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Org. Synth. 2002, 78, 82
DOI: 10.15227/orgsyn.078.0082
EFFICIENT SYNTHESIS OF HALOMETHYL-2,2'-BIPYRIDINES: 4,4'-BIS(CHLOROMETHYL)-2,2'-BIPYRIDINE
[ 2,2'-Bipyridine, 4,4'-bis(chloromethyl)- ]
Submitted by Adam P. Smith, Jaydeep J. S. Lamba, and Cassandra L. Fraser1 .
Checked by Motoki Yamane and Koichi Narasaka.
Discussion Addendum: Org. Synth. 2012, 89, 82
1. Procedure
A. 4,4'-Bis[(trimethylsilyl)methyl]-2,2'-bipyridine . A 500-mL, two-necked, round-bottomed flask (Note 1), equipped with a nitrogen inlet, magnetic stirrer, and rubber septum is charged with tetrahydrofuran (THF) (90 mL) (Note 2) and diisopropylamine (9.8 mL, 69.7 mmol) (Note 3). The reaction mixture is cooled to −78°C and a solution of butyllithium (n-BuLi) (1.7 M in hexanes, 36.0 mL, 61.4 mmol) (Note 4) is added. The solution is stirred at −78°C for 10 min, warmed to 0°C and stirred for 10 min, then cooled back to −78°C. A solution of 4,4'-dimethyl-2,2'-bipyridine (5.14 g, 27.9 mmol) (Note 5) in THF (130 mL) (Note 2), prepared in a 250-mL, two-necked, round-bottomed flask under a nitrogen atmosphere, is added via cannula to the cold lithium diisopropylamide (LDA) solution. The resulting maroon-black reaction mixture is stirred at −78°C for 1 hr, then chlorotrimethylsilane (TMSCl) (8.85 mL, 69.7 mmol) (Note 6) is rapidly added via syringe. After the solution becomes pale blue-green (≈10 sec after the TMSCl addition), the reaction is quenched by rapid addition of absolute ethanol (10 mL). (Note: the reaction should be quenched regardless of color change after a maximum of 15 seconds to avoid over silylation). The cold reaction mixture is poured into a separatory funnel (1 L) containing aqueous saturated sodium bicarbonate (NaHCO3, ≈200 mL) and allowed to warm to ≈25°C. The product is extracted with dichloromethane (CH2Cl2, 3 × 300 mL); the combined organic fractions are shaken with brine (≈200 mL) and dried over sodium sulfate (Na2SO4). Filtration and concentration on a rotary evaporator affords 8.85 g (97%) of 4,4'-bis[(trimethylsilyl)methyl]-2,2'-bipyridine as a slightly off-white crystalline solid (Note 7).
B. 4,4'-Bis(chloromethyl)-2,2'-bipyridine . Into a 500-mL, two-necked, round-bottomed flask (Note 1) equipped with a magnetic stirring bar are placed 5.22 g (15.9 mmol) of 4,4'-bis[(trimethylsilyl)methyl]-2,2'-bipyridine , 15.1 g (63.6 mmol) of hexachloroethane (Cl3CCCl3, Note 8) and 9.65 g (63.6 mmol) of cesium fluoride (CsF, Note 9) at 25°C under a nitrogen atmosphere. Acetonitrile (260 mL) (Note 10) is added and the heterogeneous reaction mixture is stirred at 60°C for ≈3.5 hr (or until TLC indicates that all TMS starting material is consumed). After the mixture is cooled to 25°C, it is poured into a separatory funnel containing ethyl acetate (EtOAc) and water (H2O, ≈100 mL each). The product is extracted with EtOAc (3 × 100 mL); the combined organic fractions are shaken with brine (≈200 mL) and dried over Na2SO4. Filtration and concentration on a rotary evaporator, followed by flash chromatography using deactivated silica gel (60% EtOAc: 40% hexanes) (Note 11), gives 3.67 g (91%) of the chloride as a white solid (Note 12).
2. Notes
1. Before use, all glassware, needles, and syringes were dried overnight in a 120°C oven.
2. THF was dried and purified by passage through alumina solvent purification columns2 or by distillation over sodium/benzophenone.
3. Diisopropylamine was purchased from Aldrich Chemical Company, Inc. , and distilled over calcium hydride (CaH2) prior to use.
4. A 1.7 M solution of n-BuLi in hexanes was obtained from Aldrich Chemical Company, Inc. The n-BuLi is titrated prior to its use in each reaction using the following procedure.3 To a 50-mL, round-bottomed flask (Note 1), equipped with nitrogen inlet and a magnetic stirrer is added N-benzylbenzamide (854 mg, 4.0 mmol) (as received from Aldrich Chemical Company, Inc.) and THF (40 mL) (Note 2). The solution is cooled to −42°C (acetonitrile/dry ice) and n-BuLi is added dropwise to the blue endpoint (color persists for >30 sec). The molarity is calculated using a 1:1 stoichiometric ratio of N-benzylbenzamide to n-BuLi. (Just greater than 1 equivalent of alkyllithium is needed to reach the endpoint).
5. 4,4'-Dimethyl-2,2'-bipyridine was obtained from GFS Chemicals, Inc. or Tokyo Chemical Industry Co. and used as received.
6. Chlorotrimethylsilane (TMSCl) was purchased from Aldrich Chemical Company, Inc. , and used as obtained.
7. The following characterization data was obtained: mp 90-92°C; 1H NMR (CDCl3, 300 MHz) δ: 0.04 (s, 18 H), 2.21 (s, 4 H), 6.94 (d, 2 H, J = 5.01), 8.05 (br s, 2 H), 8.46 (d, 2 H, J = 5.00) ; 13C NMR (CDCl3, 75 MHz) δ: −2.2, 27.1, 120.4, 123.0, 148.3, 150.8, 155.5 . Anal. Calcd for C18H28N2Si2: C, 65.79; H, 8.59; N, 8.53. Found: C, 65.78; H, 8.43; N, 8.76. It has been noted that desilylation occurs after standing in deuterochloroform (CDCl3) overnight. The resulting methyl derivatives have also been observed in certain purified TMS bipyridine samples when stored over time. Therefore, it is best to convert these intermediates to the corresponding halides in a timely fashion.
8. Hexachloroethane (Cl3CCCl3), obtained from Aldrich Chemical Company, Inc. , was used as received.
9. Cesium fluoride was purchased from Acros Organics, Inc. or Soekawa Chemicals Co. and stored in a dry box prior to use.
10. Acetonitrile was distilled over CaH2 and stored in a 500-mL Kontes flask prior to use.
11. Silica gel used for flash chromatography (particle size 0.035-0.075 mm) was obtained from VWR Scientific Products . Silica chromatography columns were deactivated by flushing with 10% triethylamine in hexanes and then were washed with hexanes prior to use.
12. Spectral properties are as follows: mp 98-100°C; 1H NMR (CDCl3, 300 MHz) δ: 4.63 (s, 4 H), 7.38 (dd, 2 H, J = 1.9, 5.0), 8.43 (s, 2 H), 8.70 (d, 2 H, J = 4.6) ; 13C NMR (CDCl3, 75 MHz) δ: 43.9, 120.1, 122.8, 146.7, 149.4, 155.8 . Anal. Calcd for C12H10Cl2N2: C, 56.94; H, 3.98; N, 11.07. Found: C, 56.82; H, 4.04; N, 11.01.
13. In some cases, particularly if the solvent or reaction conditions are not thoroughly dry, 4,4'-dimethyl-2,2'-bipyridine is formed as a byproduct during the halogenation reaction. This compound may be separated from 4,4'-bis(chloromethyl)-2,2'-bipyridine by flash chromatography on silica gel (not deactivated with Et3N) using EtOAc as the mobile phase. Alternatively, 4,4'-bis(chloromethyl)-2,2'-bipyridine may be purified by recrystallization in hot/cold absolute EtOH, with no evidence of ether formation (e.g., 4,4'-di-Ethoxymethyl-2,2'-bipyridine) by 1H NMR.
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
Halomethylbipyridines, are typically synthesized either by radical halogenation4 or from hydroxymethylbipyridine precursors.5 Radical methods often give rise to mixtures of halogenated species that are difficult to separate with flash chromatography. A solution to this problem, involving the selective reduction of polyhalogenated by-products with diisobutylaluminum hydride (DIBAL-H), has resulted in slight improvements in overall yields.6 While the synthesis of halomethyl compounds from hydroxymethyl precursors is more efficient than radical halogenation, such procedures involve many steps, each of which give intermediates in moderate to high yields.5 Direct trapping of bpy (CH2Li)n with electrophiles has proved unsuccessful for the generation of halide products.5a The quenching of LDA-generated carbanions with TMSCl prior to halogenation as described here constitutes an efficient, high yield synthesis of halomethyl bpys substituted at various positions around the ring system.7,8
Currently, 2,2'-bipyridine derivatives figure prominently in supramolecular assembly,9 in bioinorganic contexts,10 in studies of redox electrocatalysis4a and in polymeric materials.11 Halomethyl bpys and their various metal complexes have also been used as initiators for controlled polymerizations of several different monomers including styrene and 2-alkyl-2-oxazolines.12
TABLE I
SYNTHESIS OF (TRIMETHYLSILYL)METHYL-2,2'-BIPYRIDINES

Product

R1

R2

R3

R4

Yield (%)


4-(Trimethylsilyl)-methyl-2,2'-bipyridine

TMSCH2

H

H

H

93

5-(Trimethylsilyl)-methyl-2,2'-bipyridine

H

TMSCH2

H

H

99

6-(Trimethylsilyl)-methyl-2,2'-bipyridine

H

H

TMSCH2

H

97

4,4'-Bis[(trimethylsilyl)-methyl]-2,2'-bipyridine

TMSCH2

H

H

TMSCH2

97


TABLE II
SYNTHESIS OF HALOMETHYL-2,2'-BIPYRIDINES

Product

R1

R2

R3

R4

Yield (%)


4-Chloromethyl-2,2'-bipyridine

ClCH2

H

H

H

94

5-Chloromethyl-2,2'-bipyridine

H

ClCH2

H

H

98

6-Chloromethyl-2,2'-bipyridine

H

H

ClCH2

H

95

4,4'-Bis(chloromethyl)-2,2'-bipyridine

ClCH2

H

H

ClCH2

91

4-Bromomethyl-2,2'-bipyridine

BrCH2

H

H

H

92

5-Bromomethyl-2,2'-bipyridine

H

BrCH2

H

H

98

6-Bromomethyl-2,2'-bipyridine

H

H

BrCH2

H

99

4,4'-Bis(bromomethyl)-2,2'-bipyridine

BrCH2

H

H

BrCH2

97



References and Notes
  1. Department of Chemistry, University of Virginia, Charlottesville, VA 22904-4319.
  2. Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Organometallics 1996, 15, 1518.
  3. Burchat, A. F.; Chong, J. M.; Nielsen, N. J. Organomet. Chem. 1997, 542, 281.
  4. (a) Gould, S.; Strouse, G. F.; Meyer, T. J.; Sullivan, B. P. Inorg. Chem. 1991, 30, 2942 and references therein; (b) Wang, Z.; Reibenspies, J.; Motekaitis, R. J.; Martell, A. E. J. Chem. Soc., Dalton Trans. 1995, 1511; (c) Rodriguez-Ubis, J.-C.; Alpha, B.; Plancherel, D.; Lehn, J.-M. Helv. Chim. Acta 1984, 67, 2264; (d) Newkome, G. R.; Puckett, W. E.; Kiefer, G. E.; Gupta, V. K.; Xia, Y.; Coreil, M.; Hackney, M. A. J. Org. Chem. 1982, 47, 4116.
  5. (a) Della Ciana, L.; Hamachi, I.; Meyer, T. J. J. Org. Chem. 1989, 54, 1731; (b) Della Ciana, L.; Dressick, W. J.; Von Zelewsky, A. J. Heterocycl. Chem. 1990, 27, 163; (c) Newkome, G. R.; Kiefer, G. E.; Kohli, D. K.; Xia, Y.-J.; Fronczek, F. R.; Baker, G. R. J. Org. Chem. 1989, 54, 5105; (d) Imperiali, B.; Prins, T. J.; Fisher, S. L. J. Org. Chem. 1993, 58, 1613.
  6. Uenishi, J.; Tanaka, T.; Nishiwaki, K.; Wakabayashi, S.; Oae, S.; Tsukube, H. J. Org. Chem. 1993, 58, 4382.
  7. Fraser, C. L.; Anastasi, N. R.; Lamba, J. J. S. J. Org. Chem. 1997, 62, 9314.
  8. Savage, S. A.; Smith, A. P.; Fraser, C. L. J. Org. Chem. 1998, 63, 10048.
  9. (a) Boulas, P. L.; Gómez-Kaifer, M.; Echegoyen, L. Angew. Chem., Int. Ed. Engl. 1998, 37, 216; (b) Mamula, O.; von Zelewsky, A.; Bernardinelli, G. Angew. Chem., Int. Ed. Engl. 1998, 37, 290.
  10. (a) Gray, H. B.; Winkler, J. R. Annu. Rev. Biochem. 1996, 65, 537; (b) Dandliker, P. J.; Holmlin, R. E.; Barton, J. K. Science 1997, 275, 1465.
  11. For a recent review see: Matyjaszewski, K., Ed. "Controlled Radical Polymerizations"; American Chemical Society: Washington, DC, 1998.
  12. (a) Collins, J. E.; Fraser, C. L. Macromolecules 1998, 31, 6715; (b) McAlvin, J. E.; Fraser, C. L. Macromolecules 1999, 32, 1341; (c) Wu, X.; Fraser, C. L. Macromolecules 2000, 33, 4053.

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

4,4'-Bis(chloromethyl)-2,2'-bipyridines:
2,2'-Bipyridine, 4,4'-bis(chloromethyl)- (13); (138219-98-4)

4,4'-Bis[(trimethylsilyl)methyl]-2,2'-bipyridine:
2,2'-Bipyridine, 4,4'-bis[(trimethylsilyl)methyl]- (14); (199282-52-5)

Diisopropylamine (8);
2-Propanamine, N-(1-methylethyl)- (9); (108-18-9)

Butyllithium:
Lithium, butyl- (8,9); (109-72-8)

4,4'-Dimethyl-2,2'-bipyridine:
2,2'-Bipyridine, 4,4'-dimethyl- (9); (1134-35-6)

Chlorotrimethylsilane:
Silane, chlorotrimethyl- (8,9); (75-77-4)

Hexachloroethane:
Ethane, hexachloro- (8,9); (67-72-1)

Cesium fluoride (8,9); (13400-13-0)

Acetonitrile: TOXIC (8,9); (75-05-8)

N-Benzylbenzamide:
Benzamide, N-benzyl- (8);
Benzamide, N-(phenylmethyl)- (9); (1485-70-7)