Direct approaches to annulated indoles. A formal total synthesis of 0231B

Article abstract of DOI:10.1016/j.tet.2005.08.004

An advanced intermediate in the Nakatsuka synthesis of 0231B was prepared using a fluoride-mediated indole formation in the key step. Both palladium-based approaches and hydride-based approaches failed to generate the indole.

Full text of DOI:10.1016/j.tet.2005.08.004

Tetrahedron 61 (2005) 9502–9505
Direct approaches to annulated indoles.
A formal total synthesis of 0231B
*
George A. Kraus and Tao Wu
Department of Chemistry, Iowa State University, Ames IA 50011, USA
Received 24 May 2005; revised 28 July 2005; accepted 1 August 2005
Available online 19 August 2005
Abstract—An advanced intermediate in the Nakatsuka synthesis of 0231B was prepared using a fluoride-mediated indole formation in the
key step. Both palladium-based approaches and hydride-based approaches failed to generate the indole.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
in 70% yield from 3. Triflate 4 was subjected to a
Sonogashira coupling using the method of Wang4 to afford
aldehyde 5 in 86% yield.
In 2001 the structure of 0231B (1), a novel inhibitor of
3a-hydroxysteroid dehydrogenase, was reported from
Streptomyces sp. HKI0231.1 Recently, Nakatsuka reported
a clever synthesis of 1 utilizing a novel Friedel-Crafts
alkylation reaction.2 Because compounds that inhibit this
enzyme may be useful leads for new anti-inflammatory
agents, we developed a synthetic approach via 2 beginning
with known aldehyde3 3. We report herein a concise
preparation of 2b, a key intermediate in Nakatsuka’s
synthesis, from 3.
Attempts to convert acetylene 5 into an indole using
palladium chloride (10 mol%) in boiling acetonitrile failed,
despite close literature precedent.5 Using different palla-
dium catalysts was not effective. Both NMR and thin-layer
chromatography indicated that a complex mixture of
products had been produced. Base mediated indole
formation methods (KH/NMP and t-BuOK/NMP) also
failed.6 Fortunately, treatment of acetylene 5 with tetra-
butylammonium fluoride7 in THF at reflux provided indole
6 in 67% yield. Surprisingly, acetylation of 6 using a variety
of Lewis acids (AlCl3, SnCl4, Et2AlCl) and acetylating
agents (AcCl, Ac2O, CH3CN) afforded at best a 46% yield
of keto aldehyde 7.8 This modest yield may be related to
Lewis acid coordination to the aldehyde, which would be
expected to attenuate the reactivity of the indole towards
electrophiles. Steric hindrance from the phenyl group at C-2
may also have been a factor. Intramolecular aldol
condensation using potassium tert-butoxide in THF at
ambient temperature afforded enone 2a; however, the
aldol reaction was not reproducible upon scale up beyond
In our first approach, we envisioned constructing a 2,3,4,6-
tetrasubstituted indole from, which the enone moiety could
be generated by way of an intramolecular aldol reaction.
As a model system we decided to construct 2a. As shown
in Scheme 1, aldehyde 3, prepared in one step from
commercially available starting materials, underwent
reductive acetylation (Pd/C, H2, Ac2O) followed by
conversion of the phenol into a triflate to provide triflate 4
Keywords: Sonogashira coupling; Aldol condensation; 3,4,6-Trisubstituted
indole.
*
Corresponding author. Tel.: C1 5152947794; fax: C1 5152940105;
e-mail: gakraus@iastate.edu
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.08.004

G. A. Kraus, T. Wu / Tetrahedron 61 (2005) 9502–9505
9503
Scheme 1.
Scheme 2.
milligram amounts. The problems with reproducibility may
be related to substitution at C-2, since indole keto aldehydes
without a substituent at C-2 readily and reproducibly cyclize
as shown in Scheme 2.
synthesized in only six steps from 3. This strategy should
also be applicable to 3,4-annulated indoles such as the
isonitrile-containing hapalindole alkaloids,9 agroclavine10
and abeo-ergoline.11
The modest yields in the acylation step and the problematic
aldol step prompted us to evaluate the approach depicted in
Scheme 2. The objective now became 2b, an advanced
intermediate in the Nakatsuka synthesis of 0231B. The
synthesis of indole 2b began with triflate 4. This compound
underwent a Sonogashira coupling with trimethylsilyl-
acetylene (8) to provide acetylene 9 in 80% yield.
Fluoride-mediated cyclization, desilylation and deacetyl-
ation occurred in a one-pot reaction and led to the
conversion of 9 into indole 10 in 34% yield. In contrast to
the reaction with indole 6, acetylation of indole 10 at C-3
proceeded smoothly using acetic anhydride and aluminum
chloride at sub ambient temperature. The resulting keto
aldehyde 11 was produced in 72% yield. Aldol condensation
using potassium tert-butoxide in THF afforded enone 2b in
98% yield. In this case the aldol step was reproducible. The
proton NMR and 13C NMR of 2b were identical to the
literature spectra. Unfortunately, no melting point data was
reported in the literature.
2. Experimental
2.1. General
2.1.1. 2-Acetylamino-6-formyl-4-methylphenyl trifluoro-
methanesulfonate (4). To a solution of phenol 3 (906 mg,
5.0 mmol) in 50 ml of ethyl acetate was added 10% Pd on
charcoal (106 mg, 0.10 mmol) and acetic anhydride (2.4 ml,
25 mmol). The reaction mixture was stirred under a H2
atmosphere at room temperature overnight. The solid was
filtered and the solvent was removed in vacuo. The crude
product was purified by flash chromatography (ethyl
acetate/hexaneZ1:1) to give a yellow solid (715 mg, 74%
yield), mp 124–126 8C.
1H NMR (300 MHz, CDCl3): d 11.17 (s, 1H), 9.34 (s, 1H),
8.35 (s, 1H), 7.81 (br, 1H), 6.99 (s, 1H), 2.25 (s, 3H), 2.17 (s,
3H); 13C NMR (75 MHz, CDCl3): d 196.7, 168.7, 148.1,
129.6, 127.7, 127.2, 127.0, 119.5, 24.7, 20.8; MS (m/z): 193,
165, 152, 151, 150, 123, 105; HRMS: calcd for C10H11NO3:
An advanced intermediate for the synthesis of 1 was

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G. A. Kraus, T. Wu / Tetrahedron 61 (2005) 9502–9505
193.0739, found: 193.0741. Anal. Calcd for C10H11NO3: C,
62.17%; H, 5.74%; N, 7.25. Found: C, 62.30%; H, 5.77%;
N, 7.39%.
12 ml dry CH2Cl2 was added acetyl anhydride (0.14 ml,
3.0 mmol) dropwise with ice water bath cooling. The
reaction mixture was stirred at room temperature for 15 min
before cooling to K20 8C. A solution of indole 7 (118 mg,
0.5 mmol) in 3 ml dry CH2Cl2 was added dropwise. The
mixture was stirred at the same temperature for 1 h and
quenched by slow addition of crushed ice. The aqueous
layer was extracted with CH2Cl2. The combined organic
layer was washed with brine, NaHCO3, and concentrated.
The crude product was purified by flash chromatography
(ethyl acetate/hexaneZ1:1) to give a yellow oil (64 mg,
46% yield).
The product from reduction and acetylation (966 mg,
5.0 mmol), K2CO3 (898 mg, 6.5 mmol) and N-phenyl-
triflimide (1.96 g, 5.5 mmol) in 25 ml of THF were stirred
at room temperature overnight. The solid was filtered and
solvent was removed under reduced pressure. The crude
product was purified by flash chromatography (ethyl
acetate/hexaneZ1:1) to give a yellow solid (1.54 g, 95%
yield), mp 118–120 8C.
1H NMR (300 MHz, CDCl3): d 10.07 (s, 1H), 8.09 (s, 1H),
7.80 (br, 1H), 7.51 (s, 1H), 2.39 (s, 3H), 2.20 (s, 3H); 13C
NMR (75 MHz, CDCl3): d 186.9, 169.1, 140.1, 138.1,
131.7, 131.2, 139.0, 127.7, 118.7 (q, JZ319 Hz), 24.0, 21.2;
MS (m/z): 325, 193, 192, 176, 150, 122; HRMS: calcd for
C11H10F3NO5S: 325.0232, found: 325.0237.
1H NMR (300 MHz, CDCl3): d 10.48 (s, 1H), 9.12 (br, 1H),
7.57 (s, 1H), 7.49–7.51 (m, 2H), 7.40–7.43 (m, 3H), 7.36 (s,
1H), 2.27 (s, 3H), 2.25 (s, 3H); 13C NMR (75 MHz, CDCl3):
d 200.0, 193.4, 142.1, 137.0, 133.3, 132.0, 132.0, 129.8,
129.2, 129.1, 127.5, 122.1, 117.7, 117.2, 32.5, 21.5; MS
(m/z): 277, 276, 249, 248, 235, 234, 205, 204, 191, 189, 179;
HRMS: calcd for C18H15NO2: 277.1103, found: 277.1107.
2.1.2. N-[3-Formyl-5-methyl-2-(phenylethynyl)phenyl
acetamide (5). To a degassed solution of triflate 4
(650 mg, 2.0 mmol), PdCl2(PPh3)2 (42 mg, 0.06 mmol),
CuI (12 mg, 0.06 mmol) and diisopropylethylamine
(1.05 ml, 6.0 mmol) in 20 ml THF was added phenylacetyl-
ene (0.27 ml, 0.24 mmol) dropwise. The reaction mixture
was stirred at 55 8C for 6 h. The solid was filtered and the
filtrate was washed consecutively with saturated NH4Cl and
brine, dried over Na2SO4 and concentrated. The crude
product was purified by flash chromatography (ethyl
acetate/hexaneZ1:2) to give a yellow solid (477 mg, 86%
yield), mp 145–146 8C.
2.1.5. 7-Methyl-2-phenyl-1-benz[c,d]indol-3-(1H)-one
(2a). A mixture of indole 7 (7 mg, 0.025 mmol), t-BuOK
(14 mg, 0.125 mmol) in 5 ml of THF was stirred for 1 h. The
solvent was removed and the residue was diluted with
EtOAc, washed with brine, dried over Na2SO4, and
concentrated. The crude product was purified by flash
chromatography (ethyl acetate/hexaneZ1:1) to give a
yellow solid (6 mg, 92%). The yield of this reaction when
scaled up was highly variable.
Compound 2a1H NMR (300 MHz, CDCl3): 8.36 (s, 1H),
8.33 (s, 1H), 7.57–7.60 (d, JZ9.5 Hz 1H), 7.43–7.49 (m,
3H), 7.29–7.30 (m, 2H), 6.65–6.69 (d, JZ9.5 Hz, 1H), 2.51
(s, 3H); HRMS (ES) m/z calcd for C18H13NO: 259.0997,
found: 259.0999.
1H NMR (300 MHz, CDCl3): d 10.52 (s, 1H), 8.54 (s, 1H),
8.07 (br, 1H), 7.56–7.59 (m, 2H), 7.50 (s, 1H), 7.42–7.44
(m, 3H), 2.44 (s, 3H), 2.28 (s, 3H); 13C NMR (75 MHz,
CDCl3): d 191.2, 168.5, 140.2, 139.6, 135.6, 131.5, 129.5,
128.8, 125.4, 123.3, 121.7, 112.5, 102.5, 80.6, 24.9, 21.8;
MS (m/z): 277, 276, 249, 248, 247, 207, 206; HRMS: calcd
for C18H15NO2: 277.1103, found: 277.1107.
2.1.6. N-[3-Formyl-5-methyl-2-(trimethylsilylethynyl)
phenyl acetamide (9). To a degassed solution of triflate 4
(273 mg, 1.0 mmol), PdCl2(PPh3)2 (21 mg, 0.03 mmol),
CuI (6 mg, 0.03 mmol) and diisopropylethylamine (0.63 ml,
3.0 mmol) in 20 ml of THF was added trimethylsilylacetyl-
ene 8 (0.31 ml, 2.2 mmol) dropwise. The reaction mixture
was stirred at 55 8C for 5 h. The solid was filtered and the
filtrate was washed consecutively with saturated NH4Cl and
brine, dried over Na2SO4 and concentrated. The crude
product was purified by flash chromatography (ethyl
acetate/hexaneZ1:1) to give a yellow solid (191 mg, 80%
yield), mp 119–120 8C.
2.1.3. 2-Phenyl-6-methylindole-4-carboxaldehyde (6). A
mixture of aldehyde 5 (139 mg, 0.50 mmol), 1 M TBAF
(1.5 ml, 1.5 mmol) in 10 ml of THF was stirred at reflux for
1 h. Solvent was removed under reduced pressure. The
residue was diluted with water and extracted with ethyl
acetate. The ethyl acetate extract was dried over Na2SO4
and concentrated. The crude product was purified by flash
chromatography (ethyl acetate/hexaneZ1:2) to give a
yellow solid (78 mg, 67% yield), mp 187–189 8C.
1H NMR (300 MHz, CDCl3): d 10.40 (s, 1H), 8.48 (s, 1H),
8.05 (br, 1H), 7.42 (s, 1H), 2.38 (s, 3H), 2.22 (s, 3H), 0.31 (s,
9H); 13C NMR (75 MHz, CDCl3): d 191.4, 168.4, 140.7,
140.3, 135.9, 124.9, 122.7, 112.4, 109.5, 96.2, 25.0, 22.0,
0.0; MS (m/z): 273, 272, 259, 258, 230, 217, 216, 202, 200,
172, 171; HRMS: calcd for C15H19NO2Si: 273.1185, found:
273.1188.
1H NMR (300 MHz, DMSO-d): d 10.15 (s, 1H), 7.90 (s,
1H), 7.87 (s, 1H), 7.53 (s, 1H), 7.45–7.50 (m, 4H), 7.32–
7.37 (m, 1H), 2.49 (s, 3H); 13C NMR (75 MHz, DMSO-d): d
193.9, 141.3, 139.1, 132.4, 131.2, 129.7, 129.2, 128.7,
127.9, 126.0, 125.1, 118.4, 99.1, 21.7; MS (m/z): 235, 234,
207, 206, 204, 178, 103, 102; HRMS: calcd for C16H13NO:
235.0997, found: 235.1001. Anal. Calcd for C16H13NO: C,
71.68%; H, 5.57%; N, 5.95. Found: C, 81.39%; H, 5.68%;
N, 5.99%.
2.1.7. 6-Methylindole-4-carboxaldehyde (10). A mixture
of aldehyde 9 (190 mg, 0.80 mmol), 1 M TBAF (2.4 ml,
2.4 mmol) in 10 ml THF was stirred at reflux for 1 h. The
solvent was removed under reduced pressure. The residue
was diluted with water and extracted with ethyl acetate. The
2.1.4. 3-Acetyl-2-phenyl-6-methylindole-4-carboxalde-
hyde (7). To a suspension of AlCl3 (415 mg, 1.5 mmol) in

G. A. Kraus, T. Wu / Tetrahedron 61 (2005) 9502–9505
9505
ethyl acetate extract was dried over Na2SO4 and concen-
trated. The crude product was purified by flash chromato-
graphy (ethyl acetate/hexaneZ1:2) to give a yellow solid
(43 mg, 34% yield), mp 116–118 8C.
126; HRMS: calcd for C112H9NO: 183.0684, found:
183.0687.
1H NMR (300 MHz, CDCl3): d 10.22 (s, 1H), 8.55 (br, 1H),
7.47 (s, 2H), 7.34–7.36 (m, 1H), 7.27–7.29 (m, 1H), 2.53 (s,
3H); 13C NMR (75 MHz, CDCl3): d 193.5, 137.2, 131.5,
129.2, 128.2, 127.2, 124.0, 117.8, 102.8, 21.5; MS (m/z):
160, 159, 158, 131, 130, 128, 103, 77; HRMS: calcd for
C10H9NO: 159.0684, found: 159.0686.
Acknowledgements
We thank Iowa State University for partial support of this
research.
2.1.8. 3-Acetyl-6-methylindole-4-carboxaldehyde (11).
To a suspension of AlCl3 (415 mg, 1.5 mmol) in 12 ml of
dry CH2Cl2 was added acetyl anhydride (0.14 ml,
3.0 mmol) dropwise with ice water bath cooling. The
reaction mixture was stirred at room temperature for 15 min
before cooling to K20 8C. A solution of indole 10 (118 mg,
0.5 mmol) in 3 ml dry CH2Cl2 was added dropwise. The
mixture was stirred at the same temperature for 1 h and
quenched by slow addition of crushed ice. The aqueous
layer was extracted with CH2Cl2. The combined organic
layer was washed with brine, NaHCO3, and concentrated.
The crude product was purified by flash chromatography
(ethyl acetate/hexaneZ3:1) to give a yellow solid (64 mg,
72% yield), mp 200–201 8C.
References and notes
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1H NMR (300 MHz, acetone-d): d 11.33 (s, 1H), 8.48 (br,
1H), 7.65 (s, 1H), 7.62 (s, 1H), 2.48 (s, 3H), 2.54 (s, 3H),
2.26 (s, 3H); 13C NMR (75 MHz, acetone-d): d 195.5, 192.1,
139.5, 137.1, 133.1, 130.4, 122.8, 122.1, 118.8, 117.5, 27.3,
20.5; MS (m/z): 201, 200, 173, 172, 158, 157, 155, 129;
HRMS: calcd for C12H11NO2: 201.0790, found: 201.0793.
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2.1.9. 7-Methyl-1-benz[c,d]indol-3-(1H)-one (2b). A
mixture of indole 11 (15 mg, 0.075 mmol), potassium tert-
butoxide (25 mg, 0.225 mmol) in 5 ml of THF was stirred
for 30 min. The solvent was removed and the residue was
diluted with ethyl acetate, washed with brine, dried over
Na2SO4, and concentrated. The crude product was purified
by flash chromatography (100% ethyl acetate) to give a
yellow solid (13 mg, 98% yield), mp 178–180 8C.
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5451. (b) Ketcha, D. M.; Lieurance, B. A.; Homan, D. F. J.;
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1H NMR (300 MHz, CDCl3): d 11.45 (br, 1H), 8.12 (s, 1H),
7.71 (d, JZ9.5 Hz, 1H), 7.49 (s, 1H), 7.40 (s, 1H), 6.73 (d,
JZ9.4 Hz, 1H), 2.53 (s, 3H); 13C NMR (75 MHz, CDCl3): d
182.9, 138.9, 134.8, 133.8, 132.4, 131.8, 124.9, 124.1,
123.6, 116.1, 116.1, 22.2; MS (m/z): 183, 182, 154, 153,
11. Bernardi, L.; Elli, C.; Temperilli, A. Chem. Commun. 1976,
570.