Organocatalytic enantioselective oxidative C-H alkenylation and arylation of N-Carbamoyl tetrahydropyridines and tetrahydro-β-carbolines

Article abstract of DOI:10.1002/anie.201500703

The first organocatalytic enantioselective C-H alkenylation and arylation reactions of N-carbamoyl tetrahydropyridines and tetrahydro-β-carbolines (THCs) are described. The metal-free processes represent an efficient and straightforward approach to a variety of structurally and electronically diverse α-substituted tetrahydropyridines and THCs in good yields with excellent regio- and enantioselectivities. Preliminary control experiments provide important insights into the reaction mechanism.

Full text of DOI:10.1002/anie.201500703

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201500703
Synthetic Methods
German Edition:
DOI: 10.1002/ange.201500703
À
Organocatalytic Enantioselective Oxidative C H Alkenylation and
Arylation of N-Carbamoyl Tetrahydropyridines and Tetrahydro-b-
carbolines**
Xigong Liu, Zhilin Meng, Chengkun Li, Hongxiang Lou, and Lei Liu*
from isoquinolines and quinolines.[2] Substituted pyridinium
ions have been shown to be ideal intermediates for piperidine
synthesis, but the employment of transition metals is always
a prerequisite.[3] With respect to the synthesis of a-substituted
THCs, aside from the enantioselective hydrogenation of
cyclic imines,[4] the organocatalytic asymmetric Pictet–Spen-
gler reaction has recently emerged as an elegant approach
providing the scaffolds with excellent enantioselectivity.[5]
However, this transformation requires the involvement of
electron-rich tryptamines, leaving electron-deficient THCs
inaccessible. Moreover, enals and electron-rich aromatic
aldehydes also cannot be employed as substrates, rendering
a-alkenyl and electron-rich aryl-substituted THCs unavail-
able. The organocatalytic enantioselective addition of boro-
nates to cyclic iminium ions provides an impressive solution to
the above limitations by the umpolung of the two compo-
nents.[6] To the best of our knowledge, organocatalytic
asymmetric couplings of boronates with tetrahydropyridine-
or THC-derived iminium intermediates have not been
established to date.[7]
À
Abstract: The first organocatalytic enantioselective C H
alkenylation and arylation reactions of N-carbamoyl tetrahy-
dropyridines and tetrahydro-b-carbolines (THCs) are de-
scribed. The metal-free processes represent an efficient and
straightforward approach to a variety of structurally and
electronically diverse a-substituted tetrahydropyridines and
THCs in good yields with excellent regio- and enantioselectiv-
ities. Preliminary control experiments provide important
insights into the reaction mechanism.
S
ubstituted piperidines and more complex indolopiperidine
tetrahydro-b-carbolines (THCs) are key units in numerous
bioactive molecules and have been used for many pharma-
ceutical applications (Figure 1).[1] The catalytic enantioselec-
tive addition of carbon-centered nucleophiles to cyclic imine
or iminium electrophiles represents a particularly attractive
approach to synthesize these structural motifs. However,
existing catalytic asymmetric methods that proceed with high
efficiency require the use of stabilized precursors derived
Cyclic iminium intermediates can be generated through
[8]
À
the selective C H oxidation of N-heterocyclic precursors.
This strategy provides an effective alternative to conventional
methods that rely on the manipulation of functional groups.
Several impressive catalytic asymmetric variants have been
reported, but they still suffer from a limited scope.[9] N-Aryl
tetrahydroisoquinolines have always been selected as the
substrates, and Chi et al. reported that for N-aryl piperidines,
no reactivity was observed.[9c] To the best of our knowledge,
there have been no reports on a catalytic enantioselective
À
C H functionalization of tetrahydropyridines or THCs to
date. Moreover, the synthetic utility of the existing methods is
limited because removal of the N-aryl group in the presence
of other functional groups proved to be difficult.[2g,10] Herein,
Figure 1. Representative a-arylethyl and a-aryl piperidines and THCs.
À
we report the first organocatalytic asymmetric C H alkeny-
lation and arylation reactions of N-carbamoyl tetrahydropyr-
idines and THCs with excellent enantiocontrol.
[*] X. Liu,[+] Z. Meng,[+] C. Li, Prof. H. Lou, Prof. L. Liu
Key Lab of Chemical Biology of Ministry of Education
School of Pharmaceutical Sciences, Shandong University
Jinan 250012 (P.R. China)
E-mail: leiliu@sdu.edu.cn
[+] These authors contributed equally to this work.
Seminal work from the groups of Chong and Schaus
established the possibility of using chiral biphenols to
promote asymmetric boronate addition reactions.[7] More-
over, Schaus et al. also reported innovative examples using an
tartaric acid derived chiral Brønsted acid as an effective
catalyst.[7e,f] Therefore, these two types of catalysts were
explored for our boronate addition process. The regioselec-
[**] This work was supported by the National Science Foundation of
China (21202093, 21472112, 21432003), the Program for New
Century Excellent Talents in University (NCET-13-0346), the Shan-
dong Science Fund for Distinguished Young Scholars (JQ201404),
and a Young Scientist Foundation Grant of Shandong Province
(BS2013YY001).
À
tive functionalization of the C1 H bond of N-carbamoyl THC
À
2a might be challenging given that the C4 H bond adjacent
to the enamine moiety can be easily oxidized (Table 1).[9a,11]
Careful optimization of catalyst, oxidant, and solvent
unearthed promising results: Excellent regioselectivity with
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201500703.
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Table 1: Optimization of the reaction conditions.[a]
Entry
Catalyst
Additive
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
L1–L3
L4
L5 or L6
L7
L9
L13
L9
–
–
–
–
–
–
<5
33
<5
38
42
28
n.d.
36
n.d.
38
51
36
Lewis acid[d]
CF3CH2OH
<40
80
<5
94
L9
[a] Reactions conditions, unless otherwise specified: 2a (0.1 mmol), 3a
(0.2 mmol), DDQ (0.1 mmol), catalyst 1 (0.015 mmol), CH2Cl2 (2.0 mL),
À208C, 48 h. [b] Yield of isolated product. [c] Determined by HPLC
analysis on a chiral stationary phase. [d] Yb(OTf)3 or Sc(OTf)3.
Bn=benzyl, Bz=benzoyl.
À
Scheme 1. C H alkenylation and arylation of N-carbamoyl THCs. [a] L2
(30 mol%), T+BF4À (2,2,6,6-tetramethylpiperidine-1-oxoammonium tet-
rafluoroborate, 1.0 equiv), and the dimethyl boronic ester (2.0 equiv).
À
functionalization of the C1 H bond was observed, and 4a was
afforded in 36% ee when 2a was reacted with 3a in the
presence of tartaric acid (L4) and DDQ at À208C (entries 1
and 2; see also the Supporting Information). The catalyst
optimization using the modular structure of L4 implied that
the carboxylic acid and diol moieties were essential for the
reaction, and that the steric properties of the amide exerted
a pronounced effect on the enantioselectivity, and N,N-
diisobutyl-substituted L9 was found to be optimal (entries 3–
6). CF3CH2OH as an additive was established to be beneficial
to the reaction (entries 7 and 8).
closed an enantioselective addition of aryl Grignard reagents
to 4-phenylpyridine N-oxides with up to 80% ee.[3h] However,
a stoichiometric amount of a chiral lithium binolate reagent
was required. Therefore, 4-phenyl-substituted 5a was initially
explored. A similar boronate scope as for the THCs was
observed, and a broad range of electronically diverse vinyl
and electron-rich aryl boronates were well tolerated
(Scheme 2). The influence of the substituents on the tetrahy-
dropyridine scaffold was next studied. Electronically varied
4-aryl- and 4-heteroaryl-substituted tetrahydropyridines
were effective substrates, affording 6m–6q with excellent
ee values. At the C4 position, alkynyl moieties were also
tolerated, and the corresponding products (6r–6t) were
obtained with high enantiocontrol, demonstrating the capa-
bility of the method to prepare structurally diverse 2,4-
substituted piperidines through manipulation of the alkyne
moieties. 4-Alkyl-substituted 5u and non-substituted 5v
could also be converted with moderate yield and ee values.
Unfortunately, with piperidine 5w, the desired product was
not detected.
A wide range of electronically varied styrenyl boronates
with different substitution patterns participated in the highly
À
regioselective oxidative C H alkenylation of 2a, providing
the corresponding vinyl-substituted THCs 4a–4i with excel-
lent ee values (Scheme 1). Heteroaryl- (3j) and alkyl-substi-
tuted (3k) vinyl boronates were also competent nucleophiles.
À
The C H arylation process was also effective with electron-
rich aryl boronates 3l–3o and heteroaryl boronate 3p,
whereas electron-deficient 3q failed to deliver 4q. Many
different THCs could also be employed as substrates in this
transformation. Both electron-rich and -deficient THCs were
well tolerated, affording vinyl-substituted 4r–4u and aryl-
substituted 4v–4x with excellent enantioselectivities. It is
noteworthy that the products shown in Scheme 1 are inacces-
sible by catalytic asymmetric Pictet–Spengler reactions.[5]
Schaus and co-workers have demonstrated that tartaric
acid catalyzed boronate addition reactions should proceed via
the transesterification of the boronate with the catalyst to
form a chiral nucleophile.[7e,f] In consistency with the study by
1
Schaus et al., H NMR and ESI-MS analysis of a mixture of
À
The C H functionalization of N-carbamoyl tetrahydro-
L9 and 3a implied the generation of dioxaborolane 7
(Scheme 3a).[12] Moreover, the reaction of 7 (1 equiv) with
2a or 5a proceeded with comparable efficiency and enantio-
control to the corresponding catalytic reaction (Sche-
me 3b,c), implying the involvement of 7 in the catalytic
process. During the course of the reaction of 2a with 3a,
pyridines was next studied. 2,4-Substituted piperidines are
core scaffolds of a number of synthetic drugs, such as
quillifoline (1b; Figure 1) and 1c. However, practical catalytic
asymmetric methods that provide access to these structures
have not been well established. Olsson and Almqvist dis-
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were observed when the additive was absent, with 8b
affording the best yield and highest ee value, suggesting that
8b should be an intermediate of the reaction.
According to these preliminary studies, a plausible mech-
À
anism is proposed (Scheme 4). The C H oxidation of
carbamate 9 generating N-acyliminium 10 is reversible. The
À
quick reaction of CF3CH2OH with 10 completes the C H
oxidation process to give N-acyl hemiaminal 11. Then acidic
complex 7 promotes the collapse of 11 to provide acyliminium
Scheme 4. Proposed mechanism.
12 concomitant with the generation of “ate” complex 13. The
different reactivity observed for 8a and 8b in the absence of
CF3CH2OH indicates that the CF3CH2O moiety in 11 might
act as a good leaving group to facilitate the formation of
acyliminium ion 12 and ate complex 13; the different ee values
for 8a and 8b imply that the CF3CH2O moiety in boron ate
complex 13 might be relevant to the enantiocontrol of the
nucleophilic addition process, but the exact origin of the effect
remains unclear.
À
Scheme 2. C HÀalkenylation and arylation of N-carbamoyl tetrahydropyr-
idines. [a] T+BF4 (1.0 equiv) and the diisopropyl boronic ester (2.0 equiv)
in CHCl3. TMS=trimethylsilyl.
The utility of the method in complex molecule synthesis
was further demonstrated (Scheme 5). a-Arylethyl-substi-
tuted THCs are ubiquitous structural motifs in numerous
indole alkaloids, such as eudistomidin B and G (1d and 1e,
Figure 1). Previous strategies, which relied on the Pictet–
Spengler reaction, required the installation of the C10 ste-
reocenter at the beginning of the synthesis, and therefore, the
preparation of 6-bromo-substituted 16 took thirteen steps.[13]
À
With the asymmetric C H alkenylation of THCs in hand, the
C10 stereocenter can be introduced at a late stage of the
synthesis of 16 by modifying the olefin in 4a through a three-
step process consisting of diastereoselective dihydroxylation,
hydrogenation, and cyclization. The concise synthetic strategy
in combination with the diverse range of easily accessible
Scheme 3. Control experiments.
a considerable amount of an intermediate was detected by
TLC analysis, which was identified as CF3CH2OH adduct N-
acyl hemiaminal 8b (Scheme 3). Therefore, control experi-
ments were conducted to explore the roles of CF3CH2OH by
subjecting 8a and 8b to the standard conditions (Sche-
me 3d,e). Comparable results were obtained when
CF3CH2OH was present. However, obvious differences
Scheme 5. Synthetic utility.
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À
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N-carbamoyl tetrahydropyridines and THCs with a wide
range of boronates. The metal-free reaction proceeds with
excellent regio- and enantioselectivity and is applicable to
structurally and electronically diverse tetrahydropyridines
and THCs with broad synthetic utility. Mechanistic studies
indicated the intermediacy of a reactive dioxaborolane and
À
elucidated the roles of the CF3CH2OH additive in the C H
oxidation and nucleophilic addition processes.
Keywords: asymmetric organocatalysis · carbamates ·
À
C H functionalization · tetrahydropyridines ·
tetrahydro-b-carbolines
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Received: January 25, 2015
Published online: && &&, &&&&
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Chemie
Communications
Synthetic Methods
X. Liu, Z. Meng, C. Li, H. Lou,
L. Liu*
&&&& — &&&&
Organocatalytic Enantioselective
À
Oxidative C H Alkenylation and Arylation
of N-Carbamoyl Tetrahydropyridines and
Tetrahydro-b-carbolines
Without a metal: A large variety ofN-
heterocycles and boronates were sub-
jected to the title reactions, which pro-
ceeded with high efficiency and excellent
regio- and enantioselectivity. The new
method was applied in complex molecule
synthesis.
Angew. Chem. Int. Ed. 2015, 54, 1 – 5
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These are not the final page numbers!