A Nucleophilic Strategy for Enantioselective Intermolecular α-Amination: Access to Enantioenriched α-Arylamino Ketones

Article abstract of DOI:10.1021/jacs.5b04518

The enantioselective addition of anilines to azoalkenes was accomplished through the use of a chiral phosphoric acid catalyst. The resulting α-arylamino hydrazones were obtained in good yields and excellent enantioselectivities and provide access to enantioenriched α-arylamino ketones. A serendipitous kinetic resolution of racemic α-arylamino hydrazones is also described.

Full text of DOI:10.1021/jacs.5b04518

Communication
pubs.acs.org/JACS
A Nucleophilic Strategy for Enantioselective Intermolecular
α‑Amination: Access to Enantioenriched α‑Arylamino Ketones
Dillon H. Miles, Joan Guasch, and F. Dean Toste*
Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, United States
Department of Chemistry, University of California, Berkeley, California 94720, United States
S
* Supporting Information
moieties, such as arylamines, that are challenging to access
through electrophilic additions (Scheme 1b).
ABSTRACT: The enantioselective addition of anilines to
azoalkenes was accomplished through the use of a chiral
phosphoric acid catalyst. The resulting α-arylamino
hydrazones were obtained in good yields and excellent
enantioselectivities and provide access to enantioenriched
α-arylamino ketones. A serendipitous kinetic resolution of
racemic α-arylamino hydrazones is also described.
We sought to explore this regime through use of electrophilic
azoalkenes which typically undergo 1,4 addition in the presence
of various nucleophiles, with Lewis acids occasionally employed
to promote reactivity.8 Following the recent successes of chiral
phosphoric acid and phosphate catalysis reported by both our
group and others,9 we envisioned a merger of these two
concepts. Activation of an azoalkene by a chiral metal
phosphate or phosphoric acid under the appropriate conditions
would result in the formation of an activated intermediate.
Subsequent nucleophilic attack and deprotonation would yield
an enantioenriched α-amino hydrazine that could undergo
hydrolysis to afford the corresponding ketone.
On the basis of a report of copper-catalyzed conjugate
addition of amines to azoalkenes,8b we selected the reaction of
2-methoxyaniline and azoalkene 1a catalyzed by copper
phosphate Cu(3a)2 (Cu-((R,R)-TRIP)2)10 as a model. Under
these conditions, the desired product (2a) was formed with
excellent selectivity, albeit in modest yield with other side
products present (Table 1, entry 1). Other Lewis acidic
phosphates11 gave similar reactivity profiles with some
reduction in enantioselectivity (Table 1, entries 2−4).
Interestingly, we found the desired product was more cleanly
formed using the Brønsted acid catalyst H-3a ((R)-TRIP).
Moreover, the enantioselectivity of the reaction was improved
when the reaction was conducted in low polarity solvents,
benzene being optimal (Table 1, entries 5−8). With a slow
background reaction noted (Table 1, entry 13), we focused our
attention on catalyst identity as a means to improve the
enantioselectivity of the reaction. While use of H-3b resulted in
slight improvements, the choice of the more sterically
demanding H-3c catalyst resulted in excellent yield and ee of
the desired product (Table 1, entries 9−10). Use of 3d and
3e12 as catalysts gave 2a in modest yield and selectivity (Table
1, entries 11−12).
he formation and functionalization of amines has been an
Tarea of continuous interest in synthetic chemistry;
numerous applications exist in the production of both
pharmaceuticals and agrochemicals. The asymmetric α-
amination of carbonyl moieties has emerged as an area of
great interest over the past decade,1 with recent examples
utilizing chiral Brønsted or Lewis acid,2 enamine,3 and Brønsted
base4 catalysis as synthetic strategies to achieve high levels of
enantioselectivity. Interestingly, the majority of these ap-
proaches utilize electrophilic sources of nitrogen, primarily
azodicarboxylates and organonitroso compounds, with sub-
sequent derivatization of the amine functionality (Scheme 1a).5
While alternative entries into enantioenriched α-amino carbon-
yl compounds have been described,6 highly enantioselective
nucleophilic amination reactions remain illusive.7 A nucleophilic
approach would allow for a broader scope of amine
functionalization, potentially permitting incorporation of
Scheme 1. Enantioselective α-Amination Strategies
With the optimized conditions in hand, we explored the
scope of the nucleophilic α-amination reaction (Table 2). A
range of ortho-, meta-, para-substituted, electron-poor, and
electron-rich azoalkenes gave excellent enantioselectivities
utilizing 2-methoxyaniline as a nucleophile (Table 2, 2a−f).
Similarly, substitution of the aniline nucleophile was well
tolerated, with electron-rich and electron-poor anilines
providing adducts with excellent ee, although yields were
Received: April 30, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b04518
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a,
b
a
Table 1. Reaction Optimization
Table 2. Substrate Scope
c
c
d
entry
cat.
solvent
conv. (%)
yield (%)
ee (%)
1
Cu(3a)2
Mg(3a)2
Fe(3a)3
Zn(3a)2
H-3a
H-3a
H-3a
H-3a
H-3b
H-3c
3d
benzene
benzene
benzene
benzene
benzene
acetonitrile
THF
100
100
100
100
100
100
59
47
23
49
76
52
98
46
79
57
68
6
93
73
81
72
84
4
2
3
4
5
6
7
58
79
86
91
12
8
DCM
100
100
100
21
9
benzene
benzene
benzene
benzene
benzene
benzene
10
11
12
13
e
3e
85
48
4
30
-
7
-
f
14
H-3c
100
63
82
a
b
Conditions: Ar′NH2 (0.025 mmol), 1a (3 equiv), 3 (0.10 equiv),
c
1
solvent (0.25 mL), 5 Å MS (25 mg), r.t., 24 h. Determined by H
NMR with 1,3-dinitrobenzene as internal standard. Determined by
d
chiral phase HPLC. Absolute stereochemistry was assigned by analogy
e
f
to 2g (see SI). Opposite enantiomer. 5 Å MS omitted.
slightly diminished in some cases (Table 2, 2g−l). In all cases,
we noted that extended reaction times resulted in product
decomposition and lower yields. Encouragingly, addition of N-
methylaniline proceeded smoothly under the reaction con-
ditions, forming tertiary amine 2m in excellent enantioselectiv-
ity. Additionally, structurally unique products 2n and 2p could
also be formed in moderate yields and excellent enantiose-
lectivities utilizing catalyst H-3a.
In contrast, subjecting methyl-substituted azoalkene 1o to
similar reaction conditions produced 2o in modest yield (49%)
and excellent ee (90%). Further analysis of this reaction showed
that starting material was completely consumed after only 30
min; at this time 2o was produced in 67% yield but only 16%
ee, compared to 90% ee after 14 h. Moreover, further increasing
the reaction time to 28 h improved the enantioselectivity to
94%, albeit with a diminished yield of 32%.
a
Conditions (see SI for details): 1, Ar′NHR’, H-3c (0.10 equiv),
benzene (1 mL), 5 Å MS (100 mg), r.t.; Ar: 2-Me-4-NO2−C6H3-;
yields refer to isolated products; ee determined by chiral phase HPLC;
absolute stereochemistry was assigned by analogy to 2g (see SI).
mol % H-3a; Ar: 4-NO2−C6H4- . 20 mol % H-3a. 10 mol % H-3a;
values are for (Z) isomer; (E) isomer could not be separated and
formed in 18% yield and 42% ee.
b
5
c
d
This inverse relationship between yield and enantioselectivity
is characteristic of a kinetic resolution. We hypothesized that
the hydrazone, once formed, might undergo subsequent
decomposition by the catalyst, with one enantiomer highly
preferred, leading to enantioenrichment of any remaining
hydrazone. To test our hypothesis, racemic 2o was prepared
and subjected to the reaction conditions, with the starting
material recovered in 92% ee and 36% yield (Scheme 2).
Interestingly, if the reaction was stopped after 0.5 h, 30% ee was
obtained. When compared with 14% ee obtained from the
parent reaction after 0.5 h, this result is consistent with our
hypothesis: significant enantioenrichment only takes place after
the product is formed. Interestingly, subjecting racemic 2a to
analogous reaction conditions resulted in similar decomposi-
tion, although with a negligible (1%) amount of enantiomeric
excess. This result suggests that the mechanism for formation of
enantioenriched 2o differs from that for generation of
nonmethyl substituted azoalkenes.13
Analysis of the product mixture derived from the reaction of
( )-2o showed that 2-methyl-4-nitro aniline, 1-(4-tolyl)-1,2-
B
DOI: 10.1021/jacs.5b04518
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Scheme 2. Kinetic Resolution of ( )-2o
Table 3. Hydrazone Hydrolysis
a
Conditions: 2 (0.06−0.08 mmol), paraformaldehyde (5−8 equiv),
Amberlyst 15 (7−10 mg), acetone/H2O (10:1 or 1:1), r.t., 24−48 h
b
c
(see SI for details) Ar′: 2-MeO-C6H4- Isolated yield. Determined by
chiral phase HPLC; parentheses indicate ee of parent hydrazine;
absolute stereochemistry was assigned by analogy to 2 (see SI).
kinetic resolution is detailed,17 showing potential for future
exploration and expansion. Extension of this methodology to
other nucleophiles is currently underway.
propanedione, and 2-methoxyaniline were formed in modest
yields.14 In the case of racemic 2a, the analogous isopropyl-
substituted ketone is similarly observed. On the basis of the
formation of these products, a tentative reaction mechanism is
posited in Scheme 3. Protonation of the imine nitrogen of 2a or
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details, characterization data for new compounds,
and crystallographic data (CIF). The Supporting Information is
available free of charge on the ACS Publications website at
DOI: 10.1021/jacs.5b04518.
Scheme 3. Potential Kinetic Resolution Mechanism
AUTHOR INFORMATION
Corresponding Author
*fdtoste@berkeley.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the NIGMS (R01 GM104534) for
financial support. J.G. thanks Generalitat de Catalunya for a
graduate research fellowship. We gratefully acknowledge
College of Chemistry CheXray (NIH Shared Instrumentation
Grant S10-RR027172) and Antonio DiPasquale for X-ray
crystallographic data. We thank Maolu Li and Tao Wu for
initial substrate synthesis and Mark Levin, Andrew Neel, and
Chung-Yeh Wu for helpful discussions.
2o followed by an aniline-assisted [1,2]-hydride shift yields an
intermediate hydrazine, which upon proton transfer and
elimination yields a bisimine and 2-methyl-4-nitroaniline.
Subsequent hydrolysis yields the remaining products.15,16
To demonstrate the utility of this method, the hydrazone
products 3 were hydrolyzed in the presence of sacrificial
formaldehyde to furnish ketones 4 in good yields while
preserving the enantiomeric excess (Table 3).
In summary, a novel strategy for the enantioselective
synthesis of α-aminoketones has been developed. Interaction
of a chiral phosphoric acid and an azoalkene promotes addition
of anilines, yielding highly enantioenriched α-amino hydrazones
that undergo clean hydrolysis to afford the corresponding
ketones. This reaction relies on the nucleophilicity of amines
and therefore compliments previous entries to this class of
compounds employing electrophilic nitrogen sources. Addi-
tionally, the discovery of a chiral phosphoric acid-catalyzed
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DOI: 10.1021/jacs.5b04518
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