Synthesis of novel halopyridinylboronic acids and esters. Part 1: 6-Halopyridin-3-yl-boronic acids and esters

Article abstract of DOI:10.1016/S0040-4020(02)00152-7

This paper describes a general method for the synthesis and isolation of novel 6-halo-pyridin-3-yl-boronic acids and esters 2-5. These compounds are prepared taking in account a regioselective halogen-metal exchange with a trialkylborate starting from 2,5-dihalopyridines. All substrates studied to date provided a single regioisomeric boronic acid or ester product. Additionally, these compounds have been found to undergo Pd-catalysed coupling with a range of arylhalides and authorise a strategy to produce new pyridines libraries.

Full text of DOI:10.1016/S0040-4020(02)00152-7

TETRAHEDRON
Pergamon
Tetrahedron 58 <2002) 2885±2890
Synthesis of novel halopyridinylboronic acids and esters.
Part 1: 6-Halopyridin-3-yl-boronic acids and esters
a
Alexandre Bouillon, Jean-Charles Lancelot, Val e rie Collot, Philippe R. Bovy
a
a
b
a,p
and Sylvain Rault
a
Centre d'Etudes et de Recherche sur le M e dicament de Normandie, UFR des Sciences Pharmaceutiques,
Universite de Caen, 5, rue Vaub e nard, 14032 Caen Cedex, France
b
Sano®-Synthelabo Recherche, 10, rue des Carri eÁ res, 92500 Rueil-Malmaison, France
Received 19 November 2001; revised 26 December 2001; accepted 6 February 2002
AbstractÐThis paper describes a general method for the synthesis and isolation of novel 6-halo-pyridin-3-yl-boronic acids and esters 2±5.
These compounds are prepared taking in account a regioselective halogen±metal exchange with a trialkylborate starting from 2,5-dihalo-
pyridines. All substrates studied to date provided a single regioisomeric boronic acid or ester product. Additionally, these compounds have
been found to undergo Pd-catalysed coupling with a range of arylhalides and authorise a strategy to produce new pyridines libraries. q 2002
Elsevier Science Ltd. All rights reserved.
1. Introduction
synthesis and the reactivity of 6-halopyridin-3-yl-boronic
acids and esters of type I.
There are many examples of the Suzuki coupling, where the
pyridine motive is employed as electrophile in the form of
halopyridine but much less where it is used as nucleophile in
1
±5
2. Results and discussion
the form of a pyridinylboron reagent
and this for two
reasons: the pyridinylboronic acids are considered not
very stable and also because the number of available
pyridinylboronic acids remains very weak compared to
At the beginning of this work, no halopyridyl boronic acids
were described. However, during the course of a study
concerning the synthesis of terpyridines, Lehmann recently
7
6
that of the aromatic series.
described the synthesis of 2-[3-<6-bromo)pyridine]-
0 0
,4 ,5,5 -tetramethyl-1,3-dioxaborolane 2b obtained from
4
Considering the growth of Suzuki type cross-coupling
reaction applications and in order to build new pyridines
libraries, we focused on a general method for the synthesis
of new pyridinylboronic acids usable in combinatorial
approaches. With this aim, we particularly studied the
synthesis of new halopyridinylboronic acids likely to offer
a double reactivity, via their boronic moiety and their
halogen atom. In this ®rst publication, we present the
a crude 2-bromo-5-pyridylboronic acid 2a. He used the
classical preparation of boronic acids which requires the
reaction of an organolithium intermediate, generated by
deprotonation or halogen±metal exchange, with a trialkyl-
8±10
borate.
On the same basis, our ®rst attempts were carried out in a
Keywords: dihalopyridines; cross-coupling; pyridinium salts.
Corresponding author. Tel.: 133-2-31-93-64-58; fax: 133-2-31-93-11-
p
88; e-mail: rault@pharmacie.unicaen.fr
Scheme 1.
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020<02)00152-7

2886
A. Bouillon et al. / Tetrahedron 58 ꢀ2002) 2885±2890
formation of pyridinium salts. The mixture was quenched
by slow addition of 5% aqueous NaOH solution and the
resulting aqueous layer neutralised by careful addition of
concentrated HCl to prevent protodeboronation.
On one hand, our results demonstrated that the boronic acid
2a was a stable boronic acid easy to purify as a white solid,
to handle, and to crystallize.
2
Scheme 2. Reagents: <a) HCl, NaNO , CuCl; <b) AcOCl, NaI.
1
5
On the other hand, considering the amphoteric character of
this acid, we studied the direct formation of its pinacol ester
1
6
adapting the method of Coudret who described the
synthesis of 4-pyridylboronic pinacol ester in 74% yield
starting from 4-iodopyridine. These same conditions
applied to 1 gave 78% of the corresponding pinacol ester
Scheme 3. Reagents: <a) HIO
CuCl, or HBF , NaNO or HBr, NaNO
4
, I
2
, AcOH, H
2 2 4 2
O, H SO ; <b) HCl, NaNO ,
4
2
, Br ; <c) AcOCl, NaI.
2 2
2b in a one pot procedure <Scheme 1).
similar manner starting from commercially available 2,5-
dibromopyridine 1 <Acros Organics) chosen because of
the well-known difference in reactivity between its two
In order to generalize this method and considering that the
nature of halogen atoms should not considerably modify the
reactivity of the system, we decided to prepare new boronic
species from the other 2,5-dihalopyridines 7±9 and 12±15.
1
1±13
halogen atoms
<Scheme 1).
Thus, bromine±lithium exchange was carried out in ether at
788C with nBuLi followed by the reaction with a
trialkylborate, B<OMe)3, or better B<OiPr)3.
5-Bromo-2-¯uoropyridine 7 was purchased from Aldrich.
2,5-Dihalopyridines 8 and 9 <Scheme 2) were prepared
from commercially available 2-amino-5-bromopyridine 6.
2
1
4
1
7
5-Bromo-2-chloropyridine 8 was obtained via a diazo-
nium salt followed by a treatment with copper<I) chloride.
In order to obtain either the boronic acid or the correspond-
ing pinacolate ester we studied adapted works-up. At the
end of the reaction, the boronic acid derivative 2a was
obtained with 75% yield after a work-up avoiding the
1
8
Moreover, we obtained 5-bromo-2-iodopyridine 9 with
80% yield from 1 by halogen±halogen exchange according
to the method described by Corcoran et al. using 3 equiv.
1
9
Table 1. Synthesis of 6-halopyridin-3-yl-boronic acids and esters 2±5
Compounds
X
2
X
5
Boronic acid
Yield <%)
Boronic ester
Yield <%)
1
Br
Br
I
Br
I
I
Br
I
Br
Cl
I
2a
2a
3a
3a
4a
4a
4a
5a
5a
75
10
0
2b
2b
3b
3b
4b
4b
4b
5b
5b
78
10
0
1
1
9
1
8
1
1
7
4
5
I
0
0
2
Cl
Cl
Cl
F
55
87
25
25
76
20
71
20
15
65
6
3
F
Br

A. Bouillon et al. / Tetrahedron 58 ꢀ2002) 2885±2890
2887
of anhydrous sodium iodide and 2 equiv. of acetyl chloride
in re¯uxing acetonitrile.
could be obtained starting from different 2,5-dihalopyri-
dines <for example see results starting from 12, 8 and 16).
The boronic compounds in position 2 were not observed
even when we applied the peculiar conditions of Wang
which permitted a selective lithiation of 2,5-dibromopyri-
2,5-Dihalopyridines 12±15 <Scheme 3) were prepared with
the same strategy from commercially available 2-amino-
2
3
pyridine 10 which gave selectively, by treatment with
periodic acid and iodine, 2-amino-5-iodopyridine 11. We
dine <toluene, 2788C) in position 2 and this certainly
because of the instability of pyridin-2-yl boronic acid
derivatives as reported by Fischer.
2
0
2
4
adapted and optimised the access to 2-chloro-5-iodo-
pyridine 12, 2-¯uoro-5-iodopyridine 13 and 2-bromo-
2
1
22
2
-iodopyridine 14 which were obtained via a diazonium
0
5
salt and its appropriate treatment. We obtained 2,5-diiodo-
As illustrated in Table 2, the acid 2a, 4a, 5a and the ester 2b,
4b, 5b were ef®ciently coupled with sterically hindered,
electron-rich, or electron-poor halides under standard
pyridine 15 with 80% yield from 5 by halogen±halogen
exchange.
1
9
25,26
Suzuki-type conditions,
or otherwise biaryls not easily accessible, as for example
furnishing a range of unknown
All these dihalopyridines 7±9, 12±15 were engaged in the
same reaction conditions as for 2,5-dibromopyridine 1 in
order to compare their ability to produce corresponding
boronic acids and pinacol esters. The results are depicted
in Table 1. All these reactions were fruitful except for 2,5-
diiodopyridine 15 and 5-bromo-2-iodopyridine 9 from
which we could not obtain the boronic species because
these starting materials were not suf®ciently soluble in the
ethereal reaction mixture. It must be pointed out that the
best results were obtained starting from compounds pos-
sessing a bromine atom in position 5, using 1.20 equiv. of
17±19.
The yields for cross-coupling were generally good, and the
resulting 2-bromo-5-substituted pyridines 17±19 were
isolated following column chromatography. Interestingly,
no `homocoupled' products with 6-halopyridin-3-yl-boro-
nic acid or esters acting as both the aryl boronic and aryl
bromide fragments were observed. Recently, an other type
of Pd-mediated cross-coupling reaction using Li/Zn trans-
2
7
metalation was described by Karig et al.
nBuLi and 1.20 equiv. of B<OiPr) in ether at 2788C.
3
Further experiments concerning the double reactivity of
these compounds are currently under investigation in
order to use these new starting materials in the production
of new pyridine libraries. These results will be published
elsewhere.
The boronic acids 2a, 4a and 5a and the esters 2b, 4b and 5b
conveniently isolated as their 4,4,5,5,-tetramethyl-1,3,2-
dioxaborolane esters were obtained in high yields. These
optimised conditions allowed a very ef®cient synthesis of
2
a, 4a±5a and 2b, 4b±5b on a multigram scale.
3
. Experimental
All these boronic species were stable, non-hygroscopic and
easy to characterize. The reactions were generally very
clean, since the crude products obtained after aqueous
work-up could be used as reagents without further puri®ca-
tion. Moreover, this exhaustive study outlined the regio-
selectivity of the reaction as the same boronic species
3
.1. General procedures
Commercial reagents were used as received without addi-
tional puri®cation. Melting points were determined on a
Ko¯er melting point apparatus and are uncorrected. IR
spectra were taken with a Genesis Series FTIR spectro-
1
13
Table 2. Suzuki cross-couplings of pyridylboronic acid 2a, 4a, 5a or ester
2b, 4b, 5b
meter. H NMR <400 MHz) and C NMR <100 MHz)
were recorded on a JEOL Lambda 400 Spectrometer.
Chemical shifts are expressed in parts per million down®eld
from tetramethylsilane as an internal standard. The mass
spectra <MS) were taken on a JEOL JMS GCMate spectro-
meter at a ionizing potential of 70 eV. Thin-layer chromato-
graphy <TLC) was performed on 0.2 mm precoated plates of
silica gel 60F-264 <Merck). Visualization was made with
ultraviolet light. Column chromatography was carried out
using silica gel 60 <0.063±0.2 mm) <Merck). Elemental
analyses for new compounds were performed at the `Institut
de Recherche en Chimie Organique Fine' <Rouen).
3.1.1. 2,5-Dibromopyridine ꢀ1). This compound was
purchased from Acros Organics, dissolved in ether, ®ltered
off and concentrated under reduced pressure before use.
3.1.2. 5-Bromo-2-chloropyridine ꢀ8). To a stirred solution
of 2-amino-5-bromopyridine 6 <7.5 g, 43 mmol) in 65 mL
of 37% hydrochloric acid were successively added an
aqueous solution of sodium nitrite <7.8 g, 2.6 equiv.) and
copper <I) chloride <5.4 g, 1.25 equiv.), the temperature
being kept below 258C during the addition. The reaction

2888
A. Bouillon et al. / Tetrahedron 58 ꢀ2002) 2885±2890
was then continued at room temperature for 4 h and
quenched by slow addition of aqueous solution of sodium
hydroxide. The mixture was then extracted with ether and
the extract washed with brine, dried over magnesium sulfate
and concentrated on rotary evaporator yielding 4.5 g of 8
being kept below 258C during the addition. The reaction
was then continued at room temperature overnight and
quenched by slow addition of aqueous solution of sodium
hydroxide. The mixture was then extracted with ether and
the extract washed with an aqueous solution of sodium thio-
sulfate and brine, dried over magnesium sulfate and concen-
trated on rotary evaporator. Recrystallization from ethanol
1
7
<
<
55%). White solid, mp 728C <lit. 718C); IR 3105±3037
1
CH), 1556±1445±1359 <CCN); H NMR <d -DMSO) d
6
2
0
8
7
.58 <d, Jˆ2.2 Hz, 1H), 8.1<dd,
Jˆ8.5, 2.2 Hz, 1H),
gave 18 g of pure 14 <77%); white pellets, mp 1208C <lit.
125±1268C); IR 3087±3017 <CH), 1542±1438±1353
.52 <d, Jˆ8.5 Hz, 1H).
1
<
CCN); H NMR <d -DMSO) d 8.63 <d, Jˆ2.2 Hz, 1H),
6
3
.1.3. 5-Bromo-2-iodopyridine ꢀ9). A mixture of 2,5-
8.09 <dd, Jˆ8.3, 2.2 Hz, 1H), 7.49 <d, Jˆ8.3 Hz, 1H).
dibromopyridine <3.5 g, 15 mmol), potassium iodide
12.3 g, 38 mmol, 2.5 equiv.) and acetyl chloride <4.64 g,
0 mmol, 2 equiv.) were re¯uxed in dry acetonitrile under
<
3
3.1.8. 2,5-Diiodopyridine ꢀ15). The same procedure as for
compound 9 starting from 2-bromo-5-iodopyridine 14
2
0
nitrogen for 24 h. The mixture was neutralised by careful
addition of aqueous NaHCO , extracted twice by chloro-
<yield 85%) was employed; white solid, mp 1508C <lit.
148±1498C); IR 3074±3004 <CH), 1530±1435±1348
3
1
<CCN); H NMR <d
7.84 <dd, Jˆ8.2, 2.3 Hz, 1H), 7.66 <d, Jˆ8.2 Hz, 1H); MS
m/z 330.9.
form. The organic layer was dried over magnesium sulfate
and evaporated to yield 80% of a white solid, mp 1188C
6
-DMSO) d 8.60 <d, Jˆ2.3 Hz, 1H),
1
lit. 1178C); IR 3088±3011 <CH), 1541±1433±1353
8
<
<
1
CCN); H NMR <d -DMSO) d 8.52 <d, Jˆ1.4 Hz, 1H),
6
7
m/z 282.9±284.9.
.80 <d, Jˆ8.3 Hz, 1H), 7.75 <dd, Jˆ8.3, 1.4 Hz, 1H); MS
3.1.9. 2,5-Dichloropyridine ꢀ16). 2,5-Dichloropyridine
<16) was purchased from Aldrich and used without any
puri®cation.
3
.1.4. 2-Amino-5-iodopyridine ꢀ11). A mixture of
-aminopyridine 10 <47.2 g, 0.5 mol), periodic acid
2
dihydrate <22.9 g, 0.1mol, 0.2 equiv.) and iodine <5 1. 1g,
3.2. General procedure for the synthesis of 2-halogeno-5-
pyridylboronic acid ꢀ2a±5a)
0
3
.2 mol, 0.4 equiv.) was heated in a mixed solution of
00 mL of acetic acid, 60 mL of water and 9 mL of sulfuric
To a slurry of 2.5 M solution of nBuLi <9.4 mL, 24 mmol,
1.2 equiv.) in anhydrous ether, cooled to 2788C, was added
acid at 808C for 4 h. The mixture was then poured into
aqueous diluted sodium thiosulfate to remove unreacted
iodine, made alkaline with aqueous diluted sodium
hydroxide and extracted with ether. Puri®cation by column
chromatography <AcOEt) yielded 82.9 g of compound 11
a solution of 2,5-dihalopyridine <1equiv.) in ether. The
resulting dark red mixture was allowed to react at this
temperature for over 45 min. A solution of triisopropyl-
borate <4.42 g, 24 mmol, 1.2 equiv.) was then added and
the mixture allowed to warm to room temperature and left
to react for an additional hour. The mixture was quenched
by slow addition of 5% aqueous NaOH solution <200 mL).
The resulting aqueous layer was collected and acidi®ed
down to pH 6±7 by dropwise addition of 3N HCl
2
0
<
3
75%). White solid, mp 1308C <lit. 132±1338C); IR
1
092±3302 <NH ), 1546±1481±1381 <CCN); H NMR
2
<
1
d -DMSO) d 8.02 <d, Jˆ1.6 Hz, 1H), 8.56 <dd Jˆ8.6,
6
.6 Hz, 1H), 6.33 <d, Jˆ8.6 Hz, 1H), 6.11 <s, 2H).
3
.1.5. 2-Chloro-5-iodopyridine ꢀ12). Applying the method
<
<90 mL), keeping the internal temperature below 58C.
described for compound 8, starting from 2-amino-5-iodo-
pyridine 11 <16 g, 73 mmol), we obtained 9.7 g of pure 12
Extraction with ethyl acetate, evaporation of the organic
layer and recrystallization from ether gave 2a, 4a, 5a.
2
1
<
3
56%). White Solid, mp 968C <lit. 98±998C); IR 3096±
1
025 <CH), 1548±1442±1355 <CCN); H NMR <d -DMSO)
6
3.2.1. 2-Bromo-5-pyridylboronic acid ꢀ2a). White solid,
1
d 8.65 <d, Jˆ1.9 Hz, 1H), 8.20 <dd, Jˆ8.3, 1.9 Hz, 1H), 7.38
mp 1988C. H NMR <d -DMSO) d 8.63 <d, Jˆ2.0 Hz,
6
<
d, Jˆ8.3 Hz, 1H).
1
H), 8.47 <s, 2H), 7.98 <d, Jˆ8.0 Hz, Jˆ2.0 Hz, 1H), 7.62
1
3
<
d, Jˆ8 Hz, 1H). C NMR <d -DMSO) d 155.7, 144.8,
6
3
2
4
.1.6. 2-Fluoro-5-iodopyridine ꢀ13). To a solution of
-amino-5-iodopyridine 11 <6 g, 27 mmol) in 50 mL of
8% ¯uoroboric acid was added NaNO <4.9 g, 2.6 equiv.)
2
1
43.7, 127.4. Anal. Calcd for C H BBrNO : C, 29.76; H,
5 5 2
2.50; N, 6.94. Found: C, 29.83; H, 2.43; N, 6.87.
at 258C. The mixture was stirred at 40±458C for 1h and
neutralized with concentrated aqueous NaOH. The product
was extracted with ether, the organic layers washed with
3.2.2. 2-Chloro-5-pyridylboronic acid ꢀ4a). White solid,
mp 1908C. H NMR <d -DMSO) d 8.67 <s, 1H), 8.49 <s, 2H),
1
6
1
3
8.11 <d, Jˆ8.0 Hz, 1H), 7.47 <d, Jˆ8.0 Hz, 1H). C NMR
brine, dried over MgSO and concentrated under reduced
4
<d -DMSO) d 155.2, 152.1, 145.1, 123.6. Anal. Calcd for
6
pressure yielding 2.5 g of pure 13 <45%). Yellow Solid; mp
,
C H BClNO : C, 38.16; H, 3.20; N, 8.90. Found: C, 38.07;
5
H, 3.23; N, 8.94.
5
2
2
508C <lit. 338C); H NMR <d -DMSO) d 8.48 <d,
2
1
6
Jˆ2 Hz, 1H), 8.31 <dt, Jˆ8.0, 2.4 Hz, 1H), 7.10 <dd,
Jˆ8.0, 2.4 Hz, 1H).
3.2.3. 2-Fluoro-5-pyridylboronic acid ꢀ5a). White solid,
1
mp 1728C. H NMR <d -DMSO) d 8.54 <d, Jˆ2.2 Hz,
6
3
.1.7. 2-Bromo-5-iodopyridine ꢀ14). To a stirred solution
of 2-amino-5-iodopyridine 11 <18 g, 82 mmol) in 130 mL of
7% hydrobromic acid were successively added an aqueous
1H), 8.40 <s, 2H), 8.25 <dt, Jˆ8.6, 2.2 Hz, 1H), 7.12 <dd,
1
3
Jˆ8.0, 2.2 Hz, 1H). C NMR <d -DMSO) d 164.5 <d,
6
4
Jˆ236 Hz), 153.5 <d, Jˆ14 Hz), 147.7 <d, Jˆ7 Hz), 108.8
<d, Jˆ35 Hz). Anal. Calcd for C H BFNO : C, 42.62; H,
solution of sodium nitrite <14.65 g, 0.21 mol, 2.6 equiv.)
and bromine <13 mL, 0.25 mol, 3.0 equiv.), the temperature
5
5
2
3.58; N, 9.94. Found: C, 42.69; H, 3.63; N, 9.89.

A. Bouillon et al. / Tetrahedron 58 ꢀ2002) 2885±2890
2889
3
.3. General procedure for the synthesis of 2-[3-ꢀ6-
0
150.6, 149.6, 147.9, 143.3, 133.7, 130.2, 126.3, 125.7,
124.2.
0
halogeno)pyridine]-4,4 ,5,5 -tetramethyl-1,3-dioxa-
borolane ꢀ2b±5b)
3.4.2. 2-ꢀ6-Chloropyridin-3-yl)benzonitrile ꢀ18). White
solid <72%) mp 1288C. IR<KBr): 2220, 1463, 1438, 1112,
To a slurry of 2.5 M solution of nBuLi <17 mL, 43 mmol,
1
21 1
835, 761cm . H NMR <d
.2 equiv.) in anhydrous ether cooled to 2788C, was added
-DMSO) d 8.71<s, 1H), 8.20 <d,
6
a solution of 2,5-dihalogenopyridine <1equiv.) in ether. The
resulting dark red mixture was allowed to react at this
temperature for over 45 min. A solution of triisopropyl-
borate <8.0 g, 43 mmol, 1.2 equiv.) was then added drop-
wise and the mixture allowed to warm to room
temperature and left to react for an additional hour. A solu-
tion of anhydrous pinacol <5.65 g, 48 mmol, 1.35 equiv.) in
ether was added and, after 5 min, a solution of glacial acetic
acid <2.3 g, 40 mmol, 1.05 equiv.). The mixture was ®ltered
through Celite, and extracted with 5% aqueous NaOH solu-
tion <400 mL). The resulting aqueous layer was collected
and acidi®ed down to pH 6±7 by dropwise addition of 3N
HCl <<180 mL), keeping the internal temperature below
Jˆ7.5 Hz, 1H), 8.08 <d, Jˆ7.5 Hz, 1H), 7.92±7.73 <m, 4H).
1
3
C NMR <d
133.8, 133.1, 130.4, 129.3, 124.6, 118.1, 110.6.
-DMSO) d 150.6, 149.4, 140.0, 139.8, 133.9,
6
3.4.3.
2-Fluoro-5-ꢀ4-methoxyphenyl)pyridine
ꢀ19).
Orange solid <47%), mp 648C; IR<KBr): 2967, 2922,
2
1 1
2845, 1590, 1480, 1250, 1043, 1014, 835 cm . H NMR
<d
-DMSO) d 8.49 <s, 1H), 8.22 <dt, Jˆ8.3, 2.5 Hz, 1H),
7.65 <d, Jˆ8.5 Hz, 1H), 7.23 <dd, Jˆ8.3, 2.5 Hz, 1H), 7.04
6
1
3
<d, Jˆ8.5 Hz, 2H), 3.79 <s, 3H). C NMR <d
-DMSO) d
6
162.1 <d, Jˆ242 Hz), 159.4, 144.8 <d, Jˆ16 Hz), 139.8 <d,
Jˆ9 Hz), 133.8, 128.1, 128.0, 114.6, 109.5 <d, Jˆ37 Hz),
55.3.
5
8C. Extraction with ether, evaporation of the ethereal
layer and washing with acetonitrile gave 2b, 4b, 5b.
Acknowledgements
0 0
.3.1. 2-[3-ꢀ6-Bromo)pyridine]-4,4 ,5,5 -tetramethyl-1,3-
3
1
dioxaborolane ꢀ2b). White solid, mp 928C; H NMR <d6-
DMSO) d 8.53 <s, 1H), 7.89 <d, Jˆ7.7 Hz, 1H), 7.66 <d,
The authors thank the Conseil R e gional de Basse-
Normandie and FEDER <Fonds Europ e ens de D e veloppe-
ment Economique R e gional) for their ®nancial support.
1
3
Jˆ7.7 Hz, 1H), 1.30 <s, 12H); C NMR <d -DMSO) d
6
1
2
55.3, 144.9, 144.8, 128.0, 84.4, 24.6; MS m/z 282.9±
84.9; Anal. Calcd for C H BBrNO : C, 46.53; H, 5.32;
1
1
15
2
N, 4.93. Found: C, 46.62; H, 5.41; N, 4.84.
References
0 0
.3.2. 2-[3-ꢀ6-Chloro)pyridine]-4,4 ,5,5 -tetramethyl-1,3-
dioxaborolane ꢀ4b). White solid, mp 988C; H NMR
3
1
. Stavenuiter, J.; Hamzink, M.; Van der Hulst, R.; Zomer, G.;
Westra, G.; Kriek, E. Heterocycles 1987, 26, 2711±2716.
1
<
<
d -DMSO) d 8.54 <s, 1H), 7.98 <d, Jˆ7.5 Hz, 1H), 7.48
6
2. Ishiyama, T.; Kizaki, H.; Miyaura, N.; Suzuki, A. Tetrahedron
Lett. 1993, 34, 7595±7598.
1
3
d, Jˆ7.5 Hz, 1H), 1.27 <s, 12H). C NMR <d -DMSO) d
6
1
Anal. Calcd for C H BClNO : C, 55.16; H, 6.31; N,
5
54.9, 153.2, 145.1, 124.1, 84.3, 24.6. MS m/z 239±241.
3
. Lohse, O.; Thevenin, P.; Waldvogel, E. Synlett 1999, 45±48.
4. Ishikura, M.; Oda, I.; Terashia, M. Heterocycles 1985, 23,
375±2386.
1
1
15
2
.85. Found: C, 55.28; H, 6.39; N, 5.92.
2
5
. Yang, Y.; Martin, A. R. Heterocycles 1992, 34, 1395±1398.
. Only commercially available pyridyl boronic acids are
pyridyl-3-boronic acid methyl ester, pyridyl-4-boronic acid,
pyridyl-2-methoxy 5-boronic acid <Frontiers, Interchim).
0
dioxaborolane ꢀ5b). Colourless oil; H NMR <d -DMSO)
0
3
.3.3. 2-[3-ꢀ6-Fluoro)pyridine]-4,4 ,5,5 -tetramethyl-1,3-
6
1
6
d 8.43 <d, Jˆ2.0 Hz, 1H), 8.16 <dt, Jˆ8.2, 2.1Hz, 1H ), 7.18
1
3
<
dd, Jˆ8.2, 2.1 Hz, 1H), 1.29 <s, 12H). C NMR <d -
6
7. Lehmann, U.; Henze, O.; Schl uÈ ter, A. D. Chem. Eur. J. 1999,
, 854±859.
. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457±2483.
DMSO) d 164.3 <d, Jˆ238 Hz), 154.1 <d, Jˆ15 Hz),
5
1
Anal. Calcd for C H BFNO : C, 59.23; H, 6.78; N, 6.28.
47.8 <d, Jˆ8 Hz), 109.4 <d, Jˆ36 Hz). MS m/z 222.9;
8
1
1
15
2
9. Alo, B. I.; Kandil, A.; Patil, P. A.; Sharp, M. J.; Siddiqui,
M. A.; Snieckus, V. J. Org. Chem. 1991, 56, 3763±3768.
0. Rocca, P.; Marsais, F.; Godard, A.; Queguiner, G.
Tetrahedron 1993, 49, 49±64.
Found: C, 59.43; H, 6.86; N, 6.40.
1
3.4. General procedure for the palladium-assisted
coupling of pyridyl-boronate with halo compounds
11. Fletcher, S. R.; Baker, R.; Chambers, M. S.; Herbert, R. H.;
Hobbs, S. C.; Thomas, S. R.; Verrier, H. M.; Watt, A. P.; Ball,
R. G. J. Org. Chem. 1994, 59, 1771±1778.
12. Pandey, G.; Bagul, T. D.; Trusar, D.; Sahoo, A. K. J. Org.
Chem. 1998, 760±768.
A mixture of halopyridylboronate <1.2 equiv.), halo-
compound <bromobenzene, 2-bromobenzonitrile or
4
ladium<0) <6% mol) and 2N aqueous K PO solution in
-iodoanisole) <1equiv.), tetrakis-<triphenylphosphine)pal-
13. Parham, W. E.; Piccirilli, R. M. J. Org. Chem. 1977, 42, 257±
260.
3
4
DMF was heated at 658C for 3±12 h. Ethyl acetate and
water were then added. The organic layer was separated,
dried over MgSO and concentrated to dryness. The residue
4
14. Krow, G. R.; Xiao, Y.; Cannon, K.; Swan, S. A.; Nickel, A.
Synth. Commun. 2000, 30, 4093±4096.
was chromatographied on silica gel.
15. Sopkova-De Oliveira Santos, J.; Bouillon, A.; Lancelot, J. C.;
Collot, V.; Rault. S. Acta Crystallogr. C, submitted for
publication.
3.4.1. 2-Bromo-5-phenylpyridine ꢀ17). White solid <57%),
mp 808C <lit. 78±798C); H NMR <CDCl ) d 8.47 <d,
2
8
1
16. Coudret, C. Synth. Commun. 1996, 26, 3543±3547.
17. Tschitschibabin, A. E.; Bylinkin Zh. Russ. Fiz. Chim. 1920,
50, 479.
3
Jˆ2.1Hz, 1H ), 7.58 <dd, Jˆ8.1, 2.1 Hz, 1H), 7.30±7.40
1
3
<
m, 4H), 6.91<d, Jˆ8.2 Hz, 2H). C NMR <d -DMSO) d
6

2890
A. Bouillon et al. / Tetrahedron 58 ꢀ2002) 2885±2890
1
1
2
2
2
8. Wibaut, J. P.; La Bastide, G. Chem. Zentralbl., II 1927, 2198±
203.
9. Corcoran, R. C.; Bang, S. H. Tetrahedron Lett. 1990, 31,
757±6758.
23. Wang, X.; Rabbat, P.; O'Shea, P.; Tillyer, R.; Grabowski,
2
E. J. J.; Reider, P. J. Tetrahedron Lett. 2000, 41, 4335±4338.
24. Fischer, F. C.; Havinga, E. Rec. Trav. Chim. Pays-Bas 1974,
93, 21±24.
6
0. Hama, Y.; Nobuhara, Y.; Aso, Y.; Otsubo, T.; Ogura, F. Bull.
Chem. Soc. Jpn 1988, 61, 1683±1686.
1. Clayton, S. C.; Regan, A. C. Tetrahedron Lett. 1993, 34,
25. Collot, V.; Dallemagne, P.; Bovy, P. R.; Rault, S. Tetrahedron
1999, 55, 6917±6922.
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62, 7820±7826.
7493±7496.
2. Dolci, L.; Dolle, F.; Valette, H.; Vaufrey, F.; Fuseau, C.;
Bottlaender, M.; Crouzel, C. Bioorg. Med. Chem. 1999, 7,
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835±838.
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467±480.