Table 2. Cyclization of 3-chloropropyl p-hydroxyphenyl ketone (2)
entrya,b
base (equiv)
solvent
PTC added
addn. temp (°C)
rxn. temp, time
ratio of 7/1
isolated yield of 1 (%)
1
2
3
4
5
6
7
8
NaOH (2)
NaOH (4)
NaOH (6)
NaOH (6.4)
NaOH (10)
NaOH (6)
NaOH (6)
KOt-Bu (2.2)
H2O
H2O
H2O
H2O
H2O
H2O
H2O
c
Bu4NBr
-
-
22-29
21-24
23-25
22-26
23-32
0-5
rt, 3 h
rt, 1.5 h
rt, 1 h
rt, 5 h
rt, 3 h
rt, 3.5 h
rt, 5 h
rt, 30 min
78.0
20.3
12.8
7.9
5.6
4.2
6.4
0
d
62.5
d
Bu4NBr
d
-
-
-
-
44.1
92.0
91.8
95.8
-5 to 0
-5 to 0
a Entries 1-5: Adding sodium hydroxide solution to chloride 2. b Entries 6-8: Adding chloride 2 to sodium hydroxide solution. c (Entry 8) Solvents successfully
used: THF, DME, MTBE d Product not isolated.
3-Hydroxypropyl p-Hydroxyphenyl Ketone (7). A
slurry of aluminum chloride (29.6 g, 0.22 mol) in 15 mL of
chlorobenzene was cooled to 10 °C, and anisole (4, 20.0 g,
0.185 mol) was added at 10-20 °C, forming a thicker paste.
4-Chlorobutyrylchloride (5, 26.1 g, 0.185 mol) was then
added dropwise, keeping the temperature at 10-15 °C. Gas
evolution was seen during the addition of the acid chloride.
At the end of the addition, the clear solution was stirred at
room temperature for 16 h and then heated to 100 °C for 1
h to complete the reaction.
chlorobenzene was added compound 2 (2.0 g, 10 mmol).
The mixture was heated to 100 °C for 5 h. The mixture was
cooled to rt and added to 50 mL of water with vigorous
stirring. The precipitate was filtered and washed with water
until the filtrate was neutral. The product was dried in vacuo
in an oven at 45 °C to give compound 7 as a brownish solid.
Yield was 1.5 g (82.7%).
Cyclopropyl p-Hydroxyphenyl Ketone (1) A solution
of 50% NaOH (24.2 g, 0.3 mol) in 25 mL of water was
cooled to 7 °C. Solid 3-chloropropyl p-hydroxyphenyl ketone
(2, 10 g, 50 mmol) was added at 7-8 °C. Water (50 mL)
was added, and the clear, light-brown solution was stirred
at room temperature for 6 h.
A solution of phosphoric acid (34.3 g, 86%, 0.3 mol) in
30 mL of water was cooled to 5 °C. The reaction mixture
was added to the acid at 5-10 °C. Precipitate formed
immediately. NaOH (5.3 g, 50%) was added to adjust the
pH to 5. After 1 h stirring at rt, the precipitate was filtered,
washed with 150 mL water, and vacuum-dried at 30 °C to
give the crude product (7.9 g) as a light-brown solid. The
crude material can be dissolved in 20 mL of 2-propanol and
precipitated with 65 mL of water to improve the purity. Mp
107-109.5 °C. Lit. mp4 108 °C. MS: (M + H)+ ) 163. 1H
NMR (300 MHz, CDCl3, δ): 7.95 (d), 6.9 (m), 2.65 (m),
1.25 (m), 1.15 (m).
Cyclopropyl p-Hydroxyphenyl Ketone (1): Nonaque-
ous System. A solution of potassium tert-butoxide (49.7 g,
0.443 mol) in 100 mL of THF was cooled to -5 °C. To this
was added the solution of the chloride 2 (40 g, 0.20 mol) in
120 mL of THF at -5 to 0 °C. The mixture was stirred at
0 °C for 30 min and added to a stirred solution of phosphoric
acid (30.2 g, 85%, 0.26 mol) in 200 mL of water at -5 to
0 °C. The mixture was warmed to rt and stirred for 2 h. The
mixture was extracted twice with ethyl acetate (200 mL +
100 mL). The combined organic layers were washed with 2
× 160 mL of water. The aqueous layers were combined and
re-extracted with 150 mL of ethyl acetate. The ethyl acetate
extracts were combined, concentrated to oil, and azeotropi-
cally dried with ethyl acetate to give a brown oil (36.48 g)
which solidified on standing. The crude product was purified
by column chromatography (silica gel, 1:1 ethyl acetate:
hexane) to give 31.0 g of pure ketone 1.
The thick, dark-brown mixture was poured into a stirred
mixture of 150 mL of water and 50 mL of concentrated HCl
at 0-20 °C. The resulting slurry was stirred at room
temperature for 2 h. The tan-colored precipitate was filtered,
washed with water until the filtrate was neutral, and then
vacuum-dried at 45 °C to give the crude product (27.0 g) as
brown solid. The crude product could be crystallized from
heptane/ethyl acetate (5:2) with 80% recovery. Mp 143-
144 °C. Lit. mp5 144 °C. The crude product had the same
purity as the crystallized material (>96% pure by HPLC)
1
and can be used directly. MS: (M + H)+ ) 181. H NMR
(300 MHz, DMSO-d6, δ): 7.85 (d), 6.83 (d), 4.5 (broad s),
3.4 (t), 2.95 (t), 1.75 (m).
3-Chloropropyl p-Hydroxyphenyl Ketone (2). A slurry
of aluminum chloride (320.6 g, 2.4 mol) in 200 mL of
chlorobenzene was cooled to -10 °C. Anisole (4, 200 g,
1.85 mol) was added at -10 to 10 °C. 4-Chlorobutyrylchlo-
ride (5, 286.9 g, 2.04 mol) was added dropwise at 0-10 °C.
The reddish mixture was stirred at room temperature for 1 h
and then heated to 100 °C for 3 h to complete the reaction.
A solution of 1 L of water and 1.5 L of concentrated HCl
was cooled to 5 °C, and the reaction mixture was added,
forming a slurry. The slurry was heated to 100 °C for ∼9 h
until the reaction was complete and then stirred at rt
overnight. The brown precipitate was filtered, rinsed with 1
L each of water, 5% NaHCO3, and water. The wet cake was
vacuum-dried at 50 °C to give the crude product (350.7 g,
95.5%). HPLC purity 92.9%. The crude product was crystal-
lized from heptane/2-propanol (4:1) with 61% recovery. Mp
114-116 °C. Lit. mp3 114-115 °C. MS: (M + H)+ ) 199.
1H NMR (300 MHz, CDCl3, δ): 7.93 (d), 6.9 (d), 3.7 (t),
3.15 (t), 2.2 (m).
Conversion of Compound 2 to 7. To a mixture of
aluminum chloride (1.75 g, 13.1 mmol) in 30 mL of
Received for review September 25, 2000.
OP0002996
(5) Dohrn, M.; Charlottenburg, B.; Diedrich, P. U.S. Patent 2,116,104, 1938.
Vol. 5, No. 2, 2001 / Organic Process Research & Development
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