Direct Asymmetric Reductive Amination for the Synthesis of Chiral β-Arylamines

Article abstract of DOI:10.1002/anie.201601025

The highly efficient and direct asymmetric reductive amination of arylacetones catalyzed by an iridium complex for the preparation of enantiomerically pure β-arylamines is described. The monodentate phosphoramidite ligand exhibits superb reactivity (TONs of up to 20 000) and enantioselectivity (up to 99 % ee). Additives played important roles in this reductive coupling reaction. Asymmetric reductive coupling of a ketone and an amine is a straightforward and atom-economic approach for preparing optically enriched amines. The highly efficient and direct asymmetric reductive amination of arylacetones, catalyzed by an iridium complex, supplies enantiomerically pure β-arylamines. The new phosphoramidite ligands reported show superb reactivity and enantioselectivity in this reductive coupling. M.S.=molecular sieves, TFA=trifluoroacetic acid.

Full text of DOI:10.1002/anie.201601025

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International Edition: DOI: 10.1002/anie.201601025
German Edition: DOI: 10.1002/ange.201601025
Asymmetric Catalysis
Direct Asymmetric Reductive Amination for the Synthesis of Chiral
b-Arylamines
Haizhou Huang, Xiaoyan Liu, Le Zhou,* Mingxin Chang,* and Xumu Zhang
Abstract: The highly efficient and direct asymmetric reductive
amination of arylacetones catalyzed by an iridium complex for
the preparation of enantiomerically pure b-arylamines is
described. The monodentate phosphoramidite ligand exhibits
superb reactivity (TONs of up to 20000) and enantioselectivity
(up to 99% ee). Additives played important roles in this
reductive coupling reaction.
compounds[8] are two highly efficient approaches, especially
the latter, because its concise synthetic route and high atom
economy represent a greener and more promising method.
For the preparation of unfunctionalized chiral b-aryl-
amines by asymmetric reductive amination reactions, there
has been some progress in the areas of biocatalysis (mainly
using w-transaminases)[9] and organocatalysis (using chiral
phosphoric acids)[10] in recent years. In contrast, the tran-
sition-metal-catalyzed counterpart to prepare such com-
pounds lags behind. To the best of our knowledge, the only
related research was reported in 2010 for the asymmetric
reductive amination of 2-tetralone in 47% ee.[11] At the same
time, a number of transition-metal complexes succeeded in
the preparation of chiral a-arylamines by asymmetric reduc-
tive coupling reactions.[8,12] The structure of the corresponding
acetophenone is rigid (p–p conjugation), while phenylacetone
is floppy (s-bond rotations) and thus results in difficulties
regarding enantiocontrol. Other factors, such as the inhibitory
effect of amines on the catalyst and ketone reduction as
a side-reaction, also stand as obstacles to advances in this
research area.[1,8]
E
nantiomerically pure b-arylamines are ubiquitous struc-
tural motifs and key pharmacophores of many active phar-
maceutical ingredients (Figure 1),[1] for example, dextroam-
Herein, we report a highly efficient direct asymmetric
reductive amination of arylacetones using diphenylmethyl-
amine as the nitrogen source [Eq. (1); M.S. = 4 Š molecular
Figure 1. Chiral b-arylamine pharmaceuticals.
sieves, TFA = trifluoroacetic acid]. The monodentate phos-
phoramidite chiral ligand L6 (see Figure 2) along with an
iridium precursor demonstrated excellent reactivity (TONs
up to 20000) and enantioselectivity (up to 99% ee). In our
initial studies, the commonly used ketone coupling partners
aniline[8] and benzylamine[11,13] were probed for the reduc-
tive amination of 1-(4-methoxyphenyl)-propan-2-one (1a).
Molecular sieves (M.S.; 4 Š), tetraisopropoxytitanium [Ti-
(OiPr)4], and trifluoroacetic acid (TFA) were introduced as
additives based on our previous studies.[12a,f] Aniline led to
a good yield but poor enantioselectivity [Eq. (2); BINAP =
phetamine and lisdexamfetamine for ADHD,[2] (R,R)-formo-
terol for asthma and COPD,[3] (R)-tamsulosin for BPH,[4] and
titonavir and darunavir for HIV.[5,6] Among those various
methods to synthesize chiral amines, catalytic asymmetric
imine reductions[7] and reductive aminations of carbonyl
[*] H. Huang, X. Liu, Prof. Dr. L. Zhou, Prof. Dr. M. Chang
Department of Chemistry and Chemical Engineering
Northwest A&F University
22 Xinong Road, Yangling, Shaanxi 712100 (PR China)
E-mail: zhoulechem@nwsuaf.edu.cn
2,2’-bis(diphenylphosphanyl)-1,1’-binaphthyl),
cod = 1,5-
cyclooctadiene], and benzylamine furnished 65% yield and
a moderate ee value [Eq. (3)]. As benzyl is a universal
mxchang@nwsuaf.edu.cn
Prof. Dr. X. Zhang
Department of Chemistry and Chemical Biology
Rutgers, The State University of New Jersey
Piscataway, NJ 08854 (USA)
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201601025.
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protecting group of amines,[14] we decided to continue with
benzylamine and envisioned a less-electron-rich, but bulkier
amine would be of service to both reactivity and enantiose-
lectivity. So we explorated diphenylmethylamine (4) as the
ketone coupling partner. To our great delight, it provided
much better result (Table 1, entry 1). The two phenyl rings in
4 greatly limit the inhibitory effect on the catalyst and exert
positive influence during the enantioinducing process as
compared to that of the single phenyl ring of benzylamine.
Figure 2. Structures of chiral ligands.
Table 2: Studies on chiral ligands.[a]
Table 1: Studies on additives.[a]
Entry
Ligand
Yield [%][b]
ee [%][c]
Entry
Additives[b]
1a/5a/6[c]
ee [%][c]
1
2
3
4
5
6
7
8
9
10
11
12[d]
13[e]
14[f]
L1
L2
L3
L4
L5a
L5b
L5c
L5d
L5e
L5 f
L6
99
98
98
83
98
90
24
97
98
98
98
98
97
90
62
70
3
1
2
3
4
5
6
7
8
9
M.S., Ti(OiPr)4, TFA
–
M.S.
Ti(OiPr)4
TFA
M.S., Ti(OiPr)4
M.S., TFA
Ti(OiPr)4, TFA
M.S., Ti(OiPr)4, HOAc
2:98:0
12:0:88
31:36:33
29:0:71
19:27:54
10:5:85
16:36:48
9:43:48
9:46:45
62
–
57
–
61
–
59
61
53
43
51
82
69
59
86
89
98
98
98
98
[a] Reaction conditions: [Ir]/(R)-BINAP/1a/4=1:1:100:110, 1a
L6
L6
L6
0.2 mmol, 50 atm of H2, 13 h. [b] Amounts used: M.S. (0.1 grams); TFA
(30 mol%); Ti(OiPr)4 (30 mol%); HOAc (30 mol%). [c] Ratios and
enantiomeric excesses were determined by chiral-phase HPLC.
cod=1,5-cyclooctadiene, RT=room temperature, TFA=CF3COOH.
[a] Reaction conditions: [Ir]/L/1a/4=1:1:100:110, 1a (0.2 mmol),
60 atm of H2, 13 h, M.S. (0.1 grams), TFA (30 mol%), Ti(OiPr)4
(30 mol%). [b] Yields were calculated from the 1H NMR spectra.
[c] Enantiomeric excesses were determined by chiral-phase HPLC.
[d] Catalyst loading was 0.1 mol%. [e] Catalyst loading was 0.01 mol%;
TFA was 1 equiv. [f] Catalyst loading was 0.005 mol%; H2 was 80 atm;
TFA was 1 equiv.
As for the additive effects (Table 1), the desired product
was not formed in the absence of additives (entry 2). With the
addition of only either molecular sieves, TFA, or Ti(OiPr)4,
a large portion of ketone remained along with the formation
of the by-product 6 (entries 3–5), which decomposed on the
column during purification. The combination of Ti(OiPr)4 and
TFA enhanced the product yield to 43%. TFA is crucial to
this reaction. It greatly improved the enantioselectivity as
well as the reactivity (entry 1 versus 6). By replacing TFAwith
acetic acid, the reaction afforded less than 50% of the desired
product.
Next, a few other commercially available chiral ligands
(Figure 2) were screened (Table 2, entries 1–5). Even though
the BINOL-based MonoPhos L5a did not provide an out-
standing result, given the ease of its preparation and vast
applications in asymmetric hydrogenation,[15] we synthesized
a series of this type of ligand (Figure 2; L5b–g and L6) and
tested them in our reaction (Table 2, entries 6–10). L5b
afforded much better enantioselectivity than MonoPhos.
Encouragingly L5 f further improved the enantiomeric
purity to 89%, so we focused on the 3,5-dimethylpiperidine
motif and prepared L6 by partially hydrogenating the
binaphthalene of BINOL. L6 exhibited the best performance,
thus rendering 98% ee (entry 11). When the Ir/L6 complex
loading was reduced to 0.1 mol% or even to 0.01 mol%, the
reaction still ran smoothly without compromising enantiose-
lectivity (entries 12 and 13). The catalyst loading was further
decreased to 0.005 mol%, and a slightly lower conversion was
obtained (entry 14). To the best of our knowledge, this result
represents the highest reactivity (TON) in a direct asymmet-
ric reductive amination using chiral iridium catalysts.[16]
To explore the scope and limitations of this Ir/L6 catalytic
system, a range of aryl/alkyl acetones were studied under the
optimized reaction conditions. The results are summarized in
Table 3. For all chosen arylacetones, the chiral products 5a–m
were obtained in excellent selectivity (94% to 99% ee) and
good yields. For ortho-substituted arylacetones, the electronic
properties of the substituents did not exert any noticeable
effect on either the selectivity or reactivity (entries 1 and 3–5).
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Table 3: Asymmetric reductive amination of aryl-acetones.[a]
To further demonstrate the practical utility of the newly
developed method, the asymmetric reductive amination of 1a
was performed on a 5 mmol scale. The desired product 5a was
obtained in 90% yield upon isolation in 98% ee. The facile
removal of the diphenylmethyl group proceeded withpalla-
dium on carbon and H2. The product was then acylated to give
7 in 95% yield without any erosion of the enantioselectivity
(Scheme 1). We also examined the substrate 1o and the same
result was obtained [Eq. (4)]. The product 5o could be
utilized as the key intermediate for the synthesis of (R)-
Tamsulosin.[17]
Entry
R
Product
Yield [%][b]
ee [%][c]
1
2
3
4
5
4-MeOC6H4
Ph
5a
5b
5c
5d
5e
5 f
5g
5h
5i
5j
5k
5l
5m
5n
5b
5a
91
92
98
97
88
93
90
87
89
89
92
84
91
92
91
91
98
97
97
94
97
98
98
94
98
99
>99
97
98
86
4-MeC6H4
4-BrC6H4
4-tBuC6H4
3-MeOC6H4
3-MeC6H4
3-ClC6H4
2-MeOC6H4
2-ClC6H4
3,5-(MeO)2C6H3
3,5-F2C6H3
2-naphthyl
iPr
6
7
8[d]
9
10
11
12
13
14
15[e]
16[f]
Ph
97
98
In summary, we have developed a highly efficient and
direct asymmetric reductive amination of arylacetones, cata-
lyzed by an iridium complex, for the preparation of enantio-
merically pure b-arylamines. The use of diphenylmethylamine
as an amine source reduces the inhibitory effect on the
catalyst and assures the stereoselectivity. TFA as an additive
significantly improved the reaction rate and enantioselectiv-
ity. The iridium-phosphoramidite complex displayed excel-
lent reactivity and stereoselectivity. Together with the ease of
removal of the diphenylmethyl group and the bench stability
of the catalyst, this protocol is a promising method for the
synthesis of related b-arylamine pharmaceuticals. Further
applications of these chiral phosphoramidite complexes for
the asymmetric reductive amination of other ketones are
under investigation within our laboratories, and the results
will be reported in due course.
4-MeOC6H4
[a] Reaction conditions: [Ir]/L6/1a/4=1:1:1000:1100, 1a (0.2 mmol),
60 atm of H2, 13 h, M.S. (0.1 grams), TFA (30 mol%), Ti(OiPr)4
(30 mol%). [b] Yield of isolated product. [c] Enantiomeric excesses were
determined by chiral-phase HPLC. [d] Catalyst loading was 0.1 mol%;
TFA was 0.8 equiv. [e] Catalyst loading was 0.1 mol%; 4 was 0.95 equiv;
TFA was 1 equiv [f] Reaction operations were conducted open to air; H2
pressure was 30 atm.
As for the meta position, the electron-withdrawing 3-chloro
substrate (1h) required more acidic conditions to achieve
better conversion. The catalytic system worked well for the
sterically hindered ortho-substituted substrates 1i and 1j, and
multisubstituted substrates 1k and 1l (entries 9–12). The
enantioselectivity in these cases were similarly high as those
obtained for substrates with aryl groups bearing substituents
in either the meta- or para- positions. This protocol also
worked for the alkylacetone 5n (entry 14). To further Experimental Section
General procedure for asymmetric reductive amination: In a nitro-
examine the reactivity of the catalytic system, 0.005 mol%
of Ir/L6 was used for the reaction of 5b with 4, and an
excellent result was achieved (entry 15). To take advantage of
the bench-stability of the newly developed L6, the asymmet-
ric reductive coupling of 1a and 4 was operated under an air
atmosphere and H2 pressure was decreased to 30 atm, and the
same result was obtained (entry 16).
gen-filled glovebox, [{Ir(cod)Cl}2] (0.1 mmol) and L6 (0.2 mmol) were
dissolved in anhydrous CH2Cl2 (1.0 mL), stirred for 20 min, and
equally divided into 10 vials charged with a-arylacetones (0.2 mmol)
and diphenylmethylamine (0.22 mmol) in anhydrous CH2Cl2 solution
(1.0 mL). Then 4 Š molecular sieves (0.1 gram), Ti(OiPr)4 (0.3 equiv),
and trifluoroacetic acid (0.3 equiv) were added and brought to a total
volume of 2.0 mL for each vial. The resulting vials were transferred to
an autoclave, which was charged with 60 atm of H2, and stirred at
room temperature for 13 h. The solution was neutralized with
aqueous sodium bicarbonate solution. The organic phase was
concentrated and passed through a short column of silica gel to
remove the metal complex to give the chiral b-arylamine products,
which were then analyzed by chiral-phase HPLC to determine the
enantiomeric excesses.
Acknowledgements
We thank the National Natural Science Foundation of China
(No. 21402155) and Northwest A&F University for financial
support. Hongli Zhang is thanked for NMR analysis.
Scheme 1. Large-scale reductive amination of 1a and deprotection of
5a.
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Keywords: asymmetric catalysis · enantioselectivity · iridium ·
ligand design · reductions
How to cite: Angew. Chem. Int. Ed. 2016, 55, 5309–5312
Angew. Chem. 2016, 128, 5395–5398
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Received: January 29, 2016
Published online: March 16, 2016
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