Au(III)-catalyzed tandem amination - Hydration of alkynes: Synthesis of α-(N -2-pyridonyl)ketones

Article abstract of DOI:10.1021/ol203398e

A new Au(III)-catalyzed tandem amination - hydration reaction has been discovered, leading to the formation of α-(N-2-pyridonyl)ketones and heterocyclic analogues in good to excellent yields (14 examples, 48 - 90%). This reaction demonstrates the unusual use of a heterocyclic sp² nitrogen nucleophile in a gold-catalyzed 6-endo-dig cyclization. The tandem process allows rapid access to α-(N-2-pyridonyl)ketones, making them a convenient building block for the synthesis of more complex N-alkyl pyridone targets.

Full text of DOI:10.1021/ol203398e

ORGANIC
LETTERS
2012
Vol. 14, No. 3
874–877
Au(III)-Catalyzed Tandem
AminationꢀHydration of Alkynes:
Synthesis of r-(N-2-Pyridonyl)ketones
Nathan A. Romero, Benjamin M. Klepser, and Carolyn E. Anderson*
Department of Chemistry and Biochemistry, Calvin College, Grand Rapids,
Michigan 49546, United States
Carolyn.Anderson@calvin.edu
Received December 20, 2011
ABSTRACT
A new Au(III)-catalyzed tandem aminationꢀhydration reaction has been discovered, leading to the formation of R-(N-2-pyridonyl)ketones and
heterocyclic analogues in good to excellent yields (14 examples, 48ꢀ90%). This reaction demonstrates the unusual use of a heterocyclic sp2
nitrogen nucleophile in a gold-catalyzed 6-endo-dig cyclization. The tandem process allows rapid access to R-(N-2-pyridonyl)ketones, making
them a convenient building block for the synthesis of more complex N-alkyl pyridone targets.
Gold catalysis has emerged as a powerful method for
activating alkynes toward the addition of external
nucleophiles.1 These reactions benefit from the reduced
oxophilicity of gold cations relative to other transition
metals and the preference for alkyl-gold complexes to
undergo protodeauration rather than β-hydride elimin-
ation.2 Such characteristics allow for high functional
group tolerance and present an ideal platform for selective
amination of alkynes.3
First reported by Utimoto in 1987,4 both inter- and
intramolecular gold-catalyzed hydroaminations have
been demonstrated.5 However, heterocyclic sp2 nitrogens
have rarely been utilized as nucleophiles in these reac-
tions, as the resulting products would be unstable cationic
nitrogen species. Recent attempts to overcome this limit-
ation have encountered yield-limiting isomerizations6 or
the migration of nonconventional groups.7
2-Propargyloxypyridines 1 present an ideal system in
which to explore the addition of such nucleophiles to a
gold-activated alkyne, given the proximity of the nucleo-
philic sp2 pyridine nitrogen and the ability of the cationic
intermediate to undergo tautomerizationꢀrearrange-
ment to give N-alkyl pyridones (Scheme 1). The pre-
valence of N-alkyl pyridones in both natural products8
and pharmacologically relevant targets9 renders the
gold-assisted amination significant. In addition, while
several methods have been reported for initiating direct
O- to N-alkyl migration in 2-alkoxypyridine systems,10
(1) For recent reviews, see: (a) Shapiro, N. D.; Toste, F. D. Synlett
2010, 5, 675–691. (b) Wang, S.; Zhang, G.; Zhang, L. Synlett 2010, 5,
692–706. (c) Li, Z.; Brouwer, C.; He, C. Chem. Rev. 2008, 108, 3239–
3265. (d) Hashmi, S. K. Chem. Rev. 2007, 107, 3180–3211. (e) Arcadi, A.
Chem. Rev. 2008, 108, 3266–3325.
(6) Nakamura, I.; Yamagishi, U.;Song, D.;Konta, S.;Yamamoto, Y.
Angew. Chem., Int. Ed. 2007, 46, 2284–2287.
(7) (a) Seregin, I. V.; Gevorgyan, V. J. Am. Chem. Soc. 2006, 128,
12050–12051. (b) Seregin, I. V.; Schammel, A. W.; Gevorgyan, V. Org.
Lett. 2007, 9, 3433–3436.
(2) Shen, H. C. Tetrahedron 2008, 64, 3885–3903 and references
therein.
(3) Widenhoefer, R. A.; Han, X. Eur. J. Org. Chem. 2006, 20, 4555–
4563.
(4) Fukuda, Y.; Utimoto, K.; Nozaki, H. Heterocycles 1987, 25, 297–
300.
(5) Representative examples: (a) Zhang, Y.; Donahue, J. P.; Li, C.-J.
Org. Lett. 2007, 9, 627–630. (b) Mizushima, E.; Hayashi, T.; Tanaka, M.
Org. Lett. 2003, 5, 3349–3352.
(8) Representative examples: (a) Camptothecin alkaloids: Wall,
M. E.; Wani, M. C. J. Ethnopharmacol. 1996, 51, 239–253. (b) Lupin
alkaloids: Gray, D.; Gallagher, T. Angew. Chem., Int. Ed. 2006, 45,
2419–2423. (c) Mappicine: Govindachari, T. R.; Ravindranath, K. R.;
Viswanathan, N. J. Chem. Soc., Perkin Trans. 1 1974, 1215–1217.
(9) Representative examples: (a) Huffman, J. W.; Lu., J.; Hynd, G.;
Wiley, J. L.; Martin, B. R. Bioorg. Med. Chem. 2001, 9, 2863–2870. (b)
Parlow, J. J.; Kurumbail, R. G.; Stegeman, R. A.; Stevens, A. M.;
Stallings, W. C.; South, M. S. J. Med. Chem. 2003, 46, 4696–4701.
r
10.1021/ol203398e
Published on Web 01/11/2012
2012 American Chemical Society

and results in the addition of heteroatoms to both ends of the
alkyne. The formation of a viscinally substituted product is
unusual, given that the majority of other known gold-
catalyzed double additions to alkynes proceed to give pro-
ducts with geminal substitution patterns.15
Scheme 1. Predicted Pathways for Au(III)-Catalyzed Addition
Table 1. Reaction Optimization
concn
(M)
temp
time
(h)
yield
(%)a
entry
additive
(°C)
to our knowledge only one system to date enables direct
alkyne functionalization.11
1
2
3
4
5
6
7
8
9
0.12
0.12
0.12
0.24
0.95
0.95
0.95
0.95
0.95
ꢀ
rtb
rtb
40
80
80
80
80
80
80
24
24
72
72
21
21
21
21
21
NRc
NRc
11
1.0 equiv NEt3
1.0 equiv NEt3
1.0 equiv NEt3
1.0 equiv NEt3
1.5 equiv NEt3
0.30 equiv MeSO3H
20 wt % Dowex
1.5 equiv NEt3
20 wt % Dowex
1.5 equiv NEt3
20 wt % Dowex
1.5 equiv NEt3
20 wt % Dowex
We originally predicted that cyclization of pyridine 1
would proceed in a 5-exo-dig manner to give intermediate
2, given the prevalence of 5-exo-dig cyclizations in gold-
catalyzed alkynyl additions.2 Pyridinium ion 2 could then
rearrange to N-alkenyl pyridone 3, as has been previously
observed in our laboratory (Scheme 1).11 Alternatively, if
intramolecular addition occurred in the less common
6-endo-dig fashion, the pyridone product 5 would display
N-alkylation at the distal position (carbon 3).12 Forma-
tion of either product would demonstrate the successful
addition of a heterocyclic sp2 nitrogen nucleophile to an
activated alkyne. As such, efforts to develop this trans-
formation were undertaken.
28
15
63
30
48
75
10
11
0.95
0.95
90
21
21
82
89
100
a Isolated yield. b rt = room temperature. c NR = no reaction.
Pursuant to numerous examples of gold-catalyzed
alkyne amination, NaAuCl4•2H2O was selected as a
catalyst and aqueous EtOH was utilized as the solvent
for preliminary studies (Table 1).2,13 Initial efforts, how-
ever, were unsuccessful, as treatment of pyridine 1a with
5 mol % NaAuCl4•2H2O at room temperature gave only
starting material (entry 1). Given that nitrogen bases have
been observed to increase the catalytic efficiencyof Au(III),
NEt3 was explored as an additive.14 Again, no reaction was
observed at ambient temperature; however, when the reac-
tion was warmed to 40 °C, unexpected R-(N-2-pyridonyl)-
ketone 6a was isolated exclusively, albeit in only 11% yield
(entries 2 and 3). The formation of ketone 6a from
2-propargyloxypyridine 1a occurs via a 6-endo-dig cyclization
Given the unique structure and potential utility of
ketone 6a, optimization studies were pursued. Increasing
the concentration, temperature, and amount of NEt3
were found to improve the reaction efficiency, affording
product 6a in up to 63% yield after 21 h (entries 4ꢀ6).
After additional attempts to optimize these variables led
to no further improvement in yield, a Brønsted acidic
additive was evaluated as an alternative. Previous reports
suggest that many gold-catalyzed reactions are enhanced
by Brønsted acids, as they generally aid in proto-
deauration.16 When the reaction was performed in the
presence of MeSO3H, TLC analysis indicated significant
formation of pyridone 6a; however, when the crude
residue was concentrated in vacuo, rapid decomposition
of the product was observed (entry 7). To circumvent this
problem, acidic Dowex resin was employed, as it could
be easily removed prior to concentration (entry 8). While
the yield of product 6a initially decreased in the presence
of Dowex relative to that observed with NEt3, when
both additives (NEt3 and Dowex) were employed
(10) (a) Lanni, E. L.; Bosscher, M. A.; Ooms, B. D.; Shandro, C. A.;
Ellsworth, B. A.; Anderson, C. E. J. Org. Chem. 2008, 73, 6425–6428. (b)
Yeung, C. S.; Hsieh, T. H. H.; Dong, V. M. Chem. Sci. 2011, 2, 544–551.
(c) Rodrigues, A.; Lee, E. E.; Batey, R. A. Org. Lett. 2010, 12, 260–263.
(11) Tasker, S. Z.; Brandsen, B. M.; Ryu, K.-A.; Snapper, G. S.;
Staples, R. J.; DeKock, R. L.; Anderson, C. E. Org. Lett. 2011, 13, 6224–
6227.
(12) Addition to the distal position of the alkyne has been observed in
Au-catalyzed reactions of propargylic esters; see: Marion, N.; Nolan,
S. P. Angew. Chem., Int. Ed. 2007, 46, 2750–2752.
(13) (a) Arcadi, A.; Di Giuseppe, S.; Marinelli, F.; Rossi, E. Adv.
Synth. Catal. 2001, 343, 443–446. (b) Arcadi, A.; Di Giuseppe, S.; Rossi,
E. Tetrahedron: Asymmetry 2001, 12, 2715–2720. (c) Arcadi, A.; Bianchi,
G.; Marinelli, F. Synthesis 2004, 4, 610–618.
(15) (a) Teles, J. H.; Brode, S.; Chabanas, M. Angew. Chem., Int. Ed.
1998, 37, 1415–1418. (b) Antoniotti, S.; Genin, E.; Michelet, V.; Genet,
J.-P. J. Am. Chem. Soc. 2005, 127, 9976–9977. (c) Belting, V.; Krause, N.
Org. Lett. 2006, 8, 4489–4492. (d) Li, Y.; Zhou, F.; Forsyth, C. J. Angew.
Chem., Int. Ed. 2007, 46, 279–282.
(14) Ritter, S.; Horino, Y.; Lex, J.; Schmalz, H. G. Synlett 2006,
3309–3313.
(16) Hashmi, A. S. K. Catal. Today 2007, 122, 211–214and references
therein.
Org. Lett., Vol. 14, No. 3, 2012
875

simultaneously, pyridone 6a could be isolated in up to 89%
yield (entries 9ꢀ11). It is believed that NEt3 may act as a
ligand for Au(III); however, given that superstoichiometric
NEt3 is optimal, the amine may also play a role in
buffering the reaction. Gold-catalyzed reactions requir-
ing both a basic site for nucleophilic addition and an
acidic environment for successful protodeauration are
precedented.16 At this point, other low molecular weight
alcohols and different amounts of water (0%ꢀ10%) were
evaluated as solvents, but no improvement in yield was
observed (see Supporting Information). Reactions per-
formed in the presence of one or both additives (NEt3
and/or Dowex), but in the absence of NaAuCl4•2H2O,
resulted in the isolation of only starting material, con-
firming that Au(III) is playing a central role in catalyzing
these reactions.16
It is proposed that ketone 6a forms via the mechanism
shown in Scheme 2. Initial alkyne coordination to the
metal center, followed by nucleophilic addition of the
pyridine nitrogen in a 6-endo-dig manner, would provide
vinyl-gold intermediate 8. In a similar system, Tanaka
concluded that coordination of nitrogen to the gold center
was likely followed by inner-sphere CꢀN bond forma-
tion.5b This suggests that, in the present case, the pyridine
nitrogen may act as a directing group. Elimination of gold
would then give allenamide 9. Subsequent hydration of
the allene can then proceed via acid-accelerated, second-
ary catalytic activity of the gold complex or by a direct
acid-promoted hydration.17 Further mechanistic studies
are currently underway in our laboratory.
Table 2. Formation of N-Alkyl Pyridones 6
yield
entry substrate
R
R0
product (%)a
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
n-pentyl
CH2CH2Ph
Cy
H
6a
6b
6c
6d
6e
6f
89
81
76
82
84
ꢀ
H
H
Ph
H
(CH2)2OTIPS
CH2OTIPS
Et
H
H
1g
1h
Me
6g
6h
75
53
n-butyl
CH2CH(CH3)2
a Isolated yields. Mean values from multiple experiments ((3%).
systems,10c cyclohexyl- and phenyl-substituted substrates
1c and 1d revealed no such decrease in reactivity, yielding
pyridones 6c and 6d in 76% and 82% yields, respectively
(entries 3 and 4). Conversely, inclusion of a silyl ether was
met with mixed results. While silyl ether 1e underwent
clean conversion to pyridone 6e in 84% yield, homologue
1f was found to decompose, giving only 2-pyridone,
under the reaction conditions (entries 5 and 6). The failure
of silyl ether 1f to undergo the aminationꢀhydration
reaction may be due to its ability to form an R,β-unsat-
urated goldꢀcarbene complex upon β-elimation of the
silyl ether, as recently observed in an analogous platinium-
catalyzed system.18
More complex ketones can also be prepared in this way
if substitution is included at the propargylic position of
alkyne 1. For example, subjecting R-methyl and R-iso-
butyl pyridines 1g and 1h to the reaction conditions
affords the corresponding extended ketones in 75% and
53% yields, respectively (entries 7 and 8).
Scheme 2. Proposed Mechanism for the Tandem
AminationꢀHydration of 2-Propargyloxypyridines 1
Extension of the tandem aminationꢀhydration to the
synthesis of N-heterocyclic analogues 11 also proceeded
in good to excellent yields (Table 3). Methyl-substituted
substrates 10a and 10b gave the corresponding ketones
in 68% and 80% yields, respectively (entries 1 and 2).
Bromopyridine 10c also underwent rearrangement, afford-
ing product 11c in 70% yield; however in this case, the
dehalogenated pyridone 6a was also observed (entry 3).
Sterically encumbered quinoline 10d and isoquinoline 10e
also reacted smoothly to give the corresponding ketones
11d and 11e in excellent yields (entries 4 and 5). By con-
trast, however, pyrazine 10f reacts sluggishly, giving only
48% yield of product 11f after 21 h (entry 6). This attenu-
ated reactivity is thought to be a result of unproductive
gold coordination to the nitrogen at the 4-position of
the pyrazine.
Under the optimized reaction conditions a variety of
substituted 2-propargyloxypyridines 1 were evaluated in
the aminationꢀhydration reaction (Table 2). The method
proved to be robust with respect to both alkyl and aryl
substituted substrates (entries 1ꢀ4). While attenuated
yields have previously been observed in sterically crowded
(17) (a) Cramer, P.; Tidwell, T. T. J. Org. Chem. 1981, 46, 2683–2686.
(b) Rafizadeh, K.; Yates, K. J. Org. Chem. 1984, 49, 1500–1506. (c)
Smadja, W. Chem. Rev. 1983, 83, 263–320.
(18) Saito, K.; Sogou, H.; Suga, T.; Kusama, H.; Iwasawa, N. J. Am.
Chem. Soc. 2011, 133, 689–691.
876
Org. Lett., Vol. 14, No. 3, 2012

In the case of 2-quinolone 11d, the hindered CꢀN bond
rotation can be observed clearly by 1H NMR, where no
signal for methine proton H-3 is observed at room
temperature in CDCl3 and the signal for quinolone pro-
ton H-80 is broad and lacks evidence of spin coupling
(Table 3, entry 4). As the temperature is increased, the
H-3 signal becomes evident at ∼5.9 ppm and enhanced
splitting can be observed in the H-80 resonance.20 Com-
putational studies conducted at the B3LYP/6-31G(d)
level of theory predict the barrier to rotation around
the CꢀN bond in 2-quinolone 11d to be 13.98 kcal/mol
(ΔGcalc).21,22 Given these results, substituted quinolone
analogues are expected to exhibit enhanced rotameric
stability and are therefore being evaluated in our
laboratory.
Table 3. Formation N-Alkyl Heterocycles 11
In summary, we have developed a method for the
conversion of 2-propargyloxypyridines 1 and hetero-
cycles 10 into a new class of R-(N-2-pyridonyl)ketones
and heterocyclic analogues in good to excellent yields. By
exploiting the bench stability and alkynophilicity of
NaAuCl4•2H2O, an unprecedented tandem aminationꢀ
hydration of an alkyne by a heterocyclic sp2 nitrogen
nucleophile has been accomplished. Studies directed at an
asymmetric variant of this reaction are currently under-
way in our laboratory.
Acknowledgment. This work was supported by the
National Science Foundation under CHE-0911264 and
awards from the Research Corporation for Science Ad-
vancement, the Arnold and Mabel Beckman Foundation
Scholars Program, and Calvin College. Computer hard-
ware and NMR spectrometers were provided by Major
Research Instrumentation grants of the National Science
Foundation under OCI-0722819 and CHE-0922973. We
thank Drs. J. Greaves (UC-Irvine) and C. D. Anderson
(Pleotint, LLC) for work in support of this project and a
reviewer for bringing several important references to our
attention.
Supporting Information Available. Representative ex-
perimental procedures, additional optimization studies,
a Isolated yields. Mean values from multiple experiments ((3%).
1
computational studies, H and 13C NMR spectra for all
new compounds, and VT and 2D NMR spectra for
2-quinolone 11d. This material is available free of charge
via the Internet at http://pubs.acs.org.
Hindered rotation around the CꢀN bond in these
systems serves to generate transitory axial chirality.19
(21) For full compuational studies and references, see Supporting
Information.
(22) Comparable studies on BINOL have shown its barrier to rota-
tion to be 37.8 kcal/mol. See: Meca, L.; Reha, D.; Havlas, Z. J. Org.
Chem. 2003, 68, 5677–5680.
(19) Kumarasamy, E.; Jesuraj, J. L.; Omlid, J. N.; Ugrinov, A.;
Sivaguru, J. J. Am. Chem. Soc. 2011, 133, 17106–17109.
(20) For full variable temperature NMR studies, see Supporting
Information.
Org. Lett., Vol. 14, No. 3, 2012
877