Anti-selective and regioselective aldol addition of ketones with aldehydes using MgI2 as promoter

Article abstract of DOI:10.1016/j.tet.2004.09.098

The first example of a direct aldehyde-ketone coupling using the secondary amine piperidine as base in the presence of MgI₂ to generate high selectivity of anti-aldol products from unmodified ethyl ketones in high yield is reported. The couplin

Full text of DOI:10.1016/j.tet.2004.09.098

Tetrahedron 60 (2004) 11829–11835
Anti-selective and regioselective aldol addition of ketones with
aldehydes using MgI2 as promoter
a
b
a
a,
Han-Xun Wei,a, Richard L. Jasoni, Huawu Shao, Jiali Hu and Paul W. Pare
*
*
´
aDepartment of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409, USA
bInstitute for Biological Sciences, National Research Council of Canada, Ottawa, Ont., Canada K1A 0R6
Received 8 September 2004; revised 25 September 2004; accepted 28 September 2004
Available online 13 October 2004
Abstract—The first example of a direct aldehyde–ketone coupling using the secondary amine piperidine as base in the presence of MgI2 to
generate high selectivity of anti-aldol products from unmodified ethyl ketones in high yield is reported. The coupling reactions were carried
out in a one-pot reaction by mixing four reaction components at room temperature. In the case of unsymmetrical ketones, addition was made
to the less hindered a-side.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
mentioned approaches have their individual weaknesses,
some of which include long reaction times, using air and
moisture-sensitive reagents,2 two step reactions that require
enolate to be formed before aldehyde can be added,2–4 and
the random anti/syn selectivity of products.3,4 Because of
these weaknesses, the development of a general method for
synthesizing anti-aldol products from unmodified ethyl
ketones is needed.
The stereoselective synthesis of anti-aldol products from
unmodified ethyl ketones is of great interest to organic
chemists,1 especially in the area of natural product
synthesis. Several methodologies have been reported that
use boron reagents or metal complexes in the presence of a
tertiary amine to convert unmodified ethyl ketones to
enolates that then react with aldyhydes to form anti-aldol
products. For example, the use of dicyclohexylboron
chloride and triethylamine produce high selectivity for
E-enolates and correspondingly high selectivity for the anti-
aldol products;2 this two step process requires hydrogen
peroxide oxidation of the boron intermediate to obtain free
aldol products. An alternative aldol coupling reaction
eliminated this oxidation step by using ytterbium trifluoro-
methanesulfonate and a tertiary amine;3 however, high anti-
aldol products were produced only when sterically hindered
aldehydes such as trimethylacetaldehyde were employed as
the electrophilic acceptor. TiCl4 has also been used as a
reaction promoter with a tertiary amine;4 however only
when special unmodified ketones were used could high anti-
aldol product ratios be realized. All of the previously
Here we describe a direct method for the stereoselective
coupling of aromatic and non-aromatic aldehydes with
unmodified ethyl ketones to generate anti-aldol products. In
the presence of stoichiometric quantities of MgI2, the
reaction of ethyl ketones with aldehydes at room tempera-
ture results in high yields of anti-3-hydroxy ketones
(Scheme 1). In the case of unsymmetrical ketones, addition
is made to the less hindered a-side.
We have recently reported that MgI2 is a well-suited Lewis
acid for the carbon–carbon bond forming reaction during the
synthesis of b-iodo Baylis–Hillman adducts.5 MgI2 is
thought to serve as a Lewis acid as well as an iodine source
for Michael-type additions of a,b-acetylenic ketones or
Scheme 1.
Keywords: Piperidine; Anti-aldol reaction; Magnesium iodide; Ethyl ketone.
* Corresponding authors. Tel.: C1 804 6987291; fax: C1 804 6987298; e-mail addresses: hwei@rdg.boehringer-ingelheim.com; paul.parc@ttu.edu
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.09.098

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H.-X. Wei et al. / Tetrahedron 60 (2004) 11829–11835
esters. The initial ketone is proposed to be converted to an
active b-iodo allenolate intermediate, which in turn reacts
with an aldehyde to yield b-iodo Baylis–Hillman adducts. In
an attempt to broaden the scope of this reaction, MgI2 was
combined with tertiary amines to determine if such a
combination would promote formation of Mg-enolates
directly from the original ketone. When 1.0 equiv of
benzaldehyde, MgI2, propiophenone, and diisopropylethyl-
amine were added at room temperature in dichloromethane
the aldol product 1,3-diphenyl-3-hydroxy-2-methylpropa-
none was generated within 30 min with a yield of 80%. This
yield was optimized to 95% by using 1.3 equiv of
diisopropylethylamine, 1.2 equiv of propiophenone, and
1.0 equiv of benzaldehyde.
Using the secondary amine piperidine as a base for
improved selectivity, we examined various symmetric and
asymmetrical ketones that can undergo an aldol reaction. In
the first reaction listed, propiophenone coupled with
benzaldehyde in the presence of piperidine (1.2 equiv) and
MgI2 (1.1 equiv) in a 93/7 anti/syn ratio resulted in a 35%
product yield within 30 min; a 95/5 anti/syn ratio with a
91% yield was realized when the reaction was allowed to go
to completion over 2 h period using 1.5 equiv piperidine and
1.4 equiv MgI2. Other aromatic aldehydes resulted in high
diasteroselectivity (entries 2, 3 and 4, Table 2) within the 2 h
reaction time, although product selectivity diminished when
aliphatic aldehydes were employed (entries 5 and 6,
Table 2). The anti-product was exclusively obtained when
the bulkier aliphatic aldehyde trimethylacetaldehyde was
used as an electrophilic acceptor (entry 7, Table 2).
Cyclohexanone gave modest diasteroselectivity (entry 8
and 9, Table 2). The relatively low diasteroselectivity was
also observed when 3-pentanone was reacted with benzal-
dehyde (entry 10, Table 2).
The diasteroselectivity of the initial reaction was modest
(anti/synZ72/28) with negligible differences observed
when the reaction temperature or solvent system was
changed. Elevated reaction temperatures slightly improved
the anti/syn ratio (70/30 at 0 8C and 74/26 at 40 8C) while
the alternative solvents (benzene and toluene) had no effect
on diasteroselectivity. Both diethyl ether and THF were
unsuitable solvents, which required a reaction time of more
than 10 h and gave rise to less then 10% yield within a 2 h
reaction period. Other metal salts and organometallics
including MgBr2, Mg(OTf)2, MgCl2, SnCl4, Sn(OTf)2 was
either much less active or inert. In fact, Choji Kashima6 had
already reported in 1998 using MgBr2 in combination with
i-Pr2NEt mediates the aldol addition of N-acylpyrazoles to
aldehydes and in some cases this system gives products with
high anti-selectivity. This system was not suitable for the
present reaction conditions. For example, when propio-
phenone was reacted with benzaldehyde in the presence of
i-Pr2NEt with MgBr2 as the promoter, the anti/syn ratio of
the product was 70/30. When piperidine was used as the
amine base, less than 10% of the desired product was
obtained after a 24 h period when propiophenone was
reacted with benzaldehyde in the presence of MgBr2 as the
promoter. A survey of various tertiary amines was also met
with limited success (Table 1); therefore we explored the
possibility of using secondary amines as an amine base in
the reaction. All of the secondary amines that were tested
resulted in aldol products with increased anti-selectivity.
The secondary amine piperidine proved to be the best suited
for promoting the desired diastereoselectivity (Table 1).
With regard to unsymmetrical ketones, both piperidine and
the tertiary amines N,N-diisopropylethylamine and
N-ethylpiperidine are well suited for producing aldol
products with the same ratio of regioselectivity. However,
in order to obtain reasonable yields, longer reaction times
(2 h) and higher MgI2 loading (1.4 equiv) are needed when
piperidine is used as the base for the reaction. For example,
the reaction of 3-methyl-2-butanone (1.4 equiv) with
benzaldehyde (1.0 equiv) in the presence of MgI2
(1.4 equiv) and piperidine (1.5 equiv) required 2 h for
completion at room temperature with an 85% yield of
expected products and regioselectivity 100:0. However, the
same reaction took only 30 min to complete when N,N-
diisopropylethylamine or N-ethylpiperidine was used in
place of piperidine as the base for the reaction. Another
advantage for using N,N-diisopropylethylamine or
N-ethylpiperidine as the base for the reaction is that the
amount of MgI2 and starting ketone can be reduced to
1.2 equiv with no decrease in yield (entry 11–16, Table 3).
The anti/syn selectivities listed in Table 2 were measured by
1H NMR spectroscopic analyses of the crude product
mixture. In all cases, the carbinol proton signals for anti and
syn-isomers were clearly distinguishable with the proton for
Table 1. Effect of amine bases for anti/syn selectivity
Entry
Amine base
Reaction time (min)
anti/syn selectivitya
Yieldb (%)
1
2
3
4
5
6
Et3N
i-Pr2NEt
Bu3N
N-ethylpiperidine
Pyrrolidine
2,2,6,6-Tetramethylpiperi-
dine
30
30
30
30
240
30
72/28
73/27
76/24
71/29
82/18
80/20
90
95
92
92
50
90
7
8
9
Piperidine
DABCO
Pyridine
120
120
120
95/5
75/25
–
91
82
!10
1
a The isomeric ratio was determined by analysis of 300 MHz H NMR spectra of crude products.
b Yields after purification by column chromatography.

H.-X. Wei et al. / Tetrahedron 60 (2004) 11829–11835
Table 2. Anti-selective aldol addition of ketones with aldehydes using piperidine as base
11831
Entry
1
Ketone
R
Product
anti/syna
Yieldb (%)
Propiophenone
C6H5
1
95/5
91
92
90
88
92
90
82
2
3
4
5
6
7
Propiophenone
Propiophenone
Propiophenone
Propiophenone
Propiophenone
Propiophenone
4-FC6H4
2
3
4
5
6
7
94/6
90/10
92/8
4-BrC6H4
4-MeC6H4
C6H5CH]CH
CH3CH]CH
(CH3)3C–
88/12
84/16
100/0
8
Cyclohexanone
Cyclohexanone
C6H5
8
77/23
68
9
4-ClC6H4
9
76/24
76/24
70
10
3-Pentanone
C6H5
10
70c
1
a Ratios were determined by H NMR (CDCl3, 300 MHz) on the crude products.
b Yields after purification by column chromatography.
c Two stereoisomers were inseparable.
the anti-isomer upfield relative to the proton for the syn
isomer. In addition, they also appear in different vicinal
coupling constants; for anti-isomers these numbers are
approximately 8 Hz and syn isomers less than 5 Hz.
temperature, we observed the Mg-enolate of propiophenone
in its 1H NMR spectrum, in which the Z-enolate vinyl proton
showed as a quartet at d 3.46 ppm and the E-enolate as a
quartet at d 4.13 ppm. The ratio of Z/E was 78/22, based on
1
1
its H NMR spectrum analysis. Also, from its H NMR
analysis, only 5 mol% of propiophenone was converted into
Mg-enolate intermediate when stored at room temperature
for 24 h. The reaction is therefore a ‘balanced reaction’ with
aldehydes essential for the reaction to go to completion
within 2 h. This raises an important question; can the
reaction be carried out via the enamine pathway? We have
experimental evidence that suggests that the reaction is
more likely to follow the Mg-enolate pathway. (1)
Propiophenone (1.0 equiv) and MgI2 (1.0 equiv) were
dissolved in anhydrous CDCl3 and piperidine (1.2 equiv)
was added via a syringe under a nitrogen atmosphere. After
In order to better understand the mechanisms involved in
this reaction, we designed an experiment to track the
reaction intermediates. We added diisopropylethylamine
(1.2 equiv) into a mixture of propiophenone (1.0 equiv) and
MgI2 (1.0 equiv) dissolved in CDCl3, after stirring at room
1
temperature for 1 h; the mixture was directly taken for H
NMR analysis. Unfortunately, the Mg-enolate was not
observed due to the total formation of the propiophenone
self-condensation aldol product. However, when diiso-
propylethylamine in the above reaction was replaced with
piperidine (1.2 equiv) and stirred for 1 h at room

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H.-X. Wei et al. / Tetrahedron 60 (2004) 11829–11835
Table 3. Regioselective aldol addition of unsymmetrical ketones with aldehydes using N,N-diisopropylethylamine as base
Entry
11
Ketone
R
Product
Ratio a/ba
Yieldb (%)
85
2-Butanone
4-PhCH2OC6H4
11
12
96/4
12
13
2-Butanone
2-Naphthyl
C6H5
98/2
86
90
3-Methyl-2-butanone
13
14
15
16
100/0
14
15
16
3-Methyl-2-butanone
4-Phenyl-2-butanone
4-Phenyl-2-butanone
2-Naphthyl
100/0
90/10
98/2
91
81c
85
C6H5CH]CH
4-PhCH2OC6H4
a Ratios were determined by 1H NMR (CDCl3, 300 MHz) on the crude products.
b Yields after purification by column chromatography.
c Two regioisomers were inseparable.
stirring 2 h at room temperature, the solution was filtered
through a short silicon gel pad and the filtrate directly
injected into an LC-MS. No enamine peak was observed
from the LC-MS analysis (Scheme 3). (2). When piperidine
was replaced with 2,2,6,6-Tetramethylpiperidine in the
above reaction an Mg-enolate peak was observed with a
molecular weight of 284 (Scheme 2).
can be employed to satisfactorily explain our results
(Scheme 3).
In conclusion, we present here the first example of using a
secondary amine as a base in combination with MgI2 to
perform direct aldehyde–ketone coupling to generate high
anti-aldol products in high yield. Aldol coupling reactions
were carried out in a one-pot reaction by mixing the four
reaction components at room temperature under the
protection of nitrogen gas. This is in contrast to the recently
reported Lewis acid mediated aldol addition of
Since the Z-enolate was formed predominantly, the well-
known chair Zimmerman–Traxler transition state cannot be
adopted; however, the Evans’ ‘boat–metal transition state’7
Scheme 2. LC-MS confirmed the intermediates in MgI2 promoted anti-aldol reaction.
Scheme 3. Boat transition state for MgI2 promoted anti-aldol reaction.

H.-X. Wei et al. / Tetrahedron 60 (2004) 11829–11835
11833
8
unsymmetrical ketones using TiCl4 to generate high syn
(tt, JZ7.5, 1.5 Hz, 1H), 4.99 (dd, JZ8.0, 4.5 Hz, 1H), 3.83
(qn, JZ7.5 Hz, 1H), 2.98 (d, JZ4.5 Hz, OH), 1.07 (d, JZ
7.5 Hz, 3H); 13C NMR: (125 MHz, CDCl3) 204.9, 142.2,
136.7, 133.3, 128.6!2, 128.4!2, 128.4!2, 127.9,126.7!
2, 76.7, 47.9, 15.7; MS: (EI, 70 eV) 222 (MKH2O, 100),
207 (40), 193 (6.6), 179 (16), 145 (10), 105 (69.8), 91 (14),
77 (52), 51 (19); HRMS: cald for C16H16O2: 240.115;
found: 240.112.
selective products. In fact, we observed that TiCl4 as an
aldol promoter was limited in its scope to stimulate aldol
additions with aliphatic ketones. For example, when the
aromatic ketone propiophenone was tested as a substrate to
react with benzaldehyde, less than a 10% yield of the
corresponding syn product was observed after 16 h at room
temperature.9 With this new MgI2 promoting system, both
aromatic and aliphatic ketones are suitable for direct
coupling to generate anti-products without the formation
of activated silyl enol ether.
Compound 2. 238 mg, 92%, a colorless oil. Data for anti-
isomer: IR: (CHCl3) 3609 (m), 3489 (m), 1674 (s), 1604 (s),
1
1510 (s), 1448 (m), 1215 (s), 1157 (s), 970 (s); H NMR:
(500 MHz, CDCl3) 7.96 (m, 2H), 7.57 (tt, JZ7.5, 1.0 Hz,
1H), 7.47 (m, 2H), 7.38 (m, 2H), 7.04 (m, 2H) 4.98 (dd, JZ
8.0, 4.5 Hz, 1H), 3.78 (qn, JZ7.5 Hz, 1H), 3.08 (d, JZ
4.5 Hz, OH), 1.07 (d, JZ7.5 Hz, 3H); 13C NMR: (125 MHz,
CDCl3) 205.0, 163.5, 161.6, 138.2, 136.8, 133.6, 128.9!2,
128.6!2, 128.5, 115.6, 115.4, 76.2, 48.3, 15.9; MS: (EI,
70 eV) 240 (MKH2O, 100), 225 (41), 211 (5), 197 (9), 163
(9), 133 (33), 105 (91), 77 (61); HRMS: cald for C16H15O2F:
258.1056; found: 258.1051.
2. Experimental
2.1. General
All reactions were conducted at room temperature in a flask
(10.0 mL) with magnetic stirring. Dichloromethane was
dried and freshly distilled from calcium hydride under the
nitrogen atmosphere. Other commercial chemicals were
used without further purification and their stoichiometrics
were calculated based on the reported purities from the
manufacturers. Flash chromatography was performed on
Merck silica gel 60 (230–400 mesh). 1H NMR spectra were
recorded on a Varian 500 MHz NMR spectrometer.
Chemical shifts are reported in ppm (d); multiplicities are
indicated by s (singlet), d (doublet), t (triplet), q (quartet), qn
(quintet) and m (multiplet). 13C NMR spectra were recorded
at 125 MHz using CDCl3 as the solvent and the internal
reference. Chemical shifts are given in ppm from tetra-
methylsilane. GC spectra were recorded at hp 6890 with hp
5973 Mass Selective Detective. Mass spectra were recorded
with a JEOL JMS-D300 mass spectrometer using direct
inlet electron impact ionization (70 eV). The Mass Spec-
troscopy Laboratory at the Crompton Corporation and
University of Texas at Austin conducted high-resolution
Mass spectral analysis.
Compound 3. 287 mg, 90%, a colorless oil. Data for anti-
isomer: IR: (CHCl3) 3606 (m), 3485 (m), 1680 (s), 1598 (s),
1
1456 (s), 1206 (s), 970 (s); H NMR: (500 MHz, CDCl3)
7.94 (m, 2H), 7.57 (tt, JZ7.5, 1.0 Hz, 1H), 7.47 (m, 4H),
7.28 (m, 2H), 4.95 (dd, JZ8.0, 4.5 Hz, 1H), 3.77 (qn, JZ
7.5 Hz, 1H), 3.14 (d, JZ5.0 Hz, OH), 1.08 (d, JZ6.0 Hz,
3H); 13C NMR: (125 MHz, CDCl3) 204.6, 141.2, 136.4,
133.4, 131.5!2, 128.7!2, 128.4!2, 128.3!2, 121.6,
76.1, 47.7, 15.6; MS: (EI, 70 eV) 302 (71) 301 (43), 300
(MKH2O, 75), 284 (25), 221 (46), 178 (15), 144 (16) 115
(68), 105 (100), 77 (66); HRMS: cald for C16H15O2Br:
318.0255; found: 318.0251. Data for syn-isomer: 1H NMR:
(500 MHz, CDCl3) 7.95 (m, 2H), 7.61 (tt, JZ7.0, 1.5 Hz,
1H), 7.52–7.46 (m, 4H), 7.31–7.28 (m, 2H), 5.21 (t, JZ
2.4 Hz, 1H), 3.76 (d, JZ2.1 Hz, 1H, OH), 3.64 (dq, JZ7.3,
3.0 Hz, 1H), 1.16 (d, JZ7.3 Hz, 3H); 13C NMR: (125 MHz,
CDCl3) 205.4, 140.9, 135.3, 133.7, 131.2!2, 128.9!2,
128.5!2, 127.7!2, 121.1, 72.4, 46.7, 11.2.
2.1.1. General procedure A (Table 2). Anti-aldol
addition with unmodified ketones using piperidine as
base. Dichloromethane (5.0 mL), aldehyde (1.0 mmol,
1.0 equiv), ketone (1.4 mmol, 1.4 equiv), and magnesium
iodide (1.4 mmol, 398.0 mg, 98% purity) were added to a
dry 25 mL flask. The resulting mixture was protected by
nitrogen gas and at room temperature piperidine (1.5 mmol,
0.147 mL) was added dropwise via a syringe. The resulting
mixture was stirred for 2 h at room temperature and
quenched by the addition of dilute 2 N HCl (4.0 mL).
Dichloromethane was completely evaporated and 8.0 mL of
ethyl acetate was added to the mixture. The ethyl acetate
layer was separated and the aqueous layer was extracted
with ethyl acetate two more times (2!8.0 mL). The
combined organic layers were dried over anhydrous
magnesium sulfate and concentrated. Purification was
carried out by column chromatography [hexane (saturated
with acetonitrile, up layer)/ethyl acetateZ10:1] to give the
pure anti-product.
Compound 4. 224 mg, 88%, a colorless oil. Data for anti-
isomer: IR: (CHCl3) 3614 (m), 3501 (m), 1678 (s), 1609 (s),
1
1514 (s), 1218 (s), 970 (s); H NMR: (500 MHz, CDCl3)
7.99 (m, 2H), 7.56(tt, JZ7.5, 1.0 Hz, 1H), 7.46 (m, 2H),
7.29 (m, 2H), 7.16 (m, 2H), 4.95 (dd, JZ8.0, 4.5 Hz, 1H),
3.81 (qn, JZ7.5 Hz, 1H), 2.89 (d, JZ4.5 Hz, OH), 2.34 (s,
3H) 1.04 (d, JZ7.5 Hz, 3H); 13C NMR: (125 MHz, CDCl3)
204.9, 139.2, 137.6, 136.8, 133.2, 129.1!2, 128.6!2,
128.4!2, 126.6!2, 76.6, 47.9, 21.1, 15.6; MS: (EI, 70 eV)
236 (MKH2O, 54), 221 (100), 207 (6), 193 (8), 178 (7), 144
(13), 105(42) 91 (12), 77 (34); HRMS: cald for C17H18O2:
254.1307; found: 254.1310.
Compound 5. 244 mg, 92%, a colorless oil. Data for anti-
isomer: IR: (CHCl3) 3608 (w), 3065 (w), 1676 (s), 1600 (m),
1
1451 (m), 970 (s); H NMR: (500 MHz, CDCl3) 7.99 (m,
2H), 7.58(tt, JZ7.5, 1.0 Hz, 1H), 7.47 (m, 2H), 7.37 (m,
2H), 7.30 (t, JZ7.4 Hz, 2H), 7.24 (t, JZ7.4 Hz, 1H), 6.68
(d, 16.0 Hz, 1H), 6.28 (dd, JZ16.0, 7.5 Hz, 1H), 4.61 (q,
JZ6.5 Hz, 1H), 3.71 (qn, JZ7.2 Hz, 1H), 3.04 (d, JZ
5.6 Hz, OH), 1.27 (d, JZ7.2 Hz, 3H); 13C NMR: (125 MHz,
CDCl3) 204.7, 136.5, 136.5, 133.4, 132.1, 129.6!2,
Compound 1. 218 mg, 91%, a colorless oil. Data for anti-
isomer: IR: (CHCl3) 3488 (s), 3456 (s), 1676 (s), 1456 (s),
1
1215 (s), 970 (s); H NMR: (500 MHz, CDCl3) 7.98 (m,
2H), 7.57 (tt, JZ7.5, 1.0 Hz, 1H), 7.34–7.49 (m, 6H), 7.29

11834
H.-X. Wei et al. / Tetrahedron 60 (2004) 11829–11835
128.7!2, 128.5!2, 128.4!2, 127.8, 126.5, 75.3, 46.3,
15.4; MS: (EI, 70 eV) 248 (MKH2O, 52), 175 (9), 134 (87),
132 (28), 106 (11), 105 (100) 91 (18), 77 (71); HRMS: cald
for C18H18O2: 266.1307; found: 266.1311.
(m, 2H), 7.28–7.24 (m, 2H), 4.76 (dd, JZ8.5, 2.5 Hz, 1H),
3.98 (d, JZ3.0 Hz, OH), 2.60–2.52 (m, 1H), 2.51–2.45
(m, 1H), 2.40–2.31 (m, 1H), 2.13–2.02 (m, 1H), 1.82–1.77
(m, 1H), 1.72–1.62 (m, 1H), 1.61–1.51 (m, 2H), 1.33–1.22
(m, 1H); 13C NMR: (125 MHz, CDCl3) 215.3, 139.4, 133.5,
128.5!2, 128.3!2, 74.1, 57.3, 42.6, 30.74, 27.7, 24.7; MS:
(EI, 70 eV) 220 (MKH2O, 36), 140 (52), 132 (100), 104
(44), 89 (31); HRMS: cald for C13H15O2Cl: 238.0761;
found: 238.0766. Data for syn-isomer: 1H NMR: (500 MHz,
CDCl3) 7.32–7.29 (m, 2H), 7.27–7.22 (m, 2H), 5.35 (m,
1H), 3.04 (d, JZ3.0 Hz, OH), 2.60–2.52 (m, 1H), 2.49–2.41
(m, 1H), 2.41–2.32 (m, 1H), 2.13–2.06 (m, 1H), 1.89–1.82
(m, 1H), 1.73–1.64 (m, 3H), 1.57–1.47 (m, 1H); 13C NMR:
(125 MHz, CDCl3) 214.6, 139.9, 132.6, 128.3!2, 127.1!
2, 70.11, 57.0, 42.6, 27.9, 25.9, 24.8.
Data for syn-isomer: 1H NMR: (500 MHz, CDCl3) 7.98 (d,
JZ8.0 Hz, 2H), 7.61 (t, JZ8 Hz, 1H), 7.50 (t, JZ8.0 Hz,
2H), 7.39 (d, JZ7.5 Hz, 2H), 7.33 (t, JZ7.5 Hz, 2H), 7.24
(t, JZ7.5 Hz, 1H), 6.73 (d, JZ16.0 Hz, 1H), 6.26 (dd, JZ
16.0, 6.0 Hz, 1H), 4.83–4.79 (m, 1H), 3.65 (dq, JZ7.0,
3.5 Hz, 1H), 3.34 (d, JZ2.5 Hz, OH), 1.32 (d, JZ7.0 Hz,
3H); 13C NMR: (125 MHz, CDCl3) 205.3, 136.7, 135.7,
133.6, 131.2, 129.1!2, 128.7!2, 128.5!2, 127.7!2,
126.5!2, 72.0, 45.4, 11.7.
Compound 6. 183 mg, 90%, a colorless oil. Data for anti-
isomer: IR: (CHCl3) 3610 (w), 3604 (w), 1671 (s), 1446 (m),
Compound 10. 134 mg, 70%, a colorless oil, inseparable; 1H
NMR: (500 MHz, CDCl3) 7.40–7.20 (m, 5H), 5.03 (d, JZ
4.0 Hz, 0.24H, syn-isomer), 4.74 (d, JZ8.1 Hz, 0.76H, anti-
isomer), 2.83 (dq, JZ7.2, 4.0 Hz, 1H), 2.20–2.55 (m, 2H),
1.07 (d, JZ7.2 Hz, 3H), 0.99 (t, JZ7.0 Hz, 3H).
1
1211 (m), 970 (s); H NMR: (500 MHz, CDCl3) 7.96 (m,
2H), 7.60–7.56 (m, 1H), 7.50–7.46 (m, 2H), 5.77 (dq, JZ
15.1, 6.0 Hz, 1H), 5.54 (ddq, JZ15.1, 7.2, 1.1 Hz, 1H), 4.53
(m, 1H), 3.53 (q, JZ7.2 Hz, 1H), 2.74 (d, JZ6.0 Hz, OH),
1.71 (dd, JZ7.2, 1.1 Hz, 3H), 1.18 (d, JZ7.4 Hz, 3H); 13C
NMR: (125 MHz, CDCl3) 204.9, 136.7, 133.2, 131.5,
128.9!2, 128.7!2, 128.4, 75.3, 46,2, 17.7, 15.3; MS:
(EI, 70 eV) 186 (MKH2O, 78), 148 (8), 135 (15), 134 (100),
133 (61), 105 (91), 78 (5), 71 (26); HRMS: cald for
C13H16O2: 204.115; found: 204.110. Data for syn-isomer:
1H NMR: (500 MHz, CDCl3) 7.94 (d, JZ7.5 Hz, 2H), 7.61–
7.57 (m, 1H), 7.49 (t, JZ7.5 Hz, 2H), 5.78 (ddq, JZ15.0,
6.5, 1.5 Hz, 1H), 5.55 (ddq, JZ15.0, 6.5, 1.5 Hz, 1H), 4.52
(t, JZ5.0 Hz, 1H), 3.54 (dq, JZ7.3, 3.5 Hz, 1H), 2.98 (s,
1H, OH), 1.71 (d, JZ6.5 Hz, 3H), 1.27 (d, JZ7.3 Hz, 3H);
13C NMR: (125 MHz, CDCl3) 205.2, 136.1, 133.3, 130.8,
128.7!2, 128.4!2, 127.8, 72.5, 45.5, 17.7, 11.8.
2.1.2. General procedure B (Table 3). Regio selective
aldol addition with unmodified ketones using N,N-
diisopropylethylamine as base. Dichloromethane
(5.0 mL), aldehyde (1.0 mmol, 1.0 equiv), ketone
(1.2 mmol, 1.2 equiv), and magnesium iodide (1.2 mmol,
340.0 mg, 98% purity) were added to a dry 25 mL flask. The
resulting mixture was protected by nitrogen gas and at room
temperature N,N-diisopropylethylamine (1.3 mmol,
0.226 mL) was added dropwise via a syringe. The resulting
mixture was stirred for 30 min at room temperature and
quenched by addition of dilute 2 N HCl (4.0 mL).
Dichloromethane was completely evaporated and 8.0 mL
of ethyl acetate was added to the mixture. The ethyl acetate
layer was separated and the aqueous layer was extracted
with ethyl acetate two more times (2!8.0 mL). The
combined organic layers were dried over anhydrous
magnesium sulfate and concentrated. Purification was
carried out by column chromatography (hexane/ethyl
acetateZ10:1) to give the pure product.
Compound 7. 180 mg, 82%, a colorless oil. IR: (CHCl3)
3610 (w), 3500 (w), 1711 (s), 970 (s); 1H NMR: (500 MHz,
CDCl3) 7.96 (m, 2H), 7.59 (m, 1H), 7.50 (m, 2H), 4.73 (d,
JZ9.0 Hz, OH), 3.80 (dq, JZ7.5, 2 Hz, 1H), 3.43 (dd, JZ
9.0, 2.0 Hz, 1H), 1.45 (d, JZ7.0 Hz, 3H), 0.88 (s, 9H); 13C
NMR: (125 MHz, CDCl3) 208.2, 136.3, 133.6, 128.8!2,
128.1!2, 84.9, 37.5, 36.2, 26.80!3, 18.9; HRMS: cald for
C14H20O2: 220.1463; found: 220.1459.
Compound 11. 241 mg, 85%, a colorless oil. Major isomer:
mp: 80–82 8C. IR: (CHCl3) 3609 (s), 3514 (w), 3019 (m),
1678 (s), 1214 (s), 969 (s); H NMR: (500 MHz, CDCl3)
1
Compound 8. 139 mg, 68%, a white solid, mp: 40–42 8C.
Data for anti-isomer: H NMR: (500 MHz, CDCl3) 7.36–
1
7.45–7.40 (m, 2H), 7.40–7.35 (m, 2H), 7.34–7.30 (m, 1H),
7.29 (m, 2H), 6.97–6.92 (m, 2H), 5.13–5.08 (dt, JZ9.5,
3 Hz, 1H), 5.05 (s, 2H), 3.27 (d, JZ3.0 Hz, OH), 2.88–2.72
(m, 2H), 2.44 (q, JZ7.5 Hz, 2H), 1.06 (t, JZ7.5 Hz, 3H);
13C NMR: (125 MHz, CDCl3) 212.1, 158.5, 137.1, 135.5,
128.8!2, 128.2, 127.6!2, 127.1!2, 115.1!2, 70.2, 69.8,
50.8, 37.1, 7.7; MS: (EI, 70 eV) 266 (MKH2O, 16), 212 (8),
153 (0.6), 105 (0.3), 91 (100), 65 (13); HRMS: cald for
C18H20O3: 284.3550; found: 284.3556.
7.27 (m, 5H), 4.78 (dd, JZ9.2, 2.4 Hz, 1H), 3.98(d, JZ
2.4 Hz, OH), 2.64–2.58 (m, 1H), 2.50–2.45 (m, 1H), 2.40–
2.31 (m, 1H), 2.10–2.03 (m, 1H), 1.81–1.74 (m, 1H), 1.71–
1.46 (m, 3H), 1.34–1.22 (m, 1H); 13C NMR: (125 MHz,
CDCl3) 215.5, 140.8, 128.2!2, 127.8, 126.9!2, 74.6, 57.3,
42.6, 30.7, 27.7, 24.6; HRMS: cald for C13H16O2: 204.115;
found: 204.119. Data for syn-isomer: 1H NMR: (500 MHz,
CDCl3) 7.36–7.21 (m, 5H), 5.39 (m, 1H), 3.05 (d, JZ
2.1 Hz, 1H), 2.62–2.57 (m, 1H), 2.47–2.43 (m, 1H), 2.42–
2.32 (m, 1H), 2.11–2.06 (m, 1H), 1.87–1.82 (m, 1H), 1.75–
1.60 (m, 3H), 1.57–1.43 (m, 1H); 13C NMR: (125 MHz,
CDCl3) 214.9, 141.3, 128.1!2, 126.8, 125.5!2, 70.5, 57.1,
42.6, 27.9, 25.9, 24.8.
Compound 12. 196 mg, 86%, a colorless oil; Major isomer:
mp: 58–60 8C. IR: (CHCl3) 3607 (w), 3551 (w), 3001 (w),
1675 (s), 1521 (m), 969 (s); H NMR: (500 MHz, CDCl3)
1
7.85–7.80 (m, 4H), 7.49–7.44 (m, 3H), 5.33 (dt, JZ8.5,
2.5 Hz, 1H), 3.49 (d, JZ3.0 Hz, OH), 2.97–2.84 (m, 2H),
2.47 (q, JZ7.5 Hz, 2H), 1.07 (t, JZ7.5 Hz, 3H); 13C NMR:
(125 MHz, CDCl3) 211.8, 140.2, 133.2, 132.9, 128.3, 127.9,
127.6, 126.1, 125.8, 124.3, 123.7, 70.1, 50.6, 36.8, 7.4; MS:
Compound 9. 167 mg, 70%, a colorless oil. Data for anti-
isomer: IR: (CHCl3) 3591 (w), 3077 (w), 1771 (s), 1452 (s),
1209 (m), 902 (m); 1H NMR: (500 MHz, CDCl3) 7.34–7.30

H.-X. Wei et al. / Tetrahedron 60 (2004) 11829–11835
11835
(EI, 70 eV) 210 (MKH2O, 38), 181 (100), 152 (46), 127 (8),
126 (6); HRMS: cald for C15H16O2: 228.1412; found:
228.1416.
and Dr. Zhengrong Li for recording IR data. Financial
support was generously provided by a grant (D-1478) from
the Robert A. Welch Foundation. The preliminary results of
this work have been presented at the 226th ACS National
Meeting, New York, NY, September, 20003.
Compound 13. 173 mg, 90%, a colorless oil. IR: (CHCl3)
3605 (w), 3514 (w), 2956 (m), 1699 (s), 1514 (m), 1066 (m),
1
973 (m); H NMR: (500 MHz, CDCl3) 7.37–7.31 (m, 4H),
7.29–7.24 (m, 1H), 5.13 (dt, JZ9.0, 3.5 Hz, 1H), 3.54 (d,
JZ3.5 Hz, OH), 2.92–2.78 (m, 2H), 2.62–2.52 (m, 1H),
1.08 (dd, JZ7.0, 1.5 Hz, 6H); 13C NMR: (125 MHz,
CDCl3) 215.1, 142.9, 128.4!2, 127.5, 125.5!2, 69.8,
48.7, 41.4, 17.7!2; MS: (EI, 70 eV) 174 (MKH2O, 1), 159
(2), 135 (3), 119 (100), 105 (6), 91 (4); HRMS: cald for
C12H16O2: 192.1150; found: 192.1154.
References and notes
1. (a) Heathcock, C. H. In Comprehensive Organic Synthesis,
Trost B. M., Ed.; Pergamon: Oxford, 1991; Vol. 1, pp 181–237.
(b) Kim, B. M.; Williams, S. F.; Masamune, S. In Comprehen-
sive Organic Synthesis, Trost, B. M., Ed.; Pergamon: Oxford,
1991; Vol. 2, pp 239–275.
Compound 14. 220 mg, 91%, a white solid; mp: 54–56 8C.
IR: (CHCl3) 3609 (w) 3600 (s), 3000 (m), 1699 (s), 1467
(m), 1386 (m), 1221 (s), 1035 (s), 858 (m); 1H NMR:
(500 MHz, CDCl3) 7.84–7.79 (m, 4H), 7.48–7.42 (m, 3H),
5.29 (dt, JZ8.5, 3.5 Hz, 1H), 3.65 (d, JZ3.0 Hz, OH),
2.97–2.85 (m, 2H), 2.62–2.52 (m, 1H), 1.08 (dd, JZ7.0,
1.5 Hz, 6H); 13C NMR: (125 MHz, CDCl3) 215.1, 140.3,
133.2, 132.8, 128.2, 127.9, 127.5,126.1, 125.7, 124.2, 123.7,
70.0, 48.6, 41.4, 17.8!2; MS: (EI, 70 eV) 224 (MKH2O,
23), 181 (100), 152 (41), 127 (7), 115 (1); HRMS: cald for
C16H18O2: 242.1307; found: 242.1302.
2. (a) Brown, H. C.; Dhar, R. K.; Bakshi, R. K.; Pandiarajan, P. K.;
Singaram, B. J. Am. Chem. Soc. 1989, 111, 3441–3442. (b)
Brown, H. C.; Ganesan, K.; Dhar, R. K. J. Org. Chem. 1992, 57,
3767–3772.
3. Fukuzawa, S. I.; Tsuchimoto, T.; Kanai, T. Bull. Chem. Soc. Jpn
1994, 67, 2227–2232.
4. Evans, D. A.; Nelson, J. V.; Vogel, E.; Taber, T. R. J. Am.
Chem. Soc. 1981, 103, 3099–3111.
´
5. (a) Wei, H. X.; Hu, J. L.; Purkiss, D. W.; Pare, P. W.
Tetrahedron Lett. 2003, 44, 949–952. (b) Wei, H. X.; Chen,
´
D. J.; Xu, X.; Li, G.; Pare, P. W. Tetrahedron: Asymmetry 2003,
Compound 15. 227 mg, 81%, a colorless oil, inseparable; 1H
NMR: (300 MHz, CDCl3) 7.40–7.15 (m, 10H), 6.40 (dd,
JZ16.0, 1.1 Hz, 1H), 6.17 (dd, JZ16.0, 6.1 Hz, 1H), 4.75
(m, 0.9H), 4.41 (m, 0.1H), 3.07 (d, JZ3.7 Hz, OH), 3.0–
2.85 (m, 2H), 2.84–2.75 (m, 2H), 2.74–2.67 (m, 2H).
14, 971–974.
6. Kashima, C.; Fukuchi, I.; Takahashi, K.; Fukusaka, K.; Hosomi,
A. Heterocycles 1998, 47, 357–365.
7. Evans, D. A.; Downey, C. W.; Shaw, J. T.; Tedrow, J. S. Org.
Lett. 2002, 4, 1127–1130.
Compound 16. 300 mg, 83%, a white solid; mp: 87–89 8C.
IR: (CHCl3) 3608 (w), 3512 (w), 2945 (w), 1680 (S), 1600
8. Mahrwald, R.; Gundogan, B. J. Am. Chem. Soc. 1998, 120,
413–414.
1
(m), 1289 (m), 1211 (m), 970 (s); H NMR: (500 MHz,
9. Procedure for reacting propiophenone with benzaldehyde (see
Ref. 8): benzaldehyde (0.1 mL, 1.0 mmol) and propiophenone
(0.13 mL, 1.0 mmol) were dissolved in 2.0 mL of anhydrous
toluene. Under a nitrogen atmosphere and at room temperature,
0.1 mL (0.1 mmol, 1.0 M solution in toluene, Aldrich) of TiCl4
was added dropwise via a syringe to the solution. The solution
CDCl3) 7.42–7.35 (m, 4H), 7.34–7.14 (m, 8H), 6.96–6.92
(m, 2H), 5.08 (dt, JZ9.0, 3.0 Hz, 1H), 5.05 (s, 2H), 3.15 (d,
JZ3.0 Hz, OH), 2.90 (t, JZ7.5 Hz, H), 2.88–2.70 (m, 4H);
13C NMR: (125 MHz, CDCl3) 210.3, 158.3, 140.6, 136.9,
135.2, 128.5!2, 128.5!2, 128.2!2 127.9, 127.4!2,
126.9!2, 126.2, 114.8!2, 70.0, 69.5, 51.2, 45.1, 29.4;
MS: (EI, 70 eV) 342 (MKH2O, 10), 212 (18), 181 (1), 152
(1), 91 (100), 65 (25); HRMS: cald for C24H24O3: 360.1725;
found: 360.1728.
1
was stirred for an additional 16 h at room temperature. The H
NMR of the crude mixture showed that less than 10% of
benzaldehyde was converted to an aldol product. This
conclusion was based on the comparison of peak integrations
of the carbinol proton of aldol the product (5.23 ppm) with the
benzaldehyde proton (10.01 ppm).
Acknowledgements
We thank D.W. Purkiss for expert technical NMR assistance