Checked by Chris H. Senanayake and Ichiro Shinkai.
1. Procedure
The
acid chloride, 12.7 g, is dissolved in
60 mL of dichloromethane and transferred to a
300-mL, round-bottomed flask fitted with a magnetic stirring bar and a
100-mL, pressure-equalizing dropping funnel. The solution is cooled to 0°C in an
ice bath.
2-Amino-2-methyl-1-propanol (12.5 g, 0.140 mol) dissolved in
50 mL of dichloromethane is added dropwise to the cold solution over 15 min. The reaction mixture is allowed to warm to room temperature and stirring is continued for 2 hr. The white precipitate (Note
4) is removed by filtration and the mother liquor is removed by rotary evaporation to afford
15.7 g of the
amido alcohol (Note
5). The amido alcohol is redissolved in
100 mL of dichloromethane and added to a 300-mL round-bottomed flask fitted with a reflux condenser and a magnetic stirring bar.
Thionyl chloride (24.5 g, 0.206 mol) is added dropwise and the resulting mixture is stirred at room temperature for 1.5 hr (Note
6). The reaction mixture is cooled to 0°C (ice-water bath) and to it is added slowly 50 mL of cold water followed by approximately
50 mL of aqueous 40% sodium hydroxide solution, which basifies the reaction mixture to approximately pH 11. Saturated
sodium chloride solution (approximately 50 mL) is added and the contents of the flask are transferred to a
1-L separatory funnel. The lower phase (CH
2Cl
2 solution) is removed and set aside while the upper, aqueous phase is extracted once with
50 mL of dichloromethane. The
dichloromethane extracts are combined and dried over
magnesium sulfate. The solution is then filtered through Celite and concentrated under reduced pressure to leave crude
2-(2,3-dimethoxyphenyl)-4,4-dimethyl-2-oxazoline (1). The latter is distilled in a Kugelrohr apparatus at 110°C (0.05 mm) to give
12.7–13.3 g (
81–85%) (Note
7).
B.
2,2'-Dimethoxy-6-(4",4"-dimethyloxazolinyl)biphenyl.
Magnesium turnings (3.3 g, 0.14 g-atom, (Note 8)) and
100 mL of dry ether (Note
9) are added to a flame-dried,
1-L, round-bottomed flask under a
nitrogen atmosphere. The flask is fitted with a
250-mL addition funnel, reflux condenser, and magnetic stirring bar, and placed under a slow
nitrogen flow. A few crystals of
iodine are added to the reaction vessel followed by dropwise addition of
18 g (0.12 mol) of 2-bromoanisole (Note
10) in
150 mL of anhydrous ether (Note
11). When the addition is complete, the reaction mixture is stirred for 2 hr at room temperature. When it is apparent that formation of the Grignard solution has consumed most of the
magnesium turnings, a solution of the
dimethoxyphenyloxazoline, 11.2 g (0.048 mol) in
300 mL of anhydrous tetrahydrofuran (Note
12), is added dropwise at room temperature to the stirred Grignard solution. After addition is complete, stirring of the dark solution is continued for 24 hr or until reaction is complete (Note
13). The reaction mixture is quenched by careful addition of saturated
ammonium chloride (50 mL) followed by addition of 50 mL of water. The contents are transferred to a 1-L separatory funnel and the lower aqueous phase is separated while the upper organic phase is set aside. The aqueous phase is returned to the separatory funnel and extracted once with
50 mL of ether; both ethereal phases are then combined, dried over
magnesium sulfate, and filtered and concentrated under reduced pressure. There is obtained
19.2 g of a yellow solid that contains, in addition to the biphenyl, some anisole and other contaminants (e.g., starting materials). The volatile impurities are removed by Kugelrohr or other short path distillation (105°C, 0.05 mm, 15 min) to leave
14.2 g (
96%) of crude biphenyl product. Purification is performed by recrystallization from
ethyl acetate-hexane (1:1) to give
12.2–13.0 g (
80–85%) of pure material (Note
14), (Note
15).
C.
2,2'-Dimethoxy-6-formylbiphenyl. To a flame-dried, 1-L, round-bottomed flask, under
nitrogen, and fitted with a magnetic stirring bar is added
12.2 g (0.039 mol) of pure biphenyloxazoline 2 in
300 mL of dry dichloromethane (Note
16). To this is added
7.9 g (0.048 mol) of methyl trifluoromethanesulfonate (Note
17) and the chilled solution is stirred at room temperature for 2–3 hr (Note
18). The solution of quaternized oxazoline is cooled to 0°C in an ice-water bath. Separately,
3.3 g (0.87 mol) of sodium borohydride is slurried at 0°C with
125 mL of absolute ethanol. The chilled slurry is added slowly, to control foaming, to the reaction mixture. When the addition is complete, the mixture is stirred at 0°C for 45 min and the contents of the flask are evaporated under reduced pressure. The resulting solid residue is dissolved in
400 mL of 4:1 tetrahydrofuran-water and
19.5 g (0.217 mol) of oxalic acid is added in portions (exotherm). The mixture is stirred at room temperature for 16–18 hr (Note
19).
Tetrahydrofuran is removed under rotary evaporation to leave behind an aqueous slurry that is washed in a separatory funnel with
pentane-ether (1:1, 2 × 100 mL). The upper layer is removed and the aqueous layer is extracted again with
50 mL of pentane-ether. The organic layers are combined and washed with
50 mL of aqueous 10% sodium bicarbonate and then with
50 mL of saturated brine. The aqueous washes are also back-extracted with
pentane-
ether which is combined with the other organic solutions. The organic layers are dried over
sodium sulfate (anhydrous) and the solution is filtered through Celite. Concentration of the solution under reduced pressure gives
7.5 g (
75–83%) of the final biphenyl aldehyde, mp
65–67°C. Recrystallization from
2-propanol gives
6.5 g of pure material (Note
20), (Note
21).
2. Notes
3. The melting point was
53–54°C.
5. The melting point was
77–80°C after air drying for several hours.
6. The formation of the 2,3-dimethoxyphenyloxazoline
(1) can be readily followed by removing aliquots, neutralizing with aqueous
sodium hydroxide, and checking on TLC using
silica gel and eluting with
hexane-acetone, 85:15; R
f is 0.29.
7. The physical properties are as follows: mp
44–46°C,
1H-NMR (250 MHz, CDCl
3) δ: 1.36 (s, 6 H), 3.83 (s, 6 H), 4.08 (s, 2 H), 6.96 (dd, 1 H, J = 8.2, 1.9), 7.02 (dd, 1 H, J = 8.2, 7.5), 7.29 (dd, 1 H, J = 7.5, 1.9).
9.
Ether was distilled from
benzophenone ketyl under
nitrogen. The checkers used
ether dried over 4 Å molecular sieves, under
nitrogen, for 2 days and obtained the same results.
10.
2-Bromoanisole was purchased, and used without further purification, from Aldrich Chemical Company, Inc.
11. Warming of the reaction vessel with a
water bath (

30°C) tends to expedite the initiation of the Grignard reagent.
12. Anhydrous
tetrahydrofuran (THF) was distilled from
benzophenone ketyl under
nitrogen. The checkers used THF dried over 4 Å molecular sieves, under
nitrogen, for 2 days and obtained the same results.
13. The reaction is followed by TLC (
silica,
hexane-
acetone, 85:15) and shows the disappearance of the dimethoxyphenyloxazoline
1 at R
f 0.29 and the appearance of the biphenyl
2 at R
f 0.18.
14. The physical properties are as follows: mp
127–129°C;
1H NMR (250 MHz, CDCl
3) δ: 1.18 (s, 3 H), 1.19 (s, 3 H), 3.59 (d, 1 H, J = 8.1), 3.72 (d, 1 H, J = 8.1), 3.75 (s, 6 H), 6.98 (om, 2 H), 7.05 (dd, 1 H, J = 7.1, 2.4), 7.15 (dd, 1 H, J = 7.4, 1.7), 7.29 (dd, 1 H, J = 7.6, 1.8), 7.34–7.39 (om, 2 H).
15. If crude material is used in Step C, the yield of final product is approximately
50–58%.
18. Stirring is continued until quaternization of the oxazoline
2 is complete. This is easily monitored by TLC which shows only baseline salt (
silica,
hexane-
acetone) and complete absence of the biphenyloxazoline at R
f 0.18.
19. The checkers report that the reaction can be followed by TLC, indicating disappearance of starting material and appearance of the aldehyde (R
f = 0.75,
hexane-
ethyl acetate, 75:25).
20. The physical properties are as follows: mp
75–76°C;
1H NMR (250 MHz, CDCl
3) δ: 3.74 (s, 3 H), 3.78 ( s, 3 H), 7.01 (d, 1 H, J = 8.3), 7.06 (m, 1 H), 7.22 (dd, 1 H, J = 7.9, 17), 7.23 (dd, 1 H, J = 7.4, 1.8), 7.39–7.49 (om, 2 H), 7.63 (dd, 1 H, J = 7.8, 1.0), 9.68 (d, 1 H, J = 0.8).
21. The submitters report that this procedure can also produce the corresponding biphenyl carboxylic acid by omitting the quaternization-reduction step and subjecting the biphenyloxazoline
2 to hydrolysis as follows:
A slurry of
2 (0.1 M) in
4 M hydrochloric acid is heated at reflux for 16 hr. The solution is concentrated to dryness by rotary evaporation and the crude carboxylic acid, derived from
2, is recrystallized from
hexane-ethyl acetate-isopropyl alcohol (2:1:1) furnishing pure material in
80% yield, mp
196–197°C.
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
The use of oxazolines in aromatic substitution is a valuable synthetic tool.
2 The
o-methoxy- or o-fluorophenyloxazoline reacts readily with a variety of organolithium or Grignard reagents to displace only the ortho substituent. In this fashion a number of ortho-substituted benzoic acids, benzaldehydes, and unsymmetrical biphenyls are accessible. The reaction takes place under very mild conditions, usually at or below room temperature, and thus allows a number of other sensitive groups to be present.
Appendix
Compounds Referenced (Chemical Abstracts Registry Number)
silica gel
benzophenone ketyl
silica
brine
2,2'-Dimethoxy-6-(4'',4''-dimethyloxazolinyl)biphenyl
o-methoxy- or o-fluorophenyloxazoline
(−)-steganone
podophyllotoxin
(−)-schizandrin
(+)-phylictralin
ethanol (64-17-5)
hydrochloric acid (7647-01-0)
ethyl acetate (141-78-6)
ether (60-29-7)
ammonium chloride (12125-02-9)
sodium hydroxide (1310-73-2)
thionyl chloride (7719-09-7)
sodium bicarbonate (144-55-8)
magnesium turnings (7439-95-4)
sodium chloride (7647-14-5)
sodium sulfate (7757-82-6)
Oxalic acid (144-62-7)
nitrogen (7727-37-9)
iodine (7553-56-2)
acetone (67-64-1)
isopropyl alcohol,
2-propanol (67-63-0)
Pentane (109-66-0)
dichloromethane (75-09-2)
magnesium sulfate (7487-88-9)
Tetrahydrofuran (109-99-9)
2-amino-2-methyl-1-propanol (124-68-5)
hexane (110-54-3)
calcium hydride (7789-78-8)
sodium borohydride (16940-66-2)
ethyl acetate-hexane (2639-63-6)
2,3-dimethoxybenzoic acid (1521-38-6)
methyl trifluoromethanesulfonate (333-27-7)
2,2'-Dimethoxy-6-formylbiphenyl,
(1,1'-Biphenyl)-2-carboxaldehyde, 2',6-dimethoxy- (87306-84-1)
2-(2,3-Dimethoxyphenyl)-4,4-dimethyl-2-oxazoline (57598-32-0)
2,3-dimethoxybenzoyl chloride
2-bromoanisole (578-57-4)
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