One-pot three component α-aminoalkylation of conjugated nitroalkenes and nitrodienes

Article abstract of DOI:10.1016/j.tetlet.2009.12.015

Nitroethylenes possessing aryl, heteroaryl, and alkyl substituents at the β-position as well as δ-substituted nitrobutadienes undergo facile aminoalkylation at the α-position upon treatment with formaldehyde and a secondary amine in the presence of imidazole and trifluoroacetic acid to afford α-aminoalkylated nitroalkenes and nitrodienes in good to excellent yield and stereoselectivity.

Full text of DOI:10.1016/j.tetlet.2009.12.015

Tetrahedron Letters 51 (2010) 846–849
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-pot three component
and nitrodienes
a-aminoalkylation of conjugated nitroalkenes
*
Kunjanpillai Rajesh, Pramod Shanbhag, Manjoji Raghavendra, Pallavi Bhardwaj, Irishi N. N. Namboothiri
Department of Chemistry, Indian Institute of Technology, Bombay, Mumbai 400 076, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Nitroethylenes possessing aryl, heteroaryl, and alkyl substituents at the b-position as well as d-substi-
tuted nitrobutadienes undergo facile aminoalkylation at the -position upon treatment with formalde-
Received 31 October 2009
Revised 1 December 2009
Accepted 4 December 2009
Available online 11 December 2009
a
hyde and a secondary amine in the presence of imidazole and trifluoroacetic acid to afford
a-
aminoalkylated nitroalkenes and nitrodienes in good to excellent yield and stereoselectivity.
Ó 2009 Elsevier Ltd. All rights reserved.
The C–C or C–N bond formation via coupling of an activated al-
kene with an electrophile, mediated normally by a Lewis base, has
emerged as a highly atom-efficient strategy for the synthesis of
small multi-functional molecules.1–3 The enormous diversity in
the components and conditions for this reaction, commonly known
as Morita–Baylis–Hillman (MBH) reaction, has enthralled organic
chemists in the last two decades.3 The scope of this reaction in gen-
erating novel building blocks via inter- and intra-molecular reac-
tions and asymmetric versions as well as applications in the
synthesis of complex molecules is ever expanding.3
as formaldehyde and other carbonyl compounds, activated alkenes,
imines, and azo compounds.11 This strategy enabled us to synthe-
size a diverse array of potentially useful nitroethylenes replete
with a range of functional groups.
We regarded the aminoalkylation of nitroalkenes using imini-
um salts generated in situ from aldehyde and amine as a simple
and convenient method to synthesize 1,2-nitramines12 which can
be easily transformed to unsymmetrical 1,2-diamines which, be-
sides being important synthetic intermediates, are prospective li-
gands and organocatalysts. 1,2-Nitramines are also immediate
The reaction of an activated alkene with an imine or iminium
electrophile under the MBH conditions (aza-MBH reaction) is par-
ticularly attractive as it generates synthetically and biologically
precursors to a-amino-oximes and a-amino-ketones.
Our preliminary optimization studies using b-furyl nitroethyl-
ene 1a as the model substrate and formaldehyde–morpholine sys-
tem 2–3a as the electrophile revealed that DABCO, DMAP and
imidazole were suitable catalysts for the desired transformation
(Table 1, entries 1–6). Among these, imidazole provided the prod-
uct in better yield in 24 h (entry 4) and after further optimization
of the quantity of imidazole and solvent (Table 1, entries 7–14), it
became apparent that stoichiometric amounts of imidazole in THF
at room temperature offered satisfactory conditions for the
relevant a
-aminoalkylated activated alkenes.4 The aminoalkylation
relied primarily on activated imines such as sulfonylimines,5 sulfi-
nylimines,6 phosphinoylimines,7 and related species8 which pro-
vided secondary amines with the activating group still attached
to the products. Removal of such activating groups to liberate the
amine requires an additional step which can be cumbersome.
An alternative means to generate
a-aminoalkylated activated
alkenes via MBH reaction is to employ iminium salts as electro-
philes for which there are only two examples in the literature.9,10
Azizi and Saidi reported the first MBH reaction of iminium salt as
electrophile.9 The salt which was generated in situ from benzalde-
hyde and N-trimethylsilyl pyrrolidine was reacted with methyl
acrylate in the presence of DBU/LiClO4 as the catalyst to afford
the MBH adducts. More recently, Aggarwal and co-workers em-
a
-aminoalkylation.13
Our further attempts to improve the yield via dual activation
employing LiCl or a Brønsted acid such as acetic acid as co-catalyst
showed only marginal improvement in the yield (Table 1, entries
15 and 16). However, remarkable rate acceleration and enhance-
ment in the yield was observed when TFA (10 mol %) was used
as the co-catalyst (Table 1, entry 17, 7 h, 82% yield)14 though the
reaction in water alone (entry 18) and under microwave irradiation
conditions (entry 19) did not proceed well. Therefore, the condi-
tions described in Table 1, entry 17 were applied to aminoalkyla-
tion of other b-heteroaryl and b-aryl nitroethylenes 1b–j
(Table 2). Thus, 3-furyl and 2-thienyl nitroethylenes, 1b and 1c,
ployed a-methoxypyrrolidine, a cyclic N,O-acetal and an iminium
salt surrogate, as electrophile with a variety of activated alkenes
in the presence of Me2S/TMSOTf as the catalyst system.10
In recent years, we have reported the Morita–Baylis–Hillman
reaction of conjugated nitroalkenes with various electrophiles such
were subjected to a-aminomethylation to afford the MBH adducts
4b and 4c in 65% and 71% yields, respectively (Table 2, entries 2
and 3). As for the reactivity of b-aryl nitroethylenes, no appreciable
* Corresponding author. Tel.: +91 22 2576 7196; fax: +91 22 2576 7152.
E-mail address: irishi@iitb.ac.in (I.N.N. Namboothiri).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.015

K. Rajesh et al. / Tetrahedron Letters 51 (2010) 846–849
847
Table 1
a
Table 3
-Aminoalkylation of nitroalkene 1a with formaldehyde 2a and morpholine 3a:
a
-Aminoalkylation of nitrodienes 5 with formaldehyde 2a and morpholine 3a
catalyst and solvent screening
NO2
O
NO2
Ar
Ar
imidazole
catalyst
(mol %)
O
NO2
N
(100 mol %)
O
NO2
+
O
+
5
6
N
TFA (10 mol %)
co-catalyst
(mol %)
HCHO
2
THF, rt
O
N
H
1a
3a
4a
N
H
3a
HCHO
2
O
solvent, rt
Entry
5, Ar
Time (h)
% Yieldb,c
Entry
Catalyst (mol %), solvent
Time
% Yieldb
58
1
2
3
4
5a, 2-Furyl
5b, Ph
5c, 2-MeO–Ph
5d, 2-NO2–Ph
15
20
20
24
71
68
76
63
1
2
DABCO (100), THF
DBU (100), THF
24 h
48 h
48 h
24 h
96 h
60 h
48 h
48 h
36 h
24 h
24 h
24 h
48 h
24 h
36 h
36 h
7 h
c
—
3
DMAP (100), THF
40
60
23
27
30
42
55
56
50
30
17
56
66
65
82
4
Imidazole (100), THF
a
b
c
5
Me3N (100), THF
38% aqueous.
6
Ph3P (100), THF
Isolated yield after purification by silica gel column chromatography.
10–20% of nitrodiene 5 polymerized.
7
Imidazole (10), THF
8
Imidazole (20), THF
9
Imidazole (50), THF
reaction was scarcely investigated.17,18 Thus imidazole-catalyzed
reaction of d-heteroaryl and d-aryl nitrodienes 5 afforded the
10
11
12
13
14
15
16
17
18
19
Imidazole (200), THF
Imidazole (100), CH3CN
Imidazole (100), methanol
Imidazole (100), DMF
Imidazole (100), acetone
Imidazole (100), LiCl (10), THF
Imidazole (100), AcOH (10), THF
Imidazole (100), TFA (10), THF
Imidazole (100), TFA (10), water
Imidazole (100), TFA (10), MW
a-
aminoalkylated products 6 in good to high yield. As in the case
of b-aryl and b-heteroaryl nitroethylenes 1, nitrodienes 5 did not
exhibit any appreciable effect of the nature of the aryl group. While
d-furyl nitrodiene 5a and d-phenyl nitrodiene 5b underwent the
one-pot three component aminoalkylation in good yield (Table 3,
entries 1 and 2), the yield was marginally higher (76%) for 5c with
an electron donating substituent and lower (63%) for 5d with an
electron withdrawing substituent on the aromatic ring (Table 3,
entries 3 and 4).
d
24 h
1–2 min
—
—
e
a
b
c
38% aqueous.
Isolated yield after purification by silica gel column chromatography.
No reaction.
Traces.
Nitroalkene polymerized.
Having successfully generated the
a-aminoalkylated products
d
e
of aromatic and heteroaromatic nitroalkenes 1 and nitrodienes 5
using the iminium electrophile generated in situ from formalde-
hyde 2 and morpholine 3a, we investigated further scope of this
reaction using other amines such as piperidine 3b and thiomorph-
oline 3c (Table 4). We also employed a b-alkyl nitroethylene 7 for
the first time in this aminoalkylation.
Although the yield is low (48%) and the product is prone to un-
dergo decomposition, the MBH adduct of b-furyl nitroethylene 1a
with formaldehyde–piperidine system 2–3b was isolated as a sin-
gle E-stereoisomer (Table 4, entry 1). This is consistent with the
product stereochemistry of all the MBH adducts of b-aryl and b-
heteroaryl nitroethylenes 4 reported in Table 1. By contrast, the
reaction of b-alkyl nitroethylene 7 with formaldehyde–morpholine
2–3a and formaldehyde–thiomorpholine 2–3c provided the amin-
oalkylated products in good to excellent yield, but as a mixture of E
and Z isomers (8 + 9) in ꢀ 9:1 ratio (Table 4, entries 2 and 3).
Finally, the reaction of nitrodienes 5 with formaldehyde–piper-
idine 2–3b and formaldehyde–thiomorpholine 2–3c systems was
Table 2
a
-Aminoalkylation of nitroalkenes 1 with formaldehyde 2a and morpholine 3a
NO2
imidazole
O
Ar
NO2
(100 mol %)
Ar
+
N
TFA (10 mol %)
N
H
THF, rt
4
1
3a
O
HCHO
2
Entry
1, Ar
Time (h)
% Yieldb,c
1
2
3
1a, 2-Furyl
1b, 3-Furyl
1c, 2-Thienyl
1d, Ph
7
82
65
71
65
68
95
72
65
68
68
12
10
7
10
10
10
10
12
6
4
5
1e, 4-MeO–Ph
6
7
8
1f, 3,4-(MeO)2Ph
1g, 3,4-OCH2O–Ph
1h, 4-Cl–Ph
9
1i, 4-F–Ph
Table 4
10
1j, 2-NO2–Ph
a
-Aminoalkylation of nitroalkenes with formaldehyde 2a and various secondary
a
b
c
38% aqueous.
amines 3a–c
Isolated yield after purification by silica gel column chromatography.
10–20% of nitroalkene 1 polymerized.
R
NO2
NO2
N
NO2
N
imidazole
R
R
substituent effect15 was observed except in the case of 1f (Table 2,
entry 6, 95% yield). Parent b-nitrostyrene 1d (entry 4), nitrosty-
renes with electron donating (1e and 1g, entries 5 and 7), weakly
electron withdrawing (1h–i, entries 8 and 9) and strongly electron
withdrawing substituents (1j, entry 10) at the para position under-
went aminoalkylation in comparable yield (65–72%, Table 2) over
6–12 h.
Subsequent to the above aminoalkylation of b-aryl and b-het-
eroaryl nitroethylenes 1, we turned our attention to the reactivity
of nitrodienes 5 (Table 3). Although nitrodiene can be easily pre-
+
(100 mol %)
1, 7
X
TFA (10 mol %)
+
HCHO
THF, rt
X
X
8
9
N
H
2
3
Entry
1/7, R
3, X
Time (h)
% Yieldb (8 + 9)
Ratio (8:9)
1
2
3
1a, 2-Furyl
7, Cy
7, Cy
3b, CH2
3a, O
3c, S
5
24
24
8a + 9a, 48c
8b + 9b, 83
8c + 9c, 62
100:0
93:07
89:11
a
b
c
38% aqueous.
pared by condensing an
a,b-unsaturated aldehyde with nitrometh-
Isolated yield after purification by silica gel column chromatography.
Partially decomposed during purification.
ane,16 the reactivity of nitrodiene in Michael addition and MBH

848
K. Rajesh et al. / Tetrahedron Letters 51 (2010) 846–849
investigated (Table 5). These results further confirmed the general-
ity of our methodology for the facile -aminoalkylation of acti-
NOE
δ 7.43 (d, J 15.8)
δ 7.92 (d, J 11.7)
a
Hc Ha
vated alkenes and dienes. As is discernible from Table 5, the
reaction of nitrodienes 5a–c with formaldehyde–piperidine system
2–3b proceeded satisfactorily to afford the MBH adducts 10a–c in
good yields (54–63%, Table 5, entries 1–3). Similar reaction of nit-
rodienes 5a–c with formaldehyde–thiomorpholine system 2–3c
provided the MBH adducts 10d–f in good to high yield (59–72%,
Table 5, entries 4–6).
NO2
Hb
O
N
NOE
O
δ 7.18 (dd, J 15.8, 11.7)
The structures of all the aminoalkylated products were con-
firmed by their IR, 1H and 13C NMR as well as mass spectral char-
acteristics. The geometry of the nitroethylenic double bond was
found to be E in all the products which were formed as single iso-
mers. In the case of mixtures (Table 4, entries 2 and 3, Table 5, en-
try 6), E geometry was assigned for the nitroethylenic double bond
in the major products. These assignments are based on the deshiel-
ding effect experienced by the proton b to nitro group in E isomers
by 1.2–1.4 ppm in the 1H NMR spectrum (Tables S1–S2, see Sup-
plementary data). This was further confirmed by 1H–1H 2D NOESY
experiment with a representative adduct 4j. A medium NOE be-
tween the allylic CH2 and one of the aromatic protons, presumably,
the one ortho to the nitroethylenic moiety was observed for 4j (see
Figure 1. Structural assignment of 6c.
H
N
H
N
N
N
O
O
O
N
O
H
N
H O
F3C
R
O
R
O
O
I
II
F3C
H
H
H
H
O
O
H
Supplementary data). In the case of a-aminoalkylated nitrodienes
N
X
O
X
N H
2
III
6 and 10, both the double bonds were assigned E configuration
based on the coupling characteristics of the three protons in the
dienic moiety. In general, the proton b to nitro group coupled with
F3C
O
H
3
OH
O
the
c-proton with a J value of ꢀ10.5–12.0 Hz and the
c-proton cou-
F3C
NO2
N
R
pled with the d-proton with a J value of ꢀ15.0–16.0 Hz suggesting
that both the double bonds have E configuration. Further confirma-
tion of this assignment was obtained from 1H–1H 2D COSY and
NOESY experiments with a representative adduct 6c (Fig. 1). A
strong NOE between Ha and Hc and a medium NOE between Hb
and the allylic methylene were indicative of the EE geometry of
the two double bonds in 6c (see also Supplementary data).
II + III
X
4, 6, 8-10
Scheme 1.
The catalytic role of imidazole and TFA involving a dual activa-
tion mechanism is depicted in Scheme 1. While imidazole func-
tions as the nucleophilic Lewis base which adds to nitroalkene in
a Michael fashion, TFA could act as Brønsted acid by (a) activating
the nitroalkene for conjugate addition and stabilizing the nitronate
via hydrogen bonding (I to II) and (b) facilitating the formation of
iminium by activating the aldehyde (2 + 3 to III) and (c) activating
the iminium III towards addition of nitronate II by stabilizing the
counter ion (Scheme 1). It is important to note that stoichiometric
amount of imidazole is required to obtain high yield of the product.
This suggests that high concentration of the nitronate II arising
from conjugate addition of imidazole to nitroalkenes is necessary
for the success of the reaction.19
In conclusion, conjugated nitroalkenes and nitrodienes have
been aminoalkylated at the a-position via a one-pot multi-compo-
nent, room temperature and atom economical reaction using form-
aldehyde and a secondary amine in the presence of a nucleophilic
Lewis base Brønsted acid catalyst system, viz. imidazole and TFA.20
The products, isolated in good to excellent yield, are prospective
synthetic intermediates and precursors to unsymmetrical diamine
ligands and organocatalysts. Our future work will be directed to-
wards expanding the scope of this reaction, including the asym-
Table 5
a
-Aminoalkylation of nitrodienes
5
with formaldehyde 2a and piperidine
3b/thiomorpholine 3c
NO2
X
NO2
Ar
imidazole
Ar
metric version, and exploring the applications of the novel
aminoalkylated nitroalkenes.
a-
(100 mol %)
5
10
+
N
TFA (10 mol %)
HCHO
THF, rt
X
N
H
2
3
Acknowledgments
Entry
5
X
Time (h)
% Yieldb,c
We thank DST, India, for financial assistance, SAIF, IIT Bombay,
for analytical support and Mr. Rajesh Gunjal and Dr. Mayuri Gandhi
for mass spectral data.
1
2
3
4
5
6
5a, 2-Furyl
5b, Ph
5c, 2-MeO–Ph
5a, 2-Furyl
5b, Ph
3b, CH2
3b, CH2
3b, CH2
3c, S
3c, S
3c, S
6
10a, 54d
10b, 63
10c, 57
10d, 59
10e, 71
10f, 72e
24
16
20
24
24
Supplementary data
5c, 2-MeO–Ph
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.12.015.
a
b
c
38% aqueous
Isolated yield after purification by silica gel column chromatography.
ꢀ15–20% of nitroalkene polymerized.
d
e
Decomposed during purification.
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imines: (f) Rastogi, N.; Mohan, R.; Panda, D.; Mobin, S. M.; Namboothiri, I. N. N.
Org. Biomol. Chem. 2006, 4, 3211. Azodicarboxylates; (g) Dadwal, M.; Mobin, S.
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19. For a detailed discussion on the superior role of imidazole in catalyzing the
MBH reaction of nitroalkenes, see Ref. 11d. In this context, the term ‘catalyst’ is
used to indicate that imidazole can in principle be recovered and recycled.
20. General procedure for the a-aminoalkylation of nitroalkenes and nitrodienes: To a
stirred solution of nitroalkene or nitrodiene (1 mmol) and imidazole (1 mmol)
in THF (2 mL) was added morpholine or piperidine or thiomorpholine
(4 mmol) followed by 38% aqueous formaldehyde (4 mL, excess) and TFA
(8 lL, 10 mol %). The reaction mixture was stirred at rt until the completion of
the reaction (see Tables 1–5). Then THF was removed in vacuo, the aqueous
layer was diluted with water (10 mL), extracted with EtOAc (3 Â 10 mL) and
the combined organic layer was concentrated in vacuo. The residue was
purified by silica gel column chromatography to afford pure aminoalkylated
nitroalkene or nitrodiene.
12. (a) Krowczynski, A.; Kozerski, L. Synthesis 1983, 6, 489; (b) Freeman, J. P.;
Emmons, W. D. J. Am. Chem. Soc. 1956, 78, 3405; (c) Heath, R. L.; Rose, J. D. J.