Ruthenium-Catalyzed Direct Asymmetric Reductive Amination of Diaryl and Sterically Hindered Ketones with Ammonium Salts and H2

Article abstract of DOI:10.1002/anie.201915459

A Ru-catalyzed direct asymmetric reductive amination of ortho-OH-substituted diaryl and sterically hindered ketones with ammonium salts is reported. This method represents a straightforward route toward the synthesis of synthetically useful chiral primary diarylmethylamines and sterically hindered benzylamines (up to 97 % yield, 93–>99 % ee). Elaborations of the chiral amine products into bioactive compounds and a chiral ligand were demonstrated through manipulation of the removable and convertible -OH group.

Full text of DOI:10.1002/anie.201915459

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Accepted Article
Title: Ruthenium-Catalyzed Direct Asymmetric Reductive Amination of
Diaryl and Sterically Hindered Ketones with Ammonium Salts and
H2
Authors: Le’ an Hu, Yao Zhang, Qing-wen Zhang, Qin Yin, and Xumu
Zhang
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10.1002/anie.201915459
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COMMUNICATION
Ruthenium-Catalyzed Direct Asymmetric Reductive Amination of
Diaryl and Sterically Hindered Ketones with Ammonium Salts and
H2
Le’ an Hu,a,c Yao Zhang,a Qing-Wen Zhang,c Qin Yin,a,b,* and Xumu Zhanga
Dedication ((optional))
Abstract: Herein,
a
Ru-catalyzed direct asymmetric reductive
inhibition.
amination of ortho-OH-substituted diaryl and sterically hindered
ketones with ammonium salts has been disclosed for the first time,
offering a straightforward route toward the synthesis of synthetically
useful chiral primary diarylmethylamines and sterically hindered
benzylamines (up to 97% yield, 93−>99% ee). The elaborations of
chiral amine products into bioactive compounds have been exhibited
through manipulations on the removable and convertible -OH group.
Chiral diarylmethylamines and sterically hindered amines are
essential building blocks and have found broad applications in
the asymmetric syntheses of natural products, pharmaceuticals,
and biologically active compounds.[1] Moreover, they also serve
as key elements in ligand or catalyst designs for organic
synthesis[2] (Figure 1). Therefore, the synthesis of these
enantiopure amines has attracted increasing attention.[3-8]
Reported approaches toward them include resolution of
racemates,[4] asymmetric addition of an arylmetal or arylboron
species to imines,[5] and rare examples through imine
reduction,[6,7] etc.[8] However, resolution often suffers from low
efficiency and the latter two methods require pre-preparation of
imines. In comparison, catalytic direct asymmetric reductive
amination (ARA) of ketones constitutes one of the most
straightforward methods considering step and atom economy.[9]
While transition metal-catalyzed ARA of ketones bearing at least
one relatively small alkyl substituent attached to the carbonyl
group has been well developed (eq 1, Scheme 1),[9] direct ARA
of diaryl or sterically hindered ketones remains to be conquered
(eqs 2-3, Scheme 1).[10] The following obstacles have possibly
thwarted attempts of using these kinds of substrates in ARA: (i)
the difficulty on imine formation caused by decreased
electrophilicity and steric bulkiness; (ii) the interconversion of
E/Z stereoisomers of generated imine intermediates leads to
poor enantioinduction; (iii) the challenge on differentiation of two
sterically similar aryl or bulky groups; (iv) the incompatibility of
transition-metal hydrides with ketones and coordination of the
amine products to the metal catalyst which results in activity
Figure 1. Selected examples of biologically active compounds and ligands
containing chiral diarylmethylamines or sterically hindered amines moieties.
On the other hand, transition metal-catalyzed ARA of ketones
with ammonia or its equivalents capable of directly outputting
chiral primary amines is highly desirable but still
underdeveloped.[11] Very recently, the scope of ARA with
ammonia or ammonium salts has been expanded from β-keto
carboxylic derivatives to simple arylalkyl ketones by Schaub’s
and our group independently.[12] Given that ammonia is a small-
size amine source, we envisaged that direct ARA of diaryl or
sterically hindered ketones with ammonia or its equivalents
would be feasible, thus allowing for a straightforward synthesis
of chiral primary diarylmethylamines or bulky amines (eq 4,
Scheme 1). Herein, we report our recent efforts toward direct
ARA of diaryl and sterically hindered ketones with ammonium
salts.
[a]
Shenzhen Grubbs Institute and Department of Chemistry, Southern
University of Science and Technology, Shenzhen, Guangdong
518055, People’s Republic of China
E-mail: yinq@sustech.edu.cn
[b]
[c]
Academy for Advanced Interdisciplinary Studies, Southern
University of Science and Technology, Shenzhen, Guangdong
518000, People’s Republic of China
State Key Laboratory of Quality Research in Chinese Medicine,
Institute of Chinese Medical Sciences, University of Macau, Macao,
People’s Republic of China
Scheme 1. Asymmetric reductive amination for the synthesis of chiral amines.
Supporting information for this article is given via a link at the end
of the document.((Please delete this text if not appropriate))
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yield of imine intermediate was observed. [e] Reaction was carried out with 0.3
equiv of Ti(Oi-Pr)4. TFA = trifluoroacetic acid, PTSA = p-toluenesulfonic acid.
With 5a as the model substrate, the influence of acid additives
on the reaction was first explored. In the absence of Ti(Oi-Pr)4,
only a handful amount of product 6a was obtained, with about
half amount of starting material untouched. Side products
include the imine intermediate (44% yield) and trace amount of
etherification product 7 (Table 1, entry 1). This observation
indicates that Ti(Oi-Pr)4 also plays an important role in the imine
reduction step.[6b,9a-b,9h] Screening of other titanium Lewis acids
revealed that Ti(Oi-Pr)4 is the best in terms of both yield and ee
of 6a (Table 1, entries 2-4). Some other Lewis acids or Brϕnsted
acids were also tested and in most cases the ketone reduction
product 8 predominated (Table 1, entries 5-10). When the
reaction was carried out with sub-stoichiometric amount of Ti(Oi-
Pr)4, the yield of the amine product dropped to 76%, coupling
with etherification product 7 and some unidentified side-products
(Table 1, entry 11).
Scheme 2. Preliminary studies.
Ortho-Me-substituted diphenyl ketone
1
was initially
considered and subjected to our previously developed reaction
conditions[11f,12b] in the presence of 1 equiv of Ti(Oi-Pr)4. As
expected, the reaction was sluggish and only afforded small
amount of desired product 2 with most starting material
recovered. With regard to more electron-rich ketone 3, decent
yield of product 4 was obtained albeit in a nearly racemic form.
We hypothesized that introduction of an ortho-hydroxyl group in
the substrate would not only accelerate the imine formation
process by activating the carbonyl group but also stabilize the
labile imine intermediate through an intramolecular hydrogen
bonding.[13,14] Meanwhile, the intramolecular hydrogen bonding
or Lewis acid coordination of the generated imine intermediate
will make the imine exist exclusively as E isomer and thus
supply a more rigid steric environment benefiting to the
enantioinduction process (Scheme 2).[7c-d,14] To our delight, the
ortho-hydroxyl substituted substrate 5a reacted smoothly and
delivered the primary amine 6a in 85% yield and 98% ee.[15]
Notably, this method would provide a direct synthetic route to
the optically active Betti base and its derivatives.[16]
We next evaluated the performance of various chiral
diphosphine ligands, as depicted in Table 2. Overall, all tested
axially chiral ligands, including BINAP, SegPhos series and
BIPHEP, displayed excellent enantiocontrol and considerable
isolated yield (Table 2, entries 1-5). SegPhos was selected as
the optimal ligand for testing the generality of substrate scope.
Attempts of other metal precursors provided negligible amount
of desired amine product (Table 2, entries 6-8).
Table 2. Screening of catalysts.[a]
Table 1. Evaluation of additive effect.[a]
Entry
Cat.
Yield (%)[b]
ee (%)[c]
1
Ru[(S)-BINAP](OAc)2
Ru[(S)-DM-BINAP](OAc)2
Ru[(S)-SegPhos](OAc)2
Ru[(R)-DTBM-SegPhos](OAc)2
Ru[(R)-MeO-BIPHEP](OAc)2
[Rh(COD)Cl]2/(S)-BINAP
[Ir(COD)Cl]2/(S)-BINAP
Ni(OTf)2/(S)-BINAP
86
89
90
75
90
0
98
98
99
-92
-99
−
2
Entry
Additives
5a/6a/7/8 (%)[b]
ee of 6a (%)[c]
3
1[d]
2
−
44/11/1/0
0/88/12/0
0/72/28/0
0/94/6/0
−
4
Ti(Oi-Pr)4
Ti(OEt)4
TiCl4
98
97
84
77
−
5
6[d]
7[d]
8[d]
3
4
trace
0
−
5
B(Oi-Pr)3
AlCl3
0/66/10/0
2/7/4/87
−
6
[a] Reaction conditions: 5a (0.05 mmol), NH4OAc (0.25 mmol), cat. (1 mol%),
Ti(Oi-Pr)4 (0.05 mmol), MeOH (0.5 mL), H2 (50 atm), 80 °C, 24 h. [b] Isolated
yield. [c] Determined by chiral HPLC analysis. [d] The catalyst was prepared in
situ by mixing the metal precursor (1 mol%) and (S)-BINAP (1 mol%) in MeOH
for 30 min before use.
7
ZnCl2
13/57/10/20
0/40/5/55
0/26/5/69
0/46/8/46
0/76/6/0
89
93
91
81
98
8
HOAc
9
TFA
With optimal conditions in hand, a series of OH-substituted
diaryl ketones were subjected to the standard conditions.
Various substituents, including electron-donating (Me, MeO,
etc.) and electron-withdrawing groups (F, Cl, Br, CF3, CO2Me,
etc.) at different positions of the two aryl moieties had limited
influence on the enantiocontrol, affording the desired amines in
generally good to high yields (55%−97%) with excellent
enantioselectivities (93%−>99% ee, 6b-6s, 6v-6x). It’s worth
10
11[e]
PTSA•H2O
Ti(Oi-Pr)4
[a] Reaction conditions: 5a (0.05 mmol), NH4OAc (0.25 mmol), Ru[(S)-
BINAP](OAc)2 (1 mol%), additive (0.05 mmol), MeOH (0.5 mL), H2 (50 atm),
80 °C, 24 h. [b] Ratios are based on 1H NMR analysis of reaction mixture with
CH2Br2 as internal standard. [c] Determined by chiral HPLC analysis. [d] 44%
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10.1002/anie.201915459
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mentioning that the catalyst system can successfully
differentiate two aryl groups that both contain an ortho-
substituent, giving the corresponding amines in superb
enantioselectivities (6b, 6e, 6j). Moreover, heteroaryl
substrates(5t-5u) were also applicable, offering 6t and 6u in
decent yields (40% or 65% yield, respectively) but excellent
enantiocontrol (99% or 97% ee, respectively).
Removal of the hydroxyl group in the products can be easily
accomplished and was demonstrated in the synthesis of a key
chiral intermediate 11 to antiallergic drug levocetirizine (eq 1,
Scheme 3).[1d] In addition, NH isoindolinone 14, a typical unit
existed in numerous biologically active molecules and naturally
occurring alkaloids,[19] was easily accessed through
a
carbonylation/intramolecular amidation process and subsequent
N-Boc deprotection (eq 2, Scheme 3).
Table 3. Scope of diaryl ketone substrates.
Scheme 3. Product transformations.
We are also attracted by the potential application of the bulky
primary amines in the synthesis of new chiral ligands. To this
end, we performed a gram-scale reaction on 5ac, which
provided t-Bu substituted chiral amine 6ac in 70% yield and
>99% ee. Upon condensation of 6ac with diethyl malonimidate
dihydrochloride, chiral benzo-bisoxazine 15, a new ligand
scaffold, could be concisely prepared with excellent
enantioselectivity (Scheme 4).[2c]
Encouraged by excellent enantioselectivities obtained in OH-
assisted ARA of diaryl ketones, we wondered if this strategy
could be further extended to sterically hindered mono-aryl
ketones. To our delight, substrates containing a benzyl (5y), 2-i-
butyl (5z), i-propyl (5aa), c-hexyl (5ab), t-butyl (5ac) and even
adamantly (5ad) part proceeded very well to yield the
corresponding bulky aminobenzylphenols products in good to
high yields (82%−94%) with perfect enantioselectivities
(98−>99% ee) (Table 4).[17] In comparison, substrate 5ac’
lacking an ortho-OH group showed almost no reactivity.
Scheme 4. Gram-scale synthesis of chiral amine 6ac and its application to
prepare chiral benzo-bisoxazine 15.
Table 4. Scope of sterically hindered ketone substrates.[a]
In summary, we have developed a highly enantioselective
direct ARA of diaryl and sterically hindered ketones with
ammonium salts for the first time, providing a straightforward
route toward the synthesis of enantioenriched chiral primary
diarylmethylamines and sterically bulky benzylamines. With the
assistance of an ortho-OH group in substrates, the reactivity and
enantiocontrol are generally in a good to excellent level (up to
97% yield, 93−>99% ee) for a broad range of substituted diaryl
ketones and sterically hindered ketones. The reaction could be
performed on a gram scale and was applied to the syntheses of
chiral drug levocetirizine, an isoindolinone compound and a new
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[6]
[7]
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Y. Wang, M. Zhao, I. D. Gridnev, T. Imamoto, W. Zhang, Nat. Commun.
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Acknowledgements
We are grateful to the National Natural Science Foundation of
China (No. 21801119), Shenzhen Science and Technology
Innovation Committee (No. JCYJ20170817110055425 and
KQTD20150717103157174), Shenzhen Nobel Prize Scientists
Laboratory Project (C17783101) for financial support.
Keywords: chiral primary amines • ruthenium • reductive
amination • diaryl ketones • sterically hindered ketones
[8]
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[9]
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[2]
[10] To our knowledge, only one elegant paper reported few examples on
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[3]
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a
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C. Bolm, Chem. Soc. Rev. 2006, 35, 454.
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[15]
For comparison, the meta- and para-hydroxyl substituted substrates
were also subjected to the same reaction conditions: (3-
hydroxyphenyl)(phenyl)methanone could deliver the corresponding
primary amine in 53% yield and 12% ee, together with recovery of
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starting material, while (4-hydroxyphenyl)(phenyl)methanone only gave
the desired amine in 13% yield with most starting material recovered.
[16] A. Olyaei, M. Sadeghpour, RSC Adv., 2019, 9, 18467.
and 6af were obtained in good yields (95% or 80% yield, respectively)
with excellent enantioselectivity (both >99% ee).
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Synthesis 1995, 766.
[17] 1-(2-hydroxyphenyl)ethan-1-one (5ae) and 1-(2-hydroxyphenyl)pentan-
1-one (5af) were also subjected to the standard conditions to test the
substrate generality of this reaction, and the corresponding amines 6ae
[19] M. Chrzanowska, A. Grajewska, M. D. Rozwadowska, Chem. Rev. 2016,
116, 12369.
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Layout 2:
COMMUNICATION
Le’ an Hu, Yao Zhang, Qing-Wen
Zhang, Qin Yin,* and Xumu Zhang
Page No. – Page No.
Ruthenium-Catalyzed Direct
Asymmetric Reductive Amination of
Diaryl and Sterically Hindered
Ketones with Ammonium Salts and
H2
-OH makes it: A highly enantioselective OH-assisted direct asymmetric reductive
amination of diaryl and sterically hindered ketones with ammonium salts and H2 has
been realized for the first time, offering a straightforward route toward the synthesis
of synthetically useful chiral primary diarylmethylamines and sterically hindered
benzylamines.
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