Palladium-catalyzed γ-arylation of β,γ-unsaturated ketones: Application to a one-pot synthesis of tricyclic indolines

Article abstract of DOI:10.1002/anie.200704529

(Chemical Equation Presented) Indolines in short order: A catalyst system which allows for efficient γ-arylation of β,γ-unsaturated ketones is described (see scheme; dippf = 1,1′-bis(diisopropylphosphanyl) ferrocene, dba = trans,transdibenzylideneacetone). This method can be applied to a one-pot, two-step synthesis of polycyclic indolines from simple starting materials.

Full text of DOI:10.1002/anie.200704529

Angewandte
Chemie
DOI: 10.1002/anie.200704529
Tricyclic Indolines
Palladium-Catalyzed g-Arylation of b,g-Unsaturated Ketones:
Application to a One-Pot Synthesis of Tricyclic Indolines**
Alan M. Hyde and Stephen L. Buchwald*
Extensive work has been carried out to develop the palla-
dium-catalyzed a-arylation of ketones and related carbonyl
functional groups,[1] providing a very simple and dependable
route to a-aryl and a-vinyl ketones. However, less attention
has been directed to the palladium-catalyzed arylation of
dienolates,[2] which would allow for rapid construction of g-
aryl-a,b-unsaturated ketone motifs (Scheme 1) found in a
alkylation with the use of copper,[4d,e] germanium,[4f] tin,[4g] or
zinc[4h,i] dienolates.
Building upon this concept, Yamamoto et al. reported
that preformed tin dienolates will undergo cross-coupling at
the g-position with aryl bromides in the presence of [Pd-
(PPh3)4] with high selectivity.[2a,b] However, low yields and the
use of stoichiometric amounts of tin compounds preclude this
method from being generally applicable. An
alternative method for this transformation
was published in 1998 by Miura and co-
workers, demonstrating that a,b-unsatu-
rated ketones and aldehydes react with
aryl bromides under basic conditions selec-
tively at the g-position using a Pd(OAc)2/
PPh3-based catalyst.[2c] However, no exam-
Scheme 1. Regioselective dienolate arylation.
ples were described in which a quaternary
carbon center was formed by a regioselec-
tive g-arylation.
number of natural products.[3] Many methods already exist to
produce a-arylated or a-vinylated a,b-unsaturated ketones[4]
from a variety of precursors, but the means to produce g-aryl-
or g-vinyl-a,b-unsaturated ketones[2,5] are limited. Several
factors contribute to the difficulty of developing such a
process: 1) dienolates are less nucleophilic than enolates,
2) dienolates are more prone to self-condensation through
Michael reactions, and 3) there is the potential for the
generation of regioisomeric products.
A number of approaches have been developed to control
the regioselectivity in the alkylation of a,b-unsaturated
ketones and esters. For example, if a,b-unsaturated ketones
or carboxylic acid derivatives are treated with an alkyl halide
in the presence of alkali-metal bases such as KOtBu[4a] or
lithium diethylamide (LDE),[4b,c] alkylation occurs at the a-
position preferentially over the g- or a’-positions. The
regioselectivity of this reaction may be reversed to favor g-
Herein, we show that with the proper choice of ligand and
base, quaternary carbon centers can be formed by arylation or
vinylation at the g-position of b,g-unsaturated ketones. We
then apply this methodology to a convenient two-step, one-
pot synthesis of ketoindolines that allows for the rapid
construction of compounds that contain a polycyclic alkaloid
framework.
We first sought to react 4-methylcyclohex-2-en-1-one (1)
with bromobenzene using conditions established for the a-
arylation of ketones[1b] using NaOtBu as the base and a
Pd(OAc)2/Xantphos-based
catalyst
(Xantphos = 9,9-
dimethyl-4,5-bis(diphenylphosphino)xanthene). This reaction
was unsuccessful, however, resulting only in self-condensation
of the ketone (Scheme 2).
[*] A. M. Hyde, Prof. Dr. S. L. Buchwald
Department of Chemistry, Room 18-490
Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
Scheme 2. Unsuccessful attempt to arylate a,b-unsaturated ketone 1.
Fax: (+1)617-253-3297
E-mail: sbuchwal@mit.edu
[**] We are grateful to the National Institutes of Health (GM46059) as
well as to Merck, Amgen, and Boehringer Ingelheim for support of
this research. BASF (Pd(OAc)2), Chemetall (Cs2CO3), and Takasago
(Segphos and DTBM-Segphos) are thanked for generous gifts of
chemicals. We are indebted to Prof. Dr. Arnold Reingold and Dr.
Antonio DiPasquale for determining the absolute configuration of 8
by X-ray crystallography.
We then began screening reaction conditions with b,g-
unsaturated ketone 2, since it was easier to prepare than 1. We
discovered that the use of a weak base such as Cs2CO3 was
crucial to obtain any arylated product. We also found that the
optimal ligands used for a-arylation, such as Xantphos
(Table 1, entry 2) or binap (2,2’-bis(diphenylphosphanyl)-
1,1’-binaphthyl, Table 1, entry 8) gave poor yields when used
Supporting information for this article is available on the WWW
under http://www.angewandte.org or fromthe author.
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Table 1: Ligand effect on regioselectivity.
Table 2: g-Arylation of unsaturated ketones.[a]
Entry
1
Ketone
Product
Yield [%][b]
Entry
Ligand
Yield [%][a]
3
4
5
6
70
1
2
3
4
5
6
7
8
9
10
P(o-tol)3
Xantphos
CyJohnPhos
Xphos
dppe
dppp
dppb
rac-binap
dppf
35
11
41
0
84
56
50
50
28
7
0
23
49
17
50
0
26
0
14
0
0
5
0
0
0
0
12
7
4
0
0
2
2
3
3
81
80
0
7
7
32
53
27
25
0
P(tBu)3·HBF4
2
[a] Yields determined by GC using an internal standard of dodecane.
CyJohnPhos=2-(dicyclohexylphosphino)biphenyl, Xphos=2-(dicyclo-
hexylphosphino)-2’,4’,6’-tri-iso-propyl-1,1’-biphenyl,
dppe=1,2-bis(di-
phenylphosphino)ethane, dppp=1,3-bis(diphenylphosphino)propane,
4
5
61
dppb=1,4-bis(diphenylphosphino)butane,
phosphino)ferrocene, o-tol=ortho-tolyl.
dppf=1,1’-bis(diphenyl-
for g-arylation, producing a mixture of g-arylated (3), a-
arylated (4), and doubly arylated (5) products. Arylation at
the a’-position is never observed. Upon screening a variety of
other ligands, we found that the use of a bidentate ligand with
a narrow bite angle[6] is necessary to achieve high selectivity
(Table 1, entries 5–7). The small diphosphine dppe was
particularly effective, giving exclusively the g-arylated prod-
uct in 84% yield (Table 1, entry 5).
2
7
66[c]
6
7
54[d]
70[d,e]
We do not yet understand the nature of the influence of
ligand structure on the observed regioselectivity. We postu-
late that the selectivity reflects the relative rate of reductive
elimination from the a- and g-positions and is very sensitive to
both the electronic and steric environment at the Pd center.
It is also noteworthy that b,g-unsaturated ketones give
higher yields than a,b-unsaturated ketones as substrates
(Table 2, entries 1 and 2). This difference can likely be
attributed to the greater acidity and lower tendency for self-
condensation of b,g-unsaturated ketones. The required b,g-
unsaturated cyclohexenones are conveniently prepared by a
Birch reduction–hydrolysis sequence from the corresponding
anisoles.[7]
Once reliable conditions to synthesize g-arylated a,b-
unsaturated ketones were established, the scope of the
process was examined (Table 2). The reaction can be per-
formed in the presence of a methyl ketone substituent with no
arylation of this ketone (Table 2, entry 3). This example
clearly demonstrates that the conditions needed for the g-
arylation of ketones are orthogonal to those for a-arylation.
Entry 4 (Table 2) shows that selective arylation at carbon 4
may be achieved; in contrast, if the isomeric a,b-unsaturated
ketone 3,4-dimethylcyclohex-2-en-1-one, is used, a mixture of
products is obtained owing to competitive arylation at
carbons 4 and 7. This reaction also works well with vinyl
bromides under slightly modified conditions, producing g-
[a] The nature of the halide reagent can be deduced fromthe products.
[b] Yields of isolated product are based on an average of two runs.
[c] Reaction run at 1108C in 3:1 dioxane/THF. [d] Greater than 98:2 ratio
of E/Z isomers are formed. [e] Reaction run at 1108C in dioxane using
dppb as the ligand.
vinyl-a,b-unsaturated ketones (Table 2, entry 5). g-Arylation
of acyclic a,b-unsaturated ketone 7 proceeds in moderate to
good yield (Table 2, entries 6 and 7). In these cases, the
commercially available ketone 7 is used, as it gives similar
yields to the isomeric b,g-unsaturated ketone. The reaction
proved to be sensitive to steric hindrance, as the reaction of an
aryl bromide possessing an ortho-methyl group under the
standard conditions gives a mixture of a-, g-, and doubly
arylated products. However, changing the ligand to dppb and
the solvent to dioxane provides the g-arylated isomer as the
exclusive product in 70% yield (Table 2, entry 7).
With an efficient procedure for the g-arylation of ketones
in hand, we wondered whether it would be possible to
combine a b,g-unsaturated ketone with an ortho-bromoani-
line to provide intermediate A (Scheme 3). We reasoned that
subsequent intramolecular conjugate addition would produce
the indoline shown in Scheme 3. Methods to prepare cyclo-
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Table 3: One-pot ketoindoline synthesis.[a]
Entry
1
Base
T [8C]
Product
Yield [%][b]
81
Cs2CO3
100
2
3
K2CO3
K2CO3
110
110
63
60
Scheme 3. Proposed sequence to generate ketoindolines.
hexanone-fused indolines have been reported[8] but either
involve multiple steps or start with an indole. Heterocycles of
this type are of interest, as they are precursors in the synthesis
of a number of the Aspidosperma alkaloids including vindo-
line,[9] aspidophytine,[10] and the “Büchi ketone” intermedi-
ate.[8a]
4
5
K2CO3
110
100
64
66
Cs2CO3
Our initial attempts to carry out the transformation shown
in Scheme 3 quickly revealed that the choice of the ligand was
again critical; the use of dppe gave none of the desired
product. Of the ligands tested, only 1,1’-bis(di-iso-propyl-
phosphino)ferrocene (dippf) gave consistently good yields.
When coupling ortho-bromoaniline derivatives, a-arylation
was never observed, and the two-step domino process
proceeded with complete regioselectivity and cis-diastereo-
selectivity. For this process, it was found in all instances that
a,b-unsaturated ketones gave significantly lower yields than
the isomeric b,g-unsaturated ketones.
6
7
K2CO3
K2CO3
110
110
50
69
8
Cs2CO3
100
70
[a] dba=trans,trans-dibenzylideneacetone. [b] Yields of isolated product
We initially suspected that an aniline derivative bearing a
protected amino group would provide better results. How-
ever, N-protected 2-bromoaniline derivatives proved to be
very poor substrates in the arylation reaction, and only the use
of 2-bromoaniline gave satisfactory yields.
are based on an average of two runs.
enantiomeric excess of up to 92% could be achieved using
DTBM-Segphos as the supporting ligand (Table 4). The
absolute stereochemistry of indoline 8 was established by
As shown in Table 3, the substrate scope for the indoline-
forming process is quite broad, and the reaction demonstrates
a high level of functional-group tolerance. Electron-rich and
electron-neutral bromoanilines can be transformed in the
presence of Cs2CO3 at 1008C (Table 3, entries 1, 5, and 8).
However, electron-poor bromoanilines necessitate the use of
K2CO3 at 1108C for their reactions to reach full conversion
(Table 3, entries 2–4, 6, and 7). Notably, the indolines
produced may be acyclic (Table 3, entry 8), mono- (Table 3,
entries 1–5) or disubstituted (Table 3, entries 6 and 7), at the
2- and 3-positions. Unfortunately, to date, all attempts to
perform this reaction with either a,b- or b,g-unsaturated
cyclopentenones have been unsuccessful.
We next turned our attention to developing an asymmet-
ric version of this indoline synthesis. Successful protocols have
been developed for both nickel-catalyzed[11a] and palladium-
catalyzed[11b–d] asymmetric a-arylation of ketones. Given
these precedents we were optimistic that a chiral ligand
could be found that would impart high facial selectivity to the
ketone. An extensive ligand screening revealed that an
Table 4: Asymmetric synthesis of indolines.
Entry
R1
R2
Yield [%][a]
ee [%][b]
1 (8)
2 (9)
Me
OMe
Me
H
50
32
90
92
[a] Yields of isolated product are based on an average of two runs.
[b] Determined by chiral HPLC with an OJ column.
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Communications
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generate quaternary carbon centers. We have applied this
method to a two-step, one-pot indoline synthesis with 2-
bromoanilines as coupling partners. We have also made initial
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effects on the regioselectivity of arylation and the extension
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Received: October 1, 2007
Published online: November 21, 2007
Keywords: g-arylation · asymmetric catalysis · domino reactions ·
.
indolines · palladium
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[12] CCDC-662975 (8) contains the supplementary crystallographic
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