Conjugate Addition-Enantioselective Protonation of N-Aryl Glycines to α-Branched 2-Vinylazaarenes via Cooperative Photoredox and Asymmetric Catalysis

Article abstract of DOI:10.1021/jacs.8b01575

An enantioselective protonation strategy has been successfully applied to the synthesis of chiral α-tertiary azaarenes. With a dual catalytic system involving a chiral phosphoric acid and a dicyanopyrazine-derived chromophore (DPZ) photosensitizer that is mediated by visible light, a variety of α-branched 2-vinylpyridines and 2-vinylquinolines with N-aryl glycines underwent a redox-neutral, radical conjugate addition-protonation process and provided valuable chiral 3-(2-pyridine/quinoline)-3-substituted amines in high yields with good to excellent enantioselectivities (up to >99% ee). An application of this methodology to a two-step synthesis of the enantiomerically pure medicinal compound pheniramine (Avil) is also presented.

Full text of DOI:10.1021/jacs.8b01575

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Conjugate Addition-Enantioselective Protonation of
N-Aryl Glycines to #-Branched 2-Vinylazaarenes via
Cooperative Photoredox and Asymmetric Catalysis
Yanli Yin, Yating Dai, Hongshao Jia, Jiangtao Li, Liwei Bu, Baokun Qiao, Xiaowei Zhao, and Zhiyong Jiang
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 10 Apr 2018
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Journal of the American Chemical Society
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Conjugate Addition−Enantioselective Protonation of N-Aryl Glycines
to α-Branched 2-Vinylazaarenes via Cooperative Photoredox and
Asymmetric Catalysis
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†
,‡,¶
†,¶
†,¶
†
†
†
Yanli Yin,
Zhao, and Zhiyong Jiang*
Yating Dai, ,†Hongshao Jia, Jiangtao Li, Liwei Bu, Baokun Qiao, Xiaowei
†
†
Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng, Henan, P. R. China
4
‡
75004
College of Bioengineering, Henan University of Technology, Zhengzhou, Henan, P. R. of China 450001
KEYWORDS. Asymmetric Photoredox Catalysis, Hydrogen-Bonding Catalysis, Conjugate Addition−Protonation,
Radical, 2-Vinylazaarenes
ABSTRACT: An enantioselective protonation strategy has been successfully applied to the synthesis of chiral α-tertiary
azaarenes. With a dual catalytic system involving a chiral phosphoric acid and a dicyanopyrazine-derived chromophore
(
DPZ) photosensitizer that is mediated by visible light, a variety of α-branched 2-vinylpyridines and 2-vinylquinolines
with N-aryl glycines underwent a redox-neutral, radical conjugate addition−protonation process and provided valuable
chiral 3-(2-pyridine/quinoline)-3-substituted amines in high yields with good to excellent enantioselectivities (up to >99%
ee). An application of this methodology to a two-step synthesis of the enantiomerically pure medicinal compound
pheniramine (Avil®) is also presented.
INTRODUCTION
Scheme 1. Outline of This Work.
Enantioselective protonation is a bio-inspired method
widely used to synthesize valuable carbonyl compounds
1
with various chiral α-tertiary carbon scaffolds. Notably,
azaarenes bearing embedded C=N imine fragments such
as pyridines and quinolines are electron deficient. In the
past few years, the direct exploitation of such azaarenes as
the analogs of carbonyls to trigger the reaction, thus fur-
nishing the enantioselective functionalization of prochiral
azaarenes, has become an attractive method due to its
2-8
atom and step economy. In this regard, a synthetic
methodology involving an enantioselective protonation
would provide an expedient and complementary ap-
3
this is probably due to the unfavorable formation of the
tetra-substituted enamine intermediates via a transient
dearomatization step. This dilemma has inspired the ex-
ploration of visible-light-driven photoredox catalysis,
which often permits otherwise inaccessible modes of mo-
proach to accessing significantly enantioenriched α-
tertiary azaarenes, which are ubiquitous in pharmaceuti-
9
cals, agrochemicals and natural products, thus leveraging
the broad applicability of this modular strategy.
10
lecular transformations. As a result, in recent years, the
Among the established enantioselective protonation
protocols, conjugate addition−protonation to α-branched
carbonyl-activated terminal alkenes can be used to as-
semble a range of crucial molecular motifs at the β-
11a
11b
11c
11d
groups of Rueping, Ngai, Ravelli and Ley have de-
veloped racemic conjugate addition reactions of distinct
radical species to α-branched vinylpyridines by exploiting
this powerful synthetic technique. Radical-based ap-
proaches of this type feature high reactivity, and in most
cases, an extra catalyst is not required for promoting the
transformation. This catalyst-free reactivity is a substan-
tial problem for the development of an enantioselective
version of the reaction since it means a competitive achi-
ral background reaction that would deteriorate the enan-
1h-m
position of carbonyls in a straightforward manner.
Accordingly, the platform of using α-branched vinyl-
azaarenes as electrophiles would be a viable and produc-
tive strategy. However, the ground-state ionic reaction
approach is likely not tolerant of terminal alkenes given
that no examples of such substrates have been reported;
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Page 2 of 7
tioselectivity would be active. More importantly, control-
ling the stereochemistry during the construction of chiral
6,6’-positions of SPINOL have a substantial influence on
the enantioselectivity of the reaction; as an example, cata-
lysts C2 and C3 afforded 3a in 56% ee and 72% ee, respec-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
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2
2
2
2
2
2
2
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3
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4
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4
4
4
5
5
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5
5
5
6
azaarenes via asymmetric photoredox catalysis still con-
12
stitutes a formidable challenge.
tively (entries 2−3). In the absence of LiPF , the ee of 3a
6
fell to 88% (entry 4). Other plausible photoredox catalysts,
including rose bengal and [Ru(bpy) ]Cl , were tested (en-
3 2
Recently, we reported visible-light-driven, organocata-
lytic enantioselective photoreductions of 1,2-diketones
1
3a
tries 5−6), but the reaction became very sluggish, and
trace or no 3a was obtained probably due to the very low
catalyst loading. Interestingly, the reaction conducted
under the standard conditions but in the absence of cata-
lyst C1 did not produce 3a (entry 7). The control experi-
ments confirmed that DPZ, visible light and the oxygen-
free environment are essential to the transformation (en-
tries 8−10).
and α-keto ketimines. The hydrogen-bonding interac-
tion between the chiral catalysts and the ketyl intermedi-
ates effectively overcame the remarkable background re-
action and allowed precise kinetic control of the delivery
of a proton. Although the substantially lower electronega-
tivity of the neutral N atom of the azaarene over the
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
14
strongly basic oxygen anion of the ketyl radical should
12
considerably deteriorate the enantiocontrol effect, we
were inspired to explore this highly desirable but elusive
task via H-bonding catalysis. In particular, we sought to
solve asymmetric conjugate addition of α-amino radi-
a
Table 1. Optimization of Reaction Conditions
1
5e,g,j
cals
to α-branched 2-vinylpyridines and 2-
vinylquinolines since the produced chiral 3-(2-
pyridine/quinoline)-3-substituted amines are featured in
9
b-e
many drugs and bioactive molecules (Figure 1).
Asym-
metric hydrogenations of 3-aryl-3-(2-pyridyl)allylamines
catalyzed by chiral transition-metal complexes is the only
b
c
entry
Variation from standard conditions
none
yield (%)
ee (%)
3
a-b
reported method of approaching the pyridine entities.
1
2,
3
4
5
6
7
8
9
90
86
75
34
<5
0
94
However, this methods suffers from unsatisfactory enan-
tioselectivity, and the low yield stemmed from the una-
voidable hydrogenolysis of the C−N bond. Here, we report
the development of a redox-neutral, enantioselective rad-
ical conjugate addition−protonation of N-aryl glycines to
C2 instead of C1
C3 instead of C1
56
72
without LiPF
6
88
α-branched 2-vinylpyridines and 2-vinylquinolines under
14-15
Rose Bengal instead of DPZ
87
the cooperative catalysis
of a dicyanopyrazine-derived
13
chromophore (DPZ) photosensitizer
and
a
1,1’-
[Ru(bpy)
no C1
3
]Cl
2
instead of DPZ
N.A.
N.A.
N.A.
N.A.
N.A.
spirobiindane-7,7’-diol (SPINOL)-based chiral phosphoric
acid (CPA, Figure 1). The desired chiral amine entities
were prepared in high yields with good to excellent enan-
tioselectivities.
d
0
d
no DPZ
no light
0
d
0
RESULTS AND DISCUSSION
e
10
under air
0
α-Amino acids are non-fossil fuel-based, environmentally
benign carbon sources and have therefore been pursued
a
Reaction conditions: 1a (0.05 mmol), 2a (0.06 mmol),
16
as starting substrates for organic synthesis. Many re-
search groups, with the MacMillan group as a representa-
b
c
solvent (2.0 mL). Yield of isolated product. Determined by
HPLC analysis on a chiral stationary phase. No reaction was
observed. 1a was consumed, but 3a was not obtained.
d
1
5h,17
tive,
have reported that N-protected α-amino acids
e
can undergo visible-light-driven, single-electron oxidative
decarboxylation to efficiently generate α-amino radicals.
As such, we began our investigation by exploring the
model reaction between N-phenyl glycine (1a) and 2-(1-
phenylvinyl)pyridine (2a) with our developed metal-
With the optimal reaction conditions in hand, the
scope of this asymmetric radical conjugate addition pro-
tocol was examined (Table 2). From the reactions of 2a
with N-aryl glycines 1 that feature electron-withdrawing
or electron-donating substituents on the aryl ring, ad-
ducts 3a-j were obtained in 75 to 88% yields with 90 to 95%
ees. A methoxy substituent at the 4-position of the sub-
strate (3h) made the reaction sluggish and lead to a de-
creased yield (35%, footnote c), but the higher tempera-
ture (0 °C) or the introduction of an additional electron-
withdrawing group such as F (3i) and CF3 (3j) at the 3-
position could efficiently mitigate this drawback. With
respect to the pyridine-based terminal alkene component,
the reaction tolerated a wide range of α-aryl and 2-
pyridine substrates regardless of their electronic proper-
ties and substitution patterns, and corresponding prod-
10e
free DPZ as the photoredox catalyst (Table 1). The initial
study showed that the transformation furnished racemic
product 3a in 87% yield after 12 hours when only using 0.5
mol% DPZ at 25 °C, revealing a high reactivity of this rad-
ical-based transformation (See entry 1, Table S1 in the
Supporting Information [SI]). Nevertheless, we explored a
range of chiral H-bonding catalysts and reaction parame-
ters (See Table S1 in SI). To our delight, the reaction per-
formed in THF at −35 °C for 72 hours in the presence of
18
0
.2 mol% DPZ, 15 mol% chiral SPINOL-CPA (C1) and 40
mol% LiPF as an additive afforded chiral product 3a in
90% yield and 94% ee (entry 1). The substituents at the
6
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Journal of the American Chemical Society
ucts 3k-3zf were generated in 72 to 97% yields and 88 to
5% ees. The excellent chemical yields and enantioselec-
slightly decreased yield compared to the pyridine-based
1
2
3
4
5
6
7
8
9
9
products is due to a few unknown side products observed
in this reaction system. Notably, the reaction proceeded
very slowly for α-alkyl 2-vinylquinolines.
tivities achieved with fused aromatic (3x-y) and heteroar-
omatic (3za-zb) rings at the α-position of the alkene un-
derscore the generality of this catalytic system. The abso-
lute configuration of 3u was assigned to be R based on
Table
3.
Enantioselective
Conjugate
Addi-
tion−Protonation of N-Aryl Glycines to α-Branched 2-
19
single-crystal X-ray diffraction analysis. We also tested
an α-methyl-substituted terminal alkene (3zg), and mod-
erate yield and enantioselectivity were observed.
a
Vinylquinolines
Table
2.
Enantioselective
Conjugate
Addi-
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
tion−Protonation of N-Aryl Glycines to α-Branched 2-
Vinylpyridines
a
a
Reaction conditions: 1 (0.1 mmol), 4 (0.12 mmol), DPZ
(
−
0.2 mol%), C2 (15 mol%), LiPF
35 C. Yield of isolated product. Ee was determined by
HPLC analysis on a chiral stationary phase. T = −20 C. 20
mol% of C2 was used.
6
(40 mol%), THF (4.0 mL),
o
b
o
c
The products derived from these two chemical trans-
formations are not only potentially bioactive but also ex-
cellent precursors to many drugs and bioactive com-
pounds (Scheme 1). For example, adduct 3h could be rap-
idly transformed to an enantiomerically enriched antihis-
tamine drug i.e., (R)-pheniramine. As shown in Scheme 2,
treatment of 3h with N,N’,N”-trichloroisocyanuric acid
TCAA) cleaved the N-protecting group. The resulting
amine (6) was subsequently converted to pheniramine in
6% yield over two steps and without erosion of the ee via
reductive amination with formaldehyde and NaBH CN.
(
7
3
The synthetic procedure was also effective to the trans-
formation of 3i to (R)-pheniramine.
a
19
Reaction conditions: 1 (0.1 mmol), 2 (0.12 mmol), DPZ
(
0.2 mol%), C1 (15 mol%), LiPF
6
(40 mol%), THF (4.0 mL),
35 C. Yield of isolated product. Ee was determined by
c
Scheme 2. Preparation of Enantiomerically Pure
Pheniramine.
o
−
b
o
HPLC analysis on a chiral stationary phase. T = 0 C.
o
d
When T = −35 C, yield = 35%, ee = 94%. 20 mol% of C1 was
used.
The success inspired us to evaluate this method in the
construction of important chiral 3-(2-quinoline)-3-
9c-d
substituted amines
with α-branched 2-vinylquinolines
4
as electrophiles. As shown in Table 3, under the estab-
lished reaction conditions but using C2 as the catalyst, all
reactions completed within 60−72 hours, providing the
desired products 5a-l with diverse substituents on the α-
aromatic ring and 5m from N-(3-F-4-methoxy)-phenyl
glycine in 68 to 85% yields and 91% to >99% ee. The
1
1,17a-b,g
Based on the previous reports
ture, the conjugate addition of α-amino radicals derived
from N-aryl glycines to terminal alkenes is feasible. Nota-
and product struc-
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Journal of the American Chemical Society
Page 4 of 7
bly, the subsequently yielded α-carbon radical variants of
azaarenes could undergo two possible C−H bond forming
A plausible mechanism was proposed based on this ev-
idence (Figure 1B). *DPZ first undergoes a single-electron
transfer (SET) reductive quenching by the N atom of 1,
which was verified by our Stern-Volmer experiments and
analysis of the electrochemical properties (carboxylate ion
of 1a, Ep = +0.52 [for the N moiety] and +1.09 V [for the
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
pathways, namely, protonation after catalyst turnover
11d
enables the second single-electron reduction and direct
11a-c
hydrogen atom transfer (HAT)
with another N-aryl
20
glycine molecule via radical chain propagation. We thus
performed control experiments to elucidate this crucial
stereocenter-forming process (Figure 1A). We first at-
tempted the reaction of N-Boc-protected glycine 7 with
alkene 2a in the presence of 2 mol% DPZ and 20 mol%
−
19
COO moiety] vs Ag/AgCl in CH
3
CN). After a cascade
1
6b
reaction process involving a deprotonation, HAT and
decarboxylation, generated α-amino radical 9 undergoes
conjugate addition to CPA (C1)-activated alkene 2 to pro-
duce intermediate radical 10. The presence of this H-
bonding interaction is clearly demonstrated by the results
shown in entry 7, Table 1 and that rac-3a with a poor 12%
yield was obtained after 72% hours when with C1-derived
chiral lithium phosphate C29 as the catalyst (See entry 63,
Cs
2 3
CO in THF at 25 °C. As expected, no reaction was ob-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
t •−
served as photo-induced DPZ (*DPZ, E (S*/S ) = +0.91 V
vs a saturated calomel electrode (SCE) in CH
13
2 2
Cl ) cannot
oxidize carboxylate via a single-electron process (carbox-
red
17c-f
ylate ions, E1/2 ≈ +1.10 vs SCE in CH CN).
The photore-
oxidizes these
ions due to its strongly oxidizing excited state
3
2
2
dox catalyst Ir[dF(CF
3
)ppy]
2
(dtbbpy)PF
6
Table S1). The strength of this mutual effect would be
further enhanced by using LiPF as an additive to increase
6
1
7c-f
(
Ir(III)*/Ir(II) = +1.21 vs SCE in CH
3
CN).
Therefore, the
the acidity of C1, thus improving yield and enantioselec-
tivity (entries 1 and 4, Table 1). Following the single-
electron reduction, the pivotal H-bonding induction from
C1 provides a stereocontrol for the protonation of the
prochiral carbanion intermediate, leading to chiral ad-
reaction was tested with this Ir catalyst, and product 8
was obtained in 95% yield within 12 hours. The results
demonstrate the viability and rather high reactivity of the
N-Boc-based α-amino radical in this conjugate addition. A
mixture of 1a (0.5 equiv), 7 (10 equiv), 2a (1.0 equiv) and
DPZ (2 mol%) in THF at 25 °C was then stirred for 24
hours. If a HAT mechanism is operative, it may be possi-
ble to detect adduct 8; however, only rac-3a was obtained
19
ducts 3 in high enantioselectivities. Such an embedded
proton would come from the free proton in the reaction
system such as the secondary amine and carboxylic acid
of N-aryl glycines 1 and C1 on the basis of the deuterium
19
(93% yield). This result was consistent with the reaction
labelling experiments.
performed under the established asymmetric reaction
CONCLUSIONS
21
conditions. Therefore, the protonation is an important
In summary, we have developed redox-neutral, enanti-
oselective, radical conjugate addition−protonation reac-
tions of α-aryl glycines to α-branched 2-vinylpyridines
and 2-vinylquinolines via visible-light-driven cooperative
photoredox and chiral H-bonding catalysis. The current
organocatalytic method provides access to a range of
pharmaceutically and biologically important enantioen-
riched 3-(2-pyridine/quinoline)-3-substituted amines in
high yields and ees. This work demonstrates a new appli-
cation of an enantioselective protonation and opens an
unexplored avenue for the synthesis of chiral α-tertiary
azaarenes. Furthermore, this is the first highly enantiose-
lective synthesis of chiral azaarenes via the direct exploi-
tation of azaarenes to trigger transformations in asym-
metric photoredox catalysis. We anticipate that this result
will inspire the pursuit of asymmetric protonation reac-
tions and other valuable transformations for the synthesis
of useful chiral azaarenes through this versatile, radical-
based dual catalysis platform.
step in the construction of the tertiary carbon center.
ASSOCIATED CONTENT
Supporting Information Available: [General information,
general procedures, mechanistic studies, characterization
data, determination of the absolute configurations, plausible
transition states, and HPLC and NMR spectra.] This material
is available free of charge via the Internet at
http://pubs.acs.org.
Figure 1. Evidence for protonation and the proposed
mechanism.
AUTHOR INFORMATION
Corresponding Author
*chmjzy@henu.edu.cn
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Author Contributions
Am. Chem. Soc. 2011, 133, 12439. (f) Li, T.; Zhu, J.; Wu, D.; Li, X.;
1
2
3
4
5
6
7
8
9
¶
Wang, S.; Li, H.; Li, J.; Wang, W. Chem. Eur. J. 2013, 19, 9147. (g)
Roy, I. D.; Burns, A. R.; Pattison, G.; Michel, B.; Parker, A. J.; Lam,
H. W. Chem. Commun. 2014, 50, 2865. (h) Wang, Y.-Y.; Kanoma-
ta, K.; Korenaga, T.; Terada, M. Angew. Chem., Int. Ed. 2016, 55,
These authors contributed equally.
Notes
The authors declare no competing financial interests.
9
27.
7) For an example of building γ-tertiary azaarenes, see: Wang,
(
ACKNOWLEDGMENT
S.; Li, X.; Liu, H.; Xu, L.; Zhuang, J.; Li, J.; Li, H.; Wang, W. J. Am.
Grants from the NSFC (21672052), Provincial Innovation
Scientists and Technicians Troop Construction Projects and
Henan Provincial Science and Technology Department
Natural Science Project (162300410002, 162102210193) are
gratefully acknowledged. We also appreciate Miss Xinyi Ye
and Prof. Choon-Hong Tan (NTU) for their generous help in
the analysis of the HRMS data, Dr. Yuan Zhao (HENU) for
the theoretical calculation and Mr. Yangyang Shen (ICIQ) for
constructive discussions.
Chem. Soc. 2015, 137, 2303.
(8) For an example of building δ-quaternary azaarenes, see:
Bai, X.; Zeng, G.; Shao, T.; Jiang, Z. Angew. Chem., Int. Ed. 2017,
5
6, 3684.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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4
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4
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