Propargylation of 1,3-dicarbonyl compounds with 1,3-diarylpropynes via oxidative cross-coupling between sp3 C-H and sp3 C-H

Article abstract of DOI:10.1021/jo8010039

(Chemical Equation Presented) A highly efficient oxidative-coupling reaction between diarylpropargylic sp³ C-H and active methylenic sp³ C-H was achieved with DDQ as oxidant. The reaction afforded a direct method for the propargylation of 1,3-dicarbonyl compounds, thus providing a concise synthesis of the corresponding products.

Full text of DOI:10.1021/jo8010039

the adjacent sp3 C-H bond and further stabilizes the in situ
formed intermediate. In contrast, the activation of the C-H bond
adjacent to the carbon atom has scarcely been explored. Only
a few reactions were reported. For example, the allylic sp3 C-H
bond of cyclohexene was coupled with the methylenic sp3 C-H
bond with copper(I) bromide and cobalt(II) chloride as the
catalyst.2e The coupling of cyclohexane or diarylmethane with
methylene compounds catalyzed by the system of FeCl2/(t-
Bu)2O2 was reported.2b,c In these cases, one or two metal
catalysts were usually coordinated with an oxidative reagent to
activate the C-H bond. Li’s group has also reported a highly
efficient coupling reaction between benzyl ethers and simple
ketones mediated by DDQ without using any metal catalyst.2f
With the interest in activation of the C-H bond,3 we herein
wish to report a highly efficient and concise oxidative cross-
coupling reaction between diarylpropargylic sp3 C-H and active
methylenic sp3 C-H mediated by DDQ.
Propargylation of 1,3-Dicarbonyl Compounds
with 1,3-Diarylpropynes via Oxidative
Cross-Coupling between sp3 C-H and sp3 C-H
Dongping Cheng†,‡ and Weiliang Bao*,†
Department of Chemistry, Zhejiang UniVersity (Xixi
Campus), Hangzhou 310028, People’s Republic of China,
and College of Pharmaceutical Science, Zhejiang UniVersity
of Technology, Hangzhou 310032, People’s Republic of
China
wlbao@css.zju.edu.cn
ReceiVed May 8, 2008
The alkylation of 1,3-dicarbonyl compounds represents one
of the most common C-C bond formation methodologies in
organic synthesis. An efficient and atom economical approach
to the alkylation of 1,3-dicarbonyl compounds is to use alcohols
as electrophiles with such catalysts as transition metals, Brønsted
acids, or Lewis acids.4 However, such a strategy has been
applied mostly to the synthesis of allyl- and benzyl-substituted
1,3-dicarbonyl compounds, and little attention has been paid to
the propargylation of 1,3-dicarbonyl compound, although the
corresponding products are useful synthetic intermediates. Very
recently, three examples concerning the propargylation of 1,3-
dicarbonyl compounds with propargylic alcohols were reported.5
However, the propargylation with use of the propargylic C-H
bond directly still remains a challenge.
A highly efficient oxidative-coupling reaction between dia-
rylpropargylic sp3 C-H and active methylenic sp3 C-H was
achieved with DDQ as oxidant. The reaction afforded a direct
method for the propargylation of 1,3-dicarbonyl compounds,
thus providing a concise synthesis of the corresponding
products.
C-C bond formation by direct oxidative cross-coupling of
two unfunctionalized substrates has attracted great interest
recently. In such transformation, starting materials could be used
directly in C-H form without prefunctionalization and thus the
synthetic procedure could be shorter, simpler, and atom
economical. A number of excellent achivements have been
made.1,2 The developed C-C bond formation by oxidative
cross-coupling included the following types: (1) sp3 C-H and
sp3 C-H; (2) sp2 C-H with sp2 C-H; (3) sp3 C-H with sp2
C-H; and (4) sp3 C-H with sp C-H. However, the sp3 C-H
bonds that undergo the cross-coupling reaction usually locate
at the R-position of a heteroatom such as nitrogen, oxygen, or
sulfur atom.2 The reason may lie in that the heteroatom activates
(2) (a) Li, Z.; Li, H.; Guo, X.; Cao, L.; Yu, R.; Li, H.; Pan, S. Org. Lett.
2008, 10, 803. (b) Li, Z.; Cao, L.; Li, C.-J. Angew. Chem., Int. Ed. 2007, 46,
6505. (c) Zhang, Y.; Li, C.-J. Eur. J. Org. Chem. 2007, 4654. (d) Li, Q.; Wei,
Y.; Hao, J.; Zhu, Y.; Wang, L. J. Am. Chem. Soc. 2007, 129, 5810. (e) Li, Z.;
Li, C.-J. J. Am. Chem. Soc. 2006, 128, 56. (f) Zhang, Y.; Li, C.-J. J. Am. Chem.
Soc. 2006, 128, 4242. (g) Zhang, Y.; Li, C.-J. Angew. Chem., Int. Ed. 2006, 45,
1949. (h) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2005, 127, 3672. (i) Li, Z.; Li, C. J.
Eur. J. Org. Chem. 2005, 3173. (j) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2005,
127, 6968. (k) DeBoef, B.; Pastine, S. J.; Sames, D. J. Am. Chem. Soc. 2004,
126, 6556. (l) Li, Z.; Li, C.-J. Org. Lett. 2004, 6, 4997. (m) Li, Z.; Li, C.-J.
J. Am. Chem. Soc. 2004, 126, 11810. (n) Brown, S. H.; Crabtree, R. H. J. Am.
Chem. Soc. 1989, 111, 2935.
(3) Cheng, D. P.; Bao, W. L. AdV. Synth. Catal. 2008, 350, 1263.
(4) (a) Jana, U.; Biswas, S.; Maiti, S. Tetrahedron Lett. 2007, 48, 4065. (b)
´
´
´
Sanz, R.; Miguel, D.; Martlnez, A.; Alvarez-Gutie´rrez, J. M.; Rodrlguezb, F.
Org. Lett. 2007, 9, 2027. (c) Motokura, K.; Nakagiri, N.; Muzugaki, T.; Ebitani,
K.; Kaneda, K. J. Org. Chem. 2007, 72, 6006. (d) Kischel, J.; Mertins, K.;
Michalik, D.; Zapf, A.; Beller, M. AdV. Synth. Catal. 2007, 349, 865. (e) Noji,
M.; Konno, Y.; Ishii, K. J. Org. Chem. 2007, 72, 5161. (f) Reping, M.;
Nachtsheim, B. J.; Kuenkel, A. Org. Lett. 2007, 9, 825. (g) Huang, W.; Wang,
J. L.; Shen, Q. S.; Zhou, X. G. Tetrahedron Lett. 2007, 48, 3969. (h) Reping,
M.; Nachtsheim, B. J.; Ieawsuwan, W. AdV. Synth. Catal. 2006, 348, 1033. (i)
† Zhejiang University (Xixi Campus).
‡ Zhejiang University of Technology.
(1) (a) Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 11904. (b)
Lu, J.; Tan, X.; Chen, C. J. Am. Chem. Soc. 2007, 129, 7768. (c) Chiong, H. A.;
Daugulis, O. Org. Lett. 2007, 9, 1449. (d) Dwight, T. A.; Rue, N. R.; Charyk,
D.; Josselyn, R.; DeBoef, B. Org. Lett. 2007, 9, 3137. (e) Rech, J. C.; Yato, M.;
Duckett, D.; Ember, B.; LoGrasso, P. V.; Bergman, R. G.; Ellman, J. A. J. Am.
Chem. Soc. 2007, 129, 490. (f) Cai, G.; Fu, Y.; Li, Y.; Wan, X.; Shi, Z. J. Am.
Chem. Soc. 2007, 129, 7666. (g) Yokota, T.; Tani, M.; Sakaguchi, S.; Ishii, Y.
J. Am. Chem. Soc. 2003, 125, 1476. (h) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem.
ReV. 2002, 102, 1731. (i) Tsuji, J.; Nagashima, H. Tetrahedron 1984, 40, 2699.
(j) Nicolaou, K. C.; Zipkin, R. E.; Petasis, N. A. J. Am. Chem. Soc. 1982, 104,
5558. (k) Nicolaou, K. C.; Petasis, N. A.; Zipkin, R. E. J. Am. Chem. Soc. 1982,
104, 5560. (l) Nicolaou, K. C.; Petasis, N. A.; Uenishi, J.; Zipkin, R. E. J. Am.
Chem. Soc. 1982, 104, 5557. (m) Nicolaou, K. C.; Petasis, N. A.; Zipkin, R. E.;
Uenishi, J. J. Am. Chem. Soc. 1982, 104, 5555.
´
´
´
Sanz, R.; Martlnez, A.; Miguel, D.; Alvarez-Gutie´rrez, J. M.; Rodrlguezb, F.
AdV. Synth. Catal. 2006, 348, 1841. (j) Motokura, K.; Fujita, N.; Mori, K.;
Mizugaki, T.; Ebitani, K.; Kaneda, K. Angew. Chem., Int. Ed. 2006, 45, 2605.
(k) Yasuda, M.; Somyo, T.; Baba, A. Angew. Chem., Int. Ed. 2006, 45, 793. (l)
Kinoshita, H.; Shinokubo, H.; Oshima, K. Org. Lett. 2004, 6, 4085. (m) Kayaki,
Y.; Koda, T.; Ikariya, T. J. Org. Chem. 2004, 69, 2595. (n) Manabe, K.;
Kobayashi, S. Org. Lett. 2003, 5, 3241. (o) Ozawa, F.; Okamoto, H.; Kawagishi,
S.; Yamamoto, S.; Minami, T.; Yoshifuji, M. J. Am. Chem. Soc. 2002, 124,
10968.
´
(5) (a) Sanz, R.; Miguel, D.; Mart´ınez, A.; Alvarez-Gutie´rrez, J. M.;
Rodr´ıguez, F. Org. Lett. 2007, 9, 727. (b) Huang, W.; Wang, J.; Shen, Q.; Zhou,
X. Tetrahedron Lett. 2007, 63, 11636. (c) Cadierno, V.; Gimeno, J.; Nebra, N.
AdV. Synth. Catal. 2007, 349, 382.
10.1021/jo8010039 CCC: $40.75
Published on Web 07/26/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 6881–6883 6881

TABLE 1. Study of DDQ-Promoted C-C Bond-Forming Reaction
TABLE 2. DDQ-Promoted C-C Bond-Forming Reaction with
3-(4-Methoxylphenyl)-1-phenylpropyne 1c and Active Methylenic
Compoundsa
with 1,3-Diarylpropynesa
entry
1c
2
3
4
R1, R2
time (h)
yield (%)b
product
entry
R3, R4
time (h)
yield (%)b
product
H, H (1a)
H, H (1a)
CH3, H (1b)
CH3O, H (1c)
Cl, H (1d)
10
10
6
3
12
10
49
56
75
91
44
52
3a
3a
3b
3c
3d
3e
1
2
3
4
5
6
7
8
4-CH3C6H4, C6H5 (2b)
4-CH3OC6H4, C6H5 (2c)
4-ClC6H4, C6H5 (2d)
4-BrC6H4, C6H5 (2e)
3-ClC6H4, C6H5 (2f)
3-CH3OC6H4, C6H5 (2g)
2-CH3C6H4, C6H5 (2h)
thienyl, C6H5 (2i)
furanyl, C6H5 (2j)
C6H5, CH3 (2k)
C6H5, OEt (2l)
CH3, CH3 (2m)
1
1
4
4
5
92
83
64
70
76
80
82
81
74
92
48
47
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
5
6
H, CH3O (1e)
2
a Conditions: 0.5 mmol of 2a, 0.6 mmol of 1, 1.5 mL of MeNO2, 0.6
mmol of DDQ. b Isolated yield. c 1.5 mL of CH2Cl2 was used as
solvent.
0.5
0.5
1.5
1.0
7
9
10
11c
12c
Montevecchi has reported that phenylalkylacetylenes were
oxidized to conjugated (Z)-enynes by DDQ.6 The first step of
the reaction was described as a single-electron-transfer process
between the alkyne triple bond and DDQ, which generates the
radical ion pair. Then it transforms into its ion pair through
hydrogen atom transfer from the alkyne radical cation to DDQ•-.
In light of the mechanism and our recent findings, we explored
the coupling between 1,3-diphenylpropyne 1a and dicarbonyl
compound 2a. The reaction was carried out with DDQ in
CH2Cl2 at room temperature. A color change from colorless to
deep blue was observed, which may indicate the formation of
a complex.7 The desired product 3a was obtained in 49% yield
in 10 h (Table 1, entry 1). Then a number of solvents were
screened to optimize the reaction conditions. No coupling
product was obtained when the reaction was carried out in THF
or dioxane. The reaction could proceed in DMSO, DMF, CHCl3,
CH2Cl2, DCE, MeNO2, and NMP. The highest yield (56%)
resulted from the reaction in MeNO2 (Table 1, entry 2). The
yield did not improve markedly when the temperature was raised
to 90 °C in MeNO2. It seemed that the reaction was insensitive
to temperature. As for the influence of DDQ dosage on the
reaction, it was found that decreasing the amount of the DDQ
resulted in reduced yield, while increasing the amount to 1.5
equiv did not make the reaction system complex and the yield
was just a little lower.
The scope of the coupling reaction was explored. Thus the
electronic effect of the benzylic ring was first examined.
Compounds 1b and 1c possessing an electron-donating group
on the benzylic ring coupled with dicarbonyl compound 2a
efficiently and products 3b and 3c were obtained in 75% and
91% yield, respectively (Table 1, entries 3 and 4). In compari-
son, the reaction of 1d possessing a p-chloro group on the
benzylic ring proceeded slowly and gave product 3d in 44%
yield only (Table 1, entry 5). Electron-donating substituents such
as methyl and methoxyl group can efficiently stabilize the
benzylic cationic species and hence promote the desired C-C
bond-forming process. On the other hand, treatment of 1-(4-
methoxylphenyl)-3-phenylpropyne 1e with 2a at room temper-
ature afforded 52% yield (Table 1, entry 6). The “R2” substituent
on the benzene ring exerts little influence on the coupling
reaction.
10
a Conditions: 0.5 mmol of 2, 0.6 mmol of 1c, 1.5 mL of MeNO2, 0.6
mmol of DDQ. b Isolated yield. c 0.5 mmol of 2l or 2m, 0.6 mmol of
1c, 0.6 mmol of DDQ, 90 °C.
SCHEME 1. A Possible Mechanism
electron-donating substituents on the aromatic ring of substrates
2 also exhibited a positive effect. For example, dicarbonyl
compounds 2b, 2c, 2g, and 2h, which bear electron-donating
substituents on the aromatic ring, reacted rapidly with propar-
gylic compound 3c and satisfactory yields were obtained (Table
2, entries 1, 2, 6, and 7). For substrates 2d, 2e, and 2f, which
bear electron-withdrawing groups, longer time was required for
the reaction to be completed and relatively lower yields
(64-76%) were afforded (Table 2, entries 3-5). Heterocyclic
aryl groups such as furanyl and thienyl were compatible with
the present procedure (Table 2, entries 8 and 9). Benzoylacetone
was a suitable candidate here (Table 2, entry 10). Acetylacetone
and ethyl benzoylacetate could also be used as the substrates
despite the lower rate and yields. Again, raising the reaction
temperature to 90 °C did not result in considerable yield
improvement (Table 2, entries 11 and 12).
According to literature7 and based on our experiments, a
possible mechanism was proposed in Scheme 1. The formation
of product may have two pathways, hydride transferred directly
from propargylic position and/or hydrogen abstraction after an
electron was transferred from the propargylic triple bond to
DDQ. However, compounds 1c and 1e reacted with dicarbonyl
compound 2a to give the sole products 3c and 3e, respectively.
The incoming nucleophile attacks mainly at the original benzylic
cation position. This means the mechanism of hydride abstrac-
tion may be more possible.
Various substrates were subjected to this cross-coupling
reaction (Table 2). It could be concluded from the table that
In summary, we have developed an efficient coupling reaction
between diarylpropargylic compounds and active methylenes
using DDQ as a promoter. It is the first C-C bond-formation
(6) Montevecchi, P. C.; Navacchia, M. L. J. Org. Chem. 1998, 63, 8035.
(7) Fu, P. P.; Harvey, R. G. Chem. ReV. 1978, 78, 317.
6882 J. Org. Chem. Vol. 73, No. 17, 2008

example by activating the diarylpropargylic sp3 C-H bond
directly. It avoids prefunctionalization of the starting materials
and thus provides a concise synthesis of propargyl-substituted
carbonyl compounds.
3H), 7.01 (d, J ) 6.8 Hz, 2H), 6.80 (d, J ) 8.8 Hz, 2H), 5.88 (d,
J ) 10.4 Hz, 1H), 5.14 (d, J ) 9.6 Hz, 1H), 3.74 (s, 3H); 13C
NMR (100 MHz, CDCl3/TMS) δ 193.4, 192.6, 158.8, 137.0, 136.5,
133.5, 133.4, 131.4, 131.2, 129.6, 129.1, 128.8, 128.6, 128.5, 127.9,
127.88, 122.9, 114.0, 89.7, 85.0, 63.3, 55.2, 38.0; ESI-MS m/z 467.2
[M + Na]. Anal. Calccd for C31H24O3: C, 83.76; H, 5.44. Found:
C, 83.54; H, 5.61. For more details, see the Supporting Information.
Experimental Section
Acknowledgment. This work was financially supported by
the Specialized Research Fund for the Doctoral Program of
Higher Education of China (20060335036).
To a 10 mL two-necked round-bottomed flask containing
methylenic compound 2a (0.5 mmol, 0.112 g), 1,3-diarylpropyne
1c (0.6 mmol, 0.133 g), and MeNO2 (1.5 mL) was added DDQ
(0.6 mmol, 0.136 g). The resulting mixture was stirred for 3 h at
room temperature. Purification was done by column chromatogra-
phy on silica gel (200-300 mesh) with petroleum ether and ethyl
acetate (10:1) as the eluent to give the pure product 3c (0.203 g,
91%). Mp 116-118 °C; 1H NMR (400 MHz, CDCl3/TMS) δ 8.13
(d, J ) 7.6 Hz, 2H), 7.78 (d, J ) 7.2 Hz, 2H), 7.59 (t, J ) 7.4 Hz,
1H), 7.51-7.44 (m, 5H), 7.31 (t, J ) 7.6 Hz, 2H), 7.26-7.13 (m,
Supporting Information Available: Experimental proce-
dures and compound characterization data for products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO8010039
J. Org. Chem. Vol. 73, No. 17, 2008 6883