Synthesis of riboflavines, quinoxalinones and benzodiazepines through chemoselective flow based hydrogenations

Article abstract of DOI:10.3390/molecules19079736

Robust chemical routes towards valuable bioactive entities such as riboflavines, quinoxalinones and benzodiazepines are described. These make use of modern flow hydrogenation protocols enabling the chemoselective reduction of nitro group containing building blocks in order to rapidly generate the desired amine intermediates in situ. In order to exploit the benefits of continuous processing the individual steps were transformed into a telescoped flow process delivering selected benzodiazepine products on scales of 50 mmol and 120 mmol respectively.

Full text of DOI:10.3390/molecules19079736

Molecules 2014, 19, 9736-9759; doi:10.3390/molecules19079736
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molecules
ISSN 1420–3049
www.mdpi.com/journal/molecules
Article
Synthesis of Riboflavines, Quinoxalinones and Benzodiazepines
through Chemoselective Flow Based Hydrogenations
Marcus Baumann 1,2, Ian R. Baxendale 1,2,*, Christian H. Hornung 2, Steven V. Ley 2,
Maria Victoria Rojo 2 and Kimberley A. Roper 2
1
Department of Chemistry, University of Durham, South Road, Durham DH1 3LE, UK
2
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
* Author to whom correspondence should be addressed; E-Mail: i.r.baxendale@durham.ac.uk;
Tel.: +44-191-334-2185.
Received: 4 June 2014; in revised form: 25 June 2014 / Accepted: 2 July 2014 /
Published: 8 July 2014
Abstract: Robust chemical routes towards valuable bioactive entities such as riboflavines,
quinoxalinones and benzodiazepines are described. These make use of modern flow
hydrogenation protocols enabling the chemoselective reduction of nitro group containing
building blocks in order to rapidly generate the desired amine intermediates in situ. In
order to exploit the benefits of continuous processing the individual steps were transformed
into a telescoped flow process delivering selected benzodiazepine products on scales of
50 mmol and 120 mmol respectively.
Keywords: flow chemistry; hydrogenation; riboflavine; benzodiazepine; micro reactor
1. Introduction
The quest to develop efficient and economic routes towards molecules with potential biomedical
applications continues to be one of the most challenging tasks of modern synthetic organic chemistry [1–3].
As such medicinal chemistry programs commonly seek to identify valuable heterocyclic core
structures that can subsequently be diversified delivering libraries of new compounds for high
throughput screenings. While the most recent drug candidates entering clinical trials are likely to be
based on new scaffolds it might be surprising to learn that at least two thirds of today’s top-market
drugs are based on venerable classical heterocyclic cores clearly indicating the value of such privileged
structures [4–6].

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Even though the search for new promising lead compounds continues to be a constant within
pharmaceutical and agrochemical research environments, the last 15 years have witnessed a true step
change in how such structures are prepared and evaluated [7–9]. This includes the before-mentioned
high-throughput screening efforts in order to test compounds rapidly as well as the incorporation of
so-called enabling technologies such as microwave and flow reactors [10–16]. The latter have now
gained widespread acceptance in the field as they typically offer improvements in efficiency and safety
when accessing valuable chemicals on scales ranging from the initially required milligrams to
kilograms and indeed metric ton-scale production [17–21]. Importantly, both industry and academia
are driving research in these areas at an impressive rate aiming to improve the often low success rates
of current drug development programs [22–25].
Research in our team over the last decade has focused on the development of new
instrumentation [26–31] and methodologies [32–34] geared towards efficient and innovative flow
synthesis. One key area has been the assembly and elaboration of numerous heterocyclic scaffolds and
target molecules as required in medicinal chemistry programs [35–40]. For example, one of our recent
research programs was directed at the synthesis of diversely functionalized pyrrolidines achieved by
means of chemoselective hydrogenation of N-benzyl-protected 4-nitropyrrolidines which was
successfully performed using the H-Cube™ flow system [41–43]. This small foot-print flow
instrument conveniently and safely performs the electrolysis of water and mixes the in situ generated
hydrogen gas with the substrate stream. Subsequent passage of the resulting mixture through a heated
cartridge containing a heterogeneous catalyst allows for the rapid hydrogenation of various functional
groups with residence times typically ranging from 1–5 min. We now wish to disclose our continuation
of our earlier findings which further harnesses the many advantages of flow-based synthesis in
generating libraries of important bioactives such as riboflavines and benzodiazepins. Riboflavine
(vitamin B2) is the central component of the redox cofactors flavine adenine dinucleotide (FAD) and
flavine mononucleotide (FMN), and its analogues have been reported to display anti-inflammatory,
antihyperalgesic, anticancer and antimalarial activities [44–46]. The non-natural benzodiazepines on
the other hand constitute of a class of molecules possessing psychoactive activity acting on the
gamma-aminobutyric acid receptors (GABA receptors) [47–49]. Consequently, several of today’s
widely prescribed medications such as olanzapine, alprazolam, clonazepam and diazepam contain the
benzodiazepine pharmacophore highlighting its continued importance [50,51].
2. Results and Discussion
2.1. Synthesis of Riboflavins Derivatives
Most commonly, riboflavine analogues can be accessed by the direct condensation of
1,2-diaminobenzene derivatives 2 and alloxane (3) [52–57]. This transformation renders the tricyclic
riboflavines directly if performed in acidic conditions, whereas quinoxalinone derivatives are obtained
under neutral conditions. One major drawback of this strategy, however, lies in the limited commercial
availability and unstable nature of many 1,2-diaminobenzenes. We therefore elected to use the
H-Cube™ flow hydrogenation system in order to prepare the required 1,2-diaminobenzene substrates 2
in situ from low cost and easily sourced 2-nitroaniline starting materials 1.

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To this end stock solutions of various 2-nitroanilines in methanol/ethyl acetate (1:1 by volume,
0.1–0.25 M) were prepared and pumped into the H-Cube™ system where after mixing with the in situ
generated hydrogen gas the stream was directed into a pre-packed cartridge containing a heterogeneous
metal catalyst. Initial experiments established that the best results were obtained when using a
cartridge filled with palladium on carbon (10 wt %). Passing the solution of substrate through this
cartridge maintained at slightly elevated temperature (45 °C) delivered a colourless product
stream within a residence time of 4–6 min. While this colour change conveniently served as an
indication of the complete reduction of the typically yellow 2-nitroaniline starting materials, it was
observed that this solution would turn yellow then to brown upon standing, correlating to slow
re-oxidation/decomposition of these unstable intermediates. For this reason the 1,2-diaminobenzene
intermediates 2 were not isolated, but rather collected in a stirred vial containing alloxane (3)
(equimolar concentration 0.1–0.25 M) dissolved in methanol containing HCl (5 mol %, rt) to afford the
desired riboflavine adducts (4). It was found that the final cyclocondensation was best performed in
batch at ambient temperature allowing for the isolation of the precipitated products in good yields and
excellent purity (Scheme 1).
Scheme 1. Riboflavine analogues prepared.
a PtO2 used instead of Pd/C. b from 3,5-dibromo-1-nitro-2-aminobenzene. * single regioisomer.
During our study we found that using a Pd/C catalyst cartridge reliably reduced the 2-nitroaniline
inputs, however, in case of substrates containing sensitive chloro- or bromo-substituents concomitant
dehalogenation was observed. However, this could be avoided by substituting the Pd/C catalyst for
PtO2 allowing access to the riboflavine analogues functionalized by chloro and bromo groups which
are valuable materials for further elaboration using transition metal coupling chemistries.
In addition to this series of riboflavines we also decided to study the synthesis of the related
quinoxalinone structures 13 which are obtained when treating the in situ generated
1,2-diaminobenzenes with alloxane under neutral conditions. The desired structures were again
isolated in good to excellent yields using the H-Cube™ in combination with Pd/C or PtO2 as catalysts
in the first step (Scheme 2). These materials were extremely polar adducts which were difficult to

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isolate using standard chromatographic methods, however, a slight modification of the reaction solvent
system (3:1 EtOAc/MeOH) furnished the desired products in high isolated yield.
As expected, regioisomeric products were obtained in both series when non-symmetrical starting
materials were used. The ratio of the regioisomers was strongly dependent upon the specific
substitution pattern mainly arising from electronic differentiation of the 1,2-dinitrogen functionality
biasing the initial nucleophilic attack on the alloxane (3). As these mixtures could not be separated by
column chromatography the combined yield and the corresponding ratio is reported for each pairing.
Taking an isolated mixture of compound (13) and subjecting it to the acidic conditions used to form
the equivalent cyclised structure (4) gave a very slow transformation to the desired material (6 days,
45% conversion). Heating the reaction mixture aided solubility and increased the rate of the
transformation as did adding polar solvents such as DMSO and DMF. In each case the resulting
regioisomeric ratio was directly translated from the starting material (13) into the regioisomeric
composition of compound (4).
Scheme 2. Quinoxalinone analogues prepared.
a PtO2 used instead of Pd/C. b from 3,5-dibromo-1-nitro-2-aminobenzene. * from regioisomeric substrates.
2.2. Synthesis of Dibenzodiazepine Structures
Despite the significant pharmacological potential of various dibenzodiazepine scaffolds very little
progress has been made towards developing improved synthetic procedures since the pioneering
studies of Schmutz et al. in the early 1960s [58–60]. In part this might be due to the now well-known
side-effects such as long-term tolerance and dependence symptoms of the related benzodiazepine
structures [61,62]. However, given the growing demand for medications treating neurological
disorders one can expect a renewed interest into these structures, especially if compounds with more

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desirable long-term profiles can be identified. Furthermore, recent reports have started to reveal the
binding mode of benzodiazepines within the GABAA receptor and have consequently stimulated the
synthesis and testing of new analogues [63]. Crucial for further advancement will be the availability of
robust and efficient methodology delivering new sets of analogues based on this classical scaffold. For
this reason we decided to establish a concise route combining a SNAr reaction to first build a
nitrodiarylamine intermediate 25, which upon reduction of the pendant nitro group would furnish an
amine, which subsequently undergoes a cyclodehydration reaction affording the desired dibenzodiazepine
scaffold (Scheme 3). This process is particular desirable with respect to its atom- and step-economy.
Scheme 3. Synthetic route for the synthesis of dibenzodiazepines.
We initiated our studies by subjecting several 2-aminobenzophenones 24 to SNAr reactions with
2-fluoronitroarenes 23 in the presence of LiHMDS as a base. It was discovered that microwave heating
effectively and conveniently generated the desired products 25 in high yields within short reaction
times. Following aqueous work-up these diarylamine intermediates were redissolved in acetonitrile or
a mixture of CH2Cl2/MeOH (depending on solubility) and passed through an H-Cube™ flow system
operated at slightly elevated temperature (60 °C) in order to accomplish full conversion within ~5 min
residence time. Based on the previously observed benefits of using PtO2 instead of Pd/C as catalyst
within the flow cartridges we decided to use this catalyst throughout this study. Anhydrous MgSO4
was placed in-line using a packed glass Omnifit column to assist in the final cyclodehydration process.
The desired dibenzodiazepines were typically isolated in high yield following solvent evaporation and
chromatographic purification (Table 1).
However, the initial batch microwave SNAr reaction significantly restricted our ability to easily
scale up the sequence. This was particularly frustrating as the subsequent flow hydrogenation process
was an essentially quantitative transformation completed in a short residence time. Consequently, we
wished to establish a more direct and streamlined delivery of material from the SNAr step to create a
fully integrated multi-step process.

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Table 1. Dibenzodiazepine derivatives prepared.
Entry
Dibenzodiazepine
Product
Step 1:
Step 2:
Solvent
Yield
Time/min
60 a,b
MeCN
65%
1
2
30
MeCN
66%
72%
30
CH2Cl2/MeOH
(3:1)
3
30
30 a
30
MeCN
MeCN
MeCN
59%
70%
67%
58%
4
5
6
30 a
CH2Cl2/MeOH
(3:1)
7
8
9
60
MeCN
43%
51%
150
CH2Cl2/MeOH
(3:1)
90
CH2Cl2/MeOH
(5:1)
37%
48%
10
11
90 a
CH2Cl2/MeOH
(3:1)
a 2 equiv. of nitrobenzene used. b KHMDS in toluene was used.
From initial base screening we had also identified that KOtBu and n-BuLi were effective for the
SNAr transformation. Therefore, in order to create a potentially continuous process we elected to use
stock solutions comprising of 1.6 M n-BuLi in hexanes (channel A, Scheme 4) and 0.3 and 0.25 M
solutions of 2-fluoronitroarene (23; channel C) and 2-aminobenzophenone (24; channel B) respectively
in 3-methyltetrahydrofuran (3-MeTHF). A simple flow reactor was assembled using two low volume
PTFE pre-cooling loops (1 mL, cooled to 0 °C - channels A and B) linked by a T-mixer to a short tube
reactor (0.10 mL, rt) in which the rapid deprotonation occurs. A second T-mixer successively unites
the third flow stream containing the electrophile (channel C) before the reaction enters a 52 mL heated

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reactor coil (115 °C) to promote the substitution step. Optimised flow rates of 0.1 mL/min-channel A,
0.5 mL/min-channel B and 0.5 mL/min-channel C, gives corresponding residence times of 10 s and
47.3 min in the two reactor zones. The downstream work-up and purification was performed by the
introduction of an aqueous solution of NaHCO3 (1 M, 2.5 mL/min) mixed within a 2.5 mL Uniqsis
mixer chip and directed into a 10 mL PTFE coil reactor where the mixture developed into plug flow.
The resultant biphasic feed was collected into a continuous separation tank (70 mL Biotage Universal
Phase Separator-Cat No. 120-1930-V). The aqueous phase was constantly removed using a positioned
side arm run off to maintain a fixed liquid volume (~45 mL). The separated organic layer was dried by
passage through an exchangeable column of oven dried alumina (120 g) then diluted (1:1) with a
MeOH make-up stream prior to entering the H-cube MIDI™ hydrogenator (5 bar, 45 °C, 2.2 mL/min,
116 mm × 9.2 mm, PtO2). The reaction step within the H-cube™ was started with a delay of 90 min
relative to the first reactor; a buffering reservoir was placed between the two stages to compensate for
the volume. Solvent evaporation of the processed solutions allowed isolation of the crude materials
(entry 3 and 8 above; 27c = 50 mmol scale, crude 13.7 g, ~83% purity: 27h = 120 mmol scale, crude
38.1 g, ~69% purity) in comparable purities and isolated yields (27c 68% and 27h 51%) to the original
two-step process. Isolation was achieved by loading the crude material onto samplet cartridges (10 g)
followed by chromatography using a Biotage SP4 instrument.
Scheme 4. Continuous flow synthesis of dibenzodiazepines.
A particularly notable feature of these dibenzodiazepine structures is the prevalence of different
tautomers A and B that form in a pH-dependent manner (Scheme 5). Based on our observations we
conclude that tautomer A is the predominant species formed during the cyclodehydration event, which
interconverts into tautomer B upon exposure to acidic media such as the silica gel used in the
purification. In order to prove this assumption, mixtures of both tautomers were dissolved in formic
acid (0.15 M, in MeOH/EtOAc, 1:1) leading over the course of 30 min to full conversion into tautomer B
as evidenced by the results of several single crystal X-ray diffraction experiments. Moreover, these
X-ray structures reveal the distinct non-planar shape of these molecules due to the steric impact of the
attached aryl substituent resulting in an unusual three-dimensional orientation of these
dibenzodiazepine derivatives.

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Scheme 5. Tautomer interconversion and X-ray crystal structures of compounds 27b, 27d
and 27e (nitrogen: blue; chlorine: green).
3. Experimental
Full experimental details and spectroscopic characterization data is given is the proceeding section:
3.1. General Information
Unless otherwise specified, reagents were obtained from commercial sources and used without
further purification. Solvents were obtained from Fisher Scientific and distilled before use.
1H-NMR spectra were recorded on a Bruker Avance DPX-400, DPX-500, or DPX-600 spectrometer
with the residual solvent peak as the internal reference (CDCl3 = 7.26 ppm, d6-DMSO = 2.50 ppm).
13C-NMR spectra were recorded on the same spectrometers with the central resonance of the solvent
peak as the internal reference (CDCl3 = 77.16 ppm, d6-DMSO = 39.52 ppm). DEPT135, COSY and
HMQC experiments were used to aid structural determination and spectral assignment.
IR spectra were recorded neat on a PerkinElmer Spectrum One FTIR spectrometer with Universal
ATR sampling accessories. Letters in parentheses refer to the relative absorbance of the peak: w = weak
(<40% of the most intense peak), m = medium (40%–70% of the most intense peak), s = strong (>70% of
the most intense peak).
High resolution mass spectra (HRMS) were recorded on a Waters Micromass LCT Premier Q-TOF
spectrometer by electrospray ionisation (ESI) or an ABI/MDS Sciex Q-STAR Pulsar. The mass
reported is containing the most abundant isotopes. Limit: ±5 ppm. LC-MS analysis was performed on
an Agilent HP 1100 series chromatograph (Mercury Luna 3μ C18 (2) column) attached to a Waters
ZQ2000 mass spectrometer with ESCi ionisation source in ESI mode.
3.2. General Procedure for the Hydrogenation Reactions in Flow Using the H-Cube®
A solution of the nitroaniline (1 mmol, 0.1–0.25 M, MeOH/EtOAc, 1:1) was passed through the
H-Cube®, which was equipped with a cartridge filled with the corresponding Pd/C or PtO2/C catalyst.
Extra back pressure regulators were added to the H-Cube® set-up, with a pressure of 100 psi (6.9 bar)
being applied before the solution entered the H-Cube® and a pressure of 250 psi (17.2 bar) applied to
the exiting solution. The nitroanilines were pumped at different temperatures and flow rates depending

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on the substrate using full H2 mode. The exiting solutions were concentrated to determine the reaction
1
conversion by H-NMR analysis and used subsequently due to the instability of the diamines. The
catalyst cartridge was exchanged approximately every 8 runs.
3.3. General Procedure for the Formation of the Riboflavine Analogues 5–12
The diamines generated by the hydrogenation process in flow were mixed with alloxane monohydrate
(0.160 g, 1 mmol) and hydrogen chloride in methanol (1 mL of approx. 1.25 M concentration) and left to
stir at room temperature overnight. The product was then filtered and the solid product was dried in vacuo.
7,8-Dimethylbenzo[g]pteridine-2,4(3H,10H)-dione (5). Prepared from 4,5-dimethyl-2-nitroaniline
1
(0.166 g, 1 mmol) to give a yellow solid (0.147 g, 61% yield). H-NMR (500 MHz, d6-DMSO):
δ/ppm = 11.82 (1H, d, J = 1.8 Hz, NH), 11.65 (1H, s, NH), 7.90 (s, 1H), 7.69 (s, 1H), 3.15 (s, 6H, 2 ×
CH3); 13C-NMR (125 MHz, d6-DMSO): δ/ppm = 160.7 (C), 150.1 (C), 146.5 (C), 144.7 (C), 141.7 (C),
139.0 (C), 138.4 (C), 130.3 (C), 128.8 (CH), 125.9 (CH), 55.0 (CH3), 48.6 (CH3). IR (neat) /cm−1 =
3445.6 (w), 3187.7 (w), 3145.6 (w), 3073.2 (w), 2985.0 (w), 2951.7 (w), 2848.1 (w), 1734.3 (m),
1693.0 (s), 1629.8 (w), 1587.9 (m), 1578.0 (m), 1486.7 (w), 1441.5 (w), 1423.8 (w), 1386.7 (w),
1363.8 (m), 1349.3 (m), 1285.7 (s), 1221.3 (w), 1192.6 (w), 1143.9 (w), 1097.6 (w), 1035.0 (m),
1023.5 (w), 1001.9 (w), 911.5 (w), 882.9 (m), 816.2 (m), 797.9 (w), 770.5 (w), 754.5 (m), 736.2 (w),
683.9 (w), 661.9 (w). LC-MS: Rt = 4.57 min; HRMS (ESI): m/z calculated for C12H9N4O2 [M+H+]:
213.0731; found 241.0732.
Benzo[g]pteridine-2,4(3H,10H)-dione (6). Prepared from 2-nitroaniline (0.138 g, 1 mmol) to give a pale
1
green solid (0.131 g, 61% yield). H-NMR (500 MHz, d6-DMSO): δ/ppm = 11.94 (d, J = 1.6 Hz, 1H,
NH), 11.75 (s, 1H, NH), 8.16 (d, J = 8.2 Hz, 1H), 7.92 (m, 2H, 2 and 3), 7.77 (m, 1H); 13C-NMR
(125 MHz, d6-DMSO): δ/ppm = 160.5 (C), 150.2 (C), 146.9 (C), 142.7 (C), 139.3 (C), 133.4 (CH),
131.8 (C), 130.2 (CH), 128.5 (CH), 127.0 (CH). IR (neat) /cm−1: 3173.4 (w, br), 3084.4 (w, br),
28.43.1 (w, br), 1813.8 (w), 1786.4 (w), 1733.6 (m), 1687.9 (s), 1618.5 (w), 1582.9 (m), 1505.4 (w),
1485.5 (w), 1447.4 (m), 1390.4 (m), 1364.0 (m), 1334.4 (m), 1316.1 (m), 1271.4 (s), 1248.8 (m),
1212.6 (s), 1153.6 (w), 1144.9 (w), 1034.9 (w), 1015.0 (w), 989.7 (w), 915.6 (w), 866.9 (w), 811.8
(w), 763.6 (s, br), 705.1 (m), 677.8 (m). LC-MS: Rt 1.82 min; HRMS (ESI): m/z calculated for
C10H5N4O2 [M+H+]: 213.0418; found 213.0411.
7-Methylbenzo[g]pteridine-2,4(3H,10H)-dione and 8-methylbenzo[g]pteridine-2,4(3H,10H)-dione (7).
Prepared from 4-methyl-2-nitroaniline (0.152 g, 1 mmol) to give a yellow solid, with two regioisomers
1
found in a 4:3 ratio (0.212 g, 96% yield). H-NMR gave broad peaks and not all quaternary centres
13
were observed in the C-NMR. 1H-NMR (500 MHz, d6-DMSO): δ/ppm = 12.99 (s, 1H, NH), 11.15 (s,
1H, NH), 7.68 (d, br, J = 18 Hz, 2H), 7.51 (d, J = 9 Hz, 1H), 7.27 (dd, J = 6.5 Hz, 20.3 Hz, 2H), 7.15
1
(s, 1H), 2.50 (m, 3H), 2.49 (m, 3H). To separate broad peaks: H-NMR (400 MHz, d6-DMSO + 3
drops TFA): δ/ppm = 8.03 (1H from major regioisomer, d, J = 8.5 Hz, H3), 7.96 (1H from minor
regioisomer, s, H1), 7.71 (1H from minor regioisomer, dd, J = 8.4 Hz, 1.9 Hz, H2), 7.48 (1H from
major regioisomer, dd, J = 8.9 Hz, 1.3 Hz, H2), 7.41 (1H from minor regioisomer, d, J = 8.4 Hz, H3),
7.27 (1H from major regioisomer, s, H1) 2.62 (3H from major regioisomer, s, CH3), 2.56 (3H from

Molecules 2014, 19
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13
minor regioisomer, s, CH3); C-NMR (125 MHz, d6-DMSO): δ/ppm = 163.7 (C), 154.5 (C), 153.2
(C), 143.7 (C), 134.1 (CH), 132.7 (C), 131.4 (C), 130.5 (C), 129.8 (CH), 129.5 (CH), 129.0 (C), 125.9
(CH), 115.5 (CH), 115.3 (CH), 21.6 (CH3), 20.4 (CH3). IR (neat) /cm−1: 3395.5 (w), 3134.2 (w, br),
1724.7 (s), 1693.2 (s), 1656.2 (m), 1626.1 (m), 1583.3 (m), 1533.1 (w), 1509.2 (m), 1465.3 (w),
1371.3 (s), 1290.6 (w), 1278.8 (w), 1248.7 (w), 1199.4 (w), 1185.1 (w), 1146.0 (w), 1116.6 (w),
1025.9 (w), 961.8 (w), 914.6 (w), 883.2 (w), 860.5 (w), 825.8 (s), 810.3 (s), 758.4 (w), 719.8 (w),
697.7 (w), 681.6 (w). LC-MS: Rt 3.49 min; HRMS (ESI): m/z calculated for C11H9N4O3 [M+H+]:
227.0574; found 227.0571.
7-Methylbenzo[g]pteridine-2,4(3H,10H)-dione and 8-methyl-benzo[g]pteridine-2,4(3H,10H)-dione
(7). Prepared from 5-methyl-2-nitroaniline (0.152 g, 1 mmol) to give a yellow solid, with two
1
regioisomers found in a 4:3 ratio (0.140 g, 61% yield). This was indicated by H-NMR to be identical
to tne above compounds 7.
7-Methoxybenzo[g]pteridine-2,4(3H,10H)-dione and 8-methoxybenzo[g]pteridine-2,4(3H,10H)-dione (8).
Prepared from 4-methoxy-2-nitroaniline (0.206 g, 1 mmol) to give an orange solid, with two
regioisomers found in a 3:2 ratio (0.1043 g, 43% yield). 1H-NMR (500 MHz, d6-DMSO): δ/ppm = 11.86
(1H from minor regioisomer, d, J = 1.7 Hz, NH), 11.82 (1H from major regioisomer, d, J = 1.7 Hz,
NH), 11.69 (1H from major regioisomer, s, NH), 11.66 (1H from minor regioisomer, s, NH), 8.02 (1H
from minor regioisomer, d, J = 9.2 Hz, H3), 7.83 (1H from major isomer, d, J = 9.2 Hz, H3), 7.59 (1H
from major regioisomer, dd, J = 9.2 Hz, 2.7 Hz, H2), 7.54 (1H from major regioisomer, d, J = 2.8 Hz,
H1), 7.40 (1H from minor regioisomer, dd, J = 9.3 Hz, 2.3 Hz, H2), 7.22 (1H from minor regioisomer,
d, J = 2.7 Hz, H1), 3.97 (3H from minor regioisomer, s, CH3), 3.80 (3H from major regioisomer, s,
13
CH3); C-NMR (125 MHz, d6-DMSO): δ/ppm = 163.25 (C), 160.7 (C), 160.6 (C), 159.1 (C), 150.3
(C), 150.1 (C), 147.2 (C), 145.5 (C), 145.1 (C), 145.1 (C), 140.8 (C), 138.8 (C), 135.6 (C), 131.5 (CH),
130.9 (C), 128.4 (C), 128.0 (CH), 126.9 (CH), 107.5 (CH), 104.9 (CH), 56.3 (CH3), 56.0 (CH3). IR
(neat) /cm−1: 3258.9 (w), 3071.0 (w, br), 2851.2 (w), 1726.3 (m), 1694.1 (s), 1621.3 (w), 1556.8 (m),
1509.3 (w), 1458.9 (w), 1439.0 (m), 1399.2 (w), 1354.6 (s), 1340.8 (m), 1330.1(m), 1314.0 (w),
1233.5 (m), 1212.9 (s), 1158.8 (w), 1142.7 (w), 1120.4 (w), 1008.4 (m), 960.0 (w), 877.6 (w), 850.7
(m), 794.2 (m), 763.1 (m), 749.2 (m), 704.8 (w), 659.4 (w). LC-MS: Rt 3.42 min; HRMS (ESI): m/z
calculated for C11H7N4O3 [M+H+]: 243.0524; found 243.0527.
7-Fluorobenzo[g]pteridine-2,4(3H,10H)-dione and 8-Fluorobenzo[g]pteridine-2,4(3H,10H)-dione (9).
Prepared from 4-fluoro-2-nitroaniline (0.106 g, 1 mmol) to give a green solid with two regioisomers
1
found in a 5:3 ratio (0.1678 g, 73% yield). H-NMR (500 MHz, d6-DMSO): δ/ppm = 12.04 (1H from
minor regioisomer, d, J = 1.8 Hz, NH), 11.98 (1H from major regioisomer, d, J = 1.8 Hz, NH), 11.81
(1H from each regioisomer, br s, 2 × NH), 8.27 (1H from minor regioisomer, dd, J = 9.2 Hz, 6.1 Hz,
H3), 8.02–7.99 (2H from major regioisomer, m, H1 and H2), 7.91–7.87 (1H from major regioisomer,
m, H3), 7.74–7.69 (2H from minor regioisomer, m, H1 and H2); 13C-NMR (125 MHz, d6-DMSO):
δ/ppm = 164.4 (C from minor regioisomer, d, J = 250.0 Hz, C-F), 164.4 (C from major regioisomer, d,
J = 37.5 Hz, C-F), 160.4 (C), 160.3 (C), 150.1 (C, major regioisomer), 150.0 (C, minor regioisomer),
147.5 (C), 146.7 (C, d, J = 2.1 Hz), 143.9 (C from minor regioisomer, d, J = 14.4 Hz), 140.0 (C from

Molecules 2014, 19
9746
major regioisomer), 139.5 (C from major regioisomer, d, J = 13.1 Hz), 136.6 (C), 133.0 (CH from
minor regioisomer, d, J = 11.2 Hz, C3), 132.5 (C from major regioisomer), 131.3 (C from minor
regioisomer, d, J = 3.0 Hz), 129.3 (CH from major regioisomer, d, J = 9.9 Hz, C3), 123.5 (CH from
major regioisomer, d, J = 18.5 Hz, C2), 118.8 (CH from minor regioisomer, d, J = 26.2 Hz, C2), 113.3
(CH from major regioisomer, d, J = 21.5 Hz, C1), 110.7 (CH from minor regioisomer, d, J = 22.0 Hz,
C1). IR (neat) /cm−1: 3182.7 (w), 3086.6 (w, br), 2845.9 (w), 1733.7 (m), 1691.9 (s), 1626.7 (m),
1583.9 (m), 1571.6 (m), 1510.4 (m), 1482.0 (w), 1455.3 (m), 1398.4 (w), 1354.5 (m), 1334.9 (s),
1298.6 (w), 1278.3 (s), 1243.1 (w), 1213.1 (s), 1157.4 (w), 1139.3 (w), 1108.9 (w), 1035.9 (w), 975.4
(w), 856.9 (s), 835.3 (s), 808.0 (m), 767.4 (m), 753.1 (s), 703.3 (w), 684.0 (w), 663.0 (m). LC-MS: Rt
2.85 min (mass peak of 233), another weaker peak seen at 3.45 min; HRMS (ESI): m/z calculated for
C10H4N4O2F, [M+H+]: 231.0324; found 231.0323.
7-(Trifluoromethyl)benzo[g]pteridine-2,4(3H,10H)-dione or 8-(trifluoromethyl)benzo[g]pteridine-
2,4(3H,10H)-dione (10). Prepared from 2-nitro-5-(trifluoromethyl)-aniline (0.206 g, 1 mmol) to give a
1
pale yellow solid, one regioisomer was cleanly isolated (0.059 g, 21% yield). H-NMR (500 MHz,
d6-DMSO): δ/ppm = 12.11 (br s, 1H, NH), 11.87 (br s, 1H, NH), 8.35 (d, J = 8.7 Hz, H3), 8.21 (d,
13
J = 0.6 Hz, H1), 7.98 (dd, J = 8.7 Hz, 2.0 Hz, H2); C-NMR (125 MHz, d6-DMSO): δ/ppm = 160.1
(C), 150.1 (C), 148.0 (C), 141.7 (C), 140.2 (C), 134.4 (C) 132.3 (C-CF3) 132.0 (CH), 124.7 (CH),
124.0 (CF3), 123.4 (CH). IR (neat) /cm−1: 3456.0 (w), 3054.8 (w, br), 2898.1 (w), 2825.2 (w), 1733.4
(w), 1689.9 (s), 1631.4 (w), 1584.7 (w), 1507.7 (w), 1489.4 (w), 1454.8 (w), 1394.7 (m), 1367.9 (w),
1336.9 (w), 1318.3 (m), 1290.0 (s), 1266.5 (m), 1257.6 (m), 1244.0 (m), 1205.2 (m), 1166.9 (s),
1158.8 (s), 1136.1 (s), 1111.1 (m), 1086.1 (w), 1031.0 (w), 997.5 (m), 941.0 (w), 908.4 (w) 900.3 (w),
859.9 (s), 823.3 (w) 804.2 (m), 774.2 (w), 755.8 (w), 710.3 (s), 678.7 (w), 655.8 (w). LC-MS: Rt 3.85 min;
HRMS (ESI): m/z calculated for C11H4F3N4O2 [M+H+]: 281.0292; found 281.0287.
8-Chlorobenzo[g]pteridine-2,4(3H,10H)-dione and 7-chloro-benzo[g]pteridine-2,4(3H,10H)-dione (11).
Prepared from 4-chloro-2-nitroaniline (0.172 g, 1 mmol) to give a pale yellow solid, with two
1
regioisomers found in a 5:1 ratio (0.121 g, 49% yield). H-NMR gave broad peaks. 1H-NMR (500 MHz,
d6-DMSO): δ/ppm = 13.09 (1H from major regioisomer, br s, NH), 12.61 (1H from minor regioisomer,
br s, NH), 10.98 (1H from major regioisomer, br s, NH), 8.25 (1H from minor regioisomer, s), 8.17
(1H from minor regioisomer, d, J = 9.0 Hz), 7.97–7.73 (4H, three from major regioisomer, one from
1
minor regioisomer, br m). To separate broad peaks: H-NMR (400 MHz, d6-DMSO + 3 drops TFA):
δ/ppm = 8.23 (1H from minor regioisomer, d, J = 1.5Hz, H1), 8.15 (1H from minor regioisomer, d,
J = 9.0 Hz, H3), 7.93 (1H from major regioisomer, dd, J = 9.0 Hz, 2.1 Hz, H2), 7.74 (1H from minor
regioisomer, dd, J = 9.0 Hz, 2.3 Hz, H2), 7.81 (1H from major regioisomer, m, H3), 6.70 (1H from major
13
regioisomer, m, H1); C-NMR (125 MHz, d6-DMSO): δ/ppm = 160.3 (C), 153.1 (C), 150.1 (C), 147.6
(C), 147.2 (C), 143.1 (C), 141.4 (C), 141.4 (C), 139.4 (C), 137.8 (C), 133.7 (CH), 132.8 (C), 132.3 (C),
132.0 (CH), 131.7 (C), 131.4 (C), 128.6 (CH), 125.7 (CH), 117.5 (CH), 115.1 (CH). IR (neat) /cm−1:
3149.8 (w), 3085.3 (w, br), 2852.0 (w), 1728.1 (m), 1693.9 (s), 1661.4 (m), 1610.7 (m), 1578.6 (m),
1534.2 (w), 1490.7 (m), 1457.6 (w), 1365.9 (m), 1354.6 (s), 1335.6 (m), 1292.9 (m), 1274.7 (m),
1237.1 (w), 1190.2 (w), 1173.0 (w), 1145.2 (w), 1160.2 (w), 1082.7 (w), 1029.3 (w), 938.3 (w), 912.9

Molecules 2014, 19
9747
(w), 876.5 (w), 826.9 (m), 807.5 (m), 751.1 (w), 738.5 (w), 682.0 (w), 666.8 (w). LC-MS: Rt 3.60 min;
HRMS (ESI): m/z calculated for C10H4N4O2Cl [M+H+]: 247.0028; found 247.0039.
6,8-Dibromobenzo[g]pteridine-2,4(3H,10H)-dione or 7,9-dibromobenzo[g]pteridine-2,4(3H,10H)-
dione (12). Prepared from 2,4-dibromo-6-nitroaniline (0.294 g, 1 mmol) to give a pale green solid, one
1
regioisomer was cleanly isolated (0.096 g, 26% yield). H-NMR (500 Hz, d6-DMSO): δ/ppm = 12.21
(s, 1H, NH), 11.85 (s, 1H, NH), 8.45 (d, J = 2.1 Hz, 1H), 8.43 (d, J = 2.1 Hz, 1H); 13C-NMR (125 MHz,
d6-DMSO): δ/ppm = 159.9 (C), 150.0 (C), 147.8 (C), 139.9 (C), 139.4 (C), 138.2 (CH), 133.6 (C),
131.9 (CH), 122.0 (C), 120.2 (C). IR (neat) /cm−1: 3491.0 (w), 3183.1 (w) 3072.6 (w), 2849.1 (w),
1704.0 (s), 1603.2 (m), 1575.7 (w), 1558.3 (w), 1497.1 (w), 1468.2 (m), 1445.5 (m), 1386.8 (m),
1347.8 (m), 1319.7 (w), 1286.5 (s), 1210.7 (w), 1181.7 (w), 1136.6 (w), 1076.6 (w), 1028.2 (m), 1010.7
(m), 949.6 (m), 869.9 (m), 833.0 (m), 814.7 (m), 750.9 (w), 732.6 (w), 710.1 (w), 670.6 (w). LC-MS: Rt
4.02 min; HRMS (ESI): m/z calculated for C10H3N4O2Br2 [M+H+]: 368.8642; found 368.8628.
3.4. General Procedure for the Formation of the Dehydroquinoxalines Analogues 14–22
The diamines generated by the hydrogenation process in flow were mixed with alloxane monohydrate
(0.160 g, 1 mmol) and left to stir at room temperature overnight. The product was then filtered and the
solid product was dried in vacuo.
N-Carbamoyl-6,7-dimethyl-3-oxo-3,4-dihydroquinoxaline-2-carboxamide (14). Prepared from
4,5-dimethyl-2-nitroaniline (0.166 g, 1 mmol) to give a dull yellow solid (0.212 g, 84% yield).
1H-NMR (500 MHz, d6-DMSO): δ/ppm = 12.97 (br s, 1H, NH), 11.21 (br s, 1H, NH), 7.74 (br s, 1H,
NH from NH2), 7.69–7.65 (br m, 2H), 7.54 (br s, 1H, NH from NH2). To separate broad peaks:
1H-NMR (400 MHz, d6-DMSO + 3 drops TFA): δ/ppm = 6.55 (s, 1H), 6.45 (s, 1H), 5.72 (s, 2H from
13
NH2); C-NMR (125 MHz, d6-DMSO): δ/ppm = 159.6 (C), 155.2 (C), 153.2 (C), 142.0 (C), 141.9
(C), 131.2 (C), 128.8 (C), 123.4 (C), 115.8 (CH), 115.6 (CH), 20.2 (CH3), 19.0 (CH3). IR (neat)
/cm−1: 3377.1 (m), 3148.1 (w, br), 2823.3 (w, br), 1690.1 (s), 1645.9 (m), 1570.3 (s), 1487.5 (s),
1446.3 (s), 1390.6 (s), 1390.6 (s), 1367.5 (s), 1331.5 (m), 1286.8 (w), 1253.5 (m), 1196.5 (m), 1167.9
(s), 1111.9 (m), 1032.3 (w), 1011.4 (w), 967.3 (w), 919.9 (w), 860.8 (w), 820.5 (w), 801.8 (s), 752.8
(w), 741.6 (w), 683.7 (m). LC-MS: Rt 3.69 min; HRMS (ESI): m/z calculated for C12H11N4O3 [M+H+]:
259.0837; found 259.0841.
N-Carbamoyl-3-oxo-3,4-dihydroquinoxaline-2-carboxamide (15). Prepared from 2-nitroaniline (0.138 g,
1 mmol) to give a light green solid (0.228 g, 98% yield). 1H-NMR gave broad peaks. 1H-NMR (500 MHz,
d6-DMSO): δ/ppm = 13.03 (s, 1H, NH), 11.09 (s, 1H, NH), 7.92–7.37 (m br, 6H, NH2 + 4CH). To
1
separate broad peaks: H-NMR (400 MHz, d6-DMSO + 3 drops TFA): δ/ppm = 8.97 (br s, 1H, NH2),
13
7.37 (br s, 1H, NH2), 6.83 (m, 2H), 6.68 (m, 2H); C-NMR (125 MHz, d6-DMSO): δ/ppm = 163.8
(C), 154.1 (C), 153.2 (C), 149.3 (C), 132.6 (CH), 131.3 (C), 129.7 (CH), 124.3 (CH), 124.0 (C), 115.8
(CH). IR (neat) /cm−1: 3366.5 (w), 3152.2 (w, br), 2969.0, (w), 2813.8 (w, br), 1718.3 (m), 1685.2
(s), 1643.2 (m), 1609.6 (w), 1571.0 (m), 1495.8 (m), 1433.8 (m), 1391.0 (s), 1360.1 (m), 1336.6 (w),
1293.6 (w), 1270.1 (w), 1249.6 (w), 1232.8 (w), 1183.2 (w), 1146.8 (m), 1100.7 (m), 1049.0 (w),

Molecules 2014, 19
9748
969.8 (w), 929.1 (w), 912.1 (m), 796.1 (m), 764.1 (s), 723.9 (w), 680.4 (w). LC-MS: Rt 2.63 min;
HRMS (ESI): m/z calculated for C10H7N4O3 [M+H+]: 213.0524; found 231.0527.
N-Carbamoyl-7-methyl-3-oxo-3,4-dihydroquinoxaline-2-carboxamide and N-carbamoyl-8-methyl-3-
oxo-3,4-dihydroquinoxaline-2-carboxamide (16). Prepared from 4-methyl-2-nitroaniline (0.152 g,
1 mmol) to give a bright yellow solid, with two regioisomers in a 3:2 ratio (0.187 g, 76% yield).
1H-NMR (500 MHz, d6-DMSO): δ/ppm = 11.86 (1H from minor regioisomer, d, J = 1.7 Hz, NH),
11.84 (1H from major regioisomer, d, J = 1.7 Hz, NH) 11.68 (1H from major regioisomer, s, NH),
11.69 (1H from minor regioisomer, s, NH) , 8.00 (1H from minor regioisomer, d, J = 8.6 Hz, H1) 7.89
(1H from major regioisomer, s, H3), 7.78 (1H from major regioisomer, d, J = 8.6 Hz, H1), 7.72 (1H
from major isomer, dd, J = 8.6 and 1.9 Hz, H2), 7.66 (1H from minor regioisomer, s, H3), 7.57 (1H
from minor regioisomer, dd, J = 8.6 and 1.9 Hz, H2), 2.54 (3H from minor regioisomer, s, CH3), 2.48
(3H from major regioisomer, m, CH3). 13C-NMR (125 MHz, d6-DMSO): δ/ppm = 160.6 (C), 160.6 (C),
150.2 (C), 150.1 (C), 147.0 (C), 146.4 (C), 144.3 (C), 142.8 (C), 141.1 (C), 139.4 (C), 138.6 (C), 137.9
(C), 135.7 (CH), 131.3 (C), 130.8 (CH), 130.6 (C), 129.7 (CH), 128.7 (CH), 126.6 (CH), 125.7 (CH),
21.7 (CH3), 21.1 (CH3). IR (neat) /cm−1: 3171.9 (w), 3075.1 (w), 2990.5 (w),2852.3 (w), 1726.5 (m),
1701.1 (s), 1622.7 (w), 1581.9 (m), 1564.7 (w), 1511.5 (w), 1476.0 (w), 1446.6 (w), 1392.9 (w),
1354.4 (m), 1337.5 (m), 1307.9 (w), 1281.0 (s), 1249.4 (w), 1207.9 (w), 1151.2 (w), 1121.8 (w),
1027.5 (w), 982.2 (w), 948.9 (w), 907.4 (w), 874.6 (w), 830.1 9s), 810.0 (m), 760.8 (w), 704.4 (w),
682.0 (w), 661.8 (w). LC-MS: Rt 3.43 min; HRMS (ESI): m/z calculated for C11H9N4O3 [M+H+]:
245.0680; found 245.0681.
N-Carbamoyl-7-methyl-3-oxo-3,4-dihydroquinoxaline-2-carboxamide and N-carbamoyl-8-methyl-3-
oxo-3,4-dihydro-quinoxaline-2-carboxamide (17). Prepared from 5-methyl-2-nitroaniline (0.152 g,
1 mmol) to give a bright yellow solid, with two regioisomers found in a 3:2 ratio (0.215 g, 87% yield).
This was gave an identical 1H-NMR to 16.
N-Carbamoyl-7-methoxy-3-oxo-3,4-dihydroquinoxaline-2-carboxamide and N-carbamoyl-8-methoxy-
3-oxo-3,4-dihydroquinoxaline-2-carboxamide (18). Prepared from 4-methoxy-2-nitroaniline (0.206 g,
1 mmol) to give an orange solid, with two regioisomers found in a 5:2 ratio (0.231 g, 88% yield).
13
1
1H-NMR gave broad peaks and not all quaternary centres were observed in the C-NMR. H-NMR
(500 MHz, d6-DMSO): δ/ppm = 13.03 (s, 1H, NH), 11.23 (s, 1H, NH), 7.83-7.30 (br m, 6H), 7.03 (d,
J = 8.7 Hz, 2H, NH2), 6.81 (d, J = 2.9 Hz, 2H, NH2), 3.88 (s, 3H, CH3), 3.84 (s, 3H, CH3). To separate
1
broad peaks: H-NMR (400 MHz, d6-DMSO + 3 drops TFA): δ/ppm = 7.79 (1H from minor
regioisomer, d, J = 9.0 Hz, CH, 2 or 3), 7.58 (1H from major regioisomer, s, H1), 7.00 (1H from minor
regioisomer, d, J = 9.5 Hz, H2 or H3), 6.81 (1H from minor regioisomer, d, J = 2.5 Hz, H1) 6.69 (1H
from major regioisomer, d, J = 9.3 Hz, H2 or H3), 6.60 (1H from major regioisomer, d, J = 9.3 Hz, H2
or H3), 6.44 (2H, one from each regioisomer, d, J = 6.9 Hz, 2NH from the NH2), 6.24 (2H, one from
13
each regioisomer, d, J = 6.6 Hz, 2NH from the NH2); C-NMR (125 MHz, d6-DMSO): δ/ppm = 162.9
(C), 153.2 (C), 153.2 (C), 134.89 (C), 131.6 (CH), 126.9 (C), 116.7 (CH), 114.1 (CH), 110.5 (CH),
103.7 (CH), 97.6 (CH), 56.0 (CH3), 55.8 (CH3). IR (neat) /cm−1: 3394.4 (w), 3315.5 (w), 3149.3
(w,br), 2976.0 (w), 1731.0 (s), 1697.5 (s), 1676.5 (w), 1648.2 (s), 1618.5 (s), 1583.6 (s), 1502.4 (s)

Molecules 2014, 19
9749
1487 (s), 1471.4 (m), 1455.1 (m), 1441.4 (w), 1381.8 (s), 1370.6 (s)., 1280.7 (w), 1249.7 (m), 1222.3
(s), 1184.2 (s), 1150.6 (m), 1110.4 (m), 1031.7 (m), 1012.8 (m), 969.4 (w), 914.1 (w), 839.5 (s), 822.0
(s), 801.6 (s), 751.8 (w), 682.0 (w). LC-MS: Rt 3.44 min; HRMS (ESI): m/z calculated for C11H9N4O4
[M+H+]: 261.0629; found 261.0634.
N-Carbamoyl-7-fluoro-3-oxo-3,4-dihydroquinoxaline-2-carboxamide and N-carbamoyl-8-fluoro-3-
oxo-3,4-dihydro-quinoxaline-2-carboxamide (19). Prepared from 4-fluoro-2-nitroaniline (0.106 g,
1 mmol) to give a pale green solid, with two regioisomers found in a 5:1 ratio (0.165 g, 66% yield).
13
1
1H-NMR gave broad peaks and not all quaternary centres were observed in the C-NMR. H-NMR
(500 MHz, d6-DMSO): δ/ppm = 13.07 (1H from major regioisomer, br s, NH), 12.55 (1H from minor
regioisomer, br s, NH), 11.03 (1H from major regiosiomer, br s, NH), 10.34 (1H from minor
regioisomer, br s, NH), 7.94 (1H from major regioisomer, br s, NH from NH2) 7.76–7.57 (5H from
minor regioisomer and 1H from major regioisomer, br m, 2NH from NH2, 4CH), 7.38 (1H from major
regioisomer, br s, NH from NH2), 7.25 (1H from major regioisomer, s), 7.07 (1H from major
regioisomer, d, J = 4.1 Hz); 13C-NMR (125 MHz, d6-DMSO): δ/ppm = 163.7 (C), 159.1 (C), 157.2 (C),
154.0 (C-F), 134.4 (C), 132.4 (CH), 131.5 (C), 129.6 (CH), 128.4 (C), 121.0 (CH), 117.4 (C), 114.5
(CH), 112.6 (CH), 101.6 (CH). IR (neat) /cm−1: 3380.2 (w), 3152.2 (w, br), 2732.4 (w,br) 1721.4 (s),
1698.5 (s), 1649.5 (s), 1596.5 (m), 1578.9 (m), 1504.1 (s), 1485.6 (s), 1403.6 (s), 1364.1 (s), 1284.1
(w), 1246.3 (m), 1201.8 (m), 1179.4 (m), 1144.7 (w), 1120.1 (w), 1099.3 (m), 978.9 (w), 939.0 (w),
912.9 (w), 847.0 (m), 823.2 (s), 805.3 (s), 752.8 (w), 698.9 (w), 680.7 (m). LC-MS: Rt 3.23 min;
HRMS (ESI): m/z calculated for C10H6N4O3F [M+H+]: 249.0429; found 249.0421.
N-Carbamoyl-3-oxo-7(trifluoromethyl)-3,4-dihydro-quinoxaline-2-carboxamide and N-carbamoyl-3-oxo-
8(trifluoromethyl)-3,4-dihydroquinoxaline-2-carboxamide (20). Prepared from 2-nitro-5-(trifluromethyl)-
aniline (0.206 g, 1 mmol) to give a pale yellow solid, with two regioisomers in a 5:2 ratio (0.178 g,
13
59% yield). 1H-NMR gave broad peaks and not all quaternary centres were observed in the C-NMR.
1H-NMR (500 MHz, d6-DMSO): δ/ppm = 13.21 (1H from major regioisomer, s, NH), 12.78 (1H from
minor regioisomer, br d, J = 40.35 Hz, NH), 10.95 (1H from major regioisomer, s, NH), 10.39 (1H
from minor regioisomer, br, s, NH), 8.23–7.51 (6H, three from each regioisomer, m), 6.96 (2H, one
from each regioisomer, br s, 2NH from the NH2’s), 6.23 (2H, one from both compounds, br s, 2NH
from the NH2’s). To separate broad peaks: 1H-NMR (400 MHz, d6-DMSO + 3 drops TFA): δ/ppm = 7.97
(1H from minor regioisomer, s, NH from NH2), 7.92 (1H from minor regioisomer, s, NH from NH2),
7.76 (1H from minor regioisomer, s, H1), 7.62 (1H from minor regioisomer, s, H2 or H3), 7.51 (1H
from minor regioisomer, d, J = 8.4 Hz, H2 or H3), 7.17 (1H from major regioisomer, d, J = 8.3, H2 or
H3), 7.07 (1H from major regioisomer, s, H1), 7.01 (1H from major regioisomer, d, J = 8.3 Hz, NH
from NH2), 6.96 (1H from major regioisomer, d, J = 8.3 Hz, NH from NH2), 6.81 (1H from major
regioisomer, J = 8.3 Hz, H2 or H3); 13C-NMR (125 MHz, d6-DMSO): δ/ppm = 166.5 (CF3), 163.8 (C),
153.0 (C-CF3), 135.4 (C), 133.0 (C), 130.9 (CH), 130.4 (C), 128.4 (CH), 126.9 (CH), 125.1 (C), 124.7
(C, minor regioisomer), 122.8 (C, minor regioisomer), 122.5 (C, minor regioisomer), 120.1 (CH),
117.2 (CH), 113.0 (CH). IR (neat) /cm−1: 3520.9 (w), 3411.4 (w), 3243.7 (w), 3159.1 (w), 1736.8
(m), 1692.7 (s), 1674.6 (s), 1662.0 (s), 1625.9 (m), 1568.0 (w), 1506.1 (w), 1466.7 (w). 1412.1 (w),
1376.5 (m), 1320.3 (m), 1285.7 (w), 1260.6 (w), 1242.3 (w), 1189.4 (w), 1166.3 (w), 1148.9 (s),

Molecules 2014, 19
9750
1135.7 (s), 1112.7 (m), 1091.4 (m), 1064.7 (m), 957.1 (w),901.4 (m), 847.0 (m), 832.5 (m), 820.7 (w),
779.8 (w), 738.9 (w), 687.3 (m), 655.3 (m). LC-MS: Rt 3.80 min; HRMS (ESI): m/z calculated for
C11H4F3N4O2 [M+H+]: 281.0292; found 281.0287.
N-Carbamoyl-6-chloro-3-oxo-3,4-dihydroquinoxaline-2-carboxamid and N-carbamoyl-7-chloro-3-
oxo-3,4-dihydro-quinoxaline-2-carboxamide (21). Prepared from 4-chloro-2-nitroaniline (0.172 g,
1
1 mmol) to give a pale yellow solid, with two regioisomers in an unknown ratio due to overlapping H
signals (0.157 g, 59% yield). 1H-NMR (500 MHz, d6-DMSO): δ/ppm = 12.02 (s, 2H, 2NH), 11.79 (s, 2H,
2NH), 8.17 (d, J = 9.0 Hz, 2xH3), 7.97 (d, J = 2.3 Hz, 2 × H1), 7.93 (4H, m, 2H, 2NH2), 7.78 (dd,
13
J = 2.3 Hz, 9.0 Hz, 2 × H2); C-NMR (125 MHz, d6-DMSO): δ/ppm = 160.3 (br, 2C), 150.1 (br, C),
147.6 (C), 147.2 (C), 143.1 (C), 141.4 (C), 139.4 (C), 137.9 (C), 137.8 (C), 133.7 (CH), 132.8 (C),
132.5 (C), 132.3 (C), 132.0 (CH), 129.1 (CH), 128.8 (CH), 128.6 (CH), 125.7 (CH). IR (neat) /cm−1:
3457.6 (w, br), 3184.9 (w), 3068.7 (w, br), 2850.5 (w), 1727.7 (m), 1697.9 (s), 1614.5 (m), 1578.8
(m), 1562.0 (w), 1489.7 9(w), 1449.0 (w), 1388.9 (m), 1354.7 (m), 1335.8 (m), 1292.5 (m), 1275.0
(m), 1245.9 (w), 1196.3 (w), 1145.6 (w), 1112.4 (w), 1071.0 (w), 1029.8 (m), 939.2 (w), 876.7 (w), 847.5
(s), 806.6 (m), 751.5 (m), 738.1 (m), 692.8 (w), 666.2 (w). LC-MS: Rt 3.60 min; HRMS (ESI): m/z
calculated for C10H4N4O2Cl [M+H+]: 266.0207; found 266.0211.
6,8-Dibromo-N-carbamoyl-3-oxo-3,4-dihydroquinoxaline-2-carboxamide or 7,9-dibromo-N-carbamoyl-3-
oxo-3,4-dihydroquinoxaline-2-carboxamide (22). Prepared from 2,4-dibromo-6-nitroaniline (0.294 g,
1 mmol) to give a mixture of a green solid and a liquid component in approximately a 1:2 ratio. Upon
purification one regioisomer was cleanly isolated (estimated yield 8%). HRMS (ESI): m/z calculated for
1
C10H5N4O3Br2 [M+H+]: 386.8734; found 386.8716. H-NMR (400 MHz, d6-DMSO): δ/ppm = 11.20
(s, 1H, NH), 11.04 (s, 1H, NH), 8.16 (d, J = 2.6 Hz, 1H), 8.05 (d, J = 2.2 Hz, 1H).
3.5. General Procedure for the Formation of 1,5-Dibenzodiazepines 27a–k
A mixture of the fluoro nitrobenzene derivative and the corresponding amino benzophenone/
fluorenone (1:1) was dissolved in dry THF in a microwave vial. Lithium bis(trimethylsilyl)amide
(LiHMDS, 1.0 M solution in THF) was added dropwise and the mixture heated to 100 °C for 30 to 90 min
using a Biotage Initiator microwave instrument. The reaction was quenched by addition of water and
the mixture extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4
and the solvent evaporated under vacuum. Most of the intermediate products (25) were not further
purified but directly hydrogenated in flow, although some of them were subjected to column
chromatography and fully characterised to confirm the structure and complete data is shown below.
(2-((5-Chloro-2-nitrophenyl)amino)phenyl)(phenyl)-methanone. 1H-NMR (400 MHz, CDCl3):
δ/ppm = 10.98 (s, 1H, NH), 8.09 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 1.1 Hz, 1H), 7.79 (d, J = 1.5 Hz, 1H),
7.62–7.56 (m, 4H), 7.47–7.44 (m, 3H), 7.20 (dd, J = 7.6 Hz, 1.5 Hz, 1H), 6.80 (dd, J = 9.0 Hz, 2.0 Hz,
13
1H); C-NMR (100 MHz, CDCl3): δ 196.7 (C=O), 141.7 (C), 141.3 (C), 139.7 (C), 138.1 (C), 134.2
(C), 133.3 (CH), 133.3 (2 × CH), 130.5 (2 × CH), 129.8 (C), 128.8 (2 × CH), 128.5 (CH), 123.8 (CH),
122.5 (CH), 119.7 (CH), 117.1 (CH). IR (neat) /cm−1: 3301.0 (w), 3062.6 (w), 1643 (w), 1608.2 (m),
1596.2 (m), 1562.6 (s), 1486.6 (s), 1449.3 (m), 1409.4 (w), 1312.5 (m), 1335.1 (w), 1297.1 (m),

Molecules 2014, 19
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1248.8 (s), 1211.5 (m), 1180.2 (w), 1164.3 (w), 1103.8 (w), 1070.6 (w), 921.6 (m), 841.4 (w), 749.9
(m), 700.8 (m). HRMS (m/z) calculated for C19H14O3N2Cl, (M-H), 353.0687; found 353.0678
(5-Chloro-2-((5-chloro-2-nitrophenyl)amino)phenyl)-(phenyl)methanone. 1H-NMR (400 MHz,
CDCl3): δ/ppm = 10.82 (s, 1H, NH), 8.11 (d, J = 9.2 Hz, 1H), 7.82 (d, J = 1.5 Hz, 1H), 7.80 (d, J = 1.4
Hz, 1H), 7.65–7.58 (m, 2H), 7.56 (s, 1H), 7.54 (d, J = 2.0 Hz, 1H), 7.53–7.48 (m, 2H), 7.40 (d, J = 2.0
13
Hz, 1H), 6.80 (dd, J = 9.2 Hz, 2.2 Hz, 1H); C-NMR (100 MHz, CDCl3): δ 195.3 (C=O), 141.8 (C),
140.9 (C), 138.2 (C), 137.1 (C), 134.1 (C), 133.4 (CH), 132.8 (CH), 132.2 (CH), 130.9 (C), 130.1 (2 x
CH), 128.7 (C), 128.6 (2 × CH), 128.2 (CH), 123.6 (CH), 119.7 (CH), 116.6 (CH). IR (neat) /cm−1:
2673.4 (w), 2319.2 (w), 1646.9 (w), 1607.9 (m), 1568.3 (m), 1488.2 (s), 1395.9 (w), 1336.5 (w),
1294.2 (w), 1259.7 (m), 1240.5 (m), 1163.3 (w), 1104.2 (w), 930.4 (w), 826.6 (w), 752.2 (w). HRMS
(m/z) calculated for C19H13O3N2Cl2, (M-H), 387.0298; found 387.0289.
1
(5-Chloro-2-((5-chloro-2-nitrophenyl)amino)phenyl)(3-chlorophenyl)methanone. H-NMR (400 MHz,
CDCl3): δ/ppm = 11.33 (s, 1H, NH), 8.14 (d, J = 9.1 Hz, 1H), 7.57–7.40 (m, 8H), 6.94 (dd, J = 9.1 Hz,
2.2 Hz, 1H); 13C-NMR (100 MHz, CDCl3): δ 195.7 (C=O), 140.2 (C), 140.1 (C), 138.3 (C), 135.8 (C),
134.6 (CH), 133.5 (CH), 132.4 (CH), 131.8 (C), 130.7 (CH), 130.0 (CH), 128.5 (CH), 128.5 (C), 128.2
(C), 127.4 (CH), 122.2 (CH), 121.1 (CH), 118.3 (CH). IR (neat) /cm−1: 2738.9 (w), 1648.0 (w),
1607.8 (m), 1570.8 (m), 1488.2 (s), 1397.9 (w), 1336.5 (w), 1293.2 (s), 1247.5 (m), 1072.3 (w), 951.9
(w), 929.7 (w), 828.3 (w), 748.9 (w), 699.8 (w). HRMS (m/z) calculated for C19H11O3N2Cl3Na,
442.9727; found 442.9724.
1
5-Chloro-2-((5-chloro-2-nitrophenyl)amino)phenyl)(2-fluoro-phenyl)methanone. H-NMR (400 MHz,
CDCl3): δ/ppm = 11.09 (s, 1H, NH), 8.11 (d, J = 9.2 Hz, 1H), 7.64–7.48 (m, 5H), 7.44 (d, J = 2.2 Hz,
1H), 7.28 (td, J = 7.7 Hz, 1.1 Hz, 1H), 7.13 (app t, 1H), 6.88 (dd, J = 9.0 Hz, 2.0 Hz, 1H); 13C-NMR
(100 MHz, CDCl3): δ 192.7 (C=O), 160.1 (d, J = 253.6 Hz, C-F), 141.7 (C), 140.4 (C), 138.6 (C),
134.8 (C), 134.3 (d, J = 8.4 Hz, CH), 133.7 (CH), 132.5 (d, J = 2.3 Hz, CH), 131.0 (d, J = 1.9 Hz,
CH), 130.2 (C), 128.5 (CH), 128.1 (C), 126.4 (d, J = 13.6 Hz, C), 124.7 (d, J = 3.6 Hz, CH), 122.6
(CH), 120.2 (CH), 117.4 (CH), 116.5 (d, J = 21.6 Hz, CH). IR (neat) /cm−1: 2338.9 (w), 1648.9 (w),
1608.6 (m), 1570.1 (m), 1488.6 (s), 1453.1 (w), 1398.5 (w), 1336.3 (w), 1308.8 (w), 1259.7 (m),
1243.7 (m), 1213.9 (w), 1072.1 (w), 931.2 (w), 753.12 (m). HRMS (m/z) calculated for
C19H12O3N2Cl2F (M+H), 405.0204; found 405.0197.
The nitro phenylamino derivatives 25 were hydrogenated in flow at 60 °C using a flow rate of
0.5 mL/min, following the general procedure described before. The generated diamines were
collected over MgSO4 and stirred for a further 1–2 h at room temperature to enhance the cyclisation
process. After filtration to remove the drying agent, catalytic formic acid was added to the remaining
solution and the mixture was stirred at room temperature overnight. The solvent was then removed
under vacuum and the final benzodiazepines were purified by column chromatography and fully
characterised by NMR.
11-Phenyl-5H-dibenzo[b,e][1,4]diazepine (27a). Prepared from 1-fluoronitrobenzene and
2-aminobenzophenone (175 mg, 65% yield). 1H-NMR (600 MHz, CDCl3): δ/ppm = 7.76 (d, J = 7.1 Hz,

Molecules 2014, 19
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2H), 7.48–7.42 (m, 3H), 7.36 (dd, J = 7.7 Hz, 1.0 Hz, 1H), 7.29 (td, J = 7.6 Hz, 1.1 Hz, 1H), 7.08 (td,
J = 7.5 Hz, 1.0 Hz, 1H), 7.04 (m, 2H), 6.94 (t, J = 7.5 Hz, 1H), 6.77 (d, J = 7.9 Hz, 1H), 6.70 (dd,
J = 7.6 Hz, 0.8 Hz, 1H), 5.03 (s, 1H); 13C-NMR (150 MHz, CDCl3): δ 169.6 (C), 154.5 (C), 142.7 (C),
141.4 (C), 140.9 (C), 132.2 (CH), 132.0 (CH), 130.0 (CH), 129.6 (2xCH), 128.7 (CH), 128.0 (2 × CH),
127.6 (C), 126.9 (CH), 124.2 (CH), 122.4 (CH), 119.8 (2 × CH); IR (neat) cm−1: 3354.0 (w), 3273.2 (w),
3051.8 (w), 2850.2 (w), 1601.9 (w, N=C), 1494.8 (w), 1460.2 (m), 1401.3 (w), 1317.0 (w), 1283.1
(w), 1234.6 (w), 1151.7 (w), 1108.2 (w), 958.5 (w), 944.3 (w), 853.1 (w), 802.7 (w), 756.4 (s), 694.7
(s), 657.7 (m); LC-MS: tr = 4.68, m/z = 271.32 (C19H14N2)+.
7-Chloro-11-phenyl-5H-dibenzo[b,e][1,4]diazepine (27b). Prepared from 4-chloro-2-fluoro-1-
nitrobenzene and 2-aminobenzophenone (201 mg, 66% yield). 1H-NMR (600 MHz, CDCl3): δ/ppm = 7.70
(d, J = 7.1 Hz, 2H), 7.47–7.40 (m, 3H), 7.32 (t, J = 7.0 Hz, 1H), 7.22 (d, J = 8.3 Hz, 1H), 7.02 (d,
J = 8.0 Hz, 2H), 6.97 (t, J = 7.4 Hz, 1H), 6.77 (d, J = 7.8 Hz, 1H), 6.72 (d, J = 1.8 Hz, 1H), 4.97 (s,
1H); 13C-NMR (150 MHz, CDCl3): δ 169.8 (C), 153.6 (C), 143.4 (C), 141.0 (C), 139.5 (C), 132.3 (C),
132.2 (CH), 132.1 (CH), 130.2 (CH), 129.6 (CH), 129.5 (2 × CH), 128.0 (2xCH), 127.5 (C), 124.2
(CH), 122.8 (CH), 119.9 (CH), 119.7 (CH); IR (neat) cm−1: 3359.8 (w, NH), 3053.7 (w), 1607.9 (s,
N=C), 1573.1 (w), 1455.8 (s), 1433.3 (w), 1317.6 (w), 1285.6 (m), 1250.0 (w), 1117.5 (w), 1089.7
(w), 957.6 (w), 915.0 (m), 855.7 (m), 815.9 (s), 778.8 (s), 742.5 (s), 722.6 (m), 692.8 (s), 681.2 (s),
666.1 (m); LC-MS: tr = 5.13, m/z = 304.90 (C19H13ClN2)+. The structure was unambiguously
confirmed by X-ray crystallography and deposited at the Cambridge Crystallographic Data Centre with
the unique reference number CCDC 867823; Formula: C19H13ClN2, unit cell parameters: a =
16.4748(5) Å, b = 5.6296(2) Å, c = 16.0146(7) Å,  = 90°, β = 102.528(2)°, γ = 90°, space group: P21/c.
2-Chloro-11-phenyl-5H-dibenzo[b,e][1,4]diazepine (27c). Prepared from 1-fluoronitrobenzene and
1
2-amino-4-chlorobenzophenone (110 mg, 72% yield). H-NMR (600 MHz, CDCl3): δ/ppm = 7.71 (d,
J = 7.1 Hz, 2H), 7.49-7.42 (m, 3H), 7.32 (dd, J = 7.6 Hz, 1.4 Hz, 1H), 7.27–7.25 (m, 1H), 7.09–7.03
(m, 2H), 6.99 (d, J = 2.3 Hz, 1H), 6.74 (d, J = 8.5 Hz, 1H), 6.71 (dd, J = 7.5 Hz, 1.3 Hz, 1H), 5.02 (s,
13
1H); C-NMR (150 MHz, CDCl3): δ 153.0 (C), 142.2 (C), 140.5 (C), 140.4 (C), 131.8 (CH), 131.6
(CH), 130.2 (CH), 129.5 (2 × CH), 128.8 (CH), 128.2 2 × (CH), 127.9 (C), 127.8 (C), 127.7 (C), 127.2
(CH), 124.5 (CH), 121.1 (CH), 119.8 (CH); IR (neat) cm−1: 3269.5 (w, NH), 3053.0 (w), 1610.6 (w,
N=C), 1569.3 (w), 1489.0 (w), 1461.7 (w), 1421.2 (w), 1318.9 (w), 1280.2 (w), 1234.7 (w), 1120.4
(w), 964.9 (w), 823.2 (m), 806.3 (m), 760.2 (s), 738.6 (s), 698.1 (s), 667.8 (w); LC-MS: tr = 5.09,
m/z = 305.03 (C19H13ClN2)+.
2,7-Dichloro-11-phenyl-5H-dibenzo[b,e][1,4]diazepine (27d). Prepared from 4-chloro-2-fluoro-1-
1
nitrobenzene and 2-amino-4-chlorobenzophenone (99 mg, 59% yield). H-NMR (600 MHz, CDCl3):
δ/ppm = 7.69 (d, J = 7.2 Hz, 2H), 7.49-7.40 (m, 3H), 7.27 (m, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.04 (dd,
J = 8.4 Hz, 2.2 Hz, 1H), 6.99 (d, J = 2.3 Hz, 1H), 6.73–6.71 (m, 2H), 4.99 (s, 1H); 13C-NMR (150 MHz,
CDCl3): δ 168.2 (C), 152.0 (C), 142.9 (C), 140.3 (C), 139.2 (C), 132.4 (C), 131.9 (CH), 131.6 (CH),
130.5 (CH), 129.7 (CH), 129.6 (2 × CH), 129.4 (C), 128.9 (C), 128.3 (2 × CH), 124.5 (CH), 121.2
(CH), 119.8 (CH); IR (neat) cm−1: 3359.6 (w), 3259.7 (w), 3054.2 (w), 1608.7 (m, N=C), 1573.9 (w),
1454.7 (m), 1316.9 (m), 1287.3 (w), 1249.8(w), 1117.0 (w), 1087.6 (w), 957.9 (w), 915.2 (m), 858.1

Molecules 2014, 19
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(m), 816.5 (m), 778.8 (m), 742.8 (m), 691.9 (s); LC-MS: tr = 5.35, m/z = 339.22 (C19H12Cl2N2)+. The
structure was unambiguously confirmed by X-ray crystallography and deposited at the Cambridge
Crystallographic Data Centre with the unique reference number CCDC 867824; Formula: C19H12Cl2N2,
unit cell parameters: a = 14.2135(5) Å, b = 9.2512(4) Å, c = 25.0981(10) Å, α = 90°, β = 103.764(2)°,
γ = 90°, space group: C2/c.
2,7-Dichloro-11-(2-chlorophenyl)-5H-dibenzo[b,e][1,4]-diazepine (27e). Prepared from 4-chloro-2-
1
fluoro-1-nitrobenzene and 2-amino-2’,4-dichloro-benzophenone (131 mg, 70% yield). H-NMR (600
MHz, CDCl3): δ/ppm = 7.54 (m, 1H), 7.40–7.36 (m, 3H), 7.18 (dd, J = 8.5 Hz, 2.4 Hz, 1H), 7.14 (d, J =
8.4 Hz, 1H), 6.98 (dd, J = 8.4 Hz, 2.2 Hz, 1H), 6.70 (d, J = 2.1 Hz, 1H), 6.65–6.63 (m, 2H), 5.47 (s,
1H); 13C-NMR (150 MHz, CDCl3): δ 167.7 (C), 151.5 (C), 143.6 (C), 140.0 (C), 138.4 (C), 133.6 (C),
132.6 (C), 132.2 (CH), 130.8 (CH), 130.6 (CH), 130.3 (CH), 130.2 (CH), 130.1 (CH), 129.7 (C), 128.4
(C), 127.0 (CH), 124.3 (CH), 120.9 (CH), 120.0 (CH); IR (neat) cm−1: 3257.3 (w, NH), 3051.1 (w),
2919.2 (w), 2850.0 (w), 1605.9 (m, N=C), 1489.2 (w), 1446.1 (m), 1434.2 (m), 1390.9 (w), 1315.9
(m), 1258.5 (w), 1236.7 (w), 1204.1 (w), 1155.6 (w), 1123.8 (w), 1085, 2 (w), 1057.6 (w), 968.8 (w),
942.8(w), 916.4(m), 880.9 (m), 857.7 (s), 822.1 (s), 747.5 (s), 727.9 (s); LC-MS: tr = 5.26, m/z = 374.94
(C19H11Cl3N2)+. The structure was unambiguously confirmed by X-ray crystallography. and deposited at
the Cambridge Crystallographic Data Centre with the unique reference number CCDC 867822; Formula:
C19H11Cl3N2, unit cell parameters: a = 15.5464(3) Å, b = 9.3738(2) Å, c = 24.0677(5) Å,  = 90°,
β = 107.942(1)°, γ = 90°, space group: C2/c.
8-Fluoro-11-phenyl-5H-dibenzo[b,e][1,4]diazepine (27f). Prepared from 1,4-difluoro-2-nitrobenzene
1
and 2-aminobenzophenone (192 mg, 67% yield). H-NMR (600 MHz, CDCl3): δ/ppm = 7.71 (d,
J = 7.3 Hz, 2H), 7.48–7.40 (m, 3H), 7.32 (td, J = 7.6 Hz, 1.2 Hz, 1H), 7.04 (d, J = 9.2 Hz, 2H), 6.96
(t, J = 7.5 Hz, 1H), 6.79 (d, J = 7.9 Hz, 1H), 6.75 (td, J = 8.2 Hz, 2.8 Hz 1H), 6.66–6.63 (m, 1H), 4.95
(s, 1H); 13C-NMR (150 MHz, CDCl3): δ 170.6 (C), 159.8 (d, J = 240.7 Hz, C-F), 154.5 (C), 142.1 (d,
J = 10.6 Hz, C), 140.9 (C), 138.7 (d, J = 2.5 Hz, C), 132.2 (d, J = 9.2 Hz, CH), 130.3 (CH), 129.7
(2 × CH), 128.0 (2 × CH), 127.5 (C), 122.6 (CH), 120.2 (d, J = 9.1 Hz, CH), 119.7 (2 × CH), 114.7 (d,
J = 23.4 Hz, CH), 113.0 (d, J = 22.9 Hz, CH); IR (neat) cm−1: 3350.8 (w), 3061.9 (w), 1600.9 (m,
N=C), 1570.4 (w), 1497.7 (m), 1461.6 (s), 1389.2 (w), 1318.2 (w), 1285.9 (w), 1257.3 (m), 1169.8 (w),
1135.0 (w), 1099.1 (w), 970.8 (m), 906.5 (w), 869.2 (w), 807.7 (m), 750.1 (s), 721.8 (s), 694.3 (s), 660.3
(m); LC-MS: tr = 4.99, m/z = 288.92 (C19H13FN2)+.
2-Chloro-8-fluoro-11-phenyl-5H-dibenzo[b,e][1,4]diazepine (27g). Prepared from 1,4-difluoro-2-
1
nitrobenzene and 2-amino-4-chlorobenzophenone (81 mg, 50% yield) H-NMR (600 MHz, CDCl3):
δ/ppm = 7.70 (d, J = 7.4 Hz, 2H), 7.50-7.42 (m, 3H), 7.28 (dd, J = 8.5 Hz, 2.3 Hz, 1H), 7.03 (dd,
J = 9.5 Hz, 2.8 Hz, 1H), 7.00 (d, J = 2.3 Hz, 1H), 6.77–6.73 (m, 2H), 6.64 (m, 1H), 4.93 (s, 1H);
13C-NMR (150 MHz, CDCl3): δ 169.0, 159.9 (d, J = 241.4 Hz, C-F), 153.0, 141.8 (d, J = 10.8 Hz),
140.2, 138.2 (d, J = 2.6 Hz), 131.9, 131.6, 130.6, 129.5, 128.8, 128.3, 128.1, 121.1, 120.2 (d, J = 9.0 Hz),
114.8 (d, J = 23.5 Hz), 113.3 (d, J = 22.9 Hz); IR (neat) cm−1: 3272.0 (w, NH), 3064.0 (w), 1598.2 (w),
15.72.3 (w), 1491.6 (w), 1463.7 (s), 1318.2 (w), 1258.0 (s), 1206.4 (w), 1138.9 (w), 1119.2 (m),

Molecules 2014, 19
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1100.9 (w), 976.8 (w), 954.8 (w), 909.0 (w), 868.1 (m), 820.2 (m), 774.6 (w), 755.5 (m), 721.9 (s),
692.3(s); LC-MS: tr = 5.15, m/z = 322.84 (C19H12ClFN2)+.
2,7-Dichloro-11-(2-fluorophenyl)-5H-dibenzo[b,e][1,4]diazepine (27h). Prepared from 4-chloro-2-
1
fluoro-1-nitrobenzene and 2-amino-4-chloro-2’-fluoro-benzophenone (105 mg, 33% yield). H-NMR
(400 MHz, CDCl3): δ/ppm = 7.67 (td, J = 7.6 Hz, 1.9 Hz, 1H), 7.46–7.40 (m, 1H), 7.25 (dd, J = 7.5 Hz,
1.0 Hz, 1H), 7.22–7.19 (m, 1H), 7.15 (d, J = 8.5 Hz, 1H), 7.09–7.04 (m, 1H), 6.98 (dd, J = 8.6 Hz, 2.0 Hz,
1H), 6.83 (d, J = 2.4 Hz, 1H), 6.82–6.80 (m, 1H), 5.83 (s, 1H); 13C-NMR (100 MHz, CDCl3): δ 164.9
(C), 160.5 (d, J = 250.0 Hz, C-F), 151.1 (C), 143.6 (C), 138.7 (C), 133.2 (C), 132.1 (CH), 131.7 (d,
J = 8.3 Hz, CH), 131.3 (d, J = 2.5 Hz, CH), 130.1 (CH), 130.1 (d, J = 1.7 Hz, C), 130.0 (C), 129.0 (d,
J = 12.4 Hz, C), 128.4 (C), 124.3 (d, J = 3.3 Hz, CH), 124.2 (CH), 121.2 (CH), 120.0 (CH), 116.2 (d,
J = 17.5 Hz, CH); IR (neat) cm−1: 3235.0 (w), 2949.9 (w), 2663.3 (w), 1610.7 (m), 1482.9 (m), 1454.4
(s), 1389.8 (w), 1316.2 (w), 1290.5 (w), 1237.0 (w), 1161.9 (w), 1089.1 (w), 1035.0 (w), 919.2 (w),
838.7 (w), 756.5 (w); HRMS (m/z) calculated for C19H12N2Cl2F (M+H) 357.0356; found 357.0349.
13H-Benzo[b]fluoreno[1,9-ef][1,4]diazepine (27i). Prepared from 1-fluoronitrobenzene and
1
2-aminofluorenone (120 mg, 51% yield). H-NMR (400 MHz, CDCl3): δ/ppm = 7.55 (d, J = 7.5 Hz,
1H), 7.28 (m, 2H), 7.20 (m, 1H), 6.85 (dd, J = 7.7 Hz, 1.5 Hz, 1H), 6.70 (t, J = 7.7 Hz, 1H), 6.66 (td,
J = 7.7 Hz, 1.5 Hz, 1H), 6.45 (d, J = 7.4 Hz, 1H), 6.52 (dt, J = 7.4 Hz, 1.5 Hz, 1H), 5.82 (dd, J = 8.0 Hz,
13
1.5 Hz, 1H), 5.61 (d, J = 7.8 Hz, 1H), 4.41 (s, 1H, NH); C-NMR (100 MHz, CDCl3): δ 165.1 (C),
147.3 (C), 144.5 (C), 142.0 (C), 141.0 (C), 138.5 (C), 137.7 (C), 136.0 (CH), 135.4 (CH), 131.5 (CH),
130.9 (CH), 128.4 (CH), 123.3 (CH), 122.8 (CH), 121.8 (C), 120.2 (CH), 119.2 (CH), 114.3 (CH),
111.9 (CH). IR (neat) cm−1: 3400.1 (w), 3061.8 (w), 2925 (w), 1645.6 (w), 1623.4 (m), 1597.0 (m),
1466.0 (s), 1454.0 (m), 1434.5 (w), 1412.5 (w), 1321.8 (m), 1157.0 (w), 1058.7 (w), 958.5 (w), 779.1
(w), 747.5 (s). HRMS (m/z) calculated for C19H13N2 (M+H), 269.1073; found 269.1068.
10-Fluoro-13H-benzo[b]fluoreno[1,9-ef][1,4]diazepine (27j). Prepared from 1,4-difluoro-2-
nitrobenzene and 2-aminofluorenone (105 mg, 37% yield). 1H-NMR (500 MHz, d6-DMSO): δ/ppm = 7.42
(dd, J = 7.2 Hz, 1.0 Hz, 1H), 7.37 (d, J = 1.0 Hz, 1H), 7.34 (m, 1H), 7.20 (td, J = 7.5 Hz, 1.0 Hz, 1H),
6.99 (m, 1H, NH), 6.70 (td, J = 7.5 Hz, 1.7 Hz, 1H), 6.53 (m, 1H), 6.46 (dd, J = 7.2 Hz, 0.7 Hz, 1H),
6.35 (dd, J = 9.8 Hz, 3.0 Hz, 1H), 6.02 (dd, J = 8.9 Hz, 5.8 Hz, 1H), 5.73 (dd, J = 7.5 Hz, 0.7 Hz, 1H);
13C-NMR (125 MHz, d6-DMSO): δ 166.0 (C), 157.6 (d, 295.2, C-F), 148.7 (C), 143.5 (C), 141.4 (C),
138.8 (d, J = 9.1 Hz, C), 138.7 (d, J = 3.3 Hz, C), 136.2 (CH), 136.0 (C), 131.9 (CH), 122.1 (CH),
120.8 (d, J = 28.4 Hz, CH), 120.4 (C), 120.4 (CH), 119.9 (d, J = 10.1 Hz, CH), 116.8 (d, J = 27.1 Hz,
CH), 114.7 (C), 111.1 (CH). IR (neat) cm−1: 3390.0 (w, NH), 3060.0 (w), 2327.6 (w), 1650.0 (w),
1597.8 (s), 1468.1 (s), 1455.1 (m), 1421.7 (m), 1320.0 (w), 1266.3 (m), 1210.5 (w), 1160.3 (w), 974.7
(w), 957 (w), 878.5 (w), 749.4 (m). HRMS (m/z) calculated for C19H12N2F (M+H), 287.0979; found
287.0972.
11-Chloro-13H-benzo[b]fluoreno[1,9-ef][1,4]diazepine (27k). Prepared from 4-chloro-2-fluoro-1-
nitrobenzene and 2-aminofluorenone (105 mg, 42% yield). 1H-NMR (500 MHz, d6-DMSO): δ/ppm = 7.43
(dd, J = 7.1 Hz, 1.0 Hz, 1H), 7.37 (d, J = 1.4 Hz, 1H), 7.34 (dd, J = 7.8 Hz, 1.0 Hz, 1H), 7.21 (td,
J = 7.5 Hz, 1.0 Hz, 1H), 7.18 (m, 1H, NH), 6.73 (t, J = 8.0 Hz, 1H), 6.56 (d, J = 8.1 Hz, 1H), 6.52 (d,

Molecules 2014, 19
9755
J = 7.5 Hz, 1H), 6.41 (dd, J = 8.5 Hz, 2.4 Hz, 1H), 6.09 (d, J = 2.4 Hz, 1H), 5.73 (dd, J = 8.2 Hz, 0.7 Hz,
1H); 13C-NMR (125 MHz, d6-DMSO): δ 164.2 (C), 147.4 (C), 143.4 (C), 1471.3 (C), 136.6 (CH),
136.5 (C), 136.0 (C), 135.9 (CH), 134.8 (C), 131.8 (CH), 128.3 (CH), 122.0 (CH), 121.4 (CH), 120.8
(C), 120.5 (CH), 118.2 (CH), 114.7 (CH), 111.81 (CH). IR (neat) cm−1: 3395.1 (w, NH), 2926.3 (m),
2851.7 (m), 2308.1 (w), 1720.5 (w), 1650.0 (w), 1627.2 (w), 1598.5 (m), 1575.6 (m), 1464.8 (s),
1422.2 (m), 1314.2 (w), 1104.5 (w), 966.6 (w), 806.7 (w), 778.7 (w), 750.4 (m). HRMS (m/z)
calculated for C19H12N2Cl (M+H), 303.0684; found 303.0675.
Crystallographic data for compounds 27b, 27d and 27e have been deposited with the accession
numbers CCDC 867822, 867823 and 867824contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html
(or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: +44 1223 336033; E-mail:
deposit@ccdc.cam.ac.uk)
4. Conclusions
In summary, we have successfully extended on our earlier reports detailing the flow-based
chemoselective reduction of important nitro substituted building blocks. This efficient methodology
allowed the rapid generation of valuable aminobenzene intermediates, which were used as starting
points in accessing important heterocyclic scaffolds such as riboflavines, quinoxalinones and
dibenzodiazepines. Importantly, the mild reaction conditions of the developed protocols allow for
directly employing substrates bearing valuable yet sensible halide functionalities.
Acknowledgments
We gratefully acknowledge financial support from the Royal Society (IRB, MB).
Author Contributions
All authors contributed equally in performing the research, analyzing the data and writing the
manuscript. All authors read and approved the final manuscript.
Conflicts of Interest
The authors declare no conflict of interest.
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Sample Availability: Not available.
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