Asymmetric Synthesis of α,α-Disubstituted Allylic Amines through Palladium-Catalyzed Allylic Substitution

Article abstract of DOI:10.1002/anie.201705825

The first asymmetric synthesis of important α,α-disubstituted N-alkyl allyl amine scaffolds through allylic substitution is reported. This approach is based on palladium catalysis and features ample scope with respect to both the allylic precursor and amine reagent, and high asymmetric induction with enantiomeric ratios (e.r.) up to 98.5:1.5. The use of less-reactive anilines is also feasible, providing enantioenriched α,α-disubstituted N-aryl allylic amines.

Full text of DOI:10.1002/anie.201705825

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Accepted Article
Title: Asymmetric Synthesis of alfa,alfa-Disubstituted Allylic Amines via
Pd-Catalyzed Allylic Substitution
Authors: Arjan Willem Kleij, Wusheng Guo, Aijie Cai, and Jaining Xie
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201705825
Angew. Chem. 10.1002/ange.201705825
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Asymmetric Synthesis of -Disubstituted Allylic Amines via Pd-
Catalyzed Allylic Substitution
[a][+]
[a][+]
[a]
[a][b]
Wusheng Guo,
Aijie Cai,
Jianing Xie, and Arjan W. Kleij*
Abstract: The first asymmetric synthesis of important -
disubstituted N-alkyl allyl amine scaffolds via allylic substitution is
reported. This approach is based on palladium catalysis and
features ample scope in both allylic precursor and amine reagent,
and high asymmetric induction with the enantiomeric ratio (er) up to
98.5:1.5. The use of less reactive anilines is also feasible providing
enantioenriched -disubstituted N-aryl allylic amines.
Controlling the regioselectivity in Pd-catalyzed allyl substitution
towards branched allylic amines has traditionally been extremely
challenging. The nucleophilic attack of the amine on the less
crowded terminal carbon of the Pd(allyl) intermediate is favored
over the attack on the sterically hindered internal carbon thus
giving the linear derivative as the major product. In this context,
rather few examples succeeded in the preparation of sterically
demanding (rac)-α,α-disubstituted allylic amines via Pd-
catalyzed allylic substitution with limitations in the -
disubstitution pattern (often two methyl groups) and functional
Scheme 1. Enantioselective synthesis of -disubstituted allylic amines. LG
stands for leaving group.
Based on our previous success with the Pd-catalyzed
[10]
decarboxylative amination protocol (Scheme 1a),
we
[
1,2]
group diversity.
reasoned that in the presence of a suitable palladium precursor
and a chiral ligand, the conversion of allylic precursors with an
appropriate leaving group (LG) into -disubstituted allylic
amines (Scheme 1b) could be achieved. Such an approach
would offer a general and tunable route towards chiral -
disubstituted allylic amines.
Chiral α,α-disubstituted allylic amines represent a class of
amines featuring a tetrasubstituted tertiary carbon center which
have found important applications in biology and pharmaceutical
[
3]
[4]
industry, and their synthesis is thus of high significance.
Despite notable success in the preparation of allylic amines via
transition metal (TM) catalyzed allylic substitution in the last
[
1-2,4-7]
decade,
the asymmetric synthesis of -disubstituted
allylic amines based on allylic substitution using palladium
catalysis has remained extremely challenging and to date
[
8,9]
underdeveloped.
We recently reported a Pd-catalyzed
decarboxylative amination process toward the synthesis
enantioenriched -disubstituted allylic N-aryl amines from
[
10]
substituted vinyl cyclic carbonates and anilines (Scheme 1a).
Although successful, the cyclic carbonate precursor A was found
[
11]
to be a requisite, and as a consequence this decarboxylative
approach was limited to the use of aryl amines only as the more
nucleophilic aliphatic amines quickly convert the cyclic
carbonate into undesired carbamate through ring-opening
[
12,13]
aminolysis.
To the best of our knowledge, there is still no
approach available for the asymmetric synthesis of -
disubstituted allylic N-alkyl amines based on TM-catalyzed
[
14]
allylic substitution.
Figure 1. Preliminary screening of allylic precursors: BG and H (0.15 mmol),
BnNH
14 mol%), open to air, rt, 12 h. [a] Isolated yield, er determined by UPC2 (see
Supporting information (SI) for details). [b] 36 h.
2
(0.23 mmol, 1.5 equiv), THF (150 L), Pd
2 3 3
(dba) ·CHCl (3.5 mol %), L1
[
a]
b]
Dr. W. Guo, A. Cai, J. Xie, Prof. Dr. A. W. Kleij, Institute of Chemical
Research of Catalonia (ICIQ), the Barcelona Institute of Science and
Technology, Av. Països Catalans 16, 43007 Tarragona, Spain
Prof. Dr. A. W. Kleij
(
[
Catalan Institute of Research and Advanced Studies (ICREA), Pg.
Lluís Companys 23, 08010 Barcelona, Spain
E-mail: akleij@iciq.es
These authors contributed equally to this work
Supporting information for this article is given via a link at the end of
the document
Therefore, we started our investigation using the model reaction
between benzyl amine and a series of highly substituted allylic
[+]
precursors BG (Figure 1). In the presence of Pd2(dba)3·CHCl3
[15]
(
3.5 mol %) and phosphoramidite ligand L1 (14 mol %), allylic
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COMMUNICATION
precursor B (a Me-protected linear analogue of carbonate A,
Scheme 1a), was converted quantitatively into a linear allylic
[
10]
amine
affirming the challenging nature of -disubstituted
allylic amine formation.
N
We reasoned that the steric impediment in the allylic
precursor would probably be crucial to bias the regio-selectivity
towards the branched product. A less bulky, ethyl-substituted
precursor (C) was then tested but no reaction (conversion) was
noted. To our delight, by decreasing the bulkiness of the alkyl
group to methyl, conversion of allyl precursor D resulted in
substantial amount of branched product (59% isolated yield) with
Cl
[
16]
a high enantiomeric ratio (er 92.5:7.5).
observed when the Me was replaced by a CF
Changing the leaving group from OBoc to OCO
No reaction was
3
group (E).
Me did not
2
significantly affect the reaction outcome (F vs. D), while the
presence of an OAc leaving group (G) slowed down the reaction.
A control reaction using vinyl cyclic carbonate H under similar
conditions gave virtually quantitatively formation of a carbamate
[
12]
product (Figure 1).
Then, the phosphoramidite ligand (L1L7) and the solvent
were systematically optimized using allyl precursor D and benzyl
amine as reaction partners (see Table S1; Supporting
Information). The use of CH
2
Cl
2
and acetonitrile (ACN)
increased the yield of the branched allylic amine but with slightly
lower enantioselectivity (Table S1, entries 1-4). A higher (80%)
isolated yield was achieved when the reaction was performed in
a mixed solvent system consisting of THF/ACN (er 86:14, entry
Figure 2. Scope in allyl precursors: allylic precursor (0.15 mmol), BnNH
2
(0.17
mmol, 1.1 equiv), Pd (dba) CHCl (2 mol %), L1 (10 mol%), THF/ACN (3:1;
2
3
3
o
0.35 mL), 0 C, open to air, 12 h. Isolated yields are reported, and the er values
were determined by UPC2. [a] The er values were determined by using a
chiral shift reagent (SI for details). [b] 24 h. [c] 36 h.
5). Upon increasing the amount of THF in the mixed solvent
medium (THF/ACN, 3:1) the enantioselectivity could be
improved without affecting the overall reactivity (entries 5-7).
Other phosphoramidite ligands L2L7 proved to be less efficient
under these conditions (entry 5 vs 813). The increase of the
amount of solvent and decreasing the amount of amine reagent
Various highly functionalized alkyl amines were found to be
suitable reaction partners (Figure 3, 1429). Importantly, more
functional amines showed appreciable reactivity and provided
good to high er values (18, 22-26) unlike in previous reports.
The presence of a thiophene group did not hamper the
(
entry 14) or catalyst loading (entry 15) did not significantly
[
9]
change the reaction outcome. The reaction was further
optimized using more diluted conditions and lowering the
reaction temperature to 0 ºC giving the allylic amine target in
successful preparation of 21 despite the potential for catalyst
[
18]
poisoning in the presence of sulfur-containing compounds.
Although the use of a propargylic amine reagent resulted in a
78% yield and with an er of 95.5:4.5 (entries 16-18).
[
19]
The scope of allyl Boc-protected precursors was then
examined under the optimized conditions (Figure 2, products 1-
sluggish reaction,
amine 25 may be useful for in vivo bio-
[20]
orthogonal applications through the use of click chemistry.
1
3). The absolute configuration for 1 (S) was unambiguously
The amine products comprising of an indole (27) or 1,3-
benzodioxole fragment (8 and 20) are of interest for
[
17]
confirmed by X-ray analysis of its HCl salt (Figure 2).
Both
[
21]
electron-donating (6, 8, 9, 12 and 13) and withdrawing (2, 3, 5
and 11) groups in the aryl substituents were tolerated while
providing high levels of enantio-induction with er´s up to 98.5:1.5.
The presence of meta-, para- or ortho-substitutions in the aryl
group proved to be feasible (2-6, 9, 1113). The presence of
larger aromatic fragments did not affect the efficiency of the
catalysis (7 and 8), while the preparation of enantioenriched
allylic amines with two -alkyl substituents was also endorsed as
exemplified by the synthesis of compound 10 though with a
moderate er value.
pharmaceutical development.
It is interesting to note that in
most cases only trace amounts of the corresponding linear allylic
amine product were observed (Figures 2 and 3). However, in
some cases (Figure 2; for 14, 17 and 29) substantial amount of
[22]
a 1,3-diene elimination product
was detected under the
optimized reaction conditions thus resulting in a poorer yield of
the desired allylic amine. This side-reaction could be suppressed
by addition of CsF which significantly improved the yield of the
branched product though with somewhat lower enantio-
[
22]
induction.
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can also be transformed into highly functionalized aziridines as
[
23]
reported previously.
Figure 4. Scope in allylic precursors and anilines: allylic precursor (0.15 mmol),
aniline reagent (0.23 mmol), Pd (dba) CHCl (1.25 mol %), L1 (5 mol %), THF
0.2 mL), 0 C, open to air, 12 h. Isolated yields are reported.
2
3
3
o
(
Figure 3. Scope in aliphatic amines: allylic precursor D (0.15 mmol), amine
(
0.17 mmol, 1.1 equiv), Pd
2
(dba)
3 3
CHCl (2 mol %), L1 (10 mol %), THF/ACN
o
(3:1; 0.35 mL), 0 C, open to air, 12 h; isolated yields are reported and the er
values were determined by UPC2. [a] 24 h. [b] CsF (3 equiv) was added,
THF/ACN/H O (3:1:0.4). [c] Amine (1.5 equiv). [d] 36 h. [e] The er values were
determined by using a chiral shift reagent (SI for details).
Figure 5. Various conversions of allylic amine 1: (i) Benzoyl chloride (1.3
equiv), NEt (5 equiv), CH Cl , rt, 50 min. (ii) m-CPBA (2.3 equiv), CH Cl , 0-rt,
h. (iii) Phenyl isocyanate (1.3 equiv), NEt (10 equiv), CH Cl , rt, 10 min. (iv)
TsOH (1.02 equiv), m-CPBA (1.2 equiv), CH Cl , 0-rt, 3 h; see SI for details.
2
3
2
2
2
2
2
3
2
2
2
2
Encouraged by the asymmetric synthesis of various N-alkyl
allyl amines (Figures
2 and 3), the preparation of -
In summary, chiral -disubstituted allylic N-alkyl amines
are important building blocks in organic synthesis and medicinal
chemistry, but to date no general approach has been developed
regarding their synthesis. The regio- and enantioselectivity of
Pd-catalyzed allylic substitution toward -disubstituted allylic
disubstituted N-aryl allylic amines was then probed (Figure 4).
The reaction of allylic precursor D and aniline gave product 30
with an er of 80:20 under the optimized conditions (Table 1,
entry 17). By further optimization (see Table S2 in the SI) the er
could be improved to 88:12 when the reaction was performed in
THF and with a lower catalyst loading (1.25 mol% Pd precursor
and 5 mol% L1). Subsequently, both the aniline and allylic
precursor with either electron-donating (31, 34 and 35) or
withdrawing (32 and 33) aryl substituents were tested, and
afforded the allylic amine products in good isolated yields and
appreciable enantioselectivities. The use of N-methyl aniline,
however, resulted in quantitative formation of the linear product.
N-alkyl amines has been
a long-standing challenge. Our
contribution represents a first, huge step forward in this area.
Despite the fact that some substrate combinations deliver
moderately high asymmetric induction levels and some
limitations are pertinent to the allylic precursors, this new
catalytic approach represents the most effective method
reported to date. Our work here also highlights the key role of
the steric modulation in the allylic substrate to prepare
challenging chiral allylic amines via attractive palladium catalysis.
The catalytic system could be easily performed on a 5 mmol
scale which was exemplified by the successful isolation of 1.24 g
(
75% yield) of allylic amine 1 with high enantioselectivity (er
9
5:5). The synthetic potential of these allylic amines was Acknowledgements
demonstrated by further transformation of 1 into enantioenriched
amide 36, allylic nitrone 37, asymmetric urea 38 and epoxide 39
via simple procedures (Figure 5) retaining the chiral integrity of
the starting allylic amine. The -disubstituted allylic amines
We thank the CERCA Program/Generalitat de Catalunya,
ICREA, the Spanish MINECO (CTQ-2014–60419-R, Severo
Ochoa Excellence Accreditation SEV-2013–0319, and FPI
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fellowship to A.C.) and the Chinese Research Council (CSC-
enantioenriched -disubstituted allylic N-alkyl amines or phthalimides
though with limited substrate scope, see: a) B. M. Trost, C. Jiang, K.
Hammer, Synthesis 2005, 3335; b) B. M. Trost, R. C. Bunt, R. C.
Lemoine, T. L. Calkins, J. Am. Chem. Soc. 2000, 122, 5968. The
asymmetric formation of -disubstituted allylic trifluoroacetimidates
via Pd-catalyzed aza-Claissen arrangement has also been reported: c)
D. F. Fischer, Z. Xin, R. Peters, Angew. Chem. Int. Ed. 2007, 46, 7704.
10] A. Cai, W. Guo; L. Martínez-Rodríguez, A. W. Kleij, J. Am. Chem. Soc.
2016-06200061) for support. We also thank Dr. Eva Raluy and
Dr. Luca Buzzetti for help with UPC2 analyses. Eduardo C.
Escudero-Adán and Dr. Eddy Martin are acknowledged for the
X-ray analysis of 1·HCl.
[
[
Keywords: Allylic amines • palladium • allylic substitution •
enantioselectivity • regioselectivity
2
016, 138, 14194.
11] The use of Me-protected linear carbonate analogue of cyclic
carbonate (Scheme 1) in this decarboxylative process resulted
a
A
[
[
1]
2]
a) I. Dubovyk, I. D. G. Watson, A. K. Yudin, J. Am. Chem. Soc. 2007,
mainly in linear allylic amine formation pointing toward a privileged
selectivity for branched product when using vinyl cyclic carbonate and
aromatic amines. See for more details reference 10.
129, 14172; b) A. M. Johns, Z. Liu, J. F. Hartwig, Angew. Chem. Int. Ed.
2007, 46, 7259; c) I. Dubovyk, I. D. G. Watson, A. K. Yudin, J. Org.
Chem. 2013, 78, 1559; d) K. F. Johnson, R. V. Zeeland, L. M. Stanley,
Org. Lett. 2013, 15, 2798; e) I. D. G. Watson, A. K. Yudin, J. Am. Chem.
Soc. 2005, 127, 17516.
[
2 2
12] The reaction of cyclic carbonate H (Figure 1) with BnNH or BuNH (4
equiv) at rt for 10 min gave rise to quantitative yield of carbamate
product. For relevant contributions describing this aminolysis reactivity:
a) M. Blain, L. Jean-Gérard, R. Auvergne, D. Benazet, S. Caillol, B.
Andrioletti, Green Chem. 2014, 16, 4286; b) W. Guo, V. Laserna, E.
Martin, E. C. Escudero-Adán, A. W. Kleij, Chem. Eur. J. 2016, 22,
The regioselective allylic substitution toward branched -mono-
substituted allylic amines based on palladium catalysis is already
challenging with few exceptions, see: a) O. G. Mancheno, J. Priego, S.
Cabrera, R. G. Arrayas, T. Llamas, J. C. Carretero, J. Org. Chem. 2003,
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Chiral Amine Synthesis; T. C. Nugent, Ed.; Wiley-VCH: New York, 2008.
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Huang, M. Arndt, K. Gooßen, H. Heydt, L. J. Gooßen, Chem. Rev.
o
observed between carbonate precursor H and aniline at 100 C for 20 h,
[
[
3]
4]
see: d) W. Guo, J. Gónzalez-Fabra, N. A. G. Bandeira, C. Bo, A. W.
Kleij, Angew. Chem. Int. Ed. 2015, 54, 11686.
[
[
13] A pendent hydroxymethyl group in the final product produced after the
decarboxylative process limits the product scope.
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2921; c) B. M. Trost, T. Zhang, J. D. Sieber, Chem. Sci. 2010, 1, 427;
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ring-opening of cyclopropenes toward (rac)--disubstituted allylic N-
alkyl amines and asymmetric synthesis was also attempted though with
low enantioselectivity (<10% ee): a) Phan, D. T. H.; Dong, V. M.
d) M. Johannsen, K. A. Jørgensen, Chem. Rev. 1998, 98, 1689; e) B. M.
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a Rh-
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Aldrichimica Acta 2007, 40, 59.
mediated asymmetric synthesis of α,α-disubstituted allylic N-aryl
amines: b) J. S. Arnold, H. M. Nguyen, J. Am. Chem. Soc. 2012, 134,
8380.
[
5]
For representative examples using Ir catalysis: a) M. J. Pouy, A. Leitner,
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[
[
15] The use of chiral phosphoramidites is based on our previous success
toward branched N-aryl amines, see ref. 10; the use of other type of
(bidentate) ligands leads to the linear product, see: W. Guo, L.
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16] Allylic precursor
reactivity of cyclic carbonate H, no reaction is observed for D in the
presence of 4 equiv of BnNH or BuNH at rt for 20 h.
D represents a linear carbonate and unlike the
f) S. Shekhar, B. Trantow, A. Leitner, J. F. Hartwig, J. Am. Chem. Soc.
2006, 128, 11770; g) A. Leitner, C. Shu, J. F. Hartwig, Org. Lett. 2005,
2
2
7, 1093; h) R. Takeuchi, N. Ue, K. Tanabe, K. Yamashita, N. Shiga, J.
[
[
[
17] For more details see the SI and CCDC-1554683.
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reaction times did not lead to higher conversion.
[
[
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Cao, N. Sharova, M. Stevenson, T. M. Rana, ChemMedChem 2012, 7,
[
[
6]
7]
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1
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33, 9716. Base was found to increase the isomerization rate from
3
[
[
For utilization of Ru catalysis: a) M. Kawatsura, K. Uchida, S. Terasaki,
H. Tsuji, M. Minakawa, T. Itoh, Org. Lett. 2014, 16, 1470; b) S. Mizuno,
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Comparing with Ir, Ru and Rh catalysis often used for allylic substitution
reactions, palladium catalysis is more attractive, see references 4-7.
In previous seminal contributions, the Trost group reported the Pd-
catalyzed ring-opening of isoprene monoxide with amines toward
1
linear allylic amine to branched product, see reference 1c. In our case,
all the compounds are stable under the applied reaction conditions.
[
[
8]
9]
23] S. Hayashi, H. Yorimitsu, K. Oshima, Angew. Chem. Int. Ed. 2009, 48,
7224.
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COMMUNICATION
Entry for the Table of Contents:
COMMUNICATION
Widen up: The first asymmetric
synthesis of invaluable -
Wusheng Guo, Aijie Cai, Jianing
Xie and Arjan W. Kleij*
disubstituted
N-alkyl
allylic
amines is reported using an
allylic substitution approach. The
catalytic method relies on Pd-
catalysis, is user-friendly and can
be accomplished under mild and
additive-free conditions. The
Page No. – Page No.
product
scope
for
these
challenging
scaffolds is the widest reported
to date with er values of up to
allylic
amine
Asymmetric Synthesis of -
Disubstituted Allylic Amines via
Pd-Catalyzed Allylic Substitution
98.5:1.5.
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