TBD/Al2O3: A novel catalytic system for dynamic intermolecular aldol reactions that exhibit complex system behaviour

Article abstract of DOI:10.1039/c2ob06648c

The heterogeneous system TBD/Al₂O₃ is an efficient catalyst for the intermolecular aldol reaction between ketones and aromatic aldehydes. This system operates with low catalysts loading (10%), in water or organic solvents, and with s

Full text of DOI:10.1039/c2ob06648c

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
Organic &
Biomolecular
Chemistry
Cite this: Org. Biomol. Chem., 2012, 10, 1976
www.rsc.org/obc
PAPER
TBD/Al2O3: a novel catalytic system for dynamic intermolecular aldol
reactions that exhibit complex system behaviour†
Ángel Martínez-Castañeda, Humberto Rodríguez-Solla, Carmen Concellón* and Vicente del Amo*
Received 28th September 2011, Accepted 19th December 2011
DOI: 10.1039/c2ob06648c
The heterogeneous system TBD/Al2O3 is an efficient catalyst for the intermolecular aldol reaction
between ketones and aromatic aldehydes. This system operates with low catalysts loading (10%), in water
or organic solvents, and with short reaction times. The desired aldol products are rendered cleanly.
Experiments confirmed that this aldol protocol is reversible, and allowed for the preparation of dynamic
combinatorial libraries (DCLs) of interconverting aldols. Analysis of these DCLs showed up how
properties such as diastereoselectivity can emerge unpredictably from the library when it is considered as
a whole.
reactions (imines, hydrazones, oximes, nitrones), alkene and
alkyne metathesis, Diels–Alder/retro-Diels–Alder reactions,
Introduction
In recent years, the chemistry of the reversible covalent bond
(dynamic covalent chemistry (DCC)1) has been exploited in the
generation of dynamic combinatorial libraries (DCLs).2 DCLs
can be defined as mixtures of different interconverting com-
pounds operating under thermodynamic control. That is, the
entire distribution of library components is governed by their
relative free energies, and so, processes that are capable of alter-
ing the free energy relationships within the DCL can ultimately
influence the distribution (population) of the integrating library
members. Nowadays the utility of DCLs cannot be questioned:
these libraries have shown considerable potential in the develop-
ment of sensors,3 the preparation of interlocked chemical archi-
tectures4 and the discovery of ligands for artificial receptors and
large biomolecules,5 among others.
An obvious condition to create a DCL is to find an appropriate
reversible process, which has to fulfil a number of prerequisites.
Firstly, it has to be reversible on a reasonable time scale under
mild experimental conditions (considering the slow kinetics of
the covalent bond formation it is often necessary to make use of
catalysts) and, it cannot interfere with other processes of the
library or destroy the chemical integrity of the library members.
Accordingly, the reversible reactions suitable for DCC are rare
compared to the large number of irreversible processes found
in classical synthetic chemistry. To our knowledge, disulfide
exchange reactions, acyl transfer reactions (from esters, thio-
esters, and amides), acetal exchange reactions, CvN exchange
Michael addition/retro-Michael reactions, and very few others
only have been used to generate DCLs to date. In this communi-
cation we report an efficient catalytic system that promotes fast
and efficient dynamic aldol reactions between ketones and aro-
matic aldehydes allowing for the preparation of DCLs of aldols
in water or, alternatively, in non-polar organic solvents.6
Although organocatalyzed7 aldol reactions are admittedly revers-
ible, known to proceed through aldol/retro-aldol reaction chan-
nels, only recent contributions8 have exploited this character.
Results and discussion
Initially, we looked for a simple and mild system capable of cata-
lyzing the direct aldol reaction between ketones and aromatic
aldehydes to full conversion. The reaction between cyclohexa-
none, 1, and 4-chlorobenzaldehyde, 2a, a not too reactive alde-
hyde, was used as a model system to screen different reaction
conditions. Inspired by the work of Mioskowski and Baati9 on
triazabicyclo[4.4.0]dec-5-ene (TBD)-catalyzed intramolecular 5-
and 6-enolexo aldolizations of ketoaldehydes in THF, and based
on our recent finding of TBD-derived guanidinium salts as suit-
able additives for proline-catalyzed aldol reactions,10 we turned
our attention to this inexpensive, readily available, guanidine
base.11 Early experiments showed that aldol 3a was rendered in
71% conversion when a solution of aldehyde 2a and cyclohexa-
none, 1, in THF, was stirred for 5 days in the presence of 10 mol
% TBD (Table 1, entry 1). After several trials toluene turned out
to be a better solvent for this reaction. When a solution of alde-
hyde 2a (1 equiv.) and cyclohexanone (10 equiv.) containing
10 mol% of TBD was stirred for 5 days in toluene (0.2 M
for 2a) at room temperature, the desired aldol adduct 3a
was obtained cleanly in 98% conversion as a mixture of
Departamento de Química Orgánica e Inorgánica, Universidad de
Oviedo, C/Julián Clavería 8, 33006 Oviedo, Spain. E-mail: ccf@uniovi.
es, vdelamo@uniovi.es; Tel: +34 (0) 985 10 3457 +34 (0) 985 10 3075
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c2ob06648c
1976 | Org. Biomol. Chem., 2012, 10, 1976–1981
This journal is © The Royal Society of Chemistry 2012

View Article Online
Table 1 Initial screening of conditions for the formation of aldol 3aa
Table 2 Scope of the TBD/Al2O3-catalyzed intermolecular aldol
reacion in toluenea
Entry
Ar
Product
Anti/synb
Yield (%)c
1d
4-ClC6H4
C6H5
4-FC6H4
4-CF3C6H4
4-NO2C6H4
3-ClC6H4
4-NO2C6H4
4-NO2C6H4
3a
3b
3c
3d
3e
3f
47 : 53
50 : 50
50 : 50
44 : 56
42 : 58
45 : 55
38 : 62
50 : 50
85
97
95
98
70
92
75
78
Entry
Solvent
Time
Anti/synb
Conversion (%)b
2d
3d,e
4d,e
5d,e
6d
1
THF
5 days
5 days
3 h
45 min
3 h
3 h
45 min
40 : 60
47 : 53
47 : 53
47 : 53
63 : 37
52 : 48
51 : 49
71
98
99
99
84
99
99
2
Toluene
Toluene
Toluene
H2O
H2O
H2O
3c
4d
5
7f
4e
5e
8g
6c
7d
a General reaction conditions: ketone (10 equiv.), 2a–f (1 equiv.),
toluene (0.15 M for 2a–f), 45 min, rt, sonic waves. b Determined by H
1
a General conditions: 1 (10 equiv.), 2a (1 equiv.), solvent (0.2 M for 2a).
b Determined by 1H NMR analysis from crude reaction mixtures. Anti
and syn diastereoisomers were identified by comparison with similar
compounds previously described in the literature. c Neutral Al2O3
(10 mol%) was used as co-catalyst. d Neutral Al2O3 (10 mol%) was used
as co-catalyst. The reaction mixture was sonicated.
NMR on crude reaction mixtures. c Isolated yield of pure products 3, 4
and 5 purified by flash chromatography on silica gel. Products 3, 4 and 5
were isolated as a mixture of diastereoisomers. d Cyclohexanone was
used as ketone. e Reaction was carried out for 3 h at rt without
sonication. f Cyclopentanone was employed as ketone. g 3-Pentanone
was employed as ketone.
diastereoisomers, with no significant diastereoselectivity
(Table 1, entry 2). Aiming to shorten the reaction time we inves-
tigated the effect of incorporating a Lewis acid (l.a.) to our cata-
lytic system. Whereas most of the l.a. explored led to
dehydration products (α,β-unsaturated ketones), addition of
10 mol% of neutral alumina (Al2O3), a rather mild hetero-
geneous l.a., quantitatively afforded aldol 3a in 3 h (Table 1,
entry 3). Moreover, when this reaction was performed under
sonic waves a strong acceleration was observed, the desired aldol
3a being quantitatively formed in 45 min (Table 1, entry 4). To
our surprise, the catalytic system TBD-Al2O3 was also effective
when distilled water was used as solvent (Table 1, entries 5–7).
Blank experiments confirmed that Al2O3 itself, with no TBD,
was unable to catalyze the aldol reaction in any solvent and
under neither of the conditions experienced.
Table 3 Scope of the TBD/Al2O3-catalyzed intermolecular aldol
reacion in watera
Entry
Ar
Product
Anti/synb
Yield (%)c
1d
2d
3d
4d
5d
6e
7e
4-ClC6H4
C6H5
4-FC6H4
4-NO2C6H4
4-CO2MeC6H4
4-FC6H4
3a
3b
3c
3e
3g
4c
4e
52 : 48
58 : 42
59 : 41
57 : 43
60 : 40
57 : 43
43 : 57
98
97
95
98
92
98
98
4-NO2C6H4
Following this methodology, employing toluene as solvent, a
collection of aldols 3a–f (derived from cyclohexanone, Table 2,
entries 1–6), 4e (from cyclopentanone, Table 2, entry 7) and 5e
(from 3-pentanone, Table 2, entry 8), could be prepared in
optimum yield after purification by flash chromatography. All
these aldols were isolated as a mixture of diastereoisomers with
low levels of diastereoselectivity, the syn-disposition being
slightly favoured. In general, the reaction tolerates a wide diver-
sity of electron-donating or electron-withdrawing functional
groups anchored on either position of the aromatic ring. Reac-
tions carried out on electron poor aldehydes (Table 2, entries
3–5) do not tolerate sonication, leading to complex crude reac-
tion mixtures.
Similarly, TBD-Al2O3-catalyzed aldol reactions were per-
formed in water (Table 3). Products 3a–c, 3e, 3g, 4c and 4e were
obtained in high yields in a process where purification is no
longer required. It is significant to point out that the anti-
configuration of these aldols was slightly favoured (except for
4e, Table 3, entry 7), as opposed to those presented in Table 2.
a General reaction conditions: ketone (10 equiv.), 2a–f (1 equiv.),
distilled water (0.15 M for 2a–f), 45 min, rt, sonic waves. b Determined
by 1H NMR on crude reaction mixtures. c Isolated yield of pure products
3 and 4. Products 3 and 4 were isolated as a mixture of diastereoisomers.
d Cyclohexanone was used as ketone. e Cyclopentanone was employed
as ketone.
Aldol 3g, equipped with an ester group, does not suffer from
hydrolysis during the course of the reaction.
Aldols 6c and 6e, prepared from acetone, were also rendered
in good yield by means of our methodology (Table 4). In this
occasion, acetone has to be used as reagent and solvent under
sonication. This type of aldol adduct are known to suffer rapid
dehydration to afford the corresponding enones. In this respect,
aldol 6c was prepared in 79% yield in a significant 4.0 mmol
scale.
In order to study the reversibility of the aldol reaction under
our experimental conditions, thus the ability to give rise to
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 1976–1981 | 1977

View Article Online
Table 4 TBD/Al2O3-catalyzed intermolecular aldol reaction with
to generate libraries LB1 and LB2, respectively (Scheme 1).
Excess of ketones must be added to guarantee full conversion to
the desired aldol products. To “freeze” the exchanging process,
and the population of the different library components, the cata-
lysts were removed by a standard work up. Analysis of LB1 and
LB2 by 1H and 19F NMR spectroscopy (samples reconstituted in
CDCl3)12 confirmed the presence of the eight possible aldol pro-
ducts expected to occur from recombination through an aldol/
retro-aldol mechanism. It is important to point out that the pres-
ence of undesired side products is negligible amid the mixtures of
aldols. Deconvolution of the appropriate resonances allowed
identification, calculation (Table 5), and plotting the concentration
of each aldol featured in both of the libraries (Fig. 1). Exper-
iments carried out for longer reaction times (overnight for LB1,
and 5 h for LB2) showed up an identical distribution of library
members in each library. It confirms that the ratios outlined in
Table 5 correspond to truly equilibrium positions (energy mini-
mums) for LB1 and LB2. Decomposition of the aldol products
was not observed in the reaction times experienced.
acetonea
Entry
Ar
Product
Yield (%)b
1
4-NO2C6H4
4-FC6H4
6e
6c
60
79
2c
a General reaction conditions: aromatic aldehyde (1 equiv.), in neat
acetone (0.2 M for 2), 45 min, rt, sonic waves. b Isolated yield of pure
products 6 after flash chromatography. c Reaction carried out on a scale
of 4.0 mmol.
DCLs, we designed and implemented the following experiment:
equimolar mixtures of the cyclohexanone-containing aldol 3e
(0.15 mmol, anti/syn 57 : 43), and cyclopentanone-containing
aldol 4c (0.15 mmol, anti/syn 57 : 43), were stirred for 5 h, in
toluene (2 mL), or sonicated for 2 h in water (2 mL), in the pres-
ence of cyclohexanone (1.5 mmol, 10 equiv.), cyclopentanone
(1.5 mmol, 10 equiv.), TBD (0.03 mmol) and Al2O3 (0.03 mmol)
Scheme 1 Preparation of dynamic libraries LB1 and LB2 through an aldol/retro-aldol process mediated by catalytic amounts of TBD-Al2O3.
1978 | Org. Biomol. Chem., 2012, 10, 1976–1981 This journal is © The Royal Society of Chemistry 2012

View Article Online
Table 5 Distribution of components in dynamic libraries LB1 and
LB2a
Compound
[ ] in LB1 (mM)b
[ ] in LB2 (mM)b
4-NO2-C6H4-CHO
4-F-C6H4-CHO
Anti-3e
Syn-3e
Anti-3c
0
2.5
7.4
11.7
8.8
0.04
0.5
19.1
28.0
8.0
Syn-3c
Anti-4e
Syn-4e
Anti-4c
9.6
5.0
8.9
18.5
21.0
40.5
19.3
36.6
23.3
30.8
Syn-4c
a Libraries LB1 and LB2 were prepared as detailed in the experimental
section. b Volumes of cyclohexanone and cyclopentanone were ignored
for calculating the concentration of aldols.
Fig. 2 (a) Bar-chart graphic comparing the percentage of anti (dark
grey) and syn (light grey) diastereoisomers of aldol 4c obtained as indi-
cated in Table 3 (top bar) or in library LB2 (bottom bar), respectively.
(b) Bar-chart graphic comparing the percentage of anti (dark grey) and
syn (light grey) diastereoisomers of aldol 4e obtained as indicated in
Table 3 (top bar) or in library LB2 (bottom bar), respectively.
ratio of around 1 : 2 (Fig. 2). For 4c, this relationship is signifi-
cantly different from that obtained for the same aldol when it is
prepared separately under analogous reaction conditions, as in
Table 3, entry 6 (Fig. 2a). This selectivity for 4c shows how
properties (i.e. diastereoselectivity), which could not be pre-
dicted in principle by taking into account the subcomponents of
the network in isolation, can emerge even from small system/
network of interconverting molecules, interacting through supra-
molecular contacts,13 competing for a catalyst and for molecular
building blocks. Accordingly, the system of aldols 3c, 3e, 4c, 4e,
involved in thermodynamically controlled reactions, approaches
equilibrium in a complex way to render the most stable set of
products from the network as a whole. We believe that this kind
of approach, a Systems Chemistry strategy,14 the deliberate cre-
ation of mixtures/collections of compounds, commonly avoided
in classical organic synthesis, may open untrodden paths for hot
areas such as organocatalysis.
Fig. 1 (a) Pie-chart graphic representing the percentage and mmols (in
brackets, of a maximum of 0.3 mmol) of cyclopentyl aldols (dark grey)
versus cyclohexyl aldols (light grey) in DCLs LB1 (left) and LB2
(right), respectively. (b) Pie-chart graphic representing the percentage
and mmols (in brackets, of a maximum of 0.3 mmol) of syn aldols (dark
grey) versus anti aldols (light grey) in DCLs LB1 (left) and LB2 (right),
respectively.
A look at Table 5, gathering the results from the previous
experiments, confirms that the concentrations of aldols in
libraries LB1 and LB2 are unlike. Firstly, it is important to note
the preference of LB1 for selecting cyclopentyl aldols, which are
populated in a 3-fold excess with respect to the cyclohexyl ones
(Fig. 1a). It reveals the larger thermodynamic stability in toluene
of structures 4c and 4e with respect to the cyclohexyl aldols 3c
and 3e.
Conclusion
Summarizing, herein we have developed a novel catalytic system
(TBD/Al2O3), which is rather straightforward and effective for
the synthesis of aldols in water and non-polar organic solvents
(toluene). The transformation is fast, allowing the preparation of
pools of aldols interconverting through an aldol/retro-aldol
sequence, a reaction that has not yet been broadly considered in
the construction of DCLs. We have demonstrated how moderate
levels of diastereoselectivity, which unfortunately could not be
Although in both libraries the syn aldols are favoured at
expense of those with an anti configuration (Fig. 1b), particularly
in LB2, the cyclopentyl aldols 4c and 4e present an anti/syn
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 1976–1981 | 1979

View Article Online
anticipated, can emerge from basic thermodynamically-con-
trolled network of molecules when supramolecular interactions
between the library members, and competition for the catalyst
and for molecular building blocks come to play. The intercon-
verting library members approach equilibrium in a complex way
to render the thermodynamically most stable set of products
from the network as a whole entity. This manuscript discloses a
comprehensible proof of principle showing that a Systems
Chemistry approach is workable. Experiments aiming to couple
an irreversible reaction to our DCLs, capable of selecting15
specific library members, are currently being investigated in our
laboratory.
CH2Cl2 (2 × 15 mL). The organic liquors were dried (MgSO4),
and the solvents and volatiles evaporated under reduced pressure
to afford crude material, which were purified further by flash
chromatography on silica gel.
Standard procedure for the synthesis of dynamic library LB1
A mixture of cyclohexanone-derived aldol 3e (37.4 mg,
0.15 mmol, anti/syn 57 : 43) and cyclopentanone-derived aldol
4c (31.2 mg, 0.15 mmol, anti/syn 57 : 43), weighed in closed a
test tube, were dissolved in toluene (2 mL). Cyclohexanone
(148 mg, 156 μL, 1.5 mmol), cyclopentanone (126 mg, 132 μL,
1.5 mmol), triazabicyclo[4.4.0]dec-5-ene (TBD, 4.2 mg,
0.03 mmol) and neutral Al2O3 (3.1 mg, 0.03 mmol) were added
to the former solution and it was vigorously stirred for 5 h at
room temperature. The reaction mixture was quenched with
NH4Cl aq. sat. (10 mL), and extracted with CH2Cl2 (2 ×
15 mL). The organic liquors were dried (MgSO4), and the sol-
vents and volatiles evaporated under reduced pressure to afford a
solid material, which was redissolved in CDCl3 and analyzed by
1H and 19F NMR spectroscopy.
Experimental
All commercially available reagents and solvents were used
without further purification. Samples of TBD were taken from a
Schlenk flask stored in the dark under argon atmosphere. Flash
chromatography of reaction products, when required, was carried
out using Silica 60A, particle size 230-400 micron (Merck).
Analytical thin layer chromatography (TLC) was performed on
DC-Alufolien Kieselgel 60F254 0.2 mm plates (Merck) and com-
pounds were visualised by UV fluorescence or 5% phospho-
1
molybdic acid in methanol. H NMR, 13C NMR and 19F NMR
Standard procedure for the synthesis of dynamic library LB2
spectra were recorded on a Bruker AC-300 or a Bruker DPX-300
spectrometer, using deuterated solvents and were referenced
To a suspension of cyclohexanone-derived aldol 3e (37.4 mg,
0.15 mmol, anti/syn 57 : 43) and cyclopentanone-derived aldol
4c (31.2 mg, 0.15 mmol, anti/syn 57 : 43), in distilled water
(2 mL), cyclohexanone (148 mg, 156 μL, 1.5 mmol), cyclopen-
tanone (126 mg, 132 μL, 1.5 mmol), triazabicyclo[4.4.0]dec-5-
ene (TBD, 4.2 mg, 0.03 mmol) and neutral Al2O3 (3.1 mg,
0.03 mmol) were added sequentially. This mixture was sonicated
for 2 h before it was quenched with NH4Cl aq. sat. (10 mL), and
extracted with CH2Cl2 (2 × 15 mL). The organic liquors were
dried (MgSO4), and the solvents and volatiles evaporated under
reduced pressure to afford a solid material, which was redis-
solved in CDCl3 and analyzed by 1H and 19F NMR
spectroscopy.
internally to the residual solvent peak (δH = 7.26 ppm, δC
=
77.36 ppm) signal,16 or to CFCl3 (δF = 0.00 ppm) for 19F
spectra. Coupling constants (J-values) are given in Hertz (Hz).
The DEPT 135 technique was used to assign methylene (CH2)
signals if necessary. NMR spectra assignation was aided by com-
parison with literature values for similar compounds.
Standard procedure for the synthesis of aldols (as in Tables 2
and 3)
A suspension of triazabicyclo[4.4.0]dec-5-ene (TBD, 4.2 mg,
0.03 mmol) and neutral Al2O3 (3.1 mg, 0.03 mmol) in toluene
(2 mL), or alternatively distilled water (2 mL), was prepared
inside a closed test tube. The corresponding aromatic aldehyde
(0.3 mmol) and ketone (3.0 mmol) were added sequentially to
the former suspension. The reaction mixture was then sonicated
for 45 min before it was poured onto NH4Cl aq. sat. (10 mL)
and extracted with CH2Cl2 (2 × 15 mL). The organic liquors
were dried (MgSO4), and the solvents and volatiles evaporated
under reduced pressure to afford crude material, which were
purified further, only if required, by a brief filtration through a
plug of silica gel.
Acknowledgements
The authors thank MICINN (CTQ2010-14959) for financial
support. C. C. and V. d. A. thank MICINN for a Juan de la
Cierva contract, and a Ramón y Cajal contract, respectively. We
gratefully thank Dr Francisco J. González (Universidad de
Oviedo) for his useful discussions and advice.
References
1 (a) J.-M. Lehn, Chem.–Eur. J., 1999, 5, 2455–2463; (b) S. J. Rowan, S.
J. Cantrill, G. R. L. Cousins, J. K. M. Sanders and J. F. Stoddart, Angew.
Chem., Int. Ed., 2002, 41, 898–952; (c) P. T. Corbett, J. Leclaire, L. Vial,
K. R. West, J.-L. Wietor, J. K. M. Sanders and S. Otto, Chem. Rev., 2006,
106, 3652–3711; (d) S. Ladame, Org. Biomol. Chem., 2008, 6, 219–226;
(e) V. del Amo and D. Philp, Chem.–Eur. J., 2010, 16, 13304–13318.
2 J.-M Lehn, Chem.–Eur. J., 1999, 5, 2455–2463.
3 For recent selected examples, see: (a) S. Rochat and K. Severyn,
J. Comb. Chem., 2010, 12, 595–599; (b) J. Gao, A. Granzhan, X. Qian
and K. Severin, Chem. Commun., 2010 (30), 5515–5517; (c) S. Rochat,
J. Gao, X. Qian, F. Zaubitzer and K. Severin, Chem.–Eur. J., 2010, 16,
104–113; (d) T. Zhang, N. Y. Edwards, M. Bonizzoni and E. V. Anslyn,
Standard procedure for the synthesis of acetone-derived aldols
(as in Table 4)
Either 4-nitrobenzaldehyde (0.4 mmol), or 4-fluorobenzaldehyde
(0.4 mmol), was added to a suspension of triazabicyclo[4.4.0]
dec-5-ene (TBD, 5.6 mg, 0.04 mmol) and neutral Al2O3
(4.1 mg, 0.04 mmol) in acetone (2 mL) inside a closed test-tube.
The reaction mixture was then sonicated for 45 min before it was
poured onto NH4Cl aq. sat. (10 mL) and was extracted with
1980 | Org. Biomol. Chem., 2012, 10, 1976–1981
This journal is © The Royal Society of Chemistry 2012

View Article Online
J. Am. Chem. Soc., 2009, 131, 11976–11984; (e) M. Kitamura,
S. H. Shabbir and E. V. Anslyn, J. Org. Chem., 2009, 74, 4479–4489.
4 For recent selected examples, see: (a) F. B. L. Cougnon, H. Y. Au-Yeung,
G. Dan Pantos and J. K. M. Sanders, J. Am. Chem. Soc., 2011, 133,
3198–3207; (b) H. Y. Au-Yeung, G. Dan Pantos and J. K. M. Sanders,
J. Org. Chem., 2011, 76, 1257–1268; (c) M.-K. Chung, P. S. White, S.
J. Lee and M. R. Gagné, Angew. Chem., Int. Ed., 2009, 48, 8683;
(d) K. R. West, R. F. Ludlow, P. T. Corbett, P. Besenius, F. M. Mansfeld,
P. A. G. Cormack, D. G. Sherrington, J. M. Goodman, M. C. A. Stuart
and S. Otto, J. Am. Chem. Soc., 2008, 130, 10834–10835;
(e) R. T. S. Lam, A. Belenguer, S. L. Roberts, C. Naumann, T. Jarrosson,
S. Otto and J. K. M. Sanders, Science, 2005, 308, 667.
5 For recent selected examples, see: (a) M.-K. Chung, K. Severin,
S. J. Lee, M. L. Waters and M. R. Gagné, Chem. Sci., 2011, 2, 744–747;
(b) V. T. Bhat, A. M. Caniard, T. Luksch, R. Brenk, D. J. Campopiano
and M. F. Greaney, Nat. Chem., 2010, 2, 490–497; (c) P.-K. Müller-Graff,
H. Szelke, K. Severin and R. Krämer, Org. Biomol. Chem., 2010, 8,
2327–2331; (d) L. A. Ingerman, M. E. Cuellar and M. L. Waters, Chem.
Commun., 2010, 46, 1839–1841.
8 A. M. Flock, C. M. M. Reucher and C. Bolm, Chem.–Eur. J., 2010, 16,
3918–3921.
9 C. Ghobril, C. Sabot, C. Mioskowski and R. Baati, Eur. J. Org. Chem.,
2008, 4104.
10 A. Martínez-Castañeda, B. Poladura, H. Rodríguez-Solla, C. Concellón
and V. del Amo, Org. Lett., 2011, 13, 3032–3035.
11 For some recent reviews on the chemistry of guanidines, see:
(a) T. Ishikawa and T. Kumamoto, Synlett, 2006, 737; (b) D. Leow and
C.-H. Tan, Chem.–Asian J., 2009, 4, 488; (c) M. P. Coles, Chem.
Commun., 2009, 3659; (d) D. Leow and C.-H. Tan, Synlett, 2010, 1589;
(e) X. Fu and C.-H. Tan, Chem. Commun., 2011, 47, 8210–8222.
12 Mixtures of aldols in CDCl3 are inert, exchange processes were not
observed in the absence of the catalysts.
13 (a) G. Gasparini, M. Martin, L. J. Prins and P. Scrimin, Chem. Commun.,
2007, 1340; (b) A. G. Orrillo and R. L. E. Furlan, J. Org. Chem., 2010,
75, 211.
14 For a discussion on the chemistry and possibilities of complex systems
(Systems Chemistry), see: (a) M. Kindermann, I. Stahl, M. Reimold,
W. M. Pankau and G. von Kiedrowski, Angew. Chem., Int. Ed., 2005, 44,
6750; (b) R. F. Ludlow and S. Otto, Chem. Soc. Rev., 2008, 37, 101–108;
(c) J. R. Nitschke, Nature, 2009, 462, 736–738; (d) G. von Kiedrowski,
S. Otto and P. Herdewijn, J. Syst. Chem., 2010, 1, 1; (e) R. A. R. Hunt
and S. Otto, Chem. Commun., 2011, 47, 847–858.
15 (a) S. M. Turega, C. Lorenz, J. W. Sadownik and D. Philp, Chem.
Commun., 2008, 4076; (b) J. W. Sadownik and D. Philp, Angew. Chem.,
Int. Ed., 2008, 47, 9965; (c) P. Vongvilai, M. Angelin, R. Larsson and
O. Ramström, Angew. Chem., Int. Ed., 2007, 46, 948; (d) M. Angelin,
P. Vongvilai, A. Fischer and O. Ramström, Chem. Commun., 2008, 768;
(e) P. Vongvilai and O. Ramström, J. Am. Chem. Soc., 2009, 131, 14419;
(f) P. Vongvilai, M. Linder, M. Sakulsombat, M. S. Humble, P. Berglund,
T. Brinck and O. Ramström, Angew. Chem., Int. Ed., 2011, 50, 6592.
16 H. E. Gottlieb, V. Kotlyar and A. Nudelman, J. Org. Chem., 1997, 62,
7512.
6 N. Mase and C. F. Barbas III, Org. Biomol. Chem., 2010, 8, 4043–4050,
and references therein.
7 For some recent reviews on organocatalyzed transformations, with special
emphasis to the aldol reaction, see: (a) W. Notz, F. Tanaka and
C. F. Barbas, Acc. Chem. Res., 2004, 37, 580; (b) J. Seayad and B. List,
Org. Biomol. Chem., 2005, 3, 719; (c) B. List, Chem. Commun., 2006,
819; (d) G. Lelais and D. W. C. MacMillan, Aldrichimica Acta, 2006, 39,
79; (e) S. Mukherjee, J. W. Yang, S. Hoffmann and B. List, Chem. Rev.,
2007, 107, 5471; (f) A. Dondoni and A. Massi, Angew. Chem., Int. Ed.,
2008, 47, 4638; (g) P. Melchiorre, M. Marigo, A. Carlone and G. Bartoli,
Angew. Chem., Int. Ed., 2008, 47, 6138; (h) C. F. Barbas, Angew. Chem.,
Int. Ed., 2008, 47, 42; (i) Z. Shao and H. Zhang, Chem. Soc. Rev., 2009,
38, 2745; ( j) S. Bertelsen and K. A. Jørgensen, Chem. Soc. Rev., 2009,
38, 2178; (k) X. Liu, L. Lin and X. Feng, Chem. Commun., 2009, 6145.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 1976–1981 | 1981