Parallel synthesis and spectroscopic analysis of a collection of heterocycles based on the diazabenz[e]aceanthrylene core structure

Article abstract of DOI:10.1016/j.tet.2008.10.049

A practical strategy for the synthesis of diazabenz[e]aceanthrylene-based heterocycles is reported. The key step in this approach is a microwave-assisted condensation and cyclisation reaction between an anthranilic acid derivative and a 2′-carbomethoxy substituted N-aryl lactam. The scope of the reaction has been explored as a function of both the nature and position of substituents in both components and variations in lactam ring size. Interesting structural and spectroscopic variations observed across the compound collection are described and explored using NMR, X-ray crystallography and computational techniques.

Full text of DOI:10.1016/j.tet.2008.10.049

Tetrahedron 65 (2009) 563–578
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Parallel synthesis and spectroscopic analysis of a collection of heterocycles
based on the diazabenz[e]aceanthrylene core structure
Alan M. Jones, Tomas Lebl, Stephen Patterson, Tanja van Mourik, Herbert A. Fru¨chtl, Douglas Philp,
*
Alexandra M.Z. Slawin, Nicholas J. Westwood
School of Chemistry and Centre for Biomolecular Sciences, EaStChem, University of St Andrews, North Haugh, St Andrews, Fife, Scotland, KY16 9ST, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A practical strategy for the synthesis of diazabenz[e]aceanthrylene-based heterocycles is reported. The
key step in this approach is a microwave-assisted condensation and cyclisation reaction between an
anthranilic acid derivative and a 20-carbomethoxy substituted N-aryl lactam. The scope of the reaction
has been explored as a function of both the nature and position of substituents in both components and
variations in lactam ring size. Interesting structural and spectroscopic variations observed across the
compound collection are described and explored using NMR, X-ray crystallography and computational
techniques.
Received 6 August 2008
Received in revised form
30 September 2008
Accepted 16 October 2008
Available online 1 November 2008
Keywords:
Heterocycles
Ó 2008 Elsevier Ltd. All rights reserved.
Zipper reaction
Microwave
Variable temperature NMR analysis
Computational analysis
O
1. Introduction
( )n
10
R
( )n
CO2R1
NH2
MW,190 °C
A
B
C
275 W, 0.5-1 h
N
O
R
We have previously reported the microwave-mediated synthe-
sis of heterocycles 1a–1d (Scheme 1).1 Limited examples of three
alternative synthetic approaches were described, the key step of
each approach being an intramolecular attack on the anthranilate
ester by the in situ generated N,N-dienamine functionality shown
in general structure 2 (Scheme 1). This cyclisation reaction results
in the formation of the second of two new six-membered rings (B
and D rings in general structure 1, Scheme 1). We also argued that
to generate a diverse range of analogues, the two methods high-
lighted in Scheme 1 would be the most useful as they enable the
preparation of differentially substituted analogues (where R differs
from R2 in 1).1 The first of these, method 1, combines anthranilates
of general structure 3 and N-aryl lactams of general structure 4
directly in one pot, whereas method 2 requires an alternative
synthesis of the more complex starting amide 5, a proposed in-
termediate in method 1.1,2
N
N
12
D
MeO2C
METHOD 1
14
R2
O
R2
E
2
3 R1 = Me or H
4
1a R = R2 = H, n =1
1b R = H, R2 = 2-OMe, n = 1
1c R = 10-OMe, R2 = H, n =1
1d R = R2 = H, n = 2
CO2R1
CO2Me
MW, 190 °C
275 W, 20 min
( )n
( )n
R
R
R1 = Me
METHOD 2
NH
N
O
N
N
2
5
O
O
R2
R2
Here we report the details of further studies on these two
methods with a focus on exploring the reaction scope as a function
of R, R2 and n. We demonstrate that method 1 can tolerate a range
of substituents in the A and E-rings (Scheme 1) and clear trends
5 R1 = Me
2
Scheme 1. Two routes for the synthesis of diazabenz[e]aceanthrylene-based
heterocycles.
with regards to substituent position also emerged from these
studies. Several limitations to method 1 were, however, identified.
For example, when attempts were made to incorporate hetero-
aromatic and non-aromatic A-rings into the core structure, or to
* Corresponding author. Tel.: þ44 (0)1334 463816; fax: þ44 (0)1334 462595.
E-mail address: njw3@st-andrews.ac.uk (N.J. Westwood).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.10.049

564
A.M. Jones et al. / Tetrahedron 65 (2009) 563–578
Table 1
prepare analogues containing rings where n>2, method 1 failed. In
Exploring the reaction scope of method 1
most cases, these problems were overcome by the use of method 2.
Several of the compounds that were prepared exhibited interesting
spectroscopic properties, the details of which are also described
here.
O
n
C
N
6
10
CO2R1
NH2
R
O
n
B
N
A
C
N
MW, 190 °C
5
4
R
A
3
CO2Me
12
275 W, 30 min
D
E
2. Results and discussion
O
E
R2
4
3
1
2
2.1. Exploring the scope of method 1
R2
The direct combination of a range of methyl anthranilates 3
(R1¼Me) and N-aryl lactams 4 was explored as a function of the
type and position of substituents in 3. Our previously reported1
reaction conditions, further optimised by reduction of the reaction
time to 30 min (cf. 1 h1) were used unless otherwise stated. This
involved the mixing of the two reactants in a microwave tube fol-
lowed by microwave irradiation at 190 ꢀC, 275 W for 30 min under
‘powermax’ operating conditions.3 No solvent is used in these re-
actions and given the melting points of the various anthranilates 3
and lactams 4, it is assumed that a melt containing both reactants is
formed. In most cases, the two reactants were briefly heated using
a heat gun prior to running the reaction in the microwave. This
caused them to both melt and mix effectively. Analysis of reactions
after this brief period of heating outside the microwave indicated
that no reaction had occurred prior to the microwave irradiation.
Upon completion of the microwave reaction, the mixture was
cooled and poured into diethyl ether whereupon, in most cases,
precipitation of a pure sample of the desired product occurred
(see Table S1 for details3). For those reactions where no precipitate
was formed the reaction mixture was concentrated in vacuo
and purified by standard chromatographic techniques. The
results of these experiments are given in Table 1 and a description
of the product numbering system used is provided in the table
legend.4
Whilst care must be taken in interpreting the data presented in
Table 1, as all reactions were carried out under one standard set of
conditions and in several cases the yields reflect only the amount of
product that precipitated following addition of the reaction mix-
ture to diethyl ether, it was clear that both electron-withdrawing
and electron-donating substituents were tolerated at C4 of 3. For
example, for the n¼1 series both 1(1,1,2) and 1(1,1,3) were obtained
in reasonable yield, 53% and 46%, respectively. The same two sub-
stituents at the C5-position also gave pure samples of the desired
compounds in 66 and 65% yields for 1(1,1,4) and 1(1,1,5), re-
spectively, when only the precipitated material was collected.
These yields increased to 79% for 1(1,1,4) and 80% for 1(1,1,5) when
purification of the crude reaction mixture by chromatography was
employed. However, when methyl-5-bromoanthranilate was used
in this reaction, none of the desired compound 1(1,1,10) (Scheme
3c) was isolated presumably reflecting either the decreased nu-
cleophilicity of the amino group in the presence of the para-bromo
substituent,5 or an alternative reaction path possibly involving
homolytic cleavage of the aryl-bromine bond.6 In practice, a sharp
rise in pressure was observed during this particular microwave
reaction along with extensive decomposition of the starting ma-
terials. Compound 1(1,1,10) was subsequently prepared using
method 2 (Scheme 3c). The inclusion of an ester functional group at
C4 in 3 also proved successful giving 1(1,1,6) in good yield despite
the fact that the C4-ester group in 3(6) could compete for reaction
of the anthranilate amine with the ester functional group in 4.7
Subsequent further functionalisation of the A-ring substituents in
several of the products, for example, 1(1,1,2) and 1(1,1,6), could be
envisaged using standard chemical approaches.
I
I
CO2Me
CO2Me
6(1)
OMe
6(2)
O
O
N
H
N
H
N
H
7(2)
O
N
H
7(2)
O
7(1)
7(1)
CO2Me
1a
1d
1b
1(2,2,1)
3(1)
3(2)
67a; 70b
78a,þ
18a; 93b,þ
59a; 74b
NH2
CO2Me
NH2
1(1,1,2)
1(1,2,2)
1(2,1,2)
1(2,2,2)
53b
33b
81b
60b
Cl
CO2Me
NH2
1(1,1,3)
1(1,2,3)
1(2,1,3)
1(2,2,3)
(s)
3(3)
3(4)
46b
55b
34b
Me
Me
CO2Me
NH2
1(1,1,4)
1(1,2,4)
1(2,1,4)
1(2,2,4)
66a; 79b
60a; 64b
45a
33a; 45b
Cl
CO2Me
NH2
1(1,1,5)
1(1,2,5)
1(2,1,5)
(s)
1(2,2,5)
(s)
3(5)
3(6)
65a; 80b
64a
CO2Me
NH2
1(1,1,6)
1(1,2,6)
1(2,1,6)
1(2,2,6)
(s)
88b
78a; 83
57a
MeO2C
CO2Me
NH2
1(1,1,7)
1(1,2,7)
1(2,1,7)
1(2,2,7)
3(7)
27a; 39b
24a
21a
21a; 24b
Me
Me
CO2Me
NH2
1(1,1,8)
(s)
1(1,2,8)
(s)
1(2,1,8)
1(2,2,8)
3(8)
3(9)
85b
75b
Cl
1(1,1,9)
1(1,2,9)
1(2,1,9)
1(2,2,9)
(s)
CO2H
NH2
16a
15a
15a
The compound numbers were assigned according to a literature protocol4 that
emphasises the structure of the components used (e.g., 1(1,2,7) is made up from
components 6(1), 7(2), 3(7)); the isolated yield for each compound is also provided
under varying reaction conditions.
þ
The symbol (s) indicates no product isolated,
cf. previously reported1 un-
optimised yields for synthesis of 1d (28%) and 1b (31%). HPLC analysis of the ma-
jority of the compounds described in Table 1 is provided.3
a
Isolated yield after precipitation using diethyl ether.
Isolated yield after purification by flash chromatography.
For substrates 3 containing C4 or C5 substituents, the yields of
the reaction remained good to average as the ring size of the lactam
was varied from n¼1 to n¼2 in the R2¼H series. For example,
b

A.M. Jones et al. / Tetrahedron 65 (2009) 563–578
565
Table 2
Use of anthranilic acids in the two-component microwave approach
CO2H
CO2H
NH2
CO2H
NH2
CO2H
NH2
NH2
3(1,R1=H)
OMe
3(11)
Cl
3(12)
Me
3(7, R1=H)
1a
67
146.5 ꢀ
Ref. 8a
1(1,1,11)
10
165–166.5 ꢀ
Ref. 8b
1(1,1,12)
1(1,1,7)
I
37
29
174–176 ꢀ
Ref. 8d
CO2Me
C
C
189 ꢀ
C
C
O
N
H
Ref. 8c
7(1)
6(1)
CO2H
NH2
MeO
CO2H
NH2
CO2H
NH2
Me
3(3,R1 = H)
3(13)
3(14)
1(1,1,3)
55
176–177.2 ꢀC
Ref. 8e
1cþ
40
140–142 ꢀ
Ref. 8f
1(1,1,14)
10
213–214 ꢀ
Ref. 8g
I
CO2Me
O
C
C
N
H
7(1)
6(1)
The compound numbers were assigned according to a literature protocol4 (see Scheme and Table 1 legend for details); reaction yields and melting points of the starting
þ
anthranilate acids with references are provided. cf. this yield with the previously reported1 unoptimised yield for the synthesis of 1c (20%).
1(1,2,4) was formed in 64% yield compared to 79% yield for the
formation of 1(1,1,4). However, when R2 in aryl lactam 4 was
changed to methoxy in both the n¼1 and the n¼2 series, the re-
action yields fell and in several cases none of the desired product
could be isolated for anthranilates containing a C4 or C5 substituent
with the exception of anthranilate 3(2).9
in 2 (Scheme 1 for numbering) when the starting lactam 4 contains
an electron-donating methoxy group may help to overcome the
challenge of forming the final ring in this system. This may occur
through an increase in electron density associated with N5 of the
N,N-dienamine functionality and hence an increase in overall
nucleophilicity associated with this functional group. In other
words, in the absence of an increase in reactivity of the N,N-dien-
amine, the final cyclisation reaction to form 1 cannot occur. To date
no intermediates have been isolated from this reaction to provide
evidence to support this suggestion, with only extensive de-
composition being observed when 4 (R2¼H) is used.
When substituents were incorporated at either the C3 or C6-
position in 3 a reduction in the isolated yield was observed (cf. the
following pairs of compounds, which have the substituents posi-
tioned in such a way that differences resulting from electronic ef-
fects would be expected to be minimal; 1(1,1,4) vs 1(1,1,7) and
1(1,1,3) vs 1(1,1,8) where none of the desired product was isolated).
In the case of substitution at the C3-position in 3 the drop in yields
was found to be independent of the ring size (n) of the lactam 4
used or the nature of R2 in 4. It is likely that the reduced yields in
these reactions stem from increased steric hindrance to the
expected initial reaction of the anthranilate amine with the lactam
ester functionality in 4. Despite the reduction in yield, analytically
pure samples of compounds 1(1,1,7), 1(1,2,7), 1(2,1,7) and 1(2,2,7)
were obtained and interesting observations relating to their
structure and spectroscopic details are discussed in detail below.
When a methyl substituent was incorporated at C6 in 3, a remark-
able result was obtained. Excellent yields of the desired compounds
1(2,1,8) and 1(2,2,8) were obtained in the series using 4 (R2¼OMe),
whereas none of the desired compounds were obtained when
lactam 4 (R2¼H) was used. This was the case in both the n¼1 and
n¼2 series (cf. 1(1,1,8) and 1(2,1,8)). It is difficult to assign a clear
explanation to this result. However, it is interesting to note that the
C1-ester group in 3 (C6¼Me) will be expected to adopt a preferred
conformation in which the carbonyl group is no longer conjugated
with the aromatic ring resulting in increased nucleophilicity of the
anthranilate nitrogen for this substrate compared to 3 (C6¼H). It is
therefore likely that the initial reaction between the nitrogen in 3
and the ester group in 4 will proceed well for substrate 3 (C6¼Me)
regardless of the structure of 4. However, the change in preferred
conformation of the ester as a result of the presence of the C6-
sustituent may result in difficulties in the final cyclisation step in
which an intermediate of the general type 2 (Scheme 1) reacts to
give 1. The presence of the additional C2-electron-donating group
Whilst 22 novel heterocycles were prepared with relative ease
using this approach, the synthesis of 1 containing, for example,
heteroaryl A-rings (see Scheme 1 for numbering) including thio-
phene, pyrazine, nicotinic and isonicotinic rings was unsuccessful.
In addition replacement of the A-ring with an aliphatic chain also
failed.
2.2. Use of anthranilic acids in method 1
Although a significant number of anthranilates are commer-
cially available, there is considerably more diversity available for
anthranilic acids. To avoid having to convert the anthranilic acids to
the corresponding esters prior to reaction with 4, we decided to
assess whether the acids could be used directly in this chemistry.
Initial results were encouraging with the synthesis of 1a being
achieved in 67% (Table 2) using optimised conditions in which a 6:1
ratio of anthranilic acid/lactam was heated under microwave irra-
diation at 190 ꢀC, 275 W for 60 min using ‘powermax’ conditions
(see Table S2 for details3). This yield was comparable to that
obtained when using the corresponding anthranilate ester (Table 1)
although an increased amount of the anthranilic acid was used
compared to the ester. It should be remembered, however, that the
overall sequence using the anthranilic acids is typically one step
shorter than with the corresponding esters and in the case of 3
(C6¼Me) a significantly longer reaction sequence is required to
convert the acid to the ester.3 Using these reaction conditions, it
was also possible to prepare 10 analogues in low to average yields
(Tables 1 and 2).

566
A.M. Jones et al. / Tetrahedron 65 (2009) 563–578
This approach, however, proved far from general with reactions
(a)(i)
proving unsuccessful when R¼4-CO2H, 4-NO2, 5-OH, 5-I, 5-NO2 and
6-Me in 3. In addition, attempted reactions using nicotinic and
isonicotinic acid failed. One possible explanation for the failure of
these substrates comes from an observed correlation between the
success of the reaction and the melting point of the anthranilic acid.
Acids with melting points significantly above the reaction tem-
perature (190 ꢀC) failed (the melting points of the examples listed
above range from 213 to 324 ꢀC) whereas in cases where the
melting point of the acid is below or close to the reaction temper-
ature some success was observed (Table 2). Interestingly, pre-
liminary studies using a CEM microwave equipped with a camera
supported the view that in successful reactions a melt was formed
,
between the reacting anthranilic acid and lactam (see Fig. S13).
Additional factors relating to a lack of solubility of the acid in the
molten lactam 4, reduced nucleophilicity of the anthranilic acid
amino-functional group in the presence of electron-withdrawing
substituents and possible decarboxylation of the anthranilic acid10
leading to a dramatic increase in the reaction pressure may also
play a role in limiting this particular approach.
(a)(ii)
2.3. The structure of C12 substituted heterocycles
The 1H NMR spectrum of 1a has been reported by us1 and
others2 to include a proton that experiences an unexpectedly
(b)
strong downfield shift (d, CHCl3, 400 MHz, 9.52 ppm). We have
7
6
suggested previously1 that this signal corresponds to the C12-H in
1a (Scheme 1) and is shifted downfield as a result of its proximity to
the C14-carbonyl group. Here we provide further evidence in sup-
port of this proposal by reporting a small molecule X-ray structure
of 1a (Fig. 1a). By placing the C12-H in the idealised position, the
planar nature of 1a implies that the C12-H must be positioned
within 2.52(1) Å of the C14 oxygen atom. In the light of this, it was
surprising to us that it was possible to form analogues using C3-
substituted anthranilates or anthranilic acids at all. X-ray crystal-
lographic analysis of 1(1,1,7) (Fig. 1b) showed that incorporation of
a substituent at C12 in 1 can only be achieved at the expense of the
planar structure of this heterocycle. The methyl group is accom-
modated via a distortion of the complete structure as exemplified
by the C(12)–C(12a)–N(13)–C(14) torsional angle of 38ꢀ in 1(1,1,7)
compared with a value of 0.7ꢀ in 1a (Fig. 1b and c, entry 1). The
amide bond in 1(1,1,7) is also forced to adopt a less than optimal
arrangement with the torsional angle C(12a)–N(13)–C(14)–O(14)
being 7.3ꢀ (Fig. 1c, entry 2). In addition, there is significant distor-
tion of the A and B-rings in 1(1,1,7), which is not observed in the
structure of 1a (Fig. 1c, entries 3–5). However, little or no distortion
of the E-ring in 1(1,1,7) is observed (Fig. 1c, entry 6).
8
10
12
9
5
4
13
11
3
14
1
2
(c)
Entry
Torsion Angle
1a
1(1,1,7)
+37.7(2)
+7.3(2)
-10.8(2)
-14.2(2)
-6.9(3)
1
2
3
4
5
6
C(12)-C(12a)-N(13)-C(14)
C(12a)-N(13)-C(14)-O(14)
C(9)-C(8a)-C(12a)-C(12)
C(8)-C(8a)-C(12a)-N(13)
O(8)-C(8)-C(8a)-C(9)
+0.7(3)
-1.4(3)
-0.4(3)
+1.1(3)
+0.5(3)
-2.1(3)
C(4)-C(3)-C(2)-C(1)
+1.3(3)
Figure 1. (a) X-ray crystal structure of 1a. (b) X-ray crystal structure of 1(1,1,7). (c)
Analysis of key torsional angles (ꢀ) for 1a and 1(1,1,7). Crystallographic data (excluding
structure factors) for the structures in this paper have been deposited with the Cam-
bridge Crystallographic Data Centre as supplementary publication nos. CCDC 697507
and 697508. Copies of the data can be obtained, free of charge, on application to CCDC,
12 Union Road, Cambridge CB2 1EZ, UK, (fax: þ44 (0)1223 336033 or e-mail:
deposit@ccdc.cam.ac.uk).
It is also of interest to compare the 1H NMR spectra of 1a and
1(1,1,7) as in the aliphatic region there is a noticeable line broad-
ening of the signals corresponding to the C6- and C7-methylene in
1(1,1,7) compared with the analogous signals in 1a (Fig. 2a(i) and
a(ii)). This broadening results from the restricted ability of the C12-
methyl group in 1(1,1,7) to pass the C14-carbonyl functionality. The
restriction is apparently increased when a chlorine substituent is
incorporated at the C12 position as the corresponding signals in the
1H NMR analysis of 1(1,1,12) are considerably broader and the
methylene protons are now diastereotopic (Fig. 2a(iii)). Further-
more, the effect of incorporating a methyl group at the analogous
position (C13) in the n¼2 series is even more pronounced com-
pared to the n¼1 series with the diastereotopic nature of the C6-,
C7- and C8- methylene protons in 1(1,2,7) clearly differing from the
situation for 1d (cf. Fig. 2b(i) and b(ii)). In order to investigate this
further, compounds 1(1,1,7), 1(1,1,12) and 1(1,2,7) were studied by
variable temperature 1H NMR spectroscopy. Due to the poor solu-
bility of 1(1,1,12) in toluene and the fact that low temperature
spectra were needed to analyse 1(1,1,7) and 1(1,1,12), it was not
possible to study all the compounds in one solvent. Therefore, the
low temperature spectra for 1(1,1,7) and 1(1,1,12) were recorded in
CD2Cl2 and the 1H NMR spectra for 1(1,2,7) and 1(1,1,7) were
recorded in toluene-d8 across the temperature range 318–373 K.
The rate constants for the movement of the C12 (n¼1) or C13
(n¼2)-substituent past the C14 (n¼1) or C15 (n¼2)-carbonyl group
at particular temperatures were determined by complete lineshape
analysis of the variable temperature spectra using the Bruker
TOPSPIN DNMR module. The temperature dependence of the rate
constants was used to determine the activation parameters of the
exchange process by fitting the experimental data to the Eyring
equation. The plots of ln(k/T) against 1/T overall show a very good
linear dependence (see Fig. S2,3) and the resulting activation pa-
rameters
The Gibbs free energy of activation (
suspected, substitution of C12-methyl in 1(1,1,7) by chlorine in
D
Gz,
D
Hz and
D
Sz are summarised in Figure 2c.
Gz) clearly shows that, as
D

A.M. Jones et al. / Tetrahedron 65 (2009) 563–578
567
(a)
(i)
(ii)
(iii)
(b)
(i)
(ii)
(c)
‡
298
‡
S‡
Compd. #
3-subst.;
ring size
NMR
solvent
k298
s-1
t
½
s
kJ mol-1 kJ mol-1 JK-1 mol-1
1.71x10-4
9.53x10-5
1(1,1,7)
CD2Cl2
d8-PhMe
CD2Cl2
54.1
52.7
61.6
74.2
50.0
42.9
49.8
65.9
-14
-33
-39
-28
2032
12-Me; n=1
1(1,1,7)
12-Me; n=1
3635
100
3.43x10-3
0.57
1(1,1,12)
12-Cl; n=1
1(1,2,7)
13-Me; n=2
d8-PhMe
0.61
Figure 2. (a) Comparison of the aliphatic region (2ꢂCH2 triplets) for C(12)¼H, Me and
Cl for n¼1. 1H NMR spectra recorded in CDCl3 at 298 K. (b) Comparison of the aliphatic
region (3ꢂCH2) for C(13)¼H and Me when n¼2. 1H NMR spectra recorded in CDCl3 at
298 K. (c) Table of rate constants and barriers to rotation for C(12)¼Me and Cl (n¼1)
and C(13)¼Me (n¼2).
1(1,1,12) reduces the ability of the substituent to pass the C14-car-
bonyl functionality. An increase in the lactam ring size whilst
retaining the methyl substituent (cf. 1(1,1,7) vs 1(1,2,7)) gives
a similar result. The change from n¼1 to n¼2 induces mainly a rise
in the activation enthalpy (
D
Hz¼65.9 kJ molꢁ1 for 1(1,2,7)) vs
42.9 kJ molꢁ1 for 1(1,1,7)) while the activation entropies of the two
compounds remain approximately the same. It seems likely that
incorporation of the additional methylene group in the C-ring of
1(1,2,7) forces the C13-methyl and C14-carbonyl closer together
leading to a greater repulsive interaction as the methyl group tries
to pass the carbonyl oxygen. On the contrary, comparison of the
activation parameter data obtained for 1(1,1,7) and 1(1,1,12) in
Figure 3. Ball and stick representations of (a) ground state of 1(1,1,12); (b) ground state
of 1(1,1,7); (c) transition state for racemisation of 1(1,1,12) and (d) transition state for
racemisation of 1(1,1,7). The key torsional parameter
present in the fused ring framework. For the structures shown,
(c) 1.2ꢀ, (d) 1.3ꢀ. Carbon atoms are green, oxygen atoms are red, nitrogen atoms are
a indicates the degree of bending
a
¼(a) 53.4ꢀ, (b) 49.6ꢀ,
blue and hydrogen atoms are grey.
CD2Cl2 demonstrates that there is little difference in
D
Hz values but
(47.4ꢀ)). The pathway for the racemisation process was then cal-
culated. Using the semi-empirical RM1 method, the torsion angle
that the entropy of activation differs by 25 J Kꢁ1 molꢁ1
(D
Sz¼ꢁ14 J Kꢁ1 molꢁ1 for 1(1,1,7) vs ꢁ39 J Kꢁ1 molꢁ1 for 1(1,1,12)).
a
was progressively driven in 2ꢀ steps from þ50ꢀ to ꢁ50ꢀ. Un-
Given this somewhat unexpected result, it was decided to es-
surprisingly, the maximum energy structures were all located
around
tablish computationally that the activation parameters derived
from the 1H NMR studies did, indeed, correspond to those associ-
ated with the racemisation process. Calculation of the ground state
structures of 1(1,1,7) and 1(1,1,12) at the B3LYP/6-31G(d,p) level of
theory afforded the geometries shown in Figure 3a and b. In the
case of 1(1,1,7), where X-ray data is available for comparison, the
agreement between the diffraction and the calculated structures is
a
¼0ꢀ. Using the maximum energy structure, the transition
state for racemisation was located at the RM1 level of theory and
these structures were used as initial guesses for refinement of the
transition state structures at the B3LYP/6-31G(d,p) level of theory.
The calculated transition states for the racemisation of 1(1,1,7) and
1(1,1,12) are shown in Figure 3c and d, respectively. Using standard
methods, the calculated
extracted for the racemisation process. For 1(1,1,7), the calculated
Gz is 48.7 kJ molꢁ1 and for 1(1,1,12), the calculated Gz is
D D D
Gz, Hz and Sz parameters were
excellent and, in particular, the torsion angle
duced well (calculated structure (49.6ꢀ) vs diffraction structure
a (Fig. 3a) is repro-
D
D

568
A.M. Jones et al. / Tetrahedron 65 (2009) 563–578
60.0 kJ molꢁ1. These results are in good agreement with the ex-
perimental data, however, the question of the low value of
Sz for
D
1(1,1,7) remained. The methyl group rotation is clearly restricted in
the transition state for racemisation. It was reasoned that, if re-
stricted rotation of the methyl group was also present in the ground
state of 1(1,1,7), the net change in entropy on moving from the
1(1,1,7) ground state to the transition state would be less, i.e., the
observed entropy change is influenced by a ground state effect in
1(1,1,7). In simple aromatic compounds such as toluene, there is
essentially no activation barrier for methyl group rotation. There-
fore, the pathway for the rotation of the methyl group in 1(1,1,7)
was calculated using the semi-empirical RM1 method by driving
the torsion angle of one of the methyl hydrogens with respect to the
adjacent aromatic ring in 2ꢀ steps from 0ꢀ to 360ꢀ. The results
(Fig. 4) indicate that there are three clearly preferred orientations
for the methyl group and the barrier (at the RM1 level of theory) for
their interconversion is around 12 kJ molꢁ1. As before, this structure
was then used as an initial guess for refinement of the transition
state structure at the B3LYP/6-31G(d,p) level of theory. The calcu-
lated barrier (
D
Gz) at this higher level of theory is larger than that
suggested by the semi-empirical RM1 method at 28.7 kJ molꢁ1
.
Armed with the knowledge that there is a significant barrier to
methyl group rotation in the ground state of 1(1,1,7), we looked for
experimental evidence for restricted rotation to support the cal-
culations. Close examination of the 1H NMR data for 1(1,1,7) reveals
that the resonance arising from the methyl group has a significantly
increased line width. At room temperature, the line width at half
peak height for the singlet arising from the methyl group in toluene
is 0.7 Hz. By contrast, the line width at half peak height for the
singlet arising from the methyl group in 1(1,1,7) is 2.5 Hz. This
broadening is consistent with restricted rotation of the C12-methyl
group in the ground state. This observation rationalises the ap-
parently small D
Sz for racemisation of 1(1,1,7). Although the chiral
nature of these compounds has been shown by 1H NMR, resolution
of enantiomers by chiral HPLC is impossible due to the relatively
298
low barriers to interconversion (t
1
⁄
rac less than 1s, Fig. 2c).
2
2.4. Applications of method 2
During the exploration of the scope of method 1 both with
anthranilic esters and acids, several limitations were identified. In
particular, attempts to incorporate a 5-Br-substituent, a range of
heteroatomic A-rings and large ring lactams 4 (n>2) failed despite
significant attempts to optimise the microwave reaction conditions.
A probable explanation for these observations is failure of the initial
amide bond forming reaction to generate intermediates of the
general structure 5 (Scheme 1). It was, therefore, decided to focus
on alternative methods of forming this amide bond. We have pre-
viously reported1 the formation of this bond through reaction of
o-iodo-benzoyl chloride with methyl anthranilate 3 (R¼H, R1¼Me)
to give 8 in excellent yield (Scheme 2). Although the subsequent
N-arylation of 2-pyrrolidinone using 8 resulted in formation of the
N-aryl-lactam 5 in low yield, we demonstrated that 5 was effi-
ciently converted to 1a under microwave irradiation conditions.
Here we report that this reaction sequence can also be used to
prepare 1(1,3,1) (Scheme 2), a compound containing a seven-
Figure 4. Torsional energy profile for the rotation of the methyl group in 1(1,1,7) at the
RM1 level of theory. The torsion angle is the angle subtended between the C–H bond in
the methyl group and the C–C bond in the adjacent aromatic ring. The torsional pa-
rameter
a is defined in the same manner as in Figure 3 and indicates the degree of
bending present in the fused ring framework. The distance shown is that between the
carbonyl oxygen atom and the nearest hydrogen atom on the methyl group. Carbon
atoms are green, oxygen atoms are red, nitrogen atoms are blue and hydrogen atoms
are grey.
membered ring, by initial N-arylation of
d
-caprolactam with 8,
the desired cyclisation precursors in moderate to good yields,
providing improved access compared to our previous route.1 The
use of carbodiimide-based reagents in this reaction was less suc-
cessful consistent with PyBroP’s reported improved performance
compared to other coupling reagents when weak amine nucleo-
philes are used.11 Whilst access to 5(1,4,1) was achieved in good
yield, attempts to cyclise 5(1,4,1) proved unsuccessful with no re-
action occurring under the standard microwave conditions. Ex-
tensive decomposition resulted from the use of more forcing
microwave conditions or high temperatures in a sealed tube.12
followed by microwave irradiation of 5(1,3,1) to give 1(1,3,1) in 72%
yield for the key zipper reaction (Scheme 2). It is of interest to note
that attempts to form 1(1,3,1) using method 1 resulted in formation
of only trace amounts of the desired product (see Fig. S3,3).
In an attempt to avoid the low yielding copper-catalysed N-
arylation reaction, the lactam esters 4 (n¼1, 2 or 3) were hydrolysed
to give the corresponding carboxylic acids 9–11 in good yield
(Scheme 2). Subsequent amide bond coupling with methyl an-
thranilate 3(R¼H, R1¼Me) using PyBroP resulted in formation of

A.M. Jones et al. / Tetrahedron 65 (2009) 563–578
569
( )n
O
N
CO2Me
( )n
CO2Me
O
N
n = 3
MW, 190 °C
275 W, 20 min
O
H
NH
N
NH
I
N
CuI, DMED
K3PO4, PhMe
reflux, 40 h
5(1,1,1) n=1 27%
5(1,3,1) n=3 35%
O
O
O
n = 1
n = 5
5
8
1(1,3,1)
72%
1a
70%1
( )n
O
N
1(1,4,1)
PyBroP, DIPEA
NaOH
H2O/THF
rt, 12 h
5(1,1,1) n=1 43%
5(1,3,1) n=3 77%
5(1,4,1) n=5 83%
R = Me 4
0%
RO2C
R = H
DCM, 0 °C to rt
16 h
9
R=H, n=1 85%
10 R=H, n=3 71%
11 R=H, n=5 60%
12 R=H, n=2 60%
Scheme 2. Alternative approaches for the synthesis of 1(1,3,1) using method 2.
Having established a relatively rapid method for preparing sub-
strates for method 2, this approach was successfully applied to the
synthesis of thiophene and isothiophene containing heterocycles
1(1,1,15) and 1(1,2,16) (Scheme 3a), compounds that were not ac-
cessible using method 1. PyBroP-mediated coupling of 3(15) with 9
and 3(16) with 12 (Scheme 2) led to the formation of 5(1,1,15) and
5(1,2,16), respectively. Compound 5(1,1,15) was converted in 68%
yield to the desired compound 1(1,1,15) and 1(1,2,16) was formed
from 5(1,2,16), albeit in significantly lower yield. The reduced yield
for formation of 1(1,2,16) was interesting and may have its origins in
an analogous effect to that observed when a C6-substituent is
present in 3 as discussed above (e.g., for formation of 1(1,1,7)). At-
tempts to use method 2 as a means of incorporating nitrogen atoms
in ring-Aof 1 proved unsuccessful for both the pyridine and pyrazine
cases with the sequence failing at the amide bond forming stage.
However, it was possible to replace the A-ring in 1 with a simple
alkyl backbone by using -amino acid ester 3(17) (Scheme 3b). The
major compound 1313 formed in this reaction presumably results
from a -elimination reaction under the MW conditions as shown
for the proposed intermediate 14 (Scheme 3b). Method 2 also
allowed the synthesis of the 10-Br containing 1(1,1,10) in acceptable
yield through microwave reaction of the 5(1,1,10) (Scheme 3c). It
has not been possible to prepare 1(1,1,10) using method 1.
b
b
2.5. Computational analysis of observed 1H chemical shifts
Use of method 2 enabled the synthesis of 1(1,3,1) (Scheme 2)
allowing a detailed comparison of the 1H NMR spectra obtained for
1a (n¼1), 1d (n¼2) and 1(1,3,1) (n¼3), compounds that differ only
in the number of methylene groups present in the C-ring (Fig. 5a). A
O
CO2Me
X1
(a)
X1
( )n
( )n
9 or 12
X1
X2
CO2Me
NH2
X2
X2
O
MW, 190 °C
PyBroP
N
N
NH
N
275 W, 80 min
DIPEA, DCM
rt, 16 h
O
O
1(1,1,15) X1 = CH, X2 = S, n = 1 (68%)
1(1,2,16) X1 = S, X2 = CH, n = 2 (17%)
5(1,1,15) X1 = CH, X2 = S, n = 1 (43%)
5(1,2,16) X1 = S, X2 = CH, n = 2 (65%)
3 (15) X1 = CH, X2 = S
3 (16) X1 = S, X2 = CH
O
N
H
(b)
O
CO2Et
EtO
9
HO
O
CO2Et
NH
N
PyBroP
MW, 140 °C
N
N
N
N
N
DIPEA, DCM
rt, 16 h, 68%
275 W, 20 min
O
O
NH2.HCl
O
O
3(17)
14
13 (54%)
1(1,1,17) (16%)
5(1,1,17)
O
N
(c)
Br
CO2Me
O
Br
9
Br
CO2Me
MW, 190 °C
275 W, 80 min
50%
PyBroP
DIPEA, DCM
rt, 16 h, 37%
NH
N
N
NH2
O
O
1(1,1,10)
3(10)
5(1,1,10)
Scheme 3. Examples of the use of method 2 for the synthesis of (a) sulfur containing heterocycles (thiophene and isothiophene), (b) heterocycles in which the aromatic A-ring has
been replaced by an alkyl chain and (c) 1 containing an EWG in the 5-position to access 1(1,1,14), 1(1,2,15), 1(1,1,16) and 1(1,1,10).

570
A.M. Jones et al. / Tetrahedron 65 (2009) 563–578
(i)
(a)
O
N
N
12
H
14
O
1a
(ii)
O
N
N
13
H
15
O
1d
(iii)
O
N
N
14
H
16
O
1(1,3,1)
(b)
n=1
(i)
(ii)
n=1
n=3
n=2
n=3
n=2
τ(OCCH) [º]
R(OH) [Å]
Figure 5. (a) 1H NMR analysis of three closely related heterocyclic structures as a function of the size of the C-ring in 1. A significant downfield shift is observed for the C12H proton
in 1a (n¼1) compared to other ring sizes. (b) Computational studies at the B3LYP level to explore the dependence of the chemical shift of the signal corresponding to the A-ring
ortho-proton as a function of (i)
s(O14–C14–C12–H12) dihedral angle and (ii) O–H distance in the n¼1 system (solid circles). The calculated chemical shifts of the signal for the
A-ring ortho-proton in 1a (n¼1), 1d (n¼2) and 1(1,3,1) (n¼3) are represented by *(n¼x).
striking difference in the 1H NMR spectrum of 1a compared with 1d
and 1(1,3,1) was observed with the chemical shift of the signal
corresponding to the ortho-proton in the A-ring being significantly
more downfield for 1a (9.52 ppm) than for 1d (8.66 ppm) and
1(1,3,1) (8.70 ppm) (Fig. 3a). We became interested in the origins of
this variation and decided to probe this using computational
analysis at the B3LYP/6-31G(d,p) level of theory.
To investigate if the large change in chemical shift observed for
the ortho-proton in the A-ring on going from 1a (C12H) to 1d
(C13H) and 1(1,3,1) (C14H) was due to a move away from a planar
structure in 1d and 1(1,3,1), we computed theoretical chemical shift
values not only for the three compounds, but also for an artificially
twisted version of the n¼1 system. To this end, we optimised the
structure of 1a with the O14–C14–C12–H12 dihedral angle (Fig. 5a)
frozen at step intervals between 0ꢀ and 60ꢀ. The computational
studies suggested that to accommodate variation in this dihedral
angle, the structure of 1a distorts away from the planar structure, in
agreement with our previous X-ray crystallographic studies in the
n¼2 system.1 Figure 5b shows the calculated chemical shifts for the
A-ring ortho-proton in the artificially generated geometries in
comparison to the chemical shift values calculated for the fully
optimised structures of 1a, 1d and 1(1,3,1). In Figure 5b(i) the de-
pendence of the calculated chemical shift on the O14–C14–C12–
H12 dihedral angle is shown. The chemical shifts calculated for 1d
(n¼2) and 1(1,3,1) (n¼3) systems are extremely close to the curve of
the distorted 1a (n¼1) system, confirming that the change in
chemical shift is nearly entirely due to the non-planarity of the ring
systems. These calculations also agree with the trend observed in
the chemical shift of the A-ring ortho-proton in practice (i.e., in
order of decreasing parts per million value 1a>1(1,3,1)>1d).

A.M. Jones et al. / Tetrahedron 65 (2009) 563–578
571
Figure 5b(ii) shows calculated chemical shifts plotted as a function
of the O–H distance. Interestingly, for 1d (n¼2) and 1(1,3,1) (n¼3)
the calculations show near-identical O–H distances, but signifi-
cantly different chemical shift values for the C13H in 1d and C14H
in 1(1,3,1), respectively. We can conclude from this that the tor-
sional angle used in these calculations is a better predictor of the
change in the chemical shift of the A-ring ortho-proton than the
mere distance from the oxygen atom, consistent with a complex
view of the carbonyl deshielding cone that contains subtle differ-
ences in deshielding strength as the cone is traversed.14
running MassLynxÔ 4.0.Global. Separations were performed using
a Waters XterraÔ RP18 (5
Microwave-assisted reactions were performed using a CEM
Discover microwave operated in ‘powermax’ mode.
mm, 3.0ꢂ50 mm) HPLC column.
The geometries of the n¼1, n¼2 and n¼3 pentacycles were
optimised using density functional theory (DFT) using the B3LYP15
functional and the 6-31þG(d) basis set. The shielding tensors were
computed using the gauge-independent atomic orbital (GIAO)16,17
method, employing the B97-218 functional and the 6-311G(d,p)
basis set. The 1H isotropic chemical shifts were referenced to tet-
ramethylsilane (TMS), the shielding tensor of which was de-
termined with the same methodology. All calculations were
performed with the Gaussian 03 program package19 on the EaSt-
CHEM Research Computing Facility.
3. Conclusions
These studies have shown that it is possible to access rapidly
a wide range of structures based on the diazabenz[e]aceanthrylene
core structure using two complementary microwave-assisted ap-
proaches. We have explored the scope of these reactions particu-
larly focussing on variation of substituents in both the anthranilic
esters and acids 3 and the N-aryl lactam esters 4 in method 1.
Subsequent studies on the chemical reactivity of these heterocyclic
systems will be reported in the near future. During the course of
these studies a range of interesting structural and spectroscopic
issues arose and these have been investigated further with the aid
of NMR, X-ray crystallographic and computational techniques.
4.2. General procedure for the synthesis of 1(1–2,1–4,1–17)
4.2.1. Ester route
A
mixture of the methyl anthranilate 3(1–8,10,14–16)
(4.00 mmol) and the N-aryl lactam 4(1–2,1–2) (1.00 mmol) in
a sealed glass microwave tube was heated to 190 ꢀC, (maximum
275 W), with air flowing through the reaction chamber, for 30 min.
Upon cooling the reaction mixture was added to diethyl ether
(30.0 mL) and the resultant precipitate filtered. The precipitate was
purified by flash column chromatography over silica gel (99:1,
chloroform/methanol) to afford the title compound. An analytically
pure sample of 1 was prepared by recrystallisation from acetic acid.
4. Experimental
4.1. General
4.2.2. Acid route
Chemicals and solvents were purchased from the Aldrich
Chemical Company, Fisher Chemicals and Lancaster and were used
as received unless otherwise stated. Air and moisture sensitive
reactions were carried out under an inert atmosphere of dried ar-
gon and glassware was oven-dried (145 ꢀC).
Analytical thin-layer chromatography (TLC) was performed on
pre-coated TLC plates SIL G-25 UV254 (layer 0.25 mm silica gel with
fluorescent indicator UV254) (Aldrich). Developed plates were air-
dried and analysed under a UV lamp, Model UVGL-58 (Mineralight
LAMP, Multiband UV254/365 nm) and where necessary, stained with
a solution of ceric ammonium molybdate, ninhydrin or iodine on
silica to aid identification. Flash column chromatography was per-
A mixture of the anthranilic acid 3(1,3,7,9,11–13) (6.00 mmol)
and methyl 2-(2-oxo-pyrrolidin-1-yl)-benzoate 4(1,1) (1.00 mmol)
in a sealed glass microwave tube was heated to 190 ꢀC, (maximum
275 W), with air flowing through the reaction chamber, for 60 min.
Upon cooling the reaction mixture was added to chloroform
(30.0 mL) and washed with saturated sodium hydrogen carbonate
solution (2ꢂ30.0 mL). The organic layer was then dried (MgSO4),
filtered and concentrated in vacuo to give a solid, which was pu-
rified by flash column chromatography (99:1, chloroform/metha-
nol) to afford the title compound. An analytically pure sample of 1
was prepared by recrystallisation from acetic acid.
formed using silica gel (40–63
mm) (Fluorochem). Copper(I) iodide
4.2.3. Intramolecular cyclisation
catalyst was purified according to a literature method.
Melting points were determined using an Electrothermal 9100
capillary melting point apparatus. Values are quoted to the nearest
1 ꢀC and are uncorrected.
Compound 5 (1.00 mmol) was heated in a sealed glass micro-
wave tube to 190 ꢀC, (maximum 275 W) for 20 min (unless other-
wise stated). The resultant yellow/brown solid was purified by
column chromatography over silica gel (99:1, chloroform/metha-
nol) to give a yellow solid 1a, 1(1,1,10), 1(1,3,1), 1(1,1,15), 1(1,2,16) or
1(1,1,17).
1H NMR spectra were recorded on a Bruker Avance 300
(300.1 MHz) spectrometer. 13C NMR spectra using the DEPTQ
sequence were recorded on a Bruker Avance 300 (75.5 MHz)
spectrometer. Chemical shifts (
d) are recorded using the residual
solvent as the internal reference in all cases (CDCl3 dH 7.27 ppm,
d
C
4.3. General procedure for the synthesis of 5
77.0 ppm). Coupling constants (J) are quoted to the nearest 0.1 Hz.
The following abbreviations are used; s, singlet; d, doublet; dd,
doublet of doublets; ddd, doublet of doublets of doublets; dt,
doublet of triplets; t, triplet; m, multiplet and br, broad. IR spectra
were recorded on a Perkin Elmer Spectrum GX FT-IR spectrometer.
Low resolution and high resolution (HR) electrospray mass
spectral (ES-MS) analyses were recorded on a high performance
orthogonal acceleration reflecting TOF mass spectrometer, coupled
to a Waters 2975 HPLC. Only the major peaks are reported and
intensities are quoted as percentages of the base peak.
4.3.1. PyBroP amide bond coupling
To a solution of 2-(N-lactam)-benzoic acid 9–12 (1.5 mmol),
methyl anthranilate 3 (1.0 mmol), and PyBroPÒ (0.70 g, 1.5 mmol)
coupling reagent in DCM (8 mL) was treated under stirring with
DIPEA (0.70 mL, 4.0 mmol) at 0 ꢀC. The ice bath was removed after
1 min and the stirring continued at room temperature for 15 h. The
mixture was poured into ethyl acetate (300 mL) and the solution
treated with NaHCO3 (10% w/v) (100 mL) and the solution extracted
with ethyl acetate (3ꢂ150 mL). The organic layer was washed with
brine (100 mL) and then dried (MgSO4). The solvent was removed
in vacuo to yield a bright yellow powder. The powder was purified
by flash column chromatography on silica gel (6:4 ethyl acetate/
hexane) to give the title compound 5 as a pale brown oil.
The purity of precipitated products was measured using liquid
chromatography mass spectrometry (LCMS). The LCMS system in-
cludes a Waters 2996 photodiode array detector, Waters 2795 Al-
liance HT Separations Module, Micromass LCT, Thinkcenter IBM

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A.M. Jones et al. / Tetrahedron 65 (2009) 563–578
4.3.2. 1(2,2,1) 2-Methoxy-6,7,8-trihydro-9H,15H-5,14-diaza-
dibenzo[a,de]anthracen-9,15-dione
(C6), 23.3 (C7); IR (KBr): nmax¼2949 (m), 1709 (s) (C]O), 1700 (m)
(C]O), 1601 (s), 1557 (w), 1499 (m), 1318 (m), 1158 (m) (C–O) cmꢁ1
;
Yield 1(2,2,1) (0.246 g, 0.74 mmol, 74%) (LCMS purity 99%) as
LRMS (CIþ): m/z (%) 353.07 (100) [MþH]þ; HRMS (ESþ): m/z calcd
a brown powder using ester route. Mp 209–210 ꢀC; 1H NMR
for C19H14N2O3Cl [MþH]þ: 353.0693; found: 353.0692.
(300 MHz, CDCl3):
d
¼8.65 (dd, 3J¼9.0 Hz, 4J¼1.0 Hz, 1H, C13-H),
8.39 (dd, 3J¼8.0 Hz, 4J¼2.0 Hz, 1H, C10-H), 7.73 (d, 3J¼3.0 Hz, 1H,
C1-H), 7.61–7.54 (m,1H, C12-H), 7.50–7.44 (m,1H, C11-H), 7.34–7.29
(m, 1H, C3-H), 7.26–7.20 (m, 1H, C4-H), 4.00 (t, 3J¼6.0 Hz, 2H, C6-
H2), 3.91 (s, 3H, OCH3), 2.90 (t, 3J¼6.0 Hz, 2H, C8-H2), 2.18–2.09 (m,
4.3.6. 1(2,2,2) 2-Methoxy-12-chloro-6,7,8-trihydro-9H,15H-5,14-
diaza-dibenzo[a,de]anthracen-9,15-dione
Yield 1(2,2,2) (0.220 g, 0.60 mmol, 60%) as a yellow powder
using the ester route. Mp 233–234 ꢀC; 1H NMR (300 MHz, CDCl3):
2H, C7-H2); 13C NMR (75.5 MHz, CDCl3):
d
¼175.0 (C9), 160.3 (C15),
d
¼8.75 (d, 4J¼2.0 Hz,1H, C13-H), 8.29 (d, 3J¼8.6 Hz,1H, C10-H), 7.70
155.3 (C2), 144.5 (C5a), 135.5 (C4a), 135.2 (C13a), 129.8 (C12), 126.4
(C9a), 126.3 (C11), 125.3 (C10), 125.0 (C3), 122.3 (C13), 116.0 (C15a),
114.6 (C4), 110.2 (C1), 101.6 (C8a), 56.0 (OCH3), 47.1 (C6), 20.1 (C8),
19.8 (C7); IR (KBr): nmax¼2936 (m), 1699 (s) (C]O), 1610 (s), 1591
(s), 1534 (m), 1483 (m), 1146 (w) (C–O), 759 (m) (Ar–H) cmꢁ1; LRMS
(ESþ): m/z (%) 333.01 (100) [MþH]þ; HRMS (ESþ): m/z calcd for
C20H17N2O3 [MþH]þ: 333.1239; found: 333.1228.
(d, 4J¼3.0 Hz, 1H, C1-H), 7.41 (dd, 3J¼8.6 Hz, 4J¼2.0 Hz, 1H, C11-H),
7.32 (dd, 3J¼9.0 Hz, J¼3.0 Hz, C3-H), 7.23 (d, 3J¼9.0 Hz, 1H, C4-H),
4
4.00 (t, 3J¼6.0 Hz, 2H, C6-H2), 3.91 (s, 3H, ArOCH3), 2.87 (t,
3J¼6.0 Hz, 2H, C8-H2), 2.12 (qt, 3J¼6.0 Hz, 2H, C7-H2); 13C NMR
(75.5 MHz, CDCl3):
d¼174.2 (C9), 160.7 (C15), 155.5 (C2), 145.2
(C5a),136.2 (C12),136.0 (C13a),135.2 (C4a), 126.9 (C11),126.8 (C10),
125.5 (C3), 124.9 (C9a), 122.3 (C13), 115.9 (C15a), 114.8 (C4), 110.3
(C1), 101.9 (C8a), 56.2 (ArOCH3), 47.2 (C6), 20.1 (C7), 19.9 (C8); IR
(KBr): nmax¼2950 (m) (CH), 1664 (s) (C]O), 1599 (m), 1497 (m),
1353 (m), 1099 (m) (C–O), 766 (m) (Ar–H) cmꢁ1; LRMS (CIþ): m/z
(%) 367.09 (100) [MþH]þ; HRMS (CIþ): m/z calcd for C20H16N2O3Cl
[MþH]þ: 367.0849; found: 367.0854.
4.3.3. 1(1,1,2) 11-Chloro 8,14-dioxo-6,7-dihydro-8H,14H-5,13-
diazabenz[e]aceanthrylene
Yield 1(1,1,2) (0.171 g, 0.53 mmol, 53%) (LCMS purity 94%) as
a pale brown powder using the ester route. Mp 276 ꢀC (dec); 1H
NMR (300 MHz, CDCl3):
d
¼9.59 (d, 4J¼2.0 Hz, 1H, C12-H), 8.37 (d,
3J¼8.5 Hz, 1H, C9-H), 8.26 (d, 3J¼8.0 Hz, 4J¼1.5 Hz, 1H, C1-H), 7.76–
7.70 (m, 1H, C3-H), 7.42 (dd, 3J¼8.5 Hz, 4J¼2.0 Hz, 1H, C10-H), 7.30–
7.24 (m, 1H, C2-H), 6.97 (d, 3J¼8.0 Hz, 1H, C4-H), 4.30 (t, 3J¼9.5 Hz,
2H, C6-H2), 3.36 (t, 3J¼9.5 Hz, 2H, C7-H2); 13C NMR (75.5 MHz,
4.3.7. 1(1,1,3) 12-Methyl-8,14-dioxo-6,7-dihydro-8H,14H-5,13-
diazabenz[e]aceanthrylene
Yield 1(1,1,3) (0.139 g, 0.46 mmol, 46%) as a yellow powder
using the ester route. Mp 286 ꢀC (dec); 1H NMR (300 MHz, CDCl3):
CDCl3):
d
¼171.7 (C8), 159.7 (C14), 148.8 (C5a), 139.0 (C4a), 137.5
d
¼9.26 (s, 1H, C12-H), 8.26 (d, 3J¼8.0 Hz, 1H, C9-H), 8.19 (dd,
(C12a), 136.6 (C3), 130.1 (C1), 127.0 (C10), 126.6 (C9), 123.8 (C11),
122.8 (C2), 121.1 (C12), 120.7 (C8a), 115.0 (C14a), 112.4 (C4), 102.8
(C7a), 47.1 (C6), 22.8 (C7); IR (KBr): nmax¼1707 (s) (C]O), 1604 (s),
1582 (s), 1498 (s), 1466 (m), 1425 (w), 1324 (w), 1157 (w) (C–O), 746
(m) (Ar–H) cmꢁ1; LRMS (ESþ): m/z (%) 323.04 (100) [MþH]þ,
345.03 (20) [MþNa]þ, 667.07 [2MþNa]þ; HRMS (ESþ): m/z calcd for
C18H11N2O2NaCl [MþNa]þ: 345.0407; found: 345.0402.
3J¼8.0 Hz, 4J¼1.3 Hz, 1H, C1-H), 7.67 (ddd, 3J¼7.7 Hz, 3J¼7.7 Hz,
4J¼1.3 Hz, 1H, C3-H), 7.22–7.16 (m, 2H, C10-H, C2-H), 6.90 (d,
3J¼8.2 Hz, 1H, C4-H), 4.23 (t, 3J¼8.8 Hz, 2H, C6-H2), 3.31 (t,
3J¼8.8 Hz, 2H, C7-H2), 2.47 (s, 3H, ArCH3); 13C NMR (75.5 MHz,
CDCl3):
d¼172.7 (C8), 160.2 (C14), 148.4 (C5a), 141.7 (C12a), 138.8
(C4a), 136.6 (C11), 136.2 (C3), 130.0 (C1), 127.8 (C10), 125.5 (C8a),
125.4 (C9), 122.4 (C2), 121.3 (C12), 114.7 (C14a), 112.3 (C4), 101.2
(C7a), 47.3 (C6), 23.5 (C7), 22.4 (ArCH3); IR (KBr): nmax¼2924 (m),
1717 (s) (C]O), 1705 (m) (C]O), 1599 (m), 1556 (m), 1497 (m),
1308 (m), 1143 (m) (C–O) cmꢁ1; LRMS (CIþ): m/z (%) 303.11 (100)
[MþH]þ; HRMS (CIþ): m/z calcd for C19H15N2O2 [MþH]þ:
303.1134; found: 303.1128.
4.3.4. 1(1,2,2) 12-Chloro 6,7,8-trihydro-9H,15H-5,14-diaza-
dibenzo[a,de]anthracen-9,15-dione
Yield 1(1,2,2) (0.11 g, 0.33 mmol, 33%) (LCMS purity 99%) as
a brown powder using the ester route. Mp 241–242 ꢀC; 1H NMR
(300 MHz, CDCl3):
d
¼8.68 (d, 4J¼2.0 Hz, 1H, C13-H), 8.25–8.20 (m,
2H, C10-H, C1-H), 7.69–7.63 (m, 1H, C3-H), 7.36 (dd, 3J¼8.5 Hz,
4J¼2.0 Hz, 1H, C11-H), 7.24–7.18 (m, 2H, C2-H, C4-H), 3.95 (t,
3J¼6.0 Hz, 2H, C6-H2), 2.81 (t, 3J¼6.0 Hz, 2H, C8-H2), 2.12–2.02 (m,
4.3.8. 1(1,2,3) 12-Methyl-6,7,8-trihydro-9H,15H-5,14-diaza-
dibenzo[a,de]anthracen-9,15-dione
Yield 1(1,2,3) (0.194 g, 0.55 mmol, 55%) as a yellow powder us-
2H, C7-H2); 13C NMR (75.5 MHz, CDCl3):
d
¼174.3 (C9), 160.2 (C15),
ing the ester route. Mp 162–163 ꢀC; 1H NMR (300 MHz, CDCl3):
144.2 (C5a), 140.7 (C4a), 136.4 (C3), 136.2 (C13a), 136.1 (C9a), 129.6
(C10), 126.8 (C11), 126.7 (C1), 124.1 (C12), 122.9 (C2), 122.3 (C13),
115.3 (C15a), 112.8 (C4), 102.6 (C8a), 47.0 (C6), 20.0 (C8), 19.7 (C7);
IR (KBr): nmax¼3445 (w) (OH), 1708 (s) (C]O), 1582 (w), 1521 (s),
1473 (s), 1369 (m), 1320 (w), 1286 (w) (C–O), 1179 (w) (C–O), 746
(m) (Ar–H) cmꢁ1; LRMS (ESþ): m/z (%) 337.09 (100) [M35ClþH]þ;
HRMS (ESþ): m/z calcd for C19H14ClN2O2 [MþH]þ: 337.0744; found:
337.0741.
d
¼8.47 (s, 1H, C13-H), 8.31 (dd, 3J¼8.3 Hz, 4J¼1.9 Hz, 1H, C10-H),
8.27 (d, 3J¼8.0 Hz, 1H, C1-H), 7.73 (ddd, 3J¼7.3 Hz, 3J¼7.3 Hz,
4J¼1.7 Hz, 1H, C3-H), 7.31–7.25 (m, 3H, C11-H, C2-H, C4-H), 4.03 (t,
3J¼6.0 Hz, 2H, C6-H2), 2.90 (t, 3J¼6.0 Hz, 2H, C8-H2), 2.52 (s, 3H,
ArCH3), 2.16 (qt, 3J¼6.0 Hz, 2H, C7-H2); 13C NMR (75.5 MHz, CDCl3):
d¼175.7 (C9), 160.5 (C15), 144.5 (C5a), 140.9 (C13a), 140.7 (C4a),
136.0 (C3), 135.8 (C12), 129.6 (C1), 127.8 (C11), 125.4 (C10), 124.3
(C9a), 122.6 (C2), 122.4 (C13), 115.7 (C15a), 112.7 (C4), 102.3 (C8a),
47.0 (C6), 22.3 (ArCH3), 20.3 (C7),19.9 (C8); IR (KBr): nmax¼2925 (m)
(CH), 1671 (s) (C]O), 1599 (m), 1535 (m), 1475 (m), 1320 (w), 1173
(m) (C–O), 773 (m) cmꢁ1; LRMS (CIþ): m/z (%) 317.13 (100) [MþH]þ;
HRMS (CIþ): m/z calcd for C20H17N2O2 [MþH]þ: 317.1290; found:
317.1290.
4.3.5. 1(2,1,2) 2-Methoxy-11-chloro-8,14-dioxo-6,7-dihydro-
8H,14H-5,13-diazabenz[e]aceanthrylene
Yield 1(2,1,2) (0.183 g, 0.81 mmol, 81%) as a yellow powder us-
ing the ester route. Mp 308–309 ꢀC; 1H NMR (300 MHz, CDCl3):
d
¼9.63 (s, 1H, C12-H), 8.42 (d, 3J¼8.4 Hz, 1H, C9-H), 7.71 (d,
4J¼2.9 Hz, 1H, C1-H), 7.47 (dd, 3J¼8.4 Hz, 4J¼2.9 Hz, 1H, C10-H), 7.35
(dd, 3J¼8.8 Hz, 4J¼2.9 Hz, 1H, C3-H), 6.94 (d, 3J¼8.8 Hz, 1H, C4-H),
4.30 (t, 3J¼8.8 Hz, 2H, C6-H2), 3.92 (s, 3H, ArOCH3), 3.37 (t,
4.3.9. 1(2,1,3) 2-Methoxy-11-methyl-8,14-dioxo-6,7-dihydro-
8H,14H-5,13-diazabenz[e]aceanthrylenes
Yield 1(2,1,3) (0.077 g, 0.23 mmol, 34%) as a yellow powder us-
3J¼8.8 Hz, 2H, C7-H2); 13C NMR (75.5 MHz, CDCl3):
¼171.2 (C8),
d
ing the ester route. Mp 116–117 ꢀC; 1H NMR (300 MHz, CDCl3):
159.9 (C14), 155.8 (C2), 148.6 (C5a), 136.9 (C4a), 136.5 (C11), 133.2
(C12a), 129.2 (C10), 127.2 (C9), 126.4 (C8a), 126.1 (C3), 121.2 (C12),
115.1 (C14a), 114.2 (C4), 110.8 (C1), 102.2 (C7a), 56.1 (OCH3), 47.7
d
¼9.22 (s, 1H, C12-H), 8.24 (d, 3J¼8.0 Hz, 1H, C9-H), 7.56 (d,
4J¼3.0 Hz, 1H, C1-H), 7.23 (dd, 3J¼9.0 Hz, 4J¼3.0 Hz, 1H, C3-H), 7.17
(d, 3J¼8.0 Hz, 1H, C10-H), 6.81 (d, 3J¼9.0 Hz, 1H, C4-H), 4.15 (t,

A.M. Jones et al. / Tetrahedron 65 (2009) 563–578
573
3J¼8.8 Hz, 2H, C6-H2), 3.83 (s, 3H, ArOCH3), 3.27 (t, 3J¼8.8 Hz, 2H,
4.3.13. 1(2,2,4) 2-Methoxy-11-methyl-6,7,8-trihydro-9H,15H-5,14-
diaza-dibenzo[a,de]anthracen-9,15-dione
C7-H2), 2.43 (s, 3H, ArCH3); 13C NMR (75.5 MHz, CDCl3):
d¼171.9
(C8), 160.0 (C14), 155.4 (C2), 148.3 (C5a), 141.4 (C12a), 136.3 (C4a),
133.0 (C11), 127.8 (C10), 127.4 (C8a), 125.6 (C9), 125.2 (C3), 121.1
(C12), 115.1 (C14a), 114.1 (C4), 110.4 (C1), 101.6 (C7a), 56.1 (ArOCH3),
47.5 (C6), 23.4 (C7), 22.1 (ArCH3); IR (KBr): nmax¼2947 (m), 1718 (s)
(C]O), 1701 (m) (C]O), 1607 (s), 1556 (m), 1499 (w), 1318 (w), 1153
(m) (C–O) cmꢁ1; LRMS (CIþ): m/z (%) 333.12 (100) [MþH]þ; HRMS
(CIþ): m/z calcd for C20H17N2O3 [MþH]þ: 333.1239; found: 333.1236.
Yield 1(2,2,4) (0.166 g, 0.45 mmol, 45%) (LCMS purity 90%) as
a brown powder using the ester route. Mp 255 ꢀC (dec); 1H NMR
(300 MHz, CDCl3):
d
¼8.57 (d, 3J¼9.0 Hz, 1H, C13-H), 8.17 (d,
3J¼2.0 Hz, 1H, C10-H), 7.73 (d, 3J¼3.0 Hz, 1H, C1-H), 7.39 (dd,
3J¼9.0 Hz, 4J¼2.0 Hz, 1H, C12-H), 7.33–7.29 (m, 1H, C3-H), 7.26–
7.20 (m, 1H, C4-H), 4.00 (t, 3J¼6.0 Hz, 2H, C6-H2), 3.91 (s, 3H,
ArOCH3), 2.89 (t, 3J¼6.0 Hz, 2H, C8-H2), 2.50 (s, 3H, ArCH3), 2.17–
2.08 (m, 2H, C7-H2); 13C NMR (75.5 MHz, CDCl3):
d¼175.4 (C9),
4.3.10. 1(1,1,4) 10-Methyl 8,14-dioxo-6,7-dihydro-8H,14H-5,13-
diazabenz[e]aceanthrylene
Yield 1(1,1,4) (0.239 g, 0.79 mmol, 79%) (LCMS purity 99%) as
a yellow solid using the ester route or (0.110 g, 0.36 mmol, 36%)
using the acid route. Mp 299 ꢀC (dec); 1H NMR (300 MHz, CDCl3):
160.5 (C15), 155.3 (C2), 144.5 (C5a), 136.4 (C13a), 135.2 (C4a), 133.5
(C11), 131.1 (C12), 126.4 (C9a), 125.0 (C3 & C10), 122.2 (C13), 116.1
(C15a), 114.5 (C4), 110.2 (C1), 101.6 (C8a), 56.0 (OCH3), 47.1 (C6),
21.1 (ArCH3), 20.3 (C8), 20.0 (C7); IR (KBr): nmax¼2923 (m), 1701 (s)
(C]O), 1604 (m), 1587 (s), 1522 (m), 1472 (m), 1291 (w) cmꢁ1
;
d
¼9.36 (d, 3J¼9.0 Hz, 1H, C12-H), 8.25–8.22 (m, 2H, C9-H, C1-H),
LRMS (ESþ): m/z (%) 369.13 (100) [MþNa]þ, 715.29 (30)
[2MþNa]þ; HRMS (ESþ): m/z calcd for C21H18N2O3Na [MþNa]þ:
369.1215; found 369.1217.
7.64 (ddd, 3J¼7.0 Hz, 3J¼7.0 Hz, 4J¼1.5 Hz, 1H, C3-H), 7.41 (dd,
3J¼9.0 Hz, 4J¼1.5 Hz, 1H, C11-H), 7.26–7.20 (m, 1H, C2-H), 6.90 (dd,
3J¼7.0 Hz, 4J¼1.5 Hz, 1H, C4-H), 4.30 (t, 3J¼9.0 Hz, 2H, C6-H2), 3.34
(t, 3J¼9.0 Hz, 2H, C7-H2), 2.42 (s, 3H, CH3); 13C NMR (75.5 MHz,
4.3.14. 1(1,1,5) 10-Chloro 8,14-dioxo-6,7-dihydro-8H,14H-5,13-
diazabenz[e]aceanthrylene
CDCl3):
d¼172.6 (C8), 159.9 (C14), 148.4 (C5a), 138.6 (C4a), 136.6
(C12a), 136.0 (C3), 134.3 (C10), 131. 9 (C11), 130.0 (C1), 127.4 (C8a),
125.3 (C9), 122.5 (C2), 120.8 (C12), 114.9 (C14a), 112.2 (C4), 102.2
(C7a), 47.3 (C6), 234 (C7), 20.9 (CH3); IR (KBr): nmax¼2924 (m)
(CH2), 1708 (s) (C]O), 1583 (m), 1549 (m), 1499 (s), 1451 (w), 1324
(w), 751 (m) (Ar–H) cmꢁ1; LRMS (ESþ): m/z (%) 303.11 (100)
[MþH]þ; HRMS (ESþ): m/z calcd for C19H15N2O2Na [MþH]þ:
303.1134; found: 303.1140.
Yield 1(1,1,5) (0.258 g, 0.80 mmol, 80%) (LCMS purity 96%) as
a pale brown powder using the ester route. Mp 301 ꢀC (dec); 1H
NMR (300 MHz, CDCl3):
d
¼9.52 (d, 3J¼9.5 Hz, 1H, C12-H), 8.45 (d,
4J¼2.5 Hz, 1H, C9-H), 8.29 (d, 3J¼8.5 Hz, 4J¼1.5 Hz, 1H, C1-H), 7.76
(ddd, 3J¼8.5 Hz, 3J¼8.5 Hz, 4J¼1.5 Hz, 1H, C3-H), 7.58 (dd, 3J¼9.5 Hz,
4J¼2.5 Hz 1H, C11-H), 7.30 (d, 3J¼8.5 Hz, 1H, C2-H), 7.00 (d,
3J¼8.5 Hz, 1H, C4-H), 4.34 (t, 3J¼9.0 Hz, 2H, C6-H2), 3.40 (t,
3J¼9.0 Hz, 2H, C7-H2); 13C NMR (75.5 MHz, CDCl3):
¼171.2 (C8),
d
4.3.11. 1(1,2,4) 11-Methyl 6,7,8-trihydro-9H,15H-5,14-diaza-
dibenzo[a,de]anthracen-9,15-dione
157.8 (C14), 148.8 (C5a), 138.6 (C4a), 136.4 (C3), 132.9 (C12a), 130.8
(C11), 130.2 (C1), 125.2 (C9), 123.8 (C10), 122.9 (C2), 122.7 (C12),
120.7 (C8a),114.5 (C14a),112.4 (C4),102.8 (C7a), 47.4 (C6), 23.4 (C7);
IR (KBr): nmax¼3449 (w) (OH), 2360 (w) (CH2), 1706 (s) (C]O), 1604
(s), 1583 (s), 1541 (m), 1497 (m), 1324 (m), 1161 (m) (C–O), 747 (m)
(Ar–H) cmꢁ1; LRMS (ESþ): m/z (%) 345.08 (70) [MþNa]þ, 667.12
(100) [2M (35Cl35Cl)þNa]þ, 669.12 [2M (35Cl37Cl)þNa]þ; HRMS
(ESþ): m/z calcd for C36H22N4O4NaCl [2MþNa]þ: 667.0916; found:
667.0906.
Yield 1(1,2,4) (0.203 g, 0.64 mmol, 64%) as a pale brown powder
using the ester route. Mp 260 ꢀC (dec); 1H NMR (300 MHz, CDCl3):
d
¼8.56 (d, 3J¼9.0 Hz, 1H, C13-H), 8.28 (dd, 3J¼8.0 Hz, 4J¼1.5 Hz, 1H,
C1-H), 8.17–8.15 (m, 1H, C10-H), 7.73–7.67 (m, 1H, C3-H), 7.39 (ddd,
3J¼9.0 Hz, 4J¼2.5 Hz, 1H, C12-H), 7.28–7.22 (m, 2H, C2-H, C4-H),
4.01 (t, 3J¼6.0 Hz, 2H, C6-H2), 2.89 (t, 3J¼6.0 Hz, 2H, C8-H2), 2.48 (s,
3H, CH3), 2.18–2.09 (m, 2H, C7-H2); 13C NMR (75.5 MHz, CDCl3):
d¼175.5 (C9), 160.2 (C15), 144.3 (C5a), 140.7 (C4a), 136.2 (C13a),
135.8 (C3), 133.5 (C9a), 131.2 (C12), 129.4 (C1), 126.1 (C11), 124.8
(C10), 122.5 (C2), 122.1 (C13), 115.4 (C15a), 112.7 (C4), 102.3 (C8a),
46.8 (C6), 21.0 (CH3), 20.1 (C8), 19.8 (C7); IR (KBr): nmax¼3449 (w)
(OH), 2949 (w) (CH2), 2361 (w) (CH2), 1703 (s) (C]O),1588 (s), 1533
(s), 1474 (s), 1360 (m), 1152 (m) (C–O), 746 (m) (Ar–H) cmꢁ1; LRMS
(ESþ): m/z (%) 339.13 (50) [MþNa]þ, 655.25 (100) [2MþNa]þ; HRMS
(ESþ): m/z calcd for C40H32N4O4Na [2MþNa]þ: 655.2321; found:
655.2327.
4.3.15. 1(1,2,5) 11-Chloro 6,7,8-trihydro-9H,15H-5,14-diaza-
dibenzo[a,de]anthracen-9,15-dione
Yield 1(1,2,5) (0.215 g, 0.64 mmol, 64%) (LCMS purity 99%) as
a pale brown powder using the ester route. Mp 236 ꢀC (dec); 1H
NMR (300 MHz, CDCl3):
d
¼8.64 (d, 3J¼9.0 Hz, 1H, C13-H), 8.32 (d,
4J¼3.0 Hz, 1H, C10-H), 8.28 (dd, 3J¼8.0 Hz, 4J¼1.5 Hz, 1H, C1-H),
7.77–7.71 (m, 1H, C3-H), 7.50 (dd, 3J¼9.0 Hz, 4J¼3.0 Hz, 1H, C12-H),
7.32–7.26 (m, 2H, C2-H, C4-H), 4.03 (t, 3J¼6.0 Hz, 2H, C6-H2), 2.88 (t,
3J¼6.0 Hz, 2H, C8-H2), 2.19–2.10 (m, 2H, C7-H2); 13C NMR
4.3.12. 1(2,1,4) 2-Methoxy-10-methyl-8,14-dioxo-6,7-dihydro-
8H,14H-5,13-diazabenz[e]aceanthrylene
(75.5 MHz, CDCl3):
d¼174.5 (C9), 160.5 (C15), 144.9 (C5a), 141.0
(C4a), 136.5 (C3), 134.3 (C13a), 132.6 (C9a), 130.4 (C10), 130.0 (C12),
128.0 (C11), 125.1 (C1), 124.4 (C2), 123.3 (C13), 115.7 (C15a), 113.2
(C4),103.0 (C8a), 47.4 (C6), 20.4 (C8), 20.2 (C7); IR (KBr): nmax¼3449
(w) (OH),1707 (s) (C]O),1585 (w),1526 (s),1476 (s),1406 (m),1363
(m), 1321 (w), 1289 (w) (C–O), 1181 (w) (C–O), 1087 (w), 756 (m)
(Ar–H) cmꢁ1; LRMS (ESþ): m/z (%) 337.07 (100) [M35ClþH]þ, 339.07
(30) [M37ClþH]þ; HRMS (ESþ): m/z calcd for C19H14ClN2O2 [MþH]þ:
337.0744; found: 337.0742.
Yield 1(2,1,4) (0.146 g, 0.45 mmol, 45%) (LCMS purity 90%) as
a yellow powder using the ester route. Mp 305–306 ꢀC; 1H NMR
(300 MHz, CDCl3):
d
¼9.43 (d, 3J¼9.0 Hz, 1H, C12-H), 8.32 (d,
3J¼2.0 Hz, 1H, C9-H), 7.75 (d, 3J¼3.0 Hz, 1H, C1-H), 7.47 (dd,
3J¼9.0 Hz, 4J¼2.0 Hz, 1H, C11-H), 7.35 (dd, 3J¼9.0 Hz, 4J¼3.0 Hz, 1H,
C3-H), 6.96 (d, 3J¼9.0 Hz, 1H, C4-H), 4.31 (t, 3J¼9.0 Hz, 2H, C6-H2),
3.92 (s, 3H, OCH3), 3.40 (t, 3J¼9.0 Hz, 2H, C7-H2), 2.50 (s, 3H, ArCH3);
13C NMR (125.5 MHz, CD3COOD):
d
¼173.4 (C8), 156.6 (C14), 156.1
(C2), 147.0 (C5a), 137.2 (C4a), 136.7 (C11), 135.8 (C12a), 132.1 (C10),
131.8 (C12), 128.0 (C8a), 125.6 (C9), 122.5 (C3), 115.2 (C14a), 115.0
(C14), 110.4 (C1), 103.8 (C7a), 56.7 (OCH3), 48.2 (C6), 22.5 (C7), 21.5
(ArCH3); IR (KBr): nmax¼3024 (m), 2925 (m), 1691 (s) (C]O), 1629
4.3.16. 1(1,1,6) 11-Methyl carboxylate-8,14-dioxo-6,7-dihydro-
8H,14H-5,13-diazabenz[e]aceanthrylene
Yield 1(1,1,6) (0.305 g, 0.88 mmol, 88%) (LCMS purity 78%) as
a dark yellow powder using the ester route. Mp 160 ꢀC (dec); 1H
(m), 1583 (s), 1548 (m), 1507 (s), 1284 (m), 1167 (w) (C–O) cmꢁ1
;
NMR (300 MHz, CDCl3):
d
¼10.14 (d, 4J¼1.5 Hz, 1H, C12-H), 8.48 (d,
LRMS (ESþ): m/z (%) 333.06 (45) [MþH]þ, 355.03 (100) [MþNa]þ,
687.15 (90) [2MþNa]þ; HRMS (ESþ): m/z calcd for C20H17N2O3
[MþH]þ: 333.1239; found: 333.1237.
3J¼8.0 Hz, 1H, C9-H), 8.25 (dd, 3J¼8.0 Hz, 4J¼1.5 Hz, 1H, C1-H), 8.08
(dd, 3J¼8.0 Hz, 4J¼1.5 Hz, 1H, C10-H), 7.71–7.65 (m, 1H, C3-H),
7.25–7.19 (m, 1H, C2-H), 6.93 (d, 3J¼8.0 Hz, 1H, C4-H), 4.27 (t,

574
A.M. Jones et al. / Tetrahedron 65 (2009) 563–578
3J¼9.5 Hz, 2H, C6-H2), 3.94 (s, 3H, CO2CH3), 3.33 (t, 3J¼9.5 Hz, 2H,
(ESþ): m/z (%) 325.29 (100) [MþNa]þ, 627.09 (25) [2MþNa]þ;
HRMS (ESþ): m/z calcd for C19H14N2O2Na [MþNa]þ: 325.0953;
found: 325.0944.
C7-H2); 13C NMR (75.5 MHz, CDCl3):
d
¼171.7 (C8), 166.7 (CO2Me),
160.1 (C14), 149.5 (C5a), 138.7 (C4a), 136.8 (C3), 136.2 (C12a), 135.5
(C8a), 132.3 (C11), 130.5 (C10), 127.5 (C1), 126.1 (C9), 123.5 (C2),
123.0 (C12), 114.9 (C14a), 112.9 (C4), 103.9 (C7a), 53.0 (CO2CH3),
47.8 (C6), 23.7 (C7); IR (KBr): nmax¼3422 (w) (OH), 2924 (m) (CH2),
1719 (s) (C]O), 1584 (s), 1535 (m), 1497 (s), 1429 (m), 1324 (w),
1261 (m) (C–O), 1164 (m) (C–O), 756 (m) (Ar–H) cmꢁ1; LRMS
(ESþ): m/z (%) 369.13 (100) [MþNa]þ, 715.28 (50) [2MþNa]þ;
HRMS (ESþ): m/z calcd for C20H14N2O4Na [MþNa]þ: 369.0851;
found: 369.0852.
4.3.20. 1(1,2,7) 13-Methyl 6,7,8-trihydro-9H,15H-5,14-diaza-
dibenzo[a,de]anthracen-9,15-dione
Yield 1(1,2,7) (0.075 g, 0.24 mmol, 24%) (LCMS purity 94%) as
a brown powder using the ester route. Mp 194–195 ꢀC; 1H NMR
(300 MHz, CDCl3):
d
¼8.22 (dd, 3J¼8.0 Hz, 4J¼2.0 Hz, 1H, C10-H),
8.20–8.16 (m, 1H, C1-H), 7.76–7.70 (m, 1H, C3-H), 7.47–7.45 (m, 2H,
C11-H, C12-H), 7.29–7.24 (m, 2H, C2-H, C4-H), 4.19–4.10 (m, 1H, C6-
H), 3.93–3.84 (m, 1H, C6-H), 2.93–2.72 (m, 2H, C8-H2), 2.33–2.21
(m, 1H, C7-H), 2.25 (s, 3H, ArCH3), 2.15–2.00 (m, 1H, C7-H); 13C NMR
4.3.17. 1(1,2,6) 12-Methyl carboxylate 6,7,8-trihydro-9H,15H-5,14-
diaza-dibenzo[a,de]anthracen-9,15-dione
(75.5 MHz, CDCl3):
d
¼176.6 (C9), 158.6 (C15), 145.4 (C5a), 141.2
Yield 1(1,2,6) (0.296 g, 0.83 mmol, 83%) (LCMS purity 93%) as
(C4a), 138.2 (C13a), 135.6 (C3), 135.0 (C9a), 133.0 (C12), 132.2 (C13),
129.1 (C10), 126.5 (C11), 123.0 (C1), 122.4 (C2), 115.8 (C15a), 112.8
(C4), 102.9 (C8a), 46.2 (C6), 21.4 (ArCH3), 20.4 (C8), 19.5 (C7); IR
(KBr): nmax¼2933 (m), 1709 (s) (C]O), 1601 (s), 1538 (m), 1417 (m),
1225 (m), 755 (w) (Ar–H) cmꢁ1; LRMS (ESþ): m/z (%) 339.15 (100)
[MþNa]þ, 655.31 (90) [2MþNa]þ; HRMS (ESþ): m/z calcd for
C20H16N2O2Na [MþNa]þ: 339.1109; found: 339.1108.
a bright orange powder using the ester route. Mp 97–98 ꢀC; 1H
NMR (300 MHz, CDCl3):
d
¼9.36 (d, 4J¼1.5 Hz, 1H, C13-H), 8.45 (d,
3J¼8.0 Hz, 1H, C10-H), 8.34 (dd, 3J¼8.0 Hz, 4J¼2.0 Hz, 1H, C1-H),
8.11 (dd, 3J¼8.0 Hz, 4J¼1.5 Hz, 1H, C11-H), 7.79–7.73 (m, 1H, C3-
H), 7.35–7.29 (m, 2H, C2-H, C4-H), 4.06 (t, 3J¼6.0 Hz, 2H, C6-H2),
4.00 (s, 3H, CO2CH3), 2.92 (t, 3J¼6.0 Hz, 2H, C8-H2), 2.22–2.13 (m,
2H, C7-H2); 13C NMR (75.5 MHz, CDCl3):
d¼174.6 (C9), 166.4
(CO2CH3), 160.1 (C15), 145.0 (C5a), 140.6 (C4a), 136.1 (C3), 134.5
(C13a), 131.1 (C9a), 129.7 (C10), 128.9 (C12), 126.6 (C11), 125.6
(C1), 124.1 (C2), 123.1 (C13), 115.5 (C15a), 112.9 (C4), 103.2 (C8a),
52.6 (CO2CH3), 47.0 (C6), 20.0 (C8), 19.8 (C7); IR (KBr): nmax¼3449
(m) (OH), 2363 (w) (CH2), 1719 (s) (C]O), 1588 (s), 1528 (m),
1475 (s), 1362 (w), 1260 (m) (C–O), 755 (m) (Ar–H) cmꢁ1; LRMS
(ESþ): m/z (%) 383.07 (100) [MþNa]þ, 743.20 (15) [2MþNa]þ;
HRMS (ESþ): m/z calcd for C21H16N2O4Na [MþNa]þ: 383.1008;
found: 383.1013.
4.3.21. 1(2,1,7) 2-Methoxy-12-methyl-8,14-dioxo-6,7-dihydro-
8H,14H-5,13-diazabenz[e]aceanthrylene
Yield 1(2,1,7) (0.070 g, 0.21 mmol, 21%) (LCMS purity 94%) as
a light yellow powder using the ester route. Mp 239.0 ꢀC (dec); 1H
NMR (300 MHz, CDCl3):
d
¼8.30–8.24 (m, 1H, C9-H), 7.65 (d,
3J¼3.0 Hz, 1H, C1-H), 7.49–7.47 (m, 2H, C10-H, C11-H), 7.33 (dd,
3J¼9.0 Hz, 4J¼3.0 Hz, 1H, C3-H), 6.97 (d, 3J¼9.0 Hz, 1H, C4-H), 4.30
(t, 3J¼9.0 Hz, 2H, C6-H2), 3.91 (s, 3H, OCH3), 3.35 (t, 3J¼9.0 Hz, 2H,
C7-H2), 2.32 (s, 3H, ArCH3); 13C NMR (75.5 MHz, CDCl3):
d¼173.0
(C8), 158.1 (C14), 155.4 (C2), 150.7 (C5a), 134.2 (C4a), 133.5 (C12a),
133.2 (C11), 132.0 (C12), 130.2 (C8a), 126.8 (C10), 124.8 (C3), 123.3
(C9), 116.3 (C14a), 114.6 (C4), 110.9 (C1), 101.6 (C7a), 56.0 (OCH3),
48.7 (C6), 23.6 (C7), 22.5 (ArCH3); IR (KBr): nmax¼2930 (m), 1702 (s)
(C]O), 1632 (m), 1608 (m), 1589 (m), 1559 (m), 1505 (s), 1319 (m),
1029 (w), 767 (m) (Ar–H) cmꢁ1; LRMS (ESþ): m/z (%) 333.14 (100)
[MþH]þ; HRMS (ESþ): m/z calcd for C20H17N2O3 [MþH]þ: 333.1239;
found: 333.1234.
4.3.18. 1(2,1,6) 2-Methoxy-11-methyl carboxylate-8,14-dioxo-6,7-
dihydro-8H,14H-5,13-diazabenz[e]aceanthrylene
Yield 1(2,1,6) (0.214 g, 0.57 mmol, 57%) as a yellow solid using
the ester route. Mp 206–207 ꢀC; 1H NMR (300 MHz, CDCl3):
d
¼10.28 (d, 4J¼1.2 Hz, 1H, C12-H), 8.63 (d, 3J¼8.4 Hz, 1H, C9-H),
8.23 (dd, 3J¼8.4 Hz, 4J¼1.2 Hz, 1H, C10-H), 7.82 (d, 4J¼2.6 Hz, 1H,
C1-H), 7.40 (dd, 3J¼9.0 Hz, 4J¼2.6 Hz, 1H, C3-H), 7.02 (d, 3J¼9.0 Hz,
1H, C4-H), 4.38 (t, 3J¼8.7 Hz, 2H, C6-H2), 4.02 (s, 3H, CO2CH3), 3.94
(s, 3H, OCH3), 3.44 (t, 3J¼8.7 Hz, 2H, C7-H2); 13C NMR (125.5 MHz,
4.3.22. 1(2,2,7) 2-Methoxy-13-methyl-6,7,8-trihydro-9H,15H-5,14-
diaza-dibenzo[a,de]anthracen-9,15-dione
CD3COOD):
d
¼169.3 (C8), 166.2 (CO2Me), 159.4 (C14), 156.4 (C2),
149.8 (C5a), 135.2 (C14a), 132.1 (C11a), 131.5 (C12a), 129.4 (C8a),
127.0 (C9), 125.7 (C3), 125.1 (C10), 122.2 (C12), 115.6 (C14a), 115.4
(C4), 109.9 (C1), 104.5 (C7a), 55.4 (OCH3), 52.2 (CO2CH3), 48.1 (C6),
22.7 (C2); IR (KBr): nmax¼2923 (m), 1701 (s) (C]O), 1600 (m), 1540
(m), 1581 (m), 1506 (m), 1363 (m), 1327 (m), 1281 (w), 1160 (m),
764 (m) (Ar–H) cmꢁ1; LRMS (ESþ): m/z (%) 377.10 (100) [MþH]þ;
HRMS (ESþ): m/z calcd for C21H17N2O5 [MþH]þ: 377.1137; found:
377.1147.
Yield 1(2,2,7) (0.083 g, 0.24 mmol, 24%) as a red powder using
the ester route. Mp 233–234 ꢀC; 1H NMR (300 MHz, CDCl3):
d
¼8.19–8.14 (m, 1H, C10-H), 7.64 (d, 3J¼3.0 Hz, 1H, C1-H), 7.44–7.42
(m, 2H, C11-H, C12-H), 7.32–7.28 (m, 1H, C3-H), 7.22–7.18 (m, 1H,
C4-H), 4.17–4.08 (m, 1H, C6-H), 3.91 (s, 3H, ArOCH3), 3.86–3.77 (m,
1H, C6-H), 2.90–2.70 (m, 2H, C8-H2), 2.92–2,16 (m, 1H, C7-H), 2.23
(s, 3H, ArCH3), 2.12–1.97 (m, 1H, C7-H); 13C NMR (75.5 MHz, CDCl3):
d¼175.9 (C9), 159.1 (C15), 155.2 (C2), 145.7 (C5a), 135.4 (C4a), 134.9
(C13a), 132.9 (C12), 132.1 (C13), 128.7 (C9a), 126.5 (C11), 124.3 (C3),
122.9 (C10), 116.5 (C15a), 114.6 (C4), 110.3 (C1), 101.9 (C8a), 56.0
(ArOCH3), 46.3 (C6), 21.5 (ArCH3), 20.4 (C7), 19.5 (C8); IR (KBr):
nmax¼2935 (m), 1706 (s) (C]O), 1604 (s), 1592 (m), 1533 (s), 1427
(m), 1038 (m), 771 (m) (Ar–H) cmꢁ1; LRMS (ESþ): m/z (%) 347.10
(100) [M]þ, 348.14 (30) [MþH]þ, 369.17 (45) [MþNa]þ; HRMS (ESþ):
m/z calcd for C21H18N2O3Na [MþNa]þ: 369.1215; found: 369.1219.
4.3.19. 1(1,1,7) 12-Methyl-8,14-dioxo-6,7-dihydro-8H,14H-5,13-
diazabenz[e]aceanthrylene
Yield 1(1,1,7) (0.082 g, 0.27 mmol, 27%) (LCMS purity 95%) as
a yellow powder using the ester route. Mp 238–239 ꢀC; 1H NMR
(300 MHz, CDCl3):
d
¼8.27–8.22 (m, 1H, C9-H), 8.18 (dd, 3J¼8.0 Hz,
4J¼1.5 Hz, 1H, C1-H), 7.73 (ddd, 3J¼7.5 Hz, 3J¼7.5 Hz, 4J¼1.5 Hz,
1H, C3-H), 7.48–7.45 (m, 2H, C10-H, C11-H), 7.27–7.21 (m, 1H, C2-
H), 6.98 (d, 3J¼7.5 Hz, 1H, C4-H), 4.30 (t, 3J¼9.0 Hz, 2H, C6-H2),
3.33 (t, 3J¼9.0 Hz, 2H, C7-H2), 2.32 (s, 3H, ArCH3); 13C NMR
4.3.23. 1(2,1,8) 2-Methoxy-9-methyl-8,14-dioxo-6,7-dihydro-
8H,14H-5,13-diazabenz[e]aceanthrylene
(75.5 MHz, CDCl3):
d¼173.9 (C8), 158.5 (C14), 151.0 (C5a), 140.2
Yield 1(2,1,8) (0.284 g, 0.85 mmol, 85%) as a yellow powder
(C4a), 136.2 (C3), 134.0 (C10), 133.9 (C12a), 132.4 (C12), 130.4
(C8a), 130.1 (C1), 127.2 (C11), 123.7 (C9), 123.0 (C2), 116.2 (C14a),
113.3 (C4), 102.5 (C7a), 48.6 (C6), 24.0 (C7), 22.9 (ArCH3); IR
(KBr): nmax¼3339 (m) (OH), 1712 (s) (C]O), 1602 (m), 1556 (s),
1492 (s), 1320 (m), 1157 (m) (C–O), 747 (m) (Ar–H) cmꢁ1; LRMS
using the ester route. Mp 339–340 ꢀC; 1H NMR (300 MHz, CDCl3):
d
¼9.33 (d, 3J¼8.6 Hz, 1H, C12-H), 7.75 (d, 4J¼3.0 Hz, 1H, C1-H), 7.51
(dd, 3J¼8.6 Hz, 4J¼1.4 Hz, 1H, C11-H), 7.34 (dd, 3J¼8.8 Hz, 4J¼3.0 Hz,
1H, C3-H), 7.30 (d, 3J¼8.6 Hz, 1H, C10-H), 6.93 (d, 3J¼9.0 Hz, 1H, C4-
H), 4.28 (t, 3J¼8.8 Hz, 2H, C6-H2), 3.92 (s, 3H, ArOCH3), 3.35 (t,

A.M. Jones et al. / Tetrahedron 65 (2009) 563–578
575
4
3J¼8.8 Hz, 2H, C7-H2), 3.03 (s, 3H, ArCH3); 13C NMR (75.5 MHz,
(dd, 3J¼8.0 Hz, J¼1.5 Hz, 1H, C12-H), 7.72 (d, 3J¼3.0 Hz, 1H, C1-H),
7.56–7.46 (m, 2H, C10-H, C11-H), 7.35 (dd, 3J¼9.0 Hz, 4J¼3.0 Hz, 1H,
C3-H), 6.98 (d, 3J¼9.0 Hz, 1H, C4-H), 4.28 (t, 3J¼9.0 Hz, 2H, C6-H2),
3.91 (s, 3H, OCH3), 3.35 (t, 3J¼9.0 Hz, 2H, C7-H2); 13C NMR
CDCl3):
d¼176.9 (C8), 159.1 (C14), 155.1 (C2), 148.0 (C5a), 140.0
(C4a), 136.6 (C12a), 134.3 (C9), 129.2 (C11), 129.0 (C10), 125.4 (C3),
122.4 (C8a), 119.2 (C12), 113.5 (C4), 113.4 (C14a), 110.9 (C1), 101.4
(C7a), 55.9 (OCH3), 51.5 (C6), 31.0 (C6), 24.4 (ArCH3); IR (KBr):
nmax¼2945 (m), 1717 (s) (C]O), 1700 (m) (C]O), 1601 (w), 1556
(m), 1499 (m), 1318 (m), 1159 (m) (C–O) cmꢁ1; LRMS (CIþ): m/z (%)
333.12 (100) [MþH]þ; HRMS (ESþ): m/z calcd for C20H17N2O3
[MþH]þ: 333.1239; found: 333.1234.
(75.5 MHz, CD3COOD):
(C5a), 146.1 (C9), 141.8 (C4a), 131.1 (C11), 130.5 (C10), 130.2 (C12a),
127.3 (C8a), 126.1 (C3), 120.7 (C12), 116.1 (C4), 113.4 (C14a), 111.0
d¼175.3 (C8), 160.4 (C14), 159.9 (C2), 149.6
(C1), 103.7 (C7a), 55.6 (CH3), 48.6 (C6), 23.5 (C7); IR (KBr): nmax
¼
2939 (w), 1693 (s) (C]O), 1615 (s), 1592 (s), 1580 (s), 1507 (s), 1458
(w), 1231 (m), 1063 (m), 761 (m) (Ar–H) cmꢁ1; LRMS (ESþ): m/z (%)
375.05 (100) [MþNa]þ; HRMS (ESþ): m/z calcd for C19H14N2O3Cl
[MþH]þ: 353.0693; found: 353.0691.
4.3.24. 1(2,2,8) 2-Methoxy-10-methyl-6,7,8-trihydro-9H,15H-5,14-
diaza-dibenzo[a,de]anthracen-9,15-dione
Yield 1(2,2,8) (0.261 g, 0.75 mmol, 75%) as a yellow powder
using ester route. Mp 147–148 ꢀC; 1H NMR (300 MHz, CDCl3):
4.3.28. 1(1,1,10) 10-Bromo 8,14-dioxo-6,7-dihydro-8H,14H-5,13-
diazabenz[e]aceanthrylene
d
¼8.23 (d, 3J¼8.7 Hz, 1H, C13-H), 7.67 (d, 4J¼3.1 Hz, 1H, C1-H), 7.38–
7.33 (m, 1H, C11-H), 7.24 (dd, 3J¼9.2 Hz, 4J¼3.1 Hz, 1H, C3-H), 7.18
(dd, 3J¼7.4 Hz, 4J¼1.0 Hz, 1H, C12-H), 7.14 (d, 3J¼9.2 Hz, 1H, C4-H),
3.90 (t, 3J¼6.0 Hz, 2H, C6-H2), 3.83 (s, 3H, ArOCH3), 2.89 (s, 3H,
ArCH3), 2.77 (t, 3J¼6.0 Hz, 2H, C8-H2), 2.08 (qt, 3J¼6.0 Hz, 2H, C7-
Methyl 5-bromo-2-[2-(2-oxo-pyrrolidin-1-yl)-benzoylamino]-
benzoate 5(7) (0.17 g, 0.40 mmol) was heated in a sealed glass mi-
crowave tube to 190 ꢀC, (maximum 275 W) for 80 min. The resultant
yellow/brown solid was purified by flash column chromatography
over silica gel (1:99, methanol/chloroform) to afford the title com-
pound 1(1,1,10) (0.073 g, 0.20 mmol, 50%) (LCMS purity 96%) as
H2); 13C NMR (75.5 MHz, CDCl3):
d
¼178.1 (C9), 160.7 (C15), 155.3
(C2), 143.4 (C5a), 139.4 (C13a), 136.7 (C9a), 135.5 (C4a), 129.7 (C12),
128.5 (C11), 125.4 (C10), 124.9 (C3), 121.0 (C13), 116.0 (C15a), 114.3
(C4), 110.5 (C1), 102.6 (C8a), 55.9 (ArOCH3), 46.5 (C6), 23.7 (ArCH3),
20.4 (C7), 19.8 (C8); IR (KBr): nmax¼2948 (m), 1719 (s) (C]O), 1698
(m) (C]O), 1601 (m), 1559 (w), 1499 (m), 1318 (w), 1158 (m) (C–
O) cmꢁ1; LRMS (CIþ): m/z (%) 347.14 (100) [MþH]þ; HRMS (CIþ): m/z
calcd for C21H19N2O3 [MþH]þ: 347.1396; found: 347.1390.
a yellow powder. Mp 346–347 ꢀC; 1H NMR (300 MHz, CDCl3):
d¼9.48
(d, 3J¼9.5 Hz, 1H, C12-H), 8.67 (d, 4J¼2.5 Hz, 1H, C9-H), 8.33 (dd,
3J¼8.0 Hz, 4J¼1.5 Hz, 1H, C1-H), 7.80–7.75 (m, 2H, C11-H, C3-H), 7.30
(ddd, 3J¼8.0 Hz, 3J¼8.0 Hz, 4J¼1.5 Hz,1H, C2-H), 7.02(d, 3J¼8.0 Hz,1H,
C4-H), 4.36(t, 3J¼9.0 Hz, 2H, C6-H2), 3.42(t, 3J¼9.0 Hz, 2H, C7-H2);13
C
NMR (75.5 MHz, CDCl3):
d¼171.1 (C8), 157.6 (C14), 148.7 (C5a), 138.6
(C4a),136.5 (C3),133.4 (C12a),131.3 (C11),130.3 (C1),128.3 (C9),122.8
(C2), 122.7 (C12), 121.0 (C8a), 120.1 (C10), 114.6 (C14a), 112.5 (C4),
102.7 (C7a), 47.4 (C6), 23.5 (C7); IR (KBr): nmax¼2924 (w), 1715 (s)
(C]O),1700 (s) (C]O),1600 (s),1580 (s),1498 (s),1325 (m),1160 (m)
(C–O), 749 (m) (Ar–H) cmꢁ1; LRMS (CIþ): m/z (%) 367.10 (100)
[M79BrþH]þ, 369.01 (70) [M81BrþH]þ; HRMS (CIþ): m/z calcd for
C18H12N2O729Br [MþH]þ: 367.0082; found: 367.0078.
4.3.25. 1(1,1,9) 9-Chloro 8,14-dioxo-6,7-dihydro-8H,14H-5,13-
diazabenz[e]aceanthrylene
Yield 1(1,1,9) (0.052 g, 0.16 mmol, 16%) as a yellow solid using
the acid route. Mp 187 ꢀC (dec); 1H NMR (300 MHz, CDCl3):
d
¼9.42
(d, 3J¼8.0 Hz, 4J¼2.0 Hz, 1H, C12-H), 8.29 (dd, 3J¼8.0 Hz, 4J¼1.5 Hz,
1H, C1-H), 7.76–7.70 (m,1H, C11-H), 7.55–7.50 (m, 2H, C10-H, C3-H),
7.29–7.23 (m, 1H, C2-H), 6.97 (d, 3J¼8.0 Hz, 1H, C4-H), 4.29 (t,
3J¼9.1 Hz, 2H, C6-H2), 3.36 (t, 3J¼9.1 Hz, 2H, C7-H2); 13C NMR
4.3.29. 1(1,1,11) 12-Methoxy 8,14-dioxo-6,7-dihydro-8H,14H-5,13-
diazabenz[e]aceanthrylene
(75.5 MHz, CD3COOD):
d¼171.3 (C8), 159.2 (C14), 149.4 (C5a), 137.6
(C3), 137.0 (C4a), 134.2 (C12a), 132.7 (C1), 131.9 (C11), 130.1 (C10),
127.4 (C8a), 123.8 (C9), 119.8 (C12), 115.9 (C4), 114.4 (C14a), 102.3
(C7a), 51.9 (C6), 31.5 (C7); IR (KBr): nmax¼2951 (m) (CH2), 1723 (s)
(C]O), 1600 (s), 1548 (w),1492 (m), 1459 (m), 1384 (m), 1261 (w)
(C–O), 1119 (w) (C–O), 751 (w) (Ar–H) cmꢁ1; LRMS (ESþ): m/z (%)
345.09 (100) [MþNa]þ; HRMS (ESþ): m/z calcd for C18H11N2O2NaCl
[MþNa]þ: 345.0407; found: 345.0412.
Yield 1(1,1,11) (0.031 g, 0.10 mmol, 10%) using the acid route. Mp
251–252 ꢀC; 1H NMR (300 MHz, CDCl3):
d
¼8.19 (m, 3J¼8.5 Hz, 1H,
C9-H), 8.00 (d, 3J¼8.0 Hz, 1H, C1-H), 7.71–7.67 (m, 1H, C3-H), 7.55–
7.49 (m, 2H, C10-H, C11-H), 7.26–7.22 (m, 1H, C2-H), 6.98 (d,
3J¼8.0 Hz,1H, C4-H), 4.30 (t, 3J¼9.0 Hz, 2H, C6-H2), 3.87 (s, 3H, CH3),
3.35 (t, 3J¼9.0 Hz, 2H, C7-H2); 13C NMR (75.5 MHz, CDCl3):
¼173.0
d
(C8), 157.0 (C14), 152.4 (C12), 150.5 (C5a), 139.4 (C4a), 135.4 (C3),
131.2 (C12a), 129.7 (C1), 127.6 (C10), 124.2 (C8a), 122.6 (C2), 117.5
(C11), 116.2 (C14a), 114.4 (C9), 113.1 (C4), 102.0 (C5a), 56.7 (OCH3),
48.2 (C6), 23.8 (C7); IR (KBr): nmax¼2949 (m), 1718 (s) (C]O), 1700
(m) (C]O), 1601 (s), 1559 (s), 1499 (m), 1318 (m), 1158 (m) (C–
O) cmꢁ1; LRMS (ESþ): m/z (%) 341.11 (100) [MþNa]þ; HRMS (ESþ):
m/z calcd for C19H14N2O3Na [MþNa]þ: 341.0902; found: 341.0903.
4.3.26. 1(1,2,9) 10-Chloro 6,7,8-trihydro-9H,15H-5,14-diaza-
dibenzo[a,de]anthracen-9,15-dione
Yield 1(1,2,9) (0.051 g, 0.15 mmol,15%) as a yellow powder using
the acid route. Mp 126–127 ꢀC; 1H NMR (300 MHz, CDCl3):
d
¼8.36
(dd, 3J¼8.5 Hz, 4J¼1.5 Hz, 1H, C13-H), 8.27 (dd, 3J¼8.0 Hz, 4J¼1.5 Hz,
1H, C1-H), 7.75–7.66 (m,1H, C12-H), 7.46–7.40 (m, 2H, C3-H, C11-H),
7.28–7.21 (m, 2H, C2-H, C4-H), 3.98 (t, 3J¼6.0 Hz, 2H, C6-H2), 2.84 (t,
3J¼9.0 Hz, 2H, C8-H2), 2.19–2.10 (m, 2H, C7-H2); 13C NMR
4.3.30. 1(1,1,12) 12-Chloro 8,14-dioxo-6,7-dihydro-8H,14H-5,13-
diazabenz[e]aceanthrylene
(75.5 MHz, CDCl3):
d¼174.6 (C9), 160.2 (C15), 143.4 (C5a), 140.8
Yield 1(1,1,12) (0.144 g, 0.45 mmol, 45%) (LCMS purity 97%) as
(C4a), 137.6 (C13a), 136.3 (C3), 132.4 (C10), 129.7 (C12), 129.6 (C1),
129.0 (C11), 123.6 (C9a), 122.6 (C2), 121.9 (C13), 115.1 (C15a), 112.8
(C4), 104.0 (C8a), 46.3 (C6), 20.2 (C8), 19.7 (C7); IR (KBr): nmax¼1706
(s) (C]O), 1582 (m), 1471 (s), 1403 (m), 1359 (m), 1289 (w) (C–O),
1179 (w) (C–O), 1082 (w), 754 (m) (Ar–H) cmꢁ1; LRMS (ESþ): m/z
(%) 359.09 (100) [MþNa]þ, 695.21 (10) [2MþNa]þ; HRMS (ESþ): m/z
calcd for C19H13N2O2NaCl [MþNa]þ: 359.0563; found: 359.0563.
a pale brown powder using the acid route. Mp 271–272 ꢀC; 1H NMR
(300 MHz, CDCl3):
d
¼8.21 (d, 3J¼8.0 Hz, 4J¼1.5 Hz, 1H, C9-H), 8.09
(dd, 3J¼8.0 Hz, 4J¼1.0 Hz, 1H, C1-H), 7.64–7.55 (m, 2H, C10-H, C11-
H), 7.42–7.35 (m, 1H, C3-H), 7.20–7.14 (m, 1H, C2-H), 6.89 (d,
3J¼8.0 Hz, 1H, C4-H), 4.45–3.96 (m, 2H, C6-H2), 3.45–3.03 (m, 2H,
C7-H2); 13C NMR (75.5 MHz, CDCl3):
d¼171.9 (C8), 157.0 (C14), 150.8
(C5a), 139.3 (C4a), 135.9 (C3), 132.6 (C11), 131.8 (C12a), 131.7 (C12),
129.7 (C1), 127.8 (C8a), 127.5 (C10), 124.3 (C9), 123.1 (C2), 115.8
(C14a), 113.2 (C4), 102.5 (C7a), 48.4 (C6), 23.6 (C7); IR (KBr):
nmax¼1776 (s) (C]O), 1753 (m) (C]O), 1720 (s) (C]O), 1578 (s),
1536 (s), 1489 (s), 1397 (m), 1318 (m), 1158 (m), 749 (s) (Ar–
H) cmꢁ1; LRMS (ESþ): m/z (%) 323.04 (100) [M35ClþH]þ, 325.06
4.3.27. 1(2,1,9) 2-Methoxy-9-chloro-8,14-dioxo-6,7-dihydro-
8H,14H-5,13-diazabenz[e]aceanthrylene
Yield 1(2,1,9) (0.053 g, 0.15 mmol, 15%) as a yellow powder using
the ester route. Mp 309 ꢀC (dec); 1H NMR (300 MHz, CDCl3):
d
¼9.42

576
A.M. Jones et al. / Tetrahedron 65 (2009) 563–578
(30) [M37ClþH]þ; HRMS (ESþ): m/z calcd for C18H12N2O2Cl [MþH]þ:
4.3.34. 1(1,2,16) 8,13-Dioxo-6,7-dihydro-8H,13H-5,12-
diazathieno[2,3-e]aceanthrylene
323.0587; found: 323.0589.
Yield 1(1,2,16) (0.032 g, 0.10 mmol, 17%) as a brown powder
using the zipper route on a 0.6 mmol scale. Mp 210–211 ꢀC;
4.3.31. 1(1,1,14) 8,16-Dioxo-6,7-dihydro-8H,16H-5,15-
diazanaphtho[e]aceanthrylene
1H NMR (300 MHz, CDCl3):
d
¼8.60 (d, 3J¼5.6 Hz, 1H, C12-H), 8.30
Yield 1(1,1,14) (0.035 g, 0.010 mmol, 10%) as a yellow solid using
(dd, 3J¼7.6 Hz, 4J¼1.7 Hz, 1H, C1-H), 7.72 (ddd, 3J¼7.2 Hz,
3J¼7.2 Hz, 4J¼1.7 Hz, 1H, C3-H), 7.61 (d, 3J¼5.6 Hz, 1H, C11-H),
7.30–7.23 (m, 2H, C2-H, C4-H), 4.05 (t, 3J¼6.0 Hz, 2H, C6-H2), 2.94
(t, 3J¼6.0 Hz, 2H, C8-H2), 2.15 (qt, 3J¼6.0 Hz, 2H, C7-H2); 13C NMR
the acid route. Mp 232 ꢀC (dec); 1H NMR (300 MHz, CDCl3):
d
¼10.05
(s,1H, C14-H), 8.96 (s,1H, C9-H), 8.56 (s,1H, C1-H), 8.23 (d, 3J¼8.0 Hz,
1H, C3-H), 8.01–7.95 (m, 2H, C10-H, C13-H), 7.71–7.63 (m, 1H,
C12-H), 7.59–7.48 (m,1H, C11-H), 7.25–7.13 (m,1H, C2-H), 6.95–6.89
(m, 1H, C4-H), 4.18 (t, 3J¼9.0 Hz, 2H, C6-H2), 3.36 (t, 3J¼9.0 Hz,
(75.5 MHz, CDCl3):
d¼171.6 (C9), 158.6 (C14), 143.0 (C5a), 140.8
(C4a), 136.7 (C12a), 136.1 (C3), 130.9 (C9a), 129.4 (C11), 128.9
(C12), 123.7 (C1), 122.5 (C2), 113.8 (C14a), 112.8 (C4), 102.9 (C8a),
47.4 (C6), 20.0 (C8), 19.8 (C7); IR (KBr): nmax¼2926 (m) (CH), 1696
(s) (C]O), 1596 (m), 1499 (s), 1366 (m), 1197 (m) (C–O), 767 (m)
(Ar–H) cmꢁ1; LRMS (CIþ): m/z (%) 309.07 (100) [MþH]þ; HRMS
(CIþ): m/z calcd for C17H13N2O2S [MþH]þ: 309.0693; found:
309.0698.
2H, C7-H2); 13C NMR (75.5 MHz, CDCl3):
d
¼170.1 (C8), 158.8 (C16),
149.8 (C5a), 140.3 (C14a), 138.3 (C4a), 136.0 (C3), 133.3 (C13a), 130.7
(C9a), 129.9 (C1), 128.8 (C10), 127.8 (C12), 126.9 (C9), 126.5 (C8a),
123.1 (C2), 121.3 (C13), 120.2 (C11), 115.0 (C16a), 113.2 (C14), 112.5
(C4),101.2 (C7a), 47.5 (C6), 23.2 (C7); IR (KBr): nmax¼1708 (m) (C]O),
1611 (m), 1579 (m), 1546 (s), 1484 (m), 1353 (m), 1150 (w) (C–O),
743 (m) (Ar–H) cmꢁ1; LRMS (ESþ): m/z (%) 339.11 (100) [MþH]þ;
HRMS (ESþ): m/z calcd for C22H15N2O2 [MþH]þ: 339.1134; found:
339.1141.
4.3.35. 1(1,1,17) 1,2,3,4,5,7-Hexahydropyrrolo[1,2-a]pyrido[2,1-
b]quinazoline-3,7-dione
Ethyl 3-[2-(2-oxo-pyrrolidin-1-yl)-benzoylamino]-propionate
5(1,1,17) (0.05 g, 0.15 mmol) dissolved in methanol (0.5 mL) in
a sealed glass microwave tube was heated to 100 ꢀC, (maximum
275 W), with air flowing through the reaction chamber, for 30 min.
Upon cooling the reaction mixture was purified by flash column
chromatography over silica gel (98:2, chloroform/methanol) to af-
ford the title compound 1(1,1,17) (0.006 g, 0.025 mmol, 16%) as
a pale brown powder. Mp 139 ꢀC (dec); 1H NMR (300 MHz, CDCl3):
4.3.32. 1(1,3,1) 6,7,8,9-Tetrahydro-10H,16H-5,15-diaza-
dibenzo[a,de]anthracen-10,16-dione
Methyl 2-(2-(2-oxoazepan-1-yl)benzamido)benzoate 5(1,3,1)
(0.73 g, 2.00 mmol) was heated in a sealed glass microwave tube to
190 ꢀC, (maximum 275 W), for 30 min. The resultant yellow/brown
solid was purified by flash column chromatography over silica gel
(1:99, methanol/chloroform) to afford the title compound 1(1,3,1)
(0.455 g, 1.44 mmol, 72%) as a yellow powder. Mp 187–188 ꢀC; 1H
d
¼8.12 (dd, 3J¼7.5 Hz, 4J¼1.5 Hz 1H, C8-H), 7.63 (ddd, 3J¼7.5 Hz,
NMR (300 MHz, CDCl3):
d
¼8.70 (dd, 3J¼8.5 Hz, 4J¼1.0 Hz, 1H, C11-
3J¼7.5 Hz, 4J¼1.5 Hz, 1H, C10-H), 7.19 (ddd, 3J¼7.5 Hz, 3J¼7.5 Hz,
4J¼1.0 Hz, 1H, C9-H), 6.87 (d, 3J¼7.5 Hz, 1H, C11-H), 4.25 (t, 3J¼
7.5 Hz, 2H, C1-H2), 4.10 (t, 3J¼9.0 Hz, 2H, C5-H2), 3.07 (t, 3J¼9.0 Hz,
2H, C4-H2), 2.63 (t, 3J¼7.5 Hz, 2H, C2-H2); 13C NMR (75.5 MHz,
H), 8.35 (dd, 3J¼8.5 Hz, 4J¼1.0 Hz, 1H, C12-H), 8.26 (dd, 3J¼8.0 Hz,
4J¼1.5 Hz, 1H, C1-H), 7.68 (ddd, 3J¼8.0 Hz, 3J¼8.0 Hz, 4J¼1.5 Hz, 1H,
C3-H), 7.60 (ddd, 3J¼7.2 Hz, 3J¼7.2 Hz, 4J¼1.9 Hz, 1H, C14-H), 7.45
(ddd, 3J¼7.2 Hz, 3J¼7.2 Hz, 4J¼1.0 Hz, 1H, C13-H), 7.21 (ddd,
3J¼7.2 Hz, 3J¼7.2 Hz, 4J¼1.0 Hz, 1H, C4-H), 7.17 (d, 3J¼8.7 Hz, 1H, C2-
H), 4.17 (t, 3J¼6.2 Hz, 2H, C6-H2), 3.05–3.00 (m, 2H, C9-H2), 2.16 (qt,
3J¼6.4 Hz, 2H, C7-H2), 2.02–1.92 (m, 2H, C8-H2); 13C NMR
CDCl3):
d
¼184.1 (C3), 152.8 (C7), 139.2 (C11a), 135.4 (C10), 129.5
(C8), 122.7 (C9), 115.3 (C12a), 113.9 (C7a), 112.6 (C11), 93.7 (C2a),
46.7 (C5), 40.6 (C1), 34.4 (C2), 22.5 (C4); IR (KBr): nmax¼2922 (m),
2361 (m), 1685 (s) (C]O), 1602 (s), 1561 (m), 1523 (m), 1183 (m)
(C–O), 762 (s) (Ar–H) cmꢁ1; LRMS (CIþ): m/z (%) 241.10 (100)
[MþH]þ, 240.09 (30) [M]þ; HRMS (ESþ): m/z calcd for C14H13N2O2
[MþH]þ: 241.0977; found: 241.0976.
(75.5 MHz, CDCl3):
d¼177.5 (C10), 160.1 (C16), 149.6 (C5a), 142.0
(C4a), 136.1 (C10a), 136.1 (C14a), 136.0 (C3), 130.7 (C14), 129.8 (C1),
126.1 (C13), 125.9 (C12), 122.4 (C11), 122.2 (C4), 114.9 (C16a), 112.4
(C2), 111.3 (C9a), 51.6 (C6), 25.4 (C7), 23.8 (C9), 22.8 (C8); IR (KBr):
nmax¼2935 (m), 1715 (s) (C]O), 1701 (m) (C]O), 1603 (s), 1560 (m),
1499 (m), 1313 (m), 1153 (m) (C–O) cmꢁ1; LRMS (CIþ): m/z (%)
317.13 (100) [MþH]þ; HRMS (CIþ): m/z calcd for C20H17N2O2
[MþH]þ: 317.1290; found: 317.1287.
4.3.36. 5(1,3,1) Methyl 2-(2-(2-oxoazepan-1-
yl)benzamido)benzoate
Using the PyBroP procedure the title compound was afforded
(0.81 g, 0.77 mmol, 77%) as a pale brown oil. 1H NMR (300 MHz,
CDCl3):
d
¼11.34 (s, 1H, NH), 8.78 (dd, 3J¼9.5 Hz, 4J¼1.0 Hz, 1H, C3-
4
4.3.33. 1(1,1,15) 8,13-Dioxo-6,7-dihydro-8H,13H-5,12-
diazathieno[3,2-e]aceanthrylene
H), 8.05 (dd, 3J¼8.0 Hz, J¼1.5 Hz, 1H, C60-H), 7.73 (dd, 3J¼8.0 Hz,
4J¼1.5 Hz, 1H, C6-H), 7.57 (ddd, 3J¼8.0 Hz, 3J¼7.5 Hz, 4J¼1.5 Hz, 1H,
C40-H), 7.51 (ddd, 3J¼9.5 Hz, 3J¼8.0 Hz, 4J¼1.5 Hz, 1H, C4-H), 7.39
(ddd, 3J¼8.0 Hz, 3J¼8.0 Hz, 4J¼1.5 Hz, 1H, C50-H), 7.25 (dd,
Methyl 2-[2-(2-oxo-pyrrolidin-1-yl)-benzoylamino]-thiophene-
3-carboxylate 5(1,1,15) (0.05 g, 0.15 mmol) was heated in a sealed
glass microwave tube to 190 ꢀC, (maximum 275 W) for 80 min. The
resultant yellow/brown solid was purified by flash column chro-
matography over silica gel (1:199, methanol/chloroform) to afford
the title compound 1(1,1,15) (0.030 g, 0.10 mmol, 68%) (LCMS purity
96%) as a pale yellow powder. Mp 316–317 ꢀC; 1H NMR (300 MHz,
3J¼8.0 Hz, J¼1.5 Hz, 1H, C30-H), 7.12 (ddd, 3J¼8.0 Hz, 3J¼7.5 Hz,
4
4J¼1.5 Hz, 1H, C5-H), 3.94–3.64 (m, 2H, NCH2CH2), 3.90 (s, 3H,
CO2CH3), 2.67–2.57 (m, 2H, CH2CH2CO), 2.04–1.63 (m, 6H,
CH2CH2CO, NCH2CH2CH2, NCH2CH2CH2); 13C NMR (75.5 MHz,
CDCl3):
d
¼176.1 (NCOCH2), 168.4 (CO2CH3), 166.5 (ArCONH),
CDCl3):
d
¼8.26 (dd, 3J¼8.0 Hz, 4J¼1.5 Hz, 1H, C1-H), 7.71 (ddd,
142.9 (C2), 141.6 (C20), 134.6 (C10), 134.5 (C4), 131.7 (C40), 130.9
(C6), 128.3 (C60), 128.1 (C50), 127.4 (C30), 122.9 (C5), 120.7 (C3), 115.9
(C1), 53.8 (NCH2CH2), 52.5 (CO2CH3), 37.6 (CH2CH2CO), 30.2
(NCH2CH2CH2), 28.4 (NCH2CH2), 23.2 (CH2CH2CO); IR (KBr):
nmax¼3426 (s) (NH), 2953 (m), 2849 (w), 1638 (s) (C]O), 1159 (m)
(C–O), 749 (m) (Ar–H) cmꢁ1; LRMS (ESþ): m/z (%) 389.22 (100)
[MþNa]þ; HRMS (ESþ): m/z calcd for C21H22N2O4Na [MþNa]þ:
389.1477; found: 389.1471. An analytical sample of 5(1,3,1) was
prepared by recrystallisation from ethyl acetate/hexanes. Anal.
Calcd for C21H22N2O4: C, 68.84; H, 6.05; N, 7.65. Found: C, 68.95;
H, 6.02; N, 7.60.
3J¼8.0 Hz, 3J¼8.0 Hz, 3J¼1.5 Hz,1H, C3-H), 7.60 (d, 3J¼6.0 Hz,1H, C9-
H), 7.25–7.19 (m, 2H, C2-H, C4-H), 6.97 (d, 3J¼6.0 Hz,1H, C10-H), 4.36
(t, 3J¼8.5 Hz, 2H, C6-H2), 3.39 (t, 3J¼8.5 Hz, 2H, C7-H2); 13C NMR
(75.5 MHz, CDCl3):
d¼171.2 (C8), 161.8 (C13), 156.2 (C11a), 146.1
(C5a),139.5 (C4a),136.8 (C3),130.0 (C10),122.8 (C1),122.5 (C2),121.2
(C9), 120.0 (C8a), 112.6 (C4), 112.2 (C13a), 48.3 (C6), 23.9 (C7); IR
(KBr): nmax¼3423 (s) (OH), 1702 (s) (C]O), 1561 (s), 1528 (m), 1490
(m), 752 (m) (Ar–H) cmꢁ1; LRMS (ESþ): m/z (%) 295.05 (100)
[MþH]þ; HRMS (ESþ): m/z calcd for C16H11N2O2S [MþH]þ:
295.0541; found: 295.0533.

A.M. Jones et al. / Tetrahedron 65 (2009) 563–578
577
4
4.3.37. 5(1,4,1) Methyl 2-(2-(2-oxoazonan-1-yl)-
benzamido)benzoate
CDCl3):
d
¼7.53 (dd, 3J¼8.0 Hz, J¼1.5 Hz, 1H, C30-H), 7.46 (ddd,
3J¼8.0 Hz, 3J¼8.0 Hz, J¼1.5 Hz, 1H, C50-H), 7.34 (dd, 3J¼8.0 Hz,
4
4
Using the PyBroP procedure the title compound was afforded
4J¼1.5 Hz, 1H, C40-H), 7.20 (dd, 3J¼8.0 Hz, J¼1.5 Hz, 1H, C60-H),
(0.18 g, 0.46 mmol, 83%) as a pale brown oil. 1H NMR (300 MHz,
6.82 (s, 1H, NH), 4.16 (q, 3J¼7.0 Hz, 2H, CH3CH2O), 3.81 (t,
3J¼7.0 Hz, 2H, C5-H), 3.64 (dt, JCH¼JNH¼6.0 Hz, 2H, CH2NH), 2.60 (t,
3J¼6.0 Hz, 2H, C3-H), 2.53 (t, 3J¼8.0 Hz, 2H, CO2CH2), 2.25–2.15 (m
2H, C4-H), 1.25 (t, 3J¼7.0 Hz, 3H, CH3CH2O); 13C NMR (75.5 MHz,
CDCl3):
d
¼11.31 (s, 1H, NH), 8.75 (dd, 3J¼8.0 Hz, 4J¼1.5 Hz, 1H, C3-
H), 8.02 (dd, 3J¼8.0 Hz, 4J¼1.5 Hz, 1H, C6-H), 7.73 (dd, 3J¼7.5 Hz,
4J¼1.5 Hz, 1H, C60-H), 7.55 (ddd, 3J¼8.0 Hz, 3J¼8.0 Hz, 4J¼1.5 Hz, 1H,
C4-H), 7.49 (dd, 3J¼7.5 Hz, 4J¼1.5 Hz, 1H, C40-H), 7.40 (ddd,
CDCl3):
d
¼175.9 (C2), 172.2 (CO2Et), 168.0 (NHCO), 136.1 (C10or
3J¼7.5 Hz, 3J¼7.5 Hz, J¼1.5 Hz, 1H, C50-H), 7.31 (dd, 3J¼7.5 Hz,
C20), 134.9 (C10 or C20), 131.1 (C50), 128.8 (C30), 127.9 (C40), 127.2
(C60), 60.8 (CH3CH2O), 51.8 (C5), 35.5 (CH2NH), 34.0 (C3), 31.5
(CO2CH2), 18.9 (C4), 14.2 (CH3CH2O); IR (Nujol): nmax¼3341 (m)
(OH), 2932 (m) (CH), 1732 (s) (C]O), 1601 (w), 1535 (w), 1490 (w),
1451 (w), 1409 (w), 1307 (m), 1188 (m) (C–O), 1073 (w), 1025 (w),
764 (m) (Ar–H) cmꢁ1; LRMS (ESþ): m/z (%) 327.04 (100) [MþNa]þ;
HRMS (ESþ): m/z calcd for C16H20N2O4Na [MþNa]þ: 327.1321;
found: 327.1314.
4
4J¼1.5 Hz, 1H, C30-H), 7.10 (ddd, 3J¼8.0 Hz, 3J¼8.0 Hz, 4J¼1.5 Hz, 1H,
C5-H), 4.15–3.53 (m, 2H, C900-H2), 3.88 (s, 3H, CO2CH3), 2.83–2.37
(m, 2H, C300-H2), 1.91–1.54 (m, 10H, C400-H2, C800-H2, C700-H2, C600-H2,
C500-H2); 13C NMR (75.5 MHz, CDCl3):
d
¼176.2 (NCOCH2), 168.3
(CO2CH3), 166.4 (ArCONH), 141.3 (C2), 141.2 (C20), 134.6 (C10), 134.5
(C4), 131.4 (C40), 131.0 (C6), 129.8 (C30), 128.8 (C60), 127.9 (C50), 123.0
(C5), 120.7 (C3), 116.0 (C1), 53.2 (C900), 52.5 (CO2CH3), 34.2 (C300),
28.2 (C500), 27.6 (C600), 25.3 (C700), 24.7 (C400), 23.1 (C800); IR (KBr):
nmax¼3296 (m) (NH), 2929 (s) (CH), 1679 (s) (C]O), 1606 (m), 1588
(m), 1450 (m), 1270 (m), 1093 (m) (C–O) cmꢁ1; LRMS (ESþ): m/z (%)
417.08 (100) [MþNa]þ, 811.17 (100) [2MþNa]þ; HRMS (ESþ): m/z
calcd for C23H26N2O4Na [MþNa]þ: 417.1790; found: 417.1784. An
analytical sample of 5(1,4,1) was prepared by recrystallisation from
ethyl acetate/hexanes. Anal. Calcd for C23H26N2O4: C, 70.03; H, 6.64;
N, 7.10. Found: C, 69.97; H, 6.73; N, 7.03.
4.3.41. 5(1,1,10) Methyl 5-bromo-2-[2-(2-oxo-pyrrolidin-1-yl)-
benzoylamino]-benzoate
Using the PyBroP procedure the title compound was afforded
(0.156 g, 0.37 mmol, 37%) as a pale brown solid. Mp 187–188 ꢀC; 1H
NMR (300 MHz, CDCl3):
d
¼11.38 (s, 1H, NH), 8.74 (d, 3J¼9.0 Hz, 1H,
C3-H), 8.17 (d, 4J¼2.5 Hz, 1H, C6-H), 7.77 (dd, 1H, 3J¼8.0 Hz,
4J¼1.5 Hz, C60-H), 7.66 (dd, 3J¼9.0 Hz, 4J¼2.5 Hz, 1H, C4-H), 7.54
(ddd, 3J¼8.0 Hz, 3J¼8.0 Hz, 4J¼1.5 Hz, 1H, C40-H), 7.40 (ddd,
3J¼8.0 Hz, 3J¼8.0 Hz, 4J¼1.5 Hz, 1H, C50-H), 7.34–7.29 (m, 1H, C30-H),
3.94 (t, 3J¼7.0 Hz, 2H, CH2N), 3.92 (s, 3H, CO2CH3), 2.49 (t, 3J¼8.5 Hz,
2H, CH2CO), 2.25–2.13 (m, 2H, CH2CH2CH2); 13C NMR (75.5 MHz,
4.3.38. 5(1,1,15) Methyl 2-[2-(2-oxo-pyrrolidin-1-yl)-
benzoylamino]-thiophene-3-carboxylate
Using the PyBroP procedure the title compound was afforded
(0.14 g, 0.41 mmol, 41%) as a pale brown oil. 1H NMR (300 MHz,
CDCl3):
d
¼175.1 (NCOCH2), 167.4 (CO2CH3), 166.3 (ArCONH), 140.7
CDCl3):
d
¼11.45 (s, 1H, NH), 7.78 (dd, 3J¼8.0 Hz, 4J¼1.5 Hz, 1H, C60-
(C2), 137.3 (C4), 136.9 (C20), 133.5 (C10), 133.4 (C6), 131.6 (C40), 128.4
(C60), 127.3 (C50), 126.4 (C30), 122.3 (C3), 117.0 (C5), 115.1 (C1), 52.7
(CO2CH3), 51.0 (NCH2CH2), 31.6 (CH2CH2CO), 18.8 (CH2CH2CH2); IR
(KBr): nmax¼3417 (s) (NH), 2959 (m) (CH2) 1700 (s) (C]O), 1680 (s)
(C]O), 1670 (s) (C]O), 1600 (m), 1576 (m), 1507 (s), 1439 (m), 1394
(m), 1310 (m), 1239 (m), 1120 (w) (C–O), 963 (w), 842 (s) (C–
Br) cmꢁ1; LRMS (ESþ): m/z (%) 439.11 (100) [M79BrþNa]þ, 441.11
(80) [M81BrþNa]þ; HRMS (ESþ): m/z calcd for C19H17N2O4Na79Br
[M79BrþNa]þ: 439.0269; found: 439.0283.
H), 7.50 (ddd, 3J¼7.5 Hz, 3J¼7.5 Hz, J¼1.5 Hz, 1H, C40-H), 7.36–7.30
(m, 2H, C30-H, C50-H), 7.15 (d, 3J¼6.0 Hz, 1H, C4-H), 6.70 (dd,
3J¼6.0 Hz, 4J¼1.0 Hz, 1H, C5-H), 3.85 (t, 3J¼7.0 Hz, 2H, CH2N), 3.80
(s, 3H, CO2CH3), 2.45 (t, 3J¼8.0 Hz, 2H, CH2CO), 2.19–2.10 (m, 2H,
4
CH2CH2CH2); 13C NMR (75.5 MHz, CDCl3):
d¼176.0 (NCOCH2), 166.3
(CO2CH3), 164.4 (ArCONH), 149.3 (C2), 137.7 (C20), 132.8 (C40), 131.2
(C10), 129.8 (C60), 127.9 (C4), 126.9 (C50), 124.3 (C30), 116.7 (C5), 113.5
(C3), 52.5 (CO2CH3), 51.4 (NCH2), 31.9 (CH2CO), 19.0 (CH2CH2CH2);
IR (KBr): nmax¼2928 (m) (CH2), 1635 (s) (C]O), 1535 (m), 1489 (w),
1303 (m), 1224 (m), 843 (w), 749 (m) cmꢁ1; LRMS (ESþ): m/z (%)
367.04 (100) [MþNa]þ; HRMS (ESþ): m/z calcd for C17H16N2O4NaS
[MþNa]þ: 367.0728; found: 367.0737.
4.4. Computational methods
Semi-empirical electronic structure calculations were carried
out using the RM1 method20 as implemented in MOPAC200721
(Version 8.148L) running on a Linux cluster. DFT calculations
were carried out using GAMESS22 running on a Linux cluster.
The 64-bit Linux version dated 11 Apr 2008 (Revision 1) was
used in all calculations. The transition states were located by
generation of an initial guess using the results of the RM1 cal-
culations. This model transition state was refined at the B3LYP/6-
31G(d,p) level of theory to a transition state structure possessing
single imaginary vibration that corresponded to the racemisation
coordinate.
4.3.39. 5(1,2,16) Methyl 3-(2-(2-oxopiperidin-1-
yl)benzamido)thiophene-2-carboxylate
Using the PyBroP procedure the title compound was afforded
(0.23 g, 0.68 mmol, 68%) as a pale brown oil. 1H NMR (300 MHz,
CDCl3):
d
¼10.54 (br s, 1H, NH), 8.22 (d, 3J¼5.4 Hz, 1H, C5-H), 7.73
(dd, 3J¼7.5 Hz, 4J¼1.5 Hz, 1H, C60-H), 7.54 (ddd, 3J¼7.5 Hz, 3J¼7.5 Hz,
4J¼1.5 Hz, 1H, C40-H), 7.48 (d, 3J¼5.4 Hz, 1H, C4-H), 7.40 (ddd,
3J¼7.5 Hz, 3J¼7.5 Hz, J¼1.5 Hz, 1H, C50-H), 7.27 (dd, 3J¼7.5 Hz,
4
4J¼1.5 Hz,1H, C30-H), 3.86 (s, 3H, CO2CH3), 3.75–3.65 (m, 2H, NCH2),
2.50–2.43 (m, 2H, COCH2), 1.98–1.85 (m, 4H, NCH2CH2, COCH2CH2);
13C NMR (75.5 MHz, CDCl3):
d¼170.8 (NCOCH2), 164.8 (CO2CH3),
164.6 (ArCONH), 144.6 (C3), 141.8 (C20), 132.2 (C4), 131.6 (C40), 128.8
(C30), 128.5 (C60), 128.4 (C50), 128.3 (C10), 122.6 (C5), 111.1 (C2), 52.3
(NCH2), 52.2 (CO2CH3), 32.7 (CH2CO), 23.4 (COCH2), 21.4
(NCH2CH2); IR (KBr): nmax¼3418 (s) (NH), 2954 (m), 2844 (w), 1648
(s) (C]O), 1451 (w), 1110 (m) (C–O), 1017 (w), 856 (m) cmꢁ1; LRMS
(ESþ): m/z (%) 381.06 (100) [MþNa]þ; HRMS (ESþ): m/z calcd for
C18H18N2O4NaS [MþNa]þ: 381.0885; found: 381.0885.
Acknowledgements
We would like to thank The Royal Society (University Re-
search Fellowships to N.J.W. and T.v.M.), the BBSRC (A.M.J.), the
Wellcome Trust (S.P.) and The University of St Andrews for
funding. We would also like to thank Dr. Grace Vanier (CEM
Labs, NC, USA) for photographic analysis of the microwave re-
actions. Mrs. M. H. Smith, Dr. C. Botting and Mrs. C. E. R. Hors-
burgh are kindly acknowledged for performing and assisting
with NMR and MS analyses. We acknowledge EaStCHEM for
computational support via the EaStCHEM Research Computing
Facility (http://www.eastchem.ac.uk/rcf).
4.3.40. 5(1,1,17) Ethyl 3-[2-(2-oxo-pyrrolidin-1-yl)-benzoylamino]-
propionate
Using the PyBroP procedure the title compound was afforded
(0.208 g, 0.68 mmol, 68%) as a pale brown oil. 1H NMR (300 MHz,

578
A.M. Jones et al. / Tetrahedron 65 (2009) 563–578
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Additional compound characterisation, LCMS data and a table of
microwave optimisation reactions are provided. In addition, details
of the methods used to calculation activation parameters and im-
ages from microwave reactions are included. Supplementary data
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