A novel generation of indole-2,3-quinodimethanes

Article abstract of DOI:10.1021/ol060418n

A novel and efficient procedure for the generation of the reactive indole-2,3-quinodimethane intermediates from the allenylanilines is described. The indole-2,3-quinodimethane intermediates were captured by several dienophiles to afford the corresponding

Full text of DOI:10.1021/ol060418n

ORGANIC
LETTERS
2006
Vol. 8, No. 9
1843-1845
A Novel Generation of
Indole-2,3-quinodimethanes
Norikazu Kuroda, Yukie Takahashi, Kazuo Yoshinaga, and Chisato Mukai*
DiVision of Pharmaceutical Sciences, Graduate School of Natural Science and
Technology, Kanazawa UniVersity, Kakuma-machi, Kanazawa 920-1192, Japan
cmukai@kenroku.kanazawa-u.ac.jp
Received February 17, 2006
ABSTRACT
A novel and efficient procedure for the generation of the reactive indole-2,3-quinodimethane intermediates from the allenylanilines is described.
The indole-2,3-quinodimethane intermediates were captured by several dienophiles to afford the corresponding tetrahydro- and dihydrocarbazole
derivatives. This method is significantly different from the previously reported ones, which involve the 1,4-elimination or its related reactions
of the indole derivatives that possess suitable substituents at both the C-2 and C-3 positions.
The 2,3-bis(methylene)-2,3-dihydroindole system, the so-
called indole-2,3-quinodimethane 2,1 is a kind of o-quin-
odimethane2 and well-known to be a powerful diene in the
Diels-Alder reaction resulting in the efficient formation of
tetrahydro- and dihydrocarbazoles and their related com-
pounds 3. As described in Scheme 1, almost all of the
Recent efforts in this laboratory5 disclosed a one-step
preparation of the 2,3-disubstituted indoles 7 by the Stille
coupling reaction of the N-(tert-butoxycarbonyl)-2-iodo-
anilines 4 with the 1-(tert-butyldimethylsiloxy)methyl-1-
(tributylstannyl)allenes 5 via the 2-allenylanilines 6 (Scheme
2). When this ring-closing reaction was carried out in the
absence of tetra-n-butylammonium chloride (TBAC), the
allenyl derivatives 6 could be isolated in high yields.
Therefore, we postulated that adjustment of the siloxy
functionality of 6 with a suitable leaving group (e.g.,
compound 8), followed by the intramolecular SN2′ reaction
by the nitrogen functionality, as depicted in Scheme 2, would
lead to the novel generation of the indole-2,3-quinodimethane
2, which should react with dienophiles already present in
the reaction vessel. This letter describes a new and efficient
synthesis of the indole-2,3-quinodimethane, which results
Scheme 1
procedures1,3 hitherto reported for in situ generation of this
reactive indole-2,3-quinodimethane 2 take advantage of the
1,4-elimination-type or related reactions of the 2,3-disubsti-
tuted indole derivatives 1.4
(3) For recent references, see: (a) Vice, S. F.; Nandin de Carvalho, H.;
Taylor, N. G.; Dmitrienko, G. I. Tetrahedron Lett. 1989, 30, 7289-7292.
(b) Fray, E. B.; Moody, C. J.; Shah, P. Tetrahedron 1992, 49, 439-450.
(c) Rao, M. V. B.; Satyanarayana, J.; Ila, H.; Junjappa, H. Tetrahedron
Lett. 1995, 36, 3385-3388. (d) Ciganek, E.; Schubert, E. M. J. Org. Chem.
1995, 60, 4629-4634. (e) Jakiwczyk, O. M.; Nielsen, K. E.; Nandin de
Carvalho, H.; Dmitrienko, G. I. Tetrahedron Lett. 1997, 38, 6541-6544.
(f) Laronze, M.; Sapi, J. Tetrahedron Lett. 2002, 43, 7925-7928.
(4) The formation of the indole-2,3-quinodimethane by the sulfur dioxide
extrusion of the thieno[3,4-b]indole dioxide was also reported.3a
(5) Mukai, C. Takahashi, Y. Org. Lett. 2005, 7, 5793-5796.
(1) (a) Magnus, P.; Gallagher, T.; Brown, P.; Pappalardo, P. Acc. Chem.
Res. 1984, 17, 35-41. (b) Pindur, U.; Erfanian-Abdoust, H. Chem. ReV.
1989, 89, 1681-1689 and references therein.
(2) (a) Oppolzer, W. Synthesis 1978, 793-802. (b) Charlton, J. L.;
Alauddin, M. M. Tetrahedron 1987, 43, 2873-2889. (c) Martin, N.; Seoane,
C.; Hanack, M. Org. Prep. Proc. Int. 1991, 23, 237-272. (d) Segura, J. L.;
Martin, N. Chem. ReV. 1999, 99, 3199-3246.
10.1021/ol060418n CCC: $33.50
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Published on Web 04/06/2006

instability8 of the mesylate 9a. Therefore, we next examined
the reactivity of the corresponding acetate 9b,6 which is more
stable and easier to handle than the mesylate 9a. Treatment
of 9b with the two carbonates afforded the desired product
11a in high yields without the formation of the dimer 12a
(entries 4 and 5). Furthermore, the better result was obtained
when the reaction was performed using a syringe pump9
(entry 6). Thus, the allenyl acetate group was shown to be a
suitable functionality for our purpose.
Scheme 2
Our next step was to determine the electronic effect of
the substituent on the benzene ring of the allenylanilines10
in the above procedure. These results are summarized in
Table 2. The allenylanilines 9c,d, having a methoxy group,
from the simultaneous construction of both the indole nucleus
and a 2,3-bis(methylene) functionality by a one-pot synthesis.
Our initial evaluation of this proposed methodology was
carried out using the mesylate 9a6 and dimethyl fumarate
(10) under basic conditions (Table 1). A solution of 9a and
Table 2. Reaction of Allenylanilines 9c-g with Dimethyl
Fumarate
Table 1. Reaction of Allenylanilines 9a,b with Dimethyl
Fumarate
carbazole
11 (%)
dimer
12 (%)
entry substrate
R1
R2
R3
1
2
3
4
5
9c
9d
9e
9f
OMe
H
H
H
H
H
OMe
-OCH2O-
CO2Et
Cl
H
H
11c (81)
11d (79)
11e (54)
11f (69)
11g (56)
base
(3 equiv)
carbazole
11a (%)
dimer
12a (%)
entry
substrate
R
H
H
12f (25)
a
1
2
3
4
5
6
7
9a
9a
9a
9b
9b
9b
9b
Ms
Ms
Ms
Ac
Ac
Ac
Ac
K2CO3
Cs2CO3
NaH
K2CO3
Cs2CO3
76
81
77
87
84
93
84
13
13
10
9g
a A trace of 12g was detected.
a
K2CO3
Cs2CO3
provided the corresponding tetrahydrocarbazole 11c,d in the
respective yields of 81 and 79% (entries 1 and 2). Similarly,
the methylenedioxy derivative 11e was obtained in 54% yield
without the formation of the dimer 12e (entry 3). The
electron-withdrawing groups, such as the ethoxycarbonyl and
chloro groups, seemed not to disturb the production of the
indole-2,3-quinodimethane intermediate, but the formation
of the dimers increased (entries 4 and 5). In particular, a
significant amount of the dimer 12f was observed when the
ethoxycarbonyl derivative 9f was exposed to the reaction
conditions (entry 4).11
a
a Reaction was carried out using a syringe pump.
10 in DMF was treated with K2CO3 at 0 °C for 2 h to afford
the desired tetrahydrocarbazole derivative 11a in 76% yield
along with the known dimer 12a7 of the indole-2,3-
quinodimethane intermediate in 13% yield (entry 1). Cs2-
CO3 in DMF provided a slightly better result (81% yield)
than the other bases (entry 2). Similarly, NaH effected the
formation of the indole-2,3-quinodimethane to produce 11a
in 77% yield (entry 3). Other solvents, such as DMSO, THF,
benzene, and CH2Cl2, were more ineffective than DMF.
Although the simultaneous formation of the indole-2,3-
quinodimethane intermediate and the [4 + 2] cycloaddition
could be achieved, the reliable reproducibility of this
transformation was not realized, presumably due to the
Our efforts then turned to investigating the [4 + 2]
cycloaddition of the indole-2,3-quinodimethane with several
(8) The mesylate 9a spontaneously collapsed when kept in the solvent
at room temperature.
(9) Typical procedure. To a suspension of the dienophile (0.30 mmol)
and K2CO3 (0.30 mmol) in DMF (1.0 mL) was added at 0 °C a solution of
9 (0.30 mmol) in DMF (1.0 mL) over a period of 2 h using a syringe pump
under a nitrogen atmosphere. The reaction mixture was diluted with saturated
aqueous NH4Cl and extracted with Et2O. The extract was washed with water
and brine, dried, and concentrated to dryness. The residue was chromato-
graphed with AcOEt-hexane to afford the [4 + 2] cycloaddition products.
(10) Preparation and characterization of the unknown allenylanilines are
described in the Supporting Information.
(6) Compounds 9a,b were prepared from 6 (R ) H) by the successive
desilylation and acylation. The details are described in the Supporting
Information.
(7) Marinelli, E. R. Tetrahedron Lett. 1982, 23, 2745-2748.
1844
Org. Lett., Vol. 8, No. 9, 2006

dienophiles. Exposure of 9a and the cis-isomer of 10,
dimethyl maleate (13a), to the optimized conditions provided
the [4 + 2] cycloadduct 14a12 in 7% yield, in sharp contrast
to the reaction with dimethyl fumarate (10), and the major
product was the dimer 12a (Table 3, entry 1). The reactive
acetylenic dienophile, dimethyl acetylenedicarboxylate (13d),
produced the desired 14d in a yield similar to that of 14c7
(entry 4), but methyl propiolate (13e) was found to have low
reactivity12 toward the indole-2,3-quinodimethane, the same
as 13a, to afford the dihydrocarbozole derivative 14e14 in a
low yield (entry 5). Thus, the reactivities of several dieno-
philes toward the indole-2,3-quinodimethane, as shown in
Table 3, are in accordance with those previously reported.12
Finally, the transformation of the allenylaniline derivative,
which has an alkyl appendage at the allenic position, into
the tetrahydrocarbazole derivative was investigated hoping
to apply this newly developed methodology to the intramo-
lecular version. As a result, compound 1510 was exposed to
the optimized conditions9 with dimethyl fumarate (10) to
produce the desired carbazole derivative 16 as a mixture of
two diastereoisomers15 in 61% yield (Scheme 3).
Table 3. Reaction of Allenylanilines 9a with Dienophiles
Scheme 3
In summary, we have developed a novel procedure for
the generation of the reactive indole-2,3-quinodimethane
intermediates from the allenylanilines. This method is entirely
different from the previously reported ones, which were
based on the 1,4-elimination or its related reactions of the
indole derivatives, possessing suitable substituents at both
the C-2 and C-3 positions. Determining the scope and
limitations of this method as well as its application to the
synthesis of natural products is now in progress.
N-phenylmaleimide (13b) afforded 14b7 in 87% yield (entry
2). The reaction with an additional olefinic dienophile, methyl
acrylate (13c), proceeded to furnish the cycloaddition product
14c as a mixture of two regioisomers13 (entry 3). The
Acknowledgment. This work was supported in part by
a Grant-in Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology, Japan,
for which we are thankful.
(11) The electron-deficient substituent on the benzene ring might decrease
the reactivity of the indole-2,3-quinodimethane as a diene in the [4 + 2]
cycloaddition.1a
(12) Pindur reported that the N-benzoylindole-2,3-quinodimethane, gener-
ated from 2,3-bis(bromomethyl)indole, failed to react with acrolein, diethyl
maleate, or the propiolates: Haber, M.; Pindur, U. Tetrahedron 1991, 47,
1925-1936.
Supporting Information Available: General procedure
for preparation of allenylanilines 9a-g and 15, characteriza-
tion for data for compounds 9a-g, 11a,c-g, 12f, 14a,d,e,
(13) Compound 14c is a known compound7 and obtained as a mixture
of the 2- and 3-methoxycarbonyl derivatives in the ratio of 4:1.
(14) Compound 14e was obtained as a mixture of the 2- and 3-meth-
oxycarbonyldihydrocarbazole derivatives. The ratio of the two isomers (4:
1) was determined by the conversion of 14e into 14c under hydrogenation
conditions.
1
15, and 16, and H and 13C NMR spectra for compounds
9b,d,e,g, 12f, and 15. This material is available free of charge
via Internet at http://pubs.acs.org.
(15) A mixture of two isomers was obtained in the ratio of 3:2.
OL060418N
Org. Lett., Vol. 8, No. 9, 2006
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