Zvarec et al.
JOCArticle
-
1
reported are isolated yields judged to be homogeneous by TLC
and NMR spectroscopy.
acetate/hexane); νmax (film)/cm 2981, 2933, 2105, 1633, 1039;
(300 MHz; CDCl ) 1.22 (3H, d, J = 6.77 Hz), 2.55 (1H, dd,
δ
H
3
General Procedure for the Synthesis of 3,6-Dihydro-1,2-dioxi-
nes 12a-c. To a solution of the respective 3,6-dihydro-1,2-
dioxine (1 equiv) in acetonitrile/water (1: 1, 20 mL/1.0 g of 1,2-
dioxine) were added BAIB (2.2 equiv) and TEMPO (0.2 equiv)
in a single portion, and the mixture was protected from light and
stirred until the reaction was complete by TLC. The reaction
mixture was extracted with ethyl acetate (4ꢀ) followed by 5%
J=14.82, 3.26 Hz), 2.87 (1H, dd, J=14.16, 8.09 Hz), 4.75-4.87
(2H, m), 5.39 (1H, bs), 5.87-5.97 (2H, m); δ (75 MHz; CDCl )
C
3
þ
191.7, 129.9, 126.3, 75.1, 74.4, 55.8, 44.4, 17.6; m/z (EI) (M 182,
1), 154 (5), 110 (14), 81 (100), 67 (30), 55 (30); HRMS calcd for
þ
þ
(M þNa ) C
(± )-1-Diazo-3-[(3S,6S)-6-phenyl-3,6-dihydro-1,2-dioxin-3-yl]-
acetone (1b): yield 120 mg, 54% yellow oil; R 0.55 (2:3 ethyl
8 10 2 3
H N O Na: requires 205.0589, found 205.0586.
f
-
1
NaHCO
3
(4ꢀ). The aqueous solution was acidified using con-
acetate/hexane); νmax (film)/cm 3103, 2104, 1644, 1372, 1142;
centrated HCl and extracted with ethyl acetate (4ꢀ). The
δH (300 MHz; CDCl ) 2.63 (1H, dd, J = 14.98, 4.10 Hz), 2.93
3
organic layer was then dried (MgSO ) and filtered, and the
4
(1H, dd, J = 14.86, 8.16 Hz), 4.88-5.01 (1H, m), 5.36 (1H, s),
volatiles were removed in vacuo. The crude residue was purified
by column chromatography to afford the desired 3,6-dihydro-
5.64 (1H, d, J = 1.59 Hz), 6.08-6.20 (2H, m), 7.32-7.40
(5H, m); δC (75 MHz; CDCl ) 191.4, 136.1, 129.2, 128.6,
3
1
1
11
1
,2-dioxines 12a-c. 3,6-Dihydro-1,2-dioxines 12a and 12b
have previously been reported.
± ) (3S)-3,6-Dihydro-1,2-dioxin-3-ylacetic acid (12c): yield
0.43 (2:3 ethyl
(Nujol)/cm 3200-2359, 1714, 1192,
128.6, 127.6, 127.4, 80.5, 75.2, 55.8, 44.2; HRMS calcd for
(M þNa ) C H N O Na requires 267.0746, found 267.0748.
þ
þ
1
3
12
2
3
(
(± )-1-Diazo-3-[(3S)-3,6-dihydro-1,2-dioxin-3-yl]acetone (1c):
yield 129 mg, 55% yellow oil; R 0.30 (2:3 ethyl acetate/hexane);
7
01 mg, 53% as white crystals; mp 82-84 °C; R
f
f
-
1
-1
acetate/hexane); ν
νmax (film)/cm 3101, 2107, 1633, 1371, 1141; δH (300 MHz;
max
1
5
4
194, 1064; δ
H
(300 MHz; CDCl
3
) 2.68 (1H, dd, J = 16.28,
CDCl ) 2.42-2.62 (1H, m), 2.66-2.86 (1H, m), 4.33-4.49
3
.50 Hz), 2.88 (1H, dd, J=16.29, 7.97 Hz), 4.42-4.50 (1H, m),
(1H, m), 4.52-4.71 (1H, m), 4.83-5.00 (1H, m), 5.37 (1H, s),
.64-4.71 (1H, m), 4.91-4.96 (1H, m), 5.97-6.01 (2H, m);
5.85-6.07 (2H, m); δC (75 MHz; CDCl ) 191.3, 126.6, 124.8,
3
þ
δ (75 MHz; CDCl ) 176.6, 126.0, 125.3, 74.7, 69.8, 37.8; m/z
75.4, 69.8, 55.6, 43.7; m/z (EI) (M 168, 1%), 140(15), 111(100),
83(28), 55(85); HRMS calcd for (M þ Na ) C H N O Na
C
3
þ
þ
þ
(
EI) (M 144, 1), 126 (50), 81 (100), 53 (30); HRMS calcd for
Na requires 167.0320, found 167.0323.
General Procedure for the Synthesis of 1,2-Dioxines 12d,e. To
7
8
2
3
þ
þ
(
M þNa ) C
6
H
8
O
4
requires 191.0433, found 191.0436.
(± )-1-Diazo-4-[(3S,6S)-6-methyl-3,6-dihydro-1,2-dioxin-3-yl]-
a solution of respective 3,6-dihydro-1,2-dioxine (1 equiv) in
acetone (20 mL/1.0 g of 1,2-dioxine) at 0 °C was added 2.67 M
Jones reagent dropwise, and the solution was allowed to stir for
30 min at 0 °C then 1.5 h at ambient temperature. To the solution
was added water and the resulting solution extracted with ethyl
butan-2-one (1d): yield 70 mg, 61% yellow oil; R 0.41 (2:3 ethyl
f
-
1
acetate/hexane); νmax (film)/cm 2979, 2105, 1643, 1378, 1138;
δ (300 MHz; CDCl ) 1.24 (3H, d, J=6.72 Hz), 1.75-2.13 (2H,
m), 2.51 (2H, m), 4.41 (1H, dd, J=6.87, 5.13 Hz), 4.69 (1H, dq,
H
3
J = 6.70, 1.72 Hz), 5.33 (1H, s), 5.88 (2H, s); δC (75 MHz;
acetate (4ꢀ). The organic layer was washed with water until the
CDCl ) 194.3, 129.3, 126.8, 77.1, 74.2, 54.5, 36.3, 27.9, 17.9; m/z
(EI) (M 196, 1), 168 (15), 125 (60), 97 (70), 55 (100); HRMS
3
þ
yellow color subsided, followed by brine (2ꢀ), dried (MgSO
4
),
þ
þ
and filtered, and the volatiles were removed in vacuo. The crude
residue was purified by column chromatography to afford the
desired 1,2-dioxines 12d,e.
calcd for (M þ Na ) C H N O Na requires 219.0746, found
9
12
2
3
219.0737.
(± )-1-Diazo-4-[(3S,6S)-6-phenyl-3,6-dihydro-1,2-dioxin-3-yl]-
butan-2-one (1e): yield 90 mg, 49% yellow oil; R 0.50 (2:3 ethyl
(± )-3-[(3S,6R)-6-Methyl-3,6-dihydro-1,2-dioxin-3-yl]propanoic
acid (12d): yield 1 g, 58% as a yellow oil; R 0.29 (2:3 ethyl
f
-
1
f
acetate/hexane); νmax (film)/cm 3101, 2104, 1634, 1379, 1070;
-
1
acetate/hexane); νmax (film)/cm 3044, 1714, 1445, 1260, 1052;
(300 MHz; CDCl ) 1.24 (3H, d, J=6.73 Hz), 1.92-2.21 (2H,
δH (300 MHz; CDCl ) 1.92-2.22 (2H, m), 2.50 (1H, s), 4.45-
3
δ
H
3
4.77 (2H, m), 5.25 (1H, s), 5.39-5.65 (1H, m), 6.00-6.25 (2H,
m), 7.36 (5H, s); δ (75 MHz; CDCl ) 194.1, 136.8, 128.9, 128.5,
128.5, 128.0, 126.9, 80.2, 77.3, 54.6, 36.2, 27.9; m/z (EI) (M 258,
m), 2.35-2.58 (2H, m), 4.32-4.75 (1H, m), 4.70 (1H, dq, J =
C
3
þ
1
1
1
1
.59, 6.68 Hz), 5.89 (2H, s); δ
C
(75 MHz; CDCl
26.5, 76.9, 74.3, 29.8, 27.8, 17.9; m/z (EI) (M 172, 1), 154 (25),
3
) 179.5, 129.7,
þ
75), 213 (25), 170 (100), 157 (85), 128 (25), 77 (10); HRMS calcd
for (M þ Na ) C H N O Na requires 281.0902, found
þ
þ
þ
08 (8), 96 (100); HRMS calcd for (M - H) C
71.0657, found 171.0657.
H
8 11
O
4
requires
1
4
14
2
3
281.0893.
(
± )-3-[(3S,6S)-6-Phenyl-3,6-dihydro-1,2-dioxin-3-yl]propanoic
General Procedure for Cyclization: Synthesis of 2a-e, 3a-e,
and 14. To a solution of the respective diazoketones in dichlor-
omethane (1 mL/1 g of diazoketone) was added Rh (OAc)
4
(10% by weight) in one portion and the mixture stirred for 10 min.
Volatiles were removed in vacuo, and the crude residue was puri-
fied by column chromatography to afford compounds 2a-c, 3a,
b, and 14.
acid (12e): yield 750 mg, 56% as a white needles; δ (300 MHz;
CDCl ) 2.36-1.82 (2H, m), 2.94-2.38 (2H, m), 4.59 (1H, dd,
J = 8.68, 3.34 Hz), 5.58 (1H, s), 6.11 (2H, s), 7.38 (5H, m); δ
H
3
2
C
(
75 MHz; CDCl
3
) 179.1, 136.8, 129.0, 128.6, 128.6, 127.8, 127.4,
80.4, 77.1, 29.7, 27.9; remaining physical and chemical proper-
ties as per literature.
2
3
General Procedure for the Synthesis of Diazoketones 1a-e.
The respective 1,2-dioxines (1 equiv) in thionyl chloride (20 mL/
(± )-(3R,6S)-3-Methyl-2,9-dioxabicyclo[4.2.1]non-4-en-8-one
(2a) and (± )-(3R,5aS)-3-methylhexahydro-4H-1,2-dioxacyclo-
propa[cd]inden-4-one (3a): yield 16 mg, 55% as a yellow oil.
(± )-(3R,6S)-3-Methyl-2,9-dioxabicyclo[4.2.1]non-4-en-8-one (2a):
1
.0 g of 1,2-dioxine) were stirred for 24 h, and then the volatiles
were carefully removed in vacuo and the acid chlorides used
without further purification. Into a solution of the acid chloride
yield 12 mg, 41%; R 0.75 (2:3 ethyl acetate/hexane); ν
(film)/
f
max
-
1
(
1 equiv) in ether (20 mL/g of acid chloride) was directly distilled
H 3
cm 2987, 2936, 1771, 1037; δ (600 MHz; CDCl ) 1.31 (3 H, d,
diazomethane in ether, derived from reaction of diazald (67 equiv)
with KOH solution in carbitol and ether. The mixture was
allowed to stir at ambient temperature for 24 h. Volatiles were
removed in vacuo, and the crude residue was purified by column
chromatography to afford the desired diazoketones 1a-e.
J=6.94 Hz), 2.43 (1H, ddd, J=18.08, 2.11, 0.84 Hz), 2.60 (1H,
dd, J = 18.08, 8.97 Hz), 4.78 (1H, dq, J = 6.94, 1.57 Hz), 5.02
(1H, s), 5.19 (1H, m), 5.68 (2H, m); δ (150 MHz; CDCl ) 205.9,
C
3
þ
136.4, 131.7, 93.7, 78.1, 66.4, 38.6, 21.3; m/z (EI) (M 154, 1),
126 (35), 108 (33), 83 (80), 79 (100), 55 (80); HRMS calcd for
þ
þ
(
± )-1-Diazo-3-[(3S,6R)-6-methyl-3,6-dihydro-1,2-dioxin-3-yl]-
(M þ Na ) C H O Na requires 177.0528, found 177.0524.
8
10 3
acetone (1a): yield 57 mg, 50% yellow oil; R 0.41 (2:3 ethyl
f
(± )-(3R,5aS)-3-Methylhexahydro-4H-1,2-dioxacyclopropa[cd]-
inden-4-one (3a): yield 4 mg, 14%; R 0.30 (2:3 ethyl acetate/
hexane); νmax (film)/cm 2995, 2932, 1732, 1099; δ (600 MHz;
f
-
1
(23) Culbert, J. A. Ph.D. Thesis, 2005, Department of Chemistry, The
University of Adelaide, South Australia, Australia.
H
CDCl ) 1.21 (3H, d, J = 6.38 Hz), 2.05 (1H, dd, J = 9.24,
3
J. Org. Chem. Vol. 75, No. 2, 2010 453