Enhanced efficiency of thiourea catalysts by external Bronsted acids in the Friedel-Crafts alkylation of indoles

Article abstract of DOI:10.1002/ejoc.201100506

A novel study on the influence of external Bronsted acids on thiourea catalysts in the asymmetric Friedel-Crafts alkylation of indoles with nitroalkenes is reported. The final 3-substituted indole derivatives were synthesized with better results because o

Full text of DOI:10.1002/ejoc.201100506

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201100506
Enhanced Efficiency of Thiourea Catalysts by External Brønsted Acids in the
Friedel–Crafts Alkylation of Indoles
Eugenia Marqués-López,[a] Ana Alcaine,[a] Tomás Tejero,[a] and Raquel P. Herrera*[a,b]
Keywords: Alkylation / Nitrogen heterocycles / Organocatalysis / Brønsted acids / Nitroalkenes
A novel study on the influence of external Brønsted acids on
thiourea catalysts in the asymmetric Friedel–Crafts alkylation
of indoles with nitroalkenes is reported. The final 3-substi-
tuted indole derivatives were synthesized with better results
because of cooperative effects between the chiral thiourea
and a Brønsted acid additive (1a·HA). The effects of diverse
catalysts, different acid additives, solvents, and temperatures
in the reaction were also explored. The high reactivity and
selectivity of the reaction is presumptively attributed to an
appropriate assembly between the Brønsted acid and the
thiourea structure, affording a more acidic and rigid catalytic
complex.
Recently, chiral thioureas have been shown to be versatile
and efficient organocatalysts in many organic transforma-
tions.[9] In this context, during our ongoing studies on or-
ganocatalysis we have centered part of our research interest
on the application of thiourea catalysts[7a,8a,10] for the dis-
covery of new asymmetric procedures. In this area, efforts
are now being devoted to the development of more reactive
structures to overcome some drawbacks, such as high cata-
lyst loadings and low turnover rates. A recent study re-
vealed that both the reaction rate and the enantioselectivity
were correlated to catalyst acidity, and it could be efficiently
used for the modulation of catalyst structure in hydrogen-
bond-catalyzed enantioselective reactions.[11] On the basis
of this idea, other authors have designed new, more efficient
catalysts by introducing internal acidic elements,[7d,12] dif-
ferent to the frequently used 3,5-bis(trifluoromethyl)phenyl
group, in the (thio)urea skeleton (Figure 1).
Introduction
In the last decades, the Friedel–Crafts alkylation reac-
tion[1] has attracted much attention for the formation of
new carbon–carbon bonds, and it has become a powerful
tool in organic synthesis. In this field great efforts have been
paid to develop new catalytic enantioselective variants.[2,3]
In this context, the addition of indole derivatives to elec-
tron-deficient olefins enables direct access to 3-substituted
indole analogues with potential applications, as the indole
framework has been identified in a great number of natural
and unnatural products and medicinal agents with interest-
ing biological activities.[4] Therefore, the preparation of
products with this privileged structural motif is nowadays
a significant aim of investigation and the discovery of new
catalytic enantioselective procedures is still an important
challenge. Although this area of research has been more
extensively explored using metal catalysis,[2] important or-
ganocatalytic enantioselective examples have been also re-
ported.[3] Among the explored efficient electrophiles, nitro-
alkenes are one of the most attractive Michael acceptors
in organic synthesis[5] due to their versatility to be readily
transformed into a variety of different functionalities.[6]
Nevertheless and in spite of their importance, the organo-
catalytic version of this process using nitroolefins remains
scarcely explored.[7,8]
Figure 1. Representative examples of efficient thiourea catalysts.
We envisioned that higher enantioselectivity and reactiv-
ity might also be achieved by using a suitable and tunable
external Brønsted acid additive (HA) with a chiral thiourea
catalyst if appropriate assembly could be accomplished be-
tween them.[13] In this communication, we wish to report
our preliminary results concerning this alternative approach
to the establishment of cooperative effects between
Brønsted acid additives and chiral thiourea organocatalysts,
which may lead to the development of a novel activity
pattern as a new promising concept (Figure 2).
[a] Laboratorio de Síntesis Asimétrica, Departamento de Química
Orgánica, Instituto de Síntesis
Química y Catálisis Homogénea (ISQCH), CSIC – Universidad
de Zaragoza,
50009 Zaragoza, Aragón, Spain
Fax: +34-976-762075
E-mail: raquelph@unizar.es
[b] ARAID, Fundación Aragón I+D,
50004 Zaragoza, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100506.
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Enhanced Efficiency of Thiourea Catalysts in F–C Alkylations
Table 1. Screening of the cooperative effect of 1a·HA.[a]
Figure 2. New concept explored. Brønsted acid assisted thiourea
organocatalysts.
Results and Discussion
Entry
HA
Indole
t
[d]
Yield
[%][b]
ee
[%][c]
With the aim of increasing the acidity of chiral thioureas
so that they can be more efficient catalysts, we thought that
it would be easier to control and modulate the catalyst acid-
ity by using an external additive instead of modifying the
thiourea skeleton. The use of a carefully chosen acidic or
basic additive has been extensively studied in aminocataly-
sis;[14] however, it has been less considered in the field of
(thio)urea catalysis; in these few cases the thiourea was the
additive in the catalytic system, and it was used to enhance
the activity of the corresponding acid catalyst.[15] To evalu-
ate the potential of this idea, we started our investigation
by exploring the reactivity of thiourea 1a with l-mandelic
acid in a comparative study in the Friedel–Crafts alkylation
reaction described in Scheme 1.
1
2
3
4
5
6
d-mandelic acid
(Ϯ)-mandelic acid
(R)-PhCH(OMe)CO2H
PhCH2CO2H
PhCO2H
2-chloronicotinic acid
–
l-mandelic acid
d-mandelic acid
–
4a
4a
4a
4a
4a
4a
4b
4b
4b
4c
4c
4c
4a
4a
4a
4
4
4
4
3
3
3
3
3
4
5
5
4
4
4
79
83
71
65
47
39
94
95
95
58
71
70
90
69
96
70
70
71
58
58
44
20
38
38
7[d]
8
9
10[d]
11
12
13
14
15
rac.[e]
rac.[e]
rac.[e]
65
70
49
l-mandelic acid
d-mandelic acid
CH3CO2H
CH2ClCO2H
CF3CO2H
[a] Experimental conditions: To
a mixture of catalyst 1a
(0.02 mmol), HA (0.02 mmol), and nitroalkene 5a (0.1 mmol) in a
test tube at room temperature was added indole 4a–c (0.15 mmol)
and then CH2Cl2 (500 μL). After the reaction time, adduct 6 was
isolated by flash chromatography. [b] Isolated yield. [c] Determined
by chiral HPLC analysis (see Supporting Information). [d] Reac-
tion performed in the absence of a Brønsted acid. [e] Racemic mix-
ture.
assembling some of the reagents into the transition state by
itself. In such a case, the stereochemistry in the acid might
be determinant for the sign of the final enantiomer. On the
other hand, catalyst complex 1a·HA was significantly less
effective when indole derivatives 4b and 4c were also consid-
ered (Table 1, Entries 7–12). It is noteworthy that better
enantioselectivities were also achieved with 2-methylindole
Scheme 1. l-Mandelic acid assisted thiourea 1a.
To our surprise, the enantioselectivity of final adduct 6aa (4b; Table 1, Entries 8 & 9) compared with those obtained
in the presence of both l-mandelic acid and catalyst 1a was in the absence of acid (Table 1, Entry 7). However, with N-
quite a bit higher (70%ee) than that obtained in the ab- methylindole 4c, the catalytic system afforded a racemic
sence of acid (38%ee). It is also remarkable that in presence mixture regardless of whether the acid was present or not
of l-mandelic acid as the sole catalyst, the reaction leads to (Table 1, Entries 10–12). This suggests that the acid is able
a racemic mixture, exemplifying that the synergic effect of to improve the results when a thiourea catalyst renders final
both species is higher than the effect of each catalyst sepa- non-racemic mixtures. A variety of additives with differing
rately. This initial promising result encouraged us to exam- levels of steric hindrance and acidity were then explored.
ine this reaction more extensively by exploring other suit- Although the data do not display a clear correlation be-
able acids and indole derivatives (Table 1).
tween steric factors and acidity (Table 1, Entries 1–6 and
We first tested d- and (Ϯ)-mandelic acid (Table 1, En- 13–15), the acidity could affect both the enantioselectivity
tries 1 & 2) to study the match/mismatch effect, and the and the reactivity of the process. In this respect, with a
same results as those obtained with the enantiomeric l- stronger acid, the acid-catalyzed reaction could compete
form (Scheme 1) were achieved. Interestingly the sense of with the 1a·HA-promoted reaction (Table 1, Entry 15).
the stereoselection was the same as that when only thiourea Even if the presence of the OH group in mandelic acid
1a was used. This fact shows that chirality is preferentially seemed important for the enantioselectivity of the process
governed by catalyst 1a, and this outcome prompted us to (Table 1, Entry 1 vs. 4) similar and promising results were
think that the acid activated the thiourea moiety rather than also obtained with (R)-PhCH(OMe)CO2H (Table 1, En-
Eur. J. Org. Chem. 2011, 3700–3705
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E. Marqués-López, A. Alcaine, T. Tejero, R. P. Herrera
SHORT COMMUNICATION
try 3) and CH2ClCO2H (Table 1, Entry 14). Our attention mation). Among the solvents tested, CHCl3 and CH2Cl2
next turned to explore different synthesized thiourea cata- allowed the obtainment of higher ee values. We decided to
lysts 1b–g under the same reaction conditions towards a continue with CH2Cl2 in the ensuing screening.
better understanding of both the mode of action of the cat-
alyst and the origin of the enantioselectivity in this process.
To this purpose, different structural parameters were varied
Table 2. Screening of catalytic complexes (1b–g)·HA.[a]
(Figure 3, Table 2).
Entry
Catalyst
t
[d]
Yield
[%][b]
ee
[%][c]
1
1b
1b
1c
1c
1d
1d
1e
1e
1f
5
5
4
4
7
7
7
7
6
7
7
8
24
rac.[d]
rac.[d]
rac.[d]
rac.[d]
60
45
63
36
8
2[e]
3
n.d.[f]
n.d.[f]
n.d.[f]
68
4[e]
5
6[e]
7
24
77
57
30
8[e]
9
10[e]
11
12[e]
1f
21
14
7
6
1g
1g
n.d.[f]
26
[a] Experimental conditions: To
a mixture of catalyst 1b–g
(0.02 mmol), (Ϯ)-mandelic acid (0.02 mmol), and nitroalkene 5a
(0.1 mmol) in a test tube at room temperature was added indole 4a
(0.15 mmol) and then CH2Cl2 (500 μL). After the reaction time,
compound 6aa was isolated by flash chromatography. [b] Isolated
yield. [c] Determined by chiral HPLC analysis (Chiralpak IA, flow
hexane/iPrOH = 90:10, 1 mL/min). [d] Racemic mixture. [e] In the
absence of (Ϯ)-mandelic acid. [f] Not determined.
Figure 3. Chiral thioureas 1b–g tested.
Although we could not improve the results achieved with
1a·HA, several important aspects can be deduced from
these results. The presence of an OH group in the skeleton
of 1a with cis configuration seems to be crucial for both the
By lowering the reaction temperature to –25 from 25 °C
enantioselectivity and the reactivity as previously report- we could increase the enantioselectivity up to 89% (Table 3,
ed,[7a,10c] as catalysts 1b and 1f (Table 2, Entries 1 & 9) and Entries 11 & 15) although the reaction rate was lower. How-
catalysts 1c and 1g (Table 2, Entries 3 & 11) afforded poorer ever, additional variations in the concentration and equiva-
results compared with those obtained by using catalyst 1a. lents of acid did not lead to improved results. We tested the
This fact indicates that even though the presence of an OH same reaction in the absence of acid at different tempera-
group in the skeleton is important, the hydroxy group must tures under different conditions (Table 3, Entries 2, 4, 8,
be placed in the appropriate position to direct efficiently the and 12), and in all cases lower values were obtained relative
attack of the external nucleophile, as previously report- to those obtained with 1a·HA in terms of enantioselectivity
ed.[7a,10c] The electronic effects of the CF3 groups in the and reactivity. Unfortunately, the large differences achieved
aromatic ring of thiourea catalyst 1a seem to be also essen- at room temperature between the reaction performed in the
tial for the enantioselectivity, as catalysts 1d and 1e bearing presence or absence of acid are not maintained at low tem-
different electron-withdrawing groups provided lower en- perature, and this may be due to a different mode of coordi-
antioinduction (Table 2, Entries 5 & 7). These results al- nation between the thiourea catalyst and the acid. We real-
lowed the identification of system 1a·HA as the most ef- ized that at low temperature the amount of active complex
ficient in terms of enantioselectivity and reactivity. After 1a·HA could depend on the number of equivalents and the
these results, we decided to continue in the subsequent enantiomeric form used. Comparative experiments per-
screening with catalyst 1a and (Ϯ)-mandelic acid or formed with (Ϯ)-, l-, and d-mandelic acid showed identical
CH2ClCO2H as additives. To optimize our cooperative cat- results, although 2 equiv. of d-mandelic acid gave slightly
alyst system we also tested other parameters such as sol- improved results in terms of enantioselectivity and reactiv-
vent, temperature, and variation in the concentration and ity (Table 3, Entry 15). Interestingly, in the absence of cata-
equivalents of acid. On the basis of our experience we real- lyst 1a, the reaction did not proceed even after 4 d (Table 3,
ized that solvent polarity might play an important role in Entry 19), supporting the fact that the acid activates the
governing the enantioselectivity of the reaction. In this con- catalyst more than one of the reagents.
text, we explored different solvents in the 1a·HA-promoted
Finally, with the optimal reaction conditions in hand, we
Friedel–Crafts alkylation process (see Supporting Infor- investigated the scope of our protocol by using catalyst 1a
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Enhanced Efficiency of Thiourea Catalysts in F–C Alkylations
Table 3. Screening of different reaction conditions using 1a·HA.[a]
Entry Volume of CH2Cl2
HA (equiv.)[b]
Temperature
[°C]
t
[d]
Yield
[%][c]
ee
[μL]
[%][d]
1
2
3
4
5
6
500
500
500
500
100
250
250
250
250
250
250
250
250
250
250
250
250
250
250
(Ϯ)-mandelic acid (1)
no acid
(Ϯ)-mandelic acid (1)
no acid
(Ϯ)-mandelic acid (1)
CH2ClCO2H acid (1)
(Ϯ)-mandelic acid (1)
no acid
(Ϯ)-mandelic acid (1)
l-mandelic acid (1)
d-mandelic acid (1)
no acid
(Ϯ)-mandelic acid (2)
l-mandelic acid (2)
d-mandelic acid (2)
d-mandelic acid (0.5)
d-mandelic acid (3)
d-mandelic acid (5)
d-mandelic acid (2)
3
3
4
4
4
4
3
4
4
4
3
3
3
3
3
3
3
4
4
4
4
59
21
32
24
61
64
45
34
63
55
53
40
53
56
60
55
64
67
n.r.[g]
74
40
82
66
87
84
88
77
88
88
89
82
88
88
89
87
87
86
n.r.[g]
–10
–10
–25
–25
–25
–25
–25
–25
–25
–25
–25
–25
–25
–25
–25
–25
–25
7[e]
8[e]
9
10
11
12
13
14
15
16
17
18
19[f]
[a] Experimental conditions: To a mixture of catalyst 1a (0.02 mmol), HA (0.02 mmol), and nitroalkene 5a (0.1 mmol) in a test tube at
the indicated temperature was added indole 4a (0.15 mmol) and then CH2Cl2 (the corresponding amount). After the reaction time,
compound 6aa was isolated by chromatography. [b] Equivalents of acid with respect to catalyst 1a. [c] Isolated yield. [d] Determined by
chiral HPLC analysis (Chiralpak IA, flow hexane/iPrOH = 90:10, 1 mL/min). [e] 10 mol-% of 1a. [f] Reaction was performed in the
absence of catalyst 1a. [g] No reaction observed.
and d-mandelic acid in a comparative study by performing Table 4. Final scope of the 1a·HA-catalyzed Friedel–Crafts alkyl-
ation reaction.[a]
the reaction in the absence of an additive (Table 4, values
in parentheses).
The reactions were stopped, even when they were not
complete, after a reasonable number of days to compare the
results with 1a·HA to those obtained by using only catalyst
1a. The procedure was successfully extended to different
Entry
Indole;
R1,R2
Nitroalkene;
R3
Product
t
[d]
Yield
[%][b]
ee
substituted nitroalkenes 5a–g and indoles 4a–f, furnishing
corresponding adducts 6 in useful yields and very good
enantioselectivities, as summarized in Table 4. Although in
a few cases just slightly higher values were achieved in com-
parison to that obtained in the absence of acid (Table 4,
Entries 7 & 10), in general the presence of acid provides
better results in terms of both reactivity and enantio-
selectivity. Aromatic and heteroaromatic nitroolefins with
electron-withdrawing and electron-donating groups reacted
well with indole to afford alkylated adducts 6ab–ag in good
yields with high enantioselectivities (Table 4, Entries 1–6).
Even though nitrostyrenes containing electron-donating
groups showed a slightly lower reaction rate than the reac-
[%][c]
1
2
3
4
5
6
7
4a; H,H
4a; H,H
4a; H,H
4a; H,H
4a; H,H
4a; H,H
4b; H,Me
4d; Cl,H
4e; F,H
5b; 4-MePh
5c; 4-MeOPh
5d; 2-furyl
5e; 4-ClPh
5f; 4-BrPh
5g; 4-FPh
5a; Ph
6ab
6ac
6ad
6ae
6af
6ag
6ba
6da
6ea
6fa
3
3
3
3
3
3
4
5
5
4
50 (39)
45 (24)
58 (27)
75 (33)
30 (17)
67 (42)
94 (91)
25 (n.d.)
28 (12)
88 (74)
88 (62)
84 (66)
82 (68)
88 (75)
87 (68)
88 (64)
58 (52)
86 (70)
86 (72)
86 (82)
8[d]
9
10
5a; Ph
5a; Ph
5a; Ph
4f; MeO,H
[a] Experimental conditions: To
(0.02 mmol), d-mandelic acid (0.04 mmol), and nitroalkene 5a–g
(0.1 mmol) in a test tube at low temperature (–25 °C) was added
a mixture of catalyst 1a
tion of nitrostyrenes containing an electron-withdrawing indole 4a–f (0.15 mmol) and then CH2Cl2 (0.25 mL). After the re-
action time, product 6 was isolated by flash chromatography.
group (Table 4, Entries 1–3 vs. Entries 4 & 6; except using
4-Br, Entry 5), the enantioselectivity was independent of the
substituent on the aromatic ring. The electronic effects on
[b] Isolated yield. [c] Determined by chiral HPLC analysis (see Sup-
porting Information). [d] 100 μL of solvent.
the indole ring were also considered (Table 4, Entries 7–10).
In this sense, when a Me group was introduced at the 2- try 7). On the other hand, electron-withdrawing groups in
position of the indole structure, the enantioselectivity the 5-position of the indole did not affect the enantio-
dropped, although the reactivity was higher (Table 4, En- selectivity of the process, but the reaction rate was dramati-
Eur. J. Org. Chem. 2011, 3700–3705
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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E. Marqués-López, A. Alcaine, T. Tejero, R. P. Herrera
SHORT COMMUNICATION
cally lower compared to that obtained with indoles bearing and NMR experiments[18] are being performed to shed light
electron-donating groups (Table 4, Entries 8 & 9 vs. 7 & 10). onto this interesting and novel reactivity, and the results
The absolute configurations of adducts 6 were assigned by will be published in due course.
comparison of their optical rotation with those reported in
the literature for the same products.[7]
Some authors have previously proposed active complexes
Conclusions
I[15b–15d,16] and II[15a] (Figure 4) as suitable modes of inter-
The results show that Brønsted acid assisted thiourea
catalysts are very effective catalyst complexes for the enan-
tioselective Friedel–Crafts reaction of indoles with nitroal-
kenes. The synergic effect between both species is higher
than the effect promoted by each one separately. Easy mod-
ulation of the nature of the acid allows the convenient alter-
ation of the chiral environment and the pKa of the donor
hydrogen, which in our case is thiourea catalyst 1a. These
results could open a new interesting line of research related
to the effect of additives in thiourea-catalyzed reactions,
which is a concept that is scarcely considered in the litera-
ture. Moreover, this contribution could become an impor-
tant starting point for further investigations. Additional
studies to clarify our plausible mechanistic hypothesis by
NMR spectroscopy and computational calculations, as well
as its following application to other enantioselective thio-
urea-catalyzed systems, are in progress in our laboratories.
action between an acid catalyst and a thiourea additive in
the transition state. Although at this stage we cannot ensure
the role of the acid in our mechanism, according to the
experimental results we believe that in this reaction the
mode of activation could be different to those previously
invoked. Firstly, if III was the mode of activation in our
mechanism, the chirality of the acid would influence which
of the enantiomers is obtained, more than the catalyst chi-
rality. Different signs and values of enantioselectivity
should be expected using d-, l-, or (Ϯ)-mandelic acid as
additives, but this is not the case. Moreover, III would not
be in agreement with the good results obtained with (R)-
PhCH(OMe)CO2H (Table 1, Entry 3). On the basis of all
these results we consider that the activation of the thiourea
moiety with the acid IV in an upper face might explain the
outcome better, although more experiments are necessary
to clarify this mode of action. From the experimental re-
sults we can assume that the catalytic complex 1a·HA is a
more reactive species, maybe due to the lower pKa of thio-
urea, therefore increasing the reaction rate. It is also re-
markable that a stronger union between both species clearly
worked against the independent activation of each one with
the substrates. Furthermore, the improvement in the
enantioselectivity could be explained by generating a more
rigid assembly in the transition state, as a combination of
both structures.
Experimental Section
General Information: Purification of reaction products was carried
out by flash chromatography using silica gel (0.063–0.200 mm) or
medium-pressure liquid chromatography using prepacked silica col-
umns. Analytical thin-layer chromatography was performed on
1
0.25 mm silica gel 60-F plates. H NMR spectra were recorded at
400 MHz and 13C NMR spectra were recorded at 100 MHz by
using CDCl3 as solvent. Chemical shifts are reported relative to
residual CHCl3 (δ = 7.26 ppm) for 1H NMR and relative to
77.0 ppm for 13C NMR.
Materials: All commercially available solvents and reagents were
used as received. CH2Cl2 was filtered through basic alumina prior
to use to avoid the presence of trace amounts of acid. Chiral thio-
urea catalysts were obtained following literature procedures: 1a,[10c]
1b,[10c] 1c,[19] and 1f.[7c] Starting materials, yields, and spectroscopic
data for compounds 1d, 1e, 1g, and 6ea are described in the Sup-
porting Information. 1H and 13C NMR spectra for compounds
6aa,[7a] 6ab–af,[7d] 6ag,[20] and 6ba–da,fa[7a] are consistent with val-
ues previously reported in the literature.
General Procedure for the 1a·HA-Catalyzed Friedel–Crafts Alkyl-
ation Reaction: To a mixture of catalyst 1a (20 mol-%), d-mandelic
acid (40 mol-%), and nitroalkene 5a–g (0.1 mmol) at low tempera-
ture (–25 °C) in a test tube was added indole 4a–f (0.15 mmol) and
then CH2Cl2 (0.25 mL). After the appropriate reaction time (see
Table 4), the residue was purified by flash chromatography or me-
dium-pressure liquid chromatography (SiO2; hexane/EtOAc, 8:2) to
afford final adducts 6. Yields and enantioselectivities are reported
in Table 4. Spectral and analytical data for compounds 6 are in
agreement with those previously reported in the literature.
Figure 4. Hydrogen-bonding-mediated cooperative catalysis.
However, we cannot discard the possible simultaneous
coordination of the acid and the thiourea moiety to one of
the reagents involved in our reaction, as proposed by Shi
Supporting Information (see footnote on the first page of this arti-
cle): Detailed experimental procedures and characterization data
for compounds 1d, 1e, 1g, and 6ea and HPLC chromatograms for
and co-workers.[17] Additional computational calculations all final products.
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Enhanced Efficiency of Thiourea Catalysts in F–C Alkylations
K. Nagasawa, Angew. Chem. Int. Ed. 2010, 49, 7299–7303; i)
N. Takenaka, J. Chen, B. Captain, R. S. Sarangthem, A. Chan-
drakumar, J. Am. Chem. Soc. 2010, 132, 4536–4537; j) T. Hir-
ata, M. Yamanaka, Chem. Asian J. 2011, 6, 510–516.
[8] For non-chiral organocatalyzed examples, see: a) G. Dessole,
R. P. Herrera, A. Ricci, Synlett 2004, 2374–2378; b) L.-T. An,
J.-P. Zou, L.-L. Zhang, Y. Zhang, Tetrahedron Lett. 2007, 48,
4297–4300.
[9] a) P. R. Schreiner, Chem. Soc. Rev. 2003, 32, 289–296; b) Y.
Takemoto, Org. Biomol. Chem. 2005, 3, 4299–4306; c) S. J.
Connon, Chem. Eur. J. 2006, 12, 5418–5427; d) M. S. Taylor,
E. N. Jacobsen, Angew. Chem. Int. Ed. 2006, 45, 1520–1543; e)
A. G. Doyle, E. N. Jacobsen, Chem. Rev. 2007, 107, 5713–5743;
f) Z. Zhang, P. R. Schreiner, Chem. Soc. Rev. 2009, 38, 1187–
1198; g) E. Marqués-López, R. P. Herrera, An. Quim. 2009,
105, 5–12; h) M. Kotke, P. R. Schreiner in Hydrogen Bonding
in Organic Synthesis (Ed.: P. M. Pihko), Wiley-VCH,
Weinheim, 2009, pp. 141–351.
[10] a) D. Pettersen, R. P. Herrera, L. Bernardi, F. Fini, V. Sgarzani,
R. Fernández, J. M. Lassaletta, A. Ricci, Synlett 2006, 239–
242; b) L. Bernardi, F. Fini, R. P. Herrera, A. Ricci, V. Sgarz-
ani, Tetrahedron 2006, 62, 375–380; c) R. P. Herrera, D. Monge,
E. Martín-Zamora, R. Fernández, J. M. Lassaletta, Org. Lett.
2007, 9, 3303–3306; d) A. Alcaine, E. Marqués-López, P. Me-
rino, T. Tejero, R. P. Herrera, Org. Biomol. Chem. 2011, 9,
2777–2783.
Acknowledgments
We thank the Ministry of Science and Innovation (MICINN),
Madrid, Spain (Project CTQ2010-19606), and the Government of
Aragón, Zaragoza, Spain (Project PI064/09 and Research Groups,
E-10), for financial support of our research. We are also grateful
to Prof. Luca Bernardi for useful comments. E.M.-L. thanks CSIC
for a JAE-Doc postdoctoral contract. R.P.H. thanks the Aragón
I+D Foundation for her permanent position.
[1] C. Friedel, J. M. Crafts, C. R. Hebd. Seances Acad. Sci. 1877,
84, 1392–1395.
[2] For reviews on Friedel–Crafts metal-catalyzed alkylation reac-
tions, see: a) K. A. Jørgensen, Synthesis 2003, 1117–1125; b)
M. Bandini, A. Melloni, A. Umani-Ronchi, Angew. Chem. Int.
Ed. 2004, 43, 550–556; c) M. Bandini, A. Melloni, S. Tommasi,
A. Umani-Ronchi, Synlett 2005, 1199–1222; d) T. B. Poulsen,
K. A. Jørgensen, Chem. Rev. 2008, 108, 2903–2915; e) M. Ban-
dini, A. Umani-Ronchi (Eds.), Catalytic Asymmetric Friedel–
Crafts Alkylations, Wiley-VCH, Weinheim, 2009.
[3] For reviews on Friedel–Crafts organocatalyzed alkylation reac-
tions, see: a) E. Marqués-López, A. Diez-Martinez, P. Merino,
R. P. Herrera, Curr. Org. Chem. 2009, 13, 1585–1609; b) S.-L.
You, Q. Cai, M. Zeng, Chem. Soc. Rev. 2009, 38, 2190–2210;
c) V. Terrasson, R. M. de Figueiredo, J. M. Campagne, Eur. J.
Org. Chem. 2010, 2635–2655; d) M. Zeng, S.-L. You, Synlett
2010, 1289–1301.
[11] K. H. Jensen, M. S. Sigman, Angew. Chem. Int. Ed. 2007, 46,
4748–4750.
[12] a) M. T. Robak, M. Trincado, J. A. Ellman, J. Am. Chem. Soc.
2007, 129, 15110–15111; b) S. S. So, J. A. Burkett, A. E. Matt-
son, Org. Lett. 2011, 13, 716–719.
[13] For a review on combined acid catalysis, see: H. Yamamoto,
K. Futatsugi, Angew. Chem. Int. Ed. 2005, 44, 1924–1942.
[4] a) G. A. Olah (Ed.), Friedel–Crafts and Related Reactions,
Wiley, New York, 1963, vols. 1–4; b) G. A. Olah (Ed.), Friedel–
Crafts Chemistry, Wiley, New York, 1973; c) R. M. A. Roberts,
A. Khalaf in Friedel–Crafts Alkylation Chemistry: A Century
of Discovery, Marcel Dekker, New York, 1984; d) R. J. Sund- [14] E. Marqués-López, R. P. Herrera, Curr. Org. Chem. 2011, 15,
berg (Ed.), Indoles, Academic Press, London, 1996; e) A. Klee-
man, J. Engel, B. Kutscher, D. Reichert (Eds.), Pharmaceutical
Substances, Thieme, New York, 2001; f) H.-J. Borschberg, Curr.
Org. Chem. 2005, 9, 1465–1491; g) S. Cacchi, G. Fabrizi, Chem.
Rev. 2005, 105, 2873–2920.
2311–2327.
[15] a) T. Weil, M. Kotke, C. M. Kleiner, P. R. Schreiner, Org. Lett.
2008, 10, 1513–1516; b) X. Companyó, G. Valero, L. Crovetto,
A. Moyano, R. Rios, Chem. Eur. J. 2009, 15, 6564–6568; c) Ö.
Reis, S. Eymur, B. Reis, A. S. Demir, Chem. Commun. 2009,
1088–1090; d) N. El-Hamdouni, X. Companyó, R. Rios, A.
Moyano, Chem. Eur. J. 2010, 16, 1142–1148; e) R. S. Klausen,
E. N. Jacobsen, Org. Lett. 2009, 11, 887–890; f) H. Xu, S. J.
Zuend, M. G. Woll, Y. Tao, E. N. Jacobsen, Science 2010, 327,
986–990.
[5] O. M. Berner, L. Tedeschi, D. Enders, Eur. J. Org. Chem. 2002,
1877–1894.
[6] a) N. Ono (Ed.), The Nitro Group in Organic Synthesis, Wiley-
VCH, New York, 2001; b) R. Ballini, M. Petrini, Tetrahedron
2004, 60, 1017–1047.
[7] For scarce examples, see: a) R. P. Herrera, V. Sgarzani, L. Ber-
nardi, A. Ricci, Angew. Chem. Int. Ed. 2005, 44, 6576–6579; b)
W. Zhuang, R. G. Hazell, K. A. Jørgensen, Org. Biomol. Chem.
2005, 3, 2566–2571; c) E. M. Fleming, T. McCabe, S. J. Con-
non, Tetrahedron Lett. 2006, 47, 7037–7042; d) M. Ganesh, D.
Seidel, J. Am. Chem. Soc. 2008, 130, 16464–16465; e) J. Itoh,
K. Fuchibe, T. Akiyama, Angew. Chem. Int. Ed. 2008, 47,
4016–4018; f) Y.-F. Sheng, G.-Q. Li, Q. Kang, A.-J. Zhang, S.-
L. You, Chem. Eur. J. 2009, 15, 3351–3354; g) Y.-F. Sheng, Q.
Gu, A.-J. Zhang, S.-L. You, J. Org. Chem. 2009, 74, 6899–6901;
h) Y. Sohtome, B. Shin, N. Horitsugi, R. Takagi, K. Noguchi,
[16] For the same mode of activation using a urea catalyst, see:
S. L. Poe, A. R. Bogdan, B. P. Mason, J. L. Steinbacher, S. M.
Opalka, D. T. McQuade, J. Org. Chem. 2009, 74, 1574–1580.
[17] Y.-L. Shi, M. Shi, Adv. Synth. Catal. 2007, 349, 2129–2135.
[18] See Supporting Information for a preliminary NMR spec-
troscopy experiment.
[19] C. Gioia, L. Bernardi, A. Ricci, Synthesis 2010, 161–170.
[20] Y.-X. Jia, S.-F. Zhu, Y. Yang, Q.-L. Zhou, J. Org. Chem. 2006,
71, 75–80.
Received: April 10, 2011
Published Online: June 7, 2011
Eur. J. Org. Chem. 2011, 3700–3705
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3705