PdCl2-catalyzed oxidative cycloisomerization of 3-cyclopropylideneprop-2-en-1-ones

Article abstract of DOI:10.1021/ol300927n

A novel PdCl₂-catalyzed oxidative cycloisomerization of 3-cyclopropylideneprop-2-en-1-ones, providing a facile synthesis of highly strained functionalized 2-alkylidenecyclobutanones via furan-fused cyclobutene intermediates, is reported. An interesting route to 2(3H)-furanones with a spiro-cyclopropane unit from the obtained 2-alkylidenecyclobutanones via a ring-contraction rearrangement reaction is also realized.

Full text of DOI:10.1021/ol300927n

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
PdCl2-Catalyzed Oxidative
Cycloisomerization of
3-Cyclopropylideneprop-2-en-1-ones
Maozhong Miao,† Jian Cao,† Jingjing Zhang,† Xian Huang,‡,§ and Luling Wu*,†
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
wululing@zju.edu.cn
Received April 10, 2012
ABSTRACT
A novel PdCl2-catalyzed oxidative cycloisomerization of 3-cyclopropylideneprop-2-en-1-ones, providing a facile synthesis of highly strained
functionalized 2-alkylidenecyclobutanones via furan-fused cyclobutene intermediates, is reported. An interesting route to 2(3H)-furanones with a
spiro-cyclopropane unit from the obtained 2-alkylidenecyclobutanones via a ring-contraction rearrangement reaction is also realized.
The four-membered ring is an important structural
motif, existing in many bioactive natural products,1 and
also serves as a key intermediate in the synthesis of struc-
turally complex targets by ring-opening reactions2 which
make its preparation of great interest in organic synthesis.
However, efficient methods for the synthesis of these
compounds are limited compared to those for other car-
bocyclic systems.3 In the past, several advanced strategies
involving transition-metal-catalyzed ring expansion of cy-
clopropanes via cyclopropyl carbenes have been established
for the synthesis of cyclobutanes and cyclobutenes.4 The
€
groups of Trost, Echavarren, and Furstner reported the
synthesis of various isomeric bicyclic cyclobutenes by trans-
tition-metal-mediated cycloisomerization of tethered en-
ynes via cyclopropyl metal carbenes.5 Alternatively, Shi
€
and Furstner discovered that monosubstituted cyclobutenes
could be prepared through cyclopropyl metal carbenes
derived from methylenecyclopropanes (MCPs).6 Further-
more, Tang reported the synthesis of cyclobutenyl esters
via silver(I)-catalyzed decomposition of diazocarbonyl
precursors forming the cyclopropyl metal carbenes,7a and
Liu developed a gold-catalyzed oxidative ring expansion
of alkynylcyclopropanes via cyclopropyl gold carbenes
to afford cyclobutenyl ketone.7b Despite these elegant
achievements, the progress of novel synthetic methods
† Zhejiang University.
‡ Chinese Academy of Sciences.
§ Prof. Huang passed away on March 6, 2010. He had been fully in charge
of this project. At this moment, Prof. Luling Wu is finishing all the projects
with help from Prof. Shengming Ma.
(1) (a) Hansen, T. V.; Stenstrom, Y. Organic Synthesis: Theory and
Applications, Vol. 5; Elsevier Science: Dordrecht, 2001, p 1. (b) Dembitsky,
V. M. J. Nat. Med. 2008, 62, 1.
(2) (a) Lee-Ruff, E.; Mladenova, G. Chem. Rev. 2003, 103, 1449. (b)
Gauvry, N.; Lescop, C.; Huet, F. Eur. J. Org. Chem. 2006, 5207.
(3) (a) Winkler, J. D.; Bowen, C. M.; Liotta, F. Chem. Rev. 1995, 95,
2003. (b) Hoffmann, N. Chem. Rev. 2008, 108, 1052. (c) Inanaga, K.;
Takasu, K.; Ihara, M. J. Am. Chem. Soc. 2005, 127, 3668. (d) Canales,
E.; Corey, E. J. J. Am. Chem. Soc. 2007, 129, 12686. (e) Shibata, T.;
Takami, K.; Kawachi, A. Org. Lett. 2006, 8, 1343.
(5) (a) Trost, B. M.; Tanoury, G. J. J. Am. Chem. Soc. 1988, 110,
1636. (b) Trost, B. M.; Trost, M. K. Tetrahedron Lett. 1991, 32, 3647. (c)
Nieto-Oberhuber, C.; Lopez, S.; Echavarren, A. M. J. Am. Chem. Soc.
2005, 127, 6178. (d) Nieto-Oberhuber, C.; Lopez, S.; Munoz, M. P.;
Cardenas, D. J.; Bunuel, E.; Nevado, C.; Echavarren, A. M. Angew.
€
Chem., Int. Ed. 2005, 44, 6146. (e) Furstner, A.; Davies, P. W.; Gress, T.
J. Am. Chem. Soc. 2005, 127, 8244. (f) Hashmi, A. S. K. Angew. Chem.,
Int. Ed. 2008, 47, 6754.
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(b) Furstner, A.; Aıssa, C. J. Am. Chem. Soc. 2006, 128, 6306.
€
(4) (a) Masarwa, A.; Furstner, A.; Marek, I. Chem. Commun. 2009,
5760. (b) Kleinbeck, F.; Toste, F. D. J. Am. Chem. Soc. 2009, 131, 9178.
(c) Trost, B. M.; Xie, J.; Maulide, N. J. Am. Chem. Soc. 2008, 130, 17258.
(d) Markham, J. P.; Staben, S. T.; Toste, F. D. J. Am. Chem. Soc. 2005,
127, 9708.
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Chem., Int. Ed. 2008, 47, 8933. (b) Li, C.-W.; Pati, K.; Lin, G.-Y.; Abu
Sohel, S. M.; Hung, H.-H.; Liu, R.-S. Angew. Chem., Int. Ed. 2010, 49,
9891.
r
10.1021/ol300927n
XXXX American Chemical Society

via cyclopropyl metal carbene intermediates leading read-
ily to the selective formation of the four-membered ring
with new structural features for further elaboration is still
of current interest.
yield after flash chromatography on neutral Al2O3. We
determined the scope of the reaction when R1 = alkyl
groups with 10 mol % PdCl2 under N2 at rt and the furan-
fused cyclobutenes 2b, 2c, and 2d were obtained in
82À87% yield (Scheme 2).
Yet, increasing attention has been paid to a metal-
catalyzed cyclization/1,2-migration domino methodology
which provides rapid access to complex molecular frame-
works.8 Particularly, the cyclization of allenyl ketones via 1,2-
migration of various groups is an efficient approach for the
synthesis of highly substituted furans (Scheme 1).9 Marshall
and Hashmi have shown an efficient approach for the
assembly of the furan ring via a formal 1,2-hydrogen shift
of allenyl ketones.9bÀd Gevorgyan has reported the metal-
catalyzed cyclization of allenyl ketones with 1,2-alkyl migra-
tion as a key step in the formation of highly substituted
furans.9e
Scheme 2. Cycloisomerization of 3-Cyclopropylideneprop-2-
en-1-ones 1 To Afford Furan-Fused Cyclobutenes 2
To further expand the scope of this reaction, we carried
out the reaction of 1e wherein R1 is an aryl group; however
the desired furan-fused cyclobutene product was not iso-
lated presumably because this compound is unstable under
the reaction conditions. Surprisingly, the reaction proceeded
smoothly to give two new products, 2-alkylidenecyclobuta-
none (3e) in 43% yield and 2(3H)-furanone (4e) in 28%
yield, in the presence of 10 mol % PdCl2 in an open air
flask (Scheme 3). The structures of 3e11 and 4e12 were further
confirmed by the single crystal X-ray diffraction analysis.
We next carried out the reaction of 3e in the presence of
10 mol % PdCl2; however, 4e was not formed, indicating that
the formation of 3e and 4e are competitive in the reaction
(Scheme 3).
Scheme 1. Transition Metal Catalyzed Cycloisomerization of
1,2-Allenylketones and 3-Cyclopropylideneprop-2-en-1-ones 1
Based on these reports and our interest in the chemistry
of cyclopropane,10 we envisioned that under the activation
of π-carbophilic metals, cyclization of cyclopropylidene-
prop-2-en-1-ones 1 would afford cyclopropyl metal car-
benes Y, which could undergo CÀC bond cleavage and a
subsequent 1,2-shift to form furan-fused cyclobutenes 2,
which are interesting precusors for the synthesis of other
important molecules (Scheme 1).
Scheme 3. Reaction of 1e in the Presence of 10 mol % PdCl2
under Open Air Conditions
We first examined the reaction of 1a (R1 = n-Pr) in the
presence of a catalytic amount of a metal salt under N2 at rt
to explore the possibility of forming furan-fused cyclobu-
tene 2a (Scheme 2). Fortunately, 2a was obtained in 89%
We proposed a plausible mechanism for for the prepara-
tion of 3e and 4e (Scheme 4). PdCl2 may activate the
relatively electron-rich CÀC double bond and trigger the
nucleophilic attack of the carbonyl oxygen at the C4 atom
of the allenone moiety to form the spirocyclic oxonium X.
The latter intermediate would evolve into the Pd(II) car-
benoid Y, and subsequent bond cleavage followed by
elimination of the metal would provide the intermediate
compound 2e. The next step is most likely to be a single-
electron oxidation of 2e by the oxygen in air to furnish the
radical cation A. The cationic center in intermediate A is
trapped by water to afford the radical species B, which
after proton elimination gives the hydroxy radical C. The
latter could be further oxidized into the corresponding
(8) (a) Patil, N. T.; Yamamoto, Y. Chem. Rev. 2008, 108, 3395. (b)
Lautens, M.; Klute, W.; Tam, W. Chem. Rev. 1996, 96, 49. (c) Shapiro,
N. D.; Toste, F. D. J. Am. Chem. Soc. 2008, 130, 9244. (d) Kirsch, S. F.;
ꢀ
Binder, J. T.; Liebert, C; Menz, H. Angew. Chem., Int. Ed. 2006, 45, 5878.
(e) Trost, B. M; Xie, J. J. Am. Chem. Soc. 2008, 130, 6231.
(9) (a) Sheng, H.; Lin, S.; Huang, Y. Z. Tetrahedron Lett. 1986, 27,
4893. (b) Marshall, J. A.; Robinson, E. D. J. Org. Chem. 1990, 55, 3450.
(c) Marshall, J. A.; Wallace, E. M. J. Org. Chem. 1995, 60, 796. (d)
Hashmi, A. S. K.; Schwarz, L.; Choi, J.-H.; Frost, T. M. Angew. Chem.,
Int. Ed. 2000, 39, 2285. (e) Dudnik, A. S.; Gevorgyan, V. Angew. Chem.,
Int. Ed. 2007, 46, 5195. (f) Kim, J. T.; Kel’in, A. V.; Gevorgyan, V.
Angew. Chem., Int. Ed. 2003, 42, 98. (g) Sromek, A. W.; Rubina, M.;
Gevorgyan, V. J. Am. Chem. Soc. 2005, 127, 10500. (h) Sromek, A. W.;
Kel’in, A. V.; Gevorgyan, V. Angew. Chem., Int. Ed. 2004, 43, 2280. (i)
Dudnik, A. S.; Xia, Y.; Li, Y.; Gevorgyan, V. J. Am. Chem. Soc. 2010,
132, 7645.
(10) (a) Su, C.; Cao, J.; Huang, X.; Wu, L.; Huang, X. Chem.;Eur. J.
2011, 17, 1579. (b) Huang, X.; Zhou, H. Org. Lett. 2002, 4, 4419. (c)
Chen, W.; Cao, J.; Huang, X. Org. Lett. 2008, 10, 5537. For synthesis of
MCPs, see: (d) Brandi, A.; Goti, A. Chem. Rev. 1998, 98, 589. For recent
reviews, see: (e) Brandi, A.; Cicchi, S.; Cordero, F. M.; Goti, A. Chem.
Rev. 2003, 103, 1213. (f) Nakamura, E.; Yamago, S. Acc. Chem. Res.
2002, 35, 867.
(11) For X-ray crystal data for 3e, see Supporting Information.
(12) For X-ray crystal data for 4e, see Supporting Information.
B
Org. Lett., Vol. XX, No. XX, XXXX

cation D, and subsequent loss of a proton and cleavage of
the dihydrofuran ring would lead to the 1,4-dicarbonyl
compound 3e with a four-membered ring (Path a). Alter-
natively, elimination of a proton and ring contraction
would produce the furanone derivative 4e with a spiro-
cyclopropane at the 3-position (Path b).
Table 1. Optimization of the Reaction Conditions for the
Selective Formation of 3ea
Scheme 4. Plausible Mechanism for the Formation of 3e and 4e
MXn
[O]
yield of
3e (%)c
yield of
4e (%)c
(10 mol %)
(equiv)
solventb
1
2
PdCl2
air
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
43
33
11
14
36
42
44
32
33
24
28
6
AgNO3
Pd(OAc)2
AgOTf
Au(PPh3)OTf
PdCl2
air
3
air
trace
0
4
air
5
air
22
19
22
30
37
17
6
air
7
PdCl2
air
CH3OH
toluene
CH2Cl2
CH2Cl2
8
PdCl2
air
9
PdCl2
O2
10
PdCl2
PhI(OAc)2
(2.5)
DMP
(2.5)
DTBP
(2.5)
MCPBA
(2.5)
DMP
(2.5)
11
12
13
14
PdCl2
PdCl2
PdCl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
84
0
16
trace
trace
0
trace
77
Efforts were made to optimize the reaction conditions
and improve the selectivity of the reaction. As indicated in
Table 1, AgNO3, Pd(OAc)2, AgOTf, and Au(PPh3)OTf all
sluggishlycatalyzed the reactionand onlygavelower yields
of a mixture of 3e and 4e, compared to PdCl2 (Table 1,
entries 2À5). The reaction proceeded smoothly in THF,
CH3OH, and toluene, but the yield and selectivity were not
obviously improved (Table 1, entries 6À8). Considering the
oxidation of the intermediate might be the key step in the
reaction, various oxidants were then screened13 (Table 1,
entries 9À13). Gratifyingly, the yield of 3e was improved to
84% when 2.5 equiv of Dess-Martin periodinane (DMP)
were employed, and the formation of 4e was not observed
(Table 1, entry 11). The yield dropped to 77% when the
loading of PdCl2 was reduced to 5 mol % (Table 1, entry 14).
Thus, using DMP as the oxidant and 10 mol % PdCl2 as
the catalyst, this reaction could highly selectively produce
functionalized 2-alkylidenecyclobutanones 3.
d
PdCl2
a Unless otherwise specified, the reaction was carried out using 1e
(0.15 mmol) in 3 mL of solvent in an open air atmosphere at room
temperature. b The solvent was used as received without further puri-
fication. c Isolated yields. d 5 mol % PdCl2 was used.
give the products 3mÀ3p in good yields from 1mÀ1p,
which have different aromatic R2 substitutions (Table 2,
entries 11À14). However, when R2 was a 2-naphthyl
group, 3q was obtained in 56% yield (Table 2, entry 15).
We also examined the reactivity of furan-fused cyclobu-
tenes 2c and 2d upon treatment with DMP (2.5 equiv).
These products were successfully converted to functiona-
lized 2-alkylidenecyclobutanones 3c and 3d in 64% and
66% yields (Scheme 5), confirming that the furan-fused
cyclobutene is the key intermediate in the formation of 3e
from 1e (Scheme 4).
The scope of the reaction is described in Table 2. When
R2 was an aryl group, the R1 substituent could be an aryl, a
heteroaryl, or an alkyl group and the corresponding
products 3 were obtained in moderate to good yields
(Table 2, entries 1À9). As for the more electron-deficient
1h and 1i, 3h and 3i were produced in moderate yields
(Table 2, entries 4 and 5). When R1 was a 2-thienyl group,
the reaction only afforded 3k in 32% yield (Table 2, entry
7). The nature and position of substituents on the aromatic
R2 seem to have little effect on this reaction with R1 being
Ph or Tol. Thus the reactions all proceeded smoothly to
Attempts to selectively form furanones 4 from allenyl
ketones 1 by screening various reaction conditions were
unsuccessful. As a result of the inherent ring strain, func-
tionalized 2-alkylidenecyclobutanones 3 may show inter-
esting reactivity in organic synthesis. Thus, considering the
ready availability of 3 with our protocol, we envisioned
that a possible route to 4 from 3 may be realized via a ring-
contraction reaction of cyclobutane mediated by a Brønsted
acid as shown in Scheme 6. The proton may selectively
activate the cyclic carbonyl oxygen of 3 to form E; intramo-
lecular nucleophilic attack of the acyclic carbonyl oxygen at
(13) (a) Brasholz, M.; Reissig, H.-U. Angew. Chem., Int. Ed. 2007, 46,
1634. (b) Alcaide, B.; Almendros, P.; Carrascosa, R.; Torres, M. R. Eur.
J. Org. Chem. 2010, 5, 823. (c) Li, Y.; Pattenden, G.; Rogers, J.
Tetrahedron Lett. 2010, 51, 1280.
(14) The reaction of 1e could be easily scaled up to 1.084 g, conducted
with just 3 mol % of PdCl2 and 2.1 equiv of DMP, affording 3e in 72%
yield.
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 2. Scope of the Reaction for the Highly Selective For-
mation of 3a
Table 3. Scope of the Reaction of 3 with TfOH for the Highly
Selective Formation of 4a
3
1
R1
R2
3 (yield %)b
entry
R1
R2
4 (yield %)b
entry
3e (84)14
3f (91)
1
2
(3e) 4-MeC6H4
(3f) Ph
Ph
Ph
Ph
Ph
Ph
4e (82)
4f (88)
4g (83)
4h (72)
4b (91)
4l (66)
4m (77)
4n (82)
4o (80)
4q (84)
1
(1e) 4-MeC6H4
(1f) Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2
3
(3g) 4-FC6H4
(3h) 4-MeOC6H4
(3b) i-Bu
3
(1g) 4-FC6H4
(1h) 4-MeOC6H4
(1i) 3,4,5-(MeO)3C6H2
(1j) 2-furyl
(1k) 2-thienyl
(1a) n-Pr
3g (70)
3h (55)c
3i (64)c
3j (63)
4
4
5
5
6
(3l) 4-ClC6H4
(3m) 4-MeC6H4
(3n) Ph
2-MeOC6H4
4-MeC6H4
3-MeC6H4
4-MeOC6H4
2-naphthyl
6
7
7
3k (32)
3a (83)
3b (85)
3l (93)
8
8
9
(3o) Ph
9
(1b) i-Bu
10
(3q) Ph
10
11
12
13
14
15
(1l) 4-ClC6H4
(1m) 4-MeC6H4
(1n) Ph
2-MeOC6H4
4-MeC6H4
3-MeC6H4
4-MeOC6H4
4-FC6H4
3m (72)
3n (77)
3o (90)
3p (81)
3q (56)
a Unless otherwise specified, the reaction was carried out using 3e
(0.1 mmol) mediated by 30% TfOH in 3 mL of CH2Cl2 in open air at rt.
b Isolated yields.
(1o) Ph
(1p) Ph
(1q) Ph
2-naphthyl
Table 3 show that various furanones of type 4 could be
obtained smoothly in moderate to high yields using the
current protocol. Here, It should be mentioned that the
2(3H)-furanones with the spiro-three-membered ring
should be valuable intermediates in organic synthesis due
to the presence of a highly strained spiro-cyclopropyl ring.
In conclusion, we have developed a cyclization of
3-cyclopropylideneprop-2-en-1-ones in the presence of
π-philic metals leading to furan-fused cyclobutenes, which
are versatile intermediates for further elaboration. In the
presence of PdCl2 and DMP, a highly selective formation
of functionalized 2-alkylidenecyclobutanones can be real-
ized. Furthermore, we have developed an efficient route
toward2(3H)-furanones with a spiro-three-memberedring
at the 3-position from 2-alkylidenecyclobutanones. Due to
the easy availability of the starting materials and synthetic
potential of these products, this method should be useful
in organic synthesis, and further studies in this area are
underway in our laboratory.
a Unless otherwise specified, the reaction was carried out using 1e
(0.15 mmol) in the presence of 10 mol % PdCl2 and 2.5 equiv of DMP in
3 mL of CH2Cl2 in open air at rt. b Isolated yields. c The reaction was
conducted at 0 °C.
Scheme 5. Conversion of 2 upon Treatment with DMP
Scheme 6. Proposed Reaction Pathways for the Formation of 4
from 3 Mediated by Brønsted Acid
Acknowledgment. We are grateful to the National Nat-
ural Science Foundation of China (Project Nos. 20872127,
20732005, and J0830431), National Basic Research Pro-
gram of China (973 Program, 2009CB825300), CAS Aca-
demician Foundation of Zhejiang Province, and the
Fundamental Research Funds for the Central Universities
for financial support.
the cationic carbon atom would take place to yield the
intermediate D which are proposed in Scheme 4. D would
then undergo ring contraction and subsequent loss of a
proton to finally afford 4.
Thus, we started to examine the reactivity of 3e in the
presence of TfOH (30 mol %) in CH2Cl2 at rt. To our
delight, the expected product 4e was cleanly obtained in
82% yield (Table 3, entry 1). The results summarized in
Supporting Information Available. Experimental pro-
cedure and characterization of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX