pubs.acs.org/joc
of ancient alchemy, organic chemists have had a troubled
Uncatalyzed, Diastereoselective Vinylogous
Mukaiyama Aldol Reactions on Aqueous Media:
Pyrrole vs Furan 2-Silyloxy Dienes
relationship with water, and it is only in recent times with old
prejudices set aside that they have started to consider aque-
ous media as a plausible and clean alternative to customary
2
organic solvents.
,
†
†
Claudio Curti,* Lucia Battistini, Franca Zanardi,
†
For the past several years, we have been active in the
vinylogous Mukaiyama-type aldol reaction (VMAR) do-
main exploiting a novel progeny of five-membered nitrogen,
oxygen, and sulfur silyloxy diene heterocycles that emerged
‡
Gloria Rassu, Vincenzo Zambrano, Luigi Pinna, and
‡
§
,
†
Giovanni Casiraghi*
†
Dipartimento Farmaceutico, Universit aꢀ degli Studi di Parma,
Viale G. P. Usberti 27A, I-43124 Parma, Italy, Istituto di
‡
4
as a versatile d -donor pool with which highly decorated car-
3
bon segments and important molecular targets were realized.
Chimica Biomolecolare del CNR, Traversa La Crucca 3,
I-07100 Li Punti, Sassari, Italy, and Dipartimento di
§
On this wave, our aim here was to develop environmentally
fair VMAR on aqueous media using pyrrole- and furan-based
2-silyloxy dienes, with the potential for preparation of varied
Chimica, Universit aꢀ degli Studi di Sassari, Via Vienna 2,
I-07100 Sassari, Italy
4
,5
butenolide-type functional frameworks. To the best of our
knowledge, this is the first report on uncatalyzed vinylogous
Mukaiyama-type aldol addition reactions occurring in a het-
erogeneous aqueous environment.
claudio.curti@unipr.it; giovanni.casiraghi@unipr.it
Received September 13, 2010
At first, we set out to determine whether our proposal
would allow access to vinylogous aldol products of type 3a,
by reacting N-Boc-2-(trimethylsilyloxy)pyrrole (1a) and ben-
5
zaldehyde (2a) on aqueous media, without the use of any
other catalyst or promoter (Table 1). To ensure optimal con-
ditions for a viable diastereoselective VMAR, we elected to
survey a set of aqueous and nonaqueous reaction media vis-
ꢀ
a-vis conventional control experiments in organic solvents.
6
Using pure water at ambient temperature, or better, at 38-40 °C
in an open-air environment, at atmospheric pressure, the
heterogeneous reaction proceeded under ultrasonic irradia-
tion (US) and product 3a was obtained after 8 h in 25-35%
combined yield (entries 2 and 3), with almost complete γ-site
selectivity and about 70:30 diastereomeric ratio in favor of the
anti-configured isomer. On the contrary, without US irra-
diation (entry 1), the reactivity dropped, with a 15% yield of
The first uncatalyzed, diastereoselective vinylogous Mukaiyama
aldol reaction is reported, between pyrrole/furan-based dienoxy
silanes and aromatic aldehydes on salty water/methanol med-
ium, at almost human body temperature, under ultrasonic irradi-
ation. With pyrrole dienes the reaction is anti-selective, while
that of furan dienes is syn-selective. The dual role of water as
both reaction medium and promoter is highlighted.
3
a obtained after 24 h. Of note, control experiments car-
ried out under neat conditions (entry 4), or uncatalyzed, homo-
geneous solutions in organic solvents such as CH Cl and
2
2
MeOH (entries 5 and 6), did not afford any appreciable result,
thereby confirming the crucial role exerted by water in these
processes. Next, we focused our attention on the optimiza-
tion of yield and diastereomeric ratio. Inspired by the pioneer-
ing work of Breslow on the effect of hydrophobic interac-
tions between organic reactants in an aqueous medium, we
9
3
With a global volume of about 1.3 ꢀ 10 km , water is one
of the most abundant chemical substances on the Earth’s sur-
face, where countless terrestrial and marine organisms live,
1
grow, and propagate. Water is a benign medium that assists
the complex molecular machinery of living systems, and governs
a myriad of vital biochemical transformations. From the times
(3) (a) Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G. Chem. Rev.
2
2
000, 100, 1929. (b) Casiraghi, G.; Zanardi, F.; Battistini, L.; Rassu, G. Synlett
009, 1525. See also: (c) Denmark, S. E.; Heemstra, J. R., Jr.; Beutner, G. L.
*
To whom correspondence should be addressed. Phone: þ39-0521905079
C.C.), þ39-0521-905080 (G.C.). Fax: þ39-0521-905006.
1) (a) Gleick, P. H. In Encyclopedia of Climate and Weather; Schneider,
S. H., Ed.; Oxford University Press: New York, 1996; Vol. 2, pp 817-823.
b) Debenedetti, P. G.; Stanley, H. E. Phys. Today 2003, 56, 40.
2) For authoritative reviews about the state of the art of organic reactions
Angew. Chem., Int. Ed. 2005, 44, 4682. (d) Hosokawa, S.; Tatsuta, K. Mini-Rev.
Org. Chem. 2008, 5, 1. (e) Brodmann, T.; Lorenz, M.; Schackel, R.; Simsek, S.;
Kalesse, M. Synlett 2009, 174.
(
(
(4) Despite the importance and the tremendous impact on organic synthe-
sis, only a few reports on uncatalyzed, Mukaiyama-type aldol reactions
promoted by an aqueous medium could be found in the literature: (a) Lubineau,
A. J. Org. Chem. 1986, 51, 2142. (b) Lubineau, A.; Meyer, E. Tetrahedron 1988,
44, 6065. (c) Loh, T. P.; Feng, L. C.; Wei, L. L. Tetrahedron 2000, 56, 7309.
(5) The term “on aqueous media” refers to a heterogeneous reaction
according to the definition given by Sharpless and co-workers: (a) Narayan,
S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2005, 44, 3275. (b) Klijn, J. E.; Engberts, B. F. N.
Nature 2005, 435, 746. See also refs 2e and 2f.
(
(
carried out in/on aqueous media, see: (a) Organic Synthesis in Water; Grieco,
P. A., Ed.; Blakie Academic & Professional: London, UK, 1998. (b) Li, C.-J.
Chem. Rev. 2005, 105, 3095. (c) Pirrung, M. C. Chem.;Eur. J. 2006, 12, 1312.
(
d) Lindstr o€ m, U. M. Organic Reactions in Water: Principles, Strategies and
Applications, 1st ed.; Blackwell Publishing: Oxford, UK, 2007. (e) Chanda, A.;
Fokin, V. V. Chem. Rev. 2009, 109, 725. (f) Butler, R. N.; Coyne, A. G. Chem.
Rev. 2010, 110, 6302. For stereoselective organic reactions, see also: (g) Lindstr o€ m,
U. M. Chem. Rev. 2002, 102, 2751. (h) Gruttadauria, M.; Giacalone, F.; Noto, R.
Adv. Synth. Catal. 2009, 351, 33. (i) Mase, N.; Barbas, C. F., III Org. Biomol.
Chem. 2010, 8, 4043.
(6) In the present work, the term “water” refers to deionized water obtained
by reverse osmosis (conducibility: 0 < C < 50 μS). The term “brine” refers to
saturated aqueous NaCl solution.
DOI: 10.1021/jo101799e
r 2010 American Chemical Society
Published on Web 11/18/2010
J. Org. Chem. 2010, 75, 8681–8684 8681