Isoindolo[2,1-a]indol-6-one-a new pyrolytic synthesis and some unexpected chemical properties

Article abstract of DOI:10.1039/b802273a

Isoindolo[2,1-a]indol-6-one 1 is formed by a sigmatropic shift-elimination-cyclisation cascade by flash vacuum pyrolysis (FVP) of methyl 2-(indol-1-yl)benzoate 7 at 950 °C. The dihydro compound 16 is easily obtained by catalytic reduction of 1, but the reaction is very sensitive to steric effects at the 11-position. Attempted ring-opening of 1 in basic methanol provides an equilibrium of isoindolo[2,1-a]indol-6-one 1 and the ester 19. Lithium aluminium hydride reduction of 1 provides the alcohol 22 which can be dehydrated to a mixture of 23 and 24 by FVP at 800-950 °C.

Full text of DOI:10.1039/b802273a

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Isoindolo[2,1-a]indol-6-one—a new pyrolytic synthesis and some unexpected
chemical properties
Lynne A. Crawford, Nathan C. Clemence, Hamish McNab* and Richard G. Tyas
Received 11th February 2008, Accepted 18th March 2008
First published as an Advance Article on the web 25th April 2008
DOI: 10.1039/b802273a
Isoindolo[2,1-a]indol-6-one 1 is formed by a sigmatropic shift–elimination–cyclisation cascade by flash
◦
vacuum pyrolysis (FVP) of methyl 2-(indol-1-yl)benzoate 7 at 950 C. The dihydro compound 16 is
easily obtained by catalytic reduction of 1, but the reaction is very sensitive to steric effects at the
1
1-position. Attempted ring-opening of 1 in basic methanol provides an equilibrium of
isoindolo[2,1-a]indol-6-one 1 and the ester 19. Lithium aluminium hydride reduction of 1 provides the
◦
alcohol 22 which can be dehydrated to a mixture of 23 and 24 by FVP at 800–950 C.
Introduction
Results and discussion
We report a new synthetic route to isoindolo[2,1-a]indol-6-one
derivatives 1, from 1-arylindoles, based upon application of the
sigmatropic shift–elimination–cyclisation pyrolytic cascade which
The known 1-arylindole derivative 7 was made by an Ullmann-
type coupling of indole 9 with 2-iodobenzoic acid, using a mod-
ification of the literature procedure. The 1-arylindole carboxylic
acid was then esterified to give 7 (35%, unoptimised) directly,
without isolation (Scheme 2). The method was trivially extended
to the 3-methyl derivative 8 (72%) using 3-methylindole as the
starting material.
8
1
we reported in 1999. Derivatives of this heterocyclic system
have attracted recent interest in the field of medicinal chemistry,
for example as high affinity ligands for the melatonin MT3
2
3,4
binding site, as potential anti-tumour agents, as synthetic
5
intermediates en route to bacterial NorA pump inhibitors, or
as conformationally-restricted model compounds for structure–
6
activity investigation.
Scheme 2 Reagents and conditions: (i) 2-iodobenzoic acid, K
2
CO3, Cu,
The isoindolo[2,1-a]indol-6-one system 1 is a dibenzo analogue
of pyrrolizin-3-one 2 and we also show how the chemical
◦
DMF, reflux, 48 h; (ii) MeI, K
2
CO
3
DMF, 20 C, 48 h.
7
properties of 1 compare and contrast with those of 2 and with
the pyrroloisoindolone (benzopyrrolizinone) 3.
FVP of 7 successfully provided 1 in reasonable yield, though
the pyrolysis conditions are more vigorous than those required for
the formation of 3. Thus, the pyrrole derivative 11 is transformed
1
Our approach to 1 is summarised by the retrosynthetic analysis
1
shown in Scheme 1. By analogy with our previous work,
◦
exclusively to the pyrroloisoindolone 3 at 925 C in our apparatus.
the isoindoloindolone system 1 should be formed by thermal
elimination of methanol from the 2-arylindole 5 which in turn
can be generated in situ from the 1-arylindole 7 by thermal 1,5-
sigmatropic shift.
◦
However, only 84% conversion of 7 was obtained at 950 C, even
in the presence of silica tubes at the trap end of the furnace which
have the effect of increasing the contact time in the hot zone of the
9
tube. Clearly the involvement of quinonoid intermediates (e.g.
12, Scheme 3) in this process leads to the increase in activation
energy, by comparison with the cyclisation mechanism of the
pyrrole analogue (see below).
Scheme 1
On a preparative scale (up to at least 2 g), isoindolo[2,1-a]indol-
-one 1 was obtained by 950 C pyrolysis in up to 76% yield
after chromatography. The 11-methyl derivative 4 was formed
in similar yield, with no evidence of substituent migration to
◦
6
School of Chemistry, The University of Edinburgh, West Mains Road,
Edinburgh, EH9 3JJ, UK. E-mail: H.McNab@ed.ac.uk; Fax: +44 131 650
4
743; Tel: +44 131 650 4718
2
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NOESY interaction between H(4) and H(6). Extension to the
carbon dimension was carried out by an HSQC experiment.
Both 1 and 13 were unchanged by FVP under the conditions
of their formation showing that neither are intermediates on the
route to the other. Compound 13 is therefore likely to be formed
by a competitive mechanism in which cyclisation precedes the
Scheme 3
other sites at the extreme conditions of the pyrolysis. Previous
routes to 1 include photochemical cyclisations, intramolecular
Wittig reactions and various palladium-catalysed and copper-
10
1
,5-sigmatropic aryl shift. In addition, a trace of pyrrolo[3,2,1-
11
12
jk]indole 14 was also obtained. This compound is probably formed
by cyclisation of a phenyl radical obtained by cleavage of the entire
ester group; a related substituent cleavage provides 14 as the major
13
catalysed methods. The FVP route has the major advantage that
only two synthetic steps are required from easily available starting
materials, but the potential generality of the method is likely to be
compromised by the very high furnace temperature required for
the sigmatropic shift (see below).
An assignment of the NMR spectra of 1 is shown in Fig. 1. The
two 4-spin systems were readily located by a COSY experiment and
NOESY interactions with the H(11) singlet allowed assignment of
H(1) and H(10). Zig-zag coupling from H(11) to H(4), well known
16
product when the nitro compound 15 is pyrolysed.
The functionality shared by compounds 1–3 include the
core fused 5-membered bridgehead-nitrogen system and the
lactam unit. Our study of the chemistry of 1 has focused on
hydrogenation and on its reactions with nucleophiles.
Catalytic hydrogenation of 1 at 40 psi over Pd/C gives a
17
quantitative yield of the known dihydro-compound 16 after
14
6
h. Analogous reduction of a 2-substituted example has been
for indole systems, allowed the identification of the ‘left-hand’
ring and completion of the analysis. The carbon atoms due to
3
reported. Under similar conditions, the 11-methyl derivative 4
is recovered unchanged, and even at 60 psi using 5% Rh/C
only a trace of the dihydro derivative 17 could be identified
from the NMR spectrum of the mixture. At higher pressure
the two overlapping signals at d
H
7.51 were distinguished by their
multiplicities in the HSQC spectrum.
(
(
400 psi), using 5% Rh–Al
3 h, 20 C), a mixture of products was obtained from which
2
O
3
in an ethanol–acetic acid mixture
◦
18
19
the dihydro-compound 17 could be isolated in 80% yield. The
relative stereochemistry of the two asymmetric centres follows
from the magnitude of the coupling constant JH(11)–Me (7.2 Hz)
which is sensitive to the configuration of 7-methylpyrrolizidin-3-
one isomers [cis-isomer (c.f. 15) 7.4 Hz; trans-isomer 6.0 Hz ] and
is consistent with a cis-hydrogenation mechanism.
20
1
13
2
Fig. 1 H and C NMR parameters (d
compound 1.
H C
and d , [ H]chloroform), of
Minor products which could be isolated from the pyrolysates
15
include the isoindolo[1,2-a]indol-10-one 13 (ca. 3%). This com-
pound was characterised by its spectra; in particular the mass
spectrum showed a strong molecular ion at m/z 219 and the
1
3
C NMR spectrum showed a carbonyl resonance at d
very different from the lactam carbonyl resonance of 1 at d
62.51. The NMR spectra of 13 were fully resolved at 360 MHz
C
181.55,
C
1
2
in [ H ]acetone solution and the assignments are shown in Fig 2.
6
14
Zig-zag coupling from the ‘indole’ proton [H(11)] to H(4) again
provided the starting point for the analysis of the ‘left-hand’ ring
and extrapolation to the ‘right-hand’ ring was possible by the
Hydrogenation of 4 over the same catalyst but with extended
reaction times (18 h), afforded a mixture of perhydro-derivatives
18 of which one isomer constituted ca. 80% of the mixture.
Further analysis was not carried out, but our experience with
pyrrolizinone hydrogenation would suggest that 18a, formed by
20b
cis-hydrogenation from the least hindered face, is the most
likely product. All other hydrogenation conditions attempted were
ineffective.
Pyrrolizin-3-one 2 and its benzo-analogues are ring-opened
7
quantitatively in basic alcoholic solution. Isoindolo[2,1-a]indol-
6-one 1 can be ring opened to 2-(2-indolyl)benzoic acid in the
1
13
2
Fig. 2 H and C NMR parameters (d
H
and d
C
, [ H
6
]acetone) for 13.
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2
1
presence of potassium tert-butoxide. In contrast, reaction of
with methanol in the presence of H u¨ nig’s base gave only
is therefore the thermodynamic product. There is significant loss
of resonance energy in the formation of the xylylene intermediate,
accounting for the high furnace temperatures needed for these
transformations and allowing the C=C bond rotation required
1
partial conversion to the ring-opened ester 19; in one set of
conditions, equilibrium was reached at about 70% conversion
after 60 min (Scheme 4). There is some indication that increasing
the amount of base causes recyclisation to isoindolo[2,1-a]indol-
for the rearrangement to 24 (Scheme 6).
6
-one 1, and this transformation may also take place during
chromatography. Similarly, attempted methylation of 2-(indol-
-yl)benzoic acid (MeI, K CO , DMF) gave only isoindolo[2,1-
a]indol-6-one 1. The ester 19 was not obtained pure and was
2
2
3
1
3
identified only by C NMR spectroscopy in the presence of 1.
Joule and co-workers have also noted the tendency of 2-(indol-
2
-yl)benzoic acid derivatives to cyclise to isoindolo[2,1-a]indol-6-
22
ones. Nevertheless, this behaviour is unexpected because of the
ring strain associated with the two fused 5-membered rings in
1
. The mixture of 19 and 1 was completely converted into 1 by
◦
FVP at 800 C. This result confirms that the extreme temperatures
required for the formation of 1 by FVP of 7 are due to the high
energy barrier of the sigmatropic shift to give 10, (which is the first
step of the cascade sequence) rather than the ketene generation
step (Scheme 3).
◦
Scheme 6 Reagents and conditions: (i) LiAlH
.01 Torr).
4
; (ii) FVP (800–950 C, ca.
0
Scheme 4 Reagents and conditions: (i) MeOH, Hunig’s base.
Conclusions
We have shown that reduction of the benzopyrrolizinone 3
followed by FVP of the resulting 2-(pyrrol-2-yl)benzyl alco-
hol 20 causes elimination of water and cyclisation to form
benzopyrrolizine 21 (Scheme 5), thereby providing a two-step
We conclude that the thermal cascade illustrated in Scheme 3
provides a viable synthetic route to isoindolo[2,1-a]indol-6-one 1,
though a high temperature is required for the initial sigmatropic
migration. The chemistry of isoindolo[2,1-a]indol-6-one 1 shows
significant differences from that of pyrrolizin-3-one 2 and its
mono-benzo derivatives such as 3. Catalytic hydrogenation of the
23
deoxygenation of the lactam starting material.
1
0b–11 site is unexpectedly sensitive to substituents and the nature
of the catalyst. Isoindolo[2,1-a]indol-6-one 1 exists in equilibrium
with the ester 19 in basic methanol, whereas both 2 and 3 are
rapidly ring opened under such conditions. FVP of the benzyl
alcohol 22 provides two isomeric cyclised products, whereas a
single product is obtained by FVP of the pyrrole analogue 20.
Further studies of pyrrolizinones and their benzo-analogues will
be reported in future publications.
Experimental
◦
Scheme 5 Reagents and conditions: (i) LiAlH
Torr).
4
; (ii) FVP (700 C, 0.01
1
13
H and C NMR spectra were recorded at 250 or 63 MHz re-
2
spectively for solutions in [ H]chloroform unless otherwise stated.
1
3
C NMR signals refer to CH resonances unless otherwise stated.
Lithium aluminium hydride reduction of 1 under the conditions
used for 3, gave the alcohol 22 (76%); similar ring-opening has
been reported for a substituted isoindolo[2,1-a]indol-6-one. In
contrast to the behaviour of 20, FVP of the alcohol 22 at 800–
Mass spectra were recorded under electron impact conditions.
23
3
Methyl 2-(indol-1-yl)benzoate 7
◦
9
50 C gave two products in varying ratio (Scheme 6). These were
A suspension of indole 9 (2.93 g, 25 mmol), o-iodobenzoic acid
separated by chromatography and identified as the known isomers
(5.70 g, 23 mmol) and anhydrous potassium carbonate (6.91 g,
50 mmol) in dimethylformamide (50 cm ) was heated under reflux,
with stirring, for 48 h to give 2-(indol-1-yl)-benzoic acid. The
product was not isolated but treated with iodomethane (3.55 g,
25 mmol) and anhydrous potassium carbonate (6.91 g, 50 mmol)
3
2
3 and 24. At the lower pyrolysis temperatures, 23 is the major
◦
isomer (e.g. 800 C, 23 : 24 75 : 25) and is therefore the kinetic
product whereas 24 predominates at higher furnace temperatures
◦
(
e.g. 950 C with silica tubes in the furnace, 23 : 24 25 : 75) and
2
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and the reaction left to stir at room temperature for 48 h. Upon
126.22, 125.19, 123.78, 122.16, 121.13, 113.24 and 103.37; m/z 219
(M , 100%), 191 (42), 190 (80), 164 (44), 163 (46), 110 (56), 96 (48)
and 82 (56).
3
+
completion of the reaction, water (120 cm ) was added and the
3
product was extracted into ether (3 × 40 cm ), washed with water
3
(
3 × 50 cm ) and dried over anhydrous MgSO
4
. The product
The first fraction from the column (ca. 2 mg) was pyrrolo[3,2,1-
3
3
was purified by vacuum distillation (Kugelrohr) to give methyl
-(indol-1-yl)benzoate 7 (2.18 g, 35%) bp 108–110 C (0.4 Torr);
8.02 (1H, d, J 8.2), 7.74–7.62 (2H, m), 7.55–7.47 (2H, m),
.25–7.12 (4H, m), 6.71 (1H, d, J 3.1) and 3.48 (3H, s); d
jk]carbazole 14 d
H
8.09 (1H, d, J 7.1), 7.92 (1H, d, J 7.3), 7.82
◦
3
2
d
7
(1H, d, J 7.5), 7.70 (2H, m), 7.54 (1H, m), 7.37 (2H, m) and 6.87
(1H, d, J 3.1); d 140.71 (quat), 139.24 (quat), 130.81 (quat),
3
3
H
C
3
C
166.58
126.41, 123.31, 123.02, 122.33, 122.03, 121.54 (quat), 120.95,
+
(
(
quat), 138.49 (quat), 137.03 (quat), 132.61, 131.09, 128.70, 128.44
118.82 (quat), 117.25, 111.31 and 109.26; m/z 191 (M , 100%),
2C, quat), 128.27, 127.42, 122.09, 120.77, 119.94, 109.58, 103.04
163 (44), 139 (23), 96 (52), 82 (45), 63 (29) and 39 (25) (spectra
+
25
and 52.05; m/z 251 (M , 95%), 232 (24), 231 (80), 229 (36), 228
compatible with literature data ). A third fraction was shown to
◦
(
26), 220 (41), 203 (50), 191 (47) and 117 (100) (spectra compatible
be isoindolo[1,2-a]indol-10-one 13, (9 mg, 3%) mp 166–168 C
24
15
◦
2
with published data ).
(lit., 169 C) d
.34–7.45 (2H, m) and 7.05–7.16 (3H, m); d
(quat), 145.43 (quat), 135.66 (quat), 135.41, 134.18 (quat), 132.49
quat), 129.28 (quat), 128.00, 125.06, 124.94, 123.75, 121.87,
H
(C[ H]Cl
3
) 7.63–7.67 (2H, m), 7.48–7.55 (2H, m),
2
7
C
(C[ H]Cl ) 181.55
3
Methyl 2-(3-methylindol-1-yl)benzoate 8
(
3
-Methylindole 10 (3.28 g, 25 mmol) was reacted under the
1
[
11.21 (2CH) and 107.92 (NMR spectra are better dispersed in
conditions above to give methyl 2-(3-methylindol-1-yl)-benzoate 8
2
+
H
6
]acetone solution—see Fig. 2); m/z 219 (M , 100%), 190 (44),
◦
◦
+
(
4.74 g, 72%) mp 96–98 C, bp 103–104 C (1 Torr) (Found: M
1
63 (18), 69 (22) and 32 (45).
2
5
5
65.1094. C17
.75; N, 5.3. C17
.3%); d 7.85 (1H, m), 7.53–7.49 (2H, m), 7.39–7.33 (2H, m),
.08–7.03 (3H, m), 6.90 (1H, m), 3.37 (3H, s) and 2.29 (3H, d,
H
15NO
2
requires M 265.1103) (Found: C, 76.3; H,
H
15NO
2
·0.1H O requires C, 76.45, H, 5.65, N,
2
H
1
1-Methylisoindolo[2,1-a]indol-6-one 4
7
4
J 1.1); d
C
166.93 (quat), 138.73 (quat), 137.22 (quat), 132.55,
31.01, 128.54 (quat), 128.07, 126.95, 126.19, 122.12, 119.39,
18.91, 112.42 (quat), 109.49, 52.07 (CH ) and 9.49 (CH ) (one
FVP of methyl 2-(3-methylindol-1-yl)-benzoate 8 (265 mg,
1
1
◦
◦
1
.0 mmol, T
f
950 C with silica tubes, T
i
120 C, Prange 0.01–
3
3
0
.11 Torr, t 40 min) using a dry ice–acetone cold-finger trap
+
quaternary signal overlapping); m/z 265 (M , 100%), 264 (71),
63 (31), 262 (82), 250 (40), 232 (54), 231 (89), 204 (72) and 203
63).
gave a solid yellow pyrolysate containing 11-methylisoindolo[2,1-
a]indol-6-one 4 that was purified by dry flash chromatography on
silica (20–50% DCM in hexane as eluent) to afford yellow needles
2
(
◦
12c
◦
◦
(
121 mg, 72%) mp 173–174 C (lit., 173–175 C), bp 177 C (4.5
Torr) (Found: C, 81.65; H, 4.65; N, 6.2. C16 O requires
11NO·0.1H
C, 81.75, H, 4.7, N, 5.95%) (Found: M , 233.0840. C16
Flash vacuum pyrolysis experiments
H
2
+
H
11NO
The substrate was sublimed under vacuum into a horizontal
silica furnace tube (35 × 2.5 cm) heated by an electrical furnace.
For some of the high temperature pyrolyses, the contact time
was increased by packing the exit end of the furnace tube with
3
4
requires M, 233.0841); d 7.75 (1H, dt, J 7.9, J 0.8), 7.63 (1H, d,
J 7.5, J 1.0), 7.42 (1H, m), 7.38 (1H, td, J 7.5, J 1.0), 7.26 (1H,
H
3
4
3
4
3
4
m), 7.22–7.14 (2H, m), 7.05 (1H, td, J 7.5, J 1.0) and 2.37 (3H,
s); d 162.15 (quat), 135.68 (quat), 134.95 (quat), 134.49 (quat),
33.87, 133.47 (quat), 133.31, 127.94, 126.39, 125.19, 123.48,
21.02 (quat), 120.05, 115.24 (quat), 113.19 and 9.35 (CH ); m/z
33 (M , 99%), 232 (77), 219 (100), 204 (59), 203 (79) and 102 (34).
9
C
silica tubes. Products were collected in a U-tube, cooled by
1
1
2
liquid nitrogen, situated at the exit point of the furnace. When
the pyrolysis was complete, the trap was allowed to warm to
room temperature under an atmosphere of dry nitrogen. Pyrolysis
parameters are quoted as follows: quantity of substrate, inlet
3
+
temperature (T
i
), furnace temperature (T ), pressure range (Prange)
f
and time of pyrolysis (t).
10b,11-Dihydroisoindolo[2,1-a]indol-6-one 16
A solution of isoindolo[2,1-a]indol-6-one 1 (51 mg, 0.23 mmol)
in ethanol (25 cm ) was hydrogenated over 5% Pd–C (5 mg) at
Isoindolo[2,1-a]indol-6-one 1
3
Conditions were optimised by small scale pyrolyses of methyl 2-
40 psi using a Parr apparatus for 6 h during which time the
solution decolourised. The catalyst was removed by filtration
through Celite and the filtrate was concentrated to provide 10b,11-
dihydroisoindolo[2,1-a]indol-6-one 16 as a colourless solid (50 mg,
◦
(
indol-1-yl)-benzoate 7 (ca. 30 mg, 0.12 mmol, T
i
100 C, Prange
0
.02–0.10 Torr, t 10 min), in the presence of silica tubes placed
at the exit end of the furnace. The following conversions were
◦
◦
◦
◦
◦
17
◦
+
observed: 800 C, 15%; 850 C, 23%; 900 C, 54%; 950 C, 84%.
98%) mp 127–129 C (lit., 136–137 C) (Found: M 221.0840.
11NO requires M 221.0841); d 7.80 (1H, m), 7.60 (1H, d,
J 7.8), 7.52 (1H, m), 7.44–7.38 (2H, m), 7.27–7.13 (2H, m), 6.98
◦
A preparative pyrolysis (400 mg, 1.6 mmol, T
f
950 C with silica
C
15
H
H
◦
3
tubes T
i
100 C, Prange 0.01–0.12 Torr, t 40 min) gave a solid yellow
3
3
3
pyrolysate that was purified by dry flash chromatography on silica
50% DCM in hexane as eluent) to give isoindolo[2,1-a]indol-6-
(1H, t, J 7.5), 5.52 (1H, apparent t, J ca. 9.5), 3.37 (1H, dd, J
3
(
15.2 and 8.7) and 2.95 (1H, dd, J 15.0 and 10.4); d 168.25 (quat),
C
◦
12a
◦
one 1 (220 mg, 76%) mp 153–154 C (lit., 154 C); d
7
H
(360 MHz)
145.87 (quat), 140.43 (quat), 135.82 (quat), 134.01 (quat), 132.42,
3
3
4
.88 (1H, d, J 7.9), 7.75 (1H, dd, J 7.9, J 0.8), 7.51 (2H, m), 7.44
128.56, 127.83, 125.21, 124.66, 124.30, 122.70, 116.31, 65.29 and
3
3
+
(
1H, d, J 7.8), 7.34 (1H, m), 7.27 (1H, m), 7.14 (1H, td, J 7.6,
33.61 (CH
2
); m/z 221 (M , 86%), 220 (89), 219 (77), 193 (81), 192
4
J 1.0) and 6.60 (1H, s); d
C
162.54 (quat), 138.74 (quat), 134.60
(64), 191 (80), 190 (62), 165 (71), 130 (52), 105 (53) and 95 (100)
17
(
quat), 134.41 (quat), 133.80 (quat), 133.59, 133.52 (quat), 128.70,
(spectra compatible with those previously reported )
This journal is © The Royal Society of Chemistry 2008
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1
0b,11-Dihydro-11-methylisoindolo[2,1-a]indol-6-one 17
alumina (ethyl acetate, hexane) gave only 1, suggesting that 19 had
recyclised on the column.
1
1-Methylisoindolo[2,1-a]indol-6-one 4 (30 mg, 0.13 mmol) was
hydrogenated in a 10 : 1 mixture of ethanol and acetic acid over 5%
Rh–Al (5 mg) at room temperature and a pressure of 400 psi for
h and gave a mixture of three hydrogenation products. Separation
by dry flash chromatography, using a 2–40% ethyl acetate in
hexane gradient as eluent, afforded one major product which
was identified as 10b,11-dihydro-11-methylisoindolo[2,1-a]indol-
2
-(Indol-2-yl)benzoic acid and its attempted methylation under
2
O
3
basic conditions
3
21
Using Itahara’s method, isoindolo[2,1-a]indol-6-one 1 (0.22 g,
1 mmol) was dissolved in t-butanol and water (5 cm ) and
potassium t-butoxide (1.12 g, 10 mmol) was added. The mixture
was heated under reflux, with stirring, under nitrogen for 60 h. The
solvent was removed, the mixture was diluted with water, acidified
3
1
9
3
6
-one 17 (24 mg, 80%)
d
H
7.91 (1H, m), 7.71 (1H, dd, J 7.8,
4
3
4
J 0.4), 7.62 (1H, td, J 7.5, J 1.3), 7.54–7.49 (2H, m), 7.35–7.26
2H, m), 7.11 (1H, td, J 7.5, J 0.9), 5.53 (1H, d, J 7.9), 3.62 (1H,
3
4
3
3
(
with HCl, then extracted with diethyl ether (3 × 20 cm ). The
3
3
apparent quin, J ca. 7.4) and 0.76 (3H, d, J 7.2); d
C
168.00 (quat),
42.98 (quat), 141.65 (quat), 138.82 (quat), 134.98 (quat), 132.00,
28.52, 127.99, 124.77, 124.44 (2CH), 123.55, 116.22, 68.65, 37.73
).
organic extracts were dried (MgSO ) and the ether was evaporated
4
1
1
to give 2-(indol-2-yl)benzoic acid (0.23 g, 97%) after trituration
with ether and hexane, mp 156–158 C (lit., 155–157 C); dH
9.25 (1H, s), 7.96 (1H, d, J 8.2), 7.72 (1H, d, J 7.8), 7.62
(2H, m), 7.42 (2H, m), 7.21 (2H, m) and 6.72 (1H, s); d 136.48
◦
21
◦
3
3
and 18.22 (CH
3
When solutions of 11-methylisoindolo[2,1-a]indol-6-one 4
C
3
(
30 mg, 0.13 mmol) in toluene (25 cm ) were subjected to
(quat), 133.58 (quat), 132.47, 131.45, 131.03, 128.19 (quat), 127.63,
hydrogenation at 600, 850, 1000 Bar at room temperature and
122.37, 120.53, 119.92, 111.14 and 103.46.
A solution of 2-(indol-2-yl)benzoic acid (0.23 g, 0.97 mmol)
and iodomethane (0.14 g, 1 mmol) in dimethylformamide (15 cm )
◦
1
000 Bar with heating at 50 C over 5% Pd–C, 10% Pd–C or 5%
3
Rh–C for 6 h, no reaction was observed.
containing potassium carbonate (0.28 g, 2 mmol) was stirred at
3
room temperature for 24 h. Water (40 cm ) was added and the
1
1-Methyltetradecahydro-isoindolo[2,1-a]indol-6-one 18
3
product was extracted into ether (3 × 20 cm ). The organic extracts
3
A hydrogenation of 4 (30 mg, 0.13 mmol) at room temperature and
a pressure of 400 psi under the conditions used for 17, but with a
reaction time of 18 h, gave 11-methyltetradecahydro-isoindolo[2,1-
were washed with water (3 × 10 cm ), dried (MgSO
4
) then the
solvent was evaporated to give 1 as the sole product.
a]indol-6-one 18 (29 mg, 97%) with one stereoisomer present as
FVP of a mixture of isoindolo[2,1-a]indol-6-one 1 and methyl
2-(indol-2-yl)benzoate 19
+
ca. 80% of the mixture (Found: M 247.1939. C16
H
25NO requires
3
M 247.1936); d
H
3.82 (1H, dd, J 7.6 and 4.6), 3.52 (1H, m), 2.63
3
A 30 : 70 mixture of 1 and 19 (0.006 g), was subjected to FVP at
(
(
1H, t, J 5.3), 2.42–2.27 (2H, m), 2.22–0.87 (17H, m) and 1.11
◦
◦
3
800 C with silica tubes (T
i
90–150 C, Prange 0.009–0.012 Torr, t
3H, d, J 7.5); d
C
152.52 (quat), 65.89, 52.98, 48.10, 42.60, 40.47,
), 25.44 (CH ), 24.33 (CH ), 24.11 (CH ), 23.47
), 23.08 (CH ), 22.79 (CH ), 22.07 (CH ) and 14.08 (CH );
m/z 247 (M , 86%), 204 (79), 190 (51), 152 (55), 138 (83), 95 (70),
1 (89), 67 (84) and 55 (100).
2
5 min). NMR analysis of the product indicated that recyclisation
37.54, 27.65 (CH
2
2
2
2
to 1 was complete under these conditions.
(
CH
2
2
2
2
3
+
2-(2-Hydroxymethylphenyl)indole 22
8
Lithium aluminium hydride (0.076 g, 2 mmol) was dissolved in
3
Reaction of isoindolo[2,1-a]indol-6-one 1 with H u¨ nig’s base in
methanol
dry THF (10 cm ), and a solution of isoindolo[2,1-a]indol-6-one
3
1 (0.219 g, 1 mmol) in THF (10 cm ) was added dropwise under
nitrogen. The mixture was heated under reflux, under nitrogen,
with stirring, for 3 h. Wet ether was then added to quench excess
Isoindolo[2,1-a]indol-6-one 1 (0.009 g, 0.04 mmol) was dissolved
2
3
1
in [ H
4
]methanol (0.5 cm ), and its H NMR spectrum showed a
6.76 (1H, s)]. H u¨ nig’s base
0.013 g, 0.1 mmol) was added and the spectrum immediately
LiAlH , and the inorganic residue was filtered through Celite.
4
characteristic signal due to H-11 [d
(
H
3
Water (20 cm ) was added to the filtrate and the product was
3
extracted into ether (3 × 10 cm ). The organic extracts were washed
showed a new peak at d
H
6.45 due to H-3 of compound 19 (20%
3
with water (3 × 5 cm ), dried (MgSO
4
) and the solvent was removed
conversion). The following conversions were recorded: 15 min,
0%; 60 min, 70%; 150 min, 70%; showing the reaction had reached
to give a brown oil, which was distilled (Kugelrohr) to give 2-(2-
5
hydroxymethylphenyl)indole 22 (0.17 g, 76%) as a pale orange
equilibrium at 70% conversion under these conditions.
The following reaction conditions allowed a sample of 19 to
be isolated as a mixture with 1. Isoindolo[2,1-a]indol-6-one 1
◦
22
◦
oil, bp 160–162 C (0.8 Torr) (lit., mp 85 C); d
7
H
10.15 (1H, s),
.68 (1H, d, J 7.3), 7.59 (1H, d, J 7.7), 7.31 (4H, m), 7.09 (2H,
m), 6.68 (1H, s), 4.67 (2H, s) and 2.21 (1H, s); d 137.69 (quat),
36.61 (quat), 135.70 (quat), 133.88 (quat), 130.75, 130.09, 129.07,
28.45 (quat), 127.80, 121.87, 120.36, 119.72, 111.23, 101.66 and
5.13 (CH ).
3
3
C
(
(
0.022 g, 0.1 mmol) was dissolved in methanol and H u¨ nig’s base
1
1
6
0.026 g, 0.2 mmol) was added. The mixture was left at room
1
temperature for 1 h and the methanol was evaporated. H NMR
2
analysis showed 47% conversion to 19 and elimination of the
1
3
signals of the C spectrum of 1 reported above enabled those
of 19 to be identified; d 169.94 (quat), 136.69 (quat), 136.41
quat), 134.52 (quat), 131.55, 130.74, 130.06, 129.80 (quat), 128.18
quat), 127.30, 125.15, 122.24, 120.43, 119.82, 111.17, 103.10,
). Attempted separation by chromatography on
FVP of 2-(2-hydroxymethylphenyl)indole 22
C
(
(
The following optimisation experiments were carried out. 2-
(2-Hydroxymethylphenyl)indole 22 (0.028 g, 0.13 mmol) was
◦
◦
and 52.69 (CH
3
subjected to FVP at 800 C (T
i
90–150 C, Prange 0.008–0.013 Torr, t
2
338 | Org. Biomol. Chem., 2008, 6, 2334–2339
This journal is © The Royal Society of Chemistry 2008

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3
5 min). The white solid obtained contained 22, 23 and 24, with an
4 J. Guillaumel, S. L e´ once, A. Pierr e´ , P. Renard, B. Pfeiffer, L. Peruchon,
P. B. Arimondo and C. Monneret, Oncol. Res., 2003, 13, 537–
549.
approximately 3 : 1 ratio of 23 to 24. Repetition of this experiment
at 900 C (0.044 g, 0.2 mmol, T
t 15 min) gave a ca. 1 : 1 mixture of 6H-isoindolo[2,1-a]indole 23
and 5,10-dihydroindeno[1,2-b]indole 24. At 950 C (with silica
tubes inserted in the furnace tube) FVP of 22 (0.023 g, 0.1 mmol,
T
which contained 23 and 24 in 1 : 3 ratio.
◦
◦
i
90–120 C, Prange 0.008–0.009 Torr,
5
S. Samosorn, J. B. Bremner, A. Ball and K. Lewis, Bioorg. Med. Chem.,
2006, 14, 857–865.
◦
6 K. Dinnell, G. G. Chicchi, M. J. Dhar, J. M. Elliott, G. J. Hollingsworth,
M. M. Kurtz, M. P. Ridgill, W. Rycroft, K.-L. Tsao, A. R. Williams
and C. J. Swain, Bioorg. Med. Chem. Lett., 2001, 11, 1237–1240.
◦
i
90–120 C, Prange 0.009–0.012 Torr, t 15 min) gave a pyrolysate
7
H. McNab and C. Thornley, Heterocycles, 1994, 37, 1977–2008.
8 M. A. Khan and J. B. Polya, J. Chem. Soc. C, 1970, 85–91.
9
E. F. Duffy, J. S. Foot, H. McNab and A. A. Milligan, Org. Biomol.
Chem., 2004, 2, 2677–2683.
On a larger scale, 2-(2-hydroxymethylphenyl)indole 22 (0.104 g,
◦
0
.47 mmol) was sublimed into the FVP furnace at 900 C (T
i
1
0 W. Carruthers and N. Evans, J. Chem. Soc., Perkin Trans. 1, 1974,
523–1525.
11 M. D. Crenshaw and H. Zimmer, J. Heterocycl. Chem., 1984, 21, 623–
24.
◦
90–150 C, Prange 0.011–0.017 Torr, t 45 min). The cream–yellow
1
solid obtained was separated using dry flash chromatography
6
(
(
dichloromethane, hexane) to give 6H-isoindolo[2,1-a]indole 23
0.03 g, 31%) mp 214–218 C (lit., 209–211 C); d
1
2 (a) T. Itahara, Synthesis, 1979, 151–152; (b) T. Itahara, M. Ikeda and
T. Sakakibara, J. Chem. Soc., Perkin Trans. 1, 1983, 1361–1363; (c) R.
Grigg, V. Sridharan, P. Stevenson, S. Sukirthalingam and T. Warakun,
Tetrahedron, 1990, 46, 4003–4018; (d) A. P. Kozikowski and D. Ma,
Tetrahedron Lett., 1991, 32, 3317–3320; (e) A. Garcia, D. Rodriguez,
L. Castedo, C. Saa and D. Dominguez, Tetrahedron Lett., 2001, 42,
◦
22
◦
H
7.78 (1H, m),
.61 (1H, t, J 8.1), 7.18 (6H, m), 6.55 (1H, s) and 5.00 (2H, s); d
44.36 (quat), 141.59 (quat), 134.29 (quat), 133.48 (quat), 133.19
3
7
1
C
(
quat), 130.75, 128.87, 127.45, 123.95, 122.11, 121.91, 121.34,
+
120.03, 109.65, 91.68 and 48.82 (CH
2
); m/z 240 (45%), 205 (M ,
1
903–1905; (f) G. Kim, J. H. Kim, W. Kim and Y. A. Kim, Tetrahedron
3
3%), 161 (100), 129 (60), 102 (76), 76 (37) and 51 (53) (spectra
Lett., 2003, 44, 8207–8209; (g) T. A. Dwight, N. R. Rue, D. Charyk, R.
Josselyn and B. DeBoef, Org. Lett., 2007, 9, 3137–3139.
3 F. J. Reboredo, M. Treus, J. C. Estevez, L. Castedo and R. J. Estevez,
Synlett, 2003, 1603–1606.
22
compatible with literature data ).
1
The second component obtained from the column was impure
◦
5
,10-dihydroindeno[1,2-b]indole 24 (0.02 g, 21%) mp 230–234 C
14 For example, L. M. Jackman and S. Sternhell, Applications of Nuclear
Magnetic Resonance Spectroscopy in Organic Chemistry, Pergamon
Press, Oxford, 2nd edn, 1969, p. 333.
26
◦
(
lit., 258–259 C); d
H
8.34 (1H, s), 7.63 (1H, m), 7.54 (1H, d,
J 6.6), 7.1–7.5 (6H, m) and 3.73 (2H, s); d 147.69 (quat), 143.22
quat), 140.51 (quat), 134.90 (quat), 126.41, 125.35, 124.63, 121.53,
20.05, 118.82, 117.21, 111.96 and 30.83 (CH ) (2 quaternary
signals overlap with impurity peaks in aromatic region); m/z
3
C
1
1
5 D. A. Shirley and P. A. Roussel, J. Am. Chem. Soc., 1953, 75, 375–8.
6 L. A. Crawford, H. McNab, A. R. Mount and S. I. Wharton,
unpublished results.
(
1
2
1
7 W. Zhang and G. Pugh, Tetrahedron, 2003, 59, 3009–3018.
+
18 T. L. Gilchrist and K. Graham, Tetrahedron, 1997, 53, 791–798.
2
05 (M , 100%), 204 (78), 102 (24), 76 (41) and 51 (49) (spectra
1
2
2
9 This compound has been reported but no spectroscopic data are
27
compatible with literature data, recorded in a different solvent ).
given, O. Tsuge, T. Hatta and H. Tsuchiyama, Chem. Lett., 1998, 155–
1
56.
0 (a) D. A. Burnett, J. K. Choi, D. J. Hart and Y. M. Tsai, J. Am. Chem.
Soc., 1984, 106, 8201–8209; (b) X. L. M. Despinoy, PhD thesis, The
University of Edinburgh, 1998.
Acknowledgements
We are grateful to the EPSRC and The University of Edinburgh
for research studentships (to L. A. C. and R. G. T.).
1 T. Itahara, Bull. Chem. Soc. Jpn., 1981, 54, 305–306.
22 L. Dalton, G. L. Humphrey, M. M. Cooper and J. A. Joule, J. Chem.
Soc., Perkin Trans. 1, 1983, 2417–2422.
2
3 B. A. J. Clark, X. L. M. Despinoy, H. McNab, C. C. Sommerville and
E. Stevenson, J. Chem. Soc., Perkin Trans. 1, 1999, 2049–2051.
4 D. W. Old, M. C. Harris and S. L. Buchwald, Org. Lett., 2000, 2,
1403–1406.
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