Reduction of indolo[2,3-b]quinoxalines

Article abstract of DOI:10.1016/j.tet.2005.02.060

Reduction of indolo[2,3-b]quinoxalines with zinc in the presence of an anhydride gave N,N-diacyl trapped 6,11-dihydroindolo[2,3-b]quinoxalines in 43-92% yields. When the reduction with zinc was performed in TFA/TFAA, an unexpected ring opened product was isolated in 49% yield. The structure of this product could be identified as 1,2-dihydro-1-trifluoroacetyl-3-[(2- trifluoroacetylamino)phenyl]quinoxaline.

Full text of DOI:10.1016/j.tet.2005.02.060

Tetrahedron 61 (2005) 4495–4500
Reduction of indolo[2,3-b]quinoxalines
Robert Engqvist,a Birgitta Stenslandb and Jan Bergmana,
*
aUnit for Organic Chemistry, CNT, Department of Biosciences at Novum, Karolinska Institute, Novum Research Park, SE-141 57 Huddinge,
¨ ¨
Sweden and Sodertorn University College, SE-141 04 Huddinge, Sweden
b
¨
¨
AstraZeneca PAR & D, Preformulation and Biopharmaceutics, Solid State Analysis/SBBG BV341:3, SE-151 85 Sodertalje, Sweden
Received 5 October 2004; revised 28 January 2005; accepted 10 February 2005
Available online 22 March 2005
Abstract—Reduction of indolo[2,3-b]quinoxalines with zinc in the presence of an anhydride gave N,N-diacyl trapped 6,11-
dihydroindolo[2,3-b]quinoxalines in 43–92% yields. When the reduction with zinc was performed in TFA/TFAA, an unexpected ring
opened product was isolated in 49% yield. The structure of this product could be identified as 1,2-dihydro-1-trifluoroacetyl-3-[(2-
trifluoroacetylamino)phenyl]quinoxaline.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Ellipticine (1) and a large numbers of its derivatives and
analogues have potent antitumour activities.1 Several
indolo[2,3-b]quinoxalines have been studied in this context,
which led us to the development of the lead compound
6-(N,N-dimethylaminoethyl-)2,3-dimethylindolo[2,3-b]-
quinoxaline, 2a (B-220), which contrary to ellipticine B-220
is inactive in most cancer models but does show potent
activity against certain types of viruses (HSV-1, VZV,
CMV).2 The molecule B-220 exerts also a stabilizing effect
on the formation of triple helixes of nucleic acids.3
Merour et al. have published an alternative route to
tetracyclic indolic and azaindolic derivatives starting from
1-acetyl-2-bromo-3-indolinone and the appropriate
diamine.4 This reaction gave a mixture of dihydro
compounds (e.g., 3a) and the fully aromatized compounds
(e.g., 2b). Hydrolysis of 3a gave the highly unstable parent
dihydro compound 3b.4 At that point we wanted to
synthesize dihydro derivatives of 2a, such as 4a and 4b,
because the dihydro derivative 4a might be an active
metabolite of 2a and the diacetyl derivative 4b might in vivo
be hydrolysed to 4a.
Figure 1.
2. Results and discussion
In this paper we report the outcome of the reduction of
indolo[2,3-b]quinoxalines with Zn in the presence of
anhydrides (Fig. 1).
As a part of our ongoing development of B-220 we aimed to
have methodology to synthesize 5,11-dihydroindolo[2,3-
b]quinoxalines (potential metabolites). Reducing reagents
such as Pd(C)/H2,5 Na2S2O4,6 LiAlH4,7 Zn in acetic acid8
are known to reduce, the structurally related, phenazines to
Keywords: Reduction; Indolo[2,3-b]quinoxaline.
*
the corresponding 5,10-dihydrophenazines. Reduction of
phenazine itself with zinc in acetic anhydride was found, as
Corresponding author. Tel.: C46 8 6089204; fax: C46 8 6081501;
e-mail: jabe@cnt.ki.se
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.02.060

4496
R. Engqvist et al. / Tetrahedron 61 (2005) 4495–4500
expected, to give N,N-diacetyl-5,10-dihydrophenazine (5)
in a good yield (79%) (Scheme 1).
Similar reduction of 2b gave the desired product 6a albeit
contaminated with the N-acetylated product 2c. Attemps to
reduce 2c failed. The formation of this by-product could be
avoided by running the reaction in THF which exclusively
gave 6a. Recrystallisation of 6a (Scheme 2) from ethyl
acetate provided good quality crystals, which were used to
confirm the structure of 6a by X-ray crystallography
(Fig. 2). According to this analysis, the dihedral angle
between the two planes intersecting along the N,N-axis in
the N,N-dihydropyrazine is 1398. This value could be
compared with the corresponding angle reported for N,N-
dihydrodimethylphenazine (1448).9
Scheme 1. (i) Ac2O, Zn, reflux.
The corresponding dipropionylated compound, 6b, could
similarly be prepared (43%) using propionic anhydride
without any co-formation of 2d. When 2b was treated with
zinc in boiling propionic anhydride (neat) for 20 h even the
tripropionylated compound 6c could be obtained. Triacetyl
or trifluoroacetyl derivatives could not be obtained even
under forcing conditions, which most likely can be
explained in terms of the relatively high boiling point
(167 8C) of propionic anhydride compared to the boiling
points of TFAA and acetic anhydride. When the reduction
of 2a and 2b was performed with TFAA and zinc in THF the
mono trifluoroacetylated compounds 6d and 6f, respect-
ively, were isolated. To characterize 6d, NOE experiments
were performed at 25 8C in DMSO. Due to the bent structure
a very weak NOE interaction between the NH peaks
(d 11.11 and 9.72) could be observed. Because of a very
weak NOE interaction between the NH peaks 6d was
acetylated to attach a substituent (CH3) which will be closer
to the NH. This would corroborate the structure of the
product to be 6d and exclude the structure 6i. The initial
attempts were made with acetic anhydride with and without
a solvent (THF) at room temperature and under heating
failed and the product formed was 2c (quantitatively). The
acetylation was successful under reductive conditions (zinc,
THF, acetic anhydride) and the product thus formed was 6e.
Figure 2. Atom numbering scheme for 6a used in the crystal structure
investigation. The displacements of the non-H atoms are drawn as ellipsoid
at 50% probability level. H-atoms are shown as spheres with arbitrary radii.
Scheme 2. (i) Ac2O, THF, Zn, reflux.
Figure 3.

R. Engqvist et al. / Tetrahedron 61 (2005) 4495–4500
4497
Scheme 3. Reduction of indolo[2,3-b]quinoxalines to the corresponding mono-, di- or triacylated dihydro indolo[2,3-b]quinoxalines. * From 6d.
confirmed to be 6h rather than the isomer 6j (Fig. 3).
Attempted hydrolysis of e.g. 6h failed because the intended
product 4a is too prone to undergo dehydrogenation back to
2a (Scheme 3).
When 2b was reduced with zinc in a mixture of TFA and
TFAA at room temperature a compound with the molecular
weight of 415 was obtained. With this information the two
structures 7 and 8 were contemplated (Scheme 4). Both
trifluoroacetyl groups could be removed by KOH in
refluxing ethanol. By reduction of the known nitro
derivative 910 with Pd(C)/H2 to 10 we could exclude the
Scheme 4. (i) Zn, TFAA, TFA, rt, 5 min.
Scheme 5. (i) KOH, EtOH, reflux, 48 h. (ii) Pd(C), H2, rt, 70 h.
imine derivative 7 and confirm the structure as the
dihydroquinoxaline derivative 8 (Scheme 5) (Fig. 4).
In summary, we have described the reduction of the
biologically interesting indolo[2,3-b]quinoxalines with
zinc and an appropriate anhydride delivering the corre-
sponding dihydroindolo[2,3-b]quinoxalines in 43–92%
yields (Scheme 3, Table 1).
3. Experimental
3.1. General
Melting points were recorded on a Bu¨chi Melting Point
B-545 apparatus and are uncorrected. NMR spectra were
recorded on a Brucker Advance 300 DPX spectrometer
operating at 300 MHz (1H)/75 MHz (13C) and a Jeol
EclipseC500 FT NMR spectrometer operating at
500 MHz (1H) (NOE experiments). DMSO-d6 was used as
solvent and internal standard if not otherwise noted. The IR
spectra were recorded on an Avatar 330 FT-IR Thermo-
Nicolet. Solvents were of analytical grade and used as
received. Compound 9 was prepared according to a
literature procedure.10 Crystallographic data (excluding
structure factors) for the structure in this paper have been
deposited with the Cambridge Crystallographic Data Centre
as supplementary publication numbers CCDC 251958.
Figure 4.
To corroborate the structure of 6e NOE experiments were
performed, at 25 8C in DMSO, an NOE interaction between
the NH peak and the methyl peak, from the acetyl group (d
9.65 and 2.83) could be observed. Similarly, the product
obtained by reduction of 2a in the presence of zinc was

4498
R. Engqvist et al. / Tetrahedron 61 (2005) 4495–4500
Table 1. Reduction of indolo[2,3-b]quinoxalines with zinc in the presence of an appropriate anhydride
Entry
S.m.
Solvent
Anhydride
Time (h)
Product (6)
Yield (%)
1
2
3
4
5
6
7
8
2b
2b
2b
2b
6d
2a
2a
2a
THF
THF
—
THF
THF
—
(CH3CO)2O
(C2H5CO)2O
(C2H5CO)2O
(CF3CO)2O
(CH3CO)2O
(CH3CO)2O
(C2H5CO)2O
(CF3CO)2O
20
32
20
2
24
2
a
b
c
d
e
f
G
H
68
43
40
92
26
71
66
50
—
THF
2
1
Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK [fax: C44-(0)1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk].
2.07 g (white crystals, double scale, 68%); mp: 201–
204 8C; IR (neat): 3343, 1696, 1656, 1480, 1371, 1307,
1
1282, 752, and 746 cmK1; H NMR: d 9.18 (s, 1H, NH),
7.77 (d, JZ8.2 Hz, 1H, ArH), 7.42 (d, JZ7.9 Hz, 1H, ArH),
7.36–7.32 (m, 2H, ArH), 7.24 (t, JZ7.3 Hz, 1H, ArH),
7.17–7.11 (m, 2H, ArH), 6.98 (dt, JZ7.6, 1.2 Hz, 1H, ArH),
2.82 (s, 3H, Me), 2.14 (s, 3H, Me); 13C NMR: d 170.9 (s),
170.8 (s), 138.9 (s), 136.9 (s), 131.3 (s), 128.3 (d), 126.9 (s),
126.1 (d), 125.5 (d), 124.5 (s), 123.4 (d), 121.2 (d), 117.1
(s), 116.7 (d), 114.5 (d), 103.2 (s), 26.8 (q), 21.9 (q). HR-MS
(FAB): [MC], found 305.1156. C18H15N3O2 requires
305.1164.
3.1.1. Synthesis of N,N-diacetyl-5,10-dihydrophenazine
(5). Phenazine (3.60 g, 20 mmol) was heated at reflux with
zinc powder (3.0 g, 46 mmol) in acetic anhydride (40 mL)
for 3 h. The filtered mixture upon cooling deposited white
crystals, 1.60 g. Concentration of the mother liquor gave a
second crop 2.60 g, resulting in a total yield of 79%. Mp:
184–185 8C (lit.11 mp: 180 8C). IR (neat): 3044, 2928, 1669,
1480, 1372, 1326, 1267, 1017, 780 cmK1; 1H NMR: d 7.68–
7.62 (m, 4H, ArH), 7.33–7.27 (m, 4H, ArH), 2.30 (s, 6H,
2Me); 13C NMR: d 167.8 (s), 136.2 (s), 125.8 (d), 125.2 (d),
23.0 (q).
3.2.2. Synthesis of 6,11-dipropionyl-5,11-dihydro-6H-
indolo[2,3-b]quinoxaline (6b) via method A. 2.5 equiv
of propionic anhydride was used. 1.6 mL. Yield: 0.71 g
(white crystals, 43%); mp: 120–123 8C; IR (neat): 3393,
2983, 2939, 1700, 1674, 1480, 1458, 1365, 1272, 1202 and
741 cmK1; 1H NMR: d 9.25 (s, 1H, NH), 7.76 (d, JZ8.3 Hz,
1H, ArH), 7.41 (d, JZ7.8 Hz, 1H, ArH), 7.35–7.29 (m, 2H,
ArH), 7.23 (t, JZ7.4 Hz, 1H, ArH), 7.16–7.08 (m, 2H,
ArH), 7.00 (t, JZ7.8 Hz, 1H, ArH), 3.20 (q, JZ7.0 Hz, 2H,
CH2), 2.47 (q, JZ7.2 Hz, 2H, CH2), 1.23 (t, JZ7.0 Hz, 3H,
Me), 0.98 (t, JZ7.2 Hz, 3H, Me); 13C NMR (50 8C): d 174.3
(s), 174.0 (s), 138.8 (s), 137.0 (s), 131.0 (s), 126.8 (s), 125.8
(d), 125.5 (d), 124.5 (s), 123.1 (d), 121.0 (d), 120.9 (d),
116.6 (d), 116.4 (d), 114.4 (d), 103.0 (s), 31.1 (t), 26.0 (t),
8.8 (q), 8.1 (q). HR-MS (FAB): [MC], found 333.1491.
C20H19N3O2 requires 333.1477.
3.2. General procedure for the reduction of indolo-
[2,3-b]quinoxalines
Method A. Zinc powder (1.30 g; 20 mmol) was added to a
solution of the appropriate indoloquinoxaline (2a or 2b,
5 mmol) in THF (50 mL) containing the appropriate
anhydride (5 mL). The reaction mixture was heated under
reflux until no starting material was left (determined by
TLC). Thereafter the solution was poured into cold water
and after a while a solid was formed. The crude product was
isolated by filtration and washed with water and purified by
recrystallisation.
Method B. Zinc powder (1.30 g; 20 mmol) was added to a
solution of the appropriate indoloquinoxaline (2a or 2b,
5 mmol) containing the appropriate anhydride (10 mL). The
reaction mixture was heated under reflux until no starting
material was left (determined by TLC). Thereafter, the
solution was poured into cold water and extracted with ethyl
acetate. The organic phase was washed with aq. NaHCO3,
brine, dried with MgSO4 and purified by chromathography
(ethyl acetate–hexane).
3.2.3. Synthesis of 5,11-dihydro-5,6,11-tripropionyl-6H-
indolo[2,3-b]quinoxaline (6c) via method B. Yield: 0.77 g
(yellowish solid, 40%); mp: 165–166 8C; IR (neat): 2997,
2977, 2938, 2877, 1712, 1685, 1671, 1357, 1266, 1199,
1
1136, 767, 760, and 751 cmK1; H NMR: d 8.24 (d, JZ
7.5 Hz, 1H, ArH), 7.81–7.77 (m, 2H, ArH), 7.61 (d, JZ
6.8 Hz, 1H, ArH), 7.41–7.29 (m, 4H, ArH), 2.98–2.40 (m,
6H, 3CH2), 1.17–0.97 (m, 9H, 3Me); 13C NMR (75 8C): d
174.4 (s), 172.8 (s), 171.8 (s), 138.2 (s), 136.4 (s), 133.1 (s),
130.6 (s), 126.5 (d), 126.1 (s), 125.8 (d), 125.4 (d), 124.8 (s),
124.5 (d), 123.0 (d), 121.6 (s), 119.1 (d), 118.8 (s), 115.3
(d), 29.2 (t), 27.1 (t), 26.8 (t), 8.7 (q), 8.4 (q) and 8.2 (q).
HR-MS (FAB): [MC], found 389.1743. C23H23N3O3
requires 389.1739.
Method C. Zinc powder (1.30 g; 20 mmol) was carefully
added to mixture of 2b (1.09 g; 5 mmol), TFA (2 mL) and
TFAA (15 mL) at room temperature and the reaction
mixture was stirred for 5 min and thereafter poured into
ice-water. The solid thus formed was collected by filtration
and washed with water. The solid was dissolved in EtOAc
and washed with aq. NaHCO3 (sat.), brine, dried with
MgSO4 and purified by chromatography (ethyl acetate–
hexane, 3:7).
3.2.4. Synthesis of 5,11-dihydro-11-trifluoroacetyl-6H-
indolo[2,3-b]quinoxaline (6d) via method A. Yield: 2.93 g
(yellowish solid, double scale, 92%); mp: 231–232 8C; IR
(neat): 3359, 3287, 1665, 1608, 1578, 1494, 1147, 1131,
1
758, 735, and 722 cmK1; H NMR: d 11.11 (s, 1H, NH),
3.2.1. Synthesis of 6,11-diacetyl-5,11-dihydro-6H-
indolo[2,3-b]quinoxaline (6a) via method A. Yield:
9.72 (s, 1H, NH), 7.44 (d, JZ8.0 Hz, 1H, ArH), 7.35–7.15
(m, 4H, ArH), 7.02–6.94 (m, 3H, ArH); 13C NMR (75 8C): d

R. Engqvist et al. / Tetrahedron 61 (2005) 4495–4500
4499
154.7 (s, q, JCFZ35.6 Hz), 139.4 (s), 137.2 (s), 132.1 (s),
127.1 (d), 124.2 (d), 123.9 (d), 123.8 (d), 121.5 (s), 120.4
quinoxaline (6h) via method B. Yield: 1.03 g (yellowish
solid, 50%); mp: 170–173 8C; IR (neat): 3053, 2955, 2796,
1
(d), 119.3 (d), 118.5 (d), 117.0 (d), 116.7 (s, q, JCF
288.5 Hz), 110.6 (d) and 97.0 (s). HR-MS (FAB): [MC],
found 317.0773. C18H15N3O2 requires 317.0776.
Z
1676, 1494, 1463, 1141, 855, and 723 cmK1; H NMR: d
9.88 (s, 1H, NH), 7.34 (d, JZ6.6 Hz, 1H, ArH), 7.29 (d, JZ
7.2 Hz, 1H, ArH), 7.22 (s, 1H, ArH), 7.00–6.95 (m, 3H,
ArH), 4.29 (t, JZ6.0 Hz, 2H, –CH2–), 2.60 (t, JZ6.0 Hz,
2H, –CH2–), 2.27 (s, 6H, 2Me), 2.22 (s, 3H, Me), 2.18 (s,
3H, Me). No 13C NMR could be recorded due to low
solubility and instability in warm DMSO. HR-MS (FAB):
[MC], found 416.1823. C22H23F3N4O requires 416.1824.
3.2.5. Synthesis of 6-acetyl-5,11-dihydro-11-trifluoro-
acetyl-6H-indolo[2,3-b]quinoxaline (6e) via method A.
Yield: 0.23 g (yellowish crystals, 1/2 scale, 26%); mp: 193–
194 8C; IR (neat): 3336, 3061, 2995, 2940, 1704, 1686,
1479, 1203, 1138, 1109, 995, 760, 744, and 720 cmK1;. 1H
NMR: d 9.65 (s, 1H, NH), 7.79 (d, JZ8.2 Hz, 1H, ArH),
7.51 (d, JZ8.1 Hz, 1H, ArH), 7.46 (d, JZ8.1 Hz, 1H, ArH),
7.36 (d, JZ7.6 Hz, 1H, ArH), 7.29–7.23 (m, 2H, ArH), 7.18
(t, JZ8.2 Hz, 1H, ArH), 7.08 (t, JZ7.6 Hz, 1H, ArH), 2.83
(s, 3H, Me); 13C NMR (55 8C): d 170.7 (s), 155.4 (s, q,
JCFZ36.5 Hz), 138.7 (s), 137.5 (s), 131.1 (s), 127.5 (d),
123.8 (d), 123.4 (s), 123.2 (d), 121.7 (d), 121.5 (d), 117.5
(d), 171.1 (d), 115.9 (s, q, JCFZ287.9 Hz), 114.2 (d), 101.2
(s), and 26.5 (q). HR-MS (FAB): [MC], found 359.0876.
C18H12F3N3O2 requires 359.0882.
3.2.9. Synthesis of 1,2-dihydro-1-trifluoroacetyl-3-[(2-
trifluoroacetylamino)phenyl]-quinoxaline (8) via method
C. Yield: 1.02 g (yellowish solid, 49%). mp: 150–151 8C;
IR (neat): 2858, 1706, 1542, 1266, 1190, 1155, 1138, 1091,
749, 727, and 703 cmK1; 1H NMR (CDCl3): d 14.49 (s, 1H,
NH), 8.80 (d, JZ8.4 Hz, 1H, ArH), 7.85–7.75 (m, 2H,
ArH), 7.61 (dt, JZ7.9 Hz, 1.2, 1H, ArH), 7.54–7.30 (m, 4H,
ArH), 4.90 (s, 2H, –CH2–). Due to instability in most
solvents no 13C NMR could be recorded. HR-MS (FAB):
[MCCH], found 416.0840. C18H12F6N3O2 requires
416.0834.
3.2.6. Synthesis of 5,11-diacetyl-5,11-dihydro-2,3-
dimethyl-6-(2-dimethylaminoethyl)-6H-indolo[2,3-b]-
quinoxaline (6f) via method B. Yield: 1.43 g (white
crystals, 71%); mp 86–88 8C; IR (neat): 3051, 2940, 2820,
3.2.10. Syntheses of 2-(2-aminophenyl)-quinoxaline (10).
From compound 8. A solution of KOH (0.41 g; 7.3 mmol), 8
(0.75 g; 1.8 mmol) and ethanol (10 mL) was refluxed for
48 h. The reaction mixture was poured into water (100 mL)
and the solid thus formed was collected by filtration, washed
with water, dried and purified by chromatography (EtOAc–
Hexane, 1:4). Yield: 0.30 g (yellow solid, 75%).
2768, 1682, 1493, 1454, 1366, 1314, 1266, 1017, 743 cmK1
;
1H NMR: d 7.64–7.54 (m, 3H, ArH), 7.45 (s, 1H, ArH), 7.22–
7.10 (m, 2H, ArH), 4.39–4.15 (m, 2H, –CH2–), 2.52–2.48 (m,
2H, –CH2–), 2.35 (s, 3H, Me), 2.32 (s, 3H, Me), 2.25 (s, 3H,
Me), 2.23 (s, 3H, Me), 2.06 (s, 6H, 2Me); 13C NMR (110 8C): d
169.5 (s), 167.6 (s), 136.0 (s), 134.2 (s), 133.5 (s), 133.4 (s),
133.2 (s), 133.0 (s), 125.6 (d), 125.3 (d), 121.0 (d), 119.7 (s),
119.3 (d), 118.0 (d), 112.6 (s), 110.0 (d), 56.9 (t), 44.3 (q), 41.7
(t), 21.8 (q), 21.4 (q), 18.0 (q) and 17.9 (q). HR-MS (FAB):
[MCCH], found 405.2299. C24H29N4O2 requires 405.2291.
From compound 9. A solution of 910 (0.50 g; 2 mmol),
Pd(C) (5%, 0.05 g) and ethanol (100 mL) was treated under
H2 at for 70 h. The reaction mixture was filtered through
Celite, the solvent was removed under reduced pressure and
the solid thus formed was purified by chromatography
(EtOAc–Hexane, 1:4). Yield: 0.26 g (yellow solid, 59%).
3.2.7. Synthesis of 5,11-dipropionyl-5,11-dihydro-2,3-
dimethyl-6-(2-dimethylaminoethyl)-6H-indolo[2,3-b]-
quinoxaline (6g) via method B. Yield: 1.43 g (white
crystals, 66%); At larger scales a convenient work-up
consist of: removing the remaining zinc by filtration and
thereafter treating the reaction mixture with water and
separating the two phases thus formed. The water phase was
cooled and basified with ammonia (aq., conc.). The solid
thus formed was collected by filtration and washed with
water and dried. Yield: 6.90 g (80%, from 20 mmol B-220).
mp: 66–68 8C; IR (neat): 2973, 2939, 2821, 2769, 1678,
Mp: 127 8C (dec.); IR (neat): 3340, 3148, 1613, 1538, 1472,
1249, 760, and 735 cmK1.; 1H NMR (CDCl3): d 9.34 (s, 1H,
ArH), 8.10 (dd, JZ8.0 Hz, 1.9, ArH), 8.05 (dd, JZ7.5 Hz,
2.0, ArH), 7.78–7.73 (m, 2H, ArH), 7.28 (dt, JZ7.7 Hz, 1.3,
ArH), 6.90–6.83 (m, 2H, ArH), 6.21 (s, 2H, –NH2); 13C
NMR (CDCl3): d 153.8 (s), 148.4 (s), 145.0 (d), 140.8 (s),
140.5 (s), 131.6 (d), 130.5 (d), 129.7 (2C, d), 128.9 (d),
118.5 (s), 117.9 (d), 117.8 (d). HR-MS (FAB): [MCCH],
found 222.1039. C14H12N3 requires 222.1031.
1
1490, 1452, 1358, 1244, 1173, and 742 cmK1; H NMR: d
7.55–7.48 (m, 3H, ArH), 7.45 (s, 1H, ArH), 7.19 (t, JZ
7.3 Hz, 1H, ArH), 7.11 (t, JZ7.3 Hz, 1H, ArH), 4.37–4.17
(m, 2H, –CH2–), 2.94–2.65 (m, 3H), 2.55–2.39 (m, 3H),
2.24 (s, 3H, Me), 2.22 (s, 3H, Me), 2.06 (s, 6H, 2Me), 1.02
(q, JZ7.4 Hz, 6H, 2Me); 13C NMR (110 8C): d 173.3 (s),
171.4 (s), 136.3 (s), 134.1 (s), 133.7 (s), 133.6 (s), 133.4 (s),
133.0 (s), 125.8 (d), 125.4 (d), 121.0 (d), 119.8 (s), 119.4
(d), 117.7 (d), 112.5 (s), 110.1 (d), 57.0 (t), 44.4 (q), 41.6 (t),
26.6 (t), 26.4 (t), 18.1 (q), 18.0 (q), 8.5 (q) and 8.1 (q). HR-
MS (FAB): [MCCH], found 433.2601. C26H33N4O2
requires 433.2604.
References and notes
1. Gribble, G. W. In The Alkaloids; Academic: London, 1990;
Vol. 39, p 239.
˚
2. (a) Harmenberg, J.; Wahren, B.; Bergman, J.; Akerfeldt, S.;
Lundblad, L. Antimicrob. Agents Chemother. 1988, 32, 1720.
˚
(b) Harmenberg, J.; Akesson-Johansson, A.; Graslund, A.;
˚
Malmfors, T.; Bergman, J.; Wahren, B.; Akerfeldt, S.;
¨
Lundblad, L.; Cox, S. Antiviral Res. 1991, 15, 193.
3. (a) Behravan, G.; Leijon, M.; Vallberg, H.; Bergman, J.;
¨
Graslund, A. Biopolymers 1994, 34, 599. (b) Sehlstedt, U.;
3.2.8. Synthesis of 5,11-dihydro-11-trifluoroacetyl-2,3-
dimethyl-6-(2-dimethylaminoethyl)-6H-indolo[2,3-b]-

4500
R. Engqvist et al. / Tetrahedron 61 (2005) 4495–4500
´
¨
Aich, P.; Bergman, J.; Vallberg, H.; Norden, B.; Graslund, A.
8. Koegl, F.; Postowsky, J. Justus Liebigs Ann. Chem. 1930, 480,
280.
J. Mol. Biol. 1998, 278, 31.
´
4. Alphonse, F.-A.; Routier, S.; Coudert, G.; Merour, J-Y.
Heterocycles 2001, 55, 925.
9. Holzapfel, M.; Lambert, C.; Selinka, C.; Stalke, D. J. Chem.
Soc., Perkin Trans. 2 2002, 1553.
5. Birkofer, L. Chem. Ber. 1952, 85, 1029.
6. Scholl, R. Monatsh. Chem. 1918, 39, 238.
7. Birkofer, L.; Birkofer, A. Chem. Ber. 1952, 85, 286.
10. Steinbach, L.; Becker, E. J. Am. Chem. Soc. 1954, 76, 580.
11. Birkofer, L. Chem. Ber. 1952, 85, 1023.