InBr3-catalyzed Friedel-Crafts addition of indoles to chiral aromatic epoxides: A facile route to enantiopure indolyl derivatives

Article abstract of DOI:10.1021/jo0256235

Aromatic optically active epoxides can be opened in a regioselective and clean way with indoles in the presence of catalytic amount of InBr3 (1 mol %). The reaction takes place with a S_N2 pathway affording the 2-aryl-2-(3′-indolyl)-ethan-l-ols with excellent enantioselectivity (ee up to 99%).

Full text of DOI:10.1021/jo0256235

SCHEME 1. Regio- a n d Ster eoselective Rin g
Op en in g of Op tica lly Active Styr en e Oxid e by
In d ole
In Br 3-Ca ta lyzed F r ied el-Cr a fts Ad d ition of
In d oles to Ch ir a l Ar om a tic Ep oxid es: A
F a cile Rou te to En a n tiop u r e In d olyl
Der iva tives
Marco Bandini, Pier Giorgio Cozzi,*
Paolo Melchiorre, and Achille Umani-Ronchi*
Dipartimento di Chimica “G. Ciamician”, Via Selmi 2,
40126 Bologna, Italy
catalytic or stoichiometric amount of Lewis acids.8 Re-
cently, however, an interesting preparation of optically
active compounds bearing aromatic systems was reported
in the literature.9 Focusing on indole-type frameworks,
an elegant catalytic asymmetric Lewis acid mediated
F-C protocol was introduced by J ørgensen et al.10
However, the F-C reaction is particularly critical with
indoles. In fact, their tendency to react with carbonyls
producing diindolyl compounds,11 significantly limited
their use in catalytic strategies. On the other hand, indole
can be added to optically active aromatic epoxides.12
Aromatic epoxides are an ideal source for diversity,
because they can be easily opened with nucleophiles13
furnishing functionally diverse compounds. However, in
the Friedel-Crafts reaction conditions, aromatic optically
active epoxides could rearrange to isomeric carbonyl
compounds or racemize.14 Herein, we report on a straight-
forward InBr3-catalyzed approach toward the preparation
of optically active indolyl derivatives in good yield and
high enantioselectivity (ee up to 99%, Scheme 1).
pgcozzi@ciam.unibo.it; umani@ciam.unibo.it
Received February 18, 2002
Abstr a ct: Aromatic optically active epoxides can be opened
in a regioselective and clean way with indoles in the presence
of catalytic amount of InBr3 (1 mol %). The reaction takes
place with a SN2 pathway affording the 2-aryl-2-(3′-indolyl)-
ethan-1-ols with excellent enantioselectivity (ee up to 99%).
The preparation of enantiopure chiral compounds for
searching biologically active molecules is becoming an
important issue for pharmaceutical industries.1 Diver-
sity,2 exploited in synthesizing arrays of compounds and
coupled with highthroughput screening methodologies,3
is helping for the fast discovery of new active compounds.
In this context, simply synthetic methodologies focused
toward the preparation of chiral optically active com-
pounds can be beneficial to the discovery of new leads.4
Indole is a key motif in many pharmacologically and
biologically active compounds5 as well as in many natural
products it belongs to the class of the alkaloids6 and a
direct synthesis of optically active indolyl derivatives is
desired. Normally, Friedel-Crafts (F-C) reactions7 are
performed in a non-enantioselective way, via the use of
Procedures for the indole ring-opening reaction of
aromatic epoxides are reported in the literature and can
be catalyzed by high pressure (10 kbar) or by the use of
SiO2.12 While the employment of high pressure requires
the use of special equipment, for the latter method,
although simple, several days were necessary in order
(6) (a) The Alkaloids; Specialist Periodical Reports; The Chemical
Society: London, 1971. (b) Saxton, J . E. Nat. Prod. Rep. 1989, 6, 1. (c)
Hesse, M. Alkaloid Chemistry; Wiley: New York, 1978. (d) Cordell, G.
A. Introduction to Alkaloids: A Biogenetic Approach; Wiley: New York,
1981. (e) Gilchrist, T. L. Heterocyclic Chemistry; Pitman: London, 1981.
(f) Pindur, A. R. J . Heterocycl. Chem. 1988, 25, 1. (g) Rainier, J . D.;
Smith, A. B., III. Tetrahedron Lett. 2000, 41, 9419. (h) Bennasar, M.-
L.; Vidal, B.; Bosch, J . J . Org. Chem. 1997, 62, 3597. (i) Amat, M.;
Hadida, S.; Pshenichnyi, G.; Bosch, J . J . Org. Chem. 1997, 62, 3158.
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p 1313.
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3, p 293.
(9) Ishii, A.; Soloshonok, V. A.; Mikami, K. J . Org. Chem. 2000, 65,
1597 and references therein.
(10) (a) Gathergood, N.; Zhuang, W.; J ørgensen, K. A. J . Am. Chem.
Soc. 2000, 122, 12517. (b) J ensen K. B.; Thorhauge, J .; Hazel, R. G.;
J ørgensen, K. A. Angew. Chem., Int. Ed. 2001, 40, 160.
(11) (a) Yadav, J . S.; Subba Reddy, B. V.; Murthy, C. V. S. R.;
Mahesh Kumar, G.; Madan, C. Synthesis 2001, 783. (b) Hao, J .;
Taktak, S.; Aikawa, K.; Yusa, Y.; Hatano, M.; Mikami, K. Synlett 2001,
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H. J . Org. Chem. 1996, 61, 984. (b) Kotsuki, H.; Nishiuchi, M.;
Kobayashi, S.; Nishizawa, H. J . Org. Chem. 1990, 55, 2969.
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123, 2687. (b) Ready, J . M.; J acobsen E. N. J . Am. Chem. Soc. 1999,
121, 6086. (c) Allen A. A.; J acobsen E. N. J . Am. Chem. Soc. 1999,
121, 4147. (d) Hansen, K. B.; Leighton, J . L.; J acobsen E. N. J . Am.
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* To whom correspondence should be addressed. Tel: +39-051-
2099509. Fax: +39-2099456.
(1) Chem. Eng. News 2001, 28, 79.
(2) (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int.
Ed. 2001, 40, 2004. (b) Brown, R. C. D. J . Chem. Soc., Perkin Trans
1988, 3293. (c) Blackbourn, C.; Albericio, F.; Kates, S. A. Drugs future
1997, 22, 1007. (d) Fruchtel, J . S.; J ung, G. Angew. Chem., Int. Ed.
Engl. 1996, 35, 17. (e) Balkenhohl, F.; Von dem Bussche-Hunnefeld,
C.; Lansky, A.; Zechel, C. Angew. Chem., Int. Ed. Engl. 1996, 35, 2288.
(f) Hermkens, P. H.; Ottenheijm, H. C. J .; Rees, D. Tetrahedron 1996,
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(3) Fenniri, H. Combinatorial Chemistry; Oxford University Press:
Oxford, 2000.
(4) (a) Smith, A. L.; Stevenson, G. I.; Lewis, S.; Patel, S.; Castro, J .
L. Biorg. Med. Chem. Lett. 2000, 10, 2693. (b) Liu, Y.; Gribble, G. W.
Tetrahedron Lett. 2000, 41, 8717. (c) Spadoni, G.; Balsamini, C.; Bedini,
A.; Diamantini, G.; Di Giacomo, B.; Tontini, A.; Tarzia, G.; Mor, M.;
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F.; Stankov, B. M. J . Med. Chem. 1998, 41, 3624. (d) Andersen, K.;
Liljefors, T.; Hyttel, J .; Perregaard, J . J . Med. Chem. 1996, 39, 3723.
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10.1021/jo0256235 CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/18/2002
5386
J . Org. Chem. 2002, 67, 5386-5389

TABLE 1. Lew is Acid Med ia ted Ad d ition of In d ole to
Styr en e Oxid e
compound 3a in 75% ee (Table 1, entry 8). The lower
enantiomeric excess could be ascribed to the attack of
indole via an SN1-type mechanism. For general interest,
it should be noted that BF3 was an effective promoter
even in low catalytic amount (1 mol %, entry 6, Table 1).
However, in this case the reaction suffered of scarce
regioselectivity. In fact, after chromatographic separa-
tion, the regioisomer 1-(1H-indol-3-yl)-2-phenylethanol,
derived from the nucleophilic attack of indole to the less
substituted carbon, was isolated in 12% yield.
In general, aliphatic epoxides were not suitable sub-
strates for our reaction conditions, giving indolyl alcohols
in low isolated yields and with negligible regiocontrol.
For example, when the reaction of 2a with (S)-(-)-
propylene oxide in the presence of 10 mol % InBr3 was
performed, two regioisomers were isolated in 1:1 ratio
and in 35% yield.
The absolute configuration of the product obtained by
the attack of 2a to (R)-(+)-styrene oxide was assigned
by comparison with the chiral HPLC analysis previously
reported in the literature for the compound 3a .18 The
generality and the scope of this Lewis acid catalyzed
reaction is summarized by the data reported in Table 2.
Substituted indoles were reacted with a few representa-
tive optically active aromatic epoxides (Scheme 2).19 In
general, indoles bearing electron-donating groups fur-
nished higher reaction rates, affording the corresponding
alcohols in moderate to good yields (entries 4 and 6, Table
2). On the other hand, electron-withdrawing groups
significantly decreased the reactivity of indoles in this
Friedel-Crafts process. In fact, when 5-nitro- and 5-cy-
anoindole were used as nucleophiles, low yields (24-41%)
and partial racemization (ee ) 70%) were observed
(entries 2 and 5, Table 2). The dropped ee of the
compound 3b can be imputable to the extremely slow
reaction rate (96 h). With different aromatic optically
active epoxides such as (R)-(+)-3-chlorostyrene oxide 4
and (1R,2S)-1,2-dihydronaphthalene oxide 5,20 remark-
able enantioselectivity was always recorded (ee up to
99%, entries 9 and 10, Table 2) showing the effectiveness
of InBr3 in the synthesis of indolyl derivatives in enan-
tiomerically pure form. It is worthy to note that the
presence of strongly coordinating groups in this Lewis
acid catalyzed reaction is well tolerated. Indium salts and
in particular Lewis acid catalyzed reactions promoted by
InBr3 shown this interesting feature.16 This properties
can be understood taking into account the low hetero-
philcity exhibited by indium species.14
Lewis acid
(mol %)
entrya
yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
Cu(OTf)2 (10)
Zn(OTf)2 (10)
Sc(OTf)3 (10)
Sc(OTf)3 (1)
ZnI2 (10)
BF3‚OEt2 (1)
InCl3 (10)
InBr3 (10)
InBr3 (5)
33d
29
54
52
57
54
55
60
64
70f
20g
e
69
99
99
90
99
99
75
99
99
e
10
11
InBr3 (1)
InBr3 (1)
a
All the reactions were carried out in anhydrous CH2Cl2 at 0
b
°C for 4 h unless otherwise specified. The chemical yields are
given on the isolated product after chromatographic purification.
c The enantiomeric excess of the indolyl alcohol was determined
by chiral HPLC analysis (column: Chiralcel OD). Racemic 3a was
d
obtained starting from (()-1a . A 1:1 mixture of regioisomers was
observed. e Not determined. f The reaction was performed at room
temperature. g The reaction was carried out in THF (isolated yield
after 5 days).
to obtain good conversions. In fact, it was reported that
indole 2a adsorbed with styrene oxide 1 on silica gel
allowed to react in 1 week affording the 2-(1H-indol-3-
yl)-2-phenylethanol (3a ) in 88% yield. Most importantly,
the reported methodologies gave the desired (R)-(-)-3a
in 92 and 88% ee, respectively. In such conditions, a slight
racemization of the product was observed due to the
partial formation of benzylic carbocations.
In the course of our investigations toward the develop-
ment of new reactions promoted by indium salts,15 we
were pleased to discovered that anhydrous InBr3 was able
to promote the addition of indole16 2a to (R)-(+)-styrene
oxide in mild experimental conditions (cat. 1 mol %, room
temperature, 8-18 h). Although other Lewis acids were
able to perform the attack of indole to styrene oxide
(Scheme 1), indium tribromide was the unique Lewis
acids that allowed low loading of catalyst (1 mol %),
furnishing clean reactions and the highest chemical
yields (entries 9 and 10, Table 1).17 For instance, the use
of Zn(OTf)2 as the Lewis acid furnished the product in
low chemical and optical yields (yield 29%, ee 70%). The
partial racemization must be ascribed to an SN1-type
mechanism. Only Sc(OTf)3-catalyzed the ring-opening
reaction with comparable stereoselection to indium tri-
bromide (entries 3, 4 and 9, 10, Table 1). However, in
terms of activity, functional group tolerance and regio/
stereoselectivity, InBr3 was significantly superior and the
catalytic system was investigated further.
Enantiomeric excesses were established by chiral
HPLC analysis (Chiralcel OD column), and the absolute
configuration of the indolyl compounds 3b-j was as-
signed by analogy considering the correlation of elution
order made for 3a .
The loading of the catalyst (optimal 1 mol %) appeared
to be crucial for the effectiveness of the protocol. In fact,
initial attempts to carry out the indium-mediated process
in the presence of 10 mol % catalyst furnished the
(18) Carrying out the ring-opening reaction of 1a with 2a in the
presence of SiO2 (500 mg, mesh 270 nm), the indolyl alcohol 3a was
isolated in 86% ee (see ref 12). However, although the elution order
(chiral HPLC) of (R)-3a and (S)-3a was in agreement with the
literature, the measured optical rotation value shown opposite sign:
+13.6 (c 1.3, CHCl3) [lit. -0.435 (c 0.46, CHCl3)].
(19) Aromatic optically active epoxides can be easily obtained by [Co-
(Salen)] mediated hydrolytic kinetic resolution of the corresponding
racemic epoxides; see: Tokunaga, M.; Larrow, J . F.; Kakiuchi, F.;
J acobsen, E. N. Science 1997, 277, 936.
(15) Bandini, M.; Cozzi, P. G.; Melchiorre, P.; Umani-Ronchi, A.
Tetrahedron Lett. 2001, 42, 3041.
(16) Several aromatic compounds were considered as nucleophiles
for the F-C reaction such as pyrroles, thiophenes, and furans.
However, due to the instability of the F-C products (pyrroles) and
due to the decomposition of the aromatic epoxides (thiophenes and
furans), unclear reaction mixtures were always observed.
(17) No appreciable formation of â-bromohydrines was observed on
the crude reaction mixtures.
(20) Bellucci, M. C.; Bergamini, A.; Cozzi, P. G.; Papa, A.; Tagliavini,
E.; Umani-Ronchi, A. Tetrahedron: Asymmetry 1997, 8, 859.
J . Org. Chem, Vol. 67, No. 15, 2002 5387

TABLE 2. Ad d ition of In d oles to Ar om a tic Ep oxid es
SCHEME 2. Rea ction of Su bstitu ted In d oles w ith
Ar om a tic Ep oxid es Ca ta lyzed by In Br 3
a
Ca ta lyzed by In Br 3
In summary, we have described a new direct protocol
for the preparation of enantiomerically pure indolyl
derivatives via a Friedel-Crafts-catalyzed ring opening
of optically active aromatic epoxides. The use of the InBr3
as catalyst besides to guarantee a general tolerance
toward the presence of different functional groups on the
indole motif, allows the isolation of the indolyl alcohols
in excellent ees and good chemical yields via a rigorous
SN2 pathway. Although Lewis acids are normally respon-
sible for the rearrangement of aromatic epoxides to the
corresponding carbonyls, the mild Lewis acid character
exploited by InBr3 allowed the isolation of the desired
compounds in high yields and without significant race-
mization.
Exp er im en ta l Section
Gen er a l Meth od s. Chemical shifts of the 1H NMR spectra
are reported in δ (ppm) with respect to TMS, and coupling
constants J were 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 ppm from tetramethylsilane with the solvent as the
internal standard (deuteriochloroform, δ ) 77.0 ppm; deuteri-
odimethyl sulfoxide, δ ) 39.0 ppm). GC-MS spectra were taken
by EI ionization at 70 eV with GC injection. They are reported
as m/z (relative intensity). Column flash chromatographies were
run over 270-400 mesh silica gel. Elemental analyses were
carried out by using a CHNOS analyzer. IR analyses were
performed with an FT-IR spectrophotometer. IR spectra of neat
compounds are expressed by wavenumber (cm-1). Αnalytical
high-performance liquid chromatograph (HPLC) was performed
on a liquid chromatograph equipped with a variable-wavelength
UV detector (deuterium lamp 190-600 nm), using a Daicel
Chiralcel OD column (0.46 cm i.d. × 25 cm) (Daicel Inc.). HPLC-
grade 2-propanol and hexane were used as the eluting solvents.
Optical rotations were determined in a 1 mL cell with a path
length of 10 mm (NaD line). The melting points were uncorrected.
All the commercially available epoxides and indoles were utilized
as received.
Typ ica l Exp er im en ta l P r oced u r e for In Br 3-Med ia ted
Rin g-Op en in g of Ep oxid es. A flamed two-necked flask was
charged, under a nitrogen atmosphere, with 3 mL of anhydrous
CH2Cl2, InBr3 (5.5 mg, 0.015 mmol), and 2.25 mmol of indole.
The mixture was stirred for a few minutes, and then 1.5 mmol
of epoxide was added. This clear solution was then stirred at
room temperature until the disappearance of the epoxide (8-
16 h, checked by GC). Then the reaction was quenched with a
saturated solution of NaHCO3 and extracted with Et2O. The
organic portions were dried (Na2SO4) and concentrated under
reduced pressure, and the crude product mixture was purified
by flash chromatography.
a
All the reactions were carried out in anhydrous CH2Cl2 at
room temperature, employing 1 mol % of InBr3 for 8-16 h unless
b
otherwise specified. The chemical yields are given on the isolated
product after chromatographic purification. c The enatiomeric
excesses were determined by HPLC analysis with chiral column
(Chiralcel OD). Racemic products were obtained performing the
d
reaction on racemic epoxides with InBr3. The reaction was
performed using 10 mol % of InBr3 at room temperature for 16 h.
e The reaction was performed using 10 mol % of InBr3 at room
temperature for 96 h. f The enantiomeric excess was not evaluated.
g
The optically active epoxide (1R,2S)-5 was prepared using the
asymmetric J acobsen epoxidation in 83% ee.20
5388 J . Org. Chem., Vol. 67, No. 15, 2002

Su p p or tin g In for m a tion Ava ila ble: Analytical and spec-
tral characterization data for the indole derivatives 3a -j. 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-
oni”) and by Bologna University (Funds for selected
research Topics).
J O0256235
J . Org. Chem, Vol. 67, No. 15, 2002 5389