Efficient method for the synthesis of polysubstituted benzenes by one-pot tandem reaction of vinyl malononitriles with nitroolefins

Article abstract of DOI:10.1021/jo070766i

(Chemical Equation Presented) The one-pot synthesis of polysubstituted benzene derivatives was achieved via vinylogous Michael addition of vinyl malononitriles and nitroolefins as the key step and a sequential tandem reaction. A series of complex aryl com

Full text of DOI:10.1021/jo070766i

approaches that construct the aromatic backbone from acyclic
precursors have received growing interest due to their short
synthetic steps and the avoidance of regioisomeric problems.7
These general features are common in the most useful benzan-
nulation reactions such as the [3 + 2 + 1] Dotz reaction of
Fisher carbene complexes,8 alkyne-cyclobutenone [4 + 2]
cyclization,9 [4 + 2] cycloaddition of metalacyclopentadienes
and alkynes,10 transition metal catalyzed [2 + 2 + 2] and [4 +
2] cycloadditions,11 [4 + 2] benzannulation of o-alkynyl
benzaldehyde and alkyne,12 [3 + 3] cyclocondensation between
bielectrophiles and binucleophiles,13 1,6-electrocyclization reac-
tion,14 [5 + 1] benzannulation strategy between alkenoyl ketene-
acetals and nitroalkane,15 synthesis of acetophenones and methyl
benzoates via the reaction of 1,3-dinitroalkanes with 2-ene-1,4-
dione or 2-ene-4-oxo ester derivatives,16 and [4 + 2] annulation
strategy from the Baylis-Hillman reaction.17 Recently, we
reported that the electron-deficient dicyanoalkenes could behave
as good hydride acceptors in conjugate reduction reactions18
and also act as versatile direct vinylogous donors in asymmetric
Michael addition reactions with excellent chemo- and stereo-
selectivity.19 The concept of γ-position activation according to
strong electron-withdrawing groups was expressed adequately.
Efficient Method for the Synthesis of
Polysubstituted Benzenes by One-Pot Tandem
Reaction of Vinyl Malononitriles with
Nitroolefins
Dong Xue,*,† Jie Li,† Zun-Ting Zhang,† and Jin-Gen Deng*,‡
Key Laboratory of Applied Surface and Colloid Chemistry,
Ministry of Education, School of Chemistry and Materials
Science, Shaanxi Normal UniVersity, Xi’an, 710062, People’s
Republic of China, and National Engineering Research Center
of Chiral Drugs and Key Laboratory of Asymmetric Synthesis
and Chirotechnology of Sichuan ProVince, Chengdu Institute of
Organic Chemistry, Chinese Academy of Sciences, Chengdu
610041, People’s Republic of China
xuedong_welcome@snnu.edu.cn; jgdeng@cioc.ac.cn
ReceiVed April 14, 2007
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H.-J. J. Am. Chem. Soc. 2002, 124, 6512-6513.
The one-pot synthesis of polysubstituted benzene derivatives
was achieved via vinylogous Michael addition of vinyl
malononitriles and nitroolefins as the key step and a
sequential tandem reaction. A series of complex aryl
compounds such as biphenyls and terphenyls can be obtained
with satisfactory yields.
(9) (a) Danheiser, R. L.; Brisbois, R. G.; Kowalczyk, J. J.; Miller, R. F.
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Polysubstituted benzenes are highly useful compounds in
organic chemistry, natural product chemistry, and materials
science. The regioselective preparation of polysubstituted
aromatic compounds is one of the challenging problems in
organic synthesis.1 Classical approaches are based on aromatic
substitution, which introduces a substituent to the given arene.
A variety of synthetic methodologies based on this route has
been developed including electrophilic2 or nucleophilic substitu-
tions,3 coupling reactions4 catalyzed by transition metals, and
metalation-functionalization reactions.5 However, these ap-
proaches have some drawbacks from the viewpoint of atom
economy6 or environmental concern. Conceptually different
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Chem. Soc. 2005, 127, 4578-4579. (b) Barun, O.; Nandi, S.; Panda, K.;
Ila, H.; Junjappa, H. J. Org. Chem. 2002, 67, 5398-5401.
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(18) (a) Chen, Y.-C.; Xue, D.; Deng, J.-G.; Cui, X.; Zhu, J.; Jiang, Y.-
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X.; Wang, Q.-W.; Zhu, J.; Deng, J.-G. J. Org. Chem. 2005, 70, 3584-
3591.
* Corresponding author. Tel.: 86-2985303940; fax: 86-2985307774.
† Shaanxi Normal University.
‡ Chinese Academy of Sciences.
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10.1021/jo070766i CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/13/2007
J. Org. Chem. 2007, 72, 5443-5445
5443

TABLE 2. Synthesis of Polysubstituted Benzenes via One-Pot
Tandem Reactiona
SCHEME 1. Strategy for Synthesis of Polyfunctionalized
Aromatic Compounds from Ketones
TABLE 1. Optimization of Reaction Conditions of Aromatization
Reactiona
entry
substrate
R3
product
T (h)b
yield (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
1a
1b
1c
1a
1a
1d
1e
1a
1f
Ph
Ph
Ph
4a
4b
4c
4d
4e
4f
4g
4h
4i22
4j
12
62
10
80
20
72
72
12
16
12
60
30
40
68
62
63
62
61
63
79
68
71
65
64
67
64
CH3CH2CH2
p-MeOC6H4
Ph
Ph
naphl
Ph
Ph
Ph
Ph
entry
base (mol %)
solvent
T (°C)
T (h)
yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
K2CO3 (50)
K2CO3 (100)
K2CO3 (50)
KOH (100)
NaH (100)
nitrobenzene
nitrobenzene
CH3CN
CH3CN
toluene
THF
CH2Cl2
CH2Cl2
MeOH
EtOH
THF
nitrobenzene
DMF
DMSO
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
120
120
reflux
reflux
100
60
30
rt
60
60
20
2
2
70
72
24
27
56
38
18
40
40
38
56
73
c
1g
1h
1i
4k
4l
4m
4
1j
Ph
10
30
32
18
13
28
60
2
20
20
2
4
2
a All reactions were performed under air; vinyl malononitriles 1 (0.1
mmol), nitroolefins 2 (0.1 mmol), and Et3N (0.01 mmol, 10%) were reacted
in 1 mL of CH2Cl2 and then CH3CN (5 mL) and EtONa (0.1 mmol) were
added. For the detailed procedure, see Supporting Information. b Total
reaction time for two steps. c Isolated yields.
NaH (100)
NaOMe (100)
NaOEt (100)
NaOEt (100)
NaOEt (100)
NaOEt (100)
NaOEt (100)
NaOEt (100)
NaOEt (100)
NaOEt (100)
NaOEt (50)
NaOEt (100)
NaOEt (100)
NaOEt (100)
60
120
120
120
60
obtained with 100 mol % NaOEt in refluxing CH3CN
(Table 1, entry17). Oxygen is important for the reaction. When
the reaction was run under air or oxygen, compound 4a was
obtained with 76 or 65% yield, respectively, (Table 1, entries
17 and 18). While the reaction was run under argon, a mixture
was obtained, and 4a was not observed (Table 1, entry 19).
c
70
65
76
65d
0e
60
reflux
reflux
reflux
2
2
a All reactions were performed at 0.1 mmol scales and operated under
air; for the detailed procedure, see Supporting Information. b Isolated yields.
c No reaction. d Reaction was performed under oxygen. e Reaction was
performed under argon.
From a synthetic point of view, one-pot procedures beginning
with simple, readily available substrates provide ideal strategies
for the regioselective formation of substituted benzene. We
found that the vinylogous Michael addition and aromatization
of addition products can be processed in one pot and that
polysubstituted benzenes can be obtained with satisfactory
yields. In our previous work,19a we found that tertiary amine
can catalyze the vinylogous Michael reaction between vinyl
malononitriles and nitroolefins, and thus, NEt3 was used as the
catalyst in the first step.20 The intermediate was not separated,
and the base NaOEt was added with optimized reaction
conditions as shown in Table 1. As is shown in Table 2, a wide
range of nitroolefins bearing aliphatic, aryl, and heteroaryl
groups is reacted with vinyl malononitriles 1a-j (for the
structure, see Figure 1) derived from corresponding ketones and
malononitrile, and a series of polysubstituted benzenes is
obtained in all the one-pot processes. Polysubstituted biphenyl
could be obtained when aliphatic vinyl malononitrile 1b reacts
with aryl nitroolefin (Table 2, entry 2) or when aryl vinyl
malononitrile 1a reacts with aliphatic nitroolefin (Table 2, entry
4). Polysubstituted terphenyl could be obtained when aryl vinyl
malononitrile 1a reacts with aryl nitroolefin (Table 2, entries
1, 5, and 8). Polycyclic compounds could be obtained when
cyclic vinyl malononitriles 1c, 1f, 1g, and 1h reacted with
nitroolefins, respectively (Table 2, entries 3 and 9-11). Reaction
of heteroarylvinyl malononitrile 1i or 1j with aryl nitroolefin
was found to produce the corresponding adducts 4 with
heteroaromatic substituents with good yields (Table 2, entries
In this paper, we found that vinyl malononitriles, obtained from
ketones via a Knoevenagel reaction, can react with nitroolefins
in the presence of a base and that polysubstituted benzenes are
obtained under air via a one-pot tandem addition process
(Scheme 1). This introduces a new strategy for the synthesis of
polyfunctionalized aromatic compounds using ketones as the
starting materials.
In our initial study, we found that the vinylogous Michael
addition product 319a could undergo an intermolecular nucleo-
philic addition and that polysubstituted benzene 4a was obtained
under air in the presence of a base. The primary inspiring results
draw our attention to a new construction method of polysub-
stituted benzenes. First, we investigated the condition of the
aromatization reaction. The aromatization of vinylogous Michael
addition product 3 was selected as a model reaction. All
reactions were performed under air. The results are shown in
Table 1. The base has an obvious effect on this reaction. Among
the selected bases, commercially available NaOEt was proven
to be the most promising one (Table 1, entries 12 and 15-17).
Several solvents have been investigated (Table 1, entries 8-15),
and CH3CN was selected as the best one (Table 1, entries 15-
17), although nitrobenzene also showed comparable results
(Table 1, entry 12). It is surprising that no reaction was found
when DMSO or DMF was used as a solvent (Table 1, entries
13 and 14). Temperature and base loading have an obvious
influence on reaction yield. The best result (76% yield) was
(20) When NaOEt was used as a base, a complex mixture was obtained.
5444 J. Org. Chem., Vol. 72, No. 14, 2007

easily can be prepared from the corresponding ketones via a
Knoevenagel reaction. According to this methodology, a series
of complex aryl compounds such as biphenyls and terphenyls
could be obtained with satisfactory yields. Current studies are
actively underway to extend this methodology to the synthesis
of complex aryl compounds and their function in materials
science.
Experimental Section
Procedure for Synthesis of Compound 3 ([2-(4-Nitro-1,3-
diphenylbutylidene)malononitrile]). A 25 mL round-bottomed
flask was charged with 2-(1-phenylethylidene)malononitrile25
(168.1 mg, 1 mmol), (E)-(2-nitrovinyl)benzene (149 mg, 1 mmol),
10 mL of CH2Cl2, and 14 µL of Et3N (0.01 mmol). The solution
was stirred at room temperature and monitored by TLC. After the
completion of the reaction, the solvent was removed under reduced
pressure. The raw product was purified by silica gel column
chromatography (EtOAc/hexanes, 1:10) to yield 307 mg of a white
FIGURE 1. Structure of vinyl malononitriles.
SCHEME 2. Postulated Reaction Course
1
solid; yield: 97%; mp: 88.0-89.1 °C; HNMR (300 Hz, CDCl3)
δ (ppm): 3.38-3.50 (m, 3H), 4.53-4.70 (m, 2H), 6.98 (s, 2H),
7.29-7.63 (m, 8H); 13C NMR (75 Hz, CDCl3) δ (ppm): 175.4,
133.4, 132.6, 129.4, 129.0, 127.6, 127.5, 112.3, 112.1, 79.2, 42.7,
40.1; IR (KBr): 3417, 2947, 2879, 2231, 1636, 1587, 1557, 1496,
1454, 1326, 1052, 767, 702 cm-1; HRMS (ESI) (M + Na)+:
C19H15N3O2 + Na, calcd: 340.1056, found: 340.1058.
Optimization of Reaction Conditions of Aromatization Reac-
tion. A 5 mL tube was charged with 2-(4-nitro-1,3-diphenylbutyl-
idene)malononitrile 3 (50 mg, 0.159 mmol), a base, and a solvent
(1.6 mL). The mixture was stirred with the time and temperature
shown in Table 1. After the completion of the reaction, the solvent
was removed under reduced pressure. The raw product was purified
by silica gel column chromatography (EtOAc/hexanes, 1:8) to give
a light yellow solid with the yield shown in Table 1.
Typical One-Pot Procedure for the Synthesis of 4a. The
following typical procedure has been adopted for the synthesis of
all the products. A 5 mL tube was charged with vinyl malononitrile25
1a (0.1 mmol), nitroolefins25 (0.1 mmol), 1 mL of CH2Cl2, and
1.4 µL of Et3N (0.01 mmol). The solution was stirred at room
temperature and monitored by TLC. After the reaction was
completed (10 h), CH2Cl2 was removed under reduced pressure,
and 5 mL of CH3CN and 6.8 mg of EtONa (0.1 mmol) were added.
The mixture was refluxed and monitored by TLC. After the reaction
was completed (2 h), the solvent was removed under reduced
pressure. The product was purified by silica gel column chroma-
tography (EtOAc/hexanes, 1:8) to yield the polysubstituted benzene
4a as a yellow solid with 76% yield. mp: 204.2-205.8 °C; 1HNMR
(300 Hz, CDCl3) δ (ppm) 5.81 (s, 2H), 6.74 (s, 1H), 7.18-7.51
(m, 10H); 13CNMR (75 Hz, CDCl3) δ (ppm) 149.5, 144.8, 142.9,
137.3, 137.0, 129.8, 128.9, 128.5, 127.2, 121.2, 115.8, 97.8; IR
(KBr): 3469, 3363, 2923, 2214, 1619, 1559, 1497, 1445, 1328,
1277, 1076, 865, 821, 770, 698, 636 cm-1; HRMS (ESI) (M +
Na)+: C19H13N3O2+Na, calcd: 338.0900, found: 338.0898.
12 and 13). The possibility of one-pot introduction of aromatic
and heteroaromatic substituents avoids the need for the cross-
coupling reactions that are usually employed in the preparation
of biphenyl systems.21,22
To explain the mechanism of the tadem reaction, a postulated
reaction course is illustrated in Scheme 2. In the first step, adduct
3 was obtained according to the vinylogous Michael addition
of 1a to nitrolefin under the catalysis of a base.19a In the second
step, the proton adjacent to the NO2 group of compound 3 was
deprived by NaOEt to produce a carbon nucleophilic center.
Then, the carbon anion in 5 attacked the carbon center of the
triplet bond in CN by an intermolecular nucleophilic addition
to produce imine 6,23 and then isomeration of 6 gave diene 7.24
After one molecule of hydrogen was released via an oxidation
process, aromatized compound 4a was obtained. For the
elimination of hydrogen in the process, we supposed that oxygen
in air played a key role (Table 1, entries 17-19).
In summary, we have developed a new and efficient method
to obtain polysubstituted benzenes via a one-pot tandem process
with vinylogous Michael addition of vinyl malononitriles and
nitroolefins as the key step. This provides a new strategy for
the synthesis of polyfunctionalized aromatic compounds using
ketones as the starting materials because vinyl malononitriles
(21) (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508-524.
(b) Suzuki, A. J. Organomet. Chem. 1999, 576, 147-168. (c) Bellina, F.;
Carpita, A.; Rossi, R. Synthesis 2004, 2419-2440.
Acknowledgment. We are grateful for financial support from
the National Science Foundation (20602024). The authors are
grateful for fruitful discussions with Dr. Ying-Chun Chen of
Sichuan University.
(22) For the synthesis of compound 4i in reported papers, see: El-Taweel,
F. M. A.; Sofan, M. A.; Abu El-Maati, T. M.; Elagamey, A. A. Boll. Chim.
Farm. 2001, 140, 306-310; earlier examples of the synthesis of o-
nitroaniline derivatives via condensation of alkylidene malononitriles with
nitroolefins (found from SciFinder) see: (a) Elagamey, A. A.; El-Taweel,
F. M. A.; Khodeir, M. N. M. Pharmazie 1992, 47, 418-420. (b) Schaefer,
H.; Gewald, K. J. Fue. Prak. Chem. 1985, 327, 328-323. (c) Bogdanowicz-
Szwed, K.; Lipowska, M. Pol. Chem. Scr. 1988, 28, 319-322.
(23) For the self-dimerization of vinyl malononitriles, see: Weir, M. R.
S.; Hyne, J. B. Can. J. Chem. 1964, 42, 1440-1445 and references therein.
(24) For similar synthesis of chiral diene, see ref 19e.
Note Added after ASAP Publication. References 2 and 21
were corrected in the version published ASAP June 13, 2007.
Supporting Information Available: Experimental procedures
1
for the synthesis of 4a-4m and copies of H and 13C NMR and
HRMS spectra of new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
(25) For the synthesis of vinyl malononitriles 1a-j and nitroolefins in
detail, see refs 18b and 19a.
JO070766I
J. Org. Chem, Vol. 72, No. 14, 2007 5445