Palladium-catalyzed synthesis of substituted nitroolefins

Article abstract of DOI:10.1016/j.tetlet.2013.04.038

A one-pot protocol toward several substituted nitroolefins 4 and 6 starting with substituted acetones 2 and 5 was described. A facile process was carried out for the triflation of substituted acetones 2 and 5 with triflic anhydride (Tf₂O) under the basic condition (Cs₂CO₃) and then palladium-catalyzed cross-coupling of enol triflates 3 with NaNO ₂ and BINAP in the presence of phase-transfer reagents (n-Bu ₄NBr) under the refluxing 1,2-dimethoxyethane (DME) in acceptable yields.

Full text of DOI:10.1016/j.tetlet.2013.04.038

Tetrahedron Letters 54 (2013) 3194–3198
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium-catalyzed synthesis of substituted nitroolefins
⇑
Meng-Yang Chang , Chung-Han Lin, Hang-Yi Tai
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
A one-pot protocol toward several substituted nitroolefins 4 and 6 starting with substituted acetones 2
and 5 was described. A facile process was carried out for the triflation of substituted acetones 2 and 5
with triflic anhydride (Tf2O) under the basic condition (Cs2CO3) and then palladium-catalyzed
cross-coupling of enol triflates 3 with NaNO2 and BINAP in the presence of phase-transfer reagents
(n-Bu4NBr) under the refluxing 1,2-dimethoxyethane (DME) in acceptable yields.
Received 4 January 2013
Revised 8 April 2013
Accepted 11 April 2013
Available online 17 April 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Amphetamine
Nitroolefins
Arylacetones
Cross-coupling
Triflation
Introduction
reaction conditions, we want to explore a one-pot palladium-
catalyzed methodology for preparing substituted nitroolefins using
Nitroolefins and related derivatives are very important precur-
sors of some functionalized amines due to their pharmacological
and biological activities.1 The versatility of these compounds in
organic synthesis is largely due to the properties of nitro groups.
Among the diversified nitroolefins, substituted 2-nitropropenes
(e.g., b-nitrostyrenes) are a subclass in regard to the applications
of amphetamine analog 1 and the related biological activities of
monoamine oxidase (MAO) inhibitors (Fig. 1).1c–h
Depending on reports in the literature, nitroolefins can be
directly obtained from their remote precursors, namely nitroalk-
anes and aldehydes. There are a number of processes available to
generate this skeleton of substituted nitroolefins, but generally, a
reagent-mediated one-pot nitroaldol/elimination process (Henry
reaction)2 under different conditions is described as the major
route,3,4 such as amine/ammonium-catalyzed condensation of
arylaldehydes with nitroalkanes under ultrasound-,3a,b,h micro-
wave-,3e,h or ionic liquid-accelerated conditions,3l and several
functionalized zeolites,4a silicas,4b,d silicas-aluminas,4c or meso-
structured polymer-mediated1b facile intermolecular heteroge-
neous condensation. While many substituted nitroolefins with
this specific substitution pattern have been developed, newly pre-
pared methodologies are needed.
the treatment of substituted acetones with triflic anhydride (Tf2O)
and Cs2CO3 via triflation, followed by an intermolecular cross-cou-
pling of corresponding (E)-enol triflates with NaNO2 and racemic
BINAP in the presence of phase-transfer reagents. There have been
few investigations for synthesizing the skeleton of nitroolefins
using a transition metal-mediated cross-coupling approach.5
The reaction route is shown in Scheme 1. Compound 2a was
chosen as the starting material and used with Tf2O for triflation
in 1,2-dimethoxyethane (DME) at rt for 5 h. Without further
purification, palladium-catalyzed cross-coupling of corresponding
(E)-enol triflates 3a with NaNO2 and racemic BINAP provided b-
nitrostyrenes 4a as the sole E-isomer with 70% in two-steps. The
DME solution of the reaction mixture is mainly an insoluble state.
By adding phase-transfer reagents, we found that better results
were clearly detected in DME solution. To prepare compound 4a,
experimental conditions are shown in Table 1.6
After screening four catalysts (Pd(OAc)2, PdCl(MeCN)2, PdCl2,
and Pd2(dba)3), three ligands (BINAP, Ph3P, and JohnPhos), and
two phase-transfer reagents (n-Bu4NBr, n-Bu4NF), we found that
entry
1 provided the optimized condition and better yield.
Therefore, this reaction must be controlled in the presence of tet-
ra-n-butylammonium bromide or fluoride (1.0 equiv); otherwise,
compound 2a was recovered (entry 4). When Pd(OAc)2 was chosen
as the catalyst and racemic BINAP was applied as the diphosphane
ligand, a better yield of compound 4a (70%) was isolated. Based on
the abovementioned phenomenon, 21 compounds 4b–4v were ob-
tained by the one-pot palladium-catalyzed methodology; they are
summarized in Table 2. Skeleton 4, with different aromatic or ali-
phatic groups, was also synthesized with 20–75% yields. Compared
with the isolated yields of products with different substituents, it
Results and discussion
Since the synthetic procedures of substituted nitroolefins are
almost all Henry nitroaldol-mediated condensation under different
⇑
Corresponding author. Tel.: +886 7 3121101x2220.
E-mail address: mychang@kmu.edu.tw (M.-Y. Chang).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.04.038

M.-Y. Chang et al. / Tetrahedron Letters 54 (2013) 3194–3198
3195
Me
NH
Me
reduction
FG =
functional group
NO
2
2
FG
amphetamine analogs 1
FG
nitrostyrenes
Figure 1. Route toward amphetamine analogs 1.
O
O
O
Me
Me
OTf
Cs CO , Tf O
2
3
2
O
O
DME
2a
3a
O
O
Pd(OAc) , BINAP, NaNO
Me
NO
2
2
DME, n-Bu NBr
4
2
4a (70%)
Scheme 1. Synthesis of compound 4a.
Table 1
Reaction conditionsa,b,c
O
O
Me
Me
1) Cs CO , Tf O, DME
2
3
2
E
O
O
O
NO
2) Pd(II), Ligand, NaNO , PTR
2
2
2a
(E)-4a
Entry
Catalyst (mmol %), ligand (mmol %), PTR (equiv)
Yield (%)
1
2
3
4
5
6
7
8
9
10
Pd(OAc)2 (15), BINAP (16), n-Bu4NBr (1.0)
Pd(OAc)2 (15), BINAP (5), n-Bu4NBr (1.0)
Pd(OAc)2 (15), BINAP (16), n-Bu4NBr (0.4)
Pd(OAc)2 (15), BINAP (16), n-Bu4NBr (0)
Pd(OAc)2 (15), BINAP (16), n-Bu4NF (1.0)
Pd(OAc)2 (15), Ph3P (16), n-Bu4NF (1.0)
Pd(OAc)2 (15), JohnPhos (16), n-Bu4NBr (1.0)
PdCl2(MeCN)2 (15), BINAP (16), n-Bu4NBr (1.0)
PdCl2 (15), BINAP (16), n-Bu4NBr (1.0)
Pd2(dba)3 (115), BINAP (16), n-Bu4NBr (1.0)
70
42
38
NRc
60
29
55
51
38
45
n
a
The reactions were run on
a 1.0 mmol scale with compound 2a, Cs2CO3
(2.0 equiv), Tf2O (1.03 equiv), NaNO2 (5.0 equiv), and DME (10 mL).
b
The product 4a was >95% pure as determined by NMR analysis.
The starting material 2a was recovered.
c
was found that skeleton 4, with a nitrogen atom (4m, indole; 4n,
pyrrole; 4i–4v, pyridine) was slightly poorer than the other ana-
logs. Attempts to increase the yield of a one-pot reaction to ali-
phatic group (4q) were unsuccessful.
A plausible mechanism is shown in Scheme 2. The initial event
may be considered as the generation of enolate (E)-A via deproto-
nation of compound 2a. Triflation of intermediate (E)-A affords
enol triflate 3a. Next, trans-complexation of intermediate 3a with
Pd(II) and racemic BINAP (L) yields intermediate (E)-B. Intermedi-
ate (E)-C should be afforded via the intermolecular cross-coupling
with n-Bu4NNO2 (in situ generated from the reaction between
NaNO2 and n-Bu4NBr). Followed by the reduction elimination,
product 4a is generated.
To further examine palladium-catalyzed cross-coupling reac-
tion, methyl group (skeleton 2) was changed to ethyl or aryl group
(skeleton 5). Compounds 6a–6i were isolated in 30–68% yields by
the above-mentioned conditions (see Table 3).7 Comparing the
shown yields in Tables 2 and 3, compounds 4i, 4m–4n, 4u–4v,
and 6c with nitrogen-containing heterocycles provided lower
yields (28–46%) along with a complex mixture and trace starting
materials. Therefore, we believed that the reason of poorer yields
should come from the competition of Tf2O (1.05 equiv) between

Table 2 (continued)
Entry
Reactants 2
Products 4/yield
Entry
11
Reactants 2
Products 4/yield
Entry
18
Reactants 2
Products 4/yield
Me
Me
F
F
MeO
MeO
Me
Me
NO
Me
Me
NO
MeO
MeO
MeO
O
O
2
2
Me
Me
Me
NO
4
2l
2s
4s/69%
4l/75%
O
MeO
2
2e
4e/60%
Ph
Ph
NC
NC
Me
Me
NO
Me
Me
NO
MeO
MeO
MeO
O
O
N
H
N
H
2
2
Me
NO
5
12
19
2t
4t/44%
O
MeO
2m
Me
4m/34%
2
2f
4f/55%
Me
Me
Me
Me
Me
Me
NO
OMe
OMe
MeO
MeO
O
NO
2
N
H
N
H
N
O
N
2
Me
NO
6
7
13
14
20
21
2u
2n
4u/32%
4n/28%
O
2
2g
4g/50%
Me
Me
O
O N
2
N
Me
N
Me
NO
Me
Me
NO
Me
Me
O
NO
2
O
O
O
2
O
2
2h
2v
4h/75%
4v/40%
2o
4o/62%
a
For the best one-pot reaction conditions: 2 (1.0 mmol), Cs2CO3 (2.0 mmol), Tf2O (1.03 mmol), DME (10 mL), rt, 5 h; then Pd(OAc)2 (15 mmol %), racemic BINAP (16 mmol %), NaNO2 (5.0 mmol), n-Bu4NBr (1.0 mmol), reflux, 5 h.
b
The isolated products were >95% pure as determined by 1H NMR analysis.

M.-Y. Chang et al. / Tetrahedron Letters 54 (2013) 3194–3198
3197
lone pair of nitrogen atom and enolate of intermediate (E)-A during
the triflation procedure. For synthesizing compounds 4q and 6e–6f
with aliphatic groups, different isomers with lower to trace yields
(4q, 20%; 6e, 15%; 6f, 10%) were observed and major starting mate-
rials 2q or 5e–5f were recovered. The results showed that the
intermediate (E)-A of compounds 2q or 5e–5f should not be easy
to generate under Cs2CO3-mediated triflation conditions.
O
O
Me
Cs CO
Tf O
2
2
3
3a
2a
deprotonation
triflation
O
(E
)-A
Pd (II)
BINAP (L)
complexation
O
Me
Pd
NO
O
cross-
coupling
O
O
Me
2
(E)-C
PdL
2
Conclusion
reductive
elimination
(
E
)-B
n
-Bu NNO + NaBr
4 2
A synthetic methodology for producing several substituted
nitroolefins 4 and 6 has been successfully presented using the
one-pot facile palladium-catalyzed cross-coupling of enol triflates
with NaNO2 and racemic BINAP in acceptable yields in the pres-
ence of a n-Bu4NBr condition. Further investigation is required
regarding the transition metal-catalyzed cross-coupling of enol tri-
flate with other heteroatoms.
NaNO2 + n-Bu NBr
4a
4
Scheme 2. The possible reaction mechanism of product 4a.
Table 3
Synthesis of substituted nitroolefins 6a
Acknowledgments
R
R
1
1
1) Cs2CO3, Tf2O, DME
R
R
NO
O
2
2) Pd(OAc)2, BINAP, NaNO2, n-Bu4NBr
(R, R1 = aromatic or aliphatic group)
The authors would like to thank the National Science Council of
the Republic of China for its financial support.
(E)-6
5
Entry
1
Reactants 5
Products 6/yield
Supplementary data
O
O
Supplementary data (experimental procedure and scanned pho-
tocopies of NMR (CDCl3) spectral data were supported) associated
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2013.04.038.
O
O
O
NO
2
5a
6a/65%
OMe
MeO
OMe
MeO
MeO
2
3
References and notes
O
MeO
NO
2
5b
6b/66%
1. (a) Karmarkar, S. N.; Kelkar, S. L.; Wadia, M. S. Synthesis 1985, 510; (b) Yan, S.;
Gao, Y.; Xing, R.; Shen, Y.; Liu, Y.; Wu, P.; Wu, H. Tetrahedron 2008, 64, 6294; (c)
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Rebolledo, F.; Gotor, V. Org. Biomol. Chem. 2011, 9, 2274; (f) Robaa, D.;
Enzensperger, C.; AbulAzm, S. E.; Hefnawy, M. M.; El-Subbagh, H. I.; Wani, T.
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W.; Marks, R. C.; Knapp, F. F.; Lee, J.; Liang, Y. J. Med. Chem. 1992, 35, 280; (h)
Vilches-Herrera, M.; Miranda-Sepulveda, J.; Rebolledo-Fuentes, M.; Fierro, A.;
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2009, 17, 2452; (i) Grant, T. G.; Sarshar, S. US 2008/0045588 A1.
2. For reviews on the Henry (nitroaldol) reaction, see: (a) Luzzio, F. A. Tetrahedron
2001, 57, 915; (b) Ballini, R.; Petrini, M.; Rosini, G. Molecules 2008, 13, 319; (c)
Alvarez-Casao, T.; Marques-Lopez, E.; Herrera, R. P. Symmetry 2011, 3, 220; (d)
Rosini, G. In Comprehensive Organic Synthesis; Trost, B. M., Ed.; ; Pergamon:
Oxford, 1991; Vol. 2, p 321; (e) Ono, N. In The Nitro Group in Organic Synthesis;
Wiley-VCH: New York, 2001; (f) Henry, L. Compt. Rend. Hebd. Seances Acad. Sci.
1895, 120, 1265.
3. (a) McMulty, J.; Steere, J. A.; Wolf, S. Tetrahedron Lett. 1998, 39, 8013; (b) Ayoubi,
S. A. E.; Boullet, F. T.; Hamelin, J. Synthesis 1994, 258; (c) Mathieu, J.; Weill-
Raynal, L. In Formation of C–C Bonds In ; George Thieme: Stuttgart, 1975; Vol. 2,
(d) Heinzelman, R. V. Org. Synth. 1963, 4, 573; (e) Valma, R. S.; Dahiya, R.; Kumar,
S. Tetrahedron Lett. 1997, 38, 5131; (f) Bandgar, B. P.; Zirange, M. B.;
Wadgaonkar, P. P. Synlett 1996, 149; (g) Ballini, R.; Petrini, M.; Rosini, G.;
Sorrenti, P. Synthesis 1985, 515; (h) Rodriguez, J. M.; Pujol, M. D. Tetrahedron Lett.
2011, 52, 2629; (i) Varma, R.; Dahiya, R.; Kumar, S. Tetrahedron Lett. 1997, 38,
5131; (j) Campos, P.; Garcia, B.; Rodriguez, M. Tetrahedron Lett. 2000, 41, 979; (j)
Varma, S.; Naicker, P.; Liesen, J. Tetrahedron Lett. 1998, 39, 3977; (k) Rao, M.; Rao,
S.; Srinivas, P.; Suresh, B. K. Tetrahedron Lett. 2005, 46, 8141; (l) Alizadeh, A.;
Khodaei, M. M.; Eshghi, A. J. Org. Chem. 2010, 75, 8295; (m) Mhamdi, L.; Bohli, H.;
Moussaoui, Y.; Salem, R. B. Int. J. Org. Chem. 2011, 1, 119.
4. (a) Ballini, R.; Bigi, F.; Gogni, E.; Maggi, R.; Sartori, G. J. Catal. 2000, 191, 348; (b)
Sartori, G.; Bigi, F.; Maggi, R.; Sartorio, R.; Macquarrie, D. J.; Lenarda, M.; Storaro,
L.; Coluccia, S.; Martra, G. J. Catal. 2004, 222, 410; (c) Motokura, K.; Tomita, M.;
Tada, M.; Iwasawa, Y. Chem. Eur. J. 2008, 14, 4017; (d) Sartori, G.; Bigi, F.;
Demicheli, G.; Maggi, R.; Mazzacani, A.; Righi, P. Tetrahedron Lett. 2001, 42, 2401.
5. (a) Fors, B. P.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 12898; (b) Saito, S.;
Koizumi, Y. Tetrahedron Lett. 2005, 46, 4715; (c) Al-Masum, M.; Saleh, N.; Islam,
T. Tetrahedron Lett. 2013, 54, 1141.
O
NO
N
H
N
H
2
5c
6c/35%
4
O
NO
2
5d
6d/68%
6e/15%
6f/10%
5
6
O
NO
2
5e
O
NO
2
5f
MeO
MeO
7
8
O
NO
2
5g
6g/60%
O
NO
2
5h
6h/66%
OMe
OMe
9
O
NO
2
5i
6. A representative synthetic procedure of skeleton 4 is as follows: Cs2CO3 (652 mg,
6i/60%
2.0 mmol) was added to
dimethoxyethane (DME, 10 mL) at rt. Then triflic anhydride (Tf2O, 290 mg,
a solution of skeleton 2 (1.0 mmol) in 1,2-
The isolated products 6a–6i were >95% pure as determined by 1H NMR analysis.
a

3198
M.-Y. Chang et al. / Tetrahedron Letters 54 (2013) 3194–3198
1.03 mmol) was slowly added to the reaction mixture. The reaction mixture was
CDCl3): d 163.17, 159.03, 148.32, 127.25, 120.49, 103.37, 90.48 (2Â), 55.65 (2Â),
55.44, 15.46. Single-crystal X-ray diagram: crystal of 4c was grown by slow
diffusion of EtOAc into a solution of 4c in CH2Cl2 to yield colorless prisms. The
compound crystallizes in the orthorhombic crystal system, space group Pca21,
a = 16.0963(9) Å, b = 4.0501(2) Å, c = 18.9224(10) Å, V = 1233.58(11) Å3, Z = 4, d
stirred at rt for 5 h. The reaction was traced by TLC until skeleton 2 was
consumed. Next, Pd(OAc)2 (34 mg, 0.15 mmol) and racemic BINAP (100 mg,
0.16 mmol) were added to the stirred solution at rt for 10 min. Then NaNO2
(280 mg, 5.0 mmol) and n-Bu4NBr (322 mg, 1.0 mmol) were added to the
reaction mixture. The reaction mixture was stirred at reflux for 5 h. The reaction
mixture was cooled to rt. NH4Cl (aq) (1 N, 5 mL) was added to the reaction
mixture and the solvent was concentrated. The residue was diluted with water
(10 mL) and the mixture was extracted with EtOAc (3 Â 20 mL). The combined
organic layers were washed with brine, dried, filtered, and evaporated to afford
crude product. Purification on silica gel (hexanes/EtOAc = 20/1–6/1) afforded
skeleton 4. For 4c, Yield = 58% (147 mg); Pale yellowish solid; mp = 146–148 °C
(recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C12H16NO5
254.1029, found 254.1030; 1H NMR (400 MHz, CDCl3): d 7.95 (d, J = 1.2 Hz, 1H),
6.15 (s, 2H), 3.85 (s, 3H), 3.82 (s, 6H), 2.10 (d, J = 1.2 Hz, 3H); 13C NMR (100 MHz,
calcd = 1.364 g/cm3, F(000) = 536, 2h range 2.53–26.5°,
R indices (all data)
R1 = 0.0430, wR2 = 0.0748. CCDC 916960 (4c) contains the supplementary
crystallographic data for this Letter. This data can be obtained free of charge
via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK; fax: +44-1223-336033; e-mail:
deposit@ccdc.cam.ac.uk).
7. (a) Ganesh, M.; Namboothiri, N. N. Tetrahedron 2007, 63, 11973; (b) Das, J. P.;
Sinha, P.; Roy, S. Org. Lett. 2002, 4, 3055; (c) Kanchala, P. K.; Reddy, Y. S.;
Dharuman, S.; Vankar, Y. D. J. Org. Chem. 2011, 76, 5832; (d) Campos, P. J.; Garcia,
B.; Rodriguez, M. A. Tetrahedron Lett. 2000, 41, 979.