Regioselective palladium-catalyzed aminations of 3,5-dibromo-2-pyrone with various aryl and alkyl amines

Article abstract of DOI:10.1016/S0040-4039(02)02484-X

3,5-Dibromo-2-pyrone underwent facile palladium-catalyzed coupling reactions with various primary and secondary alkyl and aryl amines to furnish a variety of the previously unknown 3-arylamino- and 3-alkylamino-5-bromo-2-pyrones with good to excellent regioselectivity and chemical yields.

Full text of DOI:10.1016/S0040-4039(02)02484-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 65–67
Regioselective palladium-catalyzed aminations of
3,5-dibromo-2-pyrone with various aryl and alkyl amines
Jin-Hee Lee and Cheon-Gyu Cho*
Department of Chemistry, Hanyang University, 133-791 Seoul, Republic of Korea
Received 18 October 2002; revised 1 November 2002; accepted 6 November 2002
Abstract—3,5-Dibromo-2-pyrone underwent facile palladium-catalyzed coupling reactions with various primary and secondary
alkyl and aryl amines to furnish a variety of the previously unknown 3-arylamino- and 3-alkylamino-5-bromo-2-pyrones with
good to excellent regioselectivity and chemical yields. © 2002 Elsevier Science Ltd. All rights reserved.
Substituted 2-pyrones are important structural subunits
present in a number of naturally occurring products1
and versatile synthetic building blocks for the produc-
tion of various structurally and physiologically impor-
tant molecules, primarily via their Diels–Alder
cycloadditions with appropriate dienophiles.2
Palladium-catalyzed amination of 3,5-dibromo-2-
pyrone may result in the cleavage of the lactone ring as
the reaction requires the presence of a base. In fact,
3,5-dibromo-2-pyrone completely disappeared within a
few hours when heated with aniline in the presence of
NaOtBu or K2CO3. Thus, the reaction conditions must
be controlled in order to achieve a successful reaction.
With aniline as a model, we studied the aminations of
3,5-dibromo-2-pyrone under various amination condi-
tions reported in the literature.4 Despite our initial
doubt, however, the amination proceeded reasonably
well, as can be seen in Table 1.
As a part of our ongoing research program on 3,5-
dibromo-2-pyrone,3 we have recently reported that it
undergoes regioselective Sonogashira couplings and
stannylations to afford 3-alkynyl-5-bromo-2-pyrones
and 3-trialkylstannyl-5-bromo-2-pyrones, respectively.3a
Also reported was the Stille coupling reactions of 3-
trimethylstannyl-5-bromo-2-pyrone with various aryl
and vinyl halides for the synthesis of various 3-aryl-
and 3-vinyl-5-bromo-2-pyrones.3b
Table 1. Palladium-catalyzed amination of 3,5-dibromo-2-
pyrone with aniline under various conditions
In this account, we wish to report regioselective amina-
tion reactions of 3,5-dibromo-2-pyrone with aryl and
alkyl amines for the synthesis of a variety of previously
unknown 3-arylamino- and 3-alkylamino-5-bromo-2-
pyrones. The amino groups at the C3 position in the
resulting 2-pyrones would push the electrons into the
pyrone unit. Such electronic perturbation may lead to a
substantial change in their dienyl characters. In addi-
tion, the resulting stereochemically defined bicyclolac-
tones would be useful synthetic intermediates for
various systems including a-amino acids with substi-
tuted cyclohexenyl residues.
Entry Condition
Yield
1
2
3
4
5
6
7
8
9
Pd2(dba)3/dppf/NaOtBu/dioxane/110°C/5 h
Trace
Trace
42%
54%
Trace
57%
Pd(OAc)2/BINAP/Cs2CO3/toluene/110°C/5 h
Pd(OAc)2/BINAP/K2CO3/toluene/110°C/0.5 h
Pd(OAc)2/BINAP/K2CO3/toluene/120°C/0.5 h
Pd(OAc)2/P(tBu)3/Cs2CO3/toluene/110°C/2 h
Pd2(dba)3/xantphos/K2CO3/toluene/100°C/4 h
Pd2(dba)3/xantphos/Cs2CO3/toluene/100°C/4 h
76%
Pd2(dba)3/xantphos/NaOtBu/toluene/100°C/4 h Trace
Pd(OAc)2/xantphos/Cs2CO3/toluene/110°C/0.5 h 82%
* Corresponding author. Tel.: +82-2-2290-0936; fax: +82-2-2299-0762;
e-mail: ccho@hanyang.ac.kr
0040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02484-X

66
J.-H. Lee, C.-G. Cho / Tetrahedron Letters 44 (2003) 65–67
NaOtBu cleaved the lactone ring and was thus ineffec-
tive, regardless of the type of palladium catalyst and
ligand. Pd(OAc)2 gave better results than Pd2(dba)3.
Only a trace of the product was obtained with the
catalytic system of Pd(OAc)2/P(tBu)3.5 The results in
entries 2 and 3 are quite unusual in that the reaction
does proceed with K2CO3, but not with Cs2CO3. Use of
xantphos6 improved both reaction rate and yield. The
best result was obtained under the condition 9, using
the Pd(OAc)2/xantphos system. Running the reaction at
a slightly elevated temperature (110°C) shortened the
reaction time, suppressing the lactone ring cleavage
reaction, thus improving the product yield. Further
increase of reaction temperature, however, resulted in a
decrease of the product yield (55% at 120°C, data not
shown in Table 1).
the C5 position of 3,5-dibromo-2-pyrone were
observed.
Unlike the aminations with aromatic amines, however,
the catalytic system Pd(OAc)2/xantphos was not effec-
tive in the couplings with alkyl amines, providing only
a trace of the desired products. We have found that the
catalytic system BINAP/Pd(OAc)2/K2CO3 is much bet-
ter suited in this case, affording the corresponding
products in reasonable isolated yields. The actual cou-
pling reactions turned out to be highly dependent upon
the reaction temperature. Each reaction shown in Table
3 was optimized by running the reactions at various
temperatures.8 Secondary amines gave better results
than primary amines, presumably due to their lower
nucleophilicity.
Table 2 summarizes the results of the amination reac-
tions with various other aryl amines under the condi-
tion 9.
In summary, we have found that 3,5-dibromo-2-pyrone
undergoes facile palladium-catalyzed amination reac-
tions with various aryl and alkyl amines, regioselec-
tively at C3, to provide a series of previously unknown
3-aryl- and 3-alkylamino-5-bromo-2-pyrones.9 Their
dienyl properties will be studied and presented in due
course.
As shown, various types of aryl amines underwent
coupling reactions, providing 3-arylamino-5-bromo-2-
pyrones in fair to good isolated yields.7 No couplings at
Table 2. Palladium-catalyzed amination with aniline
Table 3. Palladium-catalyzed aminations with alkyl amines

J.-H. Lee, C.-G. Cho / Tetrahedron Letters 44 (2003) 65–67
67
Acknowledgements
1999, 576, 125; (b) Hartwig, J. F. Angew. Chem., Int. Ed.
Engl. 1998, 37, 2046.
5. Watanabe, M.; Yamamoto, T.; Nishiyama, M. Chem.
We would like to thank the financial support of
Hanyang University, Korea, made in the program year
of 2002.
Commun. 2000, 133.
6. Ali, M. H.; Buchwald, S. L. J. Org. Chem. 2001, 66, 2560.
7. Representative procedure: A sealed tube was charged with
50 mg (0.197 mmol) of 3,5-dibromo-2-pyrone, 2 mol% of
Pd(OAc)2, 4 mol% of xantphos (ligand/Pd=2), and cesium
carbonate (0.296 mmol). After adding 1 mL of toluene, the
mixture was degassed and backfilled with argon where-
upon was added aniline (0.236 mmol, 1.2 equiv.), while
cooling with an ice bath. After stirring for 30 min at
110°C, the reaction mixture was cooled to room tempera-
ture, diluted with CH2Cl2, filtered through a thin layer of
Celite, and concentrated. The crude material was purified
by using column chromatography (hexanes:EtOAc=80:1)
to give the product 3a in 82% yield.
8. Representative procedure: A sealed tube was charged with
50 mg (0.197 mmol) of 3,5-dibromo-2-pyrone, 3 mol% of
Pd(OAc)2, 6 mol% of BINAP(ligand/Pd=2), and potas-
sium carbonate (0.296 mmol). After adding 1 mL of
toluene, the mixture was degassed and backfilled with
argon whereupon was added pyrrolidine (0.236 mmol, 1.2
equiv.), while cooling with an ice bath. After stirring for 20
min at 80°C, the reaction mixture was cooled to room
temperature, diluted with a mixture of CH2Cl2 and
methanol (30:1, v/v), filtered through a thin layer of Celite,
and concentrated. The crude material was purified using
column chromatography (CH2Cl2:MeOH=40:1) to give
the product 3i in 77% yield.
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