Organocatalytic enantioselective aza-Friedel-Crafts reaction of sesamols with N-sulfonylimines catalyzed by 6′-OH Cinchona alkaloids

Article abstract of DOI:10.1016/j.tetlet.2013.06.032

An unprecedented asymmetric aza-Friedel-Crafts reaction of sesamol with N-sulfonylimines has been reported. A variety of N-sulfonylimines reacts with sesamol derivatives in the presence of 6′-OH Cinchona alkaloids to provide a new series of chiral aminophenol adducts in good yield and good to high level of enantioselectivity.

Full text of DOI:10.1016/j.tetlet.2013.06.032

Tetrahedron Letters 54 (2013) 4613–4616
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Organocatalytic enantioselective aza-Friedel–Crafts reaction
of sesamols with N-sulfonylimines catalyzed by 60-OH Cinchona
alkaloids
⇑
Pankaj Chauhan, Swapandeep Singh Chimni
U.G.C. Sponsored Centre for Advance Studies in Chemistry, Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An unprecedented asymmetric aza-Friedel–Crafts reaction of sesamol with N-sulfonylimines has been
reported. A variety of N-sulfonylimines reacts with sesamol derivatives in the presence of 60-OH Cinchona
alkaloids to provide a new series of chiral aminophenol adducts in good yield and good to high level of
enantioselectivity.
Received 8 March 2013
Revised 4 June 2013
Accepted 8 June 2013
Available online 22 June 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Friedel–Crafts reaction
Cinchona alkaloids
Imines
Sesamol
Organocatalysis
Asymmetric organocatalytic Friedel–Crafts (F–C) reaction has
emerged as a powerful tool for the synthesis of highly functional-
ized chiral arene and heteroarene derivatives.1,2 One of the impor-
tant parts of this reaction is stereoselective aza-Friedel–Crafts
reaction, which involves 1,2-addition of aromatic and hetero-aro-
matic compounds to the imines to provide chiral amines bearing
arene/heteroarene substituents.3–7 In 2004, Terada and co-workers
developed the first organocatalytic asymmetric aza-Friedel–Crafts
reaction, employing chiral phosphoric acid as catalyst for 1,2-addi-
tion of furan derivatives to aldimines.4 Since then, asymmetric
organocatalytic aza-Friedel–Crafts reaction of indole and pyrrole
derivatives3 has been at the center stage for obtaining bioactive
molecules, but organocatalytic enantioselective aza-Friedel–Crafts
reactions of other arene derivatives have scarcely been investi-
gated. In 2011, our group5 and Wang’s group6 independently re-
ported the enantioselective aza-Friedel–Crafts reaction of
naphthols with N-sulfonylimines catalyzed by 60-OH Cinchona
alkaloids. Recently, Qu’s group has published an enantioselective
aza-Friedel–Crafts reaction of phenols with N-tosylaldimines.7
An electron rich phenol, sesamol is a very useful molecule
which can be functionalized by asymmetric as well as nonasym-
metric F–C reaction.8,9,11–13 Sesamol has a 1,3-benzodioxol moiety,
which is found in many synthetic bioactive and natural molecules
such as (+)-bicuculline, paroxetine, tadalafil, and 5,6-methylenedi-
oxy-2-aminoindane (MDAI) (Fig 1).10 The reactivity of sesamol
derivatives was exploited independently by Zhang’s11 and Nagasa-
wa’s12 groups for enantioselective Michael-type Friedel–Crafts
reaction with nitro-olefins catalyzed by cinchonidine derived thio-
urea-tertiary amine and C3-linked guanidine/bis-thiourea organo-
catalyst, respectively. Very recently, Feng and co-workers
published an enantioselective 1,4-addition of activated phenols
including sesamol to (E)-4-oxo-4-arylbutenoates promoted by
N,N0-dioxide-scandium (III) complex as the catalyst.13 The use of
sesamol derivatives in catalytic enantioselective Friedel–Crafts
reaction is limited to 1,4-addition on unsaturated acceptors and
1,2-addition remains elusive. To the best of our knowledge, the
enantioselective aza-Friedel–Crafts reaction of sesamol derivatives
is not known.
Among various organocatalysts, the C6’-OH Cinchona alkaloids
have emerged as powerful bifunctional catalysts for various asym-
metric transformations.14 Owing to the biological importance of
1,3-benzodioxol moiety and synthetic importance of the enantio-
selective aza-Friedel–Crafts reaction, we have explored the cata-
lytic ability of C60-OH Cinchona alkaloids to develop the
enantioselective aza-Friedel–Crafts reaction of sesamol derivatives
with N-sulfonylimines.
We started our investigation by screening different bifunctional
Cinchona-derived organocatalysts (Fig. 2) (10 mol %) for the aza-
Friedel–Crafts reaction of sesamol (1a) with N-tosylimine 2a in tol-
uene as solvent and 4 Å molecular sieves as an additive at rt (Ta-
⇑
Corresponding author. Fax: +91 183 2258820.
E-mail addresses: sschimni@yahoo.com, sschimni.chem@gndu.ac.in (S.S. Chim-
ni).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.06.032

4614
P. Chauhan, S. S. Chimni / Tetrahedron Letters 54 (2013) 4613–4616
Table 1
O
H
N
Me
O
O
Catalyst screening and optimization of reaction conditions for the aza-Friedel–Crafts
O
N
O
O
H
reaction of sesamol with iminea
H
O
O
O
Ts
O
H
N
H
H
NH
O
H
N
O
Ts
O
O
Me
Catalyst (10 mol%)
O
O
N
N
H
+
O
Solvent, 4Å MS, rt
O
OH
OH
F
F
NH2
F
O
1a
2a
Solvent
3a
(+)-Bicuculline
MDAI
Paroxetine
Tadalafil
Entry
Catalyst
Time (h)
Yieldb (%)
eec (%)
Figure 1. Medicinally important compounds containing 1,3-benzodioxol
1
2
3
4
5
6
7
8
I
II
III
IV
V
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Xylene
CH2Cl2
CHCl3
48
50
48
48
50
50
48
48
48
48
48
48
48
48
48
65
65
48
65
48
48
72
72
88
90
85
87
92
93
81
79
86
93
93
91
89
82
90
77
73
69
78
61
40
0
framework.
VI
VII
VIII
IX
X
OH
N
X
N
OR
X
N
OR
0
N
9
ꢀ60
ꢀ45
ꢀ43
ꢀ40
66
65
80
—
N
N
10
11
12
13
14
15
16
17
18
19
20
21d
22e
23f
H
H
XI
XII
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
NH
IX (R = 1'-C10H7CO)
S
NH
I (R = Bz, X= OH)
II (R = Ac, X= OH)
III (R = COtBu, X-OH)
OH
IV (R = 1'-C10H7CO, X = OH)
V (R = Bn, X = OH)
VI (R = H, X= OH)
F3C
CF3
MTBE
Traces
Traces
34
O
1,4-dioxane
MeOH
—
XI (X = H)
N
8
0
43
63
81
82
XII (X = MeO)
VII (R = H, X= H)
DMF
VIII (R = H, X= OMe)
N
H
CH3CN
CHCl3
CHCl3
21
93
88
66
X
Figure 2. Structure of the catalyst used.
CHCl3
a
Reaction condition: 0.1 mmol of 1a, 0.2 mmol of 2a, 10 mol % of catalyst, 50 mg
of 4 Å molecular sieves. 0.5 mL of solvent.
b
ble 1). As observed in the enantioselective addition of naphthol to
imines,5 the 60-OH Cinchona alkaloids bearing ester moiety at C-9
position provide better enantioselectivity (Table 1, entries, 1–4)
of 3a than the catalyst bearing the ether (V, Table 1, entry 5) or hy-
droxyl (VI, Table 1, entry 6) group at this position. Among different
ester bearing cupreine derivatives the catalyst bearing the 10-naph-
thoyl group provides highest enantioselectivity of aza-F–C adduct
with good level of enantioselectivity (Table 1, entry 4). The natural
Cinchona alkaloids (VII and VIII) resulted in no enantioinduction in
3a (Table 1, entries 7–8). The pseudoenantiomer of IV that is, IX
provides opposite enantiomer of 3a in 86% yield and 60% ee (Ta-
ble 1, entry 9). Other Cinchona-derived bifunctional organocata-
lysts such as b-isocupreidine (X) and thioureas (XI and XII),
however provide high yield, but the enantioselectivity was moder-
ate (Table 1, entries 10–12).
Yield after column chromatography.
ee determined by chiral HPLC.
0.25 mL of CHCl3 was used.
1 mL of CHCl3 was used.
c
d
e
f
2 mL of CHCl3 was used.
adducts in good yield and moderate to high enantioselectivity (Ta-
ble 2, entries 15–17).
The aza-F–C reaction catalyzed by IX provides desired products
with opposite configuration in high yield and slightly lower enanti-
oselectivity than IV (entries 1, 3, 6, 9, and 10).
In order to demonstrate the practical and preparative utility of
the present methodology, a gram-scale reaction was performed be-
tween sesamol 1a (8 mmol) and imine 2a (16 mmol) catalyzed by
10 mol % of IV (Scheme 1). The aza-F–C adduct 3a was obtained in
85% yield after 72 h without any change of enantioselectivity
(80%).
Further, different solvents were screened by using 10 mol % of
IV as catalyst (Table 1, entries, 13–20). After screening, chloroform
was identified as the best solvent in terms of asymmetric induction
(Table 1, entry 15).
Further, we have tried to demonstrate the mechanism of the
aza-F–C reaction catalyzed by C60-OH Cinchona alkaloid by design-
ing some new experiments. The model reaction catalyzed by XIII
having no free hydroxyl group provided 3a in low yield and poor
enantioselectivity, which suggests the role of phenolic OH for high
asymmetric induction in this reaction (Scheme 2, 1). The catalyst
XIV, having no free amine moiety failed to catalyze the model reac-
tion, highlighting the role of tertiary amine moiety for hydrogen
bonding activation of sesamol. This fact was further proved by
the failure of the reaction of OH protected sesamol (1d) with 2a
(Scheme 2, 2), due to the unavailability of free OH for hydrogen
bonding within quinuclidine moiety of the catalyst. These results
suggest that the simultaneous activation of both sesamol and
imine is required in order to provide the aza-F–C product with high
enantioselectivity. On the basis of these results a transition state
(TS1) was proposed, in which catalyst IV behaves as bifunctional
catalyst by providing favorable orientation and synergistic activa-
tion of both the substrate via hydrogen bonding activation of
After optimizing the conditions, the substrate scope was evalu-
ated by screening different N-sulfonylimines with sesamol. Differ-
ent N-tosyl- and N-benzenesulfonylimines bearing electron
withdrawing groups at different positions of the phenyl ring pro-
vide high yield and very good level of enantioselectivity (Table 2,
entry 1–8). The N-sulfonylimines derived from benzaldehyde and
1-naphthaldehyde react efficiently with sesamol to provide good
yield and good enantioselectivity of corresponding aza-F–C ad-
ducts (entries Table 2, 8–11). The reaction of sesamol with imines
bearing electron releasing groups provides the desired adduct in
good yield and very good enantioselectivity (Table 2, entries 12
and 13). The imine bearing the heteroaromatic group was also tol-
erated under the optimized reaction condition, which reacts with
sesamol to provide aza-F–C adduct in 80% yield and good enanti-
oselectivity (Table 2, entry 14).
Sesamol substituted with methyl and iodo groups reacts effi-
ciently with N-sulfonylimines to provide corresponding aza-F–C

P. Chauhan, S. S. Chimni / Tetrahedron Letters 54 (2013) 4613–4616
4615
Table 2
Substrate scope of the aza-Friedel–Crafts reactiona
PG
NH
∗
O
O
O
O
IV (10 mol%)
R1
PG
+
R1
N
CHCl3, 4Å MS, rt
OH
OH
R2
R2
2
1
3
1a. R2 = H; 1b. R2 = Me; 1c. R2 = I
Entry
1
2
3
Time (h)
Yield (%)b
eec (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1c
R1 = 4-FC6H4, PG = Ts (2a)
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
72
72
72
72
72
72
72
72
84
84
96
96
96
72
72
96
96
88 (85)d
90
81 (ꢀ62)d
R1 = 4-FC6H4, PG = SO2Ph (2b)
R1 = 2-FC6H4, PG = Ts (2c)
80
91 (88)d
93
90 (ꢀ75)d
R1 = 2-FC6H4, PG = SO2Ph (2d)
R1 = 3-ClC6H4, PG = SO2Ph (2e)
R1 = 2-ClC6H4, PG = Ts (2f)
R1 = 2-ClC6H4, PG = SO2Ph (2g)
R1 = 2-CF3C6H4, PG = SO2Ph (2h)
R1 = C6H5, PG = Ts (2i)
81
70
86
96 (86)d
97
91 (ꢀ72)d
91
87
96
9
86 (85)d
84 (81)d
79
84 (ꢀ69)d
10
11
12
13
14
15
16
17
R1 = C6H5, PG = SO2Ph (2j)
79 (ꢀ70)d
R1 = 1’-C10H7, PG = SO2Ph (2k)
R1 = 4-MeC6H4, PG = SO2Ph (2l)
R1 = 4-MeOC6H4, PG = SO2Ph (2m)
R1 = Furyl, PG = SO2Ph (2n)
67
90
81
85
89
95
62
77
71
81
90
86
81
R
1 = 4-FC6H4, PG = SO2Ph (2b)
R1 = 2-ClC6H4, PG = SO2Ph (2g)
R1 = 4-FC6H4, PG = SO2Ph (2b)
a
b
c
Reaction condition: 0.1 mmol of 1, 0.2 mmol of 2, 10 mol % of IV, 50 mg of 4 Å molecular sieves in CHCl3 at rt.
Yield after column chromatography.
ee determined by chiral HPLC.
d
Results in the parenthesis were obtained with 10 mol % of IX.
sesamol with quinuclidine nitrogen and activation of imine by
phenolic –OH of the catalyst.
Ts
NH
∗
O
O
O
Ts
In conclusion, we have developed a new asymmetric aza-Fri-
edel–Crafts reaction of sesamols with N-sulfonylimines catalyzed
by 60-OH Cinchona alkaloids. A new series of chiral aminophenols
have been synthesized in good yield and good enantioselectivity
under mild reaction conditions. On the basis of experimental
observations a bifunctional mode of activation by IV has been dem-
onstrated. Further, development of new asymmetric Friedel–Crafts
reaction of sesamol derivatives is under progress and the results
will be presented in due course.
IV (10 mol%)
N
+
CHCl3, 4Å MS, rt
OH
F
O
OH
F
3a
1a
2a
85% yield; 80% ee
Scheme 1. Gram scale enantioselective aza-F–C reaction of sesamol with N-
tosylimine.
Ts
NH
O
O
Ts
O
O
XIII or XIV (10 mol%)
Acknowledgments
N
(1)
+
CHCl3, 4Å MS, rt
OH
OH
3a
F
F
Our research work was supported by the research project sanc-
tioned to S.S.C. by the Department of Science and Technology
(DST), India [SR/S1/OC 35/2011]. PC acknowledges CSIR India for
providing Senior Research Fellowship.
1a
2a
OMe
Br
OBn
OH
N
N
Ph
H
N
N
XIII
XIV
96h, No reaction
96h, 53% yield, 7% ee
Supplementary data
Supplementary data (Experimental procedure, compound char-
acterization and copies of NMR and Mass spectra, and HPLC chro-
matograms) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.tetlet.2013.06.032.
Ts
N
O
O
VI (10 mol%)
(2)
No rection
+
CHCl3, 4Å MS, rt
96 h
OMOM
F
1d
2a
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OR
N
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