The asymmetric synthesis of CF3- or -CF2-substituted tetrahydroquinolines by employing a chiral phosphoric acid as catalyst

Article abstract of DOI:10.1039/c2cc18064b

CF₃- or -CF₂-containing tetrahydroquinolines have been asymmetrically synthesized from the reaction of fluorinated N-arylimines with benzyl N-vinylcarbamate in the presence of a chiral phosphoric acid.

Full text of DOI:10.1039/c2cc18064b

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COMMUNICATION
The asymmetric synthesis of CF3- or –CF2-substituted
tetrahydroquinolines by employing a chiral phosphoric acid as catalystw
Jin-Hong Lin,a Guoqiang Zong,a Ruo-Bing Du,a Ji-Chang Xiao*a and Shubin Liu*b
Received 24th December 2011, Accepted 11th June 2012
DOI: 10.1039/c2cc18064b
CF3- or –CF2-containing tetrahydroquinolines have been asym-
metrically synthesized from the reaction of fluorinated N-aryli-
mines with benzyl N-vinylcarbamate in the presence of a chiral
phosphoric acid.
Sometimes slow addition of the starting material was necessary
to obtain good enantioselectivities. Combined with the potential
importance of CF3- or –CF2-substituted tetrahydroquinolines,
we explored their asymmetric synthesis by chiral phosphoric acid
catalysis.
Under the catalysis of phosphoric acid 3a (7 mol%), the
reaction of N-(2,2,2-trifluoroethylidene)-4-methoxyaniline
(1a) (1 equiv.) with benzyl N-vinylcarbamate (2a) (2 equiv.)
in dichloromethane proceeded smoothly to give the desired
tetrahydroquinoline in 53% yield (Table 1, entry 1). However,
the enantioselectivity was very poor. Then a series of phosphoric
acids with different substituents at the 3- and 30-positions of the
binaphthyl scaffold were investigated (entries 2–6). Introducing
bulky substituents gave rise to a dramatic increase in enantio-
selectivity (entry 2). With further increasing of the size of the
substituent at the 3 position on the binaphthyl skeleton, a 96% ee
value could be obtained (entry 3), but the reaction became
a little complex in this case. Some side products could be
Organofluorine compounds show so many unusual properties
that they have found widespread application in dyes, polymers,
agrochemicals and pharmaceuticals.1 The incorporation of
CF3- or –CF2-groups into organic molecules would affect their
biological properties. In pharmaceuticals, the asymmetric
introduction of CF3- or –CF2-groups always significantly
improves their bioactivities.2 Therefore, the enantioselective
construction of CF3- or –CF2-substituted stereogenic centers has
attracted much attention. In the past years, great progress has
been made in the field of asymmetric formation of CF3-substituted
stereogenic centers.3 But for the construction of –CF2-substituted
stereogenic centers, only a few methods have been developed and
few examples achieve excellent enantioselectivities.4
Tetrahydroquinoline derivatives exhibit interesting biological
activities.5 Preparation of these novel compounds continues to be
an important goal of synthetic organic chemists. Although CF3-
substituted tetrahydroquinoline derivatives have been previously
obtained,6 the asymmetric synthesis of CF3- or –CF2-substituted
tetrahydroquinolines has never been realized.
Table 1 Screening of reaction conditions
Chiral BINOL-derived phosphoric acids, as an efficient class
of organocatalyst, have been applied in a variety of asymmetric
organic synthesis.7 Tetrahydroquinoline derivatives have been
prepared by chiral phosphoric acid catalysis from different
reaction routes.8 Akiyama et al. reported the synthesis of
tetrahydroquinolines from a vinyl ether and N-arylimines.8a
Masson et al. synthesized the same derivatives in excellent
enantioselectivities through a three-component reaction.8b,c
Ricci et al. found that the reaction between 2- or 3-vinylindoles
with aldimines afforded tetrahydroquinolines in good yields.8d
However, there still remain some problems to be solved. For
example, low temperature was usually needed. In some cases,
the use of o-hydroxyaniline as starting material was mandatory.
Entry Catalyst (mol%) Solvent 1a : 2a T (h) Yield (%)a ee (%)b
1
2
3
4
5
6
7
8
9
10
3a (7)
3b (7)
3c (7)
3d (7)
3e (7)
3f (7)
3d (7)
3d (15)
3d (15)
3d (15)
CH2Cl2 1 : 2
CH2Cl2 1 : 2
CH2Cl2 1 : 2
CH2Cl2 1 : 2
CH2Cl2 1 : 2
CH2Cl2 1 : 2
PhCH3 1 : 2
CH2Cl2 1 : 2
CH2Cl2 1 : 2
5
4
53
47
58
71
39
77
96
99
97
—
99
99c
99
99
23
22
30
48
27
22
36
69
Trace
53
82
82
47
a Key Laboratory of Organofluorine Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 345 Lingling
Road, Shanghai, 200032, P. R. China. E-mail: jchxiao@sioc.ac.cn
b Research Computing Center, University of North Carolina,
Chapel Hill, NC, 27599-3420, USA. E-mail: shubin_liu@unc.edu
w Electronic supplementary information (ESI) available: See DOI:
10.1039/c2cc18064b
CH2Cl2 1 : 1.1 22
a
b
Isolated yield of cis isomer. Enantiomeric excess was determined by
chiral HPLC analysis. cis : trans 4 98: 2 determined by 19F NMR.
c
c
7738 Chem. Commun., 2012, 48, 7738–7740
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observed by 19F NMR. The side reactions could be suppressed
when the more bulky phosphoric acid 3d was used as the
catalyst, and the trifluoromethylated tetrahydroquinoline 4a
was obtained with excellent enantioselectivity (entry 4). The
reaction catalyzed by 3e also proceeded smoothly. However,
longer reaction time was necessary for the completion of the
reaction (entry 5). 3f was not a suitable catalyst for this
reaction (entry 6). Therefore, 3d was chosen as the appropriate
catalyst for this transformation.
Fig. 1 NOESY of cycloadduct 4a.
The relative configuration of the cycloadduct 4a was determined
by NOESY (Fig. 1). The NOE experiment showed a correlation
between Ha and Hd, which means that the two hydrogens exist in a
cis configuration. Besides this, the correlation between Ha and Hc
and the correlation between Hc and Hd provided further evidence
for the cis configuration (see ESIw). The configurations of other
cycloadducts were surmised by analogy.
Dichloromethane was found to be a better solvent than toluene
(entry 7 vs. 4). Increasing the amount of 3d from 7 mol% to
15 mol% resulted in higher yield with excellent diastereoselectivity
(cis : trans 4 98 : 2 determined by 19F NMR) (entry 8 vs. 4).
Prolonging the reaction time made no improvement in the
conversion (based on 19F NMR) or the yield (entry 9 vs. 8).
Lowering the ratio of aldimine 1a to enamine 2a from 1 : 2 to
1 : 1.1 greatly decreased the yield (entry 10 vs. 8). These results
showed that using 3d (15 mol%) as the catalyst, dichloro-
methane as the solvent and 1 : 2 of aldimine to enamine is the
suitable reaction conditions for the asymmetrical synthesis of
CF3-substituted tetrahydroquinolines.
Computational studies using density functional theory
(DFT) have been conducted to understand the reaction
mechanism of these reactions. The model system employed
3d as the catalyst. Two possible pathways with 2a aligned
differently on top of 1a to form different products were
separately considered. The calculations were performed at
the B3LYP/6-311+G(d,p)9 level of theory. The transition
states of these two pathways, as shown below, were obtained
(Fig. 2). We found that the first pathway (TS1) is much more
favourable than the second one (TS2), with a 15.0 kcal molꢀ1
lower barrier height. This difference results from the strong
hydrogen-bonding interactions between 1a and chiral phosphoric
acid. This result is in good agreement with our experimental finding.
Moreover, we find that the two pathways have a different reaction
mechanism. The first pathway takes the step-wise mechanism with
the terminal carbon atom of 2a forming a C–C bond with 1a at
first, whereas the second mechanism is concerted. We performed
intrinsic reaction coordinate (IRC) calculations, whose results have
confirmed this observation.
Combining our present results with the literature reports,8c,10
we propose a stepwise mechanism (Fig. 3). Chiral phosphoric
acid acts as a bifunctional catalyst that activates both the
nucleophile and electrophile. The acidic proton and phosphoryl
oxygen of the catalyst form the hydrogen bond with imine and
2a, respectively (transition state A). Subsequently, 2a attacks
the imine to give the intermediate B. The CQN bond of the
intermediate B is activated by the chiral phosphoric acid and
then easily attacked by the aromatic ring. After the intra-
molecular Friedel–Crafts reaction, the cycloadduct is formed
and the catalyst is regenerated.
The reaction could be applied to a variety of aldimines
under these optimal reaction conditions (Table 2). All of
the reactions proceeded smoothly to give the corresponding
cycloadducts 4a–4l in high yields (81% to 97%), excellent
diastereoselectivities (cis : trans
4 97 : 3 determined by
19F NMR) and enantioselectivities (89% to 99% ee). Just as
1a, similar results were obtained when 1b or 1c was used as the
starting material. The reactions proceeded quickly in the first
24 h and then the conversion almost stopped in the next
12 hours (determined by 19F NMR). Even prolonging the
reaction time to 50 h or 70 h, the yield was not greatly
increased (entries 2 and 3). Complete conversions of the other
starting materials were achieved in less than 24 h and excellent
results were obtained (entries 4–12).
Table 2 Scope of the Brønsted acid-catalyzed enantioselective reactionsa
In conclusion, CF3- or –CF2-substituted stereogenicity in
tetrahydroquinolines has been constructed based on the reaction
of N-arylimines with benzyl N-vinylcarbamates in the presence of
Entry Rf
R
T (h) Product, yield (%)b ee (%)c
1
2
CF3 (1a)
CF2Br (1b)
OMe 22
OMe 50
OMe 70
OMe
OMe
4a, 82
4b, 84
4c, 82
4d, 84
4e, 91
4f, 81
4g, 97
4h, 96
4i, 93
4j, 94
4k, 89
4l, 90
99
99
98
89
97
99
98
97
97
98
98
98
3
4
CF2Cl (1c)
CF2H (1d)
3
9
5
6
7
C4H9CF2 (1e)
CH2QCHCF2 (1f)
PhCF2 (1g)
OMe 24
OMe 25
8
9
10
11
12
(4-Br)-C6H4CF2 (1h) OMe 17
(4-OMe)-C6H4CF2 (1i) OMe 18
(4-Me)-C6H4CF2 (1j) OMe 18
(3-Me)-C6H4CF2 (1k) OMe 23
PhCF2 (1l)
Me 13
a
In all cases, cis : trans 4 97 : 3 based on 19F NMR. Reaction
conditions: 1 (0.2 mmol), 2a (0.4 mmol) and 3d (15 mol%) were
b
stirred in CH2Cl2 (2 mL). Isolated yield of cis isomer. Enantio-
c
meric excess was determined by chiral HPLC analysis.
Fig. 2 DFT-optimized transition states (hydrogen atoms not shown).
Chem. Commun., 2012, 48, 7738–7740 7739
c
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Fig. 3 The proposed reaction mechanism.
a chiral phosphoric acid. The results presented here provide a
versatile platform for the asymmetrical synthesis of tetrahydro-
quinoline derivatives with potential interesting bioactivities.
Studies to apply the chiral phosphoric acid to other enantioen-
riched CF3- or –CF2-group substituted compounds are currently
underway.
We thank the National Natural Science Foundation (21032006,
21172240), the 973 Program of China (2012CBA01200) and the
Chinese Academy of Sciences for financial support.
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c
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This journal is The Royal Society of Chemistry 2012