Palladium-catalyzed intramolecular ipso-Friedel-Crafts alkylation of phenols and indoles: Rearomatization-assisted oxidative addition

Article abstract of DOI:10.1002/anie.201209317

Inspiroation: A novel synthesis of spirocycles based on a palladium-catalyzed intramolecular ipso-Friedel-Crafts alkylation of phenols (see scheme; dba=dibenzylideneacetone) and indoles is described. Mechanistic studies show that the reaction proceeds through an unprecedented rearomatization-assisted oxidative addition. Copyright

Full text of DOI:10.1002/anie.201209317

Angewandte
Chemie
DOI: 10.1002/anie.201209317
Homogeneous Catalysis
Palladium-Catalyzed Intramolecular ipso-Friedel–Crafts Alkylation of
Phenols and Indoles: Rearomatization-Assisted Oxidative Addition**
Tetsuhiro Nemoto, Zengduo Zhao, Takuya Yokosaka, Yuta Suzuki, Riliga Wu, and
Yasumasa Hamada*
Spirocyclohexadienones are recognized as versatile inter-
mediates for complex molecule syntheses. Functionalization
of the cyclohexadienone unit provides efficient and rapid
access to multicyclic molecular frameworks.[1] A number of
natural product syntheses have been achieved using spiro-
cyclohexadienones as key intermediates.[2] The development
Scheme 1. Reaction design.
of an innovative method for synthesizing spirocyclohexa-
dienones is therefore in high demand because of its potential
impact on synthetic organic chemistry.
Dearomatization of phenols is one of the most straight-
forward approaches to the synthesis of spirocyclohexa-
dienones. Among such methods, transition-metal-catalyzed
intramolecular nucleophilic dearomatization of phenols has
attracted recent attention.[3,4] Key to the success of this
dearomatization process is whether the intramolecular C al-
kylation can be preferentially promoted over the competitive
intermolecular O alkylation. We recently demonstrated that
the present chemoselectivity issue was successfully controlled
in a palladium-catalyzed intramolecular ipso-Friedel–Crafts
allylic alkylation of para-substituted phenols with an allylic
carbonate unit to give spiro[4.5]cyclohexa-dienones in excel-
lent yield.[3a]
Reaction of propargyl carbonates with a palladium cata-
lyst provides an equilibrium mixture of h1-allenyl-
palladium(II) complexes and h3-propargyl-palladium(II)
complexes.[5] Various catalytic transformations have been
developed based on the electrophilic reactivity of these
palladium complexes.[6] We envisioned that these complexes
would be adaptable to palladium-catalyzed intramolecular
nucleophilic dearomatization of phenols, thus providing novel
access to functionalized spirocyclohexadienones (Scheme 1).
Moreover, the use of indole variants in the same catalytic
process would result in the formation of aza-spirocycles.[7]
Herein, we report a novel synthetic method for spirocyclic
molecules based on palladium-catalyzed intramolecular ipso-
Friedel–Crafts alkylation of phenols and indoles. Mechanistic
studies revealed that the reaction proceeds through an
unprecedented rearomatization-assisted oxidative addition.
Our studies began with the model substrate 1a
(Table 1).[8] We first examined the reaction using 5 mol%
[Pd(dba)2] and 12 mol% PPh3 in CH2Cl2, which are the
Table 1: Optimization of the reaction conditions.
Entry
Solvent
T
t
[h]
Yield [%][b]
(2a/3a)
[8C][a]
1
2
3
4
5
6
7
8
CH2Cl2
THF
DMF
MeOH
CH2Cl2/MeOH (4:1)
CH2Cl2/MeOH (4:1)
CH2Cl2/MeOH (4:1)
(CH2Cl)2/MeOH (4:1)
RT
RT
RT
RT
RT
RT
40
60
18
18
18
18
18
48
10
4
15 (94:6)
no reaction
15 (88:12)
22 (94:6)
78 (61:39)
96 (13:87)
100 (4:96)
100 (95)[c] (0:100)
[a] RT: 20–258C. [b] Yield of the mixture of 2a and 3a, which are
inseparable by chromatography. Yield and ratio were determined by
1H NMR analysis of the crude reaction mixture. [c] Yield of isolated
product. dba=dibenzylideneacetone, DMF=N,N’-dimethylformamide,
THF=tetrahydrofuran.
optimum reaction conditions for the palladium-catalyzed
intramolecular ipso-Friedel–Crafts allylic alkylation of phe-
nols.[3a] The reaction proceeded sluggishly to afford a mixture
of spirocyclic adducts, 2a and 3a in a ratio of 94:6, in 15%
yield. The use of other common solvents failed to improve the
yield of spirocyclic adducts, and 2a was mainly obtained in all
cases (entries 1–4). The reactivity increased when the reaction
was performed in a CH2Cl2/MeOH solvent mixture, and the
ratio of 2a and 3a changed to 61:39 (entry 5). A prolonged
reaction time resulted in consumption of most of the starting
material, and interestingly, the ratio of 2a and 3a changed to
[*] Dr. T. Nemoto, Z. Zhao, T. Yokosaka, Y. Suzuki, R. Wu,
Prof. Dr. Y. Hamada
Graduate School of Pharmaceutical Sciences, Chiba University
1-8-1, Inohana, Chuo-ku, Chiba 260-8675 (Japan)
E-mail: hamada@p.chiba-u.ac.jp
[**] This work was supported by Grant-in Aid for Scientific Resarch from
the JSPS (Japan), the Research Foundation for Pharmaceutical
Sciences, Chiba Univsersity, and the Inohana Foundation (Chiba
University).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201209317.
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13:87 (entry 6). Similar results were obtained when the
reaction was performed at 408C (entry 7). The best result
was obtained when the reaction was performed at 608C in
a (CH2Cl)2/MeOH solvent mixture, and 3a was isolated in
95% yield as the sole product (entry 8).[9]
As shown in Table 1, characteristic reaction profiles were
observed in this spirocyclization. We performed the following
experiments to gain preliminary insight into the reaction
mechanism (Scheme 3). First, to elucidate the reactivity, 2a
We next examined the scope and limitations of different
substrates under the optimized reaction conditions. Spirocyc-
lization of 1a could be performed even in the presence of
1 mol% of the palladium catalyst, thus giving 3a in 97% yield
(Table 2, entry 1). The ortho-disubstituted phenol derivatives
Table 2: Substrate scope.
Scheme 3. Experiments for elucidating the reaction mechanism.
was prepared from 6a in 90% yield using a base-promoted
nucleophilic dearomatization. Although no reaction occurred
when 2a was heated in a (CH2Cl)2/MeOH solvent mixture,
clean transformation of 2a into 3a was observed in the
presence of a palladium catalyst. When either 1a or 2a were
treated with the palladium catalyst in a (CH2Cl)2/MeOD
solvent mixture, [D]-3a was obtained in excellent yield. In
addition, 3a was not converted into [D]-3a under the same
reaction conditions. These results indicated that both 1a and
2a were converted into 3a through the same h3-propargyl-
palladium(II) intermediate. A time-course experiment using
the optimized conditions revealed interesting reaction pro-
files (Figure 1).[8] In the initial stage, 1a was preferentially
Entry
Substrate
Pd cat.
(mol%)
T
t
[h]
Product
Yield
[%][a]
[8C][a]
1[b]
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1 f
1g
1h
1i
1
5
5
5
5
5
5
5
5
60
80
80
60
80
60
60
60
60
21
5
5
3a
3b
3c
3d
3e
3 f
3g
3h
3i
97
99
93
85
94
72
93
92
91
4
21
18
2
6
0.5
[a] Yield of isolated product. [b] [1a]=0.1m.
1b and 1c, as well as the meta-substituted phenol derivatives
1d–f, were also effective substrates for this reaction, and
products having a spiro[5.5]cyclohexadieneone skeleton (3b–
f) were obtained in 72–99% yield (entries 2–6). Moreover,
spirocyclization of 1g and 1h, bearing a bulky di(tert-
butyl)malonate tether and a dimethyl acetal tether, respec-
tively, proceeded smoothly to give the corresponding prod-
ucts 3g and 3h in high yield (entries 7 and 8). The biphenyl-
type substrate 1i was also applicable to this reaction, thus
providing the corresponding product 3i in 93% yield
(entry 9). Furthermore, this catalytic system was effective
for nucleophilic dearomatization of indoles (Scheme 2).
When the tryptamine derivatives 4a–c were treated under
the optimized reaction conditions, aza-spirocyclic adducts
with a diene motif (5a–c) were obtained in good yield.
Figure 1. Time-course experiments using 1a.
transformed into 2a, and then 3a gradually formed in
proportion to the increase in the production of 2a. In the
second half of the reaction, 3a was mainly produced from 2a.
These findings led us to propose a plausible reaction
pathway for this process (Scheme 4). First, oxidative addition
of 1a to Pd0 forms the h1-allenylpalladium(II) species A. The
formation of the palladacycle intermediate B and subsequent
reductive elimination, proceeds rapidly to give 2a as an initial
product. A rearomatization-assisted oxidative addition of 2a
to Pd0 subsequently occurs to afford an equilibrium mixture
Scheme 2. Indole-type substrates.
2
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yield (2 steps). These results demonstrate the high
potential of the developed method in organic
synthesis.
In striking contrast to 2a, no reaction occurred
when compound 14, which was prepared using
Buchwaldꢀs method,[3c,8] was treated with a palla-
dium catalyst in MeOH under a CO atmosphere.
This finding clearly indicated that the allenyl
spirocyclohexadienone motif in 2a is essential for
oxidative addition (Scheme 6). The p orbital on the
terminal double bond of the allene is coplanar with
À
the s orbital of the Csp3 Csp2 bond, which is cleaved
during the oxidative addition process. We speculate
that this coplanarity would facilitate the electron
transfer from Pd0 to the cyclohexadienone moiety,
À
thus promoting oxidative addition of the Csp3 Csp2
bond to the palladium catalyst through an SN2’
Scheme 4. Proposed reaction mechanism.
of the h1- and h3-propargylpalladium(II) complexes C and D.
Intramolecular ipso-Friedel–Crafts alkylation of the phenol
proceeds on the central carbon atom of the h3-propargyl-
palladium(II) moiety to affords the palladacyclobutene
intermediate E.[10] Subsequent protonation by MeOH gen-
erates the p-allylpalladium(II) complex F, which is finally
converted into 3a.
2a and 3a could be utilized as versatile intermediates for
synthesizing multicyclic molecules (Scheme 5). When 2a was
treated with a palladium catalyst in MeOH under a CO
Scheme 6. The mode of oxidative addition.
mechanism. To the best of our knowledge, this is the first
À
example of an oxidative addition of C C bond based on the
rearomatization of spirocyclohexadienones.[12]
In conclusion, we developed a novel method for synthe-
sizing spirocycles based on a palladium-catalyzed intramo-
lecular ipso-Friedel–Crafts alkylation of phenols and indoles
to h3-propargylpalladium(II) complexes. Preliminary mecha-
nistic studies revealed that the reaction proceeds through an
unprecedented rearomatization-assisted oxidative addition.
Further studies of an asymmetric version of this process, as
well as a more detailed mechanistic investigation, are in
progress.
Received: November 21, 2012
Published online: && &&, &&&&
Scheme 5. Derivatization of 2a and 3a. mCBPA=meta-chloroperben-
zoic acid, PMHS=poly(methylhydroxysilane).
Keywords: alkylation · oxidation · palladium · spiro compounds ·
synthetic methods
.
atmosphere, 7 was obtained in 72% yield, accompanied by
the formation of 8.[8] A copper-catalyzed conjugate reduction
of 3a provided the spirocyclohexanone derivative 9 in 75%
yield, and epoxidation of 3a preferentially occurred at the
exocyclic olefin, thus affording 10 in 82% yield. A palladium-
catalyzed reductive epoxide-opening reaction of 10[11] and
subsequent base-promoted intramolecular conjugate addition
gave the tricyclic fused heterocycle 12 in 75% yield (2 steps).
Luche reduction of 3a and subsequent treatment with p-
toluenesulfonic acid, gave the bicyclic compound 13 in 88%
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[8] For detailed data, see the Supporting Information.
[9] No reaction occurred when a propargyl alcohol derivative was
treated under the same reaction conditions. The reaction was
very sluggish when using a propargyl acetate derivative as the
substrate.
[10] It is proposed that h3-propargylpalladium(II) species react with
nucleophiles on the central carbon atom to produce metal-
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À
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4
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Angewandte
Chemie
Communications
Homogeneous Catalysis
T. Nemoto, Z. Zhao, T. Yokosaka,
Y. Suzuki, R. Wu,
Y. Hamada*
&&& — &&&
Inspiroation: A novel synthesis of spiro-
cycles based on a palladium-catalyzed
intramolecular ipso-Friedel–Crafts alkyla-
tion of phenols (see scheme; dba=
dibenzylideneacetone) and indoles is de-
scribed. Mechanistic studies show that
Palladium-Catalyzed Intramolecular ipso-
Friedel–Crafts Alkylation of Phenols and
Indoles: Rearomatization-Assisted
Oxidative Addition
the reaction proceeds through an unpre-
cedented rearomatization-assisted oxida-
tive addition.
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!