Solid-Phase Synthesis of 3,4-Dihydroquinoxalin-2(1H)-ones via the Cyclative Cleavage of N-Arylated Carboxamides

Article abstract of DOI:10.1002/adsc.201500826

We describe a practical (time-efficient, with commercially available building blocks, user friendly reaction conditions, high purity of products) synthesis of pharmacologically relevant quinoxalinones with three points of diversification that takes advantage of solid-phase synthesis and cyclative cleavage. Resin-bound (S)-2-(N-alkyl-2-nitrophenyl)sulfonamide-3-alkyl-N-(2-hydroxyethyl)propanamides, which are accessible from Fmoc-protected α-amino acids, 2-nitrobenzenesulfonyl chloride and alcohols, underwent base-mediated N-arylation. The reduction of the nitro group produced acyclic intermediates that were subjected to acid-mediated cyclative cleavage to yield 3,4-dihydroquinoxalin-2(1H)-ones.

Full text of DOI:10.1002/adsc.201500826

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DOI: 10.1002/adsc.201500826
Solid-Phase Synthesis of 3,4-Dihydroquinoxalin-2(1H)-ones via
the Cyclative Cleavage of N-Arylated Carboxamides
a,b
c
d
a,c,
ˇ
ˇ
Benoit Carbain, Eva Schütznerovµ, Adam Pribylka, and Viktor Krchnµk *
a
Department of Chemistry and Biochemistry, 251 Nieuwland Science Center, University of Notre Dame, Notre Dame,
Indiana 46556, USA
Fax: (+1)-574-631-6652, phone: (+1)-574-631-5113; e-mail: vkrchnak@nd.edu
Department of Organic Chemistry, Faculty of Science, Masaryk University, Kamenice 753/5, Bohunice, 625 00 Brno,
b
Czech Republic
c
´
Department of Organic Chemistry, Faculty of Science, Palacky University, 17. listopadu 12, 771 46 Olomouc, Czech
Republic
d
´
Department of Analytical Chemistry, Faculty of Science, Palacky University, 17. listopadu 12, 771 46 Olomouc, Czech
Republic
Received: September 4, 2015; Revised: December 22, 2015; Published online: February 15, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500826.
Abstract: We describe a practical (time-efficient,
with commercially available building blocks, user
friendly reaction conditions, high purity of prod-
ucts) synthesis of pharmacologically relevant qui-
noxalinones with three points of diversification that
takes advantage of solid-phase synthesis and cycla-
tive cleavage. Resin-bound (S)-2-(N-alkyl-2-nitro-
phenyl)sulfonamide-3-alkyl-N-(2-hydroxyethyl)pro-
panamides, which are accessible from Fmoc-pro-
tected a-amino acids, 2-nitrobenzenesulfonyl chlo-
ride and alcohols, underwent base-mediated N-ary-
lation. The reduction of the nitro group produced
acyclic intermediates that were subjected to acid-
mediated cyclative cleavage to yield 3,4-dihydroqui-
noxalin-2(1H)-ones.
cept to the synthesis of nitrogen heterocycles.[5] More
especially, we report here the synthesis of 3,4-dihydro-
quinoxalin-2(1H)-ones from advanced intermediates
using the discovery of a base-mediated intramolecular
N-arylation of N,N-disubstituted 2-nitrobenzene-
sulfonamides, a Smiles-type like rearrangement, as
observed on secondary amide-based linker substrates
as we previously reported.[6]
The ring system of 3,4-dihydroquinoxalin-2(1H)-
ones, which are also classified as benzopiperazinones,
is structurally related to the pharmacologically impor-
tant benzodiazepine moiety. Examples of biologically
active 3,4-dihydroquinoxalin-2(1H)-ones include in-
hibitors of aldose reductase[7] and partial agonists of
the g-aminobutyric acid (GABA)/benzodiazepine re-
ceptor complex.[8,9] The corresponding N-oxides are
angiotensin II receptor antagonists.[10] The pharmaco-
logical profile of quinoxalinones has recently been re-
viewed.[11]
À
Keywords: C N bond formation; cyclization; het-
erocycles; N-arylation; nitrobenzenesulfonamides;
solid-phase synthesis; traceless synthesis
Numerous solid-phase syntheses of quinoxalinones
have been developed and published. Typically, the
synthesis is based on the bifunctional behaviour of
the key building block, 4-fluoro-3-nitrobenzoic acid,
As the method of choice for the synthesis of peptides, which is attached to a solid support via the acid
solid-phase synthesis is a convenient and efficient group[12–16] (none of these syntheses was traceless).
methodology which allows the development of novel The immobilization is followed by fluorine displace-
and practical routes to prepare libraries of com- ment with amines, and the subsequent reduction of
pounds, a desirable asset for drug discovery purposes the nitro group enables the spontaneous intramolecu-
(reactions driven to completion using excess of re- lar cyclization. The heterocycle may be further deriv-
agents and simple filtrations as work-up methods).[1] atized and finally cleaved from the resin. In an analo-
In recent decades, solid-phase synthesis has been gous reaction sequence reported by Laborde,[17] 4-
tuned to the synthesis of small organic molecules in- fluoro-3-nitrobenzoic acid is attached via fluorine nu-
cluding heterocycles and, by doing so, it has enabled cleophilic displacement, and during the reduction
the discovery of new synthetic steps allowing diversi- step, the product is spontaneously released from the
ty-oriented synthesis.[2–4] We recently applied this con-
Adv. Synth. Catal. 2016, 358, 701 – 706
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Benoit Carbain et al.
rearrangement. DBU-mediated rearrangement of the
ester or tertiary amide model compounds yields C-
aryl derivatives.[6]
In this communication, we report the use of N-aryl
derivatives 7 as advantageous advanced intermediates
for the synthesis of quinoxalinones via reduction of
the nitro group and subsequent cyclization
(Scheme 3). Resin-bound acyclic precursors 12 were
synthesized on an Fmoc-ethanolamine linker 9 at-
tached to Wang resin 8[27] using the CDI coupling
method that we described recently.[6] Wang resin is
the most frequently used resin for the synthesis of
Scheme 1. C-arylation of Nos amides.
resin. The traceless synthesis of quinoxalinones using peptides and small molecules.[1,28] The Fmoc protect-
2-fluoronitrobenzenes has also been reported.[18]
ing group of resin-bound Fmoc-ethanolamines was
In this contribution, we report the traceless synthe- cleaved using piperidine and resin-bound amines were
sis of quinoxalinones via a cyclative cleavage mecha- acylated with Fmoc-a-amino acids followed by anoth-
nism using N,N-disubstituted-2-nitrobenzenesulfon- er Fmoc group cleavage. Polymer-supported amines 9
amide 1 (Nos amides) as a key advanced intermedi- were reacted with 2-Nos-Cls and alkylated with alco-
ate.[2] Resin-bound N,N-disubstituted Nos amides are hols using the Fukuyama protocol[29] to yield resin 10.
an intriguing class of acyclic intermediates that can be Exposure to DBU triggered N-arylation and afforded
converted to diverse nitrogen heterocycles. The criti-
cal feature of these advanced intermediates is an
acidic proton on the alpha carbon of the N-alkyl
group due to the presence of an electron-withdrawing
substituent, R2 (Scheme 1). Exposure to a base, typi-
cally DBU, triggers C-arylation[6,19,20] via a type of
Smiles rearrangement[21] involving the spiro-Meisen-
heimer intermediate 2. These C-aryl derivatives 3
have been used to prepare various nitrogen heterocy-
cles, including indazoles and their N-oxides,[19,22] qui-
nazolines,[23] indoles[24] and indolin-2-ones.[25]
Interestingly, N,N-disubstituted-2-nitrobenzenesul-
fonamides prepared from the polymer-supported a-
amino acid secondary amides 4 undergo another type
of Smiles rearrangement, leading to N-aryl derivatives
7.[6] The mechanism of N-arylation can be explained
via a Smiles-type rearrangement[21;26] (Scheme 2). The
presence of the secondary amide is essential for this
Scheme 3. Solid-phase synthesis of 3,4-dihydroquinoxalin-
2(1H)-ones. Reagents and conditions: (i) CCl3CN, DBU, di-
chloromethane (DCM), 1 h, then Fmoc-ethanolamine,
BF3·Et2O, THF, 30 min; (ii) piperidine, DMF, 15 min; (iii)
Fmoc-amino acid, HOBt, DIC, DCM/DMF (1:1), 16 h; (iv)
2-Nos-Cl, 2,6-lutidine, DCM, 16 h; (v) alcohol, PPh3, DIAD,
THF, 2 h; (vi) DBU, anhydrous DMF, room temperature, 2–
3 days; (vii) Na2S2O4, K2CO3, tetrabutylammonium hydro-
gen sulfate, H2O/DCM (1:1), 1–4 h; (viii) TFA/DCM (1:1),
Scheme 2. Putative mechanism of N-arylation.
1 h; (ix) 5% AcOH/DMSO, 708C, 3 days.
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Solid-Phase Synthesis of 3,4-Dihydroquinoxalin-2(1H)-ones
nitro derivatives 11. Subsequent reduction of the nitro drawing substituents (H, Cl, CF3). Cyclative cleavage
group with sodium dithionate[30] provided acyclic in- of derivatives containing an electron-donating group
termediates 12.
(R2 =OMe) failed to yield the desired product.
The use of the ethanolamine linker allowed us to
Chiral analysis of model compound 14e revealed
compare the cyclization of 13 in solution (after cleav- the presence of the (R)-enantiomer, affording 92% ee
age of 12 from the resin by TFA) with the direct cy- (see the Supporting Information for details).
clative cleavage of 12 from the resin. TFA release of
N-Aryl derivatives 11 were difficult to prepare via
compounds 13 from the resin resulted in partial cycli- the usual aromatic nucleophilic substitution of 1-
zation to 14, whereas cyclative cleavage allowed com- fluoro-2-nitrobenzenes with N-alkyl-a-amino acid
plete conversion to quinoxalinones. In fact, cyclative esters because the nitrogen of the N-alkyl-a-amino
cleavage is a very effective method to access nitrogen acid is a poor nucleophile;[18] only derivatives with R1
heterocycles in solid-phase synthesis (reviewed in[2]). or R3 =H or R2 as an electron-withdrawing substitu-
The traditional scenario involves nucleophilic attack ent could be prepared.
on an electrophilic carboxylate immobilized on
To extend the diversity of the products, resin-bound
a solid support; esters of the Merrifield resin are the compounds 12 that were not N-alkylated (R3 =H)
typical precursors for cyclative cleavage. Esters can were also subjected to DBU-mediated N-arylation
also be replaced by amides.[31,32]
followed by nitro-reduction and subsequent acid-
To address the scope and limitation of this synthetic mediated cyclization. Compound 15 prepared from
route, we prepared model compounds from a set of Fmoc-Ala-OH yielded (after cyclative cleavage) (S)-
Fmoc-a-amino acids, Nos-Cls and alcohols. Table 1 3-alkyl-3,4-dihydroquinoxalin-2(1H)-ones 16, which
lists synthesized compounds, comparison of purity of were air oxidized to 3-alkylquinoxalin-2(1H)-ones 17
crude products obtained by cyclative cleavage and (Scheme 4). Compound 15 prepared from Fmoc-
TFA cleavage and the overall yield of the synthesis Glu(O-t-Bu)-OH yielded (after TFA cleavage from
calculated from the initial loading of the resin (R1 the resin and reduction with zinc powder in AcOH)
represents the substitution in a-position of the amino the fused ring (S)-3,3a-dihydropyrrolo[1,2-a]quinoxa-
acid used, R2 represents the substitution of the 2-Nos- line-1,4(2H,5H)-dione, 18.
Cl used and R3 represents the alcohol used in the Mit-
To conclude, we have developed an efficient solid-
sunobu reaction). The reaction route was compatible phase synthesis of pharmacologically relevant 3,4-di-
with all tested amino acids and most alcohols. Howev- hydroquinoxalin-2(1H)-ones via cyclative cleavage of
er, we only obtained the target compounds when the N-arylated carboxamides under mild acidic condi-
Nos-Cls contained electron-neutral and electron-with- tions. The key step of the synthesis is the base-mediat-
Table 1. List of 3,4-dihydroquinoxalin-2(1H)-ones.
Entry
Compound
R1
R2
R3
Purity [%][a]
Yield [%][b]
1
2
3
4
5
5
6
7
14a
14b
14c
14d
14e
14f
14g
14h
14i
14j
14k
14l
14m
14n
17
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
H
H
CF3
Cl
H
H
H
H
H
propyl
allyl
66/NT
82/49
93/33
44
47
41
21
31
26
25
49
30
31
55
22
47
44
11[d]
34
propargyl
Boc-aminoethyl
aminoethyl
benzyl
4-CF3-C6H4
2,6-diCl-C6H3
2-pyridylmethyl
benzyl
benzyl
benzyl
benzyl
benzyl
90/29
NA/39c
95/44
NT/82
84/53
NT/58
85/47
8
9
CH3
CH3
CH3
10
11
12
13
14
15
95/77
CH2-O(t-Bu)
(CH2)4-NH(Boc)
(CH2)2-COO-t-Bu
CH3
58/56[c]
86/68[c]
78/73[c]
92/NT
NA
NA
NA
18
(CH2)2-COOH
[a]
Purity of crude products estimated from LC traces. The first number corresponds to crude purity after cyclative cleavage,
the second number to crude purity after TFA cleavage (typically lower because of other impurities being cleaved from
the resin and thus present in a crude sample).
The overall yield corresponds to the yield of the isolated product after all of the synthetic steps achieved by solid phase
chemistry and final cyclative cleavage from the resin. NT=not tested; NA=not applicable.
Protecting groups removed by TFA cleavage.
[b]
[c]
[d]
The low yield is caused by incomplete cleavage from the resin.
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Benoit Carbain et al.
Scheme 4. Quinoxalinone derivatives 17 and 18 prepared from non-alkylated intermediates. Reagents and conditions: (i) 5%
AcOH/DMSO, 708C, 2 days; (ii) 50% TFA/DCM, room temperature, 1 h.
by LC/MS and the quantity was compared with analysis of
the standard (Fmoc-Ala-OH; concentration 1 mgmLÀ1).
The loading of the resin was determined by external stan-
dard method by integration of the UV response at 300 nm.
ed N-arylation of resin-bound (S)-2-(N-alkyl-2-nitro-
phenyl)sulfonamide-3-alkyl-N-(2-hydroxyethyl)pro-
panamides, which are easily accessible using commer-
cially available building blocks. This synthetic route
takes specific advantages of solid-phase synthesis, par-
ticularly (i) the use of high boiling solvents without
a need to evaporate them, (ii) brisk isolation of inter-
mediates by washing resin beads, and (iii) cyclative
cleavage that yielded high purity crude products.
General Procedure B: Acylation with Amino Acid
(Fmoc-Ala-OH or Fmoc-d-Ala-OH, Fmoc-Val-OH or
Fmoc-Glu(OtBu)-OH or Fmoc-Ser(tBu)-OH or
Fmoc-Lys(Boc)-OH)
The ꢁalkylatedꢂ Wang resin, 1 g, was washed with DCM (3”
10 mL) and DMF (3”10 mL) and treated with a solution of
50% piperidine in DMF (10 mL), in order to cleave the
Fmoc protecting group, for 20 min at room temperature.
The resin was thoroughly washed with DMF (5”10 mL),
MeOH (3”10 mL) and DCM (3”10 mL). A solution of the
appropriate amino acid (2 mmol) and DIC (2 mmol,
0.312 mL) and HOBt (2 mmol, 306 mg) in 10 mL of DCM/
DMF (1:1) was added to the resin, and the reaction slurry
was shaken overnight at room temperature. A sample of
resin was reacted with a 0.5M solution of Fmoc-OSu
(169 mg in 1 mL of DCM), the product cleaved by 50%
TFA in DCM and analyzed by LC/MS in order to check
that the reaction was complete.
Experimental Section
General Procedures
For convenience, each procedure is described for 1 g of
resin.
General Procedure A: Alkylation of Wang Resin
using Trichloroacetimidate
Wang resin (1 g, 100–200 mesh, 1% DVB, 1 mmolgÀ1) was
swollen with anhydrous DCM (3”10 mL washes). A solu-
tion of CCl3CN (15 mmol, 1.5 mL) in 10 mL of anhydrous
DCM was drawn into the reaction vessel containing the
resin and the mixture was put in the freezer for 30 min.
Under an atmosphere of nitrogen, 1,8-diazabicyclo[5.4.0]un-
dec-7-ene (DBU) (0.67 mmol, 0.1 mL) was added and the
resulting mixture was shaken at room temperature for 2 h
Resin was washed with anhydrous DCM and anhydrous
THF. A solution of N-Fmoc-ethanolamine (3 mmol, 0.852 g)
in 10 mL of anhydrous THF was added to the resin, fol-
lowed by dropwise addition of BF3·Et2O (46.5% BF3 min.)
(0.58 mmol, 0.072 mL) while degassing the mixture with ni-
trogen. The slurry was shaken 1 hour at room temperature.
The resin was washed with THF (3”10 mL), MeOH (3”
10 mL) and DCM (5”10 mL). Loading of the resin was
quantified.
General Procedure C: Nosylation
The latter resin, 1 g, was washed with DCM (3”10 mL) and
DMF (3”10 mL) and treated with a solution of 50% piperi-
dine in DMF (10 mL), in order to cleave the Fmoc protect-
ing group, for 20 min at room temperature. The resin was
thoroughly washed with DMF (5”10 mL), MeOH (3”
10 mL) and DCM (3”10 mL). A solution of 2-nitrobenzene-
sulfonyl chloride (3 mmol, 0.664 g) (or derivatives of 2-nitro-
benzenesulfonyl chloride) and 2,6-lutidine (3.3 mmol,
0.384 mL) in 10 mL of DCM was added to the syringe with
resin, and the reaction mixture was shaken overnight at
room temperature. The resin was washed with DCM (3”
10 mL). A sample of resin was reacted with Fmoc-OSu,
cleaved by 50% TFA in DCM and analyzed by LC/MS, in
order to check that the reaction was complete.
Quantification of Resin Loading: A sample of resin
washed 5” with DCM, 3” with MeOH and dried with nitro-
gen. 10 mg of resin were cleaved with 50% TFA in DCM
for 30 min. The cleavage cocktail was evaporated by
a stream of nitrogen, and cleaved compound extracted into
1 mL of MeOH. This sample of Fmoc derivate was analyzed
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Solid-Phase Synthesis of 3,4-Dihydroquinoxalin-2(1H)-ones
General Procedure D: Mitsunobu Reaction
General Procedure I: Cleavage with TFA 50% in
DCM and Reduction with Zn
The ꢁnosylatedꢂ resin, 1 g, was washed with anhydrous THF
(3”10 mL). A solution of alcohol (2 mmol, 0.208 mL for
benzyl alcohol) and PPh3 (2 mmol, 0.524 g) in 8 mL of anhy-
drous THF was added to the resin and the mixture was left
in the freezer for 30 min. Under an atmosphere of nitrogen,
diisopropyl azodicarboxylate (DIAD) (2 mmol, 0.396 mL)
was added and the reaction vessel was closed. The reaction
mixture was shaken at room temperature for 2 h unless
stated otherwise (depending on the alcohol used). The resin
was washed with THF (3”10 mL) and DCM (3”10 mL).
The ꢁrearrangedꢂ resin, 0.3 g, was cleaved from resin with
50% TFA in DCM (4 mL) for 30 min at room temperature.
The solution was extracted and the resin washed with 50%
TFA in DCM (3”2 mL). The combined extracts were
evaporated. The residue was dissolved in AcOH (4 mL) and
zinc powder was added (the tip of a spatula). The mixture
was put in an oven at 708C for 85 min. The solution was fil-
tered and evaporated. The crude material was dissolved in
MeOH/CH3CN (1:1; 4 mL) and purified directly by semi-
preparative HPLC.
General Procedure E: Smiles-Type Rearrangement
Reaction
The ꢁalkylatedꢂ resin, 1 g, was washed with anhydrous DMF
(3”10 mL). A solution of DBU (4 mmol, 0.6 mL) in 8 mL
of anhydrous DMF was added to the resin and the mixture
was shaken at room temperature for 3 days unless stated
otherwise. The resin was washed with DMF (3”10 mL) and
DCM (3”10 mL).
Acknowledgements
This work was supported by the University of Notre Dame
and by the Project “Employment of Best Young Scientists for
International Cooperation Empowerment” (grant number
CZ.1.07/2.3.00/30.0037) and co-financed by the European
Social Fund, the state budget of the Czech Republic, National
Program of Sustainability LO1304 and project CZ.1.07/
2.3.00/30.0060 supported by the European Social Fund and
the Ministry of Education, Youth and Sport of the Czech Re-
public.
General Procedure F: Reduction with Na2S2O4,
K2CO3 and Tetrabutylammonium Hydrogen Sulfate
The ꢁrearrangedꢂ resin, 1 g, was washed with DCM (3”
10 mL). The reaction vessel was opened, 10 mL of DCM
and 10 mL of H2O were poured in, followed by the addition
of Na2S2O4 (11.74 mmol, 2.046 g), K2CO3 (14 mmol, 1.93 g)
and tetra-n-butylammonium hydrogen sulfate (1 mmol,
0.34 g). The reaction vessel was immediately closed and the
mixture shaken for 4 h. The resin was washed with H2O/
DCM (1:1; 3”10 mL), DMSO (3”10 mL), MeOH (3”
10 mL), DMSO/AcOH 5% (3”10 mL) and DCM (3”
10 mL).
References
[1] J. M. Palomo, RSC Adv. 2014, 4, 32658–32672.
[2] V. Krchnak, M. W. Holladay, Chem. Rev. 2002, 102, 61–
91.
[3] J. Hlavac, M. Soural, V. Krchnak, Solid-Phase Organic
Synthesis: Concepts, Strategies, and Applications, (Eds.:
P. H. Toy, Y. Lam), John Wiley & Sons, 2012, pp 95–
130.
General Procedure G: Cyclative Cleavage with
AcOH 5% in DMSO
[4] N. Cankarova, V. Krchnak, Diversity-Oriented Synthe-
sis: Basics and Applications in Organic Synthesis Drug
Discovery, and Chemical Biology, (Ed.: A. Trabocchi),
Wiley, New York, 2013, pp 201–252.
[5] V. Fulopova, M. Soural, ACS Comb. Sci. 2015, 17, 570–
591.
The ꢁreducedꢂ resin, 1 g, was washed with DCM (3”10 mL)
and DMSO (3”10 mL). 8 mL of a solution of AcOH 5% in
DMSO were added to the resin and the mixture was heated
to 708C for 2 days unless stated otherwise. The reaction
vessel content was extracted, the resin was washed with
AcOH 5% in DMSO (3”4 mL) and the combined extracts
were purified direcly by semi-preparative HPLC.
[6] P. Smyslova, K. Kisseljova, V. Krchnak, ACS Comb.
Sci. 2014, 16, 500–505.
[7] R. Sarges, J. W. Lyga, J. Heterocycl. Chem. 1988, 25,
1475–1479.
General Procedure H: Acid-Promoted Cleavage and
Cyclization with TFA 50% in DCM
[8] R. E. TenBrink, W. B. Im, V. H. Sethy, A. H. Tang,
D. B. Carter, J. Med. Chem. 1994, 37, 758–768.
[9] E. J. Jacobsen, R. E. TenBrink, L. S. Stelzer, K. L. Be-
longa, D. B. Carter, H. K. Im, W. B. Im, V. H. Sethy,
A. H. Tang, P. F. VonVoigtlander, J. D. Petke, J. Med.
Chem. 1996, 39, 158–175.
[10] K. S. Kim, L. Qian, J. E. Bird, K. E. J. Dickinson, S.
Moreland, T. R. Schaeffer, T. L. Waldron, C. L. Dela-
ney, H. N. Weller, A. V. Miller, J. Med. Chem. 1993, 36,
2335–2342.
The ꢁreducedꢂ resin, 1 g, was washed with DCM (3”10 mL).
The resin was treated with 8 mL of a solution of TFA 50%
in DCM for 1 h. The TFA solution was collected; the resin
was washed with TFA 50% in DCM (3”4 mL) and the com-
bined extracts were evaporated by a stream of nitrogen. The
crude product was dissolved in acetonitrile and purified by
semi-preparative HPLC.
[11] Y. Ramli, A. Moussaif, K. Karrouchi, M. Essassi, J.
Chem. 2014, DOI: org/10.1155/2014/563406.
[12] J. Lee, W. V. Murray, R. A. Rivero, J. Org. Chem. 1997,
62, 3874–3879.
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COMMUNICATIONS
Benoit Carbain et al.
[13] G. A. Morales, J. W. Corbett, W. F. DeGrado, J. Org.
Chem. 1998, 63, 1172–1177.
[23] S. Krupkova, G. A. Slough, V. Krchnak, J. Org. Chem.
2010, 75, 4562–4566.
[14] F. Zaragoza, H. Stephensen, J. Org. Chem. 1999, 64,
2555–2557.
[15] A. V. Purandare, A. Gao, M. A. Poss, Tetrahedron Lett.
2002, 43, 3903–3906.
[16] A. N. Acharya, J. M. Ostresh, R. A. Houghten, Tetrahe-
dron 2002, 58, 221–225.
[24] E. Schütznerova, V. Krchnak, ACS Comb. Sci. 2015, 17,
137–146.
[25] V. Gimenez-Navarro, T. Volna, V. Krchnak, ACS
Comb. Sci. 2015, 17, 433–436.
[26] K. G. Kleb, Angew. Chem. 1968, 80, 284; Angew. Chem.
Int. Ed. Engl. 1968, 7, 291.
[27] S.-S. Wang, J. Am. Chem. Soc. 1973, 95, 1328–1333.
[28] L. Y. Mo, Y. L. Wu, M. R. Liu, X. L. Chen, Y. P. Ding,
W. Zhang, Adv. Mater. Res. 2014, 215–219.
[29] T. Fukuyama, C.-K. Jow, M. Cheung, Tetrahedron Lett.
1995, 36, 6373–6374.
[30] R. Kaplanek, V. Krchnak, Tetrahedron Lett. 2013, 54,
2600–2603.
[31] C. Neagoie, V. Krchnak, ACS Comb. Sci. 2012, 14, 399–
402.
[17] E. Laborde, B. T. Peterson, L. Robinson, J. Comb.
Chem. 2001, 3, 572–577.
[18] V. Krchnak, L. Szabo, J. Vagner, Tetrahedron Lett.
2000, 41, 2835–2838.
[19] I. Bouillon, J. Zajicek, N. Pudelova, V. Krchnak, J. Org.
Chem. 2008, 73, 9027–9032.
[20] K. Kisseljova, P. Smyslova, V. Krchnak, ACS Comb.
Sci. 2014, 16, 573–577.
[21] A. A. Levy, H. C. Rains, S. Smiles, J. Chem. Soc. 1931,
3264–3269.
[22] N. Pudelova, V. Krchnak, J. Comb. Chem. 2009, 11,
370–374.
[32] A. P. Kesarwani, R. K. Grover, R. Roy, B. Kundu, Tet-
rahedron 2005, 61, 629–635.
706
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