The Mitsunobu 1-O-esterification of 1-hydroxy-3-phenyl-1H-quinoxalin-2-one 4-oxide

Article abstract of DOI:10.1007/s11172-008-0162-0

1-Hydroxy-2-oxo-3-phenyl-1,2-dihydroquinoxaline 4-oxide under conditions of the Mitsunobu reaction reacts with alcohols giving the corresponding esters at the hydroxy group in position 1. Other representatives of hydroxamic acids such as 1,4-dihydroxyperh

Full text of DOI:10.1007/s11172-008-0162-0

Russian Chemical Bulletin, International Edition, Vol. 57, No. 6, pp. 1264—1267, June, 2008
1264
The Mitsunobu 1ꢀOꢀesterification
of 1ꢀhydroxyꢀ3ꢀphenylꢀ1Hꢀquinoxalinꢀ2ꢀone 4ꢀoxide
T. A. Kropacheva and V. K. Khlestkin
N. N. Vorozhtsov Institute of Organic Chemistry,
Siberian Branch of the Russian Academy of Sciences,
9 prosp. Akad. Lavrent’eva, 630090 Novosibirsk, Russian Federation.
Fax: +7 (383) 330 9752. Еꢀmail: vadim@nioch.nsc.ru
1ꢀHydroxyꢀ2ꢀoxoꢀ3ꢀphenylꢀ1,2ꢀdihydroquinoxaline 4ꢀoxide under conditions of the Mitsunoꢀ
bu reaction reacts with alcohols giving the corresponding esters at the hydroxy group in position 1.
Other representatives of hydroxamic acids such as 1,4ꢀdihydroxyperhydroquinoxalineꢀ2,3ꢀdione
and 1,4ꢀdihydroxyꢀ3,3,6,6ꢀtetramethylpiperazineꢀ2,5ꢀdione undergo destruction under these conꢀ
ditions.
Key words: hydroxamic acids, esterification, the Mitsunobu reaction, quinoxalinones, piperaꢀ
zinediones.
The Mitsunobu reaction discovered in 1967 is widely
In the literature, the Mitsunobu reaction with Nꢀhydrꢀ
oxysuccinimide is described, which similarly to hydroxꢀ
amic acids contains the CO—NOH group (Scheme 2)2,4—6
and gives the corresponding Oꢀesters, though, in the case
of alcohols of a complex structure,7 problems with
the synthesis of desired products were found.
used in organic synthesis as an efficient instrument for
preparing Oꢀ and Nꢀalkylated compounds.1,2 In the key
step of the reaction, the hydroxy group of an alcohol
by the action of the system of reagents triphenylphosꢀ
phine—diethyl azodicarboxylate (DEAD) is transformed
into a good leaving group, which is able to be replaced
by a wide number of nucleophiles (Scheme 1).
Earlier,3 we studied methods for modification of hetꢀ
erocyclic hydroxamic acid, in particular, preparation of
their Oꢀesters. As a rule, Oꢀesters are synthesized by
alkylation of hydroxamic acids with alkyl halides. Howꢀ
ever, consideration of a possibility of broadening of
a number of alkylating agents due to the involvement into
this process of alcohols (including sterically hindered
and/or chiral ones) by the Mitsunobu method was of
a certain interest.
Scheme 2
Only several examples of intramolecular arylation of
hydroxamic acids or their esters containing hydroxy group
Scheme 1
XH is an acid
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1240—1243, June, 2008.
1066ꢀ5285/08/5706ꢀ01264 © 2008 Springer Science+Business Media, Inc.

The Mitsunobu reaction of hydroxamic acids
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 6, June, 2008
1265
at the carbon atom in the presence of the Mitsunobu
reagents are known, which can proceed either at the oxyꢀ
gen atom for Nꢀesters8 (Scheme 3) or at the nitrogen
atom for Оꢀesters.9 Examples of the intermolecular Miꢀ
tsunobu reaction for hydroxamic acids with alcohols,
in contrast to Nꢀhydroxysuccinimide, are not known.
dihydroquinoxaline 4ꢀoxide (1) was chosen as the model
compound, which was used for the selection of the ratio
and the order of addition of reagents, the temperature and
the reaction time (Scheme 4). Butanꢀ1ꢀol was used as
a model primary alcohol. The results obtained are preꢀ
sented in Table 1.
Scheme 4
Scheme 3
R = Pri, But, Ph, cycloꢀC6H11
Rґ = H, Me, CHO, NO2, NHAc
R = Bun (a), Pri (b), But (c), Bn (d), menthyl (e)
In the present work, we for the first time studied
a behavior of hydroxamic acids (HA) 1—3 of heteroꢀ
cyclic series (see Refs 3 and 10—12) under conditions of
the Mitsunobu reaction. 1ꢀHydroxyꢀ2ꢀoxoꢀ3ꢀphenylꢀ1,2ꢀ
As one can see from Table 1 (entry 1), when ratio of
reagents is equimolar, the formation of ester 4a is not
observed for 1 day at room temperature. In this case,
the starting HA 1 was recovered from the reaction mixꢀ
ture virtually quantitatively. When the reaction time was
increased to 5.5 days, the conversion of HA reached 72%
(entry 2), however, the yield of the desired ester of HA
was only 20%. The change in the ratio of reagents in favor
of alcohol, DEAD, and PPh3 (entry 3), apparently, acꢀ
celerates the formation of the target product (the yield
increases to 40%) in higher degree than the side processes
Table 1. Alkylation of hydroxamic acids (HA) 1—3 with alcohols by the Mitsunobu reaction
Entrya ROH
HA
Ratiob
t/h
Methodc
Yield of ester
Conversion of HA
%
1
2
3
4
5
6
7
8
BunOH
BunOH
BunOH
BunOH
BunOH
BunOH
BunOH
BunOH
PriOH
1
1
1
1
1
1
1
1
1
1
1
1
2
2
3
1 : 1 : 1 : 1
1 : 1 : 1 : 1
1.22 : 2 : 2 : 2
1 : 4 : 4 : 4
1 : 2 : 2 : 2
1 : 4 : 4 : 4
1 : 2 : 2 : 2
1 : 3 : 3 : 3
1 : 3 : 3 : 3
1 : 3 : 3 : 3
1 : 3 : 3 : 3
1 : 3 : 3 : 3
1 : 6 : 6 : 6
1 : 6 : 6 : 6
1 : 6 : 6 : 6
24
A
A
A
A
A
A
B
B
B
B
B
B
B
B
B
0
20
40
45
42
32
57
98
38
10
16
25
0
0
72
55
100
80
100
80
100
100
88
100
100
100
100
100
132
132
132
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
9
10
11
12
13
14
15
ButOH
BnOH
(–)ꢀMenthol
BunOH
(–)ꢀMenthol
BunOH
0
0
a Experiments 1—4 were carried out at ~20 °C, 5—15 under reflux.
b HA : alcohol : PPh3 : DEAD.
c A: HA, alcohol, PPh3, THF were mixed under argon, a solution of DEAD in THF was added dropwise with stirring; B: alcohol,
PPh3, THF were mixed, a solution of HA and DEAD in THF was added dropwise with stirring for 1 h (for compound 2,
in THF+DMF).

1266
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 6, June, 2008
Kropacheva and Khlestkin
Branch of the Russian Academy of Sciences. Highꢀresolution mass
spectra of compound 4e was recorded on a Finnigan MAT 8200
mass spectrometer.
(conversion of HA is 55%). Further increase in amount of
reagents (entry 4) does not lead to noticeable increase in
the yield of the ester, however, it gives an opportunity to
reach 100% degree of conversion of HA owing to the side
processes. It can be suggested that a cleavage of the weak
N—O bond in HA takes place in the presence of PPh3 with
the formation of Ph3P=O. Carrying out the reaction at
elevated temperature (entry 5) with 2 equiv. of reagents
leads to 80% conversion of HA and virtually does not
change the yield of the ester. An increase in the amounts
of reagents (entry 6) causes a complete conversion of HA
and a decrease in the yield of the ester to 32%. Thus, it is
clear that HA under the reaction conditions decomposes
before entering of the reaction with alcohol and should be
added gradually. In fact, when the order of addition of
reagents is reversed (entries 7 and 8), virtually quantitative
conversion of HA into the corresponding ester 4a can be
reached.
Reaction progress was monitored by TLC on Silufol UVꢀ254
plates, hexane—EtOAc from 5 : 2 was used as the eluent. Visualization
was made in aqueous KMnO4 or under the UV light. Solvents were
distilled before use. Commercial reagents were used as purchased.
1ꢀButoxyꢀ3ꢀphenylꢀ1Hꢀquinoxalinꢀ2ꢀоne 4ꢀoxide (4а). Methꢀ
od A. Diethyl azodicarboxylate (0.310 mL, 2 mmol) in THF (2 mL)
was added to a mixture of 1ꢀhydroxyꢀ3ꢀphenylꢀ1Hꢀquinoxalinꢀ2ꢀ
оne 4ꢀoxide (1) (0.508 g, 2 mmol), Ph3P (0.524 g, 2 mmol), and
BunOH (0.185 mL, 2 mmol) in THF (8 mL) under argon for 1 h.
The reaction mixture was kept for 132 h at ~20 °C, treated with 10%
aq. NaOH (10 mL), extracted with EtOAc (3×10 mL). The aqueous
layer was acidified with aq. HCl to pH = 2, and HA 1 was filtered off
(0.15 g, 72% conversion). Organic layer was dried with anhydrous
MgSO4, filtered, and concentrated. From the residue thus obtained,
compound 4a (0.13 g, 20%) was isolated by column chromatograꢀ
phy (SiO2, hexane—EtOAc (5 : 2) as the eluent).
Method B. Diethyl azodicarboxylate (0.522 g, 3 mmol) in THF
(2 mL) and compound 1 (0.25 g, 1 mmol) in THF (2 mL) were
added simultaneously with the use of two syringes to a solution of
Ph3P (0.786 g, 3 mmol) and BunOH (0.278 mL, 3 mmol) in THF
(6 mL) under argon for 1 h. The mixture was refluxed for 3.5 h,
cooled to ~20 °C, treated with 10% aq. NaOH (10 mL), and
extracted with EtOAc (3×10 mL). The organic layer was dried with
anhydrous MgSO4, filtered, and concentrated. From the residue
thus obtained, compound 4a (0.305 g, 98%) was isolated by column
chromatography (SiO2, hexane—EtOAc (5 : 2) as the eluent), m.p.
122—125 °С. Found (%): С, 69.37; Н, 5.91; N, 8.84. C18H18N2O3.
Calculated (%): С, 69.66; H, 5.85; N, 9.03. 1Н NMR (CDCl3), δ:
1.01 (t, 3 Н, CH3, J = 7.0 Hz); 1.48—1.69 (m, 2 H, CH2CH3);
1.80—1.97 (m, 2 H, OCH2CH2); 4.33 (t, 2 H, OCH2, J = 6.5 Hz);
7.34—7.90 (m, 8 H, H arom.); 8.46 (dd, 1 H, CH arom., J = 8.3 Hz,
J = 1.1 Hz). IR, ν/cm–1: 1657 (C=O), 2868—3245 (C—H).
1ꢀIsopropoxyꢀ3ꢀphenylꢀ1Hꢀquinoxalinꢀ2ꢀоne 4ꢀoxide (4b) was
obtained similarly (method B), the yield was 0.113 g (38%), m.p.
146—149 °С. Found (%): С, 68.65; Н, 5.67; N, 9.22. C17H16N2O3.
Calculated (%): С, 68.68; H, 5.38; N, 9.43. 1Н NMR (CDCl3), δ:
1.43 (d, 6 Н, 2 СН3, J = 6.24 Hz); 4.95 (t, 1 Н, СН, J = 6.24 Hz);
7.36—7.56, 7.65—7.74, 7.79—7.88 (all m, 8 Н, CH arom.); 8.46
(dd, 1 H, CH arom., J = 8.19 Hz, J = 0.8 Hz). IR, ν/cm–1: 1664
(C=O), 2863.0—3100.0 (C—H).
1ꢀtertꢀButoxyꢀ3ꢀphenylꢀ1ꢀquinoxalinꢀ2ꢀоne 4ꢀoxide (4c) was
synthesized similarly (method B), the yield was 0.031 g (10%), m.p.
170—174 °С. Found (%): С, 69.71; Н, 6.00; N, 8.93. C18H18N2O3.
Calculated (%): С, 69.67; H, 5.80; N, 9.03. 1Н NMR (CDCl3), δ:
1.51 (s, 9 Н, But); 7.33—7.56, 7.60—7.75, 7.78—7.87 (all m, 8 Н,
CH arom.); 8.46 (dd, 1 H, CH arom., J = 7.59 Hz, J = 0.8 Hz).
IR, ν/cm–1: 1656 (C=O), 2850.9—3090.2 (C—H). The aqueous
layer, obtained after treatment of the reaction mixture with 10% aq.
NaOH and extraction with EtOAc, was acidified to рН = 2,
the precipitated unreacted HA 1 was filtered off and dried to give
compound 4c (0.22 g, 88% conversion).
The selected conditions were used by us for the study
of behavior of various alcohols and hydroxamic acids.
Thus, it was shown (entries 8—12) that the model HA 1
reacts with primary aliphatic (98%), benzylic (16%),
secondary (38 and 25%), and even tertiary (10%) alcoꢀ
hols to form the corresponding esters 4a—e.
The other HA under study, viz., 1,4ꢀdihydroxyperꢀ
hydroquinoxalineꢀ2,3ꢀdione (2) and 1,4ꢀdihydroxyꢀ
3,3,6,6ꢀtetramethylpiperazineꢀ2,5ꢀdione (3), do not give
target diesters under similar conditions (entries 13—15)
despite of their complete conversion. The starting alcoꢀ
hol was quantitatively recovered from the reaction of HA
2 with (–)ꢀmenthol, whereas TLC method (a compariꢀ
son with the authentic sample) showed formation of
Ph3P=O, which confirmed our suggestion on the side
process involving the cleavage of the N—O bond in HA
with triphenylphosphine. The difference in behavior of
HA 2 and 3 from 1, apparently, is caused by their lower
OHꢀacidity, which is a principal factor for successful
proceeding of the Mitsunobu reaction (see review 2).
In conclusion, we for the first time synthesized esters
of HA 1 with primary, benzylic, secondary, and even
tertiary alcohols under conditions of the Mitsunobu reꢀ
action, which allows one to increase a variety of derivaꢀ
tives of quinoxaline series.
Experimental
Melting points of the synthesized compounds were determined
on a Boetius heating stage (Kofler apparatus). IR spectra were
recorded on a Bruker Vektor 22 spectrometer in KBr pellets
(the concentration was 0.25%, l = 1 mm). 1Н NMR spectra were
recorded on a Bruker WPꢀ200ꢀSY (200.13 MHz), Bruker АСꢀ200
(200.13 MHz), and Bruker АМꢀ400 (400.13 MHz) spectrometers,
CDCl3 was used as the solvent, the signal of the residual protons of
the deuterated solvent was used as the reference. Elemental analysis
of new compounds was performed in the Laboratory of Microanaꢀ
lysis of the N. N. Vorozhtsov Institute of Organic Chemistry, Siberian
1ꢀBenzyloxyꢀ3ꢀphenylꢀ1Hꢀquinoxalinꢀ2ꢀоne 4ꢀoxide (4d) was
obtained similarly (method B), the yield was 0.054 g (16%), m.p.
172—175 °С. Found (%): С, 73.46; Н, 5.12; N, 7.73. C21H16N2O3.
Calculated (%): С, 73.25; H, 4.65; N, 8.14. 1Н NMR (CDCl3), δ:
5.35 (s, 2 Н, CH2); 7.37—7.45, 7.45—7.72, 7.81—7.89 (all m,
13 Н, CH arom.); 8.45 (dd, 1 H, CH arom., J = 7.2 Hz, J = 0.8 Hz).
IR, ν/cm–1: 1666.6 (C=O), 2853.0—3091.0 (C—H).

The Mitsunobu reaction of hydroxamic acids
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 6, June, 2008
1267
1ꢀ(2ꢀIsopropylꢀ5ꢀmethylcyclohexyloxy)ꢀ3ꢀphenylꢀ1Hꢀquinꢀ
oxalinꢀ2ꢀоne 4ꢀoxide (4e) was obtained similarly (method B), the
yield was 0.099 g (25%), m.p. 27—35 °С. Н NMR (CDCl3), δ:
0.82 (d, 3 Н, СН3, J = 7.0 Hz); 0.92 (dd, 6 Н, CH(СН3)2, J
= 7.0 Hz, J = 4.9 Hz); 1.00—2.30 (m, 8 Н, CH(СН3)2, СН,
cyclohexane); 3.45 (m, 1 H, СН, cyclohexane); 5.47 (m, 1 H,
OCH); 6.30—7.55, 7.65—7.90 (all m, 8 Н, CH arom.); 8.46 (dd,
1 Н, CH arom., J = 8.46 Hz, J = 1.32 Hz). IR, ν/cm–1: 1667.5
(C=O), 2870.7—2957.0 (C—H). MS, m/z: 392.2104 [M]+.
С24Н28N2O3. Mcalc 392.2100.
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Received September 25, 2007;
in revised form February 6, 2008