Versatile one-step one-pot direct aldol condensation promoted by MgI 2

Article abstract of DOI:10.1002/hlca.200490211

A true one-step one-pot aldol-reaction procedure has been developed for the synthesis of β-hydroxy ketones and esters. The reaction can be run at room temperature by simply mixing four components in CH₂Cl₂, with medium-to-high yields of aldol products obtained after regular workup. Mechanistically, the process probably proceeds via Mg-enolate formation of the ketone or ester component, followed by addition to the electrophilic aldehyde.

Full text of DOI:10.1002/hlca.200490211

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Helvetica Chimica Acta Vol. 87 (2004)
Versatile One-Step One-Pot Direct Aldol Condensation Promoted by MgI2
by Han-Xun Wei*1), Kunyu Li, Qian Zhang, Richard L. Jasoni, Jiali Hu, and Paul W. Pare¬*
Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409, USA
(e-mail: hweij@hotmail.com)
A true one-step one-pot aldol-reaction procedure has been developed for the synthesis of b-hydroxy
ketones and esters. The reaction can be run at room temperature by simply mixing four components in CH2Cl2,
with medium-to-high yields of aldol products obtained after regular workup. Mechanistically, the process
probably proceeds via Mg-enolate formation of the ketone or ester component, followed by addition to the
electrophilic aldehyde.
Introduction. The development of new multicomponent-coupling processes for
the construction of complex target molecules from simple starting materials has
attracted much attention in recent years. Aldol reactions, i.e., the condensation of a
nucleophilic enolate with an electrophilic carbonyl compound, are considered to be
among the most-powerful C,C-bond-forming reactions. The development of direct
aldol reactions from unmodified ketones and aldehydes does not require the pre-
conversion of a ketone or an ester to a more-reactive species (e.g., an enol silyl ether or
a ketene silyl acetal) and has, thus, attracted considerable attention.
Generally, direct aldol reactions fall into one out of two categories: 1) the carbonyl
compound is first converted to its Li (or other metal) enolate by treatment with a strong
base, typically lithium diisopropylamide (LDA) or a metal hexamethyldisilazide
(MHMDS), followed by the addition of a carbonyl acceptor; or 2) the carbonyl
compound is converted to its metal enolate under relatively mild conditions by
treatment with a Lewis acid and a tertiary amine, followed by the reaction with the
carbonyl acceptor. Both methods are two-step one-pot reactions, since the enolate
needs to be formed before the addition of the carbonyl acceptor [1][2].
Recently, we found that MgI2 is an excellent Lewis acid for C,C-bond-forming
reactions in the synthesis of b-iodo BaylisÀHillman adducts [3]. We think that, in this
process, MgI2 serves both as a Lewis acid and an iodine source for a Michael-type
addition in which an a,b-ethynyl ketone (or ester) is converted to an active −b-iodo-
allenolate× intermediate, which, in turn, reacts with aldehydes to yield b-iodo
BaylisÀHillman adducts. Consequently, we were interested in testing whether MgI2,
in the presence of a tertiary amine, would be a suitable reagent for the mild in situ
formation of Mg enolates.
1
)
Present address: Department of Chemical Process and Development, Boehringer Ingelheim Pharama-
ceuticals, Inc., 800 East Leigh Street, Suite 205, Richmond, VA 23219, U.S.A.
¹ 2004 Verlag Helvetica Chimica Acta AG, Z¸rich

Helvetica Chimica Acta Vol. 87 (2004)
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Results and Discussion. Generally, all reactions were carried out by simply adding
a tertiary amine to a CH2Cl2 solution containing aldehyde, ketone (or ester), and MgI2
at room temperature under N2 atmosphere. This gave rise to the desired b-hydroxy
adducts in moderate-to-high yields (Table). In a first attempt to condense benzalde-
hyde with acetophenone in the presence of EtN(i-Pr)2 and MgI2, product 1 was
obtained in 85% yield after only 30 min (TLC monitoring). The yield of this reaction
could be readily increased to 98% (Entry 1 of the Table) by optimization of the reaction
conditions.
Table. Direct, MgI2-Promoted Aldol Reaction of Various Ketones and Esters (Nucleophiles) with Aromatic
Aldehydes (Electrophiles). Conditions: electrophile, 1 mmol; nucleophile, MgI2, and EtN(i-Pr)2, 1.2 mmol
each; CH2Cl2, r.t., 30 min; aqueous workup followed by flash chromatography.
Entry
R (nucleophile)
R' (electrophile)
Product
Isolated yield [%]
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
4-F-C6H4
4-MeO-C6H4
[1,1'-Biphenyl]-4-yl
Ph
Ph
Ph
1
2
3
4
5
6
7
8
9
98
94
98
98
96
98
68
70
72
60
65
72
4-MeO-C6H4
4-F-C6H4
Ph
Ph
Ph
MeÀCHˆCH
Et
Ph
Ph
Ph
Ph
Me
10
11
12
MeO
EtO
PhO
10
11
12
To find the optimum conditions, we varied the Lewis acid in the above model
reaction between benzaldehyde and acetophenone, giving rise to 3-hydroxy-1,3-
diphenylpropan-1-one (1). The following metal salts and organometallics were tested:
2
Sn(OTf)2, SnCl4, TiCl4, Mg(OTf)2, MgBr2, MgCl2, Mg(ClO4)2, LiI, and MgI2 ).
However, except for MgBr2 and MgI2, which afforded 1 in 71 and 98% yield,
respectively, all other additives were found to be much less active or completely inert.
Surprisingly, both TiCl4 and Sn(OTf)2, common reagents for direct aldol reactions,
failed to promote the condensation, offering only trace amounts (< 5%) of the aldol
product, even at a prolonged reaction time of 2 h at room temperature. This might be
attributed to the propensity of these strong Lewis acids to form tight complexes with
amines, which competes with enolate-intermediate production.
Upon varying the solvent, CH2Cl2, benzene, and toluene gave the best results, in
terms of yield, when benzaldehyde was used as the electrophile (30 min at r.t. to
completion). In Et2O or THF, the reaction required 10 h to go to completion; and after
30 min, only 10% of the desired product had been formed.
2
)
Tf ˆ Trifluoromethanesulfonyl

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Helvetica Chimica Acta Vol. 87 (2004)
Both aromatic and aliphatic aldehydes were successfully used as electrophiles in the
new one-pot reaction system. Especially high yields (94 98%) were obtained with
aromatic aldehydes (Table, Entries 1 6). The somewhat lower yields (ca. 70%) for the
condensation of aliphatic aldehydes (Entries 7 and 8) could be rationalized by side
reactions arising from the self-condensation of acetophenone. This result indicates that
aliphatic aldehydes are generally less active than aromatic ones in this new system.
Acetone also underwent the reaction with benzaldehyde, however, in lower yield
(Entry 9). Esters were found to react with aldehydes as well, which gave rise to the
corresponding b-hydroxy esters in yields of 60 72% (Entries 10 12). The new system,
thus, may extend the scope to which esters are generally used as reaction substrates in
aldol condensations.
A mechanistic working hypothesis of this new process is represented in the Scheme.
The initial reaction step probably involves the formation of a Mg enolate, which reacts
with aldehydes to form the classical aldol products.
Scheme
Conclusions. A true one-step one-pot aldol-reaction protocol has been success-
fully developed based on MgI2 as a Lewis acid promoter. The reaction proceeds rapidly
under mild conditions and provides b-hydroxy ketones and esters in medium-to-
excellent yields (60 98%). The scope of the reaction and an extension of this new
system to other applications will be published in due course.
Experimental Part
General. CH2Cl2 was freshly distilled from CaH under N2 atmosphere. MgI2 (98%) and all other chemicals
were commercially available and used without further purification; the stoichiometrics were calculated based on
the purities reported by the manufacturers. All reactions were conducted under N2 gas in dry glassware
equipped with a magnetic stirring bar. Flash chromatography (FC) was performed on Silica Gel 60 (230
400 mesh; Merck). Infrared (IR) spectra were recorded on a Shimadzu FT-IR-8400 spectrophotometer; in cmÀ1
.
1H- and 13C-NMR Spectra were recorded on a Varian spectrometer (at 500 and 125 MHz, resp.) in CDCl3;
chemical shifts d in ppm rel. to Me4Si (ˆ0 ppm); coupling constant J in Hz Mass spectra were recorded on a
JEOL JMS-D300 mass spectrometer; in m/z. High-resolution (HR) mass spectra were recorded at the Mass
Spectroscopy Laboratory at the Crompton Corporation.
Typical Procedure (see the Table, Entry 1). A 25-ml dry flask was loaded with CH2Cl2 (5.0 ml),
benzaldehyde (1.0 equiv), acetophenone (1.2 equiv.), and MgI2 (340.0 mg, 1.2 mmol). Under N2 EtN(i-Pr)2
(0.23 ml, 1.3 mmol) was added dropwise via syringe, and the resulting mixture was stirred for 30 min at r.t. Then,
the reaction was quenched with 2n HCl (4.0 ml), the org. solvent (CH2Cl2) was evaporated, and the aq. phase
was extracted with AcOEt (8.0 ml). The org. layer was separated, and the aq. layer was re-extracted with AcOEt
(2 Â 8.0 ml). The combined org. layers were dried (MgSO4) and concentrated, and the crude product (1) was
purified by FC (hexane/AcOEt 10 :1).
1-Hydroxy-1,3-diphenylpropan-1-one (1). Yield: 221.5 mg (98%). Colorless oil. IR (neat): 3477, 3061, 2975,
1679, 1601, 1576. 1H-NMR (500 MHz, CDCl3): 3.33 (m, 2 H); 3.68 (d, J ˆ 3.0, OH); 5.32 (m, 1 H); 7.31 (m, 1 H);
7.39( m, 2 H); 7.46 (m, 4 H); 7.59( m, 1 H); 7.9 5 (m, 2 H). 13C-NMR (125 MHz, CDCl3): 47.3; 69.9; 125.6; 127.5;

Helvetica Chimica Acta Vol. 87 (2004)
2357
‡
‡
‡
128.1; 128.4; 128.6; 133.5; 136.4; 142.9; 200.0. CI-MS (CH4): 226 (M ). HR-MS: 226.0998 (M ; C15H14O2 ; calc.
226.0994).
3-Hydroxy-3-(4-methoxyphenyl)-1-phenylpropan-1-one (2). Yield: 240.6 mg (94%). Colorless oil. IR
(neat): 3611, 3490, 3056, 1678, 1600. 1H-NMR (500 MHz, CDCl3): 3.32 (m, 2 H); 3.60 (d, J ˆ 3.0, OH); 3.78 (s,
3 H); 5.27 (m, 1 H); 6.88 (m, 2 H); 7.33 (m, 2 H); 7.44 (m, 2 H); 7.56 (m, 1 H); 7.9 3 m( , 2 H). 13C-NMR
(125 MHz, CDCl3): 47.2; 55.1; 69.5; 113.8; 126.9; 128.0; 128.5; 133.4; 135.1; 136.5; 158.9; 200.0. CI-MS (CH 4): 240
‡
‡
‡
(M ). HR-MS: 256.1095 (M , C16H16O3 ; calc. 256.1099).
3-(4-Fluorophenyl)-3-hydroxy-1-phenylpropan-1-one (3). Yield: 239.2 mg (98%). Colorless oil. IR (neat):
3622, 3002, 2901, 1678, 1678. 1H-NMR (500 MHz, CDCl3): 3.33 (m, 2 H); 3.68 (d, J ˆ 3.0, OH); 5.32 (m, 1 H);
7.04 (m, 2 H); 7.40 (m, 2 H); 7.46 (m, 2 H); 7.59 (m, 1 H); 7.9 3 (m, 2 H). 13C-NMR (125 MHz, CDCl3): 47.3; 69.3;
‡
115.2; 115.4; 127.3; 127.4; 128.1; 128.7; 133.7; 136.4; 138.6; 161.1; 163.1; 200.0. CI-MS (CH4): 244 (M ). HR-MS:
‡
‡
244.0903 (M , C15H13FO2 ; calc. 244.0900).
1-(4-Fluorophenyl)-3-Hydroxy-3-phenylpropan-1-one (4). Yield: 239.3 mg (98%). Colorless oil. IR (neat):
3611, 2977, 2880, 1678, 1672. 1H-NMR (500 MHz, CDCl3): 3.32 (m, 2 H); 3.59( d, J ˆ 3.0, OH); 5.32 (m, 1 H);
7.10 (m, 2 H); 7.28 (m, 1 H); 7.35 (m, 2 H); 7.41 (m, 2 H); 7.9 5 (m, 2 H). 13C-NMR (125 MHz, CDCl3): 47.2; 69.9;
‡
115.6; 115.8; 125.6; 127.6; 128.5; 130.7; 130.8; 132.9; 142.8; 164.9; 166.9; 198.3. CI-MS (CH 4): 244 (M ). HR-MS:
‡
‡
244.0905 (M , C15H13FO2 ; calc. 244.0900).
3-Hydroxy-1-(4-methoxyphenyl)-3-phenylpropan-1-one (5). Yield: 245.7 mg (96%). Colorless oil. IR
(neat): 3609, 3483, 3064, 1678, 1598. 1H-NMR (500 MHz, CDCl3): 3.28 (m, 2 H); 3.82 (d, J ˆ 3.0); 3.83 (s, 3 H);
5.29( m, 1 H); 6.90 (m, 2 H); 7.27 (m, 1 H); 7.35 (m, 2 H); 7.42 (m, 2 H); 7.9 0 (m, 2 H). 13C-NMR (125 MHz,
‡
CDCl3): 46.8; 55.3; 70.0; 113.7; 125.6; 127.4; 128.4; 129.5; 130.4; 143.0; 163.8; 198.6. CI-MS (CH4): 256 (M ).
‡
‡
HR-MS: 256.1103 (M , C16H16O3 ; calc. 256.1099).
1-[1,1'-Biphenyl]-4-yl-3-hydroxy-3-phenylpropan-1-one (6). Yield: 296.0 mg (98%). Yellowish oil. IR
(neat): 3608, 2977, 1679, 1674, 1596, 1479. 1H-NMR (500 MHz, CDCl3): 3.39( m, 2 H); 3.63 (d, J ˆ 3.0, OH); 5.36
(m, 1 H); 7.30 (m, 1 H); 7.39 (m, 3 H); 7.46 (m, 4 H); 7.61 (m, 2 H); 7.67 (m, 2 H); 8.01 (m, 2 H). 13C-NMR
(125 MHz, CDCl3): 47.3; 70.1; 125.7; 127.23; 127.28; 127.6; 128.3; 128.5; 128.7; 128.9; 135.2; 139.6; 142.9; 146.2;
‡
‡
‡
199.7. CI-MS (CH4): 302 (M ). HR-MS: 302.1311 (M , C21H18O2 ; calc. 302.1307).
3-Hydroxy-1-phenylhex-4-en-1-one (7). Yield: 129.2 mg (68%). Colorless oil. IR (neat): 3437, 2919, 1714,
1445. 1H-NMR (500 MHz, CDCl3): 1.70 (m, 3 H); 3.17 (m, 2 H); 3.28 (d, J ˆ 3.0, OH); 4.70 (m, 1 H); 5.59( m,
1 H); 5.78 (m, 1 H); 7.46 (m, 2 H); 7.57 (m, 1 H); 7.9 4 (m, 2 H). 13C-NMR (125 MHz, CDCl3): 17.6; 45.1; 68.6;
‡
‡
‡
127.0; 128.0; 128.5; 132.0; 133.4; 136.6; 200.2. CI-MS (CH4): 190 (M ). HR-MS: 190.0990 (M , C12H14O2 ; calc.
190.0994).
1-Phenyl-3-hydroxypentan-1-one (8). Yield: 124.6 mg (70%). Colorless oil. IR (neat): 3435, 3011, 2889,
1
1713, 1443. H-NMR (500 MHz, CDCl3): 1.01 (t, J ˆ 7.5, 3 H); 1.60 (m, 2 H), 3.03 (dd, J ˆ 17.5, 9.5, 1 H); 3.17
(dd, J ˆ 18.0, 3.0, 1 H); 3.32 (d, J ˆ 3.0, OH); 4.14 (m, 1 H); 7.46 (m, 2 H); 7.57 (m, 1 H); 7.9 5 m( , 2 H).
‡
13C-NMR (125 MHz, CDCl3): 9.9; 29.3; 44.5; 69.0; 128.0; 128.5; 133.4; 136.7; 200.9. CI-MS (CH4): 178 (M ).
‡
‡
HR-MS: 178.0990 (M , C11H14O3 ; calc. 178.0994).
4-Hydroxy-4-phenybutan-2-one (9). Yield: 118.0 mg (72%). Colorless oil. IR (neat): 3424, 3061, 2961, 1712,
1604. 1H-NMR (500 MHz, CDCl3): 2.16 (s, 3 H); 2.77 (dd, J ˆ 17.5, 3.3, 1 H); 2.87 (dd, J ˆ 17.5, 9.0, 1 H); 3.47 (d,
J ˆ 3.1, 1 H); 5.12 (m, 1 H); 7.26 7.34 (m, 5 H). 13C-NMR (125 MHz, CDCl3): 30.7; 51.8; 125.4; 127.5; 128.5;
142.7; 209.0.
Methyl 3-Hydroxy-3-phenylpropanoate (10). Yield: 108.0 mg (60%). Colorless oil. IR (neat): 3450, 3061,
2953, 1732, 1604. 1H-NMR (500 MHz, CDCl3): 2.71 (dd, J ˆ 16.5, 4.1, 1 H); 2.77 (dd, J ˆ 16.5, 6.2, 1 H); 3.30 (d,
J ˆ 3.3, OH); 3.69( s, 3 H); 5.12 (m, 1 H); 7.20 7.40 (m, 5 H). 13C-NMR (125 MHz, CDCl3): 43.2; 52.1; 70.2;
‡
‡
125.6; 127.9; 128.6; 142.5; 172.9. HR-MS: 180.0788 ( M , C10H12O3 ; calc. 180.0786).
Ethyl 3-Hydroxy-3-phenylpropanoate (11). Yield: 126.1 mg (65%). Colorless oil. IR (neat): 3438, 3060,
1
2976, 1719, 1490. H-NMR (500 MHz, CDCl3): 1.27 (t, J ˆ 7.2, 3 H); 2.71 (dd, J ˆ 16.5, 2.6, 1 H); 2.77 (dd, J ˆ
16.5, 6.3, 1 H); 3.32 (d, J ˆ 3.3, OH); 4.19( q, J ˆ 7.2, 2 H); 5.15 (m, 1 H); 7.26 7.38 (m, 5 H). 13C-NMR
‡
‡
(125 MHz, CDCl3): 14.1; 43.4; 61.0; 70.4; 125.6; 127.9; 128.5; 142.4; 172.6. HR-MS: 194.0940 (M , C11H14O3
;
calc. 194.0943).
Phenyl 3-Hydroxy-3-phenylpropanoate (12). Yield: 174.0 mg (72%). Colorless oil. IR (neat): 3610, 3019,
1747, 1496. 1H-NMR (500 MHz, CDCl3): 2.87 3.08 (m, 2 H); 3.09( d, J ˆ 3.4, OH); 5.24 (m, 1 H); 7.06 (d, J ˆ
7.1, 2 H); 7.14 7.48 (m, 8 H). 13C-NMR (125 MHz, CDCl3): 174.2; 150.6; 141.5; 129.6; 128.4; 128.1; 126.4; 126.2;
121.4; 74.6; 47.

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Helvetica Chimica Acta Vol. 87 (2004)
We thank D. Pukiss for expert NMR support. Financial support was kindly provided by the Robert A. Welch
Foundation (Grant No. D-1478).
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Received May 17, 2004