DMAP-catalyzed benzannulation of ethyl propiolate with β-dicarbonyl moieties

Article abstract of DOI:10.1055/s-2007-984904

4-Dimethylaminopyridine (DMAP)-catalyzed benzannulation reaction of ethyl propiolate with β-dicarbonyl compounds at room temperature providing highly substituted benzenes is described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-984904

LETTER
2073
DMAP-Catalyzed Benzannulation of Ethyl Propiolate with b-Dicarbonyl
Moieties
DMAP-Catalyzed
i
Benza
n
n
nulation of
E
thyl Propiol
-
ate
w
ith
F
b
-Dicarbonyl
aMoieties Zhou, Fei Yang, Qing-Xiang Guo, Song Xue*
Department of Chemistry, University of Science and Technology of China, Hefei 230026, P. R. of China
Fax +86(551)3606689; E-mail: xuesong@ustc.edu.cn
Received 18 May 2007
54% yield. This compound was satisfactorily character-
ized by NMR and MS spectroscopic analyses. This metal-
free organocatalyzed process created a 1,2,3,5-tetrasub-
stituted benzene with three electron-withdrawing groups,
which was difficult to construct by other conventional
methods. This finding prompted us to explore the feasibil-
ity of the construction of polysubstituted benzenes based
on utilization of readily available acetylenic esters and
1,3-dicarbonyl moieties.
Abstract: 4-Dimethylaminopyridine (DMAP)-catalyzed benzan-
nulation reaction of ethyl propiolate with b-dicarbonyl compounds
at room temperature providing highly substituted benzenes is
described.
Key words: ethyl propiolate, DMAP, benzannulation, b-dicarbon-
yl compounds
The regioselective generation of highly substituted ben-
zenes represents a great challenge in synthetic chemistry.1
Classical approaches use aromatic substitution, which in-
troduces a substituent to a pre-existing arene.2 However,
these synthetic routes suffer from a long multi-step reac-
tion sequence, low product yield, and poor regioselective
control. Many modern methods for the synthesis of highly
substituted aromatic compounds have been developed.
These include transition-metal-catalyzed cycloaddition,3,4
Dötz reaction,5 carbonyl condensation reaction,6 and elec-
trocyclic reaction.7 Nevertheless, the problems of regio-
selectivity and the need to prepare the starting materials
always limit the general application of these methods to
the synthesis of highly substituted benzenes.
We first chose ethyl propiolate and 2,4-pentanedione as
the substrates to search for a potential catalyst and opti-
mized reaction conditions (Table 1). It was observed that
moderate yield was obtained when the reaction was stirred
at room temperature for three days. Prolonging the reac-
tion time resulted in no obvious effect on the reaction
yield. However, the choice of solvent had some effects on
the reaction. With THF, Et2O, DMF, and DMSO as the
solvent, the corresponding product 3a was generated in a
relatively lower yield. When toluene was used as the sol-
vent, only a trace amount of 3a was formed. Dichlo-
romethane was found to be the best solvent for this
reaction. In addition, the nature of amines played an im-
portant role in this reaction. The reaction of ethyl propi-
olate and 2,4-pentanedione catalyzed by Et3N (20 mol%)
could afford the desired product 3a in 29% yield. Pyridine
as a catalyst gave a complex mixture of unidentified prod-
ucts. When 1,4-diazabicyclo[2,2,2]octane (DABCO) was
used in this reaction, a Michael adduct 4 between 2,4-pen-
tanedione and ethyl propiolate was formed in 57% yield
(Scheme 1). However, when the reaction was carried out
using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as a
catalyst, no reaction was observed. Therefore, it seemed
that the best reaction conditions were to carry out this
reaction in dichloromethane with DMAP as a catalyst.
1,3-Dicarbonyl compounds constitute an important class
of synthetic intermediates, used as nucleophilic or electro-
philic species in a variety of synthetic transformations.8,9
Recently, we reported a Ph3P-catalyzed a-C-addition of
1,3-dicarbonyl compounds to acetylenic ketones.9b How-
ever, no reaction occurred when ethyl propiolate (2) was
used as the alkyne partner under similar conditions. When
DMAP was tested as a catalyst in the reaction of 1,3-di-
carbonyl compounds with ethyl propiolate, a new benzan-
nulation reaction happened.10,11 Treatment of 2,4-
pentanedione with ethyl propiolate (2) in the presence of
DMAP (20 mol%) gave the benzannulation product 3a in
O
O
O
EtO
OEt
O
O
O
O
DABCO
DMAP
+
OEt
OEt
O
1a
2
O
3a
4
Scheme 1
SYNLETT 2007, No. 13, pp 2073–2076
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3
.0
8
.2
0
0
7
Advanced online publication: 17.07.2007
DOI: 10.1055/s-2007-984904; Art ID: W09807ST
© Georg Thieme Verlag Stuttgart · New York

2074
Q.-F. Zhou et al.
LETTER
Table 1 Reaction of 2,4-Pentanedione (0.3 mmol) with Ethyl Pro-
piolate (0.66 mmol) Catalyzed by Nitrogen Lewis Bases
Table 2 Reaction of b-Dicarbonyl Moieties with Ethyl Propiolate
Catalyzed by DMAP
Entry Lewis base
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
THF
Time (d) Yield (%)a
Entry R1
R2
Product
3a
3b
3c
Yield (%)a
1
2
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
Et3N
1
3
5
3
3
3
3
3
3
1
3
24
54
58
36
24
22
21
trace
29
57b
0
1
2
Me
Me
54
65
59
69
79
68
22b
Ph
Me
3
3
4-FC6H4
4-ClC6H4
4-BrC6H4
4-CNC6H4
4-MeC6H4
4-MeOC6H4
2-MeOC6H4
3-BrC6H4
3-NO2C6H4
2-Naphthyl
Ph
Me
4
4
Me
3d
3e
5
Et2O
5
Me
6
DMF
6
Me
3f
7
DMSO
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
7
Me
3g
–
b
8
8
Me
–
62b
51
73
43
28
62
60
45
51b
63
62
64
54
9
9
Me
3h
3i
10
11
DABCO
DBU
10
11
12
13
Me
Me
3j
a Isolated yield.
Me
3k
3l
b Yield of compound 4.
Pr
A variety of 1,3-dicarbonyl compounds were found to be 14
applicable to this reaction to give product 3 in moderate to
Ph
Ph
3m
3n
3o
3p
3q
3r
15
4-ClC6H4
Ph
4-ClC6H4
OEt
OEt
OEt
OEt
OEt
OEt
good yields under the optimized reaction conditions
(Table 2 and Scheme 2).12 Aromatic 1,3-diketones pro-
16
vided the corresponding products in good isolated yields.
For example, exposure of 1-phenylbutane-1,3-dione (0.3
17
4-MeC6H4
4-FC6H4
4-BrC6H4
4-CNC6H4
2-Naphthyl
mmol) to ethyl propiolate (0.66 mmol) and DMAP (20
mol%) gave the desired product 3b in 65% yield (Table 1,
entry 2). Its regioisomer 5 could not be detected from the
reaction mixture. The structure of compound 3b was eas-
ily assigned on the basis of 13C NMR spectral data as the
13C carbon signal of the methyl group (R2) was at d = 30.4.
If the methyl group (R2) was directly attached to the ben-
zene ring, its carbon signal would have been positioned at
about d = 18.2. The nature of the R1 substituent on the
benzene ring also had a remarkable effect on the reaction.
As can be seen from Table 2, substrates bearing an elec-
tron-withdrawing group on the aromatic ring reacted
smoothly and gave the desired product in good yield. On
the other hand, substrates containing an electron-donating
group reacted poorly. For example, when a methyl group
was attached to the aromatic ring, the desired product 3g
was obtained in only 22% yield along with a small amount
of the corresponding regioisomer 5 (<5%), whereas
18
19
20
21
3s
3t
a Isolated yield.
b Reaction for five days.
having a methoxy group at the para position completely
retarded the reaction (Table 2, entry 8). Highly hindered
1,3-diketones were also identified as reluctant coupling
partners in this reaction. When R1 was phenyl, and R2 was
changed from a methyl to a propyl group, the yield of the
corresponding product 3j decreased to 28%, and a small
amount of its isomer 5 was formed as well. When R2 was
the very bulky tert-butyl group, no reaction occurred
under the same conditions.
O
O
O
O
O
EtO
OEt
EtO
OEt
O
O
+
DMAP (20 mol%)
CH2Cl2, r.t., 3 d
+
R1
R2
OEt
R1
R2
1
2
R1
O
R2
O
3
5
Scheme 2
Synlett 2007, No. 13, 2073–2076 © Thieme Stuttgart · New York

LETTER
DMAP-Catalyzed Benzannulation of Ethyl Propiolate with b-Dicarbonyl Moieties
2075
O
O
O
O
O
O
DMAP (20 mol%)
CH2Cl2, r.t., 4–5 d
O
EtO
OEt
EtO
OEt
OEt
+
+
OEt
O
x
CO2Et
O
OEt
2
6a: X = H
6b: X = Br
6c: X = OMe
X
X
7a: 45%
7b: 34%
7c: 36%
8a: 16%
8b: 7%
8c: <2%
Scheme 3
Benzannulation of b-ketoesters with ethyl propiolate also tion. The substrate with a bromo or methoxyl group at the
proceeded smoothly to generate the corresponding prod- para position gave similar results (Scheme 3). On the
ucts (Table 2, entries 16–21). Similar to 1,3-diketones, basis of these findings, a new procedure for the synthesis
aromatic b-ketoesters with an electron-withdrawing of 1,2,3,5-tetrasubstituted benzenes has been developed.
group on the benzene ring gave the desired products in Since the starting materials are readily available, and the
good yields. When ethyl acetoacetate was subjected to the reaction conditions are mild, this methodology represents
same conditions, no reaction was observed even after a powerful diversity route for the convergent construction
prolonged reaction time (6 d). It was notable that a new of highly substituted benzenes. To the best of our knowl-
compound 7a was obtained as a major product along with edge, there is no report of organocatalyzed benzannula-
a minor benzannulation product 8a when b-ketoester 6a tion of acetylenic esters with 1,3-dicarbonyl compounds.
derived from trans-cinnamaldehyde was used in this reac-
O
O
EtO
OEt
O
O
S
O
C
DMAP (20 mol%)
CH2Cl2, r.t., 3 d
R3
CH2
R4
+
R4
OEt
O
O
S
O
R3
9a: R3 = 4-MeC6H4, R4 = Ph
9b: R3 = 4-MeC6H4, R4 = 4-MeC6H4
9c: R3 = Ph, R4 = Me
10a: 67%
10b: 76%
10c: 50%
Scheme 4 Reaction of b-ketosulfones and ethyl propiolate
O
O
NR3
O
O
O
O
O
O
R1
R2
R2
O
R3N
OEt
H
R3N
OEt
OEt
H
R1
R2
14
O
O
R1
OEt
O
R3N
OEt
R3N
OEt
EtO
O
EtO
12
O
EtO
O
11
13
15
O
O
O
NR3
O
O
O
NR3
O
NR3
O
O
OEt
proton
transfer
OEt
R2
OEt
– R3N
– H2O
H
O
R1 = R2 = Me
OEt
HO
R1
H
H
H
O
OEt
OEt
O
O
OEt
O
3a
18
EtO
17
16
R1 = PhCH=CH
R2 = OEt
O
O
NR3
NR3
O
O
O
O
proton
transfer
EtO
EtO
EtO
Ph
OEt
– R3N
OEt
OEt
H
O
O
Ph
O
H
Ph
CO2Et
O
O
7a
EtO
EtO
19
Scheme 5 Possible reaction mechanisms
Synlett 2007, No. 13, 2073–2076 © Thieme Stuttgart · New York

2076
Q.-F. Zhou et al.
LETTER
(7) (a) Serra, S.; Fuganti, C.; Moro, A. J. Org. Chem. 2001, 66,
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To further extend this reaction, b-ketosulfones were also
applied to this reaction, and were found to undergo this
benzannulation reaction. Hence, reaction of ethyl propi-
olate with b-ketosulfones 9a and 9b gave the correspond-
ing products 10a and 10b, respectively, in 67% and 76%
yields. Moderate yield was also obtained when alkyl b-ke-
tosulfone 9c was submitted to this reaction (Scheme 4).
(9) (a) Hanedanian, M.; Loreau, O.; Sawiki, M.; Taran, F.
Tetrahedron 2005, 61, 2287. (b) Xue, S.; Zhou, Q.-F.;
Zheng, X.-Q. Synth. Commun. 2005, 35, 3027. (c) Trost, B.
M.; Dake, G. R. J. Am. Chem. Soc. 1997, 119, 7595.
(10) We recently reported cyclotrimerization of acetylenic
ketones catalyzed by DMAP in the presence of 2,4-
pentanedione: Zhou, Q.-F.; Yang, F.; Guo, Q.-X.; Xue, S.
Synlett 2007, 215.
(11) For selective recent phosphine- and amine-catalyzed
heterocyclization, see: (a) Xu, Z.; Lu, X. Tetrahedron Lett.
1997, 38, 3461. (b) Xu, Z.; Lu, X. J. Org. Chem. 1998, 63,
5031. (c) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001,
34, 535; and references therein. (d) Du, Y.; Lu, X.; Yu, Y. J.
Org. Chem. 2002, 67, 8901. (e) Zhu, X.-F.; Lah, J.; Kwon,
O. J. Am. Chem. Soc. 2003, 125, 4716. (f) Zhu, X.-F.;
Henry, C. E.; Wang, J.; Dudding, T.; Kwon, O. Org. Lett.
2005, 7, 1387. (g) Zhu, X.-F.; Henry, C. E.; Wang, J.;
Dudding, T.; Kwon, O. Org. Lett. 2005, 7, 2977. (h) Shi,
Y.-L.; Shi, M. Org. Lett. 2005, 7, 3057. (i) Zhao, G. L.; Shi,
M. J. Org. Chem. 2005, 70, 9975. (j) Bi, X.; Dong, D.; Liu,
Q.; Pan, W.; Zhao, L.; Li, B. J. Am. Chem. Soc. 2005, 127,
4578. (k) Cui, S.-J.; Lin, X.-F.; Wang, Y.-G. Eur. J. Org.
Chem. 2006, 5174. (l) Wang, Y.-G.; Cui, S.-L.; Lin, X.-F.
Org. Lett. 2006, 8, 1241.
(12) Typical Procedure: A round-bottomed flask, equipped with
a stirring bar, was charged with b-dicarbonyl moieties (0.3
mmol) and DMAP (0.06 mmol) in CH2Cl2 (3 mL) followed
by ethyl propiolate (0.66 mmol) via a syringe. After stirring
for the specific time at r.t., the reaction was concentrated
under reduced pressure on a rotary evaporator and purified
by silica gel chromatography using PE–EtOAc (10:1–5:1) to
afford the corresponding product. Compound 3a: 1H NMR
(300 MHz, CDCl3): d = 8.39 (d, J = 1.7 Hz, 1 H), 8.18 (d,
J = 1.7 Hz, 1 H), 4.30–4.39 (m, 4 H), 2.57 (s, 3 H), 2.55 (s,
3 H), 1.37 (t, J = 7.8 Hz, 6 H). 13C NMR (75 Hz, CDCl3):
d = 202.3, 167.2, 165.2, 142.1, 141.8, 133.7, 132.7, 130.9,
128.2, 61.71, 61.68, 30.7, 18.2, 14.4, 14.3. IR (neat): 1725,
1259 cm–1. HRMS (ESI): m/z [M+] calcd for C15H18O5:
278.1154; found: 278.1147.
A possible mechanism for the present catalytic reaction
was proposed (Scheme 5). DMAP acted as a nucleophilic
promoter to initiate the reaction and produced a zwitteri-
onic intermediate 11, which then added to a second ethyl
propiolate to give the intermediate 12. The intermediate
12 may then deprotonate the active methylene proton of
the 1,3-dicarbonyl compound to generate the stabilized
enolate 14 together with compound 13. Enolate 14 was
then added to 13, followed by electron transfer to give the
intermediate 16 and subsequent generation of 18 through
intramolecular nucleophilic attack and proton transfer.
DMAP and H2O were eliminated from the intermediate 18
to afford the product 3a. The intermediate 16 might under-
go proton transfer to give enolate 19, followed by Michael
addition and elimination of Lewis base to generate prod-
uct 7a.
In summary, we have shown that 1,3-dicarbonyl com-
pounds undergo a new benzannulation reaction with ethyl
propiolate catalyzed by DMAP under mild conditions.
This methodology offers a facile way to synthesize highly
substituted benzenes from simple and commercially
available starting materials.
Acknowledgment
We express our appreciation to the National Natural Science Foun-
dation of China (20572104) and Program for NCET.
References and Notes
(1) (a) Modern Arene Chemistry; Astruc, D., Ed.; Wiley-VCH:
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(c) Chauder, B.; Green, L.; Snieckus, V. Pure Appl. Chem.
1999, 71, 1521.
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Chem. 2005, 4741. (b) Saito, S.; Yamamoto, Y. Chem. Rev.
2000, 100, 2901. (c) Vollhardt, K. P. C. Angew. Chem., Int.
Ed. Engl. 1984, 23, 539.
(4) (a) Oppolzer, W. In Comprehensive Organic Synthesis, Vol.
5; Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991,
315–399. (b) Xi, Z.; Sato, K.; Gao, Y.; Lu, J.; Takahashi, T.
J. Am. Chem. Soc. 2003, 125, 9568. (c) Takahashi, T.;
Ishikawa, M.; Huo, S. J. Am. Chem. Soc. 2002, 124, 388.
(d) Langer, P.; Bose, G. Angew. Chem. Int. Ed. 2003, 42,
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Compound 7a: 1H NMR (300 MHz, CDCl3): d = 8.01 (d, J =
15.8 Hz, 1 H), 7.69 (s, 1 H), 7.55 (d, J = 7.9 Hz, 2 H), 7.34–
7.43 (m, 4 H), 5.84 (dd, J = 3.2, 10.2 Hz, 1 H), 4.23–4.35 (m,
4 H), 4.15–4.19 (m, 2 H), 2.86 (dd, J = 10.2, 15.2 Hz, 1 H),
2.54 (dd, J = 3.2, 15.2 Hz, 1 H), 1.31–1.41 (m, 6 H), 1.24 (t,
J = 7.2 Hz, 3 H). 13C NMR (75 MHz, CDCl3): d = 169.6,
165.0, 164.3, 162.1, 140.0, 136.0, 132.6, 129.9, 129.0,
128.2, 120.0, 117.9, 105.6, 71.9, 60.96, 60.92, 60.88, 37.8,
14.53, 14.45, 14.39. HRMS (EI): m/z [M+] calcd for
C23H26O7: 414.1679; found: 414.1674.
Compound 10a: 1H NMR (300 MHz, CDCl3): d = 9.20 (d,
J = 1.8 Hz, 1 H), 8.55 (d, J = 1.8 Hz, 1 H), 7.30 (m, 1 H),
7.12–7.17 (m, 2 H), 6.97–7.06 (m, 4 H), 6.87 (d, J = 7.5 Hz,
2 H), 4.49 (q, J = 7.2 Hz, 2 H), 3.99 (q, J = 7.2 Hz, 2 H), 2.33
(s, 3 H), 1.48 (t, J = 7.2 Hz, 3 H), 0.87 (t, J = 7.2 Hz, 3 H).
13C NMR (75 Hz, CDCl3): d = 166.7, 164.4, 144.8, 143.9,
142.1, 137.3, 136.6, 134.6, 134.2, 131.8, 130.5, 130.1,
129.2, 128.2, 127.9, 127.1, 62.1, 61.7, 21.6, 14.4, 13.6. IR
(neat): 1727, 1248 cm–1. HRMS (EI): m/z [M+] calcd for
C25H24O6S: 452.1294; found: 452.1302.
Synlett 2007, No. 13, 2073–2076 © Thieme Stuttgart · New York

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