Thermally induced electrocyclic reaction of methylenecyclopropane methylene diketone derivatives: A facile method for the synthesis of spiro[2.5]octa-3,5- dienes

Article abstract of DOI:10.1021/ol102002f

Thermally induced electrocyclic reactions of methylenecyclopropane (MCP) methylene diketone derivatives afford a novel method for the synthesis of spiro[2.5]octa-3,5-dienes in moderate to good yields. Applying this methodology in a one-pot manner for the

Full text of DOI:10.1021/ol102002f

ORGANIC
LETTERS
2010
Vol. 12, No. 22
5120-5123
Thermally Induced Electrocyclic
Reaction of Methylenecyclopropane
Methylene Diketone Derivatives: A
Facile Method for the Synthesis of
Spiro[2.5]octa-3,5-dienes
Xiang-Ying Tang, Yin Wei,* and Min Shi*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
weiyin@mail.sioc.ac.cn; mshi@mail.sioc.ac.cn
Received August 24, 2010
ABSTRACT
Thermally induced electrocyclic reactions of methylenecyclopropane (MCP) methylene diketone derivatives afford a novel method for the
synthesis of spiro[2.5]octa-3,5-dienes in moderate to good yields. Applying this methodology in a one-pot manner for the reactions of MCP
aldehydes with 1,3-diketones, catalyzed by L-proline, also afforded the corresponding spiro derivatives.
Methylenecyclopropanes (MCPs) are generally used as
building blocks in organic synthesis for their ready acces-
sibility as well as diverse reactivity driven by the relief of
ring strain.1 The ring-opening reactions of MCPs are
synthetically useful protocols in the construction of complex
product structures that have been studied extensively thus
far. Over the past decades, Lewis acid- and transition metal-
catalyzed reactions involving ring-opening of MCPs to form
a variety of different carbocycles and heterocycles have been
extensively investigated in our group and others.2-4 To the
best of our knowledge, the ring-opening reactions of MCPs
(2) For Lewis acid-catalyzed ring opening reactions of MCPs, see: (a)
Hu, B.; Xing, S. Y.; Wang, Z. W. Org. Lett. 2008, 10, 5481–5484. (b)
Huang, X.; Yang, Y. Org. Lett. 2007, 9, 1667–1670. (c) Lautens, M.; Han,
W. J. Am. Chem. Soc. 2002, 124, 6312–6316. (d) Lautens, M.; Han, W.;
Liu, J. H. J. Am. Chem. Soc. 2003, 125, 4028–4029. (e) Scott, M. E.;
Bethuel, Y.; Lautens, M. J. Am. Chem. Soc. 2007, 129, 1482–1483. (f)
Scott, M. E.; Schwarz, C. A.; Lautens, M. Org. Lett. 2006, 8, 5521–5524.
(g) Scott, M. E.; Han, W.; Lautens, M. Org. Lett. 2004, 6, 3309–3312. (h)
Scott, M. E.; Lautens, M. Org. Lett. 2005, 7, 3045–3047. (i) Yu, L.; Meng,
J. D.; Xia, L.; Guo, R. J. Org. Chem. 2009, 74, 5087–5089. (j) Lu, L.;
Chen, G.; Ma, S. Org. Lett. 2006, 8, 835–838. (k) Scott, M. E.; Lautens,
M. J. Org. Chem. 2008, 73, 8154–8162. (l) Taillier, C.; Lautens, M. Org.
Lett. 2007, 9, 591–593. (m) Diev, V. V.; Tung, T. Q.; Molchanov, A. P.
Eur. J. Org. Chem. 2009, 525–530. (n) Hu, B.; Zhu, J. L.; Xing, S. Y.;
Fang, J.; Du, D.; Wang, Z. W. Chem.sEur. J. 2009, 15, 324–327. (o)
Bagutski, V.; de Meijere, A. AdV. Synth. Catal. 2007, 349, 1247–1255. (p)
Hang, X.-C.; Chen, Q.-Y.; Xiao, J.-C. Eur. J. Org. Chem. 2008, 1101–
(1) For selected reviews on MCPs, see: (a) Lautens, M.; Klute, W.; Tam,
W. Chem. ReV. 1996, 96, 49–92. (b) de Meijere, A.; Kozhushkov, S. I.;
Khlebnikov, A. F. Top. Curr. Chem. 2000, 207, 89–147. (c) Binger, P.;
Wedemann, P.; Kozhushkov, S. I.; de Meijere, A. Eur. J. Org. Chem. 1998,
113–119. (d) de Meijere, A.; Kozhushkov, S. I. A. Eur. J. Org. Chem.
2000, 3809–3822. (e) Nakamura, I.; Yamamoto, Y. AdV. Synth. Catal. 2002,
344, 111–129. (f) Brandi, A.; Cicchi, S.; Cordero, F. M.; Goti, A. Chem.
ReV. 2003, 103, 1213–1270. (g) Nakamura, E.; Yamago, S. Acc. Chem.
Res. 2002, 35, 867–877. (h) Shao, L.-X.; Shi, M. Curr. Org. Chem. 2007,
11, 1135–1137. (i) Rubin, M.; Rubina, M.; Gevorgyan, V. Chem. ReV. 2007,
107, 3117–3179. (j) Yamago, S.; Nakamura, E. Org. React. 2002, 61, 1–
217. (k) de Meijere, A.; Kozhushkov, S. I.; Spath, T.; von Seebach, M.;
Lohr, S.; Nuske, H.; Pohomann, T.; Es-Sayed, M.; Brase, S. Pure. Appl.
Chem. 2000, 72, 1745–1756.
1106. (q) Huang, X.; Miao, M.-Z. J. Org. Chem. 2008, 73, 6884–6887
.
10.1021/ol102002f  2010 American Chemical Society
Published on Web 10/29/2010

by thermally induced rearrangements seldom have been
reported. Since high temperature is usually required for the
thermally induced rearrangements of the analogues of MCPs,
such as cyclopropenes and vinylcyclopropanes due to certain
activation energy required,5 this may account for the ring-
opening reactions of MCPs by thermally induced rearrange-
ments normally being difficult to occur. Previously, we
reported a synthetic route to 2,3-disubstituted pyrrolamides
by ring-opening recyclization of benzylidene and alkyl-
idenecyclopropylcarbaldehydes with hydrazides upon heating
in toluene in moderate to good yields (Scheme 1).6
diketone might also undergo a rearrangement reaction upon
heating, but with a different outcome due to the unique
properties of diketones. Herein, we wish to report a novel
thermally induced electrocyclic reaction of MCP methylene
diketone derivatives to synthesize spiro[2.5]octa-3,5-dienes
upon heating.
We initially utilized (E)-3-((2-benzylidenecyclopropyl)-
methylene)pentane-2,4-dione 1a as the substrate to investi-
gate its behavior upon heating in toluene at 100 °C. To our
surprise, a new cyclopropane-containing product 2a, which
was later confirmed as trans-spiro[2.5]octa-3,5-diene, was
obtained in 56% yield instead of the cyclopentene product
derived from a Cope rearrangement (Table 1, entry 1). When
Scheme 1
.
Previous Studies on the Ring-Opening Reactions of
MCP Derivatives upon Heating
Table 1. Optimization of the Reaction Conditions
temp
(°C)
time
(min)
yield of
2a (%)a
entry
additive
solvent
1
2
toluene 100
20
56
Ph PO H
2
2
(10 mol %)
FeCl3 (1 0 mol %) toluene
DCE
50
60
9 h
30
22
complex
3
4
Later, we also reported an efficient method to stereospe-
cifically synthesize trans-substituted cyclopentene derivatives
via the thermally induced Cope rearrangement of readily
available MCP alkenyl ketone derivatives in moderate to
good yields (Scheme 1).7 Furthermore, Renaud and co-
workers reported the addition of enolizable 1,3-diketone to
R,ꢀ-unsaturated aldehydes leading to substituted 2H-pyrans
via a formal [3 + 3] cycloaddition.8 On the basis of these
previous works, we hypothesized that MCP methylene
CF CO2H
3
(5 mol %)
tartaric acid
(20 mol %)
DCM
rt
20
15
complex
48
5
toluene
DCM
toluene
toluene
100
rt
100
100
6
7
8
9
1 day 19b
30
10
46c
42d
tBu4NOAc
(1 equiv)
TEMPO (1 equiv) xylene
toluene
100
120
20
10
54
56
10
a Isolated yields. b The reaction mixture was irradiated by ultraviolet
light. c The reaction was kept in the dark. d The reaction was conducted
under microwave.
(3) For transition metal-catalyzed ring reactions of MCPs, see: (a)
Lautens, M.; Ren, Y. J. Am. Chem. Soc. 1996, 118, 10668–10669. (b) Ma,
S.; Zhang, J. Angew. Chem., Int. Ed. 2003, 42, 183–187. (c) Ma, S.; Lu,
L.; Zhang, J. J. Am. Chem. Soc. 2004, 126, 9645–9660. (d) Smolensky, E.;
Kapon, M.; Eisen, M. S. Organometallics 2007, 26, 4510–4527. (e)
Nakamura, I.; Oh, B. H.; Saito, S.; Yamamoto, Y. Angew. Chem., Int. Ed.
2001, 40, 1298–1300. (f) Kurahashi, T.; de Meijere, A. Angew. Chem., Int.
Ed. 2005, 44, 7881–7884. (g) Huang, X.; Zhou, H. Org. Lett. 2002, 4, 4419–
4422.
several acids such as Ph2PO2H, FeCl3, CF3CO2H, and tartaric
acid were present in the reaction system, the yields of product
2a were lower than 56%, indicating that this reaction was
not tolerant to acidic conditions (Table 1, entries 2-5). The
UV photolytic reaction of 1a in DCM at room temperature
required a reaction time of 1 day, and the yield of 2a was
only 19% (Table 1, entry 6). When this reaction was kept in
the dark or heated by microwave at 100 °C, the yields of 2a
dropped to 46% and 42%, respectively (Table 1, entries 7
(4) For work from our group, see: (a) Shi, M.; Xu, B.; Huang, J.-W.
Org. Lett. 2004, 6, 1175–1178. (b) Jiang, M.; Shi, M. Tetrahedron 2009,
65, 5222–5227. (c) Shi, M.; Liu, L.-P.; Tang, J. Org. Lett. 2006, 8, 4043–
4046. (d) Yao, L.-F.; Shi, M. Eur. J. Org. Chem. 2009, 4971–4983. (e)
Jiang, M.; Liu, L.-P.; Shi, M.; Li, Y.-X. Org. Lett. 2010, 12, 116–119. (f)
Shao, L.-X.; Shi, M. Tetrahedron 2010, 66, 4551–4554. (g) Jiang, M.; Shi,
M. Org. Lett. 2010, 12, 2606–2609. (h) Huang, X.; Miao, M.-Z. J. Org.
Chem. 2008, 73, 6884–6887.
(5) The thermally induced rearrangements for the analogues of MCPs,
such as cyclopropenes and vinylcyclopropanes, have been investigated;
please see: (a) Houk, K. N.; Nendel, M.; Wiest, O.; Storer, J. W. J. Am.
Chem. Soc. 1997, 119, 10545–10546. (b) Baldwin, J. E.; Bonacorsi, S., Jr.
J. Am. Chem. Soc. 1996, 118, 8258–8265. (c) Gajewski, J. J. Hydrocarbons
Thermal Isomerizations; Academic: New York, 1980; pp 81-87. (d) Baird,
M. S. Chem. ReV. 2003, 103, 1271–1294. (e) Baldwin, J. E. Chem. ReV.
2003, 103, 1197–1212.
t
and 8). Furthermore, phase transfer catalyst Bu4NOAc did
not work well either in this reaction (Table 1, entry 9).
Finally, it was found that free radical scavenger 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO) did not inhibit this
reaction, rendering unlikely the involvement of a simple
radical pathway (Table 1, entry 10).
Repeated attempts to increase the yield of 2a were
unsuccessful. In fact, as shown by TLC, there was a product
in addition to 2a, which was easily decomposed during
(6) Tang, X.-Y.; Shi, M. J. Org. Chem. 2009, 74, 5983–5986.
(7) Tang, X.-Y.; Shi, M. J. Org. Chem. 2010, 75, 902–905.
(8) (a) Hubert, C.; Moreau, J.; Batany, J.; Duboc, A.; Hurvois, J.-P.;
Renaud, J. L. AdV. Synth. Catal. 2008, 350, 40–42. (b) Moreau, J.; Hubert,
C.; Batany, J.; Toupet, L.; Roisnel, T.; Hurvois, J.-P.; Renaud, J.-L. J. Org.
Chem. 2009, 74, 8963–8973.
Org. Lett., Vol. 12, No. 22, 2010
5121

purification. Fortunately, the structure of 2a was finally
confirmed as trans-spiro[2.5]octa-3,5-diene by its analogue
2j, whose structure was unambiguously determined by X-ray
diffraction (Figure 1).9 In addition, 3j, the configurational
Table 2. Reaction Scope of This Rearrangement
entry
R
2:3
yield of 2 + 3 (%)a
b
1
2
3
4
5
6
7
8
1b, p-BrC6H4
1c, p-ClC6H4
1d, p-MeC6H4
1e, p-PhC6H4
Z-1a, C6H5
1f, p-MeOC6H4
1g, m-MeC6H4
1h, 3,4,5-(MeO)3C6H2
b
-
2b, 62
2c, 58
b
-
2.3:1
2.4:1
2d/3d, 86
2e/3e, 64
2a, 42
2f/3f, 74
2g/3g, 76
2h, 55
b
-
2.7:1
2:1
b
-
Figure 1. X-ray crystal structure of 2j.
a Isolated yields. As detected by H NMR, product 3 was isolated as
1
complex mixtures due to its instability.
isomer of 2j, was also obtained and characterized as cis-
spiro[2.5]octa-3,5-diene on the basis of its spectral and
analytical data. According to this result, it was unlikely to
increase the yield of 2a due to the formation of its unstable
isomer.
mol % of L-proline at 100 °C. Instead of L-proline, another
less expensive base, such as piperidine, has also been tried
as a catalyst in this reaction. However, some Michael addition
byproduct were generated, leading to low yields of the
desired products. With MCP aldehyde 4b and 1,3-diketone
pentane 5b as the substrates, the reaction became more
sluggish, giving the corresponding product 2b in very low
yield (27%) (Table 3, entry 6). It was found that 1,3-
We next turned our attention to the generality of this
reaction in toluene. A variety of MCP methylene diketones
having either electron-donating or electron-withdrawing
groups on the benzene ring as substituents, 1, were examined
under these optimal conditions. When the electron-withdraw-
ing groups Br or Cl were present on the benzene ring (1b
and 1c), the corresponding trans-spiro[2.5]octa-3,5-diene
derivatives 2b and 2c were obtained in 62% and 58% yields.
The cis-isomers were also isolated but were complex
Table 3. Tandem Knoevenagel Condensation-Cope
Rearrangement of MCP Aldehydes with 1,3-Diketones in
One-Pot
1
mixtures as shown by H NMR spectra (Table 2, entries 1
and 2). Using (Z)-3-((2-benzylidenecyclopropyl)methyl-
ene)pentane-2,4-dione (Z-1a) or 1h bearing three strongly
electron-donating MeO groups on the benzene ring as the
substrates, the trans-isomers were afforded in 42% and 55%
yields, respectively; but the pure cis-isomers 3a and 3h could
not be isolated due to their instability (Table 2, entries 5
and 8). As was the case for 1d, 1f, and 1g having electron-
donating groups on the benzene ring as well as 1e bearing a
p-phenyl group, both the trans- and cis-isomers could be
isolated and the total yields were 64-86% (Table 2, entries
3-4 and 6-7). Unfortunately, 1 with aliphatic substituents
did not give good results, affording complex mixtures of
unidentified products.
Considering that it might be feasible to synthesize the spiro
product from more common starting materials, therefore, the
reaction was carried out using a one-pot manner by heating
MCP aldehyde and 1,3-diketones in toluene catalyzed by 10
a Isolated yields. b None of the product 3 was obtained. c A new product
was formed.
(9) The crystal data of 2j have been deposited with the Cambridge
Crystallographic Data Centre; deposition no. 757321. These data can be
obtained free of charge from the Cambridge Crystallographic Data Centre,
12 Union Rd., Cambridge CB2 1EZ, UK or via www.ccdc.cam.ac.uk/conts/
retrieving.html. Empirical formula: C19H19BrO2; formula weight: 359.25;
crystal size: 0.396 × 0.267 × 0.175; crystal color, habit: colorless, prismatic;
crystal system: orthorhombic; lattice type: primitive; lattice parameters: a
) 25.683(3) Å, b ) 12.1372(13) Å, c ) 11.0178(12) Å, R ) 90°, ꢀ ) 90°,
γ ) 90°, V ) 3434.5(6) Å3; space group: Pbcn; Z ) 8; Dcalc ) 1.390 g/cm3;
F000 ) 1472; R1 ) 0.0488, wR2 ) 0.1294. Diffractometer: Rigaku
AFC7R.
cyclohexanedione 5a possessed higher activity than 5b and
such reactions were completed within 20 min, giving the
configurational isomers (2i/3i, 2j/3j, 2k/3k, 2l/3l) in 58-81%
yields, respectively (Table 3, entries 1, 2, 4, and 5). Probably
the pKa values of cyclic diketones are lower than those
5122
Org. Lett., Vol. 12, No. 22, 2010

of the corresponding acyclic diketones, then the synthesis
of the Knoevenagel adducts is faster, leading to the whole
reaction rate being faster. With 1,3-cyclohexanedione 5d
instead of 5a, as for substrates 4a, as well as 4b and 4c
having a para-substituent on the benzene ring, the reaction
time was lengthened to 90-120 min and the total yields of
the cis- and trans-spiro[2.5]octa-3,5-diene derivatives were
61-69%, respectively (Table 3, entries 10-12). In addition,
1,3-cyclopentanedione 5c exhibited unique properties as the
reaction of 5c with 4a, 4e (p-Cl substituted), and 4f (p-phenyl
substituted) gave the corresponding isomers in 28-73%
yields along with a set of new products 6 which are discussed
later (Table 3, entries 7-9). When Z-4a was used as the
substrate, the reaction went through smoothly to deliver the
same isomers 2i/3i in 80% yield (Table 3, entry 3).
Unfortunately, 4 with aliphatic substituents did not give good
results either, affording complex mixtures of unidentified
products.
Interestingly, a new product 6a was obtained in the
reaction of MCP aldehyde 4a with 5c though the yield of
6a was low. On the basis of Renaud’s finding and its spectral
and analytical data,8 6a was identified as 3-methylene-2-
phenyl-7,8-dihydro-2H-cyclopenta[b]oxepin-6(3H)-one. Fur-
ther investigation revealed that if the reaction mixture was
heated for 1.5 h, 6a was obtained in higher yield (25%).
Simultaneously, the corresponding spiro[2.5]octa-3,5-diene
isomers 2m and 3m were formed in 62% yield (Scheme 2,
Scheme 3. A Plausible Reaction Mechanism
cis-spiro[2.5]octa-3,5-diene derivatives 2 and 3 (Scheme 3).
In addition, 2 is the major product due to its small steric
hindrance and stability. It should also be noted that the
reaction of 4 with 1,3-cyclopentanedione 5c may generate
intermediate M1, which undergoes electrocyclic reaction to
give product 6a (Scheme 3). In principle, we should obtain
the six-membered analogue of product 6a in a low yield in
the reaction of 4 with 5d. However, under our standard
reaction conditions, we observed that the reactions of 4 with
5d afforded several products mixed with small amounts of
decomposed compounds from starting materials, which made
it very difficult to identify the six-membered analogue of
product 6a. The theoretical investigations are in progress to
elucidate further mechanistic details of these reactions.
In conclusion, we have found a thermally induced reaction
of MCP methylene diketone derivatives, affording a novel
synthetic protocol for the preparation of spiro[2.5]octa-3,5-
dienes as well as 3-methylene-2-aryl-7,8-dihydro-2H-cyclo-
penta[b]oxepin-6(3H)-ones in some cases. A plausible mech-
anism was proposed. The potential utilization and extension
of the scope of the methodology are currently under
investigation. Detailed mechanistic investigations are also
under way.
Scheme 2
.
The Reaction of MCP Aldehydes 4 with
1,3-Diketone 5
eq 1), slightly lower than 73% (Table 3, entry 7). With 4e
and 4f as the substrates, the same results were observed as
the two isomers were obtained in 19% and 6% yields,
respectively (Scheme 2, eqs 2 and 3), suggesting that 6 was
a thermally stable product because longer reaction time favors
its formation.
A plausible reaction mechanism is outlined in Scheme 3.
Initially, 1a was converted to intermediate A upon heating
at 100 °C,10 presumably via a simple sigmatropic rearrange-
ment. After formation of the intermediate A, an electrocyclic
reaction took place to furnish the corresponding trans- and
Acknowledgment. We thank the Shanghai Municipal
Committee of Science and Technology (08dj1400100-2),
National Basic Research Program of China (973)-
2009CB825300, and the National Natural Science Foun-
dation of China for financial support (20472096, 20872162,
20672127, 20821002, and 20732008) and Dr. Donald D.
Bretches for revising our English.
Supporting Information Available: The spectroscopic
data (1H, 13C spectroscopic data), HRMS of the compounds
shown in Tables 1-3 and Scheme 2, the X-ray crystal
structures of compound 2j, and a detailed description of
experimental procedures. This material is available free of
charge via the Internet at http://pubs.acs.org.
(10) (a) Skancke, A.; Schaad, L. J.; Hess, B. A., Jr. J. Am. Chem. Soc.
1988, 110, 5315–5318. (b) Patrick, T. B.; Haynie, E. C.; Probst, W. J.
Tetrahedron Lett. 1971, 12, 423. (c) Patrick, T. B.; Haynie, E. C.; Probst,
W. J. J. Org. Chem. 1972, 37, 1553.
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