Platinum-catalyzed oxoarylations of ynamides with nitrones

Article abstract of DOI:10.1021/ol302621z

A new platinum-catalyzed oxoarylation of ynamides with nitrones is reported. Cascade sequences for the synthesis of indolin-2-ones via NaBH ₃CN reduction in situ of the initially formed oxoarylation products are also developed.

Full text of DOI:10.1021/ol302621z

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Platinum-Catalyzed Oxoarylations of
Ynamides with Nitrones
Sabyasachi Bhunia, Chin-Jung Chang, and Rai-Shung Liu*
Department of Chemistry, National Tsing-Hua University, Hsinchu, Taiwan, ROC
rsliu@mx.nthu.edu.tw
Received September 24, 2012
ABSTRACT
A new platinum-catalyzed oxoarylation of ynamides with nitrones is reported. Cascade sequences for the synthesis of indolin-2-ones via
NaBH3CN reduction in situ of the initially formed oxoarylation products are also developed.
Gold-catalyzed intermolecular oxidations of alkynes
with organic oxides presumably involve the generation of
R-oxo gold carbenes I;1ꢀ6 pyridine-based oxides2 are
superior to sulfur oxides3 for generating such reac-
tive intermediates. This new synthetic method provides
potential access to valuable R-functionalized carbonyl
compounds through a subsequent attack on the gold
carbenes I with an external nucleophile, as depicted in
eq 1. Nevertheless, at the outset of the present study, there
was only one successful example7 of such a conversion
because of the following problems: (1) a competitive attack
of this external nucleophile at the gold-π-alkyne; (2) a
complexation of gold-carbene I with newly released pyr-
idine, and (3) a second oxidation of gold carbenes I with
organic oxides.8 Recently, we proposed a distinct route, as
depicted in eq 2, in which a nucleophile is embedded within
the organic oxide AþꢀOꢀ (A = nucleophile).4a At the end
of the initial alkyne oxidation, the released nucleophile A is
easily trapped with gold-carbene I within an inner sphere,
so eliminating the preceding problems. This new approach
also fulfills atom economy because the reduced form A is a
part of product skeleton.
(1) Xiao, J.; Li, X. Angew. Chem., Int. Ed. 2011, 50, 7226.
(2) For pyridine-based oxides, see selected examples: (a) Ye, L.; Cui,
L.; Zhang, G.; Zhang, L. J. Am. Chem. Soc. 2010, 132, 3258. (b) Ye, L.;
He, W.; Zhang, L. J. Am. Chem. Soc. 2010, 132, 8550. (c) He, W.; Li, C.;
Zhang, L. J. Am. Chem. Soc. 2011, 133, 8482. (d) Davies, P. W.;
Cremonesi, A.; Martin, N. Chem. Commun. 2011, 47, 379. (e) Lu, B.;
Li, C.; Zhang, L. J. Am. Chem. Soc. 2011, 132, 14070. (f) Dateer, R.-B.;
Pati, K.; Liu, R.-S. Chem. Commun. 2012, 48, 7200. (f) Dateer, R. B.;
Shaibu, B. S.; Liu, R.-S. Angew. Chem., Int. Ed. 2012, 51, 113.
(3) For sulfur oxides, see: (a) Shapiro, N. D.; Toste, F. D. J. Am.
Chem. Soc. 2007, 129, 4160. (b) Li, G.; Zhang, L. Angew. Chem., Int. Ed.
2007, 46, 5156. (c) Cuenca, A. B.; Montserrat, S.; Hossain, K. M.;
ꢀ
ꢀ
Mancha, G.; Lledos, A.; Medio-Simon, M.; Ujaque, G.; Asensio, G.
Org. Lett. 2009, 11, 4906. (d) Davies, P. W.; Albrecht, S. J. C. Angew.
Chem., Int. Ed. 2009, 48, 8372. (e) Li, C.-W.; Pati, K.; Lin, G.-Y.; Sohel,
S. M. A.; Hung, H.-H.; Liu, R.-S. Angew. Chem., Int. Ed. 2010, 49, 9891.
(4) For nitrones, see: (a) Mukherjee, A.; Dateer, R. B.; Chaudhuri,
R.; Bhunia, S.; Karad, S. N.; Liu, R.-S. J. Am. Chem. Soc. 2011, 133,
15372. (b) Yeom, H. S.; Lee, J. E.; Shin, S. Angew. Chem., Int. Ed. 2008,
47, 7040. (c) Yeom, H. S.; Lee, Y.; Lee, J. E.; Shin, S. Org. Biomol. Chem.
2009, 7, 4744. (d) Yeom, H. S.; Lee, Y.; Jeong, J.; So, E.; Hwang, S.; Lee,
J. E.; Lee, S. S.; Shin, S. Angew. Chem., Int. Ed. 2010, 49, 1611.
(5) For epoxides, see: (a) Li, C. W.; Lin, G. Y.; Liu, R.-S. Chem.;
Eur. J. 2010, 16, 5803. (b) Lin, G.-Y.; Li, C.-W.; Hung, S.-H.; Liu, R.-S.
Org. Lett. 2008, 10, 5059. (c) Hashmi, A. S. K.; Buhrle, M.; Salathe, R.;
Bats, J. W. Adv. Synth. Catal. 2008, 350, 2059.
Shown in Scheme 1 is our recent practice4a of this new
1,2-difunctionalization on arenynamide 1. In this transfor-
mation, gold-catalyzed nitrone oxidation of alkyne 1
produces an imine that reacts efficiently with carbene I to
give the R-aminoamide 3. In a further development of this
chemistry, we report a new discovery that applies platinum
catalysis to ynamides 4, to deliver products 5 through an
(6) For nitro group, see: Jadhav, A. M.; Bhunia, S.; Liu, R.-S. J. Am.
Chem. Soc. 2011, 133, 1769–1771.
(7) He, W.; Li, C.; Zhang, L. J. Am. Chem. Soc. 2011, 13, 1738.
(8) Xu, C.-F.; Xu, M.; Jia, Y.-X.; Li, C.-Y. Org. Lett. 2011, 13, 1556.
r
10.1021/ol302621z
XXXX American Chemical Society

Scheme 1. Gold-Catalyzed 1,2-Difunctionalization of Activated
Alkynes
Scheme 2. Reaction Scope for Pt-Catalyzed Oxoarylation Re-
actionsa
oxoarylation reaction. Notably, this new alkyne 1,2-di-
functionalization proceeds via a distinct mechanism that
excludes the intermediacy of gold carbenes I.
Shown in Table 1 is the reaction of nitrone 2a (2 equiv)
with ynamide 4a (1 equiv) in dichloroethane (DCE) in the
presence of various gold and platinum catalysts at 5 mol %
loading. We observed the complete consumption of start-
ing ynamide 4a under the reaction conditions. We tested
first the reactions with gold catalysts including P(t-Bu)2-
(o-biphenyl)AuNTf2,IPrAuNTf2 (IPr = 1,3-bis(diisopropyl-
phenyl)imidazol-2-ylidene), and AuCl3 in DCE at 28 °C, and
all gave rise to a messy mixture, due to rapid decomposition
Table 1. Catalytic Activity over Gold and Platinum Catalysts
a [Ynamide] = 0.17 M, reactions performed at 28 °C. b Product yields
are reported after purification from silica column.
temp
time
(h)
5a
entry
catalystb
(0 °C)
(yields, %)c
the reaction with PtCl4, which gave compound 5a in 65%
yield (entry 7).
1
2
3
4
5
6
7
LAuCl/AgNTf2
IPrAuCl/AgNTf2
AuCl3
28
28
28
28
28
80
28
2
ꢀ
3
ꢀ
Shown in Scheme 2 is the generalization of this plati-
num-catalyzed oxoarylation reaction with various yna-
mides 4bꢀ4d (1.0 equiv) and nitrones 2bꢀ2m (2.0 equiv).
The reactions were performed with PtCl2 catalyst (5 mol %)
in dichloroethane at 28 °C. The duration of the reaction
(0.3ꢀ0.8 h) determines whether there is a complete con-
sumption of the ynamides 4bꢀ4d. We examined first the
reactions using nitrones 2bꢀe bearing alterable 4-subsi-
tuted phenylimines (Ar = 4-MeOC6H4,4-FC6H4,4-ClC6H4,
and 4-CF3C6H4); these afforded the desired products
5bꢀ5e in satisfactory yields (90ꢀ94%, entries 1ꢀ4). The
reaction was further applied to the additional nitrones
2fꢀ2h, bearing heteroaryl imines (Ar = 2,3-thienyl and
2-furanyl). These delivered the oxoarylation products 5fꢀ
5h in excellent yields (90ꢀ93%, entries 5ꢀ7). For nitrone
2i, bearing a naphthylimine, its corresponding product
2
ꢀ
AuCl
0.3
0.5
0.7
0.5
57
95
15
65
PtCl2
PtI2
PtCl4
a [4a] = 0.17 M. b L = P(t-Bu)2(o-biphenyl), IPr = 1,3-bis-
(diisopropylphenyl)imidazol-2-ylidene. c Product yields are reported
after purification from silica column.
of the starting ynamide 4a (entries 1ꢀ3). To our delight,
use of the less acidic AuCl gave an oxoarylation pro-
duct 5a in 57% yield. The yield of desired 5a was further
increased up to 95% with PtCl2 in DCE at 28 °C (entry 5).
In contrast, PtI2 led only to unreacted ynamide 4a with a
32% recovery, in DCE at 28 °C, but a thermal activation
gave the desired 5a in 15% yield (entry 6). We also tested
B
Org. Lett., Vol. XX, No. XX, XXXX

5i was obtained in 91% yield (entry 8). Such reactions also
worked for the nitrones 2jꢀ2m with various 4-substituted
anilines (X = MeO, Cl, Br, and CO2Et); these gave the
desired products 5jꢀ5m in 88ꢀ92% yield (entries 9ꢀ12).
We tested this reaction on other ynamides 4bꢀ4d and
found their reactivities varied with the sulfonamide func-
tionalities. For ynamides 4b and 4c bearing ꢀNTs(Ph) and
ꢀNMs(Ph), the resulting products 5n and 5o were ob-
tained in 88ꢀ90% yields (entries 13ꢀ14). In contrast,
ynamide 4d gave many minor products because of its facile
decomposition with the PtCl2 catalyst within 0.15 h (entry 15).
The reactions failed to work with other sulfonamides
including NMs(n-Bu), NTs(n-Bu).
Scheme 4. Cascade Sequence for the Synthesis of Indolin-2-
onesa
Scheme 3 depicts an efficient transformation of an
oxoarylation product 5a into indolin-2-one 6a. In this
process, initially present 5a was reduced with NaBH3CN
(1 equiv) in THF under ambient conditions (28 °C, 20 min),
and the solution was filtered through a Celite bed. The
THF filtrate was heated with silica gel (SiliaFlashG60) at
80 °C for 1 h to ensure a complete conversion to the
indolin-2-one 6a (89%).
Scheme 3. Formation of an Indolin-2-one
a [Ynamide] = 0.17 M, reactions performed at 28 °C. b Product yields
are reported after purification from silica column.
d0-5a had no deuterium content at all. Nitrone 2a is clearly
the source of both the oxygen and imine groups of the
resulting product 5a.
To highlight the utility of this platinum-catalyzed ox-
oarylation of ynamides, we developed a one-pot synthesis
of useful indolin-2-ones 6bꢀ6m from ynamide 4a and
nitrones 2bꢀ2m, as depicted in Scheme 4. In a typical
operation, when the oxoarylation reaction of ynamide 1a
was complete in dichloroethane, a THF solution of
NaBH3CN was added. The mixture was stirred for
20 min before being filtered through a Celite bed. The
filtrate was heated with silica gel (SiliaFlashG60) at 80 °C
for 1 h before workup. We used the same nitrones 2bꢀ2m
as those in Scheme 2 to exemplify the generality of this
indolin-2-one synthesis. Entries 1ꢀ8 show the efficient
production of indolin-2-ones 6bꢀ6iin 74ꢀ84% yield, from
nitrones 2bꢀ2i bearing alterable phenylimines 2bꢀ2e (Ar=
4-MeOC6H4, 4-FC6H4, 4-ClC6H4, and 4-CF3C6H4), het-
eroaryl imines 2fꢀ2h (Ar = 2,3-theinyl and 2-furanyl),
and 2-naphthylimine 2i. For nitrones 2jꢀ2m bearing
varied aniline substitutents, the resulting indolin-2-ones
6jꢀ6m were obtained in 53ꢀ79% yields (entries 9ꢀ12).
Scheme 5 shows deuterium labeling experiments that
assist our understanding of the reaction mechanism. Treat-
ment of ynamide 4a and the deuterated nitrone d5-2a with
PtCl2 under our standard conditions afforded the desired
d5-5a with one methylene proton bearing X = 0.70 D. We
performed this platinum-catalyzed reaction on ynamide 4a
and d0-2a (2 equiv) in the presence of deuterated imine
d5-7a (2 equiv), but the resulting oxoarylation product
Scheme 5. Deuterium-Labeling Experiments
We propose the mechanism as depicted in Scheme 6 to
rationalize our resulting oxoarylation compound 5a. We
postulate that nitrone 2a initially attacks at the CR-carbon
of π-ynamide 4a, which also has a ketene resonance hybrid
(9) For chemistry of ynamides, see reviews: (a) DeKorver, K. A.; Li,
H.; Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang, Y.; Hsung, R. P. Chem.
Rev. 2010, 110, 5064. (b) Evano, G.; Coste, A.; Jouvin, K. Angew. Chem.,
Int. Ed. 2010, 49, 2840–2859.
Org. Lett., Vol. XX, No. XX, XXXX
C

platinum-containing amide C, ultimately giving the ob-
served product 5a through a proton transfer. This noncar-
bene route is analogous to that proposed for the 1,2-difunc-
tionalization of alkynes via diphenylsulfur oxide.3c,e,11
In summary, a new platinum-catalyzed oxoarylation of
ynamides with nitrones is reported. These reactions work
well with a reasonable range of substrates. Cascade se-
quences for the synthesis of indolin-2-ones via NaBH3CN
reduction in situ of the initially formed oxoarylation
products are also developed. On the basis of deuterium
labeling experiments, we postulate a noncarbene route, in
which the key step is a [3,3]-sigmatropic shift of the β-oxy
alkenylplatinum intermediate B.
Scheme 6. A Plausible Reaction Mechanism
form A0.9,10 A subsequent [3,3]-sigmatropic shift of the
β-oxy alkenylplatinum intermediate B generates the
(10) For gold-catalyzed electrophilic activation of ynamides, see
ref 3e and (a) Li, C.; Zhang, L. Org. Lett. 2011, 13, 1738. (b) Vasu,
D.; Hung, H. H.; Bhunia, S.; Gawade, S.; Das, A.; Liu, R.-S. Angew.
Chem., Int. Ed. 2011, 50, 6911. (c) Kramer, S.; Odabachian, Y.; Over-
gaard, J.; Rottander, M.; Gagosz, F.; Skrydstrup, T. Angew. Chem., Int.
Acknowledgment. The authors wish to thank the Na-
tional Science Council, Taiwan for supporting this work.
€
+
Ed. 2011, 50, 5090. (d) Hashmi, A. K. S.; Buhrle, M.; Wolfle, M.;
Rudolph, M.; Wieteck, M.; Rominger, F.; Frey, W. Chem.;Eur. J.
2010, 16, 9846. (e) Davies, P. W.; Cremonesi, A.; Dumitrescu, L. Angew.
Chem., Int. Ed. 2011, 50, 8931. (f) Karad, S. N.; Bhunia, S.; Liu, R.-S.
Angew. Chem., Int. Ed. 2012, 51, 8722. (g) Dateer, R. B.; Pati, K.; Liu,
R.-S. Chem. Commun. 2012, 48, 7200. (h) Dateer, R. B.; Shaibu, B. S.;
Liu, R.-S. Angew. Chem., Int. Ed. 2012, 51, 113.
Supporting Information Available. Experimental pro-
cedures, NMR spectra, and characterization data of new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
(11) Wang, Y.; Ye, L.; Zhang, L. Chem. Commun. 2011, 47, 7815.
D
Org. Lett., Vol. XX, No. XX, XXXX