Generation of N-(tert-butoxycarbonyl)indole-2,3-quinodimethane and its [4+2]-type cycloaddition

Article abstract of DOI:10.1021/jo901325d

(Chemical Equation Presented) The two conditions for the preparation of the reactive N-(tert-butoxycarbonyl)indolo-2,3-quinodimethane intermediate were developed by the reaction of the N-(tert-butoxycarbonyl)-2-(1- ethoxycarbonyloxymethylallenyl) aniline

Full text of DOI:10.1021/jo901325d

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SCHEME 1. Generation of Indole-2,3-quinodimethanes
Generation of N-(tert-Butoxycarbonyl)indole-2,3-
quinodimethane and Its [4þ2]-Type Cycloaddition
Fuyuhiko Inagaki, Masaya Mizutani, Norikazu Kuroda,
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 June 22, 2009
starting indole derivatives 13 possessing suitable substituents
at the C2- and/or C3-positions except for several alternatives.4
Recent efforts in this laboratory5 developed a novel
procedure for the facile preparation of the reactive indole-
2,3-quinodimethane intermediates 2 (R = Boc) by the in-
tramolecular base-catalyzed SN20-type reaction of the 2-(1-
acetoxymethylallenyl)aniline derivatives 4 (Scheme 1). The
produced indole-2,3-quinodimethane intermediates 2 (R =
Boc) were captured by dienophiles to afford the correspond-
ing tetrahydro- and dihydrocarbazole derivatives 3 (R =
Boc), the chemical yields of which, however, depended on
the property of the dienophiles. If the dienophiles are un-
stable under basic conditions, this ring-closing reaction
produces 3 (R = Boc) in poor yields accompanied by the
formation of significant amounts of the known dimer of 26
(R = Boc, see compound 7 in Table 1). Our continuous
interest in this field prompted us to optimize the reaction
conditions aiming at improvement of the chemical yields of
the cycloadducts in order to make our method more useful.
This paper provides the alternative conditions for the in situ
generation of the indole-2,3-quinodimethane, which led to
the better results of the [4þ2]-type cycloaddition of 2, when
compared to the previously reported ones.
The two conditions for the preparation of the reactive
N-(tert-butoxycarbonyl)indolo-2,3-quinodimethane in-
termediate were developed by the reaction of the
N-(tert-butoxycarbonyl)-2-(1-ethoxycarbonyloxymethy-
lallenyl)aniline with K2CO3 or Pd2(dba)3 in refluxing
toluene. The resulting N-(tert-butoxycarbonyl)indolo-
2,3-quinodimethane was captured by several alkenyl
and alkynyl dienophiles to provide the corresponding
tetrahydro- and dihydrocarbazole derivatives.
The indole-2,3-quinodimethane 21 is well-known to be a
powerful enophile for the [4þ2]-type cycloaddition reaction,
which produces tetrahydro- and dihydrocarbazoles and their
related compounds 3. Almost all of the procedures1,2 for the in
situ generation of this reactive indole-2,3-quinodimethane 2
involve the 1,4-elimination-type or its related reactions of the
In a previous study,5 the tetrahydrocarbazole derivative
6b5 could be synthesized in 93% yield when 4 was treated
with dimethyl fumarate in the presence of 3 equiv of K2CO3
at 0 °C for 2 h, whereas dimethyl maleate was shown to be an
unsuitable dienophile in this [4þ2] cycloaddition with 2 (R=
Boc) to give the cyclized product 6a5 in a poor yield (7%)
along with the known dimer 7,6 in 85% yield, which should
have occurred from the dimerization of 2. Thus, at the
beginning of this research, several leaving groups instead
of the acetoxy group of 4 and some types of bases were
evaluated by using dimethyl maleate as a dienophile, thereby
we finally determined the conditions consisting of the com-
bination of ethyl carbonate and a catalytic amount of
K2CO3. As a result, a solution of 5 and dimethyl maleate
in toluene was refluxed (condition A) in the presence of 0.2
equiv of K2CO3 for 1 h to afford 6a in 82% yield and its
isomer 6b (4%) together with the dimer 7 (13%) (Table 1,
*To whom correspondence should be addressed. Phone: þ81-76-234-
4411. Fax: þ81-76-234-4410.
(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 cited therein.
(2) 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.
(3) The formation of the indolo-2,3-quinodimethane by the sulfur dioxide
extrusion of the thieno[3,4-b]indole dioxide was also reported.2a
(4) Fuwa and Sasaki very recently reported a new method for the
generation of the indole-2,3-quinodimethane based on the intramolecular
Heck reaction. (a) Fuwa, H.; Sasaki, M. Chem. Commun. 2007, 2876–2878.
(b) Fuwa, H.; Tako, T.; Ebine, M.; Sasaki, M. Chem. Lett. 2008, 37, 904–905.
(5) Kuroda, N.; Takahashi, Y.; Yoshinaga, K.; Mukai, C. Org. Lett.
2006, 8, 1843–1845.
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6402 J. Org. Chem. 2009, 74, 6402–6405
Published on Web 07/21/2009
DOI: 10.1021/jo901325d
r
2009 American Chemical Society

Inagaki et al.
JOCNote
entry 1). Significant improvement in the chemical yield of 6a
was attained. Compound 6b was also obtained in a yield as
high as that of the previous one (entry 2). Although methyl
acrylate provided 6c5 in a moderate yield under the previous
conditions, condition A afforded 6c with a much better yield
(91%) (entry 3). Additionally, two typical olefinic dieno-
philes, acrylonitirle and methyl vinyl ketone, reacted under
condition A to yield both of the corresponding cycloadducts
6d4 and 6e4 in satisfactory yields (entries 4 and 5), although
DMAP was used instead of K2CO3 in the case of 6d. The
acetylenic dienophiles were also found to be suitable sub-
strates under condition A. In fact, dimethyl acetylenedicar-
boxylate furnished 6f5 in a fairly improved yield (93%) (entry
6). It should be noted that a significant improvement was
recorded for the cycloaddition with methyl propiolate to
produce 6g5 in 70% yield (entry 7), whereas 6g was only
obtained in 8% yield under the previous conditions. Conse-
quently, it became clear that condition A can be applied to
not only the olefinic dienophiles 6a-e, but also the acetylenic
ones 6f,g with almost total suppression of the formation of
the dimer 7. Contrary to our prediction, N-phenylmaleimide,
which produced 6h5 in 87% yield under the previous condi-
tions, gave an intractable mixture under condition A. Chan-
ging the base from K2CO3 to DMAP produced 6h in 34%
yield along with the dimer 7 (23%) (entry 8). Electron-rich
olefins are generally regarded as an ineffective counterpart in
the intermolecular [4þ2] cycloaddition of 2.2 In fact, the
capture of 2 with olefins possessing an electron-donating
group such as ethyl vinyl ether, vinyl acetate, and styrene
under the previous conditions led to failure and the exclusive
formation of the dimer 7 was observed. When styrene reacted
with 5 under condition A, however, the desired cyclo-
adduct 6i could be isolated in 40% yield along with 7 (11%).
Our efforts then turned to investigating the [4þ2] cycl-
oaddition of the indolo-2,3-quinodimethane 2 with quinone
derivatives. Treatment of the carbonate 5 with p-quinone
under condition A unexpectedly gave an intractable mixture.
No improvement could be realized by changing the base. 1,4-
Naphthoquinone also did not furnish any desired products.
Allyl carbonate groups were well-known to produce the
corresponding (π-allyl)palladium complex7 when treated
with a palladium(0) catalyst. We tentatively assumed that
treatment of 5 with a palladium(0) catalyst would result in
the formation of the vinylidene(π-allyl)palladium complex
8,8 that might collapse to the indole-2,3-quinodimethane 2
and/or its related palladium complexes 9 and 109 via the
intramolecular attack of the nitrogen atom under nearly
neutral conditions, in which both the base-sensitive p-qui-
none and 1,4-naphthoquinone must be tolerable (Scheme 2).
Thus, a solution of 5 and p-quinone in toluene was heated
under reflux for 10 min in the presence of 5 mol % of
Pd2(dba)3 (condition B) to produce the cycloadduct 6j in
40% yield (Table 2, entry 1). Similar treatment of 5 with 1,4-
naphthoquinone provided 6k in 70% yield (entry 2). These
results are in sharp contrast to the fact that neither 6j nor 6k
TABLE 1. Base-Catalyzed Reaction of Allenylanilines 5 with Dieno-
philes
aA mixture of 6a and 6b (82:4) was obtained. bA mixture
of the 2-CO2Me and 3-CO2Me derivatives (61:30) was obta-
ined. cA mixture of the 2-CN and 3-CN derivatives (62:20)
d
was obtained. DMAP (0.2 equiv) was used instead of K2C-
O3. eA mixture of the 2-COMe and 3-COMe derivatives
f
(62:20) was obtained. A mixture of the 2-CO2Me and 3-C-
O2Me derivatives (47:23) was obtained. gA mixture of the
2-Ph and 3-Ph derivatives (36:4) was obtained.
could be prepared under the previous conditions or condi-
tion A. Other successful examples under condition B are
summarized in Table 2. Methyl acrylate and methyl vinyl
ketone afforded the corresponding cycloadducts 6c,e in
reasonable yields (entries 3 and 4). N-Phenylmaleimide
furnished the cycloadduct 6h in a much better yield than
that under condition A (entry 5).
(7) (a) Tsuji, J.; Minami, I. Acc. Chem. Res. 1987, 20, 140–145.
(b) Consiglio, G.; Waymouth, R. M. Chem. Rev. 1989, 89, 257–276.
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7, 3645–3648. (b) Schneekloth, J. S. Jr.; Pucheault, M.; Crew, C. M. Eur. J.
Org. Chem. 2007, 40–43.
Table 3 shows the reactions under condition B, the
chemical yields of which did not exceed those obtained
(9) Yoshida, H.; Nakano, S.; Yamaryo, Y.; Ohshita, J.; Kunai, A. Org.
Lett. 2006, 8, 4157–4159.
J. Org. Chem. Vol. 74, No. 16, 2009 6403

Inagaki et al.
JOCNote
SCHEME 2. Pd(0)-Catalyzed Generation of Indole-2,3-quino-
dimethane Derivatives
TABLE 3. Pd-Catalyzed Reaction of Allenylanilines 5 with Other
Dienophiles
TABLE 2. Pd-Catalyzed Reaction of Allenylanilines 5 with Dienophiles
b
aA mixture of 6a and 6b (6:2) was obtained. A mixture of
c
2-CN and 3-CN derivatives (28:9) was obtained. 3-Ph deriv-
ative was obtained.
toluene. Thus, exposure of the allenylanilines and a proper
dienophile to one of the three conditions (the present two
conditions and the previously reported one) would provide the
desired carbazole derivatives in reasonable yields.
aA mixture of the 2-CO2Me and 3-CO2Me derivatives
(53:18) was obtained. . bA mixture of the 2-COMe and 3-CO-
Me derivatives (59:15) was obtained.
Experimental Section
General Procedure for Reaction of 2-Allenylaniline 5 with
K2CO3. To a solution of allenylaniline 5 (33.3 mg, 0.100 mmol)
in toluene (1 mL) were added dienophile (1.0 mmol) and
K2CO3 (2.8 mg, 2.0ꢀ10-2 mmol) at room temperature. The
reaction mixture was heated at 120 °C (oil bath temperature)
until the complete disappearance of the starting mater-
ial (monitored by TLC). After cooling, the reaction mixture
was quenched by addition of saturated aqueous NH4Cl
and extracted with AcOEt. The extract was washed with
water and brine, dried, and concentrated to dryness. Chro-
matography of the residue with hexane-AcOEt gave the
products.
under condition A. In the cases of dimethyl acetylenedi-
carboxylate and methyl propiolate, the palladium-cata-
lyzed trimerization10 proceeded (entries 4 and 5). In
particular the trimethoxycarbonylbenzene derivatives
were obtained in a 77% total yield and any other products
derived from 5 could not be observed in the reaction
mixture (entry 5).
In summary, we have developed two alternative conditions
for the preparation of carbazole derivatives via the reactive
indolo-2,3-quinodimethane intermediate, which was gener-
ated in situ by the reaction of the 2-(1-ethoxycarbonyloxy-
methyl allenyl)aniline with K2CO3 or Pd2(dba)3 in refluxing
tert-Butyl 2-Acetyl-1,2,3,4-tetrahydro-9H-carbazole-9-carbo-
xylate and tert-Butyl 3-Acetyl-1,2,3,4-tetrahydro-9H-carbazole-
9-carboxylate (6e). A mixture of 2-COMe-6e and 3-COMe-6e in
the ratio of 75 to 25 was obtained as a colorless oil: IR 1720 cm-1
;
(10) (a) Maitlis, P. M. Acc. Chem. Res. 1976, 9, 93–99. (b) tom Dieck, H.;
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Yamamoto, Y. Chem. Rev. 2000, 100, 2901–2916.
1H NMR 8.12-8.10 (m, 1H), 7.40-7.37 (m, 1H), 7.26-7.19
(m, 2H), 3.30 (dd, 75/100 ꢀ1H, J = 17.7, 5.5 Hz), 3.22 (dt,
6404 J. Org. Chem. Vol. 74, No. 16, 2009

Inagaki et al.
JOCNote
25/100ꢀ1H, J=18.3, 3.1 Hz), 3.12-3.07 (m, 75/100ꢀ1H),
3.02-2.94 (m, 25/100 ꢀ 1H), 2.92-2.89 (m, 25/100 ꢀ 1H),
2.86-2.78 (m, 2H), 2.68-2.61 (m, 75/100 ꢀ 1H), 2.31-2.21
(m, 1H), 2.279 (s, 25/100ꢀ3H), 2.276 (s, 75/100ꢀ3H), 1.88-
tert-Butyl 7,10-Dioxo-5H-benzo[b]carbazole-5-carboxylate
(6j). Compound 6j was a yellow plate: mp 210-213 °C (from
hexane); IR 1732, 1666 cm-1; 1H NMR δ 8.96 (s, 1H), 8.65 (s,
1H), 8.35 (d, 1H, J=8.5 Hz), 8.09 (d, 1H, J=7.8 Hz), 7.60-7.56
(m, 1H), 7.47-7.42 (m, 1H), 6.96 (d, 2H, J=2.0 Hz), 1.81 (s, 9H);
13C NMR δ 184.90, 184.87, 150.2, 141.0, 140.2, 139.2, 138.9,
130.7, 129.7, 129.4, 127.4, 124.6, 124.0, 120.9, 118.7, 116.5,
114.9, 85.5, 28.3; MS m/z 347 (Mþ, 7.5). HRMS calcd for
C21H17NO4 347.1158, found 347.1154.
1.75 (m, 1H), 1.670 (s, 75/100ꢀ9H), 1.666 (s, 25/100ꢀ9H); 13
C
NMR δ 210.7, 210.2, 150.52, 150.50, 136.02, 136.00, 134.7,
133.8, 129.3, 129.2, 123.65, 123.63, 122.50, 122.47, 117.5,
117.4, 116.0, 115.5, 115.4, 115.0, 83.5, 83.4, 48.5, 47.1, 28.3,
28.2, 28.1, 27.51, 25.8, 25.3, 24.6, 23.0, 20.4; MS m/z 313 (Mþ
10.0). HRMS calcd for C19H23NO3 313.1678, found
313.1671.
General Procedure for Reaction of 2-Allenylaniline 5 with Pd2-
(dba)3. To a solution of allenylaniline 5 (33.3 mg, 0.100 mmol) in
toluene (1 mL) were added dienophile (1.0 mmol) and Pd2(dba)3
(4.6 mg, 5.0ꢀ10-3 mmol) at room temperature. The reaction
mixture was heated at 120 °C (oil bath temperature) until the
complete disappearance of the starting material (monitored by
TLC). Chromatography of the residue with hexane-AcOEt
gave the products.
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 grateful.
Supporting Information Available: 1H and 13C NMR spec-
tra for compounds 5 and 6a-k and characterization data for
compounds 5, 6a-d, 6f-i, and 6k. This material is available free
of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 16, 2009 6405