Gold-catalyzed oxidative cyclizations of cis-3-En-1-ynes to form cyclopentenone derivatives

Article abstract of DOI:10.1002/anie.201108027

Golden tendencies: The title reaction for synthesizing cyclopentenone derivatives utilizes a gold complex and 8-methylquinoline oxide as the catalyst system (see scheme; IPr=1,3-bis(diisopropylphenyl)imidazol-2-ylidene). Such products are not attainable using diazocarbonyl reagents, as the gold carbenoids tend to react with C-H bonds. Copyright

Full text of DOI:10.1002/anie.201108027

Angewandte
Chemie
DOI: 10.1002/anie.201108027
À
C H Insertion
Gold-Catalyzed Oxidative Cyclizations of cis-3-En-1-ynes To Form
Cyclopentenone Derivatives**
Sabyasachi Bhunia, Satish Ghorpade, Deepak B. Huple, and Rai-Shung Liu*
Table 1: Gold-catalyzed oxidative cyclization of cis-substituted 3-en-1-
yne.
Cycloisomerizations of 1,n-enynes (n = 5, 6) catalyzed by
transition metals are powerful tools for accessing complicated
carbocycles.[1,2] Such reactions have been intensively studied
for many transition metals having diverse reaction mecha-
nisms. Metal-catalyzed oxidative cyclizations of 1,n-enynes
(n = 5, 6) are synthetically appealing because the product
skeletons incorporate oxy or oxo functionalities,[3,4] but there
are fewer reported examples for enyne oxidative cyclizations
than for their cycloisomerzation reactions.[1,2] Our group and
the groups of others have reported the catalytic cycloisome-
rizations of cis-3-en-1-ynes to form cyclopentadiene deriva-
tives using ruthenium or platinum catalysts, respectively
(Scheme 1a);[5] the corresponding oxidative cyclization
Entry
Catalyst[b]
T
t
Yield [%][c]
[8C]
[h]
1
2
3
4
5
6
7
8
[PPh3AuCl]/AgNTf2
[LAuCl]/AgNTf2
[LAuCl]/AgSbF6
[IPrAuCl]/AgNTf2
[IPrAuCl]/AgSbF6
[IPrAuCl]/AgNTf2
AuCl3
80
80
80
80
80
25
80
80
10
3
3
2.5
3
24
10
10
42
70
65
83
77
80
26[d]
AgNTf2
no reaction[d]
[a] [3a]=0.17m. [b] L=P(tBu)2(o-biphenyl). [c] Product yields are
reported for products isolated from a silica gel column. [d] Starting 3a
was recovered in 60% in entry 7, and 72% in entry 8. IPr=1,3-
bis(diisopropyl phenyl)imidazol-2-ylidene), Tf=trifluoromethanesul-
fonyl.
(entry 1). Catalytic efficiencies were improved with [ClAuP-
(tBu)2(o-biphenyl)]/AgNTf2 and [ClAuP(tBu)2(o-biphenyl)]/
AgSbF6, both of which gave the desired 4a in 70% and 65%
yield, respectively (entries 2–3). We enhanced the yields of 4a
to 83% and 77% using [IPrAuCl]/AgNTf2 and [IPrAuCl]/
AgSbF6, respectively (entries 4–5). At 258C with an extended
reaction time (24 h), the conversion was complete for the
[IPrAuCl]/AgNTf2 catalyst to give compound 4a in 80% yield
(entry 6). AuCl3 gave 4a in a low yield (26%) together with
unreacted 3a in 60% recovery (entry 7). AgNTf2 was inactive
in this oxidative cyclization and 72% of 3a was recovered
(entry 8).
Scheme 1. a) Cycloisomerizations and b) oxidative cyclizations of 3-en-
1-ynes.
remains undocumented. Herein, we report new gold-cata-
lyzed oxidative cyclizations of cis-3-en-1-ynes to give cyclo-
pentenone skeletons using 8-methylquinoline oxide (Sche-
À
me 1b). Notably, the mechanistic transformation of this C H
activation is proven to proceed through a noncarbene route,
thus excluding the intermediacy of the a-carbonyl carbene
A.[6,7]
The reaction of the cis-3-en-1-yne 3a in the presence of
various gold catalysts and 8-methylisoquinoline oxide[7]
(3 equiv) as the oxidant were investigated (Table 1). The use
of [PPh3AuCl]/AgNTf2 (5 mol%) resulted in the complete
consumption of 3a in hot 1,2-dichloroethane (DCE, 808C,
10 h), thus giving 3-phenylindanone (4a) in 42% yield
We prepared various benzene-derived substrates (3b–3p)
to examine the scope of this oxidative cyclization. In a typical
operation, the starting substrate was treated with 8-methyl-
quinoline oxide (3 equiv) and [IPrAuCl]/AgNTf2 in hot DCE
(808C) to give the corresponding indanone products 4b–4p
almost exclusively. We obtained satisfactory yields (84–86%)
of the indanones 4b, c bearing an electron-deficient benzene
(Table 2, entries 1–2), whereas a complex mixture of products
was obtained for substrate 3d, which has an electron-rich 4-
methoxyphenyl group (entry 3). This oxidative cyclization
worked well also with substrates 3e and 3 f, thus giving the
desired products in 68 and 78% yields, respectively (entries 4
and 5). This new reaction is applicable to the substrates 3g–3l
bearing alkyl substituents, and the corresponding products
4g–4l were obtained in 67–90% yields (entries 6–11). The
[*] Dr. S. Bhunia, S. Ghorpade, D. B. Huple, Prof. Dr. R.-S. Liu
Department of Chemistry, National Tsing Hua University
Hsinchu, 30013 (Taiwan)
E-mail: rsliu@mx.nthu.edu.tw
[**] We thank the National Science Council, Taiwan, for financial support
of this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201108027.
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Table 2: Reaction scope for the synthesis of indanones.
Table 3: Reaction scope for the synthesis of cyclopentenones.
Entry
3-En-1-ynes[a]
t [h]
Products[b]
Entry
3-En-1-ynes[a]
t [h]
Products[b]
1
2
3
4
5
R=C6H5 (5a)
0.8
0.5
2.0
0.5
0.5
6a (88%)
6b (87%)
6c (67%)
6d (81%)
6e (90%)
1
2
3
4
5
Ar=4-FC6H4 (3b)
Ar=4-ClC6H4 (3c)
Ar=4-MeOC6H4 (3d)
Ar=2-thienyl (3e)
Ar=3-thienyl (3 f)
3
2
2
2.5
3
4b (86%)
4c (84%)
complex mixture
4e (68%)
4 f (78%)
R=CH2Cl (5b)
R=CH2OTBS (5c)
R=benzyl (5d)
=
R=CH2CH CH2 (5e)
6
7
8
9
R=C6H5 (5 f)
0.8
0.5
2.0
0.5
6 f (85%)
6g (81%)
6h (64%)
6i (82%)
6
7
8
9
10
11
R=H (3g)
R=benzyl (3h)
R=CH2Cl (3i)
R=CH2OTBS (3j)
R=CH2OMOM (3k)
R=CH2CH CH2 (3l)
2.5
0.5
2.5
2
1.5
0.5
4g (83%)
4h (85%)
4i (71%)
4j (67%)
4k (71%)
4l (90%)
R=CH2Cl (5g)
R=CH2OTBS (5h)
R=CH2Ph (5i)
=
10
0.5
11
0.4
12
13
14
15
X=F, Y=H (3m)
X=H, Y=F (3n)
X=MeO, Y=H (3o)
X=H, Y=OMe (3p)
6
7
6
12
4m (67%)
4n (63%)
4o (63%)
4p (62%)
[a] [3-En-1-ynes]=0.17m, reactions performed at 808C. [b] Product yields
are reported for products isolated from a silica gel column.
[a] [3-en-1-ynes]=0.17m, reactions performed at 808C. [b] Product yields
are reported for products isolated from a silica gel column. MOM=
methoxymethyl, TBS=tert-butyldimethylsilyl.
reactions can also be extended to substrates 3m–3p bearing
a fluoro and methoxy group at either the C4- or C5-carbon
atoms of the bridging benzenes, thus giving the expected
indanone derivatives 4m–4p in 62–67% yields (entries 12–
15).
The scope of this oxidative cyclization is substantially
expanded with its application to the nonbenzene-derived
substrates 5a–5k, as shown in Table 3. In most instances, the
conversions were complete within a short period (0.4–0.8 h).
The results demonstrate the efficient syntheses of the useful
hexahydro-1H-inden-1-ones 6a–6e (67–90%) from gold-
catalyzed oxidative cyclizations of the 3-en-1-ynes 5a–5e
bearing a bridging cyclohexene (entries 1–5). To our delight,
this new synthesis is additionally applicable to the synthesis of
the bicyclo[5.3.0]decen-10-ones 6 f–6i (64-85%) using sub-
strates 5 f–5i (entries 6–9). We tested the reactions on acyclic
3-en-1-yne 5j, which gave desired cyclopentenone 6j in 82%
yield (entry 10). The reaction proceeded well with starting 5k,
bearing a bridging dihydronaphthalene, thus giving com-
pound 6k in 80% yield.
Scheme 2. The effects of substituents. [a] 3s was recovered in 51%
yield after 12 h.
recovered. The presence of an electron-withdrawing substitu-
ent as in substrates 3h–3l (Table 2, entries 7–11) is clearly
indispensable for this oxidative cyclization, thus reflecting the
À
importance of the C H acidity.
We also prepared [D2]-3a, which was deuterated 100% at
the methylene position, and the gold-catalyzed reactions
provided a 63% yield of the indanone [D2]-4a having a 50%
and 48% deuterium content for the methylene positions,
which is indicative of a 1,2-hydrogen shift. As shown in
Scheme 3, we studied the kinetic isotope effect using the
monodeuterated sample [D1]-3a and the corresponding
indanone 4a has different deuterium distributions with [D1]-
4a/[D1]-4a’ having a kH/kd = 1.5. Although a three-centered
À
An understanding the effects of the C H acidity is
discussed (Scheme 2). We found that the transformation of
3q, bearing a 4-chlorophenyl substituent, proceeded more
rapidly and efficiently than its 4-methoxyphenyl analogue 3r
in the formation of the corresponding cyclized products 4q
and 4r. We observed no desired product for the substrate,
even after a longer reaction time (12 h); 51% of 3s was
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Scheme 3. Deuterium-labeling experiments.
Scheme 5. The nature of C H insertion.
concerted mechanism (B) is well accepted for most metal–
carbene species that give a kH/kd = 1–2.5, such reactions are
assisted by an electron-donating group (X = EDG) because of
the positive character that develops on the reacting carbon
atom.[8,9] This model, however, is incompatible with our
observation that an electron-withdrawing group enhances the
À
C H activation.
We assessed the role of the a-carbonyl carbenoid A using
the authentic diazocarbonyl species 7a.[8d] Treatment of 7a
with [IPrAu]/AgNTf2 (5 mol%) in DCE at 258C for 15 hours
led to its complete consumption, but the desired 4a was
delivered in low yield (13%) together with the arylation
product 8a (21%) and aldehyde 9a (46%).[10,11] This infor-
mation reveals that the a-carbonyl carbeniod A was actually
generated from the diazocarbonyl species 7a, but it lacks
Scheme 6. A plausible reaction mechanism.
and 5). We envisage that the initially formed gold-containing
enol ether C has a high barrier to overcome for the formation
of the hypothetical carbenoid A. Instead, this species under-
goes a rapid 1,5-hydrogen shift[13] to form the species D. We
propose that such a shift has a proton character because it is
captured by the electron-rich gold/alkenyl moiety. A subse-
quent cyclization of D is expected to give the observed
product (4a or 6a). This proposed mechanism explains the
À
chemoselectivity toward the C H bond insertion.
À
We also studied the C H insertion reactions of the a-
carbonyl carbeniod A using the diazocarbonyl species 7b–d
À
(Scheme 5). We obtained no C H insertion product for the
methyl derivative 7b, but the desired indanones 4s and 4t
were isolated (37 and 67% yield, respectively) from the 7c
À
À
and 7d, respectively. The C H insertion of the carbeniod A
observation that an acidic C H bond accelerates this
seems to follow a concerted mechanism (B; Scheme 3),[9] thus
showing the reactivity order: tert-C-H > sec-CH > CH3. This
trend is opposite to that of our oxidation system which has the
order: CH3 @ sec-CH and tert-C-H.[12]
oxidative cyclization. The nonbenzene-derived substrate 5a
is more active than its benzene-derived analogue 3a because
the 1,5-hydrogen shift of the former avoids dearomatiza-
tion.[14]
A plausible mechanism to rationalize the formation of
indanone (4a) and cyclohexenone (6a) products is proposed
(Scheme 6). The intermediacy of the a-carbonyl carbenoid A
In summary, we report the first successful catalytic
oxidative cyclization of cis-substituted 3-en-1-ynes using
a suitable gold complex and 8-methylquinoline oxide. The
value of such reactions is reflected by their applicability to
a broad range of benzene- and nonbenzene-derived sub-
strates, thus giving various indanone and cyclopentenone
derivatives, respectively. Similar products are not attainable
efficiently using diazocarbonyl reagents because the gold
À
is excluded because it behaves very differently for the C H
activation according to our control experiment (Schemes 4
À
carbenoid was proven to be unviable for the same C H bonds.
Accordingly, we hypothesize a 1,5-hydrogen shift of initially
formed gold-containing enol ether C as the key step.
Received: November 15, 2011
Revised: December 21, 2011
Published online: February 1, 2012
À
Keywords: C H insertion · cyclizations · gold · heterocycles ·
synthetic methods
.
Scheme 4. The reaction using diazocarbonyl.
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tentative mechanism is proposed in the Supporting Information.
[11] Organic oxide and base may affect product distribution in
Scheme 4. In the presence of 8-methylquinoline oxide (3 equiv),
the reaction of dazocarbonyl species 7a (1 equiv) and
IPrAuNTf2 (5 mol%) in DCE (258C, 25 h) only gave a 86%
recovery of starting 7a. The presence of 8-methylquinoline
(1 equiv) retarded the reaction of diazocarbonyl species 7a with
IPrAuNTf2 in DCE (258C, 35 h), giving desired 4a (7%),
arylation product 8a (10%), aldehyde (19%) and unreacted 7a
(50%); the product distribution is analogous to that in
Scheme 4.
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catalyzed oxidative cyclization; its spectroscopic data is provided
in the Supporting Information.
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