Iridium-catalyzed, asymmetric amination of allylic alcohols activated by lewis acids

Article abstract of DOI:10.1021/ja0730718

The direct, Ir-catalyzed, regio- and enantioselective amination of allylic alcohols with Lewis acid activators to form branched allylic amine products is reported. The reactions of arylamines, benzylic amines, and secondary aliphatic amines in the presence of Nb(OEt)₅ as activator occurred with high regioselectivities and high enantioselectivities. These results led to the development of Ir-catalyzed reactions of allylic alcohol with arylamines and BPh₃ as activator in catalytic amounts. These reactions are rare examples of enantioselective substitutions of allylic alcohols. They are particularly unusual examples of the substitution of allylic alcohols to generate branched substitution products from monosubstituted allylic alcohols and of enantioselective substitutions of allylic alcohols with amine nucleophiles. Copyright

Full text of DOI:10.1021/ja0730718

Published on Web 05/25/2007
Iridium-Catalyzed, Asymmetric Amination of Allylic Alcohols Activated by
Lewis Acids
Yasuhiro Yamashita, Apsara Gopalarathnam, and John F. Hartwig*
Department of Chemistry, Yale UniVersity, P.O. Box 208107, New HaVen, Connecticut 06520-8107, and School of
Chemical Sciences, UniVersity of Illinois, 600 South Mathews AVenue, Urbana, Illinois 61801
Received May 1, 2007; E-mail: jhartwig@uiuc.edu
Table 1. Ir-Catalyzed Asymmetric Allylic Amination in the
Enantioselective substitution of allylic esters by carbon and
heteroatom nucleophiles has become a classic catalytic asymmetric
transformation,1 but enantioselective substitution of allylic alcohols
is more challenging. Because allylic esters are typically prepared
from allylic alcohols, the use of allylic alcohols in asymmetric allylic
substitution would streamline synthetic sequences and would be
more atom economic.
Presence of Lewis Acidsa
activator
(equiv)
yieldb
(%)
ee
(%)
entry
3/4c
1
Ti(OiPr)4 (1.2)
Ti(OtBu)4 (1.2)
Ta(OEt)5 (1.2)
Nb(OEt)5 (1.2)
Nb(OEt)5 (1.2)
Nb(OEt)5 (0.5)
Nb(OEt)5 (1.2)
Nb(OEt)5 (1.2)
Nb(OEt)5 (1.2)
16
30
62
82
47
64
85
64
42
89/11
94/6
96/4
98/2
91/9
84/16
97/3
98/2
98/2
81
89
81
92
92
63
92
94
95
2
3
4
5d
6
The poor leaving-group ability of a hydroxyl group causes the
substitutions of allylic alcohols typically2 to require high temper-
atures, neat conditions,3 or an activator.4-6 Thus far, most published
reactions of allylic alcohols form achiral products. Direct asym-
metric substitutions7-10 of allylic alcohols have only recently been
conducted with substantial enantiomeric excess,8,9,11 and only one
enantioselective substitution of a terminal allylic alcohol9,10 to form
preferentially the branched substitution product over the linear
product (73:27 ratio, 81% ee) in substantial yield has been reported.
Using the catalyst we developed for enantioselective allylic
amination of terminal allylic esters to form branched substitution
products,12,13 we sought to develop enantioselective aminations of
allylic alcohols. We report enantioselective Ir-catalyzed aminations
of terminal allylic alcohols activated with a niobium alkoxide and
enantioselective aminations of terminal allylic alcohols activated
with catalytic amounts of triphenylborane. A series of these
reactions form branched allylic amine products with high regio-
selectivity and enantioselectivity.
We began our investigation of the amination of allylic alcohols
by studying the reaction of cinnamyl alcohol 1a with aniline 2a to
form the branched and linear substitution products 3 and 4 in the
presence of the cyclometalated iridium catalysts prepared in situ
from the chiral phosphoramidite ligands 5a and 5b.12 This catalyst
was generated from [Ir(COD)Cl]2 and 5a or 5b by heating with
propylamine, as described previously.13,14 Reactions conducted with-
out any activator of the allylic alcohol formed only trace amounts
of the allylic amine, even in refluxing THF. Thus, we studied reac-
tions in the presence of Lewis acid activators of the hydroxyl group.
Although the activation of allylic alcohols has precedent,4,5 a strong
Lewis acid could affect the reactivity and selectivity of a late metal
catalyst, particularly one containing P-O, P-N, and M-C bonds.
Table 1 summarizes studies with a variety of early metal
activators. Although titanium alkoxides have been used to activate
allylic alcohols for Pd-catalyzed aminations to form linear allylic
amines,5 Ir-catalyzed reactions conducted with Ti(OiPr)4 or
Ti(OtBu)4 occurred with low conversions, albeit with substantial
selectivities (Table 1, entries 1 and 2), even after extensive
experimentation (Table S1 of Supporting Information).
7e
8f
9e,g
a The reaction was performed with cinnamyl alcohol (1.0 mmol) and
aniline (1.2 mmol) in THF (0.5 mL) at 50 °C for 24 h, and the Ir complex
(2 mol %) prepared from [Ir(COD)Cl]2 (0.010 mmol) and 5a (0.020 mmol),
Lewis acid activator, and powdered 4 Å molecular sieves (4 Å MS, 50
mg) were used unless otherwise noted. b Isolated yield of branched product
3. c Ratio of 3:4 determined by 1H NMR analysis of the crude reaction
mixture. d Without 4 Å MS. e 1.5 mmol of aniline was used. f Ligand 5b
was used. g Conducted at room temperature.
occurred with high branched-to-linear selectivity (entry 4). Nb(OEt)5
has not been used previously to activate allylic alcohols.15
Further studies on reaction conditions with Nb(OEt)5 as activator
showed that the identity of the solvent (toluene, DME, TBME, 1,4-
dioxane) had little effect on yield and selectivities, but that omission
of the 4 Å molecular sieves (4 Å MS) led to a decrease in reaction
yield (entry 5). Reactions conducted with substoichiometric amounts
of Nb(OEt)5 occurred with lower conversions and selectivities (entry
6) than those with 1.2 equiv of Nb(OEt)5. However, reactions with
larger quantities of aniline occurred in higher yields based on the
allylic alcohol (entry 7).
A comparison of reactions conducted with the catalyst formed
from ligands 5a and 5b showed that the rate was faster with the
catalyst generated from 5a, but that the enantioselectivity was
slightly higher with the catalyst generated from 5b (entry 8).
Reactions catalyzed by the complex generated from 5a occurred
even at room temperature, although slowly (entry 9).
The scope of the reaction under the conditions of entry 7 of Table
1 is summarized in Table 2. Reactions of arylamines containing
electron-donating and electron-withdrawing substituents occurred
in high yield and with high regioselectivities and enantioselectivities.
Slightly lower yields were obtained from reactions of haloanilines
(entries 5 and 6) and ortho-substituted anilines (entry 3). Even
reactions of benzylic and aliphatic amines occurred (entries 7-9),
despite their greater Lewis basicity. Substituted cinnamyl and
3-substituted aliphatic allylic alcohol derivatives reacted with aniline
in the presence of the chiral Ir catalyst to afford the desired branched
product 3 with high enantioselectivities.
Our success using a combination of allylic alcohol and stoichio-
metric amounts of Lewis acid as electrophile led us to develop
conditions for the reactions of allylic alcohols with aromatic amines
in the presence of a catalytic amount of Lewis acid. After exploring
a series of Lewis acids in different solvents, we found that reactions
conducted with a catalytic amount of triphenylboron (BPh3) as an
Experiments conducted with a variety of related Lewis acids
(Table S2) showed that reactions with Ta and Nb alkoxides occur
with moderate to high conversion of allylic alcohol (Table 1, entries
3 and 4). High yield of the allylic amine was obtained from reactions
containing niobium ethoxide (Nb(OEt)5), and these reactions also
9
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J. AM. CHEM. SOC. 2007, 129, 7508-7509
10.1021/ja0730718 CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Ir-Catalyzed Asymmetric Allylic Amination of Allylic
Alcohols in the Presence of Nb(OEt)5
reactions of the electron-rich p-methoxy-substituted cinnamyl alco-
hol. Arylamines bearing substituents in the 2-, 3-, and 4-position
reacted, and anilines containing p-chloro groups reacted without
cleaving the C-Cl bond. The major competing process was forma-
tion of diallyl ethers; thus, the reactions were conducted with 1.5
equiv of the alcohol. These reactions constitute a rare example of
the activation of allylic alcohols using a catalytic amount of transi-
tion metal complex, as well as a catalytic amount of Lewis acid.
In summary, two procedures have been developed for iridium-
catalyzed allylic amination of allylic alcohols to form branched
allylic amine products with high regio- and enantioselectivity. Nb-
(OEt)5 was found to serve as an activator of the allylic alcohol in
situ, and BPh3 was found to act as an activator in catalytic amounts.
Further investigation of the scope and mechanism of this process
is ongoing.
a
yieldc
eee
(%)
(%)
entry
1, R1
)
2b, R2
)
3/4d
1
2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
p-MeC6H4
85
84
66
83
79
82
72
66
90
85
78
70
70
45
67
>96/<4f
96/4f
92
89
92
81
86
87
93
90
94
89
70
92
90
82
89
p-MeOC6H4
3
o-MeOC6H4
>96/<4f
4
m-MeOC6H4
96/4f
5g,h
6g,h
7g
8g
9
p-IC6H4
95/5
p-ClC6H4
96/4
Bn
96/4
p-MeOC6H4CH2
93/7
2)morpholine
98/2
10
11
12i
13
14j
15
p-MeOC6H4
o-MeOC6H4
2-furyl
propyl
isopropyl
1-propenyl
Ph
Ph
Ph
Ph
Ph
Ph
98/2
99/1
81/19
92/8
88/12f
79/14/7k
a The reaction was performed with 1 (1.0 mmol) and 2 (1.5 mmol) in
THF (0.5 mL) at 50 °C for 24 h in the presence of 2 mol % of catalyst
prepared from [Ir(COD)Cl]2 (0.010 mmol), and 5a (0.020 mmol), Nb(OEt)5
(1.2 mmol), and 4 Å MS (50 mg) were used unless otherwise noted. b Except
entry 10, R3 ) H. c Isolated yield of branched product 3. d Ratio of 3 and
4 was determined by 1H NMR analysis of the crude reaction mixture.
e Enantiomeric excess of 3. f Determined after isolation. g The Ir catalyst
(3 mol %) was used. h 2 (2.0 mmol) was used. i The reaction was carried
out at 40 °C. j The Ir catalyst (5 mol %) and aniline (2.0 mmol) were used.
k Branched/5-phenylamino-1,3-hexadiene/linear.
Acknowledgment. We thank the NSF (CHE-0414542) for
support of this work.
Note Added after ASAP Publication. Table 1, foonote a
was corrected on May 29, 2007.
Supporting Information Available: Experimental procedures and
spectroscopic data of the reaction products (PDF). This material is
available free of charge via Internet at http://pubs.acs.org.
References
Scheme 1
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Table 3. Ir-Catalyzed Asymmetric Allylic Substitutions of 1 with 2
in the Presence Catalytic BPh3
a
yieldb
(%)
ee
(%)
entry
1, R1
)
2, R2
)
3/4c
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
p-MeC6H4
p-MeOC6H4
o-MeOC6H4
p-ClC6H4
p-MeC6H4
m-MeOC6H4
p-ClC6H4
74
72
52d
53
72
61
66
66d
61
97/3
88
93
94
92
92
83
93
94
87
94/6
95/5
>94/<6
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-MeC6H4
p-BrC6H4
96/4
>97/<3
95/5
p-MeC6H4
p-MeC6H4
>95/<5
>92/<8
a The reaction was performed by using 1 (1.5 mmol) and 2 (1.0 mmol)
in dioxane (2.0 mL) at 50 °C for 24 h in the presence of a chiral Ir complex
(5 mol %) prepared from [Ir(COD)Cl]2 (0.025 mmol) and 5a (0.050 mmol),
BPh3 (0.08 mmol), and 4 Å MS (300 mg) unless otherwise noted. b Isolated
yield of branched product 3. c Ratio of 3 and 4 was determined by GC
analysis of the crude reaction mixture. d The reaction was conducted for
40 h.
activator in dioxane solvent containing 4 Å molecular sieves
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in moderate to excellent yields with excellent regioselectivities and
enantioselectivities.
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The scope of the reactions containing catalytic amounts of BPh3
is summarized in Table 3. The reactions of substituted cinnamyl
alcohols with various anilines proceeded in moderate to good yield
with excellent regioselectivities and good to excellent enantio-
selectivities in the presence of the catalyst generated from [Ir(COD)-
Cl]2 and ligand 5a developed in our laboratory for iridium-catalyzed
allylic substitution.13 Reactions conducted with the more common
phosphoramidite ligand 5b16 occurred with much lower conversions.
The reactions occurred in acceptable yields with the parent cinnamyl
alcohol (entries 1-4), and the highest yields were observed from
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