TiCl2(OTf)-SiO2: A solid stable lewis acid catalyst for Michael addition of α-Aminophosphonates, Amines, Indoles and Pyrrole

Article abstract of DOI:10.1080/10426507.2017.1417298

TiCl₂(OTf)-SiO₂ is simply prepared by immobilization of TiCl₃(OTf) on silica gel surface and introduced as a non-hygroscopic Lewis acid catalyst for C-N and C-C bond formation via Michael addition reaction. A variety of structurally diverse nitrogen nucleophiles including α-aminophosphonates, aliphatic and aromatic amines and imidazole were evaluated as Michael donors. Friedel–Crafts alkylation of indoles and pyrrole was also investigated through Michael addition reaction in the presence of TiCl₂(OTf)-SiO₂ as a catalyst. The reactions were conducted at room temperature or 60 °C under solvent-free conditions and the desired Michael adducts were obtained in high to excellent yields.

Full text of DOI:10.1080/10426507.2017.1417298

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
TiCl2(OTf)-SiO2: A solid stable lewis acid catalyst
for Michael addition of α-Aminophosphonates,
Amines, Indoles and Pyrrole
Habib Firouzabadi, Naser Iranpoor & Soghra Farahi
To cite this article: Habib Firouzabadi, Naser Iranpoor & Soghra Farahi (2017): TiCl2(OTf)-
SiO2: A solid stable lewis acid catalyst for Michael addition of α-Aminophosphonates,
Amines, Indoles and Pyrrole, Phosphorus, Sulfur, and Silicon and the Related Elements, DOI:
10.1080/10426507.2017.1417298
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PHOSPHORUS, SULFUR, AND SILICON
https://doi.org/./..
TiCl(OTf)-SiO: A solid stable lewis acid catalyst for Michael addition
of α-Aminophosphonates, Amines, Indoles and Pyrrole
Habib Firouzabadia, Naser Iranpoora, and Soghra Farahib
aDepartment of Chemistry, College of Sciences, Shiraz University, Shiraz, Iran; bDepartment of Chemistry, Faculty of Sciences, Behbahan Khatam
Alanbia University of Technology, Behbahan, Iran
ABSTRACT
ARTICLE HISTORY
Received  October 
Accepted  December 
TiCl2(OTf)-SiO2 is simply prepared by immobilization of TiCl3(OTf) on silica gel surface and introduced
as a non-hygroscopic Lewis acid catalyst for C-N and C-C bond formation via Michael addition reaction.
A variety of structurally diverse nitrogen nucleophiles including α-aminophosphonates, aliphatic and
aromatic amines and imidazole were evaluated as Michael donors. Friedel–Crafts alkylation of indoles and
pyrrole was also investigated through Michael addition reaction in the presence of TiCl2(OTf)-SiO2 as a
catalyst. The reactions were conducted at room temperature or 60 °C under solvent-free conditions and
the desired Michael adducts were obtained in high to excellent yields.
KEYWORDS
Michael reaction;
titanium(IV) triflate;
α-aminophosphonates;
heterogeneous catalysts;
electron deficient olefins
GRAPHICAL ABSTRACT
TiCl2(OTf)-SiO2
R'RN
R2
RR'NH
+
R2
no solvent, r.t. or 60 °C
Ar
PO(OEt)2
RR'NH =
, benzylamine,
NH2
piperidine, morpholine, aniline, imidazole
R2
= COCH3, COO-n-Bu, CN, CONH2
Introduction
Despite some success achieved, many of the reports suffer
from at least one of the following disadvantages: the use of
expensive catalysts, stoichiometric amounts of the promoters,
using hazardous organic solvents and extended reaction times.
In addition, some reactions are limited in substrate scope to
aliphatic amines and exhibit poor compatibility with various
substrate functional groups.
Indole derivatives occur in many biologically active com-
pounds and natural products.[64–66] Pyrroles are important
building blocks in various natural products such as chloro-
phyll, porphyrin, hemoglobin, vitamin B12, indigo and bile
pigment.[67] A useful method for C-alkylation of indoles
and pyrroles is the Friedel-Crafts type conjugate addition of
these compounds to electron deficient olefins. However, indoles
and pyrroles are both acid sensitive compounds and the acid-
catalyzed conjugate addition of indoles requires careful control
of acidity to prevent side reactions.
The development of synthetic approaches to β-amino carbonyl
compounds has received great attention because of their numer-
ous synthetic applications as versatile intermediates for the
synthesis of a variety of complex natural products, antibiotics,
chiral auxiliaries and useful building blocks in fine chemicals
and pharmaceuticals.[1–4] The Mannich-type reaction is a con-
ventional method for the preparation of these compounds.[5]
On the other hand, due to the atom economy and simplicity,
the aza-Michael addition reaction provides a special route for
the synthesis of β-amino carbonyl compounds.[6,7] Tradition-
ally, aza-Michael addition reactions proceed under strongly
acidic[8] or basic conditions,[9] which often lead to undesirable
side reactions and are incompatible with green chemistry.
In recent decades, various materials including transition
metal based catalysts,[10–19] organocatalysts,[20–26] supported
reagents,[27–33] ionic liquids,[34–40] metal nitrates,[41–43] and
solid heterogeneous materials[44–50] have been developed to
promote the aza-Michael addition reaction. This reaction has
also been conducted in different media such as water,[51–61] with
Many useful methods have been reported in the litera-
ture to promote C-alkylation of indoles and pyrroles through
Michael addition reaction.[68–85] Among them, the use of CeCl3.
7H2O-NaI,[71] Bi(OTf)3,[73,74] iodine,[77] [Al(DS)3] 3 H2O,[78]
or without promoters, polyethylene glycol[62] and glycerol[63]
.
CONTACT Soghra Farahi
Iran.
farahi@bkatu.ac.ir
Department of Chemistry, Faculty of Sciences, Behbahan Khatam Alanbia University of Technology, Behbahan ,
Supplemental data for this article can be accessed on the publisher’s website.
©  Behbahan Khatam Alanbia University of Technology

2
H. FIROUZABADI ET AL.
Table . Aza-Michael addition of α-aminophosphonatesa .
and ionic liquid[83] can be mentioned. Although these methods
are useful, yet, there is a room for a more practical method.
Carbon-phosphorus bonds are present in many organic
compounds and natural products.[86] Among organophos-
phorus compounds, α-aminophosphonic acid derivatives have
attracted much attention and their preparation, reactivity,
as well as biological and medicinal applicability has been
investigated.[87–95] To the best of our knowledge, functionaliza-
tion of α-aminophosphonates through Michael addition reac-
tion and C-N bond formation has not yet been reported in the
literature.
Titanium tetrachloride, TiCl4, is a highly aggressive Lewis
acid, which is extensively used in industrial processes as a
catalyst. Handling of TiCl4 needs serious precautions. Exposure
of TiCl4 to moisture creates clouds of HCl. In order to overcome
these problems, TiCl3(OTf) is a good alternative for fuming
TiCl4,[96] which has been employed as an efficient catalyst in
some organic transformations.[97–102]
Due to the ease of handling, easy workup procedure, min-
imization of waste generation as well as environmental and
economical advantages, supported acid catalysts have received
much attention in organic synthesis. On the other hand, silica
gel has a high surface area and can be easily functionalized,
which makes it a well-known support. We have also intro-
duced TiCl2(OTf)-SiO2 as a moisture insensitive Lewis acid
catalyst for silylation of -OH groups and cyanosilylation of
aldehydes.[103]
Herein, we describe another application of TiCl2(OTf)-SiO2
as an effective heterogeneous catalyst for conjugate addition of
α-aminophosphonates, amines, imidazole, indoles and pyrrole
to electron deficient olefins under neat conditions.
NHCH2CH2R2
NHR1
TiCl2(OTf)-SiO2
R2
+
Ar
P(OEt)2
O
Ar
P(OEt)2
O
no solvent, 60 °C
3a-h
2a-d
1
2a (R2 = COCH3), 2b (R2 = COO-n-Bu)
2c (R2 = CN), 2d (R2 = CONH2)
Entry
Ar
R

Product
Time
yield %b

Ph
Ph
H
H
H
H
H
H
H
H
a
b
a
b
a
b
a
b
3a
3b
3c
3d
3e
3f
 min
 h
 min
 h
 min
 h














p-CH-CH-
p-CH-CH-
p-Cl-CH-
p-Cl-CH-
-Naphthyl
-Naphthyl
3g
3h
 min
 h

aThe molar ratio of α-aminophosphonate: Michael acceptor: catalyst was : .: ..
The products have been fully characterized based on their spectral data.
bYield of isolated product.
diethyl phenyl (α-amino) methylphosphonate, though methyl
vinyl ketone was much more reactive than n-butyl acrylate
(Table 1, entry 1). This observation is consistent with the higher
reactivity of α,β-unsaturated ketones towards conjugate addi-
tion. However, the reaction of other Michael acceptors such as
acrylonitrile and acrylamide was not successful.
Next, aza-Michael reaction of structurally different
α-aminophosphonates with electron deficient olefins was
investigated and similar results were obtained (Table 1, entries
3–8). In addition, secondary α-aminophosphonates were inert
under this reaction conditions.
Results and discussion
Then, the generality of the method was explored through the
TiCl3(OTf) has been reported as a catalyst for the conver- reaction of different amines with various Michael acceptors in
sion of epoxides to 1,3-dioxolanes,[97] aldol condensation of the presence of TiCl2(OTf)-SiO2 (1 mol %) under solvent-free
cycloalkanones with aromatic aldehydes[98] and conversion conditions. Herein, the reactions were conducted at room
of acetophenones to 1,3,5-triarylbenzenes.[99] We have also temperature unless otherwise stated. First, Michael reaction
reported some other applications of TiCl3(OTf) as a catalyst of benzyl amine to methyl vinyl ketone was investigated. The
for esterification reactions,[100] protection of aldehydes as their reaction resulted in a mixture of mono and disubstituted
acylals[101] and silylation of hydroxyl groups.[102] We also products. Attempts to obtain the monosubstituted compound
introduced TiCl2(OTf)-SiO2 as a moisture tolerant alternative as the major product even using an excess of benzyl amine
to TiCl3(OTf), which was further applied as a catalyst for remained unsuccessful. On the other hand, the reaction of
silylation of -OH groups and cyanosilylation of aldehydes.[103] benzyl amine with weaker Michael acceptors such as n-butyl
In continuation to our studies, we investigated aza-Michael acrylate and acrylonitrile provided only the monosubstituted
addition reaction in the presence of TiCl2(OTf)-SiO2 as a product in high yields (Table 2, entries 1,2). Aza-Michael addi-
catalyst. Due to the biological and medicinal application of tion reaction of piperidine and morpholine to n-butyl acrylate
α-aminophosphonates, aza-Michael addition reaction of α- and acrylonitrile also proceeded with good yields (Table 2,
aminophosphonates was first investigated. For this purpose, in entries 3–5).
a typical experiment, diethyl phenyl (α-amino) methylphos-
Due to the weaker nucleophilicity of aniline, conjugate addi-
phonate was treated with n-butyl acrylate in the presence of tion of aniline to electron deficient olefines at room temperature
TiCl2(OTf)-SiO2 as a catalyst. We observed that using 1 mol % of was a rather difficult task. Therefore, Michal addition reaction
the catalyst at 60 °C under solvent-free conditions, the reaction of aniline was conducted at higher temperature. The reaction
proceeded efficiently and after 48 h the desired N-substituted with Michael acceptors such as methyl vinyl ketone, n-butyl
α-aminophosphonate was obtained in 84% isolated yield acrylate and acrylonitrile was performed at 60 °C in high yields
(Table 1, entry 2).
(Table 2, entries 6–8). The reaction of imidazole with the same
Next, the reaction was extended to different electron defi- Michael acceptors was performed at room temperature (Table 2,
cient olefins. We observed that only methyl vinyl ketone and entries 9–11). However, conjugate addition of imidazole to acryl
n-butyl acrylate were reactive towards conjugate addition of amide was accomplished at 60 °C (Table 2, entry 12).

PHOSPHORUS, SULFUR, AND SILICON
3
Table . Amine and Michael acceptor scopea .
entries 1–3). However, due to the higher reactivity of pyr-
role, preparation of monoalkylated product upon treatment
of pyrrole with methyl vinyl ketone was not successful. In
addition, Michael addition reaction of indoles and pyrrole to
β-nitrostyrene was satisfactory and provided the corresponding
products in high to excellent yields (Table 3, entries 4–7).
In order to show the merit of TiCl2(OTf)-SiO2 we compared
the catalytic activity of TiCl2(OTf)-SiO2 with that of some other
promoters used for 1,4-conjugate addition of aniline, imidazole
and 2-methylindole to electron deficient olefins (Table 4). As
the results in Table 4 show, TiCl2(OTf)-SiO2 is an efficient cat-
alyst for a broad range of substrates, which provides the corre-
sponding Michael addition product in high yields at a reasonable
time.
Recyclability of the catalyst was also investigated upon the
reaction of imidazole with n-butyl acrylate. After completion of
the reaction, the catalyst was simply separated by addition of
ethyl acetate to the reaction mixture and filtration. The recov-
ered catalyst was dried in oven and reused for a similar reac-
tion. For the first run, either the reaction time or the conversion
yield was unchanged. However, for further runs, the reaction
time was increased and after four consecutive runs, the catalytic
activity was considerably decreased (Table S 1, Supplemental
Materials).
TiCl2(OTf)-SiO2
no solvent, r.t.
R'RN
R2
2a-d
R2
+
RR'NH
4a-e
5aa-ed
4a (RR'NH = PhCH2NH2), 4b(RR'NH = piperidine),
4c (RR'NH= morpholine), 4d (RR'NH = PhNH2), 4e (RR'NH = imidazole)
Entry
RR’NH

Product
Time
Yield %b












a
a
b
c
c
d
d
d
e
e
e
e
b
c
b
b
c
a
b
c
a
b
c
d
5ab
5ac
5bb
5cb
5cc
5da
5db
5dc
5ea
5eb
5ec
5ed
 min
 min
 min
 min
 min
 min
 h





c
c
c

 h
 h
. h
. h


 h
c
aAll products were identified by comparison of their spectral data with those of
known samples.[,,,,,] The molar ratio of nucleophile: Michael acceptor:
catalystwas:.:..b Isolatedyieldoftheproduct. c Thereactionwasperformed
at  °C.
Indoles and pyrroles are important building blocks in many
biologically active compounds and natural products. Both
are acid sensitive structure units. Therefore, introducing mild
reaction procedure for Michael addition reaction of these
compounds is advantageous. In this regard, conjugate addition
of indoles and pyrrole in the presence of TiCl2(OTf)-SiO2
was investigated. Using TiCl2(OTf)-SiO2 (1 mol %), indole,
2-methylindole and N-methylindole were treated with methyl
vinyl ketone under neat reaction conditions at 60 °C. The
corresponding 3-alkylated indole derivatives were obtained
in high yields after appropriate reaction times (Table 3,
Due to the Lewis acidic nature of TiCl2(OTf)-SiO2, the
possible mechanism of the reaction might be the activation
of conjugated β carbon atom towards nucleophiles through
a resonance form which accommodates positive charge on
Cβ. Then, nitrogen or carbon nucleophile reacts with Michael
acceptor at Cβ and enol equivalent intermediate is obtained
which simultaneously releases the catalyst and tautomerizes to
the keto-form product (Scheme 1).
Conclusions
Table . Michael addition of indoles and pyrrolea .
In conclusion, in this study we have introduced another appli-
cation of solid TiCl2(OTf)-SiO2 as a new heterogeneous and
recyclable catalyst for aza-Michael addition reaction. The
generality of the catalyst for C–C and C–N bond formation
reactions through 1,4-conjugate addition of structurally diverse
nitrogen nucleophiles to electron deficient C-C double bonds
has been shown. By this method, the reactions proceeded in
short reaction times and the desired Michael adducts were
obtained in high to excellent yields. Herein, for the first time,
we have reported N-derivatization of α-aminophosphonate via
Michael addition reaction. The use of solid heterogeneous easy
handling catalyst and its tolerance towards moisture combined
with an easy work-up procedure are the strong points of the
presented catalytic protocol for C–C and C–N bond formation
via Michael addition reactions.
COCH3
H(CH3)
N
2a
H(CH3)
7aa-da
TiCl2(OTf)-SiO2
H(CH3)
or
Ph
or
+
no solvent, 60 °C
N
NO2
H(CH3)
Ph
NO2
6a-d
2e
H(CH3)
6a (indole), 6b(2-methyl indole),
6c (N-methyl indole), 6d (pyrrole)
N
H(CH3)
7ae-de
Entry
Donor
Acceptor
Product
Time
yield %b

a
b
c
a
b
c
d
a
a
a
e
e
e
e
7aa
7ba
7ca
7ae
7be
7ce
7de
 min
 min
 min
 min
 min
 min
 min













Experimental section
Chemicals were either prepared in our laboratories or were
purchased from Fluka and Merck Chemical Companies. The
purity determination of the products was accomplished by
GC on a Shimadzu model GC-14A instrument or by TLC
on silica gel polygram SIL G/UV 254 plates. The IR spectra
were recorded with a Perkin Elmer 781 spectrophotometer.
aAll products were identified by comparison of their spectral data with those of
known samples.[,,,] The molar ratio of nucleophile: Michael acceptor: cat-
alyst was : .: .. b Isolated yield of the product.

4
H. FIROUZABADI ET AL.
Table . Comparison data.
Entry
Catalystref
Molar ratio of donor: acceptor: cat.
imidazole + n-butyl acrylate
Condition, Time, Yielda



Y(NO) ·  HO[]
: : .
: .: .
: .: .
r.t.,  h, %
r.t.,  h, %
r.t., . h, %
Polyaniline supported CuI[]
TiCl(OTf)-SiO
aniline + acrylonitrile



NaCO(aq.)[]
: : . M
: .: .
: .: .
r.t.,  h, %
 °C,  h, %
 °C,  h, %
CuCl, Ligand, KOt-Bu[]
TiCl(OTf)-SiO
-methyl indole + methyl vinyl ketone
[]



CeCl ·  HO-NaI/ SiO
: : .
r.t.,  h, %
r.t., . h, %
 °C,  min, %
[]
InCl
: : .
: .: .
TiCl(OTf)-SiO
aIsolated yield of the product.
The NMR spectra were recorded with a Bruker Avance DPX Diethyl [(3-oxo-butylamino)-phenyl-methyl]
250 MHz spectrometer. Elemental analyses were obtained using phosphonate (3a)
ThermoFinnigan Flash EA 1112 Series. The Supplemental
1
Oil, 86% yield. H NMR (CDCl3, 250 MHz), δ = 1.14 (t, J =
1
Materials contains sample H and 13C NMR spectra of the
7.0 Hz, 3H), 1.26 (t, J = 7.0 Hz, 3H), 2.12 (s, 3H), 2.55–2.65
(brs, 1H), 2.60 (t, J = 6.1 Hz, 2H), 2.69–2.76 (m, 2H), 3.74–4.08
(m, 4H), 4.01 (d, J = 19.5 Hz, 1H), 7.25–7.44 (m, 5H). 13C NMR
(CDCl3, 62.9 MHz), δ = 14.1, 16.1 (d, 4JPC = 5.7 Hz), 16.3 (d,
products 3 and 5 (Figures S 1 – S 11).
Preparation of the catalyst
4JPC = 5.7 Hz), 30.0, 42.6 (d, JPC = 17.8 Hz), 61.1 (d, JPC
=
3
1
153.4 Hz), 62.7 (d, 3JPC = 6.3 Hz), 62.8 (d, 3JPC = 6.6 Hz), 127.8
(d, 4JPC = 3.1 Hz), 128.1, 128.4 (d, 3JPC = 5.8 Hz), 135.6 (d, 2JPC
= 4.0 Hz), 207.9; IR (neat): 3317, 2981, 2904, 1712 cm−1; Anal.
Calcd. for (C15H24NPO4): C, 57.54; H, 7.66; N, 4.47; Found: C,
57.44; H, 7.69; N, 4.46%.
TiCl3(OTf) was prepared according to the literature upon reac-
tion of TiCl4 with TfOH.[96] As we have reported previously,[103]
TiCl2(OTf)-SiO2 was also obtained through treatment of
TiCl3(OTf) with dry silica gel in dry CH2Cl2 under nitrogen
atmosphere at room temperature.
Butyl 3-[(diethoxy-phosphoryl)-phenyl-methyl]amino-
propanoate (3b)
General procedure for aza-Michael addition of α-amino
phosphonates
To a mixture of α-amino phosphonate[104] 1 (1 mmol) and
Michael acceptor 2 (1.1 mmol) TiCl2(OTf)-SiO2 (30 mg,
1 mol %) was added and the resulting mixture was stirred at 60
ºC for the appropriate time. Then, EtOAc (10 mL) was added
to the reaction mixture and the reaction mixture was filtered
off. The solvent was evaporated in vacuo and the resulting crude
material was purified by chromatography on a short column of
silica gel (EtOAc: petroleum ether, 1: 3) to give the desired N-
substituted aminophosphonate 3a-h.
Oil, 84% yield.1H NMR (CDCl3, 250 MHz), δ = 0.89 (t, J =
7.3 Hz, 3H), 1.11 (t, J = 7.0 Hz, 3H), 1.23 (t, J = 7.0 Hz, 3H),
1.28–1.34 (m, 2H), 1.53–1.58 (m, 2H), 2.29 (s, 1H), 2.43 (t, J =
6.6 Hz, 2H), 2.68–2.77 (m, 2H), 3.70–4.23 (m, 6H), 4.01 (d, J =
20.9 Hz, 1H), 7.22–7.44 (m, 5H). 13C NMR (CDCl3, 62.9 MHz),
δ = 13.6, 16.2 (d, 4JPC = 5.7 Hz), 16.3 (d, 4JPC = 5.7 Hz), 19.0,
30.5, 34.6, 43.4 (d, 3JPC = 17.8 Hz), 60.0 (d, 1JPC = 153.3 Hz),
62.7 (d, 3JPC = 6.9 Hz), 62.9 (d, 3JPC = 7.1 Hz), 64.3, 127.8 (d,
3
2
4JPC = 3.2 Hz), 128.4, 128.4 (d, JPC = 4.7 Hz), 135.6 (d, JPC
= 4.3 Hz), 172.4; IR (neat): 3317, 2931, 2869, 1732 cm−1; Anal.
Calcd. for (C18H30NPO5): C, 58.25; H, 8.08; N, 3.77; Found: C,
58.19; H, 8.05; N, 3.78%.
Diethyl [(3-oxo-butylamino)-p-tolyl-methyl] phosphonate
(3c)
1
Oil, 87% yield. H NMR (CDCl3, 250 MHz), δ = 1.15 (t, J =
7.0 Hz, 3H), 1.26 (t, J = 7.0 Hz, 3H), 2.11 (s, 3H), 2.32 (s, 3H),
2.43 (s, 1H), 2.58 (t, J = 6.1 Hz, 2H), 2.67–2.75 (m, 2H), 3.80–
4.26 (m, 4H), 3.97 (d, J = 19.9 Hz, 1H), 7.16 (AAꢀ, 2H), 7.28
4
(BBꢀ, 2H); 13C NMR (CDCl3, 62.9 MHz), δ = 16.2 (d, JPC
=
5.6 Hz), 16.3 (d, 4JPC = 5.7 Hz), 21.0, 30.0, 42.6 (d, 3JPC = 17.8
Hz), 43.4, 60.8 (d, 1JPC = 154.1 Hz), 62.6, 62.7 (d, 3JPC = 6.9 Hz),
128.2 (d, 3JPC = 6.1 Hz), 129.0 (d, 4JPC = 2.4 Hz), 132.4 (d, 2JPC
Scheme . Suggested mechanism for TiCl(OTf)-SiO catalyzed aza-Michael
addition to methyl vinyl ketone.

PHOSPHORUS, SULFUR, AND SILICON
5
= 4.2 Hz), 137.4 (d, 5JPC = 3.3 Hz), 207.9; IR (neat): 3325, 2981,
2904, 1712 cm−1; Anal. Calcd. for (C16H26NPO4): C, 58.74; H,
7.94; N, 4.28; Found: C, 58.72; H, 7.95; N, 4.29%.
3JPC = 17.8 Hz), 61.4 (d, 1JPC = 153.3 Hz), 62.8 (d, 3JPC = 7.2
3
Hz), 62.9 (d, JPC = 7.4 Hz), 126.0, 126.1, 127.6, 126.7, 127.8,
127.9, 128.1, 128.2, 133.1, 133.2, 208.0; IR (neat): 3317, 2948,
2908, 1712 cm−1; Anal. Calcd. for (C19H26NPO4): C, 62.84; H,
7.16; N, 3.85; Found: C, 62.74; H, 7.19; N, 3.84%.
Butyl 3-[(diethoxy-phosphoryl)-p-tolyl-methyl]amino-
propanoate (3d)
Butyl 3-[(diethoxy-phosphoryl)-(naphthalen-2-yl)-
methyl]amino-propanoate (3h)
1
Oil, 85% yield. H NMR (CDCl3, 250 MHz), δ = 0.92 (t, J =
7.2 Hz, 3H), 1.16 (t, J = 7.0 Hz, 3H), 1.27 (t, J = 7.0 Hz, 3H),
1.30–1.34 (m, 2H), 1.56–1.59 (m, 2H), 2.33 (s, 3H), 2.34 (s, 1H),
2.46 (t, J = 6.6 Hz, 2H), 2.60–2.81 (m, 2H), 3.8–4.21 (m, 6H),
1
Oil, 87% yield. H NMR (CDCl3, 250 MHz), δ = 0.90 (t, J
= 7.1 Hz, 3H), 1.13 (t, J = 7.0 Hz, 3H), 1.22–1.35 (m, 5H),
1.55–1.58 (m, 2H), 2.49 (t, J = 6.2 Hz, 2H), 2.42–2.54 (brs, 1H),
2.72–2.88 (m, 2H), 4.02–4.10 (m, 6H), 4.22 (d, J = 20.1 Hz,
1H), 7.45–7.53 (m, 2H), 7.60–7.65 (m, 1H), 7.82–7.90 (m, 4H).
13C NMR (CDCl3, 62.9 MHz), δ = 13.6, 16.2 (d, 4JPC = 6.2 Hz),
4.00 (d, J = 19.8 Hz, 1H), 7.22 (AAꢀ, 2H), 7.32 (BBꢀ, 2H). 13
C
NMR (CDCl3, 62.9 MHz), δ = 13.6, 16.2 (d, 4JPC = 5.9 Hz), 16.4
(d, 4JPC = 5.7 Hz), 19.0, 21.1, 30.5, 34.5, 43.3 (d, 3JPC = 17.9 Hz),
60.6 (d, 1JPC = 153.9 Hz), 62.7 (d, 3JPC = 7.3 Hz), 62.8 (d, 3JPC
=
8.4 Hz), 64.3, 128.3 (d, 4JPC = 6.1 Hz), 129.1 (d, 3JPC = 2.5 Hz),
132.4, 137.6, 172.5; IR (neat): 3317, 2931, 2869, 1732 cm−1; Anal.
Calcd. for (C19H32NPO5): C, 59.25; H, 8.30; N, 3.63; Found: C,
59.19; H, 8.33; N, 3.62%.
4
3
16.4 (d, JPC = 6.7 Hz), 19.1, 30.5, 34.4, 43.4 (d, JPC = 17.4
Hz), 61.3 (d, 1JPC = 153.4 Hz), 62.9 (d, 3JPC = 6.9 Hz), 63.0 (d,
3JPC = 9.8 Hz), 64.4, 126.0, 126.1, 127.6, 127.7, 127.8, 127.9,
128.1, 128.2, 133.1, 133.2, 172.4; IR (neat): 3317, 2927, 2869,
1732 cm−1; Anal. Calcd. for (C22H32NPO5): C, 62.73; H, 7.59;
N, 3.32; Found: C, 62.67; H, 7.58; N, 3.31%.
Diethyl [(4-chloro-phenyl)-(3-oxo-butylamino)-methyl]
phosphonate (3e)
1
Oil, 90% yield. H NMR (CDCl3, 250 MHz), δ = 1.19 (t, J =
General procedure for Michael addition of amines and
imidazole
7.0 Hz, 3H), 1.7 (t, J = 7.0 Hz, 3H), 2.13 (s, 3H), 2.32 (s, 1H),
2.60 (t, J = 4.5 Hz, 2H), 2.67–2.71 (m, 2H), 3.91–4.30 (m, 4H),
3.95 (d, J = 20.1 Hz, 1H), 7.30–7.40 (m, 4H). 13C NMR (CDCl3,
62.9 MHz), δ = 16.2 (d, 4JPC = 6.5 Hz), 16.3 (d, 4JPC = 6.2 Hz),
30.1, 42.6 (d, 3JPC = 17.6 Hz), 43.4, 60.6 (d, 1JPC = 153.4 Hz),
To a mixture of amine or imidazole 4a-e (1 mmol) and Michael
acceptor 2a-d (1.1 mmol), TiCl2(OTf)-SiO2 (30 mg, 1 mol %)
was added. The reaction mixture was stirred at room tempera-
ture or 60 °C. After completion of the reaction, EtOH (8 mL)
was added to the reaction mixture and stirred for 15 min, fol-
lowed by filtration and evaporation of the solvent. The resulting
crude product was purified by crystallization or column chro-
matography to provide pure Michael adducts 5.
62.8 (d, 3JPC = 7.2 Hz), 62.9 (d, 3JPC = 7.2 Hz), 128.5 (d, 4JPC
=
2.6 Hz), 129.7 (d, 3JPC = 6.0 Hz), 133.6, 134.3 (d, 2JPC = 4.7 Hz),
207.9; IR (neat): 3325, 2970, 2858, 1712 cm−1; Anal. Calcd. for
(C15H23NPO4Cl): C, 51.83; H, 6.61; N, 4.03; Found: C, 51.72; H,
6.64; N, 4.01%.
Butyl 3-[(4-chloro-phenyl)-(diethoxy-phosphoryl)-
methyl]amino-propanoate (3f)
General procedure for Michael addition of indoles and
pyrrole
1
Oil, 89% yield. H NMR (CDCl3, 250 MHz), δ = 0.89 (t, J
TiCl2(OTf)-SiO2 (30 mg, 1 mol %) was added to a mixture of
indoles or pyrrole 6a-d (1 mmol) and Michael acceptor 2a or
2e (1.5 mmol) at 60 °C. The mixture was stirred for appropri-
ate time. After completion of the reaction CH2Cl2 (15 mL) was
added to the reaction mixture and filtered. Evaporation of the
filtrate gave the crude product, which was further purified by
column chromatography, eluting with the appropriate solvents
to furnish pure Michael adduct 7.
= 7.2 Hz, 3H), 1.18 (t, J = 7.3 Hz, 3H), 1.24–1.37 (m, 3H),
1.56–1.62 (m, 2H), 2.42–2.52 (brs, 1H), 2.47 (t, J = 6.3 Hz, 2H),
2.73–2.78 (m, 2H), 3.99–4.09 (m, 6H), 4.05 (d, J = 18.1 Hz,
1H), 7.19–7.84 (m, 4H). 13C NMR (CDCl3, 62.9 MHz), δ =
13.6, 16.2 (d, 4JPC = 6.2 Hz), 16.3 (d, 4JPC = 6.7 Hz), 19.1, 30.5,
3
1
34.4, 43.4 (d, JPC = 17.4 Hz), 60.4 (d, JPC = 153.4 Hz), 62.9
(d, 3JPC = 6.9 Hz), 63.0 (d, 3JPC = 9.8 Hz), 64.4, 128.6 (d, 4JPC
=
2.6 Hz), 135.6 (d, 2JPC = 6.0 Hz), 172.4; IR (neat): 3317, 2931,
2869, 1728 cm−1; Anal. Calcd. for (C18H29NPO5Cl): C, 53.43;
H, 7.16; N, 3.46; Found: C, 53.45; H, 7.19; N, 3.44%.
Acknowledgements
We are grateful to Shiraz University Research Council for support of
this work.
Diethyl [(naphthalen-2-yl)-(3-oxo-butylamino)-methyl]
phosphonate (3g)
1
Oil, 84% yield. H NMR (CDCl3, 250 MHz), δ = 1.13 (t, J =
Author contribution statement
7.0 Hz, 3H), 1.26 (t, J = 7.0 Hz, 3H), 2.08 (s, 3H), 2.60 (t, J =
6.1 Hz, 2H), 2.55–2.65 (brs, 1H), 2.72–2.77 (m, 2H), 3.85–4.08
(m, 4H), 4.20 (d, J = 20.1 Hz, 1H), 7.43–7.50 (m, 2H), 7.56–7.60
(m, 1H), 7.80–7.85 (m, 4H). 13C NMR (CDCl3, 62.9 MHz), δ =
The data of this manuscript are taken from the corresponding author PhD
Thesis, Shiraz University: ‘New applications of trichlorotitanium(IV) tri-
fluoromethanesulfonate, TiCl3(OTf) & preparation and application of sil-
ica bound Ti(IV), TiCl2(OTf)-SiO2 as a heterogeneous catalyst in organic
4
4
16.2 (d, JPC = 5.7 Hz), 16.4 (d, JPC = 5.7 Hz), 30.0, 42.8 (d, transformations’. Professor Habib Firouzabadi: Thesis Director.

6
H. FIROUZABADI ET AL.
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Supplementary material
Electronic Supplementary Information (ESI) available: copies of NMR
spectra of the new compounds and characterization data of known
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