The Journal of Organic Chemistry
Article
13C NMR (C6D6, 100 MHz) δ 51.3, 58.2, 72.7, 126.7, 127.4, 130.5,
reaction flask. The blue color dissipated after addition of the first few
drops of iodomethane after which the remaining iodomethane was
added in one portion. The mixture was stirred for 50 min at −67 °C,
and 1.60 g (30 mmol) of solid ammonium chloride was added through
the stoppered hole. The coldfinger condenser was quickly removed
(after removing the nitrogen line), emptied, and returned to the
reaction flask (without the nitrogen line), and the cold bath was
removed. The stirred solution was allowed to warm to approximately
−25 °C over a period of 25 min. A water bath was carefully placed
under the reaction flask, and the reaction temperature increased to 22
°C over a period of 80 min. To the residual solution containing white
solid was added 40 mL of water followed by 80 mL of benzene. The
phases were separated, and the organic phase was dried (Na2SO4) and
concentrated in vacuo (25−45 Torr at a temperature below 40 °C) to
132.2, 141.9, 167.0. One aromatic carbon signal was obscured.
Methyl 5-Methoxy-3-(tert-butyldimethylsilyloxymethyl)benzoate
(4). Compound 34 was prepared by a modification of a known
procedure (see the Supporting Information for details).16b Compound
34 was converted to TBS-ether 4 (colorless liquid) as described for the
preparation of 6 (see the Supporting Information for details): IR
(neat) 1726 cm−1; 1H NMR (CDCl3, 400 MHz) δ 0.2 (s, 6H), 0.93 (s,
9H), 3.8 (s, 2H), 3.9 (s, 2H), 4.7 (s, 2H), 7.1 (s, 1H), 7.4 (s, 1H), 7.55
(s, 1H); 13C NMR (CDCl3, 100 MHz) δ −5.1, 18.6, 26.1, 52.3, 55.7,
64.6, 112.8, 117.6, 119.75, 131.4, 143.68, 159.9, 167.2; exact mass calcd
for C16H26O4Si (M + Na)+ m/z 333.1498, found m/z 333.1496.
Preparation of Anticipated Reductive Alkylation Products.
Methyl 1,3-Dimethyl-2,5-cyclohexadiene-1-carboxylate (26). This
known compound was prepared for comparison by a variation of a
known procedure (see the Supporting Information for details).20
Compound 26 was obtained as a colorless oil: IR (neat) 1734 cm−1;
1H NMR (C6D6, 400 MHz) δ 1.37 (s, 3H), 1.5 (s, 3H), 2.22 (d, J = 22
1
give 2.92 g of residue. H NMR analysis indicated this material was
mainly the desired product (29a) contaminated by 6 mol % of starting
9. The residue was purified by chromatography over 100 g of flash
silica gel (loaded and eluted with hexanes−ethyl acetate = 9:1) with
collection of 50 mL fractions. Fractions 5−9 were pooled and
concentrated in vacuo to give 2.43 g (82%) of 29a as a colorless oil
(contaminated with 6 mol % of 9 by 1H NMR): IR (neat) 1735 cm−1;
1H NMR (C6D6, 400 MHz) δ 0.0 (s, 6H), 0.90 (s, 9H), 1.35 (s, 3H),
Hz, 1H), 2.29 (d, J = 22 Hz, 1H) 3.30 (s, 3H), 5.6 (m, 2H), 5.87 (dq, J
= 10, 2 Hz, 1H); 13C NMR (C6D6, 100 MHz) δ 23.0, 27.6, 30.7, 45.3,
51.4, 124.0, 129.1, 131.5, 175.1. One vinylic carbon signal was
obscured.
Methyl 1,4-Dimethyl-2,5-cyclohexadiene-1-carboxylate (27).
This known compound was prepared for comparison by a variation
of known procedures (see the Supporting Information for details).21
Compound 27 was obtained as a colorless oil: IR (neat, mixture of
2.43 (br s, 2H), 3.28 (s, 3H), 3.90 (s, 2H), 5.14 (m, 1H), 5.8−6.0 (m,
2H); 13C NMR (C6D6, 100 MHz) δ −5.3, 18.4, 25.9, 26.6, 27.4, 44.9,
51.5, 66.9, 123.8, 124.0, 129.2, 134.1, 174.8; exact mass calcd for
C16H28O3Si (M + Na)+ m/z 319.1705, found m/z 319.1701. The
presence of 9 (6 mol %) was apparent from 1H NMR signals at δ −0.1,
3.45, and 4.45 and appropriate 13C NMR signals.
1
diastereomers) 1732 cm−1; H NMR signals for major diastereomer
(C6D6, 400 MHz) 0.85 (d, J = 8 Hz, 3H), 1.36 (m, 3H), 2.52 (m, 1H),
1
3.50 (s, 3H), 5.55 (t, J = 10 Hz, 2H), 5.85 (d, J = 10 Hz, 2H); H
Table 1, Entry 2: Reductive Alkylation of Methyl 3-(tert-
Butyldimethylsilyloxymethyl)benzoate (9) with Allyl Bromide. This
experiment was performed in a manner similar to that described for
the preparation of 29a (R = TBS). Details are provided in the
Supporting Information. Compound 29b was obtained as a colorless
NMR signals for minor diastereomer (C6D6, 400 MHz) 0.92 (d, J = 8
Hz, 3H), 1.35 (m, 1H), 2.48 (m, 3H), 3.48 (s, 3H), 5.55 (t, J = 10 Hz,
2H), 5.85 (d, J = 10 Hz, 2H).
Methyl 1,2-Dimethyl-2,5-cyclohexadiene-1-carboxylate (28).
This known compound was prepared for comparison by a variation
of known procedures (see the Supporting Information for details):22
IR (neat) 1733 cm−1; 1H NMR (C6D6, 400 MHz) δ 1.42 (s, 3H), 1.69
(q, J = 1.5 Hz, 3H), 2.40 (d, J = 22 Hz, 1H), 2.50 (d, J = 22 Hz, 1H),
3.31 (s, 3H), 5.37 (br s, 1H), 5.6 (m, 2H); 13C NMR (C6D6, 400
MHz) δ 19.9, 24.3, 26.9, 47.7, 51.5, 121.4, 124.6, 129.9, 133.6, 174.5.
Methyl 5-Methoxy-1,3-dimethyl-2,5-cyclohexadiene-1-carboxy-
late (36). This experiment was performed in a manner similar to
that described for the preparation of 29a (R = TBS). Details are
provided in the Supporting Information. Compound 36 was obtained
as a colorless oil: IR (neat) 1731 cm−1; 1H NMR (C6D6, 400 MHz) δ
1.48 (s, 6H), 2.54 (d, J = 21 Hz, 1H), 2.62 (d, J = 21 Hz, 1H), 3.25 (s,
3H), 3.36 (s, 3H), 4.82 (s, 1H), 5.6 (s, 1H); 13C NMR (C6D6, 100
MHz) δ 22.4, 28.6, 33.6, 46.9, 51.4, 53.6, 96.9, 124.3, 130.6, 154.1,
175.9; exact mass calcd for C11H16O3 (M + Na)+ m/z 219.0997, found
m/z 219.0990.
Reductive Alkylations: Experiments Shown in Tables 1−3.
Table 1, Entry 1: Reductive Alkylation of Methyl 3-[[(tert-
Butyldimethylsilyl)oxy]methyl]benzoate (9) with Iodomethane. A
mixture of 2.80 g (10 mmol) of ester 9 and 0.74 g (10 mmol) of tert-
butyl alcohol was placed in a dry 250 mL, three-necked round-bottom
flask equipped with a magnetic stir bar, a coldfinger condenser topped
with a nitrogen line, a low temperature thermometer, and a septum.
The system was placed under a nitrogen atmosphere and dry
tetrahydrofuran (25 mL) was added via syringe. The septum was
replaced with a gas inlet adapter attached to an ammonia tank. The
coldfinger condenser was charged with dry ice-acetone, and the
reaction flask was cooled in a dry ice-acetone bath. Ammonia
(approximately 100 mL) was condensed in the reaction vessel over a
period of about 15 min, and then the gas inlet adapter was replaced
with a glass stopper. The stirred solution was cooled to an internal
temperature of −65 °C, and 167 mg (23.8 mmol) of lithium metal was
added in small pieces (97 mg + 54 mg + 4 mg + 12 mg = 167 mg),
through the stoppered hole of the reaction flask, over a period of 25
min. The solution maintained a deep blue color for 5 min after
addition of the last piece of lithium at which point 4.26 g (30 mmol) of
iodomethane was added via syringe through the stoppered hole of the
1
oil: IR (neat) 1732 cm−1; H NMR (C6D6, 400 MHz) δ 0.0 (two s,
6H), 0.91 (s, 9H), 2.40 (br s, 2H), 2.5 (d, J = 7 Hz, 2H), 3.26 (s, 3H),
3.90 (s, 2H), 4.95 (br s, 1H), 5.0 (d, J = 6 Hz, 1H), 5.65−5.95 (m,
4H); 13C NMR (C6D6, 100 MHz) δ −5.0, 18.4, 26.0, 26.8, 44.9, 48.8,
51.4, 66.8, 118.0, 122.2, 125.2, 130.5, 133.7, 136.3, 174.0; exact mass
calcd for C18H30O3Si (M + Na)+ m/z 345.1861, found m/z 345.1853.
The presence of 9 (11−12 mol %) was apparent from 1H NMR signals
at δ −0.1, 3.45, and 4.45 and appropriate 13C NMR signals.
Table 1, Entry 3: Reductive Alkylation of Methyl 3-(tert-
Butyldimethylsilyloxymethyl)benzoate (9) with Iodomethyl Piva-
late. This experiment was performed in a manner similar to that
described for the preparation of 29a (R = TBS). Details are provided
in the Supporting Information. Compound 29c was obtained as a
1
colorless oil: IR (neat) 1738 cm−1; H NMR (C6D6, 400 MHz) δ 0.0
(two s, 6H), 0.90 (s, 9H), 1.12 (s, 9H), 2.38 (s, 2H), 3.28 (s, 3H), 3.9
(s, 2H), 4.30 (d, J = 10 Hz, 1H), 4.37 (d, J = 10 Hz, 1H), 5.70 (dt, J =
10, 3 Hz, 1H), 5.89 (dq, J = 10, 2 Hz, 1H), 5.96 (m, 1H); 13C NMR
(C6D6, 100 MHz) δ −5.4, 18.4, 25.9, 26.8, 27.1, 38.7, 49.6, 51.6, 66.5,
69.2, 119.0, 124.6, 126.7, 138.2, 172.3, 177.1; exact mass calcd for
C21H36O5Si (M + Na)+ m/z 419.2230, found m/z 419.2223. The
following peaks in NMR spectra were indicative of the aldehyde (see
text): 1H NMR (C6D6, 400 MHz) δ −0.02 (s, 6H), 0.89 (s, 9H), 1.10
(s, 9H), 2.30 (br s, 2H), 3.89 (s, 2H), 4.22 (d, J = 10 Hz, 1H), 4.30 (d,
J = 10 Hz, 1H), 5.38 (dm, J = 10 Hz, 1H), 5.52 (m, 1H), 9.2 (s, 1H,
CHO); 13C NMR (C6D6, 100 MHz) δ 55.0, 65.9, 66.3, 116.1, 122.1,
128.5, 129.0, 140.5, 177.2, 196.6. The iodomethyl pivalate used in this
reaction was prepared in a manner similar to that described be
Knochel (see the Supporting Information for details).32
Table 1, Entry 4: Reductive Alkylation of Methyl 3-(tert-
Butyldimethylsilyloxymethyl)benzoate (9) with 1-Iodopropane.
This experiment was performed in a manner similar to that described
for the preparation of 29a (R = TBS). Details are provided in the
Supporting Information. Compound 29d was obtained as a colorless
1
oil: IR (neat) 1734 cm−1; H NMR (C6D6, 400 MHz) δ 0.0 (two s,
6H), 0.75 (t, J = 7 Hz, 3H), 0.90 (s, 9H), 1.24 (m, 2H), 1.70 (m, 2H),
2.40 (br s, 2H), 3.28 (s, 3H), 3.90 (s, 2H), 5.7 (dt, J = 10, 3 Hz, 1H),
5.85 (dq, J = 10, 2 Hz, 1H), 5.9 (br s, 1H); 13C NMR (C6D6, 100
G
dx.doi.org/10.1021/jo301872n | J. Org. Chem. XXXX, XXX, XXX−XXX