Synthesis of substituted α-(hydroxymethyl)-β-iodoacrylates via MgI2-promoted stereoselective aldol coupling

Article abstract of DOI:10.1002/hlca.200490212

The efficient and highly stereoselective syntheses of a variety of (Z)-configured, substituted α-(hydroxymethyl)-β-iodo-acrylates from prop-2-ynoate and various aldehydes was achieved. The synthetic protocol involves a simple one-pot coupling reaction und

Full text of DOI:10.1002/hlca.200490212

Helvetica Chimica Acta Vol. 87 (2004)
2359
Synthesis of Substituted a-(Hydroxymethyl)-b-iodoacrylates via
MgI2-Promoted Stereoselective Aldol Coupling
by Han-Xun Wei*1), Jiali Hu, Richard L. Jasoni, Guigen Li, and Paul W. Pare¬*
Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409, U.S.A.
(e-mail: hweij@hotmail.com)
The efficient and highly stereoselective syntheses of
a variety of (Z)-configured, substituted a-
(hydroxymethyl)-b-iodo-acrylates from prop-2-ynoate and various aldehydes was achieved. The synthetic
protocol involves a simple one-pot coupling reaction under mild conditions, promoted by MgI2, which serves
both as a Lewis acid and iodine source for a BaylisÀHillman-type reaction. All adducts were generated in good-
to-excellent yields, the (Z)-isomers being formed in high selectivity (> 98%). The conversion of methyl prop-2-
ynoate into an active −b-iodo allenolate× intermediate, which then nucleophilically attacks an aldehyde, is
proposed as a plausible reaction mechanism.
Introduction. BaylisÀHillman (BH)-type couplings belong to the most-important
C,C-bond-forming processes in organic synthesis [1 3]. Highly functionalized BH
adducts can be subjected to transformations for the synthesis of natural products and
synthetic derivatives [4].
Recently, we have developed several methodologies [5] for the synthesis of
substituted −a-(hydroxymethyl)-b-iodoacrylates× (ˆ(Z)-2-(hydroxymethyl)-3-iodo-
prop-2-enoates; A) and substituted −a-(hydroxymethyl)-b-iodovinyl ketones× (ˆ2-
(hydroxymethyl)-3-iodoprop-2-enyl alkyl ketones; B), as shown in Scheme 1. These
methods allowed us to react b-substituted acrylate olefins, which, in the original BH
reaction, could not be used as substrates [1a][6][7]. Moreover, Et2AlI (Scheme 1,a) is
a moisture-sensitive reagent difficult to handle, and the route via the intermediary
cumulene C (Scheme 1,b) suffers from long reaction times, in contrast to the synthesis
of ketones of type B, which proceeds both rapidly and efficiently.
Because esters of type A are more-useful than the corresponding ketones B, we
focused our efforts on extending the scope of our modified BH reaction by means of
MgI2 catalysis.
Results and Discussion. In our initial synthetic protocol, Et2AlI had been used as
the promoter [5d]. When methyl prop-2-ynoate (1.3 mmol) and benzaldehyde
(1.0 mmol) were dissolved at 08 in CH2Cl2 in the presence of MgI2 (1.2 mmol), only
low rates of conversion were observed (after 1 h and 24 h, 50 and 60% consumption,
respectively, of the aldehyde). At ambient temperature (258), the reaction did not
proceed faster (55% consumption after 24 h), which called for further modifications.
Screening different solvents to improve the yield of the reaction also met with limited
1
)
Present address: Department of Chemical Process and Development, Boehringer Ingelheim Pharmaceu-
ticals, Inc., 800 East Leigh Street, Suite 205, Richmond, VA 23219, U.S.A.
¹ 2004 Verlag Helvetica Chimica Acta AG, Z¸rich

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Helvetica Chimica Acta Vol. 87 (2004)
Scheme 1
success. However, after several experiments, we determined that the order in which the
starting materials had to be introduced was a critical parameter. We found that the
aldehyde and MgI2 had to be mixed in CH2Cl2 at room temperature for 20 min before
addition of the propargylic ester. Under these conditions, the reaction between, e.g.,
benzaldehyde and methyl prop-2-ynoate was complete within 1 h, and the desired
product 1 was obtained in 90% yield with a (Z)/(E) ratio of ca. 9 8 :2 (Table).
In general, good-to-excellent yields (82 91%) were achieved for compounds 1 10,
derived from a variety of aldehydes, and the (Z)/(E) ratio was, in all cases, at least 98 :2.
A somewhat lower yield (60% after 1 h, but 78% after 24 h; Entry 11 in the Table) was
observed in the case of the less-reactive acetophenone.
CH2Cl2 provided the best results in terms of both yield (90%) and (Z)/(E) ratio
(> 98 :2), when benzaldehyde was used as the electrophile. Et2O, benzene, and toluene
gave considerably poorer results in this respect (40, 50, and 45% yield, resp.) after a 1-h
reaction time. However, all these solvents gave rise to (Z)/(E) selectivities above 98 :2.
Interestingly, attempts to run the reaction in THF completely failed.
Both aromatic and aliphatic aldehydes were found to be suitable electrophiles for
this new catalytic system, and high yields were realized in all experiments conducted
(Table). For aromatic aldehydes, substitution by electron-withdrawing (Entries 2 4)
or an electron-donating groups (Entries 5 and 6) on the aromatic ring had no obvious
effect on the reaction in terms of yield and selectivity. In contrast, with the Et2AlI-based
system [5d], the reaction with, e.g., 4-methoxybenzaldehyde, required much longer to
go to completion under standard conditions.
With regard to aliphatic aldehydes (Entries 7 10), our new reaction protocol was
also more effective at generating the desired product than that of the Et2AlI-based
system. For example, the reaction between valeraldehyde (Entry 9) and methylprop-2-

Helvetica Chimica Acta Vol. 87 (2004)
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Table. MgI2-Mediated Synthesis of the BaylisÀHillman b-Iodo Adducts 1 11
a
b
Entry
R
Product
(Z)-Isomer [%]
)
Yield [%]
)
1
2
3
4
5
6
7
8
9
Ph
1
2
3
4
5
6
7
8
9
> 9
> 9
> 9
> 9
> 9
> 9
> 9
> 9
> 9
> 9
> 9
8
8
8
8
8
8
8
8
8
8
8
9
9
9
4-F-C6H4
4-Cl-C6H4
Naphthalen-2-yl
4-MeO-C6H4
4-Me-C6H4
PhCH2
87
88
9
86
84
85
82
60
Prop-1-en-1-yl
Bu
10
11
t-Bu
10
11
c
d
)
)
a) Determined by 1H-NMR analysis of the crude mixture. b) After column-chromatographic purification of the
1-h reaction mixture. c) Acetophenone (PhC(O)Me) was used as the substrate instead of an aldehyde, giving
rise to a tertiary OH group in 11 (C-methylated analog of 1). d) After 24 h, 78% of 11 were isolated.
ynoate afforded 85% vs. 58% of 9, with (Z)/(E) selectivities of > 98% vs. 60%,
respectively, for the MgI2- vs. Et2AlI-catalyzed systems. These results may be due, in
part, to MgI2 being a weaker Lewis acid than Et2AlI, which reduces side reactions. The
lower reactivity of MgI2 also rationalizes the observation that this new system is
somewhat less-efficient when ketones, e.g., acetophenone (Entry 11), rather than
aldehydes are used as electrophiles.
1
(Z)/(E) Ratios were determined by H-NMR spectroscopic analyses of the crude
product mixtures. In all cases, the a-H-atom signals for the (Z)- and (E)-isomers were
clearly distinguishable, the former being shifted upfield relative to the (E)-isomer. The
isomers could be readily separated by flash chromatography, and the geometries were
confirmed by ROESY-NMR experiments in the case of (E)- and (Z)-1. Thereby, for
(Z)-1, irradiation of the vinyl H-atom resulted in an enhancement of the HOÀCH2
resonance, whereas the (E)-isomer gave rise to an enhancement of the MeO signal.
The mechanism of this new process, as represented in Scheme 2, can be formulated
as discussed in [5c]. By means of a cyclic transition-state model, Kishi and co-workers
[8] suggested that the (Z)- and (E)-stereoisomers correspond to the kinetically and
thermodynamically controlled products, respectively. However, in the system reported
here, the (Z)-isomer was strongly favored at different temperatures, suggesting that
kinetic control plays a significant role in determining the geometric selectivity even at
ambient temperature. Our results, thus, are contrary to those previously reported for
TiCl4-mediated reactions carried out at room temperature, in which the thermody-
namically controlled (E)-isomers had been obtained predominantly [9].

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Helvetica Chimica Acta Vol. 87 (2004)
Scheme 2
In summary, we have developed a simple and efficient synthesis of substituted a-
(hydroxymethyl)-b-iodoacrylates. Our new protocol functions under mild conditions
and uses, instead of the moisture-sensitive Et2AlI, MgI2 both as an IÀ source and a
Lewis acid catalyst. All examples presented here gave better yields and higher
stereoselectivities than obtained with our previously reported method [5c][5d].
Experimental Part
General. CH2Cl2 was freshly distilled from CaH under N2 atmosphere. All chemicals used 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 constants 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 moisture-free standard-glass test tube (150 Â 22 mm),
equipped with a magnetic stirring bar, was flushed with N2 at r.t., and loaded with MgI2 (340 mg, 1.2 mmol),
benzaldehyde (0.1 ml, 1.0 mmol), and anh. CH2Cl2 (8.0 ml). The mixture was stirred at r.t. for 20 min. Then,
methyl prop-2-ynoate (0.12 ml, 1.3 mmol) was added dropwise via syringe, and the mixture was stirred at r.t. for
1 h. Then, the reaction was quenched by dropwise addition of 2n aq. HCl soln. The two phases were separated,
and the aq. layer was extracted with AcOEt (3 Â 15 ml). The combined org. phases were washed with brine,
dried (MgSO4), and concentrated. The remaining residue was purified by FC (hexane/AcOEt 5 :1) to give the
pure condensation product (1).
Methyl (Z)-2-[Hydroxy(phenyl)methyl]-3-iodoprop-2-enoate (1). Colorless oil. IR (neat): 3443, 3063,
2950, 1714. 1H-NMR (300 MHz, CDCl3): 2.91 (d, J ˆ 5.5, 1 H); 3.72 (s, 3 H); 5.54 (dd, J ˆ 5.5, 1.5, 1 H); 7.27 (d,
J ˆ 1.5, 1 H); 7.30 7.36 (m, 5 H). 13C-NMR (75 MHz, CDCl3): 51.9; 76.0; 87.1; 126.5; 128.3; 218.6; 140.0; 145.1;
‡
‡
‡
166.3. CI-MS (CH4): 318.1 (M ). HR-MS: 317.9756 (M , C11H11IO3 ; calc. 317.9753).
Methyl (Z)-2-[(4-Fluorophenyl)(hydroxy)methyl]-3-iodoprop-2-enoate (2). Colorless oil. IR (neat): 3499,
1
3071, 2952, 1731. H-NMR (300 MHz, CDCl3): 2.93 (d, J ˆ 6.0, 1 H); 3.72 (s, 3 H); 5.52 (dd, J ˆ 6.0, 1.5, 1 H);
7.00 7.06 (m, 2 H); 7.28 7.32 (m, 2 H). 13C-NMR (75 MHz, CDCl3): 51.9; 73.9; 87.1; 115.4; 115.7; 128.4; 135.8;
‡
‡
144.9; 160.8; 164.1; 166.2. HR-MS: 335.9655 ( M , C11H10FIO3 ; calc. 335.9659).
Methyl (Z)-2-[(4-Chlorophenyl)(hydroxy)methyl]-3-iodoprop-2-enoate (3). Colorless oil. IR (neat): 3453,
1
3068, 2958, 2359, 1720. H-NMR (300 MHz, CDCl3): 3.23 (d, J ˆ 6.0, 1 H); 3.72 (s, 3 H); 5.48 (dd, J ˆ 6.0, 1.4,

Helvetica Chimica Acta Vol. 87 (2004)
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1 H); 7.22 7.32 (m, 4 H). 13C-NMR (75 MHz, CDCl3): 51.9; 75.4; 87.7; 127.8; 128.8; 134.1; 138.5; 144.6; 166.1.
‡
‡
HR-MS: 351.9368 (M , C11H10ClO3 ; calc. 351.9363).
Methyl (Z)-2-[Hydroxy(naphthalen-2-yl)methyl]-3-iodoprop-2-enoate (4). Colorless oil. IR (neat): 3447,
1
3055, 2949, 1715. H-NMR (300 MHz, CDCl3): 3.04 (d, J ˆ 6.0, 1 H); 3.70 (s, 3 H); 5.69( dd, J ˆ 6.0, 1.5, 1 H);
7.29( s, 1 H); 7.47 7.50 (m, 3 H); 7.80 7.84 (m, 4 H). 13C-NMR (75 MHz, CDCl3): 51.9; 76.1; 87.5; 124.2; 125.6;
‡
‡
126.3; 127.6; 128.1; 128.5; 133.1; 137.3; 145.0; 166.3. HR-MS: 367.9903 (M , C15H13IO3 ; calc. 367.9909).
Methyl (Z)-2-[Hydroxy(4-methoxyphenyl)methyl]-3-iodoprop-2-enoate (5). Colorless oil. IR (neat): 3448,
3001, 2950, 2835, 1718. 1H-NMR (300 MHz, CDCl3): 3.06 (d, J ˆ 6.0, 1 H); 3.69( s, 3 H); 3.77 (s, 3 H); 5.45 (dd,
J ˆ 6.0, 1.5, 1 H); 6.83 6.86 (d, J ˆ 6.0, 2 H); 7.19 7.22 ( m, 3 H). 13C-NMR (75 MHz, CDCl3): 51.9; 55.2; 75.6;
‡
‡
86.4; 114.0; 127.9; 132.1; 145.4; 159.5; 166.4. HR-MS: 347.9862 (M , C12H13IO4 ; calc. 347.9859).
Methyl (Z)-2-[Hydroxy(4-methylphenyl)methyl]-3-iodoprop-2-enoate (6). Colorless oil. IR (neat): 3450,
3024, 2949, 1713. 1H-NMR (300 MHz, CDCl3): 2.32 (s, 3 H); 3.07 (d, J ˆ 6.0, 1 H); 3.68 (s, 3 H); 5.46 (dd, J ˆ 6.0,
1.5, 1 H); 7.11 7.20 (m, 4 H). 13C-NMR (75 MHz, CDCl3): 21.1; 51.8; 75.8; 86.7; 126.4; 129.3; 137.0; 138.1; 145.2;
‡
‡
166.3. HR-MS: 331.9912 (M , C12H13IO3 ; calc. 331.9909).
Methyl (Z)-3-Hydroxy-2-(iodomethylidene)-4-phenylbutanoate (7). Colorless oil. IR (neat): 3477, 3102,
1
2899, 1716. H-NMR (500 MHz, CDCl3): 2.42 (d, J ˆ 5.5, 1 H); 2.79( dd, J ˆ 13.5, 8.0, 1 H); 3.01 (dd, J ˆ 13.5,
4.5, 1 H); 3.84 (s, 3 H); 4.63 (m, 1 H); 7.10 (d, J ˆ 1.0, 1 H); 7.19 7.32 ( m, 5 H). 13C-NMR (125 MHz, CDCl3):
‡
‡
42.9; 51.9; 75.3; 85.7; 126.8; 128.5; 129.4; 129.4; 136.8; 166.4. HR-MS: 331.9905 (M , C12H13IO3 ; calc. 331.9909).
Methyl (2Z,4E)-3-Hydroxy-2-(iodomethylidene)hex-4-enoate (8). Colorless oil. 1H-NMR (500 MHz,
CDCl3): 1.71 (m, 3 H); 2.65 (d, J ˆ 5.5, 1 H); 3.83 (s, 3 H); 4.89( m, 1 H); 5.51 (m, 1 H); 5.77 (m, 1 H); 7.20
‡
(d, J ˆ 1.0). 13C-NMR (125 MHz, CDCl3): 17.7; 51.9; 74.7; 85.6; 129.5; 129.7; 145.4; 166.5. HR-MS: 281.9758 (M ,
‡
C8H11IO3 ; calc. 281.9753).
Methyl (Z)-3-Hydroxy-2-(iodomethylidene)heptanoate (9). Colorless oil. 1H-NMR (500 MHz, CDCl3):
0.90 (t, J ˆ 7.0, 3 H); 1.26 1.40 (m, 4 H); 1.60 (m, 2 H); 2.62 (d, J ˆ 6.0, 1 H); 3.84 (s, 3 H); 4.39( m, 1 H); 7.12 (d,
J ˆ 1.0, 1 H). 13C-NMR (125 MHz, CDCl3): 13.8; 22.3; 27.5; 35.7; 51.9; 74.8; 84.4; 146.9; 166.9. HR-MS: 298.0069
‡
‡
(M , C9H15IO3 ; calc. 298.0066).
Methyl (Z)-3-Hydroxy-2-(iodomethylidene)-4,4-dimethylpentanoate (10). Colorless oil. IR (neat): 3401,
3009, 1716, 1614. 1H-NMR (500 MHz, CDCl3): 0.89( s, 9H); 2.68 ( d, J ˆ 6.1, 1 H); 3.82 (s, 3 H); 4.25 (dd, J ˆ 6.1,
1.4, 1 H); 7.07 (s, 1 H). 13C-NMR (125 MHz, CDCl3): 25.5; 36.0; 52.0; 82.5; 85.6; 145.5; 167.9. HR-MS:
‡
‡
298.0061(M , C9H15IO3 ; calc. 298.0066).
We thank D. Purkiss for expert NMR support. Financial support was kindly provided, in part, by a Robert
A. Welch Foundation research grant (D-1478 and D-1361).
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ReceivedMay 17, 2004