Direct aldol reactions catalyzed by a heterogeneous guanidinium salt/proline system under solvent-free conditions

Article abstract of DOI:10.1021/ol200890r

The combined activity of (S)-proline and an achiral cocatalyst (a TBD-derived guanidinium salt) allow direct aldol reactions to be carried out with high diastereoselectivity and enantioselectivity under solvent-free conditions with a rather simple reactio

Full text of DOI:10.1021/ol200890r

ORGANIC
LETTERS
2011
Vol. 13, No. 12
3032–3035
Direct Aldol Reactions Catalyzed by a
Heterogeneous Guanidinium Salt/Proline
System under Solvent-Free Conditions‡
ꢀ
Angel Martınez-Castaneda, Belen Poladura, Humberto Rodrıguez-Solla,
~
Carmen Concellon,* and Vicente del Amo*
ꢀ
´
´
ꢀ
´
Departamento de Quımica Organica e Inorganica, Universidad de Oviedo, C/Julian
Claveria 8, 33006, Oviedo, Spain
ꢀ
ꢀ
ccf@uniovi.es; vdelamo@uniovi.es
Received April 5, 2011
ABSTRACT
The combined activity of (S)-proline and an achiral cocatalyst (a TBD-derived guanidinium salt) allow direct aldol reactions to be carried out with
high diastereoselectivity and enantioselectivity under solvent-free conditions with a rather simple reaction setup where stirring is not required.
The aldol reaction is certainly one of the most renowned
transformations in organic synthesis.1 However, since the
breakthrough discovery of the first proline-catalyzed inter-
molecular aldol reaction by List, Lerner, and Barbas,2 and
the blossoming of general asymmetric organocatalyzed
reactions3 from the past decade, the aldol reaction is
experiencing its second youth. Considering its ready
availability and low price, it is evident that (S)-proline
would be a first-choice catalyst for preparing aldol adducts
with high diastereo- and enantioselectivity. However, pro-
line itself presents some major drawbacks, namely: poor
performance in direct aldol reactions with aromatic alde-
hydes, rather limited solubility and reactivity in nonpolar
organic solvents, and potential parasitic side reactions that
make using high catalyst loadings necessary to achieve
acceptable conversions. To avoid these undesired issues
different solutions were adopted: (A) in fully rational
approaches, large efforts are devoted to the careful design
(computer aided) and synthesis of novel tailor-made cata-
lysts to be ultimately tested on aldol reactions. Evaluation
of such catalysts in terms of reactivity, selectivity, and
reaction scope allows judging of their efficiency and to
propose a second generation of more active catalysts,
normally based on the original design. Although impressive
catalysts have been discovered by this approach, the time-
consuming nature of this iterative method may reveal
limitations (it has to be noted that before having found a
good catalyst many analogs of a proposed design are
normally prepared and evaluated); (B) an alternative con-
sists of adding simple, readily available additives4 to reac-
tions containing known catalysts (ideally proline), whose
behavior is thus re-evaluated under these new conditions.
This late approach is clearly beneficial in evading tedious
‡
ꢀ
ꢀ
This work is dedicated to the memory of Professor Jose M. Concellon.
(1) For some recent monographs and reviews, see: (a) Modern Aldol
Reactions, Vol. 1À2; Mahrwald, Ed.; Wiley-VCH: Weinheim, 2004. (b)
Schetter, B.; Mahrwald, R. Angew. Chem., Int. Ed. 2006, 45, 7506. (c)
ꢀ
ꢀ
Guilena, G.; Najera, C.; Ramon, D. J. Tetrahedron: Asymmetry 2007,
18, 2249. (d) Geary, L. M.; Hultin, P. G. Tetrahedron: Asymmetry 2009,
20, 131.
(2) (a) List, B.; Lerner, A. R.; Barbas, C. F., III. J. Am. Chem. Soc.
2000, 122, 2395. (b) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III. J.
Am. Chem. Soc. 2001, 123, 5260. (c) Notz, W.; List, B. J. Am. Chem. Soc.
2000, 122, 7386.
(3) For some authoritative reviews on organocatalysis, see: (a)
Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001, 40, 3726. (b) List,
B. Synlett 2001, 1675. (c) List, B. Tetrahedron 2002, 58, 2481. (d) Dalko,
P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138. (e) Notz, W.;
Tanaka, F.; Barbas, C. F. Acc. Chem. Res. 2004, 37, 580. (f) Seayad, J.;
List, B. Org. Biomol. Chem. 2005, 3, 719. (g) List, B. Chem. Commum.
2006, 819. (h) Lelais, G.; MacMillan, D. W. C. Aldrichimica Acta 2006,
39, 79. (i) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev.
2007, 107, 5471. (j) Dondoni, A.; Massi, A. Angew. Chem., Int. Ed. 2008,
47, 4638. (k) Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli, G.
Angew. Chem., Int. Ed. 2008, 47, 6138. (l) Barbas, C. F. Angew. Chem.,
Int. Ed. 2008, 47, 42. (m) Shao, Z.; Zhang, H. Chem. Soc. Rev. 2009, 38,
2745. (n) Bertelsen, S.; Jørgensen, K. A. Chem. Soc. Rev. 2009, 38, 2178.
(o) Liu, X.; Lin, L.; Feng, X. Chem. Commun. 2009, 6145.
r
10.1021/ol200890r
Published on Web 05/13/2011
2011 American Chemical Society

proline-catalyzed intermolecular direct aldol reaction be-
tween ketones and aromatic aldehydes using TBD
(triazabicyclo[4.4.0]dec-5-ene)-derived guanidinium salts
1aÀe (Figure 1) as additives.
The reaction between cyclohexanone, 2, and 4-chloro-
benzaldehyde, 3a, to afford aldol 4a, was used as a model
system to screen different reaction conditions (Table 1).
Looking for an inexpensive and green process, we decided
to avoid the use of any organic solvent, apart from 2 (10-
fold excess), which acts as both reagent and reaction
media.12 Under these conditions, we postulate that the
guanidinium core of salts 1 could form doubly H-bonded
motifs with the carboxylate function of proline (model A,
Figure 1. TBD-derived guanidinium salts 1aÀe used in this
work. Possible doubly H-bonded motifs formed by interaction
of the TBD-derived guanidinium salt with the carboxylate
function of (S)-proline A, or the carbonyl moiety of a ketone B,
or an aromatic aldehyde C.
chemical syntheses and would ultimately allow the con-
struction of libraries of catalyst5 systems by simply chan-
ging the additives of choice. In this sense, researchers have
shown that the addition of catalytic or substoichiometric
amounts of water,6 chiral diols,7 Schreiner’s thiourea,8 or
other diarylthioureas9 accelerates the reaction rate and
increases the diastereo- and enantioselectivity of proline-
catalyzed aldol reactions. Although a full-bodied picture of
the role played by these additives in the reaction mechanism
has not been disclosed, it seems clear that, in nonpolar
solvents, a network of H-bonding interactions between the
carboxylate function of proline, the corresponding addi-
tive, and the reaction substrates in the transition state is
established.
Table 1. Initial Screening of Conditions for the Formation of
Aldol 4aa
entry
temp (°C)
time (h)
conversionb
anti/synb
ee %c
1d
2
20
48
48
96
96
96
94
99
98
96
81
60:40
76:24
93:7
56
82
96
98
54
20
3
0
4e
5d,e
0À3
94:6
0À3
69:31
Inspired by the aforementioned contributions, and con-
sidering the probed ability of guanidinium salts in binding
carboxylic acids and carboxylates,10 we contemplated the
possibility of using guanidinium salts as new additives in
the aldol reaction.11 Herein, we report the results of the
a General conditions: 2 (4.0 mmol, 0.41 mL), 3a (0.4 mmol) (S)-
proline (15 mol %), 1a (10 mol %), no solvent, reaction mixture was
stirred. Results are determined as an average of two experiments.
b Determined by 1H NMR spectroscopy from crude reaction mixtures.
Anti and syn diastereoisomers were identified by comparison with
similar compounds previously described in the literature. c Enantiomeric
excess of the major diastereoisomer, as determined by chiral HPLC on
crude reaction mixtures. d No guanidinium salt 1a was used. e The
reaction mixture was left to stand inside a fridge (0À3 °C) with no
stirring.
(4) For a high throughput screening of additives in organocatalyzed
reactions, see: (a) Mase, N.; Tanaka, F.; Barbas, C. F. Org. Lett. 2003, 5,
4369. (b) Mase, N.; Tanaka, F.; Barbas, C. F. Angew. Chem., Int. Ed.
2004, 43, 2420. (c) Tanaka, F.; Thayumanavan, R.; Mase, N.; Barbas,
C. F. Tetrahedron Lett. 2004, 45, 325.
(5) (a) Gennari, C.; Piarulli, U. Chem. Rev. 2003, 103, 3071. (b) Reetz,
M. T. Angew. Chem., Int. Ed. 2001, 40, 284. (c) Reetz, M. T.; Sell, T.;
Meiswinkel, A.; Mehler, G. Angew. Chem., Int. Ed. 2003, 42, 790. (d)
Ding, K. L.; Ishii, A.; Mikami, K. Angew. Chem., Int. Ed. 1999, 38, 497.
(e) Bolm, C.; Tanyeli, C.; Grenz, A.; Dinter, C. L. Adv. Synth. Catal.
2002, 344, 649.
(6) (a) Nyberg, A. I.; Usano, A.; Pihko, P. M. Synlett 2004, 1891. (b)
Amedjkouh, M. Tetrahedron: Asymmetry 2005, 16, 1411. (c) Ward,
D. E.; Jheengut, V. Tetrahedron Lett. 2004, 45, 8347. (d) Pihko, P. M.;
Laurikanien, P. M.; Usano, A.; Nyberg, A. I.; Kaavi, J. A. Tetrahedron
2006, 62, 317.
Figure 1), as well as with the carbonyl moieties of cyclo-
hexanone (model B, Figure 1) and the aromatic aldehyde
(model C, Figure 1), thus enhancing their electrophilicity.
In ideal cases, these interactions could, in principle, mod-
ulate to our favor the reactivity and selectivity of proline in
the aldol reaction. Nonetheless, we could also presume the
participation of the anion counterpart XÀ of salts 1 in the
reaction scheme. An early blank experiment showed that
aldol 4a was rendered in 94% conversion (60:40 anti/syn,
56% ee) when a suspension of 4-chlorobenzaldehyde 3a
(1.0 equiv) and (S)-proline (15 mol %), in cyclohexanone 2
(10 equiv), was vigorously stirred for 48 h at 20 °C inside a
(7) Zhou, Y.; Shan, Z. J. Org. Chem. 2006, 71, 9510.
€
(8) Reis, O.; Eymur, S.; Reis, B.; Demir, A. S. Chem. Commun. 2009,
1088.
ꢀ
(9) (a) El-Hamdouni, N.; Companyo, X.; Rios, R.; Moyano, A.
ꢀ
Chem.;Eur. J. 2010, 16, 1142. (b) Companyo, X.; Valero, G.; Crovetto,
L.; Moyano, A.; Rios, R. Chem.;Eur. J. 2009, 15, 6564.
(10) Reviews: (a) Schmidtchen, F. P.; Berger, M. Chem. Rev. 1997,
97, 1609. (b) Fitzmaurice, R. J.; Kyne, G. M.; Douheret, D.; Kilburn,
J. D. J. Chem. Soc., Perkin Trans. 1 2002, 841. (c) Blondeau, P.; Segura,
ꢀ
ꢀ
M.; Perez-Fernandez, R.; de Mendoza, J. Chem. Soc. Rev. 2007, 36, 198.
(d) Coles, M. P. Chem. Commun. 2009, 3659. (e) Kim, S. K.; Sessler, J. L.
Chem. Soc. Rev. 2010, 39, 3784.
(12) For recent examples of aldol reactions carried out under solvent-
free conditions, see: (a) Almasi, D.; Alonso, D. A.; Balaguer, A. N.;
Najera, C. Adv. Synth. Catal. 2009, 351, 1123. (b) Worch, C.; Bolm, C.
Synlett 2009, 2425. (c) Almasi, D.; Alonso, D. A.; Najera, C. Adv. Synth.
Catal. 2008, 350, 2467. (d) Rodrıguez, B; Rantanen, T.; Bolm, C. Angew.
Chem., Int. Ed. 2006, 45, 6924. (e) Rodrıguez, B.; Bruckmann, A.; Bolm,
C. Chem.;Eur. J. 2007, 13, 4710.
(11) The Liebscher group has reported improvements in (S)-proline
catalyzed aldol reactions using guanidinium salts and ionic liquids as
solvents: (a) Shah, J.; Blumenthal, B.; Yacob, Z.; Liebscher, J. Adv.
Synth. Catal. 2008, 350, 1267. (b) Shah, J.; Liebscher, J. Z. Naturforsch.
B 2011, 66, 88.
Org. Lett., Vol. 13, No. 12, 2011
3033

screwed-capped test tube (Table 1, entry 1). To our delight,
when a similar reaction mixture was treated with tetra-
fluoroborate guanidinium salt 1a (10 mol %), anti-aldol 4a
was afforded with a comparable conversion although with
a significantly higher diastereo- and enantioselectivity,
revealing the advantageous effect of this additive
(Table 1, entry 2). Aiming to improve further our catalytic
system we next investigated the effect of temperature.
Stirring the reaction mixture at 0 °C gives aldol anti-4a
with high diastereoselectivity (93:7) and enantioselectivity
(96%), although after a longer reaction time (Table 1,
entry 3). Moreover, when a suspension of aldehyde 3a, (S)-
proline (15 mol %), and 1a (10 mol %), in cyclohexanone,
was left to stand for 96 h inside a standard laboratory
fridge (temperature was set up and checked to be 0À3 °C),
without needing any sort of stirring or mechanical agita-
tion, aldol 4a was produced in 96% conversion (anti/syn
94:6), peaking at 98% enantiomeric excess (Table 1, entry
4). When an analogous reaction was performed with 15
mol % of (S)-proline, with no additive 1a, modest figures
were observed for both the diastereo- and enantioselec-
tivity of aldol 4a (Table 1, entry 5). The efficiency of the
aldol reaction is remarkable under these rather mild con-
ditions taking into account that the reaction mixture is
heterogeneous (neither proline nor aldehyde 3a is fully
soluble in the little excess of cyclohexanone used) and that
it remains so all along the course of the reaction.
Table 2. Screening of Different Guanidinium Salts 1bÀe as
Additives in the Proline-Catalyzed Aldol Reactiona
entry
guanidine salt
conversionb
anti/synb
ee %c
1
2
3
4
1b
1c
1d
1e
98
94
92
60
48:52
84:16
75:25
77:23
À75, À67d
86
77
87
a General conditions: 2 (4.0 mmol, 0.41 mL), 3a (0.4 mmol), (S)-
proline (15 mol %), guanidinium salt 1aÀe (10 mol %), no solvent,
reaction mixture was left to stand 96 h inside a fridge (0À3 °C) with no
stirring. Results are determined as an average of two experiments.
b Determined by 1H NMR spectroscopy from crude reaction mixtures.
Anti and syn diastereoisomers were identified by comparison with
similar compounds previously described in the literature. c Enantiomeric
excess of the major diastereoisomer, as determined by chiral HPLC on
crude reaction mixtures. d Enantiomeric excess of anti and syn aldol,
respectively. Both anti and syn diols are obtained with the opposite
absolute configuration.
Other TBD-derived guanidinium salts 1bÀe, featuring
anions with different electronegativities and geometries,
were also investigated as additives (Table 2). Again, sus-
pensions of aldehyde 3a (0.4 mmol), (S)-proline (15 mol
%), and either of a guanidinium salt 1bÀe (10 mol %), in
Table 3. (S)-Proline/Guanidinium Salt 1a Cocatalyzed Synthesis of Aldols 4bÀ4h, 5À7a
a General conditions: ketone (4.0 mmol), ArCHO (0.4 mmol), (S)-proline (15 mol %), 1a (10 mol %), nosolvent, reactionmixturewas lefttostand96h
1
inside a fridge (0À3 °C) with no stirring. b Isolated yield of analytically pure products. c Determined by H NMR spectroscopy from crude reaction
mixtures. Anti and syn diastereoisomers were identified by comparison with similar compounds previously described in the literature. d Enantiomeric
excess of isolated pure products, as determined by chiral HPLC on crude reaction mixtures. e Cyclohexanone, 2, was used as ketone. f 4-
Methylcyclohexanone was used as ketone. g Only two diastereoisomers were detected by 1H NMR spectroscopy. h Cyclopentanone was used as ketone.
i Acetone was used as ketone.
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Org. Lett., Vol. 13, No. 12, 2011

cyclohexanone 2 (4.0 mmol, 0.41 mL), were left to stand
for 96 h inside a laboratory fridge (0À3 °C) without
stirring, before they were worked up and analyzed by 1H
NMR spectroscopy and chiral HPLC. From the collection
of experiences outlined in Table 2 we can conclude that all
the salts 1bÀe improve the efficiency of proline in the aldol
reaction in terms of diastereo- and enantioselectivity. Salts
1bÀe are less efficient additives for the aldol reaction than
the tetrafluoroborate salt 1a previously examined. Satisfy-
ingly, as we anticipated, participation of the tetraphenyl-
borate derivative 1b suffices for reverting the absolute
configuration of both the anti and syn aldols 4a without
changing the source of chiral information ((S)-proline).
Although the justification for this result is not clear for us,
we believe the bulkiness of the anion forcing an alternative
reaction mechanism.
To establish the scope of our aldol protocol a selection of
aldehydes 3bÀh bearing diverse functional groups and
substitution patterns were reacted with cyclohexanone
(or other ketones) under our finest reaction conditions
(Table 3). A 10-fold excess of the ketones investigated
proved to be sufficient as reagent and reaction media
(solvent). All reactions shown in Table 3 proceeded
smoothly. Aldols 4bÀf, derived from cyclohexanone
(Table 3, entries 1À5), were isolated in good or very good
yield, and with very high diastereo- and enantioselectivity.
Particularly relevant are aldols 4g and 4h, prepared from
2-furfural, 3g, and 2-thiophenecarboxaldehyde, 3h, respec-
tively, which are challenging substrates for the direct aldol
reaction (Table 3, entries 6À7). 4-Methylcyclohexanone
was successfully desymmetrized by means of this metho-
dology, affording aldol 5 with high diastereo- and enan-
tioselectivity, in a process where the absolute configuration
of three stereogenic centers is fixed (Table 3, entry 8).
Reactions carried out with cyclopentanone or acetone
were also successful. Aldol reactions performed without
additive 1a showed lower conversion, as well as poorer
diastereoisomeric ratios and enantiomeric excesses, thus
demonstrating the positive effect of this salt on the reaction
course (see Supporting Information for details).
Figure 2. ZimmermanÀTraxler-type transition state proposed
to explain the observed stereochemistry of aldols 4.
course. Then, as proposed by other authors,2,8b,14 the stereo-
chemical outcome of the reaction could be explained con-
sidering that it operates through a ZimmermanÀTraxler
transition state. Therefore, the formation of a 1:1 complex
between the guanidinium cation of additive 1a and the
solubilized (S)-proline would stabilize the chairlike transi-
tion state TS I (Figure 2) that leads to the observed aldols.
Notwithstanding this mechanistic hypothesis, issues such as
the role played by the anion counterpart of salts 1 in the
reaction mechanism are still unclear and are the subject of
further investigations currently underway in our laboratory.
In summary, we have developed and implemented a
simple, green, efficient, and highly selective methodology
for the direct aldol reaction of ketones with aromatic
aldehydes using (S)-proline as a chiral catalyst. Catalytic
amounts of TBD-derived guanidinium salts have been used
for the first time as an additive for this reaction. This aldol
protocol works under solvent-free conditions, in closed-cap
test tubes placed inside a standard laboratory fridge, without
agitation or mechanical stirring. The development of other
enantioselective reactions promoted by guanidinium salts is
ongoing in our laboratory and will be reported in due course.
Acknowledgment. We thank MICINN (CTQ2010-
14959) for financial support. B.P., C.C., and V.d.A. thank
MICINN for an FPI predoctoral fellowship, a Juan de la
Cierva contract, and a Ramon y Cajal contract,
respectively.
Different papers have appeared in the literature that give
remarkable insights into the behavior of proline and other
amino acids under heterogeneous conditions.13 It has been
accepted that, in the case of proline, a saturated solution lives
in equilibrium with a crystalline phase. Taking this consid-
eration as a working basis, we believe that, in our system,
there is some (S)-proline dissolved in cyclohexanone (or
alternatively the ketone used), and it controls the reaction
Supporting Information Available. General procedures,
spectroscopic data, copies of 1H and 13C NMR spectra,
and chromatographic data for compounds 4aÀh, 5À7.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(13) For a discussion on the crystallization behaviour of proline and
its role in asymmetric organocatalysis, see: Kellogg, R. M. Angew.
Chem., Int. Ed. 2007, 46, 494 and references therein.
(14) Bahmanyar, S.; Houk, K. N.; Martin, H. J.; List, B. J. Am.
Chem. Soc. 2003, 125, 2475.
Org. Lett., Vol. 13, No. 12, 2011
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