Diels-Alder and Michael addition reactions of indoles with masked o-benzoquinones: Synthesis of highly functionalized hydrocarbazoles and 3-arylindoles

Article abstract of DOI:10.1039/a904366g

Highly functionalized hydrocarbazoles and 3-arylindoles are prepared from commercially available 2-methoxyphenols and indoles.

Full text of DOI:10.1039/a904366g

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Diels–Alder and Michael addition reactions of indoles with
masked o-benzoquinones: synthesis of highly functionalized hydrocarbazoles
and 3-arylindoles
Ming-Fang Hsieh, Polisetti Dharma Rao and Chun-Chen Liao*
Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan 300. E-mail: ccliao@faculty.nthu.edu.tw
Received (in Cambridge, UK) 1st June 1999, Accepted 16th June 1999
OH
Highly functionalized hydrocarbazoles and 3-arylindoles are
OMe
prepared from commercially available 2-methoxyphenols
and indoles.
The chemistry of indole1 has been extensively investigated
because of the wide-spread occurrence of its skeleton as a basic
R
2a R = CO2Me
structural unit of various types of natural products with
2b R = COMe
interesting and useful physiological properties.2 It is well-
2c R = CN
H
H
known that indole behaves as an enamine towards electrophiles
and undergoes Michael addition to electron-deficient alkenes.1
In contrast, its dienophilic behavior has been reported only on a
few occasions.3–8 Indoles have been found to react as
dienophiles in formal [4 + 2] cycloaddition reactions with
3,6-disubstituted 1,2,4,5-tetrazines,3 tetrachlorothiophene
1,1-dioxide,4 isoprene,5 buta-1,3-diene,5 cyclohexa-1,3-dienes6
and quinodimethanes.7 Indole magnesium salts were found to
undergo facile cycloaddition reactions with 2-phenylsulfonyl-
1,3-dienes.8 However, indole participates in other types of
cycloadditions as an electron-rich alkene.1
HN
HN
H
Me
MeOH
0 °C
O
O
DAIB
OMe
OMe
R
MeO2C
OMe
4a–c
OMe
O
3a
OMe
OMe
3e
8a
rt
rt
R
Masked o-benzoquinones (MOBs) are one of the most readily
accessible types of cyclohexa-2,4-dienones with immense
synthetic potential.9,10 MOBs have been shown to be efficient
dienes and they have been extensively used in this capacity in
our laboratory.9 Following our studies on Diels–Alder reactions
of furans with MOBs,11 we turned our attention to indoles. It
was envisioned that if indoles could react with MOBs by
cycloaddition, easy access to a variety of potentially useful
hydrocarbazoles could be achieved. On the other hand, if
indoles add to MOBs by a Michael addition a facile synthesis of
highly substituted 3-arylindoles could be achieved. Accord-
ingly, the reactions of selected MOBs 1a–c, generated from
phenols 2a–c with a variety of indoles, were examined. We
herein report that indoles 3a–e undergo Diels–Alder or Michael
addition to MOBs 1a–c depending on the reaction temperature
and substitution pattern, to furnish Diels–Alder adducts 4–8 or
aromatized Michael adducts 9–11 in good yields.
1a R = CO2Me
1b R = COMe
1c R = CN
3b
3d
Br
rt
reflux
3c
reflux
CH2CO2Et
HN
H
H
HN
H
O
O
OMe
OMe
R
OMe
7a–c
Me
H
R
OMe
5a–c
HN
O
OMe
OMe
6a–c
R
In order to avoid their dimerization, MOBs were usually
generated in situ from the corresponding 2-methoxyphenols in
the presence of a reactive dienophile at a suitable temperature
using (diacetoxyiodo)benzene (DAIB) in MeOH. Since indoles
are known to react with DAIB,12 an alternative procedure
needed to be developed. Consequently, 1a–c were generated
from 2a–c in MeOH by adding DAIB (1.0 equiv.) at 0 °C in
MeOH and then an indole derivative was added. After the
addition of an indole derivative, the temperature was elevated
either to room temperature or to reflux (Schemes 1 and 2,
Table 1).13
R2
R3
N
R1
H
3a R1 = R2 = R3 = H
3b R1 = R2 = H, R3 = Br
3c R1 = R3 = H, R2 = Me
3d R1 = R3 = H, R2 = CH2CO2Et
3e R1 = Me, R2 = R3 = H
Scheme 1
3-Methylindole (3c) reacted efficiently only at reflux to
furnish the Diels–Alder adducts 6a–c and products which could
result via Michael addition were not descernible. The reactions
of 3d with 1a–c were found to be sluggish and only Diels–Alder
adducts 7a–c were obtained in poor yields. At both room
temperature and reflux, 2-methylindole (3e) underwent Michael
addition to MOBs 1b and 1c followed by aromatization of the
adducts to provide compounds 11b and 11c exclusively in
excellent yields. Intriguingly, indole (3a) underwent cycloaddi-
tion at room temperature to furnish Diels–Alder adducts 4a–c
and Michael addition at reflux temperature to afford aromatized
Michael adducts 9a–c in good yields. 6-Bromoindole exhibited
the same behavior as indole albeit with low efficiency.
The gross structures of all the products were determined by
1
their IR, H and 13C NMR, DEPT, low- and high-resolution
mass spectral analysis. The majority of these products provided
satisfactory elemental analyses. The regioselectvity of the
1
Diels–Alder reactions was determined by H–1H decoupling
Chem. Commun., 1999, 1441–1442
1441

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2a–c
on the 2- or 3-position of indole prevents both cycloaddition and
Michael addition.
OH
R
OH
R
MeOH
0 °C
In conclusion these reactions are mechanistically interesting
and help unravel a new class of dienes that can force indoles to
act as dienophiles. These reactions provided easy access to a
variety of multifunctional tetracyclic compounds and 3-aryl-
indoles whose synthesis is otherwise difficult. The Diels–Alder
adducts of indoles could potentially be useful starting materials
in the total synthesis of indole monoterpenoid alkaloids and
ellipticine-type compounds with antitumor activity.
We thank the National Science Council (NSC) of Taiwan,
R.O.C for financial support. One of us, (P. D. R.) thanks NSC
for a postdoctoral fellowship.
DAIB
OMe
OMe
3e
reflux
3a
1a–c
reflux
N
N
Me
H
H
3b
reflux
OMe
11a–c
9a–c
OH
Br
References and notes
1 R. J. Sundberg, The Chemistry of Indoles, Academic Press, New York,
1971; D. J. Chadwick, in Comprehensive Heterocyclic Chemistry, ed.
A. R. Katritzky and C. W. Rees, Pergamon, Oxford, 1984, vol. 4, p. 155;
R. A. Jones, in Comprehensive Heterocyclic Chemistry, ed. A. R.
Katritzky and C. W. Rees, Pergamon, Oxford, 1984, vol. 4, p. 201; R. J.
Sundberg, in Comprehensive Heterocyclic Chemistry, ed. A. R.
Katritzky and C. W. Rees, Pergamon, Oxford, 1984, vol. 4, p. 313.
2 J. E. Saxton, The Monoterpenoid Indole Alkaloids, Wiley-Interscience,
Chichester, 1994; J. E. Saxton, Nat. Prod. Rep., 1997, 14, 559 and
references cited therein.
3 S. C. Benson, C. A. Polabrica and J. K. Snyder, J. Org. Chem., 1987, 52,
4610; M. Takahashi, H. Ishida and M. Kohmoto, Bull. Chem. Soc. Jpn.,
1976, 49, 1725.
4 M. S. Raasch, J. Org. Chem., 1980, 45, 856.
5 E. Wenkert, P. D. R. Moeller and S. R. Piettre, J. Am. Chem. Soc., 1988,
110, 7188.
R
N
H
10a–c
Scheme 2
Table 1 Diels–Alder and Michael addition reactions of indoles 3a–c with
MOBs 1a–c
Indole
Diels–Alder Yield
adduct
Michaelb
adduct
Yield
(%)
Entry derivative MOB
(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
3a
3b
3c
3d
3e
3a
3b
3c
3d
3e
3a
3b
3c
3d
3e
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1c
1c
1c
1c
1c
4aa
5aa
6ab
7ab
8aa
4ba
5ba
6bb
7bb
—
4ca
5ca
6cb
7cb
—
65
50
71
15
24
9a
10a
—
—
11a
9b
10b
—
—
11b
9c
10c
—
96
92
—
—
86
91
90
—
—
96
53
67
—
—
75
6 A. Gieseler, E. Steckhan, O. Wiest and F. Knoch, J. Org. Chem., 1991,
56, 1405.
7 J. H. Markgraff and D. E. Patterson, J. Heterocycl. Chem., 1996, 33,
109.
70
c
54
37
—
45
23
39
8
8 J.-E. Backvall and N. A. Plobeck, J. Org. Chem., 1990, 55, 4528.
9 D.-S. Hsu, P. D. Rao and C.-C. Liao, Chem. Commun., 1998, 1795; P. D.
Rao, C.-H. Chen and C.-C. Liao, Chem. Commun., 1998, 155; P.-Y.
Hsu, Y.-C. Lee and C.-C. Liao, Tetrahedron Lett., 1998, 39, 659; W.-C.
Liu and C.-C. Liao, Synlett, 1998, 912; P.-Y. Hsiu and C.-C. Liao,
Chem. Commun., 1997, 1085; C.-S. Chu, P. D. Rao and C.-C. Liao,
Chem. Commun., 1996, 1537 and references cited therein.
10 R. Carlini, K. Higgs, C. Older and S. Randhawa, J. Org. Chem., 1997,
62, 2330; R. S. Coleman and E. B. Grant, J. Am. Chem. Soc., 1995, 117,
10889; K. S. Feldman and S. M. Ensel, J. Am. Chem. Soc., 1994, 116,
3357; A. S. Mitchell and R. A. Russell, Tetrahedron Lett., 1993, 34,
545; M. G. Banwell and M. P. Collis, J. Chem. Soc., Chem. Commun.
1991, 1343 and references cited therein.
—
11c
—
a Add indole 3 to a solution of 1 in MeOH at 0 °C, then stir for 1 h at rt.
b Add indole 3 to a solution of 1 in MeOH at 0 °C, then reflux for 1 h. c Not
isolable.
experiments in all cases. Their stereoselectivity was predicted to
be as shown based on our earlier results with furans11 and is
confirmed in the case of the adduct 7b by its single crystal X-ray
diffraction analysis.14 Since in all cases the reactions furnished
adducts resulting from endo-addition, these cycloaddition
reactions appear to have followed all the ground rules of Diels–
Alder reactions. On the other hand, the Michael addition
appears to be highly regioselective. In all cases, only 1,6-addi-
tion took place. This result was confirmed by the NMR spectra
of the aromatic Michael adducts 9–11 and by single crystal X-
ray analysis in the case of 10a.14
The exclusive cycloaddition of 3-substituted indoles 3c,d and
exclusive Michael addition of 2-methylindole to MOBs at both
temperatures is probably due to steric factors. The dual
reactivity of indoles lacking substituents needs to be under-
stood. It was reasoned that the initially formed Diels–Alder
adducts rearrange to the observed products 9–11 at high
temperature. In order to test this hypothesis, the Diels–Alder
adduct 4a was refluxed in MeOH in the presence of indole and
AcOH but only a complex mixture of products which contained
no trace of 9a was obtained. Hence an alternative mechanism,
with 9–11 being produced via a Michael addition–aromatization
sequence, is proposed. This concept has also gained support
from the substitution pattern required for the success of these
reactions. The presence of electron-withdrawing groups on C-4
of MOBs is essential for the success of these reactions. On the
other hand, the presence of electron-withdrawing substituents
11 C.-H Chen, P. D. Rao and C.-C. Liao, J. Am. Chem. Soc., 1998, 120,
13254; P. D. Rao, C.-H. Chen and C.-C. Liao, Chem. Commun., 1999,
713.
12 R. M. Moriarty, C. J. Chany II and J. W. Kosmeder II, in Encyclopedia
of Reagents for Organic Synthesis, ed. L. A. Paquette, Wiley,
Chichester, 1995, vol. 2, p. 1479.
13 Procedure for Diels–Alder or Michael addition reactions of indoles 3
with 1a–c. To a solution of 2 (1.0 mmol) in MeOH (10 ml) at 0 °C was
added DAIB (1.0 mmol). After 10 min of stirring, an indole derivative
3 (5–20 mmol) was added at that temperature and the flask was rapidly
warmed up to room temperature or to that of reflux by either removing
the ice bath or transferring the reaction vessel to a preheated (100 °C) oil
bath. The reaction mixture was stirred at either temperature for 1 h. Then
MeOH was removed and the residue obtained was purified by flash
chromatography on silica gel using 20% of ethyl acetate in hexanes as
eluent to obtain Diels–Alder adducts or aromatized Michael adducts.
14 Crystal data for 7b: C22H25NO6, M = 399.43, monoclinic, a =
10.6487(1), b = 22.172(3), c = 8.588(2) Å, b = 95.726(1)°, V =
2017.5(5) Å3, T = 293(2) K, space group P21/c, Z = 4, m(Mo-Ka) =
0.096 mm21, 3545 reflections measured, 3545 unique (Rint = 0.0000).
Final R indices [I > 2s(I)] R1 = 0.0430, wR2 = 0.1261. For 10a:
C17H14BrNO4, M = 376.20, triclinic, a = 9.0176(2), b = 9.4144(2), c
= 10.3637(1) Å, a = 90.7060(1), b = 96.9180(1), g = 117.1930(1)°,
¯
V = 774.62(2) Å3, T = 293(2) K, space group P1, Z = 2, m(Mo-Ka)
= 2.673 mm21, 7349 reflections measured, 3317 unique (Rint
=
0.0347). Final R indices [I > 2s(I)] R1 = 0.0349, wR2 = 0.0893.
CCDC 182/1310. See http://www.rsc.org/suppdata/cc/1999/1441/ for
crystallographic data in .cif format.
Communication 9/04366G
1442
Chem. Commun., 1999, 1441–1442
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