Enantioselective, iridium-catalyzed monoallylation of ammonia

Article abstract of DOI:10.1021/ja905059r

(Chemical Equation Presented) Highly enantioselective, iridium-catalyzed monoallylations of ammonia are reported. These reactions occur with electron-neutral, -rich, and -poor cinnamyl carbonates, alkyl and trityloxy-substituted allylic carbonates, and di

Full text of DOI:10.1021/ja905059r

Published on Web 07/24/2009
Enantioselective, Iridium-Catalyzed Monoallylation of Ammonia
Mark J. Pouy,‡ Levi M. Stanley,† and John F. Hartwig*,†
Department of Chemistry, UniVersity of Illinois, 600 South Matthews AVenue, Urbana, Illinois 61801-3602, and
Department of Chemistry, Yale UniVersity, P.O. Box 208107, New HaVen, Connecticut 06520-8107
Received June 19, 2009; E-mail: jhartwig@illinois.edu
Enantioselective allylic substitution with metalacyclic iridium-
phosphoramidite catalysts1 has become a convenient method to
prepare a variety of allylic amines from achiral allylic carbonates
in high yield, branched-to-linear selectivity, and enantiomeric
excess.2 Although these reactions encompass a wide variety of
amine nucleophiles, reactions of the simplest and most abundant
nitrogen nucleophile, ammonia, have not been reported to form
primary allylic amines in the presence of iridium catalysts, such as
1 (eq 1). Instead, enantioselective, iridium-catalyzed allylic substitu-
tion to form primary allylic amine derivatives has been conducted
with ammonia equivalents, such as trifluoroacetamide,3 imides,3,4
and sulfonamides.4-6 More generally, the enantioselective allylation
of ammonia with any catalyst is limited to just one example.7 This
reaction was conducted with a palladium catalyst and the widely
explored 1,3-diphenylallyl acetate electrophile, and it occurred with
modest enantioselectivity (87% ee).
p-methoxycinnamyl carbonate with a mixture of ammonia and
1-phenylprop-2-en-1-amine 2 in the presence of iridium catalyst 1b
(eq 1). This reaction formed diallylamine 4 in 84% yield as determined
by 1H NMR spectroscopy; no 1-(4-methoxyphenyl)prop-2-en-1-amine
5 was detected. In addition, we conducted a competition between
ammonia and 2 for reaction with the recently reported, discrete iridium-
allyl complex 6.9 This reaction formed N-(1-phenylallyl)prop-2-en-1-
1
amine 7 in 70% yield, as determined by H NMR spectroscopy;
allylamine 8 and diallylamine 9 were not detected (eq 4).
The results from these competition experiments imply that the selective
monoallylation of ammonia with this catalyst requires a large excess of
ammonia. The metalacyclic catalyst [Ir(COD)(κ2-L1)(L1)] (1a) previously
studied for iridium-catalyzed allylation reactions requires an additive, such
as [Ir(COD)Cl]2, to bind the liberated κ1-phosphoramidite ligand and to
promote formation of the catalytically active 16-electron intermediate.8
Although 1a is stable to the large excess of ammonia, [Ir(COD)Cl]2 reacts
with ammonia to precipitate an unidentified species that did not bind the
κ1-phosphoramidite ligand. Consistent with this observation, the reaction
of ammonia with ethyl cinnamyl carbonate catalyzed by 2 mol % 1a with
1 mol % added [Ir(COD)Cl]2 occurred to only 76% conversion and formed
2 in 45% yield (Table 1, entry 1).
To avoid this need for a Lewis acid, we studied reactions
catalyzed by the ethylene complex [Ir(COD)(κ2-L1)(ethylene)] (1b)
that operates without additives.8 Although ammonia might be
expected to displace ethylene from 1b, complex 1b is stable to
2000 equiv of ammonia, as determined by 31P NMR spectroscopy.
Thus, a selective reaction with ammonia might be achieved by
simply conducting the allylation process with a large excess of
ammonia and 1b as the catalyst precursor.
The development of a more general, asymmetric monoallylation
of ammonia presents a series of challenges. Ammonia can form
stable metal complexes that may be catalytically inactive or, if chiral
ligands are displaced, generate achiral catalysts. Moreover, the
selective monoallylation of ammonia is difficult to achieve because
the allylic amine product is more nucleophilic than ammonia. Here,
we describe iridium-catalyzed monoallylations of ammonia with
achiral allylic esters that occur with excellent enantioselectivity with
a series of allylic carbonate electrophiles to form the branched allylic
amine products. This process was made possible by the recent
development of a single-component,8 metalacyclic catalyst, which
we show to be stable to high concentrations of ammonia.
Indeed, the monoallylation product 2 was increasingly favored with
increasing amounts of ammonia, and the catalyst remained active under
these conditions. The reaction of methyl cinnamyl carbonate with 16
equiv of ammonia formed a 65:35 ratio of mono- to diallylation
products (2/3) and a 59% yield of the primary allylic amine 2 (entry
In previous work,3 we demonstrated that the allylation of ammonia
could be conducted with the metalacylic iridium catalyst 1a in eq 1
generated from [Ir(COD)Cl]2 and L1, but the diallylamine 3 was the
only amine product detected (eq 1). To assess directly the relative
nucleophilicity of ammonia versus the monoallylamine 2, which we
presumed to be the initial product, we conducted the reaction of ethyl
1
2) as determined by H NMR spectroscopy of the reaction mixture.
Reaction with 100 equiv of ammonia formed a higher 90:10 ratio of
the monoallylation product 2 to diallylation product 3 (entry 3).
Reactions of ethyl carbonates, rather than methyl carbonates, formed
less side products and formed 2 in higher yields (entry 4). In addition,
‡ Yale University.
† University of Illinois.
9
11312 J. AM. CHEM. SOC. 2009, 131, 11312–11313
10.1021/ja905059r CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
reactions at 30 °C in THF occurred with even higher selectivity for
the monoallylation product (92:8 2/3, entry 5) and yield of 2 (81%).
Table 1. Development of Reaction Conditions for the
Iridium-Catalyzed Monoallylation of Ammoniaa
enantiomerically enriched N-allylamides that are inaccessible by
direct reaction of an amide (Table 3). After venting the excess
ammonia from the reaction of ethyl cinnamyl carbonate, acylation
of the product with 4-chlorobenzoyl chloride, trimethylacetyl
chloride, or phenylacetyl chloride in the presence of triethylamine
or K3PO4 base formed the N-allylamides 12a-c in 63-75% yield
and 98% ee (entries 1-3). Enantioenriched R,ꢀ-unsaturated N-allyl
amides were synthesized by an analogous procedure. Monoallyla-
tion, followed by acylation with methacryloyl anhydride or crotonic
anhydride in the presence of triethylamine, formed the R,ꢀ-
unsaturated amides 12d and 12e in 72% and 65% yield, respec-
tively, and in 98% ee (entries 4 and 5).
equiv
of NH3
T
(°C)
time
(h)
yield
(%)b
entry
R
Ir cat. (mol %)
2:3b
1
Et
1a (2) +
100
30
15
45
94:6
[Ir(COD)Cl]2 (1)
1b (4)
2
3
Me
Me
Et
16
100
100
100
rt
rt
rt
30
24
24
48
15
59
63
66
81
65:35
90:10
91:9
1b (4)
4
1b (4)
5c
Et
1b (4)
92:8
a Reactions were conducted in 1:1 THF-d8/ethanol-d6 in a medium-wall
NMR tube with 4.0 mol % Ir catalyst, 0.15 mmol of cinnamyl carbonate, and
b
1
hexamethylbenzene or mesitylene as an internal standard. Determined by H
NMR spectroscopy of the reaction mixture. c Performed in THF-d8.
Table 3. One-Pot Allylation and Acylation To Form Chiral
N-Allylamidesa
The results of reactions of ammonia with a series of ethyl allylic
carbonates under the conditions of entry 5 in Table 1 are shown in
Table 2. The ammonium salts 11 were isolated and characterized after
protonation of the primary amine products in situ with HCl. The
reactions of ammonia with electron-neutral, -rich, and -poor cinnamyl
carbonates occurred in moderate to good yield and with excellent
enantioselectivity (entries 1-6). Furthermore, the reactions of aliphatic
allylic carbonates as well as dienyl carbonates occurred with high
enantioselectivity (entries 7-9). Reaction of ammonia with the
trityloxy-substituted allylic carbonate (entry 8) generated a product
containing a conveniently protected 1,2-aminoalcohol in high ee.
entry
R
base
12
yield (%)b
ee (%)c
1
p-ClsC6H4
t-Bu
Et3N
Et3N
K3PO4
Et3N
Et3N
12a
12b
12c
12d
12e
63
72
75
72
65
98
98
98
98
98
2
3d
4
Bn
C(CH3)dCH2
(E)-CHdCHCH3
5
a For experimental details see the Supporting Information. b Yields are
for isolated amides 12a-e. c Enantiomeric excess was determined by chiral
HPLC. d The solvent for the acylation reaction was THF.
Table 2. Ir-Catalyzed Allylic Amination with Ammoniaa
In summary, we have demonstrated the first series of mono-
allylations of ammonia to form primary allylic amines with high
enantioselectivity. This process is enabled by the use of a recently
prepared iridium precursor that is stable toward excess ammonia,
presumably due to chelation of the COD ligand and the metalacyclic
nature of the chiral ligand. This process allows for formation of
primary amines, as well as derivatives of primary amines that are
inaccessible by direct N-allylation.
entry
R
11
yield (%)b
time (h)
ee (%)c
1
2
3
4
C6H5
11a
11b
11c
11d
11e
11f
11g
11h
11i
73
63
58
57
51
66
49
53
57
4
4
97
99
98
99
99
98
96
97
99
p-MeC6H4
p-MeOC6H4
p-BrC6H4
p-CF3C6H4
m-MeOC6H4
n-heptyl
14
12
12
12
24
5
5
6
7d
8e
9f
Acknowledgment. We thank the NIH (GM-55382 for J.F.H.
and GM-084584 for L.M.S.) for support of this work and Johnson-
Matthey for iridium complexes.
TrOCH2
1-cyclohexenyl
12
a Reactions were conducted on a 0.5 mmol scale in THF (0.5 mL) in a 10
mL pressure vessel with a vacuum side arm. Yields and enantioselectivities are
averages from two independent runs. Products were characterized as their HCl
salts. b Isolated yields of branched monoallylation products 11. c Determined by
chiral HPLC. d Conducted at room temperature. e Isolated as the free amine.
f Conducted with 5 mol % 1b.
Supporting Information Available: Experimental procedures and
characterization of reaction products. This material is available free of
charge via the Internet at http://pubs.acs.org.
References
(1) (a) Kiener, C. A.; Shu, C. T.; Incarvito, C.; Hartwig, J. F. J. Am. Chem.
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J. F. J. Am. Chem. Soc. 2005, 127, 15506.
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Shu, C. T.; Leitner, A.; Hartwig, J. F. Angew. Chem., Int. Ed. 2004, 43,
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(3) Pouy, M. J.; Leitner, A.; Weix, D. J.; Ueno, S.; Hartwig, J. F. Org. Lett.
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(6) For an example with sulfamic acid as ammonia equivalent, see: Defieber, C.; Ariger,
M. A.; Moriel, P.; Carreira, E. M. Angew. Chem., Int. Ed. 2007, 46, 3139.
(7) Nagano, T.; Kobayashi, S. J. Am. Chem. Soc. 2009, 131, 4200.
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This direct access to primary allylic amines allowed the development
of sequential reactions of allylic carbonates without blocking or protective
groups. For example, two sequential allyations of ammonia form a chiral,
unsymmetrical diallylamine with high enantio- and diastereoselectivity.
After venting the ammonia from the reaction of ethyl cinnamyl carbonate
in the presence of 5 mol % 1b and addition of ethyl p-methoxycinnamyl
carbonate, the heterodiallylation product 4 was isolated in 71% yield as a
single diastereomer in 97% ee (eq 3).
The monoallylation of ammonia also provides access to allylic
amine derivatives that are not directly accessible by Ir-catalyzed
allylic substitution. The allylation of ammonia with a linear allylic
carbonate, followed by quenching the product with an acid chloride
or anhydride, represents a simple, one-pot process to synthesize
JA905059R
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J. AM. CHEM. SOC. VOL. 131, NO. 32, 2009 11313