986
LETTER
Enantioselective Catalysis of Intramolecular Morita–Baylis–Hillman and
Related Reactions by Chiral Rhenium-Containing Phosphines of the Formula
(h5-C5H5)Re(NO)(PPh3)(CH2PAr2)
Enantiosel ctiveCat lysi ofIntramolecularMorita–Baylis–HilmanandRelateSeidel,
Florian
dReactions
John A. Gladysz*
Institut für Organische Chemie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Henkestraße 42, 91054 Erlangen, Germany
E-mail: John.Gladysz@chemie.uni-erlangen.de
Received 7 December 2006
Key words: Morita–Baylis–Hillman, Rauhut–Currier, phosphine,
enantioselective catalysis, organocatalysis, cyclization
Numerous types of carbon–carbon bond-forming reactions can be catalyzed by phosphorus Lewis bases.1,2 In
many cases, achiral reactants are converted to chiral products. Vast numbers of chiral phosphines are now readily
available in enantiomerically pure form.3 Accordingly,
there is much interest in developing enantioselective versions of these reactions.
We have had a long-standing interest in transition-metalcontaining phosphorus Lewis bases of the formulae
LnMPR2 or LnMCH2PR2.4–6 Increasing numbers of chiral
LnM fragments are easily accessed in enantiomerically
pure form.7 Furthermore, it is now well established that
eighteen-valence-electron metal fragments enhance the
Lewis basicities and nucleophilicities of directly bound
donor atoms (D:), and homologues with an intervening
methylene group (CH2D:).4–6,8,9 The origins of these electronic effects, which should in many cases lead to superior
Lewis base catalysts, have been summarized.8
In a previous paper,9 we established that the chiral rhenium-containing phosphine (h5-C5H5)Re(NO)(PPh3)(CH2PPh2) (1a)5a,6a catalyzes the [3+2] cycloaddition of
the allene ethyl 2,3-butadienoate and aromatic N-tosyl
aldimines, and related transformations. Yields and enantioselectivities of 94–84% and 60–51% ee (er 80:20 to
76:24) could be realized. This air-stable eighteen-valenceelectron species – which may be regarded as a metal-containing ‘organocatalyst’ – can be prepared in racemic
form in six steps and 44% overall yield from commercial
SYNLETT 2007, No. 6, pp 0986–098803.04207
Advanced online publication: 26.03.2007
DOI: 10.1055/s-2007-973859; Art ID: G34706ST
© Georg Thieme Verlag Stuttgart · New York
Re2(CO)10, or in enantiopure form in nine steps and 36%
overall yield. We sought to extend the applicability of this
catalyst family to a wider range of reactions.
Accordingly, intramolecular Morita–Baylis–Hillman reactions of the dicarbonyl compounds R(CO)CH=CH(CH2)nCH2CHO (2) were selected for study. Such transformations had been examined by Koo [n/R = 1/H, 1/Ph
(2a), 1/Me, 1/Et, 1/Bu, 2/H],10 who found that stoichiometric quantities of PPh3 were required for efficient
cyclization, presumably via intermediates such as I
(Scheme 1). Marked solvent effects were also noted. Similar reactions had been described by Murphy and Fráter.11
In this communication, we report that substoichiometric
amounts of 1a or substituted derivatives catalyze the
cyclization of 2 and related compounds. Furthermore,
appreciable enantioselectivities can be realized.
O–
O
H
H +
n
a: n = 1, R = Ph
b: n = 1, R = S-i-Pr
c: n = 2, R = p-Tol
d: n = 2, R = Me
R
O
4
+
PR3
O–
R
n
2
R
a: n = 1, R = Ph
b: n = 1, R = S-i-Pr
H
R
n
O
O
1:2
stoichiometry
+
PR3
H
R
+
PPh3
O
O
1:1
stoichiometry
R
O–
R
O
O
I
II
Scheme 1 Syntheses of dicarbonyl compounds, and key intermediates in cyclization reactions (I, II)
The substrates 2a–d were prepared by reactions of a,w-dialdehydes with equimolar amounts of carbonyl-stabilized
Wittig reagents, as shown in Scheme 1. The compounds
2a,d have been previously reported,11a,12 whereas 2b,c are
new. In one series of reactions, benzene solutions of 2a
(0.100 M) and 1a (0.0100 M, 10 mol%) were combined at
20 °C.13 After 1.5 hours, a chromatographic workup gave
2-benzoylcyclopent-2-en-1-ol (3a),14 shown in Scheme 2,
in 91% yield as a spectroscopically pure oil. NMR monitoring showed nearly quantitative conversions, with significant amounts of catalyst remaining.
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Abstract: The racemic rhenium-containing phosphine (h5C5H5)Re(NO)(PPh3)(CH2PPh2) catalyzes intramolecular Morita–
Baylis–Hillman reactions of four R(CO)CH=CH(CH2)nCH2CHO
species (n = 1 or 2; R = Ph, S-i-Pr, p-Tol, Me) in benzene or chlorobenzene at 20 °C. The products R(CO)CH=CH(CH2)nCH2CHOH
are isolated in 88–99% yields and 38–74% ee when enantiopure Sconfigured
catalyst
is
used.
Similar
reactions
of
R(CO)CH=CHCH2CH2CH=CH(CO)R (R = Ph, S-i-Pr) give
R(CO)C=CHCH2CH2CHCH2(CO)R in 63–87% yields and 42–
56% ee.
Re
ON
PPh3
H2C
PPh2
O
H
2
a: R = Ph
b: R = S-i-Pr
O
R
2
c: R = p-Tol
d: R = Me
benzene,
20 °C
When (S)-1b was used, enantioselectivities decreased to
41–0% ee. The much more basic phosphido complex (h5C5H5)Re(NO)(PPh3)(PPh2)4a was rapidly consumed under
the reaction conditions, and no catalysis occurred.
O
R
3
a, 91% (isol.), 62% ee
(er 81:19)
b, 99% (isol.), 74% ee
(er 87:13)
OH
O
H
OH
1a or (S)-1a
(10 mol%)
R
O
987
Enantioselective Catalysis of Intramolecular Morita–Baylis–Hillman and Related Reactions
O
R
3
c, 91% (isol.), 38% ee
(er 69:31)
d, 88% (isol.), 70% ee
(er 85:15)
In the course of synthesizing 2a–d (Scheme 1), it was a
simple matter to modify the stoichiometry such that
bis(enone) systems (e.g., 4a,b) were obtained. These
types of substrates are capable of intramolecular Rauhut–
Currier reactions, presumably via intermediates II.2,19 As
shown in Scheme 3, the reaction of 4a and 1a (10 mol%)
gave the 1-benzoylcyclopentene 5a in 87% yield (benzene
solvent) or 67% yield (chlorobenzene) after workup.
When (S)-1a was used, 5a was obtained in 42% ee (er
71:29) and 56% ee (er 78:22), respectively. The cyclization of the bis(thioester) 4b to 5b could be effected with
comparable yields and enantioselectivities. To our knowledge, enantioselective versions of the Rauhut–Currier reaction have not been previously described.
Scheme 2 Intramolecular Morita–Baylis–Hillman reactions catalyzed by rhenium-containing phosphine 1a
The substrates 2c,d, which feature an additional methylene group between the carbonyl moieties, were similarly
treated with 1a. These cyclizations were somewhat slower. After three days, chromatography gave the six-membered-ring products 3c,d (Scheme 2) in 91–88% yields.
We also sought to vary the ketone functionality. Accordingly, an analogous reaction of the thioester 2b (6 h) gave
the five-membered-ring product 3b in 99% yield. However, related esters and amides underwent such cyclizations
in much lower yields.
The preceding reactions were repeated on 0.010–0.020 g
scales using enantiopure (S)-1a. As summarized in
Scheme 2, 3a,b,d were obtained with quite high enantioselectivities (74–62% ee, or er 87:13 to 81:19), as analyzed by HPLC. The enantiomeric purity of 3c was
somewhat lower (38% ee, or er 69:31).
Re
ON
PPh3
H2C
PPh2
1a or (S)-1a
(10 mol%)
O
R
R
O
4
chlorobenzene
or benzene,
20 °C
a: R = Ph
b: R = S-i-Pr
R
O
O
R
5
a, 67% (isol., chlorobenzene),
56% ee (er 78:22)
87% (isol., benzene),
42% ee (er 71:29)
b, 81% (isol., benzene),
52% ee (er 76:24)
Scheme 3 Intramolecular Rauhut–Currier reactions catalyzed by
rhenium-containing phosphine 1a
Reactions were screened in other solvents. In chlorobenzene, the rates of formation of 3a,b were slower, but those
of 3c,d were comparable. Except for 3c, enantioselectivities were uniformly lower (45%, 62%, 38%, 47% ee).
Since chlorobenzene has a lower freezing point than benzene, the reaction of 2a and (S)-1a was repeated at –25 °C.
Surprisingly, selectivity decreased; several new products
formed. Reactions could also be conducted in acetonitrile
and ethylene dichloride, but required a minimum of several days. Yields of 3a did not exceed 50%, as assayed by
GC, and higher temperatures decreased selectivity.
Several related contributions of other groups deserve emphasis. First, while our work was in progress, enantioselective Morita–Baylis–Hillman reactions of the phenyl
analogue of 2c and substituted derivatives were reported
by Miller.20 A co-catalyst system involving pipecolinic
acid and N-methylimidazole was employed. Second, other transition-metal-containing Lewis bases are known, but
are to date almost exclusively confined to ferrocene derivatives, as exemplified in the elegant studies of Fu.21
Third, six commercial chiral, enantiopure ferrocenylphosphines have recently been screened as catalysts for bimolecular Morita–Baylis–Hillman reactions, and gave ee
values ranging from 4% to 65% (average, 39%).22
A p-methoxy group normally increases the basicity of an
aryl phosphine.17,18 Accordingly, racemic and enantiopure
(h5-C5H5)Re(NO)(PPh3)[CH2P(p-C6H4OMe)2] (1b) were
synthesized by sequences analogous to those used for 1a.
Racemic 1b was also an effective catalyst for the cyclizations of 2a–d. Although reactions in chlorobenzene were
distinctly faster, yields of 3a–d were somewhat lower, reflecting decreased product selectivities (isolated yields:
55%, 58%, 40%, 50%; NMR yields: 3c, 70%; 3d, 85%).
In summary, 1a and (S)-1a represent an effective new catalyst family for intramolecular (and likely intermolecular)
Morita–Baylis–Hillman and Rauhut–Currier reactions
(Scheme 2 and Scheme 3). The loadings can be much
lower than those required with organophosphines, presumably due to the transition-metal-enhanced phosphorus
nucleophilicities. While significant enantioselectivities
can be achieved, the yields and ee values are very solvent
and temperature dependent. However, the catalysts feaSynlett 2007, No. 6, 986–988
© Thieme Stuttgart · New York
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LETTER
F. Seidel, J. A. Gladysz
ture many diversity elements that can be exploited to optimize performance (e.g., the cyclopentadienyl ligand, the
rhenium-bound phosphine, substituents on the spacer carbon or the Lewis basic phosphorus atom). Applications to
additional reactions, and second-generation systems that
afford improved yields and enantioselectivities, will be reported in due course.
Acknowledgment
We thank the Deutsche Forschungsgemeinschaft (DFG, GL 300/81; SPP 1179) for support.
References and Notes
(1) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev.
2003, 103, 811.
(2) Methot, J. L.; Roush, W. R. Adv. Synth. Catal. 2004, 346,
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(3) Lead references to two large families within this extensive
literature: (a) Grabulosa, A.; Granell, J.; Muller, G. Coord.
Chem. Rev. 2007, 251, 25. (b) Gómez Arrayás, R.; Adrio, J.;
Carretero, J. C. Angew. Chem. Int. Ed. 2006, 45, 7674;
Angew. Chem. 2006, 118, 7836.
(4) (a) Buhro, W. E.; Zwick, B. D.; Georgiou, S.; Hutchinson, J.
P.; Gladysz, J. A. J. Am. Chem. Soc. 1988, 110, 2427.
(b) Zwick, B. D.; Dewey, M. A.; Knight, D. A.; Buhro, W.
E.; Arif, A. M.; Gladysz, J. A. Organometallics 1992, 11,
2673. (c) Giner Planas, J.; Hampel, F.; Gladysz, J. A. Chem.
Eur. J. 2005, 11, 1402.
(5) (a) Kromm, K.; Zwick, B. D.; Meyer, O.; Hampel, F.;
Gladysz, J. A. Chem. Eur. J. 2001, 7, 2015. (b) Kromm, K.;
Hampel, F.; Gladysz, J. A. Organometallics 2002, 21, 4264.
(c) Kromm, K.; Osburn, P. L.; Gladysz, J. A.
Organometallics 2002, 21, 4275.
(6) (a) Eichenseher, S.; Delacroix, O.; Kromm, K.; Hampel, F.;
Gladysz, J. A. Organometallics 2005, 24, 245. (b) Kromm,
K.; Eichenseher, S.; Prommesberger, M.; Hampel, F.;
Gladysz, J. A. Eur. J. Inorg. Chem. 2005, 2983.
(c) Friedlein, F. K.; Hampel, F.; Gladysz, J. A.
Organometallics 2005, 24, 4103.
(7) Brunner, H. Angew. Chem. Int. Ed. 1999, 38, 1194; Angew.
Chem. 1999, 111, 1248.
(8) Delacroix, O.; Gladysz, J. A. Chem. Commun. 2003, 665.
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(10) Yeo, J. E.; Yang, X.; Kim, H. J.; Koo, S. Chem. Commun.
2004, 236.
(11) (a) Richards, E. L.; Murphy, P. J.; Dinon, F.; Fratucello, S.;
Brown, P. M.; Gelbrich, T.; Hursthouse, M. B. Tetrahedron
2001, 57, 7771. (b) Roth, F.; Gygax, P.; Fráter, G.
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Synlett 2007, No. 6, 986–988
© Thieme Stuttgart · New York
LETTER
(13) General Procedures
(a) Racemic catalysts: A Schlenk flask was charged with the
educt (typically 0.060–0.080 g). Then C6H5Cl or C6H6
solutions that were 0.0125 M in ClCH2CH2Cl (reference for
1
H NMR integration) were added to give 0.100 M educt
solutions. These were equilibrated to 20 °C using a cryostat.
Solutions of C6H5Cl or C6H6 that were 0.0100 M in catalyst
and 0.0125 M in ClCH2CH2Cl were cooled to 0 °C. Equal
volumes, corresponding to 10 mol% loading, were added
dropwise over ca. 5 min to the educt solutions. An aliquot
(0.6 mL) was transferred to an NMR tube, and 1H NMR
spectra were periodically recorded. When the reaction was
complete (or no further reaction took place), 5 volumes of
hexane were added with stirring. The mixture was filtered
through a short plug of silica gel (removing catalyst), and the
plug was washed with hexane–EtOAc (9:1 v/v). The solvent
was removed from the filtrates by rotary evaporation.
Reactions conducted in C6H5Cl were further purified by
silica gel column chromatography, except in the case of 5a.
(b) Enantiopure catalysts: The preceding reactions were
repeated on 0.0010–0.0020 g scales. The products were
analyzed by HPLC using Chiralcel OD, Chiralpak AD-H or
Chiralpak AS-H columns.
(14) All products were characterized by NMR (1H, 13C) and IR
spectroscopy, and these data are available from the authors
upon request; 3a,d and 5a have been reported
previously.11a,15,16
Typical data (3b): 1H NMR (400 MHz, CDCl3): d = 1.39 [d,
(CH3)2CH, 3J(H,H) = 7.2 Hz, 6 H], 1.82–1.91 (m,
C=CHCHH¢, 1 H), 2.27–2.46 (2 m, C=CHCHH¢,
CHH¢CHOH, 2 H) 2.62–2.73 (m, CHH¢CHOH, 1 H), 2.78
(br s, CHOH, 1 H), 3.74 [sep, 3J(H,H) = 7.2 Hz, (CH3)2CH,
1 H], 5.13–5.16 (m, CHOH, 1 H), 6.89 [dd, 3J(H,H) = 2.8,
2.8 Hz, C=CHCHH¢, 1 H] ppm. 13C{1H} NMR (101 MHz,
CDCl3): d = 23.0 [s, (CH3)2CH], 30.9 (s, C=CHCH2), 31.8 (s,
CH2CHOH), 34.3 [s, (CH3)2CH], 75.7 (s, CHOH), 144.4 [s,
(CO)C=CH], 145.2 [s, (CO)C=CH], 190.1 [s, (CO)C=CH]
ppm. IR (thin film): 1613 (s, nC=C), 1648 (s, nCO), 3450 (br,
nOH) cm–1.
(15) Graff, M.; Dilaimi, A. A.; Seguineau, P.; Rambaud, M.;
Villieras, J. Tetrahedron Lett. 1986, 27, 1577.
(16) (a) Brown, M. B.; Käppel, N.; Murphy, P. J. Tetrahedron
Lett. 2002, 43, 8707. (b) Wang, L.-C.; Luis, A. L.; Agapiou,
K.; Jang, H.-Y.; Krische, M. J. J. Am. Chem. Soc. 2002, 124,
2402.
(17) Allman, T.; Goel, R. G. Can. J. Chem. 1982, 60, 716.
(18) Bush, R. C.; Angelici, R. J. Inorg. Chem. 1988, 27, 681.
(19) Wang, J.-C.; Ng, S.-S.; Krische, M. J. J. Am. Chem. Soc.
2003, 125, 3682; and references therein.
(20) Aroyan, C. E.; Vasbinder, M. M.; Miller, S. J. Org. Lett.
2005, 7, 3849.
(21) Fu, G. C. Acc. Chem. Res. 2004, 37, 542.
(22) Pereira, S. I.; Adrio, J.; Silva, A. M. S.; Carretero, J. C. J.
Org. Chem. 2005, 70, 10175.
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988