Switchable highly regioselective synthesis of 3,4-dihydro-quinoxalin-2(1H)ones from o-phenylenediamines and aroylpyruvates

Article abstract of DOI:10.3762/bjoc.13.132

3-Acylmethylidene-3,4-dihydroquinoxalin-2(1H)-ones are compounds which possess a wide range of physical and pharmaceutical applications. These compounds can be easily prepared by cyclocondensation of o-phenylenediamines and aroylpyruvates. Unsymmetrically

Full text of DOI:10.3762/bjoc.13.132

Switchable highly regioselective synthesis of 3,4-dihydro-
quinoxalin-2(1H)ones from o-phenylenediamines
and aroylpyruvates
Juraj Dobiaš*1, Marek Ondruš1, Gabriela Addová2 and Andrej Boháč*1,3
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 1350–1360.
1Department of Organic Chemistry, Faculty of Natural Sciences,
Comenius University in Bratislava, Mlynská dolina, Ilkovičova 6,
842 15 Bratislava, Slovakia, 2Institute of Chemistry, Faculty of Natural
Sciences, Comenius University in Bratislava, Mlynská dolina,
Ilkovičova 6, 842 15 Bratislava, Slovakia and 3Biomagi, Ltd.,
Mamateyova 26, 851 04 Bratislava, Slovakia
doi:10.3762/bjoc.13.132
Received: 10 March 2017
Accepted: 21 June 2017
Published: 10 July 2017
Associate Editor: J. A. Murphy
Email:
Juraj Dobiaš* - jur.dobias@gmail.com; Andrej Boháč* -
© 2017 Dobiaš et al.; licensee Beilstein-Institut.
License and terms: see end of document.
andrej.bohac@fns.uniba.sk
* Corresponding author
Keywords:
controlled regioselectivity; cyclocondensation;
3,4-dihydroquinoxaline-2(1H)one; HOBt/DIC; mechanism
Abstract
3-Acylmethylidene-3,4-dihydroquinoxalin-2(1H)-ones are compounds which possess a wide range of physical and pharmaceutical
applications. These compounds can be easily prepared by cyclocondensation of o-phenylenediamines and aroylpyruvates. Unsym-
metrically substituted o-phenylenediamines can be obtained form regioisomeric mixtures of 3,4-dihydroquinoxalin-2(1H)-ones. It is
often quite difficult to get a pure regioisomer and determine its structure without controlling the reaction selectivity and exploita-
tion of complex NMR techniques (HSQC, NOESY, HMBC). This article examines the regioselectivity of the cyclocondensation
between six monosubstituted o-phenylenediamines (-OMe, -F, -Cl, -COOH, -CN, -NO2) and the derivatives of p-chloroben-
zoylpyruvate (ester or acid) which we studied. Six regioisomeric 3,4-dihydroquinoxalin-2(1H)-one pairs were selectively prepared
and characterised. Based on our experiences, a simplified methodology for determining the structure of the regioisomers was pro-
posed. We developed two general and highly selective methodologies starting from the same o-phenylenediamines and activated
4-chlorobenzoylpyruvates (ester or acid) enabling switching of 3,4-dihydroquinoxalin-2(1H)-one regioselectivity in a predictable
manner. For comparison, all regioselective cyclocondensations were performed with the same standardized conditions (DMF, rt,
3 days), differing only by the additives p-TsOH or HOBt/DIC (hydroxybenzotriazole/N,N’-diisopropylcarbodiimide). Both selected
methods are simple, general and highly regioselective (72–97%). A mechanism for the regioselectivity was also proposed and dis-
cussed. This study can be used as a guide when choosing the most optimal reaction conditions for the synthesis of the desired 3,4-
dihydroquinoxalin-2(1H)-one regioisomers with the best selectivity. The demonstrated methodologies in this article may also be
applied to differently substituted 3,4-dihydroquinoxalin-2(1H)-ones in general, which could expand the synthetic impact of our
results.
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Introduction
The quinoxalin-2(1H)-one moiety is frequently found in com- The keto–enamine arrangement in 3 is capable of specific
pounds that exhibit biological activity, particularly antimicrobi- binding of Cu(II) ions like in 4, which was proved by red shifts
al, anticancer, anti-HIV, antithrombotic, analgesic and antidia- in the UV–vis spectra [6-8]. The pseudo ring can also accom-
betic [1-3]. Substitution on C(3) of quinoxalin-2(1H)-ones 1 by modate BF2 moiety, yielding compounds like 5 with interesting
substituents that possess a carbonyl group in a β side chain posi- fluorescent properties [9,10]. Compounds 3 have described sim-
tion 2, 3 significantly alters their chemical properties as sug- ilar biological activities to the parent quinoxalin-2(1H)-ones 1.
gested by 1H NMR, IR spectra and X-ray crystallography of the Mashevskaya et al. reported about an antimicrobial activity for
studied derivatives [4,5]. In this case, their tautomeric equilib- compound 6 at 1 mg/mL for S. aureus P-209 and E. coli M17
rium is shifted to enamines 3 that have been stabilized by an strains [11]. Several recent studies have identified 3,4-dihydro-
intramolecular hydrogen bond (Scheme 1). A new pseudo-ring quinoxalin-2(1H)-ones 7–10 as hits for distinct biological
is formed via the hydrogen bond in 3, which further spreads the targets [12-20], particularly antidiabetic 7 [20], anticancer 8
planarity of the 3,4-dihydroquinoxalin-2(1H)-one system.
[18], anti-inflammatory 9 [16], and antibacterial 10 [19]
(Figure 1).
The described compounds 4–6 were prepared from
o-phenylenediamine. Compounds 7–10 may be prepared from
monosubstituted o-phenylenediamines 11. In this case the
amino groups usually have different reactivity and thus produce
a mixture of regioisomeric products. If both regioisomers are
needed, one can separate them [21]. Separation can be difficult
to such an extent that some of the Cu(II) chelators were charac-
terised as regioisomeric mixtures [22]. Nevertheless, most of
the nonsymmetrical 3,4-dihydroquinoxalin-2(1H)-ones are re-
quired in their pure form (Figure 1).
Scheme 1: The structures of quinoxalin-2(1H)-ones 1, 2 and 3,4-dihy-
droquinoxalin-2(1H)-ones 3. An acylmethyl group in imines 2 shifts
their tautomeric equilibrium to enamines 3.
Figure 1: The structures including some of their physical and biological properties of 3,4-dihydroqunoxalin-2(1H)-ones 4–10. Abbreviations used:
F-1,6-BP = fructose 1,6-bisphosphatase; Eya2 = eyes absent homolog 2; HNE = human neutrophil elastase; MurF = muramyl ligase F;
REA = remaining activity.
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To the best of our knowledge, there is only one paper which opposite regioisomer 26 (SYN) by masking the more reactive
deals with the regioselective synthesis of 3-acylmethylidene- amino group in 11f through the acetamide intermediate 25 and
3,4-dihydroquinoxalin-2(1H)-ones 3. Andreichikov et al. re- its subsequent reaction with acid chloride 24, forming a stable
ported controlled synthesis of both SYN and ANTI regio- N-acetamide-N’-acylamide intermediate (not shown). The acet-
isomers [23] (Scheme 2). For the sake of simplicity, we intro- amide group was then selectively cleaved and the liberated
duced SYN and ANTI descriptors for regioisomers according to amino group spontaneously cyclised to SYN quinoxalin-2(1H)-
the relative positions of two substituents on 3,4-dihydroquinox- one 26 [27] (Scheme 4).
alin-2(1H)-one skeleton (e.g., -CN and 4-chlorobenzoylmethyli-
dene groups in 16e (SYN) and 17e (ANTI)). The reaction of Complete regioselectivity can be obtained if one does not begin
3,4-diaminobenzonitrile (11e) with α,γ-diketoester 12a provi- from the substituted o-phenylenediamine 11. Sakata et al. re-
ded the product 16e (SYN) through an enamine intermediate 14, ported an interesting one-pot procedure yielding 6-substituted
formed by the reaction of the most reactive α-keto group in 12a SYN quinoxalin-2(1H)-ones from substituted N-(2-
with the more nucleophilic m-amino group of 11e. The oppo- nitrophenyl)-3-oxobutanamides [28].
site regioisomer 17e (ANTI) was selectively prepared by reac-
tion of the more nucleophilic m-amino group of 11e Another example for preparation of the desired regioisomer
with the most reactive lactonic carbonyl group in 5-(4-chloro- starts from the nucleophilic substitution of o-fluoronitroben-
phenyl)furan-2,3-dione (13) through an amide intermediate 15 zenes 28 with the derivatives of α-amino acids [29-31]. The
(Scheme 2).
product of spontaneous cyclization of 30 was obtained after
reduction of nitro derivative 29. Through mild oxidation, com-
Abasolo et al. studied the reaction of monosubstituted pound 30 provides the required quinoxalin-2(1H)-one 31
o-phenylenediamines 11a,f–i with pyruvic ethyl ester (18a) or (Scheme 5). The obvious disadvantage in this case is the initial
its acid 18b and postulated that an equilibrium between Z E aromatic substitution step from 28 to 29 and the additional two
imines 19, 20 and enamine 21 is quickly reached and the rate- reactions to 31, compared to the direct synthesis of both regio-
determining reaction step is a subsequent intramolecular cycli- isomers depicted in Scheme 2.
zation yielding the regioisomeric products 22 and 23 [24]
(Scheme 3). The proposed mechanism was based on the isola- Results and Discussion
tion of the 4-nitrodiaminobenzene imine intermediate which A study to control the regioselectivity in the synthesis of 17d
possessed reduced reactivity for intramolecular cyclisation. This (ANTI) (Table 1) was motivated by our ongoing medicinal
type of reaction was exploited in the literature several times chemistry research. According to the literature, the synthesis of
for the synthesis of quinoxalin-2(1H)-one regioisomers 3-acylmethylidene-3,4-dihydroquinoxalin-2(1H)-ones 3 can be
[10,25,26].
performed by simple cyclocondensation of an appropriate
o-phenylenediamine 11 with α,γ-diketoester 12a (Scheme 2). In
Cyclocondensation between 11f and 24 provided mainly our case, starting from 3,4-diaminobenzoic acid (11d) (natively
quinoxalin-2(1H)-one 27 (ANTI). Sherman et al. prepared the preferring SYN regioselectivity, see Table 1, entry 4, column 3)
Scheme 2: Selective synthesis of both 3,4-dihydroquinoxalin-2(1H)-one regioisomers 16e (SYN) and 17e (ANTI).
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Scheme 3: The proposed mechanism for the synthesis of 3-methylquinoxalin-2(1H)-one regioisomers 22 and 23. In the case of starting 11g (Y: -H),
22g is the same as 23g and no SYN/ANTI regioisomerism exists.
Scheme 4: The regioselective syntheses of both quinoxalin-2(1H)-ones 27 (ANTI) and 26 (SYN).
Scheme 5: The selective synthesis of substituted quinoxalin-2(1H)-ones 31 from 28 via three reaction steps.
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Table 1: The regioisomeric ratios (17 (ANTI)/16 (SYN)) and conversions depending on used diamine 11a–f, dicarbonyl compound 12a,b and reac-
tion conditions.
The below specified conditions dependent ratiosa and conversions.b
Entry
Diamine 11a–f
Ester 12ac
Ester 12ac,d
Acid 12bc,d
Ester 12ac,e
Acid 12bf
85/15a
(100%)b
91/09
(100%)
67/33
(100%)
14/86
(100%)
15/85
(100%)
1
2
3
4
5
6
11a (-OMe)
11b (-F)
80/20
(95%)
89/11
(100%)
85/15
(100%)
17/83
(80%)
14/86
(100%)
65/35
(100%)
72/28
(100%)
70/30
(100%)
28/72
(75%)
23/77
(100%)
11c (-Cl)
38/62
(100%)
13/87
(100%)
12/88
(100%)
88/12
(50%)
93/07
(100%)
11d (-COOH)
11e (-CN)
11f (-NO2)
17/83
(100%)
15/85
(100%)
11/89
(100%)
100/0
(25%)
93/07
(100%)
18/82
(90%)
20/80
(100%)
05/95
(100%)
68/32
(22%)
97/03
(100%)
aThe ratios for both regioisomers 16 and 17 (mol %) were determined by 1H NMR spectra from evaporated reaction mixtures (based on characteristic
singlet signals of each regioisomer =CHCO– (6.8–6.9 ppm)) and are depicted here in the order 17 (ANTI)/16 (SYN). The ratios marked in bold repre-
sent the best selectivities with cut-off ≥85% for the main ANTI or SYN regioisomer. bThe % number in brackets describes conversion of the appro-
priate starting o-phenylenediamine 11a–f obtained from the crude 1H NMR spectra. cGeneral procedure A was used. dTsOH (1 mol equiv) was
added. eDMAP (1 mol equiv) was added. Reaction proceeds through in situ formed intermediate 12c (Scheme 6). fGeneral procedure B (HOBt/DIC)
was used. Reaction proceeds through in situ formed intermediate 12d (Scheme 6).
complicated the desired reaction. The other possibility was to TEA (Et3N) in DMF at rt within 3 days. The reaction yielded a
perform the regioselective synthesis of 17d (ANTI) from an crude mixture with a predominant 17d (ANTI) regioisomer
appropriate furan-2,3-dione 13 (Scheme 2). The preparation of (70/30, not shown elsewhere). For the same reaction, we also
13 failed in our hands. Therefore, we decided to perform the used less basic DMAP instead of TEA. This cyclocondensation
cyclocondensation of 11d with ethyl 4-chlorobenzoylpyruvate formed a crude mixture with even better 17d (ANTI) selec-
(12a) and separate the less abundant 17d (ANTI) from a mix- tivity (88/12) (Table 1, entry 4, column 5). DMAP is also
ture of regioisomers. The cyclocondensation of 11d with 12a in known as an acyl activation reagent (similar to: HOBt, HATU,
refluxing dioxane within 1 hour yielded a precipitate that con- T3P, etc.). Therefore, we concluded that switching in regiose-
sisted of a balanced (50/50) mixture of both SYN/ANTI regio- lectivity (from native SYN to ANTI) could be a matter of
isomers 16d and 17d (confirmed by 1H NMR). The low solu- DMAP activation of the acyl group in 12a.
bility of the crude products in DCM, THF, EtOAc or MeOH
combined with an unfavourable ratio of regioisomers prevented The above controlled ANTI cyclocondensation (88/12) per-
their separation by FLC or crystallisation. Based on these formed in the presence of DMAP enabled us to obtain pure 17d
results we realised that it would be difficult to obtain pure (ANTI) regioisomer in a 36% yield after crystallisation from
ANTI regioisomer 17d without controlling the reaction selec- DMSO. To prove the exact structure of 17d (ANTI) was not
tivity. In order to influence the regioselectivity, cyclocondensa- easy and we had to combine the more complex 2D NMR tech-
tion of 11d with 12a was performed in the presence of basic niques (HSQC, NOESY and HMBC). At first, we assigned
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Beilstein J. Org. Chem. 2017, 13, 1350–1360.
Scheme 6: Regioselectivity switching based on carbonyl activation of 4-chlorobenzoylpyruvates 12a,b by p-TsOH or acyl activation in 12c,d
(prepared in situ from ester 12a by DMAP – 12c or from acid 12b and HOBt/DIC – 12d).
hydrogens and carbons in the main regioisomer. Next, we hydrogen of the methylene C(3)=CH- group and the quaternary
proved for 17d its ANTI isomerism by HMBC analysis, which carbon C(4a) (Figure 2). The carbon C(4a) was interconnected
showed an important four-bonded interaction between the in the HMBC with 2 other three-bonded interactions with
Figure 2: The interactions and assignments, obtained after analyses of NMR spectra, allowed us to distinguish between the 16d and 17d regio-
isomers. The important 1H and 13C NMR chemical shifts are depicted close to each appropriate atom in the structures accompanied with an coupling
constant in brackets, if there was any. The double-headed red arrows represent important space interactions observed in NOESY spectra. The green-
coloured bonds in the structures represent some of the most important HMBC interactions that helped us when assigning the right regioisomers. The
HMBC signals between the skeletal proton and carbon are limited to 2, 3 and sometimes also to 4 bonds.
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hydrogen H-C(8) and H-C(6), whereas for the 16d (SYN) (EWG) groups (Table 1, Scheme 6). Using the general proce-
isomer the H-C(6) interaction should be missing (see also the dure A without any additives, diamine 11 was always almost
HMBC diagrams and spectra in Supporting Information File 1). quantitatively consumed (90–100%), and for both clusters of
substituents on 11, the main regioisomer of 3,4-dihydroquinox-
After we had proved the structure of the 17d (ANTI) regio- alin-2(1H)-one was formed with average to good selectivity
isomer, we decided to elucidate the structure for the 16d (SYN) (62–85%) (Table 1, column 3).
isomer as well, in order to complementary validate the above
assignments. In regards to the absence of regioselectivity by b) Utilizing the general procedure A with p-TsOH as an addi-
heating of 3,4-diaminobenzoic acid (11d, -COOH) with 12a in tive to diamine from 11a–f and ester 12a caused greater reactiv-
dioxane for 1 hour (50/50), a reaction under milder conditions ity of the α-carbonyl group in 12a (Scheme 6), quantitative
(DMF, rt, 3 days) was performed resulting in ANTI/SYN selec- consumption of diamine 11, and production of the main regio-
tivity (38/62, Table 1, entry 4, columns 3 and 4). In order to isomer of 3,4-dihydroquinoxalin-2(1H)-one with good to excel-
positively influence the regioselectivity, cyclocondensation was lent selectivity (72–91%) for both clusters of substituents
performed in the presence of p-TsOH (DMF, rt, 3 days). This (Table 1, column 4).
reaction resulted in high SYN regioselectivity (13/87). The en-
hanced selectivity was explained by the elevation of electrophi- c) Ester 12a to acid 12b modification with other parameters as
licity of the α-ketone in 12a by p-TsOH. After the crystallisa- in (b) resulted in the preservation of complete conversions of
tion from DMSO, pure 16d (SYN) was isolated. We elucidated 11, a decrease of ANTI selectivity (67–85%) for EDG/HG sub-
its structure in similar manner as for the 17d (ANTI) isomer stituents in 11a–c (Table 1, entries 1–3, column 5), however, a
(Figure 2) and confirmed that the 1H NMR (DMSO-d6) higher SYN selectivity boost (88–95%) for EWG substituents in 11d–f
shifted signal for the H-N(4) group is the one that forms a intra- (Table 1, entries 4–6, column 5).
molecular hydrogen bond with the carbonyl group from a side
chain like in 3 (Scheme 1). This knowledge, in combination d) In order to investigate the contrary (switched) regioselectivi-
with a simple NOE experiment (interaction H-N(4) with a ty, DMAP was added to diamine from 11a–f and ester 12a, and
narrow doublet of H-C(5) (ca 1.5 Hz) in SYN or H-N(4) with a standard general procedure A was used. In these cases, DMAP
broad doublet of H-C(5) (8.4 Hz) in ANTI, allows for the deter- activated the acyl moiety in ester 12a via 12c (Scheme 6) and
mination of the regioisomerism more effectively (no need for caused the formation of the predominant regioisomer of 3,4-
HMBC), in the case that the NOE experiment was performing dihydroquinoxalin-2(1H)-one with reversed selectivity as deter-
(which was not always the case). The same approach to distin- mined before (a)–(c). The consumption of 11a–c (Table 1,
guish regioisomers can be applied on space interactions be- entries 1–3, column 6) was good (75–100%), but insufficient
tween H-N(1) and H-C(8) signals (NOESY in Figure 2 or for for 11d–f (22–50%, Table 1, entries 4–6, column 6). Our expla-
NOE see the Supporting Information File 1).
nation for the low conversions is a diminished amine nucleophi-
licity in the EWG-substituted dianilines 11d–f and reduced
Finally, all six regioisomeric 3,4-dihydroquinoxalin-2(1H)-one electrophilicity of the 12a due to a partial formation of a stabi-
pairs were selectively prepared and characterised (Table 1 and lized enolate anion by DMAP deprotonation. Therefore, using
Supporting Information File 1). Their condensations were in- DMAP activation is not recommended for EWG-substituted di-
vestigated under five different reaction conditions:
amines.
a) Cyclocondensations of diamines 11a–f and ethyl ester of 12a e) The reaction of activated ester 12d (obtained in situ after
were performed by our standardized conditions: DMF, rt, treatment of carboxylic acid 12b with HOBt/DIC, Scheme 6)
3 days (General procedure A). In all cases, the most nucleo- and a diamine 11a–f (general procedure B) was found to be the
philic amine from diamine 11 predominantly reacts with the most convenient method to produce contrary product regiosel-
most reactive α-carbonyl group from ester 12a to form an electivity. In this case, the consumption of diamine 11 was
imine/enamine bond followed by amidic intramolecular cycliza- always quantitative. The regioselectivity was opposite in com-
tion to yield the main regioisomer of 3,4-dihydroquinoxalin- parison to the reactions from (a)–(c) and similar to the reaction
2(1H)-one. The regioselectivity was dependent on the character exploiting DMAP activation of ester 12a in (d). HOBt/DIC acti-
of substituent Y in diamines 11a–f (Table 1). According to ob- vation of acid 12b resulted in the synthesis of the main regio-
tained selectivities (Table 1), the substituents on diamines 11 isomers of 3,4-dihydroquinoxalin-2(1H)-ones with good to
were divided into two clusters causing either the same or the excellent SYN selectivity (77–86%) for EDG/HG cluster of
contrary regioselectivity: (a) with electron-donating groups and substituents in 11a–c (Table 1, entries 1–3, column 7) and
halogens (EDG or HG) or (b) with electron-withdrawing excellent ANTI selectivity (93–97%) for EWG substituents in
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Beilstein J. Org. Chem. 2017, 13, 1350–1360.
11d–f (Table 1, entries 4–6, column 7). The HOBt/DIC method- A limitation for regioselectivity is the fact that it is dependent
ology seems to be better than the one described with DMAP on the character of the substituent in aryldiamine 11. If the
due to its clean reaction course and high regioselectivity in nucleophilicity of the two amino groups in 11 are not differenti-
general (Table 1, column 7). The HOBt methodology is com- ated enough, the obtained selectivity will be less synthetically
plementary in regioselectivity to cycloadditions performed by useful. In that case, a different synthesis will be required, e.g.,
p-TsOH (Table 1, column 4).
masking amino with the nitro group. The HOBt/DIC procedure
performs with contrary regioselectivity to p-TsOH. We believe
From the above experimental results, we have proved that the that the other acyl activated agents like T3P (propylphosphonic
regioselectivity of the cyclocondensation depends on both (a) anhydride) or HATU should produce similar results as well.
the different nucleophilicity of the two amines from The demonstrated findings could be applied also to differently
o-phenylenediamines 11a–f and (b) the electrophilicity of the substituted 3,4-dihydroquinoxalin-2(1H)-ones in general, which
α-carbonyl in 12a or the contrary regioselectivity of activated can expand the synthetic impact of our study.
species 12c,d (prepared in situ from appropriate 12 by DMAP –
12c or HOBt/DIC additives – 12d) (Scheme 6).
Experimental
Syntheses and characterisation of compounds 16d (SYN) and
Conclusion
17d (ANTI) are described below. The synthesis of all prepared
Simple reaction conditions were discovered for predictable and compounds 12a,b, 16a–f (SYN) and 17a–f (ANTI) together
switchable highly regioselective synthesis of 3,4-dihydro- with their characterisation, spectral diagrams and spectra can be
quinoxaline-2(1H)-ones 16 or 17 starting from monosubstituted found in Supporting Information File 1.
o-phenylenediamines 11 and 4-chlorobenzoylpyruvates 12 in
DMF at rt. These conditions were tested by cyclocondensations General procedure A
on six diamines 11a–f with two pyruvates 12a,b and allowed us A solution of ethyl 4-chlorobenzoylpyruvate (100 mg,
to prepare, purify and characterise twelve (six pairs) of regioiso- 0.39 mmol, 1.00 equiv) (12a) or 4-chlorobenzoylpyruvic acid
meric 3,4-dihydroquinoxaline-2(1H)-ones. Their ANTI (17) or (12b) (88.4 mg, 0.39 mmol, 1.00 equiv), o-phenylenediamine
SYN (16) structures were assigned by complex 2D NMR tech- 11a–f (1.00 equiv) with or without an additive (1.00 equiv)
niques (HSQC, NOESY and HMBC) or by a proposed simpli- (p-TsOH or DMAP) was stirred in 3.0 mL of DMF (abs) at rt
fied method (NOE interaction between higher 1H NMR under Ar for 72 hours. A low soluble mixture of ANTI/SYN
(DMSO-d6) shifted H-N(4), bonded by intramolecular hydro- regioisomers slowly precipitated within the reaction. The pre-
gen bond, and H-C(5) or interaction of lower shifted H-N(1) cipitate was collected by filtration or centrifugation, triturated
and H-C(8), whereby coupling of HC(5 and 8) depends on type by 3 mL of Et2O and crystallized from DMSO
of the regioisomer). It was proved that observed regioselectivi- (if not otherwise stated) to yield the main solid regioisomer 16
ty of performed cyclocondensations depends on both a/ the dif- or 17.
ferent nucleophilicity of amine groups in diamine 11 (with two
clusters of substituents: EDGs + halogens (HG) and comple- General procedure B
mentary operating EWGs) and (b) the different activation of Diisopropylcarbodiimide 82 μL (66.9 mg, 0.53 mmol,
4-benzoylpyruvates 12a,b (p-TsOH; contrarily by DMAP or 1.20 equiv, DIC) was added to a solution of 4-chloroben-
HOBt/DIC). Obtained selectivities were discussed and their zoylpyruvic acid (100 mg, 0.44 mmol, 1.00 equiv, 12b) and
mechanism proposed (Scheme 6). Our study can act as a guide 73.8 mg (0.53 mmol, 1.20 mol equiv) of HOBt [CAS: 123333-
for choosing the optimal reaction conditions for the synthesis of 53-9, 97% wetted with ≥14 wt % H2O] in 3.0 mL of DMF (abs)
the desired regioisomer of 3,4-dihydroquinoxaline-2(1H)-one under Ar. The reaction mixture was stirred for 5 min. Then
16 or 17 with the best selectivity (activation of 12a,b by acid or o-phenylenediamine (1.00 equiv, 11a–f) was added and the
opposite selectivity obtained from activated species 12c,d) mixture was stirred at rt under Ar for 72 h. The precipitated
(Scheme 6, Table 2).
product mixture obtained after filtration (or centrifugation) was
Table 2: The guide for reaction conditions for obtaining the desired regioisomer of 3,4-dihydroquinoxaline-2(1H)one 16 (SYN) or 17 (ANTI) with the
best selectivity.
Starting pyruvate 12 with additive/
substituted diamine 11
Ester 12a Acid 12b
p-TsOH
Acid 12b
HOBt/DIC
11a–c (EDG or halogen)
11d–f (EWG)
17 (ANTI) (72–91%)
16 (SYN) (88–95%)
16 (SYN) (77–86%)
17 (ANTI) (93–97%)
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triturated by 3 mL of Et2O and crystallized from DMSO 1486 (w), 1366 (m), 1247 (m), 1218 (m), 1095 (m), 1065 (w),
(if not otherwise stated) to yield the main solid regioisomer 16 1011 (w), 787 (w), 750 (m) cm−1; MS (ESI m/z): 341.2 [M −
or 17.
H]−; anal. calcd for C17H11ClN2O4 (342.73): C, 59.57; H, 3.23;
Cl, 10.34; N, 8.17; found: C, 59.75; H, 3.38; Cl, 10.23; N, 8.01.
Compound 16d (SYN)
The compound 16d (SYN) (Figure 3) was prepared according Compound 17d (ANTI)
the general procedure A from diamine 11d, ester 12a and Compound 17d (ANTI) (Figure 4) was prepared according
p-TsOH as an additive. The crude mixture of ANTI/SYN regio- general procedure A from diamine 11d, ester 12a and
isomers was purified by crystallization from DMSO to yield (1.00 equiv) of DMAP as an additive. The crude product was
64.6 mg (0.19 mmol, 48%) of 16d (SYN). Mp: 363.0–365.0 °C crystallized from DMSO and obtained as salt with DMAP. To
(DMSO), yellow solid compound. 1H NMR (600 MHz, DMSO- liberate the free acid 17d (ANTI), the salt was suspended in 1
d6) δ 13.48 (s, 1H, H-NA(4)), 12.92 (br s, 1H, -COOH), 12.26 M HCl, stirred for 24 hours, the solid material was filtered off,
(s, 1H, H-NA(1)), 8.04 (d, J(A5,A7) = 1.5 Hz, 1H, H-CA(5)), washed with water and dried to yield 48.4 mg (0.14 mmol,
7.99 (d, J(B2,B3) = 8.4 Hz, 2H, 2 × H-CB(2)), 7.69 (dd, 36%) of 17d (ANTI).
J(A7,A8) = 8.3 Hz, J(A5,A7) = 1.5 Hz, 1H, H-CA(7)), 7.57 (d,
J(B2,B3) = 8.4 Hz, 2H, 2 × H-CB(3)), 7.18 (d, J(A7,A8) = 8.3 Alternatively 17d (ANTI) was also prepared according to
Hz, 1H, H-CA(8)), 6.79 (s, 1H, -COCH=); 13C NMR (150 general procedure B from diamine 11d, acid 12b and HOBt/
MHz, DMSO-d6) δ 187.7 (CB(1)C=O), 167.0 (-COOH), 156.4 DIC. The crude product was crystallized from DMSO to yield
(CA(2)), 145.8 (CA(3)), 137.8 (CB(1)), 137.2 (CB(4)), 130.8 105.9 mg (0.31 mmol, 70%) of 17d (ANTI). Mp: 391.0–392.0
(CA(8a)), 129.4 and 129.3 (2 × CB(2 and 3)), 126.4 (CA(6)), °C [DMSO], yellow solid compound. 1H NMR (300 MHz,
125.6 (CA(7)), 124.4 (CA(4a)), 118.3 (CA(5)), 115.8 (CA(8)), DMSO-d6) δ 13.44 (s, 1H, H-NA(4)), 12.95 (br s, 1H, -COOH),
90.0 (-COCH=). FTIR cm−1 (solid): 3184 (s, -COOH), 2925 12.14 (s, 1H, H-NA(1)), 8.02 (d, J(B2,B3) = 8.6 Hz, 2H, 2 ×
(m), 1732 (w), 1688 (s, C=O), 1615 (s), 1586 (s), 1550 (w), H-CB(2)), 7.73 (d, J(A6,A8) = 1.6 Hz, 1H, H-CA(8)), 7.67 (dd,
Figure 3: NMR assignments for compound 16d.
Figure 4: NMR assignments for compound 17d.
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Beilstein J. Org. Chem. 2017, 13, 1350–1360.
11.Mashevskaya, I. V.; Tolmacheva, I. A.; Voronova, E. V.;
J(A5,A6) = 8.4 Hz, J(A6,A8) = 1.6 Hz, 1H, H-CA(6)), 7.61 (d,
J(A5,A6) = 8.4 Hz, 1H, H-CA(5)), 7.60 (d, J(B2,B3) = 8.6 Hz,
2H, 2 × H-CB(3)), 6.87 (s, 1H, -COCH=); 13C NMR (150 MHz,
DMSO-d6) δ 188.3 (CB(1)C=O), 167.0 (-COOH), 156.1
(CA(2)=O), 145.6 (CA(3)), 2 × 137.6 (CB(1 and 4)), 129.5 and
129.3 (2 × CB(2 and 3)), 128.1 (CA(4a)), 2 × 126.9 (CA(7 and
8a)), 125.2 (CA(6)), 2 × 116.9 (CA(5 and 8)), 90.8 (-COCH=);
FTIR cm−1 (solid): 3486 (m), 3206 (s, -COOH), 2634 (w), 1706
(s, C=O), 1661 (w), 1628 (m), 1586 (s, C=O), 1522 (w), 1398
(m), 1374 (w), 1291 (m), 1248 (m), 1184 (m), 1093 (w), 1056
(m), 1009 (w), 899 (w), 781 (w), 764 (w), 721 (w) cm−1; MS
(ESI m/z): 341.0 [M − H]−; anal. calcd for C17H11ClN2O4
(342.73): C, 59.57; H, 3.23; N, 8.17; found: C, 59.82; H, 3.10;
N, 8.32.
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Supporting Information
Supporting Information File 1
Additional experimental and characterisation data.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-13-132-S1.pdf]
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