An efficient direct-aldol addition of methyl ketones with aldehydes promoted by MgI2 etherate

Article abstract of DOI:10.1515/mgmc-2012-0029

Direct aldol addition of ketones with aromatic aldehydes and vinyl aldehyde was carried out efficiently in the presence of MgI₂ etherate and Et₃N using untreated reagent grade CH₂Cl₂ under atmospheric conditions in a mild, efficient and highly chemoselective manner. Iodide counterion and non-coordinating reaction media (i.e., CH ₂Cl₂) are among the critical factors for the unique reactivity of this reaction system.

Full text of DOI:10.1515/mgmc-2012-0029

DOI 10.1515/mgmc-2012-0029ꢀ
ꢀMain Group Met. Chem. 2012; 35(3-4): 111–115
Yingshuai Liu, Hangzhou Shen and Xingxian Zhang*
An efficient direct-aldol addition of methyl
ketones with aldehydes promoted by MgI2
etherate
Abstract: Direct aldol addition of ketones with aromatic been developed recently in organic synthesis (Zhang and
aldehydes and vinyl aldehyde was carried out efficiently Li, 2003). In our previous paper, we have demonstrated
in the presence of MgI2 etherate and Et3N using untreated that MgI2 etherate could efficiently catalyze Mukaiyama-
reagent grade CH2Cl2 under atmospheric conditions in a type aldol reaction of aldehydes with trimethylsilyl eno-
mild, efficient and highly chemoselective manner. Iodide lates and allylation of aldehydes with allylstannane (Li
counterion and non-coordinating reaction media (i.e., and Zhang, 2002; Zhang, 2008). We have also found
CH2Cl2) are among the critical factors for the unique reac- that MgI2 etherate promoted halo-aldol addition of
tivity of this reaction system.
cyclopropyl methyl ketone with aldehydes under mild
reaction conditions via ring opening of cyclopropane
Keywords: aldehydes; direct-aldol; ketones; MgI2 etherate. (Zhang, 2009). Herein, we report unique chemoselec-
tive direct-aldol promoted by MgI2 etherate under atmos-
pheric conditions.
*Corresponding author: Xingxian Zhang, College of Pharmaceutical
Sciences, Zhejiang University of Technology, Hangzhou, 310032,
PR China, e-mail: zhangxx@zjut.edu.cn
Yingshuai Liu: College of Pharmaceutical Sciences, Zhejiang
Results and discussion
University of Technology, Hangzhou, 310032, PR China
Hangzhou Shen: College of Pharmaceutical Sciences, Zhejiang
At the onset of this work, we investigated a variety of
conditions with a model reaction of acetophenone with
3-nitrobenzaldehyde using MgI2 etherate as promoter in
the presence of Et3N. When 1.0 equiv. of acetophenone,
3-nitrobenzaldehyde and Et3N were added at room tem-
perature in untreated reagent grade dichloromethane, the
University of Technology, Hangzhou, 310032, PR China
Introduction
The aldol reaction is considered to be one of the most aldol product was generated within 30 min with a good
powerful methods for preparing β-hydrxoy carbonyl yield of 92%. This yield was optimized to a quantitative
compounds. Substantial effort has gone into its develop- yield of 99% by using 1.2 equiv. of acetophenone, 1.2 equiv.
ment using preformed enolates, resulting in a remark- of Et3N and 1.0 equiv. of 3-nitrobenzaldehyde. Of various
able level of regio- and stereochemical control (Carreira, untreated solvents screened, excellent yield was obtained
1999; Mahrwald, 2004). Recently, considerable effort in non-coordinating reaction media CH2Cl2. Low yields
has been applied to the development of direct-aldol were provided in non-polar solvent, such as benzene or
reaction. The development of direct-aldol reaction from toluene. The reaction was carried out very sluggishly in
unactivated ketones and aldehydes does not require the the coordinative polar solvents, such as Et2O, dimethyl-
preconversion of a ketone or an ester to a more reactive formamide and tetrahydrofuran. To examine the halide
species (e.g., a silyl enol ether or a silyl ketene acetal) anion effect, halogen analogs of MgI2 etherate, MgBr2
and has attracted a great deal of attention from synthetic etherate and MgCl2 etherate, were compared under par-
organic chemists (Evans et al., 2002a,b, 2003; Lalic et al., allel reaction conditions (1.0 equiv. of promoters). MgCl2
2003; Magdziak et al., 2005). Evans and co-workers have etherate was almost inactive. MgBr2 etherate is less effec-
demonstrated that magnesium halide catalyzed aldol tive in terms of substrate conversion and yield.
reactions of chiral N-acyloxazolidinones and N-acylthi-
With these optimal conditions in hand, we explored
azolidinethiones (Evans et al., 2002a,b). Magnesium is the scope and limitation of this simple process by the reac-
an abundant, cheap and benign element which exists in tion of electronically and functionally diverse aldehydes
nature, and many reactions using magnesium salts have under the same conditions. There is no need to exclude
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ꢀY. Liu et al.: Direct-aldol promoted by MgI2 etherate
moisture and oxygen from the reaction system. The experi- of the carbonyl group. Heteroaromatic aldehyde, such as
mental results are summarized in Table 1. As shown in 2-thiophenealdehyde, was also a good substrate (Table 1,
Table 1, MgI2 etherate-Et3N could promote direct-aldol entry 14). Acid-sensitive aldehyde, such as cinnamalde-
coupling of acetophenone and substituted acetophenone hyde, reacted with cyclopropyl methyl ketone to afford a
with aromatic aldehydes in good to excellent yields in a good yield of the 1,2-adduct without any decomposition
short period (Table 1, entries 1–5). Interestingly enough, or polymerization under the present reaction conditions
the nucleophilic addition of cyclopropyl methyl ketone (Table 1, entry 15). In general, both aromatic, heteroaro-
with benzaldehyde in the presence of MgI2 etherate and matic and α,β-unsaturated aldehydes underwent the con-
Et3N was also processed efficiently without ring opening version efficiently in a short period, whereas ketones did
reaction of cyclopropane (Table 1, entry 6). Moreover, the not yield any product even prolonging the reaction times
aromatic aldehydes bearing electron-donating and elec- in the presence of MgI2 etherate and Et3N.
tron-withdrawing groups in the aromatic ring were reacted
This interesting chemoselectivity was further evalu-
smoothly to afford the desired aldol adducts in good to ated by crossover experiments of various aromatic alde-
excellent yields (Table 1, entries 6–13). Furthermore, we hydes with ketones, respectively. MgI2 etherate shows
observed the following delicate electronic effects: (1) aro- high levels of aromatic aldehydes discrimination in the
matic aldehydes with an electron-donating substituent competitive reactions with ketone. MgI2 etherate can
(i.e., OMe) afforded the corresponding adducts in lower effectively recognize the delicate difference in electronic
yields than benzaldehyde (Table 1, entries 6–9). (2) Aro- effect involved in benzaldehyde (Table 2). Expectedly,
matic aldehydes with an electron-withdrawing substituent 4-anisaldehyde is much less reactive than benzaldehyde,
(i.e., Cl, F, NO2) reacted much faster than benzaldehyde and 4-nitrobenzaldehyde and 3-nitrobenzaldehyde in the
provided the corresponding adducts in excellent yields MgI2 etherate-promoted process. Only the aldol adduct of
(Table 1, entries 11–13). It is noteworthy that 3-anisalde- benzaldehyde, 4-nitrobenzaldehyde and 3-nitrobenzalde-
hyde is more reactive than 4-anisaldehyde (Table 1, entries hyde was obtained, respectively (Table 2, entries 1–3). In
9 and 10). Seemingly, this reactivity of aromatic aldehydes crossover-aldol addition of benzaldehyde with 4-nitroben-
is principally dependent on the inherent electrophilicity zaldehyde or 3-nitrobenzaldehyde, the former shows less
Entry
R
R'
Room temperature (h)
Ratio 1/2b
Overall yield (%)c
1
2
C6H5
C6H5
3-NO2C6H4
3-CH3OC6H4
0.5
2
82:18
54:46
99
95
3
4
5
6
C6H5
C6H5
C6H5
C6H5
C6H5
2
2
2
1
ꢁ>ꢁ99:ꢁ<ꢁ1
ꢁ>ꢁ99:ꢁ<ꢁ1
ꢁ>ꢁ99:ꢁ<ꢁ1
ꢁ<ꢁ1/ꢁ>ꢁ99
84
85
90
88
4-CH3OC6H4
4-FC6H4
Cyclopropyl
7
8
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Piperonal
4
5
55:45
60:40
ꢁ>ꢁ99:ꢁ<ꢁ1
ꢁ>ꢁ99:ꢁ<ꢁ1
ꢁ>ꢁ99:ꢁ<ꢁ1
ꢁ>ꢁ99:ꢁ<ꢁ1
73:27
83
85
81
94
98
99
91
87
86
4-CH3COOC6H4
4-CH3OC6H4
3-CH3OC6H4
3-NO2C6H4
9
6
10
11
12
13
14
15
1
0.5
0.5
1
4-NO2C6H4
2-Cl-6-F-C6H3
2-thiophenyl
(E)-C6H5CHꢁ=ꢁCH
1
2
ꢁ>ꢁ99:ꢁ<ꢁ1
ꢁ>ꢁ99:ꢁ<ꢁ1
Table 1 MgI2-promoted direct-aldol addition of ketones with various aldehydes.a
O
O
O
OH
R
R' +
(OEt2)n , Et3N
MgI2
+
R'
R
CH3 R' CHO
R
Untreated CH2Cl2, r.t.
atmospheric condition
1
2
aConducted under atmospheric conditions by combining 1.2 mmol of ketone, 1.0 mmol of aldehyde and 1.0 mmol of MgI2‧(OEt2)n in untreated
reagent grade CH2Cl2, followed by addition of 1.2 mmol of Et3N.
bThe ratio was determined by flash column chromatography.
cOverall isolatedyield.
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ꢀ113
accomplished by thin layer chromatography on silica gel polygram
SILG/UV 254 plates. Elemental analysis was performed on a VarioEL-3
instrument (Elementar, Germany).
reactivity than the latter (Table 2, entries 5–7) and the
reaction exclusively gave the aldol adduct of 4-nitrobenz-
aldehyde and 3-nitrobenzaldehyde, respectively. Similarly,
the reactivity of 4-nitrobenzaldehyde and 3-nitrobenzal-
dehyde is much better than that of 3-anisaldehyde (Table
2, entries 8–10). More significantly, MgI2 etherate shows
the remarkable preference for 3-anisaldehyde over 4-anis-
aldehyde (Table 2, entry 4). These results suggest that the
relative reactivity of aromatic aldehydes in the MgI2 ether-
ate-promoted process is determined almost solely by elec-
trophilicity of aromatic aldehydes themselves.
Representative experimental procedure of
MgI2 etherate-promoted direct-aldol reaction
To a stirred mixture solution of 3-nitrobenzaldehyde (151 mg, 1 mmol)
and acetophenone (144 mg, 1.2 mmol) in CH2Cl2 (10 ml) was added a
freshly prepared MgI2 etherate (Arkley et al., 1962) (1 mmol) at room
temperature, followed by addition of Et3N (121 mg, 1.2 mmol). The
resulting reaction mixture was stirred at room temperature for 30 min
In summary, we have demonstrated the unique reac-
tivity of MgI2 etherate in the chemoselective direct-aldol and quenched with saturated aqueous Na2SO3. Extractive workup
with ether and chromatographic purification of the crude product on
coupling of aromatic aldehydes with ketones. This magne-
sium-promoted direct-aldol addition is mild, efficient and
silica gel gave the desired aldol adduct in 99% yield.
operationally simple. Iodide counterion and non-coordi-
nating reaction media are critical factors for the unique
reactivity of this reaction system. Further investigation on
the reactivity of MgI2 etherate in other C-C bond construct-
ing reactions is underway.
3-Hydroxy-1,3-diphenyl-propan-1-one (Diana et al., 1977): color-
less oil. lH-NMR (500 MHz, CDC13): δꢀ=ꢀ3.31–3.36 (m, 2H), 3.65–3.66 (m,
1H), 5.31–5.34 (m, 1H), 7.26–7.29 (m, 1H), 7.34–7.37(m, 2H), 7.41–7.45 (m,
4H), 7.55–7.58 (m, 1H), 7.92–7.93 (m, 2H).
3-Hydroxy-3-(3-methoxy-phenyl)-1-phenyl-propan-1-one (Yutaka
et al., 1995): colorless oil. lH-NMR (500 MHz, CDC13): δꢀ=ꢀ3.35 (s, 1H),
3.36 (d, Jꢀ=ꢀ2.5 Hz, 1H), 3.63 (d, Jꢀ=ꢀ2.5 Hz, 1H), 3.81 (s, 3H), 5.30–5.33
(m, 1H), 6.83 (dd, Jꢀ=ꢀ2.0, 8.0 Hz, 1H), 6.98–7.01 (m, 2H), 7.28 (t, Jꢀ=ꢀ7.5
Hz, 1H), 7.45 (t, Jꢀ=ꢀ7.5 Hz, 2H), 7.58 (t, Jꢀ=ꢀ7.5 Hz, 1H), 7.9–7.95 (m, 2H).
Experimental section
(E)-3-(3-Methoxy-phenyl)-1-phenyl-propenone (Rao et al., 2008):
l
colorless oil. H-NMR (500 MHz, CDC13): δꢀ=ꢀ3.82 (s, 3H), 6.94 (dd,
General methods
Jꢀ=ꢀ2.0, 8.5 Hz, 1H), 7.14 (t, Jꢀ=ꢀ1.5 Hz, 1H), 7.21–7.24 (m, 1H), 7.29–7.32
(m, 1H), 7.46–7.49 (m, 3H), 7.51–7.57 (m, 1H), 7.76 (d, Jꢀ=ꢀ15.5 Hz, 1H),
8.00–8.01 (m, 2H).
For product purification by flash column chromatography, silica gel
(200–300 mesh) and light petroleum ether (PE, b.p. 60–90°C) were
1
3-Hydroxy-3-(3-nitro-phenyl)-1-phenyl-propan-1-one (Wang et
used. H NMR spectra were taken on a Bruker Avance III 500 MHz
spectrometer (Switzerland) with TMS (tetramethylsilane) as an inter- al., 2004): pale yellowish oil. lH-NMR (500 MHz, CDC13 ) δ: 3.34–3.46
nal standard and CDCl3 as solvent. The reactions monitoring was (m, 2H), 3.87 (s, 1H), 5.46 (dd, Jꢀ=ꢀ2.5, 9.0 Hz, 1H), 7.47–7.50 (m, 2H), 7.56
Entry
R
Ar
Ar'
Ratio (1/1')b
Overall yield (%)c
1
2
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Ph
Cyclopropyl
Cyclopropyl
Cyclopropyl
Ph
C6H5
4-CH3OC6H4
4-CH3OC6H4
4-CH3OC6H4
4-CH3OC6H4
C6H5
ꢁ>ꢁ99/ꢁ<ꢁ1
ꢁ>ꢁ99/ꢁ<ꢁ1
ꢁ>ꢁ99/ꢁ<ꢁ1
80:20
ꢁ>ꢁ99/ꢁ<ꢁ1
ꢁ>ꢁ99/ꢁ<ꢁ1
ꢁ>ꢁ99/ꢁ<ꢁ1
92:8
85
96
94
96
92
91
95
93
94
94
4-NO2C6H4
3-NO2C6H4
3-CH3OC6H4
3-NO2C6H4
3-NO2C6H4
4-NO2C6H4
3-NO2C6H4
4-NO2C6H4
3-NO2C6H4
3
4
5
6
C6H5
7
C6H5
8
3-CH3OC6H4
3-CH3OC6H4
3-CH3OC6H4
9
ꢁ>ꢁ99/ꢁ<ꢁ1
ꢁ>ꢁ99/ꢁ<ꢁ1
10
Table 2 MgI2‧(OEt2)n-promoted crossover direct-aldol reaction.a
OH
O
O
OH
O
(OEt2)n , Et3N
MgI2
+
+
ArCHO
Ar'CHO
+
Ar
R
R
CH3
Ar'
R
Untreated CH2Cl2, r.t.
atmosphere condition
1
1'
aReactions were run with a mixture of 1.0 mmol of each aromatic aldehyde, 1.0 mmol of ketone and 1.0 mmol of MgI2‧(OEt2)n in untreated
CH2Cl2, followed by addition of 1.2 mmol of Et3N at room temperature under atmospheric condition.
bThe ratio was determined by flash column chromatography.
cOverall isolated yield.
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ꢀY. Liu et al.: Direct-aldol promoted by MgI2 etherate
(t, Jꢀ=ꢀ8.0 Hz, 1H), 7.60–7.63 (m, 1H), 7.80 (d, Jꢀ=ꢀ8.0 Hz, 1H), 7.95–7.97 1.06 (m, 2H), 1.20–1.25 (m, 2H), 2.23–2.28 (m, 1H), 6.98 (d, Jꢀ=ꢀ16.0 Hz,
(m, 2H), 8.15–8.17 (m, 1H), 8.33 (t, Jꢀ=ꢀ1.5 Hz, 1H).
1H), 7.61 (d, Jꢀ=ꢀ16.0 Hz, 1H), 7.71–7.73 (m, 2H), 8.25–8.28 (m, 2H).
1-Cyclopropyl-3-hydroxy-3-(3-nitro-phenyl)-propan-1-one (Siyut-
(E)-3-(3-Nitro-phenyl)-1-phenyl-propenone (Giancarlo et al.,
2003): pale yellowish oil. lH-NMR (500 MHz, CDC13): δ: 7.54–7.57
(t, Jꢀ=ꢀ8.0 Hz, 2H), 7.62–7.65 (m, 2H), 7.68 (d, Jꢀ=ꢀ16.0 Hz, 1H), 7.86 (d,
Jꢀ=ꢀ15.5 Hz, 1H), 7.94 (d, Jꢀ=ꢀ7.5 Hz, 1H), 8.07 (d, Jꢀ=ꢀ7.5 Hz, 2H), 8.28 (dd,
Jꢀ=ꢀ2.0, 8.0 Hz, 1H), 8.53 (s, 1H).
l
kin et al., 2010): pale yellowish oil. H-NMR (500 MHz, CDC13): δ:
0.96–1.00 (m, 2H), 1.01–1.15 (m, 2H), 1.92–1.97 (m, 1H), 2.98 (dd, Jꢀ=ꢀ9.0,
18.0 Hz,1H), 3.06 (dd, Jꢀ=ꢀ3.5, 17.5 Hz, 1H), 3.87 (d, Jꢀ=ꢀ3.0 Hz, 1H), 5.24–
5.27 (m, 1H), 7.53 (t, Jꢀ=ꢀ8.0 Hz, 1H), 7.72 (d, Jꢀ=ꢀ8.0 Hz, 1H), 8.12–8.14 (m,
1H), 8.26 (t, Jꢀ=ꢀ1.5 Hz, 1H).
3-Hydroxy-3-phenyl-1-(4-fluorophenyl)-propan-1-one (Wei et al.,
l
3-(2-Chloro-6-fluoro-phenyl)-1-cyclopropyl-3-hydroxy-propan-
2004): colorless oil. H-NMR (500 MHz, CDC13): δ: 7.92–7.96 (m, 2H),
l
1-one colorless oil. H-NMR (500 MHz, CDC13): δ: 0.92–0.95 (m, 2H),
7.38–7.44 (m, 2H), 7.33–7.36 (m, 2H), 7.28–7.31 (m, 1H), 7.09–7.12 (m, 1H),
5.31–5.34 (m, 1H), 3.31–3.34 (m, 2H).
1.10 (t, Jꢀ=ꢀ4.5 Hz, 2H), 1.94–1.99 (m, 1H), 2.97 (dd, Jꢀ=ꢀ3.5, 17.0 Hz, 1H),
3.37 (s, 1H), 3.44 (dd, Jꢀ=ꢀ9.5, 17.5 Hz, 1H), 5.76 (d, Jꢀ=ꢀ9.5 Hz, 1H), 6.98–
7.02 (m, 1H), 7.16–7.28 (m, 2H). Elemental analyses: calculated (%) for
C12H12ClFO2 (242.05 g/mol): C 59.39, H 4.98, found: C 59.46, H 4.91.
(E)-1-Cyclopropyl-3-phenyl-propenone (Galina et al., 2005): color-
l
less oil. H-NMR (500 MHz, CDC13): δ: 0.96–0.99 (m, 2H), 1.15–1.18
(m, 2H), 2.23–2.28 (m, 1H), 6.88 (d, Jꢀ=ꢀ16.0 Hz, 1H), 7.38–7.40 (m, 3H),
(E)-3-(2-Chloro-6-fluoro-phenyl)-1-cyclopropyl-propenone color-
less oil. lH-NMR (500 MHz, CDC13): δ: 0.99–1.03 (m, 2H), 1.18–1.21 (m,
2H), 2.22–2.27 (m, 1H), 7.03–7.07 (m, 1H), 7.14 (d, Jꢀ=ꢀ1.0 Hz, 1H), 7.25–7.27
(m, 2H), 7.81 (d, Jꢀ=ꢀ16.5 Hz, 1H). Elemental analyses: calculated (%)
for C12H10ClFO (224.04 g/mol): C 64.15, H 4.49, found: C 64.28, H 4.43.
7.55–7.63 (m, 3H).
3-Benzo[1,3]dioxol-5-yl-1-cyclopropyl-3-hydroxy-propan-1-one
l
(Diana et al., 1977): colorless oil. H-NMR (500 MHz, CDC13): δ: 0.92
(dd, Jꢀ=ꢀ3.5, 8.0 Hz, 2H), 1.08 (dd, Jꢀ=ꢀ5.0, 8.5 Hz, 2H), 1.90–1.93 (m, 1H),
2.88–2.98 (m, 2H), 3.53 (d, Jꢀ=ꢀ3.0 Hz, 1H), 5.04–5.06 (m, 1H), 5.93 (d,
Jꢀ=ꢀ1.0 Hz, 2H), 6.75–6.81 (m, 2H), 6.88 (d, Jꢀ=ꢀ1.0 Hz, 1H).
1-Cyclopropyl-3-hydroxy-3-thiophen-2-yl-propan-1-one (Downey
and Johnson, 2007): colorless oil. lH-NMR (500 MHz, CDC13 ): δ: 0.92
(dd, Jꢀ=ꢀ3.5, 8.0 Hz, 2H), 1.04–1.09 (m, 2H), 1.91–1.95 (m, 1H), 3.02–3.12
(m, 2H), 3.88 (d, Jꢀ=ꢀ3.5 Hz, 1H), 5.35–5.38 (m, 1H), 6.94 (d, Jꢀ=ꢀ3.0 Hz,
2H), 7.22 (t, Jꢀ=ꢀ3.0 Hz, 1H).
(E)-3-Benzo[1,3]dioxol-5-yl-1-cyclopropyl-propenone (Diana et
al., 1977): colorless oil. lH-MR (500 MHz, CDC13): δ: 1.12–1.15 (m, 2H),
1.25 (s, 2 H), 2.18–2.22 (m, 1H), 5.96 (d, Jꢀ=ꢀ1.0Hz, 2H), 6.70 (d, Jꢀ=ꢀ16.0
Hz, 1H), 6.80 (d, Jꢀ=ꢀ8.0 Hz, 1H), 7.03 (dd, Jꢀ=ꢀ1.5, 8.0 Hz, 1H), 7.06 (d,
Jꢀ=ꢀ1.5Hz, 1H), 7.51 (d, Jꢀ=ꢀ16.0 Hz, 1H).
(E)-1-Cyclopropyl-3-hydroxy-5-phenyl-pent-4-en-1-one colorless
l
oil. H-NMR (500 MHz, CDC13 ): δ: 0.92–0.97 (m, 2H), 1.07–1.14 (m,
1-Cyclopropyl-3-hydroxy-3-(4-methoxy-phenyl)-propan-1-one
colorless oil. lH-NMR (500 MHz, CDC13): δ: 0.88–0.91 (m, 2H), 1.05 (dd,
Jꢀ=ꢀ4.0, 8.0 Hz, 2H), 1.87–1.92 (m, 1H), 2.88 (dd, Jꢀ=ꢀ3.5, 17.0 Hz, 1H), 2.96
(dd, Jꢀ=ꢀ9.0, 17.5 Hz, 1H), 3.66 (d, Jꢀ=ꢀ3.0 Hz, 1H), 3.76 (s, 3H), 5.05–5.08
(m, 1H), 6.85 (d, Jꢀ=ꢀ8.5 Hz, 2H), 7.26 (d, Jꢀ=ꢀ8.5 Hz, 2H). Elemental
analyses: calculated (%) for C13H16O3 (220.11 g/mol): C 70.89, H 7.32,
found: C 70.98, H 7.26.
2H), 1.93–1.98 (m, 1H), 2.86 (dd, Jꢀ=ꢀ8.5, 17.0 Hz, 1H), 2.90 (dd, Jꢀ=ꢀ3.5,
17.5 Hz, 1H), 3.32 (d, Jꢀ=ꢀ2.0 Hz, 1H), 4.76 (s, 1H), 6.22 (dd, Jꢀ=ꢀ6.0, 16.0
Hz,1H), 6.65 (dd, Jꢀ=ꢀ0.5, 16.0 Hz, 1H), 7.22–7.26 (m, 1H), 7.30–7.37(m,
2H), 7.39 (d, Jꢀ=ꢀ1.5 Hz, 2H). Elemental analyses: calculated (%) for
C14H16O2 (216.12 g/mol): C 77.75, H 7.46, found: C 77.83, H 7.40.
3-Hydroxy-3-phenyl-1-(4-methoxy-phenyl)-propan-1-one (Wei et
l
al., 2004): pale yellowish oil. H-NMR (500 MHz, CDC13): δ: 7.90–7.92
1-Cyclopropyl-3-hydroxy-3-(3-methoxy-phenyl)-propan-1-one
(m, 2H), 7.40–7.43 (m, 2H), 7.33–7.35 (m, 2H), 7.27–7.30 (m, 1H), 6.90–
6.92 (m, 2H), 5.29–5.31 (m, 1H), 3.83 (s, 3H), 3.27–3.30 (m, 2H).
l
colorless oil. H-NMR (500 MHz, CDC13): δ: 0.88–0.92 (m, 2H), 1.03–
1.09 (m, 2H), 1.87–1.92 (m, 1H), 2.90 (dd, Jꢀ=ꢀ3.5, 17.5 Hz, 1H), 2.96 (dd,
Jꢀ=ꢀ8.5, 17.5 Hz, 1H), 3.77 (d, Jꢀ=ꢀ6.5 Hz, 3H), 4.58 (s, 1H), 5.10 (dd, Jꢀ=ꢀ3.5,
8.5 Hz, 1H), 6.80 (dd, Jꢀ=ꢀ2.5, 8.5 Hz, 1H), 6.88–6.92 (m, 2H), 7.21–7.25
(m, 1H). Elemental analyses: calculated (%) for C13H16O3 (220.11
g/mol): C 70.89, H 7.32, found: C 70.96, H 7.25.
Typical experimental procedure of the MgI2
etherate-promoted crossover direct-aldol of
various aromatic aldehydes
A freshly prepared MgI2 etherate (1 mmol) was added to a solution of
4-nitrobenzaldehyde (151 mg, 1 mmol), 4-anisaldehyde (136 mg, 1 mmol)
and cyclopropyl methyl ketone (84 mg, 1.0 mmol) in CH2Cl2 (10 ml) at
room temperature, followed by addition of Et3N (121 mg, 1.2 mmol).
After stirring for 30 min at room temperature, the reaction mixture was
poured into saturated aqueous Na2SO3 solution. The resulting mixture
was extracted with Et2O and combined organic layers were washed with
water, brine, dried over MgSO4 and concentrated. The crude product
was purified by flash chromatography on silica gel eluting with PE/
EtOAc to provide aldol adduct (Rꢀ=ꢀ4-NO2C6H4) in 96% yield.
Acetic acid 4-(3-cyclopropyl-1-hydroxy-3-oxo-propyl)-phenyl
l
ester colorless oil. H-NMR (500 MHz, CDC13): δ: 0.91–0.93 (m, 2H),
1.06–1.09 (m, 2H), 1.89–1.93 (m, 1H), 2.28 (d, Jꢀ=ꢀ2.0 Hz, 3H), 2.93 (dd,
Jꢀ=ꢀ0.5, 8.0 Hz, 2H), 3.67 (d, Jꢀ=ꢀ3.0 Hz, 1H), 5.12–5.15 (m, 1H), 7.04–7.07
(m, 2H), 7.33–7.38 (m, 2H). Elemental analyses: calculated (%) for
C14H16O4 (248.10 g/mol): C 67.73, H 6.50, found: C 67.85, H 6.56.
(E)-Acetic acid 4-(3-cyclopropyl-3-oxo-propenyl)-phenyl ester
colorless oil. lH-NMR (500 MHz, CDC13): δ: 0.96–1.00 (m, 2H), 1.15–1.18
(m, 2H), 2.22–2.25 (m, 1H), 2.32 (d, Jꢀ=ꢀ3.5 Hz, 3H), 6.83 (d, Jꢀ=ꢀ16.0 Hz,
1H), 7.12–7.15 (m, 2H), 7.57–7.60 (m, 3H). Elemental analyses: calculated
(%) for C14H14O3 (230.09 g/mol): C 73.03, H 6.13, found: C 73.16, H 6.21.
1-Cyclopropyl-3-hydroxy-3-(4-nitro-phenyl)-propan-1-one (Siyut-
Acknowledgments: We acknowledge financial support
from the Zhejiang Province Natural Science Foundation of
China (Project Y4100692).
l
kin et al., 2010): pale yellowish oil. H-NMR (500 MHz, CDC13): δ:
0.96–1.01(m, 2H), 1.08–1.16 (m, 2H), 1.91–1.96 (m, 1H), 2.95 (dd, Jꢀ=ꢀ9.0,
18.0 Hz, 1H), 3.03 (dd, Jꢀ=ꢀ3.0, 15.0 Hz, 1H), 3.82 (d, Jꢀ=ꢀ3.0 Hz, 1H), 5.25–
5.28 (m, 1H), 7.54–7.57 (m, 2H), 8.20–8.23 (m, 2H).
(E)-1-Cyclopropyl-3-(4-nitro-phenyl)-propenone (Hercouet and Le
Received June 14, 2012; accepted July 4, 2012; previously published
online August 7, 2012
l
Corre, 1977): pale yellowish oil. H-NMR (500 MHz, CDC13): δ: 1.03–
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