An efficient synthesis of polysubstituted tetrahydrofuran and indene derivatives via the Lewis acid-mediated cycloadditions of VCPs with aldehydes

Article abstract of DOI:10.1016/j.tetlet.2009.05.038

A variety of polysubstituted tetrahydrofuran and indene derivatives were prepared in moderate to excellent yields via the cycloadditions of vinylidenecyclopropanes with common aldehydes in the presence of Lewis acid. The polysubstituted tetrahydrofuran 3

Full text of DOI:10.1016/j.tetlet.2009.05.038

Tetrahedron Letters 50 (2009) 4381–4383
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An efficient synthesis of polysubstituted tetrahydrofuran and indene derivatives
via the Lewis acid-mediated cycloadditions of VCPs with aldehydes
Chenliang Su a, QingYang Liu a, Yong Ni a, Xian Huang a,b,
*
a Department of Chemistry, Zhejiang University (Xixi Campus), Hangzhou 310028, People’s Republic of China
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
A variety of polysubstituted tetrahydrofuran and indene derivatives were prepared in moderate to excel-
lent yields via the cycloadditions of vinylidenecyclopropanes with common aldehydes in the presence of
Lewis acid. The polysubstituted tetrahydrofuran 3 could undergo further transformations to the indene
product 4 and furan derivatives 5.
Received 11 March 2009
Revised 13 May 2009
Accepted 15 May 2009
Available online 20 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Vinylidenecyclopropanes (VCPs)1 show unique reactivity in or-
ganic synthesis due to the presence of the cumulated C@C double
bonds adjacent to the highly strained cyclopropyl ring, and yet
they are thermally stable.2 An attractive but often troublesome fea-
ture of VCPs is their multiform reactivities that may lead to forma-
tion of a variety of products through various reaction pathways:
selective addition to a cumulated C@C double bond3 or cleavage
of proximal4 and distal bonds.5 Thus, controlling the regio- and
stereoselective reactions of VCPs is a formidable challenge in or-
ganic synthesis.
Shi and co-workers reported the Lewis acid-catalyzed reactions
of vinylidenecyclopropanes with activated aldehyde, providing an
efficient access to polysubstituted tetrahydrofuran.5c However, the
scope of the reaction is limited. For example, all the substituents
of VCP on the cyclopropane moiety are methyl groups, and only
the activated aldehyde is allowed. Recently, we have disclosed
three kinds of Lewis acid-mediated reactions of vinylidenecyclo-
propanes and aromatic aldehydes, providing an efficient and
selective synthesis of a variety of functionalized benzo[c]fluorene,
furan, and furo[2,3-b]furan derivatives (Scheme 1).6 As a continual
research, we wish to report the selective synthesis of polysubsti-
tuted tetrahydrofuran or indene derivatives via BF3ꢀEtO2-mediated
cycloadditions of VCPs with normal aldehydes, which was con-
trolled by the electronic nature of aldehydes and the temperature.
In this Letter, we also disclosed that the substituents effects on the
polysubstituted tetrahydrofuran 3 could result in its further trans-
formation to the indene product 4 or furan derivatives 5.
yield. Further investigations indicated that when the catalyst
amount was enhanced to 30%, the yield of product was efficiently
improved to 93%.
The results summarized in Table 1 prove that this method in-
deed provides a straightforward entry to a variety of polysubstitut-
ed tetrahydrofuran in moderate to excellent yields.7 As can be seen
from Table 1, the VCP 1a smoothly reacted with normal aldehydes
2a–e affording the corresponding tetrahydrofuran derivatives in
moderate to excellent yields (Table 1, entries 1ꢁ5). We also found
that VCPs 1b–c, in which R1 = R2 = Ar and Ar is electron-poor or
electron-rich aromatic groups, the corresponding tetrahydrofurans
3g–h were obtained in good yields. For substrate 1d, in which
R1 = Ph, R2 = R3 = R4 = R5 = R6 = Me, the reaction furnished 3h in
78% yield with high selectivity (E-isomer). The configuration was
established by the NOESY studies (Fig. 1). When bicyclic VCP 1e
was employed as substrate, tetrahydrofuran 3i was obtained in
68% yield (1:1). Moreover, for substrate 1f, where R1 = R2 = R3 = Ph,
R4 = R5 = R6 = H, the polysubstituted tetrahydrofuran 3j was ob-
tained only in 31% yield along with 6-methyl-7-(4-nitrophenyl)-
5-phenyl-7H-benzo[c]fluorene in a 22% yield.
Surprisingly, for aldehyde with an electron-donating methyl-
oxyl group on the benzene ring, the tetrahydrofuran product was
observed in a trace amount, and the indene product 4a was ob-
Ph
We initiated our study by performing the reaction of 1a and 2a
in the presence of BF3ꢀEtO2 (10%) in CH2Cl2 at ꢁ10 °C. After stirring
for 48 h, polysubstituted tetrahydrofuran 3a was obtained in 46%
NOE
H
O
O2N
3h
* Corresponding author. Tel./fax: +86 571 88807077.
E-mail address: huangx@mail.hz.zj.cn (X. Huang).
Figure 1. Configurations of E-3h.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.038

4382
C. Su et al. / Tetrahedron Letters 50 (2009) 4381–4383
R2
R1
R
FeCl3,TMSCl
-10oC
X
Ar
Ar
R2
R1
H
H
Ar
Ar
Proximal Cleavage
Distal Cleavage
+
RCHO
•
X
R1,R2= -O(CH2)2
-
R
FeCl3, TMSCl, -10oC
O
O
Ar
Ar
Ar
R1,R2 = -(CH2)n-
Ar
•
1.BF3.Et2O -10oC
n
H
ZnCl2
R
O
2.TMSCl, rt
R
O
O
H
Scheme 1. Lewis acid-mediated selective cycloadditions of vinylidenecyclopropanes with aromatic aldehydes.
tained in 18% yield.5a When the reaction was performed in CH2Cl2
at rt for 24 h, 4a could be improved to 61%.
Table 1
The Lewis acid-mediated cycloadditions of VCPs 1 with aldehydes 2 to synthesis of
polysubstituted tetrahydrofurana
With these observations, we next examined the reaction of var-
ious vinylidenecyclopropanes 1 and aldehyde under identical con-
ditions.8 As indicated in Table 2, it is noteworthy that substituents
on the benzene ring of aldehydes significantly affected the reac-
tion. When the aldehydes with an electron-donating group on
the benzene ring were employed, the reaction proceeded to give
the indene derivatives 4 in moderate yields (Table 2, entries 1–3,
6). For benzaldehyde 2d, the indene derivative 4d was obtained
only in 29% yield along with the tetrahydrofuran product 3d in
32% yield. When the aldehyde 2a with an electron-withdrawing
group on the benzene ring was employed, the indene product
was obtained only in 5% yield and the polysubstituted tetrahydro-
furan 3a was observed as the main product.
R1
R6
R6
R4
R2
R5
R4
R3
R1
R2
R5
R3
30% BF3.EtO2
CH2Cl2, -10 oC
•
+ R CHO
R
O
1
2
3
Entry VCP 1b (R1/R2)
R (2)
p-NO2C6H4 (2a)
m-NO2C6H4 (2b) 12
Time (h) Yield of 3c (%)
1
2
3
4
5
6
7
C6H5/C6H5(1a)
12
3a, 93
3b, 90
3c, 61
3d, 53
3e, 63
3f, 87
3g, 85
1a
1a
1a
1a
o-NO2C6H4 (2c)
12
24
24
12
12
Ph (2d)
C2H5 (2e)
2a
We also found that the substituents effects on the polysubsti-
tuted tetrahydrofuran 3 could result in its further transformation
p-FC6H4/p-FC6H4(1b)
p-MeOC6H4/p-
MeOC6H4(1c)
Ph/Me(1d)
Ph/Ph (1e)
Ph/Ph (1f)
2a
to the indene product
4 or furan derivatives 5. When
R3 = R4 = R5 = R6 = Me, 3 could smoothly change to the indene
derivatives 4 in the presence of BF3.Et2O in ClCH2CH2Cl at 60 °C
(Eq. 1); when R4 = R6 = H, tetrahydrofuran derivatives 3j and 3k
could isomerize to furan derivatives 5 in high yield (Eq. 2).
8
2a
2a
2a
8
24
12
3h, 78 (E)
3i, 68 (1:1)
3j, 31
9d
10e
a
The reaction was carried out using 1 (0.3 mmol), 2 (0.36 mmol), and BF3ꢀEtO2
(0.09 mmol) in CH2Cl2 at ꢁ10 °C.
Unless otherwise specified, R3 = R4 = R5 = R6 = Me.
b
X
c
Isolated yields.
R3, R5 = –(CH2)4–, R4 = R6 = H, and the catalyst amount was enhanced to 70%.
d
R3 = Ph,
R4 = R5 = R6 = H,
and
6-methyl-7-(4-nitrophenyl)-5-phenyl-7H-
e
Ph
benzo[c]fluorene was obtained in 22% yield.
Ph
30% BF3.EtO2
H
ð1Þ
ClCH2CH2Cl, 60 oC
O
Ph
X
mediate D in the presence of Lewis acid at higher temperature
(path a); when R4 = R6 = H, 3 may undergo an intramolecular isom-
erization to give furan derivatives 5. The intermediate D might also
come from C by the H+ elimination (path b), which then transforms
to E. The tandem intramolecular Friedel–Crafts reaction from E fur-
nishes the indene derivatives 4.5a
In conclusion, we have developed a cycloaddition of VCPs with
normal aldehydes in the presence of Lewis acid, providing a conve-
nient access to a variety of polysubstituted tetrahydrofuran and in-
dene derivatives. The electronic nature of aldehydes and the
temperature effect play a crucial role in controlling the selectivity
of the reactions of vinylcyclopropenes and aldehyde. Attractively,
the polysubstituted tetrahydrofuran 3 could transform further to
the indene product 4 and furan derivatives 5 due to the substituent
effects. A plausible mechanism for the reactions has also been pro-
posed. Further studies to expand the scope and synthetic utility of
the method are underway.
4
X=H, 4d 81%
X=NO2, 4e 76%
Ph
Ph
R5
Ph
R5
R3
Ph
70% BF3.EtO2/TMSCl
CH2Cl2, rt, 24 h
R3
O
ð2Þ
O
O2N
O2N
5
3
1. R6=H,R3,R5= -(CH2)4-
90%
88%
2. R5=R6=H,R3= Ph
A possible mechanism is proposed as depicted in Scheme 2.5a,c,6
Initially, the electrophilic addition of intermediate A with VCPs 1
produces cationic intermediate B,5c which then rearranges to give
the cyclopropyl ring-opened intermediate C. The intramolecular
O-attacked cyclization of C produces the tetrahydrofuran product
3.5c,6 When R3 = R4 = R5 = R6 = Me, 3 can further furnish the inter-

C. Su et al. / Tetrahedron Letters 50 (2009) 4381–4383
LA
4383
R1
R6
LA
R6
R2
R6
R5
R4
R3
O
R
O
R
R1
R2
R1
R2
R5
R3
R5
R3
H
R
Path a
-LA
LA
1
C
O LA
2
R
O
R4
R4
C
3
A
B
R3=R4=
Path
b
R3=R4=R5=R6=Me
-H+
R4=R6=H
R5=R6=Me
R1
R1
R1
R2
R2
R5
R3
R2
H+
R2=Ar
4
-LA-OH
R
R
O
LA
O
Field-Craft
R
5
D
E
Scheme 2. A plausible mechanism for the cycloadditions of VCPs with common aldehydes.
Table 2
Sequential reactions for the synthesis of indene derivativesa
2. 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.
R
3. (a) Li, W.; Shi, M. Tetrahedron 2007, 63, 6654; (b) Liu, L. P.; Lu, J. M.; Shi, M. Org.
Lett. 2007, 9, 1303.
X
Ar
Ar
R
30% BF3.EtO2
CH2Cl2, rt
•
+
CHO
4. (a) Mizuno, K.; Maeda, H.; Sugita, H.; Nishioka, S.; Hirai, T.; Sugimoto, A. Org.
Lett. 2001, 3, 581; (b) Mizuno, K.; Sugita, H.; Hirai, T.; Maeda, H.; Otsuji, Y.;
Yasuda, M.; Hashiguchi, M.; Shima, K. Tetrahedron Lett. 2001, 42, 3363; (c) Shi,
M.; Lu, J. M.; Xu, G. C. Tetrahedron Lett. 2005, 46, 4745; (d) Su, C. L.; Huang, X.;
Liu, Q. Y. J. Org. Chem. 2008, 73, 6421; (e) Li, W.; Shi, M. J. Org. Chem. 2008, 73,
4151.
Ar
1
2
4
Entry
VCP 1 (R1/R2)
R (2)
Time (h)
Yield of 4b (%)
1
2
3
4
5
6
1a
1a
1a
1a
1a
1c
p-OMeC6H4 (2g)
p-CH3C6H4 (2h)
o-OMeC6H4 (2i)
2d
2a
2g
24
36
36
48
24
60
4a, 61
4b, 57
4c, 36
4d, 29c
4e, 5d
4f, 53
5. (a) Lu, J. M.; Shi, M. Org. Lett. 2006, 8, 5317; (b) Lu, J. M.; Shi, M. Org. Lett. 2007,
9, 1805; (c) Lu, J. M.; Shi, M. J. Org. Chem. 2008, 73, 2206; (d) Huang, X.; Su, C.
L.; Liu, Q. Y.; Song, Y. T. Synlett 2008, 229; (e) Shi, M.; Yao, L. F. Chem. Eur. J.
2008, 14, 8725; (f) Lu, J. M.; Zhu, Z. B.; Shi, M. Chem. Eur. J. 2009, 15, 963; (g) Li,
W.; Shi, M. J. Org. Chem. 2009, 74, 856; (h) Li, W.; Shi, M. Org. Biomol. Chem.
2009, 7, 1775.
6. Su, C. L.; Huang, X. Adv. Synth. Catal. 2009, 351, 135.
a
7. Typical procedure for synthesis of polysubstituted tetrahydrofuran 3: Under an
atmosphere of dry nitrogen, BF3ꢀEt2O (0.09 mmol) was added to a solution of
aldehyde 2 (0.36 mmol) in 2 mL of dry CH2Cl2 at ꢁ10 °C. Then a solution of VCP
1 (0.3 mmol) in 2 mL CH2Cl2 was added slowly. The progress of the reaction was
monitored by TLC, and the mixture was stirred until the starting material
disappeared. The reaction mixture was quenched with 5 mL of water and
extracted with EtOAc (3 ꢂ 5 mL). The combined organic layers were dried over
anhydrous MgSO4. Evaporation and column chromatography on silica gel
Unless otherwise specified, the reaction was carried out using 1 (0.3 mmol), 2
(0.36 mmol), and BF3ꢀEtO2 (0.09 mmol) in CH2Cl2.
b
Isolated yields.
Compound 3d was obtained in 32% yield.
Compound 3a was obtained in 71% yield.
c
d
afforded 3. Spectral data for 3a: 1H NMR (400 MHz, CDCl3):
d 8.17 (d,
Acknowledgments
J = 8.8 Hz, 2H), 7.41 (d, J = 9.2 Hz, 2H), 7.17ꢁ7.32 (m, 6H), 7.12 (t, J = 7.2 Hz,
2H), 6.88 (d, J = 7.2 Hz, 2H), 5.15 (s, 1H), 1.67 (s, 3H), 1.62 (s, 3H), 1.35 (s, 3H),
1.22 (s, 3H); 13C NMR (100 MHz, CDCl3): d 21.1, 25.0, 28.5, 29.1, 79.4, 81.6, 123.6,
126.9, 127.6, 127.8, 128.3, 128.7, 128.7, 129.7, 137.2, 140.4, 142.3, 142.9, 147.1,
151.8; IR (neat): 2967, 1598, 1517, 1343, 1266, 1010, 762, 734, 699 cmꢁ1. MS
(70 eV, EI) m/z: 425 (M+). HRMS (EI): m/z calcd for C28H27NO3 (M+): 425.1991.
Found, 425.1986.
We are grateful to the National Natural Science Foundation of
China (Project Nos. 20732005, 20872127, and J0830413) and Na-
tional Basic Research Program of China (973 Program,
2009CB825300), and CAS Academician Foundation of Zhejiang
Province for financial support.
8. Typical procedure for synthesis of indene derivatives 4: Under an atmosphere of
dry nitrogen, BF3ꢀEt2O (0.09 mmol) was added to a solution of aldehyde 2
(0.36 mmol) in 2 mL of dry CH2Cl2 at rt. Then a solution of VCP 1 (0.3 mmol) in
2 mL CH2Cl2 was added slowly. The progress of the reaction was monitored by
TLC, and the mixture was stirred until the starting material disappeared. The
reaction mixture was quenched with 5 mL of water and extracted with EtOAc
(3 ꢂ 5 mL). The combined organic layers were dried over anhydrous MgSO4.
Evaporation and column chromatography on silica gel afforded 4. Spectral data
for 4a: 1H NMR (400 MHz, CDCl3): d 7.50 (d, J = 7.6 Hz, 2H), 7.10ꢁ7.43 (m, 7H),
6.95 (d, J = 8.4 Hz, 2H), 6.75 (d, J = 8.8 Hz, 2H), 4.98 (s, 1H), 4.63 (s, 1H), 4.45 (s,
1H), 3.76 (s, 3H), 1.76 (s, 3H), 1.51 (s, 3H), 1.10 (s, 3H); 13C NMR (100 MHz,
CDCl3): d 21.5, 22.2, 23.2, 55.1, 57.3, 113.4, 115.5, 119.8, 123.9, 125.1, 126.5,
126.9, 128.2, 128.5, 129.6, 131.5, 131.6, 131.6, 136.1, 140.2, 144.5, 145.7, 147.5,
148.6, 158.1; IR (neat): 2956, 2922, 2852, 1606, 1510, 1460, 1248, 1034, 756,
700 cmꢁ1. MS (70 eV, EI) m/z: 392 (M+). HRMS (EI): m/z calcd for C29H28O (M+):
392.2140. Found, 392.2138.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.05.038.
References and notes
1. For synthesis of vinylidenecyclopropanes, see: (a) Isagawa, K.; Mizuno, K.;
Sugita, H.; Otsuji, Y. J. Chem. Soc., Perkin Trans. 1 1991, 2283. and references
therein; (b) Al-Dulayymi, J. R.; Baird, M. S. J. Chem. Soc., Perkin Trans. 1994, 1,
1547; (c) Maeda, H.; Hirai, T.; Sugimoto, A.; Mizuno, K. J. Org. Chem. 2003, 68,
7700.