Nickel-catalyzed cross-electrophile coupling of 2-chloropyridines with alkyl bromides

Article abstract of DOI:10.1055/s-0033-1340151

The synthesis of 2-alkylated pyridines by the nickel-catalyzed cross-coupling of two electrophiles, a 2-chloropyridine and an alkyl bromide, is described. Compared with our previously published conditions for aryl halides, this method uses a different, more rigid, bathophenanthroline ligand and is conducted at high concentration in N,N-dimethylformamide as solvent. The method displays promising functional group compatibility and the conditions are orthogonal to those for the Stille coupling.Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0033-1340151

LETTER
▌233
lNettierckel-Catalyzed Cross-Electrophile Coupling of 2-Chloropyridines with
Alkyl Bromides
Cross-Electrophile Coupling
Daniel A. Everson, Joseph A. Buonomo, Daniel J. Weix*
Department of Chemistry, University of Rochester, Rochester, NY 14627-0216, USA
Fax +1(585)2760205; E-mail: daniel.weix@rochester.edu
Received: 11.08.2013; Accepted after revision: 16.09.2013
In addition to the challenges associated with pyridine sub-
strates, all of the approaches described above require the
synthesis of functionalized organometallic reagents. Be-
sides the additional steps required for their preparation,
Abstract: The synthesis of 2-alkylated pyridines by the nickel-cat-
alyzed cross-coupling of two electrophiles, a 2-chloropyridine and
an alkyl bromide, is described. Compared with our previously pub-
lished conditions for aryl halides, this method uses a different, more
rigid, bathophenanthroline ligand and is conducted at high concen- organometallic reagents have limited functional-group
tration in N,N-dimethylformamide as solvent. The method displays
promising functional group compatibility and the conditions are
orthogonal to those for the Stille coupling.
compatibility. For example, the most-general approaches
to 2-alkylpyridines are the iron-catalyzed8b,c,10 and nickel-
catalyzed8a,d,11 coupling of alkyl Grignard reagents with 2-
halopyridines (Scheme 1, A; [M] = MgX). The synthesis
Key words: nickel, catalysis, alkylations, pyridines, cross-coupling
of the Grignard reagents adds an extra step, and the high
reactivity of alkyl Grignard reagents places limitations on
Alkylated pyridines represent an important class of azines the choice of electrophilic and acidic functional groups.
that have appeared in several launched drugs such as The anionic Mg–C bond also causes problems with
esomeprazole (Nexium), used to treat acid reflux,1 and β-elimination of leaving groups.12 Although methods for
eszopiclone (Lunesta), used in the treatment of insomnia.2 the synthesis of functionalized Grignard reagents have ad-
Whereas the Suzuki–Miyaura reaction (C– + C+) is the vanced considerably,13 it would be easier to avoid this
dominant cross-coupling reaction used in both the discov- problem entirely.
ery and production of pharmaceuticals,3 the coupling of
One underexplored approach that avoids the need to syn-
heteroarenes is generally more challenging than that of
thesize organometallic reagents is the direct cross-cou-
aryl halides.4 For example, 2-pyridylboronic acid esters
pling of 2-halopyridines (C+) with alkyl halides (C+)
are difficult to synthesize and handle.5 In general, the
(Scheme 1, B). Although we14 and others15–17 have made
cross-coupling of an alkyl halide with a pyridyl organo-
great progress on cross-coupling methods for catalytically
metallic reagent (diorganozinc or tin reagent) remains
joining two electrophiles, the best reported yield for pyri-
challenging.6 A more developed approach involves the
dine alkylation is only 26% (for 2-chloro-6-methylpyri-
cross-coupling of 2-halopyridines with alkyl organome-
dine).14a Whereas Gong and co-workers reported the
tallic reagents, such as trialkylaluminum reagents,7 alkyl
alkylation of 8-bromoquinoline in good yield (96%), their
Grignard reagents,8 or alkylzinc reagents (Scheme 1, A).9
one alkylation of 2-bromopyridine gave only 38% of the
desired product, and they did not examine the reaction of
2-chloropyridines.15c We present here our progress
A. cross-coupling with alkyl organometallic reagents
towards a more general method for the alkylation of
2-halopyridines.
cat. [Ni], [Co],
[Fe] or [Pd]
R2
R1
+
[M]
R2
N
Cδ+
X1
Cδ–
additives
Studies on the cross-coupling of 2-chloropyridine (1a)
with ethyl 4-bromobutanoate (2a) to give ethyl 4-pyridin-
2-ylbutanoate (3a) identified the optimal conditions
shown in Table 1 (See Supplementary Information, Table
S1 for product-distribution data). Comparable yields were
obtained at substrate concentrations ranging from 0.25 M
to 1.7 M, but concentrations higher than 1.7 M produced
gels that complicated workup and gave inconsistent re-
sults. To ensure complete conversion of 1a, reactions
were conducted with a slight excess of the alkyl bromide
2a. Reactions performed with equimolar amounts of each
reactant or with a slight excess of 1a provided similar re-
sults (Table 1; entries 3 and 4).
B. cross-electrophile coupling – this work
cat. [Ni]
Mn(0)
R2
R2
R1
+
X2
N
Cδ+
X1
Cδ+
X1, X2 = halogen; R2 = alkyl; [M] = SnR3, BX2, SiR3, ZnX, MgX
Scheme 1 Comparison of cross-coupling of alkyl organometallic re-
agents (A) with cross-electrophile coupling (B)
Several ligands were examined, but bathophenanthroline
(4; 4,7-diphenyl-1,10-phenanthroline) gave the highest
yields of the cross-coupled product 3a. Substitution of 4
SYNLETT 2014, 25, 0233–0238
Advanced online publication: 05.11.2013
DOI: 10.1055/s-0033-1340151; Art ID: ST-2013-R0770-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

234
D. A. Everson et al.
LETTER
for less-expensive 1,10-phenanthroline (5) gave the prod- chloropyridine. The use of solvents other than N,N-di-
uct in an appreciable yield and this should be considered methylformamide resulted in poor selectivity toward 3a,
in process applications where ligand cost might be a lim- partial conversion after 24 hours, or both (4–45% yield).
iting factor (Table 1, entries 1 and 5). Other bidentate im- Lastly, the use of zinc(0) or aluminum(0)–lead(II)
ine ligands gave lower yields (entries 6 and 7). The bromide18 instead of manganese(0) as the reducing agent
tridentate imine ligand 4,4′,4′′-tri-tert-butyl-2,2′:6′,2′′-ter- resulted in a lower yield and a lower selectivity toward 3a
pyridine (8) gave a very low yield of 3a and favored the (entries 13 and 14). Specifically, the use of zinc(0) rapidly
dimerization of 2a instead.14c Replacement of nickel(II) resulted in hydrodehalogenation of 2-chloropyridine, pos-
bromide trihydrate with nickel chloride–glyme gave sim- sibly through direct insertion of zinc(0) into the C–Cl
ilar results (entries 1 and 9), whereas other nickel sources bond with subsequent protonation; this, in turn, resulted in
produced lower yields (35–58%). Lowering the tempera- dimerization of 2a once 1a was consumed. The use of alu-
ture to 20 °C resulted in slow reactions and partial conver- minum(0)–lead(II) bromide gave the dimer product of 2a
sion of the starting materials (entry 10), whereas raising exclusively, with almost no conversion of 1a (entry 15).
the temperature to 60 or 80 °C decreased selectivity to-
To examine the scope of this new method, we coupled
ward 3a (entries 11 and 12). Reactions at these higher
several different alkyl halides with 2-chloropyridine (1a)
temperatures resulted in more hydrodehalogenation of 2-
to give 2-alkylated pyridines (Table 2). Nonfunctional-
Table 1 Results of Optimization of the Cross-Coupling of 2-Chloropyridine (1a) with Ethyl 4-Bromobutanoate (2a)
CO2Et
NiBr2⋅3H2O (5 mol%)
4 (5 mol%)
+
Br
CO2Et
3
N
Mn(0) (2 equiv)
DMF (1.7 M), 40 °C
N
Cl
2a
1.1 equiv
3a
1a
Ph
Ph
N
N
4
Entrya
Changes from standard conditions
Yieldb (%)
1
2
none
82
10 mol% NiBr2·3H2O/4
74c
78
3
1 equiv each 1a and 2a
4
1.1 equiv 1a
71
5
1,10-phenanthroline (5) instead of 4
4,4′-di-tert-butyl-2,2′-bipyridine (6) instead of 4
4,4′-dimethoxy-2,2′-bipyridine (7) instead of 4
4,4′,4′′-tri-tert-butyl-2,2′:6′,2′′-terpyridine (8) instead of 4
NiCl2(glyme) instead of NiBr2·3H2O
reaction run at 20 °C
64
6
66
7
69
8
15
9
79
10
11
12
13
14
15
55c
70c
62c
15d
19e
2e,f
reaction run at 60 °C
reaction run at 80 °C
25% DMA in THF instead of DMF
Zn(0) (<10 μm) instead of Mn(0)
Al(0)/PbBr2 instead of Mn(0)
a Standard reaction conditions: DMF (1 mL), NiBr2·3H2O (0.15 mmol), 1a (3.00 mmol), 2a (3.30 mmol), ligand (0.15 mmol), and Mn(0) (6.00
mmol) were added to a 1 dram vial on the bench top and heated under air at 40 °C for 4–22 h.
b Yield by GC (corrected) with dodecane as internal standard.
c Isolated yield.
d Partial conversion of starting material after 24 h.
e The major coupled product was the alkyl dimer.
f No reaction of 1a was observed.
Synlett 2014, 25, 233–238
© Georg Thieme Verlag Stuttgart · New York

LETTER
Cross-Electrophile Coupling
235
ized 1-bromooctane (2b) coupled with 2-chloropyridine one bearing a tert-butoxycarbonyl-protected primary
efficiently under the optimized conditions to give 2-octyl- amine (entry 3). An alkyl bromide containing a tri-substi-
pyridine (3b) in 72% yield (entry 2). As we had discov- tuted olefin group gave a lower yield (entry 4), consistent
ered during the optimization process, an alkyl bromide with a problem that we observed in coupling this bromide
bearing an ester group coupled efficiently (entry 1) as did with bromobenzene.14a
Table 2 Scope of the Electrophile Cross-Coupling of 2-Chloropyridines with Alkyl Halides
FG
NiBr2⋅3H2O (5 mol%)
4 (5 mol%)
FG
Br
R
R
+
Mn(0) (2 equiv)
DMF (1.7 M), 40 °C
2
N
N
Cl
1.1 equiv
3
1
Entrya
1
Reactants
Product
Yieldb (%)
72
CO2Et
1a
2a
N
3a
C8H17
2
3
4
5
6
1a
1a
1a
1a
1a
2b
2c
2d
2e
2f
72c
60d
33c
48e
45f
N
3b
NHBoc
N
3c
N
3d
N
3e
N
OTBS
3f
Bu3Sn
CO2Et
7
1b
2a
48
N
3g
t-Bu
CO2Et
8
9
1c
2a
2a
50
N
3h
F3C
CO2Et
1d
46g
N
3i
a Reaction conditions: Chloropyridine 1 (3.00 mmol), alkyl bromide 2 (3.30 mmol), Mn(0) (6.00 mmol), NiBr2·3H2O (0.15 mmol), ligand 4
(0.15 mmol), and DMF (1 mL) were added to a 15 ml round-bottom flask and heated for 4–22 h.
b Yield of isolated and purified product.
c 10 mol% NiBr2·3H2O/4; the yield was 65% at 5 mol%.
d Reaction performed on 0.75 mmol scale with 1.1 equiv 1a and 10 mol% NiBr2·H2O/4.
e Reaction performed with 2 equiv 2e; the yield with 1.1 equiv was 33%.
f Reaction performed with 10 mol% NiBr2·3H2O/4; the yield with 5 mol% was 37%.
g Reaction performed with 10 mol% NiBr2·3H2O/4, 25 mol% NaI, and 10 mol% AIBN as additives; the yield under the standard conditions was
27%.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 233–238

236
D. A. Everson et al.
LETTER
In addition to these primary halides, bromocyclohexane these conditions might show similar reactivity to terpyri-
(2e) coupled in reasonable yield (Table 2, entry 5), show- dine nickel complexes, such as 16,21 which are efficient
ing that the method has promise for coupling of secondary catalysts of alkyl dimerization reactions (Figure 1).14c
alkyl bromides, which are challenging substrates because
of their propensity to undergo β-hydrogen elimination. An
Ph
Ph
Ph
Ph
alkyl bromide bearing a β-siloxy leaving group, 2f, also
coupled in reasonable yield if a higher catalyst loading of
10 mol% was used (entry 6). The corresponding organo-
metallic reagent (TBSOCH2CH2-[M]) is prone to undergo
β-elimination and presents a particular challenge.12 In our
case, the parent alkane of 2f was the predominant byprod-
uct rather than its β-elimination product. The product 3f is
a precursor to enediynes of tetrahydropyridine that exhibit
antitumor activity.19 The synthetically useful tributylstan-
nyl group on the pyridyl chloride 1b was tolerated with no
observable destannylation (entry 7). The tributylstannyl
functional group can be used in subsequent steps to
achieve polyfunctionalization of the pyridine core by
means of the well-established Stille reaction.20
N
N
N
N
N
Ni
Ni
Cl
N
14
15
t-Bu
–
•
t-Bu
t-Bu
N
N
Ni
N
Alkyl
16
Figure 1 Postulated nickel complexes and terpyridine complex 16
Finally, we briefly explored the effects of electron density
in the pyridine core. Coupling of 4-tert-butyl-2-chloro-
pyridine (1c) with ethyl 4-bromobutanoate (2a) gave a
50% yield of the desired alkylated pyridine 3h (Table 2,
entry 8). The electron-deficient pyridine 1d suffered from
long induction periods and long reaction times that per-
mitted competing side reactions to occur, resulting in a
low yield (27%) in the absence of additives. Halogen ex-
change with conversion of the alkyl bromide into the
much less reactive alkyl chloride was the major compet-
ing reaction. The yield of product 3i could be improved
from 27% to 46% by the addition of a catalytic amount (25
mol%) of sodium iodide, which converted the alkyl chlo-
ride into the corresponding alkyl iodide in situ;14c addition
of a catalytic amount (10 mol%) of azobisisobutyronitrile
(AIBN) reduced the reaction time from 48 to 19 h. The ob-
servation that the radical initiator AIBN significantly de-
creased the reaction time is suggestive of a mechanism
that involves radicals. AIBN might decrease the reaction
times by generating alkyl radicals.
Our success with the use of AIBN made us consider the
possibility that Minisci chemistry22 rather than cross-elec-
trophile coupling was responsible for the observed prod-
ucts (Scheme 2). However, neither of the products 3a and
3i was formed in reactions performed with added AIBN in
the absence of nickel. In fact, the addition of AIBN low-
ered the yield of 3a (Table 2, entry 1 and Scheme 2) as a
result of increased alkyl dimerization, which is consistent
with overproduction of alkyl radicals being detrimental to
the reaction.
R1
R1
AIBN
Br R2
+
2a
1.1 equiv
N
1
Cl
N
R2
Mn(0) (2 equiv)
DMF (1.7 M), 40 °C
3
1a, 3a: R1 = H
1d, 3i: R1 = CF3
AIBN (0.05 equiv) 3a, 0% yield
3a, 48% yield
3i, 0% yield
AIBN (0.05 equiv) with NiBr2⋅3H2O/4
AIBN (0.1 equiv)
Scheme 2 Reactions with AIBN require nickel to form the cross-
With the exception of 2-{2-[tert-butyl(dimethyl)si-
loxy]ethyl}pyridine (3f), the major challenge to overcome
in the cross-coupling reactions of 2-chloropyridines with
alkyl bromides was competing dimerization of the alkyl
bromide (See Supporting Information, Table S2, for prod-
uct-distribution data and the structures of compounds 9–
13). The synthesis of ethyl 4-[5-(trifluoromethyl)pyridin-
2-yl]butanoate (3i) in the presence of AIBN as an additive
to decrease the reaction time showed a poor mass balance
of only 50% with respect to the alkyl bromide and 41%
with respect to the chloropyridine (See Supporting Infor-
mation, Table S2). Unproductive side reactions with
AIBN might account for the lost mass, but no such prod-
ucts could be identified by gas chromatographic analysis
of the crude reaction mixtures. The propensity of some of
these coupling reactions to show selectivity toward dimer-
ization of the alkyl bromide over the cross-coupling reac-
tion is reminiscent of the chemistry of nickel terpyridine
complexes.14c,15g Nickel complexes 14 or 15 formed under
product
Pyridines halogenated at the 3- or 4-postion cannot cur-
rently be coupled in acceptable yields under the reaction
conditions that we have developed (Scheme 3). Similarly,
a few other heterocycles that were examined (2-chloro-
thiophene, 2-chlorobenzo[d]oxazole, 2-chloro-1H-ben-
zo[d]imidazole, and 2-bromopyrazine) failed to couple in
high yields. New reaction conditions and catalysts for
coupling of these compounds are an active area of re-
search in our laboratory.
NiBr2⋅3H2O (10 mol%)
Br
C8H17
4 (10 mol%)
Br C8H17
+
Mn(0)
2b
N
N
DMF (0.25 mmol/mL)
40 °C, 21% (corrected GC)
17, 1.1 equiv
18
Scheme 3 Electrophile cross-coupling of 3-bromopyridine (17) with
1-bromooctane (2b)
Synlett 2014, 25, 233–238
© Georg Thieme Verlag Stuttgart · New York

LETTER
Cross-Electrophile Coupling
237
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2-alkylated pyridines permits the synthesis of functional-
ized molecules not readily accessible by coupling reac-
tions of Grignard reagents. The products are obtained in a
single step from easily available organic halides and 2-
chloropyridines. Although future studies will seek to im-
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Coupling of 2-Halopyridines 1 with Alkyl Bromides 2: General
Procedure
In a well-ventilated fume hood, a 15 mL round-bottomed flask
equipped with a Teflon-coated magnetic stirrer bar was charged
with NiBr2·3H2O (40.9 mg, 0.150 mmol, 0.05 equiv), bathophenan-
throline (4; 49.9 mg, 0.150 mmol, 0.05 equiv), DMF (2.0 mL), and
alkyl bromide 2 (3.3 mmol, 1.1 equiv). The vessel was stoppered
with a rubber septum and heated to 40 °C in a fume hood until a
green homogeneous solution formed (~20 min). The vessel was
then removed from the heat and 2-halopyridine 1 (3.00 mmol, 1.00
equiv) and manganese(0) (–325 mesh; 330 mg, 6.00 mmol, 2.00
equiv) were added. The vessel was resealed with the septum, purged
with argon, and heated again to 40 °C while the progress of the re-
action was monitored by GC analysis of aliquots of the crude reac-
tion mixture. In general, the mixtures turned dark brown or black
when the reaction was complete. Upon completion of the reaction,
the mixture was cooled to r.t., diluted with Et2O (10 mL), and fil-
tered through a short pad of Celite 545 (approx. 1 × 1 × 1 inch) wet-
ted with Et2O (~10 mL) to remove metal salts. The Celite pad was
washed with additional Et2O (2 × 10 mL), and the filtrate was trans-
ferred to a separatory funnel and washed with 1 M aq NH4Cl (10
mL). The layers were separated and the aqueous layer was washed
with additional Et2O (3 × 10 mL). The organic extracts were com-
bined, washed with brine (10 mL), dried (MgSO4), filtered, and con-
centrated under reduced pressure. The crude products were purified
by flash column chromatography on silica gel.
Acknowledgment
This work was supported by the University of Rochester, the NIH
(R01 GM097243), and the NSF (Graduate Research Fellowship to
D.A.E. and Research Experience for Undergraduates Fellowship to
J.A.B.). Analytical data were obtained from the CENTC Elemental
Analysis Facility at the University of Rochester, funded by NSF
CHE-0650456. We thank David George (University of Rochester)
for running the control reactions in Scheme 2. We also thank the re-
viewers for helpful suggestions.
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Supporting Information for this article is available online at
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Primary Data for this article are available online at
http://www.thieme-connect.com/ejournals/toc/synlett and can be
cited using the following DOI: 10.4125/pd0052th. mPiDrayramPtirDayra4t0.125p/d0Pm0hirt.Dyraenat1
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i
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