Gold-catalyzed stereoselective synthesis of azacyclic compounds through a redox/[2 + 2 + 1] cycloaddition cascade of nitroalkyne substrates

Article abstract of DOI:10.1021/ja110514s

We report a new redox/cycloaddition cascade on readily available 1-alkynyl-2-nitrobenzenes that produces complex azacyclic compounds stereoselectively. The core structures of the resulting products are constructed through a formal [2 + 2 + 1] cycloaddition among α-carbonyl carbenoids, nitroso species, and external alkenes.

Full text of DOI:10.1021/ja110514s

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Gold-Catalyzed Stereoselective Synthesis of Azacyclic Compounds
through a Redox/[2 þ 2 þ 1] Cycloaddition Cascade of Nitroalkyne
Substrates
Appaso Mahadev Jadhav,† Sabyasachi Bhunia,† Hsin-Yi Liao,‡ and Rai-Shung Liu*,†
†Department of Chemistry, National Tsing-Hua University, Hsinchu, Taiwan, ROC
‡Department of Science Education, National Taipei University of Education, Taipei, Taiwan, ROC
S Supporting Information
b
epimer 1a0 in 2-5% yield (entries 5 and 6). AgNTf2 alone gave an
ABSTRACT: We report a new redox/cycloaddition cascade
on readily available 1-alkynyl-2-nitrobenzenes that produces
complex azacyclic compounds stereoselectively. The core
structures of the resulting products are constructed through
a formal [2 þ 2 þ 1] cycloaddition among R-carbonyl
carbenoids, nitroso species, and external alkenes.
exclusive recovery of unreacted 1 (65%; entry 7). The structure of
compound 1a was determined with 1H nuclear Overhauser effect
(NOE) spectra and confirmed by an X-ray diffraction study of its
relative 6a.8 Compound 1a and its epimer 1a0 were not inter-
convertible in the presence of PPh3AuSbF6 or PPh3AuNTf
catalyst (5 mol %) under the reaction conditions (DCE, 25 °C,
2 h), although 1a is more thermodynamically favorable than 1a0.9
The scope of this catalysis is demonstrated by its applicability
to diverse electron-rich alkenes and dienes b-n (4 equiv), as
depicted in Table 2. The resulting azacyclic products 1b-1n
were obtained exclusively as single diastereomers from starting 1,
except in the case of n (entry 14), for which some of the epimer
1n0 (8%) was formed. The efficiency of this catalysis is reflected
by the fact that the yields of products exceeded 68%. Entries 1-3
show the workability of various enol ethers b-d (R = trimethyl-
silyl, benzyl, tert-butyl) that delivered the corresponding prod-
ucts 1b-1d. This catalysis is compatible with ethyl and phenyl
vinyl sulfides e and f, which gave sulfur-containing compounds 1e
and 1f in 92 and 76% yield, respectively (entries 4 and 5). Cyclic
enol ethers g and h gave stereoselective formation of complex
azacyclic products 1g and 1h in 79 and 83% yield, respectively
(entries 6 and 7). The structures of azacycles 1g and 1h were
etal-catalyzed cycloadditions are powerful tools for generat-
M
ing complex molecular frameworks.1 Metal carbenoids are
valuable intermediates in organic reactions because of their potent
reactivities in cycloadditions with alkenes.2 In gold catalysis, the
internal redox reactions on alkynes are among the most efficient
methods for generating R-carbonyl carbenoids;3,4 suchapproaches
are safe and convenient because stable alkyne and organic oxides
replace hazardous diazocarbonyl species. We envisage that the
development of new redox/cycloaddition cascades on alkynes will
represent a viable route toward products with molecular complex-
ity, but existing examples are few.5 Herein, we report such cascade
reactions on cheap and readily available 1-alkynyl-2-nitrobenzenes
using the protocol shown in Scheme 1. Notably, the core struc-
tures of the resulting cycloadducts are constructed through a
formal [2 þ 2 þ 1] cycloaddition among R-carbonyl carbenoids,
nitroso species,6 and external alkenes, as depicted by species B.
In a standard operation, 4 equiv of ethyl vinyl ether (a) mixed
with PPh3AuNTf2 (5 mol %) in dichloroethane (DCE) at 25 °C
was treated slowly with nitrobenzene 1 via a syringe pump for
0.5 h; this procedure circumvents the gold-catalyzed dimeriza-
tion of starting 1 in the absence of olefin (eq 1).7
determined by 1H NOE spectra; the corresponding value J23
=
0 Hz is consistent with a dihedral angle of ∼90° expected for this
geometry. For 2-substituted enol ether i with Z/E = 1 (entry 8),
the gold catalysis gave compound 1i with the same stereochem-
istry (J23 = 0 Hz). We obtained the same product in decreased
yield (31%) using starting i with Z/E = 1/3 (entry 9), with a side
product 12 (46%) from the dimerization of starting 1 (eq 1). The cis
isomer of species i appeared to be more active than the trans form in
this cycloaddition. The structures of 1g, 1h, and 1i were confirmed by
1H NOE spectra. The workability of this synthesis with aryl alkenes
j-m to give the expected products 1j-1m stereoselectively and
efficiently (entries 10-13) further demonstrates its broad utility,.
This reaction was extensible even to electron-rich diene n, which
afforded azacyclic product 1n in 68% yield (entry 14).
As shown in Table 1, the use of AuCl3 and PtCl2/CO gave a
messy mixture of products, from which the desired cycloadduct
1a was isolated in 8% yield in the Pt catalysis. In contrast, use of
ClAuP(t-Bu)2(o-biphenyl)/AgNTf2 and IPrAuCl/AgNTf2 [5 mol %;
IPr = 1,3-bis(diisopropylphenyl)imidazol-2-ylidene] enabled com-
plete conversion to give 1a and 1a0 as a diastereomeric mixture
(entries 3 and 4) that was separable on a silica column. The
stereoselectivity was greatly enhanced with PPh3AuCl/AgSbF6 or
PPh3AuCl/AgNTf2, giving cycloadduct 1a in 85-89% yield with
Table 3 shows the applicability of this catalysis with nitro-
benzenes 2-9 bearing various substituents on their phenyl
groups. For substrates 2-5 having electron-withdrawing groups
at C4, the reactions with ethyl vinyl ether a proceeded smoothly
to give the desired compounds 2a-5a in 68-84% yield.
Received: November 22, 2010
Published: January 18, 2011
r
2011 American Chemical Society
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Scheme 1. Gold-Catalyzed Redox/Cycloaddition Cascade
Table 2. Cycoadditions of Compound 1 with Various Alkenesa
Table 1. Catalyst Screening for the Reaction of 1 and Enol
Ether a
entry
catalysta
AuCl3
time (h)
productsb
1
2
3
4
5
6
7
2
2
complicated mixture
1a (8%)
PtCl2/CO
LAuCl/AgNTf2
IPrAuCl/AgNTf2
PPh3AuCl/AgSbF6
PPh3AuCl/AgNTf2
AgNTf2
2
1a (65%), 1a0 (35%)
1a (54%), 1a0 (39%)
1a (85%), 1a0 (5%)
1a (89%), 1a0 (2%)
1 (65%)
2
2
2
12
a L = P(t-Bu)2(o-biphenyl). The reaction was performed using
[substrate] = 0.05 M and 4 equiv of enol ether a. b Reported product
yields were obtained after separation on a silica column.
a Using [substrate] = 0.05 M and 4 equiv of alkene. b Reported product
yields were obtained after separation on a silica column.
Substrate 6 bearing a methyl group was also suitable for this
catalysis, giving the desired product 6a in 67% yield; its structure
was confirmed by X-ray diffraction.8 Similar products 7a-9a were
also obtained in good yields (73-82%) from substrates 7-9
bearing fluoro, chloro, and methyl groups, respectively, at the
phenyl C5 carbon (entries 6-8).10
Table 3. Cycloadditions with Various Nitrobenzenes
Scheme 2 presents data to assist an understanding of the
reaction mechanism. Treatment of nitrobenzene 1 with styrene
and the gold catalyst (5 mol %) delivered deoxygenated cyclo-
propane 10 in 23% yield, with dimerization product 12. Forma-
tion of compound 10 apparently proceeded through the inter-
mediacies of R-carbonyl carbenoid B and species C and D. Using
a chiral gold complex to probe the reaction mechanism, we
obtained the resulting product (-)-1g with 73.1% ee. Such a
chirality induction provides evidence for the participation of a
gold fragment to generate new stereogenic centers; 1,3-dipolar
cycloaddition on metal-free nitrone E is thus excluded11
The isolation of the cyclopropane compound 10 asserts the
intermediacy of R-carbonyl carbenoids B. A formal [2 þ 2 þ 1]
cycloaddition, as depicted in Scheme 1, provides a suitable
formula for these products, but such a three-component cyclo-
addition probably begins from an initial intramolecular cycliza-
tion of gold carbenoid B to form ketonyl oxonium F, as depicted
in Scheme 3. We envisage that the keto-enol tautomerism of
species F generates enol G, which is also characterized by the
resonance structure G0. A subsequent [3 þ 2] cycloaddition of
species G0 with enol ether in a concerted exo-addition mode
would give the observed products 1a-1i. This proposed mech-
anism rationalizes not only the product stereoselectivity but also
the observations in the control experiments. We performed
theoretical calculations (B3LYP/LANL2DZ) to examine the
entry
nitrobenzenea
product (yieldb)
1
2
3
4
5
6
7
8
X = F, Y = H (2)
X = Cl, Y = H (3)
X = Br, Y = H (4)
X = CF3, Y = H (5)
X = Me, Y = H (6)
X = H, Y = F (7)
X = H, Y = Cl (8)
X = H, Y = Me(9)
2a (68%)
3a (80%)
4a (80%)
5a (84%)
6a (67%)
7a (73%)
8a (82%)
9a (77%)
a Using [substrate] = 0.05 M and 4 equiv of enol ether a. b Reported
product yields were obtained after separation on a silica column.
feasibility of this hypothetical cycloaddition using ethyl vinyl
ether a and PH3Auþ catalyst. This reaction pathway appears to
be very facile and highly exothermic, with Ea = 0.5 kcal/mol and
ΔH = -32.3 kcal/mol.12 Although the Au-catalyzed cycloaddi-
tion of nitrone E with enol may rationalize the asymmetric
induction, as depicted in Scheme 2, this route fails to explain the
stereoselectivity of products.
In summary, we have reported a new redox/cycloaddition
cascade on readily available 1-alkynyl-2-nitrobenzenes13,14 that
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Scheme 2. Experiments To Elucidate the Mechanism
(2) For selected examples, see: (a) Shapiro, N. D.; Toste, F. D. J. Am.
Chem. Soc. 2008, 130, 9244. (b) Shapiro, N. D.; Shi, Y.; Toste, F. D.
J. Am. Chem. Soc. 2009, 131, 11654. (c) Zhang, G.; Zhang, L. J. Am.
Chem. Soc. 2008, 130, 12598. (d) Li, C. W.; Lin, G.-Y.; Lin, R.-S.
Chem.;Eur. J. 2010, 16, 5803. (e) Davies, H. M. L.; Xiang, B.; Kong, N.;
Stafford, D. G. J. Am. Chem. Soc. 2001, 123, 7461. (f) Davies, H. M. L.;
Hu, B.; Saikali, E.; Bruzinski, P. R. J. Org. Chem. 1994, 59, 4535–4541.
(3) Generation of R-carbonyl carbenoids using Ph2SO2a-2d remains
controversial (see refs 3d and 3e). (a) Shapiro, N. D.; Toste, F. D. J. Am.
Chem. Soc. 2007, 129, 4160. (b) Witham, C. A.; Mauleoꢀn, P.; Shapiro,
N. D.; Sherry, B. D.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 5838.
(c) Li, G.; Zhang, L. Angew. Chem., Int. Ed. 2007, 46, 5156. (d) Cuenca,
A. B.; Montserrat, S. K.; Hossain, M.; Mancha, G.; Lledꢀos, A.; Medio-
Simꢀon, M.; Ujaque, G.; Asensio, G. Org. Lett. 2009, 11, 4906. (e) Li, C.-W.;
Pati, K.; Lin, G.-Y.; Abu Sohel, S. M.; Hung, H.-H.; Liu, R.-S. Angew.
Chem., Int. Ed. 2010, 49, 9891.
(4) R-Carbonyl carbenoids are generated from nitrogen-based
oxides. See: (a) Cui, L.; Zhang, G.; Peng, Y.; Zhang, L. Org. Lett. 2009, 11,
1225–1228. (b) Cui, L.; Peng, Y.; Zhang, L. J. Am. Chem. Soc. 2009, 131, 8394.
(c) Yeom, H.-S.; Lee, J.-E.; Shin, S. Angew. Chem., Int. Ed. 2008, 47, 7040.
(d) Ye, L.; Cui, L.; Zhang, G.; Zhang, L. J. Am. Chem. Soc. 2010, 132, 3258.
(5) One example was reported for this redox/cycloaddition cascade
on substrates tethered with nitrone/alkyne/alkene functionalities, whereas
our new system employs external alkenes (see ref 4c).
Scheme 3. Proposed Mechanism for Azacycles 1a-1i
(6) For selected examples of cycloaddition reactions of nitroso-
benzenes, see: (a) Benbow, J. F.; McClure, K. F.; Danishefsky, S. J. J. Am.
Chem. Soc. 1993, 115, 12305. (b) McClure, K.; Benbow, J. F.;
Danishefsky, S. J. J. Am. Chem. Soc. 1991, 113, 8185. (c) Yamamoto,
Y.; Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 4128. (d) Wang, T.;
Huang, X.-L.; Ye, S. Org. Biomol. Chem. 2010, 8, 5007.
(7) Structural characterization of the dimerization product 12 relied on
an X-ray diffraction study of its analogue; the X-ray data and a mechanism of
formation of species 12 are presented in the Supporting Information.
(8) X-ray crystallographic data for compound 6a appear in the
Supporting Information.
(9) In the presence of PPh3AuNTf2, we observed a gradual change of
species 1a to a mixture in which 1a/1a0 = 6:1 after 24 h in DCE at 25 °C.
Under the same conditions, its epimer 1a0 gave a composition 1a/1a0 =
2:1. A complete equilibrium requires a much longer time.
(10) Substrates bearing methoxy groups at the phenyl C4 or C5
atoms are imcompatible with this catalysis because they tend either to
stabilize the nitro group or to reduce the alkyne electrophilicity.
(11) Nitrone E may be generated from R-carbonyl carbenoid B, and
its role is inferred from the mechanism of formation of the dimerization
product 12.7 We envisage that the resulting cycloadduct H is somewhat
strained and subject to gold-catalyzed rearrangement to the observed
azacyclic product through intermediates I and J. Nevertheless, this mecha-
nism is expected to give a mixture of isomeric products 1a and 1a0 because of
free rotation around the C3-C4 bond in intermediates I and J.
produces complex azacyclic compounds with high stereoselec-
tion. Such a cascade reaction is mechanistically interesting in that
the central cores of the products are constructed through a formal
[2 þ 2 þ 1] cycloaddition among R-carbonyl carbenoids, nitroso
species, and external alkenes. The utility of this catalysis includes
diverse electron-rich alkenes and various substituents on the phenyl
groups. The enantioselective synthesis of these azacyclic com-
pounds is currently under investigation.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental and computational
b
procedures, characterization data for new compounds, and X-ray
crystallographic data for compound 6a and a relative of 12 (CIF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
’ AUTHOR INFORMATION
(12) See the Supporting Information for the details of the calculation pro-
cedures and the energy profiles of a concerted [3 þ 2] cycloaddition pathway.
(13) We also examined this reaction with internal alkyne 11, but its
gold catalysis gave benzo[c]isoxazole 12 in 76% yield. This transformation
was previously reported by Yamamoto et al.,14 but we have revised their
mechanism involving gold R-carbonyl carbenoids as depicted below:
Corresponding Author
rsliu@mx.nthu.edu.tw
’ ACKNOWLEDGMENT
The authors thank the National Science Council, Taiwan, for
supporting this work.
’ REFERENCES
This reaction outcome also supports our hypothetical mecha-
nism involving gold R-carbonyl carbenoids B.
(14) Asao, N.; Sato, K.; Yamamoto, Y. Tetrahedron Lett. 2003, 44,
5675.
(1) For reviews of gold-catalyzed cycloaddition reactions, see:
(a) Patil, N. T.; Yamamoto, Y. Chem. Rev. 2008, 108, 3395. (b) Abu
Sohel, S. M.; Liu, R.-S. Chem. Soc. Rev. 2009, 38, 2269. (c) Shapiro, N. D.;
Toste, F. D. Synlett 2010, 675.
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