Ferrocenylphosphines as new catalysts for Baylis-Hillman reactions

Article abstract of DOI:10.1021/jo051701n

Readily available ferrocenyldialkylphosphines are effective air-stable catalysts for Baylis-Hillman reaction between aldehydes and acrylates, affording the corresponding adducts in high yields and short reaction times. A set of readily accessible planar c

Full text of DOI:10.1021/jo051701n

acids,5 ionic liquids6) and physical methods (high pres-
sure,7 ultrasounds,8 microwave irradiations9) have been
described in recent years.
Ferrocenylphosphines as New Catalysts for
Baylis-Hillman Reactions
With the aim of developing more active Lewis base
catalysts for Baylis-Hillman reaction, phosphines,10
especially the highly nucleophilic trialkylphosphines,11
constitute a very interesting alternative to the more basic
tertiary amines. However, unlike tertiary amines, tri-
alkylphosphines must be used under careful experimen-
tal conditions due to their high sensitivity to air oxidation
and in some cases pyrophoric character.12 Having in mind
the idea of developing a phosphine catalyst enjoying
simultaneously stability to air oxidation and high nu-
cleophilicity, we envisaged that due to the electron-rich
character of the ferrocene moiety, ferrocenyldialkylphos-
phines could be interesting catalysts in Baylis-Hillman
reaction. Additionally, planar chiral ferrocenylphos-
phines, which have provided countless examples of excel-
lent enantiocontrol in catalytic asymmetric metal-
catalyzed reactions,13 could offer a new alternative in
asymmetric Baylis-Hillman reaction.
Susana Isabel Pereira,† Javier Adrio,†
Artur M. S. Silva,‡ and Juan Carlos Carretero*,†
Departamento de Quı´mica Orga´nica, Universidad
Auto´noma de Madrid, Cantoblanco, 28049 Madrid, Spain,
and Departamento de Quı´mica, Universidade de Aveiro,
Campus de Santiago, 3810-183 Aveiro, Portugal
juancarlos.carretero@uam.es
Received August 11, 2005
On the basis of these considerations, the ferroce-
nylphosphines 1a-c were readily prepared according to
literature procedures by reaction of ferrocenyllithium
with the corresponding chlorophosphine.14 Table 1 sum-
marizes the results obtained in the model reaction
between benzylacrylate and p-nitrobenzaldehyde (in THF
at rt) in the presence of 15 mol % of the phosphine
catalyst (ferrocenylphosphines 1a-c and the commer-
cially available PPh3 and PCy3).15 For comparison pur-
poses, all reactions were stopped after 1 h of reaction.
To our delight, we observed that the diphenylphosphi-
noferrocene 1a (entry 1) was not only much more reactive
than PPh3 (entry 4), but even more reactive than the
aliphatic trialkylphosphine PCy3 (entry 5, 24% conver-
sion). Interestingly, in agreement with the increase in
nucleophilicity with the alkyl substitution, ferrocenyl-
dialkylphosphines 1b and 1c proved to be more effective.
Readily available ferrocenyldialkylphosphines are effective
air-stable catalysts for Baylis-Hillman reaction between
aldehydes and acrylates, affording the corresponding ad-
ducts in high yields and short reaction times. A set of readily
accessible planar chiral ferrocenyldialkylphosphines have
been tested in asymmetric Baylis-Hillman reactions. The
best enantioselectivities were obtained using Mandyphos as
chiral catalyst (up to 65% ee).
The development of catalytic carbon-carbon bond-
forming reactions leading to highly functionalized build-
ing blocks from simple starting materials is a fundamen-
tal challenge in organic chemistry. The Baylis-Hillman
reaction,1 which allows the direct preparation of R-me-
thylene-â-hydroxycarbonyl products from Michael accep-
tors and aldehydes, is a clear example of this kind of
outstanding process. This reaction is promoted by Lewis
bases, among which nucleophilic nonhindered tertiary
amines, such as diaza[2.2.2]bicyclooctane (DABCO), have
been the most widely used. Nevertheless, the great
synthetic potential of the Baylis-Hillman reaction is
often hampered by low reaction rates (reactions lasting
a week or more are common) and chemical yields highly
sensitive to the substitution at both aldehyde and Michel
acceptor partners. In attempts to overcome these limita-
tions, a wide variety of chemical (more activated carbonyl
compounds,2 hydrogen bonds donors,3 metal salts,4 Lewis
(5) (a) Aggarwal, V. K.; Mereu, A.; Tarver, G. J.; McCague, R. J.
Org. Chem. 1998, 63, 7183. (b) Pei, W.; Wei, H.-X.; Li, G. Chem.
Commun. 2002, 1856. (c) Yang, K.; Lee, W.; Pan, J.; Chen, K. J. Org.
Chem. 2003, 68, 915. (d) You, J.; Xu, J.; Verkade, J. G. Angew. Chem.,
Int. Ed. 2003, 42, 5054.
(6) (a) Rosa, J. N.; Afonso, C. A. M.; Santos, A. G. Tetrahedron 2001,
57, 4189. (b) Aggarwal, V. K.; Emme, I.; Mereu, A. Chem. Commun.
2002, 1612. (c) Pe´got, B.; Vo-Thanh, G.; Gori, D.; Loupy, A. Tetrahedron
Lett. 2004, 45, 6425.
(7) Hayashi, Y.; Okado, K.; Ashimine, I.; Shoji, M. Tetrahedron Lett.
2002, 43, 8683.
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Lopes, E. C.; Rossi, R. C.; Silveira, G. P. C.; Pavam, C. H. Tetrahedron
2002, 58, 7437.
(9) Kundu, M. K.; Mukherjee, S. B.; Balu, N.; Padmakumar, R.;
Bhat, S. V. Synlett. 1994, 444.
† Universidad Auto´noma de Madrid.
(10) (a) Rauhut, M. M.; Currier, H. U. S. Patent, 1963, 3074999;
Chem. Abstr. 1963, 58, 11224a. (b) Rafel, S.; Leahy, J. W. J. Org. Chem.
1997, 62, 1521 and references therein.
‡ Universidade de Aveiro.
(1) For recent reviews, see: (a) Methot, J. L.; Roush, W. R. Adv.
Synth. Catal. 2004, 346, 1035. (b) Basavaiah, D.; Rao, A. J.; Satya-
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P. Tetrahedron 1988, 44, 4653. (d) Ciganek, E. In Organic Reactions;
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(b) Auge, J.; Lubin, N.; Lubineau, A. Tetrahedron Lett. 1994, 35, 7947.
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mixtures of dioxane/H2O, MeOH/H2O afforded lower yields.
10.1021/jo051701n CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/08/2005
J. Org. Chem. 2005, 70, 10175-10177
10175

TABLE 1. Ferrocenylphosphines as Catalysts in the
Baylis-Hillman Reaction between Benzylacrylate and
p-Nitrobenzaldehyde
FIGURE 1. Tested chiral nonracemic ferrocenylphosphines.
lis-Hillman reaction with both branched and linear
aliphatic aldehydes (entries 6 and 7), providing the
corresponding alcohols in satisfactory yields after chro-
matographic purification (69-72%).
In the past few years, great progresses toward the
development of a enantioselective version of the Baylis-
Hillman reaction,16 including the use of chiral auxilia-
ries,17 chiral Lewis bases,18 and chiral Lewis5c or Brøn-
sted19 acids, have been described. Despite all these
improvements, the identification of a broad scope, asym-
metric version of this reaction remains an unsolved
problem. Until now, concerning the use of chiral phos-
phines in asymmetric Baylis-Hillman reaction with
aldehydes, only moderate enantioselectivities have been
reported (up to 44% ee with BINAP).20,21
Encouraged by the results illustrated in Tables 1 and
2, we decided to explore the potential of planar chiral
ferrocenylphophines in asymmetric Baylis-Hillman re-
actions (Figure 1).22 To this end, we tested sulfenylphos-
phinoferrocenes 9 and 10 developed by our group as
bidentate planar chiral P,S-ligands in enantioselective
metal-catalyzed reactions,23 as well as the commercially
available aminophosphinoferrocenes 11-13 and the
diphosphinoferrocene 14, combining both planar and
central chirality (Table 3).
a Determined by 1H NMR analysis of the crude reaction mixture.
b Isolated yield after flash chromatography.
TABLE 2. Baylis-Hillman Reaction Catalyzed by
Ferrocenyldiethylphosphine 1c
entry
R1
R2
compd
t (h)
yielda (%)
1
2
3
4
5
6
7
p-NO2C6H4
p-NO2C6H4
p-FC6H4
C6H5
Bn
Me
Bn
Bn
Bn
Bn
Bn
2
3
4
5
6
7
8
1
98
84
85
76
62
72
69
1
(16) For a review, see: Langer, P. Angew. Chem., Int. Ed. 2000, 39,
3049.
3
3
1.5
3
3
(17) (a) Brzezinski, L. J.; Rafel, S.; Leahy, J. J. Am. Chem. Soc. 1997,
119, 4317. (b) Yang, K.-S.; Chen, K. Org. Lett. 2000, 2, 729. (c) W.
Krishna, P. R.; Sachwani, R.; Kannan, V. Chem. Commun. 2004, 2580.
(18) (a) Shi, M.; Jiang, J.-K.; Tetrahedron: Asymmetry 2002, 13,
1951. (b) Kawahara, S.; Nakano, A.; Esumi, T.; Iwabuchi, Y.; Hatakeya-
ma, S. Org. Lett. 2003, 5, 3103.
2-Py
Cy
Me
a Isolated yield after flash chromatography.
(19) (a) McDougal, N. T.; Schaus, S. E. J. Am. Chem. Soc. 2003,
125, 12094. (b) McDougal, N. T.; Trvellini, W. L.; Rodgen, S. A.; Kliman,
L. T.; Schaus, S. Adv. Synth. Catal. 2004, 346, 1231.
(20) (a) Roth, F.; Crygak, P.; Fra´ter, G. Tetrahedron Lett. 1992, 33,
1045. (b) Hayase, T.; Shibata, T.; Soai, K.; Wakatsuki, Y. Chem.
Commun. 1998, 1271. (b) Li, W.; Zhang, Z.; Xiao, D.; Zhang, X. J. Org.
Chem. 2000, 65, 3489.
(21) The best results to date using chiral phosphines were obtained
in the aza-Baylis-Hillman reaction of N-sulfonilated imines with
methyl vinyl ketone using 2′-diphenylphosphanyl[1,1′]binaphthalenyl-
2-ol as catalyst (76-94% ee). Shi, M.; Chen L.-H. Chem. Commun.
2003, 1310.
(22) Although, to the best of our knowledge, there is not cases of
the utilization of chiral ferrocene phosphines in the Baylis-Hillman
reaction, an example of its utilization in the aza-Baylis-Hillman
reaction has been recently described. Shi, M.; Chen L.-H. Li, C.-Q. J.
Am. Chem. Soc. 2005, 127, 3790.
(23) (a) Priego, J.; Garc´ıa Manchen˜o, O.; Cabrera, S.; Go´mez-
Arraya´s, R.; Llamas T. Carretero, J. C. Chem. Commun. 2002, 2512.
(b) Garc´ıa Manchen˜o, O.; Priego, J.; Cabrera, S.; Go´mez-Arraya´s, R.;
Llamas T.; Carretero, J. C. J. Org. Chem. 2003, 68, 3679. (c) Garc´ıa
Manchen˜o O.; Go´mez-Arraya´s, R.; Carretero, J. C. J. Am. Chem. Soc.
2004, 125, 456. (d) Cabrera, S.; Go´mez-Arraya´s, R.; Carretero, J. C.
Angew. Chem., Int. Ed. 2004, 43, 3944.
In particular, the least hindered diethylphosphine 1c
promoted a complete conversion within 1 h, providing the
Baylis-Hillman adduct 2 in an excellent 98% yield (entry
3). Ferrocenylphosphines 1a-c are perfectly stable com-
pounds that can be handled in air, affording very similar
results in the Baylis-Hillman reaction either under inert
atmosphere or in open-air flasks.
With the optimized catalyst 1c in hand, we next
explored the scope of the process by studying a variety
of aldehydes. As shown in Table 2, several aromatic
aldehydes with varied subtitution provided good yields
(76-98%, entries 1-5) in short reaction times (1-3 h).
Because aliphatic aldehydes are very prone to suffer
aldolic condensation, most of the reported Baylis-Hill-
man reactions involve the use of aromatic aldehydes,
especially those promoted by basic tertiary amines.
Remarkably, ferrocenylphosphine 1c catalyzed the Bay-
10176 J. Org. Chem., Vol. 70, No. 24, 2005

TABLE 3. Asymmetric Baylis-Hillman Reaction
phine (25 mg, 0.0912 mmol) and p-nitrobenzaldehyde (91.9 mg,
0.608 mmol) in dry THF (1,8 mL) was added benzyl acrylate
(394.1 mg, 2.43 mmol) at room temperature under nitrogen
atmosphere. The resulting mixture was stirred for 1 h, after
which time the solvent was removed under reduced pressure.
The residue was purified by flash chromatography (SiO2, Hex/
EtOAc 3:1) to afford 2 (195 mg, 98%) as a colorless oil. 1H NMR
(CDCl3): δ 8.15 (d, J ) 8.8 Hz, 2H), 7.53 (d, J ) 8.4 Hz, 2H),
7.36-7.23 (m, 5H), 6.45 (s, 1H), 5.91 (s, 1H), 5.63 (s, 1H), 5.15
(s, 2H), 3.38 (br, 1H). 13C NMR (CDCl3): δ 165.6, 148.5, 147.5,
141.0, 135.1, 128.6 (×2), 128.5, 128.3 (×2), 127.5, 127.3 (×2),
123.6 (×2), 72.8, 67.0.
Catalyzed by Chiral Phosphinoferrocenes
entry
catalyst
t (h)
yielda (%)
eeb (%)
1
2
3
4
5
6
9
22
16
22
22
22
22
84
74
78
40
28
51
4 (S)
29 (R)
65 (R)
55 (R)
55 (R)
24 (R)
10
11
12
13
14
Benzyl 3-Hydroxy-3-(4-fluorophenyl)-2-methylenepro-
panoate (4). Colorless oil. Yield: 85%. 1H NMR (CDCl3):
δ
7.37-7.23 (m, 7H), 7.05-6.96 (m, 2H), 6.40 (s, 1H), 5.91 (s, 1H),
5.55 (s, 1H), 5.13 (s, 2H), 3.45 (br, 1H). 13C NMR (CDCl3): δ
166.0, 142.0, 137.1, 135.4, 128.6 (×2), 128.6, 128.4, 128.4, 128.1
(×2), 126.3 (×2), 115.4 (×2), 72.5, 66.7. IR: 3431.1, 3035.1,
2953.8, 1716.5, 1508.8, 1267.2, 1155.3, 1097.5, 837.4, 737.2. MS
(EI+) m/z: 195 (M+ - Bn, 49), 177 (56), 134 (25), 123 (67), 91
(100). HRMS (EI+): calcd for (C10H8O3F) [M+ - Bn] 195.0457,
found 195.0456.
a Isolated yield after flash chromatography. b Determined by
Chiral HPLC analysis (Daicel Chiralcel AD column, hexane/iPrOH
91/9, 0.5 mL/min.). c Absolute configuration determined by com-
parison with previously described data.5c
Benzyl 3-Hydroxy-3-(2-pyridyl)-2-methylenepropanoate
(6). Colorless oil. Yield: 62%. 1H NMR (CDCl3): δ 8.42-8.40
(m, 1H), 7.53 (dt, J 7.6, 1.7 Hz, 1H), 7.30-7.06 (m, 8H), 6.33 (s,
1H), 5.90 (s, 1H), 5.56 (s, 1H), 5.07 (s, 2H). 13C NMR (CDCl3):
δ 165.9, 159.5, 148.3 (×2), 141.8, 136.8 (×2), 135.6 128.5, 128.2,
128.1, 127.2, 122.6, 121.2, 72.2, 66.5. IR: 3445, 3064.6, 1956.40,
1715.8, 1437.5, 1046.8, 952.5, 736.4. MS (FAB+) m/z: 270 (M+
+ 1, 49), 162 (56), 91 (100). HRMS (electrospray+): calcd for
(C16H16NO3) [M+ + 1] 270.1124, found 270.1123.
Benzyl 3-Cyclohexyl-3-hydroxy-2-methylenepropanoate
(7). Colorless oil. Yield: 72%. 1H NMR (CDCl3): δ 7.39-7.34
(m, 5H), 6.30 (d, J 0.8 Hz, 1H), 5.75 (d, J 0.8 Hz, 1H), 5.22 (s,
2H), 2.49 (d, J 8.1 Hz, 1H), 1.9-0.88 (m, 11H). 13C NMR
(CDCl3): δ 165.5, 141.2, 135.7, 128.6 (×2), 128.3, 128.1 (×2),
126.4, 66.5, 42.5, 29.9, 28.2, 26.3, 26.1, 25.9. IR: 3493.0, 3035.2,
2929.4, 2853.4, 1718.4, 1627.9, 1498.5, 819.9, 737.1. MS (EI+)
m/z: 274 (M+ + 1, 0.4), 256 (1), 222 (0.1), 91 (100). HRMS
(EI+): calcd for (C17H22O3) [M+] 274.1568, found 274.1563.
According to the bulkier character of these catalysts,
compared to the parent ferrocene 1c, the reaction with
p-nitrobenzaldehyde was slower (16-22 h), giving rise
to the product 2 in yields highly depending on the catalyst
used (28-84% yield). Disappointingly, from a stereo-
chemical point of view, the enantioselectivities were low
to moderate. The Mandyphos-type ferrocenylphosphine
11, with two pendant dicyclohexylphosphine and di-
methylamino groups, proved to be the best catalyst
providing the Baylis-Hillman adduct 2 in 78% yield and
65% ee24 (entry 3). No improvement in the enantioselec-
tivity was observed when this reaction was performed
at 0 °C instead of room temperature.
In summary, the readily available and air-stable
ferrocenyldiethylphosphine is a highly active catalyst in
the Baylis-Hillman reaction between acrylates and
aldehydes. Good to excellent yields have been obtained
with a range of aldehydes within low reaction times.
Enantioselectivities up to 65% ee were obtained in the
asymmetric Baylis-Hillman reaction using planar chiral
ferrocenylphosphines.
Acknowledgment. This work was supported by the
Ministerio de Educacio´n y Ciencia (Project BQU2003-
0508) and Consejer´ıa de Educacio´n de la Comunidad de
Madrid (Project GR/MAT/0016/2004). J.A. thanks the
MEC for a Ramo´n y Cajal contract. S.I.P. thanks FCT
and FEDER for a Ph.D. grant (SFRH/BD/12757/2003).
Prof. Jose´ L. Garc´ıa-Ruano is gratefully acknowledged
for unrestricted access to the HPLC equipment of his
group. We also thank Solvias for the generous gift of
several chiral ligands.
Experimental Section
The Baylis-Hillman adducts 2, 3, 5, and 8 have been
previously reported.5c
Typical Procedure for the Baylis-Hillman Reaction.
Synthesis of Benzyl 3-Hydroxy-3-(4-nitrophenyl)-2-meth-
ylenepropanoate (2). To a solution of diethylferrocenylphos-
Supporting Information Available: Copies of 1H and 13
C
NMR spectra of all compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
(24) For deracemization of Baylis-Hillman adducts, see: Trost, B.
M.; Tsui, H.-C.; Toste, F. D. J. Am. Chem. Soc. 2000, 122, 3534.
JO051701N
J. Org. Chem, Vol. 70, No. 24, 2005 10177