Total Syntheses of the 3 H-Pyrrolo[2,3- c]quinolone-Containing Alkaloids Marinoquinolines A-F, K, and Aplidiopsamine A Using a Palladium-Catalyzed Ullmann Cross-Coupling/Reductive Cyclization Pathway

Article abstract of DOI:10.1021/acs.joc.9b02725

Compounds 1-6 and 11 representing key members of the marinoquinoline family of natural products, together with the related marine alkaloid aplidiopsamine A (12), have been synthesized using various combinations of palladium-catalyzed Ullmann cross-coupling and reductive cyclization processes involving a C3-arylated pyrrole as the common intermediate. These natural products have been characterized by single-crystal X-ray analyses and evaluated as inhibitors of acetylcholinesterase (AChE) with congener 2 proving to be the most active.

Full text of DOI:10.1021/acs.joc.9b02725

Subscriber access provided by Bibliothèque de l'Université Paris-Sud
Article
Total Syntheses of the 3H-Pyrrolo[2,3-c]quinolone-containing Alkaloids
Marinoquinolines A-F, K and Aplidiopsamine A Using a Palladium-
catalysed Ullmann Cross-coupling/Reductive Cyclization Pathway
Benoit Bolte, Christopher S Bryan, Phillip P. Sharp, Soheil Sayyahi, Charly Rihouey, Amy Kendrick,
Ping Lan, Martin G Banwell, Colin J. Jackson, Nicholas J Fraser, Anthony C. Willis, and James S Ward
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02725 • Publication Date (Web): 19 Nov 2019
Downloaded from pubs.acs.org on November 23, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
Total Syntheses of the 3H-Pyrrolo[2,3-c]quinolone-containing Alkaloids
Marinoquinolines A-F, K and Aplidiopsamine A Using a Palladium-catalysed
Ullmann Cross-coupling/Reductive Cyclization Pathway
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Benoit Bolte,† Christopher S. Bryan,† Phillip P. Sharp,† Soheil Sayyahi†
Charly Rihouey,† Amy Kendrick,† Ping Lan,‡ Martin G. Banwell,†,‡, * Colin J.
Jackson,† Nicholas J. Fraser,† Anthony C. Willis† and James S. Ward†
† Research School of Chemistry, Institute of Advanced Studies,
The Australian National University, Canberra, ACT 0200, Australia
‡ Institute for Advanced and Applied Chemical Synthesis, Jinan University,
Guangzhou 519070, China
–––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––
H
NH
NH
NH
O
NH2
N
N
1 (R = Me)
NH
R
2 (R = CH2CHMe2)
3 (R = Bn)
4 (R = p-HOBn)
11 (R = H)
N
N
N
N
N
N
N
N
H
12
5
6
Compounds 1-6 and 11 representing key members of the marinoquinoline family of
natural products, together with the related marine alkaloid aplidiopsamine A (12),
have been synthesized using various combinations of palladium-catalyzed Ullmann
cross-coupling and reductive cyclization processes involving a C3-arylated pyrrole as
the common intermediate. These natural products have been characterized by single-
crystal X-ray analyses and evaluated as inhibitors of acetylcholine esterase (AChE)
with congener 2 proving to be the most active.
Introduction
Marinoquinolines A-K (1-11, respectively) (Figure 1) are the currently known
members of a family of natural products that embody the 3H-pyrrolo[2,3-c]quinoline
ring system. They have been isolated from a range of bacterial sources. Thus,
marinoquinoline A (MQ-A or 1) was first isolated by Plubrukarn and co-workers from
Rapidithrix thailandica TISTR 1742, a gliding bacterium associated with seaweed
collected from Yong Ling beach on the coast of Southern Thailand.1 Its structure was
established by single-crystal X-ray analysis.2 Subsequently, marinoquinoline A (1)
together with congeners B-F (2-6, respectively), that only differ in the nature of the
substituent at C4, were isolated by Müller and co-workers from the gliding bacterium
Ohtaekwangia kribbensis (PWU 25) obtained from a soil sample collected in the
Northern Indian state of Uttar Pradesh.3 More recently, Fenical has reported the
isolation of congeners 7-11 (viz. marinoquinolines G-K, respectively) from cultures of
the marine bacterium Mooreia alkaloidigena (CNX-216T).4 On the other hand, the
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 40
1
2
3
4
5
6
7
8
9
structurally related alkaloid aplidiopsamine A (12), that features a methylene-linked
adenine residue attached at C4 of the above-mentioned heterocyclic ring system, was
obtained from the ascidian Aplidiopsis confluata found in temperate Australian waters.
Its structure was proposed based on analyses of the derived mass and NMR spectral
data.5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2
1
NH
NH
9b
NH
3a
3
9a
N
N
4
N
1
2
3
H
NH
NH
NH
N
OH
N
N
N
O
N
H
4
5
6
NH
NH
N
N
N
NHAc
N
OH
7
8
9
NH
N
NH
NH2
N
N
N
N
N
N
N
12
10
11
Figure 1: The structures of currently known members, A-K (1-11), of the
marinoquinoline family of natural products and the related 3H-pyrrolo[2,3-
c]quinolone aplidiopsamine A (12)
The biological evaluation of alkaloids 1-12 has been the subject of a number of
reports, the first of these1 identifying MQ-A (1) as an inhibitor (IC50 = 4.9 M) of
Torpedo californica-derived acetylcholinesterase (AChE).6 The IC50 of the positive
control galanthamine tested in the same assay was 0.6 M. Furthermore, MQ-A as
well as congeners 2-6 were shown to be weak anti-bacterial and anti-fungal agents and
proved to be modestly cytotoxic against the mammalian cells L929, MCF-7, KB-3-1
and HUVEC (IC50s ranging from 0.3 to 8.0 g/mL vs 1.2 to 18 x 10–3 for epothilon
and vinblastine).3 More interestingly, MQs A-F (viz. compounds 1-6) displayed
significant activity against the malarial parasite Plasmodium falciparum K1 (IC50s
ranging from 1.7 to 15 M),3 while aplidiopsamine A (12) showed values of 1.47 to
ACS Paragon Plus Environment

Page 3 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1.65 M against chloroquinine-sensitive and -resistant strains, respectively, while only
completely inhibiting the growth of the normal cell line HEK-293 at the highest tested
dose of 120 M.5 More recently,4 MQ-A, MQ-B and MQ-C have been shown to
display antibiotic activity against Pontibacillus sp. (strain CNJ-912). Aplidiopsamine
A (12) is also a highly selective PDE4 inhibitor7 and may thus serve as a lead for the
development of new treatments for depression and various forms of psychosis.
Neuroprotective agents based on compound 12 have also been proposed. 7
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The biosynthetic origins of compounds 1-12 have been the subject of various studies
and proposals5,8 while the significant range of biological activities attributed to these
natural products have prompted a number of synthetic efforts. The parent ring system
11 (also now known as MQ-K) was first prepared in 19619 and then again in 197810
and 200911 with the last approach, involving a domino condensation-Heck reaction,
providing material for evaluation that revealed it possessed anti-protozoal and
cytotoxic effects.11 Various targeted syntheses of certain of the marinoquinolines and
of aplidiopsamine A have been reported with several of these7,12,13,14 involving
biomimetic C3a-C4 bond formation (see structure 1 in Figure 1 for atom numbering)
including via cyclodehydration of a C3-arylated pyrrole bearing an acetamido residue
at the ortho-position of the benzenoid ring. In another approach,15 and during the
course of synthesizing marinoquinolines C and E, Sperry and his co-worker employed
the Bartoli indolization protocol to annulate the required pyrrole ring to 2-chloro-3-
nitroquinoline. Mhaske and co-workers16 were able to effect the palladium-catalyzed
cyclisation of a iodinated imine derived from the Schiff base condensation of o-
iodoaniline with a C2-acylated pyrrole and thereby generating, via C9a-C9b bond
formation, the required ring system and then elaborating this to targets 1 and 12. Our
own synthesis of marinoquinoline A (1)17 involved a reversal of the sequence of steps
employed by Mhaske and used a palladium-catalyzed Ullmann cross-coupling
reaction18 of o-bromonitrobenzene with a 3-iodopyrrole-2-carboxaldehyde and thus
forming what would become the C9a-C9b bond within the developing 3H-pyrrolo[2,3-
c]quinolone framework. Subsequent reactions, including a reductive cyclisation step
resulting in formation of the C4-N5 bond, then provided the target natural product 1.
Various of these studies and certain others19,20,21,22,23 have been extended to analogues
of the marinoquinolines including ones displaying superior activities.19,23 Taken
together these studies have led to total syntheses of marinoquinolines A, B, C and E
(1, 2, 3 and 5, respectively) as well as aplidiopsamine A (12). However, the structures
assigned to marinoquinolines D (4) and F (6) have yet to be prepared by any of the
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 40
1
2
3
4
5
6
7
8
9
methods just described. Accordingly, we report herein total syntheses of all six of
these members of the marinoquinoline class of natural product, as well as the parent
system 11 and congener 12, using a divergent approach from a common precursor.
Results and Discussion
Chemical Synthesis Studies
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(i)
Initial Approach
In our initial efforts to identify a late-stage precursor to all of the marinoquinolines
and following the approach17 used in our synthesis of congener 1, the 3-iodopyrrole-2-
carboxaldehyde 1324 (Scheme 1) was subjected to a palladium-catalyzed Ullmann
cross-coupling reaction with o-bromonitrobenzene (14) to give the previously
reported17 product 15 (74%). However, when compound 15 was treated with iso-
butylmagnesium bromide [in an effort to establish a route to MQ-B (2)] the iso-
butylated aromatics 16 (25%) and 17 were obtained rather than the anticipated
secondary alcohol arising from addition of the Grignard reagent to the aldehyde
moiety within the substrate. Presumably product 16 arises from nucleophilic addition
of the organometallic reagent to the electron-deficient aromatic ring of nitroarene 15 at
the position (C5) remote from the nitro-group and the adduct so-produced, or a
protonated form derived from this, is then oxidized (perhaps on work-up) to re-
establish the aromatic character of the benzenoid ring. Alcohol 17, on the other hand,
probably results from initial addition of the Grignard reagent to the unsubstituted
position (C3) of the benzenoid ring adjacent to the nitro-group within compound 15
and with the resulting stabilized carbanion adding to the pendant aldehyde moiety to
afford a cyclopentanol. Elimination of the elements of nitrous acid from within this
last species and accompanying re-aromatization of the six-membered ring would then
afford product 17. Since compound 17 could not be purified very readily, it was
oxidized, using the Dess-Martin periodinane (DMP), to the corresponding ketone 18
and upon hydrogenation of this under conventional conditions it was converted into
the crystalline pyrrolidine 19 (20% from 15) for which a single-crystal X-ray analysis
could be carried out (see the Experimental Section and Supporting Information – SI –
for details).
ACS Paragon Plus Environment

Page 5 of 40
The Journal of Organic Chemistry
1
2
3
Scheme 1: Initial Attempts to Establish a Synthesis of MQ-B (2)
4
5
6
7
8
9
NTs
NTs
I
CHO
NO2
CHO
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Cu[I]/Cu[0]
PdCl2(dppf)2
16 (25%)
NTs
13
5'
i-BuMgBr
+
+
CHO
NO2
THF, –78 °C
DMSO, 75 °C
74%
3'
NTs
Br
NO2
15
OH
14
17
DMP
CH2Cl2
22 °C
H
H2,
10% Pd on C
NTs
NTs
H
MeOH
22 °C
O
O
20% from 15
18
19
(ii)
Synthesis of Marinoquinoline K (11) and a Late-Stage Precursor to Others
In light of the outcomes detailed immediately above, reductive cyclisation of
compound 15 (Scheme 2) was undertaken in order to both remove the nitro-group and
establish the target 3H-pyrrolo[2,3-c]quinoline ring system bearing functionality
allowing for introduction of the required C4 substituent. When such a cyclization
reaction was carried out using hydrogen gas in the presence of W-7 Raney nickel then
(Scheme 2) complete reduction took place to give, via N-oxide 20, compound 21
(80%). The structures of both of these products were confirmed by single-crystal X-
ray analysis. Treatment of compound 21 with m-chloroperbenzoic acid (m-CPBA)
allowed for its ready conversion into N-oxide 20 (83%) but this was a thermally
sensitive material and on heating in moist DMSO at 80 °C for relatively short periods
of time it isomerized to the previously unreported lactam 22 (91%). In anticipation of
the necessary removal of the sulfonamide group at the conclusion of the syntheses of
the target marinoquinolines, it was established that when compound 21 was treated
with freshly prepared sodium methoxide in methanol then the parent 3H-pyrrolo[2,3-
c]quinolone (11) (a.k.a. MQ-K) could be obtained in 95% yield. Once again the
structure of this material was confirmed by a single-crystal X-ray analysis. All of the
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 40
1
2
3
4
5
6
7
8
9
other spectral data acquired on the bulk material, and involving the use of (CD3)2CO
as the solvent for acquiring NMR spectra, were also entirely consistent with the
assigned structure. We were unable to dissolve the synthetically-derived sample of
compound 11 in CD3OD, the NMR solvent used in characterizing the natural product
MQ-K4 so completely “legitimate” comparisons (see SI) of the two 13C NMR data sets
could not be made. However, these do suggest they are one and the same compound.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 2: Synthesis of Marinoquinoline K (11) and
3,5-Dihydro-4H-pyrrolo[2,3-c]quinolin-4-one 22
H2,
Ra-Ni
H2,
Ra-Ni
NTs
NTs
NR
CHO
NO2
THF, 22 °C
80%
THF, 22 °C
N
O
N
m-CPBA
21 (R=Ts)
11 (R=H)
15
20
NaOMe, MeOH
22 °C, 95%
CH2Cl2, 22 °C
83%
DMSO
80 °C
91%
NTs
O
N
H
22
(iii)
Synthesis of Marinoquinolines A, B and C from the N-oxide 20
With a concise and reliable route to the N-oxide 20 established, efforts were focused
on the capacity to engage this compound in a nucleophilic addition at C4 with the
relevant Grignard reagent. In the event, reaction of compound 20 with
methylmagnesium bromide (Scheme 3) gave a product (presumed to be alcohol 23 or
the corresponding conjugate base) that upon treatment with sodium methoxide in
methanol afforded marinoquinoline A (1) in 57% yield. The spectral data obtained on
this product were completely consistent with the assigned structure and in good
agreement with those derived from sample of marinoquinoline A obtained by our
earlier route17 (and for which a single-crystal analysis had been obtained). A
13
comparison of the C NMR data recorded for compound 1 obtained by the present
route with those reported for the natural product revealed good agreement (see SI) but
it should be noted that minor variations in the water content and/or the pH of the
medium used in acquiring such spectra can impact significantly on the chemical shifts
of some resonances.
Extensions of this synthesis of marinoquinoline A to congeners B (2) and C (3) proved
straightforward. Thus, treatment of compound 20 with either iso-butylmagnesium
ACS Paragon Plus Environment

Page 7 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
bromide or its benzyl counterpart and then with sodium methoxide gave, presumably
via intermediates 24 or 25, marinoquinolines B (2) (69%) and C (3) (55%),
respectively. While all the spectral data obtained on these products were in complete
accord with the assign structures, final confirmation of these followed from single-
crystal X-ray analyses, details of which are presented in the Experimental Section and
the SI. In addition the acquired NMR, IR and mass spectral data matched those
reported3 for the natural products, especially when account is taken, as mentioned
above, of the impacts of the water content and pH of the medium used in acquiring
NMR spectra.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 3: Syntheses of Marinoquinolines 1, 2 and 3 from N-Oxide 20
NTs
MeMgBr,
NTs
BnMgBr or
NH
R
NaOMe,
MeOH
i-BuMgBr
N
R
65 °C
OH
N
O
THF, 0 to 22 °C
N
23 (R=Me)
24 (R=i-Bu)
25 (R=Bn)
1 (R=Me) (57%)
2 (R=i-Bu) (69%)
3 (R=Bn) (55%)
20
(iv)
Synthesis of Marinoquinoline D
The reaction sequence used to produce compound 4, the structure assigned to the
hitherto previously unsynthesized marinoquinoline D, is shown in Scheme 4. Thus, as
before, the N-oxide 20 was treated with the relevant Grignard reagent (in this case p-
1
methoxybenzylmagnesium bromide). H NMR and mass spectral analysis of an
aliquot of the reaction mixture suggested that the major component of this initial
reaction was the C4 substituted N-oxide 26, presumably arising from re-oxidation of
the initially formed adduct (analogous to compounds 23-25 shown in Scheme 3).
Accordingly, the mixture was exposed to dihydrogen in the presence of 5% palladium
on carbon in methanol. Under such conditions both the N-oxide and tosyl residues
were cleaved and thus affording, in 68% yield, the O-methyl ether derivative 27 of
target 4. Finally, reaction of compound 27 with boron tribromide in dichloromethane
at 0 to 22 °C resulted in the required demethylation and formation of compound 4
which was obtained in 89% yield. All the spectral data acquired on this material were
consistent with the assigned structure but final confirmation of this also followed from
1
a single-crystal X-ray analysis. Significantly, the H and 13C NMR spectra of
compound 4 recorded in CD3OD did not match those reported3 for marinoquinoline D
until a drop of acetic acid was added to the sample being analyzed and then the
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 40
1
2
3
4
5
6
7
8
9
matches between the relevant data sets were very good (see SI). It should be noted that
13
over the time needed to acquire C NMR spectra data on the synthetically-derived
compound 4 decomposition of the acetic acid-treated sample became evident.
Scheme 4: The Total Synthesis of MQ-D (4)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NTs
NTs
OMe
p-MeOC6H4CH2MgBr
N
O
N
O
THF, 22 °C
20
26
H2,
22 °C
68%
5% Pd on C
MeOH
NH
OH
NH
OMe
BBr3
CH2Cl2
0 to 22 °C
89%
N
N
4
27
(v)
Synthesis of Marinoquinoline E
In order to exploit indole as the nucleophilic species that would become attached at C4
of the 3H-pyrrolo[2,3-c]quinolone framework [and thus producing marinoquinoline E
(5)], the pivotal N-oxide 20 was activated (Scheme 5) by in situ treatment with p-
toluenesulfonic anhydride. The resulting sulfonate was then treated with indole
followed by sodium methoxide and so producing target 5 in 73% yield. All the
spectral data recorded on adduct 5 were in accord with the assigned structure which
was confirmed by a single-crystal X-ray analysis. In addition these spectral data
proved to be an excellent match with those reported for the natural product
marinoquinoline E (see SI for a tabular comparison of the two sets of 13C NMR
spectral data). In the 13C NMR spectrum, the doubling-up or fine splitting of the
resonances due to those carbons adjacent to the linkage between the indole and 3H-
pyrrolo[2,3-c]quinolone subunits of compound 5 suggests that, on the NMR time-
scale, there may be some restricted rotation between them.
ACS Paragon Plus Environment

Page 9 of 40
The Journal of Organic Chemistry
1
2
3
Scheme 5: The Synthesis of Marinoquinoline E (5).
4
5
6
7
8
NH
(i) Ts2O,
indole, THF
22 °C
NTs
N
NH
(ii) NaOMe,
MeOH, 65 °C
73%
N
O
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5
20
(vi)
Synthesis of Marinoquinoline F
In an initial attempt to prepare the structure, 6, assigned to marinoquinoline F the
pivotal N-oxide 20 was treated (Scheme 6) with ClCONMe2 and TMS-CN25 and
thereby affording, via a modified Reissert-Henze reaction, the 2-cyano-substituted 3H-
pyrrolo[2,3-c]quinolone 28 (82%). While the success of this conversion was evident
from the spectral data obtained on the product final confirmation of its structure
followed from a single-crystal X-ray analysis (see Experimental Section and SI for
details). Compound 28 was itself treated with indole in the presence SnCl4, conditions
defined by Ottoni26 for C3-acylation (of indoles), but rather than obtaining the hoped-
for target MQ-F (6) only CN group clevage was observed. As such a new approach to
this natural product was pursued.
Scheme 6: The Synthesis of Nitrile 28.
NTs
NTs
CN
ClCONMe2,
TMSCN
CH2Cl2,
10 °C, 82%
N
O
N
20
28
The ultimately successful but non-regioselective route to MQ-F established during the
course of the present study is shown in Scheme 7. This involved treating the N-oxide
20 with POBr3 and thereby providing bromide 29 (81%), the structure of which was
established by single-crystal X-ray analysis. Treatment of this last compound with n-
BuLi, with the intention of forming the halogen-for-lithium exchange product 30, then
quenching the reaction mixture with the readily prepared indole-3-carboxaldehyde
3127 afforded, after aqueous work-up and chromatographic purification, the anticipated
adduct 32 (52%) together with its separable regio-isomer 33 (24%). The latter product
presumably arises through reaction of the C2-lithiated isomer of compound 30 with
the added electrophile. Separate treatment of each of alcohols 32 and 33 with activated
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 40
1
2
3
4
5
6
7
8
9
manganese dioxide in dichloromethane afforded the corresponding ketones, 34 (99%)
and 35 (93%), respectively and independent treatment of each of these with sodium
methoxide in methanol resulted in cleavage of the associated tosyl residues and the
formation of corresponding free pyrroles 36 (85%) and 6 (85%). The spectral data
derived from compounds 6 and 36 were entirely consistent with assigned structures
but confirmation of these followed from single-crystal X-ray analyses on each of them
(see Experimental Section and SI for details). Furthermore, a comparison of the
spectral data derived from compound 6 with those reported3 for MQ-F (see SI)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
revealed a good match. As appeared to be the case with congener 5, in the C NMR
spectrum the doubling-up or fine splitting of the resonances due to those carbons
involved in or adjacent to the carbonyl-linked indole and 3H-pyrrolo[2,3-c]quinolone
subunits of compound 6 suggests there may be some restricted rotation between them.
ACS Paragon Plus Environment

Page 11 of 40
The Journal of Organic Chemistry
1
2
3
Scheme 7: The Synthesis of MQ-F (6).
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
On one occasion, after oxidation of compound 32 with manganese dioxide then the
mono-tosylate 37 (21%) was obtained alongside the previously observed bis-tosylate
35 and so suggesting that the sulfonamide residue attached to the 3H-pyrrolo[2,3-
c]quinolone framework is more labile than its counterpart associated with the indole
moiety.
(vii)
Synthesis of Aplidiopsamine A
The adaptation of the synthetic sequences described above to the preparation of
aplidiopsamine A (12) is shown in Scheme 8. Thus, the initial step involves the same
one as employed earlier, namely the palladium-catalyzed Ullmann cross-coupling of
iodopyrrole 13 with bromobenzene 14 to afford product 15. However, at this point
rather than effecting reductive cyclization of the last compound this was, instead,
reacted with methyl lithium and the product alcohol immediately oxidized with
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 40
1
2
3
4
5
6
7
8
manganese dioxide and so producing the previously reported17 and crystalline methyl
ketone 38 (42% over two steps). Interestingly, reactions analogous to those observed
on treating compound 15 with iso-butylmagnesium bromide (see Scheme 1), and
wherein nucleophilic addition to the nitroaromatic takes place, were not observed on
reaction of the same substrate with methyl lithium.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The conversion of compound 38 into the corresponding mono-bromide 39 (that would
serve as the electrophile in a reaction with adenine) proved challenging due to the co-
production of its di-bromo derivative. Eventually, it was established that copper(II)
bromide was the most effective reagent for this purpose28 and the ca. 10% of
contaminating di-bromide could be removed by treating the brominated mixture with
diethyl phosphite and so providing compound 39 in 94% yield after purification by
flash chromatography. Treatment of a 1:1 mixture of the last compound and adenine
with sodium hydride and using DMF as the solvent then afforded adduct 40 (84%) in
which the N-tosyl moiety associated with substrate 39 had been cleaved. The structure
of compound 40 was confirmed by single-crystal X-ray analysis. Exposure of a THF
solution of this adduct to an atmosphere of dihydrogen in the presence of Raney nickel
for 24 h effected a reductive cyclization to afford the N-oxide 41 (33%), a rather
intractable compound that proved difficult to fully dissolve in a range of standard
solvents. By using Raney cobalt as the catalyst, ethyl acetate as the solvent and
heating the reaction under reflux for 60 h then complete conversion of substrate 40
into target 12 (92%) could be realized. Product 12 proved much more tractable than
congener 41 and its structure was confirmed by single-crystal X-ray analysis of the
dihydrate of its bis-hydrochloride salt. A comparison (see SI) of the 13C NMR
spectroscopic data recorded on this synthetically-derived material with the
corresponding data reported5 for the natural product aplidiopsamine A clearly
established that they are one and the same compound.
ACS Paragon Plus Environment

Page 13 of 40
The Journal of Organic Chemistry
1
2
3
Scheme 8: A Total Synthesis of Aplidiopsamine A (12)
4
5
6
7
NTs
I
CHO
8
NO2
NO2
9
(i) MeLi, THF
–78 °C, 57%
Cu[I]/Cu[0]
PdCl2(dppf)2
NTs
CHO
NTs
13
+
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(ii) DMP
CH2Cl2
0 °C, 74%
DMSO, 75 °C
74%
O
NO2
Br
15
38
CuBr2,
EtOAc/CHCl3, reflux
then (EtO)2POH, Et3N
THF, 0 to 22 °C
94%
14
NO2
NO2
adenine, NaH
DMF, 0 to 22 °C
NTs
Br
NH
NH2
N
N
N
84%
O
O
N
39
40
H2,
H2,
Raney nickel,
THF, 22 °C,
33%
Raney cobalt
EtOAc, 78 °C,
92%
NH
NH2
N
NH
N
NH2
N
N
N
N
N
N
O
N
N
12
41
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 40
1
2
3
Biological Evaluation and Docking Studies
The evaluation of compounds 1-6 and 11 together with synthetically-derived
aplidiopsamine A (12) as inhibitors of acetylcholine esterase (AChE) was undertaken
using the same protocols1 as employed by those researchers who identified and
evaluated the naturally-derived marinoquinoline A (1). Lactam 22 and compound 36,
the regioisomer of marinoquinoline F (6), were also evaluated in the same assay. As
shown in Table 1, the most active of all these heterocyclic compounds was MQ-B (2)
while congeners 1, 3 and 5 also displayed notable inhibitory properties. The
significantly less potent activities of MQ-D (4) and the “parent” heterocycle (viz. MQ-
K or 11) as well as as the lack of any inhibitory effects of compounds 6, 12, 22 and 36
clearly demonstrate that the precise nature of the C4 substituent on the 3H-
pyrrolo[2,3-c]quinolone framework plays a major role in determining activity.
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1: Results of Testing Compounds 1-6, 11, 12, 22 and 36 as AChE Inhibitorsa
Entry
Compound
Entry
Compound
IC50 (M)
5.5 (± 0.8)b
3.6 (±1.8)
8.1 (±1.5)
31.8 (±3.1)
5.8 (±01.8)
IC50 (M)
No inhib.
42.7 (±3.4)
No inhib.
No inhib.
No inhib.
1
2
3
4
5
1
2
3
4
5
6
7
6
11
12
22
36
8
9
10
a: see experimental section for details of the assay employed; b Sangnoi et al report1 an IC50 of 4.9 M for compound 1.
In an effort to understand how such substituent effects might be arising, the structure
of the active marinoquinoline B (2) was docked into that of human
acetylcholinesterase (4BDT) using Autodock Vina29 with tacrine removed from the
active site gorge of this enzyme. As revealed in Figure 2, the 3H-pyrrolo[2,3-
c]quinolone framework of compound 2 participates, on its opposite faces, in -
stacking interactions with the aromatic residues of tyrosine Y337 and tryptophan W86
and in an orientation that allows the C4 iso-butyl group to insert into a nearby pocket
and so enhancing binding, presumably through van der Waals interactions.
ACS Paragon Plus Environment

Page 15 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 2: Marinoquinoline B (2) docked into the structure of human
acetylcholinesterase (4BDT) showing the main interactions between W86, Y337 and
this inhibitor.
Conclusions
The chemical synthesis studies detailed herein serve to confirm the structures of a
significant fraction of the currently known members of the marinoquinoline family of
natural products, most notably congeners 4 and 6 that have not been been the subject
of previous such efforts. This work, when considered alongside the outcomes of the
evaluation of these compounds and certain analogues as inhibitors of AChE, should
form the basis for the development of even more potent compounds that may,
themselves, allow for the development of useful new therapeutic agents. Work
directed towards such ends is now underway in our laboratories, including through
various efforts to find analogues with enhanced lipophilic properties that address the
solubility issues that are otherwise likely to compromise the development of the title
compounds in medical settings.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 40
1
2
3
4
5
Experimental Section
Chemical Synthesis Studies
6
7
8
(i) General Experimental Procedures
Unless otherwise specified, proton (1H) and proton-decoupled carbon [13C{1H}] NMR
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
spectra were recorded at 18 °C in base-filtered CDCl3 on a Varian spectrometer
1
operating at 400 MHz for proton and 100 MHz for carbon nuclei. For H NMR
spectra, signals arising from the residual protio-forms of the solvent were used as the
internal standards. 1H NMR data are recorded as follows: chemical shift
(multiplicity, coupling constant(s) J (Hz), relative integral] where multiplicity
is defined as: s = singlet; d = doublet; t = triplet; q = quartet; m = multiplet or
combinations of the above. The signal due to residual CHCl3 appearing at H 7.26 and
the central resonance of the CDCl3 “triplet” appearing at C 77.0 were used to
reference 1H and 13C NMR spectra, respectively. Infrared spectra (max) were recorded
on a Perkin-Elmer 1800 Series FTIR Spectrometer. Samples were analyzed as thin
films on KBr plates. A VG Fisons AutoSpec mass spectrometer was used to obtain
low- and high-resolution electron impact (EI) mass spectra. Low- and high-resolution
electrospray (ESI) mass spectra were obtained on a VG Quattro II triple-quadrupole
MS instrument operating in positive ionization mode. Melting points were measured
on an Optimelt automated melting point system and are uncorrected. Analytical thin
layer chromatography (TLC) was performed on aluminum-backed 0.2 mm thick silica
gel 60 F254 plates as supplied by Merck. Eluted plates were visualized using a 254 nm
UV lamp and/or by treatment with a suitable dip followed by heating. These dips
included phosphomolybdic acid : ceric sulfate : sulfuric acid (conc.) : water (37.5 g :
7.5 g : 37.5 g : 720 mL) or potassium permanganate : potassium carbonate : 5%
sodium hydroxide aqueous solution : water (3 g : 20 g: 5 mL : 300 mL). Flash
chromatographic separations were carried out following protocols defined by Still et
al.30 with silica gel 60 (40-63 m) as the stationary phase and using the AR- or
HPLC-grade solvents indicated. Starting materials and reagents were generally
available from the Sigma-Aldrich, Merck, TCI, Strem or Lancaster Chemical
Companies and were used as supplied. Drying agents and other inorganic salts were
purchased from the AJAX, BDH or Unilab Chemical Companies. Tetrahydrofuran
(THF), methanol and dichloromethane (DCM) were dried using a Glass Contour
solvent purification system that is based upon a technology originally described by
Grubbs et al.31 Where necessary, reactions were performed under an argon
atmosphere.
ACS Paragon Plus Environment

Page 17 of 40
The Journal of Organic Chemistry
1
2
3
4
5
(ii) Specific Experimental Procedures and Product Characterization
3-(5-Isobutyl-2-nitrophenyl)-1-tosyl-1H-pyrrole-2-carbaldehyde (16) and 7-
Isobutyl-1-tosyl-1,8-dihydroindeno[2,1-b]pyrrol-8-ol (17). A magnetically stirred
solution of compound 1517 (248 mg, 0.67 mmol) in THF (7 mL) was cooled to –78 °C
and while being maintained under nitrogen was treated, dropwise, with i-BuMgBr
(370 L of a 2.0 M solution in diethyl ether, 0.74 mmol) and the ensuing mixture
warmed to 0 °C over 2 h. The reaction mixture was then quenched with NH4Cl (10 mL
of a saturated aqueous solution) and extracted with ethyl acetate (3  20 mL). The
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
combined organic phases were washed with water (2  50 mL) before being dried
(MgSO4), filtered and concentrated under reduced pressure. The residue thus obtained
was subjected to flash column chromatography (silica, 9:1 v/v hexane/ethyl acetate
elution) and so giving two fractions, A and B.
Concentration of fraction A (Rf = 0.4) gave compound 16 (73 mg, 25%) as an
amorphous, yellow solid. 1H NMR (400 MHz, CDCl3)  9.84 (s, 1H), 7.98 (d, J = 8.3
Hz, 1H), 7.81 (d, J = 8.2 Hz, 2H), 7.69 (d, J = 3.2 Hz, 1H), 7.36 (d, J = 8.2 Hz, 2H),
7.28 (dd, J = 8.3 and 1.9 Hz, 1H), 7.09 (d, J = 1.9 Hz, 1H), 6.39 (d, J = 3.2 Hz, 1H),
2.53 (d, J = 7.2 Hz, 2H), 2.43 (s, 3H), 1.88 (m, 1H), 0.90 (d, J = 6.7 Hz, 6H).
13C{1H}NMR (100 MHz, CDCl3)  178.8, 147.7, 146.8, 146.0, 136.3, 135.2, 132.9,
130.2, 129.9, 128.5, 128.3, 128.2, 127.4, 124.6, 113.9, 44.9, 30.0, 22.2, 21.7. IR max
2958, 1674, 1612, 1586, 1549, 1522, 1446, 1375, 1178, 1089, 1027, 966, 910 cm–1.
MS (ESI, +ve) 449 [(M+Na)+, 100%], 427 [(M+H)+, 35]; HRMS (ESI, +ve) [M+H]+
32
calcd. for C22H23N2O5 S 427.1328, found 427.1327.
Concentration of fraction B (Rf = 0.35) afforded a brown oil presumed to
contain compound 17. This material was subjected, without further purification, to the
transformation detailed immediately below.
(rel-3aS,8aS)-7-Isobutyl-1-tosyl-2,3,3a,8a-tetrahydroindeno[2,1-b]pyrrol-8(1H)-
one (19). The oil presumed to contain alcohol 17 (and obtained as detailed
immediately above) was dissolved in dichloromethane (10 mL). While being
maintained at 22 °C under nitrogen, the resulting and magnetically stirred solution was
treated with the Dess-Martin periodinane32 (106 mg, 0.25 mmol). After a further 1 h
the reaction mixture was concentrated under reduced pressure and the residue
subjected to flash chromatography (silica, 9:1 v/v 40-60 petroleum spirits/ethyl acetate
elution). Concentration of the relevant fractions (Rf = 0.5) gave a clear, yellow oil (44
mg) presumed to contain compound 18. This oil was dissolved in methanol (4 mL)
and the resulting solution treated with Pd/C (10 mg of 10% w/w material) then stirred
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 40
1
2
3
4
5
6
7
8
9
magnetically under an atmosphere of hydrogen at 22 °C for 16 h. The reaction mixture
was then filtered through a pad of diatomaceous earth and the filtrate concentrated
under reduced pressure. The residue thus obtained was subjected to to flash
chromatography (silica, 9:1 v/v hexane/ethyl acetate elution) to afford, after
concentration of the appropriate fractions (Rf = 0.35), the title compound 19 (36 mg,
20% over 3 steps) as a white, crystalline solid, no melting point, slow decomposition
above ca. 100 °C. 1H NMR (400 MHz, CDCl3)  7.85 (d, J = 8.3 Hz, 2H), 7.48 (t, J =
7.5 Hz, 1H), 7.32 (d, J = 7.7 Hz, 2H), 7.22 (m, 1H), 7.11 (d, J = 7.4 Hz, 1H), 4.62 (d,
J = 7.2 Hz, 1H), 3.81 (m, 1H), 3.71 (m, 1H), 2.96-2.87 (complex m, 2H), 2.80 (dd, J
= 12.5 and 7.3 Hz, 1H), 2.44 (s, 3H), 1.97 (m, 1H), 1.85-1.74 (complex m, 2H), 0.87
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
(d, J = 6.6 Hz, 3H), 0.85 (d, J = 6.6 Hz, 3H). C{1H} NMR (100 MHz, CDCl3) 
201.1, 155.3, 143.7, 143.5, 136.6, 135.0, 132.8, 130.4, 129.7, 127.6, 123.4, 66.3, 47.9,
42.4, 40.5, 32.6, 29.8, 22.4, 22.3, 21.6. IR max (neat) 2955, 1717, 1593, 1350, 1161,
1091, 966, 717, 661 cm–1. MS (EI, 70 eV) 383 (M+•, 50%), 228 (100), 210 (25), 199
32
(40), 185 (30), 91 (38). HRMS (EI, 70 eV) M+• calcd. for C22H25NO3 S, 383.1555,
found 383.1554.
3-Tosyl-3H-pyrrolo[2,3-c]quinolone (21). A magnetically stirred a solution of
compound 1517 (4.33 g, 11.7 mmol) in THF (35 mL) maintained at 22 °C was treated
with W-7 Raney-nickel33 (430 mg of 10% w/w material) and the resulting suspension
stirred vigorously under an atmosphere of hydrogen for 4 h. The ensuing mixture was
concentrated under reduced pressure and the residue subjected to flash
chromatography (silica, 9:1 v/v dichloromethane/diethyl ether then 9:1 v/v
dichloromethane/methanol elution) to yield, after concentration of the appropriate
fractions (Rf = 0.5 in 7:2:1 v/v/v dichloromethane/40-60-petroleum spirit/diethyl ether
elution) compound 21 (1.20 g, 80%) as an amorphous yellow solid. A fraction of this
solid was crystallized (dichloromethane) to give a spectroscopically pure sample of
1
compound 21 as yellow crystals, m.p. = 215-216 °C. H NMR (CDCl3, 400 MHz) 
9.58 (s, 1H), 8.19 (d, J = 8.3 Hz, 1H), 8.09 (dd, J = 8.0 and 1.5 Hz, 1H), 7.83 (d, J =
8.4 Hz, 2H), 7.79 (d, J = 3.5 Hz, 1H), 7.66 (m, 1H), 7.59 (m, 1H), 7.22 (d, J = 8.4 Hz,
2H), 7.16 (d, J = 3.5 Hz, 1H), 2.31 (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz)  145.8,
143.7, 137.8, 134.9, 132.6, 130.2, 129.7, 128.6, 127.9, 127.8, 127.0, 126.9, 123.1,
122.5, 106.5, 21.5. IR max (thin film) 3129, 3041, 1592, 1511, 1493, 1375, 1362,
1164, 1136, 1086, 939, 671, 586 cm–1. MS (ESI, +ve) 323 [(M + H)+, 100%]. HRMS
32
(EI, 70 eV) M+• calcd. for C18H14N2O2 S, 322.0776, found 322.0776.
3-Tosyl-3H-pyrrolo[2,3-c]quinoline 5-oxide (20). A solution of compound 21 (1.42
g, 4.4 mmol) in dichloromethane (15 mL) was treated with m-CPBA (1.30 g of 70%
ACS Paragon Plus Environment

Page 19 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
w/w peracid material, 5.3 mmol) and the resulting solution stirred magnetically at 22
°C for 2 h. After this time flash chromatography-grade silica (5 g) was added to the
reaction mixture before it was concentrated under reduced pressure. Then resulting
free-flowing solid was subjected to flash chromatography (silica, 9:1 v/v
dichloromethane/methanol elution) to give, after concentration of the appropriate
fractions (Rf = 0.2 in 4:1 v/v dichloromethane/acetone), compound 20 (1.23 g, 83%) as
a light-brown amorphous solid. Crystallization of a fraction of this material (from
warm DMSO) gave yellow crystals, no melting point, slow decomposition between 80
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
and 300 °C. H NMR (CDCl3, 400 MHz)  9.37 (s, 1H), 8.86-8.79 (complex m, 1H),
8.11-8.08 (complex m, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.77 (m, 1H), 7.76-7.68
1
(complex m, 2H), 7.28 (d, J = 8.4 Hz, 2H), 7.11 (m, 1H), 2.36 (s, 3H). H NMR
(acetone-D6, 400 MHz)  9.15 (s, 1H), 8.72-8.67 (complex m, 1H), 8.38-8.33
(complex m, 1H), 8.03 (d, J = 8.4 Hz, 2H), 7.98 (d, J = 3.5 Hz, 1H), 7.82-7.75
(complex m, 2H), 7.49-7.43 (complex m, 3H), 2.38 (s, 3H). IR max 3048, 1593, 1424,
1376, 1211, 1170, 1129, 936, 668 cm–1. MS (EI, 70 eV) 338 (M+•, 30%) 322 [(M–
32
O•)+, 100]. HRMS (EI, 70 eV) M+• calcd. for C18H14N2O3 S 338.0725, found
338.0730. Due to its limited solubility in all commonly available deuterated solvents a
13C NMR spectrum of this compound could not be obtained.
3-Tosyl-3,5-dihydro-4H-pyrrolo[2,3-c]quinolin-4-one (22). In an attempt to dissolve
it, a suspension of compound 20 (34 mg, 0.1 mmol) in DMSO-D6 (0.5 mL containing
traces of water) was heated to 80 °C for 0.25 h. The cooled mixture was concentrated
overnight under a stream of nitrogen and the residue subjected to flash
chromatography (silica, 4:1 v/v dichloromethane/ethyl acetate elution) to afford, after
concentration of the appropriate fractions (Rf = 0.4), a pale-brown, amorphous solid,
crystallization (dichloromethane/methanol) of which gave lactam 22 (30.9 mg, 91%)
1
bright-yellow crystals, m.p. = 265-266 °C. H NMR (400 MHz, CDCl3)  11.07
(broad s, 1H), 8.06-8.00 (complex m, 3H), 7.85 (d, J = 7.9 Hz, 1H), 7.47 (m, 1H),
7.38 (m, 1H), 7.30-7.25 (complex m, 3H), 6.96 (d, J = 3.4 Hz, 1H), 2.37 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3)  145.2, 135.9, 135.7, 135.1, 131.2, 129.7, 129.5,
128.7(1), 128.6(5), 126.4, 123.5, 122.8, 116.1, 116.1, 104.7, 21.7. IR max 1600, 1593,
1417, 1373, 1360, 1170, 1121, 1084, 1`008, 807, 783, 731, 748, 736, 666, 603 cm–1.
MS (ESI, +ve) 699 [(2M + Na)+, 80%], 361 [(M + Na)+, 100], 339 [(M + H)+, 20].
32
HRMS (ESI, +ve) (M+Na)+ calcd. for C18H14N2O3 S23Na 361.0623, found 361.0624.
3H-Pyrrolo[2,3-c]quinoline (11). A magnetically stirred solution of compound 21
(100 mg, 0.31 mmol) in methanol (5 mL) maintained at 22 °C was treated with sodium
methoxide (30 mg, 0.62 mmol) and the resulting mixture heated under reflux for 2 h.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 40
1
2
3
4
5
Flash chromatography-grade silica gel (1.0 g) was then added to the cooled reaction
mixture that was then concentrated under reduced pressure. The resulting free-flowing
solid
was
subjected
to
flash
chromatography
(silica,
95:5
v/v
6
7
8
9
dichloromethane/methanol elution) to give, after concentration of the appropriate
fractions (Rf = 0.2), a yellow solid that upon recrystallization (acetone) gave
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
compound 11 (49.7 mg, 95%) as pale-yellow crystals, m.p. = 226-227 °C. H NMR
(400 MHz, acetone-D6)  11.22 (broad s, 1H), 9.09 (s, 1H), 8.29 (m, 1H), 8.09 (m,
1H), 7.65 (d, J = 2.8 Hz, 1H), 7.56 (m, 2H), 7.15 (d, J = 2.8 Hz, 1H). 13C NMR (100
MHz, acetone-D6)  143.7, 139.0, 130.6, 128.6, 127.8, 127.7, 126.4, 126.1, 124.7,
123.9, 101.5. IR max 2812, 1590, 1483, 1366, 1347, 793, 750 cm–1. MS (ESI, +ve)
169 [(M + H)+, 100%]. HRMS (ESI, +ve) (M + H)+ calcd. for C11H9N2 169.0766,
found 169.0766.
4-Methyl-3H-pyrrolo[2,3-c]quinoline (1). Methylmagnesium bromide (750 L of a
2.0 M solution in THF, 1.5 mmol) was added, dropwise, to a magnetically stirred
solution of compound 20 (100 mg, 0.3 mmol) in THF (3 mL) maintained at 0 °C and
the ensuing mixture was then allowed to warm to 22 °C. After 6 h the reaction mixture
was quenched with NH4Cl (10 mL of a saturated solution) then extracted with ethyl
acetate (3  10 mL). The combined organic phases were washed with brine (1  30
mL) before being dried (MgSO4), filtered and concentrated under reduced pressure.
The residue thus obtained, and presumed to contain compound 23, was dissolved in
methanol (10 mL) and the ensuing solution treated with sodium methoxide (32 mg, 0.6
mmol) then heated under reflux for 16 h. reflux overnight. The cooled reaction
mixture was concentrated under reduced pressure and the residue so obtained
subjected to flash chromatography (silica, 9:1 v/v dichloromethane/methanol elution)
to afford, after concentration of the relevant fractions (Rf = 0.4), compound 1 (31 mg,
57%) as a pale-yellow and amorphous solid. 1H NMR (400 MHz, acetone-D6)  11.39
(broad s, 1H), 8.24 (m, 1H), 8.05 (m, 1H), 7.63 (d, J = 3.0 Hz, 1H), 7.52 (m, 2H), 7.14
(d, J = 2.9 Hz, 1H), 2.87 (s, 3H). C{1H} NMR (100 MHz, acetone-D6)  146.8,
13
143.0, 129.6, 129.2, 128.7, 127.8, 126.3, 125.9, 124.0, 123.8, 102.1, 20.9. IR max
3119, 3082, 2952, 2795, 1587, 1533, 1481, 1364, 1198, 1137, 751 cm–1. MS (ESI,
+ve) 183 [(M + H)+, 100%]. HRMS (ESI, +ve) (M + H)+, calcd. for C12H11N2
183.0922, found 183.0922.
4-Isobutyl-3H-pyrrolo[2,3-c]quinoline (2). iso-Butylmagnesium bromide (750 L of
a 2.0 M solution in Et2O, 1.5 mmol) was added, dropwise, to a magnetically stirred
solution of compound 20 (100 mg, 0.3 mmol) in THF (3 mL) maintained at 0 °C. The
ACS Paragon Plus Environment

Page 21 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
ensuing mixture was then allowed to warm to 22 °C and after 24 h treated with
methanol (1 mL) before being concentrated under reduced pressure. The residue thus
obtained, and presumed to contain compound 24, was dissolved in methanol (10 mL)
and the ensuing solution treated with sodium methoxide (32 mg, 0.6 mmol) before
being heated under reflux for 16 h. The cooled reaction mixture was concentrated
under reduced pressure and the resulting brown solid subjected to flash
chromatography (silica, 19:1 v/v dichloromethane/methanol elution) to afford, after
concentration of the relevant fractions (Rf = 0.3), an amorphous white solid.
Crystallization (acetone) of this material gave compound 2 (48 mg, 69%) as a
colorless crystals, m.p. = 189-191 °C. 1H NMR (400 MHz, acetone-D6)  11.20
(broad s, 1H), 8.24 (m, 1H), 8.04 (m, 1H), 7.57 (d, J = 3.0 Hz, 1H), 7.55-7.46
(complex m, 2H), 7.13 (d, J = 3.0 Hz, 1H), 3.08 (d, J = 7.3 Hz, 2H), 2.45 (m, 1H),
0.99 (d, J = 6.6 Hz, 6H). 13C{1H} NMR (100 MHz, acetone-D6)  150.0, 143.7, 130.1,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
128.6, 127.0, 126.8, 126.0, 125.6, 124.1, 123.7, 101.9, 44.1, 29.0, 23.0. IR max 3080,
2957, 2794, 1586, 1481, 1361, 1195, 1139, 876, 846, 751 cm–1. MS (ESI, +ve) 225
[(M + H)+, 100%]. HRMS (ESI, +ve) (M + H)+ calcd. for C15H17N2 225.1392, found
225.1392.
4-Benzyl-3H-pyrrolo[2,3-c]quinoline (3). Benzylmagnesium bromide (750 L of a
2.0 M solution in THF, 1.5 mmol) was added, dropwise, to a magnetically stirred
solution of compound 20 (100 mg, 0.3 mmol) in THF (3 mL) maintained at 0 °C and
the ensuing mixture then allowed to warm to 22 °C. After 24 h methanol (1 mL) was
added to the reaction mixture that was then concentrated under reduced pressure. The
ensuing residue, presumed to contain compound 25, was dissolved in methanol (10
mL) and the solution so-formed treated with sodium methoxide (32 mg, 0.6 mmol)
then heated under reflux for 16 h. The cooled reaction mixture was concentrated under
reduced pressure and resulting brown solid subjected to flash chromatography (silica,
19:1 v/v dichloromethane/methanol elution). Concentration of the relevant fractions
(Rf = 0.3) gave a light-yellow and amorphous solid that upon crystallization (acetone)
gave compound 3 (42 mg, 55%) as yellow crystals, m.p. = 176-178 °C. 1H NMR (400
MHz, acetone-D6)  11.19 (broad s, 1H), 8.25 (dd, J = 7.8 and 1.9 Hz, 1H), 8.10 (dd, J
= 7.4 and 2.2 Hz, 1H), 7.58 (d, J = 3.0 Hz, 1H), 7.54 (m, 2H), 7.44 (d, J = 7.6 Hz,
2H), 7.23 (m, 2H), 7.15 (m, 2H), 4.60 (s, 2H). 13C{1H} NMR (100 MHz, acetone-D6)
 148.8, 143.3, 139.8, 129.7(7), 129.7(5), 129.5, 129.2, 127.9 (broadened), 127.1,
126.4, 126.1, 124.1, 123.8, 102.2, 41.3 (one signal obscured or overlapping). IR max
3429, 3059, 2924, 2853, 1646, 1479, 1361, 878, 748 cm–1. MS (EI, 70 eV) 258 (M+•,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 40
1
2
3
4
5
6
60%), 257 [(M – H•)+, 100]. HRMS (EI, 70 eV) M+• calcd. for C18H14N2 258.1157,
found 258.1158; [(M – H•)+ calcd. for C18H13N2 257.1079, found 257.1067.
4-(4-methoxybenzyl)-3H-pyrrolo[2,3-c]quinolone
(27).
p-Methoxybenzyl-
7
8
9
magnesium bromide (6.0 mL of a 0.25 M solution in THF, 1.5 mmol) was added,
dropwise, to a magnetically stirred solution of compound 20 (101 mg, 0.3 mmol) in
THF (3 mL) maintained at 22 °C under nitrogen and then the ensuing mixture heated
under reflux for 16 h. After this time, methanol (1 mL) was added to the cooled
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
reaction mixture that was then concentrated under reduced pressure. H NMR and
mass spectral analysis of the ensuing residue suggested the presence of significant
quantities of oxide 26 and so it (the residue) was dissolved in methanol (10 mL) and
the resulting solution treated with Pd/C (100 mg of 5% w/w material) and the
suspension so-formed stirred at 22 °C under an atmosphere of hydrogen for 16 h. The
reaction mixture was then filtered through a short pad of TLC-grade silica that was
itself washed with methanol (15 mL). The combined filtrates were concentrated under
reduced pressure and the resulting brown oil subjected to flash chromatography (silica,
4:1 v/v dichloromethane/ethyl acetate elution) to afford, after concentration of the
relevant fractions (Rf = 0.3), compound 27 (58 mg, 68%) as a white, amorphous solid.
1H NMR (400 MHz, CD3OD)  8.33 (broad s, 1H), 8.18 (dd, J = 7.3 and 2.0 Hz, 2H),
7.64-7.53 (complex m, 2H), 7.27 (d, J = 8.3 Hz, 2H), 7.23 (m, 1H), 7.00 (m, 1H), 6.86
13
(d, J = 8.6 Hz, 2H), 4.54 (s, 2H), 3.78 (s, 3H). C{1H} NMR (100 MHz, CD3OD) 
160.0, 149.1, 140.9, 131.9, 131.4, 130.7, 130.6, 128.9, 127.9, 127.2, 126.7, 124.5,
124.2, 115.1, 102.9, 55.6, 39.3. MS (EI, 70 eV) 288 (M+•, 98%), 287 [(M – H•)+, 100],
273 [(M – Me•)+, 80]. HRMS (EI, 70 eV) M+• calcd. for C19H16N2O 288.1263, found
288.1262; (M – H•) calcd. for C19H15N2O 287.1184, found 287.1188.
4-((3H-Pyrrolo[2,3-c]quinolin-4-yl)methyl)phenol (4). Boron tribromide (500 L of
a 1 M solution in dichloromethane, 0.5 mmol) was added, dropwise, to a magnetically
stirred solution of compound 27 (60 mg, 0.2 mmol) in dichloromethane, maintained at
0 °C. After 1 h the reaction mixture was allowed to warm to 22 °C over 2 h then
treated with NaHCO3 (20 mL of a saturated aqueous solution). The ensuing biphasic
mixture was stirred for an additional 1 h then diluted with water (30 mL) and extracted
with dichloromethane (3  30 mL). The combined organic phases were washed with
water (1  50 mL) before being dried (MgSO4), filtered then concentrated under
reduced pressure. The residue thus obtained was subjected to flash chromatography
(silica, 9:1 v/v dichloromethane/methanol elution) to afford, after evaporation of the
appropriate fractions (Rf = 0.3), compound 4 (51 mg, 89%) as a white, crystalline
1
solid, no melting point, degradation above 180 °C. H NMR (400 MHz, CD3OD with
ACS Paragon Plus Environment

Page 23 of 40
The Journal of Organic Chemistry
1
2
3
4
5
a trace of AcOH)  8.37 (m, 1H), 8.09 (m, 1H), 7.84 (dd, J = 2.9 and 1.2 Hz, 1H),
7.75-7.65 (complex m, 2H), 7.28 (d, J = 2.9 Hz, 1H), 7.14 (d, J = 8.5 Hz, 2H), 6.70
(d, J = 8.5 Hz, 2H), 4.57 (s, 2H) (signals due to NH and OH group protons not
6
7
8
13
observed). C{1H} NMR (100 MHz, CD3OD)  157.1, 150.0, 142.7, 130.8, 130.6,
9
130.2, 129.3, 128.2, 127.1, 126.6, 124.5, 124.2, 116.3, 102.3, 40.1 (one signal
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
obscured or overlapping). C NMR (100 MHz, CD3OD with a trace of AcOH) 
157.7, 148.5, 138.4, 134.1, 133.3, 130.6, 129.0, 128.4, 128.0, 124.9, 124.6, 123.7,
116.7, 103.7, 38.2. IR max 3438, 3223, 2926, 1586, 1513, 1480, 1360, 1250, 750 cm–1.
MS (ESI, +ve) 275 [(M + H)+, 100%]. HRMS (ESI, +ve) (M + H)+ calcd. for
C18H15N2O 275.1184, found 275.1183.
4-(1H-Indol-3-yl)-3H-pyrrolo[2,3-c]quinoline (5). A magnetically stirred solution of
compound 20 (101 mg, 0.3 mmol), tosic anhydride (108 mg, 0.36 mmol) and indole
(70 mg, 0.6 mmol) in THF (10 mL) was maintained at 22 °C under nitrogen for 1 h
then heated under reflux for 12 h. The cooled reaction reaction mixture was treated
with methanol (10 mL) then sodium methoxide (32 mg, 0.6 mmol) and the resulting
mixture heated under reflux for a further 2 h. The cooled reaction mixture was then
concentrated under reduced pressure and the residue partitioned between NH4Cl (20
mL of a saturated aqueous solution) and ethyl acetate (20 mL). The separated aqueous
phase was extracted with ethyl acetate (2  20 mL) then the combined organic layers
were dried (MgSO4), filtered and concentrated under reduced pressure. The residue
thus obtained was subjected to flash chromatography (silica, 19:1 v/v
dichloromethane/methanol elution) to afford, after concentration of the appropriate
fractions (Rf = 0.2), a yellow and amorphous solid, crystallization (acetone) of which
1
gave compound 5 (61 mg, 73%) as bright-yellow crystals, m.p. = 251-252 °C. H
NMR (400 MHz, acetone-D6)  10.96 (broad s, 1H), 10.79 (broad s, 1H), 8.79 (d, J =
7.7 Hz, 1H), 8.27 (m, 2H), 8.16 (dd, J = 8.1 and 1.1 Hz, 1H), 7.60 (d, J = 3.1 Hz, 1H),
7.59-7.48 (compound m, 3H), 7.28-7.18 (compound m, 3H). 13C{1H} NMR (100
MHz, acetone-D6)  144.5, 144.0, 137.9, 130.0, 129.5, 128.1, 127.8, 127.4, 126.9,
126.3, 125.5, 123.6(4), 123.5(9), 123.5(6), 123.3, 121.0, 115.2, 112.3, 102.1. IR max
3401, 3167, 2920, 2850, 1703, 1581, 1452, 1380, 1241, 1116, 886 cm–1. MS (ESI,
+ve) 284 [(M + H)+, 100%]. HRMS (ESI, +ve) (M + H)+, calcd. for C19H14N3
284.1188, found: 284.1183.
3-Tosyl-3H-pyrrolo[2,3-c]quinoline-4-carbonitrile (28). A magnetically stirred
solution of compound 20 (338 mg, 1.0 mmol) in dichloromethane (10 mL) maintained
under nitrogen at 10 °C was treated with dimethylaminocarbamoyl chloride (110 L,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 40
1
2
3
4
5
6
7
8
9
1.2 mmol) then TMSCN (150 L, 1.2 mmol). The resulting mixture was stirred at 10
°C for 48 h and after this time treated with K2CO3 (10 mL of a saturated aqueous
solution) then stirred vigorously for 1 h before the separated aqueous phase was
extracted with dichloromethane (2  20 mL). The combined organic phases were dried
(MgSO4), filtered and concentrated under reduced pressure. The residue thus obtained
was subjected to flash chromatography (silica, 2:1 v/v 40-60 petroleum spirit/ethyl
acetate elution) to afford, after concentration of the appropriate fractions (Rf = 0.5 in
dichloromethane), a white amorphous solid, crystallization (acetone) of which gave
compound 28 (82 mg, 82%) as white, crystalline masses, m.p. = 194-196 °C. 1H NMR
(400 MHz, acetone-D6)  8.47 (m, 1H), 8.36 (d, J = 3.6 Hz, 1H), 8.17 (m, 1H), 8.07
(d, J = 8.5 Hz, 2H), 7.88-7.82 (complex m, 2H), 7.70 (d, J = 3.6 Hz, 1H), 7.49 (d, J =
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
8.5 Hz, 2H), 2.41 (s, 3H). C{1H} NMR (100 MHz, acetone-D6)  147.4, 144.1,
137.0, 135.7, 133.6, 131.3, 130.8, 130.6, 130.2, 128.8, 126.6, 124.5, 124.3, 121.2,
116.7, 107.2, 21.6. IR max 3148, 2925, 2235, 1512, 1493, 1380, 1175, 1135, 672, 600
cm–1. MS (ESI, +ve) 717 [(2M + Na)+, 40%], 370 [(M + Na)+, 50], 348 [(M + H)+,
32
100]. HRMS (ESI, +ve) (M + Na)+ calcd. for C19H13N3O2 S23Na 370.0626, found
370.0627.
4-Bromo-3-tosyl-3H-pyrrolo[2,3-c]quinoline (29). A magnetically stirred solution of
compound 15 (1.02 g, 3.0 mmol) in THF/dichloromethane (20 mL of a 1:1 v/v
mixture) maintained at 22 °C under a nitrogen atmosphere was treated with
phosphorus oxytribromide (1.29 g, 4.5 mmol) and the ensuing mixture stirred for 16 h
then treated with NH4OH (20 mL of a 10% w/w aqueous solution) before being
extracted with dichloromethane (3  20 mL). The combined organic phases were dried
(Na2SO4), filtered then concentrated under reduced pressure. The residue thus obtained
was subjected to flash chromatography (silica, dichloromethane elution) and gave,
after concentration of the appropriate fractions (Rf = 0.5), an off-white solid,
recrystallization (dichloromethane) of which gave compound 29 (970 mg, 81%) as
white, crystalline masses, m.p. = 146-151 °C. 1H NMR (400 MHz, CDCl3)  8.22 (d, J
= 3.6 Hz, 1H), 8.14 (m, 1H), 8.06 (m, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.70-7.61
(complex m, 2H), 7.29 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 3.6 Hz, 1H), 2.41 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3)  145.4, 143.6, 136.8, 136.6, 133.2, 129.9, 128.8,
128.6, 127.5, 127.3(1), 127.2(8), 126.0, 123.1, 121.9, 104.7, 21.7. IR max 3153, 1562,
1481, 1369, 1324, 1193, 1170, 1122, 1088, 942 cm–1. MS (ESI, +ve) 403 and 401 [(M
32
+ H)+, 95 and 100%). HRMS (ESI, +ve) (M + H)+ calcd. for C18H1481BrN2O2 S
32
402.9939, found 402.9940; calcd. for C18H1479BrN2O2 S 400.9959, found 400.9960.
ACS Paragon Plus Environment

Page 25 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(1-Tosyl-1H-indol-3-yl)(3-tosyl-3H-pyrrolo[2,3-c]quinolin-4-yl)methanol (32) and
(1-Tosyl-1H-indol-3-yl)(3-tosyl-3H-pyrrolo[2,3-c]quinolin-2-yl)methanol (33). A
magnetically stirred solution of compound 29 (555 mg, 1.38 mmol) in diethyl ether
(14 mL) maintained at –78 °C under a nitrogen atmosphere was treated rapidly with n-
BuLi (1.1 mL of a 1.31 M solution in hexanes, 1.45 mmol) and the ensuing mixture
stirred for a further 0.25 h then a solution of N-tosylindole-3-carboxaldehyde (31)27
(495 mg, 1.66 mmol) in THF (10 mL) added in one portion. The reaction mixture thus
formed was stirred at –78 °C for an additional 1 h, quenched with NH4Cl (10 mL of a
saturated aqueous solution) then allowed to warm to 22 °C before being extracted with
ethyl acetate (3  30 mL). The combined organic phases were washed with brine (1 
50 mL) then dried (MgSO4), filtered and concentrated under reduced pressure. The
residue thus obtained was subjected to flash chromatography (silica, 9:1 v/v
dichloromethane/diethyl ether elution) and so affording two fractions, A and B.
Concentration of fraction A gave (Rf = 0.3) gave a pale-yellow solid,
recrystallization (dichloromethane) of which gave compound 32 (444 mg, 52%) as
pale-yellow crystals, m.p. = 179-181 °C. 1H NMR (400 MHz, CDCl3)  8.15 (broad s,
1H), 8.12 (d, J = 8.0 Hz, 1H), 7.95 (m, 1H), 7.83-7.63 (complex m, 3H), 7.60 (t, J =
7.5 Hz, 1H), 7.47 (d, J = 7.9 Hz, 2H), 7.25 (m, 1H), 7.22-7.09 (complex m, 3H), 7.07-
7.00 (complex m, 4H), 6.76 (d, J = 8.0 Hz, 2H), 6.33 (s, 1H), 5.80 (broad s, 1H), 2.20
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
(s, 3H), 2.14 (s, 3H). C{1H} NMR (100 MHz, CDCl3)  148.0, 145.5, 144.8, 141.4,
136.8, 135.1, 135.0, 134.6, 133.8, 129.9, 129.8, 128.8, 128.4, 127.4, 126.7, 125.9,
125.6, 125.3, 124.7, 123.9, 123.3, 123.2, 122.4, 120.9, 113.2, 106.7, 65.3, 21.5(2),
21.4(7) (one signal obscured or overlapping). IR max 3339, 1595, 1447, 1370, 1321,
1189, 1174, 1121, 1094, 1019, 990, 965, 811 cm–1; MS (ESI, +ve) 685 [(M + Na +
MeCN)+, 20%], 644 [(M + Na+) 10], 622 [(M + H)+, 100]. HRMS (ESI, +ve) (M + H)+
32
calcd. for C34H28N3O5 S2 622.1470, found 622.1472 .
Concentration of fraction B (Rf = 0.2) gave a light-brown solid,
recrystallization (dichloromethane) of which gave compound 33 (204 mg, 24%) as
1
white, crystalline masses, m.p. = 234-236 °C. H NMR (400 MHz, CDCl3)  9.69 (s,
1H), 8.15 (d, J = 8.4 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.85 (dd, J = 8.2 and 1.4 Hz,
1H), 7.78 (d, J = 8.2 H, 2H), 7.66-7.60 (complex m, 4H), 7.51 (m, 1H), 7.28 (m, 1H),
7.22 (d, J = 8.1 Hz, 2H), 7.13-7.02 (complex m, 4H), 6.89 (s, 1H), 6.73 (s, 1H), 4.25
13
(broad s, 1H), 2.34 (s, 3H), 2.31 (s, 3H). C{1H} NMR (100 MHz, CDCl3)  146.0,
145.1, 144.7, 143.4, 138.3, 135.3, 135.0(9), 135.0(6), 130.9, 130.4, 130.2, 129.9,
129.2, 128.5, 128.2, 127.1, 126.9, 126.4, 124.9, 123.3, 123.2, 122.4, 122.3, 122.0,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 40
1
2
3
4
5
120.0, 113.8, 108.5, 63.1, 21.6 (one signal obscured or overlapping). IR max 3116,
1710, 1364, 1169, 669, 570 cm–1. MS (ESI, +ve) 644 [(M + Na)+, 20%], 622 [(M +
32
H)+, 100]. HRMS (ESI, +ve) (M + H)+ calcd. for C34H28N3O5 S2 622.1470, found
6
7
8
622.1470.
9
(1-Tosyl-1H-indol-3-yl)(3-tosyl-3H-pyrrolo[2,3-c]quinolin-2-yl)methanone (34). A
magnetically stirred solution of compound 33 (404 mg, 0.65 mmol) in
dichloromethane (10 mL) maintained under nitrogen at 22 °C was treated with
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
34
activated MnO2 (1.13 g, 13.0 mmol). The resulting suspension was stirred for 2 h
then filtered through a pad of diatomaceous earth and the solids so-retained washed
with dichloromethane (2  10 mL). The combined filtrates were concentrated under
reduced pressure and the residue subjected to flash chromatography (silica,
dichloromethane elution) to afford, after concentration of the appropriate fractions (Rf
1
= 0.5), compound 34 (398 mg, 99%) as a bright-yellow oil. H NMR (400 MHz,
CDCl3)  9.78 (s, 1H), 8.41 (dd, J = 6.6 and 2.2 Hz, 1H), 8.34 (d, J = 8.4 Hz, 1H),
8.18 (s, 1H), 8.15 (d, J = 8.0 Hz, 1H), 8.10 (d, J = 8.2 Hz, 2H), 8.02-7.96 (complex m,
1H), 7.85 (d, J = 8.1 Hz, 2H), 7.77 (m, 1H), 7.69 (m, 1H), 7.47 (s, 1H), 7.47-7.40
(complex m, 2H), 7.34 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 2.40 (s, 3H), 2.38
(s, 3H). 13C{1H} NMR (100 MHz, CDCl3)  181.2, 146.3, 146.2, 142.9, 140.1, 138.3,
135.4, 135.1, 134.6, 134.1, 131.0, 130.4, 130.1, 129.9, 129.2, 128.7, 128.1, 127.9,
127.5, 127.3, 126.3, 125.2, 123.2, 123.0, 122.3, 121.8, 113.3, 110.9, 21.7(0), 21.6(5).
IR max 1650, 1532, 1381, 1190, 1176, 1131, 1086, 662, 570 cm–1. MS (ESI, +ve) 683
[(M + Na + MeCN)+ 25%], 642 [(M + Na)+, 25], 620 [(M + H)+, 100]. HRMS (ESI,
32
+ve) (M + H)+ calcd. for C34H26N3O5 S2 620.1314, found 620.1315.
(1-Tosyl-1H-indol-3-yl)(3-tosyl-3H-pyrrolo[2,3-c]quinolin-4-yl)methanone
(35)
and (3H-Pyrrolo[2,3-c]quinolin-4-yl)(1-tosyl-1H-indol-3-yl)methanone (37). A
magnetically stirred solution of compound 32 (879 mg, 1.41 mmol) in
dichloromethane (20 mL) maintained at 22 °C under a nitrogen atmosphere was
treated with activated MnO2 (2.45 g, 28.2 mmol) and the resulting suspension stirred
for 1 h then filtered through a pad of diatomaceous earth and the solids thus retained
washed with dichloromethane (2  20 mL). The combined filtrates were concentrated
under reduced pressure and the residue subjected to flash chromatography (silica,
dichloromethane elution). Concentration of the appropriate fractions (Rf = 0.85) gave a
pale-orange solid, recrystallization (dichloromethane/diethyl ether/acetone) of which
afforded compound 35 (816 mg (93%), as yellow, crystalline masses, m.p. = 237-239
°C. 1H NMR (400 MHz, CDCl3)  8.49-8.43 (complex m, 1H), 8.25-8.19 (complex m,
ACS Paragon Plus Environment

Page 27 of 40
The Journal of Organic Chemistry
1
2
3
4
5
2H), 8.07 (s, 1H), 8.00-7.93 (complex m, 2H), 7.79 (d, J = 8.2 Hz, 2H), 7.77-7.67
(complex m, 4H), 7.45-7.38 (complex m, 2H), 7.35 (d, J = 3.6 Hz, 1H), 7.27 (d, J =
13
8.1 Hz, 4H), 2.39 (s, 3H), 2.35 (s, 3H). C{1H} NMR (100 MHz, CDCl3)  187.5,
6
7
8
9
145.8, 145.5, 145.4, 142.1, 135.7, 135.4, 135.0(4), 135.0(2), 134.5, 131.6, 130.2,
129.8, 129.7, 128.5, 128.4, 127.9, 127.4, 127.2, 125.7, 124.9, 124.7, 123.1(0),
123.0(8), 123.0, 120.4, 113.2, 106.8, 21.7, 21.6. IR max 3139, 3057, 1661, 1538,
1445, 1377, 1326, 1190, 1177, 1135, 1088, 962, 816, 750, 666, 572 cm–1. MS (ESI,
+ve) 700 [(M + Na + acetone)+, 50%], 683 [(M + Na + MeCN)+, 15], 642 [(M + Na)+,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
32 23
10], 620 [(M + H)+, 100]. HRMS (ESI, +ve) (M + Na)+ calcd. for C34H25N3O5 S2 Na
642.1133, found 642.1133.
On one occasion during the preparation of compound 35 small amounts of congener
37 were obtained as a brown oil, Rf = 0.4 (in 3:2 v/v dichloromethane 40-60 petroleum
spirit). 1H NMR (400 MHz, CDCl3)  10.73 (broad s, 1H), 9.92 (s, 1H), 8.55 (m, 1H),
8.40 (dd, J = 6.3 and 3.4 Hz, 1H), 8.26 (dd, J = 6.3 and 3.4 Hz, 1H), 8.04 (m, 1H),
7.96 (d, J = 8.2 Hz, 2H), 7.70 (dd, J = 6.3 and 3.4 Hz, 2H), 7.55 (m, 1H), 7.40 (m,
13
2H), 7.27 (d, J = 8.0 Hz, 2H), 7.11 (m, 1H), 2.23 (s, 3H). C{1H} NMR (100 MHz,
CDCl3)  188.9, 145.7, 141.3, 140.2, 138.0, 134.8, 134.2, 130.9, 130.7, 130.2, 129.2,
128.3, 128.2, 127.6, 127.3, 126.6, 125.4, 125.0, 124.8, 123.0, 123.0, 118.4, 113.1,
101.1, 21.6. IR max 3437, 1626, 1525, 1377, 1176, 1134, 1103, 979, 797, 747, 665,
574 cm–1. MS (ESI, +ve) 488 [(M + Na)+, 21%], 466 [(M + H)+, 31], 102 (100).
HRMS (ESI, +ve) (M + H)+ calcd. for C27H20N3O3S 466.1225, found 466.1226.
(1H-Indol-3-yl)(3H-pyrrolo[2,3-c]quinolin-2-yl)methanone (36). A magnetically
stirred solution of compound 34 (390 mg, 0.63 mmol) in methanol (10 mL)
maintained at 22 °C under a nitrogen atmosphere was treated with sodium methoxide
(78 mg, 1.44 mmol) and the resulting mixture heated under reflux for 1 h then cooled
to 22 °C and treated with flash chromatography-grade silica (2 g) before being
concentrated under reduced pressure. The resulting free-flowing solid was subjected to
flash chromatography (silica, 19:1 v/v dichloromethane/methanol elution) and
concentration of the appropriate fractions (Rf = 0.35) gave compound 36 (166 mg,
85%) as a yellow, crystalline solid, no melting point, decomposition above ca. 150 °C.
1H NMR (400 MHz, DMSO-D6)  11.72 (broad s, 1H), 11.29 (broad s, 1H), 9.25 (s,
1H), 8.67 (m, 1H), 8.50-8.34 (complex m, 2H), 8.12 (m, 1H), 8.04 (s, 1H), 7.68-7.52
13
(complex m, 3H), 7.33-7.24 (complex m, 2H). C{1H} NMR (100 MHz, DMSO-D6)
 179.9, 142.2, 139.5, 137.4, 136.6, 134.7, 130.2, 129.5, 126.8, 126.4(3), 126.4(1),
126.0, 123.8, 123.5, 123.3, 122.0, 121.6, 114.9, 112.3, 105.5. IR max 3127, 2925,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 40
1
2
3
4
5
6
2854, 1708, 1604, 1519, 1426, 1374, 1244, 1189, 854 cm–1. MS (ESI, +ve) 334 [(M +
Na)+, 30%], 312 [(M + H)+, 55], 169 (100). HRMS (ESI, +ve) (M + H)+ calcd. for
C20H14N3O 312.1137, found 312.1137.
7
8
9
(1H-Indol-3-yl)(3H-pyrrolo[2,3-c]quinolin-4-yl)methanone (6). A magnetically
stirred solution of compound 35 (328 mg, 0.52 mmol) in methanol (10 mL)
maintained at 22 °C under a nitrogen atmosphere was treated with sodium methoxide
(115 mg, 2.1 mmol) and the resulting mixture heated under reflux for 16 h. The cooled
reaction was concentrated under reduced pressure and the resulting yellow solid
subjected to flash chromatography (silica, 99:1 v/v dichloromethane/diethyl ether
elution) to afford, after concentration of the relevant fractions (Rf = 0.55), a bright-
yellow, amorphous solid that was crystallized (dichloromethane) to give compound 6
(140 mg, 85%) yellow crystals, m.p. = 225-228 °C. 1H NMR (400 MHz, acetone-D6) 
11.61 (broad s, 1H), 11.23 (broad s, 1H), 9.72 (s, 1H), 8.67 (d, J = 6.7 Hz, 1H), 8.38
(m, 1H), 8.31 (m, 1H), 7.79 (broad s, 1H), 7.72-7.64 (complex m, 2H), 7.60 (m, 1H),
7.35-7.25 (complex m, 2H), 7.24 (broad s, 1H). 13C{1H} NMR (100 MHz, acetone-D6)
 189.0, 143.1, 142.3, 139.3, 137.2, 131.5, 131.4, 129.3, 129.0, 128.6, 128.3, 126.9,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
125.8, 124.0, 123.9(5), 123.2, 123.1, 115.9, 112.8, 101.3. IR max 3418, 3238, 1589,
1553, 1507, 1439, 1382, 1365, 1235, 1160, 1097, 1076, 866 cm–1. MS (ESI, +ve) 645
[(2M + Na)+, 5%], 334 [(M + Na)+, 20], 312 [(M + H)+, 100]. HRMS (ESI, +ve) (M +
H)+ calcd. for C20H14N3O 312.1137, found 312.1138.
1-(3-(2-Nitrophenyl)-1-tosyl-1H-pyrrol-2-yl)ethan-1-one (38). This compound was
prepared according to a previously reported procedure17 and after chromatographic
purification and recrystallization (diethyl ether) obtained, in 42% yield from
compound 15, as a light-yellow, crystalline solid, m.p. = 114-116 °C (lit.17 m.p. = 111-
1
113 °C). H NMR (400 MHz, CDCl3)  8.00 (dd, J = 8.0 and 2.0 Hz, 1H), 7.89-7.80
(complex m, 2H), 7.68 (d, J = 4.0 Hz, 1H), 7.65-7.50 (complex m, 2H), 7.40-7.30
13
(complex m, 3H), 6.25 (d, J = 4.0 Hz, 1H), 2.44 (s, 3H), 1.96 (s, 3H). C{1H} NMR
(100 MHz, CDCl3)  189.2, 148.9, 145.0, 136.1, 132.7, 132.4, 131.2, 131.0, 129.6,
129.5, 129.3, 127.8, 127.6, 124.5, 113.0, 29.9, 21.7. IR max 1675, 1527, 1402, 1354,
1175, 1137, 674, 578 cm–1. MS (ESI, +ve) 791 [(2M + Na)+, 11%], 407 [(M + Na)+,
100], 385 [(M + H)+, 20]. HRMS (ESI, +ve) (M + Na)+ calcd. for C19H16N2O5S23Na
407.0678, found: 407.0678.
2-Bromo-1-(3-(2-nitrophenyl)-1-tosyl-1H-pyrrol-2-yl)ethan-1-one (39). A magnet-
ically stirred solution of compound 3817 (1.35 g, 3.5 mmol) in ethyl acetate/chloroform
(30 mL of a 1:1 v/v mixture) maintained under nitrogen at 22 °C was treated CuBr2
(1.73 g, 7.7 mmol) and the ensuing mixture heated under reflux for 16 h. The cooled
ACS Paragon Plus Environment

Page 29 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
reaction mixture was filtered through a pad of diatomaceous earth, the solids thus
retained washed with dichloromethane (2  25 mL) and the combined filtrates
concentrated under reduced pressure. 1H NMR spectroscopic analysis of the solid thus
obtained suggested this was comprised of a ca. 9:1 mixture of the target mono-
bromide 39 and its dibrominated-counterpart. Accordingly, the solid was dissolved in
dry THF (20 mL) and the resulting solution was treated, while being maintained at 0
°C under a nitrogen atmosphere, with Et3N (1 mL) and diethylphosphite (100 L, 0.8
mmol). The ensuing mixture was warmed to 22 °C over 1 h then concentrated under
reduced pressure and the residue so formed subjected to flash chromatography (silica,
12:6:1 v/v/v 40-60 petroleum spirit/dichloromethane/diethyl ether elution).
Concentration of the relevant fractions (Rf = 0.3) gave compound 39 (1.27 g, 94%) as
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
a pale-yellow and amorphous solid. H NMR (400 MHz, CDCl3)  8.22 (dd, J = 7.9
and 1.6 Hz, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.62 (td, J = 7.4 and 1.6 Hz, 1H), 7.60-7.55
(complex m, 2H), 7.38-7.33 (complex m, 3H), 6.27 (d, J = 3.2 Hz, 1H), 3.96 (s, 2H),
13
2.44 (s, 3H). C{1H} NMR (100 MHz, CDCl3)  184.3, 148.9, 145.6, 135.2, 132.8,
132.4, 131.9, 129.9, 129.8, 128.4, 127.8(9), 127.8(5), 127.7, 124.6, 114.2, 34.4, 21.7.
IR max 1683, 1528, 1402, 1371, 1350, 1191, 1175, 1141, 673, 575 cm–1. MS (ESI,
+ve) 487 and 485 [(M + Na)+, 100 and 95%], 465 and 463 [(M + H)+, 52 and 50].
32
HRMS (ESI, +ve) (M + Na)+ calcd. for C19H1581BrN2O5 S23Na 486.9762, found
32
486.9759; calcd. for C19H1579BrN2O5 S23Na 484.9783, found 484.9794.
2-(6-Amino-9H-purin-9-yl)-1-(3-(2-nitrophenyl)-1H-pyrrol-2-yl)ethan-1-one (40).
A magnetically stirred solution of compound 39 (1.27 g, 2.7 mmol) and adenine (910
mg, 6.8 mmol) in DMF (32 mL) maintained at 0 °C under a nitrogen atmosphere was
treated, in portions, with NaH (220 mg, of a 60% suspension in mineral oil, 5.4
mmol). The ensuing mixture was allowed to warm to 22 °C and then stirred at this
temperature or 24 h before being quenched with NH4Cl (50 mL of a saturated aqueous
solution) (CAUTION: POSSIBILITY OF HYDROGEN GENERATION) then
extracted with dichloromethane (4  50 mL). The combined organic phases were
washed with brine (1  75 mL) then dried (MgSO4), filtered and concentrated under
reduced pressure. The residue thus obtained was subjected to flash chromatography
(silica, 9:1 v/v dichloromethane/methanol elution) and so affording, after
concentration of the appropriate fractions (Rf = 0.45), compound 40 (839 mg, 84%) as
1
a clear, orange oil. H NMR (400 MHz, acetone-D6)  11.74 (broad s, 1H), 8.16 (s,
1H), 8.01 (dd, J = 8.1 and 1.3 Hz, 1H), 7.98 (s, 1H), 7.74 (m, 1H), 7-68-7.60 (complex
m, 2H), 7.27 (t, J = 2.8 Hz, 1H), 7.08 (broad s, 2H), 6.30 (t, J = 2.3 Hz, 1H), 5.19 (s,
ACS Paragon Plus Environment