Efficient cesium carbonate promoted N-alkylations of aromatic cyclic imides under microwave irradiation

Article abstract of DOI:10.1055/s-0030-1258398

We present here an efficient and simple method for the N-alkylation of aromatic cyclic imides employing cesium carbonate as the base in anhydrous N,N-dimethylformamide at low temperatures (20-70 °C). The employment of microwave irradiation presents noteworthy advantages over conventional heating. The method is compatible with base labile functional groups. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1258398

PAPER
571
Efficient Cesium Carbonate Promoted N-Alkylations of Aromatic Cyclic
Imides Under Microwave Irradiation
C
esium Carbonate Pro
e
moted N
-
A
r
lkylation
c
s
of
A
rom
a
e
tic Cyclic
Id
mides es Isasmendi Escudero,a Lautaro D. Kremenchuzky,a Isabel A. Perillo,a Hugo Cerecetto,b María M. Blanco*a
a
Departamento de Química Orgánica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires,
Junín 956, 1113 Buenos Aires, Argentina
Fax +54(11)49648250; E-mail: mblanco@ffyb.uba.ar
Facultad de Ciencias, Universidad de la República, Iguá 4225, 11400 Montevideo, Uruguay
b
Received 22 September 2010; revised 3 December 2010
ble in organic solvents. Furthermore, cesium carbonate is
the most basic alkali carbonate of the group I metals in
aqueous solution and mostly likely in other solvents. Its
effect has also been tentatively explained in terms of po-
Abstract: We present here an efficient and simple method for the
N-alkylation of aromatic cyclic imides employing cesium carbonate
as the base in anhydrous N,N-dimethylformamide at low tempera-
tures (20–70 °C). The employment of microwave irradiation pre-
sents noteworthy advantages over conventional heating. The tential surfaces.9 In addition, cesium carbonate is a com-
method is compatible with base labile functional groups.
mercially available and environmentally benign reagent,
easy to handle and compatible with green chemistry pro-
tocols.
Key words: cesium carbonate, imides, N-alkylation, microwave ir-
radiation, nitrogen heterocycles
Cesium carbonate has been successfully used for the N-
alkylation of sulfonamides,10 amines,11 b-lactams,12 in-
doles,13 and other heterocycles.14 However, to the best of
our knowledge, the direct N-alkylation of imides promot-
ed by cesium carbonate has not been practically explored.
In 1989, a patent described the N-alkylation of a substitut-
ed glutarimide using such base.15 Other related literature
antecedents are found in the synthesis of an N-substituted
succinimide from an asparagine derivative16 and in the N-
alkylation of 1,2,4-dithiazolidine-3,5-diones, a heterocy-
cle containing the imide moiety.17
N-Substituted aromatic imides (such as phthalimides and
analogues) are well-known and extensively investigated
compounds, not only because of the biological activity of
some examples,1 but also because of their use in synthetic
chemistry.2 Therefore, there is a great deal of interest in
the synthesis of this type of compounds.
A useful method for the synthesis of N-alkyl derivatives
involves the reaction of the corresponding imide with
electrophiles. The most common procedure makes use of
alkyl halides, either in a reaction with the isolated imide
salt,3 or generating the stabilized imide anion in situ in
basic media (Scheme 1). Several bases have been used for
this purpose: alkoxides4 and triethylamine,5 among oth-
ers.6
As part of our ongoing investigations, we required N-sub-
stituted imides to use as synthetic intermediates. This led
us to explore the use of cesium carbonate as the base in the
preparation of such compounds. We present herein the re-
sults of the N-alkylation of several aromatic cyclic imides
1a–5a, Figure 1) with alkylating agents of different reac-
tivities.
O
O
O
O
–
B–
RX
Ar
N
Ar
N
Ar
Ar
NR
NH
O
O
O
O
–
O
OH
O
O
NR
N-R
O
NR
NR
N
N
Scheme 1
4
O
3
1
O
2
O
O
a, R = H
b, R = n-Bu
c, R = CH2CO2Me
d, R = (CH2)2CO2Et
e, R = (CH2)3CO2Et
N
N
In recent years, methods employing cesium carbonate
have been successfully applied to selective alkylations
among other synthetically useful transformations.7 The
high yields and chemoselectivity of reactions that involve
SN2 nucleophilic substitution were attributed to the ‘cesi-
um effect’, which has been analyzed by different authors.8
Many of the properties of cesium carbonate are due to the
softness of the cesium cation, which makes cesium car-
bonate (and the corresponding organic salts) rather solu-
NR
5
O
f, R = CH2CONMePh
Figure 1
In order to optimize the reaction conditions, the choice of
solvent was first examined. As a representative procedure,
a mixture of phthalimide (1a, 1 mmol), butyl bromide (1
mmol), and cesium carbonate (1 mmol) was stirred at 60–
70 °C in the presence of different polar aprotic solvents.
The results are summarized in Table 1. Anhydrous N,N-
SYNTHESIS 2011, No. 4, pp 0571–0576
x
x
.
x
x
.2
0
1
1
Advanced online publication: 11.01.2011
DOI: 10.1055/s-0030-1258398; Art ID: M06310SS
© Georg Thieme Verlag Stuttgart · New York

572
M. I. Escudero et al.
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Therefore, we used different amounts of cesium carbonate
for the reaction to give 1b (entries 1, 7, and 8). Results
showed that good yields are obtained only using at least 1
mole of the base for each mole of imide. This shows that
phthalimide does not have the acidity necessary to be
deprotonated by cesium hydrogen carbonate (CsHCO3).
Table 1 Effect of Solvents and the Ratio 1a/Cesium Carbonate on
the Conversion of 1a into 1b
O
O
Cs2CO3
n-BuBr
+
N-Bu
NH
60–70 °C
O
1b
O
1a
Employing the optimized reaction conditions, we carried
out the alkylation of different aromatic imides 1a–5a
(Figure 1) at varying the temperature to give the best
yields. As demonstrated in Table 2, various primary ali-
phatic halides with different functionality reacted at 70 °C
with phthalimide (1a) and 1,8-naphthalimide (2a), pro-
viding the corresponding N-substituted imides with excel-
lent yields (entries 1, 2, 5–7).
Entry
Solvent (mL)
DMF (0.6)
NMP (0.6)
MeCN (3.0)
acetone (3.0)
DMSO (0.6)
none
Cs2CO3
Time (h) Yield (%)
1
2
3
4
5
6
7
8
1 mmol
1 mmol
1 mmol
1 mmol
1 mmol
1 mmol
0.5 mmol
1.1 mmol
2
96
94
2
a
3
–
5
60
73
Reactions employing ethyl 4-chlorobutanoate (a poor
alkylating agent) at 70 °C gave acceptable results (67%
and 70% yields of compounds 1e and 2e). In order to en-
hance the yields of the N-alkyl derivatives, the reaction of
phthalimide (1a) was examined employing several addi-
tives in different amounts (Table 3). Several inorganic io-
dides in different molar ratios were tested, obtaining the
best results when sodium iodide was employed. Catalytic
amounts (20% mol) are sufficient to give satisfactory
yields (entry 3). Tetrabutylammonium bromide (1 equiv)
acting as a phase-transfer catalyst also facilitates the alky-
lation reaction improving yields of compound 1e (entry
8). The reaction fails, however, using silica gel supported
cesium carbonate under solvent free conditions;12a un-
changed starting material was recovered (entry 9).
2.5
b
10
–
DMF (0.6)
DMF (0.6)
2
2
41
98
a No reaction after refluxing for 3 h.
b Decomposition of reactants. At lower times variable quantities of 1b
were recovered.
dimethylformamide proved to be the best solvent accord-
ing to yields and easy workup (entry 1). Solvent-free reac-
tions were also tested; however these conditions proved to
be unsatisfactory (entry 6). Next, the optimum stoichio-
metric imide/cesium carbonate ratio was investigated.
Table 2 Cesium Carbonate Promoted N-Alkylation of Imides 1a–5a
O
O
NR
RX (1.1 mmol)
(1 mmol)
Ar
NH
Ar
Cs2CO3 (1.1 mmol)
O
O
1a–5a
Entry Imide RX
Additivesa
Product
Conventional heating
Microwave heating
Temp (°C) Time (h) Yieldb (%) Temp (°C) Time (min) Yieldb (%)
1
2
1a
1a
1a
1a
1a
2a
2a
2a
2a
3a
3a
BuBr
–
1b
1c
1d
1e
1f
70
70
20
70
70
70
70
40
70
50
50
2
2
98
95
75c
83d
94
92
98
70
–
10
–
99
–
ClCH2CO2Me
Br(CH2)2CO2Et
Cl(CH2)3CO2Et
ClCH2CONMePh
BuBr
–
3
NaI, MS 4 Å
120
2
55
70
–
35
10
–
84
88
–
4
NaI
–
5
1
6
–
2b
2c
2d
2e
3b
3c
2.5
70
–
10
–
97
–
7
ClCH2CO2Me
Br(CH2)2CO2Et
Cl(CH2)3CO2Et
BuBr
–
1
e
8
120
–
55
70
50
–
40
10
15
–
81
95
79
–
9
NaI
2.5
91f
64
70
10
11
MS 4 Å
MS 4 Å
3.5
2
ClCH2CO2Me
Synthesis 2011, No. 4, 571–576 © Thieme Stuttgart · New York

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Cesium Carbonate Promoted N-Alkylations of Aromatic Cyclic Imides
573
Table 2 Cesium Carbonate Promoted N-Alkylation of Imides 1a–5a (continued)
O
O
NR
RX (1.1 mmol)
(1 mmol)
Ar
NH
Ar
Cs2CO3 (1.1 mmol)
O
O
1a–5a
Entry Imide RX
Additivesa
Product
Conventional heating
Microwave heating
Temp (°C) Time (h) Yieldb (%) Temp (°C) Time (min) Yieldb (%)
12
13
14
15
16
17
18
19
20
21
22
3a
3a
3a
4a
4a
4a
4a
4a
5a
5a
5a
Br(CH2)2CO2Et
Cl(CH2)3CO2Et
ClCH2CONMePh
BuBr
NaI, MS 4 Å
NaI, MS 4 Å
MS 4 Å
3d
3e
3f
40
50
50
40
20
40
20
20
60
45
60
3
2
16
67
69
68
74
15
48
77
47
–
45
50
–
45
15
–
85
80
–
3
MS 4 Å
4d
4c
4d
4e
4f
2
50
50
45
50
–
15
15
40
15
–
83
86
74
82
–
ClCH2CO2Me
Br(CH2)2CO2Et
Cl(CH2)3CO2Et
ClCH2CONMePh
BuBr
MS 4 Å
120
5
NaI, MS 4 Å
NaI, MS 4 Å
NaI, MS 4 Å
NaI, MS 4 Å
NaI, MS 4 Å
NaI, MS 4 Å
120
120
3
5b
5d
5e
60
45
60
25
40
25
78
73
72
Br(CH2)2CO2Et
Cl(CH2)3CO2Et
120
3
38
a MS 4 Å = 4 Å molecular sieves.
b Isolated yields.
c 18% at 70 °C without additives.
d 67% without NaI.
e No reaction is observed due to the insolubility of 2a at 40 °C.
f 70% without NaI.
Working at 70 °C, the reaction with ethyl 3-bromopro-
panoate gave a disappointing yield of N-alkylated com-
pound 1d. The formation of the acrylic derivative was
easily recognized by its odor, thus making evident the
competitive elimination reaction. Instead, working at
room temperature, imide 1a was slowly converted into the
corresponding N-substituted compound 1d in good yield
(Table 2, entry 3). In this case, the addition of sodium io-
dide and molecular sieves in order to maintain an anhy-
drous reaction medium is of importance.
Table 3 The Use of Additives in the Cesium Carbonate Promoted
Synthesis of 1e
O
O
Cl(CH2)3-CO2Et
N–(CH2)3CO2Et
NH
Cs2CO3, DMF
70 °C
O
O
1a
1e
Entry
Additive (mmol)
Yield (%)
1
2
3
4
5
6
7
8
9
–
67
83
83
78
78
70
70
81
–
Yields obtained in the N-alkylation of pyridine- and pyra-
zinedicarboximides 3a–5a are poorer than those for com-
pounds 1a and 2a due to the well documented reactivity
of the pyridine nucleus in basic medium conferred by its
nitrogen atom. However, working between 20 °C and 60
°C in strictly anhydrous media gave the expected products
with variable yields and with long times in some cases
(Table 2, entries 16, 18, and 19).
NaI (1.0)
NaI (0.2)
KI (1.0)
KI (0.2)
CsI (1.0)
CsI (0.2)
TBAB (1.0)
silica gel (support)
With the aim of optimizing the reactions we employed mi-
crowave irradiation, a valuable technique that has re-
ceived increased attention over the last few decades.18
Reactions were conducted at a low irradiation power
(100–200 W). In general a notable decrease in reaction
times and an increase in yields are observed (Table 2).
Synthesis 2011, No. 4, 571–576 © Thieme Stuttgart · New York

574
M. I. Escudero et al.
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was extracted with CHCl3 and the organic layer was washed with
H2O, dried, concentrated in vacuo and purified by chromatographic
methods. Temperature, times of reaction, and yields are given in
Table 2.
The most remarkable results were observed in micro-
wave-promoted alkylations with ethyl bromopropanoate,
where reaction times are dramatically reduced (from 3–
120 h) to 35–45 minutes, base-induced elimination is min-
imized and yields increase (73–85%) (entries 3, 8, 12, 17,
and 21).
N-Alkylation of Imides 1a–5a; General Procedure under
Microwave Irradiation
The reaction mixture, prepared as indicated above, was placed in a
5-mL glass tube. The tube was closed with a septum and placed into
the microwave cavity. The mixture was subjected to microwave ir-
radiation at 100–200 W for 10–45 min. The mixture was allowed to
cool to r.t., the reaction vessel was opened and the reaction products
were isolated as was indicated in the conventional procedure.
On the other hand when the N-alkylations of labile base
imides 3a–5a were carried out at 45–60 °C (100 W) full
conversions were achieved in 15–40 minutes (entries 10,
12, 13, 15–18, and 20–22). In comparison to the corre-
sponding reactions under conventional heating, notable
diminution of byproducts, higher yields (72–86%), and
easier workup were also observed.
N-Butyl-1,8-naphthalenedicarboximide (2b)
Mp 96–97 °C (i-PrOH).
In summary, we have demonstrated that cesium carbonate
is a suitable base for the microwave promoted N-alkyla-
tion of aromatic cyclic imides in N,N-dimethylform-
amide. Reactions proceed efficiently with various
functionalized primary alkyl halides, including 3-bro-
mopropanoic acid derivatives. The method is specially
suitable for pyridine- and pyrazinedicarboximides having
a base-labile nucleus due to the presence of pyridine nitro-
gen.
1H NMR (CDCl3): d = 8.58 (d, J = 7.4 Hz, 2 H, H2), 8.20 (d, J = 7.4
Hz, 2 H, H4), 7.74 (t, J = 7.4 Hz, 2 H, H3), 4.20 (t, J = 7.5 Hz, 2 H,
NCH2), 1.71 (p, J = 7.5 Hz, 2 H, NCH2CH2), 1.45 (s, J = 7.5 Hz, 2
H, CH2CH3), 0.97 (t, J = 7.5 Hz, 3 H, CH3).
13C NMR (CDCl3): d = 164.2, 133.8, 131.5, 131.1, 128.1, 126.9,
122.7, 40.2, 30.2, 20.4, 13.9.
MS (EI, 20 eV): m/z (%) = 253 (M+, 100).
HRMS (EI): m/z [M]+ calcd for C16H15NO2: 253.1103; found:
253.1115.
N-[(Methoxycarbonyl)methyl]-1,8-naphthalenedicarboximide
(2c)
Mp 81–83 °C (EtOH).
1H NMR (CDCl3): d = 8.60 (dd, J = 7.2, 1.0 Hz, 2 H, H2), 8.23 (dd,
J = 8.3, 1.0 Hz, 2 H, H4), 7.75 (dd, J = 8.3, 7.2 Hz, 2 H, H3), 4.96
(s, 2 H, NCH2), 3.78 (s, 3 H, CH3).
13C NMR (CDCl3): d = 168.6, 163.8, 134.4, 131.7, 131.6, 128.3,
126.9, 122.2, 52.5, 41.2.
Melting points were taken on a Büchi capillary apparatus and are
uncorrected. The 1H and 13C NMR spectra were recorded on a Bruker
MSL 500 MHz spectrometer relative to TMS as an internal stan-
dard; standard concentration of the samples was 10 mg/mL. EI MS
were recorded with a GC-MS Shimadzu QP-1000 spectrometer op-
erating at 70 eV and Thermo DSQ II spectrometer operating at 20
eV. HRMS, were acquired with a model GCT (Waters, Milford,
MA, USA), operating at a 8000 resolving power (50% valley defi-
nition) using heptacose (m/z 219) as the reference compound. TLC
analyses were carried out on silica gel 60 F254 using CHCl3–MeOH
(9:1) as solvent. Preparative thin-layer separations (PLC) were car-
ried out by centrifugally accelerated, radial chromatography using
Chromatotron model 7924T. The rotors were coated with silica gel
60 PF254 and the layer thickness was 2 mm. CHCl3 and increasing
percentages of MeOH were used as eluent. Reagents, solvents and
starting materials were purchased from standard sources and puri-
fied according to literature procedures. The microwave-assisted re-
actions were carried out in a Reactor Microwave Digestion System
WX-4000, EU chemical instruments.
MS (EI, 20 eV): m/z (%) = 269 (M+, 66), 210 (100).
HRMS (EI): m/z [M]+ calcd for C15H11NO4: 269.0688; found:
269.0695.
N-[2-(Ethoxycarbonyl)ethyl]-1,8-naphthalenedicarboximide
(2d)
Mp 94–96 °C (EtOH).
1H NMR (CDCl3): d = 8.62 (dd, J = 7.3, 1.1 Hz, 2 H, H2), 8.24 (dd,
J = 8.3, 1.1 Hz, 2 H, H4), 7.78 (dd, J = 8.3, 7.3 Hz, 2 H, H3), 4.52
(t, J = 7.4 Hz, 2 H, NCH2), 4.17 (q, J = 7.1 Hz, 2 H, OCH2), 2.79 (t,
J = 7.4 Hz, 2 H, CH2CO), 1.25 (t, J = 7.1 Hz, 3 H, CH3).
13C NMR (CDCl3): d = 171.3, 164.0, 134.1, 131.6, 131.3, 128.2,
127.0, 122.5, 60.7, 36.2, 32.8, 14.2.
Melting points, recrystallization solvents, analyses, and spectro-
scopic data of new compounds are given, known compounds had
characteristic data as follows: 1b, mp 33–34 °C (Lit.19 32–34 °C);
1c, mp 112–114 °C (Lit.20 112–113 °C); 1d, mp 64–65 °C (Lit.21
60–61 °C); 1e, mp 70–72 °C (Lit.22 70–72 °C); 1f, mp 176–178 °C
(Lit.3d 177 °C); 3b, mp 83–85 °C (Lit.23 84–85 °C); 3c, mp 102–103
°C (Lit.6a 103 °C); 3f, mp 150–152 °C (Lit.24 152 °C); 4c, mp 61–
63 °C (Lit.25 61–63 °C); 4d,e, oil (Lit.25; these compounds were ob-
MS (EI, 20 eV): m/z (%) = 297 (M+, 39), 251 (100).
HRMS (EI): m/z [M]+ calcd for C17H15NO4: 297.1001; found:
297.1018.
1
tained as oils and were characterized by H and 13C NMR and
N-[3-(Ethoxycarbonyl)propyl]-1,8-naphthalenedicarboximide
(2e)
HRMS); 4f, mp 116–118 °C (Lit.5a 116–118 °C).
Mp 89–91 °C (EtOH).
N-Alkylation of Imides 1–5; General Procedure under Conven-
tional Heating
1H NMR (CDCl3): d = 8.58 (dd, J = 7.3, 1.1 Hz, 2 H, H2), 8.20 (dd,
J = 8.3, 1.1 Hz, 2 H, H4), 7.75 (dd, J = 8.3, 7.3 Hz, 2 H, H3), 4.24
(t, J = 7.3 Hz, 2 H, NCH2), 4.09 (q, J = 7.2 Hz, 2 H, OCH2), 2.44 (t,
J = 7.3 Hz, 2 H, CH2CO), 2.10 (p, J = 7.3 Hz, 2 H, CH2CH2CH2),
1.21 (t, J = 7.2 Hz, 3 H, CH3).
13C NMR (CDCl3): d = 172.3, 164.2, 134.0, 131.6, 131.3, 128.0,
126.9, 122.6, 60.4, 39.6, 32.0, 23.5, 14.2.
A mixture of imide 1a–5a (1 mmol), Cs2CO3 (1.1 mmol), and halo-
gen derivative (1.1 mmol) in DMF (0.6 mL) was maintained at the
appropriate temperature and monitored by TLC. In some cases NaI
(0.2 mmol) and 4 Å molecular sieves (30–40 mg) were added (see
Table 2). When the reaction was complete, the mixture was poured
into ice-water. If the product crystallized, the resulting solid was fil-
tered, washed with H2O and recrystallized. If not, the suspension
MS (EI, 20 eV): m/z (%) = 311 (M+, 60), 224 (100).
Synthesis 2011, No. 4, 571–576 © Thieme Stuttgart · New York

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Cesium Carbonate Promoted N-Alkylations of Aromatic Cyclic Imides
575
HRMS (EI): m/z [M]+ calcd for C18H17NO4: 311.1157; found:
N-[3-(Ethoxycarbonyl)propyl]-2,3-pyrazinedicarboximide (5e)
311.1163.
Mp 115–116 °C (MeOH).
1H NMR (CDCl3): d = 9.00 (s, 2 H, H5, H6), 4.03 (q, J = 7.1 Hz, 2
H, OCH2), 3.71 (t, J = 7.0 Hz, 2 H, NCH2), 2.42 (t, J = 7.0 Hz, 2 H,
CH2CO), 1.89 (p, J = 7.0 Hz, 2 H, CH2CH2CH2), 1.17 (t, J = 7.1 Hz,
3 H, CH3).
13C NMR (CDCl3): d = 168.5, 160.9, 144.4, 143.2, 55.9, 30.0, 26.7,
19.2, 10.2.
MS (EI, 20 eV): m/z (%) = 263 (M+, 80), 189 (100).
HRMS (EI): m/z [M]+ calcd for C12H13N3O4: 263.0906; found:
N-[2-(Ethoxycarbonyl)ethyl]-2,3-pyridinedicarboximide (3d)
Mp 59–61 °C (i-PrOH).
1H NMR (CDCl3): d = 8.98 (dd, J = 4.9, 1.5 Hz, 1 H, H6), 8.17 (dd,
J = 7.7, 1.5 Hz, 1 H, H4), 7.63 (dd, J = 7.7, 4.9 Hz, 1 H, H5), 4.13
(q, J = 7.1 Hz, 2 H, OCH2), 4.07 (t, J = 7.2 Hz, 2 H, NCH2), 2.75 (t,
J = 7.2 Hz, 2 H, CH2CO), 1.23 (t, J = 7.1 Hz, 3 H, CH3).
13C NMR (CDCl3): d = 170.6, 166.0, 165.8, 155.3, 151.6, 131.3,
127.5, 127.3, 60.9, 34.0, 32.8, 14.1.
MS (EI, 70 eV): m/z (%) = 248 (M+, 3), 55 (100).
263.0910.
HRMS (EI): m/z [M]+ calcd for C12H12N2O4: 248.0797; found:
248.0782.
Acknowledgment
This work was financially supported by the Universidad de Buenos
Aires.
N-[3-(Ethoxycarbonyl)propyl]-2,3-pyridinedicarboximide (3e)
Mp 60–61 °C (i-PrOH).
1H NMR (CDCl3): d = 8.96 (dd, J = 4.8, 1.6 Hz, 1 H, H6), 8.15 (dd,
J = 7.5, 1.6 Hz, 1 H, H4), 7.61 (dd, J = 7.5, 4.8 Hz, 1 H, H5), 4.09
(q, J = 7.1 Hz, 2 H, OCH2), 3.81 (t, J = 7.3 Hz, 2 H, NCH2), 2.37 (t,
J = 7.3 Hz, 2 H, CH2CO), 2.03 (p, J = 7.3 Hz, 2 H, CH2CH2CH2),
1.22 (t, J = 7.1 Hz, 3 H, CH3).
13C NMR (CDCl3): d = 172.5, 166.3, 166.0, 155.2, 151.7, 131.1,
127.4, 127.3, 60.6, 37.5, 31.5, 23.7, 14.2.
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MS (EI, 20 eV): m/z (%) = 262 (M+, 27), 175 (100).
HRMS (EI): m/z [M]+ calcd for C13H14N2O4: 262.0953; found:
262.0958.
N-Butyl-3,4-pyridinedicarboximide (4b)
Oil.
1H NMR (CDCl3): d = 9.14 (s, 1 H, H2), 9.05 (d, J = 4.9 Hz, 1 H,
H6), 7.74 (d, J = 4.9 Hz, 1 H, H5), 3.70 (t, J = 7.4 Hz, 2 H, NCH2),
1.66 (p, J = 7.4 Hz, 2 H, NCH2CH2), 1.37 (s, J = 7.4 Hz, 2 H,
CH2CH3), 0.94 (t, J = 7.4 Hz, 3 H, CH3).
13C NMR (CDCl3): d = 167.2, 166.8, 155.5, 144.6, 139.5, 125.9,
116.7, 38.1, 30.4, 20.0, 13.5.
MS (EI, 70 eV): m/z (%) = 204 (M+, 44), 50 (100).
HRMS (EI): m/z [M]+ calcd for C11H12N2O2: 204.0898; found:
204.0910.
N-Butyl-2,3-pyrazinedicarboximide (5b)
Mp 129–131 °C (MeOH).
(3) Among others, see: (a) Abdel-Monem, M. M.; Newton, N.
E.; Weeks, C. E. J. Med. Chem. 1974, 17, 447.
1H NMR (CDCl3): d = 8.94 (s, 2 H, H5, H6), 3.85 (t, J = 7.3 Hz, 2
H, NCH2), 1.74 (p, J = 7.3 Hz, 2 H, NCH2CH2), 1.42 (s, J = 7.3 Hz,
2 H, CH2CH3), 0.98 (t, J = 7.3 Hz, 3 H, CH3).
13C NMR (CDCl3): d = 164.1, 148.9, 146.9, 38.5, 30.5, 20.1, 13.6.
MS (EI, 20 eV): m/z (%) = 205 (M+, 100).
(b) Gnichtel, H. Chem. Ber. 1965, 98, 567. (c) Furukawa,
Y.; Miki, Y. US 7,135,576, 2006. (d) Schapira, C. B.;
Abasolo, M. I.; Perillo, I. A. J. Heterocycl. Chem. 1985, 22,
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M.; Inomata, K.; Uehara, A.; Mizutani, Y.; Kitagawa, T.;
Maeda, Y. J. Am. Chem. Soc. 1995, 117, 11220.
HRMS (EI): m/z [M]+ calcd for C10H11N3O2: 205.0851; found:
205.0869.
(4) (a) Śladowska, H.; Filipek, B.; Szkatula, D.; Sapa, J.;
Bednarski, M.; Ciolkowska, M. Farmaco 2005, 60, 53; and
references cited therein. (b) Hara, H. JP 8285386, 1982;
Chem. Abstr. 1982, 97, 198187.
(5) (a) Perillo, I. A.; Kremenchuzky, L.; Blanco, M. M. J. Mol.
Struct. 2009, 921, 307. (b) Blanco, M. M.; Levin, G. J.;
Schapira, C. B.; Perillo, I. A. Heterocycles 2002, 57, 1881.
(6) Among others, see: (a) Blanco, M. M.; Lorenzo, M. G.;
Perillo, I. A.; Schapira, C. B. J. Heterocycl. Chem. 1996, 33,
361. (b) Johnston, T. P.; Piper, J. R.; Stringfellow, C. R.;
Elliot, R. D. J. Med. Chem. 1971, 14, 345. (c) Jacobs, R. L.
US 3525747, 1970; Chem. Abstr. 1970, 73, 98985.
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45, 1371.
N-[2-(Ethoxycarbonyl)ethyl]-2,3-pyrazinedicarboximide (5d)
Mp 111–113 °C (MeOH).
1H NMR (CDCl3): d = 9.02 (s, 2 H, H5, H6), 4.07 (q, J = 7.1 Hz, 2
H, OCH2), 3.91 (t, J = 7.5 Hz, 2 H, NCH2), 2.71 (t, J = 7.5 Hz, 2 H,
CH2CO), 1.17 (t, J = 7.1 Hz, 3 H, CH3).
13C NMR (CDCl3): d = 166.5, 160.4, 144.8, 144.7, 56.3, 30.0, 28.2,
10.1.
MS (EI, 20 eV): m/z (%) = 249 (M+, 31), 203 (100).
HRMS (EI): m/z [M]+ calcd for C11H11N3O4: 249.0749; found:
249.0756.
Synthesis 2011, No. 4, 571–576 © Thieme Stuttgart · New York

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