Chiral β-Keto Propargylamine Synthesis via Enantioselective Mannich Reaction of Enamides with C-Alkynyl N-Boc N, O-Acetals

Article abstract of DOI:10.1021/acs.orglett.9b03181

Propargylamines are an important class of compounds in organic synthesis and drug discovery, yet the synthesis of chiral β-keto propargylamines remains underdeveloped. Herein, we describe a streamlined and general enantioselective Mannich reaction of enamides with C-alkynyl N-Boc N,O-acetals, which serve as readily available C-alkynyl imine precursors, to access a broad range of chiral β-keto N-Boc-propargylamines bearing single stereogenic centers in high yields (up to 98%) and in high enantioselectivities (up to 95% ee).

Full text of DOI:10.1021/acs.orglett.9b03181

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Chiral β‑Keto Propargylamine Synthesis via Enantioselective
Mannich Reaction of Enamides with C‑Alkynyl N‑Boc N,O‑Acetals
Fang-Fang Feng,†,‡ Shen Li,†,‡ Chi Wai Cheung,*,†,‡ and Jun-An Ma*,†,‡
†Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, and Tianjin Collaborative Innovation
Centre of Chemical Science & Engineering, Tianjin University, Tianjin 300072, P.R. China
‡Joint School of NUS & TJU, International Campus of Tianjin University, Fuzhou 350207, P.R. China
S
* Supporting Information
ABSTRACT: Propargylamines are an important class of compounds in organic synthesis and drug discovery, yet the synthesis
of chiral β-keto propargylamines remains underdeveloped. Herein, we describe a streamlined and general enantioselective
Mannich reaction of enamides with C-alkynyl N-Boc N,O-acetals, which serve as readily available C-alkynyl imine precursors, to
access a broad range of chiral β-keto N-Boc-propargylamines bearing single stereogenic centers in high yields (up to 98%) and
in high enantioselectivities (up to 95% ee).
Scheme 1. Methods for Synthesis of β-Keto
Propargylamines from Alkynyl Imine Derivatives
ropargylamines, particularly their chiral forms, are
1
2
Pimportant structural motifs and synthetic intermediates
of natural products and biologically active molecules. In
particular, chiral keto-substituted propargylamines are an
attractive class of functionalized propargylamines in organic
synthesis owing to the potential transformations of both keto
and alkynyl groups to multiple functionalities.3 Over the past
decades, a diverse set of functionalized chiral propargylamines
have been accessed by employing the asymmetric additions of
alkynyl nucleophiles to imines4 as well as the asymmetric
additions of nucleophilic substrates to C-alkynyl imine
derivatives.5−8 In this context, only one report by Snapper
and Hoveyda et al. has presented the Ag-catalyzed asymmetric
reaction between 3-phenylpropynyl N-arylimine and silyl vinyl
ethers to obtain two examples of chiral β-keto propargylamines
(Scheme 1a).5b On the other hand, enamides have been
utilized as readily available and bench-stable carbon
nucleophiles in organic synthesis, especially in asymmetric
catalysis.9 Recently, our group demonstrated the enantiose-
lective addition of enamides to in situ generated cyclic
ketimines to give a myriad of chiral β-keto amine
derivatives.10,11 Therefore, we envisioned that the asymmetric
reaction of enamides with C-alkynyl N-Boc N,O-acetals
recently introduced by the Shao group, which are a class of
easily accessible C-alkynyl imine precursors in asymmetric
catalysis,7 would be viable, providing a general and
complementary method to access enantioenriched β-keto
propargylamines (Scheme 1b). Herein, we report our
preliminary findings on this subject.
Received: September 7, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03181
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
We commenced the study of the asymmetric synthesis of β-
keto propargylamine 4a using C-alkynyl N-Boc N,O-acetal 1a
and α-arylenamide 2a as the model substrates (Table 1). Initial
However, further reducing the loading of 2a to 1 equiv resulted
in the diminishment of product yield (entry 19).
The asymmetric reaction of N,O-acetals with enamides
proved to be general (Scheme 2) under the optimized
a
Table 1. Catalyst Screening and Reaction Optimization
Scheme 2. Substrate Scope of C-Alkynyl N-Boc N,O-
Acetals*
b
c
entry catalyst (mol %) 2a (equiv)
solvent
yield (%) ee (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
(S)-3a (10)
(S)-3b (10)
(S)-3c (10)
(S)-3d (10)
(S)-3e (10)
(S)-3f (10)
(S)-3g (10)
(S)-3f (10)
(S)-3f (10)
(S)-3f (10)
(S)-3f (10)
(S)-3f (10)
(S)-3f (10)
(S)-3f (10)
(S)-3f (10)
(S)-3f (10)
(S)-3f (5)
2
2
2
2
2
2
2
2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
80
70
72
68
69
83
75
50
86
85
82
80
50
70
83
84
86
88
75
81
0
58
30
55
86
49
85
88
89
55
84
80
51
91
90
92
90
88
d
e
2
e
e
e
e
e
e
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.0
CCl4
Et2O
MeCN
toluene
toluene
toluene
toluene
toluene
ef
,
e
e
e
(S)-3f (1)
(S)-3f (5)
a
Reaction conditions: 1a (0.2 mmol), 2a (0.2/0.3/0.4 mmol), chiral
phosphoric acid (1−10 mol %), solvent (2 mL), and additive, rt, 12 h.
b
c
Isolated yield. Enantiomeric excess (ee) was determined by chiral
d
e
HPLC analysis. 50 mg of 4 Å molecular sieves was added. 50 mg of
Na2SO4 was added. Reaction was conducted at 0 °C.
f
*
Reaction conditions: 1 (0.2 mmol), 2a (0.3 mmol), CPA (S)-3f (5
a
mol %), Na2SO4 (50 mg), toluene (2 mL), rt, 12 h. Based on 1.0
mmol of 1a. The reaction was conducted at 0 °C.
b
screening of organocatalysts (3a−3g, entries 1−7) indicated
that BINOL-based chiral phosphoric acid (CPA) (S)-3f was
the optimal catalyst to facilitate the reaction of 2a (2 equiv)
with 1a (1 equiv) in CH2Cl2 solvent at ambient conditions,
affording the desired product 4a in 83% yield and in 86%
enantiomeric excess (ee, entry 6). In addition, Na2SO4 was
found to be the superior additive compared to 4 Å molecular
sieves, further promoting the yield and ee to 86% and 88%,
respectively (entries 8 and 9). In the presence of Na2SO4, the
loading of 2a could be reduced to 1.5 equiv without
diminishment of yield and erosion of ee (entry 10). Based
on this improved protocol, we subsequently screened various
solvents (entries 11−15). The use of toluene as nonpolar
solvent could enhance the enantioselectivity to 91% ee (entry
15). In order to further improve the enantioselectivity, the
reaction temperature and catalyst loading were optimized
(entries 16−18). By reducing the loading of (S)-3f to 5 mol %,
4a was obtained in 86% yield and in 92% ee (entry 17).
conditions (Table 1, entry 17). A wide range of β-keto 3-
arylpropargyl amides (4a−4n) could be synthesized in high to
excellent yields (78−95%) with high enantioselectivities (89−
95% ee). Electron-neutral (4a), electron-rich (4b−4g), and
electron-deficient aryl groups (4h−4n) were all compatible in
the N,O-acetal reaction partners. Among these substrates,
functional groups such as trifluoromethoxy (4h), trifluor-
omethyl (4i), fluoro (4j−4l), and chloro groups (4m, 4n)
were tolerated as well. Notably, the protocol allowed for the
reactions with various para-, meta-, and ortho-substituted
arylpropargylamines to afford the products in similar yields and
ee. In addition, N,O-acetals bearing naphthyl (4o) and thienyl
groups (4p) were also suitable electrophiles to afford the
corresponding products in equally high yields with high ee
values. On the other hand, 3-butyl- (4q) and 3-cyclo-
hexylpropargylamines (4r) were formed in lower ee (70−
B
DOI: 10.1021/acs.orglett.9b03181
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
82%) despite the high product yields (82%). Large-scale
reaction based on 1 mmol of N,O-acetal afforded the product
4a without diminishment in yield and ee, suggesting that the
reaction was scalable. The product 4n could be isolated as a
crystalline compound, and its structure was further charac-
terized by X-ray crystallographic analysis. The absolute
configuration of the stereogenic carbon center formed in the
reaction was assigned as S-stereochemistry.
Scheme 4. Synthetic Transformations of Products
The protocol was also applicable to the chiral β-keto
propargylamine synthesis with various enamides (Scheme 3).
a
Scheme 3. Substrate Scope of Enamides
a
Reaction conditions: 1a (0.2 mmol), 2 (0.3 mmol), CPA (S)-3f (5
mol %), Na2SO4 (50 mg), toluene (2 mL), rt, 12 h.
A myriad of electron-rich (5a−5d) and electron-deficient α-
arylenamides (5e−5o) could be utilized as carbon nucleo-
philes, delivering the desired products in good to excellent
yields (65−98%) with high enantioselectivities (86−91%).
Remarkably, a series of functional groups, including iodo (5e),
bromo (5f), chloro (5g, 5h), fluoro (5i−5k), trifluoromethyl
(5l−5n), and nitro groups (5o), were all tolerated in the
enamide substrates. Furthermore, propargylamines containing
3,4-dichlorophenyl- (5p), naphthyl- (5q), and thienyl-sub-
stituted ketone moieties (5r) could be accessed under this
protocol. In addition, propargylamine-bearing cyclohexyl-
substituted ketone moieties (5s) were also synthesized in
41% yield and in 78% ee.
To demonstrate the synthetic utility of the chiral β-keto
propargylamine products, several transformations were con-
ducted (Scheme 4). β-Keto propargylamine 4a could be
selectively reduced by NaBH4 to generate the β-hydroxy
propargylamines 6a and 6a′ in 1:1 diastereomeric ratio. On the
other hand, the alkynyl moiety of 4a could be partially reduced
to alkenyl group (6b) or fully reduced to alkyl group (6c),
respectively, via different Pd-catalyzed hydrogenation pro-
cesses. Likewise, β-keto propargylamine 5d was hydrogenated
to deliver the β-amino ketone 6d, which could be further
converted to the corresponding β-amino ester 6e under the
Baeyer−Villiger oxidation conditions. Furthermore, the Boc
group of 4a can be removed under acidic medium to form the
primary β-keto propargylamine with a free NH2 group in situ,
which could further react with benzoyl chloride under basic
conditions to afford the corresponding β-keto propargyl amide
6f. Importantly, all chemical transformations proceeded
smoothly without the loss of enantioselectivity.
To gain mechanism insights of the asymmetric reaction
between N,O-acetals and enamides, several control experi-
ments were carried out (Scheme 5). By employing N-methyl
enamide in place of enamide 2a as nucleophile, no reaction
occurred to give the β-keto propargylamine 4i (Scheme 5a),
suggesting that the N−H group of enamide substrate is
necessary for the CPA-assisted activation of reaction
substrates.10 Moreover, the reaction did not proceed when
acetophenone was employed instead of enamide 2a (Scheme
5b), indicating that prior hydrolysis of enamide to
C
DOI: 10.1021/acs.orglett.9b03181
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
single stereogenic centers in high yields (up to 98%) with high
enantioselectivities (up to 95% ee). A wide range of readily
available C-alkynyl N-Boc N,O acetals and enamides can be
utilized as reaction substrates. The derivatizations of propargyl-
amine products are accessible via various transformations. An
aza-ene-type reaction mechanism is proposed, involving the
cooperative activation of both C-alkynyl imine and enamide by
chiral phosphoric acid via the hydrogen-bonding interaction.
Scheme 5. Control Experiments for Mechanistic Elucidation
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03181.
acetophenone as nucleophilic substrate is not involved for
subsequent product formation.
On the basis of the control experiments as well as the related
CPA-catalyzed reactions,7,10 a plausible mechanism was
proposed (Scheme 6). Initially, CPA catalyzes the elimination
Experimental details and spectral data of all the new
compounds and HPLC analytical results (PDF)
Accession Codes
CCDC 1948170−1948171 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Scheme 6. Proposed Mechanism and Transition-State
Model
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: majun_an68@tju.edu.cn.
*E-mail: zhiwei.zhang@tju.edu.cn.
ORCID
Shen Li: 0000-0002-8376-5329
Chi Wai Cheung: 0000-0003-4415-0767
Jun-An Ma: 0000-0002-3902-6799
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(No. 21532008, 21772142, 21901181, and 21971186) and
Tianjin University for financial support.
of ethanol from N,O-acetal 1 to form the C-alkynyl imine
intermediate.7a,b Na2SO4 additive likely behaves as a scavenger
of ethanol to promote its elimination from 1. The OH group of
CPA forms hydrogen bond with the nitrogen atom of C-
alkynyl imine to form species A, enhancing the electrophilicity
of imine group. Meanwhile, the nitrogen atom of enamide 2
forms hydrogen bond with the PO bond of CPA to form
species B, enhancing the nucleophilicity of β-carbon of 2. At
this point, enamide reacts with C-alkynyl imine via an aza-ene-
like reaction pathway,10 forming the chiral β-iminyl propargyl-
amine C and regenerating the CPA for subsequent catalytic
cycle. Finally, the hydrolysis of C upon water addition in the
reaction workup provides the chiral β-keto propargylamine
products 4 or 5. Notably, the bifunctional nature of CPA
allows the simultaneous activation of both C-alkynyl imine and
enamide via the intermolecular hydrogen bondings.7b The
chiral environment of the BINOL backbone facilitates the
preferential nucleophilic attack of enamide to imine electro-
phile from the Si face, resulting in the formation of
propargylamine product with (S)-configuration.
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D
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