Synthesis of Halomethyl and Other Bipyridine Derivatives by Reaction of 4,4′-Bis[(trimethylsilyl)methyl]-2,2′-bipyridine with Electrophiles in the Presence of Fluoride Ion

Article abstract of DOI:10.1021/jo971685x

Bipyridine (bpy) ligands figure prominently in many areas of chemistry. Common precursors to many derivatives are the halomethyl-substituted analogues. This report describes a new, high yield route to these valuable compounds via a trimethylsilyl (TMS) in

Full text of DOI:10.1021/jo971685x

9
314
J . Org. Chem. 1997, 62, 9314-9317
Syn th esis of Ha lom eth yl a n d Oth er Bip yr id in e Der iva tives by
Rea ction of 4,4′-Bis[(tr im eth ylsilyl)m eth yl]-2,2′-bip yr id in e w ith
Electr op h iles in th e P r esen ce of F lu or id e Ion
Cassandra L. Fraser,* Natia R. Anastasi, and J aydeep J . S. Lamba
Department of Chemistry, University of Virginia, Charlottesville, Virginia 22901
Received September 8, 1997X
Bipyridine (bpy) ligands figure prominently in many areas of chemistry. Common precursors to
many derivatives are the halomethyl-substituted analogues. This report describes a new, high
yield route to these valuable compounds via a trimethylsilyl (TMS) intermediate. 4,4′-Dimethyl-
2
,2′-bpy was reacted with lithium diisopropylamide, and the dianion thus formed was trapped with
TMSCl to generate 4,4′-bis[(trimethylsilyl)methyl]-2,2′-bpy (1). The TMS group was removed using
-
2 2 2 3 3
dry F sources (TBAF/SiO in THF or CsF in DMF) in the presence of BrF CCF Br or Cl CCCl to
produce the bromide 2 or chloride 3 analogues of 4,4′-bis(halomethyl)-2,2′-bipyridine, respectively.
The CsF/DMF methodology extends to other electrophiles, including benzaldehyde to give 4,4′-
bis(2-hydroxy-2-phenethyl)-2,2′-bpy, 6, as well as to alkyl halides. Benzyl Br, dodecyl Br, and
R-chloroacetonitrile gave mixtures of di- and monoalkylated products along with the diprotonated
product, 4,4′-dimethyl-2,2′-bpy.
In tr od u ction
Some of the most widely used ligands in chemistry are
derivatives are rarely trivial. Typically they are prepared
either by radical halogenation of the appropriate methyl
7,10
11
derivatives, or from hydroxymethyl precursors. Radi-
cal methods usually give rise to mixtures of halogenated
products that are difficult to separate by column chro-
matography. One solution to this problem has been to
carry out selective reduction of polyhalogenated byprod-
ucts with diisobutylaluminum hydride (DIBALH), but
this has resulted in only slight improvements in overall
bipyridine (bpy) and its various derivatives. From foun-
1
dational studies in coordination chemistry to the present
day, this family of nitrogen heterocycles has played a
central role. Currently bpy derivatives figure promi-
2
nently in supramolecular chemistry, conformationally
constrained peptides, in sensors and receptors,4 in
3
5
,6
7
polymer chemistry, studies of redox electrocatalysis,
12
yields. A more efficient approach involves the conver-
8
9
electron transfer, photochemistry, electroluminescence,
sion of alcohol functionalities to halides; however the
synthesis of the hydroxymethyl compounds from methyl
precursors typically involves multiple steps, each of
and a variety of other fields. Halomethyl bipyridines are
particularly useful since they serve as precursors to
numerous other analogues. Despite their widespread
application, the synthesis and purification of halide
11
which give intermediates in moderate to high yields.
2 n
Generation of bpy(CH Li) anions with strong bases,
followed by trapping with electrophiles, has not proven
successful for halide products.
X
11a,13
Abstract published in Advance ACS Abstracts, December 1, 1997.
(1) Reedijk, J . In Comprehensive Coordination Chemistry; Wilkinson,
In trying to develop more efficient routes to 4,4′-
bis(halomethyl)-2,2′-bpy ligands for use as metalloinitia-
Sir G.; Gillard, R. D., McCleverty, J . A., Eds.; Pergamon Press: Oxford
and NY, 1987; Vol. 2, pp 73-98 and references therein.
6
(2) (a) Philp, D.; Stoddart, J . F. Angew. Chem., Int. Ed. Engl. 1996,
tors for living polymerization reactions, it was discovered
3
5, 1154-96. (b) Achar, S.; Puddephatt, R. J . Angew. Chem., Int. Ed.
that halides and other bpy analogues can be conveniently
obtained via the trimethylsilyl (TMS) derivative, 1. Our
approach employs TMS as a carbanion protecting group
Engl. 1994, 33, 847-9. (c) Hasenknopf, B.; Lehn, J . M.; Kneisel, B.
O.; Baum, G.; Fenske, D. Angew. Chem., Int. Ed. Engl. 1996, 35, 1838-
4
0. (d) Woods, C. R.; Benaglia, M.; Cozzi, F.; Siegel, J . S. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 1830-3. (e) See: Tzalis, D.; Tor, Y. J . Am.
-
that may be removed by F in situ for reaction with
Chem. Soc. 1997, 119, 852-3 and references therein.
(3) (a) Cheng, R. P.; Fisher, S. L.; Imperiali, B. J . Am. Chem. Soc.
electrophiles. Though this methodology has precedent
1
996, 118, 11349-56. (b) Ghadiri, M. R.; Soares, C.; Choi, C. J . Am.
14
in reactions with carbonyl substrates, the use of halide
Chem. Soc. 1992, 114, 825-31, 4000-2. (c) Sardesai, N.; Lin, S. C.;
Zimmermann, K.; Barton, J . K. Bioconjugate Chem. 1995, 6, 302-12.
and RX electrophiles is less common. Described below
are investigations of the reactivity of 1 with halide,
aldehyde, and alkyl halide electrophiles.
(
d) Harding, M. M.; Lehn, J . M. Aust. J . Chem. 1996, 49, 1023-27.
(
4) (a) Torrado, A.; Imperiali, B. J . Org. Chem. 1996, 61, 8940-8.
(
b) Szemes, F.; Hesek, D.; Chen, Z.; Dent, S. W.; Drew, M. G. B.;
Goulden, A. J .; Graydon, A. R.; Grieve, A.; Mortimer, R. J .; Wear, T.;
Weightman, J . S.; Beer, P. D. Inorg. Chem. 1996, 35, 5868-79.
(10) (a) Wang, Z.; Reibenspies, J .; Motekaitis, R. J .; Martell, A. E.
J . Chem. Soc., Dalton Trans. 1995, 1511-8. (b) Rodriguez, J .-C.; Alpha,
B.; Plancherel, D.; Lehn, J .-M. Helv. Chim. Acta 1984, 67, 2264-9. (c)
Newkome, G. R.; Puckett, W. E.; Kiefer, G. E.; Gupta, V. K.; Xia, Y.;
Coreil, M.; Hackney, M. A. J . Org. Chem. 1982, 47, 4116-20.
(11) (a) Della Ciana, L.; Hamachi, I.; Meyer, T. J . J . Org. Chem.
1989, 54, 1731-5. (b) Della Ciana, L.; Dressick, W. J .; von Zelewsky,
A. J . Heterocyc. 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, 5105-10. (d) Imperiali, B.; Prins, T. J .; Fisher, S. L. J . Org.
Chem. 1993, 58, 1613-6.
(
5) Matyjaszewski, K.; Patten, T. E.; Xia, J . J . Am. Chem. Soc. 1997,
1
19, 674-80.
(6) Lamba, J . J . S.; Fraser, C. L. J . Am. Chem. Soc. 1997, 119, 1801-
2
.
(7) See: Gould, S.; Strouse, G. F.; Meyer, T. J .; Sullivan, B. P. Inorg.
Chem. 1991, 30, 2942-9 and references therein.
8) (a) Gray, H. B.; Winkler, J . R. Annu. Rev. Biochem. 1996, 65,
(
5
37-61. (b) Holmlin, R. E.; Stemp, E. D. A.; Barton, J . K. J . Am. Chem.
Soc. 1996, 118, 5236-44. (c) Dandliker, P. J .; Holmlin, R. E.; Barton,
J . K. Science 1997, 275, 1465-8.
(9) (a) J uris, A.; Balzani, V.; Barigelletti, F.; Campagna, S.; Belser,
(12) Uenishi, J .-I.; Tanaka, R.; Nishiwaki, K.; Wakabayashi, S.; Oae,
S.; Tsukube, H. J . Org. Chem. Soc. 1993, 58, 4382-8.
P.; von Zelewsky, A. Coord. Chem. Rev. 1988, 84, 85-277. (b) Sauvage,
J .-P.; Collin, J .-P.; Chambron, J .-C.; Guillerez, S.; Coudret, C.; Balzani,
V.; Barigelletti, F.; De Cola, L.; Flamigni, L. Chem. Rev. (Washington,
D.C.) 1994, 94, 993-1019. (c) Balzani, V.; J uris, A.; Venturi, M.;
Campagna, S.; Serroni, S. Chem. Rev. 1996, 96, 659-833.
(13) Attempts to react 4,4′-bis-(LiCH
2
)-2,2′-bpy with halide electro-
Br, were unsuccessful in
philes, including NBS, Br , and BrF CCF
2
2
2
yielding 2. Addition of the lithiated bpy to a THF solution of Cl
produced the less reactive dichloro product 3 in impure form.
3 3
CCCl
S0022-3263(97)01685-X CCC: $14.00 © 1997 American Chemical Society

4
,4′-Bis[(trimethylsilyl)methyl]-2,2′-bipyridine
J . Org. Chem., Vol. 62, No. 26, 1997 9315
Resu lts a n d Discu ssion
over time, other more convenient sources of fluoride ion
were sought. Anhydrous cesium fluoride was selected
for its good solubility in polar organic solvents such as
The TMS derivative, 1 is prepared in essentially
quantitative yield15 by deprotonation of 4,4′-dimethyl-
CH
anionic alkylations. Reaction of the TMS compound, 1,
with CsF and halide electrophiles, BrF CCF Br or
(X sources), in dry DMF solution produces 2
or 3 cleanly and nearly quantitatively after 2 h at room
temperature (eq 2). Since BrF CCF Br is volatile, the
CN18 and DMF, the latter also being favorable for
3
2
,2′-bipyridine with LDA followed by trapping of the
resulting dianion with TMSCl (eq 1). To prevent over-
silylation16 it is crucial that the reaction be quenched with
EtOH immediately after silylation is complete. This
occurs ∼5-10 s after TMSCl addition and is indicated
by a color change from brown to pale blue-green. The
resulting crystalline TMS-bpy product, 1, serves as a
stable “dianion equivalent” and as a starting material
in the synthesis of other bpy analogues.
2
2
+
3 3
Cl CCCl
2
2
halide product 2 may be very conveniently isolated pure,
in essentially quantitative yield after a standard aqueous
workup. Hexachloroethane, in contrast, is a solid and
must be separated either by column chromatography or
by acidification, ether washes, neutralization, and back
extraction of the bpy product. Typically 2 equiv of the
halide electrophile was used per TMS group in these
reactions. This increases the reaction rate and is neces-
sary for clean conversion to product by the standard
conditions. A mixture of mono- and dichlorinated bpy
products was obtained when only 1 equiv of halide per
TMS group was utilized. To gain a better understanding
of the origin of the protonated byproducts and to see
Since removal of the TMS groups with F- produces a
highly basic carbanion-like functionality, dry fluoride
-
sources were utilized for this reaction. Two different F
4 2
reagents, Bu NF supported on SiO
(dry TBAF)17 and
CsF, were compared under different reaction conditions.
Our initial studies employed dry TBAF for the reaction
of 1 with the halide electrophiles, BrF
3 3
Cl CCCl
2 2
CCF Br and
, in THF solution.6 Reactions run at -78 °C and
at room temperature proceeded similarly and were
complete within e15 min. For ease of product isolation
and subsequent purification by column chromatography,
3 3
whether the reaction between 1 and Cl CCCl might be
2
the amount of TBAF/SiO reagent was kept to a mini-
induced thermally, a control reaction was run at 65 °C
in DMF solution in the absence of CsF. GC/MS analysis
showed primarily the diprotonated 4,4′-dimethyl-2,2′-
bipyridine product. There was no evidence of either
mono- or dichlorinated bpy. This suggests that the
protonation side reaction may not necessarily be CsF
dependent.
mum. The halide products 2 and 3 were produced cleanly
and in high yield by this route (2: 73%; 3: 96%).
Attempts to extend this methodology to other electro-
philes, including benzyl or allyl bromide, or methyl
R-bromoacetate met with very limited success. Some
alkylated products were obtained with the ester reagent,
but in the other cases primarily the diprotonated product,
To further explore the scope of this reaction, benzal-
dehyde, a carbonyl electrophile, was also tested. A mix-
ture of TMS ether products 4 and 5 was isolated after
reaction of the TMS bpy starting material 1 with benz-
aldehyde under the standard conditions (eq 2) and
aqueous workup. Treatment of the mixture of 4 and 5
thus isolated with 1 M HCl yielded the diol 6. This
4
,4′-dimethyl-2,2′-bipyridine was formed, indicating that
protonation is more favorable than alkylation under these
conditions.
Since the TBAF/SiO
2
methodology was somewhat
limited in scope and the activity of dry TBAF diminishes
(14) (a) Majetich, G.; Hull, K.; Casares, A. M.; Khetani, V. J . Org.
Chem. 1991, 56, 3958-73 and references therein. (b) Ricci, A.; Fiorenza,
product 6 was obtained more directly by addition of H
2
O
M.; Grifagni, M. A.; Bartolini, G. Tetrahedron Lett. 1982, 23, 5079-
to the reaction mixture once alkylation was complete
(TLC) and stirring for ∼30 min prior to workup (eq 3).
The CsF methodology also extends to reactions of 1
with alkyl halide electrophiles, RX (eq 4), though these
reactions are not as selective as those with halide or
benzaldehyde electrophiles. Benzyl and dodecyl bromide
and chloroacetonitrile were selected for careful screening
since these commercially available compounds span a
range of reactivities and some of the likely reaction
products are of interest to us for other purposes. Reac-
tion times were extended to ensure the complete con-
sumption of TMS starting material and intermediates as
8
2. (c) Hosomi, A.; Hayashi, S.; Hoashi, K.; Kohara, S.; Tominaga, Y.
J . Org. Chem. 1987, 52, 4424-6. (d) Shair, M. D.; Yoon, T. Y.; Mosny,
K. K.; Chou, T. C.; Danishefsky, S. J . J . Am. Chem. Soc. 1996, 118,
9
1
509-25. (e) Danishefsky, S. J .; Shair, M. D. J . Org. Chem. 1996, 61,
6-44.
(15) In some reactions the TMS product 1 was contaminated with
trace amounts of the 4,4′-dimethyl-2, 2′-bipyridine starting material
and/or a yellow impurity. If only the dimethyl compound is present,
crude 1 may be separated either by column chromatography (SiO
.5% EtOAc in hexanes, TMS compound elutes first) or more conve-
niently, by recrystallization from a minimal amount of hexanes at -4
C. The TMS bpy 1 precipitates and may be collected by filtration. The
2
,
3
°
yellow impurity may be removed from the solid thus collected by
washing with copious quantities of very cold hexanes, leaving the TMS
product 1 as a white crystalline solid.
(
16) Oversilylation is most clearly indicated by more than one singlet
1
in the 0-0.10 ppm region of the H NMR spectrum. Oversilated product
∼2 g) may be recycled to valuable dimethyl bpy starting material by
stirring a CH
CN solution (∼100 mL) with 48% HF (∼2-3 mL) at 25
C for several hours. The dimethyl compound precipitates from the
(
(18) Acetonitrile was also tested as a solvent for reactions using CsF
and the TMS bpy substrate 1. This approach works well for the
preparation of the chloro bpy ligand 3, and many alkylated products
may be accessed by this route. However, elevated temperatures (∼50
3
°
reaction mixture as its HF salt, a white solid, and is collected by
filtration. The free base is obtained by dissolving the white precipitate
3
°C) are required for reactions in CH CN which not only precludes the
in CH
of the organic layer.
17) Clark, J . H. J . Chem. Soc., Chem. Commun. 1978, 789.
2
Cl
2
, washing with aqueous Na
2
CO
3
, followed by concentration
2 2
synthesis of the bromide ligand 2 (BrF CCF Br: bp ) 47 °C), but also
leads to side products and depressed yields in the alkylation reactions
as compared with reactions run in DMF solution.
(

9
316 J . Org. Chem., Vol. 62, No. 26, 1997
Fraser et al.
for flash column chromatography (particle size 0.040-0.063
mm) was obtained from Merck. Reactions were run in DMF
obtained from Aldrich in Sureseal bottles. THF was dried and
purified by passage through alumina solvent purification
columns.21 CH
CN was distilled from CaH
were run under a nitrogen atmosphere and were monitored
by TLC on SiO (typically 20% EtOAc in hexane; UV detection).
Silica plates and chromatography columns were deactivated
with 10% Et N in hexanes prior to use. (NOTE: For the TMS
bpy starting material, 1, R
≈ 0.5. All products appear at R
0.5. Reaction intermediates sometimes appear at R > 0.5.)
3
2
. All reactions
2
3
f
f
<
f
For reactions run in DMF, silica plates were dried under high
vacuum for at least ∼10 min prior to developing. Typical
procedures for dry TBAF and CsF reactions are provided
below. Alkylation reactions were typically run using ∼100 mg
of 1. Deviations from these procedures and purification
methods for each compound are indicated below. Initial
product percentages for reaction mixtures were determined
by GC after the standard workup. Isolated product yields are
based on 1.
indicated by TLC. Typically mixtures of dialkylated,
monoalkylated, and diprotonated (i.e. dimethyl) bpy were
obtained in different amounts with these and other alkyl
halide reagents. In most cases, particularly with more
reactive electrophiles, highly colored, polar byproducts
were also formed. These water soluble species could be
alkyl pyridinium species resulting from reaction of RX
reagents with the bpy nitrogens. For each reaction, the
major product was separated from reaction byproducts
by fractional crystallization or by column chromatogra-
phy prior to characterization. Generally this was the
dialkylated product; however, for reaction of 1 with
chloroacetonitrile, the monoalkylated product 9 predomi-
P r ep a r a tion of n -Bu
was prepared by the procedure of Clark with the following
modifications. n-Bu NF (1 M in THF, 20 mL, 20 mmol) and
Et
4 2
NF /SiO (“Dr y TBAF ”). Dry TBAF
1
7
4
3
N (1 mL) were added to silica gel (8 g) in MeOH (∼60 mL).
The solvents were removed by evaporation at 25 °C,22 and the
residual solvent in the resulting white gummy solid was
nated. Yields are reported after purification based on
azeotroped with benzene (3 × 100 mL). The SiO
2
-supported
starting material 1 (eq 4).19 Though direct reaction of
TBAF was then dried under high vacuum for ∼14 h at 25 °C.
The reagent remains “active” for ∼2 weeks if stored under
nitrogen at 4 °C. Dry TBAF gradually turns yellow as it
decomposes.
alkyl halides with dimethyl bpy dianion is more efficient
in certain cases,20 it might be possible to further optimize
the conditions of our reactions to give better selectivity
for mono- or dialkylated products.
Syn th esis of 4,4′-Bis[(tr im eth ylsilyl)m eth yl]-2,2′-bip yr -
id in e (1). To diisopropylamine (1.75 mL, 12.5 mmol) in THF
(
16 mL) at -78 °C was added n-BuLi (1.6 M in hexanes, 6.9
mL, 11 mmol). The solution was stirred at -78 °C for 20 min.
,4′-Dimethyl-2,2′-bipyridine (0.921 g, 5 mmol) was dissolved
4
in dry THF (22 mL) and was transferred dropwise via cannula
to the LDA solution. The flask and cannula were rinsed with
THF (2 × 2 mL). The brown mixture was stirred at -78 °C
for 20 min, was warmed to -10 °C for 25 min, and then was
cooled to -78 °C before addition of TMSCl (1.65 mL, 13 mmol).
As soon as the brown reaction mixture became pale blue-green
in color (∼5-10 s after TMSCl addition), the reaction was
quenched with EtOH (3 mL). Saturated aqueous NaHCO
3
was
Con clu sion
added to the cold reaction mixture, which was then allowed
These investigations illustrate that 4,4′-bis(TMSCH
,2′-bipyridine is a versatile starting material for the
2
)-
to warm to ∼25 °C. The product was extracted into EtOAc (3
×
200 mL), and then combined organic fractions were washed
2
2 4
with brine (200 mL) and were dried over Na SO . Filtration
synthesis of bpy derivatives bearing halide, alcohol,
nitrile, and other functionalities. Though different dry
and concentration afforded the product, 1, as a slightly off-
white crystalline solid: 1.632 g (99%);15 mp 90-92 °C; H NMR
1
-
F sources, reaction conditions, and solvents may be used
(
5
CDCl , 300 MHz) δ 0.04 (s, 18 H), 2.21 (s, 4 H), 6.94 (d, J )
3
for these reactions, for convenience, optimal yield, and
purity of products, CsF in DMF is the method of choice
for both halogenation and alkylation reactions. This
approach, which allows for the synthesis of halomethyl
bpys in two nearly quantitative yield steps, constitutes
a dramatic improvement over existing methodologies for
making these widely used compounds. This TMS/CsF
chemistry should readily extend to bipyridines with
different substitution patterns, to related nitrogen het-
erocycles, and to new classes of electrophiles.
13
.01 Hz, 2 H), 8.05 (br s, 2 H), 8.46 (d, J ) 5.00 Hz, 2 H).
C
NMR (CDCl , 75 MHz) δ -2.2, 27.1, 120.4, 123.0, 148.3, 150.8,
155.5.
3
Gen er a l P r oced u r e for TBAF /SiO
th esis of 4,4′-Bis(ch lor om eth yl)-2,2′-bip yr id in e (3). To
,4′-bis[(trimethylsilyl)methyl]-2,2′-bipyridine (1) (0.500 g, 1.52
mmol) and Cl CCCl (1.44 g, 6.1 mmol) in THF (20 mL) at
78 °C was added TBAF/SiO
(3.0 g, ∼4.6 mmol). If the
reaction was not complete after 15 min (TLC), additional
TBAF/SiO (0.2 g) was added. After complete conversion, the
2
Rea ction s. Syn -
4
3
3
-
2
2
heterogeneous mixture was concentrated in vacuo. Crude 3
was loaded onto a deactivated silica gel column (pretreated
with 10% triethylamine in hexane) and was eluted with
Exp er im en ta l Section
2 2
CH Cl . Concentration of the appropriate fractions afforded
Gen er a l Con sid er a tion s. All chemicals were obtained
from Aldrich or Acros and were used as received unless
otherwise indicated. Silica gel used to prepare dry TBAF and
the chloride 3 as a white solid: 0.357 g (94%); mp 98-100
1
°C; H NMR (CDCl , 300 MHz) δ 4.63 (s, 4 H), 7.38 (dd, J )
3
5.01, 1.93 Hz, 2 H), 8.43 (s, 2 H), 8.70 (d, J ) 4.62 Hz, 2 H).
1
3
C NMR (CDCl
3
, 75 MHz) δ 43.9, 120.1, 122.8, 146.7, 149.4,
(19) Though the phenethyl product 7 is produced in good yield (83%,
155.8. Anal. Calcd for C12H N Cl : C, 56.94; H, 3.98; N,
10 2 2
GC) by the CsF reaction, this drops dramatically during purification
due to the difficulties of separation from the dimethyl bpy byproduct
of similar polarity.
11.07. Found: C, 56.82; H, 4.04; N, 11.01.
(20) (a) el Torki, F. M.; Schmehl, R. H.; Reed, W. F. J . Chem. Soc.,
(21) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.;
Timmers, F. J . Organometallics 1996, 15, 1518-20.
(22) Rotoevaporation at elevated temperature results in decomposi-
tion of the “dry TBAF” reagent.
Faraday Trans. 1 1989, 85, 349-62. (b) For related compounds see:
Griggs, C. G.; Smith, D. J . H. J . Chem. Soc., Perkin Trans. 1 1982,
3
041-3.

4
,4′-Bis[(trimethylsilyl)methyl]-2,2′-bipyridine
J . Org. Chem., Vol. 62, No. 26, 1997 9317
Gen er a l P r oced u r e for CsF Rea ction s. Syn th esis of
monoalkyl, 19% diprotonated bpy products (GC). Improved
yields were obtained using only 1 mL of DMF/0.1 g of 1 for
the reaction combined with the following modified workup.
Alkylated products precipitated from the DMF reaction mix-
ture, were collected by filtration, and then were washed with
4
,4′-Bis(br om om eth yl)-2,2′-bip yr id in e (2).7 To a dry DMF
solution (5 mL) of 4,4′-bis[(trimethylsilyl)methyl]-2,2′-bipyri-
dine (1) (0.104 g, 0.317 mmol) and BrF CCF Br (0.152 mL,
.27 mmol) was added anhydrous CsF (0.193 g, 1.27 mmol).
2
2
1
The reaction was stirred at ∼25 °C for ∼2 h (or until TLC
indicated that all TMS starting material and intermediates
were consumed). The reaction mixture was poured into a
H
2
O. The major dialkyl product 8 was obtained after fractional
crystallization from EtOH according to the procedure of el
2
0
24
Torki et al.: 0.37 g (46%); 76-77 mp °C, lit. mp 64-5 °C.
1
20
separatory funnel containing EtOAc and H
The aqueous layer was extracted with EtOAc (3 × 50 mL),
and then combined organic fractions were washed with H
2 × 100 mL), were shaken with brine (200 mL), and then were
dried over Na SO . Filtration, and concentration in vacuo gave
2
O (100 mL each).
H NMR coincident with data reported by el Torki et al.
4-(2-cya n oeth yl)-4′-m eth yl-2,2′-bip yr id in e (9). Reaction
2
O
of 1 with chloroacetonitrile at rt for 1 d produced 26% dialkyl,
49% monoalkyl, and 25% diprotonated bpy products (GC).
(
2
4
After purification by chromatography on deactivated SiO (1:1
2
EtOAc/hexane), the monoalkylated product, 9 was obtained
as a thick water white oil that crystallized upon standing: 0.03
1
pure 2 as a white solid: 0.105 g (97%); mp 116-118 °C.
H
NMR coincident with data reported by Gould et al.7
1
4
,4′-Bis(2-h yd r oxy-2-p h en eth yl)-2,2′-bip yr id in e (6). A
mixture of the mono- and bis-TMS protected alcohol products
and 5 was isolated using the standard procedure. To obtain
the alcohol 6 directly, H O (2 mL) was added to the reaction
mixture after alkylation was complete (TLC) and the DMF/
O mixture was stirred at rt for ∼30 min. The reaction was
poured into EtOAc/H O (100 mL each), and a white solid
precipitated immediately and remained suspended in the
EtOAc layer. The EtOAc suspension was washed with H
2 × 50 mL) and then was concentrated in vacuo. The
resulting white crystalline solid 6 was suspended in a minimal
amount of Et O and then was collected by filtration and dried
g (40%); H NMR (CDCl , 300 MHz) δ 2.43 (s, 3 H), 2.72 (t, J
3
) 7.45 Hz, 2 H), 3.04 (t, J ) 7.46 Hz, 2 H), 7.13 (m, 1 H), 7.19
(dd, J ) 2.01, 5.23 Hz, 1 H), 8.22 (br s, 1 H), 8.25 (br s, 1 H),
4
1
3
2
8.51 (d, J ) 5.23 Hz, 1 H), 8.62 (d, J ) 5.24 Hz, 1 H).
C
NMR (CDCl , 75 MHz) δ 17.8, 20.8, 30.6, 118.1, 120.4, 121.7,
123.1, 124.6, 147.3, 148.0, 148.6, 149.3, 155.0, 156.5. IR (KBr,
3
H
2
-
1
2
cm ) 2249 (CN).
2
O
Ack n ow led gm en t. This work was supported by the
National Science Foundation, the American Chemical
Society Petroleum Research Fund, the J effress Founda-
tion, and the University of Virginia. We also gratefully
acknowledge Dr. J ames E. Collins for his assistance on
this project.
(
2
1
in vacuo: 0.121 g (99%); mp 202-204 °C; H NMR (d
6
-DMSO,
00 MHz) δ 2.93 (m, 4H), 4.81 (br m, 2 H), 5.35 (br m, 2 H),
.17-7.34 (m, 12 H), 8.22 (s, 2 H), 8.46 (d, J ) 5.01 Hz, 2 H).
3
7
1
3
C NMR (d
6
-DMSO, 75 MHz) δ 45.0, 72.8, 121.8, 125.3, 126.0,
26.9, 126.9, 127.98, 128.04, 145.5, 148.6, 149.3, 155.1. IR
KBr, cm ) 3282 (OH).
,4′-Bis(2-p h en eth yl)-2,2′-bip yr id in e (7). Reaction of 1
with benzyl bromide gave 83% dialkyl, trace monoalkyl, and
7% diprotonated bpy products (GC). Dialkylated product 7
1
(
Su p p or tin g In for m a tion Ava ila ble: Copies of 300 MHz
H and 75 MHz C spectra for compounds 1, 6, and 9 (6 pages).
-
1
1
13
4
This material is contained in libraries on microfiche, im-
mediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
1
was obtained by the following procedure. The crude solid
obtained after the standard workup was triturated with EtOH,
was collected by filtration, and then was washed with ad-
ditional EtOH. The resulting white solid 7 was recrystallized
J O971685X
1
from hot EtOH (2× or until H NMR indicated the absence of
(
23) Bos, K. D.; Kraaijkamp, J . G.; Noltes, J . G. Synth. Commun.
1979, 9(6), 497-504.
24) Melting points in ref 20a for mono- and dialkylated products
the dimethyl bpy impurity at 2.4 ppm) to give pure 7 as white
1
9
needles: 0.5 g (35%); mp 147-149 °C, lit. mp 147-149 °C.
(
1
H NMR coincident with data reported by Bos et al.23
appear to be transposed. The melting point reported for the monoalkyl
bpy (76-77 °C) is coincident with what we measured for the dialkylated
product.
4
,4′-Bis(tr id ecyl)-2,2′-bip yr id in e (8). Reaction of 1 with
1
-bromododecane for 1 d at 25 °C produced 68% dialkyl, 13%