Phosphoric acid catalyzed diastereo- and enantioselective synthesis of substituted 1,3-diaminotetralins

Article abstract of DOI:10.1021/ol500946w

The reaction of anilines and phenylacetaldehydes in the presence of chiral phosphoric acid afforded optically active 1,2-trans, 2,3-cis 1,3-diaminotetralins in high yields with excellent diastereo- and enantioselectivities. The trans/cis product was readily isomerized to a trans/trans stereoisomer with no significant loss of enantiomeric purity.

Full text of DOI:10.1021/ol500946w

Letter
pubs.acs.org/OrgLett
Phosphoric Acid Catalyzed Diastereo- and Enantioselective Synthesis
of Substituted 1,3-Diaminotetralins
Guillaume Dagousset,† William Erb,† Jieping Zhu,‡ and Geraldine Masson*,†
́
†Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France
‡Laboratory of Synthesis and Natural Products, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fed
́ ́
erale de
Lausanne (EPFL), EPFL-SB-ISIC-LSPN, CH-1015 Lausanne, Switzerland
S
* Supporting Information
ABSTRACT: The reaction of anilines and phenylacetaldehydes in the presence of chiral phosphoric acid afforded optically
active 1,2-trans, 2,3-cis 1,3-diaminotetralins in high yields with excellent diastereo- and enantioselectivities. The trans/cis product
was readily isomerized to a trans/trans stereoisomer with no significant loss of enantiomeric purity.
he medicinal importance of the aminotetralins has been
known for a long time. For instance, sertraline is a much
In our previous studies on the phosphoric acid catalyzed8
three-component reaction of anilines 1, aldehydes 2, and
enecarbamates 3, we have provided convincing evidence that
this reaction went through a stepwise7a−d,9 process involving
the N-acyliminium intermediate 4.10 Therefore, we thought
that it might be possible to interrupt9−11 the Povarov process
by trapping the iminium function in 4 by the aromatic ring of
the phenylacetaldehyde derivative 2 (Ar2 = R2-C6H4) rather
than that of the aniline, which would lead to 1,3-
diaminotetralins 5 (Scheme 1).
T
studied antidepressant,1 and 2-aminotetralins such as [(S)-
(−)-5-OH-DPAT] and [(R)-(+)-7-OH-DPAT] are popular
targets in asymmetric synthesis because of their dopamine
agonist activity (Figure 1).2 Surprisingly, the great majority of
We therefore first investigated the three-component reaction
of 4-nitroaniline 1a (1.1 equiv), phenyl-acetaldehyde 2a (1.0
equiv), and enecarbamate 3a (1.0 equiv) in CH2Cl2 in the
presence of phosphoric acid 6a (0.1 equiv, Scheme 1). The
reaction was carried out at −30 °C to avoid the potential
isomerization of aliphatic N-arylimines as described in previous
works.12 To our surprise, we observed the formation of neither
desired 1,3-diaminotetralin 5a nor the Povarov adduct, even
when a large excess of 3a (5.0 equiv) was used. Instead, 1,3-
diaminotetralin 7a was produced in 61% yield as one
diastereomer with a 1,2-trans, 2,3-cis relative stereochemistry
assigned by NOESY experiments.13 The formation of 7a is
postulated to arise from a tandem sequence described in
Scheme 2. After condensation of the aniline 1a with
phenylacetaldehyde 2a, the resulting imine 8a would partially
isomerize into enamine 9a even at −30 °C, probably due to the
great stability of its CC double bond conjugated with the
aromatic ring. Then, nucleophilic attack of the enamine 9a onto
imine 8a would afford a new iminium intermediate 10a with
Figure 1. Examples of bioactive aminotetralins.
existing routes for the synthesis of these compounds are
generally limited to classical methods such as catalytic
hydrogenation3 or reductive amination,4 using the correspond-
ing tetralone derivatives as starting materials.5
Only rare examples of aminotetralin syntheses are based on
the construction of the saturated cycle. For example, Zard
developed a racemic synthesis of 4-substituted 2-aminotetralins
via a radical-based multistep route.6 The development of an
enantioselective one-pot synthesis of substituted aminotetralins
via the construction of the saturated cycle is therefore highly
desirable. Being involved in the enantioselective synthesis of
aza-heterocycles,7 we report herein the development of a short
and rapid one-pot domino synthesis of enantioenriched
substituted 1,3-diaminotetralins from easily available starting
materials.
Received: April 1, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol500946w | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. A Proposed Route for the Synthesis of 1,3-
Diaminotetralins via Intramolecularly Interrupted Povarov
Reaction
Table 1. Synthesis of 1,3-Diaminotetralins: A Survey of
a
Phosphoric Acid Catalysts
loading of 6
(mol %)
yield
7a (%)
ee
(%)
b
c
entry
Ar/6
1
2
3
4
5
6
7
4-ClC6H4/6a
Ph/6b
10
10
10
10
10
10
10
61
85
90
57
72
56
37
65
65
60
20
28
72
66
4-MeOC6H4/6c
4-tBuC6H4/6d
β-Naph/6e
CH(Ph)2/6f
CH(4-MeOC6H4)2/
6g
8
2,4,6-(iPr)3C6H2/6h
10
10
2.5
1
65
91
90
86
81
88
88
87
87
84
Scheme 2. Plausible Mechanism of the Reaction
d
9
6h
6h
6h
6h
d
10
d
11
d
12
0.5
a
General conditions: aniline 1a (0.10 mmol), aldehyde 2a (0.15
b
mmol), and 6 in CH2Cl2 (1.0 mL). Yields referred to a
chromatographically pure product. Enantiomeric excess was deter-
mined by chiral HPLC analysis (see Supporting Information). The
c
d
reaction was performed with the slow addition of 2a within 12 h.
very high (>95:5 dr) in favor of the trans/cis diastereomer, even
though the trans/trans diastereomer could sometimes be
isolated in small quantities (8:1 < dr < 17:1, entries 2, 5, 6,
and 9). Reactions with ortho-substituted anilines did not
proceed, probably due to steric reasons. Several ortho- or para-
substituted electron-poor or -rich phenylacetaldehydes were
also suitable reaction partners, leading to the corresponding
diaminotetralins 7j−l in good to high yields with good
diastereoselectivities and excellent enantioselectivities (up to
96% ee, entries 10−12). Notably, when meta-methylphenyl-
acetaldehyde was used, only one regioisomer bearing the
methyl group in position 7 of the tetralin was isolated in 77%
yield with good selectivites (dr = 7:1 and ee = 95%, entry 13),
with no trace of the 9-methylated regioisomer. Based on our
previous work, the phosphoric acid may act as a bifunctional
catalyst activating both 8 and 9 to allow a pseudointramolecular
si-face attack of enamine 9. Then, the intramolecular Friedel−
Crafts reaction would occur to form (1S,2S,3R)-1,3-diaminote-
tralins 7 (Scheme 3).
concurrent creation of two stereocenters. Subsequent intra-
molecular trapping of the Mannich-type adduct 10a would lead
to diaminotetralin 11a, and its condensation with another
molecule of phenylacetaldehyde 2a would finally afford 1,3-
diaminotetralin 7a, having an enamine function on the 3-N
position. Notably, the Doebner−von Miller14 tetrahydroquino-
line 12a obtained from the aza-Friedel−Crafts reaction of the
aromatic ring of aniline onto 10a was never observed.
Encouraged by the promising enantioselectivity (65% ee)
observed in this reaction, we further investigated the
asymmetric synthesis of 1,3-diaminotetralins 7 (Table 1). A
large number of phosphoric acid derivatives were tested, and
the best enantioselectivity was obtained with catalyst 6h having
a bulky 2,4,6-triisopropylphenyl (TRIP) group on the 3,3′
positions (88% ee, entry 8). The yield could also be improved
to 91% by adding 2a (1.5 equiv) within 12 h by means of a
syringe pump. We were also pleased to see that the catalyst
loading could be decreased to 1 mol % without any significant
loss of enantioselectivity or reactivity (entry 11).
The scope of this Brønsted acid catalyzed reaction was next
investigated using our optimized conditions. In order to avoid
the formation of the Doebner−von Miller tetrahydroquinoline
12 (Scheme 2), only electron-poor anilines were screened.15 As
shown in Table 2, all kinds of electron-poor meta- or para-
substituted anilines were appropriate substrates, affording
various diaminotetralins 7 in good to excellent yields with
high enantioselectivities. Diastereoselectivities were generally
During the NMR analysis of these diaminotetralins, we also
observed in some cases partial degradation and isomerization of
7trans/cis into 7trans/trans in CDCl3. We thought that this
isomerization could come from the slight acidity of this solvent,
which would probably enable a retro-Friedel−Crafts reaction as
shown in Scheme 4, leading to the thermodynamically more
stable diastereomer 7trans/trans
.
We then tried to optimize this reaction of isomerization
(Table 3). We first let the reaction mixture warm to room
temperature, hoping that the phosphoric acid itself could
catalyze this isomerization process. Unfortunately, even if some
desired product was obtained, we could only recover 53% of
B
dx.doi.org/10.1021/ol500946w | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 2. Scope of the Enantioselective Phosphoric Acid
Catalyzed Synthesis of 1,3-Diaminotetralins
Table 3. Optimization of the Isomerization of 7
a
f
dr
yield of 13 yield of 7 7trans/trans
:
ee
g
e
e
entry R1
R2
7
(%)
(%)
7trans/cis
(%)
a
1
2
3
4
5
6
4-Cl
4-Cl
4-Cl
4-Cl
4-Br
H
H
H
H
H
7e
7e
7e
7e
7i
25
53
95
9:1
1:2
9:1
9:1
8:1
8:1
90
90
b
c
c
traces
48
dr
7trans/cis
:
traces
86
ND
90
b
d
entry
R1
4-NO2
R2
7
yield (%)
7trans/trans ee (%)
d
d
d
traces
traces
5
1
H
H
H
H
H
H
H
H
H
7a
7b
7c
7d
7e
7f
91
99
90
95
82
68
85
98
95
92
71
92
77
>95:5
16:1
>95:5
>95:5
11:1
17:1
>95:5
8:1
88
90
75
84
94
89
81
88
94
93
95
96
95
82
90
2
4-CO2Et
3,5-di-Br
4-CF3
4-Cl
4-Br 4-OMe
7j
70
89
3
a
Solvent: CH2Cl2; temp: 25 °C; acidic conditions: 6h (0.1 equiv), 24
b
4
h. Solvent: CH2Cl2; temp: −30 °C; acidic conditions: 6h (0.1 equiv),
c
5
48 h. Solvent: CH2Cl2; temp: −30 °C; acidic conditions: HCl (2M,
d
e
6
4-Me-3-NO2
3-NO2
3-I
0.1 equiv), 2 h. Solvent: CHCl3; temp: 25 °C; 15 h. Yields referred
f
7
7g
7h
7i
to a chromatographically pure mixture of diastereomers. Diastereo-
meric ratio was determined by NMR spectra analysis. Enantiomeric
g
8
excess was determined by chiral HPLC analysis (see Supporting
Information). ND: not determined.
9
4-Br
10:1
7:1
10
11
12
13
4-Br
4-OMe
4-Br
7j
4-Br
7k
7l
>95:5
>95:5
7:1
tried to keep the temperature at −30 °C in order to avoid this
side reaction, but, in this case, the isomerization was incomplete
(7trans/trans:7trans/cis = 1:2, entry 2). Finally, the best conditions
included dissolving the diaminotetralin into chloroform and
letting the solution stir overnight at room temperature. Using
these conditions, we were pleased to see that isomerization
readily took place in good yields and with only a slight loss of
enantioselectivity (entries 4−6).
4-Br
2-Br
4-Br
3-Me
7m
a
General conditions: amine 1 (0.10 mmol), 6h (0.005 mmol) in
CH2Cl2 (1.0 mL), and slow addition of aldehyde 2 (0.15 mmol).
b
Yields referred to a chromatographically pure mixture of diaster-
c
eomers. Diastereomeric ratio was determined by NMR spectra
analysis. Enantiomeric excess was determined by chiral HPLC
analysis (see Supporting Information).
d
In summary, chiral phosphoric acid 6h successfully catalyzed
the enantioselective reaction between two molecules of aniline
1 and three molecules of phenylacetaldehyde 2, to provide
enantioenriched 1,2-trans, 2,3-cis 2-aryl-1,3-diaminotetralins 7.
By simply stirring a CHCl3 solution of 7, it isomerized readily
to the 1,2-trans, 2,3-trans diastereomer in high yields without
loss of enantiopurities.
Scheme 3. Activation Model and Possible Reaction
Mechanism
ASSOCIATED CONTENT
* Supporting Information
■
S
Catalysis optimization, spectroscopic data, and ee measure-
ments. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
Scheme 4. Mechanistic Proposal for the Isomerization of 7
■
*E-mail: geraldine.masson@cnrs.fr.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from CNRS is gratefully acknowledged. G.D.
and W.E. thank MESR for doctoral fellowships.
■
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