Novel approach to arylhydrazones, the precursor for Fischer indole synthesis, via diazo esters derived from α-amino acid esters

Article abstract of DOI:10.1016/j.tetlet.2005.11.126

A novel method for synthesizing arylhydrazones, the precursor for Fischer indole synthesis, using aryllithium reagents and α-diazo esters that are easily obtained from α-amino acid esters, is described.

Full text of DOI:10.1016/j.tetlet.2005.11.126

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 743–746
Novel approach to arylhydrazones, the precursor for Fischer
indole synthesis, via diazo esters derived from a-amino acid esters
Eiko Yasui, Masao Wada and Norio Takamura*
Research Institute of Pharmaceutical Sciences, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo 202-8585, Japan
Received 31 October 2005; revised 18 November 2005; accepted 18 November 2005
Abstract—A novel method for synthesizing arylhydrazones, the precursor for Fischer indole synthesis, using aryllithium reagents
and a-diazo esters that are easily obtained from a-amino acid esters, is described.
Ó 2005 Elsevier Ltd. All rights reserved.
H
Indole compounds have important biological activities.
N
NHNH2
R2
R3
N
N
For example, melatonin and indole-3-propionic acid
(IPA) reduce reactive oxygen species that cause cellular
damage and prevent death of neurons exposed to amyl-
oid b-proteins, the agent responsible for AlzheimerÕs
disease.1 Some indole derivatives function as dopamine
agonists and/or selective serotonin reuptake inhibitors
(SSRIs), the latter being a class of anti-depressants.2
Acemetacin3 and indometacin4 are clinically used as
anti-inflammatory drugs and fluvastatin sodium5 is a
well-known HMG-CoA reductase inhibitor. During
the course of our investigations on the synthesis of low
molecular weight compounds for use as anti-aging
drugs, we developed a novel method for synthesizing
arylhydrazones, the precursor for Fischer indole
synthesis.
(1)
(2)
O
R2
R3
R1
R1
H
N
CO2Et
CO2Et
N2Cl
R5
CO2Et
R4
R4
R5
Scheme 1. Methods for synthesizing arylhydrazone.
1 was treated with n-BuLi in THF at ꢀ78 °C, the
reagent acted as a nucleophile rather than a base to give
hydrazone 28 (Scheme 2 (1)). Therefore, we expected
that arylhydrazone 3, the precursor for Fischer indole
synthesis, would be obtained when 1 was reacted with
aryllithium reagent (Scheme 2 (2)).
Many methods for synthesizing indole derivatives have
so far been developed.6 Although Fischer indole synthe-
sis is a classic one, it is still a good tool for synthesizing
bioactive compounds. There are two ways to prepare
arylhydrazones: the condensation of carbonyl com-
pound with arylhydrazine (Scheme 1 (1)) and the
Japp–Klingemann reaction7 between an arenediazonium
salt and a malonic acid derivative (Scheme 1 (2)). We
report herein a novel method for synthesizing a variety
of arylhydrazones from a-diazo esters.
First, 4a, which was obtained by the diazotization of
ethyl phenylalaninate,9 was treated with 1 equiv of
R
R
CO2R'
R
R
CO2R' n-BuLi, THF, –78 oC;
AcOH
(1)
(2)
N
N2
NHBu
1
2
Takamura et al. reported the reaction of a-substituted-
a-diazo esters 1 with some bases and found that when
CO2R'
ArLi, THF, –78 oC;
AcOH
CO2R'
N
N2
NHAr
1
Keywords: Fischer indole synthesis; Arylhydrazone; a-Diazo ester.
Corresponding author. Tel./fax: +81 424 68 9278; e-mail: noritaka@
musashino-u.ac.jp
3
*
Scheme 2. Reaction of a-diazo esters with lithium reagents.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.126

744
E. Yasui et al. / Tetrahedron Letters 47 (2006) 743–746
phenyllithium in THF at ꢀ68 °C for 20 min. The reac-
tion mixture was neutralized with acetic acid and puri-
fied by silica gel column chromatography to give anti-
hydrazone 5a in 86% yield together with trace amounts
of minor syn product 5a0.10 The stereochemistry of the
hydrazone was assigned according to a reported proce-
dure using NMR analysis.11 As the reaction was exo-
thermic, it was necessary to keep the reaction
temperature below ꢀ60 °C to prevent decrease in yield.
Grignard reagent was also used as a nucleophile for this
reaction. To a cooled solution (ꢀ68 °C) of 4a in THF
was added 1 equiv of phenylmagnesium bromide. The
reaction proceeded smoothly but more slowly than the
phenyllithium case. The yield was almost the same
(86%) and the stereochemistry of the major product
was also anti. Next, hydrazone 5a was subjected to
Fischer indole synthesis according to the reported meth-
od.12 Hydrazone 5a was treated with thionyl chloride in
ethanol for 40 min at 80 °C in a sealed tube, and the
reaction mixture was worked up and purified by silica
gel column chromatography to give the desired indole
6a in good yield (95%)13 (Scheme 3).
This reaction was then applied to other amino acid
esters that have a methylene group adjacent to the a-
carbon. The results are summarized in Table 1.
Diazo esters 4a–h were easily obtained according to a
known method.9 The diazo esters were reacted with
phenyllithium to give corresponding hydrazones 5a–h
OEt
CO2Et
Ph
CO2Et
CO2Et
O
a)
b)
N
N2
N
N
HN
HN
Ph
5a
N
H
CO2Et
NH
Ph
Ph
5a
anti
4a
6a
5a'
syn
Scheme 3. Reagents and conditions: (a) PhLi (1.0 equiv), THF, ꢀ68 °C; AcOH, 86%; (b) SOCl2, EtOH, 80 °C in a sealed tube, 95%.
Table 1. Yields of indole synthesis from a-diazo esters
R
PhLi, THF, –68 oC;
AcOH
SOCl2
CO2R'
CO2R'
Ref 9)
CO2R'
NH2
R
R
R
N2
N
R'OH
80o
in a sealed tube
N
H
CO2R'
NHPh
4
5
6
Amino acid
R
R0
Et
4
5
6
Phenylalanine
4a, 93%
5a, 86% (86%)a
6a, 95%
Leucine
Et
4b, 94%
4c, 97%
5b, 67%
5c, 72%
6b, 86%c
6c, 70%
Tyrosine
Me
BnO
MeS
Methionine
Me
Et
4d, 85%
4e, 73%
5d, 79%
5e, —b
6d, 59%
Glutamic acid
6e, 47%d
EtO2C
ZHN
Lysine
Me
Me
Et
4f, 89%
4g, 51%
4h, 80%
5f, 88%b
5g, 82%
5h, 97%
6f, 78%
—
Tryptophan
S-Bn-Cysteine
N
H
6h, 67%
BnS
a The result of the reaction with PhMgBr.
b 2 equiv of PhLi was used.
c The reaction was performed at 100 °C.
d Isolation yield for two steps.

E. Yasui et al. / Tetrahedron Letters 47 (2006) 743–746
745
in good yields. Even glutamic acid and lysine derivatives
(4e and 4f) having acidic proton in the molecule gave
hydrazones 5e and 5f, respectively, in good yields. How-
ever, in the case of the diazo compound derived from
aspartic acid ester, the reaction gave a complex mixture.
From NMR analysis, the stereochemistry of all the
hydrazones was confirmed to be anti. Hydrazones 5a–h
were subjected to the indole cyclization reaction. Most
substrates gave the desired indoles in moderate to good
yields. The cyclization reaction of 5b hardly proceeded
at 80 °C, whereas 6b was obtained in 86% yield when
5b was cyclized at 100 °C. Only tryptophan derivative
5g did not give any product.
2). The lithiation of aryl bromides and the subsequent
nucleophilic attack of the lithium reagents on diazo
compound 4a proceeded successfully (Table 2).
The anion of a-carbon of 90, which was formed by the
addition of aryllithium to the diazo moiety, stabilized
the ester carbonyl to give enolate 9 as shown in Scheme
4, and the ester survived despite the existence of excess
aryllithium species. However, when the nitrile group
was substituted on the para-position of phenyllithium,
the excess lithiated compound further reacted with the
ester moiety of 7o to give 7o0 in 28% yield together with
the desired 7o in 46% yield.
It became clear that many diazo esters derived from a-
amino acid esters could be converted into the corre-
sponding indoles. The diversity of aryllithium reagents
was next examined. If aryllithium reagents generated
in situ could react with diazo esters, the application of
this reaction would be extended because commercially
available aryllithium reagents are limited. For that pur-
pose, 4-substituted aryl bromides (1.5 equiv) were trea-
ted with n-BuLi (1.5 equiv) in THF at ꢀ68 °C to
produce aryllithium reagents and to the mixture was
added diazo compound 4a (1.0 equiv) (scheme in Table
All hydrazones 7i–o were converted into the correspond-
ing indoles 8i–o. The reaction time was dependent on the
electron density of the aromatic ring. In most cases (5a–
h, 7i–l), the cyclization was completed within 1 h, but
when an electron-withdrawing group (7m–o) was substi-
tuted on the aromatic ring, the reaction time became
longer. In the case of 7o, 23% of the starting material
was recovered even after heating at 80 °C for 3 h.
In summary, we developed a novel method for synthe-
sizing various aryl hydrazones, the precursor for Fischer
Table 2. Yields of indole derivatives
n-BuLi, THF,
–68 C;
X
˚
CO2Et
SOCl2
4a;
X
Br
N
EtOH
AcOH
N
H
CO2Et
HN
Ar
80 C
˚
in a sealed tube
8
7
X
7
8
OMe
Me
7i, 79%
7j, 77%
7k, 74%
8i, 92%
8j, 82%
8k, 92%
O
Ph
n-Bu
N
HN
CN
t-Bu
Br
7l, 78%
8l, 83%
7m, 69%
8m, 81%
7o'
CF3
CN
7n, 76%
7o, 46%
8n, 76%
8o, 49%
CN
O
O
O
O
R
OEt
R
OEt
R
OEt
R
OEt
N
N
N
N
N
N
N
N
Ar
Ar
Ar
4
9
9'
Scheme 4. Reaction mechanism of diazo ester and aryllithium.

746
E. Yasui et al. / Tetrahedron Letters 47 (2006) 743–746
stirred at ꢀ68 °C under nitrogen atmosphere. To this
solution was slowly added phenyllithium (0.48 ml, 2.1 M
in Bu2O). The reaction mixture was stirred for 20 min at
the same temperature, neutralized with acetic acid
(0.06 ml, 1 mmol), diluted with an aqueous saturated
NaHCO3 solution and extracted three times with ethyl
acetate. The combined organic phase was washed with
brine, dried over Na2SO4, and concentrated in vacuo. The
resulting residue was purified by silica gel column chro-
matography (hexane/ethyl acetate: 5/1) to give 5a as pale
yellow crystals (242 mg, 86%). Recrystallization from
isopropylether afforded slightly yellow crystals, mp (88–
89 °C) (lit.;14 89 °C, lit.;11 92–94 °C). Data for 5a: 1H
NMR (CDCl3, 400 MHz) d 8.08 (s, 1H), 7.29–7.20 (m,
7H), 7.06 (m, 1H), 6.91 (m, 1H), 4.31 (q, J = 7.2 Hz,
2H), 3.98 (s, 2H), 1.35 (t, J = 7.2 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) d 165.33, 142.87, 135.00, 133.59,
129.08, 129.04, 127.85, 126.93, 122.04, 113.90, 61.23,
indole synthesis, from a-substituted-a-diazo esters 1.
Utilizing the diazo compounds derived from various a-
amino acid esters and aromatic bromides having appro-
priate substituents, structurally complicated indoles can
be easily synthesized in short steps by this method.
Acknowledgments
This work was financially supported by MEXT.
HAITEKU (2005).
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(204 mg, 1 mmol) was dissolved in THF (10 ml) and