An entry to the azocino[4,3- b ]indole framework through a dehydrogenative activation of 1,2,3,4-tetrahydrocarbazoles mediated by DDQ: Formal synthesis of (±)-uleine

Article abstract of DOI:10.1021/jo1021663

It is presented that hexahydro-1,5-methano[4,3-b]indoles were efficiently synthesized in high yields (up to 89% yield) through the cyclization reaction of starting tetrahydrocarbazoles bearing a monoalkylaminocarbonylmethyl moiety at the C-2 position medi

Full text of DOI:10.1021/jo1021663

pubs.acs.org/joc
An Entry to the Azocino[4,3-b]indole Framework
through a Dehydrogenative Activation of
1,2,3,4-Tetrahydrocarbazoles Mediated by DDQ:
Formal Synthesis of (()-Uleine
,†
Suleyman Patir* and Erkan Erturk*
,‡
€
€
†Department of Chemistry Education, Faculty of Education,
Hacettepe University, 06800 Beytepe, Ankara, Turkey, and
‡Chemistry Institute, TUBITAK Marmara Research Center,
41470 Gebze, Kocaeli, Turkey
FIGURE 1. Structure of uleine-type alkaloids.
Strychnos alkaloids, such as strychnine, akuammicine, tubi-
folidine, etc.2 A rather large number of synthetic pathways
have been developed for the construction of the azocino[4,3-b]-
indole skeleton so far. The majority of the reported methods
for the synthesis of these tetracyclic ring systems start either
from 2-(4-piperidinylmethyl)indole,3 3-(2-piperidinylmethyl)-
indole,4 or Fisher indolization of 2-azabicyclo[3.3.1]no-
nane.5 There also have been a few reports for the building
of the D-ring from tetrahydrocarbazole derivatives in quite
different ways.6,7 Recently, we reported the synthesis of
patir@hacettepe.edu.tr; erkan.erturk@mam.gov.tr
Received October 30, 2010
ꢀ
(2) For the synthesis of strychnine, see: (a) Bonjoch, J.; Sole, D. Chem.
Rev. 2000, 100, 3455–3482. and references cited therein. (b) Ohshima, T.; Xu,
Y.; Takita, R.; Shimizu, S.; Zhong, D.; Shibasaki, M. J. Am. Chem. Soc.
2002, 124, 14546–14547. (c) Mori, M.; Nakanishi, M.; Kajishima, D.; Sato,
Y. J. Am. Chem. Soc. 2003, 125, 9801–9807. (d) Kaburagi, Y.; Tokuyama,
H.; Fukuyama, T. J. Am. Chem. Soc. 2004, 126, 10246–10247. (e) Zhang, H.;
Boonsombat, J.; Padwa, A. Org. Lett. 2007, 9, 279–282. (f) Sirasani, G.; Paul,
T.; Dougherty, W., Jr.; Kassel, S.; Andrade, R. B. J. Org. Chem. 2010, 75,
3529–3532.
(3) (a) Jackson, A.; Gaskell, A. J.; Wilson, N. D. V.; Joule, J. A. Chem.
Commun. 1968, 364. (b) Dolby, L. J.; Biere, H. J. Am. Chem. Soc. 1968, 90,
2699–2700. (c) Jackson, A.; Wilson, N. D. V.; Joule, J. A. J. Chem. Soc. C
1969, 2738–2747. (d) Forns, P.; Diez, A.; Rubiralta, M.; Solans, X.; Font-
Bardia, M. Tetrahedron 1996, 52, 3563–3574. (e) Saito, M.; Kawamura, M.;
Hiroya, K.; Ogasawara, K. Chem. Commun. 1997, 765–766. (f) Amat, M.;
It is presented that hexahydro-1,5-methano[4,3-b]indoles
were efficiently synthesized in high yields (up to
89% yield) through the cyclization reaction of starting
tetrahydrocarbazoles bearing a monoalkylaminocarbo-
nylmethyl moiety at the C-2 position mediated by
2,3-dichloro-5,6-dicyanobenzoquinone (DDQ). A mech-
anistic proposal is also given that mainly includes two
cascade reactions: (i) formation of a vinylogous iminium
cation via DDQ-mediated dehydrogenation of tetrahydro-
carbazole functionality and (ii) intra-molecular and syn-
selective addition of the amide functionality as the nucleo-
phile to the vinylogous iminium cation. Furthermore, this
cyclization reaction was successfully utilized in the formal
total synthesis of (()-uleine, an Aspidospermatan skeletal
type alkaloid.
ꢀ
Perez, M.; Llor, N.; Escolano, C.; Luque, F. J.; Molins, E.; Bosch, J. J. Org.
Chem. 2004, 69, 8681–8693.
(4) (a) Dolby, L. J.; Biere, H. J. Org. Chem. 1970, 35, 3843–3845. (b)
€
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Buchi, G.; Gould, S. J.; Naf, F. J. Am. Chem. Soc. 1971, 93, 2492–2501. (c)
Kametani, T.; Suzuki, T. J. Org. Chem. 1971, 36, 1291–1293. (d) Kametani,
T.; Suzuki, T. Chem. Pharm. Bull. 1971, 19, 1424–1425. (e) Natsume, M.;
Kitagawa, Y. Tetrahedron Lett. 1980, 21, 839–840. (f) Harris, M.;
Besselievre, R.; Grierson, D. S.; Husson, H.-P. Tetrahedron Lett. 1981, 22,
331–334. (g) Grierson, D. S.; Harris, M.; Husson, H.-P. Tetrahedron 1983,
39, 3683–3694. (h) Natsume, M.; Utsunomiya, I.; Yamaguchi, K.; Sakai,
S.-I. Tetrahedron 1985, 41, 2115–2123. (i) Blechert, S.; Knier, R.; Schroers,
H.; Wirth, T. Synthesis 1995, 592–604. (j) Tanaka, K.; Katsumura, S. J. Am.
Chem. Soc. 2002, 124, 9660–9661. (k) Tasber, E. S.; Garbaccio, R. M.
Tetrahedron Lett. 2003, 44, 9185–9188. (l) Tanaka, K.; Kobayashi, T.; Mori,
H.; Katsumura, S. J. Org. Chem. 2004, 69, 5906–5925.
Efficient and atom-economic total synthesis of complex
molecules is a great endeavor in organic synthesis.1 Conse-
quently, applications of new (catalytic) reactions in total
synthesis are of particular interest for demonstrating their
efficiency and generality. Uleine-type indole alkaloids (e.g.,
1-4) constitute an important subgroup of the Strychnos
alkaloids. The 1,5-methanoazocino[4,3-b]indole moiety
bearing an ethyl chain at the bridge carbon atom is the
common key structure of the uleine alkaloids (Figure 1). On
the other hand, azocino[4,3-b]indole and azocino[4,3-b]indo-
line skeletons are also found as the key elements in other
ꢁ
(5) Gracia, J.; Casamitjana, N.; Bonjoch, J.; Bosch, J. J. Org. Chem. 1994,
59, 3939–3951.
(6) (a) Schmitt, M. H.; Blechert, S. Angew. Chem., Int. Ed. 1997, 36, 1474–
1476. (b) Jiricek, J.; Blechert, S. J. Am. Chem. Soc. 2004, 126, 3534–3538.
(c) Akdag, R.; Ergun, Y. J. Heterocycl. Chem. 2007, 44, 863–866.
(7) For the other synthetic studies leading to methanoazocino[4,3-
b]indole-6-one derivatives, see: (a) Kametani, T.; Suzuki, T. J. Chem. Soc.
ꢀ
C 1971, 1053–1054. (b) Feliz, M.; Bosch, J.; Mauleon, D.; Amat, M.;
Domingo, A. J. Org. Chem. 1982, 47, 2435–2440. (c) Bosch, J.; Rubiralta,
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M.; Domingo, A.; Bolos, J.; Linares, A.; Minguillon, C.; Amat, M.; Bonjoch,
J. J. Org. Chem. 1985, 50, 1516–1522. (d) Rubiralta, M.; Torrens, A.; Reig, I.;
Grierson, D. S.; Husson, H.-P. Heterocycles 1989, 29, 2121–2133. (e) Teuber,
H.-J.; Tsaklakidis, C.; Bats, J. W. Liebigs Ann. Chem. 1992, 461–466. (f) Diez,
A.; Castells, J.; Forns, P.; Rubiralta, M.; Grierson, D. S.; Husson, H.-P.;
(1) (a) Nicolaou, K. C.; Sorensen, E. J. Classcis in Total Synthesis; VCH:
Weinheim, Germany, 1996. (b) Nicolaou, K. C.; Vourloumis, D.;
Winssinger, N.; Baran, P. S. Angew. Chem., Int. Ed. 2000, 39, 44–122.
(c) Trost, B. M. Science 1991, 254, 1471–1477.
Solans, X.; Font-Bardıa, M. Tetrahedron 1994, 50, 6585–6602. (g) Amat, M.;
´
ꢀ
Perez, M.; Llor, N.; Martinelli, M.; Molins, E.; Bosch, J. Chem. Commun.
2004, 1602–1603. (h) Ishikura, M.; Takahashi, N.; Takahashi, H.; Yanada,
K. Heterocycles 2005, 66, 45–50.
DOI: 10.1021/jo1021663
r
Published on Web 12/13/2010
J. Org. Chem. 2011, 76, 335–338 335
2010 American Chemical Society

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Patir and Erturk
JOCNote
SCHEME 1. Selective Oxidation of the Side Chain at C-3 of
of 3-indolylmethyl C-H bonds with 1,3-dicarbonyls medi-
ated by DDQ was published.12
Indoles by DDQ10
Inspired by the dehydrogenative imine generation from
indole derivatives by DDQ that was originally developed by
Oikawa and Yonemitsu,10 we discussed that imine inter-
mediate could also be able to add amide nucleophiles. Thus,
azocino[4,3-b]indoles such as 10a-d could be easily synthe-
sized by treating the tetrahydrocarbazole-amide derivatives
9a-d with DDQ (Scheme 2). For this purpose, the tetrahy-
drocarbazole-amide derivatives 9a-d were first prepared in
high yields from the carboxylic acid 8 by reacting it with an
appropriate amine in the presence of ethyl chloroformate as
the coupling reagent. Next, our attention was focused on the
construction of azocino[4,3-b]indole skeletons 10a-d from
the tetrahydrocarbazole derivatives 9a-d by reacting them
with DDQ (Scheme 2). Fortunately, treatment of the amides
9a-d with DDQ at room temperature in THF under strictly
anhydrous conditions afforded the formation of the target
tetracyclic compounds 10a-d. In this way, the azocino[4,3-b]-
indole skeletons 10a-d could be obtained in high yields (up
to 89% yield) within 3 h under mild reaction conditions. An
X-ray single crystal analysis of 10c confirmed the expected
structure.13
Our next goal was to extend this procedure to the formal
total synthesis of the natural product (()-uleine (Scheme 3).
For this purpose, the 4-oxo-tetrahydrocarbazole 118a with
an amide side chain was selectively reduced to the corre-
sponding tetrahydrocarbazole 12. It is noteworthy that the
amide side chain of the 4-oxo-tetrahydrocarbazole 11 re-
mained intact while the 4-oxo functionality of 11 was chemo-
selectively transformed to the dihydro-functionality.14 Then,
the tetrahydrocarbazole 12 was converted into the tetracyc-
lic hexahydro-1,5-methanoazocino[4,3-b]indole system 13,
which was used as a precursor for the total synthesis of
(()-uleine (rac-1) in our previous report.8c The spectral data
of compound 13 were found to be identical with those
reported in the literature.8c
azocino[4,3-b]indole skeleton via acid-catalyzed D-ring cy-
clization of an appropriate 4-oxo-1,2,3,4-tetrahydrocarba-
zole derivative.8 In our former studies, we had also shown
that azocino[4,3-b]indoles can be formed from 4-amino-1-
oxo-1,2,3,4-tetrahydrocarbazoles.9 In conjunction with our
ineterest in the synthesis of indole-type alkaloids, we focused
our attention on the facile and efficient construction of the
azocino[4,3-b]indole skeleton toward the synthesis of uleine
(1). We herein present a 2,3-dichloro-5,6-dicyanobenzoqui-
none (DDQ)-mediated cyclization reaction of tetrahydro-
carbazoles bearing monosubstituted amide side chains that
makes the corresponding azocino[4,3-b]indole derivatives
efficiently accessible. Furthermore, we have also demon-
strated the efficiency of this new cyclization method in the
formal synthesis of (()-uleine (rac-1).
In 1977, Oikawa and Yonemitsu reported that 2,3-disub-
stituted indole derivatives such as 5 can be selectively oxi-
dized at C-3 side chain by treatment with 2.00 equiv of DDQ
in the presence of H2O (Scheme 1).10 A number of corre-
sponding keto products 6 could be conveniently prepared by
employing this procedure (up to 96% yield). According to
the proposed mechanism as depicted in Scheme 1, four
consecutive reactions take place during the DDQ-mediated
oxidation of 3-alkyl-substituted indole derivatives (5) giving
keto products (6): DDQ can first dehydrogenate the indole
derivative 5 to form the imine intermediate I, which can then
add one H2O molecule to form the corresponding hydroxy
intermediate II, then the hydroxy intermediate II can be
dehydrogenated to form the enol intermediate III, which can
finally isomerize to furnish the keto product 6. The chemistry
developed by Oikawa and Yonemitsu, that is the DDQ-
mediated dehydrogenative imine formation from 3-alkyl-
substituted indoles, was also utilized in the asymmetric
synthesis of (-)-tubifolidine,11a (-)-19,20-dihydroakuammi-
cine,11b and (þ)-ajmaline,11c as well as gardnutine.11d Very
recently, an enantioselective oxidative cross-coupling reaction
According to our tentatively proposed reaction mecha-
nism as illustrated in Scheme 4, the formation of the vinylo-
gous iminium cation VI in turn seems to be unequivocal.
However, for the DDQ-mediated dehydrogenation pathway
of the tetrahydrocarbazole 12 generating VI there are several
possible reaction mechanisms, e.g. single electron transfer
(SET) and direct hydride transfer (DHT) mechanisms.12,15
Although further studies, such as ESR studies, are needed to
elucidate the reaction mechanism more accurately we are
expecting a SET governed mechanism for the formation of
the iminium cation VI since DDQ most frequently oxidize
substrates via the SET mechanism.15,16 On the other hand,
the phenoxide anion VII can act as a Brønsted-base to drive
the syn-selective cyclization to completion of the reaction
(12) Guo, C.; Song, J.; Luo, S.-W.; Gong, L.-Z. Angew. Chem., Int. Ed.
2010, 49, 5558–5562.
€
(8) (a) Uludag, N.; Hokelek, T.; Patir, S. J. Heterocycl. Chem. 2006, 43,
€
€
(13) Tercan, B.; Yuksel, F.; Patir, S.; Hokelek, T. Acta Crystallogr. 2010,
E66, o1275–o1276.
(14) (a) Vogel, T.; Huth, H.-U.; Fritz, H. Liebigs Ann. 1982, 739–744. (b)
585–591. (b) Uludag, N.; Patir, S. J. Heterocycl. Chem. 2007, 44, 1317–1322.
(c) Patir, S.; Uludag, N. Tetrahedron 2009, 65, 115–118.
(9) (a) Patir, S. Liebigs. Ann. 1995, 1562–1562. (b) Patir, S.; Rosenmund,
€
P.; Gotz, P. H. Heterocycles 1996, 43, 15–22. (c) Uludag, N.; Uyar, T.; Patir,
S. Org. Prep. Proced. Int. 2003, 35, 397–400.
€
Patir, S.; Okay, G.; Gulce, A.; Salih, B.; Hokelek, T. J. Heterocycl. Chem.
1997, 34, 1239–1242.
€
€
(10) Oikawa, Y.; Yonemitsu, O. J. Org. Chem. 1977, 42, 1213–1216.
(11) (a) Shimizu, S.; Ohori, K.; Arai, T.; Sasai, H.; Shibasaki, M. J. Org.
Chem. 1998, 63, 7547–7551. (b) Ohori, K.; Shimizu, S.; Ohshima, T.;
Shibasaki, M. Chirality 2000, 12, 400–403. (c) Wang, T.; Xu, Q.; Yu, P.;
Liu, X.; Cook, J. M. Org. Lett. 2001, 3, 345–348. (d) Zhou, H.; Han, D.; Liao,
X.; Cook, J. M. Tetrahedron Lett. 2005, 46, 4219–4224.
(15) Hofler, C.; Ruchardt, C. Liebigs Ann. 1996, 183–188.
(16) For the recent works on the oxidative C-H activation reactions
mediated by DDQ, see: (a) Zhang, Y.; Li, C.-J. J. Am. Chem. Soc. 2006, 128,
4242–4243. (b) Tu, W.; Floreancig, P. E. Angew. Chem., Int. Ed. 2009, 48,
4567–4571. (c) Benfatti, F.; Capdevila, M. G.; Zoli, L.; Benedetto, E.; Cozzi,
P. G. Chem. Commun. 2009, 5919–5921.
336 J. Org. Chem. Vol. 76, No. 1, 2011

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Patir and Erturk
JOCNote
SCHEME 2. Preparation of the Tetrahydrocarbazole-Amide Derivatives 9a-d and the DDQ-Mediated Cyclization Thereof Yielding the
Azocino[4,3-b]indole Derivatives 10a-da
aReagents and conditions: (a) (1) KOH, H2O-MeOH-THF, rt, 5 h, (2) HCl; (b) (1) Et3N (1.50 equiv), EtOCOCl (1.50 equiv), -5 °C, 5 h, CHCl3, (2)
RNH2 (3.00 equiv), -5 °C, 3 h; (c) DDQ (1.20 equiv), THF, rt, 3 h, N2.
SCHEME 3. Formal Synthesis of (()-Uleine (rac-1)a
aReagents and conditions: (a) BH3 pyridine, HCl (20%), EtOH, 0 °Cfrt, overnight, 75%; (b) DDQ (1.20 equiv), THF, rt, 3 h, 83%.
3
SCHEME 4. Tentative Mechanism for the DDQ-Mediated Cyclization of Tetrahydrocarbazoles Bearing a Monosubstituted Amide Side
Chain
and 2,3-dichloro-5,6-dicyanohydroquinone (14) is formed as
a side product subsequently.
We have shown that tetracyclic hexahydro-1,5-methano-
[4,3-b]indole derivatives could be obtained by reacting an
cyclization reaction in the formal total synthesis of (()-
uleine,8c an Aspidospermatan skeletal-type alkaloid. Appli-
cation of this strategy toward the synthesis of other alkaloids
bearing azocino[4,3-b]indole moiety is underway in our
laboratory.
appropriate tetrahydrocarbazole derivative carrying
a
monosubstituted amide side chain with DDQ. The reaction
mechanism likely proceeded through formation of a vinylo-
gous iminium cation, which was formed from dehydrogena-
tion of the tetrahydrocarbazole moiety by DDQ, followed by
intra-molecular and syn-selective addition of the amide
nucleophile to the vinylogous iminium cation. Furthermore,
we have also successfully demostrated the feasibility of this
Experimental Section
Tetrahydrofuran (THF) was freshly distilled under N2 from
sodium/benzophenone immediately prior to use. Chloroform
(CHCl3) and triethylamine (Et3N) were distilled under N2 from
calcium hydride (CaH2). All synthetic compounds are in their
racemic form. 2,3-Dichloro-5,6-dicyanobenzoquinone (DDQ),
J. Org. Chem. Vol. 76, No. 1, 2011 337

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Patir and Erturk
JOCNote
ethyl chloroformate, and the amines, which were used for the
preparation of the amides 10a-d, were purchased from com-
mercial suppliers and used as received. All melting points were
determined in an open glass capillary tube and values are
uncorrected. Infrared (FT-IR) spectra were recorded on a FT-
IR spectrometer, νmax in cm-1. Bands are characterized as broad
eluting with EtOAc/acetone/Et3N (75:25:7). Combined fractions
containing the lactam 13 were then concentrated by rotary eva-
poration in vacuo, crystallization of which from Et2O/EtOAc (1:2)
yielded 0.82 g (2.29 mmol, 83%) of the title compound (13) as a
white solid. Mp 208 °C; Rf 0.76 (silica gel; EtOAc/acetone/Et3N,
75:25:7); FT-IR (KBr) νmax (cm-1) 3434 (br s), 3213 (br m), 3060
(w), 2964 (m), 2925 (m), 1623 (s), 1492 (w), 1455 (s), 1394 (m), 1314
(w), 1276 (w), 1239 (m), 1196 (w), 1161 (w), 1092 (m), 1012 (w), 963
(w), 790 (m), 741 (s), 708 (m), 661 (w), 581 (w), 571 (w), 530 (w); 1H
NMR (500 MHz, CDCl3) δ 0.98 (t, J = 7.3 Hz, 3H), 1.38-1.46
(m, 1H), 1.67-1.74 (m, 1H), 2.48 (t, J = 7.4 Hz, 1H), 2.71-2.80
(m, 2H), 3.00 (s, 3H), 3.25-3.37 (m, 3H), 3.42-3.53 (m, 2H), 4.32
(d, J = 1.4 Hz, 1H), 7.05 (td, J = 7.6 Hz, J = 0.9 Hz, 1H), 7.13 (td,
J = 7.6 Hz, J = 0.9 Hz, 1H), 7.26 (d, J = 8.1 Hz, 1H), 7.49 (d, J =
7.9 Hz, 1H), 8.30 (br s, 1H); 13C NMR (125 MHz, CDCl3) δ 12.7
(q), 24.4 (t), 34.5 (q), 39.7 (t), 40.2 (t), 41.2 (t), 44.9 (d), 46.1 (d), 53.8
(d), 66.9 (s), 111.4 (d), 113.3 (s), 118.4 (d), 120.2 (d), 123.1 (d), 126.4
(s), 132.9 (s), 136.4 (s), 169.4 (s); HR-MS (ESIþ) calcd for
C19H23N2OS2 ([M þ H]þ) 359.1252, found 359.1254. Elemental
Anal. Calcd for C19H22N2OS2: C, 63.65; H, 6.19; N, 7.81. Found:
C, 63.63; H, 6.17; N, 7.78.
1
(br), strong (s), medium (m), and weak (w). H and 13C NMR
spectra were recorded on a NMR spectrometer (500 MHz).
Chemical shifts, δ, are reported in parts per million (ppm)
relative to the residual protons in the NMR solvent (CHCl3: δ
7.24; DMSO-d6: δ 2.50) and carbon resonance of the solvent
(CDCl3: δ 77.00; DMSO-d6: δ 39.43). NMR peak multiplicities
were given as follows: s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet, br = broad. Mass spectra were recorded
on a gas chromatograph with mass sensitive detector (EI, 70 eV).
High-resolution electrospray ionization mass spectra (HR-ESI-
MS) were obtained with MeOH. Elemental analyses (EA) were
performed with an elemental analyzer instrument.
12-Ethyl-2-methyl-6,6-ethylenedithio-1,2,3,4,5,6-hexahydro-
1,5-methanoazacino[4,3-b]indole-3-one (13) (representative proce-
dure for DDQ-mediated cyclization). Amide 12 (1.00 g, 2.77 mmol)
was placed in a 50 mL oven-dried round-bottomed Schlenk flask
and dissolved in 20 mL of absolute THF under an atmosphere of
dry N2. DDQ (0.75 g, 3.30 mmol) was added in one portion and the
resulting reaction mixture was stirred at rt for 3 h under N2. After
the reaction mixture was quenched with 10% NaOH solution
(50 mL), the mixture was extracted with EtOAc (100 mL). The
separated organic layer was dried over Na2SO4. After all volatile
components were removed by rotary evaporation in vacuo, the
residue was first purified by silica gel column chromatography
Acknowledgment. This work was supported by the Scien-
tific and Technological Research Council of Turkey
(TUBITAK).
Supporting Information Available: Experimental proce-
dures and characterization data for compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
338 J. Org. Chem. Vol. 76, No. 1, 2011