Bioinspired Metal-Catalysed Doebner–Knoevenagel Condensations
CDCl3): δ = 190.9 (C-3), 170.9 (C-1), 136.5, 129.0, 128.9, 127.7,
FULL PAPER
16.0 Hz, 1 H, 3-H), 7.30–7.07 (m, Ph), 6.01 (dt, JH,H = 15.5,
1.5 Hz, 1 H, 2-H), 4.09 (s, 2 H, 1Ј-H), 3.75 (dd, 3JH,H = 6.5, 1.5 Hz,
2 H, 4-H) ppm. 13C NMR (125 MHz, CDCl3): δ = 189.0 (C-1),
149.0, 141.5 (C-3), 137.6, 133.6, 132.4 (C-2), 129.9, 128.9, 128.7,
128.3, 127.4, 125.3, 35.7 (C-4), 33.2 (C-1Ј) ppm. MS (ESI, MeOH):
m/z: 336 [M + Na]+.
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48.6 (C-2), 34.1 (C-4) ppm. IR: ν = 3453 (OH), 1726 (CO), 1687
˜
(CO), 1496, 1454 cm–1. MS (ESI, MeOH): m/z: 209 [M – H]–.
S-Benzyl Methylmalonic Acid Half Thioester 2Ј: Colourless oil;
1
purified by flash chromatography; 1.79 g or 64% isolated yield. H
NMR (500 MHz, CDCl3): δ = 11.05 (brs, OH), 7.25–7.40 (m, 5 H,
Ph), 4.23 (m, 2 H, H-4), 3.75 (q, 1 H, J = 7.3 Hz, H-2), 1.52 (d, 3
H, J = 7.3 Hz, H-5) ppm. 13C NMR (125 MHz, CDCl3): δ = 195.1
(C-3), 174.8 (C-1), 136.6, 128.8, 128.7, 127.5, 53.5 (C-2), 33.7 (C-
4), 14.1 (C-5) ppm. MS (ESI, MeOH): m/z: 223 [M – H]–.
β,γ-Unsaturated Thioester: 1H NMR (500 MHz, CDCl3): δ = 7.86
3
(brd, JH,H = 8.0 Hz, 1 H), 7.60–7.40 (m, Ph), 7.30–7.07 (m, Ph),
3
3
6.96 (d, JH,H = 15.0 Hz, 1 H, 4-H), 6.21 (dt, JH,H = 15, 7.5 Hz,
3
1 H, 3-H), 4.08 (s, 2 H, 1Ј-H), 3.47 (dd, JH,H = 7.5, 1.5 Hz, 2 H,
2-H) ppm. 13C NMR (125 MHz, CDCl3): δ = 196.3 (C-1), 147.7,
137.3, 133.3, 130.2 (C-4), 129.0, 128.8, 128.4, 127.5, 126.5, 124.7
(C-3), 47.5 (C-2), 33.6 (C-1Ј) ppm. MS (ESI, MeOH): m/z: 336 [M
+ Na]+.
Procedure for the Catalytic Aldol Reactions between MAHTs and
Phenylacetaldehyde (1): 5-Methoxybenzimidazole (0.057 mmol,
0.22 equiv.) and Cu(2-ethylhexanoate)2 (0.052 mmol, 0.20 equiv.)
were added at 25 °C to a stirred solution of S-benzyl malonic acid
half thioester 2 (55 mg, 0.26 mmol) in THF (5 mL). Phenylacetal-
dehyde (1, 0.26 mmol, 1 equiv.) was added after homogenisation of
the solution (≈ 2 min), which was then stirred for 16 h at 25 °C and
quenched with an aqueous solution of HCl (0.5 , 10 mL). The
resulting mixture was diluted with EtOAc and washed successively
with aq. HCl (0.5 ), saturated aq. NaHCO3 and brine. The or-
ganic layer was dried with MgSO4, filtered and concentrated under
reduced pressure. The product was purified by flash column
chromatography on silica gel (from n-hex to EtOAc) to afford pure
compound 3.
S-Benzyl
(E)-4-(2,6,6-Trimethylcyclohex-1-enyl)but-3-enethioate
(Table 2, Entry 3): Colourless oil; purified by flash chromatog-
1
raphy; 67 mg or 82% isolated yield. H NMR (200 MHz, CDCl3):
3
δ = 7.09–7.28 (m, 5 H, Ph), 5.98 (d, JH,H = 15.4 Hz, 1 H, 4-H),
3
5.40 (dt, JH,H = 15.4 7.2 Hz, 1 H, 3-H), 4.21 (s, 2 H, 1Ј-H), 3.28
(d, 3JH,H = 7.2 Hz, 2 H, 2-H), 1.90 (m, 2 H, H-3ЈЈ), 1.65–1.28 (m, 7
H, 4ЈЈ,5ЈЈ,9ЈЈ-H), 0.91 (s, 6 H, 7ЈЈ,8ЈЈ-H) ppm. 13C NMR (50 MHz,
CDCl3): δ = 197.6 (C-1), 137.9, 137.0 (C-1ЈЈ), 134.0 (C-4), 129.5
(C-2ЈЈ), 128.9, 128.7, 127.3, 124.5 (C-3), 48.1 (C-2), 39.5 (C-5ЈЈ),
34.2 (C-6ЈЈ), 33.4 (C-1Ј), 32.8 (C-3ЈЈ), 28.8 (C-7ЈЈ, C-8ЈЈ), 21.6 (C-
4ЈЈ), 19.4 (C-9ЈЈ) ppm. MS (ESI, MeOH): m/z: 337 [M + Na]+.
HRMS (ESI, MeOH): m/z: 337.1616 [M + Na]+; 337.1602 calcd.
for C20H26ONaS.
S-Benzyl 3-Hydroxy-4-Phenylbutanethioate (3): Colourless oil;
48 mg or 48% isolated yield. 1H NMR (500 MHz, CDCl3): δ =
3
7.15–7.34 (m, 10 H, Ph), 4.25 (m, 1 H, 3-H), 4.08 (d, JH,H
=
3
13.8 Hz, 1 H, 1Јa-H), 4.04 (d, JH,H = 14.1 Hz, 1 H, 1Јb-H), 2.70
(m, 2 H, 4-H), 2.66 (m, 2 H, 2-H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 198.2 (C-1), 137.4, 137.1, 129.4, 128.7, 128.6, 128.5,
127.3, 126.7, 69.6 (C-3), 49.6 (C-2), 42.9 (C-4), 33.3 (C-1Ј) ppm.
S-Benzyl (E)-4-Phenylpent-2-enethioate (Table 2, Entry 4): Colour-
less oil; purified by flash chromatography; 25 mg or 35% isolated
1
yield. H NMR (500 MHz, CDCl3): δ = 7.09–7.25 (m, 10 H, Ph),
3
3
7.00 (dd, JH,H = 15.6, 6.4 Hz, 1 H, 3-H), 6.01 (dd, JH,H = 15.6,
1.8 Hz, 1 H, 2-H), 4.10 (s, 2 H, 1Ј-H), 3.54 (m, 1 H, 4-H), 1.36 (d,
3JH,H = 6.4 Hz, 3 H, 5-H) ppm. 13C NMR (125 MHz, CDCl3): δ =
189.5 (C-1), 149.3 (C-3), 143.1, 137.8, 129.0, 128.9, 128.7, 127.5,
IR: ν = 3540 (OH), 1686 (CO), 1495, 1453 cm–1. MS (ESI, pos,
˜
MeOH): m/z: 309 [M + Na]+. HRMS (ESI, pos, MeOH): m/z:
309.0928 [M + Na]+; 309.0925 calcd. for C17H18O2NaS.
General Procedure for the Yb(OTf)3-Catalyzed Doebner–Knoevena-
gel Condensation between MAHTs and Aldehydes: The base
(0.26 mmol, 1 equiv.) and Yb(OTf)3 (0.026 mmol, 10 mol-%) were
added at 25 °C to a stirred solution of S-benzyl malonic acid half
thioester 2 (55 mg, 0.26 mmol) in THF (5 mL). The aldehyde
(0.26 mmol, 1 equiv.) was added after homogenization of the solu-
tion (≈ 2 min), which was then stirred for 16 h at 25 °C and concen-
trated under reduced pressure to yield a yellow oil. The oil was
purified by flash chromatography on silica gel [n-hexane/CH2Cl2
(1:1) then CH2Cl2 (100%)] to afford the following unsaturated thio-
esters.
127.4, 127.0 (C-2), 42.2 (C-4), 21.9 (C-5), 37.4 (C-1Ј) ppm. IR: ν =
˜
1671 (CO), 1627, 1493, 1452 cm–1. MS (ESI, MeOH): m/z: 305 [M
+ Na]+. HRMS (ESI, MeOH): m/z: 305.1014 [M + Na]+; 305.0996
calcd. for C18H18OSNa.
S-Benzyl (E)-But-2-enethioate (Table 2, Entry 5): Colourless oil;
purified by flash chromatography; 17 mg or 34% isolated yield. 1H
NMR (500 MHz, CDCl3): δ = 7.16–7.24 (m, 5 H, Ph), 6.86 (dq,
3
3JH,H = 15.6, 6.9 Hz, 1 H, 3-H), 6.07 (dq, JH,H = 15.6, 1.8 Hz, 1
3
H, 2-H), 4.11 (s, 2 H, 1Ј-H), 1.80 (dd, JH,H = 6.9, 1.8 Hz, 3 H, 4-
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 189.3 (C-1), 141.4 (C-
3), 137.9, 129.9 (C-2), 129.0, 128.7, 127.3, 33.0 (C-1Ј), 18.1 (C-
S-Benzyl (E)-4-Phenylbut-3-enethioate (5, Table 2, Entry 1):
4) ppm. IR: ν = 1671 (CO), 1630 cm–1. MS (ESI, MeOH): m/z: 215
˜
Colourless oil; purified by flash chromatography; 52 mg or 75%
[M + Na]+. HRMS (ESI, MeOH): m/z: 215.0489 [M + Na]+;
1
isolated yield. H NMR (500 MHz, CDCl3): δ = 7.15–7.50 (m, 10
215.0507 calcd. for C11H12ONaS.
H, Ph), 6.65 (d, 3JH,H = 16.0 Hz, 1 H, 4-H), 6.40 (dt, 3JH,H = 16.0,
3
7.3 Hz, 1 H, 3-H), 4.26 (s, 2 H, 1Ј-H), 3.57 (d, JH,H = 7.3 Hz, 2
S-Benzyl (E)-Pent-2-enethioate (Table 2, Entry 6): Colourless oil;
purified by flash chromatography; 19 mg or 35% isolated yield. 1H
NMR (500 MHz, CDCl3): δ = 7.16–7.24 (m, 5 H, Ph), 6.90 (dt,
H, H-2) ppm. 13C NMR (125 MHz, CDCl3): δ = 196.9 (C-1), 137.5,
136.7, 135.1 (C-4), 129.0, 128.7, 127.9, 127.4, 126.5, 120.9 (C-3),
3
˜
3JH,H = 15.6, 6.4 Hz, 1 H, 3-H), 6.04 (dt, JH,H = 15.6, 1.8 Hz, 1
47.5 (C-2), 33.5 (C-1Ј) ppm. IR: ν = 1683 (CO), 1648, 1494,
1400 cm–1. MS (ESI, MeOH): m/z: 269 [M + H]+. HRMS (ESI,
3
H, 2-H), 4.12 (s, 2 H, 1Ј-H), 2.16 (qdd, JH,H = 6.9, 6.4, 1.8 Hz, 2
+
Na]+; 291.0820 calcd. for
3
H, 4-H), 0.99 (t, JH,H = 6.8 Hz, 3 H, 5-H) ppm. 13C NMR
MeOH): m/z: 291.0814 [M
C17H16ONaS.
(125 MHz, CDCl3): δ = 189.5 (C-1), 147.5 (C-3), 137.9, 129.0,
128.7, 127.5 (C-2), 127.3, 33.0 (C-1Ј), 25.5 (C-4), 12.2 (C-5) ppm.
S-Benzyl (E)-4-(2-Nitrophenyl)but-3-enethioate and S-Benzyl (E)-4-
(2-Nitrophenyl)but-2-enethioate (Table 2, Entry 2): Colourless oil;
purified by flash chromatography; 74 mg or 91% isolated yield in
a 7:3 mixture.
IR: ν = 1673 (CO), 1631 cm–1. MS (ESI, MeOH): m/z: 229 [M +
˜
Na]+. HRMS (ESI, MeOH): m/z: 229.0682 [M + Na]+; 229.0663
calcd. for C12H14ONaS.
1
α,β-Unsaturated Thioester: H NMR (500 MHz, CDCl3): δ = 7.95
S-Benzyl (E)-Non-2-enethioate (Table 2, Entry 7): Colourless oil;
(dd, 3JH,H = 8.0, 1.5 Hz, 1 H), 7.60–7.40 (m, Ph), 7.36 (m, JH,H
=
purified by flash chromatography; 22 mg or 32% isolated yield. 1H
3
Eur. J. Org. Chem. 2007, 1743–1748
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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