A novel approach to isoindolo[2,1-a]indol-6-ones

Article abstract of DOI:10.1039/c2ob25314c

A convenient route to isoindolo[2,1-a]indol-6-ones has been developed starting from the appropriate 2-(N-phthaloyl)benzoic acids. Formation of the acid chlorides with thionyl chloride followed by heating with triethyl phosphite in a suitable solvent resulted in a multistep reaction giving tetracyclic β-ketophosphonates that on reduction with sodium borohydride gave the required indolones in good overall yields. Analogous β-ketophosphonates were also prepared starting with N,N-(1,8-naphthaloyl)-2-aminobenzoic acid and 2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)benzoic acids although of these only the naphthaloyl product could be reduced with sodium borohydride without cleaving the amide bond in the ring system.

Full text of DOI:10.1039/c2ob25314c

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PAPER
A novel approach to isoindolo[2,1-a]indol-6-ones†
Philip Duncanson, Yuen-Ki Cheong, Majid Motevalli and D. Vaughan Griffiths*
Received 12th February 2012, Accepted 2nd April 2012
DOI: 10.1039/c2ob25314c
A convenient route to isoindolo[2,1-a]indol-6-ones has been developed starting from the appropriate
2-(N-phthaloyl)benzoic acids. Formation of the acid chlorides with thionyl chloride followed by heating
with triethyl phosphite in a suitable solvent resulted in a multistep reaction giving tetracyclic
β-ketophosphonates that on reduction with sodium borohydride gave the required indolones in good
overall yields. Analogous β-ketophosphonates were also prepared starting with N,N-(1,8-naphthaloyl)-
2-aminobenzoic acid and 2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)benzoic acids although of these only
the naphthaloyl product could be reduced with sodium borohydride without cleaving the amide bond in
the ring system.
Introduction
We have previously shown that trialkyl phosphites react with
benzoylphosphonates 1 to initially give the anionic intermediates
2 which, in the absence of electrophiles, undergo α(C–O) bond
cleavage to give reactive carbene intermediates 3 (Scheme 1).1
For the unsubstituted benzoylphosphonate 1 (R = H) the carbene
intermediate then reacts intermolecularly with the trialkyl
phosphite in the reaction mixture to give an ylidic phosphonate 4
(R = H).
However, if a suitable ortho substituent is present on the
phenyl ring an intramolecular trapping reaction may occur invol-
Scheme 12
ving the substituent, either via the initially formed anionic centre
in 2 or the subsequently formed carbene centre in 3. Both these
alternative pathways have been observed in the case of ortho-
substituted benzoylphosphonates 1 where the substituent con-
tains a carbonyl group.
Thus, for example, in the case of the 2-benzoylbenzoyl-
phosphonate system 1a (R = PhCO, R′ = Me) the carbonyl
group cannot adopt a position that facilitates its attack by the
anionic centre in 2a. As a consequence the carbene intermediate
3a forms which then inserts into the carbonyl group to give the
isobenzofuran system 5 (Scheme 2).3
School of Biological and Chemical Sciences, Queen Mary University of
London, London E1 4NS, UK. E-mail: d.v.griffiths@qmul.ac.uk;
Fax: +(44) 20 7882 7427; Tel: +(44) 20 7882 5389
†Electronic supplementary information (ESI) available: A. Preparation,
isolation and characterisation information for benzoic acids 13a–d, 24,
31a and 31c, and benzoyl chlorides 14a–d, 25, 32a, 32c and 41. B. X-
ray crystallographic data for 15a, 28, 35c and 37c. C. Selected NMR
spectra for 13a,b, 15a–d, 16a, 20a–d, 23a–d, 26–29, 35a,c, 38c, 40, 44,
50 and 52. CCDC 865150 (15a), 865151 (28), 865152 (35c) and
865153 (37c). For ESI and crystallographic data in CIF or other elec-
tronic format see DOI: 10.1039/c2ob25314c
Scheme 2
In contrast, with the 2-benzoyloxybenzoylphosphonate system
1b (R = PhCO2, R′ = Me) the carbonyl group is accessible to the
anionic centre in 2b leading to the initial formation of the dioxa-
phospholane 6 (Scheme 3).4
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Scheme 4
Scheme 3
This particular cyclisation is of interest since the resulting
dioxaphospholane
6 then undergoes further reaction, the
outcome of which depends on whether excess trialkyl phosphite
is still present. In the presence of trialkyl phosphite the reaction
is faster leading to the formation of the benzofuran 7 by a
pathway thought to be that shown in Scheme 4.4
However, in the absence of excess phosphite, the dioxa-
phospholane 6 undergoes a novel rearrangement in which tri-
methyl phosphate is lost and the phosphonate group migrates to
give the β-ketophosphonate 8.4 Moreover, the subsequent
reduction of this β-ketophosphonate with sodium borohydride
led smoothly to 2-phenylbenzofuran
(Scheme 5).
9 in good yields
We have recently been investigating whether we could exploit
these interesting pathways to provide routes to some synthetically
useful products. As part of these studies we have developed a
novel, convenient route to the isoindolo[2,1-a]indol-6-one ring
system 10. Compounds of this type have attracted interest
because of their biomedical applications. Their anticancer
activity5 and ability to bind to the nNK1 receptor6 have been
investigated, as has their use as high affinity ligands for the mel-
atonin MT3 binding site.7 They can also be used as synthetic
precursors for other bioactive molecules.8 It would therefore be
useful to develop a convenient route to such systems that would
offer the flexibility of introducing substituents at a wide range of
positions on the ring system.
Scheme 5
in essentially quantitative yield by the action of thionyl chloride
and then onto the corresponding β-ketophosphonates 15a–d by
their reaction with triethyl phosphite in effectively a one pot
reaction (Scheme 6).
The reaction pathway by which the acid chlorides 14 are con-
verted to the corresponding β-ketophosphonates 15 by the action
of triethyl phosphite was determined for the parent system 15a
by monitoring the various steps in the pathway using NMR and
is shown in Scheme 7. This showed that the reaction of the acid
chloride 14a with triethyl phosphite initially proceeded cleanly
to give the corresponding aroylphosphonate 16a which exhibited
a characteristic 31P NMR resonance around δP −2 ppm and a
large low-field doublet in the 13C NMR spectrum (δC 200 ppm,
JPC 178.5 Hz) for the α-carbonyl resonance. Although this
material could be isolated in an analytically pure state by column
chromatography on silica and fully characterized, significant
losses occurred during this process due to decomposition on the
column. For this reason, it was generally found preferable to
prepare the aroylphosphonates 16a–d in situ and to react them
further with triethyl phosphite without attempting to isolate
them.
Results and discussion
Syntheses based on the 2-(phthalimido)benzoic acids 13a–d
Our strategy for the preparation of the isoindolo[2,1-a]indol-6-
one involved the initial preparation of the 2-(N-phthaloyl)
benzoic acids 13a–d from the reaction of the appropriate 2-ami-
nobenzoic acids 12 and phthalic anhydrides 11 (Scheme 6),
which generally proceeded in good yield. The resulting acids
were then converted into the corresponding acid chlorides 14a–d
The outcome of the reaction of the aroylphosphonate 16a with
further triethyl phosphite was found to depend on the conditions
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Fig. 1 X-ray crystal structure of the β-ketophosphonate 15a.9
Scheme 6
Scheme 8
5-coordinated ring phosphorus atom with coupling (JPP 51.5 Hz)
to the phosphonate group at δP 15.0 ppm. However, if the aroyl-
phosphonate 16a was heated with triethyl phosphite in toluene
the reaction proceeded smoothly to give the β-ketophosphonates
15a in excellent yield (ca. 95% by NMR). The X-ray crystal
structure of 15a is shown in Fig. 1.
This formation of 15a from 19a (Scheme 7) is analogous to
the decomposition of the dioxaphospholane 6 previously dis-
cussed (Scheme 5) with both processes involving loss of phos-
phate, migration of the phosphonate group and formation of a
β-ketophosphonate. However, it is interesting to note that while
the decomposition of 6 to give 8 only occurred in the absence of
trimethyl phosphite, the formation of 15a occurred even in the
presence of triethyl phosphite. An analogous decomposition
pathway to that shown in Scheme 4 was not observed in the case
of the dioxaphospholane 19a.
The formation of the β-ketophosphonate 15a was also
observed when the reaction of the aroylphosphonate 16a with
triethyl phosphite was carried out in boiling DCM although with
this solvent an additional product, the phosphate 20a was also
formed (15a : 20a = 80 : 15). This phosphate can be seen to arise
Scheme 72
used. If the reaction was carried out at room temperature the
dioxaphospholane 19a formed giving a characteristically high
field doublet in the 31P NMR spectrum at δP −51.8 ppm for the
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Scheme 9
Scheme 10
Table 1 Effect of reaction solvent on product ratio when the acid
chlorides 14a–d react with excess triethyl phosphite
Acid
chloride
With toluene as the reaction With DCM as the reaction
solvent
solvent
14a
14b
14c
14d
15a (96%), 20a (1.5%),
22a (2.5%)a
15a (80%), 20a (15%),
22a (5%)a
15b (92%), 20b (2.5%),
15b (45%), 20b (39%),
22b (5.5%)a
22b (16%)a
15c (85%), 20c (<1%), 22c 15c (78%), 20c (11%), 22c
(∼14%)a
(11%)a
15d (93%), 20d (∼1%),
15d (86%), 20d (10%),
22d (6%)a
22d (4%)a
a No 22a–d could form if further steps were taken to rigorously exclude
proton donors from the reaction mixture.
via an alternative decomposition pathway for the intermediate
18a (Scheme 8).
As anticipated, small quantities of the phosphate–phosphonate
22a were also seen in those reactions where there was either
ingress of moisture or incomplete formation of the acid chloride
14a from the acid 13a prior to addition of the triethyl phosphite.
The presence of a proton donor in the reaction mixture results
in protonation of the initially formed intermediate 17a, and
subsequent dealkylation of the resulting quasiphosphonium
salt 21a gives the observed phosphate–phosphonate 22a
(Scheme 9).
The reactions of the substituted acid chlorides 14b–d with
triethyl phosphite were also investigated to demonstrate that this
approach could be also be used to prepare the tetracyclic phos-
phonates 15b–d in which the ring system contains substituents
on either or both of the phenyl rings. As with the parent system
14a, these reactions too proceeded cleanly in boiling toluene to
give the required β-ketophosphonates 15b–d in good yields.
They also led to the formation of some of the phosphates 20b–d
with DCM as the reaction solvent (Table 1).
The conversion of the β-ketophosphonates 15a–d to the corre-
sponding isoindolo[2,1-a]indol-6-ones 23a–d was then investi-
gated using sodium borohydride as previously used for the
conversion of the β-ketophosphonates 8 to the benzofuran 9
(Scheme 5). These reactions (Scheme 10) proceeded cleanly
to give the desired isoindolo[2,1-a]indol-6-ones 23a–d
which usually precipitated from the reaction mixture in good
yield.
Scheme 11
Syntheses based on N,N-(1,8-naphthaloyl)-2-aminobenzoic
acid 24
We have also shown that further variations in the structure of the
final polycyclic ring system are possible using modifications of
this same basic approach. So, for example, the benzoylphos-
phonate 26 (Scheme 11) reacted with triethyl phosphite in
boiling toluene to give largely the corresponding β-ketophospho-
nate 27 which on reduction with sodium borohydride gave the
pentacyclic system 29 in good yield (75%).
However, this system once again illustrated the impact of
changing the reaction solvent and temperature. Thus, while the
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Fig. 2 X-ray crystal structure of the enolphosphate 28.9
Fig. 3 X-ray crystal structure of one of the two arrangements adopted
by the β-ketophosphonate 35c in the solid state.9,10
dominant product (Scheme 12). Moreover, as expected, when
excess triethyl phosphite was added to a cooled solution of the
acid chloride 32c, the formation of the intermediate dioxapho-
spholane 34c was observed. This dioxaphospholane sub-
sequently decomposed at room temperature over a period of time
with the loss of triethyl phosphate to give the β-ketophosphonate
35c. The X-ray crystal structure of one of the two10 arrangements
adopted by the β-ketophosphonate 35c in the solid phase is
shown in Fig. 3. Unsurprisingly, this ring structure is very
similar to that of the corresponding portion of the β-ketophos-
phonate structure displayed for 15a in Fig. 1.10
A number of additional compounds were also formed during
this extended period of reaction most of which are thought to
arise from reaction of the chlorinated ring with the excess triethyl
phosphite present in the reaction mixture. We have previously
observed that chlorinated maleimide type-systems will undergo
reaction with trialkyl phosphites under appropriate conditions.11
A small quantity of the hydroxy compound 37c was also isolated
from this reaction mixture and converted into the corresponding
acetylated derivative 38c for characterisation purposes. The pres-
ence of the enol group in 37c was confirmed by its X-ray crystal
structure (Fig. 4), which shows the enol C(5)–O(2) bond length
(1.325 Å) to be significantly longer than that of the carbonyl
C(1)–O(1) double bond (1.231 Å) and the C(5)–C(4) bond
length (1.358 Å) of comparable length to the C(3)–C(2) carbon–
carbon double bond (1.349 Å).10 It seems likely that this com-
pound arises from hydrolysis of an initially formed enolpho-
sphate 36c during its isolation by column chromatography. Such
an enolphosphate could form by a pathway analogous to that
used to explain the formation of the enolphosphates 20a–d
(Scheme 8) although it is interesting to note that none of the
intact enolphosphate 36c was isolated from the reaction mixture.
An attempt to reduce the β-ketophosphonate 35c with sodium
borohydride to give 39 was unsuccessful since reduction of the
amide bond also occurred to give the ring-opened system 40.
Scheme 12
reaction of the benzoylphosphonate 26 with triethyl phosphite in
boiling toluene gave mainly the β-ketophosphonate 27 and only
a little of the enolphosphate 28 (see X-ray structure in Fig. 2)
[27 : 28 = 92 : 8] this product ratio changed to 52 : 48 when the
reaction was carried out in DCM at room temperature. As usual
in these types of reaction, some of the corresponding phosphate–
phosphonate 30 was also formed due to the incomplete exclusion
of proton donors, such as moisture, from the reaction mixture.
Syntheses based on 2-(N-maleimido)benzoic acids 31a and 31c
The possible use of the maleimido-substituted benzoic acids 31a
and 31c (Scheme 12) as the starting materials for the preparation
of the analogous β-ketophosphonate 35a and 35c was also
investigated.
With the dichloro-substituted system 31c the synthesis of 35c
proceeded satisfactorily. Thus, when the initially formed acid
chloride 32c was heated with two molar equivalents of triethyl
phosphite in either DCM or toluene under reflux, the reaction
proceeded cleanly to give the β-ketophosphonate 35c as the
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Fig. 4 X-ray crystal structure of the hydroxy compound 37c.9
Scheme 14
these β-ketophosphonates were isolated by chromatography
although it is interesting to note that the quantity of the unsatu-
rated β-ketophosphonate 35a isolated exceeded the quantity of
the unsaturated acid chloride 32a initially present in the reaction
mixture. This clearly indicated that some of the unsaturated
β-ketophosphonate 35a was being derived from the chlorinated
acid chloride 41. The formation of some of the phosphate–phos-
phonates 46 and 47 during the reaction suggests that the anionic
intermediate 45 may be the base causing this elimination of HCl.
We were also able to show that a further quantity of the β-keto-
phosphonate 35a could be obtained from the β-ketophosphonate
44 we had isolated by the action of a base such as triethylamine.
Interestingly, reduction of the β-ketophosphonate 35a with
sodium borohydride in methanol gave the indolylacrylate 50 and
the lactone 52 (Scheme 14) rather than formation of the expected
ring system 53. While the formation of the acrylate 50 might be
viewed as the product arising from the methanolysis of the
amide bond in 53 we isolated none of this latter compound from
the reaction mixture. An alternative pathway that would account
for the formation of both 50 and 52 is shown in Scheme 14 and
involves cleavage of the amide bond in the β-ketophosphonate
35a prior to reduction of the ‘keto’ group. Reduction of the
‘keto’ group in the resulting methyl ester 48 then gives the inter-
mediate 49 which can then either lose phosphate to give the
acrylate 50 or lose methoxide to give the lactone 51 which
clearly then undergoes further reduction to give the observed
product 52. An analogous reduction of an α,β-unsaturated
Scheme 13
With the corresponding non-chlorinated acid 31a further
complications arose. In particular, attempts to prepare the acid
chloride 32a using oxalyl chloride led also to the formation of
the chlorinated ring system 41. These two systems proved
difficult to separate and so a preliminary investigation of the
reaction of triethyl phosphite with this mixture was carried out
using NMR to monitor the progress of the reaction. This showed
the formation of intermediates that were consistent with the reac-
tion pathways shown in Schemes 12 and 13. Thus resonances
characteristic of the dioxaphospholanes 34a and 43 were initially
observed which were then replaced by signals for triethyl phos-
phate and β-ketophosphonates 35a and 44. Samples of both
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δ-lactone with sodium borohydride in the presence of triethyl-
All reactions involving the acid chlorides 14, 25 and 32 and
benzoylphosphonates 16, 26 and 33 should be carried out with
the rigorous exclusion of moisture.
amine has been previously reported.12
Conclusions
The reaction of the benzoyl chloride 14a with triethyl phosphite
We have developed a simple and convenient procedure for the
preparation of a range of substituted isoindolo[2,1-a]indol-6-
ones 23 and related compounds from readily prepared 2-(phtha-
limido)benzoic acids 13. Reaction of the corresponding benzoyl
chlorides 14 with trialkyl phosphites in boiling toluene (we
found triethyl phosphite to be the most convenient) proceeds
cleanly to give the β-ketophosphonates 15, the immediate precur-
sors of the required heterocyclic systems, in good yield (typically
>80%). This reaction was shown to proceed via a multistep reac-
tion pathway (see Scheme 7) involving initial formation of the
benzoylphosphonates 16 which then react further with the phos-
phite to give the 1,3,2-dioxaphospholanes 19. These dioxapho-
spholanes then decompose under the reaction conditions with
loss of trialkyl phosphate and migration of a phosphonate group
to give the required β-ketophosphonates 15. Analogous reactions
occur with some other 2-‘imido’-benzoic acids (see Schemes
11–13).
It is worth noting that the choice of reaction solvent in the
reactions of the acid chlorides 14 with triethyl phosphite is
important since if they are carried out in DCM rather than
toluene an alternative reaction pathway giving the enolpho-
sphates 20 (see Scheme 8) becomes significant (see Table 1).
Subsequent reaction of the β-ketophosphonates 15 with
sodium borohydride results in reduction of the ‘keto’ group and
loss of diethyl phosphate (Scheme 10), usually resulting in the
precipitation of the required isoindolo[2,1-a]indol-6-ones 23 in
good yields (typically ca. 70%) and requiring minimal further
purification. A similar reduction/elimination reaction occurs with
the β-ketophosphonate 27 derived from N,N-(1,8-naphthaloyl)-
2-aminobenzoic acid 24, but with the β-ketophosphonate 35a
and 35c from 2-(N-maleimido)benzoic acids 31a and 31c the
reduction products showed additional cleavage of the amide
bond.
The preparation of the benzoylphosphonate 16a. To a sol-
ution of the benzoyl chloride 14a (570 mg, 2 mmol) in DCM
(15 cm3) was added dropwise triethyl phosphite (335 mg,
2 mmol). After stirring this solution for 15 min at room tempera-
ture volatile components were removed under reduced pressure
(30 °C at 15 mmHg) and the residue analysed by 31P NMR spec-
troscopy. This showed the major product to be the benzoylpho-
sphonate 16a (70%) although a quantity of the tetracyclic
phosphonate 15a (22%) and a little enolphosphate 20a (2%) and
phosphate–phosphonate 22a (6%) were also present. A pure
sample of the benzoylphosphonate 16a (150 mg, 20%), mp
126–127 °C, isolated by column chromatography on silica gel
using ethyl acetate as the eluant; δP(109.3 MHz, CDCl3) −2.3;
δH(270 MHz, CDCl3) 1.23 (6 H, t, JHH 7, Me), 4.13 (4 H, m,
POCH2), 7.36 (1 H, ddd, JHH 7.7 and 1.5, JPH 1.5, 3-H), 7.54
(1 H, td, JHH 7.7 and 1.5, 5-H), 7.67 (1 H, td, JHH 7.7 and 1.5,
4-H), 7.68–7.73 (2 H, m, 4′/7′-H), 7.80–7.85 (2 H, m, 5′/6′-H),
8.50 (1 H, dd, JHH 7.7 and 1.5, 6-H); δC(67.9 MHz, CDCl3)
16.3 (×2)(d, JPC 5, Me), 64.3 (×2)(t, JPC 7, POCH2), 123.8 (×2)
(C-4′/7′), 129.0 (C-5), 129.9 (d, JPC 6, C-2), 130.3 (d, JPC 2,
C-3), 132.0 (×2)(C-3a′/7a′), 132.4 (C-6), 133.2 (d, JPC 64, C-1),
134.3 (C-4), 134.4 (×2)(C-5′/6′), 167.1 (×2)(C-1′/3′), 200.0 (d,
JPC 179, CvO); νmax/cm−1 (ATM) 2973, 1715, 1655, 1596,
1486, 1465, 1451, 1366, 1281, 1253, 1222, 1162, 1132, 1104,
1067, 1012, 980, 963, 925, 885, 795, 724; m/z (ESI) 387.0812
(M+. C19H18NO6P requires 387.0872).
Reaction of the benzoylphosphonate 16a with further triethyl
phosphite
1. In DCM at room temperature. Triethyl phosphite
(600 mg, 3.6 mmol) was added in one portion to a solution of
the benzoylphosphonate 16a (150 mg, 0.39 mmol) in dry
dichloromethane (2 cm3) and the mixture stirred at room temp-
erature and monitored by 31P NMR to optimise formation of the
initially formed dioxaphospholane 19a. Volatile components
were then removed in vacuo (20 °C at 0.01 mmHg) to leave a
viscous yellow oil which was shown to contain >80% of the
dioxaphospholane 19a together with a little triethyl phosphate.
NMR analysis was carried out on this product since attempts to
remove the remaining triethyl phosphate in vacuo, by increasing
the temperature, caused some decomposition of the dioxaphos-
pholane. The diethyl (2,2,2-triethoxy-9-oxo-3aH,9H-2λ5-[1,3,2]
dioxaphospholo[4,5-b]isoindolo[2,1-a]indol-3a-yl)phosphonate
19a gave δP(109.3 MHz, CDCl3) −51.8 [d, JPP 51.5, P(OEt)3],
15.0 [d, JPP 51.5, P(O)(OEt)2]; δH(270 MHz, CDCl3)13 7.11
(1 H, t, JHH 7.5, 2-H), 7.37 (1 H, t, JHH 7.5, 8-H), 7.44 (1 H, t,
JHH 7.5, 3-H), 7.49–7.55 (1 H, m, 1-H), 7.57 (1 H, d, JHH 7.5,
4-H), 7.69 (1 H, d, JHH 7.5, 10-H), 7.73 (1 H, d, JHH 7.5, 7-H),
7.76–7.9 (1 H, m, 9-H); δC(67.9 MHz, CDCl3)13 81.0 (dd, JPC
187 and 5, C-12), 98.7 (t, JPC 7.5, C-11), 117.1 (C-7), 123.4
(C-9), 125.1 (CH), 126.6 (CH), 127.4 (CH), 129.4 (C-6a), 130.3
Experimental
General details10
NMR (1H, 13C, 31P, COSY and HSQC correlated) spectra were
recorded on JEOL EX-270 and Bruker AMX400, AV400 and
1
AV600 spectrometers. H NMR spectra in CDCl3 are referenced
to TMS and those in d6-DMSO to the residual CD2H signal at
δH 2.50 ppm unless otherwise indicated. 13C NMR spectra are
referenced to the solvent resonance, i.e. CDCl3 at δC 77.23 ppm
or d6-DMSO at δC 39.51 ppm unless otherwise indicated.
J values are given in Hz. ‘J’ indicates an apparent coupling con-
stant in a second order spin system or in a resonance showing
substantial line broadening, q indicates an unassigned quaternary
carbon resonance.
Details of the preparation and characterisation of the acids
13a–d, 24, 31a and 31c and the acid chlorides 14a–d, 25, 32a,
32c and 41 are provided in the ESI.†
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3. In toluene with heating (via preparation of the benzoyl-
phosphonate 16a in situ). The benzoyl chloride 14a (5.7 g,
20 mmol) was heated with toluene (25 cm3) at 80 °C until it dis-
solved and then triethyl phosphite (8.7 g, 52.4 mmol) was added
over a period of about 5 min. The mixture was then heated at
100 °C for 16 h. Volatile components were removed under
reduced pressure and the resulting oil then warmed in vacuo
(75 °C at 0.01 mmHg) to give a yellow solid that was shown to
be the phosphonate 15a in a good state of purity (see Table 1).
Slow evaporation of a solution of the solid in MeOH–DCM
95 : 5 gave crystals of the pure phosphonate 15a (6.2 g, 82%).
(CH), 130.9 (CH), 132.6 (CH), 133.8 (d, JPC 4, C-12a), 139.4
(d, JPC 7, C-4a), 143.6 (C-10a), 167.4 (C-6).
2. In DCM with heating. Triethyl phosphite (2.3 g,
13.8 mmol) was added dropwise to a stirred solution of the
benzoyl chloride 14a (1.6 g, 5.6 mmol) in dry DCM (15 cm3) at
room temperature to generate the benzoylphosphonate 16a
in situ. The solution was then heated at 40 °C for 20 h, cooled
and volatile components removed under reduced pressure (70 °C
at 0.015 mmHg) to leave a yellow oil which solidified on stand-
ing. This solid was triturated with a hexane–DCM (98 : 2)
mixture and then dried. 31P NMR analysis showed the resulting
solid to consist largely of a phosphonate component 15a (δP
12.6 ppm)(ca. 80%), a phosphate 20a (δP −4.4 ppm)(ca. 15%)
The reaction of the benzoyl chloride 14b with excess triethyl
phosphite
and a small quantity of the phosphate–phosphonate 22a (δP
=
−1.0 [d, JPP 28, P(OEt)3], 16.8 [d, JPP 28, P(O)(OEt)2]) The
major components were isolated by chromatography on silica gel
eluting with DCM–EtOAc mixtures.
1. In DCM with heating. To a solution of the benzoyl chlor-
ide 14b (1.05 g, 3.3 mmol) in dry DCM (20 cm3) was added
dropwise, over a period of 5 min, triethyl phosphite (1.3 g,
7.8 mmol). The solution was then stirred at room temperature
and monitored by 31P NMR. After initial formation of the ben-
zoylphosphonate 16b (δP = −3.0 ppm) further reaction occurred
leading after 1 h to the formation of the dioxaphospholane 19b
(δP = −51.9 [d, JPP 51.6, P(OEt)3], 14.4 [d, JPP 51.6, P(O)
(OEt)2]) (32.5%) together with some of the phosphate 20b (δP =
−4.5 ppm) (38.5%), the phosphonate 15b (δP = 12.1 ppm)
(13%) and the phosphate–phosphonate 22b (δP = −1.2 [d, JPP
28, P(OEt)3], 16.0 [d, JPP 28, P(O)(OEt)2]) (16%). The reaction
mixture was then heated under reflux for 16 h. This resulted in
loss of the signals for the dioxaphospholane 19b and the for-
mation of a mixture containing the phosphate 20b (39%), the
phosphonate 15b (45%) and the phosphonate phosphate (16%).
Volatile components were removed under reduced pressure
(75 °C at 0.01 mmHg) and samples of the two major com-
ponents isolated by chromatography on silica gel eluting with
DCM–EtOAc mixtures.
Diethyl 3-chloro-6-oxo-6H-isoindolo[2,1-a]indol-11-yl phos-
phate 20b [rf = 0.8 DCM–EtOAc (9 : 1)] was isolated as a
yellow solid, mp 105–106 °C; δP(109.3 MHz, CDCl3) −4.3;
δH(400 MHz, CDCl3) 1.27 (6 H, td, JHH 7, JPH 1, Me),
4.11–4.26 (4 H, m, POCH2), 7.04 (1 H, dd, JHH 8 and 2, 2-H),
7.24 (1 H, t, JHH 7.5, 8-H), 7.35 (1 H, d, JHH 8, 1-H), 7.44 (1 H,
t, JHH 7.5, 9-H), 7.64 (1 H, d, JHH 7.5, 7-H), 7.66 (1 H, d, JHH
7.5, 10-H), 7.75 (1 H, d, JHH 2, 4-H); δC(100.6 MHz, CDCl3)
16.3 (×2)(d, JPC 6, Me), 65.6 (×2)(d, JPC 7, POCH2), 113.8
(C-4), 120.7 (C-1), 123.1 (C-10), 124.6 (C-2), 125.5 (C-7),
126.5 (d, JPC 6, C-10b), 126.7 (d, JPC 3, C-11a), 128.8 (d, JPC 9,
C-11), 129.0 (C-8), 132.0 (C-6a), 132.8 (C-10a), 133.0 (C-3),
133.5 (C-4a), 134.2 (C-9), 162.2 (C-6); νmax/cm−1 (ATM) 3098,
2978, 1728, 1605, 1442, 1384, 1352, 1278, 1224, 1173, 780,
763, 755, 729, 658; m/z (ESI)14 405.0538 (M+. C19H17ClNO5P
requires 405.0527).
Diethyl 6-oxo-6H-isoindolo[2,1-a]indol-11-yl phosphate 20a
(100 mg, 9%) [rf = 0.6 DCM–EtOAc (9 : 1)] was isolated as
yellow needle shaped crystals, mp 142–143 °C, following its
crystallisation by the slow evaporation of a hexane–DCM solu-
tion; δP(109.3 MHz, CDCl3) −4.4; δH(400 MHz, CDCl3) 1.27
(6 H, td, JHH 7, JPH 1, Me), 4.11–4.26 (4 H, m, POCH2), 7.08
(1 H, t, JHH 7.5, 2-H), 7.21 (1 H, t, JHH 8, 3-H), 7.22 (1 H, t,
JHH 7.5, 8-H), 7.42 (1 H, t, JHH 7.5, 9-H), 7.45 (1 H, d, JHH 8,
1-H), 7.64 (1 H, d, JHH 7.5, 7-H), 7.70 (1 H, d, JHH 7.5, 10-H),
7.77 (1 H, d, JHH 8, 4-H); δC(100.6 MHz, CDCl3) 16.3 (×2)(d,
JPC 6, Me), 65.5 (×2)(d, JPC 7, POCH2), 113.6 (C-4), 119.9
(C-1), 123.1 (C-10), 124.1 (C-2), 125.4 (C-7), 126.2 (d, JPC 6,
C-10b), 127.5 (C-3), 128.4 (d, JPC 2, C-11a), 128.8 (C-8), 129.4
(d, JPC 9, C-11), 131.9 (C-6a), 133.3 (d, JPC 2, C-10a), 133.4
(C-4a), 134.0 (C-9), 162.4 (C-6); νmax/cm−1 (ATM) 2992, 1721,
1612, 1448, 1391, 1365, 1312, 1243, 1152, 1020, 975, 914, 891,
884, 819, 748, 690; m/z (ESI) 371.0866 (M+. C19H18NO5P
requires 371.0917).
Diethyl (6,11-dioxo-6H-isoindolo[2,1-a]indol-10b(11H)-yl)-
phosphonate 15a (800 mg, 72%) [rf = 0.4, DCM–EtOAc (9 : 1)]
was isolated as a yellow solid. Crystallisation of this material by
the slow evaporation of a hexane–DCM solution yielded crystals
suitable for X-ray diffraction studies, mp 159–160 °C;
δP(109.3 MHz, CDCl3) 12.6; δH(400 MHz, CDCl3) 1.06 (3 H, q,
J 7, Me), 1.07 (3 H, q, JHH 7, Me), 3.88 (1 H, ddq, JAB 10.3,
JPH 8.7, JHH 7, POCH), 4.01 (2 H, dq, JPH 8.2, JHH 7, POCH),
4.03 (1 H, m, POCH), 7.20 (1 H, td, JHH 7.5, JHH 1, 2-H), 7.49
(1 H, tdd, JHH 7.5 and 1, JPH 2, 8-H), 7.65 (2 H, td, JHH 7.5 and
1, 3/9-H), 7.69 (1 H, ddd, JHH 7.5 and 1, JPH 1.5, 1-H), 7.80
(1 H, dm, JHH 7.5, 7-H), 7.93 (1 H, dt, JHH 7.5 and 1, 4-H), 7.99
(1 H, ddt, JHH 7.5 and 1, JPH 2, 10-H); δC(67.9 MHz, CDCl3)
16.3 (×2)(d, JPC 6, Me), 65.0 (d, JPC 7, POCH2), 65.3 (d, JPC 7,
POCH2), 76.6 (d, JPC 148, C-10b), 118.2 (C-4), 124.5 (d, JPC 3,
C-10), 125.3 (C-1), 125.5 (C-7), 125.6 (C-2), 129.1 (C-11a),
130.2 (C-8), 132.1 (d, JPC 4, C-6a), 134.5 (d, JPC 3, C-9), 137.5
(C-3), 139.4 (d, JPC 5, C-10a), 152.4 (d, JPC 2, C-4a), 169.5
(d, JPC 2, C-6), 190.8 (C-11); νmax/cm−1 (ATM) 2985, 1716,
1601, 1464, 1332, 1298, 1258, 1233, 1200, 1154, 1087, 1044,
1010, 969, 800, 776, 762, 740; m/z (ESI) 371.0963
(M+. C19H18NO5P requires 371.0917).
Diethyl (3-chloro-6,11-dioxo-6H-isoindolo[2,1-a]indol-10b-
(11H)-yl)phosphonate 15b [rf = 0.45 DCM–EtOAc (9 : 1)] was
isolated as a yellow solid, mp 164–165 °C; δP(109.3 MHz,
CDCl3) 12.3; δH(400 MHz, CDCl3) 1.08 (3 H, t, JHH 7, Me),
1.09 (3 H, t, JHH 7, Me), 3.85–3.95 (1 H, m, POCH2), 3.97–4.06
(3 H, m, POCH2), 7.17 (1 H, dd, JHH 8 and 2, 2-H), 7.50 (1 H, t,
JHH 7.5, 8-H), 7.61 (1 H, d, JHH 8, 1-H) 7.67 (1 H, t, JHH 7.5,
This journal is © The Royal Society of Chemistry 2012
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9-H), 7.80 (1 H, d, JHH 7.5, 7-H), 7.93 (1 H, d, JHH 2, 4-H),
7.95 (1 H, dd, JHH 7.5, JPH 1, 10-H); δC(100.6 MHz, CDCl3)
16.3 (×2)(d, JPC 5, Me), 65.0 (d, JPC 7, POCH2), 65.3 (d, JPC 7,
POCH2), 76.8 (d, JPC 146.5, C-10b), 118.5 (C-4), 124.4 (d, JPC
3, C-10), 125.6 (C-7), 125.95 (C-2), 126.02 (C-1), 127.5
(C-11a), 130.2 (d, JPC 2, C-8), 131.6 (d, JPC 4, C-6a), 134.6
(d, JPC 3, C-9), 139.2 (d, JPC 6, C-10a), 143.9 (C-3), 152.8
(d, JPC 3, C-4a), 169.1 (d, JPC 2, C-6), 189.5 (C-11); νmax/cm−1
(ATM) 2982, 1724, 1600, 1470, 1431, 1301, 1258, 1203, 1011,
957, 906, 833, 802, 762, 684; m/z (ESI)14 406.0600 (M + H+.
C19H18ClNO5P requires 406.0606).
POCH2), 4.08–4.18 (3 H, m, POCH2), 7.30 (1 H, t, JHH 7.5, 2-
H), 7.74 (1 H, t, JHH 7.5, 3-H), 7.76 (1 H, d, JHH 7.5, 1-H), 7.92
(1 H, s, 7-H), 7.96 (1 H, d, JHH 7.5, 4-H), 8.11 (1 H, d, JPH 2,
10-H); δC(100.6 MHz, CDCl3) 16.3 (d, JPC 6, Me), 16.4 (d, JPC
6, Me), 65.3 (d, JPC 7, POCH2), 65.6 (d, JPC 7, POCH2), 75.8
(d, JPC 145.6, C-10b), 118.3 (C-4), 125.5 (C-1), 126.0 (C-2),
126.4 (d, JPC 3, C-10), 127.0 (d, JPC 2, C-7), 128.9 (C-11a),
131.7 (d, JPC 4, C-8), 135.4 (d, JPC 3, C-9), 137.8 (C-3), 138.4
(d, JPC 6, C-10a), 139.4 (C-6a), 152.0 (d, JPC 2, C-4a), 167.4
(d, JPC 6, C-6), 189.9 (C-11); νmax/cm−1 (ATM) 2985, 1721,
1601, 1464, 1389, 1289, 1258, 1200, 1162, 1097, 1044, 1009,
956, 789, 762; m/z (ESI)14 439.0184 (M+. C19H16Cl2NO5P
requires 439.0143).
2. In toluene with heating. The benzoyl chloride 14b (4.8 g,
15 mmol) was warmed at 70 °C with toluene (25 cm3) until it
had dissolved and triethyl phosphite (5 cm3, 30 mmol) was then
added and the mixture stirred and heated at 100 °C for 6 h. The
solvent was removed by evaporation and the residue warmed in
vacuo (75 °C at 0.01 mmHg) to give a solid that was shown to
be the phosphonate 15b (92%) (Table 1). Crystallisation of this
solid from MeOH–DCM 95 : 5 gave the pure phosphonate 15b
(4.0 g, 66%).
2. In toluene with heating. The benzoyl chloride 14c
(1.06 g, 3 mmol) was warmed at 100 °C with toluene (15 cm3)
until it had dissolved and triethyl phosphite (1.1 g, 6.6 mmol)
was then added dropwise over a period of about 5 min. The
mixture was stirred and heated at 100 °C for 3 h and the solvent
then removed by evaporation. The residue was then heated in
vacuo (80 °C at 0.01 mmHg) to give a viscous oil that was
shown to contain only two significant products, the phosphonate
15c (ca. 85%) and the phosphate–phosphonate 22c (ca. 14%),
there was no evidence for the formation of the phosphate 20c. A
quantity of the pure phosphonate 15c (650 mg, 50%) was
obtained by chromatography on silica gel eluting with DCM–
EtOAc mixtures.
The reaction of the benzoyl chloride 14c with excess triethyl
phosphite
1. In DCM with heating. Triethyl phosphite (1.6 g,
9.6 mmol) was added dropwise to a solution of the benzoyl
chloride 14c (1.06 g, 4.5 mmol) in dry DCM (15 cm3) and the
mixture warmed at 40 °C for 16 h. The solvent was then
removed by evaporation and the residue warmed in vacuo (75 °C
at 0.01 mmHg) to give a viscous yellow residue that was shown
to be largely the phosphonate 15c (78%) together with a little of
the phosphate 20c (11%). Some of the phosphate–phosphonate
22c (δP = −0.8 [d, JPP 28, P(OEt)3], 16.6 [d, JPP 28,
P(O)(OEt)2]) (11%) was also present. Pure samples of the phos-
phonate 15c and the phosphate 20c were isolated by chromato-
graphy on silica gel eluting with DCM–EtOAc mixtures.
The reaction of the benzoyl chloride 14d with excess triethyl
phosphite
1. In DCM with heating. Triethyl phosphite (1.1 g,
6.6 mmol) was added dropwise to a solution of the benzoyl
chloride 14d (1.25 g, 3.2 mmol) in dry DCM (15 cm3) and the
mixture heated under reflux for 24 h. Volatile components were
then removed under reduced pressure to give a yellow oil. Analy-
sis of this residue by NMR spectroscopy indicated that the major
product was the tetracyclic phosphonate 15d (δP 11.4 ppm)
(75%) although a little of the enolphosphate 20d (δP −4.4 ppm)
(8%) was also present together with some of the initially formed
benzoylphosphonate 16d (δP −2.7 ppm)(15%). Pure samples of
15d and 20d were isolated by chromatography on silica gel
eluting with DCM–EtOAc mixtures.
Diethyl 3,8,9-trichloro-6-oxo-6H-isoindolo[2,1-a]indol-11-yl-
phosphate 20d [rf = 0.75 DCM–EtOAc (19 : 1)] was isolated,
after recrystallisation from a hexane–DCM (95 : 5) mixture, as
yellow crystals, mp 191–192 °C; δP(109.3 MHz, CDCl3) −4.4;
δH(400 MHz, CDCl3) 1.39 (6 H, td, JHH 7, JPH 1, Me),
4.15–4.17 (4 H, m, POCH2), 7.20 (1 H, dd, JHH 8 and 1.5, 2-H),
7.47 (1 H, d, JHH 8, 1-H), 7.82 (1 H, s, 7-H), 7.89 (1 H, d, JHH
1.5, 4-H), 7.91 (1 H, s, 10-H); δC(100.6 MHz, CDCl3) 16.4 (×2)
(d, JPC 6, Me), 65.9 (×2)(d, JPC 7, POCH2), 114.2 (C-4), 121.1
(C-1), 124.6 (d, JPC 6, C-11), 125.1 (C-10), 125.3 (C-2), 126.8
(d, JPC 4, C-11a), 127.3 (C-8), 127.4 (C-7), 130.1 (d, JPC 9,
C-11), 132.2 (C-6a). 132.4 (C-10b), 133.6 (C-4a), 134.5 (C3),
139.0 (C-9), 160.2 (C-6); νmax/cm−1 (ATM) 2978, 1743, 1613,
1458, 1440, 1390, 1349, 1312, 1279, 1245, 1164, 1154, 1054,
1020, 995, 974, 912, 832, 771, 761, 751; m/z (ESI)14 473
(M+. C19H15Cl3NO5P requires 473).
Diethyl
8,9-dichloro-6-oxo-6H-isoindolo[2,1-a]indol-11-yl-
phosphate 20c (80 mg, 6%) [rf = 0.62 DCM–EtOAc (19 : 1)]
was isolated, after recrystallisation from a hexane–DCM mixture,
as pale yellow crystals, mp 142–143 °C; δP(109.3 MHz, CDCl3)
−4.5; δH(400 MHz, CDCl3) 1.29 (6 H, td, JHH 7, JPH 1, Me),
4.13–4.27 (4 H, m, POCH2), 7.09 (1 H, t, JHH 7.5, 2-H), 7.22
(1 H, t, JHH 7.5, 3-H), 7.40 (1 H, d, JHH 7.5, 1-H), 7.63 (1 H, s,
7-H), 7.70 (1 H, d, JHH 7.5, 4-H), 7.76 (1 H, s, 10-H);
δC(100.6 MHz, CDCl3) 16.3 (×2)(d, JPC 6, Me), 65.6 (×2)-
(d, JPC 7, POCH2), 113.5 (C-4), 120.0 (C-1), 124.0 (d, JPC 6,
C-11), 124.6 (C-2), 124.8 (C-10), 126.9 (C-7), 127.6 (d, JPC 13,
C-10b), 128.1 (C-3), 130.3 (d, JPC 9, C-11a), 131.9 (C-6a),
132.2 (d, JPC 2, C-10a), 132.6 (C-8), 133.1 (C-9), 138.4 (C-4a),
160.1 (C-6); νmax/cm−1 (ATM) 2975, 1742, 1612, 1456, 1438,
1387, 1347, 1310, 1278, 1243, 1231, 1163, 1152, 1053, 1024,
993, 972, 911, 830, 769, 759, 700; m/z (ESI)14 439.0133
(M+. C19H16Cl2NO5P requires 439.0143).
Diethyl
(8,9-dichloro-6,11-dioxo-6H-isoindolo[2,1-a]indol-
10b(11H)-yl)phosphonate 15c (650 mg, 50%) [rf = 0.43 DCM–
EtOAc (9 : 1)] was isolated as a yellow solid, mp 122–123 °C;
δP(109.3 MHz, CDCl3) 11.8; δH(400 MHz, CDCl3) 1.17 (3 H, t,
JHH 7, Me), 1.19 (3 H, t, JHH 7, Me), 3.95–4.08 (1 H, m,
4274 | Org. Biomol. Chem., 2012, 10, 4266–4279
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Diethyl (3,8,9-trichloro-6,11-dioxo-6H-isoindolo[2,1-a]indol-
10b(11H)-yl)phosphonate 15d [rf = 0.45 DCM–EtOAc (19 : 1)]
was isolated, after recrystallisation from hexane–DCM, as a
yellow solid, mp 134–135 °C; δP(109.3 MHz, CDCl3) 11.5;
δH(400 MHz, CDCl3) 1.13 (3 H, t, JHH 7, Me), 1.15 (3 H, t, JHH
7, Me), 3.96–4.17 (4 H, m, POCH2), 7.20 (1 H, dd, JHH 8 and
1.5, 2-H), 7.61 (1 H, d, JHH 8, 4-H), 7.86 (1 H, s, 7-H), 7.90
(1 H, d, JHH 1.5, 1-H), 8.02 (1 H, d, JPH 2, 10-H);
δC(100.6 MHz, CDCl3) 16.2 (d, JPC 6, Me), 16.2 (d, JPC 6, Me),
65.3 (d, JPC 7, POCH2), 65.6 (d, JPC 7, POCH2), 76.1 (d, JPC
144.5, C-10b), 118.6 (C-11), 126.3 (C-1), 126.4 (d, JPC 3,
C-10), 126.6 (C-2), 127.1 (d, JPC 2, C-7), 127.2 (C-11a), 131.3
(d, JPC 4, C-8), 135.2 (d, JPC 4, C-6a), 138.3 (d, JPC 6, C-10a),
139.7 (d, JPC 4, C-9), 144.4 (C-3), 152.5 (d, JPC 1, C-4a), 167.1
(C-6), 188.6 (C-11); νmax/cm−1 (ATM) 3106, 2989, 1718, 1596,
1427, 1388, 1281, 1200, 1171, 1142, 1065, 1009, 983, 922, 832,
799, 768, 738; m/z (ESI)14 472.9742 (M+. C19H15ClNO5P
requires 472.9753).
If necessary, the remaining ketophosphate 26 can be recovered
from the filtrate and purified by chromatography on silica gel
using DCM–EtOAc mixtures as the eluant (rf = 0.5, DCM–
EtOAc 1 : 1).
Reaction of the benzoylphosphonate 26 with further triethyl
phosphite
1. In toluene. The benzoylphosphonate 26 (1.4 g,
3.2 mmol) was heated (ca. 100 °C) with toluene (10 cm3) until it
dissolved and triethyl phosphite (1.1 cm3, 6.5 mmol) was then
added and the mixture heated at 115 °C for 17 h. 31P NMR of
the resulting mixture showed that, in addition to triethyl phos-
phate, the major product was the phosphonate 27 (83%). A little
of the phosphate 28 (7%) and a small quantity of the phosphate–
phosphonate 30 (10%) (δP = −0.5 [d, JPP 21, P(OEt)3],
16.9 [d, JPP 21, P(O)(OEt)2]) were also present. Samples of the
phosphonate 27 and the phosphate 28 were isolated by chrom-
atography on silica gel eluting with DCM–EtOAc mixtures.
2. In toluene with heating. The benzoyl chloride 14d
(1.24 g, 3.2 mmol) was warmed at 100 °C with toluene (15 cm3)
until it had dissolved and triethyl phosphite (1.08 g, 6.5 mmol)
was then added dropwise over a period of about 2 min and the
mixture then stirred and heated at 100 °C. After 3 h NMR indi-
cated the formation of only one major product in addition to
triethyl phosphate, the phosphonate 15d (93%). Small quantities
of the phosphate–phosphonate 22d (6%) and the phosphate 20d
(∼1%) were also present. Volatile components were removed in
vacuo (80 °C at 0.01 mmHg) and the pure phosphonate 15d iso-
lated by chromatography on silica gel eluting with DCM–EtOAc
mixtures.
Diethyl
7-oxo-7H-benzo[de]indolo[2,1-a]isoquinolin-13-yl
phosphate 28 (60 mg, 5%) [rf = 0.9 DCM–EtOAc (9 : 1)] was
isolated, after recrystallisation from hexane–DCM, as yellow
crystals suitable for X-ray diffraction studies, mp 100–101 °C;
δP(109.3 MHz, CDCl3) −4.2; δH(400 MHz, CDCl3) 1.18 (6 H,
td, JHH 7, JPH 1, Me), 4.06–4.18 (4 H, m, POCH2), 7.20 (1 H,
td, JHH 7.5 and 1, 11-H), 7.25 (1 H, td, JHH 7.5 and 1, 10-H),
7.33 (1 H, t, JHH 8, 2-H), 7.35 (1 H, t, J 8, 5-H), 7.49 (1 H, d,
JHH 8, 3-H), 7.72 (2 H, br d, JHH 7.5, 4/12-H), 8.22 (1 H, d, JHH
8, 1-H), 8.29 (1 H, d, JHH 8, 5-H), 8.57 (1 H, d, JHH 7.5, 9-H);
δC(100.6 MHz, CDCl3) 16.2 (×2)(d, JPC 6, Me), 65.2 (×2)(d,
JPC 6, POCH2), 116.9 (C-9), 118.8 (C-12), 121.0 (d, JPC 2,
C-13b), 122.2 (d, JPC 8, C13), 123.7 (q), 123.7 (d, JPC 2,
C-12a), 124.4 (C-11), 124.5 (C-1), 126.0 (q), 126.1 (C-10),
126.4 (C-5), 126.8 (C-2), 127.8 (C-3), 129.2 (C-6), 131.2 (d, JPC
2, C-13a), 132.0 (q), 132.5 (C-8a), 133.8 (C-4), 160.5 (C-7);
νmax/cm−1 (ATM) 3055, 2963, 1688, 1598, 1508, 1451, 1363,
1319, 1263, 1229, 1216, 1193, 1093, 1008, 984, 953, 917, 797,
771, 740, 705, 686; m/z (ESI) 422.1146 (M + H+. C23H21NO5P
requires 422.1152).
The reaction of 25 with triethyl phosphite in toluene.
The preparation of the benzoylphosphonate 26. Triethyl phos-
phite (600 mg, 3.6 mmol) was added dropwise with stirring to a
solution of the freshly prepared benzoyl chloride 25 (1.0 g,
3.3 mmol) dissolved in dry toluene (25 cm3) warmed at 70 °C.
The resulting yellow solution was stirred at this temperature for
30 min and volatile components were then removed in vacuo to
leave an essentially quantitative recovery of the phosphonate 26
as a yellow solid. Recrystallisation of this material from a
hexane–DCM mixture gave diethyl {2-(1,3-dioxo-1H-benzo[de]-
Diethyl (7,13-dioxo-13,13a-dihydro-7H-benzo[de]indolo[2,1-a]-
isoquinolin-13a-yl)phosphonate 27 (950 mg, 75%) [rf = 0.55
DCM–EtOAc (9 : 1)] was isolated, after recrystallisation from
isoquinolin-2(3H)-yl}benzoylphosphonate 26 as
a
yellow
hexane–DCM, as a yellow powder, mp 175–176 °C;
powder (1.1 g, 76%); mp 150–151 °C; δP(109.3 MHz, CDCl3)
−1.9; δH(270 MHz, CDCl3) 1.28 (6 H, t, JHH 7, Me), 4.11 (2 H,
qd, JHH 7, JPH 3, POCH2), 4.14 (2 H, qd, JHH 7, JPH 3, POCH2),
7.39 (1 H, d, JHH 7.5, 3-H), 7.65 (1 H, t, JHH 7.5, 5-H), 7.74 (2
H, t, JHH 8, 5′/8′-H), 7.79 (1 H, t, JHH 7.5, 4-H), 8.21 (2 H, d,
JHH 8, 6′/7′-H), 8.54 (2 H, d, JHH 8, 4′/9′-H), 8.76 (1 H, d, JHH
7.5, 6-H); δC(100.6 MHz, CDCl3) 16.4(×2)(d, JPC 5, Me), 64.3
(×2)(d, JPC 7, POCH2), 123.0 (×2)(C-3a′/9a′), 127.0 (×2)(C-5′/
8′), 128.9 (C-9b′), 129.3 (C-5), 131.2 (d, JPC 3, C-3), 131.6 (×2)
(C-4′/9′), 132.0 (C-6a′), 133.0 (d, JPC 65, C-1), 133.6 (C-6),
134.5 (×2)(C-6′/7′), 134.7 (d, JPC 7.5, C-2), 134.9 (C-4), 164.5
(×2)(C-1′/3′), 199.4 (d, JPC 176.5, PCvO); νmax/cm−1 (ATM)
2989, 1703, 1661, 1588, 1375, 1357, 1262, 1240, 1198, 1046,
1016, 984, 930, 903, 777, 691; m/z (ESI) 438.1101 (M + H+.
C23H21NO6P requires 438.1107).
δP(109.3 MHz, CDCl3) 13.0; δH(400 MHz, CDCl3) 0.67 (3 H, t,
JHH 7, Me), 0.84 (3 H, t, JHH 7, Me), 3.26–3.32 (1 H, m,
POCH2), 3.61–3.73 (3 H, m, POCH2), 7.19 (1 H, t, JHH 8, 11-
H), 7.49 (1 H, t, JHH 8, 2-H), 7.51 (1 H, t, JHH 8, 5-H), 7.64 (1
H, t, J 8, 10-H), 7.73 (1 H, dd, JHH 8, JPH 2.5, 1-H), 7.78 (1 H,
d, JHH 8, 12-H), 7.86 (1 H, d, JHH 8, 4-H), 8.37 (1 H. d, JHH 8,
6-H), 8.57–8.59 (1 H, m, 3-H), 8.61 (1 H, d, JHH 8, 9-H);
δC(100.6 MHz, CDCl3) 15.87 (d, JPC 6, Me), 15.99 (d, JPC 6,
Me), 64.91 (d, JPC 7.5, POCH2), 65.04 (d, JPC 7.5, POCH2),
72.2 (d, JPC 135.5, C-13a), 117.9 (C-9), 122.8 (d, JPC 7.5,
C-13b), 124.23 (C-12a), 124.26 (C-12), 124.5 (d, JPC 5, C-2),
127.8 (d, JPC 2, C-6), 128.3 (d, JPC 4.5, C-1), 129.3 (d, JPC 4,
C-13c), 132.4 (d, JPC 3, C-3a), 133.0 (d, JPC 1, C-4), 137.5
(C-10), 152.3 (d, JPC 1.5, C-8a), 161.5 (C-7), 191.6 (d, JPC 2,
C-13); νmax/cm−1 (ATM) 2982, 1706, 1672, 1601, 1460, 1363,
This journal is © The Royal Society of Chemistry 2012
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1337, 1298, 1251, 1161, 1122, 1042, 1014, 965, 832, 780, 769;
7.16 (1 H, t, J 8, 7-H), 7.39 (1 H, t, J 8, 6-H), 7.50 (1 H, d, J 8,
8-H), 7.75 (1 H, d, J 8, 5-H); δC(100.6 MHz, d6-DMSO) 112.1
(C-5), 114.7 (C-9), 118.2 (C-9a), 122.2 (C-7), 123.6 (C-8),
126.6 (C-2), 130.1 (C-6), 132.3 (C-4a), 133.9 (C-8a), 144.1
(C-1), 156.2 (C-3); νmax/cm−1 (ATM) 3386, 1710, 1672, 1636,
1521, 1463, 1430, 1346, 1297, 1204, 1107, 1014, 895, 845, 737,
674, 654.
The acetate 38c was formed by heating the hydroxy com-
pound 37c (35 mg, 0.14 mmol) with acetic anhydride (2 cm3) at
100 °C for 16 h followed by removal of the volatile components
in vacuo. Slow evaporation of a DCM–hexane solution of the
residue gave 1,2-dichloro-3-oxo-3H-pyrrolo[1,2-a]indol-9-yl
acetate 38c (35 mg, 86%) as a brown solid, mp 163–164 °C;
δH(400 MHz, CDCl3) 2.43 (3 H, s, CH3), 7.16 (1 H, t, J 8, 7-H),
7.30 (1 H, t, J 8, 8-H), 7.37 (1 H, t, J 8, 6-H), 7.68 (1 H, t, J 8,
5-H); δC(100.6 MHz, CDCl3) 20.6 (Me), 113.3 (C-5), 120.9
(C-8), 124.3 (C-8a), 124.4 (C-7), 125.3 (C-9a), 127.0 (C-2),
129.6 (C-6), 132.9 (C-4a), 133.4 (C-1), 133.8 (C-9), 157.3
(C-3), 167.4 (CvO); νmax/cm−1 (ATM) 1765, 1744, 1633, 1609,
1550, 1450, 1394, 1367, 1339, 1315, 1256, 1205, 1148, 1124,
1032, 1007, 893, 779, 760, 744, 728; m/z (ESI)14 295.9875
(M + H+. C13H8Cl2NO3 requires 295.9881).
m/z (ESI) 422.1148 (M + H+. C23H21NO5P requires 422.1152).
2. In DCM after preparation of the aroylphosphonate 26
in situ. The benzoyl chloride 25 (1.1 g, 3.6 mmol) was dis-
solved in dry DCM (20 cm3) and the solution cooled to 5 °C.
Triethyl phosphite (1.5 g, 9 mmol) was then added dropwise
keeping the reaction mixture below 5 °C. The mixture was then
stirred at 5 °C for 1 h and then at room temperature for 16 h. 31
P
NMR showed the major products to be the benzoylphosphonate
26 (30%), the pentacyclic phosphonate 27 (23%), the phosphate
28 (21%) and some phosphate–phosphonate 30 (21%).
The reaction of the benzoyl chloride 32c with triethyl phosphite
1. With excess trimethyl phosphite in DCM with initial
cooling. Triethyl phosphite (2.9 cm3, 17 mmol) was added drop-
wise to a solution of the freshly prepared benzoyl chloride 32c
(1.28 g, 4.2 mmol) in dry DCM (25 cm3) cooled in an ice bath
at such a rate that the temperature did not exceed 5 °C. Stirring
was continued at 0–5 °C for 1 h and the cooling bath was then
removed and the reaction continued at room temperature whilst
being monitored by 31P NMR. After 1 h the major product was
the dioxaphospholane 34c, δP(109.3 MHz, CDCl3) −51.5 [d, JPP
55, P(OEt)3], 13.7 [d, JPP 55, P(O)(OEt)2], but after 16 h this
had decomposed to give the phosphonate 35c together with
other components apparently arising from further reactions invol-
ving the chlorinated ring. Excess solvent was removed under
reduced pressure (50 °C at 15 mmHg) and the remaining volatile
components evaporated in vacuo (70 °C at 0.01 mmHg) to leave
a viscous oil which was subjected to column chromatography on
silica gel eluting initially with a DCM–EtOAc 1 : 1 mixture fol-
lowed by EtOAc and finally an EtOAc–MeOH mixture. This
enabled a quantity of the phosphonate 35c and a small sample of
the indolone 37c to be isolated.
The diethyl 1,2-dichloro-3,9-dioxo-9,9a-dihydro-3H-pyrrolo-
[1,2-a]indol-9a-ylphosphonate 35c (rf = 0.85 EtOAc–DCM
1 : 1) initially isolated was crystallised by the slow evaporation
of a solution in a DCM–hexane (5 : 95) mixture. This gave crys-
tals of the phosphonate 35c (360 mg, 22%) suitable for X-ray
diffraction studies, mp 116–117 °C, δP(109.3 MHz, CDCl3) 9.0;
δH(270 MHz, CDCl3) 1.16 (3 H, t, JHH 7, Me), 1.22 (3 H, t, JHH
7, Me), 4.06–4.22 (4 H, m, POCH2), 7.27 (1 H, t, JHH 8, 7-H),
7.71 (1 H, t, JHH 8, 6-H), 7.72 (1 H, d, JHH 8, 5-H), 7.81 (1 H,
d, JHH 8, 8-H); δC(67.9 MHz, CDCl3) 16.32 (d, JPC 6, Me),
16.41 (d, JPC 6, Me), 65.8 (d, JPC, POCH2), 66.0 (d, JPC 7,
POCH2), 76.9 (d, JPC 147.5, C-9a), 118.6 (C-5), 125.7 (C-7),
126.5 (C-8), 127.5 (d, JPC 8.5, C-2), 129.0 (C-8a), 138.1 (C-6),
144.4 (d, JPC 8, C-1), 151.5 (C-4a), 165.4 (C-3), 186.1 (C-9);
νmax/cm−1 (ATM) 2998, 1740, 1722, 1601, 1470, 1392, 1293,
1261, 1236, 1155, 1132, 1099, 1043, 1002, 959, 811, 798, 787,
777, 764; m/z (ESI)14 390.0064 (M+. C15H15Cl2O5P requires
390.0065).
2. In DCM with heating under reflux. Triethyl phosphite
(1.7 cm3, 10.1 mmol) was added dropwise to a freshly prepared
solution of 2-(3,4-dichloro-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-
yl)benzoyl chloride 32c (1.58 g, 5.2 mmol) in dry DCM
(20 cm3) and the mixture heated under reflux for 16 h. 31P NMR
spectroscopy indicated the formation of only one main product
[δP ca. 8.6 ppm] together with an equimolar quantity of triethyl
phosphate. Volatile components, including the triethyl phos-
phate, were then removed under reduced pressure (initially at
30 °C at 15 mmHg and then at 75 °C at 0.01 mmHg) to give
diethyl (1,2-dichloro-3,9-dioxo-9,9a-dihydro-3H-pyrrolo[1,2-a]-
indol-9a-yl)phosphonate 35c as a yellow solid (>95% purity)
[δP(CDCl3) 8.9 ppm]. This product was sufficiently pure to be
used without further purification. An analytically pure sample of
this material was obtained by chromatography on silica gel
eluting with DCM–EtOAc mixtures and characterised by com-
parison with the authentic sample of 35c isolated earlier.
3. In toluene with heating. With the exclusion of moisture,
triethyl phosphite (0.75 cm3, 4.5 mmol) was added dropwise
over 2 min to a solution of the freshly prepared benzoyl chloride
32c (0.55 g, 1.8 mmol) in dry toluene (5 cm3) at 70 °C. The
temperature of the reaction mixture was then increased to 100 °C
for 30 min. Volatile components were then removed in vacuo
(100 °C at 0.01 mmHg) to leave a brown viscous residue
which was shown by NMR to contain about 50% of the 1,3,2-
dioxaphospholane, diethyl (4,5-dichloro-2,2,2-triethoxy-6-oxo-
6H,11bH-2λ5-[1,3,2]dioxaphospholo[4,5-b]pyrrolo[1,2-a]indol-
11b-yl)phosphonate, 34c, δP(109.3 MHz, CDCl3) −51.5 [d, JPP
55, P(OEt)3], 13.7 [d, JPP 55, P(O)(OEt)2]; δC(67.9 MHz,
CDCl3)13 80.4 (dd, JPC 186 and 6, O–C–P), 97.6 (dd, JPC 10
and 5, O–C–N), 116.6 (C–H), 125.2 (C–H), 127.1 (C–H), 130.6
(C–H), 145.7 (vC–Cl), 153.7 (C–N), 162.3 (CvO). Heating
a solution of the residue in acetonitrile (20 cm3) under reflux
for 90 min converted the dioxaphospholane 34c into the
1,2-Dichloro-9-hydroxy-3H-pyrrolo[1,2-a]indol-3-one
37c
(rf = 0.2, EtOAc) was eluted with ethyl acetate and isolated as a
red solid. Slow evaporation of an acetonitrile solution of this
material gave crystals of pure 1,2-dichloro-9-hydroxy-3H-
pyrrolo[1,2-a]indol-3-one (90 mg, 9%) suitable for X-ray diffrac-
tion studies, mp 215–216 °C (dec.); δH(270 MHz, d6-DMSO)
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β-ketophosphonate 35c which was isolated using the procedure
described above.
7, POCH2), 81.2 (d, JPC 146.5, C-9a), 118.5 (C-5), 125.6 (C-8),
125.8 (C-7), 129.4 (C-8a), 129.9 (d, JPC 8.5, C-2), 137.8 (C-6),
146.0 (d, JPC 6.5, C-1), 152.0 (d, JPC 2, C-4a), 172.2 (C-3),
189.3 (C-9); νmax/cm−1 (ATM) 2986, 1714, 1601, 1464, 1297,
1259, 1204, 1161, 1041, 1011, 962, 896, 818, 772, 694; m/z
(ESI) 321.0798 (M+. C15H16NO5P requires 321.0766).
The reaction of a mixture of the benzoyl chlorides 32a and 41
with excess triethyl phosphite in DCM
Diethyl
(diethoxyphosphoryloxy)[2-(2,5-dioxo-2,5-dihydro-
A
quantity of the acid chloride mixture containing 41
1H-pyrrol-1-yl)phenyl]methylphosphonate 46 was isolated as a
viscous brown oil (rf 0.45 EtOAc–MeOH 19 : 1); δP(162.0 MHz,
CDCl3) 16.1 (d, JPP 28.5 –P(O)OEt2), −1.4 (d, JPP 28.5, –OP(O)
OEt2); δH(400 MHz, CDCl3) 1.09 (3 H, td, JHH 7, JPH 1, Me),
1.19 (3 H, t, JHH 7, Me), 1.21 (3 H, t, JHH 7, Me), 1.26 (3 H, td,
JHH 7, JPH 1, Me), 3.77–4.14 (8 H, m, POCH2), 5.58 (1 H, dd,
JPH 13.7 and 11.0, α-CH), 6.84 (1 H, JAB 6, 3′-H), 6.85 (1 H,
JAB 6, 4′-H), 7.12 (1 H, ddd, JHH 7.5 and 1.5, JPH 1.5, 3-H),
7.46 (1 H, tdd, JHH 7.5 and 2, JPH 2, 4-H), 7.48 (1 H, td, JHH 7.5
and 1.5, 5-H), 7.94 (1 H, ddd, JHH 7.5 and 2, JPH 2, 6-H);
δC(100.6 MHz, CDCl3) 15.8 (d, JPC 7, Me), 16.0 (d, JPC 7, Me),
16.35 (d, JPC 5, Me), 16.40 (d, JPC 5, Me), 63.7 (d, JPC 7,
POCH2), 63.8 (d, JPC 7, POCH2), 64.2 (d, JPC 7, POCH2), 64.3
(d, JPC 7, POCH2), 70.2 (dd, JPC 173.5 and 7, α-CH), 129.5 (d,
JPC 2.4, C-3), 129.6 (d, JPC 1, C-5), 129.9–130.1 (m, C-1/4/6),
133.0 (d, JPC 2, C-2), 134.64 (C-3′), 134.67 (C-4′), 169.2 (C-2′),
169.8 (C-5′); νmax/cm−1 (ATM) 2986, 1715, 1495, 1454, 1390,
1255, 1147, 1013, 952, 861, 827; m/z (ESI) 476.1235 (M + H+.
C19H28NO9P2 requires 476.1239).
(1.9 mmol) and 32a (0.6 mmol), prepared as previously
described, was dissolved in dry DCM (15 cm3) and triethyl
phosphite (830 mg, 5 mmol) was added. The mixture was then
heated at 40 °C for 2 h and then analysed by NMR spectroscopy.
This showed the formation of two major components, the 1,3,2-
dioxaphospholanes 43, δP(CDCl3) −53.4 [d, JPP 49, P(OEt)3],
15.2 [d, JPP 49, P(O)(OEt)2], and 34a, δP(CDCl3) −51.8 [d, JPP
47, P(OEt)3], 14.7 [d, JPP 47, P(O)(OEt)2], in the ratio of 6 : 4.
Some decomposition of these dioxaphospholanes to give triethyl
phosphate and the β-ketophosphonates 44 [δP(CDCl3) 12.9] and
35a [δP(CDCl3) 11.7] (in the ratio 4 : 1) was also observed. A
little of the phosphate–phosphonate components later identified
as 46 and 47 were also present in the product mixture.
After heating this mixture under reflux for 2 h in MeCN the
dioxaphospholanes had decomposed to the corresponding
β-ketophosphonates 44 and 35a. Samples of these two β-keto-
phosphonates (combined yield 77%) together with a small
sample of the phosphate–phosphonate 46, some of which
was derived from 47, were isolated by chromatography on
silica gel eluting with DCM–EtOAc–MeOH mixtures. A very
small impure sample of the phosphate–phosphonate 47
[δP(162.0 MHz, CDCl3) 16.2 (s, –P(O)OEt2), −4.0 (s, –OP(O)-
OEt2); δH(270 MHz, CDCl3) 4.09 (1 H, dd, JHH 8.4 and 4.2,
1-H), 5.31 (1 H, dd, JPH 11.73 and 7.8, α-CH)] was also
obtained.
Diethyl (3,9-dioxo-9,9a-dihydro-3H-pyrrolo[1,2-a]indol-9a-
yl)phosphonate 35a from diethyl (1-chloro-3,9-dioxo-2,3,9,9a-
tetrahydro-1H-pyrrolo[1,2-a]indol-9a-yl)phosphonate 44
Triethylamine (0.2 cm3, 2.0 mmol) was added dropwise to a sol-
ution of the phosphonate 44 (100 mg, 0.28 mmol) in DCM
(15 cm3) and the mixture stirred at room temperature for 1 h.
The resulting solution was then washed with water (15 cm3),
dried (MgSO4), filtered and the solvent evaporated under
reduced pressure (20 °C at 0.01 mmHg) to give the elimination
product 35a in a good state of purity. This product was purified
by column chromatography on silica gel eluting with a DCM–
EtOAc 9 : 1 mixture to give the pure diethyl (3,9-dioxo-9,9a-
dihydro-3H-pyrrolo[1,2-a]indol-9a-yl)phosphonate 35a (71 mg,
78%) as a yellow solid. It was characterised by comparison with
the authentic sample isolated above.
Diethyl (1-chloro-3,9-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]-
indol-9a(9H)-yl)phosphonate 44 (429 mg, 1.19 mmol) [rf =
0.15, (DCM–EtOAc 19 : 1)] was isolated as a pale yellow waxy
solid, δP(109.3 MHz, CDCl3) 13.2; δH(400 MHz, CDCl3) 1.09
(3 H, t, JHH 7, Me), 1.38(3 H, t, JHH 7, Me), 2.86 (1 H, d, JHH
17.5, 2-H), 3.98 (1 H, dd, JHH 17.5 and 5, 2-H), 4.01–4.29 (4 H,
m, POCH2), 5.05 (1 H, dd, JPH 7 and JHH 5, 1-H), 7.30 (1 H, t,
JHH 7.5, 7-H), 7.71 (1 H, t, JHH 7.5, 6-H), 7.76 (1 H, d, JHH 7.5,
8-H), 7.96 (1 H, d, JHH 7.5, 5-H); δC(100.6 MHz, CDCl3) 16.3
(d, JPC 5, Me), 16.6 (d, JPC 5, Me), 47.1 (C-2), 54.5 (d, JPC
10.5, C-1), 65.1 (d, JPC 7, POCH2), 65.6 (d, JPC 7, POCH2),
78.2 (d, JPC 146, C-9a), 117.0 (C-5), 125.3 (C-8), 125.7 (C-7),
126.3 (C-8a), 137.3 (C-6), 151.6 (d, JPC 2, C-4a), 171.0 (C-3),
191.0 (C-9); νmax/cm−1 (ATM) 2988, 1742, 1721, 1602, 1463,
1339, 1249, 1209, 1161, 1082, 1044, 1011, 983, 776, 757, 695;
m/z (ESI)14 357.0531 (M+. C15H17ClNO5P requires 357.0533).
Reduction of the β-ketophosphonates 15a–d, 27, 35a and 35c
with sodium borohydride
Reduction of the β-ketophosphonate 15a. Sodium borohy-
dride (250 mg, 7 mmol) was added in small portions to a stirred
solution of the β-ketophosphonate 15a (2.5 g, 6.75 mmol) in dry
methanol (50 cm3) and the mixture stirred at room temperature
for 2 h. The precipitated solid was filtered off, washed with pet-
roleum ether (bp 40–60 °C), and then dried to give the indolone
23a (860 mg, 58%). A further crop of this product (160 mg,
11%) was isolated from the filtrate by chromatography on silica
gel (rf = 0.9, DCM) using DCM–EtOAc mixtures as the eluent.
6H-Isoindolo[2,1-a]indol-6-one 23a (1.02 g, 69%) was isolated
as a yellow solid, mp 153–154 °C (lit.,15 153–154 °C);
Diethyl
3,9-dioxo-9,9a-dihydro-3H-pyrrolo[1,2-a]indol-9a-
ylphosphonate 35a (240 mg, 0.74 mmol) [rf = 0.20, (DCM–
EtOAc 9 : 1)] was isolated as a pale yellow waxy solid,
δP(109.3 MHz, CDCl3) 11.9; δH(270 MHz, CDCl3) 1.22 (3 H, t,
JHH 7, Me), 1.25 (3 H, t, JHH 7, Me), 4.09–4.25 (4 H, m,
POCH2), 6.27 (1 H, dd, JHH 5.5, JPH 4.5, 1-H), 7.27 (1 H, td,
JHH 7.5 and 1, 7-H), 7.46 (1 H, dd, JHH 5.5, JPH 3, 2-H), 7.71
(1 H, td, JHH 7.5 and 1, 6-H), 7.73 (1 H, d, JHH 7.5, 8-H), 7.83
(1 H, d, JHH 7.5, 5-H); δC(67.9 MHz, CDCl3) 16.5 (d, JPC 5,
Me), 16.5 (d, JPC 5, Me), 65.27 (d, JPC 7, POCH2), 65.35 (d, JPC
This journal is © The Royal Society of Chemistry 2012
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δH(270 MHz, CDCl3)15 6.52 (1 H, d, J 1.3, 11-H), 7.11 (1 H, td,
J 8 and 1, 2-H), 7.28–7.31 (2 H, m, 8-H, 3-H), 7.42 (1 H, d, J 8,
1-H), 7.46–7.50 (2 H, m, 9-H, 10-H), 7.69 (1 H, d, J 8, 7-H),
7.84 (1 H, dd, J 8 and 1, 4-H); δC(67.9 MHz, CDCl3)15 103.7
(C-11), 113.5 (C-4), 121.4 (C-10), 122.5 (C-1), 124.1 (C-2),
125.4 (C-7), 126.5 (C-3), 129.0 (C-8), 133.8 (C-4a), 133.9
(C-9), 134.0 (C-6a), 134.7 (C-11a), 134.9 (C-10b), 139.0 (10a),
162.8 (C-6); νmax/cm−1 (ATM) 1720, 1609, 1442, 1375, 1299,
1140, 913, 817, 802, 738, 689.
1359, 1339, 1317, 1269, 1225, 1182, 1110, 1086, 1052, 972,
927, 895, 834, 805, 780, 772, 737, 699; m/z (ESI)14 321.9585
(M + H+. C15H7Cl3NO requires 321.9588).
Reduction of the β-ketophosphonate 27. Sodium borohydride
(40 mg, 1.05 mmol) was added in small portions to a stirred sol-
ution of the β-ketophosphonate 27 (250 mg, 0.59 mmol) in dry
methanol (15 cm3). The mixture was then stirred at room temp-
erature for 16 h during which time an orange precipitate formed.
This precipitate was then filtered off and recrystallised from
chloroform to give the pure 7H-benzo[de]indolo[2,1-a]isoquino-
lin-7-one 29 as an orange solid (202 mg, 75%), mp 223–224 °C;
δH(400 MHz, CDCl3) 7.23 (1 H, s, 13-H), 7.35 (1 H, td, JHH 7.5
and 1, 11-H), 7.42 (1 H, td, JHH 7.5 and 1, 10-H), 7.61 (1 H, d,
JHH 8, 2-H), 7.65 (1 H, d, JHH 7.5, 12-H), 7.71 (1 H, t, JHH 7.5,
5-H), 7.88 (1 H, d, JHH 8, 3-H), 8.11 (1 H, d, JHH 7.5, 4-H),
8.13 (1 H, d, JHH 7.5, 1-H), 8.67 (1 H, dd, JHH 7.5 and 1, 6-H),
8.77 (1 H, d, JHH 7.5, 9-H); δC(100.6 MHz, CDCl3) 103.9
(C-13), 117.2 (C-9), 121.0 (C-12), 123.0 (C-1), 123.2 (q), 124.7
(C-11), 124.8 (q), 125.4 (C-10), 126.7 (q), 126.9 (C-5), 127.1
(C-2), 128.4 (C-3), 130.0 (C-6), 130.4 (q), 132.7 (q), 134.1
(C-4), 135.7 (q), 136.1 (q), 161.3 (C-7); νmax/cm−1 (ATM) 3098,
1690, 1569, 1506, 1453, 1382, 1358, 1323, 1237, 1215, 1186,
1156, 1105, 931, 903, 880, 859, 827, 774, 744, 670; m/z (ESI)
270.0910 (M + H+. C19H12NO requires 270.0913).
Reduction of the β-ketophosphonate 15b. Sodium borohy-
dride (35 mg, 0.92 mmol) was added to a stirred solution of the
β-ketophosphonate 15b (300 mg, 0.74 mmol) in MeOH
(15 cm3). After 5 min a yellow solid precipitated and the mixture
stirred for a further 2 h. The yellow solid was filtered off and
crystallised by the slow evaporation of a chloroform solution to
give the 3-chloro-6H-isoindolo[2,1-a]indol-6-one 23b as yellow
crystals (105 mg, 56%), mp 208–209 °C; δH(400 MHz, CDCl3)
6.50 (1 H, s, 11-H), 7.14 (1 H, dd, J 8 and 2, 3-H), 7.36 (1 H, d,
J 8, 4-H), 7.36–7.42 (1 H, m, 8-H), 7.53–7.57 (2 H, m, 9/10-H),
7.77 (1 H, d, J 7.5, 7-H), 7.91 (1 H, d, J 2, 1-H); δC(100.6 MHz,
CDCl3) 103.2 (C-11), 113.9 (C-4), 121.6 (C-10), 123.1 (C-1),
124.6 (C-2), 125.7 (C-7), 129.3 (C-8), 132.5 (C-10b), 133.2
(C-11a), 133.7 (C-3), 134.1 (C-4a), 134.2 (C-9), 134.7 (C-6a),
139.5 (C-10a), 162.6 (C-6); νmax/cm−1 (ATM) 3114, 1720, 1619,
1471, 1340, 1355, 1332, 1310, 1263, 1225, 1181, 1144, 1114,
1092, 1078, 1051, 926, 893, 846, 832, 794, 758, 734, 693, 672,
645; m/z (ESI)14 254.0386 (M + H+. C15H9ClNO requires
254.0373).
Reduction of the β-ketophosphonate 35c. Sodium borohydride
(62 mg, 1.6 mmol) was added in small portions to a stirred solu-
tion of the β-ketophosphonate 35c (160 mg, 0.41 mmol) in dry
methanol (3 cm3). The mixture was then stirred at room tempera-
ture for 1 h after which time no starting material remained. Vola-
tile components were removed under reduced pressure (50 °C at
15 mmHg) and water (20 cm3) added to the residue. This
mixture was then extracted with DCM (3 × 20 cm3) and the com-
bined extracts dried (MgSO4), filtered and volatile components
then removed under reduced pressure (35 °C at 15 mmHg). This
mixture was subjected to chromatography on silica gel eluting
with DCM followed by a DCM–EtOAc mixture (8 : 2). This
enabled a sample of (Z)-2,3-dichloro-3-(1H-indol-2-yl)prop-2-
en-ol 40 (65 mg, 65%) (rf = 0.15, DCM) to be isolated as a dark
brown solid, mp 86–88 °C; δH(400 MHz, CDCl3) 2.75 (1 H, br
s, OH), 4.56 (2 H, s, 1-H), 6.79 (1 H, s, 3′-H), 7.14 (1 H, t, J 8,
5′-H), 7.26 (1 H, t, J 8, 6′-H), 7.35 (1 H, d, J 8, 4′-H), 7.63 (1 H,
d, J 8, 7′-H), 8.92 (1 H, br s, NH); δC(100.6 MHz, CDCl3) 65.0
(C-1), 106.5 (C-3′), 111.5 (C-7′), 120.9 (C-5′), 121.5 (C-4′),
124.1 (C-6′), 126.3 (C-2′), 127.8 (C-3a′), 131.2 (C-3), 132.0
(C-2), 136.7 (C-7a); νmax/cm−1 (ATM) 3386, 1716, 1604, 1519,
1403, 1348, 1299, 1233, 1175, 1104, 1018, 971, 935, 813, 795,
745, 720, 675; m/z (ESI)14 242.0129 (M + H+. C11H10Cl2NO
requires 242.0134).
Reduction of the β-ketophosphonate 15c. Sodium borohydride
(110 mg, 3.1 mmol) was added in small portions to a stirred
solution of the β-ketophosphonate 15c (1.1 g, 2.5 mmol) in dry
methanol (10 cm3) and the mixture was stirred at room tempera-
ture for 2 h. The precipitated solid was then filtered off, washed
with petroleum ether (20 cm3, bp 40–60 °C), and dried to give
the 8,9-dichloro-6H-isoindolo[2,1-a]indol-6-one 23c (225 mg,
78%) as a yellow solid, mp >260 °C; δH(270 MHz, CCl4,
50 °C)16 6.56 (1 H, s, 11-H), 7.11 (1 H, t, JHH 8, 2-H), 7.27
(1 H, t, JHH 8, 3-H), 7.39 (1 H, t, JHH 8, 1-H), 7.57 (1 H, s,
10-H), 7.82 (1 H, s, 7-H), 7.86 (1 H, d, JHH 8, 4-H); νmax/cm−1
(ATM) 3116, 3084, 1713, 1612, 1428, 1392, 1377, 1318, 1226,
1187, 1163, 1140, 1127, 1077, 966, 896, 826, 771, 725, 664,
649; m/z (ESI)14 286.9978 (M+. C15H7Cl2NO requires
286.9905).
Reduction of the β-ketophosphonate 15d. Sodium borohy-
dride (35 mg, 1 mmol) was added in small portions to a stirred
solution of the β-ketophosphonate 15d (290 mg, 0.61 mmol) in
dry methanol (10 cm3). A brisk effervescence was observed and
the indolone 23d began to precipitate. The mixture was stirred at
room temperature for 3 h and the precipitate was then filtered off
and heated in MeCN (30 cm3). After cooling the solid was then
recovered, washed with petroleum ether (20 cm3, bp 40–60 °C)
and dried to give the pure 3,8,9-trichloro-6H-isoindolo[2,1-a]-
indol-6-one 23d as a yellow powder (229 mg, 71%); mp
>260 °C; δH(270 MHz, d6-DMSO, 60 °C16) 7.07 (1 H, s, 11-H),
7.28 (1 H, dd, J 8.5 and 1.8, 2-H), 7.66 (1 H, d, J 8.5, 1-H),
7.75 (1 H, d, J 1.8, 4-H), 8.00 (1 H, s, 10-H), 8.20 (1 H, s, 7-H);
νmax/cm−1 (ATM) 3114, 3085, 1719, 1617, 1603, 1430, 1393,
Reduction of the β-ketophosphonate 35a. Sodium borohy-
dride (11 mg, 0.29 mmol) was added to a stirred solution of the
β-ketophosphonate 35a (90 mg, 0.28 mmol) in dry methanol
(5 cm3) and the mixture stirred at room temperature for 4 h. Vola-
tile components were removed under reduced pressure (50 °C at
15 mmHg) and the residue dissolved in DCM (20 cm3). This sol-
ution was then washed with water (2 × 15 cm3), dried (MgSO4),
filtered and volatile components then removed under reduced
pressure (35 °C at 15 mmHg). NMR of the residue indicated the
4278 | Org. Biomol. Chem., 2012, 10, 4266–4279
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presence of two main compounds, the acrylate 50 and the
lactone 52. These components were isolated by chromatography
on silica gel with DCM–EtOAc–MeOH mixtures as the eluant.
Z-Methyl 3-(1H-indol-2-yl)acrylate 50 (30 mg, 54%) (rf = 0.9
DCM) was isolated as a yellow solid, δH(400 MHz, CDCl3)17
3.83 (3 H, s, OMe), 5.79 (1 H, d, J 12.5, 2-H), 6.77 (1 H, s, 3′-
H), 6.94 (1 H, d, J 12.5, 3-H), 7.10 (1 H, t, J 7.5 6′-H), 7.44
(1 H, d, J 7.5, 4′-H), 7.62 (1 H, d, J 7.5, 7′-H), 11.80 (1 H, br s,
N–H); δC(67.9 MHz, CDCl3) 52.1 (OMe), 112.1 (C-3′), 112.2
(C-7′), 112.6 (C-5′), 120.4 (C-4′), 121.7 (C-2), 125.0 (C-6′),
127.7 (C-2′), 133.9 C-3a′), 135.5 (C-3), 137.9 (C-7a′), 169.1
(C-1).
Diethyl 2-oxo-2,3,4,4a,5,9b-hexahydropyrano[3,2-b]indol-4a-
ylphosphonate 52 (10 mg, 11%) (rf = 0.4 EtOAc–MeOH 9 : 1)
was isolated as a waxy solid, δP(109.3 MHz, CDCl3) 24.3;
δH(400 MHz, CDCl3) 1.07 (3 H, t, JHH 7, Me), 1.12 (3 H, t, JHH
7, Me), 2.22–2.32 (2 H, m, 3-H, 4-H), 2.65–2.81 (1 H, m, 4-H),
3.03–2.12 (1 H, m, 3-H), 3.78–4.02 (4 H, m, POCH2), 5.05
(1 H, d, JPH 8.5, 9b-H), 7.15 (1 H, t, JHH 7.5, 8-H), 7.35 (1 H, t,
Crystallography Service, Southampton for data collection and
the EPSRC National Mass Spectrometry Service Centre
(NMSSC) at Swansea.
Notes and references
1 D. V. Griffiths, P. A. Griffiths, B. J. Whitehead and J. C. Tebby, J. Chem.
Soc., Perkin Trans. 1, 1992, 479–484.
2 Although the formation of the intermediate 2 can be represented by the
mechanistic arrows shown, they are ‘dashed’ to indicate that this is likely
to be an oversimplification of the process involved.
3 D. V. Griffiths, K. Karim and B. J. Whitehead, Zh. Obshch. Khim., 1993,
63, 2245–2251.
4 Y.-K. Cheong, P. Duncanson and D. V. Griffiths, Tetrahedron, 2008, 64,
2329–2338.
5 J. Guillaumel, S. Léonce, A. Pierré, P. Renaud, B. Pfeiffer,
P. B. Arimondo and C. Monneret, Eur. J. Med. Chem., 2006, 41, 379–
386.
6 K. Dinnell, G. G. Chicchi, M. J. Dhar, J. M. Elliot, 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.
7 M.-F. Boussard, S. Truche, A. Rousseau-Rojas, S. Briss, S. Desamps,
M. Droual, M. Wierzbicki, G. Ferry, V. Audinot, P. Delagrange and
J. A. Boutin, Eur. J. Med. Chem., 2006, 41, 306–320.
8 S. Samorson, J. B. Bremner, A. Ball and K. Lewis, Bioorg. Med. Chem.,
2006, 14, 857–865.
9 Data have been deposited with the Cambridge Crystallographic Data
Centre. For 15a as CCDC 865150, 28 as CCDC 865151, 35c as CCDC
865152, and for 37c as CCDC 865153.
10 Further relevant information is available in the ESI.†.
11 Y-K. Cheong, P. Duncanson and D. V. Griffiths, ‘The Reaction of Triva-
lent Phosphorus Compounds with Halogenated Pyrrole- and Furan-2,5-
diones’, Abstracts from XV International Conference on Chemistry of
Phosphorus Compounds, May 2008, p. 124, St. Petersburg, Russia
ISBN5-88851-065-3.
J
HH 7.5, 7-H), 7.47 (1 H, d, JHH 7.5, 9-H), 7.61 (1 H, d, JHH 7.5,
6-H); δC(100.6 MHz, CDCl3) 16.37 (d, JPC 6, Me), 16.43
(d, JPC 6, Me), 21.8 (C-4), 35.4 (C-3), 63.36 (d, JPC 7, POCH2),
63.57 (d, JPC 7, POCH2), 71.5 (d, JPC 14 C-9b), 73.0 (d, JPC
160, C-4a), 115.9 (C-6), 125.3 (C-8), 126.3 (C-9), 130.2(C-7),
135.6 (C-9a), 139.5 (C-5a), 174.7 (C-2); νmax/cm−1 (ATM)
3286, 2966, 1705, 1607, 1479, 1367, 1261, 1230, 1013, 982,
799, 657; m/z (ESI) 326.1154 (M + H+. C15H21NO5P requires
326.1157).
X-ray crystallography
Further details of the structure determination of compounds 15a,
28, 35c and 37c together with selected bond lengths and angles
are provided within the ESI.†
12 M. Bidar, G. Tokmajyan, F. Nasiri and A. Avetisyan, Arkivoc, 2011, ix,
422–428.
13 NMR resonances for the ethoxy groups in the main product were partly
obscured by other minor components present.
14 The molecular ions showed the expected isotopic ratio pattern.
15 L. A. Crawford, N. C. Clemence, H. McNab and R. G. Tyas, Org.
Biomol. Chem., 2008, 6, 2334–2339.
16 Very limited solubility in organic solvents at lower temperatures.
17 M. Eitel and U. Pindur, Synthesis, 1989, 364–367.
Acknowledgements
The authors would like to acknowledge the use of the EPSRC
Chemical Database Service at Daresbury, the EPSRC National
This journal is © The Royal Society of Chemistry 2012
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