Gold-catalyzed oxidative cycloadditions to activate a quinoline framework

Article abstract of DOI:10.1002/chem.201302533

Going for gold! Gold-catalyzed reactions of 3,5- and 3,6-dienynes with 8-alkylquinoline oxides results in an oxidative cycloaddition with high stereospecificity (see scheme; EWG = electron-withdrawing group); this process involves a catalytic activation o

Full text of DOI:10.1002/chem.201302533

COMMUNICATION
DOI: 10.1002/chem.201302533
Gold-Catalyzed Oxidative Cycloadditions to Activate a Quinoline
Framework
[
a]
Deepak B. Huple, Satish Ghorpade, and Rai-Shung Liu*
One advent in gold catalysis is to generate a-oxo gold
[1]
carbenes by an intermolecular oxidation of terminal al-
[
2,3]
kynes by using pyridine-based oxide derivatives
8
with
+
À
[3]
-alkylquinoline oxide (Z ÀO ) being the most effective.
Besides easy and safe operation, gold carbenes generated
[
3e,i]
in this method might exhibit chemoselectivity
distinct
from other metal carbenes produced from hazardous
[4]
a-diazo carbonyl reagents. Importantly, this alkyne oxida-
tion enables one-pot synthesis of a-functionalized carbonyl
products by the trapping of this carbene with a suitable sub-
[
2,3]
strate, as depicted in Equation (1). In all reports,
the
side products Z (8-alkylquinolines) are considered to be
useless waste. Catalytic activation of a pyridine-based
framework is a challenging issue in synthetic chemistry, but
Scheme 1. Catalytic generation and cycloaddition of pyridinium ylides.
[7e–k]
[7e,g,i]
[7l]
dine,
demissidine,
and solanidane (A–C), as de-
[7]
picted in Scheme 2.
Although [3+2]-cycloadditions of a-carbonyl pyridinium
ylides with alkenes or alkynes have been well documented,
their operations commonly involve initial deproponation of
2
-oxomethyl pyridinium salts with strong bases in excess
very few examples have been
reported for the pyridine cyclo-
[5]
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
addition reaction. We report
herein a new and stereocontrol-
[6]
led catalytic cycloaddition
using an a-oxo gold carbene,
tethered electron-deficient
a
alkene, and 8-alkylquinoline, as
depicted by a-carbonyl pyridi-
nium ylides I (Scheme 1). The
importance of this synthetic
method is an easy access to
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
indolizine frameworks that
are common substructures
for many bioactive alkaloids
ACHTUNGTRENNUNGi ncluding the families of solani- Scheme 2. Representative naturally occurring alkaloids.
[
8,9]
[
a] D. B. Huple, S. Ghorpade, Prof. Dr. R.-S. Liu
Department of Chemistry
National Tsing Hua University
Hsinchu, 30013 (Taiwan)
Fax : (+886)3-5711082
E-mail: rsliu@mx.nthu.edu.tw
proportions (>1.0 equiv).
The generation of reactive pyr-
idinium ylides by a base-free catalytic process is important
in this field. Although Padwa reported the generation of
a-carbonyl pyridinium ylides from rhodium carbenes and
special pyridines (X=OH, SMe, Scheme 1), the resulting
ylides I’ reacted only with dimethyl acetylenedicarboxylate
(DMAD). We sought a new catalytic generation of pyridini-
[5b]
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201302533.
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[
a]
Table 1. Reactions over various gold catalysts.
Table 2. Oxidative cycloadditions with 3,5-dien-1-ynes.
[
a]
Entry Cat. (mol%)
2a’
t
Compound yields
[
b]
A
H
U
G
R
N
N
[%]
1
a
3a
4a
1
2
3
4
5
6
7
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
[AuCl
[AuCl
[AuCl
[AuCl
[AuCl(L)] (5)/AgNTf
[AuCl(PPh )] (5)/AgNTf
AgNTf (10)
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(IPr)] (5)/AgNTf
(IPr)] (5)/AgNTf
(IPr)] (5)/AgNTf
(IPr)] (5)/AgSbF
2
2
2
(5)
0
0
1.5
1.5
1.5
9
9
9
9
9
–
–
–
–
–
37
46
78
71
35
15
–
42
41
–
11
45
25
–
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(10)
(10)
(10)
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
6
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
2
(10)
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
3
2
(10) 1.5
1.5
16
16
55
85
2
[
P
a] [1a]=0.04m, IPr=1,3-bis(diisopropylphenyl)imidazol-2-yliden, L=
(tBu) (o-biphenyl). [b] Product yields are given after separation from a
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
2
silica column.
um ylide intermediates that can react with alkenes by using
cheap and readily available alkynes.
As shown in Table 1, [AuCl
(diisopropylphenyl)imidazol-2-ylidene, 5 mol%) was tested
first because of its high activity in several alkyne oxida-
ACHTUNGTRENNUNG( IPr)]/AgNTf (IPr=1,3-bis-
2
ACHTUNGTRENNUNG
[3d–g]
tions;
the treatment of 3,5-dien-1-yne 1a and 8-methyl-
quinoline oxide 2a (1.2 equiv) in hot 1,2-dichloroethane
(
DCE, 808C, 9 h) gave an oxidative [2+2+1]-cycloadduct 3a
[
3f]
and cyclopropyl indanone 4a
in 37 and 42% yields re-
[
(
a] [substrate]=0.04m,
10 mol%). Product yields are reported after separation from a silica
Au/Ag=[AuCl
A
H
U
G
R
N
N
(IPr)]
(5 mol%):AgNTf
2
spectively (Table 1, entry 1); only one diastereomeric form
was produced for desired 3a despite its four stereogenic
centers. Notably, a change of catalyst composition, Au/Ag=
column.
1
:2, gave compounds 3a and 4a in 46 and 41% yields, re-
spectively (entry 2). The presence of external 8-methylqui-
noline (1.5 equiv) greatly improved the chemoselectivity to
give only 3a in 78% yield (entry 3). Under the same condi-
tions, [AuCl ACHTUNGTRENNUNG( IPr)]/AgSbF (Au/Ag=5:10 mol%, entry 4)
6
gave mainly cycloadduct 3a in 71% yield, together with cy-
clopropyl indanone 4a in a minor proportion (11%).
Table 2 shows the substrate scope involving various 3,5-
dien-1-ynes 1b–l bearing an E-configured electron-deficient
[3f]
alkene; the competitive cyclopropanation product 4a was
completely suppressed with added 8-methylquinoline (1.5–
2.0 equiv) in most instances. As shown in entries 1–6
(Table 2), the reactions were applicable to various benze-
noid substrates 1b–g bearing a fluoro, chloro, and methoxy
substituent at their phenyl C(4) or C(5)-carbon atoms,
giving desired cycloadducts 3b–g with yields exceeding
76%. To our pleasure, the substrate scope was further ex-
panded through its compatibility with nonbenzenoid sub-
strates 1h–i to give desired products 3h–i in 61–67% yields
(entries 7–8). We examined the reactions on distinct alkene
substrates 1j–l bearing an enal, enone, and ethyl enoate
group; their resulting products 3j–l were obtained in 61–
[
AuCl{P
gave a mixture of 3a and 4a in comparable yields (entry 5).
In contrast, [AuCl(PPh )]/AgNTf or AgNTf with the same
Au/Ag ratio were either less active or inactive (Table 1,
entries 6–7).
The structural configuration of cycloadduct 3a was deter-
ACHTUNGTRENNUNG( tBu) (o-biphenyl)}]/AgNTf (Au/Ag=5:10 mol%)
2
2
ACHTUNGTRENNUNG
3
2
2
ACHTUNGTRENNUNG
[10]
mined by X-ray diffraction of its acyl derivative 5, which
was obtained by NaBH -reduction in THF, followed by a
4
standard acetylation procedure [Eq. (2)].
7
3% yields (entries 9–11) in the presence of 8- methylquino-
line (2–4 equiv). Herein, cyclopropyl indanone 4l, an ana-
logue of 4a, was isolated in 17% yield in the ester case
(
entry 11). The compatibility with varied electron-withdraw-
ing groups (EWG) demonstrated the broad substrate scope.
Table 3 shows the reactions on distinct 3,6-dien-1-ynes
6
a–c bearing E-configured electron-deficient alkenes
(
EWG=CN, COMe, and CO Et); their corresponding prod-
2
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Gold-Catalyzed Oxidative Cycloadditions
Table 3. Reactions of additional dienynes.
COMMUNICATION
Table 4. Reactions with various quinolines.
[
a]
[b]
Substrates
[n equiv] t [h]
Compound, yield [%]
[
a]
Entry
Dienyenes
Z
t [h]
Compound,
yield [%]
[
b]
1
2
1
2
3
4
5
6
7
1a (R =CN,R =H)
2b’ (R=H)
2c’ (R=Et)
2d’ (R=iPr)
2e’ (R=Bn)
2c’
12
1a, 56
1a
1a
1a
2.5
2.5
2.5
2.5
2.5
2.5
10a, 96
10b, 96
10c, 74
10d, 84
10e, 82
10 f, 67
1
2
3
EWG=CN
6a)
EWG=COMe
6b)
EWG=CO
6c)
2
2
2
4.0
6.5
6.0
7a, 83
7b, 74
7c, 70
–
1
2
(
8a (R =H,R =CN)
–
8a
8a
2d’
2e’
(
2
Et
4c, 17
[
(
a] [substrate]=0.04m,
10 mol%). [b] Product yields are reported after separation from a silica
Au/Ag=[AuCl
A
H
N
T
E
N
G
(5 mol%):AgNTf
2
(
column.
4
5
1.5 4.5
–
that unsubstituted quinoline 2b’ greatly reduced gold acidity
because of its strong coordination with the gold catalyst.
Table 5 presents experimental data to assess the role of
a-oxo gold carbene I by using diazo carbonyl species 11 as a
probe. The treatment of diazo carbonyl species 11 with
4
6.0
–
[
a] [substrate]=0.04m, Au/Ag=[AuCl
A
H
U
G
R
N
U
G
2
(10 mol%).
[
b] Product yields are reported after separation from a silica column.
Table 5. Reactions of additional dienynes.
ucts 7a–c were produced with excellent stereoselectivity and
satisfactory yields (70–85%; Table 3, entries 1–3). The acces-
sible azacycles of expanded size, such as 7a–c, again high-
light the utility of this cycloaddition. We prepared Z-config-
ured 3,5-dien-1-yne 8a and 3,6-dien-1-yne 8b to assess the
stereospecificity (entries 4–5); their resulting products 9a
[
a]
Entry Cat. (mol%)
2a
t
Compound yields
[
b]
A
H
U
G
R
N
U
G
[%]
1
1
3a
4a
(
77%) and 9b (81%) have the cyano group trans to the two
1
2
3
4
5
A
H
U
G
E
N
N
A
T
N
R
N
G
2
2
2
(5)
0
12
9
–
–
–
12
2
–
51
bridgehead protons, reflecting the retention of the Z-alkene
geometry. The structural configuration of compound 9a was
A
H
U
T
N
N
A
H
U
T
N
U
(5) 0.5
(10) 0.5
0.5
–
–
–
–
43
51
–
A
T
N
T
N
U
A
T
N
T
N
N
9
1
confirmed by H NOE spectroscopy and X-ray diffraction
18
18
2
[10]
Rh
2
A
T
N
R
N
U
G
4
(1.0)
0.5
18
studies.
Cycloadditions using various quinolines 2b’–e’ (Z) and
[a] [11]=0.04m. [b] Product yields are reported after separation from a
silica column.
+
À
their oxides 2b–e (Z ÀO ) are shown in Table 4; electron-
+
À
deficient pyridines (Z ÀO ), such as 2-chloro- and bromo-
pyridine were unsuccessful because they tended to deacti-
vate the alkyne oxidations unless Brønsted acids were pres-
8-methylquinoline (2a’, 2.0 equiv) and [AuCl ACTHUNGTERNNUN(G IPr)]/AgNTf
2
[
2]
ent. Nevertheless, key pyridinium ylides I in our system
are intolerant to Brønsted acids. With E-configured 3,5-
dien-1-yne 1a (Table 4, entry 1) a mixture of unsubstituted
quinoline 2b’ (1.2 equiv) and its oxide 2b (1.5 equiv) gave
mainly unreacted 1a under standard conditions, but, for
(2 equiv) in hot DCE (808C, 12 h) led to a complicated mix-
ture of products (Table 5, entry 1); this procedure failed to
generate a-oxo gold carbene I. In the presence of 8-methyl-
quinoline oxide (2a, 0.5 equiv), compounds 3a and 4a were
obtained in 43 and 12% yields, respectively (entry 2); oxide
2a clearly assists the carbene formation, possibly through its
stabilization effect. We postulate that the oxide acts as a
base to coordinate with the electrophilic carbon atom of
8-ethyl-, isopropyl-, and benzyl-substituted quinolines (2c’–
e’, entries 2–4) and their oxides, their corresponding cycload-
ducts 10a–c were obtained in satisfactory yields (74–96%,
entries 2–4). The use of these quinolines 2c’–d’ and their
oxides 2c–d on Z-configured 3,5-dien-1-yne 8a gave distinct
diastereomeric cycloadducts 10d–f in 67–84% yields (en-
tries 5–7), again showing the stereospecificity. We postulate
gold carbenes. With an increased AgNTf loading (Au/Ag=
2
5:10 mol%), the yield of desired 3a was increased to 51%
(entry 3). AgNTf and Rh ACHTUNGTENRUNG( OAc) (1 mol%) were either in-
2 4
2
active or ineffective to produce cycloadduct 3a even though
oxide 2a was present (entries 4–5). Although gold carbene I
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R.-S. Liu et al.
proved to be a viable intermediate, the use of a-oxo diazo
species 11 appears to be an inferior method.
This postulated mechanism provides insight into the
newly generated “a-oxo gold carbenes I” in the alkyne oxi-
dation. Not only does the use of 8-methylquinoline oxide fa-
cilitate carbene formation through stabilization, as depicted
in a control experiment (Table 5, entry 2), but also the car-
bene forms a reversible adduct with 8-methylquinoline to
The high stereospecificity of this cycloaddition, as mani-
fested by E- and Z-configured 3,5-dien-1-ynes 1a and 8a, is
reminiscent of a dipolar [3+2]-cycloaddition, on a a-carbon-
[11,12]
yl pyridinium ylide III (or III’)
Many dipolar [3+2]-cy-
cloadditions proceed through a concerted route to exhibit
retain a carbene reactivity, as postulated in current re-
[12]
[1–3]
high stereoselectivity; some a-carbonyl pyridinium ylides
ports.
Among various N-oxides, 8-methylquinoline oxide
[9c]
have such behavior in stoichiometric reactions. We envis-
is actually a poor oxidant to oxidize a-oxo gold carbene
[14]
age that an initial alkyne oxidation of species 1a with
because of its large steric size.
+
À
8
-methylquinoline oxide 2a (Z ÀO ) generates an a-oxo
In summary, we report a gold-catalyzed oxidative cycload-
dition between 3,n-dien-1-ynes (n=5, 6) and 8-alkylquino-
line oxides in the presence of 8-alkylquinolines. This reac-
tion is applicable to a broad range of 3,5- and 3,6-dien-1-
ynes to afford different-sized azacyclic products with high
stereospecificity. The use of a-carbonyl diazo reagents is ac-
cessible to desired products, but with less efficiency. We pos-
tulate a reaction mechanism in which the cycloaddition
begins with an alkyne oxidation to give an a-oxo gold car-
bene that then reacts with 8-methylquinoline to generate a
an a-carbonyl pyridinium ylide to enable a concerted [3+2]-
cycloaddition with a tethered alkene. The generation of a re-
active pyridinium ylide from cheap alkyne highlights the
value of this gold catalysis.
gold carbene I that is shown to be a viable intermediate (see
Table 3). This gold carbene reacts reversibly with 8-methyl-
quinoline to generate adduct II, as depicted in Scheme 3. To
Acknowledgements
We thank the National Science Council, Taiwan, for financial support of
this work.
Scheme 3. A plausible mechanism to rationalize the stereospecificity.
Keywords: catalysis
cyclization · stereoselectivity
· cycloaddition · gold · oxidative
address the stereospecificity, we envisage that species II un-
+
dergoes a dissociation of AuL to give an a-carbonyl pyridi-
[
11]
nium ylide III that was shown to be a detectable species.
This process is favored by bulky 8-methylquinoline oxides
alkyl=Et and isopropyl), thus resulting in the high yields
[
1] Review: J. Xiao, X. Li, Angew. Chem. 2011, 123, 7364–7375; Angew.
Chem. Int. Ed. 2011, 50, 7226–7236.
(
of their cycloadducts 10a–b and 10d–e (Table 4, entries 2–3
and 5–6). The ylide intermediate III likely reacts with its
tethered alkene through two possible conformations III and
III’. Conformation III’ is sterically less hindered than state
III, in which the carbonyl group is too near to its methyl
substituent; its corresponding product epi-3a was not pro-
duced at all. The concerted-type [3+2]-cycloaddition, as in
conformation III’, delivers the observed cycloadduct 3a.
As external 8-methylquinoline 2a’ (Z) suppressed the
yield of side-product 4a from starting 1a, its formation
arose mainly from a-oxo gold carbene I, rather than from
the pyridine ylide III (or III’). This hypothesis was actually
inferred from a separate experiment that chiral gold catalyst
can induce asymmetric induction on cyclopropane product
[2] For other pyridine N-oxides, see selected examples: a) L. Ye, L. Cui,
G. Zhang, L. Zhang, J. Am. Chem. Soc. 2010, 132, 3258–3259; b) L.
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T. Wang, S. Shi, M. Rudolph, J. Org. Chem. 2012, 77, 7761.
[
3] See selected examples: a) B. Lu, C. Li, L. Zhang, J. Am. Chem. Soc.
010, 132, 14070–14072; b) W. He, C. Li, L. Zhang, J. Am. Chem.
2
Soc. 2011, 133, 8482–8485; c) Y. Luo, K. Ji, Y. Li, L. Zhang, J. Am.
Chem. Soc. 2012, 134, 17412–17415; d) S. Ghorpade, M.-D. Su, R.-S.
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2
Das, R.-S. Liu, Angew. Chem. 2011, 123, 7043–7046; Angew. Chem.
Int. Ed. 2011, 50, 6911; g) R. B. Dateer, K. Pati, R.-S. Liu, Chem.
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Chang, W. Shao, Z. Yang, Y. Tang, Angew. Chem. 2013, 125, 4292–
[13]
4
a, but no induction effect on desired 3a. In our prefera-
I
I
ble catalyst composition Au /Ag =1:2, we speculate that
free Ag tends to stabilize the ylide species III to improve
4
296; Angew. Chem. Int. Ed. 2013, 52, 4198–4202; i) G. Henrion,
T. E. J. Chavas, X. L. Goff, F. Gagosz, Angew. Chem. 2013, 125,
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Pawar, C.-D. Wang, S. Bhunia, A. M. Jadhav, R.-S. Liu, Angew.
+
the cycloaddition selectivity.
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Gold-Catalyzed Oxidative Cycloadditions
COMMUNICATION
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[10] CCDC-935109 (5) and -935110 (9a) contain the supplementary crys-
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p. 215.
[
[
[
7] a) W. Flitsch in Comprehensive Heterocyclic Chemistry II, Vol. 8
(
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2
2
2
2
002, 19, 742; e) A. M. Mweetwa, D. Hunter, R. Poe, K. C. Harich,
DTBM-MeO-Biphep) to perform the following cycloaddition in
DCE (288C, 36 h), giving a mixture of desired 3a and cyclopropyl
indanone (+)-4a in 62 and 18% yield, respectively. Notably, no
asymmetric induction was obtained for compound 3a, whereas cy-
clopropyl indanone (+)-4a was obtained with 17% ee.
I. Ginzberg, R. E. Veilleux, J. G. Tokuhisa, Phytochemistry 2012, 75,
3
2
2–40; f) P. Heretsch, L. Tzagkaroulaki, A. Giannis, Angew. Chem.
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4
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[
8] For the generation of 2-oxomethylpyridinium ylides with bases, see
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9] Dipolar [3+2]-cycloadditions of a-carbonyl pyridium ylides with
electron-deficient alkenes were performed only stoichiometrically,
[
14] We have been able to compare the oxidation properties of 8-methyl-
quinoline oxide and 3,5-dichloropyridine oxide toward a-oxo gold
carbene species I; their results are shown in the Supporting Informa-
tion (Scheme S1).
[
[9c,e]
and some ylides showed high stereoselectivity.
See: a) W. Sliwa,
Heterocycles 1986, 24, 181; b) A. R. Katritzky, N. E. Grzeskowiak,
J. J. Alvarez-Builla, J. Chem. Soc. Perkin Trans. 1 1981, 1180; c) O.
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Received: July 1, 2013
Published online: && &&, 0000
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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5
&
ÞÞ
These are not the final page numbers!

R.-S. Liu et al.
Organic Synthesis
D. B. Huple, S. Ghorpade,
R.-S. Liu* ...................... &&&& — &&&&
Going for gold! Gold-catalyzed reac-
tions of 3,5- and 3,6-dienynes with 8-
alkylquinoline oxides results in an oxi-
dative cycloaddition with high stereo-
specificity (see scheme); this process
involves a catalytic activation of a qui-
noline framework. The reaction mech-
anism involves the intermediacy of a-
carbonyl pyridinium ylides in a con-
certed [3+2]-cycloaddition with a teth-
ered alkene.
Gold-Catalyzed Oxidative Cycloaddi-
tions to Activate a Quinoline Frame-
work
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6
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www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!