Studies on the Claisen rearrangements in the indolo[2,3-b]quinoline system

Article abstract of DOI:10.1039/b915677a

A study of the effect of substrate structure on a Claisen-aza-Cope reaction is presented including a rationalisation of the reaction outcome using DFT calculations. An asymmetric version of the reaction is also described that is of relevance to a proposed

Full text of DOI:10.1039/b915677a

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Studies on the Claisen rearrangements in the indolo[2,3-b]quinoline system†
Nicholas Vouˆte, Douglas Philp, Alexandra M. Z. Slawin and Nicholas J. Westwood*
Received 31st July 2009, Accepted 13th October 2009
First published as an Advance Article on the web 26th November 2009
DOI: 10.1039/b915677a
A study of the effect of substrate structure on a Claisen-aza-Cope reaction is presented including a
rationalisation of the reaction outcome using DFT calculations. An asymmetric version of the reaction
is also described that is of relevance to a proposed approach to the communesin family of natural
products.
Introduction
Establishing quaternary centres in an asymmetric manner remains
a key challenge.1 An approach that has received relatively little
attention is the formation of non-aromatic products by means
of the Claisen rearrangement operating on aromatic substrates.2
Here, we report the first application of this reaction type to
the indolo[2,3-b]quinoline system and highlight its applicability
in natural product synthesis. Initial studies focused on the
rearrangement of 1 (Scheme 1) with the reaction outcome being
rationalised computationally. Insights from these studies led to the
attempted Claisen rearrangement of 2 (Scheme 2), an isomer of
1. In this second-generation system, a stable product containing
an all-carbon quaternary centre was isolated in high yield and
the scope of this rearrangement was assessed as a function of the
structure of the migrating allyl unit. Further computational studies
provided an interesting insight into the difference in behaviour of 1
and 2. Finally, an asymmetric version of this reaction, important
in our approach to the communesin family of bioactive natural
products,3 is described.
Scheme 2 Synthesis of indolo[2,3-b]quinoline 7.
Results and discussion
Compound 1 was prepared by the regioselective methylation of the
known indolo[2,3-b]quinoline 34 to give 4, followed by treatment
with sodium allyloxide. Attempts to convert 1 to 5 led to the
isolation of quinolone 6, the result of formal allyl migration from
oxygen to nitrogen. The rate of this reaction was found to be
independent of the initial concentration of 1, consistent with a
tandem Claisen–aza-Cope process,5 most likely via 5. Interestingly,
a detailed analysis of the crude reaction mixture using 2D-NMR
techniques showed the presence of trace quantities of a compound
that showed a signal at 195 ppm in the 13C dimension. This signal is
tentatively assigned to the carbonyl carbon of 5, and a correlation
between this carbon and H1 in 5 was also observed.5,6
Scheme 1 Attempted synthesis of 5.
Due to the lack of significant accumulation of 5 and in order
to better understand the reaction outcome, the entire sequence of
rearrangement reactions was investigated using DFT calculations
using the B3LYP functional and a 6-31G(d,p) basis set (see
the ESI for details†). The transition states located for the two
rearrangements both have the classical chair-like structure.5,7 The
calculated barrier for the conversion of 1 into 5 is 27.3 kcal mol-1
(Fig. 1A). Intermediate 5 is calculated to be 6.7 kcal mol-1 higher
in energy than 1. The computed barrier for the conversion of
intermediate 5 into 6 is significantly lower (23.0 kcal mol-1) than
School of Chemistry and Biomedical Sciences Research Complex, University
of St Andrews, North Haugh, St Andrews, UK KY16 9ST. E-mail: njw3@st-
andrews.ac.uk
† Electronic supplementary information (ESI) available: A more detailed
discussion of the kinetic, NMR and computational analysis, and 1H
and 13C spectra for all novel compounds. CCDC 737646–737648. For
ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/b915677a
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Fig. 1 A Calculated energy profile for the conversion of 1 to 5 to 6 and 2 to 7 to 8. All energies are in kcal mol-1. B Simulated reaction profiles generated
using COPASI5b for the conversion of: (a) 1 (full line) through 5 (dotted line) to 6 (dashed line); (b) 2 (full line) through 7 (dotted line) to 8 (dashed line).
First order rate constants at 373 K were estimated using the Eyring equation and the activation parameters derived from the described DFT calculations
and a starting concentration of 1 or 2 of 50 mM was used.
that for the first rearrangement. These calculations are consistent
with the efficient conversion of 1 to 6 via intermediate 5. The
first rearrangement step is rate limiting and therefore no useful
accumulation of 5 occurs as a result of the much faster second
rearrangement. This was best illustrated when the reaction profile
was simulated using COPASI (Fig. 1B, chart (a)).5b A kinetic
model consisting of two consecutive first order processes can
be used to describe the overall transformation of 1 to 6. The
results demonstrate clearly that for the transformation of 1 to
6, intermediate 5 is predicted to only ever be present at a very
low level in agreement with the observed experimental result. The
basis for this behaviour would appear to be the relative stability of
the aromatic quinoline ring system present in 1.
We reasoned that by changing the structure of the starting
material, it might be possible to alter the balance of the rates of the
two rearrangement reactions so that the overall process would lead
to the accumulation of an intermediate analogous to 5. Compound
2 (Scheme 2) was therefore considered as a potential substrate for
the Claisen rearrangement. The methyl group in 2 is present on the
quinoline ring nitrogen, in contrast to the situation in 1 where it
is on the indole nitrogen. This minor structural change leads to a
considerable perturbation of the ground state electronic structure
of 2 as compared to 1. The entire sequence of rearrangement
reactions was again investigated computationally. As before, the
two relevant transition states for the Claisen–aza-Cope reaction
have the classical chair-like structures.5 In this system, however,
the barrier to the conversion of 2 into 7 is 25.1 kcal mol-1 higher
in energy than 2 and the process is now essentially thermoneutral,
with 7 being just 0.3 kcal mol-1 higher in energy than 2. The
computed barrier for the conversion of 7 into 8 (26.8 kcal mol-1) is
now higher than that for the first rearrangement step as required
for the accumulation of 7 to occur. Whilst care must be taken
over the interpretation of these computational studies, given the
relatively low level of theory employed, it was clear that on moving
from 1 to 2, a potential solution to the problem was at hand. For
example, simulation of the reaction profile in an analogous manner
to that described for the conversion of 1 to 6 via 5 suggested that in
the transformation of 2 to 8, 7 is present as the dominant species
in the early stages of the reaction (Fig. 1B, chart (b)). We therefore
decided to prepare 2 and study how it behaved in this reaction.
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Novel allyl ether 2 was synthesised from known indolo[2,3-
b]quinolone 9,4 via chloride 10 (Scheme 2). Interestingly, substi-
tution of the chlorine in 10 was found to occur under milder
conditions than those required to convert 4 to 1 (Scheme 1),
probably reflecting the decrease in ground state stability of 2
compared to 1. As predicted, 2 underwent clean rearrangement
to give 7 in 89% yield after 5 h in refluxing toluene. The structural
assignment of 7 was confirmed by X-ray crystallographic analysis.8
Prolonged heating of 7 in toluene was required to form 8 and a
minor product 11, resulting from a Cope rearrangement of 7, was
also isolated in this reaction.
To the best of our knowledge, 7 is the first example of the iso-
lation of a 10b-substituted indolo[2,3-b]quinolin-11-one. Whilst
similar compounds, including 12 (Fig. 2), have been reported
by Coppola,9 it was later demonstrated that their structural
assignment was incorrect and that the compounds in question
were in fact the corresponding indolo[2,1-b]quinazololin-12-ones
(for example 13).10 The indolo[2,1-b]quinazololin-12-one 13 was
reported to be formed by reaction of 3-methylthiooxindol with
N-methylisotoic anhydride.9 This reaction could have led to 13
directly; however, in our hands, 7 was converted to 148 in quanti-
tative yield when heated at reflux in methanol. This is consistent
with an alternative route to 13 involving initial formation of 12, as
proposed by Coppola,9 followed by rearrangement of 12 to give
13 in situ.
Scheme 3 The effect of substituents in the migrating allyl substituent on
the Claisen rearrangement.
Scheme 4 illustrates this concept through the preparation of the
highly optically enriched 18, a versatile intermediate of potential
relevance to the synthesis of the communesin group of natural
products (Fig. 3).3,14,15 Indoloquinolone 19, prepared from 4-
bromomethyl indole-3-carboxylate 2016 via 21,17 was converted to
18 in 74% yield using the readily available18 (S)-(+)-3-buten-2-ol
(96 : 4 e.r.5,19) without the need to purify the intermediate chloride
and butenyl ether 22.
Fig. 2 Structures of 12 and 13.
The scope of the Claisen rearrangement described in Scheme 2
was explored further by assessing the effect of alkyl substituents in
the allyl moiety on the attempted preparation and rearrangement
of 15a–c (Scheme 3). In all three cases, pure samples of 15a–c could
not be obtained from the reaction of 10 with the corresponding
alkoxide due to the rearrangement of 15a–c at room temperature.
In the case of 15a, only low yields of 16a could be obtained due to
the formation of 17a. This was even more pronounced in the case
of 15b where it proved impossible to prepare 16b, with 17b being
the only isolated product. These observations are consistent both
with the expected increase in the rate of the Claisen rearrangement
due to the presence of the alkyl substituents,11 and with a further
increase in the rate of the aza-Cope rearrangement due to release
in steric strain on transformation of 16a and 16b into 17a and 17b,
respectively. Importantly, 16c could be prepared directly from 10
in 83% yield with no formation of 17c.
Scheme
indolo[2,3-b]quinoline 18.
4 Synthesis of the highly optically enriched bromo-
The presence of the E-geometry for the alkene in 16c was
1
confirmed by H NMR (3J (alkene protons) = 15.2 Hz) and is
20
consistent with the reaction proceeding through the expected chair
transition state in which the methyl substituent in 15c occupies an
equatorial position. This observation paved the way for the use of
an optically enriched secondary alkoxide to enable the asymmetric
synthesis of the quaternary centre (C10b, see structures 16a–c in
Scheme 3 for numbering) via intramolecular chirality transfer.12,13
It was shown by the use of the chiral shift reagent Eu(hfc)3
that the sample of 18 prepared by this method was formed as
a 93 : 7 mixture of the two enantiomers, consistent with a slight
erosion of optical purity, presumably resulting from the Claisen
rearrangement of 18 proceeding via an alternative boat transition
state in which the methyl group occupies an equatorial position.5
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Fig. 3 The communesin family of natural products.
11-Allyloxy-6-methyl-6H-indolo[2,3-b]quinoline (1)
Crystallographic analysis confirmed the absolute stereochemistry
of 18 to be the expected (S) configuration.8
A solution of the alkoxide generated from allyl alcohol (25.5 ml,
375 mmol) and sodium (2.6 g, 113 mmol) in THF (70 mL)
was added to 11-chloro-6-methyl-6H-indolo[2,3-b]quinoline (4)
(2.00 g, 7.52 mmol) in THF (25 mL), maintained under an
argon atmosphere, and the reaction mixture was heated at 70 ◦C
(bath temperature). After 48 h the reaction was cooled to room
temperature and NH4Cl(aq) (10 mL) was added. The excess of allyl
alcohol and THF were evaporated under reduced pressure and
the residue was partitioned between water (25 mL) and CH2Cl2
(25 mL). The organic phase was separated and the aqueous
phase was further extracted with CH2Cl2 (2 ¥ 25 mL). All the
organic extracts were combined, dried (MgSO4) and the solvent
was evaporated under reduced pressure. The residue was purified
by flash chromatography (10% to 20% EtOAc–hexane) followed by
crystallisation from EtOAc–hexane to afford the title compound
1 as pale yellow crystals (1.47 g, 5.10 mmol, 68%): m.p. 75-76 ◦C;
Anal. calc’d for C19H16N2O: C, 79.14; H, 5.59; N, 9.72. Found: C,
78.86; H, 5.66; N, 9.72; nmax (KBr) 3057, 2928, 1638, 1608, 1570,
1492, 1474, 1428, 1395, 1292, 1245, 1099, 993, 922, 765, 742 cm-1;
1H NMR (300 MHz, CDCl3) d 8.31 (dd, J = 8.5, 1.1, 1H, H-1),
8.24 (d, J = 7.5, 1H, H-10), 8.12 (d, J = 8.5, 1H, H-4), 7.72 (ddd,
J = 8.5, 7.0, 1.1, 1H, H-3), 7.56 (ddd, J = 8.0, 7.5, 1.0, 1H, H-8),
7.45 (ddd, J = 8.5, 7.0, 1.0, 1H, H-2), 7.39 (d, J = 8.0, 1H, H-7),
7.31 (td, J = 7.5, 1.0, 1H, H-9), 6.29 (ddt, J = 17.0, 10.5, 5.5, 1H,
This novel application of the Claisen rearrangement in the
indolo[2,3-b]quinoline system therefore culminates in access to
18, a versatile intermediate of relevance to the synthesis of the
communesin group of natural products. In particular, the presence
of both the C11 ketone and C1 bromo functional groups in
18 provides handles for subsequent incorporation of the second
quaternary centre and the 7-membered ring that make up other
key structural features in the communesins. Whilst differing in
the specifics from our N6-benzyl protection strategy, precedent
for the removal of an N-benzyl protecting group at a late stage
in the synthesis of dehaloperophoramidine does exist.15b The
novel approach reported here was developed through a detailed
understanding of the effect of structural changes in the indolo[2,3-
b]quinoline system on a tandem Clasien–aza-Cope reaction.
Further studies on reactions of the C11 ketone functionality will
be reported in the near future.
Experimental
Chemicals and solvents were purchased from commercial sup-
pliers and were used as received unless otherwise stated. Air
and moisture sensitive reactions were carried out under an
inert atmosphere of dried argon, and glassware was oven-dried.
Analytical thin-layer chromatography (TLC) was performed on
pre-coated TLC plates SIL G-25 UV254 (layer 0.25 mm silica gel
with fluorescent indicator UV254). Developed plates were air-dried
and analysed under a UV lamp and where necessary, stained
with a solution of potassium permanganate to aid identification.
Flash column chromatography was performed using silica gel (40–
63 mm). Melting points are quoted to the nearest 1 ◦C and are
uncorrected. 1H NMR spectra were recorded at 300 and 400 MHz.
13C NMR spectra using the PENDANT sequence were recorded
at 75 and 100 MHz. Chemical shifts (d) are recorded using the
residual solvent as the internal reference in all cases (CDCl3 dH
7.27 ppm, dC 77.16 ppm). Coupling constants (J) are quoted to the
nearest 0.1 Hz. The following abbreviations are used; s, singlet; d,
doublet; dd, doublet of doublets; dt, doublet of triplets; t, triplet;
m, multiplet and br, broad. Where inseparable mixtures of di-
astereoisomers were obtained, 1H NMR and 13C NMR spectra for
the major diastereoisomer only are reported. Low resolution and
high resolution (HR) electrospray mass spectral (ES-MS) analyses
were recorded on a high performance orthogonal acceleration
reflecting TOF mass spectrometer, coupled to a HPLC. Optical
rotation measurements were recorded using the D-line of sodium
at 20 ◦C in a 1 ml solution cell with a 10 cm path length. The
concentration (c) is expressed in g ml-1.
=
CH=CH2), 5.56 (dq, J = 17.0, 1.5, 1H, CH CH2), 5.37 (dq, J =
=
10.5, 1.5, 1H, CH CH2), 4.89 (td J = 5.5, 1.5, 2H, OCH2), 3.97
(s, 3H, CH3); 13C NMR (75 MHz, CDCl3) d 157.5 (C), 154.8 (C),
148.6 (C), 142.2 (C), 133.4 (CH), 129.4 (CH), 127.8 (CH), 127.7
(CH), 123.8 (CH), 122.71 (CH), 122.68 (CH), 120.7 (CH), 120.1
(C), 119.3 (C), 118.6 (CH2), 109.4 (C), 108.6 (CH), 75.2 (CH2),
28.0 (CH3); LRMS (ESI) m/z 288 (MH+, 100); HRMS (ESI) m/z
calc’d for C19H16N2O 288.1262, found 288.1263.
11-Allyloxy-5-methyl-5H-indolo[2,3-b]quinoline (2)
A solution of the alkoxide generated from allyl alcohol (7.50 mL,
110 mmol) and sodium (650 mg, 28.3 mmol) in THF (10 mL)
was added to 11-chloro-5-methyl-5H-indolo[2,3-b]quinoline (10)
(1.50 g, 5.62 mmol) in THF (30 mL), maintained under an
argon atmosphere. After stirring the reaction mixture at room
temperature for 18 h a saturated solution of NH4Cl (3 mL) was
added. The THF and allyl alcohol were removed by evaporation
under reduced pressure, water (10 mL) was added and the mixture
was extracted with ether (3 ¥ 40 mL). The ether extracts were
combined, dried (MgSO4) and were evaporated under reduced
pressure. The residue was purified by flash chromatography (the
product was eluted with 80% EtOAc–hexane) to afford the title
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=
compound (2) as a dark yellow solid. (1.46 g, 5.06 mmol, 90%):
m.p. 93-94 ◦C; nmax (KBr) 1643, 1571, 1522, 1492, 1460, 1352,
1283, 1240, 1177, 1149, 1118, 1098, 1059, 965, 909, 750, 661, 595,
5.15 (m, 1H, CH CH2), 4.92 (m, 2H, NCH2), 3.74 (s, 3H, CH3);
13C NMR (75 MHz, CDCl3) d 173.3 (C, C-11), 147.4 (C, C-5a),
140.5 (C), 137.4 (C), 133.6 (CH), 131.2 (CH), 126.0 (CH), 125.1
(C), 123.5 (C), 123.2 (CH), 122.4 (CH), 122.2 (CH), 121.2 (CH),
118.2 (CH2), 115.6 (CH), 108.9 (CH), 104.4 (C), 51.7 (CH2), 32.8
(CH3); LRMS (EI) m/z 288 (M+, 13), 247 (44), 219 (26), 86 (65),
84 (100); HRMS (EI) m/z calc’d for C19H16N2O 288.1263, found
288.1255.
1
468 cm-1; H NMR (300 MHz, CDCl3) d 8.28 (dd, J = 8.0, 1.5,
1H, H-1), 8.08 (d, J = 8.0, 1H, H-10), 7.63-7.77 (m, 3H, H-7, H-3,
H-4), 7.52 (td, J = 8.0, 1.0, 1H, H-8), 7.40 (ddd, J = 8.0, 7.0, 1.0,
1H, H-2), 7.24 (td, J = 8.0, 1.0, 1H, H-9), 6.23 (ddt, J = 17.0,
=
10.5, 1.5, 1H, CH=CH2), 5.54 (dq, J = 17.0, 1.5, 1H, CH CH2),
=
5.35 (dq, J = 10.5, 1.5, 1H, CH CH2), 4.92 (dt, J = 5.5, 1.5, 2H,
OCH2), 4.28 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3) d 158.4
(C), 156.6 (C), 153.9 (C), 138.1 (C), 132.8 (CH), 130.9 (CH), 128.3
(CH), 124.3 (CH), 123.2 (CH), 122.5 (C), 121.6 (CH), 120.0 (CH),
118.8 (CH2), 117.9 (C), 117.5 (CH), 116.4 (C), 114.2 (CH), 75.1
(CH2), 33.0 (CH3); LRMS (CI) m/z 289 (MH+, 100), 249 (27);
HRMS (CI) m/z calc’d for C19H17N2O 289.1341 found 289.1339.
5,10b-Dihydro-10b-allyl-5-methyl-10bH-indolo[2,3-b]quinolin-11-
one (7)
A solution of 11-allyloxy-5-methyl-5H-indolo[2,3-b]quinoline (2)
(1.46 g, 5.06 mmol) in toluene (50 mL) was refluxed under an
argon atmosphere for 5 h. The toluene was removed under reduced
pressure and the residue was purified by flash chromatography
(the product was eluted with 20% EtOAc–hexane) to afford the
title compound (7) as a bright yellow crystalline solid (1.30 g,
11-Chloro-6-methyl-6H-indolo[2,3-b]quinoline (4)
◦
Sodium hydride (1.58 g of a 60% dispersion in oil, 39.5 mmol)
was added to a stirred suspension of 11-chloro-6H-indolo[2,3-
b]quinoline (3) (2.00 g, 7.91 mmol) in THF (70 mL), maintained
under an argon atmosphere. When effervescence ceased, methyl io-
dide (2.50 mL, 40.1 mmol) was added and the reaction was heated
to 50 ◦C (bath temperature) for 1 h. After cooling, a saturated
solution of ammonium chloride (20 mL) was added and the solvent
was removed under reduced pressure. The residue was partitioned
between DCM (30 mL) and water (30 mL). The organic phase
was separated and the aqueous phase was further extracted with
DCM (2 ¥ 30 mL). All the DCM extracts were combined, dried
(MgSO4), and the solvent was removed under reduced pressure.
The residue was purified by flash chromatography (the product
was eluted with 20% EtOAc–hexane) to afford the title compound
(4) as a pale yellow crystalline solid (1.89 g, 7.09 mmol, 90%);
4.51 mmol, 89%); m.p. 94-95 C; Anal. calc’d for C19H16N2O: C,
79.14; H, 5.59; N, 9.72. Found: C, 79.09; H, 5.33; N, 9.56; nmax
(KBr) 3070, 2901, 1692, 1560, 1471, 1386, 1344, 1296, 1207, 1167,
1068, 1038, 985, 922, 844, 777, 762, 670, 676, 629, 504, 468 cm-1; 1H
NMR (300 MHz, CDCl3) d 7.97 (dd, J = 7.8, 1.4, 1H, H-1), 7.70
(d, J = 7.3, 1H, H-10), 7.63 (ddd, J = 8.8, 7.3, 1.4, 1H, H-3), 7.42
(d, J = 7.3, 1H, H-7), 7.35 (td, J = 7.3, 1.3, 1H, H-8), 7.12-7.19
=
(m, 3H, H-4, H-9, H-2), 5.28-5.42 (m, 1H, CH CH2), 4.99 (m,
=
=
1H, CH CH2), 4.83 (m, 1H, CH CH2), 3.72 (s, 3H, CH3), 2.80
(dd, J = 13.2, 6.8, 1H, CCH2), 2.46 (dd, J = 13.2, 7.8, 1H, CCH2);
13C NMR (75 MHz, CDCl3) d 192.9 (C), 172.4 (C), 153.6 (C),
145.4 (C), 140.0 (CH), 133.1 (C), 130.4 (CH), 128.9 (CH), 128.6
(CH), 124.7 (CH), 123.3 (CH), 122.5 (CH), 120.3 (CH2), 119.0
(C), 118.7 (CH), 114.6 (CH), 66.2 (C), 45.1 (CH2), 33.2 (CH3);
LRMS (ESI) m/z 289 (MH+, 100); HRMS (ESI) m/z calc’d for
C19H17N2O 289.1341 found 289.1346.
◦
m.p. 141-142 C; nmax (KBr) 1603, 1560, 1489, 1470, 1422, 1393,
1
1322, 1260, 1121, 1073, 944, 863, 763, 749, 629 cm-1; H NMR
(300 MHz, CDCl3) d 8.59 (d, J = 7.5, 1H, H-10), 8.39 (dd, J =
8.3, 1.2, 1H, H-1), 8.11 (d, J = 8.3, 1H, H-4), 7.74 (ddd, J = 8.3,
6.8, 1.2, 1H, H-3), 7.60 (ddd, J = 8.3, 7.5, 1.2, 1H, H-8), 7.53 (ddd,
J = 8.3, 6.8, 1.0, 1H, H-2), 7.38 (d, J = 8.3, 1H, H-7), 7.33 (td, J =
7.5, 0.8, 1H, H-9), 3.95 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3) d
152.5 (C), 147.0 (C), 142.8 (C), 135.7 (C), 129.5 (CH), 128.6 (CH),
127.9 (CH), 124.3 (CH), 124.2 (CH), 123.7 (CH), 122.4 (C), 120.4
(CH), 119.8 (C), 115.6 (C), 108.6 (CH), 27.9 (CH3); LRMS (ESI)
m/z 267 (MH+, 100); HRMS (ESI) m/z calc’d for C16H12N235Cl
267.0689, found 267.0681.
5,6-Dihydro-6-allyl-5-methylindolo[2,3-b]quinolin-11-one (8) and
5,6-dihydro-10-allyl-5-methylindolo[2,3-b]quinolin-11-one (11)
5,10b-Dihydro-10b-allyl-5-methyl-10bH-indolo[2,3-b]-quinolin-
11-one (7) (200 mg, 0.694 mmol) and PhMe (10 mL) were heated
at reflux, under an argon atmosphere, for 4 d. After cooling, the
PhMe was evaporated under reduced pressure and the residue
was purified by flash chromatography. The first, colourless
crystalline solid, compound to be eluted (1% MeOH–CHCl3)
was 5,6-dihydro-6-allyl-5-methylindolo[2,3-b]quinolin-11-one (8)
(143 mg, 0.496 mmol, 72%); m.p. 187-188 ◦C; nmax (KBr) 1619,
1594, 1509, 1467, 1384, 1311, 1242, 1158, 1125, 1039, 1014, 983,
925, 878, 740, 675, 654, 584, 545, 452 cm-1; 1H NMR (300 MHz,
CDCl3) d 8.50 (dd, J = 8.0, 1.5, 1H, H-10), 8.43 (dd, J = 8.0, 1.5,
1H, H-1), 7.49 (ddd, J = 8.5, 7.0, 1.5, 1H, H-3), 7.12-7.30 (m,
4H, H-9 H-8, H-4, H-2), 7.00 (d, J = 8.0, 1H, H-7), 6.05-6.18
5,6-Dihydro-5-allyl-6-methylindolo[2,3-b]quinolin-11-one (6)
11-Allyloxy-6-methyl-6H-indolo-[2,3-b]quinoline (1) (50 mg,
0.173 mmol) was heated at 170 ◦C (bath temperature) for 1 h, under
an argon atmosphere. After cooling the product was purified by
flash chromatography (the product was eluted with 80% EtOAc–
hexane) to yield the title compound (6) as a colourless crystalline
solid (46 mg, 0.160 mmol, 92%); m.p. 196-197 ◦C; nmax (KBr) 1613,
1591, 1535, 1510, 1467, 1396, 1242, 1126, 929, 751 cm-1; 1H NMR
(300 MHz, CDCl3) d 8.49 (dd, J = 7.5, 0.7, 1H, H-10), 8.40 (dd,
J = 7.9, 1.6, 1H, H-1), 7.44 (td, J = 8.7, 1.6, 1H, H-3), 7.30 (td, J =
7.5, 1.0, 1H, H-9), 7.16-7.26 (m, 3H, H-4, H-2, H-8), 6.97 (d, J =
=
=
(m, 1H, CH CH2), 5.30-5.37 (m, 1H, CH CH2), 5.08-5.17 (m,
1H, CH CH2), 4.72-4.76 (m, 2H, NCH2), 3.84 (s, 3H, CH3); 13C
=
NMR (75 MHz, CDCl3) d 173.3 (C), 148.5 (C), 141.3 (C), 137.5
(C), 132.9 (CH), 131.2 (CH), 126.3 (CH), 125.5 (C), 124.0 (C),
123.5 (CH), 122.6 (CH), 122.4 (CH), 121.3 (CH), 117.9 (CH2),
115.4 (CH), 109.4 (CH), 105.0 (C), 49.2 (CH2), 37.1 (CH3);
LRMS (EI) m/z 288 (M+, 12), 247 (42), 86 (66), 84 (100); HRMS
(EI) m/z calc’d for C19H16N2O 288.1263 found 288.1268. The
=
8.0, 1H, H-7), 6.28 (m, 1H, CH=CH2), 5.43 (m, 1H, CH CH2),
446 | Org. Biomol. Chem., 2010, 8, 442–450
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=
(ddt, J = 16.9, 10.1, 5.1, 1H, CH CH2), 5.13 (dq, J = 10.1, 1.7,
second, colourless crystaline solid, compound to be eluted (2%
MeOH–CHCl3) was 5,6-dihydro-10-allyl-5-methylindolo[2,3-
b]quinolin-11-one (11) (24 mg, 0.083 mmol, 12%); m.p. 270-280 ◦C
(dec.); nmax (KBr) 3052, 1617, 1576, 1546, 1510, 1433, 1380, 1303,
1273, 1217, 1165, 1133, 1057, 997, 911, 875, 787, 753, 708, 625,
=
=
1H, CH CH2), 5.04 (dq, J = 16.9, 1.7, 1H, CH CH2), 3.73 (s,
3H, CH3), 3.69 (dt, J = 5.1, 1.7, 1H, CH2); 13C NMR (75 MHz,
CDCl3) d 159.4 (C, C-12), 142.6 (C), 136.8 (CH), 135.6 (C), 134.6
(CH), 131.1 (C), 129.8 (C), 128.7 (CH), 124.2 (CH), 121.5 (CH),
120.4 (CH), 116.3 (CH), 116.14 (CH), 116.09 (CH2), 114.0 (C),
112.5 (CH), 92.5 (C, C-6), 36.2 (CH3), 28.8 (CH2); LRMS (CI)
m/z 289 (MH+, 100); HRMS (CI) m/z calc’d for C19H17N2O
289.1341 found 289.1341.
1
490 cm-1; H NMR (400 MHz, (CD3)2SO) d 12.08 (s, 1H, NH),
8.42 (d, J = 8.0, 1H, H-1), 7.70-7.78 (m, 2H, H-4, H-3), 7.36
(ddd, J = 8.0, 6.5, 1.0, 1H, H-2), 7.32 (dd, J = 7.5, 1.0, 1H, H-9),
7.20 (t, J = 7.5, 1H, H-8), 7.00 (d, J = 7.5, 1H, H-7), 6.02-6.12
=
(m, 1H, CH=CH2), 4.96-5.02 (m, 1H, CH CH2), 4.87-4.91 (m,
=
=
1H, CH CH2), 4.52 (d, J = 6.5, 2H, CH2CH CH2), 3.96 (s, 3H,
CH3); 13C NMR (101 MHz, (CD3)2SO) d 170.7 (C), 147.3 (C),
140.3 (CH), 138.7 (C), 135.5 (C), 133.8 (C), 131.2 (CH), 126.5
(CH), 124.9 (C), 123.3 (CH), 123.1 (C), 122.7 (CH), 121.6 (CH),
114.8 (CH), 113.8 (CH2), 108.7 (CH), 103.1 (C), 39.6 (CH2), 33.2
(CH3); LRMS (ESI) m/z 311 (MNa+, 100); HRMS (ESI) m/z
calc’d for C19H16N2ONa 311.1160 found 311.1154.
Rac-(1¢R,10bS)-5,10b-dihydro-10b-(1¢-methylallyl)-5-methyl-
10bH-indolo[2,3-b]quinolin-11-one (16a) and 5,6-dihydro-6-
(E-but-2-enyl)-5-methylindolo[2,3-b]quinolin-11-one (17a)
Crude 11-(E-but-2-enyloxy)-5-methyl-5H-indolo[2,3-b]quinoline
(15a) was prepared from 11-chloro-5-methyl-5H-indolo[2,3-
b]quinoline (10) (200 mg, 0.750 mmol) in THF (10 mL), with the
alkoxide generated from trans-2-buten-1-ol (0.51 mL, 6.01 mmol)
and sodium (35 mg, 1.52 mmol) in THF (0.5 mL), using the
following general method: alkoxides were formed by slowly adding
the appropriate alcohol, at a rate that maintained a steady reaction,
to sodium in THF with stirring and under an argon atmosphere.
When all the sodium had dissolved, the alkoxide was added via
cannula to a stirred mixture of the appropriate 11-chloro-5H-
indolo[2,3-b]quinoline in THF (1 vol.). The reaction mixture was
then stirred at room temperature, under an argon atmosphere,
for 18 h. After adding a saturated solution of NH4Cl(aq) (0.1
vol.), the solvent was removed under reduced pressure and the
residue was partitioned between water (1 vol.) and CH2Cl2 (1
vol.). The organic phase was separated and the aqueous phase
was further extracted with CH2Cl2 (3 ¥ 1 vol.). The combined
CH2Cl2 extracts were dried (MgSO4) and the CH2Cl2 was removed
under reduced pressure. Purification by chromatography afforded
15a. 1H NMR (300 MHz, CDCl3) d 8.34 (dd, J = 8.2, 1.3,
1H, H-1), 8.11 (d, J = 7.5, 1H, H-10), 7.72-7.83 (m, 3H, H-
7, H-3, H-4), 7.46-7.56 (m, 2H, H-8, H-2), 7.24-7.29 (m, 1H,
H-9), 5.91-5.96 (m, 1H, CH2CH), 5.66-5.70 (m, 1H, CHCH3),
4.89-4.92 (m, 2H, CH2), 4.35 (s, 3H, NCH3), 1.76-1.78 (m, 3H
CHCH3). Crude 15a was dissolved in THF (10 mL) and the
mixture was heated at reflux for 2.5 h. The reaction was cooled to
room temperature and the solvent was evaporated under reduced
pressure. The residue was purified by flash chromatography. The
first, bright yellow crystalline solid, compound to be eluted
(CHCl3) was rac-(1¢R,10bS)-5,10b-dihydro-10b-(1-methylallyl)-5-
methylindolo[2,3-b]quinolin-11-one (16a) (91 mg, 0.301 mmol,
40%); m.p. 123-124 ◦C (dec.); nmax (KBr) 3080, 2977, 2932, 1698,
1559, 1470, 1469, 1388, 1342, 1304, 1206, 1194, 1156, 1122, 1066,
1036, 970, 920, 872, 857, 801, 763, 748, 700, 644, 524, 456 cm-1;
1H NMR (300 MHz, CDCl3) d 7.90 (dd, J = 7.5, 1.5, H-10),
7.58-7.64 (m, 2H, H-1, H-3), 7.33-7.43 (m, 2H, H-7, H-8), 7.10-
7.17 (m, 3H, H-9, H-4, H-2), 5.79 (ddd, J = 17.0, 10.5, 8.5, 1H,
11-Chloro-5-methyl-5H-indolo[2,3-b]quinoline (10)
A mixture of 6-methyl-5H,6H-indolo[2,3-b]quinolin-11-one (9)
(2.50 g, 10.1 mmol) and POCl3 (50 mL) were heated at reflux,
under an argon atmosphere, for 1 h and then cooled to room
temperature. The excess of POCl3 was removed under reduced
pressure and crushed ice (ca. 50 g) was added to the residue. The
mixture was basified with NaHCO3(aq) and the orange solid product
was collected by filtration. The solids were washed with water and
then thoroughly dried (an alternative to collecting the product
by filtration is to extract it into DCM and dry the extracts with
MgSO4). There was thus obtained the title compound (10) as a
bright orange solid of sufficient purity for subsequent reactions
(2.56 g, 9.60 mmol, 95%); m.p. 182-183 ◦C; nmax (KBr) 1632, 1610,
1572, 1523, 1491, 1438, 1272, 1235, 1193, 1139, 1076, 950, 887,
850, 751, 598, 465 cm-1; 1H NMR (300 MHz, CDCl3) d 8.42-8.47
(m, 2H, H-10, H-1), 7.72-7.84 (m, 3H, H-7, H-3, H-4), 7.49-7.62
(m, 2H, H-8, H-2), 7.26-7.31 (m, 1H, H-9), 4.35 (s, 3H, CH3); 13
C
NMR (75 MHz, CDCl3) d 155.6 (C), 155.2 (C), 137.1 (C), 136.0
(C), 131.2 (CH), 129.9 (CH), 126.2 (CH), 125.0 (C), 124.1 (CH),
124.0 (C), 122.4 (CH), 120.4 (CH), 119.3 (C), 117.8 (CH), 114.4
(CH), 33.3 (CH3); LRMS (ESI) m/z 267 (MH+, 100); HRMS (ESI)
m/z calc’d for C16H12N2Cl 267.0689 found 267.0688.
Preparation of 6-allyl-5-methyl-5H-indolo[2,1-b]quinazolin-12-
one (14)
5,10b-Dihydro-10b-allyl-5-methyl-10bH-indolo[2,3-b]quinolin-
11-one (7) (25 mg, 0.087 mmol) and MeOH (2.5 mL) were
heated at reflux for 12 h. The reaction mixture was cooled to
room temperature and the MeOH was evaporated under reduced
pressure to afford the title compound 14 as a bright yellow
crystalline solid (25 mg, 0.087 mmol, 100%). Crystals suitable
◦
=
for X-ray analysis were obtained from MeOH; m.p. 160-161 C;
CH CH2), 5.11 (ddd, J = 10.5, 1.5, 1.0, 1H, CH2), 4.78 (dt,
Anal. calc’d for C19H16N2O: C, 79.14; H, 5.59; N, 9.72. Found: C,
79.04; H, 5.54; N, 9.75; nmax (KBr) 1673, 1618, 1585, 1491, 1463,
1397, 1371, 1253, 1170, 1073, 1020, 912, 879, 775, 738, 684 cm-1;
1H NMR (300 MHz, CDCl3) d 8.67-8.72 (m, 1H, H-10), 8.29
(dd, J = 7.8, 1.5, 1H, H-1), 7.57 (ddd, J = 8.5, 7.3, 1.5, 1H,
H-3), 7.34-7.38 (m, 1H, H-7), 7.28 (td, J = 7.3, 1.3, 1H, H-8),
7.18-7.24 (m, 1H, H-9), 7.02-7.12 (m, 2H, H-2, H-4), 6.01-6.14
J = 17.0, 1.5, 1H, CH2), 3.73 (s, 3H, NCH3), 2.83-2.92 (m, 1H,
CHCH3), 0.56 (d, J = 7.0, 3H, CHCH3); 13C NMR (75 MHz,
CDCl3) d 193.3 (C, C-11), 172.1 (C), 154.6 (C), 145.2 (C), 136.7
(CH), 135.7 (CH), 130.8 (C), 129.0 (CH), 128.5 (CH), 125.6 (CH),
123.0 (CH), 122.6 (CH), 119.8 (C), 118.5 (CH), 117.7 (CH2), 114.5
(CH), 70.5 (C), 46.3 (CH), 33.2 (CH3), 14.1 (CH3); LRMS (CI) m/z
303 (MH+, 68), 249 (100); HRMS (CI) m/z calc’d for C20H19N2O
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303.1497 found 303.1488. The second, colourless crystalline solid,
compound to be eluted (1% MeOH–CHCl3) was 5,6-dihydro-6-
(E-but-2-enyl)-5-methylindolo[2,3-b]quinolin-11-one (17a); m.p.
165-166 ◦C; Anal. calc’d for C20H18N2O: C, 79.44; H, 6.00; N,
9.26. Found: C, 79.11; H, 5.80; N, 9.15; nmax (KBr) 3053, 2915,
1617, 1590, 1538, 1506, 1461, 1394, 1362, 1323, 1285, 1262, 1189,
1168, 1125, 1069, 1036, 981, 927, 879, 753, 675, 606, 542, 487,
J = 8.0, 1H, H-7), 5.30-5.34 (m, 1H, CHC(CH3)2), 4.66 (d, J =
5.0, 2H, NCH2), 3.83 (s, 3H, NCH3), 1.81 (s, 3H, C(CH3)2), 1.78
(d, J = 1.0, 3H, C(CH3)2); 13C NMR (75 MHz, CDCl3) d 173.4
(C), 148.3 (C), 141.4 (C), 137.5 (C), 136.2 (C), 131.1 (CH), 126.4
(CH), 125.5 (C), 124.1 (C), 123.3 (CH), 122.5 (CH), 122.4 (CH),
121.5 (CH), 120.4 (CH), 115.3 (CH), 109.3 (CH), 105.0 (C), 45.7
(CH2), 37.6 (CH3), 25.7 (CH3), 18.6 (CH3); LRMS (ESI) m/z 339
(MNa+, 100); HRMS (ESI) m/z calcd for C21H20N2ONa 339.1473
found 339.1470.
1
456 cm-1; H NMR (300 MHz, CDCl3) d 8.52 (dd, J = 8.5, 2.0,
1H, H-1), 8.50 (d, J = 7.5, 1H, H-10), 7.52 (ddd, J = 8.5, 7.5,
2.0, 1H, H-3), 7.16-7.32 (m, 4H, H-8, H-4, H-2, H-9), 7.08 (d,
J = 8.0, 1H, H-7), 5.69-5.79 (m, 1H, CH2CH), 5.54-5.67 (m, 1H,
CHCH3), 4.68-4.73 (m, 2H, CH2), 3.90 (s, 3H, NCH3), 1.72 (dd,
J = 6.5, 1.5, 3H, CHCH3); 13C NMR (75 MHz, CDCl3) d 173.4
(C), 148.5 (C), 141.4 (C), 137.6 (C), 131.2 (CH), 129.0 (CH), 126.4
(CH), 125.7 (CH), 125.6 (C), 124.1 (C), 123.4 (CH), 122.6 (CH),
122.4 (CH), 121.4 (CH), 115.4 (CH), 109.5 (CH), 105.1 (C), 48.5
(CH2), 37.3 (CH3, NCH3), 17.9 (CH3, CHCH3); LRMS (CI) m/z
303 (MH+, 100); HRMS (CI) m/z calc’d for C20H19N2O 303.1497
found 303.1488.
5,10b-Dihydro-10b-(E-but-2-enyl)-5-methyl-10bH-indolo[2,3-
b]quinolin-11-one (16c)
Crude 5-methyl-11-(1-methylallyloxy)-5H-indolo[2,3-b]quinoline
(15c) was prepared from 11-chloro-5-methyl-5H-indolo[2,3-
b]quinoline (10) (100 mg, 0.375 mmol) in THF (5 mL), with
the alkoxide generated from 3-buten-2-ol (0.25 mL, 2.91 mmol)
and sodium (20 mg, 0.870 mmol) in THF (0.5 mL), using the
following general method: alkoxides were formed by slowly adding
the appropriate alcohol, at a rate that maintained a steady reaction,
to sodium in THF with stirring and under an argon atmosphere.
When all the sodium had dissolved, the alkoxide was added via
cannula to a stirred mixture of the appropriate 11-chloro-5H-
indolo[2,3-b]quinoline in THF (1 vol.). The reaction mixture was
then stirred at room temperature, under an argon atmosphere, for
18 h. After adding a saturated solution of NH4Cl(aq) (0.1 vol.),
the solvent was removed under reduced pressure and the residue
was partitioned between water (1 vol.) and CH2Cl2 (1 vol.). The
organic phase was separated and the aqueous phase was further
extracted with CH2Cl2 (3 ¥ 1 vol.). The combined CH2Cl2 extracts
were dried (MgSO4) and the CH2Cl2 was removed by evaporation
at reduced pressure. Purification by chromatography afforded 15c.
1H NMR (300 MHz, CDCl3) d 8.34 (dd, J = 8.4, 1.4, 1H, H-1),
8.11 (d, J = 7.7, 1H, H-10), 7.69-7.78 (m, 3H, H-7, H-3, H-4), 7.53
(ddd, J = 8.2, 7.7, 1.7, 1H, H-8), 7.42 (ddd, J = 8.4, 6.4, 1.6, 1H,
H-2), 7.22-7.27 (m, 1H, H-9), 6.10 (ddd, J = 17.2, 10.5, 6.4, 1H,
CH=CH2), 5.32-5.41 (m, 1H, CHCH3), 5.18 (dt, J = 17.2, 1.1,
5,6-Dihydro-5-methyl-6-(3-methyl-2-butenyl)indolo[2,3-b]quinolin-
11-one (17b)
Crude
5-methyl-11-(3-methyl-2-butenyloxy)-5H-indolo[2,3-
b]quinoline (15b) was prepared from 11-chloro-5-methyl-5H-
indolo[2,3-b]quinoline (10) (200 mg, 0.750 mmol) in THF
(10 mL), with the alkoxide generated from 3-methyl-2-buten-1-ol
(0.61 mL, 6.01 mmol) and sodium (35 mg, 1.52 mmol) in THF
(0.5 mL), using the following general method: alkoxides were
formed by slowly adding the appropriate alcohol, at a rate that
maintained a steady reaction, to sodium in THF with stirring and
under an argon atmosphere. When all the sodium had dissolved,
the alkoxide was added via cannula to a stirred mixture of the
appropriate 11-chloro-5H-indolo[2,3-b]quinoline in THF (1 vol.).
The reaction mixture was then stirred at room temperature, under
an argon atmosphere, for 18 h. After adding a saturated solution
of NH4Cl(aq) (0.1 vol.), the solvent was removed under reduced
pressure and the residue was partitioned between water (1 vol.)
and CH2Cl2 (1 vol.). The organic phase was separated and the
aqueous phase was further extracted with CH2Cl2 (3 ¥ 1 vol.). The
combined CH2Cl2 extracts were dried (MgSO4) and the CH2Cl2
was removed by evaporation under reduced pressure. Purification
=
=
1H, CH CH2), 5.08 (dt, J = 10.5, 1.1, 1H, CH CH2), 4.33 (s, 3H,
NCH3), 1.60 (d, J = 10.4, 3H, CHCH3). Crude 15c was dissolved
in THF and heated at reflux for 2.5 h under an argon atmosphere.
The reaction mixture was cooled to room temperature and the
solvent was removed under reduced pressure. The residue was
purified by flash chromatography (10% to 20% EtOAc–hexane) to
afford the title compound 15c as a bright yellow crystalline solid
(94 mg, 0.311 mmol, 83%); m.p. 114-116 ◦C; nmax (KBr) 3027,
2936, 1693, 1559, 1472, 1453, 1387, 1344, 1289, 1204, 1164, 1121,
1054, 1016, 964, 845, 764, 746, 690, 654, 583, 504 cm-1; 1H NMR
(300 MHz, CDCl3) d 7.96 (dd, J = 8.0, 1.5, 1H, H-1), 7.67 (d, J =
7.5, 1H, H-10), 7.62 (ddd, J = 8.5, 7.5, 1.5, 1H, H-8), 7.14 (d, J =
7.5, 1H, H-4), 7.34 (ddd, J = 7.5, 7.5, 1.5, 1H, H-3), 7.11-7.17 (m,
3H, H-2, H-7, H-9), 5.17-5.29 (m, 1H, CHCH3), 4.96-5.07 (m, 1H,
CH2CH), 3.72 (s, 3H, NCH3), 2.72 (dd, J = 13.0, 6.5, 1H, CH2),
2.36 (dd, J = 13.0, 8.0, 1H, CH2), 1.52 (d, J = 6.5, 3H, CHCH3);
13C NMR (75 MHz, CDCl3) d 193.0 (C), 172.6 (C), 153.5 (C),
145.4 (C), 135.9 (CH), 133.4 (C), 131.4 (CH), 128.8 (CH), 128.5
(CH), 124.7 (CH), 123.1 (CH), 122.7 (CH), 122.4 (CH), 119.2 (C),
118.6 (CH), 114.5 (CH), 66.6 (C), 44.4 (CH2), 33.1 (CH3), 18.0
(CH3); LRMS (EI) m/z 302 (M+, 28), 248 (100), 219 (45); HRMS
(EI) m/z calc’d for C20H18N2O 302.1419 found 302.1426.
1
by chromatography afforded 15b. H NMR (300 MHz, CDCl3)
d 8.32 (dd, J = 8.2, 1.0, 1H, H-1), 8.15 (d, J = 7.3, 1H, H-10),
7.68-7.77 (m, 3H, H-7, H-3, H-4), 7.40-7.55 (m, 2H, H-8, H-2),
7.20-7.28 (m, 1H, H-9), 5.71-5.77 (m, 1H, CH2CH), 4.97 (d, J =
7.1, 2H, CH2), 4.31 (s, 3H, NCH3), 1.81 (s, 3H, CCH3), 1.68 (s,
3H, CCH3). Crude 15b was dissolved in THF (10 mL) and the
mixture was heated at reflux for 2.5 h. The reaction was cooled to
room temperature and the solvent was evaporated under reduced
pressure. The residue was purified by flash chromatography (1%
MeOH–CHCl3) to afford the title compound 17b as a colourless
crystalline solid (208 mg, 0.657, 88%); m.p. 220-221 ◦C; Anal.
calc’d for C21H20N2O: C, 79.72; H, 6.37; N, 8.85. Found: C, 79.50;
H, 6.28; N, 8.78; nmax (KBr) 3057, 2980, 2912, 1621, 1594, 1539,
1509, 1460, 1389, 1372, 1327, 1264, 1211, 1182, 1155, 1039, 984,
926, 880, 745, 673, 610, 488, 463 cm-1; 1H NMR (300 MHz,
CDCl3) d 8.45-8.50 (m, 2H, H-1, H-10), 7.50 (ddd, J = 8.5, 7.0,
2.0, 1H, H-3), 7.17-7.30 (m, 4H, H-8, H-4, H-2, H-9), 7.05 (d,
448 | Org. Biomol. Chem., 2010, 8, 442–450
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(S)-(-)-5-Benzyl-10-bromo-10b-(E-but-2-enyl)-5H-indolo[2,3-
b]quinolin-11-one (18)
(s, 1H, NH), 8.39 (d, J = 8.0, 1H, H-1), 7.12-7.64 (m, 11H,
11 ¥ ArH) 5.77 (s, 2H, CH2); 13C NMR (75 MHz, (CD3)2SO) d
170.5 (C, C-11), 147.6 (C), 138.1 (C), 136.7 (C), 135.7 (C), 131.5
(CH), 128.9 (2 x CH), 127.5 (CH), 126.7 (CH), 126.6 (CH), 126.0
(2 x CH), 125.6 (C), 124.5 (C), 124.2 (CH), 122.0 (CH), 115.2
(CH), 112.7 (C), 110.3 (CH), 101.2 (C), 48.6 (CH2); LRMS (CI)
m/z 402 (79BrM+, 60), 403 (79BrMH+, 85), 404 (81BrM+, 78), 405
(81BrMH+, 60), 325 (70), 315 (87), 314 (100), 313 (90), 312 (89),
234 (35); HRMS (CI) m/z calc’d for C22H16N2O79Br 403.0446
found 403.0436.
A
mixture
of
5,6-dihydro-5-benzyl-10-bromoindolo[2,3-
b]quinolin-11-one (19) (200 mg, 0.496 mmol) and POCl3
(3 mL) were heated at reflux for 3 h, under an argon atmosphere.
After the excess of POCl3 had been evaporated under reduced
pressure (the addition and evaporation of a small amount of dry
PhMe was used to remove the last remaining traces of POCl3),
CH2Cl2 (10 mL) and NaHCO3(aq) (10 mL) were added and the
mixture was stirred until completely orange with no remaining
yellow solids. The organic phase was separated and the aqueous
phase was further extracted with CH2Cl2 (2 ¥ 10 mL). The extracts
were combined, dried (MgSO4) and the solvent was evaporated
under reduced pressure. The resulting bright orange residue was
dissolved in THF (10 mL), under an argon atmosphere, and
the alkoxide generated from (S)-(+)-3-buten-2-ol (1.50 mL of
a 2.7 M solution in THF, 0.556 mmol) and sodium (34 mg,
1.48 mmol) in THF (5 mL) was added. After stirring for 1.5 h,
NH4Cl(aq) (0.5 mL) was added and the solvent was evaporated
under reduced pressure. The residue was partitioned between
CH2Cl2 (5 mL) and water (5 mL), the CH2Cl2 was separated and
the aqueous phase was further extracted with CH2Cl2 (3 ¥ 5 mL),
the organic phase was combined, dried (MgSO4) and the organic
phase was evaporated under reduced pressure. The residue was
dissolved in THF and heated at reflux under an argon atmosphere
for 6 h. The THF was evaporated under reduced pressure and
the crude product was purified by flash chromatography (10%
EtOAc–hexane) to yield the title compound 18 as a bright yellow
crystalline solid (167 mg, 0.365 mmol, 74%, [a]2D0 -347.1 (c 5.80,
CHCl3)). This material was crystallised from Et2O–hexane to give
a sample for X-ray analysis; m.p. 124-125 ◦C; nmax (KBr) 1700,
1602, 1560, 1467, 1415, 1391, 1323, 1240, 1212, 1163, 1042, 965,
856, 785, 765, 693, 533 cm-1; 1H NMR (300 MHz, CDCl3) d 7.88
(dd, J = 8.0, 1.5, 1H, H-1), 7.00-7.51 (m, 11H, 11 x ArH), 5.85
(d, J = 16.5, 1H, NCH2), 5.31-5.46 (m, 1H, CHCH3), 5.04 (d,
J = 16.5, 1H, NCH2), 4.63-4.78 (m, 1H, CH2CH), 3.49 (dd, J =
13.5, 7.0, 1H, CH2CH), 2.86 (dd, J = 13.5, 7.5, 1H, CH2CH),
1.37 (dd, J = 6.5, 1.5, 3H, CH3); 13C NMR (75 MHz, CDCl3) d
193.2 (C, C-11), 171.4 (C), 156.6 (C), 144.3 (C), 136.4 (C), 135.5
(CH), 132.0 (C), 131.3 (CH), 130.5 (CH), 129.0 (2 x CH), 128.6
(CH), 128.1 (CH), 127.7 (CH), 126.9 (2 x CH), 123.0 (CH), 122.2
(CH), 120.4 (C), 119.0 (C), 117.7 (CH), 115.4 (CH), 69.7 (C), 50.1
(CH2), 38.4 (CH2), 17.9 (CH3); LRMS (CI) m/z 456 (79BrM+, 30),
457 (79BrMH+, 42), 458 (81BrM+, 41), 459 (81BrMH+, 39), 405 (65),
403 (100), 325 (75); HRMS (CI) m/z calc’d for C26H22N2O79Br
457.0915 found 457.0915.
Preparation of 2-(benzylphenylamino)-4-bromoindole-3-carboxylic
acid methyl ester (21)
N-Chlorosuccinimide (116 mg, 0.869 mmol) and N,N¢-
dimethylpiperazine (0.06 mL, 0.436 mmol) were added to a
mixture of 4-bromo-1H-indole-3-carboxylic acid methyl ester (20)
˚
(200 mg, 0.787 mmol) and powdered 4 A molecular sieves (400 mg)
in CH2Cl2 (4 mL) at 0 ◦C, maintained under an argon atmosphere.
After stirring for 2 h a solution of N-benzylaniline (288 mg,
1.57 mmol) and trichloroacetic acid (0.02 mL 0.0196 mmol) in
CH2Cl2 (4 mL) was added. The reaction mixture was allowed
to warm to room temperature and the stirring was continued
for 20 h. The molecular sieves were removed by filtration and
the filtrate was washed sequentially with 1.0 M HCl(aq) (4 mL),
NaHCO3(aq) (4 mL) and water (4 mL). The organic phase was dried
(MgSO4) and the solvent was evaporated under reduced pressure.
The residue was purified by flash chromatography (5% to 10%
EtOAc–hexane) to afford the title compound 21 as a colourless
crystalline solid (310 mg, 0.712 mmol, 90%); m.p. 156-157 ◦C; nmax
(KBr) 3267, 1672, 1599, 1543, 1498, 1446, 1325, 1253, 1172, 1127,
1083, 1029, 950, 772, 743, 690, 622, 506, 459, 437 cm-1; LRMS
(CI) m/z 434 (79BrM+,8 6), 435 (79BrMH+, 97), 436 (81BrM+, 100),
437 (81BrMH+, 85), 405 (25), 403 (26), 356 (40); HRMS (CI) m/z
calc’d for C23H20N2O281Br 437.0688, found 437.0678; The NMR
data presented shows both the 3H*- and 1H-indole tautomer. 1H
NMR (300 MHz, CDCl3) d 8.16 (s, 0.8H, NH), 6.85-7.39 (m, 13H,
7.5 x ArH, 7.5 ArH*), 5.22 (d, J = 14, 0.2H, CH2*), 5.12 (d, J =
14, 0.2H, CH2*), 4.58 (s, 0.2H, H-3*), 3.65 (s, 2.4H, CH3), 3.37 (s,
0.6H, CH3*).
Acknowledgements
We thank the EPSRC and the Royal Society (NJW University
Research Fellowship) for funding and Drs John Hollick, Edward
Makiyi, Tomas Lebl and Emma Casey for invaluable discussion
and help during the course of this project. We wish to acknowledge
the use of the Chemical Database Service at Daresbury.
5,6-Dihydro-5-benzyl-10-bromoindolo[2,3-b]quinolin-11-one (19)
Notes and references
A
solution of 2-(benzylphenylamino)-4-bromo-indole-3-
1 For some recent reviews see: (a) K. Fuji, Chem. Rev., 1993, 93, 2037–
2066; (b) J. Christoffers and A. Mann, Angew. Chem., Int. Ed., 2001,
40, 4591–4597; (c) I. Denissova and L. Barriault, Tetrahedron, 2003,
59, 10105–10146; (d) E. A. Peterson and L. E. Overman, Proc. Natl.
Acad. Sci. U. S. A., 2004, 101, 11943–11948; (e) J. Christoffers and A.
Bravo, Adv. Synth. Catal., 2005, 347, 1473–1482.
2 For a recent review of the Claisen rearrangement see: (a) A. M. M.
Castro, Chem. Rev., 2004, 104, 2939–3002. For examples in this context
see: (b) T. Kawasaki, M. Shinada, D. Kamimura, M. Ohzono and A.
Ogawa, Chem. Commun., 2006, 420–422; (c) T. Kawasaki, A. Ogawa,
R. Terashima, T. Saheki, N. Ban, H. Sekiguchi, K. Sakaguchi and M.
carboxylic acid methyl ester (310 mg, 0.714 mmol) in Ph2O
(2.5 mL) was heated at 250 ◦C, under an argon atmosphere,
for 2 h. After cooling to room temperature, the formed solids
were collected by filtration and washed with Et2O to yield the
title compound 19 as a light brown crystalline solid (241 mg,
0.598 mmol, 84%); m.p. ca. 320 ◦C (dec.); nmax (KBr) 3031, 1616,
1546, 1508, 1454, 1431, 1371, 1325, 1115, 1053, 871, 755, 739,
692, 538, 505, 458 cm-1; 1H NMR (300 MHz, (CD3)2SO) d 12.46
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 442–450 | 449
©

View Article Online
Sakamoto, J. Org. Chem., 2005, 70, 2957–2966; (d) T. Kawasaki, A.
Ogawa, Y. Takashima and M. Sakamoto, Tetrahedron Lett., 2003, 44,
1591–1593; (e) T. Kawasaki, R. Terashima, K. Sakaguchi, H. Sekiguchi
and M. Sakamoto, Tetrahedron Lett., 1996, 37, 7525–7524; (f) H.
Miyamoto, Y. Okawa, A. Nakazaki and S. Kobayashi, Angew. Chem.,
Int. Ed., 2006, 45, 2274–2277; (g) A. Nakazaki, H. Miyamoto, K.
Henmi and S. Kobayashi, Synlett, 2005, 9, 1417–1420; (h) K. I. Booker-
Milburn, M. Fedouloff, S. Paknoham, J. Strachan, J. Melville and M.
Voyle, Tetrahedron Lett., 2000, 41, 4657–4661; (i) B. J. Newhouse, J.
Bordner, D. J. Augeri, C. S. Litts and E. F. Keinman, J. Org. Chem.,
1992, 57, 6991–6995; (j) S. Kotha and K. Mandal, Tetrahedron Lett.,
2004, 45, 1391–1394.
3 (a) A. Numata, C. Takahashi, I. Yoshinori, T. Takada, K. Kawai,
U. Yoshihide, E. Matsumura, M. Imachi, T. Ito and T. Hasegawa,
Tetrahedron Lett., 1993, 34, 2355–2358; (b) R. Jadulco, R. A. Edrada,
R. Ebel, A. Berg, K. Schaumann, V. Wray, K. Stube and P. Proksch,
J. Nat. Prod., 2004, 67, 78–81; (c) H. Hayashi, H. Matsumoto and
K. Akiyama, Biosci., Biotechnol., Biochem., 2004, 68, 753–756; (d) B.
Andersen, J. Smedsgaard and J. C. Frisvad, J. Agric. Food Chem., 2004,
52, 2421–2428; (e) P. W. Dalsgaard, J. W. Blunt, M. H. G. Munro, J. C.
Frisvad and C. Christopers, J. Nat. Prod., 2005, 68, 258–261.
F(000) = 608, Z = 4, Dc = 1.365 Mg m-3, m = 0.086 mm-1(Mo-Ka, l =
˚
0.71073 A). 8730 reflections yielding 2532 unique data (Rmerg = 0.0589).
Conventional R = 0.0510 for 2172 reflections with I ≥ 2s, Final wR2 =
0.1400 for all data. 18: C26H21BrN2O, M=457.36, triclinic, space group
˚
P1, a = 8.7486(17), b = 9.◦3067(19), c = 13.714(3) A, a = 101.33(3),
3
˚
b = 99.93(3), g = 90.56(3) , U = 1077.4(4) A , F(000) = 468, Z = 2,
Dc = 1.410 Mg m-3, m = 1.928 mm-1 (Mo-Ka, l = 0.71073 A). 6436
˚
reflections yielding 4997 unique data (Rmerg = 0.0640). Conventional
R = 0.0621 for 4036 reflections with I ≥ 2s. Final wR2 = 0.1376 for all
data. Flack parameter -0.005(14).
9 G. M. Coppola, J. Heterocycl. Chem., 1980, 17, 1785–1787.
10 J. Bergman, U. Tilstam and K. W. Toernroos, J. Chem. Soc., Perkin
Trans. 1, 1987, 519–527.
11 (a) D. P. Curran and Y. G. Suh, J. Am. Chem. Soc., 1984, 106, 5002–
5004; (b) J. J. Gajewski and N. D. Conrad, J. Am. Chem. Soc., 1979,
101, 2747–2748; (c) K. D. McMichael and G. L. Korver, J. Am. Chem.
Soc., 1979, 101, 2746–2747.
12 Limited information on the absolute stereochemistry of the com-
munesin group of natural products is available and is confused by
previous structural corrections. As (R)-(-)-3-buten-2-ol is also readily
available, 18 can be prepared as either enantiomer as required. An
elegant palladium-catalyzed enantioselective allylation has been used
to generate the C11a quaternary centre in systems of this type. B. M.
Trost and J. Quancard, J. Am. Chem. Soc., 2006, 128, 6314–6315.
13 For an overview of asymmetric Claisen reactions see: (a) D. Enders, M.
Knopp and R. Schiffers, Tetrahedron: Asymmetry, 1996, 7, 1847–1882;
(b) H. Ito and T. Taguchi, Chem. Soc. Rev., 1999, 28, 43–50. For a recent
example of this approach in natural product synthesis see: B. M. Trost,
G. Dong and J. A. Vance, J. Am. Chem. Soc., 2007, 129, 4540–4541.
14 For existing approaches to the communesins see: (a) J. Yang, H. Wu, L.
Shen and Y. Qin, J. Am. Chem. Soc., 2007, 129, 13794–13795; (b) J. A.
May, R. K. Zeidan and B. M. Stoltz, Tetrahedron Lett., 2003, 44, 1203–
1205; (c) J.A. May and B. Stoltz, Tetrahedron, 2006, 62, 5262–5271;
(d) S. L. Crawley and R. L. Funk, Org. Lett., 2003, 5, 3169–3171;
(e) S. L. Crawley and R. L. Funk, Org. Lett., 2006, 8, 3995–3998; (f) J.
Yang, H. Song, X. Xiao, J. Wang and Y. Qin, Org. Lett., 2006, 8, 2187–
2190; (g) J. H. Seo, G. D. Artman III and S. M. Weinreb, J. Org. Chem.,
2006, 71, 8891–8900; (h) J. H. George and R. M. Adlington, Synlett,
2008, 14, 2093–2096; (i) J. B. Hendrickson, R. Rees and R. Goschke,
Proc. Chem. Soc., 1962, 383–384.
4 J. Bergman, R. Engqvist, C. Sta˚lhandske and H. Wallberg, Tetrahedron,
2003, 59, 1033–1048.
5 (a) For a more detailed discussion see the ESI†; (b) S. Hoops, S. Sahle,
R. Gauges, C. Lee, J. Pahle, N. Simus, M. Singhal, L. Xu, P. Mendes
and U. Kummer, Bioinformatics, 2006, 22, 3067–3074.
6 During review, it was suggested that the observed 13C signal could
correspond to the carbonyl carbon of the structure below. Whilst
this cannot be ruled out without synthesis of this compound, initial
computational studies using the Database Service suggest that the
carbonyl carbon in 5 would be expected to come at some 17 ppm
downfield of that for the structure below; D. A. Fletcher, R. F.
McMecking and D. Parkin, J. Chem. Inf. Comput. Sci., 1996, 36,
746–749. This rule-based approximation is supported by calculated
13C NMR chemical shifts (CSGT method, B3LYP/6-31++G(2d,p) at
B3LYP/6-31+G(d,p) geometry), which suggests that the 13C resonance
of the carbonyl group in 5 should appear some 15.5 ppm downfield of
the carbonyl resonance in the structure suggested by the reviewer.
15 The synthesis of the structurally related natural product, perophorami-
dine and its dehalo-analogue have also been reported recently: (a) J. R.
Fuchs and R. L. Funk, J. Am. Chem. Soc., 2004, 126, 5068–5069; (b) A.
Sabahi, A. Novikov and J. D. Rainier, Angew. Chem., Int. Ed., 2006,
45, 4317–4320.
16 4-Bromoindole derivative 20 was initially prepared according to: (a) M.
Somei, K. Kizu, M. Kunimoto and F. Yamada, Chem. Pharm. Bull.,
1985, 33, 3696–3708; (b) F. Yamada and M. Somei, Heterocycles, 1987,
26, 1173–1176; (c) E. C. Taylor, F. Kienzle, R. L. Robey, A. McKillop
and J. D. Hunt, J. Am. Chem. Soc., 1971, 93, 4845–4850. An alternative
route to 20 was also developed that was applicable to multigram scale5.
17 21 was found to undergo rapid auto-oxidation and gave poor yields of
the cyclised product 19 if not used immediately after preparation with
the cyclisation reaction being carried out under argon5.
18 (a) Y. Gao, J. M. Klunder, R. M. Hanson, H. Masamune, S. Y. Ko
and K. B. Sharpless, J. Am. Chem. Soc., 1987, 109, 5765–5780; (b) E.
Balmer, A. Germain, W. P. Jackson and B. Lygo, J. Chem. Soc., Perkin
Trans. 1, 1993, 399–400.
7 H.Y. Yoo and K. N. Houk, J. Am. Chem. Soc., 1997, 119, 2877–2884
and references therein.
8 Crystallographic data (excluding structure factors) for 7, 14 and 18 is
available in the ESI.† CCDC 737646-737648. All three structures were
determined using a Rigaku MM007 RA/Mercury system at 93 K.
¯
7 C19H16N2O, M = 288.34, triclinic, space group P1 a = 9.803(2),
˚
b = 11.370(3), c = 14.533(3) A, a = 69.857(9) b = 76.385(9) g =
◦
3
-3
˚
75.170(11) , U = 1450.7(6) A , F(000) = 608, Z = 4, Dc = 1.320 Mg m ,
-1
˚
m = 0.083 mm (Mo-Ka, l = 0.71073 A). 8213 reflections yielding
4769 unique data (Rmerg = 0.0517). Conventional R = 0.0663 for
3810 reflections with I ≥ 2s, Final wR2 = 0.1555 for all data. 14:
19 As determined by Mosher’s ester formation: J. A. Dale and H. S.
Mosher, J. Am. Chem. Soc., 1973, 95, 512–519.
20 R. R. Fraser, M. A. Petit and J. K. Saunders, J. Chem. Soc., Chem.
Commun., 1971, 1450–1451.
C19H16N2O, M=288.34, monoclinic, space group ◦P21/c, a = 11.332(3),
3
˚
˚
b = 17.217(4), c = 7.5306(19) A, b = 107.218(7) , U = 1403.4(6) A ,
450 | Org. Biomol. Chem., 2010, 8, 442–450
This journal is
The Royal Society of Chemistry 2010
©