Rhodium-catalyzed dynamic kinetic asymmetric transformations of racemic tertiary allylic trichloroacetimidates with anilines

Article abstract of DOI:10.1021/ja302223p

The rhodium-catalyzed regio- and enantioselective amination of racemic tertiary allylic trichloroacetimidates with a variety of aniline nucleophiles is a direct and efficient route to chiral α,α-disubstituted allylic N-arylamines. We describe the first dynamic kinetic asymmetric transformations of racemic tertiary allylic electrophiles with anilines utilizing a chiral diene-ligated rhodium catalyst. The method allows for the formation of α,α-disubstituted allylic N-arylamines in moderate to good yields with good to excellent levels of regio- and enantioselectivity.

Full text of DOI:10.1021/ja302223p

Communication
pubs.acs.org/JACS
Rhodium-Catalyzed Dynamic Kinetic Asymmetric Transformations of
Racemic Tertiary Allylic Trichloroacetimidates with Anilines
Jeffrey S. Arnold and Hien M. Nguyen*
Department of Chemistry, University of Iowa, Iowa City, Iowa 52242, United States
S
* Supporting Information
ABSTRACT: The rhodium-catalyzed regio- and enantio-
selective amination of racemic tertiary allylic trichloroace-
timidates with a variety of aniline nucleophiles is a direct
and efficient route to chiral α,α-disubstituted allylic
N-arylamines. We describe the first dynamic kinetic
asymmetric transformations of racemic tertiary allylic
electrophiles with anilines utilizing a chiral diene-ligated
rhodium catalyst. The method allows for the formation of
α,α-disubstituted allylic N-arylamines in moderate to good
yields with good to excellent levels of regio- and
enantioselectivity.
a wide range of substrates, affording the amination products in
he prevalence of chiral amines in bioactive natural and
non-natural products has stimulated numerous efforts
excellent yields and regioselectivity. Herein we disclose the first
rhodium-catalyzed regio- and enantioselective amination of
racemic tertiary allylic trichloroacetimidates with anilines to
provide α,α-disubstituted allylic N-arylamines (eq 2).15,16
During our previous regioselective studies,12 control experi-
ments with an enantiopure starting imidate14 (98% ee) resulted
in a nearly racemic branched amination product (<7% ee). On
the basis of this result, we hypothesized that if isomerization of
the diastereomeric π-allylrhodium intermediates17 occurs faster
than attack by the aniline nucleophile (Figure 1), the dynamic
T
toward their construction.1 Although a variety of methods are
available for the preparation of optically active amines,2 the
catalytic asymmetric synthesis of α,α-disubstituted amines
remains relatively underdeveloped. A new approach to the
asymmetric formation of α,α-disubstituted amines via palladium-
catalyzed aza-Claisen rearrangements of linear allylic trihalo-
acetimidates has recently been reported.3 Although allylic
amines are formed in good yield and enantioselectivity, full
conversion necessitates high temperatures over a period of
days.3 A more common approach to α,α-disubstituted amines
involves the addition of organometallic reagents to keti-
mines.4−7 Several challenges could potentially emerge using
this approach. First, the addition to ketimines containing an
α-hydrogen is problematic because imines have a propensity to
enolize.4b,7a Second, stereoselectivity is often moderate with
ketimines because they can exist as E and Z isomers, and
differentiation of the enantiotopic faces is often limited.5b
Third, ketimines are significantly less reactive than aldimines
and require activation by a Lewis acid.7a In response to these
challenges, Hayashi reported that rhodium−chiral diene
complexes effectively catalyze the addition of sodium
tetraarylborates to N-tosyl ketimines at 60−80 °C for 20 h.8
Transition-metal-catalyzed substitution of primary and
racemic secondary allylic carbonates or acetates has been
utilized for the regio- and enantioselective preparation of
α-substituted N-arylamines.9,10 However, only the regioselec-
tive synthesis of α,α-disubstituted N-arylamines via substitution
of primary and racemic tertiary allylic acetates and carbonates
catalyzed by palladium,11a,b iridium,10c and iron complexes11c
has been described. We recently reported the rhodium-
catalyzed regioselective amination of tertiary allylic imidates
with aniline nucleophiles (eq 1).13 Our method is applicable to
Figure 1. Strategy for DYKAT of tertiary allylic imidates.
kinetic asymmetric transformation (DYKAT) of tertiary allylic
trichloroacetimidates could be feasible.18 Ionization of the
activated rhodium−alkene complexes 1 and ent-1 (Figure 1)19
with the chiral rhodium catalyst would provide the correspond-
ing diastereomeric π-allylrhodium complexes 2 and ent-2,
respectively. We reasoned that an asymmetric environment
about the rhodium center could decrease the rate of
nucleophilic attack by anilines and increase the time allowed
for rapid π−σ−π interconversion. An unfavorable interaction
Received: March 6, 2012
Published: May 7, 2012
© 2012 American Chemical Society
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Communication
between one of the two π-allylrhodium intermediates would deter-
mine which enantiomer of the amination product 3 (k1 ≫ k2) is
preferentially formed.
significantly improved both the yield (85%) and the enantio-
selectivity (94% ee).
To rationalize the improved enantioselectivity with an
electron-withdrawing chiral diene ligand (L7 vs L5, Table 1),
the ligation of the diene ligands to rhodium was monitored by
13C NMR spectroscopy (Figure 2). It was determined that the
To test our hypothesis, we set out to explore the effects of the
chiral diene ligands20 L1−L4 (Table 1) on the enantioselectivity
a
Table 1. Optimization Studies
Figure 2. Studies of the stabilities of Rh−diene complexes.
electron density of the diene ligand significantly influences the
coordination shift (Δδ = δcomplex − δfree ligand)
20a,25 as a result of
increasing back-donation from the rhodium metal center.26 For
example, electron-withdrawing ligand L7 has a larger
coordination shift than electron-donating diene ligand L5.
This result suggests that the presence of the electron-
withdrawing group on the chiral diene L7 shifts the
hybridization of the coordinated olefinic carbon from sp2
toward more sp3 character, making the diene bind more
strongly to rhodium than electron-rich L5.26 The magnitude of
the 103Rh−13C coupling constant of 10.6−12 Hz (Figure 2)
suggests that there is considerable s character in the rhodium−
chiral diene complexes.27
a
All of the reactions were conducted at 0.2 M with 1 equiv of 4.
Isolated yields are shown; ee’s were determined by chiral HPLC.
Under these optimized conditions, the scope of the allylic
amination reaction with respect to aniline nucleophiles 5b−i
(Table 2) was explored. Electron-rich and electron-deficient
para-substituted anilines 5b−f (entries 1−5) were found to be
suitable nucleophiles, giving rise to α,α-disubstituted allylic
N-arylamines 6b−f in moderate to good yields (51−86%) with
good to high enantioselectivity (85−96% ee). In addition, all of
the reactions proceeded with excellent regioselectivity. The
amination reactions of anilines 5c (entry 2) and 5e (entry 4)
bearing the p-bromo and p-boronic acid ester substituents,
respectively, are noteworthy because the corresponding allylic N-
arylamines 6c and 6e could be amenable to subsequent cross-
coupling reactions.28 Aniline 5g containing ester functionality at
the meta position provided product 6g (entry 6) as a single
regioisomer in good yield (79%) with high levels of
enantioselectivity (94% ee). This method also worked well with
ortho-substituted anilines 5h and 5i (entries 7 and 8), and the
allylic amines were isolated with high enantioselectivity (89−94% ee)
and regioselectivity [branched/linear (b/l) ratio = 48:1−51:1].
This suggests that the system is tolerant of sterically demanding
anilines. As a result, we sought to extend this catalytic method to
the challenging acyclic secondary aniline 5j (entry 9), which is
known to provide amination products with poor regioselectivi-
ty.10a,c The reaction proceeded smoothly under our optimal
conditions, and N-arylamine 6j was isolated in 70% yield with
excellent selectivities (b/l = 30:1, 93% ee).
in the amination reaction of racemic tertiary allylic trichloro-
acetimidate 4 with aniline (5a) (Table 1). Lin ligand L121
(entry 1) and Hayashi ligand L222 (entry 2) afforded nearly
racemic α,α-disubstituted N-arylamine 6a. Use of Carreira ligand
L323 (entry 3) provided a measurable enantioselectivity (26% ee)
for the process. Hayashi ligand L424 (entry 4) was the most
enantioselective at 40 °C, providing 6a as a single regioisomer in
72% yield with 73% ee. Lowering the reaction temperature to
25 °C (entry 5) resulted in a significant enhancement of the
enantioselectivity of 6a (84% ee). Lowering the temperature fur-
ther to 0 °C (entry 6) did not impact the results. Lowering the metal
and ligand loadings to 1 mol % (entry 7) decreased both the yield
and the enantioselectivity. A number of solvents (entries 8−11)
were then investigated, and tert-butyl methyl ether (MTBE)
induced the highest enantioselectivity, providing 6a with 86% ee
(entry 11). Further optimization by lowering the equivalents of 5a
resulted in a system that afforded 89% ee with a good yield (69%)
and complete regioselectivity (entry 12).
Having established bicyclo[2.2.2]octadiene ligand L4 as the
optimal chiral ligand, we next examined the steric and elec-
tronic nature of the substituents on the phenyl ring (L5−L8,
Table 1). While the use of electron-rich 4-methoxyphenyl-
substituted diene L5 resulted in a decrease in the enantio-
selectivity (71% ee; entry 13), changing the diene substituent to
the electron-poor 4-fluorophenyl group (ligand L7, entry 15)
To establish the absolute stereochemistry of the amination
products, allylic N-arylamine 6c was converted to the
trifluoroacetate (TFA) salt and shown by X-ray crystallographic
analysis to be S-configured. The solid-state structure of the
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a
a
Table 3. Survey of Tertiary Allylic Imidates
Table 2. Survey of Aniline Nucleophiles
a
a
All of the reactions were conducted with 1 equiv of 4 and 1.5 equiv of
All of the reactions were conducted with 1 equiv of the allylic imidate
and 1.5 equiv of the aniline. Isolated yields are shown; ee’s were
determined by chiral HPLC and b/l ratios by GC.
the aniline. Isolated yields are shown; ee’s were determined by chiral
HPLC and b/l ratios by GC.
amine−TFA salt shows that it exists as two independent
cation−anion pairs through hydrogen bonding. The ammo-
nium cations have the same configuration but different
conformations.29
benzyl, phenyl, and methyl ether groups at the β-position (entries
1−5) provide additional chelation control on the rhodium
center,10a,30 whereas ester and silyl protecting groups (entries 6
and 7) reduce the ligation of the ether oxygen to the metal center.
Reductions in regio- and enantioselectivity were also observed in
the reactions of tertiary allylic imidates 14 and 15 lacking an
oxygen substituent at the β-position (entries 8 and 9). We further
examined the limitation of the current method with ethyl-
and aryl-substituted imidates. Although we were able to prepare
trichloroacetimidates having an aryl group at the α-position, these
substrates rapidly underwent [3,3]-sigmatropic rearrangement.31
We were unable to prepare allylic imidates bearing an ethyl group
at the α-position, presumably because their tertiary alcohol
precursors were too sterically hindered to react with trichloro-
acetonitrile.
In addition to tertiary allylic imidate 4, the functional-group
tolerance of the present catalysis was evaluated with a number of
branched imidates (Table 3). Both electron-rich and electron-
deficient benzyl ether derivatives (7 and 8, entries 1 and 2)
provided the amination products 16b and 17b with an
enantioselectivity (∼93% ee) comparable to that of benzyl ether
4 (96% ee; Table 2). The ester group, however, was not suitable
for this system, and allylic amine 21b (entry 6) was isolated with
59% ee. As the functional group became more bulky (entry 7),
a significant reduction in enantioselectivity was also observed
(76% ee). These results suggests that tertiary allylic imidates having
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Journal of the American Chemical Society
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In summary, we have reported the first dynamic kinetic
asymmetric transformation of racemic tertiary allylic acetimi-
dates with aniline nucleophiles using a rhodium−diene ligand
complex, providing α,α-disubstituted allylic N-arylamines in
moderate to good yields with good to excellent regio- and
enantioselectivity. Investigations into the full racemic tertiary
allylic trichloroacetimidate scope and further transformations
are ongoing and will be reported in due course.
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ASSOCIATED CONTENT
* Supporting Information
Complete experimental details and spectral data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
(15) For kinetic resolution of racemic secondary allylic electrophiles
via transition-metal-catalyzed amination reactions, see: (a) Vrieze, D. C.;
Hoge, G. S.; Hoerter, P. Z.; Van Haitsma, J. T. Org. Lett. 2009, 11, 3140.
(b) Stanley, L. M.; Bai, C.; Ueda, M.; Hartwig, J. F. J. Am. Chem. Soc.
2010, 132, 8918.
(16) For dynamic kinetic resolution of racemic secondary allylic
electrophiles via transition-metal-catalyzed amination, 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) Lafrance, M.; Roggen, M.; Carreira, E. M. Angew.
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(d) Rogen, M.; Carreira, E. M. J. Am. Chem. Soc. 2010, 132, 11917−
11919.
AUTHOR INFORMATION
Corresponding Author
hien-nguyen@uiowa.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work is dedicated in the memory of my Ph.D. mentor,
Professor David Y. Gin (05/1967 − 03/2011). We thank the
University of Iowa for financial support, Gregory T. Cizio for
preparing allylic imidates 9−11, Dr. Dale Swenson for X-ray
crystallographic analysis, and Ms. Amninder Kaur for helping
with NMR experiments. Professors Gloer and Messerle are
acknowledged for helpful discussions.
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