PAPER
Zinc Carbenoid Mediated Chain Extension
2407
IR (neat): 2972–2956, 1740, 1703, 1480, 1437 cm–1.
CH2Cl2 (8 mL) and diethylzinc (1.0 M in hexanes, 2.5 mL, 2.5
mmol). The mixture was cooled to 0 °C and a solution of benzyl
acetoacetate (96 mg, 0.5 mmol) in CH2Cl2 (1 mL) was added. After
stirring for 10 min, 1,1-diiodoethane (0.25 mL, 2.5 mmol) was add-
ed dropwise by syringe. The mixture was stirred for 1 h at r.t.,
quenched by cautious addition of sat. aq NH4Cl (5 mL) and extract-
ed with Et2O (3 × 8 mL). The combined organic extracts were
washed with brine (5 mL), and dried (Na2SO4). The resulting liquid
was filtered and concentrated under reduced pressure. The product
was purified by flash chromatography on silica gel (Rf = 0.30, hex-
ane–EtOAc, 7:1) to give 88 mg (80%) of the targeted compound 10f
as a colorless liquid.
1H NMR (500 MHz, CDCl3): d = 3.61 (s, 3 H), 3.43 (m, 1 H), 2.66
(dd, J = 8.0, 16.4 Hz, 1 H), 2.28 (dd, J = 6.3, 16.4 Hz, 1 H), 1.16 (s,
9 H), 1.05 (d, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 218.1, 172.5, 51.5, 44.5, 38.1,
36.2, 26.5, 18.3.
HRMS (EI): m/z calcd for C10H18O3: 186.1256; found: 186.1253.
Allyl 3-Methyl-4-oxopentanoate (10d)
A 25-mL oven-dried, round-bottomed flask equipped with a stir bar
and a septum with a flow of N2 through a needle was charged with
CH2Cl2 (8 mL) and diethylzinc (1.0 M in hexanes, 1.5 mL, 1.5
mmol). The mixture was cooled to 0 °C and a solution of allyl ace-
toacetate (73 mg, 0.5 mmol) in CH2Cl2 (1 mL) was added. After
stirring for 10 min, 1,1-diiodoethane (0.15 mL, 1.5 mmol) was add-
ed dropwise by syringe. The mixture was stirred for 0.5 h at r.t. Di-
ethylzinc (1.0 M in hexanes, 1.5 mL, 1.5 mmol) was added at r.t. to
the mixture and after 10 min, 1,1-diiodoethane (0.15 mL, 1.5 mmol)
was added dropwise by syringe. The mixture was stirred for 0.5 h at
r.t., quenched by cautious addition of sat. aq NH4Cl (5 mL) and ex-
tracted with Et2O (3 × 8 mL). The combined organic extracts were
washed with brine (5 mL) and dried (Na2SO4). The resulting liquid
was filtered and concentrated under reduced pressure. The product
was purified by flash chromatography on silica (Rf = 0.37, hexane–
EtOAc, 7:1) to give 63 mg (74%) of compound 10d as a colorless
liquid.
IR (neat): 2969–2934, 1734, 1715, 1456 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.38–7.30 (m, 5 H), 5.11–5.08 (d,
J = 4.7 Hz, 2 H), 3.03 (m, 1 H), 2.82 (dd, J = 8.7, 16.8 Hz, 1 H), 2.34
(dd, J = 5.4, 16.8 Hz, 1 H), 2.20 (s, 3 H), 1.15 (d, J = 7.3 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 210.6, 172.1, 135.8, 128.5, 128.2,
128.1, 66.4, 42.7, 36.8, 28.3, 16.5.
HRMS (EI): m/z calcd for C13H16O3: 220.1099; found: 220.1097.
N,N,3-Trimethyl-4-oxopentanamide (15a)
Into a 25-mL round-bottomed flask equipped with a magnetic stir
bar, septum, and N2 gas inlet were added anhyd CH2Cl2 (5 mL). The
flask was purged with N2 and cooled to 0 °C in an ice bath. Dieth-
ylzinc (1 M in hexanes, 2.5 mL, 2.5 mmol) was added to the flask
while stirring under N2. N,N-Dimethylacetoacetamide2b (65 mg, 0.5
mmol) in anhyd CH2Cl2 (5 mL), containing molecular sieves, was
added dropwise by syringe at 0 °C over 2 min and the solution was
allowed to stir for 10 min. 1,1-Diiodoethane (0.25 mL, 2.5 mmol)
was added dropwise to the flask at 0 °C. The formation of a white
precipitate was observed after 5–10 min of stirring. After stirring at
0 °C for 2 h, the reaction was quenched with sat. aq NH4Cl, and the
aqueous layer was extracted with Et2O (3 × 30 mL). The combined
organic layers were dried (Na2SO4), filtered, and concentrated on a
rotary evaporator. Column chromatography (Rf = 0.15, 1:1, hex-
ane–EtOAc) afforded 15a as a clear yellow oil (53 mg, 67%).
IR (neat): 3021–2936, 1733, 1716, 1460 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.89 (m, 1 H), 5.30 (dd, J = 1.5,
17.2 Hz, 1 H), 5.22 (dd, J = 1.3, 10.4 Hz, 1 H), 4.56 (dd, J = 1.4, 1.4
Hz, 1 H), 4.55 (dd, J = 1.4, 1.4 Hz, 1 H), 3.01 (m, 1 H), 2.79 (dd,
J = 8.7, 16.8 Hz, 1 H), 2.32 (dd, J = 5.4, 16.8 Hz, 1 H), 2.21 (s, 3 H),
1.15 (d, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 210.6, 171.9, 132.0, 118.3, 65.2,
42.7, 36.8, 28.4, 16.5.
HRMS (EI): m/z calcd for C9H14O3: 170.0943; found: 170.0946.
1H NMR (500 MHz, CDCl3): d = 3.14 (m, 1 H), 3.02 (s, 3 H), 2.91
(s, 3 H), 2.83 (dd, J = 9.5, 16 Hz, 1 H), 1.95–2.28 (m, 4 H), 1.13 (d,
J = 7.3 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 212.2, 171.4, 50.2, 42.6, 36.9,
35.1, 29.0, 16.8.
Ethyl 3-Methyl-4-oxo-4-phenylbutanoate (10e)
A 25-mL oven-dried, round-bottomed flask equipped with a stir bar
and a septum with a flow of N2 through a needle was charged with
CH2Cl2 (8 mL) and diethylzinc (1.0 M in hexanes, 2.5 mL, 2.5
mmol). The mixture was cooled to 0 °C and a solution of ethyl ben-
zoylacetate (96 mg, 0.5 mmol) in CH2Cl2 (1 mL) was added. After
stirring for 10 min, 1,1-diiodoethane (0.25 mL, 2.5 mmol) was add-
ed dropwise by syringe. The mixture was stirred for 1 h at r.t.,
quenched by cautious addition of sat. aq NH4Cl (5 mL) and extract-
ed with Et2O (3 × 8 mL). The combined organic extracts were
washed with brine (5 mL) and dried (Na2SO4). The resulting liquid
was filtered and concentrated under reduced pressure. The product
was purified by flash chromatography on silica gel (Rf = 0.52, hex-
ane–EtOAc, 7:1) to afford 92 mg (84%) of the known compound
10e18 as a colorless liquid.
HRMS (EI): m/z calcd for C8H15NO2: 157.1103; found: 157.1100.
1-(1,4-Dioxo-3-methylpentanyl)pyrrolidine (15b)
Into a 50-mL round-bottomed flask equipped with a magnetic stir
bar, septum, and N2 gas inlet were added anhyd CH2Cl2 (5 mL). The
flask was purged with N2 and cooled to 0 °C in an ice bath. Dieth-
ylzinc (1 M in hexanes, 2.5 mL, 2.5 mmol) was added to the flask
while stirring under N2. 1-(Acetoacetato)pyrrolidine2b (74 mg, 0.5
mmol) in anhyd CH2Cl2 (5 mL), containing molecular sieves, was
added dropwise by syringe at 0 °C over 2 min and the solution was
allowed to stir for 10 min. 1,1-Diiodoethane (0.25 mL, 2.5 mmol)
was added dropwise to the flask at 0 °C. The formation of a white
precipitate was observed after stirring for 5–10 min. After stirring
at 0 °C for 2 h, the reaction was quenched with sat. aq NH4Cl, and
the aqueous layer was extracted with Et2O (3 × 30 mL). The com-
bined organic layers were dried (Na2SO4), filtered, and concentrated
on a rotary evaporator. Column chromatography (Rf = 0.19,
EtOAc–hexane, 20:1) was performed to afford 15b as a clear yellow
oil (68 mg, 74%).
IR (neat): 2979, 1733, 1683, 1448, 1377 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.98–7.96 (m, 2 H), 7.54 (m, 1 H),
7.47–7.44 (m, 2 H), 4.08 (q, J = 7.1 Hz, 2 H), 3.94 (m, 1 H), 2.94
(dd, J = 8.5, 16.7 Hz, 1 H), 2.44 (dd, J = 5.7, 16.7 Hz, 1 H), 1.20 (t,
J = 7.3 Hz, 3 H), 1.18 (d, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 202.7, 172.2, 135.9, 133.0, 128.6,
128.3, 60.5, 37.5, 37.1, 17.7, 14.0.
HRMS (EI): m/z calcd for C13H16O3: 220.1099; found: 220.1101.
1H NMR (400 MHz, CDCl3): d = 3.34–3.52 (m, 4 H), 3.17 (m, 1 H),
2.76 (dd, J = 9.2, 16 Hz, 1 H), 2.26 (s, 3 H), 2.21 (dd, J = 4.5, 16 Hz,
1 H), 1.90–2.00 (m, 2 H), 1.79–1.90 (m, 2 H), 1.14 (d, J = 7.4 Hz, 3
H).
Benzyl 3-Methyl-4-oxopentanoate (10f)
A 25-mL oven-dried, round-bottomed flask equipped with a stir bar
and a septum with a flow of N2 through a needle was charged with
Synthesis 2007, No. 15, 2404–2408 © Thieme Stuttgart · New York