Access to 2-Aminopyridines - Compounds of great biological and chemical significance

Article abstract of DOI:10.1002/adsc.201000942

2-Aminopyridines are key structural cores of bioactive natural products, medicinally important compounds, and organic materials and thus, extremely valuable synthetic targets. The few reported 6-substituted 2-aminopyridines and the lack of flexible, efficient and general applicable methods for their synthesis demonstrates the urgent need of new methods for their preparation. Reactions between 2,6-dibromopyridine and primary or secondary, cyclic or acyclic, and aliphatic or aromatic amines were shown to selectively yield the respective 6-bromopyridine-2-amines in very high yields which were successfully used as substrates for subsequent C-C cross-coupling reactions. The recently introduced dichloro-bis[1-(dicyclohexylphosphanyl)piperidine]palladium (1) was used as catalyst for the cross-coupling of 6-bromopyridine-2-amines with arylboronic acids, diaryl- and dialkylzinc reagents or olefins and hence, is also an excellent C-C cross-coupling catalyst for this type of substrate. Moreover, all the reaction protocols presented were in each of the catalyses uniformly applied. The scope of both the amination and the cross-coupling reactions are well defined and allow one to simply adapt the reaction protocols directly to other amines and/or coupling partners and, thus, provide for the first time a very flexible and generally applicable reaction protocol to get access to 2-aminopyridines.

Full text of DOI:10.1002/adsc.201000942

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DOI: 10.1002/adsc.201000942
Access to 2-Aminopyridines – Compounds of Great Biological
and Chemical Significance
Jeanne L. Bolliger,a Miriam Oberholzer,a and Christian M. Frecha,*
a
Institute of Inorganic Chemistry, University of Zꢀrich, Winterthurerstrasse 190, 8057 Zꢀrich, Switzerland
Fax : (+41)-44-635-6802; phone: (+41)-44-635-6802; e-mail: chfrech@aci.uzh.ch
Received: December 14, 2010; Revised: February 22, 2011; Published online: April 13, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000942.
Abstract: 2-Aminopyridines are key structural cores pyridine-2-amines with arylboronic acids, diaryl- and
of bioactive natural products, medicinally important dialkylzinc reagents or olefins and hence, is also an
À
compounds, and organic materials and thus, extreme- excellent C C cross-coupling catalyst for this type of
ly valuable synthetic targets. The few reported 6-sub- substrate. Moreover, all the reaction protocols pre-
stituted 2-aminopyridines and the lack of flexible, ef- sented were in each of the catalyses uniformly ap-
ficient and general applicable methods for their syn- plied. The scope of both the amination and the
thesis demonstrates the urgent need of new methods cross-coupling reactions are well defined and allow
for their preparation. Reactions between 2,6-dibro- one to simply adapt the reaction protocols directly to
mopyridine and primary or secondary, cyclic or acy- other amines and/or coupling partners and, thus, pro-
clic, and aliphatic or aromatic amines were shown to vide for the first time a very flexible and generally
selectively yield the respective 6-bromopyridine-2- applicable reaction protocol to get access to 2-ami-
amines in very high yields which were successfully nopyridines.
À
used as substrates for subsequent C C cross-coupling
reactions. The recently introduced dichloro-bis[1-(di- Keywords: aminophosphines; aminopyridines; C C
À
cyclohexylphosphanyl)piperidine]palladium (1) was bond formation; palladium; pincer complexes;
used as catalyst for the cross-coupling of 6-bromo- Suzuki–Miyaura reaction
Introduction
cretion and thus, are potentially useful in the condi-
tions associated with elevated circulating levels of
Nitrogen-containing heterocyclic compounds are key Apo B, such as hyperlipidemia, hypertriglyceridemia,
structural cores of various bioactive natural products, atherosclerosis, restenosis, pancreatitis, non-insulin
medicinally important compounds, and organic mate- dependent diabetes mellitus and coronary heart dis-
rials and thus, of great biological and chemical signifi- eases,[7] which stimulated tremendeous efforts to pre-
cance.[1–3] In particular, pyridines and fused pyridines, pare compounds of this structural type. Thus, various
such as quinoline, isoquinoline alkaloids,[4] as well as methods have been applied for their preparation.[5,8]
nicotine and its analogues are frequent moieties in The most common (classical organic) methods for the
natural products.[5] The high incidence of pharmaco- synthesis of N-substituted 2-aminopyridines include
logical and biological activity of heteroaromatic N-alkylation of 2-aminopyridines,[8a] reactions of ali-
amines, such as 2-aminopyridines, on which we have phatic amines with 2-halopyridines, pyridinium salts
focused,[6] make them extremely valuable synthetic or with imidol silyl ethers derived from the corre-
targets. 2-Amino-6-(aminoethyl)pyridines, for exam- sponding pyridin-2-ones,[8g–i] aminolysis of 2-alkoxy-
ple, are potent inhibitors of nitric oxide synthase pyridines,[8i,j] reactions of a,b-unsaturated ketones
(NOS), which could find their application in the treat- with cyano derivatives and amines,[8l], or reactions of
ment of NOS-related diseases, e.g., inflammation, 2-alkoxypyridines with amines in the presence of
septic shock, rheumatoid arthritis, osteoarthritis, Par- Et2AlCl.[8m] Other, more recent strategies include
kinsonꢁs disease, cardiovascular diseases, allergy, transition metal-catalyzed reactions,[8n] such as the
cancer, obesity and pain. Furthermore, they also have Buchwald–Hartwig amination of 2-halopyridines,[8p]
been shown to inhibit apolipoprotein B (Apo B) se- which complement the classical synthetic approaches.
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However, despite all the great advantages of metal-
catalyzed methods, they often suffer from inefficient
bond formations when nitrogen-containing heterocy-
cles are involved. Moreover, catalytic aminations of
2,6-dibromopyridines, which selectively yield 6-bro-
mopyridine-2-amines have not been reported so far.
They always lead to mixtures of 2,6-dibromopyridine,
6-bromopyridin-2-amines, and pyridine-2,6-diamines,
from which the mono-aminated product is often very
difficult to isolate. Thus, even though synthetic strat-
egies exist to prepare 2-aminopyridines, the develop- room temperature from reactions of commercially
ment of more flexible, efficient, and generally applica- available [Pd(cod)(Cl)2] (cod=cyclooctadiene) with
AHCTUNGTRENNUNG
ble routes (from simple and readily available precur- 2 equiv. of ligand in toluene under N2.[9] All the cross-
sors) that allow the selective and high-yielding synthe- coupling reactions were catalyzed by 1 under uniform
sis of 6-bromopyridine-2-amines for the fast and easy conditions with a large variety of different but repre-
access to small focused libraries of 2-aminopyridines sentative 6-bromopyridine-2-amines and coupling
is of utmost importance for this biologically and partners to demonstrate the flexibility, efficiency and
chemically significant class of compound. The few re- general applicability of our reaction protocols. Fur-
ported 6-substituted 2-aminopyridines impressively thermore, this report also impressively demonstrates
demonstrate the lack of appropriate methods for their the excellent catalytic activity of dichloro-bis[1-(dicy-
À
preparation.
clohexylphosphanyl)piperidine]palladium (1) in C C
We report herein simple, short and extremely versa- cross-coupling reactions performed with 6-bromopyri-
tile reaction protocols for the high-yielding synthesis dine-2-amines as substrates. Notably, whereas essen-
of 6-substituted 2-aminopyridines. The reaction se- tially the same catalytic activity was found for di-
quence starts with the selective amination of 2,6-di- chloro-bis[1,1’,1’’-(phosphinetriyl)tripiperidine]palla-
bromopyridine to give the respective 6-bromopyri- dium, a dramatically reduced level of activity was ob-
dine-2-amines, which serve as substrates for subse- tained in the Suzuki and Heck cross-coupling reac-
quent cross-coupling reactions (Scheme 1).
tions for {[PACTHNGUTERNU(NG C6H11)3]2Pd(Cl)2} – its phosphine-based
The amination reactions were performed with vari- analogue, where palladium nanoparticles are the cata-
ous primary and secondary, cyclic and acyclic, aliphat- lytically active form. On the other hand, a similar
ic and aromatic amines and demonstrate the general level of activity was expected to be obtained in the
applicability of our reaction protocols. All the 6-bro- Negishi cross-coupling reaction, where a molecular
mopyridine-2-amines prepared were subsequently mechanism was found to be operative. This was
À
used in C C cross-coupling reactions, namely the indeed the case and demonstrates the superior prop-
Suzuki, Negishi, and Heck reactions, which were suc- erties of aminophosphine-derived systems when com-
cessfully catalyzed by the recently introduced palladi- pared with their phosphine-based analogues, since
um-based 1-(dicyclohexylphosphanyl)piperidine com- they promote (in contrast to latter) the formation of
plex [(PACHTUNGTRENNUNG(C6H11)2ACHTUNGTRENNUNG(NC5H10))2Pd(Cl)2] (1), which was palladium nanoparticles as well as can operate via a
quantitatively prepared within only a few minutes at homogeneous mechanisms.[9]
Results and Discussion
Synthesis of 6-Bromopyridine-2-amines
Reactions of aliphatic amines with 2,6-dibromopyri-
dine in dioxane at 1008C in the presence of an excess
(~4 equiv.) of K3PO4, selectively yield the respective
6-bromopyridine-2-amines.[10] Representative reac-
tions have been carried out with a wide variety of pri-
mary and secondary amines, such as n-octylamine and
1-adamantanemethylamine as well as dibutylamine,
N-methylbenzylamine, 2,3-dihydro-1H-indole, ethyl
piperidine-3-carboxylate, N,N-diethylpiperidine-3-car-
boxamide, 2-piperazin-1-ylpyrimidine, 1-methyl-1,4-
diazepane, N-methylcyclohexylamine, and N’-[2-(di-
ethylamino)ethyl]-N,N-diethylethane-1,2-diamine,
Scheme 1. General synthetic route to substituted 2-amino-
pyridines.
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Access to 2-Aminopyridines – Compounds of Great Biological and Chemical Significance
Table 1. 6-Bromopyridine-2-amines prepared.[a]
>
[a]
Reaction conditions: 10.0 mmol 2,6-dibromopyridine, 11.0 mmol amine, 40.0 mmolK3PO4 or 11.0 mmol KNACHTUNTRGNEUNG(SiMe3)2, 30 mL
dioxane, reactions performed at 1008C or at 258C. The conversions are determined by GC/MS, based on 2,6-dibromopyri-
dine; isolated yields are given in brackets.
which in all cases cleanly give the desired coupling
Overall, the applicability of both reaction protocols
products in excellent yields – typically within 12 h is well-defined, extremely simple, effective and relia-
when cyclic amines, such as pyrrolidine, piperidine, bly give the 6-bromopyridine-2-amines by reactions of
morpholine, ethyl piperidine-3-carboxylate, N,N-di- 2,6-dibromopyridines with primary and secondary,
ethylpiperidine-3-carboxamide, 1-methylpiperazine, or cyclic and acyclic, aliphatic and aromatic amines in
2-piperazin-1-ylpyrimidine were used as coupling high yields (>80%) and provide for the first time a
partners. Clean product formation but prolonged re- highly flexible and versatile synthetic access to 6-bro-
action times (up to 5 days for 1-adamantanemethyl- mopyridine-2-amines, which serve as substrates in
ACHTUNGTRENNUNGamine) were required when acyclic amines, such as n- cross-coupling reactions. All 6-bromopyridine-2-
octylamine, N-methylcyclohexylamine, N-methylben- amines shown in Table 1 were prepared accordingly
À
zylamine, dibutylamine or N’-[2-(diethylamino)ethyl]- and are used in exemplary C C bond forming reac-
N,N-diethylethane-1,2-diamine were used as coupling tions to demonstrate facile synthetic access to 6-sub-
partners.
Potassium bis(trimethylsilyl)amide on the other
hand, is the base of choice when reactions were per-
stituted 2-aminopyridines.
formed with aniline derivatives. The respective 6-bro- Suzuki Cross-Coupling
mopyridine-2-amines were selectively formed in very
high yields, generally in less than 1 hour at 258C. The Suzuki–Miyaura reaction is one of the most im-
Model reactions have been performed with aniline, portant methods for the formation of symmetrical
3,4,5-trimethoxyaniline, anthracen-2-amine, and steri- and non-symmetrical biaryls and thus, was expected
cally hindered 2-methoxyaniline, 2,6-dimethylaniline, to offer an efficient and convenient synthetic route to
and 2,6-bis(1-methylethyl)aniline as well as 2,3-dihy- access to 6-arylpyridine-2-amines.[11] Exemplary reac-
dro-1H-indole, N-methylaniline, N-ethylaniline, and tions have been performed with phenylboronic acid,
N-methylpyridine-2-amine. Reaction temperatures of (4-methoxyphenyl)boronic acid and sterically hin-
1008C were applied when (less nucleophilic) 2-amino- dered (2-methylphenyl)boronic acid. For example,
pyridine and diphenylamine were used as coupling when 6-bromopyridine-2-amines were coupled with a
partners.
slight excess (~1.1 equiv.) of arylboronic acid in tolu-
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Access to 2-Aminopyridines – Compounds of Great Biological and Chemical Significance
ene in the presence of 0.2 mol% of [(P
ACHTUNGNERTN(NUG C6H11)2 benzyl-6-bromo-N-methylpyridin-2-amine, and N,N-
ACHTUNGTRENNUNG(NC5H10))2Pd(Cl)2] (1), the respective coupling prod- dibutyl-6-bromopyridin-2-amine, 2-bromo-6-piperidin-
ucts were quantitatively formed in almost all the reac- 1-ylpyridine, 1-(6-bromopyridin-2-yl)-2,3-dihydro-1H-
tions examined within only 15 min at 808C in air. indole, 6-bromo-N-(2-methoxyphenyl)pyridin-2-amine
Model reactions have been performed with primary and 6-bromo-N,N-diphenylpyridin-2-amine. In addi-
and secondary aliphatic aminopyridines, such as 6- tion, functionalized 6-bromopyridine-2-amines, such
bromo-N-cyclohexyl-N-methylpyridin-2-amine,
bromo-N,N-dibutylpyridin-2-amine and N-(6-bromo-
pyridin-2-yl)-N-[2-(diethylamino)ethyl]-N’,N’-diethyl-
6- as
ethyl]-N’,N’-diethylethane-1,2-diamine and 6-bromo-
N-methyl-N-pyridin-2-ylpyridin-2-amine have been
N-(6-bromopyridin-2-yl)-N-[2-(diethylamino)-
ACHTUNGTRENNUNG
ethane-1,2-diamine as well as aromatic 6-bromopyri- used as coupling partner. These and many other sub-
dine-2-amines, like 6-bromo-N-(3,4,5-trimethoxyphe- strates have been successfully coupled (without modi-
nyl)pyridin-2-amine, 6-bromo-N,N-diphenylpyridin-2- fication of the reaction protocol) with representative
amine and 6-bromo-N-methyl-N-pyridin-2-ylpyridin- organozic reagents, such as diphenylzinc, electronical-
2-amine. Impressively, the same conversion rates and ly deactivated bis(4-methoxyphenyl)zinc or bis[4-(di-
yields were obtained when electronically deactivated methylamino)phenyl]zinc, sterically hindered diaryl-
(4-methoxyphenyl)boronic acid and sterically hin- zinc reagents, such as bis(2-methylphenyl)zinc,
dered (2-methylphenyl)boronic acid were applied. For bis(2,6-dimethylphenyl)zinc,
example, 1-(6-bromopyridin-2-yl)-2,3-dihydro-1H- nyl)zinc or bis(2-methoxyphenyl)zinc, bis(2,5-dime-
indole, 4-(6-bromopyridin-2-yl)thiomorpholine, and thoxyphenyl)zinc as well as dithiophen-2-ylzinc, and
N-[2,6-bis(1-methylethyl)phenyl]-6-bromopyridin-2- also aliphatic organozinc reagents, namely dibutylzinc,
amine as well as 6-bromo-N-octylpyridin-2-amine, dicyclohexylzinc, and dibenzylzinc. Impressively, any
N-(6-bromopyridin-2-yl)-N-[2-(diethylamino)ethyl]- 6-bromopyridine-2-amine applied, was almost quanti-
bis(2,4,6-trimethylphe-
N’,N’-diethylethane-1,2-diamine and 6-bromo-N-(2- tatively converted into the desired 6-substituted 2-
methoxyphenyl)pyridin-2-amine were cleanly (side-re- aminopyridine within only a few minutes. Isolated
actions have not been detectable) converted into the yields of the desired coupling products were in almost
respective coupling products. The coupling products all the reactions performed higher than 80%, which
could be isolated in all the reactions examined, in ex- impressively demonstrates the excellent catalytic ac-
cellent yields. The same level of activity was noticed tivity of 1 in the Negishi reaction and its practicabilli-
when sterically hindered 6-bromopyridine-2-amines, ty in the cross-coupling of 6-bromopyridine-2-amines
such as N-(3-bromophenyl)-2,6-bis(1-methylethyl)ani- with diaryl or dialkylzinc reagents and thus, the prep-
line were used as substrates and impressively demon- aration of 6-substituted 2-aminopyridines. Indeed, the
strates that 1 is (in contrast to the phosphine-based presented reaction protocol provides an extremely
analogue) an excellent Suzuki catalyst, which reliably flexible and versatile synthetic access to 2-aminopyri-
couples a large variety of 6-bromopyridine-2-amines dines and additionally allows its direct adaption for
at low catalyst loadings with different arylboronic the synthesis of other 2-aminopyridines, which were
acids under uniform reaction conditions to provide reliably coupled in the presence of only 0.01 mol% of
flexible and facile synthetic access to 2-aminopyri- catalyst under uniform reaction conditions. All the 2-
dines in excellent overall yields from commercially aminopyridines prepared that involve the cross-cou-
available 2,6-dibromopyridines via 6-bromopyridine- pling of a 6-bromopyridine-2-amine with diaryl- or di-
2-amines in two steps (Table 2).
alkylzinc reagents are listed in Table 3.
Negishi Cross-Coupling
Heck Cross-Coupling
À
À
Another mild, efficient and highly versatile C C The Heck reaction is the most important C C bond
bond forming reaction, which could provide facile forming process for the arylation of olefins and thus,
synthetic access to 6-substituted 2-aminopyridines is the method of choice for the preparation of 6-[(1E)-
the Negishi reaction – the cross-coupling of aryl hal- alkenyl]pyridine-2-amines.[11a,b,13] Indeed, 6-bromopyri-
ides with organozinc reagents.[11a,b,12] Indeed, 6-bromo- dine-2-amines, such as aliphatic ethyl 1-(6-bromopyri-
pyridine-2-amines were reliably coupled with a large din-2-yl)-4-methylpiperazine, ethyl 1-(6-bromopyri-
variety of representative diaryl- and dialkylzinc re- din-2-yl)piperidine-3-carboxylate, N-benzyl-6-bromo-
agents in THF/NMP mixtures in the presence of only N-methylpyridin-2-amine, as well as aromatic 6-
0.01 mol% of 1 at 1008C in air. Reactions have been bromo-N,N-diphenylpyridin-2-amine were successfully
successfully performed with various 6-bromopyridine- coupled with various, representative olefins, such as
2-amines, containing secondary and tertiary, cyclic ethenylbenzene and derivatives, 4-vinylpyridine, N,N-
and acyclic aliphatic and aromatic amine units. Exam- dimethylacrylamide, as well as butyl prop-2-enoate
ples include N-octyl-6-bromopyridin-2-amine, N- (Table 4). For example, the cross-coupling of 2-[4-(6-
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bromopyridin-2-yl)piperazin-1-yl]pyrimidine
with (phosphinetriyl)tripiperidine]palladium} are excellent
À
ethenylbenzene under a nitrogen atmosphere in DMF C C bond forming catalysts, which efficiently couple
and K2CO3 as base at 1408C in the presence of 0.05 6-bromo-2-aminopyridines with a large variety of dif-
mol% of 1 was fully converted into 2-(4-{6-[(E)-2- ferent types of coupling partners, such as arylboronic
phenylethenyl]pyridin-2-yl}piperazin-1-yl)pyrimidine
acids, dialkyl or diarylzinc reagents and olefins. This is
in 2 h. The isolated yield was 95%. 4 h of reaction in striking contrast to its phosphine-based analogue
time were required for the preparation of N-benzyl- that only shows a comparable level of activity in the
N-methyl-6-[(E)-2-phenylethenyl]pyridin-2-amine,
Negishi reaction but dramatically lower activities
which could have been isolated in 82% yield. Essen- under Suzuki and Heck reaction conditions. The 6-
tially the same catalytic performances were obtained substituted 2-aminopyridines, however, were in all the
for the cross-coupling of 6-bromopyridines with other reactions performed, cleanly and rapidly formed and
ethenylbenzene derivatives, such as 1-ethenyl-4-meth- could be isolated in excellent yields. Although one-
ylbenzene, 1-ethenyl-4-methoxybenzene, 1-chloro-3- pot protocols would be desirable for their synthesis,
ethenylbenzene, and 4-vinylpyridine. An exemplary attempts to date have not resulted in improvement
reaction includes the conversion of 6-bromo-N,N-di- and further studies are under way. However, all the
phenylpyridin-2-amine into 6-[(E)-2-(4-methoxyphe- reaction protocols presented are uniform and the
À
nyl)ethenyl]-N,N-diphenylpyridin-2-amine, which was scope of both, the amination and the C C cross-cou-
complete after 4 h. A slightly retarded conversion was pling reactions, are well defined. This allows one to
obtained by using 1-chloro-3-ethenylbenzene as sub- simply adopt the presented synthetic routes directly
strate. Comparable conversion rates and yields were to other amines and coupling partners and hence, pro-
noticed when N,N-dimethylacrylACTHNUTRGNEaUNG mide and butyl vide a powerfull tool to get facile access to 2-amino-
prop-2-enoate were used as coupling partners. In gen- pyridines via simple (systematic) modifications of the
eral, the 6-[(1E)-alkenyl]pyridine-2-amines are in amine and/or the R units, which is of great impor-
almost all the reactions examined exclusively (>95%) tance for the preparation of pharmaceuticals and tar-
formed and impressively demonstrates that the ami- gets in material science, for example. The few report-
nophosphine-derived palladium complex 1 is (in con- ed 6-substituted 2-aminopyridines and the lack of
trast to their phosphine based analogues) an efficient flexible, efficient and general applicable methods for
Heck catalyst, which smoothly couples 6-bromopyri- their synthesis impressively demonstrates the urgent
dine-2-amines at low catalyst loadings with olefins. need of new methods to obtain synthetic access to 2-
Overall, the Heck reaction is an appropriate synthetic aminopyridines – compounds, which are not only of
method for the vinylation of 6-bromopyridine-2- great chemical importance, but also for biological,
amines, even though NH-containing 6-bromopyridine- medicinal and pharmaceutical applications and mate-
2-amines were found to be incompatible under the re- rial science – and thus, the importance of this report.
action conditions applied. All the Heck coupling
products prepared are given in Table 4. The reaction
conditions applied were in all the reactions examined Experimental Section
the same.
General Remarks
All synthetic operations for the catalyst preparation were
carried out in oven-dried glassware using a combination of
Conclusions
glovebox (M. Braun 150B-G-II) and Schlenk techniques
In conclusion, simple and general applicable synthetic
methods for the selective and high-yielding synthesis
of 6-bromo-2-aminopyridines have been developed,
and the products were successfully applied in cross-
coupling reactions [catalyzed by the recently intro-
duced dichloro-bis(1-(dicyclohexylphosphanyl)piperi-
dine)palladium (1)]. The selective synthesis of 6-bro-
mopyridine-2-amines was achieved from reactions be-
tween commercially available 2,6-dibromopyridine
and amines in the presence of a base – depending on
the amine – either at room temperature or at 1008C.
The reaction protocols were successfully applied to
primary and secondary aliphatic, cyclic and acyclic,
and aromatic amines and thus, are extremely flexible.
Moreover, dichloro-bis(1-(dicyclohexylphosphanyl)pi-
under a dinitrogen atmosphere. Solvents were reagent grade
or better and freshly distilled under N2 atmosphere by stan-
dard procedures. Deuterated solvents were purchased from
Armar, dried by standard procedures, and degassed by
freeze-thaw cycles before use. All chemicals were purchased
from Aldrich Chemical Co. or Acros Organics and used as
received.
General Procedure for the Selective Synthesis of 6-
Bromopyridin-2-Amines with Aliphatic Amines
A Young Schlenk was charged (in air) with 10.0 mmol of
2,6-dibromopyridine, 11.0 mmol of amine, 40.0 mmol of
K3PO4, and 30 mL of dioxane and closed with a Teflon
screw cap. Then the reaction mixture was placed in a pre-
heated 1008C oil bath and stirred vigorously. Samples taken
peridine)palladium (1) {as well as dichloro-bis[1,1’,1’’- from the reaction mixture were quenched with water. The
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Access to 2-Aminopyridines – Compounds of Great Biological and Chemical Significance
products were extracted with ethyl acetate and analyzed by
GC/MS. At the end of the reaction the mixtures were al-
lowed to cool to room temperature, were quenched with
1M NaOH and extracted with 30–50 mL of ethyl acetate.
The combined extracts were washed with 1M NaOH (3ꢃ
50 mL), dried over MgSO4, filtered, and evaporated to dry-
ness. Where necessary, the product was purified by flash
chromatography on silica gel or on alumina.
phase was washed with basic EDTA solution. The combined
extracts were dried over MgSO4, filtered through silica or
aluminium oxide (compounds containing aliphatic tertiary
amines), respectively, and evaporated to dryness. The crude
material was purified by flash chromatography on silica gel,
as necessary.
The diarylzinc reagents were prepared in THF by convert-
ing the aryl halides to the Grignard reagents which were
then reacted with zinc dichloride to afford the correspond-
ing diarylzinc reacents. Dibutylzinc was prepared in THF by
reacting butyllithium with zinc dichloride at À788C. Diben-
zylzinc and dicyclohexylzinc were prepared by convertion
their alkyl halide to the Grignard reagent followed by the
addidion of zinc dichloride.NMP was added to the zinc re-
agents, resulting in a NMP/THF solution (2:1), which was
used within 2 days.
General Procedure for the Selective Synthesis of 6-
Bromopyridin-2-Amines with Aniline-Derived
Amines
Inside a glovebox a vial was successively charged with
11.0 mmol of amine, 11.0 mmol of KN
ACHTUNGTRENNUNG
aniline derivatives) or 15.0 mmol of KNACHTUNGTRENNNUG
aniline derivatives), respectively, 30 mL of dioxane and
10.0 mmol of 2,6-dibromopyridine. Then the reaction mix-
ture was stirred at room temperature unless otherwise
stated. Samples taken from the reaction mixture were
quenched with 1M NaOH. The products were extracted
with ethyl acetate and analyzed by GC/MS. At the end of
the reaction the mixtures were quenched with 1M NaOH
and extracted with 30–50 mL of ethyl acetate. The combined
extracts were washed with 1M NaOH (3ꢃ50 mL), dried
over MgSO4, filtered, and evaporated to dryness. Where
necessary, the product was purified by flash chromatography
on silica gel or on alumina.
General Procedure for Heck Cross-Coupling
A round-bottomed flask was charged under an N2 atmop-
shere with the appropriate olefin (3.0 mmol), 6-bromo-2-
aminopyridine (2.0 mmol), powdered K2CO3 (3.0 mmol),
and DMF (5 mL). The mixture was vigorously stirred and
heated to 1408C. Then the catalyst was added by syringe as
a toluene solution (0.05 mol%, 0.2 mL of a 5ꢃ10À3 M solu-
tion). Samples were periodically taken from the reaction
mixture, quenched with 1M NaOH, extracted with ethyl
acetate, and analyzed by GC/MS. At the end of catalysis,
the reaction mixtures were allowed to cool to room temper-
ature, quenched with water, and extracted with ethyl acetate
(2ꢃ40 mL). The combined extracts were dried (MgSO4) and
evaporated to dryness. The crude material was purified by
flash chromatography on silica gel, as necessary.
General Procedure for the Suzuki Cross-Coupling
All catalytic reactions were carried out in reaction vessels
open to the air. A round-bottomed flask was charged with
the arylboronic acid (2.2 mmol), the 6-bromo-2-aminopyri-
dine (2.0 mmol), powdered K3PO4 (3.0 mmol), and toluene
(6 mL). The mixture was vigorously stirred and heated to
808C. Then the catalyst was added by syringe as a toluene
solution (0.2 mol%, 0.4 mL of a 1ꢃ10À2 M solution). Sam-
ples were periodically taken from the reaction mixture,
quenched with 1M NaOH, extracted with diethyl ether, and
analyzed by GC/MS. At the end of catalytic reaction, the re-
action mixtures were allowed to cool to room temperature,
quenched with 1M NaOH, and extracted with diethyl ether
(2ꢃ40 mL). The combined extracts were dried (MgSO4) and
evaporated to dryness. The crude material was purified by
flash chromatography on silica gel, as necessary.
Acknowledgements
Financial support by the University of Zurich and the Swiss
National Science Foundation (SNSF) is acknowledged.
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Adv. Synth. Catal. 2011, 353, 945 – 954