 458 (M+). (8h). After Ugi-4CR, the solvent was removed under
Ugi and Diels-Alder Benzofuran, Indole Synthesis Journal of Combinatorial Chemistry, 2005, Vol. 7, No. 6 963

vacuum, the residue was mixed with activated carbon (200 1H), 7.47-7.63 (m, 6H), 7.70-7.71 (d, J ) 2.1 Hz, 1H),
mg) and xylene (30 mL), and the reaction mixture was heated 7.75-7.76 (d, J ) 1.8 Hz, 1H), 7.77 (s, 1H), 7.93 (s, 1H),
at 140 °C for 2 h under a balloon pressure of oxygen. The 8.05 (s, 1H), 8.15-8.18 (dd, J ) 8.4, 1.5 Hz, 1H). 13C NMR
activated carbon was filtered off, and the filtrate was (75 MHz, CDCl3): δ 20.8, 64.3, 89.9, 105.5, 106.8, 120.5,
concentrated. The residue was purified by flash chromatog- 121.4, 121.5, 126.3, 127.8, 128.3, 129.1, 129.8, 129.9, 130.0,
raphy (EtOAc/CH2Cl2/petroleum ether ) 1:8:8) to give 134.5, 135.0, 135.3, 135.5, 137.0, 137.1, 138.7, 147.0, 157.0,
product 8h (233 mg, 50% yield). 1H NMR (300 MHz, 166.8, 167.1. LRMS (EI): 584 (M+). HRMS (EI): calcd
CDCl3): 1.20 (s, 9H), 3.78 (s, 3H), 4.32-4.37 (d, J ) 14.4 forC30H21N2O3I (M+), 584.0597; found, 584.0590.
Hz, 1H), 4.77 (s, 1H), 4.98-5.03 (d, J ) 14.4 Hz, 1H), 5.51 6-(4-Chlorophenyl)-7-oxo-8-phenyl-6,7-dihydro-5H-1-
(s, 1H), 6.77-6.78 (m, 1H), 6.83-6.86 (d, J ) 8.7 Hz, 2H), oxa-6-aza-s-indacene-5-carboxylic Acid Cyclohexylamide
7.25-7.28 (d, J ) 8.7 Hz, 2H), 7.48-7.62 (m, 5H), 7.69- (8l). After Ugi-4CR, the solvent was removed under vacuum,
7.73 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 28.4, 45.9, and the residue was first dissolved in dichloromethane (1
51.5, 55.3, 64.2, 105.1, 106.8, 114.4, 121.1, 127.8, 128.2, mL), and then diluted with benzene (25 mL). After stirring
128.7, 129.2, 130.1, 130.2, 134.7, 139.3, 146.6, 156.8, 159.4, at 50 °C for 4 h under nitrogen, the mixture was cooled to
167.2, 169.2. LRMS (EI): 468 (M+). HRMS (EI): calcd room temperature, DDQ (227 mg, 1.0 mmol) was added,
for C29H28N2O4 (M+), 468.2049; found, 468.2048.
and the mixture was refluxed under nitrogen for an additional
6-Benzyl-5-oxo-6,7-dihydro-5H-1-oxa-6-aza-s-indacene- 12 h. After cooling again to room temperature, the reaction
7-carboxylic Acid tert-Butylamide (8i). After Ugi-4CR, the mixture was first diluted with EtOAc (30 mL) and then
solvent was removed under vacuum, and the residue was washed with NaOH solution (1 M, 10 mL), followed by brine
first dissolved in dichloromethane (1 mL) and then diluted (10 mL). The aqueous layer was extracted with dichloro-
with benzene (25 mL). After stirring at 50 °C for 4 h under methane (10 mL × 3), and the combined organic layer was
nitrogen, the mixture was cooled to room temperature, DDQ washed with brine (5 mL) and then dried over Na2SO4. The
(227 mg, 1.0 mmol) was added, and the mixture was then solvent was removed under vacuum, and the residue was
refluxed under nitrogen for an additional 12 h. After cooling purified by flash chromatography (EtOAc/CH2Cl2/petroleum
again to room temperature, the reaction mixture was first ether ) 1:1:5) to give product 8l (290 mg, 60% yield). 1H
diluted with EtOAc (30 mL), and then washed with NaOH
NMR (300 MHz, CDCl3): 0.79-0.86 (m, 2H), 0.97-1.01
solution (1 M, 10 mL), followed by brine (10 mL). The
(m, 1H), 1.15-1.28 (m, 2H), 1.47-1.61 (m, 5H), 3.63-
aqueous layer was extracted with dichloromethane (10 mL
3.67 (m, 1H), 5.61 (s, 1H), 5.73-5.76 (d, J ) 8.1 Hz, 1H),
× 3), and the combined organic layer was washed with brine
6.85-6.86 (d, J ) 2.1 Hz, 1H), 7.31-7.36 (m, 2H), 7.46-
(5 mL) and dried over Na2SO4. The solvent was removed
7.53 (m, 3H), 7.58-7.62 (m, 2H), 7.70-7.75 (m, 3H), 7.88
under vacuum, and the residue was purified by flash
(s, 1H). 13C NMR (75 MHz, CDCl3): δ 24.3, 24.4, 25.1,
chromatography (EtOAc/CH2Cl2/petroleum ether ) 1:1:5)
32.3, 48.4, 63.6, 107.1, 114.1, 121.2, 122.5, 125.5, 127.7,
to give product 8i (203 mg, 56% yield). 1H NMR (300 MHz,
128.7, 129.2, 130.2, 130.4, 130.7, 132.3, 135.4, 136.6, 148.8,
CDCl3): 1.18 (s, 9H), 4.46-4.51 (d, J ) 15.0 Hz, 1H), 4.80
153.2, 167.0, 167.5. LRMS (EI): 484 (M+). HRMS (EI):
(s, 1H), 5.08-5.13 (d, J ) 15.0 Hz, 1H), 5.72 (s, 1H), 6.84-
6.85 (d, J ) 1.8 Hz, 1H), 7.27-7.34 (m, 5H), 7.70-7.71 calcd for C29H25N2O3Cl (M+), 484.1554; found, 484.1556.
(d, J ) 2.1 Hz, 1H), 8.00-8.01 (d, J ) 1.8 Hz, 1H). 13C 7-Oxo-6-p-tolyl-6,7-dihydro-5H-1-oxa-6-aza-s-indacene-
NMR (75 MHz, CDCl3): δ 28.3, 46.5, 51.4, 65.0, 105.9, 5-carboxylic Acid tert-Butylamide (8m). After Ugi-4CR,
107.1, 117.1, 125.6, 128.0, 128.6, 128.7, 129.0, 136.6, 138.0, the solvent was removed under vacuum, and the residue was
146.8, 157.4, 166.8, 169.8. LRMS (ESI): 363 (M+H+). first dissolved in dichloromethane (1 mL) and then diluted
5-Oxo-4-phenyl-6-p-tolyl-6,7-dihydro-5H-1-oxa-6-aza- with benzene (25 mL). After stirring at 50 °C for 4 h under
s-indacene-7-carboxylic Acid (2-iodophenyl)-amide (8j). nitrogen, the mixture was cooled to room temperature, DDQ
After Ugi-4CR, the solvent was removed under vacuum, and (227 mg, 1.0 mmol) was added, and the mixture was refluxed
the residue was first dissolved in dichloromethane (1 mL) under nitrogen for an additional 12 h. After cooling again
and then diluted with benzene (25 mL). After stirring at 50 to room temperature, the mixture was diluted with EtOAc
°C for 4 h under nitrogen, the mixture was cooled to room (30 mL) and then washed with NaOH solution (1 M, 10 mL),
temperature, DDQ (227 mg, 1.0 mmol) was added, and the followed by brine (10 mL). The aqueous layer was extracted
mixture was refluxed under nitrogen for an additional 12 h. with dichloromethane (10 mL × 3), and the combined
After cooling again to room temperature, the mixture was organic layer was first washed with brine (5 mL) and then
diluted with EtOAc (30 mL) and then washed with NaOH dried over Na2SO4. The solvent was removed under vacuum,
solution (1 M, 10 mL), followed by brine (10 mL). The and the residue was purified by flash chromatography
aqueous layer was extracted with dichloromethane (10 mL (EtOAc/CH2Cl2/petroleum ether ) 1:12:12) to give product
× 3), and the combined organic layer was washed with brine 8m (174 mg, 48% yield). 1H NMR (300 MHz, CDCl3): 1.11
(5 mL) and then dried over Na2SO4. The solvent was (s, 9H), 2.37 (s, 3H), 5.53 (s, 1H), 5.55 (s, 1H), 6.88-6.89
removed under vacuum, and the residue was purified by flash (dd, J ) 2.1, 0.6 Hz, 1H), 7.23 (s, 1H), 7.26-7.27 (d, J )
chromatography (EtOAc/CH2Cl2/petroleum ether ) 1:4:20) 2.4 Hz, 1H), 7.66-7.69 (dd, J ) 6.6, 1.8 Hz, 2H), 7.79-
to give product 8j (263 mg, 45% yield). 1H NMR (300 MHz, 7.80 (d, J ) 2.4 Hz, 1H), 7.97 (s, 2H). 13C NMR (75 MHz,
CDCl3): 2.31 (s, 3H), 5.83 (d, J ) 0.9 Hz, 1H), 6.75-6.80 CDCl3): δ 20.9, 28.2, 51.5, 65.5, 107.1, 115.1, 120.2, 127.7,
(m, 2H), 7.18-7.20 (d, J ) 8.4 Hz, 2H), 7.25-7.27 (m, 129.9, 132.6, 134.6, 135.0, 135.5, 148.2, 155.2, 167.3, 168.0.
964 Journal of Combinatorial Chemistry, 2005, Vol. 7, No. 6 Lu et al.

LRMS (EI): 362 (M+). HRMS (EI): calcd forC22H22N2O3 mixture was cooled to room temperature, DDQ (227 mg,
(M+), 362.1630; found, 362.1629. 1.0 mmol) was added, and the mixture was then refluxed
1-Methyl-5-oxo-4,6-diphenyl-1,5,6,7-tetrahydro-1,6-diaza- under nitrogen for an additional 12 h. After cooling again
s-indacene-7-carboxylic Acid tert-Butylamide (9a). After to room temperature, the reaction mixture was first diluted
Ugi-4CR, the solvent was removed under vacuum, and the with EtOAc (30 mL) and then washed with NaOH solution
residue was dissolved in dichloromethane (1 mL), then (1 M, 10 mL), followed by brine (10 mL). The aqueous phase
diluted with benzene (25 mL). After stirring at 50 °C for 4 was extracted with dichloromethane (10 mL × 3), and the
h under nitrogen, the mixture was cooled to room temper- combined organic layer was washed with brine (5 mL) and
ature, DDQ (227 mg, 1.0 mmol) was added, and the mixture then dried over Na2SO4. The solvent was removed under
was then refluxed under nitrogen for an additional 12 h. After vacuum, and the residue was purified by flash chromatog-
cooling again to room temperature, the mixture was first raphy (EtOAc/CH2Cl2/petroleum ether ) 1:1:4) to give
diluted with EtOAc (30 mL) and then washed with NaOH product 9c (288 mg, 61% yield). 1H NMR (300 MHz,
(1 M, 10 mL), followed by brine (10 mL). The aqueous layer CDCl3): 1.13 (s, 9H), 3.89 (s, 3H), 5.45 (s, 1H), 5.53 (s,
was extracted with dichloromethane (10 mL × 3), and the 1H), 6.47-6.48 (d, J ) 3.3 Hz, 1H), 7.16-7.17 (d, J ) 3.3
combined organic layer was washed with brine (5 mL) and Hz, 1H), 7.33-7.36 (d, J ) 9.0 Hz, 2H), 7.46-7.59 (m,
then dried over Na2SO4. The solvent was removed under 5H), 7.68 (s, 1H), 7.76-7.79 (d, J ) 9.0 Hz, 2H). 13C NMR
vacuum, and the residue was purified by flash chromatog- (75 MHz, CDCl3): δ 28.3, 33.5, 51.6, 64.5, 102.4, 102.5,
raphy (EtOAc/CH2Cl2/petroleum ether ) 1:1:4) to give 117.5, 120.9, 127.7, 127.9, 129.2, 129.7, 130.2, 131.1, 134.5,
product 9a (355 mg, 81% yield). 1H NMR (300 MHz, 135.0, 135.5, 137.1, 139.3, 167.9, 168.4. LRMS (EI): 471
CDCl3): 1.10 (s, 9H), 3.87 (s, 3H), 5.53 (s, 1H), 5.61 (s, (M+). HRMS (EI): calcd for C28H26N3O2Cl (M+), 471.1714;
1H), 6.47-6.49 (d, J ) 3.3 Hz, 1H), 7.14-7.18 (m, 2H), found, 471.1710.
7.36-7.41 (m, 2H), 7.45-7.54 (m, 3H), 7.60-7.62 (m, 2H), 6-(4-Methoxyphenyl)-1-methyl-5-oxo-4-phenyl-1,5,6,7-
7.71 (s, 1H), 7.77-7.80 (m, 2H). 13C NMR (75 MHz, tetrahydro-1,6-diaza-s-indacene-7-carboxylic Acid tert-
CDCl3): δ 28.2, 33.3, 51.3, 64.4, 102.3, 102.4, 117.7, 120.1, Butylamide (9d). After Ugi-4CR, the solvent was removed
124.6, 127.6, 127.7, 129.1, 130.0, 131.0, 134.7, 134.7, 135.6, under vacuum, and the residue was first dissolved in
138.3, 139.2, 168.0, 168.3. LRMS (EI): 437 (M+). HRMS dichloromethane (1 mL) and then diluted with benzene (25
(EI): calcd for C28H27N3O2 (M+), 437.2103; found, 437.2095. mL). After stirring at 50 °C for 4 h under nitrogen, the
6-(4-Chlorophenyl)-1-methyl-5-oxo-1,5,6,7-tetrahydro- mixture was cooled to room temperature, DDQ (227 mg,
1,6-diaza-s-indacene-7-carboxylic Acid tert-Butylamide 1.0 mmol) was added, and the reaction mixture was then
(9b). After Ugi-4CR, the solvent was removed under refluxed under nitrogen for an additional 12 h. After cooling
vacuum, and the residue was first dissolved in dichloro- again to room temperature, the mixture was diluted with
methane (1 mL), then diluted with benzene (25 mL). After EtOAc (30 mL), then washed with NaOH solution (1 M, 10
stirring at 50 °C for 4 h under nitrogen, the mixture was mL), followed by brine (10 mL). The aqueous layer was
cooled to room temperature, DDQ (227 mg, 1.0 mmol) was extracted with dichloromethane (10 mL × 3), and the
added, and the mixture was then refluxed under nitrogen for combined organic layer was washed with brine (5 mL) and
an additional 12 h. After cooling again to room temperature, then dried over Na2SO4. The solvent was removed under
the reaction mixture was first diluted with EtOAc (30 mL) vacuum, and the residue was purified by flash chromatog-
and then washed with NaOH solution (1 M, 10 mL), followed raphy (EtOAc/CH2Cl2/petroleum ether ) 1:1:4) to give
by brine (10 mL). The aqueous layer was extracted with product 9d (351 mg, 75% yield). 1H NMR (300 MHz,
dichloromethane (10 mL × 3), and the combined organic CDCl3): 1.12 (s, 9H), 3.80 (s, 3H), 3.86 (s, 3H), 5.55 (s,
layer was washed with brine (5 mL), then dried over Na2SO4. 2H), 6.48 (d, J ) 3.0 Hz, 1H), 6.90-6.93 (d, J ) 9.0 Hz,
The solvent was removed under vacuum, and the residue 2H), 7.14-7.15 (d, J ) 3.3 Hz, 1H), 7.44-7.53 (m, 3H),
was purified by flash chromatography (EtOAc/CH2Cl2/ 7.60-7.69 (m, 5H). 13C NMR (75 MHz, CDCl3): δ 28.3,
petroleum ether ) 1:1:4) to give product 9b (285 mg, 72% 33.3, 51.3, 55.4, 64.7, 102.3, 102.4, 114.3, 117.8, 122.0,
yield). 1H NMR (300 MHz, CDCl3): 1.13 (s, 9H), 3.86 (s, 127.5, 127.6, 129.9, 130.1, 130.8, 131.4, 131.5, 134.5, 134.8,
3H), 5.51 (s, 1H), 5.58 (s, 1H), 6.63-6.64 (d, J ) 3.3 Hz, 135.6, 139.1, 156.6, 168.2. LRMS (EI): 467 (M+). HRMS
1H), 7.18-7.19 (d, J ) 3.3 Hz, 1H), 7.38-7.41 (d, J ) 9.0 (EI): calcd for C29H29N3O3 (M+), 467.2209; found, 467.2202.
Hz, 2H), 7.64 (s, 1H), 7.81-7.84 (d, J ) 9.0 Hz, 2H), 8.12 1-Methyl-5-oxo-4-phenyl-6-p-tolyl-1,5,6,7-tetrahydro-
(s, 1H). 13C NMR (75 MHz, CDCl3): δ 28.3, 33.4, 51.5, 1,6-diaza-s-indacene-7-carboxylic Acid Cyclohexylamide
65.6, 102.8, 102.9, 117.6, 120.7, 122.2, 129.3, 129.7, 129.8, (9e). After Ugi-4CR, the solvent was removed under vacuum,
131.3, 133.4, 137.3, 134.0, 167.7, 169.1. LRMS (EI): 395 and the residue was first dissolved in dichloromethane (1
(M+). HRMS (EI): calcd for C22H22N3O2Cl (M+), 395.1401; mL) and then diluted with benzene (25 mL). After stirring
found, 395.1401. at 50 °C for 4 h under nitrogen, the mixture was cooled to
6-(4-Chlorophenyl)-1-methyl-5-oxo-4-phenyl-1,5,6,7- room temperature, DDQ (227 mg, 1.0 mmol) was added,
tetrahydro-1,6-diaza-s-indacene-7-carboxylic Acid tert- and the mixture was then refluxed under nitrogen for an
Butylamide (9c). After Ugi-4CR, the solvent was removed additional 12 h. After cooling again to room temperature,
under vacuum, and the residue was first dissolved in the reaction mixture was first diluted with EtOAc (30 mL),
dichloromethane (1 mL) and then diluted with benzene (25 then washed with NaOH solution (1 M, 10 mL), followed
mL). After stirring at 50 °C for 4 h under nitrogen, the by brine (10 mL). The aqueous layer was extracted with
Ugi and Diels-Alder Benzofuran, Indole Synthesis Journal of Combinatorial Chemistry, 2005, Vol. 7, No. 6 965

dichloromethane (10 mL × 3), and the combined organic residue was purified by flash chromatography (EtOAc/
layer was washed with brine (5 mL) and then dried over CH2Cl2/petroleum ether ) 1:1:4) to give product 9g (304
Na2SO4. The solvent was removed under vacuum, and the mg, 51% yield). 1H NMR (300 MHz, CDCl3): 2.31 (s, 3H),
residue was purified by flash chromatography (EtOAc/ 3.88 (s, 3H), 5.83 (s, 1H), 6.48-6.49 (d, J ) 3.3 Hz,1H),
CH2Cl2/petroleum ether ) 1:1:4) to give product 9e (382 6.73-6.79 (dt, J ) 1.5, 8.7 Hz 1H), 7.14-7.30 (m, 4H),
mg, 80% yield). 1H NMR (300 MHz, CDCl3): 0.77-0.85 7.45-7.63 (m, 6H), 7.72 (s, 1H), 7.77-7.80 (d, J ) 8.4 Hz,
(m, 2H), 0.98-1.03 (m, 1H), 1.15-1.26 (m, 2H), 1.46- 1H), 8.11 (s, 1H), 8.18-8.21 (dd, J1 ) 8.4 Hz, J2 ) 1.5 Hz,
1.63 (m, 5H), 2.32 (s, 3H), 3.61-3.67 (m, 1H), 3.86 (s, 3H), 1H). 13C NMR (75 MHz, CDCl3): δ 20.8, 33.4, 64.4, 89.9,
5.63 (s, 1H), 5.66 (s, 1H), 6.46-6.47 (dd, J ) 3.6, 0.9 Hz, 102.5, 102.7, 117.8, 120.3, 121.3, 126.2, 127.6, 127.8, 129.0,
1H), 7.13-7.18 (m, 3H), 7.41-7.52 (m, 3H), 7.57-7.67 (m, 129.8, 130.2, 130.3, 131.1, 133.7, 134.5, 135.1, 135.5, 135.7,
4H), 7.70 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 20.7, 34.2, 137.1, 138.8, 139.1, 167.9, 168.1. HRMS (EI): calcd for
24.3, 25.0, 32.1, 32.2, 33.2, 48.1, 63.7, 102.2, 102.5, 115.6, C31H24N3O2I (M+), 597.0913; found, 597.0910.
117.8, 120.0, 127.5, 127.6, 129.5, 129.9, 130.8, 134.1, 134.4, 6-Benzyl-1-methyl-5-oxo-4-phenyl-1,5,6,7-tetrahydro-
134.5, 135.5, 135.7, 139.0, 168.1, 168.2. LRMS (EI): 477 1,6-diaza-s-indacene-7-carboxylic Acid tert-Butylamide
(M+). HRMS (EI): calcd for C31H31N3O2 (M+), 477.2416; (9h). After Ugi-4CR, the solvent was removed under
found, 477.2409. vacuum, the residue was mixed with activated carbon (200
1,4-Dimethyl-5-oxo-6-p-tolyl-1,5,6,7-tetrahydro-1,6-diaza- mg) and xylene (30 mL), and the mixture was heated 140
s-indacene-7-carboxylic Acid Cyclohexylamide (9f). After °C for 2 h under a balloon pressure of oxygen. The activated
Ugi-4CR, the solvent was removed under vacuum, and the carbon was filtered off, the filtrate was concentrated under
residue was first dissolved in dichloromethane (1 mL) and vacuum, and the residue was purified by flash chromatog-
then diluted with benzene (25 mL). After stirring at 50 °C raphy (EtOAc/CH2Cl2/petroleum ether ) 1:1:4) to give
for 4 h under nitrogen, the reaction mixture was cooled to product 9h (235 mg, 52% yield). 1H NMR (300 MHz,
room temperature, DDQ (227 mg, 1.0 mmol) was added, CDCl3): 1.16 (s, 9H), 3.81 (s, 3H), 4.41-4.46 (d, J ) 14.7
and the mixture was then refluxed under nitrogen for an Hz, 1H), 4.80 (s, 1H), 4.98-5.03 (d, J ) 14.7 Hz, 1H), 5.56
additional 12 h. After cooling again to room temperature, (s, 1H), 6.47-6.49 (d, J ) 3.3 Hz, 1H), 7.11-7.12 (d, J )
the reaction mixture was diluted with EtOAc (30 mL) and 3.3 Hz, 1H), 7.25-7.34 (m, 5H), 7.45-7.54 (m, 4H), 7.61-
then washed with NaOH solution (1 M, 10 mL), followed 7.64 (d, J ) 6.9 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ
by brine (10 mL). The aqueous layer was extracted with 28.3, 33.3, 46.6, 51.2, 64.4, 102.2, 102.5, 117.3, 127.6, 127.7,
dichloromethane (10 mL × 3), and the combined organic 127.8, 128.7, 128.9, 129.6, 130.2, 130.7, 134.2, 135.7, 136.1,
layer was first washed with brine (5 mL), then dried over 137.0, 138.9, 168.1, 170.4. LRMS (EI): 451 (M+). HRMS
Na2SO4. The solvent was removed under vacuum, and the (EI): calcd for C29H29N3O2 (M+), 451.2260; found, 451.2258.
residue was purified by flash chromatography (EtOAc/ 1-Methyl-6-(4-methylbenzyl)-5-oxo-1,5,6,7-tetrahydro-
CH2Cl2/petroleum ether ) 1:1:4) to give product 9f (187 1,6-diaza-s-indacene-7-carboxylic Acid Cyclohexylamide
mg, 45% yield). 1H NMR (300 MHz, CDCl3): 0.80-0.85 (9i). After Ugi-4CR, the solvent was removed under vacuum,
(m, 2H), 0.97-1.01 (m, 1H), 1.14-1.26 (m, 2H), 1.46- the residue was mixed with activated carbon (200 mg) and
1.60 (m, 5H), 2.33 (s, 3H), 2.92 (s, 3H), 3.60-3.67 (m, 1H), xylene (30 mL), and the mixture was heated to 140 °C for
3.83 (s, 3H), 5.58 (d, J ) 0.9 Hz, 1H), 5.76-5.79 (d, J ) 2 h under a balloon pressure of oxygen. The activated carbon
8.4, 1H), 6.65-6.67 (dd, J1 ) 3.6, J2 ) 0.9 Hz, 1H), 7.14- was filtered off, the filtrate was concentrated under vacuum,
7.15 (d, J ) 3.3, 1H), 7.19-7.22 (d, J ) 8.4, 2H), 7.52 (s, and the residue was purified by flash chromatography
1H), 7.67-7.70 (d, J ) 8.4, 2H). 13C NMR (75 MHz, (EtOAc/CH2Cl2/petroleum ether ) 1:1:2) to give product 9i
CDCl3): δ 13.6, 20.8, 24.4, 24.5, 25.2, 32.3, 33.3, 48.2, 64.3, (257 mg, 62% yield). 1H NMR (300 MHz, CDCl3): 0.76-
101.0, 118.7, 120.0, 129.7, 130.0, 130.3, 132.0, 134.2, 134.4, 0.83 (m, 2H), 0.84-1.06 (m, 1H), 1.17-1.33 (m, 2H), 1.55-
136.0, 138.7, 168.4, 170.0. LRMS (EI): 415 (M+). HRMS 1.81 (m, 5H), 2.30 (s, 3H), 3.63-3.66 (m, 1H), 3.79 (s, 3H),
(EI): calcd for C26H29N3O2 (M+), 415.2260; found, 415.2255. 4.27-4.32 (d, J ) 14.7 Hz, 1H), 4.87 (s, 1H), 5.19-5.24
1-Methyl-5-oxo-4-phenyl-6-p-tolyl-1,5,6,7-tetrahydro- (d, J ) 14.7 Hz, 1H), 5.67-5.70 (d, J ) 8.1 Hz, 1H), 6.61-
1,6-diaza-s-indacene-7-carboxylic Acid (2-Iodophenyl)- 6.62 (d, J ) 3.6 Hz, 1H), 7.10-7.25 (m, 4H), 7.50 (s, 1H),
amide (9g). After Ugi-4CR, the solvent was removed under 8.12 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 21.0, 24.8, 25.3,
vacuum, and the residue was first dissolved in dichloro- 32.5, 32.9, 33.3, 46.0, 48.5, 64.0, 102.6, 103.4, 117.1, 122.1,
methane (1 mL) and then diluted with benzene (25 mL). 128.5, 129.4, 129.6, 131.0, 133.6, 134.8, 137.7, 139.5, 168.0,
After stirring at 50 °C for 4 h under nitrogen, the mixture 171.2. LRMS (EI): 415 (M+). HRMS (EI): calcd for
was cooled to room temperature, DDQ (227 mg, 1.0 mmol) C26H29N3O2 (M+), 415.2260; found, 415.2249.
was added, and the mixture was then refluxed under nitrogen 6-(4-Chlorophenyl)-5-oxo-6,7-dihydro-5H-1-thia-6-aza-
for an additional 12 h. After cooling again to room s-indacene-7-carboxylic Acid tert-Butylamide (10a). After
temperature, the solvent was first diluted with EtOAc (30 Ugi-4CR, the solvent was removed under vacuum, and the
mL) and then washed with NaOH solution (1 M, 10 mL), residue was first dissolved in dichloromethane (1 mL) and
followed by brine (10 mL). The aqueous layer was extracted then diluted with benzene (25 mL). After stirring at 50 °C
with dichloromethane (10 mL × 3), and the combined for 4 h under a balloon pressure of nitrogen, the mixture
organic layer was washed with brine (5 mL) and dried over was cooled to room temperature, DDQ (227 mg, 1.0 mmol)
Na2SO4. The solvent was removed under vacuum, and the was added, and the reaction mixture was refluxed under
966 Journal of Combinatorial Chemistry, 2005, Vol. 7, No. 6 Lu et al.

nitrogen for an additional 12 h. After cooling again to room (235 mg, 60% yield). 1H NMR (300 MHz, CDCl3): 1.17 (s,
temperature, the reaction mixture was first diluted with 9H), 5.60 (s, 1H), 5.86 (s, 1H), 7.37-7.41 (d, J ) 13.5 Hz,
EtOAc (30 mL) and then washed with NaOH solution (1 2H), 7.46-7.63 (m, 2H), 7.81-7.85 (m, 3H), 7.92-7.96 (d,
M, 10 mL), followed by brine (10 mL). The aqueous phase J ) 12.3 Hz, 1H), 8.19-8.20 (m, 2H). 13C NMR (75 MHz,
was extracted with dichloromethane (10 mL × 3), and the CDCl3): δ 28.3, 30.9, 51.8, 65.7, 121.1, 121.7, 125.1, 127.0,
combined organic phase was washed with brine (5 mL) and 128.1, 128.4, 128.5, 129.4, 129.5, 130.6, 133.3, 134.5, 135.9,
then dried over Na2SO4. The solvent was removed under 136.7, 166.8, 167.9. LRMS (EI): 392 (M+). HRMS (EI):
vacuum, and the residue was purified by flash chromatog- calcd for C23H21N2O2Cl (M+), 392.1292; found, 392.1275.
raphy (EtOAc/CH2Cl2/petroleum ether ) 1:6:6) to give 3-Oxo-2,4-diphenyl-5-(toluene-4-sulfonyl)-1,2,3,5-tetra-
product 10a (203 mg, 51% yield). 1H NMR (300 MHz, hydropyrrolo[3,4-b]carbazole-1-carboxylic Acid tert-
CDCl3): 1.15 (s, 9H), 5.56 (s, 1H), 5.59 (s, 1H), 7.41-7.46 Butylamide (10d). After Ugi-4CR, the solvent was removed
(m, 3H), 7.58-7.60 (d, J ) 5.7 Hz, 1H), 7.81-7.84 (dd, J under vacuum, and the residue was first dissolved in
) 2.1, 7.2 Hz, 2H), 8.27 (s, 2H). 13C NMR (75 MHz, dichloromethane (1 mL) and then diluted with benzene (25
CDCl3): δ 28.3, 51.8, 65.3, 116.6, 119.7, 121.0, 124.2, 127.4, mL). After stirring at 50 °C for 4 h under nitrogen, the
128.7, 129.4, 130.5, 135.1, 136.7, 140.4, 144.9, 166.6, 168.0. mixture was cooled to room temperature, DDQ (227 mg,
LRMS (EI): 398 (M+). HRMS (EI): calcd for C21H19N2O2- 1.0 mmol) was added, and the mixture was then refluxed
SCl (M+), 398.0856; found, 398.0852. under nitrogen for an additional 12 h. After cooling again
6-(4-Methoxyphenyl)-5-oxo-4-phenyl-6,7-dihydro-5H- to room temperature, the reaction mixture was first diluted
1-thia-6-aza-s-indacene-7-carboxylic Acid tert-Butylamide with EtOAc (30 mL) and then washed with NaOH solution
(10b). After Ugi-4CR, the solvent was removed under (1 M, 10 mL), followed by brine (10 mL). The aqueous phase
vacuum, and the residue was first dissolved in dichloro- was extracted with dichloromethane (10 mL × 3), and the
methane (1 mL) and then diluted with benzene (25 mL). combined organic phase was washed with brine (5 mL) and
After stirring at 50 °C for 4 h under nitrogen, the mixture then dried over Na2SO4. The solvent was removed under
was cooled to room temperature, DDQ (227 mg, 1.0 mmol) vacuum, and the residue was purified by flash chromatog-
was added, and the mixture was refluxed under nitrogen for raphy (EtOAc/CH2Cl2/petroleum ether ) 1:1:5) to give
an additional 12 h. After cooling again to room temperature, product 10d (458 mg, 73% yield). 1H NMR (300 MHz,
the reaction mixture was first diluted with EtOAc (30 mL) CDCl3): 1.10 (s, 9H), 2.25 (s, 3H), 5.55 (m, 2H), 6.90-
and then washed with NaOH solution (1 M, 10 mL), followed 6.93 (d, J ) 8.1 Hz, 2H), 7.03-7.06 (d, J ) 8.4 Hz, 2H),
by brine (10 mL). The aqueous phase was extracted with 7.18-7.23 (m, 1H), 7.38-7.59 (m, 9H), 7.72-7.75 (dd, J1
dichloromethane (10 mL × 3), and the combined organic ) 1.2 Hz, J2 ) 8.7 Hz, 2H), 7.75-7.89 (m, 1H), 8.16-8.19
phase was washed with brine (5 mL) and then dried over (m, 2H). 13C NMR (75 MHz, CDCl3): δ 21.4, 28.2, 51.6,
Na2SO4. The solvent was removed under vacuum, and the 63.7, 113.1, 119.4, 120.5, 120.8, 125.3, 125.5, 126.3, 127.0,
residue was purified by flash chromatography (EtOAc/ 127.8, 128.0, 128.7, 128.9, 129.3, 130.9, 133.6, 133.8, 134.2,
CH2Cl2/petroleum ether ) 1:6:6) to give product 10b (259 135.1, 137.8, 138.7, 140.2, 143.0, 144.1, 166.7, 166.8. LRMS
mg, 55% yield). 1H NMR (300 MHz, CDCl3): 1.13 (s, 9H), (EI): 627 (M+). HRMS (EI): calcd for C38H33N3O4S (M+),
3.81 (s, 3H), 5.52 (s, 1H), 5.58 (d, J ) 1.2 Hz, 1H), 6.91- 627.2192; found, 627.2179.
6.94 (d, J ) 9.0 Hz, 2H), 7.25 (d, J ) 0.9 Hz, 1H), 7.49- 6-(4-(7-(Cyclohexylcarbamoyl)-1-methyl-5-oxo-4-
7.55 (m, 6H), 7.64-7.67 (d, J ) 9.0 Hz, 2H), 8.31 (s, 1H). phenylfuryl[3,4-f]indol-6(1H,5H,7H)-yl)phenyl)-N-cyclo-
13
C NMR (75 MHz, CDCl3): δ 28.3, 51.6, 55.5, 64.4, 114.4, hexyl-1,5,6,7-tetrahydro-1-methyl-5-oxo-4-phenylfuryl-
115.9, 122.2, 124.0, 127.6, 127.7, 127.8, 128.1, 129.4, 130.5, [3,4-f]indole-7-carboxamide (10e). To a solution of p-
131.0, 135.5, 136.2, 136.8, 140.6, 144.1, 157.0, 167.2. LRMS phenyldiamine (0.5 mmol) in MeOH (3.0 mL) was added
(EI): 470 (M+). HRMS (EI): calcd for C28H26N2O3S (M+), 3-(2-furyl)acrolein (1.0 mmol), and the reaction mixture was
470.1664; found, 470.1676. stirred at room temperature for 10 min after addition of
2-(4-Chlorophenyl)-3-oxo-2,3-dihydro-1H-benzo[f]iso- phenylpropiolic acid (1.0 mmol). The reaction mixture was
indole-1-carboxylic Acid tert-Butyl Amide (10c). After continually stirred for 5 min, followed by addition of tert-
Ugi-4CR, the solvent was removed under vacuum, and the butyl isocyanide (1.0 mmol) in MeOH (2 mL). The reaction
residue was first dissolved in dichloromethane (1 mL) and mixture was then stirred overnight. After the solvent was
then diluted with benzene (25 mL). After stirring at 50 °C removed under vacuum, the residue was mixed with activated
for 4 h under nitrogen, the mixture was cooled to room carbon (200 mg) and xylene (30 mL), and the reaction
temperature, DDQ was added, and the mixture was then mixture was heated at 140 °C for 2 h with stirring under a
refluxed under nitrogen for another 12 h. After cooling again balloon pressure of oxygen. The activated carbon was filtered
to room temperature, the mixture was first diluted with off, the filtrate was concentrated under vacuum, and the
EtOAc (30 mL) and then washed with NaOH solution (1 residue was purified by flash chromatography (EtOAc/
M, 10 mL), followed by brine (10 mL). The aqueous layer CH2Cl2/petroleum ether ) 1:3:3) to give product 10e (261.2
was extracted with dichloromethane (10 mL × 3), and the mg, 68% yield as a pair of diastereoisomers in a ratio of
combined organic layer was washed with brine (5 mL) and 1/1). The following are the spectroscopic data for the less
dried over Na2SO4. The solvent was removed under vaccum, polar compound. 1H NMR (300 MHz, CDCl3): 1.11 (s,
and the residue was purified by flash chromatography 18H), 5.47 (s, 2H), 5.59 (s, 2H), 6.76 (d, J ) 2.1 Hz, 2H),
(EtOAc/CH2Cl2/petroleum ether ) 1:1:5) to give product 10c 7.50-7.56 (m, 12H), 7.72-7.73 (d, J ) 2.4 Hz, 2H), 7.84
Ugi and Diels-Alder Benzofuran, Indole Synthesis Journal of Combinatorial Chemistry, 2005, Vol. 7, No. 6 967

(s, 4H), 7.90 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 28.3, (3) (a) Yasuzawa, T.; Muroi, K.; Ichimura M.; Takahashi, I.;
51.6, 64.4, 105.1, 106.8, 120.7, 121.2, 127.9, 128.3, 129.7, Ogawa, T.; Takahashi, K.; Sano, H.; Saitoh, Y. Chem.
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are for the polar compound. 1H NMR (300 MHz, CDCl3): W.; Wulff, H. J. Med. Chem. 2004, 47, 2326. (d) Jiang, W.;
1.14 (s, 18H), 5.49 (d, J ) 0.6 Hz, 2H), 5.53 (s, 2H), 6.75- Siu, Z.; Macielag, M. J.; Walsh, S. P.; Fiordeliso, J. J.; Lanter,
6.76 (dd, J1 ) 0.9 Hz, J2 ) 2.4 Hz, 2H), 7.51-7.57 (m, J. C.; Guan, J.; Qiu, Y.; Kraft, P.; Bhattacharjee, S.; Craig,
12H), 7.70-7.71 (d, J ) 2.1 Hz, 2H), 7.83 (s, 4H), 7.87 (s, E.; Haynes-Johnson, D.; John, T. M.; Clancy, J. J. Med.
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2H). 13C NMR (75 MHz, CDCl3): δ 28.3, 51.7, 64.7, 105.1,
(4) (a) Schreiber, S. L. Science 2000, 287, 1964. (b) Nicolaou,
106.8, 120.5, 121.3, 127.9, 128.3, 129.7, 130.0, 134.7, 135.1, K. C.; Pfefferkorn, J. A.; Cao, G.-Q.; Roecker, A. J.;
135.3, 138.0, 146.9, 157.1, 167.1, 167.4. LRMS (EI): 770 Barluenga, S.; Mitchell, H. J. J. Am. Chem. Soc. 2000, 122,
(M+). 9939. (c) Park. W. K. C.; Auer, M.; Jaksche, H.; Wong, C.-
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nitrogen, the reaction mixture was cooled to room temper-
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