Stereoselective synthesis of aminoindanols via an efficient cascade aza-Michael-aldol reaction

Article abstract of DOI:10.1039/c2cc37102b

An efficient organocatalyzed strategy for the synthesis of 3-amino-1-indanols has been developed. This method is complementary to the conventional Friedel-Crafts strategy. It is also applicable to the synthesis of enantioenriched 3-amino-1-indanols.

Full text of DOI:10.1039/c2cc37102b

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Stereoselective synthesis of aminoindanols via an
efficient cascade aza-Michael–aldol reaction†‡
Cite this: Chem. Commun., 2013,
49, 4361
Hui Qian, Wanxiang Zhao, Herman H-Y. Sung, Ian D. Williams and Jianwei Sun*
Received 29th September 2012,
Accepted 2nd November 2012
DOI: 10.1039/c2cc37102b
www.rsc.org/chemcomm
An efficient organocatalyzed strategy for the synthesis of 3-amino-
1-indanols has been developed. This method is complementary to
the conventional Friedel–Crafts strategy. It is also applicable to the
synthesis of enantioenriched 3-amino-1-indanols.
Indane is an important structural unit in organic synthesis and
medicinal chemistry.1 Specifically, aminoindanols represent a parti-
cularly important family of indane-containing compounds, which
are found in numerous natural products and biologically active
compounds, such as HIV protease inhibitors (e.g. I, Fig. 1)2 and
rasagiline derivatives with anti-Parkinson activity (e.g. II).3 Never-
theless, despite the significance, methods for the efficient and
stereocontrolled assembly of the aminoindanol skeletons are under-
developed. For example, currently most widely employed synthesis
of 3-amino-1-indanols and their derivatives largely relies on the
reduction of the corresponding aminoindanones obtained from an
intramolecular Friedel–Crafts acylation reaction of 3-amino-3-
phenylpropanoic acid derivatives, typically in the presence of a
strong Lewis or Brønsted acid, such as AlCl3, H2SO4, or PPA.4,5
The use of strong acids may hamper its utility when labile func-
tional groups are involved. Moreover, the inherent nature of Friedel–
Crafts reaction, which typically favors electron-rich aromatic rings,
Scheme 1 Design of the aza-Michael–aldol cascade reaction.
may limit the scope of this synthetic strategy. Furthermore,
enantioenriched aminoindanols were obtained with chiral HPLC
separation or chiral resolving agents, such as tartaric acid derivatives
and enzymes.6 Herein, we report a new organocatalyzed strategy for
the stereoselective synthesis of 3-amino-1-indanols via an efficient
aza-Michael–aldol cascade reaction under basic conditions.
Recently, organocatalytic cascade reactions have been
demonstrated as a powerful tool for rapid construction of various
complex scaffolds.7 Among them, aza-Michael and aldol reactions
proved to be successful components. Inspired by these examples,
we hypothesized that benzaldehyde substituted with a Michael
acceptor at the ortho-position may provide a good setup for an
aza-Michael–aldol cascade reaction with a nitrogen-nucleophile to
synthesize 1,3-aminoindanols (path a, Scheme 1).8 However, the
expected aza-Michael-initiated cascade may be interfered by the
initial nucleophilic attack on the more reactive aldehyde function-
ality to alter the reaction sequence (path b).9 Therefore, in order to
favor the desired path a, we reasoned that the proper choice of a
weak nitrogen-nucleophile is important.
With the above reasoning in mind, we set out to evaluate our
hypothesis with the weak nucleophile p-toluenesulfonamide 2a
(Table 1). We were pleased to find that the reaction between 1a
and 2a, in the presence of 20 mol% of tBuOK, proceeds smoothly to
afford the desired aminoindanol product 3a, albeit in low yield and
with moderate diastereoselectivity (entry 1). The structure and
stereochemistry of the product were confirmed by single crystal
X-ray diffraction.10 In the absence of a base, no desired product 3a
was observed (entry 2). Next, we examined a range of inorganic and
Fig. 1 Selected bioactive compounds with aminoindanol subunits.
Department of Chemistry, The Hong Kong University of Science and Technology,
Clear Water Bay, Kowloon, Hong Kong SAR, China. E-mail: sunjw@ust.hk;
Fax: +852 23581594; Tel: +852 23587351
† This article is part of the ChemComm ‘Emerging Investigators 2013’ themed issue.
‡ Electronic supplementary information (ESI) available: Experimental procedure
and compound characterization. CCDC 902390–902392 and 904189. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/c2cc37102b
c
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Table 1 Condition optimization
Table 2 Nucleophile scope
Entry Base
Solvent Time (h) Conv. (%) Yielda (%) drb
Entry
R–NH2
Product
Yielda (%)
dr
1
2
tBuOK
—
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
6
6
6
6
6
6
6
6
6
100
o5
o10
90
63
0
—
5 : 1
—
—
—
—
—
—
7 : 1
9 : 1
7 : 1
5 : 1
10 : 1
4 : 1
8 : 1
8 : 1
11 : 1
7 : 1
8 : 1
1
2
3
4
5
R1 = p-Me
R1 = H
R1 = p-MeO
R1 = o-NO2
R1 = p-NO2
3ab
3b
3c
3d
3e
92
88
85
72
89
8 : 1
6 : 1
8 : 1
3
4
5
6
DABCO
KHMDS
NaHMDS
Et3N
g
—
—
g
90
>30 : 1
15 : 1
o30
o60
100
100
90
100
100
100
100
100
100
90
0h
o5h
49
7
8
9
Na2CO3
K2CO3
CsCO3
K3PO4
6
7
MeSO2NH2
tBuSO2NH2
3f
3g
82
84
5 : 1
8 : 1
63
10
11
12
13
14
15c
16d
17e
18f
6
6
48h
57
8
3hb
86
5 : 1
Guanidine MeCN
DBU
DBU
DBU
DBU
DBU
DBU
DBU
MeCN
THF
EtOAc
MeCN
MeCN
MeCN
MeCN
6
6
6
6
6
12
20
82
78
76
80
72
71
92
a
b
Isolated yield. The structure was confirmed by X-ray diffraction.
Table 3 Aldehyde scope
100
a
b
Isolated yield. dr was determined by 1H NMR and represents the
ratio of the major diastereomer and the total of the minor isomers.
c
e
d
Run at 0.2
M concentration. Run at 0.05 M concentration.
f g
10 mol% of DBU was used. Run at 0 1C. A mixture of many
h
products was obtained. Product 4a was observed.
Entry R1
R2
R3–NH2 Product Yielda (%) dr
b
1
2
3
4
5
4-F
4-F
Ph (1b)
Ph (1b)
Ph (1c)
Ph (1c)
TsNH2
NosNH2 3j
TsNH2 3k
NosNH2 3l
3i
87
80
93
82
84
8 : 1
3 : 1
8 : 1
7 : 1
20 : 1
5-CF3
5-CF3
4,5-(MeO)2 Ph (1d)
NsNH2
3m
6
TsNH2
3n
3o
86
10 : 1
organic bases (entries 3–12), such as DABCO, Et3N, Na2CO3, DBU,
etc. It is worth noting that the reaction with some of these bases,
such as Na2CO3 and K3PO4 (entries 7 and 10), affords a mixture of
3a and 4a, suggesting that the proposed path b (Scheme 1) is a
competitive reaction. Among these bases, DBU provides the best
results with exclusive formation of the desired 3a (entry 12). Further
screening of reaction parameters, such as solvent, concentration,
catalyst loading, and reaction temperature, identified the best
reaction conditions (entry 18). We also employed aniline and
benzylamine as nucleophiles, but both reactions afford a complex
mixture of various products. These results corroborate our
hypothesis that the choice of a weak nucleophile is important.
With the standard conditions established (entry 18, Table 1),
we next examined the reaction scope. As shown in Table 2, a
range of electron-rich and electron-deficient arenesulfonamides
participate efficiently in the aza-Michael–aldol cascade reaction
and the desired 3-amino-1-indanol products can be obtained in
good yield and with good stereoselectivity (entries 1–5). This
process can also be applied to other weak nitrogen-nucleophiles,
such as alkyl sulfonamides and thioamides (entries 6–8).
7
8
9
10
11
H
H
H
H
H
p-MeOPh (1f) TsNH2
p-MeOPh (1f) NosNH2 3p
p-NO2Ph (1g) TsNH2
p-NO2Ph (1g) NsNH2
89
80
90
76
84
9 : 1
3 : 1
4 : 1
20 : 1
7 : 1
3q
3r
Me (1h)
NosNH2 3s
a
Isolated yield. b Ns: 2-nitrobenzenesulfonyl; Nos: 4-nitrobenzenesulfonyl.
nitrogen atom in the cyclization step. In the case of ester 1j, tricyclic
product 5c was obtained, which results from a further intramolecular
transamidation step (eqn (3)). It is noteworthy that all these reactions
are highly efficient and diastereoselective.
The aldehyde substrate scope is shown in Table 3. The
reaction efficiency is not affected by the electronic nature of
the aryl linker, which is a potential problem in the conventional
synthesis employing Friedel–Crafts reaction. Thus, substrates
with either electron-rich or electron-deficient aryl linkers all give
good to excellent yield and diastereoselectivity. Similarly, we also
evaluated the effect of the substituent (R2) on the carbonyl group.
Again, the desired aminoindanol products are efficiently formed
with either an electron-rich or an electron-poor aryl group. Alkyl
ketones are also effective substrates (entry 11).
During our scope study of the nucleophiles, we found that thiourea
as the nucleophile results in the formation of a completely different
set of products. As shown in eqn (1)–(3), regardless of the different
electron-withdrawing groups (e.g. ketone 1a, nitrile 1i, and ester 1j),
the reactions with thiourea all gave the isoindolin-1-ol type products
(5a–5c), presumably due to the relatively strong nucleophilicity of the
(1)
c
4362 Chem. Commun., 2013, 49, 4361--4363
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indanols, a privileged skeleton of significant importance in
organic synthesis and medicinal chemistry. Under mild and
basic conditions, the current reaction is complementary to the
conventional Friedel–Crafts strategy, where strong acidic con-
ditions are employed and the cyclization step highly depends
on the substrate electronic environment. Without modifica-
tion, the standard conditions can be applied to the synthesis of
enantioenriched 3-amino-1-indanols using a cleavable chiral
sulfinamide nucleophile.
This work was supported by the Hong Kong University of
Science and Technology.
Notes and references
Scheme 2 Synthesis of enantioenriched 3-amino-1-indanol derivatives.
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We were also interested in applying our method in the
synthesis of enantioenriched aminoindanol products. Gratify-
ingly, without modification of the standard conditions, the
desired aza-Michael–aldol cascade process with (R)-tert-butanesul-
finamide11 as the nucleophile proceeds smoothly to afford the
desired product 3t with excellent efficiency and stereocontrol
(Scheme 2). The structure and absolute stereochemistry of the
product were also confirmed by single crystal X-ray diffraction.10
The product can also be transformed to other useful compounds.
For example, after a simple oxidation step, sulfonamide 6 can be
obtained with >99% ee; further oxidation by MnO2 affords
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I. Ibrahem, G.-L. Zhao, L. Eriksson and A. Cordova, Adv. Synth.
Catal., 2007, 349, 827–832; (c) E. L. Richards, P. J. Murphy, F. Dinon,
S. Fratucello, P. M. Brown, T. Gelbrich and M. B. Hursthouse,
Tetrahedron, 2001, 57, 7771–7784.
9 For selected examples initiated by an attached aldehyde followed by
an intramolecular Michael reaction on the same type of substrates,
see: (a) F. A. Luzzio and O. E. Okoromoba, Tetrahedron Lett., 2011,
´
52, 6530–6533; (b) E. Sanchez-Larios, J. M. Homes, C. L. Daschner
and M. Gravel, Org. Lett., 2010, 12, 5772–5775.
enantiopure aminoindanone 7 with high efficiency (83% yield 10 CCDC 902390 (3a), 902391 (3h), 904189 (5c) and 902392 (3t).
Compounds 3a, 3h, and 5c are racemic, and compound 3t is
enantiopure‡.
11 M. T. Robak, M. A. Herbage and J. A. Ellman, Chem. Rev., 2010, 110,
based on recovered starting material, >99% ee).
In summary, we have developed an organocatalyzed strategy
for the efficient and diastereoselective synthesis of 3-amino-1-
3600–3740.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 4361--4363 4363