A variation of the Fischer indolization involving condensation of quinone monoketals and aliphatic hydrazines

Article abstract of DOI:10.1002/anie.201207533

A new twist: A one-pot nitrous acid free, diazonium-free, and transition-metal-free variation of the Fischer indole synthesis has been developed. Condensation of quinone monoketals and aliphatic hydrazine hydrochlorides afforded indoles via intermediate alkylaryldiazenes. This method will complement the classical Fischer indole synthesis by providing indoles in two steps from widely available phenols under mild conditions. Copyright

Full text of DOI:10.1002/anie.201207533

Angewandte
Chemie
DOI: 10.1002/anie.201207533
Indole Synthesis
AVariation of the Fischer Indolization Involving Condensation of
Quinone Monoketals and Aliphatic Hydrazines**
Jinzhu Zhang, Zhiwei Yin, Patrick Leonard, Jing Wu, Kate Sioson, Che Liu, Robert Lapo, and
Shengping Zheng*
Dedicated to Professors Samuel J. Danishefsky and Ronald Breslow
The indole ring system is one of the most ubiquitous
heterocycles in nature. Many indole-containing natural prod-
ucts show a wide scope of biological activities,[1] in particular
because they bind to many receptors with high affinity.[2]
Since Baeyerꢀs first synthesis of indole from oxindole in
1866 (indigo!isatin!oxindole!indole),[3] numerous meth-
ods for the synthesis of indoles have been reported.[4] One of
the most efficient and widely employed syntheses is the
Fischer indolization discovered in 1883.[5] Compared with
other indole syntheses, the importance of Fischer indolization
lies in its simplicity and convenience, that is, formation of
Scheme 1. Strategies for the synthesis of indoles.
ꢀ
a critical C C bond to an unactivated aromatic carbon
through a [3,3] sigmatropic rearrangement of enolizable N-
arylhydrazones.[6] After more than a century of development,
the Fischer indole synthesis remains a reliable and versatile
method for the preparation of a variety of indole natural
products and medicinal compounds.[7] Many new variations
have been developed in recent years.[8] Most recently, the first
catalytic asymmetric version of Fischer indole synthesis was
reported by the group of List.[9] Although the Fischer indole
synthesis is widely used, several disadvantages still remain.
The classical Fischer indole synthesis starts with arylhydra-
zines, which are generally made either from anilines through
diazonium salts, or from aryl halides through transition-
metal-mediated coupling reactions. These processes involve
the use of aniline precursors and toxic reagents (nitrous acid,
stannous chloride, etc.) and potentially explosive diazonium
intermediates, or expensive transition metals. We report
herein a novel variation of the Fischer indolization involving
a one-pot condensation of quinone monoketals[10] with
aliphatic hydrazines[11] (Scheme 1). To the best of our knowl-
edge, this is the first Fischer-type indole synthesis using an
aliphatic hydrazine as the nitrogen source and a quinone
monoketal as a masked benzene ring.
We envisioned that condensation of quinone monoketal
1 and aliphatic hydrazine 2 would ultimately lead to an indole
via alkylaryldiazene 5 and arylhydrazone intermediate 6, as
illustrated in Scheme 2. The feasibility of this method relies
on the initial formation of alkylaryldiazene 5 from a 1,2-
addition/dehydration sequence. It should be noted that there
has been no report on the synthesis of alkylaryldiazenes 5
from quinone derivatives and aliphatic hydrazines, although
arylaryldiazenes (azobenzenes) have been synthesized from
condensations of arylhydrazines with quinones,[12] quinols,[13]
quinone monoketals,[14] and quinone bisketals.[15] There is
a single report on the condensation of an aliphatic hydrazine
(N,N-dimethylhydrazine) with naphthoquinone monoketal,
which, however, gave a 1,4-addition product in high yield.[16]
Therefore, our first object was to test the practicality of the
[*] Dr. J. Zhang, Z. Yin, P. Leonard, J. Wu, K. Sioson, C. Liu, R. Lapo,
Prof. Dr. S. Zheng
Department of Chemistry and Biochemistry, Hunter College
695 Park Avenue, New York, NY 10065 (USA)
and
The Graduate Center, The City University of New York
365 5th Avenue, New York, NY 10016 (USA)
E-mail: szh0007@hunter.cuny.edu
[**] We are grateful to Professors Richard Franck, Randy Mootoo, Klaus
Grohmann, and William Berkowitz for helpful discussions. We also
thank Dr. Cliff Soll, Dr. Yashuhiro Itagaki, and Dr. Matthew Devany
for with assistance mass spectrometry and NMR spectroscopy.
Financial support from the Bertha and Louis Weinstein Research
Grant, PSC-CUNY Award, and the President’s Fund for Faculty
Advancement Award of Hunter College is gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201207533.
Scheme 2. Synthetic plan.
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synthesis of alkylaryldiazenes 5 through a 1,2-addition of
aliphatic hydrazines to quinone monoketals.
isomerized arylhydrazone 8 instead[21] (Table 1, entry 5). This
facile diazene!hydrazone isomerization is presumably
owing to the higher acidity of the benzylic protons. Bellamy
and Guthrie reported acid-mediated indole formation
directly from alkylaryldiazenes.[22] Recently, the groups of
Heinrich[23] and Knochel[8s,t] utilized this chemistry for indole
synthesis using diazonium salts as starting material. When we
treated diazene 5c with acetic acid tetrahydrocarbazole 7ac
was indeed isolated in 80% yield (Scheme 3).
Not surprisingly, when we treated methyl hydrazine or
N,N-dimethylhydrazine with quinone monoketal 1a, only
polar intractable products formed. The desired nonpolar
alkylaryldiazene could not be detected. After extensive
experimentation, we found that when acetic acid was added
to deactivate methylhydrazine, nonpolar methyldiazene 5a
was isolated in a 23% yield as a 40:1 E/Z isomeric mixture
(Table 1, entry 1). The minor Z isomer was identified by the
Table 1: Diazene synthesis.
Scheme 3. Indole formation from diazene.
Entry
1
R
Product
Yield [%][a]
We next attempted to find optimized conditions for
diazene formation, isomerization, and indole formation in
a one-pot process from quinone monoketals and aliphatic
hydrazines. The development of a one-pot synthesis is
attractive for two reasons. First, it could obviate the isolation
and purification of diazenes. Second, it would provide higher
yield as the isomerized hydrazones and even 1,4-addition
intermediates can ultimately lead to indole under one-pot
conditions. The reaction of quinone monoketal 1a with
cyclohexylhydrazine hydrochloride 2c in the presence of
triethylamine gives diazene 5c; addition of excess acetic acid
to the reaction mixture then gives tetrahydrocarbazole 7ac in
57% yield . But as this one-pot procedure uses both base
(triethylamine) and acid (acetic acid), it is not optimal with
regards to atom economy. Considering that we use hydrazine
hydrochlorides as condensation partners, we reasoned that
a weak base would accelerate diazene formation (1 + 2!5)
and its conjugate acid (hydrochloride salt) could mediate
diazene to hydrazone (5!6) isomerization, hydrazone to ene-
hydrazine isomerization, and [3,3] sigmatropic rearrangement
to the indole[6] (6!7). After screening a range of organic
bases (Et3N, pyridine, picoline, lutidine, quinoline, N-methyl-
morpholine, and 1,8-diazabicyclo[5.4.0]undec-7-ene) we
found the best yield is achieved when pyridine is used.
When 1a and 2c are heated in chloroform with 2 equivalents
of pyridine in a sealed vial, 7ac is obtained in 68% yield.[24]
When cyclohexylhydrazine hydrochloride (2c) was used
in our optimized process, tetrahydrocarbazoles, which can be
oxidized upon exposure to air, were obtained as the major
products (Table 2, entries 1–3). Therefore, we decided to
survey the scope of quinone monoketals[25] by using (2-
phenylethyl)hydrazine hydrochloride (2e)[26] as the conden-
sation partner, since 2e is more reactive than 2c and leads to
cleaner products.[27] Unsubstituted quinone monoketals gen-
erally lead to indoles in good yields (Table 2, entries 4–6).
Halogenated indoles can be easily made from halogen-
substituted quinone monoketals. For quinone monoketals
1d–1g, excellent combined yields of separable regioisomers
were obtained (Table 2, entries 7–10). Quinone monoketal 1h
gave a lower yield, presumably owing to the lower reactivity
of its vinylogous ester carbonyl group (Table 2, entry 11). For
Me
(Me2NNH2)
23; E/Z 40:1
(37; E/Z 20:1)
2
3
4
Et[b]
62; E/Z 30:1
65
cHex
tBu
60; E/Z 25:1
5
Bn
45
[a] The yield of the isolated product. [b] Oxalate salt.
characteristic upfield resonances of the arylazo ortho protons
in its 1H NMR spectrum.[17] The remainder of the mass
balance for this reaction is an unidentified mixture of polar
side products. The fact that diazene 5a was formed, albeit in
low yield, suggested that general acid catalysis facilitates the
dehydration of carbinolhydrazine 3.[18] Under similar condi-
tions the reaction of N,N-dimethylhydrazine also led to
diazene 5a as product, presumably through the demethyla-
tion of a diazenium cation intermediate.[19] Higher yields were
obtained when more-hindered alkyl hydrazine hydrochloride/
oxalate salts were used, possibly owing to steric hindrance,
which could disfavor the 1,4 addition (Table 1, entries 2–4). A
screening of various solvents (MeOH, CHCl3, CH2Cl2, PhH,
THF, CH3CN, ClCH2CH2Cl, and HOAc) for the condensation
determined that methanol, chloroform, and dichloroethane
were optimal. The reactions are easily monitored by thin layer
chromatography because the product diazenes are colored.
Once the diazenes were in hand, we next turned to the
isomerization of diazenes into arylhydrazones (5!6) and
then cyclization to indoles (6!7). It has been previously
reported that alkylaryldiazenes can be isomerized into the
corresponding hydrazones by catalysis with acid or base.[20]
Indeed, when benzylhydrazine hydrochloride was used in the
condensation with quinone monoketal 1a, we isolated the
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Table 2: Indole synthesis by a one-pot condensation.
disubstituted quinone monoketals 1i and 1j, tetra-substituted
indoles 7ie and 7je were obtained (Table 2, entries 12–13).
Quinol ethers are also suitable condensation partners and
afford substituted indoles in good to excellent yields (Table 2,
entries 14–19).
To further explore the scope of this reaction, we next
focused on the generality of the condensation partner, that is
the aliphatic hydrazine hydrochlorides, which can be easily
prepared either in one step from alkyl halides[26a] or in two
steps from ketones/aldehydes and Boc hydrazine through
reductive hydrazination and deprotection[26b] (see the Sup-
porting Information). Under microwave conditions, N-n-
alkylhydrazines afforded indoles in moderate to good yields
(Table 3, entries 1 and 2). N-sec-alkylhydrazines gave 2,3-
Entry
Quinone
monoketal
Hydrazine
Indole/Yield [%][a]
1
2
1a (R=Me)
1b (R=Et)
2c
2c
7ac (R=Me), 68
7bc (R=Et), 66
3
1c
2c
7cc, 68
Table 3: Scope of the aliphatic hydrazines.
4
5
1a
1b
2e
2e
7ae (R=Me), 75
7be (R=Et), 80
Entry
1
Hydrazine
Indole/Yield [%][a]
6
1c
2e
2 f (R=Me, R’=H)
7af, 62
7ag, 37
7ah, 71
7ai, 58
7aj, 80
7ak, 68
7al, 69
7ce, 68%
2
3
4
5
6
7
2g (R=Et, R’=H)
2h (R=Me, R’=Me)
2i (R=Me, R’=Et)
2j (R=Ph, R’=Me)
2k (R,R’=–(CH2)3–)
2l (R,R’=–(CH2)5–)
7
8
9
10
1d (X=I)
1e (X=Br)
1 f (X=Cl)
1g (X=F)
2e
2e
2e
2e
7de, 61 (17)[b]
7ee, 84 (13)[b]
7 fe, 84 (11)[b]
7ge, 75 (13)[b]
11
1h
2e
7he, 41
12
13
1i (R=Me)
1j (R=Cl)
2e
2e
7ie, 81
7je, 56
[a] Yield of the isolated product.
14
15
16
17
18
19
1k (R=Me, R1 =R2 =
R3 =H)
2e
2e
2e
2e
2e
2e
7ke, 93
7le, 84
1l (R=Et, R1 =R2 =R3 =
H)
substituted indoles in good yields (Table 3, entries 3–5). For
unsymmetrical hydrazine 2h, regioselective cyclization prod-
uct 7ah was obtained, presumably due to the weak acidity of
our reaction medium. It is known that the direction of Fischer
indole cyclization was governed by the acidity of the reaction
medium.[28] For 2j, conjugation with a phenyl ring is an
additional important factor for regioselective hydrazone to
ene-hydrazine isomerization. The reactions of cyclopentyl
and cycloheptyl hydrazines 2k and 2l gave the desired
products in a similar yield to that for 7ac (Table 3, entries 6
and 7 and Table 2, entry 1).
1m (R=Ph, R1 =R2 =
R3 =H)
7me, 93
7ne, 95
7oe, 63
7pe, 74
1n (R=R1 =R2 =Me,
R3 =H)
1o (R=R3 =Me, R1 =
R2 =H)
1p (R, R1 =–(CH2)4–,
R2 =R3 =H)
[a] Yield of the isolated product. [b] Yields in parenthesis are the yields of
separable 4-haloindole isomers. LG=leaving group.
Thus, our method, using readily accessible phenols[29] as
starting materials, offers a simple alternative to the traditional
Fischer indole synthesis. For example, by the traditional
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Fischer indole synthesis indole 7qc was made from 4-
methoxy-3-methylaniline and cyclohexanone.[30] In contrast,
our method afforded 7qc from inexpensive m-cresol
(Scheme 4).[31] Furthermore, we use aliphatic hydrazines as
Scheme 4. Synthesis of tetrahydrocarbazole from m-cresol. PIDA=(-
diacetoxy)iodobenzene.
the nitrogen source of indoles and avoid arylhydrazines,
which are more difficult to prepare and handle in some cases.
In summary, we have developed a new variation of Fischer
indole synthesis. Starting with readily available phenols and
aliphatic hydrazines it affords 5-substituted indoles in a two-
step procedure, and avoids the use of arylhydrazines, diazo-
nium intermediates, and transition metals. Applications of
this method to synthesis of natural and synthetic therapeutic
products are currently underway in our laboratory.
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Received: October 5, 2012
Published online: January 2, 2013
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Keywords: condensation · heterocycles · hydrazines ·
.
quinone monoketals · synthetic methods
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