Catalytic enantioselective Friedel-Crafts alkylation of indoles with nitroalkenes by using a simple thiourea organocatalyst

Article abstract of DOI:10.1002/anie.200500227

(Chemical Equation Presented) A facile access to optically active 2-indolyl-1-nitro derivatives, which can be easily transformed into highly valuable compounds such as tryptamines and 1,2,3,4-tetrahydro-β-carbolines, is provided by the first catalytic ena

Full text of DOI:10.1002/anie.200500227

Communications
Asymmetric Synthesis
for many enantioselective transformations.[10] Accordingly, we
have recently reported[11] the Friedel–Crafts alkylation of
aromatic and heteroaromatic compounds with nitroalkenes,
which are activated by the bidentate hydrogen-bonding motif
present in the bis[3,5-bis(trifluoromethyl)phenyl]thiourea
first developed by Schreiner for the Diels–Alder reaction.[9b,c]
Herein we present our results on the use of simply
obtainable thiourea organocatalysts for the first catalytic
enantioselective Friedel–Crafts alkylation of indoles 2 with
nitroalkenes 3 (Scheme 1). The indole skeleton is considered
DOI: 10.1002/anie.200500227
Catalytic Enantioselective Friedel–Crafts
Alkylation of Indoles with Nitroalkenes by Using
a Simple Thiourea Organocatalyst**
Raquel P. Herrera, Valentina Sgarzani, Luca Bernardi,
and Alfredo Ricci*
The addition of aromatic substrates to electron-deficient
alkenes, which in many respects may be considered a Friedel–
Crafts type alkylation, is a key reaction in synthetic organic
[1]
À
chemistry for the formation of new C C bonds. Catalytic,
enantioselective versions of this fundamental transformation
have been reported,[2] which use metal-based chiral complex
catalysts[3] or an imidazolidinone organocatalyst.[4] Both
catalysts are capable of activating a,b-unsaturated carbonyl
compounds, through a Lewis acid/Lewis base interaction with
the carbonyl moiety in the former case, or through the
formation of an iminium ion intermediate in the latter case. In
sharp contrast with these remarkable achievements in the
enantioselective Friedel–Crafts alkylation of aromatic sub-
strates with a,b-unsaturated carbonyl compounds, to the best
of our knowledge there are no reports in which nitroalkenes
are employed. Nevertheless nitroalkenes are very attractive
Michael acceptors,[5] since the nitro moiety is a strong
electron-withdrawing group[6] that can be readily transformed
into a range of different functionalities.[7]
The double hydrogen-bonding motif is becoming a power-
ful tool in organocatalysis for the activation of carbonyl
groups and related compounds through weak hydrogen-bond
interactions.[8] Considering the various molecular scaffolds
that have proved effective as bidentate hydrogen-bond
donors, urea- and thiourea-derived catalysts are certainly
amongst the most competent structures,[9] and these are useful
Scheme 1. Addition of indole 2 to trans-b-nitrostyrene 3 to give access
to optically active 2-indolyl-1-nitro derivatives 4.
to be one of the “privileged” structures in pharmaceutical
chemistry,[4b,12] and the present method provides an easy and
practical access to optically active 2-indolyl-1-nitro deriva-
tives 4. Taking into consideration the synthetic versatility of
the nitro group, these compounds are useful intermediates for
the synthesis of molecules of biological interest, such as
tryptamines[13] and 1,2,3,4-tetrahydro-b-carbolines,[14] con-
taining the indole framework in their structures.
The addition of indole 2a to trans-b-nitrostyrene 3a was
used as the test reaction to explore the feasibility of the
enantioselective Friedel–Crafts alkylation of indoles with
nitroalkenes catalyzed by chiral thiourea- and urea-based
derivatives. Besides the known C2-symmetric bis-thiourea
1a,[10c] we prepared and screened catalysts 1b–e, which were
easily obtained in one step and in nearly quantitative yields
from the coupling reaction between 3,5-bis(trifluoromethyl)-
phenyl isothiocyanate or isocyanate and the corresponding
amino alcohols, both of which are commercially available. All
[*]V. Sgarzani, Dr. L. Bernardi, Prof. A. Ricci
Dipartimento di Chimica Organica “A. Mangini”
Università di Bologna
Viale Risorgimento 4, 40136, Bologna (Italy)
Fax: (+39)051-209-3654
E-mail: ricci@ms.fci.unibo.it
Dr. R. P. Herrera[+]
Dpto Química Orgµnica
Universidad de Alicante
Apdo 99, 03080-Alicante (Spain)
[+]Current address:
Dipartimento di Chimica Organica “A. Mangini”
Università di Bologna
Viale Risorgimento 4, 40136, Bologna (Italy)
[**]We acknowledge financial support by the “Progetti FIRB”, by the
National Project “Stereoselezione in Sintesi Organica Metodologie
ed Applicazioni, 2003”, and by the EC-RTN project “Design,
Analysis and Computation for Catalytic Organic Reactions”,
contract HPRN-CT-2001-00172.
four thiourea-based organocatalysts 1a–d were able to
increase the reactivity of trans-b-nitrostyrene 3a in the
Friedel–Crafts alkylation reaction with indole 2a, performed
at room temperature in toluene (Table 1, entries 2–5), with
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
6576
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Chemie
Table 1: Catalytic enantioselective Friedel–Crafts reaction of indole 2a
with trans-b-nitrostyrene 3a in the presence of catalysts 1a–e under
different reaction conditions.[a]
atures, furnishing the corresponding derivatives 4b and 4c in
satisfactory yields and enantioselectivities at À458C (Table 2,
entries 2 and 3). Unfortunately, an electron-withdrawing
substituent such as chlorine in the 5-position of the indole
ring in 3d caused a considerable decrease in the yield of 4d,
though the enantioselectivity was only moderately lowered
(Table 2, entry 4). The generality of the reaction was further
demonstrated by variation of the nitroalkene partner. Nitro-
alkenes 3b and 3c, bearing heteroaromatic groups, reacted
smoothly with indole 2a affording the corresponding products
4e and 4 f in good yields and moderate enantioselectivities
(Table 2, entries 5 and 6). Finally we tested nitroalkenes
bearing aliphatic side chains such as 3d and 3e, and both gave
good results in terms of enantioselectivity as the expected 2-
indolyl-1-nitro derivatives 4g and 4h were produced in 83%
and 81% ee, respectively (Table 2, entries 7 and 8), although
the yield of the reaction turned out to be rather poor in the
case of the more hindered isopropyl-substituted nitroalkene
3e.[16]
[b]
Entry Catalyst Solvent T [8C] t [h]Conversion [%]
ee [%][c]
1
2
3
4
5
6
7
8
9
–
toluene
toluene
toluene
toluene
toluene
toluene
THF
20
20
20
20
20
20
20
20
À24
65
64
64
45
17
40
63
41
–
7
1a
1b
1c
1d
1e
1d
1d
1d
13
13
35
25
27
48
85
60 >95
118
110
66 >95
72 92
23
74
CH2Cl2
CH2Cl2
[a]Experimental conditions: to a solution of trans-b-nitrostyrene 3a
(0.1 mmol) and catalyst 1 (0.02 mmol) in a solvent (100 mL), indole 2a
(0.15 mmol) was added. After the stated reaction time, the product was
purified by preparative TLC. [b]Determined by 1H NMR spectroscopy of
the crude reaction mixture. [c]Determined by chiral stationary phase
HPLC (See Supporting Information).
The high synthetic potential of the present asymmetric
transformation was then demonstrated by the straightforward
conversion of the optically active product 4a into highly
valuable compounds such as tryptamine 5 and 1,2,3,4-
tetrahydro-b-carboline 7. As shown in Scheme 2, reduction
respect to the noncatalyzed reaction
(Table 1, entry 1). However, only catalyst
1d, obtained from 3,5-bis(trifluoromethyl)-
phenyl isothiocyanate and (1R,2S)-cis-1-
amino-2-indanol, showed a moderate yet
promising asymmetric induction, as the
product 4a was produced in 35% ee
(Table 1, entry 5). Catalyst 1d was also the
most active in terms of conversion, the
reaction being complete in less than 60 h; as
predicted,[9c] the corresponding urea deriv-
ative 1e gave much poorer conversion and
lower enantioselectivity (Table 1, entry 6).
We found that ethereal solvents such as
THF had a negative influence on the
activity of the catalyst 1d (Table 1,
entry 7), whereas the use of CH2Cl2 led to
a slight improvement in the enantioselec-
tivity, giving 4a in 48% ee (Table 1, entry 8).
Finally, we were pleased to find that cooling
the reaction mixture to À248C had a
remarkable positive effect on the enantio-
Table 2: Friedel–Crafts alkylation of indoles 2a–d with nitroalkenes 3a–d catalyzed by thiourea 1d.[a]
Entry
Indole
R1
R2
Nitroalkene
R3
Product
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2a
2a
2a
2a
H
Me
H
H
H
H
H
H
H
H
OMe
Cl
H
H
H
H
3a
3a
3a
3a
3b
3c
3d
3e
Ph
Ph
Ph
Ph
2-furyl
2-thienyl
n-pentyl
iPr
4a
4b
4c
4d
4e
4 f
78
85
82[d]
86[d]
35[e]
88
74[d]
89[d]
71[e]
73
70
73
4g
4h
76
83
37[f]
81[f]
[a]Experimental conditions: Indole 2 (0.15 mmol) was added to a solution of nitroalkene 3 (0.1 mmol)
and catalyst 1d (0.02 mmol) in CH2Cl2 (100 mL), cooled to À248C. After 72 h, the product was isolated
by flash chromatography. [b]Yield of isolated product. [c]Determined by chiral stationary phase HPLC
(see Supporting Information). [d]Reaction performed at À458C. [e]Reaction time: 142 h. [f]Reaction
time: 96 h.
selectivity; the product 4a was obtained in 85% ee while good
levels of conversion were maintained (Table 1, entry 9).
We next explored the scope of this new enantioselective
Friedel–Crafts alkylation of indoles with nitroalkenes, under
the optimized reaction conditions (Table 2). We first tested a
few indoles 2a–d bearing different substituents in the reaction
with trans-b-nitrostyrene 3a catalyzed by 1d.[15] Whereas the
reaction of indole 2a afforded the corresponding product 4a
in good yield and optical purity (Table 2, entry 1), when
performed at À248C, the Friedel–Crafts alkylation of elec-
tron-rich 2-methylindole 2b and 5-methoxyindole 2c pro-
ceeded at a reasonable reaction rate even at lower temper-
of the nitro group of 4a proceeded under mild reaction
conditions[17] giving tryptamine 5, which could be isolated in
good yield as the corresponding sulfonamide derivative 6.
Alternatively, crude 5 could be directly subjected to Pictet–
Spengler cyclization[18] with benzaldehyde to furnish a pre-
viously unreported 1,4-diphenyl-substituted 1,2,3,4-tetrahy-
dro-b-carboline as a 91:9 mixture of diastereoisomers. The
highly prevailing 1,4-trans isomer 7 was isolated in good yield
and in diastereomerically pure form after chromatography on
silica gel (Scheme 2). All reactions occurred without any loss
in the enantiomeric enrichment of the products, and the
relative stereochemistry of 7 was tentatively assigned as 1,4-
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hydrogen atoms activate the nitroalkene, the free
alcoholic function will interact with the indolic proton
through a weak hydrogen bond, directing the attack of
the incoming nucleophile on the Si face of the
nitroolefin as depicted in Scheme 4.
Scheme 2. Conversion of the optically active product 4a into valuable products such as
tryptamine 5 and 1,2,3,4,-tetrahydro-b-carboline 7. Ts=toluene-4-sulfonyl, TFA=trifluoro-
acetic acid.
Scheme 4. Possible bifunctional mode of action of the catalyst
1d.
trans by means of NOE experiments. Furthermore, the
formation of the sulfonamide derivative 6 allowed the
assignment of the absolute configuration of the catalytic
product 4a as 2R, from the comparison of its optical rotation
In conclusion, we have developed the first catalytic,
and HPLC retention time with those of an authentic sample
of ent-6 (in 94% ee), which was synthesized by the ring-
opening at the benzylic position of (2S)-2-phenyl-1-p-tolue-
nesulfonyl aziridine[19] with indole 2a promoted by LiClO4.[20]
The ability of thiourea 1d to promote the Friedel–Crafts
additions of indoles 2 to nitroalkenes 3 may be interpreted on
the basis of the reversible formation of a complex involving a
double hydrogen bond between the thiourea hydrogen atoms
and the two oxygen atoms of the nitroalkene. The recognition
of the nitro group by urea moieties in solution as well as in the
solid phase, leads to crystal structures that clearly present this
type of interaction.[21] To gain some insight into the substrate–
catalyst interactions that lead to the observed stereoselectiv-
ity, we prepared catalyst 1 f, in which the hydroxy group was
protected by a sterically hindering trimethylsilyl group, and
thiourea 1g, which lacks the alcoholic function. Surprisingly,
both catalysts showed poor performances in the reaction
between indole 2a and trans-b-nitrostyrene 3a, not only with
regard to the enantioselectivity but also in terms of the
catalyst activity (Scheme 3).
enantioselective Friedel–Crafts alkylation of indoles 2 with
nitroalkenes 3, which provides optically active 2-indolyl-1-
nitro derivatives 4 in fairly good yields and enantioselectiv-
ities. The reaction is efficiently catalyzed by the simple
thiourea-based organocatalyst 1d, which can be easily
accessed in both enantiomeric forms from commercially
available materials. The extremely simple operational proce-
dure and the high synthetic versatility of the products render
this new approach highly appealing for the synthesis of
optically active target compounds such as tryptamines and
1,2,3,4-tetrahydro-b-carbolines.
Received: January 20, 2005
Revised: April 19, 2005
Published online: September 19, 2005
Keywords: asymmetric synthesis · electrophilic substitution ·
.
hydrogen bonds · indoles · organocatalysis
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