Lewis acid catalyzed reactions of vinylidenecyclopropanes with activated carbon-oxygen double bond: A facile synthetic protocol for functionalized tetrahydrofuran and 3,6-dihydropyran derivatives

Article abstract of DOI:10.1021/jo702518u

(Chemical Equation Presented) A number of functionalized tetrahydrofuran and 3,6-dihydropyran derivatives are prepared selectively in moderate to good yields by the reactions of vinylidenecyclopropanes with activated carbonyl compounds in the presence of

Full text of DOI:10.1021/jo702518u

Lewis Acid Catalyzed Reactions of Vinylidenecyclopropanes with
Activated Carbon-Oxygen Double Bond: A Facile Synthetic
Protocol for Functionalized Tetrahydrofuran and 3,6-Dihydropyran
Derivatives
Jian-Mei Lu and Min Shi*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
mshi@mail.sioc.ac.cn
ReceiVed NoVember 23, 2007
A number of functionalized tetrahydrofuran and 3,6-dihydropyran derivatives are prepared selectively in
moderate to good yields by the reactions of vinylidenecyclopropanes with activated carbonyl compounds
in the presence of Lewis acid.
Introduction
yields upon heating or photoirradiation.3 Recently, we have been
investigating the Lewis acid or Brønsted acid catalyzed/mediated
ring-opening reactions of vinylidenecyclopropanes.4 Previously,
we reported the Lewis acid catalyzed reaction of vinylidenecy-
clopropanes with acetals to produce indene derivatives in good
yields (Scheme 1).5 Moreover, we recently also disclosed the
Lewis acid catalyzed reaction of vinylidenecyclopropanes with
activated imines [ethyl (arylimino)acetates] to afford pyrrolidine
and 1,2,3,4-tetrahydroquinoline derivatives in moderate to good
yields via [3 + 2] cycloaddition and aza-Diels-Alder reaction,
respectively (Scheme 2).6
Vinylidenecyclopropanes 11 are one of the most remarkable
organic compounds known. They have an allene moiety
connected by a cyclopropane ring, and yet they are thermally
stable and reactive substances. Thermal and photochemical
skeletal conversions of vinylidenecyclopropanes 1 have attracted
much attention from mechanistic, theoretical, spectroscopic, and
synthetic viewpoints.2 Vinylidenecyclopropanes can also easily
react with carbon-carbon or carbon-heteroatom multiple bonds
to produce [3 + 2] or [2 + 2] cycloaddition products in good
During our ongoing investigation, we found that functional-
ized tetrahydrofuran and 3,6-dihydropyran derivatives 9 and 10
* To whom correspondence should be addressed. Fax: 86-21-64166128.
(1) For the synthesis of vinylidenecyclopropanes, see: (a) Isagawa, K.;
Mizuno, K.; Sugita, H.; Otsuji, Y. J. Chem. Soc., Perkin Trans. 1 1991,
2283-2285 and references therein. (b) Al-Dulayymi, J. R.; Baird, M. S. J.
Chem. Soc., Perkin Trans 1 1994, 1547-1548. For some other papers related
to vinylidenecyclopropanes, see: (c) Maeda, H.; Hirai, T.; Sugimoto, A.;
Mizuno, K. J. Org. Chem. 2003, 68, 7700-7706. (d) Pasto, D. J.; Brophy,
J. E. J. Org. Chem. 1991, 56, 4554-4556.
(3) (a) Mizuno, K.; Sugita, H.; Hirai, T.; Maeda, H.; Otsuji, Y.; Yasuda,
M.; Hashiguchi, M.; Shima, K. Tetrahedron Lett. 2001, 42, 3363-3366.
(b) Mizuno, K.; Nire, K.; Sugita, H.; Otsuji, Y. Tetrahedron Lett. 1993,
34, 6563-6566. (c) Sasaki, T.; Eguchi, S.; Ogawa, T. J. Am. Chem. Soc.
1975, 97, 4413-4414.
(2) (a) Poutsma, M. L.; Ibarbia, P. A. J. Am. Chem. Soc. 1971, 93, 440-
450. (b) Smadja, W. Chem. ReV. 1983, 83, 263-320. (c) Hendrick, M. E.;
Hardie, J. A.; Jones, M. J. Org. Chem. 1971, 36, 3061-3062. (d) Sugita,
H.; Mizuno, K.; Saito, T.; Isagawa, K.; Otsuji, Y. Tetrahedron Lett. 1992,
33, 2539-2542. (e) Mizuno, K.; Sugita, H.; Kamada, T.; Otsuji, Y. Chem.
Lett. 1994, 449-452 and references therein. (f) Sydnes, L. K. Chem. ReV.
2003, 103, 1133-1150.
(4) (a) Lu, J.-M.; Shi, M. Tetrahedron 2007, 63, 7545-7549. (b) Zhang,
Y.-P.; Lu, J.-M.; Xu, G.-X. J. Org. Chem. 2007, 72, 509-516. (c) Shao,
L.-X.; Zhang, Y.-P.; Qi, M.-H.; Shi, M. Org. Lett. 2007, 9, 117-120. (d)
Xu, G.-C.; Liu, L.-P.; Lu, J.-M.; Shi, M. J. Am. Chem. Soc. 2005, 127,
14552-14553. (e) Xu, G.-C.; Ma, M.; Liu, L.-P.; Shi, M. Synlett 2005,
1869-1872.
(5) Lu, J.-M.; Shi, M. Org. Lett. 2006, 8, 5317-5320.
10.1021/jo702518u CCC: $40.75 © 2008 American Chemical Society
Published on Web 02/27/2008
2206
J. Org. Chem. 2008, 73, 2206-2210

Lewis Acid-Catalyzed Reactions of Vinylidenecyclopropanes
SCHEME 1. Sc(OTf)3-Catalyzed Reaction of Vinylidenecyclopropanes 1 with Acetals 2
SCHEME 2. BF3‚OEt2-Catalyzed Reaction of
Vinylidenecyclopropanes 1 with Imines 5
SCHEME 3. Proposed Mechanism for the Reaction of
Vinylidenecyclopropanes 1 with 8a
TABLE 1. BF3‚OEt2-Catalyzed Reaction of
with 8a under these reaction conditions. The results of these
experiments are summarized in Table 1. As can been seen from
Table 1, with respect to the electron-rich and electron-poor
vinylidenecyclopropanes 1 (R1 and R2), the corresponding
tetrahydrofuran derivatives 9 were obtained in moderate to good
yields (Table 1). For unsymmetrical vinylidenecyclopropanes
1d and 1e (R1 * R2), the corresponding tetrahydrofuran
derivatives 9d and 9e were obtained as mixtures of E/Z isomers
in 99% and 90% yields, respectively (Table 1, entries 4 and 5).
For vinylidenecyclopropane 1g (R1 ) R2 ) p-MeOC6H4), the
product 9g was obtained in 77% yield along with 7% of a
naphthalene derivative as a byproduct (Table 1, entry 7).4e
Above reaction is believed to proceed via a Lewis acid catalyzed
[3 + 2] cycloaddition pathway.6a Intermediate A, generated from
8a and BF3·OEt2, reacts with 1 to produce intermediate B, which
undergoes ring-opening to afford intermediate C. Cyclization
of intermediate C furnishes [3 + 2] cycloadduct 9 (Scheme 3).
Interestingly, when diethyl ketomalonate 8b (R ) CO2Et)
was used as the activated carbonyl compound, 3,6-dihydropyran
derivative 10a was obtained in DCE at 60 °C in 40% yield in
the presence of Nd(OTf)3 (10 mol %) (Table 2, entry 1). Using
diphenylvinylidenecyclopropane 1a as the substrate, we exam-
ined its reaction with diethyl ketomalonate 8b under a variety
of reaction conditions to develop the best one. The results are
summarized in Table 2. We found that the reaction proceeded
smoothly in hexane to give the cyclic product 10a in 67% yield
in the presence of Nd(OTf)3 (10 mol %) at 60 °C within 4 h
(Table 2, entry 9). Using THF as the solvent, the cyclic and
acyclic products 10a and 11a were obtained in 31% and 29%
yields, respectively (Table 2, entry 10). When MeCN was used
as the solvent, only acyclic product 11a was obtained in 38%
yield (Table 2, entry 11). Using other Lewis acids, such as Gd-
(OTf)3, Sc(OTf)3, Bi(OTf)3·9H2O, Cu(OTf)2, In(OTf)3, and Sn-
(OTf)2, under identical conditions, 10a was obtained in some-
what lower yields as a sole product (Table 2, entries 12-17).
In the presence of Lewis acids such as La(OTf)3, Yb(OTf)3,
Vinylidenecyclopropanes 1 with 8a
entrya
1 (R1/R2)
1a (C6H5/C6H5)
1b (p-ClC6H4/p-ClC6H4)
1c (p-FC6H4/p-FC6H4)
1d (p-ClC6H4/C6H5)
1e (p-MeOC6H4/C6H5)
1f (p-MeC6H4/p-MeC6H4)
1g (p-MeOC6H4/p-MeOC6H4)
yieldb (%)
9a, 99
1
2
3
4
5
6
7
9b, 94
9c, 97
9d, 99 (1.5:1)c
9e, 90 (2.0:1)c
9f, 98
9g, 77d
a All reactions were carried out using 1 (0.2 mmol), 8a (0.3 mmol), and
BF3‚OEt2 (10 mol %) in DCE (2.0 mL) at 60 °C. b Isolated yields. c E/Z or
Z/E. d 7% of the rearrangement product was obtained.
could be obtained in good to high yields via the Lewis acid
catalyzed reactions of vinylidenecyclopropanes 1 with activated
carbonyl compounds 8 under mild conditions. Herein, we wish
to report these results.
Results and Discussion
Initial examination revealed that the reaction of vinylidenecy-
clopropane 1a with ethyl glyoxylate 8a (R ) H) proceeded
smoothly in 1,2-dichloroethane (DCE) at 60 °C to give the
corresponding tetrahydrofuran derivative 9a in 99% yield in the
presence of BF3·OEt2 (10 mol %) within 1 h (Table 1, entry 1).
Therefore, we did not further optimize the reaction conditions
and directly examined a variety of vinylidenecyclopropanes 1
(6) (a) Lu, J.-M.; Shi, M. Org. Lett. 2007, 9, 1805-1808. (b) Shao, L.-
X.; Xu, B.; Shi, M. Org. Lett. 2003, 5, 579-582. (c) Shao, L.-X.; Shi, M.
AdV. Synth. Catal. 2003, 345, 963-966.
J. Org. Chem, Vol. 73, No. 6, 2008 2207

Lu and Shi
TABLE 2. Optimization of the Reaction Conditions of 1a with 8b
TABLE 3. Nd(OTf)3-Catalyzed Reaction of
Vinylidenecyclopropanes 1 with Diethyl Ketomalonate 8b
yieldb (%)
entrya
solvent
DCE
catalyst
time (h)
10a
11a
entrya
1 (R1/R2)
yieldb (%)/10
1
2c
3d
4
Nd(OTf)3
Nd(OTf)3
Nd(OTf)3
Nd(OTf)3
Nd(OTf)3
Nd(OTf)3
Nd(OTf)3
Nd(OTf)3
Nd(OTf)3
Nd(OTf)3
Nd(OTf)3
Gd(OTf)3
Sc(OTf)3
Bi(OTf)3‚9H2O
Cu(OTf)2
In(OTf)3
4
4
4
4
4
4
5
4
4
23
29
4
4
4
4
3
5
24
4
40
54
59
57
60
67
45
60
64
31
1
2
3
4
5
6
7
8
9
1b (p-ClC6H4/p-ClC6H4)
1c (p-FC6H4/p-FC6H4)
1d (p-ClC6H4/C6H5)
1e (p-MeOC6H4/C6H5)
1f (p-MeC6H4/p-MeC6H4)
1h (p-MeC6H4/C6H5)
1i (m-Me, p-MeC6H3/C6H5)
1j (p-MeC6H4/Me)
10b, 63
10c, 66
10d, 62c
10e, 52c
10f, 62
toluene
toluene
chlorobenzene
toluene
hexane
CH2Cl2
benzene
cyclohexane
THF
5
10g, 62c
10h, 64c
10i, 39d
10j, 30e
6
7e
8
9
1k (p-BrC6H4/Me)
10
11f
12
13
14
15
16
17
18
19
20
21g
29
38
a All reactions were carried out using 1 (0.3 mmol), 8b (0.9 mmol),
Nd(OTf)3 (10 mol %) and hexane (3 mL) at 60 °C for 4 h. b Isolated yields.
c E/Z ) 1:1. d E/Z ) 10:11. e E/Z ) 5:4.
MeCN
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
60
57
59
45
60
66
42
50
47
SCHEME 5. Yb(OTf)3-Catalyzed Reaction of
Vinylidenecyclopropane 1a with Diethyl Ketomalonate 8b
Sn(OTf)2
La(OTf)3
Yb(OTf)3
Eu(OTf)3
BF3‚OEt2
10
11
19
16
5
24
a Unless otherwise specified, all reactions were carried out using 1a (0.3
mmol), 8b (0.9 mmol), catalyst (10 mol %), and solvent (3 mL) at 60 °C.
b Isolated yields. c The ratio of 1a and 8b is 1:2. d The ratio of 1a and 8b
is 1:3.5. e The reaction was carried out under reflux temperature. f 17% of
1a was recovered. g 62% of 1a was recovered.
SCHEME 4. Transformation of 10a with Br2
and Eu(OTf)3, 10a and 11a were both obtained in good total
yields with 10a as the major product (Table 2, entries 18-20),
and when BF3·OEt2 was used as the catalyst, only 11a was
obtained in 16% yield as a sole product (Table 2, entry 21).
Different Lewis acidities between these metal triflates caused
such difference on the catalytic abilities. When BF3·OEt2 was
used as a Lewis acid, the coordination between the newly formed
hydroxy group of 11a with BF3·OEt2 might be able to take place,
leading to the formation of 11a as a sole product in 16% yield.
However, when Nd(OTf)3 was employed as a Lewis acid under
identical conditions, such coordination could be weak and the
formation of 10a was facilitated in 67% yield exclusively.
Transformation of 10a using Br2 (1.5 equiv) as the bromi-
nating agent afforded the product 12 in 86% yield (Scheme 4).
The structure of 12 was determined unambiguously by an X-ray
diffraction (see the Supporting Information), from which we
can further confirm the structure of product 10a. The structure
of 11a was determined by 1H and 13C NMR spectroscopic data,
HRMS, NOESY, HMBC, and HMQC analytic data (see the
Supporting Information).
to evaluate the scope of this reaction. As can be seen from Table
3, for almost all cases in which R1, R2 ) aryl group, the
corresponding cyclic product 3,6-dihydropyran derivatives 10
can be obtained in moderate yields within 4 h as the sole
products. For vinylidenecyclopropanes 1j and 1k in which R1
) aryl, R2 ) methyl, the reaction can also proceed smoothly to
give the corresponding 3,6-dihydropyran derivatives 10i and 10j
in 39% and 30% yields, respectively (Table 3, entries 8 and 9).
For the reactions with unsymmetrical vinylidenecyclopropanes
1 as the substrates (R1 * R2), products 10 were obtained as
mixtures of E- and Z-isomers (Table 3, entries 3, 4, 6, and 7).
When 8c (R ) Me) was used as the activated carbonyl
compound, no product was detected. It should be noted here
that only substrates 1 with four methyl groups on the cyclopropyl
ring can undergo this transformation and this result will be
further confirmed with the explanation of the reaction mecha-
nism.
In order to clarify the mechanism of this reaction, the reaction
of 1a with 8b was carried out in toluene at 60 °C using Yb-
(OTf)3 (10 mol %) as the catalyst. The reaction was completed
within 5 h; not only 10a and 11a were obtained in 7% and
With the optimized reaction conditions in hand, we next
examined an assortment of starting materials 1 and 8b in order
2208 J. Org. Chem., Vol. 73, No. 6, 2008

Lewis Acid-Catalyzed Reactions of Vinylidenecyclopropanes
SCHEME 6. Yb(OTf)3-Catalyzed Reaction of 13a with Diethyl Ketomalonate 8b
SCHEME 7. Transformation of 11a to 10a
SCHEME 9. Deuterium-Labeling Experiment of Reaction
of 1a-d with 8b
39% yields, respectively, but also triene 13a was obtained in
12% yield. When the reaction time was prolonged to 22 h, only
10a was obtained in 54% yield as the sole product (Scheme 5).
The control experiment indicated that triene 13a could also be
obtained in the presence of Lewis acid without 8b. When trienes
13a and 8b were used as the substrates under identical reaction
conditions, products 10a and 11a were obtained in 25% and
57% yields within 18 h, respectively, suggesting that a carbo-
nyl-ene reaction7 is involved in this transformation (Scheme
6). Further studies revealed that acyclic product 11a could be
easily transformed to cyclic products 10a under identical
conditions, indicating that 10a is derived from the ene reaction
product 11a (Scheme 7). The product 11a could also be detected
by GLC when the reaction was carried out using Nd(OTf)3 as
the catalyst (Supporting Information).
A plausible mechanism for the formation of 3,6-dihydropyran
derivatives 10 is outlined in Scheme 8 based on the above
control experiments. The coordination of 1 to the Lewis acid
initially gives the vinyl group stabilized cyclopropyl cationic
intermediate D, which results in the formation of cyclopropane
ring-opened zwitterionic intermediate E or the resonance-
stabilized zwitterionic intermediate F. Deprotonation of inter-
mediate F and reprotonation of intermediate G will give triene
13. The carbonyl-ene reaction7 of triene 13 with diethyl
ketomalonate 8b, which is activated by Lewis acid, generates
homoallylic alcohol 11. The subsequent ring closure of ho-
moallylic alcohol 11 and protonation of intermediate H produces
the product 10. The deuterium-labeling experiment was also
examined under the standard conditions (Scheme 9). It was
found that deuterium incorporation occurred at the olefinic
1
proton of C2 (D content 44%) based on the corresponding H
NMR spectroscopic data. The observation of 44% D content at
C2 supports the mechanism shown in Scheme 9 because it is
derived from the deprotonation of intermediate F and reproto-
nation of intermediate G. In addition, a total primary isotope
effect of kH/kD ) 5.8 was observed for this deuterium labeling
experiment, further suggesting the ene reaction pathway (see
the Supporting Information for details). Since this reaction
includes three steps, products 10 are produced in moderate
yields.
In conclusion, we have developed a Lewis acid-catalyzed
synthesis of functionalized tetrahydrofuran and 3,6-dihydropyran
derivatives by the reaction of vinylidenecyclopropanes 1 with
activated carbonyl compounds 8 under mild conditions. The
different products 9 and 10 may be caused by the electronic
SCHEME 8. Proposed Mechanism for the Formation of 10 and 11
J. Org. Chem, Vol. 73, No. 6, 2008 2209

Lu and Shi
TMS) δ 14.1, 21.0, 24.8, 28.2, 28.6, 60.8, 78.3, 82.3, 126.7, 127.6,
127.8, 128.1, 128.9, 129.8, 129.9, 135.1, 135.8, 1402, 142.6, 143.0,
172.4; IR (CH2Cl2) ν 3056, 2979, 2906, 1738, 1492, 1444, 1362,
1277, 1189, 1170, 1132, 1032, 771, 748, 701 cm-1; MS m/z 376
(12), 303 (100), 105 (50), 275 (37), 229 (22.3), 77 (21.6), 215
(19.6), 167 (19.5), 233 (18); HRMS (EI) calcd for C25H28O3
376.2038, found 376.2072.
nature and steric effect of 8. Efforts are in progress to elucidate
further mechanistic details of these reactions and to understand
their scope and limitations.
Experimental Section
General Procedure for Lewis Acid Catalyzed Reaction of
Vinylidenecyclopropanes 1 with Ethyl Glyoxylate 8a. Under an
argon atmosphere, vinylidenecyclopropane 1 (0.2 mmol), ethyl
glyoxylate 8a (0.3 mmol), and DCE (2.0 mL) were added into a
Schlenk tube, and then BF3·OEt2 (10 mol %) was added. The
reaction mixture was stirred at 60 °C for 1.0 h, and then the solvent
was removed under reduced pressure and the residue was purified
by a flash column chromatography.
1
Compound 10a: colorless liquid; H NMR (CDCl3, 300 MHz,
TMS) δ 1.25 (t, J ) 6.9 Hz, 6H, 2CH3), 1.31 (s, 3H, CH3), 1.46
(s, 6H, 2CH3), 2.43 (s, 2H), 4.21 (q, J ) 6.9 Hz, 4H), 6.20 (d, J )
1.2 Hz, 1H), 7.15-7.17 (m, 2H, Ar), 7.23-7.31 (m, 8H, Ar); 13C
NMR (CDCl3, 75 MHz, TMS) δ 13.9, 21.5, 29.0, 33.9, 61.7, 77.6,
78.2, 124.9, 125.0, 127.0, 127.4, 127.97, 128.02, 128.2, 129.7,
133.2, 140.5, 143.9, 145.1, 169.5; IR (CH2Cl2) ν 2980, 2933, 1767,
1743, 1493, 1465, 1444, 1367, 1277, 1216, 1180, 1158, 1113, 1078,
1061, 1024, 774, 699 cm-1; MS (MALDI) m/z 449 (M+ + 1);
HRMS (MALDI) calcd for C28H32O5Na 471.2142, found 471.2150.
General Procedure for Lewis Acid Catalyzed Reaction of
Vinylidenecyclopropanes 1 with Diethyl Ketomalonate 8b. Under
an argon atmosphere, vinylidenecyclopropane 1 (0.3 mmol), diethyl
ketomalonate 8b (0.9 mmol), Nd(OTf)3 (10 mol %), and hexane
(3.0 mL) were added into a Schlenk tube. The reaction mixture
was stirred at 60 °C for 4.0 h, and then the solvent was removed
under reduced pressure and the residue was purified by flash column
chromatography.
Acknowledgment. We thank the Shanghai Municipal Com-
mittee of Science and Technology (04JC14083, 06XD14005)
and the National Natural Science Foundation of China for
financial support (20472096, 203900502, 20672127, and
20732008).
Compound 9a: colorless oil; 1H NMR (CDCl3, 300 MHz, TMS)
δ 1.10 (s, 3H, CH3), 1.28 (t, J ) 7.2 Hz, 3H), 1.58 (s, 3H, CH3),
1.60 (s, 3H, CH3), 1.62 (s, 3H, CH3), 4.18 (q, J ) 7.2 Hz, 2H),
4.50 (s, 1H), 7.15-7.28 (m, 10H, Ar); 13C NMR (CDCl3, 75 MHz,
Supporting Information Available: Spectroscopic data of all
new compounds, detailed descriptions of experimental procedures,
and X-ray data for compound 12. This material is available free of
charge via the Internet at http://pubs.acs.org.
(7) (a) Yang, D.; Yang, M.; Zhou, N.-Y. Org. Lett. 2003, 5, 3749-
3752. (b) Evans, D. A.; Tregay, S. W.; Burgey, C. S.; Paras, N. A.;
Vojkovsky, T. J. Am. Chem. Soc. 2000, 122, 7936-7943.
JO702518U
2210 J. Org. Chem., Vol. 73, No. 6, 2008