Divergent product selectivity in gold- versus silver-catalyzed reaction of 2-propynyloxy-6-fluoropyridines with arylamines

Article abstract of DOI:10.1021/ol500939v

A study of the reaction of easily accessible 2-propynyloxy-6- fluoropyridines with arylamines under gold or silver catalysis is described. It has been shown that two types of isomeric oxazolopyridine imine derivatives, which represent unusual heterocyclic motifs, can be selectively obtained in moderate to excellent yields depending on the nature of the metal employed.

Full text of DOI:10.1021/ol500939v

Letter
pubs.acs.org/OrgLett
Divergent Product Selectivity in Gold- versus Silver-Catalyzed
Reaction of 2‑Propynyloxy-6-fluoropyridines with Arylamines
Colombe Gronnier, Pierre Faudot dit Bel, Guilhem Henrion, Søren Kramer, and Fabien Gagosz*
̀
Laboratoire de Synthese Organique, UMR 7652 CNRS/Ecole Polytechnique, Ecole Polytechnique, 91128 Palaiseau, France
S
* Supporting Information
ABSTRACT: A study of the reaction of easily accessible 2-propynyloxy-6-fluoropyridines with arylamines under gold or silver
catalysis is described. It has been shown that two types of isomeric oxazolopyridine imine derivatives, which represent unusual
heterocyclic motifs, can be selectively obtained in moderate to excellent yields depending on the nature of the metal employed.
Scheme 1. Potential Reactivity of 2-Propynyloxypyridines 1
under Au Catalysis by Analogy with the Chemistry of
Propargylic Carboxylates 5
fter 10 years of intensive development, homogeneous gold
catalysis1 can now be rightfully considered as a synthetic
A
tool of choice for the nucleophilic functionalization of carbon
π-systems. Indeed, electrophilic gold species have proven to
generally outperform the capacity of other metal catalysts in
this field. If cheaper silver salts can be used as substitutes to
gold in a limited number of transformations,2 they however do
not allow the same reaction diversity and are generally less
efficient and/or selective. Of the characteristic features of this
typical gold-catalyzed transformation, the possibility of employ-
ing a large variety of carbon-, nitrogen-, oxygen-, or sulfur-based
species as suitable nucleophilic partners is perhaps one of the
most valuable. In this respect, we recently realized that the
pyridine motif had received very little attention.3 This might
appear as relatively surprising when one considers the large
number of gold-catalyzed transformations involving the
nucleophilic addition of aromatic compounds or nitrogen
species to a carbon π-system that have been reported. Such a
situation may however be partly explained by the reduced
nucleophilicity of the pyridine ring when compared to aryl
derivatives, making the Friedel−Crafts type reaction more
difficult. The few gold-catalyzed transformations described to
date all involve an intra- or intermolecular initial attack of the
pyridine (or by extension azine) sp2 nitrogen atom onto a gold-
activated alkyne.3 In this context and following our continuous
interest in gold catalysis,4 we were interested in investigating
the general reactivity of the pyridine motif and more specifically
the chemistry of 2-propynyloxypyridines 1 (Scheme 1).
2-Propynyloxypyridines 1 were chosen for the following
reasons: (a) they are easily accessible by an SNAr reaction
between the commercially available 2,6-difluoropyridine 2 and a
propargylic alcohol 3;5 (b) they can be considered as stable
analogues of propargylic imidates 4 which have been rarely
studied in gold catalysis, probably due to their lability;6 and (c)
they should share some common reactivity modes with
propargylic carboxylates 5 under gold catalysis.7 We indeed
surmized that, by analogy with the chemistry of 5 (Scheme 1,
eq 1), 2-propynyloxypyridines 1 could rearrange into the 1,2-
Received: February 4, 2014
Published: April 10, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
pyridinoxy shift gold carbenoid product 6 or into the gold-
coordinated N-allenyl pyridone 7 via a 3,3-rearrangement8 and
that these potential intermediates could then be trapped by a
nucleophilic species. We report herein some preliminary results
of our studies regarding the reaction of 1 with arylamines in the
presence of a gold or a silver catalyst.9
led however to a reduced reaction rate which could be
remarkably enhanced by working under microwave irradiation
(entry 9). Under these conditions, the isomeric oxazolopyridine
imine 9a could be obtained in an optimal 91% isolated yield.14
Given the novelty of this reaction and the possibility to
selectively produce some unusual heterocyclic oxazolopyridine
motifs of type 8a or 9a, we deciced to explore its scope. The
two sets of experimental conditions noted in entries 1 and 9 of
Table 1 were retained for this purpose. We first focused our
attention on the variation of the amine nucleophilic partner in
the reaction of alkynyl substrate 1a. As seen from the results
compiled in Table 2, the reaction can be applied to a variety of
arylamines and the corresponding oxazolopyridine imines 8a−j
and 9a−j were obtained in moderate to good yields. The
transformation is compatible with the presence of various
aromatic substituents such as halogen atoms (entries 2−4) as
well as electron-donating (entries 5, 6) and electron-with-
drawing groups (entries 7, 8). Under gold catalysis, a limit in
reactivity was observed in the cases of 2-pyridylamine and
benzylamine (entries 11, 12) as the corresponding compounds
could not be formed. In contrast, the isomeric oxazolopyridine
imines 9k and 9l were produced under silver catalysis (entries
11, 12). However, they proved to be instable and could not be
isolated.
Our study started with alkyny1 substrate 1a. In a first
10
attempt, 1a was reacted with [(Ph3P)Au]NTf2 (5 mol %) in
chloroform (60 °C) and in the presence of aniline (2.1 equiv)
as a potential nucleophilic partner. A completely unexpected
result was obtained: 1a was indeed cleanly converted after 7 h
of reaction into oxazolopyridine imine 8a, which was isolated in
an excellent 97% yield (Table 1, entry 1).11 The reaction
Table 1. First Attempted Reaction with 1a and Optimization
of the Catalytic Systems towards the Selective Formations of
a
8a and 9a
We then examined the possibility of using 2-propynyloxy-
pyridines with different substitution patterns. As seen in Table
3, this chemistry can be applied with the same efficiency to the
synthesis of the isomeric oxazolopyridine imines 8m−r and
9m−r from substrates 1b−g. It should be noted that substrates
1b,c,e possessing two substituents of a different nature at the
propargylic position lead to the formation of compounds
9m,n,p as E/Z mixtures of isomers. A ketal (entry 5) and a
carbamate (entry 6) also survive the experimental conditions,
thus expanding the functional group compatibility. When aryl-
and alkyl-substituted alkynes 1h and 1i were reacted under gold
or silver catalysis, no oxazolopyridine imines of type 8 or 9
could be obtained. Instead, the reactions delivered respectively
allenes 11a and 11b, which could not be further transformed
even after a prolonged reaction time. A series of others
functionalized allenes 11c−e could be similarly obtained from
alkynes 1j−l.
A mechanistic overview that accounts for the observed
reactivities of 2-propynyloxypyridines 1 under Au or Ag
catalysis and in the presence of arylamines is proposed in
Scheme 2. Some similarities with the behavior of the analogous
propargylic carboxylates 5 can be noted. Indeed, both 5-exo and
6-endo Au- or Ag-induced cyclizations of 1 into intermediates
12 and 13 respectively seem to be possible.7 From
fluoropyridinium 12, one can explain the formation of the
oxazolopyridine imines 8 by a sequence of nucleophilic
trapping by an arylamine followed by a loss of HF and a
protodemetalation step (path A: 1 → 12 → 8).15 An alternative
reaction pathway (path C: 1 → 14 → 8) involving an initial
aromatic subtitution of the fluoride atom by the arylamine can
be ruled out. Indeed, 17 which lacks the alkyne moiety did not
lead to the formation of 18 under the typical experimental
conditions allowing the formation of 8 (bottom part of Scheme
2). Regarding the formation of the isomeric oxazolopyridine
imines 9, the N-allenyl pyridone intermediate 15, resulting from
the 3,3 rearrangement of 1 (path B: 1 → 13 → 15),16 first
undergoes a rare 5-endo cyclization at the central carbon of the
allene.17 This would generate the intermediate fluoropyridi-
nium 16 which, similarly to case of 12, would then react with an
a
b
Substrate concentration: 0.2 M. Au catalysts, 5 mol %; AgNTf2, 10
c
1
mol %. Determined by H NMR spectroscopy of the crude reaction
mixture. Isolated yields unless otherwise stated. Ar = 2,6-(t-Bu)2-
C6H3. NMR yields. Not determined. Substrate concentration: 0.05
M. No reaction observed.
d
e
f
g
h
i
proved to be less efficient when it was performed with a
reduced amount of aniline (1.1 equiv) and in the presence of an
inorganic base (1.1 equiv) to trap the HF formed as a
coproduct in the coupling process leading to 8a (entry 2). All
attempts to reduce the reaction time by employing a different
gold catalyst were unsucessful (entries 3−5).12 Interestingly,
when [(IAd)Au]NTf2 and [(ArO)3PAu]NTf2 were used, the
transformation was not selective, and the N-allenylpyridine 10
(entry 4) or the isomeric oxazolopyridine imine 9a (entry 5)
was formed alongside 8a. A low selectivity was also obtained
when the reaction was attempted with the simple AgNTf2 salt
(10 mol %, entry 6). While every attempt to selectively produce
compound 8a using AgNTf2 as the catalyst unfortunately failed,
we were however able to optimize the catalytic system toward
the formation of the isomeric compound 9a. When the quantity
of aniline was limited to 1.1 equiv and Na2CO3 (1.1−4.0
equiv)13 was added as a potential HF scavenger, the formation
of 9a was indeed favored (entries 7 and 8). This modification
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Letter
Table 2. Substrate Scope: Variation of the Amine
a
b
conditions A (Au)
conditions B (Ag)
c
c
entry
R
product
time
yield
product
time
yield
1
C6H5
8a
8b
8c
8d
8e
8f
7 h
14 h
17 h
5 h
97%
79%
84%
84%
74%
82%
9a
9b
9c
9d
9e
9f
1 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
91%
98%
36%
43%
64%
44%
60%
39%
46%
50%
50%
71%
2
4-F(C6H4)
3
4-Br(C6H4)
3-I(C6H4)
4
5
3-MeO(C6H4)
4-MeO(C6H4)
4-NO2(C6H4)
3-CF3(C6H4)
2,3-Me2(C6H3)
2-naphthyl
36 h
10 h
72 h
7.5 h
7.5 h
12 h
24 h
6
d
7
8g
8h
8i
45%
75%
80%
81%
0%
9g
9h
9i
8
9
e
e
e
10
11
12
8j
9j
2-pyridyl
8k
81
9k
91
benzyl
24 h
0%
a
b
[(Ph3P)Au]NTf2 (5 mol %), RNH2 (2.1 equiv), CHCl3 (0.2 M, 60 °C). AgNTf2 (10 mol %), RNH2 (1.1 equiv), Na2CO3 (4 equiv), CHCl3 (0.05
c
d
e
M, μw 100 °C). Isolated yields. 60% conversion. Estimated NMR yields (unstable compounds which could not be isolated).
Table 3. Substrate Scope: Variation of the Alkynyl
Substrate
Scheme 2. Mechanistic Proposal for the Reaction of 1 with
Arylamines under Au and Ag Catalysis
a
a
[(Ph3P)Au]NTf2 (5 mol %), RNH2 (2.1 equiv), CHCl3 (0.2 M, 60
b
°C). AgNTf2 (10 mol %), RNH2 (1.1 equiv), Na2CO3 (4 equiv),
CHCl3 (0.05 M, μw 100 °C). Isolated yields. E/Z selectivity from
1:1 to 1:1.6 (see Supporting Information). With aniline instead of 4-
fluoroaniline. Without aniline.
c
d
e
f
arylamine to ultimately deliver 9 after the loss of HF and
regeneration of the catalyst. While both oxazolopyridine imines
8 and 9 could be accessed under either gold or silver catalysis
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Organic Letters
Letter
Rottlander, M.; Gagosz, F.; Skrydstrup, T. Angew. Chem. Int. Ed 2011,
50, 5090.
̈
(see Table 1), the use of a gold catalyst seems to favor the
formation of 8 via path A, and the use of a silver catalyst, the
formation of 9 via path B.
(5) For recent examples of the use of 2-oxy-6-fluoropyridine
derivatives, see: (a) Charrier, N.; Quiclet-Sire, B.; Zard, S. Z. J. Am.
Chem. Soc. 2008, 130, 8898. (b) Braun, M.-G.; Quiclet-Sire, B.; Zard,
S. Z. J. Am. Chem. Soc. 2011, 133, 15954.
(6) (a) Hashmi, A. S. K.; Rudolph, M.; Schymura, S.; Visus, J.; Frey,
W. Eur. J. Org. Chem. 2006, 4905. (b) Kang, J.-E.; Kim, H.-B.; Lee, J.-
W.; Shin, S. Org. Lett. 2006, 8, 3537. (c) Huang, X.; Zhang, L. J.
Organomet. Chem. 2009, 694, 520.
(7) For reviews on Au-catalyzed reactions of propargylic carboxylates,
see: (a) Wang, S.; Zhang, G.; Zhang, L. Synlett 2010, 692. (b) Marion,
N.; Nolan, S. Angew. Chem., Int. Ed. 2007, 46, 2750. (c) Marco-
Contelles, J.; Soriano, E. Chem.Eur. J. 2007, 13, 1350.
(8) For the use of the 2-oxypyridine moiety as a 3,3-migrating group,
see for instance: With Au: Reference 3c. With Pd: (a) Rodrigues, A.;
Lee, E. E.; Batey, R. A. Org. Lett. 2010, 12, 260. (b) Itami, K.;
Yamazaki, D.; Yoshida, J.-I. Org. Lett. 2003, 5, 2161. With Pt, Sn:
(c) Stewart, H. F.; Seibert, R. P. J. Org. Chem. 1968, 33, 4560.
(9) To the best of our knowledge, there is only a single report on a
gold-catalyzed transformation of 2-propargyloxypyridines (ref 3c).
In conclusion, we have studied the reaction of 2-
propynyloxy-6-fluoropyridines with arylamines under gold and
silver catalysis. These substrates were shown to share some
common reactivity modes with propargylic carboxylates. Two
sets of catalytic conditions have been developed that allow the
divergent and selective synthesis of two types of isomeric
oxazolopyridine imines. A series of these unusual heterocyclic
motifs possessing various commonly employed functional
groups could be produced in moderate to excellent yields.
Further studies on the extension of this chemistry to the
synthesis of other heterocyclic motifs by the reaction of 2-
propynyloxypyridines with other nucleophilic partners are
underway.
ASSOCIATED CONTENT
* Supporting Information
■
S
́
(10) Mezailles, N.; Ricard, L.; Gagosz, F. Org. Lett. 2005, 7, 4133.
Experimental procedures and spectral data for new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(11) The core structures of 8a and 9a were confirmed by X-ray
diffraction studies performed on analogous compounds.
(12) The catalytic conditions noted in entry 3 were not retained in
the study of the scope and limitations, because the [(XPhos)Au]NTf2
complex is significantly more expensive than the simple [(Ph3P)Au]
NTf2.
AUTHOR INFORMATION
Corresponding Author
■
(13) The exact role played by the Na2CO3 salt remains unclear.
(14) No reaction was observed in the absence of a gold or silver
catalyst.
(15) Cheng, D.; Croft, L.; Abdi, M.; Lightfoot, A.; Gallagher, T. Org.
Lett. 2007, 9, 5175.
*E-mail: gagosz@dcso.polytechnique.fr.
Notes
The authors declare no competing financial interest.
(16) No evidence was found regarding a possible reversibility of the
3,3-rearrangment pathway (1→15): reaction of 15 under gold catalysis
and in the presence of ArNH2 did not furnish 8.
(17) For Au-catalyzed nucleophilic additions on the central carbon of
allenes, see for instance: (a) Buzas, A. K.; Istrate, F. M.; Gagosz, F. Org.
Lett. 2007, 9, 985. (b) Winter, C.; Krause, N. Angew. Chem., Int. Ed.
2009, 48, 6339. (c) Hashmi, A. S. K.; Schuster, A. M.; Litters, S.;
Rominger, F.; Pernpointner, M. Chem.Eur. J. 2011, 17, 5661.
ACKNOWLEDGMENTS
■
We are deeply appreciative of generous financial support from
the Ecole Polytechnique (C.G., G.H., and S.K.), ANR (P.F.),
the Carlsberg Foundation, the Danish National Research
Foundation, H. Lundbeck A/S, the OChem graduate school,
and Aarhus University (S.K.). The authors thank Dr. X. F. Le
Goff (Ecole Polytechnique) for X-ray analysis and Dr. F. Metz
(Rhodia Chimie Fine) for a generous gift of HNTf2.
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