Asymmetric synthesis of tetrahydroquinolines through a [3+2] cycloaddition controlled by dienamine catalysis

Article abstract of DOI:10.1002/chem.201402089

A dienamine-mediated enantioselective 1,3-dipolar cycloaddition catalyzed by a chiral prolinol silyl ether catalyst has been developed. Removal of the benzamide group of the intermediates could furnish chiral C-1 substituted tetrahydroisoquinolines (see scheme) in high yields and excellent stereoselectivities.

Full text of DOI:10.1002/chem.201402089

DOI: 10.1002/chem.201402089
Communication
&
Organocatalysis
Asymmetric Synthesis of Tetrahydroquinolines through a
[3+2] Cycloaddition Controlled by Dienamine Catalysis
Wenjun Li,[a, b] Jia Wei,[a] Qianfa Jia,[a] Zhiyun Du,*[a] Kun Zhang,[a] and Jian Wang*[a, b]
Chem. Eur. J. 2014, 20, 1 – 6
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Communication
knowledge, an example of asymmetric catalytic [3+2] cycload-
dition reactions through 4,5-reactivity of dienamines has not
been reported.
Abstract: A dienamine-mediated enantioselective 1,3-di-
polar cycloaddition catalyzed by a chiral prolinol silyl
ether catalyst has been developed. Removal of the benza-
mide group of the intermediates could furnish chiral C-
1 substituted tetrahydroisoquinolines (see scheme) in high
yields and excellent stereoselectivities.
As a model system, the reaction between C,N-cyclic azome-
thine imine 1a and a,b-unsaturated aldehyde 2a was chosen.
The high reactivity of C,N-cyclic azomethine imines 1 has previ-
ously been shown to enable successful organocatalytic cyclo-
additions of a variety of different carbonyl compounds.[9] The
reaction was tested in the presence of a number of chiral proli-
nol silyl ethers I–IV (Figure 1) as catalysts and in the presence
of different additives in various solvents. Selected results are
presented in Table 1.
The field of asymmetric organocatalysis has become extremely
attractive over the last decade.[1] The activation of carbonyl
compounds by enamines, iminium ions, or the SOMO-activa-
tion strategy has become a fundamental approach in asym-
metric synthesis.[2] Moreover, the catalytic modes of amines are
still under further investigation.[3] In 2006, Jørgensen and co-
workers first developed dienamine catalysis by inverting the in-
herent reactivity of a,b-unsaturated aldehydes, which acted as
nucleophiles for the direct enantioselective g-amination with
diethyl azodicarboxylates.[4] Although several elegant examples
have been made, the synthetic potential of dienamine catalysis
seems to be underestimated and only limited progress has
been made to date.[5] Most examples of HOMO-raising diena-
mines promote 1,3-, 1,5-, or 2,5-reactivity,[5] and only a few cat-
alytic approaches are available for the direct 4,5-reactivity of
dienamines. In 2012, the Jørgensen group reported the first H-
bond-directed inverse-electron-demand hetero-Diels–Alder re-
action ([4+2] cycloaddition) proceeding via a dienamine inter-
mediate (Scheme 1).[6] More recently, the Jørgensen[7] and Vi-
cario[8] groups independently reported a [2+2] cycloaddition
reaction of a,b-unsaturated aldehydes and nitroalkenes
through dienamine catalysis (Scheme 1). To the best of our
The limiting reagent 1a was found to be consumed within
4 h, as observed by 1H NMR spectroscopy. The reaction pro-
ceeded with good enantioselectivity and excellent diastereose-
lectivity in CH2Cl2 at room temperature (Table 1, entry 1,
84% ee, d.r.=20:1). This initial result provided an excellent
platform for further experiments and improvement of the dia-
stereoselectivity. A screening of the temperature showed that
performing the reaction at À208C improved the ee and the d.r.
(Table 1, entry 3, 92%, >25:1). It was also found that the use
of other solvents lowered the ee values considerably (en-
Figure 1. Screened catalysts.
Table 1. Optimization of reaction conditions.[a]
Entry Cat. Solvent Additive
T [8C] Yield [%][b] ee [%][c] d.r.[d]
1
I
I
I
I
I
I
I
I
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
toluene AcOH
THF AcOH
anisole AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
RT
0
83
86
86
85
85
87
55
85
72
63
81
82
81
85
87
84
90
92
92
92
80
85
80
85
87
87
94
94
94
97
20:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
2[e]
3[f]
À20
À40
À20
À20
À20
À20
À20
À20
À20
À20
4[g]
5[f]
6[f]
7[f]
8[f]
Scheme 1. Asymmetric [n+2] cycloadditions of dienamines based on 4,5-re-
activity.
9[f]
I
Et2O
AcOH
AcOH
AcOH
AcOH
CF3CO2H À20
PhCO2H
À20
2,4-DNBA À20
10[f]
11[f]
12[f]
13[f]
14[f]
II
III
IV
IV
IV
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
[a] W. Li, J. Wei, Q. Jia, Prof. Z. Du, Prof. K. Zhang, Prof. Dr. J. Wang
Allan H. Conney Laboratory for Anticancer Research
Guangdong University of Technology
Guang Dong, 510006 (China)
E-mail: zhiyundu@foxmail.com
15[f,h] IV
[a] Reaction conditions: a mixture of 1a (0.10 mmol), 2a (0.15 mmol), ad-
ditive (20 mol%), and catalyst (20 mol%) in the solvent (0.3 mL) was
stirred at room temperature for 4 h. [b] Isolated yield. [c] Determined by
HPLC. [d] Determined by crude NMR analysis. [e] The reaction was con-
ducted at 08C for 6 h. [f] The reaction was conducted at À208C for 12 h.
[g] The reaction was conducted at À408C for 24 h. [h] 2,4-DNBA=2,4-di-
nitrobenzoic acid.
[b] W. Li, Prof. Dr. J. Wang
Department of Chemistry, National University of Singapore
3 Science Drive 3, Singapore 117543 (Singapore)
Fax: (+65)6516-1691
E-mail: chmwangj@nus.edu.sg
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402089.
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tries 6–9). A survey of chiral pro-
linol silyl ethers I–IV showed
that employing catalyst IV slight-
ly increased the ee to 94%
(entry 12). The effect of acid ad-
ditives was also studied. The
presence of 20 mol% 2,4-dinitro-
benzoic acid (2,4-DNBA) en-
hanced the ee value to 97%
(entry 15).
Table 2. Substrate scope.[a]
With the optimized conditions
in hand, the generality of the re-
action was evaluated. A range of
substrates was shown to be
compatible with the developed
protocol for the [3+2] cycloaddi-
tion of C,N-cyclic azomethine
imines to a,b-unsaturated alde-
hydes by using 2-[bis(3,5-bistri-
fluoromethylphenyl)-trimethylsi-
lanyloxymethyl] pyrrolidine IV as
the catalyst (Table 2). The reac-
tion proceeds well with a,b-un-
saturated aldehydes in which R
is an aromatic ring. Aromatic
substituents on the side chain,
albeit heterocycles, all gave
good results (3aa–3aj, 92–99%
ee, d.r.>25:1, 83–91% yield).
With this promising result in
hand, we then investigated the
generality of the C,N-cyclic azo-
methine imines. An increase in
the steric bulk of the side chain,
as in 1g, led to a significantly
higher reaction time, but with
a comparable enantioselectivity
and slightly lower yield. The
presence of heteroatoms, such
as the sulfur atom in the side
chain of compound 1h, is also
[a] Reaction conditions: a mixture of 1 (0.10 mmol), 2 (0.15 mmol), 2,4-DNBA (20 mol%), and catalyst IV
(20 mol%) in CH2Cl2 (0.3 mL) was stirred at À208C for 12 h.
tolerated, and the enantiomeric excess was retained. As for the
substitution pattern of the C,N-cyclic azomethine imines, 5-, 6-,
and 7-Me/MeO/or Br substituents were all tolerated, giving the
desired products in high yields and steroselectivities (3ba–
3ha). The absolute configuration of the products was assigned
based on single-crystal X-ray analysis of Ts-protected 3aa.[10]
However, aliphatic a,b-unsaturated aldehydes 2k–n gave dif-
ferent [3+2] cycloadducts (Table 3, 3ak–3an). We speculate
that the reaction of aliphatic a,b-unsaturated aldehydes and
secondary-amine catalyst IV preferably proceeds through the
formation of an a,b-unsaturated iminium ion (3,4-reactivity of
iminium ion vs. 4,5-reactivity of dienamine), which lowers the
energy of the dienophile LUMO. The iminium ion plays a key
role in triggering the 1,3-dipolar cycloaddition reaction, which
upon reduction furnished the normal-electron-demand [3+2]
cycloaddition products 3ak–3an.[12]
The viability of trienamine activation was also investigated
[Eq. (1)].[11] The desired cycloadduct 3ao was obtained in 80%
combined yield under standard conditions, but only with mod-
erate diastereoselectivity (d.r.=4:3, 92 and 72% ee, respective-
ly). In this process, we envisioned that the condensation of cat-
alyst IV with 2,4-dienal 2o can lead to the transient formation
of the extended conjugated trienamine intermediate, which
subsequently reacts with C,N-cyclic azomethine imine 1a to
give the final cycloaddition product.
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catalyst IV and aldehyde 2a, forming iminium-ion intermedia-
te A. The iminium ion is then deprotonated to form the diena-
mine intermediate B, which reacts with the C,N-cyclic azome-
thine imine 1a to generate the polycyclic intermediate C. Inter-
mediate C is then hydrolyzed to give intermediate D, which
undergoes a reduction step to form the final product 3aa.
In summary, the first dienamine-mediated enantioselective
1,3-dipolar [3+2] cycloaddition was developed, demonstrating
the viability of this activation strategy. The reaction between
diversely substituted C,N-cyclic azomethine imines and a,b-un-
saturated aldehydes proceeded smoothly to give the desired
products in a highly stereoselective manner. Furthermore, it
was demonstrated that the obtained cycloadducts can be
transformed into useful tetrahydroisoquinoline frameworks. We
also believe that the strategy could be applicable to other 1,3-
dipolar cycloadditions. These studies are currently under way
in our laboratory and the results will be reported in due
course.
Table 3. Reactions of aliphatic a,b-unsaturated aldehydes with C,N-cyclic
azomethine imines.[a]
2k
3ak
2l
3al
2m
3am
2n
3an
[a] Reaction conditions: a mixture of 1a (0.10 mmol), 2k–n (0.15 mmol),
2,4-DNBA (20 mol%), and catalyst IV (20 mol%) in DCM (0.3 mL) was
stirred at À208C for 12 h.
Experimental Section
General procedure
Catalyst IV (0.02 mmol) and 2,4-dinitrobenzoic acid (0.02 mmol)
were added to a solution of C,N-cyclic azomethine imine 1a
(0.10 mmol) and aldehyde 2a (0.15 mmol) in CH2Cl2 (0.3 mL). The
mixture was stirred at À208C for 12 h and then the solvent was re-
moved under vacuum to give the crude product. NaBH4
(0.20 mmol) was added to a solution of the crude product in meth-
anol (2.0 mL), the reaction mixture was stirred at room tempera-
ture for 2 h, and then the solvent was removed under vacuum to
give a residue, which was purified by silica gel chromatography to
yield the desired product 3aa as yellow oil. 1H NMR (CDCl3,
500 MHz): d=7.83 (d, J=7.0 MHz, 2H), 7.46–7.33 (m, 6H), 7.28–
7.26 (m, 2H), 7.12–7.08 (m, 2H), 6.89–6.86 (m, 1H), 6.16 (d, J=
8.0 MHz, 1H), 4.82–4.77 (m, 1H), 4.37–4.35 (m, 1H), 4.31–4.28 (m,
1H), 3.78–3.69 (m, 2H), 3.49–3.42 (m, 1H), 3.40–3.38 (m, 1H), 3.35–
3.32 (m, 1H), 3.06–2.99 (m, 1H), 2.79–2.75 (m, 1H), 2.29–2.23 (m,
1H), 1.84–1.79 ppm (m, 1H). 13C NMR (CDCl3, 125 MHz): d=173.1,
138.7, 135.1, 133.8, 132.6, 130.5, 129.1, 128.6, 128.3, 127.7, 127.1,
126.7, 125.8, 69.8, 66.1, 60.2, 59.5, 49.5, 40.8, 29.7 ppm; HRMS (ESI):
m/z calcd for C26H27N2O2: 399.2067 [M]+; found: 399.2064; HPLC
(Chiralpak IA, isopropanol/hexane 10:90, flow rate:
Removal of the benzamide group of compound 3aa was per-
formed to access chiral tetrahydroisoquinoline 4. As shown in
Scheme 2, the NÀN bond (3aa) could be easily cleaved by
SmI2 to give the tetrahydroisoquinoline 4 in 90% yield. The ee
value of 4 was determined by HPLC analysis of the N-Cbz-pro-
tected compound 5 (Cbz=carbobenzyloxy).
A plausible mechanism is illustrated in Scheme 3. The reac-
tion starts with the condensation of chiral prolinol silyl ether
Scheme 2. Synthetic transformations.
1.0 mLminÀ1
,
l=254 nm): tR (major)=33.0 min, tR
(minor)=36.2 min, ee=97%, d.r.>25:1; [a]2D5 = +7.6 (c=
1.0 in CH2Cl2).
Acknowledgements
The authors acknowledge the financial support from
National University of Singapore (Academic Research
Grant: R143000532112 and NRF-CRP7-2010-03) and
Guangdong University of Technology (China). The au-
thors also thank Prof. Keiji Maruoka for providing
some important C,N-cyclic azomethine imines.
Keywords: asymmetric synthesis
imines dienamines
tetrahydroisoquinolines
·
azomethine
·
·
cycloaddition ·
Scheme 3. Plausible mechanism.
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Received: February 9, 2014
Published online on && &&, 0000
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COMMUNICATION
&
Organocatalysis
W. Li, J. Wei, Q. Jia, Z. Du,* K. Zhang,
J. Wang*
&& – &&
Asymmetric Synthesis of
A dienamine-mediated enantioselec-
tive 1,3-dipolar cycloaddition catalyzed
by a chiral prolinol silyl ether has been
developed. Removal of the benzamide
group of the intermediates afforded
chiral C1-substituted tetrahydroisoqui-
nolines in high yields and excellent ste-
reoselectivities (see scheme).
Tetrahydroquinolines through a [3+2]
Cycloaddition Controlled by
Dienamine Catalysis
Dienamine Catalysis
Typically, HOMO-raising dienamine catalysts promote1,3-,
1,5-, or 2,5-reactivity. In contrast, asymmetric catalytic [3+2]
cycloaddition reactions that promote 4,5-reactivity of
dienamines have not been reported. A dienamine-mediated
enantioselective 1,3-dipolar cycloaddition catalyzed by
a chiral prolinol silyl ether has been developed. Removal of
the benzamide group of the intermediates afforded chiral
C1-substituted tetrahydroisoquinolines in high yields and
excellent stereoselectivities. For more details see the
Communication by Z. Du, J. Wang et al. on page && ff.
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