Synthesis of 4-(1-dialkylaminoalkyl)pyrrolo[1,2-a]quinoxalines

Article abstract of DOI:10.3987/COM-01-9186

The reaction of 1-(2-isocyanophenyl)pyrroles (1), which were readily prepared from commercially available or known 1-(2-aminophenyl)pyrroles by formylation in refluxing ethyl formate followed by dehydration with POCl₃/Et₃N in THF, wi

Full text of DOI:10.3987/COM-01-9186

HETEROCYCLES, Vol. 55, No. 5, 2001, pp. 973 - 980, Received, 26th February, 2001
SYNTHESIS OF 4-(1-DIALKYLAMINOALKYL)PYRROLO[1,2-
a]QUINOXALINES
Kazuhiro Kobayashi,* Takashi Matsumoto, Susumu Irisawa, Keiichi Yoneda,
Osamu Morikawa, and Hisatoshi Konishi
Department of Materials Science, Faculty of Engineering, Tottori University,
Koyama-minami, Tottori 680-8552, Japan
Abstract- The reaction of 1-(2-isocyanophenyl)pyrroles (1), which were readily
prepared from commercially available or known 1-(2-aminophenyl)pyrroles by
formylation in refluxing ethyl formate followed by dehydration with POCl3/Et3N in
THF, with Eschenmoser's salt (2) proceeded smoothly at room temperature to give
the dimethyl(pyrrolo[1,2-a]quinoxalin-4-ylmethyl)ammonium iodides (3) in good
yields (74–75%). 1-(2-isocyanophenyl)pyrrole (1a) was also found to react with a
range of iminium salts (5) and (7), derived from secondary amines and aldehydes
in the presence of Me3SiCl/NaI/Et3N, to give 4-(1-dialkylaminoalkyl)pyrrolo[1,2-
a]quinoxaline derivatives (6), (8), and (9) in isolated yields ranging from 47 to
99%.
We have previously reported that 4-(1-hydroxyalkyl)pyrrolo[1,2-a]quinoxalines are readily prepared by
reacting 1-(2-isocyanophenyl)pyrroles (1) with aldehydes or ketones in the presence of a catalytic amount
of boron trifluoride diethyl etherate.1 In continuation of this work, we decided to develop the preparation of
pyrrolo[1,2-a]quinoxalines bearing 1-dialkylaminoalkyl group at the 4-position, and attempted the reactions
of the isocyanides (1) with Eschenmoser's salt (2) or other iminium salts (5) and (7), derived from
secondary amines and aldehydes.2 The reactions of 1 with these iminium salts proceeded without any
catalyst to allow formation of 4-(1-dialkylaminoalkyl)pyrrolo[1,2-a]quinoxaline derivatives (3), (4), (6),
(8), and (9) in fair to good yields.3,4
The reaction of isocyanides (1) with Eschenmoser's salt (2) proceeded smoothly at 0 ˚C in dichloromethane
to give dimethyl(pyrrolo[1,2-a]quinoxalin-4-ylmethyl)ammonium iodides (3), which could be isolated by
filtration after addition of diethyl ether in good yield and readily converted into the corresponding free amine
derivative (4) quantitatively by treating with aqueous NaHCO3 (Scheme 1).

N
N
N
N
CH Cl ,
aq. NaHCO
2
2
3
+
–
+
CH =N Me I
2
2
0 ˚C
+
-
R
NC
R
CH N HMe I
N
CH NMe
2 2
2
2
2
1a R=H
1b R=Me
3a R=H (76%)
3b R=Me (76%)
4 (quant)
Scheme 1
N
N
MeCN, Et N
3
+
-
N R' I
1a +
2
rt
R
CHRNR'
2
5
6
Scheme 2
Table. Yields of 4-(1-dialkylaminoalkyl)pyrrolo[1,2-a]quinoxalines (6) by
the reactions of 1-(2-isocyanophenyl)pyrrole (1a) with iminium salts (5)
6 (Yield/%)a
Entry
5
1
2
5a (R = Et, R’ = Me)
5b [R = i-Pr, R’2 = (CH2)5]
6a (98)
6b (73)
3
4
5
6
6c (47)
6d (83)
6e (85)
6f (99)
5c (R = t-Bu, R’ = Me)
5d (R = Ph, R’ = Me)
5e [R = Ph, R’2 = (CH2)4]
5f (R = p-MeOC6H4, R’ = Me)
5g (R = p-ClC6H4, R’ = Me)
5h (R = p-O2NC6H4, R’ = Me)
5i (R = 2-furyl, R’ = Me)
7
8
9
6g (74)
6h (81)
6i (57)
a Isolated yields based on purification by column chromatography on SiO2.
The iminium salts (5), prepared in situ by the treatment of a range of aldehydes with secondary amines in
the presence of chlorotrimethylsilane, sodium iodide, and triethylamine according to the procedure reported
by Arend and Risch,2 reacted slowly with the isocyanide (1a) at room temperature to give, after workup
with aqueous sodium hydrogen carbonate followed by separation using column chromatography on silica
gel, the 4-(1-dialkylaminoalkyl)pyrrolo[1,2-a]quinoxalines (6) (Scheme 2). The results are summarized in
the Table, which indicates that the yields of the products (6a,b, and d-f) were generally good-to-excellent.

+
-
N Me I
N
NMe
2
2
N
NMe
2
N
MeCN, Et N
3
+
1a +
N
rt
N
+
-
N Me I
2
Me N
N
CHO
2
7
8 (89%)
9 (9%)
Scheme 3
N
N
N
–
I
H
4 or 6
1
+
2 or 5
–
N C
I
CHRNR'
2
CHRNR'
2
11
10
Scheme 4
However, with iminium salts derived from 2,2-dimethylpropanal (Entry 3) or 2-furancarbaldehyde (Entry
9) yields of the expected products were somewhat lower than those using other iminium salts. The reduced
yield of former may be attributable to the bulkiness of tert-butyl group, which caused the reaction proceed
more reluctantly. In the latter case, the yield after workup was good, as judged by the 1H NMR spectra.
The lower yield is presumably due to the instability of the product during isolation procedure.
Similar treatment of bis-iminium salt (7) with 2 molar amounts of isocyanide (1a) under conditions similar
to those described for the preparation of 6 gave high yield of the doubly aminoalkylated product, 1,4-bis[1-
dimethylamino-1-(pyrrolo[1,2-a]quinoxalin-4-yl)methyl]benzene (8 ), as a c a . 1:1 mixture of
diastereomers, accompanied by a small quantity of the mono(aminoalkylated) product (9), as shown in
Scheme 3. The stereochemistry of each diastereomer is not determined yet.
The reaction sequence involves the addition of isocyano carbon to iminium salts, followed by cyclization by
the attack of pyrrole ring at the 2-position to the resulting imino iodide (10). The products (4) and (6) are
formed through intermediate (11),(Scheme 4).
In summary, the present procedure can offer a convenient route to 4-(1-dialkylaminioalkyl)pyrrolo[1,2-
a]quinoxalines. This method has advantages of simple manipulations as well as readily available starting
materials and may find some value in organic synthesis.
EXPERIMENTAL

The mps were determined on a Laboratory Devices MEL-TEMP II melting point apparatus and are
uncorrected. The IR spectra were determined with a Perkin-Elmer 1600 Series FT IR spectrophotometer.
1
The H NMR spectra were determined using SiMe4 as an internal reference with either a JEOL JNM-
GX270 FT NMR spectrometer operating at 270 MHz in CDCl3, unless stated otherwise. J Values are
given in Hz. Low-resolution MS spectra were recorded on a JEOL AUTOMASS 20 spectrometer (Center
for Joint Research and Development, this University). High-resolution MS analyses were performed with a
JEOL JMX-AX505HA spectrometer (Faculty of Agriculture, this University). 1-(2-
Isocyanophenyl)pyrroles (1a) and (1b) were prepared by formylation of the respective 1-(2-
aminophenyl)pyrroles [1-(2-aminophenyl)pyrrole was commercially available and 1-(2-amino-4-
methylphenyl)pyrrole was prepared by the reported method5] in refluxing ethyl formate, followed by the
dehydration of the resulting 1-(2-formylaminophenyl)pyrroles with POCl3/Et3N in THF at 0 ˚C. 1a: mp
42–43 ˚C (hexane); νmax/cm–1 (KBr disk) 2122; δ 6.39 (2H, t, J = 2.1), 7.02 (2H, t, J = 2.1), 7.3-7.55
H
(4H, m); MS (EI) m/z 168 (M+, 100). Anal. Calcd for C11H8N2: C, 78.55; H, 4.79; N, 16.66. Found: C,
78.21; H, 5.00; N, 16.80. 1b: mp 97–99 ˚C (hexane); νmax/cm–1 (KBr disk) 2125; δ 2.39 (3H, s), 6.36
H
(2H, t, J = 2.1), 6.97 (2H, t, J = 2.1), 7.25 (2H, s), 7.31 (1H, s); MS (EI) m/z 182 (M+, 100). Anal.
Calcd for C12H10N2: C, 79.10; H, 5.53; N, 15.37. Found: C, 79.13; H, 5.54; N, 15.67. Iminium salts
(5) and (7) were prepared in situ according to the procedure reported by Arend and Risch.2 All of the other
chemicals used in this study were commercially available.
Dimethyl[(pyrrolo[1,2-a]quinoxalin-4-yl)methyl]ammonium Iodide (3a). To a stirred
solution of N,N-dimethylmethyleneammonium iodide (2) (0.20 g, 1.1 mmol) in CH2Cl2 (10 mL) under
argon at rt was added a solution of 1-(2-isocyanophenyl)pyrrole (1a) (0.17 g, 1.0 mmol) in CH2Cl2 (3
mL). After 45 min stirring, the mixture was diluted by adding Et2O (30 mL). The precipitate was collected
by filtration and recrystallized from EtOH to give 3a (0.27 g, 76%) as pale-pink needles; mp 216–217 ˚C
(decomp); νmax/cm–1 (KBr disk) 3127, 2805, 1616; δ (D2O) 3.29 (6H, s), 4.89 (2H, s), 7.23 (1H, dd, J
H
= 3.7 and 3.2), 7.32 (1H, d, J = 3.7), 7.75 (1H, t, J = 7.4), 7.86 (1H, t, J = 7.4), 8.13 (1H, d, J = 7.4),
8.24 (1H, d, J = 7.4), 8.43 (1H, d, J = 3.2). Anal. Calcd for C14H16N3I: C, 47.61; H, 4.57; N, 11.90.
Found: C, 47.36; H, 4.86; N, 11.60.
Dimethyl[(7-methyl-4-pyrrolo[1,2-a]quinoxalinyl)methyl]ammonium Iodide (3b):
prepared from the isocyanide (1b) and the iminium iodide (2) in a manner similar to that described above
for the preparation of 3a; pale-pink needles; mp 244–247 ˚C (decomp) (EtOH); νmax/cm–1 (KBr disk)
3103, 2806, 1620; δ (DMSO-d6) 2.50 (3H, s), 3.03 (6H, s), 4.82 (2H, s), 6.95–7.0 (1H, m), 7.13 (1H,
H
m), 7.50 (1H, d, J = 8.4), 7.75 (1H, s), 8.22 (1H, dd, J = 8.4 and 1.1), 8.50 (1H, dd, J = 2.6 and 1.1).
Anal. Calcd for C15H18N3I: C, 49.06; H, 4.94; N, 11.44. Found: C, 49.23; H, 5.02; N, 11.44.
4-[(Dimethylamino)methyl]pyrrolo[1,2-a]quinoxaline (4).
A
suspension
of

(pyrroloquinoxalinyl)ammonium iodide (3a) (0.21 g, 0.60 mol) in saturated aqueous NaHCO3 (2 mL) was
stirred at rt for 30 min. The resulting solution was extracted with CH2Cl2 and the extract was dried over
anhydrous Na2SO4. Evaporation of the solvent gave 4 (0.13 g): a pale-yellow viscous oil; Rf 0.03 (EtOAc-
hexane 1: 2); νmax/cm–1 (neat) 3130, 1614; δ 2.43 (6H, s), 3.84 (2H, s), 6.86 (1H, dd, J = 3.9 and 3.0),
H
7.11 (1H, d, J = 3.9 and 1.3), 7.43 (1H, td, J = 7.7 and 1.7), 7.50 (1H, td, J = 7.7 and 1.7), 7.85 (1H,
dd, J = 7.7 and 1.7), 7.92 (1H, dd, J = 3.0 and 1.3), 8.00 (1H, dd, J = 7.7 and 1.7); MS (EI) m/z 225
(M+, 0.46), 182 (100). Anal. Calcd for C14H15N3: C, 74.64; H, 6.71; N, 18.65. Found: C, 75.01; H,
6.59; N, 18.49.
4-[1-(Dimethylamino)propyl]pyrrolo[1,2-a]quinoxaline (6a). General Procedure. The
imminium salt (5a) was prepared from EtCHO (60 mg, 1.0 mmol), Me2NH hydrochloride (85 mg, 1.0
mmol), Me3SiCl (0.25 g, 2.3 mmol), NaI (0.34 g, 2.3 mmol), and Et3N (0.21 g, 2.1 mmol) in acetonitrile
(2.3 mL) according to the procedure reported by Arend and Risch.3 To this CH2Cl2 (5 mL) was added.
The mixture was cooled to 0 ˚C and a solution of the isocyanide (1a) (0.17 g, 1.0 mmol) in CH2Cl2 (5 mL)
was added under stirring. After stirring overnight at rt, saturated aqueous NaHCO3 was added and the
resulting mixture was extracted with CH2Cl2. The extract was dried over anhydrous Na2SO4 and the
solvent was evaporated. The residue was subjected to column chromatography on SiO2 to give 6a (0.26 g,
98%) as a pale–yellow viscous oil; Rf 0.11 (EtOAc–hexane 1: 1); νmax/cm–1 (neat) 3146, 1613; δ 0.82
H
(3H, t, J = 7.3), 2.0–2.25 (2H, m), 2.37 (6H, s), 3.67 (1H, dd, J = 9.4 and 4.8), 6.84 (1H, dd, J = 3.9
and 2.6), 7.09 (1H, dd, J = 3.9 and 1.3), 7.35–7.55 (2H, m), 7.84 (1H, dd, J = 7.7 and 1.7), 7.91 (1H,
dd, J = 2.6 and 1.3), 8.01 (1H, dd, J = 7.7 and 1.7); MS (CI) m/z 254 [(M+1)+, 100]. Anal. Calcd for
C16H19N3: C, 75.85; H, 7.56; N, 16.59. Found: C, 75.82; H, 7.61; N, 16.71.
4-(2-Methyl-1-piperidinylpropyl)pyrrolo[1,2-a]quinoxaline (6b): a pale-yellow viscous oil; Rf
0.65 (EtOAc–hexane 1: 2); νmax/cm–1 (neat) 3134, 1612; δ 0.76 (3H, d, J = 6.9), 1.14 (3H, d, J = 6.9),
H
1.25–1.35 (2H, m), 1.45–1.6 (5H, m), 2.5–2.6 (4H, m), 3.63 (1H, d, J = 9.8), 6.82 (1H, dd, J = 3.9
and 3.0), 6.98 (1H, dd, J = 3.9 and 1.6), 7.4–7.5 (2H, m), 7.83 (1H, dd, J = 7.7 and 1.2), 7.89 (1H, dd,
J = 3.0 and 1.6), 7.96 (1H, dd, J = 7.7 and 1.2); MS (EI) m/z 307 (M+, 0.02), 224 (71), 209 (100). Anal.
Calcd for C20H25N3: C, 78.14; H, 8.20; N, 13.67. Found: C, 78.00; H, 8.28; N, 14.00.
4-(1-Dimethylamino-2,2-dimethylpropyl)pyrrolo[1,2-a]quinoxaline (6c): a pale-yellow
viscous oil; Rf 0.49 (EtOAc–hexane 1: 2); νmax/cm–1 (neat) 3136, 1614; δ 1.18 (9H, s), 2.47 (6H, s),
H
3.80 (1H, m), 6.82 (1H, dd, J = 3.8 and 2.7), 6.90 (1H, dd, J = 3.8 and 1.4), 7.40 (1H, td, J = 7.3 and
1.6), 7.47 (1H, td, J = 7.3 and 1.6), 7.82 (1H, dd, J = 7.3 and 1.6), 7.89 (1H, dd, J = 2.7 and 1.4), 7.95
(1H, dd, J = 7.3 and 1.6); MS (CI) m/z 282 [(M+1)+, 100]. Anal. Calcd for C18H23N3: C, 76.83; H,
8.24; N, 14.93. Found: C, 77.15; H, 8.30; N, 14.85.
4-(α-Dimethylaminobenzyl)pyrrolo[1,2-a]quinoxaline (6d): pale-yellow needles; mp 116–118

˚C (hexane); νmax/cm–1 (KBr disk) 3136, 1612; δ 2.34 (6H, s), 4.60 (1H, s), 6.81 (1H, dd, J = 4.3 and
H
2.6), 7.1–7.3 (4H, m), 7.35–7.5 (2H, m), 7.65–7.75 (2H, m), 7.77 (1H, dd, J = 7.9 and 1.7), 7.86 (1H,
dd, J = 2.6 and 1.6), 8.11 (1H, dd, J = 7.9 and 1.7); MS (EI)m/z 301 (M+, 0.02), 258 (100). Anal. Calcd
for C20H19N3: C, 79.70; H, 6.35; N, 13.94. Found: C, 80.03; H, 6.35; N, 13.74.
4-[α-(1-Pyrrolidinyl)benzyl]pyrrolo[1,2-a]quinoxaline (6e): a pale-yellow viscous oil; Rf 0.12
(EtOAc–hexane 1:2); νmax/cm–1 (neat) 3146, 1612; δ 1.8–1.9 (4H, m), 2.5–2.75 (4H, m), 4.73 (1H, s),
H
6.81 (1H, dd, J = 4.1 and 3.0), 7.15–7.35 (4H, m), 7.35–7.5 (2H, m), 7.65–7.8 (3H, m), 7.86 (1H, dd,
J = 3.0 and 1.4), 8.09 (1H, dd, J = 7.9 and 1.7); MS (EI) m/z 327 (M+, 0.09), 258 (100). Anal. Calcd for
C22H21N3: C, 80.70; H, 6.46; N, 12.83. Found: C, 80.67; H, 6.50; N, 12.85.
4-(α-Dimethylamino-4-methoxybenzyl)pyrrolo[1,2-a]quinoxaline (6f): pale-yellow needles;
mp 169–172 ˚C (EtOAc–hexane); νmax/cm–1 (KBr disk) 3125, 1607; δ 2.33 (6H, s), 3.73 (3H, s), 4.55
H
(1H, s), 6.75–6.85 (3H, m), 7.22 (1H, dd, J = 4.1 and 1.4), 7.4–7.5 (2H, m), 7.61 (2H, d, J = 9.0),
7.78 (1H, d, J = 7.3), 7.86 (1H, dd, J = 3.0 and 1.4), 8.11 (1H, dd, J = 7.3 and 2.1); MS (EI) m/z 331
(M+, 0.25), 288 (100). Anal. Calcd for C21H21N3O: C, 76.10; H, 6.39; N, 12.68. Found: C, 75.71; H,
6.15; N, 12.38.
4-(4-Chloro-α-dimethylaminobenzyl)pyrrolo[1,2-a]quinoxaline (6g): a pale-yellow solid; mp
152–153 ˚C (hexane); νmax/cm–1 (KBr disk) 3147, 1610; δ 2.33 (6H, s), 4.58 (1H, s), 6.83 (1H, dd, J =
H
4.2 and 3.2), 7.2–7.3 (3H, m), 7.35–7.5 (2H, m), 7.65 (2H, d, J = 8.4), 7.79 (1H, dd, J = 7.9 and 1.6),
7.88 (1H, dd, J = 3.2 and 1.4), 8.09 (1H, dd, J = 7.9 and 1.6); MS (CI) m/z 336 [(M+1)+, 100]. Anal.
Calcd for C20H18N3Cl: C, 71.53; H, 5.40; N, 12.51. Found: C, 71.33; H, 5.40; N, 12.51.
4-(α-Dimethylamino-4-nitrobenzyl)pyrrolo[1,2-a]quinoxaline (6h): a pale-yellow solid; mp
149–150 ˚C (hexane); νmax/cm–1 (KBr disk) 3159, 1605, 1345; δ 2.36 (6H, s), 4.74 (1H, s), 6.86 (1H,
H
dd, J = 4.1 and 2.7), 7.27 (1H, dd, J = 4.1 and 1.3), 7.4–7.55 (2H, m), 7.80 (1H, dd, J = 8.2 and 1.7),
7.85–7.95 (3H, m), 8.06 (1H, dd, J = 8.2 and 1.7), 8.13 (2H, d, J = 9.0); MS (CI) m/z 347 [(M+1)+,
100]. Anal. Calcd for C20H18N4O2: C, 69.35; H, 5.24; N, 16.17. Found: C, 69.67; H, 5.26; N, 16.08.
4-[1-(Dimethylamino)-1-(furan-2-yl)methyl]pyrrolo[1,2-a]quinoxaline (6i): light-brown
needles; mp 178–180 ˚C (EtOAc-hexane); νmax/cm–1 (KBr disk) 3145, 1648; δ 2.36 (6H, s), 4.84 (1H,
H
s), 6.29 (1H, dd, J = 4.1 and 3.2), 6.47 (1H, d, J = 3.0), 6.83 (1H, dd, J = 3.9 and 3.0), 7.25 (1H, dd, J
= 4.1 and 1.9), 7.35 (1H, br s), 7.38–7.55 (2H, m), 7.81 (1H, dd, J = 8.2 and 1.7), 7.90 (1H, dd, J =
3.0 and 1.1), 8.06 (1H, dd, J = 8.2 and 1.7); MS (CI) m/z 292 [(M+1)+, 100]. Anal. Calcd for
C18H17N3O: C, 74.20; H, 5.88; N, 14.42. Found: C, 74.11; H, 5.90; N, 14.50.
1,4-Bis[1-(dimethylamino)-1-pyrrolo[1,2-a]quinoxalin-4-yl)methyl]benzene (8): a mixture
of diastereomers (ca. 1:1); pale-yellow needles; mp 209–213 ˚C (EtOAc–hexane); νmax/cm–1 (KBr disk)
3136, 1612; δ 2.33 and 2.34 (combined 12H, 2s), 4.65 (2H, br s), 6.7–6.75 (2H, m), 7.1–7.15 (2H,
H

m), 7.3–7.4 (4H, m), 7.6–7.65 (6H, m), 7.7–7.75 (2H, m), 8.0–8.1 (2H, m); MS (CI) m/z 525 [(M+1)+,
100]. Anal. Calcd for C34H32N6: C, 76.83; H, 6.15; N, 16.02. Found: C, 76.80; H, 6.39; N, 15.78.
4-[1-(Dimethylamino)-1-(4-pyrrolo[1,2-a]quinoxalinyl)methyl]benzaldehyde (9): a pale-
yellow viscous oil; Rf 0.16 (EtOAc–hexane 1:2); νmax/cm–1 (neat) 3188, 2821, 2774, 1605; δ 2.36 (6H,
H
s), 4.71 (1H, s), 6.85 (1H, dd, J = 3.9 and 3.0), 7.26 (1H, dd, J = 3.9 and 1.3), 7.4–7.55 (2H, m),
7.75–7.8 (3H, m), 7.85–7.95 (3H, m), 8.08 (1H, dd, J = 7.7 and 1.7), 9.93 (1H, s); MS (CI) m/z 330
[(M+1)+, 100]. Anal. Calcd for C21H19N3O: C, 76.57; H, 5.81; N, 12.76. Found: C, 76.33; H, 6.01; N,
12.54.
ACKNOWLEDGEMENTS
The authors thank Mrs. Miyuki Tanmatsu of this Department for determining the mass spectra.
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