6,6′-dibromo-4,4′-di(hexoxymethyl)-2,2′-bipyridine: A new solubilizing building block for macromolecular and supramolecular applications

Article abstract of DOI:10.1021/jo060557i

Although brominated bipyridines and terpyridines are highly desirable synthetic building blocks for both ligand design and macro- or supramolecular applications, few such synthetic precursors have been reported that include much-needed solubilizing groups. Reported here is an inexpensive route to 2,6-dibromo-4-(hexoxymethyl)pyridine from citrazinic acid with an overall yield of 44% and its efficient conversion (60%) to 6,6′-dibromo-4,4′- di(hexoxymethyl)-2,2′-bipyridine via oxidative coupling.

Full text of DOI:10.1021/jo060557i

CHART 1. Dibromobipyridines and Dibromoterpyridine
Building Blocks
6,6′-Dibromo-4,4′-di(hexoxymethyl)-2,2′-
bipyridine: A New Solubilizing Building Block
for Macromolecular and Supramolecular
Applications
Chad M. Amb and Seth C. Rasmussen*
Department of Chemistry and Molecular Biology, North Dakota
State UniVersity, Fargo, North Dakota 58105-5516
seth.rasmussen@ndsu.edu
ReceiVed March 13, 2006
functional groups and currently only two examples have been
reported (2b3 and 4b1d) that contain solubilizing side chains.
In the application of 1a as a building block for larger, more
complicated systems, we found that solubility quickly became
a limiting factor that prohibited the successful production of
the desired targets. Thus, it was realized that a functionalized
analogue containing solubilizing side chains was required in
order to maximize the versatility of the 6,6′-dibromo-2,2′-
bipyridine unit as a useful building block. The unfunctionalized
parent 1a has been produced from 2,6-dibromopyridine by a
variety of different coupling methods,7-9 which are summarized
in Table 1. The methoxy analogue 1b has also been produced
via oxidative coupling of 2,6-dibromo-4-methoxypyridine, using
the CuCl2/O2 method shown in entry 2.10 As far as we are aware,
compound 1b is currently the only reported example of a
functionalized analogue of 1a. Here we report an improved
synthesis (3 steps, 44% overall yield) of the known compound
2,6-dibromo-4-(hexoxymethyl)pyridine (7), and its oxidative
coupling to produce the desired functionalized analogue 6,6′-
dibromo-4,4′-di(hexoxymethyl)-2,2′-bipyridine (8) in yields up
to 60%.
To produce an analogue of 1a containing the desired
solubilizing side chains, we began investigating the application
of the coupling methods from Table 1 above to the coupling of
the functionalized precursor 7. In the process, the synthesis of
precursor 7 was also significantly improved as shown in Scheme
1. The initial step involves the treatment of citrazinic acid (9)
with POBr3, which was generated in situ from a mixture of PBr3,
Br2, and P2O5. No special equipment is required for the POBr3
generation and the resulting product separation is very simple,
giving yields comparable with the previous methods of Fallah-
pour (50-55%).11 In addition, the in situ generation is consider-
ably less expensive than the use of reagent grade POBr3, which
reduces the cost of producing intermediate 10 to ∼$1/g in
comparison to ∼$7/g with the previous procedure. This reduc-
Although brominated bipyridines and terpyridines are highly
desirable synthetic building blocks for both ligand design
and macro- or supramolecular applications, few such syn-
thetic precursors have been reported that include much-
needed solubilizing groups. Reported here is an inexpensive
route to 2,6-dibromo-4-(hexoxymethyl)pyridine from cit-
razinic acid with an overall yield of 44% and its efficient
conversion (60%) to 6,6′-dibromo-4,4′-di(hexoxymethyl)-
2,2′-bipyridine via oxidative coupling.
Dibromo-2,2′-bipyridines (Chart 1, 1-3) and dibromo-
2,2′;6′,2′′-terpyridines (4 and 5) are highly desirable synthetic
building blocks for a wide variety of ligand designs,1 as well
as macromolecular2,3 and supramolecular applications.1a,2-6 The
incorporation of these units allows the production of a variety
of macromolecular systems capable of binding metal ions. Such
systems, however, often suffer from solubility problems and
thus there is a need for synthetic units containing flexible side
chains in order to render these rigid frames soluble in common
organic solvents.5 Unfortunately, the literature is limited in the
synthesis of such dihalo building blocks containing additional
(1) For examples, see: (a) Bai, X.-L. B.; Liu, X.-D.; Wang, M.; Kang,
C.-Q.; Gao, L.-X. Synthesis 2005, 485. (b) Collin, J.-P.; Jouvenot, D.;
Koizumi, M.; Sauvage, J.-P. Inorg. Chem. 2005, 44, 4693. (c) Hilmey, D.
G.; Paquette, L. A. J. Org. Chem. 2004, 69, 3262. (d) Lehmann, U.; Henze,
O.; Schluter, A. D. Chem. Eur. J. 1999, 5, 854. (e) Grosshenny, V.; Romero,
F. M.; Zeissel, R. J. Org. Chem. 1997, 62, 1491. (f) Giblin, G. M.; Box, P.
C.; Campbell, I. B.; Hancock, A. P.; Roomans, S.; Mills, G. I.; Molloy, C.;
Tranter, G. E.; Walker, A. L.; Doctrow, S. R.; Huffman, K.; Malfroy, B.
Bioorg. Med. Chem. Lett. 2001, 11, 1367. (g) Heller, M.; Schubert, U. S.
Synlett 2002, 751.
(2) Newkome, G. R.; Patri, A. K.; Holder, E.; Schubert, U. S. Eur. J.
Org. Chem. 2004, 235.
(3) (a) Maruyama, T.; Yamamoto, T. Synth. Met. 1995, 69, 553. (b)
Maruyama, T.; Kubota, K.; Yamamoto, T. Macromolecules 1993, 26, 4055.
(4) Henze, O.; Lehmann, U.; Schluter, A. D. Synthesis 1999, 683.
(5) Schubert, U. S.; Eschbaumer, C. Angew. Chem., Int. Ed. 2002, 41,
2892.
(7) Garber, T.; Rillema, D. P. Synth. Commun. 1990, 20, 1233.
(8) Parks, J. E.; Wagner, B. E.; Holm, R. H. J. Organomet. Chem. 1973,
56, 53.
(9) Uchida, Y.; Echikawa, N.; Oae, S. Heteroat. Chem. 1994, 5, 409.
(10) Neumann, U.; Vo¨gtle, F. Chem. Ber. 1989, 122, 589.
(11) Fallahpour, R.-A. Synthesis 2000, 1138.
(6) Grave, C.; Schluter, A. D. Eur. J. Org. Chem. 2002, 3075.
10.1021/jo060557i CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/13/2006
4696
J. Org. Chem. 2006, 71, 4696-4699

TABLE 1. Synthesis of 6,6′-Dibromo-2,2′-bipyridine
SCHEME 2. Species Produced during the Lithiation Studies
coupling
reagent
reported
entry
yielda (%)
ref
1
2
3
4
5
CuBr/O2
CuCl2/O2
SOCl2
POCl3
PCl3
72
50
51
35
5
7
8
9
9
9
TABLE 2. Effect of Temperature on the Lithiation of Compound
7
a Yield based on 2,6-dibromopyridine.
% yields of various productsa
temp
(°C)
time
(min)
entry
13b
14c
15b
16c
17
SCHEME 1. Synthesis of
4-Hexoxymethyl-2,6-dibromopyridine (7)
1
2
3
4
5
-40
20
15
20
50
180
40
-
-
-
-
27
73
79
67
61
4
13
14
14
10
∼1
∼4
∼4
∼3
∼3
trace
∼1
-80
-88 f -80
-90
-100
∼1
∼1
∼1
a Yield based on compound 7. b Isolated yield. c Determined from NMR
of the isolated fraction containing 14, 7, and 16.
TABLE 3. Synthesis of
6,6′-Dibromo-4,4′-di(hexoxymethyl)-2,2′-bipyridine (8)
tion in cost makes the routine production of multigram quantities
of 10 quite feasible.
coupling
reagent
yield based
on 7 (%)
yield based on
coupling reagent (%)
entry
Initial attempts to reduce the methyl ester 10 directly to
alcohol 12 via LiAlH4 resulted in poor yields, as previously
observed by Schluter1d and Schubert.1g Thus, while it added an
additional synthetic step, it was found that saponification of 10
with aqueous NaOH to give acid 11 (96-97%), followed by
borane reduction to give alcohol 12 (82-87%) gave significantly
better yields. Revisiting the initial one-step reduction, however,
revealed that changing the reducing agent from LiAlH4 to
NaBH4 did allow the direction conversion of 10 to 12 in good
yield (80-85%).12 Finally, the hexyl functionality was then
incorporated through a modification of Schluter’s procedure1d
to yield the desired 2,6-dibromo-4-(hexoxymethyl)pyridine (7)
(90-94%). The overall yield of 7 from compound 9 was 44%
in comparison to 19% with the previous conditions.1d This
higher yield could be accomplished in as little as three steps,
although there was no difference in the overall yield between
the 3-step and 4-step routes.
1
2
3
4
5
CuBr/O2
CuCl2/O2
SOCl2
POCl3
R2SnCl2/Cu(NO)3
21
25
60
37
17
21
25
90
75
17
applied to the functionalized analogue 7. Not only was it verified
that benzylic deprotonation competes with metal-halogen
exchange, but a large amount (40%) of the debrominated
bipyridine 13 was also isolated. The formation of 13 is not
dependent on the I2 quench, as quenching with H2O gave similar
results. Lowering the temperature to -80 °C eliminated the
production of 13 and greatly increased the amount of the
2-iodated product (Table 2, compound 14). It is reasonable to
propose that metal-halogen exchange readily occurs at -40
°C, but that the resulting organolithium reagent is not stable at
that temperature and decomposes to produce 13. It was found
that lowering the temperature below -88 °C had a negative
effect on lithiation of the 2-position, possibly because of the
decreased solubility of 7 at these temperatures (compound 7
begins to precipitate from solution at ca. -80 °C). As a
consequence, the optimum conditions were determined to be
the utilization of temperatures between -88 and -80 °C and
such conditions were then applied to all further coupling studies.
Conditions for coupling with each reaction were optimized
and the resulting yields for the production of bipyridine 8 are
given in Table 3. With the exception of entry 3, all methods
gave fairly low yields based on the starting pyridine 7. However,
the use of either SOCl2 or POCl3 as coupling reagents requires
>2 equiv of 7 for every equivalent of the product 8
produced.9,13-15 Thus in terms of the coupling reagents, these
two methods gave isolated yields of 90% and 75%, respectively.
Initial investigations of the oxidative coupling of 7 resulted
in a mixture of products consisting primarily of the debrominated
species 4,4′-di(hexoxymethyl)-2,2′-bipyridine (13). In addition,
some byproducts indicated that deprotonation at the benzylic
position was also a potential problem. As a result, it was decided
to investigate the conditions of the initial lithiation step in more
detail. To probe the competition between metal-halogen
exchange and any competing deprotonation, the reaction was
quenched with I2 after lithiation and the resulting iodated
products isolated (Scheme 2). The results of these studies are
given in Table 2.
It was found that the literature conditions7-9 for the mono-
lithiation of 6 (Table 2, entry 1) gave rather poor results when
(12) Fallahpour, R.-A. Synthesis 2000, 1665.
J. Org. Chem, Vol. 71, No. 12, 2006 4697

TABLE 4. Relative Solubilities of 1a and 8a
solvent
SCHEME 3. Proposed Mechanism for the Production of
Bipyridine 8 via Thionyl Chloride Coupling
bipyridine hexanes EtOAc CHCl3 CH2Cl2 CH3CN CH3OH
1a
8
ss
s
ss
s
s
vs
s
vs
ss
s
ss
s
a vs ) very soluble; s ) soluble; ss ) sparingly soluble.
As such, all three possible sulfoxide intermediates are in
equilibrium with one another and the higher ratio of Li-7a
should favor sulfoxides containing this unit. In addition, Oae
and co-workers have shown that the use of SOCl2 selectiVely
couples aryl species, in that mixtures of aryl and benzyl
substrates strongly favor aryl-aryl coupling,13 while the use of
alkyllithium species results in a complete lack of oxidative
coupling.14 Similar selectivity is also observed for POCl3.
As a result of this selectivity, these reagents produce higher
yields of the desired product 8 and result in the generation of
fewer byproducts. In addition, as these methods do not involve
transition metal reagents, removal of metal ions coordinated by
the bipyridine product is not required. The only significant
weakness in the use of either SOCl2 or POCl3 is that 3 and 4
equiv of starting material are required in order to make each
equivalent of the coupled bipyridine, respectively. However, the
use of SOCl2 reduces this weakness and the advantages of
selectivity, reaction cleanliness, and ease of separation makes
this method quite useful in the production of such bipyridine
products.
As might be expected, the solubility of 8 is significantly
enhanced in comparison to that of the unfunctionalized parent
1a. Table 4 lists the relative solubilities of both compounds in
a variety of solvents. While 1a really only shows appreciable
solubility in chlorinated solvents, compound 8 is also soluble
in both nonpolar solvents such as hexanes and significantly polar
organics such as acetonitrile and methanol. Quantification of
the compounds solubility in CHCl3 gives a maximum solubility
of ∼10 mg mL-1 for 1a, while the solubility of 8 exceeds 530
From the results of the lithiation studies given in Table 2, it
is known that even in the optimized conditions, the treatment
of 7 with BuLi generates a significant amount (∼15%) of an
undesired organolithium intermediate via deprotonation of the
benzylic carbon. Therefore, it is believed that the difference in
the yields from various methods is due to differences in
selectivity between the two organolithium species present in
the coupling reactions. The methods that give the lowest yields
depend on either transmetalation (entries 1 and 2) or metathesis/
transmetalation (entry 5) in order to generate the reactive
intermediates necessary for oxidative coupling. These reactions
are driven by the transfer of the organyl to the less electropos-
itive Cu center and the formation of the lithium halide byproduct.
As such, there is little selectivity between the possible aryl or
benzylic reagents and a variety of coupling products are possible.
In contrast, the use of SOCl2 as the coupling reagent allows
a degree of selectivity, resulting in a significantly higher yield
of bipyridine 8. A proposed coupling mechanism based on
previous studies of SOCl2-mediated aryl-aryl couplings is
shown in Scheme 3.2,15 As shown, the method involves the
reaction of the generated organolithium species with SOCl2 to
form an intermediate sulfoxide. However, as treatment of 7
results in the generation of two organolithium species (Li-7a
or Li-7b, respectively), three different sulfoxides are thus
possible. The addition of Li-7a or Li-7b to one of the sulfoxides
generates a four-coordinate sulfur species that can either give
product via oxidative coupling or eliminate an equivalent of
Li-7a or Li-7b in an exchange process to regenerate a sulfoxide.
mg mL-1
.
In conclusion, we have presented the efficient preparation of
a new, solubilizing dibromo-2,2′-bipyridine building block from
commercial citrazinic acid. This four-step synthesis has an
overall yield of 26% and can be easily prepared on large scales.
The utilization of such a building block should contribute
solubility to the resulting macromolecular and supramolecular
species, allowing both higher molecular weight materials and a
greater diversity of possible assemblies.
Experimental Methods
Unless noted, all materials were reagent grade and used without
further purification. Compound 1a was synthesized according to
Oae.9 Anhydrous diethyl ether and THF were freshly distilled from
sodium benzophenone and deoxygenated prior to use. Except for
the saponification of 11, all reactions were performed under
nitrogen. Chromatographic separations were performed by using
standard column methods with silica gel (230-400 mesh). 1H and
13C NMR spectra were obtained in CDCl3 on a Varian 400 MHz
spectrometer and referenced to the chloroform signal, and peak
multiplicity was reported as follows: s ) singlet, d ) doublet, t )
triplet, m ) multiplet.
(13) Oae, S.; Inabushi, Y.; Yoshihara, M. Heteroat. Chem. 1993, 4, 185.
(14) Oae, S.; Inabushi, Y.; Yoshihara, M.; Uchida, Y. Phosphorus, Sulfur
Silicon Relat. Elem. 1994, 95-96, 361.
(15) Oae, S.; Inabushi, Y.; Yoshihara, M. Phosphorus, Sulfur Silicon
Relat. Elem. 1995, 103, 101.
2,6-Dibromo-4-methoxycarbonylpyridine (10). PBr3 (21.8 mL,
0.232 mol) was loaded into a 250-mL three-neck flask cooled in a
rt water bath. Br2 (11.9 mL, 0.231 mol) was then added dropwise
with stirring to the PBr3 to yield a yellow solid (PBr5). P2O5 (12.0
4698 J. Org. Chem., Vol. 71, No. 12, 2006

g, 0.083 mol) was then added and this solid mixture was mixed
well with a spatula under a flow of N2. At this point, a reflux
condenser was added that was connected to a water-filled bubbler
to trap evolved HBr. Under a flow of N2, the mixture was heated
to 98 °C for 2 h and then cooled to rt. Citrazinic acid (20.0 g,
0.128 mol) was then added and the solids were mixed thoroughly
with a spatula under a flow of N2. The water bath was replaced
with an oil bath and the mixture was heated at 185 °C for 8 h
(Caution: large evolution of HBr gas occurs at ∼130 °C). The
mixture was cooled back to rt and 150 mL of CH3OH was slowly
added (Caution: the reaction with CH3OH is exothermic, causing
the solution to reflux). The mixture was stirred for 30 min., after
which solid NaHCO3 was added slowly until bubbling stopped.
CH3OH was then removed in vacuo, resulting in a thick black
sludge. CH2Cl2 (200 mL) was added, then the mixture stirred for
10 min and decanted. This was repeated 6 times. The combined
organic fractions were then concentrated and purified by column
chromatography (7.5% EtOAc/hexanes). Final recrystallization from
hexane gave 20.94 g (55%). Mp 86.8-88.2 °C (lit.1d mp 88-89
purified as above to yield 21.70 g (80%) of a white solid. Mp
110.0-111.5 °C (lit.1d mp 110-111 °C). 1H NMR (CDCl3) δ 7.46
(s, 2H), 4.72 (d, 2H, J ) 5.2 Hz), 2.37 (t, 1H, J ) 5.2 Hz). 13C
NMR (CDCl3) δ 155.7, 141.0, 124.5, 62.4.
2,6-Dibromo-4-(hexoxymethyl)pyridine (7). Triflic anhydride
(6.35 mL, 37.6 mmol) was added to 50 mL of dry CH2Cl2 and
cooled to 0 °C. A solution of 12 (10 g, 37.6 mmol) and Et3N (4.71
mL, 33.7 mmol) in 200 mL of dry CH2Cl2 was then added dropwise
over 30 min. The cooling bath was removed, and the solution was
stirred for 1 h. 1-Hexanol (100 mL, 0.796 mol) was then added
and the mixture was stirred for 1 h. Et3N (30 mL) was then added,
the solvents were evaporated, and the remaining mixture was poured
into 200 mL of water. This was then extracted with hexane and
the combined organic fractions were dried over MgSO4, evaporated,
and chromatographed on a silica column (3.5% EtOAc/hexane) to
yield 12.43 g (94%) of a colorless oil. 1H NMR (CDCl3) δ 7.36 (s,
2H), 4.40 (s, 2H), 3.45 (t, 2H, J ) 5.6 Hz), 1.58 (m, 2H), 1.33 (m,
2H), 1.26 (m, 4H), 0.85 (t, 3H, J ) 5.6 Hz). 13C NMR (CDCl3) δ
154.0, 140.9, 125.0, 71.8, 69.9, 31.8, 29.73, 26.0, 22.8, 14.3.
6,6′-Dibromo-4,4′-di(hexoxymethyl)-2,2′-bipyridine (8). Com-
pound 7 (1.0 g, 2.8 mmol) in 50 mL of ether was cooled to -88
°C producing a partially dissolved suspension. n-BuLi (1.14 mL,
2.84 mmol, 2.5 M in hexane) was added dropwise via syringe and
the suspension was stirred for 20 min while warming to -80 °C,
which resulted in a light red homogeneous solution. SOCl2 (0.069
mL, 0.95 mmol) was added dropwise via syringe, causing the
solution to first turn black then finally yellow upon complete
addition. The solution was allowed to warm to -60 °C over 20
min, resulting in precipitation. The suspension was stirred for
another 15 min at -60 °C and then warmed to rt. Water (20 mL)
was added, then the mixture was stirred for 10 min and poured
into 150 mL of water. The mixture was extracted with ether and
the organic layers were dried over MgSO4, evaporated, and applied
to a silica column (3.5% EtOAc/hexane) to yield 0.46 g (60%) of
a white solid. Recrystallization from CH3CN gave mp 69.6-70.5
1
°C). H NMR (CDCl3) δ 7.99 (s, 2H), 3.97 (s, 3H). 13C NMR
(CDCl3) δ 163.2, 141.7, 141.7, 126.9, 53.5.
2,6-Dibromopyridine-4-carboxylic Acid (11). Aqueous NaOH
(1.2 M, 150 mL) was added to 10 (14.0 g, 0.047 mol) in 100 mL
of THF, and the mixture was heated at reflux for 4 h. THF was
removed in vacuo, and the aqueous solution was washed with ether,
acidified with concentrated HCl, and extracted with CH2Cl2. The
organic fraction was dried over MgSO4 and evaporated to give 13.10
g (98%) of a light yellow powder. Recrystallization from H2O gave
1
mp 184.2-185.8 °C (lit.11 mp 184-185 °C). H NMR (CDCl3) δ
8.05 (s, 2H). 13C NMR (CDCl3) δ 166.8, 142.0, 140.6, 127.2.
2,6-Dibromo-4-(hydroxymethyl)pyridine (12). From com-
pound 11: A solution of 11 (6.72 g, 0.0239 mol) in 125 mL of dry
THF was cooled to 0 °C and borane (1 M in THF, 60 mL) was
slowly added. The cooling bath was then removed, and stirring
was continued overnight. Water was slowly added until gas
evolution ceased, and the solution was concentrated to ∼50%.
NaOH (3 M, 75 mL) was added and the mixture was heated at
reflux for 1 h. The remaining THF was then removed and the
solution was extracted with CH2Cl2. The combined organic fractions
were dried over MgSO4 and evaporated. The residue was dissolved
in a minimum of CHCl3, loaded onto a silica column, and eluted
with 30% EtOAc/hexane to yield 5.43 g (85%) of a white solid.
From compound 10: NaBH4 (19.2 g, 510 mmol) was slowly
added to a rt solution of 10 (30.0 g, 102 mmol) in 700 mL of dry
ethanol and then heated at reflux for 2 h. This solution was cooled
to toom temperature and 2 M HCl (100 mL) added slowly with
stirring until bubbling stopped. The solution was then concentrated
to ∼100 mL by rotary evaporation and solid NaOH was added until
the solution became basic. The solution was then stirred for 2 h
during which precipitation occurred. CH2Cl2 (300 mL) was added
to dissolve the precipitate, then the mixture was poured into 500
mL of water and extracted with CH2Cl2. The combined organic
fractions were dried over MgSO4 and evaporated. The residue was
1
°C. H NMR (CDCl3) δ 8.25 (s, 2H), 7.55 (s, 2H), 4.56 (s, 4H),
3.53 (t, 4H, J ) 6.8 Hz), 1.66 (p, 4H, J ) 6.8 Hz), 1.40 (m, 4H),
1.32 (m, 8H), 0.90 (t, 6H, J ) 6.8 Hz). 13C NMR (CDCl3) δ 155.5,
152.5, 142.2, 126.6, 118.6, 71.7, 70.8, 31.9, 29.8, 26.0, 22.8, 14.3.
Acknowledgment. The authors thank North Dakota State
University and the ND-EPSCoR “Network in Catalysis” pro-
gram (NSF-EPS-0132289) for support of this research. We also
wish to thank Dr. Hongshan He for his assistance with the X-ray
crystal analysis.
Supporting Information Available: Details of the lithiation
studies, NMR data and spectra for the products 14-17, and
crystallographic data for 17; synthetic methods for the preparation
of 8 via alternate coupling methods, and NMR spectra of 8. This
material is available free of charge via the Internet at http://
pubs.acs.org.
JO060557I
J. Org. Chem, Vol. 71, No. 12, 2006 4699