Intermolecular tandem addition-cyclization of bromoallenes: A facile synthesis of methylenecyclopropyl carboxylates and polysubstituted furans

Article abstract of DOI:10.1021/ol061993u

(Chemical Equation Presented) The base-mediated reactions of 1,3-dicarbonyl compounds with bromoallenes used as an allyl dication equivalent were explored. The corresponding dimethyl methylenecyclopropane-1,1-dicarboxylates and 2,3,4-trisubstituted furans

Full text of DOI:10.1021/ol061993u

ORGANIC
LETTERS
2006
Vol. 8, No. 22
5061-5064
Intermolecular Tandem
Addition Cyclization of Bromoallenes:
−
A Facile Synthesis of
Methylenecyclopropyl Carboxylates and
Polysubstituted Furans
Lubin Xu,† Xian Huang,*,†,‡ and Fangrui Zhong†
Department of Chemistry, Zhejiang UniVersity (Xixi Campus), Hangzhou 310028, PRC,
and State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai 200032, PRC
huangx@mail.hz.zj.cn
Received August 10, 2006
ABSTRACT
The base-mediated reactions of 1,3-dicarbonyl compounds with bromoallenes used as an allyl dication equivalent were explored. The
corresponding dimethyl methylenecyclopropane-1,1-dicarboxylates and 2,3,4-trisubstituted furans were efficiently synthesized.
Reactions of bromoallenes have attracted much interest in
recent years because of the interesting chemical properties
associated with their cumulated double bonds and bromine
atom.1-5 More recently, Tanaka reported6 the tandem in-
tramolecular cyclization of nitrogen binucleophilic reagents
with bromoallenes which act as allyl dication equivalents,
affording a very useful process for the synthesis of medium-
sized heterocycles. However, the intermolecular tandem
cyclizations of bromoallenes as allyl dication equivalents to
form carbocycles or heterocycles have not been reported yet.
This promoted us to investigate the intermolecular cyclization
of bromoallenes with nucleophilic reagents.
† Zhejiang University (Xixi Campus).
‡ Chinese Academy of Sciences.
(1) Modern Allene Chemistry; Krause, N., Hashmi, A. S. K., Eds; Wiley-
Vch: Weinheim, 2004; Vol. 2.
(2) For organocopper-mediated substitutions, see examples: (a) Corey,
E. J.; Boaz, N. W. Tetrahedron Lett. 1984, 25, 3059. (b) Caporusso, A.
M.; Polizzi, C.; Lardicci, L. Tetrahedron Lett. 1987, 28, 6073. (c) D’Aniello,
F.; Mann, A.; Taddei, M. J. Org. Chem. 1996, 61, 4870. (d) Chemla, F.;
Bernard, N.; Normant, J. Eur. J. Org. Chem 1999, 2067. (e) Conde, J. J.;
Mendelson, W. Tetrahedron Lett. 2000, 41, 811. (f) Caporusso, A. M.;
Zampieri, A.; Aronica, L. A.; Banti, D. J. Org. Chem. 2006, 71, 1902.
(3) For palladium-catalyzed cross-coupling reactions, see: (a) MLrkl,
G.; Attenberger, P.; Kellner, J. Tetrahedron Lett. 1988, 29, 3651. (b)
Gillmann, T.; Hu¨lsen, T.; Massa, W.; Wocadlo, S. Synlett 1995, 1257. (c)
Saalfrank, R. W.; Haubner, M.; Deutscher, C.; Bauer, W.; Clark, T. J. Org.
Chem. 1999, 64, 6166.
Dimethyl malonate was chosen as a nucleophilic reagent
for our initial study on the intermolecular cyclization of
bromoallenes. We postulated a possible pathway of the
(5) For ring-forming reactions, see: (a) Ohno, H.; Hamaguchi, H.;
Tanada, T. Org. Lett. 2001, 3, 2269. (b) Ohno, H.; Ando, K.; Hamaguchi,
H.; Takeoka, Y.; Tanaka, T. J. Am. Chem. Soc. 2002, 124, 15255.
(6) (a) Ohno, H.; Hamaguchi, H.; Ohata, M.; Tanaka, T. Angew. Chem.,
Int. Ed. 2003, 42, 1749. (b) Ohno, H.; Hamaguchi, H.; Ohata, M.; Kosaka,
S.; Tanaka, T. Heterocycles 2003, 61, 65. (c) Ohno, H.; Hamaguchi, H.;
Ohata, M.; Kosaka, S.; Tanaka, T. J. Am. Chem. Soc. 2004, 126, 8744. (d)
Hamaguchi, H.; Kosaka, S.; Ohno, H.; Tanaka, T. Angew. Chem., Int. Ed.
2005, 44, 1513.
(4) For the formation of nucleophilic allenyl metal reagents, see: (a)
Marshall, J. A.; Adams, N. D. J. Org. Chem. 1997, 62, 8976. (b) Ma, S.;
Yu, S.; Yin, S. J. Org. Chem. 2003, 68, 8996.
10.1021/ol061993u CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/29/2006

tandem reaction (Scheme 1). The carbanion 2 might attack
Table 1. Addition-Cyclization of Dimethyl Malonate 2 with
1a Under Different Conditionsa
Scheme 1. Proposed Reaction Process of Dimethyl Malonate
with Bromoallene in the Presence of a Base
bromoallene
(equiv)
temp
(°C)
time
(h)
yieldb (%)
of 3a/4a
entry
1
2
3
4
5
6
7c
1.0
1.2
1.2
1.2
1.5
1.8
1.5
rt
rt
40
55
55
55
reflux
56
53
38
26
24
24
20
65/19
69/14
71/13
73/11
76/7
76/6
73/5
the central carbon atom of bromoallene 1 to form the allyl
carbanion intermediate, and then intramolecular hydrogen
transfer would give a new carbanion B containing an allylic
bromide moiety, which may undergo an intramolecular
nucleophilic substitution to produce the methylenecyclopro-
pane-1,1-dicarboxylate 3. If it could be realized smoothly,
the tandem reaction would afford a novel and efficient
method for the synthesis of methylenecyclopropanes (MCPs)
with two carbonyl groups on the three-membered carbocycle.
These MCPs are very useful building blocks in organic
synthesis,7 and some of their nucleoside derivatives show
important antiviral and anti-HIV-1 activities.8,9 Compared
with the methods for synthesis of these MCPs in the
literature,7,8 our method presented here would require neither
the expensive transition-metal catalysts nor long reaction
steps.
a Reagents and conditions: 1mmol of 2 and 1 mmol of NaH (50%) in
6 mL of THF, N2. b Isolated yield. c Unidentified compound was observed.
it should be noted that the yield of 3a and the selectivity of
the reaction were both improved when the reaction was
conducted using 1.5 equiv of bromoallene 1a at 55 °C (entry
5, Table 1). However, adding up to 1.8 equiv of 1a failed to
increase the yield of 3a remarkably (entry 6, Table 1). It
also should be pointed out that the reaction at a temperature
higher than 55 °C produced an unidentified compound (entry
7, Table 1). Thus, we chose 1.5 equiv of bromoallene and a
temperature of 55 °C as suitable reaction conditions.
With the optimized reaction conditions in hand, the scope
and the limitation of this reaction were examined. Some
typical results are summarized in Table 2. We were pleased
Initial efforts focused on the treatment of dimethyl
malonate (1.0 mmol) with 3-(p-bromophenyl)bromoallene
1a10 (1.0 mmol) in the presence of NaH (50%, 1.0 mmol).
Luckily, the desired dimethyl 2-(4-bromobenzylidene)cy-
clopropane-1,1-dicarboxylate 3a was isolated in 65% yield
together with the product 4a in 19% yield (entry 1, Table
1). The formation of 4a most likely occurs by the intermedi-
ate A (Scheme 1) undergoing subsequent intermolecular
hydrogen transfer with dimethyl malonate and intermolecular
nucleophilic substitution to give 4a.
Table 2. Intermolecular Tandem Addition-Cyclization of 2
with Arylbromoallenes 1 Affording 3a
1
time
(h)
yield of
3/4 (%)
entry
R1
R2
Considering the forming process of 4a, we reckon that
increasing the amount of bromoallene may avoid the forma-
tion of 4a. So, we changed the amount of bromoallene and
studied the temperature effect. From the results in Table 1,
1
2
3
4
5
6
7
8d
9d
10d
1a, p-BrC6H4
1b, p-ClC6H4
1c, C6H5
1d, p-FC6H4
1e, o,o-Cl2C6H3
1f, p-F3CC6H4
1g, p-CH3C6H4
1h, C6H5
H
H
H
H
H
H
H
24
22
28
20
24
20
38
36
36
32
3a/4a (76/7)
3b/4b (73/8)
3c/4c (70/8)
3d/4d (76/6)
3e/4e (68b/6)
3f/4f (79/5)
3g/4g ( -c/6)
3h/4h (74/8)
3i/4i (76/7)
3j/4j (78/5)
(7) (a) Singleton, D. A.; Huval, C. C. J. Org. Chem. 1994, 59, 2020. (b)
Ma, S.; Zhang, J. Angew. Chem., Int. Ed. 2003, 42, 183. (c) Ma, S.; Lu, L.;
Zhang, J. J. Am. Chem. Soc. 2004, 126, 9645. (d) Ma, S.; Lu, L. J. Org.
Chem. 2005, 70, 7629. (e) Ma, S.; Lu, L.; Chen, G. Org. Lett. 2006, 8,
835.
(8) Yan, Z. H.; Kern, E. R.; Gullen, E.; Cheng, Y. C.; Drach, J. C.;
Zemlicka, J. J. Med. Chem. 2005, 48, 91 and references cited therein.
(9) Cheng, C. M.; Shimo, T.; Somekawa, K.; Baba, M. Tetrahedron 1998,
54, 2031.
C6H5
p-ClC6H4
p-FC6H4
1i, p-ClC6H4
1j, p-FC6H4
a Reagents and Conditions: 1.5 mmol of 1, 1.0 mmol of 2, and 1.0 mmol
of NaH (50%) in 6 mL of THF at 55 °C, N2. b Accompanied with 14%
uncertain byproduct. c Unidentified mixture. d Reaction temp at 60 °C.
(10) For the preparation of bromoallenes, see: (a) Landor, S. R.; Patel,
A. N.; Whiter, P. F.; Greaves, P. M. J. Chem. Soc. (C) 1966, 1223. (b)
Elsevier, C. J.; Vermeer, P.; Gedanken, A.; Runge, W. J. Org. Chem. 1985,
50, 364.
to find that both monosubstituted and disubstituted arylbro-
5062
Org. Lett., Vol. 8, No. 22, 2006

moallenes could lead to the corresponding bis(methoxycar-
bonyl)-2-arylmethylidenecyclopropanes 3. For the mono- or
diaryl substituted bromoallenes, introducing an electron-
withdrawing group (or atom) to the aryl ring may favor the
reaction because of the fact that electropositivity of the
central carbon on bromoallenes may be increased (3a,b,
entries 1 and 2; 3d-f, entries 4-6 and 8-10, Table 2). For
the diaryl substituted bromoallenes, a longer reaction time
was needed (entries 8-10, Table 2).
Table 3. Optimization of Reaction of 1a with 2,4-Pentadione 5
Used as a Binucleophilic Reagenta
1a
(equiv)
Bu4NBr
(equiv)
time
(h)
yield
(%)b
entry
solvent
The configuration of the CdC bond in the products 3a-f
was assigned on the basis of NOESY and X-ray diffraction
studies of 3a (Figure 1).11 The NOESY spectra of 3a show
1c
2
3
4
5
6
7
8
9
1.5
1.2
1.2
1.2
1.2
1.2
1.2
1.5
1.2
1.5
1.2
0
0
0.1
0
0.1
0
0.1
0.1
0.2
0.2
0.3
THF
THF
THF
DMF
54
60
60
60
60
56
46
46
42
42
42
23
14
18
22
28
48
64
64
73
73
73
DMF
acetone
acetone
acetone
acetone
acetone
acetone
10
11
a Reagents and conditions: 1.0 mmol of 5 and 1.0 mmol of base in 8
mL of solvent at 55 °C. b Isolated yield based on 5. c Using NaH as base.
Scheme 2. Possible Reaction Process of 1,3-Diketone with
Bromoallene under the Basic Conditions
Figure 1. X-ray crystal structure of 3a.
that there is a correlation between the methylene protons of
the three-membered ring and the protons on the phenyl group.
From Figure 1, we can see that the bromophenyl group is
cis oriented with the methylene of the three-membered ring.
These results demonstrate that the configuration of the Cd
C bond in 3a is E-form.
The reaction of an alkylbromoallene, such as 3-hexylbro-
moallene, with dimethyl malonate was run at the same
conditions; however, we did not obtain the corresponding
addition-cyclization product but instead obtained dimethyl
2-(non-1-yn-3-yl)malonate in 53% yield via a SN2′ reaction
process.12
Under similar conditions, the reaction of bromoallene 1a
with 2,4-pentadione 5 as a nucleophile was performed.
However, we did not isolate the desired methylenecyclo-
propyl ketone but obtained an unexpected 2,3,4-trisubstituted
furan 6a in 23% yield (entry 1, Table 3).
substitution via the attack of the oxygen to offer the five-
membered intermediate E, which finally isomerizes to the
more stable polysubstituted furan 6.
Because 1,3-diketones are more acidic than malonate
esters, a base weaker than NaH might also be suitable for
the reaction and K2CO3 was used instead. Considering the
reaction proceeded between liquid and solid phases, it might
be improved by adding a suitable amount of phase-transfer
catalyst, thus tetrabutylammonium bromide was used. So,
various reaction conditions including the solvent and the
amount of bromoallene and tetrabutylammonium bromide
were tested. Some typical results are summarized in Table
3. According to Table 3, the optimized conditions are as
follows: 1.0 equiv of K2CO3, 1.2 equiv of 1a, and 0.2 equiv
of tetrabutylammonium bromide in acetone.
As shown in Scheme 2, the diketone carbanion D existing
in its enol form undergoes intramolecular nucleophilic
(11) X-ray data for compound 3a: C14H13BrO4, MW ) 372.14, triclinic,
space group P1h, final R indices [I > 2σ(I)], R1 ) 0.0569, wR2 ) 0.1335,
a ) 7.9280 (13) Å, b ) 7.9969 (13) Å, c ) 1.261 (2) Å, R ) 83.526 (3)°,
â ) 78.836 (3)°, γ ) 62.414 (3)°, V ) 675.72 (19) Å3, T ) 293(2) K, Z
) 2, Dc ) 1.598 g/cm-1, µ ) 3.048 mm-1, λ ) 0.71073Å, reflections
collected/unique, 3979/2867 (Rint ) 0.1195), parameters 187. GOF on F2
) 0.951.
Then, the reaction of monoarylbromoallenes 1a-f with
2,4-pentadione 5 and 5,5-dimethylcyclohexane-1,3-dione 7
was tested and summarized in Table 4. In Table 4, all the
reactions proceeded smoothly to give desired furans in good
yields. A similar effect of the substituted groups on the aryl
ring was also observed. Both the rate and yield were slightly
(12) Intra- or intermolecular SN2′ reaction about bromoallenes. See
examples in refs 2 and 5.
Org. Lett., Vol. 8, No. 22, 2006
5063

improved when there was an electron-withdrawing group (or
atom) on the aryl ring (compare entries 1-4 and 7-12 with
entries 5 and 6, Table 4). However, this reaction did not
occur when an electron-donating group was introduced to
the aryl ring (entry 13, Table 4). The reactions of diaryl-
bromoallene 1h-j with 2,4-pentadione 5 under similar
conditions also failed to give the desired furans. When we
tried to extend this protocol to alkylbromoallenes, unluckily,
no reaction occurred.
Table 4. Intermolecular Tandem Addition-Cyclization of
1,3-Diketone with Arylbromoallenes 1a-f Affording
Polysubstituted Furansa
time
(h)
yield
Polysubstituted furans play an important role in organic
chemistry not only due to their presence as key structural
units in many natural products and important pharmaceuticals
but also because they can be employed in synthetic chemistry
as versatile building blocks.13,14 Thus, our method afforded
a simple and efficient method for the synthesis of 2,3,4-
trisubstituted furans.15
entry
arylbromoallene
1,3-diketone
(%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
5
7
5
7
5
7
5
7
5
7
5
7
5
42
54
46
54
46
56
40
50
28
46
26
45
60
6a (73)
8a (68)
6b (71)
8b (66)
6c (71)
8c (65)
6d (76)
8d (69)
6e (80)
8e (73)
6f (84)
8f (75)
NR
1a
1b
1c
1d
1e
In conclusion, we present the first intermolecular tandem
addition-cyclization of arylbromoallenes as allyl dication
equivalents. The described method provides a simple and
efficient method for the synthesis of (E)-dimethyl 2-aryl-
methylidenecyclopropane-1,1-dicarboxylates and 2,3,4-
trisubstituted furans by using dimethyl malonate and 1,3-
diketones as binucleophilic reagents, respectively.
1f
1g
a Reagents and conditions: 1.2 mmol of bromoallene, 1.0 mmol of 5
(or 7), 1.0 mmol of K2CO3, 0.2 equiv of PTC in 8 mL of acetone. b Isolated
yield based on 5 (or 7).
(13) Lipshutz, B. H. Chem. ReV. 1986, 86, 795.
(14) Natural Products Chemistry; Nkanishi, K., Ed.; Kondasha: Tokyo,
1974.
Acknowledgment. We are grateful to the National
Natural Science Foundation of China (Project No. 20472072,
20332060) for financial support.
(15) Some new methods have been reported for the synthesis of densely
polysubstituted furans recently. See examples: (a) Ma, S.; Li, L. Org. Lett.
2000, 2, 941. (b) Stauffer, F.; Neier, R. Org. Lett. 2000, 2, 3535. (c) Ma,
S.; Zhang, J. Chem. Commun. 2000, 117. (d) Nair, N.; Menon, R. S.; Vinod,
A. U.; Viji, S. Tetrahedron Lett. 2002, 43, 2293. (e) Nair, N.; Vinod, A.
U.; Abhilash, N.; Menon, R. S.; Santhi, V.; Varma, R. L.; Viji, S.; Mathew,
S.; Srinivas, R. Tetrahedron 2003, 59, 10279. (f) Yavari, I.; Alizadeh, A.;
Anary-Abbasinejad, M.; Bijanzadeh, H. R. Tetrahedron 2003, 59, 6083.
(g) Aurrecoechea, J. M.; Perez, E. Tetrahedron Lett. 2003, 44, 3263. (h)
Azizian, J.; Mohammadi, A. A.; Karimi, A. R. Heteroatom Chem. 2005,
16, 259. (i) Ma, S.; Zhang, J. J. Am. Chem. Soc. 2003, 125, 12386. (j)
Zhou, C. Y.; Chan, P. W. H.; Che, C. M. Org. Lett. 2006, 8, 325.
Supporting Information Available: Crystallographic
information files (CIF) for 3a and experimental procedures
and characterization data. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL061993U
5064
Org. Lett., Vol. 8, No. 22, 2006