Base-catalyzed efficient tandem [3 + 3] and [3 + 2 + 1] annulation-aerobic oxidative benzannulations

Article abstract of DOI:10.1021/ol302829f

An efficient synthesis of substituted benzenes via a base-catalyzed [3 + 3] aerobic oxidative aromatization of α,β-unsaturated carbonyl compounds with dimethyl glutaconate was reported. All the reactions were carried out under mild, metal-free conditions to afford the products in high to excellent yields with molecular oxygen as the sole oxidant and water as the sole byproduct. Furthermore, a more convenient tandem [3 + 2 + 1] aerobic oxidative aromatization reaction was developed through the in situ generation of the α,β-unsaturated carbonyl compounds from aldehydes and ketones.

Full text of DOI:10.1021/ol302829f

ORGANIC
LETTERS
2012
Vol. 14, No. 22
5776–5779
Base-Catalyzed Efficient Tandem [3 þ 3]
and [3 þ 2 þ 1] Annulation-Aerobic
Oxidative Benzannulations
Aboubacar Diallo, Yu-Long Zhao,* He Wang, Sha-Sha Li, Chuan-Qing Ren, and
Qun Liu*
Department of Chemistry, Northeast Normal University, Changchun, 130024, P. R.
China
zhaoyl351@nenu.edu.cn; liuqun@nenu.edu.cn
Received October 14, 2012
ABSTRACT
An efficient synthesis of substituted benzenes via a base-catalyzed [3 þ 3] aerobic oxidative aromatization of R,β-unsaturated carbonyl
compounds with dimethyl glutaconate was reported. All the reactions were carried out under mild, metal-free conditions to afford the products
in high to excellent yields with molecular oxygen as the sole oxidant and water as the sole byproduct. Furthermore, a more convenient tandem
[3 þ 2 þ 1] aerobic oxidative aromatization reaction was developed through the in situ generation of the R,β-unsaturated carbonyl compounds
from aldehydes and ketones.
Substituted arenes are important building blocks in
organic synthesis and key constituents of many pharma-
ceuticals and electronic materials.1 The utility of these
molecules directly reflects the identity and pattern of
substituents on the benzene ring,2 and the regiospecific
construction of polysubstituted benzene derivatives with
flexible substituent patterns are highly desirable.1ꢀ3 As an
efficient alternative to the routes established for the mod-
ification of given arenes relying on directed aromatic
functionalization (including electrophilic or nucleophilic
substitutions, catalyzed coupling, metalation functionali-
zation reactions, etc.),3 many methods have been devel-
oped to construct polysubstituted benzenes from acyclic
precursors.4ꢀ11 Although these approaches have each
contributed to the development of the synthetic pathway
for the synthesis of various substituted benzenes, to our
knowledge, there has been no report on the synthesis of
polysubstituted benzenes from commercially available
starting materials in a single step under mild conditions
with the advantage of environmentally benign, atom- and
(1) Modern Arene Chemistry; Astruc, D., Ed.; Wiley-VCH: Weinheim,
Germany, 2002.
(4) For recent reviews, see: (a) Serra, S.; Fuganti, C.; Brenna, E.
Chem.;Eur. J. 2007, 13, 6782 (benzannulation of substituted 3,5-
hexadienoic acids and 3-alkoxycarbonylhex-3-en-5-ynoic acids).
(2) (a) Izawa, Y.; Pun, D.; Stahl, S. S. Science 2011, 333, 209
(palladium-catalyzed aerobic dehydrogenation of substituted cyclohex-
anones to phenols). (b) Crone, B.; Kirsch, S. F.; Umland, K.-D. Angew.
Chem., Int. Ed. 2010, 49, 4661 (electrophilic cyclization of 1,5-enynes).
(c) Bull, J. A.; Hutchings, M. G.; Quayle, P. Angew. Chem., Int. Ed. 2007,
46, 1869 (atom-transfer radical cyclization and benzannulation se-
quences catalyzed by CuCl).
€
(b) Wessig, P.; Muller, G. Chem. Rev. 2008, 108, 2051 (the dehydro-
€
DielsꢀAlder reaction). (c) Dotz, K. H.; Stendel, J., Jr. Chem. Rev.
2009, 109, 3227 (based on Fischer carbene complexes).
(5) (a) Langer, P. Synlett 2009, 2205 (based on Mukaiyamaꢀ
DanishefskyꢀBrassard type reactions). (b) Katritzky, A. R.; Li, J.;
Xie, L. Tetrahedron 1999, 55, 8263 ([3 þ 3] benzannulations of benzenoid
and heteroaromatic ring systems).
(3) Snieckus, V. Beilstein J. Org. Chem. 2011, 7, 1215 and references
therein.
r
10.1021/ol302829f
Published on Web 11/05/2012
2012 American Chemical Society

energy-efficient processes that do not rely on toxic/pre-
cious metals.
required.6b In the present study, initially, the model reac-
tion of (E)-4-phenylbut-3-en-2-one 1a (1.0 mmol) with
dimethyl glutaconate 2 (1.2 mmol) was examined carefully
to optimize the reaction conditions (Table 1). Indeed, the
[3 þ 3] benzannulation reaction of 1a with 2 could easily
proceed to give the polysubstituted benzene 3ain93% yield
in the presence of NaOH (0.5 equiv) in CH3CN (5.0 mL)
within 15 min in open air (Table 1, entry 2). Interestingly,
either decreasing or increasing the amount of NaOH
led to lower yields of 3a (Table 1, entries 1 and 3). In
comparison, other bases such as DBU (1,8-diazabicyclo-
[5.4.0]undec-7-ene) and K2CO3 were less (Table 1, entry 4)
or not effective (Table 1, entry 5). Among the solvents
tested, acetonitrile seemed to be the best choice (Table 1,
entry 2). Other solvents, such as THF, DMF, DMSO, and
1,4-dioxane, gave lower product yields (Table 1, entries
6ꢀ9). In comparison, no desired product 3a could be
detected when the reaction was carried out in dichloro-
methane (DCE, Table 1, entry 10).
During the course of our research, we have investigated
the base-mediated [5 þ 1] benzannulation9a of alkenoyl
ketene dithioacetals or analogues with nitro alkanes9b or
aryl methyl ketones,9c [4 þ 2] benzannulation of cyclobu-
tenones and active methylene ketones,10 and [4 þ 1 þ 1]
oxidative benzannulation of acetyl ketene dithioacetals,
aromatic aldehydes, and aryl methyl ketones in aerobic
conditions.11 In a recent study, it was found that a series of
polysubstituted benzenes can be easily prepared through a
base-catalyzed [3 þ 3] aerobic oxidative benzannulation of
R,β-unsaturated carbonyl compounds with dimethyl glu-
taconate. The process proceeded under the catalysis of
sodium hydroxide at room temperature with the use of
aerial oxygen as the oxidant and afforded the products in
high to excellent yields. Furthermore, a more convenient
tandem [3 þ 2 þ 1] aerobic oxidative benzannulation
reaction was developed through the in situ generation of
the R,β-unsaturated carbonyl compounds from aldehydes
and ketones. We report here these new results, which allow
quick and atom-economical assembly of substituted ben-
zene derivatives from inexpensive and readily available
materials and tolerate a broad range of functional groups.
R,β-Unsaturated carbonyl compounds are readily avail-
able precursors. However, to the best of our knowledge,
the direct formation of multisubstituted benzenes via [3 þ
3] benzannulation with R,β-unsaturated carbonyl com-
pounds as 1,3-dielectrophiles has rarely been reported
and R,β-unsaturated aldehydes are less effective precur-
sors.5,6 In addition, an equivalent oxidant (for example
Cu(OAc)2) and harsh reaction conditions are generally
Table 1. Optimization of Reaction Conditions
base
time
yielda
(%)
entry
(equiv)
solvent
(min)
1
2
3
4
5
6
7
8
9
10
NaOH (0.4)
NaOH (0.5)
NaOH (0.6)
K2CO3 (0.5)
DBU (0.5)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
15
15
73
93
70
85
0
(6) For recent reports on [3 þ 3] benzannulations, see: (a) Ballini, R.;
Palmieri, A.; Barboni, L. Chem. Commun. 2008, 2975 (nitroalkanes as
precursors for the synthesis of benzene derivatives). (b) Li, L.; Zhao, M.-
N.; Ren, Z.-H.; Li, J.-L.; Guan, Z.-H. Org. Lett. 2012, 14, 3506 (between
enamines and enones). (c) Park, D. Y.; Lee, K. Y.; Kim, J. N. Tetra-
hedron Lett. 2007, 48, 1633 (between BaylisꢀHillman adducts and 1,
3-dinitroalkanes serving as 1,3-dinucleophiles). (d) Langer, P.; Bose, G.
Angew. Chem., Int. Ed. 2003, 42, 4033 (between 1,3-bis(silyl enol ether)s
and 1,1-diacetylcyclopropane). (e) Song, X.; Zhang, X.; Zhang, S.; Li,
H.; Wang, W. Chem.;Eur. J. 2012, 18, 9770 (synthesis of 3,4-disubstituted
benzaldehydes by dimerization of two enals).
(7) For recent reports on [3 þ 2 þ 1] benzannulations, see: (a) Zhao,
W.; Zhang, J. Org. Lett. 2011, 13, 688 (between diyne-enone and carbon
monoxide in the presence of rhodium catalyst). (b) Majumdar, N.;
Korthals, K. A.; Wulff, W. D. J. Am. Chem. Soc. 2012, 134, 1357
(between the R,β-unsaturated Fischer carbene complex of chromium
and propargyl ether and carbonoxide). (c) Offner, J. D.; Schnakenburg,
15
35
180
30
NaOH (0.5)
NaOH (0.5)
NaOH (0.5)
NaOH (0.5)
NaOH (0.5)
70
58
68
66
0
DMF
60
DMSO
1,4dioxane
DCE
60
60
180
a Isolated yields.
Next, under the optimal conditions (Table 1, entry 2),
the scope of the reaction was investigatedby the reaction of
dimethyl glutaconate 2 with selected R,β-unsaturated car-
bonyl compounds 1, and the results are summarized in
Table 2. It is obvious that the tandem reaction showed
broad tolerance for various R,β-unsaturated carbonyl
substrates 1. All of selected substrates 1aꢀk, bearing
phenyl (entry 1), electron-deficient (entries 2ꢀ5), elec-
tron-rich aryl (entries 6ꢀ8), heteroaryl (entry 9), phenylvi-
nyl (entry 10), and alkyl (entry 11) R groups at the β-
position of the enone moiety, reacted smoothly with
dimethyl glutaconate 2 to give the corresponding polysub-
stituted benzenes 3aꢀk in high to excellent yields under
very mild conditions within 10 to 90 min. Similarly, the
desired substituted benzenes 3l and 3m were prepared in
80% and 88% yields via the [3 þ 3] benzannulation of 1l
€
G.; Rose-Munch, F.; Rose, E.; Dotz, K. H. Inorg. Chem. 2011, 50, 8153.
(d) Li, C.; Zhang, H.; Feng, J.; Zhang, Y.; Wang, J. Org. Lett. 2010, 12,
3082 (between tethered ene- and yne-cyclopropenes and carbonoxide in
the presence of a rhodium catalyst).
(8) For reports on the multicomponent synthesis of polysubstituted
benzenes, see: (a) Xin, X.; Wang, Y.; Xu, W.; Lin, Y.; Duan, H.; Dong,
D. Green Chem. 2010, 12, 893 (between chalcones, malononitrile and/or
nitroethane in guanidinium ionic liquids). (b) Yan, C. G.; Song, X. K.;
Wang, Q. F.; Sun, J.; Siemeling, U.; Bruhn, C. Chem. Commun. 2008,
1440 (from ethyl R-bromoacetate, aromatic aldehydes, and malononi-
trile in the presence of pyridine (5 equiv) with 31ꢀ46% yields).
(9) For a recent review on [5 þ 1] annulation, see: (a) Pan, L.; Liu, Q.
Synlett 2011, 1073. (b) Bi, X.; Dong, D.; Liu, Q.; Pan, W.; Zhao, L.; Li,
B. J. Am. Chem. Soc. 2005, 127, 4578. (c) Fu, Z.; Wang, M.; Dong, Y.;
Liu, J.; Liu, Q. J. Org. Chem. 2009, 74, 6105.
(10) Han, X.-D.; Zhao, Y.-L.; Meng, J.; Ren, C.-Q.; Liu, Q. J. Org.
Chem. 2012, 77, 5173.
(11) Wang, M.; Fu, Z.; Feng, H.; Dong, Y.; Liu, J.; Liu, Q. Chem.
Commun. 2010, 46, 9061.
Org. Lett., Vol. 14, No. 22, 2012
5777

(R1 = Et, entry 12) and 1m (R1 = Ph, entry 13) with 2,
respectively. Moreover, the reaction of R,β-unsaturated
aldehyde 1n (R1 = H) could also give the desired product
3n in 70% yield in the presence of stoichiometric amounts
of NaOH at 50 °C in 120 min (entry 14). In addition, in the
cases of substrates 1o and 1p bearing an acetyl or ethox-
ycarbonyl group, the reaction could work well, yield-
ing the desired polysubstituted benzenes 3o and 3p in
70% and 92% yields, respectively (entries 15 and 16).
Clearly, the above-mentioned [3 þ 3] benzannula-
tion reaction provides a remarkably simple and effi-
cient access to polysubstituted benzenes, and all the
R,β-unsaturated carbonyl compounds 1 including
R,β-unsaturated aldehyde (entry 14), chalcones (entry 13),
and R,β-unsaturated ketones (entries 1ꢀ12, 15, and 16)
are effective precursors.
the based-catalyzed [3 þ 3] oxidative benzannulation
reaction between R,β-unsaturated carbonyl compounds 1
withdimethylglutaconate 2 isproposed inScheme 1. Inthe
presence of NaOH, the reaction starts from the intermo-
lecular Michael addition of 2 to 1 to give the intermediate
I.9 Subsequently, the intermediate II, generated via CdC
double bond isomerization of intermediate I under basic
conditions, undergoes an intramolecular aldol cyclization
to afford the six-membered alcohol intermediate III.12
Finally the benzannulation product 3 is formed via a
sequential dehydration (IIIfIV) and oxidative aromatiza-
tion with molecular oxygen (from air) process (IVf3,
Scheme 1).6e,11,13
Scheme 1. Proposed Mechanism for Formation of Benzenes 3
Table 2. NaOH-Catalyzed [3 þ 3] Benzannulation Reaction of
R,β-Unsaturated Carbonyl Compounds 1 with Dimethyl Glu-
taconate 2a
time
yieldb
(%)
entry
1
R
R1
Me
R2
(min) product
Multicomponent reactions (MCRs), the reactions in
which several components are combined in sequence,
and without isolation of intermediates, are greatly sought
because of the inherent molecular diversity, efficiency, and
atom economy.8,11,14,15 In contrast to the rapid develop-
ment of benzannulation reactions,1ꢀ13 only limited exam-
plesof [3 þ 2 þ 1] benzannulationhave been reported7 and,
to date, [3 þ 2 þ 1] benzannulations using three different
precursors have rarely been reported except for the case
limited to the combination of chalcone, malononitrile, and
nitroethane.8a Prompted by the success of the remarkably
simple and efficient [3 þ 3] benzannulation reaction
(Table 1 and Scheme 1) and combined with the considera-
tion of the significant advantages of multicomponent
reactions (MCRs),14 a three-component reaction ([3 þ 2
þ 1] benzannulation) combined with the in situ generation
of a Michael acceptor under basic conditions was exam-
ined. To our delight, after optimization of the reaction
conditions, it was found that the three-component reaction
of aldehydes 4, ketones 5, and dimethyl glutaconate 2 can
proceed smoothly in the presence of 1.5 equiv of NaOH in
CH3OH within 65ꢀ180 min to give the corresponding
polysubstituted benzenes 3b, 3m, and 3qꢀs in high to
excellent yields (Table 3, entries 1ꢀ5).
1
2
3
4
5
6
7
8
1a C6H5
H
H
H
H
H
H
H
H
15
30
10
45
15
30
60
60
3a
3b
3c
3d
3e
3f
93
93
94
93
88
90
90
94
1b 4-ClC6H4
1c 4-BrC6H4
1d 4-FC6H4
Me
Me
Me
1e 4-NO2C6H4 Me
1f 4-MeC6H4 Me
1g 4-MeOC6H4 Me
3g
3h
1h 3,4-
CH2O2C6H3
1i 2-furyl
Me
9
Me
H
H
H
H
H
H
60
30
3i
92
92
80
80
88
70
70
92
10
11c
12
1j PhCHdCH Me
3j
1k C6H11
1l C6H5
Me
Et
90
3k
3l
90
13d 1m C6H5
C6H5
H
60
3m
3n
3o
3p
14e
15f
16g
1n C6H5
1o C6H5
1p C6H5
120
Me
Me
COMe 120
CO2Et 150
a Reaction conditions: 1 (1.0 mmol), 2 (1.2 mmol), NaOH (0.5 mmol),
CH3CN (5.0 mL), room temperature. b Isolated yields. c The reaction
was performed at 50 °C. d The reaction was performed at 30 °C. e The
reaction was performed in the presence of NaOH (1.0 equiv) at 50 °C.
f The reaction was performed at 60 °C. g The reaction was performed at
70 °C.
On the basis of the above experimental results together
with the related reports,6b,9ꢀ13 a possible mechanism for
(14) For recent reviews, see: (a) Groenendaal, B.; Ruijter, E.; Orru,
R. V. A. Chem. Commun. 2008, 5474. (b) Tejedor, D.; Garcıa-Tellado, F.
Chem. Soc. Rev. 2007, 36, 484. (c) Toure, B. B.; Hall, D. G. Chem. Rev.
2009, 109, 4439. (d) Ganem, B. Acc. Chem. Res. 2009, 42, 463.
(15) Li, Y.; Xu, X.; Tan, J.; Xia, C.; Zhang, D.; Liu, Q. J. Am. Chem.
Soc. 2011, 133, 1775.
(12) Kiren, S.; Padwa, A. J. Org. Chem. 2009, 74, 7781.
(13) (a) Xie, P.; Huang, Y.; Chen, R. Chem.;Eur. J. 2012, 18, 7362.
(b) Nandaluru, P. R.; Bodwell, G. J. Org. Lett. 2012, 14, 310. (c) Gioia,
C.; Fini, F.; Mazzanti, A.; Bernardi, L.; Ricci, A. J. Am. Chem. Soc.
2009, 131, 9614.
ꢀ
5778
Org. Lett., Vol. 14, No. 22, 2012

carbonyl compounds with dimethyl glutaconate, which
provides a highly facile and efficient method for the rapid
construction of polysubstituted benzenes from easily avail-
ablestarting materials inhigh toexcellent yields under mild
and metal-free conditions. Most attractively, a more con-
venient tandem [3 þ 2 þ 1] aerobicoxidative aromatization
reaction was also carried out through the in situ generation
of the R,β-unsaturated carbonyl compounds from alde-
hydes and ketones, thereby greatly improving the reaction
efficiency. Further studies are in progress.
Table 3. Three-Component [3 þ 2 þ 1] Benzannulation Reac-
tion of Aldehydes 4, Ketones 5, and Dimethyl Glutaconate 2a
time
yieldb
(%)
entry
R
R1
(min)
product
1c
2
C6H5
C6H5
C6H5
C6H5
C6H5
CH3
65
3m
3q
3r
88
94
90
93
92
4-ClC6H4
4-MeC6H4
2-furyl
120
120
180
80
Acknowledgment. Financial support from the National
Natural Sciences Foundation of China (21172032 and
20972026) is gratefully acknowledged.
3
4
5d
3s
4-ClC6H4
3b
a Reaction conditions: 2 (1.2 mmol), 4 (1.0 mmol), 5 (1.0 mmol),
NaOH (1.5 mmol), CH3OH (5.0 mL), 65ꢀ180 min, room temperature.
b Isolated yields. c The reaction was performed at 30 °C. d The reaction
was performed at 50 °C.
Supporting Information Available. Experimental pro-
cedures, NMR spectra, and characterization data for new
compounds 3. This material is available free of charge via
the Internet at http://pubs.acs.org.
In summary, we have developed a novel base-catalyzed
[3 þ 3] aerobic oxidative aromatization of R,β-unsaturated
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 22, 2012
5779