Hyperbranched polyamines: Tunable catalysts for the Henry reaction

Article abstract of DOI:10.1055/s-0034-1378534

Hyperbranched polyethylenimine derivatives were successfully employed as catalyst in the Henry reaction. The nitroalcohol products were obtained in excellent yields within short reaction times. A one-pot synthesis of β-nitrostyrenes was developed by using ZnCl₂ along with hyperbranched polyethylenimine derivatives. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0034-1378534

LETTER
▌1847
letter
Hyperbranched Polyamines: Tunable Catalysts for the Henry Reaction
Hyperbranched Polyamines: A Tunable Catalyst
Subramaniapillai Selva Ganesan,* Asaithampi Ganesan, Jagatheeswaran Kothandapani
School of Chemical and Biotechnology, SASTRA University, Thanjavur-613401, India
Fax +91(4362)264120; E-mail: selva@biotech.sastra.edu
Received: 12.04.2014; Accepted after revision: 27.05.2014
recovery and reusability of such low-molecular-weight
molecules are difficult. Hyperbranched polyamines are
stable, nontoxic, easily recoverable molecules with high
stability towards moisture and air. Unlike dendritic
amines, hyperbranched polymamines are easily synthe-
Abstract: Hyperbranched polyethylenimine derivatives were suc-
cessfully employed as catalyst in the Henry reaction. The nitroalco-
hol products were obtained in excellent yields within short reaction
times. A one-pot synthesis of β-nitrostyrenes was developed by us-
ing ZnCl along with hyperbranched polyethylenimine derivatives.
2
1
4
sized by step-growth polymerization. Their applications
Key words: Henry reaction, diastereoselectivity, polyamine, ho-
mogeneous catalysis, β-nitrostyrene
1
5
extend to multicomponent reactions, phase-transfer ca-
1
6
talysis, and as fluorescent chemosensors for quantitative
2
+
17
detection of Zn ions in water. Breslow and coworkers
used chiral polyamines as catalyst in the transamination of
The Henry nitroaldol reaction is a key transformation that
18a
phenylpyruvic acid and in Michael addition reaction.
has been applied to the synthesis of novel bioactive mole-
1
cules such as epiquinamide, the α1-adrenergic receptor Commercially available unmodified linear hyperbranched
2
agonist (R)-phenylephrine, core fragments of ritonavir polyethylenimine (PEI; number average molecular weight
3
and lopinavir; HIV protease inhibitors, and (R)-isoproter- M = 1200) 1 was initially examined as a catalyst to carry
n
4
enol – a potent-β-adrenoreceptor. Henry reaction prod- out Henry reaction between 4-nitrobenzaldehyde and ni-
ucts are valuable intermediates for the preparation of tromethane. The formation of nitroalcohol product was
isoxazole 2-oxides, nitrocyclohexanols, acetophenones, observed within 15 minutes. Evaporation of nitromethane
5
and methylbenzoate derivatives. Several heterogeneous solvent from the reaction mixture led to the formation of
6
7
systems such as mesoporous silica, alumina, hydro- a gummy mass from which recovery of the polyamine cat-
8
9
10
11
talcite, nickel hydroxyapatite, zeolite, and I /K CO
alyst 1 was not successful by simple solvent workup. The
2
2
3
have been reported to catalyze the Henry reaction. Re- product 5 was isolated from the reaction mixture in 90%
cently, Kühbeck et al. reported a gelatin-mediated Henry yield by column chromatography (Scheme 2). Moreover,
1
2
reaction in DMSO solvent, and Majhi et al. obtained ni- with linear PEI catalyst 1, reaction times longer than 15
1
3
troaldol products using TMEDA as catalyst. However, minutes led to side-product formation. The reaction car-
Me
Me
N
N
Me
Me
Me
N
Me
Me
Me
Me
N
N
N
N
N
N
HCHO,
HCOOH
N
n
N
Me
Me
N
Me
Me
Me
H2O, 110 °C
N
16 h
Me
3
° polyamine 2
Ar
PEI
HN
1
Ar
1
. ArCHO
MgSO4, r.t., 24 h
N
H
N
H
H
Ar
Ar
N
N
N
N
H
N
N
2
. NaBH4, MeOH
r.t., 12 h
N
H
N
H
n
NH
Ar
Ar = Ph (3), 3-pyridyl (4)
N
H
Ar
2
° polyamine 3, 4
Scheme 1 Synthesis of secondary and tertiary PEI
SYNLETT 2014, 25, 1847–1850
Advanced online publication: 09.07.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0034-1378534; Art ID: st-2014-d0310-l
Georg Thieme Verlag Stuttgart · New York
©

1848
S. S. Ganesan et al.
LETTER
ried out with branched PEI (M = 600) also incurred sim-
n
ilar problems. We proposed that this may be due to the
presence of reactive primary amine groups and hence, the
polyamine 1 was subjected to Eschweiler–Clarke reaction
(
Scheme 1), and the resulting alkylated polyamine cata-
lyst 2 was found to form the nitroaldol product in 98%
yield (Scheme 2). At room temperature, the reaction took
1
2 hours to complete; whereas at 80 °C, the reaction was
completed in three hours. It is tentatively proposed that
the removal of primary amine functionalities in PEI (1)
could improve its basicity as well as aiding catalyst recov-
ery.
Hence, hyperbranched PEI (1) was treated with both
benzaldehyde and pyridine-3-carboxaldehyde separately. Figure 1 Recyclability of the catalyst 3
The secondary hyperbranched PEI 3 and 4 were then ob-
tained by treating the initial imine products with NaBH in
4
After standardizing the reaction conditions, the procedure
was screened with different aldehydes (Scheme 3, Table
MeOH (Scheme 1). Polyamines 3 and 4 derived from both
benzaldehyde and pyridine-3-carboxaldehyde gave the ni-
troaldol product 5 within 20 minutes in 94% and 95%
yield, respectively (Scheme 2).
1
). The reaction carried out with nitroethane gave the ni-
troaldol product in a 60:40 diastereomeric ratio with the
syn product as the major isomer.
3
° polyamine 2
OH
NO2
R2
NO2
R2
MeNO2
O2N
CHO
NO2
CHO
HO
HO
r.t., 12 h or
0 °C, 3 h
2° polyamine
PEI 1
MeNO2
NO2
8
5
98%
3 or 4
5
0%
+
9
r.t., 15 min
2
2° polyamine
MeNO2
R1
R CH2NO2
OH
r.t., 20 min
R1 = 4-NO2, 3-NO2, 2-NO2,
R1
R1
O N
2
R2 = H; up to 99%
r.t., 20 min
NO2
4
-Br, 4-F, 4-N, 3-N, 2-N
R2 = Me; R1 = 4-NO2; 92%
5
dr = 60:40 (syn/anti)
9
9
4% (with catalyst 3)
5% (with catalyst 4)
Scheme 3 2° Polyamine catalyzed Henry reaction
Scheme 2 PEI catalyst screening for Henry reaction
Although 4-chlorobenzaldehyde gave the corresponding
nitroaldol product, isolation of the product from the reac-
tion mixture was not successful. Thus, it was attempted to
acetylate the alcohol by heating the nitroalcohol with ace-
tyl chloride (Scheme 4). Under these conditions, the cor-
responding nitrostyrene product was obtained by
acetylation followed by in situ elimination.
The product was easily isolated from the catalyst by the
evaporation of excess nitromethane solvent followed by
addition of diethyl ether to the reaction mixture. The cat-
alyst was insoluble in the diethyl ether and hence easily
separated from the reaction mixture. The recyclability of
the catalyst was investigated by performing the reaction of
3-nitrobenzaldehyde with nitromethane. The catalyst re-
tained its activity up to four cycles, and the product was
obtained above 90% yield (Figure 1). From the fifth cycle
onwards, the efficiency of the catalyst decreased and
hence the reaction took nearly 12 hours to complete, al-
though the yield was not affected (Figure 1). Comparison
O2N
O N
2
HO
CHO
Cl
2
° polyamine 3
MeNO2
MeCOCl
1
r.t., 20 min
1
00 °C, 1 h
of H NMR spectrum of the recovered catalyst after the
first and fifth runs showed an increase in the number of ar-
omatic protons (see Supporting Information). This may be
due to the possible side reaction of the aromatic aldehyde
with polyamine catalyst 3. Indeed Wilhelm and coworkers
have reported the catalyst-free synthesis of imidazolidines
by the reaction of N,N′-dibenzyl-ethane-1,2-diamine with
Cl
Cl
79%
Scheme 4 β-Nitrostyrene synthesis by in situ acetylation and elimi-
nation
aromatic aldehydes in water at room temperature for three We became interested in devising a one-pot methodology
hours.1 Under our conditions, the rate of Henry reaction to synthesize β-nitrostyrenes. Longer reaction times and
should be much higher than any side reactions of the cat- higher reaction temperature were examined but formation
alyst 3 and hence the catalyst retains its activity over four of elimination product was not observed. The role of ad-
8b
cycles.
ditives was also examined. With anhydrous MgSO only
4
Synlett 2014, 25, 1847–1850
© Georg Thieme Verlag Stuttgart · New York

LETTER
Hyperbranched Polyamines: A Tunable Catalyst
1849
Table 1 Polyamine-Mediated Nitroalcohol Synthesisa
Entry
Aldehyde
Product
Catalyst 3 and 4
Time (min), temp (°C) Yield (%)b
Catalyst 2
Time (h), temp (°C)Yield (%)b
1c
2
3
4
5
6
7
4-O NC H
5
6
20, r.t.
20, r.t.
20, r.t.
20, r.t.
20, r.t.
20, r.t.
180, r.t.
180, r.t.
94 (95)d
99 (80)d
90 (89)d
96 (96)d
98 (90)d
99 (93)d
78 (68)d
83 (88)d
3, 80
3, 80
3, 80
3, 80
3, 80
3, 80
3, 80
3, 80
98 (99)e
86 (89)e
82 (84)e
89 (96)e
95 (98)e
95 (97)e
trace
2
6
4
4-C H N
5
4
3-C H N
7
5
4
2-C H N
8
5
4
3-O NC H
9
2
6
4
4
2-O NC H
10
11
12
2
6
4-BrC H
6
4
8
4-FC H
trace
6
4
a
All the reactions were carried out by the addition of 1 mmol of aldehyde to a homogeneous solution of 50 mg of catalyst 3/4 (or with 100 mg
of catalyst 2) in 3 mL of nitromethane.
b
Yields are for the isolated product.
Reaction carried out with nitroethane gave the nitroalcohol product in 60:40 (syn/anti) dr.
Reaction carried out with catalyst 4.
Reaction carried out at r.t. for 24 h.
c
d
e
trace amounts of nitrostyrene were formed; whereas with
O2N
CHO
R
P O the product was obtained in 60% yield at 140 °C.
2° polyamine 3
anhyd ZnCl2
2
5
Subsequently, anhydrous ZnCl was identified as a suit-
2
+
MeNO2
able reagent to carry out the one-pot synthesis of β-nitro-
styrenes (Scheme 5). After screening reaction parameters
with 4-nitrobenzaldehyde it was found that stirring at
60 °C, 24 h
or
1
40 °C, 6 h
R = 4-NO2, 3-NO2, 2-NO2,
-Cl, 4-Cl, 4-F, 4-OMe, H
3
R
6
2
0 °C for 24 hours gave the product in 85% yield (Table
, entry 1). This optimized protocol was then examined
up to 90%
with several other aldehydes.
Scheme 5 β-Nitrostyrene synthesis with 2° polyamine and ZnCl2
In conclusion, the catalytic activity of PEI derivatives has
been exploited in the synthesis of both nitroalcohol and
nitrostyrene derivatives. The stable, nontoxic, recyclable
PEI catalyst is a useful addition to the known array of cat-
alysts for Henry reaction and studies on asymmetric in-
duction using chiral PEI are under way in our laboratory.
Preparation of the catalysts 2, 3, 4 and spectroscopic data for the
nitroalcohols and β-nitrostyrenes are included in the Supporting
Information.
Table 2 Polyamine-Mediated Nitrostyrene Synthesisa
Entry
Aldehyde
Product
Time (h)
Temp (°C)
Yield (%)b
mp (°C)
Lit. mp (°C)
1
2
3
4
5
6
7
4-O NC H
13
14
15
16
17
18
19
20
24
24
24
24
24
24
24
24
60
60
60
60
60
60
60
60
85
79
84
63
87
62
87
90
201–202
118–120
104
202–20419
123–12420
10421
2
6
4
4
4
3-O NC H
2
6
2-O NC H
2
6
4-ClC H
110–112
57–59
113–11422
57–5822
6
4
Ph
4-MeOC H
85–87
84–8619
6
4
3-ClC H
46–48
42–4323
6
4
8
4-FC H
100–102
102–10322
6
4
a
All the reactions were carried out by the addition of 1 mmol of aldehyde to a mixture of 50 mg of catalyst 3 and 0.5 mmol of ZnCl in 3 mL
2
of nitromethane.
b
Yields are for the isolated product.
©
Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1847–1850

1850
S. S. Ganesan et al.
LETTER
General Procedure for Henry Reaction with Polyamine Cata-
lyst
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Malakondaiah, G. C.; Ravikumar, M.; Bhalerao, D.; Pratap,
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ondary polyethylenimine (50 mg) in nitromethane (3 mL), 4-nitro-
benzaldehyde (151 mg; 1 mmol) was added slowly at r.t. The
reaction mixture was stirred at r.t. (12 h) or 80 °C (3 h) for tertiary
PEI catalyst 2 or 20 min at r.t. for secondary PEI catalysts 3 or 4. To
remove excess nitromethane, the reaction mixture was concentrated
under reduced pressure, and the product was isolated from the cata-
(
4) Das, A.; Kureshy, R. I.; Prathap, K. J.; Choudhary, M. K.;
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2
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organic extracts were washed with brine (1 × 10 mL), dried over an-
Beygzadeh, M. Microporous Mesoporous Mater. 2012, 159,
hydrous Na SO , filtered, and concentrated under reduced pressure.
2
4
9
.
The crude product was purified by silica gel column chromatogra-
phy, eluting with hexane and EtOAc (7:3).
(
(
(
7) Ballini, R.; Noé, M.; Perosa, A.; Selva, M. J. Org. Chem.
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2
-Nitro-1-(4-nitrophenyl)ethanol (5)
Yield (catalyst 2–4): 98% (99%), 94%, 95%.
β-Nitrostyrene Synthesis Using Catalyst 3
To a stirred solution of secondary polyethylenimine 3 (50 mg) in ni-
2
012, 53, 2980.
(10) Devi, R.; Borah, R.; Deka, R. C. Appl. Catal., A 2012, 433–
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tromethane (3 mL), ZnCl (0.5 mmol), and 4-nitrobezaldehyde (151
2
mg; 1 mmol) were added successively at r.t., and the reaction mix-
ture was stirred at 60 °C (24 h) or 140 °C (6 h). After completion of
the reaction excess nitromethane was removed under reduced pres-
sure. The residue was extracted with EtOAc (2 × 10 mL), and the
combined organic extracts were washed with brine (1 × 10 mL),
dried over anhydrous Na SO , filtered, and concentrated under re-
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(
(
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4
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(
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1
9
mp 201–202 °C (202–204 °C ).
Acknowledgment
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boratory accommodation and NMR facilities. S.S.G. thanks Dr.
Elamparuthi for useful discussion.
(
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Synlett 2014, 25, 1847–1850
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