A useful modification of the Evans magnesium halide catalyzed anti-aldol reaction: Application to enolizable aldehydes

Article abstract of DOI:10.1055/s-0030-1258480

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. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1258480

1984
LETTER
A Useful Modification of the Evans Magnesium Halide Catalyzed anti-Aldol
Reaction: Application to Enolizable Aldehydes
M
odified anti-Ald
a
ol
C
onditio
r
ns for
A
l
o
iphatic Alde
n
hydes E. May, Nathan T. Connell, Heidi A. Dahlmann, Thomas R. Hoye*
Department of Chemistry, University of Minnesota, Minneapolis, MN 55455, USA
Fax +1(612)6267541; E-mail: hoye@umn.edu
Received 12 April 2010
X
Sn
Mg
X
X
Abstract: A practical protocol for use of the magnesium halide cat-
alyzed 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.
Mg
N
O
O
O
O
+ MgX2
– HX
1
O
N
O
Bn
Bn
Key words: aldol reaction, aldehydes, halides, catalysis
B
A
X = Cl or I
S = solvent
RCHO (3)
The stereoselective aldol reaction is a fundamental and
widely used transformation in the field of organic synthe-
sis.1 We recently needed to perform anti-selective aldol
additions with enolizable aldehyde substrates for the syn-
thesis of polyketide fragments. Of the available methods,
the magnesium halide catalyzed protocol of Evans, using
an N-acyloxazolidinone (e.g., 1), seemed quite promis-
ing.2,3 This reaction was attractive because it requires
mostly common reagents [ethyl acetate, triethylamine, tri-
methylsilyl 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
Sn
O
Mg
O
O
O
OTMS
R
O
TMSX
– MgX2
R
O
N
2
O
N
– TMS
+ H+
Bn
Bn
D
C
Scheme 1 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 ob-
tained by use of the following components and stoichiom-
etries: N-acyloxazolidinone 1 (0.5 M in EtOAc),
magnesium chloride (1 equiv), lithium iodide (2 equiv),
triethylamine (5 equiv), and TMSCl (4 equiv). Since ei-
ther 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 meth-
od, 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 re-
sults with aldehydes 3a–f are summarized in Table 1.
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 observa-
tions.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 oxazolidin-
one enolate concentration (A to B, Scheme 1) was in-
creased 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
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 ac-
cording 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 si-
lylative 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
SYNLETT 2010, No. 13, pp 1984–1986
x
x
.x
x
.2
0
1
0
Advanced online publication: 09.07.2010
DOI: 10.1055/s-0030-1258480; Art ID: S01910ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Modified anti-Aldol Conditions for Aliphatic Aldehydes
1985
Table 1 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
O
O
O
OH
O
N
O
N
R
2) p-TsOH; MeOH
Bn
Bn
2a–f
1
Entry
Aldehyde 3
Diastereoselection (%)a
Isolated yield (%) of 2b,c
56 (49)
Conversion of 1 (%)d,e
a
71
90
73
12
O
O
b
66 (66)
c
73
88
44 (43)
61 (53)
<5
<5
O
d
O
O
O
e
f
56
63
28 (30)
59 (49)
<5
20
a Percent of 2/(sum of all diastereomeric aldol adducts) in the crude product mixture (GC–MS of the silyl ethers before step 2 or 1H NMR anal-
ysis after step 2).
b Following silica gel chromatography.
c Method A (and B).
d Determined by NMR analysis of the crude reaction mixture of silylated aldol adducts.
e The following two procedures2a were examined: 1 (1 equiv, 0.5 M in EtOAc), MgCl2 (0.2 equiv), Et3N (2.0 equiv), TMSCl (1.5 equiv), 3 (1.2
equiv), 24 h or as just stated but with the following modifications 1 (1 equiv, 0.2 M in EtOAc), MgCl2 (0.1 equiv), NaSbF6 (0.3 equiv).
adducts 2 using the following aldehydes: crotonaldehyde ammonium ion present in the mixture accelerates the de-
(3b, 66%), isobutyraldehyde (3c, 44%), cyclohexanecar- carboxylation.
boxaldehyde (3d, 61%), butyraldehyde (3e, 28%), and
isovaleraldehyde (3f, 59%). In each case the major, anti
diastereomer 2 was readily separable from its minor iso-
mers; thus, in many instances this method should be of
In conclusion, we have identified modified reaction con-
ditions for the magnesium halide catalyzed anti-aldol re-
action that are compatible with the enolizable aldehydes
3.6 Improvements were realized by slow addition (syringe
preparative value.
pump) of 3 and by the inclusion of lithium iodide as a co-
Several aspects of the reaction deserve comment. Under catalyst. This method is easy to implement and applicable
the modified conditions reported here, we observed no ad- to the preparation of a variety of anti-aldol products.
vantage by including NaSbF6 as an additive. Although we
were careful to use purified reagents, the reaction showed
little sensitivity to moisture, perhaps due to the ability of
TMSCl to trap water. Reaction times (vis-à-vis conver-
sion) should be carefully monitored. As the reaction mix-
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett. Included are
1
experimental procedures and H NMR, 13C NMR, HRMS, and IR
spectral data and optical rotations for all compounds.
tures age, small amounts of product from a secondary
event, the decarboxylative isomerization of the N-acyl-
Acknowledgment
oxazolidinone product 4 to 2-oxazolines 7 (via 5 and 6,
Scheme 2),5 appear. As we previously have described,
These studies were supported by the National Cancer Institute (CA-
76497) of the United States National Institutes of Health, and the
University of Minnesota Lando Summer Research Fellowship Pro-
gram.
this process is catalytic in lithium iodide and triethyl-
Li
R
R
O
O
OLi
O
References and Notes
R
R
O
N
O
NH
Bn
O
I–
N
O
N
+ H+
– CO2
– HI
(1) Mahrwald, R. Modern Aldol Reactions; Wiley-VCH:
Weinheim, 2004.
Bn
I
Bn
I
Bn
(2) (a) Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W.
J. Am. Chem. Soc. 2002, 124, 392. (b) Evans, D. A.;
Downey, C. W.; Shaw, J. T.; Tedrow, J. S. Org. Lett. 2002,
4, 1127.
4
5
6
7
Scheme 2 Decarboxylative isomerization promoted by LiI and
triethylammonium ion
Synlett 2010, No. 13, 1984–1986 © Thieme Stuttgart · New York

1986
A. E. May et al.
LETTER
(3) For anti-aldols with custom auxiliaries, see: (a) Ghosh,
A. K.; Kim, J. H. Org. Lett. 2003, 5, 1063. (b) Ghosh,
A. K.; Onishi, M. J. Am. Chem. Soc. 1996, 118, 2527. For
anti-aldols with norephedrine-based auxiliaries, see:
(c) Abiko, A.; Liu, J.; Masamune, S. J. Am. Chem. Soc.
1997, 119, 2586. (d) Kurosu, M.; Lorca, M. J. Org. Chem.
2001, 66, 1205. For anti-aldols with sultam-based
auxiliaries, see: (e) Oppolzer, W.; Starkemann, C.;
Rodriguez, I.; Bernardinelli, G. Tetrahedron Lett. 1991, 32,
61. (f) Oppolzer, W.; Lienard, P. Tetrahedron Lett. 1993, 34,
4321. For alternative oxazolidinone-based anti-aldols, see:
(g) Walker, M. A.; Heathcock, C. H. J. Org. Chem. 1991, 56,
5747. (h) Wessjohann, L.; Gabriel, T. J. Org. Chem. 1997,
62, 3772. (i) Gabriel, T.; Wessjohann, L. Tetrahedron Lett.
1997, 38, 4387. (j) For organocatalytic methods, see:
Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc.
2002, 124, 6798. For catalytic asymmetric Mukaiyama
aldols, see: (k) Yamashita, Y.; Ishitani, H.; Shimizu, H.;
Kobayashi, S. J. Am. Chem. Soc. 2002, 124, 3292.
(l) Denmark, S. E.; Wynn, T.; Beutner, G. L. J. Am. Chem.
Soc. 2002, 124, 13405.
(4) Exceptions are: (a) Christoph, G.; Njardarson, J. T.;
Danishefsky, S. J. J. Am. Chem. Soc. 2003, 125, 6042.
(b) Nakamura, Y.; Kiyota, H.; Baker, B. J.; Kuwahara, S.
Synlett 2005, 635. (c) Schnermann, M. J.; Romero, F. A.;
Hwang, I.; Nakamaru-Ogiso, E.; Yagi, T.; Boger, D. L.
J. Am. Chem. Soc. 2006, 128, 11799. (d) Niyadurupola,
D. G.; Davies, I. R.; Wisedale, R.; Bull, S. D. Eur. J. Org.
Chem. 2007, 33, 5487. (e) McNulty, J.; Nair, J. J.; Sliwinski,
M.; Harrington, L. E.; Pandey, S. Eur. J. Org. Chem. 2007,
34, 5669.
(0.85 mL), Et3N (0.30 mL, 2.2 mmol) and TMSCl (0.22 mL,
1.7 mmol) were added sequentially. After 10 min croton-
aldehyde (3b, 107 mL, 1.28 mmol) was diluted to 0.75 mL
with EtOAc and added via syringe pump over 3 h. The
reaction mixture was analyzed by GC (90% diastereomeric
purity) and passed through a plug of silica gel using EtOAc
as the eluent. After removing the solvent in vacuo, MeOH (4
mL) and p-TsOH (25 mg) were added. After 15 min
desilylation was complete as judged by TLC. After
concentration in vacuo the desilylated mixture was purified
by MPLC (30% EtOAc–70% hexanes) to give 2b (0.086 g,
66%).
Method B: Same as method A with the following
differences: oxazolidinone 1 (0.200 g, 0.858 mmol), MgCl2
(0.084 g, 0.88 mmol), LiI (0.228 g, 1.70 mmol), EtOAc (1.7
mL), Et3N (0.60 mL, 4.3 mmol), and TMSCl (0.44 mL, 3.4
mmol). Crotonaldehyde (3b, 36 mL, 0.42 mmol, 0.49 equiv)
in EtOAc (0.21 mL) was added via syringe pump over 1 h.
The desilylated mixture was purified by MPLC (30%
EtOAc–70% hexanes) to give 2b (0.086 g, 66%).
2b:7 1H NMR (500 MHz, CDCl3): d = 7.32–7.35 (m, 2 H,
ArH), 7.23–7.29 (m, 3 H, ArH), 5.78 (ddq, J = 15.5, 6.5, 1.0
Hz, 1 H), 5.54 (ddq, J = 15.0, 7.0, 1.5 Hz, 1 H), 4.69 (dddd,
J = 10.0, 7.5, 3.0, 3.0 Hz, 1 H), 4.21 (dd, J = 9.0, 7.0 Hz, 1
H), 4.16 (dd, J = 9.0, 3.0 Hz, 1 H), 3.94 (app p, J = 7.0 Hz, 1
H), 3.29 (dd, J = 13.5, 3.5 Hz, 1 H), 2.78 (dd, J = 13.5, 9.5
Hz, 1 H), 2.54 (s, 1 H, OH), 1.73 (dd, J = 6.5, 1.0 Hz, 3 H),
1.17 (d, J = 6.5 Hz, 3 H). 13C NMR (125 MHz, CDCl3): d =
176.6, 153.7, 135.4, 131.7, 129.7, 129.3, 129.1, 127.5, 75.9,
66.2, 55.7, 43.5, 38.0, 17.9, 14.7. HRMS (ESI): m/z [M +
Na+] calcd for C17H21O4N: 326.1363; found: 326.1361. IR
(neat): 3518, 3029, 2976, 2939, 2920, 2883, 1782, 1695,
1502, 1455, 1392, 1349, 1257, 1211, 1103, 1014, 968, 923,
800, 762, 702 cm–1. TLC: Rf 0.47 (30% EtOAc in hexanes);
[a]r.t. 38.5° (c = 0.785, CHCl3).
(5) (a) May, A. E.; Willoughby, P. H.; Hoye, T. R. J. Org. Chem.
2008, 73, 3292. (b) This decarboxylative isomerization
process was first discovered during these aldol studies.
(6) General Experimental Procedure for the anti-Aldol
Reaction of an N-Acyloxazolidinone with an Enolizable
Aldehyde (Synthesis of 2b)
(7) For synthesis of ent-2b using boron enolate methodology,
see: (a) Paquette, L. A.; Peng, X.; Bondar, D. Org. Lett.
2002, 4, 937. (b) Peng, X.; Bondar, D.; Paquette, L. A.
Tetrahedron 2004, 60, 9589.
Method A: To an oven-dried reaction vessel equipped with
a stir bar, oxazolidinone 1 (0.100 g, 0.429 mmol), MgCl2
(0.042 g, 0.44 mmol), LiI (0.116 g, 0.866 mmol), EtOAc
Synlett 2010, No. 13, 1984–1986 © Thieme Stuttgart · New York

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