A facile one-pot stereoselective synthesis of (Z)-α-Acyl- αβ-Unsaturated esters from alkynyl esters and aryl acyl chlorides

Article abstract of DOI:10.3184/174751912X13445848109899

(Z)-α-Acyl-αβ-Unsaturated esters can be stereoselectively synthesised in one pot under mild conditions and in good yields by the palladium-catalysed hydrostannylation of alkynyl esters in benzene, followed by the Stille crosscoupling with aryl acyl chlorides using CuI as co-catalyst.

Full text of DOI:10.3184/174751912X13445848109899

568 RESEARCH PAPER
OCTOBER, 568–570
JOURNAL OF CHEMICAL RESEARCH 2012
A facile one-pot stereoselective synthesis of (Z)-α-acyl-α,β-unsaturated
esters from alkynyl esters and aryl acyl chlorides
Jianwen Jiang, Haiyi Liu, Jiatao Zhang and Mingzhong Cai*
Department of Chemistry, Jiangxi Normal University, Nanchang 330022, P. R. China
(Z)-α-Acyl-α,β-unsaturated esters can be stereoselectively synthesised in one pot under mild conditions and in good
yields by the palladium-catalysed hydrostannylation of alkynyl esters in benzene, followed by the Stille cross-
coupling with aryl acyl chlorides using CuI as co-catalyst.
Keywords: (Z)-α-acyl-α,β-unsaturated ester, hydrostannylation, alkynyl ester, Stille coupling, tandem reaction
The synthesis of α,β-unsaturated esters has attracted consider-
able attention because they are important intermediates in
natural product synthesis.1–4 Their great synthetic value derives
from the fact that the positions α,β and γ to the ester groups can
be activated and functionalised by various means. A variety
of methods for the synthesis of α,β-unsaturated esters have
been developed. Of these methods, the Wittig reaction using
aldehydes and phosphorus ylides is one of the most powerful
and attractive methods and still occupies a prominent posi-
tion.5–10 Recently, the synthesis of α-functionalised α,β-unsatu-
rated esters has also received considerable attention. For
example, the synthesis of α-halo-α,β-unsaturated esters11–13 and
α-trifluoromethyl-α,β-unsaturatedesters14,15 hasbeendescribed.
α-Acyl-α,β-unsaturated esters are useful synthetic intermedi-
ates and have been widely used.16–19 One general approach
for the preparation of α-acyl-α,β-unsaturated esters is the
Knoevenagel condensation of aromatic aldehydes with β-keto
esters in the presence of a base or Lewis acid.20–22 However,
this methodology gives poor stereoselectivity and α-acyl-β-
alkyl-α,β-unsaturated esters cannot be prepared by this method.
Therefore, there is still a need for the development of selective
and better strategies for the synthesis of α-acyl-α,β-unsaturated
esters.
Tandem reactions have recently been of interest for organic
synthesis because they offer convenient and economical
methods with which to prepare target organic molecules.23–26
The palladium-catalysed hydrostannylation of alkynes and the
Stille coupling reaction are acknowledged as useful tools for
constructing complex organic molecules. Recently, we reported
the stereoselective synthesis of (Z)-α-arylsulfonyl-α,β-unsatu-
rated ketones by palladium-catalysed one-pot tandem hydro-
stannylation-Stille coupling reaction of tributyltin hydride with
acetylenic sulfones and acyl chlorides.27 However, to the best
of our knowledge, there have been no reports on palladium-
catalysed tandem hydrostannylation-Stille coupling reaction
of tributyltin hydride with alkynyl esters and acyl chlorides to
date. We report here that (Z)-α-acyl-α,β-unsaturated esters can
be stereoselectively synthesised in one pot under mild condi-
tions, in good yields, by the hydrostannylation of alkynyl
esters, followed by the Stille cross-coupling with aryl acyl
chlorides.
Palladium-catalysed hydrostannylation of alkynes provides
a simple, general route for the stereoselective synthesis of
vinylstannanes.28 Rossi et al.29 reported palladium-catalysed
hydrostannylation of alkynyl esters in THF. In order to prepare
highly selectively (E)-α-stannyl-α,β-unsaturated esters, we
investigated palladium-catalysed hydrostannylation of alkynyl
esters with Bu3SnH in benzene at room temperature and found
that benzene was better solvent than THF and (E)-α-stannyl-
α,β-unsaturated esters 2 were obtained with high regio- and
stereoselectivity in high yields (Scheme 1). The reaction did
not occur in toluene.
Investigations of the crude products 2 by 1H NMR spectros-
copy (400 MHz) showed isomeric purities of more than 98%.
One olefinic proton signal of compound 2a splits characteris-
tically into a triplet at δ = 6.04 with coupling constant J =
6.8 Hz, which indicated that the hydrostannylation to the
alkynyl esters had taken place with strong preference for
the addition of the tin atom at the carbon adjacent to the
ester group. The stereochemistry of the addition was readily
apparent from the 1H NMR spectra of compounds 2a–b which
showed a (3JSn-H) coupling constant of 64 Hz, fully in accord
with an E geometry and overall cis addition of tin hydride.30
(E)-α-Stannyl-α,β-unsaturated esters 2 are difunctional
group reagents in which two synthetically versatile groups are
linked to the same olefinic carbon atom and can be considered
both as vinylstannanes and as α,β-unsaturated esters. It is well
known that vinylstannanes can undergo palladium-catalysed
cross-coupling with organic halides.31,32 Considering the fact
that both the hydrostannylation and Stille reactions were cata-
lysed by palladium complexes, we tried to combine the two
reactions, in one pot, to synthesise (Z)-α-acyl-α,β-unsaturated
esters stereoselectively (Scheme 2).
Scheme 1
Scheme 2
* Correspondent. E-mail: caimzhong@163.com

JOURNAL OF CHEMICAL RESEARCH 2012 569
Synthesis of (E)-α-stannyl-α,β-unsaturated esters 2a–b; general
procedure
We found that, after the hydrostannylation reaction of
alkynyl esters 1 with Bu3SnH using 2 mol% Pd(PPh3)4 in
benzene at 25 °C for 4 h and aryl acyl chlorides 3 and 75 mol%
CuI were added and the mixture was stirred at 80 °C for 10 h,
(Z)-α-acyl-α,β-unsaturated esters 4 were obtained in good
yields. The experimental results are summarised in Table 1. It
was found that benzene was the best solvent among those
tested, such as toluene, DMF, and THF for the Stille coupling
of the intermediates 2 with aromatic acyl chlorides. As shown
in Table 1, the hydrostannylation-Stille tandem reaction of
Bu3SnH with a variety of alkynyl esters and aromatic acyl
chlorides proceeded smoothly under mild conditions to afford
stereoselectively the corresponding (Z)-α-acyl-α,β-unsaturated
esters 4. Various electron-donating and electron-withdrawing
substituents such as methoxy, chloro, and nitro groups on
aromatic acyl chlorides were well tolerated. However, the
reactivity of 4-methoxybenzoyl chloride with its strong
electron-donating group was lower than that of other aryl acyl
chlorides. To broaden the scope of this methodology, we tried
to use aliphatic acyl chlorides as substrates. However, the Stille
coupling reaction of the intermediates 2 with aliphatic acyl
chlorides did not occur under the same conditions.
A 25 mL, two-necked, round-bottom flask equipped with a magnetic
stirrer bar and with an argon atmosphere was charged sequentially
with alkynyl ester (1 mmol), benzene (4 mL), Pd(PPh3)4 (0.02 mmol)
and Bu3SnH (1.05 mmol). The mixture was stirred at room tempera-
ture for 4 h. After removal of the solvent under reduced pressure, the
residue was diluted with light petroleum ether (20 mL) and filtered to
remove the palladium catalyst. The resulting solution was concen-
trated under reduced pressure and the residue was purified by flash
chromatography on silica gel (eluent: light petroleum ether/EtOAc,
19:1).
2a: Oil. IR (film): ν (cm−1) 2958, 2929, 1709, 1603, 1464, 1182,
1
3
1038; H NMR (400 MHz, CDCl3): δ 6.04 (t, J = 6.8 Hz, JSn-H
=
64 Hz, 1H), 4.14 (q, J = 7.2 Hz, 2H), 2.44–2.40 (m, 2H), 1.58–1.26
(m, 19H), 0.95–0.84 (m, 18H); 13C NMR (100 MHz, CDCl3): δ 171.3,
153.6, 135.6, 59.9, 31.8, 31.4, 29.9, 27.3, 22.3, 14.4, 13.9, 13.7, 10.3;
MS (EI): m/z (%) 446 (M+, 2.3), 389 (69), 387 (48), 205 (50), 105
(100), 73 (75). Anal. Calcd for C21H42O2Sn: C, 56.64; H, 9.50. Found:
C, 56.34; H, 9.25%.
2b: Oil. IR (film): ν (cm−1) 3059, 2958, 2923, 1700, 1596, 1463,
1183, 1034, 788, 695; 1H NMR (400 MHz, CDCl3): δ 7.32–7.29 (m,
5H), 6.70 (s, 3JSn-H = 64 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 1.58–1.52
(m, 6H), 1.37–1.32 (m, 6H), 1.22 (t, J = 7.2 Hz, 3H), 1.07 (t, J =
8.0 Hz, 6H), 0.91 (t, J = 7.2 Hz, 9H); 13C NMR (100 MHz, CDCl3):
δ 173.2, 142.1, 139.8, 137.0, 128.3, 128.1, 128.0, 60.3, 28.9, 27.3,
14.2, 13.7, 10.6; MS (EI): m/z (%) 466 (M+, 1.5), 409 (100), 407 (87),
179 (54), 177 (46). Anal. Calcd for C23H38O2Sn: C, 59.37; H, 8.23.
Found: C, 59.57; H, 8.35%.
It is well documented that the Stille cross-coupling reaction
of vinylstannanes with organic halides in the presence of a
palladium catalyst occurs with retention of configuration.31,32
In addition, the (Z)-configuration of the compound 4d was
1
confirmed by the NOESY in the H NMR spectrum. An
enhancement of the allylic protons was observed as the vinylic
proton (δ = 6.34) of 4d was irradiated. There was a correlation
between the vinylic proton (δ = 6.34) and aromatic protons
(δ = 7.48). Correlation between the allylic protons and aro-
matic protons (δ = 7.48) was not observed. The NOE results
indicate that the compound 4d has the expected (Z)-configura-
tion and the palladium-catalysed cross-coupling reaction of
(E)-α-stannyl-α,β-unsaturated esters 2 with aryl acyl chlorides
occurs with the retention of the configuration of the starting
intermediates 2.
In summary, we have developed an efficient and stereose-
lective one-pot method for the synthesis of (Z)-α-acyl-α,β-
unsaturated esters by the hydrostannylation–Stille coupling
tandem reaction of alkynyl esters with aryl acyl chlorides.
The present method has the advantages of readily available
starting materials, straightforward and simple procedures, mild
reaction conditions, high stereoselectivity and good yields.
Synthesis of (Z)-α-acyl-α,β-unsaturated esters 4a–h; general
procedure
A 25 mL, two-necked, round-bottom flask equipped with a magnetic
stirrer bar and with an argon atmosphere was charged sequentially
with alkynyl ester (1.0 mmol), benzene (4 mL), Pd(PPh3)4 (0.02 mmol)
and Bu3SnH (1.05 mmol). The mixture was stirred at room tempera-
ture for 4 h, then acyl chloride (1.1 mmol) and CuI (0.75 mmol) were
added and the mixture was stirred for 10 h at 80 °C and monitored by
TLC (SiO2) for the disappearance of the intermediate 2. The reaction
mixture was diluted with diethyl ether (30 mL), filtered and then
treated with 20% aqueous KF (10 mL) for 30 min before being dried
and concentrated. The residue was purified by column chromatogra-
phy on silica gel (eluent: light petroleum ether/diethyl ether, 12:1).
4a: Oil. IR (film): ν (cm−1) 2959, 2931, 2873, 1723, 1676, 1642,
1
1598, 1449, 1366, 1232, 1070, 717, 690; H NMR (CDCl3): δ 7.89
(d, J = 7.6 Hz, 2H), 7.60–7.41 (m, 3H), 7.18 (t, J = 8.0 Hz, 1H), 4.16
(q, J = 7.2 Hz, 2H), 2.15–2.09 (m, 2H), 1.45–1.36 (m, 2H), 1.33–1.24
(m, 2H), 1.13 (t, J = 7.2 Hz, 3H), 0.82 (t, J = 7.2 Hz, 3H); 13C NMR
(CDCl3): δ 194.5, 164.6, 148.6, 136.9, 135.2, 133.7, 129.1, 128.9,
61.1, 30.5, 29.4, 22.3, 14.2, 13.7; Anal. Calcd for C16H20O3: C, 73.82;
H, 7.74. Found: C, 73.56; H, 7.51%.
Experimental
1H NMR spectra were recorded on a Bruker Avance (400 MHz) spec-
trometer with TMS as an internal standard using CDCl3 as the solvent.
13C NMR (100 MHz) spectra were recorded on a Bruker Avance
(400 MHz) spectrometer using CDCl3 as the solvent. IR spectra were
determined on an FTS-185 instrument as neat films. Mass spectra
were obtained on a Finnigan 8239 mass spectrometer. Microanalyses
were measured using a Yanaco MT-3 CHN microelemental analyser.
All reactions were carried out in pre-dried glassware (150 °C, 4 h) and
cooled under a stream of dry Ar. Benzene was distilled from sodium
prior to use.
4b: Oil. IR (film): ν (cm−1) 3256, 2929, 2859, 1720, 1665, 1587,
1496, 1231, 1092, 848, 733; 1H NMR (CDCl3): δ 7.87 (d, J = 8.8 Hz,
2H), 7.13 (t, J = 8.0 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H), 4.16 (q, J =
7.2 Hz, 2H), 3.88 (s, 3H), 2.12–2.07 (m, 2H), 1.45–1.37 (m, 2H),
1.32–1.23 (m, 2H), 1.16 (t, J = 7.2 Hz, 3H), 0.82 (t, J = 7.2 Hz, 3H);
13C NMR (CDCl3): δ 193.1, 164.7, 163.5, 134.9, 133.8, 131.6, 131.5,
130.0, 61.1, 60.9, 30.5, 29.3, 22.3, 14.0, 13.8. Anal. Calcd for
C17H22O4: C, 70.32; H, 7.64. Found: C, 70.44; H, 7.45%.
4c: Oil. IR (film): ν (cm−1) 2957, 2929, 2874, 1726, 1677, 1587,
1
1465, 1400, 1231, 1092, 848, 731; H NMR (CDCl3): δ 7.83 (d,
J = 7.6 Hz, 2H), 7.45 (d, J = 7.6 Hz, 2H), 7.18 (t, J = 8.0 Hz, 1H), 4.16
(q, J = 7.2 Hz, 2H), 2.13–2.08 (m, 2H), 1.44–1.38 (m, 2H), 1.32–1.23
(m, 2H), 1.15 (t, J = 7.2 Hz, 3H), 0.83 (t, J = 7.2 Hz, 3H); 13C NMR
(CDCl3): δ 193.3, 164.4, 149.2, 140.2, 135.2, 133.3, 130.5, 129.1,
61.2, 30.5, 29.7, 22.3, 14.1, 13.9. Anal. Calcd for C16H19O3Cl: C,
65.18; H, 6.50. Found: C, 64.89; H, 6.33%.
Table 1 Synthesis of (Z)-α-acyl-α,β-unsaturated esters 4
Entry
R
Ar
Product
Yield/%a
1
2
3
4
5
6
7
8
n-C4H9
n-C4H9
n-C4H9
n-C4H9
Ph
Ph
4a
4b
4c
4d
4e
4f
79
65
82
86
84
70
84
88
4d: Oil. IR (film): ν (cm−1) 2959, 2930, 2876, 1720, 1596, 1520,
4-MeOC6H4
4-ClC6H4
4-O2NC6H4
Ph
1
1465, 1346, 1199, 1109, 855, 697; H NMR (CDCl3): δ 8.18 (d,
J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 6.34 (t, J = 7.6 Hz, 1H), 4.31
(q, J = 7.2 Hz, 2H), 2.55–2.49 (m, 2H), 1.54–1.48 (m, 2H), 1.43–1.37
(m, 2H), 1.31 (t, J = 7.2 Hz, 3H), 0.94 (t, J = 7.2 Hz, 3H); 13C NMR
(CDCl3): δ 194.6, 167.0, 147.0, 144.7, 144.4, 133.0, 128.1, 123.5,
61.1, 30.2, 29.9, 22.5, 14.3, 14.0.Anal. Calcd for C16H19O5N: C, 62.94;
H, 6.27. Found: C, 62.67; H, 6.05%.
Ph
4-MeOC6H4
4-ClC6H4
4-O2NC6H4
Ph
Ph
4g
4h
a Isolated yield based on the alkynyl esters 1 used.

570 JOURNAL OF CHEMICAL RESEARCH 2012
4e: Oil. IR (film): ν (cm−1) 2982, 1720, 1673, 1622, 1597, 1581,
1449, 1367, 1254, 1231, 1198, 1093, 734, 689; H NMR (CDCl3):
References
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2
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7
4f: Oil. IR (film): ν (cm−1) 2980, 2928, 1718, 1663, 1598, 1574,
1509, 1449, 1367, 1246, 1167, 1025; 1H NMR (CDCl3): δ 7.93–7.88
(m, 3H), 7.39–7.14 (m, 5H), 6.89 (d, J = 8.8 Hz, 2H), 4.24 (q, J =
7.2 Hz, 2H), 3.83 (s, 3H), 1.16 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3):
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129.4, 128.9, 61.5, 57.9, 14.1. Anal. Calcd for C19H18O4: C, 73.53; H,
5.85. Found: C, 73.26; H, 5.61%.
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4g: Oil. IR (film): ν (cm−1) 2956, 2927, 2873, 1720, 1674, 1586,
1464, 1406, 1197, 1091, 847, 730; 1H NMR (CDCl3): δ 7.96 (s, 1H),
7.88 (d, J = 8.8 Hz, 2H), 7.43–7.18 (m, 7H), 4.24 (q, J = 7.2 Hz, 2H),
1.19 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3): δ 194.4 164.8, 142.9,
140.4, 134.5, 132.7, 130.8, 130.5, 130.4, 130.2, 129.3, 129.1, 61.7,
14.0. Anal. Calcd for C18H15O3Cl: C, 68.67; H, 4.80. Found: C, 68.41;
H, 4.57%.
4h: Oil. IR (film): ν (cm−1) 2982, 2934, 2874, 1719, 1594, 1518,
1344, 1217, 1183, 851, 756; 1H NMR (CDCl3): δ 8.23–8.20 (m, 2H),
7.65–7.62 (m, 2H), 7.42–7.33 (m, 5H), 7.18 (s, 1H), 4.28 (q, J =
7.2 Hz, 2H), 1.20 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3): δ 194.8,
168.6, 147.4, 143.3, 134.9, 133.2, 128.6, 128.5, 128.4, 127.4, 127.2,
124.0, 61.8, 13.8. Anal. Calcd for C18H15O5N: C, 66.46; H, 4.65.
Found: C, 66.57; H, 4.43%.
We thank the National Natural Science Foundation of China
(Project No. 20862008) and the Natural Science Foundation
of Jiangxi Province of China (2010GZH0062) for financial
support.
Received 8 July 2012; accepted 17 July 2012
Paper 1201396 doi: 10.3184/174751912X13445848109899
Published online: 28 September 2012
31 J.K. Stille, Angew. Chem. Int. Ed., 1986, 25, 508.
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