Synthesis of multisubstituted cyclobutenones via copper-catalyzed intramolecular C-vinylation of ketones

Article abstract of DOI:10.1016/j.tetlet.2015.05.068

With the catalysis of CuI/3,4,7,8-tetramethyl-1,10-phenanthroline, various ketones smoothly underwent the intramolecular C-vinylation with vinyl bromides in refluxing THF leading to the efficient synthesis of the corresponding multisubstituted cyclobuteno

Full text of DOI:10.1016/j.tetlet.2015.05.068

Tetrahedron Letters 56 (2015) 4331–4333
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Synthesis of multisubstituted cyclobutenones via copper-catalyzed
intramolecular C-vinylation of ketones
⇑
Lin Zhu, Chaozhong Li
School of Chemical Engineering, Ningbo University of Technology, No. 89 Cuibai Road, Ningbo 315016, China
Collaborative Innovation Center of Chemistry for Life Sciences, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
With the catalysis of CuI/3,4,7,8-tetramethyl-1,10-phenanthroline, various ketones smoothly underwent
the intramolecular C-vinylation with vinyl bromides in refluxing THF leading to the efficient synthesis of
the corresponding multisubstituted cyclobutenones.
Received 17 April 2015
Revised 12 May 2015
Accepted 20 May 2015
Available online 21 May 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Cyclobutenones
Ullmann coupling
Copper
Catalysis
Cyclobutenones are a class of small ring compounds that have
found widespread applications in organic synthesis. For example,
proven to be uniquely advantageous in the synthesis of four-
membered rings. For example, we have shown that the copper-
1
11
they are important building blocks for the synthesis of 1,3-dienes,
catalyzed intramolecular C–C coupling of activated methylene
2
cyclopentanones,
a
,b-butenolides, etc. They serve as activated
compounds with vinyl halides provides an efficient synthesis of
3
11b
dienophiles in Diels–Alder reactions. They offer a variety of ring-
functionalized alkylidenecyclobutanes (Scheme 1, part A).
We
expansion products under thermolytic or transition metal-cat-
alyzed conditions. However, these strained four-membered rings
envisioned that this methodology might be extended to the
intramolecular vinylation of ordinary ketone enolates, thus
providing a novel route to cyclobutenones (Scheme 1, part B).
However, it should be emphasized that the C-alkenylation of
enolates is typically catalyzed by palladium or nickel
4
are not readily available. They are typically prepared by the [2+2]
cycloaddition of alkynes with ketenes or keteniminium salts gener-
5
–7
ated in situ.
Other methods include the HBr elimination of b-
8
,3a
12
bromocyclobutanone
and nucleophilic addition/cyclization
complexes. The copper-catalyzed C-vinylation reactions gener-
9
13
reactions of 2,3-allenoates with organozinc reagents. It is there-
fore highly desirable to develop general and efficient methods for
the synthesis of cyclobutenones. Herein we report that the cop-
per-catalyzed intramolecular C-vinylation of ketones provides a
novel and efficient entry to multisubstituted cyclobutenones.
Copper-catalyzed Ullmann coupling reactions leading to the
formations of C–X (N, O, S, etc.) and C–C bonds have been demon-
ally require active methylene compounds as nucleophiles while
1
4
the use of ordinary enolates is rare. Driven by our interest in
1
1,15
intramolecular vinylation reactions,
possibility.
we set out to explore this
Thus, 4-bromopent-4-en-2-one 1a was chosen as the model
substrate for the optimization of reaction conditions (Table 1).
Our initial attempt with CuI as the catalyst, 2-hydroxybenzalde-
1
0
strated to be a versatile tool in synthetic organic chemistry. The
high stability and low costs of the copper catalysts make these
transformations attractive for industrial applications. By the
appropriate choice of copper source, ligand, base, and solvent,
these reactions have been developed to include a wide range of
substrates under mild conditions. In particular, the intramolecular
vinylation reactions offer a diverse range of functionalized carbo-
or heterocycles of various sizes.1 Furthermore, this strategy has
2 3
hyde oxime (L-1) as the ligand, and Cs CO as the base in refluxing
THF for 24 h failed to give any desired product while the starting
material 1a remained unchanged (entry 1, Table 1). When the reac-
tion was carried out at a higher temperature (in refluxing dioxane),
we were delighted to find that the expected product cyclobutenone
2a was observed in 63% yield (entry 2, Table 1). Since ligands play a
vital role in Ullmann coupling reactions, the commonly used
0j
10
ligands
were
screened,
including
N,N-dimethylglycine
hydrochloride (L-2),
phenanthroline (L-4), and N,N -dimethylethylenediamine (L-5).
The highest yield (89%) of 2a was obtained when L-4 was used
L
-proline (L-3), 3,4,7,8-tetramethyl-1,10-
0
⇑
Corresponding author. Tel.: +86 21 5492 5160; fax: +86 21 5492 5099.
E-mail address: clig@mail.sioc.ac.cn (C. Li).
http://dx.doi.org/10.1016/j.tetlet.2015.05.068
040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
0

4
332
L. Zhu, C. Li / Tetrahedron Letters 56 (2015) 4331–4333
A. Previous work
CO2Et
CO2Et
Table 2
Copper-catalyzed C-vinylation of ketones in refluxing THF
CO Et
CO2Et
2
Cu(I)
Entrya
Yieldb
Substrate
Product
(
%)
X
X = Br, I
Br
Br
O
O
B. This work
Br
Bn
Ph
1
95
86
R2
O
Cu(I)
O
R
R1
Bn
O
1a
2a
Ph
R
R1 R2
R = Ar, Me
OMe
O
O
O
Bn
Scheme 1. Intramolecular C-vinylation in 4-exo mode.
2
Bn
1b
2
b
as the ligand (entries 3–6, Table 1). Furthermore, when the
amounts of CuI and L-4 were increased to 20 mol % and 40 mol %,
respectively, the reaction was complete within 12 h leading to
the formation of 2a in almost quantitative yield (entry 7,
Table 1). Switching Cs
or K CO resulted in the decreased yield of 2a (not shown in
Table 1). The control experiments indicated that both Cu(I) and
the ligand L-4 were required for the cyclization (entries 8 and 9,
Table 1).
With the optimized conditions in hand, we set out to explore
the scope of this method. The results are summarized in Table 2.
The reactions of 1-arylpent-4-en-2-ones 1b and 1c bearing either
an electron-donating group or an electron-withdrawing one pro-
ceeded smoothly (entries 2 and 3, Table 2). Substrates 1d–1f hav-
ing ortho-, meta-, or para-substitution all led to the corresponding
coupling products in excellent yields (entries 4–6, Table 2). Ketone
OMe
Cl
Br
Br
O
Bn
3
4
97
92
2
CO
3
to other bases such as Na
2
CO
3
3
, K PO
4
,
Bn
1c
2
3
2c
Cl
O
Bn
Bn
1
d
2d
O
O
Br
Br
O
Bn
O
Bn
5
6
90
86
1
e
1
g with gem-dimethyl substitution afforded the product cyclobu-
tenone 2g quantitatively (entry 7, Table 2). The above reactions
used arylmethyl ketones as substrates. We then extended the
2e
Bn
Bn
O
Table 1
1f
2
f
Optimization of reaction conditions
Br
Br
O
CuI (10 mol %)
Ph
Br
O
O
7
99
41
ligand (20 mol %)
Bn
1g
2g
Ph
Ph
O
Cs CO (2 equiv)
O
2
3
Bn
a
Ph
solvent, reflux
Bn
2h
8c
1
2a
Bn
1h
OH NOH
a
Reaction conditions: 1 (0.3 mmol), CuI (11.6 mg, 0.06 mmol), L-4 (28.4 mg,
.12 mmol), Cs CO (196 mg, 0.6 mmol), THF (3 mL), reflux, 12 h.
Isolated yield based on the corresponding vinyl bromide 1.
0
2
3
HO C
NMe2 HCl
L-2
b
2
CO H
2
N
H
c
The reaction was carried in dioxane at reflux for 24 h.
L-3
L-1
intramolecular vinylation to substrates other than arylmethyl
ketones, such as ethyl ketone 1h. The reaction of 1h under the
above optimized conditions gave no desired product. However,
when the reaction was carried out in refluxing dioxane, the cycliza-
tion product 2h was achieved in 41% yield (entry 8, Table 2). The
lower reactivity of ethyl ketone 1h than arylmethyl ketones in
vinylation might be attributed to the more difficult enolization of
the former.
b-Keto esters or 1,3-diketones that are more prone to enoliza-
tion than ketones 1 could be anticipated to participate in the above
type of intramolecular vinylation more readily. Indeed, the cycliza-
tion of b-keto ester 3 proceeded at a much faster rate, leading to
the formation of cyclobutenone 4 in a 78% yield within 20 min
(Eq. 1). However, the C-vinylation of 1,3-diketone 5 failed.
Instead, the intramolecular O-vinylation took place to give 4H-
pyran-4-one 6 (Eq. 2). It is also interesting to note that the cycliza-
tion of ketone 7 as the analog of 1a also proceeded via O-vinylation
rather than C-vinylation, presumably because of the increased
steric hindrance associated with C-vinylation (Eq. 3):
Me NH HN Me
N
N
L-5
L-4
Entrya
Ligand
Solvent
Time (h)
Yield (%)b
1
2
3
4
5
6
L-1
L-1
L-2
L-3
L-4
L-5
L-4
None
L-4
THF
Dioxane
THF
THF
THF
THF
THF
THF or dioxane
THF or dioxane
24
12
24
24
24
24
12
24
24
0
63
40
20
89
0
95
0
0
c
7
8
d
9
a
Reaction conditions: 1a (0.2 mmol), CuI (0.02 mmol), ligand (0.04 mmol),
CO (0.4 mmol), solvent (2 mL), reflux.
Cs
2
3
b
Isolated yield based on 1a.
c
CuI (20 mol %) and L-4 (40 mol %) were used.
The reaction was carried out without CuI.
d

L. Zhu, C. Li / Tetrahedron Letters 56 (2015) 4331–4333
4333
Br
O
O
21361140377) and by the National Basic Research Program of
China (973 Program) (Grant No. 2011CB710805).
Bn
Ph
1
a (R = H)
Bn R
Ph
7
(R = Me)
2a
Supplementary data
Cu(I)
Br
Supplementary data (experimental details, characterizations of
Bn
1
13
Cu(III)
O
new compounds and H and C NMR spectra of all compounds)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2015.05.068.
Cs CO3
O
- Cu(I)
2
Bn
O
R = H
(III)Cu
Bn
Ph
A
Ph
Ph
R
B
C
References and notes
2 3
R = Me Cs CO
1
2
3
.
.
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Figure 1. Proposed mechanism.
CuI (20 mol %)
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CO Et
2
ð1Þ
ð2Þ
Cs CO (2 equiv)
Bn
2
3
CO Et
2
3
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(
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T. Ketenes II; Wiley: Hoboken, 2006.
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L-4 (40 mol %)
O
O
O
Bn
Ph
Cs CO (2 equiv)
2
3
Bn
O
Ph
THF, reflux, 3 h
5
6
, 86%
6.
For recent examples, see: (a) Kohnen, A. L.; Mak, X. Y.; Lam, T. Y.; Dunetz, J. R.;
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CuI (20 mol %)
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Br
O
7.
Hoornaert, C.; Hesbain-Frisque, A. M.; Ghosez, L. Angew. Chem., Int. Ed. 1975, 14,
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ð3Þ
Cs CO (3 equiv)
2
3
Bn
dioxane, reflux, 32 h
1
0. For reviews, see: (a) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428–2439;
(b) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400–5449; (c)
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7
8
, 81%
(
1:1)
A plausible mechanism can thus be drawn based on the above
results, as depicted in Figure 1. The oxidative addition of Cu(I) with
vinyl bromide 1a generates the vinylic Cu(III) intermediate A
1450–1460; (i) Evano, G.; Toumi, M.; Coste, A. Chem. Commun. 2009, 4166–
(
R = H), which then undergoes intramolecular ligand exchange
4175; (j) Liu, Y.; Wan, J.-P. Org. Biomol. Chem. 2011, 9, 6873–6894; (k)
Sambiagio, C.; Marsden, S. P.; Blacker, A. J.; McGrowan, P. C. Chem. Soc. Rev.
with the enolate to give the five-membered metallocycle B. The
subsequent reductive elimination of B (to give C) followed by
C@C bond migration furnishes cyclobutenone 2a. It is interesting
to note that the intermediate C could not be observed in our exper-
iments, indicating the fast conversion of C to 2a. Presumably the
conjugation of the C@C bond with the carbonyl and the phenyl ring
serves as the driving force for the olefin isomerization. When R is a
methyl group, the intramolecular ligand exchange of A (R = Me) to
produce the metallocycle similar to B becomes difficult due to the
increased steric hindrance at the a-carbonyl carbon. As a result, the
intermediate D is now generated, which then affords oxetane 8 as
the final product via reduction elimination.
In summary, we have developed a novel method for the effi-
cient synthesis of multisubstituted cyclobutenones via copper-cat-
alyzed intramolecular C-vinylation of ketones. The reactions are
easy to operate and enjoy a relatively broad substrate scope,
and thus should find important applications in organic synthesis.
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1
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1
6. Typical procedure for the copper-catalyzed synthesis of multisubstituted
cyclobutenones: 3-Benzyl-4-bromo-3-methyl-1-phenylpent-4-en-2-one (1a,
68.7 mg, 0.2 mmol), CuI (7.7 mg, 0.04 mmol), 3,4,7,8-tetramethyl-1,10-
1
6
2 3
phenanthroline (18.9 mg, 0.08 mmol), and Cs CO (130 mg, 0.4 mmol) in THF
(
2 mL) were refluxed for 12 h under nitrogen atmosphere. The resulting
mixture was cooled down to room temperature and filtered. The filtrate was
concentrated in vacuo and the crude product was purified by flash
chromatography on silica gel with petroleum ether/EtOAc (10:1, v:v) as the
eluent to give the pure product 2a as a colorless oil. Yield: 50 mg (95%). For
details, see the Supplementary material.
Acknowledgments
This project was supported by the National Natural Science
Foundation of China (Grant Nos. 21272259, 21472220 and