Stereospecific approach to α,β-disubstituted nitroalkenes via coupling of α-bromonitroalkenes with boronic acids and terminal acetylenes

Article abstract of DOI:10.1016/j.tet.2007.09.012

(Z)-α-Bromo-β-substituted nitroethylenes undergo facile Suzuki coupling with aryl, heteroaryl, and vinylboronic acids in the presence of Pd(PPh₃)₄ as catalyst to afford (E)-α,β-disubstituted nitroethylenes in high yield (up to 95%) and complete specificity. Similar coupling of α-bromonitroethylenes with terminal acetylenes (Sonogashira coupling) provides a novel route to (E)-nitroenynes. These Pd-catalyzed coupling methods offer a convenient and stereospecific entry into a diverse array of synthetically and biologically useful α,β-disubstituted nitroethylenes.

Full text of DOI:10.1016/j.tet.2007.09.012

Tetrahedron 63 (2007) 11973–11983
Stereospecific approach to a,b-disubstituted nitroalkenes
via coupling of a-bromonitroalkenes with boronic
acids and terminal acetylenes
*
Madhu Ganesh and Irishi N. N. Namboothiri
Department of Chemistry, Indian Institute of Technology Bombay, Mumbai 400 076, Maharashtra, India
Received 24 June 2007; revised 20 August 2007; accepted 6 September 2007
Available online 9 September 2007
Abstract—(Z)-a-Bromo-b-substituted nitroethylenes undergo facile Suzuki coupling with aryl, heteroaryl, and vinylboronic acids in the
presence of Pd(PPh3)4 as catalyst to afford (E)-a,b-disubstituted nitroethylenes in high yield (up to 95%) and complete specificity. Similar
coupling of a-bromonitroethylenes with terminal acetylenes (Sonogashira coupling) provides a novel route to (E)-nitroenynes. These
Pd-catalyzed coupling methods offer a convenient and stereospecific entry into a diverse array of synthetically and biologically useful
a,b-disubstituted nitroethylenes.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
However, these condensations worked satisfactorily only
with aromatic aldehydes. Our own group has reported a-
hydroxyalkylation, aminoalkylation, and hydrazination of
a variety of b-aryl nitroethylenes via Morita–Baylis–
Hillman reaction.13 In most cases, the products isolated
were isomerically pure a,b-disubstituted (E)-nitroalkenes.
However, a-alkylation could be carried out only with se-
lected electrophiles such as methyl vinyl ketone and acry-
late. Therefore, simple alkylation, arylation, alkynylation,
etc. of the a-position of nitroalkenes remain largely unex-
plored.
Conjugated nitroalkenes are important building blocks in
organic synthesis by virtue of their versatile reactivity as
Michael acceptors, dipolarophiles, 1,3-dipoles, dienophiles,
and heterodienes.1 Nitroalkenes are also distinguished by
their diverse biological activities.2 Among various methods
available for the preparation of nitroalkenes, Henry reaction
(condensation of carbonyl compounds with nitroalkanes)
followed by b-elimination of the resulting 2-nitroalcohols
by direct dehydration or after activation of the hydroxyl
group is primarily the method of choice.3 However, this
method is ineffective for the preparation of isomerically
pure a,b-disubstituted nitroalkenes because of the possible
formation of (E) and (Z)-nitroalkenes from diastereomeric
nitroaldols. Similar condensation of nitroalkanes with
Schiff’s bases generally provides low yields of nitroalkenes
due to instability of Schiff’s bases and are substrate specific.4
Other methods for the preparation of nitroalkenes include di-
rect nitration of alkenes with nitryl halides,5 Cu(II)–NaNO2
complex,6 dinitrogen tetroxide,7 ceric ammonium nitrate
(CAN),8 nitrodecarboxylation,9 and treatment of nitronates
with phenylselenylbromide followed by elimination.10 How-
ever, many of these methods are prone to side reactions and
are specific to a narrow range of substrates. Recently, con-
densation of aldehydes with 1-nitroalkanephosphonates
(modified Horner–Wadsworth–Emmons reaction)11 and
nitroacetonitrile (Knoevenagel reaction)12 was reported for
the synthesis of a,b-disubstituted (E)-nitroalkenes.
In view of the above, a general and practical route to a variety
of a,b-disubstituted nitroalkenes appeared desirable. Owing
to the efficacy and functional group tolerance of transition
metal catalyzed cross-coupling reactions, particularly with
the advent of novel catalyst systems, in forming C–C and
C–X (X¼O, N, S) bonds,14 we envisioned that such coupling
of a-bromonitroethylenes with suitable nucleophilic
partners, namely, alkyl and arylboronic acids (Suzuki–
Miyaura reaction)15,16 and terminal acetylenes (Sonoga-
shira–Hagihara reaction)17–19 would provide an array of
synthetically and biologically relevant a,b-disubstituted
(E)-nitroalkenes. Although cross-coupling reactions of bo-
ronic acid derivatives with various electron-deficient haloal-
kenes were reported in the literature,20,21 such reactions of
a-halonitroalkenes has not received much attention.22 Previ-
ous attempts to carry out Pd-catalyzed reactions of a-bromo-
nitroalkenes provided mixture of products (Scheme 1a),23 or
led to the conjugate addition of the ligand (triphenylphos-
phine) and further transformation (Scheme 1b).24 In some
* Corresponding author. E-mail: irishi@iitb.ac.in
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.09.012

11974
M. Ganesh, I. N. N. Namboothiri / Tetrahedron 63 (2007) 11973–11983
cases, the nitro group was replaced by nucleophiles via one-
electron transfer processes (SRN1).25 Similarly, although
Sonogashira coupling of many activated and unactivated
haloalkenes with terminal acetylenes under the co-catalytic
influence of amines was reported in the literature,26 to our
knowledge, a-bromonitroalkenes were not employed in
such capacity. In fact, reaction of bromonitroalkene 1a
with primary amines provided aziridine 6 as the sole product
(Scheme 1c).27
(Z) based on the literature.31 An initial experiment per-
formed by refluxing (Z)-1-bromo-1-nitrophenylethene 1a
and phenylboronic acid 11a in toluene in the presence of
potassium carbonate (3 equiv) and Pd(PPh3)4 (5 mol %) as
catalyst provided the coupled product 12a in 50% yield
(Table 1, entry 1).32 Either poor yield or a complex mixture
was encountered when the reaction was carried out in other
hydrocarbon solvents (Table 1, entries 2 and 3), and polar
protic and aprotic solvents (entries 4–7). Finally, a mixture
of solvents such as toluene, ethanol, and water (in
9:0.5:0.5) provided higher yield of 12a (64%, Table 1, entry
11). At this stage, we screened other bases, which were pre-
viously employed in Suzuki–Miyaura coupling reactions.
While changing the base from K2CO3 to Na2CO3 or KOH
did not have any appreciable influence on the yield (Table
1, entries 12 and 13), Ba(OH)2$8H2O and NaH2PO4 were
not found suitable (entries 14 and 15). On the other hand,
bicarbonates provided improved yields of 12a in shorter
reaction times (1.5 h, Table 1, entries 16 and 17).
Ph
Br
Ph
Ph
Ph
Ph
Ph
Ph
Pd(OAc)2 (1 equiv)
a)
+
+
Benzene-Acetic acid
reflux, 30 h
NO2
NO2
4
NO2 Ph
NO2
1a
2
3
20 % Yield
Small amounts
+ 2 Ph3PO
b)
RCH=CBrNO2
+
Ph3P-CRCN Br
3 Ph3P
1
5
NO2
H
N
NO2
Cyclohexyl amine
c)
Br
H
Ph
Ph
1a
At this stage, it appeared necessary to optimize the amounts
of boronic acid 11a and Pd(PPh3)4, and also screen other Pd
catalysts in the reaction (Table 2). Entries 1–6 (Table 2) show
that the most economical combination is 1.5 equiv of bo-
ronic acid 11a and 2.5 mol % of Pd(PPh3)4 (entry 4). Other
Pd(0) and Pd(II) catalysts screened under the above condi-
tions in the presence and absence of additives were less
effective (Table 2, entries 7–16). Having optimized the
cross-coupling of bromonitroalkene 1a with phenylboronic
acid 11a, we turned our attention to the scope of the reaction
by screening various a-bromonitroalkenes 1b–h and phenyl-
boronic acid 11a (Table 3). The procedure was found equally
suitable for b-aryl (entries 1–4), b-heteroaryl (entries 5 and
6), and b-alkyl (entries 7 and 8) nitroethylenes 1a–h provid-
ing high yields of the coupled products 12a–h (76–86%,
Table 3).
6
Scheme 1.
It is obvious from the above discussion that controlling
chemo-, stereo-, and regioselectivities in cross-coupling reac-
tions involving highly reactive substrates, such as 1, would be
ofconsiderableinterest. Thistogetherwithourongoingefforts
toward developing new strategies involving nitroalkenes,13,28
we sought to investigate the cross-coupling reactions, viz.
Suzuki and Sonogashira reactions, of a-bromo-nitroalkene
1, for the stereospecific synthesis of a,b-disubstituted (E)-
nitroalkenes 9 and 10 (Scheme 2).
NO2
R1-B(OH)2
7
Pd catalyst,
Base
R
R
R1
Table 1. Screening of various solvents and bases in Suzuki–Miyaura cross-
coupling reaction of a-bromonitroalkene 1aa
NO2
Br
9
NO2
R
NO2
Ph
R2
Pd(PPh3)4 (5 mol %)
NO2
8
1
+
Ph-B(OH)2
base (3 equiv),
solvent(s), reflux, N2
Ph
Br
Pd catalyst,
Base
R = R1 = R2
= alkyl, aryl
Ph
12a
1a
11a
10
R2
Entry Solvent(s)
Base
Time Yieldb
(h) (%)
Scheme 2.
1
2
3
4
5
6
7
8
Toluene
n-Heptane
Cyclohexane
Ethanol
THF
Acetonitrile
DMF
Dioxane–water (8.3:1.7)
Toluene–ethanol–water (5:2.5:2.5) K2CO3
Toluene–ethanol–water (7.4:1.3:1.3) K2CO3
Toluene–ethanol–water (9:0.5:0.5) K2CO3
Toluene–ethanol–water (9:0.5:0.5) Na2CO3
Toluene–ethanol–water (9:0.5:0.5) KOH
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
8
12
12
2
8
5
5
3
12
12
4
50
40
24
12
42
—
—
50
32
40
64
2. Results and discussion
c
c
We initially set out to carry out Suzuki–Miyaura coupling of
(Z)-a-bromonitroalkenes 1. Since the C–B bond is weakly
polarized, organo-boron compounds are weakly nucleo-
philic. Therefore, they are expected to undergo fast transme-
tallation rather than taking part in conjugate addition.
However, in view of the unusual reactivity of conjugated ni-
troalkenes with metal-based reagents,29 we felt that appro-
priate choice of palladium catalyst, base, and solvent
would be necessary for obtaining the cross-coupled products
in significant yields.
9
10
11
12
13
14
15
16
17
4.5 58
2
2
3
60
45
28
Toluene–ethanol–water (9:0.5:0.5) Ba(OH)2$8H2O
Toluene–ethanol–water (9:0.5:0.5) NaH2PO4
Toluene–ethanol–water (9:0.5:0.5) KHCO3
Toluene–ethanol–water (9:0.5:0.5) NaHCO3
1.5 62
1.5 68
a
All reactions were conducted on a 0.2 mmol scale of 1a, using 1.3 equiv of
phenylboronic acid 11a.
Isolated yield after purification by silica gel column chromatography.
Complex mixture.
The a-bromonitroalkenes 1 required for the present study
were readily prepared by a one pot bromination/dehydrobro-
mination protocol.30 The stereochemistry was assigned to be
b
c

M. Ganesh, I. N. N. Namboothiri / Tetrahedron 63 (2007) 11973–11983
11975
Table 2. Screening of Pd catalyst and optimization of the amount of Pd
catalyst and boronic acid 11a
Table 4. Cross-coupling of a-bromonitrostyrene 1a with boronic acids
11b–j
Pd Catalyst (mol %),
NO2
Pd(PPh3)4 (2.5 mol %),
NaHCO3 (3 equiv)
NO2
NO2
Br
NO2
Ph
Co-Catalyst (5 mol %)
+
R-B(OH)2
+
Ph-B(OH)2
Ph
Br
Ph
R
12i-p
NaHCO3 (3 equiv),
Toluene-EtOH-H2O,
(9:0.5:0.5), reflux, N2
Toluene-EtOH-H2O,
(9.0:0.5:0.5), reflux
Ph
Ph
11b-j
1a
1a
11a
12a
Entry
11
R
12
Time (h)
Yielda (%)
Entry 11a (equiv) Pd catalyst
mol % Co-catalyst Time Yielda
(h) (%)
1
2
3
4
5
6
7
8
9
11b
11c
11d
11e
11f
11g
11h
11i
4-Me–Ph
12i
12j
12k
12l
12m
12n
12o
12p
12q
6.0
7.0
3.5
3.5
1.0
1.0
30.0
4.0
91
90
95
82
4-C2H5–Ph
4-MeO–Ph
2-Naphthyl
2-Furyl
2-Thienyl
3-Thienyl
a-Phenylvinyl
2-Phenethyl
1
2
3
4
5
6
7
8
1.3
1.5
2.0
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd–C
5.0
5.0
5.0
2.5
1.0
0.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
—
—
—
—
—
—
—
PPh3
PPh3
PPh3
Et3N
—
1.5 68
1.5 75
1.5 76
6.5 76
b
—
—
b
8.0 65
75
85
—
40.0 20b
48.0 <5c
12.0 52
c
11j
42.0
PdCl2
a
Isolated yield after purification by silica gel column chromatography.
Complex mixture.
No reaction even after using 10 mol % of Pd(PPh3)4.
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
Pd(OAc)2
Pd(dba)2
2.5 62
b
c
d
10
11
12
13
14
15
16
2.5 —
5.0 Traces
12.0 12c
e
—
—
—
8.0
4.5 56
5.0 70
4.0 56
11i by our methodology (Table 4, entry 8). We extended
the scope of Suzuki coupling of 11i with other 1-bromoole-
fins 13 for the selective formation of terminally unsubsti-
tuted dienes, which are otherwise difficult to synthesize
(Scheme 3). This coupling provides a variety of uniquely
functionalized electron-deficient dienes 14a and 14b, which
are presumably good substrates for Diels–Alder cycloaddi-
tion. The formation of the (E) isomer with high stereospeci-
ficity and high yields rules out the possible complexation of
Pd(0) species with the olefinic bond or the NO2 group and
confirms that the classical Suzuki coupling mechanism is
operational in the coupling of a-bromonitroalkene 1 with
boronic acids 11. The inability of 2-furyl- and 2-thienylboro-
nic acids, 11f and 11g, respectively, to take part in cross-
coupling is attributable to their relatively electron-deficient
nature.
PdCl2(PPh3)2 2.5
PdCl2(dppe) 2.5
PPh3
PPh3
a
Isolated yield after purification by silica gel column chromatography.
Bromonitroalkene 1a (w50%) was recovered.
By 1H NMR.
No reaction in the absence of NaHCO3.
Polymerization.
b
c
d
e
Subsequently, boronic acids other than 11a were screened
for the coupling reaction with 1a (Table 4). For instance, re-
action of arylboronic acids 11b–e with bromonitroalkene 1a
provided the coupled products 12i–l in excellent yields (82–
95%, Table 4, entries 1–4). While the cross-coupling of 1a
with 2-furyl, 2-thienyl, and 2-phenethylboronic acids, 11f,
11g, and 11j, respectively, failed to give the desired products
12m, 12n, and 12q (Table 4, entries 5, 6, and 9), similar cou-
pling of 1a with 3-thienyl and a-phenyl vinylboronic acids,
11h and 11i, respectively, provided the products 12o and 12p
in high yields (Table 4, entries 7 and 8).
B(OH)2
CH2
Pd(PPh3)4 (2.5 mol %),
KF (3 equiv)
X
Ph
X
Ph
+
Ph
Toluene-EtOH-H2O
(9.0:0.5:0.5), reflux
Ph
Br
13a-b
An electron-deficient diene with one terminal unsubstituted
12p has been synthesized in high yield (85%) from 1a and
14
11i
14a: X = CHO, 18 h, 82% yield
14b: X = CO2Et, 15 h, 88% yield
Table 3. Cross-coupling of various a-bromonitroalkenes 1a–h with phenyl-
boronic acid 11aa,b
Scheme 3.
Pd(PPh3)4 (2.5 mol %),
NO2
NO2
Br
Our next objective was to investigate the coupling of a-bro-
monitroalkenes 1 with terminal alkynes under Pd-catalyzed
conditions (Sonogashira reaction). a-Bromonitrostyrene 1a
and propargyl benzoate 15a were chosen as model substrates
for the coupling reaction in the presence of 2.5 mol % of
Pd(PPh3)4 in toluene at reflux temperature (Table 5). Several
bases were systematically screened for their co-catalytic ac-
tivity. Either no reaction or low yield of the desired product
16a was encountered when tertiary amine bases such as tri-
NaHCO3 (3 equiv)
Ph-B(OH)2
+
Toluene-EtOH-H2O,
(9.0:0.5:0.5), reflux, N2
R
R
Ph
1a-h
11a
12a-h
Entry
1
R
Time (h)
Yieldc of 12a–h (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
Ph
6.5
6
10
28
1.5
5
76
79
80
76
76
86
81
78
4-OMe–Ph
3,4-(OCH2O)–Ph
4-F–Ph
2-Furyl
€
ethylamine, DBU, pyridine, and Hunig’s base were employed
2-Thienyl
n-C6H13
Me2CHCH2
(Table 5, entries 1–4). When N-methylmorpholine was used
as the base, the cross-coupled product 16a, though isolated
in 56% yield, was contaminated by the homo-coupled prod-
uct of alkyne 15a (Table 5, entry 5). This prompted us to op-
timize the amount of cuprous iodide and other non-amine
bases, which have been extensively used in Sonogashira re-
action.17–20 Reducing the amount of CuI from 10 mol % to
1g
1h
1
1.5
a
The reaction scale w.r.t. bromonitroalkene 1 was 0.5 mmol for entries 1–7
and 0.25 mmol for entry 8.
Concentration of the reaction mixture was 0.04 M for entries 1–3 and 5–8
and 0.08 M for entry 4.
Isolated yield after purification by silica gel column chromatography.
b
c

11976
M. Ganesh, I. N. N. Namboothiri / Tetrahedron 63 (2007) 11973–11983
Table 5. Optimization of conditions for Sonogashira–Hagihara cross-
coupling
unsatisfactory results (Table 5, entries 13–15). The poor per-
formance of Pd(II) pre-catalysts is attributable to the propen-
sity of a-bromonitroalkene to react with triphenylphosphine
as discussed above (see Scheme 1b).24 Finally, when we
employed NMM as co-solvent (toluene–NMM ratio 2:1),
a fast reaction occurred providing good yield (72%) of
cross-coupled adduct (Table 5, entry 16).
NO2
NO2
Pd catalyst, CuI
CH2OCOPh
+
Base (4 equiv)
Toluene, 50-60 °C
Ph
Br
Ph
16a
1a
15a
OCOPh
Entry Pd catalyst
(2.5 mol %)
Base (4 equiv)
CuI
(mol %) (h)
Time Yielda
(%)
10
Having optimized the conditions for the cross-coupling of a-
bromonitroalkene 1a with terminal acetylene 15a, a variety
of aromatic, heteroaromatic, and aliphatic a-bromonitroal-
kenes 1a, 1b, 1e, 1f, 1h, and 1i were reacted with several ter-
minal alkynes 15a–f in the presence of 2.5 mol % each of
Pd(PPh3)4 and CuI in toluene–NMM at 50–60 ꢀC (Table
6). The coupling of bromonitroalkene 1a with phenylacety-
lene 15b provided the product 16b in 69% yield after pro-
longed heating (22 h, Table 6, entry 2). Substantial rate
acceleration with improvement in the yield (8 h, 76%) was
observed when 4-fluoro-phenylacetylene 15c was reacted
with 1a (Table 6, entry 3). In the presence of excess CuI
(10 mol % instead of 2.5 mol %), such couplings required
longer reaction times and provided the desired products in
lower yields due to homo-coupling. While terminal acety-
lenes 15e and 15f also reacted smoothly with 1a (Table 6, en-
tries 5 and 6), 2-furylacetylene 15d failed to react with 1a
even after employing a variety of conditions (entry 4). Sub-
sequently, substituted aromatic nitroalkenes 1b and 1i and
heteroaromatic ones 1e and 1f were reacted with acetylene
15a to afford the coupled products in high yield (70–84%,
Table 6, entries 7, 12, 8, and 9, respectively). The heteroaro-
matic bromonitroalkene 1f also reacted well with n-octyne
15f to provide the coupled product 16j in 86% yield (Table 6,
entry 10). However, attempted coupling of an aliphatic bro-
monitroalkene 1h with 15a yielded only a complex mixture
(Table 6, entry 11).
1
2
3
4
5
6
7
8
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(dba)2
Triethylamine
DBU
i-Pr2NEt
Pyridine
NMM
NMM
NMM
NMM
Cs2CO3
KOtBu
TBAB
10
10
10
10
10
8
8
4
12
5
b
—
29
b
—
56c
70
5.0
2.5
3
3
72
—
b
—
24
6
6
6
6
22
5
8
b
9
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
—
—
b
10
11
12
13
14
15
16
b
—
b
TBAF (in THF)
NMM
NMM
—
50d
77
42
72
e
PdCl2(PPh3)2
PdCl2(dppe)e
Pd(PPh3)4
NMM
NMMf
2
a
Isolated yield after purification by silica gel column chromatography.
No reaction.
b
c
1H NMR suggested significant amount (25–35%) of dimerized product of
alkyne 15a, even after repeated purification.
% Conversion.
d
e
f
PPh3 of 5 mol % as an additive.
Toluene–NMM (2:1).
5 mol % had a beneficial effect (Table 5, entry 6) and further
reduction in the amount of CuI to 2.5 mol % maintained
a good yield (72%, entry 7). However, there was no reaction
in the absence of CuI even after 24 h (Table 5, entry 8). Simi-
larly, no reaction was observed when non-amine bases were
employed (Table 5, entries 9–12). Finally, other catalysts
such as Pd(dba)2, PdCl2(PPh3)2, PdCl2(dppe), which are
known to promote Sonogashira coupling provided
Sonogashira coupling generally involves amines (tertiary,
secondary or primary) as primary organic bases, which are
Table 6. Palladium-catalyzed Sonogashira–Hagihara cross-coupling of a-bromonitroalkenes 1 with terminal alkynes 15
Pd(PPh3)4 (2.5 mol %),
NO2
Br
NO2
CuI (2.5 mol %)
+
R1
Toluene:NMM (2:1),
50-60 °C
R
R
1
15
16
R1
Entry
1
R
15
R1
16
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1b
1e
1f
Ph
Ph
Ph
Ph
Ph
Ph
15a
15b
15c
15d
15e
15f
15a
15a
15a
15f
CH2OCOPh
Ph
4-F–Ph
2-Furyl
CH2OBn
n-C6H13
CH2OCOPh
CH2OCOPh
CH2OCOPh
n-C6H13
CH2OCOPh
CH2OCOPh
16a
16b
16c
16d
16e
16f
16g
16h
16i
2
22
8
22
6
8
8
2
4
72
69b
76b,d
c
—
70
85
71
70
80
86
4-OMe–Ph
2-Furyl
2-Thienyl
2-Thienyl
Me2CHCH2
4-Cl–Ph
9
10
11
12
1f
1h
1i
16j
16k
16l
2
24
1.5
e
15a
15a
—
84
a
Isolated yield after purification by silica gel column chromatography.
Toluene–NMM (1.0:1.5, 0.08 M).
No reaction even after changing the solvent to dioxane, THF or CH3CN.
With excess CuI (10 mol %, see Table 5), the yields were low (61% and 62%, respectively, for entries 2 and 3) in these cases as well.
Toluene–NMM (4:1, 2:1 or 2:3), complex mixture.
b
c
d
e

M. Ganesh, I. N. N. Namboothiri / Tetrahedron 63 (2007) 11973–11983
11977
known to promote coupling by facilitating the formation of
Cu-acetylide and by reducing the Pd(II) species to the much
needed Pd(0) species.17 However, both primary and second-
ary amines are unsuitable for the cross-coupling of bromo-
nitroalkenes 1, as they would react with nitroalkenes in
a Michael fashion to form stable aziridines 6 (Scheme 1c)
or b-aminonitroalkanes.33 Although tertiary amines are
also known to react with nitroalkenes in a 1,4-fashion,
such reactions are reversible.34 Therefore, the following
mechanistic proposal rationalizes the formation of coupled
products even if reversible Michael addition of tertiary
amine to nitroalkene 1 does takes place (Scheme 4). Thus,
NMM could undergo Michael type addition to provide nitro-
nate, bearing a-halo substituent 17. Oxidative addition of
Pd(0) species to 17 will furnish the intermediate 18. Al-
though 18 could, in principle, be in equilibrium with 19,
the former is expected to be more stable due to electrostatic
attraction between the ammonium and the nitronate moieties
and the lack of such interaction in the latter. The intermedi-
ate 18 then undergoes usual transmetallation with alkynyl-
copper species 20 to afford the transmetallated adduct
21. Elimination of NMM followed by reductive elimination
of the palladium catalyst would provide the coupled
product 16.
the alkyl chain was observed in 16f indicating the (E)-
configuration of the double bond. By analogy, the double
bond geometry of other cross-coupled adducts 12b–p,
14a–b, and 16a–l was assigned. The chemical shifts of b-
hydrogens in cross-coupled adducts suggest a formidable
deshielding effect (see Fig. 1 and experimental in Supple-
mentary data), which is not consistent with (Z)-structure
where the interaction between the phenyl ring and the
olefinic proton should be the same as in analogous systems,
e.g. (Z)-a-phenyl-b-arylacrylic acids38 and the (Z)-a-
phenylcinnamic acids.39 Consequently, the (E)-configura-
tion can be unambiguously assigned to all the cross-coupled
adducts, in which a marked anisotropic deshielding of the
olefinic H occurs owing to the adjacent nitro group, again,
analogous to that in (E)-a-phenyl-b-arylacrylic acids.38
Subsequent to the above stereochemical analysis, the configu-
ration of dienes 12p, 14a, and 14b was examined. Although
NOE experiment was not very informative in the case of 12p
(weak NOE between one of the terminal vinylic protons and
the aromatic protons) due to overlapping of the aromatic pro-
tons, cisoid structure was assigned for 12p based on the un-
ambiguous assignment of analogous systems, viz. 14a and
14b (Fig. 1). Thus, the presence of a medium NOE between
the aldehyde proton and the aromatic protons, and the ab-
sence of any NOE between the aldehyde protons and the ole-
finic methylene protons confirmed the cisoid structure 14a.
Similarly, the presence of weak NOE between the methyl
group and the aromatic protons, and the absence of any
NOE between the methyl group and the terminal olefinic
methylene protons unambiguously established the cisoid
structure for 14b.
2.1. Structure and stereochemistry
The geometry of the double bond in 12a was confirmed to be
(E) by comparison of its observed mp and 1H NMR data with
those in the literature (Fig. 1).35,36 Mp and 1H NMR data of
12b,35 12c,35 12e,37 and 12f37 were also consistent with the
literature data. The stereochemistry was further indepen-
1
dently confirmed by analysis of the H–1H NOESY spec-
trum of a representative coupled product. Thus, a weak to
medium NOE between the aryl protons and the protons of
The synthetic utility of the coupled products was demon-
strated by the following representative reactions using
Br
Br
R3N
R
O
R
NO2
N
O
PdLn(0)
1
NR3
17
Pd-LnBr
R1
Pd-LnBr
R3N
R
O
O
N
O
18
- PdLn(0)
N
O
R
R3N
R1
R
Pd
Ln
19
NO2
R
16
O
Cu
R1
N
O
20
NR3
21
CuX
NR3HX
R1
R3N +
15
Scheme 4.
δ 6.83
H
δ 8.21
H
NO2
NO2
CHO
CO2Et
NOE
Ph
Ph
NO2
Ph
Ph
NOE
Ph
Ph
(E)-12a
(Z)-12a
12p
14a
14b
mp 72-74 °C (lit mp 73-73.5 °C) lit mp 127-128 °C
Figure 1.

11978
M. Ganesh, I. N. N. Namboothiri / Tetrahedron 63 (2007) 11973–11983
Pd catalysts Pd(dba)2,43 PdCl2(PPh3)2,44 and Pd(dppe)Cl2
45
nitroalkene 12a. Thus, Michael addition of diethyl malonate
to 12a, mediated by LDA/BINOL, provided the adduct 22 in
90% yield and 5:3 dr (Scheme 5). However, better diastereo-
selectivity (3.2:1)40 was obtained when the addition was per-
formed under Lewis acid catalyzed (BOX, Mg(OTf)2)
conditions.41 Similarly, 1,3-dipolar cycloaddition of 12a
with benzonitrile oxide, generated in situ from benzaldox-
ime,42 furnished 3,4,5-triphenylisoxazole 23 in moderate
(30%) yield via intermediate cycloadduct, which presum-
ably underwent elimination of HNO2.
were freshly prepared following the literature methods.
Phenylboronic acid 11a, 4-ethylphenylboronic acid 11c, 4-
methoxyphenylboronic acid 11d, and 2-furylboronic acid
11f were prepared from the corresponding halides by halo-
gen–lithium exchange followed by treatment with tri-n-
methylborate or tri-n-butylborate and acidic hydrolysis.46
Other boronic acids were commercially available. Terminal
acetylenes 15a–f47 and bromonitroalkenes 1a–i30a were pre-
pared following the literature methods (see Supplementary
data for further details).
CO2Et
Ph
Ph
Ph
4.2. General procedure for Suzuki–Miyaura
cross-coupling of a-bromonitroalkenes 1,
bromoaldehyde 13a, and bromoester 13b
with boronic acids 11 (Tables 3 and 4 and Scheme 3)
NO2
Ph
EtO2C
NO2
CH2(CO2Et)2
PhCH=NOH
Method C
O
Method A or
Method B
Ph
Ph
Ph
N
23
22
12a
Method A: LDA, ( )-BINOL (20 mol %), THF, -78 °C, 4 h
-78 °C - rt, 8 h, 90% yield, dr 5:3
To a stirred suspension of boronic acid 11 (8 mmol,
1.5 equiv w.r.t. 1 or 13), sodium bicarbonate (3 equiv for 1
and 3 equiv KF for 13a and 13b), toluene (9 ml), ethanol
(0.5 ml), and water (0.5 ml) was added a-bromonitroalkene
1 or bromoaldehyde 13a or bromoester 13b (5.3 mmol), and
the resulting mixture was stirred under nitrogen for 15 min.
Then Pd(PPh3)4 (2.5 mol %) was added in one portion and
the reaction mixture was slowly heated to reflux under
a steady stream of nitrogen. After the completion of the re-
action (monitored by TLC, see also Tables 3 and 4 and
Scheme 3), the reaction mixture was cooled to ambient tem-
perature and diluted with ether (20 ml) and filtered. After
usual workup, the organic layer was concentrated in vacuo
and the crude product was purified by silica gel column chro-
matography (EtOAc–hexanes, gradient elution) to provide
pure coupled products 12 or 14. The products were further
purified by recrystallization from ethanol or ether–hexane
mixture. Experimental data for compounds 12a–f are consis-
tent with the literature (see Supplementary data).
Method B: ( )-BOX (10 mol %), Mg(OTf)2 (10 mol %), NMM (20 mol %)
CHCl3, 4Å MS, rt, 7 d, 85% yield, dr 3.2:1
Method C: 4% aq. NaOCl (excess), Et3N (5 equiv), CH2Cl2, 0 °C - rt, 24 h
30% yield
Scheme 5.
3. Conclusions
a-Bromonitroethylenes possessing aryl, heteroaryl, and al-
kyl groups at the b-position could be utilized to synthesize
a,b-disubstituted nitroethylenes in which the new a-substit-
uent could be aryl, heteroaryl, alkynyl, etc., via Pd-catalyzed
Suzuki and Sonogashira type coupling reactions. The reac-
tion proceeded well in the presence of Pd(PPh3)4 as the cat-
alyst and provided the coupled products in good to excellent
yields. Various boronic acids and terminal acetylenes were
used as coupling partners in these reactions. The remarkable
feature of these reactions is the stereospecific formation of
(E) isomers from (Z)-a-bromonitroethylenes.
4.2.1. 1-[(E)-1-Nitrooct-1-enyl)]benzene (12g). Light yel-
low liquid; yield 0.189 g (81%); IR (film, cmꢁ1) 3055 (m),
2930 (s), 2858 (m), 1652 (w), 1557 (m), 1524 (s), 1462
(m), 1334 (s), 1265 (s), 743 (vs), 704 (s); 1H NMR
(CDCl3) d 0.79 (t, J¼7.1 Hz, 3H), 1.11–1.26 (m, 6H), 1.41
(quintet, J¼7.7 Hz, 2H), 2.04 (q, J¼7.7 Hz, 2H), 7.18–
7.22 (m, 3H), 7.33 (t, J¼8.0 Hz, 1H), 7.36–7.39 (m, 2H);
13C NMR (CDCl3) d 13.9, 22.3, 28.3, 28.4, 28.7, 31.3,
128.4, 129.4, 129.6, 130.3, 138.7, 151.1; MS (TOF ESꢁ)
m/e (rel intensity) 232 ([MꢁH]+, 20); HRMS calcd for
C14H18NO2 ([MꢁH]+) 232.1338, found 232.1346.
4. Experimental
4.1. General
Unless otherwise noted all reagents were purchased from
commercial sources and used without further treatment.
THF was freshly distilled from sodium-benzophenone ketyl
under nitrogen atmosphere. Other solvents were dried by
standard methods. The reactions were conducted using
flame-dried flasks under steady stream of dry nitrogen. All
solvents were either sonicated or degassed under vacuum be-
fore use. Melting points were uncorrected. IR spectra (KBr/
film) were recorded on a NICOLET IR 200 or Perkin–Elmer
4.2.2. 1-[(E)-4-Methyl-1-nitropent-1-enyl)]benzene
(12h). Light yellow liquid; yield 0.160 g (76%); IR (film,
cmꢁ1) 3063 (w), 2958 (m), 2929 (m), 2858 (m), 1653 (m),
1525 (s), 1462 (w), 1334 (m), 1266 (w), 1244 (w), 1048
(w), 740 (s), 703 (m); 1H NMR (CDCl3) d 0.91 (d,
J¼6.6 Hz, 6H), 1.83 (m, 1H), 2.02 (dd, J¼8.0, 6.6 Hz,
2H), 7.24–7.27 (m, 2H), 7.40–7.47 (m, 3H), 7.42 (t,
J¼8.0 Hz, 1H); 13C NMR (CDCl3) d 22.4, 28.3, 37.3,
128.5, 129.5, 129.7, 130.4, 137.8, 151.7; MS (MALDI
TOF+) m/e (rel intensity) 206 (MH+, 23); HRMS calcd for
C12H16NO2 (MH+) 206.1181, found 206.1180.
Spectrum One FT-IR spectrometer. 1H NMR, 13C NMR, 19
F
NMR, 2D-HSQC, and 2D-NOESY were recorded on a Var-
ian Mercury Plus OXFORD AS 400 NMR spectrometer
(broad band and auto-switchable probes). The chemical
shifts (d) are reported in parts per million (ppm) downfield
relative to tetramethylsilane (TMS) for 1H and 13C and
CF2Cl2 for 19F. Mass spectrometric (MS) data were obtained
by electrospray ionization (ESI) on a Micromass Q-TOF
microÔ Mass Spectrometer.
4.2.3. 1-Methyl-4-[(E)-1-nitro-2-phenylvinyl)]benzene
(12i). Yellow solid; yield 0.217 g (91%); mp 65–66 ꢀC

M. Ganesh, I. N. N. Namboothiri / Tetrahedron 63 (2007) 11973–11983
11979
(n-hexane); IR (KBr, cmꢁ1) 3057 (w), 2919 (w), 1651 (s),
1515 (s), 1446 (m), 1321 (s), 1212 (w), 1119 (w), 971 (w),
764 (m), 689 (m); H NMR (CDCl3) d 2.43 (s, 3H), 7.13
(d, J¼7.6 Hz, 2H), 7.20–7.26 (m, 5H), 7.28 (d, J¼7.6 Hz,
2H), 8.2 (s, 1H); 13C NMR (CDCl3) d 21.5, 127.5, 128.6,
129.9, 130.3, 130.6, 131.1, 131.3, 134.5, 140.2, 149.7; MS
(TOF ES+) m/e (rel intensity) 262 (MNa+, 45), 193 (100);
HRMS calcd for C15H13NO2Na (MNa+) 262.0844, found
262.0856.
4.2.8. (E)-2-Nitro-1,3-diphenylbuta-1,3-diene (12p). Dark
yellow liquid; yield 0.213 g (85%); IR (film, cmꢁ1) 3055 (s),
2985 (w), 1651 (m), 1523 (s), 1447 (m), 1317 (s), 1265 (s),
1
1
1006 (m), 927 (m), 789 (s), 745 (vs), 704 (s); H NMR
(CDCl3) d 5.53 (unresolved, 1H), 6.10 (unresolved, 1H),
7.30–7.42 (m, 5H), 7.47–7.52 (m, 3H), 7.59–7.65 (m, 2H),
8.23 (s, 1H); 13C NMR (CDCl3) d 121.3, 125.5, 128.8,
128.9, 129.0, 130.9, 131.0, 131.1, 135.7, 136.4, 139.1,
149.2; MS (TOF ES+) m/e (rel intensity) 252 (MH+, 95),
224 (10), 205 (100), 174 (25); HRMS calcd for
C16H14NO2 (MH+) 252.1024, found 252.1025. No coupling
is observed between protons resonating at d 5.53 and 6.10.
However, gHSQC confirmed that both protons are attached
to the C at d 121.3.
4.2.4. 1-[(E)-2-(4-Ethylphenyl)-2-nitrovinyl)]benzene
(12j). Yellow solid; yield 0.227 g (90%); mp 88 ꢀC (n-hex-
ane); IR (KBr, cmꢁ1) 3028 (w), 3008 (w), 2978 (w), 2935
(w), 2835 (w), 1649 (m), 1605 (m), 1515 (s), 1453 (m),
1369 (m), 1321 (s), 1292 (m), 1246 (s), 1169 (m), 1027
(m), 770 (m), 690 (m); 1H NMR (CDCl3) d 1.21 (t,
J¼7.6 Hz, 3H), 2.65 (q, J¼7.6 Hz, 2H), 7.03 (d, J¼7.7 Hz,
2H), 7.11–7.18 (m, 5H), 7.22 (d, J¼7.7 Hz, 2H), 8.12 (s,
1H); 13C NMR (CDCl3) d 15.1, 28.7, 127.6, 128.6, 128.7,
130.4, 130.6, 131.0, 131.3, 134.5, 146.3, 149.8; MS (TOF
ES+) m/e (rel intensity) 276 (MNa+, 45), 207 (100); HRMS
calcd for C16H15NO2Na (MNa+) 276.1000, found 276.1001.
4.2.9. (E)-2-Benzylidene-3-phenylbut-3-enal (14a). Off-
white solid; yield 0.191 g (82%); mp 102–103 ꢀC (n-
hexane–EtOAc–ether 7:1:2); IR (film, cmꢁ1) 3082 (w),
3057 (w), 2924 (w), 2853 (w), 1671 (s), 1630 (m), 1596
(m), 1423 (m), 1148 (m), 791 (m), 713 (m), 685 (m);
1H NMR (CDCl3) d 5.15 (s, 1H), 5.88 (s, 1H), 7.15–7.25
(m, 6H), 7.34–7.38 (m, 2H), 7.36 (s, 1H), 7.53 (m, 2H),
9.62 (s, 1H); 13C NMR (CDCl3) d 116.7, 125.7, 128.2,
128.5, 128.6, 130.5, 130.8, 133.7, 137.3, 141.4,
141.7, 150.2, 193.9; MS (TOF ES+) m/e (rel intensity) 235
(MH+, 100); HRMS calcd for C17H15O 235.1123, found
235.1126.
4.2.5. 1-[(E)-2-(4-Methoxyphenyl)-2-nitrovinyl]benzene
(12k). Yellow solid; yield 0.242 g (95%); mp 95–96 ꢀC (n-
hexane–EtOAc 9.5:0.5); IR (KBr, cmꢁ1) 3008 (w), 2974
(w), 2934 (w), 2835 (w), 1650 (w), 1606 (m), 1515 (s),
1453 (m), 1369 (m), 1321 (s), 1246 (s), 1168 (m), 1028
1
(m), 770 (m), 690 (m); H NMR (CDCl3) d 3.79 (s, 3H),
4.2.10. (E)-Ethyl-2-benzylidene-3-phenylbut-3-enoate
(14b). Light yellow liquid; yield 0.245 g (88%); IR (film,
cmꢁ1) 3058 (w), 3027 (w), 2981 (w), 1711 (vs), 1624 (w),
1494 (w), 1446 (w), 1249 (vs), 1198 (s), 1053 (m), 783
6.90 (d, J¼8.3 Hz, 2H), 7.04 (d, J¼8.3 Hz, 2H), 7.13–7.27
(m, 5H), 8.1 (s, 1H); 13C NMR (CDCl3) d 55.3, 114.7,
122.5, 128.7, 130.6, 131.0, 131.5, 132.0, 134.3, 149.6,
160.8; MS (TOF ES+) m/e (rel intensity) 278 (MNa+, 3),
209 (100); HRMS calcd for C15H13NO3Na (MNa+)
278.0793, found 278.0796.
1
(m), 696 (m); H NMR (CDCl3) d 1.07 (t, J¼7.3 Hz, 3H),
4.08 (q, J¼7.3 Hz, 2H), 5.18 (d, J¼0.7 Hz, 1H), 5.73 (d,
J¼0.7 Hz, 1H), 7.15–7.28 (m, 6H), 7.43 (dt, J¼6.8,
2.0 Hz, 2H), 7.49–7.53 (m, 2H), 7.8 (s, 1H); 13C NMR
(CDCl3) d 13.9, 60.9, 116.4, 125.7, 127.8, 128.3, 128.5,
129.2, 130.2, 132.4, 134.4, 138.6, 140.8, 143.3, 167.4; MS
(TOF ES+) m/e (rel intensity) 279 (MH+, 35), 249 (100),
233 (38), 205 (2); HRMS calcd for C19H19O2 (MH+)
279.1385, found 279.1393.
4.2.6. 2-[(E)-1-Nitro-1-phenylvinyl]naphthalene (12l).
Yellow solid; yield 0.225 g (82%); mp 120 ꢀC (n-hexane–
ether 9:1); IR (KBr, cmꢁ1) 3062 (w), 2954 (w), 2924 (w),
1651 (m), 1515 (s), 1493 (m), 1320 (s), 1283 (m), 933
1
(m), 763 (m), 741 (m); H NMR (CDCl3) d 7.10–7.18 (m,
4H), 7.27 (t, J¼7.3 Hz, 1H), 7.39 (dd, J¼7.3, 0.9 Hz, 1H),
7.52 (t, J¼7.0 Hz, 1H), 7.57 (t, J¼7.0 Hz, 1H), 7.81 (d,
J¼7.9 Hz, 1H), 7.84 (unresolved m, 1H), 7.9 (d, J¼8.3 Hz,
1H), 7.95 (d, J¼8.3 Hz, 1H), 8.3 (s, 1H); 13C NMR
(CDCl3) d 126.7, 127.2, 127.4, 127.8, 127.9, 128.5, 128.8,
129.1, 130.6, 130.8, 131.2 (ꢂ2), 133.2, 133.7, 135.0,
149.6; MS (EI) m/e (rel intensity) 275 (M+, 12), 229 (100);
HRMS calcd for C18H13 ([MꢁNO2 ]+) 229.1017, found
229.1011.
4.3. General procedure for Sonogashira–Hagihara
cross-coupling of a-bromonitroalkenes 1 with terminal
acetylenes 15 (Table 6)
To a solution of alkyne 15 (0.3 mmol) in toluene (2 ml) was
added copper(I) iodide (2.5 mol %), and the reaction mixture
was stirred at ambient temperature for 15 min. Meanwhile,
a solution of a-bromonitroalkene 1 (0.2 mmol) in toluene
(2 ml) was added and the reaction mixture was stirred for
15 min. Now, Pd(PPh3)4 (24 mg, 2.5 mol %) was added in
one portion followed by N-methylmorpholine (0.7 ml,
20 equiv, excess) over 1 min. The reaction mixture was
slowly warmed to 50–60 ꢀC and the progress of the reaction
was monitored by TLC analysis. It was cooled to ambient
temperature and diluted with ether and filtered. The organic
layer was concentrated in vacuo and the crude product was
purified by silica gel column chromatography (EtOAc–hex-
anes, gradient elution) to provide pure nitroenynes 16. The
solid products of 16 were further purified by recrystallization
from ethanol or ether–hexane mixture and stored below
10 ꢀC under N2.
4.2.7. 3-[(E)-1-Nitro-2-phenylvinyl)]thiophene (12o).
Light yellow solid; yield 0.173 g (75%); mp 102 ꢀC (n-hex-
ane); IR (KBr, cmꢁ1) 3103 (w), 2924 (w), 1649 (m), 1511
(s), 1445 (w), 1314 (s), 1212 (m), 768 (m), 752 (m), 688
(s); 1H NMR (CDCl3) d 6.98 (dd, J¼4.9, 1.3 Hz, 1H),
7.06–7.08 (m, 2H), 7.19 (td, J¼5.1, 1.8 Hz, 2H), 7.26 (tt,
J¼7.7, 1.8 Hz, 1H), 7.33 (dd, J¼2.9, 1.3 Hz, 1H), 7.39
(dd, J¼4.9, 2.9 Hz, 1H), 8.13 (s, 1H); 13C NMR (CDCl3)
d 109.9, 126.8, 128.4, 128.7, 128.8, 129.8, 130.8, 130.9,
131.3, 135.4, 144.7; MS (TOF ES+) m/e (rel intensity) 254
(MNa+, 30), 185 (100); HRMS calcd for C12H9NO2SNa
(MNa+) 254.0252, found 254.0237.

11980
M. Ganesh, I. N. N. Namboothiri / Tetrahedron 63 (2007) 11973–11983
4.3.1. (E)-4-Nitro-5-phenylpent-4-en-2-ynyl benzoate
(16a). Light yellow liquid; yield 0.221 g (72%); IR (film,
cmꢁ1) 2962 (w), 2927 (w), 2375 (w), 1723 (s), 1528 (m),
1445 (w), 1324 (m), 1265 (s), 1096 (m), 1070 (w), 1026
18); HRMS (TOF ES+) calcd for C16H19NO2Na (M+Na)+
280.1313, found 280.1076.
4.3.6. (E)-5-(4-Methoxyphenyl)-4-nitropent-4-en-2-ynyl
benzoate (16g). Light yellow solid; yield 0.232 g (69%);
mp 141 ꢀC (n-hexane); IR (film, cmꢁ1) 3054 (w), 2966
(w), 2930 (w), 2344 (w), 1723 (s), 1653 (m), 1637 (m),
1593 (s), 1502 (m), 1427 (w), 1367 (w), 1308 (m), 1267
(s), 1175 (s), 1092 (w), 1067 (w), 1026 (w), 966 (w), 833
1
(w), 711 (m); H NMR (CDCl3) d 5.28 (s, 2H), 7.40–7.52
(m, 6H), 8.0 (d, J¼7.3 Hz, 2H), 8.14 (dd, J¼8.2, 1.2 Hz,
2H), 8.35 (s, 1H); 13C NMR (CDCl3) d 52.9, 76.2, 97.9,
128.4, 128.5, 129.0, 129.8, 130.1, 131.3, 132.7, 133.4,
133.6, 140.5, 165.6; MS (TOF ES+) m/e (rel intensity) 330
(MNa+, 18); HRMS (TOF ES+) calcd for C18H13NO4Na
(MNa+) 330.0742, found 330.0753.
1
(w), 714 (m); H NMR (CDCl3) d 3.84 (s, 3H), 5.30 (s,
2H), 6.91 (dt, J¼9.3, 2.5 Hz, 2H), 7.48 (td, J¼7.3, 1.3 Hz,
2H), 7.61 (tt, J¼7.3, 1.3 Hz, 1H), 8.01 (dt, J¼9.3, 2.5 Hz,
2H), 8.13 (m, 2H), 8.33 (s, 1H); 13C NMR (CDCl3)
d 53.0, 55.5, 76.7, 97.6, 114.6, 122.7, 128.5, 129.2, 129.7,
129.8, 133.5, 133.8, 140.6, 163.4, 165.8; MS (TOF ES+)
m/e (rel intensity) 360 (MNa+, 15), 159 (100); HRMS
(TOF ES+) calcd for C19H15NO5Na (MNa+) 360.0848,
found 360.0845.
4.3.2. (E)-2-Nitro-1,4-diphenylbut-1-en-3-yne (16b).
Light yellow liquid; yield 0.171 g (69%); IR (film, cmꢁ1
)
3054 (m), 2986 (w), 2274 (w), 1633 (w), 1531 (m), 1493
(w), 1422 (w), 1327 (m), 1265 (s), 895 (w), 741 (s), 706
1
(s); H NMR (CDCl3) d 7.38–7.58 (m, 6H), 7.60–7.64 (m,
2H), 8.04–8.10 (m, 2H), 8.3 (s, 1H); 13C NMR (CDCl3)
d 79.1, 103.2, 128.6, 129.0, 129.1, 129.3, 129.8, 130.6,
131.1, 131.7, 132.3, 138.3; MS (TOF ES+) m/e (rel intensity)
203 ([MꢁNO2]+, 3); HRMS (TOF ES+) calcd for C16H11
([MꢁNO2]+) 203.0861, found 203.0871.
4.3.7. (E)-5-(Furan-2-yl)-4-nitropent-4-en-2-ynyl benzo-
ate (16h). Light brown solid; yield 0.210 g (70%); mp
77 ꢀC (n-hexane–ether 9.5:0.5); IR (film, cmꢁ1) 3063 (w),
2929 (w), 2853 (w), 2343 (w), 1721 (s), 1612 (m), 1523
(m), 1462 (m), 1317 (s), 1265 (s), 1107 (m), 1095 (m),
4.3.3. 1-Fluoro-4-(E)-(3-nitro-4-phenylbut-3-en-1-ynyl)-
benzene (16c). Light yellow solid; yield 0.200 g (76%);
mp 64–65 ꢀC (n-hexane); IR (film, cmꢁ1) 3055 (m), 2986
(w), 2250 (w), 1633 (w), 1531 (m), 1492 (w), 1422 (w),
1
1070 (w), 769 (m), 709 (m); H NMR (CDCl3) d 5.30 (s,
2H), 6.62 (dd, J¼3.5, 1.4 Hz, 1H), 7.46–7.51 (m, 3H),
7.61 (tt, J¼7.5, 1.3 Hz, 1H), 7.67 (d, J¼1.4 Hz, 1H), 8.10–
8.11 (m, 2H), 8.24 (s, 1H); 13C NMR (CDCl3) d 52.9,
76.0, 98.8, 113.9, 120.3, 120.6, 127.8, 128.5, 129.1, 129.8,
133.6, 147.2, 148.0, 165.8; MS (TOF ES+) m/e (rel intensity)
320 (MNa+, 100), 99 (25); HRMS (TOF ES+) calcd for
C16H11NO5Na 320.0535, found 320.0528.
1
1327 (m), 1265 (s), 895 (w), 741 (s), 706 (s); H NMR
(CDCl3) d 7.13 (t, J¼8.5 Hz, 2H), 7.49–7.55 (m, 3H), 7.61
(dd, J¼8.2, 5.5 Hz, 2H), 8.03 (dd, J¼8.2, 1.8 Hz, 2H),
8.34 (s, 1H); 13C NMR (CDCl3) d 79.0, 103.4, 116.3,
116.5, 121.1, 127.0 (d, JC–F¼3.0 Hz), 128.7, 130.0, 131.8,
133.4 (d, JC–F¼8.0 Hz), 136.9, 164.8 (d, JC–F¼255.0 Hz);
19F NMR (CDCl3) d ꢁ106.0; MS (TOF ES+) m/e (rel inten-
sity) 221 ([MꢁNO2]+, 12); HRMS (TOF ES+) calcd for
C16H10F ([MꢁNO2 ]+) 221.0767, found 221.0773.
4.3.8. (E)-4-Nitro-5-(thiophen-2-yl)pent-4-en-2-ynyl ben-
zoate (16i). Light yellow solid; yield 0.250 g (80%); mp 96–
97 ꢀC (n-hexane–ether 9:1); IR (film, cmꢁ1) 3045 (w), 2942
(w), 1721 (s), 1603 (s), 1520 (s), 1497 (m), 1452 (w), 1425
(w), 1381 (m), 1331 (m), 1307 (s), 1264 (m), 1248 (m),
4.3.4. (E)-(5-Benzyloxy)-2-nitropent-1-en-3-ynyl)ben-
zene (16e). Light yellow liquid; yield 0.205 g (70%); IR
(film, cmꢁ1) 3061 (w), 3032 (w), 2851 (w), 2342 (w),
1626 (m), 1532 (s), 1496 (w), 1451 (m), 1379 (w), 1325
(s), 1266 (w), 1214 (m), 1186 (w), 1118 (m), 1074 (m),
1028 (w), 936 (w), 863 (w), 766 (m), 738 (s), 699 (m),
1
1224 (w), 1099 (m), 972 (m), 714 (s), 576 (m); H NMR
(CDCl3) d 5.36 (s, 2H), 7.19 (dd, J¼5.0, 3.7 Hz, 1H), 7.48
(t, J¼7.5 Hz, 2H), 7.61 (td, J¼7.5, 1.4 Hz, 1H), 7.65 (d,
J¼5.0 Hz, 1H), 7.71 (d, J¼3.7 Hz, 1H), 8.11 (dd, J¼7.5,
1.4 Hz, 2H), 8.6 (s, 1H); 13C NMR (CDCl3) d 52.9, 76.3,
100.8, 128.2, 128.5, 129.1, 129.2, 129.8, 133.5, 134.3,
134.6, 134.7, 137.8, 165.6; MS (TOF ES+) m/e (rel intensity)
336 (MNa+, 100), 279 (2), 192 (2), 134 (3), 108 (5); HRMS
(TOF ES+) calcd for C16H11NO4NaS 336.0306, found
336.0306.
1
687 (m); H NMR (CDCl3) d 4.54 (s, 2H), 4.72 (s, 2H),
7.32–7.41 (m, 5H), 7.43–7.54 (m, 3H), 7.90–8.10 (m,
2H), 8.33 (s, 1H); 13C NMR (CDCl3) d 57.6, 72.0, 76.3,
100.3, 128.1, 128.2, 128.5, 129.0, 130.3, 131.1, 132.3,
132.5, 136.9, 139.4; MS (TOF ES+) m/e (rel intensity)
316 (MNa+, 100), 230 (28), 229 (21); HRMS (TOF ES+)
calcd for C18H15NO3Na (MNa+) 316.0950, found
316.0806.
4.3.9. (E)-2-(2-Nitrodec-1-en-3-ynyl)thiophene (16j).
Dark yellow liquid (crystallizes below 16 ꢀC); yield
0.226 g (86%); IR (film, cmꢁ1) 3061 (w), 2930 (s), 2858
(m), 2217 (m), 1610 (m), 1531 (s), 1450 (m), 1380 (w),
1323 (s), 1213 (m), 957 (m), 860 (w), 764 (m), 688 (s);
1H NMR (CDCl3) d 0.9 (t, J¼7.0 Hz, 3H), 1.30–1.38 (m,
4H), 1.45–1.54 (m, 2H), 1.73 (quintet, J¼7.4 Hz, 2H),
2.65 (t, J¼7.4 Hz, 2H), 7.20 (dd, J¼5.1, 3.7 Hz, 1H),
7.62 (d, J¼3.7 Hz, 1H), 7.67 (d, J¼5.1 Hz, 1H), 8.47 (s,
1H); 13C NMR (CDCl3) d 14.0, 20.3, 22.5, 27.7, 28.6,
31.2, 71.1, 109.7, 127.9, 130.7, 131.7, 133.2, 135.1,
136.6; MS (MALDI TOF+) m/e (rel intensity) 264 (MH+,
24); HRMS calcd for C14H18NO2S 264.1058, found
264.1100.
4.3.5. (E)-(2-Nitrodec-1-en-3-ynyl)benzene (16f). Light
yellow liquid; yield 0.218 g (85%); IR (film, cmꢁ1) 3061
(w), 2930 (s), 2859 (m), 2217 (w), 1610 (w), 1532 (s),
1450 (m), 1380 (w), 1324 (s), 1213 (m), 958 (m), 860 (w),
1
764 (m), 688 (m); H NMR (CDCl3) d 0.8 (t, J¼6.6 Hz,
3H), 1.20–1.24 (m, 4H), 1.34–1.48 (m, 2H), 1.57 (quintet,
J¼7.5 Hz, 2H), 2.48 (t, J¼7.5 Hz, 2H), 7.31–7.43 (m, 3H),
7.84–7.89 (m, 2H), 8.10 (s, 1H); 13C NMR (CDCl3)
d 13.9, 19.9, 22.4, 27.8, 28.5, 31.3, 71.0, 106.2, 128.7,
129.2, 130.7, 131.8, 133.1, 137.0; MS (TOF ES+) m/e (rel in-
tensity) 280 (MNa+, 100), 258 (MH+, 22), 211 ([(MꢁNO2)+,

M. Ganesh, I. N. N. Namboothiri / Tetrahedron 63 (2007) 11973–11983
11981
4.3.10. (E)-5-(4-Chlorophenyl)-4-nitropent-4-en-2-ynyl
benzoate (16l). Light yellow solid; yield 0.260 g (76%);
mp 110–111 ꢀC (n-hexane); IR (film, cmꢁ1) 3067 (w),
3030 (w), 2925 (m), 2853 (w), 2366 (w), 1688 (s), 1635
(s), 1521 (s), 1453 (m), 1423 (m), 1343 (s), 1093 (m),
2H), 3.88 (q, J¼7.0 Hz, 2H), 4.54 (dd, J¼11.6, 5.9 Hz,
1H), 6.34 (d, J¼11.6 Hz, 1H), 7.27–7.34 (m, 4H), 7.41–
7.49 (m, 4H), 7.63–7.68 (m, 2H); 13C NMR (CDCl3)
d 13.66, 13.71, 48.2, 54.2, 61.56, 61.64, 93.4, 128.3,
128.6, 128.9, 129.99, 129.04, 130.4, 132.0, 135.8, 167.0,
167.3; MS (TOF ES+) m/e (rel intensity) 408 (MNa+, 100),
339 (10), 249 (10), 247 (25); HRMS calcd for C21H23NO6Na
(MNa+) 408.1423, found 408.1406.
1
1072 (m), 1026 (m), 967 (w), 708 (s); H NMR (CDCl3)
d 5.29 (s, 2H), 7.41 (d, J¼8.6 Hz, 2H), 7.52 (t, J¼7.5 Hz,
2H), 7.65 (t, J¼7.5 Hz, 1H), 7.96 (d, J¼8.6 Hz, 2H), 8.13
(d, J¼7.5 Hz, 2H), 8.32 (s, 1H); 13C NMR (CDCl3) d 52.7,
76.0, 98.6, 128.5, 128.6, 129.0, 129.5, 129.9, 132.4, 133.4,
133.7, 138.9, 139.1, 165.8; MS (TOF ES+) m/e (rel intensity)
364 (MNa+, 65), 158 (55); HRMS (TOF ES+) calcd for
C18H12NO4NaCl (MNa+) 364.0353, found 364.0358.
Minor diastereomer 22b (isolated from the mother liquor via
repeated removal of major isomer 22a by recrystallization
from ether–hexane 1:7): colorless viscous oil; yield 0.020 g
(15%); IR (film, cmꢁ1) 3056 (s), 2986 (m), 1734 (s), 1557
(s), 1424 (w), 1368 (w), 1265 (s), 1171 (w), 1096 (w), 1027
(w), 896 (m), 742 (s); 1H NMR (CDCl3) d 1.08 (t,
J¼7.2 Hz, 3H), 1.20 (t, J¼7.2 Hz, 3H), 3.90 (d, J¼7.0 Hz,
1H), 4.13 (q, J¼7.2 Hz, 2H), 4.20 (q, J¼7.2 Hz, 2H), 4.62
(dd, J¼10.5, 7.0 Hz, 1H), 6.19 (d, J¼10.5 Hz, 1H), 7.20–
7.40 (m, 10H); 13C NMR (CDCl3) d 13.7, 13.9, 48.1, 54.7,
61.7, 62.0, 92.3, 125.3, 127.8, 128.2, 128.5, 128.7, 129.0,
129.6, 129.8, 167.1, 167.5; MS (TOF ES+) m/e (rel intensity)
408 (MNa+, 45), 339 (100), 247 (33); HRMS calcd for
C21H23NO6Na (MNa+) 408.1423, found 408.1434.
4.3.11. Diethyl 2-(2-nitro-1,2-diphenylethyl)malonate
(22). Method A. To a solution of diisopropyl amine
(0.06 ml, 0.53 mmol) in THF (0.5 ml) cooled to 0 ꢀC was
added n-butyllithium (0.04 ml, 0.56 mmol, 1.5 M in hex-
anes) over 1 min and the reaction mixture was stirred at
0 ꢀC for 30 min. After cooling to ꢁ78 ꢀC, a solution of
(ꢃ)-BINOL (20 mg, 0.06 mmol) in THF (0.5 ml) was added
and the reaction mixture was stirred for 30 min. A solution of
diethyl malonate (0.106 g, 0.66 mmol) in THF (1 ml) was
added dropwise over 1 min. After stirring the reaction mix-
ture at ꢁ78 ꢀC for 1 h, a solution of a-phenylnitrostyrene
12a (0.075 g, 0.33 mmol) in THF (1 ml) was added drop-
wise over 5 min and stirring continued at ꢁ78 ꢀC for 4 h
and at ambient temperature for 8 h. The reaction mixture
was quenched with ice-cold aq NH4Cl (3 ml) and diluted
with ether (10 ml). The layers were separated and the aque-
ous layer was extracted with ether (2ꢂ5 ml). The combined
organic layers were washed successively with water (5 ml)
and brine (5 ml), dried (anhyd Na2SO4), and filtered. The or-
ganic layer was concentrated in vacuo and the crude residue
was purified by silica gel column chromatography using
ethyl acetate–hexane (1:10) as eluent to provide chemically
pure 22 as a mixture of diastereomers 22a and 22b in 5:3.
4.3.12. 3,4,5-Triphenylisoxazole 23.49 To a stirred solution
of a-phenylnitrostyrene 12a (0.038 g, 0.14 mmol), cooled to
0 ꢀC, were added benzaldoxime (0.051 g, 0.42 mmol) in
CH2Cl2 (5 ml), triethyl amine (0.1 ml, 0.70 mmol), and fi-
nally 4% aq NaOCl (5 ml, excess) dropwise over 15 min.
The reaction mixture was stirred at ambient temperature
for 24 h. The organic layer was separated and washed with
5% aq HCl (10 ml), water (5 ml), and brine (5 ml), dried (an-
hyd Na2SO4), and filtered. The filtrate was concentrated in
vacuo and the crude residue was purified by silica gel
column chromatography using ethyl acetate–hexane (1:5) as
eluent to provide pure 23. Colorless solid; yield 0.013 g
(30%); mp 214–215 ꢀC (lit.49 mp 215–215.5 ꢀC); IR (KBr,
cmꢁ1) 3070 (m), 2925 (w), 1687 (m), 1600 (m), 1450 (s),
1389 (s), 1314 (m), 1291 (m), 1207 (s), 1181 (w), 1026
Method B. A solution of Mg(OTf)2 (32 mg, 0.1 mmol), (ꢃ)-
BOX ligand48 (36 mg, 0.1 mmol), and CHCl3 (1 ml) was
stirred at rt for 1 h. Then, CHCl3 (3 ml) was introduced fol-
1
(m), 931 (m), 770 (s), 691 (s); H NMR (CDCl3) d 7.53–
7.70 (m, 9H), 8.49–8.51 (m, 3H), 8.68–8.70 (m, 3H); 13C
NMR (CDCl3) d 120.2, 121.1, 126.6, 127.4, 128.3 (ꢂ2),
128.6, 128.9, 129.2, 130.0, 132.7, 133.2, 133.7, 160.9,
170.2; MS (MALDI TOF+) m/e (rel intensity) 297 (98);
HRMS calcd for C21H15NO (M+) 297.1154, found
297.2100. Only mp is reported in the literature.49
˚
lowed by powdered molecular sieves (200 mg, 4 A) and the
reaction mixture was stirred for an additional 2 h. Then, a-
phenylnitrostyrene 12a (0.225 mg, 1 mmol), diethyl malo-
nate (1.5 ml, 10 mmol), and NMM (0.02 ml, 0.2 mmol)
were introduced in succession. The reaction mixture was
then stirred at ambient temperature for 7 days. The reaction
mixture was then quenched with saturated aq NH4Cl (2 ml),
diluted with ether (10 ml), and filtered. The organic layer
was washed with water (5 ml) and brine (5 ml), dried (anhyd
Na2SO4), and concentrated in vacuo. The crude residue was
purified by silica gel column chromatography using EtOAc–
n-hexane (1:10) as eluent to provide chemically pure 22 as
a mixture of diastereomers 22a and 22b in 3.2:1.
Acknowledgements
The authors thank DST, India, for financial assistance, SAIF,
IIT Bombay, for selected NMR data, Prof. D. Panda for
selected mass data, and Dr. P. J. Biju for his support.
M. G. thanks CSIR for a senior research fellowship.
Major diastereomer 22a (isolated in pure form by repeated
recrystallization of the mixture from ether–hexane 1:7): col-
orless solid; yield 0.095 g (75%); mp 131–132 ꢀC (ether–
hexane 1:7); IR (KBr, cmꢁ1) 3055 (m), 2986 (m), 2931
(w), 1730 (s), 1557 (s), 1497 (w), 1454 (w), 1422 (w),
1368 (m), 1265 (s), 1177 (m), 1031 (w), 737 (s), 703 (s);
1H NMR (CDCl3) d 1.01 (t, J¼7.0 Hz, 3H), 1.05 (t,
J¼7.0 Hz, 3H), 3.54 (d, J¼5.9 Hz, 1H), 3.86 (q, J¼7.0 Hz,
Supplementary data
It includes experimental procedures for the preparation of
terminal acetylenes 15 and bromoalkenes 1 as well as char-
acterization table/data for bromoalkenes 1. Complete char-
acterization data for the known coupled products 12a–f.
Copies of 1H and 13C NMR spectra for all the new

11982
M. Ganesh, I. N. N. Namboothiri / Tetrahedron 63 (2007) 11973–11983
S.; Sudoh, R. Synthesis 1982, 261; (c) Denmark, S. E.;
Marcin, L. R. J. Org. Chem. 1993, 58, 3850.
11. Franklin, A. S. Synlett 2000, 1154.
12. Amantini, D.; Fringuelli, F.; Piermatti, O.; Pizzo, F.; Vaccaro,
L. Green Chem. 2001, 3, 229.
13. (a) Deb, I.; Dadwal, M.; Mobin, S. M.; Namboothiri, I. N. N.
Org. Lett. 2006, 8, 1201; (b) Dadwal, M.; Mobin, S. M.;
Namboothiri, I. N. N. Org. Biomol. Chem. 2006, 4, 2525; (c)
Rastogi, N.; Namboothiri, I. N. N.; Cojocaru, M. Tetrahedron
Lett. 2004, 45, 4745; (d) See Refs. 2d–f.
compounds and some of the known compounds for which
experimental data are not available in the literature. Copies
of 19F, 1H–1H COSY, and NOESY NMR spectra for selected
compounds. Supplementary data associated with this article
can be found in the online version, at doi:10.1016/j.tet.
2007.09.012.
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Joint International Conference on Organic Chemistry and
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131–132 ꢀC) and the minor as a colorless viscous oil. The ste-
reochemistry of these isomers was assigned by analysis of their
NMR (1H and 2D-NOE) characteristics. For instance, in the 1H
NMR spectrum of the major isomer, the Ha (hydrogen a to NO2
group) appearing at d 6.34 has a strong coupling with Hb (d,
J¼11.6 Hz), while in the minor isomer, Ha appearing at
d 6.19 has smaller coupling with Hb (d, J¼10.5 Hz). This indi-
cated that Ha and Hb are anti to each other in the major isomer
and syn to each other in the minor isomer. The 2D-NOE ana-
lysis showed very similar NOE interactions for the major and
minor isomers of 22 such as medium NOE between Ha and
Hb, weak NOE between Hb and Hg, and no NOE between Ha
and Hg. However, the positive NOE interaction between Ha
and the Ar protons (presumably the b-Ar) in the major and
the absence of such interactions in the minor confirmed the
anti relationship between Ha and Hb in the major isomer.
41. For BOX mediated Michael addition of diethyl malonate to b-
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M. A.; King, S. A.; Morton, H. E.; Plagge, F. A.; Preskill,
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ꢀ
Iodo-trifluorobutenoate: Thibonnet, J.; Prie, G.; Abarbri, M.;
Duchene, A.; Parrain, J. L. Tetrahedron Lett. 1999, 40, 3151;
^
(c) 1,1-Dibromo-1-alkene: Uenishi, J.; Matsui, K.
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€
I. J. S.; Lee, A. F.; Faidjiba, E. M.; Loe, M. E. H.; Niemela,
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28. (a) Namboothiri, I. N. N.; Ganesh, M.; Mobin, S. M.; Cojocaru,
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€
29. (a) Seebach, D.; Schafer, H. Tetrahedron 1995, 51, 2305; (b)
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44. See Ref. 14a.
45. Lassahn, P.-G.; Janiak, C.; Oh, J.-S. Macromol. Rapid
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30. (a) Parham, W. E.; Bleasdale, J. L. J. Am. Chem. Soc. 1951, 73,
4664; For direct synthesis from aldehydes: (b) Shen, Y.; Yang,
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nitrostyrene: Dauzonne, D.; Royer, R. Synthesis 1987, 1020.
31. (a) Miller, D. B.; Flanagan, P. W.; Shechter, H. J. Org. Chem.
1976, 41, 2112; (b) See Refs. 30b,c.
46. (a) Brown, H. C.; Srebnik, M.; Cole, T. E. Organometallics
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Weinheim, 2005; For preparation of other boronic acids, see:
(c) Lloyd, D. G.; Hughes, R. B.; Zisterer, D. M.; Williams,
D. C.; Fattorusso, C.; Catalanotti, B.; Campiani, G.; Meegan,
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32. The expected side products such as biphenyl arising from self-
coupling of 11a and Michael type adduct of 1a with 11a were
not isolated. IR and 1H analysis of the crude reaction mixture
indicated the presence of vinylic proton b to the NO2 group.
33. (a) Southwick, P. L.; Anderson, J. E. J. Am. Chem. Soc. 1957,
79, 6222; For addition of chiral aminoalcohols to acyclic nitro-
alkenes: (b) Morris, M. L.; Sturgess, M. A. Tetrahedron Lett.
1993, 34, 43; (c) Brimble, M. A.; Johnston, A. D.
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48. (ꢃ)-BOX ligand was prepared from (ꢃ)-1-amino-2-indanol by
following the literature method described in Ref. 41.
49. Crombie, L.; Roughley, B. S. Tetrahedron 1986, 42, 3147.