CuI/L-proline-catalyzed coupling reactions of aryl halides with activated methylene compounds

Article abstract of DOI:10.1021/ol0518838

(Chemical Equation Presented) The arylation of ethyl acetoacetate, ethyl benzoyl acetate, and diethyl malonate under the catalysis of Cul/L-proline in DMSO proceeds smoothly at 40-50°C in the presence of Cs₂CO ₃ to provide the 2-aryl

Full text of DOI:10.1021/ol0518838

ORGANIC
LETTERS
2005
Vol. 7, No. 21
4693-4695
CuI/ -Proline-Catalyzed Coupling
L
Reactions of Aryl Halides with Activated
Methylene Compounds
Xiaoan Xie,† Guorong Cai,† and Dawei Ma*,‡
Department of Chemistry, Fudan UniVersity, Shanghai 200433, China, and State Key
Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu,
Shanghai 200032, China
madw@pub.sioc.ac.cn
Received August 5, 2005
ABSTRACT
The arylation of ethyl acetoacetate, ethyl benzoyl acetate, and diethyl malonate under the catalysis of CuI/L-proline in DMSO proceeds smoothly
at 40−50 °C in the presence of Cs2CO3 to provide the 2-aryl-1,3-dicarbonyl compounds in good yields. Both aryl iodides and aryl bromides
are compatible with these reaction conditions.
In recent years, great advances have been achieved on the
modification of copper-catalyzed Ullmann-type coupling
reactions.1 By using some special ligands such as N,N- and
N,O-bidentate compounds, many CuI-catalyzed C-N,2 C-O,3
C-S,4 and C-C5 bond formation reactions could be carried
out at relatively low temperatures. Although the detailed
function for these ligands awaits further exploration,1c
discovery of new transformations using these ligands is still
actively pursued.6 This campaign would not only provide
useful synthetic processes but also shed light on mechanism
investigations.
The arylation of activated methylene compounds in the
presence of copper or copper salts, namely, the Hurtley
reaction,7 is an applicable transformation with a long history.
The scope of this reaction is very narrow, as only o-
bromobenzoic acid and its closely related bromides are
reactive.7 To overcome this drawback, numerous efforts have
† Fudan University.
‡ Chinese Academy of Sciences.
(1) For reviews, see: (a) Ley, S. V.; Thomas, A. W. Angew. Chem., Int.
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248, 2337.
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1998, 120, 12459. (b) Ma, D.; Xia, C. Org. Lett. 2001, 3, 2583. (c) Klapars,
A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2001,
123, 7727. (d) Gujadhur, R. K.; Bates, C. G.; Venkataraman, D. Org. Lett.
2001, 3, 4315. (e) Antilla, J. C.; Klapars, A.; Buchwald, S. L. J. Am. Chem.
Soc. 2002, 124, 11684. (f) Kwong, F. Y.; Klapars, A.; Buchwald, S. L.
Org. Lett. 2002, 4, 581. (g) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2003,
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Spindler, J.-F.; Taillefer, M. Chem. Eur. J. 2004, 10, 5607. (j) Ma, D.; Cai,
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P.; Reider, P. J. Org. Lett. 2002, 4, 1623. (b) Ma, D.; Cai, Q. Org. Lett.
2003, 5, 3799. (c) Nordmann, G.; Buchwald, S. L. J. Am. Chem. Soc. 2003,
125, 4978. (d) Wan, Z.; Jones, C. D.; Koenig, T. M.; Pu, Y. J.; Mitchell,
D. Tetrahedron Lett. 2003, 44, 8257. (e) Cristau, H.-J.; Cellier, P. P.;
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10.1021/ol0518838 CCC: $30.25
© 2005 American Chemical Society
Published on Web 09/23/2005

been devoted to develop new reaction conditions during the
past decades.4a,8,9 However, initial success for arylation
starting from aryl halides relies on using stoichiometic or
even excess amounts of copper salts.8a-d The first break-
through for this arylation to use catalytic amounts of CuI
was made by Miura and co-workers in 1993, in which the
coupling reaction was carried out at 120 °C in DMSO.8e
Under these conditions the products were readily decom-
posed, and therefore good yields were not obtained in some
cases. In addition, only aryl iodides were suitable for this
process and aryl bromides was found to afford poor conver-
sion under the described conditions. A milder protocol was
developed by Buchwald and Hennessy in 2002 to employ
CuI/2-phenylphenol as a catalytic system to perform the
arylation of diethyl malonate.4a Unfortunately, their substrates
are still limited to aryl iodides. Furthermore, in the above
two processes, 2 equiv of activated methylene compounds
were required to ensure good yields, which would become
problematic when some expensive activated methylene
compounds were employed. Consequently, more efficient
catalytic systems for these coupling reactions are required.
Recently, we found that under the catalysis of CuI/L-proline,
both aryl iodides and aryl bromides could couple with excess
amounts of â-keto esters and diethyl malonate to provide
the corresponding arylation products in good yields. Herein,
we wish to report these results.
As indicated in Table 1, our experiments were first
conducted by coupling 4-iodoanisole (1 equiv) with ethyl
acetoacetate (2 equiv) catalyzed by 20 mol % of CuI and 40
mol % of L-proline. This reaction proceeded at 70 °C in
DMSO in the presence of 1.5 equiv of Cs2CO3 to produce
the desired coupling product in 33% yield (entry 1).
Increasing the amounts of the base to 4 equiv gave higher
yields (compare entries 1 and 2). Under these conditions it
was determined that starting materials disappeared and some
decomposed products formed. Accordingly, we decided to
lower the reaction temperatures to improve the reaction yields
further. To our delight, when this coupling reaction was
carried out at 40 °C, a satisfactory yield was obtained (entry
3). By prolonging the reaction time the coupling could be
completed at room temperature (entry 4). Reducing the
amounts of ethyl acetoacetate to 1.2 equiv still afforded a
good yield (entry 5). Thus, in the following studies we always
used a slight excess of activated methylene compounds as
the coupling agents. For other solvents, although 1,4-dioxane
or toluene gave the coupled product at 70 °C (entries 6 and
Table 1. Coupling Reaction of 4-Iodoanisole with Ethyl
Acetoacetate under the Catalysis of CuI/Liganda
entry
base
solvent
ligandb
temp (°C)
yield (%)c
1
2
3
4
5
6
7
8
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K3PO4
DMSO
DMSO
DMSO
DMSO
DMSO
dioxane
dioxane
toluene
toluene
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
A
A
A
A
A
A
A
A
A
A
A
A
B
C
70
70
40
25
40
70
50
70
50
50
50
50
40
40
40
33d
47
83
81
84
30
0
20
0
0
0
0
54
31
0
9
10
11
12
13
14
15
NaH
Cs2CO3
Cs2CO3
Cs2CO3
a Reaction conditions: CuI (0.1 mmol), amino acid (0.2 mmol),
4-iodoanisole (0.5 mmol), ethyl acetoacetate (1.0 mmol), base (2 mmol),
DMSO (1 mL), under Ar atmosphere, 24 h. b ligand: (A) L-proline; (B)
N,N-dimethylglycine; (C) N-methylglycine. c Isolated yield. d 0.75 mmol of
base was added. e Reaction time was 72 h. f 0.6 mmol of ethyl acetoacetate
was used.
8), no conversion was seen at 50 °C in these solvents (entries
7 and 9). In addition, a switch in the base to K2CO3, K3PO4,
or NaH did not give any coupled product (entries 10-12),
which indicated that using Cs2CO3 as a base was very critical
for this reaction. For other ligands, N,N-dimethylglycine gave
a moderate yield (entry 13), whereas N-methylglycine was
even worse (entry 14). Without the addition of the ligands,
no coupling reaction occurred (entry 15), which clearly
showed that the presence of amino acids was necessary for
this reaction.
On the basis of the above studies, we concluded that using
L-proline as the ligand, DMSO as the solvent, and 4 equiv
of Cs2CO3 as the base and carrying out the reaction at 40
°C are optimized conditions. The reaction scope was next
explored with different aryl iodides and activated methylene
compounds. As summarized in Table 2, other electron-rich
aryl iodides were also compatible with these conditions,
delivering arylation products in good yields by coupling with
ethyl acetoacetate, ethyl benzoylactate, and diethyl malonate
(entries 1-7). Sterically hindered aryl iodides were less
reactive but still gave good yields by prolonging the reaction
time (entries 8 and 9). The electron-deficient aryl iodides
were generally superior to electron-rich ones, as evidenced
by completion of the coupling reaction in shorter time and
affording better yields. This trend is consistent with that
observed in our aryl amination reactions2p but is opposite to
that noticed in the coupling reactions of aryl iodides with
sodium azide2m and sodium methanesulfinate.4d These dif-
ferences implied that the mechanisms for these coupling
reactions might not be analogous.
(7) (a) Hurtley, W. R. H. J. Chem. Soc. 1929, 1870. (b) Bruggink, A.;
Ray, S. J.; McKillop, A. Org. Synth. 1978, 58, 52. For related studies, see:
(c) Cirigottis, Ritchie, E.; Taylor, W. C. Aust. J. Chem. 1974, 27, 2209. (d)
Bruggink, A.; McKillop, A. Tetrahedron 1975, 31, 2607. (e) Shinkwin, A.
E.; Whish, W. J. D.; Threadgill, M. D. Bioorg. Med. Chem. 1999, 7, 297.
(f) Bryson, T. A.; Stewart, J. J.; Gibson, J. M.; Thomas, P. S.; Berch, J. K.
Green Chem. 2003, 5, 174.
(8) (a) Setsune, J.; Matsukawa, K.; Wakemoto, H.; Kaito, T. Chem. Lett.
1981, 367. (b) Setsune, J.; Matsukawa, K.; Kaito, T. Tetrahedron Lett. 1982,
23, 663. (c) Suzuki, H.; Kobayashi, T.; Yoshida, Y.; Osuka, A. Chem. Lett.
1983, 193. (d) Suzuki, H.; Yi, Q.; Inoue, J.; Kusume, K.; Ogawa, T. Chem.
Lett. 1987, 887. (e) Okuro, K.; Furuune, M.; Miura, M.; Nomura, M. J.
Org. Chem. 1993, 58, 7606. (f) Pivsa-Art, S.; Fukui, Y.; Miura, M.; Nomura,
M. Bull. Chem. Soc. Jpn. 1996, 69, 2039.
(9) (a) Konopelski, J. P.; Hottenroth, J. M.; Oltra, H. M.; Ve´liz, E. A.;
Yang, Z. Synlett 1996, 609. (b) Hang, H. C.; Drotleff, E.; Elliott, G. I.;
Ritsema, T. A.; Konopelski, J. P. Synthesis 1999, 398. In their cases the
substrates were limited to o-bromophenols.
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Org. Lett., Vol. 7, No. 21, 2005

Table 2. Coupling Reaction of Aryl Iodides with Activated
Methylene Compounds under the Catalysis of CuI/L-Prolinea
Table 3. Coupling Reaction of Aryl Bromides with Activated
Methylene Compounds under the Catalysis of CuI/L-Prolinea
a Reaction conditions: aryl bromide (0.5 mmol), activated methylene
compound (0.6 mmol), CuI (0.1 mmol), L-proline (0.2 mmol), Cs2CO3 (2
mmol), DMSO (1 mL), 50 °C, under Ar atmosphere. b Isolated yield.
4-methylphenyl bromide with ethyl acetoacetate and ethyl
malonate took place at 50 °C, producing the desired arylation
products in good yields (Table 3, entries 1 and 2). Other
bromides, whether electron-rich or electron-deficient, all
worked well under these conditions. In these cases, good
conversions were observed, although longer reaction times
were required compared with aryl iodides. Attempts to
shorten the reaction times by raising the reaction temperature
gave slightly lower yield. Like aryl iodides, aryl bromides
with electron-withdrawing groups showed better reactivity
compared with those bearing electron-donating groups.
In summary, we have discovered that CuI/L-proline is a
useful catalytic system for arylation of activated methylene
compounds that delivered 2-aryl-1,3-dicarbonyl compounds
in great diversity. In contrast with the previous processes,4a,8e
excellent conversions were obtained when aryl bromides
were employed. This advantage would prompt the synthetic
applications of this CuI-catalyzed C-C bond formation
reaction.
a Reaction conditions: aryl iodide (0.5 mmol), activated methylene
compound (0.6 mmol), CuI (0.1 mmol), L-proline (0.2 mmol), Cs2CO3 (2
mmol), DMSO (1 mL), 40 °C, under Ar atmosphere. b Isolated yield.
Of the three activated methylene compounds we employed,
diethyl malonate displayed the best reactivity as shown by
shorter reaction time (compare entries 15-17), presumably
as a result of its lowest acidity. Noteworthy is that an
L-phenylalanine-derived iodide was also tolerated in this
reaction, giving the corresponding coupling product in 87%
yield (entry 20). This result indicated that the present method
would be useful for modifying aromatic amino acids.
Although in Buchwald’s case,4a excellent conversion was
obtained using 4-iodophenol as a substrate, no desired
coupling product was determined in our reaction system
(entry 21). The reason for this drawback is not clear yet.
Acknowledgment. The authors are grateful to the Chinese
Academy of Sciences, National Natural Science Foundation
of China (grants 20321202 and 20132030), and Science and
Technology Commission of Shanghai Municipality (grants
02JC14032 and 03XD14001) for their financial support.
Supporting Information Available: Experimental pro-
cedures and copies of 1H NMR spectrum for all new
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
We next examined aryl bromides as the substrates for our
catalytic system and were pleased to find that coupling of
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Org. Lett., Vol. 7, No. 21, 2005
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