Gold-catalyzed oxidative cyclization of 1,5-enynes using external oxidants

Article abstract of DOI:10.1002/anie.201102581

Golden circle: Two gold-catalyzed oxidative cyclizations of 1,5-enynes using 8-methylquinoline N-oxide are presented (see example). Experimental results indicate that both reactions proceed through prior oxidation of alkyne to form α-carbonyl intermediate

Full text of DOI:10.1002/anie.201102581

DOI: 10.1002/anie.201102581
Synthetic Methods
Gold-Catalyzed Oxidative Cyclization of 1,5-Enynes Using External
Oxidants**
Dhananjayan Vasu, Hsiao-Hua Hung, Sabyasachi Bhunia, Sagar Ashok Gawade, Arindam Das,
and Rai-Shung Liu*
Table 1: Oxidative cyclization of 1,5-enynes over various catalysts.
Pd-catalyzed oxidative cyclizations of 1,6-enynes have found
useful applications in organic synthesis,[1] but such reactions
with Au and Pt catalysis remain largely unexplored.[2] Gold-
catalyzed cycloisomerizations of 1,5- and 1,6-enynes provide
uncommon and useful carbocyclic frameworks.[3] In the
presence of organic oxidants, most enynes fail to produce
oxidative cyclization products because oxidations of hypo-
thetical gold–carbenoid intermediates are difficult.[4,5] Herein,
we report two new oxidative cyclizations of 1,5-enynes via 5-
endo-dig and 5-exo-dig cyclizations, respectively; both reac-
tions are implemented with AuI and 8-methylquinoline N-
oxide. The success of such reactions relies on the prior
oxidations of enyne[6] form a-carbonyl carbenoids A and B,
followed by their intramolecular cyclizations (Scheme 1).
Terminal alkynes favor the oxidation at the C2 alkynyl carbon
atom and aminoalkynes prefer the C1 carbon atom.
Entry
Catalyst[a]
n
t
Products[b]
1
2
3
4
5
6
7
8
9
10
[PPh3AuCl]/[AgNTf2]
[LAuCl]/[AgNTf2]
[LAuCl]/[AgSbF6]
[LAuCl]/[AgNTf2]
[IPrAuCl]/[AgNTf2]
AuCl3
PtCl2/CO
[AgNTf2]
HNTf2
[LAuCl]/[AgNTf2]
1.2
1.2
1.2
3.0
1.2
1.2
1.2
1.2
1.2
0
5 min
5 min
5 min
5 min
15 min
12 min
24 h
1 h
1 h
15 min
2a (25%), 3a (45%)
2a (95%)
2a (84%)
2a (75%), 3a (9%)
2a (69%), 3a (12%)
1a (24%), 3a (58%)
3a (38%)
2a (42%), 3a (22%)
complicated mixture
4a (89%)
[a] L=P(tBu)2(o-biphenyl), [substrate]=0.25m. [b] Product yields are
reported after separation on a silica column.
[PPh3AuCl]/[AgNTf2] enabled complete consumption of
starting 1a to give 3-carbonyl-1H-indene 2a and a-carbonyl
amide 3a in 25% and 45% yields, respectively. To our delight,
the use of [LAuCl]/[AgNTf2] and [LAuCl]/[AgSbF6] [L = P-
(tBu)2(o-biphenyl)] gave desired product 2a exclusively with
respective 95% and 84% yields (Table 1, entries 2 and 3). A
high loading of 8-methylquinoline N-oxide (3.0 equiv) gave a-
carbonyl amide 3a in 9% yield, accompanied by desired 2a in
75% yield (Table 1, entry 4). The presence of by-product 3a,
in addition to unreacted 1a, interfered with other catalysts
including [IPrAuCl]/[AgNTf2] [IPr= 1,3-bis(diisopropylphe-
nyl)imidazol-2-ylidene], AuCl3, and PtCl2/CO (Table 1,
entries 5–7). In the control experiments (Table 1, entries 8
and 9), AgNTf2 or HNTf2 alone failed to show activity for the
oxidative cyclization of 1,5-enyne 1a under similar conditions.
In the absence of oxidant, we only obtained aromatization
product 4a from 1,5-enyne 1a and [P(tBu)2(o-biphenyl)-
AuCl]/[AgNTf2].
Scheme 1. Gold-catalyzed oxidative cyclization of 1,5-enynes.
+
ꢀ
ꢀ
A
O =8-methylquinoline N-oxide.
Table 1 shows the oxidative cyclization of 2-aminoalky-
nylstyrene 1a[7] over commonly used AuI and PtII catalysts
(5 mol%). We employed 8-methylquinoline N-oxide, which
exhibited greater catalytic activity than diphenylsulfoxide and
other pyridine-based oxides.[8–10] Treatment of a solution of
1,5-enyne species 1a (Table 1, entry 1) and 8-methylquinoline
N-oxide (1.2 equiv) in 1,2-dichloroethane (DCE, 258C) with
We prepared various 1,5-enynes 1b–l (Table 2) bearing an
aminoalkynyl substituent to assess the generality of this
oxidative cyclization. Entries 1–5 in Table 2 show the applic-
ability of this catalysis to enynes 1b–1 f bearing varied
electron-withdrawing amino groups including R2 = Ms and
Ts (Ms = methansulfonyl, Ts = toluene-4-sulfonyl), R3 = Me,
nBu, and phenyl to produce 3-carbonyl-1H-indene products
2b–2 f in good yields (78–92%). Similar to its analogue 1a,
propan-4-sultam species 1g was compatible with this catalysis,
[*] D. Vasu, H.-H. Hung, Dr. S. Bhunia, S. A. Gawade, Dr. A. Das,
Prof. Dr. R.-S. Liu
Department of Chemistry, National Tsing Hua University
Hsinchu 30013 (Taiwan)
Fax: (+886)3-571-1082
E-mail: rsliu@mx.nthu.edu.tw
[**] We thank National Science Council, Taiwan for support of this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201102581.
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Table 2: Reaction scope for 5-exo-dig oxidative cyclizations.
entries 1 and 2). 8-Methylquinoline N-oxide in excess pro-
portion (4 equiv) gave indanone 6a with increased yields,
52% and 57%, respectively for [P(tBu)2(o-biphenyl)AuCl]/
[AgNTf2] and [IPrAuCl]/[AgNTf2] (Table 3, entries 3 and 4).
At 808C, the yields of indanone 6a were increased to 65%
and 58% for [IPrAuCl]/[AgNTf2] and [P(tBu)2(o-biphe-
nyl)AuCl]/[AgNTf2], respectively (Table 3, entries 5 and 6).
Notably, treatment of 1,5-enyne 5a with [IPrAuCl]/[AgNTf2]
in the absence of 8-methylquinoline N-oxide led to a
complicated mixture within 6 min.
The formation of indanone 6a from 1,5-enyne 5a
represents a 5-endo-dig oxidative cyclization. We prepared
various 1,5-enynes 5b–p bearing alterable alkenyl and phenyl
substituents to assess the generality of this catalysis, as
depicted in Table 4. This reaction is applicable to enyne 5b
bearing a vinyl group, giving the desired indanone 6b in 53%
yield (Table 4, entry 1). For 1,5-enynes 5c–e bearing a trans-
substituted n-butyl, phenyl, or cyclopropyl substituent, the
resulting products 6c–e were formed stereoselectively in 69–
89% yields (Table 4, entries 2–4). The stereospecificity of this
oxidative cyclization is best manifested by the two diastereo-
mers 5 f and 5g, which delivered the isomeric indanones 6 f
and 6g in 65% and 66% yields, respectively (Table 4,
Entry Enyne[a]
X=Y=R1 =H
t [min] Products[b]
1
2
3
4
5
6
R2 =Ms, R3 =Me (1b)
R2 =Ms, R3 =Ph (1c)
R2 =Ms, R3 =nBu (1d)
R2 =Ts, R3 =Me (1e)
R2 =Ts, R3 =Ph (1 f)
R2, R3 =-(CH2)3SO2- (1g)
20
10
5
20
5
2b (78%)
2c (80%)
2d (92%)
2e (84%)
2 f (89%)
2g (92%)
5
X=Y=H
7
R1 =Me, R2 =Ms, R3 =nBu (1h) 60
2h (49%), 3h (32%)
R1 =H, R2 =Ts, R3 =Me
8
9
10
11
X=Cl, Y=H (1i)
20
20
20
20
2i (83%)
2j (85%)
2k (55%), 3k (12%)
2l (75%)
X=H, Y=Cl (1j)
X=OMe, Y=H (1k)
X=H, Y=OMe (1l)
[a] [Substrate]=0.25m. [b] Product yields are reported after separation
on a silica column.
Table 4: Reaction scope for the 5-endo-dig oxidative cyclizations.
giving desired product 2g in 92% yield (Table 2, entry 6). We
examined this reaction also on 1,2-disubstituted alkene
species 1h (E/Z = 2.4:1), which gave 3-carbonyl-1H-indene
2h and a-carbonyl amide 3h (E/Z = 1:1.4) in 49% and 32%
yields, respectively (Table 2, entry 7). This catalysis is exten-
sible to 1,5-enynes 1i–l bearing a chloro and methoxy
substituents at the phenyl C4 and C5 carbon atoms, which
gave desired 2i–l in 55–85% yields (Table 2, entries 8–11). We
obtained a-carbonyl amide 3k in 12% yield from substrate 1k
bearing a methoxy group para to the alkynyl group (Table 2,
entry 10).
This gold-catalyzed reaction is applicable to 1,5-enynes
(Table 3) bearing a terminal alkyne, as represented by species
5a. The reactions on this enyne using [P(tBu)2(o-biphe-
nyl)AuCl]/[AgNTf2] and [IPrAuCl]/[AgNTf2] catalysts and 8-
methylquinoline N-oxide (1.2 equiv) in DCE (258C) led to
complete consumption of starting 5a within 4–5 h, giving the
desired indanone 6a in comparable yields (38–41%, Table 3,
Entry
Enyne[a]
t [h]
Products[b]
1
2
3
4
R1 =R2 =H (5b)
2
2.5
3
6b (53%)
6c (69%)
6d (89%)
6e (83%)
R1 =nBu, R2 =H (5c)
R1 =Ph, R2 =H (5d)
R1 =cyclopropyl,
3
R2 =H (5e)
5
6
7
R1 =Ph, R2 =Me (5 f)
R1 =Me, R2 =Ph (5g)
R1, R2 =-(CH2)5- (5h)
3.5
3.5
6
6 f (65%)
6g (66%)
6h (61%)
8
9
2
2
5i
5j
6i (78%)
6j (84%)
Table 3: Oxidative cyclizations of 1,5-enyne 5a via 5-endo-dig mode.
Entry [Au][a]
n
T [8C] t [h] Products[b]
1
2
3
4
5
6
7
[LAuCl]/[AgNTf2]
[IPrAuCl]/[AgNTf2] 1.2 25
1.2 25
4
5
4
34
1
6a (38%)
6a (41%)
6a (52%)
6a (57%)
6a (58%)
6a (65%)
complicated mixture
[LAuCl]/[AgNTf2]
[IPrAuCl]/[AgNTf2] 4.0 25
[LAuCl]/[AgNTf2] 4.0 80
[IPrAuCl]/[AgNTf2] 4.0 80
[IPrAuCl]/[AgNTf2] 25
4.0 25
10
11
12
13
X=Cl, Y=H (5k)
X=H, Y=Cl (5l)
X=OMe, Y=H (5m)
X=H, Y=OMe (5n)
3.5
3.5
3.5
3.5
6k (76%)
6l (67%)
6m (75%)
6n (71%)
3
0.1
0
[a] [Substrate]=0.25m, [IPrAuNTf2] (5 mol%), DCE, 808C, 8-methylqui-
noline N-oxide (4 equiv). [b] Product yields are reported after separation
on a silica column.
[a] L=P(tBu)2(o-biphenyl), [substrate]=0.25m. [b] Product yields are
reported after separation on a silica column.
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entries 5 and 6). The structures of compounds 6 f and 6g were
confirmed by 1H NOE spectra. The gold-catalyzed reaction of
trisubstituted alkene 5h (Table 4, entry 7) gave expected
indanone 6h in 61% yield. The scope of this oxidative
cyclization was further expanded by its applicability to non-
benzenoid substrates 5i and 5j, which gave cyclopentenone
derivatives 6i and 6j in 78% and 84% yields, respectively
(Table 4, entries 8 and 9). We prepared also new substrates
5k–n to examine the effects of their phenyl substituents.
Good yields (67–76%) were obtained for the resulting
products 6k–n bearing chloro and methoxy substituents at
the phenyl C4 and C5 carbon atoms (Table 4, entries 10–13),
further illustrating the wide scope of substrates.
Scheme 3. Control experiments to clarify the reaction mechanism.
As shown in Scheme 2, this gold-catalyzed reaction is
extensible to 1,5-enyne 5o bearing an internal alkyne, giving
desired compound 6o in 76% yield. For 1,5-enyne 5p bearing
an ester group, we observed no cycloisomerization reaction in
Scheme 4. Deuterium-labeling experiments and a plausible mecha-
nism.
intermediacy of this carbenoid is inferred from the presence
of a-carbonyl amide 3a generated from its secondary
oxidation with 8-methylquinoline N-oxide.[11] We envisage
that the amide functionality of p-alkyne D accelerates the
nucleophilic attack of 8-methylquinoline N-oxide at the
alkynyl C1 carbon atom to give alkenylgold intermediate E,
which undergoes rearrangement to gold carbenoid F. To
rationalize the deuterium-labeling experiment, species F
undergoes intramolecular carbocyclization to form benzyl
cation G that subsequently gives desired [D2]-2a by a 1,2-shift
of deuterium. We propose also a plausible mechanism to
rationalize the formation of indanone 6c from 1,5-enyne 5c
(Scheme 5). Transformation 9!10 in the control experiment
(Scheme 3) unambiguously supports the prior oxidation route
(path a). We believe that occurrence of the initial 6-endo-dig
pathway (path b) is difficult because the gold–p-alkyne
moiety of species 5c has the positive charge located primarily
at the alkynyl C2 carbon atom. We envisage also that
hypothetical benzyl cation I would be prone to aromatization
to give naphthalene product J instead. The prior 6-endo-dig
route is further excluded because 1,5-enyne 5p showed no
activity in the gold-catalyzed cycloisomerization reaction, but
it was active in this oxidative cyclization (see Scheme 2).
In summary, we report two gold-catalyzed oxidative
cyclizations of 1,5-enynes using 8-methylquinoline N-oxide.
For 1,5-enynes 1 bearing an aminoalkynyl substituent, the
Scheme 2. Applicability of gold-catalyzed oxidative cyclization to addi-
+
ꢀ
ꢀ
tional 1,5- and 1,6-enynes. A O =8-methylquinoline N-oxide.
hot DCE in the presence of [IPrAuNTf2] only; herein, starting
5p and [IPrAuNTf2] (5 mol%) were recovered in 84% and
67% yields. Interestingly, enyne 5p was efficiently trans-
formed into cyclopropyl indanone 6p as external 8-methyl-
quinoline N-oxide (3 equiv) was added to the same system. To
our delight, this oxidative cyclization is even applicable to 1,6-
enyne 7, giving desired product 8 in 61% yield under the same
conditions.
We prepared deuterated sample [D2]-1a to understand
the reaction mechanism of the 5-exo-dig oxidative cyclization
(Scheme 3). The resulting product [D2]-2a contains 0.88 and
1.0 deuterium content at the indenyl C1 and C2 carbon atoms,
respectively. We prepared also 2-benzyl-1-ethynylbenzene
(9), which produced 3-phenylindanone (10) in 84% yield in
the presence of [IPrAuCl]/[AgNTf2] (5 mol%) and 8-meth-
ylquinoline N-oxide (3 equiv) in hot dichloroethane (808C,
3 h). This transformation clearly asserts the intermediacy of
a-carbonyl gold–carbenoid C, which undergoes a subsequent
ꢀ
C H insertion to give the observed product 10.
Accordingly, we propose a plausible mechanism involving
a-carbonyl gold–carbenoid intermediate F (Scheme 4). The
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Communications
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2-bromopyridine N-oxide (2a, 83%), 3-bromo-5-methoxycarbo-
nylpyridine N-oxide (2a, 86%), and 8-isopropylquinoline N-
oxide (2a, 89%).
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Scheme 5. Proposed mechanism for formation of indanone 6c.
corresponding gold-catalyzed reactions gave 3-carbonyl-1H-
indene compounds 2 efficiently. The same catalytic reactions
on 2-ethynylstyrenes 5 and their non-benzenoid analogues
produced cyclopropyl indanone compounds 6 stereoselec-
tively. On the basis of experimental data, we propose that
both reactions proceed through prior oxidations of alkyne to
form a-carbonyl intermediates, followed by intramolecular
carbocyclizations.
Received: April 14, 2011
Published online: June 6, 2011
Keywords: cyclization · enynes · gold · homogeneous catalysis ·
.
oxidation
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6914 www.angewandte.org
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