Asymmetric organocatalytic conjugate addition of malonates to enones using a proline tetrazole catalyst

Article abstract of DOI:10.1039/b514636d

5-Pyrrolidin-2-yltetrazole performs as a useful organocatalyst for the asymmetric addition of malonates to a range of enones, with good to excellent enantioselectivities. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b514636d

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Asymmetric organocatalytic conjugate addition of malonates to enones
using a proline tetrazole catalyst
Kristian Rahbek Knudsen, Claire E. T. Mitchell and Steven V. Ley*
Received (in Cambridge, UK) 17th October 2005, Accepted 2nd November 2005
First published as an Advance Article on the web 28th November 2005
DOI: 10.1039/b514636d
Imidazoline catalyst 2 has been observed to provide good to
excellent enantioselectivities for the conjugate addition of malo-
nates to acyclic a,b-unsaturated enones (59–99%).11 Nevertheless,
although the addition of dibenzyl and diethyl malonates proceeded
with excellent enantioselectivities, the addition of methyl malonate
proceeded with lower selectivity (71% ee) and reaction times were
typically between 5 and 12 days. In addition, the malonates were
employed as the reaction solvent, and thus were used in
approximately 8–16 fold excess. Since these malonates are not
especially volatile, their eventual removal is problematic.
5-Pyrrolidin-2-yltetrazole performs as a useful organocatalyst
for the asymmetric addition of malonates to a range of enones,
with good to excellent enantioselectivities.
The asymmetric conjugate addition of carbon nucleophiles to
electron-poor alkenes is an important transformation in modern
synthetic chemistry.1 Malonates are an easily accessible source of
donors as the two electron-withdrawing esters enable enolate
formation under mild conditions. Dimethylmalonate and, to a
lesser extent, diethylmalonate, are particularly valuable units due
to their facile direct decarboxylation under Krapcho conditions.2
A variety of transition metal catalysts have been developed for
the asymmetric conjugate addition of 1,3-dicarbonyl compounds
to enones.3 The most general systems reported to date include the
BINOL–heterobimetallic complexes developed by Shibasaki et al.
which gave excellent enantioselectivities for the addition of
malonate and other closely related carbon nucleophiles to cyclic
enones;4 these have been used on a kilogram scale.5 Jacobsen and
co-workers have investigated the use of an aluminium–salen
catalyst for the addition of methylcyanoacetate to a range of
enones also in high yields and in good to excellent enantioselec-
tivity.6 Proline rubidium salts have been used similarly to catalyse
the addition of di-iso-propyl and di-tert-butyl malonates to both
acyclic and cyclic a,b-unsaturated enones; here the reaction
proceeded with low to good enantioselectivities (35–88% ee).7
Proline 1 itself (Fig. 1) has been employed for the addition of 1,3-
diketones to methylvinylketone and subsequent cyclization to
3-hydroxycoumarins.8 Cinchona alkaloid-derived phase transfer
catalysts have also been employed in the addition of malonates to
chalcone and closely related substrates, with good enantioselec-
tivity.9 Recently, use of a bifunctional hydrogen-bonding organo-
catalyst for the addition of malonitrile to a,b-unsaturated imides
with good yields and enantioselectivities has been reported.10
However, the addition of less reactive species such as malonates
and b-ketoesters could not be achieved.
We and others have previously reported on the tetrazole
analogue of proline 3 as a more soluble and effective catalyst in a
variety of transformations.12 We have shown that tetrazole 3 is an
improved catalyst for the conjugate addition of nitroalkanes to
both cyclic and acyclic enones,13 using the achiral meso base 2,5-
dimethylpiperazine 5 (Fig. 2) as an additive under conditions
adapted from those previously developed by Hanessian and Pham
for the addition of nitroalkanes to cyclic enones catalysed by
proline.14 Moderate to excellent enantioselectivities were obtained
(58–98% ee). In connection with an ongoing synthesis project in
our group, we required a scalable method for the asymmetric
addition of malonates to a wide range of enones both cyclic and
acyclic.
Initial results using the conditions optimised for the addition of
nitroalkanes to enones were promising, giving the product 9a
in 65% conversion and 77% ee (Table 1, entry 1). Malonates
(pKa diethyl malonate = 13) are less acidic than nitroalkanes
(pKa MeNO2 = 10), so the use of the stronger base piperidine (6)
was investigated next. The reaction of cyclohexenone 7 with
dibenzylmalonate 8a in CH2Cl2 in combination with 6 as the base
afforded product 9a in 63% conversion and an improved ee after 2
days (entry 2). Changing the solvent to CHCl3 gave a higher
conversion of 87% whilst maintaining the enantioselectivity
(entry 3). On the other hand, use of the non-chlorinated solvent
MeCN led to a decrease in both enantioselectivity and yield
(entry 4). Diethyl malonate 8b as the nucleophile was also found to
give improved results using piperidine 6 rather than 5 (entries 5, 6),
giving 89% conversion and 92% ee in CH2Cl2 and similar ee’s but
lower overall conversion in CHCl3 (entry 7).
Fig. 1 Proline and related organocatalysts.
Department of Chemistry, University of Cambridge, Lensfield Rd,
Cambridge, UK CB2 1EW. E-mail: svl1000@cam.ac.uk;
Fax: + 44 (0)1223 336442
Fig. 2 Bases employed.
66 | Chem. Commun., 2006, 66–68
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Table 1 Initial screening of cyclohexenone as substrate
Table 2 Optimization for acyclic substrates
Entry Malonate Catalyst Solvent Base Conv.b (%) eec (%)
1
2
3
4
5
6
7
8
8a
8a
8b
8b
8b
8b
8b
8b
8c
8c
8c
8cd
8ce
3
3
3
3
3
3
1
4
3
3
3
3
3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
MeCN
CHCl3
CH2Cl2
CH2Cl2
CHCl3
MeCN
CHCl3
CHCl3
5
6
5
6
6
6
6
6
6
6
6
6
6
59
90
29
78
82
93
82
24
97
89
89
97
92
83
83
87
87
89
85
57
42
81
85
77
83
85
Entry Malonate Catalyst Solvent Base Conv.b (%) eec (%)
1
2
3
4
5
6
7
8
8a
8a
8a
8a
8b
8b
8b
8b
8b
8b
8c
8c
3
3
3
3
3
3
3
1
4
4
3
3
CH2Cl2
CH2Cl2
CHCl3
MeCN
CH2Cl2
CH2Cl2
CHCl3
CHCl3
CHCl3
CH2Cl2
CH2Cl2
CHCl3
5
6
6
6
5
6
6
6
6
6
6
6
65
63
87
80
65
89
69
62
40
50
85
87
77
82
81
70
79
92
89
38
0
9
10
11
12
13
a
9
10
11
12
a
217
83
85
10 (0.2 mmol), 3 (10 mol%), 8a–c (0.3 mmol), base (0.2 mmol),
solvent 1 mL, rt, 3 d. Measured by 1H NMR. Determined by
chiral HPLC. 15 mol% of catalyst 3 was used, 2 d. 5 mol% of
catalyst 3 was used.
b
c
d
e
7 (0.2 mmol), catalyst (15 mol%), 8a–c (0.2 mmol), base (0.2 mmol),
b
c
solvent 1 mL, rt, 2 d. Estimated by 1H NMR. Determined by
chiral HPLC or GC. Absolute configuration determined from ref. 17.
conversion of 97%, with the reaction essentially complete within
2 days, but with a slightly decreased 83% ee (entry 12). NMR
analysis of the reaction with 10 mol% 3 demonstrated that the
reaction reached 89% conversion after 2 days, but did not progress
any further. Pleasingly, use of only 5 mol% 3 gave the product in
92% conversion and 85% ee with a slightly prolonged reaction time
of 3 days (entry 13). Again, NMR analysis indicated the reaction
did not progress to completion even after extended treatment.
Next, the addition of a range of malonates to enone 10 under
these optimised conditions was investigated (Table 3). Good yields
were obtained for all malonates. In contrast to previous work with
Proline 1, on the other hand, gave only 38% ee in 62%
conversion (entry 8). While the homologated tetrazole 4 was
effective as a catalyst in the asymmetric Michael addition of
ketones to nitroolefins,15 in this work the Michael addition of
diethyl malonate to cyclohexenone in CHCl3 provided only the
racemic product 9b (entry 9). Interestingly, in CH2Cl2 4 showed
reversed selectivity, favouring formation of the opposite enantio-
mer of the product, albeit in low ee (entry 10). This switch in
enantioselectivity was not observed in the addition of 2-nitropro-
pane to 7 when catalysed by 4. However, use of dimethyl malonate
gave the product 9c in good conversion and enantioselectivity in
both CH2Cl2 and CHCl3 (entries 11, 12), with a slightly higher ee
of 85% being observed in chloroform.
Table 3 Investigation of different malonates
We next investigated the addition of malonate to 4-phenyl-3-
buten-2-one 10 as a less reactive acceptor in these Michael addition
reactions. Reaction of 10 with dibenzyl malonate 8a (1.5 eq.) gave
the product 11a in 59% conversion and 83% ee over 3 days
(Table 2, entry 1). However, the use of base 6 in this reaction gave
the product in higher yield while maintaining the enantioselectivity
(entry 2). For diethyl malonate 8b, the added base 5 gave the
product in good ee but with low conversion (entry 3). By changing
the base to piperidine 6 we obtained good results both with
CH2Cl2 and CHCl3 (entries 4, 5), the reaction in CHCl3 providing
a slightly improved ee of 89%. Use of proline 1 gave 57% ee. The
reversal of enantioselectivity observed in the addition of diethyl
malonate to cyclohexenone with the homologated tetrazole 4
(Table 1, entry 10) was not observed for the acyclic enone 10 (entry
8). In the case of dimethyl malonate 8c, reactions in CHCl3 led to a
significantly improved enantioselectivity of 85% compared to both
CH2Cl2 and MeCN (entries 9–11). The reactions were monitored
by NMR (conversion) and HPLC (ee) over 5 days at various
catalyst loadings. Use of 15 mol% of tetrazole 3 led to a higher
Entry
Malonate
Yield (%)b
eec (%)
1
2
3
4
5
a
8a
8b
8c
8d
8e
88
82
89
68
85
89
84
93
43
67 (1 : 1.6 dr)
10 (0.5 mmol), 3 (5 mol%), 8a–e (0.75 mmol), 6 (0.5 mmol), CHCl3
b
(2 mL), rt, 3d. Isolated yield. Determined by chiral HPLC.
c
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readily apparent, since changing the base affects not only yield but
Table 4 Substrate scope
also the enantioselectivity. Studies on ammonium carbanions have
shown that in non-polar solvents the tetrabutylammonium salt
and the enolate remain associated through hydrogen bonds.16 It is
plausible that in the non-polar solvents required for these
reactions, the amine additive and the malonate remain associated,
and it is these hydrogen-bonded complexes which are involved in
the addition step. Kinetic studies are presently underway to
elucidate these pathways. Also, further investigations into the
asymmetric addition of mixed malonate type nucleophiles into
enone acceptors are ongoing.
Entry
1
Enone
Yield (%)b
87
ee (%)c
83
In conclusion, we have developed an improved organocatalytic
conjugate addition of malonates to enones. The reaction gives
good results for a range of substrates furnishing the products in
good yield with good to high enantioselectivities. As only
1.5 equivalents of enone are used as coupling partner, the reaction
is readily scaled and practical to operate.
2
84
78
3
4
64
70d
62
64d
We thank the Carlsberg Foundation (to KRK), Avecia (to
CETM), the EPSRC (to CETM), and Novartis (through a
Research Fellowship to SVL) for financial support.
5
6
a
69
82
81
84
Notes and references
1 M. P. Sibi and S. Manyem, Tetrahedron, 2000, 56, 8033; N. Krause and
A. Hoffmann-Roder, Synthesis, 2001, 171.
2 (a) A. P. Krapcho, Synthesis, 1982, 805; (b) A. P. Krapcho, Synthesis,
1982, 893.
3 (a) M. P. Sibi and S. Manyem, Tetrahedron, 2000, 56, 8033; (b)
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J. Christoffers, Eur. J. Org. Chem., 1998, 1259.
4 (a) M. Shibasaki and N. Yoshikawa, Chem. Rev., 2002, 102, 2187; (b)
K. Majima, R. Takita, A. Okada, T. Ohshima and M. Shibasaki, J. Am.
Chem. Soc., 2003, 125, 15837; (c) K. Majima, S. Y. Tosaki, T. Ohshima
and M. Shibasaki, Tetrahedron Lett., 2005, 46, 5377.
5 Y. Xu, K. Ohori, T. Ohshima and M. Shibasaki, Tetrahedron, 2002, 58,
2585.
6 (a) M. S. Taylor and E. N. Jacobsen, J. Am. Chem. Soc., 2003, 125,
11204; (b) M. S. Taylor, D. N. Zalatan, A. N. Lerchner and
E. N. Jacobsen, J. Am. Chem. Soc., 2004, 126, 1313.
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J. Org. Chem., 1996, 61, 3520–3530.
Enone (0.5 mmol), 3 (5 mol%), 8c (0.75 mmol), 6 (0.5 mmol),
b
c
CHCl3 2ml, 3 days, rt. Isolated yield. Enantiomeric excess was
determined by chiral HPLC or GC.d Two equivalents of base.
the imidazolidinone catalyst 2, the reaction was found to be
relatively insensitive to the nature of the malonate, with 84% ee
obtained with the less sterically bulky dimethyl malonate (entry 3).
The more hindered di-iso-propyl malonate reacted more slowly,
giving a 68% yield after 3 days, but with a 93% ee (entry 4).
Interestingly, preliminary results with mixed malonate 8e gave 67%
yield in a 1 : 1.6 dr with 43% ee of both diasteromers.
Although the diethyl malonate 8b gave higher enantioselectivity
than the dimethyl malonate 8c, the decarboxylation of the latter
under Krapcho conditions is more facile,2 and hence the products
are more synthetically useful. Therefore, the scope of the addition
of dimethyl malonate to a series of enones was tested. For
cyclohexenone, the isolated yield was 87% (Table 4, entry 1).
Substituted 4-phenyl-3-buten-2-ones were also examined. When
the phenyl ring was substituted with an electron-withdrawing
p-CF3 group, the product was obtained in 84% yield and 78% ee
(entry 2). The p-OH substituted enone afforded a moderate yield
of 64% in 62% ee (entry 3). As the pKa of the phenol proton is
comparable to that of the malonate, the reaction was also run with
two equivalents of base 6 present, which afforded the product in a
slightly higher yield of 70% without any significant improvement
in enantioselectivity (entry 4). Heterocyclic enones were also found
to perform well in the reaction. The furan substituted enone gave
81% ee in a 69% yield (entry 5). The thiophene derived enone gave
82% yield and 84% ee (entry 6).
8 D. Gryko, Tetrahedron: Asymmetry, 2005, 16, 1377.
9 T. Ooi, D. Ohara, K. Fukumoto and K. Maruoka, Org. Lett., 2005, 7,
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11 N. Halland, P. S Aburel and K. A. Jørgensen, Angew. Chem., Int. Ed.,
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S. Saito and H. Yamamoto, Proc. Natl. Acad. Sci. USA, 2004, 101,
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Angew. Chem., Int. Ed., 2004, 43, 1983; (f) Y. Yamamoto,
N. Momiyama and H. Yamamoto, J. Am. Chem. Soc., 2004, 126,
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16 M. T. Reetz, S. Huette and R. Goddard, J. Am. Chem. Soc., 1993, 115,
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The mechanism for these reactions has not yet been established,
although it is believed that the catalyst and enone form an
intermediate iminium ion species. The function of the base is not
17 H. Sasai, T. Arai, Y. Satow, K. N. Houk and M. Shibasaki, J. Am.
Chem. Soc., 1995, 117, 6194.
68 | Chem. Commun., 2006, 66–68
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