1984
LETTER
A Useful Modification of the Evans Magnesium Halide Catalyzed anti-Aldol Reaction: Application to Enolizable Aldehydes Modifedanti-AldolConditonsforAliphaticAldehydes E. May, Nathan T. Connell, Heidi A. Dahlmann, Thomas R. Hoye* Aaron Department of Chemistry, University of Minnesota, Minneapolis, MN 55455, USA Fax +1(612)6267541; E-mail: [email protected] Received 12 April 2010
Abstract: A practical protocol for use of the magnesium halide catalyzed anti-aldol reaction of an Evans N-acyloxazolidinone with enolizable aldehydes is reported. The yields of anti-aldol adducts for saturated or unsaturated and branched or unbranched aliphatic aldehydes are preparatively useful.
X
When we attempted to apply the reported conditions for the addition of 1 to enolizable aldehydes 3 (both with and without NaSbF6), typically low conversions of 1 into product 2 were observed, consistent with earlier observations.2a,4e Control experiments showed that the aldehydes were not stable under the reaction conditions. GC–MS analysis suggested that silyl enol ether formation and/or self-aldol reactions of 3 were the principal offenders. We reasoned that the desired crossed-aldol addition reaction between 1 and 3 might be promoted if: i) the oxazolidinone enolate concentration (A to B, Scheme 1) was increased by using more magnesium halide, ii) the reactive enolizable aldehyde 3 was added slowly to maintain a higher steady-state enolate to aldehyde ratio throughout the reaction, and/or iii) a more reactive silylating agent was used to trap more rapidly the intermediate magnesium aldolate C, thus favoring formation of D relative to the retro-aldol event. We envisioned that addition of lithium iodide might serve a dual role of enhancing both the rate
SYNLETT 2010, No. 13, pp 1984–1986xx. 201 Advanced online publication: 09.07.2010 DOI: 10.1055/s-0030-1258480; Art ID: S01910ST © Georg Thieme Verlag Stuttgart · New York
Sn Mg O O
O
O 1
+ MgX2
– HX O
N
Key words: aldol reaction, aldehydes, halides, catalysis
The stereoselective aldol reaction is a fundamental and widely used transformation in the field of organic synthesis.1 We recently needed to perform anti-selective aldol additions with enolizable aldehyde substrates for the synthesis of polyketide fragments. Of the available methods, the magnesium halide catalyzed protocol of Evans, using an N-acyloxazolidinone (e.g., 1), seemed quite promising.2,3 This reaction was attractive because it requires mostly common reagents [ethyl acetate, triethylamine, trimethylsilyl chloride (TMSCl), magnesium chloride, and sometimes NaSbF6], simple conditions, and a universal chiral auxiliary. It typically proceeds with good yields and selectivities. Many laboratories have reported using this protocol. However, most of the examples have involved nonenolizable aldehydes.4
X
X Mg
Bn
A
B RCHO (3)
O
O O – TMS + H+
O
OTMS R
N
TMSX – MgX2
O
X
Sn Mg
O
O R
N Bn
Bn D
Scheme 1
N
Bn
X = Cl or I S = solvent
2
O
C
Magnesium halide catalyzed anti-aldol reaction
of silylation (via TMSI formation) and the Lewis acidity of the magnesium halide. We screened many conditions (alternative bases, solvents, trapping agents, and additives). The best results were obtained by use of the following components and stoichiometries: N-acyloxazolidinone 1 (0.5 M in EtOAc), magnesium chloride (1 equiv), lithium iodide (2 equiv), triethylamine (5 equiv), and TMSCl (4 equiv). Since either the donor or the acceptor in an aldol reaction can be the more precious substrate, two different stoichiometric ratios of oxazolidinone 1 to aldehyde 3 were explored (Method A, 1:3 = 0.33; Method B, 1:3 = 2). In either method, aldehyde 3 was added as an ethyl acetate solution (2 M) via syringe pump at a rate of one equivalent per hour to a stirred mixture of all remaining components. The results with aldehydes 3a–f are summarized in Table 1. The g-branched a,b-unsaturated aldehyde 3a gave 56% yield of 2a using Method A. This substrate also performed well using the original conditions described by Evans. For comparison, we examined the reaction of each of 3a–f according to reference 2a; the optimal results are provided in the last column in Table 1. The success of these original conditions with substrate 3a speaks of its slow rate of silylative consumption; however, the remaining aldehydes 3b–f gave low conversions. On the other hand, through the use of lithium iodide and slow addition of aldehyde, we observed significantly higher conversions and isolated the following yields of diastereomerically pure anti-aldol
LETTER Table 1 O O
Modified anti-Aldol Conditions for Aliphatic Aldehydes
1985
Formation of anti-Aldol Adducts 2 from Addition of 1 to Enolizable Aldehydes 3 1) MgCl2, LiI, Et3N, TMSCl, EtOAc, syringe pump addition of enolizable aldehyde 3
O N
O O
O
OH
N
R
2) p-TsOH; MeOH Bn
Bn
1
2a–f
Entry
Aldehyde 3
Diastereoselection (%)a
Isolated yield (%) of 2b,c
Conversion of 1 (%)d,e
a
O
71
56 (49)
73
b
O
90
66 (66)
12
73
44 (43)
LETTER
A Useful Modification of the Evans Magnesium Halide Catalyzed anti-Aldol Reaction: Application to Enolizable Aldehydes Modifedanti-AldolConditonsforAliphaticAldehydes E. May, Nathan T. Connell, Heidi A. Dahlmann, Thomas R. Hoye* Aaron Department of Chemistry, University of Minnesota, Minneapolis, MN 55455, USA Fax +1(612)6267541; E-mail: [email protected] Received 12 April 2010
Abstract: A practical protocol for use of the magnesium halide catalyzed anti-aldol reaction of an Evans N-acyloxazolidinone with enolizable aldehydes is reported. The yields of anti-aldol adducts for saturated or unsaturated and branched or unbranched aliphatic aldehydes are preparatively useful.
X
When we attempted to apply the reported conditions for the addition of 1 to enolizable aldehydes 3 (both with and without NaSbF6), typically low conversions of 1 into product 2 were observed, consistent with earlier observations.2a,4e Control experiments showed that the aldehydes were not stable under the reaction conditions. GC–MS analysis suggested that silyl enol ether formation and/or self-aldol reactions of 3 were the principal offenders. We reasoned that the desired crossed-aldol addition reaction between 1 and 3 might be promoted if: i) the oxazolidinone enolate concentration (A to B, Scheme 1) was increased by using more magnesium halide, ii) the reactive enolizable aldehyde 3 was added slowly to maintain a higher steady-state enolate to aldehyde ratio throughout the reaction, and/or iii) a more reactive silylating agent was used to trap more rapidly the intermediate magnesium aldolate C, thus favoring formation of D relative to the retro-aldol event. We envisioned that addition of lithium iodide might serve a dual role of enhancing both the rate
SYNLETT 2010, No. 13, pp 1984–1986xx. 201 Advanced online publication: 09.07.2010 DOI: 10.1055/s-0030-1258480; Art ID: S01910ST © Georg Thieme Verlag Stuttgart · New York
Sn Mg O O
O
O 1
+ MgX2
– HX O
N
Key words: aldol reaction, aldehydes, halides, catalysis
The stereoselective aldol reaction is a fundamental and widely used transformation in the field of organic synthesis.1 We recently needed to perform anti-selective aldol additions with enolizable aldehyde substrates for the synthesis of polyketide fragments. Of the available methods, the magnesium halide catalyzed protocol of Evans, using an N-acyloxazolidinone (e.g., 1), seemed quite promising.2,3 This reaction was attractive because it requires mostly common reagents [ethyl acetate, triethylamine, trimethylsilyl chloride (TMSCl), magnesium chloride, and sometimes NaSbF6], simple conditions, and a universal chiral auxiliary. It typically proceeds with good yields and selectivities. Many laboratories have reported using this protocol. However, most of the examples have involved nonenolizable aldehydes.4
X
X Mg
Bn
A
B RCHO (3)
O
O O – TMS + H+
O
OTMS R
N
TMSX – MgX2
O
X
Sn Mg
O
O R
N Bn
Bn D
Scheme 1
N
Bn
X = Cl or I S = solvent
2
O
C
Magnesium halide catalyzed anti-aldol reaction
of silylation (via TMSI formation) and the Lewis acidity of the magnesium halide. We screened many conditions (alternative bases, solvents, trapping agents, and additives). The best results were obtained by use of the following components and stoichiometries: N-acyloxazolidinone 1 (0.5 M in EtOAc), magnesium chloride (1 equiv), lithium iodide (2 equiv), triethylamine (5 equiv), and TMSCl (4 equiv). Since either the donor or the acceptor in an aldol reaction can be the more precious substrate, two different stoichiometric ratios of oxazolidinone 1 to aldehyde 3 were explored (Method A, 1:3 = 0.33; Method B, 1:3 = 2). In either method, aldehyde 3 was added as an ethyl acetate solution (2 M) via syringe pump at a rate of one equivalent per hour to a stirred mixture of all remaining components. The results with aldehydes 3a–f are summarized in Table 1. The g-branched a,b-unsaturated aldehyde 3a gave 56% yield of 2a using Method A. This substrate also performed well using the original conditions described by Evans. For comparison, we examined the reaction of each of 3a–f according to reference 2a; the optimal results are provided in the last column in Table 1. The success of these original conditions with substrate 3a speaks of its slow rate of silylative consumption; however, the remaining aldehydes 3b–f gave low conversions. On the other hand, through the use of lithium iodide and slow addition of aldehyde, we observed significantly higher conversions and isolated the following yields of diastereomerically pure anti-aldol
LETTER Table 1 O O
Modified anti-Aldol Conditions for Aliphatic Aldehydes
1985
Formation of anti-Aldol Adducts 2 from Addition of 1 to Enolizable Aldehydes 3 1) MgCl2, LiI, Et3N, TMSCl, EtOAc, syringe pump addition of enolizable aldehyde 3
O N
O O
O
OH
N
R
2) p-TsOH; MeOH Bn
Bn
1
2a–f
Entry
Aldehyde 3
Diastereoselection (%)a
Isolated yield (%) of 2b,c
Conversion of 1 (%)d,e
a
O
71
56 (49)
73
b
O
90
66 (66)
12
73
44 (43)
