Asymmetric Aerobic Oxidative Cross-Coupling of Tetrahydroisoquinolines with Alkynes

Article abstract of DOI:10.1021/acscatal.7b01912

An efficient asymmetric aerobic oxidation of tetrahydroisoquinolines with terminal alkynes was realized under mild reaction conditions using O₂ as the sole oxidant. A chiral N,N′-dioxide/zinc(II)/iron(II) bimetallic cooperative catalytic system

Full text of DOI:10.1021/acscatal.7b01912

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Letter
Asymmetric Aerobic Oxidative Cross-Coupling
of Tetrahydroisoquinolines with Alkynes
Tianyu Huang, Xiaohua Liu, Jiawen Lang, Jian Xu, Lili Lin, and Xiaoming Feng
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b01912 • Publication Date (Web): 25 Jul 2017
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ACS Catalysis
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Asymmetric Aerobic Oxidative Cross-Coupling of Tetrahydroisoquin-
olines with Alkynes
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†
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† ‡
,
, ,
Tianyu Huang, Xiaohua Liu, * Jiawen Lang, Jian Xu, Lili Lin, and Xiaoming Feng *
†Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan Univer-
sity, Chengdu 610064, P. R. China
‡Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), P. R. China.
Supporting Information Placeholder
ABSTRACT: An efficient asymmetric aerobic oxidation of tetrahydroisoquinolines with terminal alkynes was realized under
mild reaction conditions using O2 as the sole oxidant. A chiral N,N'-dioxide/zinc(II)/iron(II) bimetallic cooperative catalytic
system proves efficient for the formation of various α-alkynyl substituted tetrahydroisoquinolines in good to excellent yields
and enantioselectivities. A primary mechanistic study supports an enantioselective electrophilic addition of zinc acetylide
to the iminium intermediates, formed through a molecular O2 involved oxidative process.
KEYWORDS: Aerobic oxidation, Alkynes, Cross-Coupling, Asymmetric catalysis, Cooperative catalysis.
The direct coupling of two C-H bonds under oxidative
condition is one of the most dynamic and synthetically
powerful research areas in current organic synthesis.1-3
Among them, the oxidation of C-H bonds adjacent to ni-
trogen coupling with a range of nucleophiles4 attracted
considerable attention. The general mechanism for cross-
dehydrogenative coupling (CDC reaction) of tertiary
amines is the formation of an intermediate iminium spe-
cies in the presence of an oxidant, following Mannich-type
reactions (Scheme 1, A). As a result, endeavors toward di-
rect asymmetric oxidative coupling of amines, for example,
tetrahydroisoquinoline (THIQ) derivatives, have been in-
vestigated because the related products represent one of
the most prevalent scaffolds created by nature.5 Chiral or-
ganocatalysts or chiral Lewis acid catalysts for the activa-
tion of nucleophiles,6-8 proved to be successful strategies.
Anion binding catalysis of the electrophile offers an alter-
native.9 However, the current oxidative processes involve
predominately synthetic oxidants, such as TBHP, DDQ,
2,2,6,6-tetramethylpiperidine N-oxide salt (T+BF4 ), etc.
-
Scheme 1. Oxidative Coupling of THIQs and the Aero-
bic Oxidative Mechanism
Economical and green aerobic oxidation with water as the
only byproduct remains limitation in the asymmetric ver-
such as (+)-dysoxyline, homoprotoberberine, and eme-
sion. Although recent advances in Cu(II)/O2 combination
tine.2i, 5 The previous examples about enantioselective al-
highlight opportunities to achieve selective aerobic oxida-
tive functionalization of N-protected THIQs and others
kynylation of THIQs involved the use of chiral PYBOX-
Cu(I) complex catalysts and synthetic oxidants.8a,
Li
8d
(Scheme 1, B),10 there are only few examples to date that
report on the asymmetric oxidative coupling of tertiary
amines using O2 as the sole oxidant.7 One novel example
from Wang’s group is through the combination of
Cu(OTf)2 with chiral cinchona alkaloids using enone and
acrylonitrile as the nucleophiles.
group merged chiral QUINAP-Cu(I) and photoredox catal-
ysis for this purpose and in one case O2 was used as the
terminal oxidant.8e In these cases, the formation of chiral
copper(I) complex with acetylene might account for the
enantioselection. However, to achieve enantioselective
aerobic oxidative reaction with terminal alkynes as the nu-
cleophiles and O2 as the sole oxidant is difficult. As re-
ported by Klussmann,10a in the Cu(II)/O2 system, Cu(II)
catalyst acts as the actual oxidant and the role of the ter-
minal oxidant O2 is the reoxidation of Cu(I) (Scheme 1, B).
We are interested in the asymmetric cross-coupling be-
tween THIQs and relatively weak nucleophiles of alkynes8
because the corresponding products could be derived into
structurally diverse and biologically active compounds,
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Table 1. Optimization of the Reaction Conditionsa
cheap and sustainable iron salt in our cooperative strat-
egy.15 The rich coordination chemistry and efficient enan-
tiocontrol of chiral N,N'-dioxide ligands in catalytic asym-
metric transformations16 encourages us to extend their ap-
plication in asymmetric activation of C-H bonds. In the
presence of chiral N,N'-dioxide, the Zn(II)-Fe(II) hetero-
bimetallic cooperative catalytic system allows facile enan-
tioselective aerobic oxidative cross-coupling of THIQs with
terminal alkynes. Optically active 1-alkynylated THIQ de-
rivatives were obtained under mild reaction conditions.
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Our investigation began with the coupling of
ethynylbenzene 2a with 2-(4-methoxyphenyl)-1,2,3,4-tet-
rahydroisoquinoline 1a in 1,2-dichloroethane under one at-
mosphere of O2 with cheap transition metal salts based on
their propensity for C-H activation (Table 1). In the pres-
ence of chiral N,N'-dioxide L-RaPr3 ligand and NaBArF4 ad-
ditive, only Cu(OTf)2 and Zn(OTf)2 afforded the desired
product 3a, but the former gave higher reactivity without
enantioselectivity (entry 1 vs entry 2). Co(BF4)2·6H2O and
Fe(OTf)2 were inactive for the aerobic cross-coupling (en-
tries 3 and 4). Zn(NTf2)2 as the metal salt precursor showed
the highest enantioselectivity reaching 35% yield with 95%
ee (entry 5). Evaluation of the structures of chiral N,N'-di-
oxides showed that L-RaPr3 outperformed the other lig-
ands bearing varied amino acid backbone and amide sub-
stituent in terms of both reactivity and enantioselectivity
(entries 5-8). We attempted to improve the yield via accel-
erating the formation of iminium species, and thus iron
salt was added as the cocatalyst. It is interesting that
Fe(OTf)2 was more efficient than Fe(OTf)3 in our cases,
which differs from iron-catalyzed aerobic oxidative Man-
nich reaction.2f, 14 The alkynylation product 3a was isolated
in a little higher yield but lower enantioselectivity after 3
mol % of Fe(OTf)2 was added (entry 9). It is possible that
the excessive metal salts might hamper the formation of
chiral L-RaPr3/Zn(II) complex catalyst which is crucial for
the enantiocontrol. Optimization of chiral ligand loading
showed delight result that the oxidative alkynylation reac-
tion could achieve a 70% yield and 88% ee (entry 10). It
implies that the formation of chiral L-RaPr3/Fe(II) com-
plex15a was compatible for both the aerobic oxidation and
the enantioselection in coupling process. The cooperation
effect of Cu(OTf)2 was not obvious, and the product 3a was
obtained in 48% yield with 81% ee (entry 11). Moreover, 5 Å
yield
(%)b
ee
entry
metal salt
Ligand
(%)c
Cu(OTf)2
L-RaPr3
L-RaPr3
L-RaPr3
L-RaPr3
L-RaPr3
L-PrPr2
L-PiPr2
L-RaPr2
L-RaPr3
L-RaPr3
L-RaPr3
L-RaPr3
L-RaPr3
L-RaPr3
L-RaPr3
1
2
59
30
0
88
ND
ND
95
70
80
90
75
Zn(OTf)2
Co(BF4)2·6H2O
Fe(OTf)2
3
trace
NR
35
4
Zn(NTf2)2
5
Zn(NTf2)2
6
21
Zn(NTf2)2
7
32
Zn(NTf2)2
8
33
9d
10e
11f
12e,g
13e,h
14i
15i,j
47
70
Zn(NTf2)2/Fe(OTf)2
Zn(NTf2)2/Fe(OTf)2
Zn(NTf2)2/Cu(OTf)2
Zn(NTf2)2/Fe(OTf)2
Zn(NTf2)2/Fe(OTf)2
Zn(NTf2)2/Fe(OTf)2
Zn(NTf2)2/Fe(OTf)2
88
81
48
54
70
67
96
87
76
78
75
a Unless otherwise noted, all reactions were performed with L-metal
salt (20 mol %, 1:1), 1a (0.05 mmol), 2a (1.2 equiv), NaBArF4 (40 mol %)
and 5 Å MS (30 mg) with oxygen balloon (1 atm) in DCE (0.5 mL) at
35 oC for 24 hours. b Isolated yield. c Determined by chiral HPLC.
d
Zn(II)/Fe(II)/L-RaPr3 (20 mol %, 20:3:20). e Zn(II)/Fe(II)/L-RaPr3 (20
mol %, 20:2:22). f Zn(II)/Cu(II)/L-RaPr3 (20 mol %, 20:2:22). g Without
5 Å MS. h Without NaBArF . i Zn(II)/Fe(II)/L-RaPr3 (20 mol %, 20:3:23)
4
in DCE (0.1 mL). j MeOH (1.0 equiv) was added. (PMP = 4-MeOC6H4;
NaBArF4 = NaB[3,5-(F3C)2C6H3]4)
The incompatible actions of Cu(II)/Cu(I) species for the
two coupling partners make the chiral copper-mediate
asymmetric aerobic process a bit more complicate and im-
practical. Chiral organocatalyst/Cu(II) combination strat-
egy seemed questionable for the reason that rare organo-
catalyst has interaction with alkynes. It is challenging and
of interest to discover a new chiral catalytic system for the
asymmetric version using dioxygen as the sole oxidant.
molecular sieves and NaBArF were indispensable part of
4
the catalytic system which is evident in entries 12 and 13.
Pleasingly, with chiral Zn(II)/Fe(II)/L-RaPr3 cooperative
catalytic system in higher concentration, the product could
be isolated in 78% yield and 96% ee (entry 14). The addi-
tion of MeOH reduced the enantioselectivity (entry 15),
thus it is too hard to further improve the yield but main-
taining the enantioselectivity via the form of N-aryl hemi-
aminal assisted by alcohols.8d, 10
We envision a new Zn(II)/Fe(II) bimetallic cooperative
system (Scheme 1, C) for the asymmetric aerobic oxidative
coupling of THIQs with alkynes. It involves the asymmet-
ric activation of alkynes with chiral zinc(II) complex which
were effective in alkynylation reactions.11-13 Although the
Doyle group used FeCl3 to promote the aerobic oxidation
of tertiary anilines with several nucleophiles,14 phenyla-
cetylene did not undergo the coupling which might due to
its weak nucleophilicity. Nevertheless, the aerobic oxida-
tion of THIQs coupling with alkynes could be mediated by
With the optimized conditions in hand (Table 1, entry
14), the substrate scope of the terminal alkynes was exam-
ined firstly. As shown in Table 2, substituted ethynylben-
zenes underwent the reaction in good yields and enanti-
oselectivities regardless of the electronic nature or position
of the substituents on the aryl group (Table 2, entries 1-19;
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ACS Catalysis
Table 3. Scope of Amines in the CDC Reactiona
Table 2. Scope of Alkynes in the CDC Reactiona
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2
3
4
5
6
7
8
9
entry
R
time (h)
yield (%)
ee (%)
93
1b
2
3
Ph (3a)
24
40
50
70
74
73
4-ClC6H4 (3b)
4-BrC6H4 (3c)
96
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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34
35
36
37
38
39
40
41
42
43
44
45
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48
49
50
51
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53
54
55
56
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58
59
60
99
4
5
4-MeC6H4 (3d)
4-EtC6H4 (3e)
24
24
24
24
24
38
40
38
72
72
24
38
24
24
24
30
74
76
72
73
68
75
50
72
65
68
71
92
95
95
96
96
96
95
86
90
85
96
99
98
93
95
88
6
4-nPrC6H4 (3f)
4-nBuC6H4 (3g)
4-nPentC6H4 (3h)
4-MeOC6H4 (3i)
4-MeCO2C6H4 (3j)
4-NCCH2C6H4 (3k)
2-FC6H4 (3l)
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8
9
10
11
12
13
14
15
16
17
18
19
2-ClC6H4 (3m)
3-FC6H4 (3n)
3-ClC6H4 (3o)
72
76
82
45
69
3-MeC6H4 (3p)
3-MeOC6H4 (3q)
3-O2NC6H4 (3r)
3,5-F2C6H3 (3s)
20
48
75
88
aThe same as in Table 2.
(3t)
product 3a in 70% yield with 93% ee (Table 2, entry 1).
21
22
23
1-naphthyl (3u)
2-thienyl (3v)
CH2CH2Ph (3w)
28
28
48
75
70
55
95
98
37
Given the remarkable efficiency of the present catalytic
system, various amine derivatives were also examined. As
shown in Table 3, for the reaction with ethynylbenzene 2a,
THIQs with electron-donating substituent at the para-po-
sition of the N-aryl group proceeded the aerobic cross-cou-
pling reaction smoothly, providing the products (4a-4e) in
60-66% yields with 94-97% ee. N-aryl groups bearing elec-
tron-withdrawing substituent at meta-position or elec-
tron-donating substituent at ortho-position were disad-
vantage to the enantioselectivity (4f-4i). The scope of sub-
stituted THIQs was next explored. Interestingly, when
THIQ with an electron-withdrawing substituent could
provide the desired product in higher yield than the ones
with electron-donating substituents (4j-4m). When the
catalytic condition was applied to N-benzyl aniline, N-phe-
nyl piperidine and others failed (see SI for details; 4n-4o).
24
48
60
61
(3x)
25
26
24
48
77
20
20
(3y)
nC10H21 (3z)
40
a The reactions were performed with Zn(NTf2)2/Fe(OTf)2/L-RaPr3 (20
mol %, 20:3:23), 1a (0.05 mmol), 2 (1.2 equiv), NaBArF4 (40 mol %) and
5 Å MS (30 mg) with oxygen balloon (1 atm) in DCE (0.10 mL) at 35 oC.
Yields of isolated products. The ee values were determined by HPLC.
b The reaction was carried out with 1a (4.0 mmol), 2a (5.0 mmol) and
5 Å MS (2.0 g) in DCE (8 mL).
45-82% yield and 85-99% ee). In addition, heterocyclic sul-
fur-containing alkyne 2t proceeded in 75% yield and 88%
ee (Table 2, entry 20). Furthermore, 1-naphthyl substituted
alkyne 2u as well as 2-ethynylthiophene 2v were also suit-
able candidates for the reaction, generating the related
THIQ derivatives 3u and 3v in 75% yield and 95% ee, 70%
yield and 98% ee, respectively (Table 2, entries 21 and 22).
The reaction of alkyl substituted terminal alkynes per-
formed smoothly, and moderate to good yields could be
obtained but the enantioselectivity dropped a lot (Table 2,
entries 23-26). It was possible owing to the weaker acidity
of alkyl terminal alkynes and larger steric hindrance of the
substituent. The CDC reaction of 1a was enlarged to a gram
scale under the optimized reaction condition, and gave the
The 1-phenylethynyl substituted THIQs could undergo
useful transformations (eq 1). Reduction of 3a gave
phenethyl substituted 5a in 80% yield and (Z)-styryl sub-
stituted 7a in 83% yield without loss of enantioselectivity.
N-PMP group of tetrahydroisoquinoline derivative could
be easily removed by using CAN (ceric ammonium nitrate)
in aqueous acetonitrile,17 giving the N-unprotected tetra-
hydroisoquinoline derivative 6a in good yield with excel-
lent ee value, which is a valuable and versatile intermediate
in organic synthesis.5 The absolute configuration of 6a was
determined to be R by comparison the optical rotatory
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with the pervious report.18 Thus, it allowed assignment of
identified, it indicates that iron accelerates the oxidation
the absolute configuration of 3a as R-isomer.19
process. In addition, light has no obvious influence on the
reaction process, and the signal remains even the test was
carried out in dark (Figure 1, g).
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4
5
6
7
8
Kinetic studies of the model CDC reaction in the
Zn(II)/Fe(II)/L-RaPr3 cooperative catalytic system with
varied concentration were conducted to detect the initial
rate of the reaction. The reaction showed clear first-order
kinetic dependence on chiral L-RaPr3/Fe(OTf)2 complex
and zero-order kinetic dependence on chiral L-
RaPr3/Zn(NTf2)2 complex (for data and assignment see
SI). The results were in agreement with the KIE experiment
that oxidative step is involved in the rate-determining step.
9
To clarify the detailed reaction course, a kinetic isotope
effect (KIE) experiment was then conducted (eq 2). Race-
mic monodeuternated substrate 1p was subjected to the
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enantiomerically
pure
or
racemic
N,N'-diox-
ide/Zn(II)/Fe(II) catalytic system. Primary KIE value kH/kD
of 5.7 and 5.3 were calculated for the two cases. This is in
accordance with CuCl2/O2 catalytic process,10a indicating a
rate-determining C-H bond cleavage. Under the optimal
reaction conditions, the formation of [L-RaPr3-Zn2+-
(NTf2)-]+ and [L-RaPr3-Zn-C ≡ CPh]+ species was con-
firmed from ESI-HRMS analysis of the catalytic reaction
system (for data and assignment see SI).
On the basis of the above results and the literature re-
ports,10 the aerobic asymmetric CDC reaction promoted by
Zn(II)/Fe(II)/N,N'-dioxide bimetallic cooperative catalysis
was rationalized (Scheme 2). In the presence of a base (tet-
rahydroisoquinoline or basic anion generated in the oxida-
tive process), chiral N,N'-dioxide-Zn(II) complex reacts
with terminal alkynes to generate zinc acetylide interme-
diate A (confirmed by HRMS spectra). On the other side,
without additional Fe(II) catalyst (path a), auto-oxidation
of chemical substances results in the formation of C con-
•
taining the amine radical cation of THIQ 1+ and superox-
-•
ide radical anion O2 (detected by EPR spectroscopy). H-
abstraction way generates hydroperoxide THIQ-OOH C
which is in equilibrium with the iminium species E'. In the
presence of aerobic iron catalyst, 14, 21 Fenton-type reactions
occur to generate Fe(III) species and HO• radical, and the
latter abstracts a H-atom from the substrate to give the
corresponding C-radical D (path b). On the other hand,
Fe(III) species convert into Fe(III)OOH species, following
the homolysis of Fe-O bond to generate HOO• radical,
which benefits the formation of hemiaminal, providing a
stabilizing reservoir for iminium species E. Finally, enanti-
oselective alkynylation controlled by the chiral N,N'-diox-
ide-Zn(II) complex provides the cross-coupling products
and regenerates the catalyst.
To elucidate the involved reactive oxygen species EPR
spectroscopic measurements were performed (Figure 1).
DMPO was employed as a probe for superoxide radical
anion. A single radical was obviously trapped upon mixing
Zn(NTf2)2, THIQ 1a and DMPO in oxygen-saturated 1,2-
dichloroethane. The spectrum and hyperfine coupling con-
stants of the characteristic signal in Figure 1d is in agree-
ment with the reported values, confirming the formation
•−
of adduct of O2 with DMPO.10b, 20 Nevertheless, complex
EPR signals appeared if Fe(OTf)2 was added (Figure 1, e and
f), although the fine structure related to which is not
Scheme 2. Proposed Mechanism
In conclusion, the first catalytic asymmetric aerobic
cross-dehydrogenative coupling of tetrahydroisoquino-
lines and terminal alkynes was established under mild re-
action conditions. The merging of chiral N,N'-dioxide,
zinc(II) and iron(II) catalysts allows an facile oxidative pro-
tocol with atom-efficient and environmentally-friend oxi-
dant (O2). The good level of yields with excellent enanti-
Figure 1. The electroparamagnetic resonance (EPR) spectra (X
band, 9.43 GHz, rt. in oxygen-saturated DCE). (a) Zn(NTf2)2/DMPO;
(b) 1a/DMPO; (c) DMPO; (d) 1a/Zn(NTf2)2/DMPO; (e)
1a/Fe(OTf)2/DMPO;
(f)
1a/Zn(NTf2)2/Fe(OTf)2/DMPO;
(g)
1a/Zn(NTf2)2/DMPO in the dark. The concentration of each compo-
nent is as follows: Zn(NTf2)2 (0.02 mol/L), DMPO (1.33 mol/L),
Fe(OTf)2 (0.003 mol/L), 1a (0.1 mol/L).
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Commun. 2009, 45, 5919-5921. (b) Zhang, B.; Xiang, S.-K.; Zhang,
oselectivities, broad substrate generality, operational sim-
1
2
3
4
5
6
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plicity, and mild reaction conditions highlighted the effi-
ciency of this new cooperative catalytic system. In addition,
this is also a breakthrough that chiral N,N'-dioxide-metal
complex was used for the activation of unfunctionalized al-
kynes. We anticipate that it would bring new light for fu-
ture efforts in the catalytic enantioselective C-H function-
alization and aerobic oxidation with a wide range of trans-
formations.
(4) (a) Li, C.-J. Acc. Chem. Res. 2009, 42, 335-344. (b) Girard, S. A.;
Knauber, T.; Li, C.-J. Angew. Chem. Int. Ed. 2014, 53, 74-100. (c)
Murahashi, S.-I.; Zhang, D. Chem. Soc. Rev. 2008, 37, 1490-1501.
Selected examples of different nucleophiles coupling with tetra-
hydroisoquinoline, see: (d) Sud, A.; Sureshkumar, D.; Klussmann,
M. Chem. Commun. 2009, 45, 3169-3171. (e) Chu, L.; Qing, F.-L.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: liuxh@scu.edu.cn.
*E-mail: xmfeng@scu.edu.cn.
ORDID
Xiaohua Liu: 0000-0001-9555-0555
Xiaoming Feng: 0000-0003-4507-0478
Lili Lin: 0000-0001-8723-6793
Notes
The authors declare no competing financial interest.
ASSOCIATED CONTENT
Supporting Information
Experimental details and analytic data (NMR, HPLC, EPR).
This material is available free of charge at http://pubs.acs.org.
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(b) Szawkało, J.; Czarnocki, Z. Monatsh. Chem. 2005, 136, 1619-1627.
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Biol. 2010, 14, 347-361. (d) Reddy, R. J.; Kawai, N.; Uenishi, J. J. Org.
Chem. 2012, 77, 11101-11108.
ACKNOWLEDGMENT
We appreciate the National Natural Science Foundation of
China (21432006, 21625205, 21321061), and National Program
for Support of Top-notch Young Professionals for financial
support.
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