Silver(I)-catalyzed addition-cyclization of alkyne-functionalized azomethines

Article abstract of DOI:10.1021/ol4000108

AgOTf can catalyze an addition-cyclization tandem between alkyne-azomethine and a nucleophile such as ketone, nitroalkane, water, and terminal alkyne to give a polycyclic amide via six-exo-trig selectivity.

Full text of DOI:10.1021/ol4000108

ORGANIC
LETTERS
2013
Vol. 15, No. 4
874–877
Silver(I)-Catalyzed Addition-Cyclization
of Alkyne-Functionalized Azomethines
Yuchen Liu,†,‡ Wencui Zhen,† Wei Dai,‡ Fen Wang,† and Xingwei Li*,†
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023,
China and College of Chemistry and Life Sciences, Zhejiang Normal University,
Jinhua 321004, China
xwli@dicp.ac.cn
Received January 2, 2013
ABSTRACT
AgOTf can catalyze an addition-cyclization tandem between alkyne-azomethine and a nucleophile such as ketone, nitroalkane, water, and terminal
alkyne to give a polycyclic amide via six-exo-trig selectivity.
Alkynes are widely used in synthetic chemistry and it has
been well documented that, upon coordination to metals
suchasAu(I), Au(III), Pt(II), Pd(II), Ag(I) andI(I), alkynes
are susceptible to nucleophilic attack, leading to cyclization
reactions.1 Such a metal-induced process has played an
important role in the synthesis of complex synthetic targets.
Compared to the vast majority of gold-catalyzed hetero-
cyclization of alkynes, related Ag(I)-catalyzed reactions are
less common, although silver catalysts are generally more
cost-effective and can offer complementary reactivity and
higher functional group compatibility.1i,j,2 When an ortho
alkyne-functionalized aldehyde was applied as a substrate
in the presence of an external nucleophile (NuH) such as an
alcohol, nucleophilic addition of the aldehyde to alkyne can
trigger a further addition of the NuH to the carbonyl group,
giving rise to cyclization with additional functionalization.2f,3
Despite the success, this type of reactivity has been mostly
observed for alkyne-tethered carbonyl compounds and in
most cases endo cyclization selectivity was followed.2k Thus
alkyne-functionalizaed imines have been less explored.4 In
order to further explore and expand the utility of Ag(I)
catalysis in cyclization reactions for molecular diversity and
complexity, it is necessary to broaden the scope of both the
alkyne-imine and the external nucleophile substrates.
† Chinese Academy of Sciences.
‡ Zhejiang Normal University.
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3149.
We recently reported rhodium-catalyzed CÀH activa-
tion of azomethine imines derived from arylaldehydes,5
(2) For selected reports on Ag(I)-catalyzed cyclization of alkynes, see
(a) Bantreil, X.; Vaxelaire, C.; Godet, T.; Parker, E.; Sauer, C.; Belmont,
P. Org. Biomol. Chem. 2011, 9, 4831. (b) Dell’Acqua, M.; Abbiati, G.;
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Zeng, M.; Yuan, J.; Yang, Q.; Peng, Y. Org. Lett. 2012, 14, 3588. (i) Niu,
Y.-N.; Yan, Z.-Y.; Gao, G.-L.; Wang, H.-L.; Shu, X.-Z.; Ji, K.-G.;
Liang, Y.-M. J. Org. Chem. 2009, 74, 2893. (j) Zhang, X.; Liu, B.; Shu,
X.; Gao, Y.; Lv, H.; Zhu, J. J. Org. Chem. 2012, 77, 501. For a recent
report on silver-catalyzed 6-exotrig cyclization, see: (k) Ishida, T.;
Kikuchi, S.; Tsubo, T.; Yamada, T. Org. Lett. 201310.1021/ol303534w.
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Soc. 2004, 126, 7458. (e) Asao, N.; Nogami, T.; Lee, S.; Yamamoto, Y.
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Takaya, J.; Iwasawa, N. Org. Lett. 2004, 6, 605.
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r
10.1021/ol4000108
Published on Web 02/07/2013
2013 American Chemical Society

where the anionic nitrogen acts as an efficient directing
group. We now report Ag(I)-catalyzed nucleophilic
addition-cyclization between azomethine-alkynes and dif-
ferent nucleophiles. A series of heterocycles bearing an
exocyclized CdC bond have been constructed via a selec-
tive 6-exo-dig cyclization pathway.
The NÀO bond in nitros, nitrones, and amine N-oxides
are known to undergo gold-catalyzed inter- and intra-
molecular oxygen transfer to alkynes, leading to R-oxo
carbenoid intermediates.6,7 Given the structural similarity
between NÀO and NÀN bonds, we think that the internal
nitrogen transfer8 of azomethine-alkyne such as 1a can
be possible. However, no analogous nitrogen transfer
occurred for 1a after extensive screenings, likely due to
the tethering effect.
Au(I)/Ag(I) catalyst failed to improve the efficiency
(entry 2). Importantly, gold catalysis proved not necessary
and a slightly higher yield was obtained when AgSbF6
(10 mol %) alonewas usedasa catalyst (entry 3). Screening
of different silver salts gave AgOTf as the best catalyst
(entries 3À6) and an isolated yield of 83% was reached
when the catalyst loading was increased to 20% (entry 7).
Addition of L-proline (20 mol %) significantly increased
the efficiency, and the reaction proceeded smoothly even at
room temperature in 90% yield (entry 8). This nucleophilic
activation of acetone by proline has been previously
reported.4a,9 Nucleophilic addition of methyl ketones
to an iminium is a well-known strategy for CÀC bond
formation as in the Mannich reaction, and there has been
increasing interest in the addition of carbon nucleophiles
to iminiums generated from the single-electron oxidation
of tertiary amines.10 In our system, acetone is added to
a unique iminium, and this process is in tandem with
nucleophilic cyclization of an alkyne.
Table 1. Optimization Studiesa
With the optimized conditions in hand, we next explored
the generality of this reaction. A broad scope of alkynes
can be applied (Scheme 1). Thus both terminal (3da)
and internal alkynes with different alkyl, benzyl, aryl
(3gaÀ3ja), and heteroaryl (3ka) groups reacted efficiently
to afford the acetone adduct in 62À90% yield (3aaÀ3ka).
For aryl-substituted alkynes, ortho, meta, and para sub-
stituents in the phenyl ring are well tolerated. In contrast, a
SiMe3-substituted alkyne underwent clean but desilylated
cyclization to give 3da in a yield (84%) higher than that
obtained using the terminal alkyne counterpart. Electron-
donating (3la, 3na) and -withdrawing (3ma) substituents
in the phenylene linker between the azomethine and the
alkyne can be accommodated without much variation of
the isolated yield. When an azomethine bearing a mono
methyl-substituted pyrazolidinone was subjected to the
same conditions, good yield but poor diastereoselectivity
(1.1:1) was achieved (3oa). We next explored the scope of
the ketone in the reaction with 1a. Other methyl ketones
and methylene ketones are viable substrates, although the
isolated yield is generally lower. In some cases a higher
reaction temperature (80 °C) is necessary (3ab, 3ac, 3ae).
When 1,1,1-trifluoroacetone was applied, 3af was isolated
together with its hydrate 3ag as a mixture in 67% com-
bined yield. In contrast, no desired ketone adduct was
observed when 3,3-dimethyl-2-butanone was allowed to
react with 1a even at 80 °C, whereas only hydration-
cyclization product 4a was isolated (62% yield) and was
characterized by X-ray crystallography. With decreased
nucleophilicity of this ketone, the adventitious water reacts
preferentially. In fact, product 4a was consistently isolated
in variable yields when 1a was allowed to react in other
(wet) solvents such as methanol, acetonitrile, and acetic
acid at 70 °C (eq 1). These results suggest a competitive
catalyst
(mol %)
additive
(mol %)
temp time yieldb
entry
(°C)
(h)
(%)
1
2
3
4
5
6
7
8
Au(PPh3)Cl (5)
Au(IPr)Cl (5)
AgSbF6 (10)
AgOTf (10)
AgPF6 (10)
AgNTf2 (10)
AgOTf (20)
AgOTf (20)
AgSbF6 (6)
AgSbF6 (6)
130
130
110
110
110
110
80
24
24
18
18
18
18
24
12
35
30
46
78
52
35
83
90
L-proline (20)
25
a Conditions: Azomethine 1a (0.3 mmol), metal catalyst (5À20 mol %),
acetone (3 mL), reaction time and temperature indicated in the table.
b Isolated yield after column chromatography.
When we switched the solvent to acetone using a
Au(PPh3)Cl/AgSbF6 (5 mol %/6 mol %) catalyst, product
3aa was isolated (35%) as a polycyclic amide bearing
an exocyclic CdC bond (Table 1, entry 1). This product
was generated as a result of a tandem of 6-exo-dig cycliza-
tion and the addition of acetone. Both the connectivity
and the (Z)-configuration of the olefin were secured by
X-ray crystallography. Further screening using another
(5) Zhen, W.; Wang, F.; Du, Z.; Li, X. Angew. Chem., Int. Ed. 2012,
51, 11819.
(6) For a recent review, see: Xiao, J.; Li, X. Angew. Chem., Int. Ed.
2011, 50, 7226.
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Chem. Soc. 2012, 134, 17412. (b) Noey, E. L.; Luo, Y.; Zhang, L.; Houk,
K. N. J. Am. Chem. Soc. 2012, 134, 1078. (c) He, W.; Li, C.; Zhang, L.
J. Am. Chem. Soc. 2011, 133, 8482. (d) Wang, Y.; Ji, K.; Lan, S.; Zhang,
L. Angew. Chem., Int. Ed. 2012, 51, 1915. (e) Mukherjee, A.; Dateer,
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Soc. 2011, 133, 15372.
(8) (a) Xiao, Y.; Zhang, L. Org. Lett. 2012, 14, 4662. (b) Yan, Z.-Y.;
Xiao, Y.; Zhang, L. Angew. Chem., Int. Ed. 2012, 51, 8624. (c) Lu, B.; Luo,
Y.; Liu, L.; Ye, L.; Wang, Y.; Zhang, L. Angew. Chem., Int. Ed. 2011, 50,
8358. (d) Wetzel, A.; Gagosz, F. Angew. Chem., Int. Ed. 2011, 50, 7354.
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G, H.; Larock., R. C. ACS Comb. Sci. 2011, 13, 265. (b) Ibrahem, I.;
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Angew. Chem., Int. Ed. 2011, 50, 11062.
Org. Lett., Vol. 15, No. 4, 2013
875

addition-cyclization reaction between nitromethane and
1a also proceeded smoothly at room temperature to
give 6aa in 72% isolated yield. Furthermore, good yield
but moderate diastereoselectivity (5:1) was achieved for
nitroethane (6ab, eq 2).
Scheme 1. Addition-Cyclization with Ketonesa
We reasoned that terminal alkynes and acetone are of
comparable reactivity and may undergo the same type of
reaction.12 Indeed, a clean reaction between PhCtCH
and 1a was achieved at 60 °C in MeCN, from which
adduct 8aa was isolated in 89% yield and no simple direct
1,2-addition was observed.13 Here the adventitious water
competes unfavorably with the alkyne substrate. The
scope of this reaction is given in Scheme 2. The efficiency
and the scope of this reaction parallel those of the methyl
ketones. Thus the internal alkyne in the azomethine-
alkyne substrate can bear an alkyl, benzyl, aryl, or hetero-
aryl group, and the coupled product was isolated in
moderate to high yield (43À89%). A low yield (45%)
was obtained for the coupling of azomethine-terminal
alkyne with PhCtCH, likely due to complications of both
homo- and cross-couplings between these two terminal
alkynes. In line with the addition of acetone, SiMe3-
substituted alkyne-azomethine reacted with PhCtCH
to furnish the desilylated product in 84% yield, which
provides a more efficient alternative. Variation of sub-
stituents in the phenylene linker is also allowed (8ma,
8na, 8oa). In addition, the terminal alkyne substrate is
not limited to PhCtCH;14 different aryl- and alkyl-
substituted terminal alkynes reacted with comparable
efficiency (8abÀ8ae).
Several experiments have been performed to probe
the reaction mechanism. We attempted but failed to
add these nucleophiles to a simple azomethine bearing
no ortho alkynyl group even at a higher temperature,
indicating that this direct 1,2-addition is thermodynami-
cally and/or kinetically unfavorable without the cycliza-
tion process. In a labeling experiment using acetone-d6 as
a solvent, 1H NMR analysis of the isolated product
indicated that H/D exchange occurred at the olefinic
and the methine positions (eq 3). The fact that the olefinic
position is mostly protio-substituted suggests that
adventitious water participates readily in protonolysis
of the AgÀC bond.
a Conditions: azomethine-alkyne (0.3 mmol), L-proline (0.06 mmol),
b
AgOTf (0.06 mmol), ketone (3 mL), 25 °C, 12 h. Isolated yield after
column chromatography. c Reaction was conducted at 80 °C.
reaction between ketones and water, but soft nucleophiles
tend to give higher reactivity. Despite the possiblility of
competitive hydration-cyclization, essentially no (<5%) 4a
was isolated in the synthesis of3abÀ3ae. In contrast to these
nucleophiles, activated methylenes such as dimethyl melon-
ate and ethyl acetylacetate failed to give any clean reaction.
(11) For selected reports on addition of nitroalkane to iminiums via
oxidation, see: (a) Zhang, B.; Cui, Y.; Jiao, N. Chem. Commun. 2012, 48,
4498. (b) Xie, J.; Li, H.; Zhou, J.; Cheng, Y.; Zhu, C. Angew. Chem., Int.
Ed. 2012, 51, 1252. (c) Meng, Q.-Y.; Liu, Q.; Zhong, J.-J.; Zhang, H.-H.;
Li, Z.-J.; Chen, B.; Tung, C.-H.; Wu, L.-Z. Org. Lett. 2012, 14, 5992.
(d) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2005, 127, 3672.
(12) For a recent review, see: (a) Li, C. J. Acc. Chem. Res. 2010, 43,
581. Addition of terminal alkynes to imines: (b) Zeng, T.; Yang, L.;
Hudson, R.; Song, G.; Moores, A. R.; Li, C.-J. Org. Lett. 2011, 13, 442.
Addition of terminal alkynes to other in situ generated electrophiles:
(c) He, C.; Guo, S.; Ke, J.; Hao, J.; Xu, H.; Chen, H.; Lei, A. J. Am.
Chem. Soc. 2012, 134, 5766. (d) Li, Z.; Li, C. J. Org. Lett. 2004, 6, 4997.
(13) For a recent report on alkyne addition to the imine group of an
azomethine, see: Imaizumi, T.; Yamashita, Y.; Kobayashi, S. J. Am.
Chem. Soc. 2012, 134, 20049.
(14) Gold-catalyzed addition-cyclization of terminal alkynes to
ortho-alkynylaryl aldehydes has been achieved, but the terminal alkyne
seems limited to aryl or alkenyl substitution because poor yield was
obtained for aliphatic alkynes. See: Yao, X.; Li, C.-J. Org. Lett. 2006, 8,
1953.
The nucleophile is not limited to a ketone. Nitromethane
can also be applied as a solvent nucleophile,11 and the
876
Org. Lett., Vol. 15, No. 4, 2013

Scheme 2. Addition-Cyclization with Terminal Alkynea
Scheme 3. Proposed Catalytic Cycle
terminal alkyne. Protonolysis of the AgÀC bond com-
pletes the catalytic cycle with the regeneration of the Ag(I)
catalyst (Scheme 3).
In summary, we have achieved a silver-catalyzed nu-
cleophilic addition-cyclization tandem between alkyne-
functionalized azomethines and soft nucleophiles, leading
to the synthesis of tricyclic products. A broad scope of
substrates has been established using AgOTf as a catalyst.
The reaction proceeded with high chemoselectivity but,
if relevant, moderate to low diastereoselectivity. Given the
broad scope and operational simplicity, this method may
find applications in the synthesis of related structures.
Future work will be conducted on the enantioselective
synthesis of these products using chiral ancillary groups.
a Conditions: azomethine-alkyne (0.4 mmol), 1-alkyne (3 equiv),
AgOTf (0.2 equiv), MeCN (3 mL), 60 °C, 20 h. Isolated yield after
column chromatography.
b
Acknowledgment. We thank the Dalian Institute of
Chemical Physics, Chinese Academy of Science and the
NSFC (21072188) for generous financial support of this work.
A general mechanism has been proposed for the forma-
tion of these adducts. Ag(I) coordination to the alkyne
activates it toward the 6-exo-dig attack of the amide
nitrogen to give a silver(I) alkenyl intermediate. This
cyclization process also renders the iminium more electro-
philic, which can be attacked by a ketone, nitroalkane, and
Supporting Information Available. Experimental pro-
cedures and spectroscopic, analytical, and crystallo-
graphic data. This material is available free of charge
via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 4, 2013
877