Catalytic Dearomative Spirocyclization via Gold Carbene Species Derived from Ynamides: Efficient Synthesis of 2-Azaspiro[4.5]decan-3-ones

Article abstract of DOI:10.1002/chem.201800314

An intramolecular catalytic dearomatization of phenols via gold carbene species proceeded to provide 2-azaspiro[4.5]decan-3-ones. The use of NHC ligand and water as a co-solvent was critical for achieving high reactivity. This reaction did not require hazardous diazo compounds as carbene sources and proceeded even under air. The obtained spirocyclic product could be readily transformed into a gabapentin derivative by hydrogenation and deprotection.

Full text of DOI:10.1002/chem.201800314

A Journal of
Accepted Article
Title: Catalytic Dearomative Spirocyclization via Gold Carbene
Species Derived from Ynamides: Efficient Synthesis of 2-
Azaspiro[4.5]decan-3-ones
Authors: Mamoru Ito, Ryosuke Kawasaki, Kyalo Stephen Kanyiva, and
Takanori Shibata
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To be cited as: Chem. Eur. J. 10.1002/chem.201800314
Link to VoR: http://dx.doi.org/10.1002/chem.201800314
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COMMUNICATION
Catalytic Dearomative Spirocyclization via Gold Carbene Species
Derived from Ynamides: Efficient Synthesis of 2-
Azaspiro[4.5]decan-3-ones
[
a]
[a]
[b]
[a,c]
Mamoru Ito, Ryosuke Kawasaki, Kyalo Stephen Kanyiva, and Takanori Shibata*
Dedication ((optional))
Abstract: An intramolecular catalytic dearomatization of phenols via
gold carbene species proceeded to provide 2-azaspiro[4.5]decan-3-
ones. The use of NHC ligand and water as a co-solvent was critical
for achieving high reactivity. This reaction did not require hazardous
diazo compounds as carbene sources and proceeded even under air.
The obtained spirocyclic product could be readily transformed into a
gabapentin derivative by hydrogenation and deprotection.
phenols via metal carbene species, and hazardous diazo
[
8]
compounds were used as carbene sources in all cases.
(a) Cyclopropanation (refs. 2d and 2e)
Ts
OH
Ts
Ts
AuCl
R2
R3
N
R2
R3
Au cat.
N
N
R1
R1
R2
R1
OH
O
R3
(b) C-H insertion (ref. 2i)
Introduction
PG
O
Ph
N
R1
cationic Au cat. R1
N-oxide
PG
H
N
[Au] PG
N
Gold-catalyzed transformations can be used to realize the various
facile syntheses of complex organic molecules generally under
Ph
R1
Ph
R2
R2
O
[
1]
mild conditions. In particular, gold carbene species exhibit
unique reactivity in cyclopropanation (Scheme 1a) and X-H (X =
R2
(
c) Concept of this work
[
2]
C, O, N) insertion (Scheme 1b). Therefore, it would be highly
desirable to explore the reactivity of gold carbene species in
organic synthesis. Among various protocols for the preparation of
PG
R
Au cat.
NPG
O
N
N-oxide
-R'
base
N
PG
R'O
O
R
R'O
[Au]
[
3]
O
R
gold carbene species,
diazo compounds are the most
gold carbene species
conventional carbene source. To avoid the use of hazardous
compounds, the oxidation of alkynes using a gold catalyst and N-
oxide as an oxidant has been developed as an attractive
Scheme 1. Reactivity of gold carbene species and concept of this work.
[
4]
alternative.
The spirocyclic structure is a common skeleton in various
[
5]
Results and Discussion
natural products and biologically active compounds. In particular,
spirocyclohexadienones, which can be synthesized by the
dearomatization of phenols, are attractive structures because of
We chose 4-methoxybenzylamine derivative 1a as a model
[
6]
substrate and subjected it to dearomative spirocyclization using a
their biological activities.
Various strategies for the
[
7]
cationic
gold
catalyst
prepared
and
from
dearomatization of phenols have been developed: oxidative
spirocyclization using hypervalent iodine, Friedel-Crafts-type
spirocyclization, and a radical-type reaction have been reported.
chloro(triphenylphosphine)gold(I)
silver
hexafluoroantimonate in a mixed solvent of 1,2-dichloroethane
DCE) and water (Table 1, Entry 1). As a result, the desired
(
Against this background, we envisioned
a
catalytic
spirocyclic compound 2a was obtained in moderate NMR yield.
The major byproduct was diketone, which was probably
generated by further oxidation of the gold carbene complex. To
accelerate the desired spirocyclization, an electron-deficient
phosphine ligand was examined, but the yield did not improve and
formation of the diketone was observed (Entries 2 and 3). The
counter anion did not affect the present reaction (Entries 4 and 5).
While only a trace amount of product was obtained under gold
complex-free conditions, a comparable yield was achieved under
silver salt-free conditions (Entries 6 and 7). We further screened
NHC ligands using neutral gold catalyst (Entries 8-13). Among
them, IPr and SIPr suppressed the formation of diketone and the
NMR yield reached ca. 80%. This results is probably due to the
fact of that bulky NHC ligands prevented the attack of N-oxide to
dearomative spirocyclization of phenols by using gold carbene
species generated from alkynes (Scheme 1c). There have been
only a few previous reports of the dearomative spirocyclization of
[a]
Department of Chemistry and Biochemistry, School of Advanced
Science and Engineering, Waseda University, Shinjuku, Tokyo 169-
8555, Japan
E-mail: tshibata@waseda.jp
http://www.chem.waseda.ac.jp/shibata/
[
b]
c]
Global Center for Science and Engineering, School of Advanced
Science and Engineering, Waseda University, Shinjuku, Tokyo 169-
8555, Japan
[
ACT-C, Japan Science and Technology Agency (JST), 4-1-8
Honcho Kawaguchi, Saitama 332-0012, Japan
[
9]
the gold carbene intermediate.
When the reaction was
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
conducted in DCE as a sole solvent, the yield was drastically
decreased and a significant amount of diketone was formed
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Chemistry - A European Journal
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COMMUNICATION
(
Entry 9). These results mean that Cl of LAuCl was replaced by
Under the reaction conditions for Entry 14 in Table 1, various
aryl-substituted ynamides were subjected to Au(I)-catalyzed
dearomative spirocyclization (Table 2). A variety of halophenyl-
substituted ynamides 1b-1e provided spirocyclic compounds 2b-
2e in good to high yield (Entries 1-4). Para-, ortho-dihalo- and
para-methoxycarbonyl-substituted phenyl groups could be used
in this reaction, but more quinoline (20 mol%) was required
(Entries 5 and 6). The reaction of para-trifluoromethyl-substituted
phenyl group-substituted ynamide 1h gave 2h in the best yield of
[
10,11]
OH from water, and LAu(OH) would be an active catalyst.
We
next added a catalytic amount of quinoline as a basic additive and
[
12]
the isolated yield improved to 85% (Entry 14).
The base
probably captured the in situ-generated hydrogen chloride. The
reaction could also be conducted on larger reaction scale (Entry
1
5). Finally, we conducted the reaction under air, and did not
observe a significant decrease in the yield, which demonstrated
the robustness of the present catalytic system (Entry 16).
9
8% (Entry 7). In contrast, an ortho-trifluoromethylphenyl group
suppressed the reaction probably due to steric hindrance, and the
yield of 2i was low (Entry 8). The reactivities of electron-rich aryl
group-substituted ynamides were low (Entries 9-12). In particular,
[
a]
Table 1. Screening of reaction conditions.
LAuCl (10 mol%)
additive (10 mol%)
quinoline N-oxide (2.0 equiv)
Ph
NTs
Ph
p-tolyl-substituted ynamide 1j required
a higher reaction
O
N
temperature with the use of Ph PAuCl as a catalyst and a
3
Ts
DCE/H O = 1/4, 80 °C
2
moderate yield was achieved (Entry 9), but the yield of p-anisyl-
substituted ynamide 1m was low even under the same reaction
conditions (Entry 12). Pyridyl-substituted ynamide 1n was a good
substrate (Entry 13). The spirocyclization of terminal alkyne 1o
was conducted with chloro(triphenylphosphine)gold(I) using 4-
phenylpyridine N-oxide as an oxidant at room temperature to
provide 2o in a moderate yield (Entry 14). In all entries, ynamides
were completely consumed, and the formation of diketones were
ascertained as by-products.
MeO
O
1
a
2a
[
b]
Entry
Ligand (L)
PPh
P(C
P(p-CF
Additive
Yield [%]
55
1
2
3
4
5
3
AgSbF
AgSbF
AgSbF
6
6
6
6
F
5
)
3
17
3
C
6
H
4
)
3
34
PPh
PPh
3
AgOTf
AgBF
55
Table 2. Scope of substituents on alkyne terminus.
3
4
56
[
c]
6
none
AgSbF
none
none
none
none
none
none
none
6
trace
51
IPrAuCl (10 mol%)
quinoline (10 mol%)
R
NTs
R
quinoline N-oxide (2.0 equiv)
7
8
PPh
IPr
3
O
N
Ts
DCE/H O = 1/4, 80 °C, 24 h
2
MeO
O
81 (75)
14
1
2
[
d]
9
IPr
[
a]
Entry
R
Yield [%]
1
1
1
1
1
0
1
2
3
4
SIPr
ICy
82 (72)
32
1
2
3
4
5
6
7
8
9
4-FC
6
H
4
(1b)
(1c)
(1d)
(1e)
68 (2b)
[
b]
4-ClC
4-BrC
3-ClC
6
H
4
4
4
6
30, 79 (2c)
IMes
SIMes
IPr
63 (57)
(63)
(85)
(79)
81
6
6
H
H
85 (2d)
82 (2e)
quinoline
quinoline
quinoline
[
b]
4-Br-2-FC
4-(CO
4-CF
2-CF
4-MeC
H
3
(1f)
(1g)
31, 69 (2f)
[
e]
1
5
IPr
2
Me)-C
6
H
4
86 (2g)
[
f]
1
6
IPr
3
C
6
H
4
(1h)
(1i)
98 (2h)
[
a] Reaction conditions: 1a (0.05 mmol), Au cat. (10 mol%), additive (10
mol%), quinoline N-oxide (0.1 mmol), DCE (0.1 mL), H O (0.4 mL), 80 °C, 1 h
Entries 1-7) or 24 h (Entries 8-14, 16). [b] NMR yields were measured by
[b]
3
C
6
H
4
27, 35 (2i)
2
(
[c]
6
H
4
(1j)
37, 51 (2j)
using 1,1,2,2-tetrachloroethane as an internal standard. Isolated yield was
shown in parentheses. [c] The reaction was conducted without gold
complexes. [d] DCE (0.5 mL) was used as a sole solvent. [e] The reaction was
conducted four times as much scale as other entries: 1a (0.20 mmol), Au cat.
1
1
1
1
1
0
1
2
3
4
3-MeC
6
H
4
(1k)
(1l)
52 (2k)
49 (2l)
2-MeC
6
H
4
(
10 mol%), additive (10 mol%), quinoline N-oxide (0.2 mmol), DCE (0.4 mL),
O (7.6 mL), 80 °C, 24 h [f] The reaction was conducted under air. IPr = 1,3-
H
2
[c]
4-MeOC
6
H
4
(1m)
trace, 14 (2m)
bis(diisopropylphenyl)imidazol-2-ylidene,
SIPr
1,3-dicyclohexylimidazol-2-
= 1,3-dimesitylimidazol-2-ylidene, SIMes = 1,3-dimesityl
=
1,3-Bis(2,6-
diisopropylphenyl)imidazolidin-2-ylidene, ICy
ylidene, IMes
imidazolidin-2-ylidene.
=
3-pyridyl (1n)
H (1o)
67 (2n)
[d]
22, 53 (2o)
[
a] Isolated yield. [b] Quinoline (20 mol%), DCE (0.2 mL) and H
2
O (0.4 mL) were
3
used. [c] Ph PAuCl (10 mol%), quinoline (20 mol%) and quinoline N-oxide (0.1
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Chemistry - A European Journal
10.1002/chem.201800314
COMMUNICATION
mmol) was used in a mixed solvent of PhCl (0.2 mL) and H
2
O (0.8 mL) at 100 °C
Next, we examined deprotection of the tosyl group, but the
for 24 h. [d] 1n (0.05 mmol), Ph
3
PAuCl (10 mol%), 4-phenylpyridine N-oxide (0.1
O (0.4 mL) at rt for 5 h.
reaction failed and diarylacetate
3
was obtained by
mmol) in a mixed solvent of DCE (0.1 mL) and H
2
rearomatization of the cyclohexadienone moiety via C-C bond
[
13]
cleavage [Scheme 3, Equation (6)].
To prevent this
rearomatization, the diene moiety was reduced by Pd-catalyzed
hydrogenation. Subsequent deprotection of the tosyl group
proceeded smoothly with Mg, and synthetically important
gabapentin lactam derivative 4 was obtained quantitatively in two
Next, we examined electron-rich arenes other than those with
a p-anisyl group. The reaction of 2,4-dimethoxybenzylamine
derivative 1p gave spirocyclic compound 2p in high yield and high
diastereoselectivity [Scheme 2, Equation (1)]. Naphthol
derivatives were subjected to the optimized conditions [Scheme
[
14]
steps [Scheme 3, Equation (7)].
with a Lewis acid induced ring expansion to give isoquinolone 5
In contrast, treatment of 2a
[
15]
in high yield [Scheme 3, Equation (8)].
Alkylation of the α-
2
, Equations (2) and (3)]. The reaction of 1-naphthol derivative 1q
position of the amide group under basic conditions proceeded
provided spirocyclic compound 2q in high yield as a mixture of
diastereomers. On the other hand, the reaction of 2-naphthol
derivative 1r gave the desired spirocyclic compound 2r in high
yield without the addition of quinoline. 3-Bromo-4-
methoxybenzylamine derivative 1s was subjected to the
optimized conditions, but only a trace amount of the desired
spirocycle 2s was obtained [Scheme 2, Equation (4)]. This result
indicated that the electron-withdrawing group on the benzyl amine
moiety decreased the nucleophilicity of the ipso position. When
smoothly to give 6 in high yield [Scheme 3, Equation (9)].
Ph
NTs
Ph
NH
Ph
Mg (2.0 equiv)
O
O
CO Me (6)
2
MeOH, reflux, 1 h
O
O
HO
2
a
N.D.
3
1%
9
NTs
Ph
NH
Pd/C (10 mol%)
Mg (20 equiv)
O
O
tert-butoxy-substituted 1t was used as
a
substrate, the
2a
(7)
EtOAc, r.t., ovn
under H2
MeOH, reflux, 2 h
dearomatized product 2a was obtained, albeit in lower yield than
with methoxy-substituted substrate 1a [Scheme 2, Equation (5)].
O
HO
Ph
4
quant.
d.r. = 2.3:1)
(
HO
IPrAuCl (10 mol%)
Ph quinoline N-oxide (2.0 equiv)
NTs
OMe
OMe
BF3•OEt2 (5.0 equiv)
MeNO2, reflux, 1 h
NTs
Ph
(8)
2
a
quinoline (10 mol%)
O
O
N
Ts
(1)
(2)
(3)
Ph
2
DCE/H O = 1/4, 80 °C, 24 h
MeO
O
5
7%
1
p
2p
8
7
8%
(
d.r. = 5.7:1)
NaH (1.5 equiv)
MeI (1.5 equiv)
NTs
O
2
a
(9)
DMF, r.t., 1 h
Ph
Me Ph
NTs
O
same as above
O
N
Ts
6
96%
MeO
O
Ph
1
q
2q
8
5%
Scheme 3. Synthetic transformations of spirocyclic compound 2a.
(
d.r. = 1.6:1)
Ph
IPrAuCl (10 mol%)
quinoline N-oxide (2.0 equiv)
NTs
Regarding the mechanism, we propose the formation of acyl
O
N
Ts
OMe
DCE/H
2
O = 1/4, 80 °C, 24 h
gold carbene species prepared from ynamide 1 and Au(I)
Ph
O
[
16]
complex with a NHC ligand as the initial step (Scheme 4, A).
1
r
2r
This electron-deficient carbene species undergoes nucleophilic
5
9%
(
d.r. = 1.4:1)
attack from the ipso position to give spirocycle B. The resulting
[
11]
IPrAuCl (10 mol%)
quinoline N-oxide (2.0 equiv)
quinoline (10 mol%)
spirocyclic compound B reacts with water to give C.
The
Ph
NTs
Br
Br
O
presence of a catalytic amount of quinoline may promote this
N
Ts
(4)
[12]
hydrolytic demethylation step by increasing the basicity. Finally,
DCE/H O = 1/4, 80 °C, 24 h
2
MeO
O
Ph
protodemetallation of C provides desired spirocyclic compound 2
1
s
2s
trace
and regenerates the gold catalyst.
Ph
NTs
Ph
same as above
O
N
Ts
(5)
t-BuO
O
1
t
2a
2%
4
Scheme 2. Scope of arylmethylamino moiety.
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Chemistry - A European Journal
10.1002/chem.201800314
COMMUNICATION
2
1 + quinoline N-oxide
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LAuX
L = IPr, X = Cl or OH)
(
quinoline
gold carbene
formation
protodemetallation
Ts
N
NTs
O
MeO
O
R
AuL
HO
R
AuL
C
A
1
0726-10729.
demethylation
spirocyclization
[
[
3]
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N
MeOH
O
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2
O
AuL
R
MeO
B
Scheme 4. Plausible reaction mechanism.
4
7, 966-977.
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[
5]
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We have described an efficient synthesis of 2-
azaspiro[4.5]decan-3-one derivatives by catalytic dearomative
spirocyclization via a gold carbene intermediate generated from
alkynes. This protocol was robust and did not require hazardous
diazo compounds as carbene sources. The obtained
spirocyclohexadienones could be transformed into synthetically
useful compounds, such as a gabapentin lactam derivative and
phenol derivatives. Further studies to explore the reactivity of the
gold carbene intermediate are now underway in our laboratory.
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This work was supported by JST, ACT-C, Japan and Waseda
University Grant for Special Research Projects. M.I. is grateful to
generous support from “Early Bird” grant for young researcher at
Waseda Research Institute for Science and Engineering.
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Keywords: gold • dearomatization • spirocyclohexadienones •
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Chemistry - A European Journal
10.1002/chem.201800314
COMMUNICATION
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COMMUNICATION
Dearomatization
Mamoru Ito, Ryosuke Kawasaki, Kyalo
Stephen Kanyiva, and Takanori Shibata*
Page No. – Page No.
Catalytic Dearomative
An intramolecular catalytic dearomatization of phenols via gold carbene species
proceeded to provide 2-azaspiro[4.5]decan-3-ones. The use of NHC ligand and
water as a co-solvent was critical for achieving high reactivity. This reaction did not
require hazardous diazo compounds as carbene sources and proceeded even
under air.
Spirocyclization via Gold Carbene
Species Derived from Ynamides:
Efficient Synthesis of 2-
Azaspiro[4.5]decan-3-one
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