Bronsted acid-catalyzed enantioselective Friedlaender condensations: Achiral amine promoter plays crucial role in the stereocontrol

Article abstract of DOI:10.1039/c1cc14873g

A highly enantioselective Friedlaender condensation has been established by using chiral Bronsted acids in combination with achiral amines to give quinolines in high yields (up to 99%) and with excellent enantioselectivities (up to 95%).

Full text of DOI:10.1039/c1cc14873g

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COMMUNICATION
Brønsted acid-catalyzed enantioselective Friedlander condensations:
achiral amine promoter plays crucial role in the stereocontrolwz
Lei Ren, Tao Lei and Liu-Zhu Gong*
Received 7th August 2011, Accepted 5th September 2011
DOI: 10.1039/c1cc14873g
A highly enantioselective Friedlander condensation has been
established by using chiral Brønsted acids in combination with
achiral amines to give quinolines in high yields (up to 99%) and
with excellent enantioselectivities (up to 95%).
Friedlander condensation reactions also commenced with
a Mannich-type pathway.10 These facts stimulated us to
envisage the use of a combined catalyst consisting of chiral
phosphoric acid 1 and achiral amine 2 to promote the
asymmetric Friedlander condensation of ortho-aminobenzal-
dehyde derivatives 3 with prochiral ketones 4, wherein an
enantioselective desymmetrization occurred.
The quinoline derivatives constitute an important class of
molecules that exhibit interesting pharmacological properties.1
Among those, tacrines have found applications in the treatment
of cognitive disorders such as Alzheimer’s disease, and are
thereby particularly synthetically appealing.2 Recent studies
on biological activities of tacrines revealed that the non-racemic
molecules showed important pharmacological activities.3 The
tacrines could be accessed from the quinolines by easily operative
reactions.4 Among numerous synthetic approaches to quinolines,
the Friedlander condensation reaction represents one of
the simplest methods.5 However, almost 130 years after the
Friedlander condensation appeared its catalytic asymmetric
version had not been described until recently Seidel established
the first enantioselective variant by using enamine catalysis,
wherein the highest level of enantioselectivity reached 95% ee,
whereas no electronically rich ortho-aminobenzaldehydes were
described as substrates.6 Moreover, no chiral catalysts other than
amino acids have yet been found to be able to offer an enantio-
selective Friedlander condensation. Herein, we demonstrate that a
chiral Brønsted acid is capable of controlling the stereochemistry
of Friedlander condensation between ortho-aminobenzaldehydes
and prochiral cyclic ketones in combination with an achiral
amine promoter. More interestingly, electronically rich ortho-
aminobenzaldehydes also participated in the current Friedlander
condensation with excellent levels of enantioselectivity (up to
95% ee).
Initially we conducted a reaction of 2-aminobenzaldehyde
3a with 4-phenylcyclohexanone 4a in toluene at room temperature
in the presence of 10 mol% of phosphoric acid 1a and 20 mol% of
4-methoxyaniline 2a (Table 1, entry 1). Encouragingly, the reaction
proceeded smoothly to give the chiral quinoline 5aa in 68% yield,
but only 8% ee was observed. However, in the absence of 2a,
the phosphoric acid 1a led to a much slower reaction.11
In an attempt to improve the stereoselectivity, we tuned the
number of equiv. of p-anisidine systematically (entries 1–5).
As a result, an increasing amount of p-anisidine not only
considerably accelerated the reaction, but also gave an
Table 1 Screening of chiral Brønsted acids and achiral amine promotersa
Entry B*–H Ar
RNH2 (2, x equiv.) Yieldc (%) Eed (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
Ph
Ph
Ph
Ph
Ph
Ph
PMP (2a, 0.2)
PMP (2a, 0.5)
PMP (2a, 1.5)
PMP (2a, 2.5)
PMP (2a, 3.0)
PMP (2a)
68
73
74
76
43
93
95
99
89
92
87
94
92
99
8
10
23
33
31
53
74
66
59
78
75
83
78
79
78
—
1a
1ab
1bb
1cb
1db
1bb
1bb
1bb
1bb
1bb
1bb
1bb
4-BiPh PMP (2a)
2-Naphthyl PMP (2a)
We have demonstrated that chiral phosphoric acids7 are
able to control the stereochemistry in a Mannich reaction8 and
a Biginelli-like reaction9 that mechanistically starts with a
Mannich-type procedure. Actually some amine-promoted
9
4-ClC6H4
4-BiPh
4-BiPh
4-BiPh
4-BiPh
4-BiPh
4-BiPh
4-BiPh
PMP (2a)
10
11
12
13
14
15
16
4-MeC6H4 (2b)
3-MeC6H4 (2c)
2-Naphthyl (2d)
4-BrC6H4 (2e)
4-FC6H4 (2f)
Hefei National Laboratory for Physical Sciences at the Microscale
and Department of Chemistry, University of Science and Technology
of China, Hefei 230026, People’s Republic of China.
E-mail: gonglz@ustc.edu.cn; Fax: (+86)-551-360-6266
w This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
z Electronic supplementary information (ESI) available: General
information, synthesis of substrates, characterization data for the
products. See DOI: 10.1039/c1cc14873g
3,4-Me2C6H3 (2g) 98
4-NO2C6H4 (2h) none
a
Reaction conditions: 3a (0.1 mmol), 4a (0.3 mmol), toluene (1 mL), 3 A
b
MS (200 mg). Acidified with 6 M HCl and 2.5 equiv. of aromatic
c
d
e
amine was used. Isolated yield. Ee determined by HPLC. Absolute
configuration was determined by comparing optical rotation with that
of the known product.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 11683–11685 11683

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improved enantioselectivity. When 2.5 equiv. of p-anisidine
was employed, the reaction delivered 76% yield and 33% ee,
whereas the further increase in the amounts of aniline 2a did
not give an enhanced result (entry 5). Interestingly, the use of
the acidified phosphoric acid 1a12 enabled the reaction to give
a significantly improved yield and enantioselectivity (entry 6).
The survey of the BINOL-based phosphoric acids, which were
all washed with 6 M HCl, revealed that 1b turned out to be the
most promising catalyst in terms of yield and enantioselectivity
(entries 6–9). With the optimal phosphoric acid 1b in hand, we
examined the effect of the aniline component on the reaction
performance. Thus, a variety of structurally diverse anilines
were surveyed as promoters in the reaction. More interestingly,
the structure of the aniline had considerable influence on the
stereoselectivity. As a result, 2-naphthylamine was found to be
the best achiral promoter capable of assisting 1b to offer 83%
ee (entries 10–16).
suitable for the reaction (entries 7–10). In particular, much
diminished ee was observed upon conducting the reaction in
CH2Cl2 and CHCl3 (entries 5 and 6). On the other hand,
variation of the experimental method also led to varied
stereoselectivity. As such, a slightly enhanced ee was obtained
by changing the sequence of adding the substrates (entry 11). The
final optimization of the conditions by investigating the reaction
parameters, including temperature, additive, concentration and
equiv. of 4-phenylcyclohexanone, found a protocol offering
5aa in 93% ee (entries 12–20).
Under the optimized conditions, we examined the substrate
scope of various 2-aminobenzaldehyde derivatives (Table 3). A
variety of electron-donating and withdrawing substituents in
the 2-aminobenzaldehydes were well tolerated, leading to the
products with excellent levels of enantioselectivity (entries 1–8).
The introduction of two strong electron-donating groups to the
substrates, as shown in 3f and 3g, resulted in an incomplete
reaction, but the enantioselectivity remained high (entries 5 and
6, 90% and 94% ee).
The further optimization of the reaction conditions was
focused on the examination of solvents (Table 2). The enantio-
selective desymmetrization proceeded smoothly to 83% ee and
94% yield when the reaction was conducted in toluene (entry 1).
The use of other non-polar solvents, including o-xylene,
m-xylene and p-xylene, gave almost identical results as that
observed in toluene (entries 2–4). A nonpolar CCl4 and
comparably less polar Et2O gave a slightly diminished ee
(entries 5 and 6). However, some polar solvents were not
Further investigation of the substrate scope was focused on
various 4-substituted cyclohexanones (Table 4). The 4-alkyl
cyclohexanones participated in the reaction in high yields and
fairly good enantioselectivities (entries 1 and 2). Notably,
when 4-aryl cyclohexanones were used as substrates, the
variation of the substituents in the aryl group has little effect
on the stereoselectivity. In this context, generally excellent
enantioselectivities ranging from 93% to 95% ee (entries 3–7).
On the basis of experimental observations, we propose a
reaction mechanism (Scheme 1). The reaction may proceed
starting with a condensation of 2-aminobenzaldehyde with
aniline to generate 2-aminobenzaldimine A. As excess
amounts of achiral aniline was required to ensure high levels
of stereocontrol, the aniline likely formed an enamine B by a
condensation reaction with 4-substituted cyclohexanone under
promotion of Brønsted acid.13 Subsequently, an enantio-
selective Mannich reaction of 2-aminobenzaldimine A with
enamine B occurred under the catalysis of the Brønsted acid,
which acts as a bifunctional catalyst to simultaneously activate
both the imine and enamine by hydrogen-bonding interaction. In
Table 2 Optimization of reaction conditionsa
Entry Additive Solvent
T/1C Methodb Yieldc (%) Eed (%)
1
2
3
4
5
6
7
8
3 A MS Toluene
3 A MS o-Xylene
3 A MS m-Xylene
3 A MS p-Xylene
3 A MS CCl4
25
25
25
25
25
25
25
25
25
25
25
0
A
A
A
A
A
A
A
A
A
A
B
B
B
B
B
B
B
B
B
B
94
67
74
92
89
75
83
87
66
60
95
80
99
85
79
70
82
83
60
83
83
83
81
83
75
76
35
33
49
45
88
91
90
91
91
92
3 A MS Et2O
3 A MS CHCl3
3 A MS CH2Cl2
3 A MS THF
Table 3 Scope of 2-aminobenzaldehyde derivativesa
9
10
11
12
13
14
15
16
17
18
19
20
3 A MS DMF
3 A MS Toluene
3 A MS Toluene
3 A MS Toluene
4 A MS Toluene
5 A MS Toluene
Na2SO4 Toluene
MgSO4 Toluene
MgSO4 Toluene
MgSO4 Toluene
MgSO4 Toluene
ꢀ10
0
0
0
0
0
0
0
Entry
5
R
Yieldb (%)
Eec (%)
92
93e
92e,f
93e,g
1
2
3
4
5
6
7
8
5ba
5ca
5da
5ea
5fa
5ga
5ha
5ia
5-MeO
5-EtO
5-BnO
86
66
66
71
50
55
94
94
87
92
95
84
90
94
87
95
a
Reaction conditions: 3a (0.1 mmol), 4a (0.3 mmol), toluene (1 mL),
b
3 A MS (200 mg). Method A: After the mixture of 3a, 2d, additive
5-F
4,5-(MeO)2
4,5-(OCH2O)–
4-Cl
and catalyst 1b was stirred for 2 h, the ketone was added; Method B:
After the mixture of 3a, 2d and additive was stirred for 2 h, the catalyst
1b was added and stirred for 0.5 h, and the ketone was finally added in
5-Me
c
d
a
dropwise for
e
1
Concentration = 0.05 M. Ratio of 3a/4a = 1/1. Ratio of
h. Isolated yield. Ee determined by HPLC.
g
Reaction conditions: 3 (0.1 mmol), 4a (0.2 mmol), 2d (0.25 mmol), 1b
b
(0.01 mmol), toluene (2 mL), MgSO4 (200 mg). Isolated yield.
f
h
3a/4a = 1/2. Absolute configuration was determined by comparing
c
d
Ee determined by HPLC. Absolute configurations were determined
optical rotation with that of the known product.
by comparing with the known products.
c
11684 Chem. Commun., 2011, 47, 11683–11685
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Table 4 Scope of 4-substituted cyclohexanone derivativesa
Notes and references
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Contemporary Heterocyclic Chemistry, Wiley, New York, 1982,
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Chemistry, Pergamon Press, Oxford, UK, 1985.
Entry
5
R
Yieldb (%)
Eec (%)
1
2
3
4
5
6
7
5ib
5ic
5id
5ie
5if
Me
Et
70
73
93
79
80
99
99
87
88
93
93
95
93
94
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4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-PhC6H4
2-Naphthyl
5ig
5ih
a
Reaction conditions: 3i (0.1 mmol), 4 (0.2 mmol), 2d (0.25 mmol), 1b
b
(0.01 mmol), toluene (2 mL), MgSO4 (200 mg). Isolated yield.
c
d
The ee was determined by HPLC. The absolute configurations
were determined by comparing with that of the known products.
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Scheme 1 The plausible reaction mechanism.
this step, the asymmetric desymmetrization occurred on the 4-sub-
stituted cyclohexanone and therefore, the variation of the aryl
substituent of the aniline affects the stereoselectivity dramatically
(Table 1, entries 10–16). Then, the aryl amine of aniline moiety in D
attacks the resultant iminium leading to the formation of inter-
mediate E, which finally undergoes aromatization to release aniline,
affording the chiral quinolines.
6 L. Li and D. Seidel, Org. Lett., 2010, 12, 5064.
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In summary, we have developed an enantioselective Friedlander
condensation catalyzed by chiral Brønsted acid in combination
with achiral aniline. The efficient desymmetrization of 4-substituted
cyclohexanones derivatives in reaction with a number of ortho-
aminobenzaldehydes gives chiral quinolines in high yields (up to
99%) and excellent enantioselectivities (up to 95%). In particular,
the protocol tolerates electronically rich ortho-aminobenaldehydes
with high levels of stereochemical control, consequently, represents
an important method complementary to the known reaction.
We are grateful for financial support from NSFC
(20732006), CAS, MOST (973 project 2010CB833300), and
the Ministry of Education.
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11 The product was isolated in 15% yield after 3 days.
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c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 11683–11685 11685