Regio- and enantioselective allylic amination of achiral allylic esters catalyzed by an iridium-phosphoramidite complex

Article abstract of DOI:10.1021/ja028614m

A new catalytic asymmetric process, the iridium-catalyzed enantioselective allylic amination of (E)-cinnamyl and terminal aliphatic allylic carbonates, was developed by exploring complexes of chiral phosphoramidites. The reaction provided branched secondary and tertiary allylic amines in high yields with excellent regio- and enantioselectivity (13 examples over 94% ee). Although the reactions in polar solvent such as DMF, EtOH, and MeOH were fast, they gave low enantiomeric excesses. In contrast, reactions in THF displayed the most suitable balance of rate and enantioselectivity. Both the binaphthol unit and the disubstituted amine in the phosphoramidite affected reactivity and selectivity, and complexes of O,O′-(R)-(1,1′-dinaphthyl-2,2′-diyl)-N,N′-di-(R,R)-1-phenylethylphosphoramidite provided the highest reactivity and selectivity. Primary and cyclic secondary amines reacted at room temperature, and acyclic diethylamine reacted at 50 °C. p-Methoxy-substituted cinnamyl carbonate reacted similarly to the unsubstituted cinnamyl carbonate, but the o-methoxy-substituted substrate gave lower enantiomeric excess. High ee's were also observed for the products from the reaction of furanyl- and alkyl-substituted (E)-allylic carbonates. Copyright

Full text of DOI:10.1021/ja028614m

Published on Web 11/20/2002
Regio- and Enantioselective Allylic Amination of Achiral Allylic Esters
Catalyzed by an Iridium-Phosphoramidite Complex
Toshimichi Ohmura and John F. Hartwig*
Department of Chemistry, Yale UniVersity, P.O. Box 208107, New HaVen, Connecticut 06520-8107
Received September 19, 2002
Enantioselective routes to optically active amines provide valu-
able synthetic building blocks.1 The enantioselective preparation
of chiral tertiary amines is particularly important because they
cannot be generated directly by enantioselective hydrogenation of
imines,2,3 and the enantioselective hydrogenation of enamines
remains a challenge.4 In addition, methods for enantioselective
coupling of two fragments by C-N bond-formation are limited.5-8
We recently reported catalysts for enantioselective hydroaminations
Figure 1. Phosphoramidite ligands used in this study.
to form allylic and benzylic amines.6,7 Because η3-π-benzyl and
-allyl complexes are intermediates in both our hydroamination
Scheme 1
chemistry and allylic amination, we sought to develop, in parallel,
catalysts for enantioselective allylic substitution.
During these studies we took notice of chiral phosphoramidites
6-8, designed by Feringa and co-workers (Figure 1).9,10 Their
π-accepting property should be favorable for nucleophilic attack
on allyl or benzyl groups. Indeed, their complexes with palladium
showed activity during our preliminary studies on hydroamination,
and as reported here, complexes with iridium show high activity
and selectivity for enantioselective substitution of (E)-cinnamyl and
terminal aliphatic allylic carbonates. These allylic aminations are
conducted with air-stable catalyst components at ambient temper-
atures.
Allyic substitution of acyclic allylic electrophiles catalyzed by
W,11 Mo,12,13 Ru,14,15 Ir,16 and Rh17,18 complexes often generate the
chiral branched substitution products. Enantioselective amination
of symmetrical 1,3-diphenylallyl carbonates,19-23 and unsymmetrical
branched allylic acetates,24 along with a single example of pal-
ladium-catalyzed asymmetric amination of a terminal allylic ester
or carbonate,25 have been reported.26 However, a general, enanti-
oselective allylic amination from an achiral, terminal allylic
electrophile has not been accomplished. Takeuchi27 and Evans28
have shown that iridium and rhodium complexes of achiral
phosphites catalyze the formation of branched amines, in some cases
with conservation of enantioselectivity.28 Helmchen reported enan-
tioselective alkylation of branched allylic acetates with modest ee’s29
in the presence of an iridium-phosphoramidite catalyst. Analogous
enantioselective aminations occurred with ee’s below 15%. Iridium
complexes that may be related to the amination chemistry were
isolated.30
regioselectivity (3/4 ) 99/1) after 1 h at room temperature but
produced lower ratios of 3/4 (3/4 ) 67/33 after 12 h and 23/77
after 24 h) and the more stable 4 as the major product (3/4 ) 10/
90) after 60 h.
Solvent influenced the reactivity, regioselectivity, and enanti-
oselectivity for the reaction of 1.2-1.3 equiv of benzylamine (2a)
with 1a. The reactivity at room temperature followed the order
DMF, EtOH (100% conversion after 1-2 h) > MeOH, THF, CH3-
CN (8-10 h) > CH3NO2, DME (20-24 h) > CH2Cl2, NEt3 (48 h)
> 1,4-dioxane, Et2O, toluene (reactions were incomplete after 72
h). Reactions in each solvent, except NEt3 and CH3NO2, occurred
with high regioselectivity (3/4/5 ) 98-94/1-4/0-3) when 1.2-
1.3 equiv of amine was used. The enantioselectivity of reactions
in different solvents followed the order THF, Et2O (95% ee), DME
(94% ee) > toluene, 1,4-dioxane, CH2Cl2 (92-90% ee) > NEt3
(86% ee) > DMF, EtOH, CH3CN (80-77% ee) > CH3NO2 (65%
ee) > MeOH (52% ee). Reactions in the polar solvents DMF, EtOH,
and MeOH were fast, but low ee’s were observed. Reactions in
THF displayed the most suitable balance of rate and enantioselec-
tivity.
The effect of ligand and temperature on selectivity is summarized
in Table 1. The reaction proceeded smoothly at room temperature
in the presence of [Ir(cod)Cl]2 (1 mol %) and (Ra,RC,RC)-6 (2 mol
%, L/Ir ) 1) to give after 10 h branched 3 with excellent
regioselectivity (3/4/5 ) 98/1/1) and 84% isolated yield of product
with 95% enantiomeric excess (entry 1). Reaction at 50 °C for 4 h
gave 89% of 3 with 94% ee (entry 2). Reactions catalyzed by
In contrast, we have found that iridium complexes of phosphora-
midite (Ra,RC,RC)-6 in Figure 1 catalyze allylic amination with high
activity to form branched product 3 with high enantioselectivity
(Scheme 1). Regioselective formation of 3 required control of the
reaction conditions. In EtOH, the phosphoramidite complex cata-
lyzed allylic transposition of the amino group in product 3: in the
presence of [Ir(cod)Cl]2 (1 mol %) and (Ra,RC,RC)-6 (2 mol %,
L/Ir ) 1), the reaction of cinnamyl methyl carbonate (1a) with
morpholine (2g, 3.0 equiv) gave complete conversion and excellent
* Corresponding author. E-mail: john.hartwig@yale.edu.
9
15164
J. AM. CHEM. SOC. 2002, 124, 15164-15165
10.1021/ja028614m CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Ligand and Temperature Effects for Ir-Catalyzed
Enantioselective Allylic Amination of 1a with 2aa
(entry 13) or neat (entry 14) with 3.0 equiv of amine to form the
allylic amine in good yield and with excellent enantioselectivity.
Two terminal carbonates reacted less selectively. p-Nitrocinnamyl
1c was only slightly soluble in THF and gave lower regioselectivity
and enantioselectivity (86% ee, entry 9). o-Methoxy-substituted
cinnamyl carbonate 1d reacted with high regioselectivity, but the
branched product formed with only 76% ee (entry 10). Branched
allylic carbonates have, thus far, reacted to give low ee’s of
branched allylic amine after full conversion.
yield of
3 (%)c
entry
ligand
temp
rt
50 °C
50 °C
50 °C
50 °C
rt
time (h)
3/4/5b
%eed
1
2
3
4
5
6
(Ra,RC,RC)-6
(Ra,RC,RC)-6
(Sa,RC,RC)-6
(R)-7
(R)-8
(R,R)-9
10
4
72
72
72
48
98/1/1
98/2/0
84
89
66
11
25
72
95 (R)
94 (R)
75 (S)
0
61 (R)
87 (R)
93/6/1
41/43/16
72/23/5
96/2/2
In conclusion, we developed a new catalytic process to produce
branched aromatic or aliphatic secondary or tertiary allylic amines
in high yield with excellent enantioselectivity from achiral allylic
actetates and carbonates. The terminal olefin in the product can be
used to generate, for example, 1,3-amino alcohols, 1,3-diamines,
and various types of amino acids. Mechanistic understanding and
further evaluation of substrate scope will comprise future studies.
a The reaction was conducted with 1 mmol of 1a and 1.2-1.3 mmol of
2a in THF (0.5 mL) in the presence of 0.01 mmol of [Ir(cod)Cl]2 and 0.02
mmol of phosphoramidite unless otherwise noted. b Determined by 1H NMR
spectroscopy of crude reaction mixtures. c Isolated yield after silica gel
chromatography. d Determined by HPLC with a Daicel Chiralcel OD-H
column and hexane/2-PrOH/Et2NH (99.74/0.25/0.01) as eluent.
Table 2. Enantioselective Allylic Amination Catalyzed by
Ir-(Ra,RC,RC)-6a
Acknowledgment. We thank the NIH (GM-58108) for support
of this work and Johnson-Matthey for a gift of IrCl3. T.O. thanks
the JSPS for a postdoctoral fellowship.
entry
allyl carbonate
amine
time (h)
3/4/5b
yield of 3 (%)c
%eed
1
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
2b
2c
2d
2e
2f
2g
2h
2a
2a
2a
2a
2a
2a
2g
18
9
12
2
10
24
16
9
12
16
10
10
16
72
99/0/1
98/2/0
na
80
88
76
75
91
92
83
88
67
77
58
66
95
87
94 (-)
96 (R)
97 (-)
97 (-)
96 (-)
97 (-)
97 (-)
96 (-)
86 (-)
76 (-)
97 (+)
95 (+)
95 (-)
96 (-)
2
3
Supporting Information Available: Experimental procedures and
spectroscopic data of the reaction products (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
4
98/2
5
97/3
6
99/1
7e
8
98/2
99/1/0
83/13/4
95/4/1
96/2/2
88/8/4
97/3/0
96/4
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9f
10
11
12
13g
14h
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such as pyrrolidine (2e), piperidine (2f), and morpholine (2g),
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