Cu(I)-catalyzed intramolecular C-C coupling of activated methylene compounds with vinyl halides: Efficient synthesis of functionalized alkylidenecyclobutanes

Article abstract of DOI:10.1021/ol802012q

(Chemical Equation Presented) With the catalysis of Cul/L-proline, a number of 2-(3-bromobut-3-enyl)malonates underwent efficient intramolecular C-vinylation leading to the synthesis of functionalized alkylidenecyclobutanes. Competition experiments reveal

Full text of DOI:10.1021/ol802012q

ORGANIC
LETTERS
2008
Vol. 10, No. 22
5285-5288
Cu(I)-Catalyzed Intramolecular C-C
Coupling of Activated Methylene
Compounds with Vinyl Halides: Efficient
Synthesis of Functionalized
Alkylidenecyclobutanes
Liqun Chen,† Min Shi,†,‡ and Chaozhong Li*,‡
School of Chemistry & Molecular Engineering, East China UniVersity of Science and
Technology, 130 Meilong Road, Shanghai 200237, P. R. China, and Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road,
Shanghai 200032, P. R. China
clig@mail.sioc.ac.cn
Received September 17, 2008
ABSTRACT
With the catalysis of CuI/L-proline, a number of 2-(3-bromobut-3-enyl)malonates underwent efficient intramolecular C-vinylation leading to the
synthesis of functionalized alkylidenecyclobutanes. Competition experiments revealed that this four-membered ring closure is fundamentally
preferred over the corresponding five-membered ring closure.
Alkylidenecyclobutanes represent a unique class of moder-
ately strained alkenes. They are structural motifs in a number
of natural products.1 In the meantime, they have recently
been shown to be versatile intermediates in organic synthe-
sis.2 However, to our surprise, methods for their synthesis
are few. A commonly used method is the Wittig reaction of
(4-bromobutyl)triphenylphosphonium bromide with a car-
bonyl compound,2a-c a method similar to that for the
synthesis of alkylidenecyclopropanes.3 However, only simple
derivatives of methylenecyclobutane were prepared by this
method, and its generality and functional group tolerance
have yet to be examined. Other methods include the 4-exo
cyclization of acetylenic alkyllithiums,4 the [2 + 2] cyclo-
addition of allenes to appropriately substituted olefins,5 and
the HX (X ) I or OH) elimination reactions.1d,2d As a result,
the chemistry of alkylidenecyclobutanes is far less explored
† East China University of Science and Technology.
(2) For selected examples, see:(a) Jiang, M.; Shi, M. Org. Lett. 2008,
10, 2239. (b) Jiang, M.; Liu, L.-P.; Shi, M. Tetrahedron 2007, 63, 9599.
(c) Shen, Y.-M.; Wang, B.; Shi, Y. Angew. Chem., Int. Ed. 2006, 45, 1429.
(d) Bondada, L.; Gumina, G.; Nair, R.; Ning, X. H.; Schinazi, R. F.; Chu,
C. K. Org. Lett. 2004, 6, 2531. (e) Fitjer, L.; Kanschik, A.; Majewski, M.
Tetrahedron Lett. 1988, 29, 5525.
‡ Chinese Academy of Sciences.
(1) (a) Stratmann, K.; Moore, R. E.; Bonjouklian, R.; Deeter, J. B.;
Patterson, G. M. L.; Schaffer, S.; Smith, C. D.; Smitka, T. A. J. Am. Chem.
Soc. 1994, 116, 9935. (b) Donnelly, D. M. X.; Konishi, T.; Dunne, O.;
Cremin, P. Phytochemistry 1997, 44, 1473. (c) McMorris, T. C.; Lira, R.;
Gantzel, P. K.; Kelner, M. J.; Dawe, R. J. Nat. Prod. 2000, 63, 1557. (d)
Zhang, A.; Nie, J. J. Agric. Food Chem. 2005, 53, 2451.
(3) Brandi, A.; Goti, A. Chem. ReV. 1998, 98, 589.
(4) Bailey, W. F.; Ovaska, T. V. J. Am. Chem. Soc. 1993, 115, 3080.
10.1021/ol802012q CCC: $40.75
Published on Web 10/16/2008
2008 American Chemical Society

compared to that of alkylidenecyclopropanes.3 It is therefore
highly desirable to develop general and efficient methods
for the synthesis of alkylidenecyclobutanes, especially the
functionalized ones. We report here that the copper-catalyzed
intramolecular C-vinylation of activated methylene com-
pounds with vinyl halides provides an efficient and con-
venient entry to functionalized alkylidenecyclobutanes.
The past few years have witnessed a rapid progress in the
formation of aryl (or vinyl) C-X (X ) O, N, S, etc.) bonds
via copper-catalyzed Ullmann coupling between aryl (or
vinyl) halides and heteroatom-centered nucleophiles.6 The
high stability and low cost of the copper catalysts enable
these transformations to be a useful complement to the more
extensively investigated Pd(0)-catalyzed processes.7 This
method was then successfully extended to the C-C bond
formation via copper-catalyzed C-arylation of active meth-
ylene compounds (the Hurtley coupling8).9 However, the
analogous C-vinylation is far less explored. Qian and Pei
reported the intermolecular cross-coupling of activated
methylene compounds with ꢀ-bromostyrenes.10 The only
other example was reported by us as the side reaction in the
intramolecular O-vinylation of 1,3-dicarbonyl compounds.11
Driven by our interest in Cu(I)-catalyzed intramolecular O-
and N-vinlyation reactions,11,12 we set out to study the Cu(I)-
catalyzed intramolecular C-vinylation.
Table 1. Optimization of the Synthesis of 2a from 1a
entrya ligand (mol %)b base (equiv) time (h) yield (%)c
1
2
3
4
5
6
7
8
L-1 (20)
L-1 (40)
L-2 (40)
L-3 (40)
L-4 (40)
L-5 (40)
L-6 (40)
L-6 (40)
L-6 (40)
L-6 (40)
L-6 (40)
none
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
K2CO3 (2)
K3PO4 (2)
Cs2CO3(3)
Cs2CO3 (3)
8
8
8
8
8
8
8
20
20
20
20
20
4
11
10
10
0
61
59
79
trace
20
92
trace
9
10
11
12
a Reaction conditions: 1a (0.3 mmol), CuI (0.03 mmol), ligand, base,
THF (10 mL), reflux. b L-1: N,N′-dimethylethylenediamine. L-2: 1,10-
phenanthroline. L-3: Me2NCH2CO2H·HCl. L-4: 2-hydroxybenzaldehyde
oxime. L-5: 2-isobutyrylcyclohexanone. L-6: L-proline. c Isolated yield based
on 1a.
Thus, diethyl 2-(3-bromobut-3-enyl)malonate (1a) was
chosen as the model substrate, which was readily available
by monoalkylation of diethyl malonates. Compound 1a was
first subjected to the following typical Ullmann coupling
conditions: CuI (10 mol %), N,N′-dimethylethylenediamine
(L-1, 20 mol %),13 Cs2CO3 (2 equiv) in refluxing THF. After
8 h, the expected cyclization product 2a was obtained in only
4% yield, while most of the starting material was recovered
(entry 1, Table 1). Increasing the amount of ligand L-1 to
40 mol % resulted in a slightly faster reaction (entry 2, Table
1). We then screened the ligands. 1,10-Phenanthroline (L-
2)14 and N,N-dimethylglycine hydrochloride (L-3)15 showed
an effect similar to L-1, while 2-hydroxybenzaldehyde oxime
(L-4)12a was inactive (entries 3-5, Table 1). On the other
hand, the use of 2-isobutyrylcyclohexanone (L-5)16 or
L-proline (L-6)17 as ligand led to a much faster reaction
(entries 6 and 7, Table 1). With the use of the more readily
available L-6, a higher yield (79%) of 2a could be achieved
by simply lengthening the reaction time to 20 h (entry 8,
Table 1).
We next examined the effects of different bases. It turned
out that Cs2CO3 is superior over K2CO3 and K3PO4 (entries
8-10, Table 1). To speed up the coupling reaction, we
increased the amount of Cs2CO3 to 3 equiv. To our delight,
a clean reaction was observed. The substrate 1a was all
consumed within 20 h, and the product cyclobutane 2a was
achieved in 92% isolated yield.
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With the optimized combination (combination A: 10 mol
% of CuI, 40 mol % of L-6, and 3 equiv of Cs2CO3) in
hand, we then examined the generality of this method. The
results are summarized in Table 2. Substrates 1b-1e bearing
different substituents at the C-3 or C-4 position, all afforded
the expected cyclization products in excellent yields (entries
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.
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Org. Lett., Vol. 10, No. 22, 2008

product 2h in 71% yield. On the other hand, the iodo-
analogue of 1h, substrate 1i, underwent efficient cyclization
at a much lower temperature (refluxing THF) to produce the
same product 2h in 88% yield. Furthermore, iodide 1j having
a 3-phenyl substituent afforded the cyclization product 2j in
almost quantitative yield within a shorter period of time. The
C-C bond formation in a 5-endo-like mode was also
successful as exemplified by the reaction of (Z)-2-(4-iodobut-
3-enyl)malonate 1k in which the expected coupling product
2k was achieved in quantitative yield under mild conditions
(entry 13, Table 2).
Table 2. Cyclization of Malonates 1
The above results clearly demonstrated the high efficiency
of copper catalysis in the intramolecualr C-vinylation of
malonates. The data in Table 2 also indicated that the
uncommon four-membered ring closure is much easier that
the corresponding five-membered cyclization. To have a
direct comparison, dibromide 3, which has two possible
modes of cyclization, was synthesized and subjected to the
above optimized conditions (Combination A). Indeed, the
four-membered ring product 4 was isolated in 96% yield,
while no five-membered cyclization product could be
detected (eq 1). This result unambiguously pointed out that
four-membered ring closure is fundamentally preferred in
the Cu(I)-catalyzed C-vinylation, a phenomenon also ob-
served in the O- and N-vinylation under the catalysis of
copper.12c,e Although the reason for such a preference
remains unclear, it could be possible that the transition state
for four-membered ring closure as a Cu-containing five-
membered ring is kinetically and thermodynamically more
favorable. Theoretical analyses on this assumption are
currently underway in our laboratory and will be reported
in due course.
The above reactions employed malonates as the nucleo-
philes. We next examined other types of nucleophiles. As
can be seen in Scheme 1, the reaction of ꢀ-keto ester 5
yielded the mixture of methylenecyclobutane 6 (22%) and
cyclic ether 7 (77%), the latter being the O-vinylation product
via a six-membered ring closure. Apparently the O-vinylation
of the enolate competes well with C-vinylation. Monoesters
such as 2-phenylacetate 8 did not undergo the C-C coupling
under the optimized conditions. This should be attributed to
the lower acidity of the 2-methylene protons. Surprisingly,
2-cyanoacetate 9a failed to give any cyclized product under
the conditions of combination A, while all the starting
material decomposed within 2 h in refluxing THF. Lowering
the reaction temperature did not help.
a E ) CO2Et. b Reaction conditions: 1 (0.3 mmol), CuI (0.03 mmol),
L-6 (0.12 mmol), Cs2CO3 (0.9 mmol), solvent (10 mL), reflux. c Isolated
yield based on 1. d R ) n-C10H21.
2-5, Table 2). The configuration of the CdC double bond
was nicely retained as evidenced by the reactions of 1f and
1g (entries 6-8, Table 2). It should be noted that the
cyclization of some substrates such as 1g was slow in
refluxing THF or CH3CN presumably because of the steric
factors. However, by simply raising the reaction temperature
(refluxing dioxane or toluene), the coupling products could
be generated in high yields.
We then extended this method to the intramolecular
coupling via a five-membered ring closure (entries 9-12,
Table 2). The cyclization of 2-(4-bromopent-4-enyl)malonate
1h in dioxane was very slow. Nevertheless, the prolonged
reaction of 1h in refluxing toluene afforded the desired
With the assumption that the combination A might not be
the right combination for the cyclization of 2-cyanoacetates,
we went on to reoptimize the conditions for 9a. Indeed,
switching the ligand back to L-1 allowed the generation of
the expected methylenecyclobutane 10a in 30% yield. Further
changing the base to K3PO4 (2 equiv) increased the yield of
Org. Lett., Vol. 10, No. 22, 2008
5287

Reactions of Esters 5, 8, and 9aa b
Scheme 2.
Reactions of Cyanoacetates 9a b c d
,
, , ,
Scheme 1
.
a Combination A: CuI (10 mol %), L-6 (40 mol %), Cs2CO3 (3 equiv).
b Isolated yield based on 5.
a Combination B: CuI (10 mol %), L-1 (40 mol %), K3PO4 (2 equiv).
b Isolated yield based on 9. c Two stereoisomers in ∼ 1.7:1 ratio determined
by 1H NMR (300 MHz). d Trans:cis ) ∼10:1 determined by 1H NMR (300
MHz).
10a to 73%. On the other hand, ligands such as L-2 or L-5
and the base K2CO3 failed to activate the coupling process.
The above reoptimized conditions (combination B: 10 mol
% of CuI, 40 mol % of L-1, and 2 equiv of K3PO4) were
then applied to other 2-cyanoacetates (Scheme 2). The
reaction of 3-phenyl-substituted 2-cyanoacetate 9b in THF
for 3 h afforded the cyclization product 10b in 62% yield.
Interestingly, a very good stereoselectivity (∼10:1) was
observed with the major isomer in a trans-configuration
(determined by 2D NOESY experiments), which might be
attributed to the steric control of the phenyl group. The five-
membered ring closure was also successful even with the
use of vinyl bromide, as evidenced by the reaction of bromide
9c in which the methylenecyclopentane 10c was achieved
in 60% yield under mild conditions (THF, reflux, 10 h). By
comparison with the reaction of malonate 1h, it seems that
2-cyanoacetates are more reactive toward C-vinylation. The
results in Table 1 and Scheme 2 also strongly implied that,
by the appropriate choice of ligand and base, other activated
methylene compounds could also undergo the corresponding
copper-catalyzed intramolecular C-vinylation.
highly efficient intramolecular C-vinylation of activated
methylene compounds with vinyl halides via four- or five-
membered ring closure can be successfully implemented
under mild conditions, leading to the convenient synthesis
of alkylidenecyclobutanes and cyclopentanes. Moreover, the
uncommon four-membered ring closure is intrinsically
preferred over the corresponding five-membered ring closure,
illustrating the unique property of Cu(I) catalysis. This
finding should be of useful application in organic synthesis.
Acknowledgment. This project was supported by the
National NSF of China (Grant Nos. 20672136, 20702060,
and 20832006) and by the Shanghai Municipal Committee
of Science and Technology (Grant No. 07XD14038). We
thank Miss Shana Zhu of Shanghai Institute of Organic
Chemistry for double-checking the experimental data.
Supporting Information Available: Experimental pro-
cedures for C-C coupling and the characterizations of 1-10.
This material is available free of charge via the Internet at
http://pubs.acs.org.
In conclusion, the chemistry detailed above has clearly
demonstrated for the first time that with the catalysis of Cu(I)
OL802012Q
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Org. Lett., Vol. 10, No. 22, 2008