Highly stereoselective imidazolethiones mediated Friedel-Crafts alkylation of indole derivatives

Article abstract of DOI:10.1016/j.tetlet.2011.11.007

The asymmetric Friedel-Crafts alkylation of indoles with α,β-unsaturated aldehydes was promoted by the novel imidazolethiones to afford the corresponding adducts in moderate to excellent yields and high enantioselectivities under mild reaction conditions.

Full text of DOI:10.1016/j.tetlet.2011.11.007

Tetrahedron Letters 53 (2012) 289–291
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Highly stereoselective imidazolethiones mediated Friedel–Crafts alkylation
of indole derivatives
⇑
Xianrui Liang, Shuangmin Li, Weike Su
Key Laboratory of Pharmaceutical Engineering of Ministry of Education, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The asymmetric Friedel–Crafts alkylation of indoles with
the novel imidazolethiones to afford the corresponding adducts in moderate to excellent yields and high
enantioselectivities under mild reaction conditions.
a,b-unsaturated aldehydes was promoted by
Received 7 September 2011
Revised 23 October 2011
Accepted 3 November 2011
Available online 17 November 2011
Ó 2011 Elsevier Ltd. All rights reserved.
The indole framework has become widely identified as a ‘priv-
ileged’ structure or pharmacaphore1 that could potentially be ac-
cessed by asymmetric Friedel–Crafts chemistry. Over the past
decade, the chemistry and biological activity of novel indole deriv-
atives, especially for chiral indole intermediates, have attracted
much attention.2 Several types of chiral amines3 and metal cata-
lysts4 have been employed for the asymmetric Friedel–Crafts-type
alkylation of indole derivatives. However, the techniques and
methodologies for the asymmetric reaction of indole derivatives
are still lagging behind.5
The first enantioselective Friedel–Crafts reaction of indole was
reported by MacMillan in 2002 using imidizolidinone as catalyst
which enriched the paths to indole derivatives.6 However, the
comparatively harsh conditions were needed for the reaction and
only 56% ee value was obtained in the case of 1a (Fig. 1) as activator
at ꢀ40 °C. Still, hunting for good chiral catalysis which requests
mild conditions, high selectivities, and yields is always the focus
of great attention for asymmetric reaction.7 In our continuous
work on investigation of the novel chiral catalysts imidazolethi-
ones,8 the efficiency of imidazolethiones prompted us to further
investigate the possibility of the Friedel–Crafts alkylation of indole
S
S
S
O
N
N
N
N
N
N
Ph
Ph
N
H
N
H
H
H
Ph
Ph
2b
2c
2a
1a
Figure 1. The imidazolethiones catalysts.
Table 1
Catalysts screening for the reaction of 3a and 4aa
Cl
O
20mol% cat
HX
H
OH
º
-25 C
N
N
Cl
4a
3a
5a
Entry
Catalysts
Yieldb (%)
eec (%)
1
2
3
4
2a
2b
2c
1a
85
77
/
96
35
/
derivatives with a,b-unsaturated systems.
Accordingly, the screening of the catalysts was conducted with
several imidazolethiones (Fig. 1), using N-methylindole (3a) and
(E)-3-(3-chlorophenyl) acrylaldehyde (4a) as a model reaction un-
der suitable reaction conditions to give the corresponding adducts
5a (Table 1). Due to the highly reactive chemical nature of alde-
hyde, all the aldehydes formed were converted to corresponding
alcohols by NaBH4 in situ.
72
26
a
Reagents and conditions: a mixture of 3a (5 mmol), 4a (2 mmol), 20%catalysts,
and 20% TFA in THF (3 mL)/i-PrOH (3 mL) stirred at ꢀ25 °C for 48 h;
b
Yields based upon isolation of the corresponding alcohol after NaBH4 reduction.
c
ee determined by chiral HPLC.
To our delight, good yields (85%) and high level of stereoselec-
tivities (96%) were achieved with imidazolethione 2a (Table 1,
entry 1), while poor results or nearly no product was obtained in
the case of 2b (Table 1, entry 2) or 2c (Table 1, entry 3). In addition,
imidazolidinone 1a was also investigated under the same
conditions, and compared to 2a, the ee value was only 26% though
with moderate yields (Table 1, entry 4).
Table 2 showed the influences of solvents, temperature, and
additives on the reactions. Mixture of THF/i-PrOH (1:1) gave both
higher yield and higher selectivity than CH2Cl2, [BMI][Br]IL, THF/
H2O, and CH2Cl2/i-PrOH. Temperature is essential to the selectivity
of the reaction, and elevating the reaction temperature resulted in
⇑
Corresponding author. Tel./fax: +86 571 88320752.
E-mail address: pharmlab@zjut.edu.cn (W. Su).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.007

290
X. Liang et al. / Tetrahedron Letters 53 (2012) 289–291
Table 2
Table 3
Reaction of
Solvents and additives screening for the reaction of 3a and 4aa
a
,b-unsaturated aldehydes 4 with indoles 3 catalyzed by 2aa
R4
Cl
R3
OH
O
20mol% 2a
TFA
R2
O
R3
R4
H
o
N
THF:i-PrOH=1:1
-25 C
R2
20mol% 2a
HX
H
R1
OH
N
ToC
N
solvent,
R1
N
Cl
4a
3
4
5
3a
5a
5a-5k: R1=Me, R2=H
5l: R1=H, R2=Me
5m-5s: R1=R2=H
c
d
Entry Solvent
Additives (HX) Temp (°C) Yield (%) ee (%)
1
2
3
CH2Cl2
[BMI][Br] IL
THF/H2O
TFA
TFA
TFA
ꢀ25
ꢀ25
ꢀ25
ꢀ25
ꢀ25
ꢀ25
ꢀ25
ꢀ25
ꢀ10
ꢀ50
ꢀ25
ꢀ25
75
90
77
74
85
65
73
78
88
56
73
69
30
/
Entry
Product
R3
R4
Time (h)
Yieldb (%)
eec (%)
33
35
96
39
46
52
56
99
76
78
4
CH2Cl2/i-PrOH TFA
1
2
3
4
5
6
7
8
9
10
11
12
12
14
15
16
17
18
19
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
5s
H
H
H
H
H
H
H
H
H
H
H
H
m-ClC6H4
m-MeC6H4
p-FC6H4
p-ClC6H4
p-MeOC6H4
p-MeC6H4
o-MeOC6H4
o-CF3C6H4
C6H5
Me
Et
Me
Me
Me
Me
p-MeOC6H4
m-ClC6H4
m-MeC6H4
m-ClC6H4
48
48
36
36
48
48
36
48
48
5
85
83
84
88
80
78
82
83
77
85
80
83
81
87
82
83
83
79
83
96
95
81
87
96
88
84
93
93
99
97
97
99
98
97
71
94
62
60
5b
THF/i-PrOH
THF/i-PrOH
THF/i-PrOH
THF/i-PrOH
THF/i-PrOH
THF/i-PrOH
THF/i-PrOH
THF/i-PrOH
TFA
6b
p-TSA
PhCOOH
Cl2CHCOOH
TFA
TFA
TFA
b
7
8b
9b
10b
11e
12f
TFA
a
Reagents and conditions: a mixture of 3a (5 mmol), 4a (2 mmol), 20% catalysts
2a, and 20% additives in solvent (6 mL) stirred for 48 h.
5
5
5
5
b
THF/i-PrOH = 1:1.
H
c
Yields based upon isolation of the corresponding alcohol after NaBH4 reduction.
ee determined by chiral HPLC.
Using 10% additives in solvent stirred for 96 h.
Using 10% catalysts.
Br
MeO
H
MeO
H
d
5
e
72
48
72
72
f
Br
the decrease of ee value (Table 2, entry 9). Keeping the reaction at
ꢀ50 °C would slightly increase ee value, but the yield decreased.
Additive acids and the amount of the catalysts loaded in the
reaction also played dramatic roles both in the activation of the
substrates and in the stability of the intermediates. Among the four
additive acids TFA, p-TSA, PhCO2H, and Cl2CHCO2H (Table 2, entries
5–8), TFA showed significant activity and gave the best result with
excellent enantioselectivity. However, the attempt to reduce the
amount of TFA (Table 2, entry 11) or catalysts (Table 2, entry 12)
failed due to the lower yield and ee value even after 4 days reaction
time.
With the optimized reaction conditions in hand, the scope of
the enantioseletive Friedel–Crafts reaction of various aldehydes
with indoles was investigated. Representative results were sum-
marized in Table 3 and most aldehydes worked well with indole
derivatives under the standard reaction conditions (Table 3, entries
1–17). As it can be seen, N-methylindole was very well tolerated in
the alkylation with various aldehydes (Table 3, entries 1–11). As
a
Reagents and conditions: a mixture of 6 (5 mmol), 4 (2 mmol), 20% catalysts 2a,
and 20% additives in THF (3 mL)/i-PrOH (3 mL) stirred at ꢀ25 °C for the given time.
b
Yields based upon isolation of the corresponding alcohol after NaBH4 reduction.
ee determined by chiral HPLC.
c
yields and high enantioselectivities under less harsh conditions,
especially for the aliphatic aldehydes. Based on this study, some re-
searches organocatalyzed by imidazolethiones are now underway
in our laboratory.
Acknowledgment
We thank the Zhejiang Natural Science Foundation (Y407287)
for the financial support.
Supplementary data
expected, the aliphatic
a,b-unsaturated aldehydes showed higher
reactivity and provided the corresponding product with the higher
ee values (Table 3, entries 10–15). Particularly, crotonaldehyde was
a very good reaction partner, moderate to excellent yields and ee
values were obtained with several indole derivatives (Table 3,
entries 12–15). However, 5r and 5s gave relatively poor enantiose-
lectivities (after 72 h, 79% yield with 62% ee in 5r, 83% yield with
60% ee in 5s) (Table 3, entries 18 and 19) and the reversibility
and racemization of the reaction might explain the low
enantioselectivity.
In summary, imidazolethiones were proven to be a kind of
excellent activator in this work in the Friedel–Crafts reaction of in-
dole derivatives with a,b-unsaturated systems with good achieve-
ments, which provided a practical method for the preparation of
chiral indole derivatives.9 Compared to MacMillan’s imidazolidi-
nones,4 the corresponding adducts hold moderate to excellent
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.11.007.
References and notes
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9. General procedure for the synthesis of 3-(indoles-2-yl)-3- arylpropanols 5:
A
mixture of catalyst 2a (0.4 mmol), TFA (0.4 mmol), and ,b-unsaturated
a
aldehydes (2 mmol) in THF (3 mL) and i-PrOH (3 mL) was stirred for 15 min at
room temperature. Then, the indoles (5 mmol) were added. The reaction
mixture was stirred at ꢀ25 °C for the given time (monitored by TLC). The
resulting solution was stirred for 30 min after equal volume of absolute EtOH
and excess of NaBH4 was added. The reaction mixture was quenched with
saturated aqueous NaHCO3, extracted with CH2Cl2 and dried over anhydrous
Na2SO4. The solvent was evaporated under vacuum, and the residue was
purified by flash column chromatography over silica gel (AcOEt/petroleum ether
1:8) to provide products 5.
(R)-3-(3-chlorophenyl)-3-(1-methyl-1H-indol-3-yl) propan-1 (5a): Yellow oil.
Yield: 85%. 1H NMR (400 MHz, CDCl3) d 7.40 (d, J = 7.9 Hz, 1H), 7.26 (t, J = 4.1 Hz,
2H), 7.18 (m, J = 11.2, 4.8, 2.5 Hz, 2H), 7.15–7.08 (m, 2H), 6.99 (t, J = 7.4 Hz, 1H),
6.87 (s, 1H), 4.34 (t, J = 7.7 Hz, 1H), 3.71 (s, 3H), 3.66–3.54 (m, 2H), 2.39 (dq,
J = 13.6, 6.8 Hz, 1H), 2.19 (dq, J = 8.2, 6.2 Hz, 1H), 1.61 (s, 1H).; 13C NMR
(100 MHz, CDCl3): d (ppm) = 146.97, 136.92, 133.91, 129.32, 127.67, 126.80,
126.09, 125.79, 125.66, 121.54, 119.25, 119.05, 118.70, 117.09, 109.10, 60.89,
38.55, 32.78; MS (ESI): m/z (%) = 300.2 (28, M+), 300.1 (100), 235.2 (39). HRMS
(ESI) exact mass calculated for [C18H18ClNONa]: 322.0967, found: 322.0975.
HPLC condition: Chiralcel OD-H column, isopropanol/hexane 18:82, flow rate
1.0 mL/min, UV detection at 214 nm, tminor = 16.3 min, tmajor = 24.4 min, 96% ee.
½ ꢁ ¼ ꢀ14:3 (c 0.56, CHCl3).
a 2D0