Aldol- and Mannich-type reactions via in situ olefin migration in ionic liquid.

Article abstract of DOI:10.1021/ol0273102

An aldol-type and a Mannich-type reaction via the cross-coupling of aldehydes and imines with allylic alcohols catalyzed by RuCl(2)(PPh(3))(3) was developed with ionic liquid as the solvent. The solvent/catalyst system could be reused for at least five times with no loss of reactivity.

Full text of DOI:10.1021/ol0273102

ORGANIC
LETTERS
2003
Vol. 5, No. 5
657-660
Aldol- and Mannich-Type Reactions via
in Situ Olefin Migration in Ionic Liquid
,†
Xiao-Fan Yang,† Mingwen Wang,† Rajender S. Varma,‡ and Chao-Jun Li*
Department of Chemistry, Tulane UniVersity, New Orleans, Louisiana 70118,
and Clean Processes Branch, National Risk Management Research Lab,
U.S. EnVironmental Protection Agency, Cincinnati, Ohio 45268
cjli@tulane.edu
Received November 19, 2002
ABSTRACT
An aldol-type and a Mannich-type reaction via the cross-coupling of aldehydes and imines with allylic alcohols catalyzed by RuCl2(PPh3)3 was
developed with ionic liquid as the solvent. The solvent/catalyst system could be reused for at least five times with no loss of reactivity.
Aldol-type reactions are recognized as one of the most
important reactions for forming carbon-carbon bonds.
However, under the classical aldol reaction conditions,1
dimerization, polymerization, and self-condensation (some
of the undesirable reactions) also occur. To avoid such
competing processes, an important modification of the
classical aldol reaction has been developed by treating enol
silyl ether with carbonyl compounds in the presence of Lewis
acids (the Mukaiyama aldol reaction).2 Recently, attention
has been focused on developing cross-aldol reactions by
alternative approaches. Toward this goal, Trost reported a
highly efficient formation of aldol-type products via vanadium-
catalyzed coupling of propargyl alcohols with aldehyde.3
Recent developments also include hydrometalation-aldol4 and
C-H activation-aldol reactions of carbonyl compounds.5
Motherwell developed the Rh- and Ni-catalyzed isomeriza-
tion of allylic lithium alkoxide to lithium enolate, which
underwent further aldol reaction.6 Gre´e and co-workers
recently reported the isomerization of allylic alcohol to enol
catalyzed by Fe(CO)5 under photolytic conditions, which then
reacted with aldehydes to give aldol products (in addition
to other products).7
Recently, interest has been growing to develop organic
reactions in environmentally friendly media, i.e., “green
solvents”.8 For aqueous aldol-type condensations, Chan
developed the tin- and zinc-mediated cross-couplings of halo-
ketones with aldehydes.9 Lubineau,10 Kobayashi,11 Loh,12 and
others13 developed the aqueous Mukaiyama-type reactions.
Another group of promising green solvents that have
(5) For examples, see: (a) Trost, B. M.; Silcoff, E. R.; Ito, H. Org. Lett.
2001, 3, 2497. (b) Murahashi, S.; Takaya, H. Acc. Chem. Res. 2000, 33,
225. (c) Lin, Y. R.; Zhou, X. T.; Dai, L. X.; Sun, J. J. Org. Chem. 1997,
62, 1799. (d) Picquet, M.; Bruneau, C.; Dixneuf, P. M. Tetrahedron 1999,
55, 3937. (f) Go´mez-Bengoa, E.; Cuerva, J. M.; Mateo, C.; Echavarren, A.
M. J. Am. Chem. Soc. 1996, 118, 8553.
(6) Gazzard, L. J.; Motherwell, W. B.; Sandham, D. A. J. Chem. Soc.,
Perkin Trans. 1 1999, 979.
† Tulane University.
‡ U.S. Environmental Protection Agency.
(7) Cre´visy, C.; Wietrich, M.; Le Boulaire, V.; Uma, R.; Gre´e, R.
Tetrahedron Lett. 2001, 42, 395. Gre´e and co-workers recently reported a
combination of n-BuLi/RuCl2(PPh3)3 as a catalyst to carry out the aldol
reaction. No reaction was observed without the lithium co-reagent. See:
Uma, R.; Davis, M.; Cre´visy, C.; Gre´e, R. Tetrahedron Lett. 2001, 42, 3069.
(8) (a). Clean SolVents: AlternatiVe Media for Chemical Reactions and
Processing; Abraham, M. A., Moens, L., Eds.; ACS Symposium Series
819, American Chemical Society: Washington, DC, 2002. (b). Li, C. J.;
Chan, T. H. Organic Reactions in Aqueous Media; John Wiley & Sons:
New York 1997. (c). Organic Synthesis in Water; Grieco, P. A., Ed.; Blackie
Academic and Professional: Glasgow, 1998.
(1) March, J. AdVanced Organic Chemistry: Reactions, Mechanisms and
Structure, 4th ed.; Wiley-Interscience: New York 1992.
(2) Mukaiyama, T. Org. React. 1982, 28, 203.
(3) Trost, B. M.; Oi, S. J. Am. Chem. Soc. 2001, 123, 1230.
(4) (a) Sato, S.; Matsuda, I.; Shibata, M. J. Organomet. Chem. 1989,
377, 347. (b) Matsuda, I.; Shibata, M.; Sato, S. J. Organomet. Chem. 1988,
340, C5. For use of Rh-enolate intermediates in aldol reactions, see: (c)
Slough, G. A.; Bergman, R. G.; Heathcock, C. H. J. Am. Chem. Soc. 1989,
111, 938. (d) Sato, S.; Matsuda, I.; Izumi, Y. Tetrahedron Lett. 1986, 27,
5517.
10.1021/ol0273102 CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/13/2003

reactivity of the dissolved catalyst and therefore improve both
reactivity and selectivity.14 Among the commonly used ionic
liquids, 1-butyl-3-methylimidazoliumhexafluorophosphate
([bmim]PF6) is a popular reaction medium for a wide variety
of transition metal catalyzed organic transformations such
as hydrogenation,20 oxidation,21 hydroformylation,22 oligo-
merization,23 etc.
Scheme 1
In initial explorations, when 3-buten-2-ol was stirred with
benzaldehyde and a catalytic amount of RuCl2(PPh3)3 (5 mol
%) in [bmim]PF6 for 24 h at room temperature, no desired
product was obtained. When the mixture was heated at 90
°C in an oil bath, the reaction mixture became homogeneous
and a smooth reaction occurred to give the desired aldol
product (with a syn:anti ratio of 71:29, stereochemistry
determined by comparison with literature data)13 in 81%
isolated yield.24 Decomposition of the desired product was
observed after prolonged reaction time, e.g. overnight,
possibly due to elimination of the hydroxy group to give an
R,â-unsaturated ketone. A small amount of 2-butanone was
detected by GC, although exact quantification was difficult
to achieve because of the volatility of the ketone. Subse-
quently, a variety of aromatic aldehydes were examined
under similar reaction conditions (Table 1). In most cases,
gained much attention recently is “ionic liquids.” Their
nonvolatile nature gives them significant advantage in
minimizing solvent consumption. Their polarity renders them
good solvents for transition metal catalysis and therefore
good reaction media for homogeneous catalysis.14 Because
of their unique solubility properties, i.e., miscibility gap
between water and organic solvents, they have become
interesting candidates for separation processes by simple
liquid-liquid extraction with either aqueous or conventional
organic solvents.15
Previously, we reported that in the presence of a catalytic
amount of RuCl2(PPh3)3 functional groups of homoallylic
alcohols and allylic alcohols underwent rearrangement in air
and water.16 A side reaction of the isomerization is the
formation of a ketone, which was rationalized by a competing
process involving the cleavage of the allylic C-H bond
(instead of the C-O bond) to form a ruthenium-enol
complex,17 followed by hydrolysis to give the ketone. We
envisioned that in the presence of an aldehyde, such a
ruthenium-enol complex may be captured,18 and indeed we
found that aldol products were formed via a RuCl2(PPh3)3-
catalyzed cross-coupling of allylic alcohols and aldehydes
in water.19 We now report for the first time aldol-type
(Scheme 1) and Mannich-type (Scheme 3) reaction between
aldehydes and imines with allylic alcohol catalyzed by RuCl2-
(PPh3)3 in ionic liquid.
Table 1. Coupling of Aldehydes with Allylic Alcohol in Ionic
Liquid
time yield
entry
aldehyde (R)
Ph
solvent
I.L.
(h)
(%)a syn/antib
1
2
3
4
5
6
7
8
9
10
11
12
13
1.5
1.5
2
1
1
1
2
1
2
2
2
5
5
81
68
75
79
80
84
94
67
46
52
65
35
70
71/29
68/32
71/29
75/25
72/28
71/29
69/31
37/63
16/84
33/67
42/58
60/40
76/26
m-F-C6H4
p-Cl-C6H4
p-Br-C6H4
p-MeO-C6H4
p-Ph-C6H4
2-naphthyl
n-C7H15
I.L.
I.L.
I.L.
I.L.
I.L.
I.L.
I.L.
In many applications ionic liquids with weakly coordinat-
-
-
ing anions, such as BF4 and PF6 , together with suitably
substituted cations often result in an altered chemical
diphenylmethyl I.L.
2-phenylethyl
cyclohexyl
p-Cl-C6H4
I.L.
I.L.
H2O
H2O-toluene
(4:1)
(9) Chan, T. H.; Li, C. J.; Wei, Z. Y. J. Chem. Soc., Chem. Commun.
1990, 505.
(10) Lubineau, A. J. Org. Chem. 1986, 51, 2142.
(11) Kobayashi, S.; Hachiya, I. Tetrahedron Lett. 1992, 33, 1625.
(12) Loh, T. P.; Pei, J.; Cao, G. Q. Chem. Commun. 1996, 1819.
(13) Tian, H. Y.; Chen, Y. J.; Wang, D.; Zeng, C. C.; Li, C. J.
Tetrahedron Lett. 2000, 41, 2529.
(14) Wasserscheid, P.; Keim, W. Angew. Chem., Int. Ed. Engl. 2000,
39, 3772.
p-Cl-C6H4
14
2-naphthyl
H2O-toluene
(4:1)
5
44
63/37
a Isolated yields were reported. b the diastereoselectivity was based on
1HNMR analysis of the crude products.
(15) Huddleston, J. G.; Willauer, H. D.; Swatloski, R. P.; Visser, A. E.;
Rogers, R. D. Chem. Commun. 1998, 1765.
(16) (a). Li, C. J.; Wang, D.; Chen, D. L. J. Am. Chem. Soc. 1995, 117,
12867. (b). Wang, D.; Chen, D.; Haberman, J. X.; Li, C. J. Tetrahedron
1998, 54, 5129. (c). Wang, D.; Li, C. J. Synth. Commun. 1998, 28, 507.
(17) For other examples of Ru enolates, see: (a) Hartwig, J. F.; Bergman,
R. G.; Anderson, R. A. Organometallics 1991, 10, 3326. (b) Rasley, B. T.;
Rapta, M.; Kulawiec, R. J. Organometallics 1996, 15, 2852. (c) Chang, S.;
Na, Y.; Choi, E.; Kim, S. Org. Lett. 2001, 3, 2089. (d) Trost, B. M.; Toste,
F. D.; Pinkerton, A. B. Chem. ReV. 2001, 101, 2067.
(18) Previously, Ru-enol intermediates have been captured by aldehydes
in a Michael addition reaction: (a) Trost, B. M.; Pinkerton, A. B. J. Am.
Chem. Soc. 2000, 122, 8081. For capturing of Pd and Pt enolates by
aldehydes, see: (b) Hagiwara, E.; Fujii, A.; Sodeoka, M. J. Am. Chem.
Soc. 1998, 120, 2474. (c) Fujimura, O. J. Am. Chem. Soc. 1998, 120, 10032.
(d) Sodeoka, M.; Ohrai, K.; Shibasaki, M. J. Org. Chem. 1995, 60, 2648.
(19) Wang, M.; Li, C. J. Tetrahedron Lett. 2002, 43, 3589.
the desired aldol products were obtained in good yields even
with less reactive aldehydes such as 2-naphthaldehyde or
p-anisaldehyde. The only exception was 4-hydroxybenzal-
dehyde, with which a very low yield was achieved. One
(20) Steines, S.; Drieben-Holscher, B.; Wasserscheid, P. J. Prakt. Chem.
2000, 342, 348.
(21) Song, C. E.; Roh, E. J. Chem. Commun. 2000, 837.
(22) Chauvin, Y.; Oliver, H.; Mubamann, L. FR 95/14,147, 1995; Chem.
Abstr. 1997, 127, P341298k.
(23) Chen, W.; Xu, L.; Chatterton, C.; Xiao, J. Chem. Commun. 1999,
1247.
658
Org. Lett., Vol. 5, No. 5, 2003

Scheme 2
Table 2. Coupling of Imines with Allyl Alcohol in Ionic
Liquid
time yield
entry
imine (R)
Ph
m-F-C6H4
p-Cl-C6H4
p-Br-C6H4
solvent
(h)
(%)a syn/antib
1
2
3
4
5
6
7
8
9
I.L
I.L
I.L
I.L
3
3
2
2.5
3
3.5
3
10
77
61
79
72
84
70
75
68
38
56/44
61/39
58/42
50/50
53/47
43/57
54/46
59/41
55/45
p-MeO-C6H4 I.L
o-Me-C6H4
2-naphthyl
p-Cl-C6H4
p-Cl-C6H4
I.L
I.L
MeOH
H2O-toluene (1:4) 10
plausible explanation was the hydroxy group on the benzene
ring coordinating with and deactivating the ruthenium
catalyst. Comparing with other solvents such as water and
water-organic solvent mixture (entries 3, 12, and 13, Table
1) the catalyst exhibits higher activity in ionic liquid, with
improved yield and shortened reaction time. Moreover, the
results exhibit a “reverse” trend in the reactivity of aldehydes
as compared to aldol condensation in organic solvents and
aqueous solutions (entries 7 and 14, Table 1), in which
electron-deficient aldehydes give better yields and electron-
rich substrates normally result in low yields or no reaction.
Although a detailed explanation is unavailable at this
moment, this trend could be a result of the unique solvation
properties of the ionic liquid, where more polarized electron-
deficient aldehydes tend to be more readily solvated by
anions and cations of the solvent and therefore less likely to
be approached by catalyst-activated enols. Nevertheless, the
reaction provides good substitution for other aldol reactions
when electron-rich aromatic aldehydes are desired reactants.
The diastereoselectivity remains relatively consistent, favor-
ing the syn product.
1
a Isolated yields were reported. b Diastereoselectivity was based on H
NMR analysis of crude products.
benzaldehyde was treated with 4-phenyl-2-hydroxy-3-butene,
elimination of water from the alcohol took place, which
indicates that the migration of the double bonds could
become difficult by stabilizing it with conjugated aromatic
systems.
Following this success, a related Mannich-type reaction
via olefin migration was also examined under similar reaction
conditions.24 As a model study, p-anisidine was used to
synthesize the imine, which was subsequently treated with
allylic alcohol and Ru catalyst. The desired Mannich products
were obtained efficiently (Scheme 3, Table 2). Compared
with other solvents, the reaction went faster in ionic liquids,
with a higher yield (entries 3, 8 and 9). Unlike the aqueous
medium, where aldol products were also formed as a result
of decomposition of imine, only Mannich products were
detected in ionic liquids.
The reaction of 3-buten-2-ol with aliphatic aldehyde in
[bmim]PF6 was also examined. Unlike the aqueous condition,
the reaction went smoothly in ionic liquid with all aliphatic
aldehydes, although the yields were considerably lower than
for aromatic substrates. It was also observed that unlike
aromatic aldehydes, which gave a relatively constant syn-
anti ratio, the diastereoselectivity in the condensation of
aliphatic aldehydes was substrate-dependent, favoring the anti
product. However, when this catalytic system was applied
to ketones, neither aromatic nor aliphatic substrates gave
satisfactory yields. Work is in progress to increase the
conversion rate of ketone condensation and subsequently
broaden the application of this methodology.
Scheme 3
Having established the viability of this reaction, attention
was focused on recycling of the Ru catalyst in [bmim]PF6.
2-Naphthaldehyde was used as substrate in view of the high
conversion rate. After ether extraction of the product, the
ionic phase was dried in air, and the catalytic system was
reloaded with 2-naphthaldehyde and 3-buten-2-ol for the next
run. As shown in Table 3, the solvent/catalyst system could
be reused for at lease five times with essentially no loss of
activity. Whether this high recycling efficiency can be
achieved with other aromatic and aliphatic aldehydes remains
to be established.
Other allylic alcohols such as 1-penten-3-ol and R-vinyl-
benzyl alcohol readily react with aldehydes in a similar way
(Scheme 2). A control reaction of methyl ethyl ketone with
benzaldehyde under the same reaction condition was carried
out and only starting material was recovered after 24 h. When
(24) Typical Experimental Procedure. A mixture of aldehyde/imine
(0.1 mmol), 3-buten-2-ol (0.25 mmol), and RuCl2(PPh3)3 (0.005 mmol) in
[bmim]PF6 (0.3 mL) was stirred at 90 °C in a sealed reaction vessel. After
1.5 h, the reaction mixture was cooled to room temperature and extracted
with ethyl ether (3 × 2 mL), and the combined ether phase was washed
with brine and dried over anhydrous Na2SO4. The mixture was then
concentrated under reduced pressure. The residue was purified by prepara-
tory TLC on silica gel to afford the desired aldol product.
In summary, we have developed an aldol-type and a
Mannich-type reaction via the cross-coupling of aldehydes
Org. Lett., Vol. 5, No. 5, 2003
659

reactivity.The scope, mechanism, and synthetic applications
of the reactions are currently under investigation
Table 3. Recycling Studies of Ru-Ionic Liquid Catalytic
System
Acknowledgment. We thank the NSF (0092001) and
NSF-EPA Joint Program for a Sustainable Environment for
partial support of our research. We are also grateful to Dr.
Luc Moens of National Renewable Energy Laboratory for
providing us with part of the ionic liquid.
cycle
yield (%)
syn/anti
time (h)
1
2
3
4
5
92
89
90
93
88
72/28
71/29
70/30
70/30
70/30
2
2
2.5
3
4
Supporting Information Available: Representative ex-
perimental procedure and the full characterization of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
and imines with allylic alcohols catalyzed by RuCl2(PPh3)3
in ionic liquid. The solvent/catalyst system is very reactive
and could be reused for at least five times with no loss of
OL0273102
660
Org. Lett., Vol. 5, No. 5, 2003