Straightforward and efficient synthesis of 3-benzyloxy-4-bromopicolinate ester and 3-benzyloxy-5-bromopicolinate ester, common building blocks for pharmaceuticals and agrochemicals

Article abstract of DOI:10.1016/j.tet.2011.09.024

A practical and rapid preparation of 3-benzyloxy-4-bromo and 3-benzyloxy-5-bromopicolinate esters 10 and 16 was developed in four steps, respectively, in 38% and 31% overall yield. Then their viability as partners for cross-coupling reactions has been evaluated in Suzuki-Miyaura, Hartwig-Buchwald, and Sonogashira reactions to synthesize biologically relevant targets. The preparation of these two highly functionalizable pyridines 10 and 16 has been never described to date in the literature and could be used as common building block for the preparation of several biologically active compounds or agrochemical products.

Full text of DOI:10.1016/j.tet.2011.09.024

Tetrahedron 67 (2011) 8757e8762
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Straightforward and efficient synthesis of 3-benzyloxy-4-bromopicolinate ester
and 3-benzyloxy-5-bromopicolinate ester, common building blocks for
pharmaceuticals and agrochemicals
,
b
,
,
b
,
,
,
,b,c,
Tristan Verdelet a y, Guillaume Merceya y, Nobi Correa a b, Ludovic Jean a b, Pierre-Yves Renard a
*
a
ꢀ
Equipe de Chimie Bio-Organique, COBRA-CNRS UMR 6014 & FR 3038, rue Lucien Tesniere, 76131 Mont-Saint-Aignan, France
b
ꢁ
Universite de Rouen, Place Emile Blondel, 76821 Mont-Saint-Aignan, France
c Institut Universitaire de France, 103 boulevard Saint Michel, 75005 Paris, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 June 2011
Received in revised form 7 September 2011
Accepted 8 September 2011
Available online 12 September 2011
A practical and rapid preparation of 3-benzyloxy-4-bromo and 3-benzyloxy-5-bromopicolinate esters 10
and 16 was developed in four steps, respectively, in 38% and 31% overall yield. Then their viability as
partners for cross-coupling reactions has been evaluated in SuzukieMiyaura, HartwigeBuchwald, and
Sonogashira reactions to synthesize biologically relevant targets. The preparation of these two highly
functionalizable pyridines 10 and 16 has been never described to date in the literature and could be used
as common building block for the preparation of several biologically active compounds or agrochemical
products.
Keywords:
Pyridines
Dehalogenation
Heterocycles
Palladium
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
targeted compound. Therefore, it would be very interesting to de-
velop a practical and rapid synthetic pathway to access to esters 10
3-Alkoxy-6-bromopicolinate esters 1 are building block widely
used in the preparation of several biologically active compounds1e5
and agrochemical products6 (Fig. 1). While syntheses of 1 are re-
ported in several patents,1e5 no preparation of 3-alkoxy-4-
bromopicolinate esters 2 and 3-alkoxy-5-bromopicolinate esters
and 16, which could be considered as common building blocks for
the drug discovery process and elaboration of new agrochemicals
compounds. Herein, the synthesis of 10 and 16 in four steps from 3-
hydroxypicolinic acid and 2-amino-3-benzyloxypyridine, re-
spectively, and their evaluation as partner in cross-coupling re-
actions, in order to access to the scaffold of biologically active
compounds, are described.
3
have been described to date. However, 3-alkoxy-4-
bromopicolinate esters 2 and derivatives could be very useful for
synthesis of HIF activity modulators,7 modulators for the treatment
of asthma and chronic obstructive pulmonary disease,8 propyl hy-
drolase
inhibitors9
and
fungicides,10
and
3-alkoxy-5-
bromopicolinate esters 3 could be key intermediates in the prep-
aration of compounds, such as pesticides,11 HIV integrase in-
hibitors,12 antidiabetic drugs,13 antiulcer agents,14 and
b-secretase
inhibitors for the treatment of neurological disorders.15
All compounds listed above have been prepared from different
pyridine derivatives (e.g., picolinic acid, 3,5-dichloro-2-
cyanopyridine, 5-bromo-2-cyano-3-nitropyridine or 3-methoxy-
4-nitropyridine N-oxide), requiring a new synthetic route for each
* Corresponding author. Tel.: þ33 2 35 52 24 14; fax: þ33 2 35 52 29 59; e-mail
addresses: ludovic.jean@univ-rouen.fr (L. Jean), pierre-yves.renard@univ-rouen.fr
(P.-Y. Renard).
Fig. 1. Structures of 3-alkoxy-bromopicolinates esters and examples of structures of
pharmaceuticals products.
y
These authors contributed equally to this work.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.024

8758
T. Verdelet et al. / Tetrahedron 67 (2011) 8757e8762
2. Results and discussion
reaction conditions to obtain 10 involves 5 (1 equiv), sodium for-
mate (1.1 equiv), Pd(PPh3)4 (5 mol %) in DMF heated at 80 ꢀC for
20 h with a concentration of 0.125 M (entry 6).
Aiming at the rapid preparation of the desired ester 2, we firstly
evaluated directed ortho-lithiation of 3-(methoxymethyl)picolinate
ester 4, followed by a treatment with bromine or iodide, which
appeared to be the most expedient way to synthesize this ester. Yet,
unexpectedly, whichever lithiated base we used, these attempts led
to a mixture of products of degradation or an intermolecular ad-
dition of the resulting organolithium on ester function (Scheme 1).
Table 1
Selective dehalogenation of 5
Entry
Solvent
Time (h) T (ꢀC)
Concentrationa
Conversionb (%)
5
10
11
1
2
3
4
5
6
7
8
MeOH
MeOH
MeOH
MeOH
DMF
DMF
DMF
DMF
3
24
48
72
20
20
20
20
65
65
65
65
80
80
80
80
0.025
0.025
0.025
0.1
0.05
0.125
0.25
0.5
97
70
40
30
13
0
2
26
36
42 (35)
51
73 (70)
68
50
0
0
0
Scheme 1. Attempts to access 4-halogenopicolinate esters from ester 4.
0
27
17
14
21
In order to obtain targeted brominated compound 2, we took
advantage of the high selectivities observed for the electrophilic
bromination of 3-hydroxypicolinate esters. The first bromination
very efficiently takes place at the 6 position, thanks to the directing
effect of the phenol then ensuring the easy access to 1 (R¼H). Ad-
dition of excess bromine cleanly leads to dibrominated product,6,12
with the second bromination selectively taking place at position 4,
which after alkylation with benzyl bromide, gives 5 (we also tested
an alternative route to access to the desired 5-bromo-4-chloro-3-
methoxypicolinic acid from the maltol,16 but contrary to the de-
scribed procedure, we obtained the desired product only in very low
yield). From this dibrominated product, we were pleased to observe
a regioselective insertion of palladium species into the CeBr bond in
position 6 of pyridine 5. Indeed, a cross-coupling reaction, realized
between 5 and methyl boronic acid, gave selectively 3-benzyloxy-4-
bromo-6-methylpicolinate ester 6 in 30% isolated yield with only
starting material remaining (Scheme 2). Thus, we decided to take
advantage of this reactivity in order to prepare 2 from 5 by using
a selective Pd-catalyzed dehalogenation.17
0
0
a
Concentration of 5 in mol/L.
b
Determined by analysis of 1H NMR spectra of crude material. In parentheses are
given the isolated yields.
In summary, 3-benzyloxy-4-dibromopicolinate ester 10 has been
synthesized in four steps from commercially available 3-
hydropicolinic acid 7 (Scheme 3). The first step consisted in the es-
terification of carboxylic acid with methanol to afford ester 8 in 80%
yield.18 Then electrophilic bromination in positions 4 and 6 of the
pyridine was performed in 76% yield. Phenol 9 was protected using
benzyl bromide and K2CO3 as a base to give 5 in 90% yield. Finally
treatment of 5 with sodium formate in presence of catalytic amount
of Pd(PPh3)4 (5 mol %) gave desired ester 10 in 70% isolated yield.
Scheme 2. Regioselective Suzuki cross-coupling reaction of 5 with methyl boronic
acid.
This last step needed optimized conditions to reach a good
conversion and to obtain selectively the desired pyridine 10 (ben-
zylated form of 2) (Table 1). Firstly, the reaction of dehalogenation
was carried out in methanol at 65 ꢀC. In a concentration of 0.025 M
(Table 1, entries 1e3), the conversion was low (36%) after 2 days
refluxing, yet the reaction proved selective, since no trace of bis
dehalogenated product neither of the other regioisomer 11 was
observed. Eventually, the desired pyridine 10 was obtained in only
35% isolated yield after a reaction time of 72 h and at higher con-
centration (entry 4). Moreover, increasing the reaction time ended
up in the degradation of both substrate and product. Using DMF as
solvent, the conversion was dramatically increased (entry 5).
However, the selectivity of this dehalogenation reaction was lower,
leading to a mixture of 10 and 11 in these conditions. We then in-
vestigated the effect of concentration and we were pleased to no-
tice that the selectivity and the conversion were enhanced by
increasing the reaction concentration. Indeed, 10 was obtained in
70% isolated yield with a concentration of 50 mg/mL (entry 6).
However, at higher concentration (entries 7 and 8), further degra-
dation of products was also observed. Finally, therefore, the best
Scheme 3. Synthesis of methyl 4-bromopicolinate ester 10.
Altogether, 10 was obtained in four steps in 38% overall yield
from commercially available 3-hydroxypicolinic acid 7.
In order to access rapidly and efficiently to the 5-
bromopicolinate ester 16, the regioselectivity of the electrophilic
bromination had to be reversed, thus we chose to start from
commercially available 2-amino-3-benzyloxypyridine 12 (Scheme
4). The amino function in position 2 was expected to control the
electrophilic bromination in position 5. Indeed, electrophilic bro-
mination19 gave a complete regioselectivity, and brominated de-
rivative 13 was obtained in 70% yield. Treatment of 13 with isoamyl
nitrite, iodine, and copper iodide in 1,2-diiodomethane gave de-
sired dihalogenated product 14 in 67% yield. Used as solvent, 1,2-

T. Verdelet et al. / Tetrahedron 67 (2011) 8757e8762
8759
diiodomethane is quite expensive and we attempted to replace it by
1,2-dichloroethane. Unexpectedly, in the same reaction conditions,
a 1/1 mixture of 3-benzyloxy-5-bromo-2-iodopyridine 11 and 3-
benzyloxy-5-bromo-2-chloropyridine was obtained. Finally,
derivatives are monoamine oxidase (MAO-B) inhibitors for the
treatment of obesity.22 Therefore, bromo-pyridines 10 and 16 have
also been evaluated as partner in HartwigeBuchwald reactions
(Scheme 6). The cross-coupling reaction with benzylamine gave
different results depending on the catalyst and solvent used. Con-
cerning the amination with a primary amine, after optimization,
synthesis of 20 was obtained in 88% yield using Pd2dba3/xantphos in
toluene, whereas 21 was obtained in 93% yield using Pd2dba3/BINAP
in 1,4-dioxane. Foramination reactions with a secondaryamine (e.g.,
piperidine), the results were dependent on the bromopyridine used.
The reaction with 16 using Pd2dba3/xantphos in toluene gave 22 in
a satisfactory 75% yield, while the cross-coupling reaction with 10
was carried out in low yield (less than 25%) whatever the conditions
used, probably due to a problem of steric hindrance.
a
straightforward sequence comprising a selective magne-
siumehalogen exchange,20 addition of the resulting Grignard re-
agent to dimethylformamide, and oxidation of the resulting
aldehyde 15 with iodide in presence of potassium hydroxide in
methanol gave the desired bromopicolinate ester 16 in 65% yield.21
Attempts to form directly methyl ester 16 by quenching the
resulting Grignard reagent with methyl chloroformate or methyl
cyanoformate failed.
R
OBn
CO2Me
88% 20 R = NHBn
Br
OBn
N
N
CO2Me
benzylamine
or piperidine (1.3 eq)
10
Pd2dba3 (2 mol%)
Ligand (4-6 mol%)
Cs2CO3 (1.5 eq)
Solvent, 100°C
Br
OBn
R
OBn
N
CO2Me
N
CO2Me
16
93% 21 R = NHBn
Ligand : BINAP or xantphos
Solvent : Toluene or 1,4-dioxane
N
75% 22 R =
Scheme 6. Pd-catalyzed aminations.
Finally, bromo-pyridines 10 and 16 have been tested as partner
in Sonogashira reaction with propargyl alcohol. The reaction with
16 gave the desired product 23 in 82% yield (Scheme 7), while the
reaction with 10 failed even using harsher conditions (DMF, 60 ꢀC).
Scheme 4. Synthesis of methyl 5-bromopicolinate 16.
In order to evaluate the functionalization of 3-benzyloxy-4-
bromo and 3-benzyloxy-5-bromopicolinate esters 10 and 16, the
scopes and limitations of cross-coupling reactions using these
brominated pyridines have been evaluated. Firstly, Suzu-
kieMiyaura reactions between bromo-pyridines 10 and 16 and
arylboronic acids have been carried out in good yields and allowed
to access to the scaffold of propyl hydrolase inhibitors (Scheme 5).9
(1 eq)
OH
Pd(PPh3)4 (5 mol%)
OH
Br
OBn
CuI (10 mol%)
OBn
CH2Cl2, NEt3 (2/1, v/v)
N
CO2Me
N
CO2Me
16
82% 23
Scheme 7. Sonogashira reaction.
3. Conclusion
We described a practical and efficient preparation of methyl 3-
(benzyloxy)-4-bromopiconinate ester 10 in four steps in 38%
overall yield and methyl 3-(benzyloxy)-5-bromopiconinate ester 16
in four steps in 31% overall yield. As reported above, the preparation
of these pyridines 10 and 16 have been never described to date in
the literature and we have demonstrated that these compounds are
highly functionalizable using cross-coupling reactions and are
useful for the preparation of several biologically active compounds
or agrochemical products.
Scheme 5. SuzukieMiyaura reactions.
4. Experimental section
4.1. General
The 4-amino-3-hydroxypicolinic acid and derivatives are also
very useful for the preparation agrochemical (e.g., fungicides10) or
pharmaceutical (e.g., modulators of CXCR-2 receptor for the treat-
ment of asthma8), whereas 5-amino-3-hydroxypicolinic acid and
Column chromatography purifications were performed on silica
gel (40e63
mm) from Merck. Thin-layer chromatography (TLC) was
carried out on Merck DC Kieselgel 60 F254 aluminum sheets.

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T. Verdelet et al. / Tetrahedron 67 (2011) 8757e8762
Compounds were visualized by one of the two following methods:
(1) illumination with a short wavelength UV lamp (
(2) staining with a 3.5% (w/v) phosphomolybdic acid solution in
absolute ethanol. All commercially available reagents and solvents
were purchased and used without further purification, except THF,
which was dried by distillation over Na/benzophenone.
Melting points were recorded on a LEICA VMHB Kofler system
at atmospheric pressure and were uncorrected. Microanalyses
were carried out on Carlo-Erba 1106. Infrared spectra were
recorded as KBr pellets using a PerkineElmer FT-IR Paragon 500
spectrometer with frequencies given in reciprocal centimeters
(cmꢁ1). 1H and 13C NMR spectra were recorded on a Bruker DPX
300 spectrometer (Bruker, Wissembourg, France). Chemical shifts
C14H11Br2NO3: C, 41.93; H, 2.76; N, 3.49. Found: C, 41.95; H, 2.81; N,
3.21.
l¼254 nm) or
4.1.5. Methyl 3-benzyloxy-4-bromobenzylpicolinate 10. Pd(PPh3)4
(140 mg, 0.05 equiv) was added to a degassed solution of 5 (1.0 g,
2.5 mmol) and sodium formate (190 mg, 1.1 equiv) in DMF (20 mL,
50 g/L). The mixture was stirred for 20 h at 80 ꢀC. DMF was re-
moved under vacuum and the crude mixture was directly absorbed
on silica gel and purified by flash chromatography (cyclohexane/
EtOAc 7/3, v/v) to give 10 (560 mg, 70%) as a beige solid. Rf¼0.3
(cyclohexane/EtOAc 7/3, v/v). Mp 78 ꢀC. 1H NMR (300 MHz, CDCl3)
d
(ppm) 3.95 (s, 3H), 5.16 (s, 2H), 7.36e7.45 (m, 3H), 7.53e7.56 (m,
2H), 7.71 (d, J¼5.1 Hz, 1H), 8.27 (d, J¼5.1 Hz, 1H). 13C NMR (75 MHz,
are expressed in parts per million (ppm) from CDCl3
(dH¼7.26,
CDCl3) d 53.1, 76.8, 128.5, 128.6, 128.7, 130.1, 131.3, 135.9, 145.3,
dC¼77.16).23 J values are expressed in hertz. Mass spectra were
obtained with a Finnigan LCQ Advantage MAX (ion trap) apparatus
equipped with an electrospray source. All analyses were per-
formed in the positive mode.
145.4, 152.5, 164.4. MS (ESIþ) m/z (%): 324 (95), 322 (100). Anal.
Calcd for C14H12BrNO3: C, 52.20; H, 3.75; N, 4.35. Found: C, 52.33; H,
3.89; N, 3.81.
4.1.6. 3-Benzyloxy-5-bromopyridin-2-ylamine 13. Sulfuric acid
(10%, 160 mL) was introduced in a three necked flask equipped with
mechanical stirrer. 3-Benzyloxypyridi-2-ylamine 12 (8 g, 40 mmol)
was added at room temperature under efficient stirring. The re-
action mixture was cooled at 0 ꢀC, where a mixture of Br2 (7.68 g,
48.1 mmol) in acetic acid (25 mL) was added dropwise over a period
of 35 min. The resulting mixture was stirred for 3 h at 0 ꢀC. Then, ice
water (160 mL) was added and the solution was basified by addition
of 30% aqueous ammonia solution. The aqueous phase was extrac-
ted with CH2Cl2 (thrice). Combined organic layers were washed
with water, dried over MgSO4, and concentrated under reduced
pressure. Purification by flash chromatography on silica gel (cyclo-
hexane/EtOAc 8/2, v/v) afforded 13 (8 g, 70%) as a yellow/orange
4.1.1. Methyl
3-benzyloxy-4-bromo-6-methylpicolinate
6. To
a degassed solution of 5 (0.60 g, 1.5 mmol) in DMF (10 mL) were
added successively MeB(OH)2 (200 mg, 2.2 equiv) and Pd(PPh3)4
(87 mg, 0.05 equiv). The mixture was stirred for 20 h at 90 ꢀC.
DMF was removed in vacuum and the resulting mixture was
absorbed on silica gel and purified by flash chromatography
(cyclohexane/EtOAc 8/2, v/v) to give 6 (152 mg, 30%) as a pale
yellow oil. 1H NMR (300 MHz, CDCl3)
3H), 5.11 (s, 2H), 7.32e7.42 (m, 3H), 7.50e7.56 (m, 2H), 7.57 (s,
d (ppm) 2.57 (s, 3H), 3.92 (s,
1H). 13C NMR (75 MHz, CDCl3)
d 23.7, 53.1, 76.7, 127.0, 127.6, 128.6,
129.9, 130.8, 126.0, 144.6, 150.0, 154.9, 164.8. MS (ESIþ) m/z: 338
(90), 336 (100). HRMS (ESIþ): calcd for C15H15BrNO3 336.0235;
found 336.0233.
solid. 1H NMR (300 MHz, CDCl3)
d 4.71 (br s, 2H), 5.05 (s, 2H), 7.08 (d,
J¼1.87 Hz, 1H), 7.37e7.42 (m, 5H), 7.73 (d, J¼1.87 Hz, 1H). 13C NMR
4.1.2. Methyl 3-hydroxypicolinate 8. H2SO4 (1.8 mL, 3 equiv) was
added dropwise to a suspension of 3-hydroxypicolinic acid 7 (1.5 g,
10.5 mmol) in MeOH (24 mL). The mixture was refluxed for 24 h.
Then, the mixture was basified with a solution of K2CO3 (pH 8.5).
The aqueous layer was extracted with EtOAc, and the organic layer
was dried over MgSO4 and concentrated under reduced pressure
to give desired methyl ester 8 (1.28 g, 80%) as a white solid. 1H and
13C NMR data were in agreement with those given in the
literature.18
(75 MHz, CDCl3) d 70.7, 107.0, 119.6, 127.8, 128.7, 128.9, 135.6, 135.6,
139.3, 141.9, 149.1. MS (ESIþ) m/z (%): 281 (98), 279 (100).
4.1.7. 3-Benzyloxy-5-bromo-2-iodopyridine 14. To a solution of 3-
benzyloxy-5-bromopyridin-2-amine 13 (3 g, 10.4 mmol), CuI (2 g,
10.4 mmol), and I2 (2.65 g, 10.4 mmol) in CH2I2 (50 mL), isoamyl
nitrite (4.3 mL, 31.2 mmol) was added at 85 ꢀC. The resulting mix-
ture was stirred at 85 ꢀC for 10 min. After cooling, the reaction
mixture was absorbed on silica gel and purified by flash chroma-
tography (cyclohexane/EtOAc 100/0 to 90/10, v/v) to afford the
desired product 14 as a white solid (2.73 g, 67%). Mp 112e113 ꢀC 1H
4.1.3. Methyl 4,6-dibromo-3-hydroxypicolinate 9. At room temper-
ature, Br2 (2.7 mL, 3 equiv) was added to a suspension of methyl
ester 8 (2.7 g, 6.5 mmol) in water (200 mL). The mixture was stirred
for 20 h at room temperature. The solution was extracted with
dichloromethane, and the organic layer was washed with an
aqueous solution of sodium thiosulfate, with brine, dried over
MgSO4, and concentrated under reduced pressure to give desired
compound 9 (4.0 g, 76%) as a white powder. 1H NMR (300 MHz,
NMR (300 MHz, CDCl3)
d
5.16 (s, 2H), 7.15 (d, J¼2.00 Hz, 1H),
7.34e7.49 (m, 5H), 8.10 (d, J¼2.00 Hz, 1H). 13C NMR (75 MHz, CDCl3)
d
71.4, 110.1, 120.4, 121.5, 127.2, 128.6, 129.0, 134.9, 143.7, 154.8. MS
(ESIþ) m/z (%): 392 (98), 390 (100). Anal. Calcd for C12H9BrINO: C,
36.95; H, 2.33; N, 3.59. Found: C, 36.88; H, 2.24; N, 3.33.
4.1.8. 3-Benzyloxy-5-bromopicolinaldehyde 15. To a solution of 14
(2.7 g, 6.94 mmol) in dry THF (70 mL) i-PrMgCl$LiCl (5.6 mL, 1.3 M
in THF, 7.30 mmol) was added dropwise at ꢁ20 ꢀC. The resulting
CDCl3)
d
(ppm) 4.06 (s, 3H), 7.86 (s, 1H), 11.35 (br s, 1H). 13C NMR
(75 MHz, CDCl3)
d 53.9, 124.7, 129.9, 130.2, 136.9, 156.0, 168.8. MS
(ESIꢁ) m/z: 312 (40), 310 (100), 308 (45).
mixture was stirred at ꢁ20 ꢀC for 1 h and dry DMF (800
mL,
10.40 mmol) was added dropwise. After stirring for additional
30 min at ꢁ20 ꢀC, the cool bath was removed and the reaction
mixture was allowed to warm at room temperature. The reaction
was quenched with a saturated aqueous solution of NH4Cl. The
phases were separated, the aqueous layer was extracted with EtOAc
(twice) and the organic layer was washed with brine. The combined
organic layers were dried over MgSO4, and concentrated under
reduced pressure. Purification by flash chromatography on silica gel
(cylclohexane/EtOAc 9/1, v/v) afforded aldehyde 15 as an yellow
4.1.4. Methyl 3-benzyloxy-4,6-dibromobenzylpicolinate 5. Benzyl
bromide (1.2 mL, 3 equiv) was slowly added to a mixture of 9 (1.0 g,
3.2 mmol) and K2CO3 (2.0 g, 4.5 equiv) in acetone (40 mL). The re-
action mixture was refluxed for 18 h. The resulting mixture was
filtered and concentrated under reduced pressure. Purification by
flash chromatography on silica gel (cyclohexane/EtOAc 9/1, v/v)
gave 5 (1.2 g, 90%) as a white solid. Mp 74 ꢀC. 1H NMR (300 MHz,
CDCl3)
d
(ppm) 3.92 (s, 3H), 5.13 (s, 2H), 7.35e7.44 (m, 3H),
53.3,
7.49e7.53 (m, 2H), 7.88 (s, 1H). 13C NMR (75 MHz, CDCl3)
d
solid (1.4 g, 69%). 1H NMR (300 MHz, CDCl3)
(m, 5H), 7.63 (d, J¼1.70 Hz, 1H), 8.44 (d, J¼1.70 Hz, 1H), 10.35 (s, 1H).
13C NMR (75 MHz, CDCl3)
71.1, 124.6, 126.1, 127.3, 128.8, 129, 134.7,
d 5.22 (s, 2H), 7.36e7.47
77.0, 128.6, 128.7, 128.8, 131.9, 134.9, 135.4, 135.5, 145.3, 151.9, 163.3.
MS (ESIþ) m/z (%): 404 (65), 402 (100), 400 (60). Anal. Calcd for
d

T. Verdelet et al. / Tetrahedron 67 (2011) 8757e8762
8761
139.8, 143.6, 157.0, 189.2. MS (ESIþ) m/z (%): 294 (98), 292 (100).
(40 mL, 1.3 equiv) were added to a degassed solution of 10 (90 mg,
HRMS (ESIþ): calcd for C13H11BrNO2 291.9973; found 291.9969.
0.28 mmol) and Cs2CO3 (137 mg, 1.5 equiv) in toluene (3 mL). The
mixture was stirred for 20 h at 100 ꢀC. Solvent was removed and
the residue was purified by flash chromatography on silica gel
(cyclohexane/EtOAc 1/1, v/v) to give 20 (86 mg, 88%) as a light
brown solid. Rf¼0.5 (cyclohexane/EtOAc 3/7, v/v). 1H NMR
4.1.9. Methyl 3-benzyloxy-5-bromopicolinate 16. To a solution of al-
dehyde 15 (0.81 g, 2.76 mmol) in methanol (15 mL) at 0 ꢀC a meth-
anolic solution of potassium hydroxide (0.53 g, 9.38 mmol, 5 mL) and
iodine (1.19 g, 4.69 mmol, 10 mL) was added dropwise. The reaction
mixture was stirred at 0 ꢀC and monitored by 1H NMR spectroscopy
for completion. Then the reaction was quenched with a 30% aqueous
sodium bisulfite solution until the brown color disappeared. The
product was extracted twice with CH2Cl2, the combined organic
layers were washed with brine, dried over MgSO4, and concentrated
under reduced pressure. The crude product was purified by flash
chromatography on silica gel (cyclohexane/EtOAc 9/1, v/v) to afford
16 as a white solid (0.846 g, 95%). Mp 110e111 ꢀC.1H NMR (300 MHz,
(300 MHz, CDCl3)
d
3.88 (s, 3H), 4.19 (d, J¼5.7 Hz, 2H), 4.96 (s, 2H),
5.16 (t, J¼5.7 Hz,1H), 6.45 (d, J¼5.1 Hz,1H), 7.06e7.34 (m, 10H), 8.01
(d, J¼5.1 Hz, 1H). 13C NMR (75 MHz, CDCl3)
d 46.8, 52.7, 76.8, 107.8,
127.0, 127.7, 128.6, 128.7, 128.8, 128.9, 136.7, 137.3, 140.3, 143.6,
145.9, 148.5, 165.6. MS (ESIþ) m/z (%): 349 [MþH]þ (100). HRMS
(ESIþ): calcd for C21H21N2O3 349.1552; found 349.1541.
4.1.14. Methyl 5-benzylamino-3-(benzyloxy)picolinate 21. Pd2dba3
(2.3 mg, 2 mol %), BINAP (3.1 mg, 4 mol %), and benzylamine (20 mL,
CDCl3)
d
3.96 (s, 3H), 5.18 (s, 2H), 7.33e7.47 (m, 5H), 7.53 (d, J¼1.75 Hz,
1.5 equiv) were added to a degassed solution of 16 (40 mg,
0.12 mmol) and Cs2CO3 (60 mg, 1.5 equiv) in 1,4-dioxane (0.5 mL).
The mixture was stirred for 20 h at 100 ꢀC. Solvent was removed
and the residue was purified by flash chromatography on silica gel
(cyclohexane/EtOAc 3/7, v/v) to give 21 (39 mg, 93%) as a colorless
1H), 8.33 (d, J¼1.75 Hz, 1H). 13C NMR (75 MHz, CDCl3)
d 52.8, 71.1,
123.9, 124.6, 127.0, 128.4, 128.9, 135.1, 137.3, 142.3, 155.0, 164.5. MS
(ESIþ) m/z (%): 324 (99), 322 (100). Anal. Calcd for C14H12BrNO3: C,
52.20; H, 3.75; N, 4.35. Found: C, 52.18; H, 3.73; N, 4.38.
oil. Rf¼0.6 (EtOAc). 1H NMR (300 MHz, CDCl3)
d 3.92 (s, 3H), 4.33 (d,
4.1.10. Methyl
3-benzyloxy-4-phenylpicolinate
17. Pd(PPh3)4
J¼5.1 Hz, 2H), 4.68 (t, J¼5.1 Hz, 1H), 5.10 (s, 2H), 6.41 (d, J¼1.5 Hz,
(16 mg, 5 mol %) was added to a degassed solution of 10 (90 mg,
0.28 mmol), phenylboronic acid (51 mg, 1.5 equiv), and K2CO3
(116 mg, 3 equiv) in DMF (2 mL). The mixture was stirred for 20 h at
90 ꢀC. DMF was removed under vacuum and the crude mixture was
directly absorbed on silica gel and purified by flash chromatogra-
phy (cyclohexane/EtOAc 7/3, v/v) to give 17 (60 mg, 67%) as a white
solid. Rf¼0.3 (cyclohexane/EtOAc 7/3, v/v). 1H NMR (300 MHz,
1H), 7.26e7.44 (m, 10H), 7.76 (d, J¼1.5 Hz, 1H). 13C NMR (75 MHz,
CDCl3) d 47.5, 52.0, 70.5, 103.0, 126.2, 126.8, 127.4, 127.9, 127.9, 128.5,
128.7, 129.0, 136.1, 137.3, 147.7, 157.7, 164.7. MS (ESIþ) m/z (%): 349
[MþH]þ (100). HRMS (ESIþ): calcd for C21H21N2O3 349.1552; found
349.1548.
4.1.15. Methyl 3-benzyloxy-5-(piperidin-1-yl)picolinate 22. Pd2dba3
(3 mg, 2 mol %), xantphos (5.6 mg, 6 mol %), and piperidine (21 mL,
CDCl3)
d
3.87 (s, 3H), 4.54 (s, 2H), 7.01e7.56 (m,11H), 8.41 (s,1H). 13
C
NMR (75 MHz, CDCl3)
d
52.9, 79.4, 127.7, 128.4, 128.8, 128.9, 129.0,
1.3 equiv) were added to a degassed solution of 16 (50 mg,
0.16 mmol) and Cs2CO3 (78 mg, 1.5 equiv) in toluene (2 mL). The
mixture was stirred for 20 h at 90 ꢀC. Solvent was removed and the
residue was purified by flash chromatography on silica gel (cyclo-
hexane/EtOAc 3/7, v/v) to give 21 (39 mg, 75%) as a white solid.
129.2, 135.1, 135.7, 135.9, 145.0, 145.2, 145.3, 152.0, 165.7. MS (ESIþ)
m/z (%): 639 [2MþH]þ (10), 320 [MþH]þ (100). HRMS (ESIþ): calcd
for C20H18NO3 320.1287; found 320.1297.
4.1.11. Methyl
3-benzyloxy-5-phenylpicolinate
18. Pd(PPh3)4
Rf¼0.6 (EtOAc). 1H NMR (300 MHz, CDCl3)
d 1.50e1.60 (m, 6H),
(12 mg, 5 mol %) was added to a degassed solution of 16 (66 mg,
0.21 mmol), phenylboronic acid (75 mg, 3 equiv), and K2CO3
(85 mg, 3 equiv) in DMF (2 mL). The mixture was stirred for 20 h at
90 ꢀC. DMF was removed under vacuum and the crude mixture was
directly absorbed on silica gel and purified by flash chromatogra-
phy (cyclohexane/EtOAc 7/3, v/v) to give 18 (46 mg, 70%) as a white
solid. Rf¼0.3 (cyclohexane/EtOAc 7/3, v/v). 1H NMR (300 MHz,
3.20e3.25 (m, 4H), 3.86 (s, 3H), 5.11 (s, 2H), 6.57 (d, J¼2.4 Hz, 1H),
7.20e7.34 (m, 3H), 7.40e7.45 (m, 2H), 7.89 (d, J¼2.4 Hz, 1H). 13C
NMR (75 MHz, CDCl3) d 24.1, 25.1, 48.4, 52.0, 70.7,105.8, 126.1,126.9,
127.9, 128.6, 129.4, 136.3, 150.1, 157.3, 164.7. MS (ESIþ) m/z (%): 327
[MþH]þ (100). HRMS (ESIþ): calcd for C19H23N2O3 327.1709; found
327.1716.
CDCl3)
d
4.01 (s, 3H), 5.29 (s, 2H), 7.33e7.55 (m, 11H), 8.51 (s, 1H).
52.7, 70.9, 120.3, 127.1, 127.5, 128.3,
4.1.16. Methyl
3-(benzyloxy)-5-(3-hydroxyprop-1-ynyl)picolinate
13C NMR (75 MHz, CDCl3)
d
23. Pd(PPh3)4 (9 mg, 5 mol %) and CuI (3 mg, 10 mol %) were added
to a degassed solution of 16 (50 mg, 0.16 mmol) and propargyl al-
cohol (9 mL, 1 equiv) in a mixture of dichloromethane (2 mL) and
128.9, 129.1, 129.3, 135.9, 136.7, 137.4, 140.0, 140.7, 155.1, 165.0. MS
(ESIþ) m/z (%): 342 [MþNa]þ (15), 320 [MþH]þ (100). HRMS (ESIþ):
calcd for C20H18NO3 320.1287; found 320.1283.
triethylamine (1 mL). The mixture was stirred for 20 h at room
temperature. Solvents were removed under vacuum and the crude
mixture was directly absorbed on silica gel and purified by flash
chromatography (cyclohexane/EtOAc 1/1, v/v) to give 23 (39 mg,
82%) as a light brown solid. Rf¼0.2 (cyclohexane/EtOAc 1/1, v/v). 1H
4.1.12. Methyl
3-benzyloxy-5-(3-chlorophenyl)picolinate
19. Pd(PPh3)4 (9 mg, 5 mol %) was added to a degassed solution of
16 (50 mg, 0.16 mmol), 3-chlorophenylboronic acid (36 mg,
1.5 equiv), and K2CO3 (64 mg, 3 equiv) in DMF (2 mL). The mixture
was stirred for 20 h at 90 ꢀC. DMF was removed under vacuum and
the crude mixture was directly absorbed on silica gel and purified
by flash chromatography (cyclohexane/EtOAc 7/3, v/v) to give 19
(51 mg, 90%) as a light brown solid. Rf¼0.7 (cyclohexane/EtOAc 1/1,
NMR (300 MHz, CDCl3)
d 3.32 (br s, 1H), 3.96 (s, 3H), 4.49 (s, 2H),
5.17 (s, 2H), 7.25e7.46 (m, 6H), 8.33 (s, 1H). 13C NMR (75 MHz,
CDCl3)
d 51.1, 52.8, 70.8, 81.0, 93.8, 123.5, 124.1, 128.3, 135.3, 137.8,
143.5, 154.1, 164.6. MS (ESIþ) m/z (%): 298 [MþH]þ (100). HRMS
(ESIþ): calcd for C17H16NO4 298.1079; found 298.1068.
v/v). 1H NMR (300 MHz, CDCl3)
d
3.91 (s, 3H), 5.19 (s, 2H), 7.22e7.35
(m, 6H), 7.40e7.42 (m, 4H), 8.38 (s, 1H). 13C NMR (75 MHz, CDCl3)
Acknowledgements
d
52.7, 71.0, 120.3, 125.6, 127.1, 127.5, 128.3, 128.8, 129.0, 130.5, 135.2,
135.6, 138.0, 138.4, 139.2, 139.6, 154.9, 164.9. MS (ESIþ) m/z (%): 354
[MþH]þ (100). HRMS (ESIþ): calcd for C20H17ClNO3 354.0897;
found 354.0901.
The Direction Generale de l’Armement (French Ministry of De-
ꢁ ꢁ
fence Procurement Agency) is acknowledged for Ph.D. Fellowship to
T.V. and for post-doctoral fellowship to G.M. (REI-DGA 2009-34-
0023), IUF (‘Institut Universitaire de France‘), ANR (‘Agence Nationale
pour la Recherche’) through ANR_06_BLAN_0163 DETOXNEURO and
4.1.13. Methyl 4-benzylamino-3-(benzyloxy)picolinate 20. Pd2dba3
ꢁ
(5.1 mg, 2 mol %), xantphos (9.7 mg, 6% mol), and benzylamine
ANR_09_BLAN_0192 ReAChE programs and the Region Haute

8762
T. Verdelet et al. / Tetrahedron 67 (2011) 8757e8762
10. (a) Hutin, P.; Muller, B.; Steele, C.; Perez, J.; Genix, P. WO 2003006456 A1; Chem.
Normandie (CPER 2007-2013 Crunch program) are gratefully ac-
knowledged for their financial support. We thank Dr. Anthony
ꢀ
Abstr. 2003, 138, 106603; (b) Bacque, E.; Barriere, J.-C.; Vors, J.-P.; Nieto-Roman,
F.; Villier, A. WO2001049667 A1; Chem. Abstr. 2001, 135, 92548; (c) Nieto-
Roman, F.; Vors, J.-P.; Villier, A.; Lachaise, H.; Mousques, A.; Hartmann, B.;
Hutin, P.; Molina, J. L.; Muller, B. WO2001049666 A1; Chem. Abstr. 2001, 135,
92547.
ꢁ
Romieu (Universite de Rouen) for M.S. analyses and Annick Leb-
oisselier(INSAdeRouen)forthedeterminationofelementalanalyses.
€
11. Jakobi, H.; Braun, R.; Schapper, W.; Krautstrunk, G.; Markl, M.; Stark, H.; Sanft,
References and notes
€
U.; Thonnessen, M.-T.; Kern, M.; Bonin, W. WO9822444 A1; Chem. Abstr. 1998,
129, 16135.
12. Kong, L. C. C.; Zhang, M.-Q.; Halab, L.; Nguyen-Ba, N.; Liu, B. WO 2005042524
1. Baell, J. B.; Bui, C. T.; Colman, P.; Dudley, D. A.; Fairbrother, W. J.; Flygare, J. A.;
Lassene, G. L. Ndubadu, C.; Nikolakopoulos, G.; Rye, C. S.; Sleebs, B. E.; Smith, B.
J.; Watson, K. G.; Elmore, S. W.; Petros, A. M.; Souers, A. J. WO 2010080478 A1;
Chem. Abstr. 2010, 153, 204335.
2. Alvaro G.; Amantini, D. WO2010072722 A1; Chem. Abstr. 2010, 153, 145491.
3. (a) Koolmeister, T.; Johansson, G.; Hartikka, A.; Berts, W.; Nilsson, B. M.; Jo-
hansson, L.; Emond, R.; Brandt, P.; Nilsson, J.; Lindqvist, B. WO2009150144;
Chem. Abstr. 2009, 152, 57327; (b) Fang, J.; Tang, J.; Carpenter, A. J.; Peckham, G.;
Conlee, C. R.; Du, K. S.; Katamreddy, S. R. WO2008070692 A2; Chem. Abstr.
2008, 149, 53877.
A1; Chem. Abstr. 2005, 142, 463613.
13. Binggeli, A.; Christ, A. D.; Grenn, L.; Guba, W.; Maerki, H. P.; Martin, R. E.; Mohr,
P. WO2007025897; Chem. Abstr. 2007, 146, 295909.
14. Coppi, L.; Berenguer Maimo, R. WO2001079194 A1; Chem. Abstr. 2001, 135,
331424.
15. Badiger, S.; Chebrolu, M.; Frederiksen, M.; Holzer, P.; Hurth, K.; Lueoend, R. M.;
Machauer, R.; Moebitz, H.; Neumann, U.; Ramos, R.; Rueeger, H.; Tintelnot-
Blomley, M.; Veenstra, S. J.; Voegtle, M. WO2011009943 A1; Chem. Abstr.
2011, 154, 207624.
16. Looker, J. H.; Prokop, R. J.; Serbousek, W. E.; Cliffton, M. D. J. Org. Chem. 1979, 44,
4. Shirai, J.; Yoshikawa, T.; Sugiyama, H. WO2007089031 A1; Chem. Abstr. 2007,
3408e3410.
147, 257652.
17. Logan, M. E.; Oinen, M. E. Organometallics 2006, 25, 1052e1054.
18. Louise-Leriche, L.; Paunescu, E.; Saint-Andre, G.; Baati, R.; Romieu, A.; Wagner,
5. Bell, I.; Gallicchio, S. N.; Zartman, C. B. WO2005009962; Chem. Abstr. 2005, 142,
176850.
ꢂ
ꢁ
A.; Renard, P.-Y. Chem.dEur. J. 2010, 16, 3510e3523.
6. Ricks, M. J.; Dent, W. H.; Rogers, R. B.; Yao, C.; Nader, B. S.; Miesel, J. L.; Fitz-
patrick, G. M.; Meyer, K. G.; Niyaz, N. M.; Morrison, I. M.; Henry, M. J.; Adamski,
B. J. L.; Gajewski, R. P. WO2001014339 A2; Chem. Abstr. 2001, 134, 207831 and
WO2001005769 A2; Chem. Abstr. 2001, 134, 131431.
7. Hong, Y. R.; Shin, D.; Ro, S.; Cho, J. M.; Kim, H. T.; Lee, J. H.; Kim, J. M.; Lee, W. S.;
Choi, J.-R. WO2010018458 A2; Chem. Abstr. 2010, 152, 286959.
8. Aciro, C.; Bagal, S. K.; Harvey, J. W.; Jones, L. H.; Mowbray, C. E.; Owen, R.;
Sabnis, Y. A.; Storer, R. I.; Yeap, S. K. WO2010131145 A1; Chem. Abstr. 2010, 153,
1434697.
19. Palmer, A. M.; Grobbel, B.; Jecke, C.; Brehm, C.; Zimmermann, P. J.; Buhr, W.;
Feth, M. P.; Simon, W.-A.; Kromer, W. J. Med. Chem. 2007, 50, 6240e6264.
20. Song, J. J.; Yee, N. K.; Tan, Z.; Xu, J.; Kapadia, S. R.; Senanayake, C. H. Org. Lett.
2004, 6, 4905e4907.
21. Silva, N. M.; Tributino, J. L. M.; Miranda, A. L. P.; Barreiro, E. J.; Fraga, C. A. M. Eur.
J. Med. Chem. 2002, 37, 163e170.
22. Mcelroy, J. F.; Chorvat, R. J.; Rajagopalan, P. WO 2007008963; Chem. Abstr. 2007,
146, 156259.
23. Gottlieb, H. E.; Kotlyar, V.; Nudelman, A. J. Org. Chem. 1997, 62, 7512e7515.
9. Kawamoto, R. M. WO2008002576 A2; Chem. Abstr. 2007, 148, 100510.