Lewis acid-mediated selective cycloadditions of vinylidene-cyclopropanes with aromatic aldehydes: An efficient protocol for the synthesis of benzo[c]fluorene, furan and furo[2,3-b]furan derivatives

Article abstract of DOI:10.1002/adsc.200800661

Three kinds of Lewis acid-mediated reactions of vinylidenecyclopropanes and aromatic aldehydes are disclosed in this paper, providing an efficient and selective synthesis of a variety of functionalized benzo[c]fluorene, furan and furo[2,3-b]-furan derivat

Full text of DOI:10.1002/adsc.200800661

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DOI: 10.1002/adsc.200800661
Lewis Acid-Mediated Selective Cycloadditions of Vinylidene-
cyclopropanes with Aromatic Aldehydes: An Efficient Protocol
for the Synthesis of Benzo[c]fluorene, Furan and
Furo[2,3-b]furan Derivatives
ACHTUNGTRENNUNG
Chenliang Sua and Xian Huanga,b,*
a
Department of Chemistry, Zhejiang University, Hangzhou 310028, Peopleꢀs Republic of China
Fax : (+86)-571-8880-7077; e-mail: huangx@mail.hz.zj.cn or huangx@zju.edu.cn
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
b
Sciences, Shanghai 200032, Peopleꢀs Republic of China
Received: October 29, 2008; Published online: January 12, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800661.
Abstract: Three kinds of Lewis acid-mediated reac-
tions of vinylidenecyclopropanes and aromatic alde-
hydes are disclosed in this paper, providing an effi-
cient and selective synthesis of a variety of func-
tionalized benzo[c]fluorene, furan and furo[2,3-b]-
ACHTUNGTRENNUNGfuran derivatives.
Keywords: benzo[c]fluorenes; furans; furo[2,3-b]-
ACHTUNGTRENNUNGfurans; Lewis acids; vinylidenecyclopropanes
Figure 1. Lewis acid- or Brønsted acid-mediated ring open-
ing reaction models for VCPs.
three-membered ring (Figure 1, path 2) are rare.[4e] In
this paper, we disclose three kinds of reaction pat-
Vinylidenecyclopropanes (VCPs)[1] show unique reac- terns of VCPs and aromatic aldehydes mediated by a
tivity in organic synthesis due to the presence of the Lewis acid which include the above two kinds of ring
cumulated C=C double bonds adjacent to the highly opening models, providing an efficient and selective
strained cyclopropyl ring, and yet they are thermal synthesis of a variety of functionalized benzo[c]fluor-
stable.[2] An attractive but often troublesome feature ene, furan and furo
ACHTUNGTRENNUNG
of VCPs is their multiform reactivities that may lead
to formation of a variety of products through various of VCP 1a and aldehyde 2a with 0.3 equiv. of FeCl3 in
reaction pathways: selective addition to a cumulated CH2Cl2 under an N2 atmosphere. After stirring for
C=C double bond[3] or cleavage of proximal[4] and 24 h at 108C, the 6-methyl-7-(4-nitrophenyl)-5-
distal bonds[5,6]. Recently, we have investigated the phenyl-7H-benzo[c]fluorene 3a was obtained in 21%
transition metal-mediated, highly selective ring open- yield. Recently, Shi et al. reported that the reaction of
ing reactions of methylenecyclopropanes (MCPs) and 1a with 1-(diethoxymethyl)benzene could also pro-
VCPs.[7] Shi et al. reported the Lewis acid-catalyzed duce 6-methyl-5,7-diphenyl-7H-benzo[c]fluorene but
reactions of vinylidenecyclopropanes with acetals, ac- only in 16% yield.[6a] We then tried to optimize the re-
tivated imines and activated carbonyl compounds to action conditions to achieve a useful synthesis of
produce many useful organic molecules.[6] The previ- these products. Various Lewis acids were carefully ex-
ous investigations have shown that Lewis acid- or amined in this reaction; however, these Lewis acids
Brønsted acid-mediated ring opening reactions of had little effect in improving the yield of 3a (Table 1,
VCPs often took place via a cleavage of distal bonds entries 1–5). Interestingly, when the reaction was car-
of the three-membered ring (Figure 1, path 1).[5,6] Re- ried in the presence of 1.2 equiv. of TMSCl, the yield
ports on Lewis acid- or Brønsted acid-mediated reac- of product 3a was sharply improved to 67%, and the
tions of VCPs via a cleavage of proximal bonds of the reaction was completed in 1 h (Table 1, entry 8). Fur-
Adv. Synth. Catal. 2009, 351, 135 – 140
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135

Chenliang Su and Xian Huang
COMMUNICATIONS
Table 1. Optimization of the reaction conditions for the syn-
thesis of 3a.[a]
isomer), the corresponding benzo[c]fluorene was ob-
tained in somewhat lower yield (Table 2, entry 12).
When bicyclic VCP 1g was employed, the reaction
furnished the corresponding benzo[c]fluorene deriva-
tive 3m in 17% yield along with the furan derivative
4a in 26% under similar conditions (Scheme 1, top).
Surprisingly, when we carried out the reaction in the
presence of BF3·Et2O (0.7 equiv.) instead of FeCl3 and
TMSCl, THF, 5a was obtained in 68% yield.[8] In the
meantime, we also found that 5a could smoothly
progress to 4a in the presence of BF3·Et2O and
TMSCl (Scheme 1). With these observations, we next
developed a one-pot synthesis of furan derivative 4.
After treatment of bicyclic VCPs 1 and aromatic alde-
hydes with 0.7 equiv. of BF3·Et2O at À108C for 24 h
in CH2Cl2, 1.2 equiv. of TMSCl was subsequently
added to the reaction mixture, which was then
warmed to room temperature for another 24 h with
stirring. With a general work-up, furan derivatives 4a–
e could be obtained in 54–72% yield (Scheme 1,
bottom). Here it should be noted that the synthesis of
multi-substituented furan derivatives is of high chemi-
cal and biochemical importance because these moiet-
ies are part of biologically important natural and un-
natural compounds.[9]
A plausible mechanism for the formation of ben-
zo[c]fluorene derivatives 3 and furan derivatives 4 is
shown in Scheme 2.[6] Initially, the electrophilic add-
tion of intermediate A with VCPs 1 produces cationic
intermediate B,[6a] which then rearranges to give the
cyclopropyl ring-opened intermediate C or the reso-
nance-stabilized intermediates C1 and C2. When R1 =
Ar, R2 =H or Me, the corresponding resonance-stabi-
lized cationic intermediate C1 may be more stable
than cationic intermediate C2, thus it undergoes an in-
tramolecular Friedel–Crafts reaction to give inter-
Entry LA (equiv.)
Temp. Time Yield of
[8C]
[h]
3a [%][b]
1
2
3
4
5
6
7
8
BF3·Et2O (0.1)
BF3·Et2O (0.3)
FeCl3 (0.3)
ZnCl2 (0.3)
ZrCl4 (0.3)
ZnCl2 (0.1)/TMSCl (1.2)
BF3·Et2O (0.1)/TMSCl (1.2) 10
FeCl3 (0.1)/TMSCl (1.2)
FeCl3 (0.1)/TMSCl (0.1)
FeCl3 (0.1)/TMSCl (2.2)
10
10
10
10
10
10
24
12
24
48
20
2
48
1
12
1
trace[c]
15
21
trace[d]
trace[e]
57
trace[f]
67
10
10
10
9
27
72
76
58
10
11
12
FeCl3
N
À10
2
0.5
FeCl3 (0.1)/TMSCl (1.2)
30
[a]
Unless otherwise specified, the reaction was carried out
using 1a (0.2 mmol), 2a (0.24 mmol) in 4 mL of CH2Cl2
at nitrogen atmosphere.
Isolated yields.
61% of 1a was recovered.
56% of 1a was recovered.
28% of 1a was recovered and 30% of 2-methyl-1,4-diphe-
nylnaphthalene was obtained.
30% of 1a was recovered and 35% of 2-methyl-1,4-diphe-
nylnaphthalene was obtained.
[b]
[c]
[d]
[e]
[f]
ther investigations disclosed that when the reaction mediate D.[5d,6a] Aromatization of D produces the
was conducted at a lower temperature (Table 1, thermodynamically favoured naphthalene intermedi-
entry 11), the yield was improved to 76%.
ate E, which could transform to the cation F in the
With the optimized conditions in hand, we next ex- presence of FeCl3/TMSCl. Then, F undergoes another
amined the reaction of various VCPs with different intramolecular Friedel–Crafts reaction to give the
aromatic aldehydes under identical conditions. The final product 3 (path a).[6a] For bicyclic VCPs, the cat-
results summarized in Table 2 prove that this reaction ionic intermediate C undergoes intramolecular O-at-
indeed provides a straightforward entry to a variety tacked cyclization instead of the intramolecular Frie-
of benzo[c]fluorene derivatives in moderate to good del–Crafts reaction to produce 5.[6b–c] The subsequent
yields. As can be seen from Table 2, the substrate 1a aromatization of 5 furnishes the thermodynamically
smoothly reacted with various aromatic aldehydes af- favoured furan derivatives 4 (path b).
fording the coresponding benzo[c]fluorene derivatives
To the best of our knowledge, there are few reports
in moderate to good yields (Table 2, entries 1–7). we on the reactions of VCPs with functional groups at-
also found that VCPs 1b–d, in which Ar is an elec- taching to the cyclopropyl ring.[10,11] We thought that
tron-poor or an electron-rich aromatic group, where the presence of functional groups may facilitate the
R1 is an aryl group and R2 is a hydrogen atom, the selective cleavage of C C bonds of VCPs, thus deli-
À
corresponding benzo[c]fluorenes 3h–k were obtained cately tunning the regio- and stereoselectivity of the
in moderate yields. For substrate 1e, in which R1 is an reactions. As a matter of fact, we found the reaction
n-C4H9 group, the corresponding benzo[c]fluorene gave another interesting product, 7a, under similar
was obtained in 61% (Table 2, entry 11). In addition, conditions when the functionalized VCPs 6a was em-
for substrate 1f, in which R1 =Ph, R2 =Me (trans ployed as substrate [Eq. (1)].
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Lewis Acid-Mediated Selective Cycloadditions of Vinylidenecyclopropanes
Table 2. Sequential intramolecular Friedel–Crafts reactions for the synthesis of benzo[c]fluorene derivatives 3.[a]
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Entry
1
R (2)
Yield of 3 [%][b]
Ar
R1
R2
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
p-Cl-C6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1b)
H (1c)
H (1d)
H (1e)
Me (1f)
p-NO2-C6H4 (2a)
p-Br-C6H4 (2b)
o-Br-C6H4 (2c)
p-Cl-C6H4 (2d)
Ph (2e)
p-Me-C6H4 (2f)
p-MeO-C6H4 (2g)
Ph (2e)
76 (3a)
65 (3b)
61 (3c)
64 (3d)
69 (3e)
65 (3f)
53 (3g)
52 (3h)
55 (3i)
57 (3j)
61 (3k)
52 (3l)
9
p-MeO-C6H4
Ph
Ph (2e)
10
11
12
Ph
Ph
Ph
p-Cl-C6H4
n-C4H9
Ph
p-Br-C6H4 (2b)
p-NO2C6H4 (2a)
p-NO2-C6H4 (2a)
[a]
Unless otherwise specified, the reaction was carried out using 1 (0.2 mmol) and 2 (0.24 mmol) in 4 mL CH2Cl2 at nitrogen
atmosphere.
Isolated yields.
[b]
Scheme 1.
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137

Chenliang Su and Xian Huang
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Scheme 2. Proposed mechanism for the synthesis of benzo[c]fluorene derivatives 3 and furan derivatives 4.
benzaldehyde was employed (Table 3, entry 6). In ad-
dition, for aldehydes with an electron-donating me-
thoxy group on the benzene ring, only a trace of prod-
uct was obtained (Table 3, entry 7).
Mechanistically, this reaction may involve a novel
À
proximal C C bond cleavage of the cyclopropyl ring.
A plausible mechanism is depicted in Scheme 3. First-
ly an electrophilic addtion of the Lewis acid-activated
aldehyde to VCP may occur to give the ring-opened
cation I[4e] via an unusual proximal cleavage of C C
À
bonds. This process may be facilitated by the O atom
We next studied the scope of this methodology by attached to the cyclopropyl ring moiety. Then an in-
examining the reaction of different VCPs 6 with vari- tramolecular cyclization of cation I along with the re-
ous aldehydes under the identified reaction conditions lease of the Lewis acid furnishes the [3+2]cycloaddi-
(Table 3). As indicated in Table 3, it is noteworthy tion product 8, which progresses to the corresponding
that substitutents on the benzene ring of the alde- product 7 via 1,3 H shift.
hydes significantly affected the reaction. For alde-
To clarify the proposed mechanism, a variety of re-
hydes 2a, 2h–2k having an electron-withdrawing action conditions were examined. When we carried
group on the benzene ring, the corresponding prod- out the reaction of 6a with aldehyde 2a with 0.1 equiv.
ucts 7a–7d were obtained in moderate yields (Table 3, of ZnCl2, the intermediate product 8a was obtained in
entries 1–5). A slightly lower yield was obtained when 42% yield. Further investigations proved that 8a
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Lewis Acid-Mediated Selective Cycloadditions of Vinylidenecyclopropanes
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Table 3. The Lewis acid-mediated cycloadditions of VCPs 6 with aldehydes for the synthesis of 7.
Entry
Ar (6)
R (2)
Yield of 7 [%][a]
1
2
3
4
5
6
7
8
Ph (6a)
Ph (6a)
Ph (6a)
Ph (6a)
Ph (6a)
Ph (6a)
Ph (6a)
p-MeO-C6H4 (6b)
p-NO2-C6H4 (2a)
m-NO2-C6H4 (2h)
o-NO2-C6H4 (2i)
p-CF3-C6H4 (2j)
3-NO2,4-ClC6H3 (2k)
Ph (2e)
64[b] (7a)
62 (7b)
57 (7c)
48 (7d)
61 (7e)
37 (7f)
trace[c]
45 (7g)
p-MeO-C6H4 (2g)
p-NO2-C6H4 (2a)
[a]
Isolated yields.
[b]
[c]
The configuration was established on the NOESY studies (see Supporting Information).
Some other unidentified products were obtained.
Scheme 3. Proposed mchanism.
could isomerize to 7a in the presence of FeCl3/TMSCl tionalized VCPs 6 were employed as substrates, the
[Eq. (2)]. These results may partially support the pro- useful furo[2,3-b]furan skeleton was formed via a very
AHCTUNGTRENNUNG
À
posed mechanism.
different and selective proximal cleavage of C C
bonds. Moreover, plausible reaction mechanisms were
also discussed based on the obtained intermediates.
Hence, the reaction may be of interest both from the
mechanistic and synthetic standpoints. Further studies
to expand the scope and synthetic utility of these re-
actions are underway.
Experimental Section
Typical Experimental Procedure for the Synthesis of
Benzo[c]fluorene Derivatives
Under an atmosphere of dry nitrogen, FeCl3 (3 mg,
10 mmol%) was added to a solution of aldehyde 2a (36 mg,
0.24 mmol) in 2 mL of dry CH2Cl2 at À108C. Then TMSCl
(26 mg, 0.24 mmol) was injected. The mixture was stirred
for 10 min, then a solution of VCP 1a (59 mg, 0.2 mmol) in
2 mL CH2Cl2 was added slowly. After stirring for 2 h (moni-
tored by TLC), the reaction mixture was quenched with
5 mL of water and extracted with EtOAc (3ꢂ5 mL). The
combined organic layers were dried over anhydrous MgSO4.
In conclusion, we have disclosed two kinds of reac-
tion patterns of VCPs 1 and aromatic aldehydes 2
mediated by Lewis acids via a classic distal cleavage
of C C bonds, providing an efficient and selective
synthesis of a variety of functionalized benzo[c]fluor-
À
ene and furan derivatives. Attractively, when the func- After filtration and removal of the solvent under vacuum,
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139

Chenliang Su and Xian Huang
COMMUNICATIONS
the residues were purified with flash chromatography (silica/
petroleum ether-ethyl acetate, 100:1 to 10:1 v/v) to afford
3a; yield: 65 mg (76%).
Perkin Trans. 1 1991, 2283, and references cited there-
in; b) J. R. Al-Dulayymi, M. S. Baird, J. Chem. Soc.,
Perkin Trans. 1 1994, 1547; c) H. Maeda, T. Hirai, A.
Sugimoto, K. Mizuno, J. Org. Chem. 2003, 68, 7700.
[2] For some reviews related to VCPs, see: a) M. L. Pouts-
ma, P. A. Ibarbia, J. Am. Chem. Soc. 1971, 93, 440;
b) W. Smadja, Chem. Rev. 1983, 83, 263; c) L. K.
Sydnes, Chem. Rev. 2003, 103, 1133; d) A. Brandi, S.
Cicchi, F. M. Cordero, A. Goti, Chem. Rev. 2003, 103,
1213.
[3] a) H. Maeda, T. Hirai, A. Sugimoto, K. Mizuno, J. Org.
Chem. 2003, 68, 7700; b) W. Li, M. Shi, Tetrahedron
2007, 63, 6654; c) L. P. Liu, J. M. Lu, M. Shi, Org. Lett.
2007, 9, 1303.
[4] a) K. Mizuno, H. Maeda, H. Sugita, S. Nishioka, T.
Hirai, A. Sugimoto, Org. Lett. 2001, 3, 581; b) K.
Mizuno, H. Sugita, T. Hirai, H. Maeda, Y. Otsuji, M.
Yasuda, M. Hashiguchi, K. Shima, Tetrahedron Lett.
2001, 42, 3363; c) M. Shi, J. M. Lu, G. C. Xu, Tetrahe-
dron Lett. 2005, 46, 4745; d) C. L. Su, X. Huang, Q. Y.
Liu, J. Org. Chem. 2008, 73, 6421; e) W. Li, M. Shi, J.
Org. Chem. 2008, 73, 4151.
[5] a) G. C. Xu, L. P. Liu, J. M. Lu, M. Shi, J. Am. Chem.
Soc. 2005, 127, 14552; b) Y. P. Zhang, J. M. Lu, G. C.
Xu, M. Shi, J. Org. Chem. 2007, 72, 509.
[6] a) J. M. Lu, M. Shi, Org. Lett. 2006, 8, 5317; b) J. M.
Lu, M. Shi, Org. Lett. 2007, 9, 1805; c) J. M. Lu, M. Shi,
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[7] a) X. Huang, H. W. Zhou, Org. Lett. 2002, 4, 4419;
b) X. Huang, Y. W. Yang, Org. Lett. 2007, 9, 1667; c) X.
Huang, M. Z. Miao, J. Org. Chem. 2008, 73, 6884; d) X.
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Typical Experimental Procedure for the One-Pot
Reaction Synthesis of Furan Derivatives
Under an atmosphere of dry nitrogen, bicyclic VCP 1g
(81 mg, 0.3 mmol) was added to a solution of aldehyde 2a
(54 mg, 0.36 mmol) in 5 mL of dry CH2Cl2 at À108C. Then
BF3·Et2O (30 mg, 70 mmol%) was injected. After stirring
for 24 h (monitored by TLC), TMSCl (39 mg, 0.36 mmol)
was injected and the reaction mixture was allowed warmed
to room temperature. After stirring for another 24 h, the re-
action mixture was quenched with 5 mL of water and ex-
tracted with EtOAc (3ꢂ5 mL). The combined organic layers
were dried over anhydrous MgSO4. After filtration and re-
moval of the solvent under vacuum, the residues were puri-
fied with flash chromatography (silica/petroleum ether-ethyl
acetate 15:1 to 10:1 v/v) to afford 4a; yield: 99 mg (65%).
Typical Experimental Procedure for the Synthesis of
FuroACHTUNGTRENNUNG[2,3-b]furan Derivatives
Under an atmosphere of dry nitrogen, FeCl3 (3 mg,
10 mmol%) was added to a solution of aldehyde 2a (36 mg,
0.24 mmol) in 2 mL of dry CH2Cl2 at À108C. Then TMSCl
(26 mg, 0.24 mmol) was injected. The mixture was stirred
for 10 min, then a solution of VCP 6a (52 mg, 0.2 mmol) in
2 mL CH2Cl2 was added slowly. The mixture was very slowly
warmed to room temperature. After the reaction was com-
plete (monitored by TLC), the reaction mixture was
quenched with 5 mL of water and extracted with EtOAc
(3ꢂ5 mL). The combined organic layers were dried over an-
hydrous MgSO4. After filtration and removal of the solvent
under vacuum, the residues were purified with flash chroma-
tography (silica/petroleum ether-ethyl acetate, 15:1 to 10:1
v/v) to afford 7a; yield: 53 mg (64%).
[8] For the details on condition screening experiments, see
Supporting Information.
[9] a) B. H. Lipshutz, Chem. Rev. 1986, 86, 795; b) F.
Stauffer, R. Neier, Org. Lett. 2000, 2, 3535, and referen-
ces cited therein; c) S. F. Kirsch, Org. Biomol. Chem.
2006, 4, 2076; d) S. Arimitsu, J. M. Jacobsen, G. B.
Hammond, J. Org. Chem. 2008, 73, 2886; e) J. M. Aur-
recoechea, A. Durana, E. Perez, J. Org. Chem. 2008,
73, 3650.
[10] M. J. Campbell, P. D. Pohlhaus, G. Min, K. Ohmatsu,
J. S. Johnson, J. Am. Chem. Soc. 2008, 130, 9180.
[11] Selected articles about the reactions of the functional-
ized MCPs: a) S. Ma, J. Zhang, Angew. Chem. 2003,
115, 193; Angew. Chem. Int. Ed. 2003, 42, 184; b) S.
Ma, L. Lu, J. Zhang, J. Am. Chem. Soc. 2004, 126,
9645; c) M. Lautens, W. Han, J. H.-C. Liu, J. Am.
Chem. Soc. 2003, 125, 4028; d) M. E. Scott, W. Han, M.
Lautens, Org. Lett. 2004, 6, 3309.
Acknowledgements
We are grateful to the National Natural Science Foundation
of China (Project Nos. 20732005 and 20872127) and National
Basic Research Program of China (973 Program,
2009CB825300) for financial support.
References
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140
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