Enantioselective iridium-catalyzed allylic amination of ammonia and convenient ammonia surrogates

Article abstract of DOI:10.1021/ol701562p

Iridium-catalyzed, asymmetric allylation of ammonia as a nucleophile occurs with stereoselectivity to form a symmetric dialiylamine, and related allylation of the inexpensive ammonia equivalent potassium trifluoroacetamide or the highly reactive ammonia equivalent lithium ditert-butyliminodicarboxylate forms a range of conveniently protected, primary, a-branched allylic amines in high yields, high branched-to-linear regioselectivities, and high enantiomeric excess. The reactions of ammonia equivalents were conducted with a catalyst generated from a phosphoramidite containing a single stereochemical element.

Full text of DOI:10.1021/ol701562p

ORGANIC
LETTERS
2007
Vol. 9, No. 20
3949-3952
Enantioselective Iridium-Catalyzed
Allylic Amination of Ammonia and
Convenient Ammonia Surrogates
Mark J. Pouy, Andreas Leitner, Daniel J. Weix, Satoshi Ueno, and
John F. Hartwig*
Department of Chemistry, UniVersity of Illinois, 600 South Matthews AVenue,
Urbana, Illinois 61801, and Department of Chemistry, Yale UniVersity,
P.O. Box 208107, New HaVen, Connecticut 06520
jhartwig@uiuc.edu
Received July 3, 2007
ABSTRACT
Iridium-catalyzed, asymmetric allylation of ammonia as a nucleophile occurs with stereoselectivity to form a symmetric diallylamine, and
related allylation of the inexpensive ammonia equivalent potassium trifluoroacetamide or the highly reactive ammonia equivalent lithium di-
tert-butyliminodicarboxylate forms a range of conveniently protected, primary,
r-branched allylic amines in high yields, high branched-to-
linear regioselectivities, and high enantiomeric excess. The reactions of ammonia equivalents were conducted with a catalyst generated from
a phosphoramidite containing a single stereochemical element.
Cyclometalated iridium-phosphoramidite complexes1 cata-
lyze the enantioselective amination of linear allylic electro-
philes to form branched allylic amines in high yield with
high branched-to-linear ratios and high enantiomeric excess.2-6
The regioselectivity of these reactions contrasts with the
regioselectivity of palladium-catalyzed allylations that typi-
cally yield linear products.7
Published examples of asymmetric allylic amination have
been conducted with alkylamines, arylamines, or ammonia
equivalents. The direct enantioselective allylation of ammonia
has not been reported with catalysts derived from any metal.8
The use of ammonia as a nucleophile is desirable because it
is inexpensive and avoids the use of protecting groups. The
direct allylation of ammonia has been a challenge, presum-
* Address correspondence to this author at the University of Illinois.
(1) Kiener, C. A.; Shu, C. T.; Incarvito, C.; Hartwig, J. F. J. Am. Chem.
Soc. 2003, 125, 14272.
(2) Ohmura, T.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 15164.
(3) (a) Leitner, A.; Shu, C. T.; Hartwig, J. F. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 5830. (b) Leitner, A.; Shu, C. T.; Hartwig, J. F. Org. Lett. 2005,
7, 1093. (c) Bartels, B.; Garcia-Yebra, C.; Rominger, F.; Helmchen, G.
Eur. J. Inorg. Chem. 2002, 2569. (d) Welter, C.; Moreno, R. M.; Streiff,
S.; Helmchen, G. Org. Biomol. Chem. 2005, 3, 3266. (e) Welter, C.; Dahnz,
A.; Brunner, B.; Streiff, S.; Dubon, P.; Helmchen, G. Org. Lett. 2005, 7,
1239. For work demonstrating branched selectivity with achiral ligands,
see: (f) Takeuchi, R.; Kashio, M. Angew. Chem., Int. Ed. 1997, 36, 263.
(g) Takeuchi, R.; Kashio, M. J. Am. Chem. Soc. 1998, 120, 8647. (h)
Takeuchi, R.; Ue, N.; Tanabe, K.; Yamashita, K.; Shiga, N. J. Am. Chem.
Soc. 2001, 123, 9525.
(4) (a) Shu, C. T.; Leitner, A.; Hartwig, J. F. Angew. Chem., Int. Ed.
2004, 43, 4797. (b) Shekhar, S.; Trantow, B.; Leitner, A.; Hartwig, J. F. J.
Am. Chem. Soc. 2006, 128, 11770.
(5) Weihofen, R.; Dahnz, A.; Tverskoy, O.; Helmchen, G. N. Chem.
Commun. 2005, 3541.
(7) For exceptions to this general trend, see: (a) You, S. L.; Zhu, X. Z.;
Luo, Y. M.; Hou, X. L.; Dai, L. X. J. Am. Chem. Soc. 2001, 123, 7471.
(b) Hou, X. L.; Sun, N. Org. Lett. 2004, 6, 4399. (c) Yan, X. X.; Liang, C.
G.; Zhang, Y.; Hong, W.; Cao, B. X.; Dai, L. X.; Hou, X. L. Angew. Chem.,
Int. Ed. 2005, 44, 6544. (d) Zheng, W. H.; Sun, N.; Hou, X. L. Org.
Lett. 2005, 7, 5151. (e) Watson, I. D. G.; Yudin, A. K. J. Am. Chem. Soc.
2005, 127, 17516. (f) Watson, I. D. G.; Styler, S. A.; Yudin, A. K. J. Am.
Chem. Soc. 2004, 126, 5086. (g) Trost, B. M.; Thiel, O. R.; Tsui, H. C. J.
Am. Chem. Soc. 2002, 124, 11616. (h) Trost, B. M.; Toste, F. D. J. Am.
Chem. Soc. 1999, 121, 4545. (i) Faller, J. W.; Wilt, J. C. Org. Lett. 2005,
7, 633.
(6) Weihofen, R.; Tverskoy, E.; Helmchen, G. Angew. Chem., Int. Ed.
2006, 45, 5546.
(8) Godleski, S. A. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, UK, 1991; Vol. 4, p 585.
10.1021/ol701562p CCC: $37.00
© 2007 American Chemical Society
Published on Web 08/29/2007

ably because ammonia poisons the catalyst or displaces the
chiral ligands to generate an achiral catalyst.
followed by separation of the iridium species from the PrNH3-
Cl salt. Ammonia was added as a 2 M solution in EtOH,
and the reaction was run in a 1:1 mixture of EtOH and THF.
Because of the challenge of conducting the allylation of
ammonia, asymmetric allylations of many ammonia equiva-
lents have been studied. Many of the ammonia equivalents
studied for the iridium-catalyzed process are either relatively
expensive or difficult to deprotect. Ir-catalyzed allylic
aminations with the most convenient ammonia equivalents,
such as amides or carbamates, have been achieved only by
tethering the amide to the allyl group in the form of an
imidodicarbonate.9 Inexpensive sulfamic acid has been shown
recently to convert allylic alcohols to allylamines, but only
one enantioselective reaction of this type (70% ee) has been
reported so far.10 Ir-catalyzed allylations of one of the more
convenient ammonia equivalents, di-tert-butyliminodicar-
boxylate (HNBoc2), have been studied, but reactions with
only two allylic carbonates were reported.5,6
We report the allylation of ammonia and of easily
deprotected ammonia equivalents catalyzed by cyclometa-
lated iridium phosphoramidite complexes. First, we show that
the allylation of ammonia forms a diallylamine with high
regio- and stereoselectivity. Second, we show that the
potassium salt of the inexpensive trifluoroacetamide under-
goes allylation with high enantioselectivity to form products
that are readily deprotected.11 Third, we show that the lithium
salt of di-tert-butyliminodicarboxylate (LiNBoc2) reacts with
a broader scope of allylic carbonate than had been reported
previously.12 Moreover, we show that the reactions of
LiNBoc2 and potassium trifluoroacetamide occur in high
yield, regioselectivity, and enantioselectivity in the presence
of a catalyst derived from a phosphoramidite containing a
single resolved stereocenter.13
Equation 1 summarizes the reaction of ammonia with
methyl cinnamyl carbonate. Despite the challenges in
conducting the asymmetric allylation of ammonia, this
reaction fully consumed the allylic carbonate to form the
symmetrical diallylamine in 93% yield, 94:6 dr, and 99%
ee. Apparently, the primary amine product of this reaction
is sufficiently more reactive than ammonia that the dially-
lation product was formed exclusively. No monoallylation
product was observed during the reaction. Related reactions
of linear aliphatic carbonates formed mixtures of products
during preliminary experiments.
C2-symmetric pyrrolidines containing stereocenters in the
2- and 5-positions have been used recently as catalysts for
the R-halogenation of aldehydes.14 These materials are now
accessible by allylation of cinnamyl carbonate with ammonia,
followed by known ring-closing metathesis and hydrogena-
tion.6,15,16
In parallel with this work on the direct allylation of
ammonia, we have sought to identify ammonia equivalents
that give rise to conveniently protected primary allylic
amines. We sought a reagent that would be low in cost, that
would possess a relatively low molecular weight, that would
react with a broad scope of allylic carbonates with high
enantioselectivity, and that would release the protective group
under mild conditions. A number of ammonia equivalents
are commercially available, but many, such as p-methoxy-
benzylamine, tosylamide, and phthalimide, require harsh
conditions for deprotection. Others, such as nosylamide, are
relatively expensive, and still others, such as ButOC(O)N-
(CHO),6 are not commercially available.
Allylic aminations catalyzed by iridium complexes of
phosphoramidite L1 occur after cyclometalation of the
phosphoramidite ligand by a basic reagent or additive to
generate the metallacyclic species [Ir(COD)(κ2-L1)(L1)] (1)
in Figure 1. The reactions of ammonia were conducted with
After surveying reactions of lithium hexamethyldisilazide,
benzophenone imine, O-benzylhydroxylamine, tritylamine,
and the alkali metal salts of trichloroacetamide in the
presence of the iridium catalyst generated from [Ir(COD)-
Cl]2, L1, and propylamine to induce cyclometalation, we
found that reactions of the alkali metal salts of trifluoro-
acetamide formed the protected allylic amine in acceptable
yield, with high branched-to-linear regioselectivity and
enantiomeric excess. To our knowledge, the base-labile tri-
fluoroacetamide has not been used as an ammonia equivalent
in allylic substitution catalyzed by any metal. Trifluoroac-
etamide is inexpensive17 and undergoes facile deprotection
under mildly basic conditions.11
Figure 1. Structure of phosphoramidite ligand L1 and the
cyclometalated, activated catalyst (1).
the catalyst generated by heating [Ir(COD)Cl]2, L1, and
propylamine at 50 °C for 30 min to induce cyclometalation,
(14) (a) Bertelsen, S.; Halland, N.; Bachmann, S.; Marigo, M.; Braunton,
A.; Jørgensen, K. A. Chem. Commun. 2005, 4821. (b) Halland, N.; Lie, M.
A.; Kjærsgaard, A.; Marigo, M.; Schiøtt, B.; Jørgensen, K. A. Chem. Eur.
J. 2005, 11, 7083.
(15) Louie, J.; Bielawski, C. W.; Grubbs, R. H. J. Am. Chem. Soc. 2001,
123, 11312.
(16) Ring-closing metathesis of related materials after formation of the
HBr salt has been reported to occur in good yield (ref 6).
(17) $0.78/g from Aldrich.
(9) Singh, O. V.; Han, H. J. Am. Chem. Soc. 2007, 129, 774.
(10) Defieber, C.; Ariger, M. A.; Moriel, P.; Carreira, E. M. Angew.
Chem., Int. Ed. 2007, 46, 3139.
(11) Newman, H. J. Org. Chem. 1965, 30, 1287.
(12) For reactions of the neutral or anionic form of this nucleophile with
two allylic carbonates, see refs 5 and 6.
(13) Leitner, A.; Shekhar, S.; Pouy, M. J.; Hartwig, J. F. J. Am. Chem.
Soc. 2005, 127, 15506.
3950
Org. Lett., Vol. 9, No. 20, 2007

Initial studies indicated that the potassium salt of trifluo-
roacetamide was most suitable for the allylic amination
process. The lithium and sodium salts both reacted with
methyl cinnamyl carbonate at room temperature in the
presence of the cyclometalated catalyst, but the yields of
these reactions (44% and 53% isolated yields, respectively)
were lower than that for the potassium salt. The potassium
salt of trifluoroacetamide reacted with cinnamyl carbonate
in the presence of L1 to form the allylation product in 68%
yield and 96% ee after 18 h (eq 2).18
Figure 2. Ligands studied for the Ir-catalyzed allylation of
potassium trifluoroacetamide.
phorus, a cyclododecyl group on nitrogen, and a phenethyl
group on nitrogen (L4)13 while the second (L5) is an o-anisyl
analogue of the simplified ligand L4. The reactions were
conducted after cyclometalation of the precatalyst by added
propylamine to form the structure in Figure 1.13
Table 1 shows the reaction of potassium trifluoroacetamide
(K-TFAc) with cinnamyl methyl carbonate, using the dif-
As shown in Table 1, the yields from reactions with
catalysts generated from the different ligands varied only
slightly, but use of simplified anisyl ligand L5 resulted in
rates that were faster than those observed when using ligands
L1-L4. In addition, the enantioselectivity was high for
reactions conducted with ligand L5. Thus, studies on the
scope of the allylation of potassium trifluoroacetamide were
conducted with this phosphoramidite.
Table 1. Allylation of Potassium Trifluoroacetamide Catalyzed
by Ir Complexes of Various Phosphoramidite Ligandsa
The scope of the allylation of potassium trifluoroacetamide
is summarized in Table 2. These reactions occurred with
entry
ligand
yieldb (%)
time (h)
ee (%)
1
2
3
4
5
L1
L2
L3
L4
L5
68
67
74
69
68
18
24
24
18
8
96
94
97
93
94
Table 2. Yields and Selectivities for the Allylations of
Potassium Trifluoroacetamidea
a Reactions were conducted at room temperature on a 0.5 mmol scale in
THF (0.5 mL) with a relative mole ratio of carbonate/nucleophile/
[Ir(COD)Cl]2/L of 100:120:1:2 unless otherwise noted. The catalyst was
preactivated with PrNH2 at 50 °C for 30 min. b Isolated yields of branched
product.
entry
R
yieldb (%)
time (h)
ee (%)
1
2
3
4
5
6
7
8c
Ph
68
74
93
64
59
47
65
79
8
5
94
96
98
94
92
85
94
96
ferent phosphoramidite ligands shown in Figure 2. These
ligands include the original ligand we used in allylic
amination (L1),2,19 the naphthyl (L2) and o-anisyl (L3)20
analogues of L1, and two phosphoramidites of the type
developed recently in our laboratory for allylic amination
possessing a single stereochemical element. One of these
simplified ligands contains a biphenylate group on phos-
p-MeC6H4
p-MeOC6H4
p-ClC6H4
p-BrC6H4
o-FC6H4
12
12
18
18
12
18
n-heptyl
cyclohexyl
a Reactions were conducted under the conditions described in Table 1.
b Isolated yields of pure branched product are an average from two
independent runs. c Conducted with 2 mol % of [Ir(COD)Cl]2 and 4 mol
% of L5.
(18) The linear monoallylation product could not be observed clearly in
the 1H NMR spectrum, and could not be quantified. Thus, we do not report
branched-to-linear selectivities for these reactions. Several signals corre-
sponding to a majority of the mass balance were observed in the region of
the 1H NMR spectrum in which the allylic hydrogens of linear products
resonate, perhaps from formation of regioisomeric diallylation products.
Nevertheless, these side products were easily removed from the branched
product by flash chromatography, and good yields of the pure branched
product were obtained. A larger excess of potassium trifluoroacetamide (2.4
equiv) increased the reaction rate and lowered the intensity of the resonances
proposed to result from regioisomeric side products; however, it also
increased the rate of decomposition of the carbonate to alcohol and did not
measurably improve the overall yield.
para-substituted cinnamyl carbonates and aliphatic allylic
carbonates to give a variety of pure branched, trifluoroace-
tate-protected primary allylic amines in 59-87% yields and
92-98% enantiomeric excess. Electron-neutral (entries 1 and
2), electron-rich (entry 3), and electron-poor (entries 4 and
5) cinnamyl carbonates, as well as aliphatic carbonates both
with and without branching R to the allyl unit (entries 7 and
(19) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346.
(20) Tissot-Croset, K.; Polet, D.; Alexakis, A. Angew. Chem., Int. Ed.
2004, 43, 2426.
Org. Lett., Vol. 9, No. 20, 2007
3951

8), all reacted with potassium trifluoroacetamide. The reac-
tion of an ortho-substituted cinnamyl carbonate (entry 6)
occurred with lower enantioselectivity, but the same lower
enantioselectivity has been observed for iridium-catalyzed
allylic substitutions of ortho-substituted cinnamyl carbonates
with all nucleophiles.2,4,21
The scope of the allylation of LiNBoc2 with the catalyst
derived from L5 is summarized in Table 4. In general, the
a
Table 4. Amination of Allylic Carbonates with LiNBoc2
In parallel with these studies on the allylation of potassium
trifluoroacetamide, we showed that the lithium salt of di-
tert-butyliminodicarboxylate (LiNBoc2) reacts with allylic
carbonates to form conveniently protected allylic amines.
This reagent is much less atom-economical and is more
expensive than trifluoroacetamide. However, it is well-
established that N-alkyl di-tert-butyliminodicarboxylates
undergo selective deprotection to form either the allylic
carbamate or the primary allylic amine.22 During the course
of this work, reactions of this nucleophile with two allylic
carbonates were reported with use of cyclometalated iridium
catalysts like those we developed for allylic amination.5,6
Here we more fully map the scope and limitations of this
reagent and show that the simplified catalyst generated from
phosphoramidite L5 leads to high yields, regioselectivities,
and enantioselectivities.
entry
R
ligand yieldb (%) time (h) b/lc ee (%)
1
2
Ph
L5
L5
L5
L5
L5
L5
L1
82
83
76
78
77
45
62
2
6
4
10
24
12
5
93/7
93/7
93
93
92
94
95
97
92
p-MeOC6H6
p-CF3C6H6
p-BrC6H6
Pr
3d
4
85/15
90/10
93/7
89/11
79/21
5e
6
i-Pr
7
2-furyl
a Reactions were conducted under the same conditions described in Table
3. b Isolated yields of branched product are an average from two independent
runs. c Branched-to-linear ratio. d Conducted with 1.5 mol % of [Ir-
(COD)Cl]2 and 3 mol % of L5. e Conducted with 2 mol % of [Ir(COD)Cl]2
and 4 mol % of L5.
Studies on the allylation of LiNBoc2 with a series of
phosphoramidite ligands are summarized in Table 3. As has
reactions of electron-neutral, electron-rich, and electron-poor
cinnamyl carbonates occurred in good yield with high
regioselectivity and enantioselectivity. In addition, the reac-
tions of aliphatic carbonates occurred with high regioselec-
tivity and enantioselectivity. Reactions of the linear, aliphatic
allylic carbonate (entry 6) occurred in high yield, regiose-
lectivity, and enantioselectivity. The reaction of an aliphatic
allylic carbonate with branching R to the allyl group (entry
7) occurred more slowly and in lower yield, but with a high
branched-to-linear ratio and enantioselectivity. In one case
(entry 7), the reaction occurred with higher branched-to-linear
ratios with the ligand L1 than with L5.
In summary, we have shown that the direct allylation of
ammonia occurs enantioselectively to form the product from
diallylation when catalyzed by the metallacyclic iridium
complex generated from [Ir(COD)Cl]2 and a common
phosphoramidite ligand. In addition, we have shown that
monoallylation products form with high enantioselectivity
when using trifluoroacetamide as an inexpensive, easily
deprotected ammonia equivalent. Finally, we have shown
that di-tert-butyliminodicarboxylate reacts with a variety of
aromatic and aliphatic allylic carbonates with high regiose-
lectivity and high enantioselectivity. Reactions of both
potassium trifluoroacetamide and lithium di-tert-butylimino-
dicarboxylate occur with high regioselectivities and enan-
tioselectivities when the catalyst is generated from a phos-
phoramidite developed in our laboratory containing a single
resolved stereochemical element.
Table 3. Amination of Cinnamyl Methyl Carbonate with
a
LiNBoc2
entry
ligand
yieldb (%)
time (h)
b/lc
ee (%)
1
2
3
4
5
L1
L2
L3
L4
L5
84
82
84
81
82
6
12
1.5
12
2
96/4
95/5
98/2
98/2
93/7
94
90
98
93
93
a Reactions were conducted at room temperature on a 0.5 mmol scale in
THF (0.5 mL) with a relative mole ratio of carbonate/nucleophile/
[Ir(COD)Cl]2/L5 of 100:120:1:2 unless otherwise noted. The catalyst was
preactivated with PrNH2 at 50 °C for 30 min. b Isolated yields of branched
product. c Branched-to-linear ratio.
been reported for amination with alkylamines,20 catalysts
generated from the anisyl ligand L3 reacted faster than those
generated from the aryl and naphthyl analogues L1 and L2.
However, reactions conducted with the catalyst containing
simplified ligand L5 occurred at rates similar to those
conducted with the more stereochemically complex ligand
L3 and with acceptable enantioselectivity. Thus, studies on
the scope of the reactions of LiNBoc2 were conducted with
L5.
Acknowledgment. We thank the NSF (CHE-0414542)
for support and Johnson-Matthey for iridium.
Supporting Information Available: Procedures and
characterization of reaction products. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(21) Lopez, F.; Ohmura, T.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125,
3426.
(22) (a) Connell, R. D.; Rein, T.; Akermark, B.; Helquist, P. J. Org.
Chem. 1988, 53, 3845. (b) van Benthem, R. A. T. M.; Michels, J. J.;
Hiemstra, H.; Speckamp, W. N. Synlett 1994, 368.
OL701562P
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Org. Lett., Vol. 9, No. 20, 2007