Nanocrystalline titanium(IV) oxide as an efficient heterogeneous catalyst for tandem Michael and nucleophilic 1,2-addition to enones

Article abstract of DOI:10.1002/adsc.200505415

Nanocrystalline titanium(IV) oxide was found to be an efficient heterogeneous catalyst for the conjugate 1,4-addition of indoles with α,β-unsaturated ketones to afford β-indolyl ketones in excellent yields. The subsequent catalytic 1,2-addition of Me

Full text of DOI:10.1002/adsc.200505415

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DOI: 10.1002/adsc.200505415
Nanocrystalline Titanium(IV) Oxide as an Efficient
Heterogeneous Catalyst for Tandem Michael and Nucleophilic
1,2-Addition to Enones
M. Lakshmi Kantam,a,* Soumi Laha,a Jagjit Yadav,a B. M. Choudary,b B. Sreedhara
a
Inorganic and Physical Chemistry Division, Indian Institute of Chemical Technology, Hyderabad-500007, India
Fax: (þ91)-40-27160921, e-mail: mlakshmi@iict.res.in, lkmannepalli@yahoo.com
b
Ogene Systems (I) Private Limited, Hyderabad, India
Received: October 21, 2005; Accepted: March 7, 2006
Abstract: Nanocrystalline titanium(IV) oxide was
found to be an efficient heterogeneous catalyst for
the conjugate 1,4-addition of indoles with a,b-unsa-
turated ketones to afford b-indolyl ketones in excel-
lent yields. The subsequent catalytic 1,2-addition of
Me3SiCN to carbonyl compounds can be performed
in one pot with moderate to good yields. Low sensi-
tivity towards traces of moisture and high tolerance
of different functional groups make nanocrystalline
titanium(IV) oxide suitable for carrying out multi-
step synthetic sequences.
tance include its use as a food additive, in cosmetics,
and as a potential tool in cancer treatment.[6]
Michael addition of indoles to a,b-unsaturated ke-
À
tones is an important C C bond forming reaction as
the resultant b-indolyl ketones are highly interesting
building blocks for the synthesis of biologically active
compounds and natural products.[7] They are usually car-
ried out in the presence of catalytic or stoichiometric
amounts of Lewis acids.[8] Recently, Marcantoni et al.
used a CeCl3 ·7 H2O-NaI combination supported on sili-
ca gel for the Michael addition of indoles to a,b-unsatu-
rated ketones.[9]
Keywords: cyanosilylation; indoles; nanocrystalline
titanium(IV) oxide; recycling; tandem reactions;
a,b-unsaturated ketones
With the aim of evolving a Lewis acid-mediated Mi-
chael addition between an indole and an enone as a
one-pot multistep transformation as discussed above,
we designed and conceived the use of nanometal oxides
composed of acidic sites, especially Lewis acidic sites.
We herein report the conjugate 1,4-addition of indoles
to a,b-unsaturated ketones to form b-indolyl ketones in-
dependently (Tables 1 and 2) as well as coupled with a
The accomplishment of successive reactions leading to subsequent nucleophilic 1,2-addition of TMSCN to the
the formation of several bonds by one-pot procedures b-substituted ketone in a single pot (Table 3) using a cat-
provides useful methodologies for the synthesis of com- alytic amount of nanocrystalline titanium (IV) oxide
plex molecules.[1] The minimization of the number of (nano TiO2). Both the reactions proceeded well with
steps not only provides more efficient synthesis but good to excellent yields.
also allows the reduction of waste production.[2] In re-
When nano TiO2 (10 mol %) was used to catalyze the
cent years, there has been increasing emphasis on the Michael addition between an indole and an enone, the
use and design of environment-friendly solid catalysts desired product was obtained in excellent yields (Ta-
to reduce the amount of toxic waste. Nanocrystalline ble 1). No trace amount of the N-substituted product
metal oxides find excellent applications as active ad- was observed. To optimize the reaction conditions, var-
sorbents for gases and destruction of hazardous chemi- ious parameters such as the effect of different nanoma-
cals and as catalysts for many organic transforma- terials and solvents were studied on the Michael addi-
tions.[3,4] These high reactivities are due to high surface tion reaction. The nano TiO2 was found to be by far
areas combined with unusually reactive morphologies.[5] the more superior catalyst than other nano metal oxides
Titanium dioxide is one of the most prominent materials such as CuO, ZnO and commercially available TiO2.
for various kinds of industrial applications related to cat- Among the solvents screened dichloromethane
alysis, e.g., the selective reduction of NOx in stationary (DCM) gave the maximum yield. The catalytic activity
sources, photocatalysis for pollutant elimination or or- of nano TiO2 was evident when the reaction was con-
ganic synthesis, as well as uses in photovoltaic devices, ducted in the absence of the catalyst, no product was ob-
sensors, and paints. Additional applications of impor- tained even after 48 h.
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M. Lakshmi Kantam et al.
Table 1. Screening of reaction parameters for the formation of 3-(3-indolyl)-1,3 diphenylpropan-2 one.[a]
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Entry
Solvent
Time [h]
Catalyst
Yield [%][b]
1
2
3
4
5
6
7
8
9
Acetonitrile
Ethanol
Methanol
THF
DCM
Toluene
DCM
24
24
24
24
6
Nano TiO2
Nano TiO2
Nano TiO2
Nano TiO2
Nano TiO2
Nano TiO2
TiO2 (commercial)
Nano ZnO
Nano CuO
22
28
31
50
75, 71[c]
52
6
36
18
18
0
42
29
DCM
DCM
[a]
Reaction conditions: indole (1.5 mmol), enone (1 mmol), catalyst (10 mol %), solvent (3 mL), room temperature.
Isolated yields.
Yield after fifth cycle.
[b]
[c]
The reaction of enone (1a) and indole (2a) (Table 2) in unsaturated ketones and subsequent 1,2-addition of
the presence of nano TiO2 (10 mol %) and DCM (3 mL) TMSCN to the enone.[8a]
at room temperature gave the 3-substituted indole in ex-
Herein, we have performed the 1,4-addition of a,b-
cellent yield in 6 h. To extend the scope of the reaction, unsaturated ketones with the appropriate nucleophiles,
indole and 2-methylindole were reacted with different followed by nucleophilic 1,2-addition with TMSCN us-
a,b-unsaturated ketones. It is evident from Table 2 ing nano TiO2 in a single pot in good yields (Table 3).
that the reaction proceeds well with different a,b-unsa- The 1,4-addition reaction was monitored by TLC. After
turated ketones. The system works well with acyclic and complete conversion of the a,b-unsaturated ketone in
cyclic substrates (Table 2, entries 1 and 6). No signifi- about 10 h, TMSCN was added, which ultimately result-
cant effect of substituted groups on the chalcone moiety ed in the formation of silylated cyanohydrins in good
was observed on the yield. (Table 2, entries 1, 3 and 4). yields. A 1:1 mixture of diastereoisomers was obtained
The chemical yield increases when an electron-rich in- with unsubstituted indole (2a) (Table 3, entries 1, 2 and
dole was used. (Table 2, entries 1 and 2). As can be 4), and a moderate diastereoselection was obtained with
seen from the Table 2, no external source of protons the substituted indole (2b) (Table 3, entries 3 and 5).
was required to increase the product yield in the case
The nanoparticles were characterized using several
of a less electron-rich indole.[8a] The reaction does not re- techniques, including XRD, TEM, TPD and BET.
quire strict anhydrous conditions (Table 2, entry 1). Both fresh and used catalysts were observed under
Treatment of indole (2a) with methyl vinyl ketone in TEM to understand the shape and size of the particles.
the presence of a catalytic amount of nano TiO2 gave As can be seen from Figure 1a – the fresh catalyst has
1-(3’-indolyl)-butan-3-one in 92% yield. (Table 2, en- particles well in the nano size range (10–20 nm) with
try 10), No by-product, N-alkylated, dimeric or poly- well-defined shapes. Figure 1b shows the TEM image
meric products was obtained.
of the used catalyst after five recycles. Interestingly it
One-pot 1,4–1,2-addition of indoles and TMSCN to is observed that the shape and size of the particles re-
a,b-unsaturated ketones: Silylated cyanohydrins are main unchanged even after recycling. This supports
highly versatile synthetic intermediates, which can be that the morphology of the catalyst remains the same
easily converted into a wide variety of important syn- even after recycling.
thetic intermediates including a-hydroxy acids, a-amino
The X-ray powder diffraction (XRD) patterns of the
acids, and b-amino alcohols.[10] There are a number of fresh and used nano TiO2 do not differ in the range
processes for the preparation of cyanohydrins from al- 2q¼08 – 808 which confirms the fact that the structure
dehydes and imines,[11] using trimethylsilyl cyanide and morphology of the catalyst remain the same during
(TMSCN) as the cyanating reagent, but the cyanation the course of the reaction. The acidic site distributions
reaction of less reactive substituted and unsubstituted are measured by ammonia TPD experiments, which
ketones has not been extensively exploited.[12] Recently were conducted on Auto Chem 2910 instrument. In a
Cozzi and Umani-Ronchi et al. used catalytic amounts typical experiment for TPD studies, the samples were
of InBr3 for the Michael 1,4-addition of indoles to a,b- pretreated by passage of high purity (99.995%) helium
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Nanocrystalline Titanium(IV) Oxide
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Table 2. Nano TiO2-catalyzed Michael addition of a,b-unsaturated ketones with indole
and 2-methylindole.[a]
[a]
Reaction conditions: all the reactions were carried out in anhydrous dichlorome-
thane at room temperature, employing 10 mol % nano TiO2, reaction time: 6 h.
Isolated yields.
Yields after fifth cycle.
Reaction was done using bottle-grade DCM.
Reaction time: 3 h.
[b]
[c]
[d]
[e]
(50 mL/min) at 473 K for 1 h. After pretreatment, the for 1 h and subsequently flushed with an He flow
sample was saturated with pure anhydrous ammonia (50 mL/min) at 378 K for 2 h to remove physisorbed am-
(75 mL/min) from a mixture of 10% NH3-He at 353 K monia. TPD analysis was carried out from ambient tem-
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M. Lakshmi Kantam et al.
Table 3. One-pot 1,4–1,2 addition of indoles to enones catalyzed by nano TiO2.[a]
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[a]
Reaction conditions: indole (1.5 mmol), enone (1 mmol), nano TiO2 (10 mol %),
TMSCN (9 mmol), anhydrous dichloromethane (3 mL), reaction time: 6 h, reaction
done at room temperature.
[b]
[c]
Isolated yields.
d.r¼diastereomeric ratio. The diastereomeric ratio was obtained from the 1H NMR
spectra of the compounds.
[d]
[e]
Relative configuration was not assigned.
Yields after fifth cycle.
perature to 1173 K at a heating rate of 10 K/min. In the
ammonia TPD test, nano TiO2 shows maximum desorp-
tion of ammonia over the commercial TiO2, nano ZnO
and nano CuO (Figure 2). Therefore the increased activ-
ity of nano TiO2 over other samples tested is due to in-
creased acidity. Besides this, nano TiO2 with a higher sur-
face area (500 m2/g) and a higher porosity than commer-
cial TiO2 (SA: 10.69 m2/g) contributes to the extraordi-
nary chemical reactivity.
In conclusion, we have developed the nano TiO2-cat-
alyzed, simple and effective one-pot conjugate 1,4-addi-
tion of indoles to a,b-unsaturated ketones and subse-
quent nucleophilic 1,2-addition of TMSCN to the result-
ing b-substituted ketone which ultimately results in the
formation of a-silyloxy-g-indolyl nitriles in good yields.
The efficiency of nano TiO2 is well demonstrated and at-
tributed to the enhanced acidic sites and surface area.
Figure 1. TEM images of the nano TiO2 catalyst (a) before
and (b) after use.
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Nanocrystalline Titanium(IV) Oxide
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the crude product. The crude product was purified by column
chromatography on silica gel (100–200 mesh) to give pure 1-
cyano-1-trimethylsilyloxy-3-(2-methyl-3-indolyl)-cyclopen-
tane; yield: 65%; Diastereomeric mixture, d.r.¼65:35. 1H
NMR (200 MHz, CDCl3) (major diastereoisomer): d¼0.34
(s, 9H), 2.06–2.61 (m, 6H), 2.39 (s, 3H), 3.49–3.59 (m, 1H),
7.08–7.14 (m, 2H), 7.27–7.29 (m, 1H), 7.58 (br, 1H), 7.70 (d,
J¼7.0 Hz, 1H); (minor diastereoisomer): d¼0.33 (s, 9H),
3.61–3.78 (m, 1H).
Acknowledgements
We wish to thank the CSIR forfinancial support underthe Task
Force Project COR-0003 and Soumi Laha and Jagjit Yadav
thank CSIR, India fortheirfellowships. Nanocrystalline TiO
,
2
ZnO, CuO samples were purchased from NanoScale Materials
Inc., Manhattan, KS 66502, USA. Commercial TiO2 sample was
purchased from LOBA Chemie, India.
References and Notes
Figure 2. The ammonia TPD patterns of (a) commercial
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Typical Experimental Procedure for the Synthesis of
3-Alkylated Indoles
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