Cooperative catalysis by palladium and a chiral phosphoric acid: Enantioselective amination of racemic allylic alcohols

Article abstract of DOI:10.1002/anie.201405511

Cooperative catalysis by [Pd(dba)₂] and the chiral phosphoric acid BA1 in combination with the phosphoramidite ligand L8 enabled the efficient enantioselective amination of racemic allylic alcohols with a variety of functionalized amines. This

Full text of DOI:10.1002/anie.201405511

Angewandte
Chemie
DOI: 10.1002/anie.201405511
Asymmetric Allylic Amination
Cooperative Catalysis by Palladium and a Chiral Phosphoric Acid:
Enantioselective Amination of Racemic Allylic Alcohols**
Debasis Banerjee, Kathrin Junge, and Matthias Beller*
Abstract: Cooperative catalysis by [Pd(dba)2] and the chiral
phosphoric acid BA1 in combination with the phosphorami-
dite ligand L8 enabled the efficient enantioselective amination
of racemic allylic alcohols with a variety of functionalized
amines. This catalytic protocol is highly regio- and stereo-
selective (up to e.r. 96:4) and furnishes valuable chiral amines
in almost quantitative yield.
an iridium-catalyzed asymmetric amination of linear allylic
alcohols activated by niobium ethoxide (Nb(OEt)5) and
triphenylborane (BPh3) to give branched allylic amines with
high regio- and enantioselectivity (Scheme 1),[7] and more
P
alladium-catalyzed asymmetric allylic substitution has
become a highly valuable tool in organic synthesis and
catalysis.[1] Following the pioneering studies by the research
groups of Tsuji and Trost, this methodology has been
expanded significantly in the last three decades, and now all
kinds of nucleophiles can be efficiently coupled with various
allylic electrophiles.[2] Among the different types of allylic
substitution reactions, the synthesis of allylic amines is of
special importance owing to the prevalence of this structural
motif in pharmaceuticals and biologically active natural
products.[3] Notably, in last decade, several elegant methods
for selective asymmetric allylic amination with palladium-,
ruthenium-, and iridium-based catalysts have been reported,
including mechanistic investigations.[4] However, despite sig-
nificant progress, most asymmetric allylic amination reactions
rely on the preactivation of allylic alcohols. In general, such
reactions are performed with allylic acetates, halides, and
carbonates and consequently generate stoichiometric
amounts of salt waste. The use of non-activated allylic
alcohols in the enantioselective synthesis of chiral amines
would streamline synthetic sequences and constitute an
efficient, straightforward, and environmentally benign
approach with water as the only by-product.[5] Unfortunately,
owing to the poor leaving ability of the hydroxy group, higher
reaction temperatures as well as external activators are
Scheme 1. Transition-metal-catalyzed enantioselective amination of
allylic esters and alcohols. dba=dibenzylideneacetone.
recently, Carreira and co-workers described the iridium-
catalyzed enantioselective amination of allylic alcohols with
sulfamic acid as an ammonia equivalent.[8] To the best of our
knowledge, no enantioselective amination of racemic allylic
alcohols to afford optically active tertiary amines has been
developed with palladium catalysts. Herein, we report an
enantioselective amination of racemic alcohols with various
amines in the presence of a Pd catalyst in combination with
a chiral phosphoramidite ligand and a chiral phosphoric acid.
As a result of our long-standing interest in the amination
of alcohols[9] and hydroamination of olefins,[10] we recently
became interested in the asymmetric allylic amination of
racemic allylic alcohols. In our initial investigations, we
treated racemic 2-cyclohexen-1-ol (1a) with aniline (2a) in
the presence of [Pd(dba)2] (5 mol%) and chiral phosphor-
amidite ligands[11] L1–L8 (Scheme 2). Unfortunately, the
application of the naphthyl Trost ligand L1 or the chiral
phosphoramidite ligands L2–L4 provided negligible conver-
sion into 3a. However, the use of ligand L5 with a 2-naphthyl
substituent in the amine moiety proved beneficial, and 3a was
obtained in 25% yield with e.r. 56:49. Variation of the binol
backbone to give the spiro ligand L6 enhanced the catalytic
activity, and the product was obtained in 75% yield with
e.r. 62:38. Furthermore, the use of ligand L7, a diastereoiso-
mer of L2, enabled the formation of 3a in 57% yield with
e.r. 60:35. To our delight, use of the phosphoramidite ligand
L8 with a 2-methoxyphenyl substituent in the amine moiety
À
required to activate the C O bond, which limits such
reactions to the formation of achiral products.[6]
The direct use of allylic alcohols for enantioselective
amination reactions constitutes a highly challenging task and
is still underdeveloped. Hartwig and co-workers introduced
[*] Dr. D. Banerjee, Dr. K. Junge, Prof. Dr. M. Beller
Leibniz-Institut fꢀr Katalyse an der Universitꢁt Rostock
Albert-Einstein-Strasse 29a, 18059 Rostock (Germany)
E-mail: matthias.beller@catalysis.de
Homepage: http://www.catalysis.de
[**] This research has been funded by the State of Mecklenburg–
Western Pomerania, the BMBF, and the DFG (Leibniz Prize). We
thank Dr. W. Baumann, Dr. C. Fischer, S. Buchholz, S. Schareina, A.
Koch, and S. Rossmeisl (all at LIKAT) for their excellent technical
and analytical support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201405511.
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Table 1: Development of an optimal catalyst system for the asymmetric
amination of racemic 2-cyclohexen-1-ol.[a]
Entry Pd catalyst
BA Solvent
T
Yield
e.r.[c]
[8C] [%][b]
1
2
[Pd(dba)2]
[{Pd(p-cinna-
myl)Cl}2]
BA1 THF
BA1 THF
25
25
95
0
96:4
n.d.
3
4
5
6
7
8
9
10
11
12
13
[{Pd(p-allyl)Cl}2]
[Pd(PPh3)4]
[Pd(dba)2]
[Pd(dba)2]
[Pd(dba)2]
[Pd(dba)2]
[Pd(dba)2]
[Pd(dba)2]
[Pd(dba)2]
[Pd(dba)2]
[Pd(dba)2]
BA1 THF
BA1 THF
BA2 THF
BA3 THF
BA4 THF
BA5 THF
BA6 THF
BA7 THF
TFA THF
BA1 CH2Cl2
BA1 1,4-diox-
ane
25
25
25
25
25
25
25
25
25
25
25
0
40
10
25
8
n.d.
–
85:15
78:22
n.d.
–
80:20
87:13
79:21
–
0
20
28
10
0
0
–
14
15
[Pd(dba)2]
–
BA1 THF
BA1 THF
BA1 THF
10
25
25
90
–
–
95:5
–
–
16[d] [Pd(dba)2]
[a] Reaction conditions: 1a (1 mmol), 2a (0.25 mmol), Pd catalyst
(5 mol%), L8 (10 mol%), BA (5 mol%), solvent (1 mL), 10–258C.
[b] Yield of the isolated product. [c] The enantiomeric ratio was
determined by GC on a chiral stationary phase. n.d. =not determined.
[d] The reaction was carried out without L8.
Scheme 2. Investigation of ligands for the enantioselective allylic
amination of 2-cyclohexen-1-ol.
Next, we studied the influence of the steric and electronic
effects of different chiral binaphthol-based phosphoric acid
derivatives.[13] Application of the 3,3’-bis(trifluoromethyl-
phenyl) derivative BA2 and (S)-trip (BA3) under the optimal
conditions resulted in the formation of 3a in only 10 and 25%
yield with e.r. 85:15 and 78:22, respectively (Table 1, entries 5
and 6). The ligand (R)-trip (BA4) offered even lower
reactivity, thus suggesting the formation of a mismatched
combination (Table 1, entry 7). Sterically hindered BA5 and
BA7 also proved inactive towards enantioselective amination
(Table 1, entries 8 and 10). Furthermore, the racemic phos-
phoric acid BA6 as well as trifluoroacetic acid gave 3a in only
low yield with poor selectivity (Table 1, entries 9 and 11). The
examination of different solvents (THF, dioxane, dichloro-
methane, and toluene) revealed that THF is a unique solvent
for this enantioselective amination (Table 1, entries 12 and
13). Under optimal conditions, the amination reaction could
also be carried out at lower temperature (108C); in this case
3a was obtained in 90% yield with e.r. 95:5 (Table 1,
entry 14). Control experiments with the individual compo-
nents of the catalyst system suggested a strong synergistic
afforded 3a in 40% yield with a more promising enantiomeric
ratio (e.r. 72:28).
To improve the stereoselectivity of the transformation
further, we studied the influence of different catalyst pre-
cursors, solvents, and additives on the model reaction. List
and co-workers demonstrated that the stereoselectivity of
asymmetric allylic alkylation reactions of aldehydes with
allylic alcohols can be efficiently controlled by a suitable
combination of a Pd complex and a chiral phosphoric acid.[12]
It was proposed that the chiral phosphoric acid facilitates the
formation of the active allyl palladium complex. Inspired by
these studies, we tested the effect of a series of chiral
phosphoric acids in combination with [Pd(dba)2] and ligand
L8 (Table 1). We were pleased to find that the use of 5 mol%
of the chiral phosphoric acid BA1 afforded 3a in 95% yield
with e.r. 96:4 (Table 1, entry 1)! Surprisingly, under similar
reaction conditions with other palladium precursors, 3a was
formed in moderate yield with no selectivity or not at all
(Table 1, entries 2–4).
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effect between the chiral phosphoric acid [Pd(dba)2] (BA1)
and the phosphoramidite ligand L8 (Table 1, entries 1, 15, and
16).
Having established optimal reaction conditions, we
explored the reaction of racemic 2-cyclohexen-1-ol (1a)
with functionalized aniline derivatives substituted with elec-
tron-donating or electron-withdrawing substituents (Table 2).
In the case of methoxy-, alkyl-, chloro-, trifluoromethyl-, and
proceeded in moderate yield and selectivity (Table 2, entry 9).
In all reactions, no bisallylic amines were observed by GC–
MS analysis of the crude reaction mixture. Whenever
possible, we also recovered the unreacted starting materials.
Unfortunately, under similar reaction conditions, we observed
poor reactivity with aliphatic amines, probably owing to their
higher nucleophilicity which leads to reduced activation of
allylic alcohol.
To further demonstrate the generality of this novel
protocol, we studied the scope of the reaction of acyclic and
cyclic racemic alkyl allylic alcohols with aniline (Table 3). The
reaction of 4-phenyl-2-butenol (1b) with 2a led to 3j in
almost quantitative yield with e.r. 85:15 (Table 3, entry 1).
Similarly, the reaction of 2-cyclopenten-1-ol (1c) and 2-
cyclohepten-1-ol (1d) with aniline (2a) afforded 3k,l in 94
and 60% yield with e.r. 92:8 and 87:13, respectively (Table 3,
entries 2 and 3).
Table 2: Palladium-catalyzed enantioselective amination of racemic
allylic alcohols with amines.[a]
Entry
1
1
2
Product 3
Yield [%][b] e.r.[c]
1a
95
90
92
96:4
94:6
95:5
Table 3: Palladium-catalyzed enantioselective amination of racemic
allylic alcohols.[a]
2
3
4
5
1a
1a
1a
1a
Entry
1[d]
Alcohol 1
Product 3
Yield [%][b]
95
e.r.[c]
93
95
90
96
95
65
95:5
92:8
90:10
94:6
91:9
85:15
2
3
94
60
92:8
87:13
6
1a
1a
1a
1b
4[e]
5[e]
6[e]
93
95
90
94:6
96:4
90:10
7
7[e]
76
94:6
8
[a] Reaction conditions: 1 (1 mmol), 2a (0.25 mmol), Pd catalyst
(5 mol%), L8 (10 mol%), BA1 (5 mol%), solvent (1 mL). [b] Yield of the
isolated product. [c] The enantiomeric ratio was determined by HPLC or
GC on a chiral stationary phase. [d] The reaction was performed at 408C
for 72 h. [e] The reaction was performed for 12 h.
9[d]
80:20
[a] Reaction conditions: 1 (1 mmol), 2 (0.25 mmol), Pd catalyst
(5 mol%), L8 (10 mol%), BA1 (5 mol%), solvent (1 mL). [b] Yield of the
isolated product. [c] The enantiomeric ratio was determined by HPLC or
GC on a chiral stationary phase. [d] The reaction was performed at 408C
for 72 h.
We also explored the reactivity of more challenging
secondary alkyl allylic alcohols. These substrates are com-
monly known to be less reactive and highly prone to form
nonchiral linear products.[6] However, the reaction of 3-buten-
2-ol (1e) with 2a gave 3m in 93% yield with e.r. 96:4 (Table 3,
entry 4). Similar reactions of 2a with 1-octen-3-ol (1 f), 1,5-
hexadien-3-ol (1g), and 2-hepten-4-ol (1h) also afforded the
corresponding products 3n–p in very good yields (76–95%)
with e.r. 90:10–96:4 (Table 3, entries 5–7).[14] Notably, these
reactions occurred with excellent (> 99%) regioselectivity for
the branched isomer. However, in the case of 3p, we observed
cyano-substituted aniline derivatives, products 3b–f were
formed in excellent yield (90–95%) with high enantioselec-
tivity (e.r. 90:10–95:5; Table 2, entries 2–6). Notably, the
reactions of 1a with sterically hindered o-toluidine (2g) and
secondary N-methylaniline (2h) afforded 3g,h in almost
quantitative yield with e.r. 94:6 and 91:9, respectively
(Table 2, entries 7 and 8). The reaction of the heterocyclic
amine 2-aminopyridine (2i) with 4-phenyl-2-butenol (1b) also
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a minor amount (ca. 5%) of another isomer by GC–MS
analysis of the crude reaction mixture (Table 3, entry 7).
We next treated the deuterated allylic alcohols 1i,j with
aniline under the optimized reaction conditions and were
pleased to find that the reaction is indeed highly regio- and
enantioselective (Scheme 3). Thus, exclusive formation of the
Experimental Section
Under an argon atmosphere, 2-cyclohexen-1-ol (1 mmol) and aniline
(0.25 mmol) were placed in an oven-dried Schlenk tube (10 mL), and
freshly prepared [Pd(dba)2] (5 mol%) and the phosphoric acid BA1
(5 mol%) were added, followed by L8 (10 mol%). Freshly distilled
THF (1 mL) and a magnetic stirrer bar were then added, and the
reaction mixture was stirred at 258C for the reported time. After
completion of the reaction, the reaction mixture was diluted with
ethyl acetate (10 mL). The filtrate was concentrated under reduced
pressure, and the residue was purified by silica-gel column chroma-
tography with ethyl acetate/hexane as the eluent to afford the
corresponding allylic amine derivatives.
Received: May 22, 2014
Revised: September 10, 2014
Published online: && &&, &&&&
Keywords: allylic alcohols · asymmetric amination ·
.
chiral phosphoric acids · palladium · phosphoramidite ligands
Scheme 3. Enantioselective amination of deuterated allylic alcohols.
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chiral deuterated amines 3q,r in almost quantitative yield
with e.r. 95:5 and 85:15 was observed. It is proposed that the
allylic palladium intermediate formed in situ is stabilized by
the ligand, and that the rate of isomerization of the two allylic
palladium intermediates is slower than the rate of nucleo-
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allylic amines. Notably, we did not observe other regioisomers
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amination reaction was performed with optically active (S)-1-
octen-3-ol, the corresponding allylic amine was formed in
92% yield with e.r. 96:4 (see Scheme S1 in the Supporting
Information).
To gain further insight into the reaction mechanism, we
prepared the defined complex [{Pd(p-cyclohexyl)Cl)}2] and
tested its behavior in the enantioselective amination in the
presence of aniline, L8, and BA1 (see Scheme S2). The
reaction gave 3a in 50% yield with e.r. 85:15. Note that when
the amination reaction was performed with allylpalladium
chloride dimer or palladium(p-cinnamyl) chloride dimer, we
did not observe any desired reactivity (Table 1, entries 2 and
3). We believe that in the presence of chloride, stable
palladium–allyl complexes form and do not undergo further
amination, whereas in the presence of dibenzylideneacetone,
the formation of a more active palladium–phosphate complex
occurs.[15] Indeed, when the amination was performed with the
defined palladium–phosphate complex 5, the desired product
was formed in 53% yield with e.r. 90:10 in the presence of
aniline and the chiral phosphoramidite ligand L8 (see
Scheme S2).
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functionalized anilines. Key to high enantioselectivity is
cooperative catalysis by [Pd(dba)2], a chiral phosphoric
acid, and the specific phosphoramidite ligand L8. The
reaction proceeded even with less reactive alkyl allylic
alcohols and furnished a number of products in almost
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[11] When amination reactions are performed with phosphoramidite
ligands, the presence of heteroatoms facilitates the partial
[15] B. M. Trost, P. E. Strege, L. Weber, T. J. Fullerton, T. J. Dietsche,
J. Am. Chem. Soc. 1978, 100, 3407.
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
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Angewandte
Communications
Communications
Asymmetric Allylic Amination
D. Banerjee, K. Junge,
M. Beller*
&&&& — &&&&
Cooperative Catalysis by Palladium and
a Chiral Phosphoric Acid:
Enantioselective Amination of Racemic
Allylic Alcohols
Teamwork enantioselectivity: An asym-
metric amination of racemic allylic alco-
hols with various functionalized amines
proceeded with high regio- and enantio-
selectivity under cooperative catalysis by
the chiral phosphoric acid 1 and a palla-
dium complex with the phosphoramidite
ligand 2 (see scheme; R1 =aryl, R2 =alkyl
or H; dba=dibenzylideneacetone). The
transformation was efficient even with
less reactive alkyl allylic alcohols.
6
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!