Gold-catalyzed redox synthesis of imidazo[1,2-a]pyridines using pyridine N-oxide and alkynes

Article abstract of DOI:10.1002/adsc.201300996

A mild, catalytic, atom economical synthesis of imidazo[1,2-a]pyridines has been developed: catalytic dichloro(2-pyridinecarboxylato)gold [PicAuCl ₂] in the presence of an acid produces a range of imidazo[1,2-a]pyridines in good yields starting

Full text of DOI:10.1002/adsc.201300996

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DOI: 10.1002/adsc.201300996
Gold-Catalyzed Redox Synthesis of Imidazo[1,2-a]pyridines using
G
Pyridine N-Oxide and Alkynes
Eric P. A. Talbot,a,b Melodie Richardson,a Jeffrey M. McKenna,a
and F. Dean Tosteb,*
a
Novartis Institutes for Biomedical Research, Wimblehurst Road, Horsham, West Sussex, RH12 5AB, U.K.
Department of Chemistry, University of California, Berkeley, California 94720, USA
b
E-mail: fdtoste@uclink.berkeley.edu
Received: November 8, 2013; Revised: January 27, 2014; Published online: March 3, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300996.
Abstract: A mild, catalytic, atom economical syn-
thesis of imidazo[1,2-a]pyridines has been devel-
oped: catalytic dichloro(2-pyridinecarboxylato)gold
[PicAuCl2] in the presence of an acid produces
formed in many ways: typically they are formed via
condensation of aminopyridines and a-halo ketones[10]
and can be formed by a one-pot condensation of an
aldehydes, isonitrile and a 2-aminopyridine although
this approach can require harsh conditions so limiting
the scope of functionalities tolerated in this reac-
tion.[11] More recently a number of copper-catalyzed
methodologies have been developed, namely a three-
component reaction of a 2-aminopyridine with an al-
dehyde and an alkyne,[12] a dehydrogenative coupling
of a ketone with a 2-aminopyridine conducted at
408C,[13] an oxidative cyclization of a haloalkyne with
an aminopyridine at 608C,[14] and an oxidative reac-
tion between a ketone and a 2-aminopyridine carried
out at 1208C.[15] Two further methods reported recent-
AHCTUNGTRENNUNG
a range of imidazoACHTNUGRTENUNG[1,2-a]pyridines in good yields
starting from alkynes and 2-aminopyridine N-
oxides. This strategy is mild and foreseen to be of
particular use for the installation of stereogenic
centers adjacent to the imidazoACHTUNTRGNEUNG[1,2-a]pyridine ring
without loss of enantiomeric excess.
Keywords: alkynes; atom economy; gold; imidazo-
ACHTUNGTRENNUNG[1,2-a]pyridines; pyridine N-oxides; redox reaction
ly are worthy of note, the ironACTHNUGRTNEUNG(III)-catalyzed reaction
between a nitroolefin and an aminopyridine achieved
The possibility of forming an a-oxo gold carbenoid at 808C,[16] and the silver-mediated oxidative coupling
species through an oxygen transfer reaction using an between terminal alkynes and a 2-aminopyridine con-
alkyne and a nucleophilic oxide (initially a sulfoxide)[1] ducted at 1108C.[17]
was first exploited in 2007 and this concept has subse-
The concept reported here offers an atom economic
[1,2-a]pyridines by em-
quently been expanded: specifically one area in which redox[18] process to imidazo
AHCTUNGTRENNUNG
this redox chemistry has been developed is the ac- ploying the pyridine component both as a nucleophile,
commodation of pyridine N-oxides[2] which serve as directly attacking the gold carbenoid intermediate,
the oxidant in the formation of the a-oxo gold carbe- and it is involved in the regioselective formation of
noid species (Scheme 1).[3] This reaction combination these N-bridgehead heterocycles [Scheme 1, Eq. (2)].
has utilized both intra- and intermolecular attack of Interestingly this combination of reagents appears to
the N-oxide moiety on the alkyne, however, in cases offer more flexibility in the choice of components in
where the N-oxide has been utilized in an intermolec- the reaction.[19] We foresaw that this new methodolo-
ular reaction a stoichiometric amount of pyridine gy might allow access to a range N-bridgehead het-
waste is produced.[4] As an alternative, we envisaged erocycles with chiral substituents which would other-
a process in which 2-aminopyridine N-oxide would wise be extremely difficult to obtain using the classi-
serve as the oxidant and be incorporated in the mo- cal routes. To test our initial hypothesis and delineate
lecular complexity of the product through trapping reaction parameters, the reaction of 2-aminopyridine
the carbenoid species.[5] Imidazo
ACTHNUTRGNE[NUG 1,2-a]pyridines have N-oxide and 1-chloro-3-ethynylbenzene was investi-
recently attracted significant interest in the pharma- gated.
ceutical industry as they exhibit antibacterial,[6] anti-
Gratifyingly, our initial efforts identified the use of
fungal,[7] antiviral,[8] and anti-inflammatory proper- 1.2 equiv. of pyridine N-oxide and 10 mol% of di-
ties.[9] The imidazo
ACTHNUTRGEN[UNG 1,2-a]pyridine ring system can be chloro(2-pyridinecarboxylato)gold [PicAuCl2] in di-
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Eric P. A. Talbot et al.
Scheme 1. Precedent using an intermolecular pyridine N-oxide and the new concept for imidazo
using a 2-aminopyridine N-oxide.
ACHTUNGTNER[NUNG 1,2-a]pyridine synthesis
chloromethane at room temperature as suitable con- tion of the sparingly insoluble starting pyridine N-
ditions for the reaction, giving a 43% conversion to oxide. This fact was particularly highlighted in the
the desired imidazoACHTUNGNRTE[NUG 1,2-a]pyridine 2 (entry 1 in case of para-nitrobenzoic acid (entry 5) where the for-
Table 1). Addition of 1 equivalent of MsOH improved mation of an insoluble salt resulted in no conversion
the conversion, with 71% of starting alkyne being to the product. The best conversion to product was
converted to the desired product. Alternative acids achieved using MsOH or TFA as the acid (entries 2
such as TFA, HNTf2, acetic acid and para-nitrobenzo- and 3). On the other hand, no product was formed in
ic acid were then tested and as previously noted, the absence of gold catalysts (entry 4).[20] Interestingly
faster reaction was seen on lowering of the pKa of the slow formation of the desired compound was ob-
acid.[2]
served when 0.5 equivalent of TFA was used
The acid appears to play a key role: this we believe (entry 7), and therefore 1 equivalent of TFA was
increases the reaction rate by promoting the dissolu- chosen for further studies. Dichloromethane proved
Table 1. Evaluation of reaction parameters.
Entry
Catalyst[a]
Additive
Conversion[b]
1
2
3
4
5
6
7
8
PicAuCl2
PicAuCl2
PicAuCl2
None
PicAuCl2
PicAuCl2
PicAuCl2
AuCl
None
43
71
70
none
none
72
54
33
MsOH (1 equiv.)
TFA (1 equiv.)
TFA (1 equiv.)
p-NO2C6H4CO2H (1 equiv.)
HNTf2 (1 equiv.)
TFA (0.5 equiv.)
TFA (1 equiv.)
TFA (1 equiv.)
TFA (1 equiv.)
TFA (1 equiv.)
TFA (1 equiv.)[c]
9
AuCl3
53
36
10
11
12
NHCAuNTf2
PPh3AuNTf2
PicAuCl2
36
89 (72)[d]
[a]
10 mol% of catalyst was used.
[b]
1
Determined by correlation between HPLC-MS and crude H NMR analysis using 3,5-dinitrobenzoic acid as internal stan-
dard.
[c]
[d]
The reaction mixture was heated at 408C for 15 h.
Isolated yield after column chromatography.
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Gold-Catalyzed Redox Synthesis of ImidazoACHTNUTRGNEUNG[1,2-a]pyridines
Scheme 2. Scope of reaction with substitution possible on all positions of the pyridine N-oxide and various terminal alkynes.
The yields were determined after column chromatography or preparative HPLC.
to be the solvent of choice; toluene, chlorobenzene alysts were screened during the optimization of the
and 1,2-dichloroethane did not give any product and catalyst: platinum and copper catalysts failed to pro-
other solvents were screened but none produced duce any of the desired product[22] and gold(I) cata-
a better conversion than dichloromethane.[21] The con- lysts, such as AuCl and Ph3PAuNTf2 (entries 8 and
centration of the reaction mixture appeared not to 11), generally reacted sluggishly and produced many
affect the reaction rate. Various alternative metal cat- impurities. Finally, heating the reaction mixture to
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Eric P. A. Talbot et al.
408C for 15 h gave the desired product 2 in 72% yield of the pyridine N-oxide to the alkyne is promoted by
(89% conversion). complexation to the gold catalyst. The resulting vinyl-
After establishing the optimal conditions, we at- gold intermediate can rearrange to form a gold-carbe-
tempted to delineate the scope of the functionalities noid intermediate.[24] This intermediate may form a-
tolerated (Scheme 2).
Pleasingly, the reaction conditions were tolerant of be converted to imidazoCATHNUGTRNE[NGU 1,2-a]pyridine; however, nei-
chloro and a-mesylate ketones[25] that are known to
various functional groups using alkylalkyne as well as ther of these a-functionalized ketones were detected
arylalkyne substrates where electron-rich and elec- in our investigations. In contrast, the mass consistent
tron-poor arylalkynes give the desired imidazoACTHNUTRGNE[UNG 1,2- with the proposed pyridinium intermediate in
a]pyridines in good conversions. Predictably, the elec- Scheme 3 was identified by crude LC-MS analysis of
tron-poor substrates were the best, as the alkyne was the reaction mixture. This species can be generated
more susceptible to nucleophilic attack from 2-amino- either by reaction of a gold carbenoid with a newly
pyridine N-oxide 1. Further heteroatom density was generated aminopyridine, or from direct rearrange-
tolerated, with 3-ethynylthiophene affording the de- ment of a vinylgold precursor.[26] Finally, condensation
sired product 9 in good yield whereas the reaction of of the amine and the generated ketone formed from
3-ethynylpyridine and 3-ethynylquinoline proceeded the pyridinium intermediate furnishes the imidazo-
in lower yields, to give 8 and 10, respectively, presum-
ACHTUNGTRENNUNG
ably due to nitrogen coordination to the gold catalyst.
We also noted that conversions were dependent on tive, atom economic synthesis of imidazoACTHUNGTRENNNUG
ACHTUNGTRENNUNG
noted that 1-ethynyl-2,4,6-trimethylbenzene and 3,3- a]pyridine ring without loss of stereochemical integri-
dimethylbut-1-yne did not produce any product ac- ty. Many functional groups are tolerated in the reac-
1
cording to crude H NMR analysis. Our preliminary tion which can conducted under mild conditions
data suggest that the pyridine reactant is tolerant of either at room temperature or more optimally at
substitution in all positions with the 6-methylpyridine reflux in dichloromethane: the reaction provides com-
N-oxide giving a significantly poorer conversion to plex core targets quickly from the vast array of com-
product when compared with the 3-methyl derivative. mercially available alkynes.
Our initial hypothesis that the efficient and mild reac-
tion conditions would be applicable to chiral alkynes
was validated by the formation of Boc-protected pro-
line derivative 17 in good yield and as a single diaste-
Experimental Section
reoisomer. Unfortunately disubstituted alkynes did
Typical Procedure
not produce any of the desired product.[23]
TFA (0.016 mL, 0.22 mmol) was added to a solution of 2-
aminopyridine N-oxide 1 (29.0 mg, 0.26 mmol) in CH2Cl2
(0.2M). The reaction mixture was stirred for 10 min, then
A mechanism for the formation of the imidazo
a]pyridine adducts is proposed in Scheme 3. Addition
ACHTUNGTNER[NUNG 1,2-
Scheme 3. Proposed mechanism for the formation of the imidazoACTHNUTRGNE[NUG 1,2-a]pyridine using gold catalysis.
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Gold-Catalyzed Redox Synthesis of ImidazoACHTNUTRGNEUNG[1,2-a]pyridines
alkyne (0.027 mL, 0.22 mmol) and PicAuCl2 (8.7 mg,
0.022 mmol) were added. After stirring overnight at 408C,
Et3N (20 mL) was added and the reaction mixture was con-
centrated under reduced pressure and purified by column
Andrei, O. Chavignon, J. C. Teulade, A. Kerbal, E. M.
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chromatography to give pure imidazo
yield: 36.2 mg (72%).
ACHTUNGTREN[NUGN 1,2-a]pyridine 2;
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We are grateful to H. Douglas for analytical support. The au-
thors thank the Novartis Education, Diversity and Inclusion
(ED&I) office for a presidential postdoctoral fellowship
(E.P.A.T.) and summer student funding (M. R.). F.D.T.
thanks NIHGMS (RO1 GM073932) for financial support.
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