Buchwald-Hartwig Mono-N-arylation with 2,6-dihaloisonicotinic acid derivatives: A convenient desymmetrization method

Article abstract of DOI:10.1055/s-2008-1067208

A method for the Buchwald-Hartwig mono-N-arylation of aniline with methyl 2,6-dichloroisonicotinate using Pd(OAc)₂, XPhos, and t-BuONa is reported. Use of m-anisidine under the same conditions resulted in the amidation of the methyl ester. Mono-N-arylation of m-anisidine with 2,6-dichloro-N,N- diisopropylisonicotinamide and 2,6-dibromo-N,N-diisopropylisonicotinamide, however, was successfully achieved using Pd(OAc)₂/XPhos/t-BuONa or Pd(OAc)₂/(±)-BINAP/K₂CO₃, respectively. The present study demonstrates the sensitivity of this cross-coupling method to both the steric and electronic nature of the coupling partners. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067208

2764
PAPER
Buchwald–Hartwig Mono-N-arylation with 2,6-Dihaloisonicotinic Acid
Derivatives: A Convenient Desymmetrization Method
M
ono-N-arylation
n
w
ith 2,6-Dih
n
aloisonicotin
a
ic
A
cid
D
erivativ
V
e
s
. Lorimer, Patrick D. O’Connor, Margaret A. Brimble*
Department of Chemistry, University of Auckland, 23 Symonds St., Auckland 1142, New Zealand
Fax +64(9)3737422; E-mail: m.brimble@auckland.ac.nz
Received 24 March 2008; revised 14 May 2008
Y
O
Y
O
Abstract: A method for the Buchwald–Hartwig mono-N-arylation
of aniline with methyl 2,6-dichloroisonicotinate using Pd(OAc)2,
XPhos, and t-BuONa is reported. Use of m-anisidine under the same
conditions resulted in the amidation of the methyl ester. Mono-N-
arylation of m-anisidine with 2,6-dichloro-N,N-diisopropylisonico-
tinamide and 2,6-dibromo-N,N-diisopropylisonicotinamide, how-
ever, was successfully achieved using Pd(OAc)2/XPhos/t-BuONa
or Pd(OAc)2/( )-BINAP/K2CO3, respectively. The present study
demonstrates the sensitivity of this cross-coupling method to both
the steric and electronic nature of the coupling partners.
N-arylation
+
R
NH2
N
X
R
N
X
N
X
H
X = Cl, Br,
R = H, OMe
Y = OMe, OtBu, NiPr2
OH
HO
Y
O
O
oxidative
X
O
Key words: Buchwald–Hartwig N-arylation, Pd(0) cross-coupling,
2,6-dihaloisonicotinates
O
cyclization
O
N
Me
N
H
R
N
HO
N
HO
H
The Buchwald–Hartwig amination occupies a prominent
position in heterocyclic chemistry and the amenability of
the reaction to scale-up is of particular relevance to the
pharmaceutical industry.1–3 Specifically, aminopyridines
can be easily prepared using this efficient palladium-cata-
lyzed carbon–nitrogen bond-forming strategy.4
mescengricin
Scheme 1 Synthesis of mono-N-arylated 2-haloisonicotinic acid
precursors
mary amine, benzylamine (3.0 equiv), in toluene using the
palladacycle generated from Pd(OAc)2 and 2-(di-tert-bu-
tylphosphino)biphenyl (JohnPhos) with excess sodium
tert-butoxide under microwave conditions (150 °C, 300
W, 10 min) affording the mono-N-arylated product 2 in
44% yield (Table 1, entry 1). Whilst this experiment was
encouraging, application of the same reaction conditions
using less reactive aniline as the amine coupling partner
only resulted in recovered starting material.
As part of a program aimed at preparing substituted a-
carbolines5 (pyrido[2,3-b]indoles) via oxidative cycliza-
tion of trisubstituted pyridine derivatives, our attention
was initially focused on the synthesis of the mono-N-ary-
lated 2-haloisonicotinic acid precursors (Scheme 1). It
was envisaged that ready access to a range of aniline-sub-
stituted 2-haloisonicotinic acid derivatives would provide
valuable trifunctional pyridine scaffolds for further syn-
thetic manipulation.
In light of the fact that there are far more reports of Buch-
wald–Hartwig reactions using standard thermal condi-
tions in the literature than the use of microwave
conditions, the reaction of methyl 2,6-dichloroisonicoti-
nate (1) with aniline was attempted under thermal condi-
tions. A number of ligands [XPhos, JohnPhos, ( )-BINAP
and DPPF] were investigated and it was found that the use
of the ligand XPhos afforded the cleanest reaction with
toluene proving it to be a better solvent than tert-butyl al-
cohol or mixtures of toluene–tert-butyl alcohol. The opti-
mum reaction time was 4 hours resulting in the formation
of the mono-N-arylation product 3 in 53% yield (Table 1,
entry 2).
Initial investigation was focused on the palladium-cata-
lyzed mono-N-arylation of aniline with methyl 2,6-
dichloroisonicotinate (1) (Table 1). The first choice of re-
action conditions was inspired by the work of Maes et
al.,6,7 who reported the palladium-catalyzed coupling of
aryl halides with primary amines under microwave condi-
tions. In light of the fact that their reported coupling of
4-bromoanisole with benzylamine to yield N-benzyl-4-
methoxyaniline was easily reproducible in our hands,
these conditions were evaluated for the attempted mono-
N-arylation with methyl 2,6-dichloroisonicotinate.
In order to demonstrate proof of principle, Buchwald–
Hartwig coupling of methyl 2,6-dichloroisonicotinate (1;
1.0 equiv) was first carried out with the more reactive pri-
Our attention next focused on the reaction of m-anisidine
with methyl 2,6-dichloroisonicotinate (1) as a possible
starting point for the synthesis of the neuroprotective a-
carboline, mescengricin (Scheme 1).8 It was hoped that
the presence of the additional methoxy group in the amine
coupling partner would improve the reactivity of the cou-
SYNTHESIS 2008, No. 17, pp 2764–2770
x
x.
x
x
.
2
0
0
8
Advanced online publication: 06.08.2008
DOI: 10.1055/s-2008-1067208; Art ID: P04408SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Mono-N-arylation with 2,6-Dihaloisonicotinic Acid Derivatives
2765
Table 1 N-Arylation of Amines with 2,6-Dichloroisonicotinic Acid Derivatives
X
O
X
O
Buchwald–Hartwig
mono-N-arylation
+
R
NH2
R
Cl
N
Cl
N
Cl
N
H
X = OMe, OtBu, NiPr2
R = Ar, Bn
Entry Amine
Dihalide
Conditions
Product; Yield (%)
OMe
O
OMe
Cl
O
1 (1 equiv), amine (3 equiv), Pd(OAc)2, (1 mol%),
JohnPhosa (2 mol%), t-BuONa (1.4 equiv), toluene,
MW, 10 min, 150 °C, 300 W
1
NH2
N
Cl
N
H
Cl
N
1
2; 44
3; 53
OMe
Cl
O
1 (1 equiv), amine (1 equiv), Pd(OAc)2, (1 mol%),
XPhosb (2 mol%), t-BuONa (1.4 equiv), Et3N (0.5
equiv), toluene, 90 °C, 4 h
2
1
1
NH2
N
N
H
H
O
N
OMe
1 (2 equiv), amine (1 equiv), Pd(OAc)2, (1 mol%),
XPhosb (2 mol%), t-BuONa (1.4 equiv), toluene
3
MeO
NH2
N
Cl
Cl
4
110 °C, 18 h
90 °C, 22 h
25 °C, 3 d
4; 28
4; 36
4; 34
OtBu
O
5 (1.5 equiv), amine (1 equiv), Pd(OAc)2, (1 mol%),
XPhosb (2 mol%), t-BuONa (1.4 equiv), toluene
4
MeO
NH2
Cl
N
Cl
5
25 °C, 4 d
80 °C, 2 d
130 °C, 3 d
4; 67
4; 66
4; 34
NiPr2
O
NiPr2
O
7 (1.5 equiv), amine (1 equiv), Pd(OAc)2, (5 mol%),
XPhosb (10 mol%), t-BuONa (1.4 equiv), toluene,
100 °C, 23 h
5
MeO
NH2
N
Cl
MeO
N
H
Cl
N
Cl
7
8; 14
a JohnPhos = 2-(di-tert-butylphosphino)biphenyl.
b XPhos = 2-dicyclohexylphosphino-2¢,4¢,6¢-triisopropylbiphenyl.
pling reaction. Initial attempts to couple m-anisidine with that the increased electron density on the aromatic ring in
methyl 2,6-dichloroisonicotinate (1) using 1 mol% m-anisidine favors displacement of the methoxy group
Pd(OAc)2/XPhos in toluene for 18 hours at 110 °C with from ester 1 rather than displacement of the chloro substit-
excess sodium tert-butoxide only afforded the amide 4 in uent.
28% yield (Table 1, entry 3). Use of lower reaction tem-
peratures (90 °C for 22 h and r.t. for 3 days) also resulted
in the formation of the amide 4 in 36% and 46% yield, re-
spectively (Table 1, entry 3). It was therefore apparent
Use of the more hindered tert-butyl 2,6-dichloroisonicoti-
nate (5) was examined in order to block the attack of m-
anisidine at the ester carbonyl group. Compound 5 was
prepared by heating citrazinic acid (6) with POCl3 at 130
Synthesis 2008, No. 17, 2764–2770 © Thieme Stuttgart · New York

2766
A. V. Lorimer et al.
PAPER
OMe
°C for 18 hours in the presence of tetramethylammonium
chloride followed by quenching with tert-butyl alcohol
and pyridine in 62% yield (Scheme 2).
O
OH
O
i. POBr3 (neat),
120 °C, 2.5 h
ii. MeOH (excess),
25 °C, 2 h
Br
N
9
Br
HO
N
6
OH
OtBu
O
54%
OH
O
i. POCl3 (3 equiv),
Me4N+Cl–, 130 °C, 18 h
i. POBr3, anisole,
ii. tBuOH (excess),
py (5 equiv), 2 d
62%
120 °C, 5 h
ii. HNiPr2 (excess), 25 °C, 1 h
Cl
N
Cl
HO
N
OH
54%
6
5
NiPr2
O
i. POCl3 (3 equiv),
Me4N+Cl–, 130 °C, 18 h
ii. HNiPr2 (excess), Et2O, 16 h
49%
Br
N
10
Br
NiPr2
O
Scheme 3 Synthesis of methyl 2,6-dibromoisonicotinate (9) and
2,6-dibromo-N,N-diisopropylisonicotinamide (10)
Cl
N
Cl
7
mo-N,N-diisopropylisonicotinamide (10) was similarly
prepared by treatment of a suspension of citrazinic acid
(6) in anisole with POBr3 at 120 °C for 5 hours followed
by reaction with diisopropylamine at ambient temperature
for 1 hour.
Scheme 2 Synthesis of tert-butyl 2,6-dichloroisonicotinate (5) and
2,6-dichloro-N,N-diisopropylisonicotinamide (7)
Attempted mono-N-arylation of m-anisidine with tert-bu-
tyl 2,6-dichloroisonicotinate (5) under the same condi-
tions as the methyl ester 1 with a range of temperatures
and reaction times only afforded amide 4 with no evi-
dence for formation of the desired mono-N-arylation
product (Table 1, entry 4). An increased reaction temper-
ature was detrimental to the reaction and the inability to
block the reaction at the ester carbonyl prompted adoption
of an alternative strategy.
With the more robust dibromoamide 10 in hand, investi-
gation of its Buchwald–Hartwig reaction with m-anisidine
was carried out hoping that the increased reactivity of the
C–Br bond would facilitate the desired cross coupling
(Table 2). Reaction of the dibromoamide 10 with m-anisi-
dine in toluene with sodium tert-butoxide as base using 10
mol% Pd(OAc)2/XPhos at 90 °C for 24 hours afforded the
desired mono-N-arylation product 11 in 19% yield
(Table 2, entry 1). Increasing the catalyst loading to 30
mol% did not improve the yield. It also appeared that
XPhos was unstable under these conditions; hence, the
ligand was changed to ( )-BINAP based on its compara-
ble reactivity to XPhos in our earlier model studies. Use
of ( )-BINAP as ligand did not improve the yield of the
mono-N-arylation product 11 either, (Table 2, entry 2)
and the palladium source was changed to Pd2(dba)3 based
on the observations by the Buchwald group11 that reac-
tions that were problematic using Pd(OAc)2 often showed
better reactivity using Pd2(dba)3. Changing the palladium
source to Pd2(dba)3 did improve the yield of 11 by 20%
(Table 2, entry 4) when using ( )-BINAP as ligand but no
improvement was observed when using XPhos (Table 2,
entry 3). Focusing on the Pd2(dba)3/( )-BINAP system it
was next observed that changing the ratio of m-anisi-
dine:dibromide 10 to 1:2 offered a further improvement in
the yield of 11 (Table 2, entries 5,6).
It was hoped that use of a more robust carboxamide group
would prevent the undesired acyl substitution from occur-
ring. It was decided to use 2,6-dichloro-N,N-diisopropyl-
isonicotinamide (7) as the substrate for the N-arylation
reaction. Reaction of esters 1 and 5 with m-anisidine leads
to the formation of a stable amide bond, thus providing a
driving force for this reaction. Replacement of the ester by
an amide group removes this driving force. Amide 7 was
therefore prepared by heating citrazinic acid (6) with
POCl3 at 130 °C for 18 hours followed by dilution with di-
ethyl ether and reaction with diisopropylamine
(Scheme 2).
Buchwald–Hartwig coupling of amide 7 with m-anisidine
using 5 mol% Pd(OAc)2/XPhos in toluene for 23 hours at
110 °C with excess sodium tert-butoxide afforded the
monoarylation product 8 in only 14% yield together with
recovered starting material (Table 1, entry 5). The lack of
reactivity of 2,6-dichloro-N,N-diisopropylisonicotin-
amide (7) as an N-arylation coupling partner prompted the
use of more reactive 2,6-dibromoisonicotinic acid deriva-
tives 9 and 10 (Scheme 3) as substrates for this reaction.
Methyl 2,6-dibromoisonicotinate (9)9 was prepared in
54% yield by treatment of citrazinic acid (6) with POBr3
at 120 °C for 2.5 hours followed by stirring with methanol
for 2 hours. Notably, it was essential to freshly prepare10
the POBr3 and distill it immediately before use. 2,6-dibro-
Surprisingly, there has been little investigation into selec-
tive monoamination reactions using Buchwald–Hartwig
catalysis. There have been a few reports of aminations that
are selective for bromide displacement over chloride,12 or
iodide over bromide,13 however, monoamination of
dichloro or dibromo coupling partners is rare. Maes et al.14
reported the selective monoamination of simple 2,6-
dichloropyridines with amines. In their case, use of a large
excess of K2CO3 rather than sodium tert-butoxide as base
Synthesis 2008, No. 17, 2764–2770 © Thieme Stuttgart · New York

PAPER
Mono-N-arylation with 2,6-Dihaloisonicotinic Acid Derivatives
2767
Table 2 N-Arylation of m-Anisidine with 2,6-dibromo-N,N-diisopropylisonicotinamide (10)
NiPr2
NiPr2
O
NiPr2
O
O
Buchwald–Hartwig
N-arylation
+
+
MeO
NH2
MeO
N
N
H
OMe
N
N
Br
MeO
N
Br
N
Br
H
H
10
12
11
Entry
Catalyst (mol%)
Ligand (mol %)
Mole ratio
Yield (%)
Base
m-anisidine:10
11
19
20
11
39
27
53
71
12
23
26
30
32
33
9
1
2
3
4
5
6
7
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd2(dba)3 (10)
Pd2(dba)3 (10)
Pd2(dba)3 (10)
Pd2(dba)3 (10)
Pd(OAc)2c (10)
XPhos (20)
1:1
1:1
1:1
1:1
1:1.5
1:2
1:1
t-BuONaa
t-BuONaa
t-BuONaa
t-BuONaa
t-BuONaa
t-BuONaa
( )-BINAP (20)
XPhos (20)
( )-BINAP (20)
( )-BINAP (20)
( )-BINAP (20)
( )-BINAP (10)
b
10
K2CO3
a Reactions were carried out in toluene for 24 h at 90 °C using t-BuONa (1.4 equiv).
b Reaction was carried out in toluene at 90 °C for 41 h.
c Pd(OAc)2 and ( )-BINAP were premixed in toluene for 10 min prior to use.
afforded good yields of the monosubstitution product. It than a diisopropyl amide group. Dibromo ester 9 also pro-
was proposed that introduction of an electron-donating vides a critical substrate on which to evaluate the scope of
amino group increases the electron density of the pyridine Buchwald–Hartwig mono-N-arylations in the presence of
ring such that oxidative addition into the second C–Cl the C-4 methyl ester group that had previously been ob-
bond is rendered less favorable.
served to undergo reaction with m-anisidine (vide supra).
Treatment of dibromo ester 9 with m-anisidine using pre-
incubated Pd(OAc)2/( )-BINAP afforded mono-N-arylat-
ed product 13 in 58% yield whereas use of the
corresponding dichloro ester 1 led to a complex mixture.
The reaction procedure developed by Maes et al.14 re-
quires preincubation of Pd(OAc)2 and ( )-BINAP in tolu-
ene for 10 minutes prior to the addition to the reaction
mixture. We were therefore interested to see whether the
conditions developed by Maes et al.14 could be extended
to the use of more reactive 2,6-dibromopyridines that also
contained a substituent at C-4 for further synthetic manip-
ulation.
OMe
O
+
MeO
NH2
58%
Br
N
9
Br
Gratifyingly, reaction of dibromo amide 10 with m-anisi-
dine using preincubated Pd(OAc)2/( )-BINAP afforded
the mono-N-arylated product 11 in a pleasing 71% yield.
Exclusive monoamination of 10 was not observed with all
reactions producing some of the diaminated product 12.
This observation can be attributed to two factors. Firstly,
bromides are better leaving groups than chlorides, hence
the second oxidative addition step could not be prevented
upon introduction of the initial m-anisidine substituent.
Secondly, the amide group at C-4 would withdraw elec-
tron density from the pyridine ring counteracting the in-
creased electron density achieved upon amination.
i. Pd(OAc)2 (10 mol%), ( )-BINAP (20 mol%),
toluene, 10 min
ii. K2CO3, toluene, 90 °C, 41 h
OMe
Br
O
N
MeO
N
H
13
The conditions used to form mono-N-arylated product 11
by reaction of dibromoamide 10 with m-anisidine
(Table 2, entry 7) were next applied to the use of methyl
2,6-dibromoisonicotinate (9) as a substrate (Scheme 4).
Use of dibromo ester 9 was considered more synthetically
useful in that the tripodal mono-N-arylation product 13
bears an ester group that can be more easily elaborated
Scheme 4 Mono-N-arylation of m-anisidine with methyl 2,6-dibro-
moisonicotinate (9)
In conclusion, several 6-anilino-2-haloisonicotinic acid
derivatives have been successfully prepared via Buch-
wald–Hartwig mono-N-arylation of amines with 2,6-
Synthesis 2008, No. 17, 2764–2770 © Thieme Stuttgart · New York

2768
A. V. Lorimer et al.
PAPER
1H NMR (300 MHz, CDCl3): d = 3.95 (s, 3 H, OCH3), 4.60 (d,
J = 5.7 Hz, 2 H, CH2N), 6.49 (br s, 1 H, NH), 6.95 (d, J = 1 Hz, 1
H, 3-H), 7.20 (d, J = 1 Hz, 1 H, 5-H), 7.37 (m, 5 H, H-2¢, H-3¢, H-
4¢, H-5¢, H-6¢).
13C NMR (75 MHz, CDCl3): d = 44.3, 54.5, 107.2, 113.9, 127.9,
128.9, 137.2, 146.8, 149.4, 164.3, 164.4.
dichloro- or 2,6-dibromoisonicotinic acid derivatives.
This methodology has extended the scope of the Buch-
wald–Hartwig N-arylation reaction to the use of C-4 func-
tionalized dihalopyridines with the usual caveat that the
observed outcome of the reaction is highly dependent on
the steric and electronic effects of the cross-coupling part-
ners.
MS (EI, 70 eV): m/z (%) = 65 (14), 81 (19), 91 (47), 106 (70), 127
(8), 143 (55), 171 (61), 241 (4), 276 (M+, 100).
HRMS: m/z calcd for C14H1335ClN2O2 [M]+: 276.0666; found:
All reactions were carried out under N2 using oven-dried glassware
using standard syringe and septum techniques, unless otherwise
stated. THF was distilled from Na/benzophenone under N2. Toluene
was distilled from Na under N2. Flash chromatography was per-
formed using Riedel-de Häen or Merck 0.032–0.063 mm silica gel.
Analytical TLC was performed with 0.20 mm silica gel 60 alumi-
num-backed plates and analyzed using 365 nm ultraviolet irradia-
tion followed by staining with either alkaline KMnO4 or vanillin/
H2SO4 solution. High-resolution mass spectra were obtained using
EI, CI, and FAB techniques on a VG70-SE spectrometer operating
at a nominal accelerating voltage of 70 eV and a nominal resolution
of 5000 to 10000 as appropriate. NMR spectra were recorded on ei-
276.0670; C14H1337ClN2O2: 278.0636; found: 278.0632.
Methyl 2-Chloro-6-(aminophenyl)isonicotinate (3)
The ester 1 (103 mg, 0.75 mmol), t-BuONa (67 mg, 0.7 mmol),
XPhos (5 mg, 0.01 mmol), and Pd(OAc)2 (1.1 mg, 0.005 mmol)
were placed in a flask and the flask was flushed with argon. Aniline
(70 mg, 0.75 mmol), Et3N (0.04 mL, 0.25 mmol), and toluene (1
mL) were added via syringe. The mixture was heated under argon
before cooling to r.t. The mixture was diluted with H2O (15 mL) and
extracted with CH2Cl2 (3 × 15 mL). The combined organic extracts
were washed with brine (10 mL), dried (MgSO4), and the solvent re-
moved in vacuo. The resultant brown residue was purified by flash
column chromatography using hexanes–EtOAc (5:1) as eluent to
afford 3 (53%) as an inseparable mixture with aniline as a cream
crystalline solid; mp 144–146 °C; Rf = 0.4 (hexanes–EtOAc, 5:1).
1
ther a Bruker DRX300 spectrometer operating at 300 MHz for H
nuclei and 75 MHz for 13C nuclei or on a Bruker DRX400 spectrom-
eter operating at 400 MHz for 1H nuclei and 100 MHz for 13C nu-
1
clei. H NMR data is reported as chemical shift in d (ppm) from
tetramethylsilane as an internal standard. 13C NMR data is reported
as follows: chemical shift in ppm from tetramethylsilane with the
solvent as an internal indicator (CDCl3 77.0 ppm), multiplicity with
respect to proton (deduced from DEPT experiments).
IR (thin film): 3295, 1657, 1599, 1539, 1445, 1382, 1360, 1327
cm–1.
1H NMR (300 MHz, CDCl3): d = 3.96 (s, 3 H, OCH3), 7.00 (d,
J = 1.1 Hz, 1 H, H-5), 7.17 (tt, J = 7.4, 1.7 Hz, 1 H, H-4¢), 7.25 (d,
J = 1.1 Hz, 1 H, H-3), 7.33 (tt, J = 7.9, 2.2 Hz, 2 H, H-3¢, H-5¢), 7.57
(d, J = 7.6 Hz, 2 H, H-2¢, H-6¢), 8.09 (s, 1 H, NH).
Methyl 2,6-Dichloroisonicotinate (1)15
Citrazinic acid (6; 5.1 g, 33.1 mmol) and Me4NCl (4.1 g, 37.7
mmol) were suspended in POCl3 (9.3 mL, 99.4 mmol) and the mix-
ture was slowly heated to 130 °C (Caution! vigorous release of gas-
eous HCl). The mixture was heated at 130 ° for 18 h. The reaction
was then cooled to 0 °C and anhyd MeOH (100 mL) was added
dropwise. (Caution! vigorous release of gaseous HCl). The mixture
was warmed to r.t. over 1 h, then neutralized with solid Na2CO3 (2
g) and the MeOH was removed in vacuo. The black residue was di-
luted with H2O (400 mL) and extracted with EtOAc (100 mL, then
3 × 50 mL). The combined organic extracts were washed with brine
(100 mL), dried (MgSO4) and the solvent removed in vacuo. The
black residue was passed through a plug of silica gel using 10:1 hex-
ane–EtOAc as eluent to afford 1 (3.9 g, 57%) as a pink solid; mp
78–80.5 °C (Lit.15 mp 80–81 °C).
13C NMR (75 MHz, CDCl3): d = 54.5, 107.2, 113.9, 120.6, 125.4,
129.1, 136.9, 147.2, 149.6, 162.9, 164.4.
MS (EI, 70 eV): m/z (%) = 39 (17), 51 (10), 65 (27), 81 (19), 85
(15), 94 (21), 146 (29), 174 (100), 262 (35ClM+, 68), 264 (37ClM+,
68).
HRMS: m/z calcd for C13H1135ClN2O2 [M]+: 262.0509; found:
262.0506; C13H1137ClN2O2: 264.0480; found: 264.0477.
2,6-Dichloro-N-(3¢-methoxyphenyl)isonicotinamide (4)
The ester 1 (412 mg, 2.0 mmol), t-BuONa (135 mg, 1.4 mmol), and
XPhos (9.5 mg, 0.02 mmol) were placed in a flask and the flask was
flushed with argon. m-Anisidine (123 mg, 1.0 mmol) was added fol-
lowed by Pd(OAc)2 (2.3 mg, 0.01 mmol) dissolved in toluene (3
mL) and the mixture was heated under argon. The mixture was
cooled to r.t., diluted with H2O (100 mL) and extracted with CH2Cl2
(3 × 50 mL). The combined organic extracts were washed with
brine (50 mL), dried (MgSO4) and the solvent was removed in vac-
uo. The resulting brown residue was purified by flash column chro-
matography using 3:1 hexanes–EtOAc as eluent to afford 4 as fine
off-white needles. Recrystallization from Et2O and hexanes (1:2)
afforded 4 (298 mg, 46%) as lilac needles; mp 160–162 °C;
Rf = 0.46 (hexanes–EtOAc, 3:1).
1H NMR (400 MHz, CDCl3): d = 3.98 (s, 3 H, OCH3), 7.81 (s, 2 H,
3-H, 5-H).
13C NMR (100 MHz, CDCl3): 53.3 (OCH3), 122.6 (C-3, C-5), 142.4
(C-2, C-6), 151.2 (C-4), 163.2 (C=O).
The 1H and 13C NMR data and melting point were in agreement with
that reported in the literature.15
Methyl 2-(Benzylamino)-6-chloroisonicotinate (2)
Benzylamine (0.33 mL, 3 mmol), methyl 2,6-dichloroisonicotinate
(1; 208 mg, 1 mmol), and t-BuONa (134 mg, 1.4 mmol) were placed
in a 10 mL microwave flask under N2. A solution of palladacycle (1
mL) prepared from Pd(OAc)2 (2.26 mg, 0.01 mmol) and di-(tert-bu-
tylphosphino)biphenyl (5.96 mg, 0.02 mmol) in toluene (5 mL) was
then added. The mixture was heated to 150 °C with microwave ir-
radiation (300 W) for 10 min, then filtered through Celite that was
then washed with CH2Cl2 (100 mL) and the solvent removed in vac-
uo. The residue was purified via flash chromatography using 5:1
hexanes–EtOAc as eluent to afford 2 (120.9 mg, 44%) as a pale
green solid; mp 154–155 °C; Rf = 0.3 (hexanes–EtOAc, 5:1).
IR (thin film): 3433, 2101, 1656, 1538, 1492, 1360, 1278 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.83 (s, 3 H, OCH3), 6.76 (ddd,
J = 8.30, 2.45, 0.78 Hz, 1 H, H-4¢), 7.08 (m, J = 8.03, 1.13 Hz, 1 H,
H-6¢), 7.28 (t, J = 9.35 Hz, 1 H, H-5¢), 7.31 (s, 1 H, H-2¢), 7.65 (s, 2
H, H-3, H-5), 7.83 (br s, 1 H, NH)).
13C NMR (100 MHz, CDCl3): d = 55.4, 106.5, 111.4, 112.6, 120.6,
130.6, 137.7, 147.7, 151.7, 160.3.
MS (EI, 70 eV): m/z (%) = 41 (12.0), 52 (13.0), 64 (8.0), 85 (17.3),
92 (5.3), 95 (16.3), 107 (5.3), 110 (8.0), 124 (22.7), 146 (34.0), 174
(91.4), 233 (2.7), 253 (4.7), 267 (3.7), 281 (1.3), 296 (35Cl2M+, 100),
298 (35Cl37ClM+, 100), 300 (37Cl2M+, 100).
IR (thin film): 3279, 1647, 1608, 1545, 1389, 1360, 1327, 895 cm–1.
Synthesis 2008, No. 17, 2764–2770 © Thieme Stuttgart · New York

PAPER
Mono-N-arylation with 2,6-Dihaloisonicotinic Acid Derivatives
2769
HRMS: m/z calcd for C13H1035Cl2N2O2 [M]+: 296.0114; found:
296.0119; C13H1035Cl37ClN2O2: 298.0090; found: 298.0101;
C13H1037Cl2N2O2: 300.0060; found: 300.0058.
2-Chloro-N,N-diisopropyl-6-(3¢-methoxyphenylamino)isonico-
tinamide (8)
Compound 7 (200 mg, 0.73 mmol), m-anisidine (59.8 mg, 0.49
mmol), X-Phos (23 mg, 0.05 mmol), Pd(OAc)2 (5.5 mg, 0.02
mmol), and t-BuONa (65.3 mg, 0.68 mmol) were mixed in toluene
(4 mL) under argon. The mixture was heated at 100 °C for 23 h, then
cooled to r.t., diluted with H2O (20 mL), and extracted with EtOAc
(3 × 35 mL). The combined organic extracts were washed with
brine (40 mL), dried (MgSO4), and concentrated in vacuo to give a
brown residue. The residue was purified by flash column chroma-
tography using 3:1 hexanes–EtOAc as eluent. The resulting mixture
of m-anisidine and the title compound was dissolved in 4% i-PrOH
in hexanes and purified on a preparative liquid chromatography col-
umn [Luna 5m Silica (2) 100A, 250 × 10.0 mm] using 3% i-PrOH in
hexanes as eluent to afford 8 (24.6 mg, 14%) as a white solid; mp
155–157 °C; Rf = 0.21 (hexanes–EtOAc, 3:1).
tert-Butyl 2,6-Dichloroisonicotinate (5)
Citrazinic acid (6; 1 g, 6.45 mmol) and Me4NCl (777 mg, 7.09
mmol) were suspended in POCl3 (20 mL, 19.34 mmol) and the mix-
ture was slowly heated to 130 °C (Caution! vigorous release of gas-
eous HCl). The mixture was heated at 130 °C for 18 h and then was
cooled to 0 °C. Anhyd tert-butyl alcohol (10 mL) and pyridine (2.60
mL, 32.25 mmol) were mixed in a flask and then added dropwise to
the above mixture. (Caution! vigorous release of gaseous HCl). The
mixture was warmed to r.t., stirred for 2 d, neutralized with aq sat.
NaHCO3 (100 mL), diluted with H2O (150 mL), and extracted with
EtOAc (3 × 75 mL). The combined organic extracts were washed
with brine (100 mL), dried (MgSO4), and the solvent removed in
vacuo. The black residue was purified by flash chromatography us-
ing 15:1 hexane–EtOAc as eluent to afford 5 (988 mg, 62%) as pink
needles; mp 75–78 °C; Rf = 0.45 (hexanes–EtOAc, 15:1).
IR (thin film): 1730, 1546, 1369, 1354, 1299, 1259, 1156 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.60 (s, 9 H, 3 × CH3), 7.74 (s, 2
H, 3-H and 5-H).
13C NMR (100 MHz, CDCl3): d = 27.9, 83.9, 122.6, 144.4, 151.2,
161.6.
IR (thin film): 3313, 1620, 1524, 1493, 1449, 1372, 1342, 1200,
1180, 1158 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.15–1.49 (m, 12 H, 4 × CH3),
3.49 [m, 1 H, CH(CH3)2], 3.76 [m, 1 H, CH(CH3)2], 3.81 (s, 3 H,
OCH3), 6.61 (d, J = 0.9 Hz, 1 H, 5-H), 6.63 (d, J = 0.8 Hz, 1 H, 3-
H), 6.67 (m, 1 H, 4¢-H), 6.80 (s, 1 H, NH), 6.86 (m, 1 H, 6¢-H), 6.93
(t, J = 2.2 Hz, 1 H, 2¢-H), 7.24 (t, J = 8.0 Hz, 1 H, 5¢-H).
13C NMR (100 MHz, CDCl3): d = 20.4, 20.7, 46.0, 50.1, 55.3,
102.4, 107.1, 109.4, 110.6, 113.4, 130.1, 140.3, 150.1, 150.3, 156.2,
160.6, 167.4.
MS (EI, 70 eV): m/z (%) = 73 (14), 76 (21), 85 (17), 100 (19), 112
(21), 128 (17), 146 (31), 156 (16), 174 (62), 191 (100), 248 (M+, 7).
MS (EI, 70 eV): m/z (%) = 41 (11), 43 (19), 100 (70), 218 (16), 234
HRMS: m/z calcd for C10H1235Cl2NO2 [M]+: 248.0245; found:
248.0250; C10H1235Cl37ClNO2: 250.0216; found: 250.0211;
C10H1237Cl2NO2: 252.0186; found: 252.0181.
(75), 261 (86), 318 (14), 361 (M+ 100).
,
HRMS: m/z calcd for C19H2435ClN3O2 [M]+: 361.1557; found:
361.1558; C19H2437ClN3O2: 363.1528; found: 363.1521.
2,6-Dichloro-N,N-diisopropylisonicotinamide (7)
Citrazinic acid (6; 1 g, 6.45 mmol) and Me4NCl (777 mg, 7.1 mmol)
were suspended in POCl3 (20 mL, 19.3 mmol) and the mixture was
slowly heated to 130 °C (Caution! release of gaseous HCl). The
mixture was heated at 130 °C for 18 h, cooled to r.t. and diluted with
anhyd Et2O (15 mL). The mixture was cooled to 0 °C and i-Pr2NH
(5.0 mL, 35.5 mmol) was added dropwise. (Caution! release of gas-
eous HCl). The mixture was warmed to r.t. and stirred overnight.
The reaction was quenched with aq sat. NH4Cl (10 mL) and diluted
with H2O (10 mL). The organic layer was separated and the aqueous
layer extracted with Et2O (50 mL). The combined organic extracts
(65 mL) were washed with aq 1 M HCl (2 × 40 mL), aq 2 M Na2CO3
(50 mL), and brine (20 mL), dried (MgSO4), and concentrated in
vacuo. The residue was purified by flash column chromatography
using 10:1 hexanes–EtOAc as eluent to afford 7 (869 mg, 49%) as
a colorless solid; mp 143–147 °C; Rf = 0.2 (hexanes–EtOAc, 10:1).
Methyl 2,6-Dibromoisonicotinate (9)
Citrazinic acid (6; 13 g, 84 mmol) and freshly prepared POBr3 (74.7
g, 261 mmol)11 were heated slowly under N2 to 120 °C (Caution!
vigorous release of gaseous HBr). The mixture was stirred at 120 °C
for 2.5 h, then cooled to 0 °C and methanol (290 mL) was added
slowly (Caution! vigorous release of gaseous HBr). The mixture
was warmed to r.t. and stirred for 2 h (timing started when the stir-
ring was restarted). The mixture was neutralized with aq sat.
NaHCO3 (50 mL) and solid NaHCO3 (3 g). The mixture was diluted
with H2O (150 mL) and extracted with EtOAc (3 × 200 mL). The
combined organic extracts were washed with brine (100 mL), dried
(MgSO4) and the solvent removed in vacuo. The brown residue was
purified via flash column chromatography using 24:1 hexanes–
EtOAc as eluent to afford 9 (13.2 g, 54%) as a colorless solid; mp
89–92 °C (Lit.10 mp 86.8–88.2 °C).
IR (thin film): 1635, 1585, 1537, 1451, 1364, 1340, 1165, 1041
cm–1.
1H NMR (400 MHz, CDCl3): d = 3.98 (s, 3 H, OCH3), 7.99 (s, 2 H,
3-H, 5-H).
1H NMR (400 MHz, CDCl3): d = 1.15 and 1.49 (m, 12 H, 4 × CH3),
3.55 [m, 1 H, CH(CH3)2], 3.65 [m, 1 H, CH(CH3)2], 7.16 (s, 2 H, 3-
H, 5-H).
13C NMR (100 MHz, CDCl3): d = 20.3, 20.7, 46.4, 51.2, 119.4,
151.0, 151.1, 165.3.
13C NMR (100 MHz, CDCl3): d = 53.3 (OCH3), 126.6 (C-3, C-5),
141.4 (C-2, C-6), 141.5 (C-4), 162.9 (C=O).
The 1H and 13C NMR data were in agreement with those reported in
the literature.10
2,6-Dibromo-N,N-diisopropylisonicotinamide (10)
MS (EI, 70 eV): m/z (%) = 41 (25), 43 (45), 85 (12), 146 (21), 174
(100), 217 (80), 231
Citrazinic acid (6; 3.96 g, 25.5 mmol) and freshly prepared POBr3
(22.7 g, 79.2 mmol)11 were suspended in anhyd anisole (27 mL).
The mixture was heated at 120 °C under N2 for 5 h. The mixture was
cooled to 0 °C and then i-Pr2NH (18.1 mL, 127.7 mmol) was added
slowly. The mixture was stirred at r.t. for 1 h, then neutralized with
aq sat. NaHCO3 (50 mL), diluted with H2O (50 mL) and extracted
with EtOAc (3 × 100 mL). The combined organic extracts were
washed with brine (100 mL), dried (MgSO4), and the solvent re-
moved in vacuo to give a brown oil, which was purified by flash
chromatography using 10:1 hexanes-EtOAc as eluent to afford 10
(57), 259 (42), 274 (M+ , 35).
HRMS: m/z calcd for C12H1635Cl2N2O [M]+: 274.0640; found:
274.0634; C14H1335Cl37ClN2O2: 276.0610; found: 276.0608;
C12H1637Cl2N2O: 278.0581; found: 278.0590.
Synthesis 2008, No. 17, 2764–2770 © Thieme Stuttgart · New York

2770
A. V. Lorimer et al.
PAPER
(5.0 g, 54%) as cream prisms; mp 145–147 °C; Rf = 0.25 (hexanes–
EtOAc, 10:1).
IR (thin film): 1625, 1517, 1462, 1371, 1355, 1341, 1157 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.19–1.51 (m, 12 H, 4 × CH3),
3.54–3.65 [m, 2 H, 2 × CH(CH3)2], 7.35 (s, 2 H, 3-H, 5-H).
13C NMR (100 MHz, CDCl3): d = 20.3, 20.6, 46.4, 51.2, 123.4,
141.2, 150.2, 164.9.
mL). The solvent was removed in vacuo yielding a brown residue
that was purified by flash column chromatography using 3:1 hex-
anes–EtOAc as eluent to afford 13 (3.4 g, 58%) as fine yellow
prisms; mp 146–149 °C; Rf = 0.27 (hexanes–EtOAc, 3:1).
IR (thin film): 3378, 1720, 1624, 1611, 1596, 1568, 1522, 1453,
1380, 1318, 1154 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.78 (s, 3 H, OCH3), 3.87 (s, 3 H,
OCH3), 6.65 (m, 1 H, 4¢-H), 6.78 (s, 1 H, NH), 6.83 (m, 1H, 6¢-H),
6.95 (t, J = 2.1 Hz, 1 H, 2¢-H), 7.23 (t, J = 8.1 Hz, 1 H, 5¢-H), 7.30
(d, J = 0.8 Hz, 1 H, 5-H), 7.37 (d, J = 0.6 Hz, 1 H, 3-H).
MS (EI, 70 eV): m/z (%) = 43 (73), 76 (22), 129 (10), 234 (21), 262
[M+ – N(i-Pr2)2, 100], 305 (72), 319 (77), 347 (53), 362 (M+, 45).
HRMS: m/z calcd for C12H1679Br2N2O2 [M]+: 361.9629; found:
361.9635; C12H1679Br81BrN2O2: 363.9609; found: 363.9611;
C12H1681Br2N2O2: 365.9588; found: 365.9595.
13C NMR (100 MHz, CDCl3): d = 52.8, 55.3, 106.5, 106.8, 109.7,
113.2, 117.3, 130.2, 140.1, 140.7, 141.2, 156.4, 160.6, 164.6.
MS (EI, 70 eV): m/z (%) = 64 (19), 77 (25), 92 (21), 107 (12), 197
(27), 214 (12), 229 (20), 257 (19), 336 (M+, 100).
2-Bromo-N,N-diisopropyl-6-(3¢-methoxyphenylamino)isonico-
tinamide (11)
HRMS: m/z calcd for C14H1379BrN2O3 [M]+: 336.0110; found:
Pd(OAc)2 (154 mg, 0.69 mmol) and ( )-BINAP (428 mg, 0.69
mmol) were placed in a flask and the flask was flushed with N2. Tol-
uene (120 mL) was added and the mixture was stirred under N2 for
10 min. m-Anisidine (846 mg, 6.87 mmol), 10 (3 g, 8.24 mmol), and
K2CO3 (18.9 g, 137 mmol) were combined in a N2-flushed flask.
The Pd(OAc)2/( )-BINAP solution was added and the flask was
washed with toluene (2 × 105 mL). The mixture was stirred at 90 °C
in an oil bath for 45 h. The mixture was cooled to r.t., the solid was
removed by filtration and washed with CH2Cl2 (300 mL). The sol-
vent was removed in vacuo to yield a brown-red residue, which was
purified by flash column chromatography using 3:1 hexanes–
EtOAc as eluent to afford 11 (2.0 g, 71%) as a pale orange solid; mp
93–96 °C; Rf = 0.20 (hexanes–EtOAc, 3:1).
336.0109; C14H1381BrN2O3: 338.0089; found: 338.0087.
Acknowledgment
We thank the University of Auckland for financial support.
References
(1) Janey, J. M. Buchwald–Hartwig Amination, In Name
Reactions for Functional Group Transformations; Li, J. J.,
Ed.; Wiley: Hoboken NJ, 2007, 566–611.
(2) Schlummer, B.; Scholz, U. Adv. Synth. Catal. 2004, 346,
1599.
IR (thin film): 3321, 3175, 2974, 2836, 2248, 2080, 1629, 1372,
1342, 1284, 1158 cm–1.
(3) Buchwald, S. L.; Mauger, C.; Mignani, G.; Scholz, U. Adv.
Synth. Catal. 2006, 348, 23.
1H NMR (400 MHz, CDCl3): d = 1.14–1.50 (m, 12 H, 4 × CH3),
3.49 [m, 1 H, CH(CH3)2], 3.79 [m, 1 H, CH(CH3)2], 6.62 (m, 1 H,
4¢-H), 6.63 (d, J = 0.9 Hz, 1 H, 5-H), 6.75 (d, J = 0.9 Hz, 1 H, 3-H),
6.85 (m, 1 H, 6¢-H), 7.03 (t, J = 2.2 Hz, 1 H, 2¢-H), 7.20 (t, J = 8.1
Hz, 1 H, 5¢-H), 7.24 (s, 1 H, NH)).
13C NMR (100 MHz, CDCl3): d = 20.4, 20.6, 46.0, 51.0, 55.2,
103.2, 106.4, 109.1, 112.8, 133.9, 129.9, 140.3, 140.5, 149.5, 156.1,
160.3, 167.3.
(4) (a) Wagaw, S.; Buchwald, S. L. J. Org. Chem. 1996, 61,
7240. (b) Li, J. J.; Wang, Z.; Mitchell, L. H. J. Org. Chem.
2007, 72, 3606.
(5) (a) Barun, O.; Patra, P. K.; Junjappa, H. Tetrahedron Lett.
1999, 40, 3797. (b) Molina, P.; Freneda, P. M.; Sanz, M. A.;
Foces-Foces, C.; Arellano, M. C. R. D. Tetrahedron 1998,
54, 9623; and references cited therein.
(6) Maes, B. U. W.; Loones, K. T. J.; Hostyn, S.; Diels, G.;
Rombouts, G. Tetrahedron 2004, 60, 11559.
(7) Maes, B. U. W.; Loones, K. T. J.; Lemiere, G. L. F.;
Domisse, R. A. Synlett 2003, 1822.
(8) Kim, J.; Shin-ya, K.; Furihata, K.; Hayakawa, Y.; Seto, H.
Tetrahedron Lett. 1997, 38, 3431.
MS (EI, 70 eV): m/z (%) = 41 (21), 43 (38), 77 (22), 100 (100), 172
(34), 198 (44), 198 (44), 305 (72), 362 (11), 405 (M+, 79).
HRMS: m/z calcd for C19H2479BrN3O2 [M]+: 405.1052; found:
405.1047; C19H2481BrN3O2: 407.1031; found: 407.1033.
(9) Amb, C. M.; Rasmussen, S. C. J. Org. Chem. 2006, 71,
4696.
(10) Kelly, T. R.; Lee, Y.-J.; Mears, R. J. J. Org. Chem. 1997, 62,
2774.
Methyl 2-Bromo-6-(3¢-methoxyphenylamino)isonicotinate (13)
Pd(OAc)2 (317 mg, 1.41 mmol), and ( )-BINAP (878 mg, 1.41
mmol) were placed in a flask and the flask was flushed with N2. Tol-
uene (250 mL) was added and the mixture was stirred under N2 for
10 min. m-Anisidine (1.74 g, 14.13 mmol), methyl 2,6-dibromo-
isonicotinate (9; 5 g, 16.95 mmol), and K2CO3 (39.06 g, 282.6
mmol) were combined in a N2-flushed flask. The Pd(OAc)2/
( )-BINAP solution was added and the flask washed with toluene
(2 × 100 mL). Toluene (100 mL) was added to the reaction vessel
and the mixture was heated at 90 °C in an oil bath for 46 h, until no
m-anisidine remained as detected by TLC. The mixture was cooled
to r.t. and the solid removed by filtration washed with CH2Cl2 (300
(11) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald,
S. L. J. Org. Chem. 2000, 65, 1158.
(12) Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999,
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(13) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L.
Acc. Chem. Res. 1998, 31, 805.
(14) Jonckers, T. H. M.; Maes, B. U. W.; Lemiere, F.; Dommisse,
R. Tetrahedron 2001, 57, 7027.
(15) Mello, J. V.; Finney, N. S. Org. Lett. 2001, 3, 4263.
Synthesis 2008, No. 17, 2764–2770 © Thieme Stuttgart · New York