New versatile route to the synthesis of tetrahydro-β-carbolines and tetrahydro-pyrano[3,4-b]indoles via an intramolecular Michael addition catalyzed by InBr3

Article abstract of DOI:10.1021/jo034466m

A simple multistep synthetic strategy to 4-sub-stituted 1,2,3,4-tetrahydro-β-carboline and 1,3,4,9-tetrahydro-pyrano[3,4-b]indole derivatives starting from commercially available indole 2-carboxylic acid (5) is described. The final intramolecular Michael addition promoted by catalytic amount of InBr3 (5-10 mol %) provided the expected polycyclic compounds in excellent yields (up to 97%) both in anhydrous organic and aqueous media.

Full text of DOI:10.1021/jo034466m

New Ver sa tile Rou te to th e Syn th esis of
Tetr a h yd r o-â-ca r bolin es a n d
Tetr a h yd r o-p yr a n o[3,4-b]in d oles via a n
In tr a m olecu la r Mich a el Ad d ition Ca ta lyzed
by In Br 3
Marianna Agnusdei, Marco Bandini,*
Alfonso Melloni, and Achille Umani-Ronchi*
F IGURE 1. Examples of C-4-substituted indolyl-based anal-
gesic agents.
Dipartimento di Chimica “G. Ciamician”, Via Selmi 2,
40126 Bologna, Italy
SCHEME 1. Use of In Br 3 in P r om otin g
F r ied el-Cr a fts Alk yla tion of In d oles
bandini@ciam.unibo.it; umani@ciam.unibo.it
Received April 13, 2003
Abstr a ct: A simple multistep synthetic strategy to 4-sub-
stituted 1,2,3,4-tetrahydro-â-carboline and 1,3,4,9-tetrahy-
dro-pyrano[3,4-b]indole derivatives starting from commer-
cially available indole 2-carboxylic acid (5) is described. The
final intramolecular Michael addition promoted by catalytic
amount of InBr3 (5-10 mol %) provided the expected
polycyclic compounds in excellent yields (up to 97%) both in
anhydrous organic and aqueous media.
well. Also in this case, the presence of substituents in
the C-4 position is crucial to guarantee a high level of
biological activity.4,5
In this contribution, we wish to describe our prelimi-
nary findings regarding a new valuable synthetic mul-
tistep alternative for the preparation of 4-functionalized
tetrahydro-â-carbolines and their tetrahydro-pyranyl
analogues by the use of inexpensive and commercially
available indole 2-carboxylic acid 5 as the starting
material.
We are currently engaged in developing catalytic
Friedel-Crafts (FC) alkylation reactions of indoles with
electrophilic carbon synthons in the presence of low
loading of anhydrous InBr3. In particular, due to the
remarkable tolerance of indium salts toward water and
strongly coordinating functional groups,6 remarkable
findings have been obtained in the 1-4 addition of
indoles to arylcrotyl ketones,7a nitro alkenes,7b and indolyl
enones7c and in the stereoselective ring-opening reaction
of enantiomerically pure aryl epoxides (Scheme 1).7d
In light of these results, we reasoned that a valuable
way to construct the carboline skeleton could involve a
Lewis acid-catalyzed intramolecular cyclization of the
appropriate ꢀ-(2′-indolyl)-R,â-unsaturated carbonyl pre-
cursor 3 (Scheme 2). To the best of our knowledge, this
kind of intramolecular ring-closing approach has never
been considered in the synthesis of polycyclic indolyl
alkaloids.
The â-carboline skeleton is frequently encountered in
pharmacology due to its activity in the CNS (central
nervous system) at serotonin receptors. In particular, it
shows prominent biological properties at the benzodi-
azepine receptor (BzR).1 Here, the specific interactions
of indolyl compounds containing the â-carboline frame-
work with BzR are strongly influenced by the presence
of substituents on the polycyclic central unit. Cook and
co-workers2 reported that the introduction of a meth-
oxymethyl arm at the C-4 position (ZK 93423, 1, Figure
1) remarkably amplifies the agonist activity of such
compounds toward BzR. Common precursors of â-carbo-
line derivatives are the 1,2,3,9-tetrahydro-â-carbolines
(THBCs) that can be easily oxidized to the aromatic
systems.2b
Although the construction of THBCs with substitution
in positions 1-3 can be conveniently accomplished by
adopting the Pictet-Spengler cyclization,1 obtaining
4-functionalized tetrahydro-â-carbolines still remains
more challenging, and multistep procedures are normally
required. In this context, Busacca and co-workers re-
cently described a useful approach for the preparation
of 4-aryl, 4-alkyl, and 4-acetyl carboline derivatives via
Pd-mediated cross-coupling of arylboronic acids and
Grignard reagents to the 4-trifloxy-â-carboline.3
It is noteworthy that, although intramolecular FC
cycloalkylations are well documented,8 they usually suffer
from moderate yields and lack of regioselectivity and
Analogously, 1,3,4,9-tetrahydro-4-functionalized-pyrano-
[3,4-b]indoles are well-known potent analgesic agents and
some 1-acetic acid derivatives, such as the pemedolac 2
(Figure 1), were tested as an antiinflammatory agent as
(4) Mobilio, D.; Humber, L. G.; Katz, A. H.; Demerson, C. A.; Hughes,
P.; Brigance, R.; Conway, K.; Shah, U.; Williams, G.; Labbadia, F.; De
Lange, B.; Asselin, A.; Schmid, J .; Newburger, J .; J ensen, N. P.;
Weichman, B. M.; Chau, T.; Neuman, G.; Wood, D. D.; Van Engen, D.;
Taylor, N. J . Med. Chem. 1988, 31, 2211.
(5) Humber, L. G. Med. Res. Rev. 1987, 7, 1.
* Corresponding author. Tel: +39-051-2099509. Fax: +39-2099456.
(1) Cox, E. D.; Cook, J . M. Chem. Rev. 1995, 95, 1797.
(2) (a) Hollinshead, S. P.; Trudell, M. L.; Skolnick, P.; Cook, J . M.
J . Med. Chem. 1990, 33, 1062. (b) Cox, E. D.; Diaz-Harauzo, H.; Huang,
Q.; Reddy, M. S.; Ma, C.; Harris, B.; McKernan, R.; Skolnick, P.; Cook,
J . M. J . Med. Chem. 1998, 41, 2537.
(6) (a) Ranu, B. C. Eur. J . Org. Chem. 2000, 2347. (b) Chauhan, K.
K.; Frost, C. G. J . Chem. Soc., Perkin Trans. 1 2000, 3015.
(7) (a) Bandini, M.; Cozzi, P. G.; Giacomini, M.; Melchiorre, P.; Selva,
S.; Umani-Ronchi, A. J . Org. Chem. 2002, 67, 3700. (b) Bandini, M.;
Fagioli, M.; Melchiorre, P.; Melloni, A.; Umani-Ronchi, A. Synthesis
2002, 1110. (c) Bandini, M.; Fagioli, M.; Melloni, A.; Umani-Ronchi,
A. Synthesis 2003, 397. (d) Bandini, M.; Cozzi, P. G.; Melchiorre, P.;
Umani-Ronchi, A. J . Org. Chem. 2002, 67, 5386.
(3) Busacca, C. A.; Eriksson, M. C.; Dong, Y.; Prokopowicz, A. S.;
Salvagno, A. M.; Tschantz, M. A. J . Org. Chem. 1999, 64, 4564.
10.1021/jo034466m CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/09/2003
7126
J . Org. Chem. 2003, 68, 7126-7129

SCHEME 2. Retr osyn th etic Ap p r oa ch for th e
Con str u ction of P olycyclic In d olyl Alk a loid s
SCHEME 4
SCHEME 3
SCHEME 5. In tr a m olecu la r Cycliza tion Ca ta lyzed
by In Br 3 for th e Syn th esis of Tetr a h yd r o-p yr a n yl
11
normally great amounts of Lewis acids are needed. On
the contrary, InBr3 was able to promote the present
intramolecular FC-Michael type reaction in mild experi-
mental conditions (rt, organic and aqueous media) in low
catalytic amount (5-10 mol %) with high yield.
one-pot two-step procedure avoided the manipulation of
the corresponding indolyl-aldehyde that was difficult to
handle due to its high sensitivity toward oxidation and
thermal instability.
Syn th esis of 4-Su bstitu ted 1,3,4,9-Tetr a h yd r o-
p yr a n o[3,4-b]in d ole. At the beginning of our study, we
considered the preparation of 4-substituted 1,3,4,9-tet-
rahydro-pyrano[3,4-b]indoles. To this aim, we first took
into account the retrosynthetic approach that allowed the
synthesis of 4 (Scheme 2). Starting with multigram
quantities of indole 2-carboxylic acid (5), after esterifi-
cation of the carboxylic moiety with MeOH/H2SO4 (cat.)
at reflux, the protection of NH proton was performed by
methylation of the methyl ester (NaH/MeI/THF, 0 °Cfrt)
to give 6 in 91% overall chemical yield.9 Finally, reduction
of the ester moiety by LAH (THF, 0 °C, 91% yield)10 and
subsequent allylation of 7 (NaH/allyl bromide/THF, 0
°Cfrt) led to the isolation of the desired allyl ether 8 in
moderate yield 56% (Scheme 3).
Allyl ether 8 was then easily transformed in the
racemic diol 9 (71% yield) via the described achiral
variant of the AD reaction of Sharpless11 in the presence
of a catalytic amount (5 mol %) of K2OsO2(OH)4 and
DABCO as the ligand.12 Finally, the desired indolyl enone
4 was synthesized solely as the (E)-isomer, by one-pot
oxidative cleavage/Wittig reaction of the glycol 9 (41%
yield, E/ Z > 98%).13 For this purpose, 9 was treated with
NaIO4 on SiO2 (20% weight) in CH2Cl2 for 20 h in the
presence of the preformed ylide 10a (Scheme 4).14 The
Initial attempts for the intramolecular cyclization were
performed with 10 mol % InBr3, and 11 was isolated in
75% yield (Scheme 5). Surprisingly, by carrying out the
same reaction with a lower catalytic loading (5 mol %),
the reaction was complete in a comparable reaction time,
but the chemical isolated yield was significantly higher
(97%). This result can be partially ascribed both to the
concomitant intermolecular Michael addition and to
undesired degrading processes of the R,â-unsaturated
indolyl ketone observed with 10 mol % catalyst loading.
Syn th esis of 4-Su bstitu ted Tetr a h yd r o-â-ca r bo-
lin es. With the aim to optimize an analogous strategy
for the synthesis of tetrahydro-â-carbolines, also starting
from indole 2-carboxylic acid (5), we first prepared the
corresponding indole 2-carboxy aldehyde 12 in two steps
and in high isolated yield (91%).15 Then, the N,N-diBoc-
indolyl derivative 14b was easily obtained in three steps
without intermediate purification (Scheme 6). The opti-
mized protocol involved the formation of the imine 13 by
condensation of 12 with allylamine in toluene at reflux
in the presence of MgSO4, and then the reduction of 13
to the corresponding allylamine 14a was accomplished
with an excess of NaBH4 in MeOH. Finally, the necessary
protection of the nitrogen atoms was performed in dry
CH2Cl2 with (Boc)2O and Et3N. The overall yield of the
last three steps was 65%.
(8) (a) Taylor, S. K.; May, S. A.; Stansby, E. S. J . Org. Chem. 1996,
61, 1, 2075. (b) Nagumo, S.; Miyoshi, I.; Akita, H.; Kawahara, N.
Tetrahedron Lett. 2002, 43, 2223 and references therein. (c) Nagumo,
S.; Miyoshi, I.; Akita, H.; Kawahara, N. Tetrahedron Lett. 2002, 43,
2223.
Trying to adopt the same experimental conditions
utilized for the pyranyl substrates, we discovered that
the one-pot oxidative cleavage/Wittig reaction of 15 did
not afford the desired indolyl enones 17 but the inter-
mediate aldehyde 16, which was isolable in pure form
(9) Protection of the NH moiety by the introduction of an alkyl group
was required to guarantee the subsequent chemoselective allylation
of alcohol 7.
(10) Faul, M. M.; Winneroski, L. L. Tetrahedron Lett. 1997, 38, 4749.
(11) Kolb, H. C.; VanNieuwenhze; M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483.
(12) Oishi, T.; Dirama, M. Tetrahedron Lett. 1992, 33, 639.
(13) Dunlap, N. K.; Mergo, W.; J ones, J . M.; Carrick, J . D. Tetra-
hedron Lett. 2002, 43, 3923.
(15) Suzuki, H.; Unemoto, M.; Hagiwara, M.; Ohyama, T.; Yokoya-
(14) Font, J .; De March, P. Tetrahedron 1981, 37, 2391.
ma, Y.; Murakami, Y. J . Chem. Soc. Perkin Trans. 1 1999, 1717.
J . Org. Chem, Vol. 68, No. 18, 2003 7127

SCHEME 6
tions are normally identified as moisture-sensitive pro-
cesses. On the other hand, due to the large number of
potential advantages of replacing organic solvents with
water (safety, costs, environmental factors), growing
interest has continuously been devoted toward the de-
velopment of water tolerant organic transformations.16
In(III) salts that are indicated as “Borderline” Lewis acids
in aqueous conditions and have been frequently utilized
to promote organic transformations in the presence of
water.17 On the basis of these considerations, we tested
the effectiveness of InBr3 (10 mol %) in promoting the
intra-FC reaction of 17b in aqueous/cosolvent system
(H2O/THF 9:1, 0.017 M). Under these conditions, the
reaction effectively occurred at room temperature, af-
fording 18a in 70% in 12 h reaction time (Scheme 8b).
In summary, this paper describes a new and efficient
protocol for the synthesis of a variety of 1,3,4,9-tetrahy-
dro-pyrano[3,4-b]indoles and 1,2,3,4-tetrahydro-â-carbo-
lines. This strategy, starting from commercially available
and inexpensive indole-2-carboxylic acid, uses as the key
final step an intramolecular cyclization by Michael ad-
dition utilizing low catalytic loadings of InBr3. This
approach furnished good ring-closing results also by
carrying out final cyclization in aqueous media. Studies
addressed toward the optimization of a stereoselective
version of the present synthetic strategy are under
investigation in our laboratories.
SCHEME 7
SCHEME 8. In tr a m olecu la r Cycliza tion Ca ta lyzed
by In Br 3 for th e Syn th esis of
Tetr a h yd r o-â-ca r bolin es 18a ,b
Exp er im en ta l Section
Gen er a l. Chemical shifts of the 1H NMR spectra are given
in δ parts per million with respect to TMS, and coupling
constants J are measured in Hz. Data are reported as follows:
chemical shifts, multiplicity (s ) singlet, d ) douplet, t ) triplet,
q ) quartet, br ) broad, m ) multiplet). 13C NMR spectra were
recorded with complete proton decoupling. Chemical shifts are
reported in parts per million from tetramethylsilane with the
solvent as the internal standard (deuteriochloroform: δ ) 77.0
ppm). Flash column chromatographies were run over 270-400
mesh silica gel. Elemental analyses were carried out by using a
CHNOS analyzer. IR analyses were performed with a FT-IR
spectrophotometer. IR spectra of neat compounds are expressed
by wavenumber (cm-1). The melting points were uncorrected.
All the commercials were utilized as received.
Typ ica l Exp er im en ta l P r oced u r e for th e Ca ta lytic In -
tr a m olecu la r Mich a el Rea ction of 4 Med ia ted by In Br 3. A
flamed two-necked flask was charged, under a nitrogen atmo-
sphere, with 6 mL of anhydrous CH2Cl2, InBr3 (1.8 mg, 0.005
mmol), and 31 mg (0.1 mmol) of indolyl enone 4. The color of
the mixture immediately turned from pale yellow to deep red.
After 30 min of stirring at room temperature, the initial enone
completely disappeared (checked by TLC). The reaction was then
quenched with a saturated solution of NaHCO3 (3 mL) and
extracted with Et2O (3 × 3 mL). The organic phases were
combined, dried over Na2SO4, and concentrated under reduced
pressure, and the crude mixture was purified by flash chroma-
tography.
after flash chromatography (overall yield of two steps was
65% on the basis on 14b). The Wittig reaction was then
performed in dry toluene at reflux with ylides 10a ,b,
affording the desired products 17a ,b in 90 and 96%
yields, respectively (Scheme 7).
Furthermore, we screened several reaction conditions
for the indium-catalyzed intramolecular cyclization of
18a ,b. We found that in the presence of 10 mol % indium
tribromide, the enone 17b (InBr3, 10 mol %) underwent
cyclization, affording the protected 1,2,3,4-tetrahydro-â-
carboline 18b in high yield (85%, Scheme 8a). The lower
yield recorded with 18b in comparison to 11 (97%, 5 mol
% InBr3) could be ascribed to the different type of
substituents present on the indolyl nitrogens of the two
precursors 4 and 17b. In fact, while the electron-donating
methyl group increases the nucleophilicity of the indole
ring, the electron-withdrawing tBu-carbonate function
present in 17b reduces the reactivity of the indolyl
system toward the intramolecular FC transformation.
2-(9-Meth yl-1,3,4,9-tetr a h yd r o-p yr a n o[3,4-b]in d ol-4-yl)-
1-p h en yl-eth a n on e (11). Yellow oil. Yield: 97%. MW ) 305.37.
Rf: 0.3 (cyclohexane/Et2O 60:40). 1H NMR (200 MHz, CDCl3):
δ 8.0 (dd, J 1 ) 1.4 Hz, J 2 ) 8.0 Hz, 2 H); 7.42-7.62 (m, 4 H);
7.08-7.4 (m, 3 H); 4.90-4.97 (m, 1 H); 4.80 (dd, J 1 ) 1.4 Hz, J 2
) 14.6 Hz, 1 H); 4.12 (dd, J 1 ) 1.8 Hz, J 2 ) 11.4 Hz, 1 H); 3.93
(dd, J 1 ) 3.0 Hz, J 2 ) 8.8 Hz, 1 H); 3.70-3.80 (m, 1 H); 3.63 (s,
Organic reactions that involve Lewis acid catalysis
must be usually carried out under strictly anhydrous
conditions to prevent the deactivation/degradation of the
catalyst. In this context, Lewis acid-promoted FC reac-
(16) For recent reviews in this field, see: (a) Lindstro¨m, U. M. Chem.
Rev. 2002, 102, 2751. (b) Manabe, K.; Kobayashi, S. Chem. Eur. J .
2002, 8, 4094.
(17) Kobayashi, S.; Manabe, K. Acc. Chem. Res. 2002, 35, 209.
7128 J . Org. Chem., Vol. 68, No. 18, 2003

3 H); 3.47-3.52 (m, 2 H). 13C NMR (75 MHz, CDCl3): δ 190.4;
137.2; 133.3; 133.1; 128.5; 128.1; 121.3; 119.3; 118.1; 109.6; 108.9;
69.6; 63.2; 41.8; 30.9; 29.7; 29.5; 28.7. IR (neat): 3045; 2926; 2846;
1739; 1666; 1600; 1461; 1374; 1242; 1082; 1036; 738 cm-1. Anal.
Calcd for (C20H19NO2): C, 78.66; H, 6.27; N, 4.59. Found: C,
78.62; H, 6.22; N, 4.58.
oni”) and by Bologna University (Funds for Selected
Research Topics).
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and analytical and spectral characterization data for
all the indole compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
Ack n ow led gm en t. This work was financially sup-
ported by MURST-Rome (Progetto Nazionale “Stereo-
selezione in Sintesi Organica. Metodologie ed Applicazi-
J O034466M
J . Org. Chem, Vol. 68, No. 18, 2003 7129