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Org. Synth. 2002, 79, 209
DOI: 10.15227/orgsyn.079.0209
NUCLEOPHILIC AROMATIC SUBSTITUTION OF ARYL FLUORIDES BY SECONDARY NITRILES: PREPARATION OF 2-(2-METHOXYPHENYL)-2-METHYLPROPIONITRILE
[ Benzeneacetonitrile, 2-methoxy-α,α-dimethyl- ]
Submitted by Stéphane Caron1 , Jill M. Wojcik, and Enrique Vazquez.
Checked by Li Dong and Marvin J. Miller.
1. Procedure
2-(2-Methoxyphenyl)-2-methylpropionitrile . A 300-mL, three-necked, round-bottomed flask equipped with a reflux condenser and a Teflon-coated magnetic stir bar is placed under a nitrogen atmosphere and charged with 2-fluoroanisole (10.00 g, 79.28 mmol) (Note 1), 100 mL of tetrahydrofuran (THF, Note 2) and potassium hexamethyldisilylamide (KHMDS, 23.72 g, 118.92 mmol) (Note 3). Isobutyronitrile (28.8 mL, 316.71 mmol) (Note 4) is added via syringe. The reaction mixture is heated to 60°C for 23 hr (Note 5). After the solution is cooled to room temperature, it is transferred to a 1000-mL separatory funnel containing 300 mL of methyl tert-butyl ether (Note 6) and 300 mL of 1 N hydrochloric acid (HCl). The organic layer is separated and washed successively with 300 mL of water and 200 mL of brine. The organic phase is dried over anhydrous magnesium sulfate (MgSO4), filtered, and concentrated to provide the desired product as a tan oil (13.75 g, 99%) (Notes 7, 8 and 9).
2. Notes
1. 2-Fluoroanisole was purchased from Aldrich Chemical Co., Inc. , and used without further purification.
2. Anhydrous tetrahydrofuran was purchased from Aldrich Chemical Co., Inc. , in a Sure/Seal™ bottle.
3. Potassium hexamethyldisilylamide was purchased from Aldrich Chemical Co., Inc. , and used without further purification. The solid was weighed on a balance without special protection from air.
4. Isobutyronitrile was purchased from Aldrich Chemical Co., Inc. , and used without further purification.
5. The reaction can be monitored by HPLC (Hewlett-Packard 1100 HPLC, Kromasil C18 column (4.6 × 150 mm), 50/50 MeCN/0.2% H3PO4, 1.0 mL/min, product = 7.8 min) or by TLC analysis ( 2-fluoroanisole Rf = 0.67, product Rf = 0.51, ethyl acetate/hexanes 20/80).
6. A.C.S. Reagent grade methyl tert-butyl ether was purchased from J. T. Baker and used as received.
7. 1H NMR and 13C NMR indicate reasonably pure product. The HPLC analysis of the crude product showed a purity >97% (same conditions as Note 5) and satisfactory elementary analysis (calculated for C11H13NO: C, 75.40; H, 7.48; N, 7.99. Found: C, 75.01; H, 7.35; N, 8.07).
8. The product shows the following physical properties: 1H NMR (CDCl3, 300 MHz) δ: 1.80 (s, 6), 3.96 (s, 3), 6.97-7.02 (m, 2), 7.29-7.39 (m, 2) ; 13C NMR δ: 27.00, 34.43, 55.51, 112.02, 120.76, 124.80, 125.92, 128.62, 129.39, 157.30 . IR cm−1: 2980, 2235, 1493, 1462, 1437, 1253, 1027, 756 .
9. If material of greater purity is necessary, the product can be purified by chromatography on silica gel (100 g) using ethyl acetate/hexanes 20/80 (900 mL) as the eluant. When 100-mL fractions were collected, fractions #2 to #5 contained the desired product in >99% purity (12.31g, 89% yield)
Handling and Disposal of Hazardous Chemicals
The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.
These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.
3. Discussion
Tertiary benzylic nitriles are useful synthetic intermediates, and have been used for the preparation of amidines,2 lactones,3 primary amines,4 5 pyridines,6 aldehydes,7 8 carboxylic acids,9 and esters.10 11 The general synthetic pathway to this class of compounds relies on the displacement of an activated benzylic alcohol or benzylic halide with a cyanide source followed by double alkylation under basic conditions. For instance, 2-(2-methoxyphenyl)-2-methylpropionitrile has been prepared by methylation of (2-methoxyphenyl)acetonitrile using sodium amide and iodomethane .12 In the course of the preparation of a drug candidate,13 the submitters discovered that the nucleophilic aromatic substitution of aryl fluorides with the anion of a secondary nitrile is an effective method for the preparation of these compounds.14 The reaction was studied using isobutyronitrile and 2-fluoroanisole . The submitters first showed that KHMDS was the superior base for the process when carried out in either THF or toluene (Table I). For example, they found that the preparation of 2-(2-methoxyphenyl)-2-methylpropionitrile could be accomplished in near quantitative yield in a single operation. Several other substrates were studied as summarized in Table II. The reaction proceeds using either electron-rich or electron-poor arenes (entries 1-11) as well as cyclic nitriles (entries 12-14). The reaction requires an excess of nitrile, which can self-condense under the reaction conditions, as well as a slight excess of base. The submitters obtained the best results when using about 1.5 equiv of base in conjunction with 4 equiv of the nitrile. The acidic work-up removes most of the impurities generated in the reaction and, in the case of a low boiling starting nitrile, the excess reagent is evaporated with the solvent to provide a crude material of high purity.
TABLE I
NUCLEOPHILIC AROMATIC SUBSTITUTION OF (2-METHOXYPHENYL)-ACETONITRILE WITH ISOBUTYRONITRILE

Entry

Base

Solvent

T

Time

Yielda

(1.5 equiv)

(°C)

(h)

(%)


1

LiHMDS

THF

60

23

3

2

NaHMDS

THF

60

23

49

3

KHMDS

THF

60

23

95

4

KHMDS

Toluene

60

18

95

5

KHMDS

DMSO

75

24

No rxn

6

KHMDS

i-Pr2O

75

24

3

7

KHMDS

NMP

75

24

1


a) Yields <5% indicates the conversion observed by HPLC analysis after the time shown. The yields of entry 2,3 and 4 are isolated yields.

TABLE II
SNArOF ARYL FLUORIDES WITH SECONDARY NITRILES AND KHMDS

Entry

Fluoride

Nitrile

Solvent

T

Time

Yield

(equiv)

(°C)

(%)


1

2-OMe

1 (4.0)

Toluene

60

18 h

99

2

3-OMe

1 (4.1)

Toluene

100

3 h

69

3

4-OMe

1 (4.0)

THF

60

50 h

66

4

3,5-OMe

1 (4.0)

Toluene

70

48 h

85

5

3,4-OMe

1 (4.0)

THF

80

4 h

28

6

2-Cl

1 (4.0)

Toluene

60

45 min

77

7

4-Cl

1 (4.0)

THF

75

2 h

72

8

H

1 (4.0)

THF

75

14 h

69

9

3-Me

1 (4.0)

THF

75

14 h

71

10

4-CN

1 (4.0)

Toluene

60

40 min

83

11

4-CF3

1 (3.3)

Toluene

60

40 min

94

12

2-OMe

2 (4.0)

Toluene

75

48 h

47

13

2-OMe

3 (4.0)

THF

75

24 h

67a

14

2-OMe

4 (4.0)

THF

75

15 h

70a


a) Provided exclusively the 2(S) isomer (exo-aryl).


References and Notes
  1. Process Research, Chemical Research and Development, Pfizer Global R&D, Groton, CT 06340-8156. E. Vazquez' current address is Merck & Co. Inc., RY-800-C367, P.O. Box 2000, Rahway NJ 07065-0900.
  2. Convery, M. A.; Davis, A. P.; Dunne, C. J.; MacKinnon, J. W. Tetrahedron Lett. 1995, 36, 4279-4282.
  3. Tiecco, M.; Testaferri, L.; Tingoli, M.; Bartoli, D. Tetrahedron 1990, 46, 7139-7150.
  4. O'Donnell, M. J.; Wu, S.; Huffman, J. C. Tetrahedron 1994, 50, 4507-4518.
  5. Okatani, T.; Koyama, J.; Tagahara, K. Heterocycles 1989, 29, 1809-1814.
  6. Chelucci, G.; Conti, S.; Falorni, M.; Giacomelli, G. Tetrahedron 1991, 47, 8251-8258.
  7. Cha, J. K.; Christ, W. J.; Kishi, Y. Tetrahedron Lett. 1983, 24, 3943-3946.
  8. Chavan, S. P.; Ravindranathan, T.; Patil, S. S.; Dhondge, V. D.; Dantale, S. W. Tetrahedron Lett. 1996, 37, 2629-2630.
  9. Leader, H.; Smejkal, R. M.; Payne, C. S.; Padilla, F. N.; Doctor, B. P.; Gordon, R. K.; Chiang, P. K. J. Med. Chem. 1989, 32, 1522-1528.
  10. Bush, E. J.; Jones, D. W. J. Chem. Soc., Perkin Trans. 1 1997, 3531-3536.
  11. Breukelman, S. P.; Meakins, G. D.; Roe, A. M. J. Chem. Soc., Perkin Trans. 1 1985, 1627-1635.
  12. Gripenberg, J.; Hase, T. Acta Chem. Scand. 1966, 20, 1561-1570.
  13. Caron, S. In Organic Reactions and Processes Gordon Research Conference 2000; Roger Williams University, 2000.
  14. Caron, S.; Vazquez, E.; Wojcik, J. M. J. Am. Chem. Soc. 2000, 122, 712-713.

Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)

2-(2-Methoxyphenyl)-2-methylpropionitrile:
Hydratroponitrile, o-methoxy-α-methyl- (8);
Benzeneacetonitrile, 2-methoxy-α,α-dimethyl- (9); (13524-75-9)

2-Fluoroanisole:
Anisole, o-fluoro- (8);
Benzene, 1-fluoro-2-methoxy- (9); (321-28-8)

Potassium hexamethyldisilylamide: Aldrich:
Potassium-(bis(trimethylsilyl)amide:
Silanamine, 1,1,1-trimethyl-N-(trimethylsilyl)-, potassium salt (9); (40949-94-8)

Isobutyronitrile (8):
Propanenitrile, 2-methyl- (9); (78-82-0)