Cooperative assistance in bifunctional organocatalysis: Enantioselective mannich reactions with aliphatic and aromatic imines

Article abstract of DOI:10.1002/anie.201203852

Hold them tight: Guided by X-ray structures, bifunctional thiourea catalysts containing an activating intramolecular hydrogen bond were redesigned. The new catalysts were used to effect a highly enantioselective Mannich reaction between malonates and both aliphatic and aromatic imines (see scheme; Boc=tert-butoxycarbonyl).

Full text of DOI:10.1002/anie.201203852

Angewandte
Chemie
DOI: 10.1002/anie.201203852
Organocatalysis
Cooperative Assistance in Bifunctional Organocatalysis:
Enantioselective Mannich Reactions with Aliphatic and Aromatic
Imines**
Nicolas Probst, ꢀdꢁm Madarꢁsz, Arto Valkonen, Imre Pꢁpai, Kari Rissanen, Antti Neuvonen,
and Petri M. Pihko*
Bifunctional catalysts that contain a Brønsted-basic amine
and a hydrogen-bond donor in the same molecule have been
very successful catalysts for numerous enantioselective reac-
tions.[1] Typical catalysts of this family include the diamino-
cyclohexane derivative A (Takemoto catalyst)[2] and the
cinchona-alkaloid-derived catalysts such as B (Soꢀs cata-
lyst),[3] both of which contain a thiourea moiety (Scheme 1).
The catalysts are capable of deprotonating suitable nucleo-
philes, such as activated carbonyl compounds. This proton-
transfer reaction generates an ion pair, which is composed of
the protonated catalyst and the anionic nucleophile interact-
ing through hydrogen bonds. At least one of the NH moieties
in the protonated catalyst is involved in activating the
electrophilic reaction partner.[4]
The inherent problem associated with this activation
mode is that the electrophilic partner and the anionic
nucleophile must compete for the same hydrogen-bond-
donor sites. As a result, only one of the hydrogen-bond donors
in the catalyst may be used for the activation of the
electrophile,[4a] thus reducing the level of activation of the
electrophile. We reasoned that the presence of an intra-
molecular hydrogen bond[5] could provide significant
improvement in the hydrogen-bond-donor capacity of the
thiourea moiety through cooperative effects,[6] as already
demonstrated by Smith and co-workers (catalyst C;
Scheme 1).[5d]
[*] Dr. N. Probst, Dr. A. Valkonen, Prof. Dr. K. Rissanen, A. Neuvonen,
Prof. Dr. P. M. Pihko
Department of Chemistry, Nanoscience Center
University of Jyvꢀskylꢀ
P.O.B. 35, 40014 JYU (Finland)
E-mail: petri.pihko@jyu.fi
Homepage: http://tinyurl.com/pihkogroup
Dr. ꢁ. Madarꢂsz, Dr. I. Pꢂpai
Institute of Organic Chemistry
Research Centre for Natural Sciences
Scheme 1. Structures of catalysts studied.
Hungarian Academy of Sciences
P.O.B. 17, 1525 Budapest (Hungary)
In the context of bifunctional catalysts, the success of such
a design is contingent on the stability of the intramolecular
[**] We thank Esa Haapaniemi, Mirja Lahtiperꢀ, and Dr. Elina Kalenius
for assistance with NMR spectroscopy and mass spectrometry. This
hydrogen bonds of the catalysts when they are strongly bound
work was supported by the Academy of Finland (Grant Nos. 139046
and 217221 to P.M.P., and 130629, 122350, and 140718 to K.R.),
to anionic substrates. The catalyst could refold, allowing the
catalyst to wrap around the substrate. In other words, the
catalyst could act as an anion receptor.[7] The thiourea moiety
must also be accessible for the activation of both substrates
simultaneously, while maintaining the conformation that
COST CM0905, and by the Hungarian Research Foundation (OTKA,
Grant NN-82955)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201203852.
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allows the intramolecular hydrogen-bond interaction intact.
As such, the design of a bifunctional catalyst that fulfils all of
these criteria is highly challenging. Herein we describe the
design of a new family of bifunctional catalysts based on
a rigid urea–thiourea scaffold where the activating intra-
molecular hydrogen bonds are maintained in both the free
catalyst as well as the catalyst–anion ion pair. These catalysts
promote Mannich reactions between Boc-protected imines
and malonates with a very wide scope: both aliphatic and
aromatic substrates can be converted into product with
excellent enantioselectivity.
In our initial design, we employed an amino-alcohol linker
similar to that used by Smith and co-workers (Scheme 1,
catalysts 1a–1d). In our 2nd-generation version, we used the
trans-1,2-aminoindanol linker (catalysts 2a–2 f; see below for
the rationale of this design). Both the 1,2-diaminocyclohex-
ane and 9-epi-aminoquinidine/quinine scaffolds were
screened (Scheme 1).[8]
hindering the simultaneous binding of two substrates to the
active site. We therefore replaced the linker with a more rigid
trans-1,2-aminoindanol subunit, thus resulting in a more
accessible active site (X-ray of 2b, Figure 1). Importantly,
the desired conformation was also observed in the hexafluor-
oacetylacetonate salt of 2a (2a·hfacac; Figure 1c), and in the
Et2O solvate of quinidine-derived compound 2c. The struc-
ture of 2a·hfacac clearly shows that even after proton transfer
and complex formation with the substrate mimic (hfacac), the
intramolecular hydrogen-bonding interaction in 2a is still
present in the resulting cation–anion complex. One of the
thiourea NH moieties is still accessible for binding of another
substrate and the rigid linker moiety ensures sufficient open
space near the thiourea moiety (compare the X-ray structures
of 1d and 2b).
We selected the Mannich reaction between dialkyl
malonates and both aromatic and aliphatic aldimines to
evaluate the activity and the selectivity of the catalysts. This
reaction is important because it provides a straightforward
access to chiral b3-amino acids. Although Mannich reactions
with aromatic imines and malonates are promoted by bifunc-
tional catalysts such as B,[10,11] aliphatic aldimines are typically
unreactive with these catalysts, thus limiting the scope of the
reaction. Aliphatic aldimines have been viable substrates in
Mannich reactions only with the use of stoichiometric
quantities of catalyst B[11] or stronger base.[12–14]
The X-ray structure of 1d[9] (Figure 1) indicated that
although the catalyst based on the l-valinol linker does fold in
such a way that allows an intramolecular hydrogen-bonding
interaction, there appeared to be a potential flaw in the initial
design: the l-valinol (Smith-type) linker causes the arene–
urea moiety to bend over the thiourea moiety, thus potentially
Consistent with the X-ray evidence (Figure 1), catalysts
with the trans-aminoindanol linker were, typically, signifi-
cantly more active and gave products with higher enantiose-
lectivity (Table 1, entries 4–8) than those with the l-valinol
linker (Table 1, entries 1–3). In the Mannich reaction with
aromatic aldimine 4a, catalyst 2c displayed very high
enantioselectivity, surpassing the selectivity observed with
the benchmark catalysts A and B under similar reaction
conditions.
In reactions of the aliphatic aldimine 6a (Table 2),
catalysts 2a and 2b, which contain the 1,2-diaminocyclohex-
ane moiety, were catalytically active and afforded the product
7aa in good yield and with good enantioselectivity (Table 2,
Table 1: Catalyst screening with aromatic aldimine 4a.[a]
Entry
Catalyst
Yield [%][b]
e.r.[c]
1
2
3
4
5
6
7
8
9
10
1a
1c
1d
2a
2c
2d
2e
2 f
A
70
29
78
81
80
44
85
73
82
88
71.2:28.8
16.8:83.2
72.8:27.2
96.9:3.1
99.6:0.4
35.0:65.0
95.7:4.3
96.4:3.6
95.0:5.0
95.8:4.2
Figure 1. Selected X-ray structures to illustrate (a) accessibility to the
active site, (b) redesign of the catalyst, and (c) demonstration of the
stability of the catalyst conformation, which is enforced by an intra-
molecular hydrogen bond, when the catalyst is bound with neutral (2c,
Et2O solvate) or anionic (2a·hfacac) hydrogen-bond acceptors. For
2a·hfacac, two slightly different binding modes were observed; only
one of them is shown.[8, 9]
B
[a] Reaction conditions: 3a (0.15 mmol, 150 mol%), 4a (0.10 mmol,
100 mol%), catalyst (0.01 mmol, 10 mol%), toluene (0.5 mL), 08C, 48 h.
[b] Yield of isolated product. [c] Determined by HPLC analysis using
a chiral column. Boc=tert-butoxycarbonyl.
2
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Table 2: Catalyst screening with aliphatic aldimine 6a.[a]
Furthermore, a range of malonate esters are tolerated
(Table 3, entries 1, 2, 8, and 9).
Aliphatic aldimines of various steric demand were viable
substrates (Table 3) in reactions catalyzed by 2a and 2b. Both
cyclic and acyclic aliphatic imines afforded the corresponding
Mannich products in excellent yield and enantioselectivity.
The Mannich products can be readily decarboxylated to give
the corresponding b-amino-acid derivatives[10,15] and, there-
fore, the present method allows the preparation of b3-amino-
acid[16] analogues of leucine (Table 3, entry 12) and valine
(Table 3, entries 13 and 30). In reactions of aliphatic imines,
various ester moieties on the malonates were tolerated, but
the presence of sterically demanding moieties, as in diiso-
propyl malonate, resulted in slower reactions (Table 3,
entry 29), and di-tert-butyl malonate was unreactive.[8] Finally,
when 1 mol% of catalyst 2a was used in a gram-scale reaction
at a temperature amenable to large-scale reactions (À208C)
the product was obtained in excellent yield and enantiose-
lectivity (Table 3, entry 30).
Entry
Catalyst
t [h][b]
Yield [%][c]
e.r.[d]
1
2
3
4
5
6
7
8
9
1a
1b
2a
2a[e]
2b
2c
2e
A
48
72
14
22
14
48
48
48
48
22
60
82
91
99
61
63
n.r.
n.r.
91.2:8.8
~20:80
92.0:8.0
96.7:3.3
3.8:96.2
59.4:40.6
91.8:8.2
n.d.
B
n.d.
[a] Reaction conditions: 3a (0.10 mmol, 100 mol%), 6a (0.30 mmol,
300 mol%), catalyst (0.01 mmol, 10 mol%), toluene (0.5 mL), 08C.
[b] Monitored by TLC. [c] Yield of isolated product. [d] Determined by
HPLC analysis using a chiral column. [e] Reaction conducted at À408C.
n.d.=not determined, n.r.=no reaction.
Further evidence for the proposed mode of action of
catalyst 2a was provided by computational studies. The
Mannich reaction between malonic ester 3a and aldimine 6d
(R’ = iPr; Table 3) catalyzed by 2a has been examined by
density functional theory (DFT) calculations.[17] Conforma-
tional analysis of the catalyst indicates that the most stable
form of 2a in solution contains internal hydrogen bonds
between the urea and thiourea moiety, allowing the cooper-
ative action of the catalyst.[17]
entries 3–5). In sharp contrast to catalysts 2a and 2b, the
benchmark thiourea catalysts A and B failed to promote the
desired Mannich reaction (Table 2, entries 8–9), underscoring
the importance of the intramolecular hydrogen-bond activa-
tion in the catalyst.
The superior activity of the indanol scaffold is even more
evident from in situ monitoring of the reaction of aliphatic
imine 6a by NMR spectroscopy (Figure 2). Catalysts 2a and
2b are significantly more active than 1a and 1b.
An extensive conformational search for transition states
À
for C C bond formation that lead to the major and minor
With these results, the scope of the Mannich reaction was
investigated using various substituted aromatic and aliphatic
aldimines (Table 3). When catalyst 2c was used, aromatic
aldimines bearing electron-donating as well as electron-
withdrawing moieties afforded the corresponding products
in excellent yield and enantioselectivity (Table 3, entries 3—
5; for more examples see the Supporting Information).
Mannich products, (R)-7ad and (S)-7ad, respectively, showed
that imine activation occurs preferentially through a hydro-
gen-bond interaction between the imine nitrogen atom and
the NH moiety proximal to the indane ring (Figure 3). The
computational data reveal substantial differences between
the relative Gibbs free energies of the TS-R and TS-S
transition states (6.8 kcalmolÀ1). This result is in line with the
high enantioselectivities observed experimentally.
Structural analysis of these transition states
suggest that the two reaction pathways have very
different steric requirements. In TS-R, the imine
fits well into the cavity formed by the catalyst and
the malonate, whereas in TS-S the Boc moiety of
the imine has unfavorable steric interactions with
the protonated amine and the indane ring units
of the catalyst. The latter interaction results in
significant charge separation because the malo-
nate ion is displaced from its optimal position.
The imine nitrogen atom in 6d is able to
make only one hydrogen-bond contact with the
catalyst in transition state TS-R (Figure 3). The
high energetic cost in displacing the malonate
from its optimal position means that only one
hydrogen-bond-donor site is available for acti-
vation of the imine. However, even a single
hydrogen-bond donor can provide significant
substrate activation if its hydrogen-bond-donor
Figure 2. Comparison of the activity of the catalysts through in situ monitoring of the
Mannich reaction of malonate 3a with aliphatic imine 6a through NMR spectroscopy
(concentration of 3a at t0 is 0.2m). Consumption of the malonate 3a is monitored.
capacity is enhanced by cooperative effects
through an intramolecular hydrogen bond.[18]
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Table 3: Substrate scope with aliphatic and selected aromatic imines.
For further examples, see the Supporting Information.[a]
Entry Product
R
R’
t [h][b] Yield [%][c] e.r.[d]
1[e]
2[e]
3
4
5
5aa
5ba
5bc
5bd
5bg
5bh
5bi
5ca
5da
7aa
7ab
7ac
7ad
7ae
7af
Me Ph
Bn Ph
48
16
24
21
21
15
24
45
96
22
14
24
22
23
20
80
95
93
94
97
89
87
95
59
91
99
96
91
99
99
99
99
99
99
99
99
98
99
99
99
99
96
73
38
98
99.6/0.4[f]
99.3/0.7[f]
98.3/1.7[f]
99.2/0.8[f]
99.8/0.2
99.5/0.5[f]
98.0/2.0
99.4/0.6
99.1/0.9
96.7/3.3
98.4/1.6
99.3/0.7[f]
99.6/0.4
99.2/0.8
98.2/1.8[f]
98.4/1.6
99.2/0.8
99.4/0.6
99.2/0.8[f]
0.3/99.7[g]
1.3/98.7[g]
0.6/99.4[g]
2.6/97.4[g]
99.9/0.1
99.6/0.4
3.3/96.7
98.2/1.2
97.6/2.4
nd
Figure 3. Transition states located for organocatalytic Mannich reac-
tion between 3a and 6d (R’=iPr). 3aÀ denotes the malonate ion. The
Bn p-CH3C6H4
Bn p-FC6H4
Bn p-NO2C6H4
Bn 2-furyl
Bn 2-naphthyl
À
developing C C bonds are illustrated by green dashed lines, whereas
hydrogen bonds between the protonated catalyst and the substrates
are illustrated as dotted lines. The urea moiety of the catalyst (linked
to the indanol moiety) and the hydrogen atoms (except those of the
NH moieties) are omitted for clarity. Computed relative Gibbs free
energies (in kcalmolÀ1) are shown in parenthesis.
6
7
8[e]
9[e]
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26[g]
27
28
29
30[h]
Et
Ph
iPr Ph
Me cyclohexyl
Me nBu
Me iBu
Me iPr
Me Et
Me PhCH2CH2
Me TBDPSO(CH2)2 17
Me cyclopentyl
Me n-Hex
Bn cyclohexyl
Bn cyclohexyl
Bn nBu
Bn iBu
Bn Et
Bn TBDPSO(CH2)2 46
as well as to understand the structural requirements for the
stability of the catalyst conformation, and the anion binding
properties of these catalysts, are in progress.
7ag
7ah
7ai
24
24
23
14
22
22
48
Received: May 18, 2012
Published online: && &&, &&&&
7ba
7ba
7bb
7bc
7be
7bg
7bh
7bh
7bi
Keywords: asymmetric catalysis · hydrogen bonds · imines ·
.
Mannich reactions · organocatalysis
Bn cyclopentyl
Bn cyclopentyl
Bn n-Hex
24
22
24
43
68
24
[1] For recent reviews, see: a) M. Kotke, P. R. Schreiner, Hydrogen
Bonding in Organic Synthesis (Ed.: P. Pihko), Wiley-VCH, 2009;
pp. 141 – 351; b) P. M. Pihko, H. Rahaman, Enantioselective
Organocatalyzed Reactions I (Ed.: R. Mahrwald), Springer,
Heidelberg, 2011, pp. 185 – 207.
7ca
7da
7bd
Et
cyclohexyl
iPr cyclohexyl
Bn iPr
98.1/1.9
[2] O. Tomotaka, Y. Hoashi, Y. Takemoto, J. Am. Chem. Soc. 2003,
125, 12672.
[3] B. Vakulya, S. Varga, A. Csꢁmpai, T. Soꢀs, Org. Lett. 2005, 7,
1967.
[4] For previous mechanistic studies involving bifunctional amine
catalysts, see: a) A. Hamza, G. Schubert, T. Soꢀs, I. Pꢁpai, J. Am.
Chem. Soc. 2006, 128, 13151; b) P. Hammar, T. Marcelli, H.
Hiemstra, F. Himo, Adv. Synth. Catal. 2007, 349, 2537; c) S. J.
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Almas¸i, D. A. Alonso, E. Gꢀmez-Bengoa, C. Nꢁjera, J. Org.
Chem. 2009, 74, 6163; e) B. Tan, Y. Lu, X. Zeng, P. J. Chua, G.
Zhong, Org. Lett. 2010, 12, 2682.
[a] Reaction conditions: malonate 3 (0.15 mmol), imine 4 or 6
(0.45 mmol), catalyst 2c (for imines 4), 2a or 2b (for aliphatic imines 6)
(0.015 mmol, 10 mol%), toluene (0.75 mL), À408C. [b] Reaction prog-
ress was monitored by TLC. [c] Yield of isolated product. [d] Determined
by HPLC analysis. [e] 3 (0.15 mmol, 150 mol%), 4 (0.10 mmol,
100 mol%), catalyst 1b (0.01 mmol, 10 mol%), toluene (0.5 mL) were
used. [f] Absolute configuration determined by comparison of optical
rotation with literature values. All other products have been assigned by
analogy. [g] Reaction performed with catalyst 2b at 08C. [h] Reaction
performed with 1.1 g of 3b using 1 mol% of catalyst 2a at À208C.
Bn=benzyl, TBDPS=tert-butyldiphenylsilyl.
[5] For a discussion of cooperative effects in intramolecular hydro-
gen bonds, and their contributions to catalysis, see: a) G. Huo,
D. R. Salahub, Angew. Chem. 1998, 110, 3155; Angew. Chem. Int.
Ed. 1998, 37, 2985; for examples of small-molecule hydrogen-
bond-donor catalysts enhanced through internal interactions
involving a Lewis acid or a hydrogen bond, see: b) M. P. Hughes,
B. D. Smith, J. Org. Chem. 1997, 62, 4492; c) M. Ganesh, D.
Seidel, J. Am. Chem. Soc. 2008, 130, 16464; d) C. R. Jones, G. D.
Pantos¸, A. J. Morrison, M. D. Smith, Angew. Chem. 2009, 121,
7527; Angew. Chem. Int. Ed. 2009, 48, 7391; e) S. S. So, J. A.
Burkett, A. E. Mattson, Org. Lett. 2011, 13, 716.
[6] For a recent study on the equilibrium acidities of catalysts A, B,
and related thiourea catalysts, see: G. Jakab, C. Tancon, Z.
Zhang, K. M. Lippert, P. R. Schreiner, Org. Lett. 2012, 14, 1724.
[7] For recent reviews of anion–receptor chemistry, see: a) “Anion
Receptor Chemistry”: J. Sessler, P. A. Gale, W.-S. Cho, Mono-
graphs in Supramolecular Chemistry (Ed.: J. F. Stoddart), RSC
In summary, we have identified bifunctional tertiary
amine–thiourea catalysts, which contain a rigid trans-1,2-
aminoindanol scaffold and a urea group that activates the
thiourea group through intramolecular hydrogen bonds in
a cooperative fashion. These catalysts promote the enantio-
selective Mannich reaction between malonates and both
aliphatic and aromatic imines, thus providing a direct route to
a wide variety of protected b3-amino acids. Computational
and X-ray data suggest that the intramolecular hydrogen
bonds and the overall fold of the catalysts are maintained
intact when the catalysts are unbound, when the catalysts are
À
bound to the anionic substrate, and during C C bond
formation. Studies to expand the scope of these new catalysts
4
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Angewandte
Chemie
´
´
Publishing, Cambridge, 2006; b) P. A. Gale, Acc. Chem. Res.
2011, 44, 216.
[14] M. Nejman, A. Sliwinska, A. Zwierzak, Tetrahedron 2005, 61,
8536.
[8] For details, see the Supporting Information.
[15] See the Supporting Information for an example of the synthesis
[9] CCDC 880524 (1d), 880525 (2a), 880908 (2b), 880526 (2a·hfa-
cac), 880527 (2a·HCl), 880528 (2c), 880529 (2g), and 880530
(2h) contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.
uk/data_request/cif. The X-ray structure of 2a·HCl reveals an
alternative anion-receptor mode for the catalyst; for details, see
the Supporting Information.
of a b3-amino acid derived from 7bd.
[16] For reviews of b-amino acids, see: a) G. Lelais, D. Seebach,
Biopolymers 2004, 76, 206; b) Enantioselective Synthesis of b-
Amino Acids, 2nded. (Eds.: E. Juaristi, V. Soloshonok), Wiley-
VCH, New York, 2005; for a previous organocatalytic approach
to aliphatic b2-amino acids, see: c) Y. Chi, S. Gellman, J. Am.
Chem. Soc. 2005, 126, 6804.
[17] For computational details, see the Supporting Information.
[18] For a review, see: H. Yamamoto, K. Futatsugi, Angew. Chem.
2005, 117, 1958; Angew. Chem. Int. Ed. 2005, 44, 1924; we note
here that binding via the carbamate oxygen atoms is also
[10] For a seminal study of this reaction with aromatic imines and
cinchona-alkaloid-derived thiourea catalysts, see: A. L. Tillman,
Y. Jinxing, D. J. Dixon, Chem. Commun. 2006, 1191.
À
[11] J. Song, Y. Wang, L. Deng, J. Am. Chem. Soc. 2006, 128, 6048.
[12] J. Song, H. Shih, L. Deng, Org. Lett. 2007, 9, 603.
[13] O. Marianacci, G. Micheletti, L. Bernardi, F. Fini, M. Fochi, D.
Pettersen, V. Sgarzani, A. Ricci, Chem. Eur. J. 2007, 13, 8338.
possible; however, such a binding does not lead to productive C
C bond formation. Studies addressing the binding of substrates
as well as expansion of the substrate scope are underway.
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Communications
Organocatalysis
N. Probst, ꢁ. Madarꢂsz, A. Valkonen,
I. Pꢂpai, K. Rissanen, A. Neuvonen,
P. M. Pihko*
&&&& — &&&&
Cooperative Assistance in Bifunctional
Organocatalysis: Enantioselective
Mannich Reactions with Aliphatic and
Aromatic Imines
Hold them tight: Guided by X-ray struc-
tures, bifunctional thiourea catalysts
containing an activating intramolecular
hydrogen bond were redesigned. The new
catalysts were used to effect a highly
enantioselective Mannich reaction
between malonates and both aliphatic
and aromatic imines (see scheme; Boc=
tert-butoxycarbonyl).
6
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Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!