Planar-chiral thioureas as hydrogen-bond catalysts

Article abstract of DOI:10.1002/ejoc.200901353

The synthesis of the first enantiopure planar-chiral thiourea catalysts is herewith described. New catalysts 1-3 were applied in asymmetric transformations, such as the FriedelCrafts alkylation of indole, as well as in the transfer hydrogenation of nitroo

Full text of DOI:10.1002/ejoc.200901353

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200901353
Planar-Chiral Thioureas as Hydrogen-Bond Catalysts
Jakob F. Schneider,[a] Florian C. Falk,[a] Roland Fröhlich,[b] and Jan Paradies*[a]
Keywords: Thioureas / Hydrogen bonds / Cyclophanes / Organocatalysis / Chirality
The synthesis of the first enantiopure planar-chiral thiourea
catalysts is herewith described. New catalysts 1–3 were ap-
plied in asymmetric transformations, such as the Friedel–
Crafts alkylation of indole, as well as in the transfer hydro-
genation of nitroolefins. Bifunctional catalysts 2 and 3 exhibit
enhanced activity in the investigated reactions, demonstrat-
ing their potential for organic synthesis.
tuted to a high degree. However, only few efficient method-
ologies for the synthesis of highly functionalized Pcs are
known.[12] The Pc-based thioureas are derived from the cor-
responding amino alcohols. This class of compounds is gen-
erally significant for organic chemists, and the synthesis of
new amino alcohols is relevant. We utilized the planar-
chiral amino alcohols in the synthesis of the first examples
of new enantiopure, bifunctional planar-chiral thiourea de-
rivatives (Figure 1, 1–3). The latter were applied in organo-
catalytic, asymmetric transformations.
Introduction
Planar-chiral motifs are typically potent structural ele-
ments of chiral ligands for transition-metal[1] or nucleo-
philic catalysis.[2] These structures are usually derived from
metallocenes, including ferrocene,[3] or from the [2.2]para-
cyclophane (Pc) framework.[4] In transition-metal catalysis,
[2.2]paracyclophane has been predominantly recognized as
a scaffold for phosphane ligands[5] or for N-heterocyclic
carbenes.[6] 4,12-Bis(hydroxy)[2.2]paracyclophane (PHANOL)
has been employed as a Brønsted acid organocatalyst.[7]
The activation of substrates by small organic molecules
through covalent- or Brønsted acid interactions has been
proved as a complementary approach to transition-metal
catalysis.[8] Hydrogen-bond catalysis[9] has attracted con-
siderable attention. Moreover, highly efficient thiourea-
based bifunctional organocatalysts have been explored in
terms of their potential in asymmetric organic synthesis.
The most commonly applied catalyst structures are derived
from trans-cyclohexyldiamine, 2,2Ј-binaphthyl, amino acids,
or the cinchona alkaloids.[10] Much to our surprise, there
are no reports to date of planar-chiral (thio)urea structures
being used as hydrogen-bond catalysts.
The [2.2]paracyclophane scaffold exhibits a rigid confor-
mation, enabling the arrangement of functional groups
within a defined distance (Figure 1, I and II). Such a rigid
alignment should be beneficial for the spacial alignment of
the catalytically active sites. Bifunctional catalysts[11] usu-
ally demonstrate greater activity and selectivity than mono-
functionalized structures. In this publication we describe
the synthesis of the first enantiopure planar-chiral thiourea
catalysts. Pc-based bifunctional thioureas 1–3 are substi-
Figure 1. Selected isomers of a disubstituted [2.2]paracyclophane
(I and II) and of planar-chiral thiourea derivatives for asymmetric
hydrogen-bond catalysis (1–3).
Results and Discussion
Generally, thioureas can be generated through the reac-
tion of amines with suitable isothiocyanates. Because
enantiopure amines 4–6 (Figure 2) are not accessible from
the chiral pool, optical resolution must be applied. For the
installation of the individual substitution pattern of the Pc
derivatives, different synthetic strategies are required: Al-
though the same functional groups are located on the
planar-chiral scaffold, the synthesis of isomeric thiourea de-
rivatives RP-2 and SP-3 demand distinct synthetic pathways.
[a] Karlsruhe Institute of Technology,
Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
Fax: +49-721-608-8581
E-mail: jan.paradies@ioc.uka.de
[b] University of Münster,
Corrensstraße 40, 48149 Münster, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901353.
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J. F. Schneider, F. C. Falk, R. Fröhlich, J. Paradies
SHORT COMMUNICATION
Generally, the pseudo-ortho position in the Pc framework
is difficult to access. The dibromination of Pc (31% yield)
and subsequent isomerization of the predominant pseudo-
para dibromo isomer (4,16-dibromo[2.2]paracyclophane) to
the 4,12-dibromo[2.2]paracyclophane (rac-14, 71%)[15] of-
fers a potential synthetic approach towards the desired sub-
stitution pattern. Thereafter, dibromide rac-14 was con-
verted into bromo alcohol rac-15, which was resolved
through the separation of the diastereomeric esters of (1S)-
camphanic acid.[16] Diastereomeric esters (1S,RP)-16 and
(1S,SP)-16 were obtained as white crystalline solids in 49
and 44% yield, respectively, after column chromatography
(Scheme 2). As depicted in Figure 3, the (1S,RP)-16 dia-
stereomer was crystallized and subjected to X-ray crystal-
structure analysis.[17]
Figure 2. Planar-chiral amines 4–6 as precursors for thioureas.
Amines SP-4 and RP-5 can be derived from a common
carboxylic acid intermediate (i.e., SP-7, Scheme 1). Carbox-
ylic acids can be converted into the corresponding amines
through Curtius rearrangement, making Pc carboxylic acid
7 a valuable starting material.[13] Additionally, readily ac-
cessible rac-7 can be resolved in large quantities through
cocrystallization with a chiral amine.[13b] Enantiopure
monofunctional amine SP-4 was synthesized in 65% yield
starting from enantiopure Pc carboxylic acid (SP-7,
Scheme 1), according to established procedures.[13b] This
procedure only required the purification of (SP)-4-
amino[2.2]paracyclophane (SP-4). However, the synthesis of
amino alcohol RP-5 relies on the selective functionalization
of position 13. It has been demonstrated that substituents
on the Pc framework – such as carboxylic acids, esters, and
nitro groups, allow regioselective electrophilic aromatic sub-
stitution in the pseudo-geminal position. This position was
accessed through the regioselective bromination of methyl
ester SP-8,[14] obtained through the reaction of the acid
chloride with methanol. The saponification of resulting
bromo ester RP-9[14] generated bromo carboxylic acid SP-
10, which then served as a precursor for the Curtius re-
arrangement (Scheme 1). The thermally generated isocyan-
ate (from RP-11) was trapped by tert-butyl alcohol to obtain
Boc-protected (Boc = tert-butoxycarbonyl) amine RP-12 in
67% yield over two steps. The Boc group facilitates the se-
lective metalation of the second aromatic ring by halogen–
lithium exchange. The resultant lithiated species was treated
Scheme 2. Optical resolution of rac-15.
The unit cell consists of three independent molecules. In
with trimethylborate. The subsequent oxidative workup contrast to the (1S,SP)-diastereomer, previously presented
produced Boc-protected amino alcohol RP-13 in 63% yield. in the literature, which exhibits an orthorhombic elemental
The protecting group was removed by trifluoroacetic acid cell, the compound crystallizes within the monoclinic space
in dichloromethane at 40 °C and free amino alcohol RP-5 group P21 (No. 4). Its structure reveals the absolute stereo-
was isolated in 68% yield.
chemistry of 1S,RP and the pseudo-ortho orientation of the
Scheme 1. Synthesis of SP-4 and RP-5.
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Planar-Chiral Thioureas as Hydrogen-Bond Catalysts
Scheme 4. Synthesis of enantiopure planar-chiral thioureas 1–3 [Ar
= 3,5-bis(trifluoromethyl)phenyl].
Figure 3. Representation of the X-ray crystal structure of (1S,RP)-
16 (the hydrogen atoms are omitted for clarity).[18]
We were able to obtain single crystals suitable for X-ray
structure determination of rac-1 (Figure 4, rac-1 was ob-
tained from amine rac-4).
bromide atom with respect to the ester functionality. The
distance between the two heteroatoms in the 4- and 12-posi-
tions is 4.183 Å, a significantly larger distance than for sub-
stituents in the 4- and 13-positions (3.009 Å, see Supporting
Information). This seemingly indicates that the difference in
distance between the two functional groups should lead to
varying activity and/or selectivity in enantioselective or-
ganic transformations Solvolysis of ester RP-16 with potas-
sium hydroxide furnished enantiopure bromo alcohol RP-
15 quantitatively (96%). To establish the amino function-
ality[9a,19] through halogen–lithium exchange and reaction
with a nitrogen electrophile, it was necessary to protect the
hydroxy group[20] as MEM ether RP-17 (64%) (MEM =
methoxyethoxymethylene; Scheme 3). After treatment of
RP-17 with n-butyllithium, the metalated [2.2]paracyclo-
phane derivative was treated with tosyl azide to generate 13-
azido-substituted ether SP-18. The latter was subsequently
reduced to amine SP-19 in 64% yield. Deprotection of the
hydroxy group produced 12-amino-4-hydroxy[2.2]para-
cyclophane (SP-6, 79%).
Figure 4. X-ray crystal structure of rac-1. (peripheral hydrogen
atoms and one molecule of chloroform are omitted for clarity).[21]
Analysis reveals the presence of both enantiomers in the
elemental cell. The two thiourea moieties exhibit s-cis, trans
conformation, resulting in a hydrogen-bonding interaction
between the two enantiomeric structures (N–H···S distances
of 2.542 and 2.688 Å).[22] These findings encouraged us to
investigate the potential of thioureas 1–3 as hydrogen-bond
donors in organic transformations.
Designed enantiopure thioureas SP-1, RP-2, and SP-3
were employed in asymmetric transformations. We selected
two reactions that require the activation of both reactants
to enable a selective process. Reactions meeting these
requirements are the asymmetric Friedel–Crafts alkylation
of indole[23] and the transfer hydrogenation of nitroole-
fins.[24] Both reactions are assumed to involve the binding
of the nitroolefin to the thiourea moiety, while the corre-
sponding heterocycle is bound simultaneously to the cata-
lyst through an additional hydrogen bond.[23] The OH
groups in the structure of the catalysts are known to be
beneficial for a selective process, encouraging us to apply
Scheme 3. Synthesis of pseudo-ortho amino alcohol SP-6 (pTos =
p-toluenesulfonyl).
Enantiopure amines SP-4, RP-5, and SP-6 were converted planar-chiral thioureas 1–3 to these reactions. Firstly, we
into enantiopure thiourea derivatives SP-1, RP-2, and SP-3 focused on the organocatalytic Friedel–Crafts alkylation re-
through reaction with 3,5-bis(trifluoromethyl)phenyl iso- action. The reaction of indole (20) with trans-β-nitrostyrene
thiocyanate in excellent yields (75–82%, Scheme 4).
(21) yielded 3-alkylindole 22 (Scheme 5).
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J. F. Schneider, F. C. Falk, R. Fröhlich, J. Paradies
SHORT COMMUNICATION
Conclusions
In conclusion, we have developed the synthesis of the
first enantiopure planar-chiral thioureas, all of which were
applied in asymmetric organocatalytic transformations. We
demonstrated that the planar-chiral [2.2]paracyclophane
scaffold is suitable to accommodate the thiourea and hy-
droxy moieties to furnish bifunctional hydrogen-bonded
catalysts. Isomeric bifunctional thiourea catalysts RP-2 and
Scheme 5. Friedel–Crafts alkylation of indole (20) and trans-β-ni-
trostyrene (21).
As hypothesized, bifunctional hydroxy-substituted thio- SP-3 display distinct selectivity, while conserving their ac-
ureas RP-2 and RP-3 catalyzed the reaction efficiently (99 tivity. This alteration in selectivity can be explained by the
and 95% yield, respectively), whereas monofunctional thio- change in orientation of the second functionality in the bi-
urea SP-1 generated the product in lower yield (31%). Al- functional catalyst structures. This discrepancy serves as a
though bifunctional thioureas RP-2 and RP-3 performed step towards the rational design of catalysts and will be fur-
very well in this reaction, the stereoselectivity was very low ther investigated with different [2.2]paracyclophane deriva-
(for more experiments see the Supporting Information). As tives.
a second application of the planar-chiral thiourea catalysts,
we investigated the asymmetric transfer hydrogenation of
nitroolefin 23 (Scheme 6).
Supporting Information (see footnote on the first page of this arti-
cle): Detailed experimental procedures, full characterization of new
compounds, NMR spectra, and HPLC traces.
Acknowledgments
We gratefully acknowledge the Fonds der Chemischen Industrie for
granting a Kekulé fellowship to J. F. S., a Fond fellowship to
F. C. F., and a Liebig fellowship to J. P. We would also like to thank
BASF SE for the donation of chemicals.
Scheme 6. Organocatalytic asymmetric transfer hydrogenation of
23 with Hantzsch ester 24
[a] reaction performed in toluene; [b] reaction was carried out at
60 °C.
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Received: November 24, 2009
Published Online: March 15, 2010
[18] Data sets were collected with a Nonius Kappa CCD dif-
fractometer. Programs used: data collection COLLECT (B. V.
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