A new focused microwave approach to the synthesis of amino-substituted pyrroloisoquinolines and pyrroloquinolines via a sequential multi-component coupling process

Article abstract of DOI:10.1055/s-2008-1067048

A multi-component reaction has been developed allowing direct access to pyrroloisoquinolines and pyrroloquinolines with new, electron-rich substitution patterns. The synthesised amino-substituted heterocyclic compounds and intermediates involved in their

Full text of DOI:10.1055/s-2008-1067048

1688
PAPER
A New Focused Microwave Approach to the Synthesis of Amino-Substituted
Pyrroloisoquinolines and Pyrroloquinolines via a Sequential Multi-Compo-
nent Coupling Process
Synthesis of
A
mino-Su
a
bstituted
P
r
yrroloiso
k
quinolines and
Pyr
D
roloquinolines . Hopkin, Ian R. Baxendale, Steven V. Ley*
Innovative Technology Centre (ACS), Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
Fax +44(1223)336442; E-mail: svl1000@cam.ac.uk
Received 25 February 2008
6
7
Abstract: A multi-component reaction has been developed allow-
ing direct access to pyrroloisoquinolines and pyrroloquinolines
with new, electron-rich substitution patterns. The synthesised ami-
no-substituted heterocyclic compounds and intermediates involved
in their formation represent novel compounds. Focused microwave
irradiation was used extensively to allow simple access to a wide
temperature range using low boiling point solvents.
5
8
N
1
R1
NHR2
NHR3
3
N
1
2
2
2
1
3
R3HN
R1
NHR2
Figure 1 Structure of pyrroloisoquinolines 1 and pyrroloquinolines
2
Key words: focused microwave irradiation, fused-ring systems,
heterocycles, multi-component reactions, pyrroloisoquinolines, sol-
id-supported reagents
Our research group has long been interested in the synthe-
sis of heterocyclic compounds utilising focused micro-
wave irradiation, both in batch and flow-mode.21 Herein,
Heterocyclic rings based on the indolizine structure have we report on a new route to pyrroloisoquinolines 1 and
received significant attention due to their extensive bio- pyrroloquinolines 2 using microwave techniques enabling
logical diversity and the richness of the target therapeutic the introduction of a more diverse and electron-rich pat-
classes they represent. Although not widely found in na- tern of functionality at the 1–3 positions.
ture, indolizines comprise an important class of pharma-
Our synthetic strategy was based upon the sequential con-
ceutical compounds that exhibit and regulate many
densation of a quinolinium or isoquinolinium salt with
different biological functions. Compounds based on these
readily available isothiocyanates and isocyanides fol-
core templates have been shown to act as powerful anti-
lowed by intramolecular rearrangement to yield the de-
mycobacterial agents,1 and inhibit a range of targets such
sired extended pyrrole structure.
as 15-lipoxygenase,2,3 secretory phospholipase A24 and
testosterone 5a-reductase,5 as well as enzymes involved
in cancers,6 and autoimmune disorders.7 In addition, they
Preparation of Isoquinolinium Salts
have also demonstrated effectiveness in the treatment of
several CNS disorders,8,9 cardiovascular complaints,10
The reaction of 2,4¢-dibromoacetophenone with isoquino-
line led to the isoquinolinium salt 3 (Scheme 1). Subse-
quent addition of triethylamine (1.1 equiv) and an
respiratory diseases11 and have shown analgesic and anti-
inflammatory activity.12 These same motifs have also
found a niche as antagonists of calcium channels13 and
isothiocyanate (1 equiv) in CH2Cl2 gave the correspond-
14
both 5-HT4 and histamine H3 receptors.15 Finally, their
ing betaine 4 (Table 1). Microwave irradiation (60 min,
application as antioxidants,16 dyes17 and spectral
100 °C) was found to accelerate the reaction but did not
sensitisers18 has also been recognised. Obviously the
increase the isolated yield. Further optimisation of these
broad utility of these indolizine compounds have made
basic reactions was not attempted at this stage. Further-
them prime synthetic candidates resulting in the develop-
more, no product arising from the secondary addition of
ment of many synthetic routes which are well reviewed in
the sulfur anion into the aromatic pyridinium ring, as has
the literature.19
been suggested in previous studies, was observed.22
Nevertheless, in spite of all this synthetic effort, routes to
structures possessing electron-rich arrangements around
the indolizine have been very few.20 This is especially true Addition of Isocyanide Components
of those with functional attachments at the 1 and 2 posi-
tions of the pyrrole-type ring system (Figure 1).
Isocyanides are well-established, versatile synthetic re-
agents used in many multi-component reactions as a result
of their unique reactivity.23 Unfortunately, they are not as
readily available as may always be desired. In this respect
we have previously shown the viability of generating
these reagents through the use of solid-supported reagents
SYNTHESIS 2008, No. 11, pp 1688–1702
Advanced online publication: 29.04.2008
DOI: 10.1055/s-2008-1067048; Art ID: P02608SS
x
x.
x
x
.
2
0
0
8
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Amino-Substituted Pyrroloisoquinolines and Pyrroloquinolines
1689
O
O
R2NCS
Et3N
24 h
CH2Cl2
N
S
O
+
N
N
conditions
(Table 1)
90%
Br
NH
R2
Br
Br
Br
Br
3
4a–c
Scheme 1 Formation of zwitterion intermediates 4a–c
Table 1 Compounds 4a–c
R
R
R
H
NR3
H
C
N
R3
R2
4
Conditionsa
Yield (%)b
N
N
N
Entry
N
R3
S
S
S
R1
R1
R1
1
2
A
B
85
83
NHR2
NHR2
NHR2
4a
6
5
4
O2N
3
4
A
B
72
54
4b
4c
R
R
R
NHR3
SH
NHR3
NHR3
+ H+
Nu
MeO
F3C
N
N
N
S
S
R1
R1
5
B
90
R1
NHR2
9
NHR2
NHR2
8
7
a Conditions A: stirred overnight, ambient temperature. Conditions B:
1 h, microwave irradiation at 100 °C.
R
b Yield of isolated product.
NHR3
NHR2
N
in conjunction with focused microwave irradiation24 giv-
ing us ready access to a variety of components.
R1
10
In our current synthetic sequence we proposed that the ad-
dition of an isocyanide to the zwitterion 4 would result in
nucleophilic attack upon the isoquinolinium ring
(Scheme 2). Indeed additions of this type to pyridinium
species by isocyanides are well precedented.25 Further-
more, in our case the presence of a second fused aromatic
ring should help to reduce the degree of aromatic charac-
ter lost upon initial attack making the attack more
favoured. The resulting addition product is then capable
of undergoing a favoured 6-exo-dig intramolecular
cyclisation26 followed by proton transfer to form the inter-
mediate 7 with an anti-aromatic structure. Next, an in-
tramolecular rearrangement driven by the thermodynamic
sink of regaining aromaticity could occur via a postulated
strained 6,5,3-tricyclic fused ring system that is likely to
ring open to yield 9. The addition of a thiophile, for exam-
ple, a phosphine would then induce elimination of the sul-
fur leading to the desired aromatic indolizine 10. An
alternative mechanistic sequence, albeit leading to the
same product, can be envisaged and involves the isocya-
nide initially behaving as an electrophile by attack of the
thiolate of 4. This would then be followed by intramolec-
ular cyclisation onto the pyridinium ring intercepting the
same intermediate compound 6.
Scheme 2 Proposed mechanism for the formation of indolizines
A solution of 4-chlorophenyl isocyanide (1 equiv) was
added to betaine 4a and the reaction heated (microwave
irradiation, 80 °C) in the following solvents: acetone,
MeCN, CHCl3, CH2Cl2, 1,4-dioxane, DMF, EtOH, and
THF, respectively. After 26 hours, HPLC-MS analysis
showed that the reactions performed in CHCl3 and CH2Cl2
no longer contained 4a but comprised a new compound,
6a (Figure 2), with a mass corresponding to the addition
adduct. The other solvents screened produced many more
by-products and issues of decreased solubility were also
encountered. Ultimately, CH2Cl2 was chosen as the sol-
vent for all further reactions in preference to CHCl3 as it
had already been used in previous steps. It was therefore
hoped that this would eventually allow starting materials
from previous stages to be used without the need for
workup or solvent change, ultimately enabling a one-pot
preparation of the desired compounds. NMR experiments
on a sample of 6a isolated by column chromatography
(22% yield27) from a CH2Cl2 solution suggested that the
aromaticity of the isoquinoline ring had been lost due to
the lowering of the chemical shift of the characteristic
doublets [positions 14 and 13 (Figure 2); d = 6.30 and
5.54]. The 1H NMR spectrum also contained a distinctive
singlet (d = 5.83) shown by COSY experimentation to
possess a weak coupling to the isoquinoline proton 14
(Figure 2).
The postulated reaction sequence was initially tested and
validated using the 4-nitrophenyl-substituted betaine 4a.
This substrate was selected as it was the most insoluble
betaine of those synthesised. Consequently it was hoped
that a general set of conditions for all other substrates
could be derived from its more difficult optimisation.
Synthesis 2008, No. 11, 1688–1702 © Thieme Stuttgart · New York

1690
M. D. Hopkin et al.
PAPER
10
11
9
R
6a
6b
R
NR3
NR3
12
13
R1 = 4-bromophenacyl
2 = 4-nitrophenyl
3 = 4-chlorophenyl
8
7 H
N
R
R
R
1 = 4-bromophenacyl
2 = 4-methoxyphenyl
3 = 4-chlorophenyl
N
R
R
S
S
NR3
R1
R1
14
6
1N
5
NHR2
NHR2
S4
2
R1
3
6
11
NHR2
path A
path B
6
R
R
NHR3
NHR2
NHR3
NHR2
Figure 2 Compounds 6a and 6b
N
N
R1
R1
C
N
R3
This suggested the structure of 6a to be that shown in
Scheme 2 (6), thus avoiding the alternative anti-aromatic
structure 7. Intermediate 6b (Figure 2), also isolated by
column chromatography (11% yield), exhibited a similar
NMR spectrum suggesting it also adopted structure 6. An
HMQC experiment revealed that proton 6 (d = 5.27) was
connected to an sp3 hybridised carbon (d = 64.21), further
supporting the proposed structure. Unfortunately, at-
tempted crystallisation of both compounds 6a and 6b
failed to produce crystals suitable for X-ray analysis mak-
ing absolute determination of these new structures diffi-
cult.
SH
S
R3NCS
H+
R
NHR3
N
R1
10
NHR2
S
Scheme 3 Possible mechanisms for sulfur extrusion
esting to note that the reaction only proceeds to the inter-
mediate structure 6a at lower temperatures (80 °C), but
can be forced to the final product 10aa without the addi-
tion of further reagents at higher temperatures. This may
be as a result of the large thermodynamic barrier associat-
Upon increasing the stoichiometry of the 4-chlorophenyl
isocyanide, the reaction rate increased as expected. Em-
ploying a two equivalent excess reduced the reaction time ed with the five-membered ring formation of 11. From the
to 11 hours as determined by depletion of 4a monitored by reactions conducted at higher temperatures, the pyrrolo-
isoquinoline 10aa could be isolated as a bright yellow
amorphous solid (35% yield) by standard column chroma-
tography. NMR analysis was entirely consistent with the
expected product structure, however, repeated attempts at
crystallisation in order to attain X-ray structural confirma-
tion were not successful.
HPLC-MS. The time to completion also followed a stan-
dard Arrhenius trend when the reaction temperature was
increased (90 °C, 6 h; 100 °C, 3 h). However, higher tem-
peratures (>100 °C) could not be used as these led to sig-
nificant decomposition of the starting materials (i.e.,
retro-addition of the isothiocyanate to the pyridinium
salts).
Table 2 Compounds 10a
Interestingly, the HPLC-MS spectrum of the reaction
mixture run at 100 °C was found to contain two additional
component signals compared to the reaction heated at
only 80 °C. One of these peaks had a mass corresponding
to the loss of a sulfur atom from 6a indicating that conver-
sion into the indolizine product 10aa had occurred. The
second signal corresponded to that of 4-chlorophenyl
isothiocyanate (authenticated against the known material)
suggesting that the excess 4-chlorophenyl isocyanide
could remove the sulfur from 6a forming the correspond-
ing isothiocyanate (Path A, Scheme 3). To test this mech-
anism, only one equivalent of 4-chlorophenyl isocyanide
was added to 4a and the reaction then heated at 100 °C un-
til all of 4a had reacted. The proposed formation of 10aa
would not be expected since all of the isocyanide should
have coupled to 4a; however, the major product was still
10aa suggesting an alternative reductive mechanism was
taking place at the elevated temperature. This could be ex-
plained by the direct extrusion of sulfur28 (Path B,
Scheme 3). It is hard to discount either potential mecha-
nistic pathway, indeed both may be acting. It has been
shown that isocyanides can also be converted into isothio-
cyanates by heating with molecular sulfur, which could be
the source of this by-product in our reactions.29 It is inter-
Entry
4
R3
Time Temp
Product Isolated yield
(h)
(°C)
100
80
10
(%)
35
22
33
27
34
23
1
2
3
4
5
6
4a
4a
4b
4b
4c
4c
Cl
6
10aa
10ab
10ba
10bb
10ca
10cb
OMe
Cl
6
15
9
100
80
OMe
Cl
6
100
80
OMe
6
a Reaction conditions: 4 (1 equiv) and an isocyanide (1 equiv) in
CH2Cl2 were heated (microwave irradiation) until no more compound
4 could be detected by HPLC-MS. Compounds were purified by col-
umn chromatography on silica gel.
Next, to demonstrate the generality of the reaction, other
betaine precursors 4 were investigated along with 4-meth-
oxyphenyl isocyanide (Table 2). The more electron-rich
methoxy-substituted isocyanide did not show the same
high temperature requirement as previously determined to
induce sulfur elimination to yield the indolizine 10. The
lower temperature of 80 °C was sufficient to promote both
Synthesis 2008, No. 11, 1688–1702 © Thieme Stuttgart · New York

PAPER
Synthesis of Amino-Substituted Pyrroloisoquinolines and Pyrroloquinolines
1691
the initial isocyanide addition and subsequent rearrange-
ment.
One-Pot Reaction
In an effort to reduce decomposition of the reaction com-
ponents and maximise yields of both 6 and 10, we aimed
to find a method by which intermediate 6 was formed ini-
tially using lower temperatures and then converted into
the pyrroloisoquinoline 10 by addition of a thiophile (such
as a phosphine) without prolonged heating. In addition, in
order to reduce the number of workup steps required dur-
ing the synthesis, a one-pot reaction was envisaged where
reaction mixtures were telescoped to the next step without
purification. This seemed feasible as CH2Cl2 had been
used successfully as a solvent in all the previous steps. Al-
so, in an attempt to gain compounds more suitable for
crystallisation and hence X-ray analysis, the problematic
nitro group introduced via 4-nitrophenyl isothiocyanate
was replaced by the corresponding cyano variant. It was
hoped that this would offer better solubility whilst retain-
ing the electron-withdrawing nature. To this end, 4-cy-
anophenyl isothiocyanate (1 equiv) was stirred for
48 hours with isoquinolinium salt 3 and diethylamino-
methyl polystyrene30 (PS-NEt2, 1.1 equiv) resulting in com-
plete conversion into the corresponding betaine 4d. The
use of a solid-supported base permitted the product to be
separated by simple filtration without the need for further
workup. Experiments performed on 4d in CH2Cl2 showed
that significant decomposition began to occur under mi-
crowave irradiation at temperatures of 100 °C and greater.
With this in mind, 4-chlorophenyl isocyanide (1.5 equiv)
was added to the crude solution of 4d and heated (micro-
wave irradiation, 90 °C, 6 h) until no betaine remained.
Reaction monitoring by HPLC-MS showed the gradual
generation of a signal with a mass corresponding to that of
the intermediate 6. This product was isolated and purified
by column chromatography and crystallised31 as red nee-
dle like crystals (32% yield). NMR and X-ray analysis of
the crystals confirmed the proposed structure 6d
(Figure 3). Comparison of the data obtained previously
for compounds 6a and 6b suggested that they similarly
adopt this same 6,6,6-tricyclic fused heterocyclic core.
This core structure with both the imine and amine substit-
uents is quite unique, representing a new and previously
unprecedented heterocyclic system. Whilst the isolated
yield of 6d was relatively poor, HPLC-MS and analysis of
Figure 3 Crystal structure of intermediate 6d
Figure 4 Crystal structure of product 10da
rather than the action of PPh3. An identical outcome was
also obtained when PPh3 was substituted for the more
electron-rich P(OEt)3.
On further consideration of the mechanism, the intramo-
lecular attack into the imine to form the five-membered
core was considered to represent the highest energy tran-
sition and therefore would determine the reaction rate.
Consequently the reaction should be promoted by acid ca-
talysis. The reaction of 6d to 10da was therefore repeated
under the same conditions (microwave irradiation, 90 °C),
but in the presence of TFA (2 equiv). HPLC-MS analysis
after only 10 minutes indicated no remaining intermediate
6d; however, a new signal with a mass corresponding to
that of the pyrroloisoquinoline 10da was present. It has
been shown previously that indolizines form salts with
strong acids,32 hence the TFA was removed with a base
rather than by evaporation. After removing the TFA by
addition of macroporous polymer-supported carbonate
(PS-CO3), crude 10da was purified by column chroma-
tography and crystallised31 as yellow crystals (47% yield).
X-ray and NMR analysis confirmed the proposed struc-
ture 10da (Figure 4). It was found that catalytic amounts
of TFA (0.2 equiv) also effected the transformation under
the same conditions, but resulted in a longer reaction time
(45 min). The similar isolated yield (45%) suggests that
the reaction is indeed catalytic in acid.
1
the crude H NMR spectrum suggested that the conver-
sion was significantly higher (>80%). This loss of yield
was attributed to the noticeably poor stability (2D TLC
analysis) of 6d on chromatography over both silica gel
and alumina.
In an attempt to convert 6d into 10da under mild condi-
tions, 6d was heated (microwave irradiation, 90 °C) with
PPh3 (1 equiv) in CH2Cl2. After one hour, only minimal
amounts of 10da were observed, likely due to the back-
ground thermal transformation as previously observed
Synthesis 2008, No. 11, 1688–1702 © Thieme Stuttgart · New York

1692
M. D. Hopkin et al.
PAPER
NC
2) 1.5 equiv
R3
Br
N
R1
R1
N
1) R2NCS
MW, 90 °C
N
S
R1
R3
O
N
NHR2
3) TFA
MW, 90 °C
1.1 equiv PS-NEt2
H
NHR2
3 R1 =
10, 13
12 R1 = CN
Br
4d–f
Scheme 4 One-pot reaction sequence for the generation of compounds 10 and 13
The NMR spectra of the six synthesised pyrroloisoquino-
lines (Table 2) contained similar key characteristics to
that of the fully characterised compound 10da supporting
1) R2NCS
1.1 equiv PS-NEt3
N
N
Br
S
Ar
Ar
their structural assignments.
NHR2
O
The reaction was also attempted using a macroporous
O
14
polymer-supported sulfonic acid33 (PS-SO3H) thus en-
abling the acid component to be simply removed by filtra-
tion at the end of the reaction. This approach was
somewhat successful although a longer reaction time was
required (1 h, 90 °C), presumably as a result of slow dif-
fusion of reagents into the polymer matrix and the weaker
nature of the acid moiety. It was also noted that some of
the product was captured by the polymer resin; however,
this was not a selective process with other impurities also
being sequestered. This meant that a ‘catch and release’
purification protocol34 would not be appropriate in this in-
stance.
NC
3) 0.2 equiv TFA
MW, 90 °C
2) 1.5 equiv
Cl
MW, 6 h, 90 °C
Cl
NH
N
Ar
NHR2
15
O
To further investigate the effect of acidity on the reaction,
a weaker acid namely AcOH (2 equiv) was also evaluated.
Scheme 5 Formation of quinoline derived pyrroloquinolines 15
In these reactions only trace amounts of the rearranged
product 10da were observed after heating (microwave ir-
radiation, 90 °C, 70 min) suggesting that a relatively
strong acid source is required for the transformation.
rity, although analysis of the crude reaction mixture
indicated a similar conversion and product profile.
Mechanistically the R1 substituent is required to be elec-
tron-withdrawing in order to stabilise the ylide formed by
deprotonation of the isoquinolinium salt; hitherto, the 4-
bromophenacyl group had been used. To demonstrate that
an alternative functionality could be used, the isoquinolin-
ium salt 12 was prepared. Compound 12 was then subject-
ed to the one-pot reaction conditions as applied previously
(Table 3). In all cases, the use of 2 equivalents of TFA re-
sulted in the formation of complex mixtures, but better re-
sults were obtained when only 0.2 equivalents were used.
The lower isolated yields of compound 13 can be partially
attributed to the difficulty in isolation of the compound as
a result of a closely-eluting impurity during chromato-
graphic purification.
To determine whether any nonthermal or specific micro-
wave effects35 were involved, the reaction utilising TFA
(0.2 equiv) was repeated using conventional heating
methods. The temperature and pressure conditions
achieved in the microwave heating experiments were sim-
ulated by submerging a sealed microwave tube into a pre-
heated oil bath and, at the end of the heating period, the
sample was rapidly cooled by submersion in cold water.
The isolated yield of 10da (45%) was identical to that ob-
tained previously, suggesting that a purely thermal pro-
cess was in operation.
Having explored the reaction conditions and devised an
optimised procedure, a small collection of compounds
were prepared using a series of different isothiocyanates
and isocyanides (Scheme 4, Table 3). Similar isolated
yields were obtained when 3,5-bis(trifluoromethyl)phenyl
isothiocyanate was used, however, when the reaction with
benzyl isothiocyanate was attempted, a complex mixture
was produced. Upon lowering the stoichiometry of TFA
to 0.2 equivalents and increasing the heating time, the re-
actions with both 4-chlorophenyl isocyanide and 4-meth-
oxyphenyl isocyanide gave better conversions to 10fa and
10fb, respectively. Unfortunately, isolation of 10fa in ac-
ceptable purity was not possible due to a co-eluting impu-
Since isoquinolinium salts had been used successfully
throughout this research, it seemed likely that the method
could also be applied to the analogous quinolinium salts.
Consequently, salt 14 was formed in high yield (83%) in
a similar procedure as used to form 3. The standard one-
pot procedure was then employed using 4-chlorophenyl
isocyanide and resulted in the isolation of the expected
product 15 in relatively good yield (Scheme 5, Table 4).
In summary, a new multi-component reaction has been
developed that allows access to pyrroloisoquinolines and
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PAPER
Synthesis of Amino-Substituted Pyrroloisoquinolines and Pyrroloquinolines
1693
Table 3 Compounds 10 and 13
Entry
R1
R2
R3
Heating time
Step 2 (h)
TFA (equiv)a
Yield (%)b
Product
Step 3 (min)
O
1
2
Cl
OMe
6
6
10
10
2
2
47
38
10da
10db
NC
Br
F3C
3
4
Cl
OMe
6
7
10
10
2
2
48
40
10ea
10eb
CF3
d
5c
6c
Cl
OMe
8
8
60
40
0.2
0.2
–
10fa
10fb
31
7
8
Cl
OMe
6
6
60
60
0.2
0.2
17
21
13da
13db
CN
NC
F3C
9
10
Cl
OMe
6
6
60
60
0.2
0.2
23
29
13ea
13eb
CF3
a Only 0.2 equiv of TFA was used for entries 5–10 since 2 equiv resulted in the generation of complex mixtures.
b Yield of isolated products, purified by column chromatography.
c In addition to stirring overnight, the reaction was microwave irradiated at 90 °C for 30 min in order to form betaine 4f.
d No 10fa could be isolated due to a co-eluting impurity.
5
4
4
3
Table 4 Compounds 15
6
7
3
2
5
6
2
Entry R2
Heating time Isolated
15
N
N
Step 3 (min)
yield (%)
8
8
7
Figure 5 Ring numbering system for NMR assignments of quinoli-
ne and isoquinoline units.
1
50
35
15da
NC
as the internal reference (DMSO dH = 2.50 and CHCl3 dH = 7.26).
COSY and HMQC experiments were used to aid in the assignment
of signals in the 1H and 13C NMR spectra. 13C NMR spectra were
recorded on the same spectrometers with the central peak of
DMSO-d6 or CDCl3 as the internal reference (DMSO-d6 dC = 39.5
and CDCl3 dC = 77.2). DEPT 135 experiments were used to aid in
the assignment of signals in the 13C NMR spectra. Coupling con-
F3C
2
30
46
15ea
CF3
pyrroloquinolines with novel substitution patterns. The
multi-component nature of the reaction allows a large de-
gree of molecular diversity to be introduced into the het-
erocyclic products by simply selecting alternative starting
materials. A variety of amine substituents can be intro-
duced bearing both electron-poor and electron-rich aryls,
1
stants (J) are quoted in Hz and recorded to the nearest 0.1 Hz. H
NMR assignments were made using the numbering system as spec-
ified in Figure 5 for the parent quinoline and isoquinoline systems
respectively. Phenyl protons were labelled according to their
IUPAC priority ring position (Figure 5).
IR spectra were recorded neat as a thin film on a PerkinElmer Spec-
in addition to benzylic systems. The reaction utilised fo- trum One FT-IR spectrometer using Universal ATR sampling ac-
cessories. Letters next to the IR absorptions refer to the relative
cused microwave irradiation as a heating protocol, en-
absorbency of the peak; w = weak, less than 40% of the main peak;
abling simple and safe access to temperatures above the
m = medium, ca. 41–74% of the main peak; s = strong, greater than
75% of the most intense peak.
standard boiling point of the solvent (CH2Cl2). The isolat-
ed yields from the one-pot protocol are reasonable consid-
High-resolution mass spectrometry (HRMS) within 5 ppm was
ering the sequence of transformations involved. Further
carried out on a Waters Micromass LCT Premier spectrometer us-
work is underway to determine alternative purification
ing time of flight with positive and negative electrospray ionisation.
procedures and to expand the range of substrates.
HPLC-MS analysis was performed via two methods; A: an Agilent
HP 1100 series chromatograph [Mercury Luna 3m C18 (2) column]
attached to a Waters ZQ2000 mass spectrometer with ESCi ionisa-
1H NMR spectra were recorded on a Bruker Avance DPX-400,
tion source in ESI mode. Elution was carried out at a flow rate of 0.6
DRX-500 or DRX-600 spectrometer with residual DMSO or CHCl3
Synthesis 2008, No. 11, 1688–1702 © Thieme Stuttgart · New York

1694
M. D. Hopkin et al.
PAPER
HRMS: m/z calcd for C17H13BrNO [M – Br]+: 328.0160; found:
328.0170.
Table 5 HPLC-MS Solvent Gradients
Gradient A
Time (min)
Gradient B
Formation of Betaines 4; General Procedure A
MeCN (%)
Time (min)
MeCN (%)
Method A1: An isothiocyanate (6.14 mmol) was added to a suspen-
sion of compound 3 (2.50 g, 6.14 mmol) in CH2Cl2 (25 mL) fol-
lowed by the dropwise addition of Et3N (0.95 mL, 6.82 mmol). The
mixture was stirred overnight at r.t. and Et2O added to effect precip-
itation of product. The solid was filtered, washed with Et2O, and
dried in vacuo.
0.0
1.0
4.0
5.0
7.0
8.0
5
0.0
3.0
5.0
5.5
8.0
5
5
5
95
95
5
95
5
Method A2: An isothiocyanate (12.3 mmol) was added to a suspen-
sion of a compound 3 (5.00 g, 12.3 mmol) in CH2Cl2 (20 mL) and
Et3N (1.70 mL, 13.5 mmol). The mixture was heated (microwave ir-
radiation, 100 °C, 1 h) then filtered, washed with Et2O, and dried in
vacuo.
5
5
(Z)-3-(4-Bromophenyl)-2-(isoquinolinium-2-yl)-1-(4-nitrophe-
nylamino)-3-oxoprop-1-ene-1-thiolate (4a)
Prepared according to the general procedure A using 4-nitrophenyl
isothiocyanate to yield the title compound as a bright orange pow-
der. No Et2O was added to effect precipitation in Method 1; yield
(Method A1): 2.62 g (85%); (Method A2): 5.18 g (83%).
mL/min using a reverse phase gradient of MeCN and H2O contain-
ing 0.1% formic acid; and B: an Agilent HP 1100 chromatograph
(Luna Max RP column) attached to an HPLC/MSD mass spectro-
meter. Elution was carried out at a flow rate of 1 mL/min using a re-
verse phase gradient of MeCN–H2O with both solvents containing
0.1% trifluoroacetic acid. The gradient runs for both methods are
described in Table 5.
IR: 3049.8 (w), 1637.7 (w), 1608.2 (w), 1571.8 (m), 1501.1 (m),
1418.0 (w), 1392.0 (m), 1366.8 (m), 1324.1 (s), 1298.1 (m), 1258.1
(m), 1200.7 (m), 1157.9 (s), 1107.4 (s), 1059.6 (m), 1002.9 (m),
909.5 (w), 874.7 (w), 842.2 (s), 819.3 (m), 772.3 (s), 761.3 (m),
753.2 (m), 740.8 (m), 704.9 (m), 681.2 (m), 658.5 (s) cm–1.
1H NMR (500 MHz, DMSO-d6): d = 15.09 (s, 1 H, NH), 10.14 (s, 1
H, 8H-isoquin), 8.61 (d, J = 6.7 Hz, 1 H, 2H-isoquin), 8.36 (d,
J = 8.3 Hz, 1 H, 7H-isoquin), 8.32 (d, J = 6.7 Hz, 1 H, 3H-isoquin),
8.27 (d, J = 9.2 Hz, 2 H, 3H-PhNO2), 8.24 (d, J = 6.9 Hz, 1 H, 4H-
isoquin), 8.23 (d, J = 9.2 Hz, 2 H, 2H-PhNO2), 8.22–8.19 (m, 1 H,
5H-isoquin), 8.01–7.97 (m, 1 H, 6H-isoquin), 7.31 (d, J = 8.5 Hz, 2
H, 2H-PhBr), 7.19 (d, J = 8.5 Hz, 2 H, 3H-PhBr).
13C NMR (125 MHz, DMSO-d6): d = 184.52 (C), 177.57 (C),
156.31 (CH), 147.31 (C), 142.26 (C), 141.22 (CH), 139.80 (C),
137.31 (CH), 136.88 (C), 130.98 (CH), 130.85 (CH), 130.45 (CH),
128.45 (CH), 127.18 (CH), 126.98 (C), 125.65 (C), 124.65 (CH),
124.38 (CH), 121.94 (C), 121.34 (CH).
Retention time (tR) is in minutes and the m/z value is reported. Un-
less otherwise specified, reagents were obtained from commercial
sources and used without further purification. Laboratory reagent
grade CH2Cl2, Et2O, EtOAc, and PE (petroleum ether used refers to
the fraction boiling in the range 40–60 °C) were obtained from
Fischer Scientific. The CH2Cl2, EtOAc, and PE were distilled be-
fore use. All heating was carried out by microwave irradiation using
a Biotage Emrys Synthesiser or Biotage Emrys Optimiser36 unless
otherwise specified. The removal of solvent under reduced pressure
was carried out on a Biotage V-10 evaporator36 or a standard rotary
evaporator. TLC was performed on Merck 60 F254 silica gel plates
and were visualised using short wave ultraviolet light. Melting
points were performed on a Reichert hot stage apparatus and are un-
corrected.
2-[2-(4-Bromophenyl)-2-oxoethyl]isoquinolinium Bromide (3)
2,4¢-Dibromoacetophenone (18.00 g, 64.76 mmol) was dissolved in
a minimum amount of CH2Cl2 (50 mL). Isoquinoline (7.56 mL,
64.34 mmol) was added dropwise to the solution and the mixture
was stirred overnight at r.t. The solvent was removed in vacuo, and
the crude solid product triturated with Et2O. The sample was filtered
and the solid dried in vacuo to yield the title compound as a cream
solid; yield: 24.0 g (90%).
HPLC-MS (B): tR = 3.67; m/z = 508.0 [M + H]+.
HRMS: m/z calcd for C24H17BrN3O3S [M + H]+: 506.0174; found:
506.0192.
(Z)-3-(4-Bromophenyl)-2-(isoquinolinium-2-yl)-1-(4-methoxy-
phenylamino)-3-oxoprop-1-ene-1-thiolate (4b)
Prepared according to the general procedure A using 4-methoxy-
phenyl isothiocyanate to yield the title compound as a bright yellow
powder; yield (Method A1): 2.17 g (72%); (Method A2): 3.26 g
(54%).
IR: 2982.9 (w), 2814.7 (w), 2340.1 (w), 1692.8 (m), 1636.8 (w),
1605.0 (w), 1584.4 (m), 1509.2 (w), 1485.7 (w), 1465.1 (w), 1396.6
(w), 1386.1 (m), 1360.5 (w), 1340.0 (w), 1287.2 (w), 1242.3 (w),
1224.4 (w), 1173.9 (m), 1071.4 (w), 996.0 (m), 980.9 (m), 893.9
(w), 850.4 (w), 816.3 (s), 775.4 (m), 744.2 (m), 706.5 (w), 688.05
(w) cm–1.
1H NMR (500 MHz, DMSO-d6): d = 10.02 (s, 1 H, 8H-isoquin),
8.73 (d, J = 6.8 Hz, 1 H, 2H-isoquin), 8.69 (d, J = 6.8 Hz, 1 H, 3H-
isoquin), 8.56 (d, J = 8.3 Hz, 1 H, 7H-isoquin), 8.42 (d, J = 8.3 Hz,
1 H, 4H-isoquin), 8.35–8.32 (m, 1 H, 5H-isoquin), 8.14–8.11 (m, 1
H, 6H-isoquin), 8.05 (d, J = 8.6 Hz, 2 H, 2H-PhBr), 7.92 (d, J = 8.6
Hz, 2 H, 3H-PhBr), 6.63 (s, 2 H, CH2).
IR: 2983.9 (w), 2124.8 (w), 1903.4 (w), 1636.2 (w), 1587.4 (w),
1536.7 (w), 1506.9 (m), 1490.3 (m), 1463.5 (m), 1414.9 (m), 1375.3
(s), 1284.5 (m), 1241.8 (s), 1202.9 (m), 1182.2 (m), 1165.4 (m),
1152.4 (m), 1106.9 (w), 1073.4 (w), 1057.7 (m), 1035.1 (m), 1009.8
(m), 953.5 (w), 867.6 (w), 836.7 (s), 822.2 (m), 790.7 (s), 757.2 (s),
738.2 (m), 679.0 (s) cm–1.
1H NMR (400 MHz, DMSO-d6): d = 14.34 (s, 1 H, NH), 10.07 (s, 1
H, 8H-isoquin), 8.51 (d, J = 6.8 Hz, 1 H, 2H-isoquin), 8.31 (d,
J = 8.3 Hz, 1 H, 7H-isoquin), 8.22 (d, J = 6.8 Hz, 1 H, 3H-isoquin),
8.18 (d, J = 7.8 Hz, 1 H, 4H-isoquin), 8.17–8.13 (m, 1 H, 5H-iso-
quin), 7.96–7.92 (m, 1 H, 6H-isoquin), 7.65 (d, J = 9.0 Hz, 2 H, 2H-
PhOMe), 7.26 (d, J = 8.6 Hz, 2 H, 2H-PhBr), 7.14 (d, J = 8.6 Hz, 2
H, 3H-PhBr), 6.89 (d, J = 9.0 Hz, 2 H, 3H-PhOMe), 3.73 (s, 3 H,
OCH3).
13C NMR (125 MHz, DMSO-d6): d = 190.45 (C), 151.80 (CH),
137.63 (CH), 137.37 (C), 136.43 (CH), 132.76 (C), 132.41 (CH),
131.53 (CH), 130.75 (CH), 130.35 (CH), 129.02 (C), 127.53 (CH),
126.96 (C), 125.60 (CH), 65.01 (CH2).
HPLC-MS (A): tR = 2.66; m/z = 328.0 [M – Br]+.
Synthesis 2008, No. 11, 1688–1702 © Thieme Stuttgart · New York

PAPER
Synthesis of Amino-Substituted Pyrroloisoquinolines and Pyrroloquinolines
1695
13C NMR (100 MHz, DMSO-d6): d = 184.60 (C), 175.77 (C),
156.05 (CH), 141.53 (CH), 140.40 (C), 136.94 (CH), 136.67 (C),
133.85 (C), 130.84 (CH), 130.60 (CH), 130.34 (CH), 128.52 (CH),
127.05 (CH), 126.79 (C), 126.73 (C) 124.70 (CH), 123.89 (CH),
123.79 (C), 121.42 (C), 113.59 (CH), 55.26 (CH3).
HPLC-MS (B): tR = 3.50; m/z = 491.0 [M + H]+.
HRMS: m/z calcd for C25H20BrN2O2S [M + H]+: 491.0429; found:
H, 2H-isoquin), 5.83 (s, 1 H, 8H-isoquin), 5.54 (d, J = 7.6 Hz, 1 H,
3H-isoquin).
HPLC-MS (B): tR = 4.71; m/z = 644.9 [M + H]+.
(4-Bromophenyl)[3-(4-methoxyphenylamino)-1-(4-methoxy-
phenylimino)-1,11b-dihydro[1,4]thiazino[3,4-a]isoquinolin-4-
yl]methanone (6b)
Prepared according to the general procedure B using 4-methoxy-
phenyl isocyanide (27 mg, 0.204 mmol), 4b (100 mg, 0.204 mmol),
heated (6 h, 80 °C), and eluted with CH2Cl2; yield: 21 mg (17%);
red solid.
491.0433.
(Z)-3-(4-Bromophenyl)-2-(isoquinolinium-2-yl)-3-oxo-1-[3-(tri-
fluoromethyl)phenylamino]prop-1-ene-1-thiolate (4c)
Prepared according to the general procedure A using 3-(trifluoro-
methyl)phenyl isothiocyanate to yield the title compound as a yel-
low-orange powder; yield (Method A2): 6.58 g (90%).
IR: 2950.9 (w), 1645.3 (w), 1604.2 (w), 1579.7 (m), 1555.7 (m),
1501.3 (s), 1457.3 (w), 1416.2 (w), 1394.9 (m), 1377.3 (m), 1326.5
(w), 1294.8 (m), 1268.8 (m), 1244.6 (s), 1169.9 (m), 1123.6 (w),
1106.1 (w), 1071.4 (m), 1034.4 (m), 1008.6 (s), 964.5 (w), 869.3
(m), 835.2 (m), 786.4 (w), 759.0 (s), 742.8 (s), 717.1 (m), 695.1 (m),
669.5 (m) cm–1.
1H NMR (500 MHz, CDCl3): d = 12.99 (s, 1 H, NH), 7.65 (d,
J = 8.6 Hz, 2 H, 2H-PhBr), 7.39 (d, J = 8.6 Hz, 2 H, 3H-PhBr),
7.26–7.23 (m, 1 H, 5H-isoquin), 7.18 (d, J = 5.8 Hz, 1 H, 7H-iso-
quin), 7.19–7.16 (m, 1 H, 6H-isoquin), 7.11 (d, J = 8.8 Hz, 2 H,
PhOMe), 7.00 (d, J = 7.5 Hz, 1 H, 4H-isoquin), 6.84 (d, J = 8.8 Hz,
2 H, PhOMe), 6.72 (d, J = 8.8 Hz, 2 H, PhOMe), 6.60 (d, J = 8.8
Hz, 2 H, PhOMe), 5.87 (d, J = 7.4 Hz, 1 H, 2H-isoquin), 5.44 (d,
J = 7.4 Hz, 1 H, 3H-isoquin), 5.27 (s, 1 H, 8H-isoquin), 3.79 (s, 3
H, OCH3), 3.72 (s, 3 H, OCH3).
13C NMR (125 MHz, CDCl3): d = 185.32 (C), 158.41 (C), 158.40
(C), 156.89 (C), 156.67 (C), 141.29 (C), 137.69 (C), 134.58 (CH),
131.79 (C), 131.20 (CH), 130.52 (CH), 129.93 (C), 128.52 (CH),
128.40 (CH), 126.84 (CH), 125.17 (C), 125.15 (CH), 125.07 (C),
123.82 (CH), 120.64 (CH), 115.27 (C), 114.45 (CH), 114.14 (CH),
102.21 (CH), 64.21 (CH), 55.45 (CH3), 55.33 (CH3).
IR: 3042.1 (w), 1635.8 (w), 1607.9 (w), 1580.5 (w), 1567.1 (m),
1530.5 (m), 1500.9 (m), 1482.2 (m), 1401.2 (m), 1381.1 (m),
1328.7 (s), 1304.5 (m), 1293.8 (m), 1274.1 (m), 1240.4 (m), 1216.9
(m), 1199.1 (m), 1183.3 (w), 1156.2 (s), 1112.2 (s), 1091.8 (m),
1063.5 (s), 1009.3 (m), 981.8 (w), 955.1 (w), 916.9 (w), 904.6 (m),
889.4 (w), 878.5 (w), 851.4 (m), 808.0 (m), 790.0 (s), 769.6 (m),
749.3 (s), 696.1 (s), 674.0 (m), 658.9 (m) cm–1.
1H NMR (500 MHz, DMSO-d6): d = 14.76 (s, 1 H, NH), 10.11 (s, 1
H, 8H-isoquin), 8.57 (d, J = 6.8 Hz, 1 H, 2H-isoquin), 8.49 [s, 1 H,
2H-(CF3)Ph], 8.34 (d, J = 8.3 Hz, 1 H, 7H-isoquin), 8.28 (d, J = 6.8
Hz, 1 H, 3H-isoquin), 8.22 (d, J = 8.1 Hz, 1 H, 4H-isoquin), 8.19–
8.17 (m, 1 H, 5H-isoquin), 7.98–7.95 (m, 1 H, 6H-isoquin), 7.91 [d,
J = 7.9 Hz, 1 H, 4H-(CF3)Ph], 7.57 [t, J = 7.9 Hz, 1 H, 5H-
(CF3)Ph], 7.44 [d, J = 7.9 Hz, 1 H, 6H-(CF3)Ph], 7.29 (d, J = 8.5
Hz, 2 H, 2H-PhBr), 7.16 (d, J = 8.5 Hz, 2 H, 3H-PhBr).
13C NMR (125 MHz, DMSO-d6): d = 184.86 (C), 176.89 (C),
156.32 (CH), 141.59 (C), 141.39 (CH), 140.02 (C), 137.20 (CH),
136.81 (C), 130.96 (CH), 130.79 (CH), 130.43 (CH), 129.80 (CH),
129.02 (C, q, J = 31.5 Hz), 128.50 (CH), 127.15 (CH), 126.91 (C),
126.45 (CH), 124.64 (C), 124.23 (C, q, J = 270.8 Hz), 124.16 (CH),
121.76 (C), 120.39 (CH, q, J = 3.8 Hz), 118.89 (CH, q, J = 4.0 Hz).
HPLC-MS (B): tR = 4.59; m/z = 624.0 [M + H]+.
(4-Bromophenyl)[1-(4-chlorophenylamino)-2-(4-nitrophenyl-
amino)pyrrolo[2,1-a]isoquinolin-3-yl]methanone (10aa)
Prepared according to the general procedure B using 4-chlorophe-
nyl isocyanide (27 mg, 0.198 mmol), 4a (100 mg, 0.198 mmol),
heated (6 h, 100 °C), and eluted with CH2Cl2; yield: 44 mg (35%);
yellow solid.
HPLC-MS (B): tR = 3.74; m/z = 528.9 [M + H]+.
HRMS: m/z calcd for C25H17BrF3N2OS [M + H]+: 529.0197; found:
529.0211.
Indolizines and Their Intermediates; General Procedure B
A mixture of isocyanide and compound 4 in CH2Cl2 (4.5 mL) was
heated (microwave irradiation). The solvent was removed in vacuo
and the residue purified by flash column chromatography using a
Varian Bond Elut SI 40 mm silica column37 and eluting with the
specified solvent system.
IR: 3328.4 (w), 1723.7 (w), 1586.0 (m), 1530.5 (m), 1490.1 (m),
1436.0 (w), 1404.4 (m), 1374.2 (m), 1318.9 (s), 1301.9 (s), 1266.9
(m), 1171.4 (m), 1109.7 (s), 1067.1 (m), 1043.1 (s), 1008.4 (m),
937.2 (m), 836.9 (m), 819.3 (m), 795.1 (m), 749.3 (m), 692.2 (m),
660.4 (m) cm–1.
1H NMR (500 MHz, DMSO-d6): d = 9.19 (d, J = 7.6 Hz, 1 H, 2H-
isoquin), 8.54 (s, 1 H, NH), 8.44 (d, J = 8.2 Hz, 1 H, 7H-isoquin),
7.84 (d, J = 7.5 Hz, 1 H, 4H-isoquin), 7.76 (d, J = 9.2 Hz, 2 H, 3H-
PhNO2), 7.63 (s, 1 H, NH), 7.58–7.55 (m, 1 H, 5H-isoquin), 7.52–
7.49 (m, 1 H, 6H-isoquin), 7.41 (d, J = 8.6 Hz, 2 H, 2H-PhBr), 7.34
(d, J = 8.6 Hz, 2 H, 3H-PhBr), 7.31 (d, J = 7.6 Hz, 1 H, 3H-iso-
quin), 6.99 (d, J = 8.9 Hz, 2 H, 3-PhCl), 6.48 (d, J = 8.9 Hz, 2 H,
2H-PhBr), 6.41 (d, J = 9.2 Hz, 2 H, 2H-PhNO2).
(4-Bromophenyl)[1-(4-chlorophenylimino)-3-(4-nitrophenyl-
amino)-1,11b-dihydro[1,4]thiazino[3,4-a]isoquinolin-4-
yl]methanone (6a)
Prepared according to the general procedure B using 4-chlorophe-
nyl isocyanide (26 mg, 0.198 mmol), 4a (100 mg, 0.198 mmol),
heated (15 h, 80 °C), and eluted with CH2Cl2; yield: 23 mg (22%);
red solid.
IR: 2924.7 (w), 1585.1 (m), 1490.4 (s), 1396.4 (w), 1374.9 (w),
1325.0 (s), 1303.2 (s), 1245.2 (s), 1173.6 (s), 1109.5 (s), 1090.7 (m),
1069.0 (m), 1038.9 (m), 1009.0 (s), 827.8 (s), 749.5 (s), 681.5 (m)
cm–1.
1H NMR (500 MHz, CDCl3): d = 9.62 (s, 1 H, NH), 8.01 (d, J = 9.2
Hz, 2 H, 3H-PhNO2), 7.67 (d, J = 8.6 Hz, 2 H, 2H-PhBr), 7.53 (d,
J = 8.6 Hz, 2 H, 3H-PhBr), 7.36 (d, J = 8.7 Hz, 2 H, 3H-PhCl), 7.34
(d, J = 7.5 Hz, 1 H, 4H-isoquin), 7.25 (td, J = 7.5, 1.4 Hz, 1 H, 5H-
isoquin), 7.19 (td, J = 7.5, 1.3 Hz, 1 H, 6H-isoquin), 7.06 (dd,
J = 7.5, 1.3 Hz, 1 H, 7H-isoquin), 6.99 (d, J = 9.2 Hz, 2 H, 2H-
PhNO2), 6.75 (d, J = 8.7 Hz, 2 H, 2H-PhCl), 6.30 (d, J = 7.6 Hz, 1
13C NMR (125 MHz, DMSO-d6): d = 183.90 (C), 152.27 (C),
145.71 (C), 138.29 (C), 137.49 (C), 131.58 (C), 130.94 (CH),
130.51 (CH), 129.47 (C), 128.83 (C), 128.77 (CH), 128.34 (CH),
128.03 (CH), 126.96 (CH), 125.35 (CH), 125.22 (C), 124.55 (CH),
124.08 (CH), 123.79 (C), 120.62 (C), 116.10 (C), 115.82 (C),
114.55 (CH), 113.29 (CH), 112.95 (CH).
HPLC-MS (B): tR = 4.61; m/z = 612.9 [M + H]+.
HRMS: m/z calcd for C31H21BrClN4O3 [M + H]+: 611.0480; found:
611.0486.
Synthesis 2008, No. 11, 1688–1702 © Thieme Stuttgart · New York

1696
M. D. Hopkin et al.
PAPER
(4-Bromophenyl)[1-(4-methoxyphenylamino)-2-(4-nitrophe-
nylamino)pyrrolo[2,1-a]isoquinolin-3-yl]methanone (10ab)
Prepared according to the general procedure B using 4-methoxy-
phenyl isocyanide (26 mg, 0.198 mmol), 4a (100 mg, 0.198 mmol),
heated (6 h, 80 °C), and eluted with CH2Cl2; yield: 25 mg (20%);
yellow solid.
heated (9 h, 80 °C), and eluted with CH2Cl2; yield: 34 mg (27%);
yellow solid.
IR: 3330.8 (w), 2928.6 (w), 2831.0 (w), 1583.7 (m), 1557.6 (w),
1505.4 (s), 1479.6 (m), 1433.7 (m), 1415.1 (m), 1396.0 (m), 1372.8
(m), 1353.3 (s), 1288.2 (w), 1230.4 (s), 1170.5 (m), 1106.9 (w),
1066.5 (m), 1032.5 (m), 1008.5 (m), 935.2 (m), 819.3 (s), 791.0 (s),
765.3 (m), 744.4 (m), 677.2 (m) cm–1.
1H NMR (500 MHz, CDCl3): d = 8.73 (d, J = 7.5 Hz, 1 H, 2H-iso-
quin), 8.68 (d, J = 8.2 Hz, 1 H, 7H-isoquin), 7.64 (d, J = 8.1 Hz, 1
H, 4H-isoquin), 7.51–7.47 (m, 5 H, PhBr and 5H-isoquin), 7.41–
7.38 (m, 1 H, 6H-isoquin), 6.89 (d, J = 7.5 Hz, 1 H, 3H-isoquin),
6.68–6.67 (m, 4 H, PhOMe), 6.66 (d, J = 8.9 Hz, 2 H, PhOMe),
6.36 (s, 1 H, NH), 6.32 (d, J = 8.9 Hz, 2 H, PhOMe), 4.60 (s, 1 H,
NH), 3.79 (s, 3 H, OCH3), 3.72 (s, 3 H, OCH3).
13C NMR (125 MHz, CDCl3): d = 183.09 (C), 155.27 (C), 152.89
(C), 139.94 (C), 139.03 (C), 138.86 (C), 136.23 (C), 132.12 (C),
131.70 (CH), 130.04 (CH), 129.71 (C), 128.20 (CH), 127.60 (CH),
126.40 (CH), 125.81 (C), 125.21 (CH), 125.07 (CH), 124.17 (C),
121.14 (CH), 114.80 (CH), 114.67 (CH), 114.32 (CH), 113.74 (C),
112.50 (C), 111.40 (CH), 55.67 (CH3), 55.63 (CH3).
IR: 3335.2 (w), 1588.2 (m), 1557.7 (w), 1507.2 (s), 1480.6 (m),
1437.1 (w), 1397.4 (m), 1374.4 (m), 1320.3 (s), 1303.3 (s), 1268.4
(m), 1233.2 (m), 1172.1 (m), 1110.1 (s), 1066.9 (w), 1033.7 (w),
1009.8 (m), 937.8 (m), 824.0 (m), 795.3 (m), 749.0 (m), 690.8 (w),
666.8 (w) cm–1.
1H NMR (500 MHz, CDCl3): d = 9.12 (d, J = 7.6 Hz, 1 H, 2H-iso-
quin), 8.62 (d, J = 8.2 Hz, 1 H, 7H-isoquin), 7.92 (d, J = 8.9 Hz, 2
H, 3H-PhNO2), 7.70 (d, J = 8.0 Hz, 1 H, 4H-isoquin), 7.55–7.52
(m, 1 H, 5H-isoquin), 7.46–7.43 (m, 1 H, 6H-isoquin), 7.41 (d,
J = 8.7 Hz, 2 H, 2H-PhBr), 7.39 (d, J = 8.7 Hz, 2 H, 3H-PhBr), 7.10
(d, J = 7.6 Hz, 1 H, 3H-isoquin), 6.66 (d, J = 8.9 Hz, 2 H, 3H-
PhOMe), 6.42 (d, J = 8.9 Hz, 4 H, 2H-PhNO2 and 2H-PhOMe),
5.79 (s, 1 H, NH), 4.80 (s, 1 H, NH), 3.69 (s, 3 H, OCH3).
13C NMR (125 MHz, CDCl3): d = 183.89 (C), 153.29 (C), 149.89
(C), 140.19 (C), 139.09 (C), 138.56 (C), 131.50 (CH), 131.07 (C),
130.83 (C), 129.95 (CH), 129.24 (C), 128.49 (CH), 128.16 (CH),
126.68 (CH), 126.41 (C), 125.77 (CH), 124.95 (CH), 124.63 (CH),
124.26 (C), 116.63 (C), 115.88 (C), 114.93 (CH), 114.90 (CH),
113.81 (CH), 113.67 (CH), 55.63 (CH3).
HPLC-MS (B): tR = 4.43; m/z = 592.0 [M + H]+.
HRMS: m/z calcd for C33H27BrN3O3 [M + H]+: 592.1236; found:
592.1235.
(4-Bromophenyl){1-(4-chlorophenylamino)-2-[3-(trifluoro-
methyl)phenylamino]pyrrolo[2,1-a]isoquinolin-3-yl}metha-
none (10ca)
HPLC-MS (B): tR = 4.30; m/z = 609.0 [M + H]+.
HRMS: m/z calcd for C32H24BrN4O4 [M + H]+: 607.0981; found:
607.0977.
Prepared according to the general procedure B using 4-chlorophe-
nyl isocyanide (26 mg, 0.189 mmol), 4c (100 mg, 0.189 mmol),
heated (6 h, 100 °C) and eluted with CH2Cl2; yield: 43 mg (34%),
yellow solid.
(4-Bromophenyl)[1-(4-chlorophenylamino)-2-(4-methoxyphe-
nylamino)pyrrolo[2,1-a]isoquinolin-3-yl]methanone (10ba)
Prepared according to the general procedure B using 4-chlorophe-
nyl isocyanide (28 mg, 0.204 mmol), 4b (100 mg, 0.204 mmol),
heated (15 h, 80 °C), and eluted with 10% PE in CH2Cl2; yield: 40
mg (33%); yellow solid.
IR: 3306.8 (w), 1584.8 (m), 1557.8 (w), 1525.7 (m), 1488.9 (s),
1445.5 (m), 1396.0 (m), 1373.6 (s), 1356.5 (m), 1331.1 (s), 1273.2
(m), 1236.6 (m), 1214.3 (w), 1163.5 (m), 1121.8 (s), 1093.6 (m),
1066.7 (s), 1009.6 (m), 942.4 (m), 885.2 (m), 818.6 (m), 787.1 (s),
745.2 (m), 696.7 (m), 662.9 (m) cm–1.
1H NMR (500 MHz, DMSO-d6): d = 9.18 (d, J = 7.5 Hz, 1 H, 2H-
isoquin), 8.41 (d, J = 8.1 Hz, 1 H, 7H-isoquin), 7.82 (d, J = 7.5 Hz,
1 H, 4H-isoquin), 7.73 (s, 1 H, NH), 7.64 (s, 1 H, NH), 7.57–7.54
(m, 1 H, 5H-isoquin), 7.50–7.47 (m, 1 H, 6H-isoquin), 7.33–7.32
(m, 4 H, PhBr), 7.26 (d, J = 7.5 Hz, 1 H, 3H-isoquin), 7.07–7.04 [m,
1 H, 5H-(CF3)Ph], 7.02 (d, J = 8.9 Hz, 2 H, 3H-PhCl), 6.81 [d,
J = 7.6 Hz, 1 H, 4H-(CF3)Ph], 6.68 [dd, J = 8.2, 1.7 Hz, 1 H, 6H-
(CF3)phenyl], 6.54 (d, J = 8.9 Hz, 2 H, 2H-PhCl), 6.50 [d, J = 1.7
Hz, 1 H, 2H-(CF3)Ph].
13C NMR (125 MHz, DMSO-d6): d = 183.89 (C), 146.62 (C),
145.95 (C), 138.24 (C), 133.88 (C), 130.73 (CH), 130.34 (CH),
129.52 (C), 129.31 (CH), 129.24 (C, q, J = 31.0 Hz), 128.94 (C),
128.77 (CH), 128.16 (CH), 127.83 (CH), 126.84 (CH), 125.03 (C),
124.55 (CH), 124.25 (C, q, J = 271.3 Hz), 124.15 (CH), 123.67 (C),
120.59 (C), 117.58 (CH), 114.75 (C), 114.69 (C), 114.58 (CH),
114.13 (CH, q, J = 3.6 Hz), 112.61 (CH), 110.03 (CH, q, J = 4.0
Hz).
IR: 2924.6 (w), 1583.8 (m), 1557.6 (m), 1506.9 (s), 1488.7 (s),
1449.7 (m), 1433.6 (m), 1415.5 (m), 1396.0 (s), 1373.1 (s), 1353.5
(s), 1291.8 (s), 1232.0 (s), 1170.2 (m), 1090.3 (w), 1067.0 (m),
1033.1 (m), 1008.9 (m), 934.7 (m), 817.1 (s), 788.7 (s), 743.7 (s),
695.1 (w), 664.3 (m) cm–1.
1H NMR (500 MHz, CDCl3): d = 8.57 (d, J = 7.5 Hz, 1 H, 2H-iso-
quin), 8.55 (d, J = 8.3 Hz, 1 H, 7H-isoquin), 7.60 (d, J = 7.8 Hz, 1
H, 4H-isoquin), 7.50–7.48 (m, 4 H, PhBr), 7.47–7.45 (m, 1 H, 5H-
isoquin), 7.37–7.34 (m, 1 H, 6H-isoquin), 6.96 (d, J = 8.8 Hz, 2 H,
3H-PhCl), 6.84 (d, J = 7.5 Hz, 1 H, 3H-isoquin), 6.67 (d, J = 9.0
Hz, 2 H, PhOMe), 6.64 (d, J = 9.0 Hz, 2 H, PhOMe), 6.51 (s, 1 H,
NH), 6.23 (d, J = 8.8 Hz, 2 H, 2H-PhCl), 4.72 (s, 1 H, NH), 3.75 (s,
3 H, OCH3).
13C NMR (125 MHz, CDCl3): d = 182.94 (C), 155.56 (C), 144.69
(C), 139.28 (C), 138.90 (C), 135.57 (C), 132.19 (C), 131.83 (CH),
129.95 (CH), 129.71 (C), 128.92 (CH), 128.36 (CH), 127.65 (CH),
126.52 (CH), 125.92 (C), 124.99 (CH), 124.86 (CH), 123.92 (C),
123.31 (C), 121.83 (CH), 114.85 (CH), 114.25 (CH), 113.69 (C),
111.37 (CH), 110.44 (C), 55.58 (CH3).
HPLC-MS (B): tR = 4.98; m/z = 636.0 [M + H]+.
HRMS: m/z calcd for C32H21BrClF3N3O [M + H]+: 634.0497;
HPLC-MS (B): tR = 4.63; m/z = 598.0 [M + H]+.
HRMS: m/z calcd for C32H24BrClN3O2 [M + H]+: 596.0740; found:
found: 634.0509.
596.0735.
(4-Bromophenyl){1-(4-methoxyphenylamino)-2-[3-(trifluoro-
methyl)phenylamino]pyrrolo[2,1-a]isoquinolin-3-yl}metha-
none (10cb)
Prepared according to the general procedure B using 4-methoxy-
phenyl isocyanide (25 mg, 0.189 mmol), 4c (100 mg, 0.189 mmol),
[1,2-Bis(4-methoxyphenylamino)pyrrolo[2,1-a]isoquinolin-3-
yl](4-bromophenyl)methanone (10bb)
Prepared according to the general procedure B using 4-methoxy-
phenyl isocyanide (27 mg, 0.204 mmol), 4b (100 mg, 0.204 mmol),
Synthesis 2008, No. 11, 1688–1702 © Thieme Stuttgart · New York

PAPER
Synthesis of Amino-Substituted Pyrroloisoquinolines and Pyrroloquinolines
1697
heated (6 h, 80 °C), and eluted with CH2Cl2; yield: 29 mg (23%);
yellow solid.
Table 6 Biotage Continuous Solvent Gradient
Column volume
% EtOAc–PE
IR: 3313.8 (w), 1584.2 (w), 1559.0 (w), 1531.8 (w), 1506.6 (s),
1473.4 (w), 1441.6 (w), 1395.7 (s), 1373.2 (s), 1356.5 (m), 1331.5
(s), 1231.3 (s), 1162.2 (s), 1119.5 (s), 1066.3 (s), 1032.7 (m), 1010.0
(m), 942.7 (m), 884.5 (m), 821.2 (m), 786.7 (s), 745.1 (m), 711.0
(s), 697.2 (s), 663.3 (m) cm–1.
0
6
1
6
16
19
21
23
40
100
100
6
1H NMR (500 MHz, CDCl3): d = 8.98 (d, J = 7.6 Hz, 1 H, 2H-iso-
quin), 8.62 (d, J = 8.2 Hz, 1 H, 7H-isoquin), 7.66 (d, J = 7.8 Hz, 1
H, 4H-isoquin), 7.51–7.48 (m, 1 H, 5H-isoquin), 7.45–7.43 (m, 1 H,
6H-isoquin), 7.39 (d, J = 7.6 Hz, 1 H, 3H-isoquin), 7.38–7.36 (m, 4
H, PhBr), 7.10 [t, J = 7.9 Hz, 1 H, 5H-(CF3)Ph], 7.01 [d, J = 7.9 Hz,
1 H, 4H-(CF3)Ph], 6.99 [d, J = 7.9 Hz, 1 H, 6H-(CF3)Ph], 6.68 [s, 1
H, 2H-(CF3)Ph], 6.65 (d, J = 8.8 Hz, 2 H, PhOMe), 6.39 (d, J = 8.8
Hz, 2 H, PhOMe), 5.91 (s, 1 H, NH), 4.80 (s, 1 H, NH), 3.69 (s, 3
H, OCH3).
13C NMR (125 MHz, CDCl3): d = 183.83 (C), 153.08 (C), 144.26
(C), 139.34 (C), 138.65 (C), 134.37 (C), 131.39 (CH), 131.27 (C, q,
J = 30.9 Hz), 131.16 (C), 129.97 (CH), 129.45 (C), 129.37 (CH),
128.37 (CH), 128.26 (CH), 128.20 (CH), 127.84 (CH), 126.55
(CH), 126.08 (C), 125.02 (CH), 124.21 (C), 123.85 (C, q, J = 273.6
Hz), 117.09 (CH, q, J = 3.8 Hz), 114.85 (CH), 114.74 (CH), 114.69
(C), 114.30 (C), 112.99 (CH, q, J = 3.8 Hz), 112.74 (CH), 55.64
(CH3).
Purification of Products by Flash Column Chromatography
Using a Biotage SP4 Purification System;36 General Procedure
C
The sample was dissolved in a minimum amount of CH2Cl2, then
loaded onto a Biotage 25+TM samplet and dried in vacuo at r.t. A 48
mL Biotage FLASH 25+TM M silica cartridge was primed with 60
mL of a 6% EtOAc–PE solution at a flow rate of 25 mL/min, then
the samplet was loaded onto the top of the column. A solvent gradi-
ent was run according to Table 6 with a flow rate of 20 mL/min,
with the initial 2 column volumes directed to waste, then the re-
maining eluent collected in 24 mL fractions.
HPLC-MS (B): tR = 4.58; m/z = 630.0 [M + H]+.
HRMS: m/z calcd for C33H24BrF3N3O2 [M + H]+: 630.1004; found:
630.1002.
4-[4-(4-Bromobenzoyl)-1-(4-chlorophenylimino)-1,11b-dihy-
dro-[1,4]thiazino[3,4-a]isoquinolin-3-ylamino]benzonitrile (6d)
A suspension of compound 3 (100 mg, 0.246 mmol), 4-cyanophe-
nyl isothiocyanate (40 mg, 0.250 mmol) and PS-NEt2 (86 mg, 0.270
mmol) in CH2Cl2 (4.5 mL) was stirred overnight at r.t. 4-Chlorophe-
nyl isocyanide (52 mg, 0.378 mmol) was added and the mixture was
heated (microwave irradiation, 90 °C, 6 h). The mixture was fil-
tered, washed with CH2Cl2 (20 mL), and the solvent removed in
vacuo. The residue was purified using the Biotage SP4 general pro-
cedure C, and the product recrystallised by dissolving the sample in
a minimum amount of CH2Cl2 and allowing n-hexane to diffuse into
the solution; yield: 50 mg (32%); red crystals; mp 174–176 °C.
(Z)-3-(4-Bromophenyl)-1-(4-cyanophenylamino)-2-(isoquino-
linium-2-yl)-3-oxoprop-1-ene-1-thiolate (4d)
A suspension of compound 3 (4.00 g, 9.83 mmol), 4-cyanophenyl
isothiocyanate (1.57 g, 9.83 mmol) and PS-NEt2 (3.38 g, 10.81
mmol) in CH2Cl2 (50 mL) was stirred overnight at r.t. The mixture
was filtered, the product washed from the polymer with CH2Cl2
(100 mL) and DMF (30 mL), and the solvent removed in vacuo. The
resultant solid was washed with PE (20 mL), a minimal volume of
CH2Cl2, and the product dried in vacuo to yield the title compound
as a bright yellow powder; yield: 4.28 g (89%).
IR: 3079.0 (w), 3027.2 (w), 2955.8 (w), 2881.7 (w), 2845.2 (w),
2223.2 (w), 1670.3 (w), 1634.2 (w), 1583.1 (m), 1564.5 (w), 1537.4
(m), 1507.8 (s), 1490.2 (m), 1416.8 (m), 1394.4 (s), 1370.0 (s),
1305.4 (m), 1271.4 (s), 1203.7 (m), 1181.4 (m), 1167.8 (s), 1155.9
(m), 1118.3 (m), 1083.0 (w), 1058.3 (m), 1008.9 (m), 968.2 (w),
949.5 (w), 934.5 (w), 890.4 (w), 874.2 (m), 840.9 (s), 820.4 (m),
783.4 (s), 766.7 (m), 754.5 (m), 745.2 (s), 732.9 (m), 709.2 (m),
692.5 (m), 672.4 (s) cm–1.
IR: 3315.2 (w), 2916.9 (w), 2217.5 (w), 1651.7 (m), 1617.8 (w),
1578.2 (m), 1546.4 (m), 1508.1 (m), 1483.2 (s), 1457.9 (m), 1413.6
(m), 1393.9 (m), 1372.5 (s), 1326.2 (m), 1294.3 (m), 1267.2 (m),
1244.1 (s), 1212.2 (s), 1173.6 (s), 1124.1 (m), 1112.7 (m), 1091.7
(m), 1069.8 (m), 1050.3 (m), 1035.9 (m), 1024.1 (m), 1008.9 (s),
962.2 (m), 941.0 (m), 896.1 (w), 880.8 (w), 867.1 (m), 844.8 (s),
832.1 (s), 779.9 (m), 768.4 (s), 758.2 (s), 729.7 (s), 713.3 (s), 702.5
(m), 680.9 (s), 657.9 (s) cm–1.
1H NMR (400 MHz, DMSO-d6): d = 14.92 (s, 1 H, NH), 10.10 (s, 1
H, 8H-isoquin), 8.57 (d, J = 6.8 Hz, 1 H, 2H-isoquin), 8.32 (d,
J = 8.3 Hz, 1 H, 7H-isoquin), 8.28 (d, J = 6.9 Hz, 1 H, 3H-isoquin),
8.20 (d, J = 7.8 Hz, 1 H, 4H-isoquin), 8.18–8.14 (m, 1 H, 5H-iso-
quin), 8.15 (d, J = 8.8 Hz, 2 H, 3H-PhCN), 7.96–7.92 (m, 1 H, 6H-
isoquin), 7.76 (d, J = 8.8 Hz, 2 H, 2H-PhCN), 7.28 (d, J = 8.6 Hz, 2
H, 2H-PhBr), 7.17 (d, J = 8.6 Hz, 2 H, 3H-PhBr).
13C NMR (100 MHz, DMSO-d6): d = 184.50 (C), 177.22 (C),
156.26 (CH), 145.20 (C), 141.25 (CH), 139.86 (C), 137.19 (CH),
136.80 (C), 132.85 (CH), 130.92 (CH), 130.76 (CH), 130.39 (CH),
128.42 (CH), 127.11 (CH), 126.91 (C), 125.28 (C), 124.23 (CH),
121.97 (CH), 121.84 (C), 119.19 (C), 105.19 (C).
1H NMR (400 MHz, DMSO-d6): d = 9.84 (s, 1 H, NH), 7.64 (d,
J = 8.6 Hz, 2 H, 2H-PhBr), 7.59 (d, J = 8.8 Hz, 2 H, 3H-PhCN),
7.50 (d, J = 8.6 Hz, 2 H, 3H-PhBr), 7.34 (d, J = 8.7 Hz, 2 H, 3H-
PhCl), 7.31 (d, J = 7.6 Hz, 1 H, 7H-isoquin), 7.24–7.20 (m, 1 H, 5H-
isoquin), 7.18–7.14 (m, 1 H, 6H-isoquin), 7.06 (d, J = 8.8 Hz, 2 H,
2H-PhCN), 7.02 (d, J = 7.5 Hz, 1 H, 4H-isoquin), 6.71 (d, J = 8.7
Hz, 2 H, 2H-PhCl), 6.23 (d, J = 7.4 Hz, 1 H, 2H-isoquin), 5.80 (s, 1
H, CH), 5.50 (d, J = 7.5 Hz, 1 H, 3H-isoquin).
13C NMR (125 MHz, DMSO-d6): d = 188.00 (C), 160.95 (C),
147.40 (C), 146.04 (C), 137.07 (C), 136.94 (C), 133.41 (CH),
131.75 (CH), 131.27 (CH), 131.24 (C), 130.61 (CH), 129.50 (CH),
129.30 (CH), 129.10 (C), 128.57 (C), 128.42 (CH), 126.14 (C),
125.58 (C), 125.39 (CH), 123.91 (CH), 120.92 (CH), 119.35 (C),
118.31 (CH), 102.98 (C), 101.91 (CH), 61.85 (CH).
HPLC-MS (A): tR = 4.65; m/z = 486.5 [M + H]+.
HRMS: m/z calcd for C25H17BrN3OS [M + H]+: 486.0276; found:
HPLC-MS (A): tR = 5.62, m/z = 625.8 [M + H]+.
HRMS: m/z calcd for C32H19BrClN4OS [M – H]–: 621.0157; found:
486.0283.
621.0140.
Synthesis 2008, No. 11, 1688–1702 © Thieme Stuttgart · New York

1698
M. D. Hopkin et al.
PAPER
X-ray Data38
4-[3-(4-Bromobenzoyl)-1-(4-methoxyphenylamino)pyrrolo[2,1-
a]isoquinolin-2-ylamino]benzonitrile (10db)
Prepared according to the general procedure D using 4-cyanophenyl
isothiocyanate (40 mg, 0.250 mmol) and 4-methoxyphenyl isocya-
nide (50 mg, 0.375 mmol); yield: 56 mg (38%); yellow solid; mp
129–132 °C.
Formula: C32H20BrClN4OS·CH2Cl2; Unit cell parameters: a =
6.3155(1), b = 13.5360(3), c = 17.2911(4), a = 92.617(1), b =
92.544(1), g = 92.462(1), space group P1.
One-Pot Preparation for Indolizines; General Procedure D
A suspension of compound 3 (100 mg, 0.246 mmol), an isothiocy-
anate, and PS-NEt2 (86 mg, 0.270 mmol) in CH2Cl2 (4.5 mL) was
stirred at r.t. overnight. An isocyanide (1 equiv) was added and the
mixture heated (microwave irradiation, 90 °C, 6 h). TFA (37 mL, 0.5
mmol) was added and the mixture again heated (microwave irradi-
ation, 90 °C, 10 min). PS-CO3 (239 mg, 0.626 mmol) was added,
and after stirring (15 min), the mixture was filtered, washed with
CH2Cl2 (20 mL) and the solvent removed in vacuo. The residue was
purified by chromatography using a Biotage SP4 following general
procedure C.
IR: 3319.0 (w), 3059.2 (w), 2831.8 (w), 2215.3 (w), 1728.1 (w),
1602.2 (m), 1584.3 (m), 1559.0 (w), 1505.9 (s), 1479.9 (m), 1435.5
(m), 1396.6 (s), 1372.3 (s), 1357.0 (s), 1319.8 (m), 1286.4 (m),
1231.6 (s), 1170.1 (s), 1127.0 (m), 1108.3 (m), 1067.2 (m), 1034.2
(m), 1009.5 (m), 937.0 (s), 891.9 (w), 857.9 (m), 821.1 (s), 794.5
(s), 766.3 (m), 744.5 (m), 713.4 (m), 691.1 (m), 679.1 (m) cm–1.
1H NMR (600 MHz, DMSO-d6): d = 9.19 (d, J = 7.6 Hz, 1 H, 2H-
isoquin), 8.45 (d, J = 8.2 Hz, 1 H, 7H-isoquin), 8.07 (s, 1 H, NH),
7.80 (d, J = 7.8 Hz, 1 H, 4H-isoquin), 7.54–7.52 (m, 1 H, 5H-iso-
quin), 7.46–7.44 (m, 1 H, 6H-isoquin), 7.37 (d, J = 8.6 Hz, 2 H, 2H-
PhBr), 7.33 (d, J = 8.6 Hz, 2 H, 3H-PhBr), 7.27 (d, J = 7.6 Hz, 1 H,
3H-isoquin), 7.21 (d, J = 8.8 Hz, 2 H, 3H-PhCN), 7.00 (s, 1 H, NH),
6.60 (d, J = 9.0 Hz, 2 H, 3H-PhOMe), 6.43 (d, J = 9.0 Hz, 2 H, 2H-
PhOMe), 6.38 (d, J = 8.8 Hz, 2 H, 2H-PhCN), 3.56 (s, 3 H, OCH3).
13C NMR (150 MHz, DMSO-d6): d = 184.19 (C), 152.12 (C),
150.42 (C), 140.85 (C), 138.68 (C), 133.13 (CH), 132.37 (C),
131.24 (CH), 130.72 (CH), 129.84 (C), 129.15 (C), 128.42 (CH),
128.15 (CH), 127.07 (CH), 125.36 (C), 124.89 (CH), 124.81 (CH),
124.28 (C), 120.62 (C), 117.63 (C), 115.95 (C), 115.00 (CH),
114.55 (CH), 114.13 (CH), 113.28 (CH), 98.47 (C), 55.62 (CH3).
4-[3-(4-Bromobenzoyl)-1-(4-chlorophenylamino)pyrrolo[2,1-
a]isoquinolin-2-ylamino]benzonitrile (10da)
Method 1: Prepared according to the general procedure D using 4-
cyanophenyl isothiocyanate (40 mg, 0.250 mmol) and 4-chlorophe-
nyl isocyanide (52 mg, 0.378 mmol). The product was recrystallised
by dissolving the sample in a minimum amount of CH2Cl2 and al-
lowing n-hexane to diffuse into the solution.
Method 2: The reaction was repeated using identical conditions to
Method 1, except TFA (3.7 mL, 0.050 mmol) followed by heating
(90 °C, 45 min) and PS-CO3 (48 mg, 0.126 mmol).
HPLC-MS (A): tR = 5.25; m/z = 589.8 [M + H]+.
HRMS: m/z calcd for C33H22BrN4O2 [M – H]–: 585.0926; found:
Method 3: The reaction was repeated using identical conditions to
Method 2, except heating was performed in both cases by immers-
ing the sealed microwave tube into a pre-heated oil bath at 90 °C.
After 6 h, the tube was removed and cooled under running cold
H2O; yield: Method 1, 70 mg (47%); Method 2, 67 mg (45%);
Method 3, 67 mg (45%); yellow solid; mp 134–136 °C.
585.0944.
{2-[3,5-Bis(trifluoromethyl)phenylamino]-1-(4-chlorophenyl-
amino)pyrrolo[2,1-a]isoquinolin-3-yl}(4-bromophenyl)metha-
none (10ea)
Prepared according to the general procedure D using 3,5-bis(tri-
fluoromethyl)phenyl isothiocyanate (46 mL, 0.251 mmol) and 4-
chlorophenyl isocyanide (52 mg, 0.378 mmol); yield: 87 mg (48%);
yellow solid; mp 103–106 °C.
IR: 3331.4 (w), 3224.1 (w), 3157.2 (w), 3049.9 (w), 2927.2 (w),
2854.1 (w), 2204.8 (m), 1733.0 (w), 1681.3 (w), 1599.2 (m), 1575.5
(s), 1554.1 (m), 1522.4 (s), 1489.4 (s), 1433.4 (m), 1404.7 (s),
1391.6 (s), 1372.8 (s), 1355.7 (s), 1320.3 (s), 1263.6 (s), 1213.3 (s),
1168.4 (s), 1144.7 (s), 1104.3 (m), 1091.4 (s), 1065.5 (s), 1033.3
(m), 1007.8 (s), 960.6 (m), 939.4 (s), 890.0 (m), 869.8 (m), 853.9
(m), 835.6 (s), 818.0 (s), 796.9 (s), 776.2 (s), 758.4 (s), 743.0 (s),
734.6 (s), 697.7 (s), 685.1 (s), 673.4 (m), 654.9 (s) cm–1.
1H NMR (400 MHz, DMSO-d6): d = 9.18 (d, J = 7.6 Hz, 1 H, 2H-
isoquin), 8.43 (d, J = 7.8 Hz, 1 H, 7H-isoquin), 8.07 (s, 1 H, NH),
7.82 (d, J = 7.9 Hz, 1 H, 4H-isoquin), 7.54 (s, 1 H, NH), 7.57–7.53
(m, 1 H, 5H-isoquin), 7.51–7.47 (m, 1 H, 6H-isoquin), 7.39 (d,
J = 8.7 Hz, 2 H, 2H-PhBr), 7.34 (d, J = 8.7 Hz, 2 H, 3H-PhBr), 7.28
(d, J = 7.6 Hz, 1 H, 3H-isoquin), 7.23 (d, J = 8.9 Hz, 2 H, 3H-Ph-
CN), 6.99 (d, J = 8.9 Hz, 2 H, 3H-PhCl), 6.48 (d, J = 8.9 Hz, 2 H,
2H-PhCl), 6.40 (d, J = 8.9 Hz, 2 H, 2H-PhCN).
13C NMR (125 MHz, DMSO-d6): d = 183.91 (C), 149.84 (C),
145.79 (C), 138.29 (C), 132.80 (CH), 132.20 (C), 130.94 (CH),
130.41 (CH), 129.45 (C), 128.85 (C), 128.75 (CH), 128.26 (CH),
127.94 (CH), 126.91 (CH), 125.11 (C), 124.54 (CH), 124.09 (CH),
123.76 (C), 120.56 (C), 120.29 (C), 115.76 (C), 115.54 (C), 114.54
(CH), 113.87 (CH), 113.01 (CH), 98.19 (C).
HPLC-MS (A): tR = 5.42; m/z = 593.8 [M + H]+.
HRMS: m/z calcd for C32H19BrClN4O [M – H]–: 589.0436; found:
IR: 3318.6 (w), 3133.2 (w), 3060.9 (w), 2968.6 (w), 2928.2 (w),
1723.0 (w), 1620.0 (w), 1585.7 (m), 1560.0 (w), 1527.5 (w), 1490.8
(m), 1471.0 (m), 1446.4 (m), 1422.0 (w), 1373.4 (s), 1357.0 (s),
1327.0 (w), 1274.0 (s), 1215.0 (w), 1168.4 (s), 1124.8 (s), 1093.8
(m), 1067.9 (m), 1045.8 (m), 1010.5 (m), 958.4 (m), 936.0 (m),
886.6 (m), 870.3 (m), 847.5 (m), 835.7 (m), 818.8 (m), 795.1 (m),
743.6 (m), 720.0 (m), 700.7 (m), 681.8 (m) cm–1.
1H NMR (600 MHz, DMSO-d6): d = 9.19 (d, J = 7.5 Hz, 1 H, 2H-
isoquin), 8.38 (d, J = 8.4 Hz, 1 H, 7H-isoquin), 8.15 (s, 1 H, NH),
7.84 (d, J = 7.8 Hz, 1 H, 4H-isoquin), 7.73 (s, 1 H, NH), 7.57–7.55
(m, 1 H, 5H-isoquin), 7.50–7.48 (m, 1 H, 6H-isoquin), 7.32–7.31
(m, 4 H, PhBr), 7.30 (d, J = 7.5 Hz, 1 H, 3H-isoquin), 7.03 [s, 1 H,
4H-bis(CF3)Ph], 7.02 (d, J = 8.4 Hz, 2 H, 3H-PhCl), 6.79 [s, 2 H,
2H-bis(CF3)Ph], 6.56 (d, J = 8.4 Hz, 2 H, 2H-PhCl).
13C NMR (125 MHz, DMSO-d6): d = 183.81 (C), 147.94 (C),
145.79 (C), 138.21 (C), 132.22 (C), 130.55 (CH), 130.43 (C, q,
J = 32.3 Hz), 130.38 (CH), 129.57 (C), 128.91 (C), 128.80 (CH),
128.26 (CH), 127.93 (CH), 126.87 (CH), 125.16 (C), 124.65 (C),
124.20 (CH), 123.70 (CH), 123.38 (C, q, J = 272.8 Hz), 120.79 (C),
115.41 (C), 115.00 (C), 114.66 (CH), 113.41 (CH, q, J = 3.4 Hz),
113.10 (CH), 109.70 (CH, sept, J = 3.8 Hz).
589.0463.
X-ray Data39
HPLC-MS (A): tR = 5.86; m/z = 704.7 [M + H]+.
Formula: C32H20BrClN4O·0.5(C6H14); Unit cell parameters: a =
24.3218(3), b = 14.9314(2), c = 7.88920(10), a = 90.00, b = 90.00,
g = 90.00, space group Pca2(1).
HRMS: m/z calcd for C33H18BrClF6N3O [M – H]–: 700.0226; found:
700.0228.
Synthesis 2008, No. 11, 1688–1702 © Thieme Stuttgart · New York

PAPER
Synthesis of Amino-Substituted Pyrroloisoquinolines and Pyrroloquinolines
1699
{2-[3,5-Bis(trifluoromethyl)phenylamino]-1-(4-methoxyphe-
nylamino)pyrrolo[2,1-a]isoquinolin-3-yl}(4-bromophenyl)me-
thanone (10eb)
Prepared according to the general procedure D using 3,5-bis(tri-
fluoromethyl)phenyl isothiocyanate (46 mL, 0.251 mmol), 4-meth-
oxyphenyl isocyanide (50 mg, 0.375 mmol), except heated (7 h)
after the addition of isocyanide; yield: 69 mg (40%); yellow solid;
mp 94–96 °C.
13C NMR (125 MHz, DMSO-d6): d = 181.42 (C), 151.55 (C),
145.14 (C), 141.59 (C), 139.74 (C), 139.44 (C), 132.05 (CH),
132.03 (C), 130.21 (CH), 129.54 (C), 128.42 (CH), 128.28 (CH),
127.34 (CH), 127.30 (CH), 127.10 (CH), 126.57 (CH), 125.11
(CH), 124.77 (C), 124.62 (CH), 123.36 (C), 115.00 (CH), 113.63
(CH), 112.15 (C), 109.79 (CH), 108.84 (C), 55.29 (CH3), 48.52
(CH2).
HPLC-MS (A): tR = 5.54; m/z = 576.3 [M + H]+.
IR: 3313.3 (w), 3067.2 (w), 2930.8 (w), 2836.7 (w), 1585.4 (m),
1560.0 (w), 1526.9 (w), 1507.8 (s), 1470.5 (m), 1445.0 (m), 1421.9
(m), 1373.1 (s), 1356.7 (s), 1327.2 (w), 1274.3 (s), 1234.6 (m),
1168.5 (s), 1124.5 (s), 1108.1 (s), 1067.8 (m), 1035.0 (m), 1010.8
(m), 958.4 (m), 935.4 (m), 886.6 (m), 869.7 (m), 847.0 (m), 821.8
(m), 794.6 (m), 744.4 (m), 720.4 (m), 700.8 (m), 681.7 (s), 654.3
(m) cm–1.
1H NMR (600 MHz, DMSO-d6): d = 9.21 (d, J = 7.5 Hz, 1 H, 2H-
isoquin), 8.43 (d, J = 8.2 Hz, 1 H, 7H-isoquin), 8.13 (s, 1 H, NH),
7.82 (d, J = 7.6 Hz, 1 H, 4H-isoquin), 7.55–7.53 (m, 1 H, 5H-iso-
quin), 7.47–7.45 (m, 1 H, 6H-isoquin), 7.31–7.29 (m, 4 H, PhBr),
7.28 (d, J = 7.5 Hz, 1 H, 3H-isoquin), 7.18 (s, 1 H, NH), 7.02 [s, 1
H, 4H-bis(CF3)Ph], 6.76 [s, 2 H, 2H-bis(CF3)Ph], 6.63 (d, J = 9.0
Hz, 2 H, 3H-PhOMe), 6.49 (d, J = 9.0 Hz, 2 H, 2H-PhOMe), 3.57
(s, 3 H, OCH3).
13C NMR (125 MHz, DMSO-d6): d = 183.72 (C), 151.84 (C),
148.12 (C), 140.49 (C), 138.24 (C), 132.01 (C), 130.52 (CH),
130.38 (C, q, J = 34.7 Hz), 130.34 (CH), 129.59 (C), 128.85 (C),
128.12 (CH), 127.82 (CH), 126.72 (CH), 125.08 (C), 124.68 (CH),
124.55 (CH), 123.86 (C), 123.39 (C, q, J = 272.8 Hz), 117.14 (C),
114.84 (C), 114.68 (CH), 114.24 (CH), 113.27 (CH, q, J = 3.3 Hz),
113.05 (CH), 109.55 (CH, septet, J = 3.8 Hz), 55.25 (CH3).
HRMS: m/z calcd for C33H27BrN3O2 [M + H]+: 576.1281; found:
576.1275.
2-(4-Nitrobenzyl)isoquinolinium Bromide
4-Nitrobenzyl bromide (10.00 g, 46.29 mmol) was dissolved in
CH2Cl2 (80 mL). Isoquinoline (5.46 mL, 46.45 mmol) was added
dropwise to the mixture followed by stirring overnight at r.t. The
mixture was filtered under suction and the product washed with ice-
cold CH2Cl2 (20 mL). The solid was dried in vacuo; yield: 14.1 g
(88%); pale yellow solid.
IR: 3442.4 (w), 3395.4 (w), 3052.2 (w), 3015.3 (w), 2968.6 (w),
2934.6 (m), 1641.7 (m), 1608.5 (m), 1532.6 (m), 1515.7 (m),
1493.8 (w), 1471.8 (w), 1393.6 (m), 1370.7 (w), 1345.0 (s), 1323.2
(m), 1284.9 (m), 1247.7 (w), 1212.4 (w), 1172.9 (w), 1150.8 (m),
1119.4 (m), 1108.5 (m), 1017.6 (w), 975.4 (w), 921.9 (w), 869.1
(w), 854.0 (m), 838.7 (m), 810.6 (m), 783.7 (w), 770.6 (w), 758.2
(m), 717.9 (s), 692.8 (m), 655.8 (w) cm–1.
1H NMR (600 MHz, DMSO-d6): d = 10.30 (s, 1 H, 8H-isoquin),
8.83 (d, J = 6.9 Hz, 1 H, 2H-isoquin), 8.63 (d, J = 6.9 Hz, 1 H, 3H-
isoquin), 8.53 (d, J = 8.3 Hz, 1 H, 7H-isoquin), 8.36 (d, J = 8.3 Hz,
1 H, 4H-isoquin), 8.30–8.27 (m, 1 H, 5H-isoquin), 8.27 (d, J = 8.7
Hz, 2 H, 3H-PhNO2), 8.11–8.08 (m, 1 H, 6H-isoquin), 7.81 (d,
J = 8.7 Hz, 2 H, 2H-PhNO2), 6.15 (s, 2 H, CH2).
HPLC-MS (A): tR = 5.67; m/z = 698.7 [M + H]+.
HRMS: m/z calcd for C34H21BrF6N3O2 [M – H]–: 696.0721; found:
696.0748.
13C NMR (150 MHz, DMSO-d6): d = 151.33 (CH), 148.35 (C),
141.70 (C), 137.82 (CH), 137.64 (C), 135.41 (CH), 131.87 (CH),
131.19 (CH), 130.60 (CH), 127.83 (CH, C), 126.88 (CH), 124.55
(CH), 62.64 (CH2).
[2-(Benzylamino)-1-(4-methoxyphenylamino)pyrrolo[2,1-a]iso-
quinolin-3-yl](4-bromophenyl)methanone (10fb)
HPLC-MS (A): tR = 3.16; m/z = 265.3 [M – Br]+.
A suspension of 3 (100 mg, 0.246 mmol), benzyl isothiocyanate (33
mL, 0.248 mmol) and PS-NEt2 (86 mg, 0.270 mmol) in CH2Cl2 (4.5
mL) was stirred overnight at r.t., and then heated (microwave irra-
diation, 90 °C, 30 min). 4-Methoxyphenyl isocyanide (50 mg, 0.375
mmol) was added and the mixture heated (microwave irradiation,
90 °C, 8 h). TFA (3.7 mL, 0.050 mmol) was then added and the mix-
ture heated (microwave irradiation, 90 °C, 40 min). PS-CO3 (48 mg,
0.126 mmol) was added, and after stirring (15 min), the mixture was
filtered, washed with CH2Cl2 (20 mL) and the solvent removed in
vacuo. The residue was purified by chromatography using a Biotage
SP4 following general procedure C; yield: 45 mg (31%); yellow
solid; mp 82–84 °C.
HRMS: m/z calcd for C16H13N2O2 [M – Br]+: 265.0977; found:
265.0974.
This compound was not used in the procedures due to the insolubil-
ity of the compound in CH2Cl2.
2-(Cyanomethyl)isoquinolinium Bromide (12)
Bromoacetonitrile (7.50 mL, 107.54 mmol) was dissolved in
CH2Cl2 (80 mL). Isoquinoline (12.64 mL, 108.62 mmol) was added
dropwise to the mixture followed by stirring overnight at r.t. The
solvent was removed in vacuo, the residue was washed with PE (20
mL) and Et2O (10 mL), and dried in vacuo; yield: 17.3 g (65%); pale
yellow solid.
IR: 3291.7 (w), 3028.9 (w), 2928.8 (w), 2831.0 (w), 1731.5 (w),
1691.3 (w), 1575.8 (m), 1558.1 (m), 1506.1 (s), 1483.1 (m), 1463.7
(m), 1449.2 (m), 1409.0 (s), 1376.4 (m), 1352.1 (s), 1288.6 (m),
1232.0 (s), 1173.0 (m), 1106.1 (m), 1067.3 (m), 1033.2 (m), 1005.4
(m), 919.5 (m), 820.1 (s), 786.1 (s), 735.1 (s), 697.0 (s), 664.6 (s)
cm–1.
IR: 3028.6 (w), 2999.2 (w), 2916.6 (w), 2885.4 (w), 2252.7 (w),
1637.6 (m), 1605.2 (w), 1505.4 (w), 1465.8 (w), 1395.8 (m), 1377.8
(m), 1332.8 (w), 1287.7 (w), 1222.7 (w), 1189.3 (m), 1158.8 (m),
1126.0 (m), 1015.4 (w), 989.6 (m), 972.0 (w), 948.5 (w), 897.7 (m),
880.8 (s), 846.3 (s), 771.6 (s), 761.2 (s), 741.1 (m) cm–1.
1H NMR (600 MHz, DMSO-d6): d = 8.54 (d, J = 8.1 Hz, 1 H, 7H-
isoquin), 8.10 (d, J = 7.4 Hz, 1 H, 2H-isoquin), 7.69 (d, J = 8.4 Hz,
2 H, 2H-PhBr), 7.65 (d, J = 7.7 Hz, 1 H, 4H-isoquin), 7.53 (d,
J = 8.4 Hz, 2 H, 3H-PhBr), 7.48–7.45 (m, 1 H, 5H-isoquin), 7.39–
7.37 (m, 1 H, 6H-isoquin), 7.21–7.17 (m, 4 H, 3H-Ph, 4H-Ph and
NH), 6.98 (d, J = 6.6 Hz, 2 H, 2H-Ph), 6.86 (d, J = 7.4 Hz, 1 H, 3H-
isoquin), 6.72 (d, J = 8.9 Hz, 2 H, 3H-PhOMe), 6.55 (d, J = 8.9 Hz,
2 H, 2H-PhOMe), 6.12 (br s, 1 H, NH), 4.27 (br s, 2 H, CH2), 3.62
(s, 3 H, OCH3).
1H NMR (500 MHz, DMSO-d6): d = 10.26 (s, 1 H, 8H-isoquin),
8.88 (d, J = 6.8 Hz, 1 H, 2H-isoquin), 8.69 (d, J = 6.8 Hz, 1 H, 3H-
isoquin), 8.59 (d, J = 8.3 Hz, 1 H, 7H-isoquin), 8.40 (d, J = 8.3 Hz,
1 H, 4H-isoquin), 8.34–8.31 (m, 1 H, 5H-isoquin), 8.13–8.10 (m, 1
H, 6H-isoquin), 6.17 (s, 2 H, CH2).
13C NMR (125 MHz, DMSO-d6): d = 151.67 (CH), 138.11 (CH),
137.57 (C), 134.70 (CH), 131.75 (CH), 131.09 (CH), 127.54 (CH),
127.09 (C), 126.38 (CH), 114.42 (C), 47.60 (CH2).
HPLC-MS (A): tR = 3.67; m/z = 169.8 [M – Br]+.
Synthesis 2008, No. 11, 1688–1702 © Thieme Stuttgart · New York

1700
M. D. Hopkin et al.
PAPER
One-Pot Preparation of Nitrile-Substituted Indolizines; Gener-
al Procedure E
13C NMR (125 MHz, DMSO-d6): d = 151.79 (C), 148.57 (C),
140.33 (C), 133.92 (C), 133.33 (CH), 128.30 (C), 128.04 (CH),
128.01 (C), 127.94 (CH), 127.18 (CH), 124.01 (C), 123.80 (CH),
123.35 (CH), 120.03 (C), 114.81 (CH), 114.68 (C), 114.66 (CH),
114.05 (CH), 113.04 (CH), 112.92 (C), 99.57 (C), 89.94 (C), 55.28
(CH3).
HPLC-MS (A): tR = 4.89; m/z = 430.3 [M + H]+.
HRMS: m/z calcd for C27H18N5O [M – H]–: 428.1511; found:
A mixture of compound 12 (63 mg, 0.253 mmol), an isothiocyanate
(1 equiv), and PS-NEt2 (86 mg, 0.270 mmol) in CH2Cl2 (4.5 mL)
was stirred at r.t. overnight. An isocyanide was then added and the
mixture heated (microwave irradiation, 90 °C, 6 h). TFA (3.7 mL,
0.050 mmol) was added and the mixture again heated (microwave
irradiation, 90 °C, 1 h). PS-CO3 (48 mg, 0.126 mmol) was added,
and after stirring (15 min), the mixture was filtered, washed with
CH2Cl2 (20 mL), and the solvent removed in vacuo. The residue
was purified by chromatography using a Biotage SP4 following
general procedure C.
428.1527.
2-[3,5-Bis(trifluoromethyl)phenylamino]-1-(4-chlorophenyl-
amino)pyrrolo[2,1-a]isoquinoline-3-carbonitrile (13ea)
Prepared according to the general procedure E using 3,5-bis(tri-
fluoromethyl)phenyl isothiocyanate (46 mL, 0.251 mmol) and 4-
chlorophenyl isocyanide (52 mg, 0.378 mmol); yield: 31 mg (23%);
pale red solid; mp 174–178 °C.
1-(4-Chlorophenylamino)-2-(4-cyanophenylamino)pyrrolo[2,1-
a]isoquinoline-3-carbonitrile (13da)
Prepared according to the general procedure E using 4-cyanophenyl
isothiocyanate (40 mg, 0.250 mmol) and 4-chlorophenyl isocyanide
(52 mg, 0.378 mmol); yield: 15 mg (14%); pale red solid; mp
206 °C (dec.).
IR: 3313.0 (w), 3075.0 (w), 2934.1 (w), 2199.3 (w), 1621.2 (w),
1597.5 (w), 1549.9 (w), 1492.0 (m), 1473.3 (m), 1450.0 (m), 1429.4
(w), 1409.8 (w), 1374.6 (s), 1302.9 (w), 1274.3 (s), 1169.2 (s),
1124.1 (s), 1046.3 (m), 1001.1 (m), 950.8 (m), 871.6 (m), 843.6 (w),
819.1 (m), 787.1 (s), 772.9 (m), 748.9 (m), 724.9 (m), 701.0 (m),
682.1 (s) cm–1.
1H NMR (600 MHz, DMSO-d6): d = 8.88 (s, 1 H, NH), 8.27 (d,
J = 7.7 Hz, 1 H, 7H-isoquin), 8.18 (d, J = 7.3 Hz, 1 H, 2H-isoquin),
7.83 (d, J = 7.7 Hz, 1 H, 4H-isoquin), 7.80 (s, 1 H, NH), 7.54–7.52
(m, 1 H, 5H-isoquin), 7.49–7.47 (m, 1 H, 6H-isoquin), 7.39 [s, 2 H,
2H-bis(CF3)Ph], 7.27 [s, 1 H, 4H-bis(CF3)Ph], 7.26 (d, J = 7.3 Hz,
1 H, 3H-isoquin), 7.01 (d, J = 8.8 Hz, 2 H, 3H-PhCl), 6.50 (d,
J = 8.8 Hz, 2 H, 2H-PhCl).
13C NMR (125 MHz, DMSO-d6): d = 145.73 (C), 145.21 (C),
133.64 (C), 130.90 (C, q, J = 32.4 Hz), 128.76 (CH), 128.73 (CH),
128.43 (C), 128.10 (CH), 127.90 (C), 127.30 (CH), 123.83 (C),
123.61 (CH), 123.47 (CH), 123.45 (C, q, J = 272.9 Hz), 120.89 (C),
114.87 (CH, q, J = 3.2 Hz), 114.62 (CH), 113.07 (CH), 112.78 (C),
112.53 (C), 111.33 (CH, sept, J = 3.6 Hz), 89.38 (C).
IR: 3362.9 (w), 3275.0 (w), 3051.3 (w), 2924.0 (w), 2853.0 (w),
2222.7 (m), 2194.7 (m), 1602.7 (m), 1578.0 (m), 1543.0 (m),
1509.3 (m), 1491.7 (s), 1455.7 (m), 1430.2 (m), 1418.9 (m), 1381.4
(m), 1357.4 (m), 1304.3 (m), 1287.3 (m), 1258.5 (m), 1240.9 (m),
1213.0 (w), 1173.4 (m), 1153.3 (m), 1114.3 (w), 1087.7 (m), 1064.4
(w), 1007.0 (w), 966.9 (w), 949.6 (w), 923.0 (w), 900.8 (w), 884.1
(w), 861.3 (w), 828.8 (m), 814.7 (s), 786.9 (s), 770.7 (m), 739.8 (m),
687.3 (w), 670.6 (m) cm–1.
1H NMR (600 MHz, DMSO-d6): d = 8.82 (s, 1 H, NH), 8.29 (d,
J = 8.0 Hz, 1 H, 7H-isoquin), 8.17 (d, J = 7.3 Hz, 1 H, 2H-isoquin),
7.83 (d, J = 7.8 Hz, 1 H, 4H-isoquin), 7.72 (s, 1 H, NH), 7.54–7.52
(m, 1 H, 5H-isoquin), 7.50 (d, J = 8.7 Hz, 2 H, 3H-PhCN), 7.50–
7.47 (m, 1 H, 6H-isoquin), 7.27 (d, J = 7.3 Hz, 1 H, 3H-isoquin),
7.01 (d, J = 8.8 Hz, 2 H, 3H-PhCl), 6.94 (d, J = 8.7 Hz, 2 H, 2H-Ph-
CN), 6.49 (d, J = 8.8 Hz, 2 H, 2H-PhCl).
13C NMR (125 MHz, DMSO-d6): d = 148.40 (C), 145.60 (C),
134.03 (C), 133.32 (CH), 128.77 (CH), 128.39 (C), 128.17 (CH),
128.13 (CH), 128.01 (C), 127.34 (CH), 123.84 (C), 123.48 (CH),
123.36 (CH), 120.73 (C), 120.01 (C), 114.91 (CH), 114.52 (CH),
113.17 (CH), 113.03 (C), 112.82 (C), 99.69 (C), 90.14 (C).
HPLC-MS (A): tR = 5.55; m/z = 545.3 [M + H]+.
HRMS: m/z calcd for C27H14ClF6N4 [M – H]–: 543.0811; found:
543.0837.
HPLC-MS (A): tR = 5.03; m/z = 576.3 [M + H]+.
HRMS: m/z calcd for C26H15ClN5 [M – H]–: 432.1016; found:
432.1036.
2-[3,5-Bis(trifluoromethyl)phenylamino]-1-(4-methoxyphenyl-
amino)pyrrolo[2,1-a]isoquinoline-3-carbonitrile (13eb)
Prepared according to the general procedure E using 3,5-bis(tri-
fluoromethyl)phenyl isothiocyanate (46 mL, 0.251 mmol), 4-meth-
oxyphenyl isocyanide (50 mg, 0.375 mmol); yield: 39 mg (29%);
pale yellow solid; mp 159–161 °C.
2-(4-Cyanophenylamino)-1-(4-methoxyphenylamino)pyrro-
lo[2,1-a]isoquinoline-3-carbonitrile (13db)
Prepared according to the general procedure E using 4-cyanophenyl
isothiocyanate (40 mg, 0.250 mmol) and 4-methoxyphenyl isocya-
nide (50 mg, 0.375 mmol); yield: 23 mg (21%); pale yellow solid;
mp 215 °C (dec.).
IR: 3326.3 (w), 3070.8 (w), 2936.7 (w), 2836.0 (w), 2197.9 (w),
1620.7 (w), 1557.5 (w), 1507.7 (s), 1471.6 (m), 1448.8 (w), 1429.0
(w), 1410.4 (w), 1368.1 (s), 1327.3 (w), 1274.4 (s), 1233.0 (m),
1168.8 (s), 1123.7 (s), 1067.1 (m), 1035.6 (m), 999.3 (m), 949.9
(m), 870.1 (m), 821.5 (m), 786.6 (m), 744.5 (m), 722.4 (m), 701.0
(m), 681.5 (m) cm–1.
1H NMR (600 MHz, DMSO-d6): d = 8.84 (s, 1 H, NH), 8.31 (d,
J = 8.2 Hz, 1 H, 7H-isoquin), 8.16 (d, J = 7.3 Hz, 1 H, 2H-isoquin),
7.81 (d, J = 7.8 Hz, 1 H, 4H-isoquin), 7.52–7.50 (m, 1H, 5H-iso-
quin), 7.46–7.44 (m, 1 H, 6H-isoquin), 7.38 [s, 2 H, 2H-
bis(CF3)Ph], 7.25 [s, 2 H, NH and 4H-bis(CF3)Ph], 7.24 (d, J = 7.3
Hz, 1 H, 3H-isoquin), 6.61 (d, J = 8.8 Hz, 2 H, 3H-PhOMe), 6.44
(d, J = 8.8 Hz, 2 H, 2H-PhOMe), 3.57 (s, 3 H, OCH3).
IR: 3369.9 (w), 3273.9 (w), 3051.1 (w), 2953.7 (w), 2833.3 (w),
2221.9 (m), 2189.2 (m), 1604.1 (m), 1578.3 (m), 1543.1 (m),
1506.7 (s), 1494.0 (s), 1456.0 (m), 1431.4 (m), 1419.8 (m), 1402.5
(s), 1378.6 (s), 1356.4 (m), 1314.9 (m), 1289.7 (m), 1257.0 (m),
1230.3 (s), 1173.6 (s), 1129.9 (m), 1107.2 (m), 1064.1 (w), 1034.8
(m), 968.0 (w), 947.9 (w), 900.6 (w), 885.1 (w), 860.3 (w), 838.6
(m), 815.4 (s), 784.0 (s), 759.3 (m), 742.5 (m), 718.4 (m), 697.1
(m), 670.0 (m) cm–1.
1H NMR (600 MHz, DMSO-d6): d = 8.77 (s, 1 H, NH), 8.32 (d,
J = 8.1 Hz, 1 H, 7H-isoquin), 8.15 (d, J = 7.3 Hz, 1 H, 2H-isoquin),
7.81 (d, J = 7.9 Hz, 1 H, 4H-isoquin), 7.52–7.50 (m, 1 H, 5H-iso-
quin), 7.49 (d, J = 8.8 Hz, 2 H, 3H-PhCN), 7.46–7.44 (m, 1 H, 6H-
isoquin), 7.24 (d, J = 7.3 Hz, 1 H, 3H-isoquin), 7.17 (s, 1 H, NH),
6.95 (d, J = 8.8 Hz, 2 H, 2H-PhCN), 6.62 (d, J = 8.9 Hz, 2 H, 3H-
PhOMe), 6.44 (d, J = 8.9 Hz, 2 H, 2H-PhOMe), 3.57 (s, 3 H,
OCH3).
13C NMR (125 MHz, DMSO-d6): d = 151.86 (C), 145.93 (C),
139.93 (C), 133.48 (C), 130.87 (C, q, J = 32.3 Hz), 128.34 (C),
127.98 (CH), 127.92 (CH), 127.86 (C), 127.15 (CH), 124.03 (C),
123.90 (CH), 123.61 (CH), 123.48 (C, q, J = 272.9 Hz), 123.45
(CH), 114.71 (CH, q, J = 3.6 Hz), 114.60 (CH), 114.24 (C), 114.13
Synthesis 2008, No. 11, 1688–1702 © Thieme Stuttgart · New York

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Synthesis of Amino-Substituted Pyrroloisoquinolines and Pyrroloquinolines
1701
(CH), 112.96 (CH), 112.87 (C), 111.12 (CH, sept, J = 3.6 Hz),
2 H, 3H-PhCl), 6.52 (d, J = 8.8 Hz, 2 H, 2H-PhCl), 6.48 (d, J = 8.7
89.22 (C), 55.25 (CH3).
Hz, 2 H, 2H-PhCN).
HPLC-MS (A): tR = 5.38; m/z = 541.3 [M + H]+.
HRMS: m/z calcd for C28H17F6N4O [M – H]–: 539.1307; found:
13C NMR (125 MHz, DMSO-d6): d = 184.39 (C), 149.53 (C),
145.78 (C), 137.57 (C), 132.81 (CH), 132.42 (C), 131.36 (CH),
131.21 (CH), 130.99 (C), 130.84 (C), 129.28 (CH), 128.51 (2 CH),
126.65 (C), 124.76 (C), 124.56 (CH), 123.91 (CH), 120.36 (C),
120.24 (C), 119.65 (C), 118.83 (CH), 115.69 (CH), 114.74 (C),
114.61 (CH), 114.14 (CH), 98.17 (C).
HPLC-MS (A): tR = 5.45; m/z = 593.2 [M + H]+.
HRMS: m/z calcd for C32H21BrClN4O [M + H]+: 591.0582; found
539.1318.
1-[2-(4-Bromophenyl)-2-oxoethyl]quinolinium Bromide (14)
To a solution of 2,4¢-dibromoacetophenone (5.56 g, 20 mmol) in
CH2Cl2 (60 mL) was added quinoline (1.90 mL, 20 mmol) drop-
wise. The mixture was stirred (r.t., 48 h), concentrated in vacuo and
filtered. The residual solid was washed with ice-cold CH2Cl2 (20
mL) and dried in vacuo; yield: 6.36 g (83%); cream solid.
591.0557.
IR: 3022.7 (w), 2957.2 (w), 1682.5 (s), 1625.5 (w), 1600.4 (w),
1585.8 (m), 1567.0 (m), 1529.5 (m), 1481.0 (w), 1458.8 (w), 1402.0
(m), 1375.2 (m), 1366.9 (m), 1347.3 (w), 1286.2 (w), 1236.7 (m),
1206.6 (w), 1187.2 (w), 1171.9 (w), 1149.0 (w), 1102.3 (w), 1075.3
(m), 1056.1 (w), 1011.3 (w), 992.8 (m), 966.4 (m), 952.6 (w), 878.2
(w), 869.5 (m), 838.8 (m), 825.9 (m), 811.0 (m), 800.5 (s), 772.8 (s),
748.9 (m), 734.0 (m), 695.7 (w) cm–1.
[2-(3,5-Bis(trifluoromethyl)phenylamino)-3-(4-chlorophenyl-
amino)pyrrolo[1,2-a]quinolin-1-yl](4-bromophenyl)metha-
none (15ea)
Prepared according to the general procedure F using 3,5-bis(tri-
fluoromethyl)phenyl isothiocyanate (46 mL, 68 mg, 0.251 mmol),
heating with TFA (30 min), and eluted with 40% PE in CH2Cl2;
yield: 80 mg (46%); yellow solid; mp 92–95 °C.
1H NMR (500 MHz, DMSO-d6): d = 9.48 (d, J = 5.9 Hz, 1 H, 2H-
quin), 9.43 (d, J = 8.4 Hz, 1 H, 4H-quin), 8.53 (dd, J = 8.2, 1.3 Hz,
1 H, 5H-quin), 8.46 (d, J = 9.0 Hz, 1 H, 8H-quin), 8.31 (dd, J = 8.4,
5.9 Hz, 1 H, 3H-quin), 8.21 (m, 1 H, 7H-quin), 8.06 (d, J = 8.6 Hz,
2 H, 2H-PhBr), 8.05 (m, 1 H, 6H-quin), 7.92 (d, J = 8.6 Hz, 2 H,
3H-PhBr), 6.98 (s, 2 H, CH2).
IR: 3315.4 (w), 3066.8 (w), 1583.5 (m), 1533.9 (m), 1505.8 (m),
1491.2 (m), 1471.1 (m), 1456.2 (m), 1404.3 (m), 1372.0 (s), 1325.4
(w), 1302.2 (w), 1275.0 (s), 1206.4 (w), 1169.8 (s), 1126.7 (s),
1107.7 (s), 1068.8 (m), 1006.2 (m), 956.1 (m), 912.5 (w), 873.9 (m),
841.9 (m), 818.6 (m), 800.0 (m), 776.3 (w), 746.4 (m), 724.5 (w),
700.9 (m), 681.8 (m) cm–1.
13C NMR (125 MHz, DMSO-d6): d = 190.61 (C), 151.45 (CH),
149.13 (CH), 139.13 (C), 136.40 (CH), 133.16 (C), 132.61 (CH),
131.08 (CH), 131.03 (CH), 130.46 (CH), 129.85 (C), 129.42 (C),
122.64 (CH), 119.65 (CH), 65.36 (CH2).
HPLC-MS (B): tR = 2.66; m/z = 328.0 [M – Br]+.
HRMS: m/z calcd for C17H13BrNO [M – Br]+: 328.0160; found
1H NMR (600 MHz, DMSO-d6): d = 8.30 (s, 1 H, NH), 7.86 (d,
J = 7.5 Hz, 1 H, 5H-quin), 7.71 (s, 1 H, NH), 7.57 (d, J = 8.5 Hz, 2
H, 2H-PhBr), 7.51 (d, J = 9.2 Hz, 1 H, 4H-quin), 7.47 (d, J = 8.7
Hz, 1 H, 8H-quin), 7.45 (d, J = 8.5 Hz, 2 H, 3H-PhBr), 7.42–7.40
(m, 1 H, 7H-quin), 7.39–7.37 (m, 1 H, 6H-quin), 7.31 (d, J = 9.2 Hz,
1 H, 3H-quin), 7.06 [s, 1 H, 4H-bis(CF3)Ph], 7.00 (d, J = 8.8 Hz, 2
H, 3H-PhCl), 6.88 [s, 2 H, 2H-bis(CF3)Ph], 6.53 (d, J = 8.8 Hz, 2 H,
2H-PhCl).
328.0163.
13C NMR (125 MHz, DMSO-d6): d = 184.33 (C), 146.94 (C),
145.25 (C), 137.60 (C), 132.48 (C), 131.26 (CH), 131.11 (CH),
130.63 (C), 130.51 (C), 130.35 (C, q, J = 32.8 Hz), 129.25 (CH),
128.46 (2 CH), 126.60 (C), 124.79 (C), 124.56 (CH), 123.92 (CH),
123.43 (C, q, J = 272.8 Hz), 120.65 (C), 119.22 (C), 118.97 (CH),
115.80 (CH), 114.70 (CH), 114.41 (C), 113.99 (CH, q, J = 3.4 Hz),
109.76 (CH, sept, J = 4.0 Hz).
Quinoline Based Indolizines; General Procedure F
A suspension of compound 14 (100 mg, 0.246 mmol), an isothiocy-
anate (1 equiv) and PS-NEt2 (86 mg, 0.270 mmol) in CH2Cl2 (4.5
mL) was stirred at r.t. (2 d). 4-Chlorophenyl isocyanide (52 mg,
0.378 mmol) was added and the mixture heated (microwave irradi-
ation, 90 °C, 6 h). TFA (3.7 mL, 0.050 mmol) was added and the
mixture again heated (microwave irradiation, 90 °C). PS-CO3 (48
mg, 0.126 mmol) was added, and after stirring (15 min), the mixture
was filtered, washed with CH2Cl2 (20 mL), and the solvent removed
in vacuo. The residue was purified by flash column chromatography
on silica gel 60 (0.040–0.063 mm) purchased from Breckland Sci-
entific Supplies.
HPLC-MS (A): tR = 5.87; m/z = 704.3 [M + H]+.
HRMS: m/z calcd for C33H18BrClF6N3O [M – H]–: 700.0226; found:
700.0253.
Acknowledgment
4-[1-(4-Bromobenzoyl)-3-(4-chlorophenylamino)pyrrolo[1,2-
a]quinolin-2-ylamino]benzonitrile (15da)
Prepared according to the general procedure F using 4-cyanophenyl
isothiocyanate (40 mg, 0.250 mmol), heating with TFA (50 min),
and eluted with 20% EtOAc in PE, then 10% PE in CH2Cl2; yield:
52 mg (35%); yellow solid; mp 114–118 °C.
We gratefully acknowledge financial support from Christopher Sel-
way and Pfizer Global R&D (M.D.H.), the Royal Society Wolfson
Fellowship (I.R.B. and S.V.L.), and the BP 1702 Professorship
(S.V.L.). We also wish to thank J. E. Davies for determining the cry-
stal structures of compounds 6d and 10da and the EPSRC for a fi-
nancial contribution toward the purchase of the X-ray
diffractometer.
IR: 3325.0 (w), 3063.1 (w), 2970.0 (w), 2217.2 (m), 1602.3 (s),
1582.7 (s), 1509.0 (s), 1489.7 (s), 1445.1 (m), 1398.7 (m), 1371.1
(s), 1345.0 (m), 1319.8 (m), 1302.8 (m), 1285.3 (m), 1250.4 (m),
1204.2 (m), 1171.2 (s), 1092.4 (m), 1068.3 (m), 1038.3 (w), 1003.7
(m), 954.8 (w), 917.8 (w), 884.8 (w), 818.5 (s), 800.1 (s), 776.2 (m),
746.6 (s), 691.1 (m), 680.5 (m) cm–1.
1H NMR (600 MHz, DMSO-d6): d = 8.24 (s, 1 H, NH), 7.85 (d,
J = 7.4 Hz, 1 H, 5H-quin), 7.58 (d, J = 8.4 Hz, 2 H, 2H-BrPh), 7.55
(s, 1 H, NH), 7.50 (d, J = 8.8 Hz, 1 H, 4H-quin), 7.48 (d, J = 8.4 Hz,
2 H, 3H-PhBr), 7.45 (d, J = 8.2 Hz, 1 H, 8H-quin), 7.42-7.39 (m, 1
H, 7H-quin), 7.39-7.36 (m, 1 H, 6H-quin), 7.29 (d, J = 8.8 Hz, 1 H,
3H-quin), 7.27 (d, J = 8.7 Hz, 2 H, 3H-PhCN), 7.00 (d, J = 8.8 Hz,
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Synthesis 2008, No. 11, 1688–1702 © Thieme Stuttgart · New York