Asymmetric Pd-Catalyzed Alkene Carboamination Reactions for the Synthesis of 2-Aminoindane Derivatives

Article abstract of DOI:10.1021/jacs.5b07203

A new type of Pd-catalyzed alkene carboamination reaction that provides direct access to enantioenriched 2-aminoindanes from 2-allylphenyltriflate derivatives and aliphatic amines is described. A catalyst generated in situ from Pd(OAc)₂ and (S)-tert-butylPHOX provides the functionalized carbocycles in good yield with up to >99:1 er. The transformations occur via a key anti-aminopalladation that involves intermolecular attack of an amine nucleophile on an arylpalladium alkene complex.

Full text of DOI:10.1021/jacs.5b07203

Communication
pubs.acs.org/JACS
Asymmetric Pd-Catalyzed Alkene Carboamination Reactions for the
Synthesis of 2‑Aminoindane Derivatives
Derick R. White, Johnathon T. Hutt, and John P. Wolfe*
Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109-1055, United States
S
* Supporting Information
Scheme 1. anti-Aminopalladation Mechanisms
ABSTRACT: A new type of Pd-catalyzed alkene
carboamination reaction that provides direct access to
enantioenriched 2-aminoindanes from 2-allylphenyltriflate
derivatives and aliphatic amines is described. A catalyst
generated in situ from Pd(OAc)2 and (S)-tert-butylPHOX
provides the functionalized carbocycles in good yield with
up to >99:1 er. The transformations occur via a key anti-
aminopalladation that involves intermolecular attack of an
amine nucleophile on an arylpalladium alkene complex.
ver the past several years our group has developed an
Oefficient and practical protocol for the generation of
could be induced to proceed via anti-aminopalladation6 under
appropriate reaction conditions (Scheme 1a, 1 → 3). In general,
conditions leading to a more electrophilic metal center (aryl
triflate substrates and relatively polar PhCF3 solvent) favored the
heterocycles via Pd-catalyzed alkene carboamination reactions
between aryl or alkenyl-X species (X = Br, I, Cl, OTf) and alkenes
bearing pendant nucleophiles.1 This method has been used to
prepare a number of heterocyclic motifs and has been applied to
enantioselective syntheses of pyrrolidines,2 imidazolidin-2-ones,3
formation of anti-addition products. It seemed that the anti-
tetrahydroquinolines, tetrahydroquinoxalines, and tetrahydroi-
soquinolines4 with excellent yields and stereoselectivity.
Although the scope of these transformations is quite broad, in
all cases the reactions involve the coupling of an alkene bearing a
tethered nucleophile with an exogenous electrophile such as an
aryl bromide or triflate. To date, no examples of Pd-catalyzed
alkene carboamination reactions have been described in which
the coupling partners are reversed such that a free amine
nucleophile is coupled with an alkene bearing a pendant
electrophile. In this communication we describe the first
examples of Pd-catalyzed alkene carboamination reactions
between amine nucleophiles and 2-allylphenyltriflate derivatives,
which afford substituted carbocycles in good yield with excellent
enantioselectivity.
We envisioned that a new synthesis of amino-substituted
carbocycles could potentially be achieved through a Pd-catalyzed
carboamination reaction between an aryl electrophile bearing a
pendant alkene and a free amine nucleophile (Scheme 1b). Most
known alkene carboamination reactions between aminoalkenes
and aryl/alkenyl electrophiles proceed via intramolecular syn-
aminopalladation of an intermediate palladium amido complex
and provide products resulting from an exocyclization process.1
However, it seemed unlikely that the syn-aminopalladation
pathway would provide access to the desired carbocycles, as this
pathway would require an endocyclization through a highly
strained transition state.
aminopalladation pathway could provide access to the desired
carbocycles in this new type of alkene carboamination reaction.
As shown in Scheme 1b, oxidative addition of aryl triflate 4 to
Pd(0) followed by alkene coordination would afford 5, which
could undergo intermolecular anti-aminopalladation followed by
reductive elimination to generate the desired product 6.
In our initial studies we elected to explore intermolecular
carboamination reactions between 2-allylphenyltriflate deriva-
tives 4 and amine nucleophiles. These transformations would
give rise to 2-aminoindane derivatives 6, which have not only
attracted attention due to their pronounced CNS activities,7 but
also appear as motifs in pharmaceutically relevant molecules
including autotaxin inhibitors8 and cathepsin d inhibitors.9 In
addition, the required substrates could be prepared from readily
available phenols in three steps via O-allylation, aromatic Claisen
rearrangement, and installation of the triflate moiety. Opti-
mization was initiated by employing conditions similar to those
used in our prior syntheses of cyclic sulfamides (which proceed
via anti-aminopalladation). Efforts to couple relatively electron-
poor nitrogen nucleophiles such as sulfonamides, amides, or
imides with 4a were unsuccessful, and unreacted starting material
was recovered (Table 1, entries 1−3). However, we were
delighted to see that the coupling of pyrrolidine with 4a led to the
formation of significant amounts of desired product 7 (entry 4).
To further improve reactivity a series of Buchwald-type
biarylphosphines were surveyed,10 and we found BrettPhos
We recently reported a new synthesis of cyclic sulfamides via
Pd-catalyzed alkene carboamination reactions.5 During the
course of those studies we discovered that transformations
Received: July 10, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b07203
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
a
Table 1. Influence of Nucleophile and Ligand on Reactivity
Table 2. Optimization of Asymmetric Reactions
a
Conditions: 1.0 equiv of 4b, 1.2 equiv of amine, 1.4 equiv ofo LiOtBu,
4 mol % Pd(OAc)2, 10 mol % ligand, PhCF3 (0.1 M), 95 °C, 16 h.
The reaction was conducted in toluene solvent.
b
a
Conditions: 1.2 equiv of 4a, 1.0 equiv of amine, 1.4 equiv of LiOtBu,
4 mol % Pd(OAc)2, 10 mol % ligand, PhCF3 (0.1 M), 95 °C, 16 h.
b
Determined by 1H NMR using phenanthrene as an internal standard.
c
previously shown utility in other asymmetric Pd-catalyzed
reactions.11,12 Ligand L8 afforded the product in 86:14 er,
which was improved to 88:12 er by conducting the reaction in
toluene. Replacement of the diphenylphosphino group with a
dicyclohexylphosphino group (L9) provided lower selectivity.
However, use of a bulky tert-butyl group rather than an isopropyl
group on the oxazoline (L10) led to significant improvement,
and the desired product (R)-8a was generated with >99:1 er in
98% isolated yield.13
With optimized conditions in hand we proceeded to explore
the scope of this transformation. The coupling reactions of 2-
allyl-1-naphthyl triflate 4b with several different amines
proceeded in good to excellent yield and enantioselectivity
(Table 3). The best results were obtained with cyclic amines
(entries 1−4); however, the use of an acyclic secondary amine
(diethylamine) proceeded in lower yield and selectivity (entry
5). Both linear and α-branched 1° amines (entries 6 and 7)
afforded the desired product in good to excellent yields with
enantioselectivities of >99:1 and 97:3 er, respectively. Trans-
formations of 4-substituted 2-allyphenyltriflate derivatives were
also successful. The coupling of electron-rich 2-allyl-4-methox-
yphenyl triflate 4c with pyrrolidine afforded a moderate yield of
56% but excellent 97:3 er (entry 8). Similar results were obtained
with n-octylamine (entry 9). The coupling of the less-electron-
rich 2-allyl-4-fluorophenyl triflate 4d with pyrrolidine proceeded
in 77% yield and 98:2 er. The modest yields obtained with
electron-rich substrate 4c could be due to the reduced
electrophilicity of cationic Pd-intermediate 5 (Scheme 1b),
which could inhibit alkene coordination and decrease the facility
Isolated yields are given in parentheses. 1.0 equiv of 2-allylphenyl
triflate and 1.2 equiv of pyrrolidine were used.
outperformed other ligands and provided a 68% isolated yield of
the desired product (entry 7). Efforts to improve yield by
decreasing reaction temperature were unsuccessful (entries 8 and
9). After continued experimentation we found that performing
the reaction with slight excess of pyrrolidine led to a cleaner
reaction with no observed byproducts by crude 1H NMR (entry
10) and provided the desired product in essentially quantitative
yield. Interestingly, despite the utility of the Buchwald ligands for
Pd-catalyzed N-arylation reactions, in this system side products
resulting from N-arylation were not observed.
Having successfully optimized the coupling of pyrrolidine with
2-allylphenyl triflate to generate the achiral 2-aminoindane
derivative 7, we turned our attention to the development of an
asymmetric variant of this reaction to generate chiral amino-
indane products. In our optimization studies we examined the
coupling of 2-allyl-1-naphthyl triflate 4b with pyrrolidine (Table
2). A series of chiral phosphine ligands were examined that have
similar steric and electronic properties as the BrettPhos ligand,
which provided good results in our achiral aminoindane
synthesis. Initial studies with MOP-type ligands (L1−L5) did
provide some asymmetric induction, but efforts to improve
enantioselectivity by modifying the alkoxy substituent, the
phosphine moiety, or use of a partially hydrogenated backbone
did not lead to satisfactory results. We subsequently turned our
attention to PHOX-type ligands L8−L10,11 as these ligands have
B
DOI: 10.1021/jacs.5b07203
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Table 3. Asymmetric Synthesis of Aminoindanes
Scheme 2. Stereochemical Model
bearing amino groups via coupling of amine nucleophiles with 2-
allylphenyltriflate derivatives. These are the first examples of Pd-
catalyzed alkene carboamination reactions in which the key
aminopalladation step is an intermolecular process. These
reactions illustrate the potential to employ Pd-catalyzed alkene
carboamination reactions for the generation of carbocycles rather
than heterocycles and provide straightforward access to
potentially useful 2-aminoindane derivatives.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.5b07203.
■
S
Experimental procedures and copies of 1H and 13C NMR
spectra (PDF)
Compound characterization data (CIF)
a
Conditions: Reactions were conducted on a 0.1 mmol scale using 1.0
equiv of 4, 1.2 equiv of amine, 1.4 equiv of LiOtBu, 4 mol %
Pd(OAc)2, 10 mol % (S)-tBu-PHOX, toluene (0.1 M), 95 °C, 3−16 h.
b
c
Isolated yields (average of two or more experiments). The reaction
AUTHOR INFORMATION
Corresponding Author
*jpwolfe@umich.edu
■
was conducted on a 1.0 mmol scale.
of nucleophilic attack on the alkene. The coupling of 4b with
pyrrolidine on a 1.0 mmol scale provided essentially identical
results to the small scale (0.1 mmol) coupling reaction (entry 2).
To further probe the mechanism of this transformation we
examined the coupling of deuterated substrate d-4a with
pyrrolidine. As shown in eq 1, this reaction provided d-7 with
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the NIH-NIGMS (GM098314) for financial
support of this work, and Dr. Nicholas Babij and Dr. Brett
Hopkins for helpful discussions.
REFERENCES
■
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carboamination reactions that generate carbocyclic products
C
DOI: 10.1021/jacs.5b07203
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Journal of the American Chemical Society
Communication
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D
DOI: 10.1021/jacs.5b07203
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX