Enantioselective Reductive Cyanation and Phosphonylation of Secondary Amides by Iridium and Chiral Thiourea Sequential Catalysis

Article abstract of DOI:10.1002/anie.202015898

The combination of transition-metal catalysis and organocatalysis increasingly offers chemists opportunities to realize diverse unprecedented chemical transformations. By combining iridium with chiral thiourea catalysis, direct enantioselective reductive cyanation and phosphonylation of secondary amides have been accomplished for the first time for the synthesis of enantioenriched chiral α-aminonitriles and α-aminophosphonates. The protocol is highly efficient and enantioselective, providing a novel route to the synthesis of optically active α-functionalized amines from the simple, readily available feedstocks. In addition, the reactions are scalable and the thiourea catalyst can be recycled and reused.

Full text of DOI:10.1002/anie.202015898

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Communications
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How to cite: Angew. Chem. Int. Ed. 2021, 60, 8827–8831
International Edition: doi.org/10.1002/anie.202015898
German Edition: doi.org/10.1002/ange.202015898
Synthetic Methods
Enantioselective Reductive Cyanation and Phosphonylation of
Secondary Amides by Iridium and Chiral Thiourea Sequential Catalysis
Dong-Huang Chen+, Wei-Ting Sun+, Cheng-Jie Zhu+, Guang-Sheng Lu, Dong-Ping Wu,
Ai-E Wang,* and Pei-Qiang Huang*
Abstract: The combination of transition-metal catalysis and
organocatalysis increasingly offers chemists opportunities to
realize diverse unprecedented chemical transformations. By
combining iridium with chiral thiourea catalysis, direct enan-
tioselective reductive cyanation and phosphonylation of sec-
ondary amides have been accomplished for the first time for
the synthesis of enantioenriched chiral a-aminonitriles and a-
aminophosphonates. The protocol is highly efficient and
enantioselective, providing a novel route to the synthesis of
optically active a-functionalized amines from the simple,
readily available feedstocks. In addition, the reactions are
scalable and the thiourea catalyst can be recycled and reused.
Development of new catalytic methods based on the trans-
formation of readily available and bench stable compounds
are still in high demand from both academic and industrial
perspectives.
Amides are a class of highly stable and readily available
feedstocks abundant in nature.[8] Secondary amides, in
particular, serve as fundamental structural units in peptides,
proteins[9] and synthetic polyamides.[10] Moreover, in recent
years, secondary amide groups have proved to be valuable
À
directing groups in transition-metal-catalyzed C H function-
alization chemistry.[11] Development of methods for modifi-
cation and application of secondary amides is therefore
important and has attracted much attention. However, the
direct use of secondary amides as synthetic intermediates has
been hampered by their low electrophilicity. In addition, the
acidic proton on the N-atom of secondary amides challenges
further their direct transformations. In the last decade, with
the efforts from the research groups of Charette,[12] Movassa-
ghi,[13] Chida/ Sato,[14] and Huang[15] et al.,[16] breakthroughs
have been achieved for the direct conversion of secondary
amides into functional groups with lower oxidation states.[17]
In this context, the reductive functionalization of secondary
amides with generation of tertiary centers a to nitrogen has
emerged as an attractive approach for a-functionalized
amines synthesis. However, the reported methods relied on
the use of stoichiometric amounts of electrophilic activating
agents (such as Tf2O[18]), or metal hydride reducing agents
(such as Cp2ZrHCl[14a,b,19]) (Scheme 1A).
T
he development of highly efficient catalytic asymmetric
methodologies to construct functionalized optically active
compounds from readily accessible starting materials is of
great importance in modern synthetic organic chemistry.
Chiral a-functionalized amines, such as a-aminonitriles[1] and
a-aminophosphonic acids,[2] are prevalent structural motifs
present in pharmaceuticals, agrochemicals, natural products
and biologically active compounds (Figure 1).
The catalytic asymmetric Strecker[3] and Pudovik reac-
tion,[4] or three-component Strecker[5] and Kabachnik-Fields
reaction,[6] are undoubtedly the most direct and widely used
strategies for the synthesis of optically active chiral a-
aminonitriles and a-aminophosphonic acid derivatives. The
enantioselective reduction of a-iminophosphonates or a-
enamido phosphonates, the electrophilic substitution of
phosphoglycines and the nucleophilic addition to a-imino-
phosphonates are alternatives for chiral aminophosphonates
synthesis.[7] These methods, however, suffer from drawbacks
such as inherent instability of starting materials (e.g. imines
and aldehydes), limited substrate scope or availability.
Recently, by combining [Ir(COE)2Cl]2 catalyzed hydro-
silylation[20] with BF3·Et2O promoted nucleophilic addition,
we have achieved the first catalytic reductive functionaliza-
tion of secondary amides to give functionalized amines,
[*] D.-H. Chen,[+] W.-T. Sun,[+] C.-J. Zhu,[+] G.-S. Lu, D.-P. Wu,
Dr. A.-E Wang, Prof. Dr. P.-Q. Huang
Department of Chemistry and Fujian Provincial Key Laboratory of
Chemical Biology, College of Chemistry and Chemical Engineering
Xiamen University
Xiamen 361005, Fujian (China)
E-mail: aiewang@xmu.edu.cn
pqhuang@xmu.edu.cn
Dr. A.-E Wang, Prof. Dr. P.-Q. Huang
State Key Laboratory of Applied Organic Chemistry
Lanzhou University
Lanzhou 730000, Gansu (China)
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202015898.
Figure 1. Representative pharmaceutical agents and natural products
containing a-aminonitriles and a-aminophosphonic acids.
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Figure 2. Chiral phosphoric acid and thiourea catalysts screened.
be seen from Table 1, this enantioselective reductive cyana-
tion reaction proceeded smoothly not only with simple aroyl
amides (1a–e) such as p-tolyl, biphenyl and naphthyl as the
aryl group, but also with benzamides bearing electron-with-
drawing or electron-donating groups at the para- position of
phenyl ring (1 f–m), to give the corresponding a-aminonitriles
in good yields and with high enantioselectivities. However,
low yield was obtained for benzamides 1r which has a methyl
group at ortho- position and a decrease in enantioselectivity
was also observed.
Scheme 1. Reductive functionalization of secondary amides for a-
functionalized amines synthesis.
The reaction was tolerant of various functional groups
including halogen (2g,h), protected phenol (2i,j), carbamate
(2k), 4-morpholinyl (2l) and pyrrolyl (2m) group, providing
a-aminonitrile products in good yield and high enantiomeric
excess. The reaction with amide 1n or 1o, which bearing an
electron-withdrawing ester or sulfonyl group, however, failed
to give the reductive cyanation product. Imine intermediates
3n and 3o were isolated in 91% and 69% yield, respectively.
This reaction was also applicable to heteroaromatic
amides like 2-furanyl carboxamide 1s and 2-chloro-6-meth-
oxynicotinamide 1t and the corresponding products 2s and 2t
were obtained with 87% and 94% ee, respectively.
The steric hindered branched alkanamides, such as
pivalamide 1u and 1-adamantanecarboxamide 1v, and
unbranched hexanamide 1w were reactive substrates for the
reaction as well, however, much lower enantioselectivities
were obtained under the standard conditions. Using toluene
as the solvent in the hydrosilylation led to a dramatic increase
in both yields and enantioselectivies.
For the reductive phosphonylation of secondary amides,
N-benzyl isobutyramide 4o was chosen as the model substrate
(see Table S2 and S3 in the Supporting Information). It was
found that the use of thiourea catalyst C2 (10 mol%) together
with di-(2-nitrobenzyl) phosphite as phosphonylation reagent
in Et2O could combine with iridium-catalyzed hydrosilylation
system (0.1 mol% of [Ir(COE)2Cl]2, 2.0 equiv of Et2SiH2,
toluene) very well, to enable the transformation of 4o to the
corresponding chiral a-aminophosphonate 5o in 69% yield
and 90% ee (Table 2).
including
a-aminonitriles
and
a-aminophosphonates
(Scheme 1B).[21,22] However, the enantioselective reductive
functionalization of secondary amides leading to optically
active a-functionalized amines remains largely unexplored.
In the past decades, organo/metal combined catalysis has
emerged as a powerful strategy for developing unprecedented
and valuable transformations that could not be achieved by
single catalyst system.[23] Here we disclose our results on the
direct transformation of secondary amides to chiral a-amino-
nitriles and a-aminophosphonates via one-pot enantioselec-
tive reductive cyanation and phosphonylation by sequential
Ir/thiourea catalysis, whereby amides are reduced in the first
Ir-catalyzed cycle to form imine intermediates which are then
converted to chiral a-functionalized amines by subsequent
organocatalysis (Scheme 1C).
Chiral phosphoric acid[24] and thiourea[25] catalysts are two
classes of powerful organocatalysts in organic chemistry,
especially in related asymmetric (three-component)
Strecker[3d–h,5a] and Pudovik[4b–d] or Kabachnik-Fields reac-
tions.[6a,d] Several of them were evaluated as potential organo-
catalysts in our combined catalysis strategy (Figure 2). Firstly,
the reductive cyanation of N-benzhydryl benzamide 1a was
chosen as the model reaction (see Table S1 in the Supporting
Information). Jacobsenꢀs thiourea catalysts C3b turned out to
be the most effective and highly enantioselective, which
produced the desired a-aminonitrile 2a in 90% yield with
96% ee, with [Ir(COE)2Cl]2 (2 mol%) as a catalyst, Et2SiH2
(2.5 equiv) as hydride source, and TMSCN/ MeOH
(2.5 equiv) as cyanide source (Table 1).
Using this one-pot protocol, a wide array of secondary
amides could be converted into the corresponding a-amino-
Under the optimized conditions, a variety of N-benzhy-
dryl secondary amides were examined in this protocol. As can
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Table 1: Scope of enantioselective reductive cyanation of secondary
Table 2: Enantioselective reductive phosphonylation of secondary
amides.[a]
amides.[a]
[a] Reaction conditions: amide 4 (1.0 mmol), [Ir(COE)2Cl]2 (0.1 mol%),
Et2SiH2 (2.0 mmol), toluene (2.0 mL), RT, then C2 (10 mol%), HPO-
(OR)2 (1.0 mmol), Et2O (4.0 mL), 08C. [b] The absolute configuration
was assigned by analogy. [c] 20 mol% of C2 was used and 3.0 mL of
toluene and Et2O was used, respectively in hydrosilylation and phos-
phonylation. [d] Performed at 3.0 mmol scale. [e] After one recrystalli-
zation.
phosphonates in good yields and high enantioselectivities
(Table 2).
For N-benzyl benzamide derivatives, the electronic prop-
erties seemed to have no obvious influence on the reaction.
Good yields (67–76%) and enantioselectivities (90–98% ee)
were obtained for benzamides bearing electron-donating or
electron-withdrawing groups at the para- or meta- position of
phenyl ring (4b–f, 4h). o-Chlorobenzamide 4g also worked
well to afford the corresponding product 5g in good yield and
high enantioselectivity (69% yield, 97% ee with 20 mol%
C2). Both halogen (5 f–h) and ester (5e) groups were robust
under this reductive phosphonylation conditions. Replace-
ment of N-substituents of benzamides from benzyl to 2-
thiophenylmethyl gave similar results (5i). Heteroaroyl-sub-
[a] Reaction conditions: amide 1 (0.20 mmol), [Ir(COE)2Cl]2 (2 mol%),
Et2SiH2 (0.50 mmol), CH2Cl2 (2.0 mL), RT, 1 h, removal of DCM, then
C3b (15 mol%), TMSCN (0.50 mmol), MeOH (0.50 mmol), toluene
(2.0 mL), À308C. [b] The absolute configuration was assigned by
analogy. [c] Toluene was used as solvent in hydrosilylation and
performed on 0.40 mmol scale. [d] Use of [Ir(COE)2Cl]2 (1 mol%) and
Et2SiH2 (2.0 equiv) in hydrosilylation. [e] Performed on 5.0 mmol scale,
along with 80% yield of C3b recovered. [f] Performed with 2nd recycled
C3b.
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stituted amides such as 2-furanyl and 2-thienyl carboxamide
4j and 4k could also be used, and the corresponding products
5j and 5k were obtained with 88% ee and 89% ee in 68% and
75% yield, respectively.
For the reductive phosphonylation of secondary alkana-
mides, not only the steric hindered branched alkanamides
4m–q but also the unbranched acetamide 4l were suitable
substrates and the former gave higher enantioselectivities
than the latter.
The reductive phosphonylation with other phosphites was
also studied. Good yield and moderate enantioselectivity
were obtained with diphenyl phosphite (5r), while low
conversion and enantioselectivity were observed when diben-
zyl or dimethyl phosphite was applied (5s,t).
ditions,[4b] (R)-phosphoalanine (9l) can be facilely prepared
from the corresponding di-(2-nitrobenzyl) aminophospho-
nate product 5l.
In conclusion, we have developed enantioselective cata-
lytic one-pot reductive cyanation and phosphonylation of
secondary amides for the synthesis of chiral a-aminonitriles
and a-aminophosphonates using a combination of iridium
and chiral thiourea catalysis. A wide range of secondary
amides could be converted into the corresponding a-amino-
nitriles and a-aminophosphonates in good yields and high
enantioselectivities.
Acknowledgements
To explore the practical utility of the protocol in organic
synthesis, the gram scale preparations of a-aminonitrile 2e
and a-aminophosphonate 5h, respectively from amides 1e
(5.0 mmol) and 4h (3.0 mmol) were performed. The desired
a-aminonitrile 2e and a-aminophosphonate 5h were pro-
duced in 89% yield with 91% ee and 67% yield with 81% ee,
respectively. The optical purity of the latter can be enhanced
to 97% ee after one recrystallization (59% overall yield from
4h). In addition, thiourea catalyst C3b can be readily recycled
from the reductive cyanation reaction system by means of
column chromatography, and reused for the next two reaction
cycles without obvious significant loss of activity or enantio-
selectivity (2e).
Financial support of this work from the National Natural
Science Foundation of China (No. 21931010), the National
Key R&D Program of China (No. 2017YFA0207302), the
PCSIRT of Ministry of Education, and the Natural Science
Foundation of Fujian Province of China (No. 2019J01018) is
gratefully acknowledged.
Conflict of interest
The authors declare no conflict of interest.
The synthetic utility of the present protocol was further
demonstrated by the transformation of a-aminonitrile 2e to
1,2-diamine derivative 7 and the preparation of biologically
important aminophosphonic acids 9l (Scheme 2). 1,2-Dia-
mine 7 is an intermediate for the synthesis imidazole-2-
carbamate 8, used as a muscle relaxant.[26] Starting from
reductive cyanation product 2e, 7 can be prepared readily by
reduction followed by deprotection and neutralization. (R)-
Phosphoalanine (9l) is the aminophosphonic acid analogue of
l-alanine, the inhibitor of alanine racemase,[27] which can be
also used for the synthesis of known antibacterial phospho-
nopeptide Alafosfalin.[28] By hydrogenolysis under mild con-
Keywords: amides · amines · enantioselectivity ·
reductive functionalization · sequential catalysis
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Manuscript received: November 29, 2020
Accepted manuscript online: January 22, 2021
Version of record online: March 8, 2021
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