Enantioselective allylation of aromatic amines after in situ generation of an activated cyclometalated iridium catalyst

Article abstract of DOI:10.1002/anie.200460276

Highly regio- and enantioselective allylation of aromatic amines is observed when a cyclometalated Ir-phosphoramidite complex is generated in situ (see scheme). The active catalyst can be formed from [{Ir(cod)Cl}₂] and ligand L with a volatile alkylamine prior to addition of the reagents or upon use of a tertiary amine additive.

Full text of DOI:10.1002/anie.200460276

Angewandte
Chemie
Catalysts based on metals other than palladium[8–16] and its
congeners often form the more hindered, branched product
from nucleophilic substitution with unsymmetrical monosub-
stituted allylic esters.[17–20] This reactivity complements the
regioselectivity of palladium catalysts, which tend to form the
linear products. We previously reported asymmetric allylic
substitution of achiral allylic carbonates with aliphatic amines
and phenoxides to form branched allylic amines and ethers
with high regio- and enantioselectivities in the presence of an
iridium complex with a phosphoramidite ligand.[21,22] Reac-
tions of aromatic amines did not occur under the conditions
developed originally.
Our mechanistic studies have shown that the cyclometa-
lated complex 1, generated in situ by treatment of
[{Ir(cod)Cl}2] (cod = cycloocta-1,5-diene) and the ligand L1
with an alkylamine base (Scheme 1), is likely to be the true
catalyst in the allylic amination.[23] Reactions conducted with
the isolated complex 1 as catalyst occurred faster and with
broader scope than those with the combination of
[{Ir(cod)Cl}2] and L1.
Synthesis of Allylic Amines
Enantioselective Allylation of Aromatic Amines
after In Situ Generation of an Activated
Cyclometalated Iridium Catalyst**
Chutian Shu, Andreas Leitner, and John F. Hartwig*
Aromatic amines with a stereocenter a to the nitrogen atom
are important structural motifs in a number of biologically
active compounds.[1] Many of approaches to such structures
have been investigated, but each method has limitations.
Thus, a highly enantioselective procedure to prepare optically
active aromatic amines would be valuable, and an enantio-
selective route to N-aryl allylic amines would be particularly
useful because of the dual functionality in these compounds.
Allylic substitution catalyzed by transition metals has
Scheme 1. Synthesis of 1; 1-Np=1-naphthyl.
We proposed that the initial system failed to catalyze
reactions of anilines because aromatic amines are not basic
enough to induce cyclometalation, not because aromatic
amines are too weakly nucleophilic to react with the iridium
allyl intermediate.[23] If so, then the reactions of aniline should
occur with a catalyst generated in situ by the action of a
separate additive. Herein we report two convenient methods
to generate the active catalyst in situ and the use of this
catalyst to develop a general reaction of allylic carbonates
with aromatic amines.[24] These reactions occur with a broad
range of achiral, linear allylic carbonates to give branched
chiral allyl aryl amines in excellent yields and with high regio-
and enantioselectivities (Scheme 2).
emerged as a powerful tool for enantioselective formation of
[2–4]
À
À
À
C C , C N, and C O bonds.
However, aromatic amines
have not been used commonly in allylic amination,[5–7]
presumably because they are less nucleophilic than the
more commonly used benzylamine or stabilized anionic
nitrogen nucleophiles. A general and highly enantioselective
reaction between an aromatic amine without an activating
group on the nitrogen atom and an achiral allylic ester or a
racemic branched allylic electrophile has not been reported.
[*] Dr. C. Shu, Dr. A. Leitner, Prof. Dr. J. F. Hartwig
Department of Chemistry
Yale University
Scheme 2. Amination of allylic carbonates 2 with aniline.
P.O. Box 208107, New Haven, CT 06520-8107 (USA)
Fax: (+1)203-432-6144
E-mail: john.hartwig@yale.edu
The cyclometalated complex 1 was generated in pure form
by reaction of [{Ir(cod)Cl}2] and L1 with an unhindered
secondary amine, such as pyrrolidine (Scheme 1). We rea-
soned that the addition of a volatile primary amine prior to
addition of aniline or a tertiary aliphatic amine would induce
[**] We thank Merck Research Laboratories and Boehringer Ingelheim
for unrestricted support. A.L. thanks the FWF Austria for an Erwin
Schrödinger fellowship.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2004, 43, 4797 –4800
DOI: 10.1002/anie.200460276
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4797

Communications
cyclometalation without interfering with the reaction of the
aniline.
Thus, one procedure (method A) involved heating
Alternatively, the reaction was conducted at room tem-
perature with a tertiary amine additive. We tested the reaction
of methyl cinnamyl carbonate with aniline in the presence of
tertiary amine additives (Table 2). The reaction in the
[{Ir(cod)Cl}2] and L1 with propylamine at 508Cfor 20 min.
After evaporation of the volatile materials, the crude yellow
solid 1 was dissolved in THF, and a portion or all of this
solution was used as catalyst for the reactions of aromatic
amines. As shown in Table 1, reactions of allylic carbonates
with electron-rich as well as electron-neutral anilines in the
presence of 2 mol% iridium catalyst occurred within 2–2.5 h,
with high regioselectivities and enantioselectivities up to
98%. Aromatic (2a) and aliphatic allylic carbonates (2b)
reacted similarly.
Table 2: Optimization of the reaction conditions with a tertiary amine
base as additive.
Ligand Additives (equiv) t [h] Conv. [%] Yield [%] 3/4
ee [%]
L1 (2%) NEt3 (0.50)
24
24 100
2
6
0
–
–
–
L1 (2%) DABCO (0.50)
L2 (1%) DABCO (0.50)
L2 (1%) DABCO (0.10)
72
77
80
>99:1 92
>99:1 95
>99:1 96
100
100
presence of the relatively unhin-
dered 1,4-diazabicyclo[2.2.2]octane
(DABCO) gave the desired
branched amine in high yield and
with 92% ee. The amount of
DABCO influenced the reaction
rate but did not significantly affect
the enantioselectivity.
Further improvement in rate
and selectivity was achieved by
conducting reactions with the bulk-
ier ligand L2 (methods B and C
Table 1). For example, the reaction
of the hexenyl carbonate 2b with
aniline in the presence of the cata-
lyst generated from L2 occurred
with 96% ee, while the same reac-
tion occurred with 92% ee when the
catalyst was generated from L1.
The results with methods B and
Cshow that the scope of the reac-
tion of aromatic amines with aro-
matic and aliphatic carbonates with
DABCO as additive is broad
(Table 1). Electron-rich and elec-
Table 1: Allylic amination of methyl cinnamyl carbonate (2a) and the methyl carbonate derived from (E)-
2-hexen-1-ol (2b) with aromatic amines (see Scheme 2).
Entry
Carbonate 2
Amine 3
t [h]
6
4
Yield [%]
4/5
ee [%]
94
Method[a]
1
2
3
4
2a
2b
2a
2b
4b
4c
4d
4e
76
94
91
95
99:1
96:4
98:2
95:5
B
A
B
A
2
93
4
95
2
95
5
6
2a
2a
4
4 f
82
86
97:3
97:3
96
96
B
A
2.5
4g
7
2a
2a
2a
2a
10
10
2.5
10
4h
4i
4i
4j
90
89
80
92
98:2
98:2
95:5
98:2
94
96
96
96
B
B
A
B
8
9
10
11
2a
10
4k
83
97:3
95
B
12
13
2a
2a
10
16
4l
89
72
99:1
94:6
95
96
B
C
4m
tron-neutral
aromatic
amines
reacted with allylic carbonates to
generate the branched N-aryl allylic
amines in high yields and with
excellent regio- and enantioselec-
tivities (entries 1, 3, 5, 7, 8, 10–12).
Unhindered aromatic amines or
sterically hindered primary aro-
matic amines, such as 2,4,6-trime-
thylaniline, reacted in high yields
14
15
2a
2a
16
2
4n
4o
66
82
93:7
97:3
94
96
B
B
16
17
2a
2a
2.5
2
4p
4q
85
90
97:3
99:1
96
95
A
B
with
(entries 14, 15). The reaction of o-
bromoaniline is noteworthy
because the ortho-bromo substitu-
ent can be used for further trans-
formations.[25] Cyclic secondary aro-
matic amines also reacted to give
the branched N-allylamine in excel-
lent yields (entries 17, 18), but acy-
excellent
selectivities
18
2a
2
4r
89
97:3
96
B
[a] Method A: The catalyst was generated from propylamine (3.6 mmol) upon heating with [{Ir(cod)Cl}2]
and L1 at 508C for 20 min. The reactions were conducted on a 1.0-mmol scale in THF (0.5 mL) with a
molar ratio for 2a/3/[{Ir(cod)Cl}2]/L1 of 1:1.2:0.01:0.02. Method B: The catalyst was generated in situ
with DABCO as additive. The reactions were conducted on a 1.0-mmol scale in THF (0.5 mL) at room
temperature with a molar ratio for 2a/3/DABCO/[{Ir(cod)Cl}2]/L2 of 100:125:10:0.5:1. Method C: The
reactions were conducted as for method B, but with a molar ratio for 2a/3/DABCO/[{Ir(cod)Cl}2]/L2 of
100:125:10:1:2.
4798
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Chemie
clic secondary aromatic amines reacted with regioselectivities
that ranged from 4:1 (in favor of the branched isomer) to 1:1.
Some electron-deficient aromatic amines required longer
reaction times and higher catalyst loadings but formed the
substitution product in acceptable yield and high enantiose-
lectivity (Table 1, entries 13, 14). More electron-deficient
anilines like p-cyanoaniline, did react, but in low yield and
regioselectivity. The extremely electron-deficient p-nitroani-
line did not react.
of 1 mol% of the iridium catalyst and 3 mol% DABCO
formed the branched allylic amine 4y with 97% ee and a
branched-to-linear ratio of 97:3 (Table 3, entry 8).[27]
The unusually fast amination of aliphatic allylic carbo-
nates allowed reactions of these substrates to be conducted
with low catalyst loadings. For example, the reaction of
carbonate 2b with p-anisidine in the presence of 0.1 mol% of
iridium catalyst afforded the allylic amine 4e in 85% yield
and with 94% ee (Scheme 3).
The scope of electrophile used encompassed both aro-
matic and aliphatic allylic carbonates (Table 3). In addition to
the parent cinnamyl carbonate (2a), p-methoxy cinnamyl
carbonate and the 2-furyl-substituted allylic carbonate
reacted to give the branched products in excellent yields
and selectivities (entries 1, 2).
In contrast to these examples, ortho-methoxy cinnamyl
carbonate reacted with aniline to give the substitution
product with the same enantiomeric excess (74% ee) that
was observed for reactions of this carbonate with aliphatic
amines and phenoxides. Thus far, we have not solved the
problem of enantioselective reactions of ortho-substituted
allylic carbonates (Table 3, entry 3).
In principle, Pd-catalyzed cross-
Table 3: Amination of allylic carbonates 2 with aniline (Scheme 2, Ar=Ph).
coupling[28–30] of an aromatic halide
Entry
Carbonate 2
t [h]
4
Yield [%]
ee [%]
b/l 4/5
97:3
Method[a]
with an enantiopure a-chiral pri-
mary or secondary amine could be
used to form the same a-chiral
amines as those generated by this
allylic substituiton. To compare aro-
matic amination to allylic amination
as a method to prepare these mate-
rials, we conducted the reaction
between phenyl bromide and an
enantioenriched primary allylic
amine (95% ee) catalyzed by a
combination of [Pd2(dba)3] and
(Æ )-binap (Scheme 4), which was
1
2
3
10
4s
4t
4u
88
81
91
96
B
B
B
10
90
94:6
10
74
99:1
4
5
6
7
3
4v
4v
4w
4x
87
93
72
87
95
92
95
97
98:2
B
A
B
B
2.5
3
92:8
97:3
98:1:1[b]
3
8
16
4y
83
97
97:3
D[c]
[a] For conditions of methods A–C see footnote [a] to Table 1. [b] The ratio of a-branched/g-branched/ shown previously[31] to couple an
linear product. [c] Method D: The reaction was conducted with the catalyst generated in situ with
aryl bromide with optically active
phenethylamine without racemiza-
tion. In contrast to reactions of
DABCO as additive. The reaction was carried out on a 1.0-mmol scale in THF (0.5 mL) at room
temperature with a relative mole ratio for 2a/3/DABCO/[{Ir(cod)Cl}2]/L2 of 100:125:5:0.5:1.
In contrast to most previous systems for allylic substitu-
tion, reactions of aliphatic allylic carbonates in the presence
of the iridium-phosphoramidite catalyst occurred in high yield
and with high regio- and enantioselectivities. Furthermore,
the aliphatic carbonates reacted even faster than the aromatic
carbonates. Thus, reactions of the methyl carbonates derived
from (E)-2-hexen-1-ol and (E)-2-buten-1-ol with aniline were
complete in 3 h and required only 5% DABCO additive
(Table 3, entries 4, 6). In contrast, the reaction of methyl
cinnamyl carbonate with aniline required 10 h under other-
wise identical conditions. The methyl carbonate derived from
(E,E)-2,4-hexadien-1-ol, a substrate recently explored by
Helmchen and Lipowsky in allylic amination with alkyl and
benzyl amines,[26] reacted with aniline to form the a-substi-
tuted 4x with excellent regio- and enantioselectivities
(entry 7).
Scheme 3. Reaction of carbonate 2b with p-anisidine in the presence
of iridium catalyst to afford the allylic amine 4e.
Even aliphatic allylic carbonates with branching points a
to the allyl unit reacted with high regio- and enantioselectiv-
ities. The branched allylic carbonate derived from (E)-4-
methyl-2-penten-1-ol gave mostly linear product upon rho-
dium-catalyzed allylic amination. In contrast, reaction of the
linear isomer of this allylic ester with aniline in the presence
Scheme 4. Reaction of PhBr with an enantioenriched primary allylic
amine catalyzed by a combination of [Pd2(dba)3] and (Æ)-binap;
dba=trans,trans-dibenzylidenacetone, binap=2,2’-bis(diphenylphos-
phanyl)-1,1’-binaphthyl.
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mixture of branched 4a (83% ee) and linear 5a products in a
moderate combined yield (53%). Presumably, isomerization
and partial racemization of the branched allylic amine by the
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of N-aryl allylic amines.
In conclusion, we have developed the first convenient and
highly selective allylic amination with “electron-neutral”
aromatic amines that lack an activating group on the nitrogen
atom. This process was developed by conversion of an iridium
precatalyst into an active cyclometalated catalyst in the
presence of an appropriate additive. This catalyst activation
was either conducted in situ prior to addition of the aromatic
amine or with DABCO additive in the presence of aniline.
This reaction occurs with electron-neutral and electron-rich
aromatic amine nucleophiles as well as aromatic or aliphatic
allylic carbonates, and displays remarkable catalyst efficiency.
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applications in synthesis, will be reported in due course.
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Received: April 9, 2004
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Keywords: allylations · aminations · asymmetric catalysis ·
iridium · regioselectivity
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