Synthesis of 4-acetoxyindoles and related derivatives by means of air oxidation of 4-oxo-4,5,6,7-tetrahydroindoles obtained from nitroalkenes and cyclohexane-1,3-diones

Article abstract of DOI:10.1055/s-0028-1087386

A novel method for synthesizing 4-hydroxyindole derivatives from cyclohexane-1,3-diones and nitroalkenes have been developed in which a newly developed air oxidation of 4-oxo-4,5,6,7-tetrahydroindoles is playing a crucial role. Georg Thieme Verlag Stuttga

Full text of DOI:10.1055/s-0028-1087386

122
LETTER
Synthesis of 4-Acetoxyindoles and Related Derivatives by Means of Air
Oxidation of 4-Oxo-4,5,6,7-tetrahydroindoles Obtained from Nitroalkenes
and Cyclohexane-1,3-diones
S
ynthesis of 4-Acetoxy
a
indoles an
s
aD
erivativeski Arai,a Yayoi Miyauchi,b Tadashi Miyahara,b Teruhiko Ishikawa,*a,b Seiki Saito*a
a
Fax +81(86)2517639; E-mail: teruhiko@cc.okayama-u.ac.jp
Graduate School of Education, Okayama University, Tsushima, Okayama 700-8530, Japan
b
Received 28 July 2008
O
Abstract: A novel method for synthesizing 4-hydroxyindole deriv-
atives from cyclohexane-1,3-diones and nitroalkenes have been de-
veloped in which a newly developed air oxidation of 4-oxo-4,5,6,7-
tetrahydroindoles is playing a crucial role.
NO2
R2
+
R1
O
1a
2
Key words: indoles, cyclohexane-1,3-diones, nitroalkenes, Michael
additions, oxidations
R1 = Me
R2 = H
NaOEt
KOt-Bu
amine base
R1 = H
R1 = H
KF
Indoles and their analogues are a very important class of
heterocyclic compounds and exhibit interesting biological
properties. Among them, 4-hydroxyindoles such as psilo-
cybin (I) and psilocin (II) exert the potent physiological
activity as a serotonin receptor agonist in the central ner-
vous system and have been considered to be responsible
for powerful psychotomimetic effects.1 Thus, there have
been considerable studies of the effects of substituents on
R2
O
O
O
R2
NOH
NO2
O
O
O
5 (ref. 4)
3 (ref. 3)
4
Scheme 1 Three representative reaction pathways for the reactions
the 4-hydroxytryptamine scaffolds.1c Superior colchicine- of cyclohexane-1,3-diones and nitroalkenes
like antimitotic activities of 4-hydroxyindole derivatives
such as III2 (Figure 1) have recently been introduced, and
Cyclohexane-1,3-diones have been playing a unique role
considerable efforts are being made to develop new anti-
cancer drugs. In order to gain more insight into the struc-
ture–activity relationship of compounds of this class,
general and effective methods for synthesizing 4-hydroxy-
indole frameworks are highly requested.
in synthetic organic chemistry. The C- and O-centered
ambident nucleophilicity stemmed from highly enolizable
property of this function is very useful for the synthesis of
various heterocycles.3–6 Our continuing efforts to develop
cyclohexane-1,3-dione-based cascade reactions,3 coupled
with the previous reports,4,5 draw our attention to the base-
Table 1 Synthesis of Hydrobenzofuran Framework
O
O
Ph
base
O
P
NMe2
NO2
NMe2
OH
Ph
+
MeO
solvent
HO
HO
OH
O
O
O
1a
2a
6a
N
Entry Base
Solvent
Temp
(°C)
Time Yield
N
H
O
N
H
Ar
(equiv)
(h)
20
23
30
19
16
21
25
(%)
1
2
3
4
5
6
7
KF (0.2)
toluene
THF
110
r.t.
r.t.
r.t.
50
0
psilocybin (I)
psilocin (II)
III Ar = 3,4,5-(MeO)3C6H2
DABCO (0.2)
KOt-Bu (1.2)
KOAc (1.5)
KOAc (1.5)
KOAc (2)
30
19
35
41
63
37
Figure 1 Typical biologically potent 4-hydroxyindoles
THF
THF
THF
SYNLETT 2009, No. 1, pp 0122–0126
Advanced online publication: 12.12.2008
DOI: 10.1055/s-0028-1087386; Art ID: U07708ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
0
8
EtOH
r.t.
r.t.
KOAc (2)
EtOH–H2O

LETTER
Synthesis of 4-Acetoxyindoles and Related Derivatives
123
dependent unique chemoselectivity of their conjugate ad- We initially examined the reaction of 1a and a,b-disubsti-
dition reactions to substituted nitroethylenes, which is tuted nitroethylene 2a (Table 1). In this case, however, the
summarized in Scheme 1. For instance, reaction of dione reported KF-mediated conditions5 did not give 3-aryl-4-
1a with b-substituted nitroethylenes in the presence of oxohydrobenzofuran 6a (entry 1) at all. After extensive
amine base selectively afforded bicyclic oximes 3.3b,4 On efforts to survey bases, we found that potassium acetate is
the other hands, alkoxide bases, such as sodium ethoxide a better reagent for realization of coupling reaction, by
or potassium tert-butoxide, catalyzed reactions of 1a and which 6a was obtained in an acceptable yield. We also
b-substituted nitroethylenes to result in the formations of found that treatment of 6a with excessive benzylamine at
Michael adducts 4. In addition, Yoshikoshi et al. reported 130 °C without solvent afforded 4-oxo-4,5,6,7-tetra-
KF-mediated hydrobenzofuran formation from 1a and hydroindole 7a in good yield (Table 2, entry 1). Results
a-methylnitroethylene.5 Taking these previous interesting for the reactions of dione 1a and various a,b-disubstituted
results into account, we have envisioned the development nitroethylenes 2 leading to 4-oxohydrobenzofurans 6 and
of novel indole synthesis utilizing such two-component 4-oxohydroindoles 7 are summarized in Table 2. In any
coupling reactions and further selective transformations cases 6 and 7 were obtained under the newly developed
of functionality involved in thus-obtained products.
conditions, indicating the generality of the two-step pro-
cess. Desired aromatic or aliphatic substituents can be in-
Table 2 Synthesis of 4-Oxotetrahydroindoles 7
O
O
R
R
1a
BnNH2
(3 equiv)
KOAc
NO2
R
EtOH
r.t., 12 h
130 °C, 12 h
O
N
Ph
2a–g
6a–g
7a–g
Entry
Nitroalkene 2
Furan 6 (yield, %)
Hydroindole 7 (yield, %)
X
X
NO2
O
O
X
N
O
Ph
1
2
3
4
2a X = H
6a X = H (63)
6b X = Me (51)
6c X = Br (43)
6d X = OMe (52)
7a X = H (85)
2b X = Me
2c X = Br
2d X = OMe
7b X = Me (86)
7c X = Br (86)
7d X = OMe (85)
NO2
O
O
NO2
NO2
NO2
5
N
O
2e
Ph
6e (41)
7e (36)
O
Fu
O
Fu
NO2
6
7
O
N
O
2f
Ph
6f (43)
7f (81)
O
O
NO2
N
O
2g
Ph
6g (37)
7g (53)
Synlett 2009, No. 1, 122–126 © Thieme Stuttgart · New York

124
M. Arai et al.
LETTER
Table 3 Synthesis of 2,3-Disubstituted 4-Hydroxyindoles via Air
Oxidation
troduced to 3-position of 6 or 7 through this sequence of
reactions.
OAc
Z
When the above sequence of reactions was applied to 5-
substituted dione such as 1b, 6-substituted oxohydro-
indole 7h was obtained likewise. Cyclic nitroalkene such
as 6i could also tolerate the same reaction conditions as
above to lead to hydrocarbazole 7i although the yield was
somewhat lower as indicated in Scheme 2.
Ac2O (3 equiv)
CSA (1 equiv)
7b,c,h,i
O2, toluene
70 °C, 6 h
X
N
Ph
8a–d
Entry Hydroindoles 7
Indoles 8 and 9 (yield, %)
Br
Br
Y
O
O
a
b
1
2
3
7b
7c
7h
8b: X = H, Y = Me (71)
8c: X = H, Y = Br (67)
8h: X = Ph, Y = Br (62)
O
OAc
2c
Ph
O
N
Ph
O
N
Ph
1b
X
Ph
Ph
6h (41%)
7h (83%)
OAc
OAc
O
O
NO2
a
b
4
7i
N
N
1a
N
Ph
Ph
O
Ph
9 (44)
8i (18)
6i (31%)
7i (65%)
2h
Scheme 2 Two additional examples. Reagents and conditions: (a)
KOAc (2 equiv), EtOH, r.t., 12 h; (b) benzylamine (3 equiv), 130 °C,
12 h.
O
R
O
O
OAc
R
H
O
X
We had the idea that a remaining task of converting 7 into
4-hydroxyindoles should be uneventful by relying on ven-
erable traditional ways. However, by contraries, it soon
turned out that such aromatization processes were trouble-
some: widely used palladium-catalyzed dehydrogena-
tion,7 direct oxidations using DDQ7 or halogenation–
elimination process9b totally resulted in almost no reac-
tion. Eventually, we have overcome this difficulty by air-
oxidation conditions8 involving oxygen, acetic anhydride,
and camphorsulfonic acid in toluene (70 °C) to obtain 2,3-
disubstituted 4-acetoxyindoles 8 in acceptable yields. Per-
tinent results are summarized in Table 3.9
H+
N
N+
X
Ph
Ph
Ph
7
OAc
R
N
O–
R
X
X
N+
I-A
Ph
O2
Possible reaction mechanism for the present air oxidation
is proposed in Scheme 3. Formation of enol acetate inter-
mediates I-A under the reaction conditions could be fol-
lowed by 1,4-addition of oxygen molecule to the 1-amino-
1,3-butadiene part of I-A to eventually result in the forma-
tion of adduct I-B.10 This adduct undergoes possible frag-
mentation reaction to give a betaine-type intermediate I-C
involving a peroxy anion and an iminium ion part. Proba-
bly, b-elimination of I-C could take place to produce an
immediate precursor I-D for 4-hydroxyindoles 8 through
deprotonation.
OAc
OAc
R
R
X
O
–O
X
H
O
+
N
N
O
Ph
Ph
I-B
I-C
–
– HO2
OAc
R
X
Thus, we have established the three-step sequences lead-
ing to polysubstituted 4-hydroxyindole derivatives from
diones 1, though yields were not necessarily optimized,
featuring experimental simplicity applicable to large-
scale preparative work.
8
+
N
Ph
H
H
I-D
Scheme 3 Possible reaction mechanism of aromatization
Synlett 2009, No. 1, 122–126 © Thieme Stuttgart · New York

LETTER
Synthesis of 4-Acetoxyindoles and Related Derivatives
125
As mentioned in Scheme 1, metal alkoxide catalyzed version of 7 into indoles 8, the desired 4-acetoxyindolines
reactions of 1a with b-substituted nitroethylenes resulted 11 were obtained as expected though the improvement of
in the formations of Michael adducts 4. This intermediate chemical yields for some products may need further in-
4, without isolation, could be converted into 4-oxo- vestigation as shown in Table 5. Nevertheless, the present
4,5,6,7-tetrahydroindoline frameworks 10 through a se- synthetic routine is a highly simple and effective chemical
ries of reactions involving reduction of a nitro group of 4 process because the complex 4-acetoxyindolines 11 were
to the corresponding amine and the following intramolec- obtained from diones 1 in two steps.
ular nucleophilic attack of the thus-produced amino
It turned out that DDQ oxidation is applicable to indolines
group. In the event, treatment of b-substituted nitroethyl-
11c,e,f to afford 12c,e,f in acceptable yields as illustrated
enes and 1 with catalytic amount of KOt-Bu followed by
in Scheme 4. Thus, 2-nonsubstituted 4-acetoxyindoles
have also become available in a conventional manner.
the addition of zinc and hydrochloric acid afforded 10 in
acceptable yields. These results are summarized in
In conclusion, we have developed novel chemical pro-
Table 4. Thus, we have developed efficient one-pot syn-
cesses for the synthesis of 4-hydroxyindole derivatives
from cyclohexane-1,3-diones and nitroalkenes. In terms
thesis of 4-oxotetrahydroindoline 10 from cyclohexane-
1,3-diones 1a–c (Table 3).When 10 were subjected to the
of diversity-oriented synthesis11 of indoles, the present
same air-oxidation conditions as those used for the con-
methods deserve consideration because of the diversity of
Table 4 Synthesis of 3-Substituted 4-Oxohexahydroindoles
O
R2
O
O
2, KOt-Bu
(10 mol%)
THF, r.t., 12 h
NO2
R1
R1
O
1a: R1 = H
1b: R1 = Ph
1c: R1 = Me
4
Zn, 6 N HCl
THF, r.t., 12 h
O
R2
R1
N
H
10
Entry
1
Nitroolefin 2
Dione 1
Dihydropyrole 10 (yield, %)
NO2
1c
10a (64)
10b (51)
NO2
Bu
2i
O
Ph
Ph
2
3
1a
1c
NO2
2j
N
H
O
CO2Me
NO2
10c (41)
10d (47)
10e (45)
10f (25)
CO2Me
N
Ph
2k
H
O
O
4
5
6
1b
1a
1b
O
NO2
2l
N
H
Ph
O
O
Ph
Ph
NO2
2m
N
H
NO2
2n
N
H
Synlett 2009, No. 1, 122–126 © Thieme Stuttgart · New York

126
M. Arai et al.
LETTER
OAc
Table 5 Synthesis of 3-Substituted 4-Acetoxyindolines via Air
Oxidation
CO2Me
12c (72%)
a
11c
OAc
R2
O
R2
80 °C, 4 h
Ac2O (3 equiv)
CSA (1 equiv)
N
Ph
Ac
O2, 110 °C, 5 h
R1
N
R1
N
OAc
Ph
H
Ac
a
10
11
11e
11f
12e (79%)
12f (66%)
80 °C, 4 h
N
Entry Hydroindoles 10 Indoline 11 (yield, %)
Me
Ac
OAc
Bu
OAc
1
2
3
10a
10b
10c
11a (59)
11b (63)
11c (28)
a
N
80 °C, 1.5 h
Ac
N
Me
OAc
Ac
Ph
Scheme 4 DDQ oxidation of indolines 11. Reagents and conditi-
ons: (a) DDQ (2 equiv), dioxane.
N
Ac
OAc
available starting diones12 as well as the convergent nature
of the two-component coupling reactions. Explorations of
these processes to the synthesis of biologically interesting
indoles or natural indole alkaloids are one of our major
concerns.
CO2Me
N
Ph
Ac
O
Supporting Information for this article is available online at
OAc
4
5
6
10d
10e
10f
11d (33)
11e (54)
11f (42)
http://www.thieme-connect.com/ejournals/toc/synlett.
N
Ph
References and Notes
Ac
(1) For recent syntheses for 4-hydroxyindoles, see:
(a) Gathergood, N.; Scammells, P. J. Org. Lett. 2003, 5, 921.
(b) Shirota, O.; Hakamata, W.; Goda, Y. J. Nat. Prod. 2003,
66, 885; and references cited therein. (c) For the structure–
activity relationship study of II, see: Repke, D. B.; Grotjahn,
D. B.; Shulgin, A. T. J. Med. Chem. 1985, 28, 892.
(2) Liou, J.-P.; Wu, Z.-Y.; Kuo, C.-C.; Chang, C.-Y.; Lu, P.-Y.;
Chen, C.-M.; Hsieh, H.-P.; Chang, J.-Y. J. Med. Chem.
2008, 51, 4351.
OAc
Ph
N
Ac
OAc
(3) (a) Ishikawa, T.; Kadoya, R.; Arai, M.; Takahashi, H.; Kaisi,
Y.; Mizuta, T.; Yoshikai, K.; Saito, S. J. Org. Chem. 2001,
66, 8000. (b) Ishikawa, T.; Miyahara, T.; Asakura, M.;
Higuchi, S.; Miyauchi, Y.; Saito, S. Org. Lett. 2005, 7, 1211.
(4) For KF-catalyzed synthesis of 2-hydroxyiminodihydro-
furans, see: Miyashita, M.; Kumazawa, T.; Yoshikoshi, A.
J. Org. Chem. 1980, 45, 2945.
(5) Yanami, T.; Ballatore, A.; Miyashita, M.; Kato, M.;
Yoshikoshi, A. J. Chem. Soc., Perkin Trans. 1 1978, 1144.
(6) For the synthesis of 4-oxo-4,5,6,7-tetrahydroindoles, see:
(a) Leonarda, P.; Chiara, G.; Giacomo, M.; Maurizio, T.
Tetrahedron Lett. 2008, 49, 459. (b) Kathriarachchi,
K. K. A. D. S.; Siriwardana, A. I.; Nakamura, I.; Yamamoto,
Y. Tetrahedron Lett. 2007, 48, 2267. (c) Nayyar, N. K.;
Hutchison, D. R.; Martinelli, M. J. J. Org. Chem. 1997, 62,
982. (d) Matsumoto, M.; Watanabe, N. Heterocycles 1984,
22, 2313. (e) Bobbitt, J. M.; Kulkarni, C. L.; Dutta, C. P.;
Kofod, H.; Chiong, K. N. J. Org. Chem. 1978, 43, 3541.
(7) 4-Oxo-4,5,6,7-tetrahydroindoles with no substituent at C(3)
can be converted into 4-hydroxyindoles by Pd-catalyzed
dehydrogenation or DDQ oxidation though in low yields,
see: Remers, W. A.; Roth, R. H.; Gibs, G. J.; Weis, M. J.
J. Org. Chem. 1971, 36, 1232.
N
Ac
(8) For aromatization of six-membered carbocycles by air
oxidation, see: (a) Kawashita, Y.; Nakamichi, N.;
Kawabata, H.; Hayashi, M. Org. Lett. 2003, 5, 3713.
(b) Ishikawa, T.; Hino, K.; Yoneda, T.; Murota, M.;
Yamaguchi, K.; Watanabe, T. J. Org. Chem. 1999, 64, 5691.
(9) For the synthesis of 4-hydroxyindoles, see: (a) Somei, M.;
Yamada, F. Heterocycles 2000, 53, 1573. (b) Matsumoto,
M.; Ishoda, Y.; Watanabe, N. Heterocycles 1986, 24, 165.
(c) Hegedus, L. S.; Mulhern, T. A.; Mori, A. J. Org. Chem.
1985, 50, 4282. (d) Remers, W. A.; Weiss, M. J. J. Am.
Chem. Soc. 1965, 87, 5262.
(10) We are considering that transformation of I-A to I-C may
involve an intermediary adduct I-B although nucleophilic
attack of electron-rich dienamine function in I-A toward
oxygen molecule, if any, might directly give I-C from I-A
and could not be ruled out.
(11) Schreiber, S. L. Science 2000, 287, 1964.
(12) For general synthesis of cyclohexane-1,3-diones, see ref. 3a.
Synlett 2009, No. 1, 122–126 © Thieme Stuttgart · New York

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