A general and practical access to chiral quinoxalinones with low copper-catalyst loading

Article abstract of DOI:10.1002/adsc.201000323

A general, straightforward, and practical access to multi-substituted chiral quinoxalin-2-ones has been achieved based on the copper(I) chloride-dimethylethylenediamine (DMEDA) catalyst system. With the use of 1 mol% copper(I) chloride, structurally diverse quinoxalin-2-ones were generated with high optical purity from readily available starting materials, 2-haloanilines and α-amino acids, in a one-pot manner.

Full text of DOI:10.1002/adsc.201000323

FULL PAPERS
DOI: 10.1002/adsc.201000323
A General and Practical Access to Chiral Quinoxalinones with
Low Copper-Catalyst Loading
Shinji Tanimori,a,* Hiroaki Kashiwagi,a Takeshi Nishimura,a
and Mitsunori Kirihataa
a
Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1–1 Gakuen-cho, Naka-ku, Sakai,
Osaka 599-8531, Japan
Fax : (+81)-72-254-9469; e-mail: tanimori@bioinfo.osakafu-u.ac.jp
Received: April 27, 2010; Revised: August 18, 2010; Published online: October 12, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000323.
Abstract: A general, straightforward, and practical high optical purity from readily available starting
access to multi-substituted chiral quinoxalin-2-ones materials, 2-haloanilines and a-amino acids, in a one-
has been achieved based on the copper(I) chloride- pot manner.
dimethylethylenediamine (DMEDA) catalyst system.
With the use of 1 mol% copper(I) chloride, structur- Keywords: copper catalyst; coupling reactions; low
ally diverse quinoxalin-2-ones were generated with catalyst loading; quinoxalinones; Ullmann reaction
Introduction
However, the amounts of copper catalyst used are
larger (usually 5 to 10 mol%) than those of palladium,
Recently, Ullmann-type coupling reactions[1] using rhodium and iridium catalysts and a decrease is
copper as catalyst introduced by Ullmann,[2] Gold- highly desirable from economical and environmental
berg,[3] Buchwald,[4] Ma[5] and Taillefer[6] are attracting viewpoints.[10]
much attention, because of the experimental simplici-
Herein, we report the unprecedented example for a
ty, economic points of view, as well as low toxicity low catalyst-loading domino-type reaction to form the
and stability of the catalyst. Therefore, various effi- multi-substituted quinoxalinones as their chiral forms
cient and useful carbon-carbon, carbon-nitrogen, from readily available starting materials (Scheme 1).
carbon-oxygen, and carbon-sulfur bond forming reac- Quinoxaline and derivatives are an important struc-
tions were developed in recent years.[1]
tural motif frequently found in pharmaceutical
The domino-type reaction which forms two or more drugs[11] and agrochemicals.[12] Representative synthe-
carbon-carbon and carbon-heteroatom bonds within a ses of quinoxalinones include the microwave assisted
one-pot process is of particular interest because the condensation of 1,2-phenylenediamine with citric
core structures (pharmaceutical fragments[7]) such as acid,[11a] nucleophilic substitution of 2-fluoronitroben-
the heterocyclic compounds found in many pharma- zene with methyl pyrrole-2-carboxylate[13] and/or an
ceuticals, agrochemicals and natural products can be a-amino acid[11b] followed by reductive cyclization, or-
constructed efficiently in a single operation.[8] There ganocatalytic hetero-Diels–Alder reaction of alde-
are a lot of examples that use the palladium catalysts hydes with o-benzoquinone diimide followed by oxi-
so far.[9] Some examples that use a copper catalyst in dation,[14] the addition of o-phenylenediamine to di-
domino reactions have appeared in recent years.[1]
ACHTUNGTRENaNGNU lkyl acetylenedicarboxylates followed by reaction
Scheme 1. Copper-mediated one-pot formation of quinoxalinones.
Adv. Synth. Catal. 2010, 352, 2531 – 2537
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2531

Shinji Tanimori et al.
FULL PAPERS
with arylsulfonyl isocyanates.[15] However, these meth-
ods might suffer from the limited availability of the
starting materials, harsh conditions, poor yield,
narrow scope, and/or expensive catalysts. Therefore,
more efficient and facile routes to these useful mole-
cules under mild onditions are needed.
Table 1. Optimization of reaction conditions for the reaction
with 2-bromoaniline 1 and l-phenylalanine 2.[a]
Entry Cat.
[mol%]
Base
T
t
L
Yield
[%][b]
Results and Discussion
[8C] [h]
Optimization of Conditions for the Reaction of
2-Bromoaniline and l-Phenylalanine
1[c]
2[c]
3
4
5
6
7
8
9
CuCl [10] K3PO4 120
12 None
12 None
12 None
12 EDA
12 TMEDA 81
12 DMEDA 93
48 DMEDA 71
48 DMEDA 19
24 DMEDA 99
24 DMEDA 2
48 DMEDA 96
85
66
91
86
CuCl [1]
CuCl [1]
CuCl [1]
CuCl [1]
CuCl [1]
K3PO4 120
K3PO4 120
K3PO4 120
K3PO4 120
K3PO4 120
In our previous paper, we reported the synthesis of
quinoxalinones from 2-haloanilines and amino acids
by the use of traditional higher loading catalytic con-
ditions (10 mol% copper(I) iodide using cesium car-
bonate as base in DMSO at 1258C for 5 h under a ni-
trogen ballon).[16] Unfortunately, we did not make a
further effort to improve the conditions. For this pur-
pose, copper(I) chloride and potassium phosphate
were newly selected as catalyst and base after the pre-
liminary survey.[17] Both of them are easy to handle,
less expensive and less toxic. 2-Bromoaniline 1 and l-
phenylalanine 2 were employed as standard substrates
to seek the optimal reaction conditions. Reaction of 1
with 2 (2 equiv.)[16,18] in the presence of 10 mol% cop-
per(I) chloride and potassium phosphate (2 equiv.) in
DMSO at 1208C for 12 h under a nitrogen balloon
gave the target quinoxalinone 3 in 85% yield
(Table 1, entry1). On decreasing the catalyst to
1 mol%, 3 was obtained in 66% yield (entry 2). To
CuCl [0.5] K3PO4 120
CuCl [0.1] K3PO4 120
CuCl [1]
FeCl3 [10] K3PO4 130
CuCl [1] DBU 110
K3PO4 110
10
11
[a]
Unless otherwise stated, reactions were carried out with
1 (1.97 mmol), 2 (3.94 mmol, 2 equiv), catalyst (1 mol%),
ligand (20 mol%), and base (3.94 mmol, 2 equiv.) in
DMSO (7 mL) under a nitrogen atmosphere in the
sealed tube.
[b]
[c]
Isolated yield.
Reaction under nitrogen baloon. DMEDA=dimethyle-
thylenediamine, EDA=ethylenediamine, TMEDA=
tetramethylethylenediamine,
AHCTUNGTREG[NNUN 5.4.0]undec-7-ene.
DBU=1,8-diazabicyclo-
our delight, satisfactory results (91%) were realized from the practical point of view to avoid the waste of
in the sealed tube (entry 3).[19] We next investigated inorganic salt.[20] Most of the cases with copper-cata-
the effect of ligand. TMEDA and EDA did not exert lyzed reaction, except for Sonogashira coupling,[21] use
a notable effect, although DMEDA[10b] gave a slight inorganic bases such as cesium carbonate, potassium
better yield (entries 4, 5, and 6). On further decreas- phosphate, potassium carbonate, sodium hydroxide,[1]
ing the catalyst to 0.5 and 0.1 mol%, the reactions af- the use of organic base is, to the best of our knowl-
forded unsatisfactory results (entries 7 and 8). The ex- edge, unprecedented. We are now seeking new reac-
cellent conversion was realized with 1 mol% cop- tion conditions based on the use of an organic base in
per(I) chloride and 20 mol% DMEDA to produce the copper-catalyzed reaction. Consequently, three
quinoxalinone 3 in 99% yield after 24 h (not shown) options for the conditions have been discovered: (i)
and the efficiency was retained even at 1108C ligand-free conditions (entry 3), (ii) conditions with
(entry 9). On lowering the temperature to 1008C, the high conversion at relatively low temperatures
yield decreased to 44% (not shown). When the (entry 9), and (iii) conditions without the use of an in-
amount of DMEDA was diminished to 1 mol%, organic salt (entry 11).
5 mol%, and 10 mol%, the yields of 3 were 94%,
95%, and 97%, respectively (not shown). In a blank
experiment, the reaction did not proceed in the ab- Copper-Catalyzed Synthesis of Substituted
sence of copper catalyst. The presence of base was Quinoxaline-2-ones via Coupling of 2-Bromoaniline
also essential. The reaction without base gave only with Diverse a-Amino Acids
1% yield of compound 3 (not shown). IronACTHNUTRGNE(NUG III) chlo-
ride was a less effective catalyst in the present system Next, we examined the scope and limitation of the a-
(entry 10). The use of the organic base DBU also af- amino acids for this transformation with the opti-
forded the desired product 3 in high yield, although a mized conditions (Table 1, entry 9) and the results are
prolonged reaction time (48 h) was needed (entry 11). summarized in Table 2. A variety of a-amino acids
The use of an organic base would be advantageous was feasible to this protocol. It was noted that the
2532
asc.wiley-vch.de
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 2531 – 2537

A General and Practical Access to Chiral Quinoxalinones
Table 2. Copper-catalyzed synthesis of substituted quinoxalin-2-ones 5 via coupling of 2-bromoaniline 1 with diverse a-amino
acids 4.[a]
Entry
1
4
5
Yield [%][b]
86
2
3
92
77
4
5
6
7
59; 62[c]
65
74
75
8
92
9
59; 58[c]
10
81
11
74
[a]
Reaction conditions: 2-bromoaniline (1.97 mmol), amino acid (3.94 mmol, 2 equiv.), CuCl (1 mol%), DMEDA
(20 mol%), and K3PO4 (3.94 mmol, 2 equiv.) in DMSO (7 mL) at 1108C under a nitrogen atmosphere in the sealed tube.
Isolated yield.
[b]
[c]
Reactions with DBU (2 equiv.) as base instead of K3PO4 for 48 h.
Adv. Synth. Catal. 2010, 352, 2531 – 2537
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2533

Shinji Tanimori et al.
FULL PAPERS
product 5c derived from l-isoleucine with 2-bromo- transformed into diastereomers 9 and 10 by the reac-
ACHTUNGTRENNUNGaniline was a single stereoisomer by NMR analysis tion of l-menthyl chloroformate 8, respectively, as
which showed that the possible epimerization of the shown in Scheme 2. None of peaks corresponding to
chiral center at C-3 position did not take place the possible diastereomer have been observed based
throughout the reaction and work-up process on NMR analysis compared to authentic samples de-
(entry 3). A high tolerance towards functional groups rived from racemic 3 and 5a so that we concluded
in the amino acids was observed when tyrosine, tryp- tentatively that the possible epimerization at the C-3
tophan and serine were employed as coupling partner position has not occured to produce final products
without protecting hydroxy and amino groups to with high optical purity. This underlines the mildness
afford the corresponding quinoxalinones 5g, 5h and of the reaction conditions.
5k in good yields (entries 7, 8, and 11). The a,a’-sub-
stituted amino acid, 2-aminoisobutyric acid, was also
tolerated for this cyclization with an acceptable yield Assumption of the Reaction Path
(entry 5). Amino acids with a secondary amine func-
tion also worked well to give tricyclic quinoxalinones It was assumed that this annulation reaction would
À
5i and 5j in good yields (entries 9 and 10). The reac- take place via the first C N coupling followed by in-
tion of the simplest amino acid, glycine, with 2-bro- tramolecular dehydrative amide bond formation.
moaniline gave only a 9% yield of 3,4-dihydro-1H- Control experiments with the use of aniline and
quinoxalin-2-one because of its high polarity which amino acid under our conditions did not give any re-
prevented an efficient isolation (not shown). No reac- action products (Scheme 3). On the other hand, the
tion was observed when cysteine was employed as a reaction of 2-bromoaniline with an amino acid afford-
coupling partner. In this case, the starting material ed the coupling product 11 in 66% yield. These results
was recovered quantitatively. Probably, cysteine might suggested the possible reaction course stated above.
work as a catalyst poison.
Convenient Synthesis of GW420867X
Copper-Catalyzed Synthesis of Multiply Substituted
Quinoxalin-2-ones via Coupling of Substituted
2-Bromoanilines with a-Amino Acids
Finally, we wanted to demonstrate the utility of this
method through the synthesis of GW420867X 14,[24]
non-nucleoside reverse transcriptase inhibitor
a
Table 3 shows the results by employing various 2-bro- (Scheme 4). 2-Bromo-4-fluoroaniline 12 was reacted
moanilines as coupling partner in this transformation. with (S)-(+)-2-aminobutyric acid under the conditions
4-Methyl-, 4-chloro-, 2-trifluoromethoxy-, pyridyl-, to give a 97% yield of quinoxalinone 13, which was
and N-alkylanilines were investigated. As a result, transformed into GW420867X 14 in 88% yield by
these substituted anilines reacted with several a- standard methods.
amino acids to generate the corresponding diverse
multiply substituted quinoxalinones 7a to 7h without
a significant loss of reactivity.
Conclusions
In conclution, we have found an efficient, low catalyst
loading protocol to synthesize optically pure quinoxa-
linones in a one-pot process without the use of pro-
Assumption of Optical Purity
As quinoxalinones are known to be useful templates tecting groups from readily accessible and inexpensive
for drug development, it is highly desirable to develop raw materials (both coupling partners, catalyst, ligand,
a general and practical method for the synthesis of and base). The efficiency was even better than that of
chiral quinoxalinones.[11c,22] To date, limited methods our previous report[16] in which 10 mol% of catalyst
have appeared for the synthesis of optically active was used. This method tolerates a variety of function-
quinoxalinones,[11c,23] which include liquid-phase syn- al groups on both coupling partners (Table 2 and
thesis under microwave irradiation,[23a] organocatalytic Table 3). Ligand-free conditions also exhibit the ex-
hetero-Diels–Alder reactions,[14,23b] enantioselective cellent efficiency (Table 1, entry 3).[25] The conditions
reduction of quinoxalines and quinoxalinones.[23d] employing an organic base instead of potassium phos-
However, they all requre multiple reaction steps.
phate also gave good yields of products which avoid-
As mentioned above, the loss of chirality of quin- ed the inorganic waste (Table 1, entry 11). Structurally
ACHTUNGTRENNUNG
2534
asc.wiley-vch.de
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 2531 – 2537

A General and Practical Access to Chiral Quinoxalinones
Table 3. Copper-catalyzed synthesis of multi-substituted quinoxalin-2-ones 7 via coupling of substituted 2-bromoanilines 6
with a-amino acids 4.[a]
Entry
1
6
4
7
Yield [%][b]
83
2
3
81
99
4
5
6
74; 82[c]
81
74
7
93
74
8
[a]
Reaction conditions: 2-bromoaniline (1.97 mmol), amino acid (3.94 mmol, 2 equiv.), CuCl (1 mol%), DMEDA
(20 mol%), and K3PO4 (3.94 mmol, 2 equiv.) in DMSO (7 mL) at 1108C under a nitrogen atmosphere in the sealed tube.
Isolated yield.
[b]
[c]
Reaction with DBU as base (2 equiv.) instead of K3PO4 for 48 h.
signed by their derivatizaion to diastereomers and Experimental Section
NMR analysis. The present method was successively
applied to a concise synthesis of the chiral drug General Procedure for Copper-Catalyzed Coupling
GW420867X and therefore may find more applica- Reaction of 2-Bromoanilines with a-Amino Acids to
tions in organic synthesis and pharmaceutical devel- form Quinoxalin-2-ones (2-mmol Scale)
opment.[11,12,22] Studies on further applications of this
After standard cycles of evacuation and back-filling with dry
strategy are underway and will be disclosed in due
and pure nitrogen, an oven-dried sealed tube equipped with
course.
Adv. Synth. Catal. 2010, 352, 2531 – 2537
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2535

Shinji Tanimori et al.
FULL PAPERS
MgSO4, filtered and concentrated under vacuum to yield the
crude product which was purified by silica gel chromatogra-
phy with an eluent of hexane and ethyl acetate. The prod-
ucts were characterized by 1H NMR, 13C NMR and mass
spectra.
Acknowledgements
We gratefully acknowledge Mrs. Minoru Ueno, Yasuyuki Ko-
bayashi, and Naomichi Nakagawa for generous supports in
some of the experiments.
Scheme 2. Derivatization of quinoxalin-2-ones 3 and 5a to
diastereomers 9 and 10.
References
[1] Recent reviews on copper-catalyzed Ullmann-type cou-
pling reaction, see: a) F. Monnier, M. Taillefer, Angew.
Chem. 2009, 121, 7088–7105; Angew. Chem. Int. Ed.
2009, 48, 6954–6971; b) G. Evano, N. Blanchard, M.
Toumi, Chem. Rev. 2008, 108, 3054–3131; c) D. Ma, Q.
Cai, Acc. Chem. Res. 2008, 41, 1045–1460; d) M.
Carril, R. SanMartin, E. Domꢃnguez, Chem. Soc. Rev.
2008, 37, 639–647; e) M. Kienle, S. R. Dubbaka, K.
Brade, P. Knochel, Eur. J. Org. Chem. 2007, 4166–
4176, and references cited therein.
Scheme 3. Reaction of aniline and bromobenzene with l-iso-
leucine under the optimized conditions.
[2] F. Ullmann, Ber. Dtsch. Chem. Ges. 1903, 36, 2382–
2384.
[3] I. Goldberg, Ber. Dtsch. Chem. Ges. 1906, 39, 1691–
1696.
[4] A. Klapars, J. C. Antilla, X. Huang, S. L. Buchwald, J.
Am. Chem. Soc. 2001, 123, 7727–7729.
[5] D. Ma, Y. Zhang, J. Yao, S. Wu, T. Tao, J. Am. Chem.
Soc. 1998, 120, 12459–12467.
[6] M. Taillefer, H.-J. Cristau, P. P. Cellier, J.-F. Spindler,
French Patents 16547, Fr 2833947–WO0353225, 2001.
[7] D. A. Erlanson, K. S. Hansen, Curr. Opin. Chem. Biol.
2004, 8, 399–406 and references cited therein.
[8] a) B. B. Tour, D. G. Hall, Chem. Rev. 2009, 109, 4439–
4486; b) K. C. Nicolaou, D. J. Edmonds, P. G. Bulger,
Angew. Chem. 2006, 118, 7292; Angew. Chem. Int. Ed.
2006, 45, 7134 À7186; c) A. de Meijere, P. von Zezsch-
witz, S. Brꢄse, Acc. Chem. Res. 2005, 38, 413–422; d) I.
Nakamura, Y. Yamamoto, Chem. Rev. 2004, 104, 2127–
2198 and references cited therein.
Scheme 4. Synthesis of GW420867X 14.
[9] J.-C. Wasilke, S. J. Obrey, R. T. Baker, G. C. Bazan,
Chem. Rev. 2005, 105, 1001–1020.
a magnetic stirring bar was charged with CuCl (2.0 mg,
0.02 mmol), DMEDA (34.0 mg, 0.40 mmol), the amino acid
(3.94 mmol), K3PO4 (0.84 g, 3.94 mmol), and the aryl bro-
mide (1.97 mmol), if a solid. The tube was evacuated, back-
filled with nitrogen. If a liquid, the aryl bromide was added
under a stream of nitrogen by syringe at room temperature,
followed by anhydrous and degassed DMSO (7 mL). The
tube was sealed under a positive pressure of nitrogen,
stirred and heated to 1108C for 24 h. After cooling to room
temperature, the mixture was diluted with ethyl acetate
[10] Limited examples have appeared for the low catalyst
loading copper-mediated reaction. Taillefer et al.
showed that only 10 ppm of Cu was enough for the
coupling at 808C of PhI and phenols, see: a) A. Ouali,
J.-F. Spindler, H.-J. Cristau, M. Taillefer, Adv. Synth.
Catal. 2006, 348, 449–505, and references cited therein.
À
Bolm recently reported the C N bond coupling reac-
tion using a part-per-million catalyst loading with an
excess (20 mol%) of ligand, see: b) P.-F. Larsson, A.
Correa, M. Carril, P.-O. Norrby, C. Bolm, Angew.
Chem. 2009, 121, 5801–5803; Angew. Chem. Int. Ed.
2009, 48, 5691–5693.
ACHTUNGTRENNUNG
(~20 mL) and filtered through a plug of celiteꢁ, the filter
cake being further washed with ethyl acetate (~5 mL). The
filtrate was washed twice with water (~10 mLꢂ2). The col-
lected aqueous phases were twice extracted with chloroform
[11] a) O. O. Ajani, C. A. Obafemi, O. C. Nwinyi, D. A.
ACHTUNGTRENNUNG(~10 mL). Organic layers were combined, dried over
Akinpelu, Bioorg. Med. Chem. 2010, 18, 214–221;
2536
asc.wiley-vch.de
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 2531 – 2537

A General and Practical Access to Chiral Quinoxalinones
b) X. Bailing, B. Xu, Y. Sun, Y. Guo, Y. Cao, T. Yu,
Bioorg. Med. Chem. 2009, 17, 2767–2774; c) D. V. Smil,
S. Manku, Y. A. Chantigny, S. Leit, A. Wahhab, T. P.
Yan, M. Fournel, C. Maroun, Z. Li, A.-M. Lemieux, A.
Nicolescu, J. Rahil, S. Lefebvre, A. Panetta, J. M. Bes-
terman, R. Dꢅziel. , Bioorg. Med. Chem. Lett. , 2009,
19, 688–692; d) Y. Mori, T. Hirokawa, K. Aoki, H.
Satomi, S. Takeda, M. Aburada, K. Miyamoto, Chem.
Pharm. Bull. 2008, 56, 682–687; e) U. J. Ries, H. W. M.
Priepke, N. H. Hauel, S. Handschuh, G. Mihm, J. M.
Stassen, W. Wienen, H. Nar. , Bioorg. Med. Chem.
Lett. , 2003, 13, 2297–2302, and references cited there-
in.
[19] It is assumed that the nitrogen-oxygen interchange
through the rubber of the balloon could occur to pre-
vent the catalytic activity.
[20] Although it is easy to remove the inorganic base from
the reaction mixture by aqueous work-up, a large
amount of aqueous waste containing inorganic salts is
produced and it is costly for disposal. Another advant-
age with the use of DBU was the ease of the purifica-
tion process, which avoided the elaboration of unsolu-
ble materials frequently observed when inorganic salts
were employed as base to prevent the easy isolation of
product.
[21] K. Sonogashira, Y. Tohda, N. Hagiwara, Tetrahedron
Lett. 1975, 4467–4470.
[22] B. Xu, Y. Sun. Y. Guo, Y. Gao, T. Yu, Bioorg. Med.
Chem. 2009, 17, 2767–2774, and references cited there-
in.
[23] Recent reports dealing with the chiral synthesis of 3-
substituted qionoxalin-2-ones, see: a) C. Tung, C. Sun,
Tetrahedron Lett. 2004, 45, 1159–1162; b) C. Y. Abra-
ham, D. H. Paull, M. T. Scerba, J. W. Grebinski, T.
Lectka, J. Am. Chem. Soc. 2006, 128, 12370–12371;
c) Q. Jiang, D. Jiang, Y. Jiang, H. Fu, Y. Zhao, Synlett
2007, 1836–1842; d) M. Rueping, F. Tato, F. R.
Schoepke, Chem. Eur. J. 2010, 16, 2688–2691.
[24] K. H. P. Moore, L. M. Cass, N. Dallow, T. C. Hardman,
A. Jones, M. Boyce, W. T. Prince, Eur. J. Clin. Pharma-
col. 2001, 56, 805–811.
[12] G. Sakata, T. Inukai, H. Hirata, K. Suzuki, J. Pestic. Sci.
1991, 16, 315–323.
[13] J. Miyashiro, K. W. Woods, C. H. Park, X. Liu, Y. Shi,
E. F. Johnson, J. J. Bouska, A. M. Olson, Y. Luo, E. H.
Fry, V. L. Giranda, T. D. Penning, Bioorg. Med. Chem.
Lett. 2009, 19, 4050–4054.
[14] J.-L. Li, B. Han, K. Jiang, W. Du, Y.-C. Chen, Bioorg.
Med. Chem. Lett. 2009, 19, 3952–3954.
[15] A. Alizadeh, M. Babaki, N. Zohreh, A. Rezvanian,
Synthesis 2008, 3793–3796.
[16] S. Tanimori, T. Nishimura, M. Kirihata, Bioorg. Med.
Chem. Lett. 2009, 19, 4119–4121.
[17] See Supporting Information.
[18] When 1.0 and 1.5 equiv. of l-phenylalanine were em-
ployed, the yields were decreased to 17% and 50%, re-
spectively, under the optimized conditions.
[25] It was assumed that the amino acid itself would work
as a ligand, see: ref.[1c]
Adv. Synth. Catal. 2010, 352, 2531 – 2537
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2537