Facile synthesis of tetrahydrofurans from cycloadditions of vinylidenecyclopropanes with aldehydes and further tunable transformations for the construction of furan, indene, and benzo[c]fluorene derivatives

Article abstract of DOI:10.1021/jo901836v

(Chemical Equation Presented) The cycloadditions of vinylidenecyclopropanes with aldehydes for the synthesis of tetrahydrofurans are detailed in this paper. The obtained polysubstituted tetrahydrofurans could serve as versatile intermediates to selectivel

Full text of DOI:10.1021/jo901836v

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Facile Synthesis of Tetrahydrofurans from Cycloadditions of
Vinylidenecyclopropanes with Aldehydes and Further Tunable Transformations
for the Construction of Furan, Indene, and Benzo[c]fluorene Derivatives
Chenliang Su,† Xian Huang,*,†,‡ Qingyang Liu,† and Xin Huang†
†Department of Chemistry, Zhejiang University, Hangzhou 310028, P. R. China, and ‡State Key Laboratory
of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, P. R. China
huangx@mail.hz.zj.cn; huangx@zju.edu.cn
Received August 27, 2009
The cycloadditions of vinylidenecyclopropanes with aldehydes for the synthesis of tetrahydrofurans are
detailed in this paper. The obtained polysubstituted tetrahydrofurans could serve as versatile intermediates
to selectively produce furan, indene, and benzo[c]fluorene derivatives depending on the substituents at the
tetrahydrofurans’ rings and the varied reaction conditions, which clearly exhibit insights into the synthetic
applications of tetrahydrofurans. The scope, limitations, and mechanisms of these transformations have
been discussed in detail. Attractively, these cycloadditions of vinylidenecyclopropanes with aldehydes and
the further transformations of the cycloadducts provide an efficient protocol for the construction of various
medium- and large-size ring-fused tetrahydrofuran, furan, and benzo[c]fluorene derivatives.
Introduction
components in many natural product-like scaffolds1 but also
useful building blocks in organic synthesis.2 Ring-opening
reactions of polysubstituted THFs are meaningful synthetic
transformations because they provide effective accesses to
monomers, particularly bifunctional intermediates, which
could serve as four-carbon building blocks for the formation
As one of the most important classes of heterocyclic
compounds, tetrahydrofurans (THFs) are not only significant
(1) (a) Oberlies, N. J.; Chang, C.; McLaughlin, J. L. J. Med. Chem. 1997,
40, 2102. (b) Figadere, B. Acc. Chem. Res. 1995, 28, 359. (c) Hoppe, R.;
Scharf, H.-D. Synthesis 1995, 1447. (d) Marshall, J. A.; Hinkle, K. W.;
Hagedorn, C. E. Isr. J. Chem. 1997, 37, 97. (e) Casiraghi, G.; Zanardi, F.;
Battistina, L.; Rassu, G.; Appendino, G. Chemtracts: Org. Chem. 1998, 11,
803. (f) Alali, F. Q.; Liu, X.-X.; McLaughlin, J. L. J. Nat. Prod. 1999, 62, 504.
(g) Elliott, M. C. J. Chem. Soc., Perkin Trans. 1 2002, 2301. (h) Marshall,
J. A.; Piettre, A.; Paige, M. A.; Valeriote, F. J. Org. Chem. 2003, 68, 1771.
(2) (a) Dreyfuss, P.; Dreyfuss, M. P.; Pruckmayr, G. Encyclopedia of Polymer
Science and Engineering, 2nd ed.; John Wiley & Sons: New York, 1989; Vol. 16,
p 649. (b) Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W. W.-L. Chem. Rev.
2002, 102, 2227. (c) Izumi, Y.; Matsuo, K.; Urabe, K. J. Mol. Catal. 1983, 18,
299. (b) Bhatt, M. V.; Kulkarni, S. U. Synthesis 1983, 249.
8272 J. Org. Chem. 2009, 74, 8272–8279
Published on Web 10/14/2009
DOI: 10.1021/jo901836v
r
2009 American Chemical Society

Su et al.
JOCArticle
of a variety of useful compounds.2,3 This has stimulated the
development of a number of approaches for the ring-opening
of THFs. Nonetheless, most of the known cases have resulted
in either monomers,3b,4 complex mixtures of oligomers,2b,5 or
dimerization of THFs.3a,6 On the other hand, nowadays
increasing attention has been paid to efficient generation of
complex structures in the context of diversity-oriented synth-
esis (DOS), which refers to an area with considerable impor-
tance in the disciplines of organic synthesis and chemical
biology.7,8 Thus, the development of tandem reactions utiliz-
ing THFs, which might be subsequently transformed to the
bifunctional intermediates for the construction of complex
molecular skeletons in a diversity-oriented manner, should be
an appealing strategy in organic synthesis.
transformations via controllable pathways could result in a
diversity-oriented synthesis of various polycyclic compounds.
Herein, we describe the full details on the scope and limitations
of the cycloaddition reaction of VCPs with aldehydes for the
synthesis of THFs (Figure 1, pattern 1) and report an inter-
esting class of Lewis acid-mediated tandem reactions based on
THFs to produce furan, indene, and benzo[c]fluorene deriva-
tives in a diversity-oriented manner. The scope, limitations,
and mechanistic insights of these cascade transformations of
THFs 3 were also discussed in the paper.
Vinylidenecycloproanes (VCPs),9-11 which contain an al-
lene moiety and a connected cyclopropane ring, are highly
strained but readily available and reactive substances that have
served as useful building blocks in organic synthesis. Pre-
viously, we have reported the Lewis acid-mediated cycloaddi-
tions of VCPs and aldehydes, providing an efficient and
selective synthesis of a variety of functionalized tetrahydrofur-
an, indene, furan, furo[2,3-b]furan, and benzo[c]fluorene deri-
vatives, which were controlled by the choice of varied reaction
conditions and the substituent effects (Figure 1, Scheme 1).12
During our ongoing investigations, we found that the
formed polysubstituted THFs played a crucial role in the
transformations of these adducts. Thus, the interesting ring-
opening of THFs mediated by Lewis acids and subsequent
FIGURE 1. Ring-opening models for [3 þ 2] cycloadditions of
VCPs and aldehydes.
Results and Discussion
Synthesis of Polysubstituted Tetrahydrofurans via BF3
3
Et2O-Catalyzed [3 þ 2] Cycloaddition of VCPs 1 with Alde-
hydes 2. The exploration was carried out by using 1a and
aldehyde 2a as model substrates. It was found that the use of
0.3equivofBF3 Et2OinDCMat-10 °C was suitable in terms
3
of practicality and yield of 3a (Table 1, entry 1).12b The reaction
conditions developed above were found to be broadly applic-
able to a wide variety of VCPs with four methyl groups at
the cyclopropane moiety (R3=R4=R5=R6=Me) and bicy-
clic VCPs. First, for VCPs with four methyl groups at the
cyclopropane moiety, significant substituent effects of aro-
matic aldehydes on the reaction outcome were found. The
intermolecular [3 þ 2] cycloaddition reactions proceeded read-
ily for all of the tested aldehydes 2 bearing strong electron-
withdrawing groups on the aromatic ring to give the tetrahy-
drofuran frameworks in good to excellent yields (Table 1,
entries 1-4); however, for aldehyde 2d with an electron-
donating group appended on the aromatic ring, the tetrahy-
drofuran product was observed in a trace amount (Table 1,
entry 6). Second, for the unsymmetrical VCP 1d, the reaction
produced 3f as a mixture of E/Z isomers in 76% yield (Table 1,
entry 7); to our delight, for the unsymmetrical VCP 1e (R1 =
Ph, R2=Me), the reaction furnished (E)-3g in 78% yield with
high selectivity (Table 1, entry 8). Finally, the reaction of
bicyclic VCPs 1f-i with variation in ring size also proceeded
successfully and gave a variety of ring-expansion products 3 as
mixtures of cis/trans isomers in moderate yields under the
established conditions (Table 1, entries 9-14).
(3) (a) Lo, H. C.; Han, H.; D’Souza, L. J.; Sinha, S. C.; Keinan, E. J. Am.
Chem. Soc. 2007, 129, 1246. (b) Wang, B.; Gu, Y.; Gong, W.; Kang, Y.;
Yang, L.; Suo, J. Tetrahedron 2004, 45, 6599.
(4) (a) Yasuhiro, T.; Hamada, M.; Kai, N.; Nagai, T.; Sakata, K.;
Hashimoto, M; Morishita, S. J. Heterocycl. Chem. 2000, 37, 1351. (b) Kwon,
D. W.; Kim, Y. H.; Lee, K. J. Org. Chem. 2002, 67, 9488. (c) Pri-Bar, I.; Stille,
J. K. J. Org. Chem. 1982, 47, 1215. (d) Miyoshi, N.; Hatayama, Y.; Ryu, I.;
Kamble, N.; Murai, T.; Muria, S.; Sonoda, N. Synthesis 1988, 175. (e) Guo,
Q.; Miyaji, T.; Hara, R.; Shen, B.; Takahashi, T. Tetrahedron 2002, 58, 7327.
(5) Kucera, M.; Zahradnickova0, A.; Majerova0, K. Polymer 1976, 17,
528.
(6) (a) Miles, W. H.; Ruddy, D. A.; Tinorgah, S.; Geisler, R. L. Synth.
Commun. 2004, 34, 1871. (b) Wuonola, M. A.; Sheppard, W. A. J. Org.
Chem. 1971, 36, 3640. (c) Alexander, K.; Schniepp, L. E. J. Am. Chem. Soc.
1948, 70, 1839.
(7) (a) Schreiber, S. L. Science 2000, 287, 1964. (b) Wess, G.; Urmann, M.;
Sickenberger, B. Angew. Chem., Int. Ed. 2001, 40, 3341.
(8) (a) Burke, M. D.; Schreiber, S. L. Angew. Chem. 2004, 116, 48; Angew.
Chem., Int. Ed. 2004, 43, 46. (c) Spring, D. R. Org. Biomol. Chem. 2003, 1,
3867. (d) Tan, D. S. Nat. Chem. Biol. 2005, 1, 74. (e) Spandl, R.; Bender, J. A.;
Spring, D. R. Org. Biomol. Chem. 2008, 6, 1149.
(9) For synthesis of vinylidenecyclopropanes, see: (a) Isagawa, K.;
Mizuno, K.; Sugita, H.; Otsuji, Y. J. Chem. Soc., Perkin Trans. 1 1991,
2283 and references cited therein. (b) Al-Dulayymi, J. R.; Baird, M. S. J.
Chem. Soc., Perkin Trans. 1 1994, 1547. (c) Maeda, H.; Hirai, T.; Sugimoto,
A.; Mizuno, K. J. Org. Chem. 2003, 68, 7700.
(10) For some reviews related to VCPs, see: (a) Poutsma, M. L.; Ibarbia,
P. A. J. Am. Chem. Soc. 1971, 93, 440. (b) Smadja, W. Chem. Rev. 1983, 83,
263. (c) Sydnes, L. K. Chem. Rev. 2003, 103, 1133. (d) Brandi, A.; Cicchi, S.;
Cordero, F. M.; Goti, A. Chem. Rev. 2003, 103, 1213.
(11) For recent examples related to VCPs, see: (a) Mizuno, K.; Sugita, H.;
Hirai, T.; Maeda, H.; Otsuji, Y.; Yasuda, M.; Hashiguchi, M.; Shima, K.
Tetrahedron Lett. 2001, 42, 3363. (b) Mizuno, K.; Maeda, H.; Sugita, H.;
Nishioka, S.; Hirai, T.; Sugimoto, A. Org. Lett. 2001, 3, 581. (c) Lu, J. M.;
Shi, M. Org. Lett. 2006, 8, 5317. (d) Lu, J. M.; Shi, M. Org. Lett. 2007, 9,
1805. (e) Liu, L. P.; Lu, J. M.; Shi, M. Org. Lett. 2007, 9, 1303. (f) Fall, Y;
Doucetb, H.; Santelli, M. Tetrahedron Lett. 2007, 48, 3579. (g) Huang, X; Su,
C. L.; Liu, Q. Y.; Song, Y. T. Synlett 2008, 229. (h) Su, C. L.; Huang, X.; Liu,
Q. Y. J. Org. Chem. 2008, 73, 6421. (i) Li, W.; Shi, M. J. Org. Chem. 2008, 73,
4151. (j) Lu, J. M.; Shi, M. J. Org. Chem. 2008, 73, 2206. (k) Lu, J. M.; Zhu, Z.
B.; Shi, M. Chem.;Eur. J. 2009, 15, 963. (l) Li, W.; Shi, M. J. Org. Chem.
2009, 74, 856.
Synthesis of Medium- and Large-Size Ring-Fused Fully
Substituted Furans via Aromatization of the Bicyclic THFs
Intermediates. Our previous studies demonstrated that the
bicyclic THFs 3 could transform to the corresponding furans
4 via an intramolecular isomerization. In addition, we devel-
oped one-pot reactions for the synthesis of furan deriva-
tives 4.12a Encouraged by the above results and considering
that the medium- and large-size ring-fused heterocyclic
ring systems are core structures of numerous natural
(12) (a) Su, C. L.; Huang, X. Adv. Synth. Catal. 2009, 351, 135. (b) Su, C.
L.; Liu, Q. Y.; Ni, Y.; Huang, X. Tetrahedron Lett. 2009, 50, 4381.
J. Org. Chem. Vol. 74, No. 21, 2009 8273

Su et al.
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SCHEME 1. Lewis Acid Mediated Selective Cycloadditions of VCPs and Aldehydes
TABLE 1. BF3 Et2O-Catalyzed [3 þ 2] Cycloaddition of VCPs 1 and Aldehydes 2a
3
entry
R3/R4/R5/R6
R1/R2 (1)
R (2)
time (h)
yield of 3 (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
R3 = R4 = R5 = R6 = Me
C6H5/C6H5 (1a)
1a
p-FC6H4/p-FC6H4 (1b)
p-MeC6H4/p-MeC6H4 (1c)
1a
1a
p-MeC6H4/p-ClC6H4 (1d)
Ph/Me (1e)
Ph/Ph (1f)
Ph/Ph (1g)
1g
1g
Ph/Ph (1h)
Ph/Ph (1i)
p-NO2C6H4 (2a)
m-NO2C6H4 (2b)
2a
2a
Ph (2c)
p-OMePh (2d)
2a
2a
12
12
12
12
24
24
12
8
3a, 93
3b, 90
R3 = R4 = R5 = R6 = Me
R3 = R4 = R5 = R6 = Me
3c, 87
3d, 82
3e, 53
R3 = R4 = R5 = R6 = Me
R3 = R4 = R5 = R6 = Me
R3 = R4 = R5 = R6 = Me
traceb
R3 = R4 = R5 = R6 = Me
3f, 76 (4:3)c
3g, 78 (E)
3h, 52 (2:1)d
3i, 68 (1:1)d
3j, 67 (1:1)d
3k, 53 (1.1:1)d
3l, 36 (1:1)d
3m, 43 (3:2)d
R3 = R4 = R5 = R6 = Me
R4 = R6 = H, R3, R5 = -(CH2)3-
R4 = R6 = H, R3, R5 = -(CH2)4-
R4 = R6 = H, R3, R5 = -(CH2)4-
R4 = R6 = H, R3, R5 = -(CH2)4-
R4 = R6 = H, R3, R5 = -(CH2)6-
2a
2a
5
24
12
24
24
24
2b
p-BrC6H4 (2e)
2a
2a
R4 = R6 = H, R3, R5 = -(CH2)10
-
aUnless otherwise specified, the reaction was carried out using 1 (0.3 mmol) and 2 (0.36 mmol) in CH2Cl2 under nitrogen atmosphere. b2-(2,4-
Dimethylpenta-1,3-dien-3-yl)-1-(4-methoxyphenyl)-3-phenyl-1H-indene was obtained in 18% yield along with an unidentified mixture.12b cDeduced by
1H NMR (Z/E or E/Z). dDeduced by 1H NMR (cis/trans or trans/cis), and 0.7 equiv of BF3 Et2O was added.
3
products,13 we then tried to enlarge their applications for the
synthesis of various-size ring fused furan frameworks. As can
be seen from Table 2, the corresponding six-, seven-, and
eight-membered bicyclic furan derivatives were obtained in
acceptable yields (Table 2, entries 1-6). For eight-membered
bicyclic vinylidenecyclopropane 1h, the corresponding pro-
duct was obtained in slightly lower yield (Table 2, entry 8).
Additionally, the large-size ring fused furan could also be
obtained in moderate yield (Table 2, entry 9).
A tentative reaction pathway of the cycloadditions of
VCPs with aldehydes is outlined in Scheme 2.12a The initial
electrophilic addition of intermediate A with VCPs 1 fur-
nishes cationic intermediate B, in which a strain release is
favorably accomplished by ring-opening of the intermediate
B to give C or the resonance-stabilized intermediate C1 and
C2. The followed intramolecular O-attacked cyclization of
intermediate C could produce the polysubstituted THFs 3.
For tetrahydrofurans with annulated carbocycles of various
ring sizes, in which R4 and R6 are hydrogen atoms, 3 may
undergo an intramolecular isomerization to give furan deri-
vatives 4 in the presense of BF3 Et2O/TMSCl.
3
Synthetic Application of Multisubstituted Tetrahydrofur-
ans for the Synthesis of Indenes 5 and Benzo[c]fluorenes 6. In
the course of our investigations on the applications of THFs,
it was surprising but also interesting to observe that the
rearrangement of THF 3a, which was mediated by FeCl3/
TMSCl, afforded indene product 5a in 42% yield together
with the benzo[c]fluorene 6a in 38% yield probably via the
intramolecular double-Friedel-Crafts reactions (Table 3,
entry 1). Efforts were made to optimize the reaction condi-
tions to afford one product predominantly. Gratifyingly, the
yield of 6a was sharply improved to 89%, and the formation
(13) Faulkner, D. J. Nat. Prod. Rep. 1986, 3, 1.
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TABLE 2. One-Pot Reactions for the Synthesis of Medium- and Large-Size Ring-Fused Furan Derivatives 4a
entry
R1/R2
n (1)
R (2)
time t1/t2 (h)
yield of 4 (%)
1
2
3
4
5
6
7
8
9
Ph/Ph
1 (1f)
1 (1j)
2 (1g)
2 (1g)
2 (1k)
2 (1l)
3 (1m)
4 (1h)
8 (1i)
2a
2a
2a
24/24
24/36
24/24
12/24
24/36
24/36
24/24
24/36
24/36
4a, 54
4b, 63
4c, 65
4d, 56
4e, 59
4f, 41
4g, 42
4h, 35b
4i, 45
p-MeC6H4/p-ClC6H4
Ph/Ph
Ph/Ph
p-ClC6H4 /p-ClC6H4
p-MeC6H4 /p-MeC6H4
Ph/Ph
o-NO2C6H4 (2f)
2a
2a
2b
2a
2a
Ph/Ph
Ph/Ph
aUnless otherwise specified, the reaction was carried out using 1 (0.3 mmol) and 2 (0.36 mmol) in dry CH2Cl2 under nitrogen atmosphere, after stirring
fot t1 h, 1.2 eq. TMSCl was added in the reaction, and the mixture was stirring for t2 h . b2.0 eq. TMSCl was added.
SCHEME 2. Proposed Mechanistic Pathway for Cycloadditions of VCPs with Aldehydes
TABLE 3. Optimization of the Reaction Conditions for the Applications of THF Derivativesa
entry
LA (equiv)
TMSCl (equiv)
solvent
time (h)
temp (°C)
yield of 5a (%)
yield of 6a (%)
1
2
3
4
5
6
FeCl3 (0.5)
FeCl3 (0.3)
FeCl3 (0.3)
FeCl3 (0.5)
FeCl3 (0.5)
0
1.2
2
2
10
0
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
24
18
12
12
12
24
rt
rt
rt
rt
rt
60
42
35
trace
trace
trace
76
38
44
62
89
85
trace
BF3 Et2O (0.3)
3
aThe reaction was carried out under nitrogen atmosphere on a scale of 0.1 mmol.
of 5a was suppressed to trace yield by the addition of 2.0
equiv of TMSCl (Table 3, entry 4). Decreasing the amount of
FeCl3 or TMSCl significantly decreased the yields (Table 3,
entries 2 and 3). Furthermore, in ClCH2CH2Cl (DCE) at
60 °C, the yield of indene 5a was improved to 76% and 6a
3e (R1=R2=R3=Ph) also readily participated in the reaction
and gave a good yield of the corresponding indene compound
(Table 4, entry 2). Interestingly, the reaction of stereoisomers
3f (R1=p-MeC6H4 or p-ClC6H4, R2 = p-ClC6H4 or p-Me-
C6H4, R=p-NO2C6H4, Z/E or E/Z=4:3) was also observed
as a clean transformation and produced 5c exclusively in 85%
yield. It should be noted that the intramolecular Friedel-
Crafts cyclization occurred preferentially at the p-MeC6H4
group rather than the p-ClC6H4 subtituent, probably due
to the fact that the intramolecular Friedel-Crafts reaction
takes place more easily for the electron-rich aromatic moiety
was observed in trace amount by employing BF3 Et2O as
3
catalyst (Table 3, entry 6).
Various substrates were prepared to test the generality of
the BF3 Et2O-mediated rearrangement of THFs for the
3
synthesis of polysubstituted indenes 5 under the established
conditions, and the results were summarized in Table 4. THFs
J. Org. Chem. Vol. 74, No. 21, 2009 8275

Su et al.
JOCArticle
(Table 4, entry 3). As for the (E)-3g (R1=Me, R2=Ph), the
reaction provided the corresponding product 5d in 73% yield
even in the presence of FeCl3/TMSCl (Table 4, entry 4).
observations, we next turned our efforts toward the synthesis
of medium- and large-size fused benzo[c]fluorene derivatives
from THFs. As indicated in Table 6, a variety of THFs with
annulated carbocycles of various ring sizes could be applied
to produce the corresponding medium- and large-size ring-
fused products in moderate to good yields from the mixture
substrates.
TABLE 4. Synthesis of Various Polysubstituted Indene Derivativesa
TABLE 6. Synthesis of Medium- and Large-Size Ring Fused Benzo-
[c]fluorene Derivativesa
yield of
5 (%)
entry
R1
R2
R (3)
1
2
3
4
Ph
Ph
Ph
Ph
p-NO2C6H4 (3a)
Ph (3e)
5a, 76
5b, 81
p-Me(Cl)C6H4 p-Cl(Me)C6H4 p-NO2C6H4 (3f, 4:3) 5c, 85b
Me
Ph
p-NO2C6H4 (3g)
5d, 73c
yield of
7 (%)
aUnless otherwise specified, the reaction was carried out using 3
(0.1 mmol) and BF3.Et2O (0.03 mmol) in DCE. bX=p-ClC6H4, Y=Me.
cX=Me, Y=H. the reaction was carried out using 3g (0.1 mmol), TMSCl
(0.2 mmol), FeCl3 (0.05 mmol) in CH2Cl2 at rt.
entry
Ar
R
n (3b)
time (h)
1
2
3
4
5
6
7
Ph
Ph
Ph
p-NO2C6H4
o-NO2C6H4
p-BrC6H4
p-NO2C6H4
p-NO2C6H4
p-NO2C6H4
p-NO2C6H4
1 (3h)
2 (3p)
2 (3k)
2 (3q)
3 (3r)
4 (3l)
6
6
6
6
6
6
6
7a, 71
7b, 68
7c, 60
7d, 46
7e, 57
7f, 52
7g, 61
p-MeC6H4
Ph
Ph
Ph
To demonstrate the efficiency and scope of the method for
the synthesis of benzo[c]fluorenes, we next applied the catalytic
system (Table 3, entry 4) to a variety of THFs. As shown in
Table 5, substitution the 5-position (R) of THFs including
ethyl, phenyl, and substituted phenyl groups were well toler-
ated (Table 5, entries 1-5). Second, the reactions of THFs 3
bearing the electron-donating substituents (Me) on the aro-
matic rings of R1 and R2 provided the corresponding benzo-
[c]fluorene 6f in acceptable yield (Table 5, entry 6). However,
variation in the electronic character of the substituents (R1, R2)
had a large influence on this reaction. Indeed, for substrate 3c
(R1=R2=p-FC6H5), the reaction gave the benzo[c]fluorene6g
only in 32% yield even with an increasing amount of catalyst
and prolonged reaction time (Table 5, entry 7).
8 (3m)
aThe reaction was carried out under nitrogen atmosphere on a scale of
0.1 mmol. b3 are mixture of cis/trans isomers.
Mechanistic Discussion
One of the proposed mechanisms for the formation of indene
and benzo[c]fluorene derivatives is outlined in Scheme 3. In-
itially, the reaction of THFs 3 with Lewis acid or TMSCl
generates oxonium intermediate D. In this case, furan deriva-
tives 4 are observed in trace yields when R4 and R6 are hydro-
gen atoms. A rational explanation of this drastic difference can
be attributed to the fact that the reaction of bicyclic-THFs 3
with TMSCl probably easily forms the oxonium intermediate
D, which may facilitate the ring-opening step of bicyclic-THFs
in the presence of FeCl3. Second, the ring-opening reaction of
oxonium intermediate D produces δ-allylic cationic intermedi-
ate E or the reversible cationic intermediate E1, E2, and E3.
When R1 is an electron-rich aromatic moiety or an electron-
neutral aromatic moiety (phenyl) and R2 is an electron-dificient
aromatic moiety or alkyl group (methyl), the intramolecular
Friedel-Crafts reaction with the aromatic R1 group exclusively
takes place to produce the intermediate F, probably due to the
nature of Friedel-Crafts reaction (Table 4, entries 3 and 4).14
The subsequent transformation of F leads to the formation of
intermediate G in the presence of Lewis acid. Then, the varied
reaction conditions and the substituent effects might result in
dramatic differences in the further transformations of G. In the
TABLE 5. Synthesis of Various Benzo[c]fluorene Derivativesa
yield of
time (h) 6 (%)
entry
R1/R2
C6H5/C6H5
C6H5/C6H5
C6H5/C6H5
C6H5/C6H5
C6H5/C6H5
R (3)
1
2
3
4
5
6
7
p-NO2C6H4 (3a)
m-NO2C6H4 (3b)
p-BrC6H4 (3n)
Ph (3e)
12
24
24
24
24
24
48
6a, 89
6b, 81
6c, 70
6d, 67
6e, 85
6f, 75
6g, 32b
C2H5 (3o)
p-MeC6H4/ p-MeC6H4 p-NO2C6H4 (3d)
p-FC6H4/p-FC6H4 p-NO2C6H4 (3c)
presence of BF3 Et2O in DCE at 60 °C, deprotonation of inter-
3
mediate G takes place to afford the corresponding indenes 5
when R1, R2, R3, and R4 are methyl groups. However, in a
FeCl3/TMSCl catalytic system, intermediate G undergoes in-
tramolecular Friedel-Crafts reaction to give intermediate H.
In addition, the intermediate H might also be generated via the
intramolecular Friedel-Crafts reaction from the indenes 5 in
aThe reaction was carried out under nitrogen atmosphere on a scale
of 0.1 mmol. bAfter the mixture was stirred for 24 h, another 0.5 equiv of
FeCl3 and 2.0 equiv of TMSCl were added, and an unidentified mixture
was obtained along with the product.
Synthetic Application of Multisubstituted Bicyclic Tetra-
hydrofuran for the Synthesis of Medium- and Large-Size
Ring-Fused Benzo[c]fluorene Derivatives. Inspired by these
(14) (a) Fleming, I. Chemtracts: Org. Chem. 2001, 14, 405–406. (b)
Chevrier, B.; Weis, R. Angew. Chem. 1974, 86, 12–21.
8276 J. Org. Chem. Vol. 74, No. 21, 2009

Su et al.
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SCHEME 3. Proposed Mechanistic Pathway for the Tunable Sequential Transformations of THFs
the presence of FeCl3/TMSCl (see eq 1). Then the intermediate
H is believed to proceed via a consecutive process including
protonation, 1,2-migration of the methyl group, and elimina-
tion of a propene molecule to afford the aromatized benzo-
[c]fluorene derivatives 6 when R1, R2, R3, and R4 are methyl
groups (path b, see eq 1 below).15 When R4 and R6 are hydro-
gen atoms, aromatization of the intermediate H takes place to
produce the corresponding benzo[c]fluorenes 7 (path c).
There is still another tentative pathway shown as follows:
intermediate D might undergo ring-opening step to produce
the cationic intermediate C (Scheme 2), which then may
proceed via a consecutive process including β-H elimination
and an intramolecular Friedel-Crafts reaction to give the
indene products 5.12b Probably, further transformation of
the indene derivatives 5 via a similar consecutive process
ultimately gave the benzo[c]fluorene derivatives 6 (Scheme 3,
path b). Accordingly, the ring-fused benzo[c]fluorenes 7 may
also be formed via the double-intramolecular Friedel-
Crafts reactions from the same cationic intermediate C.12a
Notably, the hypothesis that the formation of 6 may come
from a series of consecutive transformations of 5 is sup-
ported by the fact that treatment of indene product 5a with
FeCl3/TMSCl at room temperature in DCM successfully
delivered the benzo[c]fluorine 6a in 82% yield (eq 1), indicat-
ing the possibility of the mechanism shown as path b in
Scheme 3.
Conclusion
In summary, we present the comprehensive study of the
Lewis acid mediated cycloadditions of vinylidenecyclopro-
panes with aldehydes and demonstrate that the afforded
THFs could be used as versatile building blocks for the
construction of various polycyclic frameworks in controlla-
ble ways. It is meaningful in the aspects as follows: (1) It has
been revealed that the reaction pathway of Lewis acid
catalyzed transformtions of THFs was dramatically changed
depending on the varied catalytic systems and significant
influence of substituents. (2) These interesting sequential
(15) Li, W.; Shi, M.; Li, Y. X. Chem.;Eur. J. 2009, 15, 8852.
J. Org. Chem. Vol. 74, No. 21, 2009 8277

Su et al.
JOCArticle
transformations provide an efficient route to polysubstituted
furan, indene, and benzo[c]fluorene derivatives in moderate
to good yields in a diversity-oriented manner. (3) The
corresponding reaction mechanisms have been discussed
on the basis of the control experiments and related investiga-
tions. (4) These processes provide an efficient protocol for
the synthesis of various medium- and large-size ring-fused
tetrahydrofurans, furans, and benzo[c]fluorenes, which are
of current interest.16 (5) The detailed investigations on the
transformations of THFs would also provide insight into the
mechanism of the Lewis acid mediated selective reaction of
vinylidenecycloproanes with aldehydes.
General Experimental Procedures for the Synthesis of
Indene Derivatives 5. Under an atmosphere of dry nitrogen,
BF3 Et2O (30 mmol %) was added to a solution of tetrahydro-
3
furan 3 (0.1 mmol) in 2 mL of dry CH2Cl2 at room tempera-
ture. Then, the mixture was warmed to 60 °C. After the reaction
was complete (monitored by TLC), the reaction mixture
was quenched with 4 mL of water and extracted with EtOAc
(3 ꢀ 4 mL). The combined organic layers were dried over
anhydrous MgSO4. After filtration and removal of the sol-
vent in vacuo, the residues were purified with flash chromato-
graphy to afford 5.
3-(4-Chlorophenyl)-2-(2,4-dimethylpenta-1,3-dien-3-yl)-6-
methyl-1-(4-nitrophenyl)-1H-indene (5c). H NMR (400 MHz,
1
CDCl3): δ 8.10 (d, J = 8.8 Hz, 2H), 7.40-7.49 (m, 4H), 7.26 (d,
J = 7.6 Hz, 1H), 7.21 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 7.6 Hz,
1H), 6.97 (s, 1H), 5.04 (s, 1H), 4.74 (s, 1H), 4.41 (s, 1H), 2.32 (s,
3H), 1.81 (s, 3H), 1.55 (s, 3H), 1.14 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 21.3, 21.5, 22.4, 23.2, 57.4, 116.2, 119.9, 123.5, 124.9,
128.0, 128.7, 129.5, 129.8, 131.2, 132.6, 133.1, 134.3, 135.8,
140.5, 141.6, 145.3, 146.8, 147.2, 148.2. IR (neat): 2916, 1601,
1521, 1091, 824, 741, 693 cm-1. MS (70 eV, EI) m/z: 455 (Mþ).
HRMS (EI): m/z calcd for C29H26ClNO2 (Mþ) 455.1652, found
455.1647.
General Experimental Procedures for the Synthesis of
Benzo[c]fluorene Derivatives 6. Under an atmosphere of
dry nitrogen, TMSCl (0.2 mmol) was injected to a solution
of tetrahydrofuran 3 (0.1 mmol) in 2 mL of dry CH2Cl2
at rt. The mixture was stirred for 5 min, and then FeCl3 (0.05
mmol) was added. After being stirred for the specified time
(monitored by TLC) at rt, the reaction mixture was quenched
with 4 mL of water and extracted with EtOAc (3 ꢀ 4 mL).
The combined organic layers were dried over anhydrous
MgSO4. After filtration and removal of the solvent in
vacuo, the residues were purified with flash chromatography
to afford 6.
Experimental Section
General Experimental Procedures for the Synthesis of Tetra-
hydrofuran Derivatives 3. Under an atmosphere of dry nitrogen,
BF3 Et2O (0.09 mmol) was added to a solution of aldehyde 2
3
(0.36 mmol) in 2 mL of dry CH2Cl2 at -10 °C. Then a solution of
VCP 1 (0.3 mmol) in 2 mL of CH2Cl2 was added slowly. The
progress of the reaction was monitored by TLC analysis until
the starting material was consumed completely. The reaction
mixture was quenched with 5 mL of water and extracted with
EtOAc (3 ꢀ 5 mL). The combined organic layers were dried over
anhydrous MgSO4. Evaporation and column chromatography
on silica gel afforded 3.
4-(Di-p-tolylmethylene)-2,2-dimethyl-5-(4-nitrophenyl)-3-(propan-
2-ylidene)tetrahydrofuran (3d). 1H NMR (400 MHz, CDCl3): δ 8.16
(d, J=6.8 Hz, 2H), 7.42 (d, J=6.8 Hz, 2H), 7.02-7.13 (m, 4H),
6.84-6.96 (m, 2H), 6.66-6.80 (m, 2H), 5.12 (s, 1H), 2.33 (s, 3H),
2.28 (s, 3H), 1.65 (s, 3H), 1.59 (s, 3H), 1.31 (s, 3H), 1.21 (s, 3H). 13
C
NMR (100 MHz, CDCl3): δ 21.0, 21.1, 21.7, 25.0, 28.5, 29.51, 79.5,
81.5, 123.5, 128.0, 128.4, 128.7, 128.9, 129.6, 136.2, 136.5, 137.3,
139.6, 140.1, 140.4, 147.0, 152.1. IR (neat): 2953, 2917, 2850, 1599,
1462, 1342, 1180, 1021, 823, 768 cm-1. MS (70 eV, EI): m/z 453
(Mþ). HRMS(EI):m/zcalcd for C30H31NO3 (Mþ) 453.2304, found
453.2309.
5,6-Dimethyl-7-(4-nitrophenyl)-7H-benzo[c]fluorene (6a). 1H
NMR (400 MHz, CDCl3): δ 8.83 (d, J = 8.0 Hz, 1H), 8.38 (d,
J = 7.6 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 8.8 Hz,
2H), 7.57-7.69 (m, 2H), 7.42-7.49 (m, 1H), 7.16-7.29 (m, 4H),
5.19 (s, 1H), 2.63 (s, 3H), 2.17 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 15.0, 17.3, 54.4, 123.0, 124.1, 124.3, 124.8, 125.1,
125.6, 125.6, 126.2, 127.8, 128.2, 128.5, 130.4, 132.4, 133.4,
134.4, 141.8, 144.7, 146.8, 147.7, 149.8. IR (neat): 2923, 2852,
1593, 1518, 1342, 1275, 1260, 856, 721 cm-1. MS (70 eV, EI) m/z:
365 (Mþ). HRMS (EI): m/z calcd for C25H19NO2 (Mþ)
365.1416, found 365.1425.
General Experimental Procedures for the Synthesis of Ring-
Fused Benzo[c]fluorene Derivatives 7. Under an atmosphere
of dry nitrogen, TMSCl (0.2 mmol) was injected to a solution
of bicyclic tetrahydrofuran 3 (0.1 mmol) in 2 mL of dry CH2-
Cl2 at rt. The mixture was stirred for 5 min, and then FeCl3
(0.05 mmol) was added. After being stirred for the speci-
fied time (monitored by TLC) at rt, the reaction mixture was
quenched with 4 mL of water and extracted with EtOAc (3 ꢀ
4 mL). The combined organic layers were dried over anhydrous
MgSO4. After filtration and removal of the solvent in vacuo,
the residues were purified with flash chromatography to
afford 7.
General Experimental Procedures for the One-Pot Reaction
Synthesis of Furan Derivatives 4. Under an atmosphere of dry
nitrogen, bicyclic VCP 1 (0.3 mmol) was added to a solution of
aldehyde 2 (0.36 mmol) in 5 mL of dry CH2Cl2 at -10 °C. Then
BF3 Et2O (70 mmol %) was injected. After stirring the mixture
3
was stirred for the specified time (monitored by TLC), the
required TMSCl was injected and the reaction temperature
was warmed to rt. After being stirred for another 24-36 h, the
reaction mixture was quenched with 5 mL of water and ex-
tracted with EtOAc (3 ꢀ 5 mL). The combined organic layers
were dried over anhydrous MgSO4. After filtration and removal
of the solvent in vacuo, the residues were purified with flash
chromatography to afford 4.
3-((4-Chlorophenyl)(p-tolyl)methyl)-2-(4-nitrophenyl)-4,5,6,7-
tetrahydrobenzofuran (4b). 1H NMR (400 MHz, CDCl3): δ 8.14
(d, J = 9.2 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.4 Hz,
2H), 7.13 (d, J = 7.6 Hz, 2H), 6.98-7.05 (m, 4H), 5.65 (s, 1H),
2.66 (t, J = 5.8 Hz, 2H), 2.34 (s, 3H), 1.69-1.80 (m, 3H),
1.50-1.65 (m, 3H). 13C NMR (100 MHz, CDCl3): δ 21.0,
22.3, 22.8, 23.5, 29.6, 46.4, 120.6, 123.9, 125.8, 126.0, 128.4,
128.9, 129.3, 130.5, 132.3, 136.5, 137.3, 138.2, 141.0, 145.5,
153.0, 153.3. IR (neat): 2925, 2856, 1591, 1508, 1445, 1333,
1090, 909, 851, 801, 731 cm-1. MS (70 eV, EI): m/z 457 (Mþ).
HRMS (EI): m/z calcd for C28H24NO3Cl (Mþ) 457.1445, found
457.1452.
9-(4-Nitrophenyl)-6,7,8,9-tetrahydro-5H-indeno[2,1-l]phena-
nthrene (7a). 1H NMR (400 MHz, CDCl3): δ 8.81 (d, J = 8.4 Hz,
1H), 8.36 (d, J = 8.0 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 8.06 (d,
J = 8.8 Hz, 2H), 7.56-7.68 (m, 2H), 7.41-7.47 (m, 1H), 7.22 (d,
J = 7.6 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 5.06 (s, 1H), 3.18-
3.28 (m, 1H), 3.03-3.15 (m, 1H), 2.63-2.74 (m, 1H), 2.08-2.19
(m, 1H), 1.94-2.02 (m, 1H), 1.60-1.85 (m, 3H). 13C NMR (100
MHz, CDCl3): δ 22.5, 22.9, 26.4, 28.1, 53.9, 123.0, 124.0, 124.1,
124.3, 124.9, 125.7, 125.7, 126.2, 127.8, 128.1, 128.7, 131.7,
132.8, 133.2, 134.3, 141.8, 144.3, 146.8, 148.0, 149.5. IR (neat):
€
(16) (a) Breitenbach, J.; Boosfeld, J.; Vogtle F. In Comprehensive Supramo-
lecular Chemistry; Lehn, J. M., Ed.; Pergamon: New York, 1996; Vol. 2, pp
29-67. (b) Dietrich, B.; Viout, P.; Lehn, J. M. Macrocyclic Chemistry; VCH:
Weinheim, 1993.
8278 J. Org. Chem. Vol. 74, No. 21, 2009

Su et al.
JOCArticle
2955, 2921, 1596, 1515, 1460, 1344, 1072, 756, 726 cm-1. MS (70
eV, EI) m/z: 391 (Mþ). HRMS (EI): m/z calcd for C27H21NO2
(Mþ) 391.1572, found 391.1568.
of China (973 Program, 2009CB825300) for financial sup-
port.
Supporting Information Available: General experimental
procedures and spectroscopic data for all compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
Acknowledgment. We are grateful to the National Natur-
al Science Foundation of China (Project Nos. 20732005
and 20872127) and the National Basic Research Program
J. Org. Chem. Vol. 74, No. 21, 2009 8279