Guillena et al.
7
On the other hand, the aldol reaction is extensively applied
yields (40-91%) and diastereo- (dr’s from 77:23 to 93:7) and
6
d
in industry either in bulk or in fine chemical manufacture and
pharmaceutical target production, and therefore, the application
of “green conditions” is of great interest. This C-C bond-
forming reaction provides a molecule which bears one or more
stereogenic centers. Among other asymmetric catalytic meth-
ods, organocatalyzed processes have been extensively applied
in this reaction. Several reaction conditions have been devel-
oped in order to achieve higher efficiencies, and only recently
the use of solvent-free conditions has been reported.
L-proline (10 mol %) has been used as organocatalyst for the
aldol condensation of alkyl symmetrical ketones and aldehydes
using a ball milling technique, affording the expected aldol
with high yields (53-99%) mainly as anti-isomers (dr’s from
enantioselectivities (ee’s from 92 to 98%).
Prolinamides derived from 1,1′-binaphthyl-2,2′-diamine (1a
and 1b) have been studied as catalysts in the aldol reaction under
8
1
3
different reaction conditions using cyclic or acyclic alkyl and
9
14
R-functionalized ketones as nucleophiles. Bisprolinamides
(Sa)-binam-L-Pro 1a and its enantiomer were more efficient than
13a
10
other bis- or monoprolinamide derivative 1b, with the addition
of benzoic acid as cocatalyst in the reaction being crucial to
obtaining a great acceleration in the reaction. Under these
11
6
b,d,e
Thus,
1
3c
reaction conditions, less reactive ketones, such as butanone
and R-functionalized ketones, can be used as nucleophile source
13f,14
1
2
in organic solvents or even in the presence of water
to give
the corresponding aldols products with a high level of selectivity.
Catalyst 1a can also be recovered by simple extractive workup
1
9
:1 to 93:7) and with good enantioselectivities (ee’s from 56 to
9%) in short reaction times (5–36 h) and with 2 equiv of
1
3a,c
after the reaction completion.
6
b,e
Recently, we have reported the enantioselective direct
intermolecular aldol under solvent-free conditions catalyzed by
ketone.
The use of conventional magnetic stirring for the
same solvent-free reactions gave similar results, but longer
reaction times were required (1-4 days). These conditions have
also been applied to the aldehyde-aldehyde aldol reaction,
giving after 1-4 days mainly the anti-aldol products with good
(
S)-binam-L-prolinamide 1a (5 mol %) and benzoic acid (10
mol %) under simple conventional magnetical stirring, in short
reaction times and using only 2 equiv of several cyclic and
acyclic aliphatic and R-functionalized ketones with 4-nitroben-
zaldehyde, giving the corresponding aldol products with enan-
(
3) (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138–
175. (b) Berkessel, A.; Gr o¨ ger, H. Asymmetric Organocatalysis: From
Biomimetic Concepts to Applications in Asymmetric Synthesis; Wiley-VCH:
Weinheim, Germany, 2005. (c) Seayad, J.; List, B. Org. Biomol. Chem. 2005,
, 719–724. (d) Ko cˇ ovsk y´ , P.; Malkov, A. V. Tetrahedron 2006, 62, 255.
thematic issue on Organocatalysis in Organic Synthesis, Nos. 2 and 3). (e) Lelais,
15
tioselectivities highly dependent on the ketone. Herein, we
5
report a full account and the mechanistic studies about the aldol
reaction under solvent-free conditions, catalyzed by binam-
3
(
G.; McMillan, D. W. C. Aldrichimica Acta 2006, 39, 79–87. (f) Taylor, M. S.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520–1543. (g) List, B. Chem.
Commun. 2006, 819–824. (h) Wessig, P. Angew. Chem., Int. Ed. 2006, 45, 2168–
2171. (i) Connon, S. J. Angew. Chem., Int. Ed. 2006, 45, 3909–3912. (j) Palomo,
C.; Mielgo, A. Angew. Chem., Int. Ed. 2006, 45, 7876–7880. (k) Marigo, M.;
Jørgensen, K. A. Chem. Commun. 2006, 2001, 2011. (l) Guillena, G.; Ram o´ n,
D. J. Tetrahedron: Asymmetry 2006, 17, 1465–1492. (m) Gaunt, M. J.; Johansonn,
C. C. C.; McNally, A.; Vo, N. T. Drug DiscoVery Today 2007, 12, 8–27. (n)
Rueping, M. Nach. Chem. 2007, 55, 35–37. (o) Enders, D.; Grondal, C.; H u¨ ttl,
M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570–1581. (p) Alma s¸ i, D.; Alonso,
D. A.; N a´ jera, C. Tetrahedron: Asymmetry 2007, 18, 299–365. (q) Guillena, G.;
Ram o´ n, D. J.; Yus, M. Tetrahedron: Asymmetry 2007, 18, 693–700. (r) Pellissier,
H. Tetrahedron 2007, 63, 9267–9331. (s) EnantioselectiVe Organocatalysis;
Dalko, P. I. Ed.; Wiley-VCH: Weinheim, Germany, 2007. (t) List, B. Chem.
ReV. 2007, 107, 5413. (special issue on Organocatalysis, No. 12)
Results and Discussion
(
4) (a) Anastas, P. T.; Warner, J. C. Green Chemistry, Theory and Practice;
Oxford University Press: Oxford, 1998. (b) Noyori, R. Chem. Commun. 2005,
807–1811.
5) (a) Metzger, J. O. Angew. Chem., Int. Ed. 1998, 37, 2975–2978. (b)
Tanaka, K. SolVent-Free Organic Synthesis; Wiley-VCH: Weinheim, Germany,
003. (c) Kaupp, G. Top. Curr. Chem. 2005, 95–184.
6) For some recents examples of solvent-free asymmetric organocatalytic
Catalyst 1a was synthesized by coupling of commercially
available (S)-1,1′-binaphthyl-2,2′-diamine [(S)-binam] and the
in situ generated Fmoc-L-Pro chloride (2.1 equiv) followed by
1
(
2
(
reactions, see: (a) Berkessel, A.; Roland, K.; Neud o¨ rfl, J. M. Org. Lett. 2006, 8,
(11) For the use of proline in aqueous media, see: Cordova, A.; Notz, W.;
Barbas, C. F., III Chem Commun. 2002, 3024–3025. (b) Nyberg, A. I.; Usano,
A.; Pihko, P. M. Synlett 2004, 1891–1806. (c) Hayashi, Y.; Sumiya, T.;
Takahashi, J.; Gotoh, H.; Urushima, T.; Shoji, M. Angew. Chem., Int. Ed. 2006,
45, 958–961. (d) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.; Tanaka,
F.; Barbas, C. F., III J. Am. Chem. Soc. 2006, 128, 734–735. (e) Hayashi, Y.;
Aratake, S.; Okano, T.; Takahashi, J.; Sumiya, T.; Shoji, M. Angew. Chem., Int.
Ed. 2006, 45, 5527–5529. For the use of additives, see: (f) Wu, Y.-S.; Chen, Y.;
Deng, D.-S.; Cai, J. Synlett 2005, 1627–1629. (g) Zhou, Y.; Shan, Z. Tetrahedron:
Asymmetry 2006, 17, 1671–1677. (h) Pihko, P. M.; Laurikainen, K. M.; Usano,
A.; Nyberg, A. I.; Kaavi, J. A. Tetrahedron 2006, 62, 317–328. (i) Majewski,
M.; Niewczas, I.; Palyam, N. Synlett 2006, 2387–2390. For the use of
microwaves, see: (j) Moss e´ , S.; Alexakis, A. Org. Lett. 2006, 8, 3577–3580. (k)
Hosseini, M.; Stiasni, N.; Barbieri, V.; Kappe, C. O. J. Org. Chem. 2007, 72,
1417–1424. For the use of supported proline, see: (l) Calder o´ n, F.; Fern a´ ndez,
R.; S a´ nchez, F.; Fern a´ ndez-Mayoralas, A. AdV. Synth. Catal. 2005, 347, 1395–
1403. (m) Shen, Z.; Ma, J.; Liu, C.; Li, M.; Zhang, Y. Chirality 2005, 17, 556–
558. (n) Belli, E.; Kokotos, G. J. Mol. Catal. A: Chem. 2005, 241, 166–174. (o)
Andreae, M. R. M.; Davis, A. P. Tetrahedron: Asymmetry 2005, 16, 2487–2492.
(p) Chandrasekhar, S.; Reddy, R. N.; Sultana, S. S.; Narsihmulu, Ch.; Reddy,
K. V. Tetrahedron 2006, 62, 338–345. (q) Giacalone, F.; Gruttadauria, M.;
Marculescu, A. M.; Noto, R. Tetrahedron Lett. 2007, 48, 255–259. For high
pressure promoted reaction, see: (r) Sekiguchi, Y.; Sasaoka, A.; Shimomoto,
A.; Fujioka, S.; Kotsuki, H. Synlett 2003, 1655–1658. For the use of ionic liquids,
see: (s) Gruttadauria, M.; Riela, S.; Aprile, C.; Lo Meo, P.; D’Anna, F.; Noto,
R. AdV. Synth. Catal. 2006, 348, 82–92. (t) Kucherenko, A. S.; Struchkova, M. I.;
Zlotin, S. G. Eur. J. Org. Chem. 2006, 2000–2004.
4
195–4198. (b) Rodr ´ı guez, B.; Rantanen, T.; Bolm, C. Angew. Chem., Int. Ed.
006, 45, 6924–6926. (c) Carlone, A.; Marigo, M.; North, C.; Landa, A.;
2
Jørgensen, K. A. Chem. Commun. 2006, 4928–4930. (d) Hayashi, Y.; Aratake,
S.; Itoh, T.; Okano, T.; Sumiya, T.; Shoji, M. Chem. Commun. 2007, 957–959.
(
4
5
e) Rodr ´ı guez, B.; Bruckmann, A.; Bolm, C. Chem.—Eur. J. 2007, 13, 4710–
722. (f) Rantanen, T.; Schiffers, I.; Bolm, C. Org. Process Res. DeV. 2007, 11,
92–597.
(
7) Modern Aldol Reactions; Marhrwald, R. Ed.; Wiley-VCH: Weinheim,
Germany, 2004; Vols 1 and 2.
8) Green, M. M.; Wittcoff, H. A. Organic Chemistry Principles and
Industrial Practice; Wiley-VCH: Weinheim, Germany, 2003.
9) For general reviews on the catalytic enantioselective aldol reaction, see:
(
(
(
a) Gr o¨ ger, H.; Vogl, E. M.; Shibaski, M. Chem.—Eur. J. 1998, 4, 1137–1141.
b) Nelson, S. G. Tetrahedron: Asymmetry 1998, 9, 357–389. (c) Carreira, E. M.
(
In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., ; Platz, A., ;
Yamamoto, H. Eds.; Springer: Heidelberg; Vol. 3, pp 997-1065. (d) Mahrwald,
R. Chem. ReV. 1999, 99, 1095–1120. (e) Machajewski, T. D.; Wong, C.-H.
Angew. Chem., Int. Ed. 2000, 39, 1352–1374. (f) Alcaide, B.; Almendros, P.
Eur. J. Org. Chem. 2002, 1595–1601. (h) Palomo, C.; Oiarbide, M.; Garc ´ı a,
J. M. Chem. ReV. Soc. 2004, 33, 65–74. (i) Mestres, R. Green Chem. 2004, 6,
5
83–603. (j) Vicario, J. L.; Bad ´ı a, D.; Carillo, L.; Reyes, E.; Etxbarria, J. Curr.
Org. Chem. 2005, 9, 219–235. (k) Schetter, B.; Mahrwald, R. Angew. Chem.,
Int. Ed. 2006, 45, 7506–7525.
(
10) For a comprehensive review on the enantioselective organocatalyzed
aldol reactions, see: Guillena, G.; N a´ jera, C.; Ram o´ n, D. J. Tetrahedron:
Asymmetry 2007, 18, 2249–2293.
5
934 J. Org. Chem. Vol. 73, No. 15, 2008