Enantioselective Aerobic Oxidative C(sp3)-H Olefination of Amines via Cooperative Photoredox and Asymmetric Catalysis

Article abstract of DOI:10.1021/acscatal.6b00846

A cooperative photoredox and asymmetric catalysis for the enantioselective aerobic oxidative C(sp³)-H olefination of tetrahydro-β-carbolines (THCs) is reported. This method, which is also effective for tetrahydroisoquinolines (THIQs), features

Full text of DOI:10.1021/acscatal.6b00846

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Letter
Enantioselective Aerobic Oxidative C(sp3)-H Olefination of
Amines via Cooperative Photoredox and Asymmetric Catalysis
Guo Wei, Chenhao Zhang, Filip Bures, Xinyi Ye, Choon-Hong Tan, and Zhiyong Jiang
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b00846 • Publication Date (Web): 09 May 2016
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Enantioselective Aerobic Oxidative C(sp3)−H
Olefination of Amines via Cooperative Photoredox
and Asymmetric Catalysis
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Guo Wei,a,‡ Chenhao Zhang,a,‡ Filip Bureš,b Xinyi Ye,c ChoonꢀHong Tan,c and Zhiyong Jiang*a
a.Key Laboratory of Natural Medicine and Immuno-Engineering of Henan Province, Henan University, Kaifeng, Henan, People’s Republic of China 475004
b.Institute of Organic Chemistry and Technology, University of Pardubice, Faculty of Chemical Technology, Studentská 573, Pardubice, Czech Republic, 53210
c. Division of Chemistry and Biological Chemistry, Nanyang Technological University, 21 Nanyang Link, Singapore 637371
ABSTRACT: A cooperative photoredox and asymmetric catalysis for the enantioselective
aerobic oxidative C(sp3)−H olefination of tetrahydroꢀβꢀcarbolines (THCs) is reported. This
method, which is also effective for tetrahydroisoquinolines (THIQs), features a tripleꢀcatalyst
strategy, involving a dicyanopyrazineꢀderived chromophore (DPZ) as the metalꢀfree photoredox
catalyst, a chiral Lewis base catalyst and an inorganic salt coꢀcatalyst. The current protocol
provides straightforward access to a series of valuable αꢀsubstituted THCs and THIQs in high
yields with excellent regioꢀ and enantioselectivities (up to 95% ee).
KEYWORDS: asymmetric cooperative catalysis, photoredox catalysis, organocatalysis,
aerobic oxidative olefination, βꢀcarbolines
Asymmetric cooperative catalysis has long been acknowledged as a powerful tool for
constructing valuable and complex chiral compounds.1 Along with the rapid growth of the highly
sustainable photochemistry,2 in recent years, cooperative photoredox and asymmetric catalysis
has attracted increasing attention of chemists.3ꢀ5 A number of dual catalytic systems through
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combining photoredox catalysts with chiral catalysts have been impressively established.3ꢀ5 We
recently reported a dicyanopyrazineꢀderived chromophore (DPZ) as a new type of metalꢀfree
photoredox catalyst that facilitated a series of achiral transformations at low catalyst loadings.6aꢀb
The prominent performance of DPZ promoted us to assess its potential in the everꢀgrowing
cooperative photoredox and asymmetric catalysis. To our knowledge, rare variants using organic
photoredox catalysts have been described to date.4d
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The nucleophilic addition to iminium intermediates, which are in situ generated by photoredox
catalytic oxidation of a C(sp3)−H bond adjacent to the nitrogen atom of amines, is a
straightforward approach to provide αꢀfunctionalized Nꢀheterocyclic adducts.2d,2j,2m,7 Contributed
by the Rovis4e and Li4l groups, this strategy has also currently been merged with asymmetric
catalysis in a cooperative manner. While these elegant works demonstrated that the cooperative
catalysis involving photoreodox oxidative generation of iminium intermediates and the
simultaneous enantiocontrol is viable, they still suffer from a limited substrate scope given that
only THIQs have been chosen as the substrates. Tetrahydroꢀβꢀcarbolines (THCs) with a C1ꢀ
substituted stereogenic center are widely found as key structural motifs in numerous biologically
important molecules.8 However, there have been no reports on a photoredox catalytic C−H
functionalization of THCs, probably due to the elusive regioselectivity between C1(sp3)−H bond
and C4(sp3)−H bond in the oxidative process.9 On the other hand, the current asymmetric
reactions4e,4l are environmentally unfriendly, using excess oxidants such as mꢀDNB or (BzO)2.
When the more economical and green oxidant−molecular oxygen was used, poor compatibilities
of these cooperative catalytic systems were encountered in view of the unsatisfactory yields.
With respect to the synthesis of chiral C1ꢀfunctionalized THCs, huge efforts have been made
in several elegant catalytic asymmetric tactics, including Pictet−Spengler reaction of
tryptamines10 and transformations11 of the preformed stable THCꢀimines. Liu and coꢀworkers12
established the possibility of generating iminium intermediates of THCs by regioselective
C1(sp3)−H oxidation using stoichiometric DDQ as the oxidant, wherein a highly enantioselective
catalytic oxidative alkenylation of Nꢀcarbamoyl THCs with boronates was addressed. However,
the oxidative coupling reaction between THCs and activated alkenes has never been
achieved.13,14 Herein, we report a highly enantioselective aerobic oxidative C1(sp3)−H
olefination of THCs through developing a novel cooperative catalytic system with DPZ as the
photocatalyst.
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Our study was initiated by exploring the model reaction between Nꢀphenylꢀ9ꢀbenzyl THC (1a)
and acrolein 2a, utilizing 0.05 mol% of DPZ in CH2Cl2 under irradiation from 3 W blue LEDs (λ
= 450−455 nm) (Table 1).15 After the evaluation of distinct chiral Lewis bases, βꢀICD was
proved to be the best, affording 3a with 19% ee (entry 1). 4Å Molecular sieves (MS) were tested
as additives to prevent the nucleophilic addition of water; although the conversion of 1a was
sluggish, the chemoselectivity could be improved, affording 3a in 56% yield with 53% ee after
48 hours (entry 2). When salts with weak coordinating anions16 were used as coꢀcatalysts, the ee
value of 3a was effectively increased (entries 3−6). With NaBArF as salt additive, further
improved chemoꢀ and enantioselectivity were observed at lower temperature (entry 7). When the
amount of βꢀICD was increased to 20 mol%, the ee value of 3a was enhanced to 87% (entry 8).
While the lithium salt of βꢀICD (βꢀICDꢀLi) displayed similar efficiency as βꢀICD (entry 9), a
sharp decrease in enantioselectivity was observed when it was used in the absence of NaBArF
coꢀcatalyst (entry 10), indicating the crucial role of the coordinating anion (BArF−). Finally, 3a
was obtained with best results using guanidinium 4a as another additive (81% yield, 90% ee,
entry 11). When guanidinium 4b was used without adding additional NaBArF, the ee value
dropped to 70% (entry 12), thus implying the importance of metal cations (Na+ or Li+) for the
chiral induction. Noteworthy is that slightly decreased yield and enantioselectivity were observed
when in the absence of 4 Å MS (entry 13). Moreover, no reaction occurred when the reaction
was performed without irradiation (entry 14). When in the absence of DPZ, only trace amounts
of 3a was observed even after 72 hours, indicating the crucial participation of photocatalyst DPZ
in the oxidation process (entry 15).
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Table 1. Optimization of the Reaction Conditions.a
entry
conditions
yield (%)b
ee (%)c
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25 oC, 24 h
30
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84
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63
N.R.
15
19
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64
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83
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85
34
90
70
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N.A.
87
2
4 Å MS, 25 oC, 48 h
3
4 Å MS, LiBF4, 25 oC, 48 h
4 Å MS, NaPF6, 25 oC, 48 h
4 Å MS, NaBArF, 25 oC, 48 h
4 Å MS, LiBArF, 25 oC, 48 h
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4 Å MS, NaBArF, −10 oC, 48 h
4 Å MS, NaBArF, −10 oC, 48 h
4 Å MS, NaBArF, −10 oC, 48 h
4 Å MS, −10 oC, 48 h
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9d
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4 Å MS, NaBArF, 4a, −10 oC, 48 h
4 Å MS, 4b, −10 oC, 48 h
NaBArF, 4a, −10 oC, 48 h
4 Å MS, NaBArF, 4a, −10 oC, no light, 48 h
No DPZ, 4 Å MS, NaBArF, 4a, −10 oC, 72 h
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a
The reaction was performed on a 0.025 mmol scale. 4 Å MS (20 mg), NaBArF (20 mol%),
guanidinium 4a/4b (10 mol%). In entries 1−7, 10 mol% of βꢀICD was used; in entries 8−15, 20
b
c
mol% of βꢀICD was used. Yield of isolated product. Determined by HPLC on chiral
d
stationary phase. βꢀICDꢀLi instead of βꢀICD was used. βꢀICD = βꢀisocupreidine, MS =
molecular sieves, N.R. = no reaction, N.A. = not available.
With the newly developed DPZ/βꢀICD/NaBArF catalytic system, the scope of substrates for
the asymmetric aerobic oxidative C1(sp3)−H olefination of THCs with activated terminal alkenes
(2) was studied (Table 2). For the reaction with acrolein 2a, a series of THCs 1 having various
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substituents on the aromatic rings of 9ꢀNꢀbenzyls (1a-1i,) and 2ꢀNꢀaryls (1j-1s) as well as at C6ꢀ
positions (1t-1u) were examined. It was observed that all reactions were complete within 48
hours, and both electronꢀrich and ꢀdeficient THCs were well tolerated, thus affording the desired
products 3a-u in 69−85% yields and 88−95% ee. Acrylonitrile 2b has also been attempted in the
reaction, exhibiting unfortunately rather poor chemoselectivity in view of the failed delivery of
3v.
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Table 2. Investigation towards Tetrahydro-β-carbolines 1.
R
R
DPZ (0.05 mol%)
-ICD (20 mol%)
NaBArF (20 mol%)
Ar2
Ar2
N
N
+
N
N
EWG
4a (10 mol%), 4 Å MS
CH2Cl2, air, -10 oC
3 W blue LEDs, 48 h
EWG
Ar1
Ar1
EWG = CHO, 2a
EWG = CN, 2b
1
3
3a: Ar1 = Ph, 76% yield, 90% ee
Me
3b: Ar1 = 4-FPh, 80% yield, 90% ee
3c: Ar1 = 4-ClPh, 84% yield, 91% ee
3d: Ar1 = 3-FPh, 73% yield, 90% ee
3e: Ar1 = 4-MePh, 79% yield, 92% ee
3f: Ar1 = 3-MePh, 73% yield, 90% ee
3g: Ar1 = 4-tBuPh, 85% yield, 91% ee
3h: Ar1 = 1-naphthyl, 69% yield, 94% ee
3i: Ar1 = 2-naphthyl, 80% yield, 90% ee
N
Ph
CHO
N
Ph
N
N
CHO
MePh
4-
Ar1
3t: 76% yield, 90% ee
MeO
N
Ph
3j: Ar2 = 4-FPh, 71% yield, 95% eea
3k: Ar2 = 4-ClPh, 77% yield, 90% ee
3l: Ar2 = 4-MePh, 82% yield, 88% ee
3m: Ar2 = 3-MeFPh, 84% yield, 90% ee
3n: Ar2 = 4-tBuPh, 82% yield, 90% ee
3o: Ar2 = 4-Ph-Ph, 73% yield, 90% ee
3p: Ar2 = 3,5-Me2-Ph, 74% yield, 90% ee
3q: Ar2 = 4-MeOPh, 76% yield, 89% eea
3r: Ar2 = 3-MeOPh, 80% yield, 91% ee
3s: Ar2 = 2-naphthyl, 79% yield, 88% ee
N
CHO
4-MePh
Ar2
N
3u: 78% yield, 90% ee
N
CHO
4-MePh
N
Ph
N
CN
4-MePh
3v: N.D.
a The reaction was performed at −15 oC. N.D. = not determined.
To demonstrate the versatility of this cooperative catalytic strategy, we were next engaged in
the C−H functionalization of Nꢀaryl THIQs 5 (Table 3).14 Under slightly modified reaction
o
conditions (at −20 C and in the absence of guanidinium 4a), a broad array of THIQs with
various substituents on Nꢀaryls were first evaluated. The reactions often completed within 48
hours, affording the desired products 6a-h in 74−90% yields with 84−95% ee. THIQs with
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methoxy on the 6ꢀposition (5i) or on the 6, 7ꢀpositions (5j) also gave good yields and good to
excellent enantioselectivities (entries 9−10).
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Table 3. Investigation towards N-Aryl-tetrahydroisoquinolines 5.
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entry
1
5 (R, Ar)
yield (%)a
81
ee (%)b
94
6
5a (H, Ph)
6a
2
5b (H, 4ꢀFPh)
80
85
90
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80
82
74
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85
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84
82
90
6b
6c
6d
6e
6f
3
5c (H, 4ꢀClPh)
4
5d (H, 4ꢀMePh)
5e (H, 3ꢀMePh)
5f (H, 4ꢀtBuPh)
5g (H, 4ꢀMeOPh)
5h (H, 2ꢀMeOPh)
5i (6ꢀOMe, Ph)
5j (6,7ꢀ(MeO)2, Ph)
5
6
7
6g
6h
6i
8
9
10
6j
a Yield of isolated product. b Determined by HPLC on chiral stationary phase.
A plausible reaction pathway of our tripleꢀcatalysis oxidative olefination is described in Figure
1. It has been well established that tertiary amines (1/5) can be transformed to iminiums 7
through a photoredox catalytic C1(sp3)−H oxidation (see the photoredox catalytic cycle).7 The
asymmetric catalytic cycle includes the nucleophilc addition of βꢀICD as a Lewis base to
acrolein 2a generating the intermediate 8 and the Mannichꢀtype reaction of 7 with 8 affording
adducts 3 or 6. The inorganic salt NaBArF, which is known to have good affinities for
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carboxylate and carbonyl oxygens,16 is likely involved in activating carbonyl group of acrolein to
benefit the addition of βꢀICD, stabilizing iminiums 7, and bridging the nucleophilic intermediate
8 and iminiums 7 into the transition states 9 via multisite coordination. The forming
intermediates 10 could also be stabilized by NaBArF. The aforementioned coordination would
conceivably lower the activation energy of this transformation effectively, and thus increase the
reaction rate with improved chemoselectivity and amplified chiral induction by βꢀICD.
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N
N
SET
Ar
Ar
1/5
*DPZ
DPZ
Photoredox
Catalytic
Cycle
Visible light
DPZ
O2H
O2
NaBArF
O2
BArF
Ar
N
O
N
Na+
7
O
H
N
H
O
+Na
2a
O
H
8
9
NaBArF
Asymmetric Catalytic Cycle
O
N
O
N
H
O
N
H
Ar
N
N
N
+
N
Ar
O
O
+
O
Na
BArF
H
10
HO
O
H
Na
+
9
N
-ICD
3/6
Figure 1. Proposed Mechanism.
The synthetic value of this work was evaluated through performing a series of transformations
from the olefination products (Scheme 1). A THCꢀderived chiral alcohol 11 could be obtained
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from the reduction of 3e by LiAlH4 in 85% yield with 90% ee. Through a sequence of addition
of MeLi and DessꢀMartin oxidation, 3e was readily transformed to the chiral ketone 12 with
good yield and without compromising ee value. The THCs featuring a C1ꢀsubstituted oxaꢀ
containing fiveꢀmembered ring were found having potential bioactivity for the treatment of
severe acute respiratory syndrome (SARS).8e We were thus engaged in conducting a 1,3ꢀdipolar
cycloaddition between 3e and nitrile Nꢀoxide, generated in situ from 13; after 12 hours, the
desired product 14 with vicinal quaternary−tertiary chiral centers was obtained with a high
diastereoselectivity. The subsequent reduction of 14 by utilizing NaBH4 could conveniently
provide the alcohol 15, which was easily recrystallized to 98% enantiomeric excess. The
absolute configurations of the oxidative olefination products were assigned on the basis of Xꢀray
crystallographic analysis of a single crystal of 14.
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b) MeLi, THF
-78 oC to 0 oC
a) LiAlH4
N
N
N
Ph
OH
Ph
Ph
O
30 min
THF, 0 oC
30 min
85%
N
N
N
c) DMP, DCM
25 oC, 30 min
72%
CHO
Ar
Ar
3e
Ar
: Ar = 4-MePh
92% ee
12
: 90% ee
11: 90% ee
HO
Cl
N
d) Et3N, THF
0 oC to rt, 12 h
Ar'
N
13
N
N
Ph
Ph
OH
CHO e) NaBH4
N
H
H
THF/H2O (4:1)
0 oC to rt, 4 h
75%
O
N
O
Ar
14
Ar
N
Ar'
Ar'
: Ar' = 4-BrPh
>20:1 dr
15: 98% ee
>20:1 dr
Scheme 1. Synthetic Transformations.
In summary, we have developed the first enantioselective aerobic oxidative crossꢀcoupling
reaction between THCs and acrolein for building Csp2−Csp3 bonds through a novel cooperative
photoredox and asymmetric catalysis. The triple catalytic system comprises DPZ as a metalꢀfree
photoredox catalyst at a low loading of 0.05 mol%, a chiral Lewis base catalyst (βꢀICD) and an
inorganic salt coꢀcatalyst (NaBArF). With the assistance of 4 Å MS, the reaction proceeded
smoothly, providing structurally and electronically diverse chiral C1ꢀolefinated THCs with
excellent regioꢀ and enantioselectivity (up to 95% ee). Significantly, it represents an
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unprecedented report on visibleꢀlight photoredox catalytic C−H functionalization of THCs.
Being equally applicable to THIQs, this mild strategy represents the first successful example of
using molecular oxygen as the sustainable oxidant to address oxidative coupling reactions of
amines in asymmetric photocatalysis. Further investigations into the extension of DPZ as a
photoredox catalyst in asymmetric cooperative catalysis, and the bioactivities of these chiral Nꢀ
heterocycles are in progress in our laboratory.
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ASSOCIATED CONTENT
Supporting Information.
Supporting Information Available: [General information, optimization results, general
procedures, characterization data, determination of the absolute configuration and spectra.] This
material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: chmjzy@henu.edu.cn
Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval
to the final version of the manuscript. ‡These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We are grateful for the grants from NSFC (21072044), Henan Province (14IRTSTHN006,
152300410057) and the Czech Science Foundation (13ꢀ01061S).
REFERENCES
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X.ꢀL.; Gong, L.ꢀZ. Acc. Chem. Res. 2014, 47, 2365−2377.
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(14)(a) Feng, Z.ꢀJ.; Xuan, J.; Xia, X.ꢀD.; Ding, W.; Guo, W.; Chen, J.ꢀR.; Zou, Y.ꢀQ.; Lu, L.ꢀQ.;
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(15)See the Supporting Information for details.
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references therein.
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