Palladium-catalyzed [3+2+1] cyclocarbonylative coupling of 1,3-cyclohexanediones, alkynes, and carbon monoxide: An atom-economic route to chromene-2,5-dione derivatives

Article abstract of DOI:10.1016/j.tetlet.2010.09.132

3,4,7,8-Tetrahydro-2H-chromene-2,5(6H)-dione derivatives were efficiently synthesized with excellent selectivity via a [3+2+1] cyclocarbonylative coupling of 1,3-cyclohexanediones, terminal alkynes, and CO catalyzed by Pd(PPh ₃)₄.

Full text of DOI:10.1016/j.tetlet.2010.09.132

Tetrahedron Letters 51 (2010) 6433–6435
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium-catalyzed [3+2+1] cyclocarbonylative coupling
of 1,3-cyclohexanediones, alkynes, and carbon monoxide:
an atom-economic route to chromene-2,5-dione derivatives
⇑
Bei Wu, Ruimao Hua
Department of Chemistry, Tsinghua University, Key Laboratory of Organic Optoelectronics & Molecular Engineering of Ministry of Education, Beijing 100084, China
State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
a r t i c l e i n f o
a b s t r a c t
Article history:
3,4,7,8-Tetrahydro-2H-chromene-2,5(6H)-dione derivatives were efficiently synthesized with excellent
selectivity via a [3+2+1] cyclocarbonylative coupling of 1,3-cyclohexanediones, terminal alkynes, and
CO catalyzed by Pd(PPh3)4.
Received 4 August 2010
Revised 24 September 2010
Accepted 29 September 2010
Available online 7 October 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Alkynes
Carbon monoxide
Chromene-2,5-dione
1,3-Cyclohexanediones
Palladium
One-pot multi-component reactions are of considerable current
interest, since they can rapidly construct functionalized molecules
of great complexity.1 In the last two decades, remarkable progress
has been achieved in transition metal-catalyzed cycloaddition
reactions using alkyne as one of components to synthesize various
functionalized cyclic compounds, with the advantages of atom-
economic processes, easily available starting materials, and con-
trollable regioselectivity of cycloadducts.2 On the other hand, cyclic
b-diketones, owing to their tautomeric property have been also
well applied in the synthesis of fused cyclic compounds.3 In our
development of atom-economic reactions for the synthesis of cyc-
lic carbonyl compounds via cyclocarbonylative coupling of alkynes,
we have established the catalytic systems for highly selective syn-
thesis of furan-2(5H)-ones, p-benzoquinones, and 2-cyclopenten-
1-ones.4 In continuation of our research on the cyclocarbonylation
of alkynes, we designed, in the present work, a three-component
[3+2+1] cyclocarbonylative coupling of 1,3-cyclohexanediones,
alkynes, and CO in the presence of Pd(PPh3)4 to develop an
atom-economic process for the synthesis of 3,4,7,8-tetrahydro-
2H-chromene-2,5(6H)-dione derivatives. These derivatives are
considered to be versatile and important bicyclic intermediates
in the synthesis of biologically active and pharmaceutical
O-heterocyclic molecules (Scheme 1).
O
O
O
O
R
cat. Pd(PPh3)4
+
+
CO
R
R'
R'
O
Scheme 1. Atom-economic route for synthesis of chromene-2,5-diones.
The reactions of 1,3-cyclohexanedione (1a), phenyl acetylene,
(2a) and CO in the presence of 5 mol % of Pd(PPh3)4 at 100 °C under
different reaction conditions were examined to optimize the cata-
lytic system and the results are concluded in Table 1. We found
that when an excess amount of 2a was used (3.0 equiv),5 the cyclo-
carbonylative coupling reactions under different CO pressures (1.0,
3.0, and 5.0 MPa) and a variety of solvents such as THF, toluene,
DMSO, dioxane, DMF, CH3CN, and Cl2CHCHCl2 (TCE) furnished
the desired cycloadduct 3a in fair to moderate yields only (entries
1–10), and the best yield of 3a in 56% was achieved in THF under a
CO pressure of 5.0 MPa (initial pressure at room temperature) (en-
try 4). Therefore, under the conditions of entry 4, the reaction was
conducted again using 1.5 equiv of 1a and fortunately it was found
that 3a was formed in 82% GC yield (entry 12). In addition, the use
of Pd(II) complexes, such as PdCl2(PPh3)2, Pd(OAc)2, and PdCl2
showed no catalytic activity for the present cyclocarbonylative
coupling reaction.
It should be also noted that in all the reactions, 3a was formed
as an exclusive three-component cyclocoupling product, no other
⇑
Corresponding author. Tel.: +86 10 62792596; fax: +86 10 62771149.
E-mail address: ruimao@mail.tsinghua.edu.cn (R. Hua).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.132

6434
B. Wu, R. Hua / Tetrahedron Letters 51 (2010) 6433–6435
Table 1
Table 2
Palladium(0)-catalyzed cyclocarbonylative coupling of 1,3-cyclohexanedione (1a),
Palladium(0)-catalyzed cyclocarbonylative coupling of 1,3-cyclohexanediones,
phenylacetylene (2a), and CO under different conditionsa
alkynes, and carbon monoxidea
O
O
O
O
O
O
R
R'
Pd(PPh3)4 (5.0 mol%)
solvent, 100 oC, 15 h
Pd(PPh3)4 (5.0 mol%)
R
R'
+
Ph + CO
+
Ar
CO (5.0 MPa)
Ph
Ar
THF, 100 oC, 15 h
2
3a
2a
3
O
O
O
1a
O
1 (1.5 equiv)
Entry
1a:2a
CO (MPa)b
Solvent
GC yield (%)c
R = R' = H, 1a; R = R' = Me, 1b
R = H, R' = Ph, 1c
1
2
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1.5:1
1.0
3.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
THF
THF
THF
THF
Toluene
DMSO
Dioxane
DMF
TCE
CH3CN
THF
20
40
33
56
31
36
45
36
Entry
R
R0
Ar
Cycloadduct 3
Yield
(%)b
3d
4
O
O
5
6
7
8
p-MeC6H4
1
H
H
85
2b
3b
O
O
9
11
Me
10
10
O
O
11e
82 (77)f
a
Unless otherwise noted, reactions were carried out at 100 °C for 15 h by using
1.0 mmol of 1a and 0.05 mmol of Pd(PPh3)4 in 1.0 mL of solvent in
autoclave.
2
3
4
H
H
p-ClC6H4 2c
74
70
69
a 15 mL
3c
Cl
b
Initial pressure at ambient temperature.
GC yield based on the amount of 1a used.
O
O
c
d
11 h.
Me Me Ph 2a
e
Ph
1.5 mmol of 1a and 1.0 mmol of 2a were used.
GC yield based on the amount of 2a used. Number in parenthesis is isolated
f
3d
O
yield.
O
O
p-MeC6H4
2b
Me Me
regioisomer with the same molecular weight could be detected by
GC and GC–MS of the reaction mixture. The regioselectivity of the
3e
O
O
Me
phenyl group bonded to
a-position of carbonyl group (ester) is
O
O
supported by its 1H NMR spectroscopic data, in which only a single
proton is observed at 3.80 ppm (proton of alkyl group appears at
5
6
Me Me p-ClC6H4 2c
84
96
the lowest field) assigned to the
a-proton of ester, and which
3f
was finally confirmed by X-ray crystallography (Fig. 1).6
Cl
O
O
Ph
Utilizing optimized conditions, the [3+2+1] cyclocarbonylative
coupling process was then applied to the other alkynes. As summa-
rized in Table 2, the reaction of aromatic alkynes bearing either an
electron-donating group of methyl (2b) or an electron-withdraw-
ing group of chloro (2c) underwent the reaction smoothly to give
the corresponding cycloadducts 3b and 3c in 85% and 74% isolated
yields, respectively (Table 2, entries 1–2). Additionally, the substi-
tuted 1,3-cyclohexanesdiones such as 5,5-dimethyl-1,3-cyclohex-
anedione (1b) and 5-phenyl-1,3-cyclohexanedione (1c) were also
suitable cyclocoupling partners under the same reaction condi-
tions to give the expected products 3d–g in good to high yields
(Table 2, entries 3–6).
H
Ph
Ph 2a
Ph
3g
O
a
Reactions were carried out at 100 °C for 15 h by using 1.5 mmol of 1, 1.0 mmol
of 2 and 0.05 mmol of Pd(PPh3)4 in THF (1.0 mL) mL in a 15 mL autoclave. Isolated
yield based on 2 used.
On the basis of 13C NMR spectrum of 3g, the diastereomeric ratio is ca. 1:1.
b
tions using DMF as the solvent to replace THF afforded the cyclo-
carbonylative coupling product 3h–j in good to high isolated
yields (Scheme 2). The structure of 3j with isopropylidene group
at 3 position was unambiguously confirmed by X-ray crystallogra-
phy (Fig. 2),6 and indicated that the double bond shift isomeriza-
tion of isopropenyl group to isopropylidene occurred.
Although the use of 1-octyne in different solvents resulted in
the formation of a complicated mixture containing a low yield of
the expected bicyclic compound, it was found that the reactions
of 1a–c with 2-methyl-1-buten-3-yne (2d) under similar condi-
O
O
O
R
R'
Pd(PPh3)4 (2.5 mol%)
R
R'
+
CO (3.0 MPa)
DMF, 100 oC, 15 h
2d
O
O
1 (2.0 equiv)
O
O
R
R'
R = R' = H, 3h, 85%
R = R' = Me, 3i, 78%
R = H, R' = Ph, 3j, 98%
O
The expected 3-(2-isopropenyl)
substituted derivative
Scheme 2. Carbonylative cyclocoupling of 1,3-cyclohexanediones, 2-methyl-1-
Figure 1. Molecular structure of 3a.
buten-3-yne, and carbon monoxide.

B. Wu, R. Hua / Tetrahedron Letters 51 (2010) 6433–6435
6435
2.10–1.95 (m, 2H). 13C NMR (150 MHz, CDCl3) d 197.0, 167.9,
167.2, 135.8, 129.0, 128.1, 127.9, 114.4, 44.8, 36.5, 27.1, 24.2,
20.7. GC–MS m/z (% rel inten.): 242 (M+, 9), 214 (100), 185(16),
118 (65), 115 (42), 90 (44), 77(12). IR (KBr): 1771, 1655 cmꢀ1
(mCO). Anal. Calcd for C15H14O3: C, 74.38; H, 5.78. Found: C, 74.44;
H, 5.87.
Acknowledgment
Figure 2. Molecular structure of 3j.
This work was supported by the National Natural Science Foun-
dation of China (20972084, 21032004). The authors greatly thank
Miss Maria Victoria Abrenica, from Wellesley College, for her kind
English proofreading.
The route for the formation of chromene-2,5-dione derivatives
is proposed to involve the oxidative addition of O–H bond of enol
of 1 to Pd(0), insertion of CO, and alkyne to Pd–O bond, as well
as intramolecular cyclization.
In conclusion, we have developed a [3+2+1] cyclocarbonylative
coupling of 1,3-cyclohexanediones, terminal alkynes, and CO in the
presence of Pd(PPh3)4 to provide a straightforward and atom-eco-
nomic process for the synthesis of 3,4,7,8-tetrahydro-2H-
chromene-2,5(6H)-dione derivatives in good to high yields. The
present work extends the application of alkynes and 1,3-cyclohex-
anediones in the synthesis of bicyclic compounds.
Supplementary data
Supplementary data (General method, characterization data,
charts of 1H, 13C NMR for all the products and the X-ray structural
details for 3a and 3j are concluded) associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.2010.09.132.
A typical experimental procedure for carbonylative cyclocou-
pling of 1,3-cyclohexanedione (1a), phenylacetylene (2a), and CO
to afford 3-phenyl-3,4,7,8-tetrahydro-2H-chromene-2,5(6H)-dione
(3a) (Table 1, entry 11): 1,3-cyclohexanedione (168.0 mg,
1.5 mmol), phenylacetylene (102.0 mg, 1.0 mmol), Pd(PPh3)4
(57.8 mg, 0.05 mmol), and THF (1 mL) were placed in a 15 mL auto-
clave under a flow of nitrogen, and then carbon monoxide was
introduced at an initial pressure of 5.0 MPa at room temperature.
The autoclave was heated in an oil bath at 100 °C with stirring
for 15 h. After release of CO at room temperature, the crude reac-
tion mixture was diluted with CH2Cl2 (4.0 mL) and then n-doco-
sane (93.0 mg, 0.3 mmol) was added as an internal standard for
GC analysis. After GC and GC–MS analyses of the reaction mixture,
volatiles were removed under a reduced pressure, and the residue
was subjected to silica gel column chromatography [eluting with
petroleum ether and then with a mixture of petroleum ether and
ethyl acetate (8:1–4:1)]. 3a was obtained in 186.3 mg (0.77 mmol,
77%) as a white solid. The GC analysis of the reaction mixture dis-
closed the formation of 3a in 82% GC yield. Data for 3a: White solid,
mp 179–180 °C. 1H NMR (300 MHz, CDCl3) d 7.31–7.14 (m, 5H),
3.80 (dd, 1H, J = 10.3, 7.6 Hz), 2.95 (dd, 1H, J = 16.8, 5.8 Hz), 2.73
(dd, 1H, J = 11.3, 8.0 Hz), 2.50 (m, 2H), 2.39 (t, 2H, J = 6.3 Hz),
References and notes
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